90% (Statistics Norway, 2010))\nand the low use of antibiotics in Norway (Garcia-Rodriguez & Fresnadillo Martinez, 2002;\nNorwegian Veterinary Institute, 2014), results suggest that enrichment broth transported at\nroom temperature may be more sensitive for detection of carriage than STGG transported\nat cool temperatures. We therefore compared (1) in vitro recovery from serial dilutions in STGG and\nenrichment broth and (2) in vivo detection of nasopharyngeal carriage of pneumococci\nfrom swabs that were transported and stored in STGG at cool temperatures or in enrichment\nbroth at room temperature. ABSTRACT (2016), In vitro and in vivo comparison of transport media for detecting nasopharyngeal carriage of\nStreptococcus pneumoniae. PeerJ 4:e2449; DOI 10.7717/peerj.2449 MATERIALS AND METHODS In the in vitro component of the study, we compared recovery rates of pneumococci\nfrom serial dilutions that had been stored at different temperatures and media using (I)\nculturing, (II) a commercial latex agglutination kit and (III) quantitative real-time PCR\n(qPCR). In the in vivo component, we compared carriage using paired swabs taken from\nchildren attending day-care centres and transported in STGG or enrichment broth. In the\nsecond part, we used methods (I) and (II) for detection of pneumococci. See Fig. 1 for a\nschematic overview of the procedures. Note that we followed the recommended conditions\nfor transport and storage for each medium (wet ice/cool box for STGG and freezing (in\nvivo only), room temperature and immediate processing for enrichment broth). Steens et al. (2016), PeerJ, DOI 10.7717/peerj.2449 In vitro comparison Furthermore, 100 µL of the STGG samples was added\nto 3ml fresh enrichment broth. All was done in triplicate. Plates and tubes (broth sample\nmade from the STGG samples and the initial enrichment broth samples) were incubated\novernight at 35 ◦C with 5% CO2. Pneumococci were identified by latex agglutination (Pneumotest-Latex kit; Statens\nSerum Institut, Denmark; Slotved et al., 2004) from the incubated broths. Quantification\nof the bacterial loads was performed by qPCR (see below for details) and counting of the\ncolony forming units (CFU) from the incubated plates. In vitro comparison Three strains belonging to different serotypes were used as pneumococcal samples; two\nreference strains (ATCC49619—serotype 19F, and TIGR4—serotype 4), and a strain\nbelonging to serotype 3 obtained from the 2013 sample of a previous Norwegian carriage\nstudy (Steens et al., 2015). Colonies from each serotype were suspended in Todd-Hewitt Steens et al. (2016), PeerJ, DOI 10.7717/peerj.2449 2/10 Vortex\t\r and\t\r \nfreeze\t\r at\t\r \n-‐70°C\t\r \t\r \nSerial\t\r dilu6ons\t\r of\t\r \npneumococcal\t\r \nsuspensions\t\r in\t\r TH\t\r \nbroth\t\r \n100µL\t\r in\t\r 1ml\t\r STGG\t\r \non\t\r wet\t\r ice\t\r \n100µL\t\r in\t\r 3ml\t\r \nenrichment\t\r broth\t\r at\t\r \nroom\t\r temperature\t\r \nTIME\t\r \n3\t\r hours\t\r \nOvernight\t\r \nDay\t\r 2\t\r \nLatex\t\r agglu6na6on\t\r \nPlate\t\r 100µL\t\r on\t\r \nblood\t\r agar. Incubate\t\r at\t\r \t\r 35⁰C\t\r \nCount\t\r colonies\t\r \nIncubate\t\r in\t\r ini6al\t\r \n3ml\t\r enrichment\t\r \nbroth\t\r at\t\r 35⁰C\t\r \nPrepare\t\r 200µL\t\r \nsample\t\r for\t\r qPCR\t\r \nand\t\r freeze\t\r \nPlate\t\r 100µL\t\r on\t\r \nblood\t\r agar. Incubate\t\r at\t\r \t\r 35⁰C\t\r \nIncubate\t\r 100µL\t\r in\t\r \n3ml\t\r enrichment\t\r \nbroth\t\r at\t\r 35⁰C\t\r \nLatex\t\r agglu6na6on\t\r \nCount\t\r colonies\t\r \nPrepare\t\r 200µL\t\r \nsample\t\r for\t\r PCR\t\r and\t\r \nfrozen\t\r \nIn\t\r vitro\t\r \nIn\t\r vivo\t\r \nNasopharyngeal\t\r swab\t\r 2\t\r \nThaw\t\r STGG\t\r \nsample,\t\r and\t\r \nvortex\t\r \nPlace\t\r in\t\r 3ml\t\r \nenrichment\t\r broth\t\r at\t\r \nroom\t\r temperature\t\r \nTIME\t\r \nWithin\t\r 4\t\r hours\t\r \nOvernight\t\r \nDay\t\r 2\t\r \nLatex\t\r agglu6na6on\t\r \nPlate\t\r the\t\r swab\t\r on\t\r \nGBA\t\r for\t\r culturing. Incubate\t\r at\t\r \t\r 35⁰C\t\r \nQuellung\t\r reac6on\t\r \t\r \nIncubate\t\r in\t\r ini6al\t\r \n3ml\t\r enrichment\t\r \nbroth\t\r at\t\r 35⁰C\t\r \nPlate\t\r 20µL\t\r on\t\r GBA\t\r \nfor\t\r culturing,\t\r \nIncubate\t\r at\t\r \t\r 35⁰C\t\r \nIncubate\t\r 200µL\t\r in\t\r \n3ml\t\r enrichment\t\r \nbroth\t\r at\t\r 35⁰C\t\r \nLatex\t\r agglu6na6on\t\r \nQuellung\t\r reac6on\t\r \nPlace\t\r in\t\r 1ml\t\r \nSTGG\t\r in\t\r a\t\r \ncool\t\r box\t\r \nFreeze\t\r for\t\r minimal\t\r 18\t\r hours\t\r and\t\r \t\r \nmaximal\t\r 1\t\r months\t\r \nNasopharyngeal\t\r swab\t\r 1\t\r \nqPCR\t\r \nFigure 1 Schematic overview of the experimental designs. (A) in vitro. (B) in vivo. TH, Todd-Hewitt; STGG, skim milk, tryptone, glucose and\nglycerol; GBA, gentamycin-blood-agar. Place\t\r in\t\r 3ml\t\r \nenrichment\t\r broth\t\r at\nroom\t\r temperature Latex\t\r agglu6na6on Figure 1 Schematic overview of the experimental designs. (A) in vitro. (B) in vivo. TH, Todd-Hewitt; STGG, skim milk, tryptone, glucose and\nglycerol; GBA, gentamycin-blood-agar. (TH) broth at a concentration of 0.5 McFarland in serial 1:10 dilutions of 10−2 to 10−5\n(minimal concentration for which recovery of pneumococcal DNA was possible; see\nSupplemental Information 3). A volume of 100 µL of serotype dilution in TH broth was\nadded to each set of transport media (either 1 ml of STGG or 3 ml of enrichment broth)\nto prepare the pneumococcal samples. The samples were left for 3 h on wet ice (STGG) or\nroom temperature (enrichment broth). Subsequently, 100 µL of the samples was plated on\nColumbia horse blood agar plates. Steens et al. (2016), PeerJ, DOI 10.7717/peerj.2449 DNA extraction and amplification by qPCR From each sample 200 µL was boiled for 10 min and DNA was extracted by QIAamp\nDNA Mini QIAcube kit (Qiagen, Inc., Valencia, CA, US) according to the manufacturer’s\nrecommendations. A qPCR assay for the detection of the autolysin-encoding gene (lytA)\nwas then performed as described before by Carvalho et al. (2007). Briefly, 25 µL reaction\nvolume composed of TaqMan Fast Universal PCR Master Mix 2x, 200 nM of each primer\nand probe, 10x Exo IPC-mix, 50x Exo IPC DNA and 2 µL of DNA was run at 50 ◦C for\n2 min, denaturation at 95 ◦C for 10 min, followed by 40 amplification cycles of 95 ◦C\nfor 15 s and 60 ◦C for 1 min. Samples were considered negative if cycle thresholds (Ct) Steens et al. (2016), PeerJ, DOI 10.7717/peerj.2449 3/10 exceeded 40. A positive (ATCC49619) and a non-template control (sterile water) were\nincluded in each run, along with extraction controls. Data analysis For the in vitro analyses, Ct values and CFU counts (after a logarithmic transformation;\nlogCFU) from the two media were compared by linear regression. We used 11 mutually\nexclusive dummy variables identifying different dilution-serotype combinations, which\nenabled us to simultaneously run the comparison for all serotypes. Additionally, the analyses\nwere conducted separately per serotype. Agreement in the in vivo comparison was determined using the kappa statistic (Landis &\nKoch, 1977) and the exact McNemar’s probability test for paired data. Data were analysed\nin Stata 14.0 and GraphPad Prism 5. In vivo comparison This comparison was performed as part of a larger carriage study (sample taken in 2015\n(Steens et al., 2016)). The study was conducted in accordance with principles of the Decla-\nration of Helsinki, and approved by the Regional Committee for Medical Research Ethics,\nSouth-Eastern Norway (reference number: 2014/2046). Parents/guardians of the children\ngave written informed consent before including their child in the study. The study design\nresembles the design used in previous Norwegian carriage studies (Steens et al., 2015). Two flocked nylon nasopharyngeal swabs (E-swabsTM, Copan, Italy) taken from the\nsame nostril were collected from 100 children aged 1–6 years according to standard\nprocedures. The first swab was placed in 1 ml STGG which was subsequently stored in a\ncool box and the second swab was stored and transported in 3 ml enrichment broth at room\ntemperature. The specimens were processed within 4 h of sampling. The STGG samples\nwere vortexed at high speed and frozen at −70 ◦C , following the recommendations of\nWHO (Satzke et al., 2013). Within one month but earliest 18 h after initial freezing, the\nSTGG samples were processed further: after being thawed and vortexed, 200 µl was added\nto fresh enrichment broth and 20 µl was plated on gentamycin-blood-agar (GBA). The\nswabs from the enrichment broth samples were plated on GBA within 4 h of sampling\nand the swab was re-inserted into the enrichment broth. All broths and GBA plates were\nincubated overnight at 35 ◦C , with 5% CO2. Pneumococci were identified by latex agglutination from incubated broths. Confirma-\ntion and factor typing were performed by Quellung reaction. All morphologically different\npneumococcal colonies per plate were typed. In cases where the latex agglutination was\npositive but no colonies were found on plates after incubation overnight, samples were\nre-cultured by plating one drop of the incubated broth and incubating this for another\nnight before further analysis. In vitro results (A) serotype 19F; (B) serotype 4; (C) serotype 3. * Uncountable. The quantification of DNA by Ct value is presented in Fig. 2. The Ct values overall\ndid not differ significantly between STGG and enrichment broth samples (p = 0.853),\nthough for serotype 4, the Ct values were significantly lower for STGG samples compared\nto enrichment broth samples (p = 0.007). After culturing, no clear overall difference was\nfound in the logCFU (p = 0.593) but significant differences were observed for serotype 4\n(Fig. 3B; p = 0.008; more colonies on plates incubated with STGG samples) and serotype 3\n(Fig. 3C; p = 0.001; more colonies on plates incubated with enrichment broth samples). In vitro results The latex agglutination test was positive for both media for all serotype dilutions tested,\nwith the exception of serotype 3 at a dilution of 10−5 in STGG, where no pneumococci\nwere detected. Steens et al. (2016), PeerJ, DOI 10.7717/peerj.2449 4/10 A \nB \nC \n* # \nEnrichment broth \nSTGG \nFigure 2\nDNA quantification (Ct values) at different dilutions of enrichment broth and STGG. (A)\nserotype 19F*; (B) serotype 4; (C) serotype 3. * At a dilution of 10−5, one of the triplicates had a cycle\nthreshold (Ct) of 39.4, while the other two were above 40. This sample was therefore considered negative. # Ct above 40. ** \nA \nB \nC \nEnrichment broth \nSTGG \n** \nFigure 3\nQuantification of bacterial load (log counts of colony forming units [CFU]) at different dilu-\ntions of enrichment broth and STGG. (A) serotype 19F; (B) serotype 4; (C) serotype 3. * Uncountable. A \nB \nC \n* # \nEnrichment broth \nSTGG * # \nFigure 2\nDNA quantification (Ct values) at different dilutions of enrichment broth and STGG. (A)\nserotype 19F*; (B) serotype 4; (C) serotype 3. * At a dilution of 10−5, one of the triplicates had a cycle\nthreshold (Ct) of 39.4, while the other two were above 40. This sample was therefore considered negative. # Ct above 40. ** \nA \nB \nC \nEnrichment broth \nSTGG \n** \nFigure 3\nQuantification of bacterial load (log counts of colony forming units [CFU]) at different dilu-\ntions of enrichment broth and STGG. (A) serotype 19F; (B) serotype 4; (C) serotype 3. * Uncountable. Figure 2\nDNA quantification (Ct values) at different dilutions of enrichment broth and STGG. (A)\nserotype 19F*; (B) serotype 4; (C) serotype 3. * At a dilution of 10−5, one of the triplicates had a cycle\nthreshold (Ct) of 39.4, while the other two were above 40. This sample was therefore considered negative. # Ct above 40. Figure 2\nDNA quantification (Ct values) at different dilutions of enrichment broth and STGG. (A)\nserotype 19F*; (B) serotype 4; (C) serotype 3. * At a dilution of 10−5, one of the triplicates had a cycle\nthreshold (Ct) of 39.4, while the other two were above 40. This sample was therefore considered negative. # Ct above 40. ** \nA \nB \nC \nEnrichment broth \nSTGG \n** Figure 3\nQuantification of bacterial load (log counts of colony forming units [CFU]) at different dilu-\ntions of enrichment broth and STGG. Steens et al. (2016), PeerJ, DOI 10.7717/peerj.2449 In vivo results Forty-six percent of the swabs transported and stored in STGG and 51% of those transported\nin enrichment broth were positive for pneumococci. This resulted in a Kappa statistic for\ncarriage of 0.90 for the paired swabs (Table 1), indicating a trend towards higher sensitivity\nafter transportation in enrichment broth compared to STGG (p = 0.0625). If re-cultured\nsamples were excluded, carriage was 44% for the samples transported and stored in STGG\nand 48% for those transported in enrichment broth (Kappa = 0.92; p = 0.125). For each\nchild for whom both swabs were positive, the same serotype was obtained. In one child,\ncarriage of two serotypes was found in the enrichment broth sample, while one serotype\nwas found in the STGG sample. However, the plate incubated with the enrichment broth Steens et al. (2016), PeerJ, DOI 10.7717/peerj.2449 5/10 Table 1\nPneumococcal carriage determined by culturing paired nasopharyngeal swabs stored in\nSTGG or enrichment broth. Enrichment broth\nPositive\nNegative\nTotal\nPositive\n46\n0\n46\nSTGG\nNegative\n5\n49\n54\nTotal\n51\n49\n100\nNotes. STGG, skim milk, tryptone, glucose and glycerol. sample had only one colony of the serotype that was missed in the STGG sample (serotype 3)\nand the agglutination test was negative for this serotype, indicating presence at a very\nlow concentration. Table 1\nPneumococcal carriage determined by culturing paired nasopharyngeal swabs stored in\nSTGG or enrichment broth. Enrichment broth\nPositive\nNegative\nTotal\nPositive\n46\n0\n46\nSTGG\nNegative\n5\n49\n54\nTotal\n51\n49\n100\nNotes. STGG, skim milk, tryptone, glucose and glycerol. Table 1\nPneumococcal carriage determined by culturing paired nasopharyngeal swabs stored in\nSTGG or enrichment broth. Enrichment broth\nPositive\nNegative\nTotal\nPositive\n46\n0\n46\nSTGG\nNegative\n5\n49\n54\nTotal\n51\n49\n100\nNotes. STGG, skim milk, tryptone, glucose and glycerol. Table 1\nPneumococcal carriage determined by culturing paired nasopharyngeal swabs stored in\nSTGG or enrichment broth. STGG, skim milk, tryptone, glucose and glycerol. sample had only one colony of the serotype that was missed in the STGG sample (serotype 3)\nand the agglutination test was negative for this serotype, indicating presence at a very\nlow concentration. sample had only one colony of the serotype that was missed in the STGG sample (serotype 3)\nand the agglutination test was negative for this serotype, indicating presence at a very\nlow concentration. Steens et al. (2016), PeerJ, DOI 10.7717/peerj.2449 DISCUSSION Overall, no statistical differences in sensitivity were found between STGG stored and\ntransported at cool temperatures and enrichment broth transported at room temperature. Nevertheless, some serotype differences were observed as well as a trend towards higher\nsensitivity for detection of pneumococcal carriage after transportation in enrichment broth\ncompared to STGG. There are several possible reasons for these differences. In vitro, a pure dilution of one\nserotype was used in place of a nasopharyngeal swab. In vivo the swab contained different\nrespiratory bacteria and viruses, and was covered with mucus and cellular debris. The\npresence of other bacteria places pneumococci in competition for nutrients needed for\ngrowth and reproduction. These nutrients are available in higher concentration in enrich-\nment broth than in STGG, which may explain the small difference in sensitivity observed\nbetween the in vitro and in vivo settings. In addition to the difference in available nutrients\nin STGG and enrichment broth, the fact that STGG samples were kept in a cool box during\ntransport while the enrichment broth samples were kept at room temperature, may have\ncaused the small non-significant difference in carriage prevalence. The original carriage\nstudy presenting the use of enrichment broth as transport medium used cool transport\nconditions (Kaltoft et al., 2008) but three previous Norwegian carriage studies used room\ntemperature (Steens et al., 2015). The present study is not designed to differentiate between\nthe effect of media and temperature, but while pneumococci are thought to thrive better\nat warmer temperatures, we did not find an overall difference between the methods in\nbacterial load or DNA quantity in vitro. Whether the relative abundance of other respiratory\nbacteria/the microbiome may have changed and would no longer be representative of the\nnasopharyngeal tract after storage at room temperature should be investigated were room\ntemperature to be used in such studies. Still, for serotype 3, the bacterial load indicated\na higher sensitivity of enrichment broth compared to STGG. The serotype 3 isolate was\nobtained from a previous carriage study. For serotype 19F and 4, reference strains were\nused. The origin of the isolates (reference strains versus carriage isolate) may have induced\ndifferent bacterial growth characteristics. Further, the capsule structure differs between Steens et al. (2016), PeerJ, DOI 10.7717/peerj.2449 6/10 serotypes (serotype 3 being very mucoid). The low number of serotypes tested and the\ndifference in origin between serotypes are limitations to the in vitro part of this study. DISCUSSION The carriage prevalence found in this study is lower than observed previously in Norway\n(Steens et al., 2015), and more similar to what has been seen in other developed countries\n(Van Hoek et al., 2014; Desai et al., 2015; Andrade et al., 2014). The methods used for swab\ncollection, transport and incubation in enrichment broth and culturing were unchanged\nfrom former studies, indicating a real difference in carriage prevalence that may have\nresulted from vaccination. Advantages of molecular based techniques compared to culture techniques include the\nfact that viable organisms are not required, the original composition of the nasopharyngeal\nspecimen is preserved, and detailed quantification and characterization of the pneumococci\nwithin a sample are possible, depending on the methods used (Satzke et al., 2013). Furthermore, the sensitivity of molecular methods for detection of multiple co-colonising\nserotypes has been shown to be higher than conventional methods (Saha et al., 2015). Nevertheless, isolation of strains enables further characterization such as antimicrobial\nsusceptibility testing and sequence typing, and should not be replaced by molecular\nmethods alone, despite its high sensitivity. The additional incubation step and use of\nlatex agglutination appears to be of value for identification and isolation of pneumococci\nfrom multiple carriage (Kaltoft et al., 2008). The PneuCarriage Project concluded that\nmicroarray with a culture amplification step has the highest sensitivity for determining\ncarriage (Satzke et al., 2015). Finally, STGG is cheap, easy to make and can be stored longer than enrichment broth,\nthus enabling comparability between studies and settings, including more resource-limited\nsettings. Furthermore, STGG transported and stored at cool temperatures enables studies to\ninvestigate the microbiome (Grijalva et al., 2014; Turner et al., 2011), whereas enrichment\nbroth may selectively stimulate growth of pneumococci. Therefore, even though STGG ap-\npeared slightly less sensitive than enrichment broth for detection of nasopharyngeal carriage\nof pneumococci by culturing, we recommend the continued use of STGG for transport\nand storage of nasopharyngeal swabs at cool temperatures in future carriage studies. ACKNOWLEDGEMENTS We thank the children and parents for participating and day-care centres workers for\ntheir support. We also thank Anne Ramstad Alme, Gunnhild Rødal, Lene Haakensen,\nAnne Witsø and Martha Langedok Bjørnstad for the laboratory analyses, Ingvild Essén\nand Kristine Hartmark for the collection of nasopharyngeal swabs, and Richard White for\nstatistical advice. ADDITIONAL INFORMATION AND DECLARATIONS\nFunding\nThe authors received no funding for this work. Steens et al. (2016), PeerJ, DOI 10.7717/peerj.2449 Funding The authors received no funding for this work. Steens et al. (2016), PeerJ, DOI 10.7717/peerj.2449 Competing Interests The authors declare there are no competing interests. Supplemental Information Supplemental information for this article can be found online at http://dx.doi.org/10.7717/\npeerj.2449#supplemental-information. Supplemental information for this article can be found online at http://dx.doi.org/10.7717/\npeerj.2449#supplemental-information. Human Ethics The following information was supplied relating to ethical approvals (i.e., approving body\nand any reference numbers): The following information was supplied relating to ethical approvals (i.e., approving body\nand any reference numbers): Regional Committee for Medical Research Ethics, South-Eastern Norway (REK sør-øst\nB) Approval number: 2014/2046. Data Availability The following information was supplied regarding data availability: The following information was supplied regarding data availability: The raw data has been supplied as a Supplementary File. The raw data has been supplied as a Supplementary File. Steens et al. (2016), PeerJ, DOI 10.7717/peerj.2449 Author Contributions • Anneke Steens and Natacha Milhano conceived and designed the experiments, performed\nthe experiments, analyzed the data, contributed reagents/materials/analysis tools, wrote\nthe paper, prepared figures and/or tables, reviewed drafts of the paper. • Ingeborg S. Aaberge conceived and designed the experiments, contributed\nreagents/materials/analysis tools, reviewed drafts of the paper. • Didrik F. Vestrheim conceived and designed the experiments, performed the\nexperiments, contributed reagents/materials/analysis tools, reviewed drafts of the paper. REFERENCES Andrade AL, Ternes YM, Vieira MA, Moreira WG, Lamaro-Cardoso J, Kipnis A,\nCardoso MR, Brandileone MC, Moura I, Pimenta FC, Da Gloria Carvalho M,\nSaraiva FO, Toscano CM, Minamisava R. 2014. Direct effect of 10-valent conjugate\npneumococcal vaccination on pneumococcal carriage in children Brazil. PLoS ONE\n9(6):e98128 DOI 10.1371/journal.pone.0098128. Andrade AL, Ternes YM, Vieira MA, Moreira WG, Lamaro-Cardoso J, Kipnis A,\nCardoso MR, Brandileone MC, Moura I, Pimenta FC, Da Gloria Carvalho M,\nSaraiva FO, Toscano CM, Minamisava R. 2014. Direct effect of 10-valent conjugate\npneumococcal vaccination on pneumococcal carriage in children Brazil. PLoS ONE\n9(6):e98128 DOI 10.1371/journal.pone.0098128. Carvalho G, Tondella ML, McCaustland K, Weidlich L, McGee L, Mayer LW, Steiger-\nwalt A, Whaley M, Facklam RR, Fields B, Carlone G, Ades EW, Dagan R, Sampson\nJS. 2007. Evaluation and improvement of real-time PCR assays targeting lytA., ply,\nand psaA genes for detection of pneumococcal DNA. Journal of Clinical Microbiology\n45(8):2460–2466 DOI 10.1128/JCM.02498-06. Desai AP, Sharma D, Crispell EK, Baughman W, Thomas S, Tunali A, Sherwood\nL, Zmitrovich A, Jerris R, Satola SW, Beall B, Moore MR, Jain S, Farley MM. 2015. Decline in pneumococcal nasopharyngeal carriage of vaccine serotypes after\nthe introduction of the 13-valent pneumococcal conjugate vaccine in children\nin Atlanta, Georgia. The Pediatric Infectious Disease Journal 34(11):1168–1174\nDOI 10 1097/INF 0000000000000849 Steens et al. (2016), PeerJ, DOI 10.7717/peerj.2449 8/10 Garcia-Rodriguez JA, Fresnadillo Martinez MJ. 2002. Dynamics of nasopharyngeal col-\nonization by potential respiratory pathogens. Journal of Antimicrobial Chemotherapy\n50 Suppl S2:59–73 DOI 10.1093/jac/dkf506. Grijalva CG, Griffin MR, Edwards KM, Johnson M, Gil AI, Verastegui H, Lanata\nCF, Williams JV. 2014. Concordance between RT-PCR-based detection of res-\npiratory viruses from nasal swabs collected for viral testing and nasopharyngeal\nswabs collected for bacterial testing. Journal of Clinical Virology 60(3):309–312\nDOI 10.1016/j.jcv.2014.04.011. Kaltoft MS, Skov Sorensen UB, Slotved HC, Konradsen HB. 2008. An easy method for\ndetection of nasopharyngeal carriage of multiple Streptococcus pneumoniae serotypes. Journal of Microbiological Methods 75(3):540–544 DOI 10.1016/j.mimet.2008.08.010. Landis JR, Koch GG. 1977. The measurement of observer agreement for categorical data. Biometrics 33(1):159–174 DOI 10.2307/2529310. Norwegian Veterinary Institute. 2014. Skov Simonsen G, Urdahl AM, eds. Usage of\nantimicrobial agents and occurence of antimicrobial resistance in Norway. Tromsø:\nNorwegian Veterinary Institute. Available at http://www.vetinst.no/overvåking/ O’Brien KL, Bronsdon MA, Dagan R, Yagupsky P, Janco J, E J, Whitney CG, Yang\nY-H, Robinson L-GE, Schwartz B, Carlone GM. 2001. Steens et al. (2016), PeerJ, DOI 10.7717/peerj.2449 Steens et al. (2016), PeerJ, DOI 10.7717/peerj.2449 REFERENCES Evaluation of a medium\n(STGG) for transport and optimal recovery of Streptococcus pneumoniae from na-\nsopharyngeal secretions collected during field studies. Journal of Clinical Microbiology\n39(3):1021–1024 DOI 10.1128/JCM.39.3.1021-1024.2001. Saha S, Modak JK, Naziat H, Al-Emran HM, Chowdury M, Islam M, Hossain B,\nDarmstadt GL, Whitney CG, Saha SK. 2015. Detection of co-colonization with\nStreptococcus pneumoniae by algorithmic use of conventional and molecular\nmethods. Vaccine 33(5):713–718 DOI 10.1016/j.vaccine.2014.11.040. Satzke C, Dunne EM, Porter BD, Klugman KP, Mulholland EK, g. PneuCarriage\nproject. 2015. The pneucarriage project: a multi-centre comparative study to identify\nthe best serotyping methods for examining pneumococcal carriage in vaccine\nevaluation studies. PLoS Med 12(11):e1001903 DOI 10.1371/journal.pmed.1001903. Satzke C, Turner P, Virolainen-Julkunen A, Adrian PV, Antonio M, Hare KM,\nHenao-Restrepo AM, Leach AJ, Klugman KP, Porter BD, Sa-Leao R, Scott JA,\nNohynek H, O’Brien KL, W.H.O.P.C.W. Group. 2013. Standard method for\ndetecting upper respiratory carriage of Streptococcus pneumoniae: updated recom-\nmendations from the World Health Organization Pneumococcal Carriage Working\nGroup. Vaccine 32(1):165–179 DOI 10.1016/j.vaccine.2013.08.062. Slotved H-C, Kaltoft M, Skovsted IC, Kerrn MB, Espersen F. 2004. Simple, rapid latex\nagglutination test for serotyping of pneumococci (Pneumotest-Latex). Journal of\nClinical Microbiology 42:2518–2522 DOI 10.1128/JCM.42.6.2518-2522.2004. Statistics Norway. 2010. Norway, Child-care, 2010 [in Norwegian: Barn i barnehage—\nforeldrebakgrunn og utvikling de seneste årene]. (electronic). Statistics Norway. 2010. Norway, Child-care, 2010 [in Norwegian: Barn i barnehage—\nforeldrebakgrunn og utvikling de seneste årene]. (electronic). Steens A, Caugant DA, Aaberge IS, Vestrheim DF. 2015. Decreased carriage and genetic\nshifts in the Streptococcus pneumoniae population after changing the 7-valent to the Steens et al. (2016), PeerJ, DOI 10.7717/peerj.2449 9/10 13-valent pneumococcal vaccine in Norway. The Pediatric Infectious Disease Journal\n34:875–883. Steens A, Caugant DA, Aaberge IS, Vestrheim DF. 2016. Continued decrease in\npneumococcal carriage after implementation of PCV13 in norway. In: Abstract 370. 10th International Symposium on Pneumococci and Pneumococcal Diseases (ISPPD\n2016), Glasgow, Scotland. Turner P, Po L, Turner C, Goldblatt D, Nosten F. 2011. Detection of respiratory viruses\nby PCR assay of nasopharyngeal swabs stored in skim milk-tryptone-glucose-\nglycerol transport medium. Journal of Clinical Microbiology 49(6):2311–2313\nDOI 10.1128/JCM.00224-11. Van Hoek AJ, Sheppard CL, Andrews NJ, Waight PA, Slack MP, Harrison TG, Ladhani\nSN, Miller E. 2014. Pneumococcal carriage in children and adults two years after\nintroduction of the thirteen valent pneumococcal conjugate vaccine in England. Vaccine 32:4349–4355 DOI 10.1016/j.vaccine.2014.03.017. 10/10"}}},{"rowIdx":2198,"cells":{"identifier":{"kind":"string","value":"https://openalex.org/W4391904584"},"pdf_url":{"kind":"string","value":"http://catalog.liha-pres.eu/index.php/liha-pres/catalog/download/251/6969/15636-1"},"lang":{"kind":"string","value":"Ukrainian"},"error":{"kind":"null"},"title":{"kind":"string","value":"Національні риси китайського фортепіанного мистецтва"},"source_name":{"kind":"string","value":"ГУМАНІТАРНИЙ І ІННОВАЦІЙНИЙ РАКУРС ПРОФЕСІЙНОЇ МАЙСТЕРНОСТІ: ПОШУКИ МОЛОДИХ ВЧЕНИХ"},"publication_year":{"kind":"number","value":2023,"string":"2,023"},"license":{"kind":"string","value":"cc-by"},"word_count":{"kind":"number","value":1340,"string":"1,340"},"text":{"kind":"string","value":"DOI https://doi.org/10.36059/978-966-397-357-9-72 DOI https://doi.org/10.36059/978-966-397-357-9-72 DOI https://doi.org/10.36059/978-966-397-357-9-72 \n \nНАЦІОНАЛЬНІ РИСИ КИТАЙСЬКОГО \nФОРТЕПІАННОГО МИСТЕЦТВА \n \nВан Яньсуй \nаспірант за спеціальністю 025 – Музичне мистецтво \nНауковий керівник: Гончаренко О. В. кандидат мистецтвознавства, \nстарший викладач кафедри музикознавства та культурології \nСумський державний педагогічний університет імені А. С. Макаренка \nм. Суми, Україна \n \nФортепіанне мистецтво Китаю становить самобутній пласт світової \nкультури. Його \nсвоєрідність \nвизначається \nне \nлише \nзагальнонаціональним \nестетичними \nконстантами, \nа \nй \nвпливом – інноваційні методики навчання – запровадження розробок нових \nтехнологій навчання для системи неперервної освіти; – інноваційні методики навчання – запровадження розробок нових \nтехнологій навчання для системи неперервної освіти; – інноваційні методики навчання – запровадження розробок нових \nтехнологій навчання для системи неперервної освіти; – принципово нова система оцінки здобутої освіти – докорінна зміна \nпідходів до розуміння і визнання навчальної діяльності та її результатів, \nособливо у сфері освіти; – принципово нова система оцінки здобутої освіти – докорінна зміна \nпідходів до розуміння і визнання навчальної діяльності та її результатів, \nособливо у сфері освіти; – розвиток наставництва і консультування – забезпечення кожному \nвільного доступу до освітньої інформації та необхідних консультацій і \nрекомендацій; – розвиток наставництва і консультування – забезпечення кожному \nвільного доступу до освітньої інформації та необхідних консультацій і \nрекомендацій; – наближення освіти до місця проживання – використання мережі \nнавчальних і консультаційних пунктів, сучасних інформаційних та \nкомунікаційних технологій. – наближення освіти до місця проживання – використання мережі \nнавчальних і консультаційних пунктів, сучасних інформаційних та \nкомунікаційних технологій. Література: р\nур\n1. Національна \nдоктрина \nрозвитку \nосвіти. Книга \nкерівника \nнавчально-виховного закладу. Нормативні та інструктивно-методичні \nдокументи Міністерства освіти і науки України. Харків: ПП «Торг сін \nплюс», 2006. С. 82–96. 1. Національна \nдоктрина \nрозвитку \nосвіти. Книга \nкерівника \nнавчально-виховного закладу. Нормативні та інструктивно-методичні \nдокументи Міністерства освіти і науки України. Харків: ПП «Торг сін \nплюс», 2006. С. 82–96. 2. О.В. Вознюк. Неперервна освіта як провідна тенденція сучасного \nсвіту. Андрагогічний вісник. 2012. Вип. 1. С. 50–57. 2. О.В. Вознюк. Неперервна освіта як провідна тенденція сучасного \nсвіту. Андрагогічний вісник. 2012. Вип. 1. С. 50–57. 3. Меморандум неперервного процесу освіти Європейського Союзу. Адукатар. 2006. № 2 (8). С. 25. URL: http://adukatar.net/wpcontent/ \nuploads/2009/12/Adu_8_Pages_24-27.pdf 4. 3. Меморандум неперервного процесу освіти Європейського Союзу. Адукатар. 2006. № 2 (8). С. 25. URL: http://adukatar.net/wpcontent/ \nuploads/2009/12/Adu_8_Pages_24-27.pdf 4. НАЦІОНАЛЬНІ РИСИ КИТАЙСЬКОГО \nФОРТЕПІАННОГО МИСТЕЦТВА Ван Яньсуй \nаспірант за спеціальністю 025 – Музичне мистецтво \nНауковий керівник: Гончаренко О. В. кандидат мистецтвознавства, \nстарший викладач кафедри музикознавства та культурології \nСумський державний педагогічний університет імені А. С. Макаренка \nм. Суми, Україна Фортепіанне мистецтво Китаю становить самобутній пласт світової \nкультури. Його \nсвоєрідність \nвизначається \nне \nлише \nзагальнонаціональним \nестетичними \nконстантами, \nа \nй \nвпливом 250 фольклорних традицій, зокрема використанням ангемітонних музичних \nладів, імітуванням гри на народних інструментах. Вагомого значення \nнабуває звернення композиторів до національної народнопісенної \nскарбниці: автентичні фольклорні мелодії становлять інтонаційну \nоснову переважної більшості творів для фортепіано. Символізм, традиційно притаманний китайському світогляду, \nзалишив свій відбиток на різних елементах музичної мови, зокрема \nкожен тон китайської пентатоніки має символічне значення пов’язане з \nприродними явищами: перший тон «гун» – означає гуркіт грому, \nдругий – «шан» – шум вітру, третій – «цзює» – вогняну стихію, \nчетвертий – «чжі» і п’ятий – «юй» – пов’язані з образами води. Ця \nобразна символіка й до сьогодні використовується композиторами у \nстворенні фортепіанної музики. р\nф р\nу\nУ сучасних творах для фортепіано часто застосовується символіка \nспецифічних \nтембрових \nхарактеристик \nкитайських \nстародавніх \nмузичних інструментів. Композитори переважно використовують \nімітування музичних інструментів, що асоціативно пов’язані з голосами \nприроди, або музикуванням просто неба. Здебільшого імітуються: сона \n( 嗩吶 – китайська труба) – дерев’яний духовий інструмент, що має \nширокий діапазон і пронизливий звук, який нагадує спів птахів, \nпереважно використовується для гри на відкритому повітрі; шен (笙– \nкитайський губний орган) – багатоголосний духовий язичковий \nінструмент з співучим плавним звучанням на кшталт волинки \n(характерні квінтові та кварто-квінтові звучання), за легендою, тембр \nшена нагадує голос птаха Фенікс; сяо (簫) – традиційна китайська \nпродольна бамбукова флейта, що має м’яке, заворожуюче звучання, \nпов’язане з ліричною образністю; ді (笛) – традиційна китайська \nпоперечна флейта, має дзвінкий і чистий тембр, що асоціюється з \nнебесною височінню; пайсяо (排箫 – китайська флейта) – стародавній \nдуховий інструмент, що складається з 12 бамбукових трубочок і за \nзвучанням нагадує флейту Пана; ґуцінь, гучжен (古琴, 古箏 – китайська \nцитра), або піпа (琵琶 – китайська лютня) – струнні інструменти з \nщипковим звуковидобуванням, деякі дослідники вважають, що їх \nзвучання нагадує китайську мову; ерху і баньху (二胡, 板胡 – різновиди \nхуціня) – струнно-смичкові інструменти, що мають специфічне тихе й \nніжне звучання, яке дозволяє відтворювати приховані почуття, а також \nвикористовують такий прийом гри, як перебір струн, пов’язаний з \nзображенням водної стихії. НАЦІОНАЛЬНІ РИСИ КИТАЙСЬКОГО \nФОРТЕПІАННОГО МИСТЕЦТВА ЛНМА \nімені М. В. Лисенка, 2017. 187 с. DOI https://doi.org/10.36059/978-966-397-357-9-73 НАЦІОНАЛЬНІ РИСИ КИТАЙСЬКОГО \nФОРТЕПІАННОГО МИСТЕЦТВА Автори китайської фортепіанної музики \nтакож широко використовують імітування ударних інструментів – \nбарабанів, \nгонгів, \nякі \nпосідають \nзначне \nмісце \nв \nкитайській 251 інструментальній традиції і асоціативно пов’язані з дзвонами, або \nобразами несамовитих ударів шаленої стихії. Специфічною \nрисою \nкитайських \nфортепіанних \nтворів \nє \nпрограмність, зокрема вельми поширеним є «звукозображальний тип \nпрограмності». На відміну від європейської музики, в творчості \nкитайських авторів вона не трактується як «допоміжна», «первинна», \n«необов’язкова», – зазначає Лу Цзе: «Навпаки, для митця, вихованого в \nдусі \nнастанов \nконфуціанства, \nвслуховування, \nсприйняття \nі \nтрансформація звуків природи (особливо в такому незвичному для \nкитайського вуха тембрі як звучання фортепіано), стає однією із \nнайвищих художніх цілей, в естетиці гілозоїзму, проявом вищої \nмудрості, здатності злитись з природою, відчути її божественний голос» \n[1, с. 120]. Виявляючи концептосфери китайської фортепіанної музики \nдослідниця відзначає, що кожна з програмних назв «спрямована на \nсимволічне означення тієї чи іншої універсальної ціннісної сутності, \nвираз гармонійного ідеалу «людини – світу» (концепт природи), \n«людини – людини, людської спільноти» (концепт обрядів і ритуалів) \nабо ж «людини – непізнаваного Всесвіту, вищих сил» (міфологічний \nконцепт)» [1, c. 164]. Фортепіанним творам багатьох китайських композиторів притаманні \nриси музичного імпресіонізму і це є закономірним, адже специфіка \nтрадиційної народної музики має певні ознаки імпресіоністичної \nестетики: \nспоглядальність, \nшироке \nвикористання \nорнаментики, \nімпровізаційність, витонченість динамічних градацій, ритмічна свобода, \nгармонічна барвистість тощо. Імпресіоністична образність часто \nвідображається в програмних назвах мініатюр для фортепіано, які \nвідтворюють \nпейзаж, \nабо \nпов’язані \nз \nзображенням \nприроди: \n«Відображення місяця в джерелі Ерцуань» Чу Ванхуа; «Пейзаж Баньна» \nСя Ляна, «Пісня рибалки в ночі», «Сріблясті хмари наздоганяють \nмісяць» Ван Цзяньчжуна», «Нічна пісня гори Емий» Хуан Хувея, \n«Туман» Лі Мейцзя; «Крик восени на горі» Лю Лі; «Блукаючі тіні» Гао \nПіна, «Осінній місяць відображається в спокійному озері» Чень \nПейсюна тощо. Водночас фортепіанні твори китайських композиторів \nпоєднують національні риси письма з європейською імпресіоністичною \nстилістикою, утворюючи особливий вид китайського імпресіонізму. Отже, китайська фортепіанна музика відзначається національним \nколоритом. Її специфічними рисами є звукозображальний тип \nпрограмності, імпресіоністичний звукопис, звернення до пейзажної \nобразності, наслідування звучання народних інструментів. Саме ці \nконстанти становлять фортепіанну парадигму китайського музичного \nмистецтва. 252 Література: \n1. Лу Цзє. Концептосфери китайської програмної фортепіанної \nмузики ХХ – початку ХХ ст. : дис. … канд. мист. 17.00.03. ЛНМА \nімені М. В. Лисенка, 2017. 187 с. Література: \n1. Лу Цзє. Концептосфери китайської програмної фортепіанної \nмузики ХХ – початку ХХ ст. : дис. … канд. мист. 17.00.03. ЛНМА \nімені М. В. Лисенка, 2017. 187 с. Література: \n1. Лу Цзє. Концептосфери китайської програмної фортепіанної \nмузики ХХ – початку ХХ ст. : дис. … канд. мист. 17.00.03. ДОСЛІДЖЕННЯ ЯВИЩА САМОІДЕНТИФІКАЦІЇ \nСЕРЕД СТУДЕНТІВ ЗВО Васильченко-Деружко К. А. здобувачка вищої освіти другого (магістерського) рівня \nза спеціальністю 053 – Психологія \nУманський державний педагогічний університет імені Павла Тичини \nНауковий керівник: Гуртовенко Н. В. кандидат психологічних наук, \nдоцент кафедри психології \nУманський державний педагогічний університет імені Павла Тичини \nм. Умань, Київська область, Україна Явище самоідентифікації особистості широке, багатопоглинаюче, \nмає багатофункціональне об’єднуюче значення різних факторів, а все \nтому, що природа явища є динамічною і особистість має закономірність \nз певною періодичністю поринати в самовизначення, намагаючись \nзнайти або ж підтвердити свою значимість, особливо значення \nсамоідентифікації проявляється під час ситуативних чи вікових криз. Питанням вивчення ідентичності особистості займалися такі відомі \nзарубіжні теоретики, як А.Адлер, Г. Блумер, Е. Еріксон, С. Кіркегор, \nДж. Мід, Ж.-П. Сартр, М.Хайдеггер, Е. Фромм, К. Ясперс та ін. За \nрозмаїттям підходів, запропонованих цими й деякими іншими авторами, \nзагалом проглядається філософсько-психологічне бачення ідентичності \nяк: однієї з основних людських потреб, що складає сутність людського \nбуття і виявляється у бажанні уникнути самоти, налагодити \nвзаємозв’язок із зовнішнім світом (З. Фройд, Е. Фромм); як \nзакономірність життєвого процесу (М. Хайдеггер, Ж.-П. Сартр, \nК. Ясперс); як «егоідентичність» та групова та психосоціальна \nідентичність (Є. Еріксон). Як зазначають вчені, ідентичність охоплює \nвсе, що дає людині усвідомлення значущості в межах конкретного \nсоціуму. 253"}}},{"rowIdx":2199,"cells":{"identifier":{"kind":"string","value":"https://openalex.org/W2088735807"},"pdf_url":{"kind":"string","value":"https://europepmc.org/articles/pmc2695694?pdf=render"},"lang":{"kind":"string","value":"English"},"error":{"kind":"null"},"title":{"kind":"string","value":"A prospective Swedish study on body size, body composition, diabetes, and prostate cancer risk"},"source_name":{"kind":"string","value":"British journal of cancer"},"publication_year":{"kind":"number","value":2009,"string":"2,009"},"license":{"kind":"string","value":"cc-by"},"word_count":{"kind":"number","value":8310,"string":"8,310"},"text":{"kind":"string","value":"British Journal of Cancer (2009) 100, 1799 – 1805\n& 2009 Cancer Research UK\nAll rights reserved 0007 – 0920/09\n$32.00 British Journal of Cancer (2009) 100, 1799 – 1805\n& 2009 Cancer Research UK\nAll rights reserved 0007 – 0920/09\n$32.00 British Journal of Cancer (2009) 100, 1799 – 1805\n& 2009 Cancer Research UK\nAll rights reserved 0007 – 0920/09\n$32.00\nwww.bjcancer.com British Journal of Cancer (2009) 100, 1799 – 1805 www.bjcancer.com A prospective Swedish study on body size, body composition,\ndiabetes, and prostate cancer risk A A prospective Swedish study on body size, body composition,\ndiabetes, and prostate cancer risk Most studies have used body mass index (BMI) as a marker of\ngeneral obesity, but it has certain limitations, particularly in men,\nbecause it does not differentiate muscle from fat mass (Willett,\n1998). One solution might be to calculate fat mass and fat-free\nmass\nfrom\nbioelectrical\nimpedance\n(BIA)\nmeasurements\n(Anonymous, 1996; MacInnis et al, 2003). Tallness has also been associated with PCa risk (Engeland et al,\n2003; MacInnis and English, 2006); perhaps reflecting an influence\nof nutritional factors. *Correspondence: Dr P Wallstro¨m, Nutrition Epidemiology Research\nGroup, Department of Clinical Sciences, Clinical Research Centre, Malmo¨\nUniversity Hospital, SE-205 02, Malmo¨, Sweden; Epidemiology We investigated total, aggressive, and non-aggressive PCa in\nrelation to current obesity, body composition, height, and\nprevalence of diabetes mellitus in a population-based cohort,\nincluding a sub-cohort of younger men. 4 Department of Urology, Malmo¨ University Hospital, SE-205 02, Malmo¨,\nSweden\n5 5 Department of Oncology, Lund University Hospital, SE-221 85, Lund,\nSweden Received 9 December 2008; revised 25 March 2009; accepted 8 April\n2009; published online 12 May 2009\n*Correspondence: Dr P Wallstro¨m, Nutrition Epidemiology Research\nGroup, Department of Clinical Sciences, Clinical Research Centre, Malmo¨\nUniversity Hospital, SE-205 02, Malmo¨, Sweden;\nE-mail: peter.wallstrom@med.lu.se\n4 Department of Urology, Malmo¨ University Hospital, SE-205 02, Malmo¨,\nSweden\n5 Department of Oncology, Lund University Hospital, SE-221 85, Lund,\nSweden A prospective Swedish study on body size, body composition,\ndiabetes, and prostate cancer risk doi:10.1038/sj.bjc.6605077\nwww.bjcancer.com\nM\n2009 prostatic neoplasms; cohort studies; body composition; body fat distribution; body height (or diabetes mellitus) There is less support for the hypothesis that central adiposity\n(measured as waist circumference or waist—hip ratio, WHR) is a\nrisk marker for PCa (MacInnis and English, 2006). Only a few\nprospective studies have examined this association (Giovannucci\net al, 1997; Lee et al, 2001; MacInnis et al, 2003; Hubbard et al,\n2004). Furthermore, central adiposity is a clinically established risk\nfactor for non-insulin dependent diabetes mellitus (NIDDM)\n(Vazquez et al, 2007; Gastaldelli, 2008), and NIDDM has been\nassociated with lower risk of PCa (Bonovas et al, 2004), both low\ngrade and high grade (Gong et al, 2006). High insulin levels, as in\ninsulin resistance, which often precedes NIDDM, was recently\nassociated with lower risk of non-aggressive PCa (Stocks et al,\n2007), although there was also a non-significant positive associa-\ntion with aggressive cancer. Obesity has long been associated with increased risk of prostate\ncancer (PCa), although studies have been inconsistent (MacInnis\nand English, 2006). Risk has been suggested to differ according to\ntumour grade: obesity lowering the risk of indolent, less aggressive\ntumours, whereas increasing that of aggressive cancer (Freedland\net al, 2006), a view supported by a meta-analysis (MacInnis and\nEnglish, 2006), and, to some extent, by other work (Gong et al,\n2006; Littman et al, 2007; Rodriguez et al, 2007; Wright et al, 2007). Most studies have used body mass index (BMI) as a marker of\ngeneral obesity, but it has certain limitations, particularly in men,\nbecause it does not differentiate muscle from fat mass (Willett,\n1998). One solution might be to calculate fat mass and fat-free\nmass\nfrom\nbioelectrical\nimpedance\n(BIA)\nmeasurements\n(Anonymous, 1996; MacInnis et al, 2003). Obesity has long been associated with increased risk of prostate\ncancer (PCa), although studies have been inconsistent (MacInnis\nand English, 2006). Risk has been suggested to differ according to\ntumour grade: obesity lowering the risk of indolent, less aggressive\ntumours, whereas increasing that of aggressive cancer (Freedland\net al, 2006), a view supported by a meta-analysis (MacInnis and\nEnglish, 2006), and, to some extent, by other work (Gong et al,\n2006; Littman et al, 2007; Rodriguez et al, 2007; Wright et al, 2007). A prospective Swedish study on body size, body composition,\ndiabetes, and prostate cancer risk P Wallstro¨m*,1, A Bjartell2,4, B Gullberg1, H Olsson3,5 and E Wirfa¨lt1 P Wallstro¨m*,1, A Bjartell2,4, B Gullberg1, H Olsson3,5 and E Wirfa¨lt1\n1Nutrition Epidemiology Research Group, Department of Clinical Sciences, Lund University, Malmo¨, Sweden; 2Division of Urological Cancers, Department\nof Clinical Sciences, Lund University, Malmo¨, Sweden; 3Cancer Epidemiology Unit, Section V, Department of Clinical Sciences, Lund University, Lund,\nSweden j\ng\n1Nutrition Epidemiology Research Group, Department of Clinical Sciences, Lund University, Malmo¨, Sweden; 2Division of Urological Cancers, Department\nof Clinical Sciences, Lund University, Malmo¨, Sweden; 3Cancer Epidemiology Unit, Section V, Department of Clinical Sciences, Lund University, Lund,\nSweden Obesity may be associated with increased risk of prostate cancer (PCa). According to one hypothesis, obesity could lower the risk of\nnon-aggressive tumours, while simultaneously increasing the risk of aggressive cancer. Furthermore, central adiposity may be\nindependently associated with PCa risk; it is also associated with diabetes, which itself may influence risk of PCa. We studied the\nassociations between height, body composition, and fat distribution, diabetes prevalence and risk of total, aggressive, and non-\naggressive PCa in 10 564 initially cancer-free men (aged 45–73 years) of the population-based Malmo¨ Diet and Cancer cohort. Anthropometric and body composition measurements, including bioelectrical impedance for estimation of fat mass, were performed\nby study nurses. Diabetes prevalence was self-reported. Cancer cases and clinical characteristics were ascertained through national\nand regional registry data. Dietary and other background data were obtained through a modified diet history method and an\nextensive questionnaire. During a mean follow-up of 11.0 years, 817 incidental PCa cases were diagnosed. Of these, 281 were\nclassified as aggressive. There were 202 cases occurring before 65 years of age. Height was positively associated with total and non-\naggressive PCa risk. Waist–hip ratio (WHR), a measure of central adiposity, was positively associated with PCa before age 65, and\nless strongly, with total PCa. This association was independent of body mass index (BMI) and other potential confounders. General\nadiposity, expressed as BMI or body fat percentage, and prevalent diabetes were not associated with PCa risk. In this study, WHR and\nbody height were stronger PCa predictors than general adiposity. y\ng\ng\np\ng\np\ny\ntish Journal of Cancer (2009) 100, 1799–1805. doi:10.1038/sj.bjc.6605077\nwww.bjcancer.com\nbli h d\nli\n12 M\n2009 g\np\ng\np\ny\ncer (2009) 100, 1799–1805. MATERIALS AND METHODS Mean follow-up time for non-cases\nwas 7.7 years. y\nWaist circumference was measured midway between the lowest\nrib margin and iliac crest; hip circumference horizontally at the\nlevel of the greatest lateral extension of the hips. Bioelectrical\nimpedance was used for estimating body composition according to\nmanufacturer’s procedures (BIA 103, RJL-systems, Detroit, MI,\nUSA; single-frequency analyser). An algorithm (Sun et al, 2003)\nwas used to estimate body fat (BF) from impedance. The results\nwere highly correlated to results obtained by another algorithm,\ndeveloped in a similar population (Heitmann, 1990). Estimated BF\nwas used to calculate BF%. y\nWe examined the associations between total, aggressive, and\nnon-aggressive PCa incidence and height, waist circumference,\nwaist-hip ratio (WHR), BMI, BF%, and prevalence of diabetes. All\ncontinuous variables were divided into quintile groups. The hazard\nratios (HR) of each distribution quintile (compared with the\nlowest), and trends across the quintiles were assessed with Cox\nproportional hazards regression with adjustment for age at\nbaseline. The time variable was number of days of follow-up after\nbaseline. Additionally, in a separate Cox analysis, BMI was divided\ninto pre-defined categories (World Health Organization, 2000)\nwith tests for overall differences between categories. We also\nperformed analyses of waist circumference and WHR with\nadjustment for BMI, to assess risk associated with abdominal,\nirrespective of general, adiposity. All analyses were age-adjusted\nand were also performed in the o65 sub-cohort (202 cases). We\nthen repeated the above analyses with adjustment for a number of\npotential confounders, selected from a survey of the current\nscientific literature: co-habitation status, socioeconomic index,\nalcohol habits, BF%, smoking history, birth country (Sweden/\nother), total calcium intake, dietary intake of eicosapentaenoic acid\nand docosahexaenoic acid, consumption of fruits, vegetables, and\nred meat. The dietary variables were adjusted for total energy\nintake (residual method) (Willett and Stampfer, 1998). A structured multiple-choice questionnaire was used in the\nMDC study to collect information on sociodemographic factors,\nsmoking status, alcohol habits, health status, use of pharmaceutical\ndrugs, and several other factors. The agreement between baseline\nquestionnaire and its repeat after 3 weeks was high for most\nvariables (k values 40.75) (Manjer et al, 2002). The diabetes items\nread: ‘Have you ever been treated for diabetes? Since what year?’\nPersons who reported using oral anti-diabetic drugs were also\nclassified as diabetics. MATERIALS AND METHODS The background population of the Malmo¨ Diet and Cancer (MDC)\nstudy, in Sweden’s third largest city (Berglund et al, 1993), consists Received 9 December 2008; revised 25 March 2009; accepted 8 April\n2009; published online 12 May 2009 Body size and prostate cancer\nP Wallstro¨m et al Body size and prostate cancer P Wallstro¨m et al 1800 of all men born in 1923–1945 and all women born in 1923–1950\nwho were living in Malmo¨ during the screening period 1991–1996\n(n ¼ 74 138). This population was identified through national\npopulation\nregistries,\nthe\nfinal\ncohort\nconsisting\nof\n28 098\nindividuals (participation rate 40.8%). Participants were recruited\nthrough advertisements in local media and through invitation by\nmail. The only exclusion criteria were inadequate Swedish\nlanguage skills and mental incapacity (Manjer et al, 2001, 2002);\nthe Ethics Committee at Lund University approved the design of\nthe MDC study (LU 51–90). of all men born in 1923–1945 and all women born in 1923–1950\nwho were living in Malmo¨ during the screening period 1991–1996\n(n ¼ 74 138). This population was identified through national\npopulation\nregistries,\nthe\nfinal\ncohort\nconsisting\nof\n28 098\nindividuals (participation rate 40.8%). Participants were recruited\nthrough advertisements in local media and through invitation by\nmail. The only exclusion criteria were inadequate Swedish\nlanguage skills and mental incapacity (Manjer et al, 2001, 2002);\nthe Ethics Committee at Lund University approved the design of\nthe MDC study (LU 51–90). aggressive (total 281) if the WHO grade was 3, and Gleason score\nwas unavailable (n ¼ 6). In cases in which at least two of T stadium,\nGleason score, or PSA serum value were reported, and if none of\nthese factors indicated an aggressive tumour, the tumour was\nclassified as non-aggressive (n ¼ 530). Staging data were unavail-\nable or insufficient for 6 of the incident cases that with 530 cases of\nnon-aggressive cancers were excluded from analyses comparing\nmen with aggressive tumours with others. Details on stage and\ngrade have been reported earlier (Wallstro¨m et al, 2007). For PCa in younger people, we repeated all analyses in a sub-\ncohort, the o65 sub-cohort, the end of follow-up being either at\ndate of death, date of PCa diagnosis, 31 December 2005, or the\nman’s 65th birthday, whichever came first. This younger sub-\ncohort consisted of 8194 men, among whom 202 incident PCa\ncases (54 aggressive) occurred. MATERIALS AND METHODS The diet assessment, reported earlier (Wirfa¨lt et al, 2002),\ncombines quantitative and semi-quantitative approaches to the\nentire diet, including cooking methods (Callmer et al, 1993). It\nconsists of two parts: a ‘menu book’ for description of cooked meals\nand registration of cold (including juices and alcoholic) beverages\nand dietary supplements during seven consecutive days; and a 168-\nitem food questionnaire on regularly consumed foods during the\npast year. Data on validity (Elmsta˚hl et al, 1996b; Riboli et al, 1997)\nand reproducibility (Elmsta˚hl et al, 1996a) have been reported. Cancer cases were ascertained by record linkage with the\nNational Cancer Register. Cancer cases from the year 2005,\nadditional data on tumour stage and grade, pre-diagnostic serum\nprostate-specific antigen (PSA) value, and reason for diagnosis\n(symptoms, health examination, or other) were obtained from the\nNational Prostate Cancer Register (NPCR) (South Region). In the\nSouth Region, to which Malmo¨ belongs, registration was started in\n1996 and is at least 95% complete. For cases diagnosed in 1991–\n1995, the same data were manually extracted from medical records\nusing standard routines. The National Cancer Register is known to\nbe at least 98% complete. A validation of the NPCR data from\nanother region showed high validity for all variables, including one\nused to classify non-aggressive and aggressive tumours (Sandblom\net al, 2003). To further evaluate the consistency of our results, we repeated all\nanalyses (including subgroups) in three separate sessions. In the\nfirst, we excluded asymptomatic cases (478 cases remaining in the\ntotal group). In the second, we excluded persons not born in Sweden\n(748 cases), and in the third, we excluded cases occurring within two\nyears of the beginning of follow-up (691 remaining cases). British Journal of Cancer (2009) 100(11), 1799 – 1805 RESULTS Epidemiology An aggressive case (‘aggressive Pca’) was defined as a tumour\nwith a clinical T stage of 3 or higher or tumour-positive lymph\nnodes (N1) or one or more distant metastases (M1) or a Gleason\nscore of 8 or higher or a pre-treatment serum PSA value of at least\n50 ng ml\u00021 (Stocks et al, 2007); tumours were also classified as British Journal of Cancer (2009) 100(11), 1799 – 1805 & 2009 Cancer Research UK Body size and prostate cancer\nP Wallstro¨m et al 1801 Table 1\nAge-adjusted hazard ratios (with lower and upper limits of 95% confidence intervals) for measures of height, obesity, and diabetes prevalence and\ntotal, aggressive, and non-aggressive cases of prostate cancera\n18 ower and upper limits of 95% confidence intervals) for measures of height, obesity, and diabetes prevalence and\n prostate cancera Table 1\nAge-adjusted hazard ratios (with lower and upper limits of 95% confidence intervals) for measures of height, obesity, and diabetes prevalence and\ntotal, aggressive, and non-aggressive cases of prostate cancera total, aggressive, and non-aggressive cases of prostate cancera\nIncident prostate cancer, entire cohort (n ¼ 10 564)b\nNon-cases\n(n ¼ 9747)\nAll cases (n ¼ 817)\nAggressive cases (n ¼ 281)\nNon-aggressive cases (n ¼ 530)\nMedian\nRange\nN\nN\nHR\nLower\nUpper\nN\nHR\nLower\nUpper\nN\nHR\nLower\nUpper\nHeight (cm)\nQuintile 1\n168\np170\n1798\n144\n1.00\n50\n1.00\n93\n1.00\nQuintile 2\n173\n171 –174\n2011\n182\n1.20\n0.97\n1.49\n71\n1.40\n0.97\n2.01\n109\n1.10\n0.84\n1.46\nQuintile 3\n177\n175 –178\n2263\n182\n1.11\n0.89\n1.38\n65\n1.20\n0.83\n1.74\n115\n1.06\n0.81\n1.39\nQuintile 4\n180\n179 –181\n1536\n116\n1.09\n0.85\n1.39\n36\n1.06\n0.69\n1.63\n80\n1.12\n0.83\n1.51\nQuintile 5\n184\nX182\n2123\n193\n1.40\n1.13\n1.74\n59\n1.38\n0.95\n2.02\n133\n1.42\n1.09\n1.86\n0.016\n0.37\n0.014\nBMI\nUnderweight\nn/a\np18.49\n48\n8\n2.09\n1.03\n4.22\n4\n2.88\n1.06\n7.82\n4\n0.60\n0.22\n1.61\nNormal\nn/a\n18.50–24.99\n3627\n287\n1.00\n102\n1.00\n183\n1.00\nOverweight\nn/a\n25.00–29.99\n4803\n417\n1.04\n0.90\n1.21\n140\n0.97\n0.75\n1.25\n274\n0.65\n0.24\n1.75\nObese\nn/a\nX30.00\n1253\n105\n1.04\n0.84\n1.30\n35\n0.95\n0.65\n1.40\n69\n0.65\n0.24\n1.78\nNon-linear P\n0.24c\n0.20d\n0.65e\nBMI\nQuintile 1\n22.2\np23.4\n1949\n158\n1.00\n61\n1.00\n96\n1.00\nQuintile 2\n24.4\n23.5 –25.2\n1957\n164\n0.97\n0.78\n1.20\n53\n0.80\n0.55\n1.15\n110\n1.07\n0.82\n1.41\nQuintile 3\n26.0\n25.2 –26.8\n1928\n168\n0.98\n0.79\n1.22\n59\n0.87\n0.61\n1.25\n107\n1.04\n0.79\n1.38\nQuintile 4\n27.7\n26.8 –28.7\n1940\n175\n1.03\n0.83\n1.28\n57\n0.85\n0.59\n1.22\n117\n1.15\n0.88\n1.51\nQuintile 5\n30.6\nX28.7\n1957\n152\n0.91\n0.73\n1.14\n51\n0.77\n0.53\n1.12\n100\n1.00\n0.76\n1.33\n0.67\n0.27\n0.80\nBody fat %\nQuintile 1\n15.7\np18.3\n1952\n146\n1.00\n53\n1.00\n93\n1.00\nQuintile 2\n19.9\n18.3 –21.3\n1915\n184\n1.23\n0.99\n1.52\n72\n1.33\n0.93\n1.89\n108\n1.14\n0.86\n1.50\nQuintile 3\n22.6\n21.3 –23.8\n1941\n157\n1.04\n0.83\n1.31\n54\n0.99\n0.68\n1.44\n102\n1.06\n0.80\n1.41\nQuintile 4\n25.1\n23.8 –26.6\n1933\n166\n1.07\n0.86\n1.33\n46\n0.81\n0.55\n1.21\n120\n1.22\n0.93\n1.60\nQuintile 5\n28.8\nX26.6\n1937\n161\n1.08\n0.86\n1.35\n55\n1.01\n0.69\n1.48\n105\n1.11\n0.84\n1.47\n0.98\n0.25\n0.37\nWaist (cm)\nQuintile 1\n82\np85\n1960\n152\n1.00\n58\n1.00\n94\n1.00\nQuintile 2\n88\n86– 90\n1947\n146\n0.92\n0.74\n1.16\n49\n0.81\n0.55\n1.19\n96\n0.99\n0.74\n1.31\nQuintile 3\n93\n91– 95\n2013\n183\n1.10\n0.89\n1.37\n60\n0.94\n0.65\n1.35\n120\n1.18\n0.90\n1.54\nQuintile 4\n98\n96–101\n1893\n171\n1.09\n0.87\n1.35\n54\n0.89\n0.61\n1.29\n116\n1.20\n0.92\n1.58\nQuintile 5\n107\nX102\n1912\n165\n1.04\n0.83\n1.30\n60\n0.96\n0.67\n1.38\n104\n1.08\n0.82\n1.43\n0.35\n0.99\n0.26\nWHR\nQuintile 1\n0.87\np0.90\n1945\n161\n1.00\n58\n1.00\n96\n1.00\nQuintile 2\n0.91\n0.90 –0.93\n1949\n161\n1.02\n0.82\n1.27\n53\n0.96\n0.66\n1.39\n110\n1.04\n0.79\n1.36\nQuintile 3\n0.94\n0.93 –0.96\n1958\n152\n0.97\n0.78\n1.21\n56\n1.01\n0.70\n1.46\n107\n0.95\n0.72\n1.25\nQuintile 4\n0.97\n0.96 –0.99\n1913\n187\n1.21\n0.98\n1.50\n67\n1.23\n0.87\n1.75\n117\n1.20\n0.92\n1.56\nQuintile 5\n1.02\nX0.99\n1959\n156\n1.08\n0.87\n1.35\n47\n0.94\n0.64\n1.39\n100\n1.13\n0.86\n1.48\n0.17\n0.67\n0.21\nDiabetes? RESULTS No\nn/a\nn/a\n9336\n790\n1.00\n273\n1.00\n511\n1.00\nYes\nn/a\nn/a\n411\n27\n0.78\n0.53\n1.14\n8\n0.62\n0.31\n1.26\n19\n0.87\n0.55\n1.37\n0.20\n0.19\n0.55\nWaist, adjusted for BMI\nQuintile 1\nn/a\nn/a\n1963\n145\n1.00\n50\n1.00\n94\n1.00\nQuintile 2\nn/a\nn/a\n1943\n165\n1.19\n0.95\n1.49\n50\n1.10\n0.74\n1.62\n114\n1.25\n0.95\n1.64\nQuintile 3\nn/a\nn/a\n1963\n146\n1.01\n0.80\n1.27\n49\n1.01\n0.68\n1.50\n97\n1.02\n0.77\n1.35\nQuintile 4\nn/a\nn/a\n1930\n178\n1.26\n1.01\n1.57\n65\n1.37\n0.95\n1.98\n111\n1.20\n0.92\n1.59\nQuintile 5\nn/a\nn/a\n1925\n183\n1.21\n0.97\n1.51\n67\n1.28\n0.89\n1.85\n114\n1.17\n0.89\n1.54\n0.078\n0.083\n0.37\nWHR, adjusted for BMI\nQuintile 1\nn/a\nn/a\n1937\n169\n1.00\n57\n1.00\n112\n1.00\nQuintile 2\nn/a\nn/a\n1968\n139\n0.89\n0.71\n1.12\n48\n0.95\n0.65\n1.39\n90\n0.85\n0.64\n1.12\nQuintile 3\nn/a\nn/a\n1926\n181\n1.20\n0.97\n1.49\n65\n1.36\n0.95\n1.95\n115\n1.12\n0.86\n1.46\nQuintile 4\nn/a\nn/a\n1940\n166\n1.11\n0.90\n1.38\n56\n1.18\n0.82\n1.71\n109\n1.07\n0.82\n1.39\nQuintile 5\nn/a\nn/a\n1945\n162\n1.15\n0.93\n1.43\n55\n1.25\n0.86\n1.81\n104\n1.07\n0.82\n1.40\n0.049\n0.12\n0.24\nBMI ¼ body mass index; WHR ¼ waist–hip ratio; HR ¼ hazard ratios. P-values in italics. aAll P-values are for linear trends (categorical variables), except where noted. bNumbers\nd\nt l\ndd t\n10 564\ni\nt\ni i\nl\ni\nt\ni\ncLi\nP\nl\n0 92 dLi\nP\nl\n0 49 eLi\nP\nl\n0 55 Incident prostate cancer, entire cohort (n ¼ 10 564)b BMI ¼ body mass index; WHR ¼ waist–hip ratio; HR ¼ hazard ratios. P-values in italics. aAll P-values are for linear trends (categorical variables), except where noted. bNumbers\ndo not always add to 10 564 owing to missing values in some categories. cLinear P-value ¼ 0.92. dLinear P-value ¼ 0.49. eLinear P-value ¼ 0.55. Epidemiology o65 sub-cohort, were somewhat stronger after multivariate\nadjustment (Tables 2 and 3). The associations with being\nunderweight were also slightly stronger after adjustment (Table 2);\notherwise, the results were similar. Inspection of the data revealed o65 sub-cohort, were somewhat stronger after multivariate\nadjustment (Tables 2 and 3). The associations with being\nunderweight were also slightly stronger after adjustment (Table 2);\notherwise, the results were similar. & 2009 Cancer Research UK RESULTS Height was associated with increased risk of total PCa, although the\neffect was limited to the highest quintile (range 182–203 cm), and\nwas most evident among non-aggressive tumours (Table 1). No\nother measures of body composition or fat distribution were\nsignificantly associated with PCa risk, although being underweight\n(BMI o18.5) was associated with higher risks than normal weight\nacross all PCa categories except the non-aggressive category; an\nassociation\nwith BMI-adjusted\nWHR\nwas suggested. Neither\nprevalent diabetes was significantly associated with PCa risk nor\nheight in the o65 sub-cohort (Table 2, age-adjusted analyses), there\nwas a weak, positive association with WHR. After adjustment for\nBMI, the association was slightly stronger (HR per quintile 1.14,\n95% CI 1.03–1.26). Similarly, waist circumference (adjusted for\nBMI) was positively associated with risk in the o65 sub-cohort. After adjustment for a number of possible confounders, the\nincreased risk of total PCa associated with greater height was\nweakened (P for trend ¼ 0.08, Table 3). However, the highest\nquintile was still significantly different from the lowest (P ¼ 0.018). The associations between WHR and PCa, both in total and in the Of the 11 063 men in the MDC cohort, 485 were already\ndiagnosed with cancer (excluding basal cell carcinomas) at study\nentry, and were therefore excluded; 14 others were excluded\nbecause of PCa diagnosis at autopsy, leaving 10 564 men for\nanalysis. They were followed until date of death, date of PCa\ndiagnosis, or 31 December 2005, whichever came first. No\nparticipants were lost to follow-up of vital status. Among them,\n817 incident cases of PCa (‘total PCa’; ICD-9 code 185) occurred\nbetween baseline examination and end of follow-up. The average\nfollow-up time in participants free of PCa at death (n ¼ 1321) or at\nthe end of follow-up (n ¼ 8426) was 11.0 years. British Journal of Cancer (2009) 100(11), 1799 – 1805 RESULTS Inspection of the data revealed no suggestion of any significant interactions between any body\nmeasure and aggressive vs non-aggressive tumours. RESULTS gg\ngg\nThe association between high stature (tallest quintile) and\nrisk of total PCa was a robust finding in most models (exclusion British Journal of Cancer (2009) 100(11), 1799 – 1805 & 2009 Cancer Research UK Body size and prostate cancer\nP Wallstro¨m et al Body size and prostate cancer\nP W ll t ¨\nl 1802 1802 Table 2\nAge-adjusted and multivariatea hazard ratios (with lower and upper limits of 95% confidence intervals) for measures of height, obesity, and\ndiabetes prevalence and cases of prostate cancer occurring before age 65b\n2 Table 2\nAge-adjusted and multivariatea hazard ratios (with lower and upper limits of 95% confidence interv\ndiabetes prevalence and cases of prostate cancer occurring before age 65b\n2 Table 2\nAge-adjusted and multivariatea hazard ratios (with lower and upper limits of 95% confidence intervals) for measures of height, obesity, and\ndiabetes prevalence and cases of prostate cancer occurring before age 65b Table 2\nAge adjusted and multivariate hazard ratios (with lower and upper limits of 95% confidence intervals) for measures of height, obesity, and\ndiabetes prevalence and cases of prostate cancer occurring before age 65b\nAge-adjusted analysis (n ¼ 8194)c\nMultivariate analysis (n ¼ 8103)d\nNon-cases (n ¼ 7992)\nIncident cases (n ¼ 202)\nN\nN\nHR\nLower\nUpper\nHR\nLower\nUpper\nHeight\nQuintile 1\n1308\n32\n1.00\n1.00\nQuintile 2\n1596\n31\n0.77\n0.47\n1.27\n0.75\n0.46\n1.23\nQuintile 3\n1841\n50\n1.06\n0.68\n1.65\n1.00\n0.64\n1.58\nQuintile 4\n1330\n22\n0.62\n0.36\n1.07\n0.59\n0.34\n1.02\nQuintile 5\n1903\n67\n1.30\n0.85\n1.98\n1.22\n0.79\n1.89\n0.17\n0.28\nBMI\nUnderweight\n36\n3\n3.81\n1.20\n12.08\n4.38\n1.35\n14.17\nNormal\n3019\n78\n1.00\n1.00\nOverweight\n3896\n94\n0.97\n0.72\n1.31\n0.95\n0.70\n1.29\nObese\n1027\n27\n1.09\n0.71\n1.69\n1.09\n0.70\n1.71\nNon-linear P\n0.13e\n0.081f\nBMI\nQuintile 1\n1640\n46\n1.00\n1.00\nQuintile 2\n1608\n40\n0.89\n0.58\n1.36\n0.84\n0.55\n1.29\nQuintile 3\n1572\n32\n0.75\n0.48\n1.17\n0.71\n0.45\n1.11\nQuintile 4\n1569\n46\n1.11\n0.74\n1.67\n1.05\n0.69\n1.60\nQuintile 5\n1589\n38\n0.91\n0.59\n1.40\n0.88\n0.56\n1.36\n0.96\n0.93\nBody fat %\nQuintile 1\n1603\n36\n1.00\n1.00\nQuintile 2\n1597\n44\n1.20\n0.78\n1.87\n1.20\n0.77\n1.86\nQuintile 3\n1607\n45\n1.27\n0.82\n1.97\n1.28\n0.82\n1.99\nQuintile 4\n1558\n36\n1.08\n0.68\n1.72\n1.05\n0.66\n1.68\nQuintile 5\n1576\n39\n1.19\n0.75\n1.87\n1.20\n0.77\n1.86\n0.65\n0.69\nWaist\nQuintile 1\n1626\n40\n1.00\n1.00\nQuintile 2\n1613\n33\n0.89\n0.56\n1.41\n0.85\n0.53\n1.35\nQuintile 3\n1641\n45\n1.15\n0.75\n1.75\n1.09\n0.71\n1.69\nQuintile 4\n1553\n41\n1.17\n0.76\n1.82\n1.11\n0.71\n1.73\nQuintile 5\n1540\n43\n1.29\n0.84\n1.99\n1.24\n0.79\n1.95\n0.12\n0.19\nWHR\nQuintile 1\n1543\n34\n1.00\n1.00\nQuintile 2\n1587\n30\n0.87\n0.53\n1.42\n0.85\n0.52\n1.40\nQuintile 3\n1607\n39\n1.12\n0.71\n1.78\n1.13\n0.71\n1.80\nQuintile 4\n1580\n52\n1.52\n0.98\n2.34\n1.56\n1.01\n2.43\nQuintile 5\n1655\n47\n1.34\n0.86\n2.09\n1.40\n0.89\n2.21\n0.023\n0.012\nDiabetes? RESULTS No\n1523\n198\n1.00\n1.00\nYes\n6279\n4\n0.66\n0.24\n1.77\n0.65\n0.24\n1.75\n0.41\n0.39\nWaist, adjusted for BMI\nQuintile 1\n1562\n35\n1.00\n1.00\nQuintile 2\n1626\n39\n1.05\n0.67\n1.66\n1.05\n0.66\n1.67\nQuintile 3\n1625\n36\n1.04\n0.65\n1.65\n1.03\n0.64\n1.66\nQuintile 4\n1609\n44\n1.28\n0.82\n2.00\n1.29\n0.81\n2.07\nQuintile 5\n1551\n48\n1.57\n1.01\n2.43\n1.59\n0.98\n2.58\n0.025\n0.038\nWHR, adjusted for BMI\nQuintile 1\n1472\n26\n1.00\n1.00\nQuintile 2\n1594\n28\n0.96\n0.56\n1.64\n0.98\n0.57\n1.67\nQuintile 3\n1612\n51\n1.75\n1.09\n2.81\n1.82\n1.13\n2.92\nQuintile 4\n1627\n52\n1.78\n1.11\n2.85\n1.85\n1.15\n2.98\nQuintile 5\n1662\n45\n1.50\n0.93\n2.44\n1.64\n1.00\n2.68\n0.011\n0.004\nBMI ¼ body mass index; WHR ¼ waist–hip ratio; HR ¼ hazard ratios. P-values in italics. aAdjusted for age, height, co-habitation status, socioeconomic status, alcohol habits,\nsmoking habits, prevalent diabetes, total physical activity, birth country, and total intake of EPA, DHA, red meat, and calcium. Height and prevalent diabetes were further adjusted\nfor BMI category. bAll P-values are for linear trends (categorical variables), except where noted. cNumbers do not always add to 8194 owing to missing values in some categories. dSome persons excluded from the analyses because of missing values, which also affect the number of cases (n ¼ 200). eLinear P-value ¼ 0.86. fLinear P ¼ 0.80. RESULTS Height and prevalent diabetes were further adjusted\nical variables) except where noted cNumbers do not always add to 8194 owing to missing values in some categories Age-adjusted analysis (n ¼ 8194)c Multivariate analysis (n ¼ 8103)d Epidemiology British Journal of Cancer (2009) 100(11), 1799 – 1805 & 2009 Cancer Research UK Body size and prostate cancer\nP Wallstro¨m et al Body size and prostate cancer\nP Wallstro¨m et al 1803 Table 3\nMultivariate adjusted hazard ratiosa (with lower and upper limits of 95% confidence intervals) for measures of height, obesity, and diabetes\nprevalence and total, aggressive, and non-aggressive cases of prostate cancerb\n1 Table 3\nMultivariate adjusted hazard ratiosa (with lower and upper limits of 95% confidence intervals) for measures of height, obesity, and diabetes\nprevalence and total, aggressive, and non-aggressive cases of prostate cancerb\n8 Table 3\nl j\n(\npp\n)\ng\ny\nprevalence and total, aggressive, and non-aggressive cases of prostate cancerb\nIncident prostate cancer, entire cohort (n ¼ 10 434)c\nAll cases (n ¼ 809)\nAggressive cases (n ¼ 278)\nNon-aggressive cases (n ¼ 525)\nHR\nLower\nUpper\nHR\nLower\nUpper\nHR\nLower\nUpper\nHeight\nQuintile 1\n1.00\n1.00\n1.00\nQuintile 2\n1.18\n0.95\n1.47\n1.38\n0.96\n1.98\n1.08\n0.82\n1.43\nQuintile 3\n1.08\n0.86\n1.34\n1.14\n0.79\n1.66\n1.04\n0.79\n1.37\nQuintile 4\n1.04\n0.81\n1.34\n1.01\n0.65\n1.56\n1.08\n0.79\n1.46\nQuintile 5\n1.31\n1.05\n1.64\n1.29\n0.87\n1.91\n1.33\n1.01\n1.76\n0.081\n0.64\n0.055\nBMI\nUnderweight\n2.29\n1.13\n4.63\n3.15\n1.15\n8.62\n0.84\n0.63\n1.11\nNormal\n1.00\n1.00\n1.00\nOverweight\n1.02\n0.88\n1.19\n0.99\n0.76\n1.29\n1.16\n0.89\n1.50\nObese\n1.06\n0.84\n1.33\n1.02\n0.69\n1.52\n1.11\n0.85\n1.44\nNon-linear P\n0.15d\n0.16e\n0.65f\nBMI\nQuintile 1\n1.00\n1.00\n1.00\nQuintile 2\n0.94\n0.76\n1.17\n0.83\n0.57\n1.20\n1.01\n0.76\n1.33\nQuintile 3\n0.96\n0.77\n1.20\n0.89\n0.62\n1.29\n0.99\n0.75\n1.31\nQuintile 4\n0.99\n0.80\n1.24\n0.89\n0.61\n1.28\n1.06\n0.81\n1.40\nQuintile 5\n0.90\n0.72\n1.13\n0.83\n0.57\n1.22\n0.94\n0.71\n1.26\n0.58\n0.49\n0.86\nBody fat %\nQuintile 1\n1.00\n1.00\n1.00\nQuintile 2\n1.22\n0.98\n1.52\n1.33\n0.94\n1.91\n1.13\n0.85\n1.49\nQuintile 3\n1.03\n0.82\n1.30\n0.99\n0.67\n1.45\n1.05\n0.79\n1.39\nQuintile 4\n1.06\n0.84\n1.32\n0.83\n0.56\n1.23\n1.19\n0.90\n1.56\nQuintile 5\n1.10\n0.87\n1.38\n1.05\n0.71\n1.55\n1.12\n0.84\n1.49\n0.94\n0.35\n0.38\nWaist\nQuintile 1\n1.00\n1.00\n1.00\nQuintile 2\n0.90\n0.71\n1.13\n0.80\n0.55\n1.18\n0.94\n0.70\n1.25\nQuintile 3\n1.05\n0.84\n1.30\n0.93\n0.64\n1.34\n1.10\n0.83\n1.44\nQuintile 4\n1.04\n0.83\n1.29\n0.89\n0.61\n1.30\n1.12\n0.84\n1.47\nQuintile 5\n1.00\n0.80\n1.26\n0.99\n0.68\n1.45\n1.00\n0.75\n1.34\n0.55\n0.84\n0.58\nWHR\nQuintile 1\n1.00\n1.00\n1.00\nQuintile 2\n0.99\n0.79\n1.23\n0.94\n0.65\n1.37\n1.00\n0.76\n1.31\nQuintile 3\n0.96\n0.77\n1.21\n1.03\n0.71\n1.49\n0.93\n0.70\n1.23\nQuintile 4\n1.23\n0.99\n1.52\n1.27\n0.89\n1.82\n1.21\n0.92\n1.58\nQuintile 5\n1.12\n0.89\n1.41\n0.99\n0.66\n1.47\n1.16\n0.88\n1.53\n0.073\n0.46\n0.12\nDiabetes? RESULTS ccurring before age 65b\nAge-adjusted analysis (n ¼ 8194)c\nMultivariate analysis (n ¼ 8103)d\nnt cases (n ¼ 202)\nN\nHR\nLower\nUpper\nHR\nLower\nUpper\n32\n1.00\n1.00\n31\n0.77\n0.47\n1.27\n0.75\n0.46\n1.23\n50\n1.06\n0.68\n1.65\n1.00\n0.64\n1.58\n22\n0.62\n0.36\n1.07\n0.59\n0.34\n1.02\n67\n1.30\n0.85\n1.98\n1.22\n0.79\n1.89\n0.17\n0.28\n3\n3.81\n1.20\n12.08\n4.38\n1.35\n14.17\n78\n1.00\n1.00\n94\n0.97\n0.72\n1.31\n0.95\n0.70\n1.29\n27\n1.09\n0.71\n1.69\n1.09\n0.70\n1.71\n0.13e\n0.081f\n46\n1.00\n1.00\n40\n0.89\n0.58\n1.36\n0.84\n0.55\n1.29\n32\n0.75\n0.48\n1.17\n0.71\n0.45\n1.11\n46\n1.11\n0.74\n1.67\n1.05\n0.69\n1.60\n38\n0.91\n0.59\n1.40\n0.88\n0.56\n1.36\n0.96\n0.93\n36\n1.00\n1.00\n44\n1.20\n0.78\n1.87\n1.20\n0.77\n1.86\n45\n1.27\n0.82\n1.97\n1.28\n0.82\n1.99\n36\n1.08\n0.68\n1.72\n1.05\n0.66\n1.68\n39\n1.19\n0.75\n1.87\n1.20\n0.77\n1.86\n0.65\n0.69\n40\n1.00\n1.00\n33\n0.89\n0.56\n1.41\n0.85\n0.53\n1.35\n45\n1.15\n0.75\n1.75\n1.09\n0.71\n1.69\n41\n1.17\n0.76\n1.82\n1.11\n0.71\n1.73\n43\n1.29\n0.84\n1.99\n1.24\n0.79\n1.95\n0.12\n0.19\n34\n1.00\n1.00\n30\n0.87\n0.53\n1.42\n0.85\n0.52\n1.40\n39\n1.12\n0.71\n1.78\n1.13\n0.71\n1.80\n52\n1.52\n0.98\n2.34\n1.56\n1.01\n2.43\n47\n1.34\n0.86\n2.09\n1.40\n0.89\n2.21\n0.023\n0.012\n198\n1.00\n1.00\n4\n0.66\n0.24\n1.77\n0.65\n0.24\n1.75\n0.41\n0.39\n35\n1.00\n1.00\n39\n1.05\n0.67\n1.66\n1.05\n0.66\n1.67\n36\n1.04\n0.65\n1.65\n1.03\n0.64\n1.66\n44\n1.28\n0.82\n2.00\n1.29\n0.81\n2.07\n48\n1.57\n1.01\n2.43\n1.59\n0.98\n2.58\n0.025\n0.038\n26\n1.00\n1.00\n28\n0.96\n0.56\n1.64\n0.98\n0.57\n1.67\n51\n1.75\n1.09\n2.81\n1.82\n1.13\n2.92\n52\n1.78\n1.11\n2.85\n1.85\n1.15\n2.98\n45\n1.50\n0.93\n2.44\n1.64\n1.00\n2.68\n0.011\n0.004\nazard ratios. P-values in italics. aAdjusted for age, height, co-habitation status, socioeconomic status, alcohol habits,\nth country, and total intake of EPA, DHA, red meat, and calcium. & 2009 Cancer Research UK DISCUSSION This study showed a weak association between tallness and risk of\ntotal PCa, also shown (but not significantly) by aggressive PCa or\nPCa in the o65 sub-cohort. The role of height in PCa, if any, is\ncontroversial (Gunnell et al, 2001). A similar finding was reported\nin the largest study to date, examining 950 000 Norwegian men, in\nwhich the tallest men (X190 cm) had an RR of 1.72 (95% CI 1.46–\n2.04) compared with the shortest (Engeland et al, 2003). Although\nan RR greater than 1.00 for the tallest men has been reported\nseveral times, this was not usually significant at a 0.05 level\n(Gunnell et al, 2001). A recent study from the EPIC cohort found\nno association between height and risk, neither for aggressive nor\nfor non-aggressive tumours (Pischon et al, 2008). Furthermore,\nheight was recently associated with increased PCa mortality\n(Giovannucci et al, 2007). p\nUnderweight (BMI o18.5) was associated with all categories\nof PCa. This may represent weight loss owing to pre-clinical\ncancer,\nparticularly\nsince\nthe\nassociations\ndisappeared\nafter exclusion of cases occurring within the first 2 years after\nscreening. g\nDiabetes was not significantly associated with incidence of PCa\nin this study. Several studies linking NIDDM and/or insulin\nresistance with lower risk of PCa have been published in recent\nyears (Bonovas et al, 2004; Gong et al, 2006; Stocks et al, 2007). As\nnoted above, we used self-reported data on diabetes prevalence. However, because we also defined diabetics by their oral anti-\ndiabetic drug use, only diabetics without oral therapy (or who\nfailed to record it) and who did not answer the diabetes item\ncorrectly should be misclassified. This predominantly NIDDM\ngroup\nmay\nbe\nmixed\nwith\ntype\n1\ndiabetes,\nbecause\nthe\nquestionnaire did not differ between diabetes types. However,\nfew persons reported age at start of diabetes treatment o36 years\n(n ¼ 30, 12% of cases). Finally, it should be noted that our power to\ndetect an association was rather low, because of the relatively small\nnumber of diabetics. To our knowledge, height in itself has not been regarded as\na causal factor for PCa, but rather associations have been\nattributed to genetic, hormonal, and nutritional factors related\nto growth until adulthood, both before and after birth (Gunnell\net al, 2001). ACKNOWLEDGEMENTS We\nthank\nUlla\nLindstro¨m,\nRN,\nDepartment\nof\nUrology,\nMalmo¨ University Hospital, for retrieval of clinical data. We also\nthank the staff and participants of the Malmo¨ Diet and Cancer\nStudy. Financial support has been received from the Swedish Cancer\nSociety, the Swedish Medical Research Council, Region Ska˚ne, The\nSwedish Nutrition Foundation, and the Ernhold Lundstro¨m\nResearch Foundation. y\np\nIt is not clear why the association between WHR and PCa risk\nwas most pronounced in the o65 sub-cohort, or why height was\nnot associated with aggressive PCa. Chance findings can never be\nentirely ruled out; although the number of factors examined in this\nstudy was limited and well defined, the actual number of statistical\ntests was large. On the other hand, our findings might reflect that\nunmeasured factors associated with high WHR/waist circum-\nference become relatively less important to PCa development as Epidemiology Disclaimer: Parts of the data presented in this study are also\nincluded in a recent report from the EPIC collaboration (Pischon\net al, 2008). DISCUSSION As there is evidence of a positive association between\nbody height and socioeconomic class, perhaps reflecting factors\nsuch as a greater abundance of food during growth or lower\nincidence of infections, one could imagine socioeconomic class\nconfounding the association between height and PCa (Batty et al,\n2006). In this study, however, this was only marginally affected\nby adjustment for socioeconomic index and other potential\nconfounders. Many researchers use a Gleason score of 7 þ instead of 8 þ for\ndefining more aggressive tumours. Changing our definition of\naggressive to include Gleason 7 meant resulted in another 99 cases\namong the aggressive, with unchanged null results and weaker\npositive results (data not shown). This could be interpreted as an\neffect of diluting the aggressive group of cases by adding a large\nnumber of less malignant tumours. Few studies have reported associations between waist/WHR and\nPCa; a recent meta-analysis judged the evidence to be weak\n(MacInnis and English, 2006). In our study, WHR (and, to a\nsmaller extent, waist) was associated with PCa, particularly before\nage 65 and after adjustment for BMI. Detection bias is possible:\npersons with higher WHR may be more likely to have other health\nproblems and therefore visit a doctor, which could increase the\nchance of diagnosis. However, the sensitivity analysis showed, if\nanything, stronger associations when asymptomatic cases were\nexcluded (data not shown). Although usually highly correlated\nwith BMI, there are data to suggest that waist circumference and/or\nWHR may predict health problems independently of BMI, as in\ndiabetes mellitus (Gastaldelli, 2008) and CVD (Yusuf et al, 2005). Furthermore, there is accumulating evidence for a role of waist\ncircumference (Visscher et al, 2001; Koster et al, 2008) and WHR\n(Lahmann et al, 2002; Price et al, 2006) in predicting mortality\nindependently of BMI in men. A post hoc analysis of total PCa in\nthe present cohort shows that the increased PCa risk associated\nwith large waist circumference seemed to be greatest at low BMI\n(data not shown), a finding that was not explained by prevalent\nasymptomatic cancer. In this population-based cohort study, we noted positive\nassociations between risk of PCa and adult height, WHR, and\nwaist circumference. No other measures of obesity or body size,\nor prevalent diabetes were significantly associated with PCa\nrisk. There were no suggestions\nof significant interactions\nbetween measures of obesity and degree of aggressiveness of the\ntumours. RESULTS This was true of\nthe waist/WHR models, both univariate and multivariate. How-\never, the association between being underweight according to BMI\nclassification and increased risk of total PCa was greatly weakened\nafter removal of cases occurring within the first 2 years or\nasymptomatic cases. Apart from these, the sensitivity analyses\nyielded no consistent results. General adiposity was not associated with PCa in this study. The\nHR estimates for BF% were slightly different from those for BMI,\nbut not convincingly so. As the use of BF% as a marker of general\nadiposity has recently been criticised (Cole et al, 2008), we\nrepeated our main analyses with BF% replaced by BF mass\nadjusted for lean body mass, but with broadly similar results (data\nnot shown). One obvious explanation is that there may be no effect\nor a very small effect of general adiposity on PCa risk (MacInnis\nand English, 2006; Renehan et al, 2008), or that BF% is not\ndifferent enough from BMI to capture any differences in this\nrespect. RESULTS No\n1.00\n1.00\n1.00\nYes\n0.76\n0.51\n1.11\n0.61\n0.30\n1.25\n0.84\n0.53\n1.33\n0.15\n0.18\n0.45\nWaist, adjusted for BMI\nQuintile 1\n1.00\n1.00\n1.00\nQuintile 2\n1.17\n0.93\n1.47\n1.11\n0.75\n1.64\n1.21\n0.92\n1.60\nQuintile 3\n1.00\n0.79\n1.27\n1.04\n0.69\n1.55\n1.00\n0.75\n1.33\nQuintile 4\n1.23\n0.98\n1.55\n1.40\n0.95\n2.06\n1.16\n0.87\n1.54\nQuintile 5\n1.17\n0.92\n1.49\n1.29\n0.86\n1.93\n1.11\n0.82\n1.50\n0.18\n0.11\n0.67\nWHR, adjusted for BMI\nQuintile 1\n1.00\n1.00\n1.00\nQuintile 2\n0.89\n0.71\n1.11\n0.96\n0.65\n1.40\n0.84\n0.63\n1.11\nQuintile 3\n1.22\n0.99\n1.51\n1.34\n0.94\n1.93\n1.16\n0.89\n1.50\nQuintile 4\n1.14\n0.92\n1.42\n1.21\n0.83\n1.75\n1.11\n0.85\n1.44\nQuintile 5\n1.22\n0.98\n1.52\n1.27\n0.87\n1.86\n1.17\n0.89\n1.53\n0.012\n0.10\n0.072\nBMI ¼ body mass index; WHR ¼ waist–hip ratio; HR ¼ hazard ratios. P-values are in italics. aAdjusted for age, height, co-habitation status, socioeconomic status, alcohol habits,\nsmoking habits, prevalent diabetes, total physical activity, birth country, and total intake of EPA, DHA, red meat, and calcium. Height and prevalent diabetes were further adjusted\nfor BMI category. bAll P-values are for linear trends (categorical variables), except where noted. cSome persons excluded from the analyses because of missing values, which also\naffect the number of cases. dLinear P ¼ 0.95. eLinear P ¼ 0.72. fLinear P ¼ 0.95. Incident prostate cancer, entire cohort (n ¼ 10 434)c Epidemiology BMI ¼ body mass index; WHR ¼ waist–hip ratio; HR ¼ hazard ratios. P-values are in italics. aAdjusted for age, height, co-habitation status, socioeconomic status, alcohol habits,\nsmoking habits, prevalent diabetes, total physical activity, birth country, and total intake of EPA, DHA, red meat, and calcium. Height and prevalent diabetes were further adjusted\nfor BMI category. bAll P-values are for linear trends (categorical variables), except where noted. cSome persons excluded from the analyses because of missing values, which also\naffect the number of cases. dLinear P ¼ 0.95. eLinear P ¼ 0.72. fLinear P ¼ 0.95. British Journal of Cancer (2009) 100(11), 1799 – 1805 & 2009 Cancer Research UK Body size and prostate cancer\nP Wallstro¨m et al Body size and prostate cancer p\nP Wallstro¨m et al 1804 age increases. Similarly, height may be a marker of biological\nprocesses leading to less aggressive PCa. of persons born outside of Sweden, asymptomatic cases, and cases\noccurring within 2 year of screening, respectively). British Journal of Cancer (2009) 100(11), 1799 – 1805 REFERENCES J Intern Med\n233: 53–57 d nutrition. Cancer Epidemiol Biomarkers Prev 17: 3252–326 Price GM, Uauy R, Breeze E, Bulpitt CJ, Fletcher AE (2006) Weight, shape,\nand mortality risk in older persons: elevated waist-hip ratio, not high\nbody mass index, is associated with a greater risk of death. Am J Clin\nNutr 84: 449–460 Cole TJ, Fewtrell MS, Prentice A (2008) The fallacy of using percentage\nbody fat as a measure of adiposity. Am J Clin Nutr 87: 1959 Elmsta˚hl S, Gullberg B, Riboli E, Saracci R, Lindga¨rde F (1996a) The\nreproducibility of a novel diet history method and an extensive food\nfrequency questionnaire. The Malmo¨ Food Study. Eur J Clin Nutr 50:\n134–142 Renehan AG, Tyson M, Egger M, Heller RF, Zwahlen M (2008) Body-mass\nindex and incidence of cancer: a systematic review and meta-analysis of\nprospective observational studies. Lancet 371: 569–578 Elmsta˚hl S, Riboli E, Lindga¨rde F, Gullberg B, Saracci R (1996b) The Malmo¨\nFood Study. The relative validity of a modified diet history method and\nan extensive food frequency questionnaire for measuring food intake. Eur J Clin Nutr 50: 143–151 Riboli E, Elmsta˚hl S, Saracci R, Gullberg B, Lindga¨rde F (1997) The Malmo¨\nFood Study: validity of two dietary assessment methods for measuring\nnutrient intake. Int J Epidemiol 26(Suppl. 1): S161–S173 Rodriguez C, Freedland SJ, Deka A, Jacobs EJ, McCullough ML, Patel AV,\nThun MJ, Calle EE (2007) Body mass index, weight change, and risk of\nprostate cancer in the Cancer Prevention Study II Nutrition Cohort. Cancer Epidemiol Biomarkers Prev 16: 63–69 Engeland A, Tretli S, Bjørge T (2003) Height, body mass index, and\nprostate cancer: a follow-up of 950 000 Norwegian men. Br J Cancer 89:\n1237–1242 Freedland SJ, Giovannucci E, Platz EA (2006) Are findings from studies of\nobesity and prostate cancer really in conflict? Cancer Causes Control 17:\n5–9 p\nSandblom\nG,\nDufmats\nM,\nOlsson\nM,\nVarenhorst\nE\n(2003)\nValidity of a population-based cancer register in Sweden. Scand J Urol\n37: 112–119 Gastaldelli A (2008) Abdominal fat: does it predict the development of type\n2 diabetes? Am J Clin Nutr 87: 1118–1119 Stocks T, Lukanova A, Rinaldi S, Biessy C, Dossus L, Lindahl B, Hallmans\nG, Kaaks R, Stattin P (2007) Insulin resistance is inversely related to\nprostate cancer: a prospective study in Northern Sweden. REFERENCES representativity, cancer incidence and mortality in participants and non-\nparticipants. Eur J Cancer Prev 10: 489–499 representativity, cancer incidence and mortality in participants and non-\nparticipants. Eur J Cancer Prev 10: 489–499 Anonymous (1996) Bioelectrical impedance analysis in body composition\nmeasurement: National Institutes of Health Technology Assessment\nConference Statement 1994 Dec 12–14. Am J Clin Nutr 64(suppl):\n524S–532S Manjer J, Elmsta˚hl S, Janzon L, Berglund G (2002) Invitation to a\npopulation-based cohort study: differences between subjects recruited\nusing various strategies. Scand J Public Health 30: 103–112 Batty GD, Gunnell D, Langenberg C, Davey Smith G, Marmot MG, Shipley\nMJ (2006) Adult height and lung function as markers of life course\nexposures: associations with risk factors and cause-specific mortality. Eur J Epidemiol 21: 795–801 Pischon T, Boeing H, Weikert S, Allen N, Key T, Føns Johnsen N,\nTjønneland A, Tang Severinsen M, Overvad K, Rohrmann S, Kaaks R,\nT i h\nl\nZ i\nT i h\nl\nl\nlli\nT\ni Pischon T, Boeing H, Weikert S, Allen N, Key T, Føns Johnsen N,\nTjønneland A, Tang Severinsen M, Overvad K, Rohrmann S, Kaaks R,\nTrichopoulou A, Zoi G, Trichopoulos D, Pala V, Palli D, Tumino R,\nSacerdote C, Bueno-de-Mesquita HB, May A, Manjer J, Wallstro¨m P,\nStattin P, Hallmans G, Buckland G, Larran˜aga N, Chirlaque MD,\nMartinez C, Redondo Cornejo ML, Ardanaz E, Bingham S, Khaw KT,\nRinaldi S, Slimani N, Jenab M, Riboli E (2008) Body size and risk of\nprostate cancer in the European Prospective Investigation into cancer\nand nutrition. Cancer Epidemiol Biomarkers Prev 17: 3252–3261 Tjønneland A, Tang Severinsen M, Overvad K, Rohrmann S, Kaaks R,\nTrichopoulou A, Zoi G, Trichopoulos D, Pala V, Palli D, Tumino R,\nSacerdote C, Bueno-de-Mesquita HB, May A, Manjer J, Wallstro¨m P,\nStattin P, Hallmans G, Buckland G, Larran˜aga N, Chirlaque MD,\nMartinez C Redondo Cornejo ML Ardanaz E Bingham S Khaw KT Berglund G, Elmsta˚hl S, Janzon L, Larsson SA (1993) The Malmo¨ Diet and\nCancer Study. Design and feasibility. J Intern Med 232: 45–51 Sacerdote C, Bueno-de-Mesquita HB, May A, Manjer J, Wallstro¨m P, Stattin P, Hallmans G, Buckland G, Larran˜aga N, Chirlaque MD, y\ng\ny\nBonovas S, Filioussi K, Tsantes A (2004) Diabetes mellitus and risk of\nprostate cancer: a meta-analysis. Diabetologia 47: 1071–1078 Callmer E, Riboli E, Saracci R, kesson B, Lindga¨rde F (1993) Dietary\nassessment methods evaluated in the Malmo¨ Food Study. REFERENCES Oxford\nUniversity Press: New York\nWillett WC, Stampfer MJ (1998) Implications of total energy intake for\nepidemiologic analyses. In Nutritional Epidemiology, Willett WC (ed), pp\n273–301. Oxford University Press: New York y\nWillett WC, Stampfer MJ (1998) Implications of total energy intake for\nepidemiologic analyses. In Nutritional Epidemiology, Willett WC (ed), pp\n273–301. Oxford University Press: New York g\ng\ngy\nKoster A, Leitzmann MF, Schatzkin A, Mouw T, Adams KF, van Eijk JTM,\nHollenbeck AR, Harris TB (2008) Waist circumference and mortality. Am\nJ Epidemiol 167: 1465–1475 273–301. Oxford University Press: New York Wirfa¨lt E, Mattisson I, Johansson U, Gullberg B, Wallstro¨m P, Berglund G\n(2002) A methodological report from the Malmo¨ Diet and Cancer study:\ndevelopment\nand evaluation of altered routines in dietary data\nprocessing. Nutr J 1: 3 p\nLahmann PH, Lissner L, Gullberg B, Berglund G (2002) A prospective study\nof adiposity and all-cause mortality: the Malmo¨ Diet and Cancer Study. Obes Res 10: 361–369 Lee IM, Sesso HD, Paffenbarger Jr RS (2001) A prospective cohort study of\nphysical activity and body size in relation to prostate cancer risk (United\nStates). Cancer Causes Control 12: 187–193 World Health Organization. Obesity: Preventing and Managing the Global\nEpidemic (2000). 894 WHO: Geneva. WHO Technical Report Series. Ref\nType: Report Epidemiology Littman AJ, White E, Kristal AR (2007) Anthropometrics and prostate\ncancer risk. Am J Epidemiol 165: 1271–1279 Wright ME, Chang SC, Schatzkin A, Albanes D, Kipnis V, Mouw T, Hurwitz\nP, Hollenbeck A, Leitzmann MF (2007) Prospective study of adiposity\nand weight change in relation to prostate cancer incidence and mortality. Cancer 109: 675–684 MacInnis RJ, English DR (2006) Body size and composition and prostate\ncancer risk: systematic review and meta-regression analysis. Cancer\nCauses Control 17: 989–1003 Yusuf S, Hawken S, Ounpuu S, Bautista L, Franzosi MG, Commerford P,\nLang CC, Rumboldt Z, Onen CL, Lisheng L, Tanomsup S, Wangai Jr. P,\nRazak F, Sharma AM, Anand SS, INTERHEART Study Investigators\n(2005) Obesity and the risk of myocardial infarction in 27 000\nparticipants from 52 countries: a case–control study. Lancet 366:\n1640–1649 MacInnis RJ, English DR, Gertig DM, Hopper JL, Giles GG (2003) Body size\nand composition and prostate cancer risk. Conflict of interest The authors declare no conflict of interest. & 2009 Cancer Research UK & 2009 Cancer Research UK British Journal of Cancer (2009) 100(11), 1799 – 1805 Body size and prostate cancer\nP Wallstro¨m et al Body size and prostate cancer\nP W ll\n¨\nl 1805 REFERENCES Int J Cancer\n120: 2678–2686 Giovannucci E, Liu Y, Platz EA, Stampfer MJ, Willett WC (2007) Risk\nfactors for prostate cancer incidence and progression in the health\nprofessionals follow-up study. Int J Cancer 121: 1571–1578 Sun SS, Chumlea WC, Heymsfield SB, Lukaski HC, Schoeller D, Friedl K,\nKuczmarski RJ, Flegal KM, Johnson CL, Hubbard VS (2003) Develop-\nment of bioelectrical impedance analysis prediction equations for body\ncomposition with the use of a multicomponent model for use in\nepidemiologic surveys. Am J Clin Nutr 77: 331–340 Giovannucci E, Rimm EB, Stampfer MJ, Colditz GA, Willett WC (1997)\nHeight, body weight, and risk of prostate cancer. Cancer Epidemiol\nBiomarkers Prev 6: 557–563 Gong Z, Neuhouser ML, Goodman PJ, Albanes D, Chi C, Hsing AW,\nLippman SM, Platz EA, Pollak MN, Thompson IM, Kristal AR (2006)\nObesity, diabetes, and risk of prostate cancer: results from the\nProstate Cancer Prevention Trial. Cancer Epidemiol Biomarkers Prev\n15: 1977–1983 p\ng\ny\nVazquez G, Duval S, Jacobs Jr DR, Silventoinen K (2007) Comparison of\nbody mass index, waist circumference, and waist/hip ratio in predicting\nincident diabetes: a meta-analysis. Epidemiol Rev 29: 115–128 Visscher TL, Seidell JC, Molarius A, van der Kuip D, Hofman A, Witteman\nJC (2001) A comparison of body mass index, waist-hip ratio and waist\ncircumference as predictors of all-cause mortality among the elderly: the\nRotterdam study. Int J Obes Relat Metab Disord 25: 1730–1735 Gunnell D, Okasha M, Davey Smith G, Oliver SE, Sandhu J, Holly JMP\n(2001) Height, leg length, and cancer risk: a systematic review. Epidemiol\nRev 23: 313–342 Heitmann BL (1990) Prediction of body water and fat in adult Danes from\nmeasurement of electrical impedance. A validation study. Int J Obes 14:\n789–802 Wallstro¨m P, Bjartell A, Gullberg B, Olsson H, Wirfa¨lt E (2007) A\nprospective study on dietary fat and incidence of prostate cancer\n(Malmo¨, Sweden). Cancer Causes Control 18: 1107–1121 Hubbard JS, Rohrmann S, Landis PK, Metter EJ, Muller DC, Andres R,\nCarter HB, Platz EA (2004) Association of prostate cancer risk with\ninsulin, glucose, and anthropometry in the Baltimore longitudinal study\nof aging. Urology 63: 253–258 Willett WC (1998) Anthropometric measures and body composition. In\nNutritional Epidemiology, Willett WC (ed), pp 244–272. Oxford\nUniversity Press: New York Willett WC (1998) Anthropometric measures and body composition. In\nNutritional Epidemiology, Willett WC (ed), pp 244–272. REFERENCES Cancer Epidemiol Biomarkers\nPrev 12: 1417–1421 Manjer J, Carlsson S, Elmsta˚hl S, Gullberg B, Janzon L, Lindstro¨m M,\nMattisson I, Berglund G (2001) The Malmo¨ Diet and Cancer Study: British Journal of Cancer (2009) 100(11), 1799 – 1805 & 2009 Cancer Research UK"}}}],"truncated":false,"partial":true},"paginationData":{"pageIndex":21,"numItemsPerPage":100,"numTotalItems":93470,"offset":2100,"length":100}},"jwt":"eyJhbGciOiJFZERTQSJ9.eyJyZWFkIjp0cnVlLCJwZXJtaXNzaW9ucyI6eyJyZXBvLmNvbnRlbnQucmVhZCI6dHJ1ZX0sImlhdCI6MTc2NzA5OTA3OCwic3ViIjoiL2RhdGFzZXRzL0xMTURIL09wZW5TY2llbmNlIiwiZXhwIjoxNzY3MTAyNjc4LCJpc3MiOiJodHRwczovL2h1Z2dpbmdmYWNlLmNvIn0.4YOsal36w7x1wg_HQckP_WuDFy2liM-oWNWu5sgNRiwIyUsbipTsBNivAHcr4enCL6BjAMVTZFJYa7lURii3Bw","displayUrls":true,"splitSizeSummaries":[{"config":"default","split":"train","numRows":93470,"numBytesParquet":2772077973}]},"discussionsStats":{"closed":0,"open":1,"total":1},"fullWidth":true,"hasGatedAccess":true,"hasFullAccess":true,"isEmbedded":false,"savedQueries":{"community":[],"user":[]}}">
identifier
stringlengths 11
32
| pdf_url
stringlengths 17
4.62k
⌀ | lang
stringclasses 120
values | error
stringclasses 1
value | title
stringlengths 2
500
⌀ | source_name
stringlengths 1
435
⌀ | publication_year
float64 1.9k
2.02k
| license
stringclasses 3
values | word_count
int64 0
1.64M
| text
stringlengths 1
9.75M
|
|---|---|---|---|---|---|---|---|---|---|
https://openalex.org/W4316618279
|
http://meijournals.com/ara/index.php/mejhcs/article/download/138/146
|
Arabic
| null |
أثر إستخدام التعلم المتمازج على تحصيل طلاب الصف العاشر الأساسي في مادة التربية المهنية وإتجاهاتهم نحوها
|
Mağallaẗ al-šarq al-awsaṭ li-l-ʿulūm al-insāniyyaẗ wa-al-ṯaqāfiyyaẗ
| 2,021
|
cc-by
| 11,415
|
Middle East Journal of Humanities and Cultural Studies
Homepage: http://meijournals.com/ar/index.php/mejljs/index
ISSN: 2710-2238 (Print)
ISSN: 2788-4686 (Online)
أثر إستخدام التعلم المتمازج على تحصيل طالب الصف العاشر األساسي في مادة
التربية المهنية وإتجاهاتهم نحوها
أحمد عيد محمد الشراري
أ.د عيد حسن الصبحيين
كلية العلوم التربوية، جامعة الحسين بن طالل، المملكة االردنية الهاشمية
استالم البحث :
28/05/2021
مراجعة البحث:
15/07/2021
قيول البحث:
16/07/2021 Middle East Journal of Humanities and Cultural Studies
Homepage: http://meijournals.com/ar/index.php/mejljs/index
ISSN: 2710-2238 (Print)
ISSN: 2788-4686 (Online)
أثر إستخدام التعلم المتمازج على تحصيل طالب الصف العاشر األساسي في مادة
التربية المهنية وإتجاهاتهم نحوها
أحمد عيد محمد الشراري
أ.د عيد حسن الصبحيين
كلية العلوم التربوية، جامعة الحسين بن طالل، المملكة االردنية الهاشمية
استالم البحث :
28/05/2021
مراجعة البحث:
15/07/2021
قيول البحث:
16/07/2021 Middle East Journal of Humanities and Cultural Studies
Homepage: http://meijournals.com/ar/index.php/mejljs/index
ISSN: 2710-2238 (Print)
ISSN: 2788-4686 (Online) أثر إستخدام التعلم المتمازج على تحصيل طالب الصف العاشر األساسي في مادة
التربية المهنية وإتجاهاتهم نحوها
أحمد عيد محمد الشراري
أ.د عيد حسن الصبحيين
كلية العلوم التربوية، جامعة الحسين بن طالل، المملكة االردنية الهاشمية
استالم البحث:
28/05/2021مراجعة البحث:
15/07/2021قيول البحث:
16/07/2021 كلية العلوم التربوية، جامعة الحسين بن طالل، المملكة االردنية الهاشمية استالم البحث :
28/05/2021
مراجعة البحث:
15/07/2021
قيول البحث:
16/07/2021 ألمجلد1
. العدد3
.
0201 ملخص ا
لدراسة: هدفت هذه الدراسة إلى التعرف على أثر إستخدام التعلم المتمازج على تحصيل طالب الصف العاشر األساسي في مادة التربية
( المهنية وإتجاهاتهم نحوها، وقد تكونت عينة الدراسة من08
) طالبا وطالبة، تم توزيعهم عشوائياً على مجموعتين ضابطة
وتجريبية، واتبعت الدراسة المنهج
شبه التجريبي، ولتحقيق أهداف الدراسة تم تطوير مقياس إتجاهات الطالب، وتم بناء اختبار
.تحصيلي، وتطبيق برنامج تدريبي يقوم على استخدام استراتيجية التعلم المتمازج
وأظهرت نتائج الدراسة عدم وجود
فروق دالة
إحصائيا بين متوسطات أداء افراد المجموعتين التجريبية وا
لضابطة على االختبار البعدي لمادة التربية المهنية تعزى لطريقة
التعلم، والجنس والتفاعل بينهما، كما وأظهرت النتائج وجود فروق دالة احصائياً في اتجاهات طلبة الصف العاشر نحو مادة
التربية المهنية على المجالين (طريقة التدريس، وصعوبة تدريس مادة التربية المهنية) وكا
نت الفروق لصالح التعل م المتمازج، وقد
أظهرت النتائج عدم جود فروق دالة إحصائياً بين متوسطات أداء افراد المجموعة التجريبية التي درست بالتعلم المتمازج على
االختبار البعدي لمادة التربية المهنية تعزى للجنس، وتوصلت النتائج إلى وجود فروق في إتجاهات طلبة الصف العاش
ر
الذين
.درسوا بطريقة التعلم االعتيادية على الدرجة الكلية، وبُعد طريقة التدريس وبُعد صعوبة تدريس مادة التربية المهنية تعزى للجنس
،وتوصي الدراسة بضرورة التوسع في تدريب معلمي التربية المهنية العاملين في المدارس الحكومية على طريقة التعلم المتمازج
كإستراتيح ية تعلم حديثة، ومستخدمة بطريقة غير مباشرة على منصات التعلم عن بعد بسبب ظروف جائحة كورونا، والعمل على
بناء منهاج التربية المهنية وفقاً الستراتيجيات التدريس الحديثة. الكلمات المفتاحية :
.التعلم المتمازج، مادة التربية المهنية، طالب الصف العاشر األساسي الكلمات المفتاحية :
.التعلم المتمازج، مادة التربية المهنية، طالب الصف العاشر األساسي 28
جميع الحقوق محفوظة لمجلة
الشرق األوسط للعلوم اإلنسانية
والثقا
ية ف 28
جميع الحقوق محفوظة لمجلة
الشرق األوسط للعلوم اإلنسانية
والثقا
ية ف ألمجلد1
. العدد3
. 0201 أثر إستخدام التعلم المتمازج على تحصيل طالب الصف العاشر األساسي في مادة التربية المهنية وإتجاهاتهم نحوها أحمد
الشراري و
عيد
الصبحيين Abstract: This study aimed to identify the impact of the use of blended learning on the achievement of
students in the tenth grade of the basic subject in the subject of vocational education and their
directions towards it, the sample of the study consisted of (80) students, randomly distributed to
two controlled and experimental groups, the study followed the semi-experimental curriculum,
and to achieve the objectives of the study the measure of student trends was developed, a learning
test was built, and a training program was applied based on the use of a combined learning strategy. The results of the study showed that there were no statistically significant differences between the
average performance of the members of the two experimental groups and the officer on the
distance test of vocational education due to the method of learning, Gender and interaction between
them, and the results showed statistically significant differences in the trends of students in grade
10 towards vocational education in the two fields (teaching method, difficulty teaching vocational
education) and differences in favor of combined learning, The results showed no statistically
significant differences between the average performance of the members of the experimental group
studied in the combined learning on the distance test of the subject of vocational education
attributable to Gender, and the results found differences in the directions of tenth graders who
studied in the usual learning method at the college degree, after the method of teaching and after
the difficulty of teaching the subject of vocational education attributable to Gender. The study
recommends that vocational education teachers working in public schools should be trained in the
way of blended learning, such as modern learning strategies, used indirectly on distance learning
platforms due to corona pandemic conditions, work to build a vocational education curriculum in
accordance with modern teaching strategies to provide Internet services, expand the use of distance
learning and provide electronic simulation programs that allow for practical training for students. Keywords: Blended Learning, Vocational Education, Primary Grade 10. 29
جميع الحقوق محفوظة لمجلة
الشرق األوسط للعلوم اإلنسانية
والثقا
ية ف
ألمجلد1
. العدد3
. 0201
Keywords: Blended Learning, Vocational Education, Primary Grade 10. Abstract: المقدمة
يمثل التعلم الدعامة األساسية في تقدم وتطور الشعوب واألمم، لذلك تتسابق العديد من الدول ومن مختلف
الثقافات إلى العمل على تطوير منظومة التعلم لديها، وعند النظر إلى التعلم بشكل عام نجد أنه يعتمد في
الكثير من المراحل على التعلم والذي يقع العبء األك بر فيه على المعلم، ولهذا تسعى الكثير من المؤسسات 29
جميع الحقوق محفوظة لمجلة
الشرق األوسط للعلوم اإلنسانية
والثقا
ية ف
ألمجلد1
. العدد3
. 0201
Keywords: Blended Learning, Vocational Education, Primary Grade 10. المقدمة
يمثل التعلم الدعامة األساسية في تقدم وتطور الشعوب واألمم، لذلك تتسابق العديد من الدول ومن مختلف
الثقافات إلى العمل على تطوير منظومة التعلم لديها، وعند النظر إلى التعلم بشكل عام نجد أنه يعتمد في
الكثير من المراحل على التعلم والذي يقع العبء األك بر فيه على المعلم، ولهذا تسعى الكثير من المؤسسات Dawlat Khaled Musa Harb
Ahmed Eid Mohammed Al-Sharari
Prof. Eid Hassan Al-Subhaiyin College of Educational Sciences, Al-Hussein Bin Talal University,
Hashemite Kingdom of Jordan المقدمة يمثل التعلم الدعامة األساسية في تقدم وتطور الشعوب واألمم، لذلك تتسابق العديد من الدول ومن مختلف
الثقافات إلى العمل على تطوير منظومة التعلم لديها، وعند النظر إلى التعلم بشكل عام نجد أنه يعتمد في
الكثير من المراحل على التعلم والذي يقع العبء األك بر فيه على المعلم، ولهذا تسعى الكثير من المؤسسات ألمجلد1
. العدد3
. المقدمة 0201 أثر إستخدام التعلم المتمازج على تحصيل طالب الصف العاشر األساسي في مادة التربية المهنية وإتجاهاتهم نحوها أحمد
الشراري و
عيد
الصبحيين إلى تطوير منظومة التعلم من خالل العمل على إيجاد طرق جديدة للتعلم والتي تهدف إلى أن يكون المتعلم
ًفيه نشطاً وإيجابياً، وان يكون دور المعلم موجها ،ومرشداً(بن داده0808
.) ومن هذه الطرق الحديثة التي يجب الوص ول إليها هي طرق التعلم االلكتروني، والتي على الرغم من العديد
من المميزات واإليجابيات لها، إال أن العديد من المتخصصين يرى أنه يوجد فيها قصور في بعض الجوانب لم
يستطع التعلم االلكتروني التغلب عليها، وقد برزت الحاجة إلى مدخل جديد يجمع بين مميزات التعلم األلكتر و ني
والتعلم االعتيادي والتوصل إلى حل لكل جوانب القصور التي نعاني منها في العملية التعليمية، وعليه ظهر ما
يسمى بالتعلم المتمازج والذي يعمل على مزج ودمج كل من التعلم االعتيادي بكافة أشكاله والتعلم االلكتروني
الحديث وبأنماطه المتنوعة، بهدف زيادة الفاعلية للمو قف التعليمي وفرص،التفاعل اإلجتماعي(كزيز
2019
.) ،ويُهدف من إستعمال التعلم المتمازج العمل على وصف الحلول التي تشمل على أساليب لنقل المعلومات
كبرمجيات التعلم من خالل شبكة االنترنت، وممارسة إدارة المعلومات، كما وتستعمل هذه اإلستراتيجية لغايات
وصف التعلم ا لذي يعمل على المزج بين األنشطة المتنوعة في المواجهة الصفية والتعلم المباشر، والتقدم من
خالل التعلم الذاتي، حيث يعتبر التعلم المتمازج أسلوباً في التعلم يعتمد على مزج األساليب االعتيادية للمعلم
مع التعلم االلكتروني، ووسائل اإليضاح السمعية والبصرية، وشبكة اال
نترنت العالمية لتحسين نوعي ة التعلم
والعملية التعليمية، وللعديد من المواد و المحتويات التي تدرس في المدارس، ومنها محتوى مادة التربية المهنية
(عطية ،
2013
.) ظهرت توجهات إلى المزج ما بين الطريقة االعتيادية المتعارف عليها في المدارس، وما بين التعلم االلكتر و ،ني
وهو ما يسمى بالتعلم المتمازج أو المدمج، بحيث يعمل على توظيف كال الطريقتين في التعلم، حيث عرّفت
( الليماLalima, 2017, 132
)
التعلم المتمازج على أنه: أحد المفاهيم التي تشمل وضع األطر العامة لعملية
التعلم التي تعمل على المزج ما بين طريقة التدريس االعتيادي
ة القائمة على التفاعل المباشر بين المعل ،م والطلبة
.والتعلم المستند إلى استخدام وسائل التكنولوجيا المختلفة
ويعرف مفهوم التعلم المتمازج على أنه نوع م ن التعلم
االعتيادي المستند إلى التفاعالت المباشرة بين المعلم والطلبة، يعمل الطلبة من خالل إكمال جزء من م
ه ام
التعلم الصفية باستخدام الحاسوب أو أي نوع من وسائل التكنولوجيا وبالتزامن مع العمل مع المعلم والطلبة
،اآلخرين (الهاشمي2016
.) 30 ألمجلد1
. العدد3
. نماذج التعلم المتمازج يندرج تحت هذا العنوان ثالثة نماذج للتعلم المتمازج وهي نموذج التعلم الذي تقوده المهاره، ونموذج التعلم
ا لذي
يقوده االتجاه، ونموذج التعلم الذي تقوده الكفاءة، وفيما يلي توضيح لكل ،نموذج(الشرمان2015
:) .أوالً: نموذج التعلم الذي تقوده المهاره يجمع هذا النموذج بين التعلم ذو الخطوة الذاتية ودعم وتطوير مهارات ومعارف محددة تتطلب تغذية راجعة
ودعماً من المعلم، حي ث يدمج التفاعل مع المعلم من خالل البريد االلكتروني أو من خالل منتديات المناقشة
أو البرمجيات التي توجد خصيصاً لتحقيق هذا النوع من اإلستراتيجيات، واللقاءات وجهاً لوجه بالتعلم ذو الخطوة
.الذاتية المقدمة 0201 30
جميع الحقوق محفوظة لمجلة
الشرق األوسط للعلوم اإلنسانية
والثقا
ية ف جميع الحقوق محفوظة لمجلة
الشرق األوسط للعلوم اإلنسانية
والثقا
ية ف أثر إستخدام التعلم المتمازج على تحصيل طالب الصف العاشر األساسي في مادة التربية المهنية وإتجاهاتهم نحوها أحمد
الشراري و
عيد
الصبحيين نماذج التعلم المتمازج .ثانياً: نموذج التعلم الذي يقوده االتجاه تتمحور الفكرة في هذ ا النموذج بأنه يعمل على دمج أحداث ووسائل تقديم متنوعة لتطوير سلوكيات محددة
.تتطلب التفاعل بين الطلبة أنفسهم ومع بعضهم البعض، كما وتتطلب بيئة خالية من المخاطر ث الثاً: نموذج
التعلم الذي تقوده الكفاءة: يدمج هذا النموذج بين أدوات دعم األداء مع مصادر إدارة المع
رفة، وإستشارات
لتطوير الكفاءات إللتقاط ونقل المعرفة المتظمنة والتي تتطلب من الطلبة التفاعل مع المعلمين وكل من يقدم
لهم التعلم.(Lesmana & Basiran, 2017) وبين عدد من الخبراء والتربويين أن التعلم المتمازج قد يلقى
مقاومة تعمل على إعاقة تقدمه ونجاحه، إذا عم ل
على اإلخالل بسير العملية التدريسية الحالية أو هدد أحد أطرافها وهما المعلم والطالب اللذان يمثالن المكونات
،األساسية باإلضافة إلى المناهج التعليمية والبرامج اإلدارية، وعليه فإن أحد الشروط الهامة لنجاح هذا األسلوب
هو أن يكون مكمالً ألساليب التعلم االعتيادية ، ولكي يتم ذلك ال بد أن يكون المعلم قادراً على استخدام تقنيات
التعلم الحديثة، واستخدام الوسائل المختلفة ،والمتنوعة(العاني2015
.) أنماط التعلم المتمازج 31
جميع الحقوق محفوظة لمجلة
الشرق األوسط للعلوم اإلنسانية
والثقا
ية ف 31 31
جميع الحقوق محفوظة لمجلة
الشرق األوسط للعلوم اإلنسانية
والثقا
ية ف ألمجلد1
. العدد3
. .ثانياً: نموذج التعلم الذي يقوده االتجاه 0201 أثر إستخدام التعلم المتمازج على تحصيل طالب الصف العاشر األساسي في مادة التربية المهنية وإتجاهاتهم نحوها أحمد
الشراري و
عيد
الصبحيين لكي يتمكن المعلمين من توظيف استراتيجية التعلم المتمازج في الغرفة الصفية فال بد من توظيف هذه
االسترات ،يجية من خالل عدة أنماط، مما يساعد على توافقها مع األهداف والمتطلبات التي وضعت من أجلها
ولتحقيق أعلى مستوى من عملية التعلم، وهذه األنماط هي ،كما يلي (الريماوي2017
:) نمط التناوب: عند اإلمعان في المعنى الذي يأتي من كلمة التناوب نجد أن هذا النمط يبين لنا الت
ش اركية التي
تظهر فيما بين التعلم الصفي االعتيادي والتعلم بواسطة تطبيق استراتيجية التعلم المتمازج، كما ويظهر التبادل
في عملية تقديم الدرس الواحد أو المحتوى الدراسي المراد تقديمه للطالب، ويتم ذلك من خالل أوالً: التناوب
المتمركز، والذي يقصد به تناوب الطلبة ضم ن الدرس الواحد أو األداة الواحدة خالل جدول محدد أو من خالل
.التوجيهات التي يلقيها المعلم بين التعلم الصفي االعتيادي والتعلم المتمازج ومن ثم يأتي ثان ياً وهو التناوب
المعاملي، حيث يتناوب فيه الطلبة ضمن الدرس الواحد و وفق جدول محدد على طريقتي التعلم الصفي
االعتيادي، والتعلم المتمازج، ومن خالل نقل الطلبة من الغرفة الصفية إلى المختبرات أو الغرفة المجهزة لغايات
.التعلم المتمازج، وهذه التجهيزات تشمل على أجهزة الحاسوب، ووسائل التكنولوجيا الحديثة، وشبكة االنترنت
وفي األسلوب الثالث، وهو التناوب الذاتي يكون الجدول
للطلبة محدداً لكل منهم على حدى، حيث يقوم المعلم
بوضع هذا الجدول من خالل تقديره لما يتناسب مع قدرات وإمكانات ومهارات كل متعلم، أومن خالل استخدام
البرامج التي تتيح لنا هذا ،التقسيم(الهاشمي2016
.) :النمط المرن في هذا النمط نجد أن التعلم في الغرفة الصفية والت علم المتمازج للمادة الدراسية يكون و فق جدول
،زمني محدد بطريقة تبادلية، إال أنه يتمحور التركيز بشكل أكبر على التعلم المتمازج، وداخل الغرفة الصفية
حيث يقدم المعلم الدعم والتوجيه للطلبة عند طلبهم هم، ويكون ذلك من خالل األنشطة والتعلم من خالل
المجموعات، والمشار
يع الجماعية، والدروس الفرد( يةLesmana and Basiran, 2017
.)
نمط حسب
الطلب: في هذا النمط إن الطلبة يتلقون تعليمهم سواء لمادة تعليمية واحدة أو أكثر بشكل يعتمد بدرجة أساسية
على مقومات التعلم المتمازج وهي التكنولوجيا وتوابعها، ويتم ذلك بمساعدة من المعلم من خالل
ال تواصل مع
الطلبة عبر االنترنت والمواقع االلكترونية المخصصة لذلك، وفي ذات الوقت يستمر في الحصول على خبرات
تعليمية لمواد أخرى في المدرسة، كما يتيح هذا النمط للطلبة تعلم المادة إلكترونياً داخل حرم المدرسة أو من
،خارجها(قطيط2015
.)
نمط التعلم االفتراضي المكثف : عادة ما يبدأ نمط التعلم االفتراضي المكثف بدوام
ًكامل على شبكة االنترنت، ومن ثم توضع بعد ذلك برامج لتزويد الطلبة بتجربة التعلم، وفي هذا النمط أيضا 32 32
جميع الحقوق محفوظة لمجلة
الشرق األوسط للعلوم اإلنسانية
والثقا
ية ف 32
جميع الحقوق محفوظة لمجلة
الشرق األوسط للعلوم اإلنسانية
والثقا
ية ف ألمجلد1
. .ثانياً: نموذج التعلم الذي يقوده االتجاه 0201 أثر إستخدام التعلم المتمازج على تحصيل طالب الصف العاشر األساسي في مادة التربية المهنية وإتجاهاتهم نحوها أحمد
الشراري و
عيد
الصبحيين الذي يتم تجربته لكل مادة من المواد الدراسية، يقوم فيه الطلبة بتقسيم وقتهم بين الحضور إلى الموقف التعليمي
في الغرفة الصفية ويتلقى التعلم بشكل اعتيادي، أو من خالل التعلم عن بعد وباستخدام شبكة االنترنت، حيث
يتمكن الطلبة من الوصول إلى المحتوى( التعليمي الذي هو متوفراً في األصل على الشبكةAslam, 2015
.)
( أجرى أبو لوم2020
)دراسة هدفت إلى استقصاء اثر استخدام استرات
يجية التعلم المتمازج في تنمية المفا هيم
( الرياضية لدى طلبة الصف الثالث األساسي في األردن، وتكونت عينة الدراسة من45
) طالباً وطالبة من
( طلبة الصف الثالث األساسي من المدارس الحكومية في مدينة إربد، وتم تقسيم عينة الدراسة إلى23
ً) طالبا
وطالبة كمجموعة تجريبية ت(م تدريسهم من خالل استراتيجية التعلم المتمازج، و22
) كعينة ضابطة، ولتحقيق
أهداف الدراسة إستخدم الباحث إختبار المفاهيم الرياضية الذي تم إعداده خصيصاً ألغراض هذه الدراسة وكأداة
لها، وأظهرت نتائج الدراسة أنه توجد فروق ذات داللة إحصائية في تنمية المفاهيم الرياض ية تعز ى لطريقة
التدريس، وكانت لصالح المجموعة التجريبية، وال تظهر النتائج فروقاً ذات داللة إحصائية في تنمية المفاهيم
.الرياضية تعزى للتفاعل بين طريقة التدريس والجنس و
أجرى شاهين(
2020) دراسة بهدف التعرف على درجة استخدام طريقة التعلم المتمازج من وجهة نظر م
ع ملي
( التربية الخاصة في األردن والفروق الفردية فيها وفقاً لعدد من المتغيرات، وتكونت عينة الدراسة من209
)
معلماً ومعلمة، وتم استخدام المنهج الوصفي التحليلي، ولتحقيق أهداف الدراسة استخدم الباحث االستبانة كأداة
لجمع البيانات، وأظهرت النتائج أن درجة استخدام طر يقة التعلم المتمازج من وجهة نظر معلمي التربية الخاصة
في األردن جاءت بمتوسط حسابي ودرجة تقدير متوسطة، كما وقد تبين من النتائج أنه توجد فروق ذات داللة
إحصائية على درجة استخدام التعلم المتمازج تعزى إلى متغير تخصص المعلم ولصالح تخصص صعوبات
التعلم، في حين لم تظ هر النتائج فروقاً ذات داللة على متغير الجنس، وأن هنالك عدد من المعوقات تقف أمام
معلمي التربية الخاصة وتمنعه من تطبيق استراتيجية التعلم المتمازج في تدريس الطلبة ذوي االحتياجات
.الخاصة (قدم مصطفى2019) دراسة أجراها بهدف استقصاء اثر التعلم المتمازج في تحصي
ل طلبة الصف التاسع
( األساسي في مادة التالوة والتجويد وفي دافعيتهم نحوها، وتكونت عينة الدراسة من38
) طالباً موزعين على
( مجموعتين ضابطة وتجريبية، وكان قوام كل مجموعة منهم20
() طالباً في المجموعة التجريبية، و18
) في
المجموعة الضابطة، وقد استخدم الباحث اختبار ا
لتحصيل بعد التأكد من صدقة وثباته، وتوصلت نتائج الدراس ة 33 33
جميع الحقوق محفوظة لمجلة
الشرق األوسط للعلوم اإلنسانية
والثقا
ية ف ألمجلد1
. .ثانياً: نموذج التعلم الذي يقوده االتجاه العدد3
. .ثانياً: نموذج التعلم الذي يقوده االتجاه كما
وأجرت الصرايرة (
2019
) دراسة هدفت إلى الكشف عن اتجاهات الطلبة نحو استخدام نمط التعلم المتمازج
في دراسة المفاهيم الفيزيائية لدى طلبة الصف العاشر األساسي في منطقة معان، واعتمدت الباحثة على المنهج
الوصفي، تكونت عينة ال دراسة من جميع طالبات الصف العاشر في مدرسة معان الثانوية للبنات، ولتحقيق
أهداف الدراسة تم استخدام مقياس اتجاهات الطلبة نحو استخدام التعلم المتمازج لدراسة المفاهيم الفيزيائية كأداة
( للدراسة وتكونت من35) فقرة، وأظهرت نتائج الدراسة أنه توجد فروق ذات داللة إحص
ائية بين المتوسطات
القبلية والمتوسطات البعدية التجاهات الطلبة نحو استخدام نمط التعلم المتمازج في دراسة المفاهيم الفيزيائية
ولصالح المتوسطات البعدية في إجمالي األداة، كما وقد بينت النتائج وجود عالقة ذات داللة إحصائية التجاهات
الطلبة نحو استخدام نمط التعلم ا.لمتمازج في دراسة المفاهيم الفيزيائية بمستوى الوصول للتكنولوجيا
أما في الدراسة التي
أجراها المساعدة (
2018
)
فقد
هدف
ت إلى
التعرف على اثر استخدام استراتيجية التعلم
المتمازج في تحصيل طلبة الصف الثامن األساسي لمادة العلوم واتجاهاتهم نحوها في مديرية تربية إر
ب ،د
(وتكونت عينة الدراسة من138
) طالباً وطالبة، ولتحقيق أهداف الدراسة قام الباحث باستخدام مقياس االتجاهات
(نحو مادة العلوم وهو من إعداد الباحث، ومن خالل استخدام الرزمة اإلحصائيةSPSS
) أظهرت نتائج الدراسة
أنه توجد فروق دالة احصائياً بين متوسط درجات المجموعة ا لتجريبية والمجموعة الضابطة ولصالح المجموعة كما
وأجرت الصرايرة (
2019
) دراسة هدفت إلى الكشف عن اتجاهات الطلبة نحو استخدام نمط التعلم المتمازج
في دراسة المفاهيم الفيزيائية لدى طلبة الصف العاشر األساسي في منطقة معان، واعتمدت الباحثة على المنهج
الوصفي، تكونت عينة ال دراسة من جميع طالبات الصف العاشر في مدرسة معان الثانوية للبنات، ولتحقيق
أهداف الدراسة تم استخدام مقياس اتجاهات الطلبة نحو استخدام التعلم المتمازج لدراسة المفاهيم الفيزيائية كأداة
( للدراسة وتكونت من35) فقرة، وأظهرت نتائج الدراسة أنه توجد فروق ذات داللة إحص
ائية بين المتوسطات
القبلية والمتوسطات البعدية التجاهات الطلبة نحو استخدام نمط التعلم المتمازج في دراسة المفاهيم الفيزيائية
ولصالح المتوسطات البعدية في إجمالي األداة، كما وقد بينت النتائج وجود عالقة ذات داللة إحصائية التجاهات
الطلبة نحو استخدام نمط التعلم ا.لمتمازج في دراسة المفاهيم الفيزيائية بمستوى الوصول للتكنولوجيا أما في الدراسة التي
أجراها المساعدة (
2018
)
فقد
هدف
ت إلى
التعرف على اثر استخدام استراتيجية التعلم
المتمازج في تحصيل طلبة الصف الثامن األساسي لمادة العلوم واتجاهاتهم نحوها في مديرية تربية إر
ب ،د
(وتكونت عينة الدراسة من138
) طالباً وطالبة، ولتحقيق أهداف الدراسة قام الباحث باستخدام مقياس االتجاهات
(نحو مادة العلوم وهو من إعداد الباحث، ومن خالل استخدام الرزمة اإلحصائيةSPSS
) أظهرت نتائج الدراسة
أنه توجد فروق دالة احصائياً بين متوسط درجات المجموعة ا لتجريبية والمجموعة الضابطة ولصالح المجموعة 34 34
جميع الحقوق محفوظة لمجلة
الشرق األوسط للعلوم اإلنسانية
والثقا
ية ف ألمجلد1
. .ثانياً: نموذج التعلم الذي يقوده االتجاه العدد3
. 0201 أثر إستخدام التعلم المتمازج على تحصيل طالب الصف العاشر األساسي في مادة التربية المهنية وإتجاهاتهم نحوها أحمد
الشراري و
عيد
الصبحيين إلى أنه توجد فروق دالة إحصائياً ولصالح المجموعة التجريبية على االختبار التحصيلي البعدي وعلى مقياس
الدافعية، وعليه فقد توصي الدراسة باعتماد مفهوم التعلم المتمازج في مقرر تقنيات التعلم وطرائق التدريس في
.مؤسسات إعداد المناهج والمعلمين إلى أنه توجد فروق دالة إحصائياً ولصالح المجموعة التجريبية على االختبار التحصيلي البعدي وعلى مقياس
الدافعية، وعليه فقد توصي الدراسة باعتماد مفهوم التعلم المتمازج في مقرر تقنيات التعلم وطرائق التدريس في
.مؤسسات إعداد المناهج والمعلمين (أما في دراسة أجرتها شفيق2019) والتي هدفت إلى
معرفة تأثير استراتيجية
التعلم المتمازج في التحصي ل
وإكتساب المفاهيم التاريخية لدى طلبة قسم التاريخ في كلية التربية للعلوم اإلنسانية في جامعة المثنى، كتو و نت
عينة الدراسة(
70
) ط
الب وطالبة تم
( تقسيمهم إلى35
) من الطالب
في ال مجموعة التجر
يبي ة التي تدرس ًوفقا
(الستراتيجية التعلم المتمازج و35
) من الطالب في مجموعة ال
ضابطة
التي تم تدريسها
وفقاً لالسلوب االعتياد
ي . ولتحقيق الهدف من الدراسة
ًاعدت الباحثة اختبارا للمف
يها م تكون( من30) كما أ نها أعدت مقياساً للتعلم
المتمازج، توصلت نتائج الدراسة أنه
هناك فرق كبير بين متوسط الطالب من ال
مجموعة التجريبية وال
ضابطة
في التحصيل يعزى للمجموعة التجريبية، كما واظهرت النتائج فروقاً بين
متوسط الطالب ال
ور ذك
من المجموعة
التجريبية وال ضابطة
في تحسين المفاهيم ا لتاريخية
تعزى لل
مجموعة التجريبية. .ثانياً: نموذج التعلم الذي يقوده االتجاه 0201 جميع الحقوق محفوظة لمجلة
الشرق األوسط للعلوم اإلنسانية
والثقا
ية ف أثر إستخدام التعلم المتمازج على تحصيل طالب الصف العاشر األساسي في مادة التربية المهنية وإتجاهاتهم نحوها أحمد
الشراري و
عيد
الصبحيين التجريبية، كما وتبين أن هنالك فروقاً ذات داللة إحصائية بين نتائج التطبيق القبلي والبعدي على مقياس
.االتجاهات ولصالح التطبيق البعدي واشارت دراسة كل(من كيبولمانغ و موقويKebualemang and Mogwe, 2017
)نجد أنها هدف ت إلى
عمل تحقيق تجريبي في آثار التعلم المتمازج على طالب التعليم العالي وتصورات الطالب لهذا النهج، تكونت
( عينة الدراسة من64
) طالباً، ولتحقيق أهداف الدراسة فقد تم استخدام استبيان لمواصلة فهم تأثيرات التعلم
المتمازج على الطالب، وقد إتبعت الدراسة المنهج الكمي ، وأظهرت نتائج الدراسة أن وضع التعلم المتمازج له
.تأثير إيجابي على الطالب، كما أن تصوراتهم على التعلم المتمازج كاستراتيجية وأسلوب تدريسي كانت ايجابية أما في الدراسة التي(اجرتها يغمورYaghmour, 2016
) نجد انها قد هدفت إلى تقصي فاعلية استراتيجية
تدريسية ق ،ائمة على التعلم المتمازج في تحصيل طلبة الصف الثالث االساسي في مدينة إربد لمادة الرياضيات
( وتكونت عينة الدراسة من97
() طالباً وطالبة تم توزعيهم على مجموعتين االولى تجريبية وكان قوامها47
)
(طالباً وطالبة، والثانية ضابطة وكان قوامها50) طالب وطالبة، ولتحقيق أه داف الدراسة قامت الباحثة ببناء
إختبار تحصيلي بعد إجراء معامالت الصدق والثبات، وأظهرت نتائج الدراسة أنه توجد فروق ذات داللة
إحصائية في متوسطات عالمات الطلبة في المجموعة التجريبية التي درست وفق االستراتيجية التربوية القائمة
على التعلم المتمازج، والمجموعة الض ،ابطة التي درست وفق الطريقة االعتيادية، ولصالح المجموعة التجريبية
.كما ولم تظهر أية فروق ذات داللة إحصائية تعزى للتفاعل بين الطريقة والجنس (وفي دراسة توسونTosun, 2015
) التي هدفت إلى التعرف على اثر طريقة التعلم المتمازج في تعليم المفردات
وتصورات الطالب( لنهج التعلم المتمازج في تعلم المفردات، حيث تكونت عينة الدراسة من40
) طالباً، وتمثلت
أدوات الدراسة في اختبار معرفي لتقييم معرفة الطلبة بمفردات اللغة االنجليزية، وتم إعطاء إختبار للمفردات
ورقم لكل من المجموعتين، وجاءت نتائج الدراسة بأن التعلم المتمازج لم يح سن من مستوى المفردات لدى
.الطالب على الرغم من رضا الطالب عن هذا النوع من التدريس (أما في الدراسة التي أجراها كل من براين وكليفورد وهيالريBryan, Clifford and Hillary, 2015
)، حيث
هدفت إلى استقصاء تصورات الطالب حول التعلم المتمازج لتدريس المرحلة الثانوية لمادة علوم األر ض والفضاء
( في والية كوينزالند في استراليا، ولتحقيق أهداف الدراسة فقد استخدم الباحثون استبانةWEBLEI
) كأداة لجمع
البيانات، واعتمد الباحثون على المنهج الوصفي لإلجابة عن اسئلة االستبانة، وقد استهدفت الدراسة طلبة 35
جميع الحقوق محفوظة لمجلة
الشرق األوسط للعلوم اإلنسانية
والثقا
ية ف ألمجلد1
. .ثانياً: نموذج التعلم الذي يقوده االتجاه العدد3
. 0201 .ثانياً: نموذج التعلم الذي يقوده االتجاه العدد3
. ألمجلد1
. العدد3
.
0201 أثر إستخدام التعلم المتمازج على تحصيل طالب الصف العاشر األساسي في مادة التربية المهنية وإتجاهاتهم نحوها أحمد
الشراري و
عيد
الصبحيين المرحلة الثانوية في مدرسة ثانوية
،شمال غرب كوينزالند كعينة لها، طبقت الدراسة على مدار عشرة أسابيع
وخالل هذه الفترة درس الطالب وحدة عن األرض وعلوم الفضاء من المنهاج األسترالي من خالل استخدام
استراتيجية التعلم المتمازج، وخلصت نتائج الدراسة إلى أن تصورات الطلبة عن استراتيجية التعلم المتمازج ك انت
.ايجابية، وعليه فقد تم التوصية باستخدام التعلم المتمازج في تعليم وتدريس العلوم ( وفي دراسة أجراها كل من يابكي اكباينYapici & Akbayin, 2012
) التي و هدفت إلى معرفة ثر ا التعلم
المتمازج على تحصيل الطالب في مادة البيولوجي وموقفهم تجاه
،االنترنت وتكونت عينة الدراس
ة
( من112
)
طالباً، ولتحقيق أهداف الدراسة
إ
ستخدم الباحث مقياس
،لالتجاهات واختبار للتحصيل. أظهرت النتائج أن التعلم
المتمازج ساهم بشكل كبير في تحصيل الطالب مقارنة بالطريقة االعتيادية في الت
علم، وأن اتج
اهاتهم كانت
ا
يجابية ودالة
ًإحصائيا نحو موقفهم نم االنترنت. :التعقيب على الدراسات السابقة :التعقيب على الدراسات السابقة ،تناولت الدراسات السابقة متغير التعلم المتمازج ومن ثم بحثت فيه مع عدد من المتغيرات األخرى والمتنوعة
وكان ذلك من خالل تقصي فاعلية التعلم المتمازج في التحصيل مثل دراسة(يغمورYaghmour, 2016
)
،
والتعرف على آثار التع لم المتمازج على طلبة التعليم العالي كما ورد في در اسة كيبولمانغ و
موق وي
(
Kebualemang and Mogwe, 2017
)
، وبحثت دراسة(المساعدة2018
)ف ي التعرف على اثر استخدام
استراتيجية التعلم المتمازج في تحصيل طلبة الصف الثامن األساسي، أما دراسة كل من براين و كليفورد
وهيالري(
Bryan, Clifford and Hillary, 2015) ف نجد أنها تتفق مع الدراسة الحالية من حيث العينة
،المستهدفة كما وتتفق ال دراسة الحالية مع دراسة أبو( لوم2020
)
فقد بحثت في
استراتيجية التعلم المتمازج
واستقصاء أثرها
في تنمية المفاهيم الرياضية لدى طلبة الصف الثالث األساسي في
األردن، كم ا وتتفق الدراسة
( الحالية مع دراسة مصطفى0802
)
،حيث أنها ولغايات تحقيق أهداف الدراسة قد إستخدمت نفس األدوات
(كما وتتفق الدراسة الحالية مع دراسة شفيق0802
)
؛ ودراسة( يابكي اكباينYapici & Akbayin, 2012
)
م ن حيث الهدف، فقد تم تسليط الضوء على تأثير إستر ،اتيجية التعلم المتمازج في التحصيل و في هذا الصدد
( نجد أن دراسة توسونTosun, 2015
) التي تهدف إلى التعرف على اثر طريقة التعلم المتمازج في تعليم
،المفردات وتصورات الطلبة، وهو ما يتفق مع الدراسة الحالية من حيث الهدف وقد أفاد الباحث من الدراس ات
السابقة في تأصيل
اإلطار النظري الخاص بالدراسة الحالية، باإلضافة إلى اإلستفادة من الطرق واإلجراءات 36 36
جميع الحقوق محفوظة لمجلة
الشرق األوسط للعلوم اإلنسانية
والثقا
ية ف ألمجلد1
. العدد3
. 0201 جميع الحقوق محفوظة لمجلة
الشرق األوسط للعلوم اإلنسانية
والثقا
ية ف أثر إستخدام التعلم المتمازج على تحصيل طالب الصف العاشر األساسي في مادة التربية المهنية وإتجاهاتهم نحوها أحمد
الشراري و
عيد
الصبحيين المتبعة وتحديداً في بناء أدوات الدراسة وتحديد الم ،عالجات اإلحصائية وتفسير النتائج
إال أن الد راسة الحالية
(لم تتفق مع دراسة شاهين0808
)
.من حيث العينة المستهدفة وتتميز الدر اسة الحالية عن الدراسات السابقة في تسليط الضوء للنظر في أثر التعلم المتمازج على تحصيل
الطلبة في مادة التربية المهنية والتعرف على إتجاهاتهم نحوها، حيث أنه لم يتم تناولها في أي من الدراسات
السابقة من باب أنها قد توجهت إلى البحث في هذه االستراتيجية وتقصي أثره ا على عدد من المواد و المقررات
الدراسية األخرى، باإلضافة إلى ما يتميز به منهاج التربية المهنة من األهمية في بناء شخصية الطلبة وتنمية
.مهاراتهم التي تساعدهم على التعرف على المهن والمهارات العملية التي يجب تعلمها مشكلة الدراسة وأسئلتها: مشكلة الدراسة وأسئلتها: يحتوي منهاج التربية
المهنية العديد من المهارات الحياتية وفي مجاالت متنوعة من الحياة، إال أن عملية تنفيذ
هذا المنهاج تواجه العديد من الصعوبات في المدارس، كضعف اهتمام المعلم والمدرسة والمتعلمين لهذا ا
لمنهاج المنهاج ومقاومتهم لهُ، مما يشكل عائقاً كبيراً أمام تحقيق المنهاج لألهد.اف التي وضع من أجلها و تهدف
التربية المهنية إلى تحقيق نمو شامل متوازن في حياة المتعلم من كل الجوانب، ولتحقيق هذا الهدف كان من
،الواجب استخدام األساليب التدريسية الفعالة والحديثة والبعيدة عن تلك األساليب االعتيادية والمتعارف عليها
حيث أنه ومن المتعارف ع
ليه أن عملية تدريس التربية المهنية لم تقتصر على أساليب الحفظ والتلقين بل تعتمد
على التطبيق والممارسة من قبل الطلبة لتحقيق األهداف التي وضع من أجلها منهاج التربية المهنية، وهذا ما
تفتقر له مدارسنا في الوقت الراهن، فضعف المواد واإلمكانات تلزم المعلم إلى اتبا
ع األسلوب االعت يادي المعتمد
(على التلقين دون إكساب الطلبة أي مهارة عملية
أ ،بو شعيرة2006
.) ومن المعلوم أن التنوع في األساليب التدريسية داخل الغرفة الصفية بات ضرورة البد منها، لما لها من دور
في خلق الجو التنافسي في التحصيل واالرتقاء بجودة التعلم في ظل م
واكبة التطور الرقمي الذي نش هده في
ايامنا هذه في مجال التعلم، ويعتمد نجاح الجهود التدريسية في الغرفة الصفية على القدرة والكفاءة التي يمتلكها
المعلمين المكلفين بتدريس المواد بحسب االستراتيجيات واألساليب التدريسية الحديثة، فالتدريس المعتمد على
األساليب واالست راتيجيات الحديثة أصبح مهماً لقياس العملية التدريسية والتنافس بين المعلمين في إدخال هذه
التقنية ضمن تدريسهم وهو ما أدى إلى نقلة نوعية في استراتيجيات التدريس، ومن هنا تولدت الفكرة لدى 37 37
جميع الحقوق محفوظة لمجلة
الشرق األوسط للعلوم اإلنسانية
والثقا
ية ف ألمجلد1
. العدد3
. مشكلة الدراسة وأسئلتها: 0201 37
جميع الحقوق محفوظة لمجلة
الشرق األوسط للعلوم اإلنسانية
والثقا
ية ف أثر إستخدام التعلم المتمازج على تحصيل طالب الصف العاشر األساسي في مادة التربية المهنية وإتجاهاتهم نحوها أحمد
الشراري و
عيد
الصبحيين الباحث في مشكلة الدراسة الحالية والتي تسعى إلى معرفة أثر استخدام التعلم ال
متمازج على تحصي ل طالب
الصف العاشر األساسي في مادة التربية المهنية واتجاهاتهم نحوها، ولذلك تسعى الدراسة إلى اإلجابة عن
:األسئلة اآلتية الباحث في مشكلة الدراسة الحالية والتي تسعى إلى معرفة أثر استخدام التعلم ال
متمازج على تحصي ل طالب
الصف العاشر األساسي في مادة التربية المهنية واتجاهاتهم نحوها، ولذلك تسعى الدراسة إلى اإلجابة عن
:األسئلة اآلتية 0
-
( هل هناك فروق ذات داللة إحصائية عند مستوى داللةα≤0.05) بين متوسط ات تحصيل طلبة
الصف العاشر األساسي
في مادة التربية المهنية
تعزى
إلى طريقة التعلم، والجنس، والتفاعل ب
ينهما
؟
0
-
( هل هناك فروق ذات داللة إحصائية عند مستوى داللةα≤0.05
)في
متوسطات اتجاهات طلبة
الصف العاشر األساسي
نحو مادة التربية المهنية
تعزى إلى طريقة التعلم
والجنس والتفا
عل بينهما
؟
: الدراسة :أهمية الدراسة تكمن االهمية النظ رية للدراسة في التنوع
ب
االساليب واالستراتيجيات التدريسية المستخدمة في الغرفة الصف ،ية
وما تتيحه هذه االستراتيجيات من مزايا تعمل على المساعدة في تفعيل التعلم وزيادة مستوى التحصيل الدراسي
وتحسين مخرجاته على اعتباره من األ
ساليب التدريسية الحديثة في الع
مل
ية الت،عليمية التعلمية
وتحديداً لدى
المعلمين والمشرفين ومن يقومون على وضع
.المناهج الدراسية وتتجلى االهمية التطبيقية في
إمكانية العمل على بناء الخطط الدراسية لمادة التربية المهنية وتقديمها للطلبة
بما يسهم في تحقيق أفضل مستوى من الناحية األكاديمية وإمكانية نش
ر التعلم المتمازج في المدارس كم ا
وستساعد النتائج التي تم التوصل لها بتزويد وزارة التربية والتعليم والعاملين بها، من خالل تسليط الضوء على
دور التعلم المتمازج في زيادة تحصيل الطلبة، والتعرف على توجهاتهم نحو مادة التربية المهنية وخلق البيئة
،العلمية المناسبة وتعمل الدراسة على فتح آفاق أمام العديد من الباحثين لعمل دراسات جديدة في العديد من
.البيئات التدريسية المختلفة وعلى مجتمعات وعينات متنوعة :أهداف الدراسة :تهدف الدراسة إلى تحقيق ما يلي :تهدف الدراسة إلى تحقيق ما يلي 0
-
التحقق فيما اذا كان هناك فروقات بين طلبة الصف العاشر األساسي في مادة التر
بية ا لمهنية
في
مستويات التحصيل تعزى)إلى طريقة التعلم (التعلم المتمازج، االعتيادي . ألمجلد1
. العدد3
. 0201 ألمجلد1
. العدد3
. 0201 أثر إستخدام التعلم المتمازج على تحصيل طالب الصف العاشر األساسي في مادة التربية المهنية وإتجاهاتهم نحوها أحمد
الشراري و
عيد
الصبحيين 0
-
الكشف عن الفروقات بين طلبة الصف العاشر األساسي
في مادة التربية المهنية في مس تويات
التحصيل تعزى
إلى
.متغير الجنس
3
-
التعرف على اتجاهات طلبة الصف العاشر األساسي
نحو مادة التربية المهنية ت
بعاً لدى ا لمتغيرات
الديموغرافية. 0
-
الكشف عن الفروقات بين طلبة الصف العاشر األساسي
في مادة التربية المهنية في مس تويات
التحصيل تعزى
إلى
.متغير الجنس
3
-
التعرف على اتجاهات طلبة الصف العاشر األساسي
نحو مادة التربية المهنية ت
بعاً لدى ا لمتغيرات
الديموغرافية. الديموغرافية. :حدود الدراسة :حدود الدراسة
الحدود البشرية: اقتصرت هذه الدراسة على طلبة الصف العاشر األساسي من طلبة المدارس الحكومية التابعة
.لوزارة التربية والتعليم األردنية في محافظة العقبة
الحدود المكانية: المدارس الحكومية التابعة لوزارة ال.تربية والتعليم األردنية في محافظة العقبة
الحدود الزمانية: تم إجراء هذه الدراسة خالل الفصل الدراسي الثاني من العام الدراسي
0808
/
0800 الحدود البشرية: اقتصرت هذه الدراسة على طلبة الصف العاشر األساسي من طلبة المدارس الحكومية التابعة
.لوزارة التربية والتعليم األردنية في محافظة العقبة .لوزارة التربية والتعليم األردنية في محافظة العقبة
الحدود المكانية: المدارس الحكومية التابعة لوزارة ال.تربية والتعليم األردنية في محافظة العقبة
الحدود الزمانية: تم إجراء هذه الدراسة خالل الفصل الدراسي الثاني من العام الدراسي
0808
/
0800
. لحدود المكانية: المدارس الحكومية التابعة لوزارة ال.تربية والتعليم األردنية في محافظة العقبة :مصطلحات الدراسة :ًالتعلم المتمازج اصطالحا
هو التعلم الذي يعتمد على المزج بين األساليب االعتيادية مع التعلم االلكتروني
تسوا ،راتيجيات التدريس الحديثة، حيث تتضمن هذه األساليب مزيجاً من االلقاء المباشر في قاعة المحاضرات
والتواصل عبر االنترنت والتعلم الذاتي(
Tosun, 2015
.) :ًالتعلم المتمازج إجرائيا
هو طريقة حديثة تستخدم المواد والطرق االعتيادية وتكنولوجيا المعلومات بطريقة
،تكاملية وقد اعتمدها الباحث في تدريس م
ادة التربية المهنية باس
ت خدام تكنولوجيا المعلومات و
ا
ستراتيجيات
.التدريس الحديثة، واألساليب االعتيادية :التحصيل
هي الدرجة التي يحصل عليها المتعلمين على االختبار التحصيلي الذي أعده الباحث لتحقيق أهداف
.الدراسة الصف العاشر االساسي:
هو الصف األخير ضمن مرحلة التعليم األساسي في األردن، وتمتد من الصف
األول األساسي وحتى الصف العاشر، الذي يعتبر بمثابة المرحلة التي تساعد الطلبة على تحديد توجهاتهم
االكاديمية أو المهنية بحسب التعليمات المعمول بها في وزارة التربية والتعليم األردن
ية(سبيتان ،
2017
). ألمجلد1
. العدد3
. 0201 39
جميع الحقوق محفوظة لمجلة
الشرق األوسط للعلوم اإلنسانية
والثقا
ية ف أحمد
الشراري و
عيد
الصبحيين :مجتمع وعينة الدراسة تكوَّن مجتمع الدراسة من
جميع طلبة الصف العاشر في
ال مدارس الحكومية في محافظة العقبة
خالل ا لفصل
(الدراسي الثاني من العام الدراسي0808
/
0800
)
( وعددهم2531
) طالباً وطالبة، حيث تكونت عينة الدراسة
( من80
)
طالبا و
طالبة موزعين على اربعة شعب دراسية، شعبتين للذكور وشعبتين لإلناث
من
طل بة الصف
العاشر األساسي، تم توزيعه م
عشوائياً على مجموعتين
.ضابطة وتجريبية أوال: برنامج تدريبي يقوم على استخدام.استراتيجية التعلم المتمازج لتحقيق هدف الدراسة والمتمثل في التعرف على اثر التعلم المتمازج على التحصيل الدراسي لطلبة الصف
،العاشر األساسي في مادة التربية المهنية واتجاهاتهم نحوها تم استخدام محتوى
الوحدة الدراسية األول ى من
الجزء األول من كتاب مادة التربية المهنية لطلبة الصف العاشر األس(اسي للعام الدراسي0808
/
0800
)
كمادة
تعليمية حيث ت
أ(لف البرنامج التدريبي من9
) حص
ص
،تعليمية تعلمية
( وبلغ زمن الحصة30
) دقيقة
حسب
الخطوات المنهجية
:اآلتية 0
. ي حد ت د المادة العلمية المتمثلة في
الوحدة األولى (حاالت مرضية) من الجزء األول من كتاب التربية المهنية
حيث ت ضمنت
الدروس اآلتية الموضحة في
جدول(
0
:)
ل جدو (
0
): الدروس التي درّست للمجموع
تين التجريبية والضابطة
الرقم الدرس العنوان
رقم الصفحة الجزء
0
الدرس األول
مرض السكري
7
-
00
الجزء األول
0
الدرس الثاني ضغط الدم
02
-
02
الجزء األول
3
الدرس الثالث
االضطراب التشنجي
38
-
37
الجزء األول 0
. ي حد ت د المادة العلمية المتمثلة في
الوحدة األولى (حاالت مرضية) من الجزء األول من كتاب التربية المهنية
حيث ت ضمنت
الدروس اآلتية الموضحة في
جدول(
0
:) ل جدو (
0
): الدروس التي درّست للمجموع
تين التجريبية والضابطة
الرقم الدرس العنوان
رقم الصفحة الجزء
0
الدرس األول
مرض السكري
7
-
00
الجزء األول
0
الدرس الثاني ضغط الدم
02
-
02
الجزء األول
3
الدرس الثالث
االضطراب التشنجي
38
-
37
الجزء األول 2
. صياغة
األهداف
السلوكية الالزمة للموضوعات المحددة في
الدروس
المستخدمة في البرنامج
التدري
بي
لتال
ئ
م هدف ال
دراسة
.والمرحلة الدراسية ألمجلد1
. العدد3
. 0201 أحمد
الشراري و
عيد
الصبحيين 3
. :مجتمع وعينة الدراسة اد عد إ نماذج من الخطط الدراسية اليومية ال
تي تدرس به
ا المجموع
تين
التجريبية والضابطة ًبناء
على محتوى
ال
وحدة الدراسية والدروس لتحقيق أهداف الدراسة قام الباحث ببناء اختبار تحصيلي بعد تحليل محتوى للمادة التعليمية، وجدول م واصفات
ل،بناء اختبار تحصيلي وهو من نوع اختيار من متعدد
( حيث يتم تصحيحه بإعطاء درجة واحدة0
) لإلجابة
الصحيحة، وصفر(
8
) لإلجابة الخاطئة، وقد تم تصميمه لقياس
أ ثر
استراتيجة التعلم المتمازج على التحصي ل
الدراسي
لطلبة الصف العاشر األساسي ،
تم التحقق من ثبات االختبار
باستخدام معادلة كيودر ريتشاردس ون
(
00
KR
)
،والتجزئة النصفية
للتحقق من دالالت صدق االتساق الداخلي، حيث تم تطبيق اال
ختبار
على عينة
الدراسة االستطالعية من مجتمع الدراسة وخارج عينتها بلغ
حجمها (
08
)طالبا وطالبة ،
وقد بلغ معامل
ال ثبات
( المحسوب بهذه الطريقة8.000
). ( الجدول0
):
معامالت السهولة والصعوبة والتمييز لفقرات
االختبار التحصيلي
الفقرة
معامل
الصعوبة
معامل
السهولة
معام
ل التمييز الفقرة
معامل
الصعوبة
معامل
السهولة
معامل التمييز
1
0.93
8.87
0.50**
11
0.68
8.30
0.49**
2
0.80
8.08
0.44**
12
0.75
8.00
0.37*
3
0.63
8.37
0.41**
13
0.85
8.00
0.49**
4
0.65
8.30
0.62**
14
0.65
8.30
0.80**
5
0.60
8.08
0.51**
15
0.75
8.00
0.38*
6
0.53
8.07
0.56**
16
0.68
8.30
0.44**
7
0.65
8.30
0.43**
17
0.75
8.00
0.54**
8
0.68
8.30
0.39*
18
0.75
8.00
0.66**
9
0.93
8.87
0.38*
19
0.83
8.07
0.50**
11
0.60
8.08
0.52**
21
0.70
8.38
0.59**
ة احصائيا عند مستوى الداللة(α≤0.05)
. ا ( الجدول0
):
معامالت السهولة والصعوبة والتمييز لفقرات
االختبار التحصيلي ( الجدول0
):
معامالت السهولة والصعوبة والتمييز لفقرات
االختبار التحصيلي *دالة احصائيا عند مستوى الداللة(α≤0.05)
. ا
** دالة احصائ يا عند مستوى الداللة(α≤0.01)
. 41
جميع الحقوق محفوظة لمجلة
الشرق األوسط للعلوم اإلنسانية
والثقا
ية ف
ألمجلد1
. العدد3
. 0201
(يتضح من الجدول0
) بان معامالت السهولة تراوحت ما(بين8.87
-
8.07
) وتراوحت معامالت الصعوبة ما
(بين8.23
-
8.03) وتراوحت معامالت التميز(0.80-0.38)
وجميعها دالة احصائياً عند مستوى الداللة 41
جميع الحقوق محفوظة لمجلة
الشرق األوسط للعلو اإلنسانية
والثقا
ية ف
لد
أل1ال دد3
0201
(يتضح من الجدول0
) بان معامالت السهولة تراوحت ما(بين8.87
-
8.07
) وتراوحت معامالت الصعوبة ما
(بين8.23
-
8.03) وتراوحت معامالت التميز(0.80-0.38)
وجميعها دالة احصائياً عند مستوى الداللة 41
جميع الحقوق محفوظة لمجلة
الشرق األوسط للعلوم اإلنسانية
والثقا
ية ف
ألمجلد1
. العدد3
. ا
ستوى الداللة(α≤0.01)
. :مجتمع وعينة الدراسة 0201
(يتضح من الجدول0
) بان معامالت السهولة تراوحت ما(بين8.87
-
8.07
) وتراوحت معامالت الصعوبة ما
(بين8.23
-
8.03) وتراوحت معامالت التميز(0.80-0.38)
وجميعها دالة احصائياً عند مستوى الداللة (يتضح من الجدول0
) بان معامالت السهولة تراوحت ما(بين8.87
-
8.07
) وتراوحت معامالت الصعوبة ما
(بين8.23
-
8.03) وتراوحت معامالت التميز(0.80-0.38)
وجميعها دالة احصائياً عند مستوى الداللة ألمجلد1
. العدد3
. 0201 أثر إستخدام التعلم المتمازج على تحصيل طالب الصف العاشر األساسي في مادة التربية المهنية وإتجاهاتهم نحوها أحمد
الشراري و
عيد
الصبحيين (α≤0.05)
،
وهي مناسبة إلجراء االختبار لهذه
الفئة العمرية، مما يدل على مناسبة الفقرات إلجراء االختبار
وقد تم اعتمادها جميعا
(حيث كانت معامالت التميز اكبر من8.38
). ثالثاً: مقياس اإلتجاهات لقياس االتجاهات لدى طلبة الصف العاشر األساسي نحو مادة التربية المهنية فقد تم تطوير مقياس، بعد
مراجعة األدب ا لنظري في مجال االتجاهات لدى الطلبة و الدراسات السابقة التي طورت مقاييس لالتجاهات
لدى عينات مماثلة لعينة الدراسة الحالية
كدراسة
،(النسور2011)؛ دراسة
،(الطراونة2013
)؛
ودراسة(ال
مساعد
ة ،
2018
)
،وقد اختار الباحث اربعة مجاالت تحدد االتجاهات العلمية لطلبة الصف الع
ر اش
األساسي نحو مادة التربية المهنية وعلى النحو اآلتي: المجال األول لقياس اتجاهات الطلبة نحو حب االست طالع
في مادة التربية المهنية، والمجال الثاني يقيس اتجاهات الطلبة نحو طريقة تدريس مادة التربية المهنية،
واالتجاه
الثالث يقيس اتجاهات الطلبة نحو صعوبات تدريس مادة التربية المهنية، والمجال الرابع يقيس اتجاه
ات
الطلبة
( نحو أهمية مادة التربية المهنية، وقد تكون المقياس بصورته األولية من33) فقرة ،
و تم التحقق من ثبات مقياس
االتجاهات العلمية لدى طلبة الصف العاشر االساسي
نحو مادة
التربية المهنية بطريقتين: األولى باس
تخد ام
معامل كرونباخ ألفا للتجانس الداخلي، والتجزئة النصفية وفقا لمعامل ثبات سبيرمان
-
براون، و ذلك من خالل
تطبيق المقياس على عينة استطالعية بلغ
حجمها (
40
ً) طالبا
وطالبة ،
( والجدول3
:) يبين معامالت االرتباط ( جدول3
):
معامل ارتباط بيرسون(Pearson coefficients)
للت حقق من صدق مقياس االتجاهات العلمية في مادة التربية
المهنية ( جدول3
):
معامل ارتباط بيرسون(Pearson coefficients)
للت حقق من صدق مقياس االتجاهات العلمية في مادة التربية
المهنية ( جدول3
):
معامل ارتباط بيرسون(Pearson coefficients)
للت حقق من صدق مقياس االتجاهات العلمية في مادة التربية
المهنية
رقم الفقرة ارتباط الفقرة مع المجال ارتباط الفقرة بالدرجة الكلية
المجال األول: حب االستطالع
0
8.020
**
8.700
**
0
8.700
**
8.070
**
3
8.720
**
8.707
**
0
8.007
**
8.078
**
0
8.003
**
8.700
**
0
8.080
**
8.073
**
7
8.080
**
8.080
**
0
8.770
**
8.703
**
2
8.000
**
8.702
** 42 ألمجلد1
. العدد3
. :تصميم الدراسة اعتمدت الدراسة على المنهج شبه التجريبي، والذي يستخدم العينات العشوائية في اختيار مفردات التجربة قبل
تقسيمها إلى مجموعات، كما تم توزيع مفردات
ها بشكل عشوائي بين المجموع
ات التجريبية الض و ابطة، اذ اختار
الباحث
م ًجموعة تجريبية خضعت للتدريب وفقا
لبرنامج يستند الى
التعلم المتمازج
، في حين خض عت المجموعة
.الضابطة للتدريب وفقا للطريقة االعتيادية وهو المنهج المناسب لهذه الدراسة ثالثاً: مقياس اإلتجاهات 0201 جميع الحقوق محفوظة لمجلة
الشرق األوسط للعلوم اإلنسانية
والثقا
ية ف أثر إستخدام التعلم المتمازج على تحصيل طالب الصف العاشر األساسي في مادة التربية المهنية وإتجاهاتهم نحوها أحمد
الشراري و
عيد
الصبحيين 08
8.000
**
8.730
**
المجال الثاني: طريقة التدريس
00
8.020
**
8.000
**
00
8.700
**
8.003
**
03
8.702
**
8.020
**
00
8.000
**
8.020
**
00
8.703
**
8.782
**
00
8.020
**
8.000
**
07
8.000
**
8.000
**
00
8.700
**
8.070
**
02
8.000
**
8.330
*
08
8.730
**
8.000
**
المجال الثالث: صعوبات تدريس التربية المهنية
00
8.728
**
8.073
**
00
8.730
**
8.700
**
03
8.000
**
8.002
**
00
8.770
**
8.700
**
00
8.700
**
8.003
**
00
8.080
**
8.027
**
07
8.002
**
8.030
**
00
8.780
**
8.700
**
:المجال الرابع األهمية. 02
8.080
**
8.700
**
38
8.200
**
8.032
**
30
8.000
**
8.000
**
30
8.087
**
8.700
**
33
8.700
**
8.770
**
(مستوى الداللة .(α≤0.05
ال اللة(
0 01) 8.730
** 08 (*دالة إحصائيا عند مستوى الداللة .(α≤0.05 ا
** دالة إحصائيا عند مستوى الداللة(α≤0.01)
. ** دالة إحصائيا عند مستوى الداللة(α≤0.01)
. (تظهر نتائج الجدول3) أن معامالت ا
رتباط
(Pearson coefficients)
بين الفقرات ومجاالتها تراوحت
(بين0.454-0.894
) وجميعها دالة إحصائيا عند مستوى الداللة(α≤0.05)
، وقد تراوحت معامالت االرتباط (تظهر نتائج الجدول3) أن معامالت ا
رتباط
(Pearson coefficients)
بين الفقرات ومجاالتها تراوحت
(بين0.454-0.894
) وجميعها دالة إحصائيا عند مستوى الداللة(α≤0.05)
، وقد تراوحت معامالت االرتباط ألمجلد1
. العدد3
. 0201 ألمجلد1
. العدد3
. 0201 جميع الحقوق محفوظة لمجلة
الشرق األوسط للعلوم اإلنسانية
والثقا
ية ف أحمد
الشراري و
عيد
الصبحيين (بين الفقرة والدرجة الكلية0.338-0.873
) وهي دالة عند مستوى الداللة(α≤0.05)
وتراوحت معامالت
،االرتباط وهذ.ا يشير إلى صدق البناء للمقياس :إجراءات الدراسة :لغايات تطبيق الدراسة تم إتباع اإلجراءات اآلتية 0
. االطالع على اثر استخدام استرا
تيجة التعلم المتمازج ف
ب
ي تحسين التحصيل واالتجاهات من خالل م ا
.كتب عنها من إطار نظري ودراسات سابقة 0
. اختيار الوحدة الدراسية كبرنامج تدريبي والتي من خاللها يتم قياس التحصيل و
ا
التجاهات
لدى أفراد
.)العينة المستهدفة في التجربة (المادة التعليمية 0
. اختيار الوحدة الدراسية كبرنامج تدريبي والتي من خاللها يتم قياس التحصيل و
ا
التجاهات
لدى أفراد
.)العينة المستهدفة في التجربة (المادة التعليمية
3
.التأكد من صدق محتو.ى المادة التعليمية (الوحدة الدراسية) بعرضها على مجموعة من المحكمين .)العينة المستهدفة في التجربة (المادة التعليمية
3
. التأكد من صدق محتو.ى المادة التعليمية (الوحدة الدراسية) بعرضها على مجموعة من المحكمين
0
. .بناء اختبار لقياس التحصيل لدى طلبة الصف العاشر األساسي
0
. .تطوير استبانة لقياس االتجاهات نحو مادة التربية المهنية 3
. التأكد من صدق محتو
ى المادة التعليمية (الوحدة الدراسية) بعرضها على مجموعة من
0
. .بناء اختبار لقياس التحصيل لدى طلبة الصف العاشر األساسي 0
. .تطوير استبانة لقياس االتجاهات نحو مادة التربية المهنية 0
. الحصول على الموافقات الرسمية من جامعة الحسين بن طالل، ومديرية التربية والتعل
يم لقص بة العقبة؛
لتطبيق الدراسة في مدرسة عبدالله بن قيس الحارثي االساسية للبنين ومدرسة ذات الصواري ال ثانوية
.للبنات 0
. الحصول على الموافقات الرسمية من جامعة الحسين بن طالل، ومديرية التربية والتعل
يم لقص بة العقبة؛
لتطبيق الدراسة في مدرسة عبدالله بن قيس الحارثي االساسية للبنين ومدرسة ذات الصواري ال ثانوية
.للبنات 0
. الحصول على الموافقات الرسمية من جامعة الحسين بن طالل، ومديرية التربية والتعل
يم لقص بة العقبة؛
لتطبيق الدراسة في مدرسة عبدالله بن قيس الحارثي االساسية للبنين ومدرسة ذات الصواري ال ثانوية
.للبنات 7
. التحقق من صدق وثبات اختبار التحصيل ومقياس االتجاهات بتطبيقه على عينة استطالعية من
( مجتمع الدراسة وخارج عينتها بلغ حجمها40
.) طالب وطالبة
0
. تم ًاختيار المدرسة بطريقة قصدية؛ وتوزيع أفراد العينة عشوائيا على المجموعتين التجريبي ة والضابطة
.وتطبيق االختبار القبلي عليها 7
. التحقق من صدق وثبات اختبار التحصيل ومقياس االتجاهات بتطبيقه على عينة استطالعية من
( مجتمع الدراسة وخارج عينتها بلغ حجمها40
.) طالب وطالبة
0تًاختيار المدرسة بطريقة قصدية؛ وتوزيع أفراد العينة عشوائيا
المجموعتين التجريبي
عل
ة والضابطة 44
جميع الحقوق محفوظة لمجلة
الشرق األوسط للعلوم اإلنسانية
والثقا
ية ف ألمجلد1
. العدد3
. 0201 ألمجلد1
. العدد3
. :إجراءات الدراسة 0201 أثر إستخدام التعلم المتمازج على تحصيل طالب الصف العاشر األساسي في مادة التربية المهنية وإتجاهاتهم نحوها أحمد
الشراري و
عيد
الصبحيين 2
. قام الباحث بتدريس المجموعة التجريبية بطريقة استراتيجة التعلم المتمازج، وايضا المجموعة الضابطة
بالطريقة االعتيادية، إلضفاء درجة من الدق ة والموضوعية على نتائج الدراسة، ألن وجود معلم غير
الباحث يزيد من صعوبة رد النتائج إلى المتغير المستقل، كما أن الصفات الشخصية أو الرغبة في
.التدريس والعالقة بين المعلم والطالب قد يؤثر في دقة وموضوعية النتائج 2
. قام الباحث بتدريس المجموعة التجريبية بطريقة استراتيجة التعلم المتمازج، وايضا المجموعة الضابطة
بالطريقة االعتيادية، إلضفاء درجة من الدق ة والموضوعية على نتائج الدراسة، ألن وجود معلم غير
الباحث يزيد من صعوبة رد النتائج إلى المتغير المستقل، كما أن الصفات الشخصية أو الرغبة في
.التدريس والعالقة بين المعلم والطالب قد يؤثر في دقة وموضوعية النتائج :المعالجات اإلحصائية 0201 أثر إستخدام التعلم المتمازج على تحصيل طالب الصف العاشر األساسي في مادة التربية المهنية وإتجاهاتهم نحوها أحمد
الشراري و
عيد
الصبحيين ( جدول0
): المتوسطات الحسابية واالنحرافات المعيارية ل
لمجموعتين التجريب
ي ة والضابطة على االختبار البعدي و فقاً لطريقة
التعلم والجنس
المتغير مستويات المتغير العدد
المتوسط
الحسابي
االنحراف المعياري
طريقة التعلم
التعلم المتمازج
08
00.23
3.007
التعلم االعتيادي
08
00.88
3.080
الجنس
ذكور
08
00.28
3.800
اناث
08
00.83
3.200 ( جدول0
): المتوسطات الحسابية واالنحرافات المعيارية ل
لمجموعتين التجريب
ي ة والضابطة على االختبار البعدي و فقاً لطريقة
التعلم والجنس ( جدول0
): المتوسطات الحسابية واالنحرافات المعيارية ل
لمجموعتين التجريب
ي ة والضابطة على االختبار البعدي و فقاً لطريقة
التعلم والجنس ُت( ظهر نتائج الجدول0
) وجود فروقا ً ظاهرة بين متوسطات أداء المجموعتين التجريبية التي درست بالتعلم
المتمازج، والمجموعة الضابطة التي درست بالتعلم االعتيادي على االختبار البعدي، لمادة التربية المهنية تعزى
لطريقة التعلم (التعلم المتمازج، واالع
تيادي)، كما تظهر النتائج الواردة في نفس الجدول وجود فروق ظاهرة ب
ي ن
،متوسطات اداء الذكور واالناث على االختبار البعدي، ولبيان فيما اذا كانت الفروق حقيقة وذات داللة احصائية
فقد تم تطبيق اختبار تحليل التباين المصاحب(2way-Ancova- analysis)
،متعدد االتجاهات
وال(جدول0
:) يعرض النتائج جدول(
0
):
نتائج تحليل التباين المصاحب(Ancova- Analysis)
لبيان داللة الفروق بين متوسطات أداء
المجموعتين (التجريبية والضابطة) على االختبار البعدي
مصدر التباين مجموع المربعات درجات الحرية
متوسط
المربعات
قيمة(f)
الداللة اإلحصائية
اال
ختبار القبلي
0.080
1
0.080
0.006
0.937
طريقة التعلم
16.964
1
16.964
1.332
0.252
الجنس
15.391
1
15.391
1.208
0.275
طريقة التعلم*الجنس
0.147
1
0.147
0.012
0.915
الخطأ
955.270
75
12.737
الكلي
22669.000
80
الكلي المصحح
987.887
79
* دالة إحصائيا عند مست وى الداللة(α≤0.05)
. جدول(
0
):
نتائج تحليل التباين المصاحب(Ancova- Analysis)
لبيان داللة الفروق بين متوسطات أداء
المجموعتين (التجريبية والضابطة) على االختبار البعدي * دالة إحصائيا عند مست وى الداللة(α≤0.05)
. 46
جميع الحقوق محفوظة لمجلة
الشرق األوسط للعلوم اإلنسانية
والثقا
ية ف
ألمجلد1
. العدد3
. 0201
( تظهر نتائج الجدول0
)
عدم و جود فروق دالة إحصائيا بين متوسطات أداء افراد
المجموعتين التجريبية والضابط ة
على االختبار البعدي ،لمادة التربية المهنية تعزى لطريقة التعلم اعتمادا على قيمة(f)
البالغة(1.332)
عند
مستوى داللة(α=0.252)
وهي غير دالة إحصائيا عند مستوى الداللة(α≤0.05)
. :المعالجات اإلحصائية الستخراج النتائج تم استخدام المعالجات:االحصائية اآلتية الستخراج النتائج تم استخدام المعالجات:االحصائية اآلتية 0
. معامل ارتباط بيرسون(Pearson coefficients)
للتحقق من صدق مقياس االتجاهات العلمية في
مادة التربية ال
مهنية. 0
. معامل السهولة والصعوبة والتمييز للتحقق من القدرة التمييزية لالختبار التحصيلي. 3
. معادلة كيودر-
( ريتشاردسون00
KR
)ل
لتحقق من ثبا
ال ت ا ختبار
التحصيلي وثبات مقياس االتجاهات. 0
. معامل سبيرمان-
براون(spearman-Brown Coefficient)
للتحقق من ثبات االختبار التحصيلي
.ومقياس االتجاهات 0
. معامل ارتباط بيرسون(Pearson coefficients)
للتحقق من صدق مقياس االتجاهات العلمية في
مادة التربية ال
مهنية. 0
. معامل ارتباط بيرسون(Pearson coefficients)
للتحقق من صدق مقياس االتجاهات العلمية في
مادة التربية ال
مهنية. 0
. معامل السهولة والصعوبة والتمييز للتحقق من القدرة التمييزية لالختبار التحصيلي. 3
. معادلة كيودر-
( ريتشاردسون00
KR
)ل
لتحقق من ثبا
ال ت ا ختبار
التحصيلي وثبات مقياس االتجاهات. 0
. معامل سبيرمان-
براون(spearman-Brown Coefficient)
للتحقق من ثبات االختبار التحصيلي
.ومقياس االتجاهات 0
. ا( ختبارT
)
(
(t-test for independent sampled
إليجاد التكافؤ بين.المجموعات
0
. اختبار تحليل التباين المصاحب(ANCOVA)
ع لى اعتبار
أن االختبار القبلي متغير الضبط ولتحيي د
أثره على االختبار البعدي
.لإلجابة على سؤال الدراسة األول
قش
ة
ل تمت اإلجابة عن سؤال الدراسة الرئيس والذي ينص على :
ما اثر استخدام التعلم المتمازج على تحصيل طالب
الصف العاشر األساسي في ما
دة التربية المهنية واتجاهاتهم نحوها ؟ من خالل
اال
جابة عن األسئلة اآلتي ،ة سؤال
:الدراسة األول "
( هل هناك فروق ذات داللة إحصائية عند مستوى داللةα≤0.05
)
في تحصيل طلبة الصف
العاشر األساسي
في مادة التربية المهنية
تعزى
إلى طريقة التعلم، والجنس، والتفاعل بينهما
؟ و لإلجابة عن هذا
السؤال ولضبط
أ
ثر االختبار القبلي ولتح
ي
يد أثره،
فقد
تم استخدام تحليل التباين المصاحب(Ancova-
analysis)
على اعتبار أن درجات الطلبة( على االختبار القبلي (متغير الضبط) والجدول0
)ي:وضح النتائج 45 45
جميع الحقوق محفوظة لمجلة
الشرق األوسط للعلوم اإلنسانية
والثقا
ية ف ألمجلد1
. العدد3
. :المعالجات اإلحصائية كما اظهرت نتائج نفس ( تظهر نتائج الجدول0
)
عدم و جود فروق دالة إحصائيا بين متوسطات أداء افراد
المجموعتين التجريبية والضابط ة
على االختبار البعدي ،لمادة التربية المهنية تعزى لطريقة التعلم اعتمادا على قيمة(f)
البالغة(1.332)
عند
مستوى داللة(α=0.252)
وهي غير دالة إحصائيا عند مستوى الداللة(α≤0.05)
. كما اظهرت نتائج نفس 46
جميع الحقوق محفوظة لمجلة
الشرق األوسط للعلوم اإلنسانية
والثقا
ية ف ألمجلد1
. العدد3
. 0201 ألمجلد1
. العدد3
. 0201 أثر إستخدام التعلم المتمازج على تحصيل طالب الصف العاشر األساسي في مادة التربية المهنية وإتجاهاتهم نحوها أحمد
الشراري و
عيد
الصبحيين الجدول عدم جود فروق دالة إحصائيا بين متوسطات أداء افراد المجموعتين التجريبية والضابطة على االختبار
البعدي ،لمادة التربية المهنية تعزى للجنس ًاعتمادا
على قيمة(f)
البالغة(1.208)
عند مستوى دال لة(α=0.275)
وهي غير دالة إحصائيا عند مستوى الداللة(α≤0.05)
، وايضا عدم وجود فروق بينها يعزى للتفاعل بين طريقة
التعلم والجنس اعتمادا على قيمة(f)
( البالغة8.800
) عند مستوى داللة(0.915)
. الجدول عدم جود فروق دالة إحصائيا بين متوسطات أداء افراد المجموعتين التجريبية والضابطة على االختبار
البعدي ،لمادة التربية المهنية تعزى للجنس ًاعتمادا
على قيمة(f)
البالغة(1.208)
عند مستوى دال لة(α=0.275)
وهي غير دالة إحصائيا عند مستوى الداللة(α≤0.05)
، وايضا عدم وجود فروق بينها يعزى للتفاعل بين طريقة
التعلم والجنس اعتمادا على قيمة(f)
( البالغة8.800
) عند مستوى داللة(0.915)
. ومن التفسيرات المحتملة لهذه النتيجة ايضا ان مستوى االهتمام بمادة
التربية المهنية من قبل افراد العي نة متقارب
ًسواء تم تقديمها بطريقة التعلم المتمازج او التعلم االعتيادي انطالقا
من ان التعلم المتمازج
يعتمد
على مزج أساليب
التعلم االعتيادية مع اساليب التعلم االلكتروني،
وبالتالي فان هذه النتيجة تتفق مع رأي(أبو ل ،وم2020
،)ف هي
تغطي القصور في الجانب التعليمي، كما تتطابق هذه النتيجة مع رأي(
Yaghmour, 2016
)
الذي يرى بأن
المزاوجة بين التعلم االعتيادي بأشكاله المختلفة والتعلم االلكتروني وبأنماطه المتعددة يزيد من فاعلية الموقف
التعليمي وفرص التفاعل اإلجتماعي
بين الطلبة انفسهم وبين
الطلبة والم
علم. :المعالجات اإلحصائية :سؤال الدراسة الثاني"
( هل هناك فروق ذات داللة إحصائية عند مستوى داللةα≤0.05
)في
اتجاهات طلبة
الصف العاشر األساسي
نحو مادة التربية المهنية
تعزى إلى طريقة التعلم
والجنس والتفاعل بينهما
؟
لإلجابة عن
،هذا السؤال
فقد
تم استخدام تحليل التباين
األحادي متعدد االتجاهات(2way anova - analysis)
والجد
ا ول
(
0
( )
7
:) توضح النتائج ( جدول0
):
المتوسطات الحسابية واالنحرافات المعيارية
في اتجاهات ا
لمجموعتين التجريب
ي ة والضابطة
وفقا لطريق ة التعلم
والجنس والتفاعل بينهما
المتغير التابع
المتغير
المستقل
فئات ا
لمتغير
المتوسط
الحسابي
االنحراف
المعياري
حب االستطالع
طريقة التعلم
التعلم المتمازج
0.02
8.007
التعلم االعتيادي
0.87
8.000
الجنس
ذكور
0.33
8.000
اناث
3.20
8.703
طريقة التدريس
طريقة التعلم
التعلم المتمازج
0.00
8.003
التعلم االعتيادي
3.70
8.087
الجنس
ذكور
0.07
8.008
اناث
3.00
8.000
صعوبة تدريس مادة التربية المهنية طريقة التعلم التعلم المتمازج
0.00
8.070 ألمجلد1
. العدد3
. :المعالجات اإلحصائية 0201 أثر إستخدام التعلم المتمازج على تحصيل طالب الصف العاشر األساسي في مادة التربية المهنية وإتجاهاتهم نحوها أحمد
الشراري و
عيد
الصبحيين التعلم االعتيادي
3.00
8.002
الجنس
ذكور
0.00
8.070
اناث
3.70
8.022
أهمية تدريس مادة التربية المهنية
طريقة التعلم
التعلم المتمازج
0.08
8.703
التعلم االعتيادي
0.00
8.000
الجنس
ذكور
0.00
8.000
اناث
3.00
8.000
الدرجة الكلية
طريقة التعلم
التعلم المتمازج
0.00
8.000
التعلم االعتيادي
3.22
8.070
الجنس
ذكور
0.38
8.082
اناث
3.00
8.000 التعلم االعتيادي
3.00
8.002
الجنس
ذكور
0.00
8.070
اناث
3.70
8.022
أهمية تدريس مادة التربية المهنية
طريقة التعلم
التعلم المتمازج
0.08
8.703
التعلم االعتيادي
0.00
8.000
الجنس
ذكور
0.00
8.000
اناث
3.00
8.000
الدرجة الكلية
طريقة التعلم
التعلم المتمازج
0.00
8.000
التعلم االعتيادي
3.22
8.070
الجنس
ذكور
0.38
8.082
اناث
3.00
8.000 ( تظهر نتائج الجدول0) وجود فروق ظاهرة بي ن متوسطات اداء المجموعتين التجريبية التي درست بالتعلم
المتمازج، والمجموعة الضابطة التي درست بالتعلم االعتيادي في االتجاهات نحو مادة التربية المهنية تعزى
لطريقة التعلم (التعلم المتمازج، واالعتيادي)، والجنس، ولبيان فيما اذا كانت الفروق حقيقة وذات داللة احصائ
ي ،ة
فقد تم تطبيق اختبار تحليل التباين متعدد المتغيرات التابعة(MANOVA)
( ، والجدول7
:) يعرض النتائج جدول(
7
): نتائج تحليل التباين
المتعدد المتغيرات التابعة(
MANOVA
)
لبيان داللة الفروق بين متوسطات
اتجاهات
)المجموعتين (التجريبية والضابطة
وفقا لطريقة التعلم والجن
س والتفاعل بينهما
مصدر التباين المتغير التابع
مجموع
المربعات
درجات
الحرية
متوسط
المربعات
قيمة(f)
الداللة
اإلحصائية
طريقة التعلم
حب االستطالع
0.288
1
0.288
0.772
0.382
طريقة التدريس
1.128
1
1.128
6.443**
0.013
صعوبة تدريس مادة التربية المهنية
1.250
1
1.250
4.451*
0.038
أهمية تدريس مادة التربية المهنية
0.050
1
0.050
0.084
0.773
الدرجة الكلية
0.521
1
0.521
2.431
0.123
الجنس
حب االستطالع
3.042
1
3.042
8.153**
0.006
طريقة التدريس
3.570
1
3.570
20.389**
0.000
صعوبة تدريس مادة التربية المهنية
5.645
1
5.645
20.100**
0.000
أهمية تدريس مادة التربية المهنية
4.802
1
4.802
8.036**
0.006
الدرجة الكلية
4.036
1
4.036
18.840**
0.000
طريقة
التعلم*الجنس
حب االستطالع
0.722
1
0.722
1.935
0.168
طريقة التدريس
0.231
1
0.231
1.320
0.254
صعوبة تدريس مادة الترب
ية ال
مهنية
0.063
1
0.063
.225
0.636 48 ألمجلد1
. العدد3
. :المعالجات اإلحصائية 0201 أثر إستخدام التعلم المتمازج على تحصيل طالب الصف العاشر األساسي في مادة التربية المهنية وإتجاهاتهم نحوها أثر إستخدام التعلم المتمازج على تحصيل طالب الصف العاشر األساسي في مادة التربية المهنية وإتجاهاتهم نحوها أحمد
الشراري و
عيد
الصبحيين أثر إستخدام التعلم المتمازج على تحصيل طالب الصف العاشر األساسي في مادة التربية المهنية وإتجاهاتهم نحوها
أحمد
الشراري و
عيد
الصبحيي
أهمية تدريس مادة التربية المهنية
0.722
1
0.722
1.208
0.275
الدرجة الكلية
0.352
1
0.352
1.641
0.204
الخطأ
حب االستطالع
28.35
6
76
0.373
طريقة التدريس
13.30
8
76
0.175
صعوبة تدريس مادة التربية المهنية
21.34
2
76
0.281
أهمية تدريس مادة التربية المهنية
45.41
6
76
0.598
الدرجة الكلية
1396. 960
80
الكلي
حب االستطالع
1334. 490
80
طريقة التدريس
1300. 313
80
صعوبة تدريس مادة التربية المهنية
1412. 240
80
أهمية تدريس مادة التربية المهنية
1347. 913
80
الدرجة الكلية
1396. 960
80
الكلي المصحح
حب االستطالع
32.40
8
79
طريقة التدريس
18.23
7
79
صعوبة تدريس مادة التربية المهنية
28.30
0
79
أهمية تدريس مادة التربية المهنية
50.99
0
79
الدرجة الكلية
21.19
1
79
* دالة إحصائيا عند مستوى الد اللة(α≤0.05)
. (اظهرت النتائج المبينة في الجدول7) وجود فروق دالة احصائيا في اتجاهات طلبة الصف العاشر نحو ماد ( اظهرت النتائج المبينة في الجدول7
) وجود فروق دالة احصائيا في اتجاهات طلبة الصف العاشر نحو مادة
التربية المهنية على المجالين (طريق التدريس، وصعوبة تدريس مادة التربية المهنية) وفقا لطريقة التعلم اعتمادا ( اظهرت النتائج المبينة في الجدول7
) وجود فروق دالة احصائيا في اتجاهات طلبة الصف العاشر نحو مادة
التربية المهنية على المجالين (طريق التدريس، وصعوبة تدريس مادة التربية المهنية) وفقا لطريقة التعلم اعتمادا ألمجلد1
. العدد3
. 0201 أثر إستخدام التعلم المتمازج على تحصيل طالب الصف العاشر األساسي في مادة التربية المهنية وإتجاهاتهم نحوها أحمد
الشراري و
عيد
الصبحيين على قيم(f)
المحسوبة الظاهرة في الج دول السابق ومستوى الداللة المناظر لها، وهي دالة احصائيا عند مستوى
الداللة(α≤0.05)
(، وكانت الفروق لصالح التعلم المتمازج، حيث بلغت متوسطاتها الحسابية0.00
() و0.00
)
(وهي اكبر من المتوسطات لطريقة التعلم االعتيادية والبالغة3.70
() و3.00
)، كما اظهرت النتائج عدم و جود
فروق دالة احصائيا على الدرجة الكلية لالتجاهات والمجاالت اآلتية (حب االستطالع، واهمية تدريس مادة التربية
المهنية، اعتمادا على قيم(f)
المحسوبة الظاهرة في الجدول السابق ومستوى الداللة المناظر لها، وهي دالة
احصائيا عند مستوى الداللة(α≤0.05)
. :المعالجات اإلحصائية 0201 جميع الحقوق محفوظة لمجلة
الشرق األوسط للعلوم اإلنسانية
والثقا
ية ف أثر إستخدام التعلم المتمازج على تحصيل طالب الصف العاشر األساسي في مادة التربية المهنية وإتجاهاتهم نحوها أحمد
الشراري و
عيد
الصبحيين المساع(دة0800
)
التي بينت أن "هنالك فروقاً ذات داللة إحصائية بين نتائج التطبيق القبلي والبعدي على مقياس
ا.التجاهات ولصالح التطبيق البعدي
كما وقد اظهرت النتائج عدم وجود فروق دالة احصائياً في االتجاهات على
الدرجة الكلية والمجاالت اآلتية (حب االستطالع، واهمية تدريس مادة التربية الم .)هنية
تم التحقق من الت كافؤ بين
المجموعات باستخدام( اختبارT
) للمجموعات المستقلة(t-test for independent sample) والجدول
رقم
(
0
:) يبين النتائج المساع(دة0800
)
التي بينت أن "هنالك فروقاً ذات داللة إحصائية بين نتائج التطبيق القبلي والبعدي على مقياس
ا.التجاهات ولصالح التطبيق البعدي
كما وقد اظهرت النتائج عدم وجود فروق دالة احصائياً في االتجاهات على
الدرجة الكلية والمجاالت اآلتية (حب االستطالع، واهمية تدريس مادة التربية الم .)هنية
تم التحقق من الت كافؤ بين
المجموعات باستخدام( اختبارT
) للمجموعات المستقلة(t-test for independent sample) والجدول
رقم
(
0
:) يبين النتائج المساع(دة0800
)
التي بينت أن "هنالك فروقاً ذات داللة إحصائية بين نتائج التطبيق القبلي والبعدي على مقياس
ا.التجاهات ولصالح التطبيق البعدي
كما وقد اظهرت النتائج عدم وجود فروق دالة احصائياً في االتجاهات على
الدرجة الكلية والمجاالت اآلتية (حب االستطالع، واهمية تدريس مادة التربية الم .)هنية
تم التحقق من الت كافؤ بين
المجموعات باستخدام( اختبارT
) للمجموعات المستقلة(t-test for independent sample) والجدول
رقم
(
0
:) يبين النتائج (جدول0
):
( نتائج اختبارT
)
(t-test for independent samples)
لبيان داللة الفروق بين المجموعتين التجريبية
والضابطة على االختبار القبلي
للتحصيل في مادة التربية المهنية
المجموعة العدد
المتوسط
الحسابي
اال نحراف
المعياري
( قيمةT
)
درجات
الحرية
الداللة
اإلحصائية
التجريبية
08
00.00
3.007
0.080
70
8.000
الضابطة
08
03.08
0.200
*دالة إحصائيا عند مستوى الداللة(α≤0.05)
. ( تظهر نتائج الجدول0
ً) عدم وجود فروق دالة إحصائيا بين المجموعتين التجريبية والضابطة ع
لى االخ تبار
التحصيلي القبلي في مادة التربية المهنية لدى افراد العينة ًاعتمادا
( على قيمةT
) المحسوبة البالغة(1.608)
عند مستوى داللة(α=0.112)
ًوهي غير دالة إحصائيا
عند مستوى الداللة(α≤0.05)
، وهذا يدل على
.تكافؤ المجموعتين التجريبية والضابطة :المعالجات اإلحصائية واظهرت ا لنتائج ايضا وجود فروق دالة احصائيا في اتجاهات طلبة الصف العاشر نحو مادة التربية المهنية على
( الدرجة الكلية والمجاالت تعزى لمتغير الجنس، اعتمادا على قيم (f
المحسوبة ومستوى الداللة المناظر لها وجميعها
دالة احصائيا عند مستوى الداللة
(α≤0.05)
،وكانت الفروق لصا لح الذكور حيث بلغت متوسطاتهم الحسابية
على التوالي(4.33,4.27,4.25,4.44,4.30)
وهي اكبر من ال
متوسطات الحسابية لإلناث والبالغة
(3.94,3.85,3.72,3.88,3.85)
. كما اظهرت النتائج الظاهرة في نفس الجدول عدم وجود فروق دالة احصائيا
في اتجاهات طلبة الصف العاشر نحو مادة التربية ال
مه
نية تعزى للتفاعل بين طريقة التعلم والجنس، اعتمادا ع لى
( قيم(f
المحسوبة الظاهرة في الجدول السابق ومستوى الداللة المناظر لها وهي غير دالة احصائيا عند مستوى
الداللة
(α≤0.05)
. وقد تفسر النتيجة ان األنشطة المستخدمة في هذه االستراتيجية قد بسطت ا
لمعلومة وسهلت من اكتساب ًها وايضا
انها مشوقة للتعلم، وميل الطلبة نحو تفضيل العمل اليدوي والتدريب العملي، واستيعاب المعلومة، فالتعلم المتمازج
قد حسن من اتجاهات الطلبة نحو طريقة التدريس وصعوبة تدريس المادة، وقد يعود تفضيل التعلم المتمازج إلى
قلة الواجبات، كما
،ويعتقد الباحث أن عرض مادة التربية المهنية بطريقة التعلم المتمازج قد جعلتها مادة سهلة
ويشعر الطالب بأنها ضرورية، وتناسب المرحلة العمرية التي يوجد بها وتتفق في هذا الجانب مع نتائج دراسة
(الصرايرة2019) التي اظهرت نتائجها "وجود فروق ذات داللة إحصائية التجاها ت الطلبة نحو استخدام نمط
التعلم المتمازج" ودراسة( المساعدة0800
)
"كما وتبين أن هنالك فروقاً ذات داللة إحصائية بين نتائج التطبيق
القبلي والبعدي على مقياس االتجاهات ولصالح التطبيق
البعدي" ونتائج دراسة كل من كيبولمانغ و موقوي
(
Kebualemang and Mogwe, 2017) الت ي اظهرت نتائجها "أن وضع التعلم المتمازج له تأثير إيجابي
على الطالب، كما أن تصوراتهم على التعلم المتمازج كاستراتيجية وأسلوب تدريسي كانت ايجابية"، ودراسة 50 50
جميع الحقوق محفوظة لمجلة
الشرق األوسط للعلوم اإلنسانية
والثقا
ية ف ألمجلد1
. العدد3
. التوصيات: في ض :وء النتائج التي توصلت لها الدراسة، فإن الباحث يقترح التوصيات اآلتية في ض :وء النتائج التي توصلت لها الدراسة، فإن الباحث يقترح التوصيات اآلتية 1
- التوسع في تدريب معلمي التربية المهنية العاملين في المدارس الحكومية على طريقة التعل ،م المتمازج
ك
إستراتيحية
تعلم حديثة، ومستخدمة بطريقة غير مباشرة على منصات التعلم عن بعد بسبب ظروف
جائحة ك.ورونا 2
-
ضرورة تشجيع معلمي التربية المهنية على استخدام طريقة التعلم المتمازج في تدريس مادة التربية
المهنية لكونها طريقة حديثة في التعلم وتجمع بين خصائص ومميزات التعلم االلكتروني والتعلم
االعتيادي، حيث اظهرت النتائج عدم وجود فروق بين طريقة التعلم المتمازج وال
تعلم االعتي.ادي 51 51
جميع الحقوق محفوظة لمجلة
الشرق األوسط للعلوم اإلنسانية
والثقا
ية ف ألمجلد1
. العدد3
. 0201 أثر إستخدام التعلم المتمازج على تحصيل طالب الصف العاشر األساسي في مادة التربية المهنية وإتجاهاتهم نحوها أحمد
الشراري و
عيد
الصبحيين 3
-
ضرورة بناء منهاج التربية المهنية وفقاً الستراتيجيات التدريس الحديثة لتوفر خدمات االنترنت والتوسع
في استخدام التعلم االلكتروني عن بعد وتوفر برامج المحاكاة االلكترونية التي تتيح امكانية التدريب
العملي للطلب
ة، المستفيدين منها في المدراس الحكوم.ية والخاصة في مديريات التربية والتعليم
4
-
اجراء المزيد من الدراسات على متغيرات هذه الدراسة وعلى عينات اخرى في مديرية التربية والتعليم
التابعة لمحافظة العقبة، وعلى مجتمعات أخرى غير مجتمع الدراسة الحالية لإلستفادة من نتائج الدراسة
.الحالية وتعميماتها إ 5
-
التأكيد على أخذ نتائج الدراسة بعين اإلعتبار من قبل وزارة التربية والتعليم، لما لها من أثر في تحسين
.وتطوير عملية التعلم، والتشجيع على إستخدام العديد من اإلتراتيجيات الحديثة :المراجع
أوالً: المراجع العربية
0
-
أبو شعيرة، خالد . (
2006
). التربية المهنية بين الفكر
التربوي اإلسالمي والفكر التربوي الحديث. دار جرير
.للنشر والتوزيع
0
-
(.أبو لوم، خالد محمد2020
). اثر استخدام استراتيجية التعلم المتمازج في تنمية المفاهيم الرياضية لدى
،طلبة الصف الثالث االساسي في األردن. جامعة فلسطين ،مجلة جامعة فلسطين لألبحاث والدراسات
(
9
)
4
،
79
-
102
. 0
-
(.أبو لوم، خالد محمد2020
). اثر استخدام استراتيجية التعلم المتمازج في تنمية المفاهيم الرياضية لدى
،طلبة الصف الثالث االساسي في األردن. جامعة فلسطين ،مجلة جامعة فلسطين لألبحاث والدراسات
(
9
)
4
،
79
-
102
. 3
-
بن داده، لخضر. (
0808
.)
التعليم من أجل التغيير . .مركز الكتاب األكاديمي
0
-
الريماوي، فراس(. 0807
.)
التعلم المدمج في تدريس اللغة االنجليزية.. دار المنهل للنشر والتوزيع
0
-
سبيتان، فتحي(. التوصيات: فاعلية استخدام خرائط المفاهيم في تحصيل طلبة جامعة الزيتونة
.األردنية في مادة التربية البيئية واتجاهاتهم نحوها
مجلة جامعة القدس المفتوحة لألبحاث والدراسات ،
(
38
،)
00
،
077
-
020
. 00
-
العاني، مزهر شعبان.(
2015
.)التعليم االلكتروني التفاعلي .مركز الكتاب األكاديمي للنشر والتوزي.ع
00
-
عطية، محسن علي.(
2013
.)المناهج الحديثة وطرائق التدريس.. دار المنهل للنشر والتوزيع
03
-
قطيط، غسان.(
2015
.)تقنيات التعلم والتعليم الحديثة
. (ط1
.)، دار الثقافة للنشر والتوزيع
00
-
كزيز، آمال.(
2019
.)
الممارسات الثقافية في التربية و
التعليم
. مركز الكتاب األكاديمي للنشر. 00
-
العاني، مزهر شعبان.(
2015
.)التعليم االلكتروني التفاعلي .مركز الكتاب األكاديمي للنشر والتوزي.ع
00
-
عطية، محسن علي.(
2013
.)المناهج الحديثة وطرائق التدريس.. دار المنهل للنشر والتوزيع
03
-
قطيط، غسان.(
2015
.)تقنيات التعلم والتعليم الحديثة
. (ط1
.)، دار الثقافة للنشر والتوزيع
00
-
كزيز، آمال.(
2019
.)
الممارسات الثقافية في التربية و
التعليم
. مركز الكتاب األكاديمي للنشر. 00
-
(.المساعدة، رافع2018
). اثر استخدام استراتيجية التعلم المتمازج في تحصيل طلبة الصف الثامن
.األساسي لمادة العلوم واتجاهاتهم نحوها في مديرية تربية لواء قصبة إربد
مجلة جامعة الخليل
،للبحوث
(
13
)
1
،
176
-
194
. 00
-
(.المساعدة، رافع2018
). اثر استخدام استراتيجية التعلم المتمازج في تحصيل طلبة الصف الثامن
.األساسي لمادة العلوم واتجاهاتهم نحوها في مديرية تربية لواء قصبة إربد
مجلة جامعة الخليل
،للبحوث
(
13
)
1
،
176
-
194
. 00
-
مصطفى، مح(.مود2019
). اثر استخدام استراتيجية التعلم المتمازج في تحصيل طالب الصف التاسع
.األساسي في مادة التالوة والتجويد وفي دافعيتهم نحو تعلمها في مدارس لواء الجامعة
مجل ة جامعة
( ،)النجاح لألبحاث (العلوم اإلنسانية11
)
33
. 00
-
مصطفى، مح(.مود2019
). اثر استخدام استراتيجية التعلم المتمازج في تحصيل طالب الصف التاسع
.األساسي في مادة التالوة والتجويد وفي دافعيتهم نحو تعلمها في مدارس لواء الجامعة
مجل ة جامعة
( ،)النجاح لألبحاث (العلوم اإلنسانية11
)
33
. إأ
07
-
(. النسور، زياد عبد الكريم2011
.)اثر تدري س الرياضيات المحوسبة بطريقتي التعلم المتمازج والتعلم
،الذاتي في تحصيل الطلبة واتجاهاتهم نحوها. أطروحة دكتوراة غير منشورة، جامعة عمان العربية
.األردن إأ
07
-
(. النسور، زياد عبد الكريم2011
.)اثر تدري س الرياضيات المحوسبة بطريقتي التعلم المتمازج والتعلم
،الذاتي في تحصيل الطلبة واتجاهاتهم نحوها. أطروحة دكتوراة غير منشورة، جامعة عمان العربية
.األردن أ
00
-
الهاشمي، عبد الرحمن.(
2016
.)
استراتيجيات معاصرة في تدريس التربية اإلسالمية
. دار اليسر لل نشر
.والتوزيع
ثا
نياً: المراجع األجنبية 19- Aslam, S. (2015). التوصيات: 0807
.)
.اساليب وطرائق تدريس طلبة المرحلة االساسية االولى
دار
الخليج للنشر
.والتوزيع 3
-
بن داده، لخضر. (
0808
.)
التعليم من أجل التغيير . .مركز الكتاب األكاديمي
0
-
الريماوي، فراس(. 0807
.)
التعلم المدمج في تدريس اللغة االنجليزية.. دار المنهل للنشر والتوزيع
0
-
سبيتان، فتحي(. 0807
.)
.اساليب وطرائق تدريس طلبة المرحلة االساسية االولى
دار الخليج للنشر
.والتوزيع 0
-
(.شاهين، حسان رافع2020
). درجة استخدام طريقة التعلم المتمازج ومعوقات تطبيقها من وجهة نظر
،معلمي التربية الخاصة في األردن. جامعة الملك سعود(،المجلة السعودية للتربية الخاصة13
)
5
،
179
–
208
. 7
-
الشرمان، عاطف.(
2015
.)التعلم المدمج والتع.لم المعكوس دار المسيرة للنشر والتوزيع. 0
-
(.شفيق، ابتسام علوان2019
). اثر استراتيجية التعلم المتمازج في التحصيل واكتساب المفاهيم التاريخية
،لدى طلبة قسم التاريخ في كلية التربية للعلوم اإلنسانية في جامعة المثنى. جامعة بابل
م جلة كلية
التربية االساسية للعلوم( ،التربوية واإلنسانية42
)
5
،
991
-
1002
. 52
جميع الحقوق محفوظة لمجلة
الشرق األوسط للعلوم اإلنسانية
والثقا
ية ف ألمجلد1
. العدد3
. 0201 جميع الحقوق محفوظة لمجلة
الشرق األوسط للعلوم اإلنسانية
والثقا
ية ف أثر إستخدام التعلم المتمازج على تحصيل طالب الصف العاشر األساسي في مادة التربية المهنية وإتجاهاتهم نحوها أثر إستخدام التعلم المتمازج على تحصيل طالب الصف العاشر األساسي في مادة التربية المهنية وإتجاهاتهم نحوها أحمد
الشراري و
عيد
الصبحيين 2
-
(.الصرايرة، ثروت عبد الغفار2019
). اتجاهات طلبة الصف العاشر األساسي نحو استخدام نمط التعلم
،المتمازج في تعلمهم المفاهيم الفيزيائية. جامعة طنطا، كلية التربية( ،مجلة كلية التربية37
)
1
،
211
-
234
. 2
-
(.الصرايرة، ثروت عبد الغفار2019
). اتجاهات طلبة الصف العاشر األساسي نحو استخدام نمط التعلم
،المتمازج في تعلمهم المفاهيم الفيزيائية. جامعة طنطا، كلية التربية( ،مجلة كلية التربية37
)
1
،
211
-
234
. 2
-
(.الصرايرة، ثروت عبد الغفار2019
). اتجاهات طلبة الصف العاشر األساسي نحو استخدام نمط التعلم
،المتمازج في تعلمهم المفاهيم الفيزيائية. جامعة طنطا، كلية التربية( ،مجلة كلية التربية37
)
1
،
211
-
234
. 08
-
الطراونة، محمد حسن
(. 2013
). فاعلية استخدام خرائط المفاهيم في تحصيل طلبة جامعة الزيتونة
.األردنية في مادة التربية البيئية واتجاهاتهم نحوها
مجلة جامعة القدس المفتوحة لألبحاث والدراسات ،
(
38
،)
00
،
077
-
020
. 08
-
الطراونة، محمد حسن
(. 2013
). التوصيات: A Comparative Study of blended learning Versus Traditional in Middle
School Science, international Conference the Future of Education. Florence Italy. 19- Aslam, S. (2015). A Comparative Study of blended learning Versus Traditional in Middle
School Science, international Conference the Future of Education. Florence Italy. 20- Bryan, M. & Clifford, J. & Hillary, W. (2015). Student Perceptions of Using Blended Learning
in Secondary Science. In the proceeding of The European Conference on Technology in
the Classroom. 20- Bryan, M. & Clifford, J. & Hillary, W. (2015). Student Perceptions of Using Blended Learning
in Secondary Science. In the proceeding of The European Conference on Technology in
the Classroom. 21- Kebualemang, G, & Mogwe, a (2017). An Empirical investigation into Blended Learning
Effects on Tertiary Student and Students perception in The Approach in Botswana, 21- Kebualemang, G, & Mogwe, a (2017). An Empirical investigation into Blended Learning
Effects on Tertiary Student and Students perception in The Approach in Botswana, 53 ألمجلد1
. العدد3
. 0201 جميع الحقوق محفوظة لمجلة
الشرق األوسط للعلوم اإلنسانية
والثقا
ية ف أثر إستخدام التعلم المتمازج على تحصيل طالب الصف العاشر األساسي في مادة التربية المهنية وإتجاهاتهم نحوها أحمد
الشراري و
عيد
الصبحيين (IJACSA), International Journal of Advanced Computer Science and Applications,(8) 6. 635-648. (IJACSA), International Journal of Advanced Computer Science and Applications,(8) 6. 635-648. 22- Lalima, K. (2017). Blended Learning: An Innovative Approach. Universal Journal of
Educational Research, 5(1), 129-136. 23- Lesmana, A, and Basiran. (2017). Use of Learning in Teaching Islamic History. The Case of
the 8th Grade of Sukma Bangsa School in Aceh, Master's Thesis in education, University
of Tampere. 24- Tosun, S, (2015). The Effect Blended Learning on EFL Student Vocabulary Enhancement. Article in Procedia – Social and Behavioral Sciences- August. 25- Yaghmour, K. (2016). Effectiveness of Blended Teaching Strategy on the Achievement of
Third Grade Students in Mathematics. Journal of Education and Practice. 7 (5), 65-87. 26- Yapici, I. U. &Akbayin, H. (2012). The effect of blended learning model on high school
students’ biology achievement and on their attitudes towards the internet. The Turkish
Online Journal of Educational Technology, 11(2). 54
جميع الحقوق محفوظة لمجلة
الشرق األوسط للعلوم اإلنسانية
والثقا
ية ف 54
جميع الحقوق محفوظة لمجلة
الشرق األوسط للعلوم اإلنسانية
والثقا
ية ف ألمجلد1
. العدد3
. 0201 جميع الحقوق محفوظة لمجلة
الشرق األوسط للعلوم اإلنسانية
والثقا
ية ف
|
https://openalex.org/W2773397997
|
https://www.clei.org/cleiej/index.php/cleiej/article/download/24/5
|
English
| null |
Online Signature Verification: To What Extent Should a Classifier be Trusted in?
|
CLEI Electronic Journal
| 2,017
|
cc-by
| 11,843
|
and Juan C. G´omez
Lab. for System Dynamics & Signal Processing
Universidad Nacional de Rosario, CIFASIS, CONICET
Rosario, Argentina
gomez@cifasis-conicet.gov.ar Keywords: Online Signature Verification, Feature Combination, Score Level Fusion. Keywords: Online Signature Verification, Feature Combination, Score Level Fusion. Keywords: Online Signature Verification, Feature Combination, Score Level Fusion. CLEI ELECTRONIC JOURNAL, VOLUME 20, NUMBER 2, PAPER 5, AUGUST 2017 CLEI ELECTRONIC JOURNAL, VOLUME 20, NUMBER 2, PAPER 5, AUGUST 2017 Abstract To select the best features to model the signatures is one of the major challenges in
the field of online signature verification. To combine different feature sets, selected by
different criteria, is a useful technique to address this problem. In this line, the analysis
of different features and their discriminative power has been researchers’ main concern,
paying less attention to the way in which the different kind of features are combined. Moreover, the fact that conflicting results may appear when several classifiers are being
used, has rarely been taken into account. In this paper, a score level fusion scheme is
proposed to combine three different and meaningful feature sets, viz., an automatically
selected feature set, a feature set relevant to Forensic Handwriting Experts (FHEs), and
a global feature set. The score level fusion is performed within the framework of the
Belief Function Theory (BFT), in order to address the problem of the conflicting results
appearing when multiple classifiers are being used. Two different models, namely, the
Denoeux and the Appriou models, are used to embed the problem within this framework,
where the fusion is performed resorting to two well-known combination rules, namely,
the Dempster-Shafer (DS) and the Proportional Conflict Redistribution (PCR5) one. In
order to analyze the robustness of the proposed score level fusion approach, the com-
bination is performed for the same verification system using two different classification
techniques, namely, Ramdon Forests (RF) and Support Vector Machines (SVM). Experi-
mental results, on a publicly available database, show that the proposed score level fusion
approach allows the system to have a very good trade-offbetween verification results and
reliability. CLEI ELECTRONIC JOURNAL, VOLUME 20, NUMBER 2, PAPER 5, AUGUST 2017 offline and online systems. For offline systems, only the image of the signature is available, while for online
systems, dynamic information acquired during the signing process, such as x and y pen coordinates, pen
pressure, and even pen angles, is available. Online verification systems are believed to be more reliable than
offline ones, since it would be reasonable to expect that the incorporation of dynamic information acquired
during the signing process would make signatures more difficult to forge. In addition, although there exists
some applications that still demand the use of the offline approach, such as Forensic Handwriting Experts
(FHEs) caseworks, the use of different electronic pen-input devices, such as digitizer tablets and PDAs, has
significantly increased in recent years, making online systems the current option for signature verification. Which features should be used to model the signatures has always been a crucial issue in the field of
online signature verification. Although the effectiveness of the different features for verification purposes has
been largely discussed, the conflicting results in the literature make the discussion still open [6–11]. Despite
the lack of conclusions, researchers agree that an interesting strategy is to combine different feature sets,
selected by different criteria, in order to take advantage of their individual discriminative capabilities. In line
with this idea, different online signature verification systems have been proposed in the literature combining
different kind of features. Some of them, propose the combination of local features, which are computed for
each point in the time sequences, and global features, which are computed from the whole signatures, and
highlight the advantages of incorporating global features to the verification systems [11–14]. Some others,
propose the combination of features (independently of being local or global) obtained on the basis of different
feature extraction strategies, showing that the combination improves the performance with respect to the
case of using each of the feature sets individually [15–18]. Despite most of the works in the literature of signature verification concerning feature combination focus
their analysis on which features should be combined, it is also important to address the problem of how
to combine them. Information fusion techniques have long been used in the field of biometrics in order
to improve the systems’ accuracy by considering multiple pieces of evidence [19–22]. CLEI ELECTRONIC JOURNAL, VOLUME 20, NUMBER 2, PAPER 5, AUGUST 2017 The combination of
different authentication systems can offer substantial improvements in their accuracy depending upon the
information being combined, for instance, the different kind of features, and the fusion methodology adopted. In particular, information fusion can be performed at different levels, viz., data level, feature level, score level,
or decision level. The fusion at data or feature level, usually referred to as tightly coupled integrations [23],
assumes a strong interaction among the input measurements. On the other hand, the fusion at score or
decision level, usually called loosely coupled systems, assumes a very little or no interaction among the
inputs, since the integration occurs at the output of relatively autonomous agents, each agent independently
assessing the input from its own perspective. Several works in the literature of biometrics have shown that
the fusion at score level offers the best trade-offbetween information content and the ease in fusion [24]. Researchers in the area of signature verification agree with this idea, being score level fusion the trend in
this field [13], [15–18], [25–28]. Nevertheless, examples using feature level fusion [18], [29,30], and decision
level fusion [31], can also be found. The most commonly used technique in the literature of signature verification to perform score level fusion
consists in combining the scores of the individual classifiers with simple rules, such as, max, min, product,
simple sum, or weighted sum [20]. In [13], local and global features are combined on the basis of the sum and
max rules, while in [17], such kind of features are combined on the basis of the sum and product rules. A user
dependent weighting fusion is introduced in [25] for combining features in the Discrete Wavelet Transform
(DWT) domain, and a weighted geometrical fusion rule is used in [18] for combining three different feature
sets. To train a fusion algorithm using kernel methods, such as, Support Vector Machines (SVM) [15], [32], or
Neural Networks (NN) [33], is also a widely used technique. In [15], a combination of two different histogram
features is performed on the basis of a SVM classifier, while in [32], the SVM classifier is used to combine
offline and online features. In [33], a two-stage NN is used to perform the combination of global and local
features. 1
Introduction Biometric systems aim to automatically recognize or verify an identity. Among the numerous available
biometric techniques, signature verification is one of the most popular [1–5]. The widespread acceptance
of the signatures is due to the fact that they are recognized as a legal means of verifying an individual’s
identity by financial and administrative institutions, and that people are familiar with the use of signatures
for identity verification in their everyday life. In addition, signatures have the advantage of being easy to
collect, since no invasive methods are required to collect them. According to the signatures’ acquisition method, signature verification s to the signatures’ acquisition method, signature verification systems can be categorized into According to the signatures’ acquisition method, signature verification systems can be categor 1 1 CLEI ELECTRONIC JOURNAL, VOLUME 20, NUMBER 2, PAPER 5, AUGUST 2017 biometric applications [24], [36–39], where conflicting results are the common scenario. Although combining
multiple classifiers is a widely used technique in the field of signature verification, to the best of the authors’
knowledge, the degree of uncertainty that this technique may introduce to the classification problem has not
been significantly explored. In fact, there exist few works in the literature taking into account such situation
resorting to the BFT [27,28]. In [27], the authors propose the fusion of online and offline information using
SVM classifiers, and in [28], the fusion of SVM classifiers is proposed to combine different feature sets for
offline verification. In this paper, the combination of three different and meaningful feature sets, selected by different criteria,
is proposed on the basis of a score level fusion approach based on the BFT, which would provide the
appropriate framework to quantify the confidence in each of the classifiers, and to handle the conflicting
results that may appear. In particular, an automatically selected feature set [10], a set of features relevant
to Forensic Handwriting Experts (FHEs) [40], and a set of global features [11], are combined. These feature
sets have already shown to have interesting discriminative capabilities, resulting not only in good verification
performances, but also providing, from their own perspective, several advantages to the signature verification
system. In a previous work [18], these feature sets were combined on the basis of a simpler combination
approach, where the possibility of conflicting results among the different classifiers was not taken into account. Here, by actually incorporating this possibility to the analysis (through the BFT approach), it is expected
for the proposed combination approach to be more reliable and, in this way, to make the whole signature
verification system more secure. The idea is then to train an independent classifier using each of the three
mentioned feature sets, and combine the corresponding three output scores on the basis of a score level
fusion approach based on the BFT. The first step towards managing conflicting information, is to transform
the information (classifiers’ output scores) into evidence, in order to embed the problem within the BFT
framework. This constitutes a crucial step in the whole fusion process. In this paper, two different transfer
models, namely, the Denoeux [41] and Appriou [42] models, are proposed to perform the transformation. CLEI ELECTRONIC JOURNAL, VOLUME 20, NUMBER 2, PAPER 5, AUGUST 2017 In addition, the proposed models allow to explicitly take into account the confidence level corresponding
to each classifier, by incorporating a confidence factor when converting the classifiers’ scores into belief
assignments. The second step, is to actually perform the combination in the framework of the BFT, resorting
to combination rules specially developed (most of them based on Dempster’s rule [43]) to work within this
context. In this paper, two different and widely used rules, namely, the Dempster-Shafer (DS) [44] and the
Proportional Conflict Redistribution (PCR5) one [45], are employed. Finally, to evaluate the robustness of
the proposed score level fusion approach, two different and well-known classifiers, namely, Random Forests
(RF) [46] and SVM [47,48], are used to build two different signature verification systems where the score level
fusion approach is performed. That is, in one case, the three independent classifiers are implemented based
on RF, and in the other, they are implemented based on SVM. In addition, the verification performance
of the proposed score level fusion approach is analyzed for two different signature styles, namely, Western
(Dutch) and Chinese, in a publicly available database [49]. The paper is organized as follows. The basics of the BFT are described in Section 2. Section 3 describes
the feature sets that are to be combined. The proposed score level fusion scheme is described in Section 4. In Sections 5 and 6, the database and the evaluation protocol are described, respectively. In Section 7, the
experimental results are presented and discussed. Finally, some concluding remarks are given in Section 8. 2
Basics of BFT The BFT is a general framework for reasoning with uncertain information. It arose from the reinterpretation
and development of the work of A. P. Dempster [34] by G. Shafer [35], and it is a generalization of the Bayesian
theory of subjective probability. The BFT allows to combine evidence from different sources and arrive at a
degree of belief (or confidence, or trust), which is represented by a mathematical object called belief function,
that takes into account all the available evidence. To do so, the idea is to obtain degrees of belief for one
question from subjective probabilities for a related question, and combine such degrees of belief based on
specially developed combination rules, such as, Dempster’s rule or any other rule derived from it. y
y
Generally, signature verification leads to a two-class classification problem, in the sense that an input
signature can be either genuine or a forgery. For this reason, the main definitions regarding BFT are
presented in the following Subsections for the case of a two-class problem. CLEI ELECTRONIC JOURNAL, VOLUME 20, NUMBER 2, PAPER 5, AUGUST 2017 When combining scores obtained by multiple classifiers, conflicting results may appear, in the sense
that the different classifiers may not achieve similar scores, introducing some degree of uncertainty to the
classification problem. Given such a situation, it would be desirable to quantify to what extent each classifier
should be trusted in. In fact, to use this information for performing the combination would allow it to be more
realistic and reliable. This can be done by computing a confidence level for each classifier and embedding
the classification problem in a framework capable of handling the problem’s inherent degree of uncertainty. Although being widely used, score level fusion approaches based on simple rules and kernel techniques do not
perform well under this condition. Moreover, in such cases, the fusion performance decreases considerably. A suitable framework to address the problem of conflicting information is provided by the Belief Function
Theory (BFT) [34, 35]. The BFT is a general framework for reasoning with uncertainty, first introduced
by A. P. Dempster in the context of statistical inference [34], and developed later by G. Shafer into a
general framework for modeling epistemic uncertainty [35]. The BFT has been widely used for multi- 2 2 CLEI ELECTRONIC JOURNAL, VOLUME 20, NUMBER 2, PAPER 5, AUGUST 2017 possibility of actually measuring the degree of confidence in each classifier by letting to explicitly introduce
the confidence factor α associated with each classifier. Let θgen and θfalse be associated with the genuine and the forged classes, respectively, being Θ =
{θgen, θfalse} the so-called frame of discernment. The BFT takes into account the possibility of having
ambiguity in the results by considering also the case where the evidence is not strong enough to discern
between the two classes, assuming the power set of Θ (2Θ) to be the (extended) set of possible results
{θgen, θfalse, {θgen, θfalse}}. In this context, the Denoeux [41] model is given by mi(gen)
=
αi × Ψi(si)
mi(false)
=
1 −αi × Ψi(si)
(1)
mi(Θ)
=
0, mi(gen)
=
αi × Ψi(si)
mi(false)
=
1 −αi × Ψi(si) (1) mi(Θ)
=
0, while the Appriou [42] one is given by mi(gen)
=
αi × Ψi(si)
mi(false)
=
αi × (1 −Ψi(si))
(2)
mi(Θ)
=
1 −αi, (2) where m are the belief assignments, i corresponds to the classifier, 0 < αi < 1 is a confidence factor for
each classifier, si is the score of the classifier i for a given signature, and Ψi is a monotonically increasing
function, which maps the scores into the interval [0, 1]. In the particular signature verification application
proposed in this paper, there is no need of using the mapping function, since the scores are already in the
interval [0, 1] due to the classification methods being used. where m are the belief assignments, i corresponds to the classifier, 0 < αi < 1 is a confidence factor for
each classifier, si is the score of the classifier i for a given signature, and Ψi is a monotonically increasing
function, which maps the scores into the interval [0, 1]. In the particular signature verification application
proposed in this paper, there is no need of using the mapping function, since the scores are already in the
interval [0, 1] due to the classification methods being used. [
]
As already mentioned, the proposed transfer models allow the possibility of actually measuring the degree
of confidence in each classifier by letting to explicitly introduce the confidence factor α associated with each
classifier. This is an important step in the whole proposed score level fusion scheme, since it is a step towards
answering the question in the paper’s title. 2.2
Combination Rules To perform the combination in the framework of the BFT, that is, to combine the previously calculated
belief assignments, it is necessary to resort to combination rules specially developed to work in this context. In this paper, the DS [44] and PCR5 rules [45], are used. [
]
[
]
Let m1(.) and m2(.) be the belief assignments corresponding to two different classifiers (for instance,
computed as in Equations (1) or (2)). The DS combination rule [44] is defined as mDS(A) =
P
(X,Y ∈2Θ,X∩Y =A) m1(X).m2(Y )
1 −P
(X,Y ∈2Θ,X∩Y =∅) m1(X).m2(Y ),
(3) (3) where A ∈2Θ = {θgen, θfalse, {θgen, θfalse}}, and the denominator is a normalizing factor which quantifies
the conflict between m1(X) and m2(Y ). On the other hand, the PCR5 rule [45] is defined as where A ∈2Θ = {θgen, θfalse, {θgen, θfalse}}, and the denominator is a normalizing factor which quantifies
the conflict between m1(X) and m2(Y ). On the other hand, the PCR5 rule [45] is defined as mP CR5(A) = m12(A) +
X
(A,B∈2Θ,A∩B=∅)
m1(A)2.m2(B)
m1(A) + m2(B) + m2(A)2.m1(B)
m2(A) + m1(B)
,
(4) (4) where m12(A) = P
(X,Y ∈2Θ,X∩Y =ϕ) m1(X).m2(Y ) corresponds to the conjunctive consensus on A between
the classifiers. CLEI ELECTRONIC JOURNAL, VOLUME 20, NUMBER 2, PAPER 5, AUGUST 2017 In addition, each of the proposed models perform the conversion
and incorporates the confidence factor α resorting to different criteria, making it possible to analyze the
impact of using one model or another in the whole score level fusion process. Finally, from Equation (1), the reader can notice that Denoeux model does not actually take into account
the case of ambiguity in the classifiers’ results since mi(Θ) = 0. This is not the case for the Appriou model
(Equation (2)), where mi(Θ) = 1 −αi. In any case, that is, whether the Denouex or Appriou model is
used, the conflicting results are taken into account at the combination stage by using the DS and PCR5
combination rules described in Subsection 2.2, which explicitly handle uncertainty (see Equations (3) and
(4)). Then, even in the case of using the Denouex model, where the conflicting results are not considered in
the transformation stage, they are handled in the combination stage. 2.1
Belief Assignments To embed the problem within the framework of BFT, it is necessary to convert the scores of the classifiers,
which are the ones that are meant to be combined, into belief assignments. In this paper, the Denoeux [41]
and Appriou [42] transfer models are used to perform this transformation. Such models allow, in addition, the 3 3
Feature Sets Three different feature sets are considered. A set composed by automatically selected features (ASF), a set
of features relevant to the FHEs (FHEF), and a set of global features (GF), described in Subsections 3.1.1,
3.1.2 and 3.2, respectively. Typically, the acquired data during the signing process consists of three discrete time functions: pen
coordinates (x and y), and pen pressure p. Several extended functions can be computed from them [12], [51]. In this paper, the path-velocity (magnitude vT and direction θ), the total acceleration aT , and the log-
radius curvature ρ, are computed from the x and y pen coordinates and the pen pressure p. Before their
computation, the original x and y pen coordinates are normalized regarding scale and translation. The
initial set of time functions, on which the selection of the three different feature sets will be performed, is
composed by the x and y pen coordinates, the pen pressure p, the above mentioned extended functions, viz,
vT , θ, aT and ρ, and their first and second order time derivatives. It is important to note that, before performing the selection of the ASF and FHEF features, each of
the time functions listed above is represented on the basis of the feature extraction technique described in
Subsection 3.1. On the other hand, the GF features are computed directly from the original time functions,
without resorting to the technique described in Subsection 3.1. CLEI ELECTRONIC JOURNAL, VOLUME 20, NUMBER 2, PAPER 5, AUGUST 2017 employed. It is defined as employed. It is defined as employed. It is defined as P(θj) =
X
θj∈A⊆Θ
|A ∩θj|
|A|
m(A),
(5) (5) where |A| denotes the cardinality of A, and j = {gen, false}. The classification result is then based on
probabilities computed as in Equation (5). 3.1
Time Function based Features Each of the time functions listed above is decomposed by a Discrete Wavelet Transform (DWT) at different
resolution levels, splitting them into low (approximation) and high (details) frequency components. The
idea is to use the corresponding DWT approximation coefficients to represent the time functions. To actually perform the DWT decomposition, the mother wavelet and the resolution level have to be
chosen. In addition, previous to the DWT decomposition, the time functions have to be resampled in order to
have a fixed-length feature vector. The approximation accuracy is determined by the chosen resolution level,
which also determines the length of the resulting feature vector. This means a trade-offbetween accuracy
and feature vector length, since this length has to be kept reasonably small. Then, the design parameter
is, together with the mother wavelet, the length of the feature vector. The described feature extraction
approach has been first introduced in [10], where experiments using different mother wavelets and resolution
levels have been carried out. The best results have been obtained using the widely known db4 wavelets [52]
and a resolution level of 3, that are also the mother wavelet and resolution level used here. 2.3
Pignistic Transformation To convert the belief functions resulting from the combination of the belief assignments (for instance, com-
puted as in Equations (3) or (4)) into probability measures, the pignistic transformation [50] is usually • Dutch dataset: x, aT , y,vT , p, dp, ρ, dx, θ, dy, d2x, d2y, dvT , 3.2
Global based Features Despite being less accurate than local ones, global features are simple and intuitive, and have the advantage
of being easy to compute and compare. In [11], the discriminative power of this type of features has been
exploited by incorporating a pre-classification step to an existing signature verification system, leading to
improvements not only in the verification results but also in its simplicity and speed. Different global features can be extracted from the measured and extended time functions. In [12]
and [13], several global features were ranked on the basis of two different feature selection strategies. In [11],
in order to successfully pre-classify the signatures, some of the better ranked features in [12] and [13] were
selected. The set of global features proposed in [11] and used in this paper, is composed by: • signature total time duration (T ), • pen down duration (Tpd), • positive x velocity duration (Tvx), • average pressure ( ¯P), • maximum pressure (PM), • maximum pressure (PM), • time at which the pressure is maximum (TPM ). 3.1.2
Features Relevant to FHEs The FHEF features, first introduced in [10], are fully interpretable by FHEs, which is an important char-
acteristic, since these features allow automatic signature verification systems to be integrated into toolkits
useful for FHEs. This is a fundamental step towards bridging the gap between the Pattern Recognition (PR)
and the FHE communities, which is one of the most important current challenges in the field of signature
verification. In [14], it was shown that, despite being quite simple, these features allow to build an automatic
signature verification system based exclusively on them, obtaining competitive verification results. In general, FHEs work with the image of the signature, so it is not possible for them to look at online
features. However, they can infer some dynamic properties from the signature image. When FHEs analyze
a signature, they consider the velocity and the curvature as distinctive features, since they are hard to copy. On the other hand, the acceleration and the pen position (it can be established by striae and inkless starts),
are less useful for them. They do not take into account the local pressure for the analysis because it tends
to be easily influenced by external factors such as surface and writing material. However, they do take into
account pressure fluctuations. The set of features relevant to FHEs is then composed by: • velocity (vT (magnitude) and θ (direction)), • log-radius curvature (ρ), • first order time derivative of the pressure (dp). 3.1.1
Automatically Selected Features The ASF features are selected from the initial set of time functions listed above, based on the variable
importance given by the RF algorithm. They were first introduced in [10], achieving very good verification
results at the cost of being a large and complex feature set. The feature selection is performed over a set of signatures exclusively reserved for training purposes, that
is, the Training Set (see Table 1 in Section 5), for each dataset in the database, namely, Dutch and Chinese. The corresponding automatically selected feature sets are composed by: • Dutch dataset: x, aT , y,vT , p, dp, ρ, dx, θ, dy, d2x, d2y, dvT , • Chinese dataset: y, x, p, vT , aT , dy, dx, d2y, θ, ρ, dp, d2x, dθ, d2p, dvT , dρ, d2θ, • Chinese dataset: y, x, p, vT , aT , dy, dx, d2y, θ, ρ, dp, d2x, dθ, d2p, dvT , dρ, d2θ,
where df and d2f denote the first and second order time derivatives of the corresponding time function
respectively. Looking at the selected features for the Dutch and Chinese datasets, it can be noticed that different
features are selected for each signature style. Then, to include these features to the combination, will
improve its flexibility and capability to adapt to each type of signature. 5 CLEI ELECTRONIC JOURNAL, VOLUME 20, NUMBER 2, PAPER 5, AUGUST 2017 SVM classifiers, respectively. Of course, the performance of the proposed two-step cascade scheme (shown in
Figures 1 and 2), will depend on its implementation. That is, the performance will depend on which feature
sets are selected to train the two independent classifiers involved in the first step combination, and which
feature set is left to be combined at the second step. Then, this constitutes an important tuning decision,
and the way in which the two-cascade scheme is implemented has to be optimized. This is done, over the
corresponding set of signatures reserved exclusively for training purposes (Training Set described in Table 1,
Section 5), together with the optimization of the other tuning parameters of the verification system. Feature
Set 1
Feature
Set 2
Feature
Set 3
RF
Classifier
RF
Classifier
Conversion
Belief Assignment
Conversion
Belief Assignment
Conversion
Belief Assignment
Combination
Rule
Conversion to
Probability
Conversion
Belief Assignment
Combination
Rule
Decision
genuine/false
RF
Classifier
Figure 1: Proposed signature verification system based on a two step cascade score level fusion scheme, when
using the RF classifier. Figure 1: Proposed signature verification system based on a two step cascade score level fusion scheme, when
using the RF classifier. SVM
SVM
Feature
Set 1
Feature
Set 2
Feature
Set 3
SVM
Classifier
SVM
Classifier
SVM
Classifier
Conversion
Belief Assignment
Conversion
Belief Assignment
Conversion
Belief Assignment
Combination
Rule
Conversion to
Probability
Conversion
Belief Assignment
Combination
Rule
Decision
genuine/false
Figure 2: Proposed signature verification system based on a two step cascade score level fusion scheme, when
using the SVM classifier. Figure 2: Proposed signature verification system based on a two step cascade score level fusion scheme, when
using the SVM classifier. The proposed score level fusion is performed as follows. The combination at the first step of the cascade, is
performed between the scores corresponding to two independent classifiers (in one case RF, and in the other,
SVM) trained by two of the proposed feature sets. A value of α is computed for each of these two classifiers. Then, the scores corresponding to each of these classifiers are converted into belief assignments resorting to
Equations (1) or (2). Once the belief assignments are computed, the fusion is performed on the basis of the
proposed combination rules resorting to Equations (3) or (4). Then, the belief functions associated to this
combination are converted into probabilities resorting to Equation (5). 4
Score Level Fusion Scheme Each of the three feature sets described in Section 3 is used to train an independent classifier. The output
of each of these three independent classifiers are the scores that will be combined. Since the idea here is
to evaluate the advantages of the proposed score level fusion approach, the independent classifiers are built
on the basis of two different classifiers, one based on RF [46], and the other based on SVM [47,48]. Then,
the proposed combination is performed, in one case, by fusing the three outputs corresponding to three RF
classifiers trained by each of the three different feature sets, and in the other case, by fusing the three outputs
corresponding to each of the three SVM classifiers trained by each of the three different feature sets. In this
way, it is expected to show that the proposed score level fusion approach improves the systems’ performance
independently of the classification method being used. The proposed combination rules (DS and PCR5), are designed to perform the combination between two
sources of information. Then, to perform the combination of the scores corresponding to each of the three
classifiers trained by each of the three different feature sets, it is necessary to resort to a two-step cascade
scheme. That is, on a first step, a combination between the scores of two independent classifiers trained by
two of the proposed feature sets is performed. Then, on a subsequent step, the outcome of this combination
is combined with the scores of the third classifier trained by the remaining feature set. The details of the
proposed score level fusion scheme can be observed in Figures 1 and 2, for the case of using the RF and 6 6
Evaluation Protocol The Equal Error Rate (EER) has been widely used to evaluate the automatic signature verification systems’
performance. In this paper, the EER is computed, using the Bosaris toolkit, from the Detection Error
TradeOff(DET) Curve as the point in the curve where the False Rejection Rate (FRR) equals the False
Acceptance Rate (FAR) [54]. In recent years, several efforts have been made in order to bridge the gap
between the PR and FHE communities. In line with this idea, to use the cost of the log-likelihood ratios
to evaluate the performance of automatic signature verification systems was introduced in AFHA 2011
Workshop2 (ICDAR 2011), where the importance of computing such measurements was highlighted, since
they allow FHEs to give an opinion on the strength of the evidence [13], although they would not be in the
position to make a leap of faith and judge about guilt or no guilt. In this paper, the cost of the log-likelihood
ratios ˆCllr and its minimal possible value ˆCmin
llr
are computed using the above mentioned toolkit. A smaller
value of ˆCmin
llr
indicates a better performance of the system. llr
The optimization of the tuning parameters of the proposed verification systems is performed, for each
dataset in the SigComp2011 Dataset, over the corresponding set of signatures reserved exclusively for training
purposes, that is, the Training Set (Table 1 in Section 5), while the Testing Set (Table 1 in Section 5) is
used for independent testing purposes. To obtain statistically significant results, a 5-fold cross-validation
(5-fold CV) is performed over the Testing Set to estimate the verification errors. Either in the case of using
RF or SVM classifiers, the 5-fold CV is carried out as follows. The first step, is to train each of the three
independent classifiers, using each of the three feature sets described in Section 3. For each of these three
independent classifiers, the training procedure is the same. For each instance of the 5-fold CV, a signature
model is trained for each writer, using only genuine signatures. It is important to note that forgeries are
not usually available in real applications during the training phase, then, avoiding their use at this stage,
makes the developed system more realistic. 5
Signature Database Dutch Dataset
Chinese Dataset
Training Set
Training Set
Authors
Genuines
Forgeries
Authors
Genuines
Forgeries
10
240
119
10
230
429
Testing Set
Testing Set
Authors
Genuines
Forgeries
Authors
Genuines
Forgeries
54
1296
611
10
219
461 Table 1: Online Dutch (left) and Chinese (right) datasets. Dutch Dataset
Chinese Dataset
Training Set
Training Set
Authors
Genuines
Forgeries
Authors
Genuines
Forgeries
10
240
119
10
230
429
Testing Set
Testing Set
Authors
Genuines
Forgeries
Authors
Genuines
Forgeries
54
1296
611
10
219
461 Table 1: Online Dutch (left) and Chinese (right) datasets. CLEI ELECTRONIC JOURNAL, VOLUME 20, NUMBER 2, PAPER 5, AUGUST 2017 is a common practice to choose t as the one that minimizes the error measurement being used to evaluate
the performance of the signature verification system. Of course, the optimization of t should be performed
over the corresponding set of signatures reserved exclusively for training purposes (Training Set described
in Table 1, Section 5). 1The amount of genuine and forged signature samples may differ from those in [49] since when making signatures available
for the research community some of them were missing [53].
2AFHA 2011: 1st Int. Workshop on Automated Forensic Handwriting Analysis CLEI ELECTRONIC JOURNAL, VOLUME 20, NUMBER 2, PAPER 5, AUGUST 2017 The combination at the second step
of the cascade, is performed between the scores corresponding to the output of the combination performed
in the previous first step and the ones corresponding to the third independent classifier, trained by the
remaining of the proposed feature sets. A new value of α, associated to the output of the combination
performed at the first step, is computed, and so it is a value of α associated to the third independent
classifier (RF or SVM correspondingly). Then, the scores are converted into belief assignments resorting to
Equations (1) or (2), and the fusion is performed on the basis of the proposed combination rules resorting
to Equations (3) or (4). The output of this combination, performed at the second step of the cascade, is the
final output of the system. This output is a belief function itself, and indicates the degree of belief for the
proposed combination. Finally, to make a decision about an input signature, it is necessary to work with
probabilities rather than belief functions. Then, to arrive at the desired output of the system, that is, to
be able to decide whether the input signature corresponds to the claimed identity (is genuine) or not (is a
forgery), it is mandatory to convert the belief functions into probabilities resorting to Equation (5), and as
a subsequent stage, apply some decision rule to these probabilities. Then, a simple decision rule defined as Decision =
(
genuine,
P (θgen)
P (θfalse) ≥t
false,
otherwise. (6) Decision =
(
genuine,
P (θgen)
P (θfalse) ≥t
false,
otherwise. (6) (6) can be applied to actually decide whether the input signature is genuine or a forgery. Usually, the threshold
t can be defined by the user depending on the particular application and the required level of security. It 7 5
Signature Database The publicly available SigComp2011 Dataset [49] is used to carry out the verification experiments. It has two
separate datasets, containing Western (Dutch) and Chinese signatures, respectively. Each dataset is divided
into independent Training and a Testing Sets. Table 1, shows a detailed description of the Dutch (left) and
Chinese (right) datasets1. Skilled forgeries, which are simulated signatures in which forgers are allowed to
practice the reference signature for as long as they deem it necessary, are available. The signatures were
acquired using a ballpoint pen on paper over a WACOM Tablet, which is a natural writing process. The
measured data are the pen coordinates x and y, and the pen pressure p. Table 1: Online Dutch (left) and Chinese (right) datasets. Dutch Dataset
Chinese Dataset
Training Set
Training Set
Authors
Genuines
Forgeries
Authors
Genuines
Forgeries
10
240
119
10
230
429
Testing Set
Testing Set
Authors
Genuines
Forgeries
Authors
Genuines
Forgeries
54
1296
611
10
219
461
6
Evaluation Protocol
The Equal Error Rate (EER) has been widely used to evaluate the automatic signature verification systems’
performance. In this paper, the EER is computed, using the Bosaris toolkit, from the Detection Error
TradeOff(DET) Curve as the point in the curve where the False Rejection Rate (FRR) equals the False
Acceptance Rate (FAR) [54]. In recent years, several efforts have been made in order to bridge the gap
between the PR and FHE communities. In line with this idea, to use the cost of the log-likelihood ratios
to evaluate the performance of automatic signature verification systems was introduced in AFHA 2011
Workshop2 (ICDAR 2011), where the importance of computing such measurements was highlighted, since
they allow FHEs to give an opinion on the strength of the evidence [13], although they would not be in the
position to make a leap of faith and judge about guilt or no guilt. In this paper, the cost of the log-likelihood
ratios ˆCllr and its minimal possible value ˆCmin
llr
are computed using the above mentioned toolkit. A smaller
value of ˆCmin
llr
indicates a better performance of the system. Th
f h
f h
d
fi
f
d f
h Table 1: Online Dutch (left) and Chinese (right) datasets. 7
Results and Discussion As already mentioned in Section 6, the tuning parameters of the system are optimized over the corresponding
set of signatures exclusively reserved to training purposes (Training Set in Table 1, Section 5), for the Dutch
and Chinese datasets. In particular, for the proposed score level fusion scheme, it is necessary to optimize
the order in which the feature sets are combined, that is, the implementation of the two-step cascade scheme,
and the confidence factor α associated with each classifier’s output involved in each combination step. In
addition, the tuning parameters corresponding to both of the classification techniques that are being used,
namely, RF and SVM, have also to be optimized. The proposed two-step cascade scheme (Figures 1 and 2) can be performed in different ways depending on
which feature sets are selected to train the two independent classifiers involved in the first step combination,
and which feature set is left to be combined at the second step. Experiments taking into account all the
possible alternatives have been carried out, over the corresponding Training Sets, for the Dutch and Chinese
datasets. The best option, that is, the one that minimizes the verification errors in these Training Sets, is
the one that performs the combination between ASF and FHEF features at the first step, and leaves the
GF features to perform the combination at the second step, for both, RF and SVM classifiers, and for the
Dutch and Chinese datasets. Then, this is the chosen way for the implementation of the two-step cascade
scheme for computing the verification errors over the Testing Set. Note that, although the ASF and the
FHEF feature sets may contain features in common (it will depend on the algorithm used to perform the
automatic feature selection), they are selected by two explicitly different criteria. In fact, the FHEF features
are meaningful for FHEs, and they intend to represent some of the features they look at in their daily
work. Then, it makes sense to combine these feature sets because they represent information from two very
different sources. That is, the ASF features could be provided by a PR researcher, since automatic feature
selection is a widely used technique to choose features within researchers in the PR community, while the
FHEF could be provided by a FHE researcher, allowing a fruitful contribution between both communities. CLEI ELECTRONIC JOURNAL, VOLUME 20, NUMBER 2, PAPER 5, AUGUST 2017 model corresponding to each of the three independent classifiers that have already been trained. As a result
of this testing procedure, the three scores corresponding to the three classifiers’ outputs are available for
the current testing set of the 5-fold CV. The third step, is then to combine these three independent scores
resorting to the score level fusion described in Section 4. In this way, the final output of the system (the
combined output) is obtained for the current instance of the 5-fold CV. 6
Evaluation Protocol Then, to train the signature model for a particular writer, the
genuine class consists in the genuine signatures of the writer available in the corresponding training set of the
5-fold CV, while the forged class consists in the genuine signatures of all the remaining writers in the dataset
available in the same training set. Once the training phase is completed, the second step is to compute the
scores corresponding to each of the three independent classifiers. The genuine and forged signatures of the
writer under consideration available in the corresponding testing set of the 5-fold CV are used for testing the 8 CLEI ELECTRONIC JOURNAL, VOLUME 20, NUMBER 2, PAPER 5, AUGUST 2017 Dutch Dataset
Denoeux Model
Appriou Model
DS
PCR5
DS
PCR5
RF
SVM
RF
SVM
RF
SVM
RF
SVM
EER
6.14
4.72
6.24
6.48
7.21
6.19
6.92
6.60
ˆCmin
llr
0.1981
0.1430
0.1700
0.1967
0.1914
0.1800
0.1897
0.1875 Table 4: Verification results for the Dutch dataset. Dutch Dataset
Denoeux Model
Appriou Model
DS
PCR5
DS
PCR5
RF
SVM
RF
SVM
RF
SVM
RF
SVM
EER
6.14
4.72
6.24
6.48
7.21
6.19
6.92
6.60
ˆCmin
llr
0.1981
0.1430
0.1700
0.1967
0.1914
0.1800
0.1897
0.1875 Table 4: Verification results for the Dutch dataset. Table 5: Verification results for the Chinese dataset. Chinese Dataset
Denoeux Model
Appriou Model
DS
PCR5
DS
PCR5
RF
SVM
RF
SVM
RF
SVM
RF
SVM
EER
7.00
11.05
6.26
11.50
6.51
15.78
6.48
15.78
ˆCmin
llr
0.1777
0.3236
0.1637
0.3446
0.1682
0.4385
0.1623
0.4376 When a combination of different feature sets is proposed, such as it is here, the main objective is that the
verification performance of the combined system outperforms the corresponding to the ones obtained when
using the feature sets individually. In order to compare, Table 6 summarizes the best combination results
from Tables 4 and 5 (highlighted in boldface in Tables 4 and 5) obtained for each classification method (RF
and SVM), together with the results obtained in the case of using each feature set individually, for the Dutch
(left) and Chinese (right) datasets, respectively. From Table 6, it can be observed that the best verification
results obtained by the proposed score level fusion scheme outperform the ones obtained in the case of using
each feature set individually, for both, RF and SVM classifiers, and for the Dutch and Chinese datasets. This shows that the proposed feature combination is meaningful, since achieves the very first goal of any
feature combination, that is to improve the verification performance with respect to the case of using each
feature set individually. Note that, although only the best results obtained with the proposed combinations
are shown in Table 6, all the results in Tables 4 and 5 (except for the ones corresponding to the case of
using the Appriou model together with the SVM classifier for Chinese signatures that do not outperform the
results obtained when using the ASF features individually) are better than the ones obtained when using
the different feature sets individually. 7
Results and Discussion The value of the confidence factor α, plays a crucial role in the whole score level fusion process, and
so, it has to be carefully chosen. In this paper, α is selected by performing an exhaustive search in the
parameter space. The optimized values of α are shown in Tables 2 and 3, for the Dutch and Chinese
datasets, respectively. Table 2: Confidence factor α for the Dutch dataset. Dutch Dataset
Denoeux
Appriou
DS
PCR5
DS
PCR5
RF
SVM
RF
SVM
RF
SVM
RF
SVM
αASF
0.9
0.9
0.3
0.9
0.9
0.7
0.9
0.9
αF HEF
0.5
0.1
0.2
0.1
0.1
0.4
0.1
0.1
αComb
0.4
0.9
0.8
0.9
0.9
0.2
0.9
0.2
αGF
0.1
0.1
0.2
0.3
0.1
0.1
0.1
0.1
Table 3: Confidence factor α for the Chinese dataset. Chinese Dataset
Denoeux
Appriou
DS
PCR5
DS
PCR5
RF
SVM
RF
SVM
RF
SVM
RF
SVM
αASF
0.9
0.9
0.9
0.9
0.9
0.5
0.8
0.5
αF HEF
0.1
0.1
0.1
0.1
0.3
0.1
0.4
0.1
αComb
0.9
0.9
0.9
0.9
0.8
0.5
0.9
0.5
αGF
0.1
0.1
0.1
0.1
0.3
0.1
0.1
0.1
9 Table 2: Confidence factor α for the Dutch dataset. Dutch Dataset
Denoeux
Appriou
DS
PCR5
DS
PCR5
RF
SVM
RF
SVM
RF
SVM
RF
SVM
αASF
0.9
0.9
0.3
0.9
0.9
0.7
0.9
0.9
αF HEF
0.5
0.1
0.2
0.1
0.1
0.4
0.1
0.1
αComb
0.4
0.9
0.8
0.9
0.9
0.2
0.9
0.2
αGF
0.1
0.1
0.2
0.3
0.1
0.1
0.1
0.1 Table 2: Confidence factor α for the Dutch dataset. Table 3: Confidence factor α for the Chinese dataset. Table 3: Confidence factor α for the Chinese dataset. Chinese Dataset
Denoeux
Appriou
DS
PCR5
DS
PCR5
RF
SVM
RF
SVM
RF
SVM
RF
SVM
αASF
0.9
0.9
0.9
0.9
0.9
0.5
0.8
0.5
αF HEF
0.1
0.1
0.1
0.1
0.3
0.1
0.4
0.1
αComb
0.9
0.9
0.9
0.9
0.8
0.5
0.9
0.5
αGF
0.1
0.1
0.1
0.1
0.3
0.1
0.1
0.1 9 CLEI ELECTRONIC JOURNAL, VOLUME 20, NUMBER 2, PAPER 5, AUGUST 2017 CLEI ELECTRONIC JOURNAL, VOLUME 20, NUMBER 2, PAPER 5, AUGUST 2017 Regarding the tuning parameters of the classifiers, for the RF classifiers, the number of trees to grow and
the number of randomly selected splitting variables to be considered at each node, have to be chosen. It is
well known that, in general, the sensitivity to those parameters is not meaningful [55], and the default values
are a good choice. Then, the number of trees and the number of randomly selected splitting variables are
set to 500 and
√
P (being P the feature vector dimension), respectively, for all the verification experiments. For the SVM classifiers, it is necessary to choose the kernel and its tuning parameters. The Radial Basis
Function (RBF) kernel is used, being the scale σ2 and the regularization parameter C > 0, which provides
a trade-offbetween model complexity and the training error in the SVM cost function, the corresponding
tuning parameters. These values, optimized over the corresponding Training Sets, are σ2 = 10−7 and C = 10,
for all the verification experiments. ˆ p
The verification results are shown, in terms of the EER and the ˆCmin
llr , in Tables 4 and 5 for the Dutch and
Chinese datasets, respectively. These results are obtained resorting to a score level fusion scheme performed
as the two-step cascade shown in Figures 1 and 2 implemented as described above, the optimized values of
α shown in Tables 2 and 3, and the above mentioned optimized parameters for the RF and SVM classifiers,
respectively. Tables 4 and 5 include results obtained in the case of using the Denouex as well as the Appriou
transfer models, and using the DS combination rule as well as the PCR5 one, for the case of using the RF
and the SVM classifiers. Table 4: Verification results for the Dutch dataset. Dutch Dataset
Denoeux Model
Appriou Model
DS
PCR5
DS
PCR5
RF
SVM
RF
SVM
RF
SVM
RF
SVM
EER
6.14
4.72
6.24
6.48
7.21
6.19
6.92
6.60
ˆCmin
llr
0.1981
0.1430
0.1700
0.1967
0.1914
0.1800
0.1897
0.1875
Table 5: Verification results for the Chinese dataset. Chinese Dataset
Denoeux Model
Appriou Model
DS
PCR5
DS
PCR5
RF
SVM
RF
SVM
RF
SVM
RF
SVM
EER
7.00
11.05
6.26
11.50
6.51
15.78
6.48
15.78
ˆCmin
llr
0.1777
0.3236
0.1637
0.3446
0.1682
0.4385
0.1623
0.4376 Table 4: Verification results for the Dutch dataset. CLEI ELECTRONIC JOURNAL, VOLUME 20, NUMBER 2, PAPER 5, AUGUST 2017 that combining them properly can enhance their individual discriminative power, making the combination
to achieve better verification results, without being influenced by the chosen classification method. Then,
although the classifier makes its own contribution to the overall performance of the verification system, the
feature combination has to be useful by itself, that is, for any classification method being used. Table 6: Best combination result vs. individual results for Dutch (left) and Chinese (right) datasets
Dutch Dataset
Chinese Dataset
RF
SVM
RF
SVM
EER
Cmin
llr
EER
Cmin
llr
EER
Cmin
llr
EER
Cmin
llr
Best ASF-FHEF-GF
6.24
0.1700
4.72
0.1430
6.48
0.1623
11.05
0.3236
ASF
6.58
0.205
6.14
0.2227
7.45
0.248
11.90
0.3775
FHEF
8.88
0.2885
8.19
0.2631
8.37
0.2602
16.22
0.4509
GF
12.31
0.4168
9.70
0.3215
14.40
0.4137
32.47
0.7986 Best combination result vs. individual results for Dutch (left) and Chinese (right) datasets. As discussed above, the proposed score level fusion scheme does improve the verification performance
with respect to the ones corresponding to the case of using the feature sets individually. Nevertheless, this
is not the only goal for the proposed score level fusion approach. In fact, the idea here is to make the
score level fusion process more robust by taking into account the possibility of conflicting results appearing
when multiple classifiers are being used. To do so, the score level fusion is performed within the framework
of the BFT. From Tables 4 and 5, an analysis of the use of the BFT to perform the proposed score level
fusion can be done. When using the Appriou model, the conversion of the classifiers’ scores into belief
assignments considers the case of ambiguity in the classifiers’ results (see Equation (2)). In this case, very
similar results are obtained with both combination rules (DS and PCR5). This stands for both datasets
(Dutch and Chinese) and, even more interesting, for both classification techniques, that is, for RF and SVM
classifiers. On the other hand, when using the Denoeux model, the case of ambiguity in the classifiers’ results
is not considered when converting the classifiers’ scores into belief assignments (see Equation (1)). In this
case, there is an appreciable difference between the results achieved when using each combination rule (DS
or PCR5). Moreover, whether using the DS or the PCR5 combination rule yields better results, seems to
be influenced by the classification method (RF or SVM) being used. CLEI ELECTRONIC JOURNAL, VOLUME 20, NUMBER 2, PAPER 5, AUGUST 2017 In fact, from Tables 4 and 5 it can
be observed that, in the case of using the Denouex model, the best results are obtained when using the DS
combination rule for Dutch signatures, and when using the PCR5 combination rule for Chinese signatures. It
would then be reasonable to infer that, despite the fact that, as already mentioned above, the proposed score
level fusion approach does improve the verification performance independently of the classification method
being used, the system becomes more influenced by the chosen classification method, and thereby, weaker,
when the possibility of ambiguity in the classifiers’ results is not considered by the transfer model. In other
words, it seems that to take into account the possibility of ambiguity in the classifiers’ results at the first
stage of the process, that is, when embedding the problem within the BFT framework, makes the whole
score level fusion scheme more robust. Regarding the BFT approach, the best results are obtained when
using the DS combination rule and the Denoeux model for the Dutch data, and the PCR5 combination rule
and the Appriou model for the Chinese data. This shows that, to use the Appriou model has not only the
advantage of making the system more robust, but also of yielding improvements on the verification results
in the case of the Chinese data. Unfortunately, to improve the robustness of the system has a relatively bad
impact on the verification results for the Dutch data. Finally, the best verification results for the proposed score level fusion approach are summarized in
Table 7, for the Dutch (left) and Chinese (right) datasets. These results correspond to the ones obtained
when using the Denoeux model together with the DS combination rule and the SVM classifier, in the
case of the Dutch data, and to the ones obtained when using the Appriou model together with the PCR5
combination rule and the RF classifier, in the case of the Chinese data. In addition of the above analysis,
this explicitly shows the difference between the two signatures styles (Dutch and Chinese), since the score
level fusion scheme that obtains the best verification results, although the same in structure, is completely
different from the implementation point of view in each case. The idea of the paper is to combine three different and meaningful feature sets, paying special attention to
the way in which the combination is performed. CLEI ELECTRONIC JOURNAL, VOLUME 20, NUMBER 2, PAPER 5, AUGUST 2017 Two different classification methods, namely, RF and SVM, were used in order to evaluate the robustness
of the proposed score level fusion approach against the use of different classification methods to implement
the classifiers that are meant to be combined. For the proposed score level fusion scheme to be useful, it is
reasonable to expect it to be robust against the classification method being used to implement each indepen-
dent classifier. The verification results in Table 6, show that the proposed score level fusion scheme improves
the verification performance independently of using RF or SVM classifiers. This is an important fact, since
the idea here is to combine different meaningful feature sets, selected by different criteria, and to show 10 CLEI ELECTRONIC JOURNAL, VOLUME 20, NUMBER 2, PAPER 5, AUGUST 2017 particular, the results in [11], where a pre-classification scheme is used to combine GF and ASF features, the
results in [14], where FHEF features are combined with a subset of the GF features relevant to the FHEs,
and the results in [18], where a plain score level fusion of ASF, FHEF and GF features is performed, are
included. particular, the results in [11], where a pre-classification scheme is used to combine GF and ASF features, the
results in [14], where FHEF features are combined with a subset of the GF features relevant to the FHEs,
and the results in [18], where a plain score level fusion of ASF, FHEF and GF features is performed, are
included. Table 7: Best results for Dutch (left) and Chinese (right) dataset. Dutch Dataset
Chinese Dataset
EER
Cmin
llr
EER
Cmin
llr
Best ASF-FHEF-GF
4.72
0.1430
6.48
0.1623
GF-ASF [11]
3.09
0.112
4.99
0.17
GF-FFHE [14]
4.42
0.178
5.98
0.211
ASF-FHEF-GF [18]
6.95
0.228
7.31
0.218
1st comm. -
0.123
-
0.237
1st non-comm. -
0.237
-
0.351 Table 7: Best results for Dutch (left) and Chinese (right) dataset. From Table 7, it can be seen that, the verification results obtained with the proposed score level fusion
approach outperform the ones obtained in [14] and [18], where other combinations between FHEF and GF,
and among ASF, FHEF and GF features, respectively, are proposed. This stands for the Dutch and Chinese
data. In the case of the Chinese data, the verification results obtained with the proposed score level fusion
approach also outperforms the ones corresponding to the combination of ASF and GF features proposed
in [11]. Unfortunately, this is not the case for the Dutch data, since the verification results obtained with
the proposed score level fusion approach are not as good as in [11]. As already mentioned, the combinations
proposed in [11], [14] and [18] do not take into account the possibility of conflicting results appearing
when different classifiers are being combined. To actually taking this possibility into account, yields more
conservative results. This could be the reason for the results corresponding to the Dutch data being not as
good as the ones in [11]. Nevertheless, even for the case of the Dutch data, the verification results obtained
with the proposed score level fusion approach are good results taking into account the trade-offbetween
accuracy and reliability. CLEI ELECTRONIC JOURNAL, VOLUME 20, NUMBER 2, PAPER 5, AUGUST 2017 Finally, in order to compare the obtained verification results not only with the ones obtained when
combining similar feature sets, but also with the best ones reported in the state-of-the-art over the same
database, the best results in [49] are also included in the last two rows of Table 7. From Table 7, it can
be observed that the verification results obtained with the proposed score level fusion approach are among
the best ones in the state-of-the-art. This is particularly notorious in the case of the Chinese data. In
fact, for this data, the obtained results are specially worth highlighting, outperforming not only the ones
in [11], [14] and [18], but also the ones corresponding to the first ranked commercial and non-commercial
systems in [49]. These are very promising results, since Chinese data is one of the most challenging data
in the literature of online signature verification [49]. In the case of the Dutch data, the verification results
obtained with the proposed combination approach are not as good as in [11], but they are still competitive
within the ones in the state-of-the-art, outperforming not only the ones in [14] and [18], but also the first
ranked non-commercial system in [49]. CLEI ELECTRONIC JOURNAL, VOLUME 20, NUMBER 2, PAPER 5, AUGUST 2017 A particular score level fusion approach is proposed, where
confidence factors are introduced to quantify the confidence in each classifier, and the conflicting results
among the classifiers are handled resorting to the BFT. At this point, it is important to evaluate whether
the performance of the proposed combination approach fulfils the expectations. In order to compare, results
in previous works, where other combinations among ASF, FHEF and GF features have been proposed, but
the conflicting results among the classifiers have not been taken into account, are included in Table 7. In 11 CLEI ELECTRONIC JOURNAL, VOLUME 20, NUMBER 2, PAPER 5, AUGUST 2017 performance. The experimental results show that this objective has successfully been achieved. The proposed
score level fusion approach not only has the advantage of being more reliable and secure by taking into
account the possibility of conflicting results (specially in the case of using the Appriou model), but also
achieves competitive verification performances (which are robust, in the sense that they do not depend on
the chosen classification method), outperforming results obtained when using other proposed combination
schemes, and being among the best ones in the state-of-the-art. ,
g
g
Finally, in the case of the Chinese data, the obtained verification results are not only comparable but
even better than the best ones in the state-of-the-art. In fact, special attention should be paid for the results
obtained for this data, since they are particularly promising. References [1] R. Plamondon and G. Lorette, “Automatic Signature Verification and Writer Identification:
The
State of the Art,” Pattern Recognition, vol. 22, no. 2, pp. 107–131, 1989. [Online]. Available:
https://doi.org/10.1016/0031-3203(89)90059-9 [2] F. Leclerc and R. Plamondon, “Automatic Signature Verification: The State of the Art-1989-1993,”
Int. J. on Pattern Recognition and Artificial Intelligence, vol. 8, no. 3, pp. 643–660, June 1994. [3] R. Plamondon and S. Srihari, “Online and Offline Handwriting Recognition:
A Comprehensive
Survey,” IEEE Trans. on Pattern Analysis and Machine Intelligence, vol. 22, no. 1, pp. 63–84, Jan. 2000. [Online]. Available: http://dx.doi.org/10.1109/34.824821 [4] D. Impedovo and G. Pirlo, “Automatic Signature Verification: The State of the Art,” IEEE Trans. on
Systems, Man, and Cybernetics. Part C: Applications and Reviews, vol. 38, no. 5, pp. 609–635, Sept. 2008. [Online]. Available: http://dx.doi.org/10.1109/TSMCC.2008.923866 [5] D. Impedovo, G. Pirlo, and R. Plamondon, “Handwritten Signature Verification: New Advancements
and Open Issues,” in Proc. of 13th Int. Conf. on Frontiers in Handwriting Recognition, Bari, Italy,
Sept. 2012, pp. 367–372. [Online]. Available: http://dx.doi.org/10.1109/ICFHR.2012.211 [6] D. Yeung, H. Chang, Y. Xiong, S. George, R. Kashi, T. Matsumoto, and G. Rigoll, “SVC2004: First
International Signature Verification Competition,” in Int. Conf. on Biometric Authentication, ser. LNCS, D. Zhang and A. Jain, Eds., vol. 3072. Springer, Berlin, Heidelberg, 2004, pp. 16–22. [Online]. Available: http://dx.doi.org/10.1007/978-3-540-25948-0 3 [7] A. Kholmatov and B. Yanikoglu,
“Identity Authentication Using Improved Online Signature
Verification Method,” Pattern Recognition Letters, vol. 26, no. 15, pp. 2400–2408, 2005. [Online]. Available: https://doi.org/10.1016/j.patrec.2005.04.017 [8] D. Maramatsu and T. Matsumoto,
“Effectiveness of Pen Pressure,
Azimuth,
and
Altitude
Features
for
Online
Signature
Verification,”
in
Advances
in
Biometrics
(ICB
2007),
ser. LNCS,
vol. 4642. Springer,
Berlin,
Heidelberg,
2007,
pp. 503–512. [Online]. Available:
http://dx.doi.org/10.1007/978-3-540-74549-5 53 [9] N. Houmani, S. Garcia-Salicetti, and B. Dorizzi, “On Assessing the Robustness of Pen Coordinates,
Pen Pressure and Pen Inclination to Time Variability with Personal Entropy,” in IEEE 3rd
Int. Conf. on Biometrics:
Theory, Applications, and Systems, Sept. 2009. [Online]. Available:
http://dx.doi.org/10.1109/BTAS.2009.5339074 [10] M. Parodi, J. G´omez, M. Liwicki, and L. Alewijnse, “Orthogonal Function Representation for Online
Signature Verification: Which Features Should be Looked at?”
IET Biometrics, vol. 2, no. 4, pp. 137–150, Dec. 2013. [Online]. Available: http://dx.doi.org/10.1049/iet-bmt.2013.0025 [11] M. Parodi and J. G´omez, Emerging Aspects in Handwritten Signature Verification. World Scientific,
2014, ch. Using Global Features for Pre-classification in Online Signature Verification Systems, pp. 39–52. [12] J. Richiardi, H. Ketabdar, and A. 8
Conclusions In this paper, a feature combination for online signature verification is proposed on the basis of a score level
fusion scheme. In particular, automatically selected features, features relevant to FHEs and global features,
are combined. The idea of the paper is not only to combine three different and meaningful feature sets, but
also to pay special attention to the way in which the combination is performed. It is widely known that,
when combining scores from different classifiers, conflicting results may appear. To address this problem,
the proposed score level fusion is performed within the framework of the BFT. To work within this context,
allows to handle the uncertainty in the classifiers’ results, and allows the possibility of actually measuring
the degree of confidence in each classifier, by letting to explicitly associate a confidence factor with each
classifier. To actually perform the proposed score level fusion within the BFT framework, two different transfer
models, namely, the Denoeux and Appriou models, are used to embed the problem within the framework,
while two different combination rules, namely, the DS and PCR5 ones, are employed to combine the evidence
in such a context. The major challenge of the paper is to perform a score level fusion that actually takes into account
the conflicting results appearing when several classifiers are being used, while keeping a good verification 12 CLEI ELECTRONIC JOURNAL, VOLUME 20, NUMBER 2, PAPER 5, AUGUST 2017 [13] J. Fierrez-Aguilar, L. Nanni, J. Lopez-Pe˜nalba, J. Ortega-Garcia, and D. Maltoni, “An On-Line
Signature Verification System Based on Fusion of Local and Global Information,” in Proc. of IAPR
Int. Conf. on Audio- and Video-Based Biometrics Person Authentication (AVBPA 2005), ser. LNCS,
T. Kanade, A. Jain, and N. Ratha, Eds., vol. 3546. Springer, 2005, pp. 523–532. [Online]. Available:
http://dx.doi.org/10.1007/11527923 54 [14] M. Parodi, J. G´omez, and L. Alewijnse, “Automatic Online Signature Verification Based Only on FHE
Features: An Oxymoron?” in Proc. of 14th Int. Conf. on Frontiers in Handwriting Recognition, Crete
Island, Greece, Sept. 2014, pp. 73–78. [Online]. Available: http://dx.doi.org/10.1109/ICFHR.2014.20 [15] M. Berkay Yilmaz, B. Yanikoglu, C. Tirkaz, and A. Kholmatov, “Offline Signature Verification Using
Classifier Combination of HOG and LBP Features,” in Proc. of 2011 Int. Joint Conf. on Biometrics
(IJCB), Washington DC, USA, 2011, pp. 1–7. [16] D. Yang, Y. Qin, Z. Huang, and Y. Lu, Signal Processing, Image Processing and Pattern Recognition,
ser. Communications in Computer and Information Science. Springer, Berlin, Heidelberg, 2011, vol. 260, ch. Off-line Signature Verification Based on Combination of Modified Direction and Microstructure
Features, pp. 270–279. [Online]. Available: http://dx.doi.org/10.1007/978-3-642-27183-0 29 [17] J. Rico-Juan and J. I˜nesta, “Confidence Voting Method Ensemble Applied to Off-line Signature
Verification,” Pattern Analysis and Applications, vol. 15, no. 2, pp. 113–120, April 2012. [Online]. Available: http://dx.doi.org/10.1007/s10044-012-0270-1 [18] M. Parodi and J. G´omez, “Online Signature Verification: Is the Whole Greater Than the Sum of the
Parts?” in Progress in Pattern Recognition, Image Analysis, Computer Vision, and Applications, ser. LNCS, A. Pardo and J. Kittler, Eds., vol. 9423. Springer, Oct. 2015, pp. 1–9. [Online]. Available:
http://dx.doi.org/10.1007/978-3-319-25751-8 19 [19] L. Hong, A. Jain, and S. Pankanti, “Can Multibiometrics Improve Performance?” in Proc. of AutoID99,
ser. LNCS, T. Kanade, A. Jain, and N. Ratha, Eds., vol. 3546. Springer, Berlin, 1999, pp. 59–64. [20] A. Ross, K. Nandakumar, and A. Jain, Handbook of Multibiometrics, ser. Biometrics. Springer, US,
2006, vol. 6, no. 1. [Online]. Available: http://dx.doi.org/10.1007/0-387-33123-9 [21] M. Gudavalli, S. Raju, A. Babu, and D. Kumar, “Multimodal Biometrics - Sources, Architecture
and
Fusion
Techniques:
An
Overview,”
in
Proc. of
Int. Symposium
on
Biometrics
and
Security Technologies (ISBAST), Taipei,
Taiwan,
March 2012, pp. 27–34. [Online]. Available:
http://dx.doi.org/10.1109/ISBAST.2012.24 [22] S. Soruba Sree and N. Radha, “A Survey on Fusion Techniques for Multimodal Biometric Identification,”
Int. J. of Innovative Research in Computer and Communication Engineering, vol. 2, no. 12. [23] J. Clark
and
A. References Drygajlo, “Local and Global Feature Selection for On-line Signature
Verification,” in Proc. of 8th Int. Conf. on Document Analysis and Recognition, Seoul, South Korea,
Sept. 2005, pp. 625–629. [Online]. Available: http://dx.doi.org/10.1109/ICDAR.2005.152 13 13 CLEI ELECTRONIC JOURNAL, VOLUME 20, NUMBER 2, PAPER 5, AUGUST 2017 [29] D. Shashi Kumar, R. Ravi Kumar, K. Raja, R. Chhotaray, and S. Pattanaik, Information and
Communication Technologies, ser. Communications in Computer and Information Science. Springer,
Berlin, Heidelberg, 2010, vol. 101, ch. Combined Off-Line Signature Verification Using Neural
Networks, pp. 580–583. [Online]. Available: http://dx.doi.org/10.1007/978-3-642-15766-0 99 [30] K. Tselios, E. Zois, A. Nassiopoulos, and G. Economou, “Fusion of Directional Transitional Features
for Offline Signature Verification,” in Proc. of Int. Joint Conf. on Biometrics (IJCB), Oct. 2011. [Online]. Available: http://dx.doi.org/10.1109/IJCB.2011.6117515 [31] C. Allgrove and M. Fairhurst, “Majority Voting for Improved Signature Verification,” in Proc. of IEE Colloquium on Visual Biometrics, Lndon, UK, March 2000, pp. 1–4. [Online]. Available:
http://dx.doi.org/10.1049/ic:20000469 [32] V. Mottl, M. Lange, V. Sulimova, and A. Yermakov, “Signature Verification Based on Fusion of
On-line and Off-line Kernels,” in Proc. of 19th Int. conference on Pattern Recognition (ICPR 2008),
Tampa, FL, USA, Dec. 2008. [Online]. Available: http://dx.doi.org/10.1109/ICPR.2008.4761208 [33] H. Baltzakisa and N. Papamarkosb, “A New Signature Verification Technique Based on a Two-stage
Neural Network Classifier,” Engineering Applications of Artificial Intelligence, vol. 14, no. 1, pp. 95–103, Feb. 2001. [Online]. Available: https://doi.org/10.1016/S0952-1976(00)00064-6 [34] A. Dempster, “Upper and Lower Probabilities Induced by a Multivalued Mapping,” The Annals of
Mathematical Statistics, vol. 38, no. 2, pp. 325–339, April 1967. [35] G. Shafer, A Mathematical Theory of Evidence. Princeton University Press, Sept. 1976. [36] D. Kisku, J. Sing, and P. Gupta, “Multibiometrics Belief Fusion,” in Proc. of 2nd Int. Conf. on Machine
Vision, 2009, pp. 37–40. [Online]. Available: http://doi.ieeecomputersociety.org/10.1109/ICMV.2009.63 [37] B. Xiao, “Multi-biometric Feature Fusion Identification Based on D-S Evident Theory of Image Quality
with Different Weights,” J. of Computer Applications, vol. 32, no. 1, pp. 264–268, 2012. [38] F. Wang,
Advanced
Materials
Research,
2012,
vol. 459,
ch. Fusion
Fingerprint
and
Face
Multi-Biometrics Recognition Based on D-S Evidence Theory, pp. 580–583. [Online]. Available:
10.4028/www.scientific.net/AMR.459.644 [39] K. Nguyen,
S. Denman,
S. Sridharan,
and
C. Fookes,
“Score-level
Multibiometric
Fu-
sion
Based
on
Dempster-Shafer
Theory
Incorporating
Uncertainty
Factors,”
IEEE
Trans. Human-Machine
Systems,
vol. 45,
no. 1,
pp. 132–140,
Feb. 2015. [Online]. Available:
http://dx.doi.org/10.1109/THMS.2014.2361437 [40] M. Parodi, J. G´omez, L. Alewijnse, and M. Liwicki, “Online Signature Verification: Automatic Feature
Selection vs. FHE’s Choice,” J. of Forensic Document Examination, vol. 24, no. 1. [41] T. Denoeux and M. Masson,
“Dempster-Shafer Reasoning in Large Partially Ordered Sets:
Applications in Machine Learning,”
in Integrated Uncertainty Management
and Applications,
ser. Advances in Intelligent and Soft Computing,
V. Huynh,
Y. Nakamori,
J. CLEI ELECTRONIC JOURNAL, VOLUME 20, NUMBER 2, PAPER 5, AUGUST 2017 Yuille,
Data
Fusion
for
Sensory
Information
Processing
Systems,
ser. Engineering
and
Computer
Science. Springer,
1990,
vol. 105. [Online]. Available:
http://dx.doi.org/10.1007/978-1-4757-2076-1 [24] L. Mezai and F. Hachouf, “Score-Level Fusion of Face and Voice Using Particle Swarm Optimization
and Belief Functions,” IEEE Trans. on Human-Machine Systems, vol. 45, no. 6, pp. 761–772, June
2015. [Online]. Available: http://dx.doi.org/10.1109/THMS.2015.2438005 [25] I. Nakanishi, H. Sakamoto, Y. Itoh, and Y. Fukui, “Optimal User Weighting Fusion in DWT Domain
On-Line Signature Verification,” in AVBPA 2005, ser. LNCS, vol. 3546. Springer, Berlin, 2005, pp. 758–766. [Online]. Available: http://dx.doi.org/10.1007/11527923 79 [26] S. Koike, I. Nakanishi, and Y. Itoh, “Score Level Fusion in DWT Domain On-line Signature Verification,”
in Proc. of 23th Int. Technical Conf. on Circuits Systems , Computers and Communication, 2008, pp. 669–672. [27] N. Abbas and Y. Chibani, “Combination of Off-Line and On-Line Signature Verification Systems Based
on SVM and DST,” in Proc. of Int. Conf. on Intelligent Systems Design and Applications (ISDA), Cor-
doba, Spain, Nov. 2011, pp. 22–24. [Online]. Available: http://dx.doi.org/10.1109/ISDA.2011.6121764 [28] ——, “SVM-DSmT Combination for Off-Line Signature Verification,” in Proc. of Int. Conf. on
Computer, Information and Telecommunication Systems (CITS), Amman, Jordan, May 2012, pp. 1–5. [Online]. Available: http://dx.doi.org/10.1109/CITS.2012.6220365 14 CLEI ELECTRONIC JOURNAL, VOLUME 20, NUMBER 2, PAPER 5, AUGUST 2017 Lawry,
and
M. Inuiguchi, Eds., vol. 68. Springer, Berlin, Heidelberg, 2010, pp. 39–54. [Online]. Available:
http://dx.doi.org/10.1007/978-3-642-11960-6 5 [42] L. Fouque, A. Appriou, and W. Pieczynski, “An Evidential Markovian Model for Data Fusion and
Unsupervised Image Classification,” in Proc. of 3rd Int. Conf. on Information Fusion, Paris, France,
July 2000, pp. 25–32. [Online]. Available: http://dx.doi.org/10.1109/IFIC.2000.862671 [43] A. Dempster, “A Generalization of Bayesian Inference,” J. of the Royal Statistical Society, vol. 30,
no. 2, pp. 205–247, 1968. [Online]. Available: http://www.jstor.org/stable/2984504 [44] N. Wilson, Handbook of Defeasible Reasoning and Uncertainty Management Systems. Springer,
Dordrecht, 2000, vol. 5, ch. Algorithms for Dempster-Shafer Theory, pp. 421–475. [Online]. Available:
http://dx.doi.org/10.1007/978-94-017-1737-3 10 [45] F. Smarandache and J. Dezert, “Information Fusion Based on New Proportional Conflict Redistribution
Rules,” in Proc. of 7th Int. Conf. on Information Fusion, Philadelphia, PA, USA, July 2005, pp. 25–29. [Online]. Available: http://dx.doi.org/10.1109/ICIF.2005.1591955 [46] L. Breiman, “Random Forests,” Stat. Dep., U. of California, Berkeley, Tech. Rep., 2001. 15 CLEI ELECTRONIC JOURNAL, VOLUME 20, NUMBER 2, PAPER 5, AUGUST 2017 [47] V. Vapnik, The Nature of Statistical Learning Theory. NY: Springer, 1995. [48] ——, Statistical Learning Theory. Wiley, 1998. [49] M. Liwicki, M. Malik, C. den Heuvel, X. Chen, C. Berger, R. Stoel, M. Blumenstein, and B. Found,
“Signature Verification Competition for Online and Offline Skilled Forgeries (SigComp2011),” in Proc. of 11th Int. Conf. on Doc. Anal. and Recognit., Beijing, China, Sept. 2011. [Online]. Available:
http://dx.doi.org/10.1109/ICDAR.2011.294 [50] J. Dezert, F. Smarandache, and M. Daniel, “The Generalized Pignistic Transformation,” in Proc. of 7th
Int. Conf. on Information Fusion, Stockholm, Sweden, June 2004, pp. 384–391. [51] J. Fierrez-Aguilar,
J. Ortega-Garcia,
D. Ramos-Castro,
and J. Gonzalez-Rodriguez,
“HMM-
based
On-line
Signature
Verification:
Feature
Extraction
and
Signature
Modelling,”
Pat-
tern
Recognition
Letters,
vol. 28,
no. 16,
pp. 2325–2334,
Dec. 2007. [Online]. Available:
https://doi.org/10.1016/j.patrec.2007.07.012 [52] I. Daubechies, Ten Lectures on Wavelets. Pennsylvania: SIAM: Society for Industrial and Applied
Mathematics, 1992. [53] SigComp2011,
“ICDAR
2011
Signature
Verification
Competition,”
http://www.iapr-
tc11.org/mediawiki/index.php/Datasets List, 2011. [54] N. Brummer and J. du Preez, “Application-Independent Evaluation of Speaker Detection,” Computer
Speech & Language, vol. 20, no. 2-3, pp. 230–275, April-July 2006. [55] A. Liaw and M. Wiener, “Classification and Regression by randomForest,” R News, vol. 2, no. 3. 16 16
|
https://openalex.org/W2027002541
|
https://europepmc.org/articles/pmc3509691?pdf=render
|
English
| null |
Safety and Immunogenicity of a Plant-Produced Recombinant Hemagglutinin-Based Influenza Vaccine (HAI-05) Derived from A/Indonesia/05/2005 (H5N1) Influenza Virus: A Phase 1 Randomized, Double-Blind, Placebo-Controlled, Dose-Escalation Study in Healthy Adults
|
Viruses
| 2,012
|
cc-by
| 8,218
|
Viruses 2012, 4, 3227-3244; doi:10.3390/v4113227
viruses
ISSN 1999-4915
www.mdpi.com/journal/viruses
Article
Safety and Immunogenicity of a Plant-Produced Recombinant
Hemagglutinin-Based Influenza Vaccine (HAI-05) Derived from
A/Indonesia/05/2005 (H5N1) Influenza Virus: A Phase 1
Randomized, Double-Blind, Placebo-Controlled,
Dose-Escalation Study in Healthy Adults
Jessica A. Chichester, R. Mark Jones, Brian J. Green, Mark Stow, Fudu Miao,
George Moonsammy, Stephen J. Streatfield and Vidadi Yusibov *
Fraunhofer USA, Center for Molecular Biotechnology, Newark, DE 19711, USA;
E-Mails: jchichester@fraunhofer-cmb.org (J.A.C.); mjones@fraunhofer-cmb.org (R.M.J.);
bgreen@fraunhofer-cmb.org (B.J.G.); mstow@fraunhofer-cmb.org (M.S.);
fmiao@fraunhofer-cmb.org (F.M.); gmoonsammy@fraunhofer-cmb.org (G.M.);
sstreatfield@fraunhofer-cmb.org (S.J.S.); vyusibov@fraunhofer-cmb.org (V.Y.)
* Author to whom correspondence should be addressed; E-Mail: vyusibov@fraunhofer-cmb.org;
Tel.: +1-302-369-3766; Fax: +1-302-369-8955.
Received: 25 October 2012; in revised form: 15 November 2012 / Accepted: 16 November 2012 /
Published: 19 November 2012
OPEN ACCESS Viruses 2012, 4, 3227-3244; doi:10.3390/v4113227 viruses
ISSN 1999-4915
www.mdpi.com/journal/viruses
OPEN ACCESS Safety and Immunogenicity of a Plant-Produced Recombinant
Hemagglutinin-Based Influenza Vaccine (HAI-05) Derived from
A/Indonesia/05/2005 (H5N1) Influenza Virus: A Phase 1
Randomized, Double-Blind, Placebo-Controlled,
Dose-Escalation Study in Healthy Adults Jessica A. Chichester, R. Mark Jones, Brian J. Green, Mark Stow, Fudu Miao,
George Moonsammy, Stephen J. Streatfield and Vidadi Yusibov * Viruses 2012, 4 The immune response elicited by the HAI-05 vaccine was variable with respect to both
hemagglutination-inhibition and virus microneutralization antibody titers, with the highest
responses observed in the 90 µg unadjuvanted group. Keywords:
influenza
A;
H5N1;
recombinant
vaccine;
hemagglutinin;
plant-produced vaccine Keywords:
influenza
A;
H5N1;
recombinant
vaccine;
hemagglutinin;
plant-produced vaccine 1. Introduction Infections with influenza viruses cause a serious respiratory disease, due to which three to five
million cases of severe illness are recorded worldwide annually, with 250,000 to 500,000 deaths [3]. In addition to seasonal influenza outbreaks, occasional influenza pandemics can arise at any time when
influenza A virus containing a novel hemagglutinin (HA) subtype is introduced and effectively
transmitted among humans. In 1997, a highly pathogenic avian influenza strain of subtype H5N1
caused widespread disease in poultry in Hong Kong. The virus spread rapidly from 2004 onwards and
has now caused serious poultry disease outbreaks in several Asian countries, Europe and Africa. More
than 500 individuals have been infected with H5N1 viruses with a mortality rate of 50–60%. Fortunately, almost all reported human cases have had close contact with infected birds, with very rare
instances of presumed human to human transmission. Nevertheless, considerable concern for human
health remains, not only because of the severity of human cases, but also because the virus could
undergo adaptive mutation or re-assortment and obtain the ability to spread efficiently among
humans [4‒6]. Should these events occur, the H5N1 and/or other novel viruses could have the
potential to cause a pandemic exhibiting a very aggressive clinical progression with devastating health
and economic consequences globally. Such a scenario underscores the urgent need for rapid and robust
influenza vaccine production methods to better prevent and mitigate the effects of pandemics in
the future. The potential of plants as a platform for the production of subunit vaccines and therapeutic proteins
has been recently demonstrated [7]. We have developed an approach for transient expression of target
proteins in healthy Nicotiana benthamiana using a Tobacco mosaic virus-based ‘launch’ vector
system [8] and demonstrated its utility by producing vaccine antigens derived from Bacillus
anthracis [9], Yersinia pestis [10], and seasonal and pandemic strains of influenza virus [1,11,12]. Recently, we have developed a recombinant HA-based vaccine, HAI-05, for the prevention of
disease caused by the novel A/Indonesia/05/2005 (H5N1) strain of influenza A virus, and produced
this target in N. benthamiana at pilot plant scale under current Good Manufacturing Practice
(cGMP) guidelines [2]. Pre-clinical studies have demonstrated immunogenicity of HAI-05 in mice,
rabbits and ferrets [2] and prompted further investigation of this vaccine candidate in humans. Jessica A. Chichester, R. Mark Jones, Brian J. Green, Mark Stow, Fudu Miao,
George Moonsammy, Stephen J. Streatfield and Vidadi Yusibov * Fraunhofer USA, Center for Molecular Biotechnology, Newark, DE 19711, USA;
E-Mails: jchichester@fraunhofer-cmb.org (J.A.C.); mjones@fraunhofer-cmb.org (R.M.J.);
bgreen@fraunhofer-cmb.org (B.J.G.); mstow@fraunhofer-cmb.org (M.S.);
fmiao@fraunhofer-cmb.org (F.M.); gmoonsammy@fraunhofer-cmb.org (G.M.);
sstreatfield@fraunhofer-cmb.org (S.J.S.); vyusibov@fraunhofer-cmb.org (V.Y.) * Author to whom correspondence should be addressed; E-Mail: vyusibov@fraunhofer-cmb.org;
Tel.: +1-302-369-3766; Fax: +1-302-369-8955. Received: 25 October 2012; in revised form: 15 November 2012 / Accepted: 16 November 2012 /
Published: 19 November 2012 Received: 25 October 2012; in revised form: 15 November 2012 / Accepted: 16 November 2012 /
Published: 19 November 2012 Abstract: Recently, we have reported [1,2] on a subunit influenza vaccine candidate based
on the recombinant hemagglutinin protein from the A/Indonesia/05/2005 (H5N1) strain of
influenza virus, produced it using ‘launch vector’-based transient expression technology in
Nicotiana benthamiana, and demonstrated its immunogenicity in pre-clinical studies. Here, we present the results of a first-in-human, Phase 1 randomized, double-blind,
placebo-controlled
study
designed
to
investigate
safety,
reactogenicity
and
immunogenicity of three escalating dose levels of this vaccine, HAI-05, (15, 45 and 90 µg)
adjuvanted with Alhydrogel® (0.75 mg aluminum per dose) and the 90 µg dose level
without Alhydrogel®. Vaccine was administered intramuscularly in two injections three
weeks apart to healthy adults of 18–49 years of age. At all dose levels the vaccine was
generally safe and well tolerated, with no reported serious adverse events or
dose-limiting toxicities. Mild local and systemic reactions were observed in all vaccine
dose groups and the placebo group and their occurrence was not dose related. The incidence rates were higher in the groups receiving vaccine with Alhydrogel®. 3228 Viruses 2012, 4 Viruses 2012, 4 2. Results and Discussion This first-in-human, Phase 1 randomized, double-blind, placebo-controlled clinical trial was
conducted to evaluate safety, reactogenicity and immunogenicity of two doses of the HAI-05 vaccine
delivered at three escalating dose levels—15, 45 and 90 µg adjuvanted with Alhydrogel® and 90 µg
without Alhydrogel®—in healthy adults 18–49 years of age. Viruses 2012, 4 Viruses 2012, 4 Viruses 2012, 4 3229 discontinuation: lost to follow-up. b: The “Per-protocol” population included all subjects who received two doses of vaccine and had a complete
set of serum specimens for antibody determination. : The “Intent-to-treat” population included all subjects who received one dose of vaccine. p
y
c: Reason for discontinuation: lost to follow-up. set of serum specimens for antibody determination.
c: Reason for discontinuation: lost to follow-up. p p
j
rotocol” population included all subjects who received two doses of vaccine and had a complete
m specimens for antibody determination 1. Introduction Here, we report the results of a Phase 1 study conducted to determine safety, reactogenicity and
immunogenicity of three escalating dose levels of HAI-05 (15, 45 and 90 µg) adjuvanted with
Alhydrogel® and the 90 µg dose level without Alhydrogel®, delivered intramuscularly to healthy adults
of 18–49 years of age. p
y
c: Reason for discontinuation: lost to follow-up. 2.1. Study Population Of the 100 subjects who were randomized and treated, all received both scheduled
vaccinations (Table 1). The mean age of participants was 30–32 years for the active dose groups and
approximately 34 years for the placebo group. The proportion of female subjects was higher in the
active dose groups (55–72%), whereas equal numbers of female and male subjects were enrolled in the
placebo group. Most subjects in all groups were white (65–85% in the active dose groups and 86% in
the placebo group) (Table 2). Table 1. Subject disposition. Adjuvanted HAI-05
Unadjuvanted
HAI-05
Placebo
15 µg
n (%)
45 µg
n (%)
90 µg
n (%)
90 µg
n (%)
n (%)
All subjects treated
18 (100)
20 (100)
20 (100)
20 (100)
22 (100)
Intent-to-treat population a
18 (100)
20 (100)
20 (100)
20 (100)
22 (100)
Per-protocol population b
18 (100)
20 (100)
20 (100)
20 (100)
22 (100)
Completed the study
16 (88.9)
20 (100)
19 (95.0)
20 (100)
21 (95.5)
Discontinued from the study c
2 (11.1)
0
1 (5.0)
0
1 (4.5) Table 1. Subject disposition. Table 1. Subject disposition. b: The “Per-protocol” population included all subjects who received two doses of vaccine and ha
set of serum specimens for antibody determination. c: Reason for discontinuation: lost to follow-up. c: Reason for discontinuation: lost to follow-up. Viruses 2012, 4 3230 Table 2. Demographic characteristics. 2.2. Safety and Reactogenicity
Adjuvanted HAI-05
Unadjuvanted
HAI-05
Placebo
15 µg
N = 18
45 µg
N = 20
90 µg
N = 20
90 µg
N = 20
N = 22
Female, n (%)
13 (72.2)
11 (55.0)
12 (60.0)
12 (60.0)
11 (50.0)
Age (years)
n
18
20
20
20
22
Mean
31.8
31.1
32.0
30.1
34.1
SD
8.3
9.2
9.6
7.8
9.5
Median
(Min, Max)
30.0
(18, 46)
30.5
(18, 49)
29.5
(19, 47)
28.5
(18, 42)
32.0
(21, 49)
Race, n (%)
White
15 (83.3)
17 (85.0)
13 (65.0)
14 (70.0)
19 (86.4)
Black or African American
3 (16.7)
3 (15.0)
7 (35.0)
6 (30.0)
2 (9.1)
Asian
0
0
0
0
1 (4.5) 2.2. Safety and Reactogenicity 2.2. Safety and Reactogenicity The HAI-05 vaccine was safe and well tolerated in all groups. No deaths, serious adverse
events (SAEs), clinically significant laboratory abnormalities, or AEs of special interest were reported
during the trial. No subject withdrew from the study due to an AE (Table 3). Treatment-related AEs
that occurred after any vaccination (Table 3) included myalgia in the 15 µg adjuvanted dose group,
injection site pain, pruritus, urticaria, back pain, headache and diarrhea in the 90 µg adjuvanted dose
group, and pruritus in the 90 µg unadjuvanted dose group. Table 3. Incidence of AEs after any vaccination. a: Number (%) of subjects reporting symptom at any post-vaccination assessment. Each subject was counted
only once. AE category, n (%) a
Adjuvanted HAI-05
Unadjuvanted
HAI-05
Placebo
15 µg
N = 18
45 µg
N = 20
90 µg
N = 20
90 µg
N = 20
N = 22
Any AEs
9 (50)
8 (40)
13 (65)
10 (50)
11 (50)
Treatment-related AEs
2 (11.1)
0
4 (20)
1 (5)
0
Serious AEs
0
0
0
0
0
AEs leading to discontinuation from the study
0
0
0
0
0
AEs leading to death
0
0
0
0
0 Table 3. Incidence of AEs after any vaccination. The incidence of solicited local injection site reactions occurring within 7 days following either
vaccination was similar across different adjuvanted HAI-05 dose groups, but was greater than in the
unadjuvanted 90 µg dose group and in the placebo group. The most frequently reported reaction was
pain at the injection site, with a relatively high incidence rate in the 90 µg adjuvanted dose group after Viruses 2012, 4 Viruses 2012, 4 3231 the first dose (80%), which was mild and self-limited. Swelling was infrequent, and no redness was
reported in any of the groups following either dose of the vaccine or placebo (Table 4). The incidence of solicited systemic events occurring within 7 days following either vaccination was
similar across different active dose groups and in general was similar to the placebo group. The most
frequently reported systemic event was headache, which occurred in all dose groups, but most often in
the 90 µg adjuvanted dose group following both the first (35%) and second (30%)
vaccination (Table 5). Table 4. Incidence of solicited local injection site reactions after the first and
second vaccination. a: Number (%) of subjects reporting symptom. Each subject was counted only once. a: Number (%) of subjects reporting symptom. Each subject was counted only once.
b (
)
j
b: Between Days 1 and 8. a: Number (%) of subjects reporting symptom. Each subject was counted only once.
b: Between Days 1 and 8 : Between Days 1 and 8.
c: Between Days 22 and 29. 2.3. Immunogenicity Mean geometric mean titers (GMTs) of the serum hemagglutination-inhibition (HAI) antibodies for
the three adjuvanted dose groups were the same as the mean GMT for the placebo group on
Days 1 and 22, and only slightly increased by Day 43. In contrast, the mean GMT for the unadjuvanted
90 µg dose group increased 6.4-fold from Day 1 through 43 (Table 6). Furthermore, seroconversion
(10%) after the first vaccination (Day 22) was observed only in the unadjuvanted 90 µg dose group,
and after the second vaccination (Day 43) only in the adjuvanted and unadjuvanted 90 µg dose groups
(5% and 10%, respectively) (Table 6). The same results were obtained for the proportions of subjects
who achieved HAI titers ≥40 (Table 6). Similar immunogenicity was observed for the adjuvanted dose groups based on mean GMTs of the
virus microneutralization (MN) antibodies. In contrast to the adjuvanted dose groups, the mean GMT
increased 16-fold from baseline in the unadjuvanted 90 µg dose group after the first vaccination
(Days 22) and remained at the same level after the second vaccination (Days 43) (Table 7). At the
cut-off titer of ≥20, the unadjuvanted 90 µg dose group was the only active treatment group in which
seroconvertion was observed (10%) after the first vaccination (Day 22). However, after the second
vaccination (Day 43), some subjects in all of the active dose groups seroconverted in the range
from 5.6% to 15% (Table 7). In the post-hoc analysis using a MN antibody cut-off titer of ≥10, 40% of
subjects who received the adjuvanted 45 µg vaccine dose seroconverted on Day 43, followed by
only 20% of subjects who received the adjuvanted 90 µg dose (Table 7). Also, at the cut-off titer
of ≥10 the response rates for the unadjuvanted and adjuvanted 90 µg doses were 15% and 0% on
Day 22 and 15% and 20% on Day 43, respectively, further indicating that the presence of Alhydrogel®
had no effect on HAI-05 vaccine immunogenicity (Table 7). Surprisingly, one subject (4.5%) in the
placebo group (Table 7) who was seronegative at baseline (the titer of 5.0 on Day 1) was also
determined as seroconverted after the first vaccination (the titer of 20 on Day 22). The titer on Day 22
was just at the borderline of seropositivity (≥20) and subsequently declined to 7.07 after the second
vaccination (Day 43). Viruses 2012, 4 3232 Nearly all AEs were mild to moderate in intensity. The only notable unsolicited AE, localized rash,
occurred in one female subject in the 90 µg adjuvanted dose group approximately two days after
each vaccination. The subject was receiving chronic topical corticosteroid treatment for psoriasis and a
tranquilizer for anxiety before and during the trial. These rash events were not examined or confirmed
by the investigator, but were reported by the subject to be mild and resolve without any specific
treatment within 48 hours. The subject was lost to follow-up. Overall, at all dose levels, the HAI-05 vaccine was generally well tolerated, with only mild local
injection site reactions which did not appear to be dose related in the presence of Alhydrogel®,
but were considerably lower without adjuvant even at the highest administered vaccine dose. 2.2. Safety and Reactogenicity b: Between Days 1 and 8. c: Between Days 22 and 29. Adjuvanted HAI-05
Unadjuvanted
HAI-05
Placebo
15 µg
N = 18
45 µg
N = 20
90 µg
N = 20
90 µg
N = 20
N = 22
Vaccination
n (%) a
Dose 1 b Dose 2 c Dose 1
Dose 2
Dose 1 Dose 2 Dose 1 Dose 2 Dose 1 Dose 2
Pain at
Injection Site
11
(61.1) 10 (55.6) 12 (60.0) 11 (55.0) 16 (80.0) 10 (50.0) 1 (5.0) 3 (15.0) 3 (13.6) 1 (4.5)
Redness
0
0
0
0
0
0
0
0
0
0
Swelling
0
1 (5.6)
0
0
2 (10.0) 1 (5.0)
0
0
0
0 Table 4. Incidence of solicited local injection site reactions after the first and
second vaccination. Table 5. Incidence of solicited systemic events after the first and second vaccination. a: Number (%) of subjects reporting symptom. Each subject was counted only once. b: Between Days 1 and 8. c
Adjuvanted HAI-05
Unadjuvanted
HAI-05
Placebo
15 µg
N = 18
45 µg
N = 20
90 µg
N = 20
90 µg
N = 20
N = 22
Vaccination
n (%) a
Dose 1 b Dose 2 b Dose 1
Dose 2
Dose 1
Dose 2 Dose 1 Dose 2 Dose 1 Dose 2
Fever
0
0
0
0
0
0
0
1 (5.0) 1 (4.5)
0
Tiredness
4 (22.2) 4 (22.2) 4 (20.0) 2 (10.0) 5 (25.0) 1 (5.0) 3 (15.0) 1 (5.0) 2 (9.1) 1 (4.5)
Chills
2 (11.1) 1 (5.6)
1 (5.0)
0
1 (5.0)
0
1 (5.0)
0
2 (9.1) 1 (4.5)
Malaise-
Feeling Discomfort 1 (5.6) 2 (11.1)
0
0
3 (15.0) 4 (20.0) 1 (5.0)
0
3 (13.6) 1 (4.5)
Joint Aches
2 (11.1) 2 (11.1) 1 (5.0)
1 (5.0)
1 (5.0)
1 (5.0) 2 (10.0)
0
1 (4.5) 1 (4.5)
Muscle Aches
4 (22.2) 4 (22.2) 3 (15.0) 2 (10.0) 4 (20.0) 3 (15.0) 2 (10.0) 2 (10.0) 2 (9.1) 2 (9.1)
Headache
4 (22.2) 4 (22.2) 4 (20.0) 2 (10.0) 7 (35.0) 6 (30.0) 4 (20.0) 4 (20.0) 4 (18.2)
0 Table 5. Incidence of solicited systemic events after the first and second vaccination. ,
y
g
b: GMT, geometric mean titer.
c: CI, confidence interval. 2.3. Immunogenicity Furthermore, no seroconversion was observed in other placebo subjects after
either the first or the second vaccination, and no subjects in the placebo group seroconverted based on
HAI titers (the primary outcome measure). Taken together, these findings suggest that the single
placebo subject who appeared to have seroconverted may be as a result of the MN assay variability. Table 6. HAI titers and seroconversion. Dose of
HAI-05
A a
N subjects
per group
Pre-vaccination
(Day 1)
Post-1st vaccination
(Day 22)
Post-2nd vaccination
(Day 43)
GMT b
(95% CI c)
GMT
(95% CI)
Seroconversion
n (%)
(95% CI)
Titer ≥40
n (%)
(95% CI)
GMT
(95% CI)
Seroconversion
n (%)
(95% CI)
Titer ≥40
n (%)
(95% CI)
Placebo
–
22
5.0
(5.0, 5.0)
5.0
(5.0, 5.0)
0
0
5.0
(5.0, 5.0)
0
0
15 µg
+
18
5.0
(5.0, 5.0)
5.0
(5.0, 5.0)
0
0
6.41
(4.16, 8.66)
0
0
45 µg
+
20
5.0
(5.0, 5.0)
5.0
(5.0, 5.0)
0
0
6.16
(4.15, 8.18)
0
0
90 µg
+
20
5.0
(5.0, 5.0)
5.0
(5.0, 5.0)
0
0
6.85
(3.83, 9.88)
1 (5.0)
(0, 0.1)
1 (5.0)
(0, 0.1)
90 µg
–
20
6.75
(3.72, 9.78)
36.50
(0, 73.99)
2 (10.0)
(0, 0.2)
2 (10.0)
(0, 0.2)
43.23
(0, 89.35)
2 (10.0)
(0, 0.2)
2 (10.0)
(0, 0.2)
a: A, Alhydrogel®. b GMT
t i
tit Viruses 2012, 4 3234 Table 7. MN titers and seroconversion. b e 7. N t te s a d se oco ve s o . ,
y
g
b: GMT, geometric mean titer.
c: CI, confidence interval. 2.3. Immunogenicity Dose of
HAI-05
A a
N subjects
per group
Pre-vaccination
(Day 1)
Post-1st vaccination
(Day 22)
Post-2nd vaccination
(Day 43)
GMT b
(95% CI c)
GMT
(95% CI)
Seroconversion n (%)
[95% CI]
GMT
(95% CI)
Seroconversion n (%)
[95% CI]
Titer cut-off
≥20
Titer cut-off
≥10
Titer cut-off
≥20
Titer cut-off
≥10
Placebo
–
22
5.78
(4.60, 6.96)
7.37
(4.62, 10.13)
1 (4.5)
[0.0, 0.2]
1 (4.5)
[0.0, 0.2]
5.53
(4.77, 6.30)
0
0
15 µg
+
18
5.39
(4.88, 5.91)
5.21
(4.83, 5.59)
0
0
8.52
(5.04, 11.99)
1 (5.6)
[0.0, 0.2]
3 (16.7)
[0.0, 0.3]
45 µg
+
20
5.00
(5.00, 5.00)
5.25
(4.82, 5.68)
0
1 (5.0)
[0.0, 0.1]
11.26
(7.41, 15.11)
3 (15.0)
[0.0, 0.3]
8 (40.0)
[0.2, 0.6]
90 µg
+
20
5.10
(4.92, 5.28)
5.21
(4.96, 5.45)
0
0
11.06
(4.54, 17.58)
2 (10.0)
[0.0, 0.2]
4 (20.0)
[0.0, 0.4]
90 µg
–
20
8.33
(3.75, 12.91)
132.75
(0, 284.45)
2 (10.0)
[0.0, 0.2]
3 (15.0)
[0.0, 0.3]
133.77
(0.0, 285.35)
3 (15.0)
[0.0, 0.3]
3 (15.0)
[0.0, 0.3]
a: A, Alhydrogel®. b Viruses 2012, 4 3235 Taken together, the results of the immunogenicity analyses demonstrate that the experimental
HAI-05 vaccine generated low humoral immune responses, with no dose dependence and no
enhancing effect of adjuvant. Taken together, the results of the immunogenicity analyses demonstrate that the experimental
HAI-05 vaccine generated low humoral immune responses, with no dose dependence and no
enhancing effect of adjuvant. Currently licensed influenza vaccines, manufactured by several companies globally, are made in
embryonated eggs [13]. For the past four decades, these vaccines have been successfully used and
were proven to be safe and effective [14‒16]. Recently, safety and efficacy of several avian H5N1
influenza
A
vaccines
in
healthy
volunteers
have
been
demonstrated
[17‒23]. However, the H1N1 “swine influenza” pandemic of 2009 demonstrated that egg-based technologies do
not have the capacity to satisfy the global need for an emerging pandemic influenza vaccine in a
timely manner. Therefore, a number of countries, including the U.S., are making significant
investments in developing alternative technologies that could satisfy this unmet need. In the last several decades, an alternative, recombinant protein-based approach has been introduced
to vaccine development and manufacturing. In contrast to conventional vaccines, the recombinant,
or subunit, vaccines represent individual immunogenic proteins derived from target pathogens. 2.3. Immunogenicity The subunit vaccine approach is, therefore, considered relatively safe compared to vaccination with
whole organism and can be easily scaled up to meet healthcare needs. Some of these alternative
manufacturing approaches are based on mammalian and insect cell expression systems for the
production of recombinant proteins, including influenza vaccines [24‒31]. Over the past ten years, plants have emerged as a highly promising approach to economically
manufacture recombinant proteins, including vaccine antigens [32‒35]. There have been numerous
pre-clinical studies demonstrating the immunogenicity and protective efficacy of plant-produced
vaccine candidates against a variety of pathogens [1,2,9‒11,36]. More recently, several groups have
tested plant-produced vaccines and therapeutic products in humans and demonstrated safety and
biological relevance of these products following parenteral administration in Phase 1‒3 clinical
trials [37‒41]. We
have
engineered
and
produced
HAI-05,
a
recombinant
HA
antigen
from
A/Indonesia/05/2005 (H5N1) strain of influenza A virus in a “launch vector”-based transient
expression system. This was achieved in less than one month and was subsequently scaled up for
cGMP manufacturing at FhCMB’s pilot plant facility [2]. Following successful pre-clinical
evaluation, including a Good Laboratory Practice-compliant toxicology study in a rabbit
model [2], the experimental vaccine entered into a Phase 1 human study. The vaccine was tested at 15 and 45 µg doses with Alhydrogel® adjuvant and at 90 µg dose with
and without Alhydrogel® adjuvant and administered in a two-dose regimen three weeks apart. At these doses, the vaccine was generally shown to have a favorable safety profile in healthy
volunteers, with no reported SAEs and no evidence of any dose-limiting or dose-related toxicity. As expected, the most frequent event was local injection site reaction after either dose, which was
generally mild and self-limited. Despite the positive immunogenicity results in the pre-clinical studies [2], immune responses
elicited by the HAI-05 vaccine in this study were low and somewhat variable with respect to both
HAI and MN antibody titers, with the highest responses observed in the 90 µg unadjuvanted group,
indicating no enhancement in the presence of Alhydrogel® adjuvant. By contrast, in pre-clinical
studies, Alhydrogel® enhanced antibody responses elicited by HAI-05 and provided a dose-sparring Viruses 2012, 4 Viruses 2012, 4 3236 effect in animal models [2]. In addition, in a randomized, Phase 1 clinical trial, alum-adjuvanted
whole-virus avian A/Hong Kong/1073/99 (H9N2) vaccine was shown to be more immunogenic than
unadjuvanted vaccine [42]. 2.3. Immunogenicity The trial results reported here are consistent with findings from other
randomized, controlled influenza vaccine clinical studies in different populations of human volunteers. Indeed, several groups evaluating split-virion 2009 pandemic influenza A H1N1 vaccines [43‒45] as
well as split-virion or whole-virus influenza A H5N1 vaccines have reported that alum either failed to
enhance or even decreased antibody production [18,20,46‒50]. The reason for Alhydrogel®’s
inefficiency is not known, since potency of this adjuvant in stimulating both T helper 1 and 2 type
responses and antibody production has been well documented [51]. As suggested in a previous study
by Liang et al. [43], the absence of benefit may be due to delayed antigen release from
alum-adjuvanted formulations. The low immunogenicity observed in this study is likely attributable to the use of a suboptimal dose
of the H5 HA antigen in the HAI-05 vaccine. A post-hoc analysis of MN antibody responses using a
cut-off titer of ≥10 revealed responses that were high among responders, which is suggestive of a
threshold-like effect that may be further enhanced. Furthermore, the results of a completed Phase 1
trial
of
plant-produced
HAC1
influenza
vaccine
(recombinant
HA
derived
from
A/California/04/2009 [H1N1] strain of influenza A virus) have demonstrated that HAC1 is
immunogenic when compared with a licensed, egg-derived H1N1 vaccine [52]. Therefore, and as
further supported by studies of conventional egg-derived H5N1 vaccines and recombinant H5N1
vaccines produced in other expression systems, the underwhelming results observed with the HAI-05
vaccine in this study appear to be related to the H5 antigen itself. 3.2. Vaccine 3.2. Vaccine The HAI-05 vaccine is a recombinant subunit HA antigen from the A/Indonesia/05/2005 (H5N1)
strain of influenza A virus. The HA sequence encompassing amino acids 17–532 was optimized for
expression in plants and synthesized by GENEART AG (Regensburg, Germany). To obtain the
truncated HA molecule in the plant expression system, the transmembrane domain (a.a. 533–569) and
signal peptide (a.a. 1–16) were removed from the entire HA sequence and the pathogenesis-related
protein 1a (PR-1a) signal peptide was added to the N-terminus [1]. A poly-histidine (6 × His) affinity
purification tag followed by the endoplasmic reticulum retention signal (KDEL) were added to the
C-terminus [1]. The HA antigen has been cloned, expressed in N. benthamiana, and purified as
described previously [2]. The purified HAI-05 protein has a monomeric solution state with a purity
of >90% as determined by SDS-PAGE and reverse-phase chromatography [2]. Glycosylation analysis,
as reported previously, indicated that the core glycan structure was followed by high mannose
attachments as expected with use of the KDEL retention sequence. All six potential N-linked
glycosylation sites (Asn10, Asn23, Asn154, Asn165, Asn286 and Asn484) showed the high
mannose glycosylation [2]. The concentration of the HAI-05 formulated drug substance was 360 μg/mL in a formulation
of 0.9% normal saline (United States Pharmacopeia, Hospira, Lake Forrest, IL) with trace amounts of
phosphate buffered saline (PBS: 50 mM NaCl, 0.7 mM KCl, 3.6 mM Na2HPO4, and 0.7 mM KH2PO4)
for intramuscular administration. Viruses 2012, 4 Viruses 2012, 4 3237 3.1. Study Design This study was a first-in-human, Phase 1 randomized, double-blind, placebo-controlled,
dose-escalation clinical study conducted at two clinical centers in the U.S. The study was conducted in
accordance with the Declaration of Helsinki and the Code of Federal Regulations of the United States
Food and Drug Administration (FDA) and in compliance with the International Conference on
Harmonization Guidelines for Good Clinical Practice. The study protocol, informed consent form and
subject recruitment procedures were reviewed and approved by an Institutional Review Board and an
Independent Ethics Committee. All participants provided written informed consent prior to screening
and enrollment into the study. The primary objective of the study was to evaluate the safety, reactogenicity and tolerability of
three escalating dose levels of the HAI-05 vaccine—15, 45 and 90 µg adjuvanted with Alhydrogel®
and 90 µg without Alhydrogel®—and placebo (0.9% normal saline) delivered intramuscularly to
healthy adults 18–49 years of age. The secondary objective was to evaluate and compare
immunogenicity of these four HAI-05 vaccine formulations after two doses based on HAI and
MN antibody titers. This study was registered under clinical trial reference identifier NCT01250795 [53]. 3.3. Study Population and Treatment Healthy male and non-pregnant female adults 18–49 years of age were excluded from enrollment if
they received prior vaccination with any influenza vaccine containing H5 antigen; had any medical
condition that may be associated with impaired immune responsiveness, including diabetes mellitus,
cancer or treatment for cancer within the previous three years, excluding basal cell carcinoma or
squamous cell carcinoma; had a history of anaphylactic type reaction to injected vaccines, positive
serology for human immunodeficiency virus (HIV) types 1 and 2 (HIV-1 and HIV-2), hepatitis B
surface antigen or hepatitis C virus antibodies or any acute or chronic pulmonary, cardiovascular,
hepatic, neurologic or renal disease that might confound evaluation of the vaccine; or had recently
taken or planned to take any other experimental vaccine within 30 days prior to vaccination. A total of 100 subjects were enrolled and randomized into 4 cohorts, each with 20 subjects to
receive the HAI-05 vaccine formulation and 5 subjects to receive placebo (4:1 vaccine to
placebo ratio) (Table 8). Subjects in the study vaccine groups received two doses of HAI-05
at 15, 45 or 90 μg administered with 0.3% aluminum hydroxide (Alhydrogel®) adjuvant
(Brenntag Biosector, Denmark) or at 90 μg administered without adjuvant. Subjects in the placebo
control group received two doses of saline (0.9% sodium chloride, United States Pharmacopeia). All doses were administered in a volume of 0.5 mL. Vaccine was administered in the deltoid muscle of the same non-dominant arm on Days 1 and 22. Progression to a next higher dose was determined by a Cohort Review Committee based on the safety
of a lower dose and in accordance with specified halting rules. After the 15 and 45 μg dose levels were Viruses 2012, 4 Viruses 2012, 4 Viruses 2012, 4 3238 determined to be well tolerated, the two 90 μg dose levels (with and without Alhydrogel®) were
administered simultaneously to subjects in the respective cohorts. Table 8. Study cohorts and treatments. Cohort
HAI-05 treatment
Placebo treatment
Number of
subjects
Dose of HAI-05
(µg/0.5 mL)
Dose of Alhydrogel®
(mg aluminum/0.5 mL)
Number of
subjects
Placebo
1
20
15
0.75
5
Saline
2
20
45
0.75
5
Saline
3
20
90
0.75
5
Saline
4
20
90
–
5
Saline
3.4. Safety Assessments Table 8. Study cohorts and treatments. Table 8. Study cohorts and treatments. 3.4. Safety Assessments 3.4. 3.3. Study Population and Treatment Safety Assessments Safety assessments (primary endpoints) consisted of reactogenicity events, AEs, clinical laboratory
tests (serum chemistry, hematology and urinalysis), vital signs, and abnormal findings upon
physical examination. At 30 minutes after each dosing (Days 1 and 22), any signs or symptoms of local and systemic
reactions to the study medications (immediate complains) were recorded in an electronic
Case Report Form. In addition, vaccinees were instructed to record any occurring reactogenic events
for 7 days after each dosing (between Days 1 and 8 and Days 22 and 29, respectively) in a Subject
Diary. The solicited immediate complaints and reactogenic events included: pain, redness or swelling
at the injection site; fever; muscle or joint aches; headache; tiredness; chills; and malaise (feeling of
discomfort or uneasiness). These symptoms were not recorded as AEs unless they were SAEs or
persisted beyond Days 8 or 29. Any unsolicited symptoms (AEs) were recorded at 30 minutes after
vaccination by the clinical site staff, and thereafter through Day 43 by subjects in a
Supplemental Diary. A SAE was defined as any untoward medical occurrence that resulted in death, was life threatening,
resulted in persistent or significant disability/incapacity, required hospitalization or prolongation of
existing hospitalization, or was associated with a congenital abnormality/birth defect in the offspring
of a study subject. The occurrence of any SAE was monitored throughout the course of the study. AEs were assessed for intensity using standardized criteria adapted from the September 2007 FDA
Guidance entitled “Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in
Preventive Vaccine Clinical Trials” [54]. The intensity was determined as mild, moderate or severe,
based on the definitions provided in the Guidance. Vaccine-related AEs were those that the
investigator judged as having a reasonable possibility that the vaccine contributed to the AE. AEs were
coded to the Medical Dictionary for Regulatory Activities® (MedDRA) system organ class and
preferred terms. 3.5. Immunogenicity Assessments Sera for immunogenicity assessments were collected on Days 1 (pre-vaccination; baseline),
22 (pre-vaccination; results for the first vaccination) and 43 (results for the second vaccination), Viruses 2012, 4 Viruses 2012, 4 3239 and analysed for HAI and MN antibody titers against A/Indonesia/05/2005 (H5N1) using validated
assays at Southern Research Institute (Birmingham, AL). Immunogenicity assessments included determination of 1) GMTs of HAI and MN antibody
titers; 2) the proportion of subjects in each group who seroconverted on Days 22 and 43 based on HAI
and MN antibody titers; and 3) the proportion of subjects in each group who achieved HAI titers ≥40
on Days 22 and 43. For HAI titers, seroconversion was defined according to the FDA guidance as the
percentage of subjects with either a pre-vaccination titer <10 and a post-vaccination titer ≥40 or a
pre-vaccination titer ≥10 and a minimum 4-fold rise in a post-vaccination antibody titer. For MN titers,
seroconversion was defined as the percentage of subjects with either a pre-vaccination titer at the limit
of detection at the starting dilution of 1:20, designated to have a titer of 5, and a post-vaccination
titer ≥20, or a pre-vaccination titer ≥20 and a minimum 4-fold rise in a post-vaccination antibody titer. In a post-hoc analysis of MN seroconversion, a post-vaccination MN titer of ≥10 was used as a
cut-off value. 3.6. Statistical Analyses Statistical analyses were performed by PharmaNet Development Group, Inc. (Princeton, NJ). Safety analyses were based upon the intent-to-treat population defined as all volunteers who received
at least one dose of vaccine or placebo and one post-vaccination visit. Immunogenicity analyses were
based upon the per-protocol population defined as all subjects who received two doses of vaccine and
who had provided serum specimens for antibody determinations. All statistical analyses were performed using SAS® Version 8.2 or higher. Categorical data were
summarized using counts and percentages. Unless otherwise specified, descriptive statistics
included: n, mean, standard deviation (SD), median, coefficient of variation (CV%), and minimum and
maximum for continuous variables. In general, minimum and maximum were quoted to the number of
decimal places as recorded in the electronic case report form; means, medians, SD, and CV% were
quoted to one (1) further decimal place. Percentages were rounded to one decimal place. All statistical
tests were two-sided and were performed using a 5% significance level, unless otherwise stated,
leading to 95% (two-sided) confidence intervals (CIs). Demographic data of vaccinated subjects were summarized by treatment and analyzed by
descriptive statistics. All AEs were summarized by numbers and percentages of subjects with
corresponding AEs. Proportions of subjects in each treatment group with AEs within each body organ
system were compared in the same manner. Immediate complaints and reactogenicity events were
summarized by number of events and the percentage, and each dose group value was compared to the
placebo group value using Fisher’s exact test. Clinical laboratory results were summarized using
descriptive statistics. Proportions of subjects who developed a significant rise in antibody titers after the first dose
(secondary endpoint) and second dose (primary endpoint) in each dose group were determined using
standard statistical analyses. The HAI and MN GMTs and their 95% CIs were summarized for the two
vaccination days (Days 1 and 22) and post-second dose (Day 43) with stratification by cohort. Point estimates and the two-sided 95% CIs for these evaluations were summarized for seroconversion Viruses 2012, 4 Viruses 2012, 4 3240 and subjects achieving titers ≥40 (for HAI) and for seroconversion (for MN) for the two vaccination
days (Days 1 and 22) with stratification by cohort, along with the post-second dose (Day 43) results. 4. Conclusions The results of this first-in-human, Phase 1 randomized, double-blind, placebo-controlled,
dose-escalation clinical study demonstrated that the experimental HAI-05 vaccine was generally safe
at all dose levels. Mild local injection site reactions occurred across all dose levels, but at a
considerably lower incidence rate in the absence of Alhydrogel® adjuvant. The vaccine generated low
humoral immune responses in healthy adult subjects, with no dose dependence and no enhancing
effect of adjuvant, suggesting the use of a suboptimal dose of the H5 HA antigen. Acknowledgments The authors would like to thank PharmaNet Development Group, Inc. (Princeton, NJ) for
conducting the trial, Erika Rouvas for organizational aspects of setting up the trial, and Natasha
Kushnir for editorial assistance. The study was funded by The Bill and Melinda Gates Foundation
(grant Nr. 49840). Conflict of Interest The authors declare no conflict of interest. References 1. Shoji, Y.; Bi, H.; Musiychuk, K.; Rhee, A.; Horsey, A.; Roy, G.; Green, B.; Shamloul, M.;
Farrance, C.E.; Taggart, B.; et al. Plant-derived hemagglutinin protects ferrets against challenge
infection with the A/Indonesia/05/05 strain of avian influenza. Vaccine 2009, 27, 1087–1092. 1. Shoji, Y.; Bi, H.; Musiychuk, K.; Rhee, A.; Horsey, A.; Roy, G.; Green, B.; Shamloul, M.;
Farrance, C.E.; Taggart, B.; et al. Plant-derived hemagglutinin protects ferrets against challenge
infection with the A/Indonesia/05/05 strain of avian influenza. Vaccine 2009, 27, 1087–1092. 2. Shoji, Y.; Chichester, J.A.; Jones, M.; Manceva, S.D.; Damon, E.; Mett, V. Plant-based rapid
production of recombinant subunit hemagglutinin vaccines targeting H1N1 and H5N1 influenza. Hum. Vaccin. 2011, 7, 41–50. 3. World Health Organization. Media centre. Influenza (Seasonal); Fact sheet Nr. 211;
WHO: Geneva, Switzerland, 2009. Available online: http://www.who.int/mediacentre/
factsheets/fs211/en/index.html (accessed on 26 June 2012). 4. Centers for Disease Control and Prevention. Information on Avian Influenza. Available online:
http://www.cdc.gov/flu/avianflu/index.htm (accessed on 11 June 2012). 4. Centers for Disease Control and Prevention. Information on Avian Influenza. Available online:
http://www.cdc.gov/flu/avianflu/index.htm (accessed on 11 June 2012). 5. World
Health
Organization. Avian
Influenza
in
Humans. Available
online:
http://www.who.int/influenza/human_animal_interface/avian_influenza/en/ (accessed on 11
June 2012). 6. World Health Organization. Cumulative Number of Confirmed Human Cases for Avian
Influenza; A (H5N1) reported to WHO, 2003–2012; WHO, Geneva, Switzerland, 2012. Available online: http://www.who.int/influenza/human_animal_interface/EN_GIP_20120607
CumulativeNumberH5N1cases.pdf (accessed on 11 June 2012). Viruses 2012, 4 Viruses 2012, 4 3241 7. Yusibov, V.; Streatfield, S.J.; Kushnir, N. Clinical development of plant-produced recombinant
pharmaceuticals: Vaccines, antibodies and beyond. Hum. Vaccin. 2011, 7, 313–321. 8. Musiychuk, K.; Stephenson, N.; Bi, H.; Farrance, C.E.; Orozovic, G.; Brodelius, M.;
Brodelius, P.; Horsey, A.; Ugulava, N.; Shamloul, A.M.; et al. A launch vector for the
production of vaccine antigens in plants. Influenza Other Respi. Viruses 2007, 1, 19–25. 9. Chichester, J.A.; Musiychuk, K.; de la Rosa, P.; Horsey, A.; Stevenson, N.; Ugulava, N.;
Rabindran, S.; Palmer, G.A.; Mett, V.; Yusibov, V. Immunogenicity of a subunit vaccine against
Bacillus anthracis. Vaccine 2007, 25, 3111–3114. 10. Mett, V.; Lyons, J.; Musiychuk, K.; Chichester, J.A.; Brasil, T.; Couch, R.; Sherwood, R.;
Palmer, G.A.; Streatfield, S.J.; Yusibov, V. A plant-produced plague vaccine candidate confers
protection to monkeys. Vaccine 2007, 25, 3014–3017. 11. Shoji, Y.; Chichester, J.A.; Bi, H.; Musiychuk, K.; de la Rosa, P.; Goldschmidt, L.; Horsey, A.;
Ugulava, N.; Palmer, G.A.; Mett, V.; et al. Plant-expressed HA as a seasonal influenza
vaccine candidate. Vaccine 2008, 26, 2930–2934. Viruses 2012, 4 Viruses 2012, 4 3242 21. Patel, S.M.; Atmar, R.L.; El Sahly, H.M.; Cate, T.R.; Keitel, W.A. A phase I evaluation of
inactivated
influenza
A/H5N1
vaccine
administered
by
the
intradermal
or
the
intramuscular route. Vaccine 2010, 28, 3025–3029. 21. Patel, S.M.; Atmar, R.L.; El Sahly, H.M.; Cate, T.R.; Keitel, W.A. A phase I evaluation of
inactivated
influenza
A/H5N1
vaccine
administered
by
the
intradermal
or
the
intramuscular route. Vaccine 2010, 28, 3025–3029. 22. Treanor, J.J.; Campbell, J.D.; Zangwill, K.M.; Rowe, T.; Wolff, M. Safety and immunogenicity
of an inactivated subvirion influenza A (H5N1) vaccine. N. Engl. J. Med. 2006, 354, 1343–1351. 23. Vesikari, T.; Forstén, A.; Herbinger, K.H.; Cioppa, G.D.; Beygo, J.; Borkowski, A.; Groth, N.;
Bennati, M.; von Sonnenburg, F. Safety and immunogenicity of an MF59(®)-adjuvanted
A/H5N1 pre-pandemic influenza vaccine in adults and the elderly. Vaccine 2012, 30,
1388–1396. 24. Clark, T.W.; Pareek, M.; Hoschler, K.; Dillon, H.; Nicholson, K.G.; Groth, N.; Stephenson, I. Trial of 2009 influenza A (H1N1) monovalent MF59-adjuvanted vaccine. N. Engl. J. Med. 2009,
361, 2424–2435. 25. Khurana, S.; Wu, J.; Verma, N.; Verma, S.; Raghunandan, R.; Manischewitz, J.; King, L.R.;
Kpamegan, E.; Pincus, S.; Smith, G.; et al. H5N1 virus-like particle vaccine elicits
cross-reactive neutralizing antibodies that preferentially bind to the oligomeric form of influenza
virus hemagglutinin in humans. J. Virol. 2011, 85, 10945–10954. 26. Lakey, D.L.; Treanor, J.J.; Betts, R.F.; Smith, G.E.; Thompson, J.; Sannella, E.; Reed, G.;
Wilkinson, B.E.; Wright, P.F. Recombinant baculovirus influenza A hemagglutinin vaccines are
well tolerated and immunogenic in healthy adults. J. Infect. Dis. 1996, 174, 838–841. 27. López-Macías, C.; Ferat-Osorio, E.; Tenorio-Calvo, A.; Isibasi, A.; Talavera, J.;
Arteaga-Ruiz, O.; Arriaga-Pizano, L.; Hickman, S.P.; Allende, M.; Lenhard K.; et al. Safety and
immunogenicity of a virus-like particle pandemic influenza A (H1N1) 2009 vaccine in a
blinded, randomized, placebo-controlled trial of adults in Mexico. Vaccine 2011, 29,
7826–7834. 28. Powers, D.C.; Smith, G.E.; Anderson, E.L.; Kennedy, D.J.; Hackett, C.S.; Wilkinson, B.E.;
Volvovitz, F.; Belshe, R.B.; Treanor, J.J. Influenza A virus vaccines containing purified
recombinant H3 hemagglutinin are well tolerated and induce protective immune responses in
healthy adults. J. Infect. Dis. 1995, 171, 1595–1599. 29. Treanor, J.J.; Wilkinson, B.E.; Masseoud, F.; Hu-Primmer, J.; Battaglia, R.; O’Brien, D.;
Wolff, M.; Rabinovich, G.; Blackwelder, W.; Katz, J.M. Safety and immunogenicity of a
recombinant hemagglutinin vaccine for H5 influenza in humans. Vaccine 2001, 19, 1732–1737. 30. 32. Yusibov, V.; Rabindran, S. Recent progress in the development of plant derived vaccines.
Expert Rev. Vaccine 2008, 7, 1173–1183. References 12. Shoji, Y.; Farrance, C.E.; Bautista, J.; Bi, H.; Musiychuk, K.; Horsey, A.; Park, H.; Jaje, J.;
Green, B.J.; Shamloul, M.; et al. A plant-based system for rapid production of influenza
vaccine antigens. Influenza Other Respi. Viruses 2012, 6, 204–210. 13. Matthews, J.T. Egg-based production of influenza vaccine: 30 Years of commercial experience. Nat. Acad. Eng. 2006, 36, 17–24. 14. Schultz-Cherry, S.; Jones, J.C. Influenza vaccines: The good, the bad, and the eggs. Adv. Virus
Res. 2010, 77, 63–84. 15. Michiels, B.; Govaerts, F.; Remmen, R.; Vermeire, E.; Coenen, S. A systematic review of the
evidence on the effectiveness and risks of inactivated influenza vaccines in different
target groups. Vaccine 2011, 2, 9159–9170. 16. Osterholm, M.T.; Kelley, N.S.; Sommer, A.; Belongia, E.A. Efficacy and effectiveness of
influenza vaccines: A systematic review and meta-analysis. Lancet Infect. Dis. 2012, 12, 36–44. 17. Gillard, P.; Caplanusi, A.; Knuf, M.; Roman, F.; Walravens, K.; Moris, P.; Dramé, M.;
Schwarz, T.F. An assessment of prime-boost vaccination schedules with AS03(A)-adjuvanted
prepandemic H5N1 vaccines: A randomized study in European adults. Influenza Other Respi. Viruses 2012, doi: 10.1111/j.1750-2659.2012.00349.x. 18. Keitel, W.A.; Campbell, J.D.; Treanor, J.J.; Walter, E.B.; Patel, S.M.; He, F.; Noah, D.L.;
Hill, H. Safety and immunogenicity of an inactivated influenza A/H5N1 vaccine given with or
without aluminum hydroxide to healthy adults: results of a phase I-II randomized clinical trial. J. Infect. Dis. 2008, 198, 1309–1316. 19. Levie, K.; Leroux-Roels, I.; Hoppenbrouwers, K.; Kervyn, A.D.; Vandermeulen, C.; Forgus, S.;
Leroux-Roels, G.; Pichon, S.; Kusters, I. An adjuvanted, low-dose, pandemic influenza A
(H5N1) vaccine candidate is safe, immunogenic, and induces cross-reactive immune responses
in healthy adults. J. Infect. Dis. 2008, 198, 642–649. 20. Nolan, T.M.; Richmond, P.C.; Skeljo, M.V.; Pearce G.; Hartel, G.; Formica, N.T.; Höschler, K.;
Bennet, J.; Ryan, D.; Papanaoum, K.; et al. Phase I and II randomised trials of the safety and
immunogenicity of a prototype adjuvanted inactivated split-virus influenza A (H5N1) vaccine in
healthy adults. Vaccine 2008, 26, 4160–4167. Viruses 2012, 4 Viruses 2012, 4 Viruses 2012, 4 3243 33. Sharma,
A.K.;
Sharma,
M.K. Plants
as
bioreactors:
Recent
developments
and
emerging opportunities. Biotechnol. Adv. 2009, 27, 811–832. 33. Sharma,
A.K.;
Sharma,
M.K. Plants
as
bioreactors:
Recent
developments
and
emerging opportunities. Biotechnol. Adv. 2009, 27, 811–832. 34. D'Aoust, M.A.; Couture, M.M.; Charland, N.; Trépanier, S.; Landry, N.; Ors, F.; Vézina, L.P. The production of hemagglutinin-based virus-like particles in plants: A rapid, efficient and safe
response to pandemic influenza. Plant Biotechnol. J. 2010, 8, 607–619. 35. Rybicki, E.P. Plant-made vaccines for humans and animals. Plant Biotechnol. J. 2010, 8,
620–637. 36. D'Aoust, M.A.; Lavoie, P.O.; Couture, M.M.; Trépanier, S.; Guay, J.M.; Dargis, M.;
Mongrand, S.; Landry, N.; Ward, B.J.; Vézina, L.P. Influenza virus-like particles produced by
transient expression in Nicotiana benthamiana induce a protective immune response against a
lethal viral challenge in mice. Plant Biotechnol. J. 2008, 6, 930–940. 37. De Leede, L.G.; Humphries, J.E.; Bechet, A.C.; Van Hoogdalem, E.J.; Verrijk, R.;
Spencer,
D.G. Novel
controlled-release
Lemna-derived
IFN-alpha2b
(Locteron):
Pharmacokinetics, pharmacodynamics, and tolerability in a phase I clinical trial. J. Interferon
Cytokine Res. 2008, 28, 113–122. 38. McCormick, A.A.; Reddy, S.; Reinl, S.J.; Cameron, T.I.; Czerwinkski, D.K.; Vojdani, F.;
Hanley, K.M.; Garger, S.J.; White, E.L.; Novak, J.; et al. Plant-produced idiotype vaccines for
the treatment of non-Hodgkin's lymphoma: Safety and immunogenicity in a phase I clinical
study. Proc. Natl. Acad. Sci. USA 2008, 105, 10131–10136. 39. Landry, N.; Ward, B.J.; Trépanier, S.; Montomoli, E.; Dargis, M.; Lapini, G.; Vézina, L.P. Preclinical and clinical development of plant-made virus-like particle vaccine against avian
H5N1 influenza. PLoS One 2010, 5, e15559. 40. Medicago Inc. Medicago Reports Positive Phase II Final Results for its Avian Flu Pandemic
Vaccine;
News
Release
June
30,
2011. Available
online:
http://www.medicago.com/English/news/News-Releases/News-ReleaseDetails/2011/Medicago-
reports-positive-Phase-II-final-results-for-its-avian-flu-pandemic-vaccine1125833/default.aspx
(accessed on 15 June 2012). 41. Zimran, A.; Brill-Almon, E.; Chertkoff, R.; Petakov, M.; Blanco-Favela, F.; Muñoz, E.T.;
Solorio-Meza, S.E.; Amato, D.; Duran, G.; Giona, F.; et al. Pivotal trial with plant
cell-expressed recombinant glucocerebrosidase, taliglucerase alfa, a novel enzyme replacement
therapy for Gaucher disease. Blood 2011, 118, 5767–5773. 42. Nicholson, K.G.; Thompson, C.I.; Klap, J.M.; Wood, J.M.; Batham, S.; Newman, R.W.;
Mischler, R.; Zambon, M.C.; Stephenson, I. Safety and immunogenicity of whole-virus,
alum-adjuvanted whole-virus, virosomal, and whole-virus intradermal influenza A/H9N2
vaccine formulations. Vaccine 2010, 28, 171–178. 43. Liang, X.F.; Wang, H.Q.; Wang, J.Z.; Fang, H.H.; Wu, J.; Zhu, F.C.; Li, R.C.; Xia, S.L.;
Zhao, Y.L.; Li, F.J.; et al. Viruses 2012, 4 Treanor, J.J.; El Sahly, H.; King, J.; Graham, I.; Izikson, R.; Patriarca, P.; Cox, M. Protective efficacy of a trivalent recombinant hemagglutinin protein vaccine (FluBlok®) against
influenza in healthy adults: a randomized, placebo-controlled trial. Vaccine 2011, 29,
7733–7739. 31. Wei, C.J.; Xu, L.; Kong, W.P.; Shi, W.; Canis, K.; Stevens, J.; Yang, Z.Y.; Dell, A.;
Haslam, S.M.; Wilson, I.A.; et al. Comparative efficacy of neutralizing antibodies elicited by
recombinant hemagglutinin proteins from avian H5N1 influenza virus. J. Virol. 2008,
82, 6200–6208. 32. Yusibov, V.; Rabindran, S. Recent progress in the development of plant derived vaccines. Expert Rev. Vaccine 2008, 7, 1173–1183. Viruses 2012, 4 Safety and immunogenicity of 2009 pandemic influenza A H1N1
vaccines in China: A multicentre, double-blind, randomised, placebo-controlled trial. Lancet 2010, 375, 56–66. 44. Wu, J.; Li, W.; Wang, H.Q.; Chen, J.T.; Lv, M.; Zhou, J.C.; Liang, X.F.; Fang, H.H.; Liu, Y.;
Liu, L.Y.; et al. A rapid immune response to 2009 influenza A(H1N1) vaccines in adults:
A randomized, double-blind, controlled trial. J. Infect. Dis. 2010, 202, 675–680. Viruses 2012, 4 Viruses 2012, 4 3244 45. Zhu, F.C.; Wang, H.; Fang, H.H.; Yang, J.G.; Lin, X.J.; Liang, X.F.; Zhang, X.F.; Pan, H.X.;
Meng, F.Y.; Hu, Y.M.; et al. A novel influenza A (H1N1) vaccine in various age groups. N. Engl. J. Med. 2009, 361, 2414–2423. 45. Zhu, F.C.; Wang, H.; Fang, H.H.; Yang, J.G.; Lin, X.J.; Liang, X.F.; Zhang, X.F.; Pan, H.X.;
Meng, F.Y.; Hu, Y.M.; et al. A novel influenza A (H1N1) vaccine in various age groups. N. Engl. J. Med. 2009, 361, 2414–2423. 46. Bernstein, D.I.; Edwards, K.M.; Dekker, C.L.; Belshe, R.; Talbot, H.K.; Graham, I.L.;
Noah, D.L.; He, F.; Hill, H. Effects of adjuvants on the safety and immunogenicity of an avian
influenza H5N1 vaccine in adults. J. Infect. Dis. 2008, 197, 667–675. 47. Brady, R.C.; Treanor, J.J.; Atmar, R.L.; Keitel, W.A.; Edelman, R.; Chen, W.H.; Winokur, P.;
Belshe, R.; Graham, I.L.; Noah, D.L.; et al. Safety and immunogenicity of a subvirion
inactivated influenza A/H5N1 vaccine with or without aluminum hydroxide among healthy
elderly adults. Vaccine 2009, 27, 5091–5095. 48. Bresson, J.L.; Perronne, C.; Launay, O.; Gerdil, C.; Saville, M.; Wood, J.; Höschler, K.;
Zambon, M.C. Safety and immunogenicity of an inactivated split-virion influenza
A/Vietnam/1194/2004 (H5N1) vaccine: Phase I randomised trial. Lancet 2006, 367, 1657–1664. 49. Ehrlich, H.J.; Müller, M.; Oh, H.M.; Tambyah, P.A.; Joukhadar, C.; Montomoli, E.; Fisher, D.;
Berezuk, G.; Fritsch, S.; Löw-Baselli, A.; et al. A clinical trial of a whole-virus H5N1 vaccine
derived from cell culture. N. Engl. J. Med. 2008, 358, 2573–2584. 50. Keitel, W.A.; Dekker, C.L.; Mink, C.; Campbell, J.D.; Edwards, K.M.; Patel, S.M.; Ho, D.Y.;
Talbot, H.K.; Guo, K.; Noah, D.L.; et al. Safety and immunogenicity of inactivated, Vero cell
culture-derived whole virus influenza A/H5N1 vaccine given alone or with aluminum hydroxide
adjuvant in healthy adults. Vaccine 2009, 27, 6642–6648. 51. Brewer,
J.M.;
Conacher,
M.;
Satoskar,
A.;
Bluethmann,
H.;
Alexander,
J. Viruses 2012, 4 In interleukin-4-deficient mice, alum not only generates T helper 1 responses equivalent to
freund's complete adjuvant, but continues to induce T helper 2 cytokine production. Eur. J. Immunol. 1996, 26, 2062–2066. 52. Cummings, J.F.; Guerrero, M.L.; Moon, J.E.; Waterman, P.; Nielsen, R.K.; Jefferson, S.;
Gross, F.L.; Hancock, K.; Katz, J.M.; Yusibov, V.; et al. Safety and immunogenicity of a
plant-produced recombinant monomer hemagglutinin-based influenza vaccine derived from
influenza A (H1N1)pdm09 virus: A Phase 1 dose-escalation study in healthy adults. Vaccine. Manuscript in preparation. 53. ClinicalTrials.gov. Safety and Immunogenicity of a Recombinant H5N1 Vaccine in Adults. Available online: http://www.clinicaltrials.gov/ct2/show/NCT01250795?term=NCT01250795
&rank=1 (accessed on 14 November 2012). 54. Guidance for Industry: Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers
Enrolled in Preventive Vaccine Clinical Trials. Available online: http://www.fda.gov/
downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Va
ccines/ucm091977.pdf (accessed on 12 April, 2012). © 2012 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article
distributed under the terms and conditions of the Creative Commons Attribution license
(http://creativecommons.org/licenses/by/3.0/). © 2012 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article
distributed under the terms and conditions of the Creative Commons Attribution license
(http://creativecommons.org/licenses/by/3.0/).
|
https://openalex.org/W2338323034
|
https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0138701&type=printable
|
English
| null |
Optic Disc - Fovea Distance, Axial Length and Parapapillary Zones. The Beijing Eye Study 2011
|
PloS one
| 2,015
|
cc-by
| 8,921
|
Results Readable fundus photographs were available for 2836 (81.8%) individuals. Mean DFD was
4.76 ± 0.34mm (median: 4.74 mm; range: 3.76–6.53mm). In multivariate analysis, longer
DFD was associated with longer axial length (P<0.001; standardized correlation coefficient
beta: 0.62), higher prevalence of axially high myopia (P<0.001; beta:0.06), shallower ante-
rior chamber depth (P<0.001; beta:-0.18), thinner lens thickness (P = 0.004; beta: -0.06),
smaller optic disc-fovea angle (P = 0.02; beta: -0.04), larger parapapillary alpha zone (P =
0.008; beta: 0.05), larger parapapillary beta/gamma zone (P<0.001; beta: 0.11), larger optic
disc area (P<0.001; beta: 0.08), lower degree of cortical cataract (P = 0.002; beta: -0.08),
and lower prevalence of age-related macular degeneration (P = 0.001; beta: -0.06). Bruch´s
membrane opening-fovea distance (DFD minus disc radius minus parapapillary beta/
gamma zone width) in non-glaucomatous eyes was not significantly (P = 0.60) related with
axial length in emmetropic or axially myopic eyes (axial length 23.5 mm), while it
increased significantly (P<0.001; r: 0.32) with longer axial length in eyes with an axial length
of <23.5mm. Ratio of mean DFD to disc diameter was 2.65 ± 0.30. If the ratio of disc-fovea
distance to disc diameter was considered constant and if the individual disc diameter was
calculated as the individual disc-fovea distance divided by the constant factor of 2.65, the Copyright: © 2015 Jonas et al. This is an open
access article distributed under the terms of the
Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any
medium, provided the original author and source are
credited. Data Availability Statement: All relevant data are
within the paper. Purpose Citation: Jonas RA, Wang YX, Yang H, Li JJ, Xu L,
Panda-Jonas S, et al. (2015) Optic Disc - Fovea
Distance, Axial Length and Parapapillary Zones. The
Beijing Eye Study 2011. PLoS ONE 10(9): e0138701. doi:10.1371/journal.pone.0138701 To measure the distance between the optic disc center and the fovea (DFD) and to assess
its associations. Optic Disc - Fovea Distance, Axial Length and
Parapapillary Zones. The Beijing Eye Study
2011 Rahul Arvo Jonas1,2, Ya Xing Wang1*, Hua Yang1, Jian Jun Li1, Liang Xu1,
Songhomitra Panda-Jonas2, Jost Bruno Jonas1,2 Rahul Arvo Jonas1,2, Ya Xing Wang1*, Hua Yang1, Jian Jun Li1, Liang Xu1,
Songhomitra Panda-Jonas2, Jost Bruno Jonas1,2 1 Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical
University, Beijing Ophthalmology and Visual Science Key Lab, Beijing, China, 2 Department of
Ophthalmology, Medical Faculty Mannheim of the Ruprecht-Karls-University of Heidelberg, Mannheim,
Germany * yaxingw@gmail.com Editor: Laura Frishman, University of Houston,
UNITED STATES Editor: Laura Frishman, University of Houston,
UNITED STATES The population-based cross-sectional Beijing Eye Study 2011 included 3468 individuals
aged 50+ years. The DFD was measured on fundus photographs. Received: May 26, 2015
Accepted: September 2, 2015
Published: September 21, 2015
Copyright: © 2015 Jonas et al. This is an open
access article distributed under the terms of the
Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any
medium, provided the original author and source are
credited. Received: May 26, 2015
Accepted: September 2, 2015
Published: September 21, 2015 RESEARCH ARTICLE Conclusions DFD (mean: 4.76mm) increases with longer axial length, larger parapapillary alpha zone
and parapapillary beta/gamma zone, and larger disc area. The axial elongation associated
increase in DFD was due to an enlargement of parapapillary beta/gamma zone while the
Bruch’s membrane opening-fovea distance did not enlarge with longer axial length. This
finding may be of interest for the process of emmetropization and myopization. Due to its
variability, the disc-fovea distance has only limited clinical value as a relative size unit for
structures at the posterior pole. Introduction The optic disc-fovea distance is an anatomical landmark of the posterior fundus and has not
yet extensively been examined [1–9]. It has previously been used to estimate the optic disc
diameter or the size of other structures located in the posterior ocular segment [1–4, 6,9]. The
disc-fovea distance may be of basic importance as an anatomical measure of the posterior fun-
dus, and it may be associated with other anatomical parameters and with the prevalence of ocu-
lar abnormalities and disorders. One may postulate that a postnatally enlarged disc-fovea
distance can be associated with a stretching of the posterior fundus and thus with an increased
inter-photoreceptor distance, through which it may have a direct effect on visual acuity. The
disc-fovea distance can ophthalmoscopically be estimated without using sophisticated imaging
tools and may thus have importance in the daily routine examination of patients. Since studies
which systematically assessed the disc-fovea distance have been lacking so far, we conducted
this population-based study to measure the disc-fovea distance and to correlate it with other
ocular and systemic parameters. Data Availability Statement: All relevant data are
within the paper. Funding: This work was supported by State Natural
Sciences Fund (81041018) and the Natural Sciences
Fund of Beijing government (7092021; 7112031). Jost B. Jonas has the following financial disclosures:
Consultant for Allergan Inc.; Merck Sharp & Dohme
Co., Inc.; Alimera Co.; Boehringer Ingelheim Co.,
Sanofi Co. Patent holder with CellMed AG, Alzenau,
Germany. Competing Interests: The authors have declared
that no competing interests exist. 1 / 14 PLOS ONE | DOI:10.1371/journal.pone.0138701
September 21, 2015 Optic Disc - Fovea Distance resulting calculated disc diameter differed from the directly measured disc diameter by 0.16
±0.13 mm (median: 0.13 mm, range: 0.00–0.89 mm) or 8.9 ± 7.3% (median: 7.4%; range:
0.00–70%) of the measured disc diameter. resulting calculated disc diameter differed from the directly measured disc diameter by 0.16
±0.13 mm (median: 0.13 mm, range: 0.00–0.89 mm) or 8.9 ± 7.3% (median: 7.4%; range:
0.00–70%) of the measured disc diameter. PLOS ONE | DOI:10.1371/journal.pone.0138701
September 21, 2015 The location of
the foveola as determined on the fundus photographs was controlled by images of the macula
obtained by spectral domain optical coherence tomography (SD-OCT; Spectralis1, Wave-
length: 870nm; Heidelberg Engineering Co., Heidelberg, Germany). Seven sections, each com-
prising 100 averaged scans, were obtained in a rectangle measuring 5° x 30° and which was
centered onto the fovea. On these OCT images, the foveola was detectable as the foveal depres-
sion of the macular thickness profile. Using the optic disc photographs, we determined the
width of parapapillary beta / gamma zone defined as the parapapillary zone with visible sclera
and visible large choroidal vessels [15]. If beta / gamma zone was present, it was located at the
peripapillary ring of the optic nerve head. It usually was separated from the remaining retina
by a parapapillary alpha zone. The latter showed an irregular hyperpigmentation and hypopig-
mentation (Fig 1). Using the same disc photographs, we had previously measured the area and
diameter of the optic nerve heads [16]. To obtain the disc-fovea distance and the beta / gamma
zone measurements in real size units, i.e. to correct for the lateral magnification of the fundus
image, we used the Littmann-Bennett method to correct the image magnification which was
caused by the optic media of the eye and by the fundus camera [17–19]. For the latter, we used
the axial length as the basic principle ocular parameter for the calculations. We additionally
determined a parameter called Bruch´s membrane opening (BMO)-to-fovea distance as the
difference of the optic disc center-to-fovea distance minus the optic disc radius minus the para-
papillary beta / gamma zone width. St ti ti
l
l
i
f
d
i
i ll
il bl
t ti ti
l
ft
k
Optic Disc Fovea Distance assessment of presenting visual acuity and uncorrected visual acuity. If uncorrected visual acu-
ity was lower than 1.0 (or logMAR (negative decadal logarithm of the minimal angle of resolu-
tion) higher than 0.00), best corrected visual acuity was assessed after automatic refractometry
(Auto Refractometer AR-610, Nidek Co., Ltd, Tokyo, Japan) was carried out. Intraocular pres-
sure was determined by pneumotonometry. A slit lamp examination carried out by an experi-
enced ophthalmologist assessed lid abnormalities, Meibomian gland dysfunction, corneal
disorders, and peripheral anterior chamber depth using van Herick’s method. Gonioscopy was
routinely performed for all study participants. Applying optical low-coherence reflectometry
(Lensstar 9001 Optical Biometer, Haag-Streit, 3098 Koeniz, Switzerland), we carried out an
ocular biometry of the right eyes for assessment of the anterior corneal curvature, central cor-
neal thickness, anterior chamber depth, lens thickness and axial length. Five measurements
were performed, and the mean value was taken for further statistical analysis. After medical
dilatation of the pupil (tropicamide 1% eye drops; Mydrin; Santen; Japan), a second slit lamp
assisted biomicroscopy searched for pseudoexfoliation syndrome. Digital photographs of the
cornea and lens and retro-illuminated photographs of the lens were taken using the Neitz
CT-R camera (Neitz Instruments Co., Tokyo, Japan). Monoscopic photographs of the macula
and optic disc were taken using a fundus camera (Type CR6-45NM, Canon Inc. U.S.A.). The
degree of cataract was determined using the standardized lens photographs as described
recently [13]. Diabetic retinopathy was diagnosed on the fundus photographs [14]. Using the
fundus photographs, we measured the distance between the optic disc center and the foveola
and the angle between the disc-fovea line and the horizontal (Fig 1). The center of the disc was
assessed as the middle point of the line connecting the middle point of the minimal disc diame-
ter and the middle point of maximal disc diameter. The location of the foveola was determined
as the location of the foveal reflex in eyes with a foveal reflex, as the center of the macula wall
reflex in eyes showing a macular wall reflex but no foveal reflex, and as the center of the appar-
ently avascular zone in those eyes which did not present any macular reflexes. The location of
the foveola as determined on the fundus photographs was controlled by images of the macula
obtained by spectral domain optical coherence tomography (SD-OCT; Spectralis1, Wave-
length: 870nm; Heidelberg Engineering Co., Heidelberg, Germany). Seven sections, each com-
prising 100 averaged scans, were obtained in a rectangle measuring 5° x 30° and which was
centered onto the fovea. On these OCT images, the foveola was detectable as the foveal depres-
sion of the macular thickness profile. Using the optic disc photographs, we determined the
width of parapapillary beta / gamma zone defined as the parapapillary zone with visible sclera
and visible large choroidal vessels [15]. If beta / gamma zone was present, it was located at the
peripapillary ring of the optic nerve head. Optic Disc - Fovea Distance assessment of presenting visual acuity and uncorrected visual acuity. If uncorrected visual acu-
ity was lower than 1.0 (or logMAR (negative decadal logarithm of the minimal angle of resolu-
tion) higher than 0.00), best corrected visual acuity was assessed after automatic refractometry
(Auto Refractometer AR-610, Nidek Co., Ltd, Tokyo, Japan) was carried out. Intraocular pres-
sure was determined by pneumotonometry. A slit lamp examination carried out by an experi-
enced ophthalmologist assessed lid abnormalities, Meibomian gland dysfunction, corneal
disorders, and peripheral anterior chamber depth using van Herick’s method. Gonioscopy was
routinely performed for all study participants. Applying optical low-coherence reflectometry
(Lensstar 9001 Optical Biometer, Haag-Streit, 3098 Koeniz, Switzerland), we carried out an
ocular biometry of the right eyes for assessment of the anterior corneal curvature, central cor-
neal thickness, anterior chamber depth, lens thickness and axial length. Five measurements
were performed, and the mean value was taken for further statistical analysis. After medical
dilatation of the pupil (tropicamide 1% eye drops; Mydrin; Santen; Japan), a second slit lamp
assisted biomicroscopy searched for pseudoexfoliation syndrome. Digital photographs of the
cornea and lens and retro-illuminated photographs of the lens were taken using the Neitz
CT-R camera (Neitz Instruments Co., Tokyo, Japan). Monoscopic photographs of the macula
and optic disc were taken using a fundus camera (Type CR6-45NM, Canon Inc. U.S.A.). The
degree of cataract was determined using the standardized lens photographs as described
recently [13]. Diabetic retinopathy was diagnosed on the fundus photographs [14]. Using the
fundus photographs, we measured the distance between the optic disc center and the foveola
and the angle between the disc-fovea line and the horizontal (Fig 1). The center of the disc was
assessed as the middle point of the line connecting the middle point of the minimal disc diame-
ter and the middle point of maximal disc diameter. The location of the foveola was determined
as the location of the foveal reflex in eyes with a foveal reflex, as the center of the macula wall
reflex in eyes showing a macular wall reflex but no foveal reflex, and as the center of the appar-
ently avascular zone in those eyes which did not present any macular reflexes. PLOS ONE | DOI:10.1371/journal.pone.0138701
September 21, 2015 Methods The Beijing Eye Study 2011 is a population-based cross-sectional study in Northern China. It
has been described in detail previously [10–12]. The Medical Ethics Committee of the Beijing
Tongren Hospital approved the study protocol and all participants gave informed written con-
sent. Inclusion criterion was an age of 50+ years. In the survey, 3468 individuals (1963 (56.6%)
women) participated out of 4403 eligible individuals (response rate: 78.8%). There were 1633
(47.1%) subjects (943 (57.7%) women) from the rural region and 1835 (52.9%) subjects (1020
(55.6%) women)) for the urban region. The mean age was 64.6 ± 9.8 years (median, 64 years;
range, 50–93 years). All participants underwent a structured questionnaire by trained health staff with standard-
ized questions on their family status, level of education, income, quality of life, psychic depres-
sion, physical activity, and known major systemic diseases, systemic examinations, and a
comprehensive ophthalmic examination. The examinations were performed in the communi-
ties, either in schoolhouses or in community houses. Using a stadiometer, we measured body
height in a standardized manner with the shoes routinely removed. Body weight and the cir-
cumferences of the waist and hip were determined. The ocular examinations included PLOS ONE | DOI:10.1371/journal.pone.0138701
September 21, 2015 2 / 14 It usually was separated from the remaining retina
by a parapapillary alpha zone. The latter showed an irregular hyperpigmentation and hypopig-
mentation (Fig 1). Using the same disc photographs, we had previously measured the area and
diameter of the optic nerve heads [16]. To obtain the disc-fovea distance and the beta / gamma
zone measurements in real size units, i.e. to correct for the lateral magnification of the fundus
image, we used the Littmann-Bennett method to correct the image magnification which was
caused by the optic media of the eye and by the fundus camera [17–19]. For the latter, we used
the axial length as the basic principle ocular parameter for the calculations. We additionally
determined a parameter called Bruch´s membrane opening (BMO)-to-fovea distance as the
difference of the optic disc center-to-fovea distance minus the optic disc radius minus the para-
papillary beta / gamma zone width. Statistical analysis was performed using a commercially available statistical software package
(SPSS f
Wi d
i
IBM SPSS Chi
IL USA) I
l
i
i
i f
h Statistical analysis was performed using a commercially available statistical software package
(SPSS for Windows, version 22.0, IBM-SPSS, Chicago, IL, USA). Inclusion criteria for the
study were the availability of measurements of the disc-fovea distance and the availability of
axial length measurements. Only the right eye per individual was taken for the statistical 3 / 14 PLOS ONE | DOI:10.1371/journal.pone.0138701
September 21, 2015 Optic Disc - Fovea Distance Fig 1. Fundus photograph showing the optic disc—fovea line (black line), outer border of
parapapillary alpha zone (white arrows) and the outer border of parapapillary beta (gamma) zone (red
arrows). d i 10 1371/j
l
0138701 001 Fig 1. Fundus photograph showing the optic disc—fovea line (black line), outer border of
parapapillary alpha zone (white arrows) and the outer border of parapapillary beta (gamma) zone (red
arrows). Fig 1. Fundus photograph showing the optic disc—fovea line (black line), outer border of
parapapillary alpha zone (white arrows) and the outer border of parapapillary beta (gamma) zone (red
arrows). doi:10.1371/journal.pone.0138701.g001 analysis. In a first step, we examined the distribution of the disc-fovea distance using the Kol-
mogorov-Smirnov test. We then calculated the mean ± standard deviations of the parameter. In a second step of the analysis, we performed a univariate analysis of the associations between
the disc-fovea distance and other ocular and systemic variables. In a third step, we conducted a
multivariate regression analysis, with the disc-fovea distance as dependent variable and all
those parameters as independent variables which were significantly associated with the disc-
fovea parameters in the univariate analysis. From the list of independent parameters we then
dropped step by step those parameters which were no longer significantly associated. 95% con-
fidence intervals (CI) were presented. All P-values were two-sided and were considered statisti-
cally significant if the values were smaller than 0.05. Results Out of the 3468 subjects, readable fundus photographs for the measurement of the disc-fovea
distance and axial length measurements were available for 2836 (81.8%) individuals with a
mean age of 63.3 ± 9.3 years (range: 50 to 91 years) and a mean axial length of 23.2 ± 1.0 mm
(range: 18.96–28.87 mm). The individuals excluded from the study as compared with those
included were significantly older (70.5 ± 9.7 years versus 63.3 ± 9.3 years; P<0.001), had a lon-
ger axial length (23.8 ± 1.9 mm versus 23.2 ± 1.0 mm; P<0.001), and were significantly more
myopic (-1.29 ± 3.67 diopters versus -0.04 ± 1.65 diopters; P<0.001). Both groups did not vary
significantly in gender (P = 0.33). Mean disc-fovea distance was 4.76 ± 0.34 mm (median: 4.74 mm; range: 3.76–6.53 mm). It
was not normally distributed (P<0.001) (Fig 2). In univariate analysis, longer disc-fovea dis-
tance was significantly associated with the systemic parameters of male gender (P<0.001; 4 / 14 PLOS ONE | DOI:10.1371/journal.pone.0138701
September 21, 2015 Optic Disc - Fovea Distance Fig 2. Distribution of the Disc-Fovea Distance. doi:10.1371/journal.pone.0138701.g002 Fig 2. Distribution of the Disc-Fovea Distance. doi:10 1371/journal pone 0138701 g002 Fig 2. Distribution of the Disc-Fovea Distance. doi:10.1371/journal.pone.0138701.g002 Fig 2. Distribution of the Disc-Fovea Distance. doi:10.1371/journal.pone.0138701.g002 Fig 2. Distribution of the Disc-Fovea Distance. doi:10.1371/journal.pone.0138701.g002 correlation coefficient r: -0.12), urban region of habitation (P<0.001, r: 0.13), higher level of
education (P<0.001; r: 0.20), higher body height (P<0.001; r: 0.23), heavier body weight
(P<0.001; r: 0.08), lower systolic blood pressure (P = 0.001; r: -0.08), lower blood concentra-
tions of high-density lipoproteins (P = 0.01, r: -0.04) and lower blood concentration of glucose
(P = 0.01; r: -0.06). Results Longer disc-fovea distance was associated (univariate analysis) with the
ocular parameters of longer axial length (P<0.001; r: 0.20) (Fig 3), thicker central corneal thick-
ness (P<0.001; r: 0.001), deeper anterior chamber depth (P<0.001; r: 0.11), larger anterior cor-
neal curvature radius (P<0.001; r: 0.38), thinner lens thickness (P<0.001; r: -0.07), more
myopic refractive error (P<0.001; r: -0.08), smaller disc-fovea angle (P = 0.002; r: -0.006),
larger parapapillary alpha zone (P<0.001; r: 0.07), larger parapapillary beta/gamma zone
(P<0.001; r: 0.11), larger optic disc area (P<0.001; r: 0.07), lower prevalence of early age-
related macular degeneration (P = 0.03; r: -0.04), intermediate age-related macular degenera-
tion (P = 0.001; r: -0.07) and of any age-related macular degeneration (P = 0.001; r: -0.07),
lower degree of cortical cataract (P<0.001; r: -0.08), higher prevalence of open-angle glaucoma
(P = 0.001; r: 0.07), higher intraocular pressure (P = 0.03; r: 0.04) and higher prevalence of high
axial myopia (defined as axial length 26.5 mm) (P<0.001; r: 0.28). The disc-fovea distance
was not significantly associated with age (P = 0.89), body mass index (P = 0.11), diastolic blood
pressure (P = 0.09), blood concentration of low-density lipoproteins (P = 0.13), cholesterol
(P = 0.11), and triglycerides (P = 0.56), degree of nuclear cataract (P = 0.29) and subcapsular
posterior cataract (P = 0.10), and prevalence of angle-closure glaucoma (P = 0.86), diabetic reti-
nopathy (P = 0.16) and retinal vein occlusions (P = 0.60). correlation coefficient r: -0.12), urban region of habitation (P<0.001, r: 0.13), higher level of
education (P<0.001; r: 0.20), higher body height (P<0.001; r: 0.23), heavier body weight
(P<0.001; r: 0.08), lower systolic blood pressure (P = 0.001; r: -0.08), lower blood concentra-
tions of high-density lipoproteins (P = 0.01, r: -0.04) and lower blood concentration of glucose
(P = 0.01; r: -0.06). Results Longer disc-fovea distance was associated (univariate analysis) with the
ocular parameters of longer axial length (P<0.001; r: 0.20) (Fig 3), thicker central corneal thick-
ness (P<0.001; r: 0.001), deeper anterior chamber depth (P<0.001; r: 0.11), larger anterior cor-
neal curvature radius (P<0.001; r: 0.38), thinner lens thickness (P<0.001; r: -0.07), more
myopic refractive error (P<0.001; r: -0.08), smaller disc-fovea angle (P = 0.002; r: -0.006),
larger parapapillary alpha zone (P<0.001; r: 0.07), larger parapapillary beta/gamma zone
(P<0.001; r: 0.11), larger optic disc area (P<0.001; r: 0.07), lower prevalence of early age-
related macular degeneration (P = 0.03; r: -0.04), intermediate age-related macular degenera-
tion (P = 0.001; r: -0.07) and of any age-related macular degeneration (P = 0.001; r: -0.07),
lower degree of cortical cataract (P<0.001; r: -0.08), higher prevalence of open-angle glaucoma
(P = 0.001; r: 0.07), higher intraocular pressure (P = 0.03; r: 0.04) and higher prevalence of high
axial myopia (defined as axial length 26.5 mm) (P<0.001; r: 0.28). The disc-fovea distance
was not significantly associated with age (P = 0.89), body mass index (P = 0.11), diastolic blood
pressure (P = 0.09), blood concentration of low-density lipoproteins (P = 0.13), cholesterol
(P = 0.11), and triglycerides (P = 0.56), degree of nuclear cataract (P = 0.29) and subcapsular
posterior cataract (P = 0.10), and prevalence of angle-closure glaucoma (P = 0.86), diabetic reti-
nopathy (P = 0.16) and retinal vein occlusions (P = 0.60). For the multivariate analysis with the disc-fovea distance as dependent variable we included
all those parameters as independent variables which were significantly associated with the disc- 5 / 14 PLOS ONE | DOI:10.1371/journal.pone.0138701
September 21, 2015 Optic Disc - Fovea Distance Fig 3. Association between Axial Length and Optic Disc-Fovea Distance. doi:10.1371/journal.pone.0138701.g003 Fig 3. Association between Axial Length and Optic Disc-Fovea Distance. doi:10.1371/journal.pone.0138701.g003 doi:10.1371/journal.pone.0138701.g003 fovea distance in the univariate analysis. Due to collinearity, we dropped prevalence of early
and intermediate age-related macular degeneration (due to collinearity with any age-related
macular degeneration), and refractive error due to the collinearity with axial length. Results Since they
were no longer significantly associated with disc-fovea distance, we then deleted from the list
of independent parameters the anterior corneal curvature radius (P = 0.95), sex (P = 0.66),
blood concentration of glucose (P = 0.85), body weight (P = 0.66), intraocular pressure
(P = 0.56), central corneal thickness (P = 0.44), prevalence of open-angle glaucoma (P = 0.43),
region of habitation (P = 0.41), level of education (P = 0.38), systolic blood pressure (P = 0.27),
blood concentration of high-density lipoproteins (P = 0.24) and body height (P = 0.40). In the
final model (overall correlation coefficient r: 0.64), longer disc-fovea distance was significantly
associated with longer axial length (P<0.001), higher prevalence of axially high myopia
(P<0.001), shallower anterior chamber depth (P<0.001), thinner lens thickness (P = 0.004),
smaller optic disc-fovea angle (P = 0.02), larger parapapillary alpha zone (P = 0.008), larger
parapapillary beta/gamma zone (P<0.001), larger optic disc area (P<0.001), lower degree of
cortical cataract (P = 0.002), and lower prevalence of age-related macular degeneration
(P = 0.001) (Table 1). The ratio of the mean disc-fovea distance to optic disc diameter was 2.65 ± 0.30. If one
assumed that the ratio of disc-fovea distance to disc diameter was constant between individuals
and if the individual disc diameter was calculated as the individual disc-fovea distance divided
by the constant factor of 2.65, the resulting calculated disc diameter differed from the directly
measured disc diameter by a mean amount of 0.16 ±0.13 mm (median: 0.13 mm, range: 0.00–
0.89 mm) or 8.9 ± 7.3% (median: 7.4%; range: 0.00–70%) of the measured disc diameter. After excluding eyes with glaucomatous optic neuropathy, mean BMO-fovea distance was
3.74 ± 0.36 mm (median: 3.75 mm; range: 2.04; 5.19 mm). Mean BMO-fovea distance 6 / 14 PLOS ONE | DOI:10.1371/journal.pone.0138701
September 21, 2015 Optic Disc - Fovea Distance significantly increased with longer axial length (P<0.001; r: 0.28). Within the subgroup of eyes
with an axial length of shorter than 23.5 mm, BMO-fovea distance increased with longer axial
length (P<0.001; r: 0.32), while in the subgroup with an axial length of 23.5 mm, BMO-fovea
distance was not associated with axial length (P = 0.60) (Fig 4). In the same subgroup of indi-
viduals with an axial length of 23.5 mm, the disc-fovea distance significantly increased with
Table 1. Associations (Multivariate Analysis) between the Disc-Fovea-Distance and Ocular and Systemic Parameters in the Beijing Eye Study
2011. Parameter
P-
Value
Standardized
Correlation Beta
Non-Standardized Correlation
Coefficient B
95% Confidence
Interval
Variance Inflation
Factor
Axial Length (mm)
<0.001
0.62
0.21
0.20, 0.23
1.69
Axial High Myopia (Axial Length
26.5 mm)
0.002
0.06
0.27
0.10, 0.44
1.12
Anterior Chamber Depth (mm)
<0.001
-0.18
-0.18
-0.23, -0.13
1.96
Lens Thickness (mm)
0.004
-0.06
-0.07
-0.11, -0.02
1.41
Optic Disc-Fovea Angle
0.02
-0.04
-0.004
-0.008, -0.001
1.01
Parapapillary Alpha Zone Area
(mm2)
0.008
0.05
0.03
0.01, 0.05
1.05
Parapapillary Beta/Gamma Zone
Area (mm2)
<0.001
0.11
0.05
0.03, 0.06
1.11
Optic Disc Area (mm2)
<0.001
0.08
0.06
0.03, 0.08
1.06
Cortical Cataract
<0.001
-0.08
-0.22
-0.32, -0.12
1.02
Any Age-Related Macular
Degeneration
0.001
-0.06
-0.05
-0.07, -0.02
1.01
doi:10.1371/journal.pone.0138701.t001
Fig 4. Distribution of Axial Length and Bruch´s Membrane Opening—Fovea Distance in Non- Table 1. Associations (Multivariate Analysis) between the Disc-Fovea-Distance and Ocular and Systemic Parameters in the Beijing Eye Study
2011. Parameter
P-
Value
Standardized
Correlation Beta
Non-Standardized Correlation
Coefficient B
95% Confidence
Interval
Variance Inflation
Factor
Axial Length (mm)
<0.001
0.62
0.21
0.20, 0.23
1.69
Axial High Myopia (Axial Length
26.5 mm)
0.002
0.06
0.27
0.10, 0.44
1.12
Anterior Chamber Depth (mm)
<0.001
-0.18
-0.18
-0.23, -0.13
1.96
Lens Thickness (mm)
0.004
-0.06
-0.07
-0.11, -0.02
1.41
Optic Disc-Fovea Angle
0.02
-0.04
-0.004
-0.008, -0.001
1.01
Parapapillary Alpha Zone Area
(mm2)
0.008
0.05
0.03
0.01, 0.05
1.05
Parapapillary Beta/Gamma Zone
Area (mm2)
<0.001
0.11
0.05
0.03, 0.06
1.11
Optic Disc Area (mm2)
<0.001
0.08
0.06
0.03, 0.08
1.06
Cortical Cataract
<0.001
-0.08
-0.22
-0.32, -0.12
1.02
Any Age-Related Macular
Degeneration
0.001
-0.06
-0.05
-0.07, -0.02
1.01
doi:10.1371/journal.pone.0138701.t001 alysis) between the Disc-Fovea-Distance and Ocular and Systemic Parameters in the Beijing Eye Study s (Multivariate Analysis) between the Disc-Fovea-Distance and Ocular and Systemic Parameters in the Beijin Table 1. Optic Disc - Fovea Distance Table 2. Associations (Multivariate Analysis) between the Bruch’s Membrane Opening-Fovea-Distance and Ocular and Systemic Parameters in
Non-Glaucomatous Individuals with an Axial Length of <23.5 mm in the Beijing Eye Study 2011. Table 2. Associations (Multivariate Analysis) between the Bruch’s Membrane Opening-Fovea-Distance and
Non-Glaucomatous Individuals with an Axial Length of <23.5 mm in the Beijing Eye Study 2011. g
j
g
y
y
Parameter
P-
Value
Standardized
Correlation Beta
Non-Standardized Correlation
Coefficient B
95% Confidence
Interval
Variance Inflation
Factor
Age (Years)
0.02
-0.06
-0.002
-0.004, 0.000
1.14
Gender
0.003
-0.07
-0.05
-0.08, -0.02
1.08
Axial Length (mm)
<0.001
0.21
0.12
0.09, 0.15
1.49
Anterior Corneal Curvature
Radius (mm)
<0.001
0.15
0.22
0.14, 0.30
1.41
Parapapillary Alpha Zone Area
(mm2)
<0.001
0.09
0.06
0.03, 0.09
1.08
Parapapillary Beta/Gamma Zone
Area (mm2)
<0.001
-0.46
-0.41
-0.45, -0.37
1.06
Optic Disc Area (mm2)
<0.001
-0.17
-0.11
-0.14, -0.08
1.09
Early Age-Related Macular
Degeneration
0.03
-0.05
-0.05
-0.10, -0.01
1.01
Cortical Cataract Degree
0.02
-0.06
-0.15
-0.27, -0.03
1.11
doi:10.1371/journal.pone.0138701.t002 longer axial length (P<0.001; standardized correlation coefficient beta: 0.56; correlation coeffi-
cient B: 0.25; 95%CI: 0.22, 0.27) (Fig 3). The cut-off value of 23.5 mm was chosen since it
appeared on the scattergram that at that value the situation of a positive relationship between
longer axial length and longer BMO-fovea distance changed to the situation of a lack of such
an association (Fig 4). g
Within the subgroup with an axial length of <23.5 mm (n = 1896 individuals), BMO-fovea
distance was significantly (univariate analysis) associated with male gender (P<0.001; r: -0.12),
younger age (P<0.001, r: -0.12), rural region of habitation (P = 0.007, r: -0.07), higher body
height (P<0.001; r: 0.17), heavier body weight (P<0.001; r: 0.10), longer axial length (P<0.001;
r: 0.32) (Fig 4), larger anterior corneal curvature radius (P<0.001; r: 0.25), more myopic refrac-
tive error (P<0.001; r: -0.13), larger parapapillary alpha zone (P<0.001; r: 0.11), smaller parapa-
pillary beta/gamma zone (P<0.001; r: -0.53), and smaller optic disc area (P<0.001; r: -0.23), and
lower prevalence of early age-related macular degeneration (P = 0.049; r: -0.05), and lower
degree of cortical cataract (P<0.001; r: -0.13). Associations (Multivariate Analysis) between the Disc-Fovea-Distance and Ocular and Systemi
2011 Table 1. Associations (Multivariate Analysis) between the Disc-Fovea-Distance and Ocular and S
2011. significantly increased with longer axial length (P<0.001; r: 0.28). Within the subgroup of eyes
with an axial length of shorter than 23.5 mm, BMO-fovea distance increased with longer axial
length (P<0.001; r: 0.32), while in the subgroup with an axial length of 23.5 mm, BMO-fovea
distance was not associated with axial length (P = 0.60) (Fig 4). In the same subgroup of indi-
viduals with an axial length of 23.5 mm, the disc-fovea distance significantly increased with significantly increased with longer axial length (P<0.001; r: 0.28). Within the subgroup of eyes
with an axial length of shorter than 23.5 mm, BMO-fovea distance increased with longer axial
length (P<0.001; r: 0.32), while in the subgroup with an axial length of 23.5 mm, BMO-fovea
distance was not associated with axial length (P = 0.60) (Fig 4). In the same subgroup of indi-
viduals with an axial length of 23.5 mm, the disc-fovea distance significantly increased with Fig 4. Distribution of Axial Length and Bruch´s Membrane Opening—Fovea Distance in Non-
Glaucomatous Individuals. doi:10.1371/journal.pone.0138701.g004 Fig 4. Distribution of Axial Length and Bruch´s Membrane Opening—Fovea Distance in Non
Glaucomatous Individuals. doi:10.1371/journal.pone.0138701.g004 7 / 14 PLOS ONE | DOI:10.1371/journal.pone.0138701
September 21, 2015 Optic Disc - Fovea Distance Table 3. Associations (Multivariate Analysis) between the Bruch’s Membrane Opening-Fovea-Distance and Ocular and Systemic Parameters in
Non-Glaucomatous Individuals with an Axial Length of 23.5 mm in the Beijing Eye Study 2011. Parameter
P-
Value
Standardized
Correlation Beta
Non-Standardized Correlation
Coefficient B
95% Confidence
Interval
Variance Inflation
Factor
Parapapillary Alpha Zone Area
(mm2)
0.009
0.08
0.05
0.01, 0.08
1.01
Parapapillary Beta/Gamma Zone
Area (mm2)
<0.001
-0.66
-0.37
-0.40, -0.34
1.01
Optic Disc Area (mm2)
<0.001
-0.10
-0.09
-0.14, -0.04
1.01
doi:10.1371/journal.pone.0138701.t003 Table 3. Associations (Multivariate Analysis) between the Bruch’s Membrane Opening-Fovea-Distance and Ocular and Systemic Parameters in
Non-Glaucomatous Individuals with an Axial Length of 23.5 mm in the Beijing Eye Study 2011. Table 3. Associations (Multivariate Analysis) between the Bruch’s Membrane Opening-Fovea-Distance and
Non-Glaucomatous Individuals with an Axial Length of 23.5 mm in the Beijing Eye Study 2011. (P = 0.51), rural region of habitation (P = 0.30), body height (P = 0.55), body weight (P = 0.18),
level of education (P = 0.40), axial length (P = 0.60) (Fig 4), larger anterior corneal curvature
radius (P = 0.005; r: 0.11), thinner lens thickness (P = 0.001; r: -0.13), central corneal thickness
(P = 0.14), refractive error (P = 0.98), anterior chamber depth (P = 0.41), disc-fovea angle
(P = 0.20), and prevalence of early age-related macular degeneration (P = 0.83), intermediate
age-related macular degeneration (P = 0.39), and of late age-related macular degeneration
(P = 0.34). In this subgroup with an axial length of 23.5 mm, longer axial length was signifi-
cantly associated with the disc-fovea distance (P<0.001; r: 0.57). (P = 0.51), rural region of habitation (P = 0.30), body height (P = 0.55), body weight (P = 0.18),
level of education (P = 0.40), axial length (P = 0.60) (Fig 4), larger anterior corneal curvature
radius (P = 0.005; r: 0.11), thinner lens thickness (P = 0.001; r: -0.13), central corneal thickness
(P = 0.14), refractive error (P = 0.98), anterior chamber depth (P = 0.41), disc-fovea angle
(P = 0.20), and prevalence of early age-related macular degeneration (P = 0.83), intermediate
age-related macular degeneration (P = 0.39), and of late age-related macular degeneration
(P = 0.34). In this subgroup with an axial length of 23.5 mm, longer axial length was signifi-
cantly associated with the disc-fovea distance (P<0.001; r: 0.57). In the multivariate analysis, we dropped age (P = 0.55) and degree of cortical cataract
(P = 0.20), so that in the final model, a longer BMO-fovea distance in the subgroup with an
axial length of 23.5 mm was associated with larger parapapillary alpha zone (P = 0.009),
smaller beta/gamma zone (P<0.001), and smaller optic disc area (P<0.001) (Table 3). The BMO-fovea distance was not significantly
associated with level of education (P = 0.08), central corneal thickness (P = 0.49), anterior cham-
ber depth (P = 0.051), lens thickness (P = 0.14), disc-fovea angle (P = 0.57), and prevalence of
intermediate age-related macular degeneration (P = 0.17), and of late age-related macular
degeneration (P = 0.94). In the multivariate analysis, we first dropped refractive error due to rea-
sons of collinearity with axial length. We then deleted the parameters of body weight (P = 0.51),
region of habitation (P = 0.51), and body height (P = 0.38). In the final model, longer BMO-
fovea distance was associated with younger age (P = 0.02), male gender (P = 0.003), longer axial
length (P<0.001), longer anterior corneal curvature radius (P<0.001), larger parapapillary
alpha zone (P<0.001), smaller beta/gamma zone (P<0.001) and smaller optic disc (P<0.001),
lower prevalence of early age-related macular degeneration (P = 0.03) and lower degree of corti-
cal cataract (P = 0.02) (Table 2). In this subgroup with an axial length of <23.5 mm, longer axial
length was significantly associated with the disc-fovea distance (P<0.001; r: 0.39). Within the subgroup with an axial length of 23.5 mm (n = 940 individuals), BMO-fovea
distance was significantly (univariate analysis) associated with younger age (P<0.001, r: -0.18),
larger parapapillary alpha zone (P = 0.008; r: 0.10), smaller parapapillary beta/gamma zone
(P<0.001; r: -0.67), smaller optic disc area (P<0.001; r: -0.14), and lower degree of cortical cat-
aract (P<0.001; r: -0.13). The BMO-fovea distance was not significantly associated with gender 8 / 14 PLOS ONE | DOI:10.1371/journal.pone.0138701
September 21, 2015 PLOS ONE | DOI:10.1371/journal.pone.0138701
September 21, 2015 Optic Disc - Fovea Distance with sparing of the central visual field and longer disc margin-fovea distance. It fits with our
observation, that a longer disc-fovea distance was significantly associated with larger parapapil-
lary beta/gamma zone in the multivariate analysis in our study population. Van de Put and
coworkers measured the disc-fovea distance in 183 diabetic patients without retinopathy [7]. Similar to our study, the mean disc-fovea distance was 4.72 ± 0.27 mm, and the disc-fovea dis-
tance decreased by 0.06 mm (P<0.001) per diopter increase in spherical equivalent of refractive
error. Examining 51 preterm and full-term infants, de Silva and colleagues measured a mean
optic disc-fovea distance of 4.4 ± 0.4 mm, without difference between the preterm infants and
the full-term infants [6]. This value measured in infants was lower than the value obtained in
our adult study participants. Interestingly, the mean ratio of disc-fovea distance to optic disc
diameter was higher in the infants than in our study (3.76 versus 2.65). The association between a longer disc-fovea distance and longer axial length can be
explained by the enlargement of the posterior segment associated with the myopic axial elonga-
tion. Previous histomorphometric investigations revealed that the axial myopic elongation
leads to an enlargement of the globes mainly in its posterior segment, starting mostly at or
behind the equator and being more pronounced the closer to the posterior pole [20]. The asso-
ciation between longer disc-fovea distance and longer axial length may also explain the associa-
tion between a longer disc-fovea distance and larger parapapillary beta/gamma zone. Parapapillary beta/gamma zone was defined in this study by visible sclera and visible large cho-
roidal vessels [10,21,22]. This definition of beta/gamma zone is based on the assessment of
photographs. Recent clinical studies applying OCT imaging techniques and histologic investi-
gations have shown that the “former” beta zone can further be differentiated into an OCT
defined beta zone characterized by the presence of Bruch´s membrane and absence of retinal
pigment epithelium, and into a gamma zone, which is located between beta zone and the optic
disc border and which is characterized by an absence of Bruch´s membrane [23,24]. The (new)
beta zone is typically associated with glaucomatous optic nerve damage, and the gamma zone
is associated with axial myopia. PLOS ONE | DOI:10.1371/journal.pone.0138701
September 21, 2015 Discussion In our population-based study, the optic disc-fovea distance (mean: 4.76 ± 0.34 mm) was sig-
nificantly associated with longer axial length (P<0.001), higher prevalence of axially high myo-
pia (P<0.001), shallower anterior chamber depth (P<0.001), thinner lens thickness
(P = 0.004), smaller optic disc-fovea angle (P = 0.02), larger parapapillary alpha zone
(P = 0.008), larger parapapillary beta/gamma zone (P<0.001), larger optic disc area (P<0.001),
lower degree of cortical cataract (P = 0.002), and lower prevalence of age-related macular
degeneration (P = 0.001) (Table 1). If the disc-fovea distance was reduced by the disc radius
and by the width of parapapillary beta/gamma zone in non-glaucomatous eyes with an axial
length of 23.5 mm, the remaining so called BMO-fovea distance was not significantly associ-
ated with axial length. The mean value of the disc-fovea distance of 4.76 mm is in agreement with previous studies. In a study by Knaapi and coworkers, the disc-fovea distance was measured on digital photo-
graphs obtained from 27 prematurely born children at an age of 10–11 years [9]. The mean
disc-macula distance was 4.74 ± 0.29 mm, a value almost identical with the one obtained in our
study. In contrast to our study, Knaapi and associates did not find significant associations
between the disc-fovea distance and refractive error (or axial length), although one child with
axially high myopia had an above-average disc-fovea distance of 6.35 mm. When comparing
the results obtained in Knaapi´s study and the findings of our investigation, one has to take
into account the marked difference between both studies in the age and in the background of
the study participants. Lee and colleagues measured the distance between the temporal optic
disc margin to the fovea distance in 88 patients with normal-tension glaucoma [8]. They found
that in patients with a sparing of the central field the disc margin-fovea distance (3.88 ± 0.28
mm) was longer (P = 0.002) than in the group with glaucomatous central visual field loss
(3.64 ± 0.40 mm) [8]. Interestingly, parapapillary atrophy was wider (P = 0.03) in the group PLOS ONE | DOI:10.1371/journal.pone.0138701
September 21, 2015 9 / 14 Optic Disc - Fovea Distance length of less than 26 mm), better best corrected visual acuity was significantly associated with
thicker subfoveal choroid (P<0.001) in general and a subfoveal choroid thicker than 30 μm
(P<0.001) in particular, while it was not significantly with axial length, after adjusting for youn-
ger age (P<0.001), higher level of education (P<0.001), taller body stature (P<0.001), higher
body mass index (P = 0.005), and absence of major ocular diseases such as glaucoma [26]. The finding that the length of Bruch´s membrane as measured from the posterior pole to
the end of parapapillary beta/gamma zone and the finding of an increase in the fovea-disc bor-
der distance by an enlargement of parapapillary gamma zone may imply that Bruch´s mem-
brane is not firmly fixed on the underlying sclera through the choroid but may slightly slide. Sliding of Bruch´s membrane has already been discussed in a previous study in which parapa-
pillary gamma zone markedly decreased in size after a profound reduction in intraocular pres-
sure had occurred [27]. As an analogy, a sliding of the retinal pigment epithelium on Bruch´s
membrane has recently been proposed to be involved in the etiology of parapapillary atrophy
in glaucoma [28]. The association between longer disc-fovea distance and larger optic nerve head may be due
to at least two reasons. First, myopic, axially elongated eyes can have, due to the enlargement of
the posterior segment, a secondarily enlarged optic disc [10]. Second, non-highly myopic eyes
with primarily large discs have overall large ocular dimensions with primarily large corneas,
and long horizontal and vertical globe diameters [29,30]. It has remained unclear why a longer optic disc-fovea distance was significantly associated
with a lower degree of cortical cataract (P = 0.002), and lower prevalence of age-related macular
degeneration (P = 0.001) (Table 1). The relationship with a lower frequency of age-related mac-
ular degeneration might have been due to the association between longer axial length and
lower prevalence of age-related macular degeneration as it had been shown in the Beijing Eye
Study and other population-based investigations [31–33]. The associations of disc-fovea dis-
tance with arterial blood pressure and blood concentration of lipoproteins and of glucose were
statistically significant only in the univariate analysis, while the associations lost their signifi-
cance in the multivariate analysis. One may therefore assume that confounding factors were
the cause for the associations found in the univariate analysis. PLOS ONE | DOI:10.1371/journal.pone.0138701
September 21, 2015 We therefore excluded glaucomatous eyes in the second part of
the statistical analysis and assumed that the “former” beta zone in the remaining non-glauco-
matous eyes was mostly gamma zone. If this gamma zone and the disc radius were subtracted
from the disc-fovea distance, the remaining segment was the part in which Bruch´s membrane
was present. It was called BMO-fovea distance since Bruch´s membrane opening included the
intrapapillary optic nerve head region plus gamma zone. Interestingly, the BMO-fovea distance
was not significantly related with axial length in eyes with an axial length of equal to or larger
than 23.5 mm, roughly representing emmetropic eyes and axially myopic eyes. It suggests that
the myopic axial elongation was not associated with a stretching and lengthening of Bruch´s
membrane in the macular region but that the axial elongation associated increase in the disc-
fovea distance was due to the development or enlargement of parapapillary gamma zone. In
agreement with this observation, a recent histomorphometric study showed that Bruch´s mem-
brane thickness was not significantly associated with axial length. Axially elongated eyes
showed a markedly reduced thickness of the sclera and choroid, while Bruch´s membrane
thickness did not differ between normal eyes and eyes with axial elongation [25]. The finding that the BMO-fovea distance as a surrogate for the length of the macular Bruch´s
membrane (as measured from the posterior pole to nasal end of Bruch´s membrane in direction
to the optic disc) was mostly independent of axial length suggests that the axial elongation asso-
ciated increase in the fovea-disc distance led to the appearance or enlargement of a papillary
gamma zone. This finding makes one infer that the distance between the retinal photoreceptors
in the macular and foveal region was not markedly dependent on axial length as long as highly
myopic eyes with secondary macular Bruch´s membrane defects are excluded. Correspondingly,
a recent multivariate analysis revealed that within non-highly myopic eyes (i.e. eyes with an axial PLOS ONE | DOI:10.1371/journal.pone.0138701
September 21, 2015 10 / 14 Optic Disc - Fovea Distance Potential limitations of our study should be mentioned. First, our study had a lower age
limit of 50 years so that the findings of our study could not be transferred on younger individu-
als. Second, readable fundus photographs and axial length measurements were available for
81.8% of the participants, and the original participation rate of all eligible subjects was 78.8%. These figures may, however, be sufficient to allow conclusions on normative values such as the
disc-fovea distance and its associations. Third, the present study included Chinese individuals. Since ocular dimensions may differ between ethnicities, the measurements obtained in our
study population may not directly be transferred onto other populations. Fourth, we assumed
that the ophthalmoscopical beta/gamma zone in non-glaucomatous eyes predominantly repre-
sented gamma zone. Without having assessed OCT images in a systematic manner for the
study participants, this assumption could not be proven. Previous histological studies and clini-
cal investigations had shown however, that beta zone was usually associated with glaucoma
and that gamma zone was usually associated with axial myopia [23,24]. Since we excluded eyes
with glaucoma in our study on the parapapillary beta/gamma zone, the parapapillary beta/
gamma zone in our specific study population may predominantly have been presented gamma
zone. Fifth, the assessment of a distance on fundus photographs is a two-dimensional examina-
tion although the real distance between the disc center and the fovea is longer than the chord
length measured and presented in this study. In conclusion, the optic disc center-fovea distance (mean: 4.76 ± 0.3 4 mm) increased with
longer axial length, larger parapapillary alpha zone, larger parapapillary beta/gamma zone and
larger optic disc area. Since the Bruch´s membrane opening-fovea distance was not related
with axial length in emmetropic or myopic eyes (corresponding to an axial length of 23.5
mm), the axial elongation associated increase in the disc-fovea distance was markedly due to
an enlargement of parapapillary beta/gamma zone while Bruch´s membrane itself was presum-
ably not stretched or lengthened. This finding may be of interest for the process of emmetropi-
zation and myopization. Author Contributions Conceived and designed the experiments: RAJ YXW HY JJL LX SPJ JBJ. Performed the experi-
ments: RAJ YXW HY JJL LX JBJ. Analyzed the data: RAJ YXW SPJ JBJ. Contributed reagents/
materials/analysis tools: LX JBJ. Wrote the paper: RAJ YXW HY JJL LX SPJ JBJ. PLOS ONE | DOI:10.1371/journal.pone.0138701
September 21, 2015 The difference between the disc diameter estimation based on the disc-fovea distance and
the direct disc diameter measurement suggested that the clinical applicability of using the ratio
of disc-fovea distance to disc diameter as relative size to estimate the size of structures at the
posterior pole was limited. It relates to a study by Mok and colleagues who measured the (hori-
zontal) disc-to-fovea distance and optic disc diameter in 88 normal subjects [4]. In contrast to
our study, Mok and coworkers did not find significant differences in the disc-fovea distance
among three groups of eyes with different optic disc size. Subsequently, Mok and colleagues
reported that the ratio of the disc-fovea distance divided by the disc diameter was significantly
lower in individuals with physiological macrodiscs (ratio: 1.91 ± 0.07) than in normal individu-
als (2.54 ± 0.13) and in glaucomatous patients (2.50 ± 0.15). Mok and coworkers concluded
that the ratio of disc-fovea distance divided by the disc diameter could be used as a relative size
unit for the estimation of the optic disc size. Interestingly, longer disc-fovea distance was associated with deeper anterior chamber depth
in the univariate analysis (P<0.001; r: 0.11), while in multivariate analysis, longer disc-fovea
distance was correlated with more shallow chamber depth (P<0.001; beta: -0.18) (Table 1). This change in the direction of the association may be explained by the influence of the other
parameters in the multivariate analysis. If anterior chamber depth was dropped from the multi-
variate analysis, the parameter for lens thickness was no longer significantly associated with
disc-fovea distance (P = 0.34), while all other parameters remained to be significantly corre-
lated with the disc-fovea distance as described above. 11 / 14 References Wei WB, Xu L, Jonas JB, Shao L, Du KF, Wang S, et al. Subfoveal choroidal thickness: the Beijing Eye
Study. Ophthalmology. 2013; 120:175–180. doi: 10.1016/j.ophtha.2012.07.048 PMID: 23009895 13. Shao L, Xu L, Zhang JS, You QS, Chen CX, Wang YX, et al. Subfoveal choroidal thickness and cata-
ract. The Beijing Eye Study 2011. Invest Ophthalmol Vis Sci. 2015; 56:810–815. doi: 10.1167/iovs.14-
15736 PMID: 25604689 14. Xu J, Xu L, Wang YX, You QS, Jonas JB, Wei WB. Ten-year cumulative incidenceof diabetic retinopa-
thy. The Beijing Eye Study 2001/2011. PLoS One. 2014; 9:e111320. doi: 10.1371/journal.pone. 0111320 PMID: 25347072 15. Xu L, Wang Y, Yang H, Jonas JB. Differences in parapapillary atrophy between glaucomatous and nor-
mal eyes: the Beijing Eye Study. Am J Ophthalmol. 2007; 144:541–546. PMID: 17651676 16. Jonas JB, Xu L, Zhang L, Wang Y, Wang Y. Optic disk size in chronic glaucoma. The Beijing Eye
Study. Am J Ophthalmol. 2006; 142:168–170. PMID: 16815273 17. Littmann H. [Determination of the real size of an object on the fundus of the living eye]. Klin Monbl
Augenheilkd. 1982; 180:286–289. PMID: 7087358 18. Bennett AG, Rudnicka AR, Edgar DF. Improvements on Littmann's method of determining the size of
retinal features by fundus photography. Graefes Arch Clin Exp Ophthalmol. 1994; 232:361–367. PMID:
8082844 19. Jonas JB, Gusek GC, Guggenmoos-Holzmann I, Naumann GO. Size of the optic nerve scleral canal
and comparison with intravital determination of optic disc dimensions. Graefes Arch Clin Exp Ophthal-
mol. 1988; 226:213–215. PMID: 3402742 20. Vurgese S, Panda-Jonas S, Jonas JB. Scleral thickness in human eyes. PLoS One. 2012; 7:e29692. doi: 10.1371/journal.pone.0029692 PMID: 22238635 21. Jonas JB, Fernández MC, Naumann GO. Parapapillary atrophy and retinal vessel diameter in nonglau-
comatous optic nerve damage. Invest Ophthalmol Vis Sci. 1991; 32:2942–2947. PMID: 1917397 22. Jonas JB, Budde WM. Diagnosis and pathogenesis of glaucomatous optic neuropathy: morphological
aspects. Prog Retin Eye Res. 2000; 19:1–40. PMID: 10614679 23. Jonas JB, Jonas SB, Jonas RA, Holbach L, Dai Y, Sun X, et al. Parapapillary atrophy: Histological
gamma zone and delta zone. PLoS One. 2012; 7:e47237. doi: 10.1371/journal.pone.0047237 PMID:
23094040 24. Dai Y, Jonas JB, Huang H, Wang M, Sun X. Microstructure of parapapillary atrophy: Beta zone and
gamma zone. Invest Ophthalmol Vis Sci. 2013; 54:2013–2018. doi: 10.1167/iovs.12-11255 PMID:
23462744 25. Jonas JB, Holbach L, Panda-Jonas S. Bruch´s membrane thickness in high myopia. Acta Ophthalmol. 2014; 92:e470–474. doi: 10.1111/aos.12372 PMID: 24612938 26. References 1. Wakakura M, Alvarez E. A simple clinical method of assessing patients with optic nerve hypoplasia. The disc-fovea distance to disc diameter ratio (DM/DD). Acta Ophthalmol (Copenh). 1987; 65:612–
617. 1. Wakakura M, Alvarez E. A simple clinical method of assessing patients with optic nerve hypoplasia. The disc-fovea distance to disc diameter ratio (DM/DD). Acta Ophthalmol (Copenh). 1987; 65:612–
617. 2. Alvarez E, Wakakura M, Khan Z, Dutton GN. The disc-fovea distance to disc diameter ratio: a new test
for confirming optic nerve hypoplasia in young children. J Pediatr Ophthalmol Strabismus. 1988;
25:151–154. PMID: 3397860 3. Barr DB, Weir CR, Purdie AT. An appraisal of the disc-macula distance to disc diameter ratio in the
assessment of optic disc size. Ophthalmic Physiol Opt. 1999; 19:365–375. PMID: 10768018 4. Mok KH, Lee VW. Disc-to-macula distance to disc-diameter ratio for optic disc size estimation. J Glau-
coma. 2002; 11:392–395. PMID: 12362077 5. Rohrschneider K. Determination of the location of the fovea on the fundus. Invest Ophthalmol Vis Sci. 2004; 45:3257–3258. PMID: 15326148 6. De Silva DJ, Cocker KD, Lau G, Clay ST, Fielder AR, Moseley MJ. Optic disk size and optic disk-to-
fovea distance in preterm and full-term infants. Invest Ophthalmol Vis Sci. 2006; 47:4683–4686. PMID:
17065474 7. van de Put MA, Nayebi F, Croonen D, Nolte IM, Japing WJ, Hooymans JM, et al. Design and validation
of a method to determine the position of the fovea by using the nerve-head to fovea distance of the fel-
low eye. PLoS One. 2013; 8:e62518. doi: 10.1371/journal.pone.0062518 PMID: 23667483 12 / 14 PLOS ONE | DOI:10.1371/journal.pone.0138701
September 21, 2015 Optic Disc - Fovea Distance 8. Lee M, Jin H, Ahn J. Relationship between disc margin to fovea distance and central visual field defect
in normal tension glaucoma. Graefes Arch Clin Exp Ophthalmol. 2014; 252:307–314. doi: 10.1007/
s00417-013-2513-2 PMID: 24263528 9. Knaapi L, Lehtonen T, Vesti E, Leinonen MT. Determining the size of retinal features in prematurely
born children by fundus photography. Acta Ophthalmol. 2015; 93:339–341. doi: 10.1111/aos.12554
PMID: 25270671 10. Xu L, Li Y, Wang S, Wang Y, Wang Y, Jonas JB. Characteristics of highly myopic eyes. The Beijing
Eye Study. Ophthalmology. 2007; 114:121–126. PMID: 17070594 11. Wang YX, Xu L, Yang H, Jonas JB. Prevalence of glaucoma in North China: The Beijing Eye Study. Am
J Ophthalmol. 2010; 150:917–924. doi: 10.1016/j.ajo.2010.06.037 PMID: 20970107 12. PLOS ONE | DOI:10.1371/journal.pone.0138701
September 21, 2015 31.
Xu L, Li Y, Zheng Y, Jonas JB. Associated factors for age related maculopathy in the adult population in
China: the Beijing eye study. Br J Ophthalmol. 2006;. 90:1087–1090. PMID: 16774957 32.
Jonas JB, Nangia V, Kulkarni M, Gupta R, Khare A. Associations of early age-related macular degener-
ation with ocular and general parameters. The Central India Eyes and Medical Study. Acta Ophthalmol.
2012; 90:e185–191. doi: 10.1111/j.1755-3768.2011.02316.x PMID: 22269029 33.
Pan CW, Ikram MK, Cheung CY, Choi HW, Cheung CM, Jonas JB, et al. Refractive errors and age-
related macular degeneration: a systematic review and meta-analysis. Ophthalmology 2013;
120:2058–2065. doi: 10.1016/j.ophtha.2013.03.028 PMID: 23706699 PLOS ONE | DOI:10.1371/journal.pone.0138701
September 21, 2015 References Shao L, Xu L, Wei WB, Chen CX, Du KF, Li XP, et al. Visual acuity and subfoveal choroidal thickness. The Beijing Eye Study. Am J Ophthalmol. 2014; 158:702–709. doi: 10.1016/j.ajo.2014.05.023 PMID:
24878308 27. Panda-Jonas S, Xu L, Yang H, Wang YX, Jonas SB, Jonas JB. Optic disc morphology in young patients
after antiglaucomatous filtering surgery. Acta Ophthalmol. 2014; 92:59–64. doi: 10.1111/j.1755-3768. 2012.02570.x PMID: 23356397 28. Wang YX, Jiang R, Wang NL, Xu L, Jonas JB. Acute peripapillary retinal pigment epithelium changes
associated with acute intraocular pressure elevation. Ophthalmology 2015 Jul 15. pii: S0161-6420(15)
00551-5. doi: 10.1016/j.ophtha.2015.06.005 [Epub ahead of print]. 29. Jonas JB, Zäch FM, Gusek GC, Naumann GO. Pseudoglaucomatous physiologic large cups. Am J
Ophthalmol. 1989; 107:137–144. PMID: 2913807 30. Papastathopoulos KI, Jonas JB, Panda-Jonas S. Large optic discs in large eyes, small optic discs in
small eyes. Exp Eye Res. 1995; 60:459–461. PMID: 7789425 13 / 14 PLOS ONE | DOI:10.1371/journal.pone.0138701
September 21, 2015 Optic Disc - Fovea Distance 14 / 14
|
https://openalex.org/W2416407193
|
https://cris.unibo.it/bitstream/11585/566300/2/materials-09-00454.pdf
|
English
| null |
Chemical Characterization and in Vitro Antibacterial Activity of Myrcianthes hallii (O. Berg) McVaugh (Myrtaceae), a Traditional Plant Growing in Ecuador
|
Materials
| 2,016
|
cc-by
| 9,889
|
Chemical Characterization and in Vitro Antibacterial
Activity of Myrcianthes hallii (O. Berg) McVaugh
(Myrtaceae), a Traditional Plant Growing in Ecuador Patricia Chavez Carvajal 1, Erika Coppo 2, Arianna Di Lorenzo 1, Davide Gozzini 3,
Francesco Bracco 4, Giuseppe Zanoni 3, Seyed Mohammad Nabavi 5, Anna Marchese 2,
Carla Renata Arciola 6,7,* and Maria Daglia 1,* 1
Department of Drug Sciences, Medicinal Chemistry and Pharmaceutical Technology Section,
University of Pavia, Via Taramelli 12, 27100 Pavia, Italy; patylu_170787@hotmail.com (P.C.C.);
arianna.dilorenzo01@universitadipavia.it (A.D.L.) p
2
Microbiology Unit, DISC, University of Genoa, IRCCS-San Martino IST, Largo Rosanna Benzi 10,
16132 Genoa, Italy; erika.coppo@unige.it (E.C.); anna.marchese@unige.it (A.M.) 3
Department of Chemistry, University of Pavia, Via Taramelli 10, 27100 Pavia, Italy;
davide.gozzini@unipv.it (D.G.); gz@unipv.it (G.Z.) g
p
g
p
4
Department of Earth and Environmental Sciences, University of Pavia, Via Sant’Epifanio 14, 27100 Pavia,
Italy; francesco.bracco@unipv.it 5
Applied Biotechnology Research Center, Baqiyatallah University of Medical Sciences, Tehran 19395-5487,
Iran; nabavi208@gmail.com g
6
Research Unit on Implant Infections, Rizzoli Orthopaedic Institute, via di Barbiano 1/10,
40136 Bologna, Italy g
,
y
7
Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, 7
Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University
Via San Giacomo 14, 40126 Bologna, Italy Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bolog
Via San Giacomo 14, 40126 Bologna, Italy Via San Giacomo 14, 40126 Bologna, Italy *
Correspondence: carlarenata.arciola@ior.it (C.R.A.); maria.daglia@unipv.it (M.D.);
Tel.: +39-051-6366599 (C.R.A.); +39-0382-987388 (M.D.) *
Correspondence: carlarenata.arciola@ior.it (C.R.A.); maria.daglia@unipv.it (M.D.); *
Correspondence: carlarenata.arciola@ior.it (C.R.A.); maria.daglia
Tel.: +39-051-6366599 (C.R.A.); +39-0382-987388 (M.D.) Correspondence: carlarenata.arciola@ior.it (C.R.A.); maria.d
Tel.: +39-051-6366599 (C.R.A.); +39-0382-987388 (M.D.) Tel.: +39-051-6366599 (C.R.A.); +39-0382-987388 (M.D.) Tel.: +39-051-6366599 (C.R.A.); +39-0382-987388 (M.D.) el.: +39-051-6366599 (C.R.A.); +39-0382-987388 (M.D.) Academic Editor: Dusan Losic Received: 1 February 2016; Accepted: 1 June 2016; Published: 7 June 2016 Received: 1 February 2016; Accepted: 1 June 2016; Published: 7 June 2016 Abstract: Myrcianthes hallii (O. Berg) McVaugh (Myrtaceae) is a plant native to Ecuador, traditionally
used for its antiseptic properties. The composition of the hydro-methanolic extract of this plant was
determined by submitting it to ultra-high performance liquid chromatography (UHPLC) hyphenated
to heated-electrospray ionization mass spectrometry and UV detection. The presence of antimicrobial
components prompted us to test the extract against methicillin-resistant and methicillin-susceptible
Staphylococcus aureus, multidrug-resistant and susceptible Escherichia coli, Pseudomonas aeruginosa,
Enterococcus spp. and Streptococcus pyogenes strains. The chromatographic analysis led to the
identification of 38 compounds, including polyphenols and organic acids, and represents the first
chemical characterization of this plant. materials materials 1. Introduction The Myrtaceae family includes about 30 genera and 1500 species found in the Neotropics. In Ecuador there are 15 native genera and about 200 species. Native species are mainly grown
for their edible fruits and wood and some are used as medicinal plants due to their biological
properties [1]. In recent years, increasing interest in herbal medicine has been registered in developed
and developing countries, and much attention has been paid to natural antibacterial substances for
use in alternative therapies against conventionally resistant infections or as new antiseptic agents. In
the last decade, many species of Myrtaceae (including those from the Myrtus, Eucalyptus, Psidium, and
Syzygium genera) have been studied for their antimicrobial properties [2–5]. Myrcianthes is a genus of
Myrtaceae that includes shrubs and small trees. At present, 38 species of Myrcianthes are known to be
distributed across several countries of Central and South America, from Mexico to Chile, including
Ecuador [6]. Although Myrcianthes is closely related to the large genus Eugenia L. recent studies have
confirmed its individuality and role as a sister group to the rest of the Eugenia clades [7]. Thanks to
recent taxonomic research [8,9], new species belonging to the Myrcianthes genus have been described. Myrcianthes hallii (O. Berg) McVaugh is a medicinal and aromatic species commonly known in Ecuador
as “arrayán” [10,11]. It grows as a shrub or a tree up to 8 m high. Leaves and branchlets are nearly
glabrous, flowers are tetramerous and the hypanthium is characteristically densely pale and strigose. This species is recorded in Peru, Ecuador, Venezuela and possibly in Colombia [12,13]. In Ecuador
M. hallii is found both native and cultivated, growing in the Andean region from 2500 to 3000 metres
above mean sea level (MAMSL), and mainly in the provinces of Azuay, Bolivar, Carchi, Chimborazo,
Imbabura, Loja and Pichincha [11,13]. Its leaves and berries are used in both traditional medicine and
in cosmetics and foods, as a culinary herb or spice. In traditional medicine, arrayán is consumed as
an infusion and a decoction for its antiseptic, haemostatic, and balsamic properties. Moreover, dried
ground leaves applied to wounds aid healing and are used in baths, vapors and massages for their
stimulating and tonic properties. Green leaves are used to clean teeth and gums, with the added effect of
whitening teeth naturally. Finally, fresh leaves macerated in olive oil seem to prevent hair loss [10,11,14]. Chemical Characterization and in Vitro Antibacterial
Activity of Myrcianthes hallii (O. Berg) McVaugh
(Myrtaceae), a Traditional Plant Growing in Ecuador The extract showed modest antibacterial activity against
all tested bacteria, with the exception of E. coli which was found to be less sensitive. Whilst
methicillin-resistant strains usually display resistance to several drugs, no relevant differences were
observed between methicillin-susceptible and resistant strains. Considering its long-standing use
in folk medicine, which suggests the relative safety of the plant, and the presence of many known
antibacterial polyphenolic compounds responsible for its antibacterial activity, the results show that
M. hallii extract could be used as a potential new antiseptic agent. Moreover, new anti-infective
biomaterials and nanomaterials could be designed through the incorporation of M. hallii polyphenols. This prospective biomedical application is also discussed. Keywords: Myrcianthes hallii; acidic hydro-methanolic leaf extract; phytochemical composition;
antibacterial activity; multidrug-resistant bacteria; polyphenols; anti-infective biomaterials Materials 2016, 9, 454; doi:10.3390/ma9060454 www.mdpi.com/journal/materials Materials 2016, 9, 454 2 of 14 2.1. UHPLC-PDA-hESI-MSn Analysis of LMW Fraction of MHE
2.1. UHPLC-PDA-hESI-MSn Analysis of LMW Fraction of MHE The acidic hydro-methanolic leaf extract of M. hallii (MHE) was submitted to dialysis, using a
membrane with a nominal molecular weight cut-off (MWCO) of 3500 Da. A low molecular weight
(LMW) fraction, suitable for UHPLC-PDA-hESI-MSn analysis, was obtained. The chromatographic
profile, acquired at 280 nm, is reported in Figure 1. Thirty-eight compounds were identified based
on their chromatographic behaviour and mass spectra, in comparison with the literature. Table 1
summarizes the identified compounds, their retention times and m/z values for the parent ion and
fragment ions. The acidic hydro-methanolic leaf extract of M. hallii (MHE) was submitted to dialysis, using a
membrane with a nominal molecular weight cut-off (MWCO) of 3500 Da. A low molecular weight
(LMW) fraction, suitable for UHPLC-PDA-hESI-MSn analysis, was obtained. The chromatographic
profile, acquired at 280 nm, is reported in Figure 1. Thirty-eight compounds were identified based
on their chromatographic behaviour and mass spectra, in comparison with the literature. Table 1
summarizes the identified compounds, their retention times and m/z values for the parent ion and
fragment ions. Figure 1. UHPLC-UV chromatographic profile of the LMW fraction of MHE, registered at 280 nm. Figure 1. UHPLC-UV chromatographic profile of the LMW fraction of MHE, registered at 280 nm. Figure 1. UHPLC-UV chromatographic profile of the LMW fraction of MHE, registered at 280 nm. Figure 1. UHPLC-UV chromatographic profile of the LMW fraction of MHE, registered at 280 nm. The analysis shows the presence of 29 flavonoids, consisting of (a) 5 flavan-3-ols (gallocatechin,
catechin, epigallocatechin, epicatechin and epigallocatechin gallate); (b) 7 condensed tannin derivatives
(three isomers of procyanidin dimer, procyanidin-gallate, and three isomers of procyanidin-digallate);
(c) 12 flavonols (myricetin 3-O-galactoside/myricetin 3-O-glucoside, myricetin 3-O-arabinoside,
myricetin 3-O-rhamnoside, quercetin, quercetin hexosyl-gallate, quercetin 3-O-rhamnoside, quercetin
3-O-galactoside/quercetin 3-O-glucoside, quercetin 3-O-arabinose, acylated myricetrin, kaempferol
3-O-glucoside, aromadendrin-rhamnoside, and cypellogin A or B); (d) a flavanone derivative
(pinobanksin 3-O-butyrate); (e) a flavone derivative (apigenin-hexoside) and (f) 3 anthocyanin
derivatives (cyanidin-dihexoside, cyanidin-3-O-rutinoside, and cyanidin-3-glucoside/cyaniding-3-
galactoside). Moreover, in MHE a phenolic acid (gallic acid), 5 hydrolysable tannins
(hexahydroxydiphenoyl-glucose,
hexahydroxydiphenoyl-galloylglucose,
digalloylglucose,
trigalloylglucose, and monogalloyl-quinic acid), and 3 organic acids (quinic acid, malic acid and
gluconic acid) were detected. 1. Introduction The chemical compositions of plants belonging to the Myrtaceae family (such as Eucalyptus and Myrtus)
have been widely studied. Eucalyptus species are rich sources of biologically active terpenoids, tannins,
flavonoids and phloroglucinol derivatives [3,15,16]. In Myrtus communis L. (myrtle) the presence of
different polyphenolic classes is reported, including phenolic acids, flavonoids, galloyl derivatives
and hydrolysable tannins [2,17,18]. Some of the main polyphenols found in myrtle are also present in
green tea (catechin and gallocatechin derivatives) which is widely recognized as an excellent source of
powerful nutraceuticals [17,18]. A recent study on leaf extract obtained from Myrcianthes cisplatensis
(Cambess.) O. Berg, reported the presence of α-methyl-1-(21,41,61-trimethoxyphenyl)-1-propanone,
known as conglomerone, which shows antibacterial activity against methicillin-sensitive and resistant
Staphylococcus aureus strains [19]. Although studies reporting the composition of essential oils or the biological activity of
extracts do exist for several species of Myrcianthes (M. pungens (O. Berg) D. Legrand, M. cisplatensis
(Cambess.) O. Berg, M. pseudomato (D. Legrand) McVaugh, M. fragrans (Sw.) McVaugh, M. rhopaloides
(Kunth) McVaugh, M. osteomeloides (Rusby) McVaugh, and M. coquimbensis (Barnéoud) Landrum et
Grifo) [19–26], the available information concerning M. hallii is particularly limited. Therefore, in
view of the fact that M. hallii is commonly employed as an antibacterial agent in Ecuadorian folk
medicine, and therefore is likely safe and effective, and the importance of finding new anti-infective
extracts to be loaded into or coated onto biomaterials, the aims of this study were to investigate
the chemical composition of M. hallii and its antibacterial activity against Gram positive and Gram
negative multidrug-resistant strains. 3 of 14
3 of 13 Materials 2016, 9, 454
Materials 2016, 9, 454 2. Results
2. Results 2.1. UHPLC-PDA-hESI-MSn Analysis of LMW Fraction of MHE
2.1. UHPLC-PDA-hESI-MSn Analysis of LMW Fraction of MHE 2.1. UHPLC-PDA-hESI-MSn Analysis of LMW Fraction of MHE
2.1. UHPLC-PDA-hESI-MSn Analysis of LMW Fraction of MHE 2.1. UHPLC-PDA-hESI-MSn Analysis of LMW Fraction of MHE
2.1. UHPLC-PDA-hESI-MSn Analysis of LMW Fraction of MHE The analysis shows the presence of 29 flavonoids, consisting of (a) 5 flavan-3-ols (gallocatechin,
catechin, epigallocatechin, epicatechin and epigallocatechin gallate); (b) 7 condensed tannin
derivatives (three isomers of procyanidin dimer, procyanidin-gallate, and three isomers of
procyanidin-digallate);
(c) 12 flavonols (myricetin 3-O-galactoside/myricetin 3-O-glucoside,
myricetin 3-O-arabinoside, myricetin 3-O-rhamnoside, quercetin, quercetin hexosyl-gallate, quercetin
3-O-rhamnoside, quercetin 3-O-galactoside/quercetin 3-O-glucoside, quercetin 3-O-arabinose,
acylated myricetrin, kaempferol 3-O-glucoside, aromadendrin-rhamnoside, and cypellogin A or B);
(d) a flavanone derivative (pinobanksin 3-O-butyrate); (e) a flavone derivative (apigenin-hexoside) and
(f) 3 anthocyanin derivatives (cyanidin-dihexoside, cyanidin-3-O-rutinoside, and cyanidin-3-glucoside/
cyaniding-3-galactoside). Moreover, in MHE a phenolic acid (gallic acid), 5 hydrolysable
tannins (hexahydroxydiphenoyl-glucose, hexahydroxydiphenoyl-galloylglucose, digalloylglucose,
trigalloylglucose, and monogalloyl-quinic acid), and 3 organic acids (quinic acid, malic acid and
gluconic acid) were detected. 4 of 14 Materials 2016, 9, 454 Table 1. MS and MSn data of the compounds identified in LMW fraction of MHE. Table 1. MS and MS data of the compounds identified in LMW fraction of MHE. 2.1. UHPLC-PDA-hESI-MSn Analysis of LMW Fraction of MHE
2.1. UHPLC-PDA-hESI-MSn Analysis of LMW Fraction of MHE Peak
RT (min)
m/z
HPLC-ESI-MSn m/z (% of Base Peak)
Compound
1
2.43
191
173 (100), 127 (100)
Quinic acid
2
3.10
133
115 (100)
Malic acid
3
5.95
481
301 (100)
Hexahydroxydiphenoyl-glucose
4
11.03
169
125 (100)
Gallic acid
5
11.62
633
301 (100), 481 (5), 229 (5), 615 (2), 421 (5)
Hexahydroxydiphenoyl-
galloylglucose
6
13.44
343
169 (100), 125 (10)
Monogalloyl-quinic acid
7
13.55
881
729 (20), 577 (30), 289 (5), 711 (10)
Procyanidin digallate
8
14.1
611 +
449 (100), 287 (10)
Cyanidin-dihexoside
9
15.65
305
179 (100), 261 (45), 221 (85), 219 (80), 165 (25),
167 (30)
Gallocatechin
10
16.73
595 +
443 (100), 287 (15)
Cyanidin-3-O-rutinoside
11
18.48
881
729 (20), 577 (30), 289 (2), 711 (10)
Procyanidin digallate
12
18.65
577
425 (100), 407 (40), 289 (20)
Procyanidin dimer
13
19.07
305
261 (50), 221 (90), 219 (80), 179 (100), 165 (30),
167 (10)
Epigallocatechin
14
19.22
577
425 (100), 407 (40), 289 (20)
Procyanidin dimer
15
20.49
289
245 (100), 205 (40), 203 (20), 137 (5)
Catechin
16
21.95
577
407 (40), 289 (15), 425 (100)
Procyanidin dimer
17
22.57
881
729 (20), 577 (30), 289 (2), 711 (10)
Procyanidin digallate
18
23.11
289
245 (100), 205 (35), 203 (20), 137 (5)
Epicatechin
19
23.66
457
169 (100), 305 (35)
Epigallocatechin gallate
20
24.99
729
577 (85), 289 (25)
Procyanidin-gallate
21
25.26
479
316 (100), 317 (90)
Myricetin 3-O-galactoside or
Myricetin 3-O-glucoside
22
26.75
615
463 (100), 301 (10)
Quercetin hexosyl-gallate
23
26.93
449
316 (100), 317 (30)
Myricetin 3-O-arabinoside
24
27.43
463
316 (100), 317 (60)
Myricetin 3-O-rhamnoside
25
27.69
463
301 (100), 179 (2)
Quercetin 3-O-galactoside or
Quercetin 3-O-glucoside
26
28.56
197+
179 (100), 135 (60)
Gluconic acid
27
28.83
433
301 (100), 179 (2)
Quercetin 3-O-arabinose
28
29.23
447
284 (100), 255 (10) 257 (5), 327 (25)
Kaempferol 3-O-glucoside
29
29.25
449 +
287 (100)
Cyanidin-3-glucoside or
Cyanidin-3-galattoside
30
30.23
447
301 (100), 179 (2)
Quercetin 3-O-rhamnoside
31
31.15
433
287 (40), 269 (100), 259 (10), 179 (5), 151 (2)
Aromadendrin-rhamnoside
32
31.43
505
316 (100), 463 (15)
Acylated myricitrin
33
32.55
483
331 (20), 169 (100)
Digalloylglucose
34
36.40
629
463 (85), 301 (100), 445 (10)
Cypellogin A or B
35
37.86
301
179 (100), 151 (50), 273 (20)
Quercetin
36
37.45
635
483 (100), 465 (5)
Trigalloylglucose
37
42.89
431
269 (100)
Apigenin-hexoside
38
43.72
343 +
325 (10), 301 (2), 240 (100)
Pinobanksin 3-O-butyrate
+ Compounds revealed with positive ionization. 2.1. UHPLC-PDA-hESI-MSn Analysis of LMW Fraction of MHE
2.1. UHPLC-PDA-hESI-MSn Analysis of LMW Fraction of MHE + Compounds revealed with positive ionization. In further detail, five flavan-3-ols were identified in MHE. Peaks 9 and 13 were identified as
gallocatechin and epigallocatechin, respectively, by comparing their MS2 spectra with literature data
(MW 306). Their parent ions (m/z 305) produced characteristic fragment ions at m/z 261, 221, 219,
179, 167, and 165, generated by the cleavage of the A ring, the heterocyclic ring fission, and the
retro-Diels-Alder fission occurring during the fragmentation process as reported by Dou et al. [27]. It was possible to identify the epimers by comparison with commercial standards. Peaks 15 and 18,
which both showed a parental ion at m/z 289, were assigned to catechin and epicatechin respectively
(MW 290). Their MS2 spectra showed the presence of ions at m/z 245, 205, 203, and 137, generated by
the cleavage of ring A and the retro-Diels-Alder fission occurring during the fragmentation process [27]. It was again possible to identify the epimers by comparison with commercial standards. Peak 19,
which produced a molecular ion [M–H]´ at m/z 457, was identified as epigallocatechin-3-gallate
(MW 458) since it produced fragment ions at m/z 305 and 169 corresponding to the deprotonated ion Materials 2016, 9, 454 5 of 14 of epigallocatechin and gallic acid [27]. It was possible to identify this compound by comparison with
the commercial standard. Twelve flavonols were identified in MHE: four myricetin derivatives, five quercetin derivatives,
a quercetin aglycone, and two kaempferol derivatives. Four myricetin derivatives were identified in
MHE due to their MS and MS/MS spectra. Peaks 21, 23, 24, 32 were assigned to myricetin derivatives
due to the presence of the aglycone at m/z 317, in their MS2 spectra. Peak 21 was identified as myricetin
glucoside or galactoside (MW 480) due to the parental ion at m/z 479 producing the MS2 fragment
[M–162]´; peak 24 was assigned to myricetin rhamnoside (MW 464) due to the loss of 146 Da from the
molecular ion at m/z 463, according to Faria et al. [28]. Peak 23 was identified as myricetin arabinoside
(MW 450), since it produced the MS2 ion at m/z 317 from the molecular ion at m/z 449, due to the loss of
[M–132]´ corresponding to the arabinoil moiety. Peak 32 was assigned to acylated myricitrin (MW 506). 2.1. UHPLC-PDA-hESI-MSn Analysis of LMW Fraction of MHE
2.1. UHPLC-PDA-hESI-MSn Analysis of LMW Fraction of MHE Its molecular ion at m/z 505 produced a base peak at m/z 316, corresponding to the myricetin aglycone,
and a fragment at m/z 463, due to the loss of the acylic moiety. In MHE five quercetin derivatives were
identified, because all peaks presented the characteristic fragment ions of quercetin aglycone (e.g.,
MSn data at m/z 300, 301, 179). Peaks 25, 27, 30 were assigned to quercetin glucoside or galactoside
(MW 464), quercetin arabinoside (MW 434), and quercetin rhamnoside (MW 448), since they yielded
the fragments [M–162]´, [M–132]´, [M–146]´, respectively. Peak 22 was identified as quercetin
hexosylgallate (MW 616), since the molecular ion [M–H]´ at m/z 615 produced a fragment at m/z 463,
corresponding to the loss of a galloyl group, and a fragment at m/z 301 due to the loss of a hexosyl
group, corresponding to the aglycone [15]. Peak 34 may correspond to Cypellogin A or B (MW 630),
which is a quercetin glucoside or galactoside acylated with an oleuropeic acid residue [29]; in fact, the
compound yielded a base peak at m/z 301 corresponding to the aglycone. Quercetin (MW 302) was
identified as peak 35 due to the presence of the molecular ion [M–H]´ at m/z 301. With regards to
kaempferol derivatives, peak 28 was assigned to kaempferol 3-O-glucoside (MW 448) by observing the
MS2 data closely related to the glycosylation position. According to Ablajan et al. [30], peak 28 showed
a MS2 spectrum typical of a 3-O-glucosyl derivative. It produced a base peak at m/z 284, related to the
homolytic cleavage of deprotonated flavonoid glycosides, a fragment at m/z 255 more abundant than
that registered at m/z 257 and a fragment at m/z 327 that is not present in 7-O-glucosyl derivatives. Peak 31 was identified as aromadendrin rhamnoside (MW 434), since the molecular ion [M–H]´ at
m/z 433 produced the fragment [M–146]´ corresponding to the aglycon at m/z 287. Regarding flavanone and flavone derivatives, peak 38 was assigned to pinobanksin 3-O-butyrate,
the parent ion (m/z 343) producing fragment ions as reported by Chua et al. [31]. Peak 37 was identified
as apigenin-hexoside, since it produced a molecular ion [M–H]´ at m/z 431, and yielded a fragment ion
at m/z 269 corresponding to apigenin aglycone due to the loss of a hexosyl group. Three anthocyanidin
derivatives were identified in MHE. Peaks 8, 10, 29 showed the presence of the cyanidin aglycone
at m/z 287 in their MS2 spectra. 2.1. UHPLC-PDA-hESI-MSn Analysis of LMW Fraction of MHE
2.1. UHPLC-PDA-hESI-MSn Analysis of LMW Fraction of MHE Peak 8 was assigned to cyanidin-dihexoside (MW 610), since the
parent ion (m/z 611) produced fragment ions at m/z 449 and m/z 287, corresponding to the loss of the
sugar molecules linked to the aglycone. Peak 10 was identified as cyanidin-3-rutinoside thanks to the
pseudomolecular ion [M + H]+ at m/z 595 and its MS2 fragments at m/z 433, caused by the loss of one
of the sugar molecules linked to the aglycone, and m/z 287, corresponding to the cyaniding aglycone
(MW 594). Peak 29, which produced a molecular ion [M + H]+ at m/z 449 and yielded a fragment ion
at m/z 287 corresponding to the loss of the hexosyl moiety on MS2, may be assigned to the glucoside
or galactoside derivative of cyanidin (MW 448). With regards to benzoic acids, gallic acid (MW 170) was identified as peak 4 in MHE, since it
produced a base peak at m/z 125 corresponding to the loss of a carboxyl group [M–H–CO2]´. As far as tannins are concerned, condensed tannins and hydrolizable tannins (gallotannins and
ellagitanninis) were detected. Seven condensed tannin compounds were detected in MHE. Three peaks
(12, 14, 16) showed molecular ions at m/z 577 with the same MS2 fragmentation pattern (m/z 425,
407, 289), but different retention times: consequently they can be considered to be three isomers of
procyanidin (MW 578) [32]. Peak 20 produced a molecular ion [M–H]´ at m/z 729 and the most 6 of 14 Materials 2016, 9, 454 significant MS2 fragments at m/z 577, corresponding to the loss of a galloyl group, and at m/z 289,
corresponding to the monomer: for these reasons peak 20 was assigned to a monogalloyl procyanidin
dimer. Peaks 7, 11, 17 produced a molecular ion [M–H]´ at m/z 881, which could correspond to
procyanidin digallate, and the same MS2 fragmentation spectra. The main fragments produced were
at m/z 729 (corresponding to the loss of a galloyl group), at m/z 711 (corresponding to the loss of a
molecule of gallic acid), at m/z 577 (corresponding to procyanidin), and at m/z 289 (corresponding
to the monomer (´)-epicatechin or (´)-catechin). Consequently, peaks 7, 11, and 17 were assigned
to three different isomers of procyanidin digallate. With regards to hydrolizable tannins, peaks 3
and 5 were assigned to hesahydroxydiphenoyl-glucose and hesahydroxydiphenoyl-galloylglucose,
respectively. 2.1. UHPLC-PDA-hESI-MSn Analysis of LMW Fraction of MHE
2.1. UHPLC-PDA-hESI-MSn Analysis of LMW Fraction of MHE Peak 3 was identified as hesahydroxydiphenoyl-glucose (MW 480), since it produced a
molecular ion at m/z 481 and a MS2 fragment ion at m/z 301, corresponding to the loss of a glucose unit
as reported in the literature [33]. Peak 5 produced a molecular ion at m/z 633, an intense fragment ion
at m/z 301 suggesting the loss of a galloylglucose unit, and a fragment ion at m/z 481, corresponding
to the molecular ion of hesahydroxydiphenoyl-glucose, due to the loss of a galloyl unit. Through
comparison with data from the literature [33], the fragmentation pattern of this molecule suggests
that the galloyl moiety is directly linked to the glucose unit, so the compound was identified as
hesahydroxydiphenoyl-galloylglucose (MW 634). Peak 33 was assigned to digalloylglucose (MW 484),
since it provided the typical MS2 fragment ions at m/z 331 [M–H–152]´ and m/z 169 [M–H–162]´,
corresponding to the sequential loss of the galloyl and the glucosyl moiety, respectively [33]. Moreover,
peak 36 was identified as trigalloylglucose (MW 636), since the molecular ion at m/z 635 produced a
base peak at m/z 483, due to the loss of a galloyl group, leading to m/z typical of digalloyl glucose,
and a fragment at m/z 465 due to the loss of gallic acid. Finally, peak 6 was assigned to monogalloyl
quinic acid (MW 344). It showed a molecular ion at m/z 343 and a MS2 spectrum characterized by the
presence of fragment ions at m/z 169 and 125. The neutral loss of 174 Da corresponds to quinic acid. Finally, some organic acids (quinic acid, malic acid and gluconic acid) were identified in MHE. Peak 1 was identified as quinic acid (MW 192), with a retention time of approximately 2 min and
MS2 fragments at m/z 173 [M–H–H2O]´, corresponding to the loss of a water molecule, and at m/z
127 [M–H–CO–2H2O]´, corresponding to the loss of the carboxylic moiety and two water molecules. Peak 2, showing a retention time of 3.10 min and a MS2 fragment at m/z 115 [M–H–H2O]´, was
identified as malic acid. Peak 26 yielded to MS2 fragments at m/z 179 [M–H–H2O]´, due to the loss of
a water molecule, and at m/z 135 [M–H–CO–H2O]´ representing the 60% of the base peak, due to
the loss of the carboxylic group and a water molecule. Thus, peak 26 was identified as gluconic acid
(MW 198) [34]. 2.2. Antibacterial Activity of MHE Discussion
Thi
h
t th fi
t
t
th i
l ti
d id
tifi
ti
f
l
h
l
d
Table 2. In vitro antibacterial cumulative activity of MHE against ten S. aureus, ten E. coli,
ten P. aeruginosa, ten Enterococcus spp., and ten S. pyogenes strains. search represents the first report on the isolation and identification of polyphen
ds from M. hallii to date. UHPLC-PDA-hESI-MSn analysis revealed the pres
compounds, belonging to flavonoids, phenolic acids, tannins and organic acids. S
been previously identified in extracts obtained from plants and fruits belonging
family, whilst for others, this is the first report of their identification in a My
HE extract, 29 flavonoids were identified, consisting of flavan-3-ols, condensed
fl
l
fl
d
fl
d
i
ti
d
th
i
d
i
Strains (Number)
MIC Range (gr/mL)
50%
90%
S. aureus (10)
0.007–0.0019
0.0039
0.0039
S. pyogenes (10)
0.007–0.0039
0.0039
0.007
Enterococcus spp. (10)
0.0039–0.0019
0.0039
0.0039
E. coli (10)
0.25–>0.5
>0.5
>0.5
P. aeruginosa (10)
0.125–0.062
0.062
0.062 This research represents the first report on the isolation and identification of polyphenols and
rganic acids from M. hallii to date. UHPLC-PDA-hESI-MSn analysis revealed the presence of
hirty-eight compounds, belonging to flavonoids, phenolic acids, tannins and organic acids. Some of
hem have been previously identified in extracts obtained from plants and fruits belonging to the
Myrtaceae family, whilst for others, this is the first report of their identification in a Myrtaceae
pecies. In MHE extract, 29 flavonoids were identified, consisting of flavan-3-ols, condensed tannin
erivatives, flavonols, a flavanone and a flavone derivative and anthocyanin derivatives
lavan-3-ols were also detected in the methanolic extract of the bark of Tristaniopsis callobuxus
rongn. & Gris, by Bellosta et al. [35], which showed the presence of gallocatechin and
Strains (Number)
MIC Range (gr/mL)
50%
90%
S. aureus (10)
0.007–0.0019
0.0039
0.0039
S. pyogenes (10)
0.007–0.0039
0.0039
0.007
Enterococcus spp. (10)
0.0039–0.0019
0.0039
0.0039
E. coli (10)
0.25–>0.5
>0.5
>0.5
P. aeruginosa (10)
0.125–0.062
0.062
0.062
Table 3. MIC (mg/mL) of MHE against ten S. aureus, ten S. pyogenes, five E. faecalis, five E. faecium,
ten P. aeruginosa, and ten E. coli strains. Frequencies (%) of the different bacterial species within MIC
classes are shown. y
avan-3-ols were also detected in the methanolic extract of the bark of Tristaniopsis callobuxus
ongn. & Gris, by Bellosta et al. [35], which showed the presence of gallocatechin and
Table 3. 2.2. Antibacterial Activity of MHE MIC mode values (expressed as
log10) for the different bacterial species assayed are represented in the figure. The four Gram-positive
species (S. aureus, S. pyogenes, E. faecalis, E. faecium) exhibit equal values of MIC mode, while the MIC
mode values against the two Gram-negative species (P. aeruginosa and E. coli) are much higher (E. coli >
P. aeruginosa). Figure 2. MIC values within groups follow a modal distribution. MIC mode values (expressed as
log10) for the different bacterial species assayed are represented in the figure. The four Gram-positive
species (S. aureus, S. pyogenes, E. faecalis, E. faecium) exhibit equal values of MIC mode, while the MIC
mode values against the two Gram-negative species (P. aeruginosa and E. coli) are much higher
(E. coli > P. aeruginosa). Figure 2. MIC values within groups follow a modal distribution. MIC mode values (expressed as
log10) for the different bacterial species assayed are represented in the figure. The four Gram-positive
species (S. aureus, S. pyogenes, E. faecalis, E. faecium) exhibit equal values of MIC mode, while the MIC
mode values against the two Gram-negative species (P. aeruginosa and E. coli) are much higher (E. coli >
P. aeruginosa). Figure 2. MIC values within groups follow a modal distribution. MIC mode values (expressed as
log10) for the different bacterial species assayed are represented in the figure. The four Gram-positive
species (S. aureus, S. pyogenes, E. faecalis, E. faecium) exhibit equal values of MIC mode, while the MIC
mode values against the two Gram-negative species (P. aeruginosa and E. coli) are much higher
(E. coli > P. aeruginosa). Figure 2. MIC values within groups follow a modal distribution. MIC mode values (expressed as
log10) for the different bacterial species assayed are represented in the figure. The four Gram-positive
species (S. aureus, S. pyogenes, E. faecalis, E. faecium) exhibit equal values of MIC mode, while the MIC
mode values against the two Gram-negative species (P. aeruginosa and E. coli) are much higher (E. coli >
P. aeruginosa). Discussion
Thi
h
t th fi
t
t
th i
l ti
d id
tifi
ti
f
l
h
l
d
Table 2. In vitro antibacterial cumulative activity of MHE against ten S. aureus, ten E. coli,
ten P. aeruginosa, ten Enterococcus spp., and ten S. pyogenes strains. 2.2. Antibacterial Activity of MHE In vitro antibacterial cumulative activity of MHE against ten S. aureus, ten
ten P. aeruginosa, ten Enterococcus spp., and ten S. pyogenes strains. Strains (Number)
MIC Range (gr/mL)
50%
90%
S. aureus (10)
0.007–0.0019
0.0039
0.0039
S. pyogenes (10)
0.007–0.0039
0.0039
0.007
Enterococcus spp. (10)
0.0039–0.0019
0.0039
0.0039
E. coli (10)
0.25–>0.5
>0.5
>0.5
P. aeruginosa (10)
0.125–0.062
0.062
0.062
Table 3. MIC (mg/mL) of MHE against ten S. aureus, ten S. pyogenes, five E. faecalis, five E. ten P. aeruginosa, and ten E. coli strains. Frequencies (%) of the different bacterial species wit
classes are shown. Bacterial
Species
Number
of Strains
MIC
mg/mL
1.90
MIC
mg/mL
3.90
MIC
mg/mL
7.00
MIC
mg/mL
62.0
MIC
mg/mL
125
MIC
mg/mL
250
Gram-positive bacteria: frequencies (%)
S. aureus
10
10
80
10
-
-
-
S. pyogenes
10
-
60
40
-
-
-
E. faecalis
5
80
20
-
-
-
-
E. faecium
5
-
100
-
-
-
-
Gram-negative bacteria: frequencies (%)
P. aeruginosa
10
-
-
-
90
10
-
E. coli
10
-
-
-
-
-
30 Figure 2. MIC values within groups follow a modal distribution. MIC mode values (expressed as
log10) for the different bacterial species assayed are represented in the figure. The four Gram-positive
species (S. aureus, S. pyogenes, E. faecalis, E. faecium) exhibit equal values of MIC mode, while the MIC
mode values against the two Gram-negative species (P. aeruginosa and E. coli) are much higher
(E. coli > P. aeruginosa). Figure 2. MIC values within groups follow a modal distribution. MIC mode values (expressed as
log10) for the different bacterial species assayed are represented in the figure. The four Gram-positive
species (S. aureus, S. pyogenes, E. faecalis, E. faecium) exhibit equal values of MIC mode, while the MIC
mode values against the two Gram-negative species (P. aeruginosa and E. coli) are much higher (E. coli >
P. aeruginosa). Figure 2. MIC values within groups follow a modal distribution. MIC mode values (expressed as
log10) for the different bacterial species assayed are represented in the figure. The four Gram-positive
species (S. aureus, S. pyogenes, E. faecalis, E. faecium) exhibit equal values of MIC mode, while the MIC
mode values against the two Gram-negative species (P. aeruginosa and E. coli) are much higher
(E. coli > P. aeruginosa). Figure 2. MIC values within groups follow a modal distribution. 2.2. Antibacterial Activity of MHE The antibacterial activity of MHE obtained from M. hallii dried leaves was tested against ten MRSA
and MSSA, ten E. coli, ten P. aeruginosa, ten Enterococcus spp, and ten S. pyogenes strains. MHE showed
antibacterial activity against all the tested S. aureus (MIC range 0.007–0.0019 gr/mL), P. aeruginosa
(MIC range 0.125–0.062 gr/mL), S. pyogenes (MIC range 0.007–0.0039 gr/mL) and Enterococcus spp. (MIC range 0.0039–0.0019 gr/mL). MHE was found to be less active against E. coli strains (MIC
range 0.25 > 0.5 gr/mL) (Tables 2 and 3 and Figure 2). Our data showed that MHE extract can
inhibit bacterial strains irrespectively of their mechanisms of resistance. No significant differences
were observed between strains carrying well-known mechanisms of resistance and susceptible ones,
because one-dilution differences in this kind of analysis are taken for granted. 7 of 14 Materials 2016, 9, 454
Gram-negative bact
P. aeruginosa E. coli
10
-
-
-
-
-
30
Figure 2. MIC values within groups follow a modal distribution. MIC mode values (express
log10) for the different bacterial species assayed are represented in the figure. The four Gram-po
species (S. aureus, S. pyogenes, E. faecalis, E. faecium) exhibit equal values of MIC mode, while the
mode values against the two Gram-negative species (P. aeruginosa and E. coli) are much h
(E. coli > P. aeruginosa). 3. Discussion
This research represents the first report on the isolation and identification of polyphe
organic acids from M. hallii to date. UHPLC-PDA-hESI-MSn analysis revealed the pr
thirty-eight compounds, belonging to flavonoids, phenolic acids, tannins and organic acids
them have been previously identified in extracts obtained from plants and fruits belongi
Myrtaceae family, whilst for others, this is the first report of their identification in a M
species. In MHE extract, 29 flavonoids were identified, consisting of flavan-3-ols, condense
derivatives, flavonols, a flavanone and a flavone derivative and anthocyanin de
Flavan-3-ols were also detected in the methanolic extract of the bark of Tristaniopsis c
Brongn. & Gris, by Bellosta et al. [35], which showed the presence of gallocate
Figure 2. MIC values within groups follow a modal distribution. MIC mode values (expr
log10) for the different bacterial species assayed are represented in the figure. The four Gram-
species (S. aureus, S. pyogenes, E. faecalis, E. faecium) exhibit equal values of MIC mode, while
mode values against the two Gram-negative species (P. aeruginosa and E. coli) are much higher
P. aeruginosa). Table 2. 3. Discussion This research represents the first report on the isolation and identification of polyphenols and
organic acids from M. hallii to date. UHPLC-PDA-hESI-MSn analysis revealed the presence of
thirty-eight compounds, belonging to flavonoids, phenolic acids, tannins and organic acids. Some
of them have been previously identified in extracts obtained from plants and fruits belonging to the
Myrtaceae family, whilst for others, this is the first report of their identification in a Myrtaceae species. y
y
p
y
p
In MHE extract, 29 flavonoids were identified, consisting of flavan-3-ols, condensed tannin
derivatives, flavonols, a flavanone and a flavone derivative and anthocyanin derivatives. Flavan-3-ols
were also detected in the methanolic extract of the bark of Tristaniopsis callobuxus Brongn. & Gris,
by Bellosta et al. [35], which showed the presence of gallocatechin and epigallocatechin. Catechin
was also detected in the methanolic extracts obtained from the air-dried leaves of Myrtus communis L. (myrtle) and Eucalyptus globulus Labill [16,18]. Amongst Myrtaceae, flavonol derivatives were also
detected in the methanolic extracts of Eucalyptus globulus. For myrtle, infusions and leaf methanolic
extracts were both shown to contain myricetin and quercetin derivatives [2,18]. In the methanolic
extract obtained from the fruits of Myrciaria vexator McVaugh, Dastmalchi et al. identified the
following flavonols, quercitrin (quercetin 3-rhamnoside), quercetin 3-glucoside, and myricetin [36]. Moreover, in the fruits of Myrcianthes pungens (O. Berg) D. Legrande, De Mello Andrade et al. showed
the presence of quercitrin [24]. Regarding anthocyanins, in the fruits of Myrciaria dubia (Kunth)
McVaugh, a plant native of Amazonian rainforest, cyanidin-3-glucoside was identified as the main
pigment [37]. The other two cyanidin-derivatives identified in MHE have never been reported in
plants belonging to Myrtaceae family. Condensed tannins, such as procyanidin, were detected in
many species belonging to Eucalyptus and Eugenia genera [38]. Ellagitannis have only been found in
dicotyledoneous angiosperms and Myrtaceae are indicated as being rich in ellagitannins. In support of
this fact, ellagitannis were detected in Callistemon lanceolatus Sweet, Eucalyptus alba Reinw. Ex Blume,
Eugenia grandis Wight, Kunzea ambigua (Sm.) Druce, Melaleuca squarrosa Sm., Pimenta dioica (L.) Merr.,
Siphoneugena densiflora, Syzygium aqueum (Burm. f.) Alston, and Syzygium aromaticum (L.) Merr &
L.M. Perry [39]. In MHE, gallic acid, hydrolysable tannins and organic acids have been detected. Gallic acid is a secondary metabolite of plants, mainly formed from 3-dehydroshikimic acid through
the shikimic acid pathway [40]. 2.2. Antibacterial Activity of MHE MIC (mg/mL) of MHE against ten S. aureus, ten S. pyogenes, five E. faecalis, five E. faecium,
ten P. aeruginosa, and ten E. coli strains. Frequencies (%) of the different bacterial species within MIC
classes are shown. Bacterial
Species
Number
of Strains
MIC
mg/mL
1.90
MIC
mg/mL
3.90
MIC
mg/mL
7.00
MIC
mg/mL
62.0
MIC
mg/mL
125
MIC
mg/mL
250
MIC
mg/mL
510
Gram-positive bacteria: frequencies (%)
S. aureus
10
10
80
10
-
-
-
-
S. pyogenes
10
-
60
40
-
-
-
-
E. faecalis
5
80
20
-
-
-
-
-
E. faecium
5
-
100
-
-
-
-
-
Gram-negative bacteria: frequencies (%)
P. aeruginosa
10
-
-
-
90
10
-
-
E. coli
10
-
-
-
-
-
30
70 Materials 2016, 9, 454 8 of 14 3. Discussion It is widely distributed in many different families of higher plants,
both in the free state and as a part of more complex molecules such as ester derivatives or polymers. Amongst Myrtaceae, gallic acid was detected in the methanolic extract obtained from the leaves
of Eucalyptus globulus [16], the fruits of Rhodomyrtus tomentosa (Aiton) Hassk. [41], the methanolic
extract of the bark of Tristaniopsis callobuxus [35], leaf infusions or methanolic extract obtained from
Myrtus communis [2,18] and the seed and fruit extracts of Syzygium cumini (L.) Skeels [42]. Quinic
acid has been identified in many plants in the Myrtaceae family, such as Syzygium cumini and
Myrtus communis [17,43]. Amongst the thirty-eight compounds occurring in M. hallii leaf extract, many of them possess
well-documented antibacterial activity [44]. For example, the in vitro antibacterial activity of catechin
derivatives has been known since the 1990s and has been demonstrated against different strains, such
as Streptococcus mutans, E. coli, Clostridium perfringes and Bacillus cereus [45–47]. Moreover, flavonols,
especially myricetin, quercetin and kaempferol derivatives, are characterized by a remarkable
antibacterial activity against both Gram-positive and Gram-negative bacteria, such as S. aureus,
Lactobacillus acidophilus, Porphyromonas gingivalis and Prevotella melaninogenica [48]. Other categories
of compounds with known antibacterial activity are gallotannins and procyanidins. The former
showed antibacterial activity against Gram-positive food-borne bacteria (i.e., Clostridium botulinum,
Bacillus subtilis, B. cereus) [49]; the latter, especially those derived from berries, were found to be
active against E. coli, S. mutans and oxacillin-resistant S. aureus [50]. On this basis, we evaluated MHE
activity against different strains of S. aureus, P. aeruginosa, S. pyogenes, Enterococcus spp. and E. coli. To the best of our knowledge, no data are available on the antibacterial activity of M. hallii against
drug resistant bacteria. Although MHE was found to be as rich in polyphenolic components that 9 of 14 Materials 2016, 9, 454 could exert antibacterial activity, our results showed that the antibacterial activity of MHE against
S. aureus, P. aeruginosa, S. pyogenes and Enterococcus spp. strains is modest but appreciable, especially
against Enterococcus spp. MHE was shown to be much less active against E. coli strains. Moreover,
our data shows that, whilst methicillin-resistant strains usually display resistance to several drugs,
no relevant differences were observed between methicillin-susceptible and resistant strains. Our
results agree with earlier studies carried out on other species belonging to the Myrcianthes genus. 3. Discussion The
ethanol extract obtained from Myrcianthes discolor (Kunth) McVaugh dried leaves showed antibacterial
activity against a S. aureus strain isolated from laryngitis samples, but did not show any activity
against two E. coli strains isolated from urinary tract infection samples [51,52]. Moreover, M. cisplatensis
showed antibacterial activity against methicillin-sensitive and resistant S. aureus strains [19]. According
to the results obtained from UHPLC-PDA-hESI-MSn analysis, the appreciable antibacterial activity of
MHE against S. aureus, P. aeruginosa, S. pyogenes, and especially Enterococcus spp., could be explained
by the wide spectrum of polyphenols identified in the extract, which act as antimicrobial substances
via different mechanisms of action (MOA). In fact, many MOA are ascribed to polyphenols, such as
cytoplasmatic membrane damage, inhibition of nucleic acids, cell walls and cell membrane synthesis. Moreover, in addition to their direct antibacterial activity, a growing body of evidence suggests that
polyphenols may interfere with some bacterial virulence factors such as enzymes, toxins and signal
receptors [44]. The search for natural antimicrobial compounds is incited by the need to thwart the increasing
bacterial resistance to antibiotics. In the biomedical field, this microbial antibiotic-resistance leads to
a growing need for new, effective anti-infective materials for the prevention and delay of implant-
and device-associated infections [53]. Anti-infective biomaterials have become a primary strategy
to achieve this end. Natural polyphenols are interesting candidates for new antimicrobial agents to
be loaded into or coated onto biomaterials. The development of nanoparticles carrying bioactive
compounds with antimicrobial activity has been the target of investigations over the past years. In particular, several technologies have been developed at the nanoscale, such as nanoparticles,
nanofibers, and nanocapsules, providing targeted delivery of polyphenols for therapeutic uses [54]. Recently, polyphenol delivery systems with antimicrobial activity have been described, focusing on
nanoparticles based on chitosan as the main structural and functional material [55]. Polyphenols,
ubiquitously expressed in plants have been shown to exert anticancer and immunomodulatory
properties along with their anti-inflammatory and antimicrobial activities. However, some issues have
been raised regarding the use of free polyphenols as medical drugs due to their fast metabolism and
excretion in the human body. Indeed, this behavior might restrict or hamper their in vivo bioactive
effects [56]. Therefore, a successful strategy for the use of M. 4.1. Chemicals and Materials LC-MS grade methanol, acetonitrile and formic acid were purchased from Sigma-Aldrich
(St. Louis, MO, USA). Millipore grade water was obtained with a Milli-Q water purification system
(Millipore Corporation, Billerica, MA, USA). Filtration membranes (0.22 and 0.45 µm, cellulose
acetate/cellulose nitrate mixed esters) were purchased from Millipore (Millipore Corporation). (´)-Epicatechin, (´)-catechin, (´)-epigallogatechin, (´)-gallocatechin and (´)-epigallocatechin-3-gallate
were purchased by PhytoLab GmbH & Co.KG (Vestenbergsgreuth, Germany). 3. Discussion hallii polyphenols as antimicrobial agents
in the biomedical field may be require their administration in a form linked to or incorporated with
nanomaterials able to support their controlled and prolonged release. 4.4. UHPLC-PDA-hESI-MSn Analysis The experiment was performed using a Jasco X-LC system (Jasco, Easton, MD, USA) equipped
with a quaternary pump, an UHPLC photodiode array detector (PDA) and a linear ion trap mass
spectrometer LTQ-XL (Thermo Scientific, Waltham, MA, USA) through an h-ESI source. Separation
was achieved on a Purospher® STAR RP-18e (5 µm) LiChroCART® 250-4 (250 ˆ 4 mm2 i.d., 5 µm)
with its corresponding guard column (both from Merck KGaA, Darmstadt, Germany). The mobile
phase consisted of A (0.1% formic acid in water) and B (acetonitrile) at a flow rate of 1 mL/min with an
injection volume of 5 µL. Gradient elution was carried out using the following timetable: 98% A/2%
B 0–5 min, 60% A/40% B 5–40 min, 0% A/100% B 40–45 min, 0% A/100% B 45–47 min, 98% A/2%
B 47–52 min, 98% A/2% B 52–57 min. The resulting total run time was 57 min, including column
reconditioning. The sample tray was set at 4 ˝C and the column oven temperature was set at 24 ˝C. The chromatograms were recorded at λ 280, 220, 366 and 520 nm); spectral data were acquired in the
range of 200–650 nm for all peaks. The ion trap operated in data dependent, full scan (80–1500 m/z),
zoom scan and MSn mode. To obtain the fragment ions a collision energy of 35% and an isolation of
2 m/z were applied; the voltage was kept at 3 kV for negative ionization and 5 kV for the positive
one, the temperature of the capillary tube was 275 ˝C with a sheath gas flow rate of 45 arbitrary units
and an auxiliary gas flow rate of 20 arbitrary units, while the ionization chamber was maintained at
100 ˝C. ThermoFisher Scientific Excalibur 2.0 software (SR2, Thermo Electron Corporation 1998–2006,
Waltham, MA, USA) was used for data acquisition and processing. Three independent assays were
performed to analyze the sample (filtered through a cellulose acetate/cellulose nitrate mixed esters
membrane, 0.22 µm) and no relevant variations attributable to the nature of the detected fragments or
their relative intensities were observed. 4.3. Extraction and Dialysis Two 10 g aliquots of MHE were separately taken from the dried and finely ground leaves of
M. hallii in 100 mL of H2O/methanol solution (70:30; % v/v) containing formic acid (0.1%, v/v),
prepared in the dark, under constant stirring at room temperature for 24 h. Both extracts were
filtered on a paper filter, gathered and freeze-dried. The residue was weighted and then reconstituted
to 20 mL with Millipore-grade water and subdivided into two 10 mL aliquots. The first one was
subjected to microbiological assays, the second was submitted to dialysis. Dialysis was performed
using a Spectra/Por® Biotech Regenerated Cellulose membrane (Spectrum Europe B.V., Breda,
The Netherlands) with a nominal molecular weight cut-off (MWCO) of 3500 Da. An aliquot (10 mL) of
MHE was submitted to dialysis in 1000 mL of Millipore-grade water for 24 h at 4 ˝C under constant
stirring. The dialysate (low molecular weight fraction, LMW) was freeze-dried and the dry residue
was assessed and dissolved in 10 mL of Millipore-grade water and subjected to microbiological assays
and to UHPLC-PDA-hESI-MSn analysis, following filtration through 0.45 and 0.22 µm filters. 4.2. Plant Material M. hallii was collected in July 2013 at Quito, Pichincha Province, Ecuador. Leaves were isolated
manually from aerial parts and dried at room temperature for 3 weeks. Desiccated specimens were Materials 2016, 9, 454 10 of 14 10 of 14 identified as M. hallii (O. Berg) McVaugh (syn. Eugenia halli Berg, Amyrsia halli (Berg) Kausel). Sample
specimens have been deposited at the Herbarium of the University of Pavia (Department of Earth and
Environmental Sciences, University of Pavia, Pavia, Italy) for future reference with the code: Quito
(Pichincha, Ecuador), 26/07/2013, F. Bracco (PAV). 4.5. Bacterial Strains and Growth Conditions The bacteria were recent clinical isolates, belonging to the Institute of Microbiology
(University of Genova) collection. They comprised of: (i) ten S. aureus strains, including five
methicillin-resistant (MRSA) and five methicillin-susceptible (MSSA) strains. Of the MRSA strains,
three were multi-resistant (resistant to at least three classes of antibiotics); (ii) ten multi-resistant
Escherichia coli strains; (iii) ten Pseudomonas aeruginosa strains; (iv) ten vancomycin-resistant and
susceptible Enterococcus faecalis and Enterococcus faecium strains; and (v) ten group A streptococci
(Streptococcus pyogenes) strains, which remain universally susceptible to penicillin. All isolates were 11 of 14 Materials 2016, 9, 454 identified at the species level using clinical methods and an API STAPH, API20E, API NE and API
STREP system (bioMèrieux, Marcy l’Etoile, France) for S. aureus, E. coli, P. aeruginosa, Enterococcus spp. and S. pyogenes respectively. The antibiotype was determined using the disk diffusion test, as according
to the latest Clinical and Laboratory Standards Institute (CLSI) guidelines [57]. Strains were cultured
in Mueller-Hinton Broth, Mueller-Hinton agar, MacConkey agar and Columbia blood agar (Biolife,
Milan, Italy) at 37 ˝C. 4.6. Susceptibility (MIC Determination) The Minimum Inhibitory Concentration (MIC) of plant extract was determined using the broth
microdilution method, following the CLSI guidelines [58]. In brief, exponentially growing bacteria
(5 ˆ 105 cells per mL, final inoculum) were added to the various concentrations of plant extract, 2-fold
serially diluted in 96-well microtitre plates of Mueller-Hinton broth or cation-adjusted Mueller Hinton
broth with 5% of lysed horse blood for S. pyogenes. The following concentrations (gr/mL) of extracts
were used: 0.5, 0.25, 0.125, 0.006, 0.031, 0.015, 0.007, 0.0039, 0.019, 0.00097, 0.00048. After 18–24 h of
incubation at 37 ˝C, the concentration at which the plant extract prevented visible bacterial growth
was identified as the MIC. All tests were performed in triplicate and executed three times. S. aureus
ATCC 29213, E. coli ATCC 25922 and P. aeruginosa ATCC 27853 were added as control strains. Abbreviations The following abbreviations are used in this manuscript: MHE
Myrcianthes hallii extract
LMW
low molecular weight
MRSA
methicillin-resistant Staphylococcus aureus
MSSA
methicillin-susceptible Staphylococcus aureus
CLSI
Clinical and Laboratory Standards Institute
MIC
Minimum inhibitory concentration
MOA
mechanism of action 5. Conclusions In conclusion, this study represents the first attempt to phytochemically characterize of M. hallii
leaf extract and demonstrate its antimicrobial activity against drug resistant bacteria. The extract
exhibits antimicrobial activity against S. aureus, P. aeruginosa, S. pyogenes, and Enterococcus spp. strains
due to the presence of many different classes of polyphenolic compounds that possess antibacterial
activity. The data reported in this paper reveal that M. hallii is a potential source of polyphenols with
antimicrobial properties and shows the great potential of this species, not just for pharmaceutical
applications, but also for biomedical, food and cosmetic applications. Author Contributions: Maria Daglia and Anna Marchese designed the research, were responsible for the
correctness of the chemical and microbiological analyses, respectively, and contributed to writing the manuscript;
Patricia Chavez Carvajal collected the plant material and performed the sample preparation; Francesco Bracco
identified the collected plant material as M. hallii (O. Berg) McVaugh and deposited sample specimens at the
Herbarium of the University of Pavia; Arianna Di Lorenzo and Davide Gozzini performed the chemical analysis;
Erika Coppo performed the microbiogical tests; Arianna Di Lorenzo and Patricia Chavez Carvajal contributed to
the writing of the introduction and chemical analysis section; Giuseppe Zanoni and Seyed Mohammad Nabavi
revised the final version; Carla Renata Arciola contributed to the critical analysis of data and to the discussion,
and she revised the final version. All authors approved the final manuscript. Conflicts of Interest: The authors declare no conflict of interest. References 1. León-Yánez, S.; Valencia, R.; Pitman, N.; Endara, L.; Ulloa Ulloa, C.; Navarrete, H. (Eds.) Libro Rojo Delas
Plantas Endémicas del Ecuador, 2nd ed.; Publicaciones del Herbario QCA, Pontificia Universidad Católica del
Ecuador: Quito, Ecuador, 2011. 1. León-Yánez, S.; Valencia, R.; Pitman, N.; Endara, L.; Ulloa Ulloa, C.; Navarrete, H. (Eds.) Libro Rojo Delas
Plantas Endémicas del Ecuador, 2nd ed.; Publicaciones del Herbario QCA, Pontificia Universidad Católica del
Ecuador: Quito, Ecuador, 2011. 12 of 14 12 of 14 Materials 2016, 9, 454 2. Messaoud, C.; Laabidi, A. Myrtus communis L. Infusions: The effect of infusion time on phytochemical
composition, antioxidant, and antimicrobial activities. J. Food Sci. 2012, 77, C941–C947. [CrossRef] [PubMed] 2. Messaoud, C.; Laabidi, A. Myrtus communis L. Infusions: The effect of infusion time on phytochemical
composition, antioxidant, and antimicrobial activities. J. Food Sci. 2012, 77, C941–C947. [CrossRef] [PubMed]
3. Takahashi, T.; Kokubo, R. Antimicrobial activities of eucalyptus leaf extracts and flavonoids from composition, antioxidant, and antimicrobial activities. J. Food Sci. 2012, 77, C941–C947. [CrossRef] [PubMed]
3. Takahashi, T.; Kokubo, R. Antimicrobial activities of eucalyptus leaf extracts and flavonoids from
Eucalyptus maculata. Lett. Appl. Microbiol. 2004, 39, 60–64. [CrossRef] [PubMed] 3. Takahashi, T.; Kokubo, R. Antimicrobial activities of eucalyptus leaf extracts and flavonoids from
Eucalyptus maculata. Lett. Appl. Microbiol. 2004, 39, 60–64. [CrossRef] [PubMed] 4. Metwally, A.M.; Omar, A.A. Phytochemical investigation and antimicrobial activity of Psidium guajava L. leaves. Pharmacogn. Mag. 2010, 6, 212–218. [PubMed] 5. Chandrasekaran, M.; Venkatesalu, V. Antibacterial and antifungal activity of Syzygium jambolanum seeds. J. Ethnopharmacol. 2004, 91, 105–108. [CrossRef] [PubMed] J
p
[
] [
]
6. Royal Botanical Gardens. Available online: http://www.kew.org/ (accessed on 18 November 2015 7. Mazine, F.F.; Castro Souza, V. A preliminary phylogenetic analysis of Eugenia (Myrtaceae: Myrteae), with a
focus on Neotropical species. Kew Bull. 2014, 69, 94–97. [CrossRef] 8. Proença, C.E.B.; Jennings, L.V.S. Two new species of Myrtaceae (Myrteae) from northern South America. Brittonia 2011, 63, 46–50. [CrossRef] 9. Sobral, M.; Grippa, C.R. Fourteen new species and two taxonomic notes on Brazilian Myrtaceae. Phytotaxa
2012, 50, 19–50. [CrossRef] 10. Ministerio de, S.P.; Programa de, A.S.S.E. Medicina Tradicional Andina y Plantas Curativas, 1st ed.; Centro de
Orientamiento Educativo COE, Ed.; Ministerio de Salud: Quito, Ecuador, 2008; p. 84. 11. White, A. Herbs of Ecuador: Medicinal Plants; Libri, M., Ed.; Edicions Libri Mundi: Quito, Ecuador, 1985;
pp. 59–62. pp
12. Tropicos®. Available online: http://www.tropicos.org/ (accessed on 10 November 2015). 13. References [CrossRef] [PubMed] 13 of 14 13 of 14 Materials 2016, 9, 454 27. Dou, J.; Lee, V.S.Y. Identification and comparison of phenolic compounds in the preparation of Oolong
tea manufactured by semifermentation and drying processing. J. Agric. Food Chem. 2007, 55, 7462–7468. [CrossRef] [PubMed] 28. Faria, A.F.; Marques, M.C. Identification of bioactive compounds from jambolão (Syzygium cumini) and
antioxidant capacity evaluation in different pH conditions. Food Chem. 2011, 126, 1571–1578. [CrossRef]
[PubMed] 29. Kasajima, N.; Ito, H. Cypellogins A, B and C, acylated flavonol glycosides from Eucalyptus cypellocarpa. Chem. Pharm. Bull. 2005, 53, 1345–1347. [CrossRef] [PubMed] 30. Ablajan, K.; Abliz, Z. Structural characterization of flavonol 3,7-di-O-glycosides and determination of
the glycosylation position by using negative ion electrospray ionization tandem mass spectrometry. J. Mass Spectrom. 2006, 41, 352–360. [CrossRef] [PubMed] 31. Chua, L.S.; Rahaman, N.L. Antioxidant activity of three honey samples in relation with their biochemical
components. J. Anal. Methods Chem. 2013, 2013, 313798. [CrossRef] [PubMed] 32. Callemien, D.; Collin, S. Use of RP-HPLC-ESI(–)-MS/MS to differentiate various proanthocyanidin isomers
in lager beer extracts. J. Am. Soc. Brew. Chem. 2008, 66, 109–115. 33. Sandhu, A.K.; Gu, L. Antioxidant capacity, phenolic content and profiling of phenolic compounds in
the seeds, skin and pulp of Vitis rotundifolia (muscadine grapes) as determined by HPLC-DAD-ESI-MSn. J. Agric. Food Chem. 2010, 58, 4681–4692. [CrossRef] [PubMed] 34. Gouveia, S.C.; Castilho, P.C. Analysis of phenolic compounds from different morphological parts of
Helichrysum devium by liquid chromatography with on-line UV and electrospray ionization mass
spectrometric detection. Rapid Commun. Mass Spectrom. 2009, 23, 3939–3953. [CrossRef] [PubMed] 35. Bellosta, S.; Dell’Agli, M. Inhibition of metalloproteinase-9 activity and gene expression by polyphenolic
compounds isolated from the bark of Tristaniopsis calobuxus (Myrtaceae). Cell. Mol. Life Sci. 2003, 60,
1440–1448. [CrossRef] [PubMed] 36. Dastmalchi, K.; Flores, G. Edible Myrciaria vexator fruits: Bioactive phenolics for potential COPD therapy. Bioorg. Med. Chem. 2012, 20, 4549–4555. [CrossRef] [PubMed] 37. Zanatta, C.F.; Cuevas, E. Determination of anthocyanins from Camu-camu (Myrciaria dubia) by HPLC-PDA,
HPLC-MS, and NMR. J. Agric. Food Chem. 2005, 53, 9531–9535. [CrossRef] [PubMed] 38. Haron, N.W.; Moore, D.M. Distribution and taxonomic significance of flavonoids in the genus Eugenia
(Myrtaceae). Biochem. Syst. Ecol. 1992, 20, 266–268. [CrossRef] 39. Takashi Yoshida, T.; Amakura, Y. Structural features and biological properties of ellagitannins in some plant
families of the order Myrtales. Int. J. Mol. Sci. 2010, 11, 79–106. [CrossRef] [PubMed] 40. Daglia, M.; Di Lorenzo, A. References Holst, B.K. Myrtaceae. In Catalogue of the Vascular Plants of Ecuador; Jørgensen, P.M., León-Yánez, S., Eds.;
Missouri Botanical Garden: St. Louis, MO, USA, 1999; p. 621. 14. Ulloa, C. Usos de plantas en los Andes Centrales. In Botánica Económica de Los Andes Centrales; Moraes, M.,
Øllgard, B., Eds.; Universidad Mayor de San Andres: La Paz, Bolivia, 2006; pp. 313–328. 15. Boulekbache-Makhlouf, L.; Meudec, E. Qualitative and semi-quantitative analysis of phenolics in
Eucalyptus globulus leaves by high-performance liquid chromatography coupled with diode array detection
and electrospray ionization mass spectrometry. Phytochem. Anal. 2013, 24, 162–170. [CrossRef] [PubMed] 16. Santos, S.A.; Freire, C.S. Characterization of phenolic components in polar extracts of Eucalyptus globulus
Labill. bark by high-performance liquid chromatography–mass spectrometry. J. Agric. Food Chem. 2011, 59,
9386–9393. [CrossRef] [PubMed] 17. Yoshimura, M.; Amakura, Y. Polyphenolic compounds isolated from the leaves of Myrtus communis. J. Nat. Med. 2008, 62, 366–368. [CrossRef] [PubMed] 18. Wannes, W.A.; Mhamdi, B. Antioxidant activities of the essential oils and methanol extracts from myrtle
(Myrtus communis var. italica L.) leaf, stem and flower. Food Chem. Toxicol. 2010, 48, 1362–1370. [CrossRef]
[PubMed] 19. D’Amico, E.; Barneche, S. Identification of a bioactive compound from Myrcianthes cysplatensis. Pharmacogn. J. 2011, 3, 18–20. [CrossRef] 20. Andrade, J.M.; Aboy, A.L. Phenolic composition in different genotypes of guabiju fruits (Myrcianthes pungens)
and their potential as antioxidant and antichemotactic agents. J. Food Sci. 2011, 76, C1181–C1187. [CrossRef]
[PubMed] 1. Arze, J.B.L.; Jean, F.I. Essential oils from bolivia. VII. Myrtaceae: Myrcianthes osteomeloides (Rusby) McVa
and Myrcianthes pseudomato (Legrand) McVaugh. J. Essent. Oil Res. 2005, 17, 64–65. [CrossRef] 22. Cole, R.A.; Haber, W.A. Leaf essential oil composition of three species of Myrcianthes from Monteverde,
Costa Rica. Chem. Biodivers. 2008, 5, 1327–1334. [CrossRef] [PubMed] 23. Dalla Nora, C.; Dal-Ri Müller, C. Effect of processing on the stability of bioactive compounds from red
guava (Psidium cattleyanum Sabine) and guabiju (Myrcianthes pungens). J. Food Compos. Anal. 2014, 34, 18–25. [CrossRef] 24. De Mello Andrade, J.M.; Marin, R. Comparison of the fatty acid profiles of edible native fruit seeds from
Southern Brazil. Int. J. Food Prop. 2012, 15, 815–822. [CrossRef] 25. Marin, R.; Apel, M.A. Volatile components and antioxidant activity from some myrtaceous fruits cultivated
in Southern Brazil. Lat. Am. J. Pharm. 2008, 27, 172–177. 26. Toloza, A.C.; Zygadlo, J. Bioactivity of Argentinean essential oils against permethrin-resistant head lice,
Pediculus humanus capitis. J. Insect Sci. 2010, 10, 185. References Gallic acid and related compounds as neuroprotective agents: You are what you
eat! Curr. Pharm. Biotechnol. 2014, 15, 362–372. [CrossRef] [PubMed] 41. Lai, T.N.H.; Herent, M.-F. Piceatannol, a potent bioactive stilbene, as major phenolic component in
Rhodomyrtus tomentosa. Food Chem. 2013, 138, 1421–1430. [CrossRef] [PubMed] 42. Saha, R.K.; Zaman, N.M. Comparative evaluation of the medicinal activities of methanolic extract of seeds,
fruit pulps and fresh juice of Syzygium cumini in vitro. J. Coast. Life Med. 2013, 1, 300–308. 43. Neungchamnong, N.; Ingkaninan, K. On-line characterization of phenolic antioxidants in fruit wines
from family Myrtaceae by liquid chromatography combined with electrospray ionization tandem mass
spectrometry and radical scavenging detection. Food Sci. Technol. 2009, 42, 297–302. [CrossRef] p
y
g
g
44. Daglia, M. Polyphenols as antimicrobial agents. Curr. Opin. Biotechnol. 2012, 23, 174–181. [CrossRef]
[PubMed] 44. Daglia, M. Polyphenols as antimicrobial agents. Curr. Opin. Biotechnol. 2012, 23, 174–181. [CrossRef]
[PubMed] 45. Sakanaka, S.N.; Shimura, M. Preventive effect of green tea polyphenols against dental caries in conventional
rats. Biosci. Biotechnol. Biochem. 1992, 56, 592–594. [CrossRef] 45. Sakanaka, S.N.; Shimura, M. Preventive effect of green tea polyphenols against dental caries in conventional
rats. Biosci. Biotechnol. Biochem. 1992, 56, 592–594. [CrossRef] 46. Diker, K.S.; Akan, M. The bacterial activity of tea against Campylobacter jejuni and Campylobacter coli. Lett. Appl. Microbiol. 1991, 12, 34–35. [CrossRef] 46. Diker, K.S.; Akan, M. The bacterial activity of tea against Campylobacter jejuni and Campylobacter coli. Lett. Appl. Microbiol. 1991, 12, 34–35. [CrossRef] 47. Isogai, E.; Isogai, H. Protective effect of Japanese green tea extract on gnotobiotic mice infected with an
Escherichia coli O157:H7 strain. Microbiol. Immunol. 1998, 42, 125–128. [CrossRef] [PubMed] 47. Isogai, E.; Isogai, H. Protective effect of Japanese green tea extract on gnotobiotic mice infected with an
Escherichia coli O157:H7 strain. Microbiol. Immunol. 1998, 42, 125–128. [CrossRef] [PubMed] 48. Cushnie, T.P.T.; Hamilton, V.E.S. Aggregation of Staphylococcus aureus following treatment with the
antibacterial flavonol galangin. J. Appl. Microbiol. 2007, 103, 1562–1567. [CrossRef] [PubMed] 49. Engels, C.; Schieber, A. Inhibitory spectra and modes of antimicrobial action of gallotannins from mango
kernels (Mangifera indica L.). Appl. Environ. Microbiol. 2011, 77, 2215–2223. [CrossRef] [PubMed] Materials 2016, 9, 454 14 of 14 14 of 14 50. Côté, J.; Caillet, S. Bioactive compounds in cranberries and their biological properties. Crit. Rev. Food
Sci. Nutr. 2010, 50, 666–679. [CrossRef] [PubMed] 51. Bussmann, R.W.; Glenn, A. Antibacterial Activity of Medicinal Plants of Northern Peru—Part II. References Arnaldoa
2009, 16, 93–103. 52. Bussmann, R.W.; Glenn, A. Antibacterial activity of medicinal plants of Northern Peru—Can traditional
applications provide leads for modern science? Indian J. Tradit. Knowl. 2010, 9, 742–753. 53. Campoccia, D.; Montanaro, L. A review of the biomaterials technologies for infection-resistant surfaces. Biomaterials 2013, 34, 8533–8554. [CrossRef] [PubMed] 54. Ciurana, J.; Rodriguez, C.A. Trends in nanomaterials and processing for drug delivery of polyphenols for
cancer and other treatments. Curr. Drug Targets 2015. epub head of print. [CrossRef] 55. Madureira, A.R.; Pereira, A. Current state on the development of nanoparticles for use against
bacterial gastrointestinal pathogens. Focus on chitosan nanoparticles loaded with phenolic compounds. Carbohydr. Polym. 2015, 130, 429–439. [CrossRef] [PubMed] 56. Fantini, M.; Benvenuto, M. In vitro and in vivo antitumoral effects of combinations of polyphenols, or
polyphenols and anticancer drugs: Perspectives on cancer treatment. Int. J. Mol. Sci. 2015, 16, 9236–9282. [CrossRef] [PubMed] 57. CLSI. Methods for Dilution Antimicrobial Susceptibility Tests f or Bacteria That Grow Aerobically, Approved
Standard—Tenth Edition; CLSI Document M07-A10; Clinical and Laboratory Standards Institute: Wayne, PA,
USA, 2015. 58. CLSI. Performance Standards for Antimicrobial Disk Susceptibility Tests: Approved Standard-Twelfth Edition;
CLSI Document M02-A12; Clinical and Laboratory Standards Institute: Wayne, PA, USA, 2015. © 2016 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC-BY) license (http://creativecommons.org/licenses/by/4.0/).
|
https://openalex.org/W3170656302
|
https://discovery.ucl.ac.uk/10129968/1/Asselbergs_Routine%20clinical%20care%20data%20from%20thirteen%20cardiac%20outpatient%20clinics-%20design%20of%20the%20Cardiology%20Centers%20of%20the%20Netherlands%20%28CCN%29%20database_VoR.pdf
|
English
| null |
Routine clinical care data from thirteen cardiac outpatient clinics: design of the Cardiology Centers of the Netherlands (CCN) database
|
BMC cardiovascular disorders
| 2,021
|
cc-by
| 6,745
|
Routine clinical care data from thirteen
cardiac outpatient clinics: design
of the Cardiology Centers of the Netherlands
(CCN) database Sophie H. Bots1†, Klaske R. Siegersma1,2†, N. Charlotte Onland‑Moret3, Folkert W. Asselbergs4,5,6,
G. Aernout Somsen7, Igor I. Tulevski7, Hester M. den Ruijter1* and Leonard Hofstra2,7 Abstract Background: Despite the increasing availability of clinical data due to the digitalisation of healthcare systems, data
often remain inaccessible due to the diversity of data collection systems. In the Netherlands, Cardiology Centers of
the Netherlands (CCN) introduced “one-stop shop” diagnostic clinics for patients suspected of cardiac disease by their
general practitioner. All CCN clinics use the same data collection system and standardised protocol, creating a large
regular care database. This database can be used to describe referral practices, evaluate risk factors for cardiovascular
disease (CVD) in important patient subgroups, and develop prediction models for use in daily care. Construction and content: The current database contains data on all patients who underwent a cardiac workup in
one of the 13 CCN clinics between 2007 and February 2018 (n = 109,151, 51.9% women). Data were pseudonymised
and contain information on anthropometrics, cardiac symptoms, risk factors, comorbidities, cardiovascular and family
history, standard blood laboratory measurements, transthoracic echocardiography, electrocardiography in rest and
during exercise, and medication use. Clinical follow-up is based on medical need and consisted of either a repeat
visit at CCN (43.8%) or referral for an external procedure in a hospital (16.5%). Passive follow-up via linkage to national
mortality registers is available for 95% of the database. Utility and discussion: The CCN database provides a strong base for research into historically underrepresented
patient groups due to the large number of patients and the lack of in- and exclusion criteria. It also enables the devel‑
opment of artificial intelligence-based decision support tools. Its contemporary nature allows for comparison of daily
care with the current guidelines and protocols. Missing data is an inherent limitation, as the cardiologist could deviate
from standardised protocols when clinically indicated. Conclusion: The CCN database offers the opportunity to conduct research in a unique population referred from
the general practitioner to the cardiologist for diagnostic workup. This, in combination with its large size, the *Correspondence: H.M.denRuijter-2@umcutrecht.nl
†Sophie H. Bots and Klaske R. Siegersma have contributed equally to this
work 1 Laboratory of Experimental Cardiology, University Medical Center
Utrecht, Utrecht University, Utrecht, The Netherlands
Full list of author information is available at the end of the article 1 Laboratory of Experimental Cardiology, University Medical Center
Utrecht, Utrecht University, Utrecht, The Netherlands
Full list of author information is available at the end of the article Bots et al. BMC Cardiovasc Disord (2021) 21:287
https://doi.org/10.1186/s12872-021-02020-7 Bots et al. BMC Cardiovasc Disord (2021) 21:287
https://doi.org/10.1186/s12872-021-02020-7 Open Access Background diagnostic workup for cardiac disease and fast diagnosis
of potential life-threatening pathologies. GPs can refer
their patients to a CCN clinic for cardiac workup when
they suspect their patient suffers from cardiac disease. All CCN clinics perform the same standardised proto-
col and store their data in a shared data collection sys-
tem. Follow-up appointments and results from referrals
for advanced cardiac imaging or cardiac interventions are
stored in the same system. As a result of this set-up, CCN
offers a unique opportunity to obtain semi-structured
data on a large group of patients at an early stage of the
regular care pathway.h Cardiovascular diseases (CVD) remain an important
cause of death and disability worldwide [1, 2]. The digi-
talisation of the healthcare system has made a wealth
of clinical care data available for researchers [3–6]. This
provides a unique opportunity for researchers to evalu-
ate pressing topics in cardiovascular medicine. The added
value of clinical care data in cardiovascular research is
threefold. First, clinical care data better reflect the cur-
rent real-world situation in healthcare with regard to
clinical presentation of disease and representation of
patient groups. This is especially relevant for patient
groups that have historically been underrepresented in
clinical studies such as women [7], the elderly [8] and
patients with multimorbidity [9]. CVD in women may be
different from CVD in men in several aspects, including
the clinical presentation, the effect of traditional risk fac-
tors and presence of female-specific risk factors related to
pregnancy and menopause, and the efficacy of treatment
[10]. Elderly patients and those with multimorbidity
also need to be studied to combat the rising prevalence
of CVD risk factors such as hypertension, diabetes and
obesity [11, 12]. Second, clinical care data contain a large
number of individuals and wide range of clinical meas-
urements, a combination that is difficult to obtain within
a research setting. This facilitates the development of
prediction models and decision support tools using artifi-
cial intelligence methods that can subsequently be imple-
mented within the healthcare system. These tools can
help healthcare professionals to interpret large amounts
of patient data and assist healthcare decision-making. Third, researchers can use clinical care data to evaluate
the current state of clinical practice, adherence to guide-
lines and develop treatment and referral strategies that
better suit the current presentation of patients suspected
of CVD. Background The aim of this paper is to describe the CCN clini-
cal care database. The database contains data on a large
number of individual patients and a wide range of stand-
ardised characteristics from a unique population situated
between the GP and the hospital cardiologist. The clinical
nature of the database ensures that it reflects the patient
population currently seen in daily care, including those
that may be underrepresented in clinical research. The
database can be used to describe current clinical prac-
tice, evaluate the prevalence of cardiovascular risk factors
and their relation to cardiovascular disease, and develop
prediction algorithms that have the potential to be imple-
mented in daily care. © The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which
permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the
original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or
other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line
to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory
regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this
licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativeco
mmons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Bots et al. BMC Cardiovasc Disord (2021) 21:287 Page 2 of 9 representation of historically underrepresented patient groups and contemporary nature makes it a valuable tool for
expanding our knowledge of cardiovascular diseases. Trial registration: Not applicable. Keywords: Clinical care data, Cardiovascular care, Prevention, Big data Keywords: Clinical care data, Cardiovascular care, Prevention, Big data Construction and content
Data generation at CCN clinics
Baseline examination Every patient referred to one of the CCN clinics under-
went a standardised diagnostic workup. This protocol
consisted of transthoracic echocardiography (TTE) and
ultrasound imaging of the carotid arteries, electrocardi-
ography at rest (ECG) and during exercise (stress ECG), a
laboratory test, and a consult with a nurse during which
self-reported anthropometrics, symptoms, cardiovascu-
lar risk factors and comorbidities were registered. Past
medication use and cardiovascular history were also
recorded, as well as on site clinical diagnoses made by the
cardiologist. An overview of all the stored clinical charac-
teristics can be found in Table 1. However, data from earlier stages in the clinical care
pathway remain difficult to access due to the smaller size
of single general practitioner (GP) offices and the diver-
sity of data collection systems. To close this gap, a col-
laboration was set up between the University Medical
Center Utrecht (UMCU) and Cardiology Centers of the
Netherlands (CCN), an organisation of 13 cardiac outpa-
tient clinics that operate between the GP and the hospital
cardiologist. In the Netherlands, CCN introduced “one-
stop shop” cardiac outpatient clinics to facilitate efficient Body mass index was calculated based on self-reported
height and weight. Blood pressure was measured with a
Microlife WatchBP. TTE was performed with a General
Electric Vivid E6 or E7 echocardiography device. Blood
samples were analysed with the Roche Reflotron Sprint Bots et al. Construction and content
Data generation at CCN clinics
Baseline examination BMC Cardiovasc Disord (2021) 21:287 Page 3 of 9 Table 1 Overview of all features stored in the database
Phase
Measurement
Baseline
(2007-Feb 2018)
Consult
(-) Presence and characteristics of cardiac symptoms (chest pain, dyspnoea, fatigue, palpitations, collapse, heart murm
(-) Anthropometrics (height, weight, hip circumference, blood pressure, heart rate, heart and breathing sounds, pulse,
palpation)
Intake
(-) Behavioural cardiovascular risk factors (smoking, alcohol use)
(-) Comorbidities (diabetes mellitus, hypertension, dyslipidaemia)
(-) Family history of cardiovascular disease (atherosclerosis, sudden death, cardiomyopathy, arrhythmia)
Lab
(-) Lipids (total, high density, and low density cholesterol, triglycerides)
(-) Potassium, sodium, haemoglobin, glucose
(-) Glomerular filtration rate
(-) Lipoprotein A, brain natriuretic protein, thyroid stimulation hormone
TTE
(-) M-mode (dimensions of aorta and left heart chambers)
(-) Two-dimensional (evaluation of function and shape of all heart chambers and valves)
(-) Colour Doppler (valve insufficiencies and septum defects)
(-) Spectral Doppler (left ventricular diastolic function and gradients over valves)
(-) Intima Media Thickness (left and right, anterior and posterior)
ECG
(-) Duration of defined ECG intervals and complexes (RR, PR, QRS, QT)
(-) ST depression, elevation, negative T-top, QRS axis
(-) Dilatation of left and right atrium, intraventricular conduction delay, left ventricular hypertrophy
Stress ECG
(-) Protocol, device, target heart rate, use of β-blocker before exercise test
(-) ECG characteristics, blood pressure and heart rate before and during exercise test
(-) Duration and load of exercise test, exercise tolerance, reason to stop exercise test
(-) Arrhythmia or angina symptoms during exercise test, left ventricular hypertrophy
Decursus
(-) Cardiologist summary of visit (free text)
Medication
(-) Cardiovascular medication use grouped by researchers
(-) Date medication was started and date it was ended when applicable
Diagnosis
(-) Cardiovascular diagnosis defined by researchers
(-) Cardiovascular risk factor diagnosis defined by researchers
(-) Date of diagnosis
Follow-up
(2007—Feb 2018)
Consult, Intake, Lab, TTE, ECG, Stress ECG and Decursus as described for baseline
External procedures
(-) External procedure performed and location where it was performed
(-) External procedure grouped by researchers
(-) Date of appointment
Record linkage (2019)
All-cause mortality
Educational level
Ethnicity
Personal income
Cause-specific mortality Table 1 Overview of all features stored in the database system. The ECG was recorded with the Welch Allyn
Cardioperfect Pro recorder in supine position with 12
leads. Construction and content
Data generation at CCN clinics
Baseline examination The stress ECG was performed on a watt bike from
Lode Corival Eccentric with simultaneous blood pres-
sure measurements (Medtronic BL-6 Compact) and ECG
recording (Welch Allyn Cardioperfect recorder). Raw
data of the ECG, stress ECG and TTE were not available. Medication and diagnoses were recorded as semi-struc-
tured text. indicated. For example, the cardiologist may choose not
to perform a stress ECG in patients with a contra-indi-
cation to the procedure, such as very high systolic blood
pressure [13]. This introduces missing data, illustrated by
the baseline stress ECG data which were missing for 25%
of patients in the CCN database (Fig. 1). Information collected during a patient’s clinical trajectory
within CCNi While CCN has standardised and uniform diagnostic
workup protocols for every patient, in practice a cardiolo-
gist may deviate from this protocol when this is clinically After the first visit, patients may enter a clinical trajectory
during which one or more return visits to a CCN clinic
are planned. Information collected during these clinical Bots et al. BMC Cardiovasc Disord (2021) 21:287 Bots et al. BMC Cardiovasc Disord (2021) 21:287 Page 4 of 9 Page 4 of 9 follow-up visits was also stored in the CCN database. This clinical follow-up was not standardised but rather
based on medical need. As a result, clinical follow-up
varies across patients in frequency, duration, and meas-
urements obtained. During these clinical follow-up visits
either all or some components of the standard screening
protocol were repeated, with rest ECG being repeated
most frequently (Fig. 1). follow-up visits was also stored in the CCN database. This clinical follow-up was not standardised but rather
based on medical need. As a result, clinical follow-up
varies across patients in frequency, duration, and meas-
urements obtained. During these clinical follow-up visits
either all or some components of the standard screening
protocol were repeated, with rest ECG being repeated
most frequently (Fig. 1). Inc., North Carolina, USA) to create a relational data-
base. This process included separating first visit (base-
line) data from follow-up visits, filtering out duplicated or
empty entries and removing completely empty variables,
streamlining variable names, and organising the data by
type of clinical measurement (e.g. combine all labora-
tory measurements in one data table), among others. Raw unstructured text fields were checked for personal
information, which was subsequently either removed
while keeping the text field intact or the information was
recoded into a new variable that no longer contained the
personal information. Patients in need of additional imaging or cardiac inter-
vention based on the result of their initial CCN workup
were referred to a nearby hospital as these facilities were
not available at the CCN clinics. The referral itself and
the summarised text results of these procedures were
stored in the CCN database (Table 1). Computed Tomog-
raphy (CT) scans were performed most often, comprising
30.8% of all external procedures. The five most common
external procedures can be found in Fig. 1. Raw medication use and diagnosis text data were
structured into binary variables using text retrieval
methods in R (R Core Team, Vienna, Austria). Information collected during a patient’s clinical trajectory
within CCNi Medi-
cation entries were grouped into 23 categories of rel-
evant cardiovascular medications based on either the
brand name or the generic name, depending on which
one was available (Additional file 1: Table S1). Diag-
noses were divided into (i) Cardiovascular disease and
(ii) Conditions that are risk factors for cardiovascular
disease. The first category was subdivided into 5 sub-
groups, the second one into 4 subgroups (Additional
file 1: Table S2). Content: describing the CCN study populationh Content: describing the CCN study population
The CCN database contains data from 109,227 patients
referred to one of the CCN clinics between Febru-
ary 2007 and February 2018 (Additional file 1: Fig. S1). Patients with missing data on age or sex or without
records of their CCN visit were excluded (n = 76), bring-
ing the total to 109,151 individuals with a mean age of 56
(± 15) years, of which 51.9% were women. About a third
of the patients were 65 years or older and 12% had two
or more comorbidities. Patients had a mean body mass
index of 27.4 (± 20) kg/m2 and an average systolic blood
pressure of 141 (± 22) mmHg. The majority of patients
had a positive cardiovascular family history (65.2%) and
14.9% of patients suffered from cardiovascular disease at
baseline. Approximately one third of patients were cur-
rent smokers (36.8%), 29.7% had hypertension, 15.6%
had dyslipidaemia and 8% had diabetes mellitus (DM)
(Table 2). Access to the following data was requested and granted:
(i) all-cause and cause-specific mortality, (ii) education
level and personal income and (iii) Personal Records
Database, which among others contains information on
country of birth. Access to the Personal Records Data-
base also enables researchers to obtain a matched sam-
ple of the general population for comparison with the
CCN population. In the future, the CCN database will be
linked to other registries, such as the national hospitali-
sation registry, to obtain information on a more diverse
set of outcome measures. Patients could not be contacted for additional base-
line questionnaires or active follow-up due to the pseu-
donymised nature of the database. The majority of patients (56.1%, n = 61,232) only had
a baseline visit, 17.5% (n = 19,111) had one follow-up
visit at CCN, and 26.3% (n = 28,808) had three or more
follow-up visits at CCN. Compared with patients who
were seen once, those with at least one clinical follow-
up appointment were older at baseline (60 vs 54 years),
had a higher systolic blood pressure (145 vs 138 mmHg)
and were more often current smokers (41.1 vs 33.4%). In
addition, they more often had a history of cardiovascular Data extraction, cleaning and storage We extracted all data generated by CCN up to February
2018 from their data collection system. These raw files
were cleaned and processed using SAS (SAS Institute Fig. 1 Overview of patient flow and completeness of measurements in the CCN database Bots et al. BMC Cardiovasc Disord (2021) 21:287 Bots et al. BMC Cardiovasc Disord (2021) 21:287 Page 5 of 9 The raw data and the clean relational database are
stored within the UMCU infrastructure. The raw data is
not available for researchers due to privacy constraints
and is kept by the data manager. The anonymised ver-
sions of raw unstructured text fields are available, includ-
ing raw medication and diagnosis data. Researchers can
contact the authors for collaboration and access to the
UMCU infrastructure. When the collaboration and the
research topic have been agreed upon, external collabo-
rators can get access to both the CCN database and all
services and programmes supported by the UMCU. This
includes artificial intelligence and advanced statistical
programs. All work within the UMCU infrastructure will
be stored, including analysis scripts and results. Access to
the UMCU infrastructure will be retracted after the pro-
ject has finished. only be measured if the cardiologist suspects serious car-
diac problems. Similarly, patients without entries in the
medication or diagnosis file can be assumed to not use
medication or be free of disease. Imputation strategies
can be applied to deal with the missing values, but the
preferred strategy depends on whether the data is likely
to be missing at random or not. Researchers should be
aware of the assumptions they make and describe these
in their method section. Patient privacy
Th
CCN d The CCN data were made available under implied con-
sent and transferred to the UMCU under the Dutch
Personal Data Protection Act. Patients were assigned
a unique patient number that cannot be traced back to
an individual without access to the original CCN data
system, which is not available to UMCU researchers. This results in a pseudonymised database. The Medical
Research Ethics Committee of the UMCU declared that
the Medical Research Involving Human Subjects does
not apply to this study. Unstructured text fields con-
taining personal information were anonymised using an
anonymization programme [14] before being included in
the final research database. Passive and active follow‑up outside the clinical trajectoryh Passive and active follow up outside the clinical trajectory
The CCN database has been linked to the national data-
base of Statistics Netherlands for passive follow-up for
all-cause and cause-specific mortality, and enrichment of
the dataset with demographic and socioeconomic data. Linkage was successful for 95.9% of the database (Fig. 1). Failure to link likely occurred because a patient moved
between their CCN visit and the moment of linking, as
postal code was one of the linking factors. Linking of the
CCN database with Statistics Netherlands was deemed
appropriate by the ethical committee of Statistics Nether-
lands as it was in line with the CCN project aims. Missing data Diagnostic procedures, treatments and follow-up of the
patients were performed at the discretion of the treating
cardiologist and thus driven by medical indication. This
results in missing data for both baseline and follow-up
visits. For example, more advanced biomarkers such as
brain natriuretic peptide or high-sensitivity troponin will Bots et al. BMC Cardiovasc Disord (2021) 21:287 Page 6 of 9 disease (20.6 vs 10.5%), prevalent cardiovascular risk
conditions (30.0 vs 15.5%), and comorbidities (Additional
file 1: Table S3). approximate this comparison, we compared the socio-
economic characteristics of the CCN database to an
age- and sex-matched sample of the general population. Patients referred to CCN were more often of Dutch
descent (77.2% vs 70.8%) and had a higher median
annual personal income (€27,914 vs €22,270) than the
general population (Table 3). i
In total, 18,050 (16.5%) patients were referred for an
external procedure (Fig. 1). Compared with patients
who were not referred, patients with at least one exter-
nal procedure were older at baseline (60 vs 56 years)
and had a higher prevalence of comorbidities and
CVD history (21.3% vs 13.7%). Women were less often
referred for an external procedure (46.1 vs 53.0%)
(Additional file 1: Table S4). c History of other cardiovascular conditions = diagnosis of arrhythmia, valvular disease, cardiomyopathy, atherosclerosis, peripheral artery disease or abdominal
aneurysm before baseline appointment, or non-invasive cardiac or peripheral intervention gnosis of heart failure, coronary heart disease, cerebrovascular disease or congenital heart disease before baseline appointment, or invasi Utility: intended use and database benefitsh The main strength of the CCN database lies in its com-
bination of a large study population and a large number
of different, and sometimes longitudinal, measurements
per individual. Such data is difficult to obtain in cohorts
specifically set up for research as funds are often not suf-
ficient to cover both including a large population and col-
lecting a large number of (longitudinal) measurements. i
The CCN database consists of data derived from
medical care and thus participants were not actively
recruited, nor were there explicit in- and exclusion cri-
teria. Data on patients who were not referred to CCN
are not available, so we were unable to compare patients
referred to CCN with those who were not. Utility: intended use and database benefitsh However, to Table 2 Baseline characteristics of patients in the CCN database
All values are given as mean (SD) unless otherwise specified
a History of CVD = diagnosis of heart failure, coronary heart disease, cerebrovascular disease or congenital heart disease before baseline appointment, or invasive
cardiac intervention
Variable
Whole database
n = 109,151
Women
n = 56,628
Men
n = 52,524
Missing
data (%)
General
Women (n, %)
56,628 (51.9)
Age (years)
56 (15)
57 (15)
56 (15)
Age categories (n, %)
Under 50
33,165 (30.4)
16,954 (29.9)
16,211 (30.9)
50–64
41,273 (37.8)
20,859 (36.8)
20,414 (38.9)
65–74
22,931 (21.0)
12,152 (21.5)
10,779 (20.5)
75 and older
11,781 (10.8)
6662 (11.8)
5119 (9.7)
Body mass index (kg/m2)
27.4 (20.0)
27.3 (20.2)
27.5 (19.8)
2.9
Systolic blood pressure (mmHg)
141 (22)
140 (23)
143 (20)
2.9
Current smoker (n,%)
40,139 (36.8)
20,712 (36.6)
19,427 (37)
8.9
Ever smoker (n,%)
71,659 (65.7)
35,508 (62.7)
36,151 (68.8)
8.8
Cardiovascular disease (CVD) (n, %)
History of CVDa
16,311 (14.9)
6,483 (11.4)
9,828 (18.7)
Family history of CVDb
71,148 (65.2)
39,318 (69.4)
31,830 (60.6)
17.8
History of other cardiovascular conditionsc
23,957 (21.9)
11,804 (20.8)
12,153 (23.1)
Comorbidities (n, %)
Hypertension
32,460 (29.7)
17,290 (30.5)
15,270 (28.9)
2.5
Dyslipidaemia
16,978 (15.6)
8148 (14.4)
8830 (16.8)
2.5
Diabetes mellitus
8709 (8.0)
3967 (7.0)
4742 (9.0)
2.6
Number of comorbidities
0
64,199 (58.8)
33,799 (59.9)
30,400 (57.9)
1
28,705 (26.3)
15,081 (26.6)
13,624 (25.9)
2
11,001 (10.1)
5392 (9.5)
5609 (10.7)
3
2382 (2.2)
1125 (2.0)
1257 (2.4) Table 2 Baseline characteristics of patients in the CCN database c History of other cardiovascular conditions = diagnosis of arrhythmia, valvular disease, cardiomyopathy, atherosclerosis, peripheral artery disease or abdominal
aneurysm before baseline appointment, or non-invasive cardiac or peripheral intervention Bots et al. BMC Cardiovasc Disord (2021) 21:287 Page 7 of 9 the CCN database contains several anonymised Dutch
free text fields, which can be used for the development
of text analysis algorithms specific for Dutch clinical
notes. This is an important area of research, as many
existing text analysis resources are based on English
clinical text [17]. These programmes can subsequently
be used to extract and structure valuable informa-
tion from free text and turn it into a usable format for
researchers.hl In addition, the CCN database captures a unique popu-
lation situated between the GP and the hospital that is
rarely seen in clinical studies. Utility: intended use and database benefitsh y
Clinical care databases like the CCN database
can make important contributions to three areas of
research due to some of their inherent characteris-
tics. First, these databases reflect the population cur-
rently seen in clinical care and thus include groups that
are traditionally underrepresented in research [8]. We
show that women comprise 52% of the CCN database,
providing a valuable foundation for research into both
differences between the sexes and women-specific car-
diovascular disease presentations and risk factors [15,
16]. Similarly, the CCN dataset contains 11,781 patients
aged 75 years and older and 13,383 patients with two
or more comorbidities, offering researchers an oppor-
tunity to verify if study outcomes also apply to these
patient groups. These numbers illustrate the poten-
tial value of the CCN database for addressing research
questions about underrepresented patient groups that
have remained unanswered due to scarcity of data. Third, clinical care databases reflect medical prac-
tice allowing for comparisons between clinical care
and the recommendations in the prevailing guidelines. Such perspectives spark debate on inconsistencies that
may exist between guidelines and current practice. The
CCN database functions in this case as a tool to bridge
the gap between guidelines based mainly on clinical
research and the reality of daily cardiac care. Discussion: comparison of performance and functionality
with similar existing databases However, the CCN database also has some limitations
that need to be addressed. We will discuss the two main
ones, data quality and generalisability. Second, the size of clinical care databases that com-
bine a large study population with a large number of
measurements per individual creates opportunities for
the application of artificial intelligence methods. The
CCN database contains more than 300 informative
features on over 100.000 patients that can be used for
the development of artificial intelligence-based predic-
tion algorithms and decision support tools. In addition, a Year of birth could not be re-calculated for 160 study participants, so these could not be matched with the general population and are thus removed from this table
b Origin was defined as (i) Native Dutch; both parents born in the Netherlands, (ii) First generation immigrant; person born outside the Netherlands with at least one
parent born outside the Netherlands, (iii) Second generation immigrant; person born in the Netherlands with at least one parent born outside the Netherlands Data quality: missing data and measurement errorsh We plan to include follow-up
for non-fatal outcomes in the future, as these outcomes
are clinically relevant for the relatively young and healthy
CCN population. To alleviate the issue of missing data on
important confounders such as socioeconomic status, we
enriched the CCN database with information on ethnic-
ity, educational level and personal income through record
linkage. Text mining approaches can be used to further
enrich the CCN database if the required information can
be found within the unstructured text fields. Available
missing data techniques such as multiple imputation can
be used to address remaining missing values as long as
researchers carefully consider the assumptions underly-
ing these techniques. as highly specific biomarkers, because these are not nor-
mally collected in daily care. Furthermore, raw ECG data
and echocardiographic images were saved to a different
system than the standardised clinical data and were thus
not stored in the CCN database. These limitations are in
part inherent to the database, so researchers should con-
sider whether the CCN database is ‘fit for purpose’ for
their specific research question. However, some of these
limitations can be addressed and alleviated. To obtain
standardised follow-up for all individuals in the CCN
database, we performed record linkage for all-cause and
cause-specific mortality. We plan to include follow-up
for non-fatal outcomes in the future, as these outcomes
are clinically relevant for the relatively young and healthy
CCN population. To alleviate the issue of missing data on
important confounders such as socioeconomic status, we
enriched the CCN database with information on ethnic-
ity, educational level and personal income through record
linkage. Text mining approaches can be used to further
enrich the CCN database if the required information can
be found within the unstructured text fields. Available
missing data techniques such as multiple imputation can
be used to address remaining missing values as long as
researchers carefully consider the assumptions underly-
ing these techniques. is some selection bias occurring within the clinical care
pathway, where relatively healthy Dutch patients with
higher socio-economic status are more often referred to a
CCN clinic than those with lower socio-economic status
or those of non-Dutch descent. There are examples of other clinical care databases such
as the hospital-based UPOD database [19] and the Julius
General Practitioner’s Network [20]. However, these
include distinctively different patient populations, as the
first collects data from within the hospital and the second
from within GP practice. Abbreviations
d l CCN: Cardiology Centers of the Netherlands; CT: Computed Tomography; CVD:
Cardiovascular disease; DM: Diabetes Mellitus; ECG: Electrocardiography; GP:
General practitioner; TTE: Transthoracic echocardiography; UMCU: University
Medical Center Utrecht; Stress ECG: Stress-electrocardiography. Data quality: missing data and measurement errorsh The CCN database is unique in
that it captures the patients in between these two. Generalisability and comparison to other databasesh Additional file 1. Supplementary figure and tables. The CCN database is comprised of patients who were
referred by their GP on suspicion of cardiac disease. We were unable to compare those included in the CCN
database with those who were not referred, but we were
able to approach this comparison by using an age- and
sex-matched sample from the general population. We
show that CCN patients have a higher socio-economic
status and are more often native Dutch compared with
the general population. Moreover, the prevalence of DM
in the CCN database seems to be similar to that in the
Netherlands as a whole [18], while we expected a higher
prevalence given that CCN screens patients at elevated
cardiovascular disease risk. However, GPs may refer DM
patients with cardiac complaints to a DM-specific outpa-
tient clinic instead of a CCN clinic, resulting in a low DM
prevalence within the CCN database. This suggests there Acknowledgements The authors want to thank Aisha Gohar, Enja Blasse, Jonne Emanuel-Hos
and Gideon Valstar for their contributions to data extraction and data
management. Conclusion
Th
CCN d The CCN database is a regular care database contain-
ing data from 109.151 patients collected between 2007
and 2018. This database offers the opportunity to per-
form research in a unique study population that reflects
the patient population seen in daily cardiology practice,
including women, the elderly, and patients with multi-
ple comorbidities. The size of this database facilitates the
application of artificial intelligence methods. Moreover,
the features in the database make it possible to describe
current cardiology practice and evaluate this against
guidelines based primarily on results from clinical trials. Data collection and entry in the CCN database is
not checked as vigorously as in databases created for
research, so data entry mistakes and slightly differential
measurement practices across CCN clinics may intro-
duce measurement error and misclassification. We have
tried to correct the most obvious data entry errors to
reduce its effect, but researchers should consider the pos-
sibility of differential measurement error and the result-
ing risk of misclassification bias when interpreting their
results. Supplementary Information The online version contains supplementary material available at https://doi.
org/10.1186/s12872-021-02020-7. The online version contains supplementary material available at https://doi.
org/10.1186/s12872-021-02020-7. Authors’ contributions HR and FA designed the study. GS, IT and LH collected the data. SB and KS
cleaned and analysed the data and wrote the manuscript. NO, HR and FA
critically revised the manuscript. All authors have read and approved the
manuscript. Data quality: missing data and measurement errorsh The data within the CCN database was collected for care
purposes and not for research. As a result, data collec-
tion and follow-up during the medical trajectory are not
uniform across patients. Similarly, the database may not
contain all clinical information researchers need, such Table 3 Sociodemographic characteristics of the CCN database and a sample of the general population matched on year of birth and
sex
Values are given as median (IQR) unless otherwise specified
a Year of birth could not be re-calculated for 160 study participants, so these could not be matched with the general population and are thus removed from this table
b Origin was defined as (i) Native Dutch; both parents born in the Netherlands, (ii) First generation immigrant; person born outside the Netherlands with at least one
parent born outside the Netherlands, (iii) Second generation immigrant; person born in the Netherlands with at least one parent born outside the Netherlands
CCN database
(n = 104,519)a
General population
(n = 104,519)
Originb (n, %)
Native Dutch
80,692 (77.2)
74,042 (70.8)
First generation immigrant
15,731 (15.1)
24,592 (23.5)
Second generation immigrant
8096 (7.7)
5884 (5.6)
Annual personal income (€)
27,914 [14,822–47,344]
22,270 [11,900–38,758]
Annual personal income groups (n, %)
Negative or zero
4760 (4.6)
5701 (5.5)
< €20.000
33,209 (31.8)
33,048 (31.6)
€20.000—€50.000
42,325 (40.5)
33,906 (32.4)
€50.000—€100.000
18,204 (17.4)
10,530 (10.1)
€100.000—€200.000
4197 (4.0)
1675 (1.6)
≥ €200.000
1121 (1.1)
337 (0.3)
Not available
703 (0.7)
19,321 (18.5) hic characteristics of the CCN database and a sample of the general population matched on year of birth and Values are given as median (IQR) unless otherwise specified Bots et al. BMC Cardiovasc Disord (2021) 21:287 Page 8 of 9 as highly specific biomarkers, because these are not nor-
mally collected in daily care. Furthermore, raw ECG data
and echocardiographic images were saved to a different
system than the standardised clinical data and were thus
not stored in the CCN database. These limitations are in
part inherent to the database, so researchers should con-
sider whether the CCN database is ‘fit for purpose’ for
their specific research question. However, some of these
limitations can be addressed and alleviated. To obtain
standardised follow-up for all individuals in the CCN
database, we performed record linkage for all-cause and
cause-specific mortality. Funding g
This study was funded by the Dutch Heart Foundation (2018B017, CVON-AI)
and by ZonMw (849100003, Reviews en Kennissyntheses Gender en Gezond‑
heid). Folkert Asselbergs is supported by UCL Hospitals NIHR Biomedical
Research Centre. The funding instanced had no role in study design, data
collection, decision to publish or preparation of the manuscript. Page 9 of 9 Bots et al. BMC Cardiovasc Disord (2021) 21:287 Author details 1 Laboratory of Experimental Cardiology, University Medical Center Utrecht,
Utrecht University, Utrecht, The Netherlands. 2 Department of Cardiology,
Amsterdam University Medical Centres, location VUmc, Amsterdam, The
Netherlands. 3 Julius Center for Health Sciences and Primary Care, University
Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands. 4 Depart‑
ment of Cardiology, Division Heart and Lungs, University Medical Center Utre‑
cht, Utrecht University, Utrecht, The Netherlands. 5 Institute of Cardiovascular
Science, Faculty of Population Health Sciences, University College London,
London, UK. 6 Health Data Research UK and Institute of Health Informatics, Uni‑
versity College London, London, UK. 7 Cardiology Centers of the Netherlands,
Amsterdam, The Netherlands. 13. Gentile BA. Contraindications to Stress Testing. In: A TD, A GB, edito
Pocket Guide to Stress Testing; 2019. p. 45–52. 14. Menger V, Scheepers F, van Wijk LM, Spruit M. DEDUCE: A pattern
matching method for automatic de-identification of Dutch medical text. Telematics Inform. 2018;35(4):727–36. 15. Siegersma KR, Groepenhoff F, Onland-Moret NC, Tulevski II, Hofstra L,
Somsen GA, et al. New York Heart Association class is strongly associated
with mortality beyond heart failure in symptomatic women. Eur Heart J
Qual Care Clin Outcomes. 2021;7(2):214–5. 16. Groepenhoff F, Eikendal ALM, Onland-Moret NC, Bots SH, Menken R,
Tulevski II, et al. Coronary artery disease prediction in women and men
using chest pain characteristics and risk factors: an observational study in
outpatient clinics. BMJ Open. 2020;10(4):e035928. Received: 8 June 2020 Accepted: 18 April 2021 Received: 8 June 2020 Accepted: 18 April 2021 17. Névéol A, Dalianis H, Velupillai S, Savova G, Zweigenbaum P. Clinical Natu‑
ral Language Processing in languages other than English: opportunities
and challenges. J Biomed Semant. 2018;9(1):12. 17. Névéol A, Dalianis H, Velupillai S, Savova G, Zweigenbaum P. Clinical Natu‑
ral Language Processing in languages other than English: opportunities
and challenges. J Biomed Semant. 2018;9(1):12. 18. Volksgezondheidenzorg.info. Prevalentie diabetes in huisartsenpraktijk
naar leeftijd en geslacht 2020. https://www.volksgezondheidenzorg.info/
onderwerp/diabetes-mellitus/cijfers-context/huidige-situatie#node-
prevalentie-diabetes-huisartsenpraktijk-naar-leeftijd-en-geslacht. References 1. Roth GA, Abate D, Abate KH, Abay SM, Abbafati C, Abbasi N, et al. Global,
regional, and national age-sex-specific mortality for 282 causes of death
in 195 countries and territories, 1980–2017: a systematic analysis for the
Global Burden of Disease Study 2017. Lancet. 2018;392(10159):1736–88. 19. Berg MJt, Huisman A, Bemt PMLAvd, Schobben AFAM, Egberts ACG,
Solinge WWv. Linking laboratory and medication data: new opportunities
for pharmacoepidemiological research. Clinical Chemistry and Labora‑
tory Medicine (CCLM). 2007;45(1):13. 2. Vos T, Abajobir AA, Abate KH, Abbafati C, Abbas KM, Abd-Allah F, et al. Global, regional, and national incidence, prevalence, and years lived with
disability for 328 diseases and injuries for 195 countries, 1990–2016: a
systematic analysis for the Global Burden of Disease Study 2016. Lancet. 2017;390(10100):1211–59. 20. Smeets HM, Kortekaas MF, Rutten FH, Bots ML, van der Kraan W,
Daggelders G, et al. Routine primary care data for scientific research,
quality of care programs and educational purposes: the Julius General
Practitioners’ Network (JGPN). BMC Health Serv Res. 2018;18(1):735. 3. ten Berg MJ, Huisman A, van den Bemt PM, Schobben AF, Egberts AC,
van Solinge WW. Linking laboratory and medication data: new oppor‑
tunities for pharmacoepidemiological research. Clin Chem Lab Med. 2007;45(1):13–9. 3. ten Berg MJ, Huisman A, van den Bemt PM, Schobben AF, Egberts AC,
van Solinge WW. Linking laboratory and medication data: new oppor‑
tunities for pharmacoepidemiological research. Clin Chem Lab Med. 2007;45(1):13–9. Consent for publication
Not applicable. 10. Garcia M, Mulvagh SL, Merz CNB, Buring JE, Manson JE. Cardiovascular
disease in women. Circ Res. 2016;118(8):1273–93. Availability of data and materials predictive analytics: an applied example in bariatric surgery. Value Health. 2019;22(5):580–6. The CCN database are not publicly available due to ethical and data protec‑
tion constraints, but are available from the corresponding author on reason‑
able request. Proposals for possible collaborations should be addressed to
Dr Leonard Hofstra (L.Hofstra@cardiologiecentra.nl) or Dr Hester den Ruijter
(H.M.denRuijter-2@umcutrecht.nl). 5. Rajkomar A, Oren E, Chen K, Dai AM, Hajaj N, Hardt M, et al. Scalable and
accurate deep learning with electronic health records. NPJ Digital Med. 2018;1(1):18. 6. Samad MD, Ulloa A, Wehner GJ, Jing L, Hartzel D, Good CW, et al. Predict‑
ing survival from large echocardiography and electronic health record
datasets: optimization with machine learning. JACC Cardiovasc Imaging. 2018;12(4):681–9. Declarations 7. Pilote L, Raparelli V. Participation of women in clinical trials: not yet time
to rest on our laurels∗. J Am Coll Cardiol. 2018;71(18):1970–2. Competing interests FA is supported by UCL Hospitals NIHR Biomedical Research Centre. GS, IT and
LH are employed by Cardiology Centers of the Netherlands. The other authors
have no conflict of interest to declare. 11. Jagannathan R, Patel SA, Ali MK, Narayan KMV. Global updates on cardio‑
vascular disease mortality trends and attribution of traditional risk factors. Curr DiabRep. 2019;19(7):44. 12. Seidell JC, Halberstadt J. The global burden of obesity and the challenges
of prevention. Ann Nutr Metab. 2015;66(Suppl 2):7–12. Ethics approval and consent to participate The Medical Research Ethics Committee of the UMCU declared that the Medi‑
cal Research Involving Human Subjects Act does not apply to this study. The
CCN data were made available under implied consent and transferred to the
UMCU under the Dutch Personal Data Protection Act. 8. Sardar MR, Badri M, Prince CT, Seltzer J, Kowey PR. Underrepresentation
of women, elderly patients, and racial minorities in the randomized trials
used for cardiovascular guidelinesunderrepresentation of in randomized
trials letters. JAMA Intern Med. 2014;174(11):1868–70. 9. Van Spall HGC, Toren A, Kiss A, Fowler RA. Eligibility criteria of randomized
controlled trials published in high-impact general medical journals: a
systematic sampling review. JAMA. 2007;297(11):1233–40. Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in pub‑
lished maps and institutional affiliations. Springer Nature remains neutral with regard to jurisdictional claims in pub‑
lished maps and institutional affiliations. 4. Johnston SS, Morton JM, Kalsekar I, Ammann EM, Hsiao C-W, Reps
J. Using machine learning applied to real-world healthcare data for 4. Johnston SS, Morton JM, Kalsekar I, Ammann EM, Hsiao C-W, Reps
J. Using machine learning applied to real-world healthcare data for
|
https://openalex.org/W2030826184
|
https://publikationen.sulb.uni-saarland.de/bitstream/20.500.11880/26323/1/preprint_116_04.pdf
|
Chinese
| null |
Frobenius distributions of Drinfeld modules over finite fields
|
Transactions of the American Mathematical Society
| 2,007
|
public-domain
| 45,047
|
"!
#$% &'( )
*,+-./0
12/
3 %45
76
.8 94;:'=<
>8 94
47? @
A B 98DCE*F+3 G?/ 'H0IKJ-L/M/MN
C0DEGFIHKJ"LNM"OQP"LNOSR DALNF"MTRLUEGJ"OVE WYXZDALNJ[W\H^]NP
_
EP"M"]UHKO
Ea`GHKDcbJ"LdReH
bH^]NP"O
OQPDRSUT>VWYXBPDZ\[^]`_badcHa$XBa$P
e,fgfih'j=flknmpoqknr
sutUh'vr
wyx
z
t|{}fih
w~t|kdwlf^w
tK~f^wr=Uv
gv0wfl
gi
z,g
i}e,fgfihnhl
gt|k
tUh'~flkux
2l2,dl ,¡i¢¤£i¥u¦¨§ª©$«.¬gF®-¯§7° #
&
*
+
47? @
A B 98DCE*F+3 G?/ 'H0IKJ-L/M/MN
! 12/
3 %45
76
.8 94;:'=<
>8 94
U
N
I
V
E
R
S
I
T
A
S
S
A
R
A
V
I
E
N
S
I
S E
F
H
I
K
L
N
O
P
I
R
L
H
F
c
)$
3
d3 T
6
V
;
6
9
,
*
;
4
,
(
*
6
&
6
9
;
*
;
*
,
;
V
6
4
&
6
4
,
6393UY*"$&29
+4$ E6
C
4+,c6397*3&# fb
6
6h() *WV
&)V +4$,+
Z\]/
_
_
a
e X
Y
[
Y
^
V
&
V
4
b
`
4
&
,
b
c
V
6
4
&
6
4
*
&
d
Ygfihkj
3& l
V
& "V
4$
V *-6h(2 +
b
,8*
C
;
C
*"
639,c
S
34md)+
*"Zn'&
UY*"&9
+4 c
Sf
62
C
4$_o
6h() *pl#q
b
!4b
h
,Y,
C
V VF6),"
"
!'
*"3& # r
C
34,
fb
6ts,d)()+,
*","'"6
*-6)
&
C
,
& 6)
6)*"V $,- &u][vugw/b2b
$;< ?,"!,xV
,c
r
C
3 *"!;Pr
C
!6)& u(y,z|{}u
J\~k[
AMb
{~pac@Tc P;+6
;++&
,'639
P;<
3*"3; "+*-$,-"$;@V
6)4
& 6)
346g
wq8s[
y
z{
J\~
639Cuq:63*)oJs03*-
,
C
}-+;
"6
*" ,-*-$;T$63& ,," E4
3*
"6 63,"c639
;<
3*"3; "+*",-"$;
VF6)4
& 63 E$34$,
639
*-6)
F+&
C
,M+& 63 E6)*-V ,"
,
639Y 4$4$V; ;
C
*-(3+, 6h(3+*V & "V +4$,+
63*
TG3
V 4$b/g
M$,'E,xr
C
3*"@6)**"*"
C
; $
4Qb
$&b
$;< ;
3,-R",',-V 4$""$&edV
+4
$,8$ EQd)$& 3*- r
C
3 *"!; eb
\3b $& *-c63*c*3
mV
!c PV4
3; d!
$&V & f
6393[r
C
6!MqSc)sT n
,
9
6
*
4
4
V
;
;
C
*
(
,
b
&
C
*
4
r
C
,
6
&
,
*
,
b
d
H
S)P
<
)
)
3
! 3)
"
! c! C
D
E
F
H
J
L
M
O
P
L
O
R
D
L
F
M
R
L
E
J
O
E
W
X
D
L
J
W
H
]
P
_
E
P
M
]
H
O
Ea`GHKDcbJ"LdReH
bH^]NP"O
!"$#
%'& ()+*-,"/. !0 ,12)3*"4$3& ,
576),8"9:3;< =/>?)@>3A
))A3B @133*"
*!. C
;<#3 &
D
*" E3& F/GIH
JKB
LM)NPO)A
QRB3B)B
O
TS8 3$4UH
V *" V *"&W<XY !" Z
C
& S[,"
Z\
]^]^]_H
W-VZHa`)` bcbcbd\ E! Z
C
& eSf,-
Zgh` F/GIH
JKB
LM)NPO)A
QRB3B)B
O
TS8 3$4UH
V *" V *"&W<XY !" Z
C
& S[,"
Z\
]^]^]_H
W-VZHa`)` bcbcbd\ E! Z
C
& eSf,-
Zgh`
"#
$ %&(')
$ (* +
, -
. 0
2
4
5
7
9
. <
=
? @
-
B
-
9
-
. E
F
H
I
K
L
N
O
P
I
R
L
H
F
c
)$
3
d3 6)
,-+*-(!!"$6)&,
9
*"6)
TG
& ,"()
;
34;
C
4$!6)& ,
b
¬UY*-$&9
4$ E6
C
4+,_q:,-+f
BQj
sT
¡Y&" R63" +*0
3&b
"
*" ,
C
4,
639fe3jc4+
6
; 6)& ," +*
"
V *" ," &W
9:3;T6)*-,±}²
q>{~+s+b
3&
6
"
V *" ;+,"d,"
!V
d639
9
6)*-
C
4$
$&Tc +63*"+
N2M§
Q
,
,
&
*
&
,
;
&
*
,
6
9
,
V
*
6
4
,
&
b
6
&
;
d
&
b
&
6
b
639
$&9
63*" E!6)&¬q
$&
F63
*" ; 6)& ,s
Tfb
+&\«UY*"&9
+4? E
F
H
I
K
L
N
O
P
I
R
L
H
F
c
)$
3
d3 3$ q
n
s
]
;
V
6
4
&
6
4
,
6
9
d
(
&
,
V
;
C
4
4
;
6
9
*
6
U
*
&
S
9
+4
E6
C
4+,
S_'h
!WEh) %
3-
"c
<
"
!,:M
JCae
q
s
6
b
&
o
6
(
*
l
*
*
,
C
;
w
q
s
[
y
z
{
J
~
b
{?3&~
F+&edd)()+&
+-
3S)
$M$
$+
3
2 $+"
3 8
"+^vg >
>
h>
" ]
*
,
q
n
s
,
V
4
;
4
6
*
G
V
4
;
4
&
,
b
*
&
f
>
j
b
f
L
j
b
f
L
j
b
,"
C
!"$6)&$,' E63*"R&
()6)4()+
9
63*qSsT¡
&
63& R
!& b%qSs0,*" 4
!"+"6
;+4$3,",
&
C
R
*",
$&
$ EQd)$& 3*- r
C
3*!"$; 63*" *",
6h() *c_b
3&
3&
G2V 4$;+
9
6)*"
C
4
E
Fd3() &
(2$?
3&
!4 W;
;+4
!,",
&
C
F+*
9
6)*-
C
4
2Tc $,d,
b
63*"#3
6
C
E&
"
;
3,-b
+*" l
$,M!&c
SfV *-$
V
+4|Ye¢£[c
¤M¥
b
"
V *-$
M$ +34C¥
639c@H
," qUhLts¦b
b
$;<
344$6hb
,d9:3,-@;
34;
C
4$!6)&
639
"
&
C
F+*Y&r
C
+,86)&Z(¡Y&
R63 *Y
3&b
"
!Y9
6)*-
C
4$M9:34$,
6?
G2V 4
3&
@(3!*"
$63&639
;+6)*-*" ,"VF6)& &ed
;+4$3,",
&
C
F+*-,Yb
"
; 62+
;+$ &
,
{~h
MD
¨ ¡
C
*
&
*
,
C
4
,
T
6
*
N
§
b
b
;
G
V
*
,
,
,
b
d
;
4
,
,
&
C
F+*©ªMq>{~«¥Ds
639UY*"&9
+4
62
C
4$+,¬oK6h() *Y¢
b
:
M
®x¯Dqs[
y
z{
J£~'3,c
V *-62
C
; c6!9°
Sf462;+34
;+6)&
*-$
C
$63& ,±t²mq>{~+s¦b2b
*"°2*
C
& ,
³ ³
*
6
C
d
V
4
;
,
6
9
6
*
°
V
&
b
±
²
q
{
~
s
,
&
&
C
(
,
;
*
V
S
6)&3,M;+63&W"$&
C
6
C
,'462;+34Z & ,"f 9
C
& ; "$6)&639Acp² ¬c(²Gq>UYV & "$6)& §2MsT
]
E
C
,
,-<
! ©
ª
q>{~«¥Ds
,
8TG2V 4
!$& e=
" 9
*- r
C
& ;++,
639c E!*-$; +,
!q
QDcp²sYb
" = d)()+&
;<
3*!; *",-;EVF6)4 2&6) E$34
ayz
{
J\~b%°
*3&d)$&ed
*-6
C
d)
" _V
&@V 4
!;++, )Tc R9:!; 63*Z± q>{~+s
q
b
;< E; 6)*"*-+,-V
6)& ,
"6P" '1!"6!S
T7!
9
C
& ; "$6)&
y
kz|{
y
¤!Bt~+s
,
6!9Zd 9
S
9
+*-+&
&
C
*-"!,
,"
!V
' $,8$&d
C
$,- +, ;
!,"+,
b
+*-Y;<
3*
q8Y6s0,
6
?63*
(3+&Z
M
g
> T
6
*
N
§
,
&
4
6
d
6
C
,
b
T
6
*
>
>
6
9
f
j
b
,
4
*
*
,
C
4
9
6
*
+44$$V2$;d;
C
*-(3+,d6h()+*
V
&RV *" E(V
+4 ,
Y#
%$[
$,9
C
& &
6?&63
"
!Y"
*" ,
C
4
9
6)*c+44$V;';
C
*-(3+,
b
3,
63(!! ? E
F
H
I
K
L
N
O
P
I
R
L
H
F
c
)$
3
d3 62
C
4$+,
639
*3& #
fb
6Q3&- 4$4$V"$;R;
C
*-(3+,xeb7" +*- 3*-M*"+4$!6)& ,"6
12!6!S
T
TS[4$#3r
C
,8S
6)& , b
3&
"6
"
;+6)& ,8*
C
; "$6)&
639';
C
*8()+,E6h()+*V
& V
4$ ,
b
!&W
*!"$6)& 34
V
6)&
, b2$& "
!
" )r
C
3&
"+,
"
!
3V VF
3*
&?6
C
*
9
6)*"
C
4
3,
34$,-6
d)6h() *"& "
d3+6)
"*-
639Z;++*8<3& UY*-$&9
4$M
62
C
4
3*
;
C
*-(3+,pq
,"+f
§Mj
b6fe§Mj
sT
$
,
6
(
6
C
,
6
,
6
9
r
C
,
6
&
,
*
,
,
q
&
,
6
6
9
ET 6
,
C
,"+=3&
*-+,
C
4,
63
<3& +s'$&
" $,YV 3V
*
d3+& *34)(+
6 3*"
*"3*- aUY*"$&29
+4$
62
C
4$ ,db
6
C
@3&
=*-+,8*"; "$6)&
6)&
E*3& #
63*
& !
C
*-
639
3,"
*"&ed¬c@=]=
*"+,8*-$; "+
6
"
V *" ," &WE,"T""$&edeb
*";< +&6
C
d)
6R,- 6hb
34$4 9:!;+ ",
639
d)+&+*!4FV*"6)
4+ $bW$&
6)*" *
"6R
()63$
;< & $;+34
E;
C
4"$ ,
0b
6
C
4
6)
,";
C
*"d P6h(3+*!4$4
V ;
C
*"3
a ]
&
6
b
*
&
,
;
*
;
6
&
&
,
6
9
+
*
&
,
;
6
&
,
n
9
*
3,",-+
4$$&d
"
9
*3
b
6)*-#
$&
," ; 6)&
b
b
,-
C
$&
," ; "$6)&
Q
"
S
(
$6)*c6393g
w
C
& +*cfb
$,8,
639Ao
3&
C
"6) E63*"V ,"
,
639gc_b
!& V*"+,-+&
9
6)*"
C
4
3,
9
6)*
c3
,-6)4
C
"
"+*"
~
639/:
M
wqSTc +6)*-+
Q23Ms73&R
4$+3 $&d
;+6
;++&
d639 E
*-6)
&
C
,*"3;+{
qU5
*"6)VF6),-6)&
Q2
Beb
C
6
-
C
&ed
fe+Bj
sTCTc 6)*"
Q2)3V VF
3*-, b&E
C
;< d)*"+! *!d3+& *34f b
$&¬fe
O j.!2b
ZV
4$4
d)3V& R3*xd
C
+&
/)0214351*68793:$f&
,-+; "$6)&O
b
R ,"; *"$
FR 6/bg
w;+3&
;
34;
C
4$!
$&
V *"3; "$;+bb
;< ,
6)*"Y&
()6)4()+
"
3&
; 6)*"*-+,-V
6)&2S
$&ed
V*"6)
4+
9
6)*+44$V;
;
C
*-() ,+Cn^ md) 4 R+E; $ &W
V *-62; +
C
*"Qb
3,-+
6)&
UY+4¨d)&
Sf4$#3
; 6)&ed)*
C
+&;+
F fb
+ &'3,",-c$&
(!3*"$3&
,73&
,"+&,- $&
,-+*"+,b
$,d)() &$&
q:O
§QsT'$['b
6)*"#W,
9
6)*
V *" E)V +4$,
l
[
Y¢
6)& 4 b
3& 3,",
C
V6)&
!$&
<3& +E9
*"6)
&6/b
6)&Z;$f&,"+;T6)& BMb
P *"
$&
" d*!"$6
F fb
++&
&
C
R
*",M639)o6¤Ql_b
*-6)
&
C
,
*!;++,M6390 E G2$ E34
` & 6)&2S[ G2 34
d3*"+qSTc 6)*"
B aQsT']
,- 6hb
&¬Tc 6)*"
>2aQ2H0
6)*=<[K d¥?>
Ob
&
C
*
,
<
q
{
¥
s
q
*
,
V
©
q
{
¥
s
s
6
9
U
*
&
9
4
6
C
4
,
q
*
,
V
6
9
,
6
S
E63*"V ,"
;+4
!,"," ,'6!9AUY*-$&9
4$
62
C
4$+,s
6h()+*Y¢@b
*"6)
F+&
C
,
"*3; {
+VF+& 6)&4 ?63&?<E3&
d d)*" P6!9A{
f
" )
d"
!"
>«D
"
+
!"
F+-c3
$EQ)
3- $
&
,
;
6
&
b
b
*
4
©
ª
q
{
~
¥
s
b
;
4
,
,
&
C
*
,
6
9
d
&
*
r
C
S
* $;
63*" *",d6h()+*(cRE12 ; "$6)&
§?$,d (363 ="6" M,-
C
639!±}²mqS{~+sY9
63*
V
& °eP]=d)(3M3&
TG2V 4$;
GV*"+,-,"6)&
$&aTc 6)*"
§2gN
3&
6)*"634$4
!*-
§2gL
!& *-+,8*"; 0 dV *-626!97"6
" q:
6)*"d+4$3
F6)*!"s
;+3,"P6397;<
3*Mq
Y6s
[
QDb
,"& ;+
V *-626!9d)()+&E$&fe3j
9
6)*
P,-$
$4$3*3,-," *-6)&?! F
P
K
L
O
H
N
F
c "
)
" T
*
6
C
d
6
C
b
b
C
,
9
6
4
4
6
b
&
d
&
6
6
&
H
q8)Ms
/0
$
"$
$ E W" Y
[
Y
^
V
&
V
4
b
`
4
&
,
b
6
9
;
*
;
*
,
;
3
k
d dF)
3E$3
-$eMh)
$
3$ "+"
$ !Zk c
[
Y
f
h
j
V
6
4
&
6
4
*
&
d
6
(
*
Y
&
&
&
*
&
h
b
d3*"+d9
C
& ;T6)&- dQ
38)¦P" p
3+
k
+
33
[
Y
q
h
s
r
C
6
&
V
4
6
9
c
3x «¦
" d+)
)
33
[
Y
q
q
h
s
s
;
6
V
4
6
&
6
9
&
V
&
V
4
;
b
V *-6h(2 +
b
"
,c&6)*" E34$,(+
3
,"634
C
"Y(3!4
C
$
eb
b
*"
h [`
-
x)1SD_
^
)Y" M$+3 $
+
++
P3
!= $+
+
( ]
b
*
,
d
&
q
{
s
Y
9
6
*
4
&
d
;
6
;
&
6
9
&
4
&
{
6
9
c
b
3&
TG
"+& ,0&63<!"$6)&?"6
A
[v{ a
$
-/
+
"
-"
T
-"
$
3 ]
b
*
,
d
&
q
{
s
Y
9
6
*
4
&
d
;
6
;
&
6
9
&
4
&
{
6
9
c
b
3&
TG
"+& ,0&63<!"$6)&?"6
A
[v{ a
$
-/
+
"
-"
T
-"
$
3 l
[
V
4
V
*
6
(
b
,
*
C
;
C
*
! E
F
H
I
K
L
N
O
P
I
R
L
H
F
c
)$
3
d3 6
C
4$4$V"$;
;
C
*-(3+,
3,-$4
3
!V,6d 0V *-+," &
;
!,"0639Z6
;<
3*!; *",-;+,
$f& ," ; "$6)&ENdb
"+*- E& c,"6)
$&ed3*"+$+&
",
6!9Z
!*"4$+*
9
63*"
C
4$3, !
3*"03,-,"6
;+
+Mb
"
@V
634
& 6)
34Jayz
{
J\~bFb
$;<
4
3 ,
6E (V
&
34
*" ,
C
4)Tc 6)*"
NM§2An',
C
,
C
34>b d;+3,"d639
;<
3*!; *",-;PQ
$,
P
6),8
$&
()6)4() Z
38P3
P 3
R!"ME!!!"+
-)
E+3$
!"$)Y
-
)-E = 5
*
,
6
9
,
V
V
*
*
6
(
9
*
6
;
4
;
C
4
6
&
,
V
*
9
6
*
&
fe+BjUZn46)&ed
b
C
6)*'6!9
!0 +,", b$
b
6
C
44$#3P6ETG2V *" ,",
R
d)*
C
6 G
D
+
3*"2Y3&n& *"+3,
12;<
b
+,(++*'9
6)*
+4V9
C
4
$,-;
C
,
S
,"6)& ,+ F
P
K
L
O
H
N
F
c "
)
" -
)Y
)
$-
C
,
6
9
&
6
6
&
b
b
4
,
6
b
*
¥
9
6
*
6
&
;
*
*
C
;
4
V
6
4
S
& 6)
34
"
!
d) & +*"! ,)¥
]
+&
9
; 6)V $ ,Y639CY
$& ,-$ c
3& Y¢
*-6
C
d)
"
&
!
C
*34
E3VZ
5
4
3; +, °
639Z
+*
;+63*"*" ,"VF6)&
6
V *" E
4
,
6
9
c
b
&
b
;
;
,
b
;
4
4
°
V
&
&
C
,
,
,
6
4
°
9
6
*
-V 4$3;+ !& -V*"$
$
34meb
6)*°1[
b
$&V & "
V 4
3; 3Tc E,8
634
[
^
& 63"+,
3 "() V
6)4
& 6)
34C
^
b
*- d
!*"
3,M!&
YSf4$&
!*
+& 6) E63*"V ," K639
"
3 ()d)*-6
C
VM,";< +
6h() *lcC0+& ; 0" c*"&ed
;
D
%
¨
;
g¬ &
w
®
q
s
[
{
^
{
l
)
)- $-ER3QQ
$
-
!" 6
9
4
4
Y
S
4
&
*
&
6
6
*
V
,
,
6
9
¤
l
b
4
4
*
d
*
,
,
#
b
V
634
& 6)
34
*"&edl
[
{
g{_
l
&
& 6)&
Sf;+63 E
C
<!"()
$& *"
$&
b
"
;+6)
C
!6)&?*
C
4$
[
^
q
al,sT
8)a
!!*$&(
)+,dh)
"
3 |
/ >kg
eh 8d$@" q
Q
s
n
6
"
/
#
c
%
'
0
#
*
/
"
6
(
*
l
q
,
d
f
Q
j
b
f
Q
j
b
f
j
s
,
c
S
E6
C
4Y,-"*
C
;T
C
*-@63&- Q¤Ql\d)()+&
*"6
C
d3
*-$&edM 6)
6)
6)*"V $,-
e;
o
H
c
z
#
&
w
®
q
s
{
. F
P
K
L
O
H
N
F
c "
)
" H
c
#
l
,
!&$c
S
34md)+
* !
C
,
l
$,
3&
G2"+& ,-$6)& + *c639A
6)*c639
,-6)
ZY¢;b $&
b
;< ;+3,"db
b
*-
¥[
;<
!*&%3q>l,s
9
6)*c",c0Sf;< 3*3;T *"$,8;3%' *"
)
$:E 2$E3
-$
Y$ +36E3A Y
¢
[
c
¤
¥
b
q
G
4
s
V
*
4
¥
6
9
c
b
6!9
d)*"
<[
d
¥
3
"M3
3!)Z
3"? F
P
K
L
O
H
N
F
c "
)
" q
h
sZJ
(5
536
2
q
h
s
+M!" !"$)Z=
3
3- b
;
V
*
,
;
*
*
*
*
4
]
4
b
,
,
,
C
2
6
q
h
s
[
A
b
b
+*-87R$,
9 ;:+ =<639Co
;$f& ;+3,">7([
*!& #Jq
o6s%[Qq
+,",-+&
$34$4 ? P63& 4
;
3,-
*-
!"+
$&
" $,
!*-;+4s+b
b
b
*-o?4
[
!3qhZs
J0@
JBA
y
bCA
[
Ab
3&
*-$ & $o[ qD@/EAs
F
G,K
")" Y-$
$PE
!6Q"0" Y-$
$dE
MQ n
'
0
H
I
6
J
'
9
*
6
U
*
&
9
4
6
C
4
o
¤
l
6
U
*
&
9
4
6
C
4
L
¤
l
$,
,"6)
N¬¬l
h d,
C
;<
!N6oO[FLPQN
9
6)*{ ¬c&q
,
C
;+ ,c6
*- r
C
$*-
,9
6)*
{$[hZsT
12$
$4$3*"4 b b
M V
&
& 6!Sb
$,-6!SbI3&
C
"6) E63*"V ,"
,+
Tc
& 6)
6)*"V $,- K*-$&ed
& w6q
oJs
639
)UY*-$&9
4$@ E6
C
4o
6h(3+*%l=6!9
*3& #
7SR
AM
3,c"
9
6)4$46/b
&ed
V *-6)VF+*-"$ ,+H
t q
O
s
: q
O
s
:
[0+)
3$
" d
"$
gS)W
q
s
$
;
6
&
&
,
,
C
*
&
d
c
TU
z
#
o
q
c
s
V
#
l
h
! $8
"+p
f
2
$Y37 E ")
$-)c3P q
s
$
;
6
&
&
,
,
C
*
&
d
c
TU
z
#
o
q
c
s
V
#
l
h
! A
_
[
^
a
A
T
,
,
4
,
6
r
C
(
4
&
b
F
P
K
L
O
H
N
F
c "
)
" z
#
o/ ,
C
;
6
:
_$ q
s
o
q
s
o
[
! q
{
s
J
1
32
q
{
s
9
6
*
{
c
$
¨
+
T+-E +
" "
) q
s
o
[
! q
{
s
J
1
32
q
{
s
9
6
$
¨
+
T+-E +
" "
) $
,
C
&
r
C
4
*
&
*
6
C
d
3Z $
,
C
&
r
C
4
*
&
*
6
C
d
3Z o4
[
! F
P
K
L
O
H
N
F
c "
)
" $8
"+p
f
2
$Y37 E ")
$-)c3P q
s
q
s
q
s
,
9
*
c
S
6
C
4
6
9
&
,
6
&
(
,
6
*
6
9
7
y
q
f
B
j
b
f
Q
j
:$8d
6
6Y
K$
$")
3m)+ "
h)+
)24
*89
T q
s
q
f
j
f
j
s
q
s
&
w
q
o
s
X
%
,
(
,
6
&
4
d
*
6
(
*
q
/
0
1
3
1
6
7
3
s
" 3 -)
"
$
!3"$3
O[J>6
! F
K
L
L
R
I
R
L
H
F
:
KK q
s
I
"
*
'
"
0
:
<
%
7
0
6
"
/
#
'
0
#
*
/
"
J
0
"
l
6
J
`
"
q
`
"
z
s
3
$8$
`KK
,2G
G,K
*$GE
E
K
E
)+,E
, q
s
q
s
q
s
I
"
*
'
"
0
6
J
0
'
0
H
I
6
J
'
1
/
:
J
J
"
J
0
J
*
1
I
'
0
#
*
/
"
J
6
J
S
^MS
^M
&>
Q
4( q
`
"
z
s
q
`
z
s
J
%
q
l
ª
¤
l
ª
^
a
s
3
'
>%¦Q%
(
x,
,^ :" "Z)
M
* 1
&
;
%
q
l
ª
¤
l
ª
^
a
s
[
`
y
z
q
*
,
V
`
z
s
9
,
(
&
q
*
,
V
6
s
b
b
34$,-6V
& ZH
,&
M/
e1
&#;>,
K^
K
,
!+K5D 1
&
;
%
q
l
ª
¤
l
ª
^
a
s
[
`
y
z
q
*
,
V
`
z
s
9
,
(
&
q
*
,
V
6
s
b
b
34$,-6V
& ZH
M
e
&
>, F
+
-
L
K
L
. .
*
Y
y
,
C
&
r
C
r
C
*
;
G
&
,
6
&
6
9
Y
;
6
&
&
&
4
d
S
*!$;Y; 4$6),
C
*"
l
6393lc
")
h
3
F 3-< +
3" +8
$")
03-
!,=
3MT
")
*
6
&
6
b
6
&
b
9
&
6
,
6
*
b
,
b
b
,
,
C
l
,
&
G
&
,
6
&
6397 d)*-+
6!9:Y¢;b
!& UY*-$&9
4$
62
C
4$ ,
()P*3&# fb
6,Tc
C
,
i
Q3#i
QM
;
Q3 2
f
l
H
Y
j
[
f
l
H
Y
¢
j
f
Y
¢
H
Y
j
[ 2<
[
H
*"6) q8)\B}s
3&
q
)
>Qs
b
(d) +H
MC
8MS/ f
l
H
Y
j
[
f
l
H
Y
¢
j
f
Y
¢
H
Y
j
[
<
[
H
)
Q
() +
*
6
q
B
s
&
q
>
s
b
d
H
MC
8MS/ F
P
K
L
O
H
N
F
c "
)
" "3 )[f
ZY-$
$Y ]
V
&
,
6
4
C
&
(
*
&
Z
[
Z
q
o
s
6
9
*
&
#
S
b
6
U
*
&
9
4
6
C
4
o
[qD@/EAs3, Z [\@
^]
¤+A
Tc &
b
M
()M
9
6)44$6hb
$&edE
3,-$4
V *-6/(3+
;+*- *"6)&ZH
}C
J
$
#
¨ q
B
s
T
b
6
*
&
#
S
b
6
U
*
&
9
4
6
C
4
,
o
[
q
@
A
s
&
o
_
[
q
@
_
A
_
s
6
(
*
l
3*-0,"6)
6)*-V $;
9I3& 63& 4 R9F *"0TG2$,8,
al%ª
,
C
;< E !M@`_D[
^
@Jb
a
,c$
$
3"
!3$
0
A
_
[
^
a
A
T
,
,
4
,
6
r
C
(
4
&
b
q
s
Z
q
o
s
[
Z
q
o
_
s
&
q
$8s
@3_
¤G@E$,
qS`Zz
MsfS
VF6/b
+*0$&lq:9
Z[[ZJq>o6sC[0Z/q>oO_
s
[
Ats
A
_
¤+A
$,
qS`
y
z^sfS["
V
6hb
+*
$&$lq
9
Z[
AsT
" + P
)
)" $-
)-
3A$D/E
h) Z
$
C
*
*
b
C
6
6
*
V
,
d
*
6
C
V
6
9
o
[
q
@
A
s
6
(
*
l
,
J
)k
2 "
0+)
3$
C
*
*
b
C
6
6
*
V
,
d
*
6
C
V
6
9
o
[
q
@
A
s
6
(
*
l
,
J
)k
2 "
0+)
3$ q8
a>s
n
C
w6q
oJsC[
Y
ª
9
Z
[
A
6
*
l
6
,
&
;
6
&
&
Y
y
Y
yª
63 +*-b
,"!
Z
¨
1 q
>
s
*
Y
y
,
C
&
r
C
r
C
*
;
G
&
,
6
&
6
9
Y
;
6
&
&
&
4
d
S
*!$;Y; 4$6),
C
*"
l
6393lc
")
h
3
F 3-< +
3" +8
$")
03-
!,=
3MT
") q
s
w
6
J
6
"
#
*
1
6
/
"
0
"
3
V
H
:
7
6
1
*
/
:
<
Q
d
{
>
d
~
[ q
s
w
6
J
6
"
#
*
1
6
/
"
0
"
3
V
H
:
7
6
1
*
/
:
<
Q
d
{
>
d
~
[
3 F
K
L
L
R
I
R
L
H
F
:
KK K
0
F
2436587:9
[
`
"
[
%
q
l
s
<
I
"
"
7
I
"
J
*
'
6
J
0
"
7
I
"
6,J20G'
0G HI6,JK'
1*/$:GJEJ
"EJ
0
WoJ¤Ql:3
'
kD/E
+
h) kk2
F)
3E$3$,O+3E
'
?" n
,
o
[
q
@
A
s
,
V
&
6
(
*
l
b
V
6
4
&
6
4
,
o
;
6
C
b
=
0>K"K
6 *
J
"*/,"K'
"K
7%u
[
ugw[
" 6!9lb7Ug!mbgu
^ & w6q
oJsT
$f&=(
$Tb
639
q8)gOts¦bu
C
,-,!"$,-9
RVF6)4
& 63 E$34
r
C
!"$6)&
6h(3+*Acb
,"6Y
3,
C
& mr
C
+4
"+*- E& +
6)& $; E& $ E34FV
6)4
& 6)
34
wq8s¬cf
¬jU
/03R"
!Y
M
)
+
+
"
"e$3
'3!
"aR
= V
q
s
f
j
q
? 6
b
(
&
V
,
C
*
&
d
o
q
c
s
6
9
l
b
c
s
]
()Y" Y9
6)4$46hb
$&ed@*"+,
C
4 bb
;< ,
V
3*8c639
Y9:3*8S[*"
!;< $&ed
3&
346d3 E
S
fb
+& +4$4$V"$;';
C
*8()+,'3& UY*"&9
+4
E6
C
4+,
6!9
*"3& # fb
6
}/
3
k F
@
A
C
L
K
C
E
f
L
j
G
"
7
o
"
:
:
<
%
7
0
6
"
/
#
'
0
#
*
/
"
0
"
l
<
I
"
"
fl
H6Y¢j![;L<M
687 IN=
0>K"K
6 *
J
"K /#0G'
0G HI6,JK'
u
[
ugw
3I
I"K E"
"PO
6,J*7 J
:
H
0/RQ
0G'56:"/g
wJqsC[¬yCz£{
J
~)¬cf
¬j:<;7 I"
;<
3*"3; "+*",-"$;
VF6)4
& 6!S
E$34
0
Wo<K
687DI
7 I"W
0/8/)0! 3 F
K
L
L
R
I
R
L
H
F
:
KK 6 FS H/
0EH"K
7.6
"EJUT
:
g
6C
M
6
G
8
W
9=+
.9K$+Xgg
J>, q
s
w
q
s
[
w
q
s
0
w
q
s
y
3
V
H
:
7
6
1
*
/
:
<
w
q
u
s
[
A
3
q
$8s$
I"
6#`"
:"/AqS~s
"8Y)*=:"/
JZ¥[ZW<
7 I`*3J
~
[]\q>o6s
¥[Z^
687DI_\q
oJsk[K,«d)&:qS~+s
Y
ª
3
q:$8s
w
6,J=6 K ^"
#+*
1*6 4/,"%0! +"K
3`VK
H=:+
7.691K*/$:+ X<
Q d
{
>
d,~k[ q
s
w
q
s
[
w
q
s
0
w
q
s
y
3
V
H
:
7
6
1
*
/
:
<
w
q
u
s
[
A
3
q
$8s$
I"
6#`"
:"/AqS~s
"8Y)*=:"/
JZ¥[ZW<
7 I`*3J
~
[]\q>o6s
¥[Z^
687DI_\q
oJsk[K,«d)&:qS~+s
Y
ª q
s
w
6
J
6
"
#
*
1
6
/
"
0
"
3
V
H
:
7
6
1
*
/
:
<
Q
d
{
>
d
~
[
3
? 6
w
q
u
s
[
A
&
,
b
(
r
C
6
& ? F
C
E
K
F
:
83at@3 q
s
q
N
s
&
q
A
s
*
*
,
V
;
4
;
,
,
6
9
C
;
6
*
d
&
*
4
*" ,
C
4,b0(!34$
9
6)* 3*"
*"3*-
*"3& #W,
7
3&
UY*"$&29
+4$
*"$&d), c
&63
& ;++,-,3*-$4
V
634
& 6)
34UH7,-+ f\L j
$8pg
6Y M<
3"3 "+-$-"$
F)
3E$37!
M-+ -+" 2 q
s
w
q
s
,
;
*
;
*
,
;
V
6
4
&
6
4
6
9
u
&
*
V
*
,
&
S
< $63& ,
6397 & w6q
o6s
$&? (!3*"6
C
,±)S
! $;
T
!"
E6
C
4+,h
Qq
oJs
639
o:b b
$;< TG2V 4
!$& ,
" d&
3
/)02143%1*687
3
:$8pg
M
E$
"
)++"Y
!"Qeg
v
+
"c)Eg q
s
w
[
w
,
d
&
*
;
;
,
b
w
[
y
w
6
;
;
C
*
,
6
&
4
9
o
,
,
C
V
*","&ed
C
4$3*
/)02143%1*687R d3&
[ fil
HQY¢j
$,cT() &Z q
s
w
[
w
,
d
&
*
;
;
,
b
w
[
y
w
6
;
;
C
*
,
6
&
4
9
o
,
,
C
V
*","&ed
C
4$3*
/)02143%1*687R d3&
[ fil
HQY¢j
$,cT() &Z F
K
L
L
R
I
R
L
H
F
:
KK 6 FS
:+ ^"
"8Y)*6, G:"/,"K
7
T
:
_0+/>\+^
,28`K
G
3
I
"
0
/
/
0
6
S
:
"
"
Y
*
6
:
/
"
7
T
:
_0+/>\+^
,28`K
G
q
s
o
:
#
L
:
"
6
J
0
S
"
"
0
*
J
$8d
6
6
_
+/R
6 q
s
o
:
#
L
:
"
6
J
0
S
"
"
0
*
J
q
$8sd
6q
6s
_
+/R
6 q
s
&
w
q
o
s
X
%
:
#
&
w
q
L
s
X
%
:
"
6
J
0
'
0
H
I
6
1
%
:
/
S
"
:
J
q:$8s
w[
;
w
q
(s_g
w[
D
w
3
P3
"M-
]
6
,
C
]
6
,
C
q8
)Ms
©1q>{~l,s%[
&
C
*
6
9
,
6
6
*
V
,
;
4
,
,
,
6
9
UY*"$&29
+4$
6
C
4$ ,ko6h() *Zl
b
g
w6q8s%[
y
z
{
J~ q8
)Ms
©1q>{~l,s%[
&
C
*
6
9
,
6
6
*
V
,
;
4
,
,
,
6
9
UY*"$&29
+4$
6
C
4$ ,ko6h() *Zl
b
g
w6q8s%[
y
z
{
J~ q
s
&
,
(
*
6
&
b
{
&
~
c
,
C
;
6
;
6
&
6
&
,
d
(
&
q8)gNts
Tc +6)*-+
NM§ 2+4 ,
,"!,-9:3;T6)*8
+,-;+*-$V"$6)&
!
4$+3,-M&
"
;
3,-
b
+*-_l
[
Y¢;b
)V *" EZc0S
V +4$ F
K
L
L
R
I
R
L
H
F
:
KK 6
w
q
u
s
[
A
&
,
b
(
r
C
6
& q8
gL
s
u
y
z
o/
u^J
o
[
A
C
W
,/
6
6 q
L
s
&
l
T
r
C
&
,
{
[
{
q
o
s
&
~
[
~
q
o
s
*
;
4
4
=
0
"
6
*
J
7
;:1E"
3&
0G
'b *" ,"VF+;T(3+4 b
639Ao
CT
b
6 UY*-$&9
4$
62
C
4$ ,ko
3&
L^3*-
6,J208S`"K
"
0G*3J
9
3*-P; 6)& & ; "+" *"6
C
d) M& 6)&
S
(+ *"6
E63*"V ," ,
+&ed
$,-6d)+&+6
C
,
$,
& 9:3;
,-
E
"*";
3& ?" +*- 9
6)*-d3&
r
C
(3!4$+&;+Y*-+4
$63&Z F
E
A
C
L
K
C
E
f
L
j
G
"
7
o
:
#
L
"
:
<
%
7
0
6
"
/
#
'
0
#
*
/
"
J
0
"
l:3
I"W
0/8/)0!
F
K
L
C
K
I
R:CF
L
I1A
C
P!A
K
P
I1C
K
R/
I
R
P
L.,0
H
LE
R
.
F z
#
o
/
[
o/
9
*"6)
ogqSc)s
6 o/
qc
s
TG
& ,06
3&$,"63 E6)*-V ,"
q1s /7H
. z
#
D/[
@9
*-6)
& w6q
oJsC[
;++&
"*34)(+ *639:o3qc
s$&l
6 & :q
o Ss+b
3&= E3V ,Y"
*-6)
F+&
C
,(u
[
"
6
u $[
^
u
[
uM)nV V4
$&edaqs
"6q8)gLtsc 2+4 ,q u_s
y
zo
J
o
[KAb
"
C
,pu
y
z
o
!
F
K
L
C
K
I
R:CF
L
I1A
C
P!A
K
P
I1C
K
R/
I
R
P
L.,0
H
LE
R
.
F "
u^Jo
# "
a
[
A2
'
!:M
|
¨ ' T
(
6
*
6
9
w
C
&
*
b
,
,
o
z
#
o
,
,
4
d
4
6
*
;
6
V
4
S
;
!"+
9`ZJq>o6sC[
A2
12& ;+
,
$&+,",-+&
$3429
63*6
C
*7V
C
*"VF6),-+, bW,
4$ E &W3*-
,-
C
?b
4$4Z
F
6)
""+Z
$+
+
%
3
3
>
E
Fd3 $$
"
+
$+
"0!A 3 T
(
6
*
6
9
w
C
&
*
b
,
,
o
z
#
o
,
,
4
d
4
6
*
;
6
V
4
S
;
!"+
9`ZJq>o6sC[
A2
12& ;+
,
$&+,",-+&
$3429
63*6
C
*7V
C
*"VF6),-+, bW,
4$ E &W3*-
,-
C
?b
4$4Z
F
6)
""+Z
$+
+
%
3
3
>
E
Fd3 $$
"
+
$+
"0!A 3 n
&
4
&
$
6
9
D
4
q
l
Y
¢
s
V
V
4
6
;
6
;
&
,
6
9
o
&
*"
W
+4$,
M& b]UY*-$&9
4$
62
C
4$po
&
6h()+*Wlc;$[0$,c6)
(
$6
C
,
"
!
gt
vg q
Q
O
s
'(
w
[
w
) +( !
$
!3"$3 +@ "3
-f
3!:M q
Q
O
s
) + 6
4
,
n
&
6
*
&
(
*
&
;
V
*
6
V
*
6
9
w
*
,
C
4
,
9
*
6
G
,
&
;
639
&6)&2S["*"(2$34:Y
Sf
C
"6) E63*"V ,"
,
6)&
c@*))(Qb
4$T +
[
-,.
F
K
L
C
K
I
R:CF
L
I1A
C
P!A
K
P
I1C
K
R/
I
R
P
L.,0
H
LE
R
.
F n
,
9
6
*
b
o
[
q
@
A
s
,
*
&
#
S
b
6
U
*
&
9
4
6
C
4
6
(
*
V
&
c0S
V
+4alb%flHY¢
jA[
abD%q>l,sk[`
"
b
[
<
Y]=
4$
[
w
®
FR"
& 6)*-
E3V9
*-6) l
6Y[Y/^))n',Y*" ,
C
4,'9
*-6) *q8)\B}s+b
l%
0G K'&J06!9!o
q:Ug!mbUY*"$&29
+4$
6
C
4$ ,ko
_
¤Ql
b
$;<
;+6)
$,-6) E63*"V ;'b
o6h()+*c" )
8
)
8
4
d
*
;
;
4
6
,
C
*
l
s
*
6
C
4
,
J
(
4
d
*
;
;
4
6
,
C
*
l
s
*
6
C
4
,
J
(
q
Q
Ms
o
[
q
@
^
]
(A
s
9
Z
[
A
b
b=@
[
A
b
o
[
qUA
As
9
Z[
A
"
a%
"
p
[$"3E)- "
f
33 7+F+ q
Q
s b
l
ª
b
b
*
l
S
,
6
6
*
V
,
V
6
9
o
V
&
,
6
&
q
6
l%ª
^
xs
6)*
q-
62
l%ª
^
a
«s+b*"+,-V
; "() 4 3
MC
S/
C*(
=>+
E=+;*
K
,*
99
RG
G5",g
68¬
F
K
L
L
R
I
R
L
H
F
G
"
7
o
I
:
"
1
I
:
:
1
7
"
6
J
7
6
1
H
0
/
Q
0
'
6
:
/
w
q
s
[
ay%z|{
J
~
:+ /#
6
G:+
6:+
7
Z/q
oJs
[
A
3
I"K
%
t
;
F
K
L
L
R
I
R
L
H
F
G
"
7
o
I
:
"
1
I
:
:
1
7
"
6
J
7
6
1
H
0
/
Q
0
'
6
:
/
w
q
s
[
ay%z|{
J
~
:+ /#
6
G:+
6:+
7
Z/q
oJs
[
A
3
I"K
%
t
;
w
q
s
[
y
z
{
J
y
~
I
"
"
[
q
s
3
2
)- I
"
"
[
q
s
3
2
)- 0
0
3
6
6
,
q
`
z
s
S
*
6
6
6
9
&
V
C
l
_
[
l
q
s
T
&
o4[;o
4
b
,"6,@!&=,"6)
6)*"V $,- b
+V
&
6h()+*_l
_
b
9
*"6)
o
"6ao
$f&
V
3*8$;
C
4
!* b6o/[;o
9
6)*3*"
*"3*- {¬
c@Tc
*-$&ed $,"63 E6)*-V ,"
o/ . 9
6
*
;
"
"
S
*
G
6
(
*
Y
[
Y
^
2gt6
T'
F3)
f
"
!+
3
$
+" 9
6
*
;
"
"
S
*
G
6
(
*
Y
[
Y
^
t6
'
) 9
6
*
;
"
"
S
*
G
6
(
*
Y
[
Y
^
2gt6
T'
F3)
f
"
!+
3
$
+" q
Q
N
s
X
&
&
Y
S
,
C
,
V
;
6
9
&
,
6
&
"
6
9
l
b
b
,
,
Tc +&
+]
M
5
q
Q
N
s
X
&
&
Y
S
,
C
,
V
;
6
9
&
,
6
&
"
6
9
l
b
b
,
,
Tc +&
+]
M
5 *
q
&
s
H
[
,
/.-
U0/2143
[
q
zP
s
q
s
^
c)
$
c-$ (
6
! f$ +3 I3
2gt
*
q
Q
§
s
,
6
(
6
C
,
,
&
;
. z
#
^
,
Y
S
4
&
*
b
&
q
Q
N
s
,
6
*
6
4
4
*
)gOaN
639f
/QMjU
MC4 M/
C*A =>+S`
+^E
!+K +/,*8
KS:M
8(K
8
6
*
q
Q
§
s
,
6
(
6
C
,
,
&
;
.
F
K
L
C
K
I
R:CF
L
I1A
C
P!A
K
P
I1C
K
R/
I
R
P
L.,0
H
LE
R
.
F
F
K
L
L
R
I
R
L
H
F
V
w
q
s
[
y
z
{
J
~
7
I
"
w
q
s
[
y
z
{
2
J~
2
3
1
(
:6
!
F
K
L
L
R
I
R
L
H
F
V
w
q
s
[
y
z
{
J
~
7
I
"
w
q
s
[
y
z
{
2
J~
2
3
2
=T
1Y03P$-)E3" "
3
(
W
:6
!
F
K
L
C
K
I
R:CF
L
I1A
C
P!A
K
P
I1C
K
R/
I
R
P
L.,0
H
LE
R
.
F /
10
/N1±Y:b
N
[
A
R
F
P
& pd)*-6
C
V6h()+*Y
:$[03; ",
6)& c
" *"6
C
d)
,
C
,8
C
"$6)& , H
-ZC3A5Zx+
¬¬_6
2
q
h
s
[
q
4
q
h
s
s
c
4
[
,
. /
10
Tk
!?T
")
3}3
37 4
q
h
s
[
N
h
J
±
X
l
&
G
&
,
6
&
6
9
Y
¢
b
&
9
6
*
4
+
b
;
6
6
,
&
$,-6) E63*"V ," 4:w
H
l\z#
lW_F6391Y
S
!4¨d)
*3,Yb
$;< 3#!+,
d $Qd)*"3
q
Q
\B}s
c
z
#
Y
¢
V
#
l
489
9
4:w:9
c
z
#
Y¢1;V
#
l
_
+)
!)!A' "Z
$ -$
W
3
'E q
Q
B
s ;
6
C
(
*
¥
_
,
V
*
¥
2
b
&
4
(
*
;
4
*
*
6
b
,
q
E6
/s
. z#
{
2
q8
6
2
s
<)Y$=4:w
b
@ E
V
C
,- 9
6)*-b
3*-UY*"&9
+4
E6
C
4o£[
qD@/EAs'9
*"6)
l
6
E6
C
4o
2
[
q @
2
9
EA
2
9
s
63&
l
_
?'6hb
4
w
,
&
6
C
&
r
C
q
d
(
&
[
f
l
H
Y
¢
j
b
*
*
;
6
;
,
6
9
4
w
s
b
C
;<
3*"3; "+*-$,-"$;MVF6)4
& 6)
!4
639o
2
b
4$4
F
$& V
& &WR639
"
;< 6)$;
! Qb
C
6 q
Q2gOts
$f&9:3;T
H
MC
8M/
):M
J]a!
gQ
J]a!
F
K
L
C
K
I
R:CF
L
I1A
C
P!A
K
P
I1C
K
R/
I
R
P
L.,0
H
LE
R
.
F 0
0
3
]
G
&
4
w
6
&
,
6
6
*
V
,
6
9
l
b
l
_
4
w
q
s
[
3& pV
&
+&
"f po
2
4[4:w
oR639
*"$&dc 6)
6) E63*"V ,"
,+Gn'V V 4
&ed
4:wE6q8)gLts
b
(d3
1
1
1 A
[
4
w
u
y
z
4
w
o
u
J
4
w
o
[
upy
z
q
o
2
4As
u
J
q
o
2
4As
[
upy
z
o
2
u
J
o
2
' q
Q
s
]
&
G
b
&
6
,
;
*
;
6
;
&
\
q
o
s
[
,
d
&
q
~
s
Y
ª
"+*- E& +,
"
3
,"6)4
C
"+*-
639::w;
Dqs
]=
& + ,-6)
YV *" V
3*"!6)& ,+
6)*
&
" @34¨d)
*!$;Y; 4$6),
C
*"
l
639Alkb "
020G ^"&#`"*7("K K'56 /:+
7
q:,-+fehQ j
," ;
)gOts
,c V
&+
!, #q
sC[
T
^
^
^
^
-)F+-"$ '!"3 $
,
;
*
C
;
4
V
*
6
V
*
,
*
H
! q
Q
§s
q
s,[
q
s
q
s
)c
!<#
$W[ !""e%
h3+
/) q
Q
§
s 9
6
*
;
"
"
S
*
G
6
(
*
Y
[
Y
^
2gt6
T'
F3)
f
"
!+
3
$
+ 9
6
*
;
"
"
S
*
G
6
(
*
Y
[
Y
^
2gt6
T'
F3)
f
"
!+
3
$
+" z
#
^
,
Y
S
4
&
*
b
&
q
Q
N
s
,
6
*
6
4
4
*
)gOaN
639f
/QMjU
MC4 M/
C*A =>+S`
+^E
!+K +/,*8
KS:M
8(K
8
6
F
7
K
L
L
R
I
R
L
H
F
G
"
7
l
I
:
"
#
"
S
"
"
0
"
Y
<
:
#
/
"
7
&
"
:
9
6
7
"
%
#"6 '
"K =J*690G /:"/QY
%
JK*
KJ(H=:1E"
0
lBJ*7:[4/,"
*
/#`"K
7DI"
'
:KHu
H
;
. z
#
;
^
S"6, +"K
UQ
7 I"
=
0>K"K
6 *
J
0
Wl:3%<
687DI
*
q+&]s>:GJ
6 q
Q aNtsX<K
"
I=:> +"
®q>u
3
sC[
w
®
qxq
zPMs>=5?A@
3
*
q &]s«s
F
7
K
L
L
R
I
R
L
H
F
G
"
7
l
I
:
"
#
"
S
"
"
0
"
Y
<
:
#
/
"
7
&
"
:
9
6
7
"
%
#"6 '
"K =J*690G /:"/QY
%
JK*
KJ(H=:1E"
0
lBJ*7:[4/,"
*
/#`"K
7DI"
'
:KHu
H
;
. z
#
;
^
S"6, +"K
UQ
7 I"
=
0>K"K
6 *
J
0
Wl:3%<
687DI
*
q+&]s>:GJ
6 q
Q aNtsX<K
"
I=:> +"
>
C
x
M>5A
]«
®
q
u
3
s
[
w
®
q
q
z
s
=
? @
3
*
q
&
s
s
! 9
6
*
;
"
"
S
*
G
6
(
*
Y
[
Y
^
2gt6
T'
F3)
f
"
!+
3
$
+" !$
# 6
&
6
*
&
b
G
V
*
,
,
6
&
r
C
4
,
q
s
^
T
*
9
6
*
b
3&
q
Q2gNts¦b
«D>
%
£x
M
]« 6
&
6
*
&
b
G
V
*
,
,
6
&
r
C
4
,
q
s
^
T
*
9
6
*
b
3&
q
Q2gNts¦b
«D>
%
£x
M
]« T
®
q
u
3
s
[
q
s
^
[
q
q
zP
s
*
q
&
s
s
' q
Q
A
s
;
4
4
q
`
z
s
S
V
6
b
*
*
,
C
,
6
4
¢
9
6
*
{
c
$,c +V
&
3,
"
C
& ¨r
C
P+4+
+&
6391Y
"
!0,!"$,
V
+,c P; 6)&ed)*
C
+&;+
q
Q
A
s
;
4
4
q
`
z
s
S
V
6
b
*
*
,
C
,
6
4
¢
9
6
*
{
c
$,c +V
&
3,
"
C
& ¨r
C
P+4+
+&
6391Y
"
!0,!"$,
V
+,c P; 6)&ed)*
C
+&;+
D+ {
¥
{
^
/
^
/
q-
62
¥
s
+ +
P$
3-f''3" b
*
<
[
d
¥
$
,
G
&
4
&
*
6
*
*
*
4
,
&
,
639
[
¥MV *" E!
$[9:~
$,
_d)+&+* 6)*
6!9tb2b
34$,-6@b
*->
Y9
63*
!& 63"
>
md)& 6)*-+,
,«d3&:q>~+sT!Tc +&9
63*
fb
6 ; 6)V *-$
+4$ E &
,
{
3& ~Y639Acb
9
6)44$6hb
$&dR*" ;+V *"6
;+f
4
b
6)4$,+H
>
> {
~
~
{
[ q
zPMs
=
=
,«d)&1qS{;s
=
,«d)&Gq>~+s
=
Z
)0E -2! 9
6
*
;
"
"
S
*
G
6
(
*
Y
[
Y
^
2gt6
T'
F3)
f
"
!+
3
$
+" )e/M1c +)-+
Yg
3
gM
)0 1
f
j
O
9
6
*
V
*
6
6
9
b
6
*
f
>
j
T
6
*
,
L
O
&
>
B
9
6
*
d
&
*
4
S
)(+!6)& 6E3*-
"*3*8 E9
C
&; 6)&V
+4 ,W
}
F
A
C
L
K
C
E
F
J
"
"
:
/
J
0
f
O
j
3
<
6
7
I
0
7
:
7
6
0
:
J
"
0
"
<
7
I
"
:
J
0
/
*
7
"
7
"K
'
~0
k:
M
w6qs%6,JW~[
\
q
o6s
¥[Z
687DI
>6C
@M
F
A
C
L
K
C
E
F
J
"
"
:
/
J
0
f
O
j
3
<
6
7
I
0
7
:
7
6
0
:
J
"
0
"
<
7
I
"
:
J
0
/
*
7
"
7
"K
'
~0
k:
M
w6qs%6,JW~[
\
q
o6s
¥[Z
687DI
>6C
@M
\
q
o
s
[
q
z
s
"
q
A
s
"$)6
Z+
3" +8
$- 0
0
3
]
6
C
*
,
*
;
6
&
b
¥
[
q
h
s
b
6
*
b
,
b
*
V
4
;
h
h
_
[
h
J
)WTc &
&
H
[
;
l
eo43q
;Js[
A`
$,'
fb
6!Sf$
+& ,-$6)&
!4GY
S[,"V
!;+
,-3
4$
C
& +*Wu][
"eb 3& q8
s
T
®
q
u
3
s
[
~
h
7
-/3="
!"" -"$)Y
3
$!
= T q
s
7 T
6
V
*
6
(
,
,
*
6
&
b
b
;
4
;
C
4
*
&
&
&
+
*
&
!& & +* CTc dV
634
& 6)
34
3%
e
v
3Z«x
T
6
V
*
6
(
,
,
*
6
&
b
b
;
4
;
C
4
*
&
&
&
+
*
&
!& & +* CTc dV
634
& 6)
34
3%
e
v
3Z«x
A
o?4
q
s
[
^
a
J
q @
¤
A
s
^
J
q
! 9
6
*
;
"
"
S
*
G
6
(
*
Y
[
Y
^
2gt6
T'
F3)
f
"
!+
3
$
+" 0
0
3
X
*
G
6
9
u
3
b
*
,
,
6
9
&
Tc +&6)&
d6)&P 3& b 0
0
3
X
*
G
6
9
u
3
b
*
,
,
6
9
&
Tc +&6)&
d6)&P 3& b #q>u
s
[
q
sC[
Mq _s
q
5
s
[
®q>u
3
s
q
5
s¦
#
A
[
®
q
u
3
s
q
s
"+-")? 9
6
*
;
"
"
S
*
G
6
(
*
Y
[
Y
^
2gt6
T'
F3)
f
"
!+
3
$
+" q
h
s
b
[
@
b
y
[
A
b
&
9
*
6
o
4
[
o
4
o
4
[
o
4
o
4
b
d *"()
d*-+;
C
*","6)& ,
3Z
¨
¨
>
¨ T
&
/
[
! q
h
s
b
[
@
b
y
[
A
b
&
9
*
6
o
4
[
o
4
o
4
[
o
4
o
4
b
d *"()
d*-+;
C
*","6)& ,
3Z
¨
¨
>
¨
]
[
! 9
6
*
;
"
"
S
*
G
6
(
*
Y
[
Y
^
2gt6
T'
F3)
f
"
!+
3
$
+" q
h
s
s
¤+A
s
r
C
34,
/
1
3
q8
z
)s+b
,"6
*
q+&]sC[
!3q8h)sx¤+A
0T9
+*-*"$&d@6q
Q2gLts+b
b
()
q
Qs
®q>u
3
sC[
q
!3qhZs«¤
As
A
o?4
q
s
[
^
a
J
q @
¤
A
s
^
J
q
! q
h
s
s
¤+A
s
8
)+
"
+]C
38)x
0T
+-"$@
2gt
r
C
4
,
/
1
3
q
s
b
,
6
*
q
&
s
[
! q
h
s
¤
A
9
*
*
&
d
6
q
Q
L
s
b
b
(
q
Qs
®q>u
3
sC[
q
!3qhZs«¤
As
q
Q
s
®
q
u
3
s
[
q
! q
h
s
¤
A
s
q
Q
s
£
3Z« ³ 12$&;+
! q
h
s
Y
¢
b
,c& 6)*-
q! q
h
s
s
,
x 12$&;+
! q
h
s
Y
¢
b
,c& 6)*-
q! q
h
s
s
,
x qUOts
w
®
q
! q
h
s
s
[
®
¯
®
q
! q
h
s
s
Z
[
! 9
6
*
;
"
"
S
*
G
6
(
*
Y
[
Y
^
2gt6
T'
F3)
f
"
!+
3
$
+" q
h
^
/
^
/
s
Z
[
4
¢
Z
[
4
}
3[
S+T
)
$$8M¦1
¦1U
2+ q
O
s
,
¥
Z
[
q
~
s
6
&
&
d
q
s
b
q
Q
s
b
q
O
s
4
,
,
¥
Z
[
q
~
s
6
&
&
d
q
s
b
q
Q
s
b
q
O
s
4
,
,
¥
Z
[
q
~
s
6
&
&
d
q
s
b
q
Q
s
b
q
O
s
4
, q:B}s
~
h
h
~
[
q
As
7Q) " +
"
2ht¦3
3W$e
_ q
B
s T
6
d
*
b
q
Q
A
s
b
&
#
&
d
d
~
[
&
6
;
;
6
C
&
b
b
V
&
£qAs
[#q
zPMs
"
,xd)&:q>~+s
' T
6
d
*
b
q
Q
A
s
b
&
#
&
d
d
~
[
&
6
;
;
6
C
&
b
b
V
&
£qAs
[#q
zPMs
"
,xd)&:q>~+s
' ]
;
6
&
;
4
C
,
,
;
6
&
b
,
6
*
,
C
4
,
6
C
*
6
9
G
4
V
63,","
4$ d)*-+P$&
@
*-6)
&
C
,
*!;+({E639Ao6¤l
#
/
+
D
(
&
o
[
q
@
A
s
b
b
b
*
V
6
4
&
6
4
o
4
, q
Q
/Qs
o
4
[
/
5
5;y
m
m
al
c +
¨
3
+
/
3E
"3 q
Q
Q
s T
&
/
[
! 9
6
*
;
"
"
S
*
G
6
(
*
Y
[
Y
^
2gt6
T'
F3)
f
"
!+
3
$
+" q
h
s
^
J
@
^
J0A
^
a
;y
[
!3qhZs
¨
J
@
^
¨
J
A
^
a
¨
;y
M
[
R8!¨)
"
3-
3"
"- h
"
!= b
*
[
A
9
Z
A
$
,
,
*
d
9
6
*
b
*
6
,
6
b
,
&
$,-6)
3*-$;
TG2V *-+,",-$6)&
6!9Zb
¨d)
`
1z
Y&9@
3&
Aq
b
Eb
+md)
,`,z
Y3&
`y%z^b*"+,-V
; "() 4 s+bF3&
"
!
(
q
Q
hOts
y
[
A
^
a
/
^
a
/
¨
y
[
A
^a
/
^(a
/
/
5
5
@
^(a
A
^(a
]e^(a
^(]
/ q
Q
O
s q
Q
O
s 6
4
F
K
L
L
R
I
R
L
H
J
"E"
f
B
j
3
GC"
7
{
[
/
5
5
"
y
{
h
K"
7 I"
=
0
K"K
6 *
J
7
;:1E"
0
oJ¤QlJ<3o[ qD@/EAs 3
:
G
+K
=,*%
K
9
)
)=
+
"
9
P
K=*9G
) q
s
=
0
"
"
<
/
"
7
Y
y
"
7
I
"
*
6
Y
*
"
Y
*
:
#
:
7
6
1
"
O
7
"
J
6
0
0
Y
6
l:3
I"K
7
{
"
y
[
T
*
®
a
®
q
w
®
a
q
A
s
s
=>+ q
s
=
0
0
#
#
<
"
I
:
"
q
s
=
0
0
#
#
<
"
I
:
"
{
"
/
y
[
z
qD@
s
T
*
w
®
q
Z
q
o
s
^
^
^
a
/
]
s
@
[
A
{[
<
{[
A
@[
A
)
8
x
³
³ 0
0
3
q
s
r
C
&
d
;
6
;
&
,
6
9
y
"
&
q
L
s
b
b
V
&
k
J
z
{
"
y
"
y
"
J
\
q
o
s
"
y
"
[
A
¨
03
>6
"h
$+
2 ]
(
4
C
,
9
6
*
y
&
\
q
o
s
V
*
6
(
q
Q
O
s
&
q
Q
s
b
b
,"6)4()
9
6)*k{
"
y
b b
$;<
$+4 ,
P,8<!"+ *"+,
C
4+
:8C
P
)
R
)
$
2"$+
pc3
W3)3)
3+? " q
s
{
[
A
9
6
*
@
[
A
,
6
(
6
C
,
b
,
&
;
u
y
&
o
&
(
6
4
(
6
&
4
(
&
*
,
$&
b
b
+*-
3,o/u
$,P3&
)62e VF6)4 2&6) E$34
&
9{
[
A2X
@
[
A
qUQ2aQs+b
,
C
E; +,M6
V *-6h()?
3,",-+*-"$6)&
9
63*&@|[
63*
r
C
(3!4$+&
"4 b
Z[
A
]=d r
C
!"d" d;+6
;++&
,0639
y
"c$&q
)gLts+b b
;< d3() ,
Z
J z
{
"
/
y
"
/
y
"
J
\
q
o
s
"
y
"
[
A
3
<! 9
6
*
;
"
"
S
*
G
6
(
*
Y
[
Y
^
2gt6
T'
F3)
f
"
!+
3
$
+" eM$
M!++
'"
! q
s
4
6
,
9
6
*
C
4
,
,
4
*
6
q
Q
B
s
b
C
6
9
&
;
*
,
&
d
;
6
V
4
G
b
Pb
63*"#3
6
C
'9
6)*'6! *;+6
; $+&
",
{639
"
*"63
&
C
,
*"3;+_{
Zn4,"6eb
q
Q2
B}sq:
s
$,0E,-V
;+
!4
;+3,"@639Wf
hO jgTc
>2b
b
+*-
3,q
Q2
B}sq:$
s
3,WV
*",8
+&$d)(3+&$&f
BQjU F
L
I
L
H
N
w
F
V
&
d
,
&
d
&
&
6
6
&
,
6
9
4
,
,
;
6
&
b
b
,
#
;
6
b
6
"+*- E& :
M
w6qsd&
V *!; ;+!
+;+34$4
_V
& $&ed ?;< 3*3;T *"$,8;
V
634
& 6)
346390
*-6)
F+&
C
,
6393&
+44$$V2$;
;
C
*-()6h() *EV & "V
+4l
3
6
C
&
,
6_V
& $&edP &
C
*
639
,-6)4
C
$63& ,
6!9
R V & $&edR r
C
!"$6)&?6h(3+*
lcTc ,',
(3+*8 ,-$
V 4$Y" +63*" "$;+34$4 ?3&
34,"6
34¨d36)*"
$;+34$4 bWV *"6h(
$+
l
,Y& 63
"626 4
3*xd)3%$f&
M! F
L
I
L
H
N
w
F 00
f T2eE" R q
O
O
s 9
6
*
C
&
#
&
6
b
&
,
{
/
{
"
y
b
9
6
*
>
Z
>
Q
S
&
G
&
d
;
6
9
S
V
;++&
,
639
{
," 6/b
,
!
3
d
$3
Ugt
$c-+
3
"
Z
S
r
C
6
&
&
q
O
O
s
,
*
C
&
&
b
b
*
$
Z
[
Q
z
Q
z
O
J
9
,
(
&
b
Z
[
Q
g
Q
z
Q
J
9
$,c6
!
"+E3 $e -
-"+
$<
) "-"
3
K Z
[
Q
z
Q
z
O
J
9
,
(
&
b
Z
[
Q
g
Q
z
Q
J
9
$,c6
! F
L
I
L
H
N
w
F ," & ;+M639
," EV4$9
&ed !,",
C
EV"$6)&,qU3,
!
d
$&qUO2
§sxs+bZ" M;
34;
C
4$!6)&
639g
wq8s$,
C
;<
6)*"
&W(36)4(3+Z
))(Qb
"
r
C
!"$6)&
q
)aLs+b Ug!mb
M
6x q
O
s
y
"
z
o
"
J
\
q
o
s
o
¢
[
A
$0
3!$+
0
" R-
8+
3
$ +3
!"$) 0 q
O
s
$0
,
r
C
(
4
&
b
,
,
6
9
4
&
*
r
C
6
&
,
9
6
*
f
¤
Q
j
J
C
&
S
#W& 6hb
&;+6
; $+&
",
{: Y
6!9A{[
{mh
,"; *"$
F+
F+4$6hbd
]=*"" /
5
5
"
U
Z
?¨h
q
?: Y:
"
[KMs
!")_[ZZ@!0"
$
3,[ 9
6
*
6
&
;
d
&
*
6
*
¥
Z
q
h
s
6
9
4
¥
Z
]
l
,
&
q
Q2/Qs¦b1qUO2Ms
F+; 6)
+, qUO
aQs
y
"
z
5
"
y
{
E5;y
¨
]
"
JI\
q
o6s
5
"
E5;y
?#
¨
[
A
'3"
!c$
3 M"
"$$
e)3 M"U2M
$ q
O
Q
s ? 6
4
9
&
,
,
(
,
4
"
b
&
,
6
q
O
s
,
r
C
(
4
&
b
"
" d,-
,-"+
639*
EJ
d r
C
$63& ,
qUO
gOts
z
/
5
5
"
y
{#
¨
"
JI\q>o6s
y
5
5
"
?
¨
[
z
Z
[
Q
A
Z
Q
)
W h
)
0
_!
³
9
6
*
;
"
"
S
*
G
6
(
*
Y
[
Y
^
2gt6
T'
F3)
f
"
!+
3
$
+" 1
6
4
(
&
d
9
6
*
{
"
/
y
&
#
&
d
&
6
;
;
6
C
&
(
( A
^
a
/
^
a
/
[
A
^
/
^
/
[
q
A
s
p
W ,
&
;
,
6
b
b
V
*
,
V
&
,
&
;
,
6
b
b
V
*
,
V
&
{
"
/
y
[zA
^
/
^
a
/
/
5
5
"
A
^
a
]
^
a
^
]
/
(
e X
)@H
[
^
^
a
J
^
a
]
^
a
^(]
F?
TG2VF6)& &WE639
S["
"+*-
$&
"
3
F6/(3R,
C
6!9MA
k[BZ/q
o6s¦bI!&
4$T )_
[
fmq`!"pz|`Qs q`y!z
s7J
j¨`
F@"
TG2VF6)& +&
'639
(
( T
*
w
®
q
Z/q>o6s
^
^
^
a
/
]
s%[
z
/
5
"
Z/q>o6s
^
^
^
a
/
]
^
A
>
?'63""
! )_
,E
V
& ^
W
" ,"3 E9
6)*"
C
4
9
6)*
3;<
A
b
3&
,
V
*"62 ;qI
62v`!"Qs
b
dV
*"62
7gn
,8*!¨d)
"9
63*-b
3*"
;+34$;
C
4
!"$6)&*" (3
34,
d; 6)&ed)*
C
+& ;
)
-
2
^+
_
y
]
"
q
6
`
"
z
s
$<
$ $ 0
!"" -"$)
$
3"
"
_
y
]
"
q
6
`
"
z
s
$<
$ $ 0
!"" -"$)
(
4
9
6
*
A
>
b
b
;
4
,
,
,
*
6
&
&
(
b
6
9
6
&
,
,
639*
'
e
W
t
t¦
J '
J
F
C
E
K
F
q
s
X
#
q
N
s
&
q
A
s
b
9
6
*
C
4
q
Q
s
9
6
*
\
q
o
s
6)4 ,c$&
C
;< d)*"+! *d)+&+*!4$f Qb ," f
hOj1Tc
O)!¡
C
*
V *"6
639
9
6)4$46/b
,
+,-,"+&
"
344 0,"$P!&
C
g,b2
G; +V
9
6)*"
C
,"
639I" ' 6
6)*"
T+*- E&
3&
b
b
$;< *" V 4
!;++,c" P3*«d
C
E &W%/)02143
1*687
3
VI
Q3)
8
}¦
e
q
s
4
6
,
9
6
*
C
4
,
,
4
*
6
q
Q
B
s
b
C
6
9
&
;
*
,
&
d
;
6
V
4
G
b
Pb
63*"#3
6
C
'9
6)*'6! *;+6
; $+&
",
{639
"
*"63
&
C
,
*"3;+_{
Zn4,"6eb
q
Q2
B}sq:
s
$,0E,-V
;+
!4
;+3,"@639Wf
hO jgTc
>2b
b
+*-
3,q
Q2
B}sq:$
s
3,WV
*",8
+&$d)(3+&$&f
BQjU q
s
4
6
,
9
6
*
C
4
,
,
4
*
6
q
Q
B
s
b
C
6
9
&
;
*
,
&
d
;
6
V
4
G
b
Pb
63*"#3
6
C
'9
6)*'6! *;+6
; $+&
",
{639
"
*"63
&
C
,
*"3;+_{
Zn4,"6eb
q
Q2
B}sq:
s
$,0E,-V
;+
!4
;+3,"@639Wf
hO jgTc
>2b
b
+*-
3,q
Q2
B}sq:$
s
3,WV
*",8
+&$d)(3+&$&f
BQjU F
L
I
L
H
N
w
F q
{
s
[
\
q
o
s
w
®x¯
q
q
o
s
s
" (\e
+
2g
Y ) -
++Q
-)F+ q
O
>
s
" (\e ,
f
j
X
>
Q
n
,
;
6
&
,
r
C
&
;
b
*
6
&
C
,
*
;
{
6
9
o
,
9
C
4
4
"+*- E& +
*-6
C
d)
q>o6s9l[&Y¢;b7,-$& ;
" +&= d]{
>^
¤)Q[
<;¤)QDb
3& a{
, T+*- E& +
W ",'*-+,-$
C
R;+4
!,",
!3qS{Ds
E6
C
46¥
)¡
& @63 *
3& 6b (!,","d&W(!3*-
3&
c,"!,xV
,0" ptUY+4¨d)&;+63&ed)*
C
+& ;
U
gt
£
6
J
-
2
D+ q
O
s
q
o
s
@
q
o
s
q
6
¥
s
+-S
J'$"
!3
3
)"E3$,+
$" q
O
s
+-S b
*
@
q
o
s
,
(
4
C
6
9
&
6
*
4
(
,
&
,
&
,
*
,
6
9
b
d
`
z
Y6)&oq:,-+f
NjF," ; +c/Qd9
6)*
T<34$,s
D
(3+&E" #W& 6hb
&?*-+;
C
*",-$6)& 9
63*
@
q
/)02143
1*68793Zq:gLts«s¦bb
(d)Tc
9
6)44$6hb
$&edR,"$
V 4YV *"6
;+
C
*-3
,
MC
8MS/
C*! F
L
I
L
H
N
w
F
&
©
(
&
,
,
9
6
*
<
q
,
;
&
,
&
d
9
*
6
q
L
s
s
T
:
J
J
"
6
G:+
6:+
7
q>o6s
H
[©
q
o6s
639Ao, $,
V
+,
3>;%
6
x
>6x+
&
©
(
&
,
,
9
6
*
<
q
,
;
&
,
&
d
9
*
6
q
L
s
s
T
:
J
J
"
6
G:+
6:+
7
q>o6s
H
[©
q
o6s
639Ao, $,
V
+,
3>;%
6
x
>6x+ qUO
a>
s
! F
L
I
L
H
N
w
F
+
: ³
*
&
6
&
6
9
;
6
;
&
,
Y
6
9
¥
Z
q
h
s
q
b
;
*
$& +VF+& +&
6!9CoJs*! P "
$
$3
37"
¨
a
$< M +F+ )6*
*
&
6
&
6
9
;
6
;
&
,
Y
6
9
¥
Z
q
h
s
q
b
;
*
$& +VF+& +&
6!9CoJs*! P "
$
$3
37"
¨
a
$< M +F+ )6* s
*
&
6
&
6
9
l
q
b
;
6
V
&
6
&
o
s
! Y")
)
3
@-
3
! 8
-
3%
) ! $$
3
$3
*
&
6
&
6
9
l
q
b
;
6
V
&
6
&
o
s
! Y")
)
3
@-
3
! 8
-
3%
) ! F
L
I
L
H
N
w
F
e="
&
;
*
6
&
C
,
*
;
{
q
o
s
c
6
9
o
¤
Y
¢
,
*
&
*
6
C
d
{
\
®x¯Dq
oJs
)@
q-
62
¥Ds
3& d
{
>
<;¤)Q
?'63""
! b
3V
3*8E9
*-6)
*3,"$&d
"6
`hS[
V
6hb
+*-,q:Ug!mbc!V V 4
&ed="
*"6)
F+&
C
,
6!9Y6s+bI" Y*" ;
C
*-,"6)& 9
6)*
@
,=/
6
"
:+
3&
+3,- E6
T(!34
C
3 ? 6
b
V
*
9
*
6
*
,
&
d
6
`
S
V
6
b
*
,
q
b
V
V
4
&
d
*"6)
F+&
C
,
6!9Y6s+bI" Y*" ;
C
*-,"6)& 9
6)*
@
,=/
6
"
:+
3&
+3,- E6
T(!34
C
3 F
@
E
. C
F
X
`
[
Q
b
¥
q
h
s
[
h
J
h
J
b
&
4
o
U
*
&
9
4
E6
C
4R6h() *)Y¢ d3() &
W |qD@/EAsZ[
q8hk
MsT@]
*- d
3*-
r
C
3&
"+,)h
3&
b
4$#!M" 6),-
"69
6)44$6hbpb
3,P+4$ E &
,P639!Y¢
Tc +&
@
/
[
b
@
[&hb
@
y
[hWy7J
Qb?@
[
Ab2
C
,
g
®«¯;q8s%[
ay
J|¥Jq8hZsT
12$
$4$3*"4 bFb
d) P9
6)*>L
[ qD@/EAs
[ qhk«hZs
H8@
/
[
bC@
[
h(b
@
y
[&h
y
b F
@
E
. F
L
I
L
H
N
w
F $$
3
$
q
s
,
6
4
C
6
&
6
9
*
&
d
C
4
*
,
,
6
9
f
¤
Q
j
J
4
&
*
r
C
6
&
,
6h() *Zlb b
*"
[
<) 1
[#fil
HQYj
}
f
!M
)$h
+-+"
<
"$
+
-2 +
-Q
$<
,
6
4
C
6
&
6
9
*
&
d
C
4
*
,
,
6
9
f
¤
Q
j
J
4
&
*
r
C
6
&
,
6h() *Zlb b
*"
[
<) 1
[#fil
HQYj
f
!M
)$h
+-+"
<
"$
+
-2 +
-Q
$<
,
6
4
C
6
&
6
9
*
&
d
C
4
*
,
,
6
9
f
¤
Q
j
J
4
&
*
r
C
6
&
,
6h() *Zlb b
*"
[
<) 1
[#fil
HQYj
f
!M
)$h
+-+"
<
"$
+
-2 +
-Q
$< q
O
B
s
$
&
b
9
6
4
4
6
b
,
b
b
,
;
*
C
;
,
V
4
*
V
*
6
;
C
*
b
b
;
6hb
T() *6)& 4 b
6)*"#W,093o$,cV
& 6h() *0" p)V *-$
ZV
+4eY¢
dY"
+? 2
$
h)
3g0[<
3"3 "+"-"$)
3
- X
o
U
*
&
9
4
6
C
4
6
(
*
l
b
6
9
c
S
;
*
;
*
,
;
¥
b
&
b
*
e
>6 o
¢
[
/
5
5;y
©=
q
o
s
aU!0+3
P" +! F
L
I
L
H
N
w
F
"+E3 $e -
-"+
$<
) "-"
3
K
*
&
&
d
,
,
q
b
;
;
6
&
,
,
,
6
9
f
"
y
j
J
r
C
6
&
,
s
,
*-
3&d
C
4
!*b
" = $Qd)6)& 34;+6
; $+&
",:
¨
y
b
[
f
G¤)Q j>bf
¤)Q jz^
<A2
3$
" 8
¨
3- ,
+"
"3
++-e
-+
"")
"))
3
*
&
&
d
,
,
q
b
;
;
6
&
,
,
,
6
9
f
"
y
j
J
r
C
6
&
,
s
,
*-
3&d
C
4
!*b
" = $Qd)6)& 34;+6
; $+&
",:
¨
y
b
[
f
G¤)Q j>bf
¤)Q jz^
<A2
$
" 8
¨
3- ,
+"
"3
++-e
-+
"")
"))
3 n
,
4
4
y
*
+
*
&
9
*
6
(
*
6
b
b
*
;
C
*
,
(
4
,
6
4
(
9
6
*
{
bc$&
+; *"
!,"$&d
6)*" *+vn4" 6
C
d3
,"6)4
C
6)& ,{Y
F+4$63&ed
6Y:b
;
34;
C
4$!6)& ,
C
,8
VF+*89
6)*"
+
$&
"
4
!*«d) * V
+4
lc T76
; 6)& ;+4
C
b
;
34;
C
4$!&edR" dV
6)4
& 6)
34Jg
wJqs
*"r
C
$*-+,+H
P "
$
$3
3
6 :Z
$<$
3< 3+
U23M*
*
&
6
&
6
9
\
q
o
s
Y
b
b
;
,
;
(
q
Q
s
! F
L
I
L
H
N
w
F D/E
K9
!!*$
)+,
!+KW
G F
+
K
L
L
R
I
R
L
H
F
G
"
7
o
[
q
@
A
s
"
:
6
"
/
#
'
0
#
*
/
"
0
"
Y
¢
3
=
0
"|H<H/*7)f
";j
H
[
h
^
zh< ^"
S
:+ ;#`"
#
:GJ
:+
"*/,"K'
"K
7%0
)Y¢<
:+ /#
#`"
9M
"
@
/
[K!<C@
[
@
<
_
^ $
Q @
[
z
f
"
z
j
@
;y
A
^
a
J
@
@
^
q
"
Q
s
GE
%
G+
+
>6
8)="
_
Q
I
"
7
I
" :
J
J
"
6
:
6
:
7
q
o
s
0
o
"
Y
*
:
/
J
@
<
<
[
f
Y
¢
H
Y
j
3
'
' +
")F+
"3+$/
J
!p6
"
$
" "
I
"
7
I
" :
J
J
"
6
:
6
:
7
q
o
s
0
o
"
Y
*
:
/
J
@
<
<
[
f
Y
¢
H
Y
j
3
'
' +
")F+
"3+$/
J
!p6
"
$
" "
&
;
*
6
&
C
,
*
;
{
q
o
s
c
6
9
o
¤
Y
¢
,
*
&
*
6
C
d
{
\
®x¯Dq
oJs
)@
q-
62
¥Ds
3& d
{
>
<;¤)Q
'3""
! 3
38E
-)
3"$
"
h[
h
+-:Ug!mc! F
L
I
L
H
N
w
F C
F
X
`
[
Q
b
¥
q
h
s
[
h
J
h
J
b
&
4
o
U
*
&
9
4
E6
C
4R6h() *)Y¢ d3() &
W |qD@/EAsZ[
q8hk
MsT@]
*- d
3*-
r
C
3&
"+,)h
3&
b
4$#!M" 6),-
"69
6)44$6hbpb
3,P+4$ E &
,P639!Y¢
Tc +&
@
/
[
b
@
[&hb
@
y
[hWy7J
Qb?@
[
Ab2
C
,
g
®«¯;q8s%[
ay
J|¥Jq8hZsT
/
k«Z
(
& 1
4
*
4
b
b
d
9
6
*
L
[
q
@
A
s
[
q
h
h
s
H
@
/
[
b
@
[
h
b
@
y
[
h
y
b
³
@
[
h
b
,
6
®
¯
q
s
[
y
z
h
J
¥
q
h
s
c ?:3TR ! >6d!3$"+
3 @
! @
[
h
b
,
6
®
¯
q
s
[
y
z
h
J
¥
q
h
s
c ?:3TR ! >6d!3$"+
3 @
! T
9
;
q
o
s
(
&
,
,
&
,
o
,
J
*
H
"
J
6
S
*
/
:
!
,
,
," E4
3*
,"md)& mV ;
3& ; d3,
,
C
VF+*-,"&ed
C
4$3*"f ?6397+44$$V2$;';
C
*8() ,f
LjU F
A
C
L
K
C
E
F
:
C*
KS F
A
C
L
K
C
E
F
q:
s
GC"*7
<
K"S"
+"K
3
I"K
<3]Aq¥Ds
[
`
]
q
^
^(]
s
<
q¥Ds
[
`
q
^
^(]
s
©]Cq¥Ds
[
q`y%z
`Qs q
^
^(]
J
s
©
q¥Ds
[
q`Zz^Msq
^
^]
J
Ms
$8B
G
)
=>+ q
s
G
"
7
<
"
"
"
3
I
"
AD "
"
3
I
"
<3]Aq¥Ds
[
`
]
q
^
^(]
s
<
q¥Ds
[
`
q
^
^(]
s
©]Cq¥Ds
[
q`y%z
`Qs q
^
^(]
J
s
©
q¥Ds
[
q`Zz^Msq
^
^]
J
Ms
=>+ q
$
sB=
0G
<
0)#
#
"
I=:> +"
3CD q
$
sB=
0G
<
0)#
#
"
I=:> +"
3CD <
]
q
¥
s
[
q
`
z
s
`
q
`
z
s
<
q¥Ds
[
`
qS`
z^Ms
©]%q¥Ds [
q`)z^Ms
y«`
©
q¥Ds [
q`)z^Ms
`
)"
@ -<! $"
")
-+
9
6
*
V
*
6
(
&
d
6
*
b
,
4
,
,
6
V
*
V
*
6
*
*
,
C
4
,
1
C
8MJ
C*
_K
D
*$
P
K=*9G
`
+^E F
K
L
L
R
I
R
L
H
F
G
"
7
l
[
Y
"
7
I
"
9
"
/
#
"
O
7
"
J
6
0
0
#
"
S
"
"
<
0
Y[
Y/^
:+ /#
H
l%ªWz
#
l%ª
:
'
*/
7
6
H
/
691
:"7.6, +"
1EI=:+ ;:1*7("K
6
3"43
<
J20G'
"H
0! F
K
L C
H
R
O
I
K
P
C
L
E
R
E
.
R
C
F ]
V
G
V
*
¥
6
9
c
6
9
d
*
<
&
;
6
&
,
*
U
*
&
9
4
6
C
4
,
o
6
(
*
l
[Y¢
c
6)*c,
C
;< o1b R
*"6)
F+&
C
,c*"3;+{/q
o6scK 3,' d)*-+
>#f
<D¤3Q j
5
C
C8D
6Q
/
6C#
;) q:B
Ms
]
q
¥
s
[
o
¤
l
d
{
q
o
s
[
f
<
¤
Q
j
q8¥Ds
[
o6¤Ql
d
{/q
o6sf
<;¤)Q j
8
$T
ADY3
DF
M- P3[$-)E3 q
B
s ]
9
C
*
*
4
]
q
¥
s
&
q
¥
s
,
6
9
l
S
,
6
6
*
V
,
;
4
,
,
,
$&
]Cq¥Ds¦b
q¥Ds¦b
*" ,"VF+; "(3+4 3vTc ! , b
]Cq8¥Ds q
q¥DsxsM,
" 63*"
,"V
!;+
639
]Cq¥Dsq
q¥Dsxs
C
& *M"
3;T$63&
639
l,ª
*"6
C
d3
Jq @J^As[
q
^
(@/
^
a
;As
E]=V
& 34$4
b
*"
<Cq¥Ds¦b3©%q8¥DsY9
63*d"
;
3*- $&
!4$"$ ,Y639
,"d,"T, !Tc PV *-$& ; $V
34
*" ,
C
4'6!97" $,c,-+; "$6)&$, H
1
BD}/#F F
A
C
L
K
C
E
F
:
C*
KS I
0
/
#
J
3
k q
(
s
6
&
,
*
;
6
C
(
d
*
J
% q
(
s
6
&
,
*
;
6
C
(
d
*
J
%
z
#
Y
ª
z
#
l
ª
z
#
l
ª
¤
Y
ª
z
#
9
9
9 9
9
9
z
#
Y
ª
z
#
l
ª
z
#
l
ª
¤
Y
ª
z#
3
3"-/
R3"
" %W
h
+@ 3+
")
:$8 9
9
9
z
#
Y
ª
z
#
l
ª
z
#
l
ª
¤
Y
ª
z
#
+3
3"-/
R3"
" %W
h
+@ 3+
")
:$ b
*
(
*
;
4
*
*
6
b
,
*
"
S
V
6
b
*
V
,
*
6
q
s
b
*
d
3*"*-6hb
,c
i- ; ()b
,"6
e
> Y
ª
¤
q
Y
ª
s
TU
z
#
l
ª
¤
q
l
ª
s
3$)-
)P)- +F q
s
Y
ª
¤
q
Y
ª
s
TU
z
#
l
ª
¤
q
l
ª
s
? d-
33P$ EE3
3$)-
)P)- +F
,
&
#
4
6
d
*
6
C
V
,
(
6
*
*
@
Z
d/K
3-Y3,
,
+
-+ q
(
s
X
&
6
b
;
4
,
,
6
9
±
l
ª
C
&
*
q
s
*
V
*
,
&
±
/
Y
ª
Tc +*-?3*-EV*"+; $,-+4 q`_zs«¤G@
4$ E &W",
639,YJªEb
"
±
/
q8YJªMs
b73&
,"P3*-@!4$,"6
" d+4$ E &
,
6391YJªPb
± |q>l%ªs
[
$ EQd)QqgsT
'
1
M
e
t F
-
L
K
L
. . I
0
/
#
J
3
k K
0
<
6
7
I
0
7
:
7
6
0
:
#
:
J
J
*
'
H
7
6
0
J
:
J
6
q
B
O
s
<
:
#
H
*
7
7
6
S
!qUAtsC[
A
<
a
;7
!!J«%
p
%
;
l
T
*
w
®
q
q
;
s
s
[
A
[
`
d3 " 7!3
%c + 0
0
3
X
#
*
&
4
6
9
T
*
w
®
T
&
$EQ)
3%
¬ 0
0
3
X
#
*
&
4
6
9
T
*
w
®
T
&
$EQ)
3%
¬ 0
0
3
X
#
*
&
4
6
9
T
*
w
®
T
&
$ EQd)q
3s%[
A
A
[
;¬
l
,
\
;[
!q
s
a+
$ E
d)
q
s
[
A
A
[
;
l
,
\
;
[
q
s
a+
q
B
O
s
b %
q
q
z
A
s
d
q
s
s
[
q
`
z
s
¤
@
$ "
! -
" +-
3- -++"
M")
) E
&
9
6
*
;
;
&
,
*
*
V
*
;
,
4
@
,
6
4
C
6
&
,
6
9
;
[
q
s
b
b
$;<
$ 4$ ,
" d*"+,
C
4+
'
1
/M
e F
-
L
K
L
. . K
0
F
G
"
7
<
"
0
#
#
3
I
"
; F
A
C
L
K
C
E
F
:
C*
KS "K
0
7DI"
6#`"K
7.687 Q
'
:KH[
0
0G
#`"K _qS`
z
Msx¤G@
<J
I"K ^"@
6,J
:
#"6, 26,J20G
0
W`pz
1
0EH/
6 '
"
687 IqS`
z
Msx¤eqS`Zz
Ms43WV
6,J&:+ Y
%
JK*
KJ(H=:1E"
0
Wl
7 I"K
$x
$EQ)
g«%S
A
^M«G %
q
q
z
A
s
d
q
s
s
[
q
`
=
? @
z
s
¤
@ %
q
q
z
A
s
d
q
s
s
[
q
`
=
? @
z
s
¤
@ )
8
³
³
I
0
/
#
J
3
k 0
0
3
q
s
]
6
C
*
,
*
;
6
&
b
b
,
,
C
q
s
[
:8k
T
! T
=
)
$EQ)
gZ
)"1
g
0
0
3
q
s
]
6
C
*
,
*
;
6
&
b
b
,
,
C
q
s
[
q:8skX
T
[
q!;
. z
#
;
sT
]=
()
%
$ EQd)qgsZ[
6)*"1q
gs
[
q`
z
Ms«¤G@/b
b
+*-
@[vd); 1qS`
z
"esC[vd3;+1q`)z^"es
6
C
*03,",
C
EV2$63&63&
@F
q:$8s7]=*"
`z
[
{ ^@Jb
"[~
^@Mb
aq>{~+s%[K)ATc &`
z
[
^
^
{@
3& 34,"6 q>{
^
^
~+s%[K)%0+& ; q "J
^
^
sC[KP3,cb
+4$4U
e
Q 0
0
3
q
s
]
6
C
*
,
*
;
6
&
b
b
,
,
C
q
s
[
q:8skX
T
[
q!;
. z
#
;
sT
]=
()
%
$ EQd)qgsZ[
6)*"1q
gs
[
q`
z
Ms«¤G@/b
b
+*-
@[vd); 1qS`
z
"esC[vd3;+1q`)z^"es
6
C
*03,",
C
EV2$63&63&
@F
q:$8s7]=*"
`z
[
{ ^@Jb
"[~
^@Mb
aq>{~+s%[K)ATc &`
z
[
^
^
{@
3& 34,"6 q>{
^
^
~+s%[K)%0+& ; q "J
^
^
sC[KP3,cb
+4$4U
:e
3 " +cP )
< 3Y $Q)!
I
"
9
J
7
"
7
Q
6
J
<
q
{
¥
s
<
7
I
"
J
"
1
0
#
©
q
{
¥
s
3
)
JS«D
/
6
I
"
9
J
7
"
7
Q
6
J
<
q
{
¥
s
<
7
I
"
J
"
1
0
#
©
q
{
¥
s
3
)
JS«D
/
6 0
0
3
]
V
*
,
*
&
<
q
{
¥
s
]
(
{
q
o
s
[
A
9
&
6
&
4
9
o
,
,
C
VF+*-,"&ed
C
4$3*+%$[d$,#
&6/b
&\q«f
j
1!
(
>
aLts
!9
6)*
<$[
QDOE *"M3*-
V *" ;+,"+4 ?+`
J
,
C
VF+*-,"$&d
C
4
!*CZ)S[$&
(!3*"$3&
,&c0Sf;< 3*3;T *"$,8;¥bW3&
34$4
6!9c
4$
$&
EV *" EV
+4
Y¢
qxf
§ j
6)*"634$4
!*P>2
>QsT12$& ; +3;<
639
&d)(3+,
*-$,"
6_`
z
Y
+I *" &W
E6
C
4+,o[ qD@/EAs¦b
" 4$& «{[
AQ
*" ,
C
4,+$qS' *"
b
C
,-+
!pn
C
x®x¯Dq
oJsY34b
,Pr
C
34$,ZYJª
,"& ;+ Z [
A
,
& 63,
C
VF+*-,"$&d
C
4
!*9'< [
Q2
sTc
4$& «{
YJª
9
6)44$6hb
,'9
*-6)
q
>2Ms03&
q:B aQs
3Tc
C
,
*" 3& ,
6
() *"9
0+&
*-$ ,
</q>{«¥Ds79
63*
d|{[KQbWb
$;<
$,
"*"(
$34
9
6)*
<_[K)
f
!R
)$/
7
-
")F)")
! E 3!)
W""
+ $
&
b
9
6
4
4
6
b
,
b
b
C
,
5
*
6
V
6
,
6
&
O
§
&
&
6
6
&
&
*
6
C
;
*"!
C
*8 * bd,"& ;+
*-6)
&
C
,"*3; £{/q
oJsc
$, "+*"
$&+
*-6
C
d) R,7;+4$3,",q
62]¥Ds+b b
c*- d
3*-
3,
!&
+4+
+&
639eY¢WgTc +& q:O
§Qs
;+6) R
$&
b
qUQ23Msd)(3+,c d9
634$4$6hb
&edR(!34
C
+,
9
6)*k{/q
oJs%[v{/qD@/EAsTH
]/
/
( <
[
Q
H
{
qD@
EA
s
[
%
]
'
)
%
)
! F
-
L
K
L
.
.
K
0
F
G
"
7
<
"
0
#
#
3
I
"
; %
;
l
T7*
w
®
q
;
^
^
^
a
]
s
[
A
[
`
+
+
3-
3
$!)
$ $ 0
0
3
n
&
4
&
*
;
4
;
C
4
6
&
4
,
)+1xS
^+
M% 0
0
3
n
&
4
&
*
;
4
;
C
4
6
&
4
,
1xS
+
M% @
H
[
d
;
q
q
`
z
s
^
^
^
a
J
s
[
d
;
q
]
y
`
z
s
e
3
e
1
J
%v
G
b
(
,
6
*
6
9
`
z
X
2
(
,
6
*
6
9
d
;
q
@
^
^
s
[
d
;
q
]
y
`
z
T
2
)$h
$eR+)e3
+ )Z
b
(
,
6
*
6
9
`
z
X
2
(
,
6
*
6
9
d
;
q
@
^
^
s
[
d
;
q
]
y
`
z
T
2
)$h
$eR+)e3
+ )Z
b
(
,
6
*
6
9
`
z
X
2
(
,
6
*
6
9
d
;
q
@
^
^
s
[
d
;
q
]
y
`
z
T
2
)$h
$eR+)e3
+ )Z
b
(
,
6
*
6
9
`
z
X
2
(
,
6
*
6
9
d
;
q
@
^
^
s
[
d
;
q
]
y
`
z
^
^
sT
6
C
46
2
b2
9
6)44$6hb
$&edR;+6)&ed3*
C
& ;+ , 6)4ZH
b
(
,
6
*
6
9
`
z
X
2
(
,
6
*
6
9
d
;
q
@
^
^
s
[
d
;
q
]
y
`
z
^
^
sT
6
C
46
2
b2
9
6)44$6hb
$&edR;+6)&ed3*
C
& ;+ , 6)4ZH ^
^
s
6
C
4
6
2
b
9
6
4
4
6
b
&
d
;
6
&
d
*
C
&
;
,
6
4
H
³
`
b
C
,
A
^
^
[
J
`
J
J
`
<
&
<
J
A
Tc +*- 9
6)*-
2
[
b
!& " P3,",-+*8$63&
9
634$4$6hb
,
9
*-6)
q
B gBtsT
'
2
_
%
T
P
@3
/
(Y"$2
+$
$
b
C
,
A
^
[
J
`
J
J
`
<
&
<
J
A
+*- 9
6)*-
2
[
b
!& " P3,",-+*8$63&
9
634$4$6hb
,
9
*-6)
q
B gBtsT
'
2
_
GEK
%
T
P
+K@3 D/E(Y"$2
+$
$ '
$ ^
T
*
9
6
*
2
[
b
&
,
,
*
6
&
9
6
4
4
6
b
,
9
*
6
q
B
B
s
'
2
_
GEK
%
T
P
+K@3 D/E(Y"$2
+$
$ 0
0
0
I
"
0
"
'
B
Q
3
X
<
"
"
&
o
[
q
@
A
s
U
*
&
9
4
6
C
4
6h()+*Wlc
]
" &63<!"$6)&
!,0&
,"+;T6)& ,'Q
3& Ob
8D
>C
t« o
q
¥
s T7*
®
a
®
qA
^
/
^
a
/
s
[
A
q
,"+
q
Q
B
s
s
q
A
^
/
^(a
/
s
^
C[
zP
q
,"$&;+>A
[
As
A
^
/
^(]
/
[
z@
m
a
( T
;
6
&
6
&
,
9
C
4
V
4
4
9
6
*
^
^(]
6
9
`
z
4
&
,
A
6
9
l
ª
T76Qd) " +*
b
" )`
V
63,","
4$0(!34
C
,
639Y@/b
b
)d3
"
3,-,"+*8 ?(3!4
C
,
639
<Aq¥Ds
/
F
)
3
3
J^d3
£
3/
6
X
&
6
b
<
0
#
#
6
*
o
[
q
@
A
s
&
@
[
A
b
b
(
{
q
o
s
[
A
q
Q2
B}s¦b ,"6o¬
q8¥DsT
$[9
@
[
A
+&
(
¦ {
y
[
{
/
y
[
z @
^
/
^
/
T
*
w
®
q
Z
^
^
^
a
/
]
s
b
+*-Z[0Z/q
oJsT%' & ;+
D
%
D o
q
¥
s T7*
w
®
q$Z
^
^
^
a
]
s
[
A
)$ d
)P " +"+
!3
+P3M|
$ b
;
q
B
>
s
6
4
,
9
6
*
V
*
;
,
4
`
(
4
C
,
6
9
Z
q
&
;
4
C
&
d
Z
[
A
s
12$&;+Y9
6)*
+3;< 9ZM" +*-@!*"
`
z
V
3*",(qD@/EAs
b
Z[
@
^(]
¤+Abb
V
&
d,8<!"+
(3!4
C
,c639
<Cq8¥DsT
[d" 3 "
" h
"
)-
!
)p
C8DTc
")
)- $-
3-
3 b
;
q
B
>
s
6
4
,
9
6
*
V
*
;
,
4
`
(
4
C
,
6
9
Z
q
&
;
4
C
&
d
Z
[
A
s
12$&;+Y9
6)*
+3;< 9ZM" +*-@!*"
`
z
V
3*",(qD@/EAs
b
Z[
@
^(]
¤+Abb
V
&
d,8<!"+
(3!4
C
,c639
<Cq8¥DsT
[d" 3 "
" h
"
)-
!
)p
C8DTc
")
)- $-
3-
3 $
*
&
,
6
,
6
b
9
6
*
C
4
,
9
6
*
©
q
¥
s
T
,
6
6
*
V
,
;
4
,
,
6
9
o[
qD@/EAs0; 6)&
<3& ,qS`
z
Ms«¤%n
C
wq
o6s
+4+
+&
,bZb
+*-%n
C
w6q
oJs
[
`)z^dTG2;+ V9
63*(q.< T()+&3&
Z[
Ats¦b
$&
b
$;< ;
!,"B%n
C
w6q
oJs,[`y,z^
q:,-+q8)a>sxsTCTc P*" ,
C
4
& 6hb
9
6)44$6hb
,c
;+6
C
&W"$&ed
'
1
F
e
d" +3"+$" d!"$)
C8D«"
DC
C8D«
8D F
C
E
K
F
6
*
b
*
6
,
<
]
q
¥
s
¤
<
q
¥
s
[
©
]
q
¥
s
¤
©
q
¥
s
r
C
34
`
&
() &
3&
` z
$&
"
6
^ d)*"
;
3,-Qb0*" ,"VF+; "(3+4 3
6)*
< 6
b
,
$,
@*"!6
G2V
; 9
*"63
3&r
C
$ ,-"*"$
C
6)&
2VF63" 2S
+,-$, b2b
+*-
3,
9
6)*
T()+&?<b4
!*«d)
*-6)
&
C
,
*!;++,k{/q>o6s
6
;+;
C
*
b
md) *
9
*"r
C
+& ;T 3&
TG2VF+; "+
9
*"63
r
C
$ ,-"*"$
C
6)&ZZTc +*"M!*"R6! *Y (
eS
!6)& ,Y9
*-6)
&
3()M r
C
$,8*"
C
"$6)&
GVF+;T<3&;+E9
63*Y MV
3*",q>{~+s
[
q>{/q
oJs+ \
q
o6s
¥JqhZs«s
3V VF
3*-$&edY3,
;+6
;++&
,639J:
M
®x¯;qsT
1
$& ;
&ewGq>o6s+X
$,
(
$,"6)&
34md)+
*"be:
M
®x¯;q8s
C
,8
d$*-*"
C
;+
4$6/(3+*W
cd b
9
6)*
< [
dv¥
T()+&6bZb
V
&
*-+,8*"; "$6)&
!
VF6)4 2&6) E$34ay!z
{
y
J
\q
oJs
;
3& &630
()dfb
6
,+
+*-+&
0*"6
63,c&Y
F
C
E
K
F
6
*
b
*
6
,
<
]
q
¥
s
¤
<
q
¥
s
[
©
]
q
¥
s
¤
©
q
¥
s
r
C
34
`
&
() &
3&
` z
$&
"
6
^ d)*"
;
3,-Qb0*" ,"VF+; "(3+4 3
6)*
< 6
b
,
$,
@*"!6
G2V
; 9
*"63
3&r
C
$ ,-"*"$
C
6)&
2VF63" 2S
+,-$, b2b
+*-
3,
9
6)*
T()+&?<b4
!*«d)
*-6)
&
C
,
*!;++,k{/q>o6s
6
;+;
C
*
b
md) *
9
*"r
C
+& ;T 3&
TG2VF+; "+
9
*"63
r
C
$ ,-"*"$
C
6)&ZZTc +*"M!*"R6! *Y (
eS
!6)& ,Y9
*-6)
&
3()M r
C
$,8*"
C
"$6)&
GVF+;T<3&;+E9
63*Y MV
3*",q>{~+s
[
q>{/q
oJs+ \
q
o6s
¥JqhZs«s
3V VF
3*-$&edY3,
;+6
;++&
,639J:
M
®x¯;qsT
1
$& ;
&ewGq>o6s+X
$,
(
$,"6)&
34md)+
*"be:
M
®x¯;q8s
C
,8
d$*-*"
C
;+
4$6/(3+*W
cd b
9
6)*
< [
dv¥
T()+&6bZb
V
&
*-+,8*"; "$6)&
!
VF6)4 2&6) E$34ay!z
{
y
J
\q
oJs
;
3& &630
()dfb
6
,+
+*-+&
0*"6
63,c&Y
³
F
K
R
E
C
L
E
.
.
N
C
K
C
C
F ]
,
6
b
&
C
*
6
9
U
*
&
9
4
6
C
4
,
q
*
,
V
6
9
,
6
6
*
V
,
;+4$3,",-+,
639gUY*-$&9
4$
6
C
4$ ,s
6h()+*kl£[
Y¢db
"
_VG2+
*"6
+
F+&
C
,
"*3;
{E V
& ,'6)& 4 6)&
d
{ 3&
<[
d
¥E9
<E$,c4+,-,063*c r
C
34
6
O
3
E)
+
/>«DZ
" "Z!1>«Dx
F
3g# /E X
9
6
*
6
&
<
q
{
¥
s
q
*
,
V
©
q
{
¥
s
s
&
C
*
6
9
o
[
q
@
A
s
q:*-+,"VIc639
$,-6)
6)*"V $,"
;+4$3,",-+,6!9%o6sc6h() *WY¢
b
*!;+{
]=P,"+@9
*"6)
q
Q2aQs
"
!
M
/
«DC
JS«D
1
xDC1>«D q
>
s
<
q
{
¥
s
[
<
q
{
¥
s
&
©
q
{
¥
s
[
©
q
{
¥
s
)
J 9
6
*
Y
ª
BD}/#F
F
A
C
L
K
C
E
F
=
0
<
>
O
<
7
I
"
*
'
"
J
<
q
{
¥
s
:
#
©
q
{
¥
s
#
"
H
"
#
0
/
Q
0G ? d
{
:+ /#
<[
d
¥3
I"
Q
:+ E"
S"6, +"K
UQ
7 I"%7
:[4/,"UT
F
A
C
L
K
C
E
F
=
0
<
>
O
<
7
I
"
*
'
"
J
<
q
{
¥
s
:
#
©
q
{
¥
s
#
"
H
"
#
0
/
Q
0G ? d
{
:+ /#
<[
d
¥3
I"
Q
:+ E"
S"6, +"K
UQ
7 I"%7
:[4/,"UT
F
A
C
L
K
C
E
F
=
0
<
>
O
<
7
I
"
*
'
"
J
<
q
{
¥
s
:
#
©
q
{
¥
s
#
"
H
"
#
0
/
Q
0G ? d
{
:+ /#
<[
d
¥3
I"
Q
:+ E"
S"6, +"K
UQ
7 I"%7
:[4/,"UT
³
(³
p³
a
p³
(³
(³
_³
a
³
(³
p³
a
(³
(³
³
a
a
³
"!
F
K
R
E
C
L
E
.
.
N
C
K
C
C
F
³
a
# $³
U
I"
9M ^J*7 "K
7
Q
6,J
</qS{x¥Ds <;7 I"
J
"
1
0G /#_©1q>{«¥Ds 3
³
(³
p³
a
p³
(³
(³
_³
a
³
(³
p³
a
(³
(³
³
a
a
³
"!
³
a
# $³
U
M^* K
,
/SxD ;
G/_1>«D
³
(³
p³
a
p³
(³
(³
_³
a
³
(³
p³
a
(³
(³
³
a
a
³
"!
³
a
# $³
U
M^* K
,
/SxD ;
G/_1>«D
I
"
9
J
7
"
7
Q
6
J
<
q
{
¥
s
<
7
I
"
J
"
1
0
#
©
q
{
¥
s
3
)
JS«D
/
6 6
6
&
d
6
C
*
`
y
,
6
4
C
6
&
,
o
[
qD@
EA
s
6
9
q
s
b
*
,
V
*
;
,
4
6)& Y"
!0,!"$,
V
+,
Z/q
oJsC[
A
A
/
* q
Q
s
? 6
6
&
d
6
C
*
`
y
,
6
4
C
6
&
,
o
[
q
@
A
s
6
9
q
s
b
*
,
V
*
;
,
4
6)& Y"
!0,!"$,
V
+,
Z/q
oJsC[
A
A
/
* ? 6
b
;
6
&
,
*
;
,
<
[
O
X
H
Y
¢
z
#
Y
&
6
&
6
*
V
Tc
9
6)4$46hb
$&edR9:!; ,03*-
$
E
3H
t/
/
(
%
/
/
$J ? 6
b
;
6
&
,
*
;
,
<
[
O
X
H
Y
¢
z
#
Y
&
6
&
6
*
V
Tc
9
6)4$46hb
$&edR9:!; ,03*-
$
E
3H
( qUO
s
{
q
@
^
]
A
s
[
q
s
{
qD@
EA
s
9
Y
ª
¢
b2
C
,
{/qD@/EAsC[
qD@s
{/q
%
'
)
sc9C@
[
A!
I
"
9
J
7
"
7
Q
6
J
<
q
{
¥
s
<
7
I
"
J
"
1
0
#
©
q
{
¥
s
3
)
JS«D
/
6 :}
F)
3E$3A\
m
3
¬/f3 ) q
B
s
V
6
4
&
6
4
f
Q
j
^
J
f
j
Y
f
j
,
`
S
(
b
#
*
&
4 H
[
YgfaQMj
3& *3&ed3
H
[
Y
J
Yh
V
#
Y¢
6)&Y¢W
Sc :38+8
P"'-+
3873"-+-"$)@$
0+3E
!"
d
)-
$ q
T
9
,
,
b
6
,
4
,
,
,
*
6
&
,
6
;
6
V
*
b
9
6
*
C
4
9
6)*k{/qD@/EAs+b2b
$;<
: H/
690G
6I
F+4$63&ed),
6
M
s
e
AZ
m
m
A!J)
&
;
b
V
C
&
d
q
s
[
z
f
j
z
f
Q
j
^
b
r
C
6
&
q
;
s
[
N
,
V *" ;+,"+4 `@,"6)4
C
6)& ,
; 9CN
bb
;< 3*"
!4$4I&6)&2S
( +*-6
9CN
Y
D
(3+&
N
z
Y:b
" d r
C
!"$6)&
M
/
/
C N
z
Y
b
r
C
6
&
M q8
s
{
qD@
EA
s
[FN
3 )$ )
3
KI3
'
$ _! {
q
@
A
s
[
N
'
$ _!
I
"
9
J
7
"
7
Q
6
J
<
q
{
¥
s
<
7
I
"
J
"
1
0
#
©
q
{
¥
s
3
)
JS«D
/
6 )
+3<
v ]
(
6
,
6
b
9
6
*
;
N
Y
¢
z
Y
*
*
,-6)4
C
$63& ,(qD@/EAs Y¢
Y
ª
¢
6!9
J
/
C V
`
q
@
s
¢
¢
q8Ms
{Jq @/EAsC[
N
=
)3+Z
2 +e
R {
q
@
A
s
[
N
+e
R q
s
X
N
Y
¢
z
Y
d
(
&
1
&
;
f
j
[
A
&
Y
¢
b
*
G
,
,
C
&
r
C
A
Ye¢
,
C
;<
!>N|[
{/qUA^Asp[
z_f
j
A
^
b
(
)(!mbPA
[q
z_f
j,N
s
^
[fej,N
^
³
12$
$4$3*"4
b
9
6)*d
3;<
VG2+
(!34
C
7
Y
ª
¢
639
@
¤+A
bC7
^
]
[
qD@
¤+A
s
^
]
Y
ª
b
3&
Pr
C
!6)& {Jq @/EAsC[
N,c r
C
(3!4$+&
b
"
8e
JC 12$
$4$3*"4
b
9
6)*d
3;<
VG2+
(!34
C
7
Y
ª
¢
639
@
¤+A
bC7
^
]
[
qD@
¤+A
s
^
]
Y
ª
b
3&
Pr
C
!6)& {Jq @/EAsC[
N,c r
C
(3!4$+&
b
"
8e
JC 12$
$4$3*"4
b
9
6)*d
3;<
VG2+
(!34
C
7
Y
ª
¢
639
@
¤+A
bC7
^
]
[
qD@
¤+A
s
^
]
Y
ª
b
3&
Pr
C
!6)& {Jq @/EAsC[
N,c r
C
(3!4$+&
b
"
8e
JC fe
j
¤
qD7
^
]
z
N
s
[
A
^
$3
c
)) Y3 b
;
,
C
&
r
C
,
6
4
C
6
&
A
T
,
d
(
,
&
6
*
`
y
z
,
6
4
C
6
&
,
6
9
r
C
!"$6)&
q
Ms+b 63&
9
6)*c
3;< -7p[B@¤+A
Y
ª
¢
e
1
:#
/
1
M+ b
;
,
C
&
r
C
,
6
4
C
6
&
A
T
,
d
(
,
&
6
*
`
y
z
,
6
4
C
6
&
,
6
9
r
C
!"$6)&
q
Ms+b 63&
9
6)*c
3;< -7p[B@¤+A
Y
ª
¢
e
1
:#
/
1
M+ q
Q
s
?
I
"
9
J
7
"
7
Q
6
J
<
q
{
¥
s
<
7
I
"
J
"
1
0
#
©
q
{
¥
s
3
)
JS«D
/
6 <[
OMH]{/qD@/EAs [
y
'
%
)
')
a
%
]('*)
a
)
%
)
a
)
=
)
- h
!?
I
"
9
J
7
"
7
Q
6
J
<
q
{
¥
s
<
7
I
"
J
"
1
0
#
©
q
{
¥
s
3
)
JS«D
/
6 q
s
3 ;
&
6
4
6
&
4
9
6
*
@
[
A
b
&
,
&
(
b
6
9
q
O
s
&
q
B
s
r
C
(
4
&
b
N[
£qD@s
{/q8
%
'
)
s%[
qD@
s
3q
%
'
)
s
£q
'
)
%
s¦b
\3bb
"
q
%
'
s
[
q
%
'
s
N
$
|
S
M T
*
9
6
*
b
b
V
&
V
*
;
,
4
`
z
`
[
q
`
z
s
`
,
6
4
C
6
&
,
q
@
A
s
6
9
q
s
b
b
$;<
Eh
M &
C
E *!"+=3,Y9
6)4$46hb
,+H
6
6),-
H
[
%
'
3*"
*"3*- $&¬YJª
¢
qS`
zc;< 63$;+ ,s¦b2!& E4
;E*
C
&M" *"6
C
d)
k`Y,-6)4
C
$63& ,
639
Aq
;Js,[
£q
es
N
*"6)
[
%
'
3&
;[
%
'
)
b
V
&
;+6)*-*"+,-V
63& $&d
,"6)4
C
6)& ,P@6q
e¤
;Js
^(a
b
A
[
q
¤
;Js
^
a
FWTc $,; 6)
V 4$T+,0 @;
34;
C
4$!6)&
639'</q>{«¥Ds
3,,8<!"+
&
3
4$!
a1SxD
\
D T
©
q
{
¥
s
*
9
6
*
<
[
&
<
[
O
b
,
&
;
&
4
4
$,-6) E63*"V ,"
; 4
3,-,"+,
(3
4$+&d3
q`
z
Msx¤eqS`z
Ms¦b3&^,"6©1q>{«¥Ds¬[
</q>{«¥Ds«¤
^
^
6)*
<
[
Q
34$4
"
$,-6)
6)*"V $,"
; 4
3,-," ,
()^4+&ed3"
qS`
z
s«¤eq`z
MsC[
`J
Y
G2;++V2c9
6)*` y1z
;+4$3,",-+,
6!9
4$+&d3 ?63& Qb3& "
*" ,
C
4c9
6)4$46/b
,
9
*"6)
; 6
C
&
&ed
3&
d*-+ E3*"#¬q
Qs
' )
8
³
F
C
E
K
F
T
,
,
*
6
&
6
9
T
6
*
>
Q
;
6
,
V
&
4
b
*
6
&
d
9
3VV 4$+
6
V *-$
c0S
V
+4 ,ZY¢E639
d)*-+
R
O
6)*TG3
V 4$b
4$ )`[
Q
3& ¥[
q8h
Jh
J
Ms
ZTc R&
C
*",
</qS{x¥Ds'3& a©:qS{«¥Ds'3*-_d)() &
3
4c
4$6hbd
$[,- 6hb
,
"
!'</q>{«¥Ds3& ©1qS{x¥Ds
,+
+*T() & 6)&
fb
6
+4+
+&
,k{[
hk«h
J
P6!9
d)*" @63& 3
p
DD#8
M
F
E
.
I
"
9
J
7
"
7
Q
6
J
<
q
{
¥
s
<
7
I
"
J
"
1
0
#
©
q
{
¥
s
3
)
JS«D
/
6 C
F
`
[
Q
b
¥
[
q
h
J
h
J
s
{
</q>{«¥Ds
©1q>{«¥Ds
A
BW>
O
/>
h
A
A
h
J
Q3A
Q
h
y
>3A
B
h
y
J
O)A
Q
hWy
J
h
)A
B
h
y
J
h
J
Q3A
Q
F
-
.
H
O
E
C
K
L
K
E
O
.
F qU y
s
9
;<
!*Mq8Y6sk[Q
3&
][
Y3q
hZs+b" +&
#[
Y3f
hkj
3&
,q8¥Ds,[
A
9
6)*c
3;< $¥
c "
3
3I 3
h3Y-! E W"c3-+-" W"
3M + q
s
9
[
Y
^
a
q
h
s
b
&
[
Y
^
a
f
h
j
&
Cq¥Ds%[#q
z@Ms=
¢
! U
<
!M86k
3
]
3
Z+" +
q
¥
s
[
q
z
s
=
¢
! ]
3
Z+" + q
y
s
9
;
*
q
Y
s
[
Q
&
[
Y
q
h
s
b
&
[
Y
f
h
j
&
q
¥
s
[
A
9
6
*
;
¥
3
h3Y-! E W"c3-+-" W"
3M +
T
V
*
6
6
9
,
6
9
6
(
,
&
,
*
,
,
&
4
4
&
;
4
6
6
,
&
0&
C
F+*,V
+4 ;
!,"qxfehNMjI,-+;T
B \B}s*!
F
-
.
H
O
E
C
K
L
K
E
O
.
F q
s
X
q
{
~
¥
s
[
q
{
~
Y
¢
s
,
6
9
,
6
6
*
V
,
;
4
,
,
,
6390*3&#
S
fb
6UY*-$&9
4$
6
C
4$ ,
6h() *_Y¢ b
;<
3*"3; "+*-$,-"$;?VF6)4 2&6) E$34
q8s[
aypz{
J~hK]=
*" 4
!"
",?;
!*" &
34$f \©:qS{~«¥Ds 3& ^"
b
¨d)
"+&
C
*
S«D%
6¦ q
s
X
q
{
~
¥
s
[
q
{
~
Y
¢
s
,
6
9
,
6
6
*
V
,
;
4
,
,
,
6390*3&#
S
fb
6UY*-$&9
4$
6
C
4$ ,
6h() *_Y¢ b
;<
3*"3; "+*-$,-"$;?VF6)4 2&6) E$34
q8s[
aypz{
J~hK]=
*" 4
!"
",?;
!*" &
34$f \©:qS{~«¥Ds 3& ^"
b
¨d)
"+&
C
*
S«D%
6¦ q
s
X
q
{
~
¥
s
[
q
{
~
Y
¢
s
,
6
9
,
6
6
*
V
,
;
4
,
,
,
6390*3&#
S
fb
6UY*-$&9
4$
6
C
4$ ,
6h() *_Y¢ b
;<
3*"3; "+*-$,-"$;?VF6)4 2&6) E$34
q8s[
aypz{
J~hK]=
*" 4
!"
",?;
!*" &
34$f \©:qS{~«¥Ds 3& ^"
b
¨d)
"+&
C
* ©
ª
q
{
~
¥
s
[
1
¢
q
o
s
M
P
«xD
6¦
3- b
*
q
o
s
[
q
`
z
s
%
n
C
®
¯
q
o
s
b
b
;
4
,
,
&
C
*
,
6
9
d
&
*
r
C
3 *"!;P63*" *",« 6/(3+*
c
3&TG2V *-+,-,
*-6
C
d) R3&
34 W$;
; 4
3,-,
&
C
F+*c9
6)*"
C
4
#
A q
Q
s
n
r
C
*
;
V
4
G
&
,
6
&
6
9
,
6
'
:
S
6
:
Q
Y
*
:
#
:
7
6
1
9
V 4
!;+
639e
6
+,"&
\7,"V 4
$&b!$&db
$;< @;
3,-
3,
C
& mr
C
G
+&,"$63&b
34$,-6R4$3
4$4+
W
bW6
5
C
K9
6)* Y$&
d)*!4F; 4$6),
C
*"'6391c
&
Cn&
0G ;#`"K
&
6)*
,c
,
C
*"&ed
K639
; 6)&
<3& $&edc_3& ?9
*-+Y639
*"3& #Efb
6
6h()+*kc@'$[
&+;+ ,","3*"4
3,c"
9
6)*"
]
)v q
Q
s
n
r
C
*
;
V
4
G
&
,
6
&
6
9
,
6
'
:
S
6
:
Q
Y
*
:
#
:
7
6
1
9
V 4
!;+
639e
6
+,"&
\7,"V 4
$&b!$&db
$;< @;
3,-
3,
C
& mr
C
G
+&,"$63&b
34$,-6R4$3
4$4+
W
bW6
5
C
K9
6)* Y$&
d)*!4F; 4$6),
C
*"'6391c
&
Cn&
0G ;#`"K
&
6)*
,c
,
C
*"&ed
K639
; 6)&
<3& $&edc_3& ?9
*-+Y639
*"3& #Efb
6
6h()+*kc@'$[
&+;+ ,","3*"4
3,c"
9
6)*"
]
)v [
[
c
J
/`P
3
b
,
6
6
&
;
c
b
6
#
"
O
6
9
&
]
(
;
_
7
nV
& "+4 \d) & +*"!
YSf,
C
62
C
4$
[
A
639
[
r
C
63Mqsa[
r
C
63Mq _s,
;:1*7
690G /:"/
6#`"
:"/eq-$
34mY9
6)*
," 63*-¦s639
b
3&E,
H/
0EH"K 79
",
C
4$V4$$ *
*"$&d% q
s![
;¬
4;^Qd)*" +,b
MAT
b
6d
34,
_
*
"
Y
*
6
:
/
"
7
+
*
*
4
_
[
@
b
,
6
@
ª
]
4
q
s
F
" c,"T
639F r
C
(3!4$+&;+
; 4
3,-,"+,
6!9Aq
& 63
&+;+ ,","3*"4 @V *"6)VF+*s7$
34,
639
b3&$©:q _s",
qV & "s
;+3*"$&
34f 33n,
b
UY+ #
& ?*-$&ed),b2" Y,"T
639YV*"6)VF+*M9
*3;T6)&
34c
34,M639
9
6)*- E,
d3*"6
C
V
C
& *
C
4V 4$;
!"$6)&I
Tc
6)*- +*$©
q sE639d
3,",-62;
!"+
$ +34; 4
3,-,d)*"6
C
V^$,?*-+4$!
"6
©1qsC[©
q
s
W qU
gOts
©
q
sC[
f
ª
H
ª
j
,
¢
q8kz
%q8¥Ds
¥
s«©1q
s+
g
:g q
O
s b
*
[
b
¥
*
C
&
,
*
6
C
d
V
*
(
,
6
*
,
6
9
b
,
3
,-6)4
C
"0(!34
C
W`
=
b23&
$, ZUY$*";< 4$T;<
3*"3; "+*
!,","6
;+$! b
"
E!Tc
!0$,b
9
63*0V*"$
+,¥?639C
q:
\3be¥
,'MV *-$
639AcbF63*k¥[
$,c"
V *" EY!
$&V & f s+b
qU
\B}s
%q8¥Ds%[
A
zP
91¥?,
,"V 4
*3
mV
$& *-
&
dF)$
c
)$h
$eR"F++$3Z+3" + q
B
s ]
V
6
&
6
C
9
6
4
4
6
b
&
d
,
V
;
4
;
,
,
H
Z+
k ]
V
6
&
6
C
9
6
4
4
6
b
&
d
,
V
;
4
;
,
,
H
Z+
k ]
V
6
6
C
6
6
b
d
,
V
;
;
,
,
qU
s
9
[
Y
^
a
qhZs+b" +&
[
Y
^
a
f
hkj
3&
Cq¥Ds%[#q
z@Ms=
¢
!
F
-
.
H
O
E
C
K
L
K
E
O
.
F q
s«s+b2b
d)
"*6
SGI7("
# :+*
1*/$:GJEJ *`'K"K
qU
§
s
©
ª
q
s
[
;
©
ª
q
;
s
' h
F@E! )[f
Y"
+
E
Ph3+W q
§
s X
&
6
b
o
*
&
#
S
b
6
U
*
&
9
4
6
C
4
6
(
*
Y
¢
b
b
;
*
;
*
,
;
V
634
& 6)
34 q8sA[¬y6z${
J¬~h
6)& ," +*
c
S
34md)+
*"
]d3+& *!"+
M
*-6)
F+&
C
,Y+& 6)
6)*"V $,"
u
6!9o
6/(3+*)Y¢
R12$& ; u
,
(+ *"6
639
bJq
)aNs
,- 6hb
,
"
!
_,
3& 6)*- +*
$&M ' Qd3$&
3*8 _r
C
! *!"$;0TG
& ,"6)&
[r
C
63q s
639A
kX
d @ E G2$ E34Z6)*- +*0639
3&
#[
R3,
3
F6/(33
M
C
8M/
!
:1SMxD
F
@
K
L
L
R
I
R
L
H
J
"
"
f
L
j
<
0
0
/
/
:
Q
7
0
0
H
3
3
I
"
*
'
"
©
q
{
~
¥
s
0
6,J20G'
0G HI6,JK'
1*/$:GJEJ
"EJ
0
;:+ =<G%
7
0
6 ! !"*/$#
'
0)#+*/,"EJ
0!
F
-
.
H
O
E
C
K
L
K
E
O
.
F +"K 1Y¢
687 I
1EI=:+
%
:1*7
"K
6,J*7
691YH
0/RQ
0G'56:"/MqsA[
y
z
{
J~
"8Y)*?:"/
J
7 I" :+*
1*/$:GJEJ
*
'K"K
©1q s
0
[vcfu
j:<
I"K ^"u
6,J>:
G"K
0
0
qs43
6 '568/$:+
/RQ1<
7 I"
"*6
SGI7("
#
*
'K"K W©
ª
qS{~Mx¥DsS"8Y)*=:"/
JZ©
ª
q s43
'
c $0$'3
!$)
c
E-$
$
!c-< +
+
@ Y
-$e¬\
)
+e T
,
,
&
4
6
d
6
C
,
b
,
4
*
,
&
b
C
6
U
C
*
&
d
f
O
j
b
9
6
*
4
S
4$V;
;
C
*8()+, 6/(3+*Y¢
$[", V *-626!9
C
," , 9:3;T "
! UY*"$&29
+4$
62
C
4$ ,
o=3&oO_Z3*"@$,"6Qd)+& 6
C
,Y93&
63& 4
9
$*0;<
3*!; *",-;RVF6)4
& 63 E$34$,
Qd)*-+QbI
\3bTc +63*"+
)
Ab
3&
" +&
;+63& ,-"*
C
;T,P3&
TG2V 4$;
-+;T$63&
639
d; 4
3,-,0,-
q _s
b
q>{~«¥Ds
; 6)
V
!
4$'b
*-+,"VF+;T()db
¨d)
,
Tc 03,",
C
V6)&
639
;<
3*!; *",-;c ,+
+*-+&
9
*"63
QY !
$& f
hL j
VI
h)N
,
$*-*"+4 (!3&
9
63*
V *"6)VF6),-6)&
3,d)(3+&
3
F6h()Qb
!&
E
,
C
V V *-+,-,"+I
DE! '!
F
-
.
H
O
E
C
K
L
K
E
O
.
F $&
0fb
6RTG2;+ V6)&
34F;
3,-+,pq:
s
3& £qU y
s+b3qUgOtsc$,0
3,-$4
V *"6h()
$*-+;T4 3kTc
C
&
d)*"6
C
V# (ª
3,'6)*" *
`z
E
G2;++V2@9
6)*
[
Y
^
a
f
hkj
b
b
;<
!,@
C
&pd)*-6
C
V
639
63*" *(` yz)
5
C
""$&ed
_CS)
¬
%
+ q
s
[
q
`
z
s
%
ª
&
©
ª
q
s
[
q
s
©
q
s
b
(
qU
a>s
©
ª
q
sC[
,
¢
q
Wz
,q8¥Ds
¥
sx©
ª
q
s
2$+R
!$'
3)- +-
+)
<!$ e
3"
3$-?$ +3$
)
:
q
>
s 1
&
;
4
,
9
6
*
6
*
*
,
_
;
6
&
&
&
d
*
4
,
6
4
,
9
6
*
&
;
$ +34
639
_
3,
,"6)
_
_3,
,
C
4"$V 4$+*
*"$&deb
b
Zd3
9
63*
[
)H
1
&
;
4
,
9
6
*
6
*
*
,
_
;
6
&
&
&
d
*
4
,
6
4
,
9
6
*
&
;
$ +34
639
_
3,
,"6)
_
_3,
,
C
4"$V 4$+*
*"$&deb
b
Zd3
9
63*
[
)H
q
s
©
q
s
[
©
q
s
[
;
©
q
;
s
q
s )
8
³ b
;
b
;
4
4
*
"
6
S
I
7
"
# :
*
1
/
:
J
J
*
'
"
6
9
6
C
&
&
d
;
$ +34
639
b
"b b
+*-
v[
q.
F
-
.
H
O
E
C
K
L
K
E
O
.
F T
)"
_
' )
3m)+3+ !"+
R-23
3
G
¥
b
{
&
~
,
9
6
*
b
4
c
S
4
d
*
d
&
*
*
6
6
6
9
q8sC[
¬y!z
{
J~b b
"
][
b b
*"
,
d E G2$ E34
63*" *0&
][vr
C
63q s+b23& ?4
a[
F'" )UY*"$;< 4$ ;< 3*3;T *
;+63*"*" ,"VF6)& &ed
6
q:,-+ qU\B}sxsT
*"6) qUa>s¦b1qU
§s
3&£q:aNs
b
pd)T
U
gt
>«D%
W/
«
q
L
s
©
ª
q
{
~
¥
s
[
q
s
©
ª
q
s
" q
L
s
" b
t qU
hAts
Wq/
s
H
[
;
_
,
! "
;
q8kz
!q«°
s
°
s
p
k
/
x
_
q
A
s T
r
C
&
#
q
s
4
,
6
,
,
V
,
q
,
f
j
b
X
>
J
>
Q
s
H
MC
S/
F
K
L
L
R
I
R
L
H
F
:
BD%/
/W+^5
E 6
b
;
6
&
,
*
G
;
V
6
&
4
;
,
q
s
b
[
Y
^
a
f
h
j
]
9
6
*
4
4
V
C
@[
@q
¤MY^Ms
H
[]z@)%Tc &
g,«
|
x V
@
[
@
q
¤
Y
^
s
H
[
z
T
&
g, l
q
s
[
q
q
J
`
s
q
J
`
s
s
&
U
/ qU
/>
s
©
ª
q
s
[
q
`cJ
s
[ `
'
l
q
s
$& 34$4 bW$&
;
!," qU y
s
b
P
() @[
Ab©1qs,[
b
3&
qU
hts
©
ª
q
sC[©1qs,[ D`
'
lWq8
3s
)
"
3)
)R $ eUht
6U2h7
¬Ugt¦W q
>
s
$ 3$ q
s
)
6
4
,
*
(
4
4
6
&
&
d
q
O
s
q
s
b
q
L
s
b
b
V
&
G
V
*
,
S
,"6)&
M
>«DC
D
k
xW
g+ q
§
s
©
ª
q
{
~
¥
s
[ `
'
q
s
l
q
s
$<
!3$?$
3I+3" +
F)$
c
!03$F q
§
s
$< b
;
,
(
4
&
4
4
;
,
,
]
V
6
&
6
C
4
4
&
d
*
&
,
6
9
*"md)
c
3& ," P3*"
*"
$&
{ 3& ~/
)
+
"
c
""
)"
Y!
F
K
L
L
R
I
R
L
H
F
:
BD%/
/W+^5
E +3"U
+
&
k
=d
)"E3$ ? 6
b
;
6
&
,
*
G
;
V
6
&
4
;
,
q
s
b
[
Y
^
a
f
h
j
]
9
6
*
4
4
V
C
@[
@q
¤MY^Ms
H
[]z@)%Tc &
g,«
|
x ?
F
K
L
L
R
I
R
L
H
F
:
BD%/
/W+^5
E "K
0
8: H/
6 '
"_°7 I"K
W
/
,_
!x
«
M
^M
q
s
[_
J
q
°
z
q
°
s
s
q
°
Z
z
s
q
°
z^
s
'
q
;
4
4
b
C
,
°
6
9
6
*
V
*
4
&
9
6
*
,
6
&
;
d
&
*
S
!63*+
s
)
E3E W
f
dT2+ )
3
3-+
U
3$U
Tgc + G
;
4
C
9
6
*
6
&
b
6
G
;
V
6
&
4
;
,
,
q
s
&
q
y
s
T
&
pd) &
C
,
639
q
\3b 639
P3,-,"6
;+
+ 34md)+
*"3$;;
C
*8()sc$,d3() & qU
/Qs
@[B@6q_sC[
Q
d^;+6)& GqgsAz
+-
+3 1g
$7"
)
33
8 )
""$e q
Q
s b
*
;
6
&
q
s
,
;
6
&
C
;
6
*
6
9
C
*
*
b
V
C
&
d [ q
¤
s
[
Q
q:*-+,"VI
Ms
9>
$,E$& *-q
*" ,"VZ
*"3 EV
+sM&
¤Q£b
"
3& 34 W; ; 4
3,-,
&
C
F+*c9
6)*"
C
4
R*-
3,
t
C1
,
D
W
3 b
*
;
6
&
q
s
,
;
6
&
C
;
6
*
6
9
C
*
*
b
V
C
&
d [ q
¤
s
[
Q
q:*-+,"VI
Ms
9>
$,E$& *-q
*" ,"VZ
*"3 EV
+sM&
¤Q£b
"
3& 34 W; ; 4
3,-,
&
C
F+*c9
6)*"
C
4
R*-
3,
t
C1
,
D
W
3 qU
hO
s
©
ª
q
s
[
©
q
s
[ `
'
l
q8
s
' "
g
"
T$3 +
+
)00
M_ q
O
s
' "
*
l
q
s
,
l
S
9
C
&
;
6
&
V
&
9
6
*
q
s
R
,
6
4
C
4
;+6)&
(3+*«d3+&
V*"6
C
;
*
l
q
s
,
l
S
9
C
&
;
6
&
V
&
9
6
*
q
s
R
,
6
4
C
4
;+6)&
(3+*«d3+&
V*"6
C
; qU
B}s
lWq
gs%[
,
²
?A@
q
kz
qx°
s
°
s
)"
3U2/Q03|Uht
3-@
+$efW h
) "
+ q
B
s
6
*
C
4
,
q
Q
s
&
q
O
s
*
b
4
4
S
#
&
6
b
&
;
6
&
,
r
C
&
;
,
6
9
V
*
6
V
*
,
639" R*-+,"VF+;T()
( <
9
C
& ; "$6)&,639%
!&
q:,"
3d _fe
j8s
M?063P
RV *"6
C
;TqU
B}s
9
6)*
[
,84$4
;+6)&
() *«d) ,d;+6)& 6)&
344 q
$&
!&
6)*" *
;+6)
V
!"$
4'b
d d)*" @6!9
V *-$
+,s
6hb
!*" ,WlWq8
3s
+
&
k
6
*
C
4
,
q
Q
s
&
q
O
s
*
b
4
4
S
#
&
6
b
&
;
6
&
,
r
C
&
;
,
6
9
V
*
6
V
*
,
639" R*-+,"VF+;T()
( <
9
C
& ; "$6)&,639%
!&
q:,"
3d _fe
j8s
M?063P
RV *"6
C
;TqU
B}s
9
6)*
[
,84$4
;+6)&
() *«d) ,d;+6)& 6)&
344 q
$&
!&
6)*" *
;+6)
V
!"$
4'b
d d)*" @6!9
V *-$
+,s
6hb
!*" ,WlWq8
3s
'h
) " +
RT2 +"$)
!
F
K
L
L
R
I
R
L
H
F
:
BD%/
/W+^5
E q
s
V
_
:
"
1
0
H
6
'
"
7
I
"
#
q
_
s
[$
q
s%
q
_
s
3
q
$8s
VD % [°
Z
6,J8:>H
0! "K
0
8: H/
6 '
"_°7 I"K
W
/
,
!x
«
M
M
q
s
V
_
:
"
1
0
H
6
'
"
7
I
"
#
q
_
s
[$
q
s%
q
_
s
3
q
$8s
VD % [°
Z
6,J8:>H
0! +
F
A
C
.
L
P
.
N
C
H
R
I
0
F ]
&
6
b
b
&
6
d
(
4
6
;
4
&
4
;
&
*
V
*
6
&
6
9
9
;
6
*
,
²
q>{~+s $&
q:hNtsT
$f&^
b
6)4
," ; "$6)&b°
$,
£VG2
V *-$
639(c_b'639
3
,-6)4
C
"
(!34
C
°
[&`
=
²
b:{3&
~
!*"
+4+
+&
,d639
°
S
3$;
; 6) EV4$TS
6)&c(²2639gc_b
3&qs3[ay%z|{
J
~Z¬cp²mf
j
d + ]
V
&
M ]
V
&
q
§
Ms
}mS+ q
§
s
}mS+ §
s
±}²mqS{~+scH
[
4$
:
%
q
Q
c
¤
°
s
*
q
s
[
{
q
s
[
~
°
y
;y
q
°
y
z^Ms
"h
$+ " Y$E
T2- ,'+-
3 $
)$h
"Y-$
$
$e ±
²
q
{
~
s
H
[
4
:
%
h
$+ " Y$E ±
²
q
{
~
s
H
[
4
:
%
h
$+ " Y$E V
*
6
(
4
G
,
,
*
&
&
b
9
6
4
4
6
b
,
b
b
C
,
,
V
4
9
&
d
& 63!6)&M3&
b
*"c!
d 7*q. s%[
{P9
63**q. s{/q! E6
°
s
$[
b
$442
C
*"&
6
C
c"
!c d9
634$4$6hb
&ed
V *-6)V
*-"$+,
634$ZH
2a!cP$
$>2M
T2$8
$?:3T
$
"<!$ ? )c3
>+ q
§
Q
s
T
4
&
q
§
s
G
,
,
!
&
9
;
b
,
&
9
6
*
4
4
"
"
/
q
{
~
s
V *"6h(
$+
!Wqs
$,c& 630
,xr
C
3*"P$&c(²f
¬j.!
F
K
L
L
R
I
R
L
H
F
:
BD%/
/W+^5
E -2
33
[$
3
"
)
"
6
*
4
*
C
,
b
b
b
*
,
9
6
*
C
4
,
V
*
6
C
;
6
9
°
S
4
6
;
4
*
,
b
b
*
°W*
C
& ,
" *"6
C
d) " YV 4$3;+ ,
639:
?'3
+4 Qb24 l²
q
gs%[#q
,z
qx°
s
°
s
Y" °
S
9:3; "6)*c$&
q:+B}s+b
!& 9
63*(°DV
& "Qb
t
>+
Wx
g¦ qU
hN
s
²
q
{
~
s
H
[
q
°
Z
s
l
²
q8
s
q
N
s )
8
)
8
M¦1
MQ )
8
b
+*-
[
²
°
Z
U
C
6
qU)
s
b
qU2
§
s
*"
! ,
qU
hLts
©
ª
qS{~Mx¥Ds,[ D`
'
l; q8
3s
,
²
?A@
%
²
q>{~+s
'3"R !Y
$ "R -2
"
"
F+Y! :! qU
hL
s ? 6
&
V
&
V
*
6
C
;
C
V
6
V
&
&
C
*
6
9
9
;
6
*
,
d
*
,
b
" lWq
gs
3& $,
" +*- 9
6)*-P; 6)& 6)&
344
;+6)&
(3+*«d3+&
'"626 +
F
A
C
.
L
P
.
N
C
H
R
I
0
F 2gtJtmSZ +
c+3W"$
"$)d)
)
3 13"
pp.!( q
§
O
s
±
²
q
{
~
s
V
&
,
;
6
&
&
C
6
C
,
9
C
&
;
6
&
6
&
;
6
V
;
d
*
6
C
V
c
²
c
²
b
b
$;<
() *Qd) ,0"6
P63& cp²¬c)ª
²
! 2\}
A 8c$0EF)"-$ @< 33T "$8@F)
3E$3
)Z
SMxD q
§
B
s
9
q
s
,
V
6
,
,
4
;
*
;
*
,
;
V
6
4
&
6
4
9
6
*
o
q
{
~
¥
s
3,
&
,"+;T6)&b2" +&$±}²
q>{~+s
+,-," &W"
344 Qd)*-++,
b
6²mq>{~+s)q
," @5
*-6)V
6 S
,"$63&
NaO
9
6)*
" dV *" ;+,"d,-! E &WsT
f
3+tS+
3
m +c '
"
!7< 33T "$8Y
3
)
$
&
C
(
4
b
±
²
q
{
~
s
r
C
&
V
,
9
*
r
C
&
;
6
9
;
*
;
*
,
;
V
6
4
&
6
S
34$,
6!9cQ
Q/Sf E!"*"$; +,Y6h(3+*(c(²e5$f&
63 +*
b
63*" ,b74 ""$&ed
3&
"
& 6)*- 34)( +33* E+3,
C
*-+,
6)& !MqUQDcp²s
3& c(²4c(²bW*" ,"VF+;T(3+4 b23&
!
D«(
( ( h
H
q
Q
c
²
s
z
#
c
²
c
²
. ;
*
q
Y
s
[
Q
H
*
b
V
C
*
q
{
~
s
H
[
,
C
V
/
°
y
(
+,
q
{
~
s
C
¦q«°
s
[
q
¦
x²
a
®
s
9
*
B
3&
C¦
q«°
s%[
A
63" +*8b
$,-3
86W
$>+¬(
(p
G
¨ ;
*
q
Y
s
[
Q
H
D
(
&
q
{
~
s
c
²
c
²
b
4
Y
²
C
&
r
C
,
6
4
C
6
&
6
9
y
~ q) E6
°
s
3&~
_
H
[
y
J{
J~hWq>' *"
b
*" d)3*"
'!,3&
+4+
+&
639
c(²
$f& ,-"
3 639JYG²V
#
cp²
bWb
0;+6
C
4$
C
,"3& 63" +*,-
,8+
639I*"+V*"+,-+&
< (3+,
9
6)*c(²i¤e°cp²
H," R
+ E3*-#§2))
s
$[9 q
s
{
A
q-
62
°
s
3&
~
_
A
q-
62
°
y
s
>
%#SD
¦
A
q
s
) 6
4
,
b
V
C
q
{
~
s
[
q
{
¤
°
~
_
¤
°
y
s
U
V
&
,
*
,
6
9
V
*
,
q
{
~
s
c
²
c
²
S
>++>
E
x>
MSE 6
4
,
b
V
C
q
{
~
s
[
q
{
¤
°
~
_
¤
°
y
s
U
V
&
,
*
,
6
9
V
*
,
q
{
~
s
c
²
c
²
S
>++>
E
x>
MSE q
{
/
~
/
s
H
[
q
{
~
s
q
{
]
~
]
s
H
[
q
q
{
s
q
~
s
s
3,c4$63&ed
3,q
s
6)4 ,
9
6)*(qS{
~^SsT7$&
344 Qb
b
@V
C
*
qS{~+s
H
[
,
C
V
C
/
6q>{
~^s
$,c +V
&
}
C¦
¦x
c
3
¦x
%
M3+-
q
{
/
~
/
s
H
[
q
{
~
s
q
{
]
~
]
s
H
[
q
q
{
s
q
~
s
s
3,c4$63&ed
3,q
s
6)4 ,
9
6)*(qS{
~^SsT7$&
344 Qb
b
@V
C
S+
C
6>
+
} q
{
/
~
/
s
H
[
q
{
~
s
q
{
]
~
]
s
H
[
q
q
{
s
q
~
s
s
q
s
6)4 ,
9
6)*(qS{
~^SsT7$&
344 Q
b
@V
C
q
{
/
~
/
s
H
[
q
{
~
s
q
{
]
~
]
s
H
[
q
q
{
s
q
~
s
s
)
)(S
^ST7$
3Q
@ *
q
{
~
s
H
[
,
C
V
/
q
{
~
s
,
V
&
C¦
¦qx°
s
[
q
²
sc9
*
3&
¦qx°
s%[
AM63 +*-b
,"!
3! +
F
A
C
.
L
P
.
N
C
H
R
I
0
F z
#
q
*
q9 s¦ T q9 sxs
$
36
*
;
S
*
&
V
b
&
8
1 S%
*
;
S
*
&
V
b
&
8
1 S% q
§
a>
s
q
h
ª
s
q
{
~
s
[
²
±
²
q
{
~
s
q
{
~
s
"-)
+) 8<3
q
§
>
s
"- b
,
6
;
6
&
,
&
²
R
A
3"
-
$tm>+¦
d b
,
6
;
6
&
,
&
²
R
A
3"
-
$tm>+¦
d
9
6
*
,
C
&
d
±
²
q
{
~
s
b
b
#
,
6
V
&
6
&
,
9
6
*
,
C
&
d
±
²
q
{
~
s
b
b
#
,
6
V
&
6
&
,
q
§
s
T
0
"
1
<
"
J
Q
'
0
/
,
q
§
s
T
0
"
1
<
"
J
Q
'
0
/
,
q
{
~
°
s
H
[K<AD
z@
8(
ak
t
9
*
C
;
V
6
4
&
6
4
q
s
[
y
z
{
J
~
Y
²
f
j
,
Q
b
b
A
,+
+*-+&
@*"6
63,P$&aYG²Sb
*-+,"VF+;T()+4 )Tc
C
,
9
;<
3*
q8Y6sM$,P ,+
+*-+&
R9
*-6)
Q
3&
[
qS{~s%[{
y
z
Bt~,
d ,"; *"$
$& 3&
6393b2 &
q
{
~
°
s%[#q
°
s%[#q
YG²
s%[r
C
3 *"!;d,-
F6)4
c
F+
>+
03
8 q
§
§
s
]
V
&
&
C
*
*
[
*
q
{
~
s
/
&
,
6
4
q
°
s
A
+}b ,-"$&ed
C
$," $&edR" d;
3,-+, H
86 q
s
q
A
b
,
&
d
C
,
&
d
;
,
,
H
86 ;
*
q
Y
s
[
Q
H
*
b
V
C
;
*
q
Y
s
[
Q
H
*
b
V
C
K
0
F
I
"
/
6
'
6
7
6
q
§
s
"
O
6
J
7
J
:
#
6
J
S
6
"
Q
±t²mqS{~s%[q8kz
°
;y
s
q8
J
°
J
A
z_q
° J
Ms
°
;y
zQ
°
s+
>+ +/&
G;" F
DHG"
OE
<
P
C
¦«
4K*
`! 6
7
I
*
[
*
q
{
~
s
:
#
:
1
1
0
#
6
S
7
0
7
I
"
:
/
*
"
J
A
z
0
q
°
s
3
V
7
#
"
9
"
J
:
1
0G
7.6 *
0G*
J
*
1*7
690G a±}²
0G ac(²
cp²
<M
I691EI
6,J
/)021
:"/8/RQ
1
0G =J*7
:+
7
0
7DI"
/21K*3J
*
[
3
Ac 3-"+8)
E
+
!"? ;
*
q
Y
s
[
Q
H
*
b
V
C
M
;
G;" F 687 I
!
q
{
~
s
[
A
z
q
°
!J
s
°
y
y
zQ
°
y
:1
1
0G ;#"6 FS
7
0
7 I"
G:"/
*O"EJdQ<A
zP
0
C
+q«°
s 3
O
%D="
S+C
K ! q
s
q
s
7
I
"
:
/
*
"
J
A
z
0
q
°
s
3
O
%D="
S+C
q
s
q
s
*
H
H
0
J
"
7
I
:
7
*
q
{
~
s
[
3
I
"
>+%
;
M
M
q
s
q
s
*
H
H
0
J
"
7
I
:
7
*
q
{
~
s
[
3
I
"
>+%
;
M
M
q
s
q
s
*
H
H
0
J
"
7
I
:
7
*
q
{
~
s
[
3
I
"
>+%
;
M
M 4
q
{
~
s
[
°
y
z
°
y
y
J
q
°
z
s
y
°
y
y
(5
(
y
qUQ
z^
s
°
J
°
]
(
yq«q+"z
s q
°
z^s
J
Ms
3"
-/
e
"
)" 2
P
")
38
+)+
"$3 +
9
6
*
V
*
6
(
&
d
6
*
b
b
*
b
,
6
,
;
6
&
;
4
C
,
6
&
,
J
/M
e1
%
58
a
M
P
,* 8+/
,M",+KNU
9
6
*
V
*
6
(
&
d
6
*
b
b
*
b
,
6
,
;
6
&
;
4
C
,
6
&
,
J
/M
e1
%
58
a
M
P
,* 8+/
,M",+KNU +
F
7
-
L
K
L
. . ;
*
q
Y
s
[
Q
H
*
b
V
C
")
a:t
3
"3
-+
3 6
7
I
*
[
*
q
{
~
s
:
#
:
1
1
0
#
6
S
7
0
7
I
"
:
/
*
"
J
A
z
0
q
°
s
3
V
7
#
"
9
"
J
:
1
0G
7.6 *
0G*
J
*
1*7
690G a±}²
0G ac(²
cp²
<M
I691EI
6,J
/)021
:"/8/RQ
1
0G =J*7
:+
7
0
7DI"
/21K*3J
*
[
3
A
t
3
T
,
,
*
6
&
,
9
*
6
§
N
q
s
&
V
*
6
V
*
,
6
9
*
b
3,R46)&ed 3,
*
6)*
*
z#
bg±}²
q>{~+sP; 6)&
()+*xd)+,
"6
q
0J
°
xsx¤
q8z
°
;y
sC[
°i¤eq
°
z^MsT,¡Y&
P6! *0 3& b
9
*
[
" +&
xS+
z
°
y
s
[
°
¤
q
°
z
s
¡
&
6
*
&
b
9
*
[
&
xS+
±t²qS{~s%[
4$
:
4
q
{
~
s
°
y
;y
q
°
y
z^s
[
°
°Mz
2g:¦<! eM$
3 +
W
"
!
,
*
,
C
4
,
9
*
6
§
N
q
s
b
#
&
d
&
6
;
;
6
C
&
T 4$
(5
(
y
q
QGz^s
°
[
°
J
q
°z^Ms
y
'
E '
J
}$
/M
e1
C
`
*. G_}O>+K
1`E
P
G( (
+/ )"
,!E +
F
E$-
L
K
L
. . ;
*
q
Y
s
[
Q
H
*
b
V
C
"-+
3 )
Cc$'Ex
3"R$ $
&
4
4
;
*
;
*
,
;
,
b
*
[
9
&
6
&
4
9
q
s
,
,
r
C
*
&
c
²
f
j
b
3&
09
C
&; 6)&
*
$,462;+34$4 @; 6)& ,8<3&
6)&c(²4_c(²36"+?"
4$6
;
C
,
6!9
*
[
? 6
b
q
§
Q
s
q
§
>
s
b
4
4
;
6
&
,
r
C
&
;
,
6
9
&
*
,
C
4
6
9
,
,
;
6
&
H +
F@
BADC
L
K#CFE
F
*7
4
q
{
~
sW
0G %7DI"> *`'
"K ;:"7
0G
%
! qUQDc)¤e°
s
*
q9 s%[
{ TMq. s%[
~!
$&
q>§2s
+
F
@
A
C
L
K
C
E
F
*
7
4
q
{
~
s
0
7
I
"
*
'
"
:
7
0 )
8
P >+
q:
s
O*
H
H
0
J
"%7DI=:"7
*
[
*
q
{
~
s
:+ /#
"
Q
*
J
Q
3
I"K
4
qS{~s%[
°
y
J
°
y
J
!
qS{~s
687 I
!
qS{~s[
A
z_q
°
!J
Ms
°
y
;y
zQ
°
y
:1
1
0G ;#"6 FS
7
0
7 I"
G:"/
*O"EJdQ<A
zP
0
C
+q«°
s 3
O
%D="
S+C
K q
s
O*
H
H
0
J
"
7DI=:
7
*
[
*
q
{
~
s
:+ /#
"
Q
*
J
Q
3
I"K
4
qS{~s%[
°
y
J
°
y
J
!
qS{~s
8
S
_
! ;
*
q
Y
s
[
Q
H
*
b
V
C
9
6
*
&
Q
Q/S[ !"*"eG
b}h
q9 s%[q
*
q9 s¦ T q9 sxs+b23& £-*"
C
; "$6)&
62°P639
,";+34
3*-,c6)*
*";+ ,
b
$44Z
d & 63"+
qCs
]
P;+63& ," +*YG²I
63" 3,
r
C
63+&
'3&
,
C
V
4$639
3
H
[
c
¤
°
b
H
[
q
Q
s
b
[
y
[
C
&
Q
Q
S
*
G
! ;
*
q
Y
s
[
Q
H
*
b
V
C
K
0
F
I"C
*`
1
7
6 G
±
²O:
+"K
:
S`"EJ
7
G
c
²
c
ª
²
:+ /# J):
7
6,J
9"EJ
"8Y)*?:"7
6 G q>§
>Qs
687 I
²[Kkz
°
;y
3
Ac
"8c3-"+8)
)$h
")
+3W"$
fE!1}
3 " :3T
3
T
V
*
,
,
,
*
6
&
9
6
4
4
6
b
,
9
*
6
;
6
&
&
C
6
9
±
²
&
9
;
;M
C^M
M,
D)e
«
°
y
y
q
°
y
z
s
[
%
1
X
q
Q
c
¤
°
s
¤
°
[
()+*"Qd)d6h() *344{ c
¤e°
bb
~Z|qc
¤e°
s
ªkVG2 b
639
4
xqS{~+sT
3-" -)
"
"3
)3
#}! ;
*
q
Y
s
[
Q
H
*
b
V
C
_
s
J
y
[v~
m
&
1
C
;
&
,
C
&
r
C
4
*
&
*
6
C
d
y
[
~
D
(
&
&
!,
3
F6/(3Qb
4 p~^_1[
Mq. _sW[
yJ
{
J
~bZb
;<
&+;+ ,","3*"4
,"!,xV
,
~^_
Aeq- E6
°iy¦sT
&
1
C
;
&
,
C
&
r
C
4
*
&
*
6
C
d
y
[
~
D
(
&
&
!,
3
F6/(3Qb
4 p~^_1[
Mq. _sW[
yJ
{
J
~bZb
;<
&+;+ ,","3*"4
,"!,xV
,
~^_
Aeq- E6
°iy¦sT q
s
6
&
(
*
,
4
b
,
C
V
V
6
,
q
s
6
&
(
*
,
4
b
,
C
V
V
6
,
$
m
e q
s
{
[
A
q
b
{
A
q
6
°
s
s
&
~^_
[
y
J
{
J
~
A
q
6
°
y
s
b
+*-
( YG²S
y[
~
q
s T
,
6
4
C
6
&
,
_
,
&
q
s
;
6
*
*
,
V
6
&
;
(
4
6
,
6
4
C
6
&
,
639W*
q
¬s%[°
x{b/ q
¬s&°
;y~E_qI E6
°
;y¦s
gTc ,
6)4 ,Z,"& ;+
. ;
*
q
Y
s
[
Q
H
*
b
V
C
9
6
*
&
Q
Q/S[ !"*"eG
b}h
q9 s%[q
*
q9 s¦ T q9 sxs+b23& £-*"
C
; "$6)&
62°P639
,";+34
3*-,c6)*
*";+ ,
b
$44Z
d & 63"+
qCs
]
P;+63& ," +*YG²I
63" 3,
r
C
63+&
'3&
,
C
V
4$639
3
q
s
6
*
d
(
&
q
{
~
s
c
²
c
²
q
6
*
s
b
V
C
qS{~+s
[
°
y
J
°
y
°
y
z
°
y
;y
°
y
z
°
y
9q
²
s%[K<A z@c*-+,-V
; () 4
x>+
( T
*
*
V
*
;
,
4
q
{
~
s
*
;
,
,
C
;
h
q
s
[
q>{~+s
3&
$,?&6)&2Sf,-;
34$3* b'3&
344'" +,-
3*-
;+6)&M
C
d
!"0&
3ATc ,
,$
E
!"
9
6)*
"[Kq
,"& ;+
b
0 &Eb
6)*"#
6h(3+*
V
4$s¦bZ3&9
6)4$46hb
,'
,-"*3md)
"9
6)*8b
3*-&
C
;T$63& 9
6)*
d)+& *34
"
H%/2143
1*687
3¨beX
E E
B )
$f&V
3*-"$;
C
4
3*
b
P
()
4
/
qS{~s%[
°
y
J
q
{
~
°
s
°
E=
-@ "+ q
s
*
6
&
6
b
6
&
b
,
,
C
"
Q
]
C
,
*
&
&
C
*
6
9
Rb
,";
!4
3*
!& ah
q9 sW[
q>{~+s+bZb
;<
;
3&
6)& 4
G2$,-Y9
{[
A2CTc +&b
b
*-&ed {
[
A
T
&
b
b
*
&
d [
J
_
3
. %v
J
b
"
pY²V
#
b
_
[
AM3&
*q. _s%[v{b b
@ h(3
q. _
s
J
"*q. ;
*
q
Y
s
[
Q
H
*
b
V
C
e%
P3 3
$ E W3- T
,
;
6
&
,
,
*
6
&
*
,
C
4
,
9
*
6
(
6
4
q
²
±
²
s
[
&
&
4
&
*
;
34;
C
4$!6)&bWb
$;<
b
@6)
+
' T
,
;
6
&
,
,
*
6
&
*
,
C
4
,
9
*
6
(
6
4
q
²
±
²
s
[
&
&
4
&
*
;
34;
C
4$!6)&bWb
$;<
b
@6)
+
'
t
>
e
I
"
"
'
§
N
3
q
s
$
&
f
j
b
,
;
B
b
V
*
6
6
9
6
9
&
&
4
6
d
C
6
C
,
,-! E &W9
6)*'"
2
S
3$;P$&
d)+*-,
b
"
?&
!
C
*34
V *-$
2
$& ,8+3
639
c(²Z$,_d3() &Z?$[
3V V 4$ ,Pb
6
C
+,-," &W"
34
;<
3&ed3+,R"6 ;
3,-?639cp²
639
;<
3*"3; "+*",-"$;Y
+I *" &Wc9
*-6)
Q
]
Y" +*- 9
6)*-d3,",
C
E
9
*-6)
&6/b
6)&
;<
3*
q8Y6sW[
Q2CT
6E,-$
V 4$9
& 63< $63&b4
H
!
D
¦
/fE!""
)R!W q
s
H
[
c
¤
°
b
H
[
q
Q
s
b
[
y
[
C
&
Q
Q
S
*
G
! ;
*
q
Y
s
[
Q
H
*
b
V
C
z
#
°
$,
-+; "$6)&?9
*-6)
"6¬°
d3& TMq«°
¬s%[ °
y
Mq
¬s
T
,
6
4
C
6
&
,
_
,
&
q
s
;
6
*
*
,
V
6
&
;
(
4
6
,
6
4
C
6
&
,
639W*
q
¬s%[°
x{b/ q
¬s&°
;y~E_qI E6
°
;y¦s
gTc ,
6)4 ,Z,"& ;+
. z
#
°
$,
-+; "$6)&?9
*-6)
"6¬°
d3& TMq«°
¬s%[ °
y
Mq
¬s
)
8
q:(
s
$[9
C
,
q
s
6)4$ ,
!&
q
{
~
s
[
q
{
¤
°
~^_
¤
°
y
sc3,
V & + $&
q
§2
§
s
b
4
qS{~+s,[
q>{~+s
J
1
²
a >
4
/
q>{
~
J
s
Sc '
E!)M$
/3+cP-
-"+
3Z-+ -+"
<!")
!,
;
()E q
T
,
C
6
&
,
6
(
*
,
,
6
9
*
V
*
,
&
(
,
6
9
°
y
c
²
6
C
4
6
°
c(²e
s¡ *-b
$,-q:9q
s
9:!$4$,s+b
4
q>{~+s%[
qS{~s
H'h
P "h3d" P3"-+8$3
T$3
)
>+TK'!
q
(
s
? 6
b
b
V
*
6
(
,
,
*
6
&
&
C
;
6
&
6
&
*
[
*
q
{
~
s
? ;
*
q
Y
s
[
Q
H
*
b
V
C
"-+
"
"3E 3< $3
3 q
s
*
b
4
4
6
b
4
4
;
*
;
*
,
;
,
b
C
C
,
,
&
6
6
&
,
$&
*-62
C
;+ &
dV *-626397639qUts
:
Z=
)
>+%
S+,#
+ ")
¬(
3
U q
s
*
b
4
4
6
b
4
4
;
*
;
*
,
;
,
b
C
C
,
,
&
6
6
&
,
$&
*-62
C
;+ &
dV *-626397639qUts
:
Z=
)
>+%
S+,#
+ ")
¬(
3
U q
s
]
(
*
q
{
~
s
[
q
{
~
s
[
q
Q
y
s
b
,
6
c
²
&
4
q
Q
y
s
[
4
qUAAts+b & ;+
b
E
3,-,
C
q>{~+s [
q:A<Ats
]
"
C
,
h(3"6
"+*- E& Y d E!*-$; +,:
[ q
. /
. s
,
C
;<
Ny7J
±
[
A
:8Zc "?!"
" +$-+
;
M
<
"
c @ q
s
T
*
*
V
*
;
,
4
°
y
y
q
°
y
z
s
,
C
;
b
[
A
T
,
,
6)
(
$6
C
,
9
63*
"[KP3&9
6)44$6hb
,
9
6)*
!*"
*!*-
"? ;
*
q
Y
s
[
Q
H
*
b
V
C
6
*
qS{~+s
[
*
qS{~
J
s
9
6)*
Aeq
E6
°
y
]
y
sT
$[9
*
[
A
+&
4
qS{~sp[
qS{~s¦b
3&
M9
6)*"
C
4
?*-+,
C
4,
9
*-6)
q:
sTTc
C
,P4$
*
[
*
q>{~+s&R
A
Tc +&
*
qS{
~
s,[
*
z
)
$f&R(
$ b
6!9
"
Q
*
JMQDb b
()
":z
Q
Qeq
*
z
Ms+JMQ
3& +& ;
*
q>{
~
J
s[
*
q>{
~
s[
*
z
@9
6)*0
3;<
°
;y
kTc
$&
C
; "$6)&
2VF63" +,-$,Y!V V 4$+,c6
4
/
q>{
~
J
sc$&
q:(s+b
b
$;< 34$4
()d d,"3 EY(!34
C
4
/
q>{
~
s
54
C
dd)&ed
$&6b d*-+,
C
4c9
6)44$6hb
,+
:0+-
3$h
3$'<
3! ;
*
q
Y
s
[
Q
H
*
b
V
C
$&
C
; "$6)&I
:$8
= 3-
h
"
+="
+
"$e
M
F+d3
5
q
s
]
*
&
6
b
*
C
;
6
;
6
C
&
&
d
&
C
*
6
9
b
[
A
b
\3b639@,"634
C
"$6)& ,
N:«±/
°
6398N
y
J
±
[
A
Tc ,,
,"6)
b
!
4
3
F6)*-$6
C
,
C
4$+
+&
3*- Qb3&
b
$44
F
6) E""+Z1
C
E; ?d"6,
*"
q
°
y
zKMs
°
y
;yqUQzKMs
°
$&
,-< +
9
6)*"
C
4
d3() ,E"
&
C
F+*P639pqDN:«±/5
s'b
*"
N
3,°
S
3$;
(!34
C
!6)&
«b!& =" E4$3,-d"+*"
°
]
(
y8q«q ",z
Msq
°
z
Ms JMs
;+6
C
&
", (qDN:«±/5
sZb
+*-NE
!,
(!34
C
$63&
4
3*xd)+*
6)*c r
C
34
"6
"¤)Q2
'
J
6 e
f
¦
3-
<
3M
6£
;0
)
3
"
" "$ '
$ +
F
C
E
K
F
$
&
q
§
§
s
b
;
,
;
*
q
Y
s
[
Q
b
V
&
6
&
6
9
,
*
,
q>{
~E8s@3&
639
*
q>{~+s+b
b
C
,-YG²
V
#
c(²
3,
,-
,-"+
6!9
*"+V*"+,-+&
< (3+,
_9
6)*cp²¤e°ic(²
q
]=
$
,"6
$&
,-+4$ ; "$&ed
C
&¨r
C
,"6)4
C
6)&
£]YG²
639
y
~ q-
62°
s
s
[M$
! $
,
&
,
;
6
&
,
r
C
&
;
6
9
V
*
6
V
*
,
6
9
*
6
&
;
#
*
,
6
4
qU3&E!4$,"6d*-+,
C
4,9
*-6) K"
V *"6
639
639Aq
§2gNts q:ts«s
!&+" +*
*
[
*
qS{~s
&6)*
(!34
C
C¦
¦qx°
sC[ q
²
s
+VF+& ,'6)&
"
!0;< 6);+Qb
!4 6
C
d) ?" P3*","$&d
q>{
~E8s
;<
3&ed)d93&63 *c,-
,-"+
6397*" V *" ,"+&
!()+,
,
C
," Z @
F
K
L
L
R
I
R
L
H
F
:
PQ
G
K q
s
I
"
"
O
H
"
7
[
²
q
s
:
S
"
"
J
6
7
I
*
[
*
²
q
{
~
s
:
J
#
"
9
"
#
6
q
§
§s 3
q
$8sBGC"*7
K"
7 I"
%6
691EI/,"*7
1EI=:+ ;:1*7("K
:GJEJ21*6:"7("
#
7
J
"E"(q:
gBts
"3
I"K
!q«°
s%[
C¦
+qx°
s>:GJ
6 q
§
§s 3 q
s
I
"
"
O
H
"
7
[
²
q
s
:
S
"
"
J
6
7
I
*
[
*
²
q
{
~
s
:
J
#
"
9
"
#
6
q
§
§s 3
q
$8sBC*
K
%
9E,*
E=+;*(K
GE2*"(
E(q:
gts
" q
§
§
s
q
s
G
"
7
"
7
I
"
6
6
1
I
/
"
7
1
I
:
:
1
7
"
:
J
J
1
6
:
7
"
#
7
J
"
"
q
B
s
3
I"K
!q«°
s%[
C¦
+qx°
s>:GJ
6 q
§
§s 3
3
1
C
V
V
6
,
;
*
q
Y
s
,
6
T
&
6
&
*
*
,
;
*
3,P GO
(
/
3°
y
(2 +,k{
y
z
Bt~!}b7,"6 "
6)*" *cf
¤e°
y
j
,
°
S[ G2 34>bW3&
d*-+,
C
4
9
6)4$46hb
,+ T
C
,
4
;
*
q
Y
s
[
Q
n
;
;
6
*
&
d
6
*
#
§
b
b
C
,
{
c
d
{
d°
3,
,-
,-"+
639'*"+V*"+,-+&
< (3+, 9
63*c(²
¤e°ic(²
3&
VF+*-9
63*"
"
;+6)&,-*
C
; "$6)&q
§2
§s
gTc ,7 3,
"
!(!3&
<Qd) !734$4)"
qS{
~^sZ
3*-$,-
4$6)&d?6$cRTc +&
q:
s09
6)4$46hb
,
W
$&
C
; 6)&
6)&
q:63*
6)&
*
s+b
3VV 4
$&d
X
+
MNaQ
F+46/bd
$f& ;+*-
3,-$&ed
6)& bF" @&
G8
6!9
@6)*- +*
1[
d3+& *!"+
(+ *"6
+,@639k
qsp[
y
J{¨
Jv~^
$,P (
+
°)Tc
C
,
$,°
Sf E G2$ E34
3&
; 6)&
<3& ,
b
b
;<
," 6hb
,q:8s
34$,-6?$& ,
;
3,-3
' @
F
C
E
E
F
*
H
H
J
"
7
I
:
7
;
*
q
Y
s
[
Q
<
/
"
7
{
~
"
:
Q
"
/
"
'
"
7
J
c
JK*
1EI
7 I=:"7qsC[ayJ{
J~MS`"K
"K ;:"7
"EJ:+
6 '
:1S"6 /:+
QBY)*?:
#+ ;:"7
691
G ;#`"K
[
<:+ /#
/,"*7
[
²mq
s 3
I"K
7 I"
/8/! ;
*
q
Y
s
[
Q
H
*
b
V
C
+3-
+) -
+ 3
-)
-"$+
!0"
")+<3 E8
3 $
,
&
,
;
6
&
,
r
C
&
;
6
9
V
*
6
V
*
,
6
9
*
6
&
;
#
*
,
6
4
qU3&E!4$,"6d*-+,
C
4,9
*-6) K"
V *"6
639
639Aq
§2gNts q:ts«s
!&+" +*
*
[
*
qS{~s
&6)*
(!34
C
C¦
¦qx°
sC[ q
²
s
+VF+& ,'6)&
"
!0;< 6);+Qb
!4 6
C
d) ?" P3*","$&d
q>{
~E8s
;<
3&ed)d93&63 *c,-
,-"+
6397*" V *" ,"+&
!()+,
,
C
," Z $
,
&
,
;
6
&
,
r
C
&
;
6
9
V
*
6
V
*
,
6
9
*
6
&
;
#
*
,
6
4
qU3&E!4$,"6d*-+,
C
4,9
*-6) K"
V *"6
639
639Aq
§2gNts q:ts«s
!&+" +*
*
[
*
qS{~s
&6)*
(!34
C
C¦
¦qx°
sC[ q
²
s
+VF+& ,'6)&
"
!0;< 6);+Qb
!4 6
C
d) ?" P3*","$&d
q>{
~E8s
;<
3&ed)d93&63 *c,-
,-"+
6397*" V *" ,"+&
!()+,
,
C
," Z
@
F
A
C
P
.
H
O
E
C
K
L
K
E
O
.
H
. C
K
R
L
H
F ]
;
6
;
#
6
,
C
6
&
6
9
,
;
6
&
&
,
;
*
&
d
*
&
,
639I9
63*"
C
4$qUhLts¦b
& 63<! 4 QbW"
9:3; "6)*",
²
q>{~+s+bW ';<
!*3;T+*
%b2!& E"
d)+&
C
,
@/b
b
$;<
!*"34$4
"+*"
$&+
W
{
3& ~/Tc
C
, 4 ¥
!& °
F
V *" E ,
639Ac
q¥[
°
344$6hb
+s¦b
<[
d
¥b
3& 4$
qs,[v
y
z|{
J\~
VF6),",-$
4;<
3*!; *",-;
VF6)4
& 63 E$3439
6)*
,"6)
!UY*"$&29
+4$P
62
C
4$!oM6h(3+*
Ye¢
ATc
,+HA{~
¬c_b6q>~+s%[
¥b
3& d)+&+* +,
3&E$ EQd)$& 3*- r
C
3 *"!;
TG
& ,"6)&
639A
q
b
$;< & V 3*-"$;
C
4
3*c EV 4$ ,
Q
d{
>
<;sT
C
*-" +*b
b
4$T
E G2$ E34c0S[6)*"+*
$&
3&
][
*"&ed'
G
+&,"$63&
639
c
d) & +*"!
W ¬q
"
( +*"6
+,
639s,
0 ;
344F" $,
!& ,
"
! ][c
J
b
"
¬¬c_
6)& ;3 @
F
K
L
L
R
I
R
L
H
F
:
PQ
G
K (¬
q
s
X q
;
s
{
A
q
6
°
s
<
:
#
"
:
1
I
c
J
*
1
I
7
I
:
7
y
~
q
6
°
s
<
1G /#"687
6 G q
s
I
/$#GJ43 q
;
s
{
A
q
6
°
s
<
:
#
"
:
1
I
c
J
*
1
I
7
I
:
7
y
~
q
6
°
s
<
1G /#"687
6 G q
s
I
/$#GJ43 q
;
s
{
A
q
6
°
s
<
:
#
"
:
1
I
c
J
*
1
I
7
I
:
7
y
~
q
6
°
s
<
1G /#"687
6 G q
s
I
/$#GJ43
3
q
s q
s
H
X
*
6
6
6
9
q
s
b
[
J
°
b
c
b
EATc +&z
)[J
, (
$,-$
4c
¬°W3&
3,
E& $ E34VF6)4 2&6) E$34
y
J
{
J
y
J
{
'J
~h q:
s q:;
s
,Y*-(
34Uq
;s q:tsTH"
626),- !&W
b
y
~ q[ E6
*°
sTpTc &
qsW[¬yJ
{
J
~
b
qS{
~
s
[
q>{;¤e°
Mq
y2J {
IJ$~+s«¤e°
s3d)+& *!"+,
3&
6)*" *
b
$;< E!
°)$,
,8*"; "4
4$3*«d3+*
"
3&
'
M
C
8MS/
6S
_}
>+
3
q
s q
s
H
X
*
6
6
6
9
q
s
b
[
J
°
b
c
b
EATc +&z
)[J
, (
$,-$
4c
¬°W3&
3,
E& $ E34VF6)4 2&6) E$34
y
J
{
J
y
J
{
'J
~h q:
s q:;
s
,Y*-(
34Uq
;s q:tsTH"
626),- !&W
b
y
~ q[ E6
*°
sTpTc &
qsW[¬yJ
{
J
~
b
qS{
~
s
[
q>{;¤e°
Mq
y2J {
IJ$~+s«¤e°
s3d)+& *!"+,
3&
6)*" *
b
$;< E!
°)$,
,8*"; "4
4$3*«d3+*
"
3&
' @
F
K
L
L
R
I
R
L
H
F
I"
Y)*=:+
7
6
7
6
"EJ
²
q
{
~
s8:+ /#
±
²
q
{
~
s&:+ ^"> ^"
/$:
7("
#
Q
6S+,
}mS+ ²
q
{
~
s
[
°
Z
±
²
q
{
~
s
gC
k
!«
7 I
J*6#`"EJS"8Y)*=:"/
l
²
q8
s
[
q8
z
q
°
s
°
s
%6
²
q
s
[
A
3
Ac
)$h
")
+)
3-$e@ d$T
c
3-$ )3+
7 I
J
6#`"EJS"
Y)*=:
/
l
²
q
s
[
q
z
q
°
s
°
s
6
²
q
s
[
A
3
Ac
)$h
")
+)
3-$e@ d$T
c
3-$ )3+
3
T
,
9
6
4
4
6
b
,
9
*
6
;
6
V
*
&
d
4
9
&
,
b
d
(
&
q
N
s
3& |q:)Ms q
$
s+b b
" " R9
6)*-
C
4
q
§
aLtsc9
6)*W±}²mqS{~+s+b
3#W$&edE
6!
V
!*-,'639
qUNMs
&W"6M3;+; 6
C
&
'
3
T
,
9
6
4
4
6
b
,
9
*
6
;
6
V
*
&
d
4
9
&
,
b
d
(
&
q
N
s
3& |q:)Ms q
$
s+b b
" " R9
6)*-
C
4
q
§
aLtsc9
6)*W±}²mqS{~+s+b
3#W$&edE
6!
V
!*-,'639
qUNMs
&W"6M3;+; 6
C
&
' T
*
9
6
*
b
V
*
6
C
;
&
q
L
s
r
C
4
, qUN
\B
s
,
²
?A@
%
²
q
{
~
s
[
±
q
{
~
s
$JSC
}>+ q
N
B
s b
"
±
q
{
~
s
[
²
±
²
q
{
~
sT
@-"$$
++
"
"+-Y b
"
±
q
{
~
s
[
²
±
²
q
{
~
sT
@-"$$
++
"
"+-Y b
±
q
{
~
s
[
²
±
²
q
{
~
s
@-"$$
++
"
"+-Y )+
3
3 F
!3+
R )"
3 ]
,
4
4
&
6
G
V
*
,
,
d
&
C
,
6
9
6
*
b
r
C
(
4
&
4
b
d
*
6
9
d; 6)&
C
;T6)*
; 6)& 1q
3s
639
%b
$&?"+*"
,
6393{?3& ~hCTc $,
$,c+3,-
&
;
3,-
86 ]
,
4
4
&
6
G
V
*
,
,
d
&
C
,
6
9
6
*
b
r
C
(
4
&
4
b
d
*
6
9
d; 6)&
C
;T6)*
; 6)& 1q
3s
639
%b
$&?"+*"
,
6393{?3& ~hCTc $,
$,c+3,-
&
;
3,-
<
!86
<
@
F)"d
)
" dE)
+
+ ;<
!*
q
Y
s
[
Q
b b
;< b
@,
C
V VF6),"d9
6)*
" d E6)
+&
+ X
[
q
{
~
s
[
{
y
z
B
~
[
y
/
,
;
*
&
&
b
,
G
4
E63& $;(r
C
3 *"!;
(
,"6)*
/y
pTc +&
[
tb
3&
9
63*
3&
V
&RV *" E°
639gc_b
!q«°
s%[#q
²
sT]=d
()
q
s
A
zP+}bb
C
!E
+
$
2
q
s
[
A
*
V
&
d
/
6
b
"
) 1
3P$@" ? @
F
K
L
L
R
I
R
L
H
F
:
PQ
G
K 6 FS
7DI` ^"E"1G /#"687
6 G =J
:+ ^"
"8Y)*6, G:"/,"K
7
T
t q
s
R
A
! _
8E q
s
! q
s
{
A
q
6
°
s
<
:
#
7
I
"
"
"
O
6
J
7
J
c
J
*
1
I
7
I
:
7
q
s
y
J
{
J
~
A
q
6
°
y
s
! &
U
K
V
I
<
C
E
+
Y
?
Z
[
1
?
N
R
L
X
3
(
bcde
L
g
L
3 'P\n
B §R
CHM
bM
.n°J
´
`n2
¡
¢
¡
£
¤
¥
¤
¡
¦
¨
|
7
z
v
a
©
ª
«
|
«
ª
¬
~
ª
7
6
®
j
+
z
1
¯
±
v
²
³
a
µ
|
7
©
|
¶¸·
¬
687.7
6P®¹Jº
|2¬d}
¼»R½
:§t
½
t¾z
«|2{¿a
³
ª
®
}À
7
©|
M®
}~
7¸
{|>Á
·
M®
|
®
7´¼»
a
ÃÂ
aRÄ
l
Ç
N0N
M
7M
P
N +
1
Å
»
±
Æ
7
©
|
®
È
6
¶
{
|
}
~
|
}
6
»
ª
®
}
®
¬
É
6
»
±
6
¶
}
}
Ê
6
®
7
©
6
¶
ª
¶
|
³
ÀJ C±Ht
Z
Ê
L
8
2
N0N
Ç
+
1
6
»
±
7
©
|
®
|
6
7
©
|
{
È
6
¶
{
|
}
~
|
}
{
È
v
p
Ê
+
1
+
1
6
»
±
Ë
7
©
|
®
È
v
p
Ä
2
¿
P
N
,
+
1
+
1
6
»
±
Ë
7
©
|
®
È
v
p
Ä
2
¿
P
N
,
Ì
~
{
7
©
|
{
³
À
6
®
ª
¶
|
¶
Í
6
6
Î
ª
®
}
Í
6
6
6
Î
Ä
F
B
h
>
Ì
~
{
7
©
|
{
³
À
6
®
ª
¶
|
¶
Í
6
6
Î
ª
®
}
Í
6
6
6
Î
Ä
F
B
h
>
m
A
I
C
I
I
E
C
<
&
I
I
<
<
IN
<
I
<
S
&
K
K
EUÏN
V
I
G
<
C
<
NI
<
+ÐÑ1
? @
F
K
L
L
R
I
R
L
H
F
:
PQ
G
K
$"3
W`
"$+ " ?
&
b
;
;
,
;
6
&
q
s
,
(
,
6
*
q
/
s
b
,
&
;
*
V
;
6
&
!8
,
<3
3
C
*-" +*b
;+6)& :q
gs
[
q
/
sY9
!q
sZ[zP)0+*"
b
C
,"
C
4$V4$$;+!()
& 63!6)&
9
6)*
(2,"6)*-, b
3& q
/
s
,
V
& cV
!*-Zq:Ug!mb)"
V
3*8
;+6)V *-$
b
"
s
6!97" d (
$,-6)*
639
/
]
"
q:/Qs
b
(V
&
v
, `
'
[
`
/
y
q:*" ,"VZ
`
y
/
y
s
&
&
`
'
[`
y
q
*"+,-VZ,`
y
y
s
$cT) £
"+-Z2T
)R $ eR" $
&
;
,
d
,
(
&
q
*
,
V
6
s
6
&
&
d
,
b
q
N
B
s
b
9
6
*
C
4
qUhLts
F
b
*"- &
>«DC
6S+
>++
&
;
,
d
,
(
&
q
*
,
V
6
s
6
&
&
d
,
b
q
N
B
s
b
9
6
*
C
4
qUhLts
F
b
*"- & q
L
s
b
*
&
> qUN
a>
s
©
ª
q
{
~
¥
s
[
¥
y
±
q
{
~
s
±
q
{
~
s
q
N
>
s
b
*
b
*
± q>{~+s%[
~
y
y
^(]
`
y
!" # %$
<
! <
I
+
O
1
S
&
.
^
`
`N
N S
&
U
K
V
I
<
C
E
+
Y
? Z
[
1
? `N
R
L
X
3
(
bcde
L
g
L
3 &
U
K
V
I
<
C
E
+
Y
?
Z
[
1
?
N
R
L
X
3
(
bcde
L
g
L
3 ' HMn P\
W§q
0
.0
¼g
2N
0
Ô
bM
2
¡
¢
¡
£
¤
¥
¤
¡
¦
¨
|
7
-
/
$
¶
~
µ
Ò
|
7
7
~
{
¹
|
®
|
{
ª
¬
ª
¶
¶
~
Ó
·
7
6
®
¶
µ
|
¹
6
«
|
®
³
Õ
687
©,-ÇÖ
ÄL×'©|
®?7
©|
º§®
687
|
·
ª{
7T¼»
<
+
Ðu1
6
¶
+.-
ÂØ
1Ù:\Ä
B¼
`=
>N
Ù
Ü
h
LÞ
o
'
ä
N
N
Ú
{
»
Ä
Û
I
G
U
V
I
f
E
<
E
E
U
I
<
K
I
G
Ý
ß
? Û=
C
E
,àâá
V
Ý
ã
<
E
C
&
<
IgN
I
+.-/0$21
+.-7å/0$0å21/
/\+.-7æ2/0$0æ01q
q
3K
IN
+.Y
?dZ
1
&
AT
I
Hç
ç
ád+.-/0$21§ Üàâá+
Ø
1
? m
uu
é
n
7X
#
2
H
(
>
ä
í Ý
<
+
Ð
1
è
Ð
+
Ý
1
è
-
æ
ê
+
G
Ý
1
/
C
7070XPT
L
<
$
æ
ë
:
t
-
æ
ë
t
$
æ
+
A
I
ë
v
ß
f
ë
:
$
æ
+
G
Ý
1
1
E
C
àâá+.$
æ
1Ç
Z
? @
F
K
L
L
R
I
R
L
H
F
:
PQ
G
K
'&(
)*,+.-/0$213 54768.9;:
=<
>? C
D
'
F
H
J
L
M
N @
A
A
E
A
G
I
<
G
K
E
<
<
BPQRC
T7
N
> RW ,
&
U
K
V
I
<
C
E
+
Y
?
Z
[
1
?
N
R
L
X
3
(
bcde
L
g
L
3 +
Y
? ]
1
_
I
G
G
a
V
E
<
E
+
?
? &
<
G
K
E
A
f
I
C
<
E
f
E
1
I
<
G
f
E
<
I
<
I
<
ShA
I
G
E
i
E
C
M
kjl?nmoHK
C
,p
Iq
d
3
C
V
IN
C
Ksr
:ut
Hv
a=wl
ax
y<
E EQz
v
aC{|N}~0|N}
j
+.z1n
jq
+.z1=
C
KQr\j
+z1 z
v
z`t
p
w
? m
E E BA
I
C
E
&
K
IN
AT
<
G
U
V
C
ZB\
IN
K'?=Z?? @
F
K
L
L
R
I
R
L
H
F
:
PQ
G
K
$"3
W`
"$+ " ?
q
s
[
A
*
V
&
d
/
6
b
"
) 1
3P$@" ? &
U
K
V
I
<
C
E
+
Y
?
Z
[
1
?
N
R
L
X
3
(
bcde
L
g
L
3 @Ï
"
y m
<
I
G
C
<
>
*
¯
A
B
&
f
V
d
F
F
F
F +.Y
Z
Z
1
>
+
È
1§
C
D
E
:
;=<
8
4
+
3
68
/
9;:
G
H
I
È
C
D
E
Z
4
3
G
H
I
d
0
N
R
>
K
Wy +
Y
Z
Z
1
E
<
E
E
U
<
&
C
<
C
C
&
<
J
L
K
*
? d
>
DN
g
W
N
T
L
M3
2Ô
>
§N
bcd
¿ N
E
<
E
E
U
<
&
C
<
C
C
&
<
J
L
K
*
? d
>
DN
g
W
N
T
L
M3
2Ô
>
§N
bcd
¿ N _
C
f
E
E
U
<
I
C
V
<
-
&
A
<
G
K
E
A
I
ñ
<
K
E
<
+!M
:
1T
<
]
&
?
? &
N
Â
K
I
V
E
O
O
(P
QR.?SR´
I
7a§*g+
Z
/ÐÑ1Ù4:9q
Z
I
d
EEU
&
. d
V\
0BNÔní
W
022
X
Z
a +
Y
Z
S
1
T
U
+
/
$
/
! &
U
K
V
I
<
C
E
+
Y
?
Z
[
1
?
N
R
L
X
3
(
bcde
L
g
L
3 Û=
¸Aé
K
EdU
G
E
½
:Rtî-
½
tî$y
½
:
t
½
tzA
NlzT ì-
6:
æ
$
æ
ì-
6:
Ý
:
æ
$
æ
§
G§ NK
E
>
f
E
'?uïÔ <
àâád+z
1§ Sàâá+-10tlS
ç
t
Z&
I>
K
N
Y
?ð[
U
E
Sàâád+.-1
¯DS
ç
ÜSàâá+.-
ÂØ
1
Iq
H<
C
<
I
ñÔK
JM
Ýd? ò
<
$
æ
ë
:
t
-
æ
ë
t
$
æ
+
A
I
ë
v
ß
f
ë
:
$
æ
+
G
Ý
1
1
E
C
àâá+.$
æ
1Ç
Z
? Û=
¸Aé
K
EdU
G
E
½
:Rtî-
½
tî$y
½
:
t
½
tzA
NlzT ì-
6:
æ
$
æ
ì-
6:
Ý
:
æ
$
æ
§
G§ NK
E
>
f
E
'?uïÔ <
àâád+z
1§ Sàâá+-10tlS
ç
t
Z&
I>
K
N
Y
?ð[
U
E
Sàâád+.-1
¯DS
ç
ÜSàâá+.-
ÂØ
1
Iq
H<
C
<
I
ñÔK
JM
Ýd? ò
2Ô
o
N
N
2Ô
g
y
^
N
I
G
I
G
<
C
<
I
ñ
K
Ð
? m
C
I>
C
<
+.Y
? ]
1
&
A
+.a=/
j
1é í+! */
¯
1
? "
C
I>N
I
&
È
ð ì4
$&%('*),+.-,/
I
ÈÇv
*
? &
U
K
V
I
<
C
E
+
Y
?
Z
[
1
?
N
R
L
X
3
(
bcde
L
g
L
3 'HMn P\
W§2
7
ä
,
%7
47
0
¡
¢
¡
£
¤
¥
¤
¡
¦
1
~
·
·
¶
|
7
©
ª
7
-
Ö
³
·
~
7
z
$
Â
-
:
ª
®
}
z
4
3
Ä
×'©|
M®
}~
7¼
{l|>Á
·
M®
|
®
7q¼»
Ðܪ
7
6
¶
6
»
±L
ª
®
}g±Dt
Z
6
»
±FÆ
Ä
B¼
`=
LN
>
ìg
g
é
0
¡
¢
¡
£
¤
¥
¤
¡
¦
1
~
·
·
¶
|
7
©
ª
7
-
Ö
³
·
~
7
z
$
Â
-
:
ª
®
}
z
4
3
Ä
×'©|
M®
}~
7¼
{l|>Á
·
M®
|
®
7q¼»
Ðܪ
7
6
¶
6
»
±L
ª
®
}g±Dt
Z
6
»
±FÆ
Ä
B¼
`=
LN
>
ìg
g
é
Ú
{
»
Ä
Û
K
E
f
E
½
:
t
-
½
t
$
½
:
t
½
t
z
I
? Û=
I
I
I
C
Ed
E E\A
IN
G
+.Y
? [
1
? ò
¿
>
Ç
J
0l
X
32
Ô6 Ú
{
»
Ä
Û
K
E
f
E
½
:
t
-
½
t
$
½
:
t
½
t
z
I
? Û=
I
I
I
C
Ed
E E\A
IN
G
+.Y
? [
1
? &
U
K
V
I
<
C
E
+
Y
?
Z
[
1
?
N
R
L
X
3
(
bcde
L
g
L
3 ò
¿
>
Ç
J
0l
X
32
Ô6
C
V
<
-
Ö
&
I
E
I
E
C
+
]
? Z
5
1
I
N
C
V
UkN
E EBA
V
E
&
AT
I
%$
Â
-7:
ì4
3
. dB +
Y
Z
1
±
7
Ðé+8
1
<
+
Ðu1
7a§*,+
Z
/ÐÑ1Ù4:9
Ø
S
¯
Z
S
-H¯ÞS
Ø
:
;=<
8
%-'
Æ
/N
Z
S
-¯ÞS
Ø
tx±Dt
Z
4
+
3
68
/
9;: %-'
mD<
=
I
G
k
N
3
C
<
?>
@ *ϯ A
B
&"
f
yV
U
F
F
F
F +
1
±
7
Ð
+
1
<
+
Ð
1
7
a
*
+
Z
/
Ð
1
4
9
Ø
S
¯
Z
S
-H¯ÞS
Ø
:
;=<
8
%-'
Æ
/N
Z
S
-¯ÞS
Ø
tx±Dt
Z
4
+
3
68
/
9;: %-'
D
=
k
N
3
? &
U
K
V
I
<
C
E
+
Y
?
Z
[
1
?
N
R
L
X
3
(
bcde
L
g
L
3 1
Ø
)
+
/
$
1
/
T
Ù
dB
Ô
n\\_
WD
F
D
+
Y
Z
S
1
T
WD A
<
&
V
U
I
C
+
]
? Z
1
&
W
C
E
Y
+
Ø
/
O
1
[
]
^
`
]
Ø
? Û
W
C
U
Ø
G
U
V
I
G
V
U
E E BA
E
G
G
? '! eg
ikQ2
Ç2 2
`C¼
L
n
2y2
P
#
b
c
d
f
h
h
j
l
®
É
|
¬
|
Ó
|
®
7
È
»
*
Ó
ª
É
~
®
6
m
~
|
¬
É
µ
|
Õ
{
6
7
7
|
®
6
®
7
©
|
»
{Ó
È
ë:ét
Q
o
:
Õ
687
©ë
ë
-
³
o
o
-
v
*,Ä
×'©|
®
p
íOu+
P
!Ô1
OÑ+
P
$
1
6
¶
7
©|
{>}|2{
ß
t
osr
O
6P®tO
¾O
P
QT
³
6
Ä|
Ä
³
Ø
6
¶
7
©|éÓ
M®
6
éª
¶0¶
6
ª
7
|N}
Õ
687
©
osr
Ä
B¼
S
7
b
c
d
f
h
h
j
l
®
É
|
¬
|
Ó
|
®
7
È
»
*
Ó
ª
É
~
®
6
m
~
|
¬
É
µ
|
Õ
{
6
7
7
|
®
6
®
7
©
|
»
{Ó
È
ë:ét
Q
o
:
Õ
687
©ë
ë
-
³
o
o
-
v
*,Ä
×'©|
®
p
íOu+
P
!Ô1
OÑ+
P
$
1
6
¶
7
©|
{>}|2{
ß
t
osr
O
6P®tO
¾O
P
QT
³
6
Ä|
Ä
³
Ø
6
¶
7
©|éÓ
M®
6
éª
¶0¶
6
ª
7
|N}
Õ
687
©
osr
Ä
B¼
S
7
Ú
{
»
Ä
u
V
C
? Û
E
E
A
V
I
I
I
I
.
8
9
:
)
+
-
/
$
1
)
*
+
-
/
$
1
/ Õ
©
|
{
| )
+
-
/
$
1
#
á%$
&
(
*
+
-
)
á
+
-
/
$
1
2
7.02Ç
Ôd 6
¶
ª
®
}
6
7
6
®
ª
¬
¬
É
®
«
|
{
¹
|
®
7
·
{
}
~
7
³
7
©
|
)
á
+
-
/
$
1
ª
{
|
7
©
|
®
7
6
®
~
~
¶
¬
Nª¬"}|
®
¶
687
É
»
~
®
7
6bM®
¶
}|
º§®
|N}
6P®
+
[
Z
1ª
®
} Nª¬ 2~Ô¬dª
7
|N}
6P®
+
[
5
1
³
ª
®
}
7
©|
»
ª
7¼
{
¶
)*,+.-/0$21yª{0|
¹"6
«|
®
µ
É
+Y
(v
1yª
®
}+Y
Z
B
1
»
{
7
©|Nª
¶
|
¼»â
}7}
{
|2«|
®
0©ª{>ª
7
|2{
6
¶
7
6
¶
³
{|
¶¸·
|0
7.6
«|2¬ÉÄ
ò
=
(
§
L
H=
Ô(
"Ã2b
T
é
u
L
L
o
> L
2>
>N Û
C
E
V
<
G
K
I
A
Û
I
G
v
? v
Z
Z
&
A
I
E
E
K
<
<
C
I
ID
K
I
G
f
E
O0/âI
<
C
G
E I´A
U
? Û=
1
<
E
<
E'3
<
C
I
K
I>q
´K
I
N
T)*,+.-/0$21
N
3ï
M
ã
Ûu
´
C
<
+-/$154
¯ A
:
687
Z
¯ä-
:
Â
B
$
&
AT
I
s
BA
-
$
Æ
I
h
E
GL
N
h
f
<
GLK
E
BÏ
:9D? Û
E
E
A
V
I
I
I
I
.
Û
E
E
A
V
I
I
I
I
.
+
Y
? Z
v
1
<
<
I
<
I
<
&
A
,
.;
)
*
+
-
/
$
1
4
6
8
9
:
/
' A
W
C
E
U
E
U
<
!
? Û
I
C
E
I
G
+
Y
? Z
1
+.Y
? Z
1
. dB
K
L
.02,
Ü
.02
T
"
Nâ
N
A
W
C
E
U
E
U
<
!
? Û
I
C
E
I
G
+
Y
? Z
1
+.Y
? Z
1
. dB
K
L
.02,
Ü
.02
T
"
Nâ
N
+
Y
? Z
]
1
u
C
I
I
G
C
E
f
)
*
+
-
/
$
1
r
+
-
/
$
1
v
*
*
-
:
%$ ð/X$sÖ
w
&
G
C
ñ
I
<
N
\A5lN
I
C
Ed
C
<
=<
C
C
N
N
?Xmo
E
3
0
E
g
I
I
? Û
E
E
A
V
I
I
I
I
.
=
>
¿
L
é
B
B
D
BÜ
= Û
I
C
E
<
I
C
G
G
I
i
E
E
A
&
E
E
A
A
I
ã
V
NIIÙU
<
I
<
I
<
I
O
? '!
e :
x
'
d
NH2d
0
L22
0BNÔ
¼
P
2d¿
b
f
¡
f
h
×
©
|
Õ
|
6
¹
©
7
|
}
¬
ª
¶
¶
®
~
Ó
µ
|
{
T
U
+
-
/
$
/
! 1
»
{
6
®
»
|
¬
}
Ó
}
~Ô¬ |
¶
¼»
{>ª
®
7
Õ
«|2{JO"! Õ
687
©0©ª{>ª
7
|2{
6
¶
7
6
·
ƒ
®Q
Ó
6
ª¬
½
:
¯
-
½
tì$
ÓLªÉµ2|
Õ
{
687
7
|
®
ª
¶
V\.0BNÔní
"
.;
Q02Ù,.022 T
U
+
-
/
$
/
! 1
! &
U
K
V
I
<
C
E
+
Y
?
Z
[
1
?
N
R
L
X
3
(
bcde
L
g
L
3 ò
L
B
B
N
,
o
xJ
dB
8
dB
Ú
{
»
Ä
u
V
C
? ò
mLG
BU
BA
N
,
I
G
C
E
C
V
C
+Y
? v
1
o<
I
<
I
<
S
?xwJi&<
GV
+.Y
?dZB
18yQ+.Y
?dZB
1
&
A
f
. d
.0BNÔní
"
.;
Q02Ù,.022 ò
m
G
U
A
I
G
C
E
C
V
C
+
Y
? v
1
<
I
<
I
<
S
? w
i
&
<
G
V
+.Y
? Z
18yQ+.Y
? Z
1
&
A
f
. d
.0BNÔní
"
.;
Q02Ù,.022 +
Y
Z
B
1
T
U
+
-
/
$
/
! 1
! 8
9
:
)
+
-
/
$
1
)
*
+
-
/
$
1
/ +
Y
Z
B
1
d
T A
I
A
I
)*,+.-/0$21§
-
:
Â
$
8
9
:
>
+
$
Â
-
:
1
/
-
Ö
o
:
r
Â
$ ^8.9;:B/
-g
N
3
H
N
Û
E
E
A
V
I
I
I
I
.
Û
E
E
A
V
I
I
I
I
.
/
µ
|
7
©
|
Ì
{
µ
|
®
6
~
¶
|
®
}
Ó
{
·
©
6
¶
Ó
»
7
©
|
{
|
}
~
|
}
Ó
}
~
¬
|
H
+
! /
«
|
{
O
! ³
Õ
687
©
7
{>ª0|R- +
H
+
! /
1
Ä
Ì
{
! ¼»
}|
¹
{|0|
<
·
~
7
W
;
7 -
+
! /
-
+
H
+
! /
1
Q
6
+
6
8
/
9
:
-W+
H
+
! /
1
Q
6
9;:
6
»:<
6
¶
}
}
|2«|
®
P 0
bM
7
B
N ×
©
|
®
7
©
|
¬
¬
|
7
6
®
r
-
+
! /
!
}
}
ª
®
}
H
©
ª
¶
¹
}
{
|
}
~
7
6
®
ª
7
! w
6
¶
|
m
~
6
}
6
¶
7
{
6
µ
~
7
|N}
6P®
7
©|H{
6P®¹
*
¼»%6P®
7
|
¹
|2{
¶
¼»
*gÄ
=
g
h
N3
g
N
g
N
L
ì
×
©
|
®
7
©
|
¬
¬
|
7
6
®
r
-
+
! /
!
}
}
ª
®
}
H
©
ª
¶
¹
}
{
|
}
~
7
6
®
ª
7
! w
6
¶
|
m
~
6
}
6
¶
7
{
6
µ
~
7
|N}
6P®
7
©|H{
6P®¹
*
¼»%6P®
7
|
¹
|2{
¶
¼»
*gÄ
=
g
h
N3
g
N
g
N
L
ì
Û
V
I
V
C
I
G
E
i
I
<
-
+
! Û
E
E
A
V
I
I
I
I
.
Ç
°
=
H
>
<
>
^
N
l
L. :
N
ÃB\TN
Þ
Þ
L
yC
b
F
A
Û
I
G
B
? S
+
1
+
E
;
G
I
=
B
? ]
1
&
<
+
Y
? Z
v
1
&
I
C
Ed
Z
<
? ]
G
C
G
I
<
E
<
Z
B
&
A
I
K
IN
K
N
N
â
EE BA
o<
@?>
<
C
I
&
AT
<
K
IÙ
E¿
E
C
y
I
A
I
E
kG
C
E
lï
ã
ÛuM
3<
@?>
<
C
I
? '!CW0X0G(: R
:
J LLH2D
P
2d
¸
¼
>
b
B
¡
¦
D
f
E
¥
F
f
¨
|
7
H
+
I
/
K
1
µ
|
ª
{
6
®
»
|
¬
}
ß
Ó
}
~
¬
|
»
{
ª
®
7
Õ
}|
º§®
|N}
«|2{
Õ
687
©
~
7
Ó
·
¬ |>ÁlÓg~¬
7
6
·
¬
6
Nª
7.6bM®³
6
Ä|
Ä
³
¶
~0©
7
©ª
7
M
J
+
H
1
ß
Ä
1
~
·7·
¶
|
7
©ª
7
4M:3¯
Z
6
¶
7
©|Ǭ |Nª
¶
7l®
~ÔÓLµ2|2{kë
¶
~0©
7
©ª
7
KNM
6
¶
ª
+4
:
¯
Z
1O
7
©
·
Õ
|2{
6P®
äÄ
Ì
{,|Nª0©L! ¼»
Õ
©|2{|
H
©ª
¶
¹B
}k{|N}~
7
6bM®³
¼
´N
2 ¬
|
7
+
! Û
E
E
A
V
I
I
I
I
.
/
*
C
E
V
I
G
V
Ux
<
Ik)*,+.-/0$21 E
&
AT
<
<
0
Iq!
F
I
? N L
@>
0
N
§
W
,.02
N´
´
y
W
G
E
I
<
?
<
C
I
&
=
K
)
*
+
-
/
$
1
<
<
C
&
<
C
E
V
G
Ié!,
I
E
EE N
V
A
I
=
C
? Û=
W
C
=<
I>
EUkI
E
N
C
ã
C
1ï
M
ã
Ûu
E
A
3
&
I
G
C
E
K
IN
g
S
Mb&
EN
C
uL<
C
EdÑN¿f
I
<
GLK
E
<
E
N
I
C
E
I
K
I
N
+Ù¬
Ä3
687
Ä
? v
1
C
=
BA
'? N>
T
W
>
´W
I
K
V
E
I
<
C
C
I
I
I
<
I
V
I
T
U
+.-/0$B/N!Ô1éA
F-Lf
ñ
&
!¯
A
&
G
E
I§
Z
Z
Û=
I
G
]
? B
? "
I
fI
¿
KK
IN
<
& NkZ
.?
5D+9>91D+AF=I "
4
(
<
E
:
G
*
,
0
0
2
G
G
(
p
B
(
~
H
6
*
? G
:
@
X
? @
@
(
$
<
]
,
q
$
B
U
0
j
8
6
4
<
(
N
V
X
`
w
b
]
,
x
`
b
a
Z
w
,
<5c9G+(+@
U
BD4$K<>@DG+$KBD(+69<S2q$KB
U
0/1j5jAj)8;6947<5(+N/YX l`)ws_],>xK> a5xK`dZ50
'#1D+AFl+->R ++ A7+%nAA5+l
C5rs
)%5A);975+ISmJ_dKO'K'O'K5 c
X
]
x
! "
4
(
<
E
:
G
*
,
0
0
2
G
G
(
p
B
(
~
H
6
*
? G
:
@
,
q
$
B
U
0
j
j
j
8
6
4
<
(
N
X
`
w
w
]
,
x
`
a
w
\
0
s%l9=+=Jd
+fO5 7
n 7 9d17 AFl+AiAA> S)K
_ 5SA>OmCl9dd
!
:
N
:
G
:
4
,
0
0
2
? 4
4
(
B
U
H
:
B
(
N
&
6
<
"
4
(
<
E
:
G
*
q
6
*
? G
<
,
q
$
B
U
0
<
<
0
t
X
`
v
^
]
,
J_wlaO lv_ZA0
J%l9=+=Jk
+
/l1D+AF=-
D
)55 )579ld9ld
)S o9nS w
!
:
N
:
G
:
4
,
0
0
2
h
8
:
4
"
4
(
<
E
:
G
*
@
~
U
:
q
6
*
? G
N
? 4
&
:
<
&
6
H
g
:
~
N
:
T
L
p
,
. 6
H
p
0
q$KB
U
0O¡/uXC l`9vdd] ,>ZA l`saAZ9^950
s%l9=+=J-
R £1
M ) k +=_9
1D+AF=nAA5K%FdDMl-_d=_lOK v
!
:
N
:
G
:
4
,
0
0
2
¢
<
B
U
:
~
6
:
¤
~
(
:
<
B
@
6
E
"
4
(
<
E
:
G
*
H
6
*
? G
$
4
E
6
4
H
@
,
<
&
:
<
B
0
q
$
B
U
0
V;YX J`9v9v_],5d_wla>ws\d\50
s%l9=+=J5
+1>>¦77 5F=InAA5+ll>/5 +9l57)§Cld5J Ol_JA995 `
!
5D+9>91D+AF=I ! "
$
&
(
*
,
. 0
2
3
4
6
8
:
<
(
? @
*
(
@
B
4
(
8
? B
(
6
<
@
6
E
"
4
(
<
E
:
G
*
H
6
*
? G
:
@
6
E
$
<
L
4
$
<
N
,
P
0
Q
? H
8
0
TU
0;V/WYX[ZK\9\> J] ,
^_ZK`'aA^Kb_\50
'#1=+ d59;f / >D=i
9++=J5R+
)>Dd=k9f1D+AFl+mnAA5+llOodd7=nS>rs
/; ! "
$
&
(
*
,
. 0
2
3
4
6
8
:
<
(
? @
*
(
@
B
4
(
8
? B
(
6
<
@
6
E
"
4
(
<
E
:
G
*
H
6
*
? G
:
@
6
E
$
<
L
4
$
<
N
,
P
0
Q
? H
8
0
TU
0;V/WYX[ZK\9\> J] ,
^_ZK`'aA^Kb_\50
'#1=+ d59;f / >D=i
9++=J5R+
)>Dd=k9f1D+AFl+mnAA5+llOodd7=nS>rs
/; Z
! "
:
G
(
c
<
:
,
e
0
,
g
? @
:
H
h
6
G
G
:
4
,
"
0
2
j
? 4
&
:
L
6
E
"
4
(
<
E
:
G
*
H
6
*
? G
:
@
,
. 6
<
B
:
H
p
0
q
$
B
U
0
t
u
XC l`9v)wK] ,>Z9xJaA`5 d0
s#1=57+5>yz {1
);=#5=|i5 D+5 +ss797=57 >9}l + 5DD
l>55_D+K Z
! "
:
G
(
c
<
:
,
e
0
,
g
? @
:
H
h
6
G
G
:
4
,
"
0
2
j
? 4
&
:
L
6
E
"
4
(
<
E
:
G
*
H
6
*
? G
:
@
,
. 6
<
B
:
H
p
0
q
$
B
U
0
t
u
XC l`9v)wK] ,>Z9xJaA`5 d0
s#1=57+5>yz {1
);=#5=|i5 D+5 +ss797=57 >9}l + 5DD
l>55_D+K ^
! "
:
? 4
(
<
c
,
q
0
2
"
(
:
T
L
p
:
<
*
:
4
q
? G
B
(
p
G
(
N
$
B
6
4
:
<
4
(
<
c
:
:
G
G
(
p
B
(
@
~
U
:
4
3
? <
N
B
(
6
<5:l<5N-h
6947p/:l4l,58
U
0>qr$sB
U
0/j):=Hm0>g1$KH85?547cI)
zX J`Kb/ J],O J`_wla5Zdw9ZA0
K#1D+AFl+-9R + +ADoAA> J
>7CK;9K
K);975+>mJ_s_K9KsAd_) b
!
5D+9>91D+AF=I @
$d@D@D6A~ ($sBD:J*kB76M"47( <5EF:=G*IHn6A*A?5G+:l@l,;.o6dHp§05q$sB
U
0S5/X[ZK\9\d\d] ,AZ95 aAZKvd\50
b
! P
? <
c
,
3
0
2
. U
$
4
$
N
B
:
4
(
@
B
(
@
~
U
:
e
6
G
L
<
6
H
:
&
6
<
"
4
(
<
E
:
G
*
q
6
*
? G
<
,
"
(
p
G
6
H
$
4
8
:
(
B
jA$d$K47854Kh
?>~N9:l<IZK\d\9\50
Js¬=5)+7
5/+oo+dD
>l+I
=dDd>)57 5d=D[lDKIld95 x
! Q
:
? N
(
4
~
U
,
P
0
2
. G
$
@
@
¥
:
G
*
B
U
:
6
4
L
,
j
p
4
(
<
c
:
4
:
4
G
$
c
`
v
0
lK¬_ClS5 + >R;=
=97k+F5>7 d>=5l/)57 >9=D
!
6
@
:
<
,
q
0
2
Q
? H
8
:
4
B
U
:
6
4
L
(
<
E
? <
~
B
(
6
<
¥
:
G
*
@
,
j
p
4
(
<
c
:
4
:
4
G
$
c
Z
\
\
Z
''£A
==llR 17 5F=nAA5KM >Ddl¦
M9_ s7 d>K; w
! j
~
U
©
:
(
:
4
,
0
2
¢
<
"
4
(
<
E
:
G
*
H
6
*
? G
$
4
~
? 4
&
:
@
©
(
B
U
H
$
<
L
4
$
B
(
6
<
$
G
p
6
(
<
B
@
6
&
:
4
¥><>(¦B7:¬¥>:=G*5@l,>3( <5( BD:3(+:=G*5@ p5p5G[0/ª XZ9\9\_Z9],)b_^Kbsa)b9b_^50
lK£
57>S D
n=D
=dDK9ADddD
+£F5>7 d>lOD+>= Dd 5+9lC v
! j
U
(
H
? 4
$
,
0
2
4
(
B
U
H
:
B
(
~
B
U
:
6
4
L
6
E
$
? B
6
H
6
4
p
U
(
~
E
? <
~
B
(
6
<
@
,
e
4
(
<
~
:
B
6
<
<
(
&
:
4
@D(¦BLe47:l@7@% l`_wA 90
lK1SS/
n+Cd9l5 J 97 5F=rnAA5+l1s9l >5 D>l+5l->-5R;=
§5 `
! ®
?
5D+9>91D+AF=I
:
N
:
G
:
4
,
0
0
2
¢
<
¥
<
(
B
:
"
4
(
<
E
:
G
*
H
6
*
? G
:
@
,
P
0
G
c
:
8
4
$
X
`
`
]
,
v
w
a
Z
\
^
0
lK£%l9=+=J5
+f
+k79n¦>J ;=/ ++9¨=++ A7+£=579l
+
K97=7+CD
> \
!
:
N
:
G
:
4
,
0
0
2
g
(
c
U
G
L
4
$
H
(
¥
:
*
p
:
<
~
(
G
@
6
E
:
G
G
(
p
B
(
~
~
? 4
&
:
@
(
<
~
U
$
4
$
~
B
:
4
(
@
B
(
~
B
©
6
,
"1?5N9:qr$sB
U
0>P>0>ª;VYX J`9`)wK],5`_xJaO l\_wA0
9=£%l9=+=J'
R S>Dd/l5 /§A7D+5A7 d>S9A=+ +AD=5Ddl-sd=O>>¦757 nf>l+>= !
:
N
:
G
:
4
,
0
0
2
3
4
6
8
:
<
(
? @
*
(
@
B
4
(
8
? B
(
6
<
@
6
E
:
G
G
(
p
B
(
~
~
? 4
&
:
@
6
&
:
4
¥
<
(
B
:
p
4
(
H
:
¥
:
G
*
@
,
<_Bl0/q$sB
U
0>:J@=05Q6KBD:J@OuXZK\d\9^_],O l`d`9`'a5ZK\> lv50
Js£%_Dl5R+9D1CD7>757lKF5> D+9>l+mK7
n 7+9>)57 >9=D=7+9 ld9> X
]
,
Z
!
6
@
@
,
"
0
2
«
$
@
(
~
@
B
4
? ~
B
? 4
:
@
6
E
E
? <
~
B
(
6
<
¥
:
G
*
$
4
(
B
U
H
:
B
(
~
,
j
p
4
(
<
c
:
4
:
4
G
$
c
`
`
0
lK¬1C5
oS>+¯1°
K9 DlD7+I;9+_>9n+9+9%d=9n=D7+m579;=> > ^
! g
@
(
$
,
0
. U
0
,
®
? ,
P
0
2
¢
<
~
U
$
4
$
~
B
:
4
(
@
B
(
~
p
6
G
L
<
6
H
(
$
G
@
6
E
c
:
6
H
:
B
4
(
~
3
4
6
8
:
<
(
?
5D+9>91D+AF=I ,
P
0
0
2
@
6
c
:
<
(
:
@
6
E
"
4
(
<
E
:
G
*
H
6
*
? G
:
@
6
&
:
4
¥
<
(
B
:
¥
:
G
*
@
,
P
0
Q
? H
8
:
4
T
U
0
¡
XC l`9`_x9] ,- l5 a; sw) 90
KK1Sf/
n }5sD9
s7n+'
F91D+AF=YnAA5+llfo9nS¨s
A/[K9dd Z
\
! ®
? ,
P
0
0
2
j
$
B
6
T
$
B
:
G
$
©
E
6
4
"
4
(
<
E
:
G
*
H
6
*
? G
:
@
,
. 6
H
p
0
q
$
B
U
0
ª
X
Z
\
\
^
]
,
Jv9`'aO l`)w)0
A=¬1D+AFl+£nAA5+llsnAA5K§7
=nJ§K/£K55+=s7 d>l'DA9= A=5
+lD=Mld9> Z
! "
4
(
<
E
:
G
*
H
6
*
? G
:
@
,
H
6
*
? G
$
4
@
~
U
:
H
:
@
$
<
*
$
p
p
G
(
~
$
B
(
6
<
@
,
e
4
6
~
0
G
*
:
<
«
(
:
@
:
<
`
`
,
0
0>%:lN9:=G+:=4:=B$KG[0SXF:J*5@=0],¯6d4DG*ijA~ (+:=<_BD( ¥/~n J`9`_wA0
D M
I
ã
E
I
<
=
E
I
"
;
]
? Z
N
G
=
d
I
N
´ï
I>E
<
Z:vkZZ
v
A
ã¼]]ZDï
I
V
I
<
=
D
I
G
U
=
E
I
G
?
d㸠>V'?c M
I
ã
E
I
<
=
E
I
"
;
]
? Z
N
G
=
d
I
N
´ï
I>E
<
Z:vkZZ
v
A
ã¼]]ZDï
I
V
I
<
=
D
I
G
U
=
E
I
G
?
d㸠>V'?c M
I
ã
E
I
<
=
E
I
N
d
N
´
:
|
https://openalex.org/W4317212617
|
https://zenodo.org/records/8211289/files/Article%201024.pdf
|
English
| null |
Handling, Processing and Composition of Cow Milk Under Two Traditional Farming Systems in Kebribeyah District of Fafan Zone, Somali Regional State, Ethiopia
|
American journal of aquaculture and animal science
| 2,023
|
cc-by
| 4,033
|
INTRODUCTION protection (Merwan et al., 2018). Cow milk is the utmost
used up in the world followed by that of goat, camel, and
donkey (Cissé et al., 2019). In Ethiopia, cows contribute
around 95% of the total annual milk produced in the
country (CSA, 2021). Ethiopia possess the largest livestock population in
Africa, with 70 million cattle, 42.9 million sheep, 52.5
million goats, 2.15 million horses, 10.80 million donkeys,
0.38 million mules, 8.1 million camels, and 57 million
chickens (CSA, 2021). Livestock production in Ethiopia
is mainly on smallholder farming system, with livestock
having a multipurpose use (Tadesse et al., 2020). Milk has a complex biochemical composition and
high water activity. Due to its high nutritive value, raw
milk serves a good medium for microbial growth that
degrades the milk quality and shelf-life. The demand of
consumers for safe and high quality milk has placed a
significant responsibility on dairy producers, retailers and
manufacturers producing and marketing safe milk and milk
products (Mennane et al., 2007). Adverse environmental
condition is highly affecting the quality of milk and milk
products. In areas where the climate is hot and humid, the
raw milk gets easily fermented and spoiled during storage
unless it is refrigerated or preserved. However, such storage
facilities are not readily available in rural areas and cooling
systems are not feasible due to lack of the required dairy
infrastructure (Gemechu et al., 2015). Dairy production is used as an enterprise and economically
viable and greatly contributes to poverty reduction, food
security, increased family nutrition and income and job
opportunity creation (Kumar, 2014). It plays a vital role in
economic development, especially in developing countries
as both driving economic growth and profiting from it. It
is a valuable device to increase income, employment, food
and foreign exchange earnings as well as better nutrition
as an engine of growth. The share of animal products in
total food budget increases faster than that of cereals due
to relatively high-income elasticity of demand for animal
products (Dayanandan, 2011). Chemical composition of milk is variable and influenced
by genetic factors like breed and environmental stress
such as stage of lactation, changes in feeding, etc. Milk
composition and production are the interaction of many
elements within the cow and external environments Milk is the natural product obtained from the secretion
of the mammary gland of lactating mammals. 1 Department of Animal and Range Sciences, College of Dry Land Agriculture, Jigjiga University, Jigjiga, Ethiopia
2 Department of Clinical Studies, College of Veterinary Medicine, Jigjiga University, Jigjiga, Ethiopia
* Corresponding author’s e-mail: gaandiyare2017@gmail.com Keywords Handling, Processing Practices,
Chemical Composition,
Cow Milk 1 Department of Animal and Range Sciences, College of Dry Land Agriculture, Jigjiga University, Jigjiga, Ethiopia
2 Department of Clinical Studies, College of Veterinary Medicine, Jigjiga University, Jigjiga, Ethiopia
* C
di
th
’
il
di
2017@
il ABSTRACT Article Information
Received: January 02, 2023
Accepted: January 17, 2023
Published: January 18, 2023 The aim of this study was to assess handling, processing & chemical composition of cow
milk in Kebribeyah district. The study had a survey and laboratory works. For the survey
study, two production systems namely pastoral and agro-pastoral were considered. From
each production system, two kebeles were selected purposively based on accessibility and
potential of cow milk production. One hundred twenty households were randomly select
ed from purposively selected kebeles. For the laboratory part, forty samples of cow milk
were analysed for chemical composition. The overall average lactation length and daily
milk off-take of cow in this study were 256 days and 2.06 litres, respectively. None of
the respondents washed the udder of the cow and only 6.7% of the pastoralists and 20%
agro-pastoralists wash their hands before milking. Milk handling equipment were mainly
plastic materials. Acacia ethaica, B. minimifolia, Blanites galabra and Solanum carense were
the most commonly used smoking plant species in the area. The majority of the respon
dents (85.8%) produced traditional butter (Subag) and few households (10%) produced
sour milk (Ciir), while very few (4.2%) households produced traditional cheese (Burcad). However, milk processing in the area is limited to wet season; when there is abundance
of fodder. The average values of total solids, fat, protein, lactose and ash were 13.19%,
4.67%, 3.45%, 5.18% and 0.72%, respectively. However, significance differences (P<0.05)
were found between pastoral and ago-pastoral production systems in terms of total solids,
fat, and protein. The chemical properties of milk samples obtained from pastoral and
agro-pastoral areas were within the acceptable standard levels settled by different scholars. In general, milk producers should also be supported with strong extension service by
way of introducing improved dairy technologies, improved milk handling and processing
equipments. Furthermore, there is a need for further investigations on composition with
various farming systems. Page 1 Page 1 Page 1 American Journal of Aquaculture
and Animal Science (AJAAS)
Handling, Processing and Composition of Cow Milk Under Two Traditional Farming Systems
f
f
Z
S
S
Volume 2 Issue 1, Year 2023
ISSN: 2835-8945 (Online)
DOI: https://doi.org/10.54536/ajaas.v2i1.1024
https://journals.e-palli.com/home/index.php/ajaas American Journal of Aquaculture
and Animal Science (AJAAS)
Volume 2 Issue 1, Year 2023
ISSN: 2835-8945 (Online)
DOI: https://doi.org/10.54536/ajaas.v2i1.1024
https://journals.e-palli.com/home/index.php/ajaas Volume 2 Issue 1, Year 2023
ISSN: 2835-8945 (Online)
DOI: https://doi.org/10.54536/ajaas.v2i1.1024
https://journals.e-palli.com/home/index.php/ajaas Volume 2 Issue 1, Year 2023
ISSN: 2835-8945 (Online) Handling, Processing and Composition of Cow Milk Under Two Traditional Farming Systems
in Kebribeyah District of Fafan Zone, Somali Regional State, Ethiopia
Mohamud Mohamed1*, Yoseph Legesse2, Kawnin Abdimahad1 Data Collection
A
d A rapid survey with animal production experts and
veterinarians in the area and focused group discussions
was made with key informants after designing check lists
of issues to be covered. Semi-structured questionnaire
was prepared in a way it can address the aim of the
research. Questionnaires having open-ended and closed-
ended were developed with main focus on dairy cattle
production system, milk handling, processing techniques
and types of dairy products that has to be manufactured
and consumed in the area. In addition to this, field
observation was made to enrich the collected data. Data Analysis
D
i i
i Descriptive statistics was employed for data analysis using
Statistical Procedures for Social Sciences (SPSS version
26.0). The data related chemical composition of milk was
analysed using General Linear Model (GLM) procedure in
SAS (2008); using the following model: Yij = μ + αi + eij Where, Yij = observation, μ = overall mean, αi = production
system (i=2; pastoral & agro-pastoral), eij = error INTRODUCTION It is a
highly nutritious substance which contains macro and
micronutrients of fats, proteins, carbohydrates, vitamins,
minerals and active compounds having a role in health Am. J. Aquac. Anim. Sci. 2(1) 1-6, 2023 (O’Connor, 1995) accepted that the dairymen can alter
many of these factors to achieve milk production and
increase profit. However, it is generally accepted that the
dairymen can alter many of these factors to achieve milk
production and increase profit. and classified as agro-pastoral production system while
Adadi and Garbile kebeles were selected as pastoral
kebeles. Then, from each kebele, 30 households were
selected randomly from those have lactating cow, which
brings the total number of the households to 120. According to CSA (2021) report, Somali region with
5.9 million cattle is one of the potential regional states
in Ethiopia. Fafan Zone contributes 1.17million cattle. Among this cattle population, Kebribeyah district
contributes 125,119 of cattle. The district has a high
potential for dairy production due to high demand for
milk and milk products. However, there is no study
conducted in the area on milk handling, processing
practices and milk quality that could be affordable to
the resource poor. Thus, this study was carried out to
evaluate milk handling practices, processing and chemical
composition. Description of the Study Area This research work was conducted in Kebribeyah distict
of Fafan zone, somali regional state of Ethiopia from
2020 to 2021. Kebribeyah district is bordered on the
south by the Degahbur Zone, on the southwest by the
Fiq Zone, on the northwest by Gursum, on the north
by Jigjiga and Awbere, on the northeast by Somalia, and
on the east by Harshin districts. The district was named
after Kebribeyah town, the administrative center of the
district. The town is located 50 km and 680 km away
from the Jigjiga and Addis Ababa, respectively. It has
latitude and a longitude of 9°6′N 43°10′E with an average
elevation of 1686 meters above sea level. The district is
characterized by arid and semi-arid climate, warm climate
and low relative humidity. The mean annual maximum
and minimum temperatures of the district are 29OC
and 14OC, respectively. The district receives bimodal
rainfall, the long rainy season extending between July to
September (long rainy season) and the short rainy season
stretching from April to May; annual rainfall ranges
between 700 mm to 900 mm. The district population is
dominated by agro-pastoralists and pastoralists. Livestock
production involves cattle, camels and small ruminants. Milk Sample Collection and Analysis Raw cow milk samples were collected aseptically from
morning pooled milk container from forty households
(10 from each kebele) who were being surveyed, and
approximately 100mL of milk was collected as per the
procedure described by O’Connor (1995), in sterile
containers and after thorough mixing. The samples were
transported on ice box to Dairy Technology Laboratory
in Haramaya University for analysis. The raw milk samples
were analysed separately in duplicate using a rapid
automatic milk analyser MilkoScan (MilkoScan FT1) to
determine the percentage of fat, protein, lactose, solids-
non-fat and ash. Total solids were calculated by summing
all milk soilds. Determination of ash content was done
according to the method of the AOAC (1990). Study Design The study was conducted in two parts; briefly, household
survey and milk quality analysis. For the first part, a single-
visit formal survey method was followed to gather the data
focusing on assessing the milk handling and processing
practices. The second part dealt with evaluating chemical
composition of raw milk. Demographic Characteristics of the Households Demographic Characteristics of the Households Sex, age, and educational level of the respondents is
summarized in Table 1. About 69.2% of the respondents
were females and the rest 30.8% were males. The majority
(65%) of the respondents were in the age category of 36
to 55 years. In regard to educational level, the majority
(81.7%) of the respondents were illiterate. The increased
level of illiteracy causes a disregard for hygienic dairy
handling practices. The result indicates the need for
educating farmers to get better opportunity to implement
hygienic handling practices and efficient resource use. The role of education is obvious in affecting household MATERIALS AND METHODS Description of the Study Area https://journals.e-palli.com/home/index.php/ajaas Sampling Technique and Sample Size Kebribeyah district was selected purposively based on
cattle population and potential of milk production. Secondly, study kebeles were stratified into two farming
systems, namely pastoral and agro-pastoral. Two from
pastoral and two agro-pastoral kebeles were selected for
this study. Labashag and Qotoroble kebeles were selected https://journals.e-palli.com/home/index.php/ajaas Am. J. Aquac. Anim. Sci. 2(1) 1-6, 2023 Table 1: Sex, age, and educational level of the households (%) in the study area
Descriptor
Pastoral (n=60)
Agro-pastoral (n=60)
Overall (n=120)
p
Sex
Male
38.3
23.3
30.8
0.08
Female
61.7
76.7
69.2
Age (years)
20-35
18.3
20
19.2
36-45
26.7
25
25.8
0.8
46-55
41.7
36.7
39.2
> 55
13.3
18.3
15.8
Educational level
Illiterate
91.7
71.7
81.7
Primary school
5
10
7.5
0.03
Secondary school
0
3.3
1.7
Religious school
3.3
15
9.2
n= number of respondents n= number of respondents that 93.3% and 80% of the pastoralists and agro-
pastoralists did not wash their hands during milking. This
is a potential source for the contamination of milk with
pathogenic microorganisms during milking. It also shows
that there are no standard hygienic conditions followed
by producers during milk production. income, technology adoption, demography, health and
the whole socio-economic status of the family. Moreover,
lack of education and training on hygienic milk production
and postharvest handling practices expose raw milk for
microbial contamination (Omore et al., 2005). Milk Handling Practices This might be related to low awareness and knowledge of
the producers about sanitary milk production practices
and requirements. Zelalem (2009) noted that the hygienic
conditions are different according to the production
system, adapted practices, level of awareness, and
availability of resources. Milking and hygienic practices during milking https://journals.e-palli.com/home/index.php/ajaas Milking and hygienic practices during milking All of the interviewed households indicated that thy
milk cows twice a day i.e. morning & evening. All of the
respondents also do not wash the udder of the animal
during milking. The result of this study also showed Table 2: Hygienic milk production practices during milking in the study area
Variable
Pastoral
Agro-pastoral
Overall
p
Udder washing
Udder washing before milking
-
-
-
Not washing at all
100
100
100
Hand washing before milking
Yes
6.7
20
13.3
0.03
No
93.3
80
86.7 Milking equipment, cleaning and smoking practices
The majority (76.7%) of the respondents regularly clean
milk utensils. More than half (55.8%) of the sampled
households used plastic materials, while 25% and 19.2%
used clay pot and aluminum jars, respectively (Table 3). According to the survey, majority (75%) of the sampled
households utilized unsanitary milk containers (made
of plastic and clay pots) which facilitate spoilage of the
products, while only 25% used hygienic and appropriate
equipment for milk (stainless steel). According to
information gathered through key informant interviews
and focus group discussions, households in the area
lacked sufficient access to proper milk-related equipment
and also lacked the necessary expenditures. Lack of
knowledge on clean milk production, use of unclean milking equipment coupled with lack of potable water
for cleaning purpose contribute to the poor hygienic
quality of dairy products in Ethiopia (Yilma and Faye,
2006). Since metal (stainless steel) milk containers are
expensive, dependence on plastic containers is becoming
more common here and there (Addisu et al., 2016). The majority (85.8%) of the respondents practice
smoking milk vessels and milk containers were generally
fumigated with burned woods of selected trees. Acacia
ethaica (Sogsog), Blanites galabra (Kadi), Solanum Carense
(Kariir) and Boscia minimifolia (Maygaag) were mainly used
plants for smoking milk utensils. Similarly, Seifu (2007)
reported use of Blanites galabra, Acacia ethaica) and Olea
Africana as smoking plants in Shinile and Jigjiga zones of
Somali region. https://journals.e-palli.com/home/index.php/ajaas Am. J. Aquac. Anim. Sci. Milking and hygienic practices during milking 2(1) 1-6, 2023 Table 3: Milking equipment, cleaning and smoking practices
Variable
Pastoral
Agro-pastoral
Overall
p
Cleaning milk utensils regularly
Yes
78.3
75
76.7
0.6
No
21.7
25
23.3
Milking equipment
Stainless steel
18.3
20
19.2
0.4
Plastic materials
51.7
60
55.8
Clay pot
30
20
25
Smoking milk containers
Yes
83.3
88.3
85.8
0.4
No
16.7
11.7
14.2
Purpose of smoking containers
Give flavour & aroma
21.7
18.3
20
0.7
Increase shelf life
15
11.7
13.3
Both
63.3
70
66.7
Plants used for smoking
Acacia ethaica (Sogsog)
41.7
26.7
34.2
0.3
Blanites galabra (Kadi)
16.7
23.3
20
Solanum Carense (Kariir)
13.3
18.3
15.8
Boscia minimifolia (Maygaag)
28.3
31.7
30 Traditional Milk Processing Practices used traditional gourd (Dhiil) for milk processing. The
information obtained from key informants interview and
focus group discussion showed that milk processing is
limited during wet season; when there is abundance of
fodder and surplus milk. In general, the study indicates
that milk processing in the area is limited, hence
approaches for diversifying dairy products are essential
in addition to dairy processing equipment and facilities. The households in the study area practiced traditional
milk processing practices to increase the shelf life and
diversify the products. The majority of the respondents
(85.8%) produced traditional butter (Subag) and few
households (10%) produced sour milk (Ciir), while very
few (4.2%) households produced traditional cheese
(Burcad). The respondents in the study area mainly Table 4: Preferred milk processed product in the study area
Preferred milk processed product
Pastoral
Agro-pastoral
Overall
p
Butter (Subag)
88.3
83.3
85.8
0.4
Sour milk (Ciir)
8.3
11.7
10
Cheese (Burcad)
3.3
5
4.2 Table 4: Preferred milk processed product in the study area https://journals.e-palli.com/home/index.php/ajaas CONCLUSION sold and consumed in five localities of Burkina Faso. Veterinary World, 12(2), 295. https://www.ncbi.nlm. nih.gov/pmc/articles/PMC6460859/ In the current study, milk handling, processing of milk
products, and composition of milk was assessed. The
findings demonstrated that milk is handled improperly
without adhering to the required standard and hygienic
practices for dairy products. Milk processing in the area is
limited, hence approaches for diversifying dairy products
are essential in addition to processing equipment and
facilities. The study revealed that fat, lactose, protein,
solids non-fat, and ash contents of raw milk samples
fulfilled standards set by ESA and FDA. Therefore,
there is a need to raise producers’ awareness on proper
handling procedures of milk and milk products to reduce
post-harvest loss and their potential spread and risks to
human health and milk producers should be supported
with strong extension service by way of introducing
improved dairy technologies, improved milk handling
and processing equipments. Furthermore, there is a need
for further investigations on composition with various
farming systems. CSA (Central Statistical Agency) (2021). Agricultural
Sample Survey 2013 E.C. Volume II, Report on
Livestock and Livestock Characteristics (Private
Peasant Holdings). 39-40. Dayanandan, R. (2011). Production and marketing
efficiency of dairy farms in highland of Ethiopia-an
economic analysis. International Journal of Enterprise
Computing and Business Systems, 1(2), 1-34. http://www. ijecbs.com/July2011/16.pdf Duguma, B. (2022). Milk composition, traditional
processing, marketing, and consumption among
smallholder dairy farmers in selected towns of Jimma
Zone, Oromia Regional State, Ethiopia. Food Science &
Nutrition, 10(9), 2879-2895. https://doi.org/10.1002/
fsn3.2884 ESA (Ethiopian Standards Agency). (2009). Unprocessed
whole/raw cow milk specification (2nd ed.). ES: 3460. FAO (Food and Agriculture Organization of the United
Nations), (2007). FAOSTAT statistical database. Rome,
Italy. Available at https://www.fao.org/home/en. Milk Composition The solids-non-fat (SNF) content of raw milk in the
present study (8.52%) is higher than the minimum
standard (8.25%) for SNF content of whole cow
milk (FDA, 2010). The minimum SNF percent set by
European Quality Standards for unprocessed whole milk
is 8.5% (Tamime, 2009). The solids-non-fat (SNF) content of raw milk in the
present study (8.52%) is higher than the minimum
standard (8.25%) for SNF content of whole cow
milk (FDA, 2010). The minimum SNF percent set by
European Quality Standards for unprocessed whole milk
is 8.5% (Tamime, 2009). Generally, milk composition can be very variable depending
on many factors such as: breed and the health condition of
the animals, lactation period, feeding management (type &
quality), season, method of milking (manual or automatic),
age and the number of lactation, individual cows and
environmental factors (Pandey & Voskuil, 2011). The total solids (TS) content of milk found in the present
study is higher than the minimum standards for TS Table 4: Milk composition in the study area
Variable
Pastoral (n=20)
Agro-pastoral (n=20)
Overall (N=40)
Fat (%)
5.12±0.001a
4.21±0.002b
4.67±0.001
Protein (%)
3.28±0.02b
3.62±0.01a
3.45±0.01
Lactose (%)
5.12±0.001
5.24±0.001
5.18±0.001
Ash
0.72±0.04
0.73±0.06
0.72±0.05
SNF (%)
8.28±0.02b
8.76±0.01a
8.52±0.01
TS (%)
13.40±0.03a
12.97±0.02b
13.19±0.02
Means followed by different superscript letters within a row are significantly different at P<0.05, TS= Total Solids, SNF= solids
non-fat, n= number of samples taken, SE= standard error Milk Composition milk fat for fluid whole milk similarly to the U.S. Public
Health Service (USPHS) Milk Ordinance and Code also
recommended a minimum of 3.25% butterfat in farm
milk (Raff, 2011). Thus, the fat content obtained in the
current study fulfills the criteria set by both FDA and
USPHS. Chemical constituents such as fat, protein, total solids,
solids non-fat, lactose, and ash of cow milk in the study
area are presented in Table 5. The analysis of variance
showed significant difference between pastoral and agro-
pastoral area for fat, protein, total solids, and solids-non-
fat, although lactose and ash indicated no such difference. Fat is the most valuable constituent of milk. Milk having
a fair amount of fat is more valuable as food than
milk, which is poor in fat content (Kearsan, 2005). The
mean fat content in the study area was 4.67% which is
lower compared with the average fat content of milk
obtained in Walmera District with 5.46% as reported
by Ketema et al. (2018) and that of Yabelo with 6.01%
fat as reported by Gurmessa et al. (2015). The Food and
Drug Administration (FDA) requires not less than 3.25% The protein level of the raw milk used in this investigation
was 3.45%, which is greater than the 3.11% and 3.07 values
reported for Jimma and Walmera, respectively, by Duguma
(2022) and Ketema et al. (2018). According to Food and
Drug Administration (FDA), a minimum protein content
of whole milk is 2.73% (Raff, 2011). The value of protein
content obtained in the current study fulfills the criteria
developed by FDA for the consumers and the minimum
of 3.2% recommended by the ESA (2009). The overall average of lactose content in this study https://journals.e-palli.com/home/index.php/ajaas Am. J. Aquac. Anim. Sci. 2(1) 1-6, 2023 showed 5.18%. According to the European Union
Quality standards for unprocessed whole milk, the lactose
content should not be less than 4.2% (Tamime, 2009). content of cow milk established by the European Union,
which should be not <12.5% (FAO, 2000). According
to the standards set by the ESA, the minimum average
percent total solids content of unprocessed whole cow
milk should not be less than 12.8 percent. showed 5.18%. According to the European Union
Quality standards for unprocessed whole milk, the lactose
content should not be less than 4.2% (Tamime, 2009). REFERENCES Addisu, S., Muhammed, A., & Haile, N. (2016). Handling,
Processing and Utilization of Milk and Its Products
in Gondar Town, Ethiopia. Journal of Life Science and
Biomedicine, 6(6), 120-126; www.jlsb.science-line.comi FAO (Food and Agriculture Organization of the United
Nations), (2000). Overview of the Turkish Dairy
sector within the framework of Eu- Accession, 58. l FDA (2010). The effect of adopting California fluid milk
standards in the United States. AOAC (Association of Official Analytical Chemists). (1990). Official methods of analysis, 15th Edition,
Association
of
Official
Analytical
Chemist,
Washington DC. Gemechu, T., Beyene, F., & Eshetu, M. (2015). Physical
and chemical quality of raw cows milk produced and
marketed in Shashemene Town, Southern Ethiopia. ISABB Journal of Food and Agricultural Sciences, 5(2),
7-13. https://academicjournals.org/journal/ISABB-
JFAS/article-full-text/25A0F9150582 Cissé, H., Muandze-Nzambe, J.U., Somda, N.S., Sawadogo,
A., Drabo, S.M., Tapsoba, F., Zongo, C., Traoré, Y.,
& Savadogo, A., (2019). Assessment of safety and
quality of fermented milk of camels, cows, and goats https://journals.e-palli.com/home/index.php/ajaas Am. J. Aquac. Anim. Sci. 2(1) 1-6, 2023 S., Kang’ethe, E. (2005). Addressing the public health
and quality concerns towards marketed milk in Kenya. SDP Research and Development Report No. 3. Nairobi (Kenya): Smallholder Dairy (R&D) Project. Ketema, H., Bekuma, A., Eshetu, M., & Effa, K. (2018). Chemical quality of raw cow’s milk detection and
marketing system in Walmera district of Oromia
regional state, Ethiopia. Int. J. Adv. Res. Biol. Sci, 5(10), 38-
44. http://dx.doi.org/10.22192/ijarbs.2018.05.10.003 Seifu, E. (2007). Handling, preservation and utilization
of camel milk and camel milk products in Shinile
and Jijiga Zones, eastern Ethiopia. Marketing, 10(13). http://lrrd.cipav.org.co/lrrd19/6/seif19086.htm Kumar, N., Tkui, K., Tegegne, D. T., & Mebratu, A. T. (2014). Productive performance of crossbred dairy
cows and constraints faced by dairy farmers in
Mekelle, Ethiopia. Journal of Agriculture and Veterinary
Science, 7(1), 62-66. http://www.iosrjournals.org/ Tadesse, A., Galmessa, U., & Bekuma, A. (2020). Milk
Handling, Processing Practices and Quality Evaluation. Global Journal of Animal Scientific Research, 8(1), 56-74. http://www.gjasr.com/index.php/GJASR/article/
view/34/28 Mennane, Z., Ouhssine, M., Khedid, K., & Elyachioui,
M. (2007). Hygienic quality of raw cow’s milk feeding
from domestic waste in two regions in Morocco. International journal of agriculture and biology, 9(1), 46-48. Tamime, A. Y. (2009). Milk processing and quality
management. Society of Dairy Technology. Merwan, A., Nezif, A., & Metekia, T. (2018). Review on
milk and milk product safety, quality assurance and
control. International Journal of Livestock Production, 9(4),
67-78. https://academicjournals.org/journal/IJLP/
article-full-text-pdf/56F586B56464 Yilma, Z., & Faye, B. (2006). REFERENCES Handling and microbial load
of cow’s milk and Irgo—fermented milk collected
from different shops and producers in central
highlands of Ethiopia. Ethiopian Journal of Animal
Production, 6(2), 7-82. O’Connor, C.B. (1995). Rural Dairy Technology. ILRI
Training Manual 1, International Livestock Research
Institute, Addis Ababa, Ethiopia. Zelalem, Y. (2009). Sanitary Conditions and Microbial
Qualities of Dairy Products in Urban and Peri-Urban
Dairy Shed of the Central Ethiopia. DEA, Lyon. Omore, A., Lore, T., Staal, S., Kutwa, J., Ouma, R., Arimi, Page 6 https://journals.e-palli.com/home/index.php/ajaas
|
https://openalex.org/W4379164166
|
https://ejournal.uinsaizu.ac.id/index.php/elaqwal/article/download/7637/3044
|
English
| null |
The Influence of Dress Code on the Quality of Higher Education from a Sharia Critical Perspective: A Case Study of Umma University
|
el-Aqwal
| 2,023
|
cc-by-sa
| 8,830
|
The Influence of Dress Code on the Quality of Higher Education from a
Sharia Critical Perspective: A Case Study of Umma University The
findings show that the most prominent factor of indecent dress is “freedom of choice”
(68%), followed by the negative influence by foreign cultures through social media
(66%), implementing dress codes doesn’t solve genuine problems in the university
(57%), peer pressure (57%), and there is no specific penalty in the dress code (51%),
among others. Therefore, it is recommended to amend the student dress code in the
student information handbook 2020 while creating more awareness of the dress code
through the use of announcements on notice boards and other means in strategic
locations across the university premises. Muhammad Fuad Zain, Ahma yy
Volume 2, Issue 1, 2023 e-ISSN 2962-5289 CREATIVE COMMONS AT TRIBUTION-SHAREALIKE 4.0 INTERNATIONAL LICENSE. Published by LPPM of State Islamic University of Prof. K.H. Saifuddin Zuhri, Purwokerto 1
Al-Baqarah 2:35
2
Thaha 20:118
3
Al-A’raf 7: 22 Keyword: Dress Code, Higher Education, Umma University, Sharia law The Influence of Dress Code on the Quality of Higher Education from a
Sharia Critical Perspective: A Case Study of Umma University History of Author
Abstract
Manswab Mahsen
Abdulrahman
Umma University, Kenya
Coresponding Author:
manswab83@yahoo.com
Umma University is Kenya’s first Islamic-based university, chartered in 2019, and was
founded to improve access towards quality higher education for diverse individuals,
cultures and communities. Subsequently, the university received many students
from different religions, communities, and cultures, some of whom have violated
the dress code initiated by the university. This is the research problem. This study’s
main objective was to explore the causes of indecent dressing among the students
as well as to enhance the culture of proper dressing in higher learning institutions in
general and at Umma University in particular. The study will use both quantitative and
qualitative research methods. Open-ended questions were used. In addition to that, a
questionnaire will be used, involving 103 students as representative respondents. The
researcher will review references and study dissertations relating to dress code. The
findings show that the most prominent factor of indecent dress is “freedom of choice”
(68%), followed by the negative influence by foreign cultures through social media
(66%), implementing dress codes doesn’t solve genuine problems in the university
(57%), peer pressure (57%), and there is no specific penalty in the dress code (51%),
among others. Therefore, it is recommended to amend the student dress code in the
student information handbook 2020 while creating more awareness of the dress code
through the use of announcements on notice boards and other means in strategic
locations across the university premises. Keyword: Dress Code, Higher Education, Umma University, Sharia law Umma University is Kenya’s first Islamic-based university, chartered in 2019, and was
founded to improve access towards quality higher education for diverse individuals,
cultures and communities. Subsequently, the university received many students
from different religions, communities, and cultures, some of whom have violated
the dress code initiated by the university. This is the research problem. This study’s
main objective was to explore the causes of indecent dressing among the students
as well as to enhance the culture of proper dressing in higher learning institutions in
general and at Umma University in particular. The study will use both quantitative and
qualitative research methods. Open-ended questions were used. In addition to that, a
questionnaire will be used, involving 103 students as representative respondents. The
researcher will review references and study dissertations relating to dress code. The Influence of Dress Code on the Quality of Higher ... of nudity, something that is based on sensual nature and instinct. Allah (SWT) says: “Then Satan
tempted them in order to expose what was hidden of their nakedness”.4 All of these verses emphasize
the importance of the issue of clothing. Sheikh Islam ibn Taymiyyah clarifies the benefits of dress,
he said: «Clothing has two benefits, one of which is adornment by covering up nudes, and the second
is protection against harm from heat or cold.»5 Ibn Taymiyyah continued to say that the dress was
mentioned in Surat Al-A’raf for the benefit of adornment by covering the private parts, which is what
is considered in prayer and Hajj, Allah (SWT) says: “O children of Adam! We have provided for you
clothing to cover your nakedness and as an adornment”.6 And the dress was mentioned in Surat Nahl
for the benefit of protections. Allah (SWT) says: “He has also provided you with clothes protecting
you from the heat and cold, and as armor shielding you in battle. This is how He perfects his favour
upon you, so perhaps you will fully submit to Him”.7 Due to the importance of dress and the people’s
need for it, Islam did not leave the matter of dress to human whims, despite the fact that the right
nature of man requires clothing and covering the private parts. Furthermore, Islam specified the
provisions related to dress for men and women so that they do not deviate from them by the actions
of the devil and their ugly adornment. In response to the religious implications of the dress code,
Umma University 8 adopted their own guidelines on the mode of dressing, as it was stated clearly
in the student information handbook under the sub-title of “Student Dress Code”.9 On the other 8
Umma University is Kenya’s first Islamic-based university. It started as Thika College for Sharia and Islamic Studies, which was
founded in 1997 to provide certificate and diploma courses in Arabic and English, as well as Sharia and Islamic Studies. In 1998,
Thika College for Shariah and Islamic Studies registered its first 37 certificate students. Based on the large number of students
in the college, the college was registered by the Ministry of Education in 2001 (Reg. MOEST/PA/1592/2007, Appendix IX) and
was authorized to offer the following diploma programs: (a) Diploma in Islamic Shariah; (b) Diploma in Islamic Studies. In
2007, Thika College for Shariah and Islamic Studies applied to the Commission for Higher Education (CHE) for validation of its
programmes namely; Bachelors of Arts in Islamic Shariah and Bachelors of Arts in Islamic Studies. The Commission for Higher
Education, Kenya, granted the college authorization to provide aforementioned degrees in affiliation with the International
University of Africa, Sudan, in 2007. Thika College for Shariah and Islamic Studies has graduated 750 students in certificate
programs and 157 students in degree programs since its beginning. The college has gained valuable expertise obtained from
the International University of Africa. The sponsor believes that now is the perfect time to establish a university. In in 2013
when it was awarded the Letter of Interim Authority that transformed the Thika College of Islamic Sharia Studies to Umma
University. Following that, a Board of Trustees was constituted with the unprecedented responsibility of developing the
College into Kenya’s first fully-fledged Islamic-based university. The Board embarked on renovating the available learning
facilities at the Thika Campus and developing others under the funding of the African Muslim Agency in order to satisfy the
criteria set by the Commission for Higher Education. This project resulted in the acquisition of 75 acres of property in Kajiado
County, on which an ultra-modern main campus was later built. Along the Kajiado-Namanga Road, the main campus is around
75 kilometers from Nairobi. On October 18, 2019, President Uhuru Kenyatta awarded a charter to Umma University after the
institution met the ministry of education’s requirements. “(i) Muslim students are expected to dress in a manner considered prospered by the Shariah. (ii) Non-Muslim students may
adopt the Islamic dress if they so desire. Otherwise they should dress in accordance with the University Dress Code. Such
mode of dress shall also be decent, neat and clean (iii). All non-Muslim female students should wear long dresses or skirt to
the ankle level while within the University premises. (iv) any student who is inappropriately attired will be barred altogether
from entering all academic and administration buildings and shall be guilty of a disciplinary offence. A. Introduction The issue of dress has been associated with the existence of the human race since God created
Adam and Eve and commanded them to live in Paradise. Allah (SWT) says in the Qur’an: “And we
said, ‘O Adam! Live with your wife in Paradise and eat as freely as you please, but do not approach this
tree, or else you will be wrongdoers.”1 Another verse from the Qur’an “Indeed, it is [promised] for
you not to be hungry therein or be unclothed”.2 They fell under the influence of Satan and ate from
the tree in violation of the command of God, so they deserved His punishment, and their nakedness
was exposed unto them. Finally, they were expelled from Paradise. Allah (SWT) says “So he brought
about their fall through deception. And when they tasted the tree, their nakedness was exposed
to them, prompting them to cover themselves with leaves from Paradise. Then their Lord called
out to them, “Did I not forbid you from that tree and did I not tell you that Satan is your sworn
enemy?”3 From a review of what happened to Adam and his enemy Satan, we see that life consists 1
Al-Baqarah 2:35
2
Thaha 20:118
3
Al-A’raf 7: 22 Vol. 2. No. 1, Januari-Juni 2023 13 Ibid., 7: 22
5
Shaykh al-Islam Ibn Taymiyyah, Majmu’ Al-Fatawa, Vol. 15, 1st, (Egypt: Dar-Al-Wafa, 2005), p. 217.
6
Al A’
f 7 26 4
Ibid., 7: 22
5
Shaykh al-Islam Ibn Taymiyyah, Majmu’ Al-Fatawa, Vol. 15, 1st, (Egypt: Dar-Al-Wafa, 2005), p. 217.
6
l
’
f Ibid., 7: 22
5
Shaykh al-Islam Ibn Taymiyyah, Majmu’ Al-Fatawa, Vol. 15, 1st, (Egypt: Dar-Al-Wafa, 2005), p. 217.
6
Al-A’raf 7: 26 4
Ibid., 7: 22
5
Shaykh al-Islam Ibn Taymiyyah, Majmu’ Al-Fatawa, Vol. 15, 1st, (Egypt: Dar-Al-Wafa, 2005), p. 217.
6
Al-A’raf 7: 26
7
An-Nahl 16: 81 10 The Constitution of Kenya, 2010, Published by the National Council for Law Reporting with the Authority of the Attorney-
General, Act 32 (i) (ii) Freedom of conscience, religion, belief and opinion, p. 26
11 Al-A’raf 7: 32
12 Muhammad ibn Ahmad Al-Qurtubi, Al-Jami’ Li Ahkam Al-Quran, Vol. 5, 1st (Beirut: Dar al-kotob Al ilmiyah, 1998), p. 125
13 Ibn ‘Abidin, Radd al-Muhtār ‹ala al-Durr al-Mukhtār, Vol. 6, 1st, (Beirut: Dar al-Fikr, 2000), p. 351
14 Al-A’raf 7: 31
15 Isma`il ibn `Umar Ibn Kathir, Tafsir al-Qur’an al-`azim, Vol. 3, 2nd, (Riyadh: Dar Taibah, 1999), p. 405
16 An-Nahl 16: 81
17 Mohammad bin Abdallah Hakim al-Naysaburi, Al-Mustadrak ‘ala al-Sahihayn, Vol. 4, 1st, (Beirut: Dar al-kotob Al Ilmiyah, 1990),
p. 150, Hadīth No: 7088 Manswab Mahsen Abdulrahman hand, the constitution of Kenya (2010 Act 32) states that “Every person has the right to freedom
of conscience, religion, thought, belief, and opinion.”10 This paper therefore discusses factors that
lead to university students dressing indecently. Based on a pilot survey, many factors contribute to
indecent dress. Among them are, freedom of choice (my dress, my choice clarion), peer pressure,
freedom of expression, and student awareness of the university’s dress code, among others. It is
intended that this research will address some of the important aspects at play at various levels in
human life, such as covering the parts of the body that must be covered in public and following the
standards of modesty that are innate in all human beings. The purpose of this paper is to examine
the causes of indecent dressing among students at Umma University. The findings of this research
will help Umma University develop policies to address the issue of indecent dressing. This paper is,
therefore, a continuation of the discussion on the dress code at Umma University from an Islamic
Shariah perspective. It reviews the Islamic provision of the dress code, the perception of the students
toward the dress code, and the causes of indecent dressing in the learning institution. (v) Avoid putting on
unsuitable clothing while attending lectures such as short skirts, see through clothes, low neck line tops, tight clothing,
low riding trousers, pedal pushers, sagging clothes, caps or hats, clothing that shows inner wear, jewelers on eyebrow/lids,
belly lips, nose and tongue. Clothes that reveal body cleavages are strictly forbidden; (vi) Female students should refrain
from wearing men’s clothes such as trousers and T-Shirts and male students should avoid wearing female garments/ shoes/
ornaments such as skirts, blouses, necklaces and earrings. They should as much as possible adhere to the Islamic code of dress;
(vii) Avoid keeping dreadlocks/rasta, pank, afro-cut or unkempt hairdos, bright colored and unbecoming hair color such as
blue, red, yellow, and white; (viii) Refrain from wearing caps or hats, short miniskirts, scanty dressing, hot pants, cut off tops
and slippers in classrooms, offices and at official functions; (ix) Avoid exposed tattoos and/or wordings or writings on clothes
with abusive language”. Vol. 2. No. 1, Januari-Juni 2023 14 The Influence of Dress Code on the Quality of Higher ... neighborhood, among other places. In addition, it is preferable for Muslim scholars to dress well in
order to execute their rules and instructions while also honoring the knowledge and rhythm of their
prestige in the public’s hearts.18 The third rule (Libaas Al-Makruh) is to dress in a way that brings
arrogance and extravagance. This was forbidden in accordance with the following Hadith: «Eat and
drink, give charity and wear clothes, as long as that does not involve any extravagance or vanity».19
The fourth rule (Libas Al-Haram) it is a dress of silk and gold for men. The Prophet Mohammad (SAW)
said: “Do not wear silk (clothes). For whoever wears (them) in this life will be deprived of them in
the Hereafter.”20 Another type of clothing that is forbidden is that which bears a resemblance to the
disbeliever. The prohibition of imitating the disbeliever in clothing is one of the important principles
for which there is a lot of evidence. Therefore, it is not permissible for a Muslim, man or woman, to
wear a garment that is specifically for non-believers. The Prophet Mohammad (SAW) said: “He who
copies any people is one of them.”21 Imitating them requires the imitator to feel that they are higher
than him, so he admires their actions and is fascinated by their appearances, until that leads him to
follow them in beliefs, actions, habits, and conditions. Based on the aforementioned, the university
dress code clause (iii) grants non-Muslim females the right to wear long dresses while within the
university premises. This will create racial division among students. Furthermore, some of them will
take advantage of this by wearing thin or tight long dresses that highlight the figures and describe
the shape and size of their body. Muslim are obligatory to cover their private parts with appropriate clothing, as the Qur’an
states, “Children of Adam! We have sent down clothing to you to conceal your private parts.”22 Islam
has fixed the conditions associated with clothes. For men, he imposed covering the navel and the
knee on men. For women, they must cover their bodies except for their faces and hands. Therefore,
short skirts, see through clothes, low neck line tops, tight clothing, low riding trousers, pedal
pushers, sagging clothes, caps or hats, clothing that shows inner wear, jewelers on eyebrow/lids,
belly lips, nose and tongue. 18 Ibn Hajar al-Haytamī, Fatawa al-Kubra al-Fiqhiyyah, Vol 1, (Beirut: Dar el Fikr, n.d), p. 270
19 Abu Bakr Ibn Abi Shaybah, Al-Kitab al-Musannaf fil Ahadith wal Athar, Vol. 5, 1st, (Riyadh: Maktabah al-Rushdi, , 1409), p. 171,
Hadīth No: 24877
20 Muhammad bin Ismael Al-Bukhary, Swahih Al-Bukhary, Vol 6, 1st ed, (Cairo: Darūl Shuʿib, 1987), p. 140, Hadīth No: 477
21 Abubakar ibn Abi Sheibah, Al-Kitab Al-Musanaf fi Al-Ahadith wal Athar, Vol. 6, 1st , (Riyadh: Maktabah al-Rushdi, , 1409), p. 471,
Hadīth No: 333016
22 Al-A’raf 7: 26
23 Umma University, Student information handbook, (Umma University, 2020), Act 5.5 (v) p. 29
24 Ahmad bin Ali bin Muthana, Musnad abu ya’la, Vol. 12, 1st, (Damascus: Dar Al-Maamun, 1984), p. 46, Hadīth No: 6690
25 Ibid., p. 29
26 Ahmad bin Hanbali, Musnad Imam Ahmad bin Hanbali, Vol. 1, 1st, (Beirut: Dar Al-Alim Al-Kutub, 1998), p. 339, Hadīth No: 3151 1.
Significance and Types of clothes According to the Qur’anic verse, wearing clothing is lawful. Allah (SWT) says: Say, “Who has
forbidden the adornment of [i.e., from] Allah which He has produced for His servants and the good
[lawful] things of provision?”11 Imam Qurtubi commented that Allah has made clear that people are
forbidden on their own what is not forbidden to them, and the meaning of adornment in the verse
is good clothing.12 Nevertheless, if we look at the rules associated with dress in general, there are
several that influence the nom, as follows: To begin with, the obligatory dress (Libas al-Wajib) is that
which covers the private parts from public view.13 Allah (SWT) says: “O children of Adam, take your
adornment [i.e., wear your clothing] at every masjid, and eat and drink, but be not excessive. Indeed,
He likes not those who commit excess”.14 Ibn Arab commented that the noble verse indicates that it
is obligatory to cover the private parts during prayer. This is the result of the polytheists’ making
Tawaf around the Kaaba naked during the day and at night. Then Almighty Allah forbade that and
commanded them to take the dress.15 Also, wearing clothes becomes obligatory if it protects a person
against heat, cold, and any harm. Allah (SWT) says: “He has also provided you with clothes protecting
you from the heat and cold, and as armor shielding you in battle. This is how He perfects His favour
upon you, so perhaps you will fully submit to Him”.16 The second rule (Libaas Al-Mandub) is to dress
in a way that brings adornment and grace to the individual. In this regards the prophet Mohammad
(SAW) said: “Allah loves to see the sign of His Bounties on his slave.”17 The example of Libas Mandub
(recommended dress) used at Jumaa prayer, festival days, and when greeting people and visiting the Vol. 2. No. 1, Januari-Juni 2023 15 6 Ahmad bin Hanbali, Musnad Imam Ahmad bin Hanbali, Vol. 1, 1st, (Beirut: Dar Al-Alim Al-Kutub, 1998), p. 339, Hadīth Ibn Hajar al-Haytamī, Fatawa al-Kubra al-Fiqhiyyah, Vol 1, (Beirut: Dar el Fikr, n.d), p. 270i mmad bin Ismael Al-Bukhary, Swahih Al-Bukhary, Vol 6, 1st ed, (Cairo: Darūl Shuʿib, 1987), p. 140, Hadīth No: 477 i Umma University, Student information handbook, (Umma University, 2020), Act 5.5 (v) p. 29
4 Ahmad bin Ali bin Muthana, Musnad abu ya’la, Vol. 12, 1st, (Damascus: Dar Al-Maamun, 1984), p. 46, Hadīth No: 669
Ibid., p. 29
h
d b
b l
d
h
d b
b l
l
(
l
l
l
b
)
d h Umma University, Student information handbook, (Umma University, 2020), Act 5.5 (v) p. 29 uhammad bin Ismael Al-Bukhary, Swahih Al-Bukhary, Vol 6, 1 ed, (Cairo: Darūl Shu ib, 1987), p. 140, Hadīth No: 477
bubakar ibn Abi Sheibah, Al-Kitab Al-Musanaf fi Al-Ahadith wal Athar, Vol. 6, 1st , (Riyadh: Maktabah al-Rushdi, , 1409
adīth No: 333016
l A’
f 7 26 j
y
,
q yy
,
, (
,
), p
Abu Bakr Ibn Abi Shaybah, Al-Kitab al-Musannaf fil Ahadith wal Athar, Vol. 5, 1st, (Riyadh: Maktabah al-Rushdi, , 14
Hadīth No: 24877
0
h
d b
l
l
kh
h h l
kh
l
t d (
l h ʿ b
)
d h 2.
Conditions of Clothes Muslims Jurists set some specifications related to dress code for Muslim women to make it
acceptable and the most important issue is to cover the private parts, and the following conditions
apply: (a) it must cover her entire body, except for her face and hands, and it is forbidden to show
her private parts in front of Non-Mahram.29 Allah (SWT) says: “O Prophet, tell your wives and your
daughters and the women of the believers to bring down over themselves [part] of their outer
garments that is more suitable that they will be known and not be abused. And ever is Allah Forgiving
and Merciful”.30 As a result, the Muslim woman must cover all of her adornment and not show it except
for what is unintentionally visible on her. Allah (SWT) says: “and not expose their adornment except
that which [necessarily] appears thereof”.31 According to some Muslim scholars, the meaning of
“Except that which appears” includes the face and hands. Furthermore, there are different opinions
among Muslim jurists regarding the covering of the hands and face, The vast majority of jurists
like Hanafy, Malik, Shaffy, Hanbaly, Dhahiriyah, Zaidiyyah, Imamiyyah, and Ibadhiyyah have ruled that
a woman’s entire body is considered naked except the hands and the face.32 Another statement by
Malik and Hanbaly said the entire body of a woman is to be covered, even her hands and face, as it
is all considered nakedness.33 Based on the open-ended question, the majority of the respondents
describe indecent dress as something that exposes the private parts of the body. This indicates a lack
of knowledge of Islamic law. (b) The dress should not be so thin that what is underneath it becomes
visible, so that it covers the woman’s private parts and does not expose the color of her skin.34 It
will be regarded as worthless if it covers the entire body but still shows skin tone. This is stated in
the student handbook in Student Dress Code, Act 5.5 (v) “Clothing that shows inner wear”. And the
Prophet Mohammad (SAW) described the women who wore such clothing as being naked, meaning
that even if they wear clothes, they are in fact like the naked ones who did not wear clothes. This
group has been promised that they will not enter Paradise and will not smell its fragrance. Manswab Mahsen Abdulrahman pride and arrogance: Ibn Umar (RAA) narrated that the Messenger of Allah (SAW) said: “Allah will
not look on the Day of Judgment at him who lets his garment drag on the ground out of pride and
arrogance.”27 This is known as Libaas ash-Shuhrah (flashy clothing). In fact, this term refers to a type
of clothing that attracts the attention of people. The Prophet (SAW) said, “Whoever wears a garment
of pride and vanity, Allah will clothe him, on the Day of Resurrection, in a garment of humiliation.”28 pride and arrogance: Ibn Umar (RAA) narrated that the Messenger of Allah (SAW) said: “Allah will
not look on the Day of Judgment at him who lets his garment drag on the ground out of pride and
arrogance.”27 This is known as Libaas ash-Shuhrah (flashy clothing). In fact, this term refers to a type
of clothing that attracts the attention of people. The Prophet (SAW) said, “Whoever wears a garment
of pride and vanity, Allah will clothe him, on the Day of Resurrection, in a garment of humiliation.”28 Clothes that reveal body cleavages are strictly forbidden; are not allowed
in Umma University.23 In fact, the Prophet (SAW) warned those people who do not observe modesty
in dress, calling them “Women who are naked even though they are wearing clothes, they go astray
and make others go astray, and they will not enter the Paradise nor will not find its scent.”24 Another
type of clothing that is strictly forbidden in Islam is wearing clothing that imitates the opposite
sex. This was captured in the student handbook as follows: “Female students should refrain from
wearing men’s clothes such as trousers and T-Shirts and male students should avoid wearing female
garments/ shoes/ornaments such as skirts, blouses, necklaces and earrings”.25 This guideline was
supported by the Hadith of the prophet Mohammad (SAW) as saying: “God has cursed men who
imitate women and women who imitate men.”26 Also, Islam prohibited Clothing that is worn with Vol. 2. No. 1, Januari-Juni 2023 16 27 Ahmad bin Hussein Al-Bayhaqi, Shu’ab Al-Iman, Vol 8, 1st, (Riyadh: Maktabah al-Rushdi, 2003), p. 8, Hadīth No: 5710
28 ʽAbd al-Razzaq al-Sanʽani, Musannaf Abd al-Razzaq, Vol. 11, 2nd, (Beirut: Maktab Al-Islamy, 1403), p. 80, Hadīth No: 19979
29 Mahram: is a member of one’s family with whom marriage would be considered haram
30 Al-Ahzab 33: 59
31 An-Nur 24:31
32 Alauddin Abi Bakr Bin Mas’ud Al-Kasani, Bada’i al-Sana’i fi Tartib al-Shara’I, Vol 5, 1st, (Egypt: Sharika Matbuat Ilmiyyah, 1327),
p. 123.
33 Abu Malik ibn Abdulwahab, Ahkamu An-Nisaa, 1st, (Cairo: Daulī, 2007), p. 207-208
34 Majmuat Al-Mualifin, Al-Mausu’ah Al-fiqhiyah Al-Kuwaitiyah, Vol 35, 1st, (Egypt: Dar Al-Safwa, n.d), pp. 193-194
35 Ahmad bin Al-Hussein bin Ali Al-Baihaqi, Sunanul Al-Kubra, Vol. 2, 1st ed, (Pakistan: Majlis Dairatul Al-Marīf Al-Nidhwāmiyah,
1344), p. 234, Hadīth No: 3388 p
33 Abu Malik ibn Abdulwahab, Ahkamu An-Nisaa, 1st, (Cairo: Daulī, 2007), p. 207-208ii 34 Majmuat Al-Mualifin, Al-Mausu’ah Al-fiqhiyah Al-Kuwaitiyah, Vol 35, 1st, (Egypt: Dar Al-Safwa, n.d), pp. 193-194
35 Ahmad bin Al-Hussein bin Ali Al-Baihaqi, Sunanul Al-Kubra, Vol. 2, 1st ed, (Pakistan: Majlis Dairatul Al-Marīf A
1344), p. 234, Hadīth No: 3388 27 Ahmad bin Hussein Al-Bayhaqi, Shu’ab Al-Iman, Vol 8, 1st, (Riyadh: Maktabah al-Rushdi, 2003), p. 8, Hadīth No: 5710
28 ʽAbd al-Razzaq al-Sanʽani, Musannaf Abd al-Razzaq, Vol. 11, 2nd, (Beirut: Maktab Al-Islamy, 1403), p. 80, Hadīth No: 19979
29 Mahram: is a member of one’s family with whom marriage would be considered haram
30 Al-Ahzab 33: 59 2 Alauddin Abi Bakr Bin Mas’ud Al-Kasani, Bada’i al-Sana’i fi Tartib al-Shara’I, Vol 5, 1st, (Egypt: Sharika Matbuat Ilmi
p. 123. The Influence of Dress Code on the Quality of Higher ... that are specific to the denomination of Non-Muslims.36 This was warned in the student handbook
as follows: “Avoid exposed tattoos and/or wordings or writings on clothes with abusive language.”37
(e) Not to be perfumed because the smell of perfume attracts men to it and causes problems. In
this regards the Prophet Mohammad (SAW) said: “Any woman who puts on perfume then passes by
people so that they can smell her fragrance then she is an adulteress.”38 3.
Theoretical Framework and Theory of Reasoned Action The current study aims to promote culture of proper dressing to be promoted in Higher
education. To achieve the study’s objective, the theory of (Stanley, 1996) Uniforms had a good effect
on student behavior. (Gentile & Imberman, 2011). Uniforms speed up the process of getting ready for
school, potentially freeing up time for sleeping or studying. At the same time, it has a positive impact
on secondary school student attendance. Restrictions (Brunsma and Rockquemore, 1998; Gentile
& Imberman, 2011) restrict students’ rights and impose financial hardships. Can assist in reducing
the incidence of sexual assaults and the availability of weapons in schools (Granberg-Rademacker,
Bumgarner & Johnson, 2007). In 1998, Rockquemore and Brunsma published the following conclusion:
“Our findings indicate that student uniforms have no direct effect on substance use, behavioral
problems, or attendance.” A negative effect of uniforms on student academic achievement was found”. Eight years later, Brunsma (2006) found that uniforms have not been effective in reducing violence
and behavioral problems, fostering school unity and improving the learning environment, reducing
social pressures and leveling status differentials, increasing student self-esteem and motivation,
saving parents money on clothing for their children, improving attendance, and improving academic
achievement, according to the findings. On the other hand, Padgett (1998), conducted teacher-based
research. Teachers thought that if pupils dressed professionally, they would behave better and
perform well in class. Furthermore, what happens if students make their own choices in dress? In practice, Umma
University enforced and decided which type of clothes to wear in the university while Act 32 of the
2010 Constitution of Kenya states “Every person has the right to freedom of conscience, religion,
thought, belief and opinion.” Then, different voices in higher learning emerged. As a result, the data
collection and analysis processes were guided by the following research question: What influence
does the dress code have in the eyes of students? 2.
Conditions of Clothes (c) The
dress should be wide and loose so that it does not describe the features of the woman’s body. Tight
clothes highlight the figures and at the same time describe the shape and size of the body. Usama bin
Zaid reported that the Prophet Mohammad (SAW) clothed me with a thick garment that was given to
him by Dihiya al-Kalbī. And I gave it to my wife to clothe, so he said: “Command her to put on a veil,
because I am afraid that it will describe the size of her bones.”35 (d) The dress does not contain symbols Vol. 2. No. 1, Januari-Juni 2023 17 37 Ibid., p. 29 39 Eldabi, Tillal, Zahir Irani, Ray J. Paul, and Peter ED Love. “Quantitative and qualitative decision‐making metho
modelling.” Management Decision (2002). 40 (1), pp. 64 -73. 36 Mohammad Twijirī, Mausu’ah Al-fiqhiyah Al-Islamī, Vol 4, 1st ed, (Saudia: Bayt Al-Afkar Adawliah, 2009), p. 107
37 Ibid., p. 29
38 Ahmad b. Shueb An-Nasai, Sunan An-Nasai, Vol 8, 2nd ed, (Halab: Maktab Al-Mutbuat Al-Islamiyyah, 1986), p. 153, Hadīth No:
5126
39 Eldabi, Tillal, Zahir Irani, Ray J. Paul, and Peter ED Love. “Quantitative and qualitative decision‐making methods in simulation
modelling.” Management Decision (2002). 40 (1), pp. 64 -73. 38 Ahmad b. Shueb An-Nasai, Sunan An-Nasai, Vol 8, 2nd ed, (Halab: Maktab Al-Mutbuat Al-Islamiyyah, 1986), p. 15
5126 36 Mohammad Twijirī, Mausu’ah Al-fiqhiyah Al-Islamī, Vol 4, 1st ed, (Saudia: Bayt Al-Afkar Adawliah, 2009), p. 107
37 Ibid p 29 Manswab Mahsen Abdulrahman University-Kajiado Main Campus. The original questionnaire consists of 17 question itemized into four
sections. Section two after the introduction talks about the background information of respondents
(4 items), how to promote a culture of proper dressing (2 items), reasons for indecent dressing (10
items). Three experts with relevant backgrounds to the study reviewed the questionnaire’s structure,
flow, clarity, length, and order. The researcher uses the 3-point Likert scale to indicate “Disagree,”
“Neutral,” “agree,” The mean score of the respondents’ opinions was calculated for analysis. The
research data was collected from 103 responses from Umma University. The research also applied
statistical software, namely SPSS version 22.0, which is involved in descriptive analysis. This study
took place at Umma University, Kajido Campus. We selected this university because it has an enrolled
international range of students coming from various religions, countries, and ethnicities. In addition,
as it arranges student exchanges from various nations, this university is doubling down on its efforts
to foster diversity. On the other hand, this university is considered the first Islamic university in the
Republic of Kenya, hence the university ought to be a role model for others. C. Methodology: This study uses mixed methods. In this case, qualitative research can be collected in a number of
ways, including interviews and documentary evidence.39 At the same time, the researchers relied on a
quantitative research design for this study using primary data. In this case, information was gathered
from the university students through a survey by using a questionnaire to examine the influence of
dress code on the quality of higher education. The research data was from 103 responses from Umma Vol. 2. No. 1, Januari-Juni 2023 18 4.1 Demographic Profile of the Respondents The data for this research paper were gathered from Umma University students on the Kajiado
campus using a developed survey questionnaire, and the respondents came from a variety of
educational levels, including certificates, diplomas, and degrees. As reported in table (2), out of 103
representative respondents, 59 (57.3%) are male, 40 (38.8%) are female, and 4 (3.9%) prefer not to
say, which shows that most of the participants in this study are male. The respondents who are
within the age bracket of 16–20 are 54 (52.4%), those between the age brackets of 21–25 are 34 (33%),
those between the age brackets of 26–30 are 5 (4.9%), and those above 30 are 10 (9.7%). The majority
of the respondents are Muslim 53 (51.5%). Christian’s respondents are 47 (45.6%) while others are
3 (2.9%) out of the overall respondents. This indicates that the university enrolled students from
different religions. In terms of educational level, the majority of respondents (78.6%) were pursuing
a bachelor’s degree, followed by a diploma (12.7%) and a certificate (8.7%). This figure indicates that
the majority of respondents were well educated and were aware of the university dress code. Table 1. Demographic
Socio-Demographic Variable
Frequency
Percentage
Gender
Male
59
57.3%
female
40
38.8%
other
4
3.9%
Total
103
100%
Age
16-20
54
52.4%
21-25
34
33.0%
26-30
5
4.9%
30 above
10
9.7% Table 1. Demographic Table 1. Demographic Table 1. Demographic Vol. 2. No. 1, Januari-Juni 2023 19 The Influence of Dress Code on the Quality of Higher ... Total
103
100%
Religion
Muslim
53
51.5%
Christian
47
45.6%
others
4
2.9%
Total
103
100%
Education
Degree
81
78.6%
Diploma
9
12.7%
Certificate
12
8.7%
Total
103
100% This study’s objective was to explore the causes of indecent dress among the students at Umma
University’s Kajiado campus. The findings show that “freedom of choice” (my dress, my choice
clarion) is the most prominent factor of indecent dress. The major reason behind their justification
is that the university has accommodated a diverse range of different communities with dynamic
cultures. Hence, the mode of dressing will obviously differ, and this calls for acceptance of each
other. Moreover, they support the idea that a university is a learning center which assimilates mature
individuals & apparently their fundamental rights are protected by the Kenyan constitution. Though
so; this is a misunderstanding & misinterpretation of the constitution. 40 Ibid., p. 24 Manswab Mahsen Abdulrahman Manswab Mahsen Abdulrahman Table 2. Descriptive Statistics
Variable
Disagree
(F/P)
Neutral
(F/P)
Agree
(F/P)
Mean
Std. Deviation
Is due to freedom of choice (My dress
my choice)
15
14.6%
17
16.5%
71
68.9%
2.54
.738
negative influence of foreign cultures
through social media
25
24.3%
10
9.7%
68
66.0%
2.42
.858
Implementing dress codes doesn’t solve
genuine problems in the University
31
30.1%
13
12.6%
59
57.3%
2.27
.899
Indecent dressing is due to peer
pressure
31
30.1%
13
12.6%
59
57.3%
2.25
.915
There is no specific penalty in the dress
code
30
29.1%
20
19.4%
53
51.5%
2.22
.874
Level of students’ awareness of the
University’s Dress Code
42
40.8%
16
15.5%
45
43.7%
2.03
.923
Indecent dressing is due to family
background
44
42.7%
15
14.6%
44
42.7%
2.00
.929
Dress code is in opposition to my
religious values
53
51.5%
13
12.6%
37
35.9%
1.84
.926
Indecent dressing is due to influence of
the university environment
59
57.3%
9
8.7%
35
34.0%
1.77
.931
Dress code is in opposition to my family
values
60
58.3%
16
15.5%
27
26.2%
1.68
.866 Table 2. Descriptive Statistics 42 Muhammad bin Ismael Al-Bukhary, Rafuʿ Al-Yadein fi Swala, Vol 1, 1st ed, (Kuwait: Darūl Al-Arqam, 1983), p. 46 41 https://blogs.worldbank.org/developmenttalk/mydressmychoice-tackling-gender-discrimination-and-violence-kenya-one-
tweet-time, accessed 10 December 2021. i 4.1 Demographic Profile of the Respondents Particularly, Act 32 of 2010
states, “Every person has the right to freedom of conscience, religion, thought, belief, and opinion.”40
At the same time, the right to life is protected under Act 26 (1), which states that “Everyone has the
right to life.” This is in line with the purpose of the dress code, which is to safeguard students from
improper behavior. Without a dressing code, a student’s life would be in danger and susceptible
to many ethical and health menaces like contagious disease and physical and emotional abuse. Eventually, they will infringe on their rights to access education and their academic journey will
collapse. There was a difference of opinion between respondents regarding the statement on the causes
of indecent dress in Umma University. Table two highlights the causes of indecent dress according to
their views. About 68.9% of respondents expressed that the “ My dress my choice” is the main factor
in indecent dress, and it is considered = (high) point as a cause of indecent dress in the Likert scale
(Table 2). Another 66.0% of participants responded that “negative influence of foreign cultures” is
another leading cause of indecent dress. Whereas 57.3% of respondents mentioned that peer pressure
and implementing dress codes doesn’t solve genuine problems in the University is one of the causes
of indecent dress and followed by 51.5% of respondents who said that no specific penalty in the
dress code is one reason student wear as they want. Mean scores of “person’s freedom of expression,
students’ awareness, were higher than other factors respondents (44.7% and 43.7%, respectively). Also mean score of family background, opposition to my religious values, influence of the university
environment and opposition to my family values as the cause of indecent dress is lower than other
factors (42.7%, 35.9%, 34.0% and 26.2% respectively). Vol. 2. No. 1, Januari-Juni 2023 20 smael Al-Bukhary, Rafuʿ Al-Yadein fi Swala, Vol 1, 1st ed, (Kuwait: Darūl Al-Arqam, 1983), p. 46, Hadīth No: 98 The Influence of Dress Code on the Quality of Higher ... access to Western fashion via social media networks. Therefore, some of them wear strapless clothes,
bum shorts, short blouses, miniskirts, cleavage shirts, and sagging trousers for boys and even girls. In
this regard, the prophet Mohammad (SAW) prohibited imitating non-Muslims, particularly Jews and
Christians, and avoiding their clothing. “You will follow the ways of those nations who were before
you, span by span and cubit by cubit (i.e., inch by inch) so much so that even if they entered a hole of
a mastigure, you would follow them.” We said, “O Allah’s Messenger (SAW)! (Do you mean) the Jews
and the Christians?” He said, “Whom else?”43 Though the Western form of clothing will be accepted if
it complies with Islamic moral values, if it is violated, it will be considered an act of moral decadence
from the perspective of sharia. The finding shows that “implementing dress codes doesn’t solve genuine problems in the
university”. There are many problems facing university students such a crowding in dormitories,
food prices, health care, guaranteed employment after graduation and quality education. Instead
of spending funds on the enforcement of a dress code, that money could be used to build a hostel,
improve security, and provide quality education, among other things. According to the perception of
the students they don’t prioritize the issue related to dress. On the other hand, those who participated
in the question related to “dress code as a form of building good character” The responses indicate
that among 103 students, 66 respondents, or 64.1%, chose to agree, 15 respondents, or 14.6%, chose
undecided, and 22 respondents, or 21.4%, chose to disagree. Thus, by looking at the data percentages
above, we can conclude that most of the students agree that “dress code as a form of building good
character” is due to several negative repercussions, including rape, pregnancy, prostitution, HIV/
AID, and other infectious diseases. In this regard, Abu Hurayra reported that the Messenger of Allah
(SAW) said, “I was sent to perfect good character.”44 The respondents have indicated their perceptions of considering peer pressure as the cause
of indecent dress. The responses indicate that among 103 students, 33 students, or 32.0%, chose to
disagree, 11 students, or 10.7%, chose undecided, and 59 students, or 57.3%, chose to agree. E. Discussion Other reasons for the “freedom of choice” in indecent dress may be due to the support of the
feminist campaign after a woman was brutally assaulted and stripped naked by a group of young
men because she was wearing “indecent” clothing. The perpetrator of the violence was caught on
camera and went viral online. These videos went viral under the hashtag #mydressmychoice and
sparked the “My Dress, My Choice” movement in Kenya. The Facebook page of “My Dress My Choice
Challenge” has about 12,000 likes; the Twitter account has more than 2,300 followers.41 Indecent
dress is not considered freedom of choice. Because of the fundamental freedoms, human rights must
be accordance with Islamic law. The Prophet Mohammad (SAW) said: “None of you is a believer till
his desire follows what I have brought.”42 A person must be modest and not follow his whims, even
though the Islamic religion was founded on modesty, so how can a girl wear indecent clothes and
then say this is personal freedom?! Dressing in such a manner, all with the aim of looking tantalizing,
sexy, and attractive instead of dressing in a responsible way. The Western form of clothing is gaining popularity and admiration among university students as
a result of reading foreign fashion magazines, exposure to television music videos, and unrestricted Vol. 2. No. 1, Januari-Juni 2023 21 43 Ahmad bin Amru bin Abdulkhaliq, Musnad Al-Bazar, Vol 15, 1st ed, (Madina: Maktab Al-Ulum wal Hikam, 1988), p. 114, Hadīth
No: 8411 43 Ahmad bin Amru bin Abdulkhaliq, Musnad Al-Bazar, Vol 15, 1st ed, (Madina: Maktab Al-Ulum wal Hikam, 1988), p. 114, Hadīth
No: 8411
44 Ibid., Al-Bayhaqi, Vol 10, p. 191, Hadīth No: 20571
45 Al-Muhalab bin Ahmad, Al-Mukhtasar Nasih Fī Tahdhib Al-Kitab Al-Jamiʿ Swahih, Vol 3, 1st ed, (Riyadh: Dar-Al-Tawheed, 2009),
p. 240, Hadīth No: 1658 45 Al-Muhalab bin Ahmad, Al-Mukhtasar Nasih Fī Tahdhib Al-Kitab Al-Jamiʿ Swahih, Vol 3, 1st ed, (Riyadh: Dar-Al-Taw
p. 240, Hadīth No: 1658 in Amru bin Abdulkhaliq, Musnad Al-Bazar, Vol 15, 1st ed, (Madina: Maktab Al-Ulum wal Hikam, 1988), p. 114, Hadīth 44 Ibid., Al-Bayhaqi, Vol 10, p. 191, Hadīth No: 20571 43 Ahmad bin Amru bin Abdulkhaliq, Musnad Al-Bazar, Vol 15, 1st ed, (Madina: Maktab Al-Ulum wal Hikam, 1988), p. 114, Hadīth
No: 8411
44 Ibid., Al-Bayhaqi, Vol 10, p. 191, Hadīth No: 20571
45 Al M h l b bi Ah
d Al M kht
N ih Fī T hdhib Al Kit b Al J
iʿ S
hih V l 3 1st d (Ri
dh D
Al T
h
d 2009) No: 8411
44 Ibid., Al-Bayhaqi, Vol 10, p. 191, Hadīth No: 20571
45 Al-Muhalab bin Ahmad, Al-Mukhtasar Nasih Fī Tahdhib Al-Kitab Al-Jamiʿ Swahih, Vol 3, 1st ed, (Riyadh: Dar-Al-Tawheed, 2009),
p. 240, Hadīth No: 1658 Ibid., Al Bayhaqi, Vol 10, p. 191, Hadīth No: 20571
45 Al-Muhalab bin Ahmad, Al-Mukhtasar Nasih Fī Tahdhib Al-Kitab Al-Jamiʿ Swahih, Vol 3, 1st ed, (Riyadh: Dar-Al-Tawheed, 2009),
p. 240, Hadīth No: 1658 Manswab Mahsen Abdulrahman student who is inappropriately attired will be barred altogether from entering all academic and
administrative buildings and shall be guilty of a disciplinary offence.”46 In the opinion of the students,
preventing access to the lecture hall and administrative blocks is not a penalty. Moreover, students
are not prevented from attending the lecture hall due to a lack of departmental cooperation, starting
from the security of the university premises. The suitable penalty is to suspend the student from the
university for a specified period of time. student who is inappropriately attired will be barred altogether from entering all academic and
administrative buildings and shall be guilty of a disciplinary offence.”46 In the opinion of the students,
preventing access to the lecture hall and administrative blocks is not a penalty. Moreover, students
are not prevented from attending the lecture hall due to a lack of departmental cooperation, starting
from the security of the university premises. The suitable penalty is to suspend the student from the
university for a specified period of time. Based on the above findings, it is strongly believed that the students are not aware of the dress
code. 45 (43.7%), while 16 (15.5%) of the participants were neutral on the awareness of the dress
code, and 42 (40.8%) of the participants disagreed with the awareness of the dress code. Based on the
students’ reports, they were not given a student information handbook on the orientation day. This
calls for the immediate attention of the university management and require proper awareness and
sensitization programs to be conducted. Other findings of this study are that family background became one of the greatest causes of
indecent dress among the students. On this issue, Mr Jude Obi state that “That is why many ladies
dress indecently when they grow up and then it will be difficult for them to change their method
of dressing,”47 The Prophet Mohammad (SAW) placed the responsibility of caring for children on
parents. “All of you are guardians and are responsible for your subjects. The ruler is a guardian
and responsible for his subjects; the man is a guardian of his family; the woman is guardian in her
husband’s house and responsible for her wards; a servant is guardian of his master’s property and
responsible for his ward. 46 Ibid., p. 29
47 https://www.vanguardngr.com/2016/09/ indecent- dressing-lawyer-blames-parent, accessed 7 December 2021
48 Ibid., Al-Bukhary, Vol 2, p. 6, Hadīth No: 893
49 Holy Bible, in First Timothy chapter 2 verses 9 to 10 (New King James Version) Thus,
by looking at the data percentages above, we can conclude that most of the students agree that
Interaction with others and meetings in hostels, lecture halls, and libraries has a clear impact on
human thought and behavior. Consequently, some students take advantage of the freedom time to
let their hair down, use alcohol, sexual promiscuity, and wear indecent dress because their peers are
doing these things. The prophet Mohammad (SAW) forbade interaction with bad pious company. ‘The example of a good pious companion and an evil one is that of a person carrying musk and
another blowing a pair of bellows. The one who is carrying musk will either give you some perfume
as a present, or you will buy some from him, or you will get a good smell from him, but the one who
is blowing a pair of bellows will either burn your clothes or you will get a bad smell from him.”45 Based on the responses received from the participants, about 53 (51.5%) agreed that there is
no specific penalty in the dress code. 30 (29.1%) of the participants disagreed with the existence of
a penalty, while 20 (19.4%) of the participants were neutral on the existence of penalty questions
asked. In accordance with student information handbook 5.5 dress code clause (iv), states that: “Any Vol. 2. No. 1, Januari-Juni 2023 22 22 The Influence of Dress Code on the Quality of Higher ... The Influence of Dress Code on the Quality of Higher ... F. Conclusion Based on the finding, the majority of the respondents describe indecent dress as clothing that
exposes the private parts of the body. The study examines the causes of indecent dress among
students and highlights the conditions, types of clothing, and penalties outlined in the students’
information handbook 2020. The research finds that some conditions for women’s dress were clearly
captured in clauses (v), (vi), and (ix), while others were not reflected in the dress code, such as that
clothing must cover the entire body except for the hands and face. (b) The material should not be so
thin that it can be seen through. (c) The clothing must hang loose so that the shape or form of the
body is not apparent. Clauses (v) and (viii) identify types of clothing that are forbidden which are
comply with Islamic law. Some students thought the penalty for being inappropriately attired was
pointless for preventing them accessing the lecture hall and administrative blocks. As a result, it is
recommended that universities conduct dress code campaigns through announcement on notice
boards and other means on campus, provide regular counseling, amend the university dress code,
and enlist the cooperation of university stakeholders to enforce the dress code. So all of you are guardians and are responsible for your subjects”.48 Furthermore, 53 (51.5%) of the participants disagreed or strongly disagreed that the dress code
is in opposition to their religious values. 37 (35.9%) of the participants agreed or strongly agreed
that the dress code is in opposition to their religious values. While 13 (12.6%) of the participants
are undecided regarding this question. Similarly, 60 (58.3%) of the participants disagreed that the
dress code is in opposition to their family values; 27 (26.2%) of the participants agreed that the dress
code is in opposition to their family values; while 16 (15.5%) are undecided regarding this question. This is because African society is most known for its decent culture. Furthermore, revealed religion
encourages decent dress. In the Holy Bible, in First Timothy chapter 2 verses 9 to 10 (New King James
Version), Paul said: “I also want women to dress modestly, with decency and propriety.”49 From this
Bible passage, it can be understood that God wants us to dress modestly. The finding shows that 59 (57.3%) of the participants disagreed that indecent dressing is due to
the influence of the university environment; 35 (34.0%) of the participants agreed or strongly agreed
that indecent dressing is due to the university environment. While 9 (8.7%) of the participants are
undecided regarding this question, it is because the university was established on the basis of Islamic
values. Furthermore, some students believe that several activities, such as dancing on culture day
and some lecturers’ refusal to wear decent dress, contributed to the nudity reveal. 23 Vol. 2. No. 1, Januari-Juni 2023 REFERENCES ʽAbd al-Razzaq al-Sanʽani, Musannaf Abd al-Razzaq, Beirut: Maktab Al-Islamy, 2nd, Vol 11, 1403 H. Abu Bakr Ibn Abi Shaybah, Al-Kitab al-Musannaf fil Ahadith wal Athar, Riyadh: Maktabah al-Rushdi, 1st,
Vol 5,1409 H. Abu Malik ibn Abdulwahab, Ahkamu An-Nisaa, Cairo: Daulī, 1st, 2007 Abu Malik ibn Abdulwahab, Ahkamu An-Nisaa, Cairo: Daulī, 1st, 2007 Abubakar ibn Abi Sheibah, Al-Kitab Al-Musanaf fi Al-Ahadith wal Athar, Riyadh: Maktabah al-Rushdi, 1st,
Vol 6, 1409 H Ahmad b. Shueb An-Nasai, Sunan An-Nasai, Halab: Maktab Al-Mutbuat Al-Islamiyyah, 2nd ed, Vol 8,
1986 Ahmad bin Al-Hussein bin Ali Al-Baihaqi, Sunanul Al-Kubra, Pakistan: Majlis Dairatul Al-Marīf Al-
Nidhwāmiyah, 1st ed, Vol 2, 1344 H Ahmad bin Ali bin Muthana, Musnad abu ya’la, Damascus: Dar Al-Maamun, 1st, Vol 12, 1984 Ahmad bin Amru bin Abdulkhaliq, Musnad Al-Bazar, Madina: Maktab Al-Ulum wal Hikam, 1st ed, Vol
15, 1988 Ahmad bin Hanbali, Musnad Imam Ahmad bin Hanbali, Beirut: Dar Al-Alim Al-Kutub, 1st, Vol 1 Ahmad bin Hussein Al-Bayhaqi, Shu’ab Al-Iman, (Riyadh: Maktabah al-Rushdi, 1st, Vol 8, 2003 Alauddin Abi Bakr Bin Mas’ud Al-Kasani, Bada’i al-Sana’i fi Tartib al-Shara’I, Egypt: Sharika Matbuat
Ilmiyyah, 1st, Vol 5, 1327H. Al-Muhalab bin Ahmad, Al-Mukhtasar Nasih Fī Tahdhib Al-Kitab Al-Jamiʿ Swahih, Riyadh: Dar-Al-
Tawheed, 1st ed, Vol 3, 2009. Eldabi, Tillal, Zahir Irani, Ray J. Paul, and Peter ED Love. “Quantitative and qualitative decision‐
Ibn ‘Abidin, Radd al-Muhtār ‹ala al-Durr al-Mukhtār, Beirut: Dar al-Fikr, 1st, Vol 6, 2000. Eldabi, Tillal, Zahir Irani, Ray J. Paul, and Peter ED Love. “Quantitative and qualitative decision‐
Ibn ‘Abidin Radd al-Muhtār ‹ala al-Durr al-Mukhtār Beirut: Dar al-Fikr 1st Vol 6 2000 Eldabi, Tillal, Zahir Irani, Ray J. Paul, and Peter ED Love. “Quantitative and qualitative decision‐ Eldabi, Tillal, Zahir Irani, Ray J. Paul, and Peter ED Love. “Quantitative and qualitative decision‐
Ibn ‘Abidin, Radd al-Muhtār ‹ala al-Durr al-Mukhtār, Beirut: Dar al-Fikr, 1st, Vol 6, 2000. Ibn Hajar al-Haytamī, Fatawa al-Kubra al-Fiqhiyyah, Beirut: Dar el Fikr, Vol 1, n.d. Ibn ‘Abidin, Radd al-Muhtār ‹ala al-Durr al-Mukhtār, Beirut: Dar al-Fikr, 1st, Vol 6, 2000. Ibn Hajar al-Haytamī, Fatawa al-Kubra al-Fiqhiyyah, Beirut: Dar el Fikr, Vol 1, n.d. Vol. 2. No. 1, Januari-Juni 2023 24 Vol. 2. No. 1, Januari-Juni 2023 Manswab Mahsen Abdulrahman Indhira Santos and Bookang Seol, My Dress My Choice: Tackling gender discrimination and violence in Kenya
one tweet at a time. Official website: Indhira Santos and Bookang Seol, My Dress My Choice: Tackling gender discrimination and violence in Kenya
one tweet at a time. Official website: Indhira Santos and Bookang Seol, My Dress My Choice: Tackling gender discrimination and violence in Kenya
one tweet at a time. Official website: sma`il ibn `Umar Ibn Kathir, Tafsir al-Qur’an al-`azim, Riyadh: Dar Taibah, 2nd, Vol 3, 1999. Isma`il ibn `Umar Ibn Kathir, Tafsir al-Qur’an al-`azim, Riyadh: Dar Taibah, 2nd, Vol 3, 1999. Majmuat Al-Mualifin, Al-Mausu’ah Al-fiqhiyah Al-Kuwaitiyah, Egypt: Dar Al-Safwa, 1st, Vol 35, n.d. making methods in simulation modelling.” Management Decision. 2002. 40 (1), 64 -73. Majmuat Al-Mualifin, Al-Mausu’ah Al-fiqhiyah Al-Kuwaitiyah, Egypt: Dar Al-Safwa, 1st, Vol 35, n.d. making methods in simulation modelling.” Management Decision. 2002. 40 (1), 64 -73. making methods in simulation modelling.” Management Decision. 2002. 40 (1), 64 -73. Mohammad bin Abdallah Hakim al-Naysaburi, Al-Mustadrak ‘ala al-Sahihayn, (Beirut: Dar al-kotob Al
Ilmiyah, 1st, Vol 4, 1990), 150, Hadīth No: 7088 Mohammad Twijirī, Mausu’ah Al-fiqhiyah Al-Islamī, (Saudia: Bayt Al-Afkar Adawliah, 1st ed, Vol 4, 2009),
107 Mr Jude Obi, Indecent dressing: Lawyer blames parents, official website: https://www.vanguardngr. com/2016/09/ indecent- dressing-lawyer-blames-parent/ Accessed/ December 7, 2021 Muhammad bin Ismael Al-Bukhary, Rafuʿ Al-Yadein fi Swala, Kuwait: Darūl Al-Arqam, 1st ed, Vol 1,
1983. Muhammad bin Ismael Al-Bukhary, Swahih Al-Bukhary, Cairo: Darūl Shuʿib, 1st ed, Vol 6, 1987 Muhammad ibn Ahmad Al-Qurtubi, Al-Jami’ Li Ahkam Al-Quran, Beirut: Dar al-kotob Al ilmiyah, 1st Vol
5, 1998. No: 477 Shaykh al-Islam Ibn Taymiyyah, Majmu’ Al-Fatawa, Egypt: Dar-Al-Wafa, 1st, Vol 15, 2005. Shaykh al-Islam Ibn Taymiyyah, Majmu’ Al-Fatawa, Egypt: Dar-Al-Wafa, 1st, Vol 15, 2005. U
U i
it
St d
t i f
ti
h
db
k St d
t D
C d
A t 5 5 Umma University, Student information handbook, Student Dress Code, Act 5.5 Vol. 2. No. 1, Januari-Juni 2023 25
|
https://openalex.org/W3125800111
|
https://hal.archives-ouvertes.fr/hal-03451249/file/2021mnFrontMat.pdf
|
English
| null |
Directional Control of Rayleigh Wave Propagation in an Elastic Lattice by Gyroscopic Effects
|
Frontiers in materials
| 2,021
|
cc-by
| 13,156
|
To cite this version: M J Nieves, G Carta, Vincent Pagneux, M Brun. Directional Control of Rayleigh Wave Propagation in
an Elastic Lattice by Gyroscopic Effects. Frontiers in Materials, 2021, 7, 10.3389/fmats.2020.602960. hal-03451249 Directional Control of Rayleigh Wave Propagation in an
Elastic Lattice by Gyroscopic Effects
M J Nieves, G Carta, Vincent Pagneux, M Brun Directional Control of Rayleigh Wave Propagation in an
Elastic Lattice by Gyroscopic Effects
M J Nieves, G Carta, Vincent Pagneux, M Brun To cite this version:
M J Nieves, G Carta, Vincent Pagneux, M Brun. Directional Control of Rayleigh Wave Propagation in
an Elastic Lattice by Gyroscopic Effects. Frontiers in Materials, 2021, 7, 10.3389/fmats.2020.602960. hal-03451249 HAL Id: hal-03451249
https://hal.science/hal-03451249v1
Submitted on 26 Nov 2021 L’archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d’enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés. HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers. ORIGINAL RESEARCH
published: 27 January 2021
doi: 10.3389/fmats.2020.602960 Directional Control of Rayleigh Wave
Propagation in an Elastic Lattice by
Gyroscopic Effects
M. J. Nieves 1, G. Carta 2*, V. Pagneux 3 and M. Brun 2
1School of Computing and Mathematics, Keele University, Keele, United Kingdom, 2Department of Mechanical, Chemical and
Materials Engineering, University of Cagliari, Cagliari, Italy, 3Laboratoire D’Acoustique de L’Université Du Maine (LAUM), Le Mans,
France We discuss the propagation of Rayleigh waves at the boundary of a semi-infinite elastic
lattice connected to a system of gyroscopic spinners. We present the derivation of the
analytical solution of the equations governing the system when the lattice is subjected to a
force acting on the boundary. We show that the analytical results are in excellent
agreement with the outcomes of independent finite element simulations. In addition,
we investigate the influence of the load direction, frequency and gyroscopic properties of
the model on the dynamic behavior of the micro-structured medium. The main result is that
the response of the forced discrete system is not symmetric with respect to the point of
application of the force when the effect of the gyroscopic spinners is taken into account. Accordingly, the gyroscopic lattice represents an important example of a non-reciprocal
medium. Hence, it can be used in practical applications to split the energy coming from an
external source into different contributions, propagating in different directions. Edited by:
Andrea Bacigalupo,
University of Genoa, Italy Edited by:
Andrea Bacigalupo,
University of Genoa, Italy Reviewed by:
Andrea Colombi,
ETH Zürich, Switzerland
Enrico Radi,
University of Modena and Reggio
Emilia, Italy *Correspondence:
G. Carta Specialty section:
This article was submitted to
Mechanics of Materials,
a section of the journal
Frontiers in Materials
Received: 04 September 2020
Accepted: 05 November 2020
Published: 27 January 2021 Specialty section:
This article was submitted to
Mechanics of Materials,
a section of the journal
Frontiers in Materials Surface waves traveling on the free boundaries of periodic media are usually referred to as
Rayleigh-Bloch waves. They are of great importance in problems concerning the dynamic
propagation of cracks in discrete systems, as discussed by Marder and Gross (1995) and Slepyan
(2002) for uniform media and in successive works (Nieves et al., 2013) for non-uniform lattices. Similar localized phenomena may play a substantial role in non-uniform crack propagation as
evidenced in (Piccolroaz et al., 2020), where lattice dissimilarity has been shown to promote or
diminish localized deformations around the faces of the crack. Trapped modes associated with
Rayleigh-Bloch waves in systems incorporating periodic gratings or periodic arrays of resonators
were analyzed by Porter and Evans (1999), Porter and Evans (2005), Linton and McIver (2002) and 1 INTRODUCTION According to their original definition, Rayleigh waves are a class of elastic waves that propagate on
the surface of an infinite homogenous isotropic solid, and they are confined within a superficial
region whose thickness is comparable with their wavelength (Rayleigh, 1885). These waves are well
known by seismologists, since they are usually detected after the occurrence of an earthquake. They
are also observed in other common urban activities, such as construction and demolition works and
vehicular traffic, in addition to industrial processes and technologies, like mining exploration, non-
destructive testing and design of electronic instruments. In the literature, they have been studied in
depth especially with reference to continuous media (see, for instance, the classical treatizes by
Viktorov (1967), Achenbach (1973) and Graff (1975)). *Correspondence:
G. Carta
giorgio_carta@unica.it *Correspondence:
G. Carta Keywords: Rayleigh waves, elastic lattice, gyroscopic spinners, dispersion properties, energy flow, non-reciprocity,
energy symmetry breaking 2 MATERIALS AND METHODS The material under consideration consists of a semi-infinite two-
dimensional triangular lattice of masses m, linked by elastic
springs of stiffness γ, length L and whose inertia is negligible
in comparison with m. The planar and three-dimensional
representations of the lattice are shown in Figures 1A,C,
respectively. In addition, each mass is attached to a gyroscopic
spinner (see Figure 1B), whose configuration is described by the
Euler angles θ, ϕ and ψ, denoted as the nutation, precession and
spin angles, respectively. We assume that the nutation angle θ is
small (θ ≪1), together with the displacement of the mass
attached to the spinner. Each gyroscopic spinner has length l,
moments of inertia I1 about the axis of revolution and I0 about the
other two principal axes passing through the spinner’s base. Firstly derived by Carta et al. (2018) and Nieves et al. (2018),
the gyricity Ω is an independent parameter, representing the sum
of the initial precession and spin rates, that remains constant
throughout the motion: Ω _ϕ + _ψ Const. We also introduce
the effective gyricity Ω* Ω[I1/(I0 + ml2)] and the effective mass
m* m[1 + I0/(ml2)], that both include the inertial contribution
of the spinners. In this paper, we present for the first time the analytical
derivation of the displacement field in a semi-infinite elastic
lattice
incorporating
gyroscopic
spinners,
focusing
the
attention on Rayleigh waves. Conversely, the main objective of
previous papers (Garau et al., 2018, 2019) was related to the study
of topologically-protected waveforms in lattices incorporating
sub-domains with different values of the parameters of the
gyroscopic spinners. The analytical results of the present paper
are also verified with an independent finite element code. The
displacement field produced by a point load acting on the
boundary of the medium and the calculation of the energy
flow demonstrate that the considered system is non-reciprocal,
as the response of the forced lattice is not symmetric with respect
to the point of application of the concentrated load. The influence
of different physical quantities on the behavior of the gyroscopic
system is also investigated through a detailed parametric analysis. In practice, such a lattice can be realized by constructing a
triangular array of masses (represented, for example, by spheres)
connected by thin elastic rods. Citation: (2020), the dispersion analysis of Rayleigh waves in a semi-infinite
triangular gyroscopic lattice has been carried out. The non-
symmetry of the eigenmodes of the lattice’s particles at the free
boundary for positive and negative values of the wave number has
been linked to the non-symmetry of the system’s response to an
applied force, determined by means of finite element simulations. In
addition, a comparison with an effective gyroscopic continuum
discussed in that paper has corroborated the results for the
discrete system when low values of the wave number are considered. Citation: We observe that the gyroscopic effect plays the role of magnetic
bias (Bi et al., 2011) or angular momentum (Sounas et al., 2013) in
linear non-reciprocal electromagnetic metamaterials and of
circulating fluids in acoustic linear circulators (Fleury et al., 2014). Firstly introduced by Brun et al. (2012) and later developed by
Carta et al. (2014), a gyroscopic elastic lattice is a tunable system,
whose dispersive properties can be varied by changing the spin and
precession rates of the spinners. This type of metamaterial can be
utilized to force waves to propagate along a line, whose direction is
defined by the geometry of the medium (Carta et al., 2017). Gyroscopic spinners can also be employed to design topological
insulators, where waves travel in one direction and are immune to
backscattering (Nash et al., 2015; Süsstrunk and Huber, 2015; Wang
et al., 2015; Garau et al., 2018; Lee et al., 2018; Mitchell et al., 2018;
Carta et al., 2019; Garau et al., 2019; Carta et al., 2020). Furthermore,
systems with gyroscopic spinners can be used to design coatings to
hide the presence of objects in a continuous or discrete medium
(Brun et al., 2012; Garau et al., 2019). In a recent work by Nieves et al. (2020), the dispersion analysis of Rayleigh waves in a semi-infinite
triangular gyroscopic lattice has been carried out. The non-
symmetry of the eigenmodes of the lattice’s particles at the free
boundary for positive and negative values of the wave number has
been linked to the non-symmetry of the system’s response to an
applied force, determined by means of finite element simulations. In
addition, a comparison with an effective gyroscopic continuum
discussed in that paper has corroborated the results for the
discrete system when low values of the wave number are considered. In this paper, we present for the first time the analytical
derivation of the displacement field in a semi-infinite elastic
lattice
incorporating
gyroscopic
spinners,
focusing
the
attention on Rayleigh waves. Conversely, the main objective of
previous papers (Garau et al., 2018, 2019) was related to the study
of topologically-protected waveforms in lattices incorporating
sub-domains with different values of the parameters of the
gyroscopic spinners. The analytical results of the present paper
are also verified with an independent finite element code. Frontiers in Materials | www.frontiersin.org Citation: The non-
symmetry of the eigenmodes of the lattice’s particles at the free
boundary for positive and negative values of the wave number has
been linked to the non-symmetry of the system’s response to an
applied force, determined by means of finite element simulations. In
addition, a comparison with an effective gyroscopic continuum
discussed in that paper has corroborated the results for the
discrete system when low values of the wave number are considered. In this paper, we present for the first time the analytical
derivation of the displacement field in a semi-infinite elastic
lattice
incorporating
gyroscopic
spinners,
focusing
the
attention on Rayleigh waves. Conversely, the main objective of
previous papers (Garau et al., 2018, 2019) was related to the study
of topologically-protected waveforms in lattices incorporating
sub-domains with different values of the parameters of the
gyroscopic spinners. The analytical results of the present paper
are also verified with an independent finite element code. The
displacement field produced by a point load acting on the
boundary of the medium and the calculation of the energy
flow demonstrate that the considered system is non-reciprocal,
as the response of the forced lattice is not symmetric with respect
to the point of application of the concentrated load. The influence
of different physical quantities on the behavior of the gyroscopic
system is also investigated through a detailed parametric analysis. g
y
Firstly introduced by Brun et al. (2012) and later developed by
Carta et al. (2014), a gyroscopic elastic lattice is a tunable system,
whose dispersive properties can be varied by changing the spin and
precession rates of the spinners. This type of metamaterial can be
utilized to force waves to propagate along a line, whose direction is
defined by the geometry of the medium (Carta et al., 2017). Gyroscopic spinners can also be employed to design topological
insulators, where waves travel in one direction and are immune to
backscattering (Nash et al., 2015; Süsstrunk and Huber, 2015; Wang
et al., 2015; Garau et al., 2018; Lee et al., 2018; Mitchell et al., 2018;
Carta et al., 2019; Garau et al., 2019; Carta et al., 2020). Furthermore,
systems with gyroscopic spinners can be used to design coatings to
hide the presence of objects in a continuous or discrete medium
(Brun et al., 2012; Garau et al., 2019). In a recent work by Nieves et al. Citation: Nieves MJ, Carta G, Pagneux V and
Brun M (2021) Directional Control of
Rayleigh Wave Propagation in an
Elastic Lattice by Gyroscopic Effects. Front. Mater. 7:602960. doi: 10.3389/fmats.2020.602960 January 2021 | Volume 7 | Article 602960 1 Frontiers in Materials | www.frontiersin.org Directional Control of Rayleigh Waves Nieves et al. Antonakakis et al. (2014) for scalar problems, by Colquitt et al. (2015) for vector systems and by Haslinger et al. (2017) and
Morvaridi et al. (2018) for plates. While in (Nieves et al., 2020) the wave field produced by a
force on the boundary was determined numerically by using a
finite element code, here the response of the system is calculated
by means of a novel analytical formulation. The latter has many
advantages. First, it does not require Adaptive Absorbing Layers
(AAL) to prevent wave reflections at the boundaries of the
computational domain; in fact, AAL are frequency-dependent
and, as a consequence, their characteristic parameters need to be
tuned manually every time the frequency is changed. The
analytical formulation does not require the introduction of
fictitious boundaries as in finite element codes. Second, the
analytical formulation allows one to perform a parametric
analysis
quickly
and
efficiently,
a
task
that
is
not
straightforward in many finite element packages and that is
performed here. Third, analytical results are necessary to
validate the outcomes of finite element models. For these
reasons, it is envisaged that the proposed analytical approach
can be useful to the interested reader to tackle similar dynamic
problems in discrete elastic systems. Morvaridi et al. (2018) for plates. Recently, there has been an increasing interest in the design
and fabrication of elastic media with unusual properties, often
referred to as metamaterials (see the recent works by Filipov et al. (2015), Misseroni et al. (2016), Armanini et al. (2017), Bordiga
et al. (2018), Bacigalupo et al. (2019), Al Ba’ba’a et al. (2020),
Tallarico et al. (2020) and Wenzel et al. (2020) amongst others). In this paper, we focus the attention on an elastic metamaterial
consisting of a triangular lattice connected to a system of
gyroscopic spinners. The presence of gyroscopic spinners
breaks the time-reversal symmetry of the system and makes
the medium non-reciprocal, as proved by Nieves et al. (2020). Citation: The
displacement field produced by a point load acting on the
boundary of the medium and the calculation of the energy Recently, there has been an increasing interest in the design
and fabrication of elastic media with unusual properties, often
referred to as metamaterials (see the recent works by Filipov et al. (2015), Misseroni et al. (2016), Armanini et al. (2017), Bordiga
et al. (2018), Bacigalupo et al. (2019), Al Ba’ba’a et al. (2020),
Tallarico et al. (2020) and Wenzel et al. (2020) amongst others). In this paper, we focus the attention on an elastic metamaterial
consisting of a triangular lattice connected to a system of
gyroscopic spinners. The presence of gyroscopic spinners
breaks the time-reversal symmetry of the system and makes
the medium non-reciprocal, as proved by Nieves et al. (2020). We observe that the gyroscopic effect plays the role of magnetic
bias (Bi et al., 2011) or angular momentum (Sounas et al., 2013) in
linear non-reciprocal electromagnetic metamaterials and of
circulating fluids in acoustic linear circulators (Fleury et al., 2014). p
g
circulating fluids in acoustic linear circulators (Fleury et al., 2014). Firstly introduced by Brun et al. (2012) and later developed by
Carta et al. (2014), a gyroscopic elastic lattice is a tunable system,
whose dispersive properties can be varied by changing the spin and
precession rates of the spinners. This type of metamaterial can be
utilized to force waves to propagate along a line, whose direction is
defined by the geometry of the medium (Carta et al., 2017). Gyroscopic spinners can also be employed to design topological
insulators, where waves travel in one direction and are immune to
backscattering (Nash et al., 2015; Süsstrunk and Huber, 2015; Wang
et al., 2015; Garau et al., 2018; Lee et al., 2018; Mitchell et al., 2018;
Carta et al., 2019; Garau et al., 2019; Carta et al., 2020). Furthermore,
systems with gyroscopic spinners can be used to design coatings to
hide the presence of objects in a continuous or discrete medium
(Brun et al., 2012; Garau et al., 2019). In a recent work by Nieves et al. (2020), the dispersion analysis of Rayleigh waves in a semi-infinite
triangular gyroscopic lattice has been carried out. 2 MATERIALS AND METHODS At the bottom part of each mass a
cylindrical hole can be drilled, where the tip of the gyroscopic
spinner can be inserted. The connection needs to be frictionless,
so that the spinning motion of the gyroscope is not transmitted to
the mass, which can only move in the x1- or x2-direction without
rotating. The spinning motion of the gyroscopic spinner can be
applied by using an electric motor; in this way, its spin rate can
remain constant during the motion. Each gyroscopic spinner is
pinned at the base and its axis is parallel to the x3-direction in the
initial configuration. The boundary of the semi-infinite lattice is subjected to an
oscillatory force of amplitude P and prescribed radian frequency January 2021 | Volume 7 | Article 602960 2 Directional Control of Rayleigh Waves Nieves et al. FIGURE 1 | (A) Semi-infinite triangular array of masses, interconnected by elastic links and joined to gyroscopic spinners; a point force is applied on the boundary of
the medium. (B) Representation of a gyroscopic spinner attached to a lattice’s mass; θ, ϕ and ψ indicate the nutation, precession and spin angles, respectively. (C)
Three-dimensional sketch of the gyro-elastic lattice. FIGURE 1 | (A) Semi-infinite triangular array of masses, interconnected by elastic links and joined to gyroscopic spinners; a point force is applied on the boundary of
the medium. (B) Representation of a gyroscopic spinner attached to a lattice’s mass; θ, ϕ and ψ indicate the nutation, precession and spin angles, respectively. (C)
Three-dimensional sketch of the gyro-elastic lattice. €u
(n1,n2) −Ω*R_u(n1,n2) + a(1) · u(n1+1,n2) + u(n1−1,n2) −2u(n1,n2)a(1)
+ a(2) · u(n1,n2+1) + u(n1,n2−1) −2u(n1,n2)a(2)
+ a(3) · u(n1−1,n2+1) + u(n1+1,n2−1) −2u(n1,n2)a(3),
n1, n2 ∈Z, n2 > 0,
(2)
where ω0 (see Figure 1A), which generates Rayleigh waves localized at
the boundary and bulk waves propagating inside the medium. The displacement of a generic particle, whose position is
identified by the multi-index n (n1, n2)T, is denoted by
u(n1,n2)(t) and is a function of time t. We introduce the following normalizations: (2) where x ~xL, u(n1,n2) ~u(n1,n2)L, t ~t
m*c
,
ω0 ~ω0
cm*
, Ω* ~Ω
*
cm*
, P ~PcL,
(1) (1) u(n1,n2)(t) u(x1, x2, t),
(3)
with (3) with where the tilde symbol indicates a dimensionless quantity. 2 MATERIALS AND METHODS In the
following, the tilde is omitted for ease of notation and it is
assumed that all the appearing quantities are dimensionless. x1 n1 + n2
2 ,
x2
3
√
n2
2
. (4) x1 n1 + n2
2 ,
x2
3
√
n2
2
. (4) (4) Further, the dot denotes the time derivative, the vectors a(i)
(i 1, 2, 3) are ,
(i 1, 2, 3) are 2.2 Alternative Representations of the
Governing Equations in the Transient
Regime (15) We introduce the integer p 2 n1 and the transient solution in
the form for n2 > 0, where the factor e(−n2/2) appearing throughout due to
the application of the discrete Fourier transform has been
cancelled
(see
Eq. 10). Similar
conversions
for
Eq. 7
describing the forced boundary at n2 0 lead to u(n1,n2)(t) Re U(p,n2)(t)eiω0t
,
(10) (10) where the time-dependent complex displacement amplitude
U(p,n2)(t) U(p + n2, n2, t) satisfies the conditions of zero
initial
velocity
and
displacement. In
addition,
note
that
for α, β ∈Z (s + iω0)2I + Ω*(s + iω0)RULF
0 (s, k1) 1
s P + 2a(1)
· (cos(k1) −1)ULF
0 (s, k1)a(1) + a(2) · e−ik1/2ULF
1 (s, k1) −ULF
0 (s, k1)
a(2)
+ a(3) · eik1/2ULF
1 (s, k1) −ULF
0 (s, k1)
a(3). (s + iω0)2I + Ω*(s + iω0)RULF
0 (s, k1) 1
s P + 2a(1)
· (cos(k1) −1)ULF
0 (s, k1)a(1) + a(2) · e−ik1/2ULF
1 (s, k1) −ULF
0 (s, k1)
a(2)
+ a(3) · eik1/2ULF
1 (s, k1) −ULF
0 (s, k1)
a(3). U(p,n2)(t) n1 n1 + α
n2 n2 + β
U(p+2α+β,n2+β)(t).
(11) (11) (16) (16) In terms of these complex displacement amplitudes, Eqs. 2, 7
become: 2.2.1 Laplace and Fourier Transformed Equations for
the Complex Displacement Amplitudes (6) the Complex Displacement Amplitudes Next, we apply the Laplace transform in time t to Eqs. 12,13 and we
use the fact that the displacement amplitudes satisfy zero initial
conditions. After this, we apply the discrete Fourier transform with
respect to n1 ∈Z x1. In what follows, ULF
n2 denotes the Laplace and
discrete Fourier transform of the solution, defined as The governing equations for a mass belonging to the boundary
of the semi-infinite lattice (n2 0) are €u
(n1,0) −Ω*R_u(n1,0) + a(1) · u(n1+1,0) + u(n1−1,0) −2u(n1,0)a(1)
+ a(2) · u(n1,1) −u(n1,0)a(2) + a(3) · u(n1−1,1) −u(n1,0)a(3)
+ P cos(ω0t)δn1,0,
n1 ∈Z,
(7) ULF
n2(s, k1)
∞
n1−∞
∞
0
U(p,n2)(t)e−st+ik1(n1+n2/2)dt. (14) (14) (7) where where Here, s and k1 are the Laplace and discrete Fourier
transform parameters, respectively. The Fourier transform
parameter k1 will also be referred to as the (normalized)
wave number. δi,j 1,
i j,
0,
otherwise,
(8) (8) is the Kronecker delta. For the equations in the bulk, we obtain that the complex
displacement amplitude satisfies In addition, we assume that the lattice is at rest initially, namely: u(n1,n2)(0) _u(n1,n2)(0) 0,
n1, n2 ∈Z, n2 ≥0. (9) u(n1,n2)(0) _u(n1,n2)(0) 0,
n1, n2 ∈Z, n2 ≥0. (9) (9) (s + iω0)2I + Ω*(s + iω0)RULF
n2(s, k1) 2a(1)
· (cos(k1) −1)ULF
n2(s, k1)a(1) + a(2)
· e−ik1/2ULF
n2+1(s, k1) + eik1/2ULF
n2−1(s, k1) −2ULF
n2(s, k1)
a(2)
+ a(3) · eik1/2ULF
n2+1(s, k1) + e−ik1/2ULF
n2−1(s, k1) −2ULF
n2 (s, k1)
a(3),
(15) 2.1 Governing Equations of the Forced
Lattice in the Transient Regime a(1) (1, 0)T, a(2) 1/2,
3
√
/2
T, a(3) −1/2,
3
√
/2
T,
(5) (5) g
The equations of motion of a mass within the bulk of the lattice
are given in normalized form as (Garau et al., 2019) as shown in Figure 1A, and the matrix R is January 2021 | Volume 7 | Article 602960 Frontiers in Materials | www.frontiersin.org Directional Control of Rayleigh Waves Nieves et al. R 0
1
−1
0
. (6) R 0
1
−1
0
. Frontiers in Materials | www.frontiersin.org 2.5.1 The Rayleigh Waves UF
n2 UΛn2. (20) (20) Rayleigh waves carry some of the energy produced by the point
load in both directions along the boundary. The lack of
symmetry in the integral kernel of Eq. 23 with respect to the
zero wave number results in a disparity between amplitudes of
waves outgoing from the source to the left and to the right of
the load. Here, Λ is such that |Λ| < 1 for n2 ≥1, since we are considering
waves that decay into the bulk of the lattice. The solution in Eq. 20 is inserted into Eq. 18 in order to find
the eigensolutions for waves in the bulk; using Eq. 19 it is then
possible to satisfy conditions at n2 0 and find the response to
the applied load. The full derivation is reported in the
Supplementary Material, where it is shown that the solution
has the form The Rayleigh waves are defined by the degenerate values of the
wave number of M2 for a given frequency ω0, and these singular
points are represented by the simple poles of Eq. 21. One can
check that there exist no other singular points of this function for
ω0 ≠Ω* (the special case ω0 Ω* will be discussed later). On the
dispersion diagram, these simple poles correspond to the
intersections of the line ω ω0 with the curve ω ωR, where
ωR is given by UF
n2 U0Λn2[M2]−1P|ω0ω0−i0,
(21) (21) where U0, Λ and M2 are the matrices specified in Supplementary
Equations S8, S7, S11, respectively. Note, the right-hand side of Eq. 21 defines a 2π -periodic (4π
-periodic) function for real k1 when n2 is even (odd). ωR
3 sin2 k1
2
+ Ω*
2
2
−
⎡⎣3 sin2 k1
2
+ Ω*
2
2
⎤⎦
2
−6 sin4 k1
2
,
(24) If the gyricity is zero and the load acts in the horizontal
(vertical) direction, the solution in Eq. 21 describes a vector
function whose first component has even (odd) real and
imaginary parts as functions of k1, whereas the second
component has odd (even) real and imaginary parts. When
gyricity is non-zero, these components have neither even nor
odd real and imaginary parts. Steady-State Forced Problem y
The transformed amplitudes UF
n2 are sought in the form 2.3 Analysis of the Forced Problem in the
Steady-State Regime −ω2
0U(p,n2) + 2iω0I + Ω*R _U(p,n2) + iω0Ω*RU(p,n2) + €U(p,n2)
a(1) · U(p+2,n2) + U(p−2,n2) −2U(p,n2)
a(1)
+ a(2) · U(p+1,n2+1) + U(p−1,n2−1) −2U(p,n2)
a(2)
+ a(3) · U(p−1,n2+1) + U(p+1,n2−1) −2U(p,n2)
a(3),
n1, n2 ∈Z, n2 > 0,
(12)
d The transition to the steady-state regime (i.e. when t →+ ∞) is
made by multiplying Eqs. 15, 16 by the Laplace transform
parameter s and taking the limit as s →+ 0. In this limit, we
define the discrete Fourier transform of the displacement
amplitude in the steady-state regime as UF
n2(k1) lim
s →+0sULF
n2(s, k1),
n2 ∈Z, n2 ≥0. (17) (17) and −ω2
0U(p,0) + 2iω0I + Ω*R _U(p,0) + iω0Ω*RU(p,0) + €U(p,0)
a(1) · U(p+2,0) + U(p−2,0) −2U(p,0)
a(1)
+ a(2) · U(p+1,1) −U(p,0)
a(2)
+ a(3) · U(p−1,1) −U(p,0)
a(3) + Pδp,0,
n2 0, n1 ∈Z,
(13) From Eqs. 15, 16, these transformed amplitudes then satisfy −(ω0 −i0)2I + iΩ*(ω0 −i0)RUF
n2(k1) 2a(1)
· (cos(k1) −1)UF
n2(k1)a(1) + a(2) · e−ik1/2UF
n2+1(k1)
+ eik1/2UF
n2−1(k1) −2UF
n2(k1)
a(2) + a(3) · eik1/2UF
n2+1(k1)
+ e−ik1/2UF
n2−1(k1) −2UF
n2(k1)
a(3),
(18)
for n2 > 0 and −(ω0 −i0)2I + iΩ*(ω0 −i0)RUF
n2(k1) 2a(1)
· (cos(k1) −1)UF
n2(k1)a(1) + a(2) · e−ik1/2UF
n2+1(k1)
+ eik1/2UF
n2−1(k1) −2UF
n2(k1)
a(2) + a(3) · eik1/2UF
n2+1(k1)
+ e−ik1/2UF
n2−1(k1) −2UF
n2(k1)
a(3),
( (13) (18) where I is the identity matrix. In the last equation, the complex
representation for the applied force was used. where I is the identity matrix. In the last equation, the complex
representation for the applied force was used. for n2 > 0 and January 2021 | Volume 7 | Article 602960 January 2021 | Volume 7 | Article 602960 Frontiers in Materials | www.frontiersin.org Directional Control of Rayleigh Waves Nieves et al. −(ω0 −i0)2I + iΩ*(ω0 −i0)RUF
0(k1) P + 2a(1)
· (cos(k1) −1)UF
0(k1)a(1) + a(2) · e−ik1/2UF
1(k1) −UF
0(k1)
a(2)
+ a(3) · eik1/2UF
1(k1) −UF
0(k1)
a(3), 1The dispersion analysis for Rayleigh waves in a semi-infinite gyroscopic triangular
lattice is discussed in detail by Nieves et al. (2020), where it is explicitly shown that
the dispersion diagram remains symmetric. (19) for n2 0. Here, ω0 −i0 lims →+0(ω0 −is), and in what follows
“i0” will represent a small imaginary term with positive imaginary
part. The presence of this term enables one to determine how
singular points of the Fourier transformed solution approach the
real axis in the complex plane in passing to the steady-state
regime. In this limit, the location of these singular points in the
complex plane provides a way of ascertaining the direction of
waves propagating in the medium relative to the load position. This is linked to the causality principle (see Section 3.3.2 in
(Slepyan, 2002) for more details). u(n1,n2)(t) Re U(n1,n2)eiω0t
,
(22) (22) where U(n1,n2)
⎧
⎪
⎪
⎪
⎪
⎨
⎪
⎪
⎪
⎪
⎩
1
2π
π
−π
UF
n2e−ik1(n1+n2/2)dk1,
if n2 is even,
1
4π
2π
−2π
UF
n2e−ik1(n1+n2/2)dk1,
if n2 is odd. (23) (23) Here, we note that U(n1,n2) limt →+∞U(p,n2)(t), where p
2 n1 and the complex time-dependent amplitude U(p,n2)(t) were
introduced in Section 2.2. 2.5 The Displacements in the Forced Lattice
and Associated Wave Phenomena The displacements in the lattice can be found from inverting the
discrete Fourier transform, taking into account the periodicity
properties of Eq. 21. Then, the displacements of the nodes in the
lattice are given by (19) Frontiers in Materials | www.frontiersin.org 2.5.1 The Rayleigh Waves Such properties can be observed in
Figure 2, where we report the horizontal and vertical components
of the Fourier transform of the steady-state solution UF
0, when
Ω* 0 (parts (A) and (B)) and Ω* 1 (parts (C) and (D)) for a
load acting in the horizontal direction. By further inspection of
the analytical solution in Eq. 21, we pose the attention on the
numerator in hj (j 1, 2), belonging to U0 and M2 (see
Supplementary Equations S9, S11), where the presence of
gyricity
induces
a
competition
between
terms
and
the
amplitude of the components depends on the sign of the wave
number. This feature of the solution in Eq. 21 for Ω* ≠0 is
responsible for the symmetry breaking in the considered problem
(see also (Nieves et al., 2020)). (24) and represents the dispersion curve of the system associated
with Rayleigh waves.1 The dispersion curve is plotted in
Figure 3. In Figure 3 we limit our attention to the intervals of
periodicity for Eq. 21 mentioned in Section 2.4. Since ω0 −i0
is present in Eq. 21, as discussed in Section 2.3, the degenerate
wave numbers of Eq. 21 are perturbed and are slightly shifted
from the real k1 -axis in the complex plane. The causality
principle enables the new locations of these points to be
determined using information concerning the group velocity vg 1The dispersion analysis for Rayleigh waves in a semi-infinite gyroscopic triangular
lattice is discussed in detail by Nieves et al. (2020), where it is explicitly shown that
the dispersion diagram remains symmetric. January 2021 | Volume 7 | Article 602960 Frontiers in Materials | www.frontiersin.org 5 Directional Control of Rayleigh Waves Nieves et al. FIGURE 2 | Plots of the discrete Fourier transform of the steady-state solution in Eq. 21, for n2 0. Parts A,C (B,D) show the first (second) component of UF
0 for Ω* 0 and
Ω* 1, respectively. The real parts of the components are represented by black curves, whereas the imaginary parts are indicated by gray curves. The vertical dashed lines
represent the wave numbers ± k1R for which these components are singular, having simple poles. The computations are performed for ω0 0.8 and P (1, 0)T. FIGURE 2 | Plots of the discrete Fourier transform of the steady-state solution in Eq. 21, for n2 0. It can be verified that when Ω* ≠0 It can be verified that when Ω* ≠0 It can be verified that when Ω* ≠0 Using the above information, we can calculate the form of the
Rayleigh waves produced by the point load by determining the
simple poles of Eq. 23 and employing the residue theorem to
compute Eq. 23 at a point located far from the application point
of the oscillatory force. With this approach, it is possible to show
that for n2 0 A(n2,±)
1
k*
1
≠
A(n2,±)
1
−k*
1
and
A(n2,±)
2
k*
1
≠
A(n2,±)
2
−k*
1
. (29) (29) Hence, the resulting dynamic response at the boundary of the
semi-infinite gyro-elastic lattice to the far left and right of the point
load is different. Moreover, these outwardly-propagating boundary
waves cause the nodes to follow elliptical trajectories, as shown by
the eigenmode analysis developed by Nieves et al. (2020). u(n1,0)(t) ∼Im A(0)
+ (k1R)ei(ω0t−k1Rn1)
for n1 →∞,
(25) (25) where the term on the right-hand side is the Rayleigh wave
produced to the right of the point load. On the other hand, we
have 2.5.2 Bulk Wave Radiation 2.5.1 The Rayleigh Waves Parts A,C (B,D) show the first (second) component of UF
0 for Ω* 0 and
Ω* 1, respectively. The real parts of the components are represented by black curves, whereas the imaginary parts are indicated by gray curves. The vertical dashed lines
represent the wave numbers ± k1R for which these components are singular, having simple poles. The computations are performed for ω0 0.8 and P (1, 0)T. where the right-hand side defines the Rayleigh wave traveling
away from the load to the left. Here, dωR/dk1 (see also (Slepyan, 2002)). In particular, if at the
previously mentioned intersection points vg > 0 (vg < 0) the
frequency ω0 and the corresponding wave number k1 define
waves propagating to the right (left) of the load. Additionally,
when the frequency is ω0 −i0, the associated degenerate value of
Eq. 21 is located at k1 −i0 (k1 + i0). Consequently, the dispersion
diagram in Figure 3 predicts that the degenerate values required
later for the computation of outgoing waves from the source are at
k1 ± k1R ∓i0 and k1 ± (2π −k1R) ± i0. A(n2)
± k*
1
⎛
⎝A(n2, ± )
1
k*
1
A(n2, ± )
2
k*
1
⎞⎠
lim
k1→k*
1 ∓i0 k1 −k*
1 ± i0
UF
n2, (27)
lim
k1→k*
1∓i0 k1 −k*
1 ± i0
U0Λn2[M2]−1P
ω0ω0−i0
. (28) A(n2)
± k*
1
⎛
⎝A(n2, ± )
1
k*
1
A(n2, ± )
2
k*
1
⎞⎠
lim
k1→k*
1 ∓i0 k1 −k*
1 ± i0
UF
n2, (27) (27)
lim
k1→k*
1∓i0 k1 −k*
1 ± i0
U0Λn2[M2]−1P
ω0ω0−i0
. (28) (28) Frontiers in Materials | www.frontiersin.org 2.5.2 Bulk Wave Radiation Waves are also radiated along the rows of the lattice in the
bulk. As n2 →∞, the amplitudes of such waves decrease. These u(n1,0)(t) ∼Im A(0)
−(−k1R)ei(ω0t+k1Rn1+π)
for n1 →−∞,
(26) (26) Frontiers in Materials | www.frontiersin.org January 2021 | Volume 7 | Article 602960 6 Directional Control of Rayleigh Waves Nieves et al. FIGURE 3 | Dispersion diagram for k1 ∈[−2π, 2π], relevant for Eq. 23 when n2 is odd. The black (gray) curve indicates the function ωR for Ω* 1 (Ω* 0). The line
ω ω0 is shown for ω0 0.6. The intersections of this line with the curve of ωR for Ω* 1 (Ω* 0) are represented by black (gray) crosses. The interval [−π, π] is instead
relevant for Eq. 23 when n2 is even. Wave numbers k1 k1R and 2π −k1R, defining singular points of Eq. 21, are also shown. FIGURE 3 | Dispersion diagram for k1 ∈[−2π, 2π], relevant for Eq. 23 when n2 is odd. The black (gray) curve indicates the function ωR for Ω* 1 (Ω* 0). The line
ω ω0 is shown for ω0 0.6. The intersections of this line with the curve of ωR for Ω* 1 (Ω* 0) are represented by black (gray) crosses. The interval [−π, π] is instead
relevant for Eq. 23 when n2 is even. Wave numbers k1 k1R and 2π −k1R, defining singular points of Eq. 21, are also shown. whereas for n1 →−∞we have
u(n1,n2)(t) ∼1
2 Im A(n2)
−(−k1R) −A(n2)
−(2π −k1R)ei[ω0t+k1R(n1+n2/2)+π]
. (33) waves are again attributed to the singular points of Eq. 21
associated with k1 ± k1R ∓i0, ± (2π −k1R) ± i0, which also
define Rayleigh waves along the boundary. The form of the
waves depends on the row of the lattice considered and it is
obtained
following
the
same
procedure
outlined
in
Section 2.5.1. (33) We pointoutthattheamplitudesofthe wavesalongthe odd rowsof
the lattice, specified in Eqs. 32, 33, take into account the contributions
from the wave numbers k1 ± (2π −k1R) (see Figure 3). For n2 > 0 with n2 even, the displacements to the far right of
the lattice behave as There also exist preferential directions for energy radiation in
the bulk. 2.5.2 Bulk Wave Radiation When the gyricity is zero, along these specific lines in the
lattice, the nodal displacements decay slowly as O(n−1/3
2
) for
n2 →∞, as shown by Slepyan (2010). These directions can be
identified by determining when Λj, involved in Eq. 21, is complex
with
Λj
1, j 1, 2, for the frequency equal to ω0. As discussed
by Slepyan (2010), this effect is purely attributed to the lattice’s
micro-structure and is not found in the analogous continuous
model. When the gyricity Ω* ≠0 is introduced, preferential
directions for wave propagation can remain and increasing the
gyricity causes the associated displacement amplitudes to decrease. u(n1,n2)(t) ∼Im A(n2)
+ (k1R)ei[ω0t−k1R(n1+n2/2)]
for n1 →∞, (30) where the term on the right-hand side describes a wave traveling along
the row defined by n2 > 0 to the right. On the other hand, we have
u(n1,n2)(t) ∼Im A(n2)
−(−k1R)ei[ω0t+k1R(n1+n2/2)+π]
for n1 →−∞,
(31) where the term on the right-hand side describes a wave traveling along
the row defined by n2 > 0 to the right. On the other hand, we have
u(n1,n2)(t) ∼Im A(n2)
−(−k1R)ei[ω0t+k1R(n1+n2/2)+π]
for n1 →−∞,
(31) where the term on the right-hand side describes a wave traveling along
the row defined by n2 > 0 to the right. On the other hand, we have
u(n1,n2)(t) ∼Im A(n2)
−(−k1R)ei[ω0t+k1R(n1+n2/2)+π]
for n1 →−∞,
(31) (31) where the term on the right-hand side represents a wave propagating
to the left along the row n2 > 0. We note that for the wave numbers
k1 ± k1R, ± (2π −k1R) and the frequency ω0 −i0, the functions
Λj, j 1, 2, are complex with modulus less than unity. Hence, the
matrix Λn2 in Eq. 21 ensures that these waves have a decreasing
amplitude for increasing n2. 2.5.3 Resonant Modes Next, we discuss the resonant case when the steady-state solution
to the considered problem does not exist. We show this by
investigating
the
derived
solution
in
Eq. 21
along
the
boundary, where n2 0. For rows in the lattice defined by odd n2, we recall that Eq. 21 is a 4π -periodic function in k1. Hence, the inversion
formula for the discrete Fourier transform is as presented in
the second equation in Eq. 23. In this case, a slightly modified
procedure is required to compute the waves radiated in the
bulk, taking into account the singular points of the function
Eq. 21 on the interval [−2π, 2π]. For odd n2, the displacements
for n1 →∞are When k1 →0, for either horizontal or vertical loading at the
lattice boundary, the solution in Eq. 21 is bounded for ω0 ≠Ω*
and admits the following asymptotic representation: UF
0
C0
DΩ*, ω0
+ O(k1),
k1 →0,
(34) (34) u(n1,n2)(t) ∼1
2 Im A(n2)
+ (k1R) −A(n2)
+ (k1R −2π)ei[ω0t−k1R(n1+n2/2)]
, (32) where January 2021 | Volume 7 | Article 602960 January 2021 | Volume 7 | Article 602960 Frontiers in Materials | www.frontiersin.org Directional Control of Rayleigh Waves Nieves et al. FIGURE 4 | (A) The first component of the steady-state solution for the case of horizontal forcing on the boundary, with unit amplitude, when ω0 Ω*. The black
(gray) curve represents the real (imaginary) part of this component. (B) The dispersion diagram for ω0 Ω*. The dispersion curve for Rayleigh waves is represented by the
black curve, based on Eq. 24. The horizontal black dashed line represents ω0 0.5, which intersects the gray curves corresponding to
Λj
1 (j 1, 2). The point
(k1, ω0) (0, Ω*), indicated by the cross, corresponds to a resonance mode of the system. The computations in (A) and (B) have been performed for Ω* 0.5. FIGURE 4 | (A) The first component of the steady-state solution for the case of horizontal forcing on the boundary, with unit amplitude, when ω0 Ω*. The black
(gray) curve represents the real (imaginary) part of this component. (B) The dispersion diagram for ω0 Ω*. The dispersion curve for Rayleigh waves is represented by the
black curve, based on Eq. 24. 2.5.3 Resonant Modes Thus, the energy density at this location becomes unbounded as
t →+ ∞. In other words, in the case ω0 Ω* the steady-state
solution does not exist. (35) and C0 denotes a constant vector with non-zero entries
depending on the gyricity Ω*, the frequency ω0 and the load
amplitude P. Clearly, D(Ω*, ω0) 0 when ω0 Ω*. In this
degenerate case, the asymptote near k1 →0 takes the form UF
0 1
3
√
S0
k1 −i0
"
k1 + i0
"
+ O(1),
k1 →0,
(36) (36) that indicates the appearance of other singular points near k1 0
in the solution in Eq. 21. In the above, if the load is horizontal
(vertical) the vector S0 (−i, −1)T (S0 (1, −i)T). We note that the singular points in this asymptote approach
each other as the Laplace transform parameter s →+ 0, with their
limiting location being the real axis at k1 0. An illustration
showing the typical behavior of the first component of Eq. 21 in
this case is given in Figure 4A. There, the kernel has a simple pole
for positive wave numbers but not for negative wave numbers,
which implies that the structure does not support Rayleigh waves
propagating to the left of the load on the boundary. The second
component of Eq. 21 possesses the same singular features. Further to Eq. 36, in this situation UF
0 can be written in the form: 2.5.3 Resonant Modes The horizontal black dashed line represents ω0 0.5, which intersects the gray curves corresponding to
Λj
1 (j 1, 2). The point
(k1, ω0) (0, Ω*), indicated by the cross, corresponds to a resonance mode of the system. The computations in (A) and (B) have been performed for Ω* 0.5. DΩ*, ω0 −6ω2
0 + 3
ω2
0 3Ω*
2 + ω2
0
(3 Ω*, ω0 −6ω2
0 + 3
ω2
0 3Ω*
2 + ω2
0
The associated horizontal line on this diagram intersects the
curves along which
Λj
1 (j 1, 2), represented by gray lines. These additional curves are useful in characterizing the main
contribution of the integral contained in Eq. 23 in describing the
lattice far-field and are connected with the appearance of
waveforms and preferential directions in the bulk lattice (see
also Slepyan (2010)). At k1 0 on the dispersion diagram, the
group velocity at the associated intersection point is zero (see
Figure 4B, where at the point (k1, ω0) (0, Ω*) the group
velocity
is
zero). Physically,
such
a
point
represents
a
resonance mode of the considered system, as discussed in
(Slepyan, 2002, Section 3.3.5). The energy associated with this
mode is unable to leave the location where the force is applied. Thus, the energy density at this location becomes unbounded as
t →+ ∞. In other words, in the case ω0 Ω* the steady-state
solution does not exist. The associated horizontal line on this diagram intersects the
curves along which
Λj
1 (j 1, 2), represented by gray lines. These additional curves are useful in characterizing the main
contribution of the integral contained in Eq. 23 in describing the
lattice far-field and are connected with the appearance of
waveforms and preferential directions in the bulk lattice (see
also Slepyan (2010)). At k1 0 on the dispersion diagram, the
group velocity at the associated intersection point is zero (see
Figure 4B, where at the point (k1, ω0) (0, Ω*) the group
velocity
is
zero). Physically,
such
a
point
represents
a
resonance mode of the considered system, as discussed in
(Slepyan, 2002, Section 3.3.5). The energy associated with this
mode is unable to leave the location where the force is applied. Frontiers in Materials | www.frontiersin.org 2.6 Determination of Energy Flow in the
Steady-State Regime In this section, we analyze the energy carried by the Rayleigh
waves and by the waves radiated into the bulk of the gyroscopic
lattice by calculating the energy flow through the boundary of a
sufficiently large region of the medium, as shown in Figure 5. The
considered region is the rectangle S enclosed by the half-plane
boundary and by the segments zSi (i 1, . . . , 4), indicated in
Figure 5. UF
0 1
3
√
S0
k1 −i0
"
k1 + i0
"
+ WF
0 + BF
0,
(37) (37) where WF
0 represents the term that is singular at k1 k1R −i0 of Eq. 21 and BF
0 is a bounded function for k1 ∈[−π, π]. Upon applying
the inverse of the discrete Fourier transform, while the last two terms
in the right-hand side of Eq. 37 give bounded contributions to the
displacement, the first term leads to a function that is singular for
x1 n1 + n2/2 0 and s →+ 0. Hence, the displacement at the
location of the load is unbounded for t →+ ∞. Figure 5. In the steady-state regime, the rate at which energy is
introduced into the system through the action of an oscillating
point load applied at the node (n1, n2) (0, 0), having the vector
amplitude P and frequency ω0, can be computed using the
formula: Win 1
2 ω0Im P · U(0,0)
,
(38) The asymptotic representation in Eq. 36 is also in agreement
with the dispersion diagram for ω0 Ω*, shown in Figure 4B. (38) January 2021 | Volume 7 | Article 602960 Frontiers in Materials | www.frontiersin.org 8 Nieves et al. Directional Control of Rayleigh Waves FIGURE 5 | Region S of the gyroscopic lattice, delimited by the half-plane boundary and the segments zSi (i 1, . . . , 4), through which the energy flow is calculated. FIGURE 5 | Region S of the gyroscopic lattice, delimited by the half-plane boundary and the segments zSi (i 1, . . . , 4), through which the energy flow is calculated. by the half-plane boundary and the segments zSi (i 1, . . . , 4), through which the energy flow is calculated. where the overline denotes the complex conjugate and U(n1,n2) is
defined in Eq. 23. The rate at which energy flows through each
segment zSi is given by the classical formula introduced by
Brillouin (see Chapter V in Brillouin (1953)): governing Eq. 2. Here the computational domain is finite, while
the analytical treatment developed above is for a semi-infinite
medium. In particular, the lattice has dimensions 100 × 46
3
√
. Adaptive Absorbing Layers (AAL) are introduced close to the top
and vertical boundaries, in order to prevent waves from being
reflected at these boundaries. AAL are created by assigning to the
links located inside those regions a complex elastic modulus. A
point load is applied to the middle point of the bottom boundary
of the domain. The numerical simulations are performed in the
time-harmonic regime. Wout
i
−1
2ω0Im⎛
⎝
nj ∈Di
F(nj) · U(nj)⎞⎠,
(39) (39) for 1 ≤i ≤4. In Eq. 39, F(nj) represents the elastic force supplied by
the nodes outside the considered region and connected to the
node indicated by nj, positioned in the immediate proximity of
zSi, within S. The set of the nodes with multi-indices nj located in
the vicinity of zSi, inside S, is denoted by Di. 3.1 The Displacement Field in the
Semi-Infinite Gyro-Elastic Lattice
Loaded on the Boundary Win
4
i1
Wout
i
. (40) (40) In Section 3, the above formulae for the energy flow will be
used to show quantitatively that the presence of gyroscopic
spinners breaks the symmetry of energy propagation with
respect to a vertical line passing through the application point
of the load. In this section, we show the response of the semi-infinite lattice
with embedded gyroscopic spinners to a point force applied on
the boundary. In particular, we investigate how the gyricity affects
the behavior of Rayleigh waves traveling along the boundary and
of the waves propagating into the bulk of the medium. Figure 6 shows the total displacement amplitude calculated at
each node of the discrete system, produced by an oscillating force
applied on the boundary. The results are based on the solution in
Eq. 22, derived in Section 2. The force has unit amplitude and
frequency ω0 0.6, and it acts in the horizontal (vertical)
direction in parts (A) and (C) (parts (B) and (D)). Figure 6 shows the total displacement amplitude calculated at
each node of the discrete system, produced by an oscillating force
applied on the boundary. The results are based on the solution in
Eq. 22, derived in Section 2. The force has unit amplitude and
frequency ω0 0.6, and it acts in the horizontal (vertical)
direction in parts (A) and (C) (parts (B) and (D)). Figure 5. For the conservation
of energy law, the following equality is satisfied: 2.7 Finite Element Model The results of the analytical formulation illustrated in the
previous sections will be verified with a finite element model
built
in
the
commercial
software
Comsol
Multiphysics
(version 5.4). The numerical model consists of massless truss elements and
point masses inserted at the lattice’s nodes. The effect of gyricity is
simulated by imposing at each node a force that is proportional to
the velocity, as in the first term on the right-hand side of the In parts (A) and (B) of Figure 6 the effective gyricity is set
equal to zero. It is apparent that when Ω* 0 the response of the
system is symmetric with respect to the point of application of the
force. This in agreement with the classical theory on Rayleigh January 2021 | Volume 7 | Article 602960 Frontiers in Materials | www.frontiersin.org 9 Directional Control of Rayleigh Waves Nieves et al. FIGURE 6 | Total displacement amplitude field in the elastic lattice, obtained from the analytical formulation developed in Section 2, due to a (A,C) horizontal and
(B,D) vertical point force applied on the boundary. In each figure, the force is represented by an arrow. The effective gyricity is (A,B) Ω* 0 and (C,D) Ω* 1. FIGURE 6 | Total displacement amplitude field in the elastic lattice, obtained from the analytical formulation developed in Section 2, due to a (A,C) horizontal and
(B,D) vertical point force applied on the boundary. In each figure, the force is represented by an arrow. The effective gyricity is (A,B) Ω* 0 and (C,D) Ω* 1. symmetry is still broken, but the amplitudes of the waves
traveling to the right and to the left of the force along the
boundary are now comparable. wave propagation in elastic lattices without gyroscopic effects. We also observe that in the vicinity of the load there exist
evanescent modes, which induce localized deformations in the
neighboring links. In the bulk there are preferential directions
along which waves are radiated from the source, as described in
Section 2.5.2. The region between these rays show outwardly
propagating oscillations that decay like O(n−1/2
2
). Comparing
parts (A) and (B), we note that in (B) there exist waves with
larger amplitudes. 3.2 The Energy Flow Here, we report the analytical results concerning the energy flow
furnished by the external force, referred to as Win, and the energy
flow passing through each segment zSi in Figure 5, denoted as
Wout
i
(i 1, . . . , 4). The formulae for Win and Wout
i
are given in
Section 2.6. 2.7 Finite Element Model Moreover, by looking at the wavelengths, we
observe that the bulk waves generated by a horizontal force are of the
shear type, while the vertical force induces bulk waves of the pressure
type, as expected. We also point out that the non-symmetric displacement field
in Figure 6 can be inverted by changing the sign of the effective
gyricity Ω*. In Figure 7 we present the total displacement amplitude fields
computed by using the finite element model developed in Comsol
Multiphysics and described in Section 2.7. The values of the
parameters are the same as those considered in Figure 6. Comparing Figures 6, 7, we observe that the numerical and
analytical results show an excellent agreement. This confirms the
validity and accuracy of the analytical treatment discussed in
Section 2. yp
p
Figures 6C,D illustrate the total displacement amplitude field
produced by a horizontal and vertical force, respectively, when
the effective gyricity is Ω* 1. As in Figures 6A,B, the force has
unit amplitude and frequency ω0 0.6. The main difference
between Figures 6A–D is that when the effective gyricity is
non-zero the response of the system ceases to be symmetric
with respect to the vertical line passing through the point of
application of the force. In part (C) we note that the amplitude of
Rayleigh waves propagating to the right of the force is much
larger compared to that of the surface waves traveling to the left. In addition, the force appears to activate waves in its vicinity
having significant amplitude and propagating at 120° to the
positive horizontal axis. On the other hand, the displacement
field produced by a vertical force (see part (D)) shows that the Frontiers in Materials | www.frontiersin.org Section 2.6. As in Section 3.1, two different values of the effective gyricity
are taken, namely Ω* 0 and Ω* 1. Moreover, two directions of
the point load are considered, i.e. horizontal and vertical. The
values of Win and Wout
i
for all the examined cases are summarized
in Table 1. January 2021 | Volume 7 | Article 602960 10 Directional Control of Rayleigh Waves Nieves et al. FIGURE 7 | Same as in Figure 6, but obtained from numerical simulations performed in Comsol Multiphysics. FIGURE 7 | Same as in Figure 6, but obtained from numerical simulations performed in Comsol Multiphysics. parametric analysis where we vary the direction of the force, the
radian frequency ω0 of the force and the effective gyricity Ω* of
the spinners. The behavior of the medium is evaluated
quantitatively by calculating the percentages of the energy
flows Wout
i
passing through the boundaries zSi (i 1, . . . , 4)
(see Figure 5) with respect to the energy input Win due to the
external source. TABLE 1 | Values of energy flows in the micro-structured lattice due to a horizontal
or vertical force, when the effective gyricity is either Ω* 0 or Ω* 1. Ω* = 0
Ω* = 1
Horizontal force
Vertical force
Horizontal force
Vertical force
Win
0.214
0.322
0.119
0.227
Wout
1
0.029
0.104
0.028
0.083
Wout
2
0.078
0.057
0.030
0.031
Wout
3
0.078
0.057
0.058
0.022
Wout
4
0.029
0.104
0.003
0.091
#4
i1Wout
i
0.214
0.322
0.119
0.227 TABLE 1 | Values of energy flows in the micro-structured lattice due to a horizontal
or vertical force, when the effective gyricity is either Ω* 0 or Ω* 1. In Figure 8 we show how the energy introduced into the
system by the external oscillating force is divided into two parts,
propagating in opposite directions relative to the position of the
point force. In particular, the circles (squares) indicate the
percentages of the energy flowing to the right (left) of the
force with respect to the input energy flow. In Figure 8 it is
assumed that the force acts in the horizontal direction. The five
diagrams correspond to Ω* 0, 0.25, 0.5, 0.75, 1; in each diagram,
several values of the frequency ω0 of the point force are
considered. Section 2.6. By looking at Table 1, we notice that when the effective
gyricity is zero Wout
1
+ Wout
2
Wout
3
+ Wout
4 , implying that the
response of the system is symmetric with respect to the
application point of the force. The above equality ceases to
hold when Ω* 1. We also note that the energy partition
between vertical and horizontal boundaries depends on the
gyricity and on the direction of the force. Furthermore, for
any of the four cases considered in Table 1, the energy
balance is satisfied, since Win # 4
i1Wout
i
. In Figure 9 the values of the effective gyricity and of the
frequency of the external source are identical to those
considered in Figure 8, but the outcomes are obtained by
applying a concentrated oscillating load acting in the vertical
direction. In both Figures 8, 9, when Ω* 0 the incoming
energy is split into two equal contributions that propagate
to the left and to the right of the force, both along the
boundary and inside the bulk. Conversely, when Ω* ≠0 we 3.3 Parametric Analysis In order to assess how the response of the micro-structured
medium is affected by different physical quantities, we perform a January 2021 | Volume 7 | Article 602960 Frontiers in Materials | www.frontiersin.org 11 Directional Control of Rayleigh Waves Nieves et al. FIGURE 8 | Percentages of energy flows propagating to the right (Wout
1
+ Wout
2 ) and to the left (Wout
3
+ Wout
4 ) of the point force with respect to the energy flow
produced by the external load (Win), calculated for several values of effective gyricity Ω* and frequency ω0. The results in this figure correspond to a point force acting in
the horizontal direction. The insets illustrate the wave fields at specific frequencies ω0 and gyricities Ω*. FIGURE 8 | Percentages of energy flows propagating to the right (Wout
1
+ Wout
2 ) and to the left (Wout
3
+ Wout
4 ) of the point force with respect to the energy flow
produced by the external load (Win), calculated for several values of effective gyricity Ω* and frequency ω0. The results in this figure correspond to a point force acting in
the horizontal direction. The insets illustrate the wave fields at specific frequencies ω0 and gyricities Ω*. observe a non-symmetrical distribution of energy in the system. We also notice that even when Ω* ≠0 the symmetry in the
energy flow partition is retrieved for some specific values of the
frequency, that change with the value of the effective gyricity. The crosses in both Figures 8, 9 represent the sums of the
energy flow components traveling inside the system with
respect to the input energy; it can be seen that, for every
case considered, there is balance between input and output
energy flows. the wave pattern is clearly symmetric. When gyricity is
introduced, as in part (B), the symmetry of the displacement
field is broken, even if the frequency of the external force remains
the same. In part (C), the wave pattern for a frequency near the
intersection between the two sets of data is shown; in this case, the
energy is split into two approximately equal parts traveling to the
left and to the right of the load, but on each side the energy amounts
propagating into the bulk and on the boundary are different. Frontiers in Materials | www.frontiersin.org 3.3 Parametric Analysis Here, it
is apparent that the energy flowing into the bulk in the left-hand part
of the lattice is approximately equal to the amount of energy carried
in the right-hand part, where the energy is mainly concentrated on
the boundary. The insets in Figure 8 present the color maps of the
displacement
fields,
computed
at
given
gyricities
and
frequencies of the external force. In part (A), where Ω* 0, January 2021 | Volume 7 | Article 602960 Frontiers in Materials | www.frontiersin.org 12 Directional Control of Rayleigh Waves Nieves et al. FIGURE 9 | Same as in Figure 8, but for a vertically-acting point force. FIGURE 9 | Same as in Figure 8, but for a vertically-acting point force. u(n1,0) [(u(n1,0)
1
)
2 + (u(n1,0)
2
)
2]
1/2
. The
symmetry
of
the
displacement field in the lattice without gyroscopic spinners,
shown in Figure 10A, is broken when gyricity is incorporated
into the system, as illustrated by the non-symmetric displacement
profiles of Figures 10B,E. In Figures 10, 11 we focus the attention on Rayleigh waves,
showing how the contributions of the energy flows corresponding to
surface waves traveling to the right (Wout
1 ) and to the left (Wout
4 ) of the
point load vary with the effective gyricity of the spinners and with the
frequency of the external force. In Figure 10 (Figure 11) the force acts
in the horizontal (vertical) direction. It is apparent that the direction of
the force, the gyricity and the frequency all influence the response of
the system and, in particular, the relative amount of total and surface
energy propagating to the left and to the right of the applied force. The insets in Figure 10 illustrate, for different values of
gyricity and frequency of the excitation, the amplitudes of the
displacement components u(n1,0)
1
and u(n1,0)
2
of the lattice’s nodes
at
the
boundary
and
the
displacement
magnitude In Figures 10, 11 we focus the attention on Rayleigh waves,
showing how the contributions of the energy flows corresponding to
surface waves traveling to the right (Wout
1 ) and to the left (Wout
4 ) of the
point load vary with the effective gyricity of the spinners and with the
frequency of the external force. In Figure 10 (Figure 11) the force acts
in the horizontal (vertical) direction. Frontiers in Materials | www.frontiersin.org 2A formal proof of the non-reciprocity of the gyroscopic medium has been
presented by Nieves et al. (2020). 3.3 Parametric Analysis It is apparent that the direction of
the force, the gyricity and the frequency all influence the response of
the system and, in particular, the relative amount of total and surface
energy propagating to the left and to the right of the applied force. Now, we consider a special case, where the surface waves
propagating to the left of the point load exhibit a negligibly small
amplitude. This can be obtained by taking the effective gyricity
Ω* 0.5, the frequency of the external force ω0 0.35 and
applying a horizontally-acting force (see also Figures 8, 10). The
displacement field for this choice of the parameters, presented in
Figure 12, clearly shows that the energy coming from the external
source propagates into the bulk and practically only to the right of the The insets in Figure 10 illustrate, for different values of
gyricity and frequency of the excitation, the amplitudes of the
displacement components u(n1,0)
1
and u(n1,0)
2
of the lattice’s nodes
at
the
boundary
and
the
displacement
magnitude January 2021 | Volume 7 | Article 602960 Frontiers in Materials | www.frontiersin.org 13 Directional Control of Rayleigh Waves Nieves et al. FIGURE 10 | Energy flow percentages associated with Rayleigh waves traveling to the right and to the left of the point force, indicated by Wout
1
and Wout
4
respectively, for different values of effective gyricity and frequency of the external source. In these computations, the force acts in the horizontal direction. The insets show
the displacements of the points on the lattice boundary, calculated at the frequencies indicated by the arrows. FIGURE 10 | Energy flow percentages associated with Rayleigh waves traveling to the right and to the left of the point force, indicated by Wout
1
and Wout
4
respectively, for different values of effective gyricity and frequency of the external source. In these computations, the force acts in the horizontal direction. The insets show
the displacements of the points on the lattice boundary, calculated at the frequencies indicated by the arrows. Frontiers in Materials | www.frontiersin.org 4 DISCUSSION force along the boundary. A similar effect could also be achieved in the
resonant case ω0 Ω*, but there the steady-state solution does not
exist (see Section 2.5.3). The energy flow partition for the system in
the neighborhood of ω0 Ω* is investigated in Figure 8C, which
shows that the energy flux distributions vary rapidly in the vicinity of
ω0 Ω*. The diagrams of the displacement amplitude fields in Figures 6,
7, as well as the values of the energy flows in Table 1, show that
the gyricity is capable of breaking the symmetry in the energy
propagation of both Rayleigh and bulk waves propagating from
the external source. This is a consequence of the non-reciprocity
of the gyro-elastic lattice.2 Another interesting case is represented by the scenario where
almost all the energy propagates along the boundary. This situation
is shown in Figure 13, where Ω* 1, ω0 0.9 and the point force acts
in the vertical direction (see also Figures 9, 11). From the displacement
field in this figure, it is apparent that most of the energy is localized at
the boundary of the medium. Moreover, in this case the discrete system
shows negligible preferential directionality (see also Figure 9E). Frontiers in Materials | www.frontiersin.org January 2021 | Volume 7 | Article 602960 14 Directional Control of Rayleigh Waves Nieves et al. FIGURE 11 | Same as in Figure 10, but for a vertically-acting point load. FIGURE 11 | Same as in Figure 10, but for a vertically-acting point load. Examining the outcomes of the parametric analysis presented
in Section 3.3, in particular Figures 8, 9, it is apparent that the
distribution of energy in the system strongly depends on both the
effective gyricity Ω* of the spinners and the radian frequency ω0
of the external oscillating force. Generally, at low frequencies it is
easier to partition the energy flow into two significantly
different contributions, propagating in opposite directions. Nonetheless, for any given value of the effective gyricity, it
is possible to find one or more values of ω0 at which the energy
is split into two equal parts. The lowest value of this frequency
increases as the effective gyricity is increased. Comparing
Figures 8, 9, we observe that the energy symmetry breaking
is more evident when the force acts in the horizontal direction. 4 DISCUSSION Of course, for an inclined direction of the force, the response of
the
system
can
be
determined
from
the
principle
of superposition
by
summing
the
effects
due
to
the
horizontally-
and
vertically-acting
forces,
since
the
considered problem is linear. The investigation of the individual components of the energy
flows associated with Rayleigh waves, presented in Figures 10,
11 for a horizontally- and vertically-acting point
force
respectively, reveals that the propagation of energy along the
boundary of the medium is affected significantly by the
direction of the force. In the case when Ω* 0, the energy
flow along the boundary is the same in both directions and it
decreases (increases) as the frequency of the external source
acting in the horizontal (vertical) direction is increased. On the
other hand, when Ω* ≠0, the energy flowing to the right (left) is
larger than in the opposite direction if the direction of the force
is horizontal (vertical). Independently of the direction of the January 2021 | Volume 7 | Article 602960 Frontiers in Materials | www.frontiersin.org 15 Directional Control of Rayleigh Waves Nieves et al. FIGURE 12 | Displacement field of the lattice’s masses when Ω* 0.5, ω0 0.35 and the point force acts in the horizontal direction. GURE 12 | Displacement field of the lattice’s masses when Ω* 0.5, ω0 0.35 and the point force acts in the horizontal direction FIGURE 13 | Displacement field of the lattice’s masses when Ω* 1, ω0 0.9 and the point force acts in the vertical direction. FIGURE 13 | Displacement field of the lattice’s masses when Ω* 1, ω0 0.9 and the point force acts in the vertical direction. The capability of the considered micro-structured system in
creating preferential directionality in the propagation of waves
can be exploited to design novel energy splitters, where the
desired amount of energy propagating in a specific prescribed
direction can be varied by changing the effective gyricity of the
spinners. The tunability of the proposed model is an essential tool,
that can be used in many practical applications where it is required to
vary the output depending on the contingent needs. Important
examples include electronic instruments converting mechanical
energy into electric energy (and vice versa) and elastic filters that
can be utilized both for protection and energy harvesting. Frontiers in Materials | www.frontiersin.org REFERENCES H., Li, G., Jin, G., Liu, Y., and Zhang, X. (2018). Topological dynamics of
gyroscopic and Floquet lattices from Newton’s laws. Phys. Rev. B. 97, 085110. doi:10.1103/PhysRevB.97.085110 Bordiga, G., Cabras, L., Piccolroaz, A., and Bigoni, D. (2018). Prestress tuning of
negative refraction and wave channeling from flexural sources. Appl. Phys. Lett. 114. doi:10.1063/1.5084258 Linton, C. M., and McIver, M. (2002). The existence of Rayleigh-Bloch surface
waves. J. Fluid Mech. 470, 85–90. doi:10.1017/S0022112002002227 Brillouin, L. (1953). Wave propagation in periodic structuresElectric filters and
crystal lattices. Mineola, NY: Dover Publications, Inc. Marder, M., and Gross, S. (1995). Origin of crack tip instabilities. J. Mech. Phys. Solid. 43, 1–48. doi:10.1016/0022-5096(94)00060-I Brun, M., Jones, I. S., and Movchan, A. B. (2012). Vortex-type elastic structured
media and dynamic shielding. Proc. Roy. Soc. Lond. 468, 3027–3046. doi:10. 1098/rspa.2012.0165 Misseroni, D., Colquitt, D. J., Movchan, A. B., Movchan, N. V., and Jones, I. S. (2016). Cymatics for the cloaking of flexural vibrations in a structured plate. Sci. Rep. 6, 23929. doi:10.1038/srep23929 Mitchell, N. P., Nash, L. M., and Irvine, W. T. M. (2018). Tunable band topology
in gyroscopic lattices. Phys. Rev. B. 98, 174301. doi:10.1103/PhysRevB.98. 174301 Carta, G., Jones, I. S., Movchan, N. V., Movchan, A. B., and Nieves, M. J. (2017). Deflecting elastic prism” and unidirectional localisation for waves in chiral
elastic systems. Sci. Rep. 7, 26. doi:10.1038/s41598-017-00054-6 Morvaridi, M., Carta, G., and Brun, M. (2018). Platonic crystal with low-frequency
locally-resonant spiral structures: wave trapping, transmission amplification,
shielding and edge waves. J. Mech. Phys. Solid. 121, 496–516. doi:10.1016/j. jmps.2018.08.017 Carta, G., Brun, M., Movchan, A. B., Movchan, N. V., and Jones, I. S. (2014). Dispersion properties of vortex-type monatomic lattices. Int. J. Solid Struct. 51,
2213–2225. doi:10.1016/j.ijsolstr.2014.02.026 Carta, G., Colquitt, D. J., Movchan, A. B., Movchan, N. V., and Jones, I. S. (2020). Chiral flexural waves in structured plates: directional localisation and control. J. Mech. Phys. Solid. 137, 103866. doi:10.1016/j.jmps.2020.103866 j
p
Nash, L. M., Kleckner, D., Read, A., Vitelli, V., Turner, A. M., and Irvine, W. T. (2015). Topological mechanics of gyroscopic metamaterials. Proc. Natl. Acad. Nash, L. M., Kleckner, D., Read, A., Vitelli, V., Turner, A. M., and Irvine, W. T. (2015). Topological mechanics of gyroscopic metamaterials. Proc. Natl. Acad. Sci. U.S.A. 112, 14495–14500. doi:10.1073/pnas.1507413112 Carta, G., Colquitt, D. J., Movchan, A. B., Movchan, N. V., and Jones, I. S. (2019). One-way interfacial waves in a flexural plate with chiral double resonators. REFERENCES Filipov, E. T., Tachi, T., Paulino, G. H., and Weitz, D. A. (2015). Origami
tubes
assembled
into
stiff,
yet
reconfigurable
structures
and
metamaterials. Proc. Natl. Acad. Sci. U.S.A. 112, 12321–12326. doi:10. 1073/pnas.1509465112 Achenbach, J. D. (1973). “Wave propagation in elastic solids.” in North-holland
series in applied mathematics and mechanics. Amsterdam, London: North-
Holland Publishing Company, 16. Fleury, R., Sounas, D. L., Sieck, C. F., Haberman, M. R., and Alù, A. (2014). Sound
isolation and giant linear nonreciprocity in a compact acoustic circulator. Science. 343, 516–519. doi:10.1126/science.1246957 Al Ba’ba’a, H., Yu, K., and Wang, Q. (2020). Elastically-supported lattices for
tunable mechanical topological insulators. Extreme Mechanics Letters. 38,
100758. doi:10.1016/j.eml.2020.100758 Garau, M., Carta, G., Nieves, M. J., Jones, I. S., Movchan, N. V., and Movchan, A. B. (2018). Interfacial waveforms in chiral lattices with gyroscopic spinners. Proc. Roy. Soc. Lond. 474, 20180132. doi:10.1098/rspa.2018.0132 Antonakakis, T., Craster, R. V., Guenneau, S., and Skelton, E. A. (2014). An asymptotic
theory for waves guided by diffraction gratings or along microstructured surfaces. Proc. Math. Phys. Eng. Sci. 470, 20130467. doi:10.1098/rspa.2013.0467 Garau, M., Nieves, M. J., Carta, G., and Brun, M. (2019). Transient response of a
gyro-elastic structured medium: unidirectional waveforms and cloaking. Int. J. Eng. Sci. 143, 115–141. doi:10.1016/j.ijengsci.2019.05.007 Garau, M., Nieves, M. J., Carta, G., and Brun, M. (2019). Transient response of a
gyro-elastic structured medium: unidirectional waveforms and cloaking. Int. J. Eng. Sci. 143, 115–141. doi:10.1016/j.ijengsci.2019.05.007
Graff, K. F. (1975). Wave motion in elastic solids. Oxford, United Kingdom: Oxford
University Press. Armanini, C., Dal Corso, F., Misseroni, D., and Bigoni, D. (2017). From the elastica
compass to the elastica catapult: an essay on the mechanics of soft robot arm. Proc. Math. Phys. Eng. Sci. 473, 20160870. doi:10.1098/rspa.2016.0870 Graff, K. F. (1975). Wave motion in elastic solids. Oxford, United Kingdom: Oxford
University Press. Bacigalupo, A., De Bellis, M. L., and Gnecco, G. (2019). Complex frequency band
structure of periodic thermo-diffusive materials by Floquet–Bloch theory. Acta
Mech. 230, 3339–3363. doi:10.1007/s00707-019-02416-9 Haslinger, S. G., Movchan, N. V., Movchan, A. B., Jones, I. S., and Craster, R. V. (2017). Controlling flexural waves in semi-infinite platonic crystals with
resonator-type scatterers. Q. J. Mech. Appl. Math. 70, 216–247. doi:10.1093/
qjmam/hbx005 Bi, L., Hu, J., Jiang, P., Kim, D. H., Dionne, G. F., Kimerling, L. C., et al. (2011). On-
chip optical isolation in monolithically integrated non-reciprocal optical
resonators. Nat. Photon. 5, 758–762. doi:10.1038/nphoton.2011.270 Lee, C. FUNDING MN and MB gratefully acknowledge the financial support of the
EU H2020 grant MSCA-IF-2016-747334-CAT-FFLAP. The
program
“Mobilità
dei
giovani
ricercatori”
financed
by
Regione Autonoma della Sardegna is also acknowledged (MB
and VP). The original contributions presented in the study are included in
the article/Supplementary Material, further inquiries can be
directed to the corresponding author. 4 DISCUSSION force, the difference between the energy flows in the two
opposite directions generally decreases as the frequency is
increased. The parametric analysis discussed in Section 3.3 has been
helpful in identifying special cases, where Rayleigh waves
propagate only in one direction (see Figure 12) or where bulk
waves have very small amplitudes compared with those of surface
waves (see Figure 13). The analytical formulation also made it possible to analyze
resonant regimes where the steady-state solution cannot be
reached (see Section 2.5.3). January 2021 | Volume 7 | Article 602960 Frontiers in Materials | www.frontiersin.org 16 Directional Control of Rayleigh Waves Nieves et al. SUPPLEMENTARY MATERIAL All the authors contributed to the discussion of the results and the
revision of the manuscript. MN had a leading role in the
analytical development of the problem, GC in the numerical
computations, VP in the physical interpretation of the model and
MB in the conceptualization of the work. The Supplementary Material for this article can be found online at:
https://www.frontiersin.org/articles/10.3389/fmats.2020.602960/
full#supplementary-material. REFERENCES Philosophical Transactions of the Royal Society A. 378, 20190350. doi:10.1098/
rsta.2019.0350 Nieves, M. J., Carta, G., Jones, I. S., Movchan, N. V., and Movchan, A. B. (2018). Vibrations and elastic waves in chiral multi-structures. J. Mech. Phys. Solid. 121,
387–408. doi:10.1016/j.jmps.2018.07.020 Carta, G., Nieves, M. J., Jones, I. S., Movchan, N. V., and Movchan, A. B. (2018). Elastic chiral waveguides with gyro-hinges. Q. J. Mech. Appl. Math. 71, 157–185. doi:10.1093/qjmam/hby001 Nieves, M. J., Carta, G., Pagneux, V., and Brun, M. (2020). Rayleigh waves in micro-
structured elastic systems: non-reciprocity and energy symmetry breaking. Int. J. Eng. Sci. 156, 103365. doi:10.1016/j.ijengsci.2020.103365 Nieves, M. J., Movchan, A. B., Jones, I. S., and Mishuris, G. S. (2013). Propagation
of Slepyan’s crack in a non-uniform elastic lattice. J. Mech. Phys. Solid. 61,
1464–1488. doi:10.1016/j.jmps.2012.12.006 Colquitt, D. J., Craster, R. V., Antonakakis, T., and Guenneau, S. (2015). Rayleigh-
Bloch waves along elastic diffraction gratings. Proc. Math. Phys. Eng. Sci. 471,
20140465. doi:10.1098/rspa.2014.0465 January 2021 | Volume 7 | Article 602960 Frontiers in Materials | www.frontiersin.org 17 Directional Control of Rayleigh Waves Nieves et al. complex dispersive properties of three-dimensional structured beams and
plates. J. Sound Vib. 484, 115499. doi:10.1016/j.jsv.2020.115499 Piccolroaz, A., Gorbushin, N. A., Mishuris, G. S., and Nieves, M. J. (2020). Dynamic
phenomena and crack propagation in dissimilar elastic lattices. Int. J. Eng. Sci. 149, 103208. doi:10.1016/j.ijengsci.2019.103208 Viktorov, I. A. (1967). Rayleigh and lamb waves. New York: Plenum Press. Porter, R., and Evans, D. V. (2005). Embedded Rayleigh-Bloch surface waves along
periodic rectangular arrays. Wave Motion. 43, 29–50. doi:10.1016/j.wavemoti. 2005.05.005 Wang, P., Lu, L., and Bertoldi, K. (2015). Topological phononic crystals with
one-way elastic edge waves. Phys. Rev. Lett. 115, 104302. doi:10.1098/rspa. 2018.0132 Wenzel, M., Bursi, O. S., and Antoniadis, I. (2020). Optimal finite locally resonant
metafoundations enhanced with nonlinear negative stiffness elements for
seismic protection of large storage tanks. J. Sound Vib. 483, 115488. doi:10. 1016/j.jsv.2020.115488 Porter, R., and Evans, D. V. (1999). Rayleigh-Bloch surface waves along periodic
gratings and their connection with trapped modes in waveguides. J. Fluid Mech. 386, 233–258. doi:10.1017/S0022112099004425 386, 233–258. doi:10.1017/S0022112099004425 Rayleigh, J. W. S. (1885). On waves propagated along the plane surface of an elastic
solid. Proc. Lond. Math. Soc. 17, 4–11. doi:10.1112/plms/s1-17.1.4 Conflict of Interest: The authors declare that the research was conducted in the
absence of any commercial or financial relationships that could be construed as a
potential conflict of interest. Slepyan, L. I. (2002). Frontiers in Materials | www.frontiersin.org January 2021 | Volume 7 | Article 602960 REFERENCES Models and phenomena in fracture Mechanics. Berlin,
Germany: Springer. Slepyan, L. I. (2010). Wave radiation in lattice fracture. Acoust Phys. 56, 962–971. doi:10.1134/S1063771010060217 Copyright © 2021 Nieves, Carta, Pagneux and Brun. This is an open-access article
distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the
original author(s) and the copyright owner(s) are credited and that the original
publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with
these terms. Sounas, D. L., Caloz, C., and Alù, A. (2013). Giant non-reciprocity at the
subwavelength scale using angular momentum-biased metamaterials. Nat. Commun. 4, 2407. doi:10.1038/ncomms3407 Süsstrunk, R., and Huber, S. D. (2015). Observation of phononic helical edge states in a
mechanical topological insulator. Science 349, 47–50. doi:10.1126/science.aab0239 Tallarico, D., Hannema, G., Miniaci, M., Bergamini, A., Zemp, A., and Van
Damme,
B. (2020). Superelement
modelling
of
elastic
metamaterials: January 2021 | Volume 7 | Article 602960 Frontiers in Materials | www.frontiersin.org 18
|
https://openalex.org/W2092966960
|
https://ccforum.biomedcentral.com/counter/pdf/10.1186/cc5217
|
English
| null |
Surviving ratio of severe sepsis treated with activated protein C in one university intensive care unit during 2003–2006
|
Critical care
| 2,007
|
cc-by
| 229,685
|
P1 cells with sodium sulfide (60–300 µM) reduced the loss of cell
viability elicited by the nitric oxide donor compound (3 mM) or by
peroxynitrite (3 mM), as measured by the MTT method. Sodium
sulfide did not affect cell viability in the concentration range tested. In mice subjected to bacterial lipopolysaccharide (LPS, 5 mg/kg
i.p.), treatment of the animals with sodium sulfide (0.2 mg/kg/hour
for 4 hours, administered in Alzet minipumps) reduced the LPS-
induced increase in plasma IL-1β and TNFα levels. These
responses were attenuated when animals were pretreated with the
heme oxygenase inhibitor tin-protoporphyrin IX (6 mg/kg). The
current results point to the cytoprotective and anti-inflammatory
effects of hydrogen sulfide, in cells exposed to nitrosative stress,
and in animals subjected to endotoxemia. cells with sodium sulfide (60–300 µM) reduced the loss of cell
viability elicited by the nitric oxide donor compound (3 mM) or by
peroxynitrite (3 mM), as measured by the MTT method. Sodium
sulfide did not affect cell viability in the concentration range tested. In mice subjected to bacterial lipopolysaccharide (LPS, 5 mg/kg
i.p.), treatment of the animals with sodium sulfide (0.2 mg/kg/hour
for 4 hours, administered in Alzet minipumps) reduced the LPS-
induced increase in plasma IL-1β and TNFα levels. These
responses were attenuated when animals were pretreated with the
heme oxygenase inhibitor tin-protoporphyrin IX (6 mg/kg). The
current results point to the cytoprotective and anti-inflammatory
effects of hydrogen sulfide, in cells exposed to nitrosative stress,
and in animals subjected to endotoxemia. Infusion of sodium sulfide improves myocardial and
endothelial function in a canine model of cardiopulmonary
bypass C Szabó1, G Veres2, T Radovits2, M Karck2, G Szabó2
1Ikaria Inc., Seattle, WA, USA; 2University of Heidelberg, Germany
Critical Care 2007, 11(Suppl 2):P1 (doi: 10.1186/cc5161) Hydrogen sulfide is produced endogenously by a variety of
enzymes involved in cysteine metabolism. Clinical data indicate
that endogenous levels of hydrogen sulfide are diminished in
various forms of cardiovascular diseases. The aim of the current
study was to investigate the effects of hydrogen sulfide supple-
mentation on cardiac function during reperfusion in a clinically
relevant experimental model of cardiopulmonary bypass. Twelve
anesthetized dogs underwent hypothermic cardiopulmonary
bypass. After 60 minutes of hypothermic cardiac arrest, reper-
fusion was started after application of either saline vehicle (control,
n = 6), or the sodium sulfide infusion (1 mg/kg/hour, n = 6). Biventricular hemodynamic variables were measured by combined
pressure–volume–conductance catheters. Available online http://ccforum.com/supplements/11/S2 Available online http://ccforum.com/supplements/11/S2 P3 Epithelial cell apoptosis is similar but hypoxic-inducible
factor expression is weaker in acute acalculous
cholecystitis than in calculous cholecystitis M Vakkala1, J Laurila1, J Saarnio2, V Koivukangas2, H Syrjälä3,
T Karttunen4, Y Soini4, T Ala-Kokko1
1Department of Anesthesiology, 2Department of Surgery,
3Department of Infection Control and 4Department of Pathology,
Oulu University Hospital, Oulu, Finland
Critical Care 2007, 11(Suppl 2):P3 (doi: 10.1186/cc5163) Introduction It has been previously shown that the two forms of
acute cholecystitis, acute acalculous cholecystitis (AAC) and acute
calculous
cholecystitis
(ACC),
have
significantly
different
histopathological features suggesting that AAC is a manifestation
of systemic critical illness whereas ACC is a local disease of the
gallbladder. A balance between cell proliferation and cell death is
essential for cell homeostasis. The purpose of this study was to
compare the markers of apoptosis, cell proliferation, and
expression of hypoxic-inducible factor alpha (HIF-1α) in AAC, ACC
and normal gallbladders. Methods The AAC group consisted of 30 patients who underwent
open cholecystectomy due to acute acalculous cholecystitis during
their ICU stay. The ACC group consisted of 21 hospitalized
patients who underwent cholecystectomy due to acute calculous
cholecystitis. The control group consisted of nine samples taken
from normal gallbladders extirpated during pancreatic tumor
surgery. The immunohistochemical analysis was done according to
the manufacturer’s recommendations and they consisted of Ki-67
(proliferation), M30 (apoptosis) and HIF-1α
antibodies. Cell
proliferation and degree of apoptosis were expressed as the
percentage of positive cells. HIF-1α expression was expressed as
absent or weak (Score 1) or strong (Score 2). P2 P2
Cytoprotective and anti-inflammatory effects of hydrogen
sulfide in macrophages and mice
C Szabo, L Kiss, E Pankotai
University of Medicine and Dentistry of New Jersey, Newark, NJ, USA
Critical Care 2007, 11(Suppl 2):P2 (doi: 10.1186/cc5162) P1 Coronary and pulmonary
blood flow, vasodilator responses to acetylcholine and sodium-
nitroprusside and pulmonary function were also determined. Administration of sodium sulfide led to a significantly better
recovery of left and right ventricular systolic function (P < 0.05)
after 60 minutes of reperfusion. Coronary blood flow was also
significantly higher in the sodium sulfide-treated group (P < 0.05). Sodium sulfide treatment improved coronary blood flow, and
preserved the acetylcholine-induced increases in coronary and
pulmonary blood (P < 0.05). Myocardial ATP levels were markedly
improved in the sulfide-treated group. Thus, supplementation of
sulfide improves the recovery of myocardial and endothelial
function and energetic status after hypothermic cardiac arrest
during cardiopulmonary bypass. These beneficial effects occurred
without any detectable adverse hemodynamic or cardiovascular
effects of sulfide at the dose used in the current study. Critical Care Volume 11 Suppl 2, 2007
27th International Symposium on Intensive Care and Emergency
Medicine
Brussels, Belgium, 27–30 March 2007 Brussels, Belgium, 27–30 March 2007 Published online: 22 March 2007
These abstracts are available online at http://ccforum.com/supplements/11/S2
© 2007 BioMed Central Ltd Published online: 22 March 2007
These abstracts are available online at http://ccforum.com/supplements/11/S2
© 2007 BioMed Central Ltd Effect of prostaglandin E2 on ATP-induced Ca2+ responses
in human THP-1 monocytic cells Effect of prostaglandin E2 on ATP-induced Ca2+ responses
in human THP-1 monocytic cells M Goto1, M Murakawa1, J Kimura1, I Matsuoka2
1Fukushima Medical University, Fukusima, Japan;
2Takasaki University of Health and Welfare, Gunma, Japan
Critical Care 2007, 11(Suppl 2):P4 (doi: 10.1186/cc5164) Introduction To clarify the relation between ATP and prostaglandin
E2 (PGE2) in the immunologic system, we investigated the acute
and chronic effects of PGE2 on activation of purinergic signaling in
monocytes by measuring the ATP-induced elevation of intracellular
Ca2+ ([Ca]i) in fura-2-loaded THP-1 monocytes. Method THP-1 monocytes were grown for about 2 days. To
examine the chronic effects, PGE2 and dibutyryl cAMP (dbcAMP)
were added and incubated for another day. The cell suspensions
were washed, loaded with fura-2-AM, and transferred into a quartz
cuvette and placed in the thermostat-regulated sample chamber of
a dual excitation beam spectrophotometer. To examine the acute
effects, ATP was added immediately after PGE2 and dbcAMP into
the cuvette. In the chronic experiment, ATP alone was added into
the cuvette. Fura-2 fluorescence emission was measured at
510 nm. The [Ca]i
was calculated from the ratio of the
fluorescence at the two excitation wavelengths. sepsis [1]. IFNγ plays a critical role in host defense by promoting
Th1 phenotype and bacterial clearance. Low IFNγ levels are
associated with the Th2 phenotype consistent with critical illness
anergy [2]. It has been reported that 100 and 300 mM ATP
increased LPS/PHA-stimulated IL-10 secretion in human blood [3]. Higher IL-10/IFNγ ratio shifts the immune phenotype from Th1 to
Th2 response. We studied the effect of ATP on LPS-stimulated
IL-10 and IFNγ secretion in a standardized ex-vivo whole human
blood culture. Methods Venous blood from 10 healthy volunteers was drawn into
tubes containing 10 ng LPS/ml (ILCSÒ; EDI GmBH, Reutlingen,
Germany) and incubated with or without 100 mM ATP, respectively,
at 37°C for 24 hours. The supernates were separated and frozen
at –20°C. Cytokine levels were analysed on a robotic workstation
(epMotion 5075; Eppendorf AG, Hamburg, Germany) in duplicate
using the ELISA Cytokine kit (Luminex; Biosource Int., Camarillo,
CA, USA). Results ATP induced a transient increase in [Ca]i followed by a
sustained elevation of [Ca]i. Acutely, PGE2 inhibited both the
transient and sustained ATP-induced elevations of [Ca]i. However,
this acute inhibitory effect diminished gradually with time and
chronic PGE2 accelerated the transient and sustained ATP-
induced [Ca]i elevations for 24 hours. Cytoprotective and anti-inflammatory effects of hydrogen
sulfide in macrophages and mice Cytoprotective and anti-inflammatory effects of hydrogen
sulfide in macrophages and mice C Szabo, L Kiss, E Pankotai
University of Medicine and Dentistry of New Jersey, Newark, NJ, USA
Critical Care 2007, 11(Suppl 2):P2 (doi: 10.1186/cc5162) The aim of the current study was to test potential cytoprotective
and anti-inflammatory effects of the novel biological mediator
hydrogen sulfide in murine models. Murine J774 macrophages
were grown in culture and exposed to cytotoxic concentrations of
nitrosoglutathione, or peroxynitrite (a reactive species formed from
the reaction of nitric oxide and superoxide). Pretreatment of the Results Apoptosis (median, 25th, 75th percentiles) was significantly
increased in AAC 1.3% (1.0%, 3.3%), P = 0.001 and ACC 0.93%
(0.40%, 3.25%), P = 0.011 compared with controls 0.32% (0.20%,
0.40%). Proliferation rate was also significantly increased in AAC S1 Critical Care March 2007 Vol 11 Suppl 2
27th International Symposium on Intensive Care and Emergency Medicine Figure 1 (abstract P5) Figure 1 (abstract P5) Figure 1 (abstract P5) 8.0% (4.0%, 17.0%), P < 0.001 and ACC 14% (7.5%, 26.5%),
P = 0.001 compared with controls 1.0% (1.0%, 3.0%). Strong HIF-
1α staining was observed in 100% of ACC, in 57% of AAC and in
44% of control specimens (P < 0.001). Strong HIF-1α expression
was associated with increased cell proliferation (P = 0.002). Conclusions Cell proliferation and apoptosis were increased in
AAC and ACC. The expression of hypoxic-inducible factor was,
however, stronger in ACC compared with AAC. Effect of prostaglandin E2 on ATP-induced Ca2+ responses
in human THP-1 monocytic cells Both the acute and chronic
effects of PGE2 were mimicked by dbcAMP. In Ca2+-free solution,
ATP did not induce the sustained elevation of [Ca]i in control cells
or cells pretreated for 24 hours with dbcAMP. This indicates that
the ATP-induced sustained elevation of [Ca]i was due to Ca2+
entry. In addition, receptor-operated Ca2+
channel blockers
inhibited the sustained ATP-induced elevation of [Ca]i in control
cells and cells pretreated with for 24 hours dbcAMP. Results Added ATP reduced the mean concentration of IFNγ in LPS-
stimulated blood from 1,206 ± 1,667 pg/ml to 140 ± 128 pg/ml;
P = 0.006. There was no consistent effect of ATP on IL-10
secretion in our study (21.6 ± 16.9 pg/ml to 17.2 ± 18.8 pg/ml). Interestingly, three subjects of Indian/Indonesian origin had IL-10
levels below the assay detection limit. The mean IL-10/IFNγ ratio
was increased from 0.05 ± 0.04 to 0.16 ± 0.09 in the remaining
Caucasian subjects (P = 0.015). See Figure 1. Conclusion Acute PGE2 inhibited the ATP-induced activation of
monocytes. On the other hand, chronic PGE2 accelerated monocyte
activation by upregulation of receptor-operated Ca2+ channels
(ROCs). If this mechanism exhibits a physiological role, ROC
inhibitors should be developed as new anti-inflammatory agents. Conclusions Our results suggest an immunosuppressive effect of
extracellular ATP that is evident by the decrease of IFNγ and
therefore the relative shift of the immune response towards Th2
phenotype. Although this may represent a self-protective
mechanism, it may contribute to critical illness anergy. References Introduction Extracellular release of ATP is an important modulator
of immune response. ATP plasma concentration is increased in Available online http://ccforum.com/supplements/11/S2 P6 Methods We enrolled 30 patients with septic shock requiring
invasive hemodynamic monitoring and norepinephrine infusion ≥
0.5 µg/kg/min to maintain MAP between 65 and 75 mmHg. Patients were randomized to receive either 10, 20, or 30 mg
enteral glibenclamide. Systemic hemodynamics, global oxygen
transport, arterial lactate concentrations, gas exchange, and
plasma glucose concentrations were determined at baseline, and
following 3, 6 and 12 hours after administration of the study drug. Methods We enrolled 30 patients with septic shock requiring
invasive hemodynamic monitoring and norepinephrine infusion ≥
0.5 µg/kg/min to maintain MAP between 65 and 75 mmHg. Patients were randomized to receive either 10, 20, or 30 mg
enteral glibenclamide. Systemic hemodynamics, global oxygen
transport, arterial lactate concentrations, gas exchange, and
plasma glucose concentrations were determined at baseline, and
following 3, 6 and 12 hours after administration of the study drug. Results Glibenclamide decreased plasma glucose concentrations
in a dose-dependent manner, but failed to reduce norepinephrine
requirements. None
of
the
doses
had
any
effects
on
cardiopulmonary hemodynamics. See Table 1. Tyrosine phosphorylation modulates rat vascular response
to experimental endotoxemia in vivo and in vitro Tyrosine phosphorylation modulates rat vascular response
to experimental endotoxemia in vivo and in vitro C Lehmann, T Hammann, O Adamek, H Erber, M Manthey,
T Wenzel, A Stier, M Wendt, D Pavlovic
Ernst-Moritz-Arndt-Universität Greifswald, Germany
Critical Care 2007, 11(Suppl 2):P6 (doi: 10.1186/cc5166) Results Glibenclamide decreased plasma glucose concentrations
in a dose-dependent manner, but failed to reduce norepinephrine
requirements. None
of
the
doses
had
any
effects
on
cardiopulmonary hemodynamics. See Table 1. Introduction Endotoxemia is characterized by vascular hypo-
reactivity, hypotension and microcirculatory changes that are
partially linked to the excess of nitric oxide production. The agents
that can influence Ca2+ transport (affect Ca-ATPase) or modulate
Ca2+ sensitivity of the smooth muscle contraction (modulate phos-
phorylation) may theoretically influence some of the above-
mentioned effects. Table 1 (abstract P7)
Plasma glucose concentration (mg/dl)
Time
Glibenclamide
0 hours
3 hours
6 hours
12 hours
10 mg
118 ± 13
110 ± 9
109 ± 10
107 ± 10
20 mg
117 ± 5
106 ± 4
93 ± 7*
98 ± 9*
30 mg
113 ± 6
86 ± 3*
89 ± 4*
98 ± 3*
Data presented as mean ± SEM. *P < 0.05 vs baseline (0 hours) within
groups. Table 1 (abstract P7) Plasma glucose concentration (mg/dl) Methods We evaluated the effects of tyrosine phosphatase or
kinase inhibitors, sodium orthovanadate (SOV) or genistein (GEN). The effects of these agents were examined in vitro, in a model of
vascular hyporeactivity of sepsis, in rings of rat aorta (RA), with or
without endothelium (±ENDO), or in human mesenteric artery
(HMA). In vivo, the intestinal microcirculation (terminal ileum) of
endotoxemic rats (LEW.1A) that received i.v. lipopolysaccharide
(LPS), 15 mg/kg BW, was examined using intravital microscopy. g g
g
py
Results In vitro. The nitric oxide production inhibitor L-NAME
(5 × 10–4) and cGMP inhibitor ODQ (5 x 10–5) abolished LPS-
induced hyporeactivity. GEN attenuated maximal tension (Tmax)
while SOV increased the response to PE; Tmax (kg/g, dry muscle):
controls vs SOV, RA (–ENDO): 0.87 ± 0.19 vs 1.42 ± 0.23
(10–7); 1.56 ± 0.28 (10–6) and 2.33 ± 0.69 (10–5); RA (+ENDO):
0.88 ± 0.21 vs 1.53 ± 0.35 (10–7); 1.35 ± 0.30 (10–6) and
2.55 ± 0.68 (10–5); and HMA (+ENDO): 1.12 ± 0.23 vs
0.37 ± 0.14 (10–7); 2.06 ± 0.21 (10–6) and 3.00 ± 0.07 (10–5). Conclusion Oral glibenclamide is an ineffective adjunct in the
treatment of catecholamine-dependent human septic shock. Molecular mechanism of glutamine induction of HSP70
involves activation of the O-linked-N-acetylglucosamine
pathway in murine embryonic fibroblast cells Molecular mechanism of glutamine induction of HSP70
involves activation of the O-linked-N-acetylglucosamine
pathway in murine embryonic fibroblast cells C Hamiel1, S Pinto2, K Singleton1, P Wischmeyer1
1University of Colorado, Denver, CO, USA; 2Valparaiso University,
IN, USA
Critical Care 2007, 11(Suppl 2):P8 (doi: 10.1186/cc5168) In vivo. In the LPS group GEN increased mucosal functional
capillary density (FCD, cm/cm2; mean ± SD; LPS vs GEN,
105.5 ± 44.6 vs 174.7 ± 39.1; P = 0.018). SOV (7.5 mg/kg)
increased FCD not only in mucosa (163.7 ± 40.0; P = 0.024) but
also in the longitudinal muscular layer (LPS vs SOV, 111.9 ± 24.0
vs 172.2 ± 19.5; P < 0.001). Surprisingly, the SOV (15 mg/kg)
alone (without LPS) increased leukocyte sticking in the venules V1
(LPS vs SOV, number of stickers/mm2, 403.3 ± 113.9 vs
669.8 ± 150.8; P = 0.027). Introduction The purpose of this study was to determine whether
glutamine (GLN)-mediated cellular protection is dependent on the
O-linked-N-acetylglucosamine (O-glcNAc) pathway. GLN can
protect against critical illness via induction of HSP70. The molecular
mechanism by which GLN enhances HSP70 is unknown. GLN can
increase flux through the hexosamine biosynthetic pathway and
activate transcription factors by O-glcNAc. We investigated GLN’s
effect on O-glcNAc levels and nuclear translocation of SP1 and
HSF-1, which are vital to HSP70 expression. To determine the
importance of O-glcNAc, we used silencing RNA (siRNA) against O-
linked-N-acetylglucosamine transferase (OGT), the enzyme that
catalyzes addition of O-glcNAc to proteins. Conclusions The tyrosine phosphorylation pathway may play an
important role in modulation of the LPS-induced vascular
hyporeactivity and could enhance terminal ileum microcirculation. This might be a result of both modulation of tyrosine
phosphorylation by genistein and sodium orthovanadate, and/or
plasma membrane Ca-ATPase inhibition by SOV. P7 Methods Mouse embryonic fibroblast cells were treated with
0 mM GLN (CT) or 10 mM GLN (GLN), heat stressed (HS) and
allowed to recover for 20 minutes. Cells were stained and mean
fluorescent intensities (MFIs) measured for total O-glcNAc and
nuclear HSF-1 and SP1. For OGT silencing, cells were transfected
with either no siRNA, siRNA to OGT, or negative control oligos (nc
siRNA) and then treated as above (but with 4 hours recovery). HSP70 and OGT were evaluated by western blot. References Interferon gamma levels are reduced by adenosine
5′-triphosphate in lipopolysaccharide-stimulated whole
human blood 1. Bours MJ, Swennen EL, Di Virgilio F, et al.: Adenosine 5′-
triphosphate and adenosine as endogenous signaling
molecules in immunity and inflammation. Pharmacol Ther
2006, 112:358-404. 1. Bours MJ, Swennen EL, Di Virgilio F, et al.: Adenosine 5′-
triphosphate and adenosine as endogenous signaling
molecules in immunity and inflammation. Pharmacol Ther
2006, 112:358-404. M Nalos1, S Huang1, A Khan2, A McLean1
1Nepean Hospital, Penrith, Australia; 2Macquarie University, North
Ryde, Australia
Critical Care 2007, 11(Suppl 2):P5 (doi: 10.1186/cc5165) 2. Ertel W, Keel M, Neidhardt R, et al.: Inhibition of the defence
system
stimulating
interleukin-12
interferon-gamma
pathway during critical illness. Blood 1997, 89:1612-1620. 3. Swennen EL, Bast A, Dagnelie PC: Immunoregulatory effects
of adenosine 5′-triphosphate on cytokine release from
stimulated whole blood. Eur J Immunol 2005, 35:852-858. Introduction Extracellular release of ATP is an important modulator
of immune response. ATP plasma concentration is increased in S2 Available online http://ccforum.com/supplements/11/S2 Glibenclamide dose response in patients with septic shock A Morelli1, C Ertmer2, M Lange2, K Broeking2, H Van Aken2,
A Orecchioni1, M Rocco1, P Pietropaoli1, M Westphal2
1University of Rome ‘La Sapienza’, Rome, Italy;
2University Hospital of Muenster, Germany
Critical Care 2007, 11(Suppl 2):P7 (doi: 10.1186/cc5167) Results Microscopy showed GLN treatment increased nuclear
MFI for HSF-1 by 40% (HS-CT: 1,005 ± 146 vs HS-
GLN:1403 ± 102, P < 0.05) and SP1 by 54% (HS-CT: 214 ± 14
vs HS-GLN: 330 ± 13, P < 0.05). Total O-glcNAc levels showed
44% MFI increase in HS-GLN compared with HS-CT (HS-CT:
360 ± 24 vs HS-GLN: 518 ± 51, P < 0.05). Following OGT
silencing, HS-GLN showed a threefold increase in HSP70 Introduction
(K+ATP)
channels
are
implicated
in
the
pathophysiology of catecholamine tachyphylaxis in septic shock. This prospective, randomized, double-blinded, clinical study was
designed to determine whether different doses of glibenclamide
have any effects on norepinephrine requirements and cardio-
pulmonary hemodynamics in patients with septic shock. Introduction
(K+ATP)
channels
are
implicated
in
the
pathophysiology of catecholamine tachyphylaxis in septic shock. This prospective, randomized, double-blinded, clinical study was
designed to determine whether different doses of glibenclamide
have any effects on norepinephrine requirements and cardio-
pulmonary hemodynamics in patients with septic shock. S3 Critical Care March 2007 Vol 11 Suppl 2
27th International Symposium on Intensive Care and Emergency Medicin (P = 0.04). These increases were completely blocked by OGT
silencing (P = 0.02 vs non-siRNA GLN groups). GLN-nc siRNA
groups did not decrease in HSP70 production. OGT was knocked
down 86% compared with controls (siRNA: 0.999 ± 0.19 vs CT:
0.131 ± 0.05). N = 3. (P = 0.04). These increases were completely blocked by OGT
silencing (P = 0.02 vs non-siRNA GLN groups). GLN-nc siRNA
groups did not decrease in HSP70 production. OGT was knocked
down 86% compared with controls (siRNA: 0.999 ± 0.19 vs CT:
0.131 ± 0.05). N = 3. vasodilatory peptide hormone with anti-inflammatory properties,
may improve the oxygen delivery–demand relationship, thereby
limiting the increase in arterial lactate concentrations in ovine endo-
toxemia. Methods Fourteen adult ewes were instrumented for chronic hemo-
dynamic monitoring. Following 16 hours of endotoxemia (Salmonella
typhosa endotoxin, 10 ng/kg/min) the animals received either a
continuous infusion of AM at incremental doses (10, 50,
100 ng/kg/min; each for 30 min) or the vehicle (normal saline; n = 7
each). The effects of N-acetylcysteine on the levels of glutathione,
serum TNFα, and tissue malondialdehyde in sepsis The effects of N-acetylcysteine on the levels of glutathione,
serum TNFα, and tissue malondialdehyde in sepsis M Gul, M Ayan, A Seydanoglu, B Cander, S Girisgin, I Erayman
Selcuk University Meram Medical School, Konya, Turkey
Critical Care 2007, 11(Suppl 2):P9 (doi: 10.1186/cc5169) Objectives This study was designed to determine the effects of N-
acetylcysteine (NAC) as an antioxidant agent on the free oxygen
radicals and their plasma levels. Conclusions Despite decreasing MAP, infusion of AM reversed
pulmonary hypertension and improved the oxygen supply–demand
relationship in a dose-dependent manner, as indicated by a
reduced arterial lactate concentration. However, due to the
vasodilatory properties of AM, it may be rationale to combine AM
with a vasopressor agent. Methods In this study, 40 Sprague–Dawley rats were randomly
divided into three groups as sham (n = 10), sepsis (n = 10), and
sepsis + NAC (20 mg/kg/24 hours) (n = 10). An experimental
sepsis model was performed by a cecal ligation and perforation
(CLP). NAC was administered at 0, 8 and 16 hours after CLP. The
blood samples were taken at 24 hours to determine the levels of
serum TNFα and erythrocyte glutathione (GSH), and renal and liver
tissue malondialdehyde (MDA). P11 Results The serum TNFα levels were significantly decreased in
group 3 compared with group 2 (P < 0.05). The erythrocyte GSH
levels significantly increased in group 3 compared with group 2
(P < 0.05). In group 3, the liver MDA levels were decreased
compared with group 2, but not statistically significant (P > 0.05)
In group 3, the renal MDA levels were significantly decreased
compared with group 2 (P < 0.05). The lung tissue PMNL levels
significantly decreased in group 3 compared with group 2
(P < 0.05). Angiopoietin-2 correlates with pulmonary capillary
permeability and disease severity in critically ill patients Angiopoietin-2 correlates with pulmonary capillary
permeability and disease severity in critically ill patients M van der Heijden1, V van Hinsbergh2, G van Nieuw
Amerongen2, P Koolwijk2, R Musters2, J Groeneveld1
1VU University Medical Center, Amsterdam, The Netherlands;
2Institute for Cardiovascular Research, VU University Medical
Center, Amsterdam, The Netherlands
Critical Care 2007, 11(Suppl 2):P11 (doi: 10.1186/cc5171) Conclusion In an experimental sepsis model, with the administra-
tion of NAC as an antioxidant agent at lower doses, many meaning-
ful positive effects were detected on the levels of erythrocyte GSH,
serum TNFα, respiration function, and renal tissue MDA. In spite of
the low dose, NAC therapies decrease the organ function abnor-
malities; these effects were not reflected in the histopathological
investigations. These findings suggest that NAC could be a
possible therapeutic agent for sepsis and its mortality. However,
further studies are needed to elucidate the effects of these drugs
at higher doses. Introduction It has previously been shown that angiopoietin-1
(Ang1) protects the adult vasculature against plasma leakage,
whereas Ang2 and VEGF destabilize the vascular endothelium
resulting in vascular leakage. Consequently they might be involved
in the pathophysiology of acute lung injury (ALI) and acute
respiratory distress syndrome (ARDS) in sepsis patients. We
hypothesized that plasma Ang2 levels are associated with
pulmonary capillary protein permeability, the lung injury score (LIS),
length of stay on the ICU, the APACHE II score and survival in
septic patients with ALI or ARDS. Glibenclamide dose response in patients with septic shock Conclusions These results show GLN can activate the O-glcNAc
pathway and enhance nuclear translocation of HSF-1 and SP1. Inhibition of OGT blocked GLN-mediated induction of HSP70. Thus, it appears the mechanism of GLN-mediated HSP70 expres-
sion is dependent on enhanced O-glcNAc pathway activation. Results
Endotoxin infusion contributed to a hypotensive–
hyperdynamic circulation characterized by decreases in mean
arterial pressure (MAP) and systemic vascular resistance index as
well as increases in heart rate (HR), cardiac index (CI) and arterial
lactate concentrations. AM infusion at 100 ng/kg/min increased
the CI (12.2 ± 0.8 vs 7.8 ± 0.5 l/min) and oxygen delivery index
(1,734 ± 121 vs 1,075 ± 63 ml/min/m2), thereby decreasing the
arterial lactate concentration (0.7 ± 0.2 vs 1.7 ± 0.3 mg/dl) and
mean pulmonary arterial pressure (18 ± 1 vs 24 ± 1 mmHg; each
P < 0.001 vs control) noticed in the control group. However, AM
infusion at 100 ng/kg/min was linked to a decrease in MAP
(64 ± 2 vs 80 ± 4 mmHg, P < 0.001 vs control). P12 Dose-dependent effects of octreotide on plasma activities
of IL-6 and lung tissue levels of malondialdehyde in sepsis
M Gul, A Seydanoglu, M Ayan, B Cander, I Erayman, S Girisgin
Selcuk University Meram Medical School, Konya, Turkey
Critical Care 2007, 11(Suppl 2):P12 (doi: 10.1186/cc5172) Dose-dependent effects of octreotide on plasma activities
of IL-6 and lung tissue levels of malondialdehyde in sepsis M Gul, A Seydanoglu, M Ayan, B Cander, I Erayman, S Girisgin
Selcuk University Meram Medical School, Konya, Turkey
Critical Care 2007, 11(Suppl 2):P12 (doi: 10.1186/cc5172) Background and aim Sepsis, a complex and rapidly progressing
infectious disease with high levels of mortality, is widely regarded
as the most challenging problem in intensive care. The lung is
frequently the first failing organ during septic conditions. Although
the etiology of sepsis is multifactorial, early release of proinflam-
matory cytokines and oxidative damage are probably most impor-
tant factors that lead to cell damage, organ dysfunction, and death. This study aimed to determine the effects of treatment with octreo-
tide (OCT), on plasma activities of IL-6 and tissue levels of malon-
dialdehyde (MDA) in an experimental model of sepsis. gene expression analysis (Affymetrix) was applied to serial cardiac
biopsies of sham (n = 2) and E. coli infected pigs (n = 3). Methods Cardiac samples were taken basal and hourly after
infection for gene analysis and at the end of the experiment for
histopathological examination. Genes were determined to be
differentially regulated at a greater than or less than twofold
change and P < 0.05. gene expression analysis (Affymetrix) was applied to serial cardiac
biopsies of sham (n = 2) and E. coli infected pigs (n = 3). Methods Cardiac samples were taken basal and hourly after
infection for gene analysis and at the end of the experiment for
histopathological examination. Genes were determined to be
differentially regulated at a greater than or less than twofold
change and P < 0.05. Methods Sepsis was induced in female Sprague–Dawley rats by
cecal ligation and puncture (CLP) as previously described. Group 1
(n = 10), sham operated animals; Group 2 (n = 10), sepsis served
as control; Group 3 (n = 10) and Group 4 (n = 10), respectively,
OCT 50 µg/kg twice a day and OCT 100 µg/kg twice a day
administered subcutaneously immediately after the induction of
sepsis and at 12 hours. Rats were sacrificed 24 hours after the
surgical procedure. P12 Blood and lung tissue samples were taken
24 hours after sepsis induction. Plasma activities of IL-6 and lung
tissue levels of MDA were measured. Results Sham pigs had stable heart rate, cardiac output (CO) and
core temperature for the 5-hour period; infected pigs demon-
strated an early elevation in CO and ventricular shortening and/or
ejection (assessed by echocardiography) followed by development
of hypodynamics. In infected animals, increasing numbers of genes
were upregulated or downregulated (36, 278, 514, 842 and 1,238
at 1, 2, 3, 4 and 5 hours) (Figure 1) whereas sham infection altered
fewer (247, 67 and 384 genes at 2, 3 and 4 hours). Comparing
sham vs infected animals at the same time, numbers of significantly
altered genes increased with time (32 at basal, to 74, 189 and
601 at 2, 3 and 4 hours post infection). In hematoxylin–eosin-
stained sections, histopathological assessment revealed acute
inflammation in pericardium and myocardium in infected pigs. Results The results showed that the plasma levels of IL-6, an
inflammatory indicator, and tissue levels of MDA, an oxidative
indicator, are significantly increased during experimental model of
sepsis (P < 0.05). Increase in MDA levels and IL-6 activities after
CLP-induced sepsis was significantly prevented by OCT
(100 µg/kg, s.c.) administration (P < 0.05). Conclusions These results will provide biomarker and mechanistic
insights to pathogenesis of cardiac dysfunction of septic peritonitis
and may also help identify some altered novel gene transcription
pathways that can serve as new targets for diagnostic tools and
therapeutic strategies. All candidate genes will be validated by
quantitative PCR. Conclusion
Octreotide seems to have a dose-dependent
antioxidative and immunomodulator effect in CLP-induced sepsis in
rats. Further trials are necessary to reveal the therapeutic effect of
OCT in sepsis. On the other hand, further studies should be
performed aiming to reveal the optimal OCT doses. As a drug with a
wide margin of safety and less adverse reaction profile, OCT merits
consideration as a choice of treatment in sepsis and septic shock. P10 Methods A prospective observational study was performed in an
ICU of an university hospital on 112 patients: 38 after elective
cardiac surgery, 26 after major vascular surgery, 24 with sepsis
and 24 with trauma. Plasma levels of Ang1, Ang2 and VEGF were
measured and a mobile probe system was used to measure the
pulmonary leak index (PLI) (that is, the transvascular transport rate
of gallium-67-radiolabeled transferrin). Exogenous adrenomedullin reduces the arterial lactate
concentration and mean pulmonary arterial pressure in
ovine endotoxemia C Ertmer1, M Lange1, H Van Aken1, K Bröking1, S Vocke1,
F Daudel1, M Booke2, M Westphal3
1University of Muenster, Germany; 2Hospital of the
Main-Taunus-Kreis, Hofheim, Germany; 3UTMB, Galveston, USA
Critical Care 2007, 11(Suppl 2):P10 (doi: 10.1186/cc5170) Results Plasma levels of Ang2 and the PLI were significantly
higher in patients with sepsis compared with other patient groups. In the sepsis group, a positive linear correlation was observed
between plasma levels of Ang2 and length of stay on the ICU
(rs = 0.509, P < 0.05) as index for disease severity. For all patients
together, Ang2 had a positive linear correlation with PLI (rs = 0.374,
P < 0.01), LIS (rs = 0.489, P < 0.01) and APACHE II score
(rs = 0.287, P < 0.01). Furthermore, Ang2 was significantly increased Introduction
Sepsis-associated arterial hypotension may be
complicated by inadequate systemic and regional oxygen delivery
resulting in lactic acidosis and multiple organ failure. We hypothe-
sized that exogenous administration of adrenomedullin (AM), a Introduction
Sepsis-associated arterial hypotension may be
complicated by inadequate systemic and regional oxygen delivery
resulting in lactic acidosis and multiple organ failure. We hypothe-
sized that exogenous administration of adrenomedullin (AM), a S4 Available online http://ccforum.com/supplements/11/S2 Figure 1 (abstract P13) in nonsurvivors. Plasma Ang1 levels did not differ between groups. VEGF levels were undetectable in the plasma of the majority of
patients. Conclusions Our results suggest that Ang2 is a mediator of
pulmonary capillary permeability and a marker of disease severity in
critically ill patients. Furthermore, the plasma levels of Ang2 and
the ratio between Ang1 and Ang2 are more important in pulmonary
capillary permeability and disease severity than absolute levels of
Ang1 and VEGF. P14 Alkaline phosphatase treatment improves renal function in
patients with severe sepsis or septic shock P15 associated with proximal tubule injury. In several in vitro and animal
studies alkaline phosphatase (AP) was found to be effective in
attenuating the inflammatory response by dephosphorylating LPS
and may prevent organ damage. The objective of this study was to
investigate the effect of AP on renal iNOS expression and kidney
damage in patients with severe sepsis or septic shock. associated with proximal tubule injury. In several in vitro and animal
studies alkaline phosphatase (AP) was found to be effective in
attenuating the inflammatory response by dephosphorylating LPS
and may prevent organ damage. The objective of this study was to
investigate the effect of AP on renal iNOS expression and kidney
damage in patients with severe sepsis or septic shock. P15
Moderate hypothermia attenuates changes in respiratory
system mechanics and cytokine production during low
lung volume ventilation in rats
P Dostal1, M Senkerik1, V Cerny1, R Parizkova1, J Suchankova1,
D Kodejskova1, D Bares1, P Zivny1, H Zivna2
1University Hospital Hradec Kralove, Czech Republic; 2Charles University
in Prague, Faculty of Medicine Hradec Kralove, Czech Republic
Critical Care 2007, 11(Suppl 2):P15 (doi: 10.1186/cc5175) P15
Moderate hypothermia attenuates changes in respiratory
system mechanics and cytokine production during low
lung volume ventilation in rats
P Dostal1, M Senkerik1, V Cerny1, R Parizkova1, J Suchankova1,
D Kodejskova1, D Bares1, P Zivny1, H Zivna2
1University Hospital Hradec Kralove, Czech Republic; 2Charles University
in Prague, Faculty of Medicine Hradec Kralove, Czech Republic
Critical Care 2007, 11(Suppl 2):P15 (doi: 10.1186/cc5175) Moderate hypothermia attenuates changes in respiratory
system mechanics and cytokine production during low
lung volume ventilation in rats P Dostal1, M Senkerik1, V Cerny1, R Parizkova1, J Suchankova1,
D Kodejskova1, D Bares1, P Zivny1, H Zivna2
1University Hospital Hradec Kralove, Czech Republic; 2Charles University
in Prague, Faculty of Medicine Hradec Kralove, Czech Republic
Critical Care 2007, 11(Suppl 2):P15 (doi: 10.1186/cc5175) Fifteen patients (nine male/six female, age 55 ± 5 years) with
Gram-negative bacterial infection, two out of four SIRS criteria
(<24 hours) and acute onset of end-organ dysfunction (<12 hours)
were included in a randomized, double-blind, placebo-controlled
phase IIa study (2:1 ratio). An intravenous bolus injection of
67.5 U/kg bovine intestinal AP was followed by a maintenance
dose of 177.5 U/kg for 24 hours. Arterial blood and urine were
collected at different time points and analyzed for stable metabo-
lites of NO. iNOS mRNA was determined by quantitative real-time
RT-PCR using RNA isolated from renal cells in urine. P15 After 2 hours of
mechanical ventilation (FiO2 1,0, respiratory rate 60/min, tidal volume
10 ml/kg, PEEP 2 cmH2O) inspiratory pressures were recorded, rats
were sacrificed, the P–V curve of the respiratory system constructed,
and bronchoalveolar lavage and aortic blood samples obtained. NO metabolites in blood were not significantly different between
AP-treated (n = 10) and placebo-treated (n = 5) patients. However,
the urinary excretion of NO metabolites decreased by 80%
(75–85) from 227 (166–531) at baseline to 41 (28–84) µmol/
10 mmol creatinine (P < 0.05) after 24 hours of AP administration. After placebo treatment, the amount of urinary NO metabolites
increased by 70% (45–570) (from 81 (64–419) to 628 (65–
1,479) µmol/10 mmol creatinine, P < 0.05). Baseline expression
levels of iNOS in renal cells were 42-fold induced at baseline (vs
healthy subjects), and AP administration reduced this induction by
80 ± 5% (Figure 1). Creatinine clearance improved by 45%
(30–180) in patients treated with AP and declined by 25%
(15–35) in placebo-treated patients. During the first 24 hours the
amount of GSTA1-1 in urine of AP-treated patients decreased by
70% (50–80), compared with an increase of 200% (45–525) in
placebo-treated patients, which correlated with urinary NO
metabolites, indicating NO-induced proximal tubular damage. Methods Sixteen male adult Sprague–Dawley rats, instrumented
under ether anesthesia with vascular catheters on the previous day,
were anesthetized, tracheostomized, connected to a ventilator and
randomly allocated to groups of normothermia (37 ± 0.5°C, group N,
n = 8) or hypothermia (33 ± 0.5°C, group H, n = 8). After 2 hours of
mechanical ventilation (FiO2 1,0, respiratory rate 60/min, tidal volume
10 ml/kg, PEEP 2 cmH2O) inspiratory pressures were recorded, rats
were sacrificed, the P–V curve of the respiratory system constructed,
and bronchoalveolar lavage and aortic blood samples obtained. Results Group H animals exhibited in comparison with group N
animals a lower increase in peak inspiratory pressures (0.7 ± 1.1
vs 2.4 ± 0.5 mmHg, P < 0.001), significant shift of the P–V curve
to the left and lower total protein (113 ± 42 vs 201 ± 97 µg/ml,
P = 0.047) and TNF (23.5 ± 8.0 vs 35.2 ± 8.5 pg/ml, P = 0,022)
levels in BAL samples. In conclusion, in septic patients, infusion of AP results in an
attenuated upregulation of iNOS and, subsequent, reduced NO
production in the kidney, associated with an improvement in renal
function. Figure 1 (abstract P14) Figure 1 (abstract P14) References References Figure 1 (abstract P14) 1. Lim CM, et al.: Lung 2003, 181:23-34. 2. Suzuki S, et al.: Crit Care Med 2004, 32:144-149. 3. Hong S-B, et al.: Crit Care Med 2005, 33:2049-2055. 4. Muscedere JG, et al.: Am J Respir Crit Care Med 1994, 149:
1327-1334. 5. Fan J, et al.: J Immunol 1998, 161:440-447. 5. Fan J, et al.: J Immunol 1998, 161:440-447. 6. Kaneko A, et al.: J Surg Res 2006, 134:215-222. 6. Kaneko A, et al.: J Surg Res 2006, 134:215-222. Escherichia coli porcine peritonitis induces histological
and transcriptome evidence of cardiac injury Escherichia coli porcine peritonitis induces histological
and transcriptome evidence of cardiac injury S Heemskerk1, R Masereeuw1, O Moesker2, M Bouw2, J van
der Hoeven2,3, W Peters4, M Velders5, F Russel1, P Pickkers2
1Department of Pharmacology and Toxicology, Nijmegen Centre for
Medical Life Sciences, 2Department of Intensive Care Medicine,
3Nijmegen University Centre for Infectious Diseases and 4Department
of Gastroenterology, Radboud University Nijmegen Medical Centre,
Nijmegen, The Netherlands; 5AM-Pharma, Bunnik, The Netherlands
Critical Care 2007, 11(Suppl 2):P14 (doi: 10.1186/cc5174) R Goldfarb1, I Cinel1, S Gandhi1, L Cinel2, M Levine1, Q Wang3
A Brooks3, J Parrillo1
1Cooper University Hospital and UMDNJ, Camden, NJ, USA;
2Thomas Jefferson University Hospital, Philadelphia, PA, USA;
3EOHSI, UMDNJ, Piscataway, NJ, USA
Critical Care 2007, 11(Suppl 2):P13 (doi: 10.1186/cc5173) Introduction Cardiac dysfunction is a feature of sepsis. In order to
gain insight into the fundamental mechanisms of this phenotype, We previously demonstrated that upregulation of renal inducible
nitric oxide synthase (iNOS) during systemic inflammation is S5 P15 F Saunders1, M Westphal1, P Enkhbaatar1, J Wang1,
M Gonzalez1, Y Nakano1, A Hamahata1, C Jonkam1,
R Connelly1, R Cox1, H Hawkins2, F Schmalstieg1, E Horvath3,
M Lange1, C Szabo1, L Traber1, D Herndon2, D Traber1
1University of Texas Medical Branch, Galveston, TX, USA;
2Shriners Burns Hospital for Children, Galveston, TX, USA;
3University of Medicine and Dentistry of New Jersey, NJ, USA
Critical Care 2007, 11(Suppl 2):P16 (doi: 10.1186/cc5176) P15 The urinary
excretion of the cytosolic glutathione S-transferase-A1 (GSTA1-1),
a marker for proximal tubule damage, was measured using an
ELISA. Data are depicted as the median (25–75% range). Introduction Hypothermia was shown to attenuate ventilator-
induced lung injury (VILI) in high end-inspiratory lung volume
models of VILI [1-3]. Experimental evidence suggests that
moderate tidal volumes may, under certain clinical conditions that
induce alveolar instability, lead to a lung injury [4]. Recent studies
have also suggested that insults like shock [5] or surgery [6]
sensitize the lung to injury by priming for an exaggerated response
to a second stimulus. The aim of this study was to investigate
whether moderate hypothermia attenuates low lung volume injury
during low PEEP, high FiO2 and moderate tidal volume ventilation
in animals sensitized to injury by previous anesthesia and surgery. Methods Sixteen male adult Sprague–Dawley rats, instrumented
under ether anesthesia with vascular catheters on the previous day,
were anesthetized, tracheostomized, connected to a ventilator and
randomly allocated to groups of normothermia (37 ± 0.5°C, group N,
n = 8) or hypothermia (33 ± 0.5°C, group H, n = 8). After 2 hours of
mechanical ventilation (FiO2 1,0, respiratory rate 60/min, tidal volume
10 ml/kg, PEEP 2 cmH2O) inspiratory pressures were recorded, rats
were sacrificed, the P–V curve of the respiratory system constructed,
and bronchoalveolar lavage and aortic blood samples obtained. Introduction Hypothermia was shown to attenuate ventilator-
induced lung injury (VILI) in high end-inspiratory lung volume
models of VILI [1-3]. Experimental evidence suggests that
moderate tidal volumes may, under certain clinical conditions that
induce alveolar instability, lead to a lung injury [4]. Recent studies
have also suggested that insults like shock [5] or surgery [6]
sensitize the lung to injury by priming for an exaggerated response
to a second stimulus. The aim of this study was to investigate
whether moderate hypothermia attenuates low lung volume injury
during low PEEP, high FiO2 and moderate tidal volume ventilation
in animals sensitized to injury by previous anesthesia and surgery. Methods Sixteen male adult Sprague–Dawley rats, instrumented
under ether anesthesia with vascular catheters on the previous day,
were anesthetized, tracheostomized, connected to a ventilator and
randomly allocated to groups of normothermia (37 ± 0.5°C, group N,
n = 8) or hypothermia (33 ± 0.5°C, group H, n = 8). P15 Conclusion Moderate hypothermia attenuated lung injury during
low PEEP, high FiO2 and moderate tidal volume ventilation in
animals sensitized to injury by previous anesthesia and surgery. Acknowledgement Supported by the Research project MZO
00179906. Acknowledgement Supported by the Research project MZO
00179906. P17 Results
(1) The mean arterial pressure was higher post-
resuscitation (PR) in group III (62.9 ± 8.2 mmHg) than in groups I
and II (54.9 ± 1.7, 53.9 ± 4.3 mmHg; P < 0.01). The urine output
(I: 999 ± 428, II: 1,249 ± 180, III: 1,434 ± 325 ml) and the cardiac
output (CO) (I: 3.01 ± 0.66, II: 3.30 ± 0.49, III: 3.43 ± 0.57 l/min)
increased dose dependently. The volume of third space fluid loss
of group III decreased significantly (I: 157 ± 32, II: 138 ± 32, III:
82 ± 21 ml; P < 0.05). (2) Mean arterial pressure was higher PR
among
groups
IV,
V
and
VII
(71.4 ± 7.5,
71.0 ± 8.9,
72.9 ± 12.3 mmHg) compared with group VI (59.9 ± 10.9) and
CO of PR was higher in group VII (3.46 ± 0.56 l/min) than group
IV (2.99 ± 0.62; P < 0.01). Following resuscitation, the urine
output was higher, and the urine specific gravity and third space
fluid loss were lower in group VII (1,434 ± 325 ml, 1.0035,
82 ± 21 ml) compared with group VI (958 ± 390 ml, 1.0053,
125 ± 32 ml; P < 0.05). nNOS and Nox4 go nuclear: nNOS-derived and NADPH
oxidase-derived reactive oxygen/nitrogen species
promote oxidative nuclear damage in alveolar epithelial
cells nNOS and Nox4 go nuclear: nNOS-derived and NADPH
oxidase-derived reactive oxygen/nitrogen species
promote oxidative nuclear damage in alveolar epithelial
cells R Connelly, F Schmalstieg, D Traber
University of Texas Medical Branch, Galveston, TX, USA
Critical Care 2007, 11(Suppl 2):P17 (doi: 10.1186/cc5177) Emerging evidence implicates a role for angiotensin II (Ang II)-
stimulated reactive oxygen and nitrogen species (ROS/RNS)
formation in acute lung injury (ALI). However, details of the
mechanism are lacking. We hypothesized that compartmentalized
generation of superoxide (O2–) and nitric oxide (•NO) may be key
events in the Ang II-stimulated progression of ALI. In the present
study, we found that Ang II markedly enhanced ROS/RNS
production 7.4-fold, an effect blocked by the specific nNOS
inhibitor N(G)-propyl-L-arginine, the NADPH oxidase inhibitor
apocynin, or small interfering RNA (siRNA)-specific gene silencing
targeted against nNOS or Nox4. nNOS/Nox4 transiently co-
immunoprecipitates, and co-localizes at the peri-nuclear region 15
minutes post Ang II stimulation. Subsequently, confocal and
western blot analyses show that nNOS/Nox4 translocates to the
nucleus, suggesting that nNOS/Nox4 may directly regulate nuclear
signaling. P19 Degradation of endothelial glycocalyx provides new insights
in the pathogenesis of septic shock microvascular failure
R Nevière1, R Favory2, X Marechal1
1School of Medicine, Lille, France; 2Calmette Hospital, Lille, France
Critical Care 2007, 11(Suppl 2):P19 (doi: 10.1186/cc5179) Dose effects of recombinant human IL-11 on the systemic
hemodynamic function in hemorrhagic shock Methods Eleven ewes were surgically instrumented and randomly
allocated to either an injured untreated control group (40% total
body surface area flame burn and 48 breaths of cotton smoke,
n = 6), or an injury group treated with 7-NI (1 mg/kg/hour, n = 5). K Honma1, N Koles2, H Alam2, P Rhee2, J Keith, Jr3, M Pollack2
1Shin-Koga Hospital, Kurume, Fukuoka, Japan; 2Uniformed
Services University of the Health Sciences, Bethesda, MD, USA;
3Wyeth Research, Andover, MA, USA
Critical Care 2007, 11(Suppl 2):P18 (doi: 10.1186/cc5178) Results This insult was associated with systemic inflammation and
oxidative stress, as evidenced by a 2.5-fold increase in plasma
nitrite/nitrate (NOx) levels, as well as sixfold, twofold, threefold and
twofold increases in IL-8, myeloperoxidase (MPO), malondialde-
hyde (MDA) and poly-ADP-ribose-polymerase (PARP) lung tissue
concentrations, respectively. These molecular changes were linked
to severe pulmonary derangements. Compared with untreated
controls, 7-NI significantly reduced NOx plasma levels (8.4 ± 1 vs
26 ± 10 µmol/l) and decreased IL-8, MPO (3.9 ± 0.2 vs
5.8 ± 0.7 U/g tissue), MDA (2.7 ± 0.3 vs 6.6 ± 1.1 nmol/mg
protein) and PARP lung tissue content (3.4 ± 0.7 vs 6.7 ± 0.7),
thereby
decreasing
pulmonary
obstruction
(12.4 ± 2.2
vs
28.7 ± 5.2 obstruction score) and increasing the PaO2/FiO2 ratio
(456 ± 40 vs 313 ± 56, each P < 0.05). Introduction We have previously demonstrated that administration
of recombinant human IL-11 (rhIL-11) during resuscitation improves
the cardiovascular functions in a rodent model of hemorrhagic
shock. The purpose of this study was to elucidate: (1) whether
these beneficial effects were dose related, and (2) whether the
effects of rhIL-11 could be reproduced in a large animal model. p
g
Methods Swine (n = 56, weight = 25–35 kg) underwent 40%
blood volume hemorrhage, and a 1-hour shock period, followed by
resuscitation with 0.9% sodium chloride (three times the shed
blood volume). The animals were randomized to receive: (1) group
I, 5 µg/kg rhIL-11 (n = 6); group II, 20 µg/kg rhIL-11 (n = 5); group
III, 50 µg/kg rhIL-11 (n = 6) – and then, (2) group IV, sham
hemorrhage (sham, n = 10); group V, sham hemorrhage and
50 µg/kg rhIL-11 (sham + IL-11, n = 6); group VI, no drug (saline,
n = 15); group VII, 50 µg/kg rhIL-11 (IL-11, n = 14). Dose effects of recombinant human IL-11 on the systemic
hemodynamic function in hemorrhagic shock Blood
samples and urine were obtained and analyzed at baseline, the end
of hemorrhage, and at every hour. Conclusions These data suggest that nNOS-derived NO plays a
pivotal role in the pathophysiology of this double-hit injury and that
selective nNOS inhibition may represent a useful approach to
attenuate the degree of pulmonary damage. Effects of neuronal nitric oxide synthase in ovine lung injury Conclusions These data suggest that nNOS-derived NO plays a
pivotal role in the pathophysiology of this double-hit injury and that
selective nNOS inhibition may represent a useful approach to
attenuate the degree of pulmonary damage. P17
nNOS and Nox4 go nuclear: nNOS-derived and NADPH
oxidase-derived reactive oxygen/nitrogen species
promote oxidative nuclear damage in alveolar epithelial
cells
R Connelly, F Schmalstieg, D Traber
University of Texas Medical Branch, Galveston, TX, USA
Critical Care 2007, 11(Suppl 2):P17 (doi: 10.1186/cc5177) P18 P17 Furthermore, PAR polymers, which are undetectable in
resting conditions, were generated following Ang II stimulation, an
effect blocked with apocynin or N(G)-propyl-L-arginine. In
conclusion, these data suggest Ang II causes nNOS/Nox4 to co-
localize at the peri-nuclear region of A549 cells, where superoxide
produced by Nox4, and •NO produced by nNOS immediately react
to form peroxynitrite, which leads to subsequent nuclear oxidative
damage as evidenced by increased PAR polymer formation. Furthermore, these experiments demonstrate inflammatory-stimulated
nuclear translocalization of nNOS/Nox4, which has important
implications for direct ROS/RNS-mediated nuclear activities. Therefore, inhibition of nNOS/Nox4 may be an effective thera-
peutic target in patients with ALI. Conclusion The effects of rhIL-11 on the cardiovascular functions
were influenced by the dose of rhIL-11, although the relationship
did not follow simple linearity. A 50µg/kg dose rhIL-11 significantly
improves cardiovascular functions in a porcine model of hemor-
rhagic shock. Effects of neuronal nitric oxide synthase in ovine lung injury Effects of neuronal nitric oxide synthase in ovine lung injury F Saunders1, M Westphal1, P Enkhbaatar1, J Wang1,
M Gonzalez1, Y Nakano1, A Hamahata1, C Jonkam1,
R Connelly1, R Cox1, H Hawkins2, F Schmalstieg1, E Horvath3,
M Lange1, C Szabo1, L Traber1, D Herndon2, D Traber1
1University of Texas Medical Branch, Galveston, TX, USA;
2Shriners Burns Hospital for Children, Galveston, TX, USA;
3University of Medicine and Dentistry of New Jersey, NJ, USA
Critical Care 2007, 11(Suppl 2):P16 (doi: 10.1186/cc5176) F Saunders1, M Westphal1, P Enkhbaatar1, J Wang1,
M Gonzalez1, Y Nakano1, A Hamahata1, C Jonkam1,
R Connelly1, R Cox1, H Hawkins2, F Schmalstieg1, E Horvath3,
M Lange1, C Szabo1, L Traber1, D Herndon2, D Traber1
1University of Texas Medical Branch, Galveston, TX, USA;
2Shriners Burns Hospital for Children, Galveston, TX, USA;
3University of Medicine and Dentistry of New Jersey, NJ, USA
Critical Care 2007, 11(Suppl 2):P16 (doi: 10.1186/cc5176) Introduction Excessive production of nitric oxide is a major factor
contributing to acute lung injury and systemic inflammation after S6 Available online http://ccforum.com/supplements/11/S2 burn and smoke inhalation injury. We hypothesized that the use of
7-nitroindazole (7-NI), a selective nNOS inhibitor, blocks molecular
mechanisms in this pathogenesis. Methods Eleven ewes were surgically instrumented and randomly
allocated to either an injured untreated control group (40% total
body surface area flame burn and 48 breaths of cotton smoke,
n = 6), or an injury group treated with 7-NI (1 mg/kg/hour, n = 5). Results This insult was associated with systemic inflammation and
oxidative stress, as evidenced by a 2.5-fold increase in plasma
nitrite/nitrate (NOx) levels, as well as sixfold, twofold, threefold and
twofold increases in IL-8, myeloperoxidase (MPO), malondialde-
hyde (MDA) and poly-ADP-ribose-polymerase (PARP) lung tissue
concentrations, respectively. These molecular changes were linked
to severe pulmonary derangements. Compared with untreated
controls, 7-NI significantly reduced NOx plasma levels (8.4 ± 1 vs
26 ± 10 µmol/l) and decreased IL-8, MPO (3.9 ± 0.2 vs
5.8 ± 0.7 U/g tissue), MDA (2.7 ± 0.3 vs 6.6 ± 1.1 nmol/mg
protein) and PARP lung tissue content (3.4 ± 0.7 vs 6.7 ± 0.7),
thereby
decreasing
pulmonary
obstruction
(12.4 ± 2.2
vs
28.7 ± 5.2 obstruction score) and increasing the PaO2/FiO2 ratio
(456 ± 40 vs 313 ± 56, each P < 0.05). P18 burn and smoke inhalation injury. We hypothesized that the use of
7-nitroindazole (7-NI), a selective nNOS inhibitor, blocks molecular
mechanisms in this pathogenesis. P18
Dose effects of recombinant human IL-11 on the systemic
hemodynamic function in hemorrhagic shock
K Honma1, N Koles2, H Alam2, P Rhee2, J Keith, Jr3, M Pollack2
1Shin-Koga Hospital, Kurume, Fukuoka, Japan; 2Uniformed
Services University of the Health Sciences, Bethesda, MD, USA;
3Wyeth Research, Andover, MA, USA
Critical Care 2007, 11(Suppl 2):P18 (doi: 10.1186/cc5178) Degradation of endothelial glycocalyx provides new insights
in the pathogenesis of septic shock microvascular failure P20
Exhaled breath condensate mediators in mechanically
ventilated brain-injured patients with no acute lung injury
are mostly related to markers of systemic inflammation
I Korovesi1, E Papadomichelakis2, O Livaditi1, E Giamarellos-
Bourboulis3, C Sotiropoulou1, A Koutsoukou4, I Dimopoulou2,
A Armaganidis2, C Roussos4, N Marczin5, A Kotanidou4,
S Orfanos2
1University of Athens, Greece; 2Attikon Hospital, 2nd Critical
Care Department, Haidari (Athens), Greece; 3Attikon Hospital,
4th Department of Medicine, Haidari (Athens), Greece;
4Evangelismos Hospital, Athens, Greece; 5Imperial College
London, UK
Critical Care 2007, 11(Suppl 2):P20 (doi: 10.1186/cc5180) pathologies. In this study we identified EBC inflammatory markers
in 27 mechanically ventilated brain-injured subjects with neither
acute lung injury (ALI) nor sepsis. apparent thickness evaluated using intravital microscopy by
comparing 4 and 150 kDa dextran distribution as markers of GLX
permeable and impermeable tracers, respectively. Intravital micro-
scopy was used to characterize mesentery functional capillary
density. Because glycocalyx is extremely sensitive to free radical,
oxidative stress was evaluated by oxidation of dihydrorhodamine
(DHR) in microvascular beds and by concentrations of heart
malondialdehyde (MDA) and plasma carbonyl proteins (CP). Methods Patients were ventilated with 8 ml/kg tidal volume and
were put either on PEEP = 0 (ZEEP, n = 12) or 8 cmH2O (PEEP,
n = 15). EBC was collected using the RTube device (Respiratory
Research Inc., Charlottesville, VA, US) on the first, third, and fifth
day of mechanical ventilation, and pH, IL-10, IL-1β, IL-6, IL-8,
IL-12p70 and TNFα were measured. Applying mixed effects
models, we further investigated potential relationships of the above
EBC markers with indices of: i, lung injury (LIS score, PaO2/FiO2,
detected pathologies on lung CT); ii, brain injury (ICP, CPP, GCS,
serum (s) S100 protein, pentothal and mannitol administration); iii,
endothelial injury (sICAM-1, sVCAM-1, von Willebrand factor
antigen); iv, systemic inflammation (temperature, leukocyte counts
and neutrophil counts in blood, albumin, soluble triggering receptor
expressed on myeloid cells (sTREM), CRP, procalcitonin (PCT)
and all above-mentioned cytokines in serum or plasma); and v,
disease severity (APACHE II score, 24 hour ICU trauma score,
presence of SIRS, mean arterial pressure). Results LPS elicited a 4 hours later profound reduction in GLX
layer thickness and increase in plasma hyaluronan levels. LPS rats
had decreases in capillary continuous flow, and significant increases
in intermittent and stopped flow capillaries compared with controls. The pressor responses to norepinephrine were greatly reduced,
indicative of vascular hyporeactivity. Degradation of endothelial glycocalyx provides new insights
in the pathogenesis of septic shock microvascular failure In vivo oxidation of DHR and
levels of heart MDA and plasma CP were all increased in LPS-
treated rats. Interestingly, in LPS rats, APC reduced plasma
hyaluronan levels and GLX destruction, which was accompanied
with major improvements in vasopressor response and functional
capillary density. APC treatment also prevented increases in
biochemical and in vivo microvascular oxidative stress markers. The pressor responses to norepinephrine were greatly reduced,
indicative of vascular hyporeactivity. In vivo oxidation of DHR and
levels of heart MDA and plasma CP were all increased in LPS-
treated rats. Interestingly, in LPS rats, APC reduced plasma
hyaluronan levels and GLX destruction, which was accompanied
with major improvements in vasopressor response and functional
capillary density. APC treatment also prevented increases in
biochemical and in vivo microvascular oxidative stress markers. Results No significant differences in EBC measurements were
observed between the two groups except a time-dependent
decrease in IL-10 (P < 0.05, by ANOVA) in the PEEP group. EBC pH
and IL-10 showed no significant relationships (mixed effects models)
with any parameter measured. All other EBC cytokines were inversely
related to sTREM levels. Additional significant relationships were
obtained between individual EBC cytokines and sIL-8 (IL-8, IL-12p70,
TNFα), sIL-6 (IL-1β), PCT (IL-1β, IL-12p70), the existence of SIRS (IL-
6, IL-8), sVCAM-1 (IL-6), and pentothal administration (IL-1β). Conclusion In our model of septic shock, increased plasma
hyluronan levels and reduction in endothelial layer thickness
indicated GLX degradation. APC prevented vascular oxidative
stress and limited GLX loss. GLX degradation plays a critical role
in the septic vasculature and generation of free radicals during
septic shock is potentially toxic to GLX function. P20 Exhaled breath condensate mediators in mechanically
ventilated brain-injured patients with no acute lung injury
are mostly related to markers of systemic inflammation Reduced local inflammatory reactivity in septic patients
compared with healthy controls Introduction Mechanical ventilation may induce lung injury in
patients with normal lungs. Application of PEEP appears protective. Lung injury is associated with the production and release of
inflammatory mediators. Such mediators have been identified in
patients’ exhaled breath condensate (EBC) in various lung Introduction The aim of this study was to access the local
inflammatory reactivity by measurement of the cytokine response Exhaled breath condensate mediators in mechanically
ventilated brain-injured patients with no acute lung injury
are mostly related to markers of systemic inflammation Conclusion In our population of mechanically ventilated, brain-
injured patients with no ALI, ZEEP or applied PEEP did not induce
detectable changes in most lung inflammatory mediators in EBC;
the latter appear mostly related to markers of systemic
inflammation (especially sTREM-1) rather than to indices of brain
and endothelial injury. I Korovesi1, E Papadomichelakis2, O Livaditi1, E Giamarellos-
Bourboulis3, C Sotiropoulou1, A Koutsoukou4, I Dimopoulou2,
A Armaganidis2, C Roussos4, N Marczin5, A Kotanidou4,
S Orfanos2
1University of Athens, Greece; 2Attikon Hospital, 2nd Critical
Care Department, Haidari (Athens), Greece; 3Attikon Hospital,
4th Department of Medicine, Haidari (Athens), Greece;
4Evangelismos Hospital, Athens, Greece; 5Imperial College
London, UK
Critical Care 2007, 11(Suppl 2):P20 (doi: 10.1186/cc5180) I Korovesi1, E Papadomichelakis2, O Livaditi1, E Giamarellos-
Bourboulis3, C Sotiropoulou1, A Koutsoukou4, I Dimopoulou2,
A Armaganidis2, C Roussos4, N Marczin5, A Kotanidou4,
S Orfanos2 P21 1University of Athens, Greece; 2Attikon Hospital, 2nd Critical
Care Department, Haidari (Athens), Greece; 3Attikon Hospital,
4th Department of Medicine, Haidari (Athens), Greece;
4Evangelismos Hospital, Athens, Greece; 5Imperial College
London, UK
Critical Care 2007, 11(Suppl 2):P20 (doi: 10.1186/cc5180) Degradation of endothelial glycocalyx provides new insights
in the pathogenesis of septic shock microvascular failure R Nevière1, R Favory2, X Marechal1
1School of Medicine, Lille, France; 2Calmette Hospital, Lille, France
Critical Care 2007, 11(Suppl 2):P19 (doi: 10.1186/cc5179) Introduction Glycocalyx (GLX) is implicated in mechanotrans-
duction of shear stress and microvascular blood flow. We tested
whether GLX loss accounts for the microvascular dysfunction in
sepsis and whether activated protein C (APC) preserves
endothelial GLX integrity. Introduction Glycocalyx (GLX) is implicated in mechanotrans-
duction of shear stress and microvascular blood flow. We tested
whether GLX loss accounts for the microvascular dysfunction in
sepsis and whether activated protein C (APC) preserves
endothelial GLX integrity. Methods Endotoxin LPS (10 mg/kg) was infused in rats treated or
not with APC (240 µg/kg/hour). Changes in GLX were assessed
by circulating levels of hyaluronan (a GLX constituent) and by GLX S7 Critical Care March 2007 Vol 11 Suppl 2
27th International Symposium on Intensive Care and Emergency Medicin apparent thickness evaluated using intravital microscopy b
comparing 4 and 150 kDa dextran distribution as markers of GLX
permeable and impermeable tracers, respectively. Intravital micro
scopy was used to characterize mesentery functional capillar
density. Because glycocalyx is extremely sensitive to free radica
oxidative stress was evaluated by oxidation of dihydrorhodamine
(DHR) in microvascular beds and by concentrations of hear
malondialdehyde (MDA) and plasma carbonyl proteins (CP). Results LPS elicited a 4 hours later profound reduction in GLX
layer thickness and increase in plasma hyaluronan levels. LPS rat
had decreases in capillary continuous flow, and significant increase
in intermittent and stopped flow capillaries compared with controls
The pressor responses to norepinephrine were greatly reduced
indicative of vascular hyporeactivity. In vivo oxidation of DHR and
levels of heart MDA and plasma CP were all increased in LPS
treated rats. Interestingly, in LPS rats, APC reduced plasm
hyaluronan levels and GLX destruction, which was accompanied
with major improvements in vasopressor response and functiona
capillary density. APC treatment also prevented increases i
biochemical and in vivo microvascular oxidative stress markers. Conclusion In our model of septic shock, increased plasm
hyluronan levels and reduction in endothelial layer thicknes
indicated GLX degradation. APC prevented vascular oxidative
stress and limited GLX loss. GLX degradation plays a critical role
in the septic vasculature and generation of free radicals during
septic shock is potentially toxic to GLX function. P22 The evaluation of sivelestat sodium hydrate in acute lung
injury/acute respiratory distress syndrome patients in the
intensive care unit
T Ikeda, K Ikeda, T Ueno, Y Kuroki, T Yokoyama, K Yoshikawa
Hachiouji Medical Center, Tokyo Medical University, Tokyo, Japan
Critical Care 2007, 11(Suppl 2):P22 (doi: 10.1186/cc5182) The evaluation of sivelestat sodium hydrate in acute lung
injury/acute respiratory distress syndrome patients in the
intensive care unit Methods Male BALB/c mice were divided into three groups. Group I served for sham burns. In groups II and III, a 15% BSA full-
thickness burn was made on the dorsum under ether anesthesia,
followed by adequate fluid resuscitation. After the burn injury,
3 mg/kg prednisolone (PSL) in group III was administered sub-
cutaneously daily for 10 days. On the 11th day, 10 mg/kg
lipopolysaccharide (LPS) was injected intravenously. In the first
experiment, we observed the survival within 72 hours after LPS
injection in each group (n = 10). In the second experiment, we
sacrificed the animals at 12 hours after LPS injection, then
obtained plasma and lung tissue to determine the levels of TNFα
and macrophage inflammatory protein-2 (MIP-2, a functional homo-
logue of human IL-8 in mice) in these samples (n = 8, sandwich
ELISA). We also determined gene expression (n = 4, MIP-
2/GAPDH mRNA ratio by RT-PCR), myeloperoxidase activities
(MPO, n = 8) and histopathological findings in the lung tissue. T Ikeda, K Ikeda, T Ueno, Y Kuroki, T Yokoyama, K Yoshikawa
Hachiouji Medical Center, Tokyo Medical University, Tokyo, Japan
Critical Care 2007, 11(Suppl 2):P22 (doi: 10.1186/cc5182) The onset mechanism of ALI/ARDS and subsequent tissue injury
are considered to be associated with neutrophil elastase, and the
main causes of ALI/ARDS are considered to be sepsis or aspiration
pneumonia. In Japan, sivelestat sodium hydrate (Elaspol), a
selective elastase inhibitor, was approved in 2002 for ALI/ARDS
accompanied by SIRS, and this medicine has been evaluated in a
clinical situation. Figure 1 (abstract P21) Figure 1 (abstract P21) Figure 1 (abstract P21) S8 Available online http://ccforum.com/supplements/11/S2 Available online http://ccforum.com/supplements/11/S2 Elaspol: 75%, Group Control: 52%; P < 0.001). These results
suggest that sivelestat sodium hydrate is a good option as a
treatment strategy for neutrophil elastase-associated septic
ALI/ARDS accompanied by SIRS. after catheter insertion into subcutaneous adipose tissue (SAT) of
patients with severe sepsis compared with healthy volunteers. Elaspol: 75%, Group Control: 52%; P < 0.001). These results
suggest that sivelestat sodium hydrate is a good option as a
treatment strategy for neutrophil elastase-associated septic
ALI/ARDS accompanied by SIRS. after catheter insertion into subcutaneous adipose tissue (SAT) of
patients with severe sepsis compared with healthy volunteers. Methods Eight healthy volunteers and 10 patients with severe
sepsis were included. One 18-gauge open-flow microperfusion
double-lumen catheter was inserted into SAT of the abdominal wall
and perfused with an isotonic solution at a flow rate of 1 µl/min. Blood samples and probe effluent samples from interstitial fluid of
SAT were withdrawn in two hourly intervals for a period of 8 hours
and retrospectively analysed using a Multiplex ELISA system for
IL-1β, IL-6, IL-8 and TNFα. Methods Eight healthy volunteers and 10 patients with severe
sepsis were included. One 18-gauge open-flow microperfusion
double-lumen catheter was inserted into SAT of the abdominal wall
and perfused with an isotonic solution at a flow rate of 1 µl/min. Blood samples and probe effluent samples from interstitial fluid of
SAT were withdrawn in two hourly intervals for a period of 8 hours
and retrospectively analysed using a Multiplex ELISA system for
IL-1β, IL-6, IL-8 and TNFα. P23 Pharmacological modulation with prolonged
administration of moderate doses of steroid in a murine
model of septic acute lung injury after burn insult
J Sasaki1, S Fujishima2, K Takuma1, Y Shinozawa1, N Aikawa2
1Tohoku University Hospital, Sendai, Japan;
2Keio University, Tokyo, Japan
Critical Care 2007, 11(Suppl 2):P23 (doi: 10.1186/cc5183) Results Concentrations of IL-1β, IL-6 and IL-8 were substantially
higher in SAT (13.3 (11.2; 31.0); 1,934 (1,650; 2,730); 917 (656;
2,672) pg/ml; median (25th; 75th percentile)) than in serum (0.8
(0.6; 1.3); 49.2 (3.8; 67.6); 36.1 (6.3; 89.1) pg/ml) for both
groups, whereas TNFα concentrations were similar in serum and
SAT (Figure 1). Serum concentrations of all cytokines remained
stable over time. However, a significant increase was observed for
IL-1β and IL-8 in SAT in both groups. This increase was
significantly in septic patients vs healthy controls. ritical Care 2007, 11(Suppl 2):P23 (doi: 10.1186/cc518 Introduction
Many patients who experience surgical stress
including burn injury become susceptible to severe sepsis and
septic organ dysfunction including acute lung injury (ALI), which
remains the primary contributor to morbidity and mortality in burn
patients. Proinflammatory cytokines including several chemokines
are implicated in this process. The pharmacological modulation
with steroid inhibiting the process of cytokine synthesis may serve
as effective therapy for the prevention of tissue injury and the
resultant organ dysfunction including respiratory failure. We
developed a murine model of septic ALI after burn insult and
examined the effects of prolonged administration of moderate
doses of steroid. Introduction
Many patients who experience surgical stress
including burn injury become susceptible to severe sepsis and
septic organ dysfunction including acute lung injury (ALI), which
remains the primary contributor to morbidity and mortality in burn
patients. Proinflammatory cytokines including several chemokines
are implicated in this process. The pharmacological modulation
with steroid inhibiting the process of cytokine synthesis may serve
as effective therapy for the prevention of tissue injury and the
resultant organ dysfunction including respiratory failure. We
developed a murine model of septic ALI after burn insult and
examined the effects of prolonged administration of moderate
doses of steroid. Conclusion Insertion of a catheter into subcutaneous adipose
tissue promotes a local inflammatory response in both healthy
individuals and critically ill patients. The attenuated response in
patients with severe sepsis might be caused by reduced
inflammatory reactivity in this group. P22 In this study, we performed a retrospective
comparison of the sivelestat sodium administration between two
groups of patients: Group Elaspol, consisting of 308 patients(209
males and 99 females, aged 66 ± 15 years) with ALI/ARDS
accompanied by SIRS who were treated with sivelestat sodium at
a dose of 0.2 mg/kg/hour for 72 hours or more, after approval of
this drug; and Group Control, consisting of 41 patients (28 males
and 13 females, aged 66 ± 14 years) with ALI/ARDS accompanied
by SIRS who were treated in the ICU under similar conditions, but
using traditional methods for respiratory control, prior to approval
sivelestat sodium. The APACHE II scores of Group Elaspol and
Group Control were 23 ± 9 and 23 ± 8, SOFA scores were
8.7 ± 3.8 and 8.9 ± 4.1, and the lung injury scores were 2.1 ± 0.7
and 2.1 ± 0.6, respectively, with no significant differences between
the groups. The initial PEEP value of Group Elaspol was 5.9 ± 3.3,
which was significantly higher than that of Group Control
(3.4 ± 2.7 cmH2O). The PaO2/FIO2
ratios under mechanical
ventilation management 24, 48 and 72 hours after the beginning of
drug administration were 209 ± 87, 222 ± 92, and 222 ± 82 mmHg
in
Group
Elaspol,
and
were
191 ± 91,
207 ± 91,
and
211 ± 100 mmHg in Group Control. The ventilator-free days of
Group Elaspol and Group Control were 18 ± 9 and 10 ± 12 days,
respectively, and these values showed a significant difference
(P < 0.001). Furthermore, the survival rate after 28 days was
significantly higher in Group Elaspol than in Group Control (Group Results The survival and production of cytokines are shown in Table
1. Histopathological findings in group III were obviously attenuated. Table 1 (abstract P23)
Lung
MIP-2/
Plasma
Plasma
Lung
GAPDH
Lung
Survival
TNF
MIP-2
MIP-2
mRNA
MPO
Group
(%)
(pg/ml)
(pg/ml) (pg/mg)
ratio
(U/mg)
I (sham–LPS)
100
1,190
6,396
70.0
0.345
0.405
II (burn–LPS)
0†
3,024** 13,766** 142.5**
0.975‡
0.574**
III (PSL)
50*
749§
791§
11.6§
0.052§
0.244§
Mean values are presented. *P < 0.05 vs group II, **P < 0.005 vs group I,
†P < 0.01 vs group I, ‡P < 0.05 vs group I, §P < 0.005 vs group II. Conclusions In this animal model, a pretreatment with PSL as the
cytokine synthesis inhibitor improved the survival and attenuated
the production of cytokines. Glucosamine enhances heat shock protein 70 expression
in vitro and in vivo following injury P25
Pharmacologic inhibition of cholinesterase improves
survival in experimental sepsis
S Hofer, C Eisenbach, I Lukic, L Schneider, E Martin,
M Büchler, A Bierhaus, M Weigand
University of Heidelberg, Germany
Critical Care 2007, 11(Suppl 2):P25 (doi: 10.1186/cc5185)
Introduction Lethal sepsis occurs if an excessive inflammatory
Figure 1 (abstract 24)
Lung heat shock protein (HSP70) expression in glucosamine vs saline
following cecal ligation and puncture. K Singleton, C Hamiel, P Wischmeyer
University of Colorado Health Sciences Center, Denver, CO, USA
Critical Care 2007, 11(Suppl 2):P24 (doi: 10.1186/cc5184) Methods To investigate the therapeutic effect of nicotine and
physostigmine we performed cecal ligation and puncture (CLP) in
female C57/B6 mice (each group n = 21). Substances were
administered by intraperitoneal injection. Control groups received
the same volume (50–180 µl) of LPS-free 0.9% NaCl (solvent). CLP was performed blinded to the identity of the treatment group. In addition to survival experiments we performed measurements of
cytokines in plasma and the electrophoretic mobility shift assay
(EMSA) for NF-κB in peritoneal skin, liver and kidneys. Introduction Enhanced activity of the O-glycosylation pathway (O-
glcNAc) has been shown to enhance increase heat shock protein
(HSP70) expression. Glucosamine (GA) is a vital intermediate in
this pathway. Methods Mouse fibroblast (MEF) cells underwent heat stress (HS)
at 43°C for 45 minutes. GA doses from 1.25 to 20 mM were given
immediately prior to HS. Cell survival was assessed via MTS assay. GA’s effect on HSP70 expression in vivo was assessed using a
mouse model of cecal ligation and puncture (CLP). Mice were
given 0.26 g/kg GA i.v. 1 hour post CLP. Results
(1) Animals treated with nicotine (400 µg/kg) or
physostigmine (80 µg/kg) survived significantly better than control
mice (P < 0.05). There was no difference between the treatment
groups. (2) Dose escalation of physostigmine was not superior to
the normal dose. Survival in the high-dose group, however, was still
significantly better than in the control group. (3) Proinflammatory
cytokine levels of TNFα, IL-6 and IL-1β were significantly reduced
in animals treated with physostigmine (P < 0.01). (4) Cholin-
esterase inhibition with physostigmine in CLP reduced NF-κB
activation in the peritoneum, kidney and liver compared with the
control and sham-operated group (P < 0.01). Results In MEF cells, 10 mM GA led to a 164% increase in HSP70
expression over control 4 hours post HS (P < 0.05 vs control). Glucosamine enhances heat shock protein 70 expression
in vitro and in vivo following injury Further, GA treatment led to an increase in cell survival post HS
injury at all doses tested (P < 0.01 vs control). Following CLP-
induced sepsis, a single dose of GA led to an increase in lung and
heart HSP70 at 1 and 2 hours post CLP vs saline control (SC). This
effect was lost at 6 and 24 hours (see Figure 1, *P < 0.05 versus
SC at each timepoint). Similarly, GA led to an increase in HSP70 in
colon tissue as well, with the effect lasting to 6 hours (*P < 0.05
versus SC). The effect in colon was lost by 24 hours. Conclusion
We show that pharmacological cholinesterase
inhibition with physostigmine improves survival in experimental
sepsis, most probably by activation of the cholinergic anti-inflam-
matory pathway. One possible mechanism is modulation of the NF-
κB pathway. Therefore, cholinesterase inhibition may have
important implications for treatment of sepsis. Conclusions To our knowledge, this is the first report that shows
GA treatment can increase HSP70 expression both in vivo and in
vitro. Previous data have demonstrated beneficial effects of GA
treatment following ischemia/reperfusion injury and hemorrhagic
shock early after injury. GA’s effect on HSP70 expression in
multiple tissues may help to explain these effects. Further, GA’s
effect on HSP70 expression may be an important factor involved in
GA’s benefits in arthritis and joint disease. P24 P24 inflammatory mechanisms. Vagus nerve stimulation showed improved
survival in sepsis; however, this seems not to be feasible in septic
patients. We therefore investigated the effect of activation of the
cholinergic anti-inflammatory pathway by pharmacologic cholin-
esterase inhibition on survival and inflammation in a septic mouse
model. P24
Glucosamine enhances heat shock protein 70 expression
in vitro and in vivo following injury
K Singleton, C Hamiel, P Wischmeyer
University of Colorado Health Sciences Center, Denver, CO, USA
Critical Care 2007, 11(Suppl 2):P24 (doi: 10.1186/cc5184) Glucosamine enhances heat shock protein 70 expression
in vitro and in vivo following injury P22 The complications associated with
sepsis after burn insults, especially ALI, could be preventable by
the pharmacological modulation with prolonged administration of
moderate doses of steroid. S9 Critical Care March 2007 Vol 11 Suppl 2
27th International Symposium on Intensive Care and Emergency Medicin Glucosamine enhances heat shock protein 70 expression
in vitro and in vivo following injury Glucosamine enhances heat shock protein 70 expression
in vitro and in vivo following injury in vitro and in vivo following injury
K Singleton, C Hamiel, P Wischmeyer
University of Colorado Health Sciences Center, Denver, CO, USA
Critical Care 2007, 11(Suppl 2):P24 (doi: 10.1186/cc5184)
Introduction Enhanced activity of the O-glycosylation pathway (O-
glcNAc) has been shown to enhance increase heat shock protein
(HSP70) expression. Glucosamine (GA) is a vital intermediate in
this pathway. Methods Mouse fibroblast (MEF) cells underwent heat stress (HS)
at 43°C for 45 minutes. GA doses from 1.25 to 20 mM were given
immediately prior to HS. Cell survival was assessed via MTS assay. GA’s effect on HSP70 expression in vivo was assessed using a
mouse model of cecal ligation and puncture (CLP). Mice were
given 0.26 g/kg GA i.v. 1 hour post CLP. Results In MEF cells, 10 mM GA led to a 164% increase in HSP70
expression over control 4 hours post HS (P < 0.05 vs control). Further, GA treatment led to an increase in cell survival post HS
injury at all doses tested (P < 0.01 vs control). Following CLP-
induced sepsis, a single dose of GA led to an increase in lung and
heart HSP70 at 1 and 2 hours post CLP vs saline control (SC). This
effect was lost at 6 and 24 hours (see Figure 1, *P < 0.05 versus
SC at each timepoint). Similarly, GA led to an increase in HSP70 in
colon tissue as well, with the effect lasting to 6 hours (*P < 0.05
versus SC). The effect in colon was lost by 24 hours. Conclusions To our knowledge, this is the first report that shows
GA treatment can increase HSP70 expression both in vivo and in
vitro. Previous data have demonstrated beneficial effects of GA
treatment following ischemia/reperfusion injury and hemorrhagic
shock early after injury. GA’s effect on HSP70 expression in
multiple tissues may help to explain these effects. Further, GA’s
effect on HSP70 expression may be an important factor involved in
GA’s benefits in arthritis and joint disease. Figure 1 (abstract 24) P25
Pharmacologic inhibition of cholinesterase improves
survival in experimental sepsis
S Hofer, C Eisenbach, I Lukic, L Schneider, E Martin,
M Büchler, A Bierhaus, M Weigand
University of Heidelberg, Germany
Critical Care 2007, 11(Suppl 2):P25 (doi: 10.1186/cc5185) P25
Pharmacologic inhibition of cholinesterase improves
survival in experimental sepsis
S Hofer, C Eisenbach, I Lukic, L Schneider, E Martin,
M Büchler, A Bierhaus, M Weigand
University of Heidelberg, Germany
Critical Care 2007, 11(Suppl 2):P25 (doi: 10.1186/cc5185) P25
Pharmacologic inhibition of cholinesterase improves
survival in experimental sepsis
S Hofer, C Eisenbach, I Lukic, L Schneider, E Martin,
M Büchler, A Bierhaus, M Weigand
University of Heidelberg, Germany
Critical Care 2007, 11(Suppl 2):P25 (doi: 10.1186/cc5185) Figure 1 (abstract 24) Y Sakamoto1, K Mashiko1, H Matsumoto1, Y Hara1,
Y Yamamoto2
1Chiba Hokusou Hospital, Nippon Medical School, Chiba, Japan;
2Department of Emergency Medicine, Nippon Medical School,
Tokyo, Japan
Critical Care 2007, 11(Suppl 2):P26 (doi: 10.1186/cc5186) Introduction High-mobility-group box protein 1 (HMGB1) is a
highly conserved, ubiquitous protein present in the nuclei and
cytoplasm of nearly all cell types and, secreted into the extracellular
milieu, acts as a proinflammatory cytokine. The function of HMGB1
has been widely studied for sepsis and inflammation. HMGB1 was
reported as a late mediator in endotoxic shock and was known as
an abundant protein present in nuclei and cytoplasm and involved
in maintaining nucleosome structure and regulation of gene
transcription. Moreover, elevated, circulating levels of HMGB1 also
have been described in a case of human hemorrhagic shock due to
abdominal aortic aneurysm without evidence of infection. However,
the relationship between HMGB1 and trauma has not been
studied except for the report of a rat model of burn. Materials and methods The study cases consisted of 20 trauma
patients who were admitted to the emergency room by ambulance. As soon as they arrived in the emergency room, their blood sample
were collected, centrifuged, and stored at –80°C. The serum
HMGB1 concentration was measured by ELISA. We compared
the injury severity score (ISS), probability of survival values and the
revised trauma score (RTS) of the patients with the presence of Introduction High-mobility-group box protein 1 (HMGB1) is a
highly conserved, ubiquitous protein present in the nuclei and
cytoplasm of nearly all cell types and, secreted into the extracellular
milieu, acts as a proinflammatory cytokine. The function of HMGB1
has been widely studied for sepsis and inflammation. HMGB1 was
reported as a late mediator in endotoxic shock and was known as
an abundant protein present in nuclei and cytoplasm and involved
in maintaining nucleosome structure and regulation of gene
transcription. Moreover, elevated, circulating levels of HMGB1 also
have been described in a case of human hemorrhagic shock due to
abdominal aortic aneurysm without evidence of infection. However,
the relationship between HMGB1 and trauma has not been
studied except for the report of a rat model of burn. P26 Relationship between the presence of serum high-
mobility-group box protein 1 and the injury severity score
in trauma patients GA s benefits in arthritis and joint disease. P25
Pharmacologic inhibition of cholinesterase improves
survival in experimental sepsis
S Hofer, C Eisenbach, I Lukic, L Schneider, E Martin,
M Büchler, A Bierhaus, M Weigand
University of Heidelberg, Germany
Critical Care 2007, 11(Suppl 2):P25 (doi: 10.1186/cc5185)
Introduction Lethal sepsis occurs if an excessive inflammatory
Figure 1 (abstract 24)
Lung heat shock protein (HSP70) expression in glucosamine vs saline
following cecal ligation and puncture. Figure 1 (abstract 24) Aggressive and moderate fluid resuscitation in septic pigs:
consequences on morbidity S Brandt, A Elftheriadis, T Regueira, H Bracht, J Gorrasi,
J Takala, S Jakob
University Hospital Inselspital, Bern, Switzerland
Critical Care 2007, 11(Suppl 2):P28 (doi: 10.1186/cc5188) Results Our data showed that the number in group A was nine
cases and group B was 11 cases. The ISS of group A was
significantly higher than that in group B (P = 0.0013). The P value
of group A was significantly lower than in group B (P = 0.0131). The serum HMGB1 level of the >25 ISS group was significantly
higher than in the ≤25 ISS group. Introduction While early aggressive fluid administration has been
associated with improved outcome in sepsis [1], this approach
may increase the risk of lung edema and abdominal compartment
syndrome when capillary permeability is increased. The aim of this
study was to test two different approaches of volume resuscitation
in septic animals. Discussion These data suggest that HMGB1 seems to be a
primary mediator of trauma-induced pathology. Because the ISS
was significantly correlated with the presence of serum HMGB1,
HMGB1 may be expressed in severe injuries and it may be a
important parameter that indicates the severity of injury. Methods Thirty pigs were anaesthetized and invasively monitored
(systemic and regional flows and pressures). They were
randomized to control, moderate volume (C; n = 7), control, high
volume (CH; n = 8), peritonitis, moderate volume (P; n = 8) and
peritonitis, high volume (PH; n = 7). Peritonitis was induced by
instillation of 1 g/kg autologous faeces dissolved in glucose
solution. Ventilation was adjusted to maintain an arterial pO2
>100 mmHg. Groups CH and PH received 15 ml/kg/hour Ringer’s
solution plus 5 ml/kg/hour HES 6%, whereas groups C and P
received 10 ml/kg/hour Ringer’s solution. If clinical signs of
hypovolaemia were present, additional boluses of HES 6%
(maximally 100 ml/hour) were given. The animals were treated and
observed for 24 hours or until death. P25 S Hofer, C Eisenbach, I Lukic, L Schneider, E Martin,
M Büchler, A Bierhaus, M Weigand
University of Heidelberg, Germany
Critical Care 2007, 11(Suppl 2):P25 (doi: 10.1186/cc5185) Materials and methods The study cases consisted of 20 trauma
patients who were admitted to the emergency room by ambulance. As soon as they arrived in the emergency room, their blood sample
were collected, centrifuged, and stored at –80°C. The serum
HMGB1 concentration was measured by ELISA. We compared
the injury severity score (ISS), probability of survival values and the
revised trauma score (RTS) of the patients with the presence of Introduction Lethal sepsis occurs if an excessive inflammatory
response evolves that cannot be controlled by physiological anti- S10 Available online http://ccforum.com/supplements/11/S2 P28 serum HMGB1 (group A) and without the presence (group B). We
therefore divided into two groups, high ISS group (≤25) and low
ISS group (>25), and examined the relation with the serum
HMGB1 level. Aggressive and moderate fluid resuscitation in septic pigs:
consequences on morbidity P27 Beneficial effects of antiplatelet drugs in patients with
community-acquired pneumonia and in endotoxin shock in
mice J Winning1, J Baranyai1, R Claus1, I Eisenhut2, J Hamacher2,
K Reinhart1, M Bauer1, W Lösche1
1University Hospital Jena, Germany; 2University Hospital Homburg,
Germany
Critical Care 2007, 11(Suppl 2):P27 (doi: 10.1186/cc5187) Results Cardiac output was higher in group PH as compared with
the other groups (P < 0.05), while mean arterial pressure was Aims Systemic inflammation and sepsis are associated with blood
platelet activation, which may contribute to the development of
organ failure. In this study we proved whether antiplatelet drugs
have a benefit in patients who may develop sepsis as well as in a
mouse model of endotoxin shock. Figure 1 (abstract P28) Oxygenation index. Figure 2 (abstract P28)
Survival proportion. Oxygenation index. Methods Data obtained from 224 patients with community-
acquired pneumonia (CAP) were retrospectively analysed for an
association between prehospital treatment with long-acting
antiplatelet drugs such as acetyl salicylic acid (n = 36) or
thienopyridine ADP-receptor antagonists (clopidogrel or ticlopidin,
n = 8) and clinical outcome. Use of statins was an exclusion
criterion. BALB/c mice were pretreated with clopidogrel for 4 days
prior to an intraperitoneal injection of LPS (Escherichia coli
0111:B4). For platelet counts and blood gas analysis, standard
procedures were used. Lung tissues were stained with HE or a
FITC-labelled anti-fibrin(ogen) antibody. Results CAP patients with antiplatelet drugs (n = 44) were older
than control patients (n = 180; 69 ± 7 vs 58 ± 13 years,
P < 0.00001). At the day of hospital admission there were no
differences in platelet or leukocyte counts, CRP and SOFA scores
between both groups. However, patients on antiplatelet drugs
developed organ failure less frequently than control patients (ICU
admission: 9.1% vs 26.1%; P < 0.02). In the mouse model of
endotoxin shock, clopidogrel reduced the drop in platelet count
and the degree of lung injury. Compared with controls we found
20 hours after LPS injection in the clopidogrel-treated animals a
lower number of thrombi in the lung vasculature (6.1 ± 2.3 vs
11.5 ± 4.4 thrombi per screen, P < 0.025) as well as higher blood
pH and bicarbonate levels (7.01 ± 0.01 vs 6.93 ± 0.04, P < 0.04
and 10.2 ± 0.14 vs 7.3 ± 0.14 mmol/l, P < 0.03, respectively). P29 Effects of volume resuscitation on hepatosplanchnic
oxygen consumption, liver mitochondrial function and
mortality in endotoxemia Multiple studies have stressed the importance of the contribution
of activated complement to the pathology of reperfusion injury after
tissue ischemia. Using intravital microscopy, this study explores
functional consequences of the inhibition of the classical pathway
of complement activation with C1-esterase inhibitor (C1-INH) in
the context of superior mesenteric artery occlusion (SMAO)/
reperfusion. T Regueira1, E Borotto1, S Brandt2, H Bracht1, J Gorrasi1,
P Lepper1, J Takala1, S Jakob1
1Intensive Care Medicine and 2Department of Anesthesiology,
University Hospital, Bern, Switzerland
Critical Care 2007, 11(Suppl 2):P29 (doi: 10.1186/cc5189) Thirty anesthetized, spontaneously breathing, male Sprague–
Dawley rats underwent SMAO for 60 minutes followed by
reperfusion (4 hours). C1-esterase inhibitor (100 IU/kg, 200 IU/kg
body weight) or saline (0.9%) was given as a single bolus before
reperfusion. Sham-operated animals (n = 10) without SMAO served
as controls. Systemic hemodynamics were monitored continuously,
arterial blood gases analyzed intermittently, and leukocyte/
endothelial
interactions
in
the
mesenteric
microcirculation
quantified at intervals using intravital microscopy. Ileal lipid-binding
protein (I-LBP) levels were measured from serum samples with an
ELISA at the end of the experiments. Introduction Fluid resuscitation is necessary in sepsis, but positive
fluid balance may increase the risk of mortality. We tested the
hypothesis that a volume resuscitation strategy may modify liver
mitochondrial function and outcome. Methods Twenty-nine anesthetized pigs received for 24 hours
either endotoxin or placebo, and either Ringer’s lactate 10 ml/kg/hour
or 15 ml/kg/hour + 5 ml/hour HES. Systemic and regional hemo-
dynamics were measured. Liver mitochondrial state 3 and state 4
oxygen consumption were determined. Results Hepatosplanchnic oxygen delivery was similar in endotoxic
pigs with high (2.97 ± 1.58 ml/min/kg) vs moderate volume
administration (3.06 ± 0.6 ml/min/kg), but hepatosplanchnic VO2
was lower in animals with high (1.32 ± 0.4 ml/min/kg) vs moderate
volume administration (1.75 ± 0.3 ml/min/kg, P = 0.019). Endotoxin
high-volume pigs exhibited a decrease in state 3 respiration for
complex I and complex II (not significant) in comparison with
control high-volume and with endotoxin low-volume pigs (Figure 1). They also had an increased mortality rate during the 24-hour study
period (60% vs 0% in controls). C1-INH restored microcirculatory perfusion of postcapillary venules
to baseline levels in a dose-dependent manner and reduced
leukocyte adhesion following SMAO/reperfusion to similar levels in
both C1-INH-treated groups during reperfusion. P29 Furthermore, C1-
INH treatment efficiently prevented metabolic acidosis, and
reduced the need for intravenous fluids to support blood pressure. Furthermore, I-LBP levels decreased in a dose-dependent manner,
and were comparable with the levels of sham-operated animals at
the end of the experiments. Survival rates were 100% in controls
and after 200 IU/kg C1-INH, 90% after 100 IU/kg C1-INH, and
30% in saline-treated animals. Conclusion A prolonged high-volume resuscitation approach
during endotoxemia may be associated with impaired hepato-
splanchnic oxygen consumption, liver mitochondrial dysfunction In the setting of mesenteric ischemia, C1-INH given as a bolus
infusion shortly before reperfusion efficiently restored microcirculatory
perfusion in a dose-dependent manner, reduced local and systemic
inflammatory response, and improved outcome. I-LBP levels
correlated well with the functional consequences of mesenteric
ischemia/reperfusion and treatment at the end of the experiments. Effect of C1-esterase inhibitor treatment on
microcirculatory perfusion after superior mesenteric artery
ischemia Effect of C1-esterase inhibitor treatment on
microcirculatory perfusion after superior mesenteric artery
ischemia M Lauterbach, G Horstick, N Plum, J Lotz, E Lauterbach,
L Weilemann, O Kempski
University Hospital Mainz, Germany
Critical Care 2007, 11(Suppl 2):P30 (doi: 10.1186/cc5190) 1. Rivers E, et al.: N Engl J Med 2001, 345:1368-1377. Figure 2 (abstract P28) S
Figure 2 (abstract P28)
Survival proportion. Conclusions Antiplatelet drugs may have a beneficial effect in
systemic inflammation and sepsis, and could be a novel therapy
option, at least in patients of low bleeding risk. One mechanism of
their effects could be a reduction in the microvascular thrombus
formation. Conclusions Antiplatelet drugs may have a beneficial effect in
systemic inflammation and sepsis, and could be a novel therapy
option, at least in patients of low bleeding risk. One mechanism of
their effects could be a reduction in the microvascular thrombus
formation. Survival proportion. S11 cal Care March 2007 Vol 11 Suppl 2
27th International Symposium on Intensive Care and Emergency Medicine and high mortality. The impact of aggressive and prolonged volume
administration on hepatosplanchnic oxygenation and mitochondrial
function in human sepsis should be determined. similar in all groups. While the oxygenation index (paO2/FiO2)
decreased in all groups, group PH had the lowest values after 6 hours
and throughout the rest of the experiments (P < 0.05) (Figure 1). Survival was lowest in group PH, followed by group P, while all
animals in the control groups survived until 24 hours (Figure 2). Conclusion High-volume administration decreased oxygenation
and survival in peritonitis but not in control animals. A high-volume
approach may not be generally beneficial in abdominal sepsis. Reference
1
Rivers E et al : N Engl J Med 2001 345:1368-1377 Figure 1 (abstract P29) 12
inflammatory response, and improved outcome. I-LBP levels
correlated well with the functional consequences of mesenteric
ischemia/reperfusion and treatment at the end of the experiments. P31
Dobutamine protects lymphocyctes against staurosporin-
induced apoptosis via a receptor-independent and p38-
independent pathway
F Jans1, T Piegeler2, R De Jongh1, R Heylen1, T Loop2,
M Roesslein2
1Ziekenhuis Oost-Limburg, Genk, Belgium; 2University Hospital,
Freiburg, Germany
Critical Care 2007, 11(Suppl 2):P31 (doi: 10.1186/cc5191)
Introduction Since catecholamines have been shown to modulate
various immunological functions, the goal of this work was to
investigate their effects on staurosporin-induced apoptosis of
Jurkat T cells, a well-established model for human T lymphocytes. Figure 1 (abstract P29) P30 Conclusion High-volume administration decreased oxygenation
and survival in peritonitis but not in control animals. A high-volume
approach may not be generally beneficial in abdominal sepsis. Reference Serum vasopressin concentrations in critically ill patients
in the intensive care unit A Melissaki, A Efthymiou, T Kyriakopoulou, G Kribeni,
E Evaggelaki, A Tsikali, D Andreopoulos, A Zaglis, N Baziotis
Saint Savvas General Hospital, Athens, Greece
Critical Care 2007, 11(Suppl 2):P32 (doi: 10.1186/cc5192) Introduction The aim of the study is the measurement of serum
vasopressin concentrations in the mixed critically ill patients,
24 hours after admission to the ICU and just before the discharge. Methods In this study there were included patients admitted to the
ICU from June until November 2006 (n = 22; 12 males, 10
females), mean age 46.45 ± 22.03, APACHE II score 8.59 ± 4.76,
length of stay 9.68 ± 6.52. Patients with central nervous system
failure, neurosurgical patients and patients remaining in the ICU for
no longer than 72 hours were excluded. Serum vasopressin
concentrations were measured 24 hours after their admission to
the ICU and just before their discharge. The control group was 20
healthy volunteers (blood donors). Vasopressin was measured by
the radioimmunoassay method in pmol/l. The sensitivity of the
method is 0.5 pmol/l and the specificity is 100%. The statistical
analysis was done with the t test. Conclusions In catecholamine-dependent human septic shock,
terlipressin (with and without concomitant dobutamine) stabilizes
hemodynamics
and
reduces
norepinephrine
requirements. Dobutamine is a useful inotropic agent to reverse the depression in
global oxygen transport resulting from sole terlipressin infusion
without obvious side effects. Dobutamine protects lymphocyctes against staurosporin-
induced apoptosis via a receptor-independent and p38-
independent pathway F Jans1, T Piegeler2, R De Jongh1, R Heylen1, T Loop2,
M Roesslein2
1Ziekenhuis Oost-Limburg, Genk, Belgium; 2University Hospital,
Freiburg, Germany
Critical Care 2007, 11(Suppl 2):P31 (doi: 10.1186/cc5191) Introduction Since catecholamines have been shown to modulate
various immunological functions, the goal of this work was to
investigate their effects on staurosporin-induced apoptosis of
Jurkat T cells, a well-established model for human T lymphocytes. Introduction Since catecholamines have been shown to modulate
various immunological functions, the goal of this work was to
investigate their effects on staurosporin-induced apoptosis of
Jurkat T cells, a well-established model for human T lymphocytes. S12 Available online http://ccforum.com/supplements/11/S2 Available online http://ccforum.com/supplements/11/S2 Methods Jurkat T cells passages 1–12 were used. Apoptosis was
measured with a caspase-activity assay and with FACS analysis of
annexin–propidium iodide double-stained cells. than the value on admission and it approaches the value of
vasopressin in healthy volunteers. To confirm these results, more
studies will be needed. than the value on admission and it approaches the value of
vasopressin in healthy volunteers. To confirm these results, more
studies will be needed. p
p
Results Exposure of Jurkat T cells for 2 hours to staurosporin
(2 µM) induced apoptosis: the number of apoptotic cells increased
to 14.0 ± 0.8% versus 2.3 ± 0.4% in the control group. Pre-
treatment (4 hours) with dobutamine 100 and 500 µM decreased
the staurosporin-induced apoptosis to 11.6 ± 0.6% and 8.7 ± 0.7%,
respectively (P < 0.01, mean ± SEM, n = 44). Other catechol-
amines like epinephrine and norepinephrine (both up to 500 µM)
had no effect on staurosporin-induced apoptosis. To investigate
whether this protective effect of dobutamine was mediated via β-
receptors, specific β-blockers were used: neither atenolol (β1)
(100 mM), nor ICI 118,551 (β2) (10 mM) blocked the protective
effect of dobutamine. Furthermore, dobutamine (1–500 µM) did
not increase cAMP production in these cells. Therefore, the
protective effect of dobutamine is not β-receptor-mediated. Since it
was previously demonstrated that MAPKs p38 and JNK, but not
ERK, are activated by dobutamine in Jurkat T cells, we investigated
whether the activation of these MAPKs are involved in the
protection by dobutamine: inhibition of JNK activation with SP
600125 (1 µM) did not influence the protective effect of dobuta-
mine. Inhibition of p38 activation with SBI 202190 (5 µM) even
seemed to reinforce the protection afforded by dobutamine. Effects of simultaneously infused terlipressin and
dobutamine in septic shock Effects of simultaneously infused terlipressin and
dobutamine in septic shock A Morelli1, C Ertmer2, M Lange2, K Broeking2, A Orecchioni1,
M Rocco1, H Van Aken2, P Pietropaoli1, M Westphal2
1University of Rome ‘La Sapienza’, Rome, Italy; 2University Hospital
of Muenster, Germany
Critical Care 2007, 11(Suppl 2):P33 (doi: 10.1186/cc5193) Introduction Terlipressin is increasingly used in the treatment of
sepsis-associated hypotension. However, terlipressin may reduce
cardiac output and global oxygen supply. Introduction Terlipressin is increasingly used in the treatment of
sepsis-associated hypotension. However, terlipressin may reduce
cardiac output and global oxygen supply. Methods We performed a prospective, randomized, controlled
clinical study to determine whether dobutamine may counter-
balance the depressions in cardiac index and mixed-venous oxygen
saturation resulting from sole terlipressin infusion. We enrolled 60
septic shock patients requiring high doses of norepinephrine
(0.9 µg/kg/min) to maintain mean arterial pressure at 70 ± 5 mmHg. Patients were randomly allocated to be treated either with (a) 1 mg
terlipressin, (b) 1 mg terlipressin followed by incremental dobuta-
mine doses to reverse the anticipated reductions in mixed-venous
oxygen saturation, or (c) sole norepinephrine infusion (control;
each n = 20). Conclusions These experiments demonstrate that dobutamine
pretreatment protects T cells from staurosporin-induced apoptosis. This protective effect is not β-receptor-mediated. Also, activation of
MAPKs p38 or JNK by dobutamine is not responsible for the
protective effect. The molecular mechanisms by which dobutamine
exerts this protective effect remain to be elucidated. Results Data from right heart catheterization, thermo-dye dilution
catheter, gastric tonometry, as well as organ function and
coagulation were obtained at baseline and after 2 and 4 hours. Terlipressin (with and without dobutamine) infusion preserved the
mean arterial pressure at threshold values of 70 ± 5 mmHg, while
allowing one to reduce norepinephrine doses to 0.18 ± 0.04 and
0.2 ± 0.05 µg/kg/min, respectively (vs 1.4 ± 0.07 µg/kg/min in
controls at 4 hours; each P < 0.01). The terlipressin-linked
decrease in mixed-venous oxygen saturation was reversed by
dobutamine (at 4 hours: 59 ± 2 vs 69 ± 3%, P = 0.023). No
statistically significant differences were found intra-group and
between groups in terms of differences between gastric mucosal
and arterial carbon dioxide partial pressure, blood clearance of
indocyanine green, as well as the plasma disappearance rate of
indocyanine green P32 Serum vasopressin concentrations in critically ill patients
in the intensive care unit Serum vasopressin concentrations in critically ill patients
in the intensive care unit Vasopressin substitution causes microcirculatory changes
in patients with septic shock Vasopressin substitution causes microcirculatory changes
in patients with septic shock S Klinzing, C Reinhard, T Simon, T Schürholz, Y Sakr,
K Reinhart, G Marx
Friedrich Schiller Universität, Jena, Germany
Critical Care 2007, 11(Suppl 2):P34 (doi: 10.1186/cc5194) Results Vasopressin serum concentrations at 24 hours after
admission were 32,618 ± 20,570 pmol/l. Vasopressin serum
concentrations in critically ill patients were significantly higher than
in the healthy control group (11,302 ± 31,002, P < 0.001). Serum
vasopressin concentrations on admission compared with vaso-
pressin concentrations at discharge were statistically significantly
increased (P < 0.001). Introduction We tested the effects of arginine vasopressin on
tissue oxygenation, microvascular reactivity and oral mucosa
microcirculation in patients with septic shock. Conclusions Serum vasopressin concentrations in critically ill
patients in a mixed ICU are increased 24 hours after admission
compared with the control group. The value at discharge is lower Methods In 20 patients with septic shock, tissue microcirculation
was determined before treatment with AVP (2 IU/hour), after
2 hours of treatment and 2 hours after treatment. S13 Critical Care March 2007 Vol 11 Suppl 2
27th International Symposium on Intensive Care and Emergency Medicine Table 1 (abstract P34)
Base level
2 hours AVP
2 hours after AVP
P value step 1
P value step 2
SO2 1 mm (%)
79; 40–99
72.5; 59–88
83; 45–93
<0.05
<0.05
SO2 4 mm (%)
79; 48–97
68; 50–93
81; 24–99
<0.05
<0.01
Flow 1 mm
56; 11–390
33; 10–212
39; 10–249
<0.01
<0.01
Flow 4 mm
332.5; 149–517
280; 119–511
331; 150–581
<0.05
<0.05
Velocity 1 mm
22.5; 12–45
17.5; 11–33
20; 11–33
<0.01
<0.05 The thenar muscle StO2
was measured by near-infrared
spectroscopy (InSpectra; Hutchinson Technology, Hutchinson,
MN, USA). Oral mucosal tissue oxygen saturation, microcirculatory
blood flow and blood flow velocity were measured in depths of 1
and 4 mm with a laser Doppler flowmetry and remission
spectroscopy system (O2C). Methods Sixteen ewes were chronically instrumented to determine
the hemodynamics of the systemic and pulmonary circulation. After
16 hours of endotoxin infusion, all sheep exhibited a hypotensive–
hyperdynamic circulation. Thereafter, the animals were randomized
to be treated with either a continuous (2 mg over 24 hours) or
bolus infusion (1 mg every 6 hours) of terlipressin. y y
2
Results See Table 1. Rebound hypotension following terlipressin bolus infusion
can be prevented by continuous low-dose infusion of
terlipressin Rebound hypotension following terlipressin bolus infusion
can be prevented by continuous low-dose infusion of
terlipressin Vasopressin substitution causes microcirculatory changes
in patients with septic shock Vasopressin infusion led to a significant
decrease of oral mucosal oxygen saturation and blood flow, and a
significant decrease of flow velocity in a depth of 1 mm. Changes
in thenar tissue perfusion were not detectable. Results Continuous infusion of terlipressin reversed the endotoxin-
induced decrease in MAP during the entire 24-hour study period
(P < 0.001). Intermittent bolus injections of terlipressin contributed
to overshooting increases in MAP, as well as in systemic and
pulmonary vascular resistance index (each P < 0.001), which were
followed by sudden and strong rebound effects (Figure 1). Conclusion Vasopressin causes a deterioration of oral mucosal
blood flow but not in thenar tissue perfusion. Conclusion A goal-directed continuous infusion of terlipressin may
be superior to terlipressin bolus injection to treat patients with
sepsis-related arterial hypotension. Apparent heterogenity in splanchnic vascular response to
norepinephrine during sepsis M Lange1, K Bröking1, C Ertmer1, D Traber2, C Hucklenbruch1,
H Van Aken1, M Westphal1
1University of Münster, Germany; 2The University of Texas Medical
Branch, Galveston, TZ, USA
Critical Care 2007, 11(Suppl 2):P35 (doi: 10.1186/cc5195) J Gorrasi1, V Krejci2, L Hiltebrand2, S Brand2, H Bracht1,
B Balsiger3, J Takala1, S Jakob1
1Department of Intensive Care Medicine, 2Department of
Anesthesia and 3Departament of Gastroenterology, University
Hospital Bern, Switzerland
Critical Care 2007, 11(Suppl 2):P36 (doi: 10.1186/cc5196) Introduction Bolus infusion of terlipressin, a vasopressin analog,
increases the mean arterial pressure (MAP) in patients with sepsis-
related arterial hypotension. However, bolus infusion of terlipressin
may be associated with severe side effects like excessive systemic
and pulmonary vasoconstriction. We hypothesized that continuous
low-dose infusion of terlipressin may reverse arterial hypotension
with reduced side effects. Introduction Sepsis alters vascular reactivity. We studied the
impact of peritonitis and endotoxemia on hepatic and superior
mesenteric arterial contractility. Materials and methods We studied fecal peritonitis (P, n = 7),
endotoxin-infusion (E, n = 8) and control (C, n = 6) for 24 hours
after abdominal surgery and eight control pigs without surgery
(SPA). Systemic and regional hemodynamics and ex-vivo
splanchnic vascular reactivity to norepinephrine (NE; tissue bath)
were measured and cumulative dose–response curves to NE were
constructed. Tension was expressed in grams. Figure 1 (abstract P35) Figure 1 (abstract P35) Figure 1 (abstract P35) Figure 1 (abstract P35)
Mean arterial pressure (MAP) during continuous and intermittent bolus
infusion of terlipressin in endotexemic ewes. g
Results CO increased (P < 0.05) in P and E. SMA flow (median
(range)) decreased in C from 24 (15–30) to 15 (11–21) ml/kg/min
(P = 0.022) (Table 1). Table 1 (abstract P36)
N of arterial rings
SMA (g)
HA (g)
C (17)
3 (2–4)
2 (1–3)
P (21)
3 (2–4)
3 (2–4)
E (17)
1 (0.3–2)*;‡
2 (1–3)
SPA (18)
10 (8–16)**,†
8 (7–10)**,†
Data presented as median (range). *P = 0.002 E vs P and C; **P < 0.01 vs
C, P, and E; †P < 0.001 vs C, E and P; ‡P = 0.008 vs C. Effect of norepinephrine on cardiac output and preload in
septic shock patients Effect of norepinephrine on cardiac output and preload in
septic shock patients Methods With ethics committee approval, 10 male Sprague–
Dawley rats were studied. Anesthesia was induced with alfaxalone
and maintained with isofluorane. Mechanical ventilation was
performed via tracheostomy. All rats received 0.9% NaCl 3 ml/hour
via a carotid line. Immediately after baseline assessment (T = 0),
rats received 1 ml/kg i.v. infusion over 30 minutes (study group
(n = 5), endotoxin 10 mg/ml (Escherichia coli O55:B5; Sigma,
MO, USA); control group, 0.9% NaCl). Echocardiography was
performed (15 MHz transducer, Vivid5; GE Healthcare) at T = 0,
60 minutes (T = 60) and 2.5 hours (T = 150). Measurements
included the heart rate, mean arterial pressure (MAP), femoral
venous pressure, LV outflow tract diameter and flow (peak velocity
(Vpeak), cardiac output (CO)), peak early diastolic mitral inflow (E),
peak systolic mitral annulus velocity (S′) and E′. O Hamzaoui, H Ksouri, C Richard, J Teboul
Bicetre Hospital, Le Krêmlin Bicetre, France
Critical Care 2007, 11(Suppl 2):P37 (doi: 10.1186/cc5197) Introduction Norepinephrine (NE) is a first-line vasopressor used
in patients with septic shock. Because of its predominant α-
agonist effect, it is assumed to increase vasomotor tone and hence
the mean arterial pressure (MAP) without significant effect on the
cardiac index (CI). However, a potential beneficial effect on CI can
be expected from its venoconstrictor α-agonist-mediated effect
combined with an inotropic β1 agonist effect, provided that the
increase in left ventricular afterload is not excessive (high levels of
MAP). The aim of our study was to examine the cardiovascular
effect of NE when it induces marked changes in MAP. Results There was no significant difference in mean ± SD weight
(study 539 ± 88 g, control 504 ± 108 g, P = 0.6) or hemodynamic
variables at T = 0. At T = 60, only Vpeak was higher in the study
group compared with controls (1.29 ± 0.24 vs 0.86 ± 0.21 m/s,
P = 0.03). The study group demonstrated lower MAP, E and E′ at
T = 150 (Table 1). Methods In an observational study of patients (n = 37) resuscitated
for septic shock, we analysed hemodynamic PiCCO data at two
consecutive time points where the MAP changed by more than
15% in response to either initiation or to change of doses of NE. Two subgroups of patients were identified. P39 Hemodynamic and cardiac peptide in septic myocardial
depression: the effects of calcium sensitizer Hemodynamic and cardiac peptide in septic myocardial
depression: the effects of calcium sensitizer C Cariello, F Guarracino, L Giannecchini, P Giomi, S Lorenzini
University Hospital, Pisa, Italy
Critical Care 2007, 11(Suppl 2):P39 (doi: 10.1186/cc5199) Introduction The aim of this retrospective study is to evaluate
hemodynamic and neurohormonal effects of levosimendan in
cardiac patients with sepsis-induced cardiac dysfunction. Septic
shock is characterized by profound cardiovascular alterations
including myocardial depression. Levosimendan has recently been
shown to improve cardiac function in septic shock. Conclusion In our septic shock patients, changes in MAP resulting
from increases or decreases in the doses of NE, were associated
with changes in CI related to changes in GEDVi (cardiac preload)
and in some patients to changes in systolic left ventricular function
evaluated by GEF. These findings suggest that administration of
NE in septic shock is associated not only with an increase in MAP
but also with an increase in systemic blood flow. Methods Fifteen patients with myocardial depression related to
septic shock were enrolled. All patients had SIRS criteria, culture
isolation of one or more pathogens, positive procalcitonin, SBP
< 90 mmHg unresponsive to load challenge. We defined myo-
cardial depression as a reduced SvO2 in the presence of increased
brain natriuretic peptide secretion and Troponin I release, and
systolic and/or diastolic dysfunction by transoesophageal echo
evaluation of ejection fraction and mitral annulus tissue Doppler
imaging velocities. All patients received levosimendan infusion for
24 hours at 0.1 µg/kg/min combined with norepinephrine. Effect of norepinephrine on cardiac output and preload in
septic shock patients The first subgroup
(MAPincr) consisted of 21 patients in whom the MAP increased by
more than 15% in response to either initiation of NE infusion
(n = 8) or increase in NE dose (from 1.7 ± 1.7 to 2.2 ± 1.4 mg/hour;
n = 13). The second subgroup (MAPdecr) consisted of 16 patients
in whom the MAP decreased by more than 15% in response to the
decrease in NE doses. For both subgroups, the time between the
two consecutive sets of measurements did not exceed 2 hours and
no other treatments that may alter hemodynamics were adminis-
tered within this period (fluids, hemofiltration, diuretics or other
catecholamines). Table 1 (abstract P38)
Control
Study
P
MAP (mmHg)
118 ± 21
75 ± 35
0.05
CO (l/min)
0.156 ± 0.02
0.181 ± 0.07
0.5
E (m/s)
1.02 ± 0.2
0.76 ± 0.11
0.04
E′ (m/s)
0.095 ± 0.02
0.061 ± 0.02
0.03 Conclusion In this model, endotoxemia was associated with a
decrease in E and E′. This decrease in E′ suggests a decreased
rate of myocardial relaxation. This has not previously been reported. Results In the MAPincr subgroup, MAP increased from 56 ± 17 to
84 ± 12 mmHg (P < 0.05) while significant increases in CI (from
3.4 ± 1.0 to 3.7 ± 0.9 l/min/m2), stroke volume index (SVi) (from
37 ± 12 to 41 ± 11 ml/m2) and global end diastolic volume index
(GEDVi) (from 706 ± 203 to 767 ± 225 ml/m2) were observed. Neither the heart rate nor the global ejection fraction (GEF) signifi-
cantly changed. In seven patients, the GEF markedly increased by
>15% in parallel to the increase in SVi. In the MAPdecr subgroup,
MAP decreased from 95 ± 12 to 70 ± 9 mmHg (P < 0.05). The CI
(from 3.5 ± 1.4 to 3.0 ± 0.9 l/min/m2) and GEDVi (from 815 ± 319
to 721 ± 253 ml/m2) decreased significantly, while the heart rate,
SVi (P = 0.07) and GEF did not change. Table 1 (abstract P36) Mean arterial pressure (MAP) during continuous and intermittent bolus
infusion of terlipressin in endotexemic ewes. Conclusions
The splanchnic vascular response to NE is
heterogenous in sepsis, and SMA is most affected. This may
modify blood flow distribution if high NE doses are used. S14 Available online http://ccforum.com/supplements/11/S2 Available online http://ccforum.com/supplements/11/S2 Available online http://ccforum.com/supplements/11/S2 Available online http://ccforum.com/supplements/11/S2 P37 endotoxemia. This study sought to determine the effect of
endotoxemia upon TDI variables. Relationship of IL-12 and thyroid indices in sepsis Relationship of IL-12 and thyroid indices in sepsis E Karakoc, I Karayaylali, T Sunbul
Cukurova University, Adana, Turkey
Critical Care 2007, 11(Suppl 2):P41 (doi: 10.1186/cc5201) Table 1 (abstract P39)
T0
T1
T2
T3
T4
T5
T6
SvO2 (%)
0
4
10
17
22
19
22
Trop I (ng/ml)
0
–65
–86
–82
–78
–62
–62
BNP (%)
0
–45
–41
–56
–50
–42
–44
E′ (cm/s)
<8
>8
>8
>8
>8
>8
>8
EF (%)
<30
>40
>40
>40
>40
>40
>40
Conclusions
Levosimendan
seems
to
improve
systemic
hemodynamics and neurohormonal cardiac function in patients
with septic cardiac dysfunction. Introduction Sickeuthroid syndrome is very frequent in critically ill
patients. Cytokines may have a role in this syndrome. IL-12 is
involved in the central regulation of the hypothalamic–pituitary–
thyroid (HPT) axis during illness. The aim of this study is to evaluate
the relationship of IL-12 and thyroid functions in septic patients. Introduction Sickeuthroid syndrome is very frequent in critically ill
patients. Cytokines may have a role in this syndrome. IL-12 is
involved in the central regulation of the hypothalamic–pituitary–
thyroid (HPT) axis during illness. The aim of this study is to evaluate
the relationship of IL-12 and thyroid functions in septic patients. Materials and methods Twenty-four septic patients and 18
healthy controls were enrolled into the study with the mean ages of
49.9 ± 20.6 and 45.8 ± 22.3 years, respectively. Hyperthyroid and
hypothyroid patients were excluded. Free triiodothyronine (fT3),
free thyroxine (fT4) and TSH were measured simultaneously with
IL-12. Materials and methods Twenty-four septic patients and 18
healthy controls were enrolled into the study with the mean ages of
49.9 ± 20.6 and 45.8 ± 22.3 years, respectively. Hyperthyroid and
hypothyroid patients were excluded. Free triiodothyronine (fT3),
free thyroxine (fT4) and TSH were measured simultaneously with
IL-12. Conclusions
Levosimendan
seems
to
improve
systemic
hemodynamics and neurohormonal cardiac function in patients
with septic cardiac dysfunction. Results The mean IL-12, fT3, fT4 and TSH values of septic
patients and the control group are presented in Table 1. IL-12 was
significantly higher in septic patients (19.05 ± 10.7 pg/ml vs
4.8 ± 2.0 pg/ml, P < 0.005). fT3 and TSH values were significantly
low in septic patients. There was a significantly strong correlation
between IL-12 and fT4 in septic patients but not fT3 and TSH
(r = 0.88, P = 000). Table 1 (abstract P41) Introduction In recent years there has been increasing evidence
that a resuscitation strategy with different fluids can have widely
divergent impacts on the immune response, neutrophil activation
and tissue injury. This prospective study was undertaken to
determine the neutrophil oxidative burst in the swine model during
an acute normovolemic hemodilution (ANH) procedure with
hydroxyethyl starch. Methods
Twelve pigs were anesthetized, instrumented and
randomized into two groups: control and hemodilution (H). The
control group was only anesthetized and instrumented while
animals in the ANH group were submitted to acute normovolemic
hemodilution to a target hematocrit of 15% with volume
replacement performed with hydroxyethyl starch 130/0.4 at a 1:1
ratio. The withdrawn blood was returned to the animals
120 minutes after the end of hemodilution. Neutrophil oxidative
burst was performed with blood samples collected at the femoral
vein at the following time points: before ANH (baseline), after
instrumentation (INST), immediately after ANH (H), 60 minutes
after ANH (60H), 120 minutes after ANH (120H), 60 minutes after
blood infusion (60BI) and 120 minutes after blood infusion
(120BI), and determined with a flow cytometer. Spontaneous and
stimulated oxidative burst activation of neutrophils were performed
with dichlorofluorescein diacetate and phorbol myristate acetate. Statistical analyses were performed using one-way analysis of
variance followed by a Dunnett test or t test. A P value of 0.05 was
considered statistically significant. P42 A network system for the treatment of pediatric septic shock
M Sasse1, M Kirschstein2, H Köditz1, K Seidemann1, A Wessel1
1Medical University Children’s Hospital, Hannover, Germany;
2Children Hospital AKH Celle, Germany
Critical Care 2007, 11(Suppl 2):P42 (doi: 10.1186/cc5202) M Sasse1, M Kirschstein2, H Köditz1, K Seidemann1, A Wessel1
1Medical University Children’s Hospital, Hannover, Germany;
2Children Hospital AKH Celle, Germany
Critical Care 2007, 11(Suppl 2):P42 (doi: 10.1186/cc5202) Introduction We show the effect of a network system in the
treatment of pediatric septic shock, especially for children with
Waterhouse–Friderichsen syndrome. In 2003 we founded a
pediatric intensive care network with 15 children’s hospitals in
Lower Saxony, Germany. The aims were the standardisation of
clinical therapies, implementation of training programs and the
installation of an emergency system in the region of lower Saxony. Methods The first standard was implemented for the treatment of
the Waterhouse–Friderichsen syndrome. At first, we started with
the educational program. The program included different central
symposia about septic shock in children. The second step was the
standardisation of the diagnosis and the therapy, including the
administration of human protein C concentrate (PC), and the
clinical pathways. We implemented a round-the-clock emergency
system with the possibility for transportation of critically ill patients,
permanent consultation of the tertiary medical center and onsite
treatment through the tertiary center staff if the patient could not be
transferred. All patients were announced to the tertiary medical Introduction We show the effect of a network system in the
treatment of pediatric septic shock, especially for children with
Waterhouse–Friderichsen syndrome. In 2003 we founded a
pediatric intensive care network with 15 children’s hospitals in
Lower Saxony, Germany. The aims were the standardisation of
clinical therapies, implementation of training programs and the
installation of an emergency system in the region of lower Saxony. Results Spontaneous oxidative burst activity in group H increased
significantly from baseline (30.19 ± 4.79) to H (57.45 ± 9.86) and
60H (56.26 ± 14.64) (P < 0.01) while the control group did not
present significant variation. Between groups there were
significant differences at H (ANH = 57.45 ± 9.86; control =
23.18 ± 7.16; P = 0.0007), 60H (ANH = 56.26 ± 14.64; control =
34.53 ± 9.06; P = 0.0225), 120H (ANH = 43.59 ± 5.46; control =
28.65 ± 10.44; P = 0.0220) and 60BI (ANH = 38.60 ± 1.85;
control = 25.59 ± 8.12; P = 0.0082). Tissue Doppler imaging suggests an association between
endotoxemia and impaired myocardial relaxation D Sturgess, B Haluska, B Venkatesh
University of Queensland, Brisbane, Australia
Critical Care 2007, 11(Suppl 2):P38 (doi: 10.1186/cc5198) D Sturgess, B Haluska, B Venkatesh
University of Queensland, Brisbane, Australia
Critical Care 2007, 11(Suppl 2):P38 (doi: 10.1186/cc5198) Results Data were obtained by evaluating the average of the
percentage variation between T0
(starting infusion) and T1
(24 hours after infusion), T2
(48 hours), T3
(72 hours), T4
(96 hours), T5 (120 hours) and T6 (144 hours). Levosimendan
significantly increased SvO2 and ejection fraction, and decreased Introduction Tissue Doppler imaging (TDI) is a novel technique
that measures myocardial velocity. The peak early diastolic mitral
annulus velocity (E′) offers a relatively preload-insensitive measure
of LV relaxation. There are scant data regarding its use in sepsis or Introduction Tissue Doppler imaging (TDI) is a novel technique
that measures myocardial velocity. The peak early diastolic mitral
annulus velocity (E′) offers a relatively preload-insensitive measure
of LV relaxation. There are scant data regarding its use in sepsis or S15 Care March 2007 Vol 11 Suppl 2
27th International Symposium on Intensive Care and Emergency Medicine Troponin I and brain natriuretic peptide. Levosimendan improved
diastolic function by increasing the E′ velocity at tissue Doppler
imaging at 48 hours. All data were analysed by the Fisher F test. Troponin I and brain natriuretic peptide. Levosimendan improved
diastolic function by increasing the E′ velocity at tissue Doppler
imaging at 48 hours. All data were analysed by the Fisher F test. P41 P40 P40
Neutrophil oxidative burst evaluation during acute
normovolemic hemodilution: preliminary results
M Kahvegian, D Tabacchi Fantoni, DA Otsuki, C Holms,
C Oliveira Massoco, J Costa Auler Jr
University of São Paulo Medical School, São Paulo, Brazil
Critical Care 2007, 11(Suppl 2):P40 (doi: 10.1186/cc5200) Neutrophil oxidative burst evaluation during acute
normovolemic hemodilution: preliminary results Table 1 (abstract P41)
IL-12 (pg/ml)
TSH (mIU/l)
fT3 (pg/ml)
fT4 (ng/dl)
Control group
4.8 ± 2.1
2.25 ± 2.1
2.93 ± 0.5
1.18 ± 0.14
Septic patients
19.05 ± 10.7
1.173 ± 1.85
1.56 ± 0.6
1.06 ± 0.3
P
<0.001
0.001
<0.001
0.118
Conclusion According to our findings, IL-12 has a role in HPT
dysfunction in most critically ill patients. Relationship of IL-12 and thyroid indices in sepsis There was no correlation between IL-12 and
other thyroid indices in the control group. P44
Optimization of antibacterial treatment in pediatric
intensive care units using procalcitonin center directly after admission into the network hospitals. The final
step was the presentation of the project in the different hospitals. Results We treated 10 children with Waterhouse–Friderichsen
syndrome in the network. Three of them were attended on site and
seven were transferred in the tertiary center. The announcement
time in eight cases was 15 minutes–1 hour. Primarily, a
consultation was accomplishing routinely. The transportation team
of the tertiary center continued the treatment on site and
afterwards in the center. All patients showed typical signs of
Waterhouse–Friderichsen syndrome with purpura fulminans and
severe multiorgan failure. No patient died and only one patient had
necrosis of the skin, which existed already at admission. The others
had a restitution ad integrum. No adverse effects were observed
with the PC concentrate administration. center directly after admission into the network hospitals. The final
step was the presentation of the project in the different hospitals. Results We treated 10 children with Waterhouse–Friderichsen
syndrome in the network. Three of them were attended on site and
seven were transferred in the tertiary center. The announcement
time in eight cases was 15 minutes–1 hour. Primarily, a
consultation was accomplishing routinely. The transportation team
of the tertiary center continued the treatment on site and
afterwards in the center. All patients showed typical signs of
Waterhouse–Friderichsen syndrome with purpura fulminans and
severe multiorgan failure. No patient died and only one patient had
necrosis of the skin, which existed already at admission. The others
had a restitution ad integrum. No adverse effects were observed
with the PC concentrate administration. N Beloborodova1, D Popov1, M Traube2, E Ochakovskaya1,
E Chernevskaya1
1Bakoulev Scientific Center for Cardiovascular Surgery, Moscow,
Russian Federation; 2Filatov Children’s Hospital, Moscow, Russia
Federation
Critical Care 2007, 11(Suppl 2):P44 (doi: 10.1186/cc5204) Introduction Neonates and infants in the ICU are at high risk of
severe infections and sepsis. Often it is not easy to diagnose
sepsis based only on clinical findings; reliable biomarkers are
needed to prove the diagnosis. Conclusions The network system and the standard treatment with
PC worked without severe problems. The survival rate and the
outcome in our small study group were excellent. Our experience
allows us to enlarge the system on other diseases. Objective To study the value of procalcitonin (PCT) as a marker,
verifying the diagnosis, which enables the start of de-escalating
ABT in patients with clinical signs of sepsis. Intensive care unit outcome versus haemodynamic status
on arrival at a general intensive care unit Intensive care unit outcome versus haemodynamic status
on arrival at a general intensive care unit T Reynolds, A Theodoraki, I Ketchley, A Tillyard, R Lawson,
N Al-Subaie, M Cecconi, R Grounds, A Rhodes
St George’s Hospital, London, UK
Critical Care 2007, 11(Suppl 2):P43 (doi: 10.1186/cc5203) Introduction Goal-directed therapeutic protocols such as that
described by Rivers and colleagues [1] have taken an important
place in efforts to increase survival in septic patients. We looked at
ICU outcomes for patients meeting the haemodynamic criteria of
the Rivers trial on admission to our general ICU. Results Group A. Sepsis was diagnosed in 16/50 (32%) patients. PCT > 2 ng/ml was observed in 23/50 (46%) cases, including
15/16 (94%) patients with clinically diagnosed sepsis. In patients
with PCT > 2 ng/ml the mortality rate was 7.7% if carbapenems
(meropenem or imipenem/cilastatin) were administered (n = 13),
compared with 20% with different ABT (n = 10) – although in
patients with PCT < 2 ng/ml (n = 27), ABT with carbapenems
(n = 12) resulted in paradoxically higher mortality compared with
other ABT schemes (n = 15): 17% vs 6.6%. Group B. Sepsis was
defined in 24/324 (7.4%) patients. PCT > 2 ng/ml was in 53/324
(16%) cases, including all patients with clinically diagnosed sepsis. Early ABT with meropenem, combined with vancomycin or
linezolid, allowed one to decrease sepsis-related mortality in these
patients to 29%, which used to be as high as 74% before the
introduction of this algorithm (P = 0.0028). Methods We prospectively recorded haemodynamic parameters
of 98 consecutive patients admitted to a mixed medical/surgical
ICU and compared these with the ICU outcome. Patients who met
systemic inflammatory response syndrome (SIRS) criteria [2] and
had lactate ≥4 mmol/l or systolic blood pressure ≤90 mmHg met
the Rivers criteria. Results We included 98 patients admitted to the ICU (60 males)
of mean age 61 ± 17 years. Fourteen patients (14%) died in the
ICU, and the median length of stay was 3 (IQR 3) days. Overall 16
of the 98 patients met the Rivers criteria, four of whom died (25%). The median length of ICU stay for the Rivers patients was 5 (1.25)
days (see Table 1). Conclusions Sixteen out of 98 patients (16%) met Rivers criteria. Of medical and surgical emergency patients, this proportion rose
to 16 of 55 patients (29%). P42 Methods The first standard was implemented for the treatment of
the Waterhouse–Friderichsen syndrome. At first, we started with
the educational program. The program included different central
symposia about septic shock in children. The second step was the
standardisation of the diagnosis and the therapy, including the
administration of human protein C concentrate (PC), and the
clinical pathways. We implemented a round-the-clock emergency
system with the possibility for transportation of critically ill patients,
permanent consultation of the tertiary medical center and onsite
treatment through the tertiary center staff if the patient could not be
transferred. All patients were announced to the tertiary medical Conclusion ANH with hydroxyethyl starch influences oxidative
burst activity under experimental conditions. S16 Available online http://ccforum.com/supplements/11/S2 P44
Optimization of antibacterial treatment in pediatric
intensive care units using procalcitonin Methods Three hundred and seventy-four patients on artificial lung
ventilation from two pediatric ICUs of two Russian hospitals were
enrolled. Blood samples for PCT testing (PCT LIA; BRAHMS AG,
Germany) were taken under suspicion of sepsis or exacerbation of
bacterial infection. In the first stage (January–December 2005), 50
neonates (age 6 (4–12) days) with various perinatal pathologies
were studied (Group A), and routine ABT was prescribed, with
blood samples taken and stored for further PCT assessment. In the
second stage (January–November 2006), 324 infants (age 6
(1.5–9.4) months) after cardiac surgery were enrolled (Group B),
and ABT was adjusted based on PCT-testing results. PCT
> 2 ng/ml indicative of systemic bacterial inflammation in addition
to clinical signs of sepsis was an indication for ABT with
carbapenems. Data are shown as the median and interquartile
range. P45 approximately equivalent to an endotoxin concentration of
25–50 pg/ml, and a level of 0.6 is approximately equivalent to a LPS
concentration of 100–200 pg/ml. Data were analysed according to
EA ranges: low (EA < 0.4), intermediate (0.4 ≤EA < 0.6), and high
(EA ≥0.6). Differences between ranges of EA were assessed by
analysis of variance (Sigma Stat, SPSS), accepting P < 0.05 as
significant. Data are expressed as the mean ± SD. M Assuncao1, F Machado1, N Akamine2, G Cardoso1, P Mello3,
J Telles4, A Nunes5, M Oliveira6, A Rea-Neto7, R Clleva8, F Dias9
1Universidade Federal de Sao Paulo, Brazil; 2Latin American
Sepsis Institute, Sao Paulo, Brazil; 3Universidade Estadual do
Piaui, Teresina, Brazil; 4Hospital Portugues, Salvador, Brazil;
5Hospital Sao Camilo, Sao Paulo, Brazil; 6Hospital Santa Luzia,
Brasilia, Brazil; 7Universidade Federal do Parana, Curitiba, Brazil;
8Faculdade de Medicina da USP, Sao Paulo, Brazil; 9Hospital Sao
Lucas – PUC-RS, Porto Alegre, Brazil
Critical Care 2007, 11(Suppl 2):P45 (doi: 10.1186/cc5205) M Assuncao1, F Machado1, N Akamine2, G Cardoso1, P Mello3,
J Telles4, A Nunes5, M Oliveira6, A Rea-Neto7, R Clleva8, F Dias9
1Universidade Federal de Sao Paulo, Brazil; 2Latin American
Sepsis Institute, Sao Paulo, Brazil; 3Universidade Estadual do
Piaui, Teresina, Brazil; 4Hospital Portugues, Salvador, Brazil;
5Hospital Sao Camilo, Sao Paulo, Brazil; 6Hospital Santa Luzia,
Brasilia, Brazil; 7Universidade Federal do Parana, Curitiba, Brazil;
8Faculdade de Medicina da USP, Sao Paulo, Brazil; 9Hospital Sao
Lucas – PUC-RS, Porto Alegre, Brazil
Critical Care 2007, 11(Suppl 2):P45 (doi: 10.1186/cc5205) Results In our case mix, patients were 68 (65%) in the low group,
17 (17%) in the intermediate group and 19 (18%) in the high
group. Age (61 ± 17 years) was not significantly different in the
three groups (P = 0.493). Functional and severity scores were not
significantly different between groups. Average values were as
follows: WBC 11,093 ± 4605 n/mm3 (P = 0.385), HR 76 ± 16 bpm
(P = 0.898),
MAP
88.8 ± 13.6 mmHg
(P = 0.576),
lactate
1.18 ± 0.77 mmol/l (P = 0.370), PaO2/FiO2 383 ± 109 mmHg
(P = 0.474), APACHE II score 8.3 ± 3.7 (P = 0.542) and SOFA
score 1.5 ± 1.4 (P = 0.245). Interestingly, those patients with
higher levels of EA were characterized by longer length of stay in
the ICU. P45 The ICU length of stay was 1.9 ± 3.1 days in the low
group, 8.7 ± 6.7 days in the intermediate group and 4.7 ± 7.7 days
in the high group (P = 0.038). Introduction The aim of this study was evaluation of physicians’
knowledge about SIRS, sepsis, severe sepsis and septic shock. Methods A multicenter study in 21 ICUs in seven university, five
public and seven private hospitals. A questionnaire with five clinical
cases was first validated by five critical care boarded intensivists
(INT) with 100% agreement. All interviewed physicians (Phys)
received each question separately, in a predefined sequence, and
no answer could be reviewed. After answering, the questionnaire
was put in a sealed envelope with no identification. Statistical
analysis was performed: chi-square, Kruskall–Wallis and linear
correlation tests. P < 0.05 was considered statistically significant. Results A total of 917 Phys (mean age 32.7 ± 7.21 years, 61.9%
males, 38.1% females) were enrolled with 20.0% (n = 55) INT and
80.0% (n = 220) of nonintensivists (non-INT). Phys correctly
recognized SIRS, infection, and septic shock in 80.4%, 92.4% and
85.1% of the cases, respectively. The lowest rate of recognition
was observed in sepsis and severe sepsis cases (26.5% and
55.6%). Considering all questions, the overall percentage of
correct answers was 68.1 ± 21.1%. INT performed better than
non-INT (84.7 ± 17.2% and 64.0 ± 20.0%, P < 0.00001). Phys
working at public and university hospitals performed better
(70.2 ± 18.7% and 71.2 ± 19.5%) than those in private hospitals
(59.7 ± 23.4%, P = 0.001). Introduction The aim of this study was evaluation of physicians’
knowledge about SIRS, sepsis, severe sepsis and septic shock. Methods A multicenter study in 21 ICUs in seven university, five
public and seven private hospitals. A questionnaire with five clinical
cases was first validated by five critical care boarded intensivists
(INT) with 100% agreement. All interviewed physicians (Phys)
received each question separately, in a predefined sequence, and
no answer could be reviewed. After answering, the questionnaire
was put in a sealed envelope with no identification. Statistical
analysis was performed: chi-square, Kruskall–Wallis and linear
correlation tests P < 0 05 was considered statistically significant Conclusions A rather high number of patients admitted to the ICU
following elective surgery are characterized by intermediate-high
levels of endotoxemia, as assessed by the EA assay, despite their
relative low level of complexity on admission. Reference 1. Romaschin AD, et al.: J Immunol Methods 1998, 212:169-
185. 1. Romaschin AD, et al.: J Immunol Methods 1998, 212:169-
185. sTREM-1 is not suitable to discriminate survivors and
nonsurvivors in surgical patients with severe sepsis or
septic shock sTREM-1 is not suitable to discriminate survivors and
nonsurvivors in surgical patients with severe sepsis or
septic shock C Bopp1, S Hofer1, P Kienle1, S Meyer1, E Martin1, A Bouchon2,
M Buechler1, M Weigand1
1University of Heidelberg, Germany; 2Bayer CropScience,
Monheim, Germany
Critical Care 2007, 11(Suppl 2):P47 (doi: 10.1186/cc5207) Conclusion The recognition of sepsis and its severity are not
satisfactory, mostly among non-INT and those working at private
hospitals. Possibly, reviewing sepsis-related and organ dysfunction
concepts are necessary for early identification of septic patients. Objectives To evaluate in septic patients the plasma levels of
sTREM-1, a soluble form of TREM-1, which seems to play an
important role in inflammatory diseases, and to determine whether
plasma sTREM-1 could be used as a diagnostic and prognostic
marker in sepsis in the surgical ICU. P45 High levels of EA
were associated with a longer length of stay. correlation tests. P < 0.05 was considered statistically significant. Results A total of 917 Phys (mean age 32.7 ± 7.21 years, 61.9%
males, 38.1% females) were enrolled with 20.0% (n = 55) INT and
80.0% (n = 220) of nonintensivists (non-INT). Phys correctly
recognized SIRS, infection, and septic shock in 80.4%, 92.4% and
85.1% of the cases, respectively. The lowest rate of recognition
was observed in sepsis and severe sepsis cases (26.5% and
55.6%). Considering all questions, the overall percentage of
correct answers was 68.1 ± 21.1%. INT performed better than
non-INT (84.7 ± 17.2% and 64.0 ± 20.0%, P < 0.00001). Phys
working at public and university hospitals performed better
(70.2 ± 18.7% and 71.2 ± 19.5%) than those in private hospitals
(59.7 ± 23.4%, P = 0.001). Reference Prevalence of endotoxemia in a population of patients
admitted to an intensive care unit after elective surgery Design An observational clinical study. F Valenza, L Fagnani, S Coppola, S Froio, C Tedesco,
C Marenghi, C Galbusera, P Caironi, L Gattinoni
Fondazione IRCCS Ospedale Maggiore Policlinico Mangiagalli
Regina Elena, Milano, Italy
Critical Care 2007, 11(Suppl 2):P46 (doi: 10.1186/cc5206) Valenza, L Fagnani, S Coppola, S Froio, C Tedesco, Setting The surgical ICU of the University Hospital of Heidelberg,
Germany. Setting The surgical ICU of the University Hospital of Heidelberg,
Germany. Patients Patients admitted to the ICU over a 6-month period with
clinical evidence of severe sepsis or septic shock. Patients Patients admitted to the ICU over a 6-month period with
clinical evidence of severe sepsis or septic shock. Intensive care unit outcome versus haemodynamic status
on arrival at a general intensive care unit Conclusion Early verification of sepsis using PCT combined with
carbapenems-based ABT enables decreasing sepsis-related
mortality in critically ill infants and newborns staying in the ICU. 1. Rivers E, et al.: N Engl J Med 2001, 345:1368-1377. 2. Levy M, et al.: Crit Care Med 2003, 31:1250-1256. 1. Rivers E, et al.: N Engl J Med 2001, 345:1368-1377. 2
L
M
l C i C
M d 2003 31 1250 1256 Table 1 (abstract P43)
Patients
Patients reaching Rivers criteria
Mortality
Median length of stay
Mortality
Median length of stay
n
(n (%))
(days)
n
(n (%))
(days)
Total
98
14 (14%)
3 (IQR 3)
16
4 (25%)
5 (IQR 1.25)
Medical
33
9 (27%)
5 (IQR 2)
11
3 (27%)
5 (IQR 1.5)
Elective surgical
43
1 (2%)
2 (IQR 1)
0
Emergency surgical
22
4 (18%)
3 (IQR 4.5)
5
1 (20%)
5 (IQR 1) Table 1 (abstract P43) Table 1 (abstract P43) S17 Critical Care March 2007 Vol 11 Suppl 2
27th International Symposium on Intensive Care and Emergency Medicin Can plasma-free DNA concentration be a diagnostic tool in
critically ill septic patients? Can plasma-free DNA concentration be a diagnostic tool in
critically ill septic patients? Introduction Inadequate tissue perfusion and an uncontrolled
systemic inflammatory response are associated with poor outcome
in critically ill surgical patients. An increased concentration of un-
measured anions, reflecting hypoperfusion, and the magnitude of
the early inflammatory response both correlate strongly with
mortality. Our aim was to assess the relationship between these
factors, and their ability in combination to predict outcome. Introduction Inadequate tissue perfusion and an uncontrolled
systemic inflammatory response are associated with poor outcome
in critically ill surgical patients. An increased concentration of un-
measured anions, reflecting hypoperfusion, and the magnitude of
the early inflammatory response both correlate strongly with
mortality. Our aim was to assess the relationship between these
factors, and their ability in combination to predict outcome. Methods In a prospective study we evaluated 108 consecutive
patients admitted to a surgical high dependency unit. Regional
Ethics Committee approval was obtained. Serum electrolytes,
albumin, phosphate, lactate and C-reactive protein (CRP) were
measured on admission and on day 1. We derived the calculated
ion gap (CIG) using a simplified modification of the Stewart–Figge
equations. B Orbey1, H Cuhruk1, M Tulunay1, M Oral2, N Unal1, H Ozdag3
1Ankara University Medical Faculty, Anesthesiology and ICM,
Ankara, Turkey; 2AÜTF, Anesthesiology and ICU, Ankara, Turkey;
3Ankara University, Biotechnology Institute, Ankara, Turkey
Critical Care 2007, 11(Suppl 2):P48 (doi: 10.1186/cc5208) Methods In a prospective study we evaluated 108 consecutive
patients admitted to a surgical high dependency unit. Regional
Ethics Committee approval was obtained. Serum electrolytes,
albumin, phosphate, lactate and C-reactive protein (CRP) were
measured on admission and on day 1. We derived the calculated
ion gap (CIG) using a simplified modification of the Stewart–Figge
equations. Recent evidence suggests that the plasma-free DNA concentration
has potential use as a prognostic marker in many clinical situations
including sepsis, trauma, and acute stroke [1]. However, its
predictive value is arguable. We hypothesized that plasma DNA is
increased in septic patients admitted to the ICU compared with
nonseptic ICU patients, and it is correlated with disease severity
and clinical outcome. Results Based on previous work, thresholds of 10 mmol/l for CIG
and 100 mg/l for CRP were used to categorise patients. Of the
patients with a CRP < 100 mg/l, 15.4% had an elevated CIG. Of
the patients with a CRP > 100 mg/l, 36.7% had an elevated CIG
(P = 0.016, chi-square test). Can plasma-free DNA concentration be a diagnostic tool in
critically ill septic patients? Patients (n = 63) with a CIG
< 10 mmol/l and CRP < 100 mg/l had a 1.5% mortality, whereas
those (n = 11) with a CIG > 10 mmol/l and CRP > 100 mg/l had a
54.5% mortality (P < 0.0001, chi-square test) (Table 1). Forty-two consecutive patients (11 septic, 31 nonseptic) admitted
to a mixed ICU and mechanically ventilated were recruited. Plasma-
free DNA concentration was measured by real-time PCR assay for
the β-globin gene, and the APACHE II score, SOFA score, serum
C-reactive protein (CRP) concentrations, procalcitonin (PCT)
concentrations, serum lipid concentrations, and clinical outcome
(ICU/hospital days and mortality) were assessed on admission to
the ICU. Assessments and samplings were repeated as the
diagnosis of the patients changed (sepsis, severe sepsis and
septic shock). Finally, 86 plasma samples were collected. Descrip-
tive statistics, Mann–Whitney U, Kruskall–Wallis and Spearman’s
tests, and receiver operating characteristic analysis were used
when appropriate. Table 1 (abstract P49)
CRP < 100 mg/l,
CRP > 100 mg/l,
CIG < 10 mmol/l
CIG > 10 mmol/l
Inhospital mortality
1.5% (n = 63)
54.5% (n = 11) Demographic data were similar. ICU and hospital mortalities were
26.2% and 33.3%, respectively. The mean DNA concentrations on
admission were significantly higher in ICU patients compared with
healthy subjects (n = 11) (13,405 GE/ml versus 390 GE/ml,
P < 0.05) and septic patients compared with nonseptic patients
(33,170 GE/ml versus 1,171 GE/ml, P < 0.001). Furthermore,
during the overall ICU stay, increased DNA concentration asso-
ciated with the increase of severity of illness was noted; however,
this increase was statistically significant only between septic and
septic shock samples (26,624 GE/ml versus 42,861 GE/ml,
P < 0.05). The area under the curve obtained for the plasma-free
DNA concentration in distinguishing between septic and nonseptic
patients on admission was 0.9 (sensitivity 84%, specificity, 95%;
cutoff 4,083 GE/ml). Also, the plasma-free DNA concentration was
found to be higher in patients who died in the ICU compared with
patients who survived, although not statistically significant. The
DNA concentration demonstrated a significant correlation with
CRP (P = 0.037, r = 0.365), PCT (P = 0.007, r = 0.457) and high-
density lipoprotein (P = 0.015, r = –0.415) concentrations. Conclusion Inflammation is a potent cause of oxidative stress,
which in turn results in endothelial damage and increased
concentrations of unmeasured anions. Interventions None. Measurements and results Sixty-six intensive care patients were
enrolled in the study within the first 24 hours after the onset of
severe sepsis or septic shock. Twenty-one healthy individuals
served as controls. At day 0, day 1 and day 3 after diagnosis of
severe sepsis or septic shock, plasma sTREM-1 was measured by
ELISA. Plasma sTREM-1 concentrations of healthy controls did not
differ from patients with severe sepsis or septic shock at day 0
(42.8 ± 44.9 pg/ml vs 40.8 ± 45.5 pg/ml, not significant), day 1
(42.8 ± 44.9 pg/ml vs 48.6 ± 57.2 pg/ml, not significant) nor at
day 3 (42.8 ± 44.9 pg/ml vs 51.9 ± 52.8 pg/ml, not significant). Survivors were defined as patients surviving to at least day 28. There were no differences of plasma sTREM-1 between survivors
and nonsurvivors at day 0, day 1 and day 3 (34.8 ± 44 52.4 pg/ml Introduction The aim of this study was to investigate the
prevalence of endotoxemia early after elective surgical procedures
in patients admitted to an ICU of a university hospital. Introduction The aim of this study was to investigate the
prevalence of endotoxemia early after elective surgical procedures
in patients admitted to an ICU of a university hospital. Methods One hundred and four nonselect patients were recruited. Patients were excluded if they were admitted during the weekend
or from another ICU and if they were on chronic dialysis. Within
4 hours of admission functional data were collected and severity
scores (APACHE, SOFA) calculated. Arterial blood samples were
also taken and processed according to Spectral Diagnostics’
endotoxin activity (EA) assay [1]. The method allows one to
express EA as a function of each patient’s neutrophil chemi-
luminescence activity (on a scale from 0 to 1). An EA level of 0.4 is S18 Available online http://ccforum.com/supplements/11/S2 1.
Rhodes A, et al.: Plasma DNA concentration as a predictor
of mortality and sepsis in critically ill patients. Crit Care
2006, 10:142. Can plasma-free DNA concentration be a diagnostic tool in
critically ill septic patients? The combination of CRP
and the CIG, as markers of inflammation and inadequate tissue
perfusion, respectively, is a powerful predictor of mortality in the
critically ill surgical patient. P49 vs 49.5 ± 35.9 pg/ml, 42.6 ± 61.1 pg/ml vs 59.6 ± 47.1 pg/ml,
and 47.9 ± 60.2 pg/ml vs 58.2 ± 37.1 pg/ml, not significant). Conclusion In this study including surgical patients with severe
sepsis or septic shock, plasma sTREM-1 is not elevated compared
with healthy controls. Furthermore, the measurement of plasma
sTREM-1 did not allow one to differ between survivors and
nonsurvivors. The suggested role of sTREM-1 as a diagnostic and
prognostic marker in sepsis was not confirmed in this study. vs 49.5 ± 35.9 pg/ml, 42.6 ± 61.1 pg/ml vs 59.6 ± 47.1 pg/ml,
and 47.9 ± 60.2 pg/ml vs 58.2 ± 37.1 pg/ml, not significant). Conclusion In this study including surgical patients with severe
sepsis or septic shock, plasma sTREM-1 is not elevated compared
with healthy controls. Furthermore, the measurement of plasma
sTREM-1 did not allow one to differ between survivors and
nonsurvivors. The suggested role of sTREM-1 as a diagnostic and
prognostic marker in sepsis was not confirmed in this study. Greater than the sum of its parts: C-reactive protein and
the calculated ion gap together are superior in predicting
mortality in critically ill surgical patients F Leitch1, E Dickson1, A McBain1, S Robertson2, D O’Reilly1,
C Imrie1
1Glasgow Royal Infirmary, Glasgow, UK; 2Johannesburg Hospital,
Johannesburg, South Africa
Critical Care 2007, 11(Suppl 2):P49 (doi: 10.1186/cc5209) C-reactive protein predicts mortality on admission to a
surgical high-dependency unit Introduction C-reactive protein (CRP) is a non-specific marker that
may be used to assess the magnitude of the inflammatory response
in critically ill surgical patients. Our aim was to determine the
temporal relationship between CRP measurement and mortality. Methods In a prospective study conducted in a surgical high-
dependency unit (HDU), 132 consecutive patients were evaluated. Regional Ethics Committee approval was obtained. Serum CRP In conclusion, plasma DNA may be a potentially valuable tool to
confirm the diagnosis of sepsis on admission to the ICU and to
monitor disease severity. The biphasic aPTT waveform to diagnose sepsis in
patients with systemic inflammatory response syndrome The biphasic aPTT waveform to diagnose sepsis in
patients with systemic inflammatory response syndrome D Hagg, S Malkoski, C Phillips, D Nichols, D Jacoby
Oregon Health & Science University, Portland, OR, USA
Critical Care 2007, 11(Suppl 2):P51 (doi: 10.1186/cc5211) Results We included 65 patients. The total mortality rate was
16.9% (11 patients). Introduction We tested the ability of the biphasic aPTT waveform to
diagnosis sepsis in patients presenting to the Emergency Department
(ED) with the systemic inflammatory response syndrome (SIRS). The
biphasic aPTT waveform (BPW), which results from rapid complexing
of VLDL and C-reactive protein during aPTT testing, has
demonstrated promise as an early diagnostic test for sepsis. Table 1 (abstract P52)
n = 65
FPC
Lactate
P
Mortality (%)
Group I
30.9 ± 9
15.7 ± 5.8
<0.05
78
Group II
58.1 ± 13
1.8 ± 0.35
22
Group III
100.8 ± 12.8
1.3 ± 0.9
<0.05
0 Methods A prospective, observational study was designed in
which all patients presenting to the ED of an urban university
hospital were screened for SIRS. Patients with SIRS unrelated to
trauma or myocardial infarction were eligible. Plasma for BPW
testing was obtained at the time of enrollment and daily for 7 days
in admitted subjects. The primary outcome was a diagnosis of
sepsis related to the presence of a BPW at enrollment. Secondary
measures were mortality related to the BPW, correlation of any
positive BPW with sepsis, and of the BPW with statin therapy. Two criteria for a positive test, light transmittance at 18 seconds
(TL18) and the initial slope of the waveform (slope) are used. Two
independent experts made the final diagnosis. Conclusions We found a direct and a progressive relation with
statistical significance between the higher mortality rate and the
lower protein C values. The results could mean that the level of
protein C can be used as an evolution marker in septic patients. Functional protein C levels in septic patients E Lafuente, I Pratima, M Fernandes, J Gomes da Silva,
F Moura, F Santos, I Guimaraes, R Lopes, P Santos
Padre Americo, Penafiel, Portugal
Critical Care 2007, 11(Suppl 2):P52 (doi: 10.1186/cc5212) Table 1 (abstract P50) Objective To know whether functional protein C (FPC) levels in
critical septic patients could be intended as an evolution marker
correlated with prognosis and mortality. Materials and methods A prospective study with determination of
FPC levels in all septic patients admitted to the ICU. We used the
IL test™ PC kit (Instrumentation Laboratory; synthetic chromogenic
substrate). We considered an abnormal low FPC when levels were
below 40%, normal FPC when levels were above 80% and low
FPC when levels where between 40% and 80%. Data included
patient age, diagnosis, SAPS II, SOFA score, OSF and mortality. The analytical data included serum lactate and FPC. Patients were
divided into three groups: group I (FPC below 40%), group II (FPC
40–80%) and group III (FPC above 80%). The statistical study
was performed with the Analyse-it® program. The severity was
defined by the usual criteria of SAPS II score and lactate levels and
then compared with the different FPC groups. Mortality was
considered. Conclusion CRP on admission to the surgical HDU is a powerful
predictor of mortality (P < 0.0001), but this correlation does not
persist after the initial measurement. Our data suggest that early
CRP measurement should be undertaken in all critically ill surgical
patients in order to quantify the ultimate magnitude of the
inflammatory response and the associated mortality. Reference 1. Rhodes A, et al.: Plasma DNA concentration as a predictor
of mortality and sepsis in critically ill patients. Crit Care
2006, 10:142. S19 ritical Care March 2007 Vol 11 Suppl 2
27th International Symposium on Intensive Care and Emergency Medicin was measured on admission, day 1 and day 2 and was evaluated
with respect to inhospital mortality. Conclusion The BPW has no utility in the ED to predict the
development of sepsis in at-risk patients. The development of a
BPW at any time during the hospital stay correlates with an
increased risk of sepsis and mortality. Baseline statin therapy may
reduce the chance of developing a BPW. Results CRP on admission to HDU discriminated survivors from
nonsurvivors (P < 0.0001, analysis of variance). A CRP greater
than 100 mg/l correlated very strongly with mortality. The mortality
in patients with a CRP less than 100 mg/l (n = 93) was 2.2%. The
mortality in patients with a CRP greater than 100 mg/l (n = 39)
was 25.6% (P < 0.0001, chi-square test), (Table 1). However,
there were no significant differences in CRP with respect to
mortality on day 1 or day 2 (P = 0.136 and 0.236, respectively). Severe protein C deficiency association with organ
dysfunction and mortality in patients with severe sepsis Results We screened 5,400 consecutive admissions to the ED,
identified 207 eligible subjects and enrolled 105 participants. The
BPW was present at enrollment in 12 subjects by TL18 and in 28
subjects by slope. Forty-six out of 105 subjects eventually
developed a BPW, 54 were diagnosed with sepsis. The sensitivity
and specificity for sepsis were 17% (95% CI, 7–27.6) and 93.8%
(95% CI, 87–100) by TL18 and 26.9% (95% CI, 14.9–38.9) and
71.4% (95% CI, 58.7–84.1) by slope. The positive predictive value
of the test was 75 by TL18 and 50 by slope criteria. The AUC for
ROC analysis of the BPW for diagnosis of sepsis is 0.469 by TL18
and 0.560 by slope. The odds ratio for developing sepsis related to
any positive BPW was 2.977. The odds ratio for development of a
BPW in patients on a statin at the time of presentation was 0.597. Five subjects died by 28 days, 4/5 having a BPW. Introduction We sought to determine whether severe protein C
(PC) deficiency was associated with organ dysfunction (OD) and
mortality in adult patients with severe sepsis. Introduction We sought to determine whether severe protein C
(PC) deficiency was associated with organ dysfunction (OD) and
mortality in adult patients with severe sepsis. Introduction We sought to determine whether severe protein C
(PC) deficiency was associated with organ dysfunction (OD) and
mortality in adult patients with severe sepsis. Methods Retrospective examination of Lilly trials in adult patients
with severe sepsis in which PC measurements were obtained at
baseline. Severe PC deficiency was defined as ≤40% of normal. The Student t test was used to compare mean APACHE II and OD
differences, while the chi-squared or Fisher’s exact test was used
for mortality. Introduction We sought to determine whether severe protein C
(PC) deficiency was associated with organ dysfunction (OD) and
mortality in adult patients with severe sepsis. Methods Retrospective examination of Lilly trials in adult patients
with severe sepsis in which PC measurements were obtained at
baseline. Severe PC deficiency was defined as ≤40% of normal. The Student t test was used to compare mean APACHE II and OD
differences, while the chi-squared or Fisher’s exact test was used
for mortality. Methods Retrospective examination of Lilly trials in adult patients
with severe sepsis in which PC measurements were obtained at
baseline. Severe PC deficiency was defined as ≤40% of normal. P51 The biphasic aPTT waveform to diagnose sepsis in
patients with systemic inflammatory response syndrome The biphasic aPTT waveform to diagnose sepsis in
patients with systemic inflammatory response syndrome
D Hagg, S Malkoski, C Phillips, D Nichols, D Jacoby
Oregon Health & Science University, Portland, OR, USA
Critical Care 2007, 11(Suppl 2):P51 (doi: 10.1186/cc5211) Human protein C concentrate in the treatment of hemolytic
uremic syndrome Human protein C concentrate in the treatment of hemolytic
uremic syndrome M Sasse, L Pape, H Koeditz, A Wessel, K Seidemann,
J Thomas, B Brent
Medical University Children’s Hospital, Hannover, Germany
Critical Care 2007, 11(Suppl 2):P54 (doi: 10.1186/cc5214) In severe sepsis, microcirculatory dysfunction caused by inflam-
mation, endothelial activation and procoagulant response leads to
mithocondrial dysfunction (termed microcirculatory and mito-
chondrial distress syndrome). If undetected, this condition can lead
to parenchymal cellular distress and so to organ failure. As regional
and microcirculatory distress are independent of systemic hemo-
dynamic-derived and oxygen-derived variables, we recorded the
course of microvascular parameters with a Microscan Video Micro-
scope (Microvision, The Netherlands) in four patients with severe
sepsis. We studied the sublingual region because of its embryo-
logic correlation to splanchnic circulation, its thin mucosa. The
instrument used a new improved imaging modality for observation
of the microcirculation called sidestream dark-field imaging. We
consider here four patients with severe sepsis related to
esophagectomy, severe polytrauma with splanchnic organ damage
and mediastinitis treated with drotrecogin alpha (activated) (DA) at
24 µg/kg/hour for 96 hours. The patients were admitted to the
ICU, ventilated mechanically, monitored hemodynamically via a
PICCO system and supported with dobutamine. Videomicroscopy
was made before administration of DA and was repeated every
24 hours during the treatment with DA and at 24 hours after its
suspension. We recorded values of blood pressure, cardiac func-
tion, lactate levels, acid–base balance, temperature and dobuta-
mine dosage. Introduction Human protein C (PC) concentrate may anticipate
thrombotic microangiopathy and facilitate fibrinolysis in the severe
hemolytic uremic syndrome (HUS). We report the effects of PC in
six HUS patients. HUS is characterized by a simultaneous occur-
rence of hemolytic anemia, thrombocytopenia and acute renal
failure. Postdiarrheal HUS is often based on an infection with
EHEC producing Shiga toxins. Our current pathogenetic under-
standing is that Shiga toxins cause endothelial injury, leading to
thrombotic microangiopathy. There is still a 5% rate of mortality
particularly caused by cerebral involvement. Methods We treated six children with a severe cerebral manifes-
tation, five of them suffered from a multiple organ dysfunction
syndrome (MODS), of HUS with PC over 7–10 days. All patients
suffered peritoneal dialysis, one patient a plasmapheresis. In
addition to the treatment of the MODS, all of them received
100–200 U/day PC. Results All of the patients showed signs of disseminated
intravascular coagulation. P55 A Donati, M Romanelli, L Romagnoli, M Ruzzi, V Beato,
V Gabbanelli, S Nataloni, T Principi, P Pelaia
AOU Umberto I Ancona, Rianimazione Clinica, Ancona, Italy
Critical Care 2007, 11(Suppl 2):P55 (doi: 10.1186/cc5215) Severe protein C deficiency association with organ
dysfunction and mortality in patients with severe sepsis The Student t test was used to compare mean APACHE II and OD
differences, while the chi-squared or Fisher’s exact test was used
for mortality. S20 Available online http://ccforum.com/supplements/11/S2 Table 1 (abstract P53)
Study
EVAA
PROWESS
ENHANCE
ADDRESS
Protein C
≤40%
>40%
≤40%
>40%
≤40%
>40%
≤40%
>40%
n
65
60
615
959
795
1127
593
1154
Mean APACHE II
17.4
17.1
P = 0.79
25.9
24.1
P < 0.001
23.2
20.9
P < 0.001
18.5
18.1
P = 0.14
score
Mean OD
1.5
1.4
P = 0.42
2.8
2.2
P < 0.001
3.1
2.4
P < 0.001
1.6
1.4
P < 0.001
Placebo mortality
50.0%
20.0%
P = 0.07
41.8%
25.3%
P < 0.001
19.7%
12.0%
P = 0.002 Table 1 (abstract P53) patients yield hope that PC treatment may be an effective therapy
regimen in the treatment of severe HUS. Results Severe PC deficiency was associated with a statistically
significant increase in the mean APACHE II score in two of four
trials, a significant increase in the mean OD in three of four trials,
and a significant increase in mortality in two of three trials (Table 1). Conclusion Severe PC deficiency at baseline appears to be
associated with a greater degree of organ dysfunction, and
increased mortality in adult patients with severe sepsis. P56 Results A total number of 61 patients, aged 18–65 years, were
included in the analysis. The pathogens and infection location were
different. Patients were diagnosed according to recommendations
of the Polish Sepsis Group and treatment with APC was
introduced. The increase in number was: in 2004 vs 2003, 200%;
in 2005 vs 2004, 111%; in 2006 up to 10 December vs 2005,
57.8%. The surviving ratio increased every year but in 2006 it
decreased compared with 2005. Multicentre audit of the use of drotrecogin alfa (activated)
in UK critical care units Multicentre audit of the use of drotrecogin alfa (activated)
in UK critical care units Human protein C concentrate in the treatment of hemolytic
uremic syndrome We found typical hypodense lesions in
basal ganglia and edema of the brain in CT. During the therapy
with PC, MODS was remarkable improved and abnormal D-dimer
and PAI-1 levels could be normalised. All of the patients recovered
a nearly normal kidney function. Two patients persisted in a severe
reduced neurological status. The others showed only slight or no
neurological disabilities on discharge. No adverse effects were
observed with the PC concentrate administration. At admission the sublingual microcirculation showed a low
capillary density, vessel heterogeneity with a qualitative low flow
and flow–no flow. After the first 24 hours from the beginning of DA
infusion, sublingual flow showed an increase of vessel density,
particularly of the number of small vessels, and the number of
continuously perfused vessels increased during and post therapy
with DA. We analyzed the microvascular flow with a simple semi-
quantitative method dividing the images into four equal quadrants
and quantificating flow (hyperdynamic, continuous, sluggish,
flow–no flow, no flow) for each cohort of vessel diameter (small,
medium, large). We analyzed the mean value of results of three
images for each patient pre and post DA therapy. Data are
presented as the median. Before starting therapy with DA, the
microvascular flow index (MFI) was 2.06 for small vessels, 2.09 for
medium vessels, and 2.37 for large vessels. After DA infusion, the
MFI was 3, 3, and 3, respectively, for small, medium and large Conclusions There is no generally accepted therapy regimen to
treat HUS in case of neurological involvement. Mortality in HUS
accompanied with cerebral microangiopathy is high and difficult to
alter. This is the first trial of human PC concentrate administration
to anticipate thrombotic microangiopathy in HUS. All of our
patients
showed
rapid
clinical
improvement
under
PC
administration. Four of six patients were discharged in a healthy
condition despite their severe disease. The containment of the
severe neurological involvement and the lack of side effects in the
treatment with human PC concentrate administration in our S21 Table 1 (abstract P57) Table 1 (abstract P57)
2003
2004
2005
2006 (10 Dec)
Number of treated
3
9
19
30
patients
Surviving ratio
33% (1/3)
43.5% (4/9)
62.7%
47% Methods A data collection form was developed and tested to mirror
the information collected in PROWESS. This form was completed
for every admission that received DrotAA and a senior clinician
confirmed completeness. Data were entered centrally and validated. Analysis Admissions receiving DrotAA and with severe sepsis and
two or more organ dysfunctions in the first 24 hours following
admission to the unit were matched to controls on: source of
admission; organ dysfunctions; ICNARC physiology score; and
age. Four pools of control patients were used for matching: (a)
historic admissions (January 2000–August 2002) from the same
unit; (b) contemporaneous admissions from the same unit; (c)
contemporaneous admissions from units that never used DrotAA;
and (d) contemporaneous admissions from units prior to their first
use of DrotAA. Analyses were undertaken using conditional, fixed-
effects, Poisson regression. Discussion During 4 years of treatment of severe sepsis in the
ICU with APC, important changes were observed: faster
recognition and diagnosis, transfer to the reference hospital, and
introduction of adequate therapy. The decrease in the surviving
ratio in 2006 is probably due to a more serious state of the
admitted patients – more initial infection located in the abdomen
after surgery. Conclusion The education program is essential in increasing the
number of fast recognitions, which influences the surviving ratio. Surviving ratio of severe sepsis treated with activated
protein C in one university intensive care unit during
2003–2006 Surviving ratio of severe sepsis treated with activated
protein C in one university intensive care unit during
2003–2006 A Tokarz, T Gaszynski, W Gaszynski
Medical University of Lodz, Poland
Critical Care 2007, 11(Suppl 2):P57 (doi: 10.1186/cc5217) Introduction Treatment of severe sepsis with infusion of activated
protein C (APC) (Xigris) in the ICU of Barlicki University Hospital
was initiated in 2003. From 2003 the number of treated patients
increased significantly. This is due to better recognition. The
introduced program consists of education of working staff in all
hospitals in the region. Barlicki Hospital is a reference hospital for
treatment of sepsis, and patients with diagnosis of sepsis are
transferred to this ICU. University ICU doctors are teaching
workshops how to recognize and treat sepsis. Methods The surviving ratio in patients treated with APC was
estimated retrospectively. Analysis included the years from 2003 to
10 December 2006. P58 Results One hundred and twelve units participated in the audit;
1,079 admissions (one in 16) with severe sepsis and two or more
organ dysfunctions in the first 24 hours following admission to the
unit received DrotAA. For the four control pools, matching was
successful for: (a) 657 (61%); (b) 820 (76%); (c) 702 (65%); and
(d) 965 (89%). Matched cases were older, more acutely ill and had
higher hospital mortality than unmatched cases. The relative risks
(95% confidence interval) associated with DrotAA were: (a) 0.84
(0.77–0.92); (b) 0.85 (0.78–0.93); (c) 0.75 (0.68–0.83); and (d)
0.80 (0.73–0.86). A priori subgroup analyses indicated greater
effect for patients with three or more organ dysfunctions. Results One hundred and twelve units participated in the audit;
1,079 admissions (one in 16) with severe sepsis and two or more
organ dysfunctions in the first 24 hours following admission to the
unit received DrotAA. For the four control pools, matching was
successful for: (a) 657 (61%); (b) 820 (76%); (c) 702 (65%); and
(d) 965 (89%). Matched cases were older, more acutely ill and had
higher hospital mortality than unmatched cases. The relative risks
(95% confidence interval) associated with DrotAA were: (a) 0.84
(0.77–0.92); (b) 0.85 (0.78–0.93); (c) 0.75 (0.68–0.83); and (d)
0.80 (0.73–0.86). A priori subgroup analyses indicated greater
effect for patients with three or more organ dysfunctions. Interpretation All results were consistent with PROWESS, but
need to be interpreted with caution due to their nonrandomised
nature and the potential existence of important unknown
confounders. In addition, the fact that only one in 16 potentially
suitable admissions received DrotAA suggests a strong possibility
for treatment bias. A large, single-centre UK registry of drotrecogin
alfa-activated use Multicentre audit of the use of drotrecogin alfa (activated)
in UK critical care units K Rowan, C Welch, E North, D Harrison
Intensive Care National Audit & Research Centre, London, UK
Critical Care 2007, 11(Suppl 2):P56 (doi: 10.1186/cc5216) Background
Following
positive
results
from
PROWESS,
drotrecogin alfa (activated) (DrotAA) was approved for use in
Europe in August 2002. At this time, ICNARC commenced an
audit to monitor the diffusion of the drug into routine UK practice
and to undertake a nonrandomised evaluation of its effectiveness. P57 vessels. Differences between groups were assessed using the
Mann–Whitney U test. We showed a statistically significant differ-
ence with P < 0.0001 between MFI before and post DA therapy. We demonstrated a quantitative and qualitative improvement of
sublingual microcirculation with an increase of capillary density
distribution (area–width) and average velocity versus vessel width. The course of microvascular blood flow may play an important role
in sepsis and septic shock because of its relation to the
development of multiple organ failure and death. Several studies
have demonstrated that changes in microvascular perfusion are an
independent predictor of outcome. The improvement of the micro-
circulation and vascular tone in septic shock by DA is probably
related to its anticoagulant/antithrombotic and antiinflammatory
action, to the decrease of TNFα production and inhibition of iNOS
induction, and to improvement of endothelial barrier function and
inhibition of chemotaxis, but further investigations are required to
elucidate the exact mechanisms. These observations could
suggest that DA could have a particular interest in the early
management of severe sepsis. vessels. Differences between groups were assessed using the
Mann–Whitney U test. We showed a statistically significant differ-
ence with P < 0.0001 between MFI before and post DA therapy. We demonstrated a quantitative and qualitative improvement of
sublingual microcirculation with an increase of capillary density
distribution (area–width) and average velocity versus vessel width. The course of microvascular blood flow may play an important role
in sepsis and septic shock because of its relation to the
development of multiple organ failure and death. Several studies
have demonstrated that changes in microvascular perfusion are an
independent predictor of outcome. The improvement of the micro-
circulation and vascular tone in septic shock by DA is probably
related to its anticoagulant/antithrombotic and antiinflammatory
action, to the decrease of TNFα production and inhibition of iNOS
induction, and to improvement of endothelial barrier function and
inhibition of chemotaxis, but further investigations are required to
elucidate the exact mechanisms. These observations could
suggest that DA could have a particular interest in the early
management of severe sepsis. Surviving ratio of severe sepsis treated with activated
protein C in one university intensive care unit during
2003–2006 Available online http://ccforum.com/supplements/11/S2 Materials and methods From January 2003 to August 2006 we
used APC to treat 44 severely septic patients in our ICU. We
obtained complete data for 37 patients. We collected data from the
case notes, ICU charts and drotrecogin alfa (activated) data forms
and recorded relevant data on an Excel spreadsheet proforma. Results NICE guidelines. We were 100% compliant with patient
selection criteria for APC administration, which included a known
or suspected site of infection, SIRS criteria and organ dysfunction
criteria. All prescriptions were made by intensive care consultants. We were not fully compliant in excluding patients who met
exclusion criteria (2/37 patients), although these cases were
justified clinically by the consultants prior to administration. Data entry. In 90% of cases the patient selection fields were
completed, but only 30% of the exclusion and outcome fields were
completed. In 30% of patients where a lactate ≥1.5 times normal was
listed as one of the inclusion criteria, it was not associated with a pH
≤7.30 or a base deficit ≥5.0; however, all these patients had ≥3
organ-dysfunction criteria and hence still met the inclusion criteria. Outcomes. Seven patients (15.9%) died during or within 28 days
of APC administration. The standardised mortality ratio (SMR) was
lower in patients receiving APC when compared with the rest of
patients admitted over the same period (SMR ~0.5 vs ~1.0). Twenty-eight patients had an APACHE II score <25 and the
effective cost per survivor was ~€16,800. Patients with APACHE
II scores ≥25 had an effective cost per survivor of ~€22,400. Nine
patients (20.5%) had their drotrecogin alfa (activated) infusions
interrupted or discontinued for various reasons (including seven
patients who had hemorrhagic complications, three of which were
serious). respect to its use. The aim of this study was to demonstrate the
safety profile and efficacy of DrotAA treatment within a large, 29-
bed university hospital critical care unit. respect to its use. The aim of this study was to demonstrate the
safety profile and efficacy of DrotAA treatment within a large, 29-
bed university hospital critical care unit. Materials and methods From January 2003 to August 2006 we
used APC to treat 44 severely septic patients in our ICU. We
obtained complete data for 37 patients. We collected data from the
case notes, ICU charts and drotrecogin alfa (activated) data forms
and recorded relevant data on an Excel spreadsheet proforma. A large, single-centre UK registry of drotrecogin
alfa-activated use L Macchiavello, G Ellis, S Bowden, M Smithies
University Hospital of Wales, Cardiff, UK
Critical Care 2007, 11(Suppl 2):P58 (doi: 10.1186/cc5218) Introduction As one of the few treatment interventions to
demonstrate mortality efficacy at a randomized controlled trial level
[1], the prescription of drotrecogin alfa-activated (DrotAA) (Xigris™),
where appropriate, plays an important role in the management of
severe sepsis. However, concerns regarding the potential for
serious bleeding events have helped sustain a degree of
scepticism regarding the use of DrotAA [2]. As early adopters of
evidence-based medicine, Cardiff Critical Care Unit has prescribed
DrotAA since late 2002 and has considerable experience with Interpretation All results were consistent with PROWESS, but
need to be interpreted with caution due to their nonrandomised
nature and the potential existence of important unknown
confounders. In addition, the fact that only one in 16 potentially
suitable admissions received DrotAA suggests a strong possibility
for treatment bias. S22 References 1. Bernard GR, Vincent JL, Laterre PF, et al.: Efficacy and
safety of recombinant human activated protein C for
severe sepsis. N Engl J Med 2001, 344:699-709. 1. Bernard GR, Vincent JL, Laterre PF, et al.: Efficacy and
safety of recombinant human activated protein C for
severe sepsis. N Engl J Med 2001, 344:699-709. 1. Bernard GR, Vincent JL, Laterre PF, et al.: Efficacy and
safety of recombinant human activated protein C for
severe sepsis. N Engl J Med 2001, 344:699-709. C Cameron, W Plaxton
Grand River Hospital, Kitchener, Canada
Critical Care 2007, 11(Suppl 2):P60 (doi: 10.1186/cc5220) ritical Care 2007, 11(Suppl 2):P60 (doi: 10.1186/cc522 2. Mackenzie AF: Activated Protein C: do more survive? Inten-
sive Care Med 2005, 31:1624-1626. 2. Mackenzie AF: Activated Protein C: do more survive? Inten-
sive Care Med 2005, 31:1624-1626. 2. Mackenzie AF: Activated Protein C: do more survive? Inten-
sive Care Med 2005, 31:1624-1626. Introduction Grand River Hospital (GRH) is a 495-bed non-
teaching, acute care referral center in Southwestern Ontario,
supporting regional programs including dialysis, oncology, surgery
and stroke thrombolysis. Since the introduction of drotrecogin alfa
(activated) (DAA) in 2003, GRH has treated 58 patients with this
agent for severe sepsis and septic shock. We sought to compare,
where possible, GRH ICU/hospital outcomes and bleeding
complications with those from published literature. Available online http://ccforum.com/supplements/11/S2 Methods Demographic data were obtained from the unit’s daily
updated Riyadh ICU programme database and clinical data were
collected from patients’ medical notes and observation charts. All
data were prospectively entered into our DrotAA registry, the
results of which are shown below. Results NICE guidelines. We were 100% compliant with patient
selection criteria for APC administration, which included a known
or suspected site of infection, SIRS criteria and organ dysfunction
criteria. All prescriptions were made by intensive care consultants. We were not fully compliant in excluding patients who met
exclusion criteria (2/37 patients), although these cases were
justified clinically by the consultants prior to administration. Results Between October 2002 and November 2005, 133
patients with severe sepsis were treated with DrotAA. The mean
age was 61 years (range: 20–87 years) and 54% were male. The
mean admission APACHE II score was 22 (range: 11–48), and on
day 1 of DrotAA infusion the median number of organs that failed
was 2.0 (range: 0–4), 129/133 (97%) were mechanically
ventilated and 131/133 (98.5%) were on vasopressors. The
median time to start DrotAA after documented diagnosis of severe
sepsis was 12.6 hours (range: 0–41 hours) and the median
duration of DrotAA infusion was 89.5 hours (range: 10–105 hours). The incidence of serious (life-threatening) bleeding events was
2.3% (n = 3): gastrointestinal (n = 1), intraabdominal (n = 1) and
intrathoracic (n = 1); all were nonfatal and there were no
intracranial bleeds. The 28-day mortality was 31.6%, the ICU
mortality was 33.1%, the hospital mortality was 36.8% and the
1-year mortality was 47%. Data entry. In 90% of cases the patient selection fields were
completed, but only 30% of the exclusion and outcome fields were
completed. In 30% of patients where a lactate ≥1.5 times normal was
listed as one of the inclusion criteria, it was not associated with a pH
≤7.30 or a base deficit ≥5.0; however, all these patients had ≥3
organ-dysfunction criteria and hence still met the inclusion criteria. g
y
Outcomes. Seven patients (15.9%) died during or within 28 days
of APC administration. The standardised mortality ratio (SMR) was
lower in patients receiving APC when compared with the rest of
patients admitted over the same period (SMR ~0.5 vs ~1.0). Twenty-eight patients had an APACHE II score <25 and the
effective cost per survivor was ~€16,800. Patients with APACHE
II scores ≥25 had an effective cost per survivor of ~€22,400. P60 Retrospective observational outcomes for drotrecogin alfa
(activated) Retrospective observational outcomes for drotrecogin alfa
(activated) References Available online http://ccforum.com/supplements/11/S2 Nine
patients (20.5%) had their drotrecogin alfa (activated) infusions
interrupted or discontinued for various reasons (including seven
patients who had hemorrhagic complications, three of which were
serious). Conclusions This is one of the largest UK registries of DrotAA
usage published to date. Our results demonstrate a very low
incidence of serious bleeding events associated with DrotAA treat-
ment (2.3% vs 3.5% in PROWESS); it is interesting to note that all
three adverse events occurred prior to 2004. This detail, combined
with our low median time to start DrotAA infusion (which has
steadily decreased over the past 4 years), would suggest the
presence of a learning curve for DrotAA usage on ICUs. It is also
encouraging to note that our overall hospital mortality was lower
than the predicted APACHE II hospital mortality for these patients
(36.8% vs 42.4%). Finally, this is one of the first UK studies to
describe long-term mortality outcome in patients receiving DrotAA
therapy. Further studies are required to more formally assess the
impact of DrotAA treatment on long-term survival from severe
sepsis. Conclusions and recommendations We use APC in compliance
with the NICE guidelines. APC is cost-effective in patients with an
APACHE II score <25 in our ICU. 1. Bernard GR, et al.: N Engl J Med 2001, 334:699-709. 2. National Institute of Clinical Excellence [http://www.nice. org.uk/guidance/TA84] 2. National Institute of Clinical Excellence [http://www.nice. org.uk/guidance/TA84] P62 P62 59.4 years. Primary sources of infection were: intra-abdominal
36.2%, respiratory 27.6%, genitourinary 8.6%, and 27.6% from
other sources. GRH ICU mortality was 44.8% and hospital
mortality was 51.7%. Analysis by age revealed overall survival rates
of 78.6% for patients ≤50 years, 54.5% for 51–60 years, 52.9%
for 61–70 years, 20% for 71–80 years, and 0% for patients >80
years of age. Hemorrhagic complication rates were higher than in
published reports. Of 58 treatments, we recorded a total of nine
hemorrhages (15.5%). The mortality rate in this cohort was 33.3%. Conclusions These data suggest that ‘field performance’ of DAA
may not be replicating the favorable clinical endpoints as reported
in PROWESS. The Ontario Ministry of Health should consider
implementing a provincial registry system for patients with severe
sepsis and septic shock, empowering ICUs to track relevant
demographic, acuity, and outcome data with a view to optimizing
DAA use through patient selection and risk stratification. 59.4 years. Primary sources of infection were: intra-abdominal
36.2%, respiratory 27.6%, genitourinary 8.6%, and 27.6% from
other sources. GRH ICU mortality was 44.8% and hospital
mortality was 51.7%. Analysis by age revealed overall survival rates
of 78.6% for patients ≤50 years, 54.5% for 51–60 years, 52.9%
for 61–70 years, 20% for 71–80 years, and 0% for patients >80
years of age. Hemorrhagic complication rates were higher than in
published reports. Of 58 treatments, we recorded a total of nine
hemorrhages (15.5%). The mortality rate in this cohort was 33.3%. Conclusions These data suggest that ‘field performance’ of DAA
may not be replicating the favorable clinical endpoints as reported
in PROWESS. The Ontario Ministry of Health should consider
implementing a provincial registry system for patients with severe
sepsis and septic shock, empowering ICUs to track relevant
demographic, acuity, and outcome data with a view to optimizing
DAA use through patient selection and risk stratification. Three years experience with drotrecogin alfa (activated)
protein C in severe sepsis and septic shock at Salmaniya
Medical Complex, Bahrain H Mohamed, AA Hameed, M Al-Ansari
Salmaniya Medical Complex, Manama, Bahrain
Critical Care 2007, 11(Suppl 2):P62 (doi: 10.1186/cc5222) Objective To evaluate the role of activated protein C (APC) in
severe sepsis and septic shock. Method The data were collected in a prospective manner from July
2002 to November 2006 in the adult medical/surgical ICU at
Salmaniya Medical Complex Bahrain. The number of demographic
variables were collected from patients’ files. Risk/benefit analysis of activated protein C in patients with
intra-abdominal sepsis Risk/benefit analysis of activated protein C in patients with
intra-abdominal sepsis E Borthwick, D Stewart, E Mackle, C McAllister
Craigavon Area Hospital, Co. Armagh, UK
Critical Care 2007, 11(Suppl 2):P61 (doi: 10.1186/cc5221) E Borthwick, D Stewart, E Mackle, C McAllister
Craigavon Area Hospital, Co. Armagh, UK Out of the total 444 septic patients 149 were assessed for APC;
in the 85 patients fulfilling criteria for and receiving APC the
mortality was 43.5%, and for the 64 patients not receiving APC the
mortality was 64%. All suspected septic patients admitted to the
ICU received appropriate antibiotic therapy within 4 hours of ICU
admission and were upgraded/changed according to culture/
sensitivity reports if necessary. In the nonreceiving group (i.e. 64
patients) 12 patients could not receive APC due to financial
restriction because initially foreigners were not entitled to this drug
in Bahrain, but later this restriction was removed, and the remaining
52 patients could not receive either due to bleeding or very recent
surgeries. Some patients could not receive complete treatment
either due to bleeding complications or because they died. The
mortality was measured at 28 days. Introduction and objective To establish whether activated protein
C (APC) is safe in surgical patients with intra-abdominal sepsis
(IAS). APC has been used in the treatment of IAS in our hospital
since 2003. Fears persist regarding the potential for clinically
significant bleeding in this surgical subgroup of patients. Methods
Forty-four patients with IAS received APC as a
standardized regime between March 2003 and August 2006. A
retrospective medical and ICU chart review was undertaken. Data
collected included clinically significant bleeding episodes and
mortality. Descriptive subgroup analysis of unexpected non-
survivors(died in the ICU with APACHE II (APII) predicted mortality
< 50%) and unexpected survivors (survived to ICU discharge with
APII predicted mortality > 50%) was performed as statistical
analysis of such small patient numbers was inappropriate. Furthermore, as per our experience, if APC started in the early
stage of sepsis and the course is completed the outcome is better
– out of 85 patients who received APC, 45 patients received in the
early stage and completed the dose and 32 of these patients
survived at 28-day mortality. An average three (ventilator-free)
organs failed in the survival group and two (ventilator-free) organs
failed in the expired group. Risk/benefit analysis of activated protein C in patients with
intra-abdominal sepsis Seventeen patients started treatment in
the early stage and could not complete the course due to bleeding
or other complications, 11 patients expired; 13 patients started in
the late stage and completed the course, five patients expiring; and
10 patients started in the late stage and eight of these patients
expired. Results There was one episode of clinically significant bleeding
(from a mucous fistula: self-limiting). There were no intracranial
haemorrhagic events. ICU mortality was 38.6% with mean APII
predicted mortality of 37.16% and inhospital mortality of 47.7%. These exceeded rates for APC-treated surgical cohorts in the
literature [1]. Unexpected survivors (5/44) were more likely to have
been admitted from theatre. They had a shorter mean time from
hospital–ICU admission (10.5 vs 5.6 days), duration on a ventilator
(10.8 vs 17.5 days), vasopressor (9 vs 17.7 days) and renal
replacement therapy (10.5 vs 23.5 days) dependence. All un-
expected nonsurvivors (11/44) had a diagnosis of fistula or
perforation. They were more likely to have been transferred to the
ICU from another hospital or ward than from theatre. Co-
morbidities were more severe. Conclusion On the basis of our experience and the results of
multiple trials, we recommend APC should be given to the patients
who meet all the inclusion criteria. Conclusion 1. APC was very safe to use in this group of critically
ill surgical patients. 2. Although patients may fulfil standard criteria
for APC use, if there is no definitive surgical cure for the IAS, then
APC is inappropriate. 3. Delay in commencement of APC in
surgical patients due to bleeding concerns may be contributing to
the high mortality. Earlier perioperative use of APC in selected
cases may offer improved mortality benefit, and we are undertaking
a prospective audit to investigate this. P62 Results A total of 444 patients were admitted to the ICU with the
diagnosis of sepsis or severe sepsis. One hundred and forty-nine
severe septic patients were assessed for APC: 85 patients received
APC, and 64 patients could not receive APC due to financial
problems or due to bleeding, coagulation derangement or very
recent surgeries. In the total 444 septic patients admitted to the ICU,
152 patients expired (mortality 34.2%) and 141 had positive blood
culture; 233 patients received inotrops. The total average APACHE II
score was 28.9 and for expired patients was 35.1. P59 Audit of adherence to National Institute of Clinical Audit of adherence to National Institute of Clinical
Excellence guidelines for the use of drotrecogin alfa
(activated) Excellence guidelines for the use of drotrecogin alfa
(activated) R Vedantham, B Iyowu
University Hospital Lewisham, London, UK
Critical Care 2007, 11(Suppl 2):P59 (doi: 10.1186/cc5219) Methods All charts for patients treated with DAA in our CAICU for
severe sepsis and septic shock between February 2003 and June
2006 were reviewed retrospectively for infection source, ICU/
hospital mortality, survival by age and incidence of hemorrhagic
complications. Where possible, we compare our data with those
from PROWESS, ENHANCE and a recent Ontario/Quebec-based
multicenter usage evaluation. A two-organ system failure threshold
for DAA consideration is used. Outcomes were categorized as ICU
mortality and hospital mortality, as opposed to 28-day mortality
used in PROWESS and ENHANCE. Introduction Activated protein C (APC) is an endogenous protein,
which has fibrinolytic and anti-inflammatory properties. This is
available as human recombinant APC and is used in the treatment
of patients with severe sepsis [1]. The National Institute of Clinical
Excellence (NICE) suggested guidelines for the use of APC [2]. We retrospectively audited the records of patients who received
APC during their admission to our ICU between January 2003 and
August 2006. We audited our practice against three parameters:
compliance with the NICE guidelines, accuracy of data forms, and
outcomes of treatment. Results All 58 patients who received DAA at GRH were included
in our analysis. The mean age of patients treated with DAA was S23 P61 Risk/benefit analysis of activated protein C in patients with
intra-abdominal sepsis Available online http://ccforum.com/supplements/11/S2 Results Overall, 12,492 patients with severe sepsis from 37
countries were enrolled and 882 (7%) patients received DAA
therapy. The highest rate of use of DAA was seen in the United
States at 27% (206/760). Patients who received DAA versus
those who did not receive DAA were younger (median age 59
versus 64 years), had greater organ dysfunction (cardiovascular
dysfunction (90% versus 74%), respiratory dysfunction (90%
versus 81%), renal dysfunction (60% versus 45%), metabolic
abnormalities (63% versus 42%), three or more organ dys-
functions (84% versus 67%)) and higher median APACHE II
scores (25.0 vs 23.0), all P < 0.001. The mortality rate for patients
treated with DAA was 49.6% and for those not treated with DAA
was 49.7%. Although imbalances in other baseline characteristics,
not collected in PROGRESS, may have also been present, when
adjusted for age and number of organ dysfunctions the odds ratio
for hospital mortality associated with DAA use was 0.75
(0.63–0.90, P = 0.002). Methods Fifty-seven patients with severe sepsis (age 51 ± 15
years, range 20–77 years, male:female 32:25) admitted to the ICU
were included. All patients had three or more signs of systemic
inflammation with at least two major organ dysfunctions or the
presence of ARDS. Demographic, clinical and laboratory profiles at
baseline, and during the hospital stay, development of complica-
tions, duration of hospital/ICU stay and hospital survival were
recorded. All management decisions including initiation of DA
(24 µ/kg/hour), duration of treatment as well as its discontinuation
were the prerogative of the ICU team. Results The majority of patients had a confirmed infection (n = 36,
63.2%), with the commonest site of focus being the lung (n = 25,
43.9%) followed by the abdomen (n = 13, 22.8%). A significant
number of patients had at least three major organ dysfunctions
(n = 37, 64.9%). A large number of patients had an APACHE II
score in the range 25–29 (n = 22, 38.6%). Whereas 44 patients
(77.2%) were on some kind of vasopressor support, 51 needed
ventilatory support (89.5%). A total of 20 patients (35.1%) survived
to hospital discharge. Patients received DA for a mean duration of
74.8 ± 26.2 hours (range 25–96 hours) and only 32 patients could
complete treatment (56.1%). The outcome was significantly better
in patients who could complete therapy (53.1% vs 13.6%,
P = 0.001). Epidemiology of severe sepsis in India S Todi, S Chatterjee, M Bhattacharyya
AMRI Hospitals, Kolkata, India
Critical Care 2007, 11(Suppl 2):P65 (doi: 10.1186/cc5225) Conclusion Mortality of patients with severe sepsis remains high
despite the introduction of DA. Early institution may be associated
with better outcomes. Patients receiving a complete course of
treatment have better survival. Introduction A multicentre, prospective, observational study was
conducted in 12 intensive therapy units (ITUs) in India from June
2006 to November 2006 to determine the incidence and outcome
of severe sepsis among adult patients. Available online http://ccforum.com/supplements/11/S2 Major bleeding necessitating discontinuation was seen
in four patients (7%) whereas the other 21 patients (36.9%) died
before completing 96 hours of therapy. DA was initiated within
48 hours of development of organ dysfunction in the majority of
patients (n = 31, 54.4%), and a trend towards better outcome in
patients with early treatment was noted although the difference did
not reach statistical significance (mortality rate 58% for early
treatment vs 73.1% for delayed treatment, P = not significant). Conclusion In a large global registry, patients receiving DAA
therapy were younger with higher disease severity than patients
not treated with DAA. When adjusted for age and number of organ
dysfunctions, DAA was associated with a reduction in the odds of
hospital mortality similar to that seen at day 28 in PROWESS. These data are supportive of the effectiveness of DAA in clinical
practice. P64 Methods All patients admitted to ITUs were screened daily for
SIRS, organ dysfunction and severe sepsis. Patients with severe
sepsis were further studied. Drotrecogin alfa in patients with severe sepsis: experience
from a tertiary care center in North India Drotrecogin alfa in patients with severe sepsis: experience
from a tertiary care center in North India R Chawla, S Kansal, A Lall, M Kanwar, D Rosha, A Bansal, V Sikri
Indraprastha Apollo Hospitals, New Delhi, India
Critical Care 2007, 11(Suppl 2):P63 (doi: 10.1186/cc5223) Introduction Drotrecogin alfa (DA) remains the only approved drug
for the specific treatment of severe sepsis. Although it has been in
wide clinical usage, there are no data on its use in Indian patients. 1. Barie PS, et al.: Benefit/risk profile of drotAA in surgical
patients with severe sepsis. Am J Surg 2004, 188:212-
220. S24 Available online http://ccforum.com/supplements/11/S2 Severe sepsis and drotrecogin alfa (activated) use: results
from the PROGRESS registry Results A total of 1,344 ITU admissions were studied. There were
no SIRS in 31.3% and SIRS without organ dysfunction in 51.6%. SIRS with organ dysfunction was found in 230 (17.1%) patients,
of which 54 (23.5%) were not due to sepsis and 176 (76.5%)
were due to sepsis. The incidence of severe sepsis was 13.1% of
all admissions. The mean age of the study population was 54.9
years (SD 17.6), of which 67% were male. The median APACHE II
score was 22 (IQR 17–28) with predominant (88%) medical
admission. ITU mortality of all admissions was 13.9% and that of R Beale1, F Brunkhorst2, G Martin3, M Williams4, D Nelson4,
J Janes4
1St Thomas’ Hospital, London, UK; 2Friedrich-Schiller University,
Jena, Germany; 3Emory University School of Medicine, Atlanta, GA,
USA; 4Lilly Research Laboratories, Indianapolis, IN, USA
Critical Care 2007, 11(Suppl 2):P64 (doi: 10.1186/cc5224) Introduction Since the launch of drotrecogin alfa (activated)
(DAA) a number of institutions and countries have published data
on its use in clinical practice, based on audit or registry data. Such
publications have tended to report DAA use in higher disease
severity populations together with higher mortality outcomes
compared with clinical trials. We utilized the Global PROGRESS
(Promoting Global Research Excellence in Severe Sepsis)
database to examine the baseline characteristics and outcome of
patients with and without DAA treatment. Figure 1 (abstract P65) P66 PISA: the prevalence of infection in intensive care units in
South Africa
S Bhagwanjee, J Scribante, H Perrie, F Paruk
University of the Witwatersrand and the CCSSA, Johannesburg,
South Africa
Critical Care 2007, 11(Suppl 2):P66 (doi: 10.1186/cc5226) PISA: the prevalence of infection in intensive care units in
South Africa R Goldwasser1, C David1, R Hatum2, J Salles2, O Barbosa3,
C Piras4, M Braga5, G Macedo6, G Fundo7
1Hospital Universitario-Universidade Federal do Rio de Janeiro,
Brazil; 2HCN, Niteroi, Brazil; 3Hospital Santa Joana, Recife, Brazil;
4Hospital São Lucas, Vitoria, Brazil; 5Hospital Biocor, Belo
Horizonte, Brazil; 6Hospital Universitario Sul Fluminense,
Vassouras, Brazil; 7AMIB, São Paulo, Brazil
Critical Care 2007, 11(Suppl 2):P67 (doi: 10.1186/cc5227) R Goldwasser1, C David1, R Hatum2, J Salles2, O Barbosa3, S Bhagwanjee, J Scribante, H Perrie, F Paruk
University of the Witwatersrand and the CCSSA, Johannesburg,
South Africa
Critical Care 2007 11(Suppl 2):P66 (doi: 10 1186/cc5226) Introduction Sepsis in the ICU is a major cause of morbidity and
mortality. In addition it increases the direct and indirect cost of
care. Effective intervention to improve patient outcome and ensure
optimal use of resources depends on the availability of data. No
epidemiological data are available on the prevalence of sepsis in
South Africa. This study was a 1-day sepsis prevalence study
conducted in an attempt to address this lack of data. Introduction Sepsis occurs in 16.6% of the patients in the
Brazilian ICU and is associated with a high mortality rate (46.6%). Several studies show different pathogenic agents among countries
and increased antibiotic resistance. This study aims to describe the
pathogen profile in Brazil’s ICU septic patients. Introduction Sepsis occurs in 16.6% of the patients in the
Brazilian ICU and is associated with a high mortality rate (46.6%). Several studies show different pathogenic agents among countries
and increased antibiotic resistance. This study aims to describe the
pathogen profile in Brazil’s ICU septic patients. g
Methods A prospective cohort study involving 75 ICUs all over
Brazil was performed. All patients who were admitted or developed
sepsis during a 1-month period were enrolled and followed until
the 28th day and/or until their discharge. Method Following appropriate institutional approval, 43 ICUs were
selected using the proportional probability sampling technique. This was applied to a national database of ICUs. Every seventh
bed was selected from all the serially placed units. P67 P67
Microbiology profile of sepsis in Brazil Figure 1 (abstract P65) Methods PROGRESS is a global, noninterventional, multicenter,
prospective, observational study of severe sepsis patients treated
in ICUs. Patients must have had a diagnosis of severe sepsis and
have been treated in an ICU at a participating institution. All treat-
ment modalities were as per standard of care at the participating
institutions. We analyzed baseline characteristics and hospital
mortality. We also performed an adjusted mortality analysis for
DAA patients due to baseline imbalances in patients with and
without DAA therapy. S25 Critical Care March 2007 Vol 11 Suppl 2
27th International Symposium on Intensive Care and Emergency Medicine Table 1 (abstract P66)
Diagnostic concordance
Treating doctor
Assessors
None
169
54
SIRS
16
120
Sepsis
36
41
Severe sepsis
7
12
Septic shock
9
16 severe sepsis was 54.1%. Hospital mortality and 28-day mortality
of severe sepsis were 59.3% and 57.6%, respectively. The
standardized mortality ratio of severe sepsis patients was 1.40. The median duration of stay in ITUs of the severe sepsis cohort
who survived was 6 days (IQR 3–12). The number of episodes
where infection was the primary reason for admission to the ITU
was 89.8% and the rest of episodes were ITU acquired. See
Figure 1 for infection characteristics. severe sepsis was 54.1%. Hospital mortality and 28-day mortality
of severe sepsis were 59.3% and 57.6%, respectively. The
standardized mortality ratio of severe sepsis patients was 1.40. The median duration of stay in ITUs of the severe sepsis cohort
who survived was 6 days (IQR 3–12). The number of episodes
where infection was the primary reason for admission to the ITU
was 89.8% and the rest of episodes were ITU acquired. See
Figure 1 for infection characteristics. Conclusion
Sepsis was common in Indian ITUs and had
predominant medical populations. ITU mortality was higher
compared with western literature. Gram-positive infections were
less common although the incidence of parasitic and viral
infections were higher than in the West. P66 Data collected
identified the profile of the unit and the patient details for the day in
question (15 August 2005). The primary endpoint was a peer-
reviewed determination of the need for antibiotic prescription as
determined by two independent reviewers. Sepsis was defined
according to the ACCP/SCCM criteria. Secondary end-points
included determination of diagnostic ability of attending clinicians,
antibiotic prescribing patterns and appropriateness of modification
of therapy based on microbiological data. Results A total of 521 patients filled the criteria of sepsis and were
studied. The two main sources of infection were pneumonia and
the abdominal tract. Gram-negative bacteria were isolated in
40.1%, followed by Gram-positive (38.8%) and fungus (5%). The
most prevalent bacteria were Staphylococcus aureus (31.3%) and
Pseudomonas aeruginosa (26.8%). Methicilin-resistant Staphylo-
coccus aureus (MRSA) were present in 64.8%. Bacteria were
isolated in blood samples in 19.57% and S. aureus was prevalent. The prevalence of antimicrobial-resistant bacteria was 26.6% and
was associated with higher mortality at the 28th day (resistant
bacteria 50.9% vs nonresistant bacteria 43.5%). Septic shock was
related to the highest mortality, with rates ranging from 45.8%,
63.7% and 83.3% due to S. aureus, P. aeruginosa and Acineto-
bacter spp, respectively. Results The mean age of patients was 55 years (n = 248) with a
male:female ratio of 60:40. Sixty-eight per cent of patients were
admitted post surgery. There was reasonable concordance for
sepsis, severe sepsis and septic shock (Table 1). A total of
196/248 (79%) patients were deemed to require antibiotics by the
attending clinician, compared with 69/248 (28%) who were
deemed to have sepsis by independent review. Fifty-one per cent
of patients were inappropriately diagnosed as having sepsis. The
commonest site of sepsis (as determined by the assessors) was
the lung (45%) followed by the abdomen (10%). In 42% of cases
antimicrobial prescription was adjudged as being appropriate,
while in 11% of cases antimicrobials were appropriately modified
following microbiology results. The duration of therapy was
appropriate in 26% of cases. Conclusions Gram-negative bacteria were the most frequently
isolated pathogens in the ICU in septic patients. MRSA
represented the majority of S.aureus strains isolated. Antibiotic-
resistant bacteria were associated with higher mortality. It is
important to recognize the Brazilian ICU organisms’ profile and
their resistance pattern to guide rational administration of
antimicrobial agents. Implementation of early goal-directed therapy in Finland M Varpula
Helsinki University Hospital, Kauniainen, Finland
Critical Care 2007, 11(Suppl 2):P69 (doi: 10.1186/cc5229) Introduction The early recognition and rapid start of goal-directed
treatment (EGDT) are important elements for better outcome in
severe sepsis. These actions should take place in the emergency
department (ED) before admission to the ICU. The aim of our study
was to determine how the EGDT was performed and to evaluate
the impact of EGDT principles on mortality in septic shock in
Finland. Our study was conducted before national guidelines for
severe sepsis were published. Results There were 201 patients admitted to the unit during the
period of our study; 140 of these were neurosciences (NS)
patients and the rest (61) were general (G) (either medical or
surgical). Most of the patients were men and had a mean APACHE
II score of 39 (NS group 33, G group 45).There were in total 64
episodes of positive blood cultures (BC); 39 of these episodes
were accompanied by inflammatory signs (incidence of blood-
stream infections of 19.4% of total admissions). Twenty-five of the
episodes were not associated to clinical signs of infection. There
were more patients with at least one episode of positive BC in the
NS group (29 (20.7%)) than in the G group (10 (16.39%)). Out of
49 episodes in the NS group, 59.18% (29) were associated to
some degree of inflammatory response (SIRS, severe sepsis, and
MODS). Out of 15 episodes in the G group, 66.6% (10)
developed inflammatory response. In 59% (25) of the positive
BCs, the organism isolated was coagulase-negative staphylo-
coccus (CNS). In the G group, 47% (7) grew CNS, 33% were
diverse Gram-negatives and in 20% other Gram-positives. In the
NS group, 64% (31) of isolates grew CNS, 21% were other Gram-
positives and 15% were Gram-negatives. In 47 (73.4%) episodes
of positive BC, the patients had either a central venous catheter or
an arterial catheter. In 36 (56.2%) of the episodes the patients
were already on antibiotics at the time of the sampling. The most
frequent agent isolated was coagulase-negative Staphylococcus
aureus, in 39 (59%) of the cases. Methods A prospective observational study of patients with severe
sepsis and septic shock admitted to 21 ICUs in Finland from 1
November 2004 to 28 February 2005 (Finnsepsis). Only patients
with community-acquired sepsis, who fulfilled the criteria of septic
shock and were admitted directly from the ED to the ICU, were
included. Implementation of early goal-directed therapy in Finland The following treatment targets were evaluated: (1)
measurement of lactate during the first 6 hours from admission to
the ED; (2) obtaining the blood cultures before antibiotics; (3)
starting the antibiotics within 3 hours from admission; and reaching
the (4) mean arterial pressure over 65 mmHg, (5) central venous
pressure over 8 mmHg and (6) central venous oxygen saturation
over 70% or mixed venous oxygen saturation over 65% during the
first 6 hours with fluids and vasopressors. Results Sixty-three patients were included. The median age was
57 years (IQR 18.5) and the median APACHE II score was 28
(IQR 10). The ICU, hospital and 1-year mortality rates were 25%,
38% and 52%, respectively. Only five (8%) patients reached all
treatment targets and 24 patients (38%) reached four or more
targets (group A). The hospital mortality of group A was 29% (95% CI 15–49%)
compared with 44% (95% CI 29–59%) of those who reached only
three or less targets (group B) (P = 0.3). The median delay from
ED arrival to ICU admission in group A and group B was 1.1 and
3.7 hours (P < 0.001), and the median SOFA score for the first
day was 10 and 11 (P = 0.4), respectively. The median APACHE II
score was 28 in both groups (P = 0.9). In multivariate analysis
including all separate targets, delay for ICU admission and
APACHE II score, the APACHE II value and measurement of
lactate were independent predictors of mortality (P = 0.001 and
0.02). Only 18% of patients had serum lactate measured during
the ED stay. The 1-year mortality of group A was 42% (95% CI
24–61%) and of group B was 59% (95% CI 43–73%) (P = 0.2). Conclusions The adoption of EGDT protocol was poor in Finnish
hospitals. The impaired early recognition of sepsis may lead to a
delay in ICU admission. The rate of reached EGDT targets
reflected mortality. In this study the most critical EGDT target was
the measurement of lactate during first 6 hours after arrival in the
ED. A forthcoming follow-up study will evaluate the impact of
guidelines to treatment and outcome of septic shock in Finland. From the patients that had at least one positive BC, nine died;
seven (78%) patients were in the G group, and two (22%) in the
NS group. Available online http://ccforum.com/supplements/11/S2 Available online http://ccforum.com/supplements/11/S2 unit (NCCU) is at the moment unknown. It is known that being a
patient in the intensive care environment is in itself a risk factor for
the development of bacteraemia (3.2–4.1 per 100 admissions in
several papers). The higher amount of invasive procedures and the
severity of illness in this group of patients have been blamed. The
aims of our study are: (1) to identify the incidence of bacteraemia
in the NCCU, (2) to recognise the incidence of bloodstream
infection (SIRS with bacteraemia), (3) to identify the most common
pathogens associated with bacteraemia, and (4) to promote the
continuous collection of data aiming to follow the behaviour of this
problem in time. unit (NCCU) is at the moment unknown. It is known that being a
patient in the intensive care environment is in itself a risk factor for
the development of bacteraemia (3.2–4.1 per 100 admissions in
several papers). The higher amount of invasive procedures and the
severity of illness in this group of patients have been blamed. The
aims of our study are: (1) to identify the incidence of bacteraemia
in the NCCU, (2) to recognise the incidence of bloodstream
infection (SIRS with bacteraemia), (3) to identify the most common
pathogens associated with bacteraemia, and (4) to promote the
continuous collection of data aiming to follow the behaviour of this
problem in time. patients was almost the same for both groups. We noted, as well,
a larger number of deaths in the patients with sepsis and MOF. There needs to be more studies aiming to establish a casual
relationship to explain this. CNS was the most frequently isolated
organism and there was no difference among the groups. There is
a potential for increased mortality in the patients that develop
bloodstream infections in our unit, and we need to implement
urgent measures to decrease them while further research is done
in this area. P68 Conclusion The national prevalence of sepsis, the site of sepsis
and the patient profile in South Africa is similar to that described in
other studies [1]. Treating doctors are reasonably accurate in
diagnosing sepsis but prescribe antiobiotics inappropriately in the
vast majority of cases. Incidence of bacteraemia in a neurocritical care unit L Colorado, M Vizcaychipi, S Herbert, O Sule, R Burnstein
Addenbrooke’s Hospital, Cambridge, UK
Critical Care 2007, 11(Suppl 2):P68 (doi: 10.1186/cc5228) 1. An expert report of the European Society of Intensive
Care Medicine. The problem of sepsis. Intensive Care Med
1994, 20:300-304. Introduction The incidence of bacteraemia and bloodstream
infection, as defined by the CDC, in our neurosciences critical care S26 Available online http://ccforum.com/supplements/11/S2 P69 Methods This is a prospective observational study looking at the
presence of positive blood cultures in all the patients admitted to
the NCCU during the period from 1 June to 31 August 2006. Blood cultures were taken from a peripheral site under aseptic
conditions as per the NCCU guidelines. We tried to identify how
many of the patients with positive blood cultures had evidence of
concomitant SIRS/sepsis, as described by the modified Bone
criteria, and the severity of this. An attempt was made to identify
the most frequent microorganisms involved in this problem as well
as their antibiotic susceptibility. As a secondary aim of our study
we described the number of fatalities in the patients with
bacteraemia. We tried to focus our approach to the fact that we
serve a large neurological/surgical population as well as general
patients and to see whether we could pinpoint differences in these
two groups. Awareness of the Surviving Sepsis Campaign amongst
emergency medicine and surgical trainees A Castellanos-Ortega, B Suberviola, A González-Castro,
C Gonzalez, A Ruiz, J Teja, F Ortiz
Hospital Universitario Marqués de Valdecilla, Santander, Spain
Critical Care 2007, 11(Suppl 2):P70 (doi: 10.1186/cc5230) L Evans
Queen Elizabeth Hospital, King’s Lynn, UK
Critical Care 2007, 11(Suppl 2):P71 (doi: 10.1186/cc5231) Introduction Data presented at the 2006 Barcelona conference of
the European Society of Intensive Care Medicine showed that, where
implemented, the Surviving Sepsis Campaign guidelines have
improved mortality from sepsis. However, because of overall poor
adherence to the guidelines, the stated aim of the campaign to
reduce mortality from severe sepsis by 25% is unlikely to be met. In
the United Kingdom, patients with sepsis of surgical origin will
typically be seen by emergency medicine (EM) before being admitted
to a surgical ward and are unlikely to be initially managed by the ICU. Both the EM and surgical juniors should therefore be aware of the
guidelines. The aim of this study was to determine the level of
awareness of the SSC guidelines in surgical and EM trainees. Introduction The purpose of the study was to describe the
effectiveness of the Surviving Sepsis Campaign (SSC) bundles
with regard to both implementation and outcome in patients with
septic shock. Methods This was a single-center prospective observational study
of patients admitted to the medical–surgical ICU of an urban
tertiary care teaching hospital meeting criteria for the international
sepsis definitions. Patients were entered in the database from
September 2005 to October 2006. After a widespread 2-month
educational program, implementation of SSC Resuscitation
Bundles (RB) and Management Bundles (MB) were accomplished. We determined the rate of compliance and the prognostic value of
the RB, the MB and of each bundle element. g
g
Methods A questionnaire-based survey was undertaken of all EM
and surgical trainees in the Eastern region of the United Kingdom. Participants were recruited by post, telephone, email and in person. The questionnaire assessed whether participants had experience in
critical care, were aware of the campaign or its guidelines and
assessed the level of familiarity of key concepts of the resuscitation
bundle of the guidelines. In addition, participants were encouraged
to comment on any aspect of sepsis management. Results We analyzed 135 consecutive episodes of septic shock. The main sources of infection were: abdomen 39.5%, lung 29.9%,
and urinary tract infection 11.1%. Global hospital mortality was
44.4%. Awareness of the Surviving Sepsis Campaign amongst
emergency medicine and surgical trainees Nonsurvivors were older (71 vs 64 years; P = 0.01), and
had a higher APACHE II score (25 vs 20; P = 0.000), a higher
SOFA score (10 vs 9; P = 0.001) and a higher number or organ
dysfunctions at sepsis presentation (4 vs 3; P = 0.007). The rate of
compliance with the RB was 38%. There were significant
differences in mortality between compliant (C) and noncompliant
(NC) groups despite the similar characteristics and the severity of
septic shock. The NC group had a 58% mortality rate and the C
group 22% (RR 2.6 (95% CI 1.49–4.5, P = 0.001)). The number
needed to treat to save one life was 3. The compliance rate with
MB was only 20%, and there were no differences in mortality
between the C and NC groups (57.9% vs 52.6%). We only found
differences in mortality between the C and NC groups in four
bundle elements: serum lactate measured before 6 hours (35.2%
vs 65.4%; P = 0.007), early broad-spectrum antibiotics (36.2.5%
vs 56.1%; P = 0.051), ScvO2 > 70% (35.7% vs 52.1%; P =
0.057) and activated protein C (65% vs 11% P = 0.000). In the
multivariate analysis, activated protein C, early broad-spectrum
antibiotics, PaO2/FiO2 < 200 and complete RB were associated
independently with mortality. The questionnaire assessed whether participants had experience in
critical care, were aware of the campaign or its guidelines and
assessed the level of familiarity of key concepts of the resuscitation
bundle of the guidelines. In addition, participants were encouraged
to comment on any aspect of sepsis management. Results Summarised in Table 1. There are 29 EM and 52 surgical
trainees in the Eastern region; responses were obtained from 22
and 34, respectively. The responses to the key concepts of the
resuscitation bundle varied greatly, even between different
participants from the same speciality in the same institution,
suggesting a lack of clear direction. Free text responses included
‘the only people that know about guidelines for sepsis are the ICU
physicians’ and ‘the only time I have heard of early goal directed
therapy was on ER’. Conclusion Awareness is reasonable amongst EM trainees but
poor amongst surgeons. If the aims of the SSC are to be met,
consideration must be given to differences in healthcare systems in
different countries. P70 P70 P71 P71
Awareness of the Surviving Sepsis Campaign amongst
emergency medicine and surgical trainees P72 Compliance rates with RB during three consecutive 4.6-month
time periods were 28%, 41.4% and 33.3%, respectively. Compliance with MB was unchanged at 20%. The present dataset
is underpowered to determine whether implementation of SSC
bundles had some effect on mortality reduction. Awareness of the Surviving Sepsis Campaign amongst
emergency medicine and surgical trainees In the United Kingdom, educational activities
should be directed towards EM and surgical trainees as well as
those working in intensive care. Impact of sepsis care bundles on hospital mortality in 135
consecutive patients with septic shock Impact of sepsis care bundles on hospital mortality in 135
consecutive patients with septic shock Compliance with the surviving sepsis guidelines: a review
of South African intensive care units S Bhagwanjee, F Paruk, J Scribante, H Perrie
University of the Witwatersrand and the CCSSA, Johannesburg,
South Africa
Critical Care 2007, 11(Suppl 2):P72 (doi: 10.1186/cc5232) Conclusions Implementation of SSC bundles was associated with
less adherence than expected. However, septic shock patients
receiving the complete resuscitation bundle had substantially lower
mortality. Efforts to increase compliance with these interventions
should be made. The poor adherence to management bundles
probably shows the many uncertainties that remain within this
group of interventions. Introduction Despite the availability of guidelines for practice in
many clinical domains, it is common for clinicians to practice
outwith these guidelines. As part of a 1-day sepsis prevalence study
in ICUs in South Africa, a review was undertaken to determine the Table 1 (abstract P71)
Worked in ICU
Claimed to be
Able to name
Any training on sepsis
Claim to be
Able to name piece of
Trainees
in past 2 years? aware of campaign
SSC
in past 2 years? aware of research
relevant research
Emergency medicine
8 (36%)
15 (68%)
10 (45%)
13 (59%)
13 (59%)
10 (45%)
Surgery
2 (6%)
6 (18%)
3 (8%)
9 (26%)
13 (38%)
8 (24%) Implementation of early goal-directed therapy in Finland Twenty-five (68%) patients with at least one episode of
positive BC had a systemic inflammatory response at the time of
sampling. Seven (28%) of these died during the first 30 days in the
NCCU. Nine (23%) patients had severe sepsis and four (44%) of
these died. Four (10.2%) patients had MODS and three (75%) of
these died. Conclusions We had an incidence of positive blood cultures of
almost 32% of the total admissions; 19.4% of admissions
developed bloodstream infections. These numbers are very high if
we consider the published data. Due to the specialist origin of our
unit, we had more cases in the neurosciences group than in the
general group. However, the incidence of sepsis and MOF in these S27 Available online http://ccforum.com/supplements/11/S2 Available online http://ccforum.com/supplements/11/S2 extent to which units comply with the surviving sepsis guidelines as
promulgated by the International Sepsis Forum [1]. Methods All adult patients with an APACHE III medical admission
diagnosis of nonurinary or urinary sepsis, or nonurinary or urinary
sepsis with shock, admitted directly to the ICU from the ED between
1 January 1997 and 31 December 2005 were identified. Predictor
variables for hospital mortality were analysed using logistic
regression with cross-validation (80% determination and 20%
validation) and robust, cluster-specific (ICU site) standard errors. Method Following appropriate institutional approval, 43 ICUs were
selected using the proportional probability sampling technique. This
was applied to a national database of ICUs. Every seventh bed was
selected from all the serially placed units. Data collected included
the presence of an infection control policy (including guidelines for
performance of blood cultures), recording of culture results,
microbiological support structures, glucose control protocols and
protocols for sedation analgesia and muscle relaxation. Results A total of 7,649 patients (54% male) of mean (SD) age
60.2 (18.1) years and APACHE III score 74.0 (34.7) were
identified. The number of patients admitted per year increased
progressively (1997, n = 368 (7.7 admissions per contributing
ICU); 2005, n = 1,409 (14.0 admissions per contributing ICU)). Nonurinary sepsis with shock was the most common admission
diagnosis (n = 3,394, 44.4%) and urinary sepsis with shock the
least common (n = 607, 7.9%). Overall ICU mortality and hospital
mortality were 20.9% and 27.6%, respectively. Hospital mortality
was predicted by hospital type (tertiary: 0.67 (0.51–0.90),
P = 0.007; metropolitan: 0.63 (0.48–0.83), P = 0.001; private:
0.65 (0.47–0.91), P = 0.011; reference category rural), age
(1.026 (1.019–1.034), P = 0.0001), APACHE III score (1.043
(1.038–1.048), P = 0.0001) and APACHE III score squared
(P = 0.032), sepsis category (nonurinary shock versus the other
three categories combined, 1.79 (1.48–2.16), P = 0.001), mecha-
nical ventilation within 24 hours of ICU admission (1.38
(1.14–1.66), P = 0.001) and calendar year as a single main linear
effect (0.94 (0.90–0.97), P = 0.0001). Significant interactions
were demonstrated between (i) sepsis classification and calendar
year (linear decrease in mortality, nonurinary shock x year 0.92
(0.86–0.99), P = 0.019), (ii) sepsis classification and age
(nonurinary shock x age 0.986 (0.977–0.996), P = 0.008), and (iii)
ventilation and time from hospital to ICU admission (<4.5 hours or
≥4.5 hours 1.38 (1.12–1.69), P = 0.002). Available online http://ccforum.com/supplements/11/S2 The model ROC curve
area and the P value for the Hosmer–Lemeshow C statistic were
0.86 and 0.37, respectively. Restricting the model to only those
ICUs that contributed data for all 9 years of the study period
yielded similar parameter estimates, including calendar year effect. Conclusions The reported incidence of sepsis and septic shock in
ICU patients presenting to the ED in Australia and New Zealand
has increased since 1997; hospital mortality has decreased. These
data require confirmation with a prospective study. Results Forty-three out of a total of 458 units were sampled. The
mean age of patients was 55 years with a male:female ratio of
60:40. Sixty-eight per cent of patients were admitted post surgery. An infection control policy was present in 77% of units. A practice
procedure for blood culture sampling was used in 51% of units,
with records of culture results being documented in 56% of units. Microbiologists were available in 65% of units and they were
involved in ward rounds in 26% of units. Physical consultation by a
microbiologist in 47% of units and telephone consultations in 54%
of units were possible. Sixty-one per cent of units had a glucose
control policy. Sedation, analgesia and neuromuscular blockade
protocols were present in 33%, 26% and 21% of units,
respectively. See Table 1. Table 1 (abstract P72)
Percentage of units utilizing protocols
Domain
Use (%)
Microbiologist available
65
Infection control policy
77
Glucose control protocol
61
Sedation protocol
33
Analgesia protocol
26
Neuromuscular blockade protocol
21 Clinical simulation: caring for a critically ill patient with sepsis Clinical simulation: caring for a critically ill patient with sepsis K Giuliano, A Johannessen, S Crockett
Philips Medical Systems, Andover, MA, USA
Critical Care 2007, 11(Suppl 2):P74 (doi: 10.1186/cc5234) Reference Reference 1. Dellinger RP, Carlet JM, Masur H, et al., for the Surviving
Sepsis Campaign Management Guidelines Committee:
Guidelines for the management of severe sepsis and
septic shock. Crit Care Med 2004, 32:858-873. 1. Dellinger RP, Carlet JM, Masur H, et al., for the Surviving
Sepsis Campaign Management Guidelines Committee:
Guidelines for the management of severe sepsis and
septic shock. Crit Care Med 2004, 32:858-873. 1. Dellinger RP, Carlet JM, Masur H, et al., for the Surviving
Sepsis Campaign Management Guidelines Committee:
Guidelines for the management of severe sepsis and
septic shock. Crit Care Med 2004, 32:858-873. Introduction The purpose of this simulation research was to
assess whether bedside nurses could better apply currently
recommended therapeutic interventions for patients with sepsis by
using a horizons trends clinical decision support tool, rather than
just standard monitoring screen displays alone. Table 1 (abstract P72) Table 1 (abstract P72)
Percentage of units utilizing protocols
Domain
Use (%)
Microbiologist available
65
Infection control policy
77
Glucose control protocol
61
Sedation protocol
33
Analgesia protocol
26
Neuromuscular blockade protocol
21 Percentage of units utilizing protocols Conclusion The majority of units have an infection control policy,
utilize glucose control regimens and have access to a
microbiologist. Sedation, analgesia and neuromuscular blockade
are infrequently utilized. Despite the availability of guidelines, it is
common for many recommendations not to be implemented. Further work is required to determine the reasons for
noncompliance with attention to educational programs and other
strategies to improve practice. Table 1 (abstract P71) S28 P76 Intellivue patient monitoring. Data were collected to compare the
use of bedside monitor displays with and without horizon screen
trends in the care of patients with sepsis. Group 1 (n = 37)
completed the sepsis scenario using a standard screen display, and
group 2 (n = 38) had the addition of horizon trends on the display. Results The point that marked the onset of sepsis was when each
of the physiologic parameters met the current evidence-based
screening criteria (HR > 90, RR > 20, MAP < 65, temperature
>38°C). Results of this study found statistically significant
differences between the standard screen and horizons screen
participant groups in the speed in which clinicians were able to
reach each measured outcome. This was true in each of the five
outcome measurements: onset of sepsis (P < 0.001), initiation of
fluid bolus (P < 0.001), initiation of vasopressor (P < 0.001), blood
culture order (P = 0.012), and antibiotic administration (P = 0.020). Conclusions These results support the hypothesis that monitoring
using horizons trending does indeed contribute to faster clinical
decision-making in the simulated septic patient experience. Future
research should concentrate on replicating these results in a real
clinical environment. P75 Results The incidence of VAP was reduced in the SDD group,
even though it was not statistically significant (26.9% vs 16.3%,
P = 0.138). The mortality of VAP and septic shock was reduced
respectively from 39.6% to 16.7% (P = 0.312) and from 60% to
37.5% (P = 0.835). During the SDD period, Gram-positive
infections increased while Gram-negative infections and Candida
infections showed a reduction. The percentage of resistant
species showed a reduction from 49.1% to 30.5% in all the
categories of pathogens (Table 1). Table 1 (abstract P76) Table 1 (abstract P76)
Percentages of pathogens
no-SDD
no-SDD
SDD
SDD
Infection
total
resistant
total
resistant
Gram-positive
32.5
31%
41.5
20%
(% of all
(% of all
(% of all
(% of all
VAP)
G+)
VAP)
G+)
Gram-negative
54
69%
50
44%
(% of all
(% of all
(% of all
(% of all
VAP)
G–)
VAP)
G–)
Candida
13.5
12.5%
8.5
0%
(% of all
(% of all
(% of all
(% of all
VAP)
candida)
VAP)
candida) Methods We performed a telephone survey of all NHS critical care
units in the North West of England (n = 31). Each unit was
telephoned and the duty consultant was asked a series of
questions relating to the type of microbiology input to their critical
care unit. Results We achieved a 100% response rate. The study looked at
11 teaching hospitals and 21 district general hospitals represen-
ting 12% of UK ICUs: 26 (83%) critical care units had live
computerised access to microbiology data, 21 (68%) units had an
antibiotic policy in place, and 19 (61%) units had a formal
microbiology ward round. With the frequency ranging from once
per week (one unit) to 7 days per week (four units), most units with
a microbiology ward round had this service Monday–Friday
(12 units). When asked to rate the value of this ward round, the
mean score was 8.6 out of a possible 10 (range 10–5, mode 9). In
those units without a microbiology ward round the desirability of
such a service was scored on average at 8.5 out of 10 (range
10–3, mode 9). Conclusions SDD and mupirocin were correlated to a reduced
incidence of VAP and mortality and to a reduction of resistant
species. Impact of a selective digestive decontamination and nasal
mupirocin on the incidence of ventilatory-associated
pneumonia and the emergence of bacterial resistance Impact of a selective digestive decontamination and nasal
mupirocin on the incidence of ventilatory-associated
pneumonia and the emergence of bacterial resistance E De Blasio, A Racca, C Pellegrini, C Di Maria, L Giunta, C Lallo,
E Bizzarro, G Prizio, A Capasso
Hospital ‘G. Rummo’, Benevento, Italy
Critical Care 2007, 11(Suppl 2):P76 (doi: 10.1186/cc5236) E De Blasio, A Racca, C Pellegrini, C Di Maria, L Giunta, C Lallo,
E Bizzarro, G Prizio, A Capasso
Hospital ‘G. Rummo’, Benevento, Italy
Critical Care 2007, 11(Suppl 2):P76 (doi: 10.1186/cc5236) Introduction Selective digestive decontamination (SDD) can
reduce the incidence of ventilatory-associated pneumonia (VAP). Some concerns have been raised about the risk of selection of
resistant bacteria. We evaluated the impact of a SDD regimen on
the incidence of VAP and the development of resistant pathogens. Methods In a polyvalent eight-bed ICU, a retrospective analysis
was performed of two periods of 8 months before (no-SDD, 178
patients, mean SAPS II 44.8) and after (SDD, 110 patients, mean
SAPS II 48.9) the use of SDD with amphotericin, tobramycin and
colistin for oropharyngeal and gastric decontamination and
mupirocin for nasal decontamination. The results were analyzed
with the chi-square test. Introduction Selective digestive decontamination (SDD) can
reduce the incidence of ventilatory-associated pneumonia (VAP). Some concerns have been raised about the risk of selection of
resistant bacteria. We evaluated the impact of a SDD regimen on
the incidence of VAP and the development of resistant pathogens. Medical microbiology ward rounds in critical care L Wilson, G Dempsey
University Hospital Aintree, Liverpool, UK
Critical Care 2007, 11(Suppl 2):P75 (doi: 10.1186/cc5235) Background
Direct microbiological input to critical care is
essential for the management of the septic patient. Early broad-
spectrum antimicrobial therapy with appropriate diagnostic studies
to ascertain causative organisms is well established; there should
be reassessment with the aim of using narrow-spectrum antibiotics
to prevent the development of antimicrobial resistance, to reduce
toxicity and to reduce costs [1]. In systematic analysis of ward
rounds in ICUs the information most commonly missing from a
patient’s file concerned microbiology findings [2]. P73 The outcome of sepsis and septic shock presenting to the
Emergency Department in Australia and New Zealand Methods Simulation research participants (n = 75) were first
required to attend a didactic training session focusing on
recognition and evidence-based treatment for critically ill patients
with sepsis. Participants were then directed to apply these
treatments in a simulated sepsis experience. Data were collected
at two sites (AACN National Teaching Institute Critical Care
Nursing Conference, New Orleans, May 2005 and Long Beach
Memorial Medical Center’s Health Skills Education Center). A
METI HPS (human patient simulator) was connected to a Philips
Medical Systems Intellivue MP 70 in a simulated critical care
environment. Participants were given the patient history, and
completed the rest of their assessment using the HPS and S Peake for the ARISE Investigators, J Moran for the ANZICS
APD Management Committee
The Queen Elizabeth Hospital, Adelaide, Australia
Critical Care 2007, 11(Suppl 2):P73 (doi: 10.1186/cc5233) S Peake for the ARISE Investigators, J Moran for the ANZICS
APD Management Committee
The Queen Elizabeth Hospital, Adelaide, Australia
Critical Care 2007, 11(Suppl 2):P73 (doi: 10.1186/cc5233) Introduction The outcome of sepsis and septic shock patients
admitted to the ICU from the Emergency Department (ED) in
Australia and New Zealand was investigated using prospectively
collected data from the Australian and New Zealand Intensive Care
Society Adult Patient Database. Introduction The outcome of sepsis and septic shock patients
admitted to the ICU from the Emergency Department (ED) in
Australia and New Zealand was investigated using prospectively
collected data from the Australian and New Zealand Intensive Care
Society Adult Patient Database. S29 P76 P77 Comparison of bloodstream infections in intensive care
unit patients, due to different Gram-negative bacteria 1.
Widmer AF: Intensive Care Med 1994, 20 (Suppl 4):
S7–S11. Available online http://ccforum.com/supplements/11/S2 assess which of them is associated with higher mortality in ICU
patients. CR-BSI was used. Data were compared with historical controls at
the same ICU. Also, independent observers evaluated the
procedure for technique break (omitting any conditions listed
under MBP). Subsequently, in addition to MBP, all central venous
catheters were placed under intensivist supervision. Data analysis
included one-tailed z tests for proportions and t tests. Patients and methods This study was conducted in the 28-bed
multidisciplinary ICU of Evangelismos Hospital in Athens, during an
18-month period (August 2004–January 2006). All ICU patients
with blood cultures due to A. baumannii or P. aeruginosa or K. pneumoniae bacteremia, obtained >48 hours after ICU admission,
were studied. Patients with BSIs due to more than one of those
three pathogens were excluded. Information included patients’ age,
gender, underlying disease, admission category, hospitalization
before ICU admission, length of ICU stay, source of BSIs and ICU
mortality were compared. The illness severity was assessed by
APACHE II score on admission and on the day of BSI was
calculated prospectively for all patients. Results From 1 January 2000 to 31 December 2002 (control
period) the CR-BSI incidence was 12.1/1,000 catheter-days. Following implementation of MBP (1 January 2003–31 October
2004) the CR-BSI incidence decreased to 3.5/1,000 catheter-
days (19/5,499 catheter-days), P < 0.02; in 85 independently
observed line placements using MBP, 7/85 patients had CR-BSI
(8.2%). Technique breaks occurred in 34/85 procedures and were
associated with six CR-BSI (17.6%); the 51/85 procedures
without technique breaks had one infection (1.9%), P < 0.01. Intensivist supervision (11 January 2004 to 30 April 2006), in
addition to MBP, further reduced the incidence to 1.5/1,000
catheter-days (7/4,667 catheter-days), P < 0.04. Results During the study period, among 855 consecutively
admitted patients, with ICU stay longer than 48 hours, 197
patients developed BSIs due to A. baumannii (96 patients,
incidence 11.23%), P. aeruginosa (44 patients, incidence 5.15%)
and K. pneumoniae (57 patients, incidence 6.67%). Of these
patients, 85 developed BSIs with two or more pathogens and were
excluded. Thus, finally, 64 patients with A. baumannii BSI, 23 with
P. aeruginosa, and 25 with K. pneumoniae were compared. Hospitalization before ICU was shorter for K. pneumoniae
bacteremic patients compared with those with A. baumannii (1 vs
3 days, P = 0.028) and with those with P. aeruginosa (1 vs 6 days,
P = 0.005). On ICU admission, patients with A. P79 Risk of catheter-related bloodstream infection: higher in
more severe patients? N Cortez-Dias, A Pais de Lacerda, Z Costa e Silva, C França
Hospital de Santa Maria, Lisboa, Portugal
Critical Care 2007, 11(Suppl 2):P79 (doi: 10.1186/cc5239) Risk of catheter-related bloodstream infection: higher in
more severe patients? Risk of catheter-related bloodstream infection: higher in
more severe patients? N Cortez-Dias, A Pais de Lacerda, Z Costa e Silva, C França
Hospital de Santa Maria, Lisboa, Portugal
Critical Care 2007, 11(Suppl 2):P79 (doi: 10.1186/cc5239) Introduction Vascular devices are associated with the risk of
catheter-related bloodstream infection (Cr-BSI). The aim of this
study was to evaluate the risk of Cr-BSI in our ICU. Methods A nonconcurrent cohort study at an adult, 11-bed
medical/surgical unit, between 1 January and 31 December 2005. Data were retrospectively reviewed from clinical records and
bacteriological data concerning the presence of central venous
(CVC) or haemodialysis catheter (HDC) colonization and Cr-BSI
(no data on arterial catheters) were collected. Catheter insertion
and dressing of the insertion site were done according to CDC
guidelines for Cr-BSI prevention. Diagnosis of Cr-BSI required
microbial concordance between a culture of the removed catheter
and a separate percutaneously drawn blood culture, and the
exclusion of other overt source of bacteraemia. Intravascular
devices were cultured for evidence of colonization whenever there
was clinical suspicion of Cr-BSI. Severity scores (SOFA, SAPS II)
were assessed and analysed facing Cr-BSI data. Conclusion In ICU patients, the development of BSI due to A. baumannii is associated with a higher severity of illness on
admission compared with those due to P. aeruginosa and K. pneumoniae. However, P. aeruginosa BSI is associated with the
higher mortality. P78 y
g
Results During the study period, 378 patients were admitted to
the ICU (59% male; mean age 58.3 ± 19.8 years), the mean
SOFA score (admission) being 7.9 ± 4.0 and the mean SAPS II (at
24 hours) being 47.6 ± 19.7. In the 266 patients with CVC, the
total duration of implantation was 3.190 days, with a mean duration
of CVC placement/patient of 12 days. Positive cultures of CVC
were found in 18 patients (6.8%). The incidence density of positive
catheter cultures was 6.3/1,000 days of CVC use. CVC-related
BSI was diagnosed in 5 patients, the risk of CVC-related BSI
being 1.6/1,000 days of CVC use. Fifty-two patients also had a
HDC. Positive cultures of HDC occurred in two of these patients
(3.8%), none of them with Cr-BSI. The isolated microorganisms
from CVC and HDC were typical skin bacteria, excluding two
cases with catheter colonization in patients with other overt
sources of bacteraemia. The mean SOFA score in patients with
positive catheter cultures was 10.2 ± 3.1, the mean SAPS II was
63 ± 19.6 and the mean catheter placement duration in these
patients was 32.1 ± 15.7 days. The overall ICU mortality rate was Maximal barrier precautions, intensivist supervision, and
catheter-related bloodstream infections Available online http://ccforum.com/supplements/11/S2 baumannii had a
higher APACHE II score compared with those with K. pneumoniae
(19.53 ± 7.6 vs 15.0 ± 5.4, respectively, P = 0.017) and lower
hematocrit and hemoglobin values (29.8 ± 6.5 vs 35.4 ± 6.5,
P = 0.002 and 9.9 ± 2.2 vs 11.9 ± 2.2, P = 0.001) respectively. Also on BSI day, hematocrit was lower in patients with A. baumannii and with P. aeruginosa bacteremia, compared with
those with K. pneumoniae bacteremia (26.6 ± 4.5 vs 29.6 ± 4.5,
P = 0.016 and 26.1 ± 3.8 vs 29.6 ± 4.5, P = 0.021). The
respiratory tract was the most common source of BSIs due to A. baumannii compared with P. aeruginosa and K. pneumoniae
(56.3% vs 26.1%, P = 0.013 and 56.3% vs 12.0%, P = 0.001). Mortality was higher in the presence of P. aeruginosa and A. baumannii BSIs, compared with K. pneumoniae (56.5% vs 24.0%,
P = 0.021 and 48.4% vs 24.0%, P = 0.036, respectively). Conclusion While MBP can reduce the incidence of CR-BSI,
placement of central venous catheters by residents under
intensivist supervision can further lower the incidence. Comparison of bloodstream infections in intensive care
unit patients, due to different Gram-negative bacteria Comparison of bloodstream infections in intensive care
unit patients, due to different Gram-negative bacteria Conclusion Direct microbiological advice at the bedside is highly
valued by ICU consultants. Antibiotic prescribing is generally well
controlled, with two-thirds of units having an agreed antibiotic
policy in place. Work will continue to determine whether these
results reflect the national picture in the United Kingdom. References Conclusion Direct microbiological advice at the bedside is highly
valued by ICU consultants. Antibiotic prescribing is generally well
controlled, with two-thirds of units having an agreed antibiotic
policy in place. Work will continue to determine whether these
results reflect the national picture in the United Kingdom. M Pratikaki, E Platsouka, C Sotiropoulou, K Kritikos,
M Agrafiotis, S Kolias, S Nanas, O Paniara, C Roussos, C Routsi
Evangelismos, Athens, Greece
Critical Care 2007, 11(Suppl 2):P77 (doi: 10.1186/cc5237) Introduction To compare the incidence and risk factors of
bloodstream infections (BSIs) due to Acinetobacter baumannii,
Pseudomonas aeruginosa and Klebsiella pneumoniae and to 1. Widmer AF: Intensive Care Med 1994, 20 (Suppl 4):
S7–S11. S30 2. Friesdorf W: J Clin Monit 1994, 10:201-209. Available online http://ccforum.com/supplements/11/S2 P80 Background Nosocomial catheter-related bloodstream infections
(CR-BSI) have been associated with increased morbidity and
possibly increased mortality in critically ill patients. Central venous
catheters impregnated with rifampin and minocycline (RM) have
been shown to decrease rates of colonization and CR-BSI when
compared
with
controls
and
with
the
chlorhexidine/silver
sulfadiazine catheter. However, recent randomized trials challenged
the clinical impact of such catheters, showing decreased rates in
colonization but not in CR-BSI. We designed this pilot trial to
compare the rates of colonization and CR-BSI in RM catheters and
controls in a Brazilian population of critically ill patients. P80
Tunnelled central venous catheter-related infection in
cardiothoracic critical care
J Mitchell, P Shetty, F Cox, P Vuddamalay
Royal Brompton & Harefield NHS Trust, Harefield, UK
Critical Care 2007, 11(Suppl 2):P80 (doi: 10.1186/cc5240) Introduction Tunnelled central venous cannulae (CVC) are used in
cardiothoracic (CT) critical care for long-term inotrope, antibiotic
and renal replacement therapy (RRT). The incidence of blood-
stream-related infection (BSI) related to all types of CVC is
between 2.9 and 11.3 per 1,000 catheter-days [1]. In CT or
cardiology practice the incidence for all CVC-related infection is
2.9–4.5 per 1,000 catheter-days. The incidence of BSI is reduced
using tunnelled CVC, although there are little published data on
the incidence of BSI in tunnelled CVC in CT critical care. CVC-
related infection has been recognised as a priority in the UK
initiative ‘Saving Lives’ [2]. We reviewed tunnelled CVC-related
infection in a tertiary UK CT centre with a significant transplant
population. Methods A prospective, nonrandomized, controlled clinical trial
was conducted in one medico-surgical 19-bed ICU. Adult patients
needing a double or triple central venous catheter were
sequentially assigned in permuted blocks of five to undergo
insertion of a control or RM-impregnated catheter. After removal, all
tips were cultured by the roll-plate method in association with one
or two peripheral blood cultures. Rates of colonization and CR-BSI
were recorded and compared. Results Of 120 catheters inserted, 100 could be evaluated for
colonization and CR-BSI. Forty-nine in the uncoated group and 51
in the coated group. Clinical characteristics of patients and risk for
infection were similar in the two groups, use of propofol was more
frequent in the uncoated group and the presence of a vascular
device, other than the study catheter, was more frequent in the
antibiotic-coated group. P81 20.1%, being 40% in the subgroup of patients in whom Cr-BSI
was diagnosed. ANCCADI – Antibiotic Coated Catheter to Decrease
Infection: a pilot trial Conclusions Preventing Cr-BSI is important, but special care is
particularly relevant in patients with higher SAPS II scores and a
longer duration of catheter placement. More studies are needed to
confirm this possible higher risk of Cr-BSI in this more severe
patient subgroup. P Kurtz, M Kalichsztein, G Nobre, G Almeida, J Kezen, F Braga,
P Rosa, G Penna, L Drumond, R Vegni, M Freitas, M Pinto
Casa de Saude Sao Jose, Rio de Janeiro, Brazil
Critical Care 2007, 11(Suppl 2):P81 (doi: 10.1186/cc5241) Maximal barrier precautions, intensivist supervision, and
catheter-related bloodstream infections Maximal barrier precautions, intensivist supervision, and
catheter-related bloodstream infections T Papadimos, S Hensley, J Hofmann, A Casabianca, M Borst,
J Fath, J Duggan
University of Toledo College of Medicine, Toledo, OH, USA
Critical Care 2007, 11(Suppl 2):P78 (doi: 10.1186/cc5238) Introduction Catheter-related bloodstream infections (CR-BSI)
have significant costs. Use of maximal barrier precautions (MBP)
may reduce the incidence of CR-BSI. We studied MBP with/
without intensivist supervision of residents on CR-BSI incidence. Methods We prospectively studied CR-BSI incidence in an ICU
following the implementation of MBP (hand washing before line
placement, sterile site preparation, draping the entire patient in
sterile fashion, use of hat, mask, gloves and gown, maintenance of
a sterile field, assistants following the same precautions, and sterile
dressing application). The Centers for Disease Control definition of S31 20.1%, being 40% in the subgroup of patients in whom Cr-BSI
was diagnosed. Conclusions Preventing Cr-BSI is important, but special care is
particularly relevant in patients with higher SAPS II scores and a
longer duration of catheter placement. More studies are needed to
confirm this possible higher risk of Cr-BSI in this more severe
patient subgroup. P81 P80 Three RM-coated catheters (5.9%) were
colonized compared with nine (18.4%) control catheters (relative
risk, 0,28; 95% confidence interval, 0.07–1.096; P = 0.05). Three
cases of CR-BSI (5.9%) occurred in patients who received RM
catheters compared with five in the control group (10.2%). There
was no significant differences in the incidence of CR-BSI between
RM-coated and uncoated catheters. Uncoated catheters were
more frequently colonized but this difference just failed to show
statistical significance. When the duration of catheter placement
were taken into consideration, Kaplan–Meier analysis showed no
significant differences in the risk of colonization or CR-BSI
between RM-coated and uncoated catheters. Rates of CR-BSI
were seven per 1,000 catheter-days in the RM-coated group
compared with 11.4 per 1,000 catheter-days in the uncoated
group (P = 0.7). Gram-positive and Gram-negative organisms were
similarly responsible for colonizing catheters in our study; there
was no difference in rates of colonization by Candida species. Conclusion In this pilot study, we showed a trend toward lower
rates of colonization in RM-coated catheters when compared with
uncoated control catheters. The incidence and rates of CR-BSI
were similar in the two groups, probably because of a small
number of catheters studied. Development of a prospective
randomized trial with a larger number of patients is underway to
confirm or refute these results. Methods A retrospective analysis from November 2001 to 2006
of culture and sensitivity results of tunnelled CVC tips (Bard
Groshong® cuffed catheter and HemoGlide®) and blood cultures
from the same patients. Results Ninety-three CT critical care patients received a tunnelled
subclavian CVC. The indications were inotropes (n = 40 (43%)),
antibiotic administration (n = 27 (29%)), RRT (n = 14 (15.1%))
and unknown (n = 10 (10.8%)). The mean duration of the catheter
remaining in situ was 36 days (SD 44.0, range 1–164). Culture
results are presented in Table 1. Twelve patients had an
established CVC-related BSI. The mean infection rate/1,000
catheter-days was 3.6. Table 1 (abstract P80)
Positive CVC
Positive
Positive
tip culture
blood culture
from both
Positive culture results (%)
36.6
18.3
12.9
Mean infection rate/
10.2
5.1
3.6
1,000 catheter-days Conclusion In this pilot study, we showed a trend toward lower
rates of colonization in RM-coated catheters when compared with
uncoated control catheters. The incidence and rates of CR-BSI
were similar in the two groups, probably because of a small
number of catheters studied. J Moon J Moon
Chonnam National University Hospital, Gwang-ju, Republic of Korea
Critical Care 2007, 11(Suppl 2):P82 (doi: 10.1186/cc5242) Introduction Blood culture was commonly performed, without any
specific indication, at the Emergency Department. However, the
true positive rate was found to be very low (1.8–5%) and patients
with true bacteremia usually had such risk factors as an indwelling
catheter, severe underlying disease or an immunocompromised
state. This study was performed to determine the usefulness of
performing blood culture for managing febrile immunocompetent
patients who present to the Emergency Department. Method We prospectively analyzed the medical characteristic and
the results of blood culture of febrile immunocompetent patients
who were more than 18 years old and who presented to the
Chonnam National University Hospital Emergency Center from
April 2005 to October 2005. Fever was defined as a single axillary
temperature higher than 38.0°C. The two sets of blood for culture
were drawn at the antecubital area by the emergency physician
who knew well how to obtain blood for culture. The bacteremia
was classified as true bacteremia or contamination, based on the
presence of clinical signs and symptoms and also on the criteria of
MacGregor. For the true bacteremia group, we further investigated
the changes that occurred with the previously administered
antibiotic therapy according to the results of blood culture. facility, over a period from February to June 2006. SIRS was
defined according to the criteria proscribed by the Society of
Critical Care Medicine. A research officer stationed in the ER
identified patients. Exclusion criteria were age < 18 years, patients
transferred from other hospitals or chronic care facilities. Demo-
graphic and study-specific data were collected. The patient was
followed until subsequent death or discharge. The primary
outcome variable was survival to hospital discharge and the
secondary outcome was length of hospitalization. An independent
t-test analysis was carried out for the primary independent variable
(timing of administration of antibiotics) and primary outcome
(mortality) for significant differences between the groups. A two-
sided P value <0.05 was considered as statistical significance. Logistic regression modeling was used to examine survival as a
function of timing of antibiotic administration. Results This study included 182 patients: of the 182 cultures, only
36 were positive with 10 contaminants (5.5%) and 26 true
positives (14.3%). P84 Introduction Despite improvements in technology and healthcare
services, mortality rates from severe sepsis have remained
unchanged over the past few decades. Exciting new data are
emerging about the benefits of early, aggressive management in
the Emergency Room (ER). We carried out this study to study the
patterns of antibiotic administration in our ER and their effects on
the length of hospitalization and survival. P83 Impact of early antibiotics on severe sepsis – are we doing
a good job? N Salahuddin, S Siddiqui, J Razzak, A Raza
Aga Khan University & Hospital, Karachi, Pakistan
Critical Care 2007, 11(Suppl 2):P83 (doi: 10.1186/cc5243) J Moon The most common disease that required blood
culture in the Emergency Department was respiratory infection
(57/182) and the most common disease with true bacteremia was
urinary infection (41.9%). A low initial level of albumin was the
characteristic associated with a positive blood culture result on
multivariate analysis. Management of only five patients was
influenced by the blood culture results (2.7%). Results Patients enrolled in the study numbered 111. At presen-
tation 36 patients (32.4%) had 1/4 criteria for SIRS, 67 (60.4%)
had 2/4 criteria and only eight (7.2%) patients had 3/4 criteria. Sixteen patients (14.4%) were in shock. Sepsis was confirmed by
cultures in 96 (86.5%) patients. One hundred (90.1%) patients
received intravenous antibiotics in the ER; the average time from
triage to actual administration was 2.8 (± 1.86) hours. The timing
of administration of antibiotics was statistically significant in
determining survival. Patients with sepsis and receiving antibiotics
in <1 hour had a mean survival of 99% and a length of
hospitalization of 3 days as compared with those receiving anti-
biotics in 1–4 hours (84.5% survival, LOS 5.25 days) and patients
who received antibiotics in >4 hours (76% survival, LOS 7 days,
P < 0.003). Using a Cox regression model, we were able to
demonstrate that survival dropped acutely with an hourly delay in
antibiotic administration. Overall mortality with sepsis was 34.2%. Conclusions Administration of appropriate antibiotics within
4 hours of arrival in the ER has a significantly favorable impact on
survival in patients with sepsis. Conclusion The blood cultures, as were usually ordered for febrile
immunocompetent patients in the Emergency Department, rarely
altered patient management and the results had limited usefulness. The emergency physician who initially treats these patients has to
consider this limitation of blood culture. Also, eliminating blood
cultures for immunocompetent patients may hold down unneces-
sary medical expenses. Is the blood culture useful in febrile immunocompetent
patients in the Emergency Department? Is the blood culture useful in febrile immunocompetent
patients in the Emergency Department? P80 Development of a prospective
randomized trial with a larger number of patients is underway to
confirm or refute these results. Conclusion The incidence of tunnelled CVC colonisation and
positive blood cultures in this group of CT critical care patients is
in line with previously published data for all types of CVC. Coagulase-negative staphylococcus was the predominant isolate
in both this audit and previously published data [1]. References 1. O’Grady NP, Alexander M, Dellinger EP, et al: Guidelines for
the prevention of intravascular catheter-related infections. Centers for Disease Control and Prevention, Atlanta, USA. MMWR 2002, 51(RR-10):1-29. 2. Saving Lives: The Delivery Programme to Reduce Healthcare
Associated Infections (HCAI) including MRSA. London:
Department of Health; 2005. S32 Available online http://ccforum.com/supplements/11/S2 Figure 1 (abstract P83) P82 g Timing of admissions and outcome of pneumonia in
intensive care units in the United Kingdom H Boralessa1, C Welch2, K Raveendran1, E Veerasingam1,
N Ibrahim1, D Harrison2
1Oldchurch Hospital, Essex, UK; 2ICNARC, London, UK
Critical Care 2007, 11(Suppl 2):P86 (doi: 10.1186/cc5246) Table 1 (abstract P85) Results A total of 101 patients were enrolled, 61 patients during
period A and 40 patients during period B. No significant
differences were found between mean age (48.6 years vs 50.4
years old), SAP II score (44.5 vs 46.5), aetiology of coma (mainly
ischaemic stroke, cardiac arrest, refractory epilepsy, intoxication),
and early-onset (n = 12 vs n = 6) or late-onset pneumonia (n = 1
vs n = 2). During period B, the time for onset of colonisation (6.6
days vs 3 days, P = 0.008) or pneumonia (8.4 days vs 4.2 days,
P = 0.03) was increased compared with period A. We did not
diagnose
multidrug-resistant
infection
or
colonisation. No
difference was found with regard to mortality and morbidity:
duration of mechanical ventilation (5.7 days vs 6.7 days) or total
hospitalisation stay (26.6 days vs 16.9 days), total mortality (n = 9
vs n = 10 patients) or at day 28 (n = 6 vs n = 7 patients),
respectively, in periods A and B. In multivariate analysis, tobacco,
cardiac arrest and ischaemic stroke were independent risk factors
of pneumonia. Appropriateness of antibiotic therapy Conclusion There are significant differences in antibiotic prescribing
practices when public and private sectors are compared. Appropriate early antibiotic prescriptions reduce mortality. Attention
to education and systems that address prescribing practices is
indicated. Conclusion In our study, contrary to previous ones [1,2], anti-
bioprophylaxy did not show a decrease in the incidence of
nosocomial pneumonia in medical comatose patients with
Glasgow Coma Score < 8 under mechanical ventilation. On the
other hand, antibiotics induce a later onset of colonisation and lung
infections. Despite a prevention of early-onset nosocomial
pneumonia, our data do not support the use of regular prophylactic
antibiotics. References 1. Sirvent JM, et al.: Protective effect of intravenously admin-
istered cefuroxime against nosocomial pneumonia in
patients with structural coma. Am J Respir Crit Care Med
1997, 155:1729-1734. Introduction This study aims to assess the association between
the timing of admission and outcome in patients admitted with
pneumonia to ICUs in the United Kingdom. 2. Acquarolo A, et al.: Antibiotic prophylaxis of early onset
pneumonia in critically ill comatose patients. A random-
ized study. Intensive Care Med 2005, 31:510-516. Methods All patients admitted to an ICU with a primary reason for
admission of pneumonia were extracted from the Case Mix
Programme Database. ‘Early’ admissions, admitted to the ICU on
the day of admission to hospital (12,475), were compared with
‘late’ admissions, admitted to the ICU on a later date (21,948). The
ICU and hospital mortality, number of organs failed, renal
dysfunction, and length of stay in hospital were compared between
the two groups. An association was sought between timing of
admission and mortality. Patients were stratified by CURB 65
score on admission to the ICU. Mortality was compared between
the two groups. Odds ratios were used to analyse data. P < 0.05
was considered significant. Protective effect of antibiotic prophylaxis against early-
onset nosocomial pneumonia in comatose patients J Navellou, C Manzon, M Puyraveau, D Perez, E Laurent,
C Patry, G Capellier
CHU Jean Minjoz, Besancon, France
Critical Care 2007, 11(Suppl 2):P84 (doi: 10.1186/cc5244) J Navellou, C Manzon, M Puyraveau, D Perez, E Laurent,
C Patry, G Capellier
CHU Jean Minjoz, Besancon, France
Critical Care 2007, 11(Suppl 2):P84 (doi: 10.1186/cc5244) Methods This was a prospective, observational cohort study that
reviewed all adult patients presenting with systemic inflammatory
response syndrome (SIRS) to the ER of the Aga Khan University
Hospital, which is a 554-bed primary care/tertiary care referral Objective To study the impact of prophylactic antibiotics on the
occurrence of early-onset nosocomial pneumonia in patients with
medical coma. S33 ritical Care March 2007 Vol 11 Suppl 2
27th International Symposium on Intensive Care and Emergency Medicin postculture modification of therapy, duration of therapy and, finally,
impact of appropriate antibiotic choice on mortality. Results See Table 1. Public-sector practice is better with respect
to pretherapy sampling and duration of treatment. Better
modification of treatment occurs in the private sector. Overall mortality of both groups was 10/82 (12%) when antibiotic
choice was appropriate compared with 28/90 (31%) (P < 0.05)
when therapy was inappropriate. postculture modification of therapy, duration of therapy and, finally,
impact of appropriate antibiotic choice on mortality. Patients and methods An open, before and after, single-center
trial, in the medical ICU of the University Hospital of Besancon,
France. A first period (A, retrospective) extended during 18 months
(April 2003–October 2004) without antibiotic prophylaxis and was
followed by a second period (B, prospective) during 18 months
(November 2004–April 2006). Patients received prophylaxis
treatment by amoxicillin and clavulanic acid, shortly after intubation
and during a 24-hour period. Inclusion criteria were medical loss of
consciousness, Glasgow Coma Score < 8, and length of intubation
> 48 hours. Results See Table 1. Public-sector practice is better with respect
to pretherapy sampling and duration of treatment. Better
modification of treatment occurs in the private sector. p
Overall mortality of both groups was 10/82 (12%) when antibiotic
choice was appropriate compared with 28/90 (31%) (P < 0.05)
when therapy was inappropriate. Table 1 (abstract P85) Table 1 (abstract P85)
Appropriateness of antibiotic therapy
Intervention
Sector
Number
Percentage
Preculture sampling
Private
27/62
43*
Public
73/120
61
Modification of antibiotics
Private
49/61
80
Public
18/27
67
Duration of treatment
Private
25/134
19*
Public
26/49
53
*P < 0.05. Table 1 (abstract P85) P88 Out of these, 118 patients (120 BAL) had semiquantitative
tracheal aspirate (SQTA) performed 48 hours prior to the clinical
diagnosis of VAP (males 71/118; mean age 47 ± 16 years; SAPS II
35 ± 10). See Table 1 for pathogen prediction by SQTA surveil-
lance cultures. See Table 2 for concordance of SQTA–BAL when
only multiresistant microorganisms are considered. Negative BAL Methods This is a retrospective study with 93 cases of nosocomial
pneumonia diagnosed according to the ATS criteria, managed in
our ICU from 1 February 2005 to 16 September 2006. We
analyzed the efficacy of both guidelines, using them during all the
study period or stratifying the patients into two groups according
to the research median period (24 November 2005). Table 1 (abstract P87)
Concordance,
a) Same microorganisms SQTA–BAL
66/76 (87%)
76/120 (63%)
b) No significant growth
10/76 (13%)
Partial
a) 2 microorganisms SQTA–1 BAL
4/17 (24%)
concordance,
b) 1 microorganism SQTA–1 BAL
13/17 (76%)
17/120 (14%)
No concordance,
a) No significant growth
14/127
27/120 (23%)
SQTA–1 or 2 microorganisms BAL
b) Different microorganisms SQTA–1 BAL
13/27
Table 2 (abstract P87)
Multiresistant
microorganism
SQTA
BAL
Concordant
%
Ps. aeruginosa
22
22
20/24
83
Acinetobacter
14
11
10/15
67
MRSA
8
9
8/9
89
Klebsiella
2
2
2/2
100
Stenotrophomona
1
1
1/1
100
Total multiresistant
41/51
80
microorganisms Table 1 (abstract P87)
Concordance,
a) Same microorganisms SQTA–BAL
66/76 (87%)
76/120 (63%)
b) No significant growth
10/76 (13%)
Partial
a) 2 microorganisms SQTA–1 BAL
4/17 (24%)
concordance,
b) 1 microorganism SQTA–1 BAL
13/17 (76%)
17/120 (14%)
No concordance,
a) No significant growth
14/127
27/120 (23%)
SQTA–1 or 2 microorganisms BAL
b) Different microorganisms SQTA–1 BAL
13/27 p
Results There were 67 cases of ventilator-associated pneumonia
(VAP) and 26 cases of non-VAP. The overall result shows that the
ATS would be effective in 76% (CI 67–85%) and the BG in
87.9% (CI 81–94.7%) of the cases. This difference was
statistically significant (P = 0.035). The most prevalent bacteria
were Acinetobacter sp. and Pseudomonas aeruginosa. From
February to August 2005 there were a burden of multiresistant
(MR) GNB, only susceptible to PB. Using the ATS or the BG in
this period, the guidelines would be effective in 64% (CI 51–77%)
and 84.4% (CI 74.8–94%) respectively (P = 0.017). P88 Comparing a Brazilian guideline to treat nosocomial
pneumonia with the ATS guideline in a tertiary hospital in
Brazil
M Kalichsztein, B Wajsbrot, A dos Santos, J Camillo Jorge,
B Fabricio, K Pedro, G Nobre, E Moreira, M Freitas, A Paula
Casa de Saúde São José, Rio de Janeiro, Brazil
Critical Care 2007, 11(Suppl 2):P88 (doi: 10.1186/cc5248) Comparing a Brazilian guideline to treat nosocomial
pneumonia with the ATS guideline in a tertiary hospital in
Brazil M Kalichsztein, B Wajsbrot, A dos Santos, J Camillo Jorge,
B Fabricio, K Pedro, G Nobre, E Moreira, M Freitas, A Paula
Casa de Saúde São José, Rio de Janeiro, Brazil
Critical Care 2007, 11(Suppl 2):P88 (doi: 10.1186/cc5248) Methods Routine SQTA were performed twice weekly in all
intubated patients for over 72 hours according to the methodology
described elsewhere [1]. Fiberoptic bronchoscopy with BAL was
preformed the same day that VAP was suspected according to
Johanson criteria (fever, leucocytosis, purulent secretions and
infiltrate on radiograph) plus gas-exchange deterioration. Introduction The medical literature shows that the most important
prognosis factor in nosocomial pneumonia is the correct empirical
antimicrobial therapy. Recently the microorganisms have been
becoming more resistant to the usual antibiotics and there are
many reports of Gram-negative bacilli (GNB) only susceptible to
Polimixyn b (PB). The ATS guideline does not suggest the use of
PB as an empirical therapy, while the Brazilian Sepsis Guideline
(BG) allows the use of this antibiotic in special circumstances. The
aim of this study was to compare the efficacy of both guidelines,
based on the microbiological data. Introduction The medical literature shows that the most important
prognosis factor in nosocomial pneumonia is the correct empirical
antimicrobial therapy. Recently the microorganisms have been
becoming more resistant to the usual antibiotics and there are
many reports of Gram-negative bacilli (GNB) only susceptible to
Polimixyn b (PB). The ATS guideline does not suggest the use of
PB as an empirical therapy, while the Brazilian Sepsis Guideline
(BG) allows the use of this antibiotic in special circumstances. The
aim of this study was to compare the efficacy of both guidelines,
based on the microbiological data. Results In our 22-bed ICU, during a 27-month period, 156
patients underwent BAL procedures due to clinical suspicion of
VAP. Reference 1. James L, Hoppe-Bauer JE: Processing and interpretation of
lower resp tract in specimens. In Clinical Microbiology Pro-
cedures Handbook. Edited by Isenberg HD. Washington, DC:
ASM Press; 1992:1.15.1–1.15.8. 1. James L, Hoppe-Bauer JE: Processing and interpretation of
lower resp tract in specimens. In Clinical Microbiology Pro-
cedures Handbook. Edited by Isenberg HD. Washington, DC:
ASM Press; 1992:1.15.1–1.15.8. H Bagnulo, M Godino, A Galiana, M Bertulo, W Pedreira
Hospital Maciel, Montevideo, Uruguay
Critical Care 2007, 11(Suppl 2):P87 (doi: 10.1186/cc5247) Introduction Most investigators discuss the predictive value of
respiratory surveillance cultures in mechanically ventilated patients
and doubt on the appropriate selection of the antibiotic therapy
based on these findings, when pneumonia develops. The aim of
our study was to evaluate whether microorganisms cultured from
semiquantitative tracheal aspirates (SQTA) in the 48 hours prior to
the clinical suspicion of ventilator-associated pneumonia (VAP)
were predictive of the etiology, compared with the bronchoalveolar
lavage (BAL) results performed on the same day that the clinical
diagnosis was considered Antibiotic prescribing practices in public and private-sector
intensive care units in South Africa S Bhagwanjee, H Perrie, J Scribante, F Paruk
University of the Witwatersrand and the CCSSA, Johannesburg,
South Africa
Critical Care 2007, 11(Suppl 2):P85 (doi: 10.1186/cc5245) Results There were small but statistically significant differences
between the two groups in mean age, APACHE II score, CURB 65
score and number of organ failures, and the presence of Introduction Considerable variability exists in antibiotic prescribing Introduction Considerable variability exists in antibiotic prescribing
practices. A dichotomous health care system in South Africa has
created the opportunity for vastly differing practices. As part of a
national 1-day sepsis prevalence study (PISA), a review was
undertaken of antibiotic prescribing practices in public and private-
sector ICUs. Table 1 (abstract P86)
CURB65
Odds ratio
95% CI
P value
1
1.02
0.9–1.16
0.8
2
1.23
1.13–1.34
<0.0001
3
1.25
1.16–1.35
<0.0001
4
1.46
1.29–1.65
<0.0001
5
1.41
1.03–1.91
0.03 Method Following appropriate institutional approval, 43 ICUs were
selected using the proportional probability sampling technique. This was applied to a national database of ICUs. Every seventh
bed was selected from all the serially placed units. Antibiotic
therapy was reviewed by two independent reviewers. Data
collected included the appropriateness of pretherapy cultures, S34 Available online http://ccforum.com/supplements/11/S2 Available online http://ccforum.com/supplements/11/S2 Available online http://ccforum.com/supplements/11/S2 Available online http://ccforum.com/supplements/11/S2 cultures with SQTA growth were never found. Polymicrobial SQTA
cultures: 13 concordant, seven only partial concordant, four not
concordant. There was no incidence in our results related to
previous antibiotic therapy: 33% of the concordant, 24% of the
partial concordant and 29% of the no concordant were on
antibiotics when SQTA was obtained. respiratory organ failure. There was no difference in the presence
of renal dysfunction. Late admissions with pneumonia had higher
ICU and hospital mortality, and longer hospital stay. At each CURB
65 score the late admissions had higher hospital mortality, which
was significant at scores of 2–5 (Table 1). Conclusion Early admission may reduce mortality in patients
admitted to ICUs with pneumonia. CURB 65 scores could facilitate
triage of patients with pneumonia. Conclusions In our patient population, routine surveillance SQTA
cultures accurately predict more than 60% of the etiologic agents
of VAP. This prediction increases to 80% when multiresistant
microorganisms are considered. Due to routine surveillance
cultures, our antibiotic prescriptions can become more adequate. Are routine endotracheal aspirates predictive of the
etiology of ventilator-associated pneumonia? Are routine endotracheal aspirates predictive of the
etiology of ventilator-associated pneumonia? Are routine endotracheal aspirates predictive of the
etiology of ventilator-associated pneumonia? P89 the correlation between bronchoalveolar bacterial burden and the
lung inflammatory response. Outcomes from ventilator-associated pneumonia caused
by multidrug-resistant organisms or Pseudomonas: results
from 28 intensive care units Objective The aim of the present study was to evaluate the
relationship between bronchoalveolar cytokine expression and
bacterial burden in mechanically ventilated patients with suspected
pneumonia. C Parker1, J Kutsiogiannis2, J Muscedere3, D Cook4, P Dodek5,
A Day3, D Heyland3, for the CCCTG
1Queen’s University, Kingston, Canada; 2University of Alberta,
Edmonton, Canada; 3Queen’s University, Kingston, Canada;
4McMaster University, Hamilton, Canada; 5UBC, Vancouver, Canada
Critical Care 2007, 11(Suppl 2):P89 (doi: 10.1186/cc5249) Methods
Mechanically ventilated patients with suspected
pneumonia admitted to the ICU from November 2004 to January
2006 were prospectively enrolled. Fiberoptic bronchoalveolar
lavage (BAL) was performed with 150 ml sterile isotonic saline in
three aliquots of 50 ml; local anesthetic was not used. BAL
samples for microbiologic quantitative cultures and BAL cytokines –
IL-6, IL 8, TNFα, granulocyte colony-stimulating factor (G-CSF)
and granulocyte–monocyte colony-stimulating factor (GM-CSF) –
were measured. Introduction Patients who develop ventilator-associated pneumonia
(VAP) caused by either multidrug-resistant organisms (MDRO) or
Pseudomonas may have poor clinical outcomes. We sought to
further clarify this potential relationship using a database from a
large multicenter trial of diagnostic and therapeutic strategies in
patients who had suspected VAP. Results Fifty-nine patients were included, and most of the patients
(79.7%) had prior antibiotic therapy. Twenty-two patients (37.2%)
had a positive bacterial culture defined as a diagnostic threshold
>10,000 colony-forming units/ml. Only the concentration of TNFα
was significantly higher in the group of patients with positive BAL
(Table 1). Methods Patients receiving mechanical ventilation (MV) for ≥96 hours
and who developed suspected VAP (new or worsening pulmonary
opacities on CXR, and at least two of fever, leukocytosis, change
in sputum purulence, increased O2 needs, or isolation of potentially
pathogenic bacteria from sputum) were eligible. At enrolment, all
patients had cultures obtained from either BAL or endotracheal
aspirates. MDRO were defined as those resistant to ≥2 classes of
antibiotics. Patients were followed until 28 days after enrolment,
death, or hospital discharge. Conclusions (1) There is a significant correlation between TNFα in
BAL fluid and the lung bacterial burden. (2) BAL TNFα is an early
marker of pneumonia in mechanical ventilated patients despite
prior antibiotic therapy. Clinical implication Cytokine measurements in BAL may be a
diagnostic tool to support the diagnosis of the initial phase of
pneumonia. P91 P91
Risk factors for treatment failure in patients with ventilator-
associated pneumonia receiving appropriate antibiotic
therapy
G Gursel, M Aydogdu, E Ozyilmaz, T Ozis
Gazi University School of Medicine, Ankara, Turkey
Critical Care 2007, 11(Suppl 2):P91 (doi: 10.1186/cc5251) Risk factors for treatment failure in patients with ventilator-
associated pneumonia receiving appropriate antibiotic
therapy Conclusion The isolation of MDRO or Pseudomonas from
respiratory tract specimens of patients with suspected VAP is
associated with prolonged MV, increased ICU and hospital stay,
and increased risk of death. Inadequate initial empiric antibiotic
treatment may be a contributing factor. Introduction Treatment failure (TF) can be anticipated in 30–40%
of patients developing ventilator-associated pneumonia (VAP). Little information about lack of response of VAP to treatment is
available. The aim of the study is to evaluate potential risk factors
for TF in patients with VAP receiving appropriate antibiotic therapy. Methods A prospective observational cohort study. Microbio-
logically confirmed (>105 colony-forming units/ml) clinical findings
(CPIS > 6) were necessary for the diagnosis of VAP. TF was
defined as a lack of clinical (in first 3 days of the therapy) and
microbiological (in first 7 days of the therapy) response to therapy. All patients had surveillance cultures for endotracheal aspirate
(every second day), urine and blood (weekly). Student’s t tests, chi-
square tests and logistic regression analyses were used for
statistical analyses. P89 Results Seven hundred and thirty-nine patients from 28 ICUs in
Canada and USA were enrolled. At enrolment, cultures from
10.0% (95% CI 7.9–12.4%) of the patients grew MDRO or
Pseudomonas. The prevalence of MDRO at enrolment was 5.2%
(3.6–6.8%). There were no differences in APACHE II, MODS, or
PaO2/FiO2 at baseline between those whose specimens grew
MDRO or Pseudomonas and those whose specimens did not. Patients with MDRO or Pseudomonas had higher 28-day mortality
(RR 1.59, 95% CI 1.07–2.37, P = 0.04) and inhospital mortality
(RR 1.48, 95% CI 1.05–2.07, P = 0.05) and a trend towards
higher ICU mortality (RR 1.42, 95% CI 0.90–2.23, P = 0.14) than
those whose specimens did not grow these organisms. Median
duration of MV (12.6 vs 8.7 days), ICU length of stay (16.2 vs 12.0
days) and hospital length of stay (55.0 vs 41.8 days) was greater
in patients with MDRO or Pseudomonas than in those whose
specimens did not grow these pathogens (P = 0.05). Adequacy of
initial empiric therapy was 68.5% in patients whose specimens
grew MDRO or Pseudomonas compared with 93.9% in those
without these organisms (P < 0.001). Table 1 (abstract P90)
BAL–
BAL +
P
IL-6 BAL (pg/ml)
180.3 ± 252
293.4 ± 421
0.410
IL-8 BAL (pg/ml)
1,301 ± 1,045
1,681 ± 1,315
0.442
TNF BAL (pg/ml)
48.9 ± 80.7
222.6 ± 308
0.022
G-CSF BAL (pg/ml)
444.8 ± 565
408.1 ± 491
0.713
GM-CSF BAL (pg/ml)
14.1 ± 23.4
9.35 ± 17.32
0.126 P91 P88 In the second
half of the study we controlled the MR GNB, and the efficacy of
both guidelines were similar between ATS and BG (97% vs
93.9%; P = 1). Table 2 (abstract P87)
Multiresistant
microorganism
SQTA
BAL
Concordant
%
Ps. aeruginosa
22
22
20/24
83
Acinetobacter
14
11
10/15
67
MRSA
8
9
8/9
89
Klebsiella
2
2
2/2
100
Stenotrophomona
1
1
1/1
100
Total multiresistant
41/51
80
microorganisms Table 2 (abstract P87) Conclusions Our data show that the more restrictive ATS
guideline can significantly lead to a wrong empirical therapy in MR
GNB high-prevalence situations. The use of the BG can lead to a
better empirical treatment in this situation. This information
enhances the need for ICU flora knowledge, which are seasonal,
so there is no ‘all time and place perfect guideline’, although the
BG was a better option in our ICU than the ATS guideline. S35 Critical Care March 2007 Vol 11 Suppl 2
27th International Symposium on Intensive Care and Emergency Medicine P90 Bacterial burden and bronchoalveolar cytokines in
mechanically ventilated patients with suspected
pneumonia P92 Results We had 40 episodes (2,247 ventilator-days) of VAP
(40/133 patients) and 45 isolates. In early-onset pneumonia
(≤5 days, eight episodes, three with two isolates): six Acinetobacter
baumannii: meropenem, colistin, gentamicin (five); three Pseudo-
monas aeruginosa: piperacillin, aztreonam, imipenem, ceftazidime,
colistin, ciprofloxacin, cefepime, meropenem, aminoglycosides; one
Klebsiella pneumoniae: meropenem, colistin, tetracycline; Fungi 1:
no susceptibility results. In late-onset pneumonia (>5 days, 32
episodes, two with two isolates): 25 A. baumannii: four to
amoxicillin-clavulanic,
ceftazidime,
piperacillin-tazobactam, Intensive care nurses’ knowledge of evidence-based
guidelines for the prevention of ventilator-associated
pneumonia Intensive care nurses’ knowledge of evidence-based
guidelines for the prevention of ventilator-associated
pneumonia S Labeau1, D Vandijck2, P Van Aken3, B Claes3, S Blot2
1Hogeschool Ghent, Belgium; 2Ghent University Hospital, Ghent,
Belgium; 3Antwerp University Hospital, Antwerp, Belgium
Critical Care 2007, 11(Suppl 2):P92 (doi: 10.1186/cc5252) Introduction Nonadherence to evidence-based guidelines for the
prevention of ventilator-associated pneumonia (VAP) has been
reported. As a lack of knowledge may be a barrier for adherence,
this study aimed to determine intensive care nurses’ knowledge of
evidence-based guidelines for VAP prevention. aztreonam, imipenem, colistin, ciprofloxacin, cefepime, meropenem,
aminoglycosides, 19 to meropenem, gentamicin, colistin, tetracycline
and two to colistin; four P. aeruginosa: two to piperacillin-
tazobactam, two to colistin; one K. pneumoniae: piperacillin-
tazobactam, aztreonam, imipenem, ceftazidime, colistin, ciprofloxacin,
cefepime, meropenem, aminoglycosides, amoxicillin-clavulanic; Fungi
1: no susceptibility results and three unspecified isolates. Methods This study is a survey using a validated multiple-choice
questionnaire, developed to evaluate nurses’ knowledge of VAP
prevention and based on a recently published review by Dodek
and colleagues [1]. Knowledge of nine nursing-related strategies
was evaluated. The questionnaire was distributed and collected
during the Flemish Society for Intensive Care Nurses’ annual
congress (Ghent, 2005). Demographic data included were gender,
intensive care experience, number of critical beds and whether
nurses hold a special degree in emergency and intensive care. Excluding fungi and unspecified isolates, we had 8/45
multisensitive isolates and 32/45 isolates sensitive to colistin (32),
meropenem (26) and gentamicin (21). According to these data in
early and late VAP the most adequate therapeutic combination to
cover possible pathogens is meropenem + colistin. Using this
combination we cover all possible pathogens and then de-escalate
according to susceptibility results. Following the ATS/IDSA
guidelines we would cover only 8/45 isolates. Results We collected 638 questionnaires (response rate 75%). Nineteen per cent recognized the oral route as the recommended
way for intubation. pneumonia Á Estella García1, A Ruiz Robles2, A Sáinz de Baranda1,
M Calero Ruiz2, M Galán1, E Moreno1
1Critical Care Unit and 2Laboratory of Biochemistry, Hospital of
Jerez., Spain
Critical Care 2007, 11(Suppl 2):P90 (doi: 10.1186/cc5250) Introduction Cytokines play an important role in pulmonary host
defense. However, nonuniform findings have been reported about Results Eighty-one patients enrolled into the study; 40% of them
were female and the mean age was 71 ± 14. Fifty-one of the S36 Available online http://ccforum.com/supplements/11/S2 patients had TF. When the groups were compared (TF and
treatment success), patients with TF were older, had more
comorbidities, higher admission and VAP APACHE II scores,
Acinetobacter baumanni pneumonia, higher initial bacterial load
(colony-forming units/ml) and lower daily carbohydrate intake. Transfusions, bacteremia, infection with multidrug-resistant micro-
organismis and steroid therapy were similar across the groups. Among the significant parameters, age and comorbidity were not
entered into the logistic regression since the APACHE II score
covers these two parameters. VAP with A. baumanni (OR 4.4,
95% CI 1.2–16, P = 0.027), higher VAP APACHE II scores
(OR 12, 95% CI, 3–45, P = 0.0001) and lower daily carbohydrate
intake (OR 4.4, 95% CI 1.3–15, P = 0.016) were independent
predictors for TF in logistic regression analyses. P Myrianthefs1, C Ioannides1, G Fildissis1, S Karatzas1,
G Baltopoulos2
1KAT Hospital, Athens, Greece; 2General Hospital of Attiki ‘KAT’,
Kifissia, Greece
Critical Care 2007, 11(Suppl 2):P93 (doi: 10.1186/cc5253) P Myrianthefs1, C Ioannides1, G Fildissis1, S Karatzas1,
G Baltopoulos2
1KAT Hospital, Athens, Greece; 2General Hospital of Attiki ‘KAT’,
Kifissia, Greece
Critical Care 2007, 11(Suppl 2):P93 (doi: 10.1186/cc5253) Introduction ATS/IDSA [1] guidelines recommend consideration
of local microbiologic data when selecting empiric treatment for
ventilator-associated pneumonia (VAP) and broad-spectrum
empiric therapy for patients with pneumonia caused by MDR
pathogens. The purpose was to use local microbiologic data to
develop institution-specific guidelines for VAP. empiric therapy for patients with pneumonia caused by MDR
pathogens. The purpose was to use local microbiologic data to
develop institution-specific guidelines for VAP. Methods We prospectively recorded local microbiologic and
susceptibility data in our ICU. Respiratory specimens were tracheal
aspirates in all cases and were evaluated by quantitative criteria. Results We had 40 episodes (2,247 ventilator-days) of VAP
(40/133 patients) and 45 isolates. In early-onset pneumonia
(≤5 days, eight episodes, three with two isolates): six Acinetobacter
baumannii: meropenem, colistin, gentamicin (five); three Pseudo-
monas aeruginosa: piperacillin, aztreonam, imipenem, ceftazidime,
colistin, ciprofloxacin, cefepime, meropenem, aminoglycosides; one
Klebsiella pneumoniae: meropenem, colistin, tetracycline; Fungi 1:
no susceptibility results. In late-onset pneumonia (>5 days, 32
episodes, two with two isolates): 25 A. baumannii: four to
amoxicillin-clavulanic,
ceftazidime,
piperacillin-tazobactam,
aztreonam, imipenem, colistin, ciprofloxacin, cefepime, meropenem,
aminoglycosides, 19 to meropenem, gentamicin, colistin, tetracycline
and two to colistin; four P. aeruginosa: two to piperacillin-
tazobactam, two to colistin; one K. pneumoniae: piperacillin-
tazobactam, aztreonam, imipenem, ceftazidime, colistin, ciprofloxacin,
cefepime, meropenem, aminoglycosides, amoxicillin-clavulanic; Fungi
1: no susceptibility results and three unspecified isolates. E
l di
f
i
d
ifi d
i
l t
h d
8/45 Conclusion These results suggest that patients with higher VAP
APACHE II scores and pneumonia with A. baumanni and lower
carbohydrate intake were at risk for TF. Methods We prospectively recorded local microbiologic and
susceptibility data in our ICU. Respiratory specimens were tracheal
aspirates in all cases and were evaluated by quantitative criteria. P92 Forty-nine per cent knew that ventilator circuits
are to be changed for each new patient only. Heat and moisture
exchangers were checked as the recommended humidifier type by
55%, and 13% knew that it is recommended to change them once
weekly. Closed suction systems were identified as recommended
by 69%, and 20% knew that these must be changed for each new
patient only. Respectively 60% and 49% recognized subglottic
drainage systems and kinetic beds to reduce the incidence of VAP. Semirecumbent positioning is well known to prevent VAP (90%). The nurses’ average score was 4.2/9, while nurses with >1 year
experience and those holding a special degree both scored 4.5/9
(P < 0.001). Conclusions ATS/IDSA [1] guidelines may not be applicable in all
institutions or countries and thus clinicians should incorporate local
microbiologic data into institution-specific guidelines [2]. References 1. ATS/IDSA: Am J Respir Crit Care Med 2005, 171:388-416. 2. Beardsley JR, et al.: Chest 2006, 130:787-793. 1. ATS/IDSA: Am J Respir Crit Care Med 2005, 171:388-416. 2. Beardsley JR, et al.: Chest 2006, 130:787-793. 1.
Dodek P, et al.: Ann Intern Med 2004, 141:305-313. 1.
ATS/IDSA: Am J Respir Crit Care Med 2005, 171:388-416.
2.
Beardsley JR, et al.: Chest 2006, 130:787-793. 1.
Dodek P, et al.: Ann Intern Med 2004, 141:305-313. Administration of meropenem for the treatment of
ventilator-associated pneumonia Administration of meropenem for the treatment of
ventilator-associated pneumonia Administration of meropenem for the treatment of
ventilator-associated pneumonia K Zolotukhin, A Abubakirova
District Hospital, Ufa, Russian Federation
Critical Care 2007, 11(Suppl 2):P94 (doi: 10.1186/cc5254) K Zolotukhin, A Abubakirova
District Hospital, Ufa, Russian Federation
Critical Care 2007, 11(Suppl 2):P94 (doi: 10.1186/cc5254) Conclusion Nurses lack knowledge of evidence-based guidelines
for VAP prevention. Their schooling and continuing education
should include support from current evidence-based guidelines. Reference Conclusion Nurses lack knowledge of evidence-based guidelines
for VAP prevention. Their schooling and continuing education
should include support from current evidence-based guidelines. Reference Introduction Ventilator-associated pneumonia (VAP) is associated
with the greatest mortality among nosocomial infection. Death
rates associated with Pseudomonas spp. or with late-onset VAP
seem higher. Treatment of these infections is frequently
complicated by antibiotic resistance, a problem that has been
increasing in recent years. S37 ritical Care March 2007 Vol 11 Suppl 2
27th International Symposium on Intensive Care and Emergency Medicin infection due to pseudomonas species, acinetobacter species and
multidrug-resistant Gram-negative bacilli at enrollment (n = 56),
the adequacy of initial antibiotics was 82.4% in the combination
group versus 18.8% in the monotherapy group (P < 0.001); this
difference was associated with an increase in the microbiological
eradication of the infecting organisms (64.1% vs 29.4%, P = 0.05)
but no differences in clinical outcomes. Conclusion
In patients who have suspected VAP, empiric
treatment with combination therapy, as compared with mono-
therapy, is safe and is associated with a higher rate of adequate
antimicrobial coverage but has no effect on clinical outcomes. Acknowledgements This study was supported by grants from the
Canadian Institutes of Health Research and Physicians Services Inc. of
Ontario, and unrestricted grants from AztraZeneca Inc., and Bayer Inc. Objective and methods The goal of the study was to evaluate the
clinical efficacy of meropenem by continuous infusion administration
(CIA) or by bolus intermittent infusion (BII) for the treatment of VAP
caused by Pseudomonas aeruginosa. An historic control group with
VAP caused by P. aeruginosa who received initial empiric antibiotic
therapy with meropenem by BII (n = 32) was compared with a
prospective cohort treated with meropenem by CIA (n = 20) in a
12-bed surgical ICU, at a 400-bed surgical complex of a district
hospital. We looked for demography, APACHE II score, mortality,
attributable mortality for VAP, days on mechanical ventilation (MV),
and ICU length of stay. P96 Results Significant differences were not found between both
groups of patients in sex, age, APACHE II score, and diagnosis. The CIA group showed significantly greater clinical cure than the
BII group (CIA 18/20 (90%) vs BII 21/32 965.6%), P = 0.041)
and smaller but not significant attributable mortality to VAP (2 of
20 (10%) vs 10 of 32 (31.3%), P = 0.288). A canine model of Pseudomonas aeruginosa ventilator-
associated pneumonia using a defined bacterial inoculum A canine model of Pseudomonas aeruginosa ventilator-
associated pneumonia using a defined bacterial inoculum A Fahy1, M Gale1, N Chow2, S Webb2
1Royal Perth Hospital, Perth, Australia; 2University of Western
Australia, Perth, Australia
Critical Care 2007, 11(Suppl 2):P96 (doi: 10.1186/cc5256) Conclusion Our results suggest that administration of meropenem
by CIA may have more clinical efficacy than administration by BII for
the treatment of VAP, but more studies are required to confirm this. Introduction This prospective pilot study set out to develop an
animal model of Pseudomonas aeruginosa that would be suitable
for the application of molecular techniques to evaluate virulence in
which instillation of a reference strain of P. aeruginosa results in a
monoculture ventilator-associated pneumonia. For this purpose,
male adult greyhounds were used in an animal research laboratory. Methods The animals were anaesthetised, orally intubated and
mechanically ventilated. An inoculum of P. aeruginosa (strain PA01)
was instilled into the oropharynx at 1 hour and 8 hours post-
intubation. The animals were terminated at 78 hours. A randomized trial of combination therapy versus
monotherapy for the empiric treatment of suspected
ventilator-associated pneumonia D Heyland1, P Dodek2, J Muscedere3, A Day3, D Cook4
1Canadian Critical Care Trials Group, Kingston General Hospital,
Kingston, Canada; 2St Paul’s Hospital, Vancouver, Canada;
3Kingston General Hospital, Kingston, Canada; 4St Joseph’s
Healthcare, Hamilton, Canada
Critical Care 2007, 11(Suppl 2):P95 (doi: 10.1186/cc5255) Results Pneumonia was evaluated based on macroscopic grading
and microbiological (bacterial count) findings. We were able to
maintain anaesthetic, haemodynamic and respiratory support for
the study duration of 78 hours. A monobacterial pulmonary
infection was established in four out of five animals. Administration
of ceftriaxone 1 g daily effectively suppressed all other bacteria. This allowed proliferation of the single strain P. aeruginosa (PA01)
we had inoculated with no culture of other organisms. Introduction Delays in adequate antibiotic therapy for ventilator-
associated pneumonia (VAP) are associated with poor outcomes,
and early use of broad-spectrum antibiotics may improve clinical
outcomes. However, indiscriminant use of broad-spectrum
antibiotics is associated with the emergence of antibiotic-resistant
bacteria, fungal infections, and increased healthcare costs. The
purpose of this study was to determine optimal empiric treatment
of VAP by comparing a strategy of combination therapy to
monotherapy with broad-spectrum antibiotics. Introduction Delays in adequate antibiotic therapy for ventilator-
associated pneumonia (VAP) are associated with poor outcomes,
and early use of broad-spectrum antibiotics may improve clinical
outcomes. However, indiscriminant use of broad-spectrum
antibiotics is associated with the emergence of antibiotic-resistant
bacteria, fungal infections, and increased healthcare costs. The
purpose of this study was to determine optimal empiric treatment
of VAP by comparing a strategy of combination therapy to
monotherapy with broad-spectrum antibiotics. Conclusions Over a short period of time we were able to
reproduce a monoculture ventilator-associated pneumonia in a
significant percentage of animals. We successfully developed an
animal ICU model that we were able to sustain for 78 hours. This
canine model of P. aeruginosa (PA01) ventilator-associated
pneumonia is suitable for the application of molecular techniques
such as signature-tagged mutagenesis, differential fluorescence
induction, and in vivo expression technology. Methods In a multicenter trial, we randomized mechanically
ventilated adult patients with suspected VAP that developed after
96 hours in the ICU to receive either meropenem and ciprofloxacin
or meropenem alone, as initial therapy. In addition, before starting
antibiotics, diagnostic specimens were obtained using either
bronchoalveolar lavage with quantitative cultures or standard
endotracheal aspirates. Administration of meropenem for the treatment of
ventilator-associated pneumonia VAP was treated during 14 days with
meropenem (1 g/6 hours intravenously). The antibiotic clinical effect
was categorized as cure or failure. Difference between groups were
tested by means of Student’s t test end exact chi-square test, using
the MedCalc program. We consider values of P < 0.05 as a
significant difference. infection due to pseudomonas species, acinetobacter species and
multidrug-resistant Gram-negative bacilli at enrollment (n = 56),
the adequacy of initial antibiotics was 82.4% in the combination
group versus 18.8% in the monotherapy group (P < 0.001); this
difference was associated with an increase in the microbiological
eradication of the infecting organisms (64.1% vs 29.4%, P = 0.05)
but no differences in clinical outcomes. Conclusion
In patients who have suspected VAP, empiric
treatment with combination therapy, as compared with mono-
therapy, is safe and is associated with a higher rate of adequate
antimicrobial coverage but has no effect on clinical outcomes. Acknowledgements This study was supported by grants from the
Canadian Institutes of Health Research and Physicians Services Inc. of
Ontario, and unrestricted grants from AztraZeneca Inc., and Bayer Inc. Conclusion
In patients who have suspected VAP, empiric
treatment with combination therapy, as compared with mono-
therapy, is safe and is associated with a higher rate of adequate
antimicrobial coverage but has no effect on clinical outcomes. Acknowledgements This study was supported by grants from the
Canadian Institutes of Health Research and Physicians Services Inc. of
Ontario, and unrestricted grants from AztraZeneca Inc., and Bayer Inc. P95 A randomized trial of combination therapy versus
monotherapy for the empiric treatment of suspected
ventilator-associated pneumonia M Niederman1, J Chastre2, K Corkery3, R Fishman3, J Fink3,
C Luyt2, M Sanchez4
1Winthrop-University Hospital, Mineola, NY, USA; 25Hôpital Pitié-
Salpêtrière, Paris, France; 3Nektar Therapeutics, San Carlos, CA, USA;
4Hospital Principe de Asturias, Alcala de Henares, Madrid, Spain
Critical Care 2007, 11(Suppl 2):P97 (doi: 10.1186/cc5257) Available online http://ccforum.com/supplements/11/S2 Available online http://ccforum.com/supplements/11/S2 Figure 1 (abstract P97) Despite isolation, MRAB spread over and infected eight more
patients in separate rooms and different sections of the ICU
32 days later. Further transmission occurred within a few days:
three male patients with multiple trauma (42, 20, and 62 years old;
patients 2, 3, and 4), cardia carcinoma (female, 66 years old;
patient 5), necrotizing pancreatitis (female, 78 years old; patient 6),
splenomegaly owing to polycythaemia vera (male, 74 years old;
patient 7 – MRAB diagnosis postmortem), rectal carcinoma
(female, 76 years old; patient 8 – isolation because of MRSA
infection even before) and respiratory failure after gastric banding
(female, 41 years; patient 9). All patients suffered from septic
shock with high fever, needed high volume replacement and
catecholamines
several
times
and
prolonged
mechanical
ventilation. MRAB was isolated in the tracheal secretion or BAL in
all patients, in abdominal drainage (patient 6), and in central
venous catheter (patient 5). Environmental investigations showed
no problematic circumstances. Colistin i.v. is not available in
Germany so it had to be procured from the USA, which caused a
delay of treatment for a few days. Another delay occurred because
of the rapid growing number of patients who needed Colistin. Patients were treated with an adjusted dosage for 16 days. safety and i.v. antibiotic use with inhaled amikacin (AMK) during
adjunctive treatment of intubated patients with Gram-negative
pneumonia. Methods A double-blind, placebo-controlled, study of aerosol
AMK delivered via the Pulmonary Drug Delivery System (PDDS®;
Nektar Therapeutics) in ventilated patients with Gram-negative
pneumonia as an adjunctive to i.v. therapy per ATS guidelines. Patients were randomized to receive aerosol containing 400 mg
AMK daily with placebo (normal saline) 12 hours later, 400 mg
AMK twice daily or placebo twice daily. The i.v. antibiotics (agent
and duration) were determined by the attending physician. The
AMK peak serum concentration, trough concentrations and
tracheal aspirates were drawn. All patients of the ICU were isolated to avoid new infections as a
precaution. After convalescence of two patients, all MRAB patients
were moved to the IMC, which was converted to an ICU for this
period, to isolate infected patients from uninfected. Three out of
nine patients died. All these laborious measures with a great expenditure of logistics
worked well; no further transmissions were observed. Results The mean number of i.v. Available online http://ccforum.com/supplements/11/S2 antibiotics at the end of the study
(mean 7 days) were two times greater with placebo than with
twice-daily AMK (P < 0.02) (Figure 1). For daily and twice-daily
AMK, the serum Cmax were 1.3 and 1.8 µg/ml (respectively) on
day 1, and 2.3 and 3.2 µg/ml on day 3. Mean trough levels were
0.87 and 1.49 µg/ml. Tracheal aspirate levels (mean) on day 3
were 6.9 mg/ml (daily) and 16.2 mg/ml (twice daily). Aerosol AMK
was well tolerated with no difference in adverse events across
treatment groups. Multidrug-resistant Acinetobacter baumannii susceptible only
to colistin outbreak in a cardiac surgical intensive care unit Multidrug-resistant Acinetobacter baumannii susceptible only
to colistin outbreak in a cardiac surgical intensive care unit K Papadopoulos, A Tasouli, E Douka, E Manoli, G Saroglou,
S Geroulanos
Onassis Cardiac Surgery Center, Athens, Greece
Critical Care 2007, 11(Suppl 2):P99 (doi: 10.1186/cc5259) Conclusion Repeated doses of adjunctive inhaled AMK to
mechanically ventilated patients with Gram-negative pneumonia
was safe, well tolerated, and associated with less i.v. antibiotic use
than placebo. Objectives
Gram-negative bacilli including multidrug-resistant
Acinetobacter baumannii (MDR-AB) are responsible for severe
ICU-acquired infections, mainly pneumonia and bacteraemia. The
aim of this study was to determine the incidence and mortality of
this multiresistant strain of Acinetobacter in patients undergoing
cardiac surgery, to elucidate the effectiveness of treatment with
colistin and to identify whether additional measures were able to
prevent and control the dissemination of MDR-AB isolates in our
institution. Decrease in intravenous antibiotic use with adjunctive
aerosolized amikacin treatment in intubated mechanically
ventilated patients with Gram-negative pneumonia Decrease in intravenous antibiotic use with adjunctive
aerosolized amikacin treatment in intubated mechanically
ventilated patients with Gram-negative pneumonia Results We randomized 740 patients in 28 ICUs in Canada and
the United States. The baseline characteristics and etiologies of
VAP were similar between groups. There was no difference in 28-
day mortality between the combination and monotherapy groups
(RR = 1.05, 95% confidence interval 0.78–1.42; P = 0.74). The
duration of ICU and hospital stay, clinical and microbiological
response to treatment, emergence of antibiotic-resistant bacteria,
isolation of Clostridium difficile, and fungal colonization were
similar between groups. Combination therapy resulted in a higher
rate of adequate empiric therapy compared with monotherapy
(93.1% vs 85.3%, P = 0.01). In a subgroup of patients with M Niederman1, J Chastre2, K Corkery3, R Fishman3, J Fink3,
C Luyt2, M Sanchez4
1Winthrop-University Hospital, Mineola, NY, USA; 25Hôpital Pitié-
Salpêtrière, Paris, France; 3Nektar Therapeutics, San Carlos, CA, USA;
4Hospital Principe de Asturias, Alcala de Henares, Madrid, Spain
Critical Care 2007, 11(Suppl 2):P97 (doi: 10.1186/cc5257) Introduction
Aerosolized
antibiotics
may
increase
lung
concentration, reducing the need for i.v. antibiotics. We evaluated S38 P100 Hypercalcaemia resulting from the use of tigecycline in the
treatment of multidrug-resistant Acinetobacter in patients
with multiorgan failure
M Duffy, M Thomas, G Auzinger, W Bernal, E Sizer, J Wendon
Institute of Liver Studies, London, UK
Critical Care 2007, 11(Suppl 2):P100 (doi: 10.1186/cc5260) Hypercalcaemia resulting from the use of tigecycline in the
treatment of multidrug-resistant Acinetobacter in patients
with multiorgan failure Hypercalcaemia resulting from the use of tigecycline in the
treatment of multidrug-resistant Acinetobacter in patients
with multiorgan failure Methods A prospective pharmacokinetic evaluation of amino-
glycoside pharmacokinetics during CVVHDF was undertaken. Pharmacokinetic profiles of once-daily doses of intravenous
amikacin and gentamicin were obtained from blood and dialysate/
ultrafiltrate samples for 12 critically ill patients treated with
CVVHDF using varying flow rates (1 l/hour dialysate plus 2 l/hour
filtration fluid or 2 l/hour dialysate plus 2 l/hour filtration fluid,
extracorporeal blood flow 200 ml/min). Drug concentrations were
measured using an immunoassay. M Duffy, M Thomas, G Auzinger, W Bernal, E Sizer, J Wendon
Institute of Liver Studies, London, UK
Critical Care 2007, 11(Suppl 2):P100 (doi: 10.1186/cc5260) Introduction Tigecycline (Wyeth) is a new glycylcycline anti-
microbial that has been used in the treatment of deep-seated
multidrug-resistant Acinetobacter (MDRA) infections. Unexpected
changes in routine hematology or serum chemistry have not been
reported. Results The mean clearance of gentamicin due to CVVHDF was
2.3 ± 0.3 l/hour (82.1 ± 11.3% of total body clearance (TBC)). The sieving coefficient (SC) was 0.85 ± 0.05. The CVVHDF
clearance of amikacin was 2.8 ± 0.5 l/hour (93.0 ± 7.8% TBC). The SC for amikacin was 0.88 ± 0.06. The difference in
gentamicin clearance versus amikacin clearance reflects differ-
ences in CVVHDF conditions. The mean effluent flow rate among
the patient sample treated with gentamicin was 2.7 l/hour
compared with 3.5 l/hour for amikacin. There was a strong
correlation between creatinine clearance by the filter and
measured drug clearance (P < 0.001). Individual patient estimates
of aminoglycoside pharmacokinetic parameters (k, Vd) obtained
during CVVHDF were used to allow appropriate dosage
adjustment. Individualized
pharmacokinetic–pharmacodynamic
goals (e.g. Cpmax/MIC ratio) were used as indicators of adequate
aminoglycoside dosing. The mean gentamicin and amikacin half-
lives (approximately 8 hours) during CVVHDF therapy were far
shorter than those previously reported in the literature for less
efficient forms of renal replacement therapy. Failure to adjust for
increased aminoglycoside clearance capacity due to CVVHDF
carries a risk of subtherapeutic dosing and therapy failure. P100 Methods All patients were managed within the liver ICU and
received standard care. Laboratory data were collected daily and
entered onto a specialist database. MDRA-positive cultures from
blood, bronchoalveolar lavage, drain fluid or samples taken at
laparotomy in the context of systemic inflammatory response
syndrome resulted in the initiation of tigecycline 100 mg i.v. followed by 50 mg i.v. 12 hourly. Results Eleven patients received tigecycline treatment for MDRA
infections (seven male). Ten patients had a single course whilst
one patient had three courses. Underlying disease states were
necrotising pancreatitis (one), polytrauma (one), post hepatectomy
(one), acute and acute on chronic liver failure (four), and post-
orthotopic liver transplant (four). The median duration of treatment
was 9 days (range 4–23 days); courses <7 days were because of
patient death (2/11). The mean APACHE II score at initiation of
therapy was 18 (range 13–26). Four out of 11 survived to ICU
discharge and 3/11 to hospital discharge. Tigecycline was well
tolerated but increases in corrected calcium were observed in
9/11 patients. The patient that received three courses of treatment
had elevations in corrected calcium after each course. For the 11
patients, the mean corrected calcium before treatment with
tigecycline was 2.41 mmol/l. The mean corrected calcium on
finishing the course increased to 2.59 mmol/l (P = 0.012). There
was no correlation between duration of treatment with tigecycline
and degree of change in the corrected calcium level (r = 0.08). Hypercalcaemia resolved on discontinuation of the drug; 7/11
survived >7 days after treatment and had a mean corrected
calcium of 2.46 mmol/l, which was not significantly different from
pretreatment levels (P = 0.94). Conclusion Dosing strategies on the basis of pharmacokinetic
analysis of serum drug concentrations, effluent fluid drug
concentrations and CVVHDF conditions improved therapeutic
outcomes for aminoglycoside drug therapy. P101 Despite significant ‘in vitro’ activity of colistin against this virulent
organism and its acceptable safety profile, results were
discouraging as only 13% survived. In fact, cure or clinical
improvement was observed only in four patients (27%) while 11
patients (73%) developed sepsis and multiple organ failure. A pharmacokinetic basis for improving therapeutic
outcomes of aminoglycoside therapy during continuous
venovenous haemodiafiltration A Spooner1, O Corrigan1, M Donnelly2
1Trinity College Dublin, Dublin, Ireland; 2Tallaght Hospital, Dublin,
Ireland
Critical Care 2007, 11(Suppl 2):P101 (doi: 10.1186/cc5261) Scale 1 measures were implemented for the whole 12-month
period while Scale 2 for two separate 3-week periods. Following
this infection control strategy we achieved intermittent eradication
of the pathogen during a 12-month period with continuous function
of the SICU. Introduction The objective of this study was to quantify the impact
of continuous venovenous haemodiafiltration (CVVHDF) on amino-
glycoside pharmacokinetics and to suggest dosing strategies to
improve therapeutic outcomes for these drugs in critically ill
patients treated with CVVHDF. There has been limited published
data on aminoglycoside pharmacokinetics during CRRT. This data
deficit had led to subtherapeutic dosing, identified by a retro-
spective evaluation of amikacin and gentamicin serum concentra-
tions, in patients treated with CVVHDF, undertaken as part of this
research. Conclusions Increasing prevalence of MDR-AB in ICU patients
demands installation of strict screening and contact precautions. Due to significant mortality of MDR-AB-infected patients, additional
measurements like geographic isolation of all positive cases,
exclusive medical and nursing personnel, use of separate supplies
and facilities and intense environmental surveillance is highly
recommended. P98 Management of an outbreak of multiresistant
Acinetobacter baumanii infection in a surgical intensive
care unit J Lewejohann, M Prang, F Seyfried, A Henning,
C Zimmermann, M Hansen, E Muhl, H Bruch
University Medical Center Schleswig-Holstein – Campus Lübeck,
Germany
Critical Care 2007, 11(Suppl 2):P98 (doi: 10.1186/cc5258) Methods A total of 1,451 patients attended the surgical ICU
(SICU) after cardiovascular surgery from 1 September 2005 to 31
August 2006. We reviewed the prophylactic measures of the
SICU and tried to identify epidemiological links between MDR-AB-
infected patients. We implemented a two-scale multiple program. Scale 1 included classical infection control measures (that is, strict
contact and droplet isolation, surveillance of throat, nasal and anal
flora for MDR pathogens on all patients transferred from other
hospitals, separate nursing staff for each infected or colonized
case and strict antibiotic policy), while Scale 2 referred to
geographic isolation of MDR-AB cases with exclusive medical and
nursing personnel, use of separate supplies and facilities and
intense environmental surveillance. Critical Care 2007, 11(Suppl 2):P98 (doi: 10.1186/cc5258) The first report of multiresistant Acinetobacter baumanii (MRAB)
was published in 1994. We report about an outbreak sensitive to
Polimyxin only. In June 2006 a German holidaymaker (male, 70
years old; patient 1) in Greece felt dyspnea, thoracic pain and
fever. He went to a hospital in Crete. CT indicated left-sided
pleural empyema, mediastinal emphysema, pericardial effusion and
pneumonia. Rapid deterioration lead to septic shock with need for
mechanical ventilation. He came to our ICU (15 beds and six IMC
beds) via air transport. Endoscopy showed esophagus perforation
with need for operation and endoscopic stenting. Several BALs
and a central venous catheter from the beginning showed MRAB
with intermediate susceptibility to meropenem/aminoglycosides
only. The patient received meropenem and gentamycin at first. Results Fifteen patients were infected by MDR-AB, of which 13
presented respiratory tract infection, one suffered deep surgical
site infection and bacteraemia and one from catheter-related
infection. They were all treated with intravenous and aerolized
colistin in combination with rifampicin or ampicillin and sulbactam. S39 P Gruber, C Gomersall, Q Tian, G Joynt
The Chinese University of Hong Kong, New Territories, Hong Kong
Critical Care 2007, 11(Suppl 2):P102 (doi: 10.1186/cc5262) P103 Patients and methods We studied 146 patients with skin and
soft tissue infections co-infected by HIV and 72 noninfected
patients with soft tissue infections aged 18–45 years. All of the
patients underwent operations aimed at surgical removal of the
dead tissues and pus and received different combinations of
antibacterial agents. Twenty-three patients after adequate surgery
received Linezolid in doses of 600 mg twice a day intravenously
during 3–4 days with oral follow-up of 600 mg twice a day. Linezolid in the treatment of HIV-infected patients with
complicated skin and soft tissue infections Linezolid in the treatment of HIV-infected patients with
complicated skin and soft tissue infections N Khachatryan1, I Dizengof2, G Smirnov2
1Moscow State University of Medicine and Dentistry, Moscow,
Russian Federation; 2Hospital of Infectious Diseases N3, Moscow,
Russian Federation
Critical Care 2007, 11(Suppl 2):P104 (doi: 10.1186/cc5264) Introduction
The incidence of HIV-infected patients with
complicated skin and soft tissue infections has risen. Because of
advanced immune suppression, slower responses to antibacterial
treatment, and increased risk of bacteraemia relative to
noninfected patients, the choice of initial appropriate empiric
antibacterial therapy is an important aspect of care for HIV-infected
patients. However, in recent years a dramatic increase of the
resistance among Staphylococci to all classes of antimicrobial
agents, including glycopeptides, has been reported. Introduction
The incidence of HIV-infected patients with
complicated skin and soft tissue infections has risen. Because of
advanced immune suppression, slower responses to antibacterial
treatment, and increased risk of bacteraemia relative to
noninfected patients, the choice of initial appropriate empiric
antibacterial therapy is an important aspect of care for HIV-infected
patients. However, in recent years a dramatic increase of the
resistance among Staphylococci to all classes of antimicrobial
agents, including glycopeptides, has been reported. Conclusions Total adsorption is low and unlikely to be of clinical
significance. Adsorption
and
the
sieving
coefficient
are
independent of the type of haemofilter membrane. The sieving
coefficient of oseltamivir carboxylate is 1, therefore clearance
during haemofiltration can be estimated from the ultrafiltration rate. Available online http://ccforum.com/supplements/11/S2 influenza A/H5N1 develop acute renal failure. A proportion will
require haemofiltration. There are no data to determine the
elimination of oseltamivir carboxylate (the active metabolite) by
haemofiltration. An in vitro study to determine elimination by
measuring the adsorption and sieving coefficient of oseltamivir
carboxylate using two haemofilter types was undertaken. and 34 once daily (OD group), for nosocomial pneumonia (n = 14),
skin and soft tissue infection (burn and nonburn including diabetic
foot) (n = 13), bacteraemia (n = 10), intra-abdominal infection
(n = 8), bone and joint infection (n = 6) and as pre-emptive therapy
for severe trauma (n = 13). In the OD group, mean trough levels
remained at 9.64 µg/ml from days 2 to 4 and peak levels remained
at a mean of 24.84 µg/ml. In the BD group, mean trough levels
increased by 5.65 µg/ml/24 hours to 21.8 µg/ml by day 4; the
mean peak level increased by 5.06 µg/ml/24 hours to 43.89 µg/ml
by day 4. Methods An in vitro one-compartment model of continuous veno-
venous haemofiltration was used. In phase 1 oseltamivir carboxy-
late adsorption to the haemofilter and circuit was studied by
circulating a blood–crystalloid mixture containing clinically relevant
concentrations of oseltamivir carboxylate through a haemofilter
circuit and returning the ultrafiltrate to the mixing chamber. In
phase 2 the ultrafiltrate was removed and replaced with a
bicarbonate-based fluid to enable calculation of the sieving
coefficient. The study was repeated 10 times with two haemofilter
types: polyamide and polyacrylonitrile (PAN). Finally, oseltamivir
carboxylate was added to the blood–crystalloid mixture without
circulation through the circuit to determine its stability in solution. Blood samples collected were assayed by HPLC-MS/MS. Conclusion Higher trough levels of glycopeptides (15–20 µg/ml)
are targeted to improve efficacy and reduce resistance
development. In the OD group the conventional target of 10 µg/ml
was achieved, whilst in the BD arm 20 µg/ml was exceeded for
60% of the time by day 2 and 100% by day 4. BD dosing is
recommended for most patients with severe infections, particularly
those that are critically ill. No premature discontinuations or
adverse events were reported during the study. P104 Results Oseltamivir carboxylate remained stable in solution (mean
percentage change from baseline at 30 min: +3.97%, at 60 min:
+1.91%, at 90 min: +2.36%). The mean ± SD initial oseltamivir
carboxylate concentrations for the PAN (346 ± 85 µg/l) and
polyamide (453 ± 185 µg/l) showed no significant difference. The
mean ± SD adsorption at 90 min was 58.18 ± 17.84 µg for PAN
and 75.22 ± 36.88 µg for polyamide haemofilters. There was no
statistical difference in adsorption between the haemofilters. The
initial drug concentration was a significant predictor of adsorption
(r2 = 0.734). The mean ± SD sieving coefficient of oseltamivir
carboxylate for PAN (1.06 ± 0.04) and polyamide (1.03 ± 0.06)
haemofilters showed no statistical difference between the
haemofilters. P102 An in vitro study of elimination of oseltamivir carboxylate
by haemofiltration P Gruber, C Gomersall, Q Tian, G Joynt
The Chinese University of Hong Kong, New Territories, Hong Kong
Critical Care 2007, 11(Suppl 2):P102 (doi: 10.1186/cc5262) Conclusion Tigecycline is well tolerated but appears to be
associated with an elevated corrected calcium in critically ill
patients. This returns to baseline values on discontinuation of the
drug. Conclusion Tigecycline is well tolerated but appears to be
associated with an elevated corrected calcium in critically ill
patients. This returns to baseline values on discontinuation of the
drug. Introduction Oseltamivir is the drug of choice for treatment of
avian influenza A/H5N1 infection. One-quarter of patients with S40 Available online http://ccforum.com/supplements/11/S2 A post-authorization survey to evaluate plasma
concentrations of teicoplanin in adult hospitalized patients
treated for sepsis in Gauteng, South Africa A Brink1, G Richards2, and the G Uts Study Group
1Du Buisson, Bruinette and Partners, Johannesburg, South Africa;
2Johannesburg Hospital, Johannesburg, South Africa
Critical Care 2007, 11(Suppl 2):P103 (doi: 10.1186/cc5263) Results The most frequent pathogens are Staphylococci in both
groups of patients with soft tissue infections: 56% was noted
among the noninfected patients and 61% among the HIV-infected
patients. MRSA was identified in 30% of Staphylococci in HIV-
infected patients. Among the patients receiving Linezolid, MRSA
was identified in nine cases; in two cases vancomycin-intermediate
S. aureus strains, and in one case vancomycin-resistant S. aureus
strain. In three cases we revealed Staphylococcus bacteraemia, in
one case MRSA bacteraemia in patient with retroperitoneal
phlegmon. Objective This study measured and analyzed plasma concen-
trations of teicoplanin in patients >18 years in the first 4 days of
administration. Methods This was an open-label, multicentre, observational study
in patients receiving teicoplanin for suspected or diagnosed Gram-
positive infection. Data collection included demographics, method
of administration, loading and maintenance doses, creatinine and
adverse events. Trough and peak concentrations were determined
15 minutes prior to drug administration and 60 minutes after. Serum was separated and stored at –20°C until analysis. Levels
were determined with an Abbott TDx®/FLx® analyzer and Seradyn
Teicoplanin Innofluor assay kits. Seradyn internal teicoplanin
controls were run within and between each batch. Mean trough
and peak plasma levels were calculated for 4 days of therapy. Results Seventy-four patients with complete records were
analyzed and whilst all patients received an 800 mg loading dose
on day 1, 40 received 400 mg twice daily thereafter (BD group) A statistical difference was identified in duration of high
temperature, purulence and wound healing in comparison with
patients receiving different combinations of antibacterial agents. All
patients receiving Linezolid were discharged from the hospital. The
length of stay was 17 ± 1.67 days in comparison with patients
receiving other antibacterial agents (from 19.52 ± 1.37 to 20.3 ±
1.46 days). The length of stay in hospital among the noninfected
patients with soft tissue infection was 9.5 days. P107 Results A high incidence of ESBL producing E. coli and
Klebsiellae was observed (85.8%). Meropenem (9.3%) and
imipenem (2.8%) resistance in the ESBL producers was seen. On
multivariate analysis with logistic regression, a central venous
catheter was an independent risk factor for ESBL acquisition
(P = 0.01, OR 3.55, 95% CI 1.4–9.02). The median ICU length of
stay was 3.5 days and 3 days in the ESBL and non-ESBL groups,
respectively. The overall mortality was 13.28% and 13.6% in the
two groups, respectively. Microbiological outcomes were similar to
clinical outcome, with 83.6% microbiologic success rate among
ESBL producers. The contamination by Staphylococcus epidermidis in the
intensive care unit The contamination by Staphylococcus epidermidis in the
intensive care unit K Bruno1, D Albanese1, E Fabbri1, F Petrini1, M Scesi1,
F Bruno2
1SS Annunziata, Chieti, Italy; 2Villa Serena Clinic, Pescara, Italy
Critical Care 2007, 11(Suppl 2):P107 (doi: 10.1186/cc5267) Introduction The most important way to prevent infections in the
ICU is to respect asepsis during the numerous invasive procedures
to which patients are exposed (central venous catheter, urinary
catheter, orotracheal tube (OTT), fibrobronchoscopy (FOB),
surgical drainages, patients nursing, surgical medications). Conclusion ESBL producing E. coli
and Klebsiellae are
problematic pathogens in our ICUs. Emergence of carbapenem
resistance is of serious concern. Stringent infection control
practices such as aseptic insertion and proper handling of central
lines within the ICU should be followed by all. Methods The contaminations from Staphylococcus epidermidis
have been valued in main infection centres on 951 patients
admitted to our ICU for more than 72 hours from 1996 to 2005. From 2000, rigid asepsis protocols have been introduced for the
cleansing of staff hands with the use of disinfectants such as
Clorexidina and alcoholic gel. A clinico-microbiological study of extended spectrum
β-lactamases in the intensive care unit Y Mehta, K Bomb, S Jalota, A Arora, N Trehan
Escorts Heart Institute and Research Centre, New Delhi, India
Critical Care 2007, 11(Suppl 2):P105 (doi: 10.1186/cc5265) Introduction Extended spectrum β-lactamase (ESBL) producing
organisms are emerging as common nosocomial pathogens in the
ICU worldwide. Early detection and prevention of spread is the
primary measure to overcome the challenge posed by these
difficult to treat ESBL infections. The aim of this study was to find
the incidence, risk factors and microbiological and clinical outcome
of patients infected with ESBL producing Escherichia coli and
Klebsiellae in the ICU of a tertiary care cardiac center in India. Results Eighty-five patients in phase I and 55 patients in phase II
were enrolled. Third-generation cephalosporins were the primary
antibiotic in 75.2% of cases in phase I and in 1.8% of cases in
phase II (P < 0.001). The incidence of ESBL was 62.3% in phase I
and it came down to 34.5% in intervention phase II (P < 0.01). Conclusion Data from this intervention study support the concept
that third-generation cephalosporins are of substantial importance
in the emergence of ESBL; by decreasing the level of third-
generation cephalosporin use and increasing the piperacillin/
tazobactum use, their was a notable reduction in the acquisition
rate of ESBL producing E. coli. Methods A prospective, observational, case–control study of 150
patients was conducted from August 2004 to July 2005. ESBL
testing was performed by the phenotypic confirmatory disc
diffusion method. Clinical data and risk factors for ESBL
acquisition were analysed as well as the antimicrobial therapy, and
clinical and microbiological outcomes were studied. A post-authorization survey to evaluate plasma
concentrations of teicoplanin in adult hospitalized patients
treated for sepsis in Gauteng, South Africa Modification of
antibacterial treatment was not required in the group of patients Results Seventy-four patients with complete records were
analyzed and whilst all patients received an 800 mg loading dose
on day 1, 40 received 400 mg twice daily thereafter (BD group) S41 Critical Care March 2007 Vol 11 Suppl 2
27th International Symposium on Intensive Care and Emergency Medicin preventing their clonal outbreak, and the risk factors for ESBL
include intensive antibiotic exposure (especially third-generation
cephalosporin monotherapy). The present study was performed to
determine the impact of using piperacillin/tazobactum in reducing
the acquisition rate of ESBL producing Gram-negative bacteria in
the ICU. receiving Linezolid. No significant laboratory abnormalities and side
effects were noted. We did not reveal statistical differences in the
platelet count in group of patients receiving Linezolid (5 days after
operation 213 ± 26.0/mm3) in comparison with the group
receiving
other
antibacterial
agents
(256
±
32/mm3). Thrompocytopenia is characterized to HIV-infected patients, but
did not deteriorate in patients receiving Linezolid Methods This open-label, prospective study was carried out in
140 adult patients admitted to the ICU over a period of 9 months,
and was divided into two phases. Phase I (pre-intervention phase,
0–3 months): upon admission to the ICU, besides standard
investigations, additional rectal swab cultures were taken for
detection of ESBL within and after 48 hours of admission, and
were repeated every 7 days of the stay in the ICU. Routinely
prescribed antibiotics were allowed. Phase II (intervention phase,
4–9 months): this was subdivided into (a) first 3 months
(4–6 months): piperacillin/tazobactum was the primary antibiotic
used (more than 50% replacement of cephalosporins), and (b) last
3 months (7–9 months): here again, rectal swab cultures were
taken and piperacillin/tazobactum was the primary antibiotic used. McNemar’s test and Fisher’s exact test were used for statistical
analysis. Conclusion Linezolid in the complex treatment of HIV-infected
patients with complicated skin and soft tissue infections may
improve the results of therapy and may be used for initial empirical
intravenous-to-oral antibacterial therapy. P106 Impact of antibiotic utilization measures on acquisition
rate of extended spectrum β-lactamase enzymes
producing bacteria P108 P108 their critical illness status, some patients were subject to
quarantine. Improving HH was achieved by promoting alcohol-
based hand disinfection, refraining all health care workers (HCW)
from wearing hand jewellery or artificial fingernails, supplying HCW
with clip watches and by developing promotional material. Education of HCW regarding principles and techniques of HH was
provided by the IC department, supervised by link persons
selected among medical, nursing and domestic staff. The number
of new hospital-acquired MRSA infections per 1,000 admissions
was recorded. Compliance to HH was measured by observation,
microbiological analysis of total counts of colony-forming units on
fingerprints, and by monitoring the consumption of hand-rub
solutions (HH moments per patient-care day). Colonization and infection by MRSA in critically ill patients L Lorente, R Santacreu, J Iribarren, J Jimenez, M Martin, M Mora
Hospital Universitario de Canarias, Santa Cruz de Tenerife, Spain
Critical Care 2007, 11(Suppl 2):P108 (doi: 10.1186/cc5268) Objective To determine the incidence of colonization and infection
by MRSA in critically ill patients. Methods A prospective study during 30 months of the patients
admitted to the ICU for 24 hours or more. Throat swab, tracheal
aspirate and urine were taken on admission and twice weekly. The
colonization and infection by MRSA were registered. The infections
were diagnosed according to CDC criteria. The infections were
classified based on throat flora as: primary endogenous (PE) when
they were caused by germs that were already colonizing the throat
on the ICU admission; secondary endogenous (SE) when they
were caused by germs that were not colonizing the throat on the
ICU admission but were acquired during the stay in ICU; or
exogenous (EX) when they were caused by germs that were not
colonizing the throat. The infections were classified based on the
onset moment: early onset (EO) were those developed during the
first 4 days of the ICU stay; and late onset (LO) were those
developed 5 days after ICU admission. Results A selective MRSA admission screening policy increased
the carrier detection rate up to 15%, compared with 1–2% in our
preoperative outpatient clinic. The observed compliance to HH
increased from 49% to 79% and consumption of hand-rub solution
from 6 to 33 l per 1,000 patient-days. The number of HH moments
increased from 19 to 47. Total counts of colony-forming units less
than 50 improved from 39% of the analyses to 55%. P109 Methods A retrospective post-hoc analysis of the prospective,
multicentre VAP study, which enrolled patients with a clinical
suspicion of VAP, admitted to an ICU for >96 hours and on
mechanical ventilation (MV) for >48 hours. Airway cultures were
done on randomization. Patients with positive Candida cultures
from other sites were excluded. The remaining patients were
divided into two groups according to their Candida airway culture
status. Demographics, admission diagnosis, comorbidities, PaO2/
FiO2 ratio and APACHE II score were recorded at randomization. The length of MV, ICU and hospital stay were compared, as well as
hospital, ICU and 28-day mortality. Appropriate parametric
statistical tests were applied according to data. Methods A retrospective post-hoc analysis of the prospective,
multicentre VAP study, which enrolled patients with a clinical
suspicion of VAP, admitted to an ICU for >96 hours and on
mechanical ventilation (MV) for >48 hours. Airway cultures were
done on randomization. Patients with positive Candida cultures
from other sites were excluded. The remaining patients were
divided into two groups according to their Candida airway culture
status. Demographics, admission diagnosis, comorbidities, PaO2/
FiO2 ratio and APACHE II score were recorded at randomization. The length of MV, ICU and hospital stay were compared, as well as
hospital, ICU and 28-day mortality. Appropriate parametric
statistical tests were applied according to data. Results Of the 739 patients enrolled in the VAP study, 639 were
included for analysis: 114 had Candida airway colonization (C) and
525 did not (NC). No significant differences were noted in
demographics and APACHE II score (20 ± 6 vs 20 ± 6, P = 0.37)
except more frequent admission for sepsis (7.0% vs 2.1%,
P = 0.005) and respiratory conditions (21.9% vs 14.3%, P = 0.04)
in group C. More colonized patients were on antibiotics at
randomization (81.6% vs 56.7%, P < 0.001). A trend for increased Candida airway colonization is associated with worse
outcomes Candida airway colonization is associated with worse
outcomes M Delisle1, D Williamson2, M Perreault3, M Albert2, X Jiang4,
D Heyland4
1Hopital de l’Enfant-Jésus, Québec, Canada; 2Hopital du Sacré-
Coeur de Montréal, Canada; 3Hopital Général de Montréal, Centre
Universitaire de Santé McGill, Montréal, Canada; 4Queens
University, Kingston, Canada
Critical Care 2007, 11(Suppl 2):P110 (doi: 10.1186/cc5270) M Delisle1, D Williamson2, M Perreault3, M Albert2, X Jiang4,
D Heyland4 1Hopital de l’Enfant-Jésus, Québec, Canada; 2Hopital du Sacré-
Coeur de Montréal, Canada; 3Hopital Général de Montréal, Centre
Universitaire de Santé McGill, Montréal, Canada; 4Queens
University, Kingston, Canada
Critical Care 2007, 11(Suppl 2):P110 (doi: 10.1186/cc5270) Introduction
Candida
airway colonization is common in
mechanically ventilated ICU patients. Its significance and impact
on outcomes are not well defined. We aimed to describe Candida
airway colonization and assess clinical outcomes of patients with a
clinical suspicion of ventilator-associated pneumonia (VAP)
colonized with Candida. Conclusions In our series, most of the infections caused by MRSA
were pneumonias, had a late onset and were secondary
endogenous. P108 Concomitantly, a decrease in MRSA attack rate from six to one
new case per 1,000 patient-days was seen. Conclusion An ED tailored selective MRSA screening and contact
isolation protocol and a change in HH behaviour in the ED have
mainly contributed to a decrease of the MRSA attack rates in our
hospital far below the national rate. p
y
Results Were admitted 1,582 patients, 953 males (60.24%). The
mean age was 57.91 ± 18.83 years. The mean APACHE II score
was 13.95 ± 8.93. Admission diagnoses were: 737 (46.59%)
heart surgery, 189 cardiological (11.95%), 196 neurologic
(12.29%), 185 trauma (11.69%), 120 respiratory (7.59%), 104
digestive (6.57%) and 51 intoxication (3.22%). Mortality was
14.79% (234 patients). A total of 36 patients had colonization by
MRSA, two patients at ICU admission and 34 patients during the
ICU stay. We documented 24 infections caused by MRSA (four
EO and 20 LO; zero PE, 21 SE and three EX): 18 pneumonias
(three EO and 15 LO; zero PE, 15 SE and three EX), three primary
bacteremias (one EO and two LO; three SE), two surgical wound
infections (two LO and SE) and one pressure sore infection (one
LO and SE). Death occurred in 7/24 patients (29.17%) with
infection caused by MRSA: 6/18 (33.33%) pneumonias, 1/3
(33.33%) primary bacteremias and 0/3 other infections. Impact of an MRSA search and destroy policy in a tertiary
care emergency department Impact of an MRSA search and destroy policy in a tertiary
care emergency department Impact of antibiotic utilization measures on acquisition
rate of extended spectrum β-lactamase enzymes
producing bacteria Results From 1996 to 2005 the percentage of contamination from
S. epidermidis has been 24.7% (22% in respiratory tracts, 8% in
the urinary system, 41% in central venous catheter, 19% in the
blood, 10% in other places). From 2000 to 2005 there has been a
sensible reduction of 3%. A Gurnani1, A Jain1, S Sengupta1, G Rambhad2
1Kailash Hospital, Noida, India; 2Wyeth, Bombay, India
Critical Care 2007, 11(Suppl 2):P106 (doi: 10.1186/cc5266) A Gurnani1, A Jain1, S Sengupta1, G Rambhad2
1Kailash Hospital, Noida, India; 2Wyeth, Bombay, India
Critical Care 2007, 11(Suppl 2):P106 (doi: 10.1186/cc5266) Conclusion The introduction in the last 5 years of strict protocols
in order to control asepsis in our ICU, combined with the use of
Clorexidina and alcoholic gel, have drastically reduced the
contamination from S. epidermidis. Introduction Antibiotic resistance patterns are continually changing;
a new problem has been the emergence of Gram-negative bacteria,
primarily Escherichia coli and Klebsiellae pneumoniae, producing
extended spectrum β-lactamase enzymes (ESBL). Antibiotic use
measures are presumably the most important intervention in S42 Available online http://ccforum.com/supplements/11/S2 P112 Methods During a 2-year period (2005–2006), a study was
performed in a 17-bed general ICU, divided into two phases: a
case–control retrospective study in which controls comprising a
representative subpopulation with severe bacterial sepsis were
compared with cases (patients with Candida sepsis) with respect
to multiple demographic and clinical factors in a univariate analysis;
and a prospective phase creating a preemptive scheme based on
results from the retrospective part followed by progressively
implementing it among targeted patients. Results Over a 22-month period, 2,509 critically ill patients were
evaluated. Candida spp. was isolated from any site in 141 patients
(5.6%), while 10 patients (0.4%) presented ICU-acquired
candidemia. They were all hospitalized for more than 7 days (range
7–34 days) in the ICU and had been exposed to broad-spectrum
antibiotics (>3 agents). The mean age was 68 years (range 50–82
years) and the mean ICU stay 28 days. Candidemia appeared at a
mean of 15.8 days after ICU admission. Candida albicans was the
most common isolated pathogen. Candiduria in any count was
detected in 12 patients but none of them experienced candidemia,
while in seven patients Candida was isolated from urine and the
respiratory tract. Six patients had major postoperative complica-
tions. Mortality due to candidemia was 60%. All patients received
appropriate antifungal treatment. Prophylactic antifungal treatment
was used in patients with multifocality colonization and in patients
spending more than 7 days in the ICU after cardiac surgery. Results Identified were 28 cases with Candida sepsis and 50
controls with severe bacterial sepsis with an all-cause mortality rate
of 40.2%. The mortality rate for Candida sepsis was 46.4% with
an attributable risk of 10/100 and was associated with a worse
score of systemic injury (SAPS II = 51.7 ± 15.0), comparing with a
mortality rate of 35.7% and SAPS II = 38.8 ± 13.3 for bacterial
sepsis. Candida sepsis was always accompanied by concurrent
bacterial sepsis (2.8 ± 1.1 microorganisms/patient isolated from
blood cultures). Identified were risk factors with great significance
in addition to already known ones: Candida colonization (OR =
3.4), diabetes (OR = 3.2), number of antibiotics used (OR = 2.9),
a nothing per os regimen (OR = 2.63), ICU length of stay (OR =
1.97), length of antibiotic use (OR = 1.74), pancreatitis (OR =
1.7), shock at admission (OR = 1.54), ventilator days/ICU stay
ratio (days)(OR = 1.4), multiple resistant bacterial strains (OR =
1.5). P112 Candida colonization and risk of candidemia in a cardiac
surgical intensive care unit
E Douka, A Mastoraki, G Stravopodis, G Saroglou, S Geroulanos Candida colonization and risk of candidemia in a cardiac
surgical intensive care unit
E Douka, A Mastoraki, G Stravopodis, G Saroglou, S Geroulanos
Onassis Cardiac Surgery Center, Athens, Greece
Critical Care 2007, 11(Suppl 2):P112 (doi: 10.1186/cc5272) Candida colonization and risk of candidemia in a cardiac
surgical intensive care unit M Geube, S Milanov, G Georgiev
Pirogov Emergency Institute, Sofia, Bulgaria
Critical Care 2007, 11(Suppl 2):P111 (doi: 10.1186/cc5271) Introduction The aim of the study was to evaluate the incidence of
Candida colonization in a cardiac surgical ICU, the predisposing
risk factors and the impact of candidemia on outcome. Introduction Candida spp. is the third most common reason for
sepsis in the ICU, not differentiating our results from the classic
pattern of ICU-acquired infection. Prevention of sepsis develop-
ment and identification of potentially modifiable risk factors are
important goals in intensive care patents. Preemptive treatment of
Candida sepsis accepted by some authors is defined as an early
antifungal treatment given to patients with evidence of substantial
colonization in the presence of multiple risk factors for Candida
infection prior to establishing the diagnosis by cultures. Our aim
was to form a focused group of patients with significant risk for
Candida sepsis; to prove the feasibility and efficacy of our pre-
emptive scheme for antimycotic treatment in order to reduce the
risk of development of proved Candida sepsis. Methods In an effort to answer this question a prospective study
was conducted among patients admitted to our 16-bed cardiac
surgical intensive care unit ICU during 1 December 2004–30
October 2005. Candida
colonization and candidemia were
identified. Fungal colonization was defined as colonization index
exceeding 0.20 (3 g, at least two samples of seven growing
Candida spp.). Candidemia was defined as the isolation Candida
spp. in at least one blood culture in a patient with temporally
related clinical signs. The demographic characteristics of patients
who developed candidemia, as well as the underlying disease and
comorbidities, were recorded. E Dhondt, R Duerinckx, I Laes, A Schuermans
UZ Leuven, Leuven, Belgium
Critical Care 2007, 11(Suppl 2):P109 (doi: 10.1186/cc5269) Conclusions Based on our results, we accepted an algorithm for
performing a preemptive therapy for which we observed clinical
efficacy and which we considered indicated the following target
groups of patients: with presence of clinical features of unresolving
sepsis plus three defined risk factors (PPV > 70%) in a patient
with length of ICU stay >20 days; lack of clinical improvement with
combined antibiotic treatment against established bacterial strains;
evidence of sepsis accompanied with multifocal Candida coloniza-
tion of sterile body spaces. Candida colonization without risk
factors requires continuous monitoring. The most important pre-
sumption to accept the preemptive strategy for a certain patient is
to have a serious clinical conviction that there is an invasive fungal
infection but it is still pending to be proved. Conclusion Respiratory tract Candida colonization in patients with
clinical suspicion of VAP is associated with an increased burden of
illness. Whether Candida colonization is responsible for worse
outcomes remains to be established. P111 Fungal infections in the intensive care unit? Another
approach for defining a target group of patients who
benefit from implementing preemptive antimycotic
treatment E Dhondt, R Duerinckx, I Laes, A Schuermans
UZ Leuven, Leuven, Belgium
Critical Care 2007, 11(Suppl 2):P109 (doi: 10.1186/cc5269) E Dhondt, R Duerinckx, I Laes, A Schuermans
UZ Leuven, Leuven, Belgium
Critical Care 2007, 11(Suppl 2):P109 (doi: 10.1186/cc5269) Introduction An emergency department (ED) is a major hospital
entrance and its case mix consists of patients at high risk of both
introducing and acquiring infections. Alerted by the rise of hospital-
acquired MRSA infections, the ED of a teaching hospital set up an
ED infection control (IC) programme. The programme and its
impact are discussed. Results Of the 739 patients enrolled in the VAP study, 639 were
included for analysis: 114 had Candida airway colonization (C) and
525 did not (NC). No significant differences were noted in
demographics and APACHE II score (20 ± 6 vs 20 ± 6, P = 0.37)
except more frequent admission for sepsis (7.0% vs 2.1%,
P = 0.005) and respiratory conditions (21.9% vs 14.3%, P = 0.04)
in group C. More colonized patients were on antibiotics at
randomization (81.6% vs 56.7%, P < 0.001). A trend for increased Methods The campaign consisted of the appliance of a proactive
MRSA admission screening protocol, selective contact isolation
(quarantine) and improving hand hygiene (HH). The MRSA
admission screening strategy took into account past medical
history or actual suspicion of MRSA carriage, transfers from other
hospitals and long-term care facilities and admission of
hospitalised patients to the ED for upgrading of care. According to S43 ritical Care March 2007 Vol 11 Suppl 2
27th International Symposium on Intensive Care and Emergency Medicin ICU (21.1% vs 13.9%, P = 0.06) and 28-day mortality (23.7% vs
16.4%, P = 0.08) and a significant difference in hospital mortality
(34.2% vs 21.1%, P = 0.003) was observed in group C. A trend
was found for increased median length of ICU stay (14.1 vs 11.6
days, P = 0.07) and duration of MV (10.9 vs 8.1, P = 0.06). Hospital stay was significantly longer (59.9 vs 38.6 days,
P = 0.006) in group C. P113 reticular neoplasias, solid organ transplants, and mainly in patients
with AIDS [1]. To our knowledge, the toxoplasmosis seropositivity
rate in ICU patients who have critical illness induced immuno-
suppression is not yet investigated. We studied the seropositivity
incidence of T. gondii in ICU patients by assessing IgG and IgM
antibodies. Consequences of cytomegalovirus reactivation in patients
with severe sepsis A Heininger, K Hamprecht, I Fischer, A Baumeister, C Meisner,
H Häberle
University Hospital, Tübingen, Germany
Critical Care 2007, 11(Suppl 2):P115 (doi: 10.1186/cc5275) Introduction Sepsis has been identified as a risk factor for cyto-
megalovirus (CMV) reactivation in nonimmunosuppressed patients
in the ICU setting. Here we present a double-blinded prospective
study assessing the consequences of CMV reactivation in non-
immunosuppressed patients with severe sepsis. Conclusion The observational nature of this study precludes the
establishment of any causality. This research merely documents
the experiences of ICU patients who have been prescribed i.v. fluconazole therapy. Our results showed high mortality rates in the
enrolled ICU patients. Patients developing adverse events and
complications requiring a switch in fluconazole experienced worse
outcomes pp
p
p
Methods In three (two surgical, one medical) ICUs of a German
university hospital, adult patients were screened for severe sepsis. Patients with recently occurring severe sepsis (<72 hours) were
enrolled if their anti-CMV IgG titer was positive. The exclusion
criterion was a manifest immunodeficiency. At enrollment the
SAPS II was assessed. Patients were monitored for CMV
reactivation weekly until death or hospital discharge by qualitative
and quantitative PCR and virus culture. CMV reactivation was
defined as CMV DNA detection or virus isolation. Patients with
(CMV+) and without CMV reactivation (CMV–) were compared
regarding inhospital mortality, duration of mechanical ventilation,
length of stay (LOS) in the ICU and the hospital. Data were
analysed using the Wilcoxon score rank sum test and chi-square
test. The level of significance was set to 0.05. Results CMV reactivation was observed in 38 out of 99 patients. Both groups (CMV+/CMV– patients) were quite similar in regard
to gender and age at study enrollment. Interestingly, the median
SAPS II was higher in CMV– patients (47 vs 42; P < 0.013). Accordingly, a lower mortality rate was anticipated for CMV+
patients
compared
with
the
CMV–
group. Contrary
to
expectations, mortality did not differ between both groups (CMV+
36.8% vs CMV– 42.6%; P > 0.67). This may point to a relatively pp
p
p
Methods In three (two surgical, one medical) ICUs of a German
university hospital, adult patients were screened for severe sepsis. Patients with recently occurring severe sepsis (<72 hours) were
enrolled if their anti-CMV IgG titer was positive. The exclusion
criterion was a manifest immunodeficiency. At enrollment the
SAPS II was assessed. Longitudinal evaluation of intensive care unit-related
fluconazole use in Spain and Germany H Wissing1, J Ballus2, G Nocea3, K Krobot4, P Kaskel4,
R Kumar5, P Mavros5
1Universitatsklinkum Frankfurt, Germany; 2Hospital Universitari de
Bellvitge, L’Hospitalet del Llobregat, Barcelona, Spain;
3Universitaria de Bellvitge, Barcelona, Spain; 4MSD Sharpe and
Dohme GmbH, Munich, Germany; 5Merck and Co., Inc.,
Whitehouse Station, NJ, USA
Critical Care 2007, 11(Suppl 2):P113 (doi: 10.1186/cc5273) Wissing1, J Ballus2, G Nocea3, K Krobot4, P Kaskel4, Materials and methods One hundred and three ICU patients with
the mean age of 53.9 ± 13.9 years (51 men, 52 women) and 78
healthy volunteers with the mean age of 51.4 ± 9.2 years (39 men,
29 women) as a control group were included in the study. Anti-
T. gondii IgG and IgM antibodies were determined by ELISA. Statistical analyses were done with the chi-square test and
Kolmogorov–Smirnov one-sample test. P < 0.05 was considered
as statistical significance. Objective To evaluate utilization patterns and outcomes associated
with i.v. fluconazole therapy within ICUs in Spain and Germany. Objective To evaluate utilization patterns and outcomes associated
with i.v. fluconazole therapy within ICUs in Spain and Germany. Objective To evaluate utilization patterns and outcomes associated
with i.v. fluconazole therapy within ICUs in Spain and Germany. Methods A prospective longitudinal observational study was
conducted within 14 hospital ICUs in Spain and five in Germany. Patients on i.v. fluconazole therapy were included and were
followed over one hospitalization period (admission until
discharge). Data were collected during 2004, using electronic
case report forms. Data included patient disease characteristics,
patient risk status (APACHE scores), type of fluconazole therapy,
drug-related adverse events, length of fluconazole therapy, and
length of hospital stay. Switches in fluconazole therapy, dosing
changes, additional concomitant antifungal therapy, overall mor-
tality, and clinical outcomes were also evaluated. Logistic regres-
sion models determined univariate and multivariate associations
with mortality. Results T. gondii IgG antibodies were positive in 56.3% of ICU
patients (n = 58) and in 24.3% of healthy volunteers (n = 19)
(P < 0.031). IgM antibodies were positive in 13.8% of ICU patients
(n = 15) and in 6.4% of healthy volunteers (n = 5); however, this
difference could not reach statistical significance. Conclusion The results of the study reveal that toxoplasma
seropositivity is not uncommon in ICU patients. Therefore, to
prevent the possibility of toxoplasmosis, seropositivity should be
periodically assessed in critically ill immunocompromised ICU
patients. Reference 1. Ferreira MS, Borges AS: Mem Inst Oswaldo Cruz 2002,
97:443-457. 1. Ferreira MS, Borges AS: Mem Inst Oswaldo Cruz 2002,
97:443-457. Results A total of 303 patients were enrolled. Fluconazole was
used initially as prophylaxis in 29 (9.6%) patients, preemptive
therapy in 85 (28.1%) patients, empiric therapy in 140 (46.2%)
patients and as definitive therapy in 49 (16.2%) patients. Thirty-six
patients switched from fluconazole to a broader spectrum anti-
fungal agent, and seven received a second concomitant antifungal
drug. Reasons for switching therapies included lack of response
due to suspected resistance, documented resistance or clinical
reasons other than resistance. Thirty-two patients (10.6%)
experienced fluconazole-related adverse events. The overall study
mortality rate was 41.9% (127/303 patients). Mortality was
significantly associated with switching i.v. treatment (odds ratio
5.0; 95% CI 2.3–11.1) and the presence of adverse events (odds
ratio 4.1; 95% CI 1.8–9.2). Consequences of cytomegalovirus reactivation in patients
with severe sepsis Patients were monitored for CMV
reactivation weekly until death or hospital discharge by qualitative
and quantitative PCR and virus culture. CMV reactivation was
defined as CMV DNA detection or virus isolation. Patients with
(CMV+) and without CMV reactivation (CMV–) were compared
regarding inhospital mortality, duration of mechanical ventilation,
length of stay (LOS) in the ICU and the hospital. Data were
analysed using the Wilcoxon score rank sum test and chi-square
test. The level of significance was set to 0.05. Longitudinal evaluation of intensive care unit-related
fluconazole use in Spain and Germany It is clear that further studies are required to evaluate the
effects of seropositivity on ICU outcome. P115 Consequences of cytomegalovirus reactivation in patients
with severe sepsis P112 Patients with gastrointestinal surgery were at risk for
development of early fungal sepsis – by the 10th day of admission –
compared with the other clinical cases – by the 21st day of
admission. The incidence rate of positive blood cultures for
Candida in the group exposed to our scheme was calculated as
6.7% vs 18.5% in the control group. Conclusion C. albicans is the most common fungal pathogen in
our ICU. Seven percent of colonized patients developed
candidemia. Major
postoperative
complications,
excessive
antibiotic exposure and acute renal failure seem to predispose to
the development of candidemia. Patients with candidemia have
high inhospital mortality, perhaps as a reflection of illness severity. S44 Available online http://ccforum.com/supplements/11/S2 The role of plasminogen activator inhibitor 1 measurement
with endotoxin adsorption therapy (PMX-DHP) for
postoperative septic shock patients The role of plasminogen activator inhibitor 1 measurement
with endotoxin adsorption therapy (PMX-DHP) for
postoperative septic shock patients T Ikeda, K Ikeda, Y Kuroki, T Yokoyama, K Yoshikawa
Tokyo Medical University, Hachioji Medical Center, Tokyo, Japan
Critical Care 2007, 11(Suppl 2):P116 (doi: 10.1186/cc5276) Patients and methods We treated 27 septic shock patients using
DHP-PMX. The patients were separated into two groups for
analysis: those whose systolic blood pressure (SBP) increased by
more than 30 mmHg immediately after DHP-PMX (15 cases), and
those whose SBP did not increase by more than 30 mmHg after
DHP-PMX (12 cases). Furthermore, the patients were separated
into two other groups for analysis: those whose P/F ratio increased
by more than 20% immediately after DHP-PMX (15 cases), and
those whose P/F ratio did not increase by more 20% after DHP-
PMX (12 cases). Mediators were measured at four points: before
and after DHP-PMX, and 1 day and 3 days afterward. Introduction A polymyxin B immobilized fiber column (PMX; Toray
Industries Inc., Tokyo, Japan) was developed in Japan in 1994 and it
has been used for treatment of endotoxemia or septic shock patients. Materials and methods All patients received an urgent operation
due to intra-abdominal infection. In 88 cases treated with a poly-
myxin B immobilized column through direct hemoperfusion (PMX-
DHP), changes in hemodynamics, pulmonary oxygenation (PaO2/
FIO2) and various mediators (IL-6, IL-8, IL-ra, plasminogen activator
inhibitor 1 (PAI-1)) were examined before and after PMX-DHP,
stratifying with the outcome (64 survivors and 24 who died). PMX-
DHP was performed through a double lumen catheter (11.5 Fr),
placed in the femoral vein or internal jugular vein, at a blood flow
rate of 80 ml/min using nafamostat mesilate as an anticoagulant for
2 hours. Results The patient group consisted of 17 males and 10 females,
59.6 ± 12.7 years old. The average APACHE II score was
27.2 ± 9.1, and the average SOFA score was 11.7 ± 5.2 before
DHP-PMX. Nineteen patients survived and eight died. When the
changes in PAI-1, protein C, ATIII, IL-6 and high mobility group box
protein 1 (HMGB-1) were compared between the groups, only the
HMGB-1 levels had improved significantly in the SBP increased
group (P = 0.0125). The SBP increased significantly after DHP-
PMX in the HMGB-1-improved group (P < 0.0001). An improve-
ment in the P/F ratio and a reduction in 2-arachidonoyl glycerol
during DHP-PMX were significantly correlated (P = 0.0184). P117 increased mortality in CMV+ patients, although CMV disease did
not occur. There was a striking difference between the groups in
respect to the period on ventilator: 21.5 days vs 8.0 days (median)
in CMV+ and CMV– patients, respectively (P < 0.005). Similarly,
CMV+ patients had a longer median LOS after enrollment either in
the ICU (29.5 days vs 10 days, P < 0.001) and in the hospital
(49 days vs 23 days, P < 0.001). This difference was assured
when the analysis was restricted to survivors. increased mortality in CMV+ patients, although CMV disease did
not occur. There was a striking difference between the groups in
respect to the period on ventilator: 21.5 days vs 8.0 days (median)
in CMV+ and CMV– patients, respectively (P < 0.005). Similarly,
CMV+ patients had a longer median LOS after enrollment either in
the ICU (29.5 days vs 10 days, P < 0.001) and in the hospital
(49 days vs 23 days, P < 0.001). This difference was assured
when the analysis was restricted to survivors. Mechanism and effectiveness of polymyxin B-immobilized
fiber columns for removing mediators (HMBG-1,
2-arachidonoyl glycerol, anandamide, PAI-1, protein C and
IL-6) in septic shock patients
Y Sakamoto1, K Mashiko1, T Obata2, Y Yamamoto3
1Chiba Hokusou Hospital, Nippon Medical School, Chiba, Japan;
2Institute of DNA Medicine, Jikei University School of Medicine,
Tokyo, Japan; 3Department of Emergency Medicine, Nippon
Medical School, Tokyo, Japan
Critical Care 2007, 11(Suppl 2):P117 (doi: 10.1186/cc5277) Mechanism and effectiveness of polymyxin B-immobilized
fiber columns for removing mediators (HMBG-1,
2-arachidonoyl glycerol, anandamide, PAI-1, protein C and
IL-6) in septic shock patients Mechanism and effectiveness of polymyxin B-immobilized
fiber columns for removing mediators (HMBG-1, fiber columns for removing mediators (HMBG-1,
2-arachidonoyl glycerol, anandamide, PAI-1, protein C and
IL-6) in septic shock patients Y Sakamoto1, K Mashiko1, T Obata2, Y Yamamoto3
1Chiba Hokusou Hospital, Nippon Medical School, Chiba, Japan;
2Institute of DNA Medicine, Jikei University School of Medicine,
Tokyo, Japan; 3Department of Emergency Medicine, Nippon
Medical School, Tokyo, Japan
Critical Care 2007, 11(Suppl 2):P117 (doi: 10.1186/cc5277) Conclusion Our data suggest that CMV reactivation leads to
increased morbidity and treatment expenditure independently from
CMV disease. Further analysis points at a crucial role of lung
pathology due to CMV reactivation. The role of plasminogen activator inhibitor 1 measurement
with endotoxin adsorption therapy (PMX-DHP) for
postoperative septic shock patients Results PMX-DHP significantly increased systemic arterial pressure
and mean arterial pressure, with a greater increase in the survival
group. Also, there appeared to be a trend for PaO2/FIO2 improve-
ment as blood pressure increased. As the mechanism for improve-
ment of pulmonary oxygenation by PMX-DHP has not been shown
clearly, it remained to be examined further. PAI-1 values
significantly decreased in the survivor group (from 436 ± 549 to
251 ± 283 ng/ml) immediately after PMX-DHP; also intracellular
adhesion molecule-1 and endothelial leukocyte adhesion molecule-
1 tended to decrease in both groups. Conclusion We showed that the circulation dynamics of septic
shock patients can be improved by reducing HMGB-1 levels and
that respiratory function can be improved by reducing 2-
arachidonoyl glycerol levels using DHP-PMX. P114 Seropositivity incidence of anti-Toxoplasma gondii
antibodies in critically ill intensive care unit patients Seropositivity incidence of anti-Toxoplasma gondii
antibodies in critically ill intensive care unit patients ÖS Can, S Yalçin, O Memikoglu, E Özgencil, S Oba, M Tulunay,
N Ünal, M Oral
Ankara University Medical Faculty, Ankara, Turkey
Critical Care 2007, 11(Suppl 2):P114 (doi: 10.1186/cc5274) Results CMV reactivation was observed in 38 out of 99 patients. Both groups (CMV+/CMV– patients) were quite similar in regard
to gender and age at study enrollment. Interestingly, the median
SAPS II was higher in CMV– patients (47 vs 42; P < 0.013). Accordingly, a lower mortality rate was anticipated for CMV+
patients
compared
with
the
CMV–
group. Contrary
to
expectations, mortality did not differ between both groups (CMV+
36.8% vs CMV– 42.6%; P > 0.67). This may point to a relatively Introduction Toxoplasma gondii, a worldwide-distributed parasite,
could cause opportunistic infection with high mortality in immuno-
suppressive individuals. Its association with severe manifestations
of immunosuppression has been known for several decades, and
the occurrence of encephalitis and disseminated disease has since
been observed in different clinical conditions such as lympho- Introduction Toxoplasma gondii, a worldwide-distributed parasite,
could cause opportunistic infection with high mortality in immuno-
suppressive individuals. Its association with severe manifestations
of immunosuppression has been known for several decades, and
the occurrence of encephalitis and disseminated disease has since
been observed in different clinical conditions such as lympho- S45 S Livigni1, D Silengo1, M Maio1, V Perlo1, M Pozzato1,
P Selvaggi1, L Sereni1,2, M Wratten2
1San Giovanni Bosco, Turin, Italy; 2Bellco, Mirandola, Italy
Critical Care 2007, 11(Suppl 2):P118 (doi: 10.1186/cc5278) P116 Introduction Septic shock remains a major cause of multiple organ
failure with a high mortality rate. To remove an endotoxin in patient
plasma, direct hemoperfusion (DHP) using a polymyxin B-
immobilized fiber column (PMX; Toray Industries Inc., Tokyo Japan)
was developed in Japan in 1994 and has since been used for the
treatment of septic shock. The precise role of PMX is not clear. P118 Discussion
PAI-1 is elevated by endotoxin, thrombin and
cytokines, and is an indicator of vascular endothelial cell activation. In septic dissminated intravascular coagulation from Gram-nega-
tive bacilli, a massive amount of PAI-1 is produced on vascular
endothelial cells along with elevation of cytokine production and
coagulation activity. In addition, PAI-1, one of the fibrinolysis
inhibitory factors, plays an important role in regulating fibrinolysis
by inhibiting tissue plasminogen activator, which converts
plasminogen to active plasmin on fibrin, to block unnecessary
fibrinolysis. Characterization of the coupled plasma
filtration–adsorption resin cartridge adsorptive capacity for
cytokines and inflammatory mediators: adsorption profiles
from septic patient plasma and in vitro endotoxin-
stimulated whole blood S Livigni1, D Silengo1, M Maio1, V Perlo1, M Pozzato1,
P Selvaggi1, L Sereni1,2, M Wratten2
1San Giovanni Bosco, Turin, Italy; 2Bellco, Mirandola, Italy
Critical Care 2007, 11(Suppl 2):P118 (doi: 10.1186/cc5278) Conclusion The determination of PAI-1 may be a useful clinical
parameter for predicting PMX-DHP efficacy. Introduction Coupled plasma filtration–adsorption (CPFA) is an
extracorporeal therapy that uses plasma filtration associated with
an adsorbent cartridge and hemofiltration in postdilution to remove
cytokines and inflammatory mediators associated with septic shock
and severe sepsis. We evaluated the adsorptive capacity of the
resin cartridge to remove various inflammatory mediators and cyto-
kines in vitro and ex vivo. Introduction Coupled plasma filtration–adsorption (CPFA) is an
extracorporeal therapy that uses plasma filtration associated with
an adsorbent cartridge and hemofiltration in postdilution to remove
cytokines and inflammatory mediators associated with septic shock
and severe sepsis. We evaluated the adsorptive capacity of the
resin cartridge to remove various inflammatory mediators and cyto-
kines in vitro and ex vivo. S46 Available online http://ccforum.com/supplements/11/S2 Figure 1 (abstract P119)
Figure 2 (abstract P119) Figure 1 (abstract P119)
Figure 2 (abstract P119) Figure 1 (abstract P119) Methods
In
vitro
experiments included static and dynamic
evaluations of resin binding. Whole human blood was stimulated
with endotoxin for 4 hours at 37°C; or with the addition of added
cytokines or toxins for evaluation. For static conditions, 4 ml plasma
with 1 ml resin were incubated for up to 10 hours. Aliquots were
withdrawn between 0 and 10 hours and cytokine inflammatory
mediator and toxin adsorption were determined with standard
ELISAs, multianalyte protein arrays, HPLC and diode array
adsorption spectroscopy. Dynamic conditions involved defining the
optimal linear velocity and evaluating the adsorption capacity under
flow conditions. P118 These experiments used a closed circuit
consisting of a plasma filter and resin cartridge. Samples were
taken from a blood port and immediately before and after the
plasma cartridge. In addition, serum, pre-cartridge and post-
cartridge plasma samples were also taken from septic patients
undergoing CPFA. Results Endotoxin-stimulated blood or samples from septic patients
had high levels of cytokines and inflammatory mediators. The resin
used in the CPFA adsorptive cartridge showed higher than 80%
adsorption under both static and dynamic conditions for: IL-1α, IL-6,
IL-8, MIP-1α and MIP-1β, TNFα, MCP, myoglobin. IL-6 appeared to
be particularly adsorbed by the cartridge. Severe septic patients
had great variability and often very high levels of IL-6 ranging from
normal levels (50 pg/ml) up to 12,300 pg/ml. The mean of 10
patients treated before CPFA was 1,775 ± 3757 pg/ml, while post-
session IL-6 was 995 ± 2178 pg/ml. The plasma levels before the
cartridge ranged from 12 pg/ml to 1,750 pg/ml, while post-
cartridge levels were below the level of detection. Figure 2 (abstract P119) Conclusions The resin in CPFA has a high adsorption capacity for
several cytokines and mediators involved in severe sepsis and
septic shock. Studies are currently ongoing to correlate cytokine
reduction with clinically relevant improvements in these patients. P119 Removing endocannabinoids and reducing oxidative stress
with polymyxin-B-immobilized fibers in patients with septic
shock Y Kase, T Obata
Jikei University Hospital, Tokyo, Japan
Critical Care 2007, 11(Suppl 2):P119 (doi: 10.1186/cc5279) Y Kase, T Obata
Jikei University Hospital, Tokyo, Japan
Critical Care 2007, 11(Suppl 2):P119 (doi: 10.1186/cc5279) Introduction Arachidonylethanolamide (AEA) and 2-arachidonyl-
glycerol (2-AG) are endocannabinoids involved in septic shock,
and 8-epi prostaglandin F2α (F2-isoprostane) is a biomarker of
oxidative stress. Because the antibiotic polymyxin-B binds to
endotoxins and endocannabinoids, direct hemoperfusion therapy
with polymyxin-B-immobilized fibers (PMX-DHP) decreases serum
levels of endocannabinoids. To investigate the features of sepsis
and to determine the proper usage of PMX-DHP, we compared
perioperative changes in levels of endocannabinoids and F2-
isoprostane in patients with septic shock Conclusions Patients with septic shock are under considerable
oxidative stress, and 2-AG plays an important role in the
cardiovascular status of these patients. The removal of 2-AG by
PMX-DHP benefits patients with septic shock by stabilizing
cardiovascular status and decreasing long-term oxidative stress. Conclusions Patients with septic shock are under considerable
oxidative stress, and 2-AG plays an important role in the
cardiovascular status of these patients. The removal of 2-AG by
PMX-DHP benefits patients with septic shock by stabilizing
cardiovascular status and decreasing long-term oxidative stress. P121 P121
The effectiveness of octreotide at different doses for
sulfonylurea-induced hypoglycemia following overdose
M Gul, B Cander, S Girisgin, M Ayan, S Kocak, A Unlu
Selcuk University Meram Medical School, Konya, Turkey
Critical Care 2007, 11(Suppl 2):P121 (doi: 10.1186/cc5281) The effectiveness of octreotide at different doses for
sulfonylurea-induced hypoglycemia following overdose M Gul, B Cander, S Girisgin, M Ayan, S Kocak, A Unlu
Selcuk University Meram Medical School, Konya, Turkey
Critical Care 2007, 11(Suppl 2):P121 (doi: 10.1186/cc5281) Results Forty patients admitted to the ICU were enrolled and
followed up to discharge. The median age was 35.5 years (mini-
mum 18, maximum 66). The median APACHE II score was 10.5
(minimum 2, maximum 28) and the median duration was 6 days
(minimum 1, maximum 43). D0, D3, D7 and D/C glucose concen-
trations did not differ (Kruskal–Wallis ANOVA, P = 0.98). TNFα
peaked at D3 (4.9 pg/ml) and then started decreasing. Admini-
stered insulin (InsAd) accompanied the TNFα peak at D3 (32U)
and then decreased. Adipo peaked at D7 (10,774 pg/ml) after the
TNFα peak, which coincided with the TNFα decrease at D7 to
4.76 pg/ml. Endogenous insulin indicated by CPep peaked with
Adipo at D7 (2.8 µg/l). TG levels increased in parallel with
increasing TNFα from 0.7 mmol/l at D0 to 1.1 mmol/l at D3 and
then declined. TC was lowest at D0 and increased up to D/C but
remained relatively low. Table 1 shows several variables and their
change over time from admission to discharge. Table 2 shows the
correlations between these variables. Survivors had a lower
median TNF than nonsurvivors (Mann–Whitney U test, P = 0.066). Conclusion TNF contributes to increased insulin needs. TNF is
known to cause insulin resistance. We have shown that TNF
correlates inversely with Adipo. As Adipo increases, insulin needs
are decreased (inverse correlation with InsAd). Also, TNF
contributes to increase TG indicating increased free fatty acids
(FFA) by lipolysis, which impairs glucose clearance. Adipo, an
insulin sensitizing protein, is known to negatively regulate TNF
levels as was indicated by our study. Adipo contributed to a
decrease in TG indicating lower FFA and better glucose clearance. IL-6 at D/C also contributed to a higher glucose concentration at
D/C. Increasing age contributed to lower Adipo levels at D/C,
indicating lower insulin sensitivity. Cytokines associated with insulin resistance in critically ill
patients Cytokines associated with insulin resistance in critically ill
patients Methods Twenty-four patients with septic shock induced by
peritonitis underwent laparotomy for drainage. Endocannabinoid
absorption with PMX-DHP was examined in two groups of
patients: patients in whom systolic arterial BP had increased more
than 20 mmHg (BP elevation group; n = 12) and patients in whom
BP did not increase or had increased no more than 20 mmHg (BP
constant group; n = 12). S Omar, U Wilgen, N Crowther
University of Witwatersrand, Gauteng, South Africa
Critical Care 2007, 11(Suppl 2):P120 (doi: 10.1186/cc5280) Introduction
We
examined
the
relationship
between
proinflammatory cytokines, adipocyte-derived adiponectin and
hyperglycemia. Patients requiring long periods in the ICU have a
relatively high mortality. Tight glucose control with insulin infusions
has been shown to improve survival and prevent complications. Methods A prospective, observational study at an academic ICU. A sequential sample was taken over a 2-month period. Ethics
approval was obtained from the University Ethics Committee. Introduction
We
examined
the
relationship
between
proinflammatory cytokines, adipocyte-derived adiponectin and
hyperglycemia. Patients requiring long periods in the ICU have a
relatively high mortality. Tight glucose control with insulin infusions
has been shown to improve survival and prevent complications. Introduction
We
examined
the
relationship
between
proinflammatory cytokines, adipocyte-derived adiponectin and
hyperglycemia. Patients requiring long periods in the ICU have a
relatively high mortality. Tight glucose control with insulin infusions
has been shown to improve survival and prevent complications. Methods A prospective, observational study at an academic ICU. A sequential sample was taken over a 2-month period. Ethics
approval was obtained from the University Ethics Committee. Results Levels of AEA did not change after PMX-DHP in the either
the BP constant group or the BP elevation group, whereas levels of
2-AG decreased significantly after PMX-DHP in the BP elevation
group but not in the BP constant group (Figure 1). F2-isoprostane
gradually increased after PMX-DHP. On the other hand, levels of F2-
isoprostane remained constant in the BP elevation group (Figure 2). Methods A prospective, observational study at an academic ICU. A sequential sample was taken over a 2-month period. Ethics
approval was obtained from the University Ethics Committee. S47 ritical Care March 2007 Vol 11 Suppl 2
27th International Symposium on Intensive Care and Emergency Medicin Baseline bloods for TNFα, IL-6, adiponectin (Adipo), total
cholesterol (TC), triglycerides (TG), insulin, C-peptide (CPep) and
cortisol (Cort) were collected on admission (D0). P121 A higher BMI contributed to a Objective The aim of the study was to investigate the effectiveness
of octreotide at different doses in reducing the hypoglycemic
attacks and the need for dextrose in treatment of refractory and
recurrence hypoglycemia related to the toxicity of sulfonylurea. Methods In the study, 40 New Zealand type of rabbits were used
weighing between 2,500 and 3,000 g. The rabbits were randomly
divided into four groups consisting of 10 animals. All the animals
were given gliclazide 100 mg orally. For the treatment of
hypoglycemic attacks in Group I, only 15 cm3 50% dextrose
(7.5 g) intravenously (i.v.) was used; in Group II, Group III and
Group IV octreotide 25 µg, 50 µg and 100 µg single doses were
used subcutaneously, respectively. Octreotide was given in Groups
II and III and Group IV at the eighth hour (when hypoglycemic
attacks onset). Groups II, III and IV were given an additional 15 cm3
50% dextrose (7.5 g) i.v. infusion for each hypoglycemic attack
developed. Following the toxic dose, animals were given the amount
of dextrose used before and after octreotide administration and the
number of hypoglycemic attacks were recorded. Results There was a significant difference between Groups I, II,
and IV in the number of hypoglycemic attacks and the number of
dextrose requirement between 9 and 24 hours (P = 0.001). Groups receiving octreotide showed less hypoglycemic attacks
and dextrose requirements than controls. Conclusion Our experience suggests that octreotide may be used
to reduce the number of refractory and recurrence hypoglycemic
attacks developing due to overdose of sulfonylurea; large
prospective studies would be needed to validate these findings. Cytokines associated with insulin resistance in critically ill
patients These were
repeated on day 3 (D3), day 7 (D7) and discharge (D/C). Routine
bloods ordered were also used. Data on the ICU charts were also
used. No changes to ICU protocols were required. Of note, insulin
infusions were started for blood glucose concentrations greater
than 6 mmol/l. Exclusion criteria included all patients with diabetes
mellitus, chronic renal failure and liver failure or cirrhosis. higher glucose level at D0 and increased insulin needs at D0. Finally, a higher TNF level appears to be related to increased
mortality Influence of diabetes and HbA1c on the course and
outcome of sepsis in the intensive care unit Methods PBMC were isolated from peripheral blood of 10 healthy
volunteers via Ficoll gradient. Cells were incubated for 3 hours at
37°C with/without low/high concentrations of glucose, mannitol,
urea, insulin and stimulated with 0.5 ng/ml LPS. After 24 hours,
concentrations of IL-6 and IL-1β were measured with an ELISA
method. I Gornik1, O Gornik2, V Gasparovic1
1Clinical Hospital Centre, Zagreb, Croatia; 2University of Zagreb,
Croatia
Critical Care 2007, 11(Suppl 2):P124 (doi: 10.1186/cc5284) Introduction It is an accepted opinion that patients with diabetes
mellitus (DM) are at higher risk when treated for infections,
although published data are lacking. Our recent research on non-
ICU septic patients showed that admission HbA1c is in correlation
with outcome. The aim was to evaluate the impact of DM on the
course and outcome of patients with sepsis in ICU, as well as to
evaluate the value of HbA1c as an outcome predictor in the ICU Results Increasing concentrations of glucose, mannitol and urea
resulted in a significant increase of IL-6 and IL-1β cytokine
production. Insulin had no effect (Table 1). Table 1 (abstract P122)
No
Low
High
Substance
supplementation
concentration
concentration
Glucose
1,726
–
9,643
Insulin
609
555
636
Urea
2,056
3,421
3,835
Mannitol
367
–
3,269 evaluate the value of HbA1c as an outcome predictor in the ICU. Methods In a prospective, 3-year observational study, patients with
sepsis, severe sepsis and septic shock admitted to a medical ICU
were included. Patients with DM were compared with nondiabetics
in terms of course and outcome. HbA1c was measured for all
patients with DM. Hospital mortality and length of stay (LOS) in the
ICU and in hospital were the outcome measures. The incidence of
organ failure, ARDS, hospital-acquired pneumonia (HAP) and
ventilator-associated pneumonia (VAP) were used as indicators of
the disease course. Nonparametric tests, multiple regression and
logistic regression were used in statistical analyses. Conclusion High concentrations of glucose, mannitol and urea
lead to a significant increase in IL-6 and IL-1β cytokine production
by PBMC in vitro. The most profound effect was seen with
hyperglycemia. Besides hyperglycemia, also uremia and high
osmolarity seem to augment inflammation. Insulin could not reverse
the increase in inflammation. These findings may be relevant in
explaining the beneficial effects of normoglycemia on the
inflammatory response in critically ill patients. Results Two hundred and twenty-nine patients with sepsis at
admission (19.6% of all 1,169 ICU patients), 59 with DM, were
included. Influence of diabetes and HbA1c on the course and
outcome of sepsis in the intensive care unit Mortality in the ICU was 34.7%; the median ICU LOS
was 8 (95% CI 7–9.3) days. Patient with DM, compared with
nondiabetics, had higher mortality (38.9% vs 34.1%, P = 0.60)
and longer ICU LOS (median 6 vs 10 days, P < 0.001), and higher
incidence of renal failure, HAP, VAP. Surviving patients had
significantly lower HbA1c levels (6.6 vs 9.6, P = 0.001). In a
logistic regression, DM was found to be related to lethal outcome,
together with APACHE II and SOFA scores. In multiple regression,
DM related to LOS together with SOFA score and age. HbA1c
was found to be independently related to ICU outcome together
with SOFA score. P122 inflammatory mediator production can be modified by insulin
therapy. Rats subjected to bacterial lipopolysaccharide (LPS) with
or without insulin pretreatment were studied. LPS-induced PARP
activation in circulating leukocytes was measured by flow
cytometry, and production of TNFα was measured by ELISA. LPS
induced a significant hyperglycemic response, activated PARP in
circulating leukocytes and induced the production of TNFα. Insulin
treatment prevented the LPS-induced hyperglycemic response,
blocked the activation of PARP and blunted the LPS-induced
TNFα response. As hyperglycemia is known to induce the cellular
formation of reactive species, we propose that PARP activation in
endotoxin shock occurs as a result of hyperglycemia-induced
reactive oxidant and free radical generation. The current findings
may have significant implications in the context of the emerging
concept of tight glycemic control for critically ill patients. Hyperglycemia and changes in osmolarity lead to an
increase in IL-6 and IL-1β cytokine production of human
peripheral blood mononuclear cells in vitro Hyperglycemia and changes in osmolarity lead to an
increase in IL-6 and IL-1β cytokine production of human
peripheral blood mononuclear cells in vitro Hyperglycemia and changes in osmolarity lead to an
increase in IL-6 and IL-1β cytokine production of human
peripheral blood mononuclear cells in vitro N Otto, R Schindler, U Frei, M Oppert
Charité-Universitaetsmedizin Berlin, Germany
Critical Care 2007, 11(Suppl 2):P122 (doi: 10.1186/cc5282) Introduction Acute hyperglycemia and insulin resistance are
characteristics of metabolic and endocrine imbalances of critically
ill patients and are subject to a substantial inflammatory response
that is partly mediated by cytokines produced by peripheral blood
mononuclear cells (PBMC). Treatment with intensive insulin
therapy to keep patients normoglycemic has been shown to
reduce inflammatory responses. It is unclear whether hyper-
glycemia, insulin or osmolarity changes exert direct effects on
proinflammatory cytokines. We investigated the direct effects of
these substances on cytokine production of PBMC in vitro. Table 1 (abstract P120) Changes in glucose, insulin, cytokines and lipids in the ICU over time
Day
Glucose
InsAd
TNF
Adipo
Cpep
TG
TC
IL-6
D0
6.13
8
3.49
4,413.82
1.8
0.7
2.15
337.01
D3
6.25
32
4.9
6,925.4
2.2
1.1
2.2
127.01
D7
6.79
20
4.76
10,774.25
2.8
1
2.5
32.17
D/C
5.87
0
4.11
8,288.6
2.5
1.3
2.8
46.95
Table 2 (abstract P120)
Relevant Spearman correlations between the parameters
A
B
R
P
A
B
R
P
TNF
Adipo
–0.59
0.000
TNF
Mortality
0.25
0.060
Adipo
InsAd
–0.46
0.005
∆Adipo
LOS
0.45
0.004
TNF
TG
0.74
0.000
IL-6 D/C
Gluc D/C
0.34
0.042
Adipo
TG
–0.41
0.001
BMI
Gluc D0
0.39
0.012
TNF
Cortisol
–0.73
0.000
BMI
InsAd D0
0.31
0.053
Adipo
Cortisol
0.51
0.000
Adipo D/C
Age
–0.35
0.030
Age
InsAd D/C
0.35
0.032 Changes in glucose, insulin, cytokines and lipids in the ICU over time elevant Spearman correlations between the parameters S48 Available online http://ccforum.com/supplements/11/S2 Available online http://ccforum.com/supplements/11/S2 Available online http://ccforum.com/supplements/11/S2 Lipid metabolism and organ dysfunction in septic patients
during intensive glycemic control Lipid metabolism and organ dysfunction in septic patients
during intensive glycemic control S Cappi, F Soriano, A Nogueira, C Valeri, A Duarte, P Biselli,
W Hoshino, M Lins, J Barradas, D Noritomi, P Lotufo
Hospital Universitario da USP, Sao Paulo, Brazil
Critical Care 2007, 11(Suppl 2):P125 (doi: 10.1186/cc5285) Introduction Intensive glycemic control has been widely discussed
in critical care patients. It remains unclear whether intensive insulin
therapy also improves the prognosis of patients in a medical ICU,
who often are more severely ill than are patients in a surgical ICU
and have a higher risk of death. Recently, medical patients have
been investigated, as a special group. We decided to study
possible differences in lipid profile in septic shock patients during
the first 72 hours and correlate it with different organ dysfunctions. Methods A prospective, randomized, controlled study in a 12-bed
medico-surgical ICU in a university hospital. Inclusion criteria: all
consecutive patients admitted to the ICU with severe sepsis and or
septic shock with onset in a maximum of 24 hours. Exclusion
criteria: HIV patients, pregnancy, diagnosis of leptospirosis, age
under 18, cancer patients. On admission, patients were randomly
assigned to strict normalization of blood glucose levels (80–110 mg/dl)
or to a conventional glycemic control (180–220 mg/dl) with the
use of sealed envelopes. We collected laboratory tests at 0, 24,
48 and 72 hours after initiation. For statistical analysis we per-
formed the Student t test. g
y
Methods A prospective, randomized, controlled study in a 12-bed
medico-surgical ICU in a university hospital. Inclusion criteria: all
consecutive patients admitted to the ICU with severe sepsis and or
septic shock with onset in a maximum of 24 hours. Exclusion
criteria: HIV patients, pregnancy, diagnosis of leptospirosis, age
under 18, cancer patients. On admission, patients were randomly
assigned to strict normalization of blood glucose levels (80–110 mg/dl)
or to a conventional glycemic control (180–220 mg/dl) with the
use of sealed envelopes. We collected laboratory tests at 0, 24,
48 and 72 hours after initiation. For statistical analysis we per-
formed the Student t test. and HDL (not significant) were different between groups. The
mortality rate was the same but LDL and HDL had negative
correlation with organ function among nonsurvivors. Insulin therapy inhibits poly(ADP-ribose)polymerase
activation in endotoxin shock C Szabo1, E Horvath1, R Benko2, D Gero2
1University of Medicine and Dentistry of New Jersey, Newark, NJ,
USA; 2Semmelweis University, Budapest, Hungary
Critical Care 2007, 11(Suppl 2):P123 (doi: 10.1186/cc5283) Conclusion The ratio of patients with DM among ICU patients with
sepsis exceeds greatly the incidence of DM in the population. This
emphasizes the risk they have. DM was associated with worse
outcome, longer ICU and hospital LOS, and with higher incidence
of complications. HbA1c was confirmed as an outcome predictor
for ICU patients. The nuclear enzyme poly(ADP-ribose) polymerase (PARP) is
activated in various forms of circulatory shock. By triggering a
cellular energetic dysfunction, and by promoting proinflammatory
gene expression, PARP activation significantly contributes to the
pathogenesis of shock. The activation of PARP is usually triggered
by DNA strand breakage, which is typically the result of the
overproduction of reactive oxidant species. In the present study we
tested whether endotoxin-induced PARP activation and pro- S49 Critical Care March 2007 Vol 11 Suppl 2
27th International Symposium on Intensive Care and Emergency Medicine Figure 2 (abstract P125) Figure 2 (abstract P125) P125
Lipid metabolism and organ dysfunction in septic patients
during intensive glycemic control
S Cappi, F Soriano, A Nogueira, C Valeri, A Duarte, P Biselli,
W Hoshino, M Lins, J Barradas, D Noritomi, P Lotufo
Hospital Universitario da USP, Sao Paulo, Brazil
Critical Care 2007, 11(Suppl 2):P125 (doi: 10.1186/cc5285) Lipid metabolism and organ dysfunction in septic patients
during intensive glycemic control Conclusions Targeting blood glucose levels to below 110 mg/dl
with insulin therapy prevented morbidity, probably due to a better
control of lipid metabolism, expressed as a more rapid serum LDL
normalization and avoiding a greater decrease in serum HDL levels
in the first 72 hours of septic shock. Results We studied 58 patients with similar demographic data
between the two groups. The increases in serum LDL (P < 0.05) Figure 1 (abstract P125) Figure 1 (abstract P125) P127 Variable adsorption of insulin at catheter materials used in
intensive care units: polyethylene vs polyurethane –
possible cause for hypoglycemia during intensive insulin p
yp g y
g
treatment? Methods A retrospective observational cohort study was conduc-
ted including 130 adult patients with a microbiologically
documented BSI admitted over a 2-year period (2003–2004) to
the ICU. Blood glucose levels were evaluated from 1 day prior to
onset of BSI (d–1) until 5 days after onset of BSI (d+5). The
contribution of hyperglycemia, divided into three subgroups
(≥150 mg/dl, ≥175 mg/dl, and ≥200 mg/dl, respectively), to in-
hospital mortality was estimated by logistic regression. S Ley, J Ammann, C Herder, M Hartmann, D Kindgen-Milles
University Hospital, Duesseldorf, Germany
Critical Care 2007, 11(Suppl 2):P127 (doi: 10.1186/cc5287) Introduction Intensive insulin therapy reduces morbidity and
mortality in postoperative critical care; however, this treatment also
increases the risk of hypoglycemia. A possible cause for unstable
blood glucose (BG) levels could be a variable adsorption of insulin
at plastic material of infusion tubings. We evaluated in vitro and in
vivo the adsorption of insulin at standard tubing materials
(polyethylene (PE) and polyurethane (PU)) and the effects of this
adsorption process on blood glucose levels. Results The mean age of the study population was 54.7 ± 19.0
years. Inhospital mortality was 36.2%. Hyperglycemia (≥175 mg/dl
and ≥200 mg/dl) was observed more often among the non-
survivors. Over the seven study days, no differences were found in
daily morning blood glucose levels between survivors (n = 83) and
nonsurvivors (n = 47) (all P > 0.05). Although in the nonsurvivors
the evolution of glycemia tended to be higher, this trend was not
statistically significant compared with the survivors. Multivariate
logistic regression revealed that age (P = 0.022), APACHE II score
(P = 0.003), antibiotic resistance (P = 0.001), and hyperglycemia
(≥200 mg/dl) upon onset of BSI (P = 0.001) were independently
associated with inhospital mortality, whereas appropriate anti-
microbial therapy ≤24 hours (P = 0.016) and previous history of
diabetes (P = 0.022) were associated with better outcome. Methods (1) In vitro, a standard perfusor syringe (Perfusor®;
BBraun, Germany) was filled with 50 IE normal insulin (Actrapid®;
NovoNordisk, Germany) dissolved in 50 ml saline 0.9%. P128 Hyperglycemia upon onset of nosocomial bloodstream
infection adversely affects outcome in a mixed intensive
care unit population Hyperglycemia upon onset of nosocomial bloodstream
infection adversely affects outcome in a mixed intensive
care unit population These findings indicate that the coagulation system did not play a
key role in mediating the survival benefit of intensive insulin therapy. References D Vandijck, S Oeyen, F Buyle, B Claus, S Blot, J Decruyenaere
Ghent University Hospital, Ghent, Belgium
Critical Care 2007, 11(Suppl 2):P128 (doi: 10.1186/cc5288) 1. Van den Berghe G, et al.: N Engl J Med 2001, 345:1359-
1367. 2. Van den Berghe G, et al.: N Engl J Med 2006, 354:449-461. Introduction Hyperglycemia in critically ill patients is frequently
related to a hypermetabolic stress-response and has been
associated with increased morbidity and mortality. The aim of this
study was to assess the relationship between blood glucose levels
and clinical outcome in a mixed cohort of critically ill patients with a
nosocomial bloodstream infection (BSI). P127 The
syringe was connected to PE or PU tubings (BBraun) and, at an
infusion rate of 1 ml/hour, the insulin concentration in the syringe
and at the end of the tubings was measured at hourly intervals for
5 hours and again after 24 hours by the Bradford protein assay. Insulin concentrations were compared using the Student t test. (2) In a prospective, double-blinded, cross-over study, approved by
the ethics committee, 10 patients on the surgical ICU received
insulin via PE or PU tubing each for 24 hours in random sequence. All blood BG values, total infused insulin solution volume, and
critical care scores were documented and statistically analysed by
the Wilcoxon test. Conclusion Trends of blood glucose levels were higher among
nonsurvivors. Hyperglycemia (≥200 mg/dl) upon onset of
nosocomial BSI adversely affects outcome in a heterogeneous ICU
population. Effect of intensive insulin therapy on coagulation and
fibrinolysis of respiratory critically ill patients L Langouche1, W Meersseman1, S Van der Perre1, I Milants1,
P Wouters1, G Hermans1, J Gjedsted2, T Hansen2, J Arnout1,
A Wilmer1, M Schetz1, G Van den Berghe1
1KU Leuven, Belgium; 2Aarhus University Hospital, Aarhus,
Denmark
Critical Care 2007, 11(Suppl 2):P126 (doi: 10.1186/cc5286) Most intensive care deaths beyond the first few days of critical
illness are attributable to nonresolving multiple organ failure (MOF),
either due to or coinciding with sepsis. One of the mechanisms
that is thought to contribute to the pathogenesis of MOF is
microvascular thrombosis. Recently, we reported improved survival
and prevention of MOF of critically ill patients with the use of
intensive insulin therapy to maintain normoglycemia for at least
several days [1,2]. We hypothesize that intensive insulin therapy
also prevents severe coagulation abnormalities, thereby contribu-
ting to less organ failure and better survival. We studied a subgroup of long-stay critically ill patients with a
respiratory disease upon ICU admission, who had been enrolled in
a randomized controlled trial evaluating the impact of intensive
insulin therapy in medical ICU patients [2]. Plasma samples were
analyzed for a panel of coagulation markers (prothrombin time,
activated partial thromboplastin time, fibrinogen and D-dimer
levels) that were used to assign points towards the International
Society of Thrombosis and Haemostasis overt disseminate
intravascular
coagulation
(DIC)
score. Circulating
plasma
thrombin–antithrombin complexes and plasminogen inhibitor type
1 levels were also determined. As markers of inflammation, we
measured circulating serum levels of several cytokines and CRP. S50 Available online http://ccforum.com/supplements/11/S2 Available online http://ccforum.com/supplements/11/S2 Mortality of intensive insulin-treated patients was lower than of
conventionally treated patients for all classes of upon-admission
DIC score, except for those patients with a DIC score of 6 or
higher. There was no effect of insulin therapy on any of the
fibrinolytic, coagulation or inflammatory parameters tested. The
accuracy of the DIC score to predict mortality in this patient
sample was only moderate and comparable with that of CRP and
the SOFA score. Also, circulating plasminogen inhibitor type 1 or
thrombin–antithrombin complexes levels did not correlate well with
mortality or DIC score. insulin application to the patient is possible if different tubing
materials are used. Furthermore, variability of adsorption, a
competitive adsorption with other drugs if insulin is not infused via
a single line as well as changes of effective insulin application
following routine change of tubings, may be one cause of
unexpected hypoglycemia that can be deleterious to the patient. R Schaller1, F Feichtner1, A Fercher1, L Schaupp1,
M Bodenlenz1, H Köhler1, J Plank2, A Wutte2, M Ellmerer3,
R Hainisch4, T Pieber2
1Joanneum Research, Graz, Austria; 2Medical University Graz,
Austria; 3Medical University Hospital (MUG), Graz, Austria; 4FH
OÖ Forschungs & Entwicklungs GmbH, Linz, Austria
Critical Care 2007, 11(Suppl 2):P129 (doi: 10.1186/cc5289) P129 Hence the
usage of an automated discontinuous venous blood sampling
system might be an alternative to improve the adjustment of the
insulin therapy. The primary aim of the study was to investigate
whether the glucose concentration in manually withdrawn blood
samples correlates with automated withdrawn blood samples. Methods In a 12-hour trial, six volunteers were investigated (male/
female 5/1; age 28.2 ± 2.2 years, BMI 22.5 ± 1.3, nondiabetics). A 75 g OGTT was performed to enable a better dynamic range of
the glucose values. Two venous cannulae were inserted into the
dorsal hands for reference measurement and for connection to the
automated blood sampling system. To reduce the volunteer’s
health risk, pressure, air bubble sensor and flushing fluid monitor-
ing were integrated into the system. Blood samples were obtained
frequently in 15/30-minute intervals. Roche Microsamplers and the
OMNI S6 glucose analyser were used for determination of the
blood readings. Discussion Computerised decision-support and more intensive
monitoring did not improve BG control or reduce the incidence of
hypoglycaemia. Glargine insulin: an alternative to regular insulin for
glycemic control in critically ill patients Glargine insulin: an alternative to regular insulin for
glycemic control in critically ill patients M Bhattacharyya, SK Todi, A Majumdar
AMRI Hospitals, Kolkata, India
Critical Care 2007, 11(Suppl 2):P131 (doi: 10.1186/cc5291) Results The automated blood sampling system performed its
operation in all volunteers over the whole trial period. The median
Pearson coefficient of correlation between manual and automated
withdrawn blood was 0.983 (0.862–0.995). Furthermore, the
results (173 data pairs) were analysed via the recently published
‘Insulin Titration Error Grid Analysis’ and 99.4% were suggesting
an acceptable treatment. The results of the traditional ‘Error Grid
Analysis’ showed that 96% of the data were in zone A and 4% in
zone B. Introduction The objective of this study was to determine the
efficacy and safety of subcutaneous (s.c.) once-daily (OD) glargine
insulin, a long-acting insulin, in comparison with a s.c. regular
insulin, based on a protocolized sliding scale regimen for achieving
glycemic control in patients admitted to the ICU. Methods One hundred patients admitted to the ICU with an
admission capillary blood glucose (CBG) >150 mg/dl (8.3 mmol/l)
were involved in this prospective, randomized study. Patients with
age <18 years, pregnancy, shock, requiring continuous intra-
venous insulin infusion, renal failure were excluded. Patients were
randomly assigned to receive either s.c. glargine insulin 10 U
(CBG ≤9.9 mmol/l) or 18 U (CBG ≥10.1 mmol/l) s.c. OD (Group
G, n = 50), or s.c. regular insulin based on a 6-hourly sliding scale
(Group R, n = 50). CBGs were recorded at 6-hour intervals up to
96 hours or until ICU discharge, whichever was earlier. The target
CBG in both groups was <150 mg/dl (8.3 mmol/l). Patients in
group G received rescue doses of regular insulin, as required. Demographic characteristics, mean and median CBG, and
episodes of hypoglycemia were studied. Conclusion The automated discontinuous blood withdrawing
system provides reproducible blood samples from peripheral
venous blood. In combination with a glucose sensor and an
algorithm it might be used in future as a closed loop system for
insulin and glucose infusion at the ICU. P129 Results (1) The insulin concentration in all syringes was always
>97% of the estimated value. The initial concentrations of insulin at
the end of PE and PU tubings were lower than expected (23 ± 4%
of anticipated concentration in the first 6 min). In PE, the
concentration rose to 37 ± 2% and in PU to 78 ± 4% after
24 hours (P < 0.0001). (2) In vivo the mean BG values did not
differ
between
PE
and
PU
(PE
141 ± 17 mg/dl;
PU
132 ± 23 mg/dl (not significant)). Severity of illness was not
different between the groups: TISS 37 ± 5 (PE) vs 39 ± 5 (PU),
SAPS 43 ± 13 (PE) vs 41 ± 15 (PU) on both days; neither were
catecholamine doses and 24-hour fluid balance. However,
significantly more insulin solution was infused in PE (66 ± 18 ml/
24 hours) compared with PU (44 ± 15 ml/24 hours) (P = 0.0015). Conclusion Infusion of insulin using PE and PU tubings leads to a
relevant adsorption of the drug in both materials. Adsorption to PE
is significantly higher compared with PU. Thus, a large variation of System for automated discontinuous venous blood
withdrawal for glucose determination of patients in the
intensive care unit Introduction Intensive insulin therapy to establish normoglycaemia
reduces mortality and morbidity in critically ill patients. Frequent
glucose monitoring is restricted in critically ill patients due to the Introduction Intensive insulin therapy to establish normoglycaemia
reduces mortality and morbidity in critically ill patients. Frequent
glucose monitoring is restricted in critically ill patients due to the S51 Critical Care March 2007 Vol 11 Suppl 2
27th International Symposium on Intensive Care and Emergency Medicin 0.78 tests/hour) than the CIT group (3,609 over 8,617 hours, 0.42
tests/hour). The median (interquartile range (IQR)) proportion of
time spent in the target range 4.4–6.1 mmol/l was similar in the IIT
and CIT groups (23.21% (15.4–29.8) vs 17.9% (9.8–29.3),
respectively; P = 0.17). Similarly, time spent with a BG between
6.2 and 7.99 mmol/l was no different for the two groups (48.5%
(IQR 36.9–59.3) for IIT and 43.9% (IQR 34.7–60.9), P = 0.72). In
the IIT and CIT groups, five and six patients experienced a BG
below 2.2 mmol/l, respectively. high workload that has to be performed by the staff. Investigation of insulin clearance in severely acutely ill
patients with glucose intolerance evaluated by means of
bedside-type artificial pancreas Investigation of insulin clearance in severely acutely ill
patients with glucose intolerance evaluated by means of
bedside-type artificial pancreas M Hoshino1, Y Haraguchi2, I Mizushima1
1Tokyo Police Hospital, Tokyo, Japan; 2National Hospital
Organization Disaster Medical Center, Tokyo, Japan
Critical Care 2007, 11(Suppl 2):P132 (doi: 10.1186/cc5292) Background and purpose Glucose intolerance in acutely ill
patients is one of the risk factors of their morbidity and mortality,
and glucose control with insulin therapy improves the outcome. We investigated relationships among insulin clearance (IC), which
is considered to be one of the factors related to effectiveness of
insulin therapy, and glucose tolerance, glucose intolerance, and
severity of the diseases, in order to clarify the significance of IC on
the severity of the diseases including glucose intolerance and on
the therapies. Background and purpose Glucose intolerance in acutely ill
patients is one of the risk factors of their morbidity and mortality,
and glucose control with insulin therapy improves the outcome. We investigated relationships among insulin clearance (IC), which
is considered to be one of the factors related to effectiveness of
insulin therapy, and glucose tolerance, glucose intolerance, and
severity of the diseases, in order to clarify the significance of IC on
the severity of the diseases including glucose intolerance and on
the therapies. Methods Prospective collection of all glucose measurements for
ICU patients receiving an insulin infusion protocol between 20 May
2006 and 6 August 2006 in 64 ICU beds at a teaching hospital. We report glucose values from all ICU patients, ≥8 hours after
infusion initiation. Materials and methods Twenty-three ICU patients with glucose
intolerance in whom strict blood glucose control was performed by
means of a bedside-type artificial pancreas (NIKKISO Corp.,
Japan) were investigated. The diabetics were excluded. The items
investigated were IC (ml/kg/min) measured by the glucose clamp
method, daily mean blood glucose level as a parameter of glucose
intolerance (BGm, mg/dl), proportion of septic patients (%), SOFA
score and mortality (%) as indicators of the severity of the
diseases, and blood concentration of free fatty acid (FFA) and
stress hormones (glucagon, growth hormone, cortisol, adrenalin,
noradrenalin) as factors that might affect glucose intolerance. Evaluation of the clinical effectiveness of a computerised
decision-supported intensive insulin therapy regimen R Shulman, N Shah, P Glynne, R Greene, SJ Finney
University College Hospital, London, UK
Critical Care 2007, 11(Suppl 2):P130 (doi: 10.1186/cc5290) Introduction It has been proposed that intensive insulin therapy
(IIT) aiming for a blood glucose (BG) of 4.4–6.1 mmol/l reduces
mortality in critically ill patients when compared with conventional
insulin therapy (CIT) targeting BG at 10.0–11.1 mmol/l. Difficulties
with IIT include inadvertent hypoglycaemia and low efficacy at
achieving the target BG. We proposed that computerised decision
support may mitigate these problems. Results Demographic profiles were comparable between the two
groups. There was no significant difference in mean CBG in both
groups (Group G 152.1 mg/dl (8.4 mmol/l), Group R 149.9 mg/dl
(8.3 mmol/l), P = 0.66). Median CBGs were comparable at 6-
hourly time points in both the groups except at 0 and 6 hours in the
glargine arm (CBG at 0 and 6 hours, Group G 10.0 mmol/l and Figure 1 (abstract P131) Objective To comprehensively describe BG and outcome from
decision-supported IIT. Median capillary blood glucose (CBG) at different time points. Methods A clinical information system at each bedspace guided
staff through the IIT algorithm. The time spent within glucose
ranges was calculated assuming a linear trend between
successive measurements. Results Patient characteristics are shown in Table 1. The IIT group
had more frequent BG evaluation (7,007 over 8,944 patient-hours, 2
Table 1 (abstract P130)
IIT (n = 50)
CIT (n = 50)
P value
LOS, median (IQR)
7 (3–21)
6 (3–11)
0.05
Survivors
34 (64.2%)
24 (48.0%)
0.07
APACHE II, mean
23.2
25.4
0.17
Medical
31 (62%)
35 (70%)
0.53
Surgical
19 (38%)
15 (30%)
0.53 Table 1 (abstract P130) Median capillary blood glucose (CBG) at different time points. S52 Available online http://ccforum.com/supplements/11/S2 9.9 mmol/l, Group R 9.4 mmol/l and 8.3 mmol/l, P = 0.04 and
0.02, respectively) (Figure 1). There were three episodes of
hypoglycemia in Group G and one in Group R, which were
corrected. 9.9 mmol/l, Group R 9.4 mmol/l and 8.3 mmol/l, P = 0.04 and
0.02, respectively) (Figure 1). There were three episodes of
hypoglycemia in Group G and one in Group R, which were
corrected. Diurnal and other variations in blood glucose in intensive
care unit patients receiving insulin infusions S Smith, K Oveson, W Strauss, A Ahmann, D Hagg
OHSU, Portland, OR, USA
Critical Care 2007, 11(Suppl 2):P133 (doi: 10.1186/cc5293) Conclusion OD s.c. glargine insulin is a safe and effective
alternative to regular insulin for glycemic control in critically ill
patients. P132 Introduction Treatment of hyperglycemia in ICU patients using an
insulin infusion protocol was shown by van den Berghe and
colleagues to reduce mortality and morbidity in ICU patients. Consequently, many healthcare bodies proposed guidelines for the
control of hyperglycemia in the ICU. However, the patchy evidence
underpinning these guidelines and a high rate of complications
lead to controversy about the optimal glucose target range. Studies showing insulin infusions are effective have reported
average glucose values at single time points. However, single time
points are difficult to interpret as they do not provide information
about the proportion of glucose measurements that need to be in
range for benefit. We hypothesized that blood glucose variance
was greater if all glucose measurements were considered and
asked whether there was a diurnal pattern that accounted for some
of the variance. Investigation of insulin clearance in severely acutely ill
patients with glucose intolerance evaluated by means of
bedside-type artificial pancreas The
method of investigation involved patients being classified into four
groups according to IC, and those groups were compared with
each other; low IC group (group L: IC < 9, n = 2), normal IC group
(group N: 9 < IC < 15, n = 13), high IC group (group H: 15 < IC,
n = 8), and severely high IC group (group S: 19 < IC, n = 5)
(group S was a subgroup of group H). Results We compared the 6:00 a.m. glucose value with those
collected at all other times in 149 consecutive patients. The
6:00 a.m. values were lower than the remaining values (mean ±
SD: 112 ± 30 mg/dl (n = 477) vs 119 ± 35 mg/dl (n = 10,364);
P < 0.0001) and as hypothesized had a smaller variance by F test
(P < 0.0001). Inspection of the time-averaged data (±SE) revealed
a diurnal variation in the blood glucose with peaks occurring at
11:00 a.m. and 10:00 p.m. (Figure 1). This diurnal pattern may
account for some of the observed variation in insulin requirements
and contribute to episodes of hypoglycemia in the critically ill. Conclusion Glucose variance is increased if all time values are
considered rather than a single time point and there is a diurnal
pattern to glucose in ICU patients receiving insulin. Consideration
of this diurnal variation when treating hyperglycemia in the ICU may
avoid hypoglycemia and so facilitate better glucose control with
insulin infusions. Results (1) FFA values were low or normal in all groups. (2) There
were no significant differences in stress hormones among group N,
group H, and group S. Those hormones in group L were
significantly higher than, or had a tendency to be higher than, those
in group N, group H, and group S. (3) The mean values of BGm in
the groups had a tendency to be higher in the order of group S
(179 ± 30), group H (172 ± 25), group N (162 ± 26), and group L
(153 ± 8). (4) The severities of the diseases (sepsis (%)/SOFA
score/mortality (%)) in the groups were significantly higher in the
order group L (100%/20.0 ± 1.4/100%), group S (100%/
9.6 ± 7.0/40%), group H (88%/7.0 ± 6.5/25%), and group N
(54%/5.8 ± 5.2/15%). Severe hypoglycaemia during intensive insulin therapy: a
rare event in critically ill patients Severe hypoglycaemia during intensive insulin therapy: a
rare event in critically ill patients M Kaukonen, M Rantala, V Pettilä, M Hynninen
Helsinki University Hospital, Helsinki, Finland
Critical Care 2007, 11(Suppl 2):P134 (doi: 10.1186/cc5294) Introduction Tight glycemic control reduces mortality in surgical
intensive care patients and in long-term medical intensive care
patients. The incidence of severe hypoglycaemia (glucose
≤2.2 mmol/l) in the intensive treatment group has been 3.1–5.1%. Recently, a large study on intensive insulin therapy was
prematurely discontinued due to safety issues. The incidence of
hypoglycaemia was 9.8% in intensive treatment group and the
mortality among patients experiencing hypoglycaemia was 18.6%. As the safety of intensive insulin therapy has been questioned, we
screened all patients during a 17-month period to see the
incidence of hypoglycaemia and its effects on the prognosis of the
patients. Results Forty patients, 22 (55%) males and 18 (45%) females,
who received nutritional support for 48 hours or more were
studied. The mean (SD) age was 59.4 (14.7) years. Enteral feeding
was given in 32 (80%) and parenteral feeding in 14 (35%)
patients, while six (15%) patients received both enteral and
parenteral feeding. The mean (SD) energy in 48 hours was 3,307.4
(527.0) kcal, mean (SD) insulin was 1.37 (1.23) IU, mean (SD)
blood glucose was 7.76 (0.9) mmol/dl and total insulin to achieve
glycaemic control was 65.51 (58.6) IU. The time taken (SD) to
achieve glycaemic control was 15.16 (12.65) hours. As expected,
there was a relationship between the total insulin dose and the
time to achieve three consecutive glycaemic controls (r = –0.43,
P = 0.023). Also, between the total insulin dose and mean blood
glucose r = 0.508, P = 0.001. There was no significant relation-
ship between the total insulin dose and indication for ICU
admission, and the total insulin dose and body mass index. Methods A retrospective study was performed in two ICUs, one
eight-bed general ICU and one 10-bed surgical ICU. All patients
treated between 7 February 2005 and 30 June 2006 were
included in the study. A nurse-driven intensive insulin protocol with
a target blood glucose level of 4–6.1 mmol/l had been introduced
in 2004. All blood glucose measurements performed during the
ICU treatment were analysed. The patients were divided into two
groups according to the lowest detected blood glucose value
(≤2.2 or ≥2.3 mmol/l). Figure 1 (abstract P133) Figure 1 (abstract P133) Interpretation and conclusions The increase of IC was related to
glucose intolerance. IC increased and glucose intolerance became
severe as the severity of the diseases progressed. In the most
severe state, or in a near-terminal state, however, IC decreased
and glucose intolerance improved, although stress hormones
increased significantly. Therapies focused on the improvement of
IC were considered important in acutely ill severe patients with
glucose intolerance as well as blood glucose control by insulin
therapy. S53 Critical Care March 2007 Vol 11 Suppl 2
27th International Symposium on Intensive Care and Emergency Medicin P136 Implementation of glycemic control – problems and
solutions Implementation of glycemic control – problems and
solutions E Halbeck, U Jaschinski, A Scherer, A Aulmann,
M Lichtwarck-Aschoff, H Forst
Klinikum Augsburg, Germany
Critical Care 2007, 11(Suppl 2):P136 (doi: 10.1186/cc5296) Introduction Glycaemic control is another example of protocol-
driven therapy in intensive care medicine to improve outcome in
critically ill patients. While the advantage of this approach seems to
be obvious, little is known about the problems of implementing such
a protocol. The intention of this study was to evaluate problems of
implementation and to develop strategies to overcome them. Conclusions
Severe hypoglycaemia during intensive insulin
therapy is rare in protocol-driven ICU treatment compared with
previous clinical trials. When present, hypoglycaemia may have an
impact on the outcome of the patients Setting A 16-bed surgical ICU of a university teaching hospital
with 50 critical care nurses, about 30% in part-time employment. Severe hypoglycaemia during intensive insulin therapy: a
rare event in critically ill patients Conclusion Findings from this study showed that the indication for
admission did not affect either the total dose of insulin required to
achieve glycaemic control or the time it takes to achieve three
consecutive glycaemic controls. Results A total of 1,024 patients (1,124 treatment periods) were
included in the study. Thirty patients were excluded due to
incompleteness of the data. During the study period 61,203 blood
glucose measurements were performed, 1,578 (2.6%) of which
were below the target value of 4 mmol/l. Severe hypoglycaemia
(≤2.2 mmol/l) occurred in 25 patients (36 measurements). The
incidence was 0.059% of the measurements and 2.3% of the
patients. The median age, sex, APACHE II score, SAPS II or
diagnosis category did not differ between the groups. The median
(IQR) ICU and hospital length of stay was 4.3 (1.8–10.6) and 18
(8.5–39.5) days in patients with lowest blood glucose ≤2.2, and
2.7 (1.2–5.7) and 13 (7–23) days in patients with lowest blood
glucose ≥2.3 (P = 0.058 and P = 0.077, respectively). The
hospital mortalities were 25% and 15%, respectively; the
difference was not statistically significant. P134 efficacy of an intensive insulin therapy protocol in achieving
glycaemic control in patients presenting with different conditions. Methods A prospective observational study was performed over
8 weeks on patients admitted to an adult ICU who received
nutrition support for up to 48 hours. Intensive insulin therapy was
administered to those patients who developed hyperglycemia. The
demographics, blood glucose and insulin doses were documented. Haemoglobin, white cell count, neutrophil count, antioxidants, CRP
and prealbumin were measured. Outcome measures were the
mean and total insulin dose and the time to achieve glycaemic
control. P134
Severe hypoglycaemia during intensive insulin therapy: a
rare event in critically ill patients
M Kaukonen, M Rantala, V Pettilä, M Hynninen
Helsinki University Hospital, Helsinki, Finland
Critical Care 2007, 11(Suppl 2):P134 (doi: 10.1186/cc5294) P137 Computer-advised insulin infusion in critically ill patients –
a randomized controlled trial
J Cordingley1, N Dormand1, S Squire1, M Wilinska2, L Chassin2,
R Hovorka2, C Morgan1
1Royal Brompton Hospital, London, UK; 2University of Cambridge, UK
Critical Care 2007, 11(Suppl 2):P137 (doi: 10.1186/cc5297) Computer-advised insulin infusion in critically ill patients –
a randomized controlled trial Methods This was an open randomized controlled clinical study. Fifty mechanically ventilated medical ICU patients were included
for a study period of 72 hours. Patients were randomized either to
a control group, treated by an insulin algorithm as routinely used in
the ICU, or to the MPC group, using a laptop-based fully
automated MPC algorithm. The target range for blood glucose
(BG) was 4.4–6.1 mM for both groups. Efficacy was assessed by
calculating the median BG, hyperglycaemic index (HGI) and BG
sampling interval. Safety was assessed by the number of
hypoglycaemic BG measurements < 2.2 mM. Introduction Tight blood glucose (BG) control has been shown to
decrease morbidity and mortality in patients in the surgical ICU [1]
but is difficult to achieve using standard insulin infusion protocols. We previously evaluated a software model predictive control
(MPC) insulin administration algorithm in postcardiac surgery
patients [2]. This study investigated the use of an enhanced MPC
algorithm (eMPC) in more severely ill patients over 72 hours. Results Patients were included for 72 (69–73) hours (median
(IQR)) in the control group and 71 (70–73) hours in the MPC
group. The median BG and HGI were significantly lower in MPC vs
control patients (see Table 1). A single BG measurement
< 2.2 mM was detected in the MPC group vs 0 in the control
group. The sampling frequency was significantly higher in the MPC
group. Methods Fourteen (seven male) critically ill ventilated medical and
surgical patients, mean age 65 years, with an arterial BG
> 6.7 mmol/l within 24 hours of ICU admission (RBH) or already
receiving insulin infusion, and expected to require mechanical
ventilation for more than 72 hours, were treated either with BG
control by the standard ICU insulin intravenous infusion protocol
[2] or eMPC-advised insulin infusion (n = 6) for 72 hours. The
eMPC algorithm, installed on a bedside computer, requires input of
current insulin requirements, bodyweight, carbohydrate intake and
BG concentration. The algorithm advises the time to next BG
sample (up to 4 hours) and the insulin infusion rate, targeted to
maintain BG at 4.4–6.1 mmol/l. P135 ,
p
p y
Method Over a 7-month period all patients staying longer than 48
hours in the ICU with hyperglycaemia (>150 mg%) on three
consecutive measurements were included in the study. These
patients were treated according to a protocol at the discretion of
the attending nurse. On daily rounds and every 4–5 weeks
supervision was performed, and the protocol was modified three
times during this period according to staff comments. Further on,
medical as well as nonmedical problems of implementation were
analysed and discussed. Attitudes and perceived impeding
aspects of the implementation process were recorded by means of
a questionnaire. Intensive insulin therapy and indications for intensive care
admission A Sanusi1, I Welters2, A Shenkin2, P Turner3, B Perry2
1University of Ibadan, Ibadan, Nigeria; 2University of Liverpool, UK;
3The Royal Liverpool Hospital, Liverpool, UK
Critical Care 2007, 11(Suppl 2):P135 (doi: 10.1186/cc5295) Introduction Insulin resistance and hyperglycemia are common in
critically ill patients, and are associated with higher morbidity and
mortality in these patients if not controlled. Intensive insulin therapy
has been shown to reduce morbidity and mortality. It is not clear,
however, whether the patients’ indication for admission into the
ICU is related to the time to achieve glycaemic control or the total
dose of insulin required. This study was designed to audit the Results Since insulin sensitivity showed enormous variability,
glycaemic control required a high nursing effort. Impeding aspects
to titrate blood glucose into the target range were the absence of a
nutritional protocol (high carbohydrate intake, despite inflam-
mation/infection leading to hyperglycaemia that was difficult to S54 Available online http://ccforum.com/supplements/11/S2 Table 1 (abstract P138) Table 1 (abstract P138)
MPC group (n = 25)
Control group (n = 25)
P
BG (mM)
5.9 (5.5–6.3)
7.4 (6.9–8.6)
<0.001
HGI (mM)
0.37 (0.17–0.91)
1.56 (1.06–2.45)
<0.001
Interval (min)
105 (94–139)
173 (160–194)
<0.001
Data presented as the median (IQR). Data presented as the median (IQR). Results The mean (SD) glucose concentration was significantly
lower in the eMPC group (6.0 (0.34) vs 7.1 (0.54) mmol/l,
P < 0.001). The mean insulin infusion rate was not significantly
different (4.1 (2.7) vs 3.1 (1.8) IU/hour, eMPC vs standard care). BG sampling occurred more frequently in the eMPC group, with a
mean of every 1.1 vs 1.9 hours (P < 0.05). No patients in either
group had any BG measurements <2.2 mmol/l. Conclusion The use of MPC improved BG and the HGI. This
improvement was accompanied by an increased sampling
frequency. MPC with time-variant sampling is a reliable tool for the
implementation of TGC in patients in the medical ICU. P138 control) and fear of hypoglycaemia (<60 mg%) leading to low-dose
insulin with consecutive hyperglycaemia. Lack of communication
(and therefore a loss of information) between critical care nurses
and the intensivists and poor acceptance from physicians to leave
this field of intensive care medicine to the nurses were additional
factors that slowed the implementation process. P138
Evaluation of a model predictive control algorithm using
time-variant sampling to establish tight glycaemic control
in clinical practice
C Pachler1, J Plank1, H Weinhandl1, R Hovorka2, L Chassin2,
P Kaufmann1, KH Smolle1, TR Pieber1, M Ellmerer1
1Medical University Graz, Austria; 2Addenbrooke’s Hospital,
Cambridge, UK
Critical Care 2007, 11(Suppl 2):P138 (doi: 10.1186/cc5298) Evaluation of a model predictive control algorithm using
time-variant sampling to establish tight glycaemic control
in clinical practice
C Pachler1, J Plank1, H Weinhandl1, R Hovorka2, L Chassin2,
P Kaufmann1, KH Smolle1, TR Pieber1, M Ellmerer1
1Medical University Graz, Austria; 2Addenbrooke’s Hospital,
Cambridge, UK
Critical Care 2007, 11(Suppl 2):P138 (doi: 10.1186/cc5298) Evaluation of a model predictive control algorithm using
time-variant sampling to establish tight glycaemic control
in clinical practice Conclusion Implementation of protocol-driven medicine requires a
high quality of information flow. The lack of linearity between blood
glucose and insulin dose (variability of insulin sensitivity) required a
sometimes intuitive (experienced) decision to titrate the insulin
dose. The conflict of physicians with this new role of critical care
nurses might be due to the lack of understanding of the evolution
of the nursing profession. Introduction Tight glycaemic control (TGC) in critically ill patients
significantly improves clinical outcome. Even with increased
workload for ICU nursing staff, targets for TGC are often not
achieved. The aim of the present study was to evaluate in clinical
practice a model predictive control algorithm (MPC) using time-
variant sampling, which will be used in a fully automated insulin
titration system (CLINICIP system). P139 Conclusion The eMPC algorithm was effective in maintaining tight
BG control in this more severely ill patient group without any
episodes of hypoglycaemia (BG < 2.2 mmol/l), but required more
frequent BG measurement. The effect of tighter glucose control on outcome P137 Patients in the eMPC group had
BG measured hourly (for safety) but values were only entered if
requested by the algorithm. The effect of tighter glucose control on outcome I Meynaar, P Tangkau, S Sleeswijk Visser,
M van Spreuwel-Verheijen, L Dawson
Reinier de Graaf Gasthuis, Delft, The Netherlands
Critical Care 2007, 11(Suppl 2):P139 (doi: 10.1186/cc5299) Acknowledgements This study is part of the CLINICIP project
funded by the EC (6th Framework). The University of Cambridge
also received support from EPSRC (GR/S14344/01). Critical Care 2007, 11(Suppl 2):P139 (doi: 10.1186/ Introduction Evidence is accumulating that tight glucose control
improves outcome in critically ill patients. This study was
performed to evaluate the effect of lower blood glucose levels in
critically ill patients on outcome. References 1. Van den Berghe G, et al.: Intensive insulin therapy in criti-
cally ill patients. N Engl J Med 2001, 345:1359-1367. 1. Van den Berghe G, et al.: Intensive insulin therapy in criti-
cally ill patients. N Engl J Med 2001, 345:1359-1367. 2. Plank J, et al.: Multicentric randomized controlled trial to
evaluate blood glucose control by the MPC versus routine
glucose management protocols in ICU patients. Diabetes
Care 2006, 29:271-276. Patients and methods The unit is a 10-bed closed-format
medical–surgical ICU in a general hospital. Starting in 2003 insulin
was prescribed to ICU patients using several nurse-driven S55 Critical Care March 2007 Vol 11 Suppl 2
27th International Symposium on Intensive Care and Emergency Medicine Critical Care March 2007 Vol 11 Suppl 2
27th International Symposium on Intensive Care and Emergency Medicine ritical Care March 2007 Vol 11 Suppl 2
27th International Symposium on Intensive Care and Emergency Medicin Figure 1 (abstract P140) Figure 1 (abstract P140) computerised protocols, each subsequent protocol aiming for
lower glucose levels. From February 2004 until May 2005 protocol
1 was used, aiming for glucose between 5.0 and 9.0 mmol/l; from
July 2005 until December 2005 protocol 2 was used, aiming for
glucose between 4.5 and 7.5 mmol/l. Serum glucose was
measured at 6:00 a.m. in all patients from blood derived from
arterial lines or venous puncture. The rest of the day blood glucose
was measured either using the Glucotouch (protocol 1) or the
AccuCheck (protocol 2) devices. To eliminate differences due to
these different methods of measurement, only the 6:00 a.m. glucose measurements done by the central laboratory were
studied here. Data were derived from ICU and laboratory
databases. arterial blood measurements: Accu-chek Advantage® (Roche)
arterial, venous and capillary samples; and Precision PCx®
(Abbott) arterial samples. All samples were collected simul-
taneously. Agreement between measurements was tested with the
Bland–Altman method. Results See Table 1. The median morning glucose was reduced
from 7.5 mmol/l with protocol 1 to 6.8 mmol/l with protocol 2,
resulting in small but nonsignificant improvement in outcome. Subgroup analysis focusing on medical or surgical patients or on
patients with specific length of stay in the ICU also revealed
nonsignificant differences in outcome. Results Comparisons between pairs of measurements are shown
in Figure 1. Conclusions The two glucose meters evaluated might not be
sufficiently reliable to be used in the ICU setting, especially for
patients under strict blood glucose control. P141 Implementing tight glycaemic control: performance of
bedside glucometers D Vlasselaers1, K Vandewiele2, T Van Herpe2, B De Moor2,
G Van den Berghe1
1University Hospital Gasthuisberg, Leuven, Belgium; 2Katholieke
Universiteit Leuven, Belgium
Critical Care 2007, 11(Suppl 2):P141 (doi: 10.1186/cc5301) Introduction Implementing tight glycaemic control (TGC) in the
ICU requires accurate blood glucose (BG) monitoring. We
evaluated the performance of two bedside glucometers (GM) in
ICU patients. Methods Four hundred and fifty-two arterial blood samples were
prospectively analysed in 37 adult ICU patients subjected to TGC. Arterial BG was simultaneously determined using a reference test
(ABL®) and two GM (Accu-Chek® and HemoCue®). Data were Conclusions A small but significant decrease in serum glucose
probably results in a small but statistically nonsignificant decrease
in mortality and length of stay. References Moreover, there are
marked differences between the equipment and a decrease in
precision if capillary or venous samples are used. Table 1 (abstract P139)
Protocol 1
Protocol 2
P
Number of patients
601
413
Number of morning
1,558
1,378
glucose measurements
Morning glucose
8.23/7.5
7.48/6.8
<0.001
(mean/median)
APACHE II score at ICU
13.6/12
13.9/12
Not significant
admission (mean/median)
Age (years, mean/median)
66.4/70.3
67.1/70.6
Not significant
ICU mortality all patients (%)
10.6
9.0
Not significant
Hospital mortality all
17.6
15.0
Not significant
patients (%)
Mean ICU length of stay
3.04/1.1
2.47/1.1
Not significant
(days, mean/median)
Mean hospital length of
17.00/10.0
13.62/9.1
Not significant
stay (days, mean/median) P143 Results Correlation between the reference method and both GM
in the overall BG range was reasonable, but not perfect (r2 ≥0.93). This was further underlined by BA analysis (Figures 1 and 2),
showing a bias to overestimate BG with GM. In the TGC range
(80–110 mg/dl) correlation was low for both GM (r2 ≤0.66). This
was confirmed by BA analysis, demonstrating broad limits of
agreement: +14.2 and –26.6 mg/dl for Accu-Chek® and +5.5 and
–31.1 mg/dl for HemoCue®. Results Correlation between the reference method and both GM
in the overall BG range was reasonable, but not perfect (r2 ≥0.93). This was further underlined by BA analysis (Figures 1 and 2),
showing a bias to overestimate BG with GM. In the TGC range
(80–110 mg/dl) correlation was low for both GM (r2 ≤0.66). This
was confirmed by BA analysis, demonstrating broad limits of
agreement: +14.2 and –26.6 mg/dl for Accu-Chek® and +5.5 and
–31.1 mg/dl for HemoCue®. Conclusions The accuracy of the tested GM in our ICU patients
was insufficient for safe clinical practice. Therefore, to avoid
potentially harmful hypoglycaemia, caution is warranted when TGC
is implemented exclusively based on BG results obtained by GM. Available online http://ccforum.com/supplements/11/S2 Figure 2 (abstract P141) arterial) and on the Rapid-Lab 1265 Bayer (GO, arterial), and each
value was compared with the reference laboratory result. Results A total of 262 matched analyses were done in 60 patients. Biases are defined as the glucose laboratory value minus point-of-
care value. The bias, 95% limits of agreement, and numbers of
observed discrepancy (d) paired results >20% and >10% are
reported in Table 1. arterial) and on the Rapid-Lab 1265 Bayer (GO, arterial), and each
value was compared with the reference laboratory result. p
y
Results A total of 262 matched analyses were done in 60 patients. Biases are defined as the glucose laboratory value minus point-of-
care value. The bias, 95% limits of agreement, and numbers of
observed discrepancy (d) paired results >20% and >10% are
reported in Table 1. Conclusions GO methods underestimate while GD methods
overestimate all blood glucose levels as compared with plasma
glucose levels measured by the reference method of hexokinase. Capillary methods have wider 95% limits of agreement than
measures carried out on arterial blood. P143 Continuous glucose monitoring for intensive care patients
using whole blood microdialysis
F Feichtner1, R Schaller1, A Fercher1, L Schaupp1, J Plank2,
A Wutte2, M Ellmerer2, T Pieber2
1Joanneum Research GmbH, Graz, Austria; 2Medical University
Graz, Austria
Critical Care 2007, 11(Suppl 2):P143 (doi: 10.1186/cc5303) Continuous glucose monitoring for intensive care patients
using whole blood microdialysis analysed using linear regression and the Bland–Altman (BA)
method. Introduction The objective of this study was to investigate whether
continuous glucose monitoring for intensive care patients could be
implemented using blood microdialysis (MD) as tight glycaemic
control reduces mortality and morbidity of critically ill patients. Currently investigated is whether the subcutaneous tissue is an
adequate and representative site for glucose monitoring. We have
designed and tested a novel system that allows continuous
measurement of glucose concentration in whole blood based on MD. Methods Na-heparin is pumped to the tip of a double lumen
catheter and the blood–heparin mixture is withdrawn continuously
at a mixing ratio of 1:1 at a flow of 4 ml/hour. The blood–heparin
mixture is microdialysed in a planar flow-through MD unit and is
discarded thereafter. The dialysate is collected and analysed for
glucose concentration via Beckman analysis and referred to
venous blood samples taken from the reference arm. Eight healthy
volunteers underwent a 12-hour investigation including an OGTT. Glucose readings from dialysate and venous blood were obtained
in a 15–30 minute interval. Introduction The objective of this study was to investigate whether
continuous glucose monitoring for intensive care patients could be
implemented using blood microdialysis (MD) as tight glycaemic
control reduces mortality and morbidity of critically ill patients. Currently investigated is whether the subcutaneous tissue is an
adequate and representative site for glucose monitoring. We have
designed and tested a novel system that allows continuous
measurement of glucose concentration in whole blood based on MD. Methods Na-heparin is pumped to the tip of a double lumen
catheter and the blood–heparin mixture is withdrawn continuously
at a mixing ratio of 1:1 at a flow of 4 ml/hour. The blood–heparin
mixture is microdialysed in a planar flow-through MD unit and is
discarded thereafter. The dialysate is collected and analysed for
glucose concentration via Beckman analysis and referred to
venous blood samples taken from the reference arm. Eight healthy
volunteers underwent a 12-hour investigation including an OGTT. Glucose readings from dialysate and venous blood were obtained
in a 15–30 minute interval. Figure 1 (abstract P141) Reliability of arterial, capillary and venous point-of-care
glucose measurements in the intensive care unit setting:
evaluation of two glucometers
A Pereira, A Cavalcanti, T Correa, F Almeida, E Figueiredo, E Silva
Hospital Israelita Albert Einstein, São Paulo, Brazil
Critical Care 2007, 11(Suppl 2):P140 (doi: 10.1186/cc5300) A Pereira, A Cavalcanti, T Correa, F Almeida, E Figueiredo, E Silva
Hospital Israelita Albert Einstein, São Paulo, Brazil
Critical Care 2007, 11(Suppl 2):P140 (doi: 10.1186/cc5300) Introduction Increased risk of hypoglycemia is the major drawback
of strict glycemic control, which has been extensively used in
critically ill patients. Fast and precise glucose measurements are
therefore mandatory. Our aim was to evaluate the accuracy of two
methods of bedside point-of-care testing for glucose measure-
ments using arterial, capillary and venous blood samples in ICU
patients. Methods A cross-sectional study with prospective data collection
included 86 patients admitted to a 40-bed clinical-surgical ICU of
a tertiary care hospital. Results from two different methods of
glucose measurement were compared with central laboratory S56 Available online http://ccforum.com/supplements/11/S2 P144 Subcutaneous glucose monitoring in patients with severe
sepsis Subcutaneous glucose monitoring in patients with severe
sepsis JK Mader1, S Korsatko1, D Ikeoka1, J Plank1, M Bodenlenz2,
M Suppan2, F Sinner2, KH Smolle1, TR Pieber1, M Ellmerer1
1Medical University Graz, Austria; 2Joanneum Research GmbH,
Graz, Austria
Critical Care 2007, 11(Suppl 2):P144 (doi: 10.1186/cc5304) Results During 2 months 55 patients (male 47%, female 53%)
were admitted, including 47 (85%) emergency admissions. Thirty-
three (60%) patients stayed in the unit for >48 hours with an
average stay of 7.1 days. Thirty-two (58%) patients received NS,
and 26 (81%) of these were within 48 hours of admission. Enteral
and parenteral routes were used in 26 (81%) and six (18%)
patients, respectively. In five (15%) patients both methods were
used during the change of route of administration. The daily calorie
intake expressed as a percentage of the recommended intake is
presented in Table 1. HE was more than 300 in 70% of the 570
measurements. Blood sugar was between 6.3 and 6.9 mmol/l. Gastro Prokinetics was used in 80%. There was no feeding
protocol in the unit and low GRVTs were used before
abandonment of the enteral regime. Introduction Tight glycemic control (TGC) to improve mortality and
morbidity in ICU patients requires frequent blood glucose
measurements and thus increases the workload for medical staff. TGC could be simplified by subcutaneous glucose monitoring as
suggested for diabetes care. Due to altered tissue perfusion as
often seen in critically ill patients, it remains unclear whether
subcutaneous adipose tissue (SAT) is a reliable measurement site. In this study we evaluated clinically whether SAT can be used as
safe, alternative site to establish TGC in patients with severe sepsis. Methods For 26 hours, arterial blood and SAT microdialysis
samples were taken from 10 patients with severe sepsis. Hourly
SAT glucose concentrations were calibrated to arterial blood
glucose (Bg) by one-point calibration either 1 hour (BgSAT1h) or
6 hours (BgSAT6h) after catheter insertion. The relation between
Bg and calibrated SAT glucose readings was clinically evaluated
applying a well-established insulin titration error grid analysis. ( Table 1 (abstract P145)
Total days (%)
Calories (%)
Nitrogen (%)
Nasogastric feeds
155 (71.5)
80.21
63.5
Total parenteral nutrition
48 (22.22)
151.52
118.1
Nasogastric feeds +
13 (6.06)
158.01
126.9
total parenteral nutrition Results Arterial and SAT glucose readings were comparable (Bg:
143 (122–167) mg/dl; BgSAT1h: 147 (130–177) mg/dl; BgSAT6h:
146 (117–181) mg/dl; median (IQR)). P144 Relative differences
between Bg vs BgSAT1h and BgSAT6h indicated –2 (–193 to
30)% and –4 (–42 to 25)%; median (5th and 95th percentiles)),
respectively. Clinical evaluation of the data indicated that 86%
(BgSAT1h) and 95% (BgSAT6h) of the glucose readings from SAT
would allow correct treatment according to an insulin-titration
guideline. Fourteen percent of the data for BgSAT1h and 5% of the
data for BgSAT6h would cause a violation of the guideline and thus
unwanted glucose excursions and a possible risk for the patient. Conclusion We found that there was overfeeding in the parenteral
and combined routes. HE was satisfactory in 70% and more
patients could receive enteral feeds if a high GRVT was used. Small-bore tubes are easy to implement and were not practised. Reference 1. Dhaliwal R, Heyland DK: Nutrition and infection in the inten-
sive care unit: what does the evidence show? Curr Opin
Crit Care 2005, 11:461-467. P146 g
p
p
Conclusions
Clinical evaluation of subcutaneous glucose
monitoring to establish TGC indicated that only 86% of the
readings would allow acceptable treatment according to a titration
guideline. Although this result could be substantially improved by
introducing a 6-hour stabilisation period for the trauma caused by
catheter insertion, the clinical applicability of subcutaneous
glucose monitoring for patients with sepsis has to be considered
with care. Prokinetics effect on gastric emptying in critically ill
ventilated patients measured by the C13 breath test with a
novel device M Hersch, V Krasilnikov, S Einav, D Braverman, S Zevin,
P Risseman
Shaare Zedek Med. Centre, Jerusalem, Israel
Critical Care 2007, 11(Suppl 2):P146 (doi: 10.1186/cc5306) M Hersch, V Krasilnikov, S Einav, D Braverman, S Zevin,
P Risseman
Shaare Zedek Med. Centre, Jerusalem, Israel
Critical Care 2007, 11(Suppl 2):P146 (doi: 10.1186/cc5306) M Hersch, V Krasilnikov, S Einav, D Braverman, S Zevin,
P Risseman Shaare Zedek Med. Centre, Jerusalem, Israel
Critical Care 2007, 11(Suppl 2):P146 (doi: 10.1186/cc5306) Acknowledgement Funded by the European Commission as part
of CLINICIP FP6 IST 506965. Introduction Gastroparesis in critically ill ventilated patients is
relieved by prokinetics. The best prokinetic combination is not
known and may be identified by BreathID measurement of gastric
emptying (GE). Introduction Gastroparesis in critically ill ventilated patients is
relieved by prokinetics. The best prokinetic combination is not
known and may be identified by BreathID measurement of gastric
emptying (GE). Comparison of accuracy of glucose-oxidase-based and
glucose-dehydrogenase-based point-of-care glucometers Thirty-two (58%) patients received NS,
and 26 (81%) of these were within 48 hours of admission. Enteral
and parenteral routes were used in 26 (81%) and six (18%)
patients, respectively. In five (15%) patients both methods were
used during the change of route of administration. The daily calorie
intake expressed as a percentage of the recommended intake is
presented in Table 1. HE was more than 300 in 70% of the 570
measurements. Blood sugar was between 6.3 and 6.9 mmol/l. Gastro Prokinetics was used in 80%. There was no feeding
protocol in the unit and low GRVTs were used before adequate flushing sequences or by using it with central lines. Further long-term studies are necessary to test the system together
with online sensors. assess the compliance of nutritional practise in our ICU with some
aspects of recommendations of Canadian Clinical Guidelines. assess the compliance of nutritional practise in our ICU with some
aspects of recommendations of Canadian Clinical Guidelines. Method
Demographic data, head elevation (HE) from the
horizontal position, daily nitrogen and calorie intake were recorded. Daily
recommended
calorie
requirements
were
calculated
according to body weights on admission. The nasogastric tube
size and the gastric residual volume threshold (GRVT) before
abandoning enteral feeds were also recorded. p
Method
Demographic data, head elevation (HE) from the
horizontal position, daily nitrogen and calorie intake were recorded. Daily
recommended
calorie
requirements
were
calculated
according to body weights on admission. The nasogastric tube
size and the gastric residual volume threshold (GRVT) before
abandoning enteral feeds were also recorded. Comparison of accuracy of glucose-oxidase-based and
glucose-dehydrogenase-based point-of-care glucometers A Roman, A Janier-Dubry, C Hanicq, P Flament, F Vertongen,
E Stevens
CHU Saint-Pierre, Brussels, Belgium
Critical Care 2007, 11(Suppl 2):P142 (doi: 10.1186/cc5302) Results All eight subjects successfully completed the 12-hour trial. The coefficient of correlation between continuously withdrawn
microdialysed blood and venously taken reference blood samples
was r = 0.9834 (0.9753–0.9958). The Clark Error Grid Analysis
(EGA) revealed that 99.5% of all data pairs are in the A range (220
of 221). Applying the novel Insulin Titration EGA yielded in 100%
of data pairs the ‘acceptable treatment’ area. Introduction Bedside capillary or arterial blood glucose monitoring
is mandatory for ICU patients under tight glycemic control. Point-
of-care methods are based on glucose-oxidase (GO) or glucose-
dehydrogenase (GD) enzymatic methods whereas the laboratory
reference method is hexokinase for measuring the plasma glucose
levels. Conclusions Blood MD based on continuous blood withdrawal
and extracorporeal MD is a promising approach to obtain dialysate
reliably, safely and continuously for long-term determination of
blood glucose concentration with online sensors. The correlation
between glucose concentration of dialysate and reference venous
blood samples is excellent. The patency of the double lumen
catheter in the current form could be improved by introducing Methods In this prospective observational study, blood glucose
was simultaneously measured on the Glucocard Arkray (GO,
capillary), on the Accu-chek Inform Roche (GD, capillary and S57
Table 1 (abstract P142)
Number of
Bias
Agreement
Number >20%
Number >10%
Point-of care method
comparisons
(mg/dl)
(mg/dl)
d (%)
d (%)
Glucocard, GO capillary
262
+8.5
±36
32 (12)
103 (39)
Accu-chek, GD capillary
262
–6.3
±37
40 (15)
123 (45)
Rapid-Lab, GO arterial
262
+5.3
±11
(0)
21 (8)
Accu-chek, GD arterial
234
–7.9
±17
17 (7)
67 (29) S57 ritical Care March 2007 Vol 11 Suppl 2
27th International Symposium on Intensive Care and Emergency Medicin assess the compliance of nutritional practise in our ICU with some
aspects of recommendations of Canadian Clinical Guidelines. Method
Demographic data, head elevation (HE) from the
horizontal position, daily nitrogen and calorie intake were recorded. Daily
recommended
calorie
requirements
were
calculated
according to body weights on admission. The nasogastric tube
size and the gastric residual volume threshold (GRVT) before
abandoning enteral feeds were also recorded. Results During 2 months 55 patients (male 47%, female 53%)
were admitted, including 47 (85%) emergency admissions. Thirty-
three (60%) patients stayed in the unit for >48 hours with an
average stay of 7.1 days. P148 Proton pump inhibitors and the incidence of Clostridium
difficile on the intensive care unit
I Whitehead, J Smith, R Bellamy, S Bonner
James Cook University Hospital, Middlesbrough, UK
Critical Care 2007, 11(Suppl 2):P148 (doi: 10.1186/cc5308) Proton pump inhibitors and the incidence of Clostridium
difficile on the intensive care unit Proton pump inhibitors and the incidence of Clostridium
difficile on the intensive care unit percentage dose recovered (PDR), a measure of delta over
baseline reflecting the rate of substrate metabolized. The 13CO2
measurements and calculations were done by our BreathID
Computerized system (BreathID Ltd, Jerusalem, Israel) with its
sensor attached to the expiratory ventilator tubing. I Whitehead, J Smith, R Bellamy, S Bonner
James Cook University Hospital, Middlesbrough, UK
Critical Care 2007, 11(Suppl 2):P148 (doi: 10.1186/cc5308) Introduction Clostridium difficile associated disease (CDAD) is
recognized as a major cause of morbidity and mortality among
patients in hospital. There have been reported associations
between the use of proton pump inhibitors (PPIs) and CDAD in
community and hospital settings [1,2]. The aim of this study was to
investigate the effect of introducing PPI prophylaxis in critically ill
patients on the incidence of CDAD. Results Thirty-one patients were included. Figure 1 shows the
PDR of all patients under the different prokinetic drugs. Table 1
presents the average percentage of GE improvement over BM with
different therapies, and the average improvement of individuals’
best combination. Comparing 20 patients, BM first, with 11 at
different timings, revealed no difference of baseline or best
combination (P = 0.1, P = 0.2, respectively). p
Methods Retrospective analysis of microbiology results of patients
admitted to general and neurotrauma ICUs between February
2002 and September 2006. Prior to March 2004 the general ITU
used PPIs for all patients as gastric acid prophylaxis, and the
neurotrauma ITU used PPIs for only patients at high risk of GI
ulceration. Following instigation of ventilator care bundles in March
2004 both units gave PPIs to all ventilated patients. The incidence
of C. difficile toxin-positive samples and the number of doses of
PPI used each month were compared for before and after this time
period. The use of antibiotics was also compared between the two
units over the time period to exclude this as a confounding variable. Results We identified 92 C. difficile-positive faecal samples
during the 57-month period from February 2002 to September
2006. This averaged 1.61 cases per month. P148 The general ITU
(ITU2) presented 49 cases (53.2%), and the neurotrauma ITU
(ITU3) 43 cases (46.8%). In February 2002, PPI usage was
infrequent in the ITU3, but more common in ITU2. The C. difficile
rates were also higher in ITU2 than in ITU3. PPI usage increased in
ITU3 until, on the instigation of the ventilator care bundle, PPIs
were used for all patients from March 2004. Our preliminary data
demonstrate an increase in C. difficile rates in ITU3, to meet the
rates of ITU2, at the same time as PPI usage was increased (Figure 1). The ITUs back onto each other and share the same medical and
nursing staff. Antibiotic usage was similar across both units with
regards to cephalosporins, meropenem and pipracillin/tazobactam. Conclusion C. difficile rates have remained relatively stable on the
general ITU (ITU2) but showed a significant increase on the Conclusions In this population: 1. Metoclopramide is poor in
improving GE. 2. The combination of metoclopramide and continuous
erythromycin is the most effective. 3. The BreathID is a convenient
and novel way to monitor GE in order to study and individually tailor
the most effective (up to 85% over BM) prokinetic combination. Available online http://ccforum.com/supplements/11/S2 Figure 1 (abstract P146) Results Fifty-two patients receiving ETF were observed for a total
of 7,349 hours: 67.3% of patients were surgical and 32.7%
medical. Patients received a median of 75% of their ideal calorific
requirement. Feeding was started a median of 15 hours after
admission, and a median of 5% of feeding time was interrupted
after ETF had been started. Reasons for interruption included high
gastric aspirates, starvation for procedures and displacement/
blockage of feeding tube. The time to start ETF was significantly
different according to admission categories (P = 0.033), with
abdominal and cardiothoracic surgical patients having the greatest
delays. Abdominal surgical patients also had a higher proportion of
feeding interruptions due to high gastric aspirates and starvation
for procedures. The SOFA score on day 1 significantly correlated
with the time taken to start feeding (P = 0.008), length of total
feeding interruption (P = 0.012), length of feeding interruption due
to high gastric aspirates (P = 0.043), and length of feeding
interruption due to starvation for procedures (P = 0.026). Table 1 (abstract P146)
Metoclopramide
13.7%
Metoclopramide + erythromycin continuous
50.5%
Erythromycin continuous
33.3%
Erythromycin x 2
38.7%
Best individual
85.2% Table 1 (abstract P146)
Metoclopramide
13.7%
Metoclopramide + erythromycin continuous
50.5%
Erythromycin continuous
33.3%
Erythromycin x 2
38.7%
Best individual
85.2% Table 1 (abstract P146)
Metoclopramide
13.7%
Metoclopramide + erythromycin continuous
50.5%
Erythromycin continuous
33.3%
Erythromycin x 2
38.7%
Best individual
85.2% Conclusion The majority of patients received a high proportion of
their ideal calorific requirement and began feeding within 24 hours. The data indicate that patients having had abdominal surgery or
the sickest patients may be may be more likely to experience
delays in initiation and interruptions to feeding. Nutritional support in critically ill patients S Thanthulage1, Y Yoganathan2, S Tharmalingam1, M Kumara1
1Oldchurch Hospital, Romford, UK; 2BHR NHS Trust, Brentwood,
UK
Critical Care 2007, 11(Suppl 2):P145 (doi: 10.1186/cc5305) Methods A prospective crossover study in stable ventilated ICU
patients without upper gastrointestinal pathology. GE measure-
ment: 4-hours expiratory 13CO2 recording following intragastric
administration of C13 sodium acetate in 100 ml Osmolite. Baseline
measurement (BM) and following 24 hours i.v. therapy with:
metoclopramide (10 mg every 6 hours), metoclopramide with
continuous erythromycin (10 mg/hour), continuous erythromycin
and bolus erythromycin (200 mg every 12 hours) were done in
each patient. The BM and drug administration order was altered in
a subgroup of patients. GE was assessed by calculating the Introduction Early adequate nutritional support (NS) in critically ill
patients can improve clinical outcome [1]. Although enteral
nutrition is considered the best method, it carries a risk for
developing ventilator-associated pneumonia, particularly if patients
are nursed horizontally [1]. The aim of this prospective audit is to S58 P149 Methods CRF analysis was performed on full-thickness bowel
specimens obtained from shocked trauma patients requiring
emergency abdominal surgery for penetrating injury, and from
patients undergoing small bowel resection during elective bowel
surgery. Venous blood was taken before anaesthesia, intra-
operatively and on postoperative day 1. CRF extracted from tissue
and blood was quantified using radioimmunoassay. On day 1
postoperatively, intestinal permeability was tested by urinary
lactulose:mannitol (L:M) measurement. Institutional ethical approval
was granted and patients gave written informed consent. Intestinal corticotropin-releasing factor is decreased in
shocked trauma patients and may affect gut function Intestinal corticotropin-releasing factor is decreased in
shocked trauma patients and may affect gut function W Michell, L Hill, S Hendricks, L Weight, S Kidson
University of Cape Town, South Africa
Critical Care 2007, 11(Suppl 2):P150 (doi: 10.1186/cc5310) neurotrauma ITU (ITU3), concurrent with increased PPI usage. We
believe this worthy of further investigation. Introduction The reasons for the typical bowel dysfunction
following traumatic injury are unclear. Corticotropin-releasing factor
(CRF) in peripheral blood/tissue may induce intestinal barrier
dysfunction via receptor-mediated mechanisms independently of
the hypothalamic–pituitary–adrenal axis. This mechanism seems to
involve interactions of CRF with enteric nerves and mast cells,
which results in increased gut intercellular tight junction
permeability to macromolecules, as well as increased epithelial cell
apoptosis leading to loss of mucosal integrity. We investigated
whether blood and intestinal tissue CRF is associated with
postoperative gut dysfunction in shock. References 1. Dial S, Alrasadi K, Manoukian C: Risk of Clostridium difficile
diarrhea among hospital inpatients prescribed proton
pump inhibitors: cohort and case–control studies. CMAJ
2004, 171:33-38. 1. Dial S, Alrasadi K, Manoukian C: Risk of Clostridium difficile
diarrhea among hospital inpatients prescribed proton
pump inhibitors: cohort and case–control studies. CMAJ
2004, 171:33-38. 2. Cunnigham R: Proton pump inhibitors and the risk of
Clostridium difficile associated disease: further evidence
from the community. CMAJ 2006, 175:745-748. A study of enteral tube feeding in critically ill patients A Holdsworth, T Rahman
St George’s Hospital, London, UK
Critical Care 2007, 11(Suppl 2):P147 (doi: 10.1186/cc5307) Introduction For critically ill patients unable to eat, enteral tube
feeding (ETF) is the preferred mode of feeding. The study aimed to
investigate the amount of enteral feed obtained by patients on ICU
in a busy London Teaching Hospital, the efficiency of initiation of
feeding, and possible reasons for the failure of the above. Methods A prospective observational study was carried out over
1 month on patients admitted to a general and cardiothoracic ICU,
who received ETF. Baseline data including age, reason for
admission and illness severity score (SOFA) were documented. Length of time from admission to start of feeding was noted, and
the volume of feed delivered to patients was recorded. The
quantity of calories delivered to the patient was compared with the
patient’s ideal nutritional requirement (determined by the ICU ETF
protocol). Feeding interruptions were also recorded. S59 Critical Care March 2007 Vol 11 Suppl 2
27th International Symposium on Intensive Care and Emergency Medicine Figure 1 (abstract P148) Figure 1 (abstract P148) Figure 1 (abstract P148) between changing tracheostomy (suggesting repeat procedures)
and subsequent difficulty swallowing. One patient within this group
subsequently developed a tracheal stenosis. See Table 1. Conclusion We found the percentage of patients reporting
swallowing difficulties post percutaneous tracheostomy (PCT) (Portex
Blue Line Ultra tracheostomy tube) to be higher than one would
expect. This may be confounded by neurological injury necessitating
the need for a PCT, but we feel this may be an area of concern
meriting further investigation given frequent PCT in ICU practice. P150 Intestinal corticotropin-releasing factor is decreased in
shocked trauma patients and may affect gut function
W Michell, L Hill, S Hendricks, L Weight, S Kidson
University of Cape Town, South Africa
Critical Care 2007, 11(Suppl 2):P150 (doi: 10.1186/cc5310) Retrospective study of dysphagia following hospital
discharge of intensive care patients P Isherwood, F Baldwin
Royal Sussex County Hospital, Brighton, UK
Critical Care 2007, 11(Suppl 2):P149 (doi: 10.1186/cc5309) P Isherwood, F Baldwin Objective A retrospective study to assess the incidence and causal
factors associated with long-term dysphagia following intensive care
discharge. Results Trauma patients (n = 6, male/female = 6/0, age 27 ± 10.2
years, ISS 23 ± 6.8) were younger than elective patients (n = 6,
male/female = 4/2, age 52.8 ± 7.7 years, P < 0.0006), and had
significantly lower mean tissue [CRF] (0.034 ± 0.015 x 10–3%
total protein (TP)) than elective patients (0.117 ± 0.075 x 10–3%TP,
P = 0.023). The median (IQR) intraoperative blood CRF level was
higher in trauma patients (86.7 (5.5) pg/ml vs 59.8 (9.6) pg/ml,
P = 0.03) than elective patients. In trauma patients this correlated
negatively with postoperative L:M (r = –0.9, P = 0.037), although
intestinal permeability was greatly and equally increased in both
groups (combined mean ± SD L:M, 0.58 ± 0.55). Methods A questionnaire was sent out 4 months post ICU
discharge to 193 intensive care patients (Level 3 care with a stay
of over 48 hours). We reviewed the case notes of those patients
who reported swallowing difficulties to establish whether they had
undergone, had any characteristics of or received therapies
potentially associated with dysphagia. Results We had a 50% response rate to our questionnaire. An
overall dysphagia post ICU stay rate of 19.5% was observed. Fever and age over 65 were both common findings as one may
expect and showed the highest association with subsequent
dysphagia. We did not find any suggestion of a relationship g
p
Conclusions CRF is detectable in bowel tissue following trauma
and is significantly lower in trauma vs elective surgery patients,
while CRF in blood may be a factor associated with gut barrier
changes following shock and emergency laparotomy. Table 1 (abstract P149) 0
Table 1 (abstract P149)
Factor
Number
Percentage
Fever
14
82
Age > 65 years
11
58
Percutaneous tracheostomy
10
50
Sterds
7
37
Cardiopulmonary resuscitation
3
15
Shiley fenestrated low-pressure
2
10
cuffed tracheostomy tube
Mini-Trach II – Seldinger
1
5
(Portex Minitracheotomy Kit)
Neuromuscular Blockade
0
0 P151 Conclusions Following a severe burn, propranolol attenuates
infections, inflammatory markers and fatty acid levels while
improving cardiac work and endogenous anabolic hormone levels. We suggest that propranolol is a safe and efficacious modulator of course and analyzed for IGF-1, IGFBP-3, and HGH. Patients
underwent weekly resting energy-expenditure measurements. Statistical analysis was performed using analysis of variance with
Bonferoni’s correction and Student’s t test where applicable. Results Propranolol treatment reduced heart rates by 10% and
significantly improved stroke volume throughout the acute hospital
stay compared with controls (P < 0.05). Resting energy expendi-
ture was significantly decreased in the propranolol group when
compared with controls at discharge (P < 0.05). Infection rates on
admission were the same for both groups (17% propranolol vs
22% control). The incidence of infection throughout hospital
course was significantly lower in the propranolol group (60%)
compared with controls (87%) (P < 0.05). Propranolol significantly
increased IGF-I, IGFBP-3, GH, and prealbumin, while it
significantly decreased CRP and fatty acids (P < 0.05). Methods We enrolled patients admitted to our ICU who required
NGT insertion for EN. A Corflow NGT with Cortrak stylet was
inserted, and the position monitored using the Cortrak magnetic
sensor. The Cortrak system tracks the trail of the stylet tip as it
progresses towards the stomach and provides a visual represen-
tation of the NGT position on a video screen, allowing rapid
determination of insertion success. The position of the NGT was
also assessed using pH paper and/or CXR, as appropriate,
according to the standard UKNPSA guidelines. Data were
analysed using a paired t test and time-to-event analysis. Conclusions Following a severe burn, propranolol attenuates
infections, inflammatory markers and fatty acid levels while
improving cardiac work and endogenous anabolic hormone levels. We suggest that propranolol is a safe and efficacious modulator of
the postburn response. Results Fifty-two patients were recruited and 57 insertions were
analysed: 32 first insertions, and 25 reinsertions. Gastric content
was successfully aspirated in 40% (23/57) of insertions, and 14%
(8/57) had pH 6 or above. Forty-six CXRs were requested, with
three patients requiring multiple CXRs. The Cortrak correctly
confirmed the position of NGT in all 57 insertions. The time
required to confirm the NGT position was significantly less with the
Cortrak than with conventional methods (mean ± SE Cortrak:
9.6 ± 1.7 min; pH paper: 11.6 ± 1.7 min; CXR: 122 ± 23 min;
P < 0.0001). Early enteral immunonutrition following gastric and
oesophageal surgery S Vukosavljevic, T Randjelovic, D Pavlovic, J Danojlic
KBC ‘Bezanijska Kosa’ Beograd, Belgrade, Serbia
Critical Care 2007, 11(Suppl 2):P153 (doi: 10.1186/cc5313) Introduction The study investigates the effect of early enteral
immunonutrition on patient recovery after extensive elective surgery
in the upper abdomen [1,2]. It investigates the speed of patient
recovery administering early enteral immunonutrition combined
with total parenteral nutrition [3]. Conclusions The Cortrak demonstrated 100% accuracy in
confirming the position of NGT in this patient series. It exposes
patients to less radiation, facilitates earlier EN and is cost-effective. Consideration should therefore be given to including it into the
standard UKNPSA guideline. Materials and methods The total of 40 patients who had
undergone this type of surgery were involved in this study. Near the
end of the surgery procedure a percutaneous jejunostomy was
performed in 20 patients (G1), and enteral nutrition started on the
first postoperative day with small doses of immunonutrient
(Reconvan) 10 ml/hour. After every 12 hours the tolerance was
estimated (abdominal distension, diarrhoea, vomiting). After every
24 hours the immunonutrient dose was increased by 20 ml/hour
until we reached the maximum of 80 ml/hour. In the first three
postoperative days the patients were also administered total
parenteral nutrition, and after that only enteral nutrition. The other
group of 20 patients (G2) was administered only parenteral
nutrition from the first postoperative day. Preoperatively, every
patient was measured for body weight, body height and body mass
index, and using laboratory tests we established the levels of
albumin, transferine, blood urea nitrogen and creatinine. On the
third and ninth postoperative days we repeated the same
laboratory tests, and measured the daily loss of nitrogen by
excretion of urea in urine. Reference 1. UK National Patient Safety Agency [http://www.npsa.nhs.uk] 1. UK National Patient Safety Agency [http://www.npsa.nhs.uk] P151 There was a 1.5-hour delay in starting EN in the
standard practice group compared with the Cortrak group
(mean ± SE 3.98 ± 0.5 hours vs 2.58 ± 0.4 hours, P = 0.049). If
the Cortrak results had been acted upon, 46 CXRs could have
been avoided, which equates to a saving of £2,300 (€3,220). P153 Early enteral immunonutrition following gastric and
oesophageal surgery P152 Propranolol attenuates factors affecting hypermetabolism
in pediatric burn patients Propranolol attenuates factors affecting hypermetabolism
in pediatric burn patients W Norbury
Shriner’s Hospital for Children, Galveston, TX, USA
Critical Care 2007, 11(Suppl 2):P152 (doi: 10.1186/cc5312) P151 Using the Cortrak magnetic device to facilitate early
enteral nutrition in critically ill patients Using the Cortrak magnetic device to facilitate early
enteral nutrition in critically ill patients K Lei, J Smith, L Camporota, R Beale
St Thomas’ Hospital, London, UK
Critical Care 2007, 11(Suppl 2):P151 (doi: 10.1186/cc5311) K Lei, J Smith, L Camporota, R Beale
St Thomas’ Hospital, London, UK
Critical Care 2007, 11(Suppl 2):P151 (doi: 10.1186/cc5311) Introduction Confirmation of correct nasogastric tube (NGT)
positioning is required before commencement of enteral nutrition S60 Available online http://ccforum.com/supplements/11/S2 (EN). In the ICU, however, the use of sedation, 24-hour feeding
and proton pump inhibitors can make the standard confirmatory
methods recommended by the UK National Patient Safety Agency
(UKNPSA) [1] unreliable, and result in the need for multiple chest
X-rays (CXR), increased cost and feeding delay. We studied the
role of the Cortrak® (Viasys MedSystems, USA) against standard
practice, and assessed the following outcomes: time required to
confirm correct NGT position, time to starting feeding, and
potential cost savings. (EN). In the ICU, however, the use of sedation, 24-hour feeding
and proton pump inhibitors can make the standard confirmatory
methods recommended by the UK National Patient Safety Agency
(UKNPSA) [1] unreliable, and result in the need for multiple chest
X-rays (CXR), increased cost and feeding delay. We studied the
role of the Cortrak® (Viasys MedSystems, USA) against standard
practice, and assessed the following outcomes: time required to
confirm correct NGT position, time to starting feeding, and
potential cost savings. course and analyzed for IGF-1, IGFBP-3, and HGH. Patients
underwent weekly resting energy-expenditure measurements. Statistical analysis was performed using analysis of variance with
Bonferoni’s correction and Student’s t test where applicable. Results Propranolol treatment reduced heart rates by 10% and
significantly improved stroke volume throughout the acute hospital
stay compared with controls (P < 0.05). Resting energy expendi-
ture was significantly decreased in the propranolol group when
compared with controls at discharge (P < 0.05). Infection rates on
admission were the same for both groups (17% propranolol vs
22% control). The incidence of infection throughout hospital
course was significantly lower in the propranolol group (60%)
compared with controls (87%) (P < 0.05). Propranolol significantly
increased IGF-I, IGFBP-3, GH, and prealbumin, while it
significantly decreased CRP and fatty acids (P < 0.05). Feasibility of the REDOXS study – reducing deaths due to
oxidative stress: a randomized pilot trial of glutamine and
antioxidant supplementation in critically ill patients Feasibility of the REDOXS study – reducing deaths due to
oxidative stress: a randomized pilot trial of glutamine and
antioxidant supplementation in critically ill patients Introduction Standard selenium (Se) substitution (30–75 µg/day;
0.4–0.9 µmol/l) in the critically ill is not sufficient for a sustained
plasma level (0.58–1.82 µmol/l; 46–143 µg/l). Standard Se
substitution keeps the plasma level in the range 0.28–0.42 µmol/l. High-dose Se substitution correlated with a decrease in mortality
of patients with SIRS. The influence of high-dose substitution on
selected parameters, MAP and mortality in the critically ill were
evaluated in a prospective randomized clinical trial. D Heyland, R Dhaliwal, J Muscedere, J Drover, for the Canadian
Critical Care Trials Group
Kingston General Hospital, Kingston, Canada
Critical Care 2007, 11(Suppl 2):P154 (doi: 10.1186/cc5314) Kingston General Hospital, Kingston, Canada Introduction A large randomized trial is needed to evaluate the
safety and efficacy of glutamine (GLN) and antioxidant (AOX)
supplements. However, high doses of such nutrients via enteral
and parenteral routes early in the course of critical illness is often
interrupted by high illness acuity and other treatment priorities. The
purpose of this pilot trial was to evaluate the feasibility of delivering
high-dose GLN and AOX supplements early on in the course of
critical illness, and to estimate recruitment for the larger REDOXS
study. Methods One hundred and twenty-three patients (78 males, 45
females, median age 62.7 and 60 years, respectively) were
randomized into group A (SOFA 19.27) and group B (SOFA
10.23). Group A received standard Se substitution: 30–75 µg
NaSelenite i.v./day. Group B received high-dose Se substitution
according to a protocol: 1,000 µg at day 1, followed with 500 µg
at days 2–14 of NaSelenite i.v. The plasma levels of Se,
prealbumin, albumin, CRP, PCT, cholesterol, gluthathionperoxidase
GSHPx, D-dimer, creatinine clearance and leucocytes were
examined daily. MAP trends and 28-day mortality were evaluated
as clinical markers. Methods In six Canadian centers, using a 2 x 2 factorial design,
we randomized mechanically ventilated adults who had two or
more organ failures within 24 hours of ICU admission to one of four
groups: (1) GLN (0.35 g/kg/day i.v. plus 30 g enterally), (2) AOX
(500 µg selenium i.v. and 300 µg selenium, 20 mg zinc, 10 mg
β-carotene, 500 mg vitamin E, and 1,500 mg vitamin C enterally),
(3) both AOX + GLN, and (4) placebo. P155
Effect of high-dose selenium substitution on selected
laboratory parameters and prognosis in critically ill
patients Effect of high-dose selenium substitution on selected
laboratory parameters and prognosis in critically ill
patients 1. Delaney HM, Carenevale NH, Garvey JW: Jejunostomy by a
needle catheter technique. Surgery 1973, 73:786-945. 2. Braga M, Giannoti L, Radaelli G, et al.: Perioperative
immunonutrition in patients undergoing cancer surgery:
results of a randomized double-blinded phase 3 trial. Arch
Surg 1999, 134:428-433. 3. Moore EE, Jones TN: Benefits of immediate jejunostomy
feeding after major abdominal trauma: a prospective ran-
domized study. J Trauma 1986, 26:874-881. W Norbury
Sh i
’ H Background The aim of this study was to determine the effect of
propranolol on infections and clinical parameters during the acute
phase postburn. Severe thermal injury is followed by a period of
hypermetabolism that is directly proportional to the size of insult
sustained. Infection and multiorgan failure are now the leading
cause of death from severe thermal injuries. Propranolol, an
anticatabolic agent, improves hypermetabolism postburn. However,
there is evidence that propranolol worsens immune function and
increases the incidence of infection in critically ill patients. Results and discussion Patient recovery was faster in G1. The
average patient stay in ICU was 5 ± 1 days (G1) vs 10 ± 2 days
(G2). The average hospital stay was 22 ± 3 days (G1) vs 29 ± 5
days. Peristalsis was detected on the third day as an average (G1)
vs 4.5 days (G2). A decrease in pulmonary complications was
achieved in G1 (one pleural effusion) vs G2 (eight pleural
effusions). Laboratory tests show that patients in G1 are in lower
catabolism compared with G2 patients. Conclusion Early enteral immunonutrition through jejunostomy is
an efficient and safe method of patient nutrition with fewer
postoperative complications, and also accounts for a hospital cost
decrease of 50%. Results and discussion Patient recovery was faster in G1. The
average patient stay in ICU was 5 ± 1 days (G1) vs 10 ± 2 days
(G2). The average hospital stay was 22 ± 3 days (G1) vs 29 ± 5
days. Peristalsis was detected on the third day as an average (G1)
vs 4.5 days (G2). A decrease in pulmonary complications was
achieved in G1 (one pleural effusion) vs G2 (eight pleural
effusions). Laboratory tests show that patients in G1 are in lower
catabolism compared with G2 patients. Methods Sixty-six patients with burns >40% total body surface
area were enrolled into the study and randomized to receive
standard burn care (controls, n = 33) or standard burn plus
propranolol for more than 21 days (propranolol, 0.5–1.5 mg/kg
every 6 hours, n = 33). Biopsies were taken three times a week for
microbiological determination. Clinical parameters were collected
and blood was drawn at regular intervals throughout the hospital S61 ritical Care March 2007 Vol 11 Suppl 2
27th International Symposium on Intensive Care and Emergency Medicin P156 P156 Feasibility of the REDOXS study – reducing deaths due to
oxidative stress: a randomized pilot trial of glutamine and
antioxidant supplementation in critically ill patients Supplementation was
continued for a minimum of 5 days up to 28 days and was
provided independent of nutrition support. We recorded the time
from ICU admission to randomization, the time to start of
supplements and nutrition support parameters. Results The Se plasma level was significantly higher in high-dose
Se-substituted patients (0.56 µmol/l vs 0.88 µmol/l, P < 0.001). GSHPx was significantly higher in high-dose Se-substituted
patients (4,864 U/l vs 6,097 U/l, P < 0.001). No significant
differences were found in the level of albumin, prealbumin, CRP,
PCT, leucocytes, fibrinogen, cholesterol, D-dimer and creatinine
clearance and MAP. The 28-day mortality was lower in a high-dose
Se-substituted patients (33% vs 37%), but not significantly. Conclusion The critically ill have an increased demand for Se,
which is essential for synthesis of Se enzymes and Se proteins. The increased demand for Se is not covered by standard
substitution. High-dose Se substitution (500–1,000 µg/day)
normalizes its plasma level and increases the GSHPx plasma level. High-dose Se substitution has no adverse reactions. The decrease
of 28-day mortality in high-dose Se-substituted patients is not
significant. The trial on high-dose Se substitution further continues. Results From April 2005 to April 2006, 80 patients were
randomized (average 2.1/site/month). The median time from ICU
admission to randomization was 18.2 hours (range 11.6–21.1 hours). All patients received parenteral supplements, the median (range)
time to start was 2.7 hours (2.0–3.8 hours) and 78/80 (98%)
received enteral supplements with a median (range) of 2.6 hours
(1.9–4.5 hours) from randomization. The mean duration of
supplements was 11.1 days (enteral) and 12.2 days (parenteral). The mean volumes of enteral and parenteral supplements received
were 84% (range 45–102%) and 93% (range 54–100%)
prescribed volumes, respectively. The average prescribed energy
and protein intakes were 1,802 kcal/day and 86 g protein/day but
the average daily percentage energy and protein received from
nutrition support was only 65% (range 4–95%) and 62% (range
2–97%) of that prescribed, respectively. Magnesium deficiency in the surgical intensive care unit W Salem
National Cancer Institute, Cairo, Egypt
Critical Care 2007, 11(Suppl 2):P156 (doi: 10.1186/cc5316) Available online http://ccforum.com/supplements/11/S2 Methods Sixty adult patients admitted to the ICU after major GIT
surgery were enrolled in the study, on the basis of a documented
Mg serum level < 0.8 mmol/l on arrival at the ICU. Exclusion criteria
were cardiac disease, liver dysfunction or serum creatinine > 1.3. Patients were randomly allocated to one of two groups: the Mg
group received 20 mmol (5 g) Mg sulfate, infused daily over
6 hours for 3 days; and a control group received an equivalent
amount of 5% dextrose. In the Mg group the next scheduled dose
of MgSO4 was held if a serum magnesium level > 1.1 mmol/l,
hypotension or bradycardia was recorded. Baseline and daily
measurements of serum Mg, potassium, sodium, calcium and
creatinine were done. Twenty-four-hour urine collection was used
to determine the total urinary excretion of Mg. The net Mg balance
(total Mg given – total urine Mg) was calculated. In the Mg group,
Mg-deficient patients (retainers) who excreted < 70% of the Mg
given ((urine Mg in mmol / daily Mg given) x 100) and Mg
nondeficient patients (nonretainers) who excreted > 70% of the
total Mg given were recorded. Results One hundred and sixty-six patients were included in this
analysis. Among the main results, 63.69% were males and
77.78% were considered malnourished. The mean SOFA score
was 6.21, with a mean APACHE II score of 19.39. In total, 97.23%
of the PN used in Brazil were manufactured by third-party
companies and this was associated with a significant delay in the
beginning of the infusion (median time 29.76 hours), and elevated
in-ICU (50%) and inhospital (55.17%) mortality rates. A total
24.29% of the patients were immunosuppressed. The most used
lipid source was long-chain triglycerides/medium-chain triglycerides
(80.69%). Conclusions The use of PN in Brazil is associated with a
significant delay in the start of infusion and high mortality rates. The
most used lipid emulsion (long-chain triglycerides/medium-chain
triglycerides) has been associated with more apoptosis [2] and
compromised lymphocyte proliferation [3]. The overall findings of
these study indicate that strategies to reduce the delay in start of
PN and the use of better lipid sources must be adopted to provide
better assistance for patients in need of PN in Brazil. Parenteral nutrition in the intensive care unit: can we
deliver better care to our patients? Preliminary results
from a multicenter, prospective, cohort study Parenteral nutrition in the intensive care unit: can we
deliver better care to our patients? Preliminary results
from a multicenter, prospective, cohort study Introduction Ultrasound (US) significantly facilitates central
venous catheterization, reducing the percentage of failure, the
percentage of accidental arterial puncture, and the percentage of
complications
(haematoma,
haemothorax,
pneumothorax). Nonetheless, it is not clear whether US guidance (USG) (so-called
‘dynamic’ or ‘real-time’ US techniques: that is, venipuncture under
direct US control) may be better than US assistance (USA) (so-
called ‘static’ or ‘indirect’ US techniques: that is, US imaging of the
vein, with or without skin marking, and then blind venipuncture). Introduction Ultrasound (US) significantly facilitates central
venous catheterization, reducing the percentage of failure, the
percentage of accidental arterial puncture, and the percentage of
complications
(haematoma,
haemothorax,
pneumothorax). Nonetheless, it is not clear whether US guidance (USG) (so-called
‘dynamic’ or ‘real-time’ US techniques: that is, venipuncture under
direct US control) may be better than US assistance (USA) (so-
called ‘static’ or ‘indirect’ US techniques: that is, US imaging of the
vein, with or without skin marking, and then blind venipuncture). A Pontes-Arruda1, J Teles2, E Silva3, F Machado4, M Baptista
Filho5, E Rocha6, C Silva7
1Hospital Fernandes Távora, Fortaleza, Brazil; 2Hospital Português,
Salvador, Brazil; 3Hospital Albert Einstein, São Paulo, Brazil;
4Hospital São Paulo – UNIFESP, São Paulo, Brazil; 5Hospital
Bandeirantes, São Paulo, Brazil; 6Hospital Copa D’Or, Rio de
Janeiro, Brazil; 7Latin American Sepsis Institute, São Paulo, Brazil
Critical Care 2007, 11(Suppl 2):P157 (doi: 10.1186/cc5317) Methods From February 2005 to September 2006, our CVC Team
adopted the following protocol for internal jugular vein (IJV)
catheterization: (a) both IJVs were evaluated to assess position,
dimensions, and other features known to affect the risk of
catheterization; (b) then, a decision was made whether to continue
with USA or USG; (c) the IJV was accessed via the low lateral
Jernigan approach; (d) after two failed USA attempts, USG
venipuncture was adopted; (d) when IJVs were not available, USG
venipuncture of other central veins was the second choice; and (e)
fluoroscopy was used only in paediatric patients, but all patients had a
postoperative chest X-ray to rule out pneumothorax and malposition. Introduction Nutrition therapy is an integrant aspect of ICU
support and can influence outcomes. A delay to starting nutrition
support after 24 hours of ICU admission is associated with
increased morbidity and mortality [1], and certain lipid emulsions
can exacerbate the inflammatory cascade. Available online http://ccforum.com/supplements/11/S2 Results Patients in the Mg group showed a statistically significant
increase in mean serum Mg at days 1, 2, and 3 compared with the
control group and with day 0 (0.73 ± 0.1, 0.81 ± 0.17, 0.8 ± 0.1,
and 0.85 ± 0.11 mmol/l at days 0, 1, 2, and 3, respectively). The
mean total amount of Mg given, the mean total urine Mg excretion
and the net Mg balance were significantly higher in the Mg group
compared with the control group (58 ± 0.17 vs 11.3 ± 2.8 mmol,
P > 0.001; 34.0 ± 2.7 vs 15.5 ± 3.8 mmol, P > 0.001; 25.6 ± 1.65
vs 5.2 ± 0.93 mmol, P > 0.001). In the Mg group, the numbers of
Mg retainer patients were 24 patients on day 1, 21 on day 2 and
nine patients on day 3. Mg nonretainer patients were six patients
on day 1, nine on day 2 and 21 patients on day 3. Patients in the
Mg group showed better haemodynamic stability and fewer
ventricular arrhythmias. Acknowledgement Supported by a research grant from Baxter
Hospitalar Ltda. References 1. Simpson F, Doig GS: Parenteral vs. enteral nutrition in the
critically ill patient: a meta-analysis of trials using the
intention to treat principle. Intensive Care Med 2005, 31:
12-23. 2. Buenestado A, Cortijo J, Sanz M-J, et al.: Olive oil-based
lipid emulsion’ s neutral effect on neutrophil functions and
leucocyte–endothelial cell interactions. J Parenter Enteral
Nutr 2006, 30:286-296. 2. Buenestado A, Cortijo J, Sanz M-J, et al.: Olive oil-based
lipid emulsion’ s neutral effect on neutrophil functions and
leucocyte–endothelial cell interactions. J Parenter Enteral
Nutr 2006, 30:286-296. 3. Cury-Boaventura M, Gorjão R, Martins de Lima T, et al.: Toxic-
ity of two lipid emulsions on human lymphocytes and neu-
trophils. Crit Care, in press. 3. Cury-Boaventura M, Gorjão R, Martins de Lima T, et al.: Toxic-
ity of two lipid emulsions on human lymphocytes and neu-
trophils. Crit Care, in press. Conclusion Mg deficiency is common in ICU patients. Mg sulfate
administered according to the above regimen is safe. Early
treatment of Mg deficiency significantly increased the serum Mg
level and provided a better magnesium, potassium and calcium
balance, resulting in a shorter ICU stay. P158 Ultrasound-guided vs ultrasound-assisted central venous
catheterization M Pittiruti, A LaGreca, G Scoppettuolo, D Sermoneta
Catholic University Hospital, Roma, Italy
Critical Care 2007, 11(Suppl 2):P158 (doi: 10.1186/cc5318) W Salem Conclusion In critically ill patients with organ failure we provided
adequate amounts of study supplements via both enteral and
parenteral routes in the early phases of acute illness, independent
of nutrition support. We estimated recruitment of at least two
patients/site/month for our future trial. Introduction Magnesium (Mg) deficiency is a common and yet
underdiagnosed problem. Mg deficiency has been demonstrated in
50% of all ICU patients. These patients have significantly higher
morbidity and mortality rate. The aim of this work was to detect the
presence of Mg deficiency using a Mg loading test and to evaluate
the safety and efficacy of Mg replacement therapy in cancer
patients after major gut surgery. Acknowledgements This study was supported by grants from the
Canadian Institutes of Health Research and Fresenius-Kabi,
Germany. S62 Available online http://ccforum.com/supplements/11/S2 P159 Advantages of ultrasound-guided peripherally inserted
venous access (PICC and midline catheters) in critically ill
patients M Pittiruti, G Scoppettuolo, A LaGreca
Catholic University Hospital, Roma, Italy
Critical Care 2007, 11(Suppl 2):P159 (doi: 10.1186/cc5319) Results The central venous catheter placement was successfully
performed from the first attempt in both groups. There were no
immediate or delayed complications noted; however, the mean
time of insertion was longer in the ultrasound-guided group
(4.55 min) compared with the external anatomical landmark group
(2 min) (Figure 1). Introduction In the critically ill, a reliable peripheral or central
venous access is of paramount importance. Nonetheless, access
may be difficult or may carry a significant risk of complications
(pneumothorax, central line infection, etc.). Peripherally inserted
venous catheters – either central (PICC) or peripheral (midline
catheters (MC)) – are associated with a low risk of catheter-related
bacteremia; also, using the ultrasound guidance and the micro-
introducer technique (UG + MIT), they can be inserted in any
patient, regardless of the availability of superficial veins. Discussion Some studies have been designed to evaluate
ultrasound-guided central venous catheter placement compared
with the conventional method based on external anatomical
landmarks. These studies demonstrated the superiority of
ultrasound-guided central venous line placement over the external
anatomical landmark technique. However, there was no time gain
demonstrated in ultrasound-guided placement [2]. On the other
hand, a number of studies have expressed several reservations
concerning the systematic use of ultrasound guidance for central
line placement [3]. In our patients we found that the use of
ultrasound neither altered the rate of complication nor the number
of attempts in central venous catheter placement. Also the duration
of placement of the central line catheter using the external We have reviewed our experience of 56 peripherally inserted
catheters in 53 patients in different ICUs (surgical ICU, trauma unit,
coronary unit, neurosurgical ICU, stroke unit, pediatric ICU, etc.);
all catheters were positioned at the mid-arm, in the basilic vein or in
the brachial veins, using UG + MIT. We assessed the feasibility of
this technique in the acutely ill and the rate of complications. Methods and results We inserted 16 PICC and 40 MC in
patients requiring prolonged venous access (estimated >15 days);
nine were septic, six had coagulopathy, 21 had tracheostomy. We
used both silicone and polyurethane 4 Fr catheters. Procedures
were performed by a team of trained physicians and nurses. Parenteral nutrition in the intensive care unit: can we
deliver better care to our patients? Preliminary results
from a multicenter, prospective, cohort study For an appropriate
evaluation of the impact of these and other recent research
findings, information regarding the use of parenteral nutrition (PN)
in the ICU is needed. Introduction Nutrition therapy is an integrant aspect of ICU
support and can influence outcomes. A delay to starting nutrition
support after 24 hours of ICU admission is associated with
increased morbidity and mortality [1], and certain lipid emulsions
can exacerbate the inflammatory cascade. For an appropriate
evaluation of the impact of these and other recent research
findings, information regarding the use of parenteral nutrition (PN)
in the ICU is needed. Methods This is the interim analysis of a multicenter, prospective,
cohort study aimed to obtain information regarding the use of PN. Data were collected during 3 months from ICU patients over
18 years of age on the use of PN in 20 adult ICUs in Brazil using a
web-based clinical research form. S63 ritical Care March 2007 Vol 11 Suppl 2
27th International Symposium on Intensive Care and Emergency Medicin P160 average 5.5 years: 20 short-term + 84 tunnelled + two ports). In
adults, the procedure started as USA in 522 and as USG in 299
cases: a shift from USA to USG was necessary in 8%. USG was
the first choice in all paediatric cases. The IJV was successfully
cannulated in most adult patients, with very few exceptions
(innominate vein in 12 cases, axillary vein in two cases, femoral vein
in one case, all by USG). In one paediatric patient, the CVC was
inserted in the subclavian vein, via a supraclavicular USG
approach. Complications were: failure 0%; pneumothorax 0%;
haemothorax 0%; accidental arterial puncture 1.1% (1.7% USA vs
0.3% USG); haematoma 0.4% (only for USA); malposition (0.8%,
exclusively with the left IJV). P159 Catheter insertion was easy in most cases, and immediate
complications were few (no failure; one hematoma; no arterial or
nerve injury). Late complications were: one local infection; three
thrombosis (two requiring removal); four cases of damage of the
external catheter (due to poor nursing or to inappropriate use of
the catheter during rx procedures), all easily repaired; one
dislocation; no catheter occlusion; no catheter-related bacteremia. Most catheters stayed in place for a prolonged time (range 9–65
days, median 19 days); only three were removed because of
complications. A comparison between ultrasound-guided central venous
line placement and an anatomical landmark technique M Soliman, K Ismail
Department of Anaesthesia & Intensive Care Medicine, The Mid
Yorkshire Hospitals, UK
Critical Care 2007, 11(Suppl 2):P160 (doi: 10.1186/cc5320) Introduction Ultrasound has been introduced in the insertion of
central venous lines to reduce the complications associated with
the conventional landmark technique [1]. We compared both
techniques; we noted the number of attempts, the duration of
insertion and complications. Conclusion In conclusion, (a) we had a minimal incidence of
complications, (b) USG was associated with a relevant reduction
of the risk of accidental arterial puncture and haematoma, if
compared with USA, and (c) choosing the left IJV was associated
with a higher risk of malposition. Methods Thirty patients were randomly selected, from the
operating theatre and ICU, who required placement of a central
venous catheter. The central venous catheter placement was
performed by two experienced anaesthetists with more than
6 years experience in anaesthesia and intensive care. In 15 patients
the internal jugular venous catheter placement was performed
using the external anatomical landmark technique, and in the other
15 patients the placement was under ultrasound guidance. The
duration of insertion was recorded from the moment the needle
touched the skin until insertion of the catheter and removal of the
guide wire. The numbers of attempts as well as immediate or
delayed complications were recorded. P161 Results Out of 67 surgeries contacted, we achieved a response
rate of 65%. Thirty-three practices (49%) were able to provide
complete data, six (9%) provided partial data, and a further five
(7%) were unable or unwilling to provide any data. Twenty-three
(34%) practices did not respond. A total of 318,130 patients were
listed by the responding practices. Of these: 23 patients live with
long-term tracheostomies, a prevalence of 1 in 13,800; 65 patients
receive mechanical respiratory support at home, a prevalence of 1
in 4,900; and 207 patients receive oxygen therapy at home, a
prevalence of 1 in 1,500. P162 Thirty-three practices (49%) were able to provide
complete data, six (9%) provided partial data, and a further five
(7%) were unable or unwilling to provide any data. Twenty-three
(34%) practices did not respond. A total of 318,130 patients were
listed by the responding practices. Of these: 23 patients live with
long-term tracheostomies, a prevalence of 1 in 13,800; 65 patients
receive mechanical respiratory support at home, a prevalence of 1
in 4,900; and 207 patients receive oxygen therapy at home, a
prevalence of 1 in 1,500. Method A postal survey was sent out to practice managers in the
local catchment area. They were asked to provide data for: patients
on home ventilatory support for any reason, patients with long-term
tracheostomies, patients with COPD who are on home oxygen or
who you would classify as end stage, and the total number of
patients registered to the practice. This was followed up with a
telephone call approximately 2 weeks later. Many were then e-
mailed the same questionnaire. A further two telephone calls to
each practice were made as necessary in order to obtain data. 3. Martin MJ, Hussain, Piesman M, et al.: Is routine ultrasound
guidance for central line placement beneficial? A prospec-
tive analysis. Curr Surg 2004, 61:71-74. 3. Martin MJ, Hussain, Piesman M, et al.: Is routine ultrasound
guidance for central line placement beneficial? A prospec-
tive analysis. Curr Surg 2004, 61:71-74. Figure 1 (abstract P160) Figure 1 (abstract P160) Conclusion Our experience with PICC and MC was characterized
by an extremely low rate of infective and thrombotic complications. Venous access was achieved in any patient, even with limited
availability of peripheral veins. The use of US-inserted PICC and
MC should be considered when central access is not advisable or
is contraindicated. S64 Available online http://ccforum.com/supplements/11/S2 P162
Prevalence of respiratory support in the community – the
Surrey experience
S Burfield, L Sherrard-Smith, E Laitt, V Jamison, W Jewsbury,
S Pambakian
Frimley Park Hospital NHS Foundation Trust, Surrey, UK
Critical Care 2007, 11(Suppl 2):P162 (doi: 10.1186/cc5322) P162 P162
Prevalence of respiratory support in the community – the
Surrey experience anatomical landmark technique was shorter than in the ultrasound-
guided method. Conclusion The external anatomical landmark technique in central
line placement is considered a safe method with experienced
hands. The time of insertion of a central line using the external
anatomical landmark technique was shorter than the ultrasound-
guided placement method. It is essential for all trainees to be
taught both methods for central line placement to be able to place
a central line catheter quickly and safely in emergency situations
and when an ultrasound machine is not available. S Burfield, L Sherrard-Smith, E Laitt, V Jamison, W Jewsbury,
S Pambakian
Frimley Park Hospital NHS Foundation Trust, Surrey, UK
Critical Care 2007, 11(Suppl 2):P162 (doi: 10.1186/cc5322) Introduction This study aimed to establish the prevalence of home
ventilatory and respiratory support within the catchment area of
Frimley Park Hospital in Surrey. The number of patients receiving
respiratory support at home has been increasing nationally since
1990 [1]; however, no local data exist. This trend is likely to
continue as domiciliary ventilation gains popularity for the treatment
of obstructive sleep apnoea and certain groups of COPD patients
[2]. 1. Denys BG, Uretsky BF, Reddy PS: Ultrasound-assisted can-
nulation of the internal jugular vein. A prospective com-
parison to the external landmark-guided technique. Circulation 1993; 87:1557-1562. 2. Randolph AG, Cook DJ, Gonzales CA, Pribble CG: Ultra-
sound guidance for placement of central venous
catheters: a meta-analysis of the literature. Crit Care Med
1996, 24:2053-2058. 2. Randolph AG, Cook DJ, Gonzales CA, Pribble CG: Ultra-
sound guidance for placement of central venous
catheters: a meta-analysis of the literature. Crit Care Med
1996, 24:2053-2058. Method A postal survey was sent out to practice managers in the
local catchment area. They were asked to provide data for: patients
on home ventilatory support for any reason, patients with long-term
tracheostomies, patients with COPD who are on home oxygen or
who you would classify as end stage, and the total number of
patients registered to the practice. This was followed up with a
telephone call approximately 2 weeks later. Many were then e-
mailed the same questionnaire. A further two telephone calls to
each practice were made as necessary in order to obtain data. Results Out of 67 surgeries contacted, we achieved a response
rate of 65%. References References Data presented as the mean ± SE after 120 minutes of isolated lung perfusion. Continuous assessment of inspiratory resistive work during
different types of pulmonary oedema in isolated rat lungs Continuous assessment of inspiratory resistive work during
different types of pulmonary oedema in isolated rat lungs Y Cikirikcioglu, D Morel
University Medical Centre, Geneva, Switzerland
Critical Care 2007, 11(Suppl 2):P161 (doi: 10.1186/cc5321) We recently demonstrated in isolated blood perfused rat lungs
subjected to i.t. LPS-induced pulmonary oedema that the
continuous measurement of inspiratory resistive work is a good
indirect indicator of progressive lung oedema [1]. Here we extend
these findings to two other types of pulmonary oedema: hydrostatic
oedema induced by elevation of the left atrial pressure, and alveolar
oedema (ALV) by infusing normal saline into the trachea at two
different infusion rates (2 and 4 ml/hour for 120 min). Discussion This study suggests that the Frimley Park Hospital
population of 350,000 currently contains about 100 individuals
requiring mechanical respiratory support at home. This is of
concern as currently there is no formal support for any of these
high-risk patients other than ventilator maintenance. Simple
problems precipitate hospital admission and rapidly trigger
outreach or intensive care review. The current position is clearly
unsatisfactory and must be addressed by PCTs if patient numbers
increase. See Table 1. Our results indicate that the continuous measurement
of inspiratory resistive work is a good indicator of both permeability
and hydrostatic lung oedema, but not of pure alveolar oedema
(absence of interstitial oedema). References P163
Intensive care unit patients on mechanical ventilation at a
university hospital in southern Brazil: characteristics,
mortality, frequency, and mortality risk factors pulmonary mechanics, CO2 homeostasis and pulmonary gas
exchanges with less frequent ventilatory settings (tidal volume (TV),
respiratory rate (RR)) and lower peak inspiratory pressure (Ppeak)
and plateau pressure (Pplat) than pressure-controlled synchronised
intermittent mandatory ventilation (P-SIMV) in patients undergoing
laparocopic cholecystectomy (LP). L Fialkow1, R Sens1, L Sehn1, R Cardoso1, A Wolmeister1, A
Milani1, M Bozzetti2, S Vieira1, J Brauner1, A Guntzel1, M
Ficanha1, G Machado1
1Hospital de Clínicas de Porto Alegre, Brazil; 2FAMED-UFRGS,
Porto Alegre, Brazil
Critical Care 2007, 11(Suppl 2):P163 (doi: 10.1186/cc5323) Method The study group consisted of 40 patients (APV-SIMV
n = 20, P-SIMV n = 20). LP was performed under total intravenous
anesthesia. After induction of anesthesia, a RR of 12 breaths/
minute, and an inspiratory:expiratory rate of 1:2 and PEEP of
6 cmH2O were set for both groups. APV-SIMV was started with a
target TV of 8 ml/kg. P-SIMV was started with the inspiratory
pressure (Pins) that will provide 8 ml/kg TV. The settings were
changed until target parameters to maintain normocapnia and
normoxia
were
achieved
(ETCO2
30–35 mmHg,
PaCO2
35–45 mmHg and SaO2 >90%). When the target parameters
could not be achieved, the first RR was increased by 2 breaths/
minute up to 16 breaths/minute, then the volume or pressure was
titrated to induce 1 ml/kg increases in TV up to 10 ml/kg. The initial
FiO2 was set to 50%. FiO2 was increased with increments when
the SaO2 fell below 90%. PaO2/FiO2, static compliance, VD/VT,
Ppeak and Pplat, ETCO2, inspiratory and expiratory resistances, and
arterial blood gas analysis were recorded before, during and after
pneumoperitoneum. Statistical analysis were carried out using the
chi-square test, paired test and independent samples test when
appropriate. Introduction Acute respiratory failure (ARF) is a frequent cause of
admission to ICUs and frequently necessitates mechanical
ventilation (MV). Knowledge about the frequency and risk factors
associated with requirements for MV is crucial to improve
outcomes. The objectives of our study were to determine the
characteristics, frequency of MV, overall and specific mortality
rates and mortality risk factors in patients who required MV in the
ICU of a general university hospital in southern Brazil. Methods A prospective cohort of 751 adult patients admitted to
the ICU who needed MV for at least 24 hours, between March
2004 and July 2006. P163
Intensive care unit patients on mechanical ventilation at a
university hospital in southern Brazil: characteristics,
mortality, frequency, and mortality risk factors Data were collected on each patient at the
inclusion in the study and on a daily basis, during the course of MV
for up to 28 days. Results The frequency of MV was 30%; the overall and specific
mortality rates were 15% and 50%, respectively. The mean (±SD)
age was 57 ± 21 years; 52% were males; the mean APACHE II
score was 22.2 ± 8.2; 69% were medical patients; the mean
duration of MV was 11 ± 7.9 days; 93% were on invasive MV. A
multivariable analysis was performed to identify the variables
associated with death. These included sepsis (P = 0.02), MV
duration (P < 0.001), renal failure (P = 0.006) prior to MV, and the
following variables that occurred during the MV period: sepsis
(P = 0.004), acute lung injury/acute respiratory distress syndrome
(P = 0.001), renal failure (P < 0.001), haematological failure
(P = 0.02) and vasoactive drug use (P < 0.001). It should be noted
that selected ventilatory monitored variables were included in the
multivariate model. However, they were not associated with
mortality in our study sample. Results Demographic data were similar between groups. Pneumoperitoneum caused significant decreases in static
compliance and arterial pH, and increases in Ppeak and Pplat, VD/VT
and ETCO2 in both groups. However, APV-SIMV resulted in fewer
setting changes, lower peak and plateau pressures, VD/VT, and
ETCO2 levels when compared with P-SIMV (P < 0.025). Conclusion
APV-SIMV
may
provide
better
results
then
conventional P-SIMV in patients undergoing LP. Reference 1. Simonds A: Eur Respir J 2003, Suppl 47:38s-46s. 1. Cikirikcioglu Y, Morel D: Eur Respir J 2006, 28:345s. 2. Consensus conference report. Chest 1999, 116:521-534. Table 1 (abstract P161)
Dynamic lung compliance
Weight gain
Inspiratory resistive work
(ml/cmH2O)
(g)
Wet/dry lung weight ratio
(ml x cmH2O)
Control (n = 6)
0.35 ± 0.06
0.54 ± 0.21
6.37 ± 0.35
0.98 ± 0.35
LPS (n = 12)
0.28 ± 0.02
4.63 ± 0.63
8.92 ± 0.21
10.45 ± 1.15
Hydrostatic (n = 7)
0.38 ± 0.06
1.97 ± 0.24
6.46 ± 0.33
1.65 ± 0.54
ALV 2 ml/hour (n = 6)
0.24 ± 0.04
2.66 ± 0.14
10.22 ± 0.60
–1.09 ± 0.54
ALV 4 ml/hour (n = 4)
0.07 ± 0.02
3.74 ± 0.79
9.08 ± 0.94
0.96 ± 1.13
Data presented as the mean ± SE after 120 minutes of isolated lung perfusion. S65 Critical Care March 2007 Vol 11 Suppl 2
27th International Symposium on Intensive Care and Emergency Medicin P165 The influence of cycling-off criteria and pressure support
slope on the respiratory and hemodynamic variables in
intensive care unit patients T Correa, R Passos, S Kanda, C Tanigushi, C Hoelz, J Bastos,
G Janot, E Meyer, C Barbas
Hospital Israelita Albert Einstein, São Paulo, Brazil
Critical Care 2007, 11(Suppl 2):P165 (doi: 10.1186/cc5325) Conclusions Our results indicate a frequency of patients on MV of
30% with an elevated specific mortality rate (50%). Sepsis, MV
duration, renal failure prior to MV, and sepsis, acute lung
injury/acute
respiratory
distress
syndrome,
renal
failure,
haematological failure and vasoactive drug use during the MV
period are risk factors for mortality in 28 days after starting MV. Identification of these factors may allow early interventions to
attempt to mitigate these poor outcomes. Introduction Modern mechanical ventilators allow changes in the
flow cycling-off criteria and the pressure slope during pressure
support ventilation (PSV). Changes in the cycling-off flow criteria of
PSV can modify the expiratory synchrony between the mechanical
and neural inspiration termination. The influences of the slope
changes on the respiratory parameters in ICU patients are still
under investigation. Figure 1 (abstract P166) Figure 1 (abstract P166)
Minute volume/etCO2 relationship. P164 The effects of adaptive pressure ventilation–synchronised
intermittent mandatory ventilation and pressure-controlled
synchronised intermittent mandatory ventilation on
pulmonary mechanics and arterial gas analyses during
laparoscopic cholecystectomy Objectives To compare the effects of two different flow cycling-off
criteria and the effects of two different pressure slopes (150 ms or
300 ms) of PSV on the respiratory parameters of ICU mechanically
ventilated patients. M Akbaba, M Tulunay, O Can, Z Alanoglu, S Yalcin
Ankara University Medical Faculty, Ankara, Turkey
Critical Care 2007, 11(Suppl 2):P164 (doi: 10.1186/cc5324) Methods We prospectively evaluated 20 intubated and mechanically
ventilated adult ICU patients recovering from acute respiratory failure
who could be comfortably ventilated on pressure support mode
(PSV) with pressure support of 15 cmH2O, PEEP of 5 cmH2O and
FIO2 of 40%. Patients were ventilated on PSV, with 25% and 40%
of peak expiratory flow cycling criteria, and were submitted to
150 ms and 300 ms pressure slope delay. We evaluated the
respiratory rate, expiratory tidal volume, minute ventilation, VCO2,
VTCO2, ETCO2, mean arterial pressure (MAP), heart rate and SpO2. Background Hypercapnia and elevated intraabdominal pressure
from carbon dioxide (CO2) pneumoperitoneum can adversely
affect respiratory mechanics and arterial blood gases. We tested
the hypothesis that adaptive pressure ventilation–synchronised
intermittent mandatory ventilation (APV-SIMV) may provide better S66 Available online http://ccforum.com/supplements/11/S2 Table 1 (abstract P165) Respiratory
Tidal
Minute volume
Slope
Heart rate
SpO2
Cycling-off (%)
rate
volume (ml)
(l/min)
VCO2
VTCO2
ETCO2
MAP
0.15
83.4
98.8
25
18.2
587.5
10.6
193.6
11.2
27.8
96.4
0.15
83.9
98.8
40
19.2
560.7
10.0
183.7
10.88
28
96.2
0.30
83.6
98.7
25
19.4
588.4
10.5
192.8
11.54
28
98.2
0.30
83.6
98.9
40
19.7
565.2
10.2
187.8
10.61
28.2
97.7 Figure 2 (abstract P166)
Parametric fit of etCO2 data. Figure 2 (abstract P166)
Parametric fit of etCO2 data. Figure 2 (abstract P166) Results Comparisons between different slope and cycling-off
values did not result in any statistically significant changes for the
evaluated variables (Table 1). Conclusion Changes in cycling-off criteria from 25% to 40% of
the peak flow and on the pressure slope from 150 ms to 300 ms
do not affect other respiratory and hemodynamic variables in
mechanically ventilated patients. P167 The impact of noninvasive versus invasive mechanical
ventilatory support on survival in hematological patients
with acute respiratory failure AUTOPILOT-BT: an approach towards automatic
mechanical ventilation AUTOPILOT-BT: an approach towards automatic
mechanical ventilation AUTOPILOT-BT: an approach towards automatic
mechanical ventilation S Lozano1, K Moeller1, C Stahl2, J Guttmann2
1Furtwangen University, Villingen-Schwenningen, Germany;
2University of Freiburg, Germany
Critical Care 2007, 11(Suppl 2):P166 (doi: 10.1186/cc5326) Parametric fit of etCO2 data. Introduction The clinical use of ventilators is limited due to a huge
variety of different ventilation methods. The clinician – often under
high cognitive load from the complicated technical equipment on an
ICU – just uses a small subset of available parameter settings. The
aim of the present study was to develop a closed-loop ventilation
controller based on mathematical models and fuzzy logic. evaluating, for example, the etCO2 data. The course of etCO2
following the setting of optimal frequency was evaluated to
calculate the time required for equilibration of etCO2. Results A module automating the initial settings of the ventilator
according to local ICU rules is realized. Modules were added that
optimize breathing frequency with respect to PaCO2/etCO2 and
FiO2 according to SO2 whenever no PaO2 is available. A lung
simulator (Michigan Instruments Inc., Grand Rapids, MI, USA)
connected with the LS4000 (Dräger Medical) was used to
evaluate the system. Exemplary results are presented in the figures,
which show the minute volume/etCO2 relationship (Figure 1) and a
parametric fit of etCO2 data (Figure 2). The adjustment of the
frequency is based on the current etCO2 model. Methods The system was designed to track a desired end-tidal
CO2 pressure (PaCO2), to find a PEEP leading to maximum
estimated respiratory system compliance and to maintain the
arterial oxygen saturation (SaO2) at an optimal level. We developed
a program in LabView (National Instruments, Austin, TX, USA) on a
laptop that is able to read the internal data of a ventilator (Evita 4;
Dräger Medical, Germany) in real time. Respiratory signals (for
example, SaO2) are acquired from monitoring. Discrete measure-
ments (for example, PaO2) are either assumed constant until next
measurement or are interpolated using a model-based approach Conclusion Automation is a ‘sine qua non’ to achieve optimal
patient individualized ventilation support. Our system is enabled to
evaluate a therapeutic strategy and to base the settings of the
ventilator on current trends/drifts observed in the data. The impact of noninvasive versus invasive mechanical
ventilatory support on survival in hematological patients
with acute respiratory failure P168
Physiological variables predictive of survival in patients
with acute type II respiratory failure on noninvasive
ventilation
N Salahuddin, M Naeem, S Khan
Aga Khan University & Hospital, Karachi, Pakistan
Critical Care 2007, 11(Suppl 2):P168 (doi: 10.1186/cc5328)
Introduction There are very few data available from the Indian
subcontinent regarding the use of noninvasive ventilation (NIV). We
carried out this study to determine variables that could be used in
the emergency room to predict survival in patients placed on NIV. Methods This was a prospective
observational cohort study
statistically
significant
difference
between
the
baseline
characteristics of the groups that survived or died. The overall
survival rate for patients placed on NIV was 76.5%, the intubation
rate was 12.6% and the length of hospitalization was 11.4 days
(±10.9). Statistically significant improvements in pH and PaCO2
occurred at 24 hours and 48 hours of NIV usage compared with
Figure 1 (abstract P167)
Figure 1 (abstract P168)
Figure 2 (abstract P168) Figure 1 (abstract P167)
Figure 1 (abstract P168) Figure 1 (abstract P168) Figure 1 (abstract P167) Figure 1 (abstract P168) Figure 1 (abstract P167) Figure 1 (abstract P167) Figure 2 (abstract P168) Figure 2 (abstract P168) 62.5%, respectively (P = 0.99), but SAPS II at ICU admission was
lower in NIPPV patients (45 ± 15 vs 60 ± 18, P < 0.001). NIPPV
was the sole mode of ventilation in 15 patients and was followed
by IPPV in 41 patients (NIPPV–IPPV). ICU mortality in sole NIPPV
patients was 35% compared with 76% in NIPPV–IPPV patients. In
a multivariable analysis, the ICU mortality of ventilated patients was
associated with SAPS II at admission (OR 1.029, CI 1.009–1.048,
P = 0.003), NIPPV–IPPV (OR 2.73, CI 1.1–6.8, P = 0.03), and
bacterial infection (OR 0.39; CI 0.21–0.73, P = 0.003). The mean
change of SOFA between day 1 and day 5 was 0 (±2.6) in NIPPV
patients (n = 33) compared with –1.6 (±4.3) in IPPV patients
(n = 87) (P = 0.001) surviving beyond 5 days of ICU admission
(Figure 1). Conclusion NIPPV was not associated with better outcome in our
population of hematological patients with acute respiratory failure. NIPPV followed by IPPV was an independent predictor of mortality. P168 Physiological variables predictive of survival in patients
with acute type II respiratory failure on noninvasive
ventilation N Salahuddin, M Naeem, S Khan
Aga Khan University & Hospital, Karachi, Pakistan
Critical Care 2007, 11(Suppl 2):P168 (doi: 10.1186/cc5328) N Salahuddin, M Naeem, S Khan
Aga Khan University & Hospital, Karachi, Pakistan
Critical Care 2007, 11(Suppl 2):P168 (doi: 10.1186/cc5328) statistically
significant
difference
between
the
baseline
characteristics of the groups that survived or died. The overall
survival rate for patients placed on NIV was 76.5%, the intubation
rate was 12.6% and the length of hospitalization was 11.4 days
(±10.9). Statistically significant improvements in pH and PaCO2
occurred at 24 hours and 48 hours of NIV usage, compared with
baseline (7.28 vs 7.37, P < 0.001; 74.2 vs 65.4, P = 0.003)
(Figures 1 and 2). There was no significant change in PaO2. The
variables
predicting
survival
were
age
(62.1 ± 12.5 years,
67.8 ± 8.7 years, P = 0.025), serum creatinine (1.1 ± 0.5 mg/dl,
1.7 ± 0.8 mg/dl,
P = 0.002),
pH
at
baseline
(7.31 ± 0.09,
7.25 ± 0.9, P = 0.005), HCO3 at baseline (36.1 ± 7.5 mEq/l,
32.4 ± 9.3 mEq/l, P = 0.032), pH at 48 hours (7.39 ± 0.07, 7.33
± 0.06, P = 0.002), and need for endotracheal intubation (10%,
21%, P < 0.05). Introduction There are very few data available from the Indian
subcontinent regarding the use of noninvasive ventilation (NIV). We
carried out this study to determine variables that could be used in
the emergency room to predict survival in patients placed on NIV. Methods This was a prospective, observational cohort study
carried out from 2001 to 2005 on all patients presenting with
acute type II respiratory failure and meeting criteria for NIV use. NIV
was started in the emergency room at settings that were titrated
according to arterial blood gases. Univariate and multivariate
regression analysis was used to determine the effect on survival. P < 0.05 was considered statistically significant. The software
used was SPSS 11. Results The total number of patients enrolled was 119; 52.9%
were males, 47.1% were females. The mean age was 63.3 years
(±11.9). The most common cause of respiratory failure was COPD
in 91.6%. A total of 56.3% patients were stuporus at presentation,
and 7.5% fulfilled criteria for severe sepsis. There was no Conclusion NIV improves outcomes in our setting. The impact of noninvasive versus invasive mechanical
ventilatory support on survival in hematological patients
with acute respiratory failure P Depuydt, D Benoit, C Roosens, O Fritz, L Noens, J Decruyenaere
Ghent University Hospital, Ghent, Belgium
Critical Care 2007, 11(Suppl 2):P167 (doi: 10.1186/cc5327) Objective To assess the impact on ICU survival of noninvasive
(NIPPV) versus invasive mechanical ventilation (IPPV) as the initial
ventilatory mode in hematological patients with acute respiratory
failure. Design A retrospective evaluation of a prospectively followed
cohort of 277 hematological patients ventilated at the ICU of a
tertiary care hospital between January 1997 and June 2006. Design A retrospective evaluation of a prospectively followed
cohort of 277 hematological patients ventilated at the ICU of a
tertiary care hospital between January 1997 and June 2006. Results NIPPV was the initial ventilatory mode in 56 patients. ICU
mortality in patients with initial NIPPV versus IPPV was 62.9% and Minute volume/etCO2 relationship. Results NIPPV was the initial ventilatory mode in 56 patients. ICU
mortality in patients with initial NIPPV versus IPPV was 62.9% and S67 Critical Care March 2007 Vol 11 Suppl 2
27th International Symposium on Intensive Care and Emergency Medicine Figure 1 (abstract P168)
Figure 2 (abstract P168) 62.5%, respectively (P = 0.99), but SAPS II at ICU admission was
lower in NIPPV patients (45 ± 15 vs 60 ± 18, P < 0.001). NIPPV
was the sole mode of ventilation in 15 patients and was followed
by IPPV in 41 patients (NIPPV–IPPV). ICU mortality in sole NIPPV
patients was 35% compared with 76% in NIPPV–IPPV patients. In
a multivariable analysis, the ICU mortality of ventilated patients was
associated with SAPS II at admission (OR 1.029, CI 1.009–1.048,
P = 0.003), NIPPV–IPPV (OR 2.73, CI 1.1–6.8, P = 0.03), and
bacterial infection (OR 0.39; CI 0.21–0.73, P = 0.003). The mean
change of SOFA between day 1 and day 5 was 0 (±2.6) in NIPPV
patients (n = 33) compared with –1.6 (±4.3) in IPPV patients
(n = 87) (P = 0.001) surviving beyond 5 days of ICU admission
(Figure 1). Conclusion NIPPV was not associated with better outcome in our
population of hematological patients with acute respiratory failure. NIPPV followed by IPPV was an independent predictor of mortality. P170 Methods This was a blinded, observational cohort trial that was
approved by the Henry Ford Hospital Institutional Review Board. Henry Ford Hospital is an urban, tertiary institution in Detroit,
Michigan with an emergency department census of 95,000 patient
visits per year. Inclusion criteria: patients > 18 years of age triaged
to Cat 1 with acute respiratory distress and for whom the decision
to intubate, use NIV or discharge the patient had not been
decided. Exclusion criteria: immediate intubation, NIV, or discharge
from Cat 1. Baseline demographics and vital signs were collected
prior to the initiation of the trial (Figure 1). The CO2SMO Plus! with
the ETCO2/flow sensor was used for obtaining bedside
measurements. Patients would breathe through the ETCO2/flow
sensor for 60 seconds with nose clips. Is threshold useful in accelerating weaning from
mechanical ventilation? S Vieira1, R Condessa1, J Brauner1, A Saul1, A Silva1, M Silva1,
L Borges2, M Moura1, M Alves1, F Kutchak1, L Biz1, C Dieterich1
1Hospital de Clínicas de Porto Alegre, Brazil; 2Hospital Moinhos de
Vento, Porto Alegre, Brazil
Critical Care 2007, 11(Suppl 2):P170 (doi: 10.1186/cc5330) Introduction Threshold can be used as a physiotherapic tool in
order to increase muscle strength, and this effect can be useful in
weaning patients. However, there are still controversies considering
its advantages during weaning from mechanical ventilation (MV). The goal of this study is to evaluate its effects in such a situation. Results The threshold value for RSBI that discriminated best
between no NIV and the need for NIV was determined in 61
patients. Thirty-five patients who did not require ventilatory support
had a mean RSBI of 105, and 26 patients with NIV had a mean
RSBI of 222 (P = 0.0001). A receiver-operating-characteristic
curve was constructed based upon the dataset in increments of 10
for the RSBI (Figure 2). An RSBI > 120 yielded a sensitivity of
0.81 and a specificity of 0.74 for determining the need for NIV. A
likelihood ratio positive (LR+) of 3.14 further illustrates the
formidable predictive value of the 120 RSBI. Methods Patients under MV for more than 48 hours and prone to
weaning were studied. They were randomized to the control group
or to the threshold group and followed daily until extubation,
tracheostomy or death. The threshold group was trained twice
daily. All cardiorespiratory variables, maximal inspiratory (PImax)
and expiratory (PEmax) pressures were registered twice daily
during the observation period. P169 P169 Rapid shallow breathing index – a key predictor for
noninvasive ventilation Rapid shallow breathing index – a key predictor for
noninvasive ventilation Rapid shallow breathing index – a key predictor for
noninvasive ventilation J Crawford1, R Otero1, M Donnino2, J Garcia1, R Khazal1, T Lenoir1
1Henry Ford Hospital, Detroit, MI, USA; 2Beth Israel Deaconess
Medical Center, Boston, MA, USA
Critical Care 2007, 11(Suppl 2):P169 (doi: 10.1186/cc5329) Introduction The rapid shallow breathing index (RSBI) is the ratio
determined by the frequency (f) divided by the tidal volume (VT). An RSBI <105 has been widely accepted by healthcare
professionals as a criteria for weaning to extubation and has been
integrated into most mechanical ventilation weaning protocols. We
hypothesized that the converse of using the RSBI for weaning
might be useful in predicting the need for noninvasive ventilation. Advancements in technology have made it easier to accurately
attain bedside RSBI measurements. The purpose of this study was
to ascertain a threshold value of RSBI that could predict the need
for noninvasive ventilation (NIV) in patients presenting with acute
respiratory distress to the critical care area (Cat 1) in the
emergency department. Conclusion A RSBI of 120 or greater, as reflected by f/VT ratio,
may be a predictor of when NIV support should be considered. Further prospective randomized studies are needed to validate the
value of 120. Conclusion A RSBI of 120 or greater, as reflected by f/VT ratio,
may be a predictor of when NIV support should be considered. Further prospective randomized studies are needed to validate the
value of 120. P170 The length of weaning and success
or failure were registered. Variables were compared by analysis of
variance, Mann–Whitney U test and the chi-square test. Results
are shown as the median, mean and standard deviation or as
percentages. The significance level was P < 0.05. P168 Physiological
variables and the need for intubation can predict an improved
survival in these patients. S68 Available online http://ccforum.com/supplements/11/S2 Conclusion A RSBI of 120 or greater, as reflected by f/VT ratio,
may be a predictor of when NIV support should be considered. Further prospective randomized studies are needed to validate the
value of 120
Figure 2 (abstract P169) Figure 2 (abstract P169) Application of treatment bundles reduces days on
mechanical ventilation in critically ill patients Methods A total of 104 patients who had been ventilated for more
than 48 hours in the postoperative period from October 2005 to
October 2006 were enrolled in the study. After fulfilling the
weaning checklist they were randomly assigned into two groups:
SIMV+PSV group (n = 53), and ITSB group (n = 51). In patients
assigned to the SIMV+PSV group, the ventilator rate was initially
set at 6–8 breaths/minute plus PSV of 15 cmH2O and then both
reduced, if possible, by 2 breaths/minute and 2 cmH2O each time. Patients able to maintain adequate ventilation with SIMV of
2 breaths/minute and PSV of 5 cmH2O for at least 2 hours without
signs of distress were extubated. Patients assigned to the ITSB
group were disconnected from the ventilator and allowed to
breathe spontaneously through a T-tube circuit. The duration of the
trials was gradually increased. Between the trials, assist–control
ventilation was provided for at least 1 hour. Patients able to
breathe on their own for at least 2 hours without signs of distress
were extubated. F Bloos1, S Müller1, A Harz1, M Gugel1, D Geil1, K Reinhart2,
G Marx2
1University Hospital Jena, Germany; 2Friedrich-Schiller University
Jena, Germany
Critical Care 2007, 11(Suppl 2):P171 (doi: 10.1186/cc5331) F Bloos1, S Müller1, A Harz1, M Gugel1, D Geil1, K Reinhart2,
G Marx2 Background Reduction of time on the ventilator is a key concept
to avoid complications. Recommendations include semirecumbent
positioning (SRP) [1], low tidal volume ventilation (TV = 6 ml/kg)
[2], prophylaxis for stress ulcer (SUP) [3], and deep vein
thrombosis (DVTP) [4]. The goal of this study was to investigate
whether staff training about these treatments decreases days on
ventilation. Methods All patients of a 50-bed ICU with mechanical ventilation
>24 hours were included. From June 2005 to September 2005
(Audit I), patients were examined daily for SRP >30°, low tidal
volume ventilation, DVTP, and SUP by an independent task force. Afterwards, nurses and physicians were trained for the monitored
treatments. Audit II was then performed from March 2006 to June
2006. Results Until the first attempt was made for weaning, all patients
received assist–control ventilation because of haemodynamic
instability. The following underlying conditions were present:
chronic
obstructive
pulmonary
disease
in
67
patients,
neuromuscular disorders in nine patients, acute lung injury as a
result of surgery in 14 patients, asthma in six patients and
miscellaneous causes in eight patients. P173 3
Predicting successful weaning in a cohort of elderly
patients
C Corbellini, A Guntzel, C Trevisan, S Vieira
Hospital de Clinicas de Porto Alegre, Brazil
Critical Care 2007, 11(Suppl 2):P173 (doi: 10.1186/cc5333) Predicting successful weaning in a cohort of elderly
patients Conclusion SRP could be successfully improved by staff training. Enhanced implementation was associated with reduction in days
on ventilation. C Corbellini, A Guntzel, C Trevisan, S Vieira
Hospital de Clinicas de Porto Alegre, Brazil
Critical Care 2007, 11(Suppl 2):P173 (doi: 10.1186/cc5333) References
1. Drakulovic MB: Lancet 1999, 354:1851. 2. Amato MB: N Engl J Med 1998, 338:347. 3. Cash BD: Crit Care Med 2002, 30:S373. 4. Samama MM: N Engl J Med 1999, 341:793. 1. Drakulovic MB: Lancet 1999, 354:1851. 1. Drakulovic MB: Lancet 1999, 354:1851. 1. Drakulovic MB: Lancet 1999, 354:1851. 2. Amato MB: N Engl J Med 1998, 338:347. 3. Cash BD: Crit Care Med 2002, 30:S373. 4. Samama MM: N Engl J Med 1999, 341:793. 2. Amato MB: N Engl J Med 1998, 338:347. Introduction Aging causes structural and functional modifications
in the respiratory system. The evidence that these changes could
impair weaning in elderly patients, until now, was not clear. We
designed a protocol to study possible differences between an
adult group (AG, up to 60 years) and an elderly group (EG, >60
years) in a daily screening trial. g
3. Cash BD: Crit Care Med 2002, 30:S373. 4. Samama MM: N Engl J Med 1999, 341:793. Figure 1 (abstract P169) Figure 1 (abstract P169) Figure 1 (abstract P169) Results Sixty patients were studied (52% men, mean age
64 ± 17 years, 18% with chronic obstructive pulmonary disease in
threshold group vs 15% in control group). Comparing initial versus
final cardiorespiratory variables in both groups, no important
differences were observed with exception of PImax (increased from
–33.5 ± 14.4 to –40.2 ± 13.4 cmH2O in threshold group and
changed from –37.1 ± 9.8 to –34.4 ± 9.6 cmH2O in control
group, P < 0.05) and PEmax (increased from 24.7 ± 12.7 to
29.4 ± 12.1 cmH2O in threshold group and changed from
30.9 ± 13.5 to 27.1 ± 9.4 cmH2O in control group, P < 0.05). No
reduction was observed in the length of weaning (1.87 days with
threshold versus 1.98 days in control group, P > 0.05). There was
no difference concerning weaning success (73.5% with threshold
versus 61.5% in control group, P > 0.05). Conclusions Threshold during weaning from MV can cause an
increase in both PImax and PEmax but, at least in these preliminary
results, it was not associated with a decrease in length of weaning
or an increase in weaning success. Conclusions Threshold during weaning from MV can cause an
increase in both PImax and PEmax but, at least in these preliminary
results, it was not associated with a decrease in length of weaning
or an increase in weaning success. S69 Critical Care March 2007 Vol 11 Suppl 2
27th International Symposium on Intensive Care and Emergency Medicin P171 (ITSB) using a T-tube as two methods of weaning in a surgical
ICU. Application of treatment bundles reduces days on
mechanical ventilation in critically ill patients The duration of mechanical
ventilation before weaning was 2.5 ± 0.5 days in the SIMV+PSV
group vs 2.4 ± 0.4 days in the ITSB group (P = 0.02) and the
duration of weaning was 6.2 ± 0.23 hours vs 8.3 ± 0.44 hours in
the two groups, respectively (P < 0.01). Patients who remained
extubated for 48 hours were classified as having successful
extubation – the rate of successful extubation in the first 24 hours
of starting weaning was higher for the SIMV group (79.2%) than in
the ITSB group (64.7%, P < 0.01). The total duration of
mechanical ventilation was 3.3 ± 0.3 days vs 5.2 ± 1.1 days and
the ICU length of stay was 5.6 ± 1 days vs 7.5 ± 1.7 days in the
two groups, respectively (P < 0.01). Results One hundred and thirty-three patients (1,389 ventilator-
days) were included in Audit I, 141 patients (1,002 ventilator-days)
in Audit II. Data are expressed as the median (interquartile range)
or percentage of implementation per ventilator-days (Table 1). On
average, low tidal volume ventilation was adopted. DVTP and SUP
were well implemented without training. There was no effect on
frequency of pneumonia, ICU length of stay, or survival. Table 1 (abstract P171)
Audit I
Audit II
P
APACHE II
24 (10)
25 (11)
0.387
SRP (%)
24.9
49.6
<0.001
TV (ml/kg)
6.3 (2.2)
6.4 (2.3)
0.154
DVTP (%)
89.5
91.9
0.048
SUP (%)
94.5
94.9
0.712
Days on ventilation
6.0 (13)
4.0 (7)
0.017 Conclusions The use of SIMV+PSV as a weaning method in the
surgical ICU lead to shorter duration of weaning, a higher rate of
successful extubation, a shorter duration of mechanical ventilation
and less ICU stay than the use of ITSB. P174 Heart rate variability during weaning from mechanical
ventilation
A Guntzel, S Vieira, E Ferlim, R Moraes
Hospital de Clínicas de Porto Alegre, Brazil
Critical Care 2007, 11(Suppl 2):P174 (doi: 10.1186/cc5334) Introduction Acute illness adversely affects a patient’s circadian
rhythms. Minimising the delayed restoration of these rhythms may
have patient benefits. The aims of this study were to investigate the
acute effects of exogenous melatonin on the rest–activity rhythms
of patients recovering from critical illness, and furthermore to
analyse the rhythms and relationship between plasma melatonin
and cortisol levels. Heart rate variability during weaning from mechanical
ventilation A Guntzel, S Vieira, E Ferlim, R Moraes
Hospital de Clínicas de Porto Alegre, Brazil
Critical Care 2007, 11(Suppl 2):P174 (doi: 10.1186/cc5334) Introduction Weaning from mechanical ventilation (MV) can be
associated with cardiovascular changes including elevation of
heart rate (HR) and development of arrhythmias. The behavior is
not yet known of HR variability during weaning from MV comparing
pressure support ventilation (PSV) and the T-tube (TT) in patients
with and without heart disease. The aim of this study was to
evaluate the impact on heart rate variability (HRV) in these groups
of patients during PSV and TT. Methods A randomised controlled trial in 24 critically ill patients
weaning from mechanical ventilation. Ethics committee approval
was granted and all patients provided written consent. Twelve
patients in each group received placebo or 10 mg exogenous
melatonin at 21:00 hours for four nights. Twelve plasma samples
were taken periodically from the first 18 of these patients over a
24-hour period. Actigraphy was used to monitor patient activity. Rhythm analysis of plasma levels and activity data used single
cosinor analysis and nonparametric parameters, respectively. Methods Patients with (group 1, n = 8) and without (group 2,
n = 22) heart disease, under MV for at least 48 hours, were
observed during 30 minutes of PSV or TT, in a random order. Variables analyzed were: APACHE score, length of stay in the ICU
(LOS), and cardiorespiratory variables including the HR,
respiratory rate (RR), rapid shallow breathing index (f/VT),
maximum inspiratory (PImax) and expiratory (PEmax) pressure. Continuous ECG was recorded by the Holter method. The data of
HRV were accomplished by analysis of the frequency domain. For
statistical analyses, analysis of variance and t test were used. The
level of significance was P < 0.05. Results Both groups were well matched. P172 Comparative study of two methods of weaning from
mechanical ventilation in a cancer surgical intensive care unit Comparative study of two methods of weaning from
mechanical ventilation in a cancer surgical intensive care unit Methods One hundred and forty-four patients (79 EG and 65 AG)
were studied. The primary outcome was weaning success (48
hours of spontaneous ventilation after extubation). The secondary
outcome was differences in the conventional weaning predictors. Parameters studied included: respiratory rate (f), tidal volume (VT),
frequency–tidal volume ratio (f/VT), gasometric and ventilatory
parameters. The weaning method was a spontaneous breathing
trial. Measurements were performed twice: just before the
spontaneous breathing trial (T1) and 30 minutes after (T2). The W Salem1, N Fahmy2
1National Cancer Institute, Cairo, Egypt; 2Faculty of Medicine, Ain
Shams University, Cairo, Egypt
Critical Care 2007, 11(Suppl 2):P172 (doi: 10.1186/cc5332) W Salem1, N Fahmy2
1National Cancer Institute, Cairo, Egypt; 2Faculty of Medicine, Ain
Shams University, Cairo, Egypt
Critical Care 2007, 11(Suppl 2):P172 (doi: 10.1186/cc5332) W Salem1, N Fahmy2
1National Cancer Institute, Cairo, Egypt; 2Faculty of Medicine, Ain
Shams University, Cairo, Egypt
Critical Care 2007, 11(Suppl 2):P172 (doi: 10.1186/cc5332) Introduction The aim of the study was to compare the combination
of intermittent mandatory ventilation plus pressure-support ventila-
tion (SIMV+PSV) with intermittent trials of spontaneous breathing S70 Available online http://ccforum.com/supplements/11/S2 Table 1 (abstract P173)
Weaning criteria
T1 AG (n = 65)
T2 AG (n = 65)
T1 EG (n = 79)
T2 EG (n = 79)
f (breaths/min)
22 ± 59*
22 ± 5.2*
24 ± 5.5*
24 ± 5.4*
VT (ml)
560 ± 200*
550 ± 180*
470 ± 170*
480 ± 150*
f/VT
47 ± 24*
46 ± 19*
59 ± 28*
56 ± 24*
*P < 0.05 comparing AG and EG. chi-square test, analysis of variance and t test were used in the
analysis. Conclusion During weaning from MV, cardiac patients showed
higher RR and higher f/VT during TT when compared with PSV. Furthermore, there were significant changes in the RR and HR
intervals in TT. However, we did not find significant changes
comparing HRV in groups, perhaps because the frequency domain
analysis had low power to verify those changes. chi-square test, analysis of variance and t test were used in the
analysis. Results Weaning success was 86% both in EG and AG
(P = 0.989). There were no differences in gasometric and in
ventilatory parameters between groups. Assessment of melatonin, cortisol and rest–activity rhythms
in critically ill patients weaning from mechanical ventilation R Bourne
Sheffield Teaching Hospitals, Sheffield, UK
Critical Care 2007, 11(Suppl 2):P175 (doi: 10.1186/cc5335) P172 Comparisons in TI and T2
in AG and EG are presented in Table 1. Sensitivities of f/VT in
T1/T2 were: for EG, 94 (86–98)/96 (89–98); for AG, 95
(86–99)/100 (94.8–100). P175 Conclusion The weaning success in our study is similar to that
described in other trials. Older patients showed differences in f, VT
and f/VT when compared with adults. However, there were no
differences in weaning success. P174 There were no significant
differences between the groups in any of the rest–activity
measures, which were abnormal and comparable with those
previously reported [1]. There was a weak inverse correlation
between plasma melatonin and cortisol levels (r = –0.22,
P = 0.015). Seven of 18 patients had a circadian rhythm of plasma
cortisol levels, while only two patients had a normal acrophase. Four
of the nine placebo patients had a circadian rhythm of melatonin,
but only one of these had a normal amplitude and acrophase. The
plasma melatonin 24-hour area under the curve was significantly
reduced compared with healthy elderly people (128.4 (112.6;
217.0) versus 464.5 (372.5; 594.0), P < 0.001). A moderate
inverse relationship existed between the percentage plasma cortisol
rhythm and patient intradaily variability (r = –0.70, P < 0.002). Results Values for the APACHE score, LOS, PImax and PEmax
did not show significant differences comparing groups. The RR
was significantly higher during TT than during PSV in group 1
(25 ± 6; 20 ± 4; P < 0.01), but similar in group 2 (22 ± 5; 22 ± 5;
not significant (NS)). f/VT was significantly higher during TT in
relationship to PSV in group 1 (65 ± 35; 39 ± 17; P < 0.01), but
similar in group 2 (49 ± 19; 49 ± 22; NS). Changes in the RR
interval comparing PSV and TT were significantly different in the
entire group (0.48 ± 55; –30 ± 72; P = 0.02) as well as changes
in the HR interval (–0.3 ± 8; 8 ± 12; P < 0.001). Changes in HRV
by frequency domain were not significantly different comparing
groups 1 and 2 in PSV and TT. The high frequency was in PSV
(4 ± 21; 0.4 ± 11; NS), and in TT (–0.64 ± 12; 1 ± 12; NS). The
low frequency was in PSV (–11 ± 22; 3 ± 14; NS), and in TT
(–6 ± 17; 1.8 ± 19; NS). Conclusions Acute administration of exogenous melatonin did not
result in significant differences in rest–activity rhythms between the
groups. Most patients lacked circadian rhythms of plasma
melatonin and cortisol levels, which were no longer phase locked. The amplitude of plasma melatonin levels are significantly
suppressed. 1.
Vinzio S, Ruellan A, Perrin AE, et al.: Actigraphic assess-
ment of the circadian rest-activity rhythm in elderly
patients hospitalized in an acute care unit. Psychiatry Clin
Neurosci 2003, 57:53-58. Evaluation of patient parameters that predict success
using the SmartCare weaning system P Jackson, G Mills
Royal Hallamshire Hospital, Sheffield, UK
Critical Care 2007, 11(Suppl 2):P176 (doi: 10.1186/cc5336) Introduction Our aim was to assess the success of the SmartCare
(SC) weaning system, to see what associated factors made a
successful wean more likely. SC is a knowledge-based weaning
system integrated into the Dräger EvitaXL ventilator, designed to
optimise the ventilator settings during weaning so that patients can
be weaned as quickly as possible. Methods The first 100 consecutive general ICU patients where
SC weaning had been attempted were identified. Patient age, sex,
APACHE score, diagnosis, worst FiO2 prior to weaning, duration
of ventilation prior to weaning, duration of weaning attempt, need
for tracheostomy and duration of stay were collected. The patients
were then subdivided into unsuccessful and successful weaning
attempts based upon whether they required subsequent ventilatory
support during the first 48 hours after their weaning ended. The
two groups were then analysed to identify the characteristics of the
patients where a successful SC wean was achieved. applied to admissions during the 3 years since introduction to
estimate the cumulative excess mortality (observed minus expected
deaths). Results After excluding patients whose weaning was interrupted
by transfer or a decision to withdraw treatment, we had 89
weaning attempts to analyse. These represented 43 successful (S)
and 46 unsuccessful (US) weans. Comparison of mean ± SD ages
(S 61 ± 14.3 years, US 57.3 ± 16.1 years, P = 0.28) and
APACHE scores (S 16.2 ± 4.9, US 17.7 ± 6.5, P = 0.23) for the
two groups showed no major differences. Logistic regression
demonstrated that the worst FiO2 prior to weaning and the
duration of ventilation prior to weaning were both significantly
associated with an unsuccessful SC weaning attempt (P = 0.002
and P = 0.005, respectively). ROC curve analysis suggested patients
with an FiO2 below 0.47 and a duration of ventilation prior to
weaning of below 43 hours were more likely to be successfully
weaned. Results There were 762 ventilated admissions prior to the
introduction of the bundle and 618 since. The cumulative excess
mortality plot suggested a reduction in mortality after introduction
of the bundle (Figure 1) but this was not statistically significant
(relative risk reduction 10.9%, 95% confidence interval –10.2% to
31.8%). Reference 1. Vinzio S, Ruellan A, Perrin AE, et al.: Actigraphic assess-
ment of the circadian rest-activity rhythm in elderly
patients hospitalized in an acute care unit. Psychiatry Clin
Neurosci 2003, 57:53-58. 1. Vinzio S, Ruellan A, Perrin AE, et al.: Actigraphic assess-
ment of the circadian rest-activity rhythm in elderly
patients hospitalized in an acute care unit. Psychiatry Clin
Neurosci 2003, 57:53-58. S71 Care March 2007 Vol 11 Suppl 2
27th International Symposium on Intensive Care and Emergency Medicine Figure 1 (abstract P177) Figure 1 (abstract P177) Figure 1 (abstract P177) P178 Hemodynamic changes due to expiratory positive airway
pressure by facial mask in the postoperative period of
cardiac surgery Conclusions SC proved most successful in those patients who
had a lower worst FiO2 prior to weaning and a lower duration of
ventilation prior to commencing weaning. S Vieira1, A Sena2, S Pinto-Ribeiro1
1Hospital de Clínicas de Porto Alegre, Brazil; 2Santa Casa de
Misericórdia de Porto Alegre, Brazil
Critical Care 2007, 11(Suppl 2):P178 (doi: 10.1186/cc5338) Evaluation of patient parameters that predict success
using the SmartCare weaning system Interpretation The results suggest that it will be beneficial to carry
out a multicentre evaluation of the ventilator bundle in Case Mix
Programme units, and will inform the design of this study. P179 Methods We conducted a retrospective audit of consecutive
patients receiving APRV from January 2004 to August 2006 in
three academic ICUs in Toronto. APRV was initiated at the
discretion of the attending physician; a protocol guiding the
implementation of APRV was introduced in July 2006. We
recorded data describing: baseline characteristics; how APRV was
used; its potential ramifications including oxygenation and
sedation/analgesia doses; and outcomes. Predicting successful nasal continuous positive airway
pressure treatment in newborn infants: a multivariate
analysis J Swietlinski1, T Bachman2, K Bober3, E Gajewska4,
E Helwich5, R Lauterbach6, M Manowska1, B Maruszewski1,
J Szczapa7, L Hubicki3, on behalf of the Polish Study Group
(NRSP)
1The Children’s Memorial Health Institute, Warsaw, Poland;
2California State University, San Bernardino, CA, USA; 3Medical
University of Silesia, Katowice, Poland; 4Medical University,
Wrocùaw, Poland; 5National Research Institute of Mother & Child,
Warsaw, Poland; 6Medical College Jagiellonian University, Kraków,
Poland; 7University of Medical Sciences, Poznan, Poland
Critical Care 2007, 11(Suppl 2):P179 (doi: 10.1186/cc5339) J Swietlinski1, T Bachman2, K Bober3, E Gajewska4,
E Helwich5, R Lauterbach6, M Manowska1, B Maruszewski1,
J Szczapa7, L Hubicki3, on behalf of the Polish Study Group
(NRSP) J Swietlinski1, T Bachman2, K Bober3, E Gajewska4,
E Helwich5, R Lauterbach6, M Manowska1, B Maruszewski1,
J Szczapa7, L Hubicki3, on behalf of the Polish Study Group
(NRSP) g
;
Results Thirty patients, all with ALI/ARDS, received 39 trials of
APRV during the study period – median age 52 years, 60% male,
50% pulmonary ALI risk factor, median APACHE II score 28. They
had ALI for a median of 4.5 days with a median 135 hours of CMV
before APRV. They received a median of 38 hours APRV. By 12
hours, oxygenation improved significantly (P/F ratio from 103 to
159, P < 0.01), with a concomitant decrease in FiO2 requirements
(from 0.70 to 0.50, P < 0.0006). At 72 hours, the median P/F ratio
had improved to 196 on a median FiO2 of 0.40 (both P < 0.01). Administration and dosages of sedatives (midazolam equivalents,
propofol) and analgesics (morphine equivalents) did not change
significantly over the period from 24 hours before to 24 hours after
APRV initiation. There were two episodes of barotrauma during
APRV; neither required therapeutic drainage. The 30-day mortality
was 13/30 (43%), most commonly due to multiorgan failure and
withdrawal of life-support. P180 Results Twenty-eight patients were studied (22 men, mean age
68 ± 11 years). The most common surgery was myocardial
revascularization (n = 17). EPAP was well tolerated in the patients
studied. Comparing rest and EPAP periods, increases were
observed in: PCWP (11.9 ± 3.8 to 17.1 ± 4.9 mmHg, P < 0.001);
CVP
(8.7 ± 4.1
to
10.9 ± 4.3 mmHg,
P = 0.014);
MPAP
(21.5 ± 4.2 to 26.5 ± 5.8 mmHg, P < 0.001); MAP (76 ± 10 to
80 ± 10 mmHg, P < 0.035). All other variables did not show
significant changes. These results were observed in the total group
and when divided concerning ejection fraction >50% or <50%. Conclusions EPAP was well tolerated in this group of stable
patients after cardiac surgery and the hemodynamic changes due
to its use were an increase in the measurement of right and left
filling pressures as well as a small increase in arterial pressure. Assessing the impact of introducing the ‘ventilator bundle’
on outcomes for mechanically ventilated patients Assessing the impact of introducing the ‘ventilator bundle’
on outcomes for mechanically ventilated patients Introduction Expiratory positive airway pressure (EPAP) is used as
physiotherapic tool in the management of patients after major
surgeries such as cardiac surgery but its hemodynamic effect is
not well studied. The goal of this study was to evaluate
hemodynamic changes caused by EPAP use after cardiac surgery
in patients monitored by Swan-Ganz catheter. D Harrison, K Rowan
Intensive Care National Audit & Research Centre, London, UK
Critical Care 2007, 11(Suppl 2):P177 (doi: 10.1186/cc5337) Background The concept of bundles was developed by the
Institute for Healthcare Improvement. Individual bundle elements
are built on evidence-based practice, and the bundle concept is
that when these elements are executed together they produce
better outcomes than in isolation. There is, however, limited
evidence linking the use of bundles to demonstrable changes in
patient outcomes. As a preliminary analysis to inform a multicentre
evaluation, we explored the effect of the introduction of the
‘ventilator bundle’ on the outcomes for mechanically ventilated
patients in a single critical care unit. Methods Patients in the first or second day after cardiac surgery,
with respiratory and hemodynamic stability and with a Swan-Ganz
catheter, were included. They were evaluated at rest and after
using EPAP of 10 cm, by facial mask, in a randomized order. Variables studied were oxygen saturation (SPO2), heart rate (HR),
respiratory rate (RR), mean arterial systemic and pulmonary
pressures (MAP and MPAP), central venous pressure (CVP),
pulmonary capillary wedge pressure (PCWP), cardiac index, stroke
index, stroke work index from left and right ventricles, and systemic
and pulmonary vascular resistance. Patients were studied as a
whole group and divided into subgroups (with ejection fraction
<50% or >50%) and values were compared with a t test and
analysis of variance. Results are shown as the mean ± standard
deviation. The significance level was P < 0.05. Methods
Data were extracted for mechanically ventilated
admissions from a single unit participating in the Case Mix
Programme that was an early adopter of the ventilator bundle. A
risk prediction model was developed using data from admissions
during the 3.5 years prior to the introduction of the bundle and S72 Available online http://ccforum.com/supplements/11/S2 P179 1The Children’s Memorial Health Institute, Warsaw, Poland;
2California State University, San Bernardino, CA, USA; 3Medical
University of Silesia, Katowice, Poland; 4Medical University,
Wrocùaw, Poland; 5National Research Institute of Mother & Child,
Warsaw, Poland; 6Medical College Jagiellonian University, Kraków,
Poland; 7University of Medical Sciences, Poznan, Poland
Critical Care 2007, 11(Suppl 2):P179 (doi: 10.1186/cc5339) Background The use of nasal continuous positive airway pressure
(nCPAP) in newborn infants is common, especially for weaning
after mechanical ventilation. We have reported on the successful
transition to the use of the infant flow method as a standard of
practice in Poland. Objective The authors present results of multivariate logistic
regression (MLR) analysis of 481 newborns treated with the infant
flow method in an effort to improve related clinical guidance. Conclusions In our patients APRV use appeared safe, led to
improved
oxygenation,
but
did
not
change
needs
for
sedation/analgesia. Future studies are needed to determine the
optimal timing and methods for ARPV use; these should be
followed by randomized trials to confirm safety and document the
effects of APRV on patient-centered outcomes. Methods We collected data on the baseline demographic,
physiological characteristics and outcomes of 1,299 newborns
treated with nCPAP in 57 neonatal ICUs in Poland over a 2-year
period. We conducted a stepwise MLR of 481 newborns with the
two most common indications for use. We evaluated three
outcomes: need for intubation in newborns treated electively with
nCPAP (RDS), weaning failure requiring reintubation in the
mechanically ventilated newborns (weaning), and bad outcome. Airway pressure release ventilation in acute lung
injury/acute respiratory distress syndrome patients E Fan1, A Mullaly1, M Ko1, J Lyle1, T Pirano1, C Harris1, J Traill1,
J Rosenberg1, J Granton1, T Stewart2, N Ferguson1
1University of Toronto, Canada; 2Mount Sinai Hospital, Toronto,
Canada
Critical Care 2007, 11(Suppl 2):P180 (doi: 10.1186/cc5340) Introduction Advocates of airway pressure release ventilation
(APRV) suggest that this mode is lung-protective for patients with
ALI/ARDS, while providing additional benefits of spontaneous
breathing, including improved haemodynamics, decreased need
for sedation, and better patient comfort. However, there are few
available data on the clinical experience with APRV. P181 A
compliance-based index (CSI) directly comparable with the SI was
generated from the compliance data. convertase are scarce. We therefore investigated the expression
and activity of lung surfactant convertase and HMSE-1, a potential
macrophage-derived human convertase, under normal and acute
inflammatory conditions. Methods Convertase activity in lavage fluid (BALF) was assessed
using the in vitro cycling assay. The relative large surfactant
aggregate content was determined by phospholipid quantification
in the pellet following centrifugation at 48,000 x g. Esterase activity
was assessed by means of a chromogenic substrate assay. Expression of both convertase and HMSE upon LPS challenge
was assessed by real-time (TaqMan) PCR in murine alveolar
macrophages, murine primary type II cells, and the human
monocytic cell line U937, respectively. Results The SI and CSI highly correlated when calculation of the
CSI was based on the same database (Figure 1). According to the
resulting regression formula (Figure 1), the SI can be reliably
predicted from SLICE_SI (Figure 2). However, if SLICE_CONV
was used for calculation of the SI (Figure 3), noticeable differences
were found. Analysis of individual datasets showed three major
reasons for the observed differences: differences in excluded data
at low volumes respective to high volumes, nonlinearity of
resistance, and differences in mechanics between inspiration and
expiration. Results Lavage fluid from ARDS patients displayed an increased
esterase activity when compared with BALF from healthy controls. In addition, a pronounced large to small aggregate conversion was
observed for BALF from LPS-challenged mice or BALF from ARDS
patients. Incubation with LPS resulted in a significant increase in
convertase gene expression in primary mouse type II cells as well
as in HMSE-1 gene expression in U937 cells and monocytes from
peripheral blood. No convertase expression was found in cultured
murine alveolar macrophages. Conclusion The SI and SLICE similarly measure the nonlinearity of
compliance. The SI can be predicted from SLICE. However,
nonlinearities of the respiratory system are not restricted to
compliance alone; it might therefore be necessary to include
nonlinearities of resistance and asymmetries between inspiration
and expiration in the analysis of dynamic respiratory mechanics. Conclusions An increased convertase activity was found under
acute inflammatory conditions of the alveolar compartment, and
type II cells seem to be a relevant source of this increased
convertase activity. However, leakage of esterase activity from the
vascular space and other inflammatory cells cannot be ruled out. 1. P183 Transgenic mice expressing a surfactant protein
B–urokinase fusion protein in the distal respiratory
epithelium are protected against acute lung injury and
postinflammatory fibrosis 3. Guttmann J, et al.: Determination of volume-dependent res-
piratory system mechanics in mechanically ventilated
patients using the new SLICE method. Technol Health
Care 1994, 2:175-191. 3. Guttmann J, et al.: Determination of volume-dependent res-
piratory system mechanics in mechanically ventilated
patients using the new SLICE method. Technol Health
Care 1994, 2:175-191. P Markart1, C Ruppert1, M Wygrecka1, K Petri1, V Magdolen2,
T Weaver3, W Seeger1, A Günther1
1University of Giessen Lung Center, Giessen, Germany; 2Klinikum
rechts der Isar, Technical University of Munich, Germany;
3Children’s Hospital Medical Center, Cincinnati, OH, USA
Critical Care 2007, 11(Suppl 2):P183 (doi: 10.1186/cc5343) P181 Stahl CA, et al.: Dynamic versus static respiratory mechan-
ics in acute lung injury and acute respiratory distress syn-
drome. Crit Care Med 2006, 34:2090-2098. 2. Ranieri VM, et al.: Pressure–time curve predicts minimally
injurious ventilatory strategy in an isolated rat lung model. Anesthesiology 2000, 93:1320-1328. 2. Ranieri VM, et al.: Pressure–time curve predicts minimally
injurious ventilatory strategy in an isolated rat lung model. Anesthesiology 2000, 93:1320-1328. P181 Results In the RDS group of patients we found that nCPAP failure
was highly significantly related to estimated gestational age and
clinical risk index for babies (CRIB). While in our population less
mature RDS newborns were only slightly less likely to avoid
intubation, the MLR model showed that, controlling for initial CRIB,
they were less than one-half as likely to avoid intubation. Failure of
nCPAP in weaning was highly significantly related to only pH, prior
to beginning nCPAP. Bad outcomes were highly related to
estimated gestational age and CRIB in the RDS group, but not the
weaning population. Importance of nonlinearities to quantify mechanical
pulmonary stress under dynamic conditions: stress index
and SLICE method C Stahl1, H Meißner1, D Steinmann1, G Mols1, C Micelli2,
K Moeller3, M Ranieri4, J Guttmann1
1Anästhesiologische Universitätsklinik, Freiburg, Germany;
2Kleistek, Bari, Italy; 3HFU, Villingen-Schwenningen, Germany;
4Oespedale S. Giovanni Battista, Torino, Italy
Critical Care 2007, 11(Suppl 2):P181 (doi: 10.1186/cc5341) Conclusions We believe that understanding the risk of both
nCPAP failure and also bad outcomes for a specific patient will
enhance clinical decision-making. That is, for patients with the
highest risk of poor outcome or nCPAP failure, more aggressive
use of intubation and surfactant might be warranted. Likewise,
such aggressive therapy might also be avoided for those with a
seemingly low chance of poor outcome. Introduction Recent data suggest that dynamic measurements of
respiratory mechanics should be preferred to static measurement
for lung protection [1]. The aim of this study was to analyze
similarities and differences between dynamic methods: the stress
index (SI) [2] and SLICE [3]. S73 Critical Care March 2007 Vol 11 Suppl 2
27th International Symposium on Intensive Care and Emergency Medicine Figures 1-3 (abstract P181) Figures 1-3 (abstract P181) Figures 1-3 (abstract P181) Methods One hundred and two respiratory datasets from 70
patients (28 ARDS, 24 postanesthesia care, 18 other) were
analyzed. The SI and SLICE were performed using exactly the
same database (SLICE_SI) in addition to the conventional SLICE
that includes inspiratory and expiratory data (SLICE_CONV). A
compliance-based index (CSI) directly comparable with the SI was
generated from the compliance data. Methods One hundred and two respiratory datasets from 70
patients (28 ARDS, 24 postanesthesia care, 18 other) were
analyzed. The SI and SLICE were performed using exactly the
same database (SLICE_SI) in addition to the conventional SLICE
that includes inspiratory and expiratory data (SLICE_CONV). P184 Mini-bronchoalveolar lavage with and without surfactant in
the treatment of recurrent atelectasis in pediatric intensive
care patients M Karaman Iliã, I Škariã, I Kerovec
Children’s Hospital, Zagreb, Croatia
Critical Care 2007, 11(Suppl 2):P184 (doi: 10.1186/cc5344) M Karaman Iliã, I Škariã, I Kerovec
Children’s Hospital, Zagreb, Croatia
Critical Care 2007, 11(Suppl 2):P184 (doi: 10.1186/cc5344) Introduction Since traditional treatment of atelectasis is often
insufficient to reopen the collapsed airways, mini-bronchoalveolar
lavage (mini-BAL) is performed. We retrospectively compared the
treatment effects of mini-BAL only and mini-BAL combined with
surfactant in the treatment of pediatric ICU patients with recurrent
atelectasis. Methods A retrospective analysis included a heterogeneous group
of 18 mechanically ventilated pediatric ICU patients with recurrent
atelectasis. Nine patients (mean age, 4.4 ± 3.4 years) who received
surfactant after standard mini-BAL were compared with nine
patients (mean age, 4.7 ± 3.0 years) who underwent only standard
mini-BAL. Gas exchange and pulmonary mechanic parameters in
the two groups were compared. The peak inspiratory pressure
(PIP), positive end-expiratory pressure (PEEP), paO2/FiO2, and
partial arterial carbon dioxide pressure (paCO2) were analyzed with
3 x 2 multivariate analysis of variance, with the time of measurement
(before treatment, 6 and 12 hours after treatment) as a within-
subject factor and the type of treatment (mini-BAL only vs mini-BAL
with surfactant) as a between-subject factor. Results The computer-driven ventilator settings could stabilise the
ventilation of the lung-injured subject in the predefined thresholds. Compared with the beginning of the study, a reduction in
ventilation pressure and PaCO2 could be observed. Despite the
initial low PaO2/FiO2 ratio (<200 mmHg) of the subjects, FiO2
could be decreased by the system in the given time without
penetrating the thresholds for oxygenation. Results The groups did not differ in age (independent sample
t test = 0.698). The parameters significantly changed with time
after treatment (Wilks’ λ = 0.027, F = 25.277, P < 0.001), and the
treatment procedures had significantly different effects (time x
treatment, Wilks’ λ = 0.103, F = 6.070, P = 0.013). A significant
univariate time–treatment interaction was not present only for
SpO2 (F(2,32) = 2.167, P = 0.629). Subsequent analyses showed
different effect of surfactant administration on PEEP compared
with mini-BAL alone. In the mini-BAL only group, PEEP changed
from 6.44 ± 1.13 cmH2O before treatment to 5.22 ± 0.83 cmH2O
6 hours after the treatment (P = 0.019), and remained the same
12 hours after the treatment. P182 Contribution of HMSE-1 to surfactant conversion under
acute inflammatory conditions Contribution of HMSE-1 to surfactant conversion under
acute inflammatory conditions Contribution of HMSE-1 to surfactant conversion under
acute inflammatory conditions C Ruppert, P Markart, S Händel, W Seeger, A Günther
University of Giessen Lung Center, Giessen, Germany
Critical Care 2007, 11(Suppl 2):P182 (doi: 10.1186/cc5342) C Ruppert, P Markart, S Händel, W Seeger, A Günther
University of Giessen Lung Center, Giessen, Germany
Critical Care 2007, 11(Suppl 2):P182 (doi: 10.1186/cc5342) C Ruppert, P Markart, S Händel, W Seeger, A Günther
University of Giessen Lung Center, Giessen, Germany
Critical Care 2007, 11(Suppl 2):P182 (doi: 10.1186/cc5342) Introduction Persistent deposition of fibrin in the distal lung is
thought to play a significant role in the pathogenesis of acute lung
injury (ALI) and postinflammatory lung fibrosis. The therapeutic
concept of the correction of the alveolar hemostatic balance,
although effective in most models, needs further improvement in
view of specific targeting of surfactant-containing alveolar fibrin
clots. Introduction A reduced content of biophysically active large
surfactant aggregates is a common finding in acute inflammatory
lung disease. Cyclic surface area changes and a carboxylesterase
activity (surfactant convertase) are thought to mediate this subtype
conversion. However, data concerning regulation of surfactant Introduction A reduced content of biophysically active large
surfactant aggregates is a common finding in acute inflammatory
lung disease. Cyclic surface area changes and a carboxylesterase
activity (surfactant convertase) are thought to mediate this subtype
conversion. However, data concerning regulation of surfactant S74 Available online http://ccforum.com/supplements/11/S2 Available online http://ccforum.com/supplements/11/S2 Available online http://ccforum.com/supplements/11/S2 Methods In the present study we generated transgenic mice that
express a surfactant protein B–urokinase fusion protein (SPUC) in
the distal respiratory epithelium under the control of the 3.7 kb
human SP-C promotor. Survival was determined in a lethal ALI
model (inhalative LPS administration) in SPUC mice compared
with wild-type mice of the same genetic background. Furthermore,
the outcome, lung function, collagen content and histology were
assessed in the model of bleomycin-induced pulmonary fibrosis. had significantly lower PEEP values compared with the mini-BAL
only group 12 hours after the treatment (3.44 ± 0.72 before vs
5.22 ± 0.44 mmH2O after treatment, P = 0.025). had significantly lower PEEP values compared with the mini-BAL
only group 12 hours after the treatment (3.44 ± 0.72 before vs
5.22 ± 0.44 mmH2O after treatment, P = 0.025). P184 The group that received surfactant Conclusion Robust execution of an automated ARDS Network
protocol with an electronically controlled ventilator is possible and
leads to pulmonary stabilisation. Further trials have to be
undertaken before this successful approach can be realised in
ARDS patients. P182 2
Conclusion Mini-BAL is efficient in the treatment of recurrent
atelectasis in pediatric ICU patients. Beneficial effects of surfactant
administration after mini-BAL should be confirmed prospectively in
a larger number of patients. Results Transgenic mice showed an improved survival after
inhalative LPS or bleomycin administration as compared with wild-
type mice. The fibrotic response to inhalative bleomycin challenge
was markedly attenuated in transgenic mice, as evident by reduced
histological
appearance
of
fibrosis,
improved
pulmonary
compliance and reduced lung hydroxyproline content. As potential
underlying mechanisms for the attenuated fibrotic response we
observed an improvement in alveolar surface activity, a decrease in
pulmonary fibrin deposition, increased hepatocyte growth factor
levels and decreased gelatinase activity in the BAL fluids of
transgenic mice as compared with control animals. Automated mechanical ventilation based on the ARDS
Network protocol in porcine acute lung injury Automated mechanical ventilation based on the ARDS
Network protocol in porcine acute lung injury T Meier1, H Luepschen2, M Großherr1, J Karsten1, S Leonhardt2
1Medical University of Schleswig Holstein, Campus Lübeck,
Germany; 2Medical Information Technology, RWTH Aachen, Germany
Critical Care 2007, 11(Suppl 2):P185 (doi: 10.1186/cc5345) Introduction The results of the ARDS Network trial [1] demon-
strated a significant reduction of mortality by using a mechanical
ventilation protocol with tidal volumes (VT) of 6 ml/kg predicated
body weight. Additionally, a computer-driven weaning protocol was
successfully performed and a reduction of mechanical ventilation
duration could be demonstrated [2]. The implementation of the
ARDS Network protocol in routine ICU practice remains modest
[3]. A possible reason is the increased organisational and temporal
burden. An automated execution of the protocol would help to
propagate its day-to-day use. To test the ability to automate such a
complex protocol, we designed a pilot study in porcine acute lung
injury using an experimental medical expert system capable of
continuously controlling respiratory parameters and global as well
as regional ventilation with electrical impedance tomography (EIT). Methods After induction of saline lavage-induced lung injury in
pigs (n = 3), automated mechanical ventilation was initiated. The
medical expert system used a closed-loop fuzzy controller with a
rule base of if/then rules based on the ARDS Network protocol
reference card. The protocol’s algorithmic rules and therapeutic
goals (oxygenation, pH, I:E, VT) were continuously controlled and
ventilatory settings electronically adjusted accordingly. The medical
attendant personnel was constantly informed with status messages
about the decisions made. During the trial, all measurements were
made using an online blood gas monitor (TrendCare Satellite;
Diametrics Medical Inc., UK), a monitor for hemodynamic
parameters (Sirecust 1281; Siemens, Germany), a capnograph
(CO2SMO+; Respironics, Inc., USA), and an EIT prototype system
(EIT Evaluation Kit; Draeger Medical, Germany). Subjects were
ventilated for between 40 and 90 minutes. Conclusions Lung-specific expression of a surfactant protein
B–urokinase fusion protein protects against ALI after inhalative
LPS challenge and prevents fibrosis associated with bleomycin-
induced lung injury. P185 Automated mechanical ventilation based on the ARDS
Network protocol in porcine acute lung injury
T Meier1, H Luepschen2, M Großherr1, J Karsten1, S Leonhardt2
1Medical University of Schleswig Holstein, Campus Lübeck,
Germany; 2Medical Information Technology, RWTH Aachen, Germany
Critical Care 2007, 11(Suppl 2):P185 (doi: 10.1186/cc5345) P188 Maximal recruitment strategy guided by thoracic CT scan
in severe acute respiratory distress syndrome patients: a
case series report Methods A systematic literature search was performed between
1966 and July 2006 to identify randomised controlled trials
evaluating prone ventilation. G De Matos1, J Borges2, E Meyer1, C Hoelz1, R Passos1,
M Rodrigues1, C Carvalho2, M Amato2, C Barbas1
1Hospital Israelita Albert Einstein, São Paulo, Brazil; 2Hospital das
Clínicas Faculdade de Medicina Universidade de São Paulo, Brazil
Critical Care 2007, 11(Suppl 2):P188 (doi: 10.1186/cc5348) Measurements and results Of 229 studies evaluating prone
ventilation, five were suitable for inclusion. Prone ventilation was
not associated with a reduction in mortality (OR = 0.99; 95% CI =
0.74–1.30), but improvement in oxygenation was significant (mean
difference 21.2; P < 0.001). There was no significant difference in
the incidence of pneumonia, ICU stay and endotracheal tube
complications. There was a trend towards an increased incidence
of pressure sores in prone-ventilated patients. The data on duration
of mechanical ventilation, intravascular catheter complications or
hospital stay were not suitable for meta-analysis. No study reported
cost-effectiveness. Introduction There is great controversy concerning protective
ventilation in ARDS. Recruitment maneuvers and PEEP titration
sufficient to avoid collapse and tidal recruitment are the major
goals of the maximal recruitment strategy (MRS). Objectives To describe clinical and demographic data. To evaluate
the incidence of complications related to transportation and to the
MRS. Conclusions The use of prone ventilation is associated with
improved oxygenation. It is not associated with a reduction in
mortality, pneumonia or ICU stay and may be associated with an
increased incidence of pressure sores. Methods Forty-three patients with ARDS were transported to CT
and submitted to the MRS, which consisted of 2-minute steps of
ventilation with a fixed PCV = 15 cmH2O and progressive PEEP
levels (10–45–25–10 cmH2O), RR = 10, I:E = 1:1, and FiO2 =
1.0. Opening (recruitment) and closing (PEEP titration) pressures
were determined according to the least amount of collapse
observed at the CT, and were used to ventilate the patients
afterwards. Efficacy of prone ventilation in adult patients with acute
respiratory failure: a meta-analysis Efficacy of prone ventilation in adult patients with acute
respiratory failure: a meta-analysis R Tiruvoipati1, M Bangash1, B Manktelow2, G Peek1
1Glenfield Hospital, Leicester, UK; 2University of Leicester, UK
Critical Care 2007, 11(Suppl 2):P186 (doi: 10.1186/cc5346) Background The use of prone ventilation in acute respiratory
failure has been investigated by several randomised controlled
trials in the recent past. To date there has been no systematic
review or meta-analysis of these trials. Conclusions PPV had a positive effect on gas exchange even after
6 hours. This effect lasts through the PPV period. Because of its
effect on the LIS, a duration of 24 hours for continuous PPV could
be useful in this patient setting. Objectives The primary objective was to assess the efficacy of
prone ventilation in reducing mortality of adult patients with acute
respiratory failure. The secondary objective was to evaluate changes
in oxygenation, incidence of pneumonia, duration of mechanical
ventilation, ICU and hospital stay, and adverse effects including
pressure sores, endotracheal tube or intravascular catheter
complications and cost-effectiveness of using prone ventilation. References References 1. ARDS Network: N Engl J Med 2000, 342:1301-1308. 2. Lellouche et al.: Am J Respir Crit Care Med 2006, 174:894-
900. S75 Critical Care March 2007 Vol 11 Suppl 2
27th International Symposium on Intensive Care and Emergency Medicin P186 before PPV and 256 (170–298) mmHg after 1 hour of PPV
(P = 0.001). This difference with the supine PaO2/FIO2 ratio was
sustained until the end of PPV. Initial values of PEEP were set at
15 (12–18) cmH2O by constructing a PEEP-compliance curve;
there were no differences in PEEP values along the study. Initial
values of PaCO2 were 47 (41–69) mmHg and there were no
significant differences along the study period. After 24 hours of
PPV, the LIS was significantly decreased in comparison with the
supine value before PPV: 3 (2.25–2.7) vs 2.5 (2.25–2.75),
P = 0.001. There were no significant complications. P186
Efficacy of prone ventilation in adult patients with acute
respiratory failure: a meta-analysis
R Tiruvoipati1, M Bangash1, B Manktelow2, G Peek1
1Glenfield Hospital, Leicester, UK; 2University of Leicester, UK
Critical Care 2007, 11(Suppl 2):P186 (doi: 10.1186/cc5346) Continuous long-term prone position ventilation effects in
pulmonary acute respiratory distress syndrome patients Results Clinical data are presented in Table 1. There were no
complications due to transportation and one patient developed
pneumomediatinum after the protocol. J Gorrasi, F Pracca, A Iturralde, L Moraes, D Fischer, M Cancela
Department of Intensive Care Medicine, University Hospital, School
of Medicine, Montevideo, Uruguay
Critical Care 2007, 11(Suppl 2):P187 (doi: 10.1186/cc5347) Table 1 (abstract P188)
Mortality (%)
28
Age (years)
49 ± 17
APACHE II score
20 ± 6
SOFA D1 score
9.4 ± 3
SOFA D7 score
5.2 ± 4
Maximal recruitment pressure (cmH2O)
60 ± 5
Maximal PEEP day 1 (cmH2O)
25 ± 3
Maximal plateau pressure day 1 (cmH2O)
40 ± 5
PaO2/FiO2 ratio before recruitment protocol
130 ± 43
PaO2/FiO2 ratio after recruitment protocol
317 ± 99 P189 Paraffin blocks were sectioned with a microtome at 5 µm thickness
and stained with hematoxylin–eosin. established. The pressure dependency (or volume dependency
respectively) of respiratory resistance of these patients is mostly
ignored. This study was performed to investigate the pressure
dependency of resistance in ALI and ARDS over a wide range of
pressures. Results The wet-to-dry weight ratios rose from 4.82 ± 0.16 in
control animals to 6.34 ± 0.83 in the HTVMV group (P < 0.05,
n = 4). Light microscopic examination of histologic sections showed
mononuclear white cell infiltrates around small arteries and within
the alveolar walls of mice in the HTVMV group but not in control
mice. Elastance rose nonsignificantly during the HTVMV protocol. Conclusions In this in vivo mouse model, high tidal volume mechanical
ventilation caused pulmonary edema and lung tissue infiltration with
white blood cells. However, measurements of lung mechanics showed
minimal changes during the course of the experiment, indicating that
they are less useful in detecting early edema. Results The wet-to-dry weight ratios rose from 4.82 ± 0.16 in
control animals to 6.34 ± 0.83 in the HTVMV group (P < 0.05,
n = 4). Light microscopic examination of histologic sections showed
mononuclear white cell infiltrates around small arteries and within
the alveolar walls of mice in the HTVMV group but not in control
mice. Elastance rose nonsignificantly during the HTVMV protocol. Methods Twenty-one patients with ALI or ARDS were analyzed. Ventilation was interrupted by a respiratory manoeuvre: the volume
was increased from ZEEP in steps of 100 ml with constant
inspiratory flow until the plateau pressure reached 45 cmH2O. Each step was followed by a hold of 3 seconds. Inspiratory
resistance during each step was determined by a least-squares
fitting procedure. Conclusions In this in vivo mouse model, high tidal volume mechanical
ventilation caused pulmonary edema and lung tissue infiltration with
white blood cells. However, measurements of lung mechanics showed
minimal changes during the course of the experiment, indicating that
they are less useful in detecting early edema. Results Resistance decreased from 10.7 ± 5.1 cmH2O·s/l at
5 cmH2O to 8.1 ± 4.0 cmH2O·s/l at 40 cmH2O (P < 0.05). Figure 1
shows individual absolute values and means ± SD of all patients. Most of the decrease was found up to 20 cmH2O; at higher
pressures, changes were not uniform. P189 Low sensitivity of measurements of respiratory mechanics
in detecting lung edema from high tidal volume
mechanical ventilation Low sensitivity of measurements of respiratory mechanics
in detecting lung edema from high tidal volume
mechanical ventilation Introduction High tidal volume mechanical ventilation (HTVMV)
leads to pulmonary edema from increased endothelial permeability. The lungs show evidence of inflammation with endothelial
adhesion molecule expression, infiltrates of white blood cells and
cytokine production. In order to understand the molecular
mechanisms responsible for the pathogenesis of ventilator injury,
mouse models are beneficial but technically difficult due to the
small size of the animal. To study the time course of lung edema
formation we compared lung elastance measured by forced
oscillations with invasive methods of lung edema detection (for
example, wet–dry weight ratio and histology). Introduction High tidal volume mechanical ventilation (HTVMV)
leads to pulmonary edema from increased endothelial permeability. The lungs show evidence of inflammation with endothelial
adhesion molecule expression, infiltrates of white blood cells and
cytokine production. In order to understand the molecular
mechanisms responsible for the pathogenesis of ventilator injury,
mouse models are beneficial but technically difficult due to the
small size of the animal. To study the time course of lung edema
formation we compared lung elastance measured by forced
oscillations with invasive methods of lung edema detection (for
example, wet–dry weight ratio and histology). Figure 2 (abstract P190) Figure 2 (abstract P190) p
y
g
gy
Methods C57Black6 mice were anesthetized with i.p. sodium
pentothal and paralyzed with succinylcholine. A tracheostomy was
performed and the animals were connected to a Flexivent ventilator
(Sqirec). The HTVMV group received a tidal volume of 25 ml/kg
and 33 breaths/minute for 4 hours. The control group received
7 ml/kg at 120 breaths/minute. Temperature was kept at 36–37°C
with the aid of a heated pad. The heart rate was monitored with
surface EKG electrodes. Lung elastance and tissue energy
dissipation were measured every 30 minutes using the forced
oscillation technique. At the end of the experiment a sternotomy
was performed. A ligature was placed around the right hilum and
the right lung was cut, briefly rinsed in PBS, blotted dry and
weighed. The dry weight was obtained following desiccation at
60°C for 48 hours. The left lung was inflated with 500 µl formalin
injected slowly into the tracheal canula and embedded in paraffin. Table 1 (abstract P188) Introduction The optimal duration of prone position ventilation
(PPV) in acute respiratory distress syndrome (ARDS) is uncertain. It has been pointed out that pulmonary ARDS patients respond
less than extrapulmonary ARDS patients. Objective To study effects of continuous long-term PPV on gas
exchange, PEEP, lung injury score and multiorgan failure in
pulmonary ARDS patients. Materials and methods The design was a prospective (cohort). We studied 42 PPV periods in 33 pulmonary ARDS patients. Measures were taken in the supine position before PPV and at
1 hour after PPV, and then every 6 hours until the end of PPV. Statistical values are expressed as the median and interquartile
range. Wilcoxon and Kruskal–Wallis tests were used. P < 0.05
was considered significant. Conclusions MRS was well tolerated in this series of patients,
rendered the gas distribution through the lung more homogeneous,
improved gas exchange and was related to low mortality. A RCT to
test the MRS is necessary. Results The mean age was 44 (25–57) years, the initial lung injury
score (LIS) was 3.1 (2.75–3.6), and PPV was maintained for 91
(51–117) hours. The PaO2/FIO2 ratio was 125 (99–181) mmHg S76 Available online http://ccforum.com/supplements/11/S2 Figure 1 (abstract P190)
Figure 2 (abstract P190) Figure 1 (abstract P190) Figure 1 (abstract P190) P189 The average relative
changes in inspiratory resistance (±SD) of all patients are shown in
Figure 2. Alveolar microscopy: on the automatic determination of
alveolar size during ventilation Alveolar microscopy: on the automatic determination of
alveolar size during ventilation D Schwenninger1, K Moeller1, C Stahl2, S Schumann2,
J Guttmann2
1Furtwangen University, Villingen-Schwenningen, Germany;
2University of Freiburg, Germany
Critical Care 2007, 11(Suppl 2):P191 (doi: 10.1186/cc5351) J Karsten1, H Luepschen2, M Grossherr1, H Gehring1,
S Leonhardt2, T Meier1
1University of Lübeck, Germany; 2Medical Information Technology,
Helmholtz Institute, RWTH Aachen, Germany
Critical Care 2007, 11(Suppl 2):P192 (doi: 10.1186/cc5352) Introduction Alveolar recruitment and maintenance of lung volume
are important goals in the treatment of acute lung injury (ALI) and
essential for improving oxygenation. The most usual employed
strategy to achieve this goal is the use of positive end-expiratory
pressure (PEEP). Recruitment and collapse are highly dynamic
phenomena that are difficult to monitor. Dynamic effects of regional
ventilation can be monitored by electrical impedance tomography
(EIT) at the bedside [1]. We investigated the ability of EIT for
providing a useful tool to detect dynamic changes of regional
breath by breath recruitment at the bedside during an incremental
and decremental PEEP trial in experimental lung injury. In addition,
we analyzed pressure–volume (P–V) curves computed by EIT data. Methods ALI was induced in six pigs by repetitive lung lavage. After stabilization of the lung injury model (> 1 hour) a stepwise
PEEP trial was performed consisting of 2-minute steps of tidal
ventilation (10–30 cmH2O; 30–5 cmH2O). During the PEEP trial
subjects were ventilated pressure-controlled. Global ventilatory and
gas exchange parameters were continuously recorded. Offline we
analysed EIT data by computing the amount of breath by breath
recruitment (∆V EIT) at each pressure level before and after lung
lavage. Nondependent and dependent regions of interest were
defined in the tomograms. ∆V EIT was defined as the mean increase
or decrease in end-expiratory global impedance per breath. Introduction Alveolar microscopy seems to provide important
insight into alveolar dynamics during mechanical ventilation [1,2]. The utility of this method is limited due to high efforts needed to
evaluate sequences of images with respect to alveolar geometry. The evaluation – done by hand – is time consuming, places a high
cognitive load on the examiner and is error prone. Reproducibility
of results is low. This project aims to establish a computer-assisted
tool that provides semi-automatic evaluation of video sequences
acquired with alveolar endoscopy. Methods We developed a computer program based on Matlab
(Mathworks, Natick, MA, USA), which analyses video sequences
acquired with an alveolar endoscope (Schölly, Denzlingen,
Germany) [2]. Reference 1. Victorino et al.: Am J Respir Crit Care Med 2004, 169:791-
800. frames allows one to compensate for motion artifacts and to
analyze the intratidal changes in alveolar geometry. P193 Conclusion Given a synchronization with respiratory data, this tool
will allow one to quantify pressure-related changes of alveolar size. Thus it will allow one to monitor the alveolar distension in a variety
of animal models (for example, lavage-induced ARDS) and to
correlate these findings, for example, with outcome. R f Pressure dependency of respiratory resistance in patients with
acute lung injury and acute respiratory distress syndrome Conclusion Inspiratory resistance in ALI and ARDS is not
constant. Especially at higher pressures, individual resistance may
change unpredictably. The assumption of a constant resistance
should therefore be avoided. C Stahl1, H Knorpp1, S Schumann1, D Steinmann1, K Möller1,
J Guttmann1
1Anästhesiologische Universitätsklinik, Freiburg, Germany;
2Biomedical Engineering, HFU, Villingen-Schwenningen, Germany
Critical Care 2007, 11(Suppl 2):P190 (doi: 10.1186/cc5350) C Stahl1, H Knorpp1, S Schumann1, D Steinmann1, K Möller1,
J Guttmann1 1Anästhesiologische Universitätsklinik, Freiburg, Germany;
2Biomedical Engineering, HFU, Villingen-Schwenningen, Germany
Critical Care 2007, 11(Suppl 2):P190 (doi: 10.1186/cc5350) Introduction
The analysis of the nonlinearity of respiratory
compliance to guide ventilator settings in ALI and ARDS is well S77 P191
Alveolar microscopy: on the automatic determination of
alveolar size during ventilation
D Schwenninger1, K Moeller1, C Stahl2, S Schumann2,
J Guttmann2
1Furtwangen University, Villingen-Schwenningen, Germany;
2University of Freiburg, Germany
Critical Care 2007, 11(Suppl 2):P191 (doi: 10.1186/cc5351) Alveolar microscopy: on the automatic determination of
alveolar size during ventilation The user has to provide a pointer to the alveoli that
shall be traced and whose changes in size and shape are to be
determined. Filters, smoothing splines and expectation-driven fine
tuning is performed to achieve robust and predictable results of the
intratidal change in alveolar geometry. Results Animal studies related to alveolar mechanics during
artificial ventilation were conducted. Figure 1a shows a plot of a
frame taken from a video obtained during an experiment performed
on a healthy anesthetized rat. Overlaid circles indicate identified
boundaries of a selected alveolus. Figure 1b presents a trace of
alveolar diameter during a tidal breath. Evaluation of successive Results Ventilatory parameters clearly showed a recruitment of
nonaerated lung areas at the descending part of the pressure ramp. The shape of the P–V curve from EIT data, in particular the
increasing slope (lower level > upper level), reflected the recruitment
of poorly ventilated lung regions. The flattening of the curve at higher
pressures, especially at the upper level, reflected less amount of
recruitment
but
more
overdistension. Regional
pulmonary
recruitment/derecruitment was very high in the lower level. These
phenomena were more impressive after induced lung injury. Figure 1 (abstract 191)
(a) Marked areas of a traced alveolus. (b) Changes in diameter during
ventilation. Figure 1 (abstract 191) Conclusions Stepwise PEEP recruitment maneuvers can open
collapsed lungs and certain PEEP levels are necessary to keep the
lungs open. Monitoring of ∆V EIT is capable of detecting the
dynamic process of recruitment and derecruitment at bedside. Plotting regional P–V curves from EIT data provides continuous
information that may be of use in determining the PEEP level to
maintain recruitment in acute lung injury. (a) Marked areas of a traced alveolus. (b) Changes in diameter during
ventilation. 1.
Victorino et al.: Am J Respir Crit Care Med 2004, 169:791-
800. 1.
Schiller et al.: Crit Care Med 2001, 29:1049-1055.
(
) frames allows one to compensate for motion artifacts and to
analyze the intratidal changes in alveolar geometry.
Conclusion Given a synchronization with respiratory data, this tool
will allow one to quantify pressure-related changes of alveolar size.
Thus it will allow one to monitor the alveolar distension in a variety
of animal models (for example, lavage-induced ARDS) and to
correlate these findings, for example, with outcome.
References
1.
Schiller et al.: Crit Care Med 2001, 29:1049-1055.
2.
Stahl CA, et al.: Crit Care 2006, 10(Suppl 1):S2. 2.
Stahl CA, et al.: Crit Care 2006, 10(Suppl 1):S2. H Knorpp1, C Stahl2, S Schumann2, M Lichtwarck-Aschoff3,
J Guttmann2
1UT Southwestern, Dallas, TX, USA; 2University of Freiburg,
Germany; 3Zentralklinikum, Augsburg, Germany
Critical Care 2007, 11(Suppl 2):P193 (doi: 10.1186/cc5353) Nonlinearity of intratidal airway resistance H Knorpp1, C Stahl2, S Schumann2, M Lichtwarck-Aschoff3,
J Guttmann2
1UT Southwestern, Dallas, TX, USA; 2University of Freiburg,
Germany; 3Zentralklinikum, Augsburg, Germany
Critical Care 2007, 11(Suppl 2):P193 (doi: 10.1186/cc5353) Introduction Acute respiratory distress syndrome is a disease
associated with high mortality. Understanding the interdependence S78 Available online http://ccforum.com/supplements/11/S2 Figure 1 (abstract P194) Figure 1 (abstract P194) Figure 1 (abstract P193) objective of this study was to evaluate plasma cytokine behavior
after an ARM in healthy volunteers. Methods After obtaining ethical committee approval and informed
consent, a basal blood sample was collected in 10 healthy
volunteers. Continuous positive airway pressure (CPAP) was
noninvasively applied (BiPAP Vision®; Respironics, USA) using a
total face mask. CPAP was increased by 3 cmH2O from 5 to
20 cmH2O every five breaths. At CPAP of 20 cmH2O, an
inspiratory pressure of 20 cmH2O above CPAP was implemented
during 10 breaths. After that, CPAP was stepwise decreased in an
inverse fashion. Pulse oximetry, arterial pressure and heart rate
were measured before and after ARM. Additional blood samples
were drawn at 30 minutes, 2 and 12 hours. TNFα, IL-1β, IL-6, IL-8,
IL-10 and IL-12 were measured by the flow cytometry technique
(Cytometric Bead Array BD™ Kit). The highest cytokine value at
30 minutes or 2 hours after ARM was considered the peak value
measurement. Data were analyzed using a paired t test and one-
way RM ANOVA. P < 0.05 was significant. of ventilator settings and respiratory mechanics is crucial for further
developments of protective lung ventilation. Up to now, the
nonlinearity of compliance has mainly been the focus of interest. We hypothesized that airway resistance also changes intratidally. Therefore, this study was performed to analyze the dependence of
resistance on tidal gas volume. Methods After induction of anesthesia and tracheotomy, the lungs
of 14 surfactant-depleted piglets were ventilated at zero end-
expiratory pressure with three different tidal volumes (8, 12, 16 ml/kg)
in a randomized order. In addition, baseline measurements
(12 ml/kg) were performed before saline lavage. Before any
change of the ventilator settings a recruitment maneuver was
performed. The nonlinear intratidal airway resistance was analyzed
using the SLICE method [1]. Results Figure 1 shows the intratidal resistance before lavage
(grey) and after surfactant depletion (black) plotted against the
alveolar pressure. Each curve in the diagram represents the
intratidal course of resistance for one ventilator setting. P194 K Moeller1, T Sivenova1, C Stahl2, S Schumann2, J Guttmann2
1Furtwangen University, Villingen-Schwenningen, Germany;
2University of Freiburg, Germany
Critical Care 2007, 11(Suppl 2):P195 (doi: 10.1186/cc5355) P195 Recruitment/derecruitment models fitted to respiratory
data of acute respiratory distress syndrome/acute lung
injury patients Nonlinearity of intratidal airway resistance Resistance
is increased after surfactant depletion and is intratidally declining
before and after lavage. Results Four men and six women with a mean age of 26 ± 1 years
and mean BMI of 23.8 ± 3.6 kg/m2 were studied. No changes
were observed in heart rate or MAP after ARM, while pulse
oximetry increased from 97.2 ± 0.8% to 98.4 ± 0.7% (P = 0.009). As shown in Figure 1, ARM induced a significant increase in the
peak plasma level concentration of all cytokines that returned to
basal levels within 12 hours. No adverse effects were observed
during and after ARM. Conclusion The analysis of resistance shows a dependence on
intratidal volume. The nonlinear course of intratidal resistance can
be interpreted as a volume-related caliber effect leading to an
increase of cross-sectional area of the large and small airways. Conclusions Despite beneficial effects in reversing atelectasis,
ARM-induced lung stretching was associated with an inflammatory
response in healthy volunteers. Reference 1. Guttmann J, Eberhard L, Fabry B, et al.: Determination of
volume-dependent respiratory system mechanics in
mechanically ventilated patients using the new slice
method. Technol Health Care 1994, 2:175-191. Noninvasive alveolar recruitment maneuver induces
cytokine release in healthy volunteers The FRC, ratio (PaO2/FiO2) and static
compliance (Cstat) are registered in three clinical steps: 1: ICU
arrival; 2: after pulmonary recruitment with high inspiratory
pressure; and 3: 3 hours after recruitment. Data are shown as the
mean ± standard deviation; intragroup variables are analyzed with
the Wilcoxon test (W), and intergroups variables are analyzed with
the Mann–Whitney test (MW). P < 0.05 is taken as statistically
significant. Results A multistep optimization process is performed to reduce
the difference between measured data and model prediction. At
any moment during a tidal breath or during some respiratory
maneuver the current state of the model can be visualized. The
inflated volume splits up into extension of open alveoli and into
temporal or pressure-dependent recruitment. Distribution of these
compartments over time during a tidal inflation is depicted in Figure 1a. The pressure vs time and flow vs time curves are shown in Figure 1b. Conclusion The fitting of recruitment models provides interesting
insight into not directly observable R/D. It may be used for
monitoring trends and drifts in recruitment. Currently results rely on
certain assumptions; for example, distribution and quantity of
superimposed pressure. With modern imaging techniques (for
example, CT, EIT) a validation of the fitted models will come into
reach and will be performed as a next step. Results FRC increase in group A is statistically significant (W)
(step 1: 1,525 ± 360 ml; step 2: 1,937 ± 583 ml, P < 0.05 vs step
1; step 3: 2,592 ± 659 ml, P < 0.05 vs step 2 and P < 0.01 vs step
1) while the FRC increase in group B is not significant (step 1:
1,697 ± 210 ml; step 2: 1,757 ± 367 ml; step 3: 1,982 ± 365 ml);
the FRC of group A is statistically higher than the FRC of group B
in step 2 (P < 0.05 MW) and in step 3 (P < 0.01 MW). Noninvasive alveolar recruitment maneuver induces
cytokine release in healthy volunteers Noninvasive alveolar recruitment maneuver induces
cytokine release in healthy volunteers L Malbouisson1, T Szeles1, C Carvalho1, P Pelosi2,
M Carmona1, J Auler1
1São Paulo University Medical School, São Paulo, Brazil;
2University of Insubria, Varese, Italy
Critical Care 2007, 11(Suppl 2):P194 (doi: 10.1186/cc5354) Introduction Recruitment/derecruitment (R/D) seems to play an
important role in the development of VILI [1]. Many clinicians base
their determination of PEEP settings during mechanical ventilation
of ARDS/ALI patients on an estimate of alveolar recruitability [2]. This project aims to establish an online tool that provides estimates
of R/D in patients at the bedside. Introduction Recruitment/derecruitment (R/D) seems to play an
important role in the development of VILI [1]. Many clinicians base
their determination of PEEP settings during mechanical ventilation
of ARDS/ALI patients on an estimate of alveolar recruitability [2]. This project aims to establish an online tool that provides estimates
of R/D in patients at the bedside. Introduction Alveolar recruitment maneuver (ARM) using high
airway pressures has been shown to re-expand atelectasis and to
improve gas exchanges after general anesthesia; however, ARM
may lead to lung stretching-induced inflammatory response. The Introduction Alveolar recruitment maneuver (ARM) using high
airway pressures has been shown to re-expand atelectasis and to
improve gas exchanges after general anesthesia; however, ARM
may lead to lung stretching-induced inflammatory response. The Methods We developed a computer simulation of R/D based on
Matlab (Mathworks, Natick, MA, USA), which incorporates different S79 Critical Care March 2007 Vol 11 Suppl 2
27th International Symposium on Intensive Care and Emergency Medicine Figure 1 (abstract P195) Figure 1 (abstract P195) recruitment range (group A) and in patients with low recruitment
range (group B). approaches [1,3,4]. Our model is fitted (currently offline) to patient
data acquired during controlled mechanical ventilation. For data
acquisition the internal respiratory data of a ventilator (Evita 4;
Dräger Medical, Lübeck, Germany) is read in real time. The
simulation assumes a quantitative partition into pressure-
dependent and time-dependent recruitment. Pure pressure-related
approaches (for example [1]) are not able to describe transients
(for example, a volume shift after a change in PEEP). Methods Five patients without pulmonary disease (group A)
admitted to the ICU for a postoperative course and five patients
admitted to the ICU for acute respiratory failure (group B) were
studied with the Engström Carestation FRC system based on the
evaluation of nitrogen wash-in and washout by the COVX
metabolic module. References 1. Hickling KG: Am J Respir Crit Care Med 2001, 163:69-78. 2. Gattinoni L, et al.: N Engl J Med 2006, 354:1775-1786. 3. Bates JH, et al.: J Appl Physiol 2002, 93:705-713. 4. Möller K, et al.: Crit Care 2005, 9(Suppl 1):S44-S45. 1. Hickling KG: Am J Respir Crit Care Med 2001, 163:69-78. 2. Gattinoni L, et al.: N Engl J Med 2006, 354:1775-1786. 3. Bates JH, et al.: J Appl Physiol 2002, 93:705-713. 4. Möller K, et al.: Crit Care 2005, 9(Suppl 1):S44-S45. 1. Hickling KG: Am J Respir Crit Care Med 2001, 163:69-78. 2. Gattinoni L, et al.: N Engl J Med 2006, 354:1775-1786. 3. Bates JH, et al.: J Appl Physiol 2002, 93:705-713. 3. Bates JH, et al.: J Appl Physiol 2002, 93:705-713. 4. Möller K, et al.: Crit Care 2005, 9(Suppl 1):S44-S45. Noninvasive alveolar recruitment maneuver induces
cytokine release in healthy volunteers The ratio
increase in group A is statistically significant (W) (step 1:
256 ± 133; step 2: 407 ± 187, P < 0.01 vs step 1; step 3:
379 ± 169, P < 0.05 vs step 1) while the ratio increase in group B
is not significant (step 1: 194 ± 50; step 2: 253 ± 83; step 3:
276 ± 73); the ratio of group A is statistically higher than the ratio
of group B in step 2 (P < 0.01 MW) and in step 3 (P < 0.05 MW). The Cstat increase in both groups is not significant, but in group A
Cstat is statistically higher than Cstat of group B in every step
(P < 0.05 MW) (step 1: 38 ± 2 ml/cmH2O for group A vs
28 ± 7 ml/cmH2O for group B; step 2: 44 ± 6 ml/cmH2O vs
36 ± 8 ml/cmH2O; step 3: 47 ± 5 ml/cmH2O vs 36 ± 8 ml/cmH2O). Conclusion With the limit of low sample size, these preliminary
data suggest that the FRC evaluation system is a good parameter
to optimize pulmonary recruitment and seems to be in a position to
overcome the Cstat limit for the evaluation of pulmonary recruitable
parenchyma. High-frequency oscillatory ventilation for trauma patients
with acute respiratory distress syndrome who fail
conventional mechanical ventilation High-frequency oscillatory ventilation for trauma patients
with acute respiratory distress syndrome who fail
conventional mechanical ventilation F Eng, M Ferri, S Rizoli, L Tremblay
Sunnybrook Health Sciences Centre, Toronto, Canada
Critical Care 2007, 11(Suppl 2):P197 (doi: 10.1186/cc5357) F Eng, M Ferri, S Rizoli, L Tremblay
Sunnybrook Health Sciences Centre, Toronto, Canada
Critical Care 2007, 11(Suppl 2):P197 (doi: 10.1186/cc5357) F Eng, M Ferri, S Rizoli, L Tremblay
Sunnybrook Health Sciences Centre, Toronto, Canada
Critical Care 2007, 11(Suppl 2):P197 (doi: 10.1186/cc5357) Introduction The purpose of this study is to report our clinical
experience with high-frequency oscillatory ventilation (HFOV) for
rescuing trauma patients with acute respiratory distress syndrome
(ARDS) and severe hypoxemia despite optimal conventional
ventilation. Experimental and clinical data suggest mechanical
ventilation can contribute to mortality in ARDS, and modern
ventilatory strategies require protective measures such as low tidal
volume, low airway pressure and fraction of inspired oxygen (FIO2),
which is not always possible with conventional ventilation. HFOV
could be an alternative to achieve protective ventilation and
adequate oxygenation. Methods Patients having a PO2/FiO2 ratio ≤150, PEEP >12 cm
and FiO2 requirement ≥0.7 on VCV (6 ml/kg) were switched to
HFOV. The initial continuous distending pressure (CDP) of HFOV
was 5 cm above the mean airway pressure during VCV. Other
HFOV settings were FiO2 1, bias flow 30 l/min, amplitude 70 cm
and frequency 7 Hz. The CDP was adjusted to maintain oxygen
saturation >88%. Fluid bolus before switching to HFOV was
avoided. All the patients were sedated and paralysed during the
study period. A drop in the mean arterial pressure (MAP) ≤65 mm
or cardiac index (CI) ≤2.5 l/min/m2 were treated with escalation of
inotrope if required. Hemodynamic monitoring was done with the
Flotrac-Vigileo monitoring system. Methods We retrospectively analyzed nine trauma patients who
presented with ARDS criteria and failed conventional mechanical
ventilation requiring HFOV. The mean airway pressure was initially
set 3–5 cmH2O higher than that for conventional ventilation and
was subsequently adjusted to maintain oxygen saturation >90%
and FiO2 <0.6. The PaCO2 target range was 35–60 mmHg with a
pH >7.25. We collected demographic data, injury severity scale
(ISS), APACHE II score, time to HFOV, time spent on HFOV,
ventilation settings and arterial blood gas before and after HFOV
and mortality. Results Eight ARDS patients needing vasopressor support were
switched to HFOV from VCV. P196 A novel system for evaluation of pulmonary functional
residual capacity in the intensive care unit: preliminary data G Falzetti, T Principi, P Pelaia
Anaesthesia and Intensive Care Clinic – Politechnical University of
Marche, Ancona, Italy
Critical Care 2007, 11(Suppl 2):P196 (doi: 10.1186/cc5356) Introduction The aim of this study is to evaluate the efficacy of
pulmonary recruitment by the use of functional residual capacity
(FRC) measurement with the Engström Carestation FRC INview™
system (GE Healthcare), in patients with high pulmonary S80 Available online http://ccforum.com/supplements/11/S2 Figure 1 (abstract P198) Figure 1 (abstract P198) Figure 1 (abstract P198) Outcome predictors of high-frequency oscillatory
ventilation in acute respiratory distress syndrome S Jog, P Akole, P Rajhans, B Pawar
Deenanath Mangeshkar Hospital and Research Centre, Pune, India
Critical Care 2007, 11(Suppl 2):P199 (doi: 10.1186/cc5359) Conclusion HFOV is a possible alternative for safely correcting
oxygenation failure associated with ARDS in trauma patients. Further research is necessary to identify the best strategy and
patients for HFOV. Introduction Outcome predictors of high-frequency oscillatory
ventilation (HFOV) in severe ARDS are not well studied. Objective To evaluate outcome predictors of HFOV in adult
patients with ARDS. Introduction Outcome predictors of high-frequency oscillatory
ventilation (HFOV) in severe ARDS are not well studied. Objective To evaluate outcome predictors of HFOV in adult
patients with ARDS. Methods ARDS patients receiving mechanical ventilation as per
the ARDSnet protocol with PO2/FiO2 <150, PEEP ≥12 cm and
FiO2 ≥0.7 were considered for HFOV. The continuous distending
pressure (CDP), frequency, amplitude, inspiratory time and bias
flow of HFOV were optimised, guided by frequent blood gas
analysis. Weaning from HFOV to pressure support ventilation was
attempted once the PO2/FiO2 ratio remained ≥200 with CDP
≤18 cm FiO2 ≤0.5. Responders (R) were defined as patients who
were successfully weaned to a state without any ventilatory
support for >12 hours. Nonresponders (NR) could not be weaned
off any ventilatory assistance. High-frequency oscillatory ventilation for trauma patients
with acute respiratory distress syndrome who fail
conventional mechanical ventilation Baseline data of these patients
were: age 58.87 ± 11.69 years, APACHE II score 21.02 ± 8.14,
mean CDP of HFOV 26.67 ± 3.22 cm, frequency 7 Hz, amplitude
70 cm. Figure 1 presents the trends of hemodynamic parameters
during the study period. Only one patient needed escalation of the
dopamine dose during the trial period. Results Data on nine trauma patients were available for analysis;
the severity of respiratory dysfunction can be estimated by the
mean PaO2/FiO2 of our patients, 131. Two patients received a trial
of inhaled nitric oxide as part of the management of ARDS failing
conventional ventilation. The last mean measurements before
initiation of HFOV were: pH 7.24, PaO2 116, PCO2 67.4, FiO2
0.899. No significant hemodynamic instability was associated with
initiation and administration of HFOV. The mean frequency was 4.3
(mode 4), mean power was 8.5, mean FiO2 was 0.83. The
successful weaning rate from HFOV to extubation or trach mask
was 70%, and mean total time of mechanical ventilation
(conventional + HFOV) was 347.76 hours and the time spent on
HFOV was 107.5 hours. Conclusion Switching of an ARDS patient from VCV to HFOV
does not impart significant hemodynamic instabilities and can be
safely done. pH: an overlooked criterion for success in high-frequency
oscillatory ventilation in acute respiratory distress syndrome? pH: an overlooked criterion for success in high-frequency
oscillatory ventilation in acute respiratory distress syndrome? K Madhusudana, K Black, C Melville
Hull Royal Infirmary, Hull, UK
Critical Care 2007, 11(Suppl 2):P201 (doi: 10.1186/cc5361) K Madhusudana, K Black, C Melville Introduction High-frequency oscillatory ventilation (HFOV) is used
for patients with refractory hypoxia and or severe oxygenation
failure in our ICU. There is a unit policy regarding the timing of
initiation of HFOV, and all patients were initiated with a single
static recruitment manoeuvre and then managed according to local
guidelines. The aim of this study was to understand which
ventilatory parameters best predicted successful outcome
following HFOV. that in the NR group. The difference in improvement in the
oxygenation index (OI) of the two groups at 6 and 24 hours was
also statistically significant. The rate of improvement in the
PO2/FiO2 ratio and OI in NR was slower than that in R, and this
difference was statistically significant (trend test). See Figure 1. Conclusion A lower PO2/FiO2 ratio and higher OI prior to HFOV
and slow improvement in the PO2/FiO2 ratio and OI at 6 and 24
hours on HFOV are significant negative outcome predictors of
HFOV in ARDS. that in the NR group. The difference in improvement in the
oxygenation index (OI) of the two groups at 6 and 24 hours was
also statistically significant. The rate of improvement in the
PO2/FiO2 ratio and OI in NR was slower than that in R, and this
difference was statistically significant (trend test). See Figure 1. y
g
g
Conclusion A lower PO2/FiO2 ratio and higher OI prior to HFOV
and slow improvement in the PO2/FiO2 ratio and OI at 6 and 24
hours on HFOV are significant negative outcome predictors of
HFOV in ARDS. Methods After institutional approval, we retrospectively reviewed
the case notes all the adult patients who were ventilated with
HFOV during the 18-month period between January 2005 and July
2006. The data were analysed using SPSS® version 13 software. Results There were 33 episodes of HFOV in 31 patients; 19
females and 12 males; mean age of 56 years. First-day median
APACHE II scores and predicted mortality were 23 and 41%,
respectively. All the patients had acute respiratory distress
syndrome (ARDS) at the time of initiation of HFOV. pH: an overlooked criterion for success in high-frequency
oscillatory ventilation in acute respiratory distress syndrome? The main
causes of ARDS were pneumonia leading to sepsis (50%), sepsis
from other sources (18%), postoperative emergency laparotomy
and abdominal aortic aneurysm repair (18%). Patients were
ventilated with conventional ventilation for a median period of
35 hours (0–519 hours) before being ventilated with HFOV for a
median period of 58 hours (7–1,080 hours). Fourteen patients
(45%) were successfully weaned to conventional ventilation while
two (7%) died because of cardiac arrest and in the remaining 15
patients (48%) treatment was withdrawn. Eight patients (25.8%)
survived to discharge to the ward. An admission pH of less than
7.20 was found to be significantly associated (P = 0.09) with
failure of treatment. P200 Monitoring slow recruitment manoeuvres with high-
frequency oscillatory ventilation in adult acute respiratory
distress syndrome patients using electrical impedance
tomography
L Camporota, J Smith, K Lei, T Sherry, R Beale
Guy’s and St Thomas’ NHS Foundation Trust, London, UK
Critical Care 2007, 11(Suppl 2):P200 (doi: 10.1186/cc5360) Monitoring slow recruitment manoeuvres with high-
frequency oscillatory ventilation in adult acute respiratory
distress syndrome patients using electrical impedance
tomography L Camporota, J Smith, K Lei, T Sherry, R Beale
Guy’s and St Thomas’ NHS Foundation Trust, London, UK
Critical Care 2007, 11(Suppl 2):P200 (doi: 10.1186/cc5360) Introduction Recruitment manoeuvres (RM) during high-frequency
oscillatory ventilation (HFOV) are increasingly used in ARDS. However, the changes in lung volume during a RM (lung
recruitability) are difficult to quantify at the bedside, and the use of
CT is impractical in patients on HFOV. We studied the effects of a
standardised protocol of slow RM (SRM) on regional lung volumes
assessed noninvasively by electrical impedance tomography (EIT). y
y
g
y
Methods SRM were performed by progressive increases of
continuing distending pressure (CDP) starting from the mean airway
pressure on CMV + 5 cmH2O, by increments of 3 cmH2O every
10 minutes until a CDP of 50 cmH2O was reached or haemo-
dynamic instability ensued. Subsequently, CDP was reduced by
2 cmH2O every 5 minutes until optimal CDP was established on gas
exchange. EIT measurements were performed using 16 electrodes,
acquired via the Goe-MF II EIT system (Viasys Healthcare, USA). Offline analysis of EIT measurements was performed using the
AUSPEX software (University of Amsterdam). Changes in
impedance (∆Z) during tidal breathing were calibrated against set
tidal volumes during conventional mechanical ventilation. Changes in
lung volume after each increase in CDP on HFOV were expressed
as the fold change compared with the previous CDP level. Conclusion Although we believed that the unit’s approach to
HFOV was one of ‘treatment’ rather than ‘rescue’, our results
suggest we are still using HFOV in a ‘rescue’ mode. While our
results support the findings of other studies that earlier initiation of
HFOV shows a trend towards improved outcome in adult patients
with ARDS, further studies are still required to identify appropriate
parameters for selecting patients in a timely manner who may
benefit from HFOV. However, progressive acidosis in ARDS
appears to be a relatively more important predictive criterion than
parameters of failing oxygenation and ventilation. P202 Acoustic monitoring of one-lung ventilation with vibration
response imaging Hemodynamic effects of high-frequency oscillatory
ventilation in acute respiratory distress syndrome Hemodynamic effects of high-frequency oscillatory
ventilation in acute respiratory distress syndrome S Jog, P Akole, S Gadgil, P Rajhans
Deenanath Mangeshkar Hospital and Research Centre, Pune, India
Critical Care 2007, 11(Suppl 2):P198 (doi: 10.1186/cc5358) Introduction High-frequency oscillatory ventilation (HFOV) is a
promising ventilatory modality for ARDS patients having refractory
hypoxemia despite standard ARDS ventilation. Hemodynamic
alterations while switching the patient from volume-controlled
ventilation (VCV) to HFOV are not yet well studied. Introduction High-frequency oscillatory ventilation (HFOV) is a
promising ventilatory modality for ARDS patients having refractory
hypoxemia despite standard ARDS ventilation. Hemodynamic
alterations while switching the patient from volume-controlled
ventilation (VCV) to HFOV are not yet well studied. Results Fifteen out of the total 28 patients were R and 13 were
NR. Both the groups were similar prior to HFOV in terms of
APACHE II score, number of organ failures, PEEP and plateau
pressures, and duration of ventilation before HFOV. The baseline
PO2/FiO2 ratio and improvement in it at 6 hours and 24 hours in
the R group were statistically significantly higher as compared with Objective To evaluate immediate (within 3 hours) hemodynamic
effects of HFOV in ARDS patients with septic shock needing
vasopressor support. S81 Critical Care March 2007 Vol 11 Suppl 2
27th International Symposium on Intensive Care and Emergency Medicine Figure 1 (abstract P199)
VCV, volume controlled ventilation. Figure 1 (abstract P199) Conclusion EIT can noninvasively assess lung recruitability and
quantify the changes in global and regional lung volume during
SRM with HFOV in ARDS patients. Conclusion EIT can noninvasively assess lung recruitability and
quantify the changes in global and regional lung volume during
SRM with HFOV in ARDS patients. Correlation of lung vibration and airflow Figure 2 (abstract P202) S Jean, I Cinel, C Tay, Z Wang, D McGinly
Robert Wood Johnson School of Medicine, UMDNJ, Cooper
University Hospital, Camden, NJ, USA
Critical Care 2007, 11(Suppl 2):P203 (doi: 10.1186/cc5363) Introduction Airflow into a mechanically ventilated patient is easily
measured in the inspiratory limb of the ventilator. Regional airflow
inside the lungs, up to this point, is a black box. Vibration response
imaging (VRI) is a novel technology that measures vibration energy
from the lungs to create a real-time structural and functional image
of regional vibration during respiration. Sophisticated surface skin
sensors are placed on the subject’s back to record, analyze and
display vibrations noninvasively. Our goal was to assess the
correlation of vibration measured at the chest wall with airflow into
the lungs. Methods To assess the effect of constant inspiratory flow on lung
vibration, VRI was performed on a mechanically ventilated patient
on assist volume control, and airflow in the tubing was recorded
concurrently. To assess the effect of increasing flow rates on lung
vibration, healthy subjects were recorded several times with VRI
while taking tidal volumes of 200–1,300 ml at the same respiratory
rate. The inspiratory tidal volume was recorded. Figure 2 (abstract P202) Figure 2 (abstract P202) Figure 2 (abstract P202) S83
Figure 1 (abstract P203)
Figure 2 (abstract P203) Figure 1 (abstract P203)
Figure 2 (abstract P203) Figure 1 (abstract P203) Figure 1 (abstract P203) inaccurate for the detection of OLV with a high margin, up to 60%
error [1]. Vibration response imaging (VRI) is a novel technology
that measures vibration energy from the lungs and displays
regional intensity in both visual and graphic format. The time from
the start of the procedure to display takes less than 1.5 minutes. We investigated the effectiveness of VRI to detect OLV using a
double-lumen endotracheal tube in lung surgery patients. Methods Double-lumen tubes were placed at the time of surgery. Tracheal and endobronchial lumens were alternately clamped to
produce unilateral lung ventilation of the right and left lungs. VRI
was performed after each occlusion. Two images were excluded a
priori (prior to analysis) due to technical failure (external artifact). Figure 2 (abstract P203) Figure 2 (abstract P203) S83 Results The right and left lung distribution of vibration intensity is
shown in Figure 1. P203 Correlation of lung vibration and airflow Acoustic monitoring of one-lung ventilation with vibration
response imaging Results Four patients with ARDS, who underwent rescue HFOV,
were enrolled. Following the SRM, there was a mean 2.38-fold
increase in PaO2/FiO2 and a 19.7% reduction in PaCO2. EIT
showed a mean 4.66-fold increase in global lung volume, with
preferential ventilation of the ventral regions (59.4% of global
volume change). Despite these differences, both dorsal and ventral
regions showed a similar degree of volume change compared with
their own baseline (V/D of 4.7/4.5-fold). This may be consistent
with a more homogeneous recruitment with HFOV. The inflation
limb of the changes in lung volumes during SRM fitted the
Venegas–Harris equation (r2 = 0.99). I Cinel, S Jean, I Gratz, E Deal, C Tay, J Littman
Robert Wood Johnson School of Medicine, UMDNJ, Cooper
University Hospital, Camden, NJ, USA
Critical Care 2007, 11(Suppl 2):P202 (doi: 10.1186/cc5362) Introduction Inadvertent endobronchial intubation and one-lung
ventilation (OLV) with a standard endotracheal tube may lead to
serious complications, such as a nonventilated lung, pneumothorax
and hypoxemia. Auscultation of breath sounds was found to be Introduction Inadvertent endobronchial intubation and one-lung
ventilation (OLV) with a standard endotracheal tube may lead to
serious complications, such as a nonventilated lung, pneumothorax
and hypoxemia. Auscultation of breath sounds was found to be S82 Available online http://ccforum.com/supplements/11/S2 Figure 1 (abstract P202) P203 P205 Functional residual capacity measurement during
mechanical ventilation in order to find the optimal positive
end-expiratory pressure Introduction Focusing on lung-protective ventilation, the analysis
of nonlinear dynamic respiratory mechanics appears crucial. Based
on the SLICE method we developed the Gliding-SLICE method as
a tool to determine respiratory system mechanics. This tool was
tested in a nonlinear water-filled two-chamber lung model. I Bikker, D Reis Miranda, J Van Bommel, J Bakker, D Gommers
Erasmus MC, Rotterdam, The Netherlands
Critical Care 2007, 11(Suppl 2):P205 (doi: 10.1186/cc5365) Introduction In patients with ALI/ARDS, a protective ventilation
strategy has been introduced in order to diminish ventilator-
induced lung injury. It has become clear that these patients require
sufficient levels of PEEP to prevent alveolar derecruitment, but also
not too much PEEP that alveolar overdistension occur. To achieve
the optimal level of PEEP in patients with ALI/ARDS, different
concepts have been introduced. GE Healthcare, along with Dr Ola
Stenqvist, has developed a technology to measure functional
residual capacity (FRC) in ventilated patients without interruption
of the ventilation. The aim of this study was to test the feasibility of
this device and to test whether decreasing the PEEP affects FRC
in mechanically ventilated patients with and without lung disease. Methods The classic SLICE method [1] determines parameters of
the respiratory system for abutted volume ranges. The Gliding-
SLICE method enhances this method by moving a window of
analysis along the volume axis. This way, a quasi-continual course
of intratidal mechanics can be determined. To test the new method
we build up a physical model that consists of two connected
chambers filled with water. During inspiration water is displaced
from one chamber to the other resulting in a counter pressure. Using wedges of certain shapes we simulated volume-dependent
nonlinear compliances. Results Using the Gliding-SLICE method we determined a
nonlinear course of compliance in a patient (Figure 1) and in model
data (Figure 2). Methods For this survey we examined 10 patients under mechanical
ventilation. The FRC examinations were performed with the
Engström Carestation equipped with the FRC Inview™ monitoring
feature. FRC is determined using the change of lung nitrogen volume
after a step change in the inspired oxygen fraction. With this system,
there is no need to use supplementary gases or specialized gas
monitoring devices. Furthermore, a series of FRC measurements can
automatically be obtained at different PEEP levels that can be
chosen prior to the measurement. Correlation of lung vibration and airflow The mean percentage change of vibration
intensity clearly demonstrates the increased vibration in ventilated
lungs (89.1 ± 5.47% vs 10.9 ± 5.4%, P < 0.05) (Figure 2). Conclusions
Auscultation
is
insensitive
to
endobronchial
intubation and chest radiography may not be immediately available. VRI offers the potential to rapidly and noninvasively determine
endobronchial intubation. Currently VRI is performed in the sitting
position, but the capability of supine imaging will soon be available. Reference 1. Brunel
W,
et
al.:
Assessment
of
routine
chest
roentgenograms and the physical examination to confirm
endotracheal tube position. Chest 1989; 96:1043-1045. S83 Critical Care March 2007 Vol 11 Suppl 2
27th International Symposium on Intensive Care and Emergency Medicine ritical Care March 2007 Vol 11 Suppl 2
27th International Symposium on Intensive Care and Emergency Medicin Reference
1. Guttmann et al.: Technol Health Care 1994, 2:175-191. Figure 2 (abstract P204) Figure 2 (abstract P204) Figure 2 (abstract P204) Results In the mechanically ventilated patient, when there is
minimal flow, the vibration was at its lowest. When flow begins at
the ventilator, the vibration measured over the lungs increases and
when the flow stops, the vibration decreases. An inspiratory hold
was performed to separate inspiratory from expiratory vibrations
(Figure 1). As the subject takes increasing tidal volumes, the
vibration during the breath cycle increases linearly. A sample
subject is shown in Figure 2 (R2 = 0.81). Conclusion Vibration measured using VRI correlates with lung
airflow. Given the difficulty in assessing airflow in the lungs,
measuring lung vibration could potentially serve as a surrogate for
regional lung airflow. P204 The Gliding-SLICE method: an enhanced tool for
estimation of intratidal respiratory mechanics Reference Reference
1. Guttmann et al.: Technol Health Care 1994, 2:175-191. S Schumann1, C Stahl1, D Steinmann1, K Möller2, J Guttmann1
1University Hospital, Freiburg, Germany; 2HFU, Furtwangen,
Germany
Critical Care 2007, 11(Suppl 2):P204 (doi: 10.1186/cc5364) P205 During this procedure, all
ventilator settings will remain constant other than the FiO2 and the
PEEP settings. In patients with ALI, the PEEP was decreased from
25 to 5 cmH2O in five steps and the FRC was measured. In the
patients without lung disease, PEEP was decreased from 15 to
0 cmH2O in four steps and the FRC was measured. Conclusion The Gliding-SLICE method allows one to calculate
mechanical parameters of the respiratory system quasi-continually. This allows a more intuitive interpretation of data. The method is
not limited to principle constrictions but can be enhanced by
ventilatory maneuvers; for example, for separated view on
inspiratory and expiratory respiratory mechanics. P208 Dry powder nebulization of a recombinant surfactant
protein C-based surfactant for treatment of acute
respiratory distress syndrome C Ruppert, T Kuchenbuch, S Schmidt, P Markart, T Gessler,
T Schmehl, W Seeger, A Guenther
University of Giessen Lung Center, Giessen, Germany
Critical Care 2007, 11(Suppl 2):P208 (doi: 10.1186/cc5368) Results The R-squared (R2) values for the correlation between
lnPaO2 and %Vnon of lung and the slice combinations juxta, 3new
and 3old were 0.61, 0.60, 0.57 and 0.55, respectively. The %Vnon
of lung correlated best with the %Vnon of slice combinations juxta
and 3new (R2 = 0.96 and 0.95, respectively). Comparison of these
slice combinations with lung also resulted in the least bias in the
Bland–Altman analyses (6.3 and 5.9%, respectively). R2 for the
correlation between lung and 3old was 0.93, and the bias for lung
vs 3old in the Bland–Altman analysis was 6.8%. Introduction Nebulization of pulmonary surfactant for treatment of
ARDS represents a desirable therapeutic approach but was
hitherto impossible under clinical conditions due to the technical
limitations of currently available devices. In the present study we
investigated a new dry powder nebulizer for administration of a
recombinant surfactant protein C (rSP-C)-based surfactant. Introduction Nebulization of pulmonary surfactant for treatment of
ARDS represents a desirable therapeutic approach but was
hitherto impossible under clinical conditions due to the technical
limitations of currently available devices. In the present study we
investigated a new dry powder nebulizer for administration of a
recombinant surfactant protein C (rSP-C)-based surfactant. y
Conclusion Depending on the precision required, the use of single
juxtadiaphragmatic CT slices can help to speed up the analysis
process and thereby propel the clinical implementation of CT-
derived information. Our data suggest that juxtadiaphragmatic
slices may be better suited than the ‘traditional’ combination of
apical, hiliar and juxtadiaphragmatic slices. Methods The nebulizer device consists of a cylindrical glass
housing that, at the bottom, ends up in a spherical lower housing
part that serves as the dry powder reservoir. A gas inlet portion
with a nozzle at its end is coaxially aligned with the housing, almost
reaches the bottom of the dry powder reservoir, and induces
aerosol generation when gas pressures between 1 and 2 bar are
applied. The upper portion of the housing contains a cap with an
aerosol exit port. Several nozzles ensure a discharge of unsuitably
large aerosol particles. Aerosol characteristics were determined by
laser diffractometry. Available online http://ccforum.com/supplements/11/S2 Results At Time 1, the control group (n = 21) had ratio of arterial
partial pressure of oxygen to fraction of inspired oxygen (PaO2/
FiO2) and partial arterial carbon dioxide pressure (PaCO2) of
167.7 ± 56.2 and 40.3 ± 10.1, respectively, and the intervention
group (n = 19) had PaO2/FiO2 of 180.5 ± 67.0 and PaCO2 of
38.6 ± 10.5. At Time 2, the control group had, respectively, PaO2/
FiO2 and PaCO2 of 165.9 ± 63.8 and 38.9 ± 10.3, and the inter-
vention group of 177.2 ± 4.5 and 39.0 ± 10.8. No variable was signifi-
cantly different between the groups at Time 1 and Time 2 (P > 0.05). Conclusion The proposed maneuver was not beneficial for gas
exchange in the sample studied. Methods The patients with the diagnosis of ALI and ARDS who met
the inclusion criteria were randomized to one of the two groups:
those of the intervention group were subjected to a pulmonary
expansion and bronchial disobstruction maneuvers, for approximately
10 minutes by the association of the following physiotherapy
techniques:
sighs,
side-lying
position,
expiratory
rib-cage
compression and endotracheal suctioning with a closed system and
after observed for 10 minutes; the patients of the control group did
not receive any treatment, they were only observed for 20 minutes. Ventilatory parameters and arterial blood gases were measured
before (Time 1) and 10 minutes after the procedures (Time 2). The
analysis of variance test for repeated measurements was used for
comparing variables at different times. Results are shown as the
mean and standard deviation. The significant level was P < 0.05. P208 The efficacy of an inhalative rSP-C surfactant
application was assessed in three animal models of acute lung
injury, including rabbits with acute lung injury due to either
repetitive lavage with prolonged and injurious ventilation, or due to
inhalative application of bleomycin at day 4, and bleomycin-
challenged, spontaneously breathing mice. Analysis of the nonaerated lung volume in combinations of
single computed tomography slices – is extrapolation to
the entire lung feasible? Analysis of the nonaerated lung volume in combinations of
single computed tomography slices – is extrapolation to
the entire lung feasible? AW Reske, P Hepp, C Heine, K Schmidt, M Seiwerts,
U Gottschaldt, AP Reske
Universitaetsklinikum Leipzig, Germany
Critical Care 2007, 11(Suppl 2):P206 (doi: 10.1186/cc5366) Introduction The nonaerated lung volume (Vnon) can be quantified
from computed tomography (CT) images. Analysis of the CT slices
covering the entire lung is time-consuming and thus limits potential
clinical and experimental applications. This could be improved by
analyzing only a few representative CT slices. The number and ana-
tomical location of CT images required for analyses that are represen-
tative for the entire lung, however, is discussed controversially. Results At Time 1, the control group (n = 21) had ratio of arterial
partial pressure of oxygen to fraction of inspired oxygen (PaO2/
FiO2) and partial arterial carbon dioxide pressure (PaCO2) of
167.7 ± 56.2 and 40.3 ± 10.1, respectively, and the intervention
group (n = 19) had PaO2/FiO2 of 180.5 ± 67.0 and PaCO2 of
38.6 ± 10.5. At Time 2, the control group had, respectively, PaO2/
FiO2 and PaCO2 of 165.9 ± 63.8 and 38.9 ± 10.3, and the inter-
vention group of 177.2 ± 4.5 and 39.0 ± 10.8. No variable was signifi-
cantly different between the groups at Time 1 and Time 2 (P > 0.05). Conclusion The proposed maneuver was not beneficial for gas
exchange in the sample studied. Methods The percentage of Vnon (%Vnon) relative to the total lung
volume was quantified in CT-image series (n = 21) of sheep with
gross anesthesia-induced atelectasis. This was performed for
different combinations of number and anatomical location of CT
slices and the results were compared with the %Vnon of the entire
lung (lung). The combinations were: one juxtadiaphragmatic slice
(juxta), three apical, hiliar and juxtadiaphragmatic slices (3old), and
three consecutive juxtadiaphragmatic slices (3new). The correla-
tion between %Vnon and the arterial oxygen partial pressure (PaO2)
was examined for all combinations. The PaO2 was measured at the
time of the CT and transformed logarithmically (lnPaO2) to linearize
the relation between PaO2 and %Vnon. Linear regression and
Bland–Altman plots were used for statistical analysis. Figure 1 (abstract P204) 2
p
Results The best FRC measurements were obtained in well-
sedated patients during controlled mechanical ventilation. During
pressure support ventilation, a constant breathing pattern is
necessary for accurate FRC measurements. In patients that
received pressure support ventilation, FRC values were lower at
the highest studied PEEP level. In two patients that received
controlled ventilation, lower levels of FRC were found at the
highest PEEP level but this was due to a pneumothorax that was
diagnosed a day later. In patients with ALI, the FRC decreased
after each PEEP reduction step. However, the FRC decreased
more when PEEP was lowered from 15 to 10 cmH2O in these
patients. In patients without lung disease, the FRC did not S84 Available online http://ccforum.com/supplements/11/S2 Available online http://ccforum.com/supplements/11/S2 decrease after PEEP was reduced from 15 to 5 cmH2O but
decreased after PEEP was reduced from 5 to 0 cmH2O. Conclusion Accurate measurements of FRC are obtained during a
constant breathing pattern that is easier to obtain during controlled
ventilation in comparison with pressure-support ventilation. In
patients with ALI/ARDS, the FRC decreased during each PEEP
reduction, but whether the largest change in FRC indicates the
optimal PEEP needs further research. decrease after PEEP was reduced from 15 to 5 cmH2O but
decreased after PEEP was reduced from 5 to 0 cmH2O. Conclusion Accurate measurements of FRC are obtained during a
constant breathing pattern that is easier to obtain during controlled
ventilation in comparison with pressure-support ventilation. In
patients with ALI/ARDS, the FRC decreased during each PEEP
reduction, but whether the largest change in FRC indicates the
optimal PEEP needs further research. few studies on the effect on gas exchange in patients with acute
lung injury (ALI) and acute respiratory distress syndrome (ARDS)
and physiotherapy techniques. The purpose of this study was to
assess the effect of a pulmonary expansion and disobstruction
maneuver with a closed system on the gas exchange of patients
with ALI and ARDS. Conclusion Accurate measurements of FRC are obtained during a
constant breathing pattern that is easier to obtain during controlled
ventilation in comparison with pressure-support ventilation. In
patients with ALI/ARDS, the FRC decreased during each PEEP
reduction, but whether the largest change in FRC indicates the
optimal PEEP needs further research. Methods The patients with the diagnosis of ALI and ARDS who met
the inclusion criteria were randomized to one of the two groups:
those of the intervention group were subjected to a pulmonary
expansion and bronchial disobstruction maneuvers, for approximately
10 minutes by the association of the following physiotherapy
techniques:
sighs,
side-lying
position,
expiratory
rib-cage
compression and endotracheal suctioning with a closed system and
after observed for 10 minutes; the patients of the control group did
not receive any treatment, they were only observed for 20 minutes. Ventilatory parameters and arterial blood gases were measured
before (Time 1) and 10 minutes after the procedures (Time 2). The
analysis of variance test for repeated measurements was used for
comparing variables at different times. Results are shown as the
mean and standard deviation. The significant level was P < 0.05. P211 Results Fifty-eight critically ill patients undergoing mechanical
ventilation were included. Following the BAL, compliance of the
respiratory system (Crs) decreased from 50.9 ± 36.1 to 35.6 ±
14.8 ml/cmH2O (P < 0.01) and airway resistance increased from
16.2 ± 7.6 to 18.1 ± 11.3 cm H2O/l/seg (P < 0.05); 90 minutes
later, both parameters had returned to pre-BAL values (P = not
significant). Patients who showed >20% decrease in Crs had
higher pre-BAL Crs than patients with less severe decrease (55.8
± 20.1 vs 36.9 ± 14.1; P < 0.001). On the contrary, neither pre-
BAL airway resistance nor the extension of the radiographic
infiltrates were related to the changes in respiratory mechanics. P207 Pulmonary expansion and disobstruction maneuver with a
closed system in patients with acute lung injury and acute
distress syndrome, and its effect on gas exchange J Belato, S Barreto, C Santos, S Vieira
Hospital de Clínicas de Porto Alegre, Brazil
Critical Care 2007, 11(Suppl 2):P207 (doi: 10.1186/cc5367) Introduction Respiratory physiotherapy is ever more utilized for the
treatment of critical patients. However, it is known that there are Results The generated aerosol had a mass median aerodynamic
diameter of 1.6 µm, with 85% of all particles being smaller than S85 ritical Care March 2007 Vol 11 Suppl 2
27th International Symposium on Intensive Care and Emergency Medicin lesions at the bedside in the emergency department is difficult. Clinical examination (CE) and chest X-ray (X-ray) have limited
sensibility and specificity. Contrast-enhanced computed tomo-
graphy (CT scan) is the gold standard. CT scan has limitations: it
takes time to be performed, implies transport of severely injured
patients, and has ionising effects. Thoracic ultrasonography (US)
can be quickly performed at the bedside in the emergency room. It
has good diagnosis accuracy in ARDS patients [2]. The purpose of
this study is to evaluate the diagnosis accuracy of US in severely
injured patients in the emergency room. 5 µm, and the average mass of surfactant being nebulized under
these conditions was approximately 1 g/min. Biochemical and
biophysical studies showed that the composition and surface
tension reducing properties of the rSP-C surfactant remained
unaltered after nebulization. In both rabbit models, administration of
130 mg/kg body weight rSP-C surfactant resulted in a far-reaching
restoration of gas exchange and compliance. In bleomycin-
challenged, spontaneously breathing mice, surfactant aerosoliza-
tion resulted in a restoration of compliance. Conclusions Nebulizer characteristics and results from the in vivo
studies suggest that the herein-described dry powder nebulizer
might proffer for surfactant therapy of ARDS. Methods We prospectively evaluated 90 patients (median age: 41
(7–89) years) who were admitted to the emergency room of the
Grenoble University Hospital over a period of 9 months. Pneumothorax, hemothorax and alveolar consolidation were diag-
nosed by CE, X-ray and US. The physician who performed the US
was not involved in the patient’s management. The diagnosis
accuracy of each technique is compared with the CT scan
interpreted by the radiologist. P209 Changes in respiratory mechanics after fiberoptic
bronchoscopy with bronchoalveolar lavage in mechanically
ventilated patients
Á Estella García, A Gil Cano, J Díaz Monrove, I Monge García
Critical Care Unit, Hospital of Jerez, Spain
Critical Care 2007, 11(Suppl 2):P209 (doi: 10.1186/cc5369) Changes in respiratory mechanics after fiberoptic
bronchoscopy with bronchoalveolar lavage in mechanically
ventilated patients Á Estella García, A Gil Cano, J Díaz Monrove, I Monge García
Critical Care Unit, Hospital of Jerez, Spain
Critical Care 2007, 11(Suppl 2):P209 (doi: 10.1186/cc5369) Results Sixty percent of patients had a chest trauma IGS II 22
(8–104), ISS 20 (0–59), thorax AIS 2 (0–5), SOFA 1 (0–11),
oxygen saturation at the entrance 100% (74–100), mechanical
ventilation for 56% of patients. We studied 179 hemithorax. For
hemothorax (n = 16), the sensitivity/specificity/positive predictive
value/negative predictive values (%) were CE: 13/95/18/92; X-ray:
13/95/20/92; US: 63/95/56/96. For pneumothorax (n = 30), CE:
20/96/50/86; X-ray: 17/100/100/86; US: 53/93/62/91. For
alveolar consolidation (n
= 100), CE: 17/95/81/47; X-ray:
29/98/94/52; US: 69/82/83/67. Introduction Nonuniform findings have been reported about the
effects of bronchoalveolar lavage (BAL) on respiratory mechanics. Objectives (1) To study the effects of BAL on respiratory
mechanics in mechanically ventilated patients with suspected
pneumonia, and (2) to find out whether these effects are related to
the extension of radiographic infiltrate and preceding respiratory
mechanics measurements. Introduction Nonuniform findings have been reported about the
effects of bronchoalveolar lavage (BAL) on respiratory mechanics. Conclusion Ultrasonography has a better sensitivity than CE and
X-ray with a comparable specificity. In the emergency room it is a
reliable modality for the diagnosis of pneumothorax, hemothorax
and alveolar consolidation in the severely injured patient. References Methods BAL was performed with 150 ml sterile isotonic saline in
three aliquots of 50 ml. Respiratory mechanics (static compliance and
airway resistance) was measured using the rapid airway occlusion
technique immediately before and after the BAL and 90 minutes later. The heart rate, arterial blood pressure and body temperature were
recorded continuously in all patients. Patients were classified
according to the presence of unilateral or bilateral infiltrates. 1. Klein et al.: Anaesthesist 2006, 55:1172-1188. 2. Lichtenstein et al.: Anesthesiology 2004, 100:9-15. 1. Klein et al.: Anaesthesist 2006, 55:1172-1188. 2. Lichtenstein et al.: Anesthesiology 2004, 100:9-15. 1. Klein et al.: Anaesthesist 2006, 55:1172-1188. 2. Lichtenstein et al.: Anesthesiology 2004, 100:9-15. Prehospital emergency endotracheal intubation using the
Bonfils intubation fiberscope C Byhahn1, R Breitkreutz1, S Viehmeyer1, F Walcher1, B Zwissler2
1J.W. Goethe-University Hospital, Frankfurt, Germany; 2Klinikum
der Johann Wolfgang Goethe University, Frankfurt, Germany
Critical Care 2007, 11(Suppl 2):P211 (doi: 10.1186/cc5371) Objective Difficult intubating conditions are prevalent in 7–10% of
patients who require out-of-hospital emergency endotracheal intu-
bation. Airway anatomy can further be deteriorated through trauma,
bleeding, and the use of cervical spine (CS) immobilization collars. We evaluated the feasibility of the Bonfils intubation fiberscope for
prehospital emergency endotracheal intubation. Conclusions (1) BAL in mechanically ventilated patients can lead
to a significant but transitory deterioration on pulmonary mechanics
characterized by a decrease in Crs and an increase in airway
resistance. (2) Patients with better initial Crs showed the more
severe affectation. p
p
g
y
Materials and methods The Bonfils intubation fiberscope (Karl
Storz GmbH, Tuttlingen, Germany) is a reusable, rigid, straight
fiberoptic device with a 40° curved tip, 40 cm long and 5 mm in
diameter. A flexible eyepiece is mounted on the handle of the
scope. The fiberscope has a connector that fits onto the 15-mm
tracheal tube adapter and thereby allows oxygen insufflation. A
cold light source or a small battery handle (powered by two 1.5 V
alkaline batteries) can be attached to the stylet handle. The tip of
the Bonfils intubation fiberscope is positioned just proximal to the
tip of the attached endotracheal tube, thereby preventing the lens
from being soiled with blood or secretions. Having adopted the
Bonfils technique in our institution, we felt that because of its
battery-powered light source the Bonfils intubation fiberscope
could also be used in prehospital settings, independent of a Airway equipment on the intensive care unit for
management of the unanticipated difficult intubation J Craig1, R Green1, B Kyle1, M Jonas2
1Poole General Hospital, Poole, UK; 2Southampton General
Hospital, Southampton, UK
Critical Care 2007, 11(Suppl 2):P212 (doi: 10.1186/cc5372) Introduction This study was designed to assess the ability of ICUs
to deal with the unanticipated difficult intubation. The ICU is a
location in which the incidence of difficult intubation has been
found to be significantly higher than in theatre (8–22.5% vs 1.5%). Introduction This study was designed to assess the ability of ICUs
to deal with the unanticipated difficult intubation. The ICU is a
location in which the incidence of difficult intubation has been
found to be significantly higher than in theatre (8–22.5% vs 1.5%). Method We contacted all adult general ICUs in the South of
England and invited the physician responsible for airway
management to take part in a structured interview. The interview
was designed to follow the Difficult Airway Society (DAS)
guidelines. We designed six equipment-related questions that
identified a unit as achieving the minimum levels of equipment
necessary. These
included
availability
of
laryngoscopes,
capnography, LMA/ILMA, and rescue techniques. Method Six doctors in the emergency department were enrolled in
this study. All doctors have experienced using the AWS in cases
on the operation table but have no experience in special situations
such as patients on the ground (POG) or no space over the head
of the patient (NSH). Doctors tried intubation with the AWS and
Macintosh Laryngoscope (Mac) in the simulated POG and NSH
situations using a Laerdal Airway manikin. Technical training was
not carried out in advance. The NSH/Mac situation was not
investigated because it was theoretically impossible. The time to
intubate (TTI) was recorded. Method We contacted all adult general ICUs in the South of
England and invited the physician responsible for airway
management to take part in a structured interview. The interview
was designed to follow the Difficult Airway Society (DAS)
guidelines. We designed six equipment-related questions that
identified a unit as achieving the minimum levels of equipment
necessary. These
included
availability
of
laryngoscopes,
capnography, LMA/ILMA, and rescue techniques. Result All doctors successfully established intubation in each
situation, POG/Mac, POG/AWS and NSH/AWS. Although the
intubation of a manikin having no space over the head was thought
to be difficult without prior training, all doctors successfully
achieved the intubation from the foot using the AWS. P210 Diagnosis accuracy of thoracic ultrasonography in severely
injured patients A Hyacinthe1, C Broux1, G Francony1, G Ferretti2, J Payen1,
C Jacquot1
1Service de réanimation polyvalente et chirurgicale, CHU,
Grenoble, France; 2Radiologie, CHU, Grenoble, France
Critical Care 2007, 11(Suppl 2):P210 (doi: 10.1186/cc5370) A Hyacinthe1, C Broux1, G Francony1, G Ferretti2, J Payen1,
C Jacquot1
1 Introduction Thirty-three percent of severely injured patients suffer
from thoracic trauma [1]. Diagnosis of pleural and pulmonary Introduction Thirty-three percent of severely injured patients suffer
from thoracic trauma [1]. Diagnosis of pleural and pulmonary S86 Available online http://ccforum.com/supplements/11/S2 Figure 1 (abstract P212)
Airway equipment available on ICUs. A score of 6/6 is considered the
minimum. Figure 1 (abstract P212) 110/220 V cold light source. After appropriate inhospital training
with the Bonfils intubation in anesthetized patients, our hospital’s
mobile emergency unit staffed with an emergency physician was
equipped with a battery-powered Bonfils intubation fiberscope. Results During 123 missions, 15 adult patients underwent pre-
hospital endotracheal intubation (cardiac arrest n = 9, multiple
injuries n = 4, drug poisoning n = 1, pulmonary edema n = 1) with
the Bonfils intubation fiberscope, the use of which was either
planned (n = 13) or unplanned (n = 2). All intubations were
successful in the first attempt, even in two cardiac arrest victims
who had an unexpected difficult airway (Cormack&Lehane grade IV
under direct laryngoscopy). In those patients with multiple injuries
the cervical immobilization collar did not need to be unfastened or
removed for endotracheal intubation. Sufficient retropharyngeal
space – which is mandatory for sufficient use of the Bonfils – was
created by a digital jaw thrust maneuver in the first three patients. Using a standard Mackintosh laryngoscope blade significantly
enhanced ease of insertion of the Bonfils fiberscope and
visualization of the glottic aperture, thereby decreasing the
procedure time from 35–40 seconds to 20–25 seconds. Conclusion Despite this first promising series of in-the-field use,
physicians and paramedics should familiarize themselves with the
Bonfils device under optimal clinical conditions before using it
under emergency or prehospital conditions. In our experience, the
learning curve with the Bonfils device is steep, and 10 intubations
supervised by an instructor usually prove effective for achieving
sufficient skills to use the Bonfils on one’s own and under less
optimal conditions. In summary, we believe that the Bonfils
fiberscope will prove its value as an additional airway management
device in both, emergency and prehospital settings. P212 P212 P210 Airway equipment available on ICUs. A score of 6/6 is considered the
minimum. P213
Potential of the AirWay Scope for tracheal intubation in a
confined space
J Koyama
Shinshu University, Matsumoto, Japan
Critical Care 2007, 11(Suppl 2):P213 (doi: 10.1186/cc5373) J Koyama Acknowledgement The Bonfils intubation fiberscope was
generously provided by Karl Storz GmbH, Tuttlingen, Germany. Introduction Occasionally, rescuers are confronted with a hard
situation to establish tracheal intubation compared with doctors in
the anesthetic room. Especially in the confined space, the tracheal
intubation must enter technical difficulties with any supporting
device. This may be caused by the fact that there was no device
developed specially from a standpoint in the clinical emergency use. Objective The AirWay Scope (AWS) is one of the newest
intubation devices, manufactured using modern technology to
alleviate the tracheal intubation in emergency scenes. The AWS is
equipped with a full-colored CCD, a LCD monitor and a specially
configured introducer guiding a tracheal tube into the glottis
(Figure 1). The aim of this study is to confirm the potential of the
AWS as an intubation-supporting device in emergency scenes. M th d Si d
i
h
d
ll d i P213 Potential of the AirWay Scope for tracheal intubation in a
confined space J Koyama
Shinshu University, Matsumoto, Japan
Critical Care 2007, 11(Suppl 2):P213 (doi: 10.1186/cc5373) J Koyama
Shinshu University, Matsumoto, Japan
Critical Care 2007, 11(Suppl 2):P213 (doi: 10.1186/cc5373) A comparison of two types of new bronchial blockers,
Uniblocker™ and Coopdech endotracheal blocker tube, for
one-lung ventilation during thoracoscopy T Iizuka1, M Tanno2, Y Hamada1, T Shiga1, Y Ohe1
1Toho University Medical Center Ohashi Hospital, Meguro, Tokyo,
Japan; 2National Mito Medical Center, Mito, Japan
Critical Care 2007, 11(Suppl 2):P214 (doi: 10.1186/cc5374) Methods Benchtop model. Four tracheal tubes (8 mm internal
diameter) were studied; the LoTrach, Portex SoftSeal, Microcuff and
Mallincrokdt HiLo Evac. The model trachea had an internal diameter
of 2.4 cm and the cuff was inflated with a Tracoe constant pressure
device. The cuff was overpressured while fluid was instilled above
the cuff to a height of 50 cm. The stopwatch was started as the
pressure was reduced to the test pressure of 30 cmH2O. The rate of
fall of the resulting column of fluid was then measured. Introduction The purpose of this study was to compare the use of a
wire-guided bronchial blocker, Uniblocker™ (Fuji Systems Corporation,
Tokyo, Japan), with a spread type of bronchial blocker, Coopdech
endotracheal blocker tube (Daiken Medical Corporation, Osaka,
Japan), for lung isolation during elective thoracic surgical cases. Clinical study. Intubated patients underwent a staged recruitment
manoeuvre while the intracuff pressure was maintained with a Tracoe
cuff inflator. The PEEP was set to 15 cmH2O and then increased in
5 cmH2O increments every 5 seconds until 40 cmH2O was
achieved. A second observer auscultated the anterior neck and the
pressure at which air leak was heard was recorded. Two tubes were
studied; LoTrach (at 80 cmH2O intracuff pressure = 30 cmH2O
calculated wall pressure) and Portex Soft Seal (30 cmH2O). p
g
g
g
Materials and methods Twenty ASA I–II patients signed written
informed consent before being enrolled into the study. We
designed a prospective, randomized trial to compare the
effectiveness of lung isolation among the two types of bronchial
blockers: Uniblocker™ group (UBB; n = 10), and Coopdech
endotracheal blocker tube group (CBB; n = 10). Patients were
randomized to intubate with a single-lumen tube with concomitant
use of a UBB or a CBB. Both groups were subdivided in two:
bronchial blocker placed in the right mainstem bronchus
(UBBR/CBBR), and in the left mainstem bronchus (UBBL/CBBL). Comparisons between groups included: (1) the number of
unsuccessful placement attempts with the blinded insertion
technique, (2) the number of malpositions of the devices, (3) the
time required to place the device in the correct position, (4)
surgical satisfaction with the lung deflation, (5) complications and
(6) the quality of lung deflation. P214 A comparison of two types of new bronchial blockers,
Uniblocker™ and Coopdech endotracheal blocker tube, for
one-lung ventilation during thoracoscopy P215 Comparison of the LoTrach and the Portex Soft Seal cuff:
tracheal wall pressure and fluid leakage in a benchtop
study and a clinical study
L Evans, M Blunt, C Arunachalam, P Young
Queen Elizabeth Hospital, King’s Lynn, UK
Critical Care 2007, 11(Suppl 2):P215 (doi: 10.1186/cc5375) Comparison of the LoTrach and the Portex Soft Seal cuff:
tracheal wall pressure and fluid leakage in a benchtop
study and a clinical study L Evans, M Blunt, C Arunachalam, P Young
Queen Elizabeth Hospital, King’s Lynn, UK
Critical Care 2007, 11(Suppl 2):P215 (doi: 10.1186/cc5375) Introduction The objective of the study is to demonstrate two
methods of measuring tracheal wall pressure (in vitro and in
patients), with the LoTrach (LVLP) cuff and with conventional high-
volume low-pressure (HVLP) cuffs. The LoTrach (VTSL, Singapore)
is a new tracheal tube designed for use for mechanical ventilation
in the critically ill. The LoTrach has been shown to prevent the
ubiquitous problem of micro-aspiration of secretions associated
with conventional HVLP cuffs [1]. Aspiration prevention is achieved
by the properties of the LoTrach’s low-volume low-pressure (LVLP)
cuff, and these have been previously described [1,2]. It is important
that, alongside achieving aspiration prevention, there is also
tracheal wall pressure control. The LoTrach LVLP cuff is calibrated
such that the sum of the elastic forces within the cuff remain
constant throughout the inflation profile. Thus, at the working intra-
cuff pressure of 80 cmH2O, only a consistent and acceptable
30 cmH2O is transmitted to the tracheal wall [2]. Conclusion With its portability, easy handiness, excellent visual
information and the tube-guiding function of the introducer, the
AWS may have potential to alleviate the various difficulties in
intubation in emergency scenes, even in a confined space. Conclusion With its portability, easy handiness, excellent visual
information and the tube-guiding function of the introducer, the
AWS may have potential to alleviate the various difficulties in
intubation in emergency scenes, even in a confined space. Airway equipment on the intensive care unit for
management of the unanticipated difficult intubation The TTI (s)
was 12.0 ± 1.5 in POG/Mac, 7.4 ± 1.1 in POG/AWS and
12.9 ± 1.4 in NSH/AWS. The TTI with AWS in POG situation was
significantly shorter than that with Mac (P = 0.0135). Results Forty-five of 51 units responded (88%). Mandatory
equipment levels are shown in Figure 1. Results Forty-five of 51 units responded (88%). Mandatory
equipment levels are shown in Figure 1. Discussion Difficult intubation is more likely on the ICU, yet only
20% of units keep sufficient equipment immediately available. The
most serious omissions were the 29% of units without a rescue
technique immediately available and the one-third of units not
routinely employing capnography. S87 Care March 2007 Vol 11 Suppl 2
27th International Symposium on Intensive Care and Emergency Medicine Figure 1 (abstract P213) A comparison of two types of new bronchial blockers,
Uniblocker™ and Coopdech endotracheal blocker tube, for
one-lung ventilation during thoracoscopy 2
Results Conventional HVLP cuffs do not prevent leakage of fluid
past the cuff, hence the negative slope on the graphs. The LoTrach
cuff does not leak and therefore the line is horizontal (see Figure
1). The clinical study shows that both the LoTrach and Portex cuffs
demonstrate a gross air leak at equal and acceptable tracheal wall
pressures at 33.4 and 29.7 cmH2O, respectively (see Table 1). Table 1 (abstract P215)
Number of
Tracheal wall
Type of tube
measurements
pressure (cmH2O)
LoTrach (LVLP)
45
29.7 (SD = 3.7)
Soft Seal (HVLP)
41
33.4 (SD = 3.1) Safety of semi-open percutaneous tracheotomy when
performed in critically ill burn patients K Gerold, K Dhanjani, L Price, D Noppenberger, S Milner
Johns Hopkins School of Medicine, Baltimore, MD, USA
Critical Care 2007, 11(Suppl 2):P216 (doi: 10.1186/cc5376) Results One hundred and eight tracheostomies were performed in
intensive care in the 2-year period. Sixty-two patients were
discharged with tracheostomy in situ and were reviewed by the
outreach team for a cumulative total of 710 days until decannulation. There were 383 days whereby patients with a tracheostomy in situ
had been noninvasively ventilated. There were three reported critical
events relating to tracheostomy and no deaths. Introduction Lung injury and generalized edema from a burn and
resuscitation complicates airway management and patient care. The need for long-term ventilation and multiple surgeries warrant
early tracheostomy. Percutaneous techniques are well described;
however, the burned and swollen neck increases all of its
recognized complications. We report a modified semi-open
technique for performing percutaneous tracheotomies (PT) in
acutely burned patients, which we consider safer. Conclusion More than 60% of patients who had a tracheostomy
inserted are discharged from critical care with a tracheostomy in
situ. With the support of the outreach team these patients were
successfully managed in Level 2 and Level 1 areas. This reduced
the requirement for critical care (Level 3) bed-days. There was a
low rate of complications. We concluded that outreach services
can facilitate early and safe discharge of tracheostomy patients
from critical care. Methods We reviewed the medical records of 20 patients
admitted to a regional burn center requiring tracheostomy for
prolonged mechanical ventilation. The procedure took place in the
OR if burn excision was planned; otherwise it was performed at the
bedside. The Blue Rhino tracheostomy kit was used for all PT. Major differences from other approaches included dissecting down
to the pretracheal fascia, allowing the trachea to be seen and
palpated; bleeding was controlled using an electrocautery, and
blood vessels were retracted from the field or ligated. The trachea
was palpated as the endotracheal tube was withdrawn into the
proximal trachea and a flexible bronchoscope was used only to
confirm the proper placement of the guidewire. Proper placement
of the tracheal tube was confirmed by capnography. In patients
with a deep trachea due to severe neck swelling, a proximal-long
tracheostomy tube was substituted for the standard one. In the
event that the airway or ventilation became compromised, this
technique could be converted rapidly to an open procedure. P218 Prevention of airway control loss during percutaneous
tracheostomy References References
1. Young PJ, Pakeerathan S, Blunt MC, Subramanya S: A low-
volume, low-pressure tracheal tube cuff reduces pul-
monary aspiration. Crit Care Med 2006, 34:632-639. 2. Young PJ, Young WH: Inflation of a pressure-limited cuff
inside a model trachea. Med Eng Phys 2003, 25:465-473. 1. Young PJ, Pakeerathan S, Blunt MC, Subramanya S: A low-
volume, low-pressure tracheal tube cuff reduces pul-
monary aspiration. Crit Care Med 2006, 34:632-639. Methods A retrospective analysis of the ICU database was
undertaken to identify all patients who had a tracheostomy
(percutaneous or surgical) inserted in the ICU, and a chart review
of patients discharged from the ICU with a tracheostomy in situ
was performed. The following variables were collected: patient
demographics; diagnosis; number of days of tracheostomy in situ;
number of days on noninvasive ventilation (CPAP); and tracheos-
tomy-related complications. A review of the risk management
database was performed to identify any tracheostomy-related
reported adverse events. Available online http://ccforum.com/supplements/11/S2 Available online http://ccforum.com/supplements/11/S2 References
1. Young PJ, Pakeerathan S, Blunt MC, Subramanya S: A low-
volume, low-pressure tracheal tube cuff reduces pul-
monary aspiration. Crit Care Med 2006, 34:632-639. 2. Young PJ, Young WH: Inflation of a pressure-limited cuff
inside a model trachea. Med Eng Phys 2003, 25:465-473. P216
Safety of semi-open percutaneous tracheotomy when
performed in critically ill burn patients
K Gerold, K Dhanjani, L Price, D Noppenberger, S Milner
Johns Hopkins School of Medicine, Baltimore, MD, USA
Critical Care 2007, 11(Suppl 2):P216 (doi: 10.1186/cc5376)
Figure 1 (abstract P215) Figure 1 (abstract P215) performed within an average of 10 days from admission (range
0–32 days). Overall mortality in the tracheostomy group was 35%. There were no short-term complications associated with this
method. Conclusion PT can be performed safely in severely burned
patients using a semi-open percutaneous technique. Exposing the
trachea and palpating the trachea avoids the risk of losing the
airway and permits immediate access to the trachea in the event of
an untoward loss of the airway. We believe that this method is
safer than the more commonly used technique requiring
bronchoscopic visualization. Outreach-led tracheostomy service in a cardiothoracic
centre: early and safe facilitated discharge from critical care Outreach-led tracheostomy service in a cardiothoracic
centre: early and safe facilitated discharge from critical care
P Wilton, J Mitchell, T Apps, R Subramanian
Harefield Hospital, London, UK
Critical Care 2007, 11(Suppl 2):P217 (doi: 10.1186/cc5377) P Wilton, J Mitchell, T Apps, R Subramanian P Wilton, J Mitchell, T Apps, R Subramanian
Harefield Hospital, London, UK
Critical Care 2007, 11(Suppl 2):P217 (doi: 10.1186/cc5377) p
,
,
al Care 2007, 11(Suppl 2):P217 (doi: 10.1186/cc5377) Introduction A retrospective analysis of a year cohort of tracheos-
tomies discharged from intensive care in a specialist cardio-
thoracic centre was undertaken to analyse whether facilitated
outreach-led discharge was safe. Table 1 (abstract P215) Table 1 (abstract P215) Results The number of unsuccessful placement attempts was none
in the UBBR group (0/10) and one in the CBBR group (1/10), two
in the UBBL group (2/10) and five in the CBBL group (5/10). A
fiberoptic aided technique should be more appropriate for the left-
sided blocker in both groups. There was no statistical difference in
bronchial blocker malpositions, the lung to collapse and the number
of complications among the two groups. Furthermore, for elective
thoracic surgical cases, once the lung was isolated, the
management seemed to be similar for both groups. Discussion
This study demonstrates that the wire-guided
bronchial blocker (Uniblocker™) provides a high torque control and
can be easily manipulated into the desired site of the lungs. In
conclusion, our study shows that the Uniblocker™ is more useful
than the Coopdech bronchial blocker tube. Results The number of unsuccessful placement attempts was none
in the UBBR group (0/10) and one in the CBBR group (1/10), two
in the UBBL group (2/10) and five in the CBBL group (5/10). A
fiberoptic aided technique should be more appropriate for the left-
sided blocker in both groups. There was no statistical difference in
bronchial blocker malpositions, the lung to collapse and the number
of complications among the two groups. Furthermore, for elective
thoracic surgical cases, once the lung was isolated, the
management seemed to be similar for both groups. Conclusions In the benchtop model, the LoTrach LVLP cuff
demonstrates an acceptable wall pressure of 30 cmH2O (at an
intracuff pressure of 80 cmH2O), while achieving the prevention
of leakage of fluid past the cuff. The clinical study demonstrates
that the tracheal wall pressure was both acceptable and equal
for both the Portex HVLP and the LoTrach LVLP cuffs. The
LoTrach prevents micro-aspiration in the benchtop model with
acceptable tracheal wall pressures in both the benchtop and
clinical studies. Discussion
This study demonstrates that the wire-guided
bronchial blocker (Uniblocker™) provides a high torque control and
can be easily manipulated into the desired site of the lungs. In
conclusion, our study shows that the Uniblocker™ is more useful
than the Coopdech bronchial blocker tube. S88 Available online http://ccforum.com/supplements/11/S2 Prevention of airway control loss during percutaneous
tracheostomy A Pirogov1, M Croitoru2, R Badaev3, N Davidova1,
S Krimerman2, E Altman4
1Ural Academy of Medicine, Ekaterinburg, Russian Federation;
2Bnai Zion Medical Center, Haifa, Israel; 3Crmel Hospital, Haifa,
Israel; 4Western Galilee Hospital, Naharyia, Israel
Critical Care 2007, 11(Suppl 2):P218 (doi: 10.1186/cc5378) Background
Loss of airway control during percutaneous
tracheostomy (PCT) is one of the serious complications. It may
happen due to an unstable position of the endotracheal tube (ETT)
with its tip in the larynx and cuff above the vocal cords. This Results Of 350 patients admitted to the burn center from July
2005 to December 2006, 20 (6%) required a tracheostomy. Eighteen were performed percutaneously, 13 at the bedside. The
total burn surface area averaged 46% (range 2–95%). PT were S89 Critical Care March 2007 Vol 11 Suppl 2
27th International Symposium on Intensive Care and Emergency Medicine ritical Care March 2007 Vol 11 Suppl 2
27th International Symposium on Intensive Care and Emergency Medicin Table 1 (abstract P219)
New problem seen
Number (%)
on CXR (n (%))
Two CXRs reviewed
Uncomplicated PDT
167 (57)
15 (5)
Complicated PDT
69 (24)
10 (3)
One CXR reviewed
Uncomplicated PDT
36 (12)
0
Complicated PDT
8 (3)
0
Total
280
25 position of the ETT is the main request for PCT performance. We
retrospectively reviewed our experience with additional use of the
fiberoptic bronchoscope (FOB) and tube exchanger (TE) for
stabilization of ETT during PCT. Patients and methods From the 160 adult critically ill patients that
underwent PCT by the Griggs technique between January 2000 and
August 2001, we selected 33 patients receiving anesthesia from
the same anesthetist. From this group 12 patients were ventilated
through ETT by the standard technique: in 11 patients a pediatric
FOB was used to control and stabilize the position of ETT during
PCT, and in the remaining 10 patients a 15-Fr TE was used with
the same aim instead of a pediatric FOB. The optimal diameters of
FOB and TE suitable for ETT (7.5 mm, 8 mm) were found in our
previous experiments, using a mechanical lung simulator. Results Loss of airway control during PCT occurred in three
patients, where ventilation through the ETT was performed by the
standard technique. This complication was corrected by
expeditious actions of the anesthetist and surgeon. Routine chest radiography following percutaneous
dilatational tracheostomy F Paladino, G Guiotto, F Lanni, F Longo, E Ruggiero, F Schirald
Hospital Sao Paulo, Napoli, Italy
Critical Care 2007, 11(Suppl 2):P220 (doi: 10.1186/cc5380) M Vijaya Kumar, M Huges, E Hill, G Dempsey
University Hospital Aintree, Liverpool, UK M Vijaya Kumar, M Huges, E Hill, G Dempsey M Vijaya Kumar, M Huges, E Hill, G Dempsey
University Hospital Aintree, Liverpool, UK
Critical Care 2007, 11(Suppl 2):P219 (doi: 10.1186/cc5379) Objective To evaluate the efficacy of early electric cardioversion
(EC) with a biphasic defibrillator and the impact on atrial function in
recent-onset atrial fibrillation (AF). Critical Care 2007, 11(Suppl 2):P219 (doi: 10.1186/cc5 Background and objective The role of routine chest radiography
(CXR) following percutaneous dilatational tracheostomy (PDT) has
recently been questioned [1]. Methods The study population consisted of 21 consecutive
patients (mean age 58 years; range 35–76 years) with AF lasting
from less than 48 hours. Hemodynamically stable AF was treated
via DC shock if sinus rhythm (SR) was not restored in 6 hours after
i.v. antiarrhythmic drug therapy. All patients were pretreated with
heparin 5,000 U i.v. The defibrillator used was the Heartstart MRX
using a biphasic waveform and low energy (70–120 J). A trans-
thoracic echo was performed pre-EC and 1 hour post-EC. All
patients were sedated with midazolam (in vivo titolation). Atrial
function (ejection fraction, surface area, A wave) and ventricular
function (ejection fraction) were evaluated. The patients returned to
the emergency department after 7 days for follow-up. Data were
analyzed using descriptive statistics (Table 1). Materials
and
methods
We
performed
a
prospective
observational study, on a mixed medical–surgical critical care unit,
in 291 patients undergoing PDT under bronchoscopic guidance to
assess the utility of routine postoperative CXR. Data were
collected on all patients undergoing PDT from 1 November 2003
to 5 December 2006. Two postprocedure CXRs were reviewed
and compared with those taken prior to PDT. Significant findings
were barotraumas (pneumothorax, pneumomediastinum) and
consolidation not noted on the preprocedure film. Postprocedural
films reviewed were those taken immediately after PDT and, to
exclude the possibility of overlooking evidence of minor
barotrauma, one further film taken between 24 and 96 hours. Results DC shock was successful for all patients (100%) and in
19/21(90.4%) at first shock. There was a significant increase in
atrial function with the reappearance of the A wave. There were no Results A total of 291 patients underwent PDT. Two hundred and
six (71%) were uncomplicated. Biphasic DC shock as a first-line therapy in recent-onset
stable atrial fibrillation in the emergency department Biphasic DC shock as a first-line therapy in recent-onset
stable atrial fibrillation in the emergency department Prevention of airway control loss during percutaneous
tracheostomy In the other
patients, additional use of a pediatric FOB or TE has created
secure and proper position of the ETT and PCT passed smoothly
without complications. Moreover, we could not register a negative
influence of a pediatric FOB and 15-Fr TE presence in the ETT on
ventilation parameters during PCT performance. Conclusions
Routine
CXR
following
uncomplicated
PDT
performed under bronchoscopic guidance appears unwarranted. Review of later films failed to reveal new abnormalities. The role of
CXR following PDT appears to be restricted to those patients
undergoing complicated procedures. This will lead to reductions in
both medical costs [2] and exposure to ionising radiation. References
1. Datta D, Onyirimba F, McNamee MJ: Chest 2003, 123:1603-
1606. 2. Tarnoff M, Moncure M, Jones F, et al.: Chest 1998, 113:1647-
1649. 1. Datta D, Onyirimba F, McNamee MJ: Chest 2003, 123:1603-
1606. Conclusions Stabilization of the ETT position and prevention of
airway control loss during PCT performance can be reached by
use of a pediatric FOB or by 15-Fr TE with the same reliable
results. Employment of a pediatric FOB is more expensive than a
TE. 2. Tarnoff M, Moncure M, Jones F, et al.: Chest 1998, 113:1647-
1649. P219 Routine chest radiography following percutaneous
dilatational tracheostomy Routine chest radiography following percutaneous
dilatational tracheostomy Complications were recorded in 85
(29%) patients. Of these, 71 (24%) were minor procedural
complications (multiple attempts at needle insertion (>2), minor
bleeding, tracheal ring fracture) and there were 14 (5%) major
complications (malplacement, major bleeding). Two hundred and
thirty-six (81%) patients had two postprocedural CXRs reviewed. Of the remainder, 44 (15%) patients had at least one CXR
reviewed after PDT and in 11 (4%) patients neither the report nor
the CXR could be reviewed. New abnormalities were noted on 25
(9.0%) postprocedure CXRs. No new pneumothoraces were seen
(Table 1). In 11 (4%) patients, neither the report nor the CXR
could be reviewed. Table 1 (abstract P220)
Pre-EC
Post-EC
Number of patients
21
Age average
59
Sinusal rhythm restoration
21/21
Left atrial ejection fraction two chambers
30
35 (P = 0.02)
Left atrial ejection fraction four chambers
29
35 (P = 0.02)
Left ventricular ejection fraction
52
54 (P = NS)
A wave (m/s)
0.54 S90 Available online http://ccforum.com/supplements/11/S2 thromboembolic complications. After 7 days, results showed that
19/21 (90.4%) patients were in SR. P223 The ADHERE classification and regression tree model
overestimates mortality rates in clinical trials: results from
REVIVE I & II
R Thakkar1, J Teerlink2, W Colucci3, J Young4, B Massie2
1Abbott, Abbott Park, IL, USA; 2SFVAMC/University of California –
San Francisco, CA, USA; 3Boston University, Boston, MA, USA;
4Cleveland Clinic, Cleveland, OH, USA
Critical Care 2007, 11(Suppl 2):P223 (doi: 10.1186/cc5383) The ADHERE classification and regression tree model
overestimates mortality rates in clinical trials: results from
REVIVE I & II R Thakkar1, J Teerlink2, W Colucci3, J Young4, B Massie2
1Abbott, Abbott Park, IL, USA; 2SFVAMC/University of California –
San Francisco, CA, USA; 3Boston University, Boston, MA, USA;
4Cleveland Clinic, Cleveland, OH, USA
Critical Care 2007, 11(Suppl 2):P223 (doi: 10.1186/cc5383) Troponin T was determined in 13 patients and found to be
elevated in 10 patients (34.5% of AF patients). Transthoracic
echocardiography was performed on 10 patients with persistent
AF (34.5%). Seven patients had valve pathology whereas left
ventricular dysfunction was present in five patients. Only one
echocardiography was reported normal. Patients were treated
according to local guidelines with amiodarone (19 (65.5%)),
digoxin (5 (17.2%)) and β-blockers (4 (13.8%)), and DC cardio-
version was used in only one patient. Eighteen (62.1%) patients
were successfully cardioverted. Background Blood urea nitrogen (BUN), systolic blood pressure
(SBP), and serum creatinine (Cr) were significant predictors of
inhospital mortality by classification and regression tree (CART)
analysis of ADHERE. REVIVE I & II (REVIVE) compared levosimen-
dan with placebo, in addition to standard-of-care (SOC), in
patients with acute decompensated heart failure. We hypothesized
that mortality in REVIVE would be similar to ADHERE in all CART-
defined risk subgroups. Conclusion Apart from known risk factors for AF such as
increased age, hypertension or ischaemic heart disease, sepsis
and inotropes increase susceptibility for AF. Less frequently
associated causes such as congenital heart disease, obesity and
diabetes can contribute towards AF. Echocardiography could
reveal less obvious causes of AF like valvular pathologies and left
ventricular dysfunction, and could be a useful diagnostic tool in
critically ill patients with AF. Methods REVIVE (n = 700) mortality data were mapped using the
same variables/cut-points as the ADHERE CART analysis. Methods REVIVE (n = 700) mortality data were mapped using the
same variables/cut-points as the ADHERE CART analysis. P222 The calcium sensitizer levosimendan reduces the brain
natriuretic peptide levels as compared with dobutamine in
intensive care unit septic patients with decompensated
heart failure Conclusion
Early electric cardioversion in the emergency
department setting is a simple technique that allows the restoration
of SR without complications. The biphasic waveform uses lower
energy with a positive impact on atrial function. Higher energy can
cause transient tissue damage due to electroporation that can
affect the outcome of defibrillation therapy being both pro-
arrhythmic and anti-arrhythmic. The recovery of atrial function is
also due to the short duration of arrhythmia. The early cardioversion
avoids atrial remodelling and allows a longer duration of SR. H Michalopoulou, P Stamatis, A Bakhal, T Kelgiorgis,
A Foundouli, A Basile, J Vaitsis, E Reinou, P Batika, D Pragastis
Metaxa Hospital, Athens, Greece
Critical Care 2007, 11(Suppl 2):P222 (doi: 10.1186/cc5382) H Michalopoulou, P Stamatis, A Bakhal, T Kelgiorgis Introduction The brain natriuretic peptide (BNP) is a useful index
to follow-up patients with heart failure as well as a special
diagnostic and prognostic tool. This study aims at investigating the
impact of levosimendan in comparison with dobutamine on the
BNP levels in ICU patients with decompensated heart failure
related to septic shock. The role of levosimendan in septic patients
is still under consideration. P221 Incidence and diagnosis of patients developing atrial
fibrillation in intensive care Methods Twenty-nine patients (20 males and nine females) of a
70.5 ± 9.2 average age rate with persisting left ventricular
dysfunction related to severe sepsis, after receiving a 48-hour
conventional
treatment
including
inotropic
agents,
were
randomised to either 24-hour i.v. levosimendan (0.2 γ/kg/min) (n =
15) (Group A) or dobutamine (5 γ/kg/min) (n = 14) (Group B)
therapy. Serial BNP measurements were performed before, at 48
hours and 5 days later. R Shankar1, I Welters2
1Burton Hospitals NHS, Burton-on-Trent, UK; 2Academic Unit of
Critical Care Medicine, Liverpool, UK
Critical Care 2007, 11(Suppl 2):P221 (doi: 10.1186/cc5381) Introduction
Atrial fibrillation (AF) is a common arrhythmia
encountered in critically ill patients. In this study we evaluated the
incidence and risk factors associated with the occurrence of AF in
a general ICU. Results Levosimendan therapy significantly reduced the BNP
levels both in 48 hours and in 5 days as compared with
dobutamine. Group A: 1,138 ± 93.7, 740.2 ± 106, 445 ± 118.3
and Group B: 1,561 ± 370.2, 1,436 ± 368, 1,850 ± 520.5,
before, 48 hours and 5 days later, respectively. P = 0.025 for 48
hours and P = 0.037 for 5 days. Methods One hundred and ten patients admitted to the ICU
during a 3-month period were screened for AF. Case notes and
daily management charts of these patients were analysed
retrospectively. Results Twenty-nine (26.3%) out of 110 patients developed AF. The mean age of patients was 71.8 (±9.2) years and the APACHE
II score was 21.3 (±6.3). Electrolytes were within the normal range
in 85% of the patients. The main cardiac factors identified in our
patients with AF were hypertension (71.4%) and coronary artery
disease (48.3%). Less commonly encountered cardiac diagnoses
were congenital heart disease and history of previous atrial
fibrillation. Inotropic support and sepsis were the leading
noncardiac factors found in 24 (82.8%) and 22 (75.9%) patients,
respectively. Diabetes mellitus and obesity contributed in 17.2% of
patients. Conclusion Levosimendan therapy reduces BNP levels, reflecting
a beneficial haemodynamic effect on the ICU patient with septic
myocardial depression. Levosimendan in patients with acute cardiogenic shock,
not responders to conventional therapy Levosimendan in patients with acute cardiogenic shock,
not responders to conventional therapy L Vetrugno, F Bassi, F Giordano
Azienda Ospedaliero-Universitaria, Udine, Italy
Critical Care 2007, 11(Suppl 2):P224 (doi: 10.1186/cc5384) Introduction Levosimendan is a new, effective inodilator agent,
which is a new alternate drug beside conventional inotropic drugs
in treatment of acute and chronic heart failure. Positive inotropic
effects of levosimendan is based on myocardial Ca-sensitising. Few clinical data are available about the occurrence of
proarrhythmic effects of levosimendan, particularly administered in
parallel with catecholamines. Introduction Cardiogenic shock remains the leading cause of death
in patients hospitalized for myocardial infarction, acute valvular
disease and after cardiac surgery. Levosimendan (LS) is a new
inodilator that has been shown to improve hemodynamic function in
patients with decompensated systolic heart failure without increased
myocardial oxygen consumption. The aim of this study was to
evaluate the use of LS as rescue medication in patients with low
ejection fraction (EF) that are not responders to conventional therapy. Methods Twelve patients with acute cardiogenic shock admitted
to the ICU were enrolled. The diagnosis of cardiogenic shock was
made on cardiac index (CI) measured by thermodilution catheter
<2.5 l/min/m2, and baseline echocardiography with EF measured
by the biplan Simpson method <30%. LS (Orion Pharma, Helsinki,
Finland) at the dose of 0.1 γ/kg/min for 24 hours continuous
infusion was added to standard inotropic agents (dobutamine,
enoximone, epinephrine) or IABP when CI and EF seemed not to
improve or when the patient’s condition worsened. Hemodynamic
measurements and echocardiography data were recorded at ICU
admission and when pharmacological therapy was changed at 24,
48 and 72 hours. Method From 1 January 2006 until 30 July, 41 levosimendan-
treated patients’ data were processed in our retrospective study. Indication of levosimendan therapy was acute heart failure due to
myocardial infarction in 23 cases and acute progression of chronic
heart failure (NYHA III–IV) in 18 cases. After a 10-minute bolus
levosimendan infusion was administered at rate of 0.1 µg/kg/min
for 6 hours and 24 hours in each group, respectively. We investi-
gated the occurrence of sustained ventricular or supraventricular
arrhythmias for the first 48 hours from the beginning of infusion. Results The ratio of hypertension, diabetes, earlier myocardial
infarction and ACBG were 58%, 27%, 32% and 15%,
respectively, in the monitored population (13 females, 28 males;
mean age: 68 years). Retrospective study of proarrhythmic effects of
levosimendan during the therapy of heart failure Retrospective study of proarrhythmic effects of
levosimendan during the therapy of heart failure E Zima, G Szucs, A Soltesz, D Becker, G Fulop, L Molnar,
G Barczi, B Merkely
Semmelweis University, Budapest, Hungary
Critical Care 2007, 11(Suppl 2):P225 (doi: 10.1186/cc5385) P223 Results Compared with ADHERE, proportionately more patients in
REVIVE had SBP <115 mmHg (56.4% vs 18.6%; P < 0.001) with
more patients (3.0% vs 1.9%; P < 0.05) in the highest mortality
risk subgroup (SBP <115 mmHg, BUN ≥43 mg/dl, and Cr
≥2.75 mg/dl). For the total population and for every CART-defined
subgroup, REVIVE inhospital mortality rates were lower than those
from ADHERE. See Figure 1. S91 Critical Care March 2007 Vol 11 Suppl 2
27th International Symposium on Intensive Care and Emergency Medicine Figure 1 (abstract P224) Figure 1 (abstract P223)
Mortality rates from REVIVE for subgroups defined by the ADHERE
classification and regression tree model. Figure 1 (abstract P224) Figure 1 (abstract P224) Figure 1 (abstract P223)
Mortality rates from REVIVE for subgroups defined by the ADHERE
classification and regression tree model. Figure 1 (abstract P224) Figure 1 (abstract P223) Figure 1 (abstract P223) Mortality rates from REVIVE for subgroups defined by the ADHERE
classification and regression tree model. Conclusion Clinical trials (REVIVE) may enroll proportionately
more patients at increased risk of mortality in comparison with the
general population (ADHERE). Despite the predicted increased
mortality risk, mortality rates were lower in REVIVE than in
ADHERE for the total population and for every CART-defined risk
subgroup. Differences in SOC or additional risk factors, such as
age or other comorbid conditions, may contribute to the poorer
prognosis in nontrial populations. different mechanism of action. Catecholamines increase Ca2+
availability and LS increases myocardial cell calcium sensibility. Levosimendan in myocardial depression due to severe sepsis M Malik, Y Mandourah
Riyadh Millitary Hospital, Riyadh, Saudi Arabia
Critical Care 2007, 11(Suppl 2):P226 (doi: 10.1186/cc5386) Objective and method To assess the secondary preventative
treatment received by the elderly ACS patient. Retrospective
analysis of our Myocardial Infarction National Audit Project
(MINAP) database 2003–2006. Patients were divided into three
age groups: <50 years, 50–75 years and >75 years old. Data
were collected from hospital admission to discharge. Introduction Myocardial depression in sepsis, among other
factors, is due to calcium (Ca2+) desensitization in the myofilament. So using a Ca2+ sensitizer drug may play a beneficial role in this
situation. Levosimendan has a dual mechanism; it causes Ca2+
sensitization through binding to Troponin C and opening of ATP-
dependent K+ channels in vascular smooth muscle. Results A total of 1,501 consecutive patients were included in the
analysis, 530 patients (35.3%) were >75 years, mean age 83.6
years (±5.1). The discharge diagnosis was ST elevation myocardial
infarction in 619, UA/NSTEMI in 870 and unspecified in 12
patients. The overall inpatient all-cause mortality rate was 8.06%
(121/1,501). See Table 1. Methods A prospective observational case-series study extending
over a period of 18 months from November 2004 to April 2006. We analyze the data of 18 patients receiving levosimendan for
myocardial depression due to severe sepsis and compare them
with our historical data in the previous year of the same group of
patients regarding mortality. All those patients were included in the
study who had a pulmonary artery catheter (PAC) and who after
initial resuscitation (early goal-directed therapy (EGDT)) did not
respond to treatment and their cardiac index (CI) was <2.2. Each
patient than received an infusion of levosimendan at 0.1 µg/kg/min
without a loading dose. Hemodynamic parameters such as the CI,
mixed venous saturation (SvO2) and mean arterial pressure (MAP)
were recorded at 0, 12, 24 and 48 hours. Noradrenaline was used
to maintain a MAP above 65 mmHg. Patients were followed for
30 days to document the 7th-day and 30th-day mortality. SPSS 11
was used for statistical analysis. The Student t test was used as a
test of significance. Table 1 (abstract P227)
<50 years
50–75 years
>75 years
Total
149
822
530
STEMI
84
364
172
Inhospital mortality
0
33 (4%)
88 (17%)
Aspirin (%)
98.7
94.5
90.4*
ACE-I (%)
84.6
83.4
66.4*
β-Blocker (%)
93.8
82.4
72.9*
Statin (%)
96.5
95.6
89*
*P < 0.001, chi-squared. P226 P226 treatment strategies and secondary prevention, despite the elderly
being the fastest growing section of the population. The literature
suggests the elderly do not receive appropriate therapy in this
setting. What is the current UK experience? Long-term prognosis of octagenarian patients with
ST-elevation acute myocardial infarction treated by
primary angioplasty E Abu Assi
Hospital Clínico Universitario, Santiago de Compostela, Spain
Critical Care 2007, 11(Suppl 2):P228 (doi: 10.1186/cc5388) Conclusion It is evident from our study that levosimendan
improves hemodynamic response in septic patients. Although it
improves the mortality, we cannot say with full confidence that
these improved hemodynamic parameters are responsible. Randomised control trials are needed to answer this question,
which are underway. Introduction The incidence of acute myocardial infarction (AMI) in
old patients is increasing due to rapid aging of the population. This
is of particular concern because AMI in patients who are ≥80 years
old is associated with high mortality. However, the role of
reperfusion therapies is not clear in these patients. Levosimendan in myocardial depression due to severe sepsis Conclusions The elderly ACS patient forms a high-risk group. The
therapeutic approach in this group should be justifiably as
aggressive as that in younger patients, balancing risks with
benefits. The elderly patient should be prescribed secondary
preventative measures, and our data show considerably greater
numbers can benefit from standard treatment than suggested by
the published literature. Results The average age was 67.6 ± 10.39 years and the
APACHE II score was 26.33 ± 2.37. Patients were divided into
three subgroups: survivors, 7th-day and 30th-day mortality groups. There was no significant difference in these subgroups regarding
age and APACHE II score. Levosimendan group 7th-day and 30th-
day mortality was 33% and 66% as compared with historical data
of 37% and 71%, respectively. The change in CI in the survivor
group was significant (P = 0.021), from 2.11 ± 0.17 to 3.8 ± 0.28,
while in the 7th-day and 30th-day mortality groups it was
insignificant. SvO2 increased in the survivor and 30th-day mortality
groups significantly (P = 0.011 and P = 0.035, respectively). It did
not show any significant improvement in the other group. MAP also
showed significant improvement in the survivor group (P = 0.026)
and insignificant in others. Levosimendan in patients with acute cardiogenic shock,
not responders to conventional therapy Three ventricular arrhythmias and one
supraventricular arrhythmia were observed during the 48-hour
period, all of them occurred in acute heart failure patients with
acute myocardial infarction. Parallel usage of catecholamines
(noradrenalin and/or dopamine) and levosimendan therapy was
observed in three cases, in one of them ventricular tachycardia was
observed 3 hours after starting levosimendan infusion. No
arrhythmia was observed in chronic heart failure patients. The
incidence of proarrhythmic effects during levosimendan therapy
was 9.75% of the whole analysed population and was 17.4% at
acute heart failure during acute myocardial infarction. Results The data collection showed: an increase in CI (baseline to
standard therapy) of 2.6 ± 0.51 (P < 0.001), and standard therapy
to LS of 2.93 ± 0.67 (P < 0.003) that seem to be additive. Significant increase in EF was noted in comparison with standard
therapy
(29.88 ± 6.15,
P < 0.035)
and
after
LS
therapy
(38.44 ± 6.56, P < 0.001) (Figure 1). To find differences between
baseline and pharmacological therapy changes at 24, 48 and
72 hours a t test was performed. Conclusion With these results the authors would like to draw
attention to the proarrhythmic effects of levosimendan during acute
heart failure therapy, especially in the case of parallel usage with
catecholamines. Conclusion We found an additive effect of dobutamine,
enoximone and LS that theoretically can be explained by the S92 Available online http://ccforum.com/supplements/11/S2 P228 P228
Long-term prognosis of octagenarian patients with
ST-elevation acute myocardial infarction treated by
primary angioplasty
E Abu Assi
Hospital Clínico Universitario, Santiago de Compostela, Spain
Critical Care 2007, 11(Suppl 2):P228 (doi: 10.1186/cc5388) Long-term prognosis of octagenarian patients with
ST-elevation acute myocardial infarction treated by
primary angioplasty Long-term prognosis of octagenarian patients with
ST-elevation acute myocardial infarction treated by
primary angioplasty Outcome in myocardial infarction is related to the
morphologic pattern of ST elevation Introduction Early percutaneous coronary intervention (PCI) is the
most effective treatment for acute coronary syndrome (ACS, ST-
elevation myocardial infarction (STEMI), non-STEMI, unstable
angina pectoris) complicated by states Killip 3 and 4. R García-Borbolla1, I Nuñez Gil2, J García Rubira2,
A Fernández Ortiz2, L Perez Isla2, M Cobos2, C Macaya2
1Hospital Universitario Puerta del Mar, Cádiz, Spain; 2Hospital
Clínico San Carlos, Madrid, Spain
Critical Care 2007, 11(Suppl 2):P229 (doi: 10.1186/cc5389) Method A total of 1,187 patients suffering from high-risk acute
coronary syndrome (hrACS) were treated in our center in 2005. States Killip 3 and 4 have developed perioperatively in 186 of
these patients. International studies have proven high mortality in
these patient groups – especially in state Killip 4. Our aim was to
analyze the inhospital mortality of the state Killip 3 and 4 patient
group treated in our center in 2005. Purpose Although invasive management of ST-segment elevation
myocardial infarction (STEMI) has improved the clinical outcome,
early mortality remains an important issue. Our purpose is to
assess the utility of the initial electrocardiographic (ECG) pattern in
detecting patients who are at increased risk despite the current
recommendations of revascularization. Results Seven hundred and two patients with STEMI and 485
patients with hrACS were admitted to our center in 2005. The
mortality of these patients was 4.84% (STEMI) and 3.71%
(hrACS), and the main cause of this mortality (37.7%) was the
Killip 3/4 state, which was observed in 11.9% of the STEMI
patients and in 17.9% of hrACS patients (n = 84 and 87). The
mean age of the Killip 3/4 patients was 70 ± 10 years. Angio-
logically successful PCI was performed in 97.9% of the cases. The
ratio of revascularized coronaries was left anterior descending
coronary artery (LAD): 66 (35.9%), right coronary artery (RCA): 33
(17.9%), circumflex coronary artery (CX): 28 (15.2%), PCI in left
main coronary artery: 28 (12.5%), LAD + CX: 15 (8.15%), RCA +
LAD: 7 (3.8%), CX + RCA: 6 (3.26%), venous bypass graft: 2
(1.1%). No PCI was performed in two cases. Adjuvant therapies of
intraaortic balloon counterpulsation in 67 (36%), mechanical
ventilation in 62 (33.3%), continuous veno-venous hemofiltration in
12 (6.45%), and levosimendan therapy in 86 (46.2%) patients
were used. Ten (5.4%) of the patients had advanced adult life
support (cardiopulmonary resuscitation) (AALS) before arrival at
our center, and AALS was performed in the perioperative period in
16 (8.6%) patients. P227 Objective To evaluate the mid-term and long-term prognosis of
octogenarian patients with ST-elevation myocardial infarction
(STEMI) treated with primary coronary angioplasty (PCA). The elderly acute coronary syndrome patient: a neglected
population? A Turley1, A Roberts1, A McDermott2, P Adams2
1The James Cook University Hospital, Middlesbrough, UK; 2Royal
Victoria Infirmary, Newcastle upon Tyne, UK
Critical Care 2007, 11(Suppl 2):P227 (doi: 10.1186/cc5387) Methods We studied retrospectively, from January 2000 to March
2005, 73 patients ≥80 years with STEMI treated with PCA. At the
end of follow-up, we assessed the incidence of death, myocardial
infarction and necessity of new procedures of revascularization of
the treated vessel. Introduction Cardiovascular disease is the commonest cause of
death in the elderly (>75 years). The elderly acute coronary
syndrome (ACS) patient forms a particular high-risk cohort. Clinical
trials traditionally concentrate on younger patients for both ACS Results The average age was 84 ± 3.6 years, 39 (58%) were
women. The location of the AMI was anterior in 56%, and 25%
were diabetic. The average follow-up time was 19 ± 17 months. During the follow-up, 43 patients developed events, most of them S93 Critical Care March 2007 Vol 11 Suppl 2
27th International Symposium on Intensive Care and Emergency Medicine Figure 1 (abstract P228) Figure 1 (abstract P229) Figure 1 (abstract P229) Figure 1 (abstract P228) pattern of group 1 remained significantly related to mortality
(P = 0.013) together with the number of leads with STE. Conclusion The initial STE pattern is useful in detecting patients at
higher risk of death or cardiogenic shock, despite the adequate
revascularization therapy in STEMI. (n = 28) consisting of death (23 by cardiac death). However, most
of these events occurred in the first month after the admission, the
mortality between 1 month and 3 years being low (Figure 1). Percutaneous coronary intervention in acute coronary
syndrome complicated by states Killip 3 and 4 in 2005 Percutaneous coronary intervention in acute coronary
syndrome complicated by states Killip 3 and 4 in 2005 E Zima, G Szabo, D Becker, G Fulop, L Geller, L Molnar,
G Barczi, S Toth, A Horvath, A Apor, B Merkely
Semmelweis University, Budapest, Hungary
Critical Care 2007, 11(Suppl 2):P230 (doi: 10.1186/cc5390) P230 Conclusion Our data show that the octogenarian patients with
STEMI treated by primary PCA developed a very high mortality. However, this mortality especially concentrates in the first month
after the procedure, being low between 1 month and 3 years. Outcome in myocardial infarction is related to the
morphologic pattern of ST elevation The early inhospital mortality of hrACS
aggravated by state Killip 3/4 was 10.7% (20 patients) –
according to subgroup: Killip 3: 0.06%; Killip 4: 30.5%. Methods We analyzed 446 consecutive patients (age 61.9 ± 13.8
years, 76.5% male) admitted in the first 12 hours of STEMI to our
coronary unit. Exclusion criteria were left bundle branch block at
admission or previous myocardial infarction. Most patients (87%)
were treated with primary angioplasty. Patients treated with
thrombolytics and with early reperfusion criteria were programmed
to coronary angiography the following day. Two groups were
defined according to the presence of ST-segment elevation (STE)
together with distortion of the terminal portion of the QRS in two or
more adjacent leads (group 1) or the absence of this pattern
(group 2) (Figure 1). Results There were 102 (22.8%) patients in group 1 and 344
(77.2%) in group 2. No differences in age or risk factors were seen
between both groups. The number of diseased vessels was similar. Group 1 had higher CK, MB-CK and cardiac troponin I. The
maximal Killip class was >2 during hospitalisation in 38% of group
1 vs 24% (P = 0.009). Group 1 had more mortality (8.8% vs 2.6%,
P = 0.005) and more cardiogenic shock. Other ECG character-
istics related to mortality were the sum of STE in all leads, the
number of leads with STE and ST segment depression. After a
logistic regression analysis including all ECG characteristics, the S94 Available online http://ccforum.com/supplements/11/S2 Figure 1 (abstract P233) Figure 1 (abstract P233) Conclusion The prognosis of state Killip 3/4 and successive
multiorgan failure as the high-mortality complication of hrACS can
be improved by early successful PCI, and the concomitant
pharmacologic and nonpharmacologic supportive therapy. Figure 1 (abstract P233) Abstract withdrawn Abstract withdrawn P232 Table 1 (abstract P232)
<2
2–4
4–6
>6
Symptom to balloon time
hours
hours
hours
hours
P value
ST-segment resolution (%)
95
92
86
78
0.0001
Procedural success (%)
97
95
91
84
0.03
Mortality (%)
6
9
12
29
<0.001 Conclusion ST elevation with distortion of the terminal portion of
QRS predicts impaired CC. Early recognition of this pattern should
warrant prompt treatment. P234 Hemoglobin concentration on admission influences the
rate of inhospital 30-day mortality and complications in
patients with acute myocardial infarction: a retrospective
analysis of 660 Chinese patients Conclusion This study shows that, in patients with STEMI treated
by PCA, SBT is related to ST-segment resolution, to PS and to
mortality Y Zhao, W Gao, H Wu, J Li
Institute of Geriatric Cardiology, Beijing, China
Critical Care 2007, 11(Suppl 2):P234 (doi: 10.1186/cc5394) P232 Symptom onset to balloon time in patients with ST-
segment elevation myocardial infarction treated by primary
coronary angioplasty: influence on ST-segment resolution
and on mortality therapeutic and prognostic implications. Our purpose was to
correlate the electrocardiogram (ECG) pattern and CC in STEMI. Methods We analyzed ECG and angiographic CC in 242
consecutive patients (62 ± 14 years, 79% male) with STEMI
treated with primary angioplasty. Patients were divided into two
groups based on the magnitude of ST elevation with/without
distortion of the terminal portion of the QRS (group 1/group 2). The degree of collateral filling (Rentrop) was assessed as grade 0 =
none, grade 1 = filling of side branches of the occluded artery,
grade 2 = partial epicardial filling, and grade 3 = complete
epicardial filling of the occluded artery. therapeutic and prognostic implications. Our purpose was to
correlate the electrocardiogram (ECG) pattern and CC in STEMI. M th d
W
l
d ECG
d
i
hi
CC i
242 Introduction With controversy in the field, we wanted to assess
the influence of symptom onset to balloon time in ST-segment
elevation myocardial infarction (STEMI) treated by primary coronary
angioplasty (PCA), on ST-segment resolution and on the 1-year
mortality. Introduction With controversy in the field, we wanted to assess
the influence of symptom onset to balloon time in ST-segment
elevation myocardial infarction (STEMI) treated by primary coronary
angioplasty (PCA), on ST-segment resolution and on the 1-year
mortality. Methods
Retrospectively (January 1998–August 2004), we
studied 558 consecutive patients with STEMI treated by PCA. The
symptom to balloon time (SBT) was defined as the elapsed time
between symptom onset and the first balloon inflation, and the
procedural success (PS) as the TIMI III flow post-PCA with
estenosis <50%. Results ST elevation with distortion of the terminal portion of QRS
were present at initial ECG in 55 patients (23%). This group had a
lower incidence of Rentrop grade 2/3 than group 2 (P = 0.006,
Figure 1). Moreover, group 1 had higher enzyme release, worse
maximal Killip class and more frequently the combined variable
death/shock. Group 1 more often had proximal occlusion of the
infarction-related artery and nonreflow. Multivariate analysis found
ECG to be an independent predictor of outcome. Results Table 1 summarises clinical features according to SBT. After adjustment of potentially confounding variables, SBT was the
variable associated with less ST-segment resolution (HR 1.772,
95% CI 1.46–4.15, P = 0.02). P233 Coronary collateral circulation status is correlated with the
initial electrocardiographic pattern in ST-elevation
myocardial infarction
I Nuñez Gil1, R Garcia de la Borbolla2, J Garcia Rubira1,
A Fernandez Ortiz1, M Manzano Nieto1, R Hernandez Antolin1,
C Macaya1
1Hospital Clínico San Carlos, Madrid, Spain; 2Hospital Universitario
Puerta del Mar, Cadiz, Spain
Critical Care 2007, 11(Suppl 2):P233 (doi: 10.1186/cc5393) Objective To determine the association between hemoglobin
concentrations on admission and inhospital 30-day cardiac
mortality and complications among patients with acute myocardial
infarction during their hospital course. I Nuñez Gil1, R Garcia de la Borbolla2, J Garcia Rubira1,
A Fernandez Ortiz1, M Manzano Nieto1, R Hernandez Antolin1,
C Macaya1
1Hospital Clínico San Carlos, Madrid, Spain; 2Hospital Universitario
Puerta del Mar, Cadiz, Spain
Critical Care 2007, 11(Suppl 2):P233 (doi: 10.1186/cc5393) Methods We conducted a retrospective study of data on 660
Chinese patients who were hospitalized with acute myocardial
infarction. Patients were categorized according to the hemoglobin
concentration on admission, and data were evaluated to determine
whether there was an association between the hemoglobin
concentrations on admission and inhospital 30-day mortality and
complications. Complications were defined as cardiogenic shock,
congestive heart failure, arrhythmia, ventricular tachycardia or
fibrillation and pneumonia. Introduction The status of coronary collateral circulation (CC) in
the first hours of ST-elevation myocardial infarction (STEMI) may
influence outcome. Early recognition of the CC status may have S95 Critical Care March 2007 Vol 11 Suppl 2
27th International Symposium on Intensive Care and Emergency Medicin Results Patients with hemoglobin values between 140 and 159 g/l
were used as the reference; cardiovascular mortality increased as
hemoglobin levels fell below 140 g/l or rose ≥160 g/l. The in-
hospital 30-day mortality was 25.0% in patients with hemoglobin
concentrations <100 g/l, 20.4% in patients with hemoglobin
concentrations of 100–119 g/l, 10.6% in patients with hemoglobin
concentrations of 120–139 g/l, 4.3% in patients with hemoglobin
concentrations of 140–159 g/l, and 8.5% in patients with hemo-
globin concentrations of 160 g/l or greater. The increase in risk of
complications associated with a low hemoglobin concentration
was more pronounced in patients with anemia than in patients
without. Compared with patients with hemoglobin concentrations
of 140–159 g/l, those with hemoglobin concentrations <140 g/l
had more inhospital complications and those with hemoglobin
concentrations ≥160 g/l also had more arrhythmia and pneumonia
(P < 0.001, respectively). Long-term prognostic impact of anemia in patients with
ST-elevation acute myocardial infarction treated by primary
coronary angioplasty E Abu Assi, F Soto, R Vidal, E Pardes, A Amaro
Hospital Clínico Universitario, Santiago de Compostela, Spain
Critical Care 2007, 11(Suppl 2):P236 (doi: 10.1186/cc5396) Conclusion It is demonstrated in this study that a reverse J-shaped
relationship between baseline hemoglobin values and major
adverse cardiovascular events is observed in patients with acute
myocardial infarction. There is a greater incidence of patients with
a hemoglobin concentration on admission in the elderly population
than that in the younger one. Introduction Anemia has been shown to be a powerful and
independent predictor of 30-day outcomes among patients
presenting with acute coronary syndrome. However, there are
limited and conflicting data about its long-term independent
predictive value in this setting. Introduction Anemia has been shown to be a powerful and
independent predictor of 30-day outcomes among patients
presenting with acute coronary syndrome. However, there are
limited and conflicting data about its long-term independent
predictive value in this setting. Objectives To investigate the long-term prognostic impact of
anemia in patients with ST-elevation acute myocardial infarction
(STEMI) treated by primary coronary angioplasty (PCA). P233 As expected, a significant inverse corre-
lation between hemoglobin concentrations and ages (r = –0.51;
P < 0.001) was observed, and a significant positive correlation
between hemoglobin concentrations and albumin concentrations
and in the patients with acute myocardial infarction. worse intrahospital prognosis: major incidence of cardiac
insufficiency (42% to 20%, P = 0.0001), refractory angina pectoris
(14% to 6%, P = 0.01), more electric complications (12% to 9%,
P = 0.01) and a higher mortality (14% to 7%, P = 0.009). The
presence of anaemia was an independent predictor of cardiac
insufficiency and death at the moment of admittance to the CCU
(OR = 2.20, 95% CI = 1.10–4.35; P = 0.002) Conclusion The presence of anaemia is a powerful predictor of a
worse prognosis in patients with ACS. Anaemia is associated with
other factors of a worse prognosis such as renal dysfunction,
peripheral artery disease and diabetes mellitus. P235 Anaemia at the moment of admittance is associated with
higher heart failure and mortality among patients with
acute coronary syndrome Methods Retrospectively, from January 2001 to December 2003,
we studied 298 consecutive patients with STEMI treated with
PCA. Patients were classified into two groups according to having
anemia or nonanemia at admission (for men Hb < 13 vs ≥13 g/dl,
and for women Hb < 12 vs ≥12 g/dl). We defined the composite
endpoint as death or rehospitalization for heart failure or acute
coronary event. The average follow-up time was 24 months and
was determined in 97%. J Garcia Acuña, A López Lago, E González Babarro,
B Cid Alvarez, E Abu Assi, M Jaquet Herter, A Amaro Cendon,
M Santás Alvarez, S De Lange, J González Juanatey
Clinic Universitary Hospital of Santiago, Santiago de Compostela,
Spain
Critical Care 2007, 11(Suppl 2):P235 (doi: 10.1186/cc5395) Results Anemia was present in 41 patients (14%). At the end of
follow-up, 109 patients (37%) developed ≥1 component of the
composite endpoint (52 deaths and 66 rehospitalization). The
event-free survival was 62% in the group with anemia versus 82%
in the other group (P < 0.001). After controlling for a variety of
baseline clinical, laboratory, and angiographic variables, anemia
was a strong and independent predictor of death or rehospitaliza-
tion for heart failure or acute coronary event (HR 1.96, 95% CI
1.21–3.17, P = 0.006). Figure 1 shows that patients with anemia
present a worse prognosis. Background The search for novel and modifiable risk factors in
acute coronary syndrome (ACS) can open new strategies. We
decided to evaluate the prevalence of anaemia and determine its
influence on the prognosis of hospitalized ACS patients. Patients
and
methods
Four
hundred
and
twenty-eight
consecutive patients hospitalized for ACS between 2005 and
2006 in a coronary care unit (CCU) of a cardiology department of
a tertiary hospital were studied. During their hospitalization we
registered cardiovascular risk factors; we determined the presence
of microalbuminuria (>3 mg/dl) in a 24-hour urine sample. We also
took blood samples during the first 24 hours of their admittance to
the CCU for a complete haemogram, levels of total cholesterol,
HDL cholesterol, LDL cholesterol, triglycerides, creatinine, creatinine
clearance (Cockroft–Gault equation), glucose, HbAc1, high-
sensibility C-reactive protein and a follow-up of levels of Troponin,
CK and CK-MB. Figure 1 (abstract P236) P237 Cardiogenic shock in the Aachen Digital Myocardial
Infarction Registry
A Kersten, M Merx, H Dückers, M Kelm, W Lepper
UK Aachen, Germany
Critical Care 2007, 11(Suppl 2):P237 (doi: 10.1186/cc5397) Cardiogenic shock in the Aachen Digital Myocardial
Infarction Registry Cardiogenic shock in the Aachen Digital Myocardial
Infarction Registry Introduction Evaluation of hemodynamics in patients with acute
myocardial infarction (AMI) is crucial. Hemodynamic changes
during intra-aortic balloon counterpulsation (IABC) are monitored
using invasive methods for assessment of hemodynamics in
patients with cardiogenic shock (CS). A Kersten, M Merx, H Dückers, M Kelm, W Lepper
UK Aachen, Germany
Critical Care 2007, 11(Suppl 2):P237 (doi: 10.1186/cc5397) Introduction Guideline-oriented therapy of acute coronary
syndrome (ACS) with ST-elevation myocardial infarction (STEMI)
calls for quick and early treatment. The creation of an infarct
network has been associated with streamlined treatment and a
reduction of hospital mortality. Whether patients with cardiogenic
shock (CS) receive similar, optimized treatment as regular STEMI
patients is unclear. Objective To evaluate hemodynamic indices in patients with AMI,
complicated by CS and managed with IABC during initial days of
treatment. Methods Hemodynamic indices including cardiac output (CO),
cardiac index (CI), mean pulmonary artery pressure (MPAP) and
pulmonary capillary wedge pressure (PCWP) were measured by
pulmonary artery catheterization using an intermittent thermo-
dilution technique for patients with AMI complicated by CS,
admitted within 12 hours from the onset of pain and managed by
IABC. All measurements were performed within 48 hours after
initiation of IABC. Methods We created the Aachen Digital Myocardial Infarction
Registry (ADMIRE) database according to the European Cardiology
Audit and Registration Data standards for clinical cardiology
practice. Patients were labelled according to the presenting form
of ACS. The infarct network included local ambulance services
(LA), local hospitals (LH) and the interventional center with an
emergency department (ED) and a 24/7 cath lab crew. To improve
performance we introduced prehospital triage, fax-transmission of
ECG, and direct alert of the cath lab crew by telephone. We
determined treatment variables, median index-to-door (IDT) and
door-to-sheath (DST) times and hospital mortality. Results Twenty-nine patients were investigated according to the
study protocol: 15 (51.7%) men and 14 (48.3%) women. Average
age was 71.4 ± 6.9 years. Anterior AMI was diagnosed for 19
(65.5%) patients, and inferior in 10 (34.5%) patients. P237 Primary
percutaneous transluminal coronary angioplasty (PTCA) was
successfully performed for 22 (75.9%) patients, primary PTCA
was unsuccessful for four (13.8%) patients, and seven (24.1%)
patients underwent scheduled cardiac surgery within the first
2 weeks. The inhospital mortality rate was 41.4% (12 patients). Results Between April and December 2006 we treated 593
patients including 119 STEMI (20.1%) and 45 CS patients
(7.6%); 66.7% were male, mean age was 67.4 years. CS
presented with ST elevation in 48.9%, as non-STEMI in 33.3%,
rescue percutaneous coronary intervention (PCI) in 11.1% or with
subacute ACS in 6.7%; 30.4% of CS were admitted through LA,
67.4% through LH and only one patient through the ED. Upon
admission, 50% of CS had required CPR, 69.6% were on
mechanical ventilation. In total 89.1% of CS underwent
angiography, with revascularization in 69.8% and intra-aortal
balloon pump treatment in 68.1%. The median DST for CS vs
STEMI was 82 vs 59.5 minutes (P = 0.07), and the IDT was
shorter for CS (172 vs 385 min, P < 0.05). Stratified by admission
source, the DST was equal between LA and LH (66 vs 84 min,
P = 0.75). CS patients with ST elevation were not treated
significantly faster than those without or CS with rescue PCI (64 vs
84 vs 94 min, P > 0.05 for each). Prehospital CPR did not lead to
significantly altered DST. The DST was <60 minutes in 31.3% of
CS compared with 50% STEMI patients. Mortality in CS patients
was significantly higher than that of STEMI patients (56.5% vs
7.6%, P < 0.05) but equal among CS subgroups (50% for ST-
elevation CS, 80% for non-STEMI CS, 40% for rPCI CS, no
deaths for CS with subacute ACS). It did not differ by admission
source and was not influenced by a DST < 60 minutes, intra-aortal
balloon pump or revascularization status. The initial (after initiation of IABC) CO was 3.7 ± 1.2 l/min, CI was
1.9 ± 0.7 l/min/m2, MPAP was 30 ± 7.1 mmHg (maximum
43 mmHg), PCWP was 19.1 ± 5.1 mmHg (maximum 26 mmHg). After the first 24 hours of IABC, the CO was 3.8 ± 1.6 l/min, CI
was 2 ± 0.9 l/min/m2, MPAP was 23.7 ± 7.1 mmHg (maximum
36 mmHg), PCWP was 16.8 ± 4 mmHg (maximum 24 mmHg). P238 Conclusion Our data demonstrate that baseline anemia is a strong
and independent predictor of future adverse events at 2 years in
patients with STEMI treated with PCA. P238
Intra-aortic balloon counterpulsation: impact on patient
hemodynamics in acute myocardial infarction complicated
by cardiogenic shock
J Brazdzionyte, A Macas, A Mickeviciene, G Baksyte
Kaunas University of Medicine, Kaunas, Lithuania
Critical Care 2007, 11(Suppl 2):P238 (doi: 10.1186/cc5398) P238
Intra-aortic balloon counterpulsation: impact on patient
hemodynamics in acute myocardial infarction complicated
by cardiogenic shock
J Brazdzionyte, A Macas, A Mickeviciene, G Baksyte
Kaunas University of Medicine, Kaunas, Lithuania
Critical Care 2007, 11(Suppl 2):P238 (doi: 10.1186/cc5398) Intra-aortic balloon counterpulsation: impact on patient
hemodynamics in acute myocardial infarction complicated
by cardiogenic shock J Brazdzionyte, A Macas, A Mickeviciene, G Baksyte
Kaunas University of Medicine, Kaunas, Lithuania
Critical Care 2007, 11(Suppl 2):P238 (doi: 10.1186/cc5398) Figure 1 (abstract P236) Results The prevalence of anaemia (Hb < 11 g/dl in women and
Hb < 12 g/dl in men) in patients with an ACS was 15.4%. This
group was characterised by the following: woman (P < 0.0001),
higher age (P = 0.0001), less weight (P = 0.01), higher frequency
of high blood pressure (P
= 0.0001), diabetes mellitus
(P = 0.0001), history of ischaemic heart disease (P = 0.002) and
peripheral artery disease (P = 0.0001). This group presented a
major proportion of the NSTEMI (P = 0.015), higher level of renal
dysfunction (77% to 32%, P = 0.0001), and microalbuminuria
(61% to 32%, P = 0.0001). Patients with anaemia presented a S96 Available online http://ccforum.com/supplements/11/S2 P239 Elevation of Troponin T in critically ill septic patients is
common: but does it matter? A Thornley, A Turley, M Johnson, B Kunadian, M de Belder,
J Gedney
The James Cook University Hospital, Middlesbrough, UK
Critical Care 2007, 11(Suppl 2):P239 (doi: 10.1186/cc5399) P237 After 48 hours of IABC, CO was 4.1 ± 1.7 l/min, CI was 2.1 ± 0.8
l/min/m2, MPAP was 23.8 ± 6.5 mmHg (maximum 44 mmHg),
PCWP was 16.8 ± 4.6 mmHg (maximum 24 mmHg). Conclusion Intra-aortic balloon counterpulsation has a positive
impact on hemodynamic changes of patients with acute myocardial
infarction complicated by cardiogenic shock during the initial days
of treatment. Elevation of Troponin T in critically ill septic patients is
common: but does it matter? A Thornley, A Turley, M Johnson, B Kunadian, M de Belder,
J Gedney
The James Cook University Hospital, Middlesbrough, UK
Critical Care 2007, 11(Suppl 2):P239 (doi: 10.1186/cc5399) Background Troponin T (TnT) is an established marker of adverse
outcome in acute coronary syndrome patients and aids risk
stratification. Myocardial dysfunction and elevated of TnT are
common in critically ill patients and cardiology advice is often
sought. Conclusion Despite their higher complexity, patients with CS were
treated as fast as patients with STEMI, yet there was room for
improvement to increase the number of patients treated within the
first hour of admission for both STEMI and CS. Structural changes
and further implementation of standard operating procedures might
achieve this. We could not show a mortality difference for any of
our treatment variables, which might be due to the low number of
patients. Objective To evaluate the role of TnT as a predictor of all-cause
mortality in patients with severe sepsis/septic shock as defined by
international criteria. S97 Critical Care March 2007 Vol 11 Suppl 2
27th International Symposium on Intensive Care and Emergency Medicin (odds ratio 1.29 for 1,000 units) and no administration of inotropic
drug on day 1 (odds ratio 34.5) decrease the probability of
inhospital complications. The average efficacy of prognostication
reached 96.5%; the presence of complications was correctly
predicted in 88.9% of cases, and the absence of complications in
100% of cases. Methods A prospective observational study was performed on
patients admitted to a general adult ICU within 24 hours of the
development of severe sepsis/septic shock. Serial TnT samples
were taken over the first 96 hours. Patients were grouped into
three groups: A, TnT < 0.01 ng/ml; B, TnT 0.01–0.099 ng/ml; and
C, TnT > 0.099 ng/ml. Conclusion The HRV parameter LF on day 3, and LV ESV, atrial
fibrillation/flutter and inotropic agent administration on day 1 are
statistically significant independent predictors of inhospital
complications of MI with an average predictive efficacy of 96.5%. Results Blood from 49 patients was analysed. The peak Troponin
level was elevated (>0.01 ng/ml) in 39/49 patients (80%). There
was no significant difference between the three groups in terms of
hypertension, history of angina, myocardial infarction or systolic
blood pressure at time of ICU admission. Table 1 (abstract P239) Introduction The aim of this study was to investigate the
relationship between blood pressure and plasma magnesium levels
in patients referred to the emergency department with hypertensive
attack. Epidemiological evidence on the effects of magnesium on
blood pressure is inconsistent. Metabolic and experimental studies
suggest that magnesium may have a role in the regulation of blood
pressure. Magnesium regulates various ion channels in many
tissues, including those of the cardiovascular system. Magnesium
is the second most abundant intracellular cation, and the important
element that has numerous biological functions in the cardio-
vascular system. Furthermore, magnesium acts as a calcium
antagonist, regulating the calcium metabolism. Conclusions Elevated biochemical markers of cardiac myocyte
damage are common in patients with severe sepsis/septic shock. TnT elevation is a predictor of 6-month all-cause mortality. Clinicians should be aware of the significance of an elevated TnT
assay in this patient population. Prognostic markers in the acute phase of myocardial
infarction G Baksyte1, A Macas1, J Brazdzionyte1, V Saferis1,
M Tamosiunas2, A Krisciukaitis1
1Kaunas University of Medicine, Kaunas, Lithuania; 2Institute for
Biomedical Research, Kaunas, Lithuania
Critical Care 2007, 11(Suppl 2):P240 (doi: 10.1186/cc5400) Results Seventy-three patients (35 of whom were female, 38
males) were included in the study. The average age was 47 ± 6.3
(ranging from 33 to 68 years). The average blood pressure of the
patients was found as systolic 200 ± 10 (range 185–240) mmHg,
diastolic 105 ± 7 (range 95–110) mmHg. The average plasma
magnesium levels were 1.4 ± 0.3 (range 0.9–2.2) mg/l. The
plasma magnesium levels were low in 29 patients (ranging from
0.9 to 1.7 mg/l). There was a negative relationship systolic blood
pressure and plasma magnesium level (P < 0.05). In addition, there
was a negative relationship diastolic blood pressure and plasma
magnesium level (P < 0.05). Introduction The aim of the study was to assess the prognostic
value of heart rate variability, arrhythmias and left ventricular
systolic and diastolic function for the course and the outcome of
myocardial infarction (MI). Methods We prospectively studied 57 consecutive patients
admitted to the ICU of the Department of Cardiology of Kaunas
Medical University Hospital between 2002 and 2004 with acute
MI. The study protocol included 24-hour ECG monitoring on the
first day and the third day of admission and echocardiography
performed at days 2–4. Inhospital prognostic endpoints were
death and nonfatal events: postinfarction angina, progressive heart
failure, pulmonary edema and cardiogenic shock. Heart rate
variability (HRV) was assessed at days 1 and 3 by a 24-hour
recording using the ‘HeartLab’ system. A logistic regression model
was used to select the combination of statistically significant
variables and predict the complications. Conclusion Low plasma magnesium levels would be an important
factor for elevated blood pressure and hypertensive attack. Elevation of Troponin T in critically ill septic patients is
common: but does it matter? Patients with
undetectable TnT levels (<0.01 g/ml) had significantly lower 6-
month mortality rates than those with detectable levels (group A
2/10 (20%) vs Group B/C 23/39 (59%), P = 0.037; group B 8/15
(53%), group C 15/24 (63%)). See Table 1. The relationship between blood pressure and plasma
magnesium level in hypertensive patients The relationship between blood pressure and plasma
magnesium level in hypertensive patients The relationship between blood pressure and plasma
magnesium level in hypertensive patients A Bayir, B Cander, A Ak, S Girisgin
University, Meram Faculty of Medicine, Konya, Turkey
Critical Care 2007, 11(Suppl 2):P241 (doi: 10.1186/cc5401) Table 1 (abstract P239)
APACHE II
Mean
Inotropic
Group
Number
score
age (years)
support
Mortality
A
10
18.5 (8.2)
52 (17)
8
2/10
B
15
20 (5.7)
63 (15)
15
8/15
C
24
22.2 (6.8)
65 (14)
22
15/24 P240 Methods Patients were included who were taken to the emer-
gency department due to hypertensive attack. Their age, gender,
systolic and diastolic blood pressure were recorded. In order to
see the plasma magnesium levels, venous blood samples were
taken. The results were compared with a chi-square test. The
values P < 0.05 were accepted as significant. Prognostic markers in the acute phase of myocardial
infarction Available online http://ccforum.com/supplements/11/S2 Available online http://ccforum.com/supplements/11/S2 Figure 1 (abstract P242) Objective To investigate the clinical and prognostic value of TnI
release in adult with acute Pc. Figure 1 (abstract P242) Objective To investigate the clinical and prognostic value of TnI
release in adult with acute Pc. Methods From January 2000 to March 2006 we retrospectively
studied 89 patients with the final diagnosis of acute myocarditis
(Mc), of which 66 (74%) fulfilled at least two criteria of acute Pc
(typical chest pain, pericardial friction rub, and/or alterations in the
ECG). We only included those diagnosed with idiopathic or viral
Pc with elevation of TnI over the level of cut for AMI in our hospital
(≥0.6 ng/dl). We divided patients into tertiles according to the
value of TnI (22 in each group). An echocardiographic (Echoc)
study and a ECG monitorization was performed at admission in all. The coronariography was done in 24 (36%), which did not show
lesions. The average follow-up was 24 ± 18 months and included
Echoc in 61 (92%). Methods From January 2000 to March 2006 we retrospectively
studied 89 patients with the final diagnosis of acute myocarditis
(Mc), of which 66 (74%) fulfilled at least two criteria of acute Pc
(typical chest pain, pericardial friction rub, and/or alterations in the
ECG). We only included those diagnosed with idiopathic or viral
Pc with elevation of TnI over the level of cut for AMI in our hospital
(≥0.6 ng/dl). We divided patients into tertiles according to the
value of TnI (22 in each group). An echocardiographic (Echoc)
study and a ECG monitorization was performed at admission in all. The coronariography was done in 24 (36%), which did not show
lesions. The average follow-up was 24 ± 18 months and included
Echoc in 61 (92%). Results Age 28 ± 9 years, 87% men; two (3%) patients had
antecedents of idiopathic Pc and only one of Mc. The average of
the peak of TnI was 17 ± 11 ng/dl, being the average of the values
of TnI in each group of 6 ± 3 (first tertile), 15 ± 2 (second tertile)
and 30 ± 11 ng/dl (third tertile). LVEF% was ≥55 in 61 (92%) and
there were no differences in the age and sex between the three
groups. The elevation of TnI did not correlate with the LVEF%
(62 ± 5 vs 61 ± 4 vs 60 ± 7; P = 0.60). Available online http://ccforum.com/supplements/11/S2 Only the values of TnI in
the third tertile were associated with the elevation of the ST
segment in ≥5 derivations (P = 0.001), and with abnormal
ventricular wall motion (P = 0.046). There was no association with
the presence of pericardial effusion, arrhythmias nor cardiac failure. During follow-up, two (3%) patients presented Mc, and three Pc
without elevation of TnI. The remaining patients (92%) were
asymptomatic and without cardiac dysfunction. The average
LVEF% was >55% in all of them surgery patients as well as severely hypertensive patients. Clevidipine is an ultrashort-acting, vascular and arterial-selective
calcium antagonist currently under development for treating acute
hypertension. Methods We analyzed data from two double-blinded, placebo-
controlled trials (ESCAPE-1 and ESCAPE-2) that evaluated the
ability of clevidipine to control BP in high-risk cardiovascular
surgery patients. In addition, we evaluated the design of a recently
initiated trial that analyzes clevidipine in severe hypertension
(VELOCITY trial). Results
In
both
ESCAPE-1
and
ESCAPE-2,
clevidipine
demonstrated a statistically significant decrease in mean arterial
pressure from baseline (P < 0.0001) compared with placebo at
the 5-minute time point. A BP lowering effect was observed within
1–2 minutes with clevidipine, with the median time to achieve
target systolic blood pressure (SBP) of 6 and 5.3 minutes,
respectively (see Figure 1). In the patients with acute severe
hypertension, the VELOCITY trial studies the percentage of
patients in whom the SBP falls below the lower limit of a patient-
specific predetermined target range at the initial dose of 2.0
mg/hour within 3 minutes of initiating the infusion, as well as the
percentage of patients who reach the prespecified target SBP
range within 30 minutes of the beginning of the study drug. Conclusion In adults with acute Pc, the elevation degree of TnI is
associated with the degree of elevation of the ST segment but it is
not a negative prognosis indicator. Emergency electrocardiography-guided pericardiocentesis
in cardiac tamponade Emergency electrocardiography-guided pericardiocentesis
in cardiac tamponade E Charalambous, S Manousakis, A Kioulpalis, A Skrivanou,
G Vrouchos
Venizelio General Hospital of Heraklion, Greece
Critical Care 2007, 11(Suppl 2):P244 (doi: 10.1186/cc5404) E Charalambous, S Manousakis, A Kioulpalis, A Skrivanou,
G Vrouchos Conclusion In both the ESCAPE-1 and ESCAPE-2 studies,
clevidipine demonstrated the ability to precisely achieve target
blood pressure reductions in a short period of time, in a high-risk
patient population. Further analysis of the rapid decreases noted
with clevidipine is being conducted in patients with acute severe
hypertension in the VELOCITY trial. Introduction Pericardiocentesis (PC) and pericardial fluid drainage
is the method of choice in cardiac tamponade (CT). It is usually
performed under echocardiography control. The objective of the
study was the description of CT etiology, symptoms and clinical
findings and the evaluation of the electrocardiography (ECG)-
guided PC procedure. P242 Precise and ultrarapid control of blood pressure with
clevidipine, an arterial selective calcium channel blocker J Varon1, J Levy2, C Dyke3, P Acosta4, S Aronson5
1The University of Texas, Houston, TX, USA; 2Emory Healthcare,
Atlanta, GA, USA; 3Gaston Medical Center, Gastonia, NC, USA;
4Dorrington Medical Associates, Houston, TX, USA; 5DUMC,
Durham, NC, USA
Critical Care 2007 11(Suppl 2):P242 (doi: 10 1186/cc5402) Results In our model statistically significant independent variables
for prediction of inhospital MI complications were HRV frequency
domain parameter low-frequency power (LF) on day 3, and left
ventricular end-systolic volume (LV ESV), atrial fibrillation/flutter
and inotropic agent administration on day 1. According to the
results, atrial fibrillation/flutter (odds ratio 25.6) and increased LV
ESV (odds ratio 1.067 (6.7%) for increase in 1 ml) increase the
probability of inhospital complications, while increased LF on day 3 Introduction Precise, rapid control of blood pressure (BP) is
important in emergency and critical care settings as uncontrolled
hypertension is associated with morbidity and mortality in high-risk S98 P245 Likelihood ratios (LR) were not
Table 1 (abstract P245)
Abnormality
Kappa
Sensitivity
Rhythm
0.92 (0.84–1)
1 (0.88–1)
Other
0.68 (0.52–0.84)
1 (0.91–1) Introduction Computerised electrocardiogram (ECG) interpre-
tation is widely applied, especially within the clinical settings of
primary care and surgical preadmission. Concerns have been
raised over the accuracy of computerised ECG interpretation. Our
aim was to compare the performance of computer-based ECG
interpretation with that of a panel of experienced cardiologists. Methods All consecutive ECGs performed in a hospital cardiology
department over a 1-week period were analysed. Two cohorts
were assessed, open access patients from primary care and
surgical preoperative assessment patients. Cardiologists were
blinded
to
clinical
details
and
the
computerised
ECG
interpretation. ECGs were analysed by a panel of cardiologists
with the consensus view taken as the reference standard. ECGs
were interpreted in relation to ‘rhythm’ and ‘other abnormalities’
and were classified as normal or abnormal. Results We determined the Cystatin C level in 59 patients (16
females and 43 males). In 36% (21 patients) we found normal
levels (<0.95; 0.80 ± 0.9), called group 1. In the other group
(group 2) we found higher levels of Cystatin C (>0.95;
1.63 ± 0.77). Patients in group 2 presented a higher age, a higher
frequency of high blood pressure, worse Killip class score at the
moment of admittance, higher inflammatory activity (leucocytosis,
P = 0.001 and higher levels of C reactive protein, P = 0.005),
higher grade of renal dysfunction (P = 0.001) and anaemia
(P = 0.06). Patients in group 2 presented a worse intrahospital
prognosis with a higher incidence of cardiac insufficiency (45% to
14%, P = 0.01), ventricular arrhythmias (29% to 5%, P = 0.05),
pericardial effusion (18% to 0%, P = 0.05) and a higher mortality
(21% to 5%, P = 0.08). In the multivariant analysis, Cystatin C was
an independent predictor of cardiac insufficiency (OR = 4.5, 95%
CI 1.1–20.8, P = 0.05). Results Seventy consecutive ECGs were analysed, 47 from open
access and 23 from surgical preassessment. The cohort’s median
age was 60 years (range 27–87 years, male n = 30). Twenty-four
ECGs were normal. There was complete disagreement over the
computerised ECG interpretation of one ECG, which was deemed of
major clinical significance. Partial disagreement occurred in the
remainder. The greatest level of disagreement related to the
interpretation of left ventricular hypertrophy and ECG evidence of
myocardial ischaemia/infarction. P243 Methods Thirty-nine consecutive patients (nine females) with CT,
mean age 56 years, underwent 41 emergency PC between
November 1998 and November 2006. There was full data registry
for 31 patients and 33 PC. We used a subxiphoidal approach in
31 and an apical approach in two cases. Catheters used were
Cordigan
(Braun)
and
C-PCS-830-LOCK
(Cook). A
full
transthoracic echocardiography (TTE) study preceded and PC was
performed under ECG monitoring (intrapericardial ECG recording). Results Patients with CT had the following symptoms or clinical
findings: dyspnea (77%), pleural effusion (68%), chest pain (48%),
weight loss (29%), fever (23%), cough (19%), peripheral edema
(12%), abdominal pain (12%), hoarseness (12%), jugular vein
distension (6%). Forty-five percent of patients were hemo-
dynamically stable, while 26% had high BP. The mean heart rate
on admission was 94/minute. Seventy-one percent of patients
exhibited hypoxemia (half of them mild). Deep heart sounds were Clinical meaning and prognosis of the elevation degree of
cardiac Troponin I in pericarditis of the adult: short-term
and mid-term follow-up results E Abu Assi, C Peña Gil, R Vidal Perez, J Garcia Acuña,
A Amaro Cendon
Hospital Clínico Universitario, Santiago de Compostela, Spain
Critical Care 2007, 11(Suppl 2):P243 (doi: 10.1186/cc5403) E Abu Assi, C Peña Gil, R Vidal Perez, J Garcia Acuña,
A Amaro Cendon
Hospital Clínico Universitario, Santiago de Compostela, Spain
Critical Care 2007, 11(Suppl 2):P243 (doi: 10.1186/cc5403) Introduction The inflammatory process of acute pericarditis (Pc)
may involve the epicardium and cause myocardial damage, as
reflected by cardiac Troponin I (TnI) release. Studies performed
with TnI demonstrated that the temporal pattern of this release is
similar to that of an acute myocardial infarction (AMI); however, the
true prognostic significance of TnI remains unknown in this setting. S99 Critical Care March 2007 Vol 11 Suppl 2
27th International Symposium on Intensive Care and Emergency Medicin recognized in 39% and pulsus paradoxus was present in 29% of
cases. Only 12% had pericardial knock and pericardial friction rub
was absent in all patients. On ECG there was sinus rhythm in
71%, the rest being atrial fibrillation. Sixty-five percent of patients
showed repolarization changes, and only 16% had low voltage. On
TTE, 3/4 of patients had right atrium/right ventricle collapse and
the intapericardial space measured 1.8–3.8 cm. Only 39% of
patients exhibited cardiac enzyme increase (cardiac troponin I, CK-
MB), while the majority had elevated CRP. P246 Cystatin C in the prognostic stratification of patients with
an acute coronary syndrome A Lopez Lago, E González Babarro, J García Acuña,
S De Lange, E Abu Assi, R Vidal Pérez, M Santás Alvarez,
M Jaquet Herter, B Cid Alvárez, J González Juanatey
Clinic Universitary Hospital of Santiago, Santiago de Compostela,
Spain
Critical Care 2007, 11(Suppl 2):P246 (doi: 10.1186/cc5406) Conclusions ‘Classical’ symptoms and signs (low BP, pulsus
paradoxus, deep heart sounds or low voltage) can be absent in CT. Emergency PC with ECG intrapericardial ECG recording, after
meticulous TTE, can be safe. Appearance of nonmalignant
arrhythmias could be a rare complication. Introduction Early risk stratification is essential in the management
of
patients
with
an
acute
coronary
syndrome
(ACS). Measurements of renal function such as serum creatinine and
estimation of creatinine clearance carry independent prognostic
information in this population. Cystatin C is a new and better
marker of renal function than creatinine. The aim was therefore to
evaluate the prognostic value of cystatin C in this population. Methods Four hundred and twenty-eight patients with an ACS,
admitted to our coronary care unit (CCU), were studied
prospectively. Sixty-three per cent presented a non-ST-segment
elevation myocardial infarction (NSTEMI) and 37% a ST-segment
elevation myocardial infarction (STEMI). During their hospitalization
we registered cardiovascular risk factors: we determined the
presence of microalbuminuria (>3 mg/dl) in a 24-hour urine
sample. We also took blood samples during the first 24 hours of
their admittance to the CCU for a complete hemogram, levels of
total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides,
creatinine,
creatinine
clearance
(Cockroft–Gault
equation),
glucose, HbAc1, high-sensibility C-reactive protein, Cystatin C and
a follow-up of levels of Troponin, CK and CK-MB. All patients were
submitted to a coronary angiography in the first 72 hours to give a
clinical score to their coronary artery disease (disease of one, two
or three arteries). Introduction Early risk stratification is essential in the management
of
patients
with
an
acute
coronary
syndrome
(ACS). Measurements of renal function such as serum creatinine and
estimation of creatinine clearance carry independent prognostic
information in this population. Cystatin C is a new and better
marker of renal function than creatinine. The aim was therefore to
evaluate the prognostic value of cystatin C in this population. P243 The underlying
diagnosis for CT in 35% of cases was lung adenocarcinoma/
nonsmall cell carcinoma or breast carcinoma. In 35% the final
diagnosis was that of idiopathic pericarditis. Seventy percent of
pericardial fluid samples were exudates and 74% were
sanguineous/serosanguineous. Four patients had pericardial fluid
under pressure. The mean volume drained was 1,540 ml (850–3,010),
the mean period of drainage was 56 hours (3 hours–14 days). No
major complications occurred; 23% patients had nonmalignant
arrhythmias (AF, NSVT). calculated for negative results as there were no false negative results. LR for abnormal ECG ‘rhythm’ were 18.3 (6.7–53.4) and for
abnormal ECG ‘other abnormalities’ were 3.15 (2.13–5.11) (Table 1). Conclusions Need exists to improve the diagnostic algorithms
used by computerised ECG interpretation. It is essential that all
automated computerised ECG interpretations be over read by a
physician. P245 Diagnostic accuracy of automated computerised
electrocardiogram interpretation compared with a panel of
experienced cardiologists Methods Four hundred and twenty-eight patients with an ACS,
admitted to our coronary care unit (CCU), were studied
prospectively. Sixty-three per cent presented a non-ST-segment
elevation myocardial infarction (NSTEMI) and 37% a ST-segment
elevation myocardial infarction (STEMI). During their hospitalization
we registered cardiovascular risk factors: we determined the
presence of microalbuminuria (>3 mg/dl) in a 24-hour urine
sample. We also took blood samples during the first 24 hours of
their admittance to the CCU for a complete hemogram, levels of
total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides,
creatinine,
creatinine
clearance
(Cockroft–Gault
equation),
glucose, HbAc1, high-sensibility C-reactive protein, Cystatin C and
a follow-up of levels of Troponin, CK and CK-MB. All patients were
submitted to a coronary angiography in the first 72 hours to give a
clinical score to their coronary artery disease (disease of one, two
or three arteries). A Turley1, A Roberts1, K Evemy2, I Haq2, T Irvine2, P Adams2
1The James Cook University Hospital, Middlesbrough, UK; 2Royal
Victoria Infirmary, Newcastle upon Tyne, UK
Critical Care 2007, 11(Suppl 2):P245 (doi: 10.1186/cc5405) S100
Introduction Computerised electrocardiogram (ECG) interpre-
tation is widely applied, especially within the clinical settings of
primary care and surgical preadmission. Concerns have been
raised over the accuracy of computerised ECG interpretation. Our
aim was to compare the performance of computer-based ECG
interpretation with that of a panel of experienced cardiologists. Methods All consecutive ECGs performed in a hospital cardiology
department over a 1-week period were analysed. Two cohorts
were assessed, open access patients from primary care and
surgical preoperative assessment patients. Cardiologists were
blinded
to
clinical
details
and
the
computerised
ECG
interpretation. ECGs were analysed by a panel of cardiologists
with the consensus view taken as the reference standard. ECGs
were interpreted in relation to ‘rhythm’ and ‘other abnormalities’
and were classified as normal or abnormal. Results Seventy consecutive ECGs were analysed, 47 from open
access and 23 from surgical preassessment. The cohort’s median
age was 60 years (range 27–87 years, male n = 30). Twenty-four
ECGs were normal. There was complete disagreement over the
computerised ECG interpretation of one ECG, which was deemed of
major clinical significance. Partial disagreement occurred in the
remainder. The greatest level of disagreement related to the
interpretation of left ventricular hypertrophy and ECG evidence of
myocardial ischaemia/infarction. P247 P247
The reduction of the glomerular filtration rate and the
presence of microalbuminuria at the moment of
admittance reduce the prognostics of patients with an
acute coronary syndrome
A Lopez Lago, J Garcia Acuña, S De Lange, E González
Babarro, M Jaquet Herter, E Abu Assi, A Amaro Cendon,
M Santás Alvárez, J González Juanatey
Clinic Universitary Hospital of Santiago, Santiago de Compostela,
Spain
Critical Care 2007, 11(Suppl 2):P247 (doi: 10.1186/cc5407) P247
The reduction of the glomerular filtration rate and the
presence of microalbuminuria at the moment of
admittance reduce the prognostics of patients with an
acute coronary syndrome
A Lopez Lago, J Garcia Acuña, S De Lange, E González
Babarro, M Jaquet Herter, E Abu Assi, A Amaro Cendon,
M Santás Alvárez, J González Juanatey
Clinic Universitary Hospital of Santiago, Santiago de Compostela,
Spain
Critical Care 2007, 11(Suppl 2):P247 (doi: 10.1186/cc5407) P247
The reduction of the glomerular filtration rate and the
presence of microalbuminuria at the moment of
admittance reduce the prognostics of patients with an
acute coronary syndrome
A Lopez Lago, J Garcia Acuña, S De Lange, E González
Babarro, M Jaquet Herter, E Abu Assi, A Amaro Cendon,
M Santás Alvárez, J González Juanatey
Clinic Universitary Hospital of Santiago, Santiago de Compostela,
Spain
Critical Care 2007, 11(Suppl 2):P247 (doi: 10.1186/cc5407) The reduction of the glomerular filtration rate and the
presence of microalbuminuria at the moment of
admittance reduce the prognostics of patients with an
acute coronary syndrome Background Elevated circulating levels of TNFα, brain natriuretic
peptide (BNP) and cardiac Troponin I (cTnI) have been connected
with adverse prognosis in patients with chronic heart failure (CHF). However, there are scant data about the predictive value of these
biomarkers in combination. Methods A total of 577 consecutive patients (mean age: 73 ± 9
years), who were hospitalized for acute decompensation of NYHA
class III/IV (65.3% of ischemic etiology) low-output (mean LVEF:
22 ± 5) CHF, were studied. Biochemical markers were measured
upon admission. The incidence of 31-day death was the
prespecified primary endpoint. Introduction Determination of the glomerular filtration rate (GFR)
in patients with an acute coronary syndrome (ACS) has an
important prognostic value. The presence of microalbuminuria
(MA) is a known risk factor in patients with hypertension and
diabetes. We know less about the effect of reduction of the GFR
on patients with an ACS. Results The incidence of the primary endpoint was 17.7%. P248 Circulating levels of tumor necrosis factor alpha, brain
natriuretic peptide and cardiac Troponin I upon admission
and 31-day mortality in patients with acute
decompensated chronic heart failure P Batika Zairis1, M Zairis2, E Adamopoulou2,
H Michalopoulou1, S Foussas2
1Metaxa Hospital, Piraeus, Greece; 2Tzanio Hospital, Piraeus,
Greece
Critical Care 2007, 11(Suppl 2):P248 (doi: 10.1186/cc5408) P Batika Zairis1, M Zairis2, E Adamopoulou2, H Michalopoulou1, S Foussas2 P245 Likelihood ratios (LR) were not Table 1 (abstract P245)
Abnormality
Kappa
Sensitivity
Specificity
NPV
PPV
Rhythm
0.92 (0.84–1)
1 (0.88–1)
0.95 (0.85–0.98)
1 (0.93–1)
0.9 (0.76–0.97)
Other
0.68 (0.52–0.84)
1 (0.91–1)
0.68 (0.68–0.53)
1 (0.88–1)
0.75 (0.62–0.85) S100 Available online http://ccforum.com/supplements/11/S2 Conclusion Higher levels of Cystatin C (>0.95) in patients with an
ACS indicate a worse intrahospital prognosis and also a higher
inflammatory activity and renal dysfunction. Conclusion Higher levels of Cystatin C (>0.95) in patients with an
ACS indicate a worse intrahospital prognosis and also a higher
inflammatory activity and renal dysfunction. P247 By
multivariate Cox analysis, including baseline characteristics and the
study biomarkers, elevated circulating levels of TNFα (RR = 2.1;
P < 0.001), BNP (RR = 3.5; P < 0.001) and cTnI (RR = 3.8;
P < 0.001) were independently associated with the primary
endpoint. When the patients were divided according to the number
of positive biomarkers (estimated by ROC analysis) there was a
significant gradual increase in the rate of the primary endpoint with
increasing of the number of the positive biomarkers (4.1%, 10%,
21.5% and 53.5% 31-day mortality rate for patients with zero, one,
two and three positive biomarkers, respectively; P < 0.001) (Figure 1). Method Four hundred and twenty-eight patients with an ACS,
admitted to our coronary care unit (CCU), were studied
prospectively. Sixty-three percent presented a non-ST-segment
elevation myocardial infarction and 37% a ST-segment elevation
myocardial infarction. During their hospitalization we registered
cardiovascular risk factors; we determined the presence of MA
(>3 mg/dl) in a 24-hour urine sample. We also took blood samples
during the first 24 hours of their admittance to the CCU for a
complete hemogram, levels of total cholesterol, HDL cholesterol,
LDL cholesterol, triglycerides, creatinine, creatinine clearance
(Cockroft–Gault equation), glucose, HbAc1, high-sensibility C-
reactive protein and a follow-up of levels of Troponin, CK and CK-
MB. P250 P250
Cardiopulmonary exercise testing as a screening test for
perioperative management of major cancer surgery: a pilot
study
R Raobaikady, S Dinesh, M Hacking, T Wigmore
The Royal Marsden NHS Foundation Trust, London, UK
Critical Care 2007, 11(Suppl 2):P250 (doi: 10.1186/cc5410) Cardiopulmonary exercise testing as a screening test for
perioperative management of major cancer surgery: a pilot
study R Raobaikady, S Dinesh, M Hacking, T Wigmore
The Royal Marsden NHS Foundation Trust, London, UK
Critical Care 2007, 11(Suppl 2):P250 (doi: 10.1186/cc5410) Introduction Cardiopulmonary exercise testing is an important
screening test to evaluate cardiorespiratory function before major
body cavity surgery. Introduction Cardiopulmonary exercise testing is an important
screening test to evaluate cardiorespiratory function before major
body cavity surgery. Introduction Over the past decade, coronary revascularisation has
helped reduce mortality and morbidity rates from coronary artery
disease. In addition to revascularisation, long-term prognosis is
dependent on successful implementation of secondary prevention,
in particular the use of aspirin, statins, angiotensin-converting
enzyme (ACE) inhibitors and, in many, β-blockers. Previous studies
have highlighted the under-utilisation of secondary preventative
strategies in this patient population. A focused review of secondary
preventative medication at the time of revascularisation provides an
excellent opportunity to ensure optimal use of these agents. Our
aim was to identify the proportion of patients undergoing
nonemergency surgical revascularisation discharged on these four
secondary preventative medications. Objective To develop a clinical strategy for the identification and
management of high-risk major cancer surgical patients in order to
reduce perioperative morbidity and mortality. Methods Forty-one major cancer surgery patients underwent a
cardiopulmonary exercise test (CPX) as part of their preoperative
assessment. Their cardiac and pulmonary risk factors were
analysed. Depending on the anaerobic threshold (AT) values,
patients are considered poor risk, moderate risk or very low risk for
surgery. Results Three patients did not complete the test. Two of them had
very poor cardiopulmonary reserve and one had leg fatigue with
good pulmonary function. Seven patients were considered high
risk with AT < 10. The remaining 31 patients had AT > 11 and
underwent major cancer surgery. In total, 10 surgical procedures
were cancelled based on poor CPX performance. Two patients
with low AT underwent surgery after preoptimisation with no
complications. There are no deaths related to cardiopulmonary
complications in any patient deemed fit for major cancer surgery
and intensive care management, as determined by CPX testing. Figure 1 (abstract P248) Conclusions The present results suggest that in patients
hospitalized due to acutely decompensated severe low-output
CHF, serum levels of TNFα, BNP and cTnI can be used in
combination for enhanced early risk stratification. Results Thirty-nine percent of the patients with an ACS presented
a GFR less than 60 ml/minute, and 36% presented MA at the
moment of admittance to the CCU. Forty-four percent of the
patients with a GFR less than 60 ml/minute also presented MA; on
the contrary, only 32% of the patients with a GFR more than 60
ml/minute did so (P = 0.01). This group contains significantly more
women (P = 0.001), more history of ischemic brain events and
peripheral artery disease (P = 0.03), worse Killip score at the
moment of admittance (P = 0.001), more development of cardiac
insufficiency (P = 0.003) and a higher mortality during hospital stay
(P = 0.03). The intrahospital survival of patients with GFR less than 60
ml/minute and MA was 79%, to 96% in patients without MA and a
GFR more than 60 ml/minute (P = 0.01; Log-rank test = 6). Patients with a GFR less than 60 ml/minute but without MA
presented an intrahospital survival of 85%. In the multivariant
analysis a GFR less than 60 ml/minute (OR = 2.0; 95% CI
1.13–3.53) and the presence of MA (OR = 2.30; 95% CI
1.37–3.86) were independent predictive factors of cardiac
insufficiency and mortality. Conclusions The present results suggest that in patients
hospitalized due to acutely decompensated severe low-output
CHF, serum levels of TNFα, BNP and cTnI can be used in
combination for enhanced early risk stratification. Conclusions The presence of a GFR less than 60 ml/minute and
MA at the moment of admittance of a patient with an ACS
identifies a group of patients with a bad prognosis. Future studies
can reveal whether an improvement of the renal function can be
beneficial for this group of patients. S101 P249
Secondary prevention following surgical revascularisation:
continuing under-use of angiotensin-converting enzyme
inhibitors
A Turley, A Thornley, A Roberts, R Morley, W Owens,
M de Belder
The James Cook University Hospital, Middlesbrough, UK
Critical Care 2007, 11(Suppl 2):P249 (doi: 10.1186/cc5409) P249
Secondary prevention following surgical revascularisation:
continuing under-use of angiotensin-converting enzyme
inhibitors
A Turley, A Thornley, A Roberts, R Morley, W Owens,
M de Belder
The James Cook University Hospital, Middlesbrough, UK
Critical Care 2007, 11(Suppl 2):P249 (doi: 10.1186/cc5409) P250 The average intensive care stay was 8.9 days (range 1–19 days). The surgical procedure was altered in two patients based on CPX
results. Methods A retrospective analysis of our inhouse cardiothoracic
surgical database was performed. All patients had undergone
surgical revascularisation between January 2003 and November
2006. Only patients undergoing coronary artery bypass grafting
were included. Results A total of 2,749 consecutive patients were included in the
analysis, mean age 65.5 years (±9.2). In total, 2,302 isolated
coronary artery bypass grafting procedures and 447 combined
procedures were performed. See Table 1. Table 1 (abstract P249)
2003
2004
2005
2006
Total
522
758
767
702
Previous myocardial
296
364
353
347
infarction
(56.7%)
(48%)
(46%)
(49.4%)
Left ventricular
113
145
175
186
systolic dysfunction
(21.6%)
(19.1%)
(22.8%)
(26.5%)
EuroSCORE
3.8 (2.7)
3.9 (3)
3.9 (2.8)
4.3 (2.9)
Aspirin
490
694
700
652
(93.9%)
(91.6%)
(91.3%)
(92.9%)
ACE inhibitor/
285/34
421/43
430/53
382/49
angiotensin receptor
(61%)
(61%)
(63%)
(61%)
blocker
β-Blocker
412
632
587
540
(78.9%)
(83.4%)
(76.5%)
(76.9%)
Statin
470
700
710
638
(90%)
(92.3%)
(92.6%)
(90.9%) Discussion CPX testing is an important screening test for major
surgery to determine the cardiorespiratory risk factors. It is useful in
reducing surgical perioperative mortality and avoids unnecessary
intensive care admissions after major body cavity surgeries. The
CPX test is also useful in perioperative anaesthetic management. It
may not predict morbidity and the average intensive care stay. It is
very useful in selecting patients for preoptimisation before major
cancer surgery. Conclusion Preoperative screening using CPX testing is useful in
identification of high-risk cancer surgical patients and the
appropriate selection of perioperative management. Low-dose dobutamine after surgery in high-risk patients:
effects on postoperative complications Low-dose dobutamine after surgery in high-risk patients:
effects on postoperative complications Low-dose dobutamine after surgery in high-risk patients:
effects on postoperative complications S Lobo, A Arantes, A Christiano Junior, S de Abreu,
J de Moraes, J Gandolfi, L Leite
Faculdade de Medicina de São José do Rio Preto, Brazil
Critical Care 2007, 11(Suppl 2):P251 (doi: 10.1186/cc5411) S Lobo, A Arantes, A Christiano Junior, S de Abreu,
J de Moraes, J Gandolfi, L Leite
Faculdade de Medicina de São José do Rio Preto, Brazil
Critical Care 2007, 11(Suppl 2):P251 (doi: 10.1186/cc5411) Conclusion Although the utilisation of these preventive therapies
has improved compared with previous studies, additional
improvements could be made and in particular there is a continuing
under-utilisation of ACE inhibitors. There are several reasons why
ACE inhibitors might not be used in the early postoperative phase
(hypotension, temporary renal dysfunction, etc.). These results
reinforce the need to review these patients following recovery from
surgery with a view to optimising secondary preventive treatment. This may best be done in community secondary prevention clinics
with agreed guidelines. Introduction Dobutamine may have a role in increasing splanchnic
perfusion, thereby protecting this area from further injury. We
aimed to investigate the effects of low-dose dobutamine
(5 µg/kg/min) on tissue perfusion and postoperative complications
in high-risk patients. Introduction Dobutamine may have a role in increasing splanchnic
perfusion, thereby protecting this area from further injury. We
aimed to investigate the effects of low-dose dobutamine
(5 µg/kg/min) on tissue perfusion and postoperative complications
in high-risk patients. Methods
A prospective, randomized, blinded and placebo-
controlled study. One hundred surgical patients admitted to a step-
down unit were evaluated and 82 patients were enrolled, 42 for the
control group (saline) and 40 for the dobutamine group
(5 µg/kg/hour during 24 hours). The same therapeutic goals were S102 Available online http://ccforum.com/supplements/11/S2 P252 Methods A prospective survey was conducted among 4,588 patients
undergoing cardiac surgery and attending the surgical ICU from 1
January 2002 to 31 December 2004. All case histories of patients
were objected to meticulous analysis searching for complications
involving gastrointestinal tract and requiring surgical consultation. Patients with minor disorders were excluded from the study. We
performed a multivariable logistic regression analysis to identify the
risk factors for development of postoperative intestinal complications. Results Gastrointestinal complications occurred in 63 patients,
while in 35 patients appeared transient episodes of gut mucosal
ischemia. Sixteen patients presented mesenteric ischemia, six
paralytic ileus, six colonic obstruction, two lower gastrointestinal
bleeding, two upper gastrointestinal bleeding, two perforated
duodenal ulcer and one rectal perforation. Intestinal complications
correlated with advanced age (67.5 ± 12 years), preoperative
congestive heart failure and peripheral vascular disease, prolonged
bypass time (156 ± 91.7 min) and aortic cross-clump time
(97.6 ± 44.45 min), the number of blood and plasma transfusions,
re-exploration of the chest, the administration of inotrops (70%)
and the usage of a intra-aortic balloon pump (42%). The mean
EuroSCORE value was 12.72 ± 3.8. The majority of patients
presented at the end of the first postoperative week. Fifteen
patients died (48%). Results Gastrointestinal complications occurred in 63 patients,
while in 35 patients appeared transient episodes of gut mucosal
ischemia. Sixteen patients presented mesenteric ischemia, six
paralytic ileus, six colonic obstruction, two lower gastrointestinal
bleeding, two upper gastrointestinal bleeding, two perforated
duodenal ulcer and one rectal perforation. Intestinal complications
correlated with advanced age (67.5 ± 12 years), preoperative
congestive heart failure and peripheral vascular disease, prolonged
bypass time (156 ± 91.7 min) and aortic cross-clump time
(97.6 ± 44.45 min), the number of blood and plasma transfusions,
re-exploration of the chest, the administration of inotrops (70%)
and the usage of a intra-aortic balloon pump (42%). The mean
EuroSCORE value was 12.72 ± 3.8. The majority of patients
presented at the end of the first postoperative week. Fifteen
patients died (48%). Conclusion Various predictors of hypoperfusion have been tested
in critically ill patients and correlations have been found for O2 and
CO2 derived parameters. Long ECC time plays a major role in the
balance between VO2 and DO2; O2 and CO2 derived parameters
could be useful markers to detect anaerobic metabolism in cardiac
surgical patients. Combined metabolic parameters and gas exchange to
predict morbidity after extracorporeal circulation Combined metabolic parameters and gas exchange to
predict morbidity after extracorporeal circulation S Scolletta, E Maglioni, F Franchi, P Giomarelli, B Biagioli
University of Siena, Italy
Critical Care 2007, 11(Suppl 2):P253 (doi: 10.1186/cc5413) Results Complications occurred in 35% and 50% of the patients
in the dobutamine and control groups, respectively (RR 0.70, 95%
CI 0.41–1.17; not significant). The patients in whom dobutamine
was interrupted due to persistent tachycardia despite fluid
replacement had more complications (75% vs 40.6%; RR 1.85,
95% CI 1.03–3.29, P < 0.05), higher mortality (62.5% vs 12.5%;
RR 5.0, 95% CI 1.72–14.46, P < 0.05) and lower central venous
oxygen saturation (55% ± 15% vs 70% ± 16%; P = 0.021) in
comparison with patients tolerant to dobutamine infusion. Introduction Under normal resting conditions, the oxygen delivery
(DO2) matches the overall metabolic demands of the organs, the
oxygen consumption (VO2) is about 25% of the DO2, and energy
is produced basically through the aerobic mechanism. In cardiac
surgery with extracorporeal circulation (ECC), several factors (for
example, hemodilutional anemia, myocardial stunning resulting in a
low cardiac output (CO)) can determine an imbalance between O2
demand and DO2 and may affect the outcome. Below the critical
DO2 there is a linear decrease of both VO2 and CO2 production
(VCO2), but due to the anaerobic VCO2 the respiratory quotient
increases. This study is aimed to evaluate the role of O2 and CO2
derived parameters to predict postoperative morbidity in cardiac
surgery. Conclusion Low-dose dobutamine after surgical trauma has no
effects on the prevalence of postoperative complications in high-
risk surgical patients. Morbimortality was significantly higher in
patients with severe occult hypoperfusion. P253 applied for both groups. The presence of tachycardia or
hypotension in response to study drug infusion was considered a
signal of occult hypoperfusion and deemed a need for fluid
replacement, which was given according to an algorithm. Results Complications occurred in 35% and 50% of the patients
in the dobutamine and control groups, respectively (RR 0.70, 95%
CI 0.41–1.17; not significant). The patients in whom dobutamine
was interrupted due to persistent tachycardia despite fluid
replacement had more complications (75% vs 40.6%; RR 1.85,
95% CI 1.03–3.29, P < 0.05), higher mortality (62.5% vs 12.5%;
RR 5.0, 95% CI 1.72–14.46, P < 0.05) and lower central venous
oxygen saturation (55% ± 15% vs 70% ± 16%; P = 0.021) in
comparison with patients tolerant to dobutamine infusion. applied for both groups. The presence of tachycardia or
hypotension in response to study drug infusion was considered a
signal of occult hypoperfusion and deemed a need for fluid
replacement, which was given according to an algorithm. P252 Intestinal complications associated with cardiovascular
surgical procedures
S Mastoraki, E Mastoraki, L Douka, I Kriaras, S Geroulanos
Onassis Cardiac Surgery Center, Athens, Greece
Critical Care 2007, 11(Suppl 2):P252 (doi: 10.1186/cc5412) Intestinal complications associated with cardiovascular
surgical procedures Methods Eight hundred and twenty-seven consecutive adult
patients who underwent coronary surgery were studied. We
selected 38 intraoperative and postoperative O2 and CO2 derived
parameters, which could be associated with postoperative
morbidity. Postoperative data were collected in the first 3 hours
after admission to the ICU. The influence of each predictor on
outcome was analyzed. Morbidity was defined as one or more of
the following events: cardiovascular, respiratory, neurological,
renal, infectious, and hemorrhagic complications. Univariate and
multivariate analyses were performed. ROC curve analysis was
also used to define the best predictive variables. S Mastoraki, E Mastoraki, L Douka, I Kriaras, S Geroulanos
Onassis Cardiac Surgery Center, Athens, Greece
Critical Care 2007, 11(Suppl 2):P252 (doi: 10.1186/cc5412) Introduction Intestinal complications after cardiopulmonary bypass
procedures are infrequent but they carry a significant incidence of
morbidity and mortality. Predictors of these complications are not
well developed, and the role of fundamental variables remains
controversial. The purpose of this study was to ascertain the
frequency of intestinal complications following open heart surgery,
to assess preoperative predisposing factors and to elucidate that
prompt diagnosis and institution of therapy are the most common
factors to improve the outcome. Results Intraoperative predictors of morbidity were ECC and
aortic cross-clamp times, and lowest hematocrit during ECC. The
area under the ROC curve (AUC) was 0.74 for the lowest
hematocrit on ECC, and its cutoff value was 24%. Among the
postoperative variables, DO2, oxygen extraction ratio (O2ER),
DO2/VCO2 ratio, and VCO2/CO ratio were related to morbidity. The AUCs for oxygen and CO2 derived parameters were 0.80,
0.76, 0.75, and 0.70 (DO2, O2ER, DO2/VCO2
ratio, and
VCO2/CO ratio, respectively). The best predictive cutoff values
were 590 ml/minute, 38%, 3.9, and 40, for DO2, O2ER,
DO2/VCO2 ratio, and VCO2/CO ratio, respectively. Methods A prospective survey was conducted among 4,588 patients
undergoing cardiac surgery and attending the surgical ICU from 1
January 2002 to 31 December 2004. All case histories of patients
were objected to meticulous analysis searching for complications
involving gastrointestinal tract and requiring surgical consultation. Patients with minor disorders were excluded from the study. We
performed a multivariable logistic regression analysis to identify the
risk factors for development of postoperative intestinal complications. P255 Role of plasminogen activator inhibitor-1 polymorphism on
the development of vasoplegic syndrome associated with
cardiopulmonary bypass J Jimenez, J Iribarren, M Brouard, Y Barrios, J Raya, L Lorente,
R Perez, C Garcia, J Martinez, R Martinez, M Mora
Hospital Universitario de Canarias, La Laguna, Santa Cruz,
Tenerife, Spain
Critical Care 2007, 11(Suppl 2):P255 (doi: 10.1186/cc5415) Introduction Vasoplegic syndrome (VS) after cardiac surgery with
cardiopulmonary bypass (CPB) can vary from mild to severe
complication and it appears with an incidence ranging between
5% and 15%. The etiology is not completely elucidated but risk
factors such as temperature and duration of cardiopulmonary
bypass and preoperative treatment with angiotensin-converting
enzyme (ACE) inhibitors have been associated [1]. We wanted to
investigate the possible role of several genetic polymorphisms in
patients with VS after elective CPB. Introduction Vasoplegic syndrome (VS) after cardiac surgery with
cardiopulmonary bypass (CPB) can vary from mild to severe
complication and it appears with an incidence ranging between
5% and 15%. The etiology is not completely elucidated but risk
factors such as temperature and duration of cardiopulmonary
bypass and preoperative treatment with angiotensin-converting
enzyme (ACE) inhibitors have been associated [1]. We wanted to
investigate the possible role of several genetic polymorphisms in
patients with VS after elective CPB. Results Seventeen (34%) patients had VS, 11 (65%) men and six
(35%) women. Longer aortic clamping time (P = 0.007) and CPB
time (P = 0.013) were associated with VS. These patients showed
a higher cardiac index at 4 hours (P < 0.001) and lactic acid within
the first 24 hours. Seven of these patients (41%) fulfilled
vasoplegic shock criteria (P < 0.001). We found higher levels of
IL-6 at 0 hours (P = 0.02) and 4 hours (P = 0.001), and soluble
TNF receptor at 0 hours (P = 0.044). At ICU admission (0 hours)
there was a higher coagulation activation: INR (P = 0.005),
fibrinogen (P = 0.001), antithrombin (P = 0.007); lower levels of
plasminogen activator inhibitor-1 (P = 0.023) as well as lower
plasminogen activator inhibitor-1/tissue-plasminogen activator ratio
(P = 0.021), and higher levels of D-dimer (P = 0.041); lower levels
of C3 (P = 0.023), B factor (P = 0.013), C4 (P = 0.015) as well as
a significantly higher decrease between preoperative and 0-hour
levels of C1-inhibitor, C4, C3 and B factor. Lower levels of leptins
at 0, 4 and 24 hours were found. P254 Vasoplegic syndrome after cardiopulmonary bypass
surgery – associated factors and clinical outcomes:
a nested case–control study
J Iribarren, J Jimenez, M Brouard, J Lorenzo, R Perez,
L Lorente, C Nuñez, L Lorenzo, C Henry, R Martinez, M Mora
Hospital Universitario de Canarias, La Laguna, Santa Cruz,
Tenerife, Spain
Critical Care 2007, 11(Suppl 2):P254 (doi: 10.1186/cc5414) Vasoplegic syndrome after cardiopulmonary bypass
surgery – associated factors and clinical outcomes:
a nested case–control study J Iribarren, J Jimenez, M Brouard, J Lorenzo, R Perez,
L Lorente, C Nuñez, L Lorenzo, C Henry, R Martinez, M Mora
Hospital Universitario de Canarias, La Laguna, Santa Cruz,
Tenerife, Spain
Critical Care 2007, 11(Suppl 2):P254 (doi: 10.1186/cc5414) Conclusions Intestinal complications after cardiac surgery are
uncommon but life-threatening and may result from ischemic
mucosal injury, which increases mucosal permeability and
promotes the translocation of bacterial toxins and the release of
mediators. Clinical features are often subtle and a high index of
suspicion is necessary for an early diagnosis and the institution of
appropriate treatment. Introduction Vasoplegic syndrome (VS) following heart surgery
using cardiopulmonary bypass (CPB) has been recently
recognized and implicated in life-threatening complications. The Introduction Vasoplegic syndrome (VS) following heart surgery
using cardiopulmonary bypass (CPB) has been recently
recognized and implicated in life-threatening complications. The S103 Critical Care March 2007 Vol 11 Suppl 2
27th International Symposium on Intensive Care and Emergency Medicin Conclusions VS post-CPB was associated with activation of serin
protease systems, which leads to higher blood loss and excessive
bleeding. aim of this study was to identify associated factors for the
development of VS after CPB. Methods We performed a nested case–control study of 50
patients undergoing CPB, 27 (54%) men and 23 (46) women,
mean age 66.5 (SD 9.6) years. VS was defined as systemic
vascular resistance index <1,600 dyn•seg/cm5/m2 and cardiac
index >2.5 l/min/m2
within the first postoperative 4 hours. Vasoplegic shock was defined as vasoplegic patients that needed
norepinephrine for at least 4 hours, after failure to respond to
appropriate volume expansion. Excessive bleeding was defined as
blood loss >1 l/24 hours, while total bleeding was considered as
blood loss until chest tube withdrawal. Demographic variables,
surgical procedures and postoperative variables were collected. We recorded data related to coagulation, fibrinolysis, complement,
inflammation, blood loss at different time points, preoperative, at 0,
4 and 24 hours after surgery, and hemoderivative requirements. P254 We used the Pearson chi-squared test, the Fisher exact test, the
Student t test and the Mann–Whitney U test for nonparametric
variables. SPSS version 12.1 was used. P255 Vasoplegic patients showed
higher blood losses along all time points (Figure 1), higher
incidence of excessive bleeding (60% vs 40%; P = 0.011) and
required more hemoderivatives during the ICU stay, plasma
(P = 0.016) and platelets (P = 0.002). Methods We performed a nested case–control study of 50
patients undergoing CPB, 27 (54%) men and 23 (46) women,
mean age 66.5 (SD 9.6) years. VS was defined as systemic
vascular resistance index lower than 1,600 dyn•seg/cm5/m2 and a
cardiac index greater than 2.5 l/min/m2 within the first 4 hours after
surgery. We recorded data related to hemodynamic parameters at
different postoperative time points, at ICU admission (0 hours), 4
and 24 hours after surgery, and the polymorphism of the following
genes: plasminogen activator inhibitor-1 (PAI-1) and β-TNF + 250. In addition, 23 neutral markers were genotyped to follow genomic
control strategies that would detect spurious associations due to
population substructure. We used the Pearson chi-squared test
and binary logistic regression. SPSS version 12.1 was used. Results We observed 17 (34%) patients with vasoplegia criteria,
11 (65%) men and six (35%) women, age 67 (61–72) years. The
only one associated with VS was the PAI-1 polymorphism, and its
distribution in the study population was: 4G/G genotype in 10
(20%) patients, 4G/5G in 26 (52%) patients, and 5G/G in 14 Available online http://ccforum.com/supplements/11/S2 Methods We performed a nested case–control study of 26
patients, who did not receive antifibrinolytic prophylaxis. We used
Bray’s classification for BMI: lower than 27 kg/m2; 27–30 kg/m2;
higher than 30 kg/m2. Variables were collected preoperatively, at
ICU admission (0 hours), and at 4 and 24 hours after surgery. Excessive bleeding was defined as blood loss higher than 1 l in the
first 24 hours after intervention. The associations of BMI with
demographic factors, leptin levels, coagulation, fibrinolysis and
complement parameters were analyzed. Pearson’s chi-squared test
and Fisher’s exact test were used, the Student t test for independent
groups and the Mann–Whitney U test for nonparametric variables. Conclusions The PAI-1 polymorphism (homozygous 5G/G) was
independently associated with the onset of VS. 1. Carrel T, Englberger L, Mohacsi P, Neidhart P, Schmidli J:
Low systemic vascular resistance after cardiopulmonary
bypass: incidence, etiology, and clinical importance. J Card Surg 2000, 15:347-353. P256 Results In total, 61.5% of patients showed BMI >27 kg/m2
(median 28 kg/m2, range 25.2–30.7 kg/m2). Patients with BMI
lower than 26.4 kg/m2 (25–28 kg/m2) presented excessive
bleeding (P = 0.026). Leptin levels after adjusting by BMI were
significantly associated with excessive bleeding at all postoperative
time points (P < 0.001, P < 0.001 and P = 0.004, respectively)
(Figure 1). BMI presented a direct correlation with leptins,
fibrinogen and plasminogen activator inhibitor-1 (PAI-1) on arrival,
meanwhile 24-hour bleeding showed an inverse correlation with
the same parameters and BMI (Table 1). Patients with BMI
< 27 kg/m2 had significantly greater coagulation, fibrinolysis and
complement
activation. Therefore
these
patients
required
significantly greater hemoderivatives. Available online http://ccforum.com/supplements/11/S2 Available online http://ccforum.com/supplements/11/S2 postoperative bleeding after cardiopulmonary bypass (CPB) has
been found in several studies recently. Nevertheless the strong
relationship between a low BMI and excessive bleeding remains
unexplained. We sought to investigate the BMI role on
postoperative bleeding and its relationship with leptin levels,
coagulation, fibrinolysis and complement parameters. Methods We performed a nested case–control study of 26
patients, who did not receive antifibrinolytic prophylaxis. We used
Bray’s classification for BMI: lower than 27 kg/m2; 27–30 kg/m2;
higher than 30 kg/m2. Variables were collected preoperatively, at
ICU admission (0 hours), and at 4 and 24 hours after surgery. Excessive bleeding was defined as blood loss higher than 1 l in the
first 24 hours after intervention. The associations of BMI with
demographic factors, leptin levels, coagulation, fibrinolysis and
complement parameters were analyzed. Pearson’s chi-squared test
and Fisher’s exact test were used, the Student t test for independent
groups and the Mann–Whitney U test for nonparametric variables. Results In total, 61.5% of patients showed BMI >27 kg/m2
(median 28 kg/m2, range 25.2–30.7 kg/m2). Patients with BMI
lower than 26.4 kg/m2 (25–28 kg/m2) presented excessive
bleeding (P = 0.026). Leptin levels after adjusting by BMI were
significantly associated with excessive bleeding at all postoperative
time points (P < 0.001, P < 0.001 and P = 0.004, respectively)
(Figure 1). BMI presented a direct correlation with leptins,
fibrinogen and plasminogen activator inhibitor-1 (PAI-1) on arrival,
meanwhile 24-hour bleeding showed an inverse correlation with
the same parameters and BMI (Table 1). Patients with BMI
< 27 kg/m2 had significantly greater coagulation, fibrinolysis and
complement
activation. Therefore
these
patients
required
significantly greater hemoderivatives. (28%) patients. According to the PAI-1 polymorphism, vasoplegia
criteria were found in one (5.5%) 4G/G carrier, in seven (39%)
4G/5G carriers and in 10 (55.5%) 5G/G carriers (P = 0.012)
(Figure 1). The post-hoc power for PAI-1 polymorphism and
vasoplegia was 0.85. After controlling for temperature, clamping
time, antifibrinolytics, body mass index and ACE inhibitors, the
5G/G genotype was independently associated with vasoplegia
(P = 0.017); OR: 24.6 (95% CI: 1.8–342). postoperative bleeding after cardiopulmonary bypass (CPB) has
been found in several studies recently. Nevertheless the strong
relationship between a low BMI and excessive bleeding remains
unexplained. We sought to investigate the BMI role on
postoperative bleeding and its relationship with leptin levels,
coagulation, fibrinolysis and complement parameters. Figure 1 (abstract P257) Methods We performed a nested case–control study of 50 patients
undergoing CPB, 27 (54%) men and 23 (46) women, mean age 66.5
(SD 9.6) years. Excessive bleeding (EB) was defined as blood loss
higher than 1 l over the 24 hours. Demographic variables, comorbid
conditions, surgical procedures and postoperative variables were
collected. We recorded data related to coagulation, fibrinolysis,
complement, and blood loss at different time points, preoperative, at
ICU admission (0 hours) and 4 and 24 hours after surgery. We used
the Pearson chi-squared test, the Fisher exact test, the Student t test
and the Mann–Whitney U test for nonparametric variables and
Spearman’s rho for nonparametric correlations. Figure 1 (abstract P257) Results EB patients had higher activation of classical, alternative
and final pathways of complement at 0 and 4 hours. Also we found
a significantly higher decreasing of several components of
complement from preoperative values to postoperative values (0
and 4 hours) associated with EB. This decrease of complement
was correlated with a similar decrease of platelets and anti-
thrombin levels between the preoperative period and 0 hours, and
an increase of D-dimer levels in the first 4 hours. Conclusions Complement activation was associated with EB due, in
part, to a greater activation of platelets, coagulation and fibrinolysis. Table 1 (abstract P257)
ICU arrival
BMI
24-hour bleeding
Rho
P
Rho
P
Leptins
0.46
0.02
–0.57
0.02
Fibrinogen
0.51
<0.01
–0.49
<0.01
PAI-1
0.40
0.04
–0.64
<0.01 Table 1 (abstract P257)
ICU arrival
BMI
24-hour bleeding
Rho
P
Rho
P
Leptins
0.46
0.02
–0.57
0.02
Fibrinogen
0.51
<0.01
–0.49
<0.01
PAI-1
0.40
0.04
–0.64
<0.01
Conclusions Lower BMI was associated with higher postoperative
bleeding and lower procoagulant factor levels. Table 1 (abstract P257) P257 Impact of body mass index on postoperative bleeding in
cardiopulmonary bypass Complement activation and excessive bleeding in
cardiopulmonary bypass surgery J Iribarren, J Jimenez, M Brouard, R Galvan, L Lorente, R Perez,
B Alarco, M Diaz, J Malaga, S Huidobro, R Martinez, M Mora
Hospital Universitario de Canarias, La Laguna, Santa Cruz,
Tenerife, Spain
Critical Care 2007, 11(Suppl 2):P256 (doi: 10.1186/cc5416) Introduction Complement activation has been associated with
postoperative bleeding. We investigated the association between
complement activation, coagulation and fibrinolysis systems, and
postoperative excessive bleeding in cardiopulmonary bypass
(CPB) surgery. Introduction Complement activation has been associated with
postoperative bleeding. We investigated the association between
complement activation, coagulation and fibrinolysis systems, and
postoperative excessive bleeding in cardiopulmonary bypass
(CPB) surgery. Figure 1 (abstract P254) Figure 1 (abstract P254) 4
Figure 1 (abstract P254)
Figure 1 (abstract P255) Figure 1 (abstract P255) Figure 1 (abstract P255) S104 Available online http://ccforum.com/supplements/11/S2 E Borotto1, D Tüller1, S Krähenbühl2, D Mettler1, J Takala1,
S Jakob1
1University Hospital Bern, Switzerland; 2University Hospital Basel,
Switzerland
Critical Care 2007, 11(Suppl 2):P258 (doi: 10.1186/cc5418) Introduction Endotoxemia and hemorrhage may both affect
mitochondrial function. We aimed to characterize the impact of a
short-term, three-hit hemorrhage/endotoxemia model on liver and
skeletal muscle mitochondrial respiration. Results Hyperdynamic circulation developed in F with increasing
DO2,h and decreasing VO2,h (Table 1). Complex II activity signifi-
cantly decreased from 19.3 ± 4.2 to 9.5 ± 2.6 (P < 0.05 vs BL
and between groups) in F compared with C. Complex I–III–IV
function decreased in parallel in F. Methods Seven anesthetized pigs were bled (blood loss 20%)
and retransfused to euvolemia before and after endotoxin infusion
(0.4 µg/kg/hour for 2 hours). The cardiac index (CI) (thermodilution)
and systemic mean arterial pressure (MAP) were recorded. State
3/4 respiration (nanoatom O2/min/mg protein for glutamate) was
assayed from tissue samples at baseline (muscle) and the end of
the experiment (muscle and liver). Hepatic mitochondrial
respiration was compared with controls (n = 6). Table 1 (abstract P259)
BL
12 hours
24 hours
MAP F
78 ± 22
98 ± 25
81 ± 19
MAP C
91 ± 4
101 ± 12
94 ± 6
TLF F
17 ± 1
46 ± 11*
50 ± 5*
TLF C
23 ± 7
35 ± 4
39 ± 7†
DO2,h F
2.0 ± 0.6
3.8 ± 0.2
5.4 ± 1†
DO2,h C
1.9 ± 0.4
3.2 ± 0.4
3.5 ± 0.4
VO2,h F
0.8 ± 0.2
0.6 ± 0.1
0.5 ± 0.1
VO2,h C
1.5 ± 0.7
1.1 ± 0.1
0.9 ± 0.4
*P < 0.05 vs BL and between groups. †P < 0.05 vs BL. Results One pig died earlier (not included). Data are presented as
the median (range). P < 0.05, Friedman test. Muscle mitochondrial
respiration was similar at baseline and the end of experiment; state
3 (317 (222–594) vs 409 (295–468)), state 4 (29 (22–58) vs 40
(31–49)), respiratory control ratio (11 (7–15) vs 10 (9–11)) (not
significant). Hepatic mitochondrial state 4 was higher (27 (16–31)
vs 19 (13–22)) and respiratory control ratio lower (3 (3–4) vs 5
(4–6)) in the hemorrhage/endotoxemia group, compared with
controls. *P < 0.05 vs BL and between groups. †P < 0.05 vs BL. Real-time monitoring of mitochondrial function in the
urethral wall Real-time monitoring of mitochondrial function in the
urethral wall Real-time monitoring of mitochondrial function in the
urethral wall
S Preisman1, E Segal1, V Glauber1, E Heldenberg1, R Walden1,
D Givony2, N Dekel2, L Oren2, E Pewzner2, A Mayevsky3, A Perel1
1Sheba Medical Center, Tel-Hashomer, Rama-Gan, Israel;
2CritiSense Ltd, Givat Shmuel, Israel; 3Bar-Ilan University,
Ramat-Gan, Israel
Critical Care 2007, 11(Suppl 2):P260 (doi: 10.1186/cc5420) PAP, pulmonary artery pressure. P < 0.05, Friedman test. Conclusions Repeated ischemia/reperfusion episodes plus short-
term endotoxemia decreased the efficiency of hepatic but not
muscle mitochondrial respiration. Mitochondrial dysfunction under
these experimental circumstances seems to be organ specific. References S Preisman1, E Segal1, V Glauber1, E Heldenberg1, R Walden1,
D Givony2, N Dekel2, L Oren2, E Pewzner2, A Mayevsky3, A Perel1
1Sheba Medical Center, Tel-Hashomer, Rama-Gan, Israel;
2CritiSense Ltd, Givat Shmuel, Israel; 3Bar-Ilan University,
Ramat-Gan, Israel
Critical Care 2007, 11(Suppl 2):P260 (doi: 10.1186/cc5420) References 1. Porta F, et al.: Crit Care 2006, 10:R118. 2. Rhee P, et al.: Crit Care Med 1997, 25:166-170. Monitoring of the mitochondrial NADH redox state (an indicator of
intracellular oxygen levels) together with microcirculatory blood
flow (TBF) and with oxygenation (HbO2) could serve as a preferred
approach to evaluate tissue O2
balance or viability. We
hypothesize that in the presence of reduced oxygen delivery and
extraction, blood flow will be redistributed in order to protect the
most vital organs by increasing their regional blood flow, while O2
delivery to the less vital organs will diminish. Thus, the NADH redox
state of less vital organs could serve as an indicator of overall O2
imbalance as well as an endpoint of resuscitation. We have
therefore developed an optical device embedded in a Foley
catheter to provide real-time data on the NADH redox state, TBF
and HbO2 in critically ill patients. P258 hepatic mitochondrial dysfunction was present in a clinically
relevant porcine model of fluid-resuscitated septic shock. Impact of body mass index on postoperative bleeding in
cardiopulmonary bypass Conclusions Lower BMI was associated with higher postoperative
bleeding and lower procoagulant factor levels. Introduction Body mass index (BMI) has been described as a risk
factor for coronary artery disease, but association with S105 Critical Care March 2007 Vol 11 Suppl 2
27th International Symposium on Intensive Care and Emergency Medicine Table 1 (abstract P258) Conclusion While increasing DO2,h far exceeded decreasing
VO2,h in the setting of hyperdynamic fluid-resuscitated septic
shock, hepatic mitochondrial function was significantly impaired
compared with control. P258
Muscle versus liver mitochondrial respiration in
experimental three-hit endotoxemia hepatic mitochondrial dysfunction was present in a clinically
relevant porcine model of fluid-resuscitated septic shock. Methods Anesthetized and ventilated pigs (40 ± 3 kg) were
randomly assigned to septic shock by fecal peritonitis (F, n = 3) or
control (C, n = 3) after placement of portal/hepatic vein catheters
and portal vein and hepatic artery flow probes. F and C received
8 ± 13 ml/kg/hour and 5 ± 7 ml/kg/hour ringer lactate + starch,
respectively. The mean arterial pressure (MAP), total liver flow
(TLF), hepatic O2 delivery (DO2,h) and hepatic O2 consumption
(VO2,h) were recorded at baseline (BL), 12 and 24 hours
(ml/kg/min). Activities of mitochondrial respiratory chain enzymes
(complex I–IV) were assessed by spectrophotometry in snap-
frozen liver samples. Data are presented as the mean ± SD. E Borotto1, D Tüller1, S Krähenbühl2, D Mettler1, J Takala1,
S Jakob1
1University Hospital Bern, Switzerland; 2University Hospital Basel,
Switzerland
Critical Care 2007, 11(Suppl 2):P258 (doi: 10.1186/cc5418) Table 1 (abstract P258)
After
After
End of
Baseline
bleeding
endotoxin
experiment
MAP (mmHg)
69 (52–70)
36 (30–46)
67 (49–84)
47 (19–109)
CI (ml/kg/min)
85 (62–95)
55 (42–76)
95 (78–113)
69 (16–151)
PAP (mmHg)
14 (10–17)
12 (9–13)
45 (40–51)
32 (17–38)
SvO2 (%)
49 (41–56)
33 (25–37)
54 (47–68)
46 (14–66)
PAP, pulmonary artery pressure. P < 0.05, Friedman test. Muscle versus liver mitochondrial respiration in
experimental three-hit endotoxemia Methods Anesthetized and ventilated pigs (40 ± 3 kg) were
randomly assigned to septic shock by fecal peritonitis (F, n = 3) or
control (C, n = 3) after placement of portal/hepatic vein catheters
and portal vein and hepatic artery flow probes. F and C received
8 ± 13 ml/kg/hour and 5 ± 7 ml/kg/hour ringer lactate + starch,
respectively. The mean arterial pressure (MAP), total liver flow
(TLF), hepatic O2 delivery (DO2,h) and hepatic O2 consumption
(VO2,h) were recorded at baseline (BL), 12 and 24 hours
(ml/kg/min). Activities of mitochondrial respiratory chain enzymes
(complex I–IV) were assessed by spectrophotometry in snap-
frozen liver samples. Data are presented as the mean ± SD. Cytokines monitored by microdialysis detect rejection
earlier than current methods in liver transplantation Cytokines monitored by microdialysis detect rejection
earlier than current methods in liver transplantation L Wælgaard, EB Thorgersen, P Line, T Mollnes, T Tonnessen
Rikshospitalet, Oslo, Norway
Critical Care 2007, 11(Suppl 2):P261 (doi: 10.1186/cc5421) Introduction The outcome of liver transplantation is steadily
improving. There is still need for earlier detection of complications
such as hepatic artery thrombosis and rejection. In an earlier in
vitro study we showed that the CMA microdialysis system with a
100 kDa pore size membrane can be used to measure the
selected cytokines and complement. We monitored patients
undergoing liver transplantation with microdialysis continuously for
a week postoperatively, and analyzed both parameters to detect
ischemia, and cytokines and anaphylatoxins to explore whether
rejection was detected earlier than with the standard methods. Results During cardiac luxations, the oxygen availability in the
sublingual microcirculation decreased (µHbO2
64.2 ± 9.1 to
48.6 ± 8.7%; P < 0.01) while the functional capillary density did
not change (15.9 ± 1.1 to 15.6 ± 1.3 mm/mm2; P = 0.65). Although the small vessels (0–20 µm) did not fall out they did
show hypoperfusion (Vmax
895 ± 209 to 396 ± 178 µm/s;
P < 0.01), whereas in the medium vessels (20–50 µm) there was
no significant change in blood velocity (Vmax 751 ± 239 to
596 ± 192 µm/s; P = 0.18) as observed with sidestream dark field
imaging and calculated with microvascular analysis software. Methods Twenty patients undergoing 22 liver transplantations
were included. Two microdialysis catheter were introduced in the
liver and one in subcutaneous tissue. We analyzed metabolic
parameters (glucose, pyruvate, glycerol and lactate), and IL-6, IL-8,
MCP-1, IP-10, and C5a. Conclusion
Alterations in sublingual microcirculation hemo-
dynamics reflect the direct effects of obstructive shock and
elucidate the microcirculatory autoregulation. Results
Fourteen
patients
had
an
uneventful
course
postoperatively, judged clinically and by routine biochemical
markers and ultrasound Doppler. These patients had a median
lactate starting at 3.5 mM (2 hours after reperfusion) falling to
below 2 mM during the first 24 hours, and thereafter staying low. The L/P ratio (a specific measure of ischemia) dropped from about
20 to below 10. These patients had a steady rise in IP-10 from 200
to 3,000 pg/ml, and also a slight raise in IL-6 initially. Case 1. The
male patient had a steadily increasing L/P ratio during the 7 days
of microdialysis measurements, indicating an insufficient blood
supply. P261 Methods During cardiac luxations, in 12 patients reflectance
spectrophotometry (O2C®; Lea Medizintechnik, Germany) was
used to measure oxygen availability and in 12 other patients
sidestream dark field imaging (MicroScan®; MicroVision Medical,
The Netherlands) was used to directly visualize the sublingual
microcirculatory hemodynamics in a single network of micro-
vessels. Microvascular analysis software (MAS®; MicroVision
Medical) was used to analyze the vessel density and blood flow. Synchronously, systemic hemodynamics were recorded and the
cardiac output was calculated by pulse contour analysis of arterial
pressure (PulseCO®; LiDCO, UK) in all patients. P262 These preliminary swine model and human studies confirm the
feasibility of collecting information about mitochondrial function
from the urethral wall. The main effects of graded hemorrhage
started when the blood volume decreased by 30%. At 40% blood
loss, minimal levels of TBF and HbO2 were correlated to the
maximal NADH levels. The values of the three parameters returned
to baseline after retransfusion of the shed blood. Aortic clamping in
patients led to a significant decrease in TBF and HbO2 while
NADH levels increased. After aortic declamping, the parameters
recovered to normal values. Cytokines monitored by microdialysis detect rejection
earlier than current methods in liver transplantation He underwent surgery 5 days later and a hepatic artery
thrombosis was found. A biopsy was done during the operation
showing an acute rejection. There was a significant rise in IP-10 to
13,000 pg/ml 7 days before the diagnosis of rejection. Case 2. The female patient had an acute rejection verified by biopsies on
day 10 postoperatively. Her IL-8, IP-10 and C5a increased 10-fold
to 100-fold in the liver 3 days earlier than an increase in liver
enzymes and 5 days before the rejection was verified by biopsy. Conclusion We have described the normal course of the four
cytokines IL-6, IL-8, MCP-1 and IP-10 and complement C5a after
liver transplantation, as well as metabolic parameters to detect Microcirculatory hemodynamic alterations during cardiac
luxation in off-pump coronary artery bypass grafting surgery Microcirculatory hemodynamic alterations during cardiac
luxation in off-pump coronary artery bypass grafting surgery B Atasever1, R Speekenbrink2, J Seyffert2, C Ince3
1Erasmus Medical Center Rotterdam, The Netherlands; 2Onze
Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands; 3Academic
Medical Center, Amsterdam, The Netherlands
Critical Care 2007, 11(Suppl 2):P262 (doi: 10.1186/cc5422) Introduction During luxation of the beating heart in off-pump
coronary artery bypass grafting surgery the cardiac output drops
and causes hypotension (<60 mmHg). It is expected that this state
of obstructive shock is detrimental for adequate perfusion and
oxygenation of organ tissue. However, it is unknown whether these
luxations cause microcirculatory dysfunction. In this study we have
explored the hemodynamics of the sublingual microcirculation
during mechanical manipulations of the beating heart. Our preliminary results show that the CritiView may be a useful tool
for the detection of O2 imbalance and the development of an
emergency metabolic state in nonvital tissues. Reference 1. Mayevsky et al.: SPIE Proc 2006, 6083:OZ1-OZ10. Hepatic mitochondrial dysfunction in fluid-resuscitated
porcine septic shock Hepatic mitochondrial dysfunction in fluid-resuscitated
porcine septic shock J Wauters1, I Vanhorebeek2, A Dieudonne1, G Van den Berghe1,
A Wilmer3 J Wauters1, I Vanhorebeek2, A Dieudonne1, G Van den Berghe1,
A Wilmer3
1University Hospital Gasthuisberg, Leuven, Belgium; 2Catholic
University of Leuven, Belgium; 3UZ Gasthuisberg, Leuven, Belgium
Critical Care 2007, 11(Suppl 2):P259 (doi: 10.1186/cc5419) J Wauters1, I Vanhorebeek2, A Dieudonne1, G Van den Berghe1,
A Wilmer3
1University Hospital Gasthuisberg, Leuven, Belgium; 2Catholic
University of Leuven, Belgium; 3UZ Gasthuisberg, Leuven, Belgium
Critical Care 2007, 11(Suppl 2):P259 (doi: 10.1186/cc5419) 1University Hospital Gasthuisberg, Leuven, Belgium; 2Catholic
University of Leuven, Belgium; 3UZ Gasthuisberg, Leuven, Belgium
Critical Care 2007, 11(Suppl 2):P259 (doi: 10.1186/cc5419) Background Sepsis-induced multiple organ failure may crucially
depend on the development of mitochondrial dysfunction and
consequent cellular energetic failure. We investigated whether The CritiView is a computerized optical device that integrates
hardware and software in order to provide real-time information of S106 Available online http://ccforum.com/supplements/11/S2 Available online http://ccforum.com/supplements/11/S2 Available online http://ccforum.com/supplements/11/S2 tissue viability [1]. A modified three-way Foley catheter that
contains a fiberoptic probe connects the CritiView to the mucosal
side of the urethral wall. We have used this device in five female
pigs that underwent graded hemorrhage, and in four patients who
were monitored during aortic abdominal aneurysm operations. ischemia. In two patients with rejection we found a large increase
in IP-10, IL-8 and complement split-product C5a in the liver but not
in the subcutis 3–5 days before any other parameter of liver injury. P264 Methods Twelve patients were included. Anesthesia consisted of
thoracic epidural analgesia, restrictive peroperative fluid therapy
(net peroperative fluid balance below 4 l) and early extubation. In
the ICU, fluid infusion was adjusted in order to maintain hourly
urine production of 0.5 ml/kg. The mean arterial pressure was
maintained at or above 60 mmHg with administration of nor-
adrenalin if necessary. Microcirculation was visualized in the
sublingual tissue with the MicroScan, a sidestream dark field
imager. Data were collected at five time points: immediately after
induction, after gastric tube reconstruction, directly postoperative,
and days 1 and 2 postoperatively. Video data collected with the
MicroScan were analysed according to semiquantitative analysis
described by Boerma and colleagues [1]. We divided the vessels
into three categories: small (5–10 µm), medium (10–15 µm) and
large (>15 µm). By dividing the images into four quadrants and
categorizing the flow per vessel-size per quadrant, we calculated
the microvascular flow index (MFI) Sublingual microcirculation is impaired during
cardiopulmonary bypass in cardiac surgery C den Uil1, W Lagrand1, P Spronk2, J Hofland1, C Luthen1,
M van der Ent1, R van Thiel1, A Bogers1, M Simoons1
1Erasmus MC, Rotterdam, The Netherlands; 2Gelre Hospitals,
Apeldoorn, The Netherlands
Critical Care 2007, 11(Suppl 2):P264 (doi: 10.1186/cc5424) Introduction
Cardiac surgery patients are at low risk for
postoperative complications, but these may involve multiple organ
failure with a high mortality rate. These complications may be
related to occurrence of organ ischemia and reperfusion during
and just after surgery. We investigated whether microcirculatory
flow alterations occur during cardiac surgery. Methods We observed 10 consecutive patients who underwent
cardiac surgery with cardiopulmonary bypass (CPB). The micro-
circulation was studied using sidestream dark field (SDF) imaging. The sublingual capillary flow was estimated using a semi-
quantitative microvascular flow index (MFI) in small (diameter
10–25 µm), medium (25–50 µm), and large (50–100 µm) sized
microvessels (0 = none, 1 = intermittent, 2 = sluggish, 3 =
continuous flow). SDF imaging was performed at least three times
per time period (that is, at baseline, after starting CPB and after
surgery) in each patient. Data are presented as the median and
interquartile range. Muscle microcirculation alterations increase with disease
severity in chronic heart failure patients Muscle microcirculation alterations increase with disease
severity in chronic heart failure patients V Gerovasili, C Pierakos, S Dimopoulos, E Kaldara,
S Kourtidou, S Sarafoglou, M Kravari, J Venetsanakos,
G Tzanis, S Nanas
National and Kapodestrian University of Athens, Greece
Critical Care 2007, 11(Suppl 2):P263 (doi: 10.1186/cc5423) Objective To evaluate skeletal muscle microcirculation by near-
infrared spectroscopy (NIRS) in patients with chronic heart failure
(CHF). Background Skeletal muscle microcirculation is impaired in
patients with CHF, and this impairment seems to correlate with
disease severity. Methods We evaluated 49 patients with CHF (mean age: 58 ± 12
years) and 12 healthy volunteers. Of the CHF patients, 14 had S107 ritical Care March 2007 Vol 11 Suppl 2
27th International Symposium on Intensive Care and Emergency Medicin surgery. Despite maintaining common circulatory parameters
during CPB, the nonpulsatile status, hypothermia, and the
temporary drop in MAP after starting CPB were associated with
decreased sublingual MFI, which normalized after surgery. Further
studies should reveal whether these changes are related to outcome. end-stage heart failure (ESCHF) and were undergoing treatment
with intermittent inotropic agent infusion during the period of the
study protocol. The thenar muscle tissue oxygen saturation
(StO2%) was measured noninvasively by NIRS before, during and
after 3-minute occlusion of the brachial artery (occlusion technique). Results Patients with ESCHF (n = 14) and CHF (n = 35) presen-
ted a significantly lower tissue oxygen saturation (StO2) than healthy
subjects (75 ± 6%, 77 ± 8% and 85 ± 5%, P = 0.001 respec-
tively). The oxygen consumption rate during the occlusion of the
brachial artery differed significantly between patients with ESCHF,
CHF and healthy subjects (22.4 ± 9%/min, 29 ± 10%/min and
38.1 ± 11.1%/min, P = 0.001 respectively). The reperfusion rate
differed significantly between patients with ESCHF, CHF and
healthy
subjects
(302 ± 136%/min,
393 ± 134%/min
and
480 ± 133%/min, P = 0.002 respectively). P265 Sublingual microcirculation is impaired on the first day
postoperatively in patients undergoing gastric tube
reconstruction
J Van Bommel, H Tilanus, J Bakker, D Gommers
Erasmus MC, Rotterdam, The Netherlands
Critical Care 2007, 11(Suppl 2):P265 (doi: 10.1186/cc5425) Sublingual microcirculation is impaired on the first day
postoperatively in patients undergoing gastric tube
reconstruction Sublingual microcirculation is impaired on the first day
postoperatively in patients undergoing gastric tube
reconstruction J Van Bommel, H Tilanus, J Bakker, D Gommers
Erasmus MC, Rotterdam, The Netherlands
Critical Care 2007, 11(Suppl 2):P265 (doi: 10.1186/cc5425) Introduction Complications of oesophagectomy with gastric tube
reconstruction include leakage and stenosis. This can be explained
by compromised local perfusion, although it is unclear to which
extent local and systemic factors contribute to this process. The
aim of this study was to observe the microvascular blood flow in an
unaffected, distant tissue during the perioperative period. Conclusions Peripheral muscle microcirculation assessed by
NIRS is impaired in CHF patients. The degree of dysfunction is
associated with disease severity and is acutely partially reversed
with inotropic agent infusion. Changes in sublingual microvascular flow during
experimental human endotoxemia Changes in sublingual microvascular flow during
experimental human endotoxemia Results Nonsurvivors demonstrated a significantly higher MODS
score when compared with survivors (P = 0.004). Norepinephrine
requirements were higher in nonsurvivors (P = 0.018). Non-
survivors had higher arterial lactate levels (P = 0.046), decreased
arterial pH levels (P = 0.001), and decreased arterial PO2 values
(P = 0.013) when compared with survivors. A higher oscillation
frequency of skin microvasculature at rest (P = 0.033) and after an
ischemic stimulus (P = 0.009) was observed in nonsurvivors. No
differences were observed in reactive hyperemia response
between groups. The flowmotion frequency observed in reactive
hyperemia was associated with the severity of the MODS
(P = 0.009), and – although not statistically significant – arterial
lactate concentration (P = 0.052). R Bemelmans1, A Draisma2, J van der Hoeven2, P Pickkers2,
P Spronk1
1Gelre Ziekenhuizen, Apeldoorn, The Netherlands; 2UMCN,
Nijmegen, The Netherlands
Critical Care 2007, 11(Suppl 2):P268 (doi: 10.1186/cc5428) R Bemelmans1, A Draisma2, J van der Hoeven2, P Pickkers2,
P Spronk1 1Gelre Ziekenhuizen, Apeldoorn, The Netherlands; 2UMCN,
Nijmegen, The Netherlands
Critical Care 2007, 11(Suppl 2):P268 (doi: 10.1186/cc5428) Introduction We examined sublingual microvascular changes in
experimental human endotoxemia. Changes in microcirculation and
mitochondrial dysfunction appear to be key mechanisms in sepsis,
since they can lead to regional mismatch of oxygen supply and
demand. Lipopolysaccharide (LPS) can be used to induce endo-
toxemia as a model of sepsis, but the effects on microcirculatory
perfusion have not been tested before, particularly after tolerance
induction during repeated challenges of LPS. Conclusion An increased skin microvascular oscillation frequency
during rest and after an ischemic stimulus is associated with
increased mortality in patients suffering from MODS. We suggest
that the underlying mechanism of the increased flowmotion could
be a response of the skin microvasculature to hypoxia or to an
impaired oxygen utilization of the skin tissue. Methods Six healthy volunteers received an intravenous injection
of 2 ng/kg Escherichia coli LPS to induce endotoxemia on five
consecutive days. Microvascular perfusion was sublingually
measured using sidestream darkfield imaging just before, and 2
and 4 hours after LPS injection on day 1. All measurements were
repeated on day 5 of LPS administration. Sublingual capillary flow
was estimated using a semiquantative microvascular flow index
(MFI) in small (10–25 µm), medium (25–50 µm) and large-sized
(50–100 µm) microvessels (no flow, 0; intermittent flow, 1;
sluggish flow, 2; and continuous flow, 3). References 1. Saner FH, et al.: Eur J Anaesth 2006, 23:766-771. 2. De Backer D, et al.: Am Heart J 2004, 147:91-99. 1. Saner FH, et al.: Eur J Anaesth 2006, 23:766-771. 2. De Backer D, et al.: Am Heart J 2004, 147:91-99. 1. Saner FH, et al.: Eur J Anaesth 2006, 23:766-771. 2. De Backer D, et al.: Am Heart J 2004, 147:91-99. 1. Saner FH, et al.: Eur J Anaesth 2006, 23:766-771. 2. De Backer D, et al.: Am Heart J 2004, 147:91-99. Effect of intermittent positive pressure ventilation on the
skeletal muscle and small intestine microcirculation in rats Effect of intermittent positive pressure ventilation on the
skeletal muscle and small intestine microcirculation in rats V Cerny, Z Turek, R Parizkova, P Dostal
University Hospital Hradec Kralove, Czech Republic
Critical Care 2007, 11(Suppl 2):P267 (doi: 10.1186/cc5427) Introduction Intermittent positive pressure ventilation (IPPV) may
be accompanied by alteration of microcirculation [1,2]; however,
the effect of IPPV is not mentioned in the interpretation of the
results of studies evaluating microcirculation using orthogonal
polarization spectral or sidestream dark-field imaging. This study
aimed to evaluate the effect of IPPV on microcirculation in the
skeleton muscles and in the serosa of the small intestine in rats. Introduction Intermittent positive pressure ventilation (IPPV) may
be accompanied by alteration of microcirculation [1,2]; however,
the effect of IPPV is not mentioned in the interpretation of the
results of studies evaluating microcirculation using orthogonal
polarization spectral or sidestream dark-field imaging. This study
aimed to evaluate the effect of IPPV on microcirculation in the
skeleton muscles and in the serosa of the small intestine in rats. Methods Ten animals were tracheostomized and prepared for
microcirculation study; after tissue preparation, five rats were
allowed to breath spontaneously (Group SB = spontaneous
breathing), and five rats (Group IPPV) were connected to a small
animal ventilator (IPPV: FiO2 0.21, respiratory rate 60/min, tidal
volume 10 ml/kg, inspiratory time 50% of respiratory cycle, and Results Two hours after the induction of endotoxemia (n = 6),
sublingual flow in small (2 (1.7–2.3)), medium-sized (1.5
(1.2–1.9)), and large microvessels (2.5 (1.2–2.7)) did not differ
from baseline values (2.3 (1.5–2.8), 2.3 (1.4–2.5), and 2.3
(1.3–2.5), respectively, all P = not significant). Microvascular flow
did not change in the subsequent 2 hours. In addition, no
difference in microvascular flow could be demonstrated between
timepoints on day 1 and day 5 of intermittent endotoxemia. Conclusion In this small pilot study in experimental human
endotoxemia, no significant effect of LPS administration on
microcirculatory perfusion could be observed, nor any sign of
tolerance. Further studies should reveal whether microvascular
impairment does not occur in early human experimental Results Two hours after the induction of endotoxemia (n = 6),
sublingual flow in small (2 (1.7–2.3)), medium-sized (1.5
(1.2–1.9)), and large microvessels (2.5 (1.2–2.7)) did not differ
from baseline values (2.3 (1.5–2.8), 2.3 (1.4–2.5), and 2.3
(1.3–2.5), respectively, all P = not significant). Microvascular flow
did not change in the subsequent 2 hours. Changes in sublingual microvascular flow during
experimental human endotoxemia Changes were evaluated
with the paired Wilcoxon test and sign test. P < 0.05 was judged
to indicate a significant difference. Values are expressed as the
median (P25–P75). P266 2 cmH2O PEEP). Sidestream dark-field images were obtained from
the quadriceps femoris muscle (QFM) and serosa surface of the
ileum. The arterial blood pressure and rectal temperature were also
recorded. The functional capillary density (FCD) and small and
medium vessels rate were analysed offline using AVA V1.0 soft-
ware (AMC, University of Amsterdam, The Netherlands), P ≤0.05. Results The FCD was decreased significantly in QFM in rats with
IPPV with respect to Group SB (184 ± 27 resp. 197 ± 61 cm/cm2),
but the FCD of the intestinal serosa was not affected by IPPV
(265 ± 46 resp. 267 ± 25 cm/cm2). There were no differences in
mean blood pressure and temperature between groups (128 ± 7
Torr and 36.6 ± 0.1°C in Group SB, or 128 ± 10 Torr and
36.5 ± 0.1°C in Group IPPV). Figure 1 (abstract P265) Sublingual microvascular perfusion. Results
The MFI decreased in all sizes of microvessels
<15 minutes after starting CPB in comparison with baseline
(P < 0.05, Table 1). After starting CPB, the mean arterial pressure
(MAP) was lower (61 mmHg (53–65 mmHg)) than at baseline
(100 mmHg (92–118 mmHg); P = 0.01). After return to the ICU,
the MFI increased (P < 0.05) and returned to baseline values in all
microvessels. Sublingual microvascular perfusion. Conclusions SDF imaging can be used as a bedside tool to
evaluate sublingual microcirculatory changes during cardiac Table 1 (abstract P264)
Baseline
CPB
Postsurgery
MFI small
3 (3–3)
2 (0.4–3)
3 (2.9–3)
MFI medium
3 (2.2–3)
1.9 (0.8–3)
3 (2.9–3)
MFI large
3 (3–3)
2.4 (0.9–3)
3 (3–3)
MAP
100 (92–118)
61 (53–65)
79 (71–85) Conclusion The sublingual microcirculation is decreased on the
first day postoperatively in patients undergoing gastric tube
reconstruction. 1. Boerma EC, Mathura KR, van der Voort PH, et al.: Quantify-
ing bedside-derived imaging of microcirculatory abnor-
malities in septic patients: a prospective validation study. Crit Care 2005, 9:R601-R606. S108 Available online http://ccforum.com/supplements/11/S2 Available online http://ccforum.com/supplements/11/S2 Available online http://ccforum.com/supplements/11/S2 Oscillation frequency of skin microvascular blood flow is
associated with mortality in critically ill patients Oscillation frequency of skin microvascular blood flow is
associated with mortality in critically ill patients Oscillation frequency of skin microvascular blood flow is
associated with mortality in critically ill patients H Knotzer1, S Maier1, W Pajk1, M Dünser2, W Hasibeder3
1Innsbruck Medical University, Innsbruck, Austria; 2University
Hospital Bern, Switzerland; 3Krankenhaus der Barmherzigen
Schwestern Ried, Ried, Austria
Critical Care 2007, 11(Suppl 2):P266 (doi: 10.1186/cc5426) Introduction Microcirculatory dysfunction has been hypothesized
to play a key role in the pathophysiology of multiple organ failure,
and consequently to patient outcome. The objective of the present
study was to investigate differences in reactive hyperemia
response and oscillation frequencies in survivors and nonsurvivors
of patients with multiple organ dysfunction syndrome (MODS). Conclusion The use of IPPV should be taken into account in the
interpretation
of
the
studies
examining
the
changes
in
microcirculation in rats. Methods Twenty-nine patients (15 survivors; 14 nonsurvivors) with
two or more organ failures were eligible for study entry. All patients
were hemodynamically stabilized, and demographic and clinical
data were recorded. A laser Doppler flowmeter was used to
measure the cutaneous microcirculatory response. Reactive
hyperemia and oscillatory changes in the Doppler signal were
measured during 3 minutes before and after a 5-minute period of
forearm ischemia during hyperemia. Acknowledgement Research project MZO 00179906. References Acknowledgement Research project MZO 00179906. References Reference 1. Boekstegers P, Weidenhofer S, Kapsner T, Werdan K: Skele-
tal muscle partial pressure of oxygen in patients with
sepsis. Crit Care Med 1994, 22:640-650. 1. Boekstegers P, Weidenhofer S, Kapsner T, Werdan K: Skele-
tal muscle partial pressure of oxygen in patients with
sepsis. Crit Care Med 1994, 22:640-650. 1. Boekstegers P, Weidenhofer S, Kapsner T, Werdan K: Skele-
tal muscle partial pressure of oxygen in patients with
sepsis. Crit Care Med 1994, 22:640-650. Effect of intermittent positive pressure ventilation on the
skeletal muscle and small intestine microcirculation in rats In addition, no
difference in microvascular flow could be demonstrated between
timepoints on day 1 and day 5 of intermittent endotoxemia. Methods Ten animals were tracheostomized and prepared for
microcirculation study; after tissue preparation, five rats were
allowed to breath spontaneously (Group SB = spontaneous
breathing), and five rats (Group IPPV) were connected to a small
animal ventilator (IPPV: FiO2 0.21, respiratory rate 60/min, tidal
volume 10 ml/kg, inspiratory time 50% of respiratory cycle, and Conclusion In this small pilot study in experimental human
endotoxemia, no significant effect of LPS administration on
microcirculatory perfusion could be observed, nor any sign of
tolerance. Further studies should reveal whether microvascular
impairment does not occur in early human experimental S109 Critical Care March 2007 Vol 11 Suppl 2
27th International Symposium on Intensive Care and Emergency Medicine Figure 2 (abstract P269) Figure 2 (abstract P269) endotoxemia, or that sidestream darkfield imaging is not useful in
this specific setting. Occurrence and functional consequences of shunting of
the microcirculation after mesenteric ischemia Leukocyte–endothelial
interactions in mesenteric venules were quantified in an exteriorized
ileal loop using intravital microscopy. Abdominal blood flow was
recorded continuously, and arterial blood gases were analyzed at
intervals. Continuous SMA blood flow measurements were
performed in comparable groups without exteriorizing an ileal loop. Occurrence and functional consequences of shunting of
the microcirculation after mesenteric ischemia Occurrence and functional consequences of shunting of
the microcirculation after mesenteric ischemia M Lauterbach, G Horstick, N Plum, L Weilemann, T Münzel,
O Kempski
University Hospital Mainz, Germany
Critical Care 2007, 11(Suppl 2):P270 (doi: 10.1186/cc5430) Results In the control group, all parameters were not changed
during the observation period of 400 minutes. In the experimental
group, the mean arterial pressure (MAP) remained fairly stable until
300 minutes after injection of LPS, and the MAP gradually
decreased subsequently. While the MAP was maintained, the PtO2
gradually decreased linearly (Figure 1). TL increased with time
linearly. Meanwhile, BL did not change from 150 to 250 minutes;
after 300 minutes it increased abruptly in the experimental group
(Figure 2). Shunting of the microcirculation contributes to the pathology of
sepsis and septic shock. In this study, we hypothesize that
shunting of the microcirculation occurs after superior mesenteric
artery (SMA) ischemia (occlusion) and reperfusion, and we explore
functional consequences using intravital microscopy. Conclusions In our experimental endotoxemia model it has been
shown that partial pressure of oxygen in subcutaneous tissue
decreased even if systemic blood pressure was maintained. Boekstegers and colleagues [1] revealed that mean skeletal q
g
py
Spontaneously breathing animals (rats) (n = 30) underwent
occlusion of the SMA for 0 (controls), 30 or 60 minutes followed by
reperfusion (4 hours) with normal saline. Leukocyte–endothelial
interactions in mesenteric venules were quantified in an exteriorized
ileal loop using intravital microscopy. Abdominal blood flow was
recorded continuously, and arterial blood gases were analyzed at
intervals. Continuous SMA blood flow measurements were
performed in comparable groups without exteriorizing an ileal loop. Adherent leukocytes increased shortly after reperfusion in ischemia
groups, and plateaued in these groups. The centerline velocity and
shear rate in the recorded venules were significantly reduced after
reperfusion down to low-flow/no-flow in animals undergoing 60
minutes of mesenteric artery occlusion compared with animals with
30 minutes occlusion and controls, whereas perfusion of the SMA
and ileal vessels persisted. The microcirculatory changes in
animals with 60 minutes occlusion were accompanied by
progressive metabolic acidosis, substantially larger volumes of
intravenous fluids needed to support arterial blood pressure and
significantly reduced survival (30%). In the groups with continuous
SMA blood flow measurements, SMA blood flow increased in Spontaneously breathing animals (rats) (n = 30) underwent
occlusion of the SMA for 0 (controls), 30 or 60 minutes followed by
reperfusion (4 hours) with normal saline. P269 Biochemical changes detected by microdialysis in
subcutaneous tissue during experimental endotoxemia in
rat H Ohashi, Y Taira, Y Masui, K Morisawa, H Takahashi,
Y Fujinawa, T Kashimura, K Akashi
St Marianna University School of Medicine, Kawasaki, Japan
Critical Care 2007, 11(Suppl 2):P269 (doi: 10.1186/cc5429) Introduction Shock is defined currently as tissue oxygen metabolic
disorders. It is most important to understand oxygen metabolic
disorders in individual tissue. Microdialysis allows the deter-
mination of the metabolic condition in regional tissue and it
appears ideal to determine the regional metabolic tissue conditions
during endotoxemia. muscle PO2 was increased in patients with sepsis compared with
patients with limited infection. We obtained conflicting results to
those of Boekstegers and colleagues. The reason for this is
unknown. BL abruptly increased during 50–150 minutes, probably
from abnormal metabolism induced by LPS in whole-body organs. It is considered that BL did not show a rise during 150–250
minutes due to metabolization of lactate in liver and muscle. TL,
which is insusceptible of lactate metabolism by other organs, may
reflect abnormality of tissue metabolism precisely. Objective This study was designed to assess the regional
metabolic tissue conditions on markers of tissue metabolism
(lactate in regional tissue: tissue lactate (TL)) and tissue partial
oxygen pressure (PtO2) during severe endotoxemia and to
compare them with variables determined by standard monitoring
(hemodynamics, blood gas analysis, blood lactate (BL)). Materials and methods Male Wister rats (body weight 270–300 g)
were used for this study. The rats in the control group (n = 6) were
injected with saline of 2 ml intraperitoneally, and the rats in the
experimental group (n = 6) were treated with intraperitoneal
injection of lipopolysaccharide (LPS) of 40 mg/kg. The hemo-
dynamic parameters, arterial blood gas analysis, BL and PtO2 were
measured in both groups. TL and pyruvate in subcutaneous tissue
were measured using microdialysis. These parameters were
measured every 50 minutes until 400 minutes after LPS was
administered. P271 Changes in tissue oxygen saturation reflect changes in
targeted oxygen delivery in postoperatively optimised
patients M Hamilton, M Canete, M Cecconi, N Al-subaie, A Vercuil,
J Fawcett, D Dawson, A Rhodes
St George’s Hospital, London, UK
Critical Care 2007, 11(Suppl 2):P271 (doi: 10.1186/cc5431) use of noninvasive tissue oxygenation devices in surgical
optimisation. p
Reference Introduction Targeting oxygen delivery in the postoperative period
has been shown to reduce hospital length of stay and complica-
tions [1]. Using a near-infrared spectroscopy device such as the
Inspectra™ 325 allows the measurement of tissue oxygen satura-
tion (STO2) noninvasively as well as a rudimentary measure of
blood flow beneath the probe. It is plausible, then, that changes in
oxygen delivery (DO2) during postoperative optimisation may be
reflected in changes in STO2 and provide a noninvasive surrogate
of DO2. 1. Pearse et al.: Early goal-directed therapy after major
surgery reduces complications and duration of hospital
stay. Crit Care 2005, 9:R687-R693. Figure 1 (abstract P269) Figure 1 (abstract P269) Figure 1 (abstract P269) Adherent leukocytes increased shortly after reperfusion in ischemia
groups, and plateaued in these groups. The centerline velocity and
shear rate in the recorded venules were significantly reduced after
reperfusion down to low-flow/no-flow in animals undergoing 60
minutes of mesenteric artery occlusion compared with animals with
30 minutes occlusion and controls, whereas perfusion of the SMA
and ileal vessels persisted. The microcirculatory changes in
animals with 60 minutes occlusion were accompanied by
progressive metabolic acidosis, substantially larger volumes of
intravenous fluids needed to support arterial blood pressure and
significantly reduced survival (30%). In the groups with continuous
SMA blood flow measurements, SMA blood flow increased in S110 Available online http://ccforum.com/supplements/11/S2 use of noninvasive tissue oxygenation devices in surgical
optimisation. Reference
1. Pearse et al.: Early goal-directed therapy after major
surgery reduces complications and duration of hospital
stay. Crit Care 2005, 9:R687-R693. P272
General anesthesia impairs muscle microvascular
compliance
Figure 2 (abstract P271) Figure 2 (abstract P271) Figure 2 (abstract P271) Figure 2 (abstract P271) Figure 2 (abstract P271) relation to abdominal blood flow after reperfusion in animals with
60 minutes occlusion, and remained constant in animals under-
going 30 minutes occlusion and controls. Survival was 80% in
animals with 60 minutes occlusion without an exteriorized ileal loop. SMA occlusion for 60 minutes and subsequent reperfusion causes
perfusion abnormalities in the mesenteric microcirculation as often
seen in sepsis and septic shock with increased microcirculation
shunting, progressive metabolic acidosis and increased mortality. To
detect
these
significant
changes
requires
prolonged
observation periods and might help to find new treatments to
improve the poor prognosis of mesenteric ischemia. P272 General anesthesia impairs muscle microvascular
compliance General anesthesia impairs muscle microvascular
compliance General anesthesia impairs muscle microvascular
compliance M Boezi, S Palmisani, F Troisi, A Marcelli, R De Blasi
‘La Sapienza University’, 2nd Faculty of Medicine, Azienda
Ospedaliera Sant’Andrea, Rome, Italy
Critical Care 2007, 11(Suppl 2):P272 (doi: 10.1186/cc5432) 2
Methods All adult patients admitted to the ICU after surgery who
underwent
protocolised
haemodynamic
optimisation
were
included. All patients had STO2 recorded over the thenar eminence
using an Inspectra™ 325 for the first 8 hours of their stay. Introduction Drugs used to induce and maintain general
anesthesia have deep effects on the cardiovascular system. To our
knowledge there are no studies investigating microvascular
compliance during general anesthesia with a noninvasive approach
based on near-infrared spectroscopy (NIRS) technology. Results We found a significant correlation between the changes in
STO2 and oxygen delivery index (DO2I) over the first 8 hours of
intensive care stay (n = 40, correlation coefficient of 0.947,
P = 0.0001, Figure 1). We classified patients who achieved DO2I
> 600 ml/min/m2 as responders. These responders had higher
STO2 values by 3 hours of optimisation, a change that remained
significant throughout the duration of the study (Figure 2). Methods We randomized 36 healthy subjects undergoing maxillo-
facial surgery to receive general anesthesia with a sevofluorane–
remifentanil (Group S) or a propofol–remifentanil association
(Group P). We collected noninvasive measures of hemoglobin
concentration from the gastrocnemius muscle of the subjects
using a NIRS device (NIMO, NIROX srl, Italy), which performs
quantitative assessments of the [HbO2] and [Hb] exploiting
precise absorption measurements close to the absorption peak of
the water. Data were collected during a series of venous
occlusions at different cuff pressures, before and after 30 minutes
from induction of general anesthesia. The muscle blood volume
and microvascular compliance were obtained with a process
previously described elsewhere [1]. Data were analyzed with a
one-way analysis of variance test. Conclusion Changes in STO2 during postoperative optimisation
appear to mirror changes in DO2I and may allow more widespread Conclusion Changes in STO2 during postoperative optimisation
appear to mirror changes in DO2I and may allow more widespread Figure 1 (abstract P271) Figure 1 (abstract P271) Results Demographic data of the 36 subjects were similar in both
Groups S and P. General anesthesia reduced the heart rate and
mean arterial pressure and increased the total muscle blood
volume in both groups (Group S: from 2.4 ± 0.9 to 3.2 ± 1.2 ml/
100 ml; Group P: from 2.4 ± 1.2 to 3.5 ± 1.8 ml/100 ml;
P < 0.05). During general anesthesia, despite no differences in
muscle blood volume between the two groups, sevofluorane–
remifentanil significantly decreased microvascular compliance
(from 0.15 ± 0.08 to 0.09 ± 0.04 ml/mmHg/100 ml; P = 0.001)
whereas propofol–remifentanil did not (from 0.15 ± 0.08 to
0.16 ± 0.11 ml/mmHg/100 ml; P = 0.39). S111 Critical Care March 2007 Vol 11 Suppl 2
27th International Symposium on Intensive Care and Emergency Medicin Conclusion General anesthesia affects the microvascular bed of
skeletal muscle. An association between opioid and ipnotic agents
increases the muscle blood volume, whereas microvascular com-
pliance is reduced only by the sevofluorane–remifentanil association. Conclusion General anesthesia affects the microvascular bed of
skeletal muscle. An association between opioid and ipnotic agents
increases the muscle blood volume, whereas microvascular com-
pliance is reduced only by the sevofluorane–remifentanil association. spectroscopy is noninvasive and in the emergency setting is a
rapidly appliable method for measuring StO2. spectroscopy is noninvasive and in the emergency setting is a
rapidly appliable method for measuring StO2. Methods In a prospective observational study we included 340
consecutive medical emergency room patients. On admission,
StO2 and the rate of tissue deoxygenation during stagnant
ischemia were measured by the near-infrared spectroscopy
method (InSpectra tissue spectrometer; Hutchinson Technology
Inc., The Netherlands) and correlated with clinical signs of shock,
lactate and outcome. Methods In a prospective observational study we included 340
consecutive medical emergency room patients. On admission,
StO2 and the rate of tissue deoxygenation during stagnant
ischemia were measured by the near-infrared spectroscopy
method (InSpectra tissue spectrometer; Hutchinson Technology
Inc., The Netherlands) and correlated with clinical signs of shock,
lactate and outcome. 1. De Blasi RA, Palmisani S, Alampi D, et al.: Microvascular
dysfunction and skeletal muscle oxygenation assessed by
phase modulation near-infrared spectroscopy in patients
with septic shock. Intensive Care Med 2005, 31:1661-
1668. Results Three hundred and forty patients were included. Of 137
patients admitted, 16 (11.7%) were admitted to the ICU and 14
(10.2%) died in the hospital. P274 Introduction Near-infrared spectroscopy (NIRS) noninvasively
monitors muscle tissue oxygen saturation (StO2). It may provide a
continuous measurement to identify occult hypoperfusion, guide
resuscitation, and predict the development of multiple organ
dysfunction (MOD) after severe trauma. We evaluated the
correlation between initial StO2 and the development of MOD in
multitrauma patients. Figure 1 (abstract P271) The StO2 was higher in patients who
were not admitted compared with patients with LOS > 7 days
(80.2 ± 8.7% vs 76.9 ± 9.2%, P = 0.009). Tissue deoxygenation
was faster (16.7 ± 7.0%/min vs 12.9 ± 5.6%/min, P = 0.014) in
survivors. Tissue deoxygenation was slower in the group of
patients with clinical signs of shock compared with all patients
(11.8 ± 6.0%/min vs 16.5 ± 7.0%/min, P < 0,05). Age, lactate and
rate of tissue deoxygenation but not StO2 were significant
predictors of death (Table 1). There was weak but significant
correlation between StO2 and age (P < 0.0001, r = –0.28), StO2
and lactate (P = 0.035, r = –0.12) and StO2 and systolic blood
pressure (P < 0.0001, r = 0.26). P275 Near-infrared spectroscopy during resuscitation of trauma
patients predicts development of multiple organ
dysfunction: a prospective cohort study Conclusions Exact numerical values of StO2 are not equivalent to
those of SvO2. However, for clinical purpose, StO2 values could be
used for fast noninvasive SvO2 estimation; and the trend of StO2
may be substituted for the trend of SvO2 in severe left heart failure
without additional severe sepsis or septic shock. B Nicks, K Hill, M Chang, W Bozeman
Wake Forest University Health Sciences, Winston-Salem, NC, USA
Critical Care 2007, 11(Suppl 2):P275 (doi: 10.1186/cc5435) Skeletal muscle oxygen saturation estimates mixed venous
oxygen saturation in patients with severe left heart failure Skeletal muscle oxygen saturation estimates mixed venous
oxygen saturation in patients with severe left heart failure M Podbregar, H Mozina
University Medical Center Ljubljana, Slovenia
Critical Care 2007, 11(Suppl 2):P273 (doi: 10.1186/cc5433) M Podbregar, H Mozina
University Medical Center Ljubljana, Slovenia
Critical Care 2007, 11(Suppl 2):P273 (doi: 10.1186/cc5433) Critical Care 2007, 11(Suppl 2):P273 (doi: 10.1186 Introduction Low cardiac output states, such as left heart failure,
are characterized by a preserved oxygen extraction ratio compared
with severe sepsis. Near-infrared spectroscopy (NIRS) allows
noninvasive estimation of skeletal muscle tissue oxygenation
(StO2). The aim of study was to determine relationship between
StO2 and mixed venous oxygen saturation (SvO2) in patients with
severe left heart failure with or without additional severe sepsis or
septic shock. Table 1 (abstract P274)
Predictors of survival
Predictor
Odds ratio
P value
Age
1.083
0.004
Lactate
1.798
<0.001
Deoxygenation rate
0.895
0.046 Methods Sixty-five patients with severe left heart failure due to
primary heart disease were divided into two groups: Group A were
patients without (n = 24) and Group B were patients with (n = 41)
additional severe sepsis/septic shock. The thenar muscle StO2
was measured using NIRS. Results In Group A StO2 was lower compared with Group B and
healthy volunteers (58 ± 13% vs 90 ± 7% vs 84 ± 4%, P < 0.001). StO2 was higher in Group B compared with healthy volunteers
(P = 0.02). In Group A StO2 correlated with SvO2 (r = 0.689,
P = 0.002), and StO2 overestimated SvO2 (bias: –2.3%, precision:
4.6%). In Group A changes of StO2 correlated to changes of SvO2
(r = 0.836, P < 0.001; ∆SvO2 = 0.84 x ∆StO2 – 0.67). In Group B
important disagreement between these variables was present. Plasma lactate concentrations negatively correlated with StO2
values only in group A (r = –0.522, P = 0.009; lactate = –0.104 x
StO2 + 10.25). Conclusions StO2 and the rate of tissue deoxygenation during
stagnant ischemia are promising additional variables, which can be
measured rapidly and noninvasively in the emergency room setting. The rate of deoxygenation rather than StO2 may be helpful for early
detection of patients with inadequate tissue perfusion and worse
prognosis. Tissue oxygen saturation and the rate of tissue
deoxygenation during stagnant ischemia in the medical
emergency department M Meþnar, R Pareþnik, G Voga
General Hospital Celje, Slovenia
Critical Care 2007, 11(Suppl 2):P274 (doi: 10.1186/cc5434) P276 Setting A 16-bed medical–surgical ICU. Buccal visible light spectroscopy and laser Doppler
flowmetry: reliability analysis
V Gath, Y Sakr, S Klinzing, T Simon, K Reinhart, G Marx
Friedrich-Schiller-University Hospital, Jena, Germany
Critical Care 2007, 11(Suppl 2):P76 (doi: 10.1186/cc5436) Buccal visible light spectroscopy and laser Doppler
flowmetry: reliability analysis Materials and methods This study began about 2 years ago, and the
CVP of 41 patients in our ICU were evaluated and compared. Each
one of those 41 patients had a CVC in two different locations, one
placed in the internal jugular or subclavian veins, and a second in a
femoral vein. Simultaneous measurements of CVP were undertaken
by two different operators, with a pressure transducer zero referenced
at the mid-chest. Standard CVCs with similar features (20 cm length)
were used. The patients with an intra-abdominal pressure (IAP)
> 15 mmHg were excluded. The IAP was previously evaluated in all
patients, using the method described by Sugrue and Hillman. A linear
correlation analysis was performed, considering significance P < 0.05
and a correlation coefficient > 0.85. V Gath, Y Sakr, S Klinzing, T Simon, K Reinhart, G Marx
Friedrich-Schiller-University Hospital, Jena, Germany
Critical Care 2007, 11(Suppl 2):P76 (doi: 10.1186/cc5436) Background There are insatiable demands for new technologies
to advance basic biological investigation at the microcirculatory
level. Oxygen to see (O2C)® is a newly developed system that
combines laser Doppler flow (LDF) and visible light spectroscopy
(VLS) technology. The aim of our study was to assess the reliability
of O2C® measurements applied to the buccal mucosa and to the
thenar eminence in healthy volunteers. Results Forty-one patients were studied, and four patients were
excluded due to an IAP > 15 mmHg. The mean age was 63.7 ±
16.2 years, the ICU stay was 10.4 ± 3.5 days, the APACHE II
score was 27.8 ± 6.7, and SAPS II was 55.8 ± 11.2. The mean
CVP measured with jugular/subclavian access was 11.3 ± 4.5 mmHg,
and in the femoral access was 11.8 ± 4.4 mmHg. The linear corre-
lation between those measurements was 0.96, and P < 0.007. Methods Microcirculatory hemoglobin oxygen saturation (µHbO2,
%) and blood flow (flow, AU) were measured using an O2C® (Lea
Medizintechnik GmbH, Giessen, Germany) probe applied to the
buccal mucosa and to the thenar eminence. P277 study was the association between StO2 and the development of
MOD within the first 24 hours based on a MOD score of 6 or
greater. Clinicians were blinded from the StO2 values. Results Over a 14-month period, 78 patients were enrolled. Of the
78 patients, 26 (33.3%) developed MOD within the first 24 hours. The MOD patients had mean (SD) initial StO2 values of 53.3
(±10.3), significantly lower than those of non-MOD patients (61.1
(±10.0); P = 0.002). The MOD patient mean shock index of 0.92
(±0.28) was also significantly higher than those of non-MODS
patients (0.73 (±0.19); P = 0.0007). Lactate values were not
significantly different. study was the association between StO2 and the development of
MOD within the first 24 hours based on a MOD score of 6 or
greater. Clinicians were blinded from the StO2 values. study was the association between StO2 and the development of
MOD within the first 24 hours based on a MOD score of 6 or
greater. Clinicians were blinded from the StO2 values. P277
Central venous pressure in a femoral access: a true
evaluation? Central venous pressure in a femoral access: a true
evaluation? Results Over a 14-month period, 78 patients were enrolled. Of the
78 patients, 26 (33.3%) developed MOD within the first 24 hours. The MOD patients had mean (SD) initial StO2 values of 53.3
(±10.3), significantly lower than those of non-MOD patients (61.1
(±10.0); P = 0.002). The MOD patient mean shock index of 0.92
(±0.28) was also significantly higher than those of non-MODS
patients (0.73 (±0.19); P = 0.0007). Lactate values were not
significantly different. N Caramelo1, P Gonçalves1, A Paisana2, B Silva2, C Dias2,
S Severino2, P Henriques2, D Marcelino2, D Marum2, D Fernandes2
1Hospital Júlio de Matos, Lisbon, Portugal; 2Hospital Curry Cabral,
Lisbon, Portugal
Critical Care 2007, 11(Suppl 2):P277 (doi: 10.1186/cc5437) Introduction In patients with bad vascular access, the evaluation
of central venous pressure (CVP) obtained in a femoral vein could
be an alternative to the evaluation in central venous catheters
(CVCs) located in internal jugular or subclavian veins. Conclusions Noninvasive, continuous StO2 NIRS on initial arrival
in the TC/ED correlates with the shock index and with the
development of MOD. Objective To compare CVP measurement obtained in two different
locations (jugular or subclavian veins and femoral veins). M Meþnar, R Pareþnik, G Voga
General Hospital Celje, Slovenia
Critical Care 2007, 11(Suppl 2):P274 (doi: 10.1186/cc5434) Methods Patients presenting to our urban, academic, Level I
Trauma Center/Emergency Department (TC/ED) and meeting
standardized trauma-team activation criteria were enrolled. NIRS
monitoring with collection of StO2 at the thenar eminence was
initiated immediately on arrival at the ED and continued up to
24 hours for those admitted to the trauma ICU. Standardized
resuscitation assessment laboratory measures and clinical evalua-
tion tools were collected. The primary outcome in this prospective Hypothesis Tissue oxygen saturation (StO2) and the rate of tissue
deoxygenation during stagnant ischemia can early and reliably
detect inadequate tissue oxygenation and assess prognosis in
medical emergency room patients. Hypothesis Tissue oxygen saturation (StO2) and the rate of tissue
deoxygenation during stagnant ischemia can early and reliably
detect inadequate tissue oxygenation and assess prognosis in
medical emergency room patients. Introduction Early recognition of patients with inadequate tissue
oxygenation facilitates early diagnostic evaluation and treatment
that was correlated with improved outcome. Near-infrared S112 Available online http://ccforum.com/supplements/11/S2 P276 Measurements were
obtained simultaneously at two depths, superficial (2 mm) and
deep (6 mm), every 2 seconds for 5 minutes and were recorded for
later analysis. The procedure was repeated on another occasion at
least 1 week apart. Conclusion The CVP can be accurately measured in a femoral
vein, using standard CVC, in patients with an IAP < 15 mmHg. Results We studied 20 healthy subjects; 10 males and 10 females
(mean age = 38 ± 18 years, range 21–74 years). Both µHbO2 and
flow measurements were consistently higher when measured from
the deep tissue layers (6 mm) than those measured from the
superficial layers, regardless of the site of measurement. Buccal
mucosal µHbO2 ranged from 78% to 96% and varied only
minimally (CV: 4–7.5%), whereas there was a marked variability in
flow measurements (CV: 29–63.9%). The reproducibility of buccal
mucosal µHbO2 and flow measurements were moderate to good
(that is, intra-individual reliability, ICC: range 0.7–0.87, P < 0.05). However, only measurements from the superficial mucosal layers
showed a moderate to good degree of inter-individual agreement
(that is, inter-individual reliability, ICC: range 0.68–85, P < 0.001). LDF and VLS values measured on the thenar eminence were highly
variable, were not reproducible, and the inter-individual agreement
was poor. Table 1 (abstract P280) Methods We tested both the capability of FEER to differentiate
states of pulseless electrical activity, and its feasibility in the out-of-
hospital setting using mobile, battery-powered ultrasound systems. Trained emergency physicians (EP) applied FEER to assessing
basic ventricular function by ‘eye-balling’ in less than 10 seconds
in prehospital cardiac arrest victims who were being resuscitated. True pulseless electrical activity (PEA) was defined according to
the ERC as ‘clinical absence of cardiac output despite electrical
activity’. In contrast, any PEA was classified as a ‘pseudo-PEA’
when cardiac output was visualized by echocardiography. Conclusion We conclude that TTE is feasible in a noncoronary
ICU, most parameters being obtained. A routine utilization of TTE
detected 53 (7.5%) patients with severe unsuspected diseases. Results Seventy-eight CPR cases (age 66 ± 19 years) were
included. On arrival of the EP on the scene, a true PEA was
suspected in 31/78 cases. However, in 20/31 PEA cases cardiac
wall movement was detected (pseudo-PEA) and correctable
causes such as pericardial tamponade (four cases), poor
ventricular function (14 cases) and hypovolemia (two cases) were
treated. Fourteen out of 20 pseudo-PEA cases survived to hospital
admission. In 11/30 PEA cases, no cardiac wall movement was
visible (true PEA). All such patients died on the scene. FEER-
based changes in therapy were induced in 25/31 cases. The effectiveness of transthoracic echocardiography as a
screening examination in a noncoronary intensive care unit The effectiveness of transthoracic echocardiography as a
screening examination in a noncoronary intensive care unit P Marcelino1, S Marum1, A Fernandes1, M Lopes2, L Mourao1
1Hospital Curry Cabral, Lisbon, Portugal; 2Lisbon Faculty of
Medicine, Lisbon, Portugal
Critical Care 2007, 11(Suppl 2):P280 (doi: 10.1186/cc5440) Table 1 (abstract P278)
Variable
OR (95% CI)
P
APACHE III score (/10)
1.2 (1–1.4)
0.017
E/E′ (/10)
1.3 (0.6–2.8)
0.5
LV end diastolic volume (/100 ml)
2.0 (1.2–3.3)
0.0059
LV end systolic volume (/100 ml)
2.2 (1.3–3.8)
0.0047 Introduction The authors tested the feasibility of transthoracic
echocardiography (TTE) as a routine technique in a medical/
surgical ICU. Methods The study was carried out in a 16-bed noncoronary ICU
during 18 months. For this purpose, a TTE was performed within
the first 24 hours of admission. The issues addressed were: data
acquisition possibilities, quantification of selected echocardio-
graphic parameters (cardiac chamber dimensions, left ventricular
function, cardiac output, and Doppler examination), detection of
any structural echocardiographic alteration, as well as new severe
conditions. Conclusion In this cohort of critically ill patients, increased
echocardiographic LV end systolic volume, but not filling pressure,
is a highly significant predictor of mortality that adds incremental
value to APACHE III prediction. P279 Results In this study 704 consecutive patients were enrolled, with
a mean age of 61.5 ± 17.5 years, an ICU stay of 10.6 ± 17.1 days,
APACHE II score of 22.6 ± 8.9, and SAPS II of 52.7 ± 20.4. In
four patients TTE could not be performed. The data are presented
in Table 1. At least an echocardiographic alteration was detected
in 234 (33%) patients. The most common alterations were left
atrial enlargement (n = 163), and left ventricular dysfunction
(n = 132). Patients with these alterations were older (66 ± 16.5 vs
58.1 ± 17.4 years, P < 0.001), presented a higher APACHE II
score (24.4 ± 8.7 vs 21.1 ± 8.9, P < 0.001) and a higher mortality
(40.1 vs 25.4%, P
< 0.001). Severe previously unknown
echocardiographic diagnoses were detected in 53 (7.5%)
patients. The most frequent condition was severe left ventricular
dysfunction. By multivariate logistic regression analysis, TTE
parameters did not correlate with mortality or ICU stay. Mortality
was related to ICU stay (CI 1.0–1.019, P < 0.001). Left ventricular volumes but not filling pressure are
determinants of mortality in critically ill patients D Sturgess, T Marwick, C Joyce, M Jones, B Venkatesh
University of Queensland, Brisbane, Australia
Critical Care 2007, 11(Suppl 2):P278 (doi: 10.1186/cc5438) Introduction Transthoracic echocardiography (TTE) is gaining
acceptance as a powerful diagnostic tool in critical illness. It can
assess left ventricular (LV) volumes, as well as indices of ventri-
cular filling pressure (including the ratio of mitral E velocity/mitral
annular velocity [E/E′]). TTE evidence of raised filling pressure is
associated with mortality following myocardial infarction but its
prognostic value in critical illness is undefined. The aim of this
study was to evaluate the prognostic significance of echo-
cardiographic LV volumes and filling pressure in the critically ill. Conclusion O2C® provides reliable measurement of buccal
µHbO2 and microvascular flow. Skin measurements on the thenar
eminence are highly variable and unreliable. Methods A consecutive group of 94 patients (66 males, mean ±
SD age 61 ± 15 years) who had standard TTE supplemented by
measurement of E/E′ in a tertiary referral ICU were enrolled. TTE
was performed 5 ± 6 days after ICU admission. Severity of critical
illness was assessed using APACHE III. Cox proportional hazards
regression analysis was based on 28-day mortality from the date of
echo with survivors censored on hospital discharge. Results The mean APACHE III score was 72 ± 25. Hospital
mortality was 33% (n = 31). Table 1 summarises correlates of 28- S113 day mortality. The independent predictors of mortality were
APACHE III risk of hospital death (HR 1.3 (1.1–1.5), P = 0.003),
and increased LV end systolic volume (HR 2.1 (1.2–3.7), P = 0.007). Indices of ventricular filling pressure (E/E′, left atrial area/volume)
were not predictors of mortality. Prehospital echocardiography in pulseless electrical
activity victims using portable, handheld ultrasound C Byhahn1, E Müller2, F Walcher1, H Steiger2, F Seeger1,
R Breitkreutz1
1JW Goethe-University Hospital, Frankfurt, Germany;
2Emergency Medical Service, Darmstadt, Germany
Critical Care 2007, 11(Suppl 2):P279 (doi: 10.1186/cc5439) C Byhahn1, E Müller2, F Walcher1, H Steiger2, F Seeger1,
R Breitkreutz1
1JW Goethe-University Hospital, Frankfurt, Germany;
2Emergency Medical Service, Darmstadt, Germany
Critical Care 2007, 11(Suppl 2):P279 (doi: 10.1186/cc5439) Objective Potentially treatable causes of sudden cardiac arrest,
such as pericardial tamponade, myocardial insufficiency or hypo-
volemia, should be identified as soon as possible (that is, at the
scene). Although these diagnoses are mainly made by echo-
cardiography, old and new ERC or ILCOR guidelines only recom-
mend pauses of ventilation or chest compressions as ‘brief interrup-
tions’ at a maximum of 10 seconds, thereby potentially limiting
transthoracic ultrasound examinations. We introduced an ALS-
based algorithm of focused echocardiographic evaluation during
resuscitation (FEER) to be performed in a time-sensitive manner. Table 1 (abstract P280)
Chamber
689
Left ventricular function
670
Inferior vena cava
571
Mitral E/A
399
Isovolumetric relaxation time
569
Tricuspid regurgitation
291
Cardiac output
610
All patients
704 P282 Determination of intravascular volume status in critically ill
patients using portable chest X-rays: measurement of the
vascular pedicle width Background Assessment of preload and goal-directed resusci-
tation are crucial parts of ICU therapy. To assess preload, clinical
parameters such as filling of the jugular veins, edema and pleural
effusions as well as X-ray are used. In addition, haemodynamic
parameters such as the central venous pressure (CVP), pulmonary
arterial wedge pressure and PiCCO-derived global end-diastolic
volume index (GEDVI) are determined. The GEDVI has been
shown to be superior to pressure-based parameters with regard to
volume responsiveness in several studies. However, PiCCO data
are not available in all patients, and frequently clinical examination,
CVP and chest X-ray are the first tools for preload assessment. It
was the aim of our study to evaluate clinical assessment, X-ray and
CVP with regard to the GEDVI and extravascular lung water index
(ELWI). N Salahuddin, I Chishti, S Siddiqui
Aga Khan University & Hospital, Karachi, Pakistan
Critical Care 2007, 11(Suppl 2):P282 (doi: 10.1186/cc5442) Introduction Traditionally invasive haemodynamic measurements
of pulmonary artery occlusion pressures have been used to assess
the volume status in critically ill patients. The vascular pedicle, as
seen on chest X-ray scan, is the mediastinal silhouette of the great
vessels. We hypothesized that the vascular pedicle width (VPW)
on supine, portable chest X-ray scans could be used to predict
intravascular volume overloaded status in critically ill patients. Methods We conducted a prospective, blinded observational trial
where both pulmonary artery occlusion pressures (PAOP) and
VPWs were measured in patients admitted to the ICU. We used
measurements of PAOP ≥18 mmHg as indicative of a fluid
overloaded state, and measurements of PAOP < 18 mmHg as
normal or low volume states. Standardized, portable chest X-ray
scans in the supine position were obtained within 1 hour of PAOP
measurement. Receiver-operating characteristics (ROC) curves
were constructed using different cutoffs of the VPW measurement
to identify sensitivities and specificities for each value (see Figure 1). Results Measurements were obtained from 50 patients. Using
ROC-derived cutoffs, a VPW measurement of 74.5 mm was found
to have a sensitivity of 83% and a specificity of 78% for correctly
predicting a fluid overloaded state. Methods In 86 patients of an internal ICU, clinical examination was
independently determined by a physician and investigator not
working in the ICU. P281 The systolic velocities on the long axis were
measured by TDI, placing the sample volume 0.5 cm distance from
the mitral annular in the basic posterior interventricular septum
(Sm) and on the lateral wall (Sl). Patients with ischemic, dilated,
hypertrophic cardiomyopathy, severe valvular disease, uncontrolled
blood pressure and chronic atrial fibrillation were excluded. Results
No differences were observed in the LV systolic
performance by use of the conventional 2D echocardiography
between the two groups (EF: 63.8 ± 3.7% in Group A as
compared with 64 ± 4.8% in Group B, P = not significant). Nevertheless, differences were ascertained in the maximum
systolic velocities on the long axis using TDI. Sm: 8.2 ± 1.1 m/s in
Group A, 9.7 ± 1 m/s in Group B (P = 0.04), Sl: 10.6 ± 1.3 m/s in
Group A, 13.6 ± 1.4 m/s in Group B (P = 0.02). Conclusion
TDI echocardiography identifies LV contractility
abnormalities in ICU septic patients that appear to have a normal
EF in the conventional echocardiogram, so it provides earlier
recognition and treatment of LV dysfunction related to sepsis. left ventricular (LV) contractility abnormalities as compared with the
conventional echocardiography. This study aimed at assessing the
contribution of TDI to the early diagnosis of LV systolic dysfunction
in ICU septic patients maintaining a normal ejection fraction (EF). Methods Twenty-two ICU patients of average age 57.6 ± 7.3 years
(13 males) (Group A) and 20 seemingly healthy individuals (Group
B) were studied. The ICU patients met the sepsis criteria (infection
by Gram-negative bacterium and, at least, two of the SIRS criteria). The APACHE II score mean value was 21.2 ± 4.9. All the patients
of the study were subjected to the same session in a 2D echo-
cardiogram. The EF of the left ventricle was calculated according
to Simpson’s method. The systolic velocities on the long axis were
measured by TDI, placing the sample volume 0.5 cm distance from
the mitral annular in the basic posterior interventricular septum
(Sm) and on the lateral wall (Sl). Patients with ischemic, dilated,
hypertrophic cardiomyopathy, severe valvular disease, uncontrolled
blood pressure and chronic atrial fibrillation were excluded. Results
No differences were observed in the LV systolic
performance by use of the conventional 2D echocardiography
between the two groups (EF: 63.8 ± 3.7% in Group A as
compared with 64 ± 4.8% in Group B, P = not significant). P283 The role of clinical examination, chest X-ray and central
venous pressure in volume assessment in critically ill
patients: a comparison with PiCCO-derived data
W Huber, S Ringmaier, A Umgelter, K Holzapfel, W Reindl,
M Franzen, J Gaa, R Schmid
Klinikum Rechts der Isar, Technical University of Munich, Germany
Critical Care 2007, 11(Suppl 2):P283 (doi: 10.1186/cc5443) The role of clinical examination, chest X-ray and central
venous pressure in volume assessment in critically ill
patients: a comparison with PiCCO-derived data
W Huber, S Ringmaier, A Umgelter, K Holzapfel, W Reindl,
M Franzen, J Gaa, R Schmid
Klinikum Rechts der Isar, Technical University of Munich, Germany
Critical Care 2007, 11(Suppl 2):P283 (doi: 10.1186/cc5443) The role of clinical examination, chest X-ray and central
venous pressure in volume assessment in critically ill
patients: a comparison with PiCCO-derived data W Huber, S Ringmaier, A Umgelter, K Holzapfel, W Reindl,
M Franzen, J Gaa, R Schmid
Klinikum Rechts der Isar, Technical University of Munich, Germany
Critical Care 2007, 11(Suppl 2):P283 (doi: 10.1186/cc5443) P281 Nevertheless, differences were ascertained in the maximum
systolic velocities on the long axis using TDI. Sm: 8.2 ± 1.1 m/s in
Group A, 9.7 ± 1 m/s in Group B (P = 0.04), Sl: 10.6 ± 1.3 m/s in
Group A, 13.6 ± 1.4 m/s in Group B (P = 0.02). Receiver-operating characteristics curve for vascular pedicle width. The curve shows the ability of the vascular pedicle width to
differentiate between fluid overload and euvolemia at different cutoff
points. The area under the curve is 0.724. Increased vascular volume
is defined as pulmonary artery occlusion pressure ≥18 mmHg. Receiver-operating characteristics curve for vascular pedicle width. The curve shows the ability of the vascular pedicle width to
differentiate between fluid overload and euvolemia at different cutoff
points. The area under the curve is 0.724. Increased vascular volume
is defined as pulmonary artery occlusion pressure ≥18 mmHg. Conclusion
TDI echocardiography identifies LV contractility
abnormalities in ICU septic patients that appear to have a normal
EF in the conventional echocardiogram, so it provides earlier
recognition and treatment of LV dysfunction related to sepsis. P281 P281
Identification of contractility abnormalities in intensive care
unit patients with sepsis using tissue Doppler imaging
H Michalopoulou, P Stamatis, A Bakhal, T Kelgiorgis, A Basile,
J Vaitsis, E Reinou, P Batika, D Pragastis, A Foundouli
Metaxa Hospital, Athens, Greece
Critical Care 2007, 11(Suppl 2):P281 (doi: 10.1186/cc5441)
I t
d
ti
Ti
D
l
i
i
(TDI)
t Identification of contractility abnormalities in intensive care
unit patients with sepsis using tissue Doppler imaging H Michalopoulou, P Stamatis, A Bakhal, T Kelgiorgis, A Basile,
J Vaitsis, E Reinou, P Batika, D Pragastis, A Foundouli
Metaxa Hospital, Athens, Greece
Critical Care 2007, 11(Suppl 2):P281 (doi: 10.1186/cc5441) H Michalopoulou, P Stamatis, A Bakhal, T Kelgiorgis, A Basile,
J Vaitsis, E Reinou, P Batika, D Pragastis, A Foundouli
Metaxa Hospital, Athens, Greece
Critical Care 2007, 11(Suppl 2):P281 (doi: 10.1186/cc5441) Conclusions Application of FEER was feasible within a 10-second
time-frame of CPR interruptions. While differentiating PEA states,
FEER has the ability to identify a pseudo-PEA state, allowing
further treatment of the underlying disorder on the scene to
improve outcome. Introduction Tissue Doppler imaging (TDI), as a more recent
ultrasound technique, is a precious diagnostic tool revealing earlier S114 Available online http://ccforum.com/supplements/11/S2 Figure 1 (abstract P282)
Receiver-operating characteristics curve for vascular pedicle width. The curve shows the ability of the vascular pedicle width to
differentiate between fluid overload and euvolemia at different cutoff
points. The area under the curve is 0.724. Increased vascular volume
is defined as pulmonary artery occlusion pressure ≥18 mmHg. Figure 1 (abstract P282) Figure 1 (abstract P282) left ventricular (LV) contractility abnormalities as compared with the
conventional echocardiography. This study aimed at assessing the
contribution of TDI to the early diagnosis of LV systolic dysfunction
in ICU septic patients maintaining a normal ejection fraction (EF). Methods Twenty-two ICU patients of average age 57.6 ± 7.3 years
(13 males) (Group A) and 20 seemingly healthy individuals (Group
B) were studied. The ICU patients met the sepsis criteria (infection
by Gram-negative bacterium and, at least, two of the SIRS criteria). The APACHE II score mean value was 21.2 ± 4.9. All the patients
of the study were subjected to the same session in a 2D echo-
cardiogram. The EF of the left ventricle was calculated according
to Simpson’s method. Change of therapeutic plan following advanced
cardiopulmonary monitoring in critically ill patients: a
multicenter study Methods Cardiopulmonary assessment was done in critically ill
patients from 12 European ICUs independently by one to four
physicians per patient just before the use of the PiCCO monitor
(Pulsion, Germany). Following cardiopulmonary evaluation and
prediction of ACP (reported elsewhere), each physician suggested
a therapeutic plan before and after the first set of PiCCO measure-
ments (cardiac output, systemic vascular resistance, global end-
diastolic volume, stroke volume variation, and extravascular lung
water), and then self-rated the accuracy of his original therapeutic
plan. Methods Cardiopulmonary assessment was done in critically ill
patients from 12 European ICUs just before the use of the PiCCO
monitor (Pulsion, Germany). Independent prediction of cardiac
output (CO), systemic vascular resistance (SVR), indexed global
end-diastolic volume (GEDVi), stroke volume variation (SVV), and
indexed extravascular lung water (EVLWi) was done by one to four
physicians per patient. Following the first set of PiCCO
measurements each physician self-rated the accuracy of his pre-
PiCCO predictions. Results A total of 257 questionnaires of 165 patients (67 females
and 98 males, age 59.8 ± 16.7 (range 16–93) years) were
completed by 135 residents and 122 specialists. The main
reasons for using the PiCCO included unclear fluid status (109
cases), sepsis/septic shock (70 cases), respiratory failure (42
cases), cardiogenic shock (19 cases), renal failure (27 cases), and
other (18 cases). Only 30–50% of the predicted values were
correct (±20% of measured values) (Table 1). Ranges of errors
were:
CO
(–77/+100%),
SVR
(–94/+303%),
GEDVi
(–88/+135%), SVV (–91/+367%), EVLWi (–76/+650%). There
was a significant underestimation of CO (P < 0.00001) and
GEDVi (P < 0.0003), and overestimation of SVR (P < 0.003) and
SVV (P < 0.0002). Results A total of 257 questionnaires of 165 patients (67 females
and 98 males, age ± SD 59.8 ± 16.7 (range 16–93) years) were
completed by 135 residents and 122 specialists. The main
reasons for using the PiCCO included unclear fluid status (109
cases), sepsis/septic shock (70 cases), respiratory failure (42
cases), cardiogenic shock (19 cases), renal failure (27 cases),
other (18 cases). Changes (plan-and-not-give and no-plan-and-
give) made in the pre-PiCCO therapeutic plans included: fluid,
31.8%; inotropes, 23.3%; vasoconstrictors, 23.5%; diuretics, 15%
(Table 1). The 240 overall self-ratings of the original plan (scale of
1–5, [1] = not different; [5] = very different) included – [1] 33.7%,
[2] 23.5%, [3] 25.9%, [4] 11.5%, [5] 5.3%. Change of therapeutic plan following advanced
cardiopulmonary monitoring in critically ill patients: a
multicenter study A Perel1, M Maggiorini2, M Malbrain3, J Teboul4, J Belda5,
E Fernández Mondéjar6, M Kirov7, J Wendon8
1Sheba Medical Center, Tel Hashomer, Israel; 2Universitatsspital,
Zurich, Switzerland; 3Ziekenhuis Netwerk Antwerpen-Hospital
Campus Stuivenberg, Antwerp, Belgium; 4Hôpital De Bicêtre, Le
Kremlin-Bicêtre, France; 5Hospital Clinico Universitario, Valencia,
Spain; 6Hospital Universitario Virgen De Las Nieves, Granada,
Spain; 7Northern State Medical University, Arkhangelsk, Russian
Federation; 8King’s College Hospital, London, UK
Critical Care 2007, 11(Suppl 2):P284 (doi: 10.1186/cc5444) A Perel1, M Maggiorini2, M Malbrain3, J Teboul4, J Belda5,
E Fernández Mondéjar6, M Kirov7, J Wendon8
1Sheba Medical Center, Tel Hashomer, Israel; 2Universitatsspital,
Zurich, Switzerland; 3Ziekenhuisnetwerk Antwerpen, Campus
Stuivenberg, Antwerp, Belgium; 4Hopital De Bicetre, Le Kremlin
Bicetre, France; 5Hospital Clinico Universitario, Valencia, Spain;
6Hospital Universitario Virgen de las Nieves, Granada, Spain;
7Northern State Medical University, Arkhangelsk, Russian
Federation; 8Liver Intensive Care Unit, London, UK
Critical Care 2007, 11(Suppl 2):P285 (doi: 10.1186/cc5445) A Perel1, M Maggiorini2, M Malbrain3, J Teboul4, J Belda5,
E Fernández Mondéjar6, M Kirov7, J Wendon8 1Sheba Medical Center, Tel Hashomer, Israel; 2Universitatsspital,
Zurich, Switzerland; 3Ziekenhuisnetwerk Antwerpen, Campus
Stuivenberg, Antwerp, Belgium; 4Hopital De Bicetre, Le Kremlin
Bicetre, France; 5Hospital Clinico Universitario, Valencia, Spain;
6Hospital Universitario Virgen de las Nieves, Granada, Spain;
7Northern State Medical University, Arkhangelsk, Russian
Federation; 8Liver Intensive Care Unit, London, UK
Critical Care 2007, 11(Suppl 2):P285 (doi: 10.1186/cc5445) Introduction Lack of evidence that more advanced monitoring
techniques improve outcome may have led to insufficient
monitoring of critically ill patients. However, clinical judgment and
conventional hemodynamic monitoring alone were shown to be
inadequate for a reliable estimate of hemodynamic status. We have
therefore compared clinicians’ prediction of advanced cardio-
pulmonary parameters with actual measurements. Introduction Lack of evidence that more advanced monitoring
techniques improve outcome may have led to insufficient
monitoring of critically ill patients. However, clinical judgment and
conventional hemodynamic monitoring alone were shown to be
inadequate for a reliable estimate of hemodynamic status. We have
therefore compared clinicians’ prediction of advanced cardio-
pulmonary parameters with actual measurements. Introduction Many therapeutic decisions are made in the ICU on
the basis of clinical judgment and conventional monitoring alone,
although these may be inadequate for a reliable estimate of
hemodynamic status. We therefore measured the effects of more
advanced cardiopulmonary parameters (ACP) on major therapeutic
decisions. Clinicians’ prediction of advanced cardiopulmonary
variables in critically ill patients: a multicenter study Change of therapeutic plan following advanced
cardiopulmonary monitoring in critically ill patients: a
multicenter study Clinicians’ prediction of advanced cardiopulmonary
variables in critically ill patients: a multicenter study P282 Subsequently, chest X-ray (analysed by an
experienced radiologist), CVP and PiCCO (Pulsion Company,
Munich, Germany) measurements were performed and these data
were correlated to clinical findings. Results Patients (n = 86; 34 females, 52 males) included 25
patients with cirrhosis, 18 patients with pancreatitis, 19 patients
with sepsis; age 63.0 ± 15.5 years; APACHE II score 23.3 ± 8.4. Leg edema significantly correlated to CVP (r = 0.247; P = 0.038)
and (negatively) to GEDVI (r = –0.258; P = 0.032). CVP and
GEDVI were not associated: r = 0.035; P = 0.784. The ELWI
significantly correlated to the degree of rales (r = 0.258; P = 0.016)
and GEDVI (r = 0.557; P < 0.001). The ELWI and CVP did not
correlate (r = 0.030; P = 0.785). Global clinical preload assess- Conclusions These results suggest that serial measurements of
the VPW can reliably be used to predict intravascular volume
overload in the ICU. S115 15.1%, [5] 4.5%. The mean self-rate was 2.8 ± 0.9, with that of
residents (2.8 ± 0.9, n = 129) being similar to that of specialists
(2.7 ± 0.8, n = 111), P < 0.31. ment (scale 1–10) was not predictive for GEDVI. Radiological
assessment significantly overestimated the GEDVI (901.41 ± 139.76
vs 782.56 ± 183.80 ml/m2; P < 0.001) and underestimated the
ELWI (7.22 ± 1.38 vs 9.77 ± 4.51 ml/kg; P < 0.001). Conclusions (1) Leg edema and increased CVP do not exclude
preload deficiency determined by the GEDVI, which was
overestimated by X-ray. (2) CVP and leg edema are poor
predictors of the ELWI, which was significantly associated with
audible rales but underestimated by X-ray. ment (scale 1–10) was not predictive for GEDVI. Radiological
assessment significantly overestimated the GEDVI (901.41 ± 139.76
vs 782.56 ± 183.80 ml/m2; P < 0.001) and underestimated the
ELWI (7.22 ± 1.38 vs 9.77 ± 4.51 ml/kg; P < 0.001). Conclusions The ability of physicians to predict advanced
cardiopulmonary parameters based on clinical evaluation and
conventional monitoring alone has considerable limitations and is
not improved by experience. Conclusions (1) Leg edema and increased CVP do not exclude
preload deficiency determined by the GEDVI, which was
overestimated by X-ray. (2) CVP and leg edema are poor
predictors of the ELWI, which was significantly associated with
audible rales but underestimated by X-ray. Acknowledgement The authors of this unsupported study are
members of Pulsion’s medical advisory board. P286 Assessment of extravascular lung water and pulmonary
vascular permeability evaluated by the pulse contour
cardiac output in systemic inflammatory response
syndrome patients K Morisawa, Y Taira
St Marianna University School of Medicine, Kwasaki-shi, Japan
Critical Care 2007, 11(Suppl 2):P286 (doi: 10.1186/cc5446) Results We found a statistically significant correlation of both
inspiratory and expiratory IVC diameter with central venous
pressure (P = 0.004 and P = 0.001), extravascular lung water
index (P = 0.001 and P < 0.001), intrathoracic blood volume index
(P = 0.026 and P = 0.05), the intrathoracic thermal volume (both
P < 0.001), and the paO2/FiO2 oxygenation index (P = 0.007 and
P = 0.008, respectively). Introduction Pulse contour cardiac output (PiCCO) provides an
estimate of the intrathoracic blood volume (ITBV), extravascular
lung water (EVLW), and pulmonary vascular permeability index
(PVPI). Few investigations have prospectively examined EVLW in
patients with severe sepsis or ARDS. Introduction Pulse contour cardiac output (PiCCO) provides an
estimate of the intrathoracic blood volume (ITBV), extravascular
lung water (EVLW), and pulmonary vascular permeability index
(PVPI). Few investigations have prospectively examined EVLW in
patients with severe sepsis or ARDS. Objective The aim of this study was compare measurements of
ITBV, EVLW, and PVPI in systemic inflammatory response
syndrome (SIRS) patients. Conclusions Sonographic determination of the IVC diameter is
useful in the assessment of volume status in mechanically
ventilated septic patients. This approach is rapidly available,
noninvasive, inexpensive, easy to learn and applicable in almost any
clinical situation without doing harm. IVC sonography may
contribute to a faster, more goal-oriented optimization of fluid
status and may help to identify patients in whom deleterious
volume expansion should be avoided. It remains to be elucidated
whether this approach influences the outcome of septic patients. Materials and methods Twenty-eight adult patients with SIRS
admitted to our ICU were studied in three groups. Group A, nine
patients with pneumonia; group B, nine patients with extrathoracic
infection; group C, 10 patients without infection were enrolled. In
each patient, PiCCO was used to measure the ITBV and EVLW for
3 days of meeting criteria for SIRS. The PVPI was calculated as
the ratio of EVLW to ITBV. EVLW values were indexed by the
predicted body weight and ITBV values were indexed by the
predicted body surface. All data are presented as mean ± standard
deviation. P287
Fluid status assessment in mechanically ventilated septic
patients P287
Fluid status assessment in mechanically ventilated septic
patients J Schefold1, C Storm1, A Krüger1, M Oppert1, D Hasper2
1Charite University Medicine Berlin, Germany; 2Charite Campus
Virchow, Berlin, Germany
Critical Care 2007, 11(Suppl 2):P287 (doi: 10.1186/cc5447) Conclusions The measurement of advanced cardiopulmonary
parameters caused both specialists and residents to make
considerable changes in therapeutic decisions that were previously
made based on clinical judgment and conventional monitoring
alone. Background Early optimization of fluid status is of major
importance in the treatment of critically ill patients. It is unclear
whether sonographic measurement of the inferior vena cava (IVC)
diameter is valuable in the evaluation of fluid status in mechanically
ventilated septic patients. Acknowledgement The authors of this unsupported study are
members of Pulsion’s medical advisory board. Methods Thirty mechanically ventilated patients with severe sepsis
or septic shock (age 59.9 ± 15.4 years; APACHE II score 30.6 ± 7.7;
18 males) requiring advanced invasive hemodynamic monitoring
due to cardiovascular instability were included in a prospective
observational study in a university hospital setting with a 24-bed
medical ICU and a 14-bed anaesthesiological ICU. Volume-based
hemodynamic parameters were determined using the thermal-dye
transpulmonary dilution technique. Simultaneously, the IVC
diameter was measured throughout the respiratory cycle by trans-
abdominal ultrasonography. P286 The Kruskal–Wallis H test was performed for statistical
analysis and P < 0.05 was considered statistically significant. Change of therapeutic plan following advanced
cardiopulmonary monitoring in critically ill patients: a
multicenter study The mean self-rate
was 2.3 ± 1.2, with that of residents (2.3 ± 1.3, n = 129) being
similar to that of specialists (2.3 ± 1.1, n = 111), P < 0.88. The 240 self-ratings (scale of 1–5, [1] = excellent; [5] = poor) of
predictions accuracy included – [1] 1.6%, [2] 40%, [3] 38.8%, [4] S116
Table 1 (abstract P284)
EVLWi
%
CO
%
SVR
%
GEDVi
%
SVV
%
Under
69
29.4
127*
49.6
46
18.1
72
28
85
39.7
Correct
93
39.6
99
38.6
90
35.4
93
50.2
64
29.9
Over
73
31.1
30
11.7
116
45.7
73
21
65
30.4
*Number of predictions. S116 Available online http://ccforum.com/supplements/11/S2 B. The EVLWI and PVPI were significantly higher in group B than
in group C too. Conclusion Our data indicate that the permeability of pulmonary
vessels is increased more with infection than without infection, and
is also higher with pneumonia than with extrathoracic infection in
SIRS patients. P287
Fluid status assessment in mechanically ventilated septic
patients
J Schefold1, C Storm1, A Krüger1, M Oppert1, D Hasper2
1Charite University Medicine Berlin, Germany; 2Charite Campus
Virchow, Berlin, Germany
Critical Care 2007, 11(Suppl 2):P287 (doi: 10.1186/cc5447) Table 1 (abstract P285)
Given
%
Not given
%
Fluid P
109
43
53
21
Fluid NP
28
11
65
25
Inotropes P
33
13
46
18
Inotropes NP
14
5
164
64
Vasoconstrictors P
50
20
36
14
Vasoconstrictors NP
24
9
143
57
Diuretics P
19
7
20
8
Diuretics NP
18
7
197
78
P = planned; NP = not planned. Table 1 (abstract P285) Conclusion Our data indicate that the permeability of pulmonary
vessels is increased more with infection than without infection, and
is also higher with pneumonia than with extrathoracic infection in
SIRS patients. P288 Noninvasive cardiac output: accuracy between the
ultrasound cardiac output monitor and the esophageal
Doppler monitor Results See Table 1. One hundred and forty samples of data were
collected. The mean PVPI value was within the normal range. The
EVLWI and PVPI were significantly higher in group A than in group R Bilkovski1, J Martini1, R Phillips2
1Henry Ford Hospital, Detroit, MI, USA; 2University of Queensland,
Brisbane, Australia
Critical Care 2007, 11(Suppl 2):P288 (doi: 10.1186/cc5448) Table 1 (abstract P286)
Group A
Group B
Group C
ITBVI
933 ± 256
977 ± 197
996 ± 407
EVLWI
12 ± 5
10 ± 4*
8 ± 3*,**
PVPI
2.3 ± 1.1
1.8 ± 0.8*
1.6 ± 0.7*,**
*P < 0.05 vs group A. **P < 0.05 vs group A and group B. Introduction The hypothesis is that measurement of the cardiac
index (CI) is accurate between the ultrasound cardiac output
monitor (USCOM) and the esophageal Doppler monitor (EDM). The EDM is a minimally invasive device that has demonstrated
strong correlation with cardiac output measurements obtained by
thermodilution. A disadvantage of the EDM is the need for probe
placement in the esophagus, effectively limiting its use to S117 *P < 0.05 vs group A. **P < 0.05 vs group A and group B. Critical Care March 2007 Vol 11 Suppl 2
27th International Symposium on Intensive Care and Emergency Medicine ritical Care March 2007 Vol 11 Suppl 2
27th International Symposium on Intensive Care and Emergency Medicin Figure 1 (abstract P289) mechanically ventilated patients. The USCOM, in contrast, can
measure cardiac hemodynamics by use of a CW Doppler probe
placed on the skin to measure blood flow across either the aortic
or pulmonic valve. mechanically ventilated patients. The USCOM, in contrast, can
measure cardiac hemodynamics by use of a CW Doppler probe
placed on the skin to measure blood flow across either the aortic
or pulmonic valve. Mixed venous hemoglobin oxygen saturation (SvO2) vs cardiac output
(CO) by noninvasive cardiac output monitoring and Swan on Mister197. Methods A prospective study of adult ED patients who were
intubated and managed concurrently with an EDM. Setting: urban
tertiary care center with >90,000 annual visits. Exclusion criteria:
ESRD, ascites, known valvular heart disease and pre-existing
tracheotomy. IRB approval was obtained with waiver of informed
consent. USCOM measurements of CI were obtained, blinded to
EDM values measured concurrently. Noninvasive cardiac output monitoring: a clinical validation P Squara, P Estagnasie, A Brusset, D Denjean, J Dib, C Dubois
CERIC, Neuilly-sur-Seine, France
Critical Care 2007, 11(Suppl 2):P289 (doi: 10.1186/cc5449) M Cecconi1, J Poloniecki2, G Della Rocca3, J Ball1, R Grounds1,
A Rhodes1
1St George’s Hospital, London, UK; 2St George’s University of
London, UK; 3University of Udine, Italy
Critical Care 2007, 11(Suppl 2):P290 (doi: 10.1186/cc5450) Introduction Our objective was to evaluate the clinical utility of
noninvasive cardiac output monitoring (NICOM), a new tool for
automatic continuous cardiac output (CO) monitoring based on
chest bioreactance, using continuous thermodilution as reference
(PAC-CCO). Introduction The Bland–Altman plot is the standard way of
determining agreement between two methods of measuring the
same variable. Following work by Critchley and Critchley [1],
±30% is now accepted as the cutoff point when calculating the
percentage error. This study estimates the coefficient of variation
(CV) of three different cardiac output (CO) techniques with the aim
of assessing the relative contributions to the percentage error. Introduction The Bland–Altman plot is the standard way of
determining agreement between two methods of measuring the
same variable. Following work by Critchley and Critchley [1],
±30% is now accepted as the cutoff point when calculating the
percentage error. This study estimates the coefficient of variation
(CV) of three different cardiac output (CO) techniques with the aim
of assessing the relative contributions to the percentage error. Method We included 110 consecutive adult patients immediately
after cardiac surgery in a prospective, single-center study taking
place in the ICU. CO measurements obtained from NICOM and
PAC-CCO were simultaneously recorded minute by minute (Figure
1). We evaluated the accuracy, precision, responsiveness, and
reliability of NICOM for detecting CO changes. Tolerance for each
of these parameters was specified prospectively. Materials and methods Thirty critically ill patients had their CO
measured every hour with continuous cardiac output by Vigilance
(CCO), pulse pressure analysis by LiDCO™plus (PulseCO) and
intermittent thermodilution (ITD) (average of four ITD curves). Data
were analysed with Bland–Altman plots, calculation of the
percentage error, determination of the CV of ITD, and calculation
of the overall CV for CCO and PulseCO. Results A total of 65,888 pairs of CO measurements were
collected. Mean reference values for PAC-CCO ranged from 2.79
to 9.27 l/min. P290 Method comparison – a new approach to implementing
the Bland–Altman analysis to estimate the precision of a
new method: tested on 30 critically ill patients monitored
with pulse pressure analysis and continuous cardiac
output vs intermittent thermodilution P288 Repeated pairs were obtained
every 30–60 minutes, in a similar manner. Statistical analysis:
correlation and Bland–Altman plots using SPSS 9.0. Results A total of 95 paired measures were obtained from 20
patients with an average age of 60.1 years, 60% male and 70%
African American. The mean CI was 5.2 with a range of
1.4–6.6 l/min/m2. For the aggregate, r = 0.81 (P < 0.001) and bias
was 0.14 with limits of agreement (LOA) of –1.48 to 1.76. Excess
scatter was noted at CI > 4.0 CI. For CI < 4.0, correlation was
0.80 (P < 0.001) with bias and LOA of –0.15 and –1.01 to 0.71. At CI < 2.5, greater accuracy was noted with bias of 0.01 and
LOA of 0.73 to 0.75. Mixed venous hemoglobin oxygen saturation (SvO2) vs cardiac output
(CO) by noninvasive cardiac output monitoring and Swan on Mister197. Conclusions CI measurement with the USCOM has a high degree
of agreement with the EDM, most notably when CI is below 4.0. Of
particular interest is the high degree of accuracy seen at low CI
values (<2.5). These findings support the use of the USCOM for
CI measurement in mechanically ventilated patients and a wider
range of patients in which the EDM would be impractical or difficult
to use. Conclusion CO measured by NICOM had most often acceptable
accuracy, precision, and responsiveness in a wide range of
circulatory situations. P291 P291
Comparison of vascular pedicle width and PiCCO-derived
haemodynamic measurements in patients in a general
intensive care unit
S Aloizos1, G Liapis1, D Maragiannis1, E Tsigou2, P Aravosita2,
E Evodia2
1401 General Army Hospital Athens, Greece; 2Mother General &
Surgical Hospital, Athens, Greece
Critical Care 2007, 11(Suppl 2):P291 (doi: 10.1186/cc5451) Comparison of vascular pedicle width and PiCCO-derived
haemodynamic measurements in patients in a general
intensive care unit Methods Our study includes 140 measurements in 10 critically ill
patients (eight males, two females, age 37–84 years, mean 64.1 ±
13.0 years) requiring hemodynamic monitoring with the PiCCO
system. Five patients had septic shock, three hepatorenal
syndrome and two acute heart failure. First the CIpc was recorded
immediately before the next calibration and afterwards the CItd
was measured three times, which resulted in a simultaneous
calibration of the pulse contour algorithm of the PiCCO system. We performed a mean of 14 ± 9.4 measurements per patient. The
time-lag between the measurements was 12 hours 54 minutes ±
7 hours 47 minutes. S Aloizos1, G Liapis1, D Maragiannis1, E Tsigou2, P Aravosita2,
E Evodia2
1401 General Army Hospital Athens, Greece; 2Mother General &
Surgical Hospital, Athens, Greece
Critical Care 2007, 11(Suppl 2):P291 (doi: 10.1186/cc5451) Introduction Assessing clinically the intravascular volume status of
critically ill patients can be exceedingly difficult. Due to concerns
about the efficacy and safety (possible increase in mortality) of
using invasive haemodynamic monitoring, noninvasive diagnostic
testing has gained increasing importance. Results The comparison of the CIpc immediately before calibration
and the calibration-derived CItd resulted in a correlation coefficient
of 0.84 with a P value of 0.02. In the Bland–Altman analysis the
CIpc was a mean 0.14 l/min/m2 lower than the CItd. The standard
deviation was 0.72 l/min/m2. There was no correlation of the time-
lag between the calibrations and the difference of CIpc and CItd
(r = –0.03; P = 0.13). Objective To compare the reliability of vascular pedicle width
(VPW) as an indicator of overload, in patients of a general ICU,
with a method of invasive haemodynamic monitoring that has
proved its efficacy in the literature and in everyday practice. Patients and methods The VPW, which represents the media-
stinal silhouette of the great vessels, was compared with the
haemodynamic measurements, which were obtained with the
method of transpulmonary thermodilution (PiCCO Plus; Pulsion,
Munich, Germany). Reliability of the continuous cardiac index measurement
using the pulse contour analysis of the PiCCO system Reliability of the continuous cardiac index measurement
using the pulse contour analysis of the PiCCO system Conclusions In trying to understand the relative contributions of
error when testing two techniques to measure the same variable it
is vital to understand the CV of the reference technique. Using this
approach, both the PulseCO and Vigilance perform in a clinically
acceptable fashion. M Franzen, A Umgelter, S von Delius, A Weber,
J Reichenberger, M Dohmen, R Schmid, W Huber
Klinikum rechts der Isar, München, Germany
Critical Care 2007, 11(Suppl 2):P292 (doi: 10.1186/cc5452) Reference 1. Critchley LA, Critchley JA: A meta-analysis of studies using
bias and precision statistics to compare cardiac output
measurement techniques. J Clin Monit Comput 1999, 15:
85-91. 1. Critchley LA, Critchley JA: A meta-analysis of studies using
bias and precision statistics to compare cardiac output
measurement techniques. J Clin Monit Comput 1999, 15:
85-91. Introduction Reliable continuous hemodynamic monitoring of
critically ill patients is essential for effective volume management
and adequate administration of vasoactive drugs. The PiCCO
system allows continuous measurement of the cardiac index using
arterial pulse contour analysis. Calibration of this system by
transpulmonary thermodilution is recommended every 8 hours. In
this study we compared the difference of the continuous measure-
ment of the cardiac index using the arterial pulse contour analysis
(CIpc) with the cardiac index acquired by the transpulmonary
thermodilution (CItd) when calibrating the system. Noninvasive cardiac output monitoring: a clinical validation During periods of stable PAC-CCO (slope < ±10%,
2SD/mean <20%), the correlation between NICOM and PAC-
CCO was R = 0.82; bias was +0.16 ± 0.52 l/min (+4.0 ± 11.3%),
and the relative error was 9.1 ± 7.8%. In 85% of patients the
relative error was <20%. During periods of increasing CO, slopes
were similar with the two methods in 96% of patients and
intraclass correlation was positive in 96%. Corresponding values
during periods of decreasing CO were 90% and 84%,
respectively. Precision was always better with NICOM than with
PAC-CCO. During hemodynamic challenges, changes were 3.1 ±
3.8 minutes faster with NICOM (P < 0.01) and amplitude of
changes were not different (not significant). Finally, sensitivity of
the NICOM for detecting significant directional changes was 93%
and specificity was 93%. Results Two hundred and forty (eight per patient) measurements
of CO were obtained. CCO vs ITD had an overall bias (±2SD) of
0.2 ± 2.4 l/min (error 31%), mean CO (ITD + CCO) 7.7 l/min. PulseCO vs ITD had an overall bias of –0.1 ± 2.4 l/min, mean CO
(PulseCO + ITD) 7.5 l/min (error 33%). According to the above
criteria (without measuring the CV for ITD), CCO performed well
when compared with ITD (31%) but PulseCO (33%) was outside
clinically acceptable levels of agreement. The CV for a single ITD
CO measurement was 15%, and this decreased to 7.5% when
averaging four thermodilution curves. Using the CV for ITD of
7.5%, the relative CVs for the CCO and PulseCO were S118 Available online http://ccforum.com/supplements/11/S2 Available online http://ccforum.com/supplements/11/S2 P292
Reliability of the continuous cardiac index measurement
using the pulse contour analysis of the PiCCO system
M Franzen, A Umgelter, S von Delius, A Weber,
J Reichenberger, M Dohmen, R Schmid, W Huber
Klinikum rechts der Isar, München, Germany
Critical Care 2007, 11(Suppl 2):P292 (doi: 10.1186/cc5452) P292 determined. The CV for CCO was 13.6% and for PulseCO was
14.7%. P291 We measured the VPW in anteroposterior
chest X-rays in the supine position, with standard parameters, in
100 patients without prior cardiac surgery, prior mediastinal
irradiation, obesity, severe acute respiratory distress syndrome and
positive end-expiratory pressure > 7.5 cmH2O. In every patient we
performed invasive haemodynamic monitoring with the PiCCO
Plus. An intrathoracic blood volume index (ITBI) > 1,000 ml/m2,
global end-diastolic index (GEDI) > 800 ml/m2, and extravascular
lung water index (ELWI) > 7.0 ml/kg were considered the markers
of significant volume overload. After further refinement, 27 patients
fulfilled the above criteria and were considered eligible to be
included in the study. Conclusion The PiCCO system allows a reliable continuous
measurement of the cardiac index using the pulse contour analysis. In our study we could not find an increased difference of CIpc and
CItd even with longer time periods between the calibrations using
transpulmonary thermodilution. Because calibration is easy to
achieve and additional data for the intrathoracic blood volume and
the extravascular lung water are obtained, a 12-hour period
between the calibrations is reasonable. P295 Introd
improv
accura
cially a
the int
Metho
from p
surger
includ
Anaes
practic
perfor
2, 4 a
(LiDC
Resul
years)
tered w
and th
Linear
betwe
P < 0. index
Concl
metho
Table 1 (abstract P295)
Preoperative
Post-CPB
po
ITBVI (ml/m2) (n = 20)
739 (612–969)
1,078 (815–1,262)
1,266
PBVI (ml/m2) (n = 16)
213 (201–279)
343 (307–371)
33
CI (l/min/m2) (n = 20)
1.92 (0.45)
1.81 (0.42)
2 Introduction Pulmonary intermittent thermodilution (from the pul-
monary artery catheter), transpulmonary thermodilution (PiCCOplus;
Pulsion, Munich, Germany) and transpulmonary lithium dilution
(LiDCO™plus; LiDCO, Cambridge, UK) are all well-validated
techniques in common use in intensive care for cardiac output
estimation. The precision has been looked into previously and
strategies to improve it have been made (that is, averaging three or
four measurements over the respiratory cycle) yet not much is
known about the precision of transpulmonary techniques in terms
of repeatability. This study aims to look into the coefficient of
variation (CV) of the lithium dilution technique in a mixed
(medical/surgical) intensive care population and propose a method
to improve its precision. Method A single-centre, observational study. Consent was sought
from patients aged over 50 years undergoing elective cardiac
surgery with cardiopulmonary bypass (CPB). Exclusion criteria
included significant valvular regurgitation and lithium therapy. Anaesthetic, CPB, blood transfusion, ventilation and sedation
practices were standardised. Indicator dilution measurements were
performed following induction of anaesthesia, after CPB and then
2, 4 and 24 hours following surgery, using existing technology
(LiDCO Ltd, London, UK). Data are presented as the median (IQR). Results Twenty patients were recruited (age 70 years (64–75
years); Parsonnet score 10 (1–14)). No difficulties were encoun-
tered with the new method of ITBVI measurement. Absolute values
and the changes in the ITBVI were close to those anticipated. Linear regression analysis did not indicate mathematical coupling
between the cardiac index (CI) and the ITBVI (R2 = 0.22;
P < 0.001). The relationship between the pulmonary blood volume
index (PBVI) and the ITBVI was not constant. Materials and methods We performed four consecutive lithium
dilution cardiac output determinations on 70 critically ill patients
requiring haemodynamic monitoring. The heart rate (HR), central
venous pressure (CVP) and mean arterial pressure (mAP) were
documented in conjunction with cardiac output estimation. Data
were excluded if a ±5% change in HR, CVP or mAP occurred
during the sequential measurements. PiCCO monitoring – are two injections enough? The mean CV for single lithium dilution was
12.3%. The CV for the average of n lithium dilutions was 8.6% for
n = 2, 7.1% for n = 3, 6.1% for n = 4. Results Two hundred and forty-nine triplates were collected in 25
patients with septic shock, under mechanical ventilation. There
were no significant differences in CI at each bolus. The average of
the first two iced injections M1 = 3.28 ± 1.07 l/min/m2. The
average of the triplate M2 = 5.74 ± 1.07. Conclusions The CV for one lithium dilution was higher than
clinically acceptable (12.3 > 10%). The average of two lithium
dilution measurements improves the precision by 30% and shows
an excellent CV (that is, 8.6%). When measuring cardiac output
with LiDCO an average of two lithium dilution curves provide an
excellent precision, and we suggest that in this population
(medical/surgical) this approach should always be used when
calibrating the pulse pressure algorithm (PulseCO) at the baseline. Discussion Normally, we consider that 10–15% of variation in the
CI signifies a change in the haemodynamic state. The difference
between M1 and M2 exceeds 15%. In the literature, Nilsson and
colleagues [1] demonstrated concerning the pulmonary arterial
catheter that we need an average of at least four injections to be
95% confident. Conclusion With PiCCO monitoring, certainly two injections are
not enough to have reliable measurement of the CI. Reference Conclusion With PiCCO monitoring, certainly two injections are
not enough to have reliable measurement of the CI. 1. Nilsson LB, et al.: Acta Anaesthesiol Scand 2004, 48:1322-
1327. 1.
Nilsson LB, et al.: Acta Anaesthesiol Scand 2004, 48:1322-
1327. PiCCO monitoring – are two injections enough? S Alaya, S Abdellatif, R Nasri, H Ksouri, S Ben Lakhal
Intensive Care Unit, Tunis, Tunisia
Critical Care 2007, 11(Suppl 2):P293 (doi: 10.1186/cc5453) Results The mean VPW in overloaded patients was 75.14 mm
compared with a mean of 64.71 mm for the rest. The results were
subsequently analyzed using Spearman’s nonparametric test and
we found correlation (0.785, 0.710, and 0.510) between VPW and
the GEDI, ITBI, and ELWI, respectively. The results were
considered statistically significant (P < 0.000, P < 0.000, and
P < 0.005, respectively). Introduction
PiCCO
monitoring
using
the
thermodilution
technique has become an alternative method of invasive
haemodynamic monitoring for the critically ill patient. Usually the
results of an arbitrarily chosen number (one to five) of thermal
indicator injections are averaged to increase the reliability of the
measurement. The number of injections needed to achieve a given
level of precision has, however, not previously been systematically
investigated. We tried in this study to validate the accuracy of two
injections instead of three injections. Introduction
PiCCO
monitoring
using
the
thermodilution
technique has become an alternative method of invasive
haemodynamic monitoring for the critically ill patient. Usually the
results of an arbitrarily chosen number (one to five) of thermal
indicator injections are averaged to increase the reliability of the
measurement. The number of injections needed to achieve a given
level of precision has, however, not previously been systematically
investigated. We tried in this study to validate the accuracy of two
injections instead of three injections. Conclusion The VPW, when appropriately assessed at the
bedside by the same physician and therefore avoiding the possible
bias, using portable chest X-rays, might give very useful information
regarding the volume status of the patients, results that are
comparable in their efficacy with those obtained with invasive and
more expensive methods. Methods We analysed retrospectively all data (triplate measure-
ments) obtained during the past 2 years by PiCCO monitoring:
injection of 10 ml saline solution three times by the same operator. S119 Critical Care March 2007 Vol 11 Suppl 2
27th International Symposium on Intensive Care and Emergency Medicin We compared the cardiac index (CI) obtained at each bolus, the
average of the CI obtained at the first two injections (M1) and then
the triplate (M2). Results Sixty-five series were suitable for analysis. The CV showed
a normal distribution and no correlation with the magnitude of the
mean cardiac output. Results Sixty-five series were suitable for analysis. The CV showed
a normal distribution and no correlation with the magnitude of the
mean cardiac output. The mean CV for single lithium dilution was
12.3%. The CV for the average of n lithium dilutions was 8.6% for
n = 2, 7.1% for n = 3, 6.1% for n = 4. P295 P295 P294
Lithium dilution cardiac output measurement in the critically
ill patient: determination of precision of the technique Transpulmonary lithium indicator dilution: a new method of
intrathoracic blood volume measurement Transpulmonary lithium indicator dilution: a new method of
intrathoracic blood volume measurement Transpulmonary lithium indicator dilution: a new method of
intrathoracic blood volume measurement Lithium dilution cardiac output measurement in the critically
ill patient: determination of precision of the technique M Cecconi, N Al-Subaie, M Canete, D Dawson, M Puntis,
J Poloniecki, R Grounds, A Rhodes
St George’s Hospital, London, UK
Critical Care 2007, 11(Suppl 2):P294 (doi: 10.1186/cc5454) B Maddison, T Best, C Wolff, P Jones, C Hinds, R Pearse
Barts & The London School of Medicine & Dentistry, London, UK
Critical Care 2007, 11(Suppl 2):P295 (doi: 10.1186/cc5455) Introduction Extravascular lung water (EVLW) measurement may
improve outcome. Double indicator dilution, which is the most
accurate method of EVLW measurement, is no longer commer-
cially available. Lithium indicator dilution could be used to measure
the intrathoracic blood volume index (ITBVI) and therefore EVLW. S120
Introduction Pulmonary intermittent thermodilution (from the pul-
monary artery catheter), transpulmonary thermodilution (PiCCOplus;
Pulsion, Munich, Germany) and transpulmonary lithium dilution
(LiDCO™plus; LiDCO, Cambridge, UK) are all well-validated
techniques in common use in intensive care for cardiac output
estimation. The precision has been looked into previously and
strategies to improve it have been made (that is, averaging three or
four measurements over the respiratory cycle) yet not much is
known about the precision of transpulmonary techniques in terms
of repeatability. This study aims to look into the coefficient of
variation (CV) of the lithium dilution technique in a mixed
(medical/surgical) intensive care population and propose a method
to improve its precision. Materials and methods We performed four consecutive lithium
dilution cardiac output determinations on 70 critically ill patients
requiring haemodynamic monitoring. The heart rate (HR), central
venous pressure (CVP) and mean arterial pressure (mAP) were
documented in conjunction with cardiac output estimation. Data
were excluded if a ±5% change in HR, CVP or mAP occurred
during the sequential measurements. The CV ((SD/mean cardiac
output) x 100) was calculated for single measurements and for the
average of repeated measurements. In order to clinically accept the
precision of the technique, we aimed to obtain a CV below 10%. P296 P296
Comparison between uncalibrated cardiac output using
the femoral and radial arterial pressure waveform in
critically ill patients
J Smith1, C Wolff2, E Mills2, K Lei1, C Taylor1, L Camporota1,
R Beale1
1Guy’s & St Thomas’ NHS Foundation Trust, London, UK; 2LiDCO
Ltd, London, UK
Critical Care 2007, 11(Suppl 2):P296 (doi: 10.1186/cc5456) Introduction Cardiac output (CO) monitoring is often required to
manage critically ill patients. Nominal values can be determined
from analysis of arterial pressure waveforms. It is assumed that
arterial waveforms from different arterial sites give similar CO
values. The aim of this study was to compare the values of
uncalibrated CO derived from simultaneous radial (COr) and
femoral (COf) blood pressures. mean difference of LiDCO from PiCCO overall was –5.49 ±
21.3%. The correlation coefficient r = 0.73 (P = 0.0166). Conclusion There was general agreement between LiDCO and
PiCCO. There were significant differences (>30%) in only three
out of 10 measurements. Combining the results of >1 lithium
calibration may improve accuracy. These results are promising but
a larger trial will be required. mean difference of LiDCO from PiCCO overall was –5.49 ±
21.3%. The correlation coefficient r = 0.73 (P = 0.0166). Methods We enrolled 17 medical and surgical ICU patients,
requiring haemodynamic monitoring and vasoactive drugs. Simultaneous recordings of the arterial radial and femoral
waveforms were made from arterial pressure monitors via an A–D
converter and analysed to obtain CO values using the PulseCO®
algorithm of the LiDCOplus (LiDCO, London, UK). Paired CO
values were selected at several points on each recording. Calibrations were not done at each time point so the comparison
required examination of the ratio of uncalibrated COr and COf. Conclusion There was general agreement between LiDCO and
PiCCO. There were significant differences (>30%) in only three
out of 10 measurements. Combining the results of >1 lithium
calibration may improve accuracy. These results are promising but
a larger trial will be required. Impedance cardiography to assess hemodynamic status: a
comparison with transpulmonary thermodilution Impedance cardiography to assess hemodynamic status: a
comparison with transpulmonary thermodilution A Donati, R Nardella, V Gabbanelli, C Valentini, F Gabriele, P Pelaia
AOU Umberto I Ancona, Italy
Critical Care 2007, 11(Suppl 2):P298 (doi: 10.1186/cc5458) Introduction Measurement of extravascular lung water (EVLW)
obtained with transpulmonary thermodilution (PiCCO system) can
help the physician to guide fluid management of critically ill
patients [1]. The thoracic fluid content (TFC) is a parameter
deriving from the electric conductivity of the thorax, determined
from intravascular, alveolar and interstitial fluids [2,3]. To the
author's knowledge, there is no clinical study comparing PiCCO
EVLW and the TFC provided by the impedance cardiac output
(ICG) system. The aim of the study was to compare measurements
of cardiac index (CI) obtained with PiCCO (P) and ICG before and
after fluid challenge (FC), to evaluate whether the TFC can provide
a noninvasive estimate of lung fluid balance, compared with
PiCCO EVLW, in 10 critically ill patients. Conclusions CO derived from blood pressure records at radial
and femoral sites can appear similar when a patient population as a
whole is considered. However, in individual patients, the difference
between the two sites is large enough to be clinically unacceptable
without a site-specific recalibration. P295 The CV ((SD/mean cardiac
output) x 100) was calculated for single measurements and for the
average of repeated measurements. In order to clinically accept the
precision of the technique, we aimed to obtain a CV below 10%. Conclusion Lithium indicator dilution may be a valuable new
method of ITBVI measurement, and therefore EVLW measurement. Table 1 (abstract P295)
Time
2 hours
4 hours
24 hours
Preoperative
Post-CPB
postoperatively
postoperatively
postoperatively
ITBVI (ml/m2) (n = 20)
739 (612–969)
1,078 (815–1,262)
1,266 (1,031–1,433)
1,188 (947–1,343)
1,008 (738–1,257)
PBVI (ml/m2) (n = 16)
213 (201–279)
343 (307–371)
338 (288–449)
394 (305–545)
407 (267–464)
CI (l/min/m2) (n = 20)
1.92 (0.45)
1.81 (0.42)
2.03 (0.56)
2.20 (0.58)
2.28 (0.94) Table 1 (abstract P295) S120 Available online http://ccforum.com/supplements/11/S2 Table 1 (abstract P297)
Patient
ItbiP
ItbiL
Difference (%)
1
894
960
7.4
2a
1,517
1,990
31
2b
1,572
1,078
–31.4
3
1,069
724
–32.3
4
1,280
1,318
3.0
5a
1,478
1,213
–17.9
5b
1,324
1,058
–20.1
5c
1,429
1,797
25.8
6a
732
731
–0.01
6b
787
627
–20.3 Measurement of intrathoracic blood volume by lithium
dilution: comparison with thermodilution H Roberts, A Saayman, L Ala, G Findlay
University Hospital of Wales, Cardiff, UK
Critical Care 2007, 11(Suppl 2):P297 (doi: 10.1186/cc5457) Methods We studied 10 patients (eight males), aged 16-76 years
(mean 22 ± SD 38), admitted to our ICU for head injury (three
patients), septic shock (four patients), ARDS (one patient), and
postsurgical (two patients). Introduction The intrathoracic blood volume is usually measured
clinically by transpulmonary thermodilution (PiCCO system;
Pulsion Ltd). New software also allows measurement at the
bedside by lithium dilution (LiDCO system; LiDCO Ltd). We
sought to compare the new lithium dilution method with the
existing method. p
g
(
p
)
The APACHE II score was 26-36 (30 ± 5). They were all moni-
tored with the P system (PiCCO, V4.12; Pulsion Medical Systems
AG) and the ICG system (Solar ICG module; GE Medical Systems
Technology, Milwaukee, USA, 2001), to evaluate the CI. All
patients received FC to optimize the haemodynamic status. Haemo-
dynamic measurements were made before and after FC with
colloids (5 ml/kg in 30 min). Statistical analysis was performed with
Spearman nonparametric correlation and the Bland–Altman test. Results Twenty samples of data were collected. The CI P mean ±
SD was 3.91 ± 0.83 l/min/m2 before FC and 3.32–8.52 l/min/m2
after FC. The mean CI ICG value before FC was 3.44 ± 0.99 l/min/m2
(2.10–5.50) and was 4.56 ± 1.37 l/min/m2 after FC. The correlation
coefficient found was 0.526 (P < 0.05) and 0.588 after. The 95%
CI was 0.149–0.804. The overall mean CI P – CI ICG difference The APACHE II score was 26-36 (30 ± 5). They were all moni-
tored with the P system (PiCCO, V4.12; Pulsion Medical Systems
AG) and the ICG system (Solar ICG module; GE Medical Systems
Technology, Milwaukee, USA, 2001), to evaluate the CI. All
patients received FC to optimize the haemodynamic status. Haemo-
dynamic measurements were made before and after FC with
colloids (5 ml/kg in 30 min). Statistical analysis was performed with
Spearman nonparametric correlation and the Bland–Altman test. Results Twenty samples of data were collected. The CI P mean ±
SD was 3.91 ± 0.83 l/min/m2 before FC and 3.32–8.52 l/min/m2
after FC. The mean CI ICG value before FC was 3.44 ± 0.99 l/min/m2
(2.10–5.50) and was 4.56 ± 1.37 l/min/m2 after FC. The correlation
coefficient found was 0.526 (P < 0.05) and 0.588 after. The 95%
CI was 0.149–0.804. P298 Results The median value of the CO ratio was 0.95 (IQR
0.88–1.02), with a high variability across the patients, ranging from
0.3 to 1.41, whereas intrapatient variability was low, with a median
CV of 3.26% (IQR 1.1–5.3%). Although the ratio in COs between
the two sites varied greatly, the difference between the median
(range) arterial pressures was 2 mmHg (–3 to 8 mmHg). However,
the pulse pressure difference between the two sites was generally
large with a median (range) of 2 mmHg (–26 to 44 mmHg). Measurement of intrathoracic blood volume by lithium
dilution: comparison with thermodilution The overall mean CI P – CI ICG difference The APACHE II score was 26-36 (30 ± 5). They were all moni-
tored with the P system (PiCCO, V4.12; Pulsion Medical Systems
AG) and the ICG system (Solar ICG module; GE Medical Systems
Technology, Milwaukee, USA, 2001), to evaluate the CI. All
patients received FC to optimize the haemodynamic status. Haemo-
dynamic measurements were made before and after FC with
colloids (5 ml/kg in 30 min). Statistical analysis was performed with
Spearman nonparametric correlation and the Bland–Altman test. Methods
Ethics approval was obtained. Nonpregnant adult
patients on the ICU with PiCCO monitoring were recruited. Consent was given by patients’ representatives. Simultaneous
calibration of PiCCO and LiDCO systems with one lithium dilution
curve and the average of three thermal dilution curves allowed
comparison of results. Results Twenty samples of data were collected. The CI P mean ±
SD was 3.91 ± 0.83 l/min/m2 before FC and 3.32–8.52 l/min/m2
after FC. The mean CI ICG value before FC was 3.44 ± 0.99 l/min/m2
(2.10–5.50) and was 4.56 ± 1.37 l/min/m2 after FC. The correlation
coefficient found was 0.526 (P < 0.05) and 0.588 after. The 95%
CI was 0.149–0.804. The overall mean CI P – CI ICG difference Results Six patients were studied (five males, one female). All
were intubated but none were receiving muscle relaxation. Mean
age was 60.6 ± 21.8 years. The mean APACHE II score was
20.8 ± 2.3. Ten paired results were obtained (see Table 1). The S121 Critical Care March 2007 Vol 11 Suppl 2
27th International Symposium on Intensive Care and Emergency Medicine ritical Care March 2007 Vol 11 Suppl 2
27th International Symposium on Intensive Care and Emergency Medicin (range: 19.5–48.0 kg/m2)). CO values during the observation time
ranged from 2.4 to 9.3 l/min. Bland–Altman analysis revealed a
mean bias ± 2SD (limits of agreement) of 0.20 ± 2.3 l/min for
FCO–ICO, 0.3 ± 2.7 l/min for PCO–ICO and 0.3 ± 2.5 l/min for
CCO–ICO. Mean bias ± 2SD was –3.6 ± 59.2% for δ FCO–
δ ICO, –1.6 ± 67.1% for δ PCO–δ ICO and 2.5 ± 58.8% for δ ICO–
δ CCO. was 0.70 l/min/m2, with ±1.96 SD of –2.53 and 3.23, respectively. One measurement (5%) extended beyond the lower SD limit. P300 2. Spiess B, Patel M, Soltow L: Comparison of bioimpedance
versus thermodilution cardiac output during cardiac
surgery: evaluation of a second-generation bioimpedance
device. J Cardiothor Vasc Anesth 2001, 15:567-573. 2. Spiess B, Patel M, Soltow L: Comparison of bioimpedance
versus thermodilution cardiac output during cardiac
surgery: evaluation of a second-generation bioimpedance
device. J Cardiothor Vasc Anesth 2001, 15:567-573. Flow Trac™ cardiac output determination correlates with
echocardiography Flow Trac™ cardiac output determination correlates with
echocardiography F Turani, M Falco, A De Chiara, A Belli, C Parisi, A Marineli
Aurelia European Hospital, Rome, Italy
Critical Care 2007, 11(Suppl 2):P300 (doi: 10.1186/cc5460) 3. Kunst A, Bakker J: Electrical impedance tomography in the
assessment of extravascular lung water in noncardiogenic
acute respiratory failure. Chest 1999, 116:1695-1702. 3. Kunst A, Bakker J: Electrical impedance tomography in the
assessment of extravascular lung water in noncardiogenic
acute respiratory failure. Chest 1999, 116:1695-1702. g
References 1. Bindels A, Meinders A: Pulmonary artery wedge pressure
and extravascular lung water in patients with acute cardio-
genic pulmonary edema requiring mechanical ventilation. Am J Cardiol 1999, 84:1158-1163. 1. Bindels A, Meinders A: Pulmonary artery wedge pressure
and extravascular lung water in patients with acute cardio-
genic pulmonary edema requiring mechanical ventilation. Am J Cardiol 1999, 84:1158-1163. P299 Introduction A new device may be used in intensive care to
measure the cardiac output (CO) by arterial pulse pressure
waveform analysis, but few studies have evaluated the reliability of
this method and the correlation with other methods of CO deter-
mination. The aims of this study were to evaluate the CO obtained
using the Flow Trac™ Vigileo™ and the correlation with CO
obtained by transthoracic echocardiography (TTE). Clinical evaluation of the FloTrac/Vigileo system and two
established methods for continuous cardiac output
monitoring in patients undergoing cardiac surgery Clinical evaluation of the FloTrac/Vigileo system and two
established methods for continuous cardiac output
monitoring in patients undergoing cardiac surgery References 1. Manecke G: Edwards FloTrac sensor and vigileo monitor;
easy, accurate, reliable cardiac output assessment using
the arterial pulse wave. Expert Rev Med Devices 2005,
2:523-527. 2. Opdam HI, Wan L, Bellomo R: A pilot assessment of the
FloTrac™ cardiac output monitoring system. Intensive Care
Med 2006 [Epub ahead of print]. Measurement of intrathoracic blood volume by lithium
dilution: comparison with thermodilution The
EVLW index ranges from 3.3 to 13.7 (7.86 ± 3.27) ml/kg before
FC and 3.4 to 15.1 (8.58 ± 3.52) ml/kg after FC (P = 0.015). The
TFC before FC was 34–60 (43 ± 10) ml/kg and 32–64 (46 ± 10)
ml/kg after FC (P = 0.011). The correlation coefficient found
before FC is 0.798 (P = 0.007) with 95% CI 0.656–0.940. The
correlation coefficient found after FC is 0.802 (P = 0.005) with
95% CI 0.661–0.943. was 0.70 l/min/m2, with ±1.96 SD of –2.53 and 3.23, respectively. One measurement (5%) extended beyond the lower SD limit. The
EVLW index ranges from 3.3 to 13.7 (7.86 ± 3.27) ml/kg before
FC and 3.4 to 15.1 (8.58 ± 3.52) ml/kg after FC (P = 0.015). The
TFC before FC was 34–60 (43 ± 10) ml/kg and 32–64 (46 ± 10)
ml/kg after FC (P = 0.011). The correlation coefficient found
before FC is 0.798 (P = 0.007) with 95% CI 0.656–0.940. The
correlation coefficient found after FC is 0.802 (P = 0.005) with
95% CI 0.661–0.943. Conclusion These results indicate that the FloTrac/Vigileo system
is a reliable alternative to PiCCO and the pulmonary artery catheter
for CO measurement in cardiac surgery patients. Conclusions The main findings in this study are the great
discrepancy between the two methods. CI measurements obtained
with the ICG system underestimated CI when compared with the P
system, particularly after FC. The TFC and EVLW index trends
derived from FC appear similar; TFC measurements obtained with the
ICG system show good correlation when compared with the EVLW
index of the P system and it may be a useful index of pulmonary
overloading, if supported by further randomized clinical trials. Conclusions The main findings in this study are the great
discrepancy between the two methods. CI measurements obtained
with the ICG system underestimated CI when compared with the P
system, particularly after FC. The TFC and EVLW index trends
derived from FC appear similar; TFC measurements obtained with the
ICG system show good correlation when compared with the EVLW
index of the P system and it may be a useful index of pulmonary
overloading, if supported by further randomized clinical trials. D Button, C Hofer Triemli City Hospital, Zurich, Switzerland Triemli City Hospital, Zurich, Switzerland y
p
,
,
Critical Care 2007, 11(Suppl 2):P299 (doi: 10.1186/cc5459) y
y
Materials and methods Ten critical care patients admitted to a
general ICU were enrolled in the study. All patients were
mechanically ventilated (tidal volume 6–8 ml/kg, plateau pressure
< 30 cmH2O) and connected to an integrated monitoring system
(Flow Trac™/Vigileo™; Ewdards Lifescience, Irvine, CA, USA) that
attaches to an arterial cannula. After haemodynamic stabilization
the CO was calculated from an arterial pressure-based algorithm
that utilises the relationship between pulse pressure and stroke
volume. At the same time a TTE examination was performed
(Hewlett Packard, SONO 1000) and the CO was calculated by
Doppler measurement of the left ventricular outflow area (LVOT)
and the velocity–time integral (VTI LVOT), assuming stroke volume
= cross-sectional area x VTI. Every patient had two CO
determinations by TTE during Flow Trac™ measurement. A
regression analysis and Bland–Altman analysis were used to
compare the two methods of CO determination. Introduction A new arterial pressure waveform analysis device,
which does not need external calibration (FloTrac/Vigileo; Edwards
Lifesciences, Irvine, CA, USA), became recently available for
cardiac output (CO) measurement. However, only limited validation
data for this technique are so far available [1,2]. Objective The aim of this study was to compare cardiac output
assessed by the FloTrac/Vigileo system (FCO), the PiCCOplus
system (PCO) [1] (Pulsion Medical Systems; Munich, Germany)
and continuous cardiac output (CCO) monitoring using a pulmo-
nary artery catheter (Vigilance; Edwards Lifesciences) with inter-
mittent pulmonary artery thermodilution (ICO) in cardiac surgery
patients. Methods With ethics committee approval and written patient
informed consent, patients undergoing elective cardiac surgery
were studied. The CCO, FCO and PCO were recorded in the
perioperative period after induction of anaesthesia (= study
initiation) and 1, 4, 8, 12 and 24 hours post initiation. At each
measurement point the ICO was assessed as mean of three
repeated bolus injections. Statistical analysis was done using
Bland–Altman analysis of absolute CO values and of percentage
changes (δ) between consecutive CO measurements (= trend
analysis). Results A total of 40 CO determinations were performed in 10
patients. Table 1 reports the main results. P301 P301 P302 P302
CeVOX for continuous central venous oxygenation
measurement in patients undergoing off-pump coronary
artery bypass grafting
A Rist, S Schneider, P Fodor, L Weibel, A Zollinger, C Hofer
Triemli City Hospital, Zurich, Switzerland
Critical Care 2007, 11(Suppl 2):P302 (doi: 10.1186/cc5462) A survey of cardiac output monitoring in intensive care units CeVOX for continuous central venous oxygenation
measurement in patients undergoing off-pump coronary
artery bypass grafting A survey of cardiac output monitoring in intensive care units R Green1, J Craig1, B Kyle1, M Jonas2
1Poole General Hospital, Poole, UK; 2Southampton General
Hospital, Southampton, UK
Critical Care 2007, 11(Suppl 2):P301 (doi: 10.1186/cc5461) R Green1, J Craig1, B Kyle1, M Jonas2 1Poole General Hospital, Poole, UK; 2Southampton Gen A Rist, S Schneider, P Fodor, L Weibel, A Zollinger, C Hofer
Triemli City Hospital, Zurich, Switzerland
Critical Care 2007, 11(Suppl 2):P302 (doi: 10.1186/cc5462) al Care 2007, 11(Suppl 2):P301 (doi: 10.1186/cc5461) Introduction We surveyed adult ICUs, looking at cardiac output
monitor use with a view to demonstrating a practice change over
the last 3 years. Objective The aim of this study was to compare central venous O2
saturation (ScvO2) [1] measured continuously by the CeVOX
(Pulsion Medical System, Munich, Germany) device (CScvO2) with
ScvO2 determined by blood gas co-oximetry (BScvO2). Method The senior physicians on ICUs in the South of England
were surveyed via telephone. Information was collected as to
which cardiac output monitors were available for use, which was
their first choice and how often they measured cardiac output in
severe sepsis. 2
2
Methods
Twenty-five patients undergoing elective off-pump
coronary artery bypass grafting were studied during operation
(OP) and during their ICU stay (ICU). OP/ICU measurement
started after in vivo calibration of CeVOX. BScvO2 and CScvO2
readings were recorded at intervals of 30 minutes during OP and
120 minutes during ICU. Bland–Altman analysis and Pearson
correlation was performed for overall OP, overall ICU, consecutive
measurements during OP ≤1 hour, 1–2 hours and 2–3 hours after
initial calibration (OP1–OP3, respectively) as well as during ICU
≤4 hours, 4–8 hours, 8–12 hours and 12–16 hours after re-
calibration (ICU1–ICU4, respectively). Results Forty-nine out of 52 ICUs units contacted completed the
survey. Monitor availability can be seen in Figure 1 and use in
severe sepsis compared with 2003 can be seen in Table 1. Figure 1 (abstract P301) Results Five hundred and nine matched sets of data were
obtained; the BScvO2/CScvO2 range was 36–98.9%/46.5–99.0%,
respectively. Overall mean bias ± 2SD was –1.2 ± 13.8% for
CScvO2–BScvO2 during OP and –2.6 ± 16.2% during ICU. The
correlation coefficient (r2) for CScvO2 vs BScvO2 was 0.614 (OP)
and 0.174 (ICU). Statistics for OP1–OP3 were comparable,
whereas mean bias ± 2SD increased and r2 decreased during
ICU1–ICU4 (Table 1). Conclusions The results indicate that ScvO2 can be reliably
assessed by CeVOX. In order to maintain accurate measurements,
scheduled re-calibrations at intervals <12 hours are mandatory. Reference 1. Respiration 2001, 685:279-285. D Button, C Hofer Table 1 (abstract P300)
R2
P
Bias
SD of bias
CO Flow Trac™/CO TTE
0.85
<0.0001
0.24
0.45
Conclusion CO measurements obtained by Flow Trac™ show
agreement with CO TTE with no clear bias, but comparative
studies with thermodilution are warranted. Table 1 (abstract P300)
R2
P
Bias
SD of bias
CO Flow Trac™/CO TTE
0.85
<0.0001
0.24
0.45
Conclusion CO measurements obtained by Flow Trac™ show
agreement with CO TTE with no clear bias, but comparative
di
i h h
dil
i
d Table 1 (abstract P300)
R2
P
Bias
SD of bias
CO Flow Trac™/CO TTE
0.85
<0.0001
0.24
0.45 Results One hundred and eighty-five matched sets of data were
available for statistical analysis from 31 patients (ASA III, male/
female ratio = 26/5, mean ± SD age = 66.58 ± 0.53 years (range:
45–84 years), mean ± SD body mass index = 28.2 ± 5.3 kg/m2 Conclusion CO measurements obtained by Flow Trac™ show
agreement with CO TTE with no clear bias, but comparative
studies with thermodilution are warranted. Conclusion CO measurements obtained by Flow Trac™ show
agreement with CO TTE with no clear bias, but comparative
studies with thermodilution are warranted. Conclusion CO measurements obtained by Flow Trac™ show
agreement with CO TTE with no clear bias, but comparative
studies with thermodilution are warranted. S122 Available online http://ccforum.com/supplements/11/S2 Relative influence of hypoxemia and anemia on the
measurement of central venous oxygen saturation Relative influence of hypoxemia and anemia on the
measurement of central venous oxygen saturation F Valenza, S Froio, L Fagnani, S Coppola, M Maffioletti,
A Sicignano, E Riva, S Sibilla, L Gattinoni
Fondazione IRCCS Ospedale Maggiore Policlinico Mangiagalli
Regina Elena, Milano, Italy
Critical Care 2007, 11(Suppl 2):P304 (doi: 10.1186/cc5464) Methods Lithium indicator dilution and pulse power analysis were
used to measure cardiac output and to calculate DO2I (LiDCO-
plus system). We prospectively evaluated the oxygen delivery
pattern and perfusion variables of 26 high-risk patients (LiDCO
group) submitted to major surgeries and goal-directed therapy
during surgery and 8 hours postoperatively, aiming to maximize the
DO2I to levels higher than 600 ml/min/m2 using dobutamine and
either ‘restrictive’ (4 ml/kg/min) or ‘liberal’ (12 ml/kg/min) strategies
of intraoperative fluid management (partial results). Postoperatively
both groups received 1.5 ml/kg/min lactated ringer. Fluid challenge
with 250 ml colloid was done in the presence of signs of
hypovolemia and additional fluids were given if necessary. Patients
were considered responders if they achieved the therapeutic goal. A historical group of 42 high-risk surgical patients in whom the
therapeutic goals were to keep a mean arterial pressure between
80 and 110 mmHg, a central venous pressure between 6 and
12 cmH2O, hematocrit > 30% and urine output > 0.5 ml/kg/hour
in the first 24 hours after ICU admission was used as control. Introduction Central venous oxygen saturation (ScvO2) is frequently
used as a surrogate measurement of adequacy of perfusion. However, ScvO2 is also affected by arterial oxygen saturation
(SpO2), oxygen consumption, and hemoglobin (Hb) according to
the formula: ScvO2 = SpO2 – (VO2 / Q*1/Hb). The aim of this
study was to investigate the relative influence of hypoxemia and
anemia on the measurement of ScvO2. Methods A database of 700 pairs of arterial and central venous
blood gases drawn from 300 patients admitted to the ICU of a
university hospital was considered. After assessing for the
technical adequacy of sampling (defined as a discrepancy of
hematocrit and blood glucose between arterial and venous
samples lower than 5%), 462 couples were selected for analysis. Samples were then clustered according to ScvO2: <70% (low),
≥70% (high). SpO2, partial pressure of oxygen (PaO2) and Hb
were considered. Venous to arterial difference of partial pressure
of CO2 (DpCO2), arterial to venous difference of oxygen content
(DavO2) and the oxygen extraction ratio (ER) were also considered
as measures of perfusion adequacy. P303 Incidence of low central venous oxygen saturation after
standard postoperative intensive care management Introduction Targeted early postoperative management of high-
risk surgical patients has been reported to be associated with a
lower rate of complications and shorter hospital length of stay
(HLOS) compared with conventional management. A low
postoperative central venous oxygen saturation (ScVO2) has also
been shown to be associated with higher rates of complications
and of HLOS for high-risk surgical patients. Benefit from early goal-
directed therapy would be unlikely if ‘standard’ postoperative
management resulted in a low incidence of patients with a low
ScVO2 in the early postoperative period. Conclusion Less invasive forms of cardiac output monitor are now
used as the first line. A survey in 2005 showed 20% of units still
used the PAC as their first-line monitor. This change has been
associated with a lower threshold for use in severe sepsis. S123
Table 1 (abstract P302)
OP1
OP2
OP3
ICU1
ICU2
ICU3
ICU4
Mean bias ± 2SD (%)
–0.2 ± 13.9
+1.3 ± 9.6
+1.8 ± 16.6
–0.1 ± 12.0
–0.6 ± 15.4
–0.5 ± 13.8
–4.6 ± 16.9
r2 (P value)
0.580 (<0.001)
0.616 (<0.001)
0.513 (<0.001)
0.416 (<0.001)
0.514 (<0.001)
0.310 (0.001)
0.030 (0.247) S123 ritical Care March 2007 Vol 11 Suppl 2
27th International Symposium on Intensive Care and Emergency Medicin As expected, DpCO2, DavO2 and ER were different between high
and low ScvO2 groups (P < 0.001). However, while Hb was similar
(P = 0.670), SpO2 and PaO2 were significantly lower when ScvO2
was below 70% (P < 0.001). Normalization of ScvO2 to SpO2
(ScvO2/SpO2) allowed one to overcome the effects of hypoxemia. Values were: 0.662 (0.603–0.693) in the low group and 0.794
(0.757–0.828) in the high group (P < 0.001). Conclusions When considering ScvO2 as a surrogate measure of
perfusion adequacy, it is mandatory to consider the relative effect
of hypoxemia. Anemia was less relevant in our case mix. As expected, DpCO2, DavO2 and ER were different between high
and low ScvO2 groups (P < 0.001). However, while Hb was similar
(P = 0.670), SpO2 and PaO2 were significantly lower when ScvO2
was below 70% (P < 0.001). Normalization of ScvO2 to SpO2
(ScvO2/SpO2) allowed one to overcome the effects of hypoxemia. Values were: 0.662 (0.603–0.693) in the low group and 0.794
(0.757–0.828) in the high group (P < 0.001). Relative influence of hypoxemia and anemia on the
measurement of central venous oxygen saturation Differences between low and
high ScvO2 samples were estimated by Mann–Whitney rank sum
test (Sigma Stat, SPSS), accepting P < 0.05 as significant. Data
are presented as median (25th–75th percentile). P305 Oxygen delivery optimization using lithium indicator
dilution and pulse power analysis during major surgery in
high-risk patients S Lobo1, N Oliveira1, F Lobo1, E Rezende2, B Borges1,
G Cunrath1, J Silva2, L Ronchi1
1Faculdade de Medicina de São José do Rio Preto, Brazil;
2Hospital do Servidor Público, São Paulo, Brazil
Critical Care 2007, 11(Suppl 2):P305 (doi: 10.1186/cc5465) Conclusion A significant proportion of patients had a low ScVO2,
which was associated with increased HLOS. The results provide a
basis for the trial of postoperative early goal-directed therapy for
high-risk surgical patients admitted to our ICU. Introduction Increasing oxygen delivery in high-risk surgical
patients led to a dramatic reduction in both mortality and morbidity. Yet, it is still not widely practised due to logistical difficulties asso-
ciated with its use. We aimed to evaluate whether pulse power
analysis calibrated by the lithium dilution technique, a pragmatic
minimally invasive technique, can be used to optimize the oxygen
delivery index (DO2I) in high-risk patients during major surgery. Introduction Increasing oxygen delivery in high-risk surgical
patients led to a dramatic reduction in both mortality and morbidity. Yet, it is still not widely practised due to logistical difficulties asso-
ciated with its use. We aimed to evaluate whether pulse power
analysis calibrated by the lithium dilution technique, a pragmatic
minimally invasive technique, can be used to optimize the oxygen
delivery index (DO2I) in high-risk patients during major surgery. P303 Methods Arterial and central venous blood gas analysis was done
on admission (T1) and after 8 hours (T2) of admission to the ICU. The HLOS and the incidence of complications were determined for
patients with low (<70%) or normal (≥70%) ScVO2. Results Sixty-three postoperative patients were screened and 23
patients were analysed. Patients were excluded if they did not have
a central line positioned in the superior vena cava or blood had not
been sampled at both time points. Patients with pre-ICU HLOS
> 5 days (n = 10), acute spinal cord injury (n = 3), or admitted for
postoperative airway management (n = 4) were omitted. ScVO2
was low in 7/23 patients at T2 and six of these had lower
gastrointestinal surgery. The HLOS (median (IQR)) was longer in
those with low ScVO2 at T2 (17 (37.8) v 9.5 (5.0) days, P = 0.04). The incidence of complications was not different. There were no
differences between the ScVO2 groups at T2 with respect to age,
gender, standard base excess, lactate, haemoglobin, mean arterial
pressure or central venous pressure. The volume of colloid the two
groups received in the 8-hour observation period was not different
although there was a trend for the low group to receive more
crystalloid (P = 0.08). Conclusions When considering ScvO2 as a surrogate measure of
perfusion adequacy, it is mandatory to consider the relative effect
of hypoxemia. Anemia was less relevant in our case mix. Figure 1 (abstract P305) Results ScvO2 was 62.5% (56.3–66.2) in the low group (n = 180),
76.7% (73.6–80.7) in the high group (n = 282). In the low group
values were: SpO2 95.0% (95.1–98.3), PaO2 72.0 mmHg
(59.5–112.5), DpCO2 8 mmHg (6–9), DavO2 4.3 ml/100 ml
(3.4–5.2), ER 0.346 (0.310–0.399), Hb 9.9 g/dl (8.9–11.1). In the
high group values were: SpO2
98.3% (96.2–99.5), PaO2
106.5 mmHg (81.0–167.0), DpCO2 6 mmHg (4–7), DavO2 2.9 ml/
100 ml (2.3–3.6), ER 0.215 (0.185–0.250), Hb 9.9 g/dl (8.7–11.1). S124 Available online http://ccforum.com/supplements/11/S2 Table 1 (abstract P305)
Control
LiDCO
Age
60 ± 17
68 ± 10
Lact1
3.5 ± 1
2.6 ± 1
Lact2
2.7 ± 1
1.9 ± 1
ScvO2-1
64 ± 18
75 ± 10
ScvO2-2
68 ± 13
72 ± 14
Complications (%)
50
15
Deaths (%)
26
7.7 Table 1 (abstract P305) Table 1 (abstract P305) correlation between Lac and RQ (R = 0.66; P < 0.01) was found. For a DO2 < 9 ml/kg, SvO2 did not correlate with Lac. Opposite, a
direct correlation between Lac and RQ (R = 0.81; P < 0.01) was
found. The DO2/VCO2 ratio showed an inverse relationship with Lac
(R = –0.75; P < 0.01). ROC curves to predict Lac+ were
constructed. The areas under the ROC curves were 0.40, 0.74, and
0.81 for SvO2, RQ, and DO2/VCO2 ratio, respectively. An optimal
cutoff value of 3.1 (sensitivity = 0.70, specificity = 0.77) was
determined for the DO2/VCO2 ratio predicting the presence of Lac+. Conclusions Our findings showed that, for a DO2 > 9 ml/kg, the
SVO2, RQ, and DO2/VCO2 ratio may be used interchangeably. For
a DO2 < 9 ml/kg, the DO2/VCO2 ratio seems a more reliable
predictor of AM than SvO2 and RQ. The DO2/VCO2 ratio can be
simply and quickly calculated at the bedside because pulse wave
analysis allows the DO2 to be frequently calculated, and because
the CO2 analyzer provides VCO2 values continuously. Combined
gas exchange and pulse wave monitoring might be a valuable and
a useful approach to detect AM in trauma patients. Results Median doses of 10 µg/kg/min and 7.5 µg/kg/min
dobutamine were used intraoperatively and postoperatively, respec-
tively. A total of 75% and 84% of the patients were responders
during surgery and postoperatively. However, a much better
pattern of DO2I during surgery was seen in the liberal group than in
the restrictive group (Figure 1). P306 Methods In this prospective, intervention and response study, 30°
PLR of both legs was performed in 20 supine patients receiving
mechanical ventilation after elective cardiothoracic surgery. The
thermodilution cardiac output (COtd), heart rate, central venous
pressure (CVP), MAP, PP, SP and SVV measurements were
performed before, during and after PLR. Oxygen delivery to carbon dioxide production ratio for
continuously detecting anaerobic metabolism in trauma
patients
F Franchi1, S Scolletta1, E Casadei1, P Mongelli2, B Biagioli1,
P Giomarelli1
1University of Siena, Italy; 2Policlinico Le Scotte, Siena, Italy
Critical Care 2007, 11(Suppl 2):P306 (doi: 10.1186/cc5466) Oxygen delivery to carbon dioxide production ratio for
continuously detecting anaerobic metabolism in trauma
patients
F Franchi1, S Scolletta1, E Casadei1, P Mongelli2, B Biagioli1,
P Giomarelli1
1University of Siena, Italy; 2Policlinico Le Scotte, Siena, Italy
Critical Care 2007, 11(Suppl 2):P306 (doi: 10.1186/cc5466) Oxygen delivery to carbon dioxide production ratio for
continuously detecting anaerobic metabolism in trauma
patients Results The COtd, MAP, CVP, PP and SP increased after PLR. No change in heart rate and systemic vascular resistance was
observed. We found a significant correlation between PLR-
induced changes in COtd versus SVV during baseline (slope =
0.902, P = 0.003), changes in MAP (slope = 0.499, P = 0.003),
PP (slope = 0.190, P = 0.024) and SP (slope = 0.276, P = 0.021). Changes in CVP were not correlated to changes in COtd. The
area under the receiver operating curves was larger than 0.7 but
not different for MAP, PP, SP and SVV. Introduction Lactate levels have been shown to correlate with tissue
hypoxia. Unfortunately, due to their slow clearance, lactate levels may
not reflect the actual metabolic condition. Under tissue hypoxia the
carbon dioxide production (VCO2) should be less reduced than the
oxygen consumption, and the respiratory quotient (RQ) should
increase. The oxygen delivery (DO2)/VCO2 ratio could be used as an
indicator of anaerobic metabolism (AM) since it reflects the oxygen
demand and delivery, and the tissue oxygenation. We tested the
DO2/VCO2 ratio as a potential predictor of AM in trauma patients. Conclusion Not only baseline SVV but also PLR-induced changes
in MAP, PP and SP are reliable parameters to assess preload
dependence in cardiac surgery patients. In the clinical setting we
prefer the MAP approach, based on simplicity, availability and
robustness. Methods Eighty consecutive adult trauma patients were pros-
pectively studied. Passive leg raising-induced changes in mean radial artery
pressure can be used to assess preload dependence Passive leg raising-induced changes in mean radial artery
pressure can be used to assess preload dependence B Geerts, R de Wilde, P van den Berg, J Jansen
Leiden University Medical Centre, Leiden, The Netherlands
Critical Care 2007, 11(Suppl 2):P307 (doi: 10.1186/cc5467) Introduction
We evaluated whether changes in, routinely
measured, mean radial artery pressure (MAP) due to passive leg
raising (PLR) can be used to assess preload dependence in
nonspontaneous breathing patients. We therefore compared the
changes in cardiac output (CO) with changes in MAP, pulse
pressure (PP) and systolic pressure (SP) as well as the stroke
volume variation (SVV) before PLR. Conclusion The use of a therapeutic approach guided by DO2I
calculated by the LiDCO plus system, intraoperatively and
postoperatively, seems to be a feasible and practical approach to
guide oxygen delivery optimization therapy during major surgery in
high-risk patients. Better perfusion and a much lower rate of
complications were seen in optimized patients. P306 The DO2, VCO2, RQ, DO2/VCO2 ratio, SvO2,
and arterial lactate (Lac) values were collected at ICU admission. The DO2 was calculated using the cardiac index measured by a
pulse contour system (Hemoscan). The VCO2 was measured
under steady-state conditions using a CO2 analyzer (930 Siemens
Elema). The presence of AM (for example, hyperlactatemia, Lac+)
was defined by an increase in Lac >2 mmol/l. Correlation analysis
and the ROC test were applied. A Sami, S Abdellatif, R Nasri, H Ksouri, S Ben Lakhal
Rabta Hospital, Tunis, Tunisia
Critical Care 2007, 11(Suppl 2):P308 (doi: 10.1186/cc5468) Figure 1 (abstract P305) The values for arterial lactate and
central venous oxygen saturation (ScvO2) on ICU admission and
24 hours later for both groups are shown in Table 1. Significantly
lower arterial lactate and higher ScvO2 were seen in optimized
patients (P < 0.05 vs control group). Major complications occurred
in 50% of the patients in the historical control group (21/42) and in
15% of the LiDCO group (4/26) (RR 0.15, 95% CI 0.037–0.600,
P < 0.05). P307 Passive leg raising-induced changes in mean radial artery
pressure can be used to assess preload dependence
B Geerts, R de Wilde, P van den Berg, J Jansen
Leiden University Medical Centre, Leiden, The Netherlands
Critical Care 2007, 11(Suppl 2):P307 (doi: 10.1186/cc5467) References 1. Kakkos SK, et al.: Int Angiol 2005, 24:330-335. 2. Kakkos SK, et al.: J Vasc Surg 2005, 42:296-303. Introduction The new sequential leg compression device (SCD)
(Tyco, Mansfield, MA, USA) pneumatically applies sequential
compression to the lower limb, while maintaining a pressure
gradient throughout the compression cycle [1,2]. We hypothesized
that the SCD Response System could shift blood volume toward
the thoracic compartment comparable with a volume challenge,
with an increase in preload index such as the intrathoracic blood
volume index (ITBVI) and stroke volume index (SVI). The aim of the
study was to evaluate the relationships between changes in SVI
(∆SVI) induced by SCD and ∆SVI induced by rapid fluid loading
(RFL) in critically ill patients. 1. Kakkos SK, et al.: Int Angiol 2005, 24:330-335. 2. Kakkos SK, et al.: J Vasc Surg 2005, 42:296-303. 1. Kakkos SK, et al.: Int Angiol 2005, 24:330-335. 2. Kakkos SK, et al.: J Vasc Surg 2005, 42:296-303. 1. Kakkos SK, et al.: Int Angiol 2005, 24:330-335. 2. Kakkos SK, et al.: J Vasc Surg 2005, 42:296-303. P309 Changes in stroke volume and intrathoracic blood volume
induced by a sequential leg compression in critically ill
patients. Conclusions The SCD Response System could shift blood
volume toward the thoracic compartment comparable with RFL
better in mechanically ventilated than in spontaneously breathing
patients. Larger population studies are needed to confirm these
preliminary data. M Costa, R Casaretti, M Tuccillo, L Girardi, P Chiarandini,
G Della Rocca
University of Udine, Italy
Critical Care 2007, 11(Suppl 2):P309 (doi: 10.1186/cc5469) University of Udine, Italy
( P308 Figure 2 (abstract P309) Figure 2 (abstract P309) Discussion Patients with low ∆PP seem to be of poor prognosis
because they have a low BCL, a low maximum cortisol increase
after the ACTH test, and a high death rate. Annane and colleagues
[1] found that nonsurvivors have low MAP, high lactate level, high
basal cortisol level and low maximum cortisol level increase after
the test compared with survivors. This finding is in contrast to our
patients. index, ITBVI, and SVI were recorded in the supine position before
and after treatment with the SCD Express Compression System®. The same data where collected before and after a RFL performed
with 3 ml/kg hydroxyethyl starch 6%. The relationships between
∆SVI induced by SCD and ∆SVI induced by RFL were analyzed by
linear regression analysis. Statistical significance was considered
to be at P <0.05. Conclusion Patients with low ∆PP before realizing the ACTH test
tend to have more probability of adrenal deficiency, have more
probability to receive corticosteroid and have poor prognosis. Reference 1. Annane et al.: JAMA 2000, 283:1038-1045. Results Linear regression analysis between ∆SVI induced by SCD
(∆SCD) and ∆SVI induced by RFL (∆RFL) showed r2 = 0.50
(P = 0.0002). When analyzed in a subgroup of spontaneously
breathing versus mechanically ventilated patients, the relationships
observed were respectively r2 = 0.41 (P < 0.01) (Figure 1) and
r2 = 0.73 (P < 0.007) (Figure 2). P308 Pulse pressure variation and adrenal insufficiency in septic
shock Results For a threshold value of DO2 > 9 ml/kg, Lac showed an
inverse relationship with SvO2 (R = –0.84; P < 0.01) and
DO2/VCO2 ratio (R = –0.73; P < 0.01). Conversely, a direct Introduction It is known that corticosteroid therapy improves the
hemodynamic state in patients with septic shock and relative S125 Critical Care March 2007 Vol 11 Suppl 2
27th International Symposium on Intensive Care and Emergency Medicine ritical Care March 2007 Vol 11 Suppl 2
27th International Symposium on Intensive Care and Emergency Medicin Figure 1 (abstract P309)
Figure 2 (abstract P309) Figure 1 (abstract P309) adrenal insufficiency. This effect is partially due to a direct action
on vascular tone in the more vasoplegic patient, so they may be
more hypovolemic. We tried in this study to determine whether
pulse pressure variation measured just before the adreno-
corticotropin test can predict the adrenal state. Methods During a period of 3 years (January 2001–December
2003) we realized a prospective observational study. All patients
having septic shock were enrolled. Patients with arrhythmia were
excluded. We measured hemodynamic data (mean arterial
pressure (MAP), pulse pressure variation (∆PP)), then we realized
an ACTH short test (injection of 250 mg ACTH with dosage of the
cortisol level before the injection, at 30 and 60 minutes). Results One hundred and one patients were enrolled. Age was
48 ± 17 years. SAPS II = 45 ± 16, APACHE II score = 18 ± 8,
MAP = 52 ± 12 mmHg, lactate = 3.5 ± 2 mmol/l, and basal
cortisol level (BCL) = 278 ± 143 µg/l. We divided all patients into
two groups using the ∆PP cutoff: <12% (n = 30) and ≥12%
(n = 71). There is no difference in the two groups in age, SAPS II,
and MAP. Patients with low ∆PP (<12%) have a significantly
(P = 0.01) low BCL: 204 ± 127 µg/l vs 291 ± 133 µg/l, a low
increase of cortisol level in response to ACTH: 264 ± 144 µg/l vs
369 ± 142 µg/l (P = 0.02), and a low maximum variation after the
ACTH test: 59 ± 52 µg/l vs 79 ± 63 µg/l (not significant). The
relative adrenal deficiency (∆max < 90 µg/l) is more frequent in
patients with low ∆PP: 80% vs 60%. Survival is lower in the low
∆PP group, 13% vs 40%. P312 Results Respiratory variation in POP waveform amplitude could
accurately predict variation in arterial PP with a sensibility of
83.3%, specificity of 85.7%, positive predictive value (PPV) of
71.4 and negative predictive value (NPV) of 92.3. The area under
the ROC curve was 0.88 (0.79–0.97) with a best cutoff value of
14% to predict a variation in arterial PP of 13%. The kappa index
of agreement was 0.65 (P < 0.001). Eighteen (30%) patients had
variations in arterial PP above 13%, and 21 (35%) showed
variations in POP waveform amplitude above 14%. In patients
without ALI (P/F > 300) the sensibility was 100%, specificity was
93.3%, NPV was 100% and PPV was 80%. In the group with ALI
(P/F < 300) the kappa index measure of agreement was 0.55, and
in the group without ALI the kappa index was 0.85. PEEP levels
were not different between the groups. P311 Assessing fluid responsiveness in patients undergoing
abdominal major surgery: a comparison of the respiratory
systolic variation test and other indices
A Bisoffi Varani1, A Martini1, N Menestrina2, A Russo3, L Gottin1
1Policlinico GB Rossi, Verona, Italy; 2Hopital Erasme, Verona, Italy;
3Romano D’Ezzelino Vicenza, Italy
Critical Care 2007, 11(Suppl 2):P311 (doi: 10.1186/cc5471) Assessing fluid responsiveness in patients undergoing
abdominal major surgery: a comparison of the respiratory
systolic variation test and other indices Results The mean baseline FTc was 278 ms, and the mean target
FTc was 405 ms. The mean average blood loss was 3.77 l/patient. The mean preoperative urea and creatinine were 5.9 mmol/l and
95.3mmol/l, respectively. The mean 24-hour postoperative urea
and creatinine were 5.23 mmol/l and 76.77 mmol/l, respectively. See Figure 1. A Bisoffi Varani1, A Martini1, N Menestrina2, A Russo3, L Gottin1
1Policlinico GB Rossi, Verona, Italy; 2Hopital Erasme, Verona, Italy;
3Romano D’Ezzelino Vicenza, Italy
Critical Care 2007, 11(Suppl 2):P311 (doi: 10.1186/cc5471) Conclusion Goal-directed intraoperative fluid therapy aiming for
FTc of 375–425 ms as a target improved the 24-hour Introduction
Fluid
responsiveness
can
be
predicted
by
respiratory-induced changes in arterial blood pressure. In this study
we compare the predictive performance of various haemodynamic
parameters, including the respiratory systolic variation test (RSVT),
pulse pressure variation (DPP) and stroke volume variation (SVV),
in 18 patients undergoing abdominal major surgery. Figure 1 (abstract P312) Goal-directed intraoperative fluid therapy improved
postoperative renal functions in aortic surgical patients M Soliman, S Bajaj, K Ismail
Department of Anaesthesia and Intensive Care Medicine, The Mid
Yorkshire Hospitals, UK
Critical Care 2007, 11(Suppl 2):P312 (doi: 10.1186/cc5472) Introduction Goal-directed intraoperative fluid therapy reduced
the hospital stay after major surgery [1]. Aortic vascular surgery is
associated with excessive blood loss and massive fluid shift [2]. We found that postoperative urea and creatinine improved when
intravascular fluid volume was maintained using transoesophageal
Doppler. Conclusion Respiratory variation in arterial PP above 13% can be
accurately predicted by a variation in POP waveform amplitude of
14% with good correlation and agreement. Our results confirm the
findings of a recent trial and suggest that the correlation is even
stronger when ALI is absent. These findings raise potential clinical
applications of respiratory variation in POP waveform amplitude for
haemodynamic management of patients without an arterial catheter. Methods We randomly selected 40 patients who underwent
elective infrarenal aortic surgery (aortic aneurysm repair/aorto-
bifemoral grafting). All patients’ cardiac output was continuously
monitored using a transoesophageal Doppler probe (EDM™;
Deltex Medical, Inc., Irving, TX, USA). The corrected flow time
(FTc) was recorded immediately after induction as a baseline and
recorded again pre-extubation. A target FTc of 375–425 ms was
aimed for. The estimated total blood loss was calculated for each
patient at the end of surgery. Preoperative and 24-hour
postoperative urea and creatinine were recorded for comparison. Methods We randomly selected 40 patients who underwent
elective infrarenal aortic surgery (aortic aneurysm repair/aorto-
bifemoral grafting). All patients’ cardiac output was continuously
monitored using a transoesophageal Doppler probe (EDM™;
Deltex Medical, Inc., Irving, TX, USA). The corrected flow time
(FTc) was recorded immediately after induction as a baseline and
recorded again pre-extubation. A target FTc of 375–425 ms was
aimed for. The estimated total blood loss was calculated for each
patient at the end of surgery. Preoperative and 24-hour
postoperative urea and creatinine were recorded for comparison. Results The mean baseline FTc was 278 ms, and the mean target
FTc was 405 ms. The mean average blood loss was 3.77 l/patient. The mean preoperative urea and creatinine were 5.9 mmol/l and
95.3mmol/l, respectively. The mean 24-hour postoperative urea
and creatinine were 5.23 mmol/l and 76.77 mmol/l, respectively. See Figure 1. Respiratory pulse oximetry plethysmographic waveform
amplitude correlates with arterial pulse pressure variations PEEP le
were not different between the groups. Conclusion Respiratory variation in arterial PP above 13% can
accurately predicted by a variation in POP waveform amplitud
14% with good correlation and agreement. Our results confirm
findings of a recent trial and suggest that the correlation is e
stronger when ALI is absent. These findings raise potential clin
applications of respiratory variation in POP waveform amplitude
haemodynamic management of patients without an arterial cathe
P311
Assessing fluid responsiveness in patients undergoing
abdominal major surgery: a comparison of the respirato
systolic variation test and other indices
A Bisoffi Varani1, A Martini1, N Menestrina2, A Russo3, L Got
1Policlinico GB Rossi, Verona, Italy; 2Hopital Erasme, Verona, Ita
3Romano D’Ezzelino Vicenza, Italy
Critical Care 2007, 11(Suppl 2):P311 (doi: 10.1186/cc5471)
Introduction
Fluid
responsiveness
can
be
predicted Conclusion Functional parameters are superior to static indicators
of cardiac preload in predicting the response to fluid
administration. DPP and SVV, with their suggested threshold value,
can predict fluid responsiveness in patients undergoing major
abdominal surgery. The RSVT may be a more accurate predictor of
fluid responsiveness although its performance demands a complex
respiratory manoeuvre and is dependent on offline measurement
and calculations, which limits its clinical use. Methods Sixty patients were included in the study. Thirty-nine
(65%) had diagnosis of ALI and 21 (35%) had normal gas
exchange, defined as a relation of PaO2 to FiO2 (P/F) below and
above 300, respectively. Respiratory variation in arterial PP and
POP waveform amplitude were recorded simultaneously on a beat-
to-beat basis, and mean values of two measures for each
parameter were compared for correlation and agreement. Respiratory pulse oximetry plethysmographic waveform
amplitude correlates with arterial pulse pressure variations Respiratory pulse oximetry plethysmographic waveform
amplitude correlates with arterial pulse pressure variations Methods Twenty-seven patients (mean age 60 ± 9.1 years) admitted
to the ICU were studied. Each patient received conventional
monitoring plus hemodynamic–volumetric monitoring (PiCCO
System; Pulsion Medical Systems, Munich, Germany). The heart
rate, mean arterial pressure, central venous pressure, cardiac Introduction Arterial pulse pressure (PP) respiratory variation is a
good predictor of fluid responsiveness in ventilated patients. Recently, it has been shown that variation in PP may correlate with
variation in pulse oximetry plethysmographic (POP) waveform S126 Available online http://ccforum.com/supplements/11/S2 Available online http://ccforum.com/supplements/11/S2 between preoperative values of DPP, SVV and RSVT and
percentage changes in SVI after volume load (better than the
values of HR, AP, CVP). amplitude, as they both depend on the stroke volume. We
designed a prospective study to evaluate the correlation between
respiratory arterial PP variation and POP waveform amplitude
variations in ventilated patients and the influence of acute lung
injury (ALI) in this relationship. amplitude, as they both depend on the stroke volume. designed a prospective study to evaluate the correlation betw
respiratory arterial PP variation and POP waveform amplit
variations in ventilated patients and the influence of acute l
injury (ALI) in this relationship. Methods Sixty patients were included in the study. Thirty-n
(65%) had diagnosis of ALI and 21 (35%) had normal
exchange, defined as a relation of PaO2 to FiO2 (P/F) below
above 300, respectively. Respiratory variation in arterial PP
POP waveform amplitude were recorded simultaneously on a b
to-beat basis, and mean values of two measures for e
parameter were compared for correlation and agreement. Results Respiratory variation in POP waveform amplitude co
accurately predict variation in arterial PP with a sensibility
83.3%, specificity of 85.7%, positive predictive value (PPV
71.4 and negative predictive value (NPV) of 92.3. The area un
the ROC curve was 0.88 (0.79–0.97) with a best cutoff valu
14% to predict a variation in arterial PP of 13%. The kappa in
of agreement was 0.65 (P < 0.001). Eighteen (30%) patients
variations in arterial PP above 13%, and 21 (35%) show
variations in POP waveform amplitude above 14%. In patie
without ALI (P/F > 300) the sensibility was 100%, specificity
93.3%, NPV was 100% and PPV was 80%. In the group with
(P/F < 300) the kappa index measure of agreement was 0.55,
in the group without ALI the kappa index was 0.85. Analysis of physiological functions of different human
serum albumin pharmaceutical preparations Analysis of physiological functions of different human
serum albumin pharmaceutical preparations M Di Giambattista, L Mascio, T Branckaert, R Laub
Central Department for Fractionation, Red Cross, Brussels, Belgium
Critical Care 2007, 11(Suppl 2):P313 (doi: 10.1186/cc5473) Aims and methods A clinical scenario was used to assess current
knowledge among medical staff regarding i.v. fluid therapy. ‘An 85-
year-old lady is brought into A&E semiconscious. Temperature
32°C, blood pressure 90/50 mmHg and BM 6.5 mmol/l. Arterial
blood gases (ABG) on room air: pH 7.12 pO2 10.8 kPa, pCO2
2.6 kPa, HCO3
– 12 mmol/l, O2 saturation 94% and base excess
–19’. Medical staff were asked to complete a questionnaire
relating to the case under supervised conditions. Introduction New information is emerging as a basis for
reconsidering albumin as a key homeostatic molecule in the critically
ill. We are only beginning to understand the full spectrum of albumin
properties and action in healthy individuals and hypoalbuminaemic
patients. Besides its function in the regulation of colloidal osmotic
pressure, albumin has an important antioxidant capacity and a role in
the transport of a wide range of drugs, hormones, ions, amino acids,
and fatty acids. Few comparative studies have as yet been
performed, and they address only a restricted number of parameters
mostly defined by the European Pharmacopeia. Results Eighty-seven questionnaires were completed by seven
SpR/consultants, 48 F2/senior house officers, 13 F1 and 19 final-
year medical students. ABG interpretation was correct in 80/87
(92%). Only 52/87 (59.8%) could calculate the anion gap and only
1/87 listed fluid as a cause of a metabolic acidosis. Eighty-three
staff (93.4%) knew that a metabolic acidosis caused an increased
respiratory rate. Normal saline was the first-choice fluid for
resuscitation in almost 60% (52/87) cases. The chloride
concentration of normal saline was known by 12/87 staff (13.8%). The serum chloride concentration was known by 28/87 staff (32%). Conclusion The majority of medical staff prescribe normal saline
as their first-choice intravenous fluid. Many medical staff are
unaware of the electrolyte composition of normal saline, the
phenomenon of hyperchloraemic metabolic acidosis, or how to
differentiate hyperchloraemic metabolic acidosis from lactic
acidosis by calculating the anion gap. A good understanding of
fluid therapy is important for all medical staff. Objective To study and compare the main albumin functions of
eight preparations of pharmaceutical-grade albumin, using a
battery of different techniques. Saline-induced hyperchloraemic metabolic acidosis: an
unrecognised phenomenon among medical staff? 1. Gan et al.: Goal-directed intraoperative fluid administration
reduces length of hospital stay after major surgery. Anes-
thesiology 2002, 97:820-826. A Turley, B Bose, J Gedney
The James Cook University Hospital, Middlesbrough, UK
Critical Care 2007, 11(Suppl 2):P314 (doi: 10.1186/cc5474) 2. Miyashita T, et al.: An analysis of risk factors of periopera-
tive bleeding in surgical repair of abdominal aortic
aneurysm. J Cardiovasc Surg 2000, 41:595-599. Introduction Hyperchloraemic acidosis is well recognised within
critical care, is implicated in the development of organ dysfunction
and is an important consequence of administration of large
volumes of chloride-containing intravenous (i.v.) fluid, such as
normal (0.9%) saline [1,2]. Within most hospitals, junior medical
staff with differing levels of experience prescribe the majority of i.v. fluid therapy. Analysis of physiological functions of different human
serum albumin pharmaceutical preparations Two additional albumin prepara-
tions, a preparation without stabilisers and a recombinant albumin
from Pichia pastoris, were also included in the study. Methods The following biochemical and physicochemical
parameters were investigated: total protein concentration (Biuret
assay) and albumin antigen (nephelometry); quantitative analysis of
contaminating proteins by nephelometry, levels of polymers and
fragments by gel filtration chromatography on Superose 6, the
binding affinity of exogenous ligands for Sudlow’s site I (warfarin)
or site II (dansylsarcosine) by steady-state spectrofluorimetry, the
reactivity of Cys34 with Ellman’s reagent, and the esterase-like
activity using p-nitrophenyl acetate as substrate by spectro-
photometry. References 1. Wilkes NJ: Anesth Analg 2001, 93:811-816. 2. McFarlane C, Lee A: Anaesthesia 1994, 49:779-781. 1. Wilkes NJ: Anesth Analg 2001, 93:811 816. 2. McFarlane C, Lee A: Anaesthesia 1994, 49:779-781. Results All pharmaceutical-grade products show a purity ranging
from 95% to 108%. The main contaminant proteins are
prealbumin, transferrin, α-1 acid glycoprotein, haptoglobulin, and
retinol-binding protein. All of them are in conformity with the
European Pharmacopeia specifications. The warfarin-binding
capacity of the 10 albumin preparations was studied. An average
binding constant of 2.6 (±0.3) x 105 M–1 (n = 1) was found. The
presence of stabilisers reduced the binding of dansylsarcosine
significantly (by 27–40%). The esterase-like activity toward p-
nitrophenyl acetate and the reactivity of Cys34 differed from
product to product. Interesting is the absence of free Cys34 in the
recombinant albumin. Figure 1 (abstract P312) S127 Methods Eighteen patients, ASA I–II, were undergoing pancreatic
surgery (whipple resection). The heart rate (HR) central venous
pressure (CVP), arterial pressure (AP), cardiac output (CO),
cardiac index (CI), stroke volume (SV), stroke volume index (SVI),
SVV, DPP and RSVT were measured before and after a volume
load of 7 ml/kg hydroxyethylstarch. (CO, CI, SV, SVI and SVV were
displayed by the Edwards Vigileo monitor with FloTrac sensor.)
Receiving-operating characteristic (ROC) curves were plotted for
each parameter to evaluate its predicting value. In addition,
correlation between the baseline value of haemodynamic
parameters RSVT, DPP, SVV and change in SVI after volume
administration was made. Results DPP, SVV and RSVT demonstrate a good predicting value
(ROC area 0.870, 0.877 and 0.943 with P = 0.010, 0.009 and
0.002, respectively). A statistically significant correlation was found S127 ritical Care March 2007 Vol 11 Suppl 2
27th International Symposium on Intensive Care and Emergency Medicin postoperative urea urea and creatinine in 40 aortic surgical
patients in spite of the excessive blood loss. postoperative urea urea and creatinine in 40 aortic surgical
patients in spite of the excessive blood loss. postoperative urea urea and creatinine in 40 aortic surgical
patients in spite of the excessive blood loss. P314 P315 Low-dose
dopexamine (≤1 µg/kg/min) was associated with a 49% reduction
in 28-day mortality (6.3% vs 12.3%; OR = 0.51 (95% CI
0.29–0.89), P = 0.008). The length of postoperative stay was also
reduced in the low-dose dopexamine group compared with control
(median 13 vs 15 days, HR 0.75 (95% CI 0.65–0.88), P = 0.004). High-dose dopexamine (>1 µg/kg/min) was not associated with a
difference in mortality (14.5% vs 12.3%; OR = 1.18 (95% CI
0.67–2.08), P = 0.37) or length of stay (median 17 vs 15 days, HR
1.10 (95% CI 0.90–1.34), P = 0.37) when compared with
controls. P317 Critical care utilisation following bariatric surgery
P Whiting, A Mannings, S Reynolds, S Hutchinson, R Ackroyd
Royal Hallamshire Hospital, Sheffield, UK
Critical Care 2007, 11(Suppl 2):P317 (doi: 10.1186/cc5477) Critical care utilisation following bariatric surgery P Whiting, A Mannings, S Reynolds, S Hutchinson, R Ackroyd
Royal Hallamshire Hospital, Sheffield, UK
Critical Care 2007, 11(Suppl 2):P317 (doi: 10.1186/cc5477) Introduction Following the introduction of a new bariatric surgical
service in Sheffield, we aimed to assess the impact upon critical
care services and examine how this has changed as the service
has evolved. Conclusions
Perioperative
use
of
low-dose
dopexamine
decreases mortality and duration of hospital stay in patients
undergoing major surgery. R f References Method All admissions for bariatric surgery between 1 April 2003
and 30 April 2006 were reviewed retrospectively. These proce-
dures were performed on two sites, the Royal Hallamshire Hospital
(RHH) and Thornbury Hospital (TH). The critical care admissions
and length of hospital stay (LOS) were reviewed. 1. Boyd O, et al.: JAMA 1993, 270:2699-2707. 2. Wilson J, et al.: BMJ 1999, 318:1099-1103. 3. Takala J, et al.: Crit Care Med 2000, 28:3417-3423. 4. Stone MD, et al.: Br J Anaesth 2003, 91:619-624. Results A total of 497 patients were identified as having had
bariatric surgery. After review of hospital and critical care
admission data, a total of 473 were identified with complete data. Of these, 94 (19.9%) were open procedures (OP), 260 (55.0%)
laparoscopic bandings (LB) and 119 (25.1%) laparoscopic gastric
bypasses (LGB). The age range was 16–68 years. The average
hospital LOS for OP was 6.8 days, for LGB 4.0 days and for LB
1.9 days. Surgical procedures and HDU admissions increased
annually (2003–2006) from 74 to 249, and 21 to 107, respec-
tively. P315 An individual patient meta-analysis of clinical trials using
dopexamine to increase oxygen delivery in high-risk
surgical patients J Belsey1, R Pearse2, J Cole3, D Bennet4
1JB Medical Ltd, Sudbury, UK; 2The Royal London Hospital,
London, UK; 3Cephalon UK, Stevenage, UK; 4St George’s
Hospital, London, UK
Critical Care 2007, 11(Suppl 2):P315 (doi: 10.1186/cc5475) Introduction Postoperative outcomes may be improved if cardiac
output and oxygen delivery are maintained at optimal levels. Trials
of the use of dopexamine for this purpose have yielded
inconsistent results. This may relate to the use of high doses in
some trials. A meta-analysis of data from these trials may therefore
identify a benefit of low-dose dopexamine on postoperative
mortality and length of stay. Introduction Postoperative outcomes may be improved if cardiac
output and oxygen delivery are maintained at optimal levels. Trials
of the use of dopexamine for this purpose have yielded
inconsistent results. This may relate to the use of high doses in
some trials. A meta-analysis of data from these trials may therefore
identify a benefit of low-dose dopexamine on postoperative
mortality and length of stay. Conclusion Significant differences were observed between the 10
different human albumin preparations, recombinant or not. We
confirm that the presence of stabilisers such as tryptophan
derivatives significantly reduces the binding capacity of Sudlow’s
site II. Two important physiological properties of albumin, the
esterase-like and antioxidant activities, were also found to be
modified to different extents in all pharmaceutical-grade products
in comparison with the albumin without stabiliser. The benefits of
albumin administration should be considered carefully, taking into
account the different functions and properties of albumin. Methods A comprehensive literature review was performed to
identify published randomised trials of perioperative dopexamine
infusion in patients undergoing major surgery. Individual patient S128 Available online http://ccforum.com/supplements/11/S2 Available online http://ccforum.com/supplements/11/S2 Available online http://ccforum.com/supplements/11/S2 Available online http://ccforum.com/supplements/11/S2 between inflection point and systolic foot: mean ± SD = 40.0 ±
9.4 ms, intrasubject SD 4.6 ms). Retrograde coronary blood flow
during isovolumic ventricular contraction may be the origin of the
persistent end-diastolic pressure and distension perturbation. This
study shows that the duration of the isovolumic contraction can be
reliably extracted from the carotid artery distension waveform. data were obtained, allowing a meta-regression approach to
explore mortality outcomes after correction for age and dose of
dopexamine. A Cox proportional hazards model was constructed
to examine the length of stay. Results Five studies fulfilled the inclusion criteria [1-5]. P315 As a proportion, open procedures declined from 60% to 7%,
and laparoscopic interventions increased (LB from 40% to 63%
and LGB from 0% to 30%). There were a total of 14 admissions to
the ITU by 10 patients, of which seven had undergone an initial
OP. No admissions were elective and eight patients required
further surgical interventions. HDU admissions occurred on both
sites, with 148/277 (53.4%) of patients admitted to HDU at TH,
and 53/196 (27.6%) at RHH. At TH only three patients required
level 2 care, and 95 were discharged within 26 hours. At RHH, 16
patients required level 2 care, and 38 were discharged within 26
hours. 5. Pearse R, et al.: Crit Care 2005, 9:687-693. 5. Pearse R, et al.: Crit Care 2005, 9:687-693. Figure 1 (abstract P316) Figure 1 (abstract P316) The onset of ventricular isovolumetric contraction as
reflected in the carotid artery distension waveform The onset of ventricular isovolumetric contraction as
reflected in the carotid artery distension waveform The onset of ventricular isovolumetric contraction as
reflected in the carotid artery distension waveform M van Houwelingen, A Hoeks, R Reneman
University of Maastricht, The Netherlands
Critical Care 2007, 11(Suppl 2):P316 (doi: 10.1186/cc5476) M van Houwelingen, A Hoeks, R Reneman
University of Maastricht, The Netherlands
Critical Care 2007, 11(Suppl 2):P316 (doi: 10.1186/cc5476) The blood pressure waveform carries information about the cardiac
contraction and the impedance characteristics of the vascular bed. Here, we demonstrate that the start of isovolumic ventricular
contraction is persistently reflected as an inflection point in the
pressure wave as recorded in the aortic root (TPIC) as well as in
the carotid artery distension waveform (TDIC) as it travels down
the arterial tree. In a group of six patients with normal pressure
gradients across the aortic valve after valve replacement, the TPIC
had a small delay with respect to the onset of isovolumic
ventricular contraction (<10 ms). In a group (n = 21) of young,
presumably healthy, volunteers, the inflection point occurred
persistently in the carotid distension waveform, as recorded by
means of ultrasound, before the systolic foot (intersubject delay Discussion The requirement for ITU admission in this surgical
group is, and has remained, low, despite a significant increase in
bariatric surgical procedures. This increase is predominantly
laparoscopic surgery. HDU activity has increased as the service
has expanded; however, 90.4% of this is level 1 care, particularly
at TH, where admission to the HDU is a matter of policy rather than
clinical necessity. Availability of a level 1 facility would significantly
decrease the requirement for HDU provision – an important
consideration when introducing a new bariatric service. Figure 1 (abstract P316) Abdominal pressure volume determinants Abdominal pressure volume determinants J Mulier, B Dillemans, K Verbeke, A Luijten
AZ Sint Jan AV Brugge, Belgium
Critical Care 2007, 11(Suppl 2):P320 (doi: 10.1186/cc5480) The abdominal pressure–volume relation can be described by a
linear relation giving an elastance (E) and a pressure at zero
volume (PV0). The goal of this study was to measure this relation in
a large group of patients with different characteristics looking for
the factors that influence and explain this relation. It is believed that
obese persons have higher abdominal pressures and it is unclear
whether muscle relaxation lowers it. A large group of 70 patients, ASA class I or II, between 21 and
75 years old and scheduled for laparoscopic surgery were included
in this study with approval from the hospital ethical committee. Results CPAP determined a reduction of portal vein velocity:
30.0 ± 9.1 cm/s vs 19.7 ± 5.0 cm/s (P = 0.01). IVC diameters are
increased by CPAP: inspiratory diameter 9.49 ± 2.5 cm vs
12.05 ± 3.9 cm (P = 0.002), expiratory diameter 16.46 ± 2.9 cm
vs 18.08 ± 3.65 cm (P = 0.05). Anaesthesia was induced with propofol 200 mg, sufentanil 20 µg,
and sevoflurane 1.5 Mac in 50% O2/N2O. Some patients were fully
muscle relaxed with nimbex 20 mg while others not. Patients were
asked to empty the bladder before surgery. The stomach was
emptied by suction through a gastric tube. An Olympus insufflator
UHI-3 was initialised and the abdomen was inflated with a
stepwise flow to 7, 10, 13 and 16 mmHg. When the pressure was
reached, flow was stopped and the actual pressure and volume
measured giving four data points. E and PV0 were calculated by
fitting to a linear relation. The following recorded determinants
were evaluated by regression analysis for their effect: age, length,
weight, BMI, sex, gravidity and muscle relaxation. Conclusions The results of this study demonstrate that, in healthy
subjects, variation of intrathoracic pressure by CPAP influences
venous return. HF reduction could be due to an increased IVC
pressure, as displayed by the bigger diameters measured during
CPAP, other than a diaphragmatic descent. Ultrasonography is
able to detect this effect and could be useful in a more complete
evaluation of patient haemodynamic status in various clinical
settings. Intrathoracic pressure effects on hepatic flow and inferior
vena cava diameter: an ultrasonographic study A Graziani, E Gamberini, B Praticò, F Morgagni, F Savelli,
S Bonarelli
Oospedale Maurizio Bufalini, Cesena, Italy
Critical Care 2007, 11(Suppl 2):P318 (doi: 10.1186/cc5478) Objective To compare the effect of an increased intrathoracic
pressure on the inferior vena cava (ICV) diameter and hepatic flow
(HF) in healthy subjects. S129 ritical Care March 2007 Vol 11 Suppl 2
27th International Symposium on Intensive Care and Emergency Medicin Patients and methods Ten healthy subjects (seven females, three
males; age 27.3 ± 4.5 years) were investigated in a supine position
before and after application of continuous positive airways
pressure (CPAP) of 10 cmH2O by nasal mask. The study was
performed using sonographic equipment with a multiprobe (convex
3.5–5 MHz; sector 2.5–3.5 MHz) and color-Doppler capability
(Hitachi H 21). IVC was visualized by a two-dimensional
echographic sector probe and M-mode was used to measure the
inspiratory and expiratory diameters at the origin of the supra-
hepatic veins. HF is composed of portal flow (PF) and hepatic
artery flow (HAF). Portal velocity, assessed near the liver hilum,
was used as a measure of PF, and the left intrahepatic branch
resistivity index (RI) was used as a measure of HAF. Measures
were repeated twice for each value of intrathoracic pressure by
two different examiners and the mean value was given for the
statistical analysis. Results are given as the mean ± SD. Data were
evaluated by paired t test and P < 0.05 was taken as statistically
significant. Conclusion Development of IAH significantly increases the risk of
death in patients with severe sepsis or septic shock, but not in
nonseptic patients. Conclusion Development of IAH significantly increases the risk of
death in patients with severe sepsis or septic shock, but not in
nonseptic patients. Intra-abdominal hypertension as a risk factor of death in
patients with severe sepsis or septic shock Intra-abdominal hypertension as a risk factor of death in
patients with severe sepsis or septic shock Table 1 (abstract P320)
PV0
E
Age
0.838
0.003
Length
0.356
0.245
Weight
0.012
0.294
BMI
0.054
0.272
Sex
0.596
0.536
Gravidity
0.305
0.049
Relaxation
0.001
0.376 A Reintam1, P Parm2, R Kitus2, H Kern3, J Starkopf2
1East Tallinn Central Hospital, Tallinn, Estonia; 2Tartu University
Clinics, Tartu, Estonia; 3DRK Kliniken Berlin, Germany
Critical Care 2007, 11(Suppl 2):P319 (doi: 10.1186/cc5479) Introduction Critically ill patients with severe sepsis or septic
shock have a very high mortality rate. The aim of our study was to
investigate the impact of intra-abdominal hypertension (IAH) on the
outcome of patients with or without severe sepsis/septic shock. Introduction Critically ill patients with severe sepsis or septic
shock have a very high mortality rate. The aim of our study was to
investigate the impact of intra-abdominal hypertension (IAH) on the
outcome of patients with or without severe sepsis/septic shock. Methods Two hundred and fifty-three mechanically ventilated
patients admitted to the general ICU of Tartu University Hospital
were prospectively studied. Patients who had severe sepsis or
septic shock at admission or developed it during their first week of
stay were compared with patients not suffering from severe sepsis. IAH was defined as sustained intra-abdominal pressure above or
equal to 12 mmHg developing within the first week in the ICU. Results Severe sepsis or septic shock was observed in 123
patients (48.6%). The ICU mortality among these patients was
33.3% compared with 18.5% in nonseptic patients (P = 0.005). IAH developed in 95 patients (37.0%). The incidence of IAH was
higher among septic patients (45.5% vs 28.5%, P = 0.004). Those
septic patients who developed IAH had a mortality rate of 50.0%
compared with 19.4% in septic patients without IAH (P < 0.001). Mortality among nonseptic patients was not different between the
patients with or without IAH (18.9% vs 18.3%). Development of
IAH was a significant risk factor for death in septic patients (OR
4.15; 95% CI 1.87–9.26), but not in nonseptic patients (OR 1.04;
95% CI 0.39–2.77). Methods Two hundred and fifty-three mechanically ventilated
patients admitted to the general ICU of Tartu University Hospital
were prospectively studied. Patients who had severe sepsis or
septic shock at admission or developed it during their first week of
stay were compared with patients not suffering from severe sepsis. P319 PV0 increases significantly with body weight and decreases
significantly with muscle relaxation. Intra-abdominal hypertension as a risk factor of death in
patients with severe sepsis or septic shock IAH was defined as sustained intra-abdominal pressure above or
equal to 12 mmHg developing within the first week in the ICU. P323 Results and discussion We treated 624 CPA patients in the past
2 years, 38% were cardiac and 62% were noncardiac aetiology
(3% subarachnoid haemorrhage and 5% acute aortic dissection). Restricted in cardiac aetiology patients, 13% showed a ventricular
fibrillation (VF) as a first monitored rhythm and 33% showed a VF
during resuscitation. In all patients, 50% of VF were witnessed. In
witnessed patients, 17% were witnessed by the ELST during
transfer and 81% by a layperson, most of whom are patients'
families and patients’ friends. Fifty-three per cent were witnessed
in the patients' home (35% in patients’ private room, 1% in
bathroom and 7% in lavatory), 4% in an aged people’s residence,
1% in a hotel, restaurant, office, and 3% on the road. Only 48% of
CPA patients underwent bystander CPR, and 51% of witnessed
CPA patients (24% of all CPA patients) underwent bystander CPR
by the witness; most patients underwent bystander CPR in the
patients’ home by the patients’ families. Vasopressin alone or with epinephrine may be superior to
epinephrine in asystolic out-of-hospital cardiac arrest: an
observational study M Ðpindler, Ð Grmec, Ð Mally
Center for Emergency Medicine Maribor, Slovenia
Critical Care 2007, 11(Suppl 2):P323 (doi: 10.1186/cc5483) Background In patients undergoing cardiopulmonary resusci-
tation, circulating endogenous vasopressin concentrations were
significantly higher in successfully resuscitated patients than in
patients who died. Clinical data considering vasopressin to be an
equivalent option to epinephrine in cardiopulmonary resuscitation
(CPR) are limited. The studies of out-of-hospital cardiac arrest
(OHCA) confirm an increasing part of asystole as the initial rhythm. The hypothesis of this study was that vasopressin improves the
rate of return of spontaneous circulation (ROSC) and the survival
rate in asystolic OHCA, when used early in the resuscitation effort. Methods This was a prospective cohort study, with a historic
group compared trial set in an urban emergency medical services
system, serving a population of 200,000. All nonpregnant,
normothermic adults (>18 years) suffering nontraumatic OHCA
with asystole were eligible. We compared two treatment groups of
resuscitated patients with OHCA. In the epinephrine group (EPI)
patients received epinephrine 1 mg i.v. every 3 minutes only. In the
vasopressin group (VASO) patients received arginine vasopressin
40 IU i.v. only or followed by epinephrine 1 mg every 3 minutes
during CPR. Statistics. Exact Fisher test, Wilcoxon rank-sum test,
and analysis of independent predictors with multivariate logistic
regression were used; P < 0.05. P321 P321
Bystander CPR for out-of-hospital cardiac arrest in Japan
Y Moriwaki, M Sugiyama, H Toyoda, T Kosuge, M Iwashita,
J Ishikawa, S Matsuzaki, Y Tahara, N Suzuki
Yokohama City University Medical Center, Yokohama, Japan
Critical Care 2007, 11(Suppl 2):P321 (doi: 10.1186/cc5481) P321
Bystander CPR for out-of-hospital cardiac arrest in Japan
Y Moriwaki, M Sugiyama, H Toyoda, T Kosuge, M Iwashita,
J Ishikawa, S Matsuzaki, Y Tahara, N Suzuki
Yokohama City University Medical Center, Yokohama, Japan
Critical Care 2007, 11(Suppl 2):P321 (doi: 10.1186/cc5481) q
g
p g
Results Severe sepsis or septic shock was observed in 123
patients (48.6%). The ICU mortality among these patients was
33.3% compared with 18.5% in nonseptic patients (P = 0.005). IAH developed in 95 patients (37.0%). The incidence of IAH was
higher among septic patients (45.5% vs 28.5%, P = 0.004). Those
septic patients who developed IAH had a mortality rate of 50.0%
compared with 19.4% in septic patients without IAH (P < 0.001). Mortality among nonseptic patients was not different between the
patients with or without IAH (18.9% vs 18.3%). Development of
IAH was a significant risk factor for death in septic patients (OR
4.15; 95% CI 1.87–9.26), but not in nonseptic patients (OR 1.04;
95% CI 0.39–2.77). Background and aims The aim of this study is to clarify how
Japanese citizens are interested in the importance of immediate
cardiopulmonary resuscitation (CPR) and defibrillation, and how
they understand that importance. In Japan, the out-of-hospital
emergency medical service system has been established with the
ambulance service and an emergency life saving technician (ELST)
belonging to the fire department. Subjects and methods Patients’ records were reviewed for the
past 2 years. In Yokohama (3,700,000 people), the cardio- S130 Available online http://ccforum.com/supplements/11/S2 Available online http://ccforum.com/supplements/11/S2 Available online http://ccforum.com/supplements/11/S2 pulmonary arrest (CPA) patient is transferred to the nearest ED of
the selected 11 hospitals with adequate ability of CPR and
cerebral resuscitation. We perform ultrasound, chest X-ray, and
blood examination including Troponin in all CPA patients, and
cerebral plane CT (40%) or chest CT (7%). CT was not performed
in patients with a clearly known aetiology. coagulation system may contribute to reperfusion disorders and
possibly affect the outcome of these patients. Further studies need
to show whether elevation of the D-dimer level in patients after
CPR could be a prognostic marker. P323 Conclusions In Japan, CPA patients were witnessed mainly in
their home by their families or their friends. The aetiology of some
CPA patients is noncardiac (subarachnoid haemorrhage or acute
aortic dissection, etc.). However, only 24% CPA patients
underwent bystander CPR by the witness. D-Dimer level and outcome in patients after
cardiopulmonary resuscitation The plasma D-
dimer level was measured immediately after admission to the ICU. Conclusions Vasopressin was superior to epinephrine in patients
with asystole (better ROSC with admission, 24-hour survival and
discharge from hospital). Vasopressin followed by epinephrine was
more effective than epinephrine alone in the treatment of refractory
cardiac arrest. D-Dimer level and outcome in patients after
cardiopulmonary resuscitation H Busch, A Geibel, C Bode, T Schwab
UKL Freiburg, Germany
Critical Care 2007, 11(Suppl 2):P322 (doi: 10.1186/cc5482) Background Clinical and experimental studies have demonstrated a
marked activation of blood coagulation and fibrin formation after
prolonged cardiopulmonary resuscitation (CPR). Several experimental
studies suggest that thrombolysis therapy acts directly on thrombi or
emboli but also enhances microcirculatory reperfusion. In this
retrospective study we investigated the extent of blood coagulation
and fibrin formation via the plasma D-dimer level, an indicator of
endogenous fibrinolytic activity, in patients who underwent inhospital
and out-of-hospital cardiac arrest from nontraumatic causes. Results The investigators enrolled 227 consecutive patients: in the
EPI group 183 patients (years 2001–2003) and in the VASO
group 44 patients (year 2004). Baseline (demographic and
clinical) characteristics were similar for the two groups. Comparing
the EPI and VASO groups, any ROSC was achieved in 81/183
(44%) and 34/44 (77%), P = 0.04; ROSC with admission in
61/183 (33%) and 27/44 (61%), P = 0.03; 24-hour survival in
44/183 (24%) and 23/44 (52%), P = 0.01; and discharge from
hospital in 17/183 (9%) and 10/44 (23%), P = 0.04. Vasopressin
was an independent predictor of ROSC with admission with an
odds ratio of 2.4 (95% CI = 1.24–4.98). Methods and results Forty-five patients were included from
1 January 2004 to 31 March 2005 after CPR in the case of
restoration of spontaneous circulation (ROSC). The plasma D-
dimer level was measured immediately after admission to the ICU. Results In 38 patients (84%) cardial reasons for cardiac arrest
were found. Marked activation of blood coagulation was found in
all patients. After prolonged cardiopulmonary resuscitation (ROSC
not within the first 30 min) patients showed significant elevated
serum D-dimer level compared with patients after ROSC in the first
30 minutes (663 µg/l vs 3,328 µg/ml, P < 0.0001; normal range
<0.25 µg/ml). The time period between cardiac arrest and ROSC
and plasma D-dimer level correlated significantly (r = 0.8, P < 0.01)
after CPR. Patients who died showed significant elevated serum
D-dimer level compared with the surviving patients (1,258 ± 1,587
µg/l vs 3,164 ± 1,974 µg/l, P = 0.026 median). The plasma D-
dimer level correlated significantly to the negative outcome in these
patients (r = 0.55, P < 0.01). Methods and results Forty-five patients were included from
1 January 2004 to 31 March 2005 after CPR in the case of
restoration of spontaneous circulation (ROSC). P324 Vasopressin, epinephrine, and methylprednisolone in
inhospital cardiac arrest S Mentzelopoulos, N Katsios, A Papastylianou, S Gisioti,
A Stathopoulos, E Stamataki, C Roussos, S Zakynthinos
Evaggelismos Hospital, Athens, Greece
Critical Care 2007, 11(Suppl 2):P324 (doi: 10.1186/cc5484) Introduction Combined vasopressin, epinephrine, and methyl-
prednisolone during cardiopulmonary resuscitation (CPR) may
improve survival in inhospital cardiac arrest. Introduction Combined vasopressin, epinephrine, and methyl-
prednisolone during cardiopulmonary resuscitation (CPR) may
improve survival in inhospital cardiac arrest. Conclusions Our data demonstrate a marked time-dependent
activation of blood coagulation and fibrin formation after prolonged
cardiac arrest and CPR in humans. These changes of the S131 Critical Care March 2007 Vol 11 Suppl 2
27th International Symposium on Intensive Care and Emergency Medicine groups; however, a striking increase was observed in patients wi
bad neurologic outcome peaking after 24 hours (16.7 ± 30.0 vs 6
± 2.1 µg/l; P < 0.013). PCT values after 24 hours were the be
predictor for a bad neurologic outcome with an area under th
curve of 0.91 (cutoff value: 0.44; sensitivity 100%/specificity 62%
Conclusion TNFα, IL-6 and IL-8 serum levels are significant
Figure 1 (abstract P324)
Figure 1 (abstract P325) Figure 1 (abstract P324) groups; however, a striking increase was observed in patients with
bad neurologic outcome peaking after 24 hours (16.7 ± 30.0 vs 6.9
± 2.1 µg/l; P < 0.013). PCT values after 24 hours were the best
predictor for a bad neurologic outcome with an area under the
curve of 0.91 (cutoff value: 0.44; sensitivity 100%/specificity 62%). Conclusion TNFα IL-6 and IL-8 serum levels are significantly
Figure 1 (abstract P324)
Figure 1 (abstract P325) Figure 1 (abstract P325) Figure 1 (abstract P325) Figure 1 (abstract P325) Figure 1 (abstract P324) groups; however, a striking increase was observed in patients with
bad neurologic outcome peaking after 24 hours (16.7 ± 30.0 vs 6.9
± 2.1 µg/l; P < 0.013). PCT values after 24 hours were the best
predictor for a bad neurologic outcome with an area under the
curve of 0.91 (cutoff value: 0.44; sensitivity 100%/specificity 62%). Conclusion TNFα, IL-6 and IL-8 serum levels are significantly
elevated in the early phase after successful CPR in patients with
bad neurological outcome. PCT increases are subsequently found
and have a high prognostic value for the neurologic outcome. P325 Introduction Mortality among patients surviving to be discharged
following inhospital cardiac arrest (IHCA) is high. The present
study assesses whether this might be explained by differences in
patient factor or in factors at resuscitation. P326 Do patient characteristics or factors at resuscitation
influence long-term outcome in patients surviving to be
discharged following inhospital cardiac arrest? influence long-term outcome in patients surviving to be
discharged following inhospital cardiac arrest? M Skrifvars1, M Castrén2, J Nurmi2, A Thorén3, S Aune3,
J Herlitz3
1Helsinki EMS and 2Department of Anaesthesiology and Intensive
Care Medicine, Helsinki University Hospital, Helsinki, Finland;
3Sahlgrenska Hospital, Gothenburg, Sweden
Critical Care 2007, 11(Suppl 2):P326 (doi: 10.1186/cc5486) Results Study group patients had higher rates of ROSC (37/44 vs
24/47; P < 0.01) and discharge either to home or to a
rehabilitation facility (7/44 vs 1/47; P < 0.05). Sixty-day survival
was improved in the study group (Figure 1). M Skrifvars1, M Castrén2, J Nurmi2, A Thorén3, S Aune3,
J Herlitz3 1Helsinki EMS and 2Department of Anaesthesiology and Intensive
Care Medicine, Helsinki University Hospital, Helsinki, Finland;
3Sahlgrenska Hospital, Gothenburg, Sweden
Critical Care 2007, 11(Suppl 2):P326 (doi: 10.1186/cc5486) Conclusions Combination treatment improves survival in inhospital
cardiac arrest. P324 Methods Ninety-one adults with cardiac arrest were randomized to
receive either vasopressin (20 IU/CPR cycle for five cycles) plus
epinephrine (1 mg/CPR cycle) plus methylprednisolone (single
dose = 40 mg) or placebo plus epinephrine (1 mg/CPR cycle) plus
placebo. Primary endpoints were return of spontaneous circulation
(ROSC) for ≥15 minutes, and survival to discharge either to home
or to a rehabilitation facility. Procalcitonin is a powerful predictor of outcome after
cardiopulmonary resuscitation C Stoppe, D Brücken, J Bickenbach, R Kuhlen, M Fries
University Hospital Aachen, Germany
Critical Care 2007, 11(Suppl 2):P325 (doi: 10.1186/cc5485) Methods An analysis of IHCA data collected from one Swedish
tertiary hospital and from five Finnish secondary hospitals over a
10-year period. The study was limited to patients surviving to be
discharged from the hospital. Multiple logistic regression analysis
was used to identify factors associated with survival at 1 year from
the arrest. Introduction We evaluated the time course and relationship of
proinflammatory cytokines and procalcitonin (PCT) serum levels
after cardiopulmonary resuscitation (CPR). We hypothesized that
an increase of cytokine levels would precede a marked increase in
PCT levels and that PCT would be the best predictor of the final
neurologic outcome. Results Of a total of 1,578 resuscitated patients, 441 (28%) survived
to hospital discharge and 359 (80%) were alive at 12 months. Factors associated with survival at 12 months were age (odds ratio
(OR) 0.96, 95% confidence interval (CI) 0.935–0.979), no renal
disease (OR 0.4, CI 0.2–0.9), good functional status at discharge
(OR 2.9, CI 1.4–6.0), and arrest occurring at (compared with arrests
at general wards) the emergency ward (OR 5.8, CI 1.8–18), cardiac
care unit (OR 2.9, CI 1.3–6.3), ICU (OR 2.6, CI 1.1–6.2), ward for
thoracic surgery (OR 12.9, CI 3.4–49.1) and unit for interventional
radiology (OR 16.4, CI 4.4–61.2). There was no difference in initial
rhythm, delay to defibrillation or delay to return of spontaneous
circulation between survivors and nonsurvivors at 12 months. Results Of a total of 1,578 resuscitated patients, 441 (28%) survived
to hospital discharge and 359 (80%) were alive at 12 months. Factors associated with survival at 12 months were age (odds ratio
(OR) 0.96, 95% confidence interval (CI) 0.935–0.979), no renal
disease (OR 0.4, CI 0.2–0.9), good functional status at discharge
(OR 2.9, CI 1.4–6.0), and arrest occurring at (compared with arrests
at general wards) the emergency ward (OR 5.8, CI 1.8–18), cardiac
care unit (OR 2.9, CI 1.3–6.3), ICU (OR 2.6, CI 1.1–6.2), ward for
thoracic surgery (OR 12.9, CI 3.4–49.1) and unit for interventional
radiology (OR 16.4, CI 4.4–61.2). There was no difference in initial
rhythm, delay to defibrillation or delay to return of spontaneous
circulation between survivors and nonsurvivors at 12 months. Conclusion Several patient factors, mainly age, functional status
and co-morbid disease, influence long-term survival following
IHCA. Out-of-hospital surface cooling with a cooling-blanket to
induce mild hypothermia in humans after cardiac arrest: a
feasibility trial Methods A 77-year-old male with a history of hypertension,
previous replacement of aortic valve and a right coronary artery
bypass was admitted to our ICU after cardiac arrest. He suffered a
collapse while walking. The emergency service arrived within
5 minutes. The initial cardiac rhythm was ventricular fibrillation. The
estimated time to return to spontaneous circulation was
20 minutes. The patient arrived in the hospital 50 minutes after
collapse and was immediately admitted to the ICU. Thirty minutes
after ICU admission, he was unconscious with a Glasgow coma
score of 5. Hypothermia was induced by the Artic Sun 2000
cooling system (Medivance, Louisville, CO, USA), and the goal
temperature was obtained 105 minutes after induction. The body
temperature was monitored continuously with a Foley catheter. Hypothermia was maintained for 24 hours at 33ºC and rewarming
to the target temperature of 37ºC was achieved over 12 hours. No
electrolyte imbalances or coagulopathies were observed. No
overcooling was observed at any moment. The patient was
extubated on day 6 after admission and discharged from the ICU
on day 10 without neurological sequelae. T Uray1, R Malzer2, A Auer2, A Zajicek2, F Sterz1, J Arrich1,
R Fleischhackl1, A Janata1, M Holzer1, A Laggner1, W Behringer1
1Medical University Vienna, Austria; 2Ambulance Service of Vienna,
Austria
Critical Care 2007, 11(Suppl 2):P327 (doi: 10.1186/cc5487) Introduction Mild hypothermia (32–34°C) is a promising new
therapy for patients resuscitated from cardiac arrest. Animal
studies suggest that early and fast cooling is crucial for beneficial
effect on neurological outcome. Inducing mild hypothermia
immediately after successful restoration of spontaneous circulation
(ROSC) in the out-of-hospital setting remains a challenge. Therefore, a novel cooling-blanket (EMCOOLSpad®), independent
of any energy source during use, was developed. The aim of the
study was to evaluate feasibility and safety of out-of-hospital
surface cooling with EMCOOLSpad® in patients successfully
resuscitated from cardiac arrest. Conclusions Careful monitoring of temperature is important during
use of therapeutic hypothermia because unintentional overcooling
below 32°C may place the patient at risk for serious complications
such as arrhythmias, infection, and coagulopathy. Cooling with a
water-circulating cooling device is fast and safe. Clinicians should
work to institute protocols for mild hypothermia treatment for such
patients as a part of their critical care treatment. Methods We included patients successfully resuscitated from out-
of-hospital cardiac arrest with an oesophageal temperature (Tes)
>34°C. References 1. Bernard SA, Gray TW, Buist MD, et al.: Treatment of
comatose survivors of out-of-hospital cardiac arrest with
induced hypothermia. N Engl J Med 2002; 346:557-563. 1. Bernard SA, Gray TW, Buist MD, et al.: Treatment of
comatose survivors of out-of-hospital cardiac arrest with
induced hypothermia. N Engl J Med 2002; 346:557-563. 2. 2005
International
Consensus
on
Cardiopulmonary
Resuscitation (CPR) and Emergency Cardiovascular Care
(ECC) Science with Treatment Recommendations. Circula-
tion 2005, 112 (Suppl):III-1-III-136. Results From September 2006 to December 2006, 10 patients,
weighing 70 (64–93) kg, were included in the study. Cooling was
initiated 14 (7–20) minutes after ROSC. The cooling-blanket
decreased the Tes from 36.5 (36.2–36.7)°C at the start of cooling
to 34.0°C within 61 (47–93) minutes, and to target temperature
Tes 33°C within 83 (61–119) minutes, resulting in a cooling rate of
2.6 (1.6–3.6)°C/hour. Hospital admission was 45 (40–53) minutes
after ROSC, and Tes 33°C was achieved 78 (32–107) minutes
after admission. In eight patients, precooled parts of the cooling-
blanket had to be applied repeatedly on the chest and abdomen to
maintain the target temperature of Tes 33°C for 24 hours. No skin
lesions were observed. 2. 2005
International
Consensus
on
Cardiopulmonary
Resuscitation (CPR) and Emergency Cardiovascular Care
(ECC) Science with Treatment Recommendations. Circula-
tion 2005, 112 (Suppl):III-1-III-136. Induction of mild hypothermia in cardiac arrest survivors
with cardiogenic shock syndrome Induction of mild hypothermia in cardiac arrest survivors
with cardiogenic shock syndrome R Skulec, J Belohlavek, V Dytrych, T Kovarnik, M Aschermann,
A Linhart Conclusion Noninvasive surface cooling with the EMCOOLSpad®
immediately after resuscitation from cardiac arrest, in the out-of-
hospital setting, was shown to be feasible and safe. Whether early
cooling, as compared with delayed cooling in the hospital, will
improve neurological outcome needs to be determined in a
prospective randomized trial. Introduction Induction of mild hypothermia (MH) in patients
resuscitated from cardiac arrest can improve their outcome. However, benefits and risks of MH induction in patients who
remain in cardiogenic shock after the return of spontaneous
circulation (ROSC) are unclear. We therefore analysed a group of
all cardiac arrest survivors who were indicated for MH induction in
our coronary care unit (CCU) and compared the outcome of
patients with cardiogenic shock syndrome after ROSC with the
outcome of those who were relatively haemodynamically stable. Methods We performed retrospective analysis of all consecutive
cardiac arrest survivors treated by MH in our CCU from November
2002 to August 2006. They were classified into two groups,
according to whether they met the criteria for cardiogenic shock or
not after ROSC and just before MH initiation. Primary outcome
measures were inhospital mortality, and the best inhospital and
discharge neurological result. Predicted mortality was evaluated by
the APACHE II score, and neurological outcome by Cerebral
Performance Category score. MH was initiated as soon as Introduction Induction of mild hypothermia (MH) in patients
resuscitated from cardiac arrest can improve their outcome. However, benefits and risks of MH induction in patients who
remain in cardiogenic shock after the return of spontaneous
circulation (ROSC) are unclear. We therefore analysed a group of
all cardiac arrest survivors who were indicated for MH induction in
our coronary care unit (CCU) and compared the outcome of
patients with cardiogenic shock syndrome after ROSC with the
outcome of those who were relatively haemodynamically stable. Procalcitonin is a powerful predictor of outcome after
cardiopulmonary resuscitation Location of the arrest also influences survival, but the initial
rhythm, the delays to defibrillation and return of spontaneous
circulation do not. Methods Data were prospectively collected from 71 patients. Blood samples were taken after admission to the hospital and after
6, 12, 24, 72 and 120 hours. PCT, IL-6, IL-8 and TNFα levels were
measured using automated assays. On day 14 patients were
divided into two neurologic outcome groups according to the
Cerebral Performance Categories (CPC 1–3: bad; CPC 4–5:
good). Differences between groups were evaluated using a t test. ROC curves were computed to analyze the predictive value of the
markers for a bad outcome. Results There was an early and significant increase in TNFα, IL-6
and IL-8 after admission to the hospital (14.4 ± 5.2, 185 ± 248
and 89 ± 81 µg/l) and in the ensuing 6 hours (15.6 ± 8.7,
209 ± 239 and 176 ± 232 µg/l) in patients with bad neurologic
outcome. Initially, PCT levels were indistinguishable between the Conclusion Several patient factors, mainly age, functional status
and co-morbid disease, influence long-term survival following
IHCA. Location of the arrest also influences survival, but the initial
rhythm, the delays to defibrillation and return of spontaneous
circulation do not. S132 Available online http://ccforum.com/supplements/11/S2 P327 Nowadays, the maintenance of hypothermia can be facilitated with
new technology to avoid unintentional overcooling. Nowadays, the maintenance of hypothermia can be facilitated with
new technology to avoid unintentional overcooling. Out-of-hospital surface cooling with a cooling-blanket to
induce mild hypothermia in humans after cardiac arrest: a
feasibility trial Out-of-hospital surface cooling with a cooling-blanket to
induce mild hypothermia in humans after cardiac arrest: a
feasibility trial The EMCOOLSpad® consists of multiple cooling units
(12 mm thick), filled with a mixture of graphite/water, which are
stored in a cooling box at –3°C in the ambulance car. Cooling was
initiated as soon as feasible by the first treating paramedics and
emergency physicians, and was continued in the emergency room. The cooling-blanket was removed when the Tes reached 34°C. The
target temperature of Tes 33°C was maintained for 24 hours. Data
are presented as the median and interquartile range (25–75%). P329 Induction of mild hypothermia in cardiac arrest survivors
with cardiogenic shock syndrome
R Skulec, J Belohlavek, V Dytrych, T Kovarnik, M Aschermann,
A Linhart
General Teaching Hospital, Prague, Czech Republic
Critical Care 2007, 11(Suppl 2):P329 (doi: 10.1186/cc5489) Reduction of magnetic resonance spectroscopy brain
temperature by convective head cooling in healthy humans Reduction of magnetic resonance spectroscopy brain
temperature by convective head cooling in healthy humans Results From 50 consecutive patients, 28 fulfilled criteria of
cardiogenic shock before MH initiation (group A), and 22 were
relatively hemodynamically stable (group B). While predicted
mortality was 83.1 ± 13.1% in group A and 63.2 ± 19.0% in group
B (P < 0.001), real inhospital mortality was 55.6% in group A and
only 18.2% in group B patients (P = 0.009). The best inhospital
neurological outcome was found favourable in 71.4% patients in
group A and in 86.3% in group B (P = 0.306). Favourable
discharge neurological outcome was reached in 100% in group A
and in 94% in group B (P = 1.000). Patients in both groups did
not differ in rate of complications. B Harris1, P Andrews1, I Marshall1, T Robinson2, G Murray1
1University of Edinburgh, UK; 2KCI, Ferndown, UK
Critical Care 2007, 11(Suppl 2):P331 (doi: 10.1186/cc5491) This pilot study assessed the effect of forced convective head and
neck cooling on brain temperature, measured by magnetic resonance
spectroscopy (MRS), in five healthy adult humans (three males). Following a 10-minute baseline, subjects received 30 minutes
head cooling followed by 30 minutes head and neck cooling. The
cooling device delivered air at 11ºC and 15 m/s through a hood
and separate neck collar made of a double layer of nylon sheeting,
the inner layer pierced with holes. Subjects wore a windproof
waistcoat taped round the base of their neck and were wrapped in
blankets from the base of the neck down. Bilateral foot warming
with chemical hot packs was used to encourage heat loss in the
presence of normothermia. Conclusions While inhospital mortality in cardiac arrest survivors
treated by MH was expectably higher in those with cardiogenic
shock than in stable patients, favourable neurological outcome was
frequent and comparable in both groups of patients. Moreover, MH
application was safe in both groups. Therefore, induction of MH
should be considered also in cardiac arrest survivors with
cardiogenic shock syndrome after ROSC. MRS temperature data were collected at the level of the basal
ganglia over the baseline and the last 10 minutes of each cooling
intervention. MRS detects naturally occurring brain metabolites
and interpretation of the relative frequencies of N-acetyl aspartate
and water allows estimation of tissue temperature in 1 cm3 voxels. Reduction of magnetic resonance spectroscopy brain
temperature by convective head cooling in healthy humans For assessment of regional cooling, voxels lying within the region
formed by joining the tips of the lateral ventricles were defined as
‘core’, voxels within approximately one voxel of the brain surface
were defined as ‘outer’, and all other voxels were defined as
‘intermediate’. The oesophageal temperature was measured
continuously with a fluoroptic thermometer. P330 P330 Changes in urinary 8-hydroxy-2-deoxyguanosine in
patients with global brain ischemia undergoing brain
hypothermia therapy: comparison of whole body and
selective head cooling
K Ikeda, Y Kuroki, K Yosikawa, T Yokoyama, H Utino
Hachiouji Medical Center, Tokyo, Japan
Critical Care 2007, 11(Suppl 2):P330 (doi: 10.1186/cc5490) Changes in urinary 8-hydroxy-2-deoxyguanosine in
patients with global brain ischemia undergoing brain
hypothermia therapy: comparison of whole body and
selective head cooling Changes in urinary 8-hydroxy-2-deoxyguanosine in
patients with global brain ischemia undergoing brain
hypothermia therapy: comparison of whole body and
selective head cooling K Ikeda, Y Kuroki, K Yosikawa, T Yokoyama, H Utino
Hachiouji Medical Center, Tokyo, Japan
Critical Care 2007, 11(Suppl 2):P330 (doi: 10.1186/cc5490) The mean baseline-corrected MRS brain temperature over all
voxels reduced by –0.45ºC (SD 0.23ºC, P = 0.01, 5% CI –0.74 to
–0.17ºC) with head cooling and –0.37ºC (SD 0.30ºC, P = 0.049,
95% CI –0.74 to 0.00ºC) with head and neck cooling. Head
cooling reduced the mean baseline-corrected MRS brain
temperature in core voxels in all subjects. The formal test for
gradient was not significant (P = 0.43; 95% CI –0.15 to 0.29ºC). Head and neck cooling reduced the temperature in core voxels in
three subjects; the test for gradient was not significant (P = 0.07;
95% CI –0.03 to 0.58ºC). The mean baseline-corrected
oesophageal temperature reductions for the last 10 minutes of
each intervention were –0.16ºC (SD 0.04ºC) with head cooling
and –0.36ºC (SD 0.12ºC) with head and neck cooling. Introduction Oxygen free radicals play an important role in global
brain ischemia after cardiac arrest. Brain hypothermia therapy is
effective in suppressing free radical expression. The aim of this
study was to assess free radical expression under brain
hypothermia, and to compare the expression between whole body
and selective head cooling. Methods The subjects were 12 patients treated with mild brain
hypothermia (34 ± 1°C) after resuscitation following cardiac arrest
in our ICU; five patients received whole body cooling and seven
patients received selective head cooling. We examined the
hemodynamic changes and the urinary concentration of 8-hydroxy-
2-deoxyguanosine (determined by HPLC) during brain hypothermia
therapy. Furthermore, we compared the prognosis at 28 days after
admission to the ICU. Forced convective head cooling reduced the MRS brain
temperature at an equivalent of 1.35ºC per hour in healthy
subjects, and the reduction was apparent across the brain. P332 Results
The induction time for whole body cooling was
significantly shorter than that for selective head cooling. The
rewarming time for head cooling was significantly shorter than that
for whole body cooling. The mean arterial pressure and heart rate
were both stable in the head cooling group. The urinary 8-hydroxy-
2-deoxyguanosine concentrations decreased significantly in both
groups, but data were significantly lower in the whole body cooling
group compared with the selective head cooling group. Five and
seven patients, respectively, exhibited good recovery 28 days after
admission, in the whole body and selective head cooling groups. Conclusions Mild brain hypothermia therapy suppressed the
production of free radicals following global brain ischemia. Whole
body cooling had a stronger effect of suppression of free radicals
compare with selective head cooling. It is considered that selective
head cooling exhibits neuroprotection similar to whole body
cooling. Results
The induction time for whole body cooling was
significantly shorter than that for selective head cooling. The
rewarming time for head cooling was significantly shorter than that
for whole body cooling. The mean arterial pressure and heart rate
were both stable in the head cooling group. The urinary 8-hydroxy-
2-deoxyguanosine concentrations decreased significantly in both
groups, but data were significantly lower in the whole body cooling
group compared with the selective head cooling group. Five and
seven patients, respectively, exhibited good recovery 28 days after
admission, in the whole body and selective head cooling groups. Induction of therapeutic mild hypothermia after cardiac
arrest: a new combined method to achieve the target
temperature H Busch, T Schwab, K Fink, C Bode
UKL Freiburg, Germany
Critical Care 2007, 11(Suppl 2):P332 (doi: 10.1186/cc5492) H Busch, T Schwab, K Fink, C Bode
UKL Freiburg, Germany
Critical Care 2007, 11(Suppl 2):P332 (doi: 10.1186/cc5492) Background Clinical and experimental investigations have demon-
strated that induction of mild hypothermia works after successful
cardiopulmonal resuscitation (CPR) neuroprotection. After the
presentation of controlled studies, therapeutic hypothermia moved
into the topical international guidelines. Conclusions Mild brain hypothermia therapy suppressed the
production of free radicals following global brain ischemia. Whole
body cooling had a stronger effect of suppression of free radicals
compare with selective head cooling. It is considered that selective
head cooling exhibits neuroprotection similar to whole body
cooling. Methods and results A total of 50 patients were examined after
successful CPR. Twenty-nine patients received 4°C cold infusions
after arrival in the heart catheter laboratory. P328 Mild hypothermia induction following cardiac arrest using a
water-circulating cooling device water-circulating cooling device
E Miñambres, B Suberviola, A González-Castro, J San Jose,
J Gutierrez Morlote
Hospital Universitario Marques de Valdecilla, Santander, Spain
Critical Care 2007, 11(Suppl 2):P328 (doi: 10.1186/cc5488) Methods We performed retrospective analysis of all consecutive
cardiac arrest survivors treated by MH in our CCU from November
2002 to August 2006. They were classified into two groups,
according to whether they met the criteria for cardiogenic shock or
not after ROSC and just before MH initiation. Primary outcome
measures were inhospital mortality, and the best inhospital and
discharge neurological result. Predicted mortality was evaluated by
the APACHE II score, and neurological outcome by Cerebral
Performance Category score. MH was initiated as soon as Introduction The use of mild hypothermia for comatose survivors
of cardiac arrest has been endorsed by the American Heart
Association and the International Liaison Committee on Resusci-
tation [1,2]. Unintentional overcooling is common with some
techniques such as cool intravascular fluid or the use of ice packs. S133 Critical Care March 2007 Vol 11 Suppl 2
27th International Symposium on Intensive Care and Emergency Medicin P331 P331 possible after ROSC and patients were cooled to body
temperature 32–34ºC for 12 hours. Reduction of magnetic resonance spectroscopy brain
temperature by convective head cooling in healthy humans
B Harris1, P Andrews1, I Marshall1, T Robinson2, G Murray1
1University of Edinburgh, UK; 2KCI, Ferndown, UK
Critical Care 2007, 11(Suppl 2):P331 (doi: 10.1186/cc5491) P334 21 patients who had received a volume substitute by means of
drips from ambient temperature served as a control group. After
admission to the ICU, both groups were immediately connected to
an external cooling device (CoolGard® or Thermo Wrap®) and were
cooled to a target temperature of 33°C (bladder temperature). P332 Retrospective data of S134 Available online http://ccforum.com/supplements/11/S2 Buspirone and dexmedetomidine synergistically reduce
the shivering threshold in humans R Lenhardt, R Komatsu, M Orhan-Sungur
University of Louisville, KY, USA
Critical Care 2007, 11(Suppl 2):P334 (doi: 10.1186/cc5494) Results The average temperature at admission did not differ in
both groups (35.5 ± 0.9°C vs 35.89 ± 0.8°C). In the group with
initial cooling by means of 4°C cold infusions, a significant
temperature decrease could be reached during the invasive
coronary diagnostics to admission to the ICU of an average 0.84°C
(35.88 ± 0.9°C vs 35.04 ± 0.9°C, P < 0.0001). The middle chill
duration up to the achievement of the target temperature after
admission was significantly shorter with the combined method
(341 ± 113 min versus 553 ± 342 min, P < 0.01). The period to
the achievement of the target temperature after the beginning of
the external cooling device with the group of the combined method
was significantly shorter (163 ± 91 min versus 342 ± 258 min,
P < 0.01). Introduction Hypothermia may be therapeutically beneficial in
stroke victims; however, it provokes vigorous shivering. Buspirone,
a partial serotonin 1A antagonist, and dexmedetomidine, an α2
agonist, linearly reduce the shivering threshold (triggering core
temperature) with minimal sedation and respiratory depression. We
tested the hypothesis that buspirone and dexmedetomidine
synergistically reduce the shivering threshold without producing
substantial sedation or respiratory depression. Methods We studied four healthy male volunteers (18–40) on
4 days: (1) control (no drug); (2) buspirone only (60 mg orally); (3)
dexmedetomidine only (target plasma concentration 0.6 ng/ml);
and (4) combined buspirone and dexmedetomidine in the same
doses. Lactated Ringer’s solution (3°C) was infused via a central
venous catheter to decrease tympanic membrane temperature by
≈2.2°C/hour; the mean skin temperature was maintained at 31°C. An increase in oxygen consumption more than 25% of baseline
identified the shivering threshold. Sedation was evaluated using
the Observer’s Assessment Sedation/Alertness scale. Two-way
repeated-measures analysis of variance was used to identify
interactions between drugs. Data are presented as means ± SDs;
P < 0.05 was statistically significant. Conclusions The combined method with initial cooling with 4°C
cold solutions shows a sure and actual prestationary cooling
procedure to the introduction or realisation of mild hypothermia and
offers the possibility to reach the purpose temperature significantly
faster. Preclinical introduction of mild hypothermia by means of 4°C
cold solutions could be a beneficial criteria in the future treatment,
and probably affects the outcome of these patients. P333 A comparison of complications during therapeutic
hypothermia between surface cooling and endovascular
cooling techniques
P Hayden, A Salam, R Beale, M Gillies
Guy’s & St Thomas’ NHS Foundation Trust, London, UK
Critical Care 2007, 11(Suppl 2):P333 (doi: 10.1186/cc5493) A comparison of complications during therapeutic
hypothermia between surface cooling and endovascular
cooling techniques A comparison of complications during therapeutic
hypothermia between surface cooling and endovascular
cooling techniques Results The shivering thresholds were 36.4 ± 0.5°C on the control
day; 34.9 ± 0.6°C (P < 0.01 from control) on the buspirone only
day; 36.1 ± 0.6°C (P < 0.01 from control) on the dexmedeto-
midine only day; and 34.2 ± 0.5°C (P < 0.01 from control) on the
combined buspirone and dexmedetomidine day. The calculated
mean difference between the thresholds on the combined and the
control days was 1.9 ± 0.4°C, while the measured mean difference
derived from the difference between the combined and control
days was 2.3 ± 0.4°C. There was only trivial sedation with either
drug alone or in combination. The respiratory rate and end-tidal
PCO2 were well preserved on all days. P Hayden, A Salam, R Beale, M Gillies
Guy’s & St Thomas’ NHS Foundation Trust, London, UK
Critical Care 2007, 11(Suppl 2):P333 (doi: 10.1186/cc5493) Introduction Therapeutic hypothermia (TH) following cardiac
arrest is associated with several complications including sympto-
matic bradycardia, coagulopathy, and pneumonia [1]. Furthermore,
hyperthermia is associated with poor outcome following brain
injury. The incidence of these complications may be increased by
excessive temperature fluctuations. We sought to compare
complications between two techniques used to induce TH; surface
cooling (SC) using ice packs, and endovascular cooling (EV),
using the Coolgard™ system (Alsius Corp., USA). Conclusion Buspirone and dexmedetomidine act synergistically to
reduce the shivering threshold with only mild sedation and no
respiratory depression. This combination might be a valid treatment
to prevent shivering in stroke patients during therapeutic
hypothermia. Methods A retrospective review was performed of all cardiac
arrest patients undergoing TH and surviving ≥48 hours between
June 2005 and November 2006. P335 Results Thirty-five patients underwent our TH protocol (SC group =
21, EV group = 14). The incidence of overcooling (<32°C) in the
SC group was significantly higher than the EV group (10 vs 1,
P = 0.01), whilst a trend towards more episodes of symptomatic
bradycardia (SC 9 vs EV 2, P = 0.07) and rebound hyperthermia
(SC 9 vs EV 2, P = 0.07) was also present. The incidence of
pneumonia (SC 7 vs EV 4, P = 0.77) and coagulopathy/bleeding
(SC 2 vs EV 3, P = 0.32) were similar between groups. Bispectral index and suppression ratio are very early
predictors of neurological outcome during therapeutic
hypothermia after cardiac arrest
D Seder, R Riker, G Fraser, H Bruce, T Robbins
Maine Medical Center, Portland, ME, USA
Critical Care 2007, 11(Suppl 2):P335 (doi: 10.1186/cc5495) Bispectral index and suppression ratio are very early
predictors of neurological outcome during therapeutic
hypothermia after cardiac arrest ,
,
,
Critical Care 2007, 11(Suppl 2):P335 (doi: 10.1186/cc Introduction The bispectral index (BIS) is calculated from fronto-
temporal electroencephalogram (EEG), and the suppression ratio
(SR) estimates the percentage of EEG suppression. We monitored
the BIS and SR during therapeutic hypothermia (TH) and
compared them with neurological outcomes of encephalopathic
survivors of out-of-hospital cardiac arrest (OHCA). Conclusions (1) SC is associated with a significantly higher
incidence of overcooling than EC and may be associated with an
increase in complications such as symptomatic bradycardia. (2)
SC may also be associated with an increase in rebound
hyperthermia. yp
Reference y
Reference 1. Polderman KH: Application of therapeutic hypothermia in
the intensive care unit. Opportunities and pitfalls of a
promising treatment modality – Part 2: practical aspects
and side effects. Intensive Care Med 2004, 30:757-769. Methods Thirty-two patients with anoxic encephalopathy after
OHCA received 18 hours of TH at 32–34°C. BIS monitoring was
initiated at the onset of TH, and neuromuscular blockade (NMB)
was dosed in response to shivering. Blinded BIS and SR data 1. Polderman KH: Application of therapeutic hypothermia in
the intensive care unit. Opportunities and pitfalls of a
promising treatment modality – Part 2: practical aspects
and side effects. Intensive Care Med 2004, 30:757-769. S135 Critical Care March 2007 Vol 11 Suppl 2
27th International Symposium on Intensive Care and Emergency Medicin have hypoxic ischaemic encephalopathy (n = 15); adding/
escalating or stopping antiseizure drugs based on the presence/
absence of seizure activity (n = 12); and continuing supportive
care in comatose patients diagnosed to have metabolic encephalo-
pathy/prolonged sedation effect as the cause for coma (n = 8). Based on these results it can be concluded that, despite limitations
such as motion artifacts and influence of sedation on electrical
signals, EEG impacts on clinical decision-making processes in
critical care. Hence it is beneficial, and more widespread use
would improve its diagnostic potential. were recorded after the first dose of NMB, and compared with the
Cerebral Performance Category (CPC) at discharge and 6 months. CPC 1 or CPC 2 was considered a good outcome (GO). have hypoxic ischaemic encephalopathy (n = 15); adding/
escalating or stopping antiseizure drugs based on the presence/
absence of seizure activity (n = 12); and continuing supportive
care in comatose patients diagnosed to have metabolic encephalo-
pathy/prolonged sedation effect as the cause for coma (n = 8). Results Fourteen out of 32 patients (44%) survived, 11 (34%)
with GO. Five of the remaining 18 patients died before neuro-
logical evaluation at 72 hours, and one patient recovered
neurological function but died of cardiogenic shock. No survivor
recalled the period of NMB. First NMB was administered a median
of 5 hours after cardiac arrest or 87 minutes after initiation of TH,
at 35.6 ± 1.7°C. Patients with GO had a higher first post-NMB BIS
(39 ± 6 vs 13 ± 14, P < 0.001) and a lower SR (10 ± 12 vs
69 ± 29, P < 0.001) than those with CPC 3–5. yp
Reference Initial NMB
reduced frontotemporal electromyogram (EMG) power from
52 ± 8 to 27 ± 1 db, P < 0.001. In 17 of the patients with
downloaded EEG data, an increase in EMG power of 17 dB (IQR
10–27) from baseline was associated with clinically detectable
shivering. Epileptiform discharges were noted on the monitor
during NMB in two patients, and seizure activity was confirmed by
formal EEG in both. Based on these results it can be concluded that, despite limitations
such as motion artifacts and influence of sedation on electrical
signals, EEG impacts on clinical decision-making processes in
critical care. Hence it is beneficial, and more widespread use
would improve its diagnostic potential. References 1. Hirsch LJ, Kull LL:Am J Electroneurodiagnostic Technol
2004, 44:137-158. 2. Newton DEF: Electrophysiological monitoring of general
intensive care patients. Intensive Care Med 1999, 25:350-
352. P337
Abstract withdrawn P337 Abstract withdrawn Conclusions In cardiac arrest survivors receiving TH, a higher
post-NMB BIS score and a lower SR are very early predictors of
neurological outcome. The potential benefits of monitoring BIS and
SR, as well as EMG power for early recognition of shivering, and
continuous frontotemporal EEG to detect seizures, warrant further
study. Aneurysmal subarachnoid hemorrhage induces the
expression of Pentraxin3 in patients G Brandi1, E Roncati Zanier1, L Longhi1, G Peri2, G De Simon3,
M Tettamanti3, A Mantovani2, N Stocchetti1
1Milan University, Ospedale Maggiore Policlinico IRCCS, Milan,
Italy; 2Clinical Institute Humanitas, Milan, Italy; 3Mario Negri
Institute, Milan, Italy
Critical Care 2007, 11(Suppl 2):P338 (doi: 10.1186/cc5498) Introduction Aneurismal subarachnoid hemorrhage (SAH) is an
extremely severe illness associated with a high mortality rate and
permanent severe neurological dysfunction in two-thirds of all
affected patients. One of the major complications of SAH is
vasospasm-associated cerebral ischemia. Clinical and experi-
mental data suggest that vasospasm is linked to the inflammatory
response associated with SAH. The goal of this study was to
investigate the expression of Pentraxin3 (PTX3), a prototypic long
pentraxin protein induced by proinflammatory signals in the brain,
in SAH patients to test the hypothesis that SAH is followed by an
upregulation of PTX3, and establish a temporal relationship
between the expression of PTX3 and the induction of vasospasm. We also attempted to establish that PTX3 is detectable in cerebro-
spinal fluid (CSF). q
Results From the 102 patients (56 men and 48 women) 38
(37.5%) died within the first 30 days, most of them in the first
10 days. Age (OR 13.801, P < 0.04), APACHE II score (OR
1.114, P < 0.008), GCS (OR 2.158, P < 0.002), ICH score (OR
1.183, P < 0.001), FiO2/pO2 (OR 0.996, P < 0.009), haemodynamic
instability (OR 2.340, P < 0.002), fever (OR 1.245, P < 0.002),
and INR (OR 13.801, P < 0.04) were the strongest associated
factors of 30-day mortality. Gender (OR 0.652, P < 0.301), prior
illness (OR 1.070, P < 0.870), MODS (OR 0.978, P < 0.803),
LOS (OR 0.988, P < 0.266), MV (OR 0.994, P < 0.356) and TT
(OR 0.990 P < 0.371) were not associated with mortality. Patients
who where operated on had higher mortality but were also more
severely ill. Methods We studied eight severe SAH patients admitted to our
neuroscience ICU with a median World Federation Neurosurgical
Score of 4 and a Fisher score of 4. Arterial, jugular venous blood
and CSF samples were routinely obtained every 12 hours for
7 days. PTX3 levels were measured by ELISA in plasma and CSF
samples. Conclusion Age, severity of illness, ICH score, hypoxemia,
haemodynamic instability, and increased temperature are directly
related with the outcome of patients with SICH. Gender, LOS, MV,
TT, and MODS did not influence mortality. Maintenance of prehospital medical systems due to clinical
advance in acute stroke K Ishii1, Y Wakabayashi1, Y Momii2, T Asano2, H Kenai2,
M Yamashita2, M Mori2, Y Hori2, H Nagatomi2
1Oita University School of Medicine, Oita, Japan; 2Nagatomi
Neurosurgical Hospital, Oita, Japan
Critical Care 2007, 11(Suppl 2):P340 (doi: 10.1186/cc5500) Introduction Recently, the medical treatment in acute stroke has
been making rapid progress. Especially, in the ischemic stroke of
acute stage, the efficacy of thrombolysis, systemic t-PA or local
transarterial urokinase infusion has been proved. However, the
effective treatment time is still quite limited. The patients must be
brought to the stroke center as soon as possible. We analyzed the
reason why most stroke patients delay coming to the stroke center. We extracted the problems and proposed some solutions. Conclusions SAH is characterized by the production of PTX3 and
the induction of vasospasm is associated with an upregulation of
PTX3 in the CSF that is not detectable in plasma. Reference 1. Muller et al.: Crit Care Med 2001, 29:1404-1407. 1. Muller et al.: Crit Care Med 2001, 29:1404-1407. Patients and methods The clinical subjects consisted of 1,112
consecutive patients with ischemic stroke in the acute stage,
hospitalized in our hospital between April 2003 and September
2006. We investigated the clinical course, especially the time from
the onset to the physical examination, and radiological exami-
nations (CT, MRI, MRA and/or cerebral angiography). The mean
age was 72.3 years. Among them, 334 patients were classified as
atherothrombosis, 232 were cardiac embolism, 439 were lacunar
infarction and 107 were transient ischemic attack. Only 19 patients
underwent acute thrombolytic therapy. Aneurysmal subarachnoid hemorrhage induces the
expression of Pentraxin3 in patients Results
Compared with plasma levels of PTX3 in normal
volunteers (<2 ng/ml [1]), SAH induced a marked increase in
plasma PTX3 expression. During the first 48 hours following SAH
(acute phase), PTX3 arterial and jugular venous levels increased to
36.93 ± 24.32 ng/ml and 33.64 ± 28.76 ng/ml, respectively, and
then subsequently decreased concomitantly with the reduction of
the inflammation (48–96 hours: subacute phase). PTX3 is
detectable in the CSF: mean CSF levels of PTX3 were
4.07 ± 3.64 ng/ml during the acute phase and 0.69 ± 0.44 ng/ml
during the subacute phase (t test: P < 0.05 compared with the
acute phase). In the presence of vasospasm (four patients), we
detected a second peak of PTX3 (4.03 ± 2.85 ng/ml) in CSF
samples (t test: P < 0.05 compared with the subacute phase) that
was not detectable in plasma. P338 Patients
who where operated on had higher mortality but were also more
severely ill. M Sartzi, A Papaeveggelou, A Stogiannidi, P Kouki,
B Romanou, E Panagiotakopoulou, G Kallitsi, K Mihas,
F Tsidemiadou, P Clouva-Molyvda
General Hospital of Eleusis, Athens, Greece
Critical Care 2007, 11(Suppl 2):P339 (doi: 10.1186/cc5499) P336 Role of bedside electroencephalogram in intensive care:
a critical review
R Jayaram Ramachandran, C Hargreaves, S Sinha
Whittington Hospital NHS Trust, London, UK
Critical Care 2007, 11(Suppl 2):P336 (doi: 10.1186/cc5496) Role of bedside electroencephalogram in intensive care:
a critical review Role of bedside electroencephalogram in intensive care:
a critical review R Jayaram Ramachandran, C Hargreaves, S Sinha
Whittington Hospital NHS Trust, London, UK
Critical Care 2007, 11(Suppl 2):P336 (doi: 10.1186/cc5496) Electroencephalogram (EEG) is an appropriate monitoring tool in
intensive care because it is linked to cerebral metabolism, is
sensitive to ischaemia/hypoxia, can detect neuronal dysfunction at
a reversible stage and is the best method to detect seizure activity. Scientific data have proved utility of continuous EEG monitoring in
intensive care [1,2]. But there is a paucity of data relating to single
recordings of EEG especially in general ICUs. A retrospective chart review of patients who had bedside EEG in a
medical–surgical ICU was done. Data were collected with a focus
on: indication for requesting EEG, technical difficulties during the
study, the report and its influence on subsequent clinical manage-
ment. Forty-two charts were reviewed. The indications were: evaluation
of persistent comatose state (n = 27), to diagnose/exclude seizure
activity and nonconvulsive status epilepsy (n = 12), and as an
adjunct to support clinical diagnosis of suspected brain death prior
to formal testing (n = 3). Movement artifacts led to technical
difficulty in four studies. EEG confirmed: moderate to severe nonspecific brain dysfunction
as the cause for persistent comatose state by the presence of
either diffuse slowing with theta/delta activity, absence of cerebral
activity, continuous rhythmic and semi rhythmic lateralized/bilateral
epileptiform discharges, burst suppression pattern or continuous
bilateral slow U-shaped waves; anoxic brain damage by absence of
changes in electrical signals following external application of
noxious stimuli; and seizure activity by epileptiform discharges. Twelve reports stated that use of sedation interfered with EEG
interpretation. The following clinical decisions were made based on the EEG
report in conjunction with clinical findings: initiating withdrawal of
life support or ‘do-not-resuscitate orders’ in patients diagnosed to S136 Available online http://ccforum.com/supplements/11/S2 P338 Methods Retrospective analysis of prospectively gathered data of
102 patients with SICH treated in our ICU during the past 8 years. On admission the following data were registered: vascular risk
factors (high blood pressure, diabetes mellitus), age, gender,
APACHE II score, GCS, hemorrhage characteristics (location, side,
volume, mass effect), surgical procedure, MODS, blood pressure
(systolic, diastolic, mean), pulse pressure, pulse rate, laboratory
parameters (hemoglobin, white cell and platelet count, INR, serum
values for Na, glucose, lactate, creatinin, bilirubin). Also registered
were length of stay (LOS), duration of mechanical ventilation (MV),
time of intubation (TT) and patient outcome. Haemodynamic
instability was defined as low mean blood pressure and support with
vasoactive and inotrop drugs. Statistical evaluation was performed
using univariate and multivariate logistic regression, Student’s t test
Pearson’s chi-square test and Fisher’s exact statistic were used. Methods Retrospective analysis of prospectively gathered data of
102 patients with SICH treated in our ICU during the past 8 years. On admission the following data were registered: vascular risk
factors (high blood pressure, diabetes mellitus), age, gender,
APACHE II score, GCS, hemorrhage characteristics (location, side,
volume, mass effect), surgical procedure, MODS, blood pressure
(systolic, diastolic, mean), pulse pressure, pulse rate, laboratory
parameters (hemoglobin, white cell and platelet count, INR, serum
values for Na, glucose, lactate, creatinin, bilirubin). Also registered
were length of stay (LOS), duration of mechanical ventilation (MV),
time of intubation (TT) and patient outcome. Haemodynamic
instability was defined as low mean blood pressure and support with
vasoactive and inotrop drugs. Statistical evaluation was performed
using univariate and multivariate logistic regression, Student’s t test
Pearson’s chi-square test and Fisher’s exact statistic were used. Results From the 102 patients (56 men and 48 women) 38
(37.5%) died within the first 30 days, most of them in the first
10 days. Age (OR 13.801, P < 0.04), APACHE II score (OR
1.114, P < 0.008), GCS (OR 2.158, P < 0.002), ICH score (OR
1.183, P < 0.001), FiO2/pO2 (OR 0.996, P < 0.009), haemodynamic
instability (OR 2.340, P < 0.002), fever (OR 1.245, P < 0.002),
and INR (OR 13.801, P < 0.04) were the strongest associated
factors of 30-day mortality. Gender (OR 0.652, P < 0.301), prior
illness (OR 1.070, P < 0.870), MODS (OR 0.978, P < 0.803),
LOS (OR 0.988, P < 0.266), MV (OR 0.994, P < 0.356) and TT
(OR 0.990 P < 0.371) were not associated with mortality. P340 Maintenance of prehospital medical systems due to clinical
advance in acute stroke General Hospital of Eleusis, Athens, Greece Introduction We evaluated the factors that may influence the
outcome of patients with spontaneous intracerebral hemorrhage
(SICH). Critical Care 2007, 11(Suppl 2):P339 (doi: 10.118 P341 Effects of intraaortic balloon counterpulsation on middle
cerebral artery blood flow velocities
A Vakalos, D Setzis, P Doukelis, S Pampori, D Matamis
Papageorgiou General Hospital, Thessaloniki, Greece
Critical Care 2007, 11(Suppl 2):P341 (doi: 10.1186/cc5501) Gram-negative bacteremia is an independent predisposing
factor for critical illness polyneuromyopathy Gram-negative bacteremia is an independent predisposing
factor for critical illness polyneuromyopathy K Kritikos, E Angelopoulos, A Siafaka, M Kontogeorgi,
S Tsikriki, D Kanaloupiti, M Pratikaki, M Poriazi, V Gerovasili,
C Routsi, C Roussos, S Nanas
Medical School, National and Kapodistrian University,
Evangelismos Hospital, Athens, Greece
Critical Care 2007, 11(Suppl 2):P343 (doi: 10.1186/cc5503) Table 1 (abstract P341)
WS vs 1:1
WS vs 1:2
WS vs 1:3
Vmax
P > 0.05
P < 0.01
P < 0.01
Vmean
P > 0.05
P < 0.001
P < 0.001 Introduction Critical illness polyneuromyopathy (CIPM) is a major
clinical problem in the ICU resulting in prolonged ICU stay and
increased morbidity and mortality. Conclusions Left ventricular support with IABP significantly
changed the flow velocity pattern of our patients. The pump
significantly increased the Vmax and the Vmean at the 1:2 and 1:3
settings because of pump inflation during the diastole. We suggest
that the velocities did not change at the 1:1 setting because the
end-diastolic flow velocities reduce during every pulse, according
to pump deflation. Objective To investigate risk factors of CIPM involved, in a general
multidisciplinary ICU. Patients and participants Four hundred and seventy-four (323
males/151 females, age 55 ± 19) consecutively admitted patients
in a 28-bed university multidisciplinary ICU were prospectively
evaluated. All patients were assigned admission APACHE II
(15 ± 7) and SOFA (6 ± 3) scores and were subsequently
evaluated for newly developed neuromuscular weakness. We
examined muscle strength according to the Medical Research
Council scale, deep tendon reflexes, sensory function and muscle
wasting. Laboratory values and medical therapy were recorded
daily. Other potential causes of new-onset generalized weakness
after ICU admission were excluded before the diagnosis of CIPM
was established. Out of the 474 patients, 185 remained in the ICU
for ≥10 days. Effects of intraaortic balloon counterpulsation on middle
cerebral artery blood flow velocities Results In 1,421 ICU patients who were evaluated in 24 studies,
655 (46%) were diagnosed with CINMA. All enrolled patients were
receiving protracted mechanical ventilation, had sepsis, or had
multiple organ failure. Diagnostic criteria for CINMA were hetero-
geneous and few reports explicitly differentiated between the
polyneuropathic, myopathic and mixed types of CINMA. CINMA
was linked in several studies to hyperglycemia, the systemic inflam-
matory response syndrome, sepsis, renal replacement therapy, and
catecholamine administration. In contrast, across studies there was
no consistent relationship between CINMA and patient age,
gender, severity of illness, multiple organ failure, and use of gluco-
corticoids, neuromuscular blockers, aminoglycosides, or midazolam. Mortality was not increased in patients with CINMA, but
mechanical ventilation and ICU and hospital stays were prolonged. Conclusions The risk of CINMA is nearly 50% in a subset of ICU
patients with sepsis, multiorgan failure, or protracted mechanical
ventilation, but there were no data to support CINMA as an
independent predictor of death. The impact of frequently cited risk
factors is uncertain, but emerging data indicate glycemic control
decreases CINMA risk in vulnerable patients. A Vakalos, D Setzis, P Doukelis, S Pampori, D Matamis
Papageorgiou General Hospital, Thessaloniki, Greece
Critical Care 2007, 11(Suppl 2):P341 (doi: 10.1186/cc5501) Introduction The intraaortic balloon pump has been shown to
improve cardiac output and diastolic coronary flow. The aim of our
study was to determine the effects of intraaortic counterpulsation
(IABP) on cerebral blood flow velocities measured on the middle
cerebral artery. Methods
In 11 cardiac surgery patients receiving IABP
postoperatively, blood flow velocities in the middle cerebral artery
were assessed by transcranial Doppler (TCD). In each patient,
measurements of Vmax, Vmean and Vmin were performed at four
different pump settings: without support (WS), and at pump assist
pulse with ratio 1:1, 1:2 and 1:3. p
Results Repeated-measures analysis of variance: P = 0.0006,
considered extremely significant variation of TCD measurements
among IABP settings. Comparing all pairs of Vmax, Vmean and Vmin
values, we found that Vmax and especially Vmean are significantly
greater at the 1:2 and 1:3 pump settings, but not at the 1:1 setting. We also found that the end diastolic velocities (Vmin) were
significant lower during the pump deflation. None of our patients
had a significant diastolic flow velocity reversal during the pump
deflation. Outcome of intensive care unit patients with spontaneous
intracerebral hemorrhage Outcome of intensive care unit patients with spontaneous
intracerebral hemorrhage Results Two hundred and forty-one patients (21.7%) were
hospitalized within 3 hours from the onset, and 365 patients
(32.9%) were within 6 hours. Among them, only 438 were admitted
by ambulance. We found the following results. The main reason for Introduction We evaluated the factors that may influence the
outcome of patients with spontaneous intracerebral hemorrhage
(SICH). S137 Critical Care March 2007 Vol 11 Suppl 2
27th International Symposium on Intensive Care and Emergency Medicin the delayed admission is through another hospital, not a stroke
center. The patients denied their symptoms are not so rare. The
patients or their family often hesitate to request the emergency car. Conclusions The most significance point for rapid diagnosis and
therapy is that people must doubt ‘stroke’ at first. We should
further educate citizens to the warning signs of stroke and also the
necessity of emergency admission using an emergency car. In
addition, we should justly build a core stroke center in the district
and centralize the patients. the delayed admission is through another hospital, not a stroke
center. The patients denied their symptoms are not so rare. The
patients or their family often hesitate to request the emergency car. the delayed admission is through another hospital, not a stroke
center. The patients denied their symptoms are not so rare. The
patients or their family often hesitate to request the emergency car. been linked to peripheral nerve and muscle injury. Our aim was to
systematically review published data on the diagnosis, risk factors
and outcomes of patients with critical illness neuromuscular
abnormalities (CINMA). Conclusions The most significance point for rapid diagnosis and
therapy is that people must doubt ‘stroke’ at first. We should
further educate citizens to the warning signs of stroke and also the
necessity of emergency admission using an emergency car. In
addition, we should justly build a core stroke center in the district
and centralize the patients. Methods MEDLINE, EMBASE, CINAHL, and the Cochrane Library
were searched, and studies were included if they reported on ICU
patients > 16 years old who were evaluated for CINMA clinically
and electrophysiologically, and they contained sufficient data to
quantitatively measure the association between CINMA and
clinically relevant exposures and/or outcomes. Two reviewers
independently extracted data on study methodology and quality,
methods for diagnosing CINMA, and CINMA prevalence, risk
factors, and outcomes. P344 Introduction The objective was to determine the relationship of
early hypothermia to multiple organ failure and mortality in severely
injured trauma patients. Interhospital cooperation after critical and emergency care
for patients with cervical–thoracic–abdominal trauma and
emergency diseases in the local medical area in a typical
urban city of Japan Methods This prospective observational study was performed at
seven Level I trauma centers over 16 months. Severely injured
patients with hypoperfusion and a need for blood transfusion
during the early hospital course were followed with near-infrared
spectroscopy-derived tissue oxygen saturation (StO2) and clinical
variables. Outcomes including multiple organ dysfunction syn-
drome (MODS) and 28-day mortality were evaluated. Hypothermia
was defined as temperature < 35°C within the first 6 hours. Y Moriwaki, M Sugiyama, S Arata, N Harunari, H Manaka,
T Katsumura, T Yamada, N Suzuki
Yokohama City University Medical Center, Yokohama, Japan
Critical Care 2007, 11(Suppl 2):P344 (doi: 10.1186/cc5504) Background Capacity of the critical care and emergency center
(CCEC) is usually restricted. Transfer of patients from CCEC is
one of the most important issues in the CCEC. p
Results Hypothermia was common (43%, 155/359). Hypothermic
patients were more likely than normothermic patients to develop
MODS (21% vs 9%, P = 0.003), but did not have increased
mortality rates (16% vs 12%, P = 0.28). The maximum base deficit
(Max BD) in hypothermic patients did not discriminate between
those who did or did not develop MODS (9.8 ± 4.6 mEq/l vs
9.4 ± 4.4 mEq/l, P = 0.56) but had good discrimination for
mortality in both hypothermic and normothermic patients. Significant
predictors of MODS using multivariate analysis included minimum
StO2 (P = 0.0002) and hypothermia (P = 0.01), but not Max BD
(P = 0.09). Predictors for mortality with multivariate analysis
included minimum StO2 (P = 0.0004) and Max BD (P = 0.01), but
not hypothermia (P = 0.74). Hypothermia remained a significant
risk factor for MODS when fluid/blood infusion volumes were
included in the multivariate model. Subjects and methods We examined interhospital cooperation
after critical and emergency care for life-threatening cervical–
thoracic–abdominal trauma (n = 501) and thoracoabdominal
emergency diseases (n = 236) who were treated with intensive
care in our CCEC and were able to be discharged or transferred to
another acute treatment hospital. P345 CIPM had a higher admission APACHE II score (18.9 ± 6.6 vs
15.6 ± 6.4, P = 0.004) and SOFA score (8.4 ± 2.9 vs 7.1 ± 2.9,
P = 0.013). Multivariate logistic regression analysis showed that
risk factors independently associated with the development of
CIPM were severity of illness at the time of admission to the ICU,
administration of aminoglycoside antibiotics and high blood
glucose levels. Analysis according to severity of illness stratifica-
tion revealed the emergence of Gram-negative bacteremia as the
most important independent predisposing factor for CIPM
development in less severely ill patients. Early hypothermia in severely injured trauma patients is a
significant risk factor for multiple organ dysfunction
syndrome but not mortality G Beilman1, T Nelson2, A Nathens3, F Moore4, P Rhee5,
J Puyana6, E Moore7, S Cohn8
1University of Minnesota, Minneapolis, MN, USA; 2Princeton
Reimbursement Group, Minneapolis, MN, USA; 3St Michaels
Hospital, Toronto, Canada; 4University of Texas–Houston,
Houston, TX, USA; 5University of Southern California, San Diego,
CA, USA; 6University of Pittsburgh, PA, USA; 7University of
Colorado, Denver, CO, USA; 8University of Texas, San Antonio,
TX, USA
Critical Care 2007 11(Suppl 2):P345 (doi: 10 1186/cc5505) Conclusions CIPM has a high incidence in the ICU setting. Our
study revealed the important association that Gram-negative
bacteremia, aminoglycosides, hyperglycemia and severity of illness
have with CIPM development. al Care 2007, 11(Suppl 2):P345 (doi: 10.1186/cc5505) P342 Neuromuscular dysfunction acquired during critical illness:
a systematic review R Stevens, D Dowdy, R Michaels, P Mendez-Tellez,
P Pronovost, D Needham
Johns Hopkins University School of Medicine, Baltimore, MD, USA
Critical Care 2007, 11(Suppl 2):P342 (doi: 10.1186/cc5502) Background Patients with critical illness can acquire a syndrome
of weakness and dependence on mechanical ventilation that has Results Forty-four (23.8%) out of those 185 patients developed
generalized weakness that met the criteria for CIPM. Patients with S138 Available online http://ccforum.com/supplements/11/S2 P344 Results Of the trauma patients directly transferred to our center,
48% were transferred to the ‘affiliated hospitals’, whose medical
staffs were dispatched from the ‘departments’ in our university,
17% were transferred to the nonaffiliated hospitals, and 34% were
directly discharged from our center. Of emergency disease
patients, 28% were transferred to the affiliated hospitals, 20%
were transferred to other hospitals, and 52% were directly
discharged. Patients staying in our center for more than 14 days
tended to be transferred to the affiliated hospital. Of trauma
patients indirectly transferred from other hospital to our center,
30% and 11% were transferred to the affiliated and nonaffiliated
hospitals, and 19% were directly discharged. Of emergency
disease patients, these values were 21%, 7%, and 13%,
respectively. Patients staying in our center for more than 14 days
tended to be transferred to the affiliated hospital. Conclusions Hypothermia is common in severely injured trauma
patients and is a risk factor for MODS but not mortality. Minimum
StO2
predicts MODS and mortality in normothermic and
hypothermic patients, while the predictive effect of BD for MODS
is blunted in the presence of hypothermia. P347 Prehospital hypotension that persists on arrival at the
emergency department is a powerful predictor of mortality
following major trauma E Dickson, S Robertson, D Van Niekerk, J Goosen, F Plani,
K Boffard
Johannesburg Hospital Trauma Unit and University of the
Witwatersrand, Johannesburg, South Africa
Critical Care 2007, 11(Suppl 2):P347 (doi: 10.1186/cc5507) p
g
Results Twenty-two out of 27 patients (81%) exhibited at least
one sign of TCI, 17/27 (63%) had more than two signs: ECG
changes (18/22, 81.8%), mostly ST–T disturbances of left
precordial or inferior leads, slight CE increase (17/22, 72%), PE in
TTE or CT (12/22, 54,5%), WMA, mostly of the interventricular
septum wall (6/22, 27%), reduced LVEF (5/22, 23%), or
pericardial friction rub (5/22, 23%). Patients with TCI signs had
more frequently bilateral or right-sided hemothorax (16/22, 72%),
bilateral lung contusion (15/22, 68%), right-sided rib fracture
(15/22, 68%), abdominal organ injury (spleen, left kidney/adrenal,
liver) (14/22, 63%) or right-sided pneumothorax (13/22, 59%). Two patients (one with flail chest) exhibited PE leading to cardiac
tamponade. Pericardiocentesis was performed with success. None
of the patients had severe ventricular arrhythmia. Five young
patients had mildly reduced LVEF, in almost all cases transient. There was a positive correlation between ISS and TCI severity. Objective Outcome following major injury is time dependent. Early
identification of high-risk patients allows rapid decision-making and
correction of life-threatening disorders. Complex scoring systems
are of limited value during major trauma resuscitation. Our aim was
to evaluate the utility of a single blood pressure during the
prehospital phase in combination with the blood pressure on arrival
at the emergency department. Methods Data were collected prospectively on 1,111 patients
admitted to a Level 1 South African trauma unit over a 1-year
period. Patients were subdivided into two groups according to the
combination of their prehospital (PH) and emergency department
(ED) blood pressure. Hypotension was defined as a systolic blood
pressure less than 90 mmHg. Mortality was defined as death within
30 days. Conclusions TCI is frequent in blunt chest trauma. Additional
ECG findings and an increase in CE suggest possible TCI to be
confirmed by a bedside TTE study. TCI usually accompanies
bilateral hemothorax, lung contusion, or right-sided rib fracture. Results The mortality in patients (n = 1,031) with normal PH and
ED blood pressure was 5.4%. E Charalambous1, S Manousakis1, A Kapasaki1, C Chronaki2,
G Vrouchos1
1Venizelio General Hospital of Heraklion, Greece; 2ICS-FORTH,
Heraklion, Greece
Critical Care 2007, 11(Suppl 2):P348 (doi: 10.1186/cc5508) Table 1 (abstract P346)
Survived
Died
Total
NLG < 2 mmol/l
15 (39.5%)
0 (0%)
15 (30.6%)
NLG > 2 mmol/l
23 (60.5%)
11 (100%)
34 (69.4%)
Total
38 (100%)
11 (100%)
49 (100%) Introduction Blunt chest trauma is often accompanied by traumatic
cardiac injury (TCI), formerly called cardiac contusion. Severe TCI
can affect the prognosis of chest trauma patients due to cardiac
arrhythmias, heart failure, or cardiac tamponade. The objective of
this study was the detection and evaluation of TCI in chest trauma. Introduction Blunt chest trauma is often accompanied by traumatic
cardiac injury (TCI), formerly called cardiac contusion. Severe TCI
can affect the prognosis of chest trauma patients due to cardiac
arrhythmias, heart failure, or cardiac tamponade. The objective of
this study was the detection and evaluation of TCI in chest trauma. Methods
Twenty-seven consecutive patients without cardiac
disease history (five females), mean age 37.2 years (63% <35 years)
were admitted to the ICU with blunt chest trauma. Five patients had
minor head brain injury. The majority needed mechanical ventilation
support. The mean Injury Severity Score (ISS) was 21.1 (11–34). The following injuries/lesions of thorax or lung parenchyma were
identified on chest and abdominal CT scan: fractures of clavicle,
sternum, ribs, scapula or vertebral column, lung contusion,
hemo/pneumothorax, hemo/pneumomediastinum, abdominal organ
injury. TCI diagnosis was based on auscultation findings (pericardial
friction rub, new cardiac murmurs), electrocardiogram (ECG)
findings (ST–T disturbances, arrhythmias), cardiac enzymes (CE)
(cardiac Tropinin I, CK-MB), transthoracic echocardiography (TTE)
(wall motion abnormalities (WMA), reduced left ventricular ejection
fraction (LVEF) pericardial effusion (PE)), and thorax CT findings. Results Twenty-two out of 27 patients (81%) exhibited at least
one sign of TCI, 17/27 (63%) had more than two signs: ECG
changes (18/22, 81.8%), mostly ST–T disturbances of left
precordial or inferior leads, slight CE increase (17/22, 72%), PE in
TTE or CT (12/22, 54,5%), WMA, mostly of the interventricular
septum wall (6/22, 27%), reduced LVEF (5/22, 23%), or
pericardial friction rub (5/22, 23%). Patients with TCI signs had
more frequently bilateral or right-sided hemothorax (16/22, 72%),
bilateral lung contusion (15/22, 68%), right-sided rib fracture
(15/22, 68%), abdominal organ injury (spleen, left kidney/adrenal,
liver) (14/22, 63%) or right-sided pneumothorax (13/22, 59%). Two patients (one with flail chest) exhibited PE leading to cardiac
tamponade. Pericardiocentesis was performed with success. None
of the patients had severe ventricular arrhythmia. Five young
patients had mildly reduced LVEF, in almost all cases transient. The nonlactate gap: a novel predictor of organ failure and
mortality following major trauma The nonlactate gap: a novel predictor of organ failure and
mortality following major trauma Discussion and conclusion These results are thought to be a
common situation in a typical urban city in the world. Now, the
interhospital cooperation between city hospital and referral hospital
does not function well because of poor understanding of re-
transfer to the previous hospital, resulting in dysfunction of the
management of critical patients in the local medical area. It is
important to construct a new interhospital-cooperation system
based on the local medical area. S Robertson1, E Dickson2, G Richards1
1Johannesburg Hospital, Johannesburg, South Africa;
2Royal Glasgow Infirmary, Glasgow, UK
Critical Care 2007, 11(Suppl 2):P346 (doi: 10.1186/cc5506) y
g
y,
g
,
Critical Care 2007, 11(Suppl 2):P346 (doi: 10.1186/cc Introduction Early identification of patients who are not fully
resuscitated following major trauma improves outcome. However,
current markers of clinically occult hypoperfusion, such as lactate
and base deficit, have serious limitations, and our aim was to
establish a new endpoint of resuscitation. Methods In a prospective study conducted in a Level 1 trauma
unit, 49 consecutive patients admitted to the trauma ICU were
evaluated. Serum electrolytes, albumin, phosphate and lactate S139 ritical Care March 2007 Vol 11 Suppl 2
27th International Symposium on Intensive Care and Emergency Medicin Conclusion The combination of prehospital and emergency
department systolic blood pressure is a simple yet extremely
powerful predictor of mortality following major trauma and should
be used as a triage tool to rapidly identify the highest risk patients. were measured on admission. We derived the calculated ion gap
using a simplified Stewart–Figge equation, and subtracted the
measured serum lactate from the calculated ion gap to obtain the
nonlactate gap (NLG). Results See Table 1. The NLG discriminated survivors from non-
survivors (P = 0.008, analysis of variance). An NLG above 2 mmol/l
was associated with an increased risk of mortality (P = 0.010,
Fisher’s exact test). No patient with an NLG less than 2 mmol/l
died; 32.4% of the patients with an NLG above 2 mmol/l died. A
NLG above 2 mmol/l also correlated strongly with organ failure
(Multiple Organ Dysfunction Syndrome score P = 0.011, Sequen-
tial Organ Failure Assessment score P = 0.011, Mann–Whitney U
test). E Charalambous1, S Manousakis1, A Kapasaki1, C Chronaki2,
G Vrouchos1
1Venizelio General Hospital of Heraklion, Greece; 2ICS-FORTH,
Heraklion, Greece
Critical Care 2007, 11(Suppl 2):P348 (doi: 10.1186/cc5508) There was a positive correlation between ISS and TCI severity. C
l
i
TCI i
f
i
bl
h
Addi i
l p
y
cardiac injury (TCI), formerly called cardiac contusion. Severe TCI
can affect the prognosis of chest trauma patients due to cardiac
arrhythmias, heart failure, or cardiac tamponade. The objective of
this study was the detection and evaluation of TCI in chest trauma. Methods
Twenty-seven consecutive patients without cardiac
disease history (five females), mean age 37.2 years (63% <35 years)
were admitted to the ICU with blunt chest trauma. Five patients had
minor head brain injury. The majority needed mechanical ventilation
support. The mean Injury Severity Score (ISS) was 21.1 (11–34). The following injuries/lesions of thorax or lung parenchyma were
identified on chest and abdominal CT scan: fractures of clavicle,
sternum, ribs, scapula or vertebral column, lung contusion,
hemo/pneumothorax, hemo/pneumomediastinum, abdominal organ
injury. TCI diagnosis was based on auscultation findings (pericardial
friction rub, new cardiac murmurs), electrocardiogram (ECG)
findings (ST–T disturbances, arrhythmias), cardiac enzymes (CE)
(cardiac Tropinin I, CK-MB), transthoracic echocardiography (TTE)
(wall motion abnormalities (WMA), reduced left ventricular ejection
fraction (LVEF) pericardial effusion (PE)), and thorax CT findings. Conclusions We describe the NLG for the first time, and quantify
it using simple bedside calculations derived from routine blood
investigations. The NLG is an excellent marker for organ failure and
death following major injury, and should be used to guide trauma
resuscitation. Traumatic cardiac injury in chest trauma E Charalambous1, S Manousakis1, A Kapasaki1, C Chronaki2,
G Vrouchos1
1Venizelio General Hospital of Heraklion, Greece; 2ICS-FORTH,
Heraklion, Greece
Critical Care 2007, 11(Suppl 2):P348 (doi: 10.1186/cc5508) P347 The mortality in patients (n = 80)
with PH and ED hypotension was significantly higher at 45%
(P < 0.0001, chi-square test) (Table 1). P349 Prognosis of blunt abdominal trauma patients with contrast
medium extravasation on computed tomography scan K Lee, H Shin
Wonju Medical College, Wonju, Republic of Korea
Critical Care 2007, 11(Suppl 2):P349 (doi: 10.1186/cc5509) Table 1 (abstract P347)
SBP < 90 mmHg
SBP > 90 mmHg
Alive
55.0% (n = 44)
94.6% (n = 975)
Dead
45.0% (n = 36)
5.4% (n = 56) Introduction Until now there have been few studies concentrating
on the diagnostic and prognostic significance of contrast medium S140 Available online http://ccforum.com/supplements/11/S2 Available online http://ccforum.com/supplements/11/S2 Available online http://ccforum.com/supplements/11/S2 implementing LODOX (median time 27 min to 24 min). In 54/94
patients an additional full body CT scan was performed as adjunct
to secondary survey. In only 14/54 patients were additional
conventional X-rays necessary to visualize the skeleton. Conclusion The implementation of a modified ATLS algorithm using
LODOX allows a complete a.p. and lateral whole-body examination
without a significant increase in the time taken for resuscitation. Since we are at the very beginning of a learning curve we are
confident that in future the time for the ATLS primary survey can be
markedly reduced. The LS imaging system seems to be a useful
tool for rapid screening and management of trauma patients. implementing LODOX (median time 27 min to 24 min). In 54/94
patients an additional full body CT scan was performed as adjunct
to secondary survey. In only 14/54 patients were additional
conventional X-rays necessary to visualize the skeleton. extravasation site computed tomography (CT). In this study we
investigated the site and extent of contrast medium extravasation
on CT findings and its effect on treatment and predicting clinical
outcome in trauma patients. Conclusion The implementation of a modified ATLS algorithm using
LODOX allows a complete a.p. and lateral whole-body examination
without a significant increase in the time taken for resuscitation. Since we are at the very beginning of a learning curve we are
confident that in future the time for the ATLS primary survey can be
markedly reduced. The LS imaging system seems to be a useful
tool for rapid screening and management of trauma patients. Methods Fifty patients admitted to our emergency department
with blunt abdominal trauma showing contrast medium extravasa-
tion on abdominal–pelvic CT scan were included in our study for
33 months. Patients were prospectively collected and medical
records were reviewed and analyzed retrospectively. P351 Results The incidence of extravasation site was intraperitoneal in 33
cases (66%), retroperitoneal in 13 cases (26%), and intrapelvic in
four cases (8%). The frequency of injured vessels showing
extravasation was 18 (36%) hepatic vessels, nine (18%) splenic
vessels and six (12%) iliac vessels. There was no correlation between
the extravasation site and ICU or total hospitalization duration
(P > 0.523). Sixteen patients with intraperitoneal extravasation
required surgical intervention, six patients underwent angiography
with embolization. In patients with retroperitoneal extravasation, nine
were treated conservatively and two with embolization. Over all there
were no significant differences between the extravasation site and
treatment modality. The intraperitoneal group had the highest mortality
with 13 deaths (11/33, 39%) and the highest early mortality rate
(10/13, 76%) in the first 24 hours (P = 0.001). Peripheral oxygen extraction predicts organ failure and
mortality following major trauma Peripheral oxygen extraction predicts organ failure and
mortality following major trauma S Robertson1, E Dickson2, G Richards1
1Johannesburg Hospital, Johannesburg, South Africa;
2Royal Glasgow Infirmary, Glasgow, UK
Critical Care 2007, 11(Suppl 2):P351 (doi: 10.1186/cc5511) ritical Care 2007, 11(Suppl 2):P351 (doi: 10.1186/cc55 Introduction Current markers of occult hypoperfusion following
major trauma have serious limitations. Our aim was to evaluate
oxygen extraction as a resuscitation endpoint, and predictor of
organ failure and mortality following trauma. Methods A prospective, noninterventional study of 39 consecutive
patients admitted to a Level 1 trauma unit ICU. Blood gas analysis
was performed on samples from three locations: central venous
line, peripheral venous line, and arterial line. Blood was drawn 6-
hourly in the first 24 hours, and oxygen extraction calculated using
the Fick equation. Organ failure was assessed using MODS and
SOFA scores. Conclusion CT findings in patients with blunt abdominal trauma
showed no significant correlation between the contrast medium
extravasation site and treatment modality, ICU hospitalization
duration, or final results. However, patients with intraperitoneal
extravasation required more aggressive transfusion with packed
red cells and had a higher mortality rate in the first 24 hours. Results See Table 1. Peripheral, but not central, oxygen extraction
with a threshold of 150 ml oxygen extracted per litre of blood
distinguished survivors from nonsurvivors on admission to the trauma
ICU. Low peripheral oxygen extraction (<150 ml) had an odds ratio
for risk of death of 5.3 (P = 0.016, Fisher’s exact test) and was
associated with higher organ failure scores (P = 0.044, Mann–
Whitney U test). A trend of increasing peripheral oxygen extraction
was also a strong predictor of mortality (P = 0.019, Mann–Whitney U
test) and organ failure (P = 0.003, Mann–Whitney U test). P350 Full-body low-dosage X-ray instead of single X-ray series
in trauma: a preliminary experience report of a modified
advanced trauma life support algorithm A Exadaktylos, H Brunner, L Martinolli, L Benneker, F Gatterer,
R Soyka, H Bonel, H Zimmermann
Inselspital Bern, Switzerland
Critical Care 2007, 11(Suppl 2):P350 (doi: 10.1186/cc5510) Table 1 (abstract P351)
Survived
Died
Total
Extract < 150 ml
8
6
14
Extract > 150 ml
23
2
25
Total
31
8
39 Introduction Patients presenting with trauma normally require
resuscitation according to the advanced trauma life support (ATLS)
algorithm. Techniques suggested during primary survey include X-
ray of C-spine, chest and pelvis. This can be time consuming and
radiation intensive. In comparison with conventional multiple
radiographs, Lodox (Statscan), a full-body digital radiology device,
performs a.p. and lateral whole-body examinations in 3–5 minutes
with about one-third of the irradiation and without the necessity for
lifting patients. This is the first device installed in Europe. Conclusions With an arterial and venous blood sample, and a
simple equation, we have for the first time demonstrated that
absolute and serial peripheral oxygen extraction are powerful
predictors of organ failure and mortality following major injury. Methods This paper describes our experience with the use of a
new low-dose X-ray technique as part of our modified ATLS
algorithm, where single–total a.p./lateral body radiographs have
been implemented as adjuncts to primary survey in favour of
several conventional X-rays. P349 The patients’
clinical and laboratory findings, abdominal sonographic (FAST)
findings, and CT findings were reviewed. Extravasation sites were
classified as intraperitoneal, retroperitoneal, intrapelvic and correlated
with post-treatment complications, mortality and morbidity rates. P352 Damage control orthopedics can improve outcome in
trauma patients
A Di Filippo, A Circelli, G Cianchi, A Peris
Anesthesia and Intensive Care Unit, Florence, Italy
Critical Care 2007, 11(Suppl 2):P352 (doi: 10.1186/cc5512) Damage control orthopedics can improve outcome in
trauma patients Results There were 94 patients (males = 59; females = 35)
between 4 October and 9 December 2006; age range from 1 to
86 years. The ISS ranged from 3 to 75 (ISS > 16 in 54/94
patients). The average time for obtaining LODOX radiographs was
3.5 minutes (range 3–6 min). The mean time in the resuscitation
room (during primary and secondary surveys) was 28.7 minutes
with the new technique compared with 29 minutes before S141
Introduction Damage control orthopedics (DCO) is a reviewed
concept used in major trauma. Advances in critical care Critical Care March 2007 Vol 11 Suppl 2
27th International Symposium on Intensive Care and Emergency Medicin management enable surgical stabilization in the early phase of
trauma care. Logistical organization and accessibility to several
therapeutic solutions can influence a physician’s decisions
regarding a trauma patient. The aim of this study is to investigate
whether the timing of surgery and method of stabilization in trauma
patients with femoral fracture can influence the incidence of
pulmonary complication, MOF and the length of stay in the ICU. two groups: group 1 (n = 27), brain death occurred in the first
3 days; group 2 (n = 27), brain death occurred in the days after. Statistics were determined with the Student t and chi-squared
tests; P < 0.05 was considered significant. Results The significant differences between the two groups are
reported in Table 1. A strict relationship exists between early brain
death and prehospital treatment. During the ICU stay low levels of
ScVO2 and high levels of glycaemia are related to early brain
death. Method In a retrospective study performed at a Level I trauma
center, we considered all adult patients with major trauma (ISS
> 15) and femoral shaft fracture admitted between January 2003
and July 2006. Patients were separated into two groups according
to the management strategies for the femoral fracture: group 1, no
surgery within 72 hours after primary admission; group 2, surgical
stabilization within 72 hours (DCO). To compare the two groups
we considered age, ISS, RTS, TRISS, SAPS II, GCS, comorbidity,
and other associated surgery. Table 1 (abstract P353) Results We identified 48 patients, 24 for each group. The groups
were comparable regarding all the considered parameters except
for GCS at admission (group 1, 8.63 ± 5.12; group 2, 12.2 ± 3.99;
P = 0.01) and TRISS (group 1, 62.04 ± 34.55%; group 2,
82.37 ± 18.60%; P = 0.01). We observed in group 2 a significant
decrease of mortality (5 vs 0; P = 0.02), incidence of ALI–ARDS
(13 vs 4; P = 0.01) and pneumonia (18 vs 6; P = 0.01), a
decrease of SOFA score (mean SOFA score: 7.58 ± 4.11 vs
3.97 ± 2.39, P < 0.001; maximum SOFA score: 9.83 ± 4.36 vs
5.62 ± 2.97, P < 0.001; days with SOFA >6: 3.79 ± 3.08 vs
2.16 ± 2.18, P = 0.04). Conclusion The results of the study confirm that prehospital
hypotension is the main risk factor for an early evolution to brain
death in head trauma. Also, patients that have prolonged
hypoperfusion
and
neurohormonal
imbalance
after
the
postresuscitation phase present an increased risk of brain death. P354 P354
Sensitivity and specificity of a triage score dedicated to
trauma patients in a tertiary-level hospital: preliminary
results
P Masturzo1, R Regolo1, G Ferro2, G Nardi3, D Orazi2, V Maggi2
1Seconda Università, Napoli, Italy; 2San Camillo Forlanini, Roma,
Italy; 3Ospedale S. Camillo-Forlanini, Roma, Italy
Critical Care 2007, 11(Suppl 2):P354 (doi: 10.1186/cc5514) Sensitivity and specificity of a triage score dedicated to
trauma patients in a tertiary-level hospital: preliminary
results Conclusions
We observed an improvement of respiratory
parameters and SOFA score in patients treated with DCO. Furthermore, patients with worse neurological conditions at
admission do not undergo orthopaedic surgery because it could
worsen the cerebral perfusion (risk related to transfer to a far
operating room). The physician’s decisions (and therefore the
patient’s prognosis), in our experience, are limited by access to
optimal therapeutic solutions that could improve the clinical course
of the patient. P Masturzo1, R Regolo1, G Ferro2, G Nardi3, D Orazi2, V Maggi2
1Seconda Università, Napoli, Italy; 2San Camillo Forlanini, Roma,
Italy; 3Ospedale S. Camillo-Forlanini, Roma, Italy
Critical Care 2007, 11(Suppl 2):P354 (doi: 10.1186/cc5514) Introduction The aim of the study was to determine the sensitivity
and specificity of the triage criteria adopted for multiple trauma
patients in order to activate the Trauma Team in our tertiary-level
trauma centre. P353 Methods A cohort study. Between 1 September and 30 November
2006, all trauma patients admitted to the ED triaged red, yellow or
green on admission and discharged as a red code from the ED
following specific criteria were included. Triage criteria on
admission included at least one of the following: GCS < 13,
systolic BP > 220 and < 100 mmHg, SaO2 < 95% on oxygen
100% or intubated; clinical signs: penetrating wounds, spinal
injury, sternal or flail chest, two long-bone fractures, proximal crash
or amputation of limbs, post-traumatic seizures at any time, signs of
fracture of the skull; major accident mechanics: fatality in the same
vehicle, fall from a height >3 m, prolonged extrication time
(>20 min), pedestrian hit by a car, ejection, explosion in a close
environment. Severely injured patients at discharge from the ED
were defined by: invasive resuscitating procedures (that is,
tracheal intubation), invasive life-saving procedures (emergency
surgery, defibrillation) and need for admission to the ICU. Sensitivity and specificity of the triage criteria assigned on
admission were calculated and compared with the patients that
were triaged red at discharge from ED. Head trauma: risk factors for early brain death – our
experience P352 Parameters of evaluation were:
mortality in the ICU, ICU length of stay, respiratory failure and
length of ventilation, and daily SOFA collected for 8 days. Statistics were determined with the Student t and chi-squared
tests; P < 0.05 was considered significant. Table 1 (abstract P353)
Group 1 (n = 27)
Group 2 (n = 27)
P
Prehospital
Hypotension
22
13
<0.05
ICU stay
Glycaemia
170.8 ± 49.5
116.6 ± 24.4
<0.05
ScVO2 < 75%
15
7
<0.05 Table 1 (abstract P353)
Group 1 (n = 27)
Group 2 (n = 27)
P
Prehospital
Hypotension
22
13
<0.05
ICU stay
Glycaemia
170.8 ± 49.5
116.6 ± 24.4
<0.05
ScVO2 < 75%
15
7
<0.05 P355 Method
Female pigs, 25–30 kg body weight, were used. Retrograde catheterization of the internal jugular vein (SjO2) and
laparotomy was performed. A surgical knot 4 mm long was made
at the aorta, with a 3.0 diameter stitch. The abdomen was closed. Then a craniotomy and traumatic brain injury (TBI) was made. A
regional cerebral blood flow catheter (RoCBF) was placed under
the dura. After the TBI the intraabdominal hemorrhage was made
by pulling the titch (rupture of the aorta). The animals were
assigned into two groups: group A (fluid resuscitation) and group
B (hypotensive resuscitation). The animals that survived after 1
hour of hemorrhage were managed by surgical checking and with
1 hour more of fluid resuscitation. Head trauma: risk factors for early brain death – our
experience Out of the 76 triaged red on
admission, 53 patients were confirmed at discharge from ED. The
specificity is 70%. P356 p
y
Conclusions Even if major accident mechanics were included in
the admission triage criteria, overtriage was limited to 30%. On the
other hand, undertriage was approximate to zero, and the only two
yellow codes missed were related to miscommunication by the
prehospital team. Introduction
We
examined
the
efficacy
of
hypotensive
resuscitation, compared with fluid resuscitation, in patients with
closed abdominal trauma and coexisting severe head injury. Introduction
We
examined
the
efficacy
of
hypotensive
resuscitation, compared with fluid resuscitation, in patients with
closed abdominal trauma and coexisting severe head injury. P357 Hyperoxemia improves cerebral autoregulation in severe
traumatic brain injury
R Celis, R Hlatky, C Robertson
Baylor College of Medicine, Houston, TX, USA
Critical Care 2007, 11(Suppl 2):P357 (doi: 10.1186/cc517) Conjunctival and sublingual microcirculation alterations in
head trauma patients with increased intracranial pressure B Atasever, D Gommers, J Bakker
Erasmus Medical Center Rotterdam, The Netherlands
Critical Care 2007, 11(Suppl 2):P355 (doi: 10.1186/cc5515) B Atasever, D Gommers, J Bakker
Erasmus Medical Center Rotterdam, The Netherlands
Critical Care 2007, 11(Suppl 2):P355 (doi: 10.1186/cc5515) Introduction Both the conjunctiva and the sublingual tissue have a
common blood supply via the common carotid artery trunk. Moreover, the conjunctiva receives blood from the internal carotid
artery and the sublingual tissue receives from the external carotid
artery. We hypothesized that conjunctival and sublingual
microcirculation can be used to evaluate intracranial and
extracranial perfusion and to monitor therapy to improve cerebral
perfusion pressure in patients after head trauma. Results See Table 1: RoCBF and SjO2 before and after the
surgical checking of the hemorrhage. Conclusion In group B there was complete restoration of cerebral
blood flow and brain oxygenation, after the surgical checking of
hemorrhage. Hypotensive
resuscitation
causes
significant
reduction in mortality in patients with closed intraabdominal trauma
and coexisting head injury, without putting cerebral function in
jeopardy. Methods In three groups of patients with increased intracranial
pressure (ICP) (high ICP > 30, medium ICP 20–30 and low ICP
< 20) following head trauma, both the conjunctival and sublingual
microcirculation was measured using sidestream darkfield imaging
(MicroScan®; MicroVision Medical, The Netherlands) to evaluate
intracranial and extracranial perfusion. Using microvascular analysis
software (MAS®; MicroVision Medical), functional density of small
(<20 µm), medium (20–50 µm) and large (>50 µm) microvessels
were determined in addition to erythrocyte velocities. Head trauma: risk factors for early brain death – our
experience Head trauma: risk factors for early brain death – our
experience A Di Filippo1, S Damiani1, M Migliaccio1, M Bonizzoli2, A Peris3
1Anesthesia and Intensive Care Unit, Florence, Italy; 2Careggi
Hospital, Florence, Italy; 3Ospedale Firenze, Florence, Italy
Critical Care 2007, 11(Suppl 2):P353 (doi: 10.1186/cc5513) Introduction In a group of patients that evolved in brain death after
head trauma, we evaluated the risk factors for an early brain death
(in the first 3 days) among the parameters collected prehospital, in
the emergency room (ER) and during the ICU stay. Method All the consecutive patients admitted to the ER of Careggi
Hospital that evolved to brain death after head trauma during the
period January 2004–June 2006 were considered (n = 54). The
following parameters were considered for the study: prehospital
phase: hypoxemia (SaO2 < 95%), hypotension (SAPS II < 90 mmHg),
orotracheal intubation, fluids (>1,000 or ≤1,000 ml), and GCS; ER
phase (ATLS approach): hypoxemia, hypotension, orotracheal
intubation, fluids, GCS, blood lactate, pharyngeal temperature, and
ISS; ICU stay: SAPS II, daily SOFA score, blood lactate, core
temperature, glycaemia, and ScVO2 (>75% or ≤75%). On the
basis of the timing of brain death, the patients were divided into Results During the time span, 5,142 trauma patients were
admitted to the ED: 4,884 were triaged green, 182 yellow and 76
were triaged as red. Of the 76 red on admission, 55 patients
fulfilled the abovementioned criteria and were confirmed severely
injured at discharge from ED. Out of the 55, 53 patients were S142 Available online http://ccforum.com/supplements/11/S2 Table 1 (abstract P356) 5 minutes
15 minutes 45 minutes
5 minutes
15 minutes 45 minutes
Baseline
before
before
before
after
after
after
Mortality
Group A
RoCBF (ml/min.100 ml)
31.92
35.47
19.32
5.25***
100%
SjO2 (%)
71.2
32.8
25.7
28.7***
Group B
RoCBF (ml/min.100 ml)
30.3
14.2*
14.5*
16.4
33.47
38.24
37.67
50%
SjO2 (%)
81.1
25.8***
22.7***
24.4***
38.5**
49.5**
57.1*
*P < 0.05, **P < 0.01 and ***P < 0.001 for comparison with baseline. P356
The influence of hypotensive resuscitation in hemorrhagic
shock with coexisting severe head injury: an experimental
protocol
T Vrettos, P Athanasopoulos, N Karageorgos, S Balasis,
G Gatzounis, T Siklis, K Filos
University of Patras Medical School, Patras, Greece
Critical Care 2007, 11(Suppl 2):P356 (doi: 10.1186/cc5516) correctly identified by triage criteria, while two patients were
missed. The sensitivity is 96%. Hyperoxemia improves cerebral autoregulation in severe
traumatic brain injury The
neurobehavioral motor outcome was evaluated weekly (for 4 weeks)
by performing a neuroscore, and cognitive function was evaluated
at 4 weeks postinjury using the Morris water maze. Methods Mice were anesthetized and subjected to CCI brain
injury. At 10 minutes postinjury, animals randomly received an
intravenous infusion of either C1-INH (15 U) or saline (equal
volume, 150 µl). A second group of mice received identical
anesthesia, surgery, and saline to serve as uninjured controls. The
neurobehavioral motor outcome was evaluated weekly (for 4 weeks)
by performing a neuroscore, and cognitive function was evaluated
at 4 weeks postinjury using the Morris water maze. Results Consistently, brain-injured mice receiving C1-INH showed
attenuated neurological motor deficits during the 4-week period
compared with injured mice receiving saline (Figure 1). At 4 weeks
postinjury we observed a trend towards a better cognitive
performance in mice receiving C1-INH compared with mice
receiving saline (n = 8 per group, P = 0.08). 2
2
2
The ARI (normal 5 ± 1) in these head-injured patients averaged
2.2 ± 1.5 on day 1 and gradually improved over the 10 days of
monitoring. The ARI significantly improved with hyperoxemia,
during the first 6 days after injury when compared with the ARI
measured at normoxemia. The mean left ARI difference during
hyperoxia was 0.4069 ± 1.7948 while the right ARI difference was
0.4708 ± 1.8413. The average change in pCO2 during hyperoxia
was 35.6468 ± 5.8778. These changes in the ARI during
hyperoxia were smaller than those observed during hyper-
ventilation. Hyperventilation increased the ARI by average
0.8519 ± 0.2310 on the left and 1.0833 ± 0.4654 on the right. The ARI (normal 5 ± 1) in these head-injured patients averaged
2.2 ± 1.5 on day 1 and gradually improved over the 10 days of
monitoring. The ARI significantly improved with hyperoxemia,
during the first 6 days after injury when compared with the ARI
measured at normoxemia. The mean left ARI difference during
hyperoxia was 0.4069 ± 1.7948 while the right ARI difference was
0.4708 ± 1.8413. The average change in pCO2 during hyperoxia
was 35.6468 ± 5.8778. These changes in the ARI during
hyperoxia were smaller than those observed during hyper-
ventilation. Hyperventilation increased the ARI by average
0.8519 ± 0.2310 on the left and 1.0833 ± 0.4654 on the right. Pressure autoregulation was impaired in these head-injured
patients. Hyperoxia significantly improved pressure autoregulation. P359 Haemostatic activation markers in brain injury for mortality
prediction: comparison of blood samples from the jugular
bulb and central venous line Haemostatic activation markers in brain injury for mortality
prediction: comparison of blood samples from the jugular
bulb and central venous line N Baffoun1, C Kaddour1, Z Haddad2, R Souissi1, W Gdoura1,
L Skandrani1
1National Institute of Neurology, Tunis, Tunisia; 2CHI St-Cloud,
France
Critical Care 2007, 11(Suppl 2):P359 (doi: 10.1186/cc5519) N Baffoun1, C Kaddour1, Z Haddad2, R Souissi1, W Gdoura1,
L Skandrani1
1National Institute of Neurology, Tunis, Tunisia; 2CHI St-Cloud,
France
Critical Care 2007, 11(Suppl 2):P359 (doi: 10.1186/cc5519) Hyperoxemia improves cerebral autoregulation in severe
traumatic brain injury The very small change in pCO2 induced by hyperoxia does not
seem to explain this improvement in pressure autoregulation. Vasoconstriction induced by hyperoxia may partially contribute to
the improved pressure autoregulation. Conclusion Post-traumatic administration of the endogenous
complement inhibitor C1-INH significantly attenuates neurological
motor deficits associated with traumatic brain injury. P358 Objective Our aim was the identification of coagulopathy disorders
and their relation to outcome in severely head-injured patients. Objective Our aim was the identification of coagulopathy disorders
and their relation to outcome in severely head-injured patients. C1-inhibitor attenuates neurobehavioral deficits following
controlled cortical impact brain injury in mice y
j
p
Patients and methods A prospective study was performed June
2003–March 2004. Included were critically ill patients with
isolated closed severe head trauma. Collected data were
demographics, management prior to and during ICU hospitalization
(sedation, catecolamin drug use, blood product transfusion,
intracranial pressure monitoring, neurosurgical emergency surgery,
etc.), CT-scan results, daily worst Glasgow Coma Scale score, and
admission Simplified Acute Physiology Score II. We inserted an
arterial catheter for invasive pressure monitoring, a central venous
catheter and a unilateral jugular bulb in front of the most damaged
brain hemisphere (cf. CT scan). Jugular bulb thrombosis was
prevented by continuous infusion of 2 ml/hour isotonic serum
without heparin. Blood samples were obtained simultaneously from
the central venous line (K) and jugular bulb (B) at admission,
6 hours, 12 hours, and then in case of neurological aggravation or
daily until 5 days. We measured the platelet count, prothrombin
time (PT), activated partial thromboplastin time (ACT), fibrinogen
concentration (Fib), prothrombin fraction 1+2 (F) and thrombin–
antithrombin complex (TAT). During the study only central venous
blood samples (PT, ACT, Fib and platelet count) could be available
if necessary. Otherwise blood samples were centrifuged and
preserved refrigerated for post-hoc analysis. Statistical analysis
was by Student’s t test, paired t test for paired results and analysis
of variance. Significance was set as P < 0.05. L Longhi1, C Perego2, E Zanier1, F Ortolano1, P Bianchi1,
L Bergamaschini1, N Stocchetti3, G De Simoni2
1Milan University, Ospedale Maggiore Policlinico IRCCS, Milano,
Italy; 2Mario Negri Institute, Milano, Italy; 3Ospedale Policlinico
IRCCS, Milan, Italy
Critical Care 2007, 11(Suppl 2):P358 (doi: 10.1186/cc5518) Critical Care 2007, 11(Suppl 2):P358 (doi: 10.1186/cc5518) Introduction The goal of the study was to evaluate the neuro-
behavioral effects of the C1-inhibitor (C1-INH), an endogenous
inhibitor of complement and contact-kinin pathways, following
controlled cortical impact (CCI) brain injury in mice. Figure 1 (abstract P358) Figure 1 (abstract P358) Figure 1 (abstract P358) Results The total n = 19; nine survivors (S) and 10 deaths (NS). Hyperoxemia improves cerebral autoregulation in severe
traumatic brain injury Results Conjunctival microcirculatory flow was intermittent in
patients with highest ICP, low-continuous in patients with medium
ICP, and normal-continuous in patients with lowest ICP. Intra-
cranial perfusion pressure was lowest in patients with highest ICP
and vice versa. Functional vessel densities in the conjuctiva were in
the same range in all three groups. However, the sublingual
functional capillary densities were consistently lower in all groups
as compared with controls, suggesting an active intracranial and
extracranial regional autoregulation. R Celis, R Hlatky, C Robertson
Baylor College of Medicine, Houston, TX, USA
Critical Care 2007, 11(Suppl 2):P357 (doi: 10.1186/cc517) R Celis, R Hlatky, C Robertson
Baylor College of Medicine, Houston, TX, USA
Critical Care 2007, 11(Suppl 2):P357 (doi: 10.1186/cc517) The intrinsic autoregulation mechanisms of the cerebral vessels
that normally maintain a constant cerebral blood flow (CBF)
relatively independently from the cerebral perfusion pressure
variations are frequently impaired in the severely traumatized. It has
been shown that hyperventilation can restore the cerebral
autoregulation and controlling intracranial pressure, but much less
attention has been given to the effects of the hyperoxic state in the
restoration of cerebral autoregulation. The purpose of the study
was to compare the autoregulatory response to hyperventilation vs
hyperoxia in severe traumatic brain injury. Conclusion Conjunctival microcirculatory flow analysis reflects
alterations in cranial perfusion pressure and might be a possible
noninvasive endpoint to monitor cerebral perfusion and therapy. S143 ritical Care March 2007 Vol 11 Suppl 2
27th International Symposium on Intensive Care and Emergency Medicin We prospectively examined 186 (aged 34.4 ± 14.99 years)
patients with severe traumatic brain injury (postresuscitation GCS
5.98 ± 3.0957) following admission to the neurosurgical ICU of a
level one trauma hospital. Hyperventilation and hyperoxia studies
were conducted, recording middle cerebral artery flow velocity and
the autoregulation index (ARI) bilaterally and simultaneously at
baseline and posthyperventilation (CO2 reactivity = %∆CBF/
∆pCO2)/hyperoxia (O2 reactivity = ∆PbtO2/∆pO2). Continuous
multimodal neuromonitoring, intracranial pressure, mean arterial
blood pressure, cerebral perfusion pressure, end-tidal CO2
(ETCO2), PbtiO2, and SjvO2, was recorded. Methods Mice were anesthetized and subjected to CCI brain
injury. At 10 minutes postinjury, animals randomly received an
intravenous infusion of either C1-INH (15 U) or saline (equal
volume, 150 µl). A second group of mice received identical
anesthesia, surgery, and saline to serve as uninjured controls. P360 P360
Decreased adrenal reserve after etomidate use in
moderate and severe traumatic brain injuries: clinical
implications
P Archambault, C Dionne, G Lortie, F LeBlanc, A Rioux,
G Larouche
Université Laval, Ottawa, Canada
Critical Care 2007, 11(Suppl 2):P360 (doi: 10.1186/cc5520) Introduction Etomidate is frequently used as an anesthetic
induction agent for the intubation of head trauma patients. The
clinical impacts of its effects on adrenal function are still debated. Therefore, the primary objective of this study was to determine the
length and the importance of relative adrenal insufficiency (RAI)
induced by etomidate in moderate and severe head trauma
patients. The secondary objective was to determine etomidate’s
impacts on mortality and morbidity. Conclusions These results suggest that etomidate decreases the
adrenal reserve up to 24 hours after a single dose used for the
intubation of traumatic brain injury victims. A larger randomized
controlled trial is needed to further assess etomidate’s impacts on
morbidity and mortality. P361 Methods This was a prospective cohort study. Eligible participants
were intubated moderate to severe head trauma victims aged
≥16 years, admitted to a tertiary neurosurgical reference center
between August 2003 and November 2004. The induction agent
was chosen by the physician, without any interference by the
research team. ACTH stimulation tests (250 µg) were performed
on each participant 24, 48 and 168 hours after intubation. Responses to these tests were compared between patients having
received etomidate and those having received other induction
agents. RAI was defined as an increase in cortisol levels
<248.4 nmol/l (9 µg/dl), measured 30 and 60 minutes after the
ACTH test. Logistic and linear regression models were used to
compare the two groups of patients on outcomes while taking
confounding variables into account. Differential effects of in vitro norepinephrine on platelets
isolated from severely traumatic brain injured patients Differential effects of in vitro norepinephrine on platelets
isolated from severely traumatic brain injured patients Differential effects of in vitro norepinephrine on platelets
isolated from severely traumatic brain injured patients J Stover, C Tschuor, L Asmis, J Fehr, R Stocker
University Hospital Zürich, Switzerland
Critical Care 2007, 11(Suppl 2):P361 (doi: 10.1186/cc5521) J Stover, C Tschuor, L Asmis, J Fehr, R Stocker
University Hospital Zürich, Switzerland
Critical Care 2007, 11(Suppl 2):P361 (doi: 10.1186/cc5521) y
ritical Care 2007, 11(Suppl 2):P361 (doi: 10.1186/cc55 Introduction Norepinephrine used in clinical routine to increase
cerebral perfusion following severe traumatic brain injury (TBI) may
activate α2-adrenergic receptors on platelets, thereby possibly
promoting formation of microthrombosis and inducing additional
brain injury. Methods Arterial and jugular venous platelets isolated from nor-
epinephrine-receiving TBI patients (n = 11) and healthy volunteers
(n = 36) (cubital vein) were stimulated in vitro with increasing Results Of the 94 patients eligible for this study, 40 (43%) gave
consent for the ACTH test. Fifteen patients received etomidate and Available online http://ccforum.com/supplements/11/S2 Available online http://ccforum.com/supplements/11/S2 Available online http://ccforum.com/supplements/11/S2 difference was observed for other tests between B vs K and S vs
NS for different paired tests. 25 received other induction agents. At 24 hours, there were no
differences in the risk of RAI between groups (OR: 1.8, 95% CI:
0.2–14.3, P = 0.59). However, at 24 hours, subjects who had
received etomidate presented a significantly lower response to
ACTH (adjusted mean: 299.7 nmol/l, 95% CI: 214.7–384.8
versus 503.8 nmol/l, 95% CI: 441.8–565.7, P = 0.002). At 48 and
168 hours, this difference disappeared. For all eligible patients
(n = 94), there was a nonsignificant trend to an increased risk in
mortality in the etomidate group (adjusted OR: 4.8, 95% CI:
0.6–35.9, P = 0.13). Etomidate was also associated with an
increased risk of pneumonia (adjusted OR: 3.0, 95% CI: 1.0–8.7). The adjusted length of stay in the ICU was not different between
groups. At discharge, the adjusted motor Functional Independence
Measure (FIM) score was significantly lower for subjects in the
etomidate group (32 versus 56, P = 0.002), but the adjusted
cognitive FIM score was not significantly different in the etomidate
group (35 versus 46, P = 0.15). 25 received other induction agents. At 24 hours, there were no
differences in the risk of RAI between groups (OR: 1.8, 95% CI:
0.2–14.3, P = 0.59). However, at 24 hours, subjects who had
received etomidate presented a significantly lower response to
ACTH (adjusted mean: 299.7 nmol/l, 95% CI: 214.7–384.8
versus 503.8 nmol/l, 95% CI: 441.8–565.7, P = 0.002). At 48 and
168 hours, this difference disappeared. For all eligible patients
(n = 94), there was a nonsignificant trend to an increased risk in
mortality in the etomidate group (adjusted OR: 4.8, 95% CI:
0.6–35.9, P = 0.13). Etomidate was also associated with an
increased risk of pneumonia (adjusted OR: 3.0, 95% CI: 1.0–8.7). The adjusted length of stay in the ICU was not different between
groups. At discharge, the adjusted motor Functional Independence
Measure (FIM) score was significantly lower for subjects in the
etomidate group (32 versus 56, P = 0.002), but the adjusted
cognitive FIM score was not significantly different in the etomidate
group (35 versus 46, P = 0.15). Conclusion Procoagulant factors (F and TAT) are valuable
prognostic factors at day 1 in closed isolated severe head trauma. P358 No differences between S and NS in demographics, management
modalities, admission GCS score (7 ± 3), CT scan, and SAPS II
(27 ± 10 vs 30 ± 17, P = 0.69). The B vs simultaneous K platelet
count was significantly lower in all drawn blood samples, with a
trend to decrease over time. S vs NS at day 2 and day 3: 191 ± 60
vs 125 ± 35 (P = 0.017). The admission B thrombin fraction was
higher in NS (1,000 ± 209 vs 460 ± 294, P = 0.014). The B day 1
TAT was higher in NS: 45 ± 20 vs 9.6 ± 12 (P = 0.02). No S144 Available online http://ccforum.com/supplements/11/S2 P363 P363 norepinephrine concentrations (10 nM to 100 µM); thrombin
receptor activator peptide (TRAP) served as positive control. P-selectin expression was determined by flow cytometry (FACS). norepinephrine concentrations (10 nM to 100 µM); thrombin
receptor activator peptide (TRAP) served as positive control. P-selectin expression was determined by flow cytometry (FACS). Results Following TBI, the number of unstimulated P-selectin-
positive platelets was significantly decreased in the second week
by 60%. During the first week, the in vitro stimulatory effect was
significantly
reduced;
in
the
second
week,
however,
norepinephrine-mediated effects exceeded changes in controls
and the first week without a difference between arterial and jugular
venous platelets (Figure 1). P362 Patients We enrolled consecutive patients >12 years of age
expected to stay in the ICU >48 hours. We excluded patients on
systemic anticoagulation and patients with pulmonary embolism
(PE) or deep venous thrombosis (DVT) on admission to the ICU or
diagnosed within 24 hours of ICU admission. We recorded a priori
defined VTE risk factors at baseline and daily. Our ICU implements
a protocol for thromboprophylaxis, which is based on the evidence-
based ACCP guidelines. The primary endpoint was the develop-
ment of PE or DVT during ICU stay. We used multivariate
regression analysis to determine independent predictors of VTE. Patients We enrolled consecutive patients >12 years of age
expected to stay in the ICU >48 hours. We excluded patients on
systemic anticoagulation and patients with pulmonary embolism
(PE) or deep venous thrombosis (DVT) on admission to the ICU or
diagnosed within 24 hours of ICU admission. We recorded a priori
defined VTE risk factors at baseline and daily. Our ICU implements
a protocol for thromboprophylaxis, which is based on the evidence-
based ACCP guidelines. The primary endpoint was the develop-
ment of PE or DVT during ICU stay. We used multivariate
regression analysis to determine independent predictors of VTE. Results Among 277 patients with a mean APACHE II score of 25
(+9), the incidence of VTE was 7.2% (95% CI 4.5–11). We
identified three independent risk factors for ICU-acquired venous
thromboembolism: stroke (OR 13.5, 95% CI 1.9–91.19,
P = 0.008), femur fracture (OR 4.5, 95% CI 1.18–17.10, P = 0.03),
and ICU length of stay (OR for each day increment 1.08, 95% CI
1.03–1.13, P = 0.002). After adjustment for APACHE II score,
VTE was an independent predictor of mortality (OR 3.85, 95% CI
1.11–13.29, P = 0.03). Venous thromboembolism in critically ill patients:
incidence and risk factors Results Following TBI, the number of unstimulated P-selectin-
positive platelets was significantly decreased in the second week
by 60%. During the first week, the in vitro stimulatory effect was
significantly
reduced;
in
the
second
week,
however,
norepinephrine-mediated effects exceeded changes in controls
and the first week without a difference between arterial and jugular
venous platelets (Figure 1). S Al-Qahtani, Y Arabi, A Aldawood
KIing Abdulaziz Medical City, Riyadh, Saudi Arabia
Critical Care 2007, 11(Suppl 2):P363 (doi: 10.1186/cc5523) Objective Despite the high risk of venous thromboembolism (VTE)
in ICU patients, only few studies have examined this group of
patients systematically. The objective of this study is to examine the
incidence and risk factors of VTE among critically ill patients. Conclusion Clinically relevant norepinephrine concentrations are
<25 nM. The present in vitro effects occurred at concentrations
>500 nM. Thus, a clinically relevant impact appears doubtful. Design A prospective cohort study. Setting A closed university-affiliated ICU in a medical–surgical ICU
in the Kingdom of Saudi Arabia. Ultrasound evaluation and risk factors for deep venous
thrombosis in the intensive care unit Ultrasound evaluation and risk factors for deep venous
thrombosis in the intensive care unit M Boddi1, G Palano1, L Tini2, E Lucente1, S Berardino1,
G Gensini1, A Peris3
1Department of Medical and Surgical Critical Care, Careggi
Teaching Hospital, Florence, Italy; 2Department of Emergency,
Careggi Teaching Hospital, Florence, Italy; 3Ospedale Firenze,
Florence, Italy
Critical Care 2007, 11(Suppl 2):P362 (doi: 10.1186/cc5522) Results Among 277 patients with a mean APACHE II score of 25
(+9), the incidence of VTE was 7.2% (95% CI 4.5–11). We
identified three independent risk factors for ICU-acquired venous
thromboembolism: stroke (OR 13.5, 95% CI 1.9–91.19,
P = 0.008), femur fracture (OR 4.5, 95% CI 1.18–17.10, P = 0.03),
and ICU length of stay (OR for each day increment 1.08, 95% CI
1.03–1.13, P = 0.002). After adjustment for APACHE II score,
VTE was an independent predictor of mortality (OR 3.85, 95% CI
1.11–13.29, P = 0.03). Introduction Critically ill patients have a high risk of deep venous
thrombosis (DVT); however, data about prevalence and specific
risk factors in the ICU are conflicting and the prophylaxis strategies
are still debated. The aim of this study is to evaluate the prevalence
and risk factors in an ICU dealing with trauma and major surgery
patients. Methods We analyzed retrospectively data from 142 patients
(56 ± 4.8 years) admitted to the ICU from December 2004 to
December 2005. We recorded the history, diagnosis, SAPS II,
length of stay and major surgery. All patients received standard
prophylaxis (LMWH and/or mechanical device). For DVT diagnosis,
three compression ultrasound examinations were performed
(a) within 48 hours from admission, (b) between the 7th and 10th
days, and (c) between the 13th and 16th days. The prevalence of
DVT and risk factors were analyzed in the whole population and in
the following four groups: ≤40 years, 41–59 years, 60–74 years,
and ≥75 years. Statistics were determined using the Wilcoxon and
Mann–Whitney tests and one-way analysis of variance on SPSS;
P < 0.5 was considered significant. Conclusions VTE is relatively common complication in critically ill
patients and is associated with significant mortality. Longer ICU
length of stay, stroke and femur fracture are independent
predictors for VTE. These findings suggest the need for more
effective prophylactic strategies in critically ill patients, especially
those at higher risk. Acknowledgement Sponsored by Sanofi-Aventis. Figure 1 (abstract P361) Figure 1 (abstract P361)
Changes in P-selectin expression in isolated platelets stimulated in vitro with norepinephrine or TRAP. +P < 0.001 vs low-dose norepinephrine;
*P < 0.001 vs controls; #P < 0.001 vs first week. Changes in P-selectin expression in isolated platelets stimulated in vitro with norepinephrine or TRAP. +P < 0.001 vs low-dose norepinephrine;
*P < 0.001 vs controls; #P < 0.001 vs first week. S145 Critical Care March 2007 Vol 11 Suppl 2
27th International Symposium on Intensive Care and Emergency Medicin P364 Cardiopulmonary bypass and recombinant plasminogen
activator for treatment of experimental fatal pulmonary
embolism g
Results One hundred (70%) patients were admitted after trauma,
15 (11%) after surgery, 27 (19%) had medical disease. The mean
SAPS II score was 45 ± 15.8 and the mean length of stay was
16 ± 9.84 days. Forty-six patients (32.4%) underwent major surgery
following the admission. The overall prevalence of DVT was 17.6%
(25/142), with the highest value (24.2%) in the 41–59 year group
and the lowest (12.5%) in the >75 year group. DVT was
diagnosed in 12/25 (48%) patients within 48 hours from ICU
admission and 7/12 (58.3%) had direct venous injury. DVT was
diagnosed in the remaining patients after 10 days. We found a
strong relationship (P < 0.06) between the length of stay and DVT
in patients <40 years. No significant differences were found
regarding SAPS. Introduction Treatment of acute pulmonary embolism (PE), which
causes life-threatening cardiovascular collapse, consists of cardio-
pulmonary bypass (CPB) and surgical embolectomy. In the clinical
practice we have treated three such patients successfully with
CPB but instead of performing embolectomy, administered
recombinant plasminogen activator (rt-PA). We studied the
circulatory and respiratory effects of this combined therapy in a
swine model of fatal PE. Introduction Treatment of acute pulmonary embolism (PE), which
causes life-threatening cardiovascular collapse, consists of cardio-
pulmonary bypass (CPB) and surgical embolectomy. In the clinical
practice we have treated three such patients successfully with
CPB but instead of performing embolectomy, administered
recombinant plasminogen activator (rt-PA). We studied the
circulatory and respiratory effects of this combined therapy in a
swine model of fatal PE. Conclusions In our experience, DVT prevalence showed a bimodal
occurrence with a first short-term peak, associated with traumatic
or surgical direct venous injury, and a medium-term peak, related to
an ICU stay >10 days. We therefore oriented the surveillance to
the two periods of higher DVT prevalence and we established a
training program for the intensivists to improve DVT detection,
relieving the workload of the ultrasound physician. Methods Seven pigs (90 kg) were i.v. anesthetized, muscle
relaxed, tracheally intubated and mechanically ventilated (FiO2
1.0). Fibrinolysis during cardiopulmonary bypass detected with
thromboelastography R Hájek, J Ruþièková, I Fluger, P Nemec, V Bruk
University Hospital, Olomouc, Czech Republic
Critical Care 2007, 11(Suppl 2):P366 (doi: 10.1186/cc5526) Results Five animals developed ventricular fibrillation, while one
animal maintained sinus rhythm. After 2 hours all animals had an
atrial rhythm. All animals were weaned off CPB and survived until
the experiment ended. Values before and after CPB (median and
range): MAP (mmHg) 101 (86, 109) and 75 (46, 106); CO (l/min)
6.7 (4.3, 11) and 6.2 (3.6, 7.8); MPAP (mmHg) 22 (19, 36) and 44
(31, 82) (P < 0.05); ETCO2 (kPa) 5.6 (4.3, 6.5) and 2.7 (2.4, 3.4)
(P < 0.05); PaCO2 (kPa) 6.2 (5.2, 7.2) and 6.1 (4.8, 7.3); PaO2
(kPa) 60 (50, 68) and 55 (30, 64). Background Fibrinolysis is a common haemostatic abnormality
during cardiopulmonary bypass (CPB). Thromboelastography
(TEG) is a good method to detect both types of fibrinolysis. Methods Four hundred and ninety-nine patients during mild
hypothermic CPB and elective surgery were monitored with TEG
(first – after the induction, second – after rewarming, third and
fourth – at the end of surgery native and heparinase). No prophy-
lactic antifibrinolytics were used. The data of the study group were
compared with a control group of 475 patients monitored only with
laboratory tests (fibrin degradation products (FDP) and D-dimers). Peroperative and 24 hour postoperative bleeding, number of
transfusions, aprotinin therapy and reexploration were recorded. Correlations between the presence of fibrinolysis and blood loss
and transfusion therapy and between aprotinin administration and
blood loss and number of transfusions were evaluated. Conclusion Although there were signs – that is, lower ETCO2 and
higher MPAP – that the massive clots were not fully dissolved after
185 minutes, this study shows that fatal PE might be treated
effectively with CPB combined with simultaneous thrombolytic
therapy. P364 A large-bore catheter (8.5 mm ID) was inserted in the right
superior vena cava (for injection of preformed blood clots) and
large-bore catheters were inserted in the inferior vena cava via the S146 Available online http://ccforum.com/supplements/11/S2 Available online http://ccforum.com/supplements/11/S2 Available online http://ccforum.com/supplements/11/S2 femoral vein and in the aorta via the femoral artery (for accessing
CPB). We measured the mean arterial pressure (MAP), cardiac
output (CO), blood gases, pulmonary artery pressure measurement
(MPAP), end-tidal CO2 (ETCO2) and blood gases. Then 100–300 ml
preformed blood clot was injected until systemic circulation
ceased (systolic AP < 25 mmHg) and a 5 minute interval was
allowed before start of CPB (flow rate of 4–7 l/min). Heparin
10,000 IE was given i.v., and rt-PA 10 mg as an i.v. bolus followed
by an i.v. infusion of 90 mg during 2 hours. If ventricular fibrillation
occurred, cardioversion was performed. After 145 minutes CPB
was weaned off, and after a further 40 minutes the experiment was
ended. procoagulant pathways. Although fibrinolysis was activated, the
inhibition of fibrinolysis was more pronounced at the same time. The coagulation inhibitors and TAT levels seem to be early
predictors of ICU mortality. Early coagulation alterations in intensive care unit burn
patients A Lavrendieva1, A Parlapani2, O Thomareis2, V Soulountsi1,
M Bitzani1
1G Papanikolaou Hospital, Thessalonki, Greece; 2Aristotelian
University, Thessaloniki, Greece
Critical Care 2007, 11(Suppl 2):P365 (doi: 10.1186/cc5525) al Care 2007, 11(Suppl 2):P365 (doi: 10.1186/cc5525) Introduction The aim of the present study was to examine the
coagulation status of patients in the early postburn period. Introduction The aim of the present study was to examine the
coagulation status of patients in the early postburn period. Method Coagulation and fibrinolysis parameters – antithrombin III
(ATIII), protein C (PrC), free protein S (PrS), plasminogen activator
inhibitor 1 (PAI-1), tissue plasminogen activator (t-PA), thrombin/
antithrombin complexes (TAT), plasmin/α2-antiplasmin complexes
(PAP), fibrin degradation products (F1.2) – were measured at ICU
admission and daily thereafter for 7 postburn days. Conclusion Fibrinolysis was usually not associated with serious
bleeding. There was no positive effect of aprotinin to reduce
bleeding or transfusion therapy. FDP and D-dimers are not useful
to detect fibrinolysis in cardiac surgery. Results Forty-five patients were screened (nine nonsurvivors and
36 survivors). All patients had a severe deficiency of the coagulation
inhibitors on admission. Normalization of these levels in survivors
was observed at day 5 for ATIII and PrC, and at day 7 for PrS. All
patients had elevated levels of TAT during the investigation period,
but survivors had significantly lower levels at day 7 postburn
(6.2 ± 4.9 vs 11.4 ± 4.5 µg/l, P < 0.001). PAP levels were within
the physiological range in both groups at day 1, remained low in
survivors, but raised significantly in nonsurvivors at day 7
(19.3 ± 14 vs 80.9 ± 10.4 µg/l, P = 0.003). The t-PA levels were
elevated permanently only in nonsurvivors. PAI-1 levels were
increased at day 1 in both groups, but returned to normal values at
day 5 in survivors. The degree of PAI-1 activation was significantly
higher than this of t-PA. The F1.2 levels were permanently elevated
and there was no statistically significant difference in both groups. A logistic regression analysis revealed that ATIII and PrS at days 3,
5 and 7, Pr C at days 5 and 7 and TAT at day 7 were independent
predictors of ICU death. P365 Results The frequency of fibrinolysis measured with TEG: before
surgery – primary 3.2%/secondary 3.4%; during CPB – 18.8%/
0.6%; after surgery – 7%/1.4% (native), 5.6%/0.6% (heparinase). Positivity of fibrinolysis detected with laboratory tests was 100%. The TEG parameter of fibrinolysis (LY30) was significantly
increased during CPB. The frequency of aprotinin administration
was 12% TEG, 10.7% control. No correlation between positivity of
fibrinolysis and peroperative/postoperative blood loss and red
blood cells (RBC) and fresh frozen plasma (FFP) transfusions were
recorded. No correlation between aprotinin administration and
peroperative/postoperative blood loss and RBC transfusion were
recorded. Positive correlation between aprotinin administration and
FFP transfusion were recorded Early coagulation alterations in intensive care unit burn
patients P366 Fibrinolysis during cardiopulmonary bypass detected with
thromboelastography Fibrinolysis during cardiopulmonary bypass detected with
thromboelastography P368 Low-frequency hemoviscoelastography: a new method of
diagnostics for coagulation disorders after abdominal
surgery for cancer
O Tarabrin, A Simovskykh, V Mazur, A Suhanov
Odessa Medical University, Marine Central Hospital, Odessa,
Ukraine
Critical Care 2007, 11(Suppl 2):P368 (doi: 10.1186/cc5528) Low-frequency hemoviscoelastography: a new method of
diagnostics for coagulation disorders after abdominal
surgery for cancer Objective Cardiac surgery, in particular when done with cardio-
pulmonary bypass (CPB), is frequently associated with excessive
intraoperative and postoperative bleeding. Here we employed the
Technothrombin® thrombin generation assay (TGA; Technoclone)
to monitor changes in perioperative haemostasis. O Tarabrin, A Simovskykh, V Mazur, A Suhanov
Odessa Medical University, Marine Central Hospital, Odessa,
Ukraine
Critical Care 2007, 11(Suppl 2):P368 (doi: 10.1186/cc5528) Methods One hundred and forty-eight patients (age 66.0 ± 9.8 years;
103 males, 45 females) with elective cardiac surgery and a CPB
time >45 minutes (mean 114 ± 56 min) were enrolled. Arterial
blood samples were obtained preoperative, postoperative and
14–18 hours postoperative and centrifuged within 30 minutes
after withdrawal, for 5 minutes at 5,000 x g. Plasma samples were
stored until analysis at –80°C. Thrombin generation (TG) induced
by the TGA RC low reagent (71.6 pM tissue factor) was measured
in 96-well multiplates using a FLUOstar OPTIMA fluorescence
reader (MWG Labtech). Critical Care 2007, 11(Suppl 2):P368 (doi: 10.1186/cc5528) Critical Care 2007, 11(Suppl 2):P368 (doi: 10.1186/cc5528) Background Venous thromboembolism is one of the most
common complications seen in cancer patients and may be due to
the hypercoagulable state of the malignancy and to its surgical
treatment. Despite clinical and laboratory evidence of perioperative
hypercoagulability, there are no consistent data evaluating the
extent, duration, and specific contribution of platelets and pro-
coagulatory proteins by in vitro testing. Results Due to cardiac surgery, the lag-phase and time-to-peak of
TG increased by 45% and 35%, respectively. In parallel, the peak
thrombin concentration and maximum slope decreased by 42%
and 51%, respectively (P < 0.000001). Both the lag-phase and
time-to-peak returned to basal values within 14–18 hours
postoperative, but the peak thrombin and maximum slope of TG
rose above the preoperative values (+39% and +68%, P < 0.0005). The on-pump time was positively correlated with lag phase and
time to peak and negatively correlated with peak thrombin and
maximum slope of TG when measured at 14–18 hours
postoperative, but there was no correlation at early postoperative. P367 ROTEM® thrombelastometry in on-pump cardiac surgery
patients W Loesche, M Reinhöfer, C Macholdt, M Brauer, D Barz,
J Gummert, K Reinhart, G Marx
University Hospital Jena, Germany
Critical Care 2007, 11(Suppl 2):P367 (doi: 10.1186/cc5527) W Loesche, M Reinhöfer, C Macholdt, M Brauer, D Barz,
J Gummert, K Reinhart, G Marx
University Hospital Jena, Germany
Critical Care 2007, 11(Suppl 2):P367 (doi: 10.1186/cc5527) Objective On-pump cardiac surgery is frequently associated with
intraoperative and postoperative bleeding. ROTEM® is a point-of-
care method that reflects more closely than classical coagulation
tests the in vivo haemostatic activity and the contribution of
fibrinogen and platelets to clot formation. Methods Two hundred and thirty-two patients (age 67 ± 10 years)
with elective cardiac surgery and an on-pump time >45 minutes
(mean 112 ± 52 min) were enrolled. Preoperative, intraoperative
and postoperative blood samples were taken from an arterial
catheter. The ROTEM® system and test kits (INTEM/EXTEM = Conclusion Our findings indicate the early postburn dysregulation
of the hemostatic balance characterized by the activation of S147 Critical Care March 2007 Vol 11 Suppl 2
27th International Symposium on Intensive Care and Emergency Medicin was a 14% perioperative increase of standard MA, corresponding
to a 48% increase of Gt (P < 0. 05) and an 80–86% contribution
of the calculated Gp to Gt. We conclude that serial standard TEG
and the HVG viscoelastic test may reveal the independent
contribution of platelets and procoagulatory proteins to clot
strength. Using multiple linear regression, all coagulation, TEG and
HVG variabilities were used to model postoperative hyper-
coagulation. Results showed that some components of the TEG
failed to identify hypercoagulation (r < 0.2, P > 0.75). However,
three components of the routine coagulation assay, including
bleeding time, prothrombin time, and platelet count, could be
modeled to show prolonged postoperative hypercoagulability
(P < 0.01). We conclude that all components of the HVG test
reflect postoperative coagulopathies; these results suggest that it
may be useful in determining the coagulation status of cancer
patients perioperatively. platelets) were from Pentapharm (Munich, Germany). Results The clot formation time (CFT) and maximum clot firmness
(MCF), but not clotting time (CT), were strongly correlated with the
fibrinogen level and platelet count. Surgery significantly decreased
the ROTEM haemostatic activity, but normalised in most patients
within 14–18 h postoperation. Lowest haemostatic activity (dramatic
increase in CT and CFT, decrease in MCF) was seen when
patients were conditioned for cardiopulmonary bypass (CPB). Thrombin generation in on-pump cardiac surgery patients W Loesche, V König, V Oberle, M Reinhöfer, D Barz,
J Gummert, G Marx
University Hospital Jena, Germany
Critical Care 2007, 11(Suppl 2):P369 (doi: 10.1186/cc5529) P367 When connected to CPB, the CT and CFT turned to recover, but
MCF in EXTEM remained unchanged and MCF in FIBTEM
declined further indicating continuous fibrinogen consumption. In
12.5% of our patients, postoperative MCF in FIBTEM was reduced
to <9 mm indicating a need for fibrinogen substitution. Low
postoperative activity in ROTEM® was associated with high
postoperative blood loss. The positive predictive value and
specificity of FIBTEM were clearly superior to those of the APTT or
prothrombin time. Up to 50% of patients had an increased
haemostatic activity in preoperative ROTEM®, and this was
associated with high CRP levels and intraoperative blood loss. Conclusion Postoperative hypercoagulability, occurring for at least
1 week after major cancer abdominal surgery, may be
demonstrated by the HVG viscoelastic test. This hypercoagulability
is not reflected completely by standard coagulation monitoring and
TEG, and seems to be predominantly caused by increased platelet
reactivity. The HVG viscoelastic test provides a fast and easy to
perform bedside test to quantify in vitro hemocoagulation. Conclusions ROTEM® is a valuable tool to monitor peri-
operative haemostasis. The decreases in haemostatic activity
and postoperative bleeding are probably due to anticoagulant
therapy as well as fibrinogen and platelet consumption. An
increased preoperative haemostatic activity is probably due to
an acute phase reaction associated with advanced athero-
sclerosis, and the high intraoperative bleeding in these patients
might be due to the atherosclerotic vessels rather than due to an
insufficient haemostasis. P370 There were 12 minor bleeding events, occurring mostly during the
maintenance infusion rate adjustment period and which responded
to transient interruption and/or lowering of the infusion rate. Eleven
nonfatal major bleeding events occurred (four due to procedural
errors) and eight fatal major bleeds, two of which occurred 3 days
and 8 days after Orgaran® discontinuation. Activated clotting time (ACT) measuring devices used
simultaneously do not produce correlating ACT values I Lorenz, J Walde, C Schnuerer, C Velik-Salchner, P Muessigang,
A Jeller, J Engel, R Gruber, C Falbesoner, C Kolbitsch
University Innsbruck, Austria
Critical Care 2007, 11(Suppl 2):P370 (doi: 10.1186/cc5530) Plasma anti-FXa levels were reported for 38 patients. During seven
of the eight fatal bleeding episodes the plasma anti-FXa levels
were ≥0.8 U/ml in three patients and 0.31–0.66 U/ml (that is,
within the target range) in the other four patients. The highest anti-
FXa response of 2.00 U/ml was associated with minor bleeding
from an angiomatous malformation and stopped when the
Orgaran® dose was reduced. However, of the 11 patients
receiving >400 U/hour, four suffered major bleeding (three fatal)
and two developed minor bleeding. Most of these patients
received continuous arterio-venous haemodiafiltration treatment,
which may have been a contributory factor. Introduction The lack of a ‘gold standard’ activated clotting time
(ACT) measuring device gives rise to the broad range of ACT
measuring devices currently on the market. The present study
focused on the inter-device and intra-device differences (for
example, reproducibility of ACT measurement) in four different ACT
measuring systems. Methods (1) Hemochron celite tubes, (2) Aktalyke celite tubes,
(3) Actalyke ACT-Max tubes and (4) Hemochron Junior low-range
(LR) or high-range (HR) cartridges were simultaneously filled with
blood drawn (n = 3,997) at baseline, at 3 minutes following
administration of heparin (300 IU/ kg), 5 minutes after starting
cardiopulmonary bypass (CPB), every 30 minutes during CPB and
thereafter at 15 minutes following protamine administration. Conclusions We recommend that maintenance Orgaran® infusion
rates ≥400 U/hour should be avoided unless serious circuit
clotting is grossly affecting the haemofilter life. The infusion rate
should be monitored clinically; that is, on the basis of bleeding and
circuit clotting rather than the patients’ plasma anti-FXa responses. Results The ACT values measured simultaneously using four
different ACT measuring devices did not correlate with each other
at any measurement time. P371 Introduction Heparin-induced thrombocytopenia (HIT) presents with
thrombocytopenia and high risk for venous and/or arterial
thrombosis, as an adverse effect of heparin (especially unfractioned). Objective To evaluate the incidence of positive heparin antibody
test in a multidisciplinary ICU for the time period from 1 January
2006 to 30 November 2006. Introduction Heparin-induced thrombocytopenia (HIT) presents with
thrombocytopenia and high risk for venous and/or arterial
thrombosis, as an adverse effect of heparin (especially unfractioned). Objective To evaluate the incidence of positive heparin antibody
test in a multidisciplinary ICU for the time period from 1 January
2006 to 30 November 2006. Available online http://ccforum.com/supplements/11/S2 Conclusions The data provide clear evidence for a marked
decrease of TG during cardiac surgery followed by an excess
restoration in the postoperative phase. Factors released from
platelets and leukocytes (procoagulant microvesicles?) might
contribute to the enhanced TG observed at 14–18 hours
postoperative. Conclusions The data provide clear evidence for a marked
decrease of TG during cardiac surgery followed by an excess
restoration in the postoperative phase. Factors released from
platelets and leukocytes (procoagulant microvesicles?) might
contribute to the enhanced TG observed at 14–18 hours
postoperative. A variety of continuous extracorporeal haemofiltration circuits was
used for from 1 to 39 days (median 7 days). The Orgaran® dosing
schedule was usually initiated with a 2,000–2,500 U intravenous
bolus injection. After two step-down dose periods the subsequent
maintenance infusion was usually titrated according to each
patient’s thromboembolic and bleeding risk status. Hence most
patients received 100–400 U/hour, but 11 patients required up to
600 U/hour temporarily to control extracorporeal circuit clotting. P372 High incidence of positive heparin antibodies in a
multidisciplinary intensive care unit P Renieris, V Gerovasili, M El Ali, T Theodoridis, M Poriazi,
A Bouhla, V Markaki, S Mentzelopoulos, D Zervakis,
C Roussos, S Nanas
National and Kapodistrian University of Athens, Greece
Critical Care 2007, 11(Suppl 2):P372 (doi: 10.1186/cc5532) Conclusion The Hemochron Junior ACT measuring device
showed the smallest intra-device measuring error. No correlation,
however, could be established between ACT values measured
with the four devices tested. P370 Reproducibility of ACT measurement (for
example, intra-device difference) was, in descending order, best for
Hemochron Junior, Actalyke ACT-Max, Hemochron celite and
Aktalyke celite. P368 With respect to classical coagulation parameters, significant
correlations were observed between TG and activated partial
thromboplastin time at preoperative and 14–18 hours post-
operative, and between TG and prothrombin time at postoperative
(P < 0.025–0.001). At 14–18 hours postoperative there was a
significant correlation of TG with platelet as well as leukocyte
counts (P < 0.025). Materials and methods Patients undergoing planned curative
open surgery for abdominal cancer received MEDNORD (Ukraine
Co analyser) analysis (HVG), a viscoelastic test that measures clot
formation and includes information on the cellular, as well as the
plasmatic coagulation, system. We examined the efficacy of a
variety of coagulation tests. A complete coagulation screen,
activated clotting time, thromboelastography (TEG) and hemo-
viscoelastography (HVG) were performed before surgery, at the
end of surgery, and on postoperative days 1, 2, 3, and 7; they were
analyzed for the reaction time and the maximal amplitude (MA). We
tested the hypothesis that the parallel use of standard TEG and
HVG can assess postoperative hypercoagulability and can
estimate the independent contribution of procoagulatory proteins
and platelets. Results and discussion We calculated the elastic shear modulus
of standard MA (Gt) and HVG MA (GH), which reflect the total clot
strength and procoagulatory protein component, respectively. The
difference was an estimate of the platelet component (Gp). There S148 Available online http://ccforum.com/supplements/11/S2 P373 Moreover, 19 healthy donors
never exposed to heparin also participated as negative controls. The antibody determination was performed using commercially
available ELISA kits. In the functional assays, heparin-induced
platelet activation/aggregation (HIPA) and a flow cytometric
technique for the detection of platelet microparticles released
(platelet microparticle assay) were included. Conclusion Exclusion of female-donor FFP was associated with a
statistically significant reduction in the incidence of ALI in patients
undergoing repair of a ruptured AAA. Results None of the negative control individuals were positive in
any applied method. In contrast, all the participants of the positive
control group were found positive in all the applied methods. No
HIT was detected in 10 patients, seven of whom were pregnant at
different gestational ages. The remaining 43 thrombocytopenic
patients were positive in HIPA and 39 of them were also positive in
the platelet microparticle assay. Out of these 39 patients, only 16
were positive in the ELISA assay. Orgaran® use in intensive care unit patients with heparin-
induced thrombocytopenia and acute renal failure H Magnani1, J Wester2
1NV Organon, Oss, The Netherlands; 2Onze Lieve Vrouwe
Gasthuis, Amsterdam, The Netherlands
Critical Care 2007, 11(Suppl 2):P371 (doi: 10.1186/cc5531) Methods We retrospectively reviewed all laboratory tests for
heparin antibodies requested from the ICU for the period of
January–November 2006. The blood sample analysis was
performed with ELISA (Asserachrom® HPIA; Diagnostica Stago,
Asnieres, France). All patients were receiving fractioned heparin
subcutaneously for prophylaxis when indicated. Flushes of
unfractioned heparin for catheter clotting prevention were given to
all patients. Only ‘positive’ results were considered positive, whilst
‘mildly positive’ and ‘uncertain’ results were considered negative. Introduction Orgaran® (danaparoid sodium) is a low-molecular-
weight, nonheparin glycosaminoglycan antithrombotic that is
currently a first-line treatment for heparin-induced thrombocyto-
penia (HIT). This study reports on the safety of Orgaran® in ICU
patients suffering from HIT and acute renal failure requiring
continuous renal replacement therapy (haemofiltration). Methods Data on 96 case reports from personal experience and
publications have been collated. Results During that period 300 patients were admitted (mean
duration of stay 15 ± 16 days, 25th–75th 4–22 days) to the ICU;
212 (70%) were survivors and 88 (30%) were nonsurvivors. All
patients presenting with thrombocytopenia (platelets < 150,000/dl)
or showing a decrease >50% of their admission day’s platelet
count were checked for heparin antibodies. Fifty-two samples
retrieved from 48 patients suspicious for HIT were sent for heparin
antibody analysis. Of the 48 patients checked, 15 (31%) were
positive and 33 (68%) negative. Three of the suspected patients Results Nineteen females and 59 males (18 unknown gender)
with a median age of 60 years (range 22–95 years) presented with
a variety of clinical problems that either preceded or complicated
their HIT; for example, postoperative/accidental trauma or overt
bleeding in 61, sepsis/septicaemia/septic shock in 37, thrombo-
embolism in 23, multiple organ dysfunction syndrome in 14,
disseminated intravascular coagulation in eight and other miscel-
laneous serious problems in 38. S149 Critical Care March 2007 Vol 11 Suppl 2
27th International Symposium on Intensive Care and Emergency Medicin P374 suffered from pulmonary embolism and were treated with
therapeutic doses of i.v. unfractioned heparin; one of them was
positive for heparin antibodies. The effect of male-donor-only fresh frozen plasma on the
incidence of acute lung injury following ruptured
abdominal aortic aneurysm repair Conclusions Our findings of high incidence of positive heparin
antibodies may be mainly due to unfractioned heparin flushes. The
use of heparin flushes with the new high-quality catheters and
monitoring kit is questionable. Since low doses of unfractioned
heparin could lead to the production of antibodies and subsequently
to HIT, further studies should examine the risk-to-benefit ratio of the
use of unfractioned heparin flushes in the ICU setting. S Wright, S Athey, A Leaver, C Snowden, D Roberts,
J Clarkson, C Chapman, J Wallis
Freeman Hospital and National Blood Service, Newcastle upon
Tyne, UK
Critical Care 2007, 11(Suppl 2):P374 (doi: 10.1186/cc5534) S Wright, S Athey, A Leaver, C Snowden, D Roberts,
J Clarkson, C Chapman, J Wallis
Freeman Hospital and National Blood Service, Newcastle upon
Tyne, UK
Critical Care 2007, 11(Suppl 2):P374 (doi: 10.1186/cc5534) Introduction Transfusion-related acute lung injury, due to plasma
from female donors containing antileucocyte antibodies, may be a
common contributor to the development of acute lung injury (ALI)
in the critically ill. In July 2003 the English Blood Service stopped
using female donor plasma for the manufacture of fresh frozen
plasma (FFP). Patients undergoing repair of ruptured abdominal
aortic aneurysm (AAA) receive large amounts of FFP and often
develop ALI. We investigated whether the change to male-only
FFP was associated with a change in incidence of ALI in patients
undergoing emergency AAA repair. P373
The beneficial effects of the combined methods in
investigating heparin-induced thrombocytopenia
M Kounavi, C Kroupis, E Iliopoulou, D Karamichaleli,
M Katafigioti, D Degiannis, E Melissari
Onassis Cardiac Center, Athens, Greece
Critical Care 2007, 11(Suppl 2):P373 (doi: 10.1186/cc5533) P373 P373 The beneficial effects of the combined methods in
investigating heparin-induced thrombocytopenia M Kounavi, C Kroupis, E Iliopoulou, D Karamichaleli,
M Katafigioti, D Degiannis, E Melissari
Onassis Cardiac Center, Athens, Greece
Critical Care 2007, 11(Suppl 2):P373 (doi: 10.1186/cc5533) Methods A before-and-after, observational, single-centre study. Subjects were 211 consecutive patients undergoing open repair of
a ruptured AAA between 1998 and 2006. Primary outcome was
development of ALI (PaO2/FiO2 < 300 and bilateral pulmonary
infiltrates on chest X-ray) in the first 6 hours after surgery. Secondary outcomes were time to extubation, and survival at
30 days. Chest X-rays were examined independently by two
radiologists who were blinded to the study hypothesis. Introduction Heparin-induced thrombocytopenia (HIT) type II is a
serious side effect of unfractionated heparin, and to a lesser extent
of low molecular weight heparins. It is mediated through an
immunological mechanism and leads to platelet aggregation. The
occurrence of HIT varies between 1% and 5% of patients
receiving heparin while a substantial fraction of them develops
thrombosis (HITT). Therefore, the rapid and accurate confirmation
of HIT is a necessity. The laboratory assays available for the
diagnosis of HIT are based on the detection of HIT antibodies or
on the consequences of platelet activation (functional methods). Results One hundred and twenty-nine patients were operated on
before and 82 after the change in FFP procurement. Groups were
well matched, with respect to age, sex, co-morbidities and severity
of illness, and received similar volumes of i.v. fluids and blood
products from admission to 6 hours postoperatively (mean units of
FFP, 8.6 before and 8.39 after, P = 0.833). The maximum tidal
volume, PEEP, and CVP were similar in both groups. Norepinephrine was given to 8.5% of patients in the before group
compared with 24.4% after (P = 0.001), otherwise inotrope use
was similar. Primary outcome: there was significantly less ALI
following the change to male-only FFP (36% before vs 21% after,
P = 0.042). Secondary outcomes were not statistically different
between groups; however, patients with ALI in either group had a
poorer 30-day survival (59% vs 80%, P = 0.005). The purpose of the present study was to improve HIT recognition by
the combination of functional and antibody determination assays. Patients
and
methods
Fifty-three patients who presented
thrombocytopenia while receiving UFH or LMWH participated in
the study. A positive control group consisting of 15 patients known
to suffer from HIT/HITT was used. P375 A biochemical comparison of Octaplas with a universally
applicable development product (Uniplas) and single-
donor fresh-frozen plasmas subjected to methylene-blue
dye and white-light treatment Conclusions In comparison with the HIT-positive control group it
was found that: a 92% agreement existed between the HIPA and
the platelet microparticle assays; and the positive results in the
ELISA were significantly lower than in the functional methods,
indicating perhaps a lower sensitivity (41% agreement with the
flow cytometric method and 32% with the HIPA). Therefore, the
combination of functional and antibody detection assays is a
necessity for the HIT recognition since both could give pseudo-
positive or pseudo-negative results. A Heger, J Römisch, T Svae
Octapharma PPGmbH, Vienna, Austria
Critical Care 2007, 11(Suppl 2):P375 (doi: 10.1186/cc5535) A Heger, J Römisch, T Svae
Octapharma PPGmbH, Vienna, Austria
Critical Care 2007, 11(Suppl 2):P375 (doi: 10.1186/cc5535) Introduction The aim of this study was to perform an extensive
biochemical
comparison
of
the
pharmaceutically
licensed
coagulation active plasma Octaplas with an identical, but
universally applicable, development product (Uniplas) and single-
donor fresh-frozen plasma (FFP) units subjected to a medical
device treatment using a combination of methylene-blue dye and
subsequent white-light exposure (MB plasma). S150 Available online http://ccforum.com/supplements/11/S2 Available online http://ccforum.com/supplements/11/S2 investigators evaluated the overall efficacy of Octaplex in 84.2% of
cases as ‘very good’ and in 14.9% of cases as ‘moderate’. No
adverse drug reactions or interactions were reported. Conclusions Octaplex is effective in perioperative prophylaxis of
bleeding in patients with a coagulation deficit caused by treatment
with vitamin K antagonists. Octaplex is also effective in treatment
of acute bleeding. Octaplex was well tolerated, with no adverse
reactions being reported during the study. Methods Twenty-four batches of Octaplas of different blood
groups and different plasma sources, three batches of Uniplas
(both products manufactured by Octapharma PPGmbH, Vienna,
Austria) and 20 random commercially available bags of MB plasma
of different blood groups were analysed. Beyond the global
coagulation parameters, the activities of coagulation factors and
protease inhibitors, as well as plasminogen, activated factor VII,
plasma turbidity and lipid components, were quantified. investigators evaluated the overall efficacy of Octaplex in 84.2% of
cases as ‘very good’ and in 14.9% of cases as ‘moderate’. No
adverse drug reactions or interactions were reported. Conclusions Octaplex is effective in perioperative prophylaxis of
bleeding in patients with a coagulation deficit caused by treatment
with vitamin K antagonists. P375 Octaplex is also effective in treatment
of acute bleeding. Octaplex was well tolerated, with no adverse
reactions being reported during the study. Results Similar to Octaplas, Uniplas showed standardised levels
of coagulation factors, plasminogen and protease inhibitors
(decreased protein S and antiplasmin activities) according to the
product specifications. MB plasma revealed fibrinogen levels close
to or below the physiological range (<1.5 mg/ml). Coagulation
factor activities in single MB plasma units both below and above
the normal ranges for FFP were found in this study, reflecting the
considerable variability of clinically important plasma proteins. Moreover, MB plasma revealed a higher turbidity after thawing,
probably due to the elevated lipid parameters. P376 Octaplex in routine clinical use for prophylaxis and therapy
of bleeding in patients with prothrombin complex factor
deficiency T Franken1, W Rees2, N Hübner2, J Albers3, B Gansera4, M Uhl5,
C Niessner6, B Sedemund-Adip7, T Tödter8
1Octapharma GmbH, Langenfeld, Germany; 2Schüchtermannklinik,
Bad Rothenfelde, Germany; 3Klinikum der Joh Gutenberg Universität,
Mainz, Germany; 4Städt Krankenhaus München-Bogenhausen,
München, Germany; 5Klinikum Starnberg, Germany; 6Diakonissen
Krankenhaus, Karlsruhe, Germany; 7Universitätsklinikum Lübeck,
Germany; 8Albertinen-Krankenhaus, Hamburg, Germany
Critical Care 2007, 11(Suppl 2):P376 (doi: 10.1186/cc5536) Results The median total dose was 41.1 IU/kg body weight (range
15.3–83.3 IU/kg body weight). In total the mean infusion rate was
6.42 ml/minute for the first infusion. In about one-third of the
patients an average infusion rate of ≥8 ml/minute was used. The
median INR decreased from 2.8 (1.5–9.5) to 1.1 (1.0–1.9) after
10 minutes and remained at that level at measurements 30 and
60 minutes after infusion. There was a rapid increase in coagulation
factor activity within the first 10 minutes as well. This activity
remained stably elevated for at least 4–6 hours, confirming the INR
results. Of 56 patients evaluable for efficacy, for 51 (91%) the
geometric mean of postinfusion values was equal to or less than
the predetermined target INR. Overall haemostatic efficacy was
assessed as ‘excellent’ by investigators in all 56 patients. Three of
the 60 patients had minor adverse drug reactions possibly related
to Octaplex. No evidence of thrombotic side effects was observed. Conclusions Octaplex corrects quickly, effectively and safely the
INR to a predetermined level in patients with vitamin K antagonist-
related deficiency of prothrombin complex coagulation factors. Introduction Octaplex is a new prothrombin complex concentrate
that is indicated for treatment or perioperative prophylaxis of
bleeding in patients with deficiency of the prothrombin complex
coagulation factors, such as deficiency caused by treatment with
vitamin K antagonists or by liver failure, when rapid correction of
bleeding is required. The study was conducted to demonstrate
both prevention of bleeding and achievement of haemostasis in
acute bleeding and to obtain further information about the safety of
administration of Octaplex. Methods One hundred and one patients were included in this
observational study with determination of the INR as part of routine
clinical management. The endpoint of this study was perioperative
prophylaxis of bleeding or successful treatment of acute bleeding
according to clinical signs. P377 Reversal of oral anticoagulation with prothrombin complex
concentrate (Octaplex) H Riess1, A Meier-Hellmann2, J Motsch3, M Elias4, F Kursten5,
C Dempfle6
1Charité-Universitätsmedizin Berlin, Germany; 2HELIOS Klinikum
Erfurt GmbH, Erfurt, Germany; 3Universitätsklinikum Heidelberg,
Germany; 4HaEmek Medical Center, Afula, Israel; 5Octapharma
Pharmazeutika Produktions ges.m.b.H., Wien, Austria;
6Universitätsklinikum Mannheim, Germany
Critical Care 2007, 11(Suppl 2):P377 (doi: 10.1186/cc5537) Conclusion This study showed that there are significant differences
in the biochemical characteristics between Octaplas and MB
plasma, while Uniplas revealed the same high quality as Octaplas. The variability of several plasma proteins in the 20 individual MB
plasma units tested was high compared with Octaplas/Uniplas. For
plasma prescribers and physicians it is also important to consider
the significant loss of functional fibrinogen in MB plasma when
planning and monitoring the treatment of severely ill patients. Introduction Oral anticoagulant therapy with vitamin K antagonists
may need to be rapidly reversed if acute bleeding occurs or surgical
intervention is required. This can most effectively be achieved by
administering prothrombin complex concentrates (PCCs), which
correct the INR more quickly than fresh frozen plasma without the
problem of volume overload. Octaplex, a virus-inactivated PCC con-
taining balanced potencies of coagulation factors and the regulating
proteins C and S, was developed with the intention of making a
rapid contribution to coagulation whilst limiting the risk of thrombosis. Methods The objective of this prospective, open-label study was
to demonstrate that Octaplex, when individually dosed, efficiently
corrects the INR within 1 hour post infusion. Sixty patients were
included, 56 of them evaluable in terms of efficacy. P378 vein thrombosis and spinal cord infarction. Of these two, one died
secondary to coagulopathic complications post initiation of
warfarin therapy 2 weeks post surgery. vein thrombosis and spinal cord infarction. Of these two, one died
secondary to coagulopathic complications post initiation of
warfarin therapy 2 weeks post surgery. Conclusion Our results support the evidence that recombinant
factor VII is an effective haemostatic agent that can be used in
patients with uncontrolled bleeding in postcardiopulmonary bypass
surgery. Despite its high cost, there is an advantage in terms of
effectiveness to support its use. However, its potential thrombo-
embolic risk remains a concern and current evidence may restrict
its use only as a rescue therapy following failed conventional
treatment. Results
Indications for administration of the rFVIIa were
considered when there was a postsurgical bleeding (exceeding
400 ml/hour) in the absence of surgical sources of the bleeding
and lack of efficacy of the conventional hemostatic procedures. After administration of the first median dose (14.45–81.35 µg/kg)
rFVIIa bleeding stopped in 11 patients. A marked decrease
occurred in seven patients during 2 hours. The average blood lost
within 12 hours before treatment was 2,510 ml and the average
blood lost within 12 hours after treatment was 1,057 ml. The
average dynamic of bleeding before treatment was 1,057 ml/hour
and 87.90 ml/hour after treatment. The reduction in transfusion
requirements was statistically significant. Conclusion Our results support the evidence that recombinant
factor VII is an effective haemostatic agent that can be used in
patients with uncontrolled bleeding in postcardiopulmonary bypass
surgery. Despite its high cost, there is an advantage in terms of
effectiveness to support its use. However, its potential thrombo-
embolic risk remains a concern and current evidence may restrict
its use only as a rescue therapy following failed conventional
treatment. A Kogan1, E Sharoni2, A Stamler2, M Stein2, B Medalion2,
B Vidne2, E Raanani1
1Sheba Medical Center, Ramat Gan, Israel; 2Rabin Medical Center,
Petah Tiqwa, Israel
Critical Care 2007, 11(Suppl 2):P380 (doi: 10.1186/cc5540) A Kogan1, E Sharoni2, A Stamler2, M Stein2, B Medalion2,
B Vidne2, E Raanani1
1Sheba Medical Center, Ramat Gan, Israel; 2Rabin Medical Center,
Petah Tiqwa, Israel
Critical Care 2007, 11(Suppl 2):P380 (doi: 10.1186/cc5540) P378 Experience of NovoSeven administration in the
management of severe haemorrhage following cardiac
surgery of nonhaemophilic patients Results The total dose administered per patient varied from 5.6 to
63.5 IU/kg bodyweight with a median dose of 20.4 IU/kg bodyweight. The median infusion rate was 3 ml/minute; in some cases up to
10 ml/minute were administered without any adverse reactions. The
administration of Octaplex reduced the INR on average from 2.3 to
1.5. Infusion of 25 IU Octaplex per kg body weight resulted in an
average decrease of about 1.2 in INR. A subgroup analysis of those
patients with a postinfusion measurement within 1 hour after
application of Octaplex showed a fast onset of action. The G Michalska, R Stanek
Clinical Hospital, Szczecin-Police, Poland
Critical Care 2007, 11(Suppl 2):P378 (doi: 10.1186/cc5538) G Michalska, R Stanek
Clinical Hospital, Szczecin-Police, Poland
Critical Care 2007, 11(Suppl 2):P378 (doi: 10.1186/cc5538) S151
Introduction Severe bleeding in cardiac surgery is often difficult
to manage. The aim of this study is clinical evaluation of efficacy of Critical Care March 2007 Vol 11 Suppl 2
27th International Symposium on Intensive Care and Emergency Medicin Figure 1 (abstract P379)
Mean hourly drain output 6 hours pre and 2 hours post NovoSeven
administration. Figure 1 (abstract P379) rFVIIa in the treatment of bleeding during and after cardiac
surgery. Patients and methods rFVIIa (NovoSeven; NovoNordisk, Bagsvaerd
Denmark) was used in 20 adult patients aged between 41 and
74 years, average BMI 25.48 ± 4.03, who underwent open heart
surgery (five coronary artery bypass surgery, two valvular surgery,
four double valve operations, five combining operations (coronary
artery bypass with valve repair) and four surgery for aortic
aneurisms) in 2004–2006. All patients had normal coagulation
parameters before surgery. We used questionnaires for indications
and effectiveness of treatment. We compared the amount of blood
lost within 12 hours before and within 12 hours after giving rFVIIa,
the dynamics of bleeding (assessed in ml/hour) before and after
treatment. We also compared the haemoglobin level, haematocrit,
number of platelets and laboratory coagulation profile parameters
before treatment, 2 hours and 12 hours after treatment. NovoSeven was administered 5–49 minutes after neutralization of
heparin with protamin sulfate. The dosage of rFVIIa was 39.23 ±
20.70 µg/kg (range 14.45–81.35). We used Student’s t test for
statistical analysis the laboratory data prior to and after rFVIIa. Mean hourly drain output 6 hours pre and 2 hours post NovoSeven
administration. Factor VII for intractable bleeding after cardiac surgery Conclusions NovoSeven produces a potent haemostatic effect in
bleeding events refractory to the conventional therapy complicating
the cardiosurgical interventions, and substantially decreases the
demand for blood transfusion. The influence of severe preeclampsia on maternal cerebral
perfusion E Shifman, A Ivshin, E Gumenuk
Republican Perinatal Center, Petrozavodsk, Russian Federation
Critical Care 2007, 11(Suppl 2):P382 (doi: 10.1186/cc5542) M Liebl, F Masud, F Bostan, E Chi, S Pass, K Stuebing
The Methodist Hospital, Houston, TX, USA
Critical Care 2007, 11(Suppl 2):P381 (doi: 10.1186/cc5541) Introduction The method of transcranial color scan can be used to
improve and to simplify cerebral blood flow investigations. Combi-
nation of digital wide-range neurosonography and transcranial
energetic Doppler scan provides a possibility of effective monitoring
of cerebral blood flow. The goal of this study was to analyze
cerebral flow disturbances in pregnant patients with preeclampsia. Methods Eighty-eight patients with severe preeclampsia, age
17–32 years (mean age 26 ± 4.6 years), and 90 patients with
normal pregnancy, third trimester, without significant co-morbid
states, age 19–34 years (mean age 25.9 ± 4.2 years), were
included in the study. Patients with the following features were
excluded from both groups: potentially haemodynamically signifi-
cant stenosis or occlusion of magistral arteries of the head and
basilar region; clinical features of congestive heart failure; arrhyth-
mia. All patients underwent duplex scan of extracranial portions of
brachiocephalic arteries with a linear probe and transcranial duplex
scan (TCDS) in the area of the middle cerebral artery (MCA). By
the transtemporal approach in the MCA M1 segment we
determined the peak systolic flow velocity (Vps), maximal end-
diastolic velocity (Ved), time-adjusted maximal velocity (TAMX),
resistance index (RI), pulsative index (PI), and systolic/diastolic
ratio (S/D). Significance of mean values differences in groups was
estimated using Student t criteria. This study describes patient characteristics, recombinant activated
factor VII (RF7a) dosing and clinical outcomes of cardiovascular
surgery patients treated with RF7a for intractable bleeding. Use of
RF7a for postsurgical bleeding, trauma or other uses in non-
hemophiliac patients is considered off-label in the USA. Compre-
hensive studies evaluating RF7a in cardiac surgery patients are
limited. Published reports cite success with RF7a administration in
massive intractable bleeding. However, patient selection, dosing,
efficacy, safety and pharmacoeconomic benefit remain undefined. Patients receiving RF7a between January 2004 and September
2005 were identified via pharmacy records. Clinical databases and
electronic medical records were reviewed, collecting data
elements needed to assess study objectives. One hundred and
twenty patients were identified. Twenty-seven patients were
excluded because they lacked documentation of RF7a admini-
stration, were treated for neurologic indications or had incomplete
medical record data. Ninety-three patients were analyzed. Evaluation of the role of recombinant activated factor VII
(NovoSeven) as a rescue haemostatic therapy in
postcardiopulmonary bypass surgical patients Seven of 22 patients survived and were discharged
from the hospital surgical re-exploration and other potential related adverse events
(stroke, AMI, VTE, etc.) are forthcoming. Our study, like others
evaluating RF7a for this indication, are limited by the retrospective
scope. Randomized trials comparing RF7a doses are under way. Although RF7a therapy is costly, minimal reductions in surgical re-
exploration may offset the cost of RF7a therapy provided that
adverse events are not increased. Conclusion rFVIIa is effective in promoting hemostasis after
cardiac surgery. rFVIIa should be considered as a possible
treatment option in intractable bleeding treatment. Evaluation of the role of recombinant activated factor VII
(NovoSeven) as a rescue haemostatic therapy in
postcardiopulmonary bypass surgical patients Introduction
Recombinant
activated
factor
VII
(rFVIIa)
(NovoSeven®; Novo Nordisk, Denmark) was developed primarily
for the treatment of bleeding episodes in hemophilic patients. Little
information is available on the use of rFVIIa in other situations, such
as intractable postsurgical or post-traumatic bleeding. In the field
of cardiac surgery, only a very few cases of treatment with rFVIIa
are described. Because of the difficulty in performing randomized
trials in this setting, information based on case studies is very
valuable Z Chen1, V Rasiah1, A Dewhurst2
1St George’s Hospital NHS Trust, London, UK; 2St Georges
Hospital, London, UK
Critical Care 2007, 11(Suppl 2):P379 (doi: 10.1186/cc5539) Objective Evaluation of the safety and efficacy of recombinant
activated factor VII (NovoSeven) when used as a rescue
haemostatic agent in refractory bleeding post bypass surgery. Methods We studied 22 consecutive patients treated with rFVIIa
due to refractory postoperative bleeding. rFVIIa was given only
after all other options, including revision, to stop bleeding was
failed. The amount of bleeding, the number of transfused units of
red cells, platelets and other blood products were recorded both
before and after administration of rFVIIa. Methods A retrospective cohort study of all postcardiopulmonary
bypass patients with uncontrolled bleeding despite conventional
treatment (platelets, fresh frozen plasma, cryoprecipitate, and
Aprotonin) who received recombinant factor VII as a rescue
therapy over 12 months in a cardiothoracic centre. Results Eight patients received NovoSeven (90 µg/kg). Seven
achieved significant reduction in blood loss. The mean blood loss
via thoracic drains 6 hours before and 2 hours after NovoSeven
administration were 341 ml/hour vs 117 ml/hour (P = 0.01) (Figure 1). On average, 5.3 units/patient packed red blood cells, 2 pools/
patient platelets, 19 ml/kg/patient fresh frozen plasma and 148 ml/
patient
cryoprecipitate
were
used
prior
to
NovoSeven
administration. Five patients required further blood transfusion with
a mean of 2.2 units/patient over the next 12 hours. Two of the eight
patients developed thromboembolic complications including portal Table 1 (abstract P380)
Treatment
Before
After
Bleeding (ml/hour)
350
135
RBC
7.8 ± 2.3
1.5 ± 1.4
FFP
8.5 ± 2.4
2.5 ± 2.4
Platelets
14.5 ± 6.2
2.4 ± 2.1
Cryo
5.1 ± 1.4
0 S152 Available online http://ccforum.com/supplements/11/S2 Available online http://ccforum.com/supplements/11/S2 Available online http://ccforum.com/supplements/11/S2 Results See Table 1. In all patients, bleeding was decreased
significantly. Seven of 22 patients survived and were discharged
from the hospital Results See Table 1. In all patients, bleeding was decreased
significantly. Recombinant activated factor VII treatment of severe
bleeding in cardiac surgery patients: a retrospective
analysis of dosing, and efficacy and safety outcomes Recombinant activated factor VII treatment of severe
bleeding in cardiac surgery patients: a retrospective
analysis of dosing, and efficacy and safety outcomes The influence of severe preeclampsia on maternal cerebral
perfusion The influence of severe preeclampsia on maternal cerebral
perfusion RF7a
effectively achieves hemostasis in patients with intractable
bleeding, reducing blood product transfusions within 6 hours of
treatment (Figure 1). Our findings suggest differences in PRBC
transfusion reduction between RF7a doses. We observed no
additional reduction PRBC transfusions in patients administered
doses greater than 60–90 µg/kg (Figure 2). Effects of RF7a on Results All haemodynamic values in preeclamptic patients were
decreased in comparison with the same values in healthy pregnant
women: PI (mean 0.71 vs 0.84, P < 0.0001); RI (mean 0.49 vs
0.54, P < 0.0001); Vps (mean 72.8 vs 104.8 cm/s, P < 0.0001); Ved
(mean 34.7 vs 48.7 cm/s, P < 0.0001); TAMX (mean 48.5 vs
67.5 cm/s, P < 0.0001); S/D (mean 1.94 vs 2.05, P < 0.001). These pathophysiological changes of cerebral haemodynamics
were consistent with the Dopplerographic pattern of diminished
perfusion and are typical for vascular segments, which are located
proximally to the zone of abnormally high haemodynamic resistance. Conclusion The results of the performed study showed that
patients with severe preeclampsia had decreased cerebral
perfusion and TCDS is an effective method for estimation of
preeclampsia severity. P382 Recombinant activated factor VII treatment of severe
bleeding in cardiac surgery patients: a retrospective
analysis of dosing, and efficacy and safety outcomes
M Liebl, F Masud, F Bostan, E Chi, S Pass, K Stuebing
The Methodist Hospital, Houston, TX, USA
Critical Care 2007, 11(Suppl 2):P381 (doi: 10.1186/cc5541) Figure 1 (abstract P381) Figure 2 (abstract P381) Figure 2 (abstract P381) Stroke and pregnancy: etiology, timing and outcome Stroke and pregnancy: etiology, timing and outcome R Souissi, W Trabelsi, Z Haddad, M Boubaker, M Lamourou,
K Baccar, C Kaddour, L Skandrani
National Institute of Neurology, Tunis, Tunisia
Critical Care 2007, 11(Suppl 2):P384 (doi: 10.1186/cc5544) Patients and methods Prospective data collection as part of the
APRiMO study (Assessment of Prognosis and Risk of Mortality in
Obstetrics). Included were all obstetric patients transferred from a
referral center for high-risk pregnancies in our independent multi-
disciplinary ICU. The study period was January 1996–September
2004. Demographic data, obstetric history, morbid events, length
of stay (LOS), severity of illness scoring systems and organ
dysfunction scores at day 1 of admission were collected. Exclusion
criteria were LOS < 4 hours. The main outcome of interest was
survival status at ICU discharge. Two groups were compared:
patients with HELLP syndrome as defined alternatively by the two
classifications (Group I), and patients without hepatic dysfunction
(Group II). Results are expressed as the mean ± standard
deviation. P < 0.05 was considered significant. Discrimination of
the classifications was assessed by the area under the receiver
operator characteristic curve (AuROC). Calibration was assessed
by the Hosmer–Lemeshow (HL) goodness-of-fit test. Data were
computed on SPSS 11.5, Win-XP compatible. Background and goal Most previous studies on stroke during
pregnancy have mainly focused on incidence and risk factors. These studies have not reported details of etiology and stroke
outcome. The present study focuses on the evaluation of the
etiology, timing and outcome of stroke occurring during
pregnancy. Materials and methods We conducted a retrospective analysis
on all obstetric patients who have been diagnosed with stroke
during pregnancy or within 8 weeks postpartum. These patients
were transferred to our multidisciplinary ICU between January
1996 and December 2004. All patients were investigated with a
CT scan of the brain, and MRI and/or cerebral angiography. Results Eighty-eight patients were included, 34 of them were
excluded (incomplete investigations or nonstroke diagnosis:
reversible leucoencephalopathy, cerebral abscess, etc.). Fifty-four
patients with a diagnosis of stroke were identified: 30 patients with
ischemic stroke (IS) and 24 patients with hemorrhagic stroke (HS). The majority of events (45 patients, 83%) occurred in the third
trimester and postpartum period (P = 0.02). A specific cause was
identified in 24 patients (80%) of IS and in 21 patients (87%) of
HS. Stroke and pregnancy: etiology, timing and outcome Causes of IS include preeclampsia/eclampsia in 11 patients,
venous thrombosis and coagulopathies (deficiencies of protein C,
protein S, and activated protein C resistance) in nine patients,
valvular heart disease with history of prior stroke in four patients
and six patients had no definable cause. The major causes of HS
were preeclampsia/eclampsia in eight patients, four patients
presented with hemorrhage secondary to aneurysmal rupture,
three patients presented with bleeding from arterio-venous
malformations (AVM), bleeding as a consequence of disseminated
intravascular coagulation (DIC) occurred in two patients and seven
patients had hemorrhagic events of unknown origin. Hypertensive
disorders of pregnancy were the most common comorbid
conditions (32%). Results and discussion Differences between Group I and Group
II were statistically significant concerning obstetric hemorrhagic
complication (P < 0.001), incidence of acute renal failure
(P = 0.01), mortality (P = 0.001), LOS (6.5 ± 7 days vs 4.4 ± 4 days,
P = 0.001), SAPS-Obst score (24.5 ± 8 vs 16.8 ± 7, P < 0.001). The Mississippi classification discriminated well, but calibrated
badly. In contrary, the Tennessee classification was a poor
discriminator but calibrated very well. See Table 1. P383 HELLP syndrome: utility of specific classifications as
prognostic tools R Souissi, Z Haddad, W Trabelsi, N Baffoun, M Boubaker,
C Kaddour, L Skandrani
National Institute of Neurology, Tunis, Tunisia
Critical Care 2007, 11(Suppl 2):P383 (doi: 10.1186/cc5543) R Souissi, Z Haddad, W Trabelsi, N Baffoun, M Boubaker,
C Kaddour, L Skandrani
National Institute of Neurology, Tunis, Tunisia
Critical Care 2007, 11(Suppl 2):P383 (doi: 10.1186/cc5543) S153
Introduction HELLP syndrome is a specific complication of
pregnancy characterized by hemolysis, elevated liver enzymes and ritical Care March 2007 Vol 11 Suppl 2
27th International Symposium on Intensive Care and Emergency Medicin Table 1 (abstract P383) Number of patients, discrimination and calibration statistic tests
for each classification
Classification
Dead
Alive
Tennessee
n = 45 (20.3%)
n = 177
Mississippi
n = 20 (26.7%)
n = 55
ROC
HL
Tennessee
0.75
0.001
Mississippi
0.64
0.533 Number of patients, discrimination and calibration statistic tests
for each classification Nineteen deaths (35%) occurred in our study, eight patients with
infarction and 11 patients with hemorrhage. Thirty-one patients left
the hospital with neurologic deficits, requiring chronic care or
rehabilitation. Discussion and conclusion The results of the present study
complement the findings of previous studies on timing of stroke in
pregnancy [1,2]. We found that preeclampsia/eclampsia and
intracranial vascular malformations were the major causes of stroke
in pregnancy, which agrees with other findings [2,3]. Our study
shows a high mortality rate of 35%, which indicates that careful
management of at-risk patients during the first postpartum weeks is
warranted. Conclusion Both models classified patients according to different
criteria but were correlated with mortality. None of the
classifications discriminated and calibrated well at the same time. The two models seem to be complimentary. Development of an
aggregate classification could refine the models. criteria but were correlated with mortality. None of the
classifications discriminated and calibrated well at the same time. The two models seem to be complimentary. Development of an
aggregate classification could refine the models. The two models seem to be complimentary. Development of an
aggregate classification could refine the models. 1. Audibert F, Friedman SA, Frangieh AY, Sibai BM: Clinical
utility of strict diagnostic criteria for the HELLP syndrome. Am J Obstet Gynecol 1996, 175:460-464. P384 low platelet count. Maternal mortality was reported to be as high as
24%. Two classifications of the HELLP syndrome are widely used
(Tennessee [1] and Mississippi [2]). The aim of this study is to
determine mortality of HELLP syndrome as defined by each
classification and try assessing the most relevant. Fractional excretion of urea in the follow-up of acute renal
failure due to prerenal azotemia Fractional excretion of urea in the follow-up of acute renal
failure due to prerenal azotemia Results Six hundred and forty patients were reviewed (mortality
rate 13.3%). ARF was diagnosed in 223 patients. Main risk factors
present at admission were: acute circulatory failure, transfusion
and association with haemolysis elevated liver enzyme and low
platelet count (HELLP) syndrome. ARF patients with HELLP
syndrome on admission were most likely to develop and alter
multiple organ dysfunctions/failures. ARF is associated with an
elevated relative risk of mortality (x1.5). Anuria and a serum
creatinine level > 300 µmol/l were independent risk factors for
mortality (OR 2 and 7, respectively). The ICU mortality of ARF
patients increased with the number of failing organs on admission,
especially persistent circulatory failure over time. The LOD score is
at least as good as the SOFA score in evaluating the association
MOF–ARF with mortality. In fact, LOD cutoff values defining
cardiovascular, respiratory hepatic and hematologic organ failures
fit particularly our obstetric population. S Kuster, C Giambarba, A Kneubühl, G Keusch
Stadtspital Waid, Zürich, Switzerland
Critical Care 2007, 11(Suppl 2):P387 (doi: 10.1186/cc5547) Fractional excretion of urea (FEU) is a major issue to discriminate
between prerenal azotemia and acute tubular necrosis in acute
renal failure (ARF). Its role in the course of ARF remains unclear. The aim of this study was to evaluate FEU in the follow-up of ARF
due to prerenal azotemia in order to predict the necessity of renal
replacement therapy (RRT). The prospective study took place at the ICU of Stadtspital Waid,
Zürich. All patients admitted starting from 19 February 2006 were
evaluated for ARF according to the RIFLE classification. ARF due to
prerenal azotemia was defined as ARF combined with FEU of less
than or equal to 35%. FEU was calculated as [(urine urea/blood
urea)/(urine creatinine/plasma creatinine)] x 100. Urine specimens
were taken and FEU was calculated daily until complete or partial
renal recovery was reached or the criteria for RRT were met. The
goal of therapy was reconstitution of renal function by treatment of
the underlying condition. RRT was initiated according to the usual
criteria. Statistics were determined using Fisher’s exact test. Conclusions Most important risk factors for ARF or mortality are
often present on admission. Reference 1. Bellomo et al.: Crit Care 2004, 8:R204–R212. 1. Bellomo et al.: Crit Care 2004, 8:R204–R212. Figure 1 (abstract P387)
Fractional excretion of urea (FEU) in the follow-up of acute renal failure
(ARF) due to prerenal azotemia. Data presented as mean ± SD. n =
number of patients. Figure 1 (abstract P387) Acute renal failure in obstetrics: risk factors and outcome Methods A retrospective observational study was performed in a
general ICU at a Swedish university hospital. All adult patients
treated at the ICU during 2004–2006 were included. Reduced
kidney function was defined as ≤80 ml/min/1.73 m2. Z Haddad1, C Kaddour2, R Souissi2, T Chaaoua2,
M Laamourou2, I Pipien1, S Nagi2
1CHI St-Cloud, France; 2National Institute of Neurology, Tunis,
Tunisia
Critical Care 2007, 11(Suppl 2):P385 (doi: 10.1186/cc5545) Results GFR markers are frequently ordered in the ICU. The
majority of the patients had a reduced kidney function as evaluated
by Cystatin C and/or p-creatinine. A total 92.1% of the patient test
results had Cystatin C estimated GFR (eGFR) ≤80 ml/min/1.73 m2,
75.3% had eGFR ≤50 ml/min/1.73 m2 and 30.4% had eGFR
≤20 ml/min/1.73 m2. In contrast, only 46% of the patients had
reduced renal function assessed by plasma creatinine. Introduction Acute renal failure (ARF) was newly recognized as a
specific mortality risk factor [1] and is in general associated with a
high mortality rate. Introduction Acute renal failure (ARF) was newly recognized as a
specific mortality risk factor [1] and is in general associated with a
high mortality rate. Hypothesis Identifying risk factors for ARF could help reduce
mortality. We shall try to describe them in critically ill obstetric
patients, and explain ARF association with multiple organ failure
(MOF) and outcome using the Sequential Organ Failure Assessment
(SOFA) score and Logistic Organ Dysfunction (LOD) score. y p
Conclusions The GFR is commonly assessed in the ICU. Cystatin
C is a more sensitive GFR marker than creatinine. A majority of the
ICU patients had a reduced GFR. Many of the pharmaceuticals
used in the ICU are cleared by the glomeruli. It is thus important to
monitor kidney function regularly, using an adequate assay. When
possible, drugs with a plasma concentration that is less influenced
by the GFR should be used. Methods An open prospective observational cohort study in a
multidisciplinary ICU. All critically ill obstetric patients were
analysed unless diagnosed with chronic renal failure or kidney
transplant. ARF was defined as serum creatinine ≥100 µmol/l
and/or urine output ≤500 ml/day and/or doubling of baseline
serum creatinine levels. Fractional excretion of urea in the follow-up of acute renal
failure due to prerenal azotemia During the ICU stay, other organ
failures (especially cardiovascular) are important risk factors to
develop or alter renal function, especially persistence of circulatory
shock; thus, aggressive fluid challenge and volume infusion policy
could help ARF prevention. HELLP syndrome and ARF is a
particularly morbid association because of accumulating organ
failures. Reference P385 P385 using the creatinine and Cystatin C estimated GFRs as several
pharmaceuticals are prescribed according to renal function. using the creatinine and Cystatin C estimated GFRs as several
pharmaceuticals are prescribed according to renal function. References 1. Sharshar T, Lamy C, Mas JL: Incidence and causes of
strokes associated with pregnancy and puerperium. A
study in public hospitals of Ile de France. Stroke in Preg-
nancy Study Group. Stroke 1995, 26:930-936. 1. Sharshar T, Lamy C, Mas JL: Incidence and causes of
strokes associated with pregnancy and puerperium. A
study in public hospitals of Ile de France. Stroke in Preg-
nancy Study Group. Stroke 1995, 26:930-936. 2. Martin JN Jr, Magann EF, Blake PG, et al.: Analysis of 454
pregnancies with severe preeclampsia/eclampsia HELLP
syndrome using the 3-class system of classification. Am J
Obstet Gynecol 1993, 68:386. 2. Kittner SJ, Stern BJ, Feeser BR, Hebel R, Nagey DA, Buch-
holz DW, Earley CJ, Johnson CJ, Macko RF, Sloan MA, Wityk
RJ, Wozniak MA: Pregnancy and the risk of stroke. N Engl J
Med 1996, 335:768-774. 3. Jaigobin C, Silver FL: Stroke and pregnancy. Stroke 2000,
31:2948-2951 S154 Available online http://ccforum.com/supplements/11/S2 Available online http://ccforum.com/supplements/11/S2 Hemodynamic goal-directed intermittent hemodialysis S Jog, P Akole, N Gogate, S Gadgil
Deenanath Mangeshkar Hospital and Research Centre, Pune, India
Critical Care 2007, 11(Suppl 2):P388 (doi: 10.1186/cc5548) Introduction Intermittent hemodialysis (IH) is the commonest form
of renal replacement therapy (RRT) in the majority of Indian ICUs
as each continuous veno-venous hemofiltration session for 24 hours
costs around €250, against IH that costs around €25/4 hour
session. The major concern of IH in septic shock patients is
hemodynamic instability. Whether stringent hemodynamic monitor-
ing and maintaining preset goals would reduce these instabilities
and deliver optimal RRT is not clear. We undertook a prospective
study to evaluate this concept. Results There were 168 consecutive patients (86 males). The
mean age was 55 ± 19 years. The mean APACHE II score was
11 ± 8. Main reasons for ICU admission according to APACHE II
classification were gastrointestinal perforation/obstruction n = 100,
gastrointestinal surgery due to neoplasia n = 21, vascular surgery
n = 18, gastrointestinal bleeding n = 6, hemorrhagic shock n = 5,
sepsis n = 5, chronic cardiovascular disease n = 4, respiratory
failure n = 3, cardiovascular n = 3, metabolic disturbance n = 2
and renal surgery due to neoplasia n = 1. The mean LOS was
5 ± 13 days. The DAKI frequency was 6.5% (n = 11). By means of
univariable analysis, risk factors for DAKI were male sex, creatinine
level ≥1.5 mg/dl at admission, APACHE II score ≥25, use of a
pulmonary artery catheter, need for mechanical ventilation
≥48 hours, hemoglobin level ≤7 g/dl, and enteral and parenteral
nutritional support. In the multivariate analysis, only APACHE II
score ≥25 (OR 14.9; 95% CI 1.9–111.6, P = 0.008), use of
enteral support (OR 20.3; 95% CI 3.5–117.7, P < 0.001) and use
of pulmonary artery catheter (OR 10.7; 95% CI 1.3–88.5,
P = 0.028) were independent predictors of DAKI. The overall
postoperative mortality rate was 10.7%; it was 54% in patients
with DAKI compared with 7.6% in patients without DAKI. P389 Predictive factors of dialytic acute kidney injury in patients
admitted to the intensive care unit after nontraumatic
emergency abdominal surgery F De Marco, M Barbosa, A Fantauzzi, C Nascimento,
W Imanishi, A Guimares
Hospital Vivalle, Sao Jose dos Campos, Brazil
Critical Care 2007, 11(Suppl 2):P389 (doi: 10.1186/cc5549) F De Marco, M Barbosa, A Fantauzzi, C Nascimento,
W Imanishi, A Guimares
Hospital Vivalle, Sao Jose dos Campos, Brazil
Critical Care 2007, 11(Suppl 2):P389 (doi: 10.1186/cc5549) In patients presenting with ARF due to prerenal azotemia, an
increase of FEU above 35% within the first 48 hours after initiation
of conservative therapy for ARF is a valuable parameter to predict
renal
recovery. After
initiation
of
conservative
therapy,
measurement of FEU is of no value concerning discrimination of
prerenal azotemia and acute tubular necrosis in ARF. Introduction Although postoperative risk factors for dialytic acute
kidney injury (DAKI) are well described in a wide range of clinical
settings, we have few data regarding nontraumatic emergency
abdominal surgery. The aim of this study was to describe these
factors in this subgroup of patients. P386 The majority of patients in a Swedish university hospital
intensive care unit have reduced glomerular filtration rate
measured by Cystatin C Introduction Renal dysfunction is associated with increased
morbidity and mortality in intensive care patients. The aim of this
study was to investigate the use of laboratory markers in an ICU,
especially glomerular filtration rate (GFR) markers, and to compare
two GFR markers, creatinine and Cystatin C. A secondary aim was
to assess the frequency of reduced GFR in this patient group Fractional excretion of urea (FEU) in the follow-up of acute renal failure
(ARF) due to prerenal azotemia. Data presented as mean ± SD. n =
number of patients. S155 ritical Care March 2007 Vol 11 Suppl 2
27th International Symposium on Intensive Care and Emergency Medicin Conclusion Goal-directed hemodynamic management during IH
can reduce hemodynamic instability and deliver reasonably opti-
mum RRT in the absence of continuous veno-venous hemofiltration
facilities. By 7 December 2006, 15 patients met the inclusion criteria for
ARF due to prerenal azotemia (nine males, six females). The mean
age was 71 ± 11 (SD) years for male patients and 58 ± 31 years
for female patients. Twelve out of the 15 patients responded to
conservative management and had complete or partial renal
recovery. Three patients needed RRT. Two of them refused RRT
and died during the course of the disease. During the first 48 hours
after initiation of conservative therapy, FEU remains less than or
equal to 35% in all three patients who needed RRT. By contrast,
nine out of 12 patients in whom renal function recovered without
RRT showed a FEU of more than 35% within the first 48 hours
(P < 0.05) (Figure 1). P388 Methods We have conducted a retrospective cohort study in
order to identify independent risk factors. We reviewed data from
patients admitted to the ICU after nontraumatic emergency
abdominal surgery from April 2003 to October 2006. Epidemio-
logical data, outcome and ICU resource utilization were recorded. Statistical analysis was performed by univariate analysis (Fisher’s
exact test, chi-square test) followed by multivariate stepwise
logistic regression. Hemodynamic goal-directed intermittent hemodialysis Methods Preset goals of keeping the mean arterial pressure
(MAP) > 75 mm, cardiac output (CO) > 5 l/min and cardiac index
(CI) > 2.5 l/min/m2 throughout the session were attempted to
achieve by a stepwise protocol as follows: (1) fluid boluses,
(2) increase in vasopressor/inotrope dose, (3) adjustment in the
ultrafiltration rate between 250 and 700 ml/hour, and (4) adjust-
ment in the blood flow rate between 150 and 300 ml/minute on a
hemodialysis machine. Dopamine, norepinephrine, vasopressin and
dobutamine were used alone or in combination to achieve these
goals. Hemodynamic monitoring and data collection were done
with Datex S-5 and Flo-Trac Vigileo monitors. Results Nineteen IH sessions of seven patients with septic shock
were monitored and managed in the ICU. The baseline APACHE II
score was 24.10 ± 4.98 and all patients had at least three organ
failures. The average duration was 4.42 ± 1.30 hours and fluid
removal was 2,000 ± 527 ml per IH session. The preIH MAP, CO
and CI were 81.10 ± 10.80 mmHg, 6.23 ± 2.24 l/min and
3.45 ± 1.07 l/min/m2, respectively. The MAP, CO, CI were
81.42 ± 8.44 mmHg, 6.27 ± 2.24 l/min and 3.49 ± 1.07 l/min/m2
at 60 minutes; 79.36 ± 15.33 mmHg, 6.24 ± 2.65 l/min and
3.46 ± 1.31 l/min/m2 at 120 minutes; 82.83 ± 14.00 mmHg,
6.48 ± 2.36 l/min and 3.60 ± 1.06 l/min/m2 at 180 minutes; and
84.44 ± 13.98 mmHg, 6.46 ± 2.17 l/min and 3.6 ± 0.95 l/min/m2
at 240 minutes, respectively. Preset goals were maintained with
fluids alone in four patients, fluids and escalation of vasopressor
was required in seven patients, and fluids, vasopressor escalation
with ultrafiltration and blood flow adjustments in six patients. Only
2/19 sessions were terminated at 120 and 90 minutes, due to
development of new myocardial infarction in one and persistent
hypotension in other. Conclusions DAKI following nontraumatic emergency abdominal
surgery has a high mortality rate, and APACHE II score ≥25, use
of enteral nutritional support and use of pulmonary artery catheter
are its postoperative predictive factors. P390 Introduction Despite the use of several prophylactic approaches,
contrast-induced nephropathy (CIN) remains a clinical problem. P391 Objective To investigate the effect of the antifibrinolytic agents
aprotinin and tranexamic acid on the occurrence of acute post-
operative renal dysfunction in cardiac surgery on patients treated
preoperatively with angiotensin-converting enzyme (ACE) inhibitors. Survey of acute renal failure in patients after
cardiovascular surgery N Iguchi, H Imanaka, M Takeuchi, T Nishida, M Ichikawa,
C Takayama, S Akaeda
National Cardiovascular Center, Suita, Osaka, Japan
Critical Care 2007, 11(Suppl 2):P391 (doi: 10.1186/cc5551) Methods A total of 7,420 patients who had undergone
nonemergency coronary artery bypass graft or valve surgery in the
Bristol Royal Infirmary from January 2000 until end of March 2006
were included in a retrospective observational study. The incidence
of postoperative renal dysfunction was compared in patients given
aprotin, tranexamic acid or no antifibrinolytic agent, using
propensity-adjusted multivariable logistic regression. Further
analysis was performed comparing patients taking ACE inhibitors
preoperatively with those not taking ACE inhibitors. Renal
dysfunction was defined as creatinine higher than 200 µmol/l
and/or renal dialysis. Patients with a previous history of renal
dysfunction were excluded from the study. Introduction Acute renal failure (ARF) is one of the major
complications after cardiovascular surgery. To investigate the
incidence and prognosis of ARF after cardiac surgery, we
performed a retrospective study. Our hypothesis is that ARF is
more common in patients who underwent surgery for great vessel
diseases than in those who underwent coronary or valve surgery. Methods We enrolled patients over 18 years old who underwent
cardiovascular surgery and entered our ICU between 2004 and
2005. The background diseases were classified into two groups:
great vessel disease, and coronary/valve disease. We determined
ARF when serum creatinine increased by more than 50% of the
preoperative values, or when renal replacement therapy was newly
started. By reviewing ICU charts, we collected data before, on
admission to the ICU and during the ICU stay. Results Using propensity-adjusted multivariable logistic regression
(C-index, 0.82), the use of aprotinin in patients taking ACE
inhibitors was associated with more than doubling the risk of acute
postoperative renal failure in patients undergoing nonemergency
cardiac surgery (odds ratio 2.64; confidence interval 1.32–5.27). Tranexamic acid was also associated with a significant increase in
the risk of renal failure (odds ratio 1.59; confidence interval
1.09–2.31) in patients taking ACE inhibitors. However, in this
study, there was no association between either aprotinin (odds
ratio 1.01) or tranexamic acid (odds ratio 1.19) and postoperative
renal failure in patients not taking ACE inhibitors. Results ARF occurred more frequently in patients with great
vessel disease than in those with coronary/valve disease (33.5%
vs 11.2%, P < 0.05). The prognosis of patients with ARF was
poorer than those without ARF in both groups (Figure 1). P390 Long-term outcome of patients with contrast-induced
nephropathy Introduction Despite the use of several prophylactic approaches,
contrast-induced nephropathy (CIN) remains a clinical problem. S156 Available online http://ccforum.com/supplements/11/S2 Figure 1 (abstract P391) Figure 1 (abstract P391) CIN is the third leading cause of hospital-acquired renal failure. CIN is associated with several risk factors such as diabetes and
hypertension as well as with prolonged hospitalization and
increased mortality. Little is known about long-term renal outcome. Within the last 10 years we have performed nine controlled studies
on prophylaxis of CIN with a total number of about 1,200 patients. It was the aim of this study to investigate the long-term outcome of
patients with CIN within these studies. Within the last 10 years we have performed nine controlled studies
on prophylaxis of CIN with a total number of about 1,200 patients. It was the aim of this study to investigate the long-term outcome of
patients with CIN within these studies. Methods This study presents the data of the first 25 patients with
CIN (planned: 80 patients) including serum creatinine 1 week,
1 month, 6 months and 1 year after the contrast medium. The
outcome was investigated by chart review and telephone call. Results All patients were Caucasian and had a mean age of
69.6 ± 10.6 years. Eight were female, 17 were male. Twenty-four
patients had risk factors for CIN such as diabetes (8%), hyper-
tension (44%) or both (28%) and preexisting renal impairment
(15%) prior to contrast medium application. Their mean serum creati-
nine before contrast medium application was 1.81 ± 1.21 mg/dl. The contrast procedure was coronary angiography in 18 patients
and CT in seven patients. For prophylaxis of CIN, six patients
received N-acetylcysteine and three patients received both N-
acetylcysteine and theophylline prior to contrast medium
exposition. Mean serum creatinine 48 hours after contrast medium
was 2.36 ± 1.36 mg/dl (P < 0.01 vs 0 hours). The mean maximum
creatinine increase was 0.64 ± 0.26 mg/dl (P < 0.01 vs 0 hours). Four patients (16%) died during the first week after contrast
medium, one of them despite initiation of dialysis 2 days after
contrast application. ICU than those without ARF. Patients with ARF showed higher
incidence of liver dysfunction, and needed a longer mechanical
ventilation and ICU stay. Conclusion
ARF is common after cardiovascular surgery,
especially after surgery for great vessel disease. ARF was
associated with more postoperative organ disorders. P392 One year after CIN, the mean serum creatinine in the survivors was
1.85 ± 1.39 mg/dl (P = 0.48 vs 0 hours). A clinical relevant
increase of >0.3 mg/dl compared with baseline creatinine was
found in six (24%) patients. Antifibrinolytic agents and angiotensin-converting enzyme
inhibitors: the effect on postoperative renal dysfunction in
cardiac surgery R Mouton, A Binks, I Davies
Bristol Royal Infirmary, Bristol, UK
Critical Care 2007, 11(Suppl 2):P392 (doi: 10.1186/cc5552) R Mouton, A Binks, I Davies
Bristol Royal Infirmary, Bristol, UK
(
) Conclusion CIN is a serious complication of contrast medium
administration and is associated with an increased mortality and
long-time morbidity. Survey of acute renal failure in patients after
cardiovascular surgery Patients
with ARF showed a longer operation time, larger intraoperative
bleeding and a higher level of blood lactate on admission to the Conclusion In cardiac surgery, there is a significant association
between use of the antifibrinolytic drugs aprotinin and tranexamic S157 ritical Care March 2007 Vol 11 Suppl 2
27th International Symposium on Intensive Care and Emergency Medicin acid and the occurrence of acute postoperative renal dysfunction,
in patients taking ACE inhibitors. The potential blood-saving
benefits of antifibrinolytic drugs should be weighed up against this
serious postoperative complication. A comparison of Gc globulin and neutrophil gelatinase-
associated lipocalin in patients with liver disease Introduction A number of preoperative patient-specific risk factors
contribute to increased perioperative cardiovascular risk (myo-
cardial infarction, heart failure, death) in patients undergoing major
noncardiac surgery [1]. Renal impairment is one predictor. Creatinine values are a poor reflection of true renal function. Measures of the glomerular filtration rate provide a more accurate
measure of renal function; as such, the true prevalence of renal
impairment in this population may be significantly higher than
previously appreciated. Our aim was to identify that proportion of
elective vascular patients undergoing abdominal aortic surgery that
have CKD, assessed by the estimated glomerular filtration rate
(eGFR, ml/min/1.73 m2 body surface area; creatinine, µmol/l) [2]. A Portal, M Austin, M Bruce, E Sizer, G Auzinger, M Heneghan,
J Wendon
Kings College Hospital, London, UK
Critical Care 2007, 11(Suppl 2):P394 (doi: 10.1186/cc5554) Kings College Hospital, London, UK Introduction Gc globulin, a hepatically synthesized actin binding
protein, is known to decrease in both acute and chronic liver
disease, and low levels are associated with poor prognosis. Neutrophil gelatinase-associated lipocalin (NGAL), a member of
the lipocalin family of proteins, has been shown to be an early
biomarker of ischaemic renal damage. We prospectively
investigated the use of these proteins as markers of severity of
illness and prognostication in acute and acute-on-chronic liver
failure requiring intensive care. Introduction Gc globulin, a hepatically synthesized actin binding
protein, is known to decrease in both acute and chronic liver
disease, and low levels are associated with poor prognosis. Neutrophil gelatinase-associated lipocalin (NGAL), a member of
the lipocalin family of proteins, has been shown to be an early
biomarker of ischaemic renal damage. We prospectively
investigated the use of these proteins as markers of severity of
illness and prognostication in acute and acute-on-chronic liver
failure requiring intensive care. Methods A retrospective analysis of our ‘ABC study’ database
was undertaken. The ABC study is an ongoing study looking at
preoperative risk assessment using cardiopulmonary exercise
testing in patients undergoing elective aortic surgery. Methods NGAL and Gc globulin were measured on admission to our
unit using a sandwich ELISA technique (AntibodyShop®) in 17
patients with acute liver failure (ALF) and 11 patients with acute-on-
chronic liver disease (ACLD). Biochemical and physiological variables
were collected prospectively and entered into a physiological database
(ICARE). All measurements were taken on day 1 of admission. Results
are expressed as the median and interquartile range. P393 2. K/DOQI clinical practice guidelines for chronic kidney
disease: evaluation, classification, and stratification. Am J
Kidney Dis 2002, 39:S1-S266. P393
Preoperative assessment of patients undergoing
abdominal aortic surgery: chronic kidney disease is almost
always present
A Turley, S Owen, E Kothmann, M de Belder, A Parry, G Danjoux
The James Cook University Hospital, Middlesbrough, UK
Critical Care 2007, 11(Suppl 2):P393 (doi: 10.1186/cc5553) 3. JBS 2: Joint British Societies’ guidelines on prevention of
cardiovascular disease in clinical practice. Heart 2005, 91
(Suppl 5):v1-v52. 3. JBS 2: Joint British Societies’ guidelines on prevention of
cardiovascular disease in clinical practice. Heart 2005, 91
(Suppl 5):v1-v52. A Turley, S Owen, E Kothmann, M de Belder, A Parry, G Danjoux
The James Cook University Hospital, Middlesbrough, UK
Critical Care 2007, 11(Suppl 2):P393 (doi: 10.1186/cc5553) References acid and the occurrence of acute postoperative renal dysfunction,
in patients taking ACE inhibitors. The potential blood-saving
benefits of antifibrinolytic drugs should be weighed up against this
serious postoperative complication. 1. Eagle KA, Berger PB, Calkins H, et al.: ACC/AHA guideline
update for perioperative cardiovascular evaluation for
noncardiac surgery – executive summary. A report of the
American College of Cardiology/American Heart Associa-
tion Task Force on Practice Guidelines (committee to
update the 1996 guidelines on perioperative cardiovascu-
lar evaluation for noncardiac surgery). Anesth Analg 2002,
94:1052-1064. Acknowledgement David Finch, Audit & Information Systems,
Cardiac Services, is thanked for doing the statistical analysis. A comparison of Gc globulin and neutrophil gelatinase-
associated lipocalin in patients with liver disease Results Sixty-six patients were included in the analysis. All patients
were Caucasians, 62 males (94%). No patient had a pre-existing
diagnosis of chronic renal impairment. No patients had stage 4/5
CKD (severely reduced kidney function, eGFR < 30). Moderately
reduced kidney function (eGFR 30–59, CKD stage 3) was seen in
20 (30%) patients, and mildly reduced kidney function (eGFR
60–89, CKD stage 2) in 44 (67%). Only two patients had normal
kidney function. The mean total cholesterol for the cohort was
4.6 mmol/l (±1 mmol/l). See Table 1. g
Results Admission parameters: serum creatinine 185 µmol/l
(89–266), urine output/24 hours: 340 ml (0–1,111), APACHE II
score 20 (15–25), lactate 2.6 (1.8–4.68), INR 2.6 (1.6–3.8) and
AST 1,404 (124–6,349). There were significant differences
between median Gc globulin in ALF patients compared with
ACLD: 25 mg/l (10–50) vs 50 mg/l (25–129), P = 0.036. No
significant differences were seen for NGAL. Gc globulin correlated
with admission creatinine (r = 0.44, P < 0.01), INR (r = 0.68,
P < 0.01), and SOFA score (r = 0.419, P < 0.01) in both patient
groups. These relationships persisted when admission Gc globulin
was examined in regard to day 5 parameters. Admission Gc
globulin correlated with D3 urine output (r = 0.619, P < 0.001). NGAL correlated with urine output throughout the first 5 days of
admission (r = –0.593 on day 1, r = –0.674 on day 3, P < 0.001)
and also with SOFA score. High admission NGAL was associated
with requirement for renal replacement therapy on day 3 (ROC
AUC 0.91 (0.895–1.022, P < 0.001)), outperforming both
admission Gc globulin and admission creatinine. A low admission
Gc globulin more accurately predicted the need for haemofiltration
on day 5 (AUC 0.889, 0.734–1.044, P < 0.007) than either NGAL
or creatinine on admission. P395 Fibrinogen as a prognostic indicator in hepatic failure
M Thomas, M Duffy, G Auzinger, W Bernal, E Sizer, J Wendon
King’s College Hospital, London, UK
Critical Care 2007, 11(Suppl 2):P395 (doi: 10.1186/cc5555) M Thomas, M Duffy, G Auzinger, W Bernal, E Sizer, J Wendon
King’s College Hospital, London, UK
Critical Care 2007, 11(Suppl 2):P395 (doi: 10.1186/cc5555) Of the patients not admitted to our LITU (162 to ward and 176 to
IC), 79% were deemed too well to benefit and 2% due to no beds. the mean ± SD SOFA score for the too sick to benefit group
(19%) was 11.5 ± 4.3 (63% had decompensated chronic liver
disease (d-CLD), 36% with malignancy, major sepsis or morbid
cardiocerebral event). The mean ± SD SOFA scores for the ward,
IC and LITU groups were 2.5 ± 2.4, 7.9 ± 4.6 and 7.8 ± 4.5,
respectively. The SOFA liver score was highest in all three triage
groups, overall mean of 2.3 (ward, 1.9 ± 1.4; IC, 2.6 ± 1.2; LITU,
2.4 ± 1.2), compared with other components (respiratory 0.9,
cardiovascular 0.7, coagulation 0.9, renal 1.1, central nervous
system 0.8). Patients with INR > 6 were more likely to be triaged to
LITU (OR 4.2). Introduction Fibrinogen as a prognostic test of mortality in acute
hepatic failure has not been reported. Two hundred and sixty
patients admitted to the liver intensive therapy unit (LITU) with
hepatic failure (that is, subacute, acute and fulminant) between 1
January 2004 and 30 September 2006 were identified from the
LITU database (I-Care, UK). Twelve patients without fibrinogen
testing on admission were excluded from the analysis. Methods The mean (±SD) age was 38.1 (14) years. Ninety-seven
patients were male and 151 female; 116 had taken a paracetamol
overdose (POD). The mean (±SD) fibrinogen on admission was
1.88 (1.24) g/l. Overall ICU mortality was 30.2% (POD 43.4%;
non-POD 26.1%). Forty-nine patients received a transplant (14
POD and 35 non-POD). A total of 97 patients were admitted to our LITU (five of 17 patients
triaged at referral to our hospital liver ward); six patients died
before arrival and three patients were diverted to another liver
intensive care facility for family convenience. Fifteen patients
underwent liver transplantation (10/49 with ALDF, 5/37 with
d-CLD). Mortality in the LITU group was 36%, and highest with
d-CLD (57% vs 25% with ALDF). What is the role of carboxyhaemoglobin in patients with
liver failure? What is the role of carboxyhaemoglobin in patients with
liver failure? M Austin, A Portal, J Wendon
King’s College Hospital, London, UK
Critical Care 2007, 11(Suppl 2):P397 (doi: 10.1186/cc5557) Background Patients with liver failure have haemodynamic and
respiratory instability, the aetiology of which is unclear. Unregulated
vasoactive mediators may have an important role in this
physiological phenomenon. Carbon monoxide, a vasodilator, has
been extensively studied and is easily measured using circulating
carboxyhaemoglobin (COHb). The levels of circulating COHb have
been reported as being elevated in patients with stable cirrhosis
and hepatopulmonary syndrome. It is unknown whether the levels of
COHb are elevated in patients with liver failure. P395 Mean referral, post-transfer and
48-hour SOFA scores of LITU nonsurvivors were 10.7, 12.7 and
13.9, respectively (6.5, 7.7 and 7.5 for survivors). Results Fibrinogen levels (all in g/l) in survivors were higher than in
nonsurvivors (1.98 ± 1.26 vs 1.63 ± 1.15; P = 0.033). Fibrinogen
was higher in survivors of POD (1.81 ± 1.0 vs 1.41 ± 0.94;
P = 0.039) and not significantly different between groups in non-
POD hepatic failure (2.13 ± 1.43 vs 1.85 ± 1.31; P = 0.28). Fibrino-
gen was higher in those who survived after transplant (1.49 ± 0.83
vs 1.23 ± 0.23; P = 0.27). A cutoff value of fibrinogen of ≤1 g/l has
sensitivity 0.47 and specificity 0.74 (positive predictive value (PPV)
0.44) for prediction of death in acute hepatic failure. In POD the
sensitivity is 0.51, specificity 0.81 and PPV 0.59; in non-POD
hepatic failure the values are 0.29, 0.73 and 0.31 respectively. In
those POD who did not receive a transplant, fibrinogen ≤1 g/l has
sensitivity 0.61, specificity 0.78 and PPV of 0.57 for death. Fibrinogen is higher in survivors of hepatic failure after POD. Conclusions The refusal rate to our LITU due to no beds was low. Paracetamol remains a common cause for drug-induced liver injury,
although few are severe cases. The triage decision appeared to be
influenced by the INR, d-CLD with or without a reversible cause
and the presence/absence of morbid extrahepatic diagnoses. Available online http://ccforum.com/supplements/11/S2 Available online http://ccforum.com/supplements/11/S2 0.813, P = 0.006. There were no significant differences in NGAL
values between survivors and nonsurvivors for the whole group. NGAL was significantly lower in survivors than nonsurvivors in the
ACLD group (AUC 0.875, P = 0.47). 15-bed LITU as recorded on a standardised proforma. Data
evaluated were: referral diagnoses; reasons for refusal to LITU (‘too
well to benefit’, ‘too sick to benefit’ or ‘no beds’); triaged destination
of care (‘ward’ at referral hospital or our hospital liver ward, ‘IC’ at
referral hospital high-dependency unit/ICU or ‘LITU’); and parameters
for Sequential Organ Failure Assessment (SOFA) score. Conclusion Gc globulin and NGAL are potentially useful methods
of identifying patients with a particularly poor prognosis and those
needing renal replacement therapy. Further larger prospective
studies are needed to elucidate their exact role not only in liver
disease but also in the general ITU population. Result A total of 620 calls were received for 439 referrals (37%
during the 17:00–24:00 hours period, 11% during 00:00–08:00
hours), with 38% from the London region. Drug-induced acute liver
dysfunction/failure (ALDF) was the most common reason for
consultation (39%), with paracetamol being most common
(163/172), most of whom were triaged to a referral hospital ward
(63% vs 14% to LITU). Patients with diagnosis of ‘ischaemic
hepatitis’ tended to be triaged to IC (82%), and pancreatobiliary
disease and trauma to the LITU (69% and 80%). P397 Conclusion Fibrinogen ≤1 g/l performs better than INR > 6.5 in
predicting mortality after POD (sensitivity 0.69, specificity 0.61),
but not as well as the combined King’s College Criteria (sensitivity
0.69, specificity 0.96). Fibrinogen of ≤1 g/l in POD not meeting
King’s College Criteria for transplantation may identify a group with
poor prognosis. A low fibrinogen level on admission may predict
death after transplant (more data required). A comparison of Gc globulin and neutrophil gelatinase-
associated lipocalin in patients with liver disease S158
Table 1 (abstract P393)
CKD stage
Stage 1
Stage 2
Stage 3
Total
n
2
44
20
66
Age (years)
64.7 (3.4)
69.9 (8.3)
75.5 (7.7)
71.5 (8.4)
eGFR
92.5 (0.7)
69.4 (7.2)
52.35 (7.4)
64.9 (11.6)
Creatinine
78 (1.4)
97.8 (9)
125.2 (19.9)
105.5 (18.8)
Cholesterol
4.5 (0.5)
4.8 (1.1)
4.3 (0.9)
4.6 (1)
BP
1 (50%)
21 (48%)
9 (45%)
31 (47%)
Smoking
2 (100%)
31 (70%)
14 (70%)
49 (74%)
Diabetes
0
1 (3%)
2 (10%)
3 (5%)
Conclusion The majority of vascular patients undergoing elective
aortic surgery in our unit have impaired renal function that is not
accurately reflected by creatinine values. Management of patients
with stage 2 and 3 CKD is primarily cardiovascular risk assessment
with aggressive treatment of modifiable vascular risk factors [3]. The full impact of risk factor modification on perioperative outcome
in vascular patients requires further detailed investigation. Table 1 (abstract P393)
CKD stage
Stage 1
Stage 2
Stage 3
Total
n
2
44
20
66
Age (years)
64.7 (3.4)
69.9 (8.3)
75.5 (7.7)
71.5 (8.4)
eGFR
92.5 (0.7)
69.4 (7.2)
52.35 (7.4)
64.9 (11.6)
Creatinine
78 (1.4)
97.8 (9)
125.2 (19.9)
105.5 (18.8)
Cholesterol
4.5 (0.5)
4.8 (1.1)
4.3 (0.9)
4.6 (1)
BP
1 (50%)
21 (48%)
9 (45%)
31 (47%)
Smoking
2 (100%)
31 (70%)
14 (70%)
49 (74%)
Diabetes
0
1 (3%)
2 (10%)
3 (5%) 58
Conclusion The majority of vascular patients undergoing elective
aortic surgery in our unit have impaired renal function that is not
accurately reflected by creatinine values. Management of patients
with stage 2 and 3 CKD is primarily cardiovascular risk assessment
with aggressive treatment of modifiable vascular risk factors [3]. The full impact of risk factor modification on perioperative outcome
in vascular patients requires further detailed investigation. There were significant differences observed for Gc globulin
examining 30-day survival (transplantation from ITU being analysed
as ‘death’): 50 mg/l (29–94) vs 18 (4–40), respectively, AUC S158 Available online http://ccforum.com/supplements/11/S2 P398 Methods In 14 domestic pigs fulminant hepatic failure was
induced by surgical devascularization of the liver, and animals were
monitored postoperatively for 24 hours under general anaesthesia. Seven randomly assigned pigs (DFX group) were treated with
intravenous desferrioxamine (14.5 mg/kg/hour for 6 hours and
2.4 mg/kg/hour for the next 18 hours), whereas the remaining
(control group) received standard care. Bronchoalveolar lavage
fluid (BALF) was obtained after central line placement, after
surgery, at 7 hours, and 24 hours postoperatively and was analysed
f
ll
bi
h
i
l
d
id i
k
f l
i j Predictive value of indocyanine green clearance in acute
liver failure in children: comparison with King’s College
and Clichy scores J Quintero, J Ortega, J Bueno, S Flores, J Roqueta
Vall d’Hebron, Barcelona, Spain
Critical Care 2007, 11(Suppl 2):P398 (doi: 10.1186/cc5558) Introduction Indocyanine green clearance (ICG), measured by the
percentage disappearance rate (PDR), detects alterations in liver
function and may be used as a noninvasive determinant of hepatic
reserve in liver failure as well as a marker of graft function following
liver transplantation. The administration of blood products does not
interfere with the ICG-PDR as occurs with other prognostic scores
(King’s College and Clichy scores). The aims of this study were to
compare in acute liver failure the ICG-PDR with King’s College and
Clichy scores and to determinate its predictive value. for cell counts, biochemical and oxidative markers of lung injury. Results DFX resulted in maintenance of blood pressure (mmHg)
(84 ± 27 in DFX vs 51 ± 16 in control, P < 0.05) and attenuated
the increase of intracranial pressure (mmHg) (19 ± 10 in DFX vs
36 ± 9 in control, P < 0.01) at 24 hours. Protein levels in BALF
were increased in controls whereas in the DFX group protein
(µg/ml) was significantly lower (at 7 hours 398 ± 219 vs 187 ± 67,
respectively, P < 0.01; and at 24 hours 261 ± 112 vs 162 ± 52,
respectively, P < 0.05). Nitrites in BALF were elevated at 7 hours
in controls whereas a reduction was observed in the DFX group
(3.924 ± 3.67 µM vs 0.590 ± 0.69 µM, respectively, P < 0.05). Phospholipase A2, platelet-activating factor acetylhydrolase,
nitrates, total cell counts, neutrophils and macrophages in BALF all
increased in the control and DFX groups but did not differ
significantly between them. Pulmonary effects of desferrioxamine in the treatment of
an experimental model of fulminant hepatic failure Results DFX resulted in maintenance of blood pressure (mmHg)
(84 ± 27 in DFX vs 51 ± 16 in control, P < 0.05) and attenuated
the increase of intracranial pressure (mmHg) (19 ± 10 in DFX vs
36 ± 9 in control, P < 0.01) at 24 hours. Protein levels in BALF
were increased in controls whereas in the DFX group protein
(µg/ml) was significantly lower (at 7 hours 398 ± 219 vs 187 ± 67,
respectively, P < 0.01; and at 24 hours 261 ± 112 vs 162 ± 52,
respectively, P < 0.05). Nitrites in BALF were elevated at 7 hours
in controls whereas a reduction was observed in the DFX group
(3.924 ± 3.67 µM vs 0.590 ± 0.69 µM, respectively, P < 0.05). Phospholipase A2, platelet-activating factor acetylhydrolase,
nitrates, total cell counts, neutrophils and macrophages in BALF all
increased in the control and DFX groups but did not differ
significantly between them. Conclusions These results suggest that COHb maybe an
important mediator in haemodynamic and metabolic instability in
ALF. In DCLF, COHb is an important factor in hypoxia and possible
pulmonary shunting. P396 Telephone triage for a liver intensive care unit – advise or
admit? Telephone triage for a liver intensive care unit – advise or
admit? A Chan-Dominy, G Auzinger, W Bernal, E Sizer, J Wendon
King’s College Hospital, London, UK
Critical Care 2007, 11(Suppl 2):P396 (doi: 10.1186/cc5556) Objective To determine the referral pattern and organ dysfunction
severity of interhospital consultations, and triage practice at a
specialised liver intensive therapy unit (LITU). Objective To determine the referral pattern and organ dysfunction
severity of interhospital consultations, and triage practice at a
specialised liver intensive therapy unit (LITU). Methods Patients admitted with acute liver dysfunction to the ITU
between January 2003 and December 2005 were considered. Sixty-
eight patients with acute liver failure (ALF) and 132 patients with
decompensated chronic liver failure (DCLF) had a full dataset
available on day 1 of admission. Patient demographics, physiological Methods A prospective audit was conducted from 1 March to 30
November 2006, for all interhospital telephone referrals to our S159 Critical Care March 2007 Vol 11 Suppl 2
27th International Symposium on Intensive Care and Emergency Medicin References References 1. Crit Care Med 2004, 32:2079. 1. Crit Care Med 2004, 32:2079. 2. Am J Respir Cell Mol Biol 2003, 29:427. 1. Crit Care Med 2004, 32:2079. 2. Am J Respir Cell Mol Biol 2003, 29:427. P399 parameters, blood results and organ dysfunction were recorded
prospectively and entered into a patient management system
database (ICARE). Pulmonary effects of desferrioxamine in the treatment of
an experimental model of fulminant hepatic failure Pulmonary effects of desferrioxamine in the treatment of
an experimental model of fulminant hepatic failure Results There was no statistical difference in patient demo-
graphics, organ failure scores or physiological parameters between
the groups. The median COHb percentage for ALF was 0.9%
(0.7–1.2) and for DCLF 1.5% (1.2–1.8). In patients with DCLF,
COHb negatively correlated with PaO2 (r = –0.4, P = 0.05) and
child Pugh (r = –0.4, P = 0.07). There was significant difference
between grouped COHb and MAP in patients with ALF; there was
a trend towards statistical significance with higher COHb. The
arterial pH correlated with COHb in ALF (r = 0.4, P = 0.01). K Kalimeris, G Kostopanagiotou, C Routsi, V Smyrniotis,
N Papoutsidakis, N Arkadopoulos, G Kampouroglou,
D Kypriotis, D Panagopoulos, A Kollitza, M Lekka, G Nakos
Aretaieion Hospital, University of Athens, Greece
Critical Care 2007, 11(Suppl 2):P399 (doi: 10.1186/cc5559) Introduction Desferrioxamine (DFX) is a clinically approved iron
chelator used to treat iron overload. It has also shown beneficial
effects in experimental acute liver failure (ALF) by inhibiting oxidative
damage [1]. Lung dysfunction commonly complicates ALF. Iron-
mediated processes have been shown to contribute to it [2]. We
hypothesized that inhibition of oxidative reactions by means of iron
chelation could attenuate lung injury after ischemic ALF. Introduction Desferrioxamine (DFX) is a clinically approved iron
chelator used to treat iron overload. It has also shown beneficial
effects in experimental acute liver failure (ALF) by inhibiting oxidative
damage [1]. Lung dysfunction commonly complicates ALF. Iron-
mediated processes have been shown to contribute to it [2]. We
hypothesized that inhibition of oxidative reactions by means of iron
chelation could attenuate lung injury after ischemic ALF. Methods In 14 domestic pigs fulminant hepatic failure was
induced by surgical devascularization of the liver, and animals were
monitored postoperatively for 24 hours under general anaesthesia. Seven randomly assigned pigs (DFX group) were treated with
intravenous desferrioxamine (14.5 mg/kg/hour for 6 hours and
2.4 mg/kg/hour for the next 18 hours), whereas the remaining
(control group) received standard care. Bronchoalveolar lavage
fluid (BALF) was obtained after central line placement, after
surgery, at 7 hours, and 24 hours postoperatively and was analysed
for cell counts, biochemical and oxidative markers of lung injury. P398 Methodology Between 2003 and 2006, 114 ICG-PDRs were
performed in 38 children (mean age 2.6 years (range 1 month–
16 years)) with acute liver damage. ICG was administrated intra-
venously and its blood concentration was detected over time by
transcutaneous pulse densitometry using a commercially available
bedside monitor. The PDR was performed under hemodynamic
stability (systolic mean pressure >60 mmHg; saturation of central
venous blood saturation >70% and CO2 arterio-venous difference
<8 mmHg). Conclusion Treatment of ALF with DFX attenuates the increase of
protein and nitrites in BALF, but does not seem to significantly
affect phospholipase A2, platelet-activating factor acetylhydrolase,
nitrates, macrophages or neutrophils. The observed effects may
suggest a protective role of DFX on lung inflammation during the
first 24 hours of ALF. Results The mean number of PDRs/patient was three. The mean
PDR was 17% (range: 3.3–51%). In two out of 38 patients, the
PDR could not be detected due to hemodynamic instability. PDR <
5% was a predictor value for irreversible liver failure (P = 0.000). In
nine (25%) out of 36 patients, the PDR was <5%. Of those nine,
two patients recovered its synthetic function and seven (78%)
patients developed irreversible liver failure (four died of liver failure
and three underwent liver transplantation) (see Table 1). The relative sensitivity of serum lipase versus amylase for
radiological image-positive pancreatitis K Delaney, S Luber
UT Southwestern Medical School, Dallas, TX, USA
Critical Care 2007, 11(Suppl 2):P402 (doi: 10.1186/cc5562) Methods A retrospective study in a national four-bed liver ICU that
treated 127 patients with ALF between 2001 and 2006. Thirty-eight
of these patients were treated with terlipressin, and 10 patients
(median age 42.5 years; range 15–66 years; five females) who also
had an ICP and a microdialysis catheter placed in the cerebral cortex
were included in this study. Concomitant measurements of mean
arterial pressure (MAP), ICP, cerebral perfusion using transcranial
Doppler sonography (Vmean) and cerebral concentrations of lactate
and pyruvate were made before and after an increase in the NE
infusion rate and i.v. injection of 1 mg terlipressin. Background Due to the absence of a ‘gold standard’ test for the
diagnosis of pancreatitis, the sensitivities of pancreatic enzyme
tests for pancreatitis are still debated. We compared the relative
sensitivities of lipase and amylase at their upper limit of normal
values for image-positive pancreatitis in a large consecutive series
of patients who had simultaneous tests of amylase and lipase. Background Due to the absence of a ‘gold standard’ test for the
diagnosis of pancreatitis, the sensitivities of pancreatic enzyme
tests for pancreatitis are still debated. We compared the relative
sensitivities of lipase and amylase at their upper limit of normal
values for image-positive pancreatitis in a large consecutive series
of patients who had simultaneous tests of amylase and lipase. Methods Consecutive patients with a clinical diagnosis of
pancreatitis defined by constant epigastric pain and elevation of
the amylase or lipase to greater than 106 U/l or 59 U/l,
respectively,
were
imaged
by
abdominal
sonography
or
computerized axial tomography (CAT) scan. All included patients
had positive radiological evidence of acute pancreatitis. Results The pancreas was visualized in 399/473 (84%) patients
with suspected pancreatitis and 127/399 (38%) had radiological
evidence of pancreatitis. Elevation of the lipase to >59 U/l
detected 127/127 cases of image-positive pancreatitis, while
elevation of the amylase to >106 U/l detected 113/127 cases
(88% sensitive (0.82–0.94)). All cases of acute biliary pancreatitis
were detected by both the lipase and amylase. The amylase
missed 14 of 65 patients with nonbiliary etiologies of pancreatitis. Four of these were alcoholics. P402 aim of this study was to determine whether terlipressin increases
cerebral perfusion and to compare the effect with that of nor-
epinephrine (NE). Furthermore, the effect on intracranial pressure
(ICP) and cerebral concentrations of lactate and pyruvate were
recorded. The relative sensitivity of serum lipase versus amylase for
radiological image-positive pancreatitis P401 Relative adrenal insufficiency in patients with severe acute
pancreatitis Conclusion Our study shows a high degree of relative sensitivity
of the lipase compared with amylase for pancreatic injury that is
demonstrable on CAT or sonographic imaging. Our findings
demonstrate a relative lack of sensitivity of amylase for nonbiliary
etiologies of pancreatitis. We recognize that the absolute
sensitivity of lipase for image-positive pancreatitis cannot be
determined by this retrospective methodology that required
elevation of one marker for inclusion. J De Waele1, E Hoste1, D Baert2, K Heyndrickx3, D Rijkckaert4,
P Thibo5, P Van Biervliet6, F Colardyn1
1Ghent University Hospital, Ghent, Belgium; 2AZ Maria Middelares,
Ghent, Belgium; 3OLV, Aalst, Belgium; 4AZ St Lucas, Ghent, Belgium;
5AZ Palfijn, Ghent, Belgium; 6AZ Aurora, Oudenaarde, Belgium
Critical Care 2007, 11(Suppl 2):P401 (doi: 10.1186/cc5561) P403 Background Inadequate cortisol levels and adrenal dysfunction
may play a role in the pathophysiology of severe acute pancreatitis. This study aimed to analyse the incidence of relative adrenal
insufficiency (RAI) in these patients, to identify factors associated
with relative adrenal insufficiency and to describe how adrenal
responsiveness affects outcome. P400 Conclusions ICG-PDR < 5% is a significant predictor of
irreversible liver failure. It is a good complement of such scores for
decision-making. Comparison of terlipressin and norepinephrine on cerebral
perfusion, intracranial pressure and cerebral
concentrations of lactate and pyruvate in patients with
acute liver failure: a microdialysis study Table 1 (abstract P398)
King’s score
Clichy score
ICG-PDR
Sensitivity (%)
100
71.4
100
Specificity (%)
87
90
93
PPV (%)
64
63
78
NPV (%)
100
93
100 M Eefsen, T Dethloff, H Frederiksen, J Hauerberg,
B Adel Hansen, F Stolze Larsen
Rigshospitalet, University Hospital of Copenhagen, Denmark
Critical Care 2007, 11(Suppl 2):P400 (doi: 10.1186/cc5560) Table 1 (abstract P398) Introduction
Volume expansion and inotropic support with
catecholamines are often insufficient to ensure adequate blood
pressure and cerebral blood flow in acute liver failure (ALF). The S160 Available online http://ccforum.com/supplements/11/S2 The relative sensitivity of serum lipase versus amylase for
radiological image-positive pancreatitis Methods Consecutive patients with a clinical diagnosis of
pancreatitis defined by constant epigastric pain and elevation of
the amylase or lipase to greater than 106 U/l or 59 U/l,
respectively,
were
imaged
by
abdominal
sonography
or
computerized axial tomography (CAT) scan. All included patients
had positive radiological evidence of acute pancreatitis. Results NE infusion and terlipressin injection increased the MAP
and Vmean (P < 0.01). Also, the ICP increased during NE infusion
(P < 0.01) but not after terlipressin. The cerebral lactate
concentration was unchanged during NE infusion, while it
decreased after terlipressin (P < 0.05). p
g
p
Results The pancreas was visualized in 399/473 (84%) patients
with suspected pancreatitis and 127/399 (38%) had radiological
evidence of pancreatitis. Elevation of the lipase to >59 U/l
detected 127/127 cases of image-positive pancreatitis, while
elevation of the amylase to >106 U/l detected 113/127 cases
(88% sensitive (0.82–0.94)). All cases of acute biliary pancreatitis
were detected by both the lipase and amylase. The amylase
missed 14 of 65 patients with nonbiliary etiologies of pancreatitis. Four of these were alcoholics. Conclusion This study shows that terlipressin increases the MAP
and cerebral perfusion in patients with ALF with no influence upon
ICP and the cerebral concentrations of lactate and pyruvate. These
findings indicate that terlipressin may be valuable, as an additive, or
alternative, treatment of arterial hypotension in patients with ALF to
secure brain viability. The significance of gallbladder sludge in the patient with
acute pancreatitis The significance of gallbladder sludge in the patient with
acute pancreatitis K Delaney, L Velez
UT Southwestern Medical School, Dallas, TX, USA
Critical Care 2007, 11(Suppl 2):P403 (doi: 10.1186/cc5563) Methods In a prospective observational multicenter study, a short
Synacthen test (SST) was performed within 5 days after admission
to the hospital in 25 patients with severe acute pancreatitis, after
signed informed consent was obtained. The incidence of RAI,
defined as an increment after SST of less than 9 µg/dl, was the
primary endpoint of the study. Serum cortisol was measured at
baseline and 30 and 60 minutes after 250 µg adrenocorticotropic
hormone administration. Background The significance of gallbladder sludge as a potential
cause of acute biliary pancreatitis is debated. We report the
incidence and outcome of patients with gallbladder sludge in a
large population of patients with pancreatitis. Methods Pancreatitis was defined as constant epigastric pain with
lipase greater than three times the upper reference value for our
laboratory (177 U/l). Consecutive patients with first episodes of
acute pancreatitis were identified over a 2-year period and data
were
evaluated
retrospectively. Patients
were
followed
prospectively for 2 years more. Results The median baseline cortisol level was 26.6 µg/dl, and
increased to 43.2 µg/dl and 48.8 µg/dl after 30 and 60 minutes,
respectively. RAI was found in 16% of all patients, and in 27% of
patients with organ dysfunction. Patients with RAI were more
severely ill and had higher SOFA scores from day 4 through day 7
after admission. All patients with RAI developed pancreatic
necrosis, and all of them needed surgical intervention. Mortality
was significantly higher in patients with RAI (75% vs 10%,
P = 0.016). Patients who died had a lower increment in cortisol
levels after the SST than patients who survived. Results All patients had gallbladder ultrasound examinations. First
episodes of acute pancreatitis were identified in 356 patients. Initially 236 patients had stones directly visualized in the
gallbladder. Of the remaining 120 patients, 13 had sludge, 11 had
a dilated common bile duct, one had a positive sonographic
Murphy sign, and 95 had no abnormalities. During the time course
of the study, 23 of these 120 patients were demonstrated to have
stones; by the surgical pathology report (12), endoscopic
retrograde cholangio-pancreatography (10), and cholecystostomy Conclusion RAI is frequent in patients with severe acute pancreatitis
and organ dysfunction. Recurrence rates in patients with first episodes of acute
pancreatitis Recurrence rates in patients with first episodes of acute
pancreatitis K Delaney, S Luber
UT Southwestern Medical School, Dallas, TX, USA
Critical Care 2007, 11(Suppl 2):P404 (doi: 10.1186/cc5564) ,
,
,
Critical Care 2007, 11(Suppl 2):P404 (doi: 10.1186/cc Introduction The timing of operative intervention in patients with
suspected biliary pancreatitis is debated. Recurrence rates of
pancreatitis in patients with biliary lithiasis are compared in
operated and nonoperated patients. Recurrences in patients with
suspected nonbiliary pancreatitis are also reported. Results The two groups of 38 patients were comparable in age
(52.4 and 56.5 years), ASA physical status (1.9 and 2.0),
preoperative albumin concentration (39.0 and 38.1 g/l), duration of
operation (5.9 and 6.1 hours), transfused red blood cells (3.3 and
2.0 l) and crystalloid infusion during surgery (5.3 and 4.5 l). In both
groups there was very significant drop of albumin concentration in
the first week after surgery (P < 0.001). In group 2 albumin
concentrations were very significantly lower than in group 1 until
the fifth postoperative day (P < 0.001). The difference diminished
after the sixth postoperative day (P < 0.03). There was negative
correlation between the postoperative albumin concentration and
the duration of surgery (r = –0.44, P < 0.008). We found no
difference in the postoperative complication rate (surgical or
medical), length of stay and mortality between the groups. Introduction The timing of operative intervention in patients with
suspected biliary pancreatitis is debated. Recurrence rates of
pancreatitis in patients with biliary lithiasis are compared in
operated and nonoperated patients. Recurrences in patients with
suspected nonbiliary pancreatitis are also reported. Methods First episodes of acute pancreatitis were identified in
consecutive emergency department patients over a 2-year period. Data were evaluated retrospectively and then the identified
patients were then followed prospectively for 2 years more. Results Pancreatitis was defined clinically as constant epigastric
pain associated with elevation of the serum lipase to greater than
three times the upper reference value (177 U/l) and no other
identified cause of abdominal pain. Of 356 patients with first
episodes of acute pancreatitis, 259 had pancreatitis that was
ultimately associated with biliary lithiasis based on abdominal
ultrasound (n = 236), positive endoscopic retrograde pancreoto-
graphy (n = 11), surgical pathology report (n = 11), or cholecystos-
tomy (n = 1). Ninety-seven patients had no identified stones during
the study period. Cholecystectomy was performed in 235/259 at
the time of admission for pancreatitis. P406 Extravascular lung water following resuscitation of
hemorrhagic shock in swine: comparison between Ringers’
lactate and normal saline
C Phillips, B Tieu, D Hagg, M Schreiber
Oregon Health & Science University, Portland, OR, USA
Critical Care 2007, 11(Suppl 2):P406 (doi: 10.1186/cc5566) Extravascular lung water following resuscitation of
hemorrhagic shock in swine: comparison between Ringers’
lactate and normal saline C Phillips, B Tieu, D Hagg, M Schreiber
Oregon Health & Science University, Portland, OR, USA
Critical Care 2007, 11(Suppl 2):P406 (doi: 10.1186/cc5566) Introduction Pulmonary edema is a common consequence of
hemorrhagic shock resuscitation. The type and amount of fluid
used in resuscitation may be important determinants of the amount
of edema formed. Ringers’ lactate (RL) and normal saline (NS)
remain common resuscitative fluids. These experiments were
designed to measure the extravascular lung water (EVLW) after
resuscitation from hemorrhagic shock with RL vs NS, to determine
whether the fluid type results in differences in the amount of
EVLW, and to determine whether there exists a threshold amount
of fluid that results in the development of edema. Conclusion Cholecystectomy reduced the incidence of recurrence
of pancreatitis in patients with biliary lithiasis. The significance of gallbladder sludge in the patient with
acute pancreatitis In group 2 albumin
concentrations were very significantly lower than in group 1 until
the fifth postoperative day (P < 0.001). The difference diminished
after the sixth postoperative day (P < 0.03). There was negative
correlation between the postoperative albumin concentration and
the duration of surgery (r = –0.44, P < 0.008). We found no
difference in the postoperative complication rate (surgical or
medical), length of stay and mortality between the groups. Materials
and
methods
We
retrospectively
studied
76
successive patients operated on in the abdomen at the Oncologic
Institute in Ljubljana in 1997/98 (group 1 – postoperative
hypoalbuminemia treated with 20% albumin solution) and in
2000/01 (group 2 – no albumin treatment), because of
abandoning albumin use in our surgical department. We compared
serum albumin concentrations in the first week after surgery (three
values) as well as the postoperative complication rate and the
length of hospital stay. We looked for correlation between the
postoperative albumin concentration and the duration of surgery,
amount of transfusion and amount of infusion during surgery. Recurrence rates in patients with first episodes of acute
pancreatitis Reasons for nonoperative
management were death (three cases), medical contraindications
(15 cases), pregnancy (two cases) and delayed diagnosis due to
negative abdominal sonogram (four cases). During the study
period 10% (10/97) of patients without demonstrated stones
returned with recurrent episodes of pancreatitis. There were two
recurrences in 235 operated patients with stones (0.85%). Twelve
of 19 nonoperated survivors with biliary lithiasis returned with
complications of biliary lithiasis, including 10 recurrences of biliary
pancreatitis (53%) and two episodes of common bile duct
obstruction, one of which resulted in death from cholangitis. The
median time to recurrence of pancreatitis in nonoperated patients
with stones was 50 days, range 26–581 days. Conclusion Postoperative serum albumin concentrations were
reduced in both groups, but more in group 2 with no albumin
treatment, and in longer operations. Morbidity, mortality and length
of stay were not influenced by albumin replacement. P405 Replacement of albumin after abdominal surgery The significance of gallbladder sludge in the patient with
acute pancreatitis It occurs in patients with more severe
pancreatitis and is associated with an increased mortality rate. S161 Critical Care March 2007 Vol 11 Suppl 2
27th International Symposium on Intensive Care and Emergency Medicin no broad consensus is reached yet on abandoning the use of
albumin in intensive care and perioperative settings for the bad
prognostic value of hypoalbuminemia. As the albumin decrease in
major surgery is mostly due to extravascular leakage of albumin
(systemic inflammatory response), we regard hypoalbuminemia just
as a marker of inflammatory response to surgery that albumin
replacement cannot change. So the postoperative morbidity,
mortality and length of stay would not differ in patients without
albumin replacement. (one). Seven of 13 patients with sludge underwent cholestectomy
and all had evidence of stones. Four of six nonoperated patients
with sludge (67%) returned with recurrent pancreatitis over the
course of the study. Ten of 97 patients (10%) with suspected
nonbiliary etiology of the pancreatitis returned with recurrent
pancreatitis over the same period. The nonoperated patients with
sludge were more likely to have other risk factors for nonbiliary
pancreatitis than were the operated patients. Conclusions
The presence of sludge on the gallbladder
ultrasound suggests the presence of stones and is associated with
a high rate of recurrence of pancreatitis in nonoperated patients. Materials
and
methods
We
retrospectively
studied
76
successive patients operated on in the abdomen at the Oncologic
Institute in Ljubljana in 1997/98 (group 1 – postoperative
hypoalbuminemia treated with 20% albumin solution) and in
2000/01 (group 2 – no albumin treatment), because of
abandoning albumin use in our surgical department. We compared
serum albumin concentrations in the first week after surgery (three
values) as well as the postoperative complication rate and the
length of hospital stay. We looked for correlation between the
postoperative albumin concentration and the duration of surgery,
amount of transfusion and amount of infusion during surgery. Results The two groups of 38 patients were comparable in age
(52.4 and 56.5 years), ASA physical status (1.9 and 2.0),
preoperative albumin concentration (39.0 and 38.1 g/l), duration of
operation (5.9 and 6.1 hours), transfused red blood cells (3.3 and
2.0 l) and crystalloid infusion during surgery (5.3 and 4.5 l). In both
groups there was very significant drop of albumin concentration in
the first week after surgery (P < 0.001). Available online http://ccforum.com/supplements/11/S2 Available online http://ccforum.com/supplements/11/S2 Available online http://ccforum.com/supplements/11/S2 suprapubic Foley catheter placement, and splenectomy. The
spleen was weighed and, based on randomization, either LR or NS
solution was infused to replace three times the spleen weight in
grams. Following a 15-minute stabilization period, a standardized
Grade V liver injury (injury to a central hepatic vein) was then
created using a specialized clamp. Following 30 minutes of
uncontrolled hemorrhage, we blindly randomized the swine to
receive either NS or RL resuscitation at 165 ml/min. Resuscitation
fluid was administered to achieve and maintain the baseline mean
arterial pressure (MAP) for 90 minutes post injury. suprapubic Foley catheter placement, and splenectomy. The
spleen was weighed and, based on randomization, either LR or NS
solution was infused to replace three times the spleen weight in
grams. Following a 15-minute stabilization period, a standardized
Grade V liver injury (injury to a central hepatic vein) was then
created using a specialized clamp. Following 30 minutes of
uncontrolled hemorrhage, we blindly randomized the swine to
receive either NS or RL resuscitation at 165 ml/min. Resuscitation
fluid was administered to achieve and maintain the baseline mean
arterial pressure (MAP) for 90 minutes post injury. operatively. Thereafter fluid management was as in group A. Arterial
blood samples were taken preoperatively and at 5 minutes,
30 minutes, 60 minutes, 120 minutes, 240 minutes and 24 hours
post-tourniquet release for HNE and arterial blood gas analysis. Repeated measures of analysis of variance established a
significant difference in the pattern of change of HNE levels (log
transformed) and the PaO2/FiO2 ratios with time between the two
groups. Follow-up t tests revealed significantly lower levels of HNE
(Table 1) and also significantly higher PaO2/FiO2 ratios in Group B
post-tourniquet release. operatively. Thereafter fluid management was as in group A. Arterial
blood samples were taken preoperatively and at 5 minutes,
30 minutes, 60 minutes, 120 minutes, 240 minutes and 24 hours
post-tourniquet release for HNE and arterial blood gas analysis. Repeated measures of analysis of variance established a
significant difference in the pattern of change of HNE levels (log
transformed) and the PaO2/FiO2 ratios with time between the two
groups. Follow-up t tests revealed significantly lower levels of HNE
(Table 1) and also significantly higher PaO2/FiO2 ratios in Group B
post-tourniquet release. Toxicity of two lipid emulsions on human lymphocytes and
neutrophils Toxicity of two lipid emulsions on human lymphocytes and
neutrophils Toxicity of two lipid emulsions on human lymphocytes and
neutrophils M Cury-Boaventura1, R Gorjão2, T Martins de Lima2,
F Soriano3, R Curi2
1Cruzeiro do Sul University, São Paulo, Brazil; 2University of São
Paulo, Brazil; 3Faculdade de Medicina USP, São Paulo, Brazil
Critical Care 2007, 11(Suppl 2):P408 (doi: 10.1186/cc5568) Introduction The incorporation of lipid emulsions in parenteral
diets is a requirement for energy and essential fatty acid supply,
and may prevent many metabolic disturbances associated with
intravenous feeding amino acids and glucose alone in critically ill
patients. For different parenteral fat emulsions, a significant impact
on the immune system has been shown. In this study, the toxicity of
soybean oil-based emulsion and olive oil-based emulsion on
leukocytes from healthy volunteers was investigated. Conclusion In this swine model of traumatic hemorrhagic shock,
resuscitation with RL as compared with NS required less fluid to
maintain goal MAP and resulted in less EVLW formation. The near
fourfold difference in EVLW increase was accounted for entirely by
the differences in volumes needed to maintain goal MAP with no
differences seen with fluid type. This study suggests that, in order
to limit increases in EVLW during early resuscitation of
hemorrhagic shock prior to the arrival of blood products, RL should
be used preferentially instead of NS and the volume infused limited
to approximately 60 ml/kg. Methods
Twenty-four volunteers were recruited and blood
samples were collected before infusion of a soybean oil-based
emulsion or olive oil-based emulsion, immediately afterwards and
18 hours later. The cells were studied immediately after isolation,
and after 24 hours or 48 hours in culture. The following deter-
minations were made: composition and concentration of fatty acids
in plasma, lymphocytes and neutrophils, and lymphocyte
proliferation. The toxicity was determined by plasma membrane
integrity, DNA fragmentation, phosphatidylserine externalization,
mitochondrial depolarization, production of reactive oxygen
species and neutral lipid accumulation. Available online http://ccforum.com/supplements/11/S2 In conclusion, the results suggest that infusion of HES lowers HNE
release from activated neutrophils in postoperative knee
replacement patients and may lead to less lung injury. Results
All animals spontaneously stopped bleeding within
12 minutes of injury after losing approximately 25% of their blood
volume. There were no differences in initial blood loss between the
two groups – estimated blood loss (mean ± standard error) RL
group 22 ± 1.7 ml/kg vs NS group 19.0 ± 1.7 ml/kg, P = 0.15. During the resuscitative phase the NS group required more fluid to
maintain the goal MAP than the RL group: 330.8 ± 38.1 ml/kg vs
148.4 ± 20.2 ml/kg, P = 0.001. There was nearly a fourfold
increase in mean EVLW between the groups: 5.24 ± 1.26 ml/kg
NS vs 1.46 ± 0.57 ml/kg RL, P = 0.013. The difference in EVLW
was accounted for entirely by the difference in the volume infused
(P = 0.008), with no difference seen with fluid type (P = 0.7). The
EVLW began to increase immediately with fluid administration
without exhibiting a threshold effect. An increase of 1 ml/kg EVLW
occurred at a resuscitative volume of 63 ± 25 ml/kg. Neutrophil elastase suppression by medium-molecular-
weight hydroxyethylstarch in orthopaedic surgery Neutrophil elastase suppression by medium-molecular-
weight hydroxyethylstarch in orthopaedic surgery R Walker1, G McCarthy2
1Craigavon Area Hospital, Craigavon, UK; 2Belfast City Hospital,
Belfast, UK
Critical Care 2007, 11(Suppl 2):P407 (doi: 10.1186/cc5567) Results Both lipid emulsions decreased lymphocyte proliferation
and induced cell death, but the effects of soybean oil-based
emulsion were more pronounced. Soybean oil-based emulsion
provoked apoptosis and necrosis, whereas olive oil-based
emulsion caused neutrophil and lymphocyte necrosis only. Evidence is presented that lipid emulsion is less toxic to
neutrophils than to lymphocytes. The mechanism of cell death
induced by this lipid emulsion involved mitochondrial membrane
depolarization and neutral lipid accumulation, but did not alter
production of reactive oxygen species. The aim of this study was to compare the effect of
hydroxyethylstarch (HES) and human albumin solution (HAS) on
human neutrophil elastase (HNE) release in patients undergoing
elective knee replacement surgery. Forty-three patients (ASA 1 or 2) were randomly allocated into two
groups. Group A (n = 21) received 5 ml/kg of 4.5% HAS pre-
operatively and a further 5 ml/kg HAS as an intraoperative replace-
ment. Postoperatively the patients received Ringers’ lactate at the
discretion of the anaesthetic team. Group B was given 5 ml/kg HES
(Fresenius-Kabi) preoperatively and a further 5 ml/kg HES intra- Conclusions Olive oil-based emulsion can be an alternative to
soybean oil-based emulsion, avoiding leukocyte death and the
susceptibility of patients to infections. Table 1 (abstract P407)
Group
Preoperative, mean (SD)
5 minutes
30 minutes*
60 minutes*
120 minutes*
240 minutes*
24 hours
A
2.31 (0.21)
2.59 (0.35)
2.74 (0.34)
2.83 (0.26)
2.74 (0.24)
2.78 (0.29)
2.68 (0.19)
B
2.39 (0.25)
2.4 (0.32)
2.41 (0.15)
2.43 (0.13)
2.54 (0.2)
2.53 (0.15)
2.65 (0.31)
*P < 0.01. Replacement of albumin after abdominal surgery K Mahkovic Hergouth1, L Kompan2
1Institute of Oncology, Ljubljana, Slovenia; 2Clinical Center,
Ljubljana, Slovenia
Critical Care 2007, 11(Suppl 2):P405 (doi: 10.1186/cc5565) K Mahkovic Hergouth1, L Kompan2
1Institute of Oncology, Ljubljana, Slovenia; 2Clinical Center,
Ljubljana, Slovenia
Critical Care 2007, 11(Suppl 2):P405 (doi: 10.1186/cc5565) Methods This was a randomized controlled trial using 20 female
Yorkshire crossbred pigs. Animals were mechanically ventilated. Anesthesia was maintained using 2% isofluorane in 100% oxygen. Continuous hemodynamic monitoring, blood sampling, and
determination of EVLW by single indicator transpulmonary dilution
was done using a PiCCO plus monitor (Pulsion Medical System,
Munich, Germany). The animals underwent a midline celiotomy, Introduction Replacement of albumin in hypoalbuminemic patients
is not proven to reduce postoperative morbidity and mortality but S162 Available online http://ccforum.com/supplements/11/S2 Haemoglobin concentration influences the chloride–
bicarbonate but not the strong ion difference–bicarbonate
relationship M Mercieri, A Marcelli, C Claroni, A Mercieri
University of Rome La Sapienza, Rome, Italy
Critical Care 2007, 11(Suppl 2):P409 (doi: 10.1186/cc5569) Methods In this retrospective case–control study we identified
patients who received more than two units of high plasma volume
components from male-only donors and compared them with
patients matched by severity of illness, postoperative state and
number of transfusions but who received high plasma volume
components from female donors. Introduction Chloride and bicarbonate concentrations share an
inverse reciprocal relationship during either acidosis or alkalosis. This relationship is, in part, due to the red cell chloride shift. However, according to the Stewart quantitative approach to acid–
base balance, it seems conceivable to expect a greater relationship
between the strong ion difference (SID) and bicarbonate, rather
then between chloride and bicarbonate. We propose that, with
decreasing haemoglobin (Hb) levels, the SID preserves its
independent role with respect to bicarbonate, while chloride
gradually loses its relationship. Results From a database of 3,567 patients who received a total of
46,101 units fresh frozen plasma and 6,251 units apheresis
platelets, we identified 112 patients who received three or more
male-only donor components and 112 matched controls. Baseline
characteristics, ALI risk factors and development of ALI were
similar between the two groups. Arterial oxygenation (PaO2/FiO2)
worsened after the female donor components (mean difference
–52, 95% CI –14 to –91, P = 0.008) but not after male-only donor
product transfusion (mean difference +22, 95% CI –23 to + 67,
P = 0.325). Male-only component recipients had more ventilator-
free days (median 28 vs 27, P = 0.006) and a trend towards lower
hospital mortality (14% vs 24%, P = 0.054). Methods We retrospectively collected blood gas analysis and
electrolytes, from 206 patients, measured on a single blood
sample taken on admission. We calculated the apparent SID
through the following formula: [Na+] + [K+] + [Ca2+] + [Mg2+] –
[Cl–] – [Lact–] (mEq/l). We divided patients into three groups
based on Hb levels: group A (n = 54) with Hb levels between 12
and 15 g/dl, group B (n = 104) with Hb levels between 9 and
12 g/dl, and group C (n = 48) with Hb levels below 9 g/dl. We
calculated
Pearson’s
coefficients
between
the
SID
and
bicarbonate and between chloride and bicarbonate in these three
groups of patients. Table 1 (abstract P409) Table 1 (abstract P409)
SID–HCO3
–,
Cl––HCO3
–,
Group
Hb (g/dl)
r/r2
P
r/r2
P
A
12–15
0.76/0.58
0.001
–0.6/0.36
0.001
B
9–12
0.83/0.70
0.001
–0.56/0.32
0.001
C
<9
0.80/0.65
0.001
–0.31/0.09
ns ical Care 2007, 11(Suppl 2):P411 (doi: 10.1186/cc557 Introduction Red blood cell (RBC) transfusion is very often
performed in critically ill patients despite its potential complications. Its effects on oxygen delivery and microcirculation are not well
known. This study aimed at evaluating RBC effects in blood lactate
levels (LAC) and central venous oxygen saturation (SvcO2) in
patients with severe sepsis and septic shock. Conclusion These results give further validation to Stewart’s
theories: the SID appears to maintain the role of an independent
variable with respect to bicarbonate even at low haemoglobin
levels, while chloride loses this relationship at haemoglobin levels
below 9 g/dl. Methods A prospective study enrolling patients admitted to an
ICU at a university hospital with severe sepsis and septic shock
presenting hemoglobin (Hb) levels below 9.0 g/dl. These patients
were randomized for maintaining Hb >9 g/dl (Group 1) or >7 g/dl
(Group 2). Before (preT) and at least 1 hour after each transfusion
(postT) LAC, SvcO2 and Hb data were collected. Data were
analysed by analysis of variance, paired t test and paired Wilcoxon
test. Results were considered significant if P ≤0.05. Table 1 (abstract P407) S163 Critical Care March 2007 Vol 11 Suppl 2
27th International Symposium on Intensive Care and Emergency Medicin Haemoglobin concentration influences the chloride–
bicarbonate but not the strong ion difference–bicarbonate
relationship Conclusion In critically ill recipients of high plasma volume
components, gas exchange worsened significantly after transfusion
of female but not male donor components. Prospective studies are
needed to evaluate the effect of AABB recommendations on
outcome of transfused critically ill patients. P411 Results Correlation strength between the SID and HCO3
– was
high and significant even at a Hb concentration below 9 g/dl (see
Table 1). Pearson’s coefficients for chloride and bicarbonate
showed a moderate but significant inverse correlation in group A
and group B; eventually this correlation was completely lost in
group C. Evaluation of red blood cell transfusion effects in lactate
and central venous oxygen saturation in patients with
severe sepsis and septic shock B Mazza, M Assuncao, F Freitas, M Jackiu, H Fernandes,
F Machado
Escola Paulista de Medicina – Universidade Federal de São Paulo,
Brazil
Critical Care 2007, 11(Suppl 2):P411 (doi: 10.1186/cc5571) P409 P409
Haemoglobin concentration influences the chloride–
bicarbonate but not the strong ion difference–bicarbonate
relationship
M Mercieri, A Marcelli, C Claroni, A Mercieri
University of Rome La Sapienza, Rome, Italy
Critical Care 2007, 11(Suppl 2):P409 (doi: 10.1186/cc5569) minimize transfusion of high plasma volume components, fresh
frozen plasma and apheresis platelets, from potentially alloimunized
donors, especially females. The objective of this study was to
evaluate the effect of transfusing components from male-only vs
female donors on development of ALI, gas exchange, and outcome
in critically ill patients. Haemoglobin concentration influences the chloride–
bicarbonate but not the strong ion difference–bicarbonate
relationship O Gajic1, M Yilmaz1, R Iscimen1, D Kor1, J Winters1, B Afessa2,
J Farmer1
1Mayo Clinic, Rochester, MN, USA; 2Mayo Clinic College of
Medicine, Rochester, MN, USA
Critical Care 2007, 11(Suppl 2):P410 (doi: 10.1186/cc5570) P412 Results The mean age of the transfused patients was 35.78 years. The sex ratio was 1.2. A total of 48.3% of the patients had trans-
fusion history. Allogeneic immunization and viral serology conver-
sion were reported in 2.1% of these patients. The indications were
generally carried in front of chronic medical pathologies (36.9%),
acute medical pathologies (28.2%) and surgical pathologies
(elective 11.7%, urgent 11.2%). The haemoglobin threshold for
transfusion was 7.29 g/dl and depended on the indication of the
red cell transfusion: 6.16 g/dl for urgent medical pathologies,
6.22 g/dl for chronic medical pathologies, 7.74 g/dl for urgent
surgical pathologies, 10.38 g/dl for elective surgery, 6.15 g/dl for
urgent obstetrical pathologies. The mean platelet count was
24,000 (patients transfused by platelet units). The ABO and
rhesus determination were made in 99% of the cases. A
phenotypic determination was required in only 34.5% of the cases. The search for irregular agglutinins was made in 20.7% of the
cases. The test of compatibility at the laboratory was practiced in
95.4% of the cases. The amount of blood transfused was 2 units. Immediate incidents were reported in 2.5% of the cases. The post-
transfusion haemoglobin average was of 9.15 g/dl. Transfusion profiles in intensive care units from a
university hospital M Assuncao, I Paula, L Falcao, B Mazza, M Barros, M Jackiu,
H Fernandes, F Machado
Universidade Federal de São Paulo, Brazil
Critical Care 2007, 11(Suppl 2):P412 (doi: 10.1186/cc5572) Introduction Red blood cell (RBC) transfusion is very often
performed in critically ill patients despite its potential complica-
tions. New guidelines recommend that doctors should have
conservative behavior regarding its use. The objective of this study
was to evaluate the transfusion profile among patients in ICUs at a
university hospital in Brazil. Introduction Red blood cell (RBC) transfusion is very often
performed in critically ill patients despite its potential complica-
tions. New guidelines recommend that doctors should have
conservative behavior regarding its use. The objective of this study
was to evaluate the transfusion profile among patients in ICUs at a
university hospital in Brazil. Methods A prospective evaluation of all patients admitted to six
ICUs (surgical–medical, private, neurosurgery, medical, pneu-
mology and coronary units) that have received a RBC transfusion
as indicated by assistant physicians during October/November
2005. Clinical data as well as the characteristics of the transfusion
were collected and submitted to univariate statistical analysis (chi-
squared and Student’s t test). National survey of transfusion practices N Frikha, R Ouezini, T Mestiri, M Bechikh, M Mebazaa,
M Ben Ammar
Mongi Slim Hospital, La Marsa, Tunisia
Critical Care 2007, 11(Suppl 2):P413 (doi: 10.1186/cc5573) Introduction The awakening of the residual risks of blood trans-
fusion leads, everywhere in the world, to efforts to reduce them. The
aim of the study was to assess the transfusion practices in Tunisia. Introduction The awakening of the residual risks of blood trans-
fusion leads, everywhere in the world, to efforts to reduce them. The
aim of the study was to assess the transfusion practices in Tunisia. Patients and methods A multicentric prospective observational
study of about 1,000 transfusions practiced during 2004 in
Tunisia. Data were determined by the prescriptor of the trans-
fusion. The data were analyzed with SPSS 12.0. Conclusion In patients with SvcO2 < 70 and/or Hb < 7.0 g/dl,
transfusion seems to result in an improvement of perfusion
parameters. However, in patients with SvcO2 > 70 or normal
lactate levels, transfusion seems to impair tissue perfusion. Patients and methods A multicentric prospective observational
study of about 1,000 transfusions practiced during 2004 in
Tunisia. Data were determined by the prescriptor of the trans-
fusion. The data were analyzed with SPSS 12.0. Transfusion from male-only vs female donors in critically ill
recipients of high plasma volume components Results Thirty-six transfusions were evaluated in 21 patients (mean
age 59.0 ± 15.8 years, 11 females/10 males) with APACHE II
score of 13.8 ± 4.1. Each group included 18 patients. The levels
of Hb preT and postT were 7.51 ± 1.03 and 8.48 ± 1.15
(P < 0.05). There was a significant difference between preT and
postT SvcO2 (70.9 ± 8.66 and 73.6 ± 7.2, P = 0.01) but not in
LAC levels (24.1 ± 8.9 and 22.9 ± 7.6, P = 0.45). When groups
were analyzed separately, only in Group 2 was a significant
difference found (P = 0.0005 and 0.05, respectively for SvcO2
and LAC). In 10 transfusions a worsening of SvcO2 postT was O Gajic1, M Yilmaz1, R Iscimen1, D Kor1, J Winters1, B Afessa2,
J Farmer1
1Mayo Clinic, Rochester, MN, USA; 2Mayo Clinic College of
Medicine, Rochester, MN, USA
Critical Care 2007, 11(Suppl 2):P410 (doi: 10.1186/cc5570) O Gajic1, M Yilmaz1, R Iscimen1, D Kor1, J Winters1, B Afessa2,
J Farmer1
1Mayo Clinic, Rochester, MN, USA; 2Mayo Clinic College of
Medicine, Rochester, MN, USA
Critical Care 2007, 11(Suppl 2):P410 (doi: 10.1186/cc5570) Objective To reduce the incidence of transfusion-related acute
lung injury (ALI), the American Association of Blood Banks (AABB)
has recently recommended rapid implementation of strategies to S164 Available online http://ccforum.com/supplements/11/S2 P412 Results were considered significant
if P ≤0.05. Discussion and conclusion The evolution of the blood transfusion
was remarkable, since the use of total blood in the 1980s, with the
acquisition of the first techniques of separation of the blood
components. The transfusion practice in Tunisia is far from being to
the standards. The results obtained make it possible to transmit to
the clinician the failures of the system, to better include how to
prescribe a blood product, to follow its effectiveness and its
possible side effects, and to apprehend the impact of the
innovated biotechnologies to improve quality of transfusion
medicine in coherence with the security requirements. Results Four hundred and eight transfusions were made in 71
patients (38 females, 33 males), 35 medical/36 surgical, with a
mean age 57.2 ± 8.4 years, mean APACHE II score 17.7 ± 5.3,
and mean SOFA score on the day of transfusion 6.09 ± 3.99. At
admission, 60 patients (84.5%) had comorbidities, 10 (14.1%)
had chronic coronary disease. At transfusion, 54.9% had sepsis,
severe sepsis or septic shock, and 9.9% had acute coronary
syndrome. The mean hemoglobin (Hb) level at ICU admission was
9.69 ± 2.3 g/dl and the mean level that triggered transfusion was
6.88 ± 1.1 g/dl. The most important transfusion indication was Hb
levels (49.8%), followed by active bleeding (31.8%). The mean
number of RBC transfused per time was 1.68 ± 0.96 and the
mean age of RBC was 14.3 ± 7.83 days (46.6% had more than
14 days). Adverse events occurred in 3.4%. The 28-day mortality
rate was 47.1%. Only the SOFA score at the day of transfusion
correlated with mortality (P = 0.004). There was no correlation with
age, type of ICU, APACHE II score, total number or age of RBC,
Hb at admission or Hb pretransfusion. There was a significant
difference between the pretransfusion Hb (P < 0.00001) and the
number of RBC transfused at the same time considering all ICU
enrolled in the study (P < 0.00001). P413 observed and all these patients had preT SvcO2 > 70%. Although
there was no significant correlation between a worsening in SvcO2
and preT Hb, eight of these patients were allocated to Group 1. Another 13 transfusions were done with a SvcO2 preT < 70, and
10 of them improved (> 5%) after transfusion (mean percentage of
improvement = 18.9%). Only four of these patients were allocated
to Group 1. Patients with high levels of preT LAC (n = 21) only
improved (reduction > 10%) in 42.9% of cases. A total 53.3% of
patients with normal preT LAC levels worsened (rising > 10%)
postT. The mean preT Hb from these patients was 8.18 ± 0.9. Conclusion In patients with SvcO2 < 70 and/or Hb < 7.0 g/dl,
transfusion seems to result in an improvement of perfusion
parameters. However, in patients with SvcO2 > 70 or normal
lactate levels, transfusion seems to impair tissue perfusion. observed and all these patients had preT SvcO2 > 70%. Although
there was no significant correlation between a worsening in SvcO2
and preT Hb, eight of these patients were allocated to Group 1. Another 13 transfusions were done with a SvcO2 preT < 70, and
10 of them improved (> 5%) after transfusion (mean percentage of
improvement = 18.9%). Only four of these patients were allocated
to Group 1. Patients with high levels of preT LAC (n = 21) only
improved (reduction > 10%) in 42.9% of cases. A total 53.3% of
patients with normal preT LAC levels worsened (rising > 10%)
postT. The mean preT Hb from these patients was 8.18 ± 0.9. observed and all these patients had preT SvcO2 > 70%. Although
there was no significant correlation between a worsening in SvcO2
and preT Hb, eight of these patients were allocated to Group 1. Another 13 transfusions were done with a SvcO2 preT < 70, and
10 of them improved (> 5%) after transfusion (mean percentage of
improvement = 18.9%). Only four of these patients were allocated
to Group 1. Patients with high levels of preT LAC (n = 21) only
improved (reduction > 10%) in 42.9% of cases. A total 53.3% of
patients with normal preT LAC levels worsened (rising > 10%)
postT. The mean preT Hb from these patients was 8.18 ± 0.9. Reference 1. Geddes J, et al.: Neuropathol Appl Neurobiol 2003, 29:14-22. P416 Patients and methods Sixty-eight patients (54 males/14 females)
participated in the study. Thirty-two patients underwent valve(s)
replacement (group A) and the remaining underwent coronary
artery bypass grafting(s) (group B). The BT determination was
performed according to the Mielke technique using Surgicutt
devices (ITC, USA). Platelet function was evaluated by the
aggregation procedure using four agonists: ADP, arachidonic acid,
collagen and ristocetin at a final concentration of 4 x 10–6 M,
0.5 mg/ml, 0.19 mg/ml and 1.2 mg/ml, respectively. Shaken baby syndrome: the classical clinical triad is still
valid in recent court rulings P414 Could the combination of bleeding time and platelet
function predict the perioperative transfusion requirements
in cardiac surgery patients? M Kataphigioti, D Karamichaleli, M Kounavi, E Iliopoulou,
G Palatianos, E Melissari
Onassis Cardiac Surgery Center, Athens, Greece
Critical Care 2007, 11(Suppl 2):P414 (doi: 10.1186/cc5574) Introduction The reduction in platelet count and function is the
most important, unsolved, nonsurgical cause of postoperative
bleeding after open heart surgery. On the other hand, the bleeding
time (BT), the only comprehensive test to explore primary
haemostasis, detects otherwise unknown defects in platelet–
vessel wall interactions. The present study was undertaken in order
to clarify whether the BT and platelet function tested preoperatively
could predict the perioperative transfusion requirements in cardiac
surgery patients. Conclusions The Hb level that triggered transfusion was in
agreement with recent guidelines regarding critically ill patients,
although there was a difference between all ICUs. Despite the fact
that there is a scarceness of RBC, the RBC were higher in age. The missing correlation with mortality can be due to the small
sample size. S165 ritical Care March 2007 Vol 11 Suppl 2
27th International Symposium on Intensive Care and Emergency Medicin Shaken baby syndrome: the classical clinical triad is still
valid in recent court rulings The Geddes theory led to the speculation that
subdural and retinal haemorrhage was not caused by traumatic
shearing of subdural and retinal veins but by a combination of
cerebral hypoxia, raised intracranial pressure and raised arterial and
central venous pressure. The publication of this theory was met with
scepticism by many forensic and paediatric pathologists but was
enthusiastically embraced by defence attorneys. This dilemma
resulted in the UK with several appeals against prior convictions of
murder/manslaughter because of alleged traumatic shaking of
young children. The forensic community awaited with great interest
the ruling of the Court of Appeal in London on 21 July 2005. Conclusion In patients undergoing cardiac surgery with a negative
history of bleeding and early interruption of antiplatelet treatment,
the BT and platelet function do not offer much in the setting to
predict perioperative bleeding. g
pp
y
Court ruling of 21 July 2005 Four cases of alleged SBS were
brought to the Court of Appeal in London. Two convictions were
upheld, one conviction was dismissed and one conviction was
reduced from murder to manslaughter. In their written judgement
their Lordships clearly stated: ‘In our judgment, it follows that the
unified hypothesis can no longer be regarded as a credible or
alternative cause of the triad of injuries’. The Crown Prosecution
Service made a press release that ‘Today’s judgement sends a clear
signal validating the CPS in prosecuting Shaken Baby Syndrome
cases. The Geddes theory will no longer be used by the defence.’ Court ruling of 21 July 2005 Four cases of alleged SBS were
brought to the Court of Appeal in London. Two convictions were
upheld, one conviction was dismissed and one conviction was
reduced from murder to manslaughter. In their written judgement
their Lordships clearly stated: ‘In our judgment, it follows that the
unified hypothesis can no longer be regarded as a credible or
alternative cause of the triad of injuries’. The Crown Prosecution
Service made a press release that ‘Today’s judgement sends a clear
signal validating the CPS in prosecuting Shaken Baby Syndrome
cases. The Geddes theory will no longer be used by the defence.’ Shaken baby syndrome: the classical clinical triad is still
valid in recent court rulings M De Leeuw1, W Jacobs2
1Algemeen Stedelijk Ziekenhuis Aalst, Essene, Belgium;
2University Hospital Antwerp, Edegem, Belgium
Critical Care 2007, 11(Suppl 2):P416 (doi: 10.1186/cc5576) Introduction Subdural haemorrhage, retinal bleeding and hypoxae-
mic encephalopathy have long been considered a diagnostic clinical
triad for the so-called shaken baby syndrome (SBS). The classical
triad, however, has been challenged in the recent past by the so-
called ‘unified hypothesis’ by Geddes and colleagues [1] with
subsequent implications in court rulings in suspected cases of SBS. Judicial and scientific dilemma The unified hypothesis by Geddes
suggested an alternative cause for SBS injuries that did not involve
significant shaking. The Geddes theory led to the speculation that
subdural and retinal haemorrhage was not caused by traumatic
shearing of subdural and retinal veins but by a combination of
cerebral hypoxia, raised intracranial pressure and raised arterial and
central venous pressure. The publication of this theory was met with
scepticism by many forensic and paediatric pathologists but was
enthusiastically embraced by defence attorneys. This dilemma
resulted in the UK with several appeals against prior convictions of
murder/manslaughter because of alleged traumatic shaking of
young children. The forensic community awaited with great interest
the ruling of the Court of Appeal in London on 21 July 2005. Results (1) In the immediate postoperative time, a significant
reduction in haemoglobulin levels was observed in both groups
compared with that of the preoperative time (13.3%, P < 0.05 for
group A and 28.4%, P < 0.01 for group B). No difference existed
in haemoglobulin levels between groups postoperatively. (2) Platelet
values were slightly different between the groups. A significant
decrease in platelet count was observed in both groups
postoperatively (28.7%, P < 0.03 for group A and 22.4%, P < 0.05
for group B). (3) The results of BT and platelet activation (per-
formed preoperatively) were similar for patients who underwent
valve replacement and patients who underwent coronary artery
bypass grafting – although in this group platelet activation with
arachidonic acid and ADP was ~11% lower with both agonists. (4) The transfusion requirements were slightly higher for patients in
group A, and more patients in group B received no transfusion
(one vs four patients). Judicial and scientific dilemma The unified hypothesis by Geddes
suggested an alternative cause for SBS injuries that did not involve
significant shaking. Emergency staff is in danger B Gulalp1, O Karcioglu2
1Adana State Hospital, Adana, Turkey; 2Dokuz Eylul University,
School of Medicine, Izmir, Turkey
Critical Care 2007, 11(Suppl 2):P415 (doi: 10.1186/cc5575) Conclusions Diagnosing SBS is a very complex and delicate matter. The mere presence of the classic triad does not automatically or
necessarily lead to a diagnosis of nonaccidental head injury or a
conclusion of unlawful killing. Diagnosis of (intentional) SBS must be
based on the combination of: medical elements, elements from
police inquiry, and forensic and crime scene elements. Physicians,
particularly those working at the medico-legal interface (such as
emergency physicians), should realise that medical observations may
play a pivotal role in the diagnosis of SBS. As important is the
realisation that, despite alternative hypothesis in medical literature,
the classical triad of symptoms (subdural haemorrhage, retinal
bleeding, hypoxaemic encephalopathy) is still valid as diagnostic for
SBS according to recent (UK) court ruling. Objective
To investigate the ratio and characteristics of
aggression, threat and physical violence directed towards staff in
emergency departments as a model of state hospitals. Objective
To investigate the ratio and characteristics of
aggression, threat and physical violence directed towards staff in
emergency departments as a model of state hospitals. Methods A questionnaire were filled in by the staff working in the
emergency department of three high-volume inner-city state
hospitals. The individualized data collected were relevant to the
pattern of violence, age, sex, number of years in the profession,
nature of the job, and the behavioral characteristics of assailants,
and outcome of incidents. The data were abstracted between
1 May and 31 May 2006. Results
A total of 109 staff reports were reviewed. The
relationship of aggression with sex, age and years of experience
were insignificant (P values were 0.464, 0.692, and 0.298,
respectively), while profession was very significantly related
(P = 0.000). The relation between threat and sex is P = 0.311,
experience 0.994, profession 0.326, age 0.278. The relationship of
threat with sex, years of experience, profession and age were
insignificant (P values were 0.311, 0.994, 0.326, and 0.278,
respectively). On the other hand, physical assault was found
significantly related to sex, years of experience, profession and age
(P values were 0.042, 0.011, 0.000, and 0.000, respectively). A comparison of the confusion assessment method for the
intensive care unit and the NEECHAM confusion scale in
intensive care delirium assessment A comparison of the confusion assessment method for the
intensive care unit and the NEECHAM confusion scale in
intensive care delirium assessment Methods Were admitted to the ICU 29 patients with OPP. The data
were treated by SPSS 14 for Windows and the analysis consisted of
a descriptive study, analytic study (chi-square analysis, Spearman
association analysis) and comparison between groups (Student
t analysis, Wilcoxon Mann–Whitney and Kolmogorov–Smirnov tests). The receiver operating characteristic (ROC) was applied for the
Sequential Organ Failure Assessment (SOFA) score. B Van Rompaey1, L Bossaert2, L Shortridge-Bagett1,
M Schuurmans1, S Truijen1
1Universiteit Antwerpen, Wilrijk, Belgium; 2Universitair Ziekenhuis
Edegem, Belgium
Critical Care 2007, 11(Suppl 2):P419 (doi: 10.1186/cc5579) B Van Rompaey1, L Bossaert2, L Shortridge-Bagett1,
M Schuurmans1, S Truijen1
1Universiteit Antwerpen, Wilrijk, Belgium; 2Universitair Ziekenhuis,
Edegem, Belgium
Critical Care 2007, 11(Suppl 2):P419 (doi: 10.1186/cc5579) Results Twenty-nine patients were included in the study, 21 males
and eight females. The mean age of the males was 47.71 years
(SD = 13.58) and of females was 41.0 years (SD = 11.66), and
62.7% were from a rural area and 37.3% from an urban area. Mortality does not have a significant statistic relation (P > 0.05)
with toxicity of organophosphate, time and doses of atropine. However, statistical significance was found between mortality and:
(a) time between ingestion of the poison and treatment (Spearman
test, rs = –0.596, P < 0.05), (b) muscarinic manifestations (chi-
square
test,
χ2 = 4.152,
P < 0.05),
(c)
time
of
oximes
(Kolmogorov–Smirnov test with Z = 1.439, P < 0.05) and doses of
oximes (Kolmogorov–Smirnov test with Z = 1.412, P < 0.05). The
ROC analysis reveals that for the respiratory SOFA at 9 days, the
area under the ROC curve was 0.917; this means that this SOFA
score can predict correctly in 91.7% of the cases. Introduction Reports indicate an incidence of intensive care
delirium of 11–87%. The confusion assessment method for the
intensive care unit (CAM-ICU) is widely used in delirium assess-
ment in ICUs. However, its binomial results constrain the evaluation
of severity. The NEECHAM confusion scale has recently been
validated for use in the ICU and uses a numeric assessment. This
scale allows the patients to be classified in four categories of
delirium severity (normal, at-risk, mild to early, moderate to severe). In this study we investigated the diagnostic value of the
NEECHAM referring to the CAM-ICU. A comparison of the confusion assessment method for the
intensive care unit and the NEECHAM confusion scale in
intensive care delirium assessment Methods A consecutive sample of 106 patients in a mixed ICU
(cardiac surgery (CS) 35%, noncardiac surgery (NCS) 26%,
internal medicine (IM) 39%, age 62 ± 14 years, male 63%) was
assessed after a stay in the ICU ≥24 hours. All patients with a
Glasgow Coma Scale ≥10 and age ≥18 years were included. A
nurse researcher simultaneously assessed both scales once daily
in the morning. A total of 272 paired observations were made. Data
were analyzed using the NEECHAM cut-off values of ≤26 (at-risk),
≤24 (mild delirium), and ≤19 (severe delirium). Conclusion In our study we concluded that the mortality rate was
increased with prolonged perfusion of oximes and with muscarinic
manifestations of OPP but not with the time and dose of atropine. The respiratory SOFA score at 9 days matches with prediction in
above 90% of the cases. P418 Results Using the CAM-ICU the overall prevalence was 15%. Prevalences in CS, NCS and IM were 9%, 14% and 21%,
respectively. Using the NEECHAM scale, the overall prevalence
was 33% (16.5% mild, 16.5% severe) and 36%, 21% and 38%
for the three patient categories, respectively. Sensitivity was
100%, specificity was 79%, positive predictive value was 46% and
negative predictive value was 100%. Using the cut-off value ≤19,
sensitivity was 83% and specificity was 96%. All positive CAM-
ICU patients were detected by the NEECHAM (85% severe, 15%
mild). However, 21% of the CAM-ICU negative patients had a
NEECHAM value that diagnoses delirium (4% severe, 17% mild). Consequently, 27% of the CS group (19% severe, 8% mild), 7%
of the NCS group (7% mild) and 17% of the IM group (2% severe,
15% mild) were diagnosed to be delirious using the NEECHAM
and not delirious using the CAM-ICU. Reference organophosphate poisoning (OPP). The aim of the study was to
determine the relation between mortality and: (a) toxicity of
organophosphate, (b) time between ingestion and management of
the patient, (c) coligernic manifestations, (d) time and doses of
oximes and atropine. Reference
1. Ely EW, et al.: Crit Care Med 2004, 32:106-112. Reference
1. Ely EW, et al.: Crit Care Med 2004, 32:106-112. Approaches of Turkish anesthesiologists to delirium
observed in intensive care unit patients Approaches of Turkish anesthesiologists to delirium
observed in intensive care unit patients Approaches of Turkish anesthesiologists to delirium
observed in intensive care unit patients N Gokmen, L Iyilikci, S Kucukguclu, B Kuvaki, L Ciftci, A Gunerli
Dokuz Eylul University, School of Medicine, Izmir, Turkey
Critical Care 2007, 11(Suppl 2):P418 (doi: 10.1186/cc5578) Objective To determine attitudes and practices of the Turkish
anesthesiologists and residents about delirium in the ICU. Methods An anonymous questionnaire consisting of 22 questions
[1] was mailed to 258 anesthesiologists and residents. [ ]
g
Results One hundred and fifty-four questionnaires were returned
(60% response). Of the respondents, 57% were male and 61%
were residents. One-half of respondents work in hospitals with
more than 800 beds; 65% of respondents had an ICU facility of
7–12 beds. Seventy-two percent of the respondents had seen
delirium in the ICU and also 70.2% of these respondents observed
delirium in <25% of patients who were on mechanical ventilation. Although delirium was accepted a significant or very serious
problem by 92.5% of the respondents, underdiagnosis was
acknowledged by 74%. Routine screening for delirium was
performed by 41.6% of the anesthesiologists and 88.1% of them
were repeating daily. Clinical assessment was used in 76.7% of
the screenings. Delirium was treated with haloperidol and
benzodiazepine by 61.5% and 24% of the respondents. Of the
respondents, 93.4% were not able to attend a meeting related to
delirium and 67.6% did not read even an article about delirium. Conclusions Turkish anesthesiologists and residents consider
delirium a relatively common and serious problem. However, they
seldom perform screening tests and try to update their knowledge
regarding delirium. Conclusion The NEECHAM delirium scale identified all cases of
delirium that were detected by the CAM-ICU. Moreover, additional
delirious patients were identified, especially in the CS group. In this
pilot experience, the NEECHAM scale was a valuable screening
tool for intensive care. Organophosphate poisoning and related mortality with
oxime perfusion Organophosphate poisoning and related mortality with
oxime perfusion A Bartolo1, O Caetano1, M Costa1, R Milheiro1, A Carvalho1, A Braga2
1Hospital Senhora Oliveira, Guimaraes, Portugal; 2University of
Minho, Braga, Portugal
Critical Care 2007, 11(Suppl 2):P417 (doi: 10.1186/cc5577) Conclusion Violence to the staff is common. There is not a
significant relationship between aggression, threat and personal
characters. However, male sex, >5 years experience, emergency
doctor, ≥31 years of age are the risk factors for physical violence. Introduction A retrospective study performed between 1 January
2001 and 31 October 2006 in patients admitted to the ICU with S166 Available online http://ccforum.com/supplements/11/S2 Available online http://ccforum.com/supplements/11/S2 P422 Conclusion Delirium is badly recognized in the ICU by intensivists
and ICU nurses. In view of the impact of delirium on ICU and
hospital stay, more attention should be paid to the implementation
of a delirium screening instrument during daily ICU care. Evaluation of two sedation techniques in a casualty
department Evaluation of two sedation techniques in a casualty
department M Moustafa1, M Borai2
1Faculty of Medicine, Assiut University, Alain, United Arab
Emirates; 2Alain Hospital, Alain, AbuDhabi, United Arab Emirates
Critical Care 2007, 11(Suppl 2):P422 (doi: 10.1186/cc5582) P420 We investigated whether
intensivists and ICU nurses could clinically identify the presence of
delirium in ICU patients during daily care. Methods All patients in a 3-month period who stayed >48 hours in
the ICU were evaluated daily for the presence or absence of
delirium by treating intensivists and ICU nurses responsible for
daily care. Patients were evaluated independently for the
occurrence of delirium by a trained group of ICU nurses who were
not involved in the daily care of the patients under study. Since
communication with ventilated patients is compromised due to the
inability to speak, a specific scoring system was used (confusion
assessment method for the intensive care unit (CAM-ICU)), which
has been developed for the evaluation of the presence of delirium. Delirium as judged present by this CAM-ICU correlates well with a
DSM-IV delirium diagnosis by a trained psychiatrist. Values are
expressed as the median and interquartile range (IQR). Results During the study period, 46 patients (30 males, 16
females), age 73 (IQR = 64–80) years with an ICU stay of 6
(4–11) days were evaluated. CAM-ICU scores were obtained
during 481 patient-days. Considering the CAM-ICU as the gold
standard, delirium occurred in 50% of the patients with a duration
of 3 (1–9) days. Days with delirium were poorly recognized by
doctors (sensitivity = 29.8%; specificity = 99.7%; PPV = 99.6%)
and ICU nurses (sensitivity = 35.6%; specificity = 97.8%; PPV =
84%). Patients with a delirium were longer on the ventilator (6
(4–25) days), and had a longer ICU (9 (6–26) days) and hospital
stay (29 (21–41) days) than those without delirium during their
ICU stay (4 (1–6), P = 0.01; 5 (3–8), P = 0.002; and 19 (7–30),
P = 0.01), respectively. APACHE II and SAPS II scores were
comparable in both groups. Conclusions There is still a great educational potential for
improving the use of sedation protocols and implementing sedation
scoring systems and the wake up test in Danish ICUs. This
potential could perhaps reduce the incidence of withdrawal
symptoms. Effort should also be placed in implementing the
sedation protocol in the ICU, illustrated by the differences in
numbers of doctors and nurses having a sedation protocol. P420 The occurrence of delirium is severely underestimated by
intensivists and intensive care unit nurses during daily ICU care The occurrence of delirium is severely underestimated by
intensivists and intensive care unit nurses during daily ICU care The occurrence of delirium is severely underestimated by
intensivists and intensive care unit nurses during daily ICU care
P Spronk, B Riekerk, S Elias, J Rommes, J Hofhuis
Gelre Ziekenhuizen Location Lukas, Apeldoorn, The Netherlands
Critical Care 2007, 11(Suppl 2):P420 (doi: 10.1186/cc5580) P Spronk, B Riekerk, S Elias, J Rommes, J Hofhuis
Gelre Ziekenhuizen Location Lukas, Apeldoorn, The Netherlands
Critical Care 2007, 11(Suppl 2):P420 (doi: 10.1186/cc5580) Introduction Patients improve faster in the ICU if sedatives are
stopped as soon as possible with inherent occurrence of sleeping
disorders, and delirium, which could compromise the recovery Introduction Patients improve faster in the ICU if sedatives are
stopped as soon as possible with inherent occurrence of sleeping
disorders, and delirium, which could compromise the recovery S167 Critical Care March 2007 Vol 11 Suppl 2
27th International Symposium on Intensive Care and Emergency Medicin Results Twenty-nine (82.9%) out of a total of 35 possible hospitals
answered, including 113 (57.7%) answers out of a total of 196
possible answers. Ninety-seven per cent of the physicians were
specialists in anaesthesiology. Eighty-seven per cent of the nurses
were certified intensive care nurses. Forty-seven per cent were from
university hospitals. Twenty-six per cent had a sedation protocol,
37% of the physicians and 14% of the nurses. Only one-third of the
ICUs had a protocol for sedation. Sixty-eight per cent having a
protocol used it always or often, whereas 32% never use it. Sixty-
seven per cent had a sedation scoring system in their departments. The scoring systems used was: Ramsay 49%, Sedation Agitation
Score 10% and own (locally made) scoring system 41%. Twenty-
two per cent answered that the scoring systems was always used,
58% often and in 20% the scoring systems was seldom used. Forty
per sent use the ‘wake-up call’ test, 63% physicians and 37%
nurses. Sixty per cent answered ‘no we do not use’ the wake-up call
test, 47% physicians and 53% nurses. Withdrawal symptoms were
experienced more than three times as frequently by nurses
compared with physicians (31% vs 9%). Five times as many
experienced withdrawal symptoms in the group not having a
sedation and analgesia protocol (84% vs 16%). process and prolong the ICU stay. Sedation practices in Denmark Sedation practices in Denmark We compare the efficacy, adverse events, and recovery duration of
etomidate and propofol for use in procedural sedation in the
emergency department (ED). A randomized nonblinded prospective
trial of adult patients undergoing procedural sedation for painful
procedures in the ED was made. Patients received either propofol
or etomidate. Doses, vital signs, nasal end-tidal CO2 (etco2), pulse
oximetry, and bispectral electroencephalogram analysis scores
were recorded. Subclinical respiratory depression was defined as a
change in etco2 greater than 10 mmHg, an oxygen saturation of
less than 92% at any time, or an absent etco2 waveform at any time. Clinical events related to respiratory depression, including an
increase in supplemental oxygen, the use of a bag-valve-mask
apparatus, airway repositioning, or stimulation to induce breathing,
were noted. Etomidate and propofol appear equally safe for ED
procedural sedation. Etomidate had a lower rate of procedural
success and induced myoclonus in 20% of patients (see Table 1). K Espersen1, M Skielboe2, T Jensen1
1Rigshospitalet, Copenhagen, Denmark; 2University Hospital
Gentofte, Denmark
Critical Care 2007, 11(Suppl 2):P421 (doi: 10.1186/cc5581) Critical Care 2007, 11(Suppl 2):P421 (doi: 10.1186/cc5581) Introduction The interest of sedation in ICU patients has been
increasing the last 10 years. The benefits of protocol-driven care
have become evident. Objective The aim of the study was to describe current practice of
sedation in Danish ICUs addressing the use of protocols and the
wake-up call test. Methods Two doctors and two nurses from all the Danish adult
ICUs were identified to participate in an Internet-based survey. These persons answered questions about sedation practices, use
of sedation scorings systems, and withdrawal symptoms. 8
Table 1 (abstract P422)
Agent
Etomidate (n = 53)
Propofol (n = 55)
Subclinical respiratory depression
Yes (n = 18)
No (n = 35)
Yes (n = 23)
No (n = 32)
Increased supplemental oxygen
1/9 (2.1, 0.9–11.2)
2/34 (2.9, 0.8–7.2)
2/23 (4.4, 1.2–14.4)
1/32 (1.6, 0.2–5.5)
Bag-valve mask (%)
2/18 (6.9, 1.9–13.9)
0/34 (0, 0–2.3)
2/23 (4.4, 1.4–11.9)
0/32 (0, 0–2.7)
Airway repositioning
3/18 (9.7, 2.9–16.0)
3/34 (5.1, 1.4–8.7)
3/23 (6.5, 1.5–11.6)
3/31 (4.7, 1.1–8.0)
Stimulation to induce breathing
4/18 (11.1, 5.1–19.6)
2/34 (2.9, 0.8–7.1)
3/23 (7.6, 3.2–14.5)
3/31 (4.7, 1.8–9.6) Inhalational sedation during transport to the intensive care
unit SEV
infusion was started in the ICU after gas monitoring. Twenty-one
patients scheduled for propofol sedation served as controls. During transport all patients were ventilated with Oxylog2000
(Dräger, Germany), vital parameters were monitored, and the
Ramsay Score (RS) was assessed at five time points. If necessary,
propofol injections of 0.5 mg/kg were given. Statistics were t test
for parametric data (mean ± standard deviation), U test for
nonparametric data (median (interquartile range)), SPSS 11.04. Results The age, weight, duration of anaesthesia (ACD/controls
7.3 ± 2.0/6.3 ± 2.2 hours), total sufentanil (124 ± 75/118 ± 57 µg)
and transport time (16.3 ± 2.7/17.0 ± 2.7 min) were not different
between groups, and neither were heart rates, mean arterial
pressures and RS at five time points during transport. ACD
patients needed less propofol injections (0 (0–1)/3 (2–4), P < 0.001) Comparison of dexmedetomidine with propofol/
midazolam in sedation of long-stay intensive care patients:
a prospective randomized, controlled, multicenter trial Comparison of dexmedetomidine with propofol/
midazolam in sedation of long-stay intensive care patients:
a prospective randomized, controlled, multicenter trial J Takala1, S Nunes2, I Parviainen3, S Jakob1, M Kaukonen4,
S Shepherd5, R Bratty5, E Ruokonen3
1University Hospital Bern, Switzerland; 2Tampere University
Hospital, Tampere, Finland; 3Kuopio University Hospital, Kuopio,
Finland; 4Helsinki University Hospital, Helsinki, Finland; 5Orion
Pharma, Helsinki, Finland
Critical Care 2007, 11(Suppl 2):P423 (doi: 10.1186/cc5583) Introduction Sedation is a major problem in long-stay intensive
care patients despite use of sedation stops and scores. We
hypothesized that the α2-adrenoceptor agonist dexmedetomidine
(DEX) is at least equivalent to standard-of-care sedation (SOC),
and may reduce the length of ICU stay and improve other clinically
relevant outcomes. Results Demographic data (age, gender, trauma severity score)
were comparable in both groups. The waking time was significantly
shorter in G2 (5 ± 8 min) compared with G1 (35 ± 20 min)
(P < 0.05). The mICP was more stable in G2 (9 ± 4 mmHg)
compared with G1 (10 ± 9 mmHg) (P = 0.02). The mCPP were
comparable in G1 (62 ± 10 mmHg) and in G2 (63 ± 0.2 mmHg)
but with a 24% swing in dose requirement adaptation of Ne in G1
compared with a 6% daily swing in G2 (P < 0.02). Methods We performed a pilot (n = 85), phase III, multicenter,
prospective, randomized, double-blind, double-dummy, active
comparator (SOC: either propofol or midazolam) study to define
the feasibility and size of a pivotal trial. Patients with expected ICU
stays ≥48 hours and a need for sedation for at least 24 hours after
randomization were included within the first 72 hours of ICU stay. The maximum duration of study sedation was 14 days, with a 45-
day follow-up from randomization. Sedation was Richmond
Agitation Sedation Scale (RASS)-score targeted, with daily
sedation stops. Conclusion By using a multimodal short-acting sedation protocol
based on remifentanil and NMDA-antagonist receptors we were
able to provide adequate sedation in brain trauma patients. Neurological parameters were respected with this regimen,
avoiding the risk of secondary patient hemodynamic destabilisation
during the waking periods. Inhalational sedation during transport to the intensive care
unit Inhalational sedation during transport to the intensive care
unit M Bellgardt, C Sirtl, M Bergmann, D Weyhe, A Terporten,
H Laubenthal, A Meiser
St Josef-Hospital, Ruhr-Universität, Bochum, Germany
Critical Care 2007, 11(Suppl 2):P425 (doi: 10.1186/cc5585) Introduction Inhalational ICU sedation is increasingly applied
since the introduction of AnaConDa® (Sedana Medical, Sweden). This anaesthetic-conserving device (ACD) retains exhaled
sevofluorane (SEV) and resupplies it during inspiration [1]. A
syringe pump delivers liquid SEV into the device. Since January
2004 we have used the ACD as a standard practice. Our patients
anaesthetised with SEV in the OR and scheduled for ICU sedation
with SEV only need propofol on transport. Could this be avoided
when using the ACD during transport? Introduction Inhalational ICU sedation is increasingly applied
since the introduction of AnaConDa® (Sedana Medical, Sweden). This anaesthetic-conserving device (ACD) retains exhaled
sevofluorane (SEV) and resupplies it during inspiration [1]. A
syringe pump delivers liquid SEV into the device. Since January
2004 we have used the ACD as a standard practice. Our patients
anaesthetised with SEV in the OR and scheduled for ICU sedation
with SEV only need propofol on transport. Could this be avoided
when using the ACD during transport? Conclusion DEX is well tolerated and comparable with SOC in
long-term sedation, but not suitable as the sole agent for deep
sedation. DEX enhances the patient’s ability to communicate. Its
effects on relevant outcomes (for example, duration of mechanical
ventilation) should be tested in a large randomized controlled trial. Methods Forty-one patients after major abdominal surgery were
included in this quality assurance project. In 20 patients the ACD
was inserted into the anaesthesia circuit to take up warmth,
humidity and SEV for 15 minutes and used for transport. SEV
infusion was started in the ICU after gas monitoring. Twenty-one
patients scheduled for propofol sedation served as controls. During transport all patients were ventilated with Oxylog2000
(Dräger, Germany), vital parameters were monitored, and the
Ramsay Score (RS) was assessed at five time points. If necessary,
propofol injections of 0.5 mg/kg were given. Statistics were t test
for parametric data (mean ± standard deviation), U test for
nonparametric data (median (interquartile range)), SPSS 11.04. Methods Forty-one patients after major abdominal surgery were
included in this quality assurance project. In 20 patients the ACD
was inserted into the anaesthesia circuit to take up warmth,
humidity and SEV for 15 minutes and used for transport. Available online http://ccforum.com/supplements/11/S2 Available online http://ccforum.com/supplements/11/S2 P423 during 6.4 (± 4) days were prospectively randomized into two
groups (G1 n = 32; G2 n = 36) using different sedation protocols
to reach a mean hourly Ramsay Score of 4. Sedation in G1 was
based on morphine (0.1 ± 0.1 mg/kg/hour) and midazolam
(0.4 ± 0.4 mg/kg/hour); in G2 on remifentanil (0.25 ± 0.25 µg/kg/min),
magnesium (0.08 g/kg/day), ketamine (0.15 ± 0.15 µg/kg/min),
clonidine (0.001 ± 0.001 µg/kg/min) and propofol (2 ± 1.5 mg/kg/
hour). The cerebral parameters (mean intracranial continuous
pressure (mICP); mean cerebral perfusion pressure (mCPP)) and
the needs of norepinephrine (Ne) were evaluated hourly. Preloading was adapted by a continuous central venous pressure
measurement before Ne adaptation requirements to keep the
mCPP over 60 mmHg. For statistical analysis a Shapiro–Wilk test,
a Wilcox test and a Student t test were used. P425 Results Forty-one patients received DEX and 44 SOC (28
propofol). The goal was moderate (RASS 0 to –3) sedation in most
patients (78% in DEX and 80% in SOC). Patients were at the
target RASS 55% (DEX) and 57% (SOC) of the sedation time (not
significant): for RASS target 0 to –3, 68% (DEX) and 64% (SOC)
of the time (not significant) and for RASS target –4, 31% (DEX)
and 63% (SOC), respectively (P = 0.006). Median time from
admission/randomization to ICU discharge was similar (DEX
6.6/5.7 days, SOC 6.7/5.5 days, not significant). Mechanical
ventilation was shorter for DEX with RASS target 0 to –3 (DEX
70.2 hours, SOC 92.5 hours, P = 0.027), and patients’ ability to
communicate (multidimensional visual analog scale) was better
with DEX (P < 0.001). Occurrence rates and number of patients
with overall and serious adverse events were similar. P424 Multimodal short acting sedation using NMDA antagonist
and remifentanil in brain trauma patients: a prospective
randomised study Table 1 (abstract P422) S168 Available online http://ccforum.com/supplements/11/S2 Remifentanil vs conventional sedation in The Netherlands:
a pharmacoeconomic model analysis M Al, L Hakkaart, S Tan, P Mulder, J Bakker
Erasmus MC, Rotterdam, The Netherlands
Critical Care 2007, 11(Suppl 2):P427 (doi: 10.1186/cc5587) Conclusions AnaConDa® effectively retains SEV in patients and
permits inhalational sedation during >15 minutes transport. Hemo-
dynamic stability and depth of sedation are as good as the
standard regime with Propofol. Less SEV exhaled by the patients
during transport also means less contamination of the workplace. Reference Introduction The goal of this study was to compare the duration of
mechanical ventilation (MV), the length of stay (LOS) and the direct
medical costs of remifentanil-based sedation (RS) vs conventional
sedation (CS) in ICU patients requiring MV. 1. A Meiser, H Laubenthal: Best Pract Res Clin Anaesthesiol
2005, 19:523-538. Methods A Markov model was developed based on UltiSAFE, a
recent Dutch open-label randomized controlled study that included
patients with an expected MV time of 2–3 days. Study medication
was either CS (morphine or fentanyl combined with propofol,
midazolam or lorazepam according to Dutch guidelines) or RS
(remifentanil, combined with propofol when required). The LOS on
the ICU, the time at which the patient was eligible for weaning or
extubation and the actual time of weaning and extubation, plus all
study drugs with all adjustments in dosage, were recorded. The
model describes the patient flow on the ICU. Three states were
defined: MV before weaning, MV after weaning has started before
extubation, post-MV before discharge. At every hour, patients either
stay at the current state, move to the next state or die. Transition
probabilities and the costs of the study drugs were derived from
UltiSAFE, whereas all other direct medical costs on the ICU were
estimated in a separate Dutch monocenter micro-costing study. All
costs were measured from the hospital perspective with 2006 as
the reference year. The time horizon used in the model was 28 days. Results From the trial data, it was estimated that the costs of RS on
MV before the start of weaning amount to €22 per hour, compared
with €15 for the CS treatment. After the start of weaning, these
costs decrease to €8 per hour for RS and €2 per hour for CS. P427 and reached the ICU with a similar RS (5 (4.5–5)/5 (4.75–5)). End-tidal SEV concentrations were similar in the OR (1.3 ± 0.2/
1.2 ± 0.2 vol%), but different when arriving in the ICU (0.6 ± 0.2/
0.2 ± 0.1 vol%, P < 0.001). Pharmacokinetics of single intravenous bolus
administration of propofol in preterm and term neonates Pharmacokinetics of single intravenous bolus
administration of propofol in preterm and term neonates K Allegaert1, M Rayyan1, A Debeer1, H Devlieger2, G Naulaers1
1University Hospital Gasthuisberg, Leuven, Belgium;
2A.Z. Gasthuisberg, Leuven, Belgium
Critical Care 2007, 11(Suppl 2):P426 (doi: 10.1186/cc5586) Background The aim of this study is to describe maturational
aspects of propofol pharmacokinetics following single intravenous
bolus administration in childhood. Methods Seventy propofol blood–time profiles were collected in
nine neonates (mean weight 2.4, range 0.91–3.8 kg) by arterial
blood samples up to 24 hours after administration of a single
intravenous bolus of propofol (3 mg/kg over 10 s) before elective
chest tube removal. Concentration–time curves obtained for every
individual neonate were interpreted by two-stage analysis as two-
compartment and three-compartment open models. These newly
collected observations following intravenous bolus administration
of propofol in preterm and term neonates (n = 9) were combined
with individual pharmacokinetic estimates in toddlers (n = 12) and
young children (n = 10) [1,2]. Data were reported by the median
and range. The Wilcoxon test or linear correlation were used to
analyse the pharmacokinetic findings in neonates, toddlers and
young children. Results The blood–concentration curves obtained for every
individual patient were interpreted by two-stage analysis as a three-
compartment open model in a cohort of 31 patients with a median
weight of 11.2 (range 0.91–24) kg and a median postmenstrual
age of 108 (range 27–405) weeks. The median clearance was
36.8 (range 3.7–78.1) ml/kg/min, the median apparent volume of
distribution at steady state (Vss) was 7.6 (1.33–15.6) l/kg and the
median final serum elimination half-life was 377 (range 27–1134)
minutes. Median clearance was significantly lower in neonates
compared with toddlers and older children (P < 0.01) and these
differences remained significant after allometric scaling (ml/kg
0.75/min). A significant correlation between Vss and postmenstrual
age (r = 0.61, 95% CI 0.32–0.8, P < 0.004) was observed. Conclusion Compared with CS, RS seems to be the preferred
regimen for patients with an expected MV time of 2–3 days. It not
only significantly decreases the length of ICU stay and the total
costs but also significantly reduces the duration of MV, which is a
risk factor for ventilator-associated morbidity. Remifentanil vs conventional sedation in The Netherlands:
a pharmacoeconomic model analysis The
LOS on the ICU was 9.2 days in the CS group vs 8.1 days in the RS
group (difference 1.1, 95% CI 0.6–1.5), whereas the length of time
on MV was 6.3 days and 5.2 days, respectively, with a difference of
1.1 day (95% CI 0.6–1.6). The average total 28-day costs were
€15,911 in the CS group vs €14,855 in the RS group, resulting in
RS related cost-savings of €1,056 (95% CI €58–2,054). Multimodal short acting sedation using NMDA antagonist
and remifentanil in brain trauma patients: a prospective
randomised study F Meurant, Z Ahdach
Kirchberg, Luxembourg State, Luxembourg
Critical Care 2007, 11(Suppl 2):P424 (doi: 10.1186/cc5584) F Meurant, Z Ahdach
Kirchberg, Luxembourg State, Luxembourg
Critical Care 2007, 11(Suppl 2):P424 (doi: 10.1186/cc5584) Introduction We hypothesize that using a multimodal short-acting
sedation regimen based on remifentanil and NMDA-antagonist
receptors such as ketamine, clonidine and magnesium will improve
cerebral protection and make clinical patient examination easier
without hemodynamic impairments. Introduction We hypothesize that using a multimodal short-acting
sedation regimen based on remifentanil and NMDA-antagonist
receptors such as ketamine, clonidine and magnesium will improve
cerebral protection and make clinical patient examination easier
without hemodynamic impairments. Results The age, weight, duration of anaesthesia (ACD/controls
7.3 ± 2.0/6.3 ± 2.2 hours), total sufentanil (124 ± 75/118 ± 57 µg)
and transport time (16.3 ± 2.7/17.0 ± 2.7 min) were not different
between groups, and neither were heart rates, mean arterial
pressures and RS at five time points during transport. ACD
patients needed less propofol injections (0 (0–1)/3 (2–4), P < 0.001) Results The age, weight, duration of anaesthesia (ACD/controls
7.3 ± 2.0/6.3 ± 2.2 hours), total sufentanil (124 ± 75/118 ± 57 µg)
and transport time (16.3 ± 2.7/17.0 ± 2.7 min) were not different
between groups, and neither were heart rates, mean arterial
pressures and RS at five time points during transport. ACD
patients needed less propofol injections (0 (0–1)/3 (2–4), P < 0.001) Methods
Sixty-eight ventilated brain trauma patients (mean
Glasgow Coma Scale: 5 ± 3) with controlled invasive ventilation S169 and reached the ICU with a similar RS (5 (4.5–5)/5 (4.75–5)). End-tidal SEV concentrations were similar in the OR (1.3 ± 0.2/
1.2 ± 0.2 vol%), but different when arriving in the ICU (0.6 ± 0.2/
0.2 ± 0.1 vol%, P < 0.001). P428 Assessment and management of pain in children in A&E:
are we doing it the right way? A Kage, A Mohammed
Calderdale Royal Hospital, Halifax, UK
Critical Care 2007, 11(Suppl 2):P428 (doi: 10.1186/cc5588) Conclusions Propofol disposition is significantly different in
neonates compared with toddlers and young children, reflecting
both ontogeny and differences in body composition. Based on the
reduced clearance of propofol, accumulation during repeated
administration and longer recovery time are more likely to occur in
neonates. Introduction Pain management is one of the most important
components in patient care. The severity of the pain should be
assessed effectively and weight-based analgesia should be given. The BAEM Clinical Effectiveness Committee standard of analgesia
for moderate and severe pain within 20 minutes of arrival in A&E
should be applied to children in all A&E Departments Introduction Pain management is one of the most important
components in patient care. The severity of the pain should be
assessed effectively and weight-based analgesia should be given. The BAEM Clinical Effectiveness Committee standard of analgesia
for moderate and severe pain within 20 minutes of arrival in A&E
should be applied to children in all A&E Departments
Methods A retrospective study. Five casualty cards with soft tissue
injury and fractures in children under 16 years old were picked
randomly every day from January 2005. The assessment and
management of pain was recorded in each case. A validated pain
score tool – Alder Hey triage pain score – was introduced April 1.
Murat I, et al.: Anesthesiology 1996, 84:526-532. 1.
Murat I, et al.: Anesthesiology 1996, 84:526-532.
2
Saint-Maurice C et al : Br J Anaesth 1989 63:667-670 1.
Murat I, et al.: Anesthesiology 1996, 84:526-532.
2.
Saint-Maurice C, et al.: Br J Anaesth 1989, 63:667-670. 2.
Saint-Maurice C, et al.: Br J Anaesth 1989, 63:667-670. References P431 Intravenous anesthesia with S-(+)-ketamine for ‘on-pump’
coronary artery bypass surgery: hemodynamic profile and
effect on troponin T levels Results The maximal pain intensity was significantly higher on
POD 1 and 2 (3.7 ± 2 and 3.9 ± 1.9, respectively) and lower on
POD 3 (3.2 ± 1.5). The order of overall pain scores among
activities (P < 0.001) from highest to lowest was coughing, moving
or turning in bed, getting up, deep breathing or using the incentive
spirometer, and resting. After chest tubes were discontinued,
patients had lower pain levels at rest (P = 0.01), with coughing
(P = 0.05). Age and sex was found to have an impact on pain
intensity, with patients <60 years old and male patients having a
higher pain intensity than older patients on POD 2 (4.7 ± 2.0 vs
3.2 ± 2.4, P = 0.02 and 4.5 ± 2.3 vs 2.9 ± 2.2, respectively). C Neuhaeuser1, V Preiss1, M Mueller1, S Scholz1, M Kwapizs1,
I Welters2 C Neuhaeuser1, V Preiss1, M Mueller1, S Scholz1, M Kwapizs1,
I Welters2
1University Hospital, Giessen, Germany; 2University of Liverpool,
School of Clinical Science, Liverpool, UK
Critical Care 2007, 11(Suppl 2):P431 (doi: 10.1186/cc5591) 1University Hospital, Giessen, Germany; 2University of Liverpool,
School of Clinical Science, Liverpool, UK
Critical Care 2007, 11(Suppl 2):P431 (doi: 10.1186/cc5591) Introduction In patients with ischemic coronary artery disease the
‘sympathomimetic’ effects of ketamine can cause myocardial
damage. However, the S-isomer of ketamine may have various
advantages. We studied the cardiovascular stability and safety of
intravenous anesthesia with S-(+)-ketamine for coronary artery
bypass graft surgery (CABGS). Introduction In patients with ischemic coronary artery disease the
‘sympathomimetic’ effects of ketamine can cause myocardial
damage. However, the S-isomer of ketamine may have various
advantages. We studied the cardiovascular stability and safety of
intravenous anesthesia with S-(+)-ketamine for coronary artery
bypass graft surgery (CABGS). Conclusions Pain relief is an important outcome of care. A
comprehensive, individualized assessment of pain that incorporates
activity levels is necessary to promote satisfactory management of
pain. We recommend the use of remifentanil infusion for
postoperative pain relief in suitable cardiac surgery patients. Methods After approval of the local ethics committee and written
informed consent, 315 patients scheduled for elective ‘on-pump’
CABGS were enrolled in the study. Patients were randomly
allocated to three anesthetic protocols: sufentanil–sevofluorane–
propofol (SSP), sufentanil–propofol (SP), and S-(+)-ketamine–
midazolam–propofol (KMP). P429 Results Stimulation with TNFα increased the percentage of DOR-
expressing cells significantly from 2.1% to 12.8% positive cells
after 6 hours. After 12 hours of stimulation 28.6%, and after 24 hours
even 68.1%, of neutrophils expressed DOR. The MFI increased
during TNFα stimulation from 47.6 ± 15.7 to 254.8 ± 110 after
6 hours, staying levelled at this height. After 6 hours of stimulation,
the MFI for KOR reached a maximum, rising from 59.5 ± 19.4 to
513.9 ± 162. During TNFα stimulation, the percentage of positive
cells increased from 5.4 to 65.0% after 24 hours (17.5% at
6 hours). Fourteen per cent of neutrophils expressed MOR after
6 hours (initially 5.4%) and up to 57.2% after 24 hours. The MOR
MFI was measured at 43.4 ± 16.3 to 410 ± 263.6 6 hours after
stimulation with TNFα. Available online http://ccforum.com/supplements/11/S2 2005. Five casualty cards were picked randomly every day from
May 2005. The assessment and management of pain in each case
was recorded. immunocyte activity. These effects are mediated by opioid receptors
(OR) on peripheral white blood cells that can be detected and
quantified by flow cytometry. We investigated OR expression on
neutrophils using polyclonal antibodies against δ-opioid, κ-opioid
and µ-opioid receptors (DOR, KOR, MOR) to assess spontaneous
and TNFα-induced OR expression on neutrophils. immunocyte activity. These effects are mediated by opioid receptors
(OR) on peripheral white blood cells that can be detected and
quantified by flow cytometry. We investigated OR expression on
neutrophils using polyclonal antibodies against δ-opioid, κ-opioid
and µ-opioid receptors (DOR, KOR, MOR) to assess spontaneous
and TNFα-induced OR expression on neutrophils. Results There were 155 patients in each month. In January, none
of the patients were assessed for the severity of their pain; 34
patients received analgesia, of which 15 received weight-based
and 19 received age-based analgesia. In May, 84 patients were
assessed for the severity of their pain with the Alder Hey triage
pain score; 63 received weight-based and two received age-based
analgesia. The rest had no pain. Methods After approval by the local ethics committee and
informed consent, 100 µl whole blood samples from 11 healthy
volunteers (EDTA served as anticoagulant) was incubated with
10 µl TNF-α (100 ng/ml) for 3, 6, 12 and 24 hours. Samples were
washed and incubated with 5 µl fluorescein-isothiocynate (FITC)-
labelled polyclonal antibodies against human MOR, KOR and
DOR. Rabbit IgG antibodies served as a negative control. After red
cell lysis, flow cytometry was performed to quantify OR expression
using live gating on neutrophils. The percentage of positive cells as
well as mean fluorescent intensities (MFIs) were determined. Conclusion The Alder Hey triage pain score should be introduced
in A&E as it serves as an effective means of assessing pain in
children of all age groups. Analgesia should be prescribed based
on the weight of the children. P431 Standard invasive hemodynamic
monitoring was performed using a pulmonary artery catheter and
hemodynamic variables were reported. Measurements were taken
after induction of anesthesia, after weaning from cardiopulmonary
bypass, and 6 hours postoperatively. Serial plasma troponin T
levels were taken: before induction of anesthesia, after surgery,
and 6 and 24 hours postoperatively. All cardiovascular adverse
events were recorded (such as electrocardiographic signs of
ischemia, myocardial infarction, 28-day mortality). Pain after cardiac surgery A Kianfar1, K Shadvar1, A Mahoori2, R Azarfarin1
1Madani Heart Center, Tabriz, Israel; 2Cardiac Anesthesia, Urumie,
Israel
Critical Care 2007 11(Suppl 2):P429 (doi: 10 1186/cc5589) Critical Care 2007, 11(Suppl 2):P429 (doi: 10.1186/cc5589) Critical Care 2007, 11(Suppl 2):P429 (doi: 10.1186/cc5589) Background Acute pain is common after cardiac surgery and can
keep patients from participating in activities that prevent postoperative
complications especially respiratory complications. Accurate assess-
ment and understanding of pain are vital for providing satisfactory
pain control and optimizing recovery. This study was performed to find
the location, distribution, and intensity of pain in a sample of adult
cardiac surgery patients during their postoperative ICU stay. Conclusion Our results display that stimulation of whole blood with
TNFα amplifies OR expression of all subtypes significantly on
neutrophils. We suggest further studies to clarify the specific actions
of opioids and their receptors in health and acute inflammation. Methods In a prospective study, pain location, distribution (number
of pain areas per patient), and intensity (0–10 numerical rating
scale) were documented on 250 consecutive adult patients on the
first, second and third postoperative day (POD). Patient
characteristics (age, sex, size, and body mass index) were analyzed
for their impact on pain intensity. There were 140 male and 110
female patients, with a mean ± SD age of 65.7 ± 13.5 years. References Methods A retrospective study. Five casualty cards with soft tissue
injury and fractures in children under 16 years old were picked
randomly every day from January 2005. The assessment and
management of pain was recorded in each case. A validated pain
score tool – Alder Hey triage pain score – was introduced April S170 S170 Available online http://ccforum.com/supplements/11/S2 P433 P433 Results Groups (SSP: n = 106; SP: n = 108, KMP: n = 101) did
not differ in preoperative data (for example, biometry, cardiac and
coronary profile and risk). Intraoperative management was
comparable among groups. Tropinin T levels were rather lower in
the KMP group, but did not differ significantly between groups at
24 hours after aortic unclamping. Cardiovascular adverse events
showed the same low incidence in all groups. Hemodynamic data
were comparable; however, the heart rate (HR) and mean arterial
pressure (MAP) after induction were significantly higher in the KMP
group (HR: 59 ± 11 vs 63 ± 32 vs 66 ± 13 beats/min (P < 0.01);
MAP: 74 ± 12 vs 81 ± 16 vs 83 ± 16 mmHg (P < 0.01)). P432 Computer management systems and protocols in intensive
care units: do we have any benefit? Table 1 (abstract P433) Methods A Medline search from 1996 to 2006 with the following
key words was performed: critical care or intensive care, and
protocol, and data management system or computer management
system or computerized documentation. Results The search revealed 21 potential articles. The language
was English in 18 of the articles, two in German and one in
Japanese. Of those 21, 10 articles were not studying CMS/P. Of
those 11 that fulfilled the criteria, computer management systems
were studied in four articles and treatment protocols in 11 articles. The combination of ICU treatment protocol and computer manage-
ment system was studied in four of the 21 articles. Conclusion
Daily FAST-HUG review on ICU rounds, with
aggressive oral care, an early extubation strategy, and aggressive
infection control practices, decreases VAP rates. P430 Opioid receptor expression on neutrophils: effect of
tumour necrosis factor alpha treatment Opioid receptor expression on neutrophils: effect of
tumour necrosis factor alpha treatment A Schmidt1, I Welters2
1University of Giessen, Germany; 2Academic Unit of Critical Care
Medicine, Liverpool, UK
Critical Care 2007, 11(Suppl 2):P430 (doi: 10.1186/cc5590) Introduction Opioids and endogenous opioid peptides possess
immunomodulating properties and are involved in the regulation of S171 ritical Care March 2007 Vol 11 Suppl 2
27th International Symposium on Intensive Care and Emergency Medicin Decreasing the incidence of ventilator-associated
pneumonia using the FAST-HUG evaluation T Papadimos, S Hensley, J Duggan
University of Toledo College of Medicine, Toledo, OH, USA
Critical Care 2007, 11(Suppl 2):P433 (doi: 10.1186/cc5593) T Papadimos, S Hensley, J Duggan Introduction Ventilator-associated pneumonia (VAP) is a leading
cause of morbidity and mortality in critically ill patients. We
implemented a performance improvement project over 2 years to
reduce VAP incidence in the medical ICU (MICU) and surgical ICU
(SICU). Conclusion In our study, KMP anesthesia was safe to use for
CABGS. In comparison with SSP and SP anesthesia, no
significant rise in troponin T as a marker of myocardial damage was
observed. All three regimens resulted in stable hemodynamics. However, the use of S-(+)-ketamine as an induction agent in
patients with coronary artery disease may be limited due to its
sympathomimetic effects leading to raised HR and MAP, even if
supplemented by midazolam or propofol. Methods From 1 January 2004 to 31 December 2005 a
prospective intervention was undertaken. Results were compared
with historic controls (2003). In year 1 we introduced aggressive
oral care using chlorhexidine mouthwash, an early extubation
strategy, changing respiratory equipment only when visibly soiled
or malfunctioning, and aggressive enforcement of hand-washing
and barrier protection methods. At the end of year 1 we
augmented the project with the addition of the FAST-HUG
(feeding, analgesia, sedation, thromboembolic prevention, head of
bed elevation, ulcer prophylaxis, and glucose control) evaluation. During year 2 FAST-HUG was emphasized daily on patient rounds
by the intensivists. The CDC VAP definition was used; the
Friedman test and Wilcoxon signed ranks test were used for data
analysis. Computer management systems and protocols in intensive
care units: do we have any benefit? M Rantala, K Kaukonen, V Pettilä
Helsinki University Hospital, Helsinki, Finland
Critical Care 2007, 11(Suppl 2):P432 (doi: 10.1186/cc5592) Results The VAP rates in the MICU and SICU for the control
period, 1 January–31 December 2003, were 13.41 and 19.37
VAPs/1,000 ventilator-days, respectively. The MICU VAP rate
declined to 3.02 VAPs/1,000 ventilator-days and the SICU rate
declined to 8.16 VAPs/1,000 ventilator-days over 2 years. The
greatest declines occurred during year 2 (Table 1). Introduction
Computer management systems and treatment
protocols (CMS/P) have been recommended for their potential to
improve patient safety and outcome. Computer management systems
require substantial investments in the ICUs. In return, a high-quality,
standardised ICU treatment with software-implemented protocols as
well as decreased hand-written documentation has been aimed at. The objective of this study was to systematically review the literature
on CMS/P to evaluate their impact on outcome benefit. Table 1 (abstract P433)
2003
2004
2005
P values
MICU
13.41
10.14
3.02
NSa, <0.05b,c
SICU
19.37
16.45
8.16
NSa, <0.05b,c
NS, not significant. a2003/04. b2004/05. c2003/05. P434 Of those 11, three of the studies demonstrated that the
implementation of a protocol to computer management system
increases staff compliance to the protocol. The newer studies
showed also that the costs were not increased by the computer-
ised protocol. However, no definite benefit in patient survival or
ICU length of stay could be demonstrated (11 of 21 studies). The
combined absolute reduction rate in hospital mortality was 2%
(95% CI 0–4%) in those four (19% of 21) studies. CMS/P
increased the ICU length of stay 3.5 days (95% CI 1.6–5.4 days)
and decreased the hospital length of stay 5.9 days (95% CI
1.0–10.8 days), in two different studies. P Brindley P Brindley
University of Alberta/Capital Health, Edmonton, Canada
Critical Care 2007, 11(Suppl 2):P435 (doi: 10.1186/cc5595) This abstract outlines the use of simulated critical care telephone
calls into the education of trainees. We hope others may consider
it for their centres. Introduction A significant amount of time is spent in an ICU for
procedures and the care of critically ill patients. Introduction A significant amount of time is spent in an ICU for
procedures and the care of critically ill patients. The Capital Health Region provides advanced healthcare for
2 million people, but spread over 9,800 km. We therefore rely
heavily on transportation of critically ill patients to a single urban
centre. In addition to geographic and climatic factors, bed
pressures complicate how we triage, stabilize, transport and
receive those patients. A major strategy is the ‘Critical-Care-Line’:
a 24-hour telephone service with teleconference capabilities and
contact numbers. However, experience suggests it takes practice
to become proficient with its use. Methods We prospectively collected data regarding demo-
graphics and time in seconds required for ICU procedures. Time
was recorded as the total time (preparation and action, Time A′)
and actual time (intervention only, Time B′). Results We investigated 60 patients (43 males) of mean age
53.6 ± 3.3 years, severity of illness APACHE II score = 16.5 ± 0.3,
SAPS II = 46.4 ± 0.7 and mean ICU stay of 18.6 ± 2.9 days. The
time required for ICU procedures is shown in Table 1. Conclusions A significant amount of time is spent in an ICU for
certain procedures. The length of time required is related to
complications, failures, physicians’ level of training, and presence
of assistance. ICU staff personnel should be adequately trained to
decrease time, complications and thus the ICU stay and costs. Given the importance of optimal communication, we arrange
simulated calls. Senior trainees are paged during a normal workday
by the Critical-Care-Line: just as they will be once in independent
practice. The facilitator then assumes the role of a referring doctor
in a small town. Peer-reviewed cases are used that include
pertinent teaching points. Applicable staff at the teaching centre
are briefed of this exercise and asked to act as they normally
would. Reference 1. Royal College of Physicians and Surgeons of Canada,
CanMEDS framework [http://rcpsc] 1. Royal College of Physicians and Surgeons of Canada,
CanMEDS framework [http://rcpsc] 1. Royal College of Physicians and Surgeons of Canada,
CanMEDS framework [http://rcpsc] P435 P436 Simulated critical care calls: a simple way to teach
complex skills
P Brindley
University of Alberta/Capital Health, Edmonton, Canada
Critical Care 2007, 11(Suppl 2):P435 (doi: 10.1186/cc5595) Required time for certain intensive care unit procedures P Myrianthefs1, G Intas1, M Pitsoli1, L Louizou1, A Gavala1,
G Baltopoulos2
1KAT Hospital, Athens, Greece; 2General Hospital of Attiki ‘KAT’,
Kifissia, Greece
Critical Care 2007, 11(Suppl 2):P436 (doi: 10.1186/cc5596) P Brindley For example, emergency physicians, internists, senior
nurses and administrators are notified that they may be brought
into the call, depending on whether the trainee decides to involve
other services (for example, if he/she decides a patient requires
further work-up before deciding upon ICU or if he/she decides to
bring the patient to emergency if no ICU bed is currently available). All calls are recorded to aid debriefing. Available online http://ccforum.com/supplements/11/S2 factors in sex, age, trauma or nontrauma, whether or not PMCT,
cause of death and final diagnosis. We especially compared the
two groups: PMCT(+) and PMCT(–). referring physicians, and deal with complex ethical decisions (for
example, if a family wishes to override a patient’s previous wish; or
how aggressively to treat the terminal patient for whom no prior
discussions have occurred). It allows us to test the trainees’
knowledge, but more importantly we can determine how well that
knowledge is applied in everyday practice. Results Seventy patients (55.1%) were men, and 57 (44.9%)
were women. Autopsy was done in only three patients. The number
of trauma cases was 21 (16.5%) and nontrauma was 106
(83.5%). PMCT was done in 20 patients (15.7%) and it was
possible to decide the final diagnosis in 16 (80%). Among 20
patients, there were six trauma cases and we could diagnose the
cause of death in all of them. On the other hand, PMCT was not
done in 107 patients (84.3%) and we could estimate the cause of
death in just 43 (40.2%). In Canada, the Royal College of Physician and Surgeons has
decreed that trainees become not just medical experts, but also
proficient communicators, collaborators, and managers [1]. These
goals, while laudable, have been very difficult to capture without
novel approaches such as the one outlined. This simple and cost-
free addition to our training has been very well received. Initial
success means it will now be expanded throughout acute care
specialist training. Conclusions We must make more effort to decide the cause of
death. Reliable death diagnosis could lead to more effective
cardiopulmonary resuscitation. Our date obviously indicated that
PMCT was a very effective and powerful method for death
diagnosis, especially in trauma cases. Significance of postmortem computed tomography in
death diagnosis: investigation of the characteristics in
patients with cardiopulmonary arrest on arrival Significance of postmortem computed tomography in
death diagnosis: investigation of the characteristics in
patients with cardiopulmonary arrest on arrival Introduction Autopsy is a very useful method in analysis of the
cause of death. However, the number of those actual enforce-
ments of autopsy has been getting less and less recently. Now,
autopsy imaging is very important as an alternative method to
autopsy. We evaluated the characteristics in patients with cardio-
pulmonary arrest on arrival and studied the usefulness of
postmortem computed tomography (PMCT) in death diagnosis. Introduction Autopsy is a very useful method in analysis of the
cause of death. However, the number of those actual enforce-
ments of autopsy has been getting less and less recently. Now,
autopsy imaging is very important as an alternative method to
autopsy. We evaluated the characteristics in patients with cardio-
pulmonary arrest on arrival and studied the usefulness of
postmortem computed tomography (PMCT) in death diagnosis. Patients and methods We analyzed consecutive patients with
cardiopulmonary arrest on arrival from October 1997 to November
2006. Total number of patients was 127. We studied the multiple Introduction Autopsy is a very useful method in analysis of the
cause of death. However, the number of those actual enforce-
ments of autopsy has been getting less and less recently. Now,
autopsy imaging is very important as an alternative method to
autopsy. We evaluated the characteristics in patients with cardio-
pulmonary arrest on arrival and studied the usefulness of
postmortem computed tomography (PMCT) in death diagnosis. Conclusion Our results could not confirm any definite benefit from
computerised data management systems or treatment protocols
regarding outcome. The ICU personnel adherence to treatment
protocols seems to increase when implemented into the
computerised data management systems. Further research on this
topic is needed to justify the investments in computer management
systems. Patients and methods We analyzed consecutive patients with
cardiopulmonary arrest on arrival from October 1997 to November
2006. Total number of patients was 127. We studied the multiple S172 Available online http://ccforum.com/supplements/11/S2 Simulated critical care calls: a simple way to teach
complex skills Simulated critical care calls: a simple way to teach
complex skills P438 Robust regression methods for intensive care monitoring The ‘Aiddiag’ data-acquisition software is a standalone application
adapted to patient data recording from the biomedical devices and
caregiver’s inputs. It has a friendly designed user-interface
touchscreen at the bedside and was adapted according to
caregivers’ feedback. Data are also stored in a repository and a
selective secondary extraction is possible. Online and offline
analysis by the AI engine is allowed. Software had to consider time
specifications and uses distributed computation to achieve high
workload tasks. We complied to the French legal patient data
management constraints. M Imhoff1, K Schettlinger2, R Fried2, U Gather2, S Siebig3,
C Wrede3
1Ruhr-University Bochum, Germany; 2University of Dortmund,
Germany; 3University Hospital Regensburg, Germany
Critical Care 2007, 11(Suppl 2):P438 (doi: 10.1186/cc5598) Introduction Alarm generation of modern patient monitoring
systems still predominantly relies on simple threshold methods. This
leads to an unacceptably high rate of false positive alarms. Many
false positive alarms are generated by measurement artefacts and
measurement noise. One approach to address this problem is to
alarm on the underlying signal (that is, the noise-free time series of
the physiological variable), instead of the raw measurement. Results After 2 years, our system is fully deployed. It recorded
more than 2,500 patient-hours over a 3-month period. Signal loss
is less than 1%. Our tool allows recording of more than 40 digital
signals, eight analogical signals sampled at a rate of 1 kHz, and
caregiver comments and actions. CPU resources of the laptop are
available
for
supplemental
AI
developments
during
data
acquisition. Transfer of data to the repository is either a hotplug-
automated process or delayed with 5 days of buffering in the
laptop. Automated artefacts’ cleaning allows time-series analysis
(GARCH method) to extract behavioural models after intensive
computation. The AI engine is used for medical guideline
implementation (that is, severe brain trauma care algorithms) and
later comparison with caregiver’s behaviour. Remote use of our
system is possible and schedulable, allowing other research teams
to work on the data. Limitations have been detected during
intensive calculation. Fine-tuning of the network will suppress
these limitations. Methods Monitoring time series were simulated. Against these
data four robust regression methods were evaluated: least trimmed
squares (LTS), least median of squares (LMS), repeated median
(RM), and deepest regression (DR). Moreover, online monitoring
series from critically ill patients during multiparameter monitoring
were also compared. P439 P439
ISIS program: a new tool for medical research at the
bedside in critical care units
H Mehdaoui1, B Sarrazin1, I El Zein1, L Allart2, C Vilhelm2,
S Guerra2, D Zitouni2, M Lemdani2, R Valentino1, A Herbland1,
P Ravaux2
1Fort De France University Hospital, Fort De France, Martinique;
2Lille 2 University, Lille, France
Critical Care 2007, 11(Suppl 2):P439 (doi: 10.1186/cc5599) Results MD1 found clinically relevant events in 36%, and MD2 in
29% of all time series. In 16% of all cases both intensivists came
to different classifications. In 10% even the direction of change
was classified differently. MD2 classified 10% of all cases
differently between the first and second analysis. Even if level
changes and trends were treated as one universal pattern of
change, intra-individual variability (MD2 first analysis vs MD2
second analysis) was still 5% and inter-individual variability (MD1
vs MD2, only unequivocal classifications) was 10%. Conclusion Although this study is small with only two observers
who were investigated, it clearly shows that there is a significant
intra-individual and inter-individual variability in the classification of
monitoring events done by experienced clinicians. These findings
are supported by studies into image analysis that also found high
intra-individual and inter-individual variability. High inter-observer
and intra-observer variability is a challenge for clinical studies into
new alarm algorithms. Our findings also show a need for reliable
classification methods. Introduction The goal of this program is to develop an experi-
mental tool able to record, store and analyse data issued from
critical care patients. Due to technical limitations and medical
constraints, information systems able to manage such data flow are
difficult to deploy. Introduction The goal of this program is to develop an experi-
mental tool able to record, store and analyse data issued from
critical care patients. Due to technical limitations and medical
constraints, information systems able to manage such data flow are
difficult to deploy. Methods Data recording is done through a laptop connected to
the medical devices, allowing analogical and digital signal
transmission through a high-speed network. Several servers are
dedicated to specialised tasks: mass storage, model generation,
artificial intelligence (AI), telecommunications, and security. A 3
Teraflops supercomputer is dedicated to intensive computation
when necessary. Twenty applications are dedicated to elective
tasks, most of them running using the Linux operating system. P437 Intra-observer and inter-observer variability of clinical
annotations of monitoring data
M Imhoff1, R Fried2, U Gather2, S Siebig3, C Wrede3
1Ruhr-University Bochum, Germany; 2University of Dortmund,
Germany; 3University Hospital Regensburg, Germany
Critical Care 2007, 11(Suppl 2):P437 (doi: 10.1186/cc5597) Intra-observer and inter-observer variability of clinical
annotations of monitoring data Introduction In order to evaluate new methods for alarm genera-
tion from monitoring data, a gold standard of alarm evaluation is Introduction In order to evaluate new methods for alarm genera-
tion from monitoring data, a gold standard of alarm evaluation is Introduction In order to evaluate new methods for alarm genera-
tion from monitoring data, a gold standard of alarm evaluation is This method allows us to ascertain how trainees ask focused
histories, offer practical advice based upon the variable skill set of S173
Table 1 (abstract P436)
Failure at first
Number of
Procedure
n
Time A′
Time B′
attempt (%)
required efforts
Central line placement
120
1,791 ± 52.6
1,023.6 ± 40.3
10.4
2.6 ± 0.3
Arterial line placement
251
491.4 ± 38.5
240.6 ± 26.8
30.4
2.3 ± 0.2
Tracheal tube change
78
910.1 ± 43.7
46.4 ± 4.4
5.5
1.4 ± 0.1
Tracheostomy change
96
565.2 ± 26.8
34.3 ± 2.5
7.1
1.1 ± 7.1
Transfer for CT
76
3,375.5 ± 174.5
1,912.1 ± 87.3
0.0
1.0 Critical Care March 2007 Vol 11 Suppl 2
27th International Symposium on Intensive Care and Emergency Medicin Conclusion All four methods allow one to extract the underlying
signal from physiological time series in a way that is robust against
measurement artefacts and noise. However, there are significant
differences between the methods. Overall, repeated median
regression seems the best choice for intensive care monitoring
since it is not only the most stable but also the fastest method. needed. Nearly all clinical studies into monitoring alarms used
clinician judgement and annotation as the reference standard. We
investigated the intra-observer and inter-observer variability between
two intensivists in the classification of monitoring time series. Methods A total of 3,092 time series segments (heart rate and
blood pressures) of 30 minutes each from six critically ill patients
were presented to two experienced intensivists (MD1 and MD2)
offline and were visually classified into clinically relevant patterns
(no change, level shift, trend) by the physicians separately. One
intensivist (MD2) repeated the classification 4 weeks after the first
analysis on the same dataset. Inter-rater agreement in the triage of calls to a paediatric
interhospital transfer service The aim of this study was to evaluate
whether these initiatives led to a reduction in mobilisation time
between January 2002 and December 2006. Methods The STRS covers 24 DGHs within an 80 mile range
serving a population of 1.6 million children in the South Thames
region of Greater London. All calls to the service were logged on a
detailed database. Retrieval requests for potential PICU patients
were triaged and coordinated via a retrieval-specific telephone line. Once accepted, the onsite retrieval team was mobilised and
dispatched via a dedicated ambulance to the DGH. Mobilisation
includes assimilating and checking pre-packed equipment bags
(ventilators, drugs, intubation kit, monitors, and so on) and
organising a team of at least one retrieval nurse, doctor and
ambulance driver. Details of each retrieval request to the STRS,
including the time of the call, were captured on a database
containing the patient demographic and clinical details. The interval
between accepting the patient for retrieval and team departure
from the unit was termed the ‘mobilisation time’ (minutes). Data
were analysed over two time periods, before (n = 976 retrievals)
and after 2004 (n = 1,785), coincident with a dedicated
ambulance and driver on site. Nonparametric tests were used for
continuous data (Kruskall–Wallis test or Mann–Whitney test) and
the chi-squared test for categorical 2 x 2 comparisons. Results A total of 2,761 retrievals (median age 12 months, 78%
ventilated) were performed and included for analysis during the
study period
33 were excluded (missing mobilisation times Methods The tool was developed by three senior medical staff of
the South Thames Retrieval Service (operating from the PICU at
Evelina Children’s Hospital, London with 1,000 calls per annum
from 24 district general hospitals, resulting in 600 retrievals). A
modified Delphi method was used, which comprised an iterative
process including a literature review, knowledge of the underlying
conditions and a review of retrievals performed by the service over
the previous 7 years (n = 3,669). Inter-rater agreement was
assessed using the weighted kappa statistic, and was measured
between various pairings of junior and senior medical staff (n = 28
combinations) on 50 retrieval episodes. Methods The STRS covers 24 DGHs within an 80 mile range
serving a population of 1.6 million children in the South Thames
region of Greater London. All calls to the service were logged on a
detailed database. P440 P440 Figure 1 (abstract P440) Results A total of 2,761 retrievals (median age 12 months, 78%
ventilated) were performed and included for analysis during the
study period, 33 were excluded (missing mobilisation times
(n = 30) or elective transfers (n = 3). Figure 1 shows the process
introduced to improve mobilisation times with a dedicated onsite
ambulance service in 2004. There was a significant reduction in P438 Results LTS and LMS showed comparable behaviour, as did RM
and DR. LMS and LTS provided only 20% efficiency, DR 61% and
RM 70% (least squares regression = 100%). RM and DR had
smaller standard deviations and smaller mean-squared errors than
LMS and LTS under different noise distributions (standard
deviation of online estimates based on sliding windows of size n =
21 for simulated standard normal errors: LMS: 0.875, LTS: 0.887,
RM: 0.500, DR: 0.533). Analyses with clinical monitoring data also
showed that LMS and LTS preserve sudden level shifts but are
unstable and perform poorly with trend changes; RM and DR blur
shifts but yield more stable estimations. Conclusion ISIS is the first program to achieve an easy-to-use
recording tool able to build a very large medical repository. Data
analysis methods and AI-controlled automated complex medical
guidelines are under evaluation. S174 Available online http://ccforum.com/supplements/11/S2 Inter-rater agreement in the triage of calls to a paediatric
interhospital transfer service Retrieval requests for potential PICU patients
were triaged and coordinated via a retrieval-specific telephone line. Once accepted, the onsite retrieval team was mobilised and
dispatched via a dedicated ambulance to the DGH. Mobilisation
includes assimilating and checking pre-packed equipment bags
(ventilators, drugs, intubation kit, monitors, and so on) and
organising a team of at least one retrieval nurse, doctor and
ambulance driver. Details of each retrieval request to the STRS,
including the time of the call, were captured on a database
containing the patient demographic and clinical details. The interval
between accepting the patient for retrieval and team departure
from the unit was termed the ‘mobilisation time’ (minutes). Data
were analysed over two time periods, before (n = 976 retrievals)
and after 2004 (n = 1,785), coincident with a dedicated
ambulance and driver on site. Nonparametric tests were used for
continuous data (Kruskall–Wallis test or Mann–Whitney test) and
the chi-squared test for categorical 2 x 2 comparisons. Results The final tool comprised five categories (three levels of
severity each) allowing for a range of scores from 0 to 15
(Figure 1). Three levels of urgency were defined: semi-urgent
(score <8), urgent (score 8–10), immediate (score >10). Overall
the tool showed a good to very good strength of inter-rater
agreement (kappa scores ranging from 0.65 to 0.88; Figure 2). There were no obvious differences between levels of staff seniority. Conclusion The score showed acceptable agreement, fullfilling
the first step of validation. Inter-rater agreement in the triage of calls to a paediatric
interhospital transfer service Inter-rater agreement in the triage of calls to a paediatric
interhospital transfer service S Riphagen, M Alasnag, S Hanna, S Manna, M McDougall
Guy’s and St Thomas’ Hospital, London, UK
Critical Care 2007, 11(Suppl 2):P440 (doi: 10.1186/cc5600) M McDougall, S Riphagen, S Hanna, S Moganasundram,
F Bickell, A Durward, I Murdoch
Evelina Children’s Hospital @ Guy’s and St Thomas’ NHS
Foundation Trust, London, UK
Critical Care 2007, 11(Suppl 2):P441 (doi: 10.1186/cc5601) Introduction As a result of centralisation of PICU services in the
United Kingdom, transfer of critically ill children has become
common over the past decade. It is not uncommon to receive
multiple retrieval requests simultaneously, thus a tool to prioritise
the urgency of this would be beneficial. Our aim was to develop
such a tool and assess its inter-rater repeatability. Introduction The South Thames Retrieval Service (STRS) is a
specialised paediatric intensive care retrieval service, integrated
into the Evelina Children’s Hospital, the lead centre in the South
Thames Region, London. Over the last 5 years a number of
initiatives have been adopted to reduce mobilisation times (the
time from retrieval acceptance and activation to departure from the
lead centre) and improve service delivery to surrounding district
general hospitals (DGHs). The aim of this study was to evaluate
whether these initiatives led to a reduction in mobilisation time
between January 2002 and December 2006. Introduction The South Thames Retrieval Service (STRS) is a
specialised paediatric intensive care retrieval service, integrated
into the Evelina Children’s Hospital, the lead centre in the South
Thames Region, London. Over the last 5 years a number of
initiatives have been adopted to reduce mobilisation times (the
time from retrieval acceptance and activation to departure from the
lead centre) and improve service delivery to surrounding district
general hospitals (DGHs). The aim of this study was to evaluate
whether these initiatives led to a reduction in mobilisation time
between January 2002 and December 2006. Introduction The South Thames Retrieval Service (STRS) is a
specialised paediatric intensive care retrieval service, integrated
into the Evelina Children’s Hospital, the lead centre in the South
Thames Region, London. Over the last 5 years a number of
initiatives have been adopted to reduce mobilisation times (the
time from retrieval acceptance and activation to departure from the
lead centre) and improve service delivery to surrounding district
general hospitals (DGHs). P443 The use of a track and trigger system on general medical
wards
M Lawson, A Stone, D King, A Davison
Southend University Hospital, Southend, UK
Critical Care 2007, 11(Suppl 2):P443 (doi: 10.1186/cc5603) The use of a track and trigger system on general medical
wards
M Lawson, A Stone, D King, A Davison
Southend University Hospital, Southend, UK
Critical Care 2007, 11(Suppl 2):P443 (doi: 10.1186/cc5603) The use of a track and trigger system on general medical
wards Median retrieval mobilisation times. M Lawson, A Stone, D King, A Davison
Southend University Hospital, Southend, UK
Critical Care 2007, 11(Suppl 2):P443 (doi: 10.1186/cc5603) mobilisation time from 2002 to 2006 from 55 minutes (IQR
35–80) to 30 minutes (IQR 25–50), P < 0.0001 (Kruskall–Wallis)
(Figure 2). When comparing pre-2004 and post-2004 time
periods, the median mobilisation time was significantly lower after
2004 with a fall from 45 minutes (IQR 30–70) to 35 minutes (IQR
27–55). There was also a significant increase in the incidence of
sub-30-minute mobilisation times, which almost doubled after
2004 with the availability of an onsite dedicated ambulance service
(14.3% to 25.9%, P < 0.0001). Introduction Many groups have advocated identification of critically
ill medical patients by abnormal or deteriorating physiological
parameters. In Southend Hospital a track and trigger system has
been used since 2005 to alert nurses to abnormal physiological
parameters in order to trigger urgent medical review of the unwell
patient. It is recognised that the respiratory rate is a particularly
useful predictor of significant deterioration and should be measured
with every set of observations. This audit aimed to assess the use of
the track and trigger system on the medical wards and ensure that
deteriorating critically ill patients are promptly reviewed. Introduction Many groups have advocated identification of critically
ill medical patients by abnormal or deteriorating physiological
parameters. In Southend Hospital a track and trigger system has
been used since 2005 to alert nurses to abnormal physiological
parameters in order to trigger urgent medical review of the unwell
patient. It is recognised that the respiratory rate is a particularly
useful predictor of significant deterioration and should be measured
with every set of observations. This audit aimed to assess the use of
the track and trigger system on the medical wards and ensure that
deteriorating critically ill patients are promptly reviewed. P443 Conclusion
There has been a significant decrease in the
mobilisation time of the STRS over the last 5 years. Although the
presence of an onsite ambulance service in 2004 had a significant
impact on reducing retrieval mobilisation times, a number of other
factors and initiatives contributed to steadily reducing mobilisation
times over the study period. Methods Patient observation charts were reviewed for a specified
24-hour period. Data were gathered on the frequency and type of
observations taken. For patients who met criteria to trigger a
review, further data were abstracted about the nature of the
deterioration and the promptness of the review. Figure 1 (abstract P441) Processes introduced to improve mobilisation times. Processes introduced to improve mobilisation times. Figure 2 (abstract P440) Figure 2 (abstract P440) Figure 2 (abstract P440) S175 Critical Care March 2007 Vol 11 Suppl 2
27th International Symposium on Intensive Care and Emergency Medicine Figure 2 (abstract P441)
Median retrieval mobilisation times. Figure 2 (abstract P441)
Median retrieval mobilisation times. Table 1 (abstract P442)
Penetrating trauma
Private transport
Ambulance
Alive
98.8% (n = 254)
95.6% (n = 527)
Dead
1.2% (n = 3)
4.4% (n = 24) Figure 2 (abstract P441) Table 1 (abstract P442) Conclusion The use of ambulance transportation is associated
with a 3.7-fold increase in mortality following penetrating injury. This may be related to longer times in the field resulting in delay to
definitive care in hospital. P442 Results One hundred and sixty patient-days of observations were
evaluated over seven medical wards. Twenty-nine patients met the
trigger criteria and in 16 cases this represented a deterioration. Doctors were called in two cases. Observations were recorded
with different frequency on different wards. One ward managed to
record the respiratory rate with every set of observations. Ambulance transport is associated with a higher mortality
than private transport following major penetrating trauma
in a semi-urban environment E Dickson, D Van Niekerk, S Robertson, J Goosen, F Plani,
K Boffard
Johannesburg Hospital Trauma Unit and University of the
Witwatersrand, Johannesburg, South Africa
Critical Care 2007, 11(Suppl 2):P442 (doi: 10.1186/cc5602) Conclusions
Documented
deteriorations
in
physiological
observations did not trigger medical review. This may be a
communication failure or failure to recognise recorded observations
as abnormal. For this process to work well relevant observations
must be recorded regularly and accurately. The respiratory rate was
not consistently recorded between wards and the frequency of
measurement of observations was variable. Further education and
training is needed to improve recording of the respiratory rate and
work needs to be done to establish why doctors were not called
appropriately. Concerns about the volume of work generated by the
system are unfounded. A positive predictive value of 55% is
acceptable and 29 ‘triggers’ in a 24-hour period are manageable. Aims The use of private transportation has been associated with
improved outcomes in urban trauma patients. The need for patient
stabilization at the scene needs to be balanced with the need for
early operative intervention, and therefore the need for rapid
transportation to hospital. Our aim was to assess the relationship
between the mode of transport to hospital and outcome in a semi-
urban trauma environment. Methods Data were collected prospectively on 1,396 patients
admitted to a Level 1 South African trauma unit over a 1-year
period. The Revised Trauma Score was used to assess injury
severity and physiological derangement at the time of admission,
and to allow comparison between the groups. Mortality was
defined as death within 30 days. P444 Available online http://ccforum.com/supplements/11/S2 Available online http://ccforum.com/supplements/11/S2 was commissioned by the Ministry of Health and Long-term Care
to facilitate the improvement of inhospital emergency preparedness
through a System-Level Training Initiative. Objectives for the
program were to reduce mortality and improve efficiency of ICU
resource use through early identification of patients at risk of
deterioration and the provision of rapid resuscitation to abort
avoidable ICU admissions. The program was designed to train
nonphysician responders (primarily nurses and respiratory
therapists) supported by remote physician oversight, especially in
centres where ICU-trained physicians were not available. the ward, the presence of a CCOS was associated with significant
reductions in: the proportion of admissions receiving cardio-
pulmonary resuscitation during the 24 hours prior to admission
(odds ratio 0.84, 95% confidence interval 0.73–0.96); the
proportion of admissions between 22:00 and 06:59 (0.91,
0.84–0.97); and the mean ICNARC physiology score (absolute
reduction 1.2, 0.3–2.1). No significant effects of CCOS on
outcomes including hospital mortality and readmission to critical
care were identified for patients discharged to the ward. Interpretation The results of this study were mixed. While some
differences in the characteristics of patients admitted to critical
care units were found to be associated with the introduction of
CCOS, there was no evidence for an impact on the outcomes of
patients discharged from critical care. It was not possible to
identify any clear characteristics for an optimal CCOS. the ward, the presence of a CCOS was associated with significant
reductions in: the proportion of admissions receiving cardio-
pulmonary resuscitation during the 24 hours prior to admission
(odds ratio 0.84, 95% confidence interval 0.73–0.96); the
proportion of admissions between 22:00 and 06:59 (0.91,
0.84–0.97); and the mean ICNARC physiology score (absolute
reduction 1.2, 0.3–2.1). No significant effects of CCOS on
outcomes including hospital mortality and readmission to critical
care were identified for patients discharged to the ward. Interpretation The results of this study were mixed. While some
differences in the characteristics of patients admitted to critical
care units were found to be associated with the introduction of
CCOS, there was no evidence for an impact on the outcomes of
patients discharged from critical care. It was not possible to
identify any clear characteristics for an optimal CCOS. Methods Following an educational needs assessment of learners,
a multicomponent critical care response team (CCRT) training
course was developed. M Seubert M Seubert
Academic Medical Center, Amsterdam, The Netherlands
Critical Care 2007, 11(Suppl 2):P446 (doi: 10.1186/cc5606) Academic Medical Center, Amsterdam, The Netherlands
Critical Care 2007, 11(Suppl 2):P446 (doi: 10.1186/cc5606) Introduction Blood groups may be related to differences in
inflammatory responses [1]. We looked at blood group as a risk
factor for ICU mortality in general and for patients with sepsis. Introduction Blood groups may be related to differences in
inflammatory responses [1]. We looked at blood group as a risk
factor for ICU mortality in general and for patients with sepsis. Methods Data were retrospectively collected from all 11,553
patients that were admitted from 1997 to 2005 to our medical/
surgical ICU. Methods Data were retrospectively collected from all 11,553
patients that were admitted from 1997 to 2005 to our medical/
surgical ICU. Conclusions It has been demonstrated that unmet needs in critical
care education and training for allied healthcare professionals can
be identified and corrected through the development and
implementation of a multidisciplinary course designed to facilitate
creation of CCRTs in the Province of Ontario. Evaluation of the
effectiveness of these teams is ongoing. Results ICU mortality and SAPS II score for different blood groups
are shown in Table 1. P values are given for the difference
between blood groups A and O. No differences were found for
age, gender, and reason for admission. No influence of rhesus
blood group type was seen on mortality. Available online http://ccforum.com/supplements/11/S2 The 2-day course consisted of a series of
small group, interactive, case-based seminars, high-fidelity
simulation training, and the publication of a CCRT Provider Manual
and Quick Reference Cards. A database for monitoring the
effectiveness and impact of the CCRTs was also developed. P446 Results Beginning in October 2005, 24 CCRT physician instructors
were trained in one of two streams: (i) simulator instructors with skills
in constructive feedback and assessment of crisis management skills;
(ii) instructors who further refined the case-based seminars and
edited the Quick Reference Cards. Acquisition of equipment, liaisons
with participating hospitals and creation of the CCRT database were
completed in the spring of 2006. Since June 2006, 12 CCRT
courses have been run, and 263 participants have been trained as
CCRT Providers (87% nurses, and 13% respiratory therapists). Local
hospital implementation and preceptored programs occurred over a
12-week period before CCRTs we made available full time (24/7). Influence of ABO blood group polymorphism on mortality
in intensive care unit patients Reference Reference
1. Garratty G: Transfusion Med Rev 2000, 14:291. Reference
1. Garratty G: Transfusion Med Rev 2000, 14:291. 1. Garratty G: Transfusion Med Rev 2000, 14:291. 1. Garratty G: Transfusion Med Rev 2000, 14:291. P445 Individual patient-
level data were collapsed into monthly time series for each unit
(panel data). Population-averaged panel-data models were fitted
using a generalised estimating equation approach. Various
outcomes reflecting the stated aims of CCOS were considered for
three groups of admissions: all admissions to the unit; admissions
from the ward; and unit survivors discharged to the ward. The
primary exposure variable was the presence of a formal CCOS
with secondary exposures of CCOS activities, coverage and
staffing, identified from the survey data. P445 Table 1 (abstract P446)
ABO blood group
A
B
AB
O
P value
All patients
n = 4,787 n = 1,168 n = 479
n = 5,119
ICU death (%)
9.5
10.2
10.9
11.2
<0.01
SAPS II
32 ± 16
33 ± 17
34 ± 18
33 ± 17
NS
Severe sepsis
n = 265
n = 73
n = 34
n = 318
ICU death (%)
24.9
28.8
26.5
32.4
0.05
SAPS II
49 ± 18
49 ± 18
54 ± 19
51 ± 18
NS Multicentre evaluation of the impact of the introduction of
outreach services in the United Kingdom H Gao1, D Harrison1, G Parry2, K Daly3, C Subbe4, K Rowan1
1ICNARC, London, UK; 2Children’s Hospital Boston, MA, USA;
3St Thomas’ Hospital, London, UK; 4Wrexham Maelor Hospital,
Wrexham, UK
Critical Care 2007, 11(Suppl 2):P445 (doi: 10.1186/cc5605) Background Critical care outreach services (CCOS) have been
introduced in the United Kingdom with aims to: avert or ensure timely
admission to critical care; enable discharge from critical care; and
share skills with ward staff. We aimed to assess the impact of the
introduction of CCOS at the critical care unit level, as characterised
by the case mix, outcome and activity of critical care unit admissions. Methods An interrupted time-series analysis was carried out using
data from 108 units participating in the Case Mix Programme that
had completed a survey on CCOS provision. Individual patient-
level data were collapsed into monthly time series for each unit
(panel data). Population-averaged panel-data models were fitted
using a generalised estimating equation approach. Various
outcomes reflecting the stated aims of CCOS were considered for
three groups of admissions: all admissions to the unit; admissions
from the ward; and unit survivors discharged to the ward. The
primary exposure variable was the presence of a formal CCOS
with secondary exposures of CCOS activities, coverage and
staffing, identified from the survey data. R
lt
Of 108
it
i
th
l
i
79 (73%) h d
f
l Conclusion Blood group O is associated with a higher ICU
mortality rate than blood group A. The relative risk increase for ICU
mortality was 18% for all patients and 30% for patients with severe
sepsis. y
y
Methods An interrupted time-series analysis was carried out using
data from 108 units participating in the Case Mix Programme that
had completed a survey on CCOS provision. P444 Design and implementation of needs-specific critical care
response teams R Hodder1, A Fox-Robichaud2, R Wax3, P Cardinal1, S Reynolds3
1University of Ottawa, Canada; 2McMaster University, Hamilton,
Canada; 3University of Toronto, Canada
Critical Care 2007, 11(Suppl 2):P444 (doi: 10.1186/cc5604) Results The mortality in the blunt trauma patients (n = 527) was
higher in the ambulance transport group, but this was not
statistically significant. However, the mortality in the penetrating
trauma patients (n = 808) was significantly higher in the ambu-
lance transport group (P = 0.020, chi-square; Table 1) despite
similar Revised Trauma Scores (Table 1). Introduction Following the severe acute respiratory syndrome
epidemic in Ontario Canada, the Canadian Resuscitation Institute S176 Available online http://ccforum.com/supplements/11/S2 P447 P447 P447
Contribution of genomic variations within human β-
defensin 1 to incidence and outcome of severe sepsis
X Fang, C Lv, Q Chen, L Huang
Zhejiang University, Hangzhou, China
Critical Care 2007, 11(Suppl 2):P447 (doi: 10.1186/cc5607) Contribution of genomic variations within human β-
defensin 1 to incidence and outcome of severe sepsis X Fang, C Lv, Q Chen, L Huang
Zhejiang University, Hangzhou, China
Critical Care 2007, 11(Suppl 2):P447 (doi: 10.1186/cc5607) X Fang, C Lv, Q Chen, L Huang
Zhejiang University, Hangzhou, China
Critical Care 2007, 11(Suppl 2):P447 (doi: 10.1186/cc5607) S177
Sepsis, a systemic inflammatory response to infection, is a common
clinical syndrome in the ICU. Human β-defensin 1 (DEFB1) is a Results Of 108 units in the analysis, 79 (73%) had a formal
CCOS introduced between 1996 and 2004. For admissions from Critical Care March 2007 Vol 11 Suppl 2
27th International Symposium on Intensive Care and Emergency Medicin multifunctional mediator in infection and inflammation, which has
been largely explored in ex vivo studies. The lack of fully
representative genetic animal models increases the importance of
analyzing the impact of defensin gene polymorphisms on the
courses of infectious and inflammatory diseases such as sepsis. This study was designed to investigate whether DEFB1 genomic
variations are associated with incidence and outcome of severe
sepsis. Six reported polymorphisms were detected in 211 patients
with severe sepsis and 157 control individuals using diverse
analytic methods. Linkage disequilibrium (LD), haplotype frequen-
cy, and statistical power for this association study were analyzed. The –44G-allele and –44G-allele carrying genotypes were
significantly associated with incidence and outcome of severe
sepsis. There was enough statistical power (1 – β > 0.8 at type I
level of 0.05) to demonstrate a significant contribution of the –44G
allele to severe sepsis. The –20G allele and GG genotype were
associated with susceptibility to severe sepsis, while the –1816G-
allele and –1816G-allele carrying genotypes influenced the
outcome of severe sepsis. SNPs –20A/G, –44C/G and –52A/G
were in strong LD. Haplotype –20A/–44C/–52G showed a
protective role against severe sepsis, whereas haplotype
–20G/–44G/–52G served as a risk factor for fatal outcome of
severe sepsis. The present findings have important implications in
the understanding of the role of DEFB1 in the pathophysiology of
severe sepsis, and DEFB1 genomic variations may offer a new
means of risk stratification for patients with severe sepsis. P447 of quantification of in vivo gene expression with QRT-PCR
providing more accurate and sensitive data when compared with
prior ELISA-based assays. Indeed, the extrapolation of functionality
from in vitro functional genetic tests after lipopolysaccharide stimu-
lation may be of questionable value. We conclude that genotypic
analysis does have a place in risk stratification in sepsis and that
genetic variants at positions –863 and –308, or sites in linkage
disequilibrium with these variants, may influence TNFα production. P449 IL-1/tumor necrosis factor receptor gene expression
characterizes sepsis in critically ill systemic inflammatory
response syndrome patients IL-1/tumor necrosis factor receptor gene expression
characterizes sepsis in critically ill systemic inflammatory
response syndrome patients M Lissauer1, S Johnson1, C Feild1, C Whiteford2,
W Nussbaumer2, T Scalea1
1University of Maryland Medical Center, R Adams Cowley Shock
Trauma Center, Baltimore, MD, USA; 2BD Diagnostics, Sparks,
MD, USA
Critical Care 2007, 11(Suppl 2):P449 (doi: 10.1186/cc5609) Introduction The classic response to isolated endotoxin challenge
entails secretion of IL-1 and TNFα. The purpose of this study was to
longitudinally characterize the cytokine response to sepsis in critically
ill systemic inflammatory response syndrome (SIRS) patients. Methods Uninfected, critically ill trauma patients with SIRS were
evaluated daily for sepsis. Patients were divided into two groups:
pre-septic = SIRS patients who developed sepsis, and uninfected
SIRS = SIRS patients remaining uninfected. Plasma samples and
whole blood (PAXgene) obtained at study entry and daily for
3 days prior to sepsis were analyzed for differential gene expression
between groups (Affymetrix Hg_U133 2.0 plus microarray, false
discovery rate < 0.5%, P < 0.005) and quantitative plasma protein
TNF and IL-1 levels (Immunoassay, Luminex™, elevated if > 3 SD
above the mean for normals). Gene expression data are the median
fold change between groups (uP = pre-septic > uninfected). Results Gene expression on 90 patients and protein measure-
ments on 142 patients were available. Protein levels of both
subtypes of TNF and IL-1 were not elevated at any time point in
either group. IL-1α was noted to have differential gene expression
24 hours before sepsis. No differences were noted in gene
expression for TNFα, TNFβ, or IL-1β. Differential gene expression
for only two TNF family members (TNFSF10 and TNFSF13b) was
noted. However, differential gene expression for TNF and IL-1
receptors and IL-1 receptor antagonist was prominent (Table 1). Introduction The classic response to isolated endotoxin challenge
entails secretion of IL-1 and TNFα. The purpose of this study was to
longitudinally characterize the cytokine response to sepsis in critically
ill systemic inflammatory response syndrome (SIRS) patients. Introduction The classic response to isolated endotoxin challenge
entails secretion of IL-1 and TNFα. The purpose of this study was to
longitudinally characterize the cytokine response to sepsis in critically
ill systemic inflammatory response syndrome (SIRS) patients. P448 TNFα promoter single nucleotide polymorphisms may
influence gene expression in patients with severe sepsis
M Odwyer1, M White1, R McManus2, T Ryan1
1St James’s Hospital, Dublin, Ireland; 2Trinity College, Dublin, Ireland
Critical Care 2007, 11(Suppl 2):P448 (doi: 10.1186/cc5608) y
y
p
y
(
) p
Methods Uninfected, critically ill trauma patients with SIRS were
evaluated daily for sepsis. Patients were divided into two groups:
pre-septic = SIRS patients who developed sepsis, and uninfected
SIRS = SIRS patients remaining uninfected. Plasma samples and
whole blood (PAXgene) obtained at study entry and daily for
3 days prior to sepsis were analyzed for differential gene expression
between groups (Affymetrix Hg_U133 2.0 plus microarray, false
discovery rate < 0.5%, P < 0.005) and quantitative plasma protein
TNF and IL-1 levels (Immunoassay, Luminex™, elevated if > 3 SD
above the mean for normals). Gene expression data are the median
fold change between groups (uP = pre-septic > uninfected). TNFα promoter single nucleotide polymorphisms may
influence gene expression in patients with severe sepsis TNFα promoter single nucleotide polymorphisms may
influence gene expression in patients with severe sepsis M Odwyer1, M White1, R McManus2, T Ryan1
1St James’s Hospital, Dublin, Ireland; 2Trinity College, Dublin, Ireland
Critical Care 2007, 11(Suppl 2):P448 (doi: 10.1186/cc5608) Introduction We examined the association of TNFα promoter
single nucleotide polymorphisms and haplotypes with gene
expression in terms of mRNA levels and with outcome in a cohort
of patients with severe sepsis. Results Gene expression on 90 patients and protein measure-
ments on 142 patients were available. Protein levels of both
subtypes of TNF and IL-1 were not elevated at any time point in
either group. IL-1α was noted to have differential gene expression
24 hours before sepsis. No differences were noted in gene
expression for TNFα, TNFβ, or IL-1β. Differential gene expression
for only two TNF family members (TNFSF10 and TNFSF13b) was
noted. However, differential gene expression for TNF and IL-1
receptors and IL-1 receptor antagonist was prominent (Table 1). Methods Sixty-two Irish Caucasian patients presenting with severe
sepsis were enrolled. Blood sampling was carried out on day 1 and
on day 7. Mononuclear cells were isolated and TNFα mRNA
quantified using the technique of quantitative real-time polymerase
chain reaction (QRT-PCR). DNA was extracted and assayed for
four TNFα promoter polymorphisms. Haplotypes were inferred
using PHASE software. Results Twenty-seven patients died. Patients carrying an A allele
at position –863 produced more TNFα mRNA on day 1 than C
homozygotes (P = 0.037). There was a trend for patients
homozygous for the G allele at position –308 to produce more
TNFα mRNA on day 1 than those carrying an A allele (P = 0.059). Carrier status for haplotype 1 (with A at position –863 and G at
position –308) was associated with greater TNFα mRNA levels on
day 1 (P = 0.0374). Carrier status for haplotype 4 (with C at
position –863 and A at position –308) was associated with a
nonsignificant decrease in TNFα
mRNA levels on day 1
(P = 0.059). When directly compared, haplotype 1 was associated
with significantly greater levels of TNFα mRNA than with haplotype
4 on day 1 (P = 0.02). Patients homozygous for the A allele at
position –308 were more likely to succumb to severe sepsis than
those carrying the G allele (P = 0.01). A novel score based on age and cardiac biomarkers
predicts outcomes in severe sepsis and septic shock A Turley, A Thornley, A Roberts, M Johnson, M de Belder,
J Gedney
The James Cook University Hospital, Middlesbrough, UK
Critical Care 2007, 11(Suppl 2):P450 (doi: 10.1186/cc5610) F Leitch1, E Dickson1, A McBain1, S Robertson2, D O’Reilly1,
C Imrie1
1Glasgow Royal Infirmary, Glasgow, UK; 2Johannesburg Hospital,
Johannesburg, South Africa
Critical Care 2007, 11(Suppl 2):P451 (doi: 10.1186/cc5611) 1Glasgow Royal Infirmary, Glasgow, UK; 2Johannesburg Hospital,
Johannesburg, South Africa
Critical Care 2007, 11(Suppl 2):P451 (doi: 10.1186/cc5611) Background Myocardial dysfunction is common among critically ill
septic patients. Elevated levels of cardiac biomarkers are predictors
of mortality in acute coronary syndrome and in unselected critically
ill patients. Our aim was to evaluate the role of the cardiac markers
NT-proBNP, Troponin T (TnT) and myoglobin as predictors of
inhospital and 6-month all-cause mortality in patients admitted to a
general adult ICU with severe sepsis/septic shock. Introduction Early identification of critically ill surgical patients who
are not fully resuscitated improves outcome. Current markers of
clinically occult hypoperfusion, such as lactate, have serious limi-
tations. Increased oxidative stress as a consequence of inadequate
cellular respiration results in elevated levels of unmeasured anions. We evaluated these anions as a novel marker of outcome. Methods We prospectively evaluated 109 consecutive patients
admitted to a surgical high-dependency unit (HDU). Regional
Ethics Committee approval was obtained. Serum electrolytes,
albumin, phosphate and lactate were measured on admission and
days 1 and 2. We derived the calculated ion gap (CIG) using our
simplified modification of the Stewart–Figge equations. Methods Serial plasma samples were taken for five sequential
days on all patients admitted with severe sepsis/septic shock. Samples were analysed for NT-proBNP, TnT and myoglobin. Results
Samples were analysed on 49 patients. Elevated
myoglobin was the only predictor of ICU mortality. Age, myoglobin
and NT-proBNP levels predicted hospital mortality. Predictors of 6-
month mortality were age, peak TnT, peak myoglobin and peak NT-
proBNP levels. The APACHE II score did not predict mortality. A
score was established dependent on TnT (<0.1 = 1, ≥0.1 = 2), age
(<65 years = 1, ≥65 years = 2), BNP (<10,000 = 1, >10,000 = 2),
and myoglobin (<750 = 1, >750 = 2). Patients were placed into
tertiles (score = 4&5, 6, 7&8) to produce survival curves (Figure 1,
P < 0.01). Results The CIG on day 1 predicted mortality (P = 0.001, analysis
of variance). A CIG > 10 mmol/l correlated very strongly with
mortality. A novel score based on age and cardiac biomarkers
predicts outcomes in severe sepsis and septic shock The mortality in patients with a CIG < 10 mmol/l (n = 86)
was 4.7%. The mortality in patients with a CIG > 10 mmol/l
(n = 23) was 26.1% (P = 0.006, chi-square test). There were no
differences in CIG with respect to mortality on admission or day 2
(P = 0.273 and 0.104, respectively). The mean hospital stay was
significantly longer in patients with a CIG > 10 mmol/l (46.6 vs
18.7 days, P = 0.015, t test) (Table 1). TNFα promoter single nucleotide polymorphisms may
influence gene expression in patients with severe sepsis Table 1 (abstract P449)
Gene symbol
Fold change
Gene symbol
Fold change
TNFRSF1A
1.30 up
IL1R1
1.50 up
TNFRSF10D
1.21 up
IL1R2
2.52 up
TNFRSF25
1.19 down
IL1RN
1.48 up
Conclusion Compared with critically ill uninfected SIRS patients,
sepsis increases IL-1α but not TNFα gene expression and does
not increase TNF and IL-1 protein levels. Interestingly differential
gene expression for TNF and IL-1 receptors exists, suggesting
receptors, more than ligands, are important in differentiating sepsis
from uninfected SIRS. Table 1 (abstract P449)
Gene symbol
Fold change
Gene symbol
Fold change
TNFRSF1A
1.30 up
IL1R1
1.50 up
TNFRSF10D
1.21 up
IL1R2
2.52 up
TNFRSF25
1.19 down
IL1RN
1.48 up Conclusion Compared with critically ill uninfected SIRS patients,
sepsis increases IL-1α but not TNFα gene expression and does
not increase TNF and IL-1 protein levels. Interestingly differential
gene expression for TNF and IL-1 receptors exists, suggesting
receptors, more than ligands, are important in differentiating sepsis
from uninfected SIRS. Conclusion Compared with critically ill uninfected SIRS patients,
sepsis increases IL-1α but not TNFα gene expression and does
not increase TNF and IL-1 protein levels. Interestingly differential
gene expression for TNF and IL-1 receptors exists, suggesting
receptors, more than ligands, are important in differentiating sepsis
from uninfected SIRS. Conclusion These results contradict previous in vitro functional
studies on the TNF2 allele. This may be secondary to the method S178 Available online http://ccforum.com/supplements/11/S2 Table 1 (abstract P451) Conclusion In critically ill patients with severe sepsis/septic shock
a score based on age and increased plasma levels of cardiac
biomarkers can help risk-stratify patients and predict short-term
(<6 months) outcome. Conclusion We describe the CIG for the first time in the critically
ill surgical patient, and quantify it using simple bedside calculations
derived from routine blood investigations. Failure to normalise the
CIG by day 1 after admission to the HDU is an excellent marker for
mortality and length of hospital stay, and should be used to guide
resuscitation. Figure 1 (abstract P450) Table 1 (abstract P451)
Day 1
Day 1
CIG < 10 mmol/l
CIG > 10 mmol/l
P value
Inhospital mortality
4.7% (n = 86)
26.1% (n = 23)
P = 0.006
(χ2 test)
Length of hospital stay
18.7 days
46.6 days
P = 0.015
(t test) P454 septic shock. Secondarily, we aimed at evaluating the impact of
them in patient management Brain natriuretic peptide and left ventricular area variation
with fluid challenge in septic shock: an echocardiographic
study (preliminary results) Methods This transversal study included patients with severe
sepsis or septic shock with a central venous line in place. Blood
from a peripheral venous puncture, central venous line and arterial
line were collected, at the same timepoint each 12 hours. Peripheral lactate collection was performed carefully with the left
superior limb garroted for a maximal of 2 minutes. Data were
analysed by linear correlation test, and a Bland–Altman test was
done to verify the degree of agreement between values from
different samples. A P value <0.05 was considered significant. A Ghaddab, H Quintard, L Rami, D Grimaud, C Ichai
St Roch Hospital, Nice, France
Critical Care 2007, 11(Suppl 2):P454 (doi: 10.1186/cc5614) Introduction Myocyte stretch is the main stimulus of brain
natriuretic peptide (BNP) synthesis and release. During septic
shock, important variations of volemia can occur and a correlation
has been described between the cardiac index and the BNP level
[1]. However, the relation between the echocardiographic left
ventricule area and the BNP level has never been described. The
aim of our study was to evaluate BNP and left ventricule area
variations after an acute fluid loading in septic shock. Results Fifteen patients were enrolled, with a mean age of
57.8 years (eight males and seven females), APACHE II score of
15.3 ± 5.0 and SOFA score of 7.13 ± 3.39. A total of 129
samples were available for analysis. The linear correlation between
arterial and central venous lactate levels showed an r2 = 0.66
(95% CI: 0.71–1.12). However, Bland–Altman had a mean ±
standard deviation bias of 1.25 ± 5.0. Results were similar for
arterial and peripheral venous lactate with an r2 = 0.85 (95% CI:
0.97–1.27) and a bias of –2.44 ± 5.0. Clinical agreement between
arterial and central venous blood was 90%, arterial and peripheral
blood was 71% and central venous and peripheral blood was 64%. Conclusion Lactate from central venous blood can replaced arterial
samples. However, peripheral samples are not clinically reliable. Methods Mechanical ventilated patients with septic shock, and
without anterior cardiac disease, were included in our study. A fluid
challenge was performed with colloid (500 ml) in 30 minutes. A
BNP blood sample was drawn before and 1 hour after fluid
loading. P454 The primary endpoint was BNP variation after fluid
challenge. Median values (25–75th percentiles) were compared
with the Wilcoxon test (P < 0.05). The end-diastolic left ventricule
area was recorded before and 1 hour after fluid challenge. Linear
regression of BNP variation and left ventricular area variation was
determined and r2 was calculated. Lactate levels from arterial, central venous and peripheral
venous blood in severe sepsis and septic shock patients M Assuncao, A Nascente, C Guedes, B Mazza, M Jacki,
H Fernandes, F Machado
Universidade Federal de São Paulo, Brazil
Critical Care 2007, 11(Suppl 2):P452 (doi: 10.1186/cc5612) ,
Critical Care 2007, 11(Suppl 2):P452 (doi: 10.118 Conclusion In critically ill patients with severe sepsis/septic shock
a score based on age and increased plasma levels of cardiac
biomarkers can help risk-stratify patients and predict short-term
(<6 months) outcome. Introduction Serial lactate measurements are reliable and may be
useful as a prognostic marker in critically ill patients. Differences in
its levels, depending on the sample site, can lead to mis-
interpretation and inadequate treatment. The primary objective of
this study is to evaluate the relationship between lactate levels in
different compartments of the body, such as peripheral venous,
central venous and arterial blood in patients with severe sepsis and S179 Mid-regional pro-atrial natriuretic peptide is a strong predictor
of outcome in an unselected cohort of critically ill patients Mid-regional pro-atrial natriuretic peptide is a strong predictor
of outcome in an unselected cohort of critically ill patients Mid-regional pro-atrial natriuretic peptide is a strong predictor
of outcome in an unselected cohort of critically ill patients B Meyer1, P Wexberg1, R Berger1, D Moertl1, N Morgenthaler2,
J Struck2, A Bergmann2, G Heinz1, R Pacher1, M Huelsmann1
1Medical University of Vienna, Austria; 2B.R.A.H.M.S. Ag,
Henningdorf, Germany
Critical Care 2007, 11(Suppl 2):P456 (doi: 10.1186/cc5616) Conclusion There is no increase in BNP level in patients with
septic shock after fluid challenge. To our knowledge, this
preliminary study is the first to evaluate the relationship between
BNP and left ventricule area variation in patient with septic shock. Although no statistical significance between left ventricule area
variation and BNP variation after fluid challenge, there is a trend to
correlation between these two parameters. More patients have to
be included to confirm this result. Introduction Atrial natriuretic peptide (ANP) is a strong predictor
of outcome in patients with heart failure, various other
cardiovascular diseases and in patients with systemic inflammatory
response syndrome and sepsis. Furthermore, ANP is elevated in
patients with kidney disease. We aimed to test the prognostic
potency of the precursor molecule mid-regional pro-atrial natriu-
retic peptide (MR-pro-ANP) in an unselected cohort of critically ill
patients. 1. McLean AS: The effects of acute fluid loading on plasma
B-type natriuretic peptide levels in a septic shock patient. Anesth Intensive Care 2005, 33:528-530. 1. McLean AS: The effects of acute fluid loading on plasma
B-type natriuretic peptide levels in a septic shock patient. Anesth Intensive Care 2005, 33:528-530. 1. McLean AS: The effects of acute fluid loading on plasma
B-type natriuretic peptide levels in a septic shock patient. Anesth Intensive Care 2005, 33:528-530. Methods Between August 2004 and February 2006, a total of
294 patients (191 males, age 63.8 ± 14.7 years) admitted to our
ICU were studied. The mean SAPS2 and APACHE II score were
52 ± 23 and 24 ± 11, respectively. Two hundred and three
patients (69.1%) were on intravenous inotropic support, 30 patients
had additional mechanical circulatory support (23 intraaortic
balloon counterpulsation (7.8%), eight extracorporeal membrane
oxygenation (2.7%), three left ventricular assist device (0.9%)). Two
hundred and five patients (69.7%) were mechanically ventilated,
and 59 patients (20.1%) presented with acute renal failure. Plasma
samples for determination of MR-pro-ANP were obtained on
admission in all patients. P457 Results Intravenous infusion of ANP reduced I/R-induced increase
in serum levels of blood urea nitrogen and creatinine at 24 hours
after reperfusion. ANP inhibited I/R-induced increases in renal
tissue levels of TNF and myeloperoxidase at 3 and 6 hours after
reperfusion, respectively. ANP significantly enhanced I/R-induced
increases in renal tissue levels of CGRP and 6-keto-PGF1α, a
stable metabolite of PGI2, at 1 hour after reperfusion. ANP-induced
increases in renal tissue levels of CGRP were significantly inhibited
by pretreatment with SB366791, a specific vanilloid receptor-1
antagonist. ANP-induced increases in renal tissue levels of 6-keto-
PGF1α
were
significantly
inhibited
by
pretreatment
with
SB366791, CGRP(8-37), a CGRP receptor antagonist, and
indomethacin. Reduction of I/R-induced increases in serum levels
of blood urea nitrogen and creatinine and those in renal tissue
levels of TNF and myeloperoxidase in rats treated with ANP were
completely abrogated by pretreatment with SB366791, CGRP(8-
37), and indomethacin. ANP significantly increased CGRP release
from dorsal root ganglion neurons in vitro. Conclusions These results strongly suggested that ANP might Mid-regional pro-atrial natriuretic peptide is a strong predictor
of outcome in an unselected cohort of critically ill patients As MR-pro-ANP values were not normally
distributed, log MR-pro-ANP values were used for analysis. P455 Atrial natriuretic peptide reduces the ischemia/
reperfusion-induced renal injury in rats by enhancing
sensory neuron activation N Harada, K Okajima, Y Mizuochi
Nagoya City University Graduate School of Medical Sciences,
Nagoya, Japan
Critical Care 2007, 11(Suppl 2):P455 (doi: 10.1186/cc5615) Introduction Although carpertide, a synthetic α-human atrial
natriuretic peptide (ANP), reduces ischemia/reperfusion (I/R)-
induced tissue injury, the precise therapeutic mechanism(s)
remains to be elucidated. Calcitonin gene-related peptide (CGRP)
released from sensory neurons reduces I/R-induced liver injury by
inhibiting neutrophil activation through an increase in the
endothelial production of prostacyclin (PGI2). In the present study,
we examined in rats whether ANP reduces I/R-induced renal injury
by enhancing sensory neuron activation. Results Two hundred and thirty-five patients (79.9%) survived to
ICU discharge and 59 patients died (21.1%). Log MR-pro-ANP
plasma levels were significantly higher in patients who died than in
ICU survivors (2.76 ± 0.39 pmol/l vs 2.50 ± 0.38 pmol/l,
respectively, P < 0.0001). In the Kaplan–Meier analysis of 28-day
survival, patients with log MR-pro-ANP plasma-levels above the
median had significantly lower survival rates compared with
patients with log MR-pro-ANP plasma levels below the median
(P = 0.02). Methods The right renal vessels were clamped in rats for 45
minutes after left nephrectomy. ANP (0.3 µg/kg/min) was
continuously infused from 30 minutes before ischemia to 60
minutes after reperfusion. We attempted to determine whether
ANP promotes CGRP release from cultured dorsal root ganglion
neurons isolated from adult rats in vitro. Conclusion Our data show that elevated plasma levels of MR-pro-
ANP at ICU admission are associated with an adverse outcome in
an unselected cohort of critically ill patients. Lung nitroxidative stress as a prognostic factor in
ventilated septic patients Lung nitroxidative stress as a prognostic factor in
ventilated septic patients J Gorrasi1, H Botti2, C Batthyany2, M Naviliat2, M Cancela1, R Radi2
1University Hospital, School of Medicine, Montevideo, Uruguay;
2Center for Free Radical Biomedical Research, School of Medicine,
Montevideo, Uruguay
Critical Care 2007, 11(Suppl 2):P453 (doi: 10.1186/cc5613) Figure 1 (abstract P454) Figure 1 (abstract P454)
Figure 2 (abstract P454) Introduction During sepsis and mechanical ventilation, nitric oxide
(•NO) is produced by lung cells. We study whether pulmonary •NO
production is a prognostic factor in mechanically ventilated septic
patients. Materials and methods We studied 50 patients with sepsis
within the first 48 hours of sepsis. Operating room patients served
as control a group (ORCG). Nitrite and nitrate (NOx–) and 3-
nitrotyrosine (3NT) in plasma and bronchoalveolar lavage fluid
(BALF) were analyzed by the Griess/vanadium chloride method
and ELISA, respectively. Results were expressed as median and
interquartile range. Receiver operator curves were constructed to
compare the predictive value of NOx– values in BALF at admission
with other variables. Kaplan–Meier analysis was used to compare
survival between high and low BALF NOx– levels at admission. A P
value less than 0.05 was considered significant. Figure 2 (abstract P454) Results At study admission in the sepsis group, nonsurvivors had
higher levels of BALF NOx– than survivors: 20 (17–33) µM, 27
versus 72 (46–91) µM, 23, P = 0.0001. At day 7, BALF 3NT was
higher in nonsurvivor septic patients than in survivors: 1,666
(30–3,173) pmol/mg protein versus 291 (13–1,908) pmol/mg
protein. BALF NOx
– had the highest area under the receiver
operator curve for mortality (0.812, P = 0.001) in relation to other
variables. Septic patients with BALF NOx
– above 36 µM had a
relative risk for mortality of 4.23 and an OR of 15.84. The
difference between the low bronchoalveolar •NO group (BALF
[NOx
–] < 36 µM at admission) versus the high bronchoalveolar
•NO group (BALF [NOx
–] ≥36 µM at admission) in ICU mortality
was significant: 19% versus 78% (log rank 18.19, P = 0.00001). Conclusion During sepsis there is enhanced lung •NO production
that is associated with ICU mortality. S180 Available online http://ccforum.com/supplements/11/S2 P456 Results Eight patients (median age 68 years; six males/two females;
SOFA score = 12) were enrolled in our study. The initial BNP level
median increased from 695 (417–2,738) to 715 (478–2,596) µg/ml
after a fluid loading (P = 0.7) (Figure 1).We did not find a statistically
significant relationship between BNP variation and left ventricule
area variation after fluid challenge (P = 0.13) (Figure 2). Clinical meaning of brain natriuretic peptide in the
intensive care unit T Principi, D Elisei, M Strovegli, G Falzetti, P Pelaia
Anaesthesia and Intensive Care Clinic – Politechnical University of
Marche, Ancona, Italy
Critical Care 2007, 11(Suppl 2):P457 (doi: 10.1186/cc5617) Introduction The aim of this study is to evaluate differences in
brain natriuretic peptide (BNP) dosage (vn < 100 pg/ml) during
the weaning procedure, in patients with heart disease (HD) vs
patients without HD, admitted to the ICU. Introduction The aim of this study is to evaluate differences in
brain natriuretic peptide (BNP) dosage (vn < 100 pg/ml) during
the weaning procedure, in patients with heart disease (HD) vs
patients without HD, admitted to the ICU. Methods Ten patients with HD (group A) and 33 patients without
HD (group B) were studied by BNP dosage in three specific steps:
(1) admission to the ICU; (2) before the extubation (performed if
patients, after the end of mechanical ventilation and 1 hour of
connection to T-tube, were considered suitable for extubation); and
(3) 24 hours after extubation. Necessity of noninvasive ventilation
or reintubation after the extubation was considered as weaning
failure. Data are shown as the mean ± standard error of the mean; Conclusions These results strongly suggested that ANP might
reduce I/R-induced renal injury in rats by inhibiting neutrophil
activation through enhancement of sensory neuron activation. S181 ritical Care March 2007 Vol 11 Suppl 2
27th International Symposium on Intensive Care and Emergency Medicin Table 1 (abstract P458)
Development
Validation
Hosmer–Lemeshow
0.868
0.42
C-hat statistics test
ROC
0.936
0.945
Nonsurvivor prediction
28/46 (60.9%)
18/28 (64.3%)
Survivor prediction
364/368 (99%)
199/201 (99%) nominal variables were analyzed with the chi-square test and the
risk ratio (RR) with 95% confidence interval (IC95) was performed;
intragroup ordinal variables were analyzed with the Wilcoxon test
(W), intergroup ordinal variables were analyzed with the
Mann–Whitney test (MW). The receiver operative characteristic
test was used to discriminate the BNP cutoff value with sensibility,
specificity and respective IC95, between group A and group B. P < 0.01 is taken as statistically significant. Results Weaning failure in group A occurred in 50% of patients vs
12% of group B patients (P < 0.01 chi-square test; RR = 4.13,
IC95 = 1.36–12.49). References 1. Haddad Z, et al.: Critically ill obstetric patients: outcome
and predictability. Crit Care 2005, 9(Suppl 1):S92-S93. Conclusions Risk of weaning failure is increased four times in
patients with HD. BNP values of group B patients are higher than
normal people probably because the heart of ICU patients is
submitted to different kinds of stress; therefore the BNP cutoff
value to consider for discrimination of patients with HD from
patients without HD in the ICU should be higher. BNP production
in ICU patients with good performance of the heart is the right
protective response to stress performed by therapy adopted
during the ICU stay, this response is absent in patients with HD
because their hearts already work in safety mode. 2. Knaus WA, et al.: APACHE II: a severity of disease classifi-
cation system. Crit Care Med 1985, 13:818-829. 3. Le Gall JR, et al.: A new simplified acute physiology score
(SAPS II) based on a European/North American multicen-
ter study. JAMA 1993, 270:2957-2963. 4. Lemeshow S, et al.: Refining intensive care unit outcome
prediction by using changing probabilities of mortality. Crit
Care Med 1988, 16:470-477. P459 Combining various severity of illness scoring systems to
improve outcome prediction: pilot experience in the
critically ill obstetric population Z Haddad1, C Kaddour2, L Skandrani2, S Nagi2, T Chaaoua2,
R Souissi2
1CHI St-Cloud, France; 2National Institute of Neurology, Tunis,
Tunisia
Critical Care 2007, 11(Suppl 2):P458 (doi: 10.1186/cc5618) Z Haddad1, C Kaddour2, L Skandrani2, S Nagi2, T Chaaoua2,
R Souissi2
1CHI St-Cloud, France; 2National Institute of Neurology, Tunis,
Tunisia
Critical Care 2007, 11(Suppl 2):P458 (doi: 10.1186/cc5618) Clinical meaning of brain natriuretic peptide in the
intensive care unit BNP value differences in group A are not
significant (step 1: 662 ± 147 pg/ml; step 2: 769 ± 171 pg/ml;
step 3: 843 ± 167 pg/ml), while BNP value differences in group B
are statistically significant (W) (step 1: 130 ± 21 pg/ml; step 2:
236 ± 41 pg/ml, P < 0.01 vs step 1; step 3: 375 ± 75 pg/ml,
P < 0.001 vs step 1 and P < 0.01 vs step 2). There are statistically
significant differences between group A and group B in every step
(P < 0.01 MW). The BNP cutoff value to discriminate group A from
group B is 274 pg/ml with sensibility 90 (IC95 = 55–98) and
specificity 79 (IC95 = 61–91). Results Six hundred and forty-three patients enrolled. The overall
mortality rate was 11.51%. The new model predicted accurately
99% of survivors and more than 60% of nonsurvivors. Conclusion The ‘multiscore’ model seems to refine prognosis. This
is partly due to mixing of new evaluated parameters. Testing the
latest developed generations of scores and also organ dysfunction
systems could be interesting. Combining various severity of illness scoring systems to
improve outcome prediction: pilot experience in the
critically ill obstetric population Validation of logistic organ dysfunction score prediction
compared with APACHE II score prediction hospital
outcome in Thai patients B Khwannimit B Khwannimit
Prince of Songkla University, Songkhla, Thailand
Critical Care 2007, 11(Suppl 2):P459 (doi: 10.1186/cc5619) Introduction To assess the performance of the logistic organ
dysfunction (LOD) score and Acute Physiology and Chronic Health
Evaluation II (APACHE II) score in a mixed medical–surgical ICU of
a tertiary referral university hospital in Thailand. Introduction No perfect severity score exists to predict ICU
mortality, thus the search for new systems is still a preoccupation. Hypothesis Use of many severity of illness scores simultaneously
improves mortality prediction. Introduction No perfect severity score exists to predict ICU
mortality, thus the search for new systems is still a preoccupation. Hypothesis Use of many severity of illness scores simultaneously
improves mortality prediction. Figure 1 (abstract P459) Figure 1 (abstract P459) P460 Could we use the admission Acute Physiology and Chronic
Health Evaluation II score for outcome prediction in
critically ill obstetric patients? Objective Development of a new prognostic model based on
association of one of the generalistic severity scores (SAPS II,
APACHE II), one of the organ dysfunction scores (LOD, MODS,
SOFA) and evolution of these scores during the first 2 days of ICU
hospitalization. Z Haddad1, R Souissi2, C Kaddour2, W Trabelsi2, M Bouchnak3,
S Nagi2
1CHI St-Cloud, France; 2National Institute of Neurology, Tunis,
Tunisia; 3Centre de Maternité et de Néonatologie, Tunis, Tunisia
Critical Care 2007, 11(Suppl 2):P460 (doi: 10.1186/cc5620) Z Haddad1, R Souissi2, C Kaddour2, W Trabelsi2, M Bouchnak3,
S Nagi2 1CHI St-Cloud, France; 2National Institute of Neurology, Tunis,
Tunisia; 3Centre de Maternité et de Néonatologie, Tunis, Tunisia
Critical Care 2007, 11(Suppl 2):P460 (doi: 10.1186/cc5620) Methods An open prospective analysis part of the APRiMo study
[1] ranging from January 1996 to September 2004. Inclusion
criteria were critically ill obstetric patients with an ICU length of
stay > 24 hours. Exclusion criteria were those of the used scores. The main outcome of interest was survival status at ICU discharge. The database was divided into two samples: a development
sample by random choice of 450 patients, and the remaining
patients in the validation dataset. Multivariable logistic regression
models were developed. We chose among different developed
models the best performer as assessed by Hosmer–Lemeshow
(HL) goodness-of-fit statistics (calibration) and the area under the
receiver operating characteristic curve (AUROC) for discrimination. Accuracy of the developed model was verified on the validation
dataset using the same statistical tests. Results are expressed as
the mean ± standard deviation unless stated elsewhere. Data were
computed on SPSS 11.5 Win-XP version. Introduction The APACHE II score (APII) has widespread use in
ICUs for research and benchmarking. Physiological data for
calculation of the APII score derive from worst values in the first
24 hours after ICU admission. Hypothesis Mortality prediction by the APII system depends on
data sampling. Use of ICU admission data (first hour) could be
accurate to predict mortality. Methods An open prospective data-sampling part of the APRiMo
study. Included were critically ill obstetric patients, with ICU length
of stay (LOS) ≥6 hours. Admission (H1: first-hour worst
physiological data) and H24 (worst 24-hour physiological variables
including H1 collected data) were used to generate, respectively:
the admission APII score (H1-APII) and H24-APII. P461 Two-day intensive care unit outcome prediction score: a
trial to improve outcome prediction in critically ill obstetric
patients Z Haddad1, S Nagi2, R Souissi2, C Kaddour2 Introduction The critically ill obstetric population median ICU stay
is 4 days, thus general severity of illness scores are supposed to
be accurate in mortality prediction. A literature review makes us
sceptical. Reference 1. Knaus WA, et al.: APACHE II: a severity of disease classifi-
cation system. Crit Care Med 1985, 13:818-829. 1. Knaus WA, et al.: APACHE II: a severity of disease classifi-
cation system. Crit Care Med 1985, 13:818-829. P460 The formulae to
calculate individual mortality for H1 and H24 APII were those
validated for H24-APII as stated by Knaus and colleagues [1],
adjusting for admission diagnosis. We compared both scores by
discrimination and calibration statistical tests. P < 0.05 was the
threshold for statistical significance. Results Six hundred and forty patients included. Age 31 ± 6 years,
length of stay 5 ± 5 days, SAPS II 27 ± 16, SOFA score 5 ± 4,
LOD score 2 ± 1.7. The overall mortality rate was 13.3%. The best
model was the one combining SAPS II and LOD scores. The LOD
score and SAPS II alone discriminated well but calibrated poorly in
outcome prediction. Discrimination was optimal for the new
developed model in both development and validation datasets,
with AUROC respectively of 0.87 and 0.85. Calibration was good
in the developed and validated datasets, respectively P = 0.176
and 0.34. The developed model predicts death accurately in 2/3
cases. Results The study period was January 1996–September 2004. We included 541 patients, overall mortality was 10.5%. Mean H1-
APII and H24-APII scores. respectively. were 7.6 ± 6.1 and 8.6 ± 7,
with derived mean predicted mortality, respectively, of 8.63% and
9.86%. The H24-APII score was higher than the H1-APII score in
135 patients (25%), among those patients 32 died (24% of
patients with worsened APII) vs 6.16% if H1 = H24 (P < 0.01). Running a multiple logistic regression with mortality as the
dependent parameter, we found that worsening of the APII score
over time is not significantly associated with mortality (P = 0.791),
whereas the H1-APII score (P < 0.001) and ∆APII score (H24-APII Discussion and conclusion The SAPS II and LOD scores are
complementary. Development of dynamic models in time helps to
refine prognosis prediction. Discussion and conclusion The SAPS II and LOD scores are
complementary. Development of dynamic models in time helps to
refine prognosis prediction. Figure 1 (abstract P459) P460
Could we use the admission Acute Physiology and Chronic
Health Evaluation II score for outcome prediction in
critically ill obstetric patients? Z Haddad1, R Souissi2, C Kaddour2, W Trabelsi2, M Bouchnak3,
S Nagi2
1CHI St-Cloud, France; 2National Institute of Neurology, Tunis,
Tunisia; 3Centre de Maternité et de Néonatologie, Tunis, Tunisia
Critical Care 2007, 11(Suppl 2):P460 (doi: 10.1186/cc5620) Methods The data were collected prospectively on consecutive
patients admitted to the ICU of Songklanagarind Hospital over a
24-month period from 1 July 2004 until 30 June 2006. minus H1-APII score) (P = 0.04) are correlated with mortality. Respective ORs are 1.28 and 1.45. Overall discrimination ability
assessed by receiver operating characteristic curves was good for
H1-APII (0.78) and H24-APII (0.784) (P = 0.834). p
y
Results A total of 1,962 patients were enrolled, with 432 deaths
(22%) prior to hospital discharge. Both systems provided
overprediction of hospital mortality. LOD and APACHE II scores
predicted hospital mortality of 25.4 ± 26.5 and 29.6 ± 27.8,
respectively. Both models showed excellent discrimination. The
receiver operating characteristic curves of both systems are shown in
Figure 1. The area under the receiver operating characteristic curve
(AUROC) of LOD was 0.867 (95% CI = 0.846–0.886) and the
AUROC was 0.906 (95% CI = 0.889–0.923) for APACHE II. Both
models presented a poor calibration in overall population. However,
the LOD score had good discrimination and calibration in subgroups
of nonoperative patients (AUROC 0.854, the Hosmer–Lemeshow
goodness-of-fit H statistic 11.67, P = 0.166) and patients that
exclude coronary artery disease and cardiac surgery (AUROC 0.860,
the Hosmer–Lemeshow goodness-of-fit H statistic 10.03, P = 0.263). Conclusion The LOD score showed good accuracy to predict
hospital mortality in subgroups of nonoperative critically ill patients
and excluded coronary heart disease and cardiac surgical critically
ill patients in Thailand. Conclusion To avoid variation in APII mortality prediction caused
by variable sample rates, the admission APII is reliable. Customizing mortality formulae could improve performances of
APII-H1. Figure 1 (abstract P459) Patients and methods An open prospective observational study
as part of the APRiMo project [1]. The study period was January
1996–September 2004. Inclusion criteria were critically ill
obstetric patients and ICU length of stay >24 hours. Exclusion
criteria were those of the used scores. The main outcome of
interest was the survival status at ICU discharge. The database
was divided into two samples: development and validation
datasets. Development database patients were chosen randomly
(n = 414) and the remaining patients composed the validation
dataset (n = 229). A multivariable logistic regression model was
developed to predict mortality associating the Acute Physiology
and Chronic Health Evaluation II score [2], Simplified Acute
Physiology Score II [3], Admission Mortality Prediction Model
(MPM-H0) and Day 1 Mortality Prediction Model (MPM-H24) [4]. Discrimination and calibration were assessed by goodness-of-fit
C-hat statistics and area under the ROC curve. The developed
model was then tested in the validation dataset. Good
discrimination was retained if C-hat statistics P > 0.1 and good
calibration if area under the ROC curve > 0.8. S182 Available online http://ccforum.com/supplements/11/S2 Available online http://ccforum.com/supplements/11/S2 Methods The data were collected prospectively on consecutive
patients admitted to the ICU of Songklanagarind Hospital over a
24-month period from 1 July 2004 until 30 June 2006. Results A total of 1,962 patients were enrolled, with 432 deaths
(22%) prior to hospital discharge. Both systems provided
overprediction of hospital mortality. LOD and APACHE II scores
predicted hospital mortality of 25.4 ± 26.5 and 29.6 ± 27.8,
respectively. Both models showed excellent discrimination. The
receiver operating characteristic curves of both systems are shown in
Figure 1. The area under the receiver operating characteristic curve
(AUROC) of LOD was 0.867 (95% CI = 0.846–0.886) and the
AUROC was 0.906 (95% CI = 0.889–0.923) for APACHE II. Both
models presented a poor calibration in overall population. However,
the LOD score had good discrimination and calibration in subgroups
of nonoperative patients (AUROC 0.854, the Hosmer–Lemeshow
goodness-of-fit H statistic 11.67, P = 0.166) and patients that
exclude coronary artery disease and cardiac surgery (AUROC 0.860,
the Hosmer–Lemeshow goodness-of-fit H statistic 10.03, P = 0.263). Conclusion The LOD score showed good accuracy to predict
hospital mortality in subgroups of nonoperative critically ill patients
and excluded coronary heart disease and cardiac surgical critically
ill patients in Thailand. Model calibration and discriminatory ability: a comparison
of four derived variables from the SOFA score and the
SAPS II Model calibration and discriminatory ability: a comparison
of four derived variables from the SOFA score and the
SAPS II Median length of ICU stay in patients with an admission SOFA score
>8 vs those whose admission SOFA score was ≤8 (P = 0.001). Median length of ICU stay in patients with an admission SOFA score
>8 vs those whose admission SOFA score was ≤8 (P = 0.001). R Ouezini, N Frikha, N Belhaj, S Ouerghi, M Mebazaa,
M Ben Ammar
Mongi slim Hospital, La Marsa, Tunisia
Critical Care 2007, 11(Suppl 2):P464 (doi: 10.1186/cc5624) R Ouezini, N Frikha, N Belhaj, S Ouerghi, M Mebazaa,
M Ben Ammar
Mongi slim Hospital, La Marsa, Tunisia
Critical Care 2007, 11(Suppl 2):P464 (doi: 10.1186/cc5624) R Ouezini, N Frikha, N Belhaj, S Ouerghi, M Mebazaa,
M Ben Ammar
Mongi slim Hospital, La Marsa, Tunisia
Critical Care 2007, 11(Suppl 2):P464 (doi: 10.1186/cc5624) Figure 1 (abstract P462) Results Nine out of 11 patients survived without any residual
organ damage, and the remaining two died due to MODS (Figure 1). Both these patients had five organ dysfunctions on admission, and
their SOFA scores were 18 and 20, respectively. They had a low
parasitic index of 1% and 2.5% and their PCT levels were 0.5–2
and >10 (semiquantitative method), respectively. Their APACHE II
scores were 16 and 10. Conclusion The pretreatment APACHE II score, parasite index,
PCT levels and number of organs involved have variable correlation
with mortality and are not consistent predictors of outcome. A
higher SOFA score on admission is a more reliable predictor of
mortality in malarial MODS. Reference 1. Haddad Z, et al.: Critically ill obstetric patients: outcome
and predictability. Crit Care 2005, 9(Suppl 1):S92-S93. S183 Critical Care March 2007 Vol 11 Suppl 2
27th International Symposium on Intensive Care and Emergency Medicin Figure 1 (abstract P463) P462
The correlation of the Sequential Organ Failure
Assessment score with intensive care unit outcome
I Ketchley, A Theodoraki, T Reynolds, A Tillyard, R Lawson,
N Al-Subaie, M Cecconi, R Grounds, A Rhodes
St George’s Hospital, London, UK
Critical Care 2007, 11(Suppl 2):P462 (doi: 10.1186/cc5622) Figure 1 (abstract P463) Figure 1 (abstract P463) The correlation of the Sequential Organ Failure
Assessment score with intensive care unit outcome The correlation of the Sequential Organ Failure
Assessment score with intensive care unit outcome I Ketchley, A Theodoraki, T Reynolds, A Tillyard, R Lawson,
N Al-Subaie, M Cecconi, R Grounds, A Rhodes
St George’s Hospital, London, UK
Critical Care 2007, 11(Suppl 2):P462 (doi: 10.1186/cc5622) Methods We conducted a prospective observational review of
100 consecutive patients admitted to our ICU. We collected data
relating to daily maximum organ dysfunction scores. Outcome was
defined in terms of length of ICU stay and ICU mortality. Results We included 100 patients (62 males), mean age 60.9
years. Of these admissions, 45 were elective surgical, 22
emergency surgical, 33 medical. The median Sequential Organ
Failure Assessment (SOFA) score on admission was 4.50 (IQR 4). The median maximum SOFA score was 5.00 (IQR 5). The median
length of ICU stay was 3.0 days (IQR 3). The overall ICU mortality
rate was 14.0%. For patients with a maximum SOFA score ≤8,
mortality was 5.1% – vs 45.5% for those whose maximum SOFA
score was >8 (P < 0.001). Sixty-four per cent of patients scored
their maximum SOFA score on admission. In patients whose SOFA
score increased after admission, the mortality was 24.3%. Logistic
regression analysis showed the maximum SOFA score bore a
stronger correlation with mortality than admission SOFA score. See Figure 1. like India, and is associated with significant mortality. The outcome
of malarial MODS predicted in various studies is extremely variable
and dependent on many patient parameters. Objective We prospectively evaluated the correlation of the
APACHE II score, parasite index, procalcitonin (PCT) levels,
number of organ dysfunctions/failures and Sequential Organ Failure
Assessment (SOFA) score with the outcome of severe malaria. Methods Eleven patients with acute severe malaria with MODS
were treated in our ICU in the last 5 months. All these patients
were treated with artesunate and/or quinine as per the WHO
antimalarial treatment schedule, along with standard ICU care. The
APACHE II and SOFA scores were calculated on admission. PCT
levels were measured semiquantitatively on admission. The
parasite index was confirmed by two pathologists. Conclusion Maximum and admission SOFA scores are of
prognostic value in the intensive care setting; allowing patients
with increased risk of mortality and prolonged stay to be identified. Figure 1 (abstract P462) Figure 1 (abstract P462)
Median length of ICU stay in patients with an admission SOFA score
>8 vs those whose admission SOFA score was ≤8 (P = 0.001). P466 Results Diagnostic categories were: trauma 21.3%, postoperative
19% and medical 59.7%. Global mortality was 34.3%. Survivors had
lower average SAPS II (28.1 ± 14 against 48.6 ± 19, P < 0.01),
SOFAi score (3.7 ± 3 against 7.2 ± 4, P < 0.01), SOFAmax score
(4.6 ± 4 against 10.8 ± 3, P < 0.01), ∆SOFA (1.6 ± 6 against
4.2 ± 3, P < 0.01), DoMAX (1.6 ± 6 against 4.2 ± 3, P < 0.01)
and TMS (5 ± 3 against 11.4 ± 4, P < 0.01), and the difference
was statistically significant. Results regarding model calibration
and discriminatory ability are presented in Figure 1. Cumulative lactate load correlates with cumulative
Sequential Organ Failure Assessment score and survival in
intensive care unit patients Cumulative lactate load correlates with cumulative
Sequential Organ Failure Assessment score and survival in
intensive care unit patients Cumulative lactate load correlates with cumulative
Sequential Organ Failure Assessment score and survival in
intensive care unit patients P Spronk1, L Brander2, S Jansen1, J Rommes1
1Gelre Ziekenhuizen Location Lukas, Apeldoorn, The Netherlands;
2University Hospital, Bern, Switzerland
Critical Care 2007, 11(Suppl 2):P466 (doi: 10.1186/cc5626) Background Changes in lactate levels are used as a prognostic
marker in critically ill patients. However, the relation between the
time course of arterial blood lactate clearance and important
outcome parameters such as ICU length of stay (LOS), incidence
of organ failure and survival rate has not been established. Conclusion The SOFAmax score had the best model calibration
and could be used to compare different patient populations in
terms of mortality. Methods Case records from all ICU patients admitted between
2002 and 2004 were retrospectively identified in the ICU
database. The Sequential Organ Failure Assessment (SOFA)
score was calculated daily to assess the time course of organ
failure. All lactate levels were extracted and the total cumulative
lactate load (area under the curve above the upper normal level of
2.2 mmol/l; cum-lactate), and total cumulative SOFA score (cum-
SOFA) were calculated and related to ICU LOS and final hospital
survival. Values are the median (interquartile range). Available online http://ccforum.com/supplements/11/S2 Available online http://ccforum.com/supplements/11/S2 Figure 1 (abstract P464) Results One hundred and seventy-six patients were studied (71
males (56%), median age 51 (IQR 36–67) years, 78 (44%) with
severe sepsis, median length of ICU stay 10 days (IQR 7–16),
median admission SOFA 6 (IQR 4–9), median APACHE II score
19 (IQR 13–26), ICU mortality 27.84% (49/176 patients)). The
SOFA score and its components scores along the five admission
days
distinguished
the
survivors
from
the
nonsurvivors. Considering the SOFA score and its respiratory, neurologic and
circulatory components, survivors presented lower scores as the
days passed (P < 0.001). Mortality was increasingly higher for
those patients who persisted with a SOFA score ≥7 as the days
passed. Figure 1 (abstract P464)
*Classified as + if predicted mortality ≥0.5. Domax, the maximum
number of organ failures during ICU stay. *Classified as + if predicted mortality ≥0.5. Domax, the maximum
number of organ failures during ICU stay. Conclusion In the sample studied, the persistence of an elevated
SOFA score and its components during the first 5 days of
admission predicted a higher mortality. Survival appears to be
related to early organ dysfunction recovery. The SOFA score and
SOFA-related variables’ day-to-day changes in a population of
septic patients may have an important prognostic implication and
some patterns of daily evolution may distinguish those patients
with a more ominous outcome. ∆SOFA was defined by TMS minus admission SOFA (SOFAi). The
maximum SOFA was defined by the worst SOFA value during the
ICU stay. Logistic regression modeling techniques were used to
describe the association of derived SOFA variables and SAPS II
with mortality. ROC curves were used to assess the model’s
discriminatory ability and we examined the model calibration using
the Hosmer–Lemeshow goodness-of-fit test. P < 0.05 was con-
sidered significant. ∆SOFA was defined by TMS minus admission SOFA (SOFAi). The
maximum SOFA was defined by the worst SOFA value during the
ICU stay. Logistic regression modeling techniques were used to
describe the association of derived SOFA variables and SAPS II
with mortality. ROC curves were used to assess the model’s
discriminatory ability and we examined the model calibration using
the Hosmer–Lemeshow goodness-of-fit test. P < 0.05 was con-
sidered significant. P465 P465
Sequential Organ Failure Assessment score trends and
sepsis survival in a Brazilian university hospital intensive
care unit
D Moreira Lima, B Ferreira Cordeiro de Almeida, R Cordioli,
E Tadeu Azevedo Moura, I Schimdtbauer, A Nassar, F Maria
Queiroz Silva, R Zigaib, D Forte, F Giannini, J Coelho, M Park
Hospital das Clínicas FMUSP, São Paulo, Brazil
Critical Care 2007, 11(Suppl 2):P465 (doi: 10.1186/cc5625) Sequential Organ Failure Assessment score trends and
sepsis survival in a Brazilian university hospital intensive
care unit D Moreira Lima, B Ferreira Cordeiro de Almeida, R Cordioli,
E Tadeu Azevedo Moura, I Schimdtbauer, A Nassar, F Maria
Queiroz Silva, R Zigaib, D Forte, F Giannini, J Coelho, M Park
Hospital das Clínicas FMUSP, São Paulo, Brazil
Critical Care 2007, 11(Suppl 2):P465 (doi: 10.1186/cc5625) Results Observations in 1,711 ICU admissions were analyzed,
age was 69 (57–77) years, cum-lactate was 420 (94–419
min·mmol/l) and cum-SOFA was 11 (4–38). Cum-SOFA was
higher in patients with hyperlactatemia (cum-lactate > 0) during the
ICU stay (n = 782; 24 (7–71)) than in those without (5 (3–20);
P < 0.001). Cum-SOFA correlated with cum-lactate and with ICU
LOS, and cum-lactate correlated with ICU LOS (all P < 0.001). In
patients who died in the hospital (n = 329), cum-lactate (1,180
(203–3,427) min·mmol/l) and cum-SOFA (30 (10–95)) were
higher than in hospital survivors (n = 1,382; 298 (73–1,154)
min·mmol/l, and 22 (5–67); both P < 0.001). In emergency
admissions, cum-lactate (484 (113–2,031)) and cum-SOFA (27
(8–78)) were higher than in planned admissions (131 (37–454))
and (4 (3–28); both P < 0.001), respectively. Introduction Sepsis is associated with progressive organ failure. We sought to describe Sequential Organ Failure Assessment
(SOFA) score daily trends in septic patients and tried to correlate
those trends with survival. Methods Patients with severe sepsis or septic shock admitted for
at least 5 days in a seven-bed medicosurgical ICU of a Brazilian
university hospital were studied. The daily SOFA score for each
patient was calculated during the first 5 days of admission. Relevant data were prospectively acquired from March 2003 to
May 2006 and the latter retrieved from a electronic database. ICU
survivors
were
compared
with
nonsurvivors
using
the
Mann–Whitney U test. Day-to-day changes were verified within
each group using Friedman’s test. P ≤0.01 was elected as the
significance limit. Medians and interquartile ranges (IQRs) were
used to describe the sample. P463 P463
Sequential Organ Failure Assessment score as an
outcome predictor in malarial multiorgan dysfunction
syndrome
S Jog, P Akole, B Pawar, N Gogate, S Gadgil, P Rajhans
Deenanath Mangeshkar Hospital and Research Centre, Pune, India
Critical Care 2007, 11(Suppl 2):P463 (doi: 10.1186/cc5623)
Introduction Acute severe malaria is one of the leading causes of
multiorgan dysfunction syndrome (MODS) in a developing country Sequential Organ Failure Assessment score as an
outcome predictor in malarial multiorgan dysfunction
syndrome Introduction We sought to compare four derived variables from
the SOFA score and the SAPS II in ICU patients in terms of
discriminatory ability and model calibration. Introduction We sought to compare four derived variables from
the SOFA score and the SAPS II in ICU patients in terms of
discriminatory ability and model calibration. Patients and methods Four hundred and fourteen patients were
included; they were evaluated on admission and every 48 hours
thereafter until ICU discharge or death. Readmission and patients
with an ICU stay shorter than 48 hours were excluded. The TMS
score was calculated by summing the worst scores for each of the
organ systems. Organ failure was defined by a SOFA score ≥3. Introduction Acute severe malaria is one of the leading causes of
multiorgan dysfunction syndrome (MODS) in a developing country S184 Available online http://ccforum.com/supplements/11/S2 P469 Results PCT serum concentrations are presented in Table 1. In
groups A, B, and C, SOFA1 was 1.31 ± 1.67 vs 1.62 ± 1.65
(P > 0.05), and 4.73 ± 2.57 (P < 0.05). SOFA2 was 0.97 ± 1.56
vs 1.34 ± 1.67 (P > 0.05), vs 4.69 ± 2.47 (P < 0.05). SOFA3 was
0.63 ± 1.11 vs 1.13 ± 1.68 (P = 0.0178), and 4.04 ± 1.81,
respectively. The ICU stay was 5.74 ± 11.49 days in group A,
6.97 ± 11.61 days (P = 0.04476) in group B, and 3.5 ± 1.11 days
in group C. The postoperative hospital stay was 12.08 ± 11.28
days vs 12.93 ± 10.73 days vs 12.25 ± 2.5 days (P > 0.05) in
group A vs group B vs group C. Inhospital mortality was 3% vs 3%
vs 2.8% (P = 0.8038) in the three groups. Simple prediction of mortality in case of readmission to
the intensive care unit
A Klimasauskas, G Kekstas
Vilnius University Hospital ‘Santariskiu Clinics’, Vilnius, Lithuania
Critical Care 2007, 11(Suppl 2):P469 (doi: 10.1186/cc5629) Simple prediction of mortality in case of readmission to
the intensive care unit A Klimasauskas, G Kekstas
Vilnius University Hospital ‘Santariskiu Clinics’, Vilnius, Lithuania
Critical Care 2007, 11(Suppl 2):P469 (doi: 10.1186/cc5629) Introduction Mortality of patients readmitted to the ICU is
significantly higher than the mortality of patients treated once in the
ICU. A simple method to predict mortality of patients readmitted to
the ICU could help to select the most seriously ill readmitted
patients. Table 1 (abstract P467)
–24 hours
6 hours
24 hours
48 hours
(preoperative)
(day of
(first post-
(second post-
operation)
operative day)
operative day)
Group A
0.23
0.33
0.34
0.56
Group C
0.25
0.75
1.07
0.88 Methods Adult patients that were admitted to all three ICUs of the
same hospital twice or more times during the same stay in the
hospital during a 3-year period were retrospectively selected. The
sex and age of surviving and nonsurviving readmitted patients were
compared. The mortality rate of patients readmitted into the ICU
during 24 and 48 hours was compared with the mortality rate of all
readmitted ICU patients. The mortality of patients that were
readmitted more than once into the ICU was compared with the
mortality of patients that were readmitted once. P465 Conclusion In ICU patients, the cumulative area under the lactate
curve correlates with the ICU LOS, cumulative SOFA score, and
inhospital mortality. The prognostic value of cum-lactate requires
prospective evaluation. S185 Critical Care March 2007 Vol 11 Suppl 2
27th International Symposium on Intensive Care and Emergency Medicin V Maravic-Stojkovic1, T Spasic1, M Jovic1, M Borzanovic1,
B Djukanovic1, D Brunner2
1Dedinje Cardiovascular Institute, Belgrade, Serbia; 2Interlight,
Lozana, Swaziland
Critical Care 2007, 11(Suppl 2):P467 (doi: 10.1186/cc5627) V Maravic-Stojkovic1, T Spasic1, M Jovic1, M Borzanovic1,
B Djukanovic1, D Brunner2
1Dedinje Cardiovascular Institute, Belgrade, Serbia; 2Interlight,
Lozana, Swaziland
Critical Care 2007, 11(Suppl 2):P467 (doi: 10.1186/cc5627) V Maravic-Stojkovic1, T Spasic1, M Jovic1, M Borzanovic1,
B Djukanovic1, D Brunner2
1Dedinje Cardiovascular Institute, Belgrade, Serbia; 2Interlight,
Lozana, Swaziland
Critical Care 2007, 11(Suppl 2):P467 (doi: 10.1186/cc5627) Introduction Previously we investigated the clinical course of
patients with good left ventricle ejection fraction (EF) by assessing
the Sequential Organ Failure Assessment (SOFA) score and
procalcitonin (PCT) level early after cardiac surgery. In this study
we included patients with systolic heart failure (HF), prospectively
collecting data: B-type natriuretic peptide (BNP), PCT, and SOFA
score. Results No statistically significant difference among the three
groups was found in terms of age, gender, primary diagnosis, ICU
stay and mechanical ventilator times, and APACHE II, Glasgow
Coma Scale and SOFA scores. Also no statistically significant
difference was found between mortalities during the weekend and
a weekday. Conclusion A well-organized ICU can work functionally during the
night-time, change of shifts and weekend. In this situation, for
optimal
performance,
the
structure
and
management
of
organization come into prominence. Our results show that in ICU
patients mortality is not related to time of day when optimum
situations are provided. Methods Two hundred and seventy-five patients (subjected to
coronary artery bypass grafting, valve reconstruction or combined
operations) were divided into three groups: echocardiographically
estimated EF > 30% for the PCT group (group A, n = 102), the
control group (group B, n = 103), and patients with EF < 30% for
BNP analysis (group C, n = 70). PCT was measured pre-
operatively, 6 hours, 24 hours and 48 hours postoperatively. The
SOFA score was assessed daily as SOFA1, SOFA2, SOFA3. BNP was measured preoperatively in patients with HF. P468 Results A total of 13,343 patients were admitted. Eight hundred
and fifty-six patients were readmitted, 172 readmitted patients died
in the hospital (hospital mortality – 20.09%). The readmission rate
of men was higher in comparison with women (550 vs 306
patients). The mortality of readmitted men was lower than the
mortality of readmitted woman; 77 men (17.2%) died vs 95
(25.1%) women (P = 0.00001). The age of 565 patients was
lower than 70 years. The mortality of readmitted patients with age
lower than 70 years was lower than the mortality of patients older
than 70 years; 103 (18.2%) patients younger than 70 years died
vs 70 (24%) patients older than 70 years (P = 0.00001). Mortality
of patients that were readmitted during 24 or 48 hours was bigger
than the mortality of all readmitted patients (26.9% and 25.11% vs The relationship between mortality and its time of day in
intensive care unit patients
T Adanir, A Sencan, N Atasoy, M Aksun, N Karahan
Izmir Ataturk Training and Research Hospital, Izmir, Turkey
Critical Care 2007, 11(Suppl 2):P468 (doi: 10.1186/cc5628) P467
Sequential Organ Failure Assessment score and
procalcitonin serum concentrations in patients with
systolic heart failure early after cardiac surgery Methods Intensive care medical records between 2002 and 2005
of 242 patients (151 males and 91 females) who attended our ICU
for 48 hours or more and proceeded mortally were analyzed
retrospectively. Patients were subdivided into three groups
according to the time at which mortality occurred: Group 1 08:00
a.m.–16:00 p.m., Group 2 16:00–24:00 p.m. and Group 3
00:00–08:00 a.m. Patients were also subdivided into two groups
according to the days on which they died being the weekend and a
weekday. The age, gender, primary diagnosis, ICU stay and
mechanical ventilator times, APACHE II, Glasgow Coma Scale and
SOFA scores, and mortality ratios of patients were taken and
compared according to the time period. P469 The duration of
stay in other departments before readmission into the ICU of
survivors was compared with duration of stay in other departments
of nonsurvivors. Discussion We have found that the SOFA3 score had a
predicting value in the mortality rate as well as PCT concentrations
measured 48 hours after surgical intervention. Comparison of intensive care unit mortality performances:
standardized mortality ratio vs absolute risk reduction Comparison of intensive care unit mortality performances:
standardized mortality ratio vs absolute risk reduction Comparison of intensive care unit mortality performances:
standardized mortality ratio vs absolute risk reduction Methods
Five hundred and twenty-three tacrolimus blood
concentration levels, together with 35 other relevant variables from
56 liver transplantation patients between 2002 and 2006, were
extracted from Ghent University Hospital database (ICU Information
System IZIS) (Centricity Critical Care Clinisoft; GE Healthcare). Multiple linear regression, and support vector regression with linear
and nonlinear (RBF) kernel functions were performed, after
selection of relevant data components and model parameters. Performances of the prediction models on unseen datasets were
analyzed with fivefold cross-validation. Wilcoxon signed-rank
analysis was performed to examine differences in performances
between prediction models and to analyze differences between real
and predicted tacrolimus blood concentrations. B Afessa, M Keegan, J Naessens, O Gajic
Mayo Clinic College of Medicine, Rochester, MN, USA
Critical Care 2007, 11(Suppl 2):P470 (doi: 10.1186/cc5630) Introduction The aim of this study was to assess the role of
absolute risk reduction (ARR) to measure ICU performance as an
alternative to the standardized mortality ratio (SMR). Methods This retrospective study involves patients admitted to
three ICUs of a single tertiary medical center from January 2003
through December 2005. Only the first ICU admission of each
patient was included in the study. The ICUs were staffed similarly. We abstracted data from the APACHE III database. For each ICU,
the SMR and ARR with their 95% confidence intervals (CI) were
calculated. ICU performance was categorized as shown in Table 1. When comparing ICUs, if the 95% CI of the SMR or the ARR
overlap between the units, the performances were considered
similar. If there was no overlap, the differences in performance
were considered statistically significant. Results
The mean absolute difference with the measured
tacrolimus blood concentration in the predicted regression model
was 2.34 ng/ml (SD 2.51). Linear SVM and RBF SVM prediction
models had mean absolute differences with the measured
tacrolimus blood concentration of, respectively, 2.20 ng/ml (SD
2.55) and 2.07 ng/ml (SD 2.16). These differences were within an
acceptable clinical range. Statistical analysis demonstrated
significant better performance of linear (P < 0.001) and nonlinear
(P = 0.002) SVM (Figure 1) in comparison with linear regression. P471 20.09%; P = 0.045 and P = 0.097). The mortality of patients that
were readmitted more than once (from a total 160 patients, 41
died – 25.6%) was bigger than the mortality of patients readmitted
just once (from a total 696 patients, 131 died – 18.96%)
(P = 0.12). The length of stay of nonsurviving readmitted patients
in other departments before readmission was higher than the
length of stay of survivors (mean 7.64 days vs mean 5.71 days). Conclusion Sex and age older than 70 years of patients
readmitted to the ICU, readmission during 24 hours, and length of
stay in other departments before readmission could be used for
simple prediction of mortality of patients readmitted into the ICU. The amount of single patient readmissions to the ICU cannot be
used as a predictor of death of patients readmitted to the ICU. 20.09%; P = 0.045 and P = 0.097). The mortality of patients that
were readmitted more than once (from a total 160 patients, 41
died – 25.6%) was bigger than the mortality of patients readmitted
just once (from a total 696 patients, 131 died – 18.96%)
(P = 0.12). The length of stay of nonsurviving readmitted patients
in other departments before readmission was higher than the
length of stay of survivors (mean 7.64 days vs mean 5.71 days). Conclusion Sex and age older than 70 years of patients
readmitted to the ICU, readmission during 24 hours, and length of
stay in other departments before readmission could be used for
simple prediction of mortality of patients readmitted into the ICU. The amount of single patient readmissions to the ICU cannot be
used as a predictor of death of patients readmitted to the ICU. Prediction of the tacrolimus blood concentration in liver
transplantation patients with support vector regression
during an intensive care unit stay T Verplancke1, S Van Looy2, F De Turck2, D Benoit1, E Hoste1,
G Van Maele1, S Van Hoecke2, J Decruyenaere1
1Ghent University Hospital, Ghent, Belgium; 2Ghent University,
Ghent, Belgium
Critical Care 2007, 11(Suppl 2):P471 (doi: 10.1186/cc5631) Introduction The tacrolimus blood concentration has wide intra-
individual and inter-individual variability, especially in the initial
phase after transplantation in the ICU. To insure clinical effect and
to avoid side-effects, it is crucial to monitor concentrations very
carefully. Prediction models can save time and resources, enabling
clinicians and nurses to improve clinical care. The relationship between mortality and its time of day in
intensive care unit patients The relationship between mortality and its time of day in
intensive care unit patients T Adanir, A Sencan, N Atasoy, M Aksun, N Karahan
Izmir Ataturk Training and Research Hospital, Izmir, Turkey
Critical Care 2007, 11(Suppl 2):P468 (doi: 10.1186/cc5628) T Adanir, A Sencan, N Atasoy, M Aksun, N Karahan
Izmir Ataturk Training and Research Hospital, Izmir, Turkey
Critical Care 2007, 11(Suppl 2):P468 (doi: 10.1186/cc5628) Introduction It has been known that a lot of factors are effective on
mortality in ICU. In terms of ICU organization it has also been
known that staff might be effective on mortality and morbidity. The
aim of our study is to compare the cases in terms of significant
time periods that are followed and lost in the ICU. S186 Available online http://ccforum.com/supplements/11/S2 Comparison of intensive care unit mortality performances:
standardized mortality ratio vs absolute risk reduction Moreover, the nonlinear RBF SVM required only seven data
components to perform this prediction, compared with 10 and 12 Results During the study period, 12,447 patients were admitted to
the three ICUs: 4,334 to the medical ICU, 3,275 to the mixed ICU
and 4,838 to the surgical ICU. The predicted mortality rates were
19.5%, 16.0% and 9.0% and the observed mortality rates 14.8%,
9.7% and 4.3% for the medical, mixed and surgical ICUs,
respectively. The SMR and ARR in mortality for each ICU are
presented in Table 2. S187
p
y
y
presented in Table 2. Conclusions ICU mortality performances assessed by SMR and
ARR give different results. The ARR may be a better metric when
comparing ICUs with a different case mix. Table 1 (abstract P470)
Performance
SMR, 95% CI
ARR, 95% CI
Poor
>1
<0
Average
Includes 1
Includes 0
Good
<1
>0
Table 2 (abstract P470)
ICU
SMR, 95% CI
ARR, 95% CI
Medical
0.76, 0.70–0.82
4.7%, 3.1–6.3
Mixed
0.61, 0.54–0.68
6.3%, 4.7–7.9
Surgical
0.48, 0.41–0. 4.7%, 3.7–5.7
Figure 1 (abstract P471) S187
Figure 1 (abstract P471) S187
Figure 1 (abstract P471) Figure 1 (abstract P471) P471 The performance of
linear and nonlinear support vector machines (SVM) as prediction
models for the tacrolimus blood concentration in liver trans-
plantation patients is compared with linear regression analysis. P470 P470 Comparison of intensive care unit mortality performances:
standardized mortality ratio vs absolute risk reduction
B Afessa, M Keegan, J Naessens, O Gajic
Mayo Clinic College of Medicine, Rochester, MN, USA
Critical Care 2007, 11(Suppl 2):P470 (doi: 10.1186/cc5630) Figure 1 (abstract P471) We
wished to examine the effect of BSD on the endothelin (ET) axis. Methods Following ethics approval, 14 Wistar–Kyoto rats were
anaesthetised, with tracheostomy and arterial and venous
cannulation. A 200 µl Fogarty’s balloon catheter was inserted via a
burr hole into the subdural vault. The balloon was inflated in the
experimental group but not the control group. Four hours of
positive pressure ventilation were followed by euthanasia and
organ retrieval. Lung tissue was stained for H&E for morphology,
and alveolar macrophages (AM) were identified by anti-CD68
staining. AM were stained with a monoclonal anti-ET-1 antibody, as
well as the polyclonal anti-ET-A and ET-B. Results All animals survived the experiment. There was a
significant increase in the ratio of AM to neutrophils (P = 0.002). The ET-1 content on the AM was significantly increased in the
experimental group (27.57 ± 5.26 vs 7.01 ± 1.75, P < 0.0001). Conclusions In this model, BSD was associated with an increase
in the ratio of AM to neutrophils, and there was significant
upregulation of the endothelin axis on these AM, as evidenced by
raised levels of ET-1, ET-A and ET-B. There may be a role for
endothelin blockade in the BSD organ donor. This may increase
the yield of organs that can be accepted for transplantation and
improve early graft function in the recipient. of poor postoperative outcome in lung transplantation and may
cause primary graft dysfunction (PGD). A number of processes are
thought to contribute to PGD. Relatively little is understood of the
role of brain stem death (BSD) in subsequent organ dysfunction. We
wished to examine the effect of BSD on the endothelin (ET) axis. components needed, respectively, by multiple linear regression
and linear SVM. Conclusion Performance of SVM with linear and nonlinear kernel
function was excellent and superior in comparison with the multiple
linear regression model in predicting the tacrolimus blood
concentration. Methods Following ethics approval, 14 Wistar–Kyoto rats were
anaesthetised, with tracheostomy and arterial and venous
cannulation. A 200 µl Fogarty’s balloon catheter was inserted via a
burr hole into the subdural vault. The balloon was inflated in the
experimental group but not the control group. Four hours of
positive pressure ventilation were followed by euthanasia and
organ retrieval. Lung tissue was stained for H&E for morphology,
and alveolar macrophages (AM) were identified by anti-CD68
staining. Figure 1 (abstract P471) AM were stained with a monoclonal anti-ET-1 antibody, as
well as the polyclonal anti-ET-A and ET-B. P474 Prognosis factors in lung transplant recipients readmitted
to the intensive care unit
B Suberviola, A Gonzalez Castro, J Llorca, A Vallejo,
C Gonzalez Mansilla, E Miñambres
Hospital Universitario Marques de Valdecilla, Santander, Spain
Critical Care 2007, 11(Suppl 2):P474 (doi: 10.1186/cc5634) B Suberviola, A Gonzalez Castro, J Llorca, A Vallejo,
C Gonzalez Mansilla, E Miñambres
Hospital Universitario Marques de Valdecilla, Santander, Spain
Critical Care 2007, 11(Suppl 2):P474 (doi: 10.1186/cc5634) Introduction The short-term survival after lung transplantation has
improved gradually. Despite this the peritransplant period is of high
risk. Factors influencing the readmission of lung transplant
recipients to the ICU are diverse, but respiratory failure and sepsis
are the predominant causes. The objective of our study was to
identify outcome predictors and prognostic factors for survival Results Eighty-seven per cent (n = 69) of kidneys transplanted
from optimal donors, in fact, have turned out working, 4% (n = 3)
have re-entered haemodialysis within 5 years from the surgery, and
only 9% (n = 7) have deceased in the same period. Regarding
marginal kidney receiving, it has been possible to demonstrate that
72% (n = 52) of such subjects maintained a good function of the
transplant, 11% (n = 8) re-entered haemodialysis, and 17%
passed away within 5 years of the transplant. among lung transplant recipients on readmission to the ICU. Materials
and
methods
A retrospective study of all lung
transplant recipients achieved during a 10-year period (from 1997
to 2006). Data collection included the age, gender, reason for and
type of lung transplantation. Variables specific to individual ICU
admissions included the admission diagnosis, length of stay,
duration of mechanical ventilation, interval time from transplan-
tation, Acute Physiology and Chronic Health Evaluation (APACHE)
II score on ICU admission, and the identification of systemic organ
dysfunction. We used Student’s t test (or, where appropriate, its
nonparametric equivalent) or the χ2 test for comparisons among
the patients who died and the patients who survived their ICU
admissions. Conclusions The difference between the survival of the two
receiving groups is not such to justify the exclusion of marginal
donors from the ‘pool’ of potential kidney donors. Considering that,
the use of marginal donors can be a valid system in order to supply
the lack of organs. Moreover the histological examinations,
executed on patterns captured with wedge biopsy before the
transplant, can be an effective strategy finalized for the expansion
of potential kidney donors. P472 Effects of the clinical characteristics of the organ donor on
the long-term results of the transplant and survival of the
patient, with particular reference to kidney transplants
S Pirri, R Mastrandrea, A Barcia, A Mazzola, S Salemi
University of Palermo, Italy
Critical Care 2007, 11(Suppl 2):P472 (doi: 10.1186/cc5632) Results All animals survived the experiment. There was a
significant increase in the ratio of AM to neutrophils (P = 0.002). The ET-1 content on the AM was significantly increased in the
experimental group (27.57 ± 5.26 vs 7.01 ± 1.75, P < 0.0001). Introduction To assess the role of the single clinical parameters of
the donor on the outcome of the transplant and the variability of
this in relation to the state of an optimal or borderline donor. Methods One hundred and fifty-one receiving and deceased
donor brace subordinates to kidney transplant. Clinical parameters
investigated for every donor were: age, arterial hypertension
(≥140/80 mmHg), diabetes, blood values of creatinine. It was
chosen to classify as marginal all the donors with age >55 years,
and/or hypertension, and/or diabetes, and/or with blood values of
creatinine >1.5 mg/dl, and/or whose death has happened because
of one whichever pathology that has determined cerebral anoxia. Based on such parameters the donors’ borderline was 72/151
(47.7%), while the optimal was 79/151 (52.3%). The mean age of
the donors was 47.5 years (range 14–81 years). The population of
the 151 receiving optimal and marginal kidneys was constituted of
patients judged suitable for the transplant with typical risk factors
for a standard population of subjects on dialysis. The mean age of
receiving patients was 46 years (range 21–71 years). We have
classified receiving based on the outcome of the transplant to
5 years, as: patients alive with transplanted kidney still working,
deceased patients, and patients re-entered to haemodialysis. Conclusions In this model, BSD was associated with an increase
in the ratio of AM to neutrophils, and there was significant
upregulation of the endothelin axis on these AM, as evidenced by
raised levels of ET-1, ET-A and ET-B. There may be a role for
endothelin blockade in the BSD organ donor. This may increase
the yield of organs that can be accepted for transplantation and
improve early graft function in the recipient. Figure 1 (abstract P471) Conclusions ICU mortality performances assessed by SMR and
ARR give different results. The ARR may be a better metric when
comparing ICUs with a different case mix. Table 1 (abstract P470)
Performance
SMR, 95% CI
ARR, 95% CI
Poor
>1
<0
Average
Includes 1
Includes 0
Good
<1
>0
Table 2 (abstract P470)
ICU
SMR, 95% CI
ARR, 95% CI
Medical
0.76, 0.70–0.82
4.7%, 3.1–6.3
Mixed
0.61, 0.54–0.68
6.3%, 4.7–7.9
Surgical
0.48, 0.41–0. 4.7%, 3.7–5.7 S187 Critical Care March 2007 Vol 11 Suppl 2
27th International Symposium on Intensive Care and Emergency Medicin of poor postoperative outcome in lung transplantation and may
cause primary graft dysfunction (PGD). A number of processes are
thought to contribute to PGD. Relatively little is understood of the
role of brain stem death (BSD) in subsequent organ dysfunction. We
wished to examine the effect of BSD on the endothelin (ET) axis. Methods Following ethics approval, 14 Wistar–Kyoto rats were
anaesthetised, with tracheostomy and arterial and venous
cannulation. A 200 µl Fogarty’s balloon catheter was inserted via a
burr hole into the subdural vault. The balloon was inflated in the
experimental group but not the control group. Four hours of
positive pressure ventilation were followed by euthanasia and
organ retrieval. Lung tissue was stained for H&E for morphology,
and alveolar macrophages (AM) were identified by anti-CD68
staining. AM were stained with a monoclonal anti-ET-1 antibody, as
well as the polyclonal anti-ET-A and ET-B. Results All animals survived the experiment. There was a
significant increase in the ratio of AM to neutrophils (P = 0.002). The ET-1 content on the AM was significantly increased in the
experimental group (27.57 ± 5.26 vs 7.01 ± 1.75, P < 0.0001). Conclusions In this model, BSD was associated with an increase
in the ratio of AM to neutrophils, and there was significant
upregulation of the endothelin axis on these AM, as evidenced by
raised levels of ET-1, ET-A and ET-B. There may be a role for
endothelin blockade in the BSD organ donor. This may increase
the yield of organs that can be accepted for transplantation and
improve early graft function in the recipient. of poor postoperative outcome in lung transplantation and may
cause primary graft dysfunction (PGD). A number of processes are
thought to contribute to PGD. Relatively little is understood of the
role of brain stem death (BSD) in subsequent organ dysfunction. P475 Predictors of intensive care unit readmission within 48
hours after discharge
E Boudesteijn, S Arbous, P Berg van den
LUMC, Leiden, The Netherlands
Critical Care 2007, 11(Suppl 2):P475 (doi: 10.1186/cc5635) Methods From February 1996 until May 2006 we studied all LT
patients from a single centre initially discharged from the ICU who
needed to be readmitted. Demographic data included the type and
date of LT, best post-LT FEV1, last pre-ICU readmission FEV1,
admission diagnosis, time from LT to ICU admission, mechanical
ventilation (MV) use, rejection episodes and infections. Actuarial
survival rates (ASR) were calculated with Kaplan–Meier curves. Introduction Readmission to the ICU during the same
hospitalization is associated with significant morbidity and mortality
and results in a longer length of stay and higher costs. There is
therefore growing interest to identify reliable predictors for
readmission. The aim of our study was to assess the incidence of
ICU readmissions, identify predictors of ICU readmission, and
determine patient outcome. Results A total of 103 LT patients were discharged from the ICU,
41 patients (39.8%) were readmitted (males 53.6% (22 patients)
with a mean age of 42 years (15–66)). Indications were emphy-
sema in 13 patients (31.7%), idiopathic pulmonary fibrosis in eight
patients (19.5%), bronchiectasis in five patients (12.2%), cystic
fibrosis in five patients and others in seven patients (17%). Seventeen patients underwent bilateral LT, 11 patients right LT
(26.8%) and eight patients left LT (19.5%), while five patients
received a heart–lung transplantation. Respiratory failure was the
principal ICU admission diagnosis (68.3%), followed by seizures
(7%) and septic shock (4.8%). MV was required in 35 patients
(85.3%). ICU mortality for readmitted patients was 68.3% with a
1-year, 3-year and 5-year ASR of 67.3%, 62.9% and 47.4%. The
survival median was 1,761 days (1,134–2,388). In the MV
patients, a 1-year, 3-year and 5-year ASR of 63.1%, 58.9% and
44.2% was found with a median survival of 1,618 days
(132–3,104). The time to ICU admission was 1,303 (4–3,096
days). ICU admission timing was not found to be a predictor for
early (<30 days; 53.8%) vs late (>30 days: 46.4%), P = 0.65. Deceased patients required significantly more MV (71.4% vs
38.5%; P = 0.044 (chi-square); OR: 4; 95% CI: 1–15.99). Emphysema was not more prevalent in the deceased patient
group, and neither was the pre-ICU readmission FEV1 nor the
occurrence of opportunistic infections. Steroid-resistant acute
rejection was found to correlate with mortality. P475 Methods We performed a retrospective case–control study. The
study population consisted of all patients who were discharged
alive from our 28-bed surgical, thoracic–surgical and medical ICU
in a university teaching hospital in a 1-year period. A case was
defined as a patient readmitted to the ICU within 48 hours after
discharge. For each case, three control patients were randomly
selected from the study population. The following information was
collected: demographic parameters and APACHE II score,
parameters of hemodynamic, respiratory and renal function, length
of ICU stay, duration of invasive ventilatory support (ventilator time),
and time between extubation and discharge. To determine a
predictive model, covariate selection was done by the two-sample
t test, Mann–Whitney test and univariate logistic regression. From
significant (P < 0.10), plausible and clinically relevant variables, a
predictive model was generated using multivariate logistic
regression. Results During a 1-year period 1,635 patients were admitted to our
ICU. Of 1,393 patients at risk for readmission, 25 (1.8%)
readmissions occurred in 23 patients. Nine of the 23 (39%)
readmitted patients died during their hospitalization, while the
overall ICU mortality was 10.6%. The most important reason for
readmission (68% of the cases) was respiratory deterioration. In the
univariate analysis, age, ventilator time during first admission and
time between extubation and ICU discharge were significant
predictors of readmission. In the multivariate analysis, age (OR 1.1;
95% CI 1.00–1.13; P = 0.03) and ventilator time during first
admission (OR 1.1; 95% CI 1.00–1.10; P = 0.03) were significant
predictors, corrected for patient characteristics. Furthermore,
patients who were readmitted had a significant longer duration of
total (first and second admission) ventilator time (188 vs 106 hours,
P = 0.012), and total ICU stay (400 vs 127 hours, P = 0.009). Conclusion Patients readmitted to the ICU have significant longer
overall ventilator time, ICU stay, and a higher ICU mortality. The
ventilator time during first admission (especially beyond 300 hours)
is an important predictor of readmission. The time it takes to get
patients ready for discharge after extubation also differed
significantly. The data suggest that elderly patients who have been
ventilated for a long period are at particular risk for readmission
and should receive additional care before discharge from the ICU. Results During a 1-year period 1,635 patients were admitted to our
ICU. Of 1,393 patients at risk for readmission, 25 (1.8%)
readmissions occurred in 23 patients. Intensive care unit readmissions after lung transplantation:
epidemiology and outcome Intensive care unit readmissions after lung transplantation:
epidemiology and outcome Conclusions Admission to the ICU is common in lung transplant
recipients, and it is associated with a high mortality. Sepsis is the
main cause of ICU readmission and the most frequent cause of
death. Lung transplant recipients with higher APACHE II score and
three or more organ dysfunction present higher mortality. The delay
on ICU readmission is also associated with higher mortality. F Klein, P Klin, J Osses, J Díaz, A Bertolotti, R Favaloro
Favaloro Foundation, Buenos Aires, Argentina
Critical Care 2007, 11(Suppl 2):P476 (doi: 10.1186/cc5636) Introduction Significant improvement of short-term and long-term
survival after lung transplantation (LT) has been observed. Never-
theless, a significant number of patients need to be readmitted to
the ICU. The aim of our study was to analyse the epidemiology,
outcome and risk factors for LT patients readmitted to the ICU after
an initial discharge. Upregulation of the endothelin axis in alveolar
macrophages following brain stem death in a murine model Upregulation of the endothelin axis in alveolar
macrophages following brain stem death in a murine model Results A total of 144 lung transplants were performed at our
institution. Forty-six of them died on the ICU during the immediate
perioperative period. Finally, 98 were discharged from the ICU. Twenty-eight patients were readmitted to the ICU after discharge
(28.57%). The mean of age was 51.3 ± 11.6 years. The
male/female ratio was 23/5. The mean period transcurred between
ICU discharge and ICU readmission was 107 ± 162 days. The
admission diagnosis was sepsis in 20 cases (71.4%). Seventeen
patients died during the ICU stay (60.7%). We found that an J Fraser, A Sutherland, F Kermeen, K McNeil, J Dunning
The Prince Charles Hospital, Brisbane, Australia
Critical Care 2007, 11(Suppl 2):P473 (doi: 10.1186/cc5633) Introduction Outcomes post lung transplantation continue to
improve, but early pulmonary dysfunction dictates long-term
morbidity and mortality. Ischaemia reperfusion injury is a precipitant Introduction Outcomes post lung transplantation continue to
improve, but early pulmonary dysfunction dictates long-term
morbidity and mortality. Ischaemia reperfusion injury is a precipitant S188 Available online http://ccforum.com/supplements/11/S2 P476 increase in APACHE II score, delay to ICU readmission, need of
mechanical ventilation and three or more organ dysfunctions were
significantly associated with mortality. P475 Nine of the 23 (39%)
readmitted patients died during their hospitalization, while the
overall ICU mortality was 10.6%. The most important reason for
readmission (68% of the cases) was respiratory deterioration. In the
univariate analysis, age, ventilator time during first admission and
time between extubation and ICU discharge were significant
predictors of readmission. In the multivariate analysis, age (OR 1.1;
95% CI 1.00–1.13; P = 0.03) and ventilator time during first
admission (OR 1.1; 95% CI 1.00–1.10; P = 0.03) were significant
predictors, corrected for patient characteristics. Furthermore,
patients who were readmitted had a significant longer duration of
total (first and second admission) ventilator time (188 vs 106 hours,
P = 0.012), and total ICU stay (400 vs 127 hours, P = 0.009). Conclusion ICU readmissions are frequent among LT patients. In
our study group, respiratory failure was the more prevalent
admission diagnosis. The need for MV was associated with a worse
prognosis as well as steroid-resistant acute rejection episodes. Early or late ICU admission after LT has not influenced mortality. P478 One-year survival of patients admitted to the neurological
intensive care unit
M Puntis, H Robertshaw
St George’s Hospital, London, UK
Critical Care 2007, 11(Suppl 2):P478 (doi: 10.1186/cc5638) One-year survival of patients admitted to the neurological
intensive care unit
M Puntis, H Robertshaw
St George’s Hospital, London, UK
Critical Care 2007, 11(Suppl 2):P478 (doi: 10.1186/cc5638) One-year survival of patients admitted to the neurological
intensive care unit M Puntis, H Robertshaw
St George’s Hospital, London, UK
Critical Care 2007, 11(Suppl 2):P478 (doi: 10.1186/cc5638) p
y
Method Approval for the study was granted by the local ethics
committee. We reviewed MEWS scores from all patients
(n = 2,974) admitted to a six-bed medical and surgical adult HDU
in a general hospital from July 2002 to October 2005. The MEWS
score was calculated from observations of heart rate, blood
pressure, respiratory rate, urine output, conscious level and
temperature recorded within 24 hours of admission to the HDU. Results Of the 2,974 patients reviewed, 2,447 patients had
sufficient data. Analysis using logistic regression shows a strong
relationship between the probability of death and the MEWS
score: the odds of death increase by 1.48 (confidence interval
1.41–1.56; P < 0.001) for each unit increase in the MEWS score. However, there is no reason that these data should follow a logistic
form and the estimates of uncertainty around the point estimates
from logistic regression are poor. More accurate estimates of the
death rate for each of the MEWS scores were achieved using a
‘bootstrapping’ technique (repeated sampling, with replacement,
from the dataset) 1,000 times (see Figure 1). The median death
rate (%) for each MEWS score was: 3 = 1.5%; 4 = 0.7%; 5 =
2.2%; 6 = 3.0%; 7 = 3.0%; 8 = 5.6%; 9 = 9.7%; 10 = 13.3%; 11 = Method Approval for the study was granted by the local ethics
committee. We reviewed MEWS scores from all patients
(n = 2,974) admitted to a six-bed medical and surgical adult HDU
in a general hospital from July 2002 to October 2005. The MEWS
score was calculated from observations of heart rate, blood
pressure, respiratory rate, urine output, conscious level and
temperature recorded within 24 hours of admission to the HDU. Introduction Patient survival in neurological intensive care units
(NICUs) may be obvious; however, there is currently little evidence
regarding the longer term outcome of these patients. Use of a modified early warning system to predict
outcome in patients admitted to a high dependency unit Use of a modified early warning system to predict
outcome in patients admitted to a high dependency unit Conclusion Survival rates among those readmitted are high. Those
returning from the HDU represent a cohort at higher risk of
mortality. The functional status after 2.5 years varies particularly
with the timing of readmission, readmission diagnosis and
APACHE score at readmission. C Carle, C Pritchard, S Northey, J Paddle
Royal Cornwall Hospital, Truro, UK
Critical Care 2007, 11(Suppl 2):P479 (doi: 10.1186/cc5639) C Carle, C Pritchard, S Northey, J Paddle
Royal Cornwall Hospital, Truro, UK C Carle, C Pritchard, S Northey, J Paddle
Royal Cornwall Hospital, Truro, UK
Critical Care 2007, 11(Suppl 2):P479 (doi: 10.1186/cc5639) Introduction The modified early warning system (MEWS) is a
physiological scoring system that identifies patients at risk of
deterioration who require increased levels of care [1]. The use of a
patient’s MEWS score to predict outcome in a high-dependency
unit (HDU) has not been previously described. P478 In this study
the 1-year survival of NICU patients has been defined. Introduction Patient survival in neurological intensive care units
(NICUs) may be obvious; however, there is currently little evidence
regarding the longer term outcome of these patients. In this study
the 1-year survival of NICU patients has been defined. p
Results Of the 2,974 patients reviewed, 2,447 patients had
sufficient data. Analysis using logistic regression shows a strong
relationship between the probability of death and the MEWS
score: the odds of death increase by 1.48 (confidence interval
1.41–1.56; P < 0.001) for each unit increase in the MEWS score. However, there is no reason that these data should follow a logistic
form and the estimates of uncertainty around the point estimates
from logistic regression are poor. More accurate estimates of the
death rate for each of the MEWS scores were achieved using a
‘bootstrapping’ technique (repeated sampling, with replacement,
from the dataset) 1,000 times (see Figure 1). The median death
rate (%) for each MEWS score was: 3 = 1.5%; 4 = 0.7%; 5 =
2.2%; 6 = 3.0%; 7 = 3.0%; 8 = 5.6%; 9 = 9.7%; 10 = 13.3%; 11 = Methods Between April 2004 and April 2005, all patients
admitted to the NICU requiring ≥24 hours of ≥2 organ system
support were identified (n = 175). The year following admission
was divided into three phases – early (0–30 days), middle (31–90
days) and late (91–360 days) – and mortality was recorded. Data
were analysed using Kaplan–Meier and log-rank analysis. Results Patients were admitted from many sources; interhospital
transfers (n = 90), neurosurgical admissions (n = 26), medical
admissions (n = 36), and emergency admissions (n = 15). Reasons
for admission included haemorrhage (n = 66), trauma (n = 52) and
neoplasm (n = 19). Ninety-one patients (52.0%) spent less than
7 days on the NICU and 84 (48%) required ≥7 days. Overall
survival was 70.9% at 30 days and 61.1% at 1 year. There was no
significant variation between the young (<60 years) and older
(≥60 years) groups (62.6%, n = 115 vs 58.3%, n = 60, P > 0.5). Nor was there a difference between those receiving two organ
support and those receiving ≥3 organ support (62.1%, n = 66 vs P477 The functional outcome of patients requiring intensive care
readmission N Conlon, B O’Brien, B Marsh
Mater Misericordiae University Hospital, Dublin, Ireland
Critical Care 2007, 11(Suppl 2):P477 (doi: 10.1186/cc5637) N Conlon, B O’Brien, B Marsh
Mater Misericordiae University Hospital, Dublin, Ireland
Critical Care 2007, 11(Suppl 2):P477 (doi: 10.1186/cc5637) Conclusion Patients readmitted to the ICU have significant longer
overall ventilator time, ICU stay, and a higher ICU mortality. The
ventilator time during first admission (especially beyond 300 hours)
is an important predictor of readmission. The time it takes to get
patients ready for discharge after extubation also differed
significantly. The data suggest that elderly patients who have been
ventilated for a long period are at particular risk for readmission
and should receive additional care before discharge from the ICU. Introduction Rates of readmission to the ICU are often cited as
controversial indices of quality of intensive care, adequacy of
follow-up and as guides to resource allocation. Nonetheless there
are few data on the long-term functional outcome of ICU
recidivists: we set out to study this. S189 ritical Care March 2007 Vol 11 Suppl 2
27th International Symposium on Intensive Care and Emergency Medicin 60.6%, n = 109, P > 0.5). Mortality (deaths/30 days) varied
dramatically between the early, middle and late phases (29.1% vs
3.2% vs 0.9%, P < 0.001). Methods With ethical approval, from a prospectively collected
database of all ICU admissions from 2004, we identified all
readmissions to our ICU from within the hospital. We identified
survivors from the database, and contacted them, 2–3 years later,
to assess their functional outcome, as the Glasgow Outcome
Score (GOS) and Karnofsky score. Conclusions Although mortality is high during the first 30 days of
neurological critical illness there is a significant plateau in the
survival curve; patients surviving beyond the initial phase tend to
survive long term. Larger studies may be beneficial to further
evaluate subgroup variation in the survival curve profile. Results Of 97 readmissions, 79 (81%) survived the ICU. Most of
them (57%) came from the high-dependency unit (HDU), of whom
74% survived. Thirty-three per cent came from other wards and
10% from theatre: 90% of each of these groups survived the ICU. Further data on these groups’ interim survival and functional
outcomes are presented. Changes of the system of postoperative care decreases
mortality in a surgical unit 2), were selected for
comparative analysis. The selection was dictated by a few reasons. The Medical University in Lodz is the founding body of all hospitals
subjected to analysis. These hospitals are only a few kilometres
away from each other. The units have a similar number of beds,
and well-educated medical and nursing staff. Heads of the hospital
departments have all been awarded a professorship. Health
benefits are provided on the basis of the same list of benefits as
part of contract with the same payer – Lodz Provincial Branch of
the National Health Fund. Methods A prospective descriptive analysis of OCC in four SDUs
(18 beds) with an open model of care in a tertiary regional referral
centre. We administered a modified version of the previously
validated Shortell ICU nurse–physician questionnaire to all
healthcare professionals (HCPs) and physicians caring for patients
in the SDUs in May 2006. We measured opinion regarding patient
safety culture, organizational practices, perceived effectiveness of
practice, and job satisfaction. Responses were converted to item
scores, which reflect negative to positive opinion (0–100). Scores
were aggregated for each survey construct and for an overall SDU
rating. Results Surveys were completed by 68 HCPs and 69 physicians. Aggregated mean ± standard deviation item scores of HCP and
physician opinions were (presented as assessment area, HCPs,
physicians, P value): overall OCC in SDUs, 54.8 ± 19.9, 57.0 ± 20.3,
P = 0.52; patient safety culture, 52.2 ± 21.2, 50.9 ± 21.0, P = 0.72;
within-group relationships, 66.5 ± 16.0, 63.7 ± 18.2, P = 0.33;
between-group relationships, 53.8 ± 22.2, 62.4 ± 21.7, P = 0.02;
overall leadership, 52.2 ± 19.6, 54.8 ± 18.7, P = 0.42; conflict
management, 55.2 ± 20.1, 61.3 ± 20.1, P = 0.08; effectiveness of
care, 54.7 ± 16.8, 55.8 ± 19.3, P = 0.72; and job satisfaction,
67.5 ± 19.0, 77.9 ± 20.3, P = 0.002. The overall OCC score and
most subcategory scores were similar between HCPs and
physicians. Physicians had a better opinion of their relationships
with other groups and a higher job satisfaction than HCPs. Methods The study is a retrospective analysis of mortality in
general surgery units located at three university teaching hospitals:
UH No. 1, UH No. 2 and UH No. 5. The study comprised 25,921
patients treated in these units from 1 January 2003 to 30 June
2006. The available statistical material was analysed. P480 Introduction The purpose of this study was to examine
organizational culture and climate (OCC) in step-down units
(SDUs). Organizational culture is defined as the norms, values,
beliefs and expectations shared by those who work in a given unit. Organizational climate is the perception of unit culture by its
workers. In ICUs, organizational culture is an important determinant
of the quality of care delivered. In an attempt to alleviate ICU
demand and expenditures, many centers have opted to provide
graded levels of critical care with the creation of SDUs. There is a
paucity of literature specifically examining OCC in SDUs. Figure 1 (abstract P479) Distribution of bootstrapped estimates of death rates by MEWS score
(median, interquartile and observed range). 0
Figure 1 (abstract P478)
Distribution of bootstrapped estimates of death rates by MEWS score
(median, interquartile and observed range). Figure 1 (abstract P478) Distribution of bootstrapped estimates of death rates by MEWS score
(median, interquartile and observed range). S190 Available online http://ccforum.com/supplements/11/S2 Changes of the system of postoperative care decreases
mortality in a surgical unit M Piechota1, M Banach2
1Bolesùaw Szarecki University Hospital No. 5 in Lodz, Poland;
2University Hospital No. 3 in Lodz, Poland
Critical Care 2007, 11(Suppl 2):P480 (doi: 10.1186/cc5640) Introduction In 2005, 10 public health care institutions functioned
in the area of Lodz, having in their structure a surgical unit
classified as a general surgery unit. They were three university
teaching hospitals, three provincial hospitals, three county
hospitals and one departmental hospital. Mortality in university
teaching hospitals having 167 beds was 1.25%, in provincial
hospitals with 191 beds was 2.96%, and in county hospitals with
140 beds was 3.98%. The lowest percentage mortality was noted
in the surgical unit of Bolesùaw Szarecki University Teaching
Hospital No. 5 in Lodz (UH No. 5) and it was 0.35%. The authors
decided to analyse the causes of such low mortality in this hospital. Two remaining university teaching hospitals, N. Barlicki University
Teaching Hospital No. 1 in Lodz (UH No. 1) and WAM University
Teaching Hospital No. 2 in Lodz (UH No. 2), were selected for
comparative analysis. The selection was dictated by a few reasons. The Medical University in Lodz is the founding body of all hospitals
subjected to analysis. These hospitals are only a few kilometres
away from each other. The units have a similar number of beds,
and well-educated medical and nursing staff. Heads of the hospital
departments have all been awarded a professorship. Health
benefits are provided on the basis of the same list of benefits as
part of contract with the same payer – Lodz Provincial Branch of
the National Health Fund. Introduction In 2005, 10 public health care institutions functioned
in the area of Lodz, having in their structure a surgical unit
classified as a general surgery unit. They were three university
teaching hospitals, three provincial hospitals, three county
hospitals and one departmental hospital. Mortality in university
teaching hospitals having 167 beds was 1.25%, in provincial
hospitals with 191 beds was 2.96%, and in county hospitals with
140 beds was 3.98%. The lowest percentage mortality was noted
in the surgical unit of Bolesùaw Szarecki University Teaching
Hospital No. 5 in Lodz (UH No. 5) and it was 0.35%. The authors
decided to analyse the causes of such low mortality in this hospital. Two remaining university teaching hospitals, N. Barlicki University
Teaching Hospital No. 1 in Lodz (UH No. 1) and WAM University
Teaching Hospital No. 2 in Lodz (UH No. Organizational culture and climate in step-down units C McColl, J Muscedere, J Drover, M Squires, B Mahon,
D Heyland
Queen’s University, Kingston, Canada
Critical Care 2007, 11(Suppl 2):P481 (doi: 10.1186/cc5641) Conclusion The MEWS score can be used as a useful predictor of
outcome in a HDU. Changes of the system of postoperative care decreases
mortality in a surgical unit In the first
stage the statistical data were analysed by the Provincial Centre of
Public Health in Lodz. The obtained information concerned the
number of treated patients, the number of patients transferred,
discharged or dead, the number of man-days, mean bed use, mean
hospitalisation time, mean number of patients per bed and
mortality. The second stage focused on explaining the reasons for
significantly lower mortality among patients hospitalised in the
surgical unit of UH No. 5. Among others, the structure of the
hospitalised patients in each of these units was analysed, the
quantity and range of a contract signed with the unit financing the
benefits and internal principles of these units functioning. Conclusions Overall scores of OCC were poor and did not differ
between HCPs and physicians with the exception of between-
group relationships and job satisfaction. More research is needed
to determine the correlation between clinical outcomes and OCC
in SDUs and whether improvements in OCC result in better clinical
outcomes and job satisfaction. P481 15.9%; 12 = 20.9%; 13 = 32.0%; 14 = 47.2%; 15 = 51.9%; 16 =
54.6%; 17 = 66.7%. MEWS scores of 2 or less (n = 19) had no
deaths. Organizational culture and climate in step-down units Patient and family satisfaction with care in step-down units Service
consequences were bed blocking/increased workload in 20%,
delayed admission of another patient in 14%, cancelled elective
operations in 4%, and loss of unit capacity and cohesion in 7%. Conclusions We failed to achieve 100% successful plans. Small
numbers and failure to gather more than 40% of staff opinions on
causes and consequences of failed plans limit this pilot study. Documentation in (electronic) notes did not improve completion of
plans. The process and efficiency of care has an impact on at least
aspects of morbidity and length of stay, and deserve further study. patient-centered and family-centered quality care. Literature
examining patient or family satisfaction in SDUs is limited. patient-centered and family-centered quality care. Literature
examining patient or family satisfaction in SDUs is limited. Methods We administered a modified version of the previously
validated Family Satisfaction with ICU care survey to patients and
families of patients who were cared for in the SDUs (18 beds in
four separate units) of a tertiary regional referral center. We
obtained self-reported levels of patient and family satisfaction with
27 aspects of care related to SDU experience, communication,
and decision-making. Responses were converted to item scores,
which reflect poor to excellent satisfaction with care (0–100). Methods We administered a modified version of the previously
validated Family Satisfaction with ICU care survey to patients and
families of patients who were cared for in the SDUs (18 beds in
four separate units) of a tertiary regional referral center. We
obtained self-reported levels of patient and family satisfaction with
27 aspects of care related to SDU experience, communication,
and decision-making. Responses were converted to item scores,
which reflect poor to excellent satisfaction with care (0–100). p
Results A total of 120 patient surveys (60% response) and 99
family surveys (45% response) were completed. Patients had a
mean SDU length of stay of 2.5 days, APACHE II score of 9.9 and
an SDU mortality of 2.4%. The highest levels of satisfaction with
care were (mean ± standard deviation item score; presented as
aspect of care, patients, families, P value): overall care (aggregate
score), 81.1 ± 21.5, 80.1 ± 22.3, NS; concern and caring
received from SDU staff, 87.9 ± 17.1, 90.4 ± 5.0, NS; and nurses’
skill and competence, 88.7 ± 16.0, 88.8 ± 16.6, NS. Patient and family satisfaction with care in step-down units Patient and family satisfaction with care in step-down units Patient and family satisfaction with care in step-down units C McColl, J Muscedere, J Drover, M Squires, B Mahon, D Heyland
Queen’s University, Kingston, Canada
Critical Care 2007, 11(Suppl 2):P482 (doi: 10.1186/cc5642) Results Mortality in the general surgery unit of UH No. 5 was
0.40% within the period from 1 January 2003 to 30 June 2006. In
the general surgery unit of UH No. 1 and of UH No. 2, mortality
was respectively 2.70% and 2.13%. Introduction The purpose of this study was to determine the level
of satisfaction of patients and families with the care received in
step-down units (SDUs). In an effort to alleviate ICU demand, many
centers have opted to provide graded levels of critical care in
SDUs. However, there is a paucity of literature as to the
effectiveness of care delivered in SDUs. Measures of patient and
family satisfaction with healthcare are recognized as valuable tools
for the assessment of healthcare delivery including adherence to Conclusions Changes of the system of postoperative care
consisting of taking over postoperative care by physicians and
anaesthesiological nurses, intensive monitoring of postoperative
patients, and immediate transfer of patients with life hazard to the
ICU decreases significantly the mortality in a surgical unit. S191 Critical Care March 2007 Vol 11 Suppl 2
27th International Symposium on Intensive Care and Emergency Medicin unsuccessful plans, 36 were completed late, 22 were never
completed and nine had missing data. Thirty-six per cent, 34% and
18% of arbitrarily defined high-priority, medium-priority and low-
priority plans were unsuccessful. Most plans were to be actioned
by nurse or senior house officer, and 36% and 28% were unsuc-
cessful, respectively. More unsuccessful plans than successful
plans were recorded in the computerised notes, 79% vs 67%. Only 40% of data (staff opinions) on perceptions of causes and
consequences were gathered. Patient consequences of failed
plans included increased ICU stay in 24%, increased morbidity
such as risk of inadequate nutrition in 9%, delayed definitive treat-
ment in 7%, delayed weaning in 6%, increased risk of infection in
5% and no impact on patient in 44%. Consequences for family
included no impact in 53%, misinformation given in 8%, delayed
patient access in 2%, and delayed communication in 2%. P483 Abstract withdrawn Patient and family satisfaction with care in step-down units The lowest
levels of satisfaction were: frequency of communication with
physicians, 71.6 ± 27.8, 62.7 ± 32.2, P = 0.03 and decision-
making (aggregate score), 67.5 ± 29.9, 62.7 ± 30.5, NS. For the
decision-making process, a proportion of respondents felt they
were not included (patients, families, P value; 40.3%, 42.7%, NS),
not supported (31%, 38.6%, NS), and not in control (32.7%,
55.3%, P = 0.001). Patients and families were least satisfied with
the frequency of communication with physicians and participation
in decision-making. Patients and families were similar in their
assessments with the exception of the frequency of communication
with physicians and control of the care delivered. Outcome of very old patients on mechanical ventilation Outcome of very old patients on mechanical ventilation
R Espinoza, R Serafim, F Gago, F Saddy, B Tura, J Castro
Hospital Copa D’Or, Rio de Janeiro, Brazil
Critical Care 2007, 11(Suppl 2):P485 (doi: 10.1186/cc5645) R Espinoza, R Serafim, F Gago, F Saddy, B Tura, J Castro
Hospital Copa D’Or, Rio de Janeiro, Brazil
Critical Care 2007, 11(Suppl 2):P485 (doi: 10.1186/cc5645) Conclusions While most patients and family members were
satisfied with care received, these data identify opportunities for
improvement. Specifically,
attention
must
be
paid
to
communication and decision-making processes in SDUs. Background The population group of 85 years old or more,
classified as very old, are the most rapidly growing group in
developed countries, although it still represents 0.46% of the
Brazilian population. Aging is associated with decreased
cardiopulmonary and renal reserve as well as the development of
progressive organ failure. P484 Objective To evaluate outcomes of very old patients in mechanical
ventilation. Causes and consequences of failure of implementation of
management plans in critical care Causes and consequences of failure of implementation of
management plans in critical care Patients and methods A prospective cohort study in the
medical/surgical ICU of a tertiary-care Brazilian hospital. Two
hundred and forty-four patients aged 85 years old or more were
selected from 7,410 patients admitted to the ICU from October
2002 to September 2006. Data were extracted from the QUATI
(Dixtal-Brazil) database and included sex, age, APACHE II score,
ventilation-days, length of stay, incidence of sepsis, tracheotomy,
dialysis therapy and hemodynamic monitoring. For statistical
analysis we used the chi-square test for evaluated difference of
proportion, and considered statistical significance as P < 0.05. Results There were 168 female (68.9%) and 75 male (30.7%)
patients. The mean age of the study population and the APACHE II
score were 89.55 ± 3.61 years and 17.98 ± 6.3, respectively. Median ventilation-days and length of stay were 6 and 8.14 days,
respectively. Tracheotomy was performed in 44.1%, dialysis
therapy in 15.2% and hemodynamic monitoring in 19.8%. Only the
group above 95 years old had a significant increase of days of
ventilation and length of stay: 18.77 vs 10.47 days (P = 0.01) and
19.74 vs 12.86 days (P = 0.07), respectively. The predicted
APACHE
II
mortality
for
the
studied
population
was
26.9 ± 17.21% and the present rate to the population studied was
47.7%. Patients in dialysis and with diagnosis of sepsis at
admission had poorer prognosis (respectively a 1.6 and 1.52 times
likely ratio to die). Patients and methods A prospective cohort study in the
medical/surgical ICU of a tertiary-care Brazilian hospital. Two
hundred and forty-four patients aged 85 years old or more were
selected from 7,410 patients admitted to the ICU from October
2002 to September 2006. Data were extracted from the QUATI
(Dixtal-Brazil) database and included sex, age, APACHE II score,
ventilation-days, length of stay, incidence of sepsis, tracheotomy,
dialysis therapy and hemodynamic monitoring. For statistical
analysis we used the chi-square test for evaluated difference of
proportion, and considered statistical significance as P < 0.05. M El Toukhy, P McQuillan
Portsmouth Hospital NHS Trust, Portsmouth, UK
Critical Care 2007, 11(Suppl 2):P484 (doi: 10.1186/cc5644) Introduction We investigated patient management plans to
ascertain the total number made, types of plan, priority, personnel
responsible and expected time frame, proportion completed and
the causes and consequences of failed plans (on the patient, the
family and the critical care service). p
p
g
Results There were 168 female (68.9%) and 75 male (30.7%)
patients. P485 Outcome of very old patients on mechanical ventilation P486 Data on resource use of diagnostics, drugs, fluids, materials,
admission and discharge were acquired from the computerized
Patient Data Management System in both hospitals. Hotel and
nutrition costs were collected from the respective financial
departments. These costs were divided by the annual number of
patient-days to calculate the cost per day. The NEMS or TISS
scores in the academic or general hospital, respectively, were used
to estimate nursing time per patient per day. The costs of medical
specialists were based on the labour costs and the number of ICU
days per year. In the academic hospital, time for consultations of
medical staff attributable to each individual patient-day was
prospectively collected using patient record forms. These costs we
assumed to be comparable in the general hospital in the absence
of detailed data. Outcome of octogenarians versus nonoctogenarians
admitted to the intensive care unit with return of
spontaneous circulation after out-of-hospital cardiac arrest
I van Stijn, R Bosman, H Oudemans-van Straaten,
P van der Voort, J Wester, D Zandstra, J van der Spoel
OLVG, Amsterdam, The Netherlands
Critical Care 2007, 11(Suppl 2):P486 (doi: 10.1186/cc5646) Outcome of octogenarians versus nonoctogenarians
admitted to the intensive care unit with return of
spontaneous circulation after out-of-hospital cardiac arrest I van Stijn, R Bosman, H Oudemans-van Straaten,
P van der Voort, J Wester, D Zandstra, J van der Spoel
OLVG, Amsterdam, The Netherlands
Critical Care 2007, 11(Suppl 2):P486 (doi: 10.1186/cc5646) Introduction The aim of this study was to evaluate the outcome of
octogenarians (O, age >79 years) versus nonoctogenarians (NO,
age <80 years) in relation to predicted outcome (APACHE II
predicted mortality, AIIPM) and length of stay in the ICU in days
(LOS) after out-of-hospital cardiac arrest (OHCA). Methods From 1 January 1997 to 1 December 2006, the AIIPM,
LOS and hospital mortality were prospectively recorded and the
standardised mortality ratio (SMR) was calculated. Patients were
categorised in cohorts of AIIPM. Unit costs of diagnostics and consumables were derived from the
financial hospital databases. Labour costs were based on
standardised costs per minute, which equalled the normative
income divided by the number of workable minutes per year. Estimates of the costs of inpatient-days and nonpatient-related
care were based on the annual account for 2005 of the hospitals. Nonpatient-related care (capital, overhead) was appointed to
patients using a marginal mark-up percentage. Available online http://ccforum.com/supplements/11/S2 Available online http://ccforum.com/supplements/11/S2 Conclusion The percentage of older patients admitted to the ICU
is increasing. The need for tracheotomy and dialysis as well as the
length of stay are increasing with this population. APACHE scores
do not seem to present a good relationship with mortality in this
population. Dialysis and sepsis were associated with a significant
increase in mortality. 200 consecutive patients admitted to a 32-bed mixed adult ICU at
an academic hospital during two periods in 2006: 16 April–15
May and 5 June–23 June. For comparison, we collected detailed
data at a general hospital that has a 10 bed-adult general ICU for
the period 1 January–1 July 2003. The costs were adjusted to
2005 using the general price index. Both times, we applied a
micro-costing approach, implying that all relevant resources were
identified and valued at a detailed level. P486 Results Hospital mortality in the NO group was 58.9%, and in the
O group was 75.4% (P = 0.001, chi-square). The LOS ICU was
similar in both groups (Table 1; PM, predicted mortality). Conclusion In octogenarians admitted in the ICU after OHCA,
hospital mortality is higher than in the younger group but still an
important proportion survives. Non-octogenarians survived more
often than predicted by APACHE II. Despite the higher mortality,
ICU treatment after out of hospital resuscitation of octogenarians
seems worthwhile. Results In the academic hospital the average total costs per ICU
day amounted to €1,775, compared with €1,703 in the general
hospital. The distribution of the costs by cost component varied. Results In the academic hospital the average total costs per ICU
day amounted to €1,775, compared with €1,703 in the general
hospital. The distribution of the costs by cost component varied. Conclusions The overall costs per day for IC in an academic
hospital were slightly higher than the costs for an ICU day in a
general hospital. These derived costs fit nicely to the official
reference costs of €1,730 for an ICU day in The Netherlands,
which is based on a global top-down approach. Conclusions The overall costs per day for IC in an academic
hospital were slightly higher than the costs for an ICU day in a
general hospital. These derived costs fit nicely to the official
reference costs of €1,730 for an ICU day in The Netherlands,
which is based on a global top-down approach. P488 L Hakkaart1, S Tan1, C Bouwmans1, M Al1, P Spronk2, J Bakker3
1Institute for Medical Technology Assessment, Rotterdam, The
Netherlands; 2Gelre Hospital, Apeldoorn, The Netherlands;
3Erasmus MC, Rotterdam, The Netherlands
Critical Care 2007, 11(Suppl 2):P487 (doi: 10.1186/cc5647) Does the Glasgow Coma Scale correctly diagnose the
vegetative and minimally conscious states? Does the Glasgow Coma Scale correctly diagnose the
vegetative and minimally conscious states? Does the Glasgow Coma Scale correctly diagnose the
vegetative and minimally conscious states? C Schnakers1, J Giacino2, K Kalmar2, S Piret1, E Lopez2,
M Boly1, R Malone2, S Laureys1
1University of Liege, Belgium; 2JFK Medical Center, Edison, NJ,
USA
Critical Care 2007, 11(Suppl 2):P488 (doi: 10.1186/cc5648) C Schnakers1, J Giacino2, K Kalmar2, S Piret1, E Lopez2,
M Boly1, R Malone2, S Laureys1
1University of Liege, Belgium; 2JFK Medical Center, Edison, NJ,
USA
Critical Care 2007, 11(Suppl 2):P488 (doi: 10.1186/cc5648) Introduction For most countries, there are no good estimates for
the costs of intensive care (IC) although it is known that the ICU is
a major inpatient cost driver. The aim of this study was to estimate
the real costs of IC in two hospitals in The Netherlands using a
micro-costing methodology. al Care 2007, 11(Suppl 2):P488 (doi: 10.1186/cc5648) Introduction Progress in intensive care has led to an increase in
the number of patients who survive severe brain injury and,
therefore, the number of patients with impaired consciousness. Methods The costing study was undertaken at two hospitals in
The Netherlands. We conducted a retrospective cost analysis of Table 1 (abstract P486)
NO
O
AIIPM
n
PM (SD)
SMR
LOS (days)
n
PM (SD)
SMR
LOS (days)
0–0.2
29
0.12 (0.07)
1.72
2.1
1
0.17
5.9
0
0.2–0.4
36
0.29 (0.05)
0.96
3.0
8
0.29 (0.07)
2.6
0.25
0.4–0.6
83
0.52 (0.06)
0.93
2.9
19
0.49 (0.06)
1.18
5.6
0.6–0.8
131
0.72 (0.06)
0.88
3.9
43
0.74 (0.06)
0.85
4.1
0.8–1.0
210
0.89 (0.05)
0.81
3.7
71
0.88 (0.05)
0.99
3.0
Total
489
0.69 (0.23)
0.85
3.5 (4.4)
142
0.75 (0.18)
1.0
3.4 (4.4) Table 1 (abstract P486) Causes and consequences of failure of implementation of
management plans in critical care The mean age of the study population and the APACHE II
score were 89.55 ± 3.61 years and 17.98 ± 6.3, respectively. Median ventilation-days and length of stay were 6 and 8.14 days,
respectively. Tracheotomy was performed in 44.1%, dialysis
therapy in 15.2% and hemodynamic monitoring in 19.8%. Only the
group above 95 years old had a significant increase of days of
ventilation and length of stay: 18.77 vs 10.47 days (P = 0.01) and
19.74 vs 12.86 days (P = 0.07), respectively. The predicted
APACHE
II
mortality
for
the
studied
population
was
26.9 ± 17.21% and the present rate to the population studied was
47.7%. Patients in dialysis and with diagnosis of sepsis at
admission had poorer prognosis (respectively a 1.6 and 1.52 times
likely ratio to die). Methods Over seven consecutive days, details of all consultant
determined management plans were recorded by a dedicated
nurse auditor. A plan was defined as an identifiable do-able, short-
term action. Data on type, (arbitrary) priority, involved personnel
and time frame were noted. The auditor later returned at the end of
shift to determine whether plans had been completed in the
appropriate time frame (successful plan) or not (unsuccessful
plan). For unsuccessful plans, the nurse, senior nurse, senior
house officer, fellow and consultant were all independently quizzed
on causes and consequences (for patient, family, service) from a
predetermined list of possibilities. Results Of 200 plans, 130 were successful, for three plans data
were missing and 67 (34%) plans were unsuccessful. Of S192 Available online http://ccforum.com/supplements/11/S2 Intensive care of the elderly in Finland M Reinikainen1, A Uusaro2, M Niskanen3, E Ruokonen2
1North Karelia Central Hospital, Joensuu, Finland; 2University
Hospital, Kupio, Finland; 3Helsinki University Central Hospital,
Helsinki, Finland
Critical Care 2007, 11(Suppl 2):P489 (doi: 10.1186/cc5649) Results From 1996 to 2005, 47.3% (4,717) of admissions to the
ICU were aged ≥65 years; 24.0% (2,393) were ≥75 years. One-
year survival of the young group (51.8%) was significantly
(P < 0.001) better than the old group (37.9%). However, in those
receiving ≥3 organ support (young n = 197; old n = 199), this
significance is lost (42.2% vs 32.6%, P >0.2). Younger elective
surgical patients had better survival than older (79.4%, n = 196 vs
64.5%, n = 173). There was no survival difference between young
and old after emergency surgery (52.9%, n = 57 vs 50.4%,
n = 85; P > 0.5). There was no difference between ‘young’ and
‘old’ groups in the EQ5D weighted health index (0.67 ± 0.30 vs
0.62 ± 0.29, P > 0.5) or performance status scores (1.73 ± 0.96
vs 1.72 ± 0.98, P > 0.5). The EQ5D scores of survivors were
lower than matched population norms (0.64 vs 0.76, P < 0.01). Introduction The population is ageing. We wanted to find out how
age affects resource consumption and outcome of intensive care
in Finland. Introduction The population is ageing. We wanted to find out how
age affects resource consumption and outcome of intensive care
in Finland. Methods We analysed data on 79,361 admissions to 26 Finnish
ICUs during the years 1998–2004. We measured the severity of
illness with SAPS II scores and the intensity of care with TISS scores. Results The median age was 62 years; 8.9% of the patients were
aged 80 years or older. The hospital mortality rate was 16.2% in
the overall patient population but 28.4% for patients aged 80 years
or older. In a multivariate logistic regression analysis, old age was
an independent risk factor for hospital mortality (Table 1). Overall,
the mean length of ICU stay was 3.1 ± 5.3 days; it was 3.2 ± 5.3
days in the age group 75–79 years but only 2.4 ± 3.5 days in the
age group 80 years or older. Overall, the mean TISS score per day
was 25.8 ± 10.9; it was 27.8 ± 10.7 in the age group 75–79 years
and 25.3 ± 9.9 in the age group 80 years or older. One-year survival and functional outcome in critically ill
elderly patients M Puntis, M Cecconi, R McGoldrick, H Robertshaw, G McAnulty
St George’s Hospital, London, UK
Critical Care 2007, 11(Suppl 2):P490 (doi: 10.1186/cc5650) gy
Results Overall, 29 patients (16 acute and 13 chronic patients)
were considered as being in a vegetative state based on the GCS. The FOUR identified four out of these 29 patients (1/16 acute and
3/13 chronic patients) as not being vegetative considering the
presence of visual pursuit. The CRS-R identified an additional
seven patients (4/16 acute and 3/13 chronic patients) showing
visual fixation meeting the criteria for a minimally conscious state
set forth by the Aspen Workgroup. Therefore, the GCS diagnosed
a total of 38% (11/29) of conscious patients (5/16 acute and 6/13
chronic patients) as being in a vegetative state. Introduction The number of elderly ICU patients is increasing [1] but
limited outcome data are available. In this pilot study we evaluated
survival and quality-of-life indicators in ICU patients aged ≥65 years. Method Retrospective analysis of admissions between 1996 and
2005 defined the number of elderly ICU patients. Then between
2004 and 2006, consecutive patients ≥65 years admitted to
general (631), cardiothoracic (722) or neurological (118) critical
care units requiring ≥24 hours of ≥2 organ support were identified. Patients were divided into ‘young’ (age 65–74 years, n = 733) and
‘old’ (age ≥75 years, n = 738). Age, sex, organ support, diagnosis,
and referral source were recorded. Patients were followed-up 1 year
after discharge. A standard telephone interview of a random
sample of survivors (young n = 15, old n = 22) assessed perfor-
mance status and the EQ5D health-related quality of life [2]. Data
were analysed using Kaplan–Meier and log rank. Conclusion Using the GCS can lead one to misdiagnose
conscious patients. This misdiagnosis can lead to major clinical,
therapeutic and ethical consequences. Using additional sensitive
tools such as the CRS-R can avoid this kind of situation. Table 1 (abstract P486) Critical Care March 2007 Vol 11 Suppl 2
27th International Symposium on Intensive Care and Emergency Medicin Behavioral assessment remains the gold standard to monitor the
level of consciousness. However, about one-third of patients
diagnosed with a vegetative state are actually conscious (or in a
minimally conscious state). We compared the ability of the famous
Glasgow Coma Scale (GCS) and other standardized behavioral
scales to correctly diagnose the vegetative state in an acute
(intensive care and neurology ward) and chronic (neuro-
rehabilitation) setting. in the age distribution of the Finnish population will increase the
demand for ICU beds by 25% by 2030. Conclusions The hospital mortality rate increased with increasing
age. The mean intensity of care and length of ICU stay were lower
for the oldest patients than for patients <80 years old. The ageing
of the population will probably cause a remarkable increase in the
need for intensive care. P490 Methods Sixty postcomatose patients (that is, GCS > 8) were
prospectively assessed using the GCS, the Full Outline of
UnResponsiveness (FOUR) and the Coma Recovery Scale-Revised
(CRS-R) in randomized order. The mean age was 50 years (range
18–86); 39 were men. Etiology was traumatic in 24 patients. One-year survival and functional outcome in critically ill
elderly patients
M Puntis, M Cecconi, R McGoldrick, H Robertshaw, G McAnulty
St George’s Hospital, London, UK
Critical Care 2007, 11(Suppl 2):P490 (doi: 10.1186/cc5650) One-year survival and functional outcome in critically ill
elderly patients Intensive care of the elderly in Finland If the need for
intensive care remains unchanged in each age group, the change Conclusion Survival is worse in older ICU patients, although initial
data suggest no difference in functional outcome. Survivors have
lower quality-of-life scores than population norms [3]. Further work
is pending. References
1. Carson SS: Crit Care Clin 2003, 19:605-617. 2. Dolan P: Med Care 1997, 35:1095-1108. 3. Kind P: CHE Discussion Paper 172. York: Centre for Health
Economics, University of York; 1999. References
1. Carson SS: Crit Care Clin 2003, 19:605-617. 2. Dolan P: Med Care 1997, 35:1095-1108. 3. Kind P: CHE Discussion Paper 172. York: Centre for Health
Economics, University of York; 1999. References
1. Carson SS: Crit Care Clin 2003, 19:605-617. 2. Dolan P: Med Care 1997, 35:1095-1108. 3. Kind P: CHE Discussion Paper 172. York: Centre for Health
Economics, University of York; 1999. 1. Carson SS: Crit Care Clin 2003, 19:605-617. 3. Kind P: CHE Discussion Paper 172. York: Centre for Health
Economics, University of York; 1999. P493 Quality of life before intensive care unit admission is a
strong predictor of survival Quality of life before intensive care unit admission is a
strong predictor of survival P Spronk1, J Hofhuis1, H van Stel2, J Rommes1, A Schrijvers2,
J Bakker3
1Gelre Ziekenhuizen Location Lukas, Apeldoorn, The Netherlands;
2Julius Institute, Utrecht, The Netherlands; 3Erasmus MC,
Rotterdam, The Netherlands
Critical Care 2007, 11(Suppl 2):P493 (doi: 10.1186/cc5653) P Spronk1, J Hofhuis1, H van Stel2, J Rommes1, A Schrijvers2,
J Bakker3 Conclusion We have demonstrated that, for our unit, there was no
statistically significant difference in hospital or ICU mortality
between the two groups. In fact, the group with a haematological
malignancy had a lower mortality than the control group. The
presence of haematological malignancy, of itself, does not appear
to increase the mortality risk, when compared with a population of
patients without haematological malignancy of a similar age,
APACHE II score and admission diagnosis. Objective
To examine whether health-related quality of life
(HRQOL) before admission to the ICU can be used as a predictor
of mortality Available online http://ccforum.com/supplements/11/S2 existing
disease
and
(ii)
patients
receiving
ward-based
rehabilitation with those who receive formalised rehabilitation in
dedicated facilities. 34% and 75%. Historically, these patients have been regarded as
having a poor prognosis once admitted to the ICU. We decided to
compare the ICU and hospital mortality of these patients with
patients of a similar age and severity of acute illness. Preliminary results Ten of the required 40 interviewees have so
far been recruited. Preliminary analysis confirms that survivors
experience a range of morbidity not well captured by professionally
recommended measures, and that pre-existing disease is an
important factor in both coping with new morbidity superimposed
by critical illness, and in marshalling support. The process of
rehabilitation appears to have important effects on perceptions of
recovery, self-management strategies, and perceptions of HRQoL. Conclusions This qualitative enquiry has already provided, and will
continue to provide, new and clinically relevant insights into
patients’ experiences of morbidity, the processes of rehabilitation,
recovery and perceived HRQoL following discharge into the
community. Methods Twenty-four patients were admitted to the ICU from
August 2004 to August 2006 with a haematological malignancy. These were case-matched using sex, age (±2 years), APACHE II
score (±2) and admission diagnosis with patients admitted to the
ICU without a diagnosis of haematological malignancy. Eighteen
patients were matched to one case control; however, in six
patients, two matches were found. Where it was impossible to
differentiate between cases on the grounds of diagnosis, age or
APACHE II score they were both included. We compared ICU and
hospital mortality between the two groups. Results Patients with a haematological malignancy had an ICU
mortality of 50%, and a hospital mortality of 58%. Control patients
had an ICU mortality of 60%, and a hospital mortality of 67%
(statistically nonsignificant). The length of time to admission
between the two groups was significantly longer in the
haematology group at 12.4 days, compared with 2.8 days in the
control patients (P < 0.05). The level of organ support was the
same between the two cohorts. P492 Design and methods A prospective cohort study in an university-
affiliated teaching hospital. Patients admitted to the ICU for >48
hours were included. Close relatives completed the Short-form 36
(SF-36) within the first 48 hours of admission to assess the pre-
morbid HRQOL of the patient. Mortality was evaluated from ICU
admittance until 6 months after ICU discharge. Logistic regression
and ROC analysis were used to assess the predictive value for
mortality of the first general health question of the SF-36 (‘in
general would you say the health of your relative is excellent, very
good, good, fair or poor’), as well as HRQOL measured by the
complete SF-36. The Acute Physiologic and Chronic Health
Evaluation (APACHE) II score was used as an accepted mortality
prediction model in ICU patients. Three models were constructed
including the HRQOL (model A), APACHE II score (model B), or
both (model C) to age and gender. Percentages of correct
survival/death predictions were calculated. Quality of life following prolonged critical illness: insights
from a qualitative approach
P Ramsay
Royal Infirmary of Edinburgh, UK
Critical Care 2007, 11(Suppl 2):P492 (doi: 10.1186/cc5652) P491 Table 1 (abstract P489)
Age group (years)
Adjusted OR
95% CI
0–39
Reference
40–59
2.05
1.8–2.3
60–69
3.17
2.8–3.6
70–74
4.14
3.7–4.7
75–79
5.41
4.8–6.1
80–
7.08
6.3–8.0 The outcome of patients admitted to an intensive care unit
with haematological malignancy: a case–control study P Hampshire, K Francis, S Davies, L Dagg
Royal Liverpool University Hospital, Liverpool, UK
Critical Care 2007, 11(Suppl 2):P491 (doi: 10.1186/cc5651) Introduction The outcome of patients with haematological
malignancy admitted to the ICU has been reported as between S194 Available online http://ccforum.com/supplements/11/S2 P Ramsay Introduction The measurement of health-related quality of life
(HRQoL) among survivors of critical illness has become a
prominent feature of our outcomes research. Local research
experience suggests that existing measures may fail to capture the
broad spectrum of morbidity that survivors experience. The
purpose of this research is to explore, through predominantly
qualitative methods, critical-illness mediated morbidity among
survivors of prolonged critical illness; a group in whom this type of
morbidity appears to be most prevalent. An important secondary
aim is to explore the contribution of the processes of rehabilitation
and recovery to perceptions of HRQoL. Results Four hundred and fifty-one patients were included at
admission to the ICU. At 6 months follow-up, 159 patients had
died and 40 patients were lost to follow-up. When the general
health item was used as an estimate of HRQOL, the area under the
curve (AUC) for model A (0.719) was comparable with model B
(0.721), and slightly better in model C (0.760). The percentage of
wrong predictions was lower in model C (survival 27%; death
37%) compared with model A (30% and 41%). Similar results
were found when using the complete SF-36. Methods Survivors who experienced prolonged critical illness
(defined as ≥14 days mechanical ventilation) were identified from
the Scottish Intensive Care Society Audit Group (SICSAG)
database, Wardwatcher®. Participants were contacted ≤6 months
following ICU discharge, and were invited to complete
professionally recommended quality-of-life questionnaires (the
Short Form 36 and EuroQol-5D) and to participate in a semi-
structured interview. Interviews explored everyday experiences of
ongoing morbidity and were analysed with regard to their corre-
lation with the domains and scores of the HRQoL questionnaires. Purposive sampling provided clinically important insights into
experiences and perceptions of health and pre-existing morbidity
and, importantly, the processes of rehabilitation and recovery; that
is, through comparison of (i) patients with/without appreciable pre- Conclusions This study shows that the pre-admission HRQOL
measured with either the one-item general health question or the
complete SF-36 are as good in predicting survival/mortality in ICU
patients as the APACHE II score and improves prediction slightly
when combined. As the one-item general health question is easily
and quickly obtained, assessment of HRQOL before admission to
the ICU may facilitate the decision process in determining which
patients will benefit from ICU treatment. Intensive care unit utilization after esophagectomy R Iscimen1,2, D Brown2, F Whalen2, T Roy2, S Cassivi2,
M Keegan2
1Uludag University Faculty of Medicine, Bursa, Turkey;
2Mayo Clinic College of Medicine, Rochester, MN, USA
Critical Care 2007, 11(Suppl 2):P496 (doi: 10.1186/cc5656) Conclusions We describe the results of a bereavement follow-up
service for families whose relatives died on the critical care unit at
University Hospital of Wales, Cardiff. In total, 5.7% of families took
up the service offered. These were usually the families of younger
than average male patients, who died with a critical care stay of
less than 1 week. We believe that by answering questions still
troubling the families 2–4 months after death, we can assist them
with their grief. We also believe that this follow-up service by
providing further communication can resolve some difficult issues
before they develop into formal complaints. Introduction At our institution, postesophagectomy patients are
usually managed in a progressive care unit with ICU admission
reserved for those of high acuity. We hypothesized that ICU
admission after esophagectomy is predictable and associated with
high mortality. Introduction At our institution, postesophagectomy patients are
usually managed in a progressive care unit with ICU admission
reserved for those of high acuity. We hypothesized that ICU
admission after esophagectomy is predictable and associated with
high mortality. Methods
A
retrospective
analysis
of
all
patients
after
esophagectomy between January 2000 and June 2004 at a tertiary
referral center. Data regarding demographics, preoperative
morbidities, perioperative complications, APACHE III predictions,
mortality, and lengths of stay were collected. P494 Eighty-nine families were seen in bereavement follow-up
(5.7% of total deaths) and two families attended for a second visit. The male:female ratio was 2.18:1.0, and the average age of death
was 42.9 years. A length of stay before death of 1 week or less
occurred in 59.6%. Forty-seven per cent of families were seen
between 2 and 4 months after the death of their relative. The
issues most commonly raised were specific questions about the
patient (56.2%), review of information in the notes (34.8%),
complaints (23.6%), clarifying misunderstandings (18%) and
contacting other health professionals (21.3%). P494 A
letter is sent to the GP detailing the issues discussed. Results Seventy out of 793 patients had an oncologic diagnosis. The mean age was 52 ± 19 years, male gender 56%, medical
admission 77%, hematological malignancies 47% and mean
APACHE II score 20 ± 8. ICU mortality was 53% and inhospital
mortality was 71%. Nine (13%) patients were discharged of the
hospital with complete IADL. Mortality in the group admitted with
three or more SODs was 100%, while in the other group it was
39% (P = 0.01, OR 2.5 95% CI 1.8–3.6). During the ICU stay,
patients who developed three or more SODs had a higher ICU and
inhospital mortality than the ones who did not (89 x 23%,
P < 0.001, OR 7, 95% CI 1.8–26 and 100 x 53%, P < 0.001,
OR 2, 95% CI 1.4–2.6) and a smaller proportion of IADL after ICU
and hospital discharge (0 x 22%, P = 0.04, OR 1.7, 95% CI
1.3–2.2 and 0 x 47%, P < 0.001, OR 2, 95% CI 1.4–2.6). Methods All relatives, since January 2001, have been offered
bereavement follow-up. Following the death of a patient in critical
care, relatives are informed of the bereavement follow-up service. After death, a booklet is given to the next of kin with information
about the service. Four to six weeks later a condolence card is
sent, which includes a reminder of the follow-up service. We do
not offer a counseling service and details of other organizations
providing this are given. Appointments are made by telephone. The
interview usually takes place outside critical care and is led by a
consultant and a specially trained nurse. Relatives are given the
opportunity to ask questions. A monitoring form is completed. A
letter is sent to the GP detailing the issues discussed. Conclusion Mortality should not be the only aspect analyzed when
considering an ICU admission for an oncologic patient. The QOL,
including IADL, must be taken into account. A higher number of
SODs during the entire ICU stay is associated with higher ICU and
inhospital mortality. Beyond this association, a smaller number of
SODs may be associated with higher probability of IADL. Results In the 30-bed critical care unit in a teaching hospital,
during study period January 2001–November 2006, 8,964
admissions and 1,560 deaths (17.4% of patients) occurred
(male:female ratio 1.27:1). The average age of deaths was 64.7
years. P Ramsay S195 Critical Care March 2007 Vol 11 Suppl 2
27th International Symposium on Intensive Care and Emergency Medicin P494
Five years experience of critical care bereavement follow-up
S Voisey, J Davies, J Parry-Jones, N Stallard
University Hospital of Wales, Cardiff, UK
Critical Care 2007, 11(Suppl 2):P494 (doi: 10.1186/cc5654) P494 Methods ICU data were prospectively collected from March 2003
to November 2005. Oncologic patients were selected. QOL
aspects were evaluated through the analysis of independence to
accomplish daily living activities (IADL) after ICU discharge,
defined as the patient’s ability to walk, eat by mouth, maintain an
oriented conversation and bath himself. The number of organ
failures was assessed through the SOFA score. Severe organ
dysfunction (SOD) was defined if the patient had three or four
points in any of the six domains of the SOFA score. According to
the number of SOD, patients were divided into two groups: one
with two or less SODs and another with three or more SODs. Groups were compared using Fisher’s exact test. S Voisey, J Davies, J Parry-Jones, N Stallard
University Hospital of Wales, Cardiff, UK
Critical Care 2007, 11(Suppl 2):P494 (doi: 10.1186/cc5654) Introduction We believe that by explaining and answering the
questions of those relatives that wish it, we can alleviate the grief
caused by the death of a relative in critical care. Death is a
common outcome of critical illness and relatives are at high risk of
problems with complicated or unresolved grief due to the sudden,
often unexpected, manner of that death. We describe the
establishment and results of a bereavement follow-up service. Introduction We believe that by explaining and answering the
questions of those relatives that wish it, we can alleviate the grief
caused by the death of a relative in critical care. Death is a
common outcome of critical illness and relatives are at high risk of
problems with complicated or unresolved grief due to the sudden,
often unexpected, manner of that death. We describe the
establishment and results of a bereavement follow-up service. Methods All relatives, since January 2001, have been offered
bereavement follow-up. Following the death of a patient in critical
care, relatives are informed of the bereavement follow-up service. After death, a booklet is given to the next of kin with information
about the service. Four to six weeks later a condolence card is
sent, which includes a reminder of the follow-up service. We do
not offer a counseling service and details of other organizations
providing this are given. Appointments are made by telephone. The
interview usually takes place outside critical care and is led by a
consultant and a specially trained nurse. Relatives are given the
opportunity to ask questions. A monitoring form is completed. Visiting policies in Italian intensive care units: a national
survey Visiting policies in Italian intensive care units: a national
survey Methods We audited 28 ICU ward rounds. It was noted whether
the patient was sedated or not sedated, and whether they had their
eyes open or closed. Negative comments were recorded, and
defined as comments regarding a patient’s poor progress or
prognosis made at the bedside during the ward round. We also
noted whether the patient was informed that the ward round was in
progress, whether they were informed of the plan for the day, and
whether any reassurance was offered. The other members of the
team were not aware of the audit. A Giannini1, S Leoncino1, G Miccinesi2
1Fondazione IRCCS Ospedale Maggiore Policlinico, Mangiagalli e
Regina Elena, Milan, Italy; 2Centro per lo Studio e la Prevenzione
Oncologica, Florence, Italy
Critical Care 2007, 11(Suppl 2):P497 (doi: 10.1186/cc5657) Introduction Today no published data are as yet available on
visiting policies in Italy’s approximately 600 ICUs. We carried out a
multicentre survey to evaluate visiting policies in Italian ICUs. Results Twenty-eight ward rounds were audited, a total of 328
patient reviews. The total number of patients with their eyes open
was 171, while 157 had their eyes closed. An adverse comment
was made during 8.2% of reviews within earshot of the patient. A
negative comment was made on 27 episodes, 13 of these were
when the patient was not sedated but had their eyes closed. Four
episodes occurred when the patient was not sedated and had their
eyes open, while 10 were sedated and had their eyes closed. Of
the 171 patients with their eyes open, 74 (43%) were informed
that we were the team doing the ward round, while 97 (57%) were
not spoken to at the start of the review. Fifty-three (31%) were
informed of our management plan for the day and 43 (25%) were
offered reassurance. In total, 103/171 patients (60%) with their
eyes open were spoken to during the ward round, and we did not
speak to 68 (40%). Methods An email questionnaire was sent to all 303 ICUs (general
and specialized) in the Italian collaborative Gruppo Italiano per la
Valutazione degli Interventi in Terapia Intensiva, asking about their
visiting policies. Results The response rate was 84.8% (257/303). The median
daily visiting time was 60 minutes (10th percentile: 30 minutes;
90th percentile: 120 minutes); however, 2% of ICUs allowed no
visiting whatsoever. P498 and 17.0 (11.3–33.9) days, respectively. Compared with NICUGP,
patients in ICUGP were more likely to have developed post-
operative arrhythmia (57.9% vs 12.9%, P < 0.001), were older, of
higher ASA status, and more likely to have diabetes, coronary
artery disease, hypertension, a higher cancer stage, and to have
received more intraoperative blood products. Of 352 patients
originally not sent to the ICU, 43 (12.2%) were subsequently
admitted to the ICU. These patients had higher APACHE III scores
and were more likely to have ‘aspiration’ documented, although
their mortality was not higher than direct ICU admissions. Conclusions After esophagectomy, overall mortality is low, but
many patients require ICU admission. Postoperative arrhythmias
and aspiration pneumonitis are especially problematic. and 17.0 (11.3–33.9) days, respectively. Compared with NICUGP,
patients in ICUGP were more likely to have developed post-
operative arrhythmia (57.9% vs 12.9%, P < 0.001), were older, of
higher ASA status, and more likely to have diabetes, coronary
artery disease, hypertension, a higher cancer stage, and to have
received more intraoperative blood products. Of 352 patients
originally not sent to the ICU, 43 (12.2%) were subsequently
admitted to the ICU. These patients had higher APACHE III scores
and were more likely to have ‘aspiration’ documented, although
their mortality was not higher than direct ICU admissions. P498
Communication with patients during ward rounds on the
intensive care unit: a prospective, observational, semiblind
study
K Francis, D Langhor, J Walker, I Welters
Royal Liverpool University Hospital, Liverpool, UK
Critical Care 2007, 11(Suppl 2):P498 (doi: 10.1186/cc5658) Communication with patients during ward rounds on the
intensive care unit: a prospective, observational, semiblind
study K Francis, D Langhor, J Walker, I Welters
Royal Liverpool University Hospital, Liverpool, UK
Critical Care 2007, 11(Suppl 2):P498 (doi: 10.1186/cc5658) Introduction It is good medical practice to communicate with
patients regarding their condition and proposed treatment. Com-
munication is essential to allow them to express their concerns and
exercise their own autonomy, in a situation where they otherwise
may have little control. Poor communication may contribute to
unnecessary anxiety or depression. The aim of this audit was to
observe whether the doctors communicated with patients on ward
rounds. Conclusions After esophagectomy, overall mortality is low, but
many patients require ICU admission. Postoperative arrhythmias
and aspiration pneumonitis are especially problematic. P495 Results
Four hundred and thirty-two patients underwent
esophagectomy during the study period: 123 (28.5%) were
admitted to the ICU (ICUGP) and 309 (71.5%) were not
(NICUGP). Overall mortality was 3.7% (16 of 432 patients). Fifteen of 123 in ICUGP died in hospital (12.2%) compared with
one of 309 in NICUGP. For ICUGP, mean (±standard deviation)
acute physiology and APACHE III scores were 41.8 (±16.6) and
54.5 (±18.1), respectively. Forty-seven percent of ICUGP had a
new (versus pre-existing postoperative) infiltrate on chest X-ray,
21.8% had positive sputum/bronchial culture and 5% positive
blood culture within 48 hours of ICU admission. A total 13.8% of
ICUGP had ‘aspiration’ documented in physician notes. The
median (IQR) ICU and hospital lengths of stay were 3.6 (1.7–9.9) Quality of life aspects in oncologic patients who survived
an intensive care unit admission D Forte, O Ranzani, N Stape, F Gianinni, R Cordioli, D Lima,
J Coelho, P Nassar, R Zigaib, E Azevedo, I Schimidtbauer,
F Silva, B Cordeiro, A Toledo-Maciel, M Park
University of São Paulo, Brazil
Critical Care 2007, 11(Suppl 2):P495 (doi: 10.1186/cc5655) D Forte, O Ranzani, N Stape, F Gianinni, R Cordioli, D Lima,
J Coelho, P Nassar, R Zigaib, E Azevedo, I Schimidtbauer,
F Silva, B Cordeiro, A Toledo-Maciel, M Park
University of São Paulo, Brazil
Critical Care 2007, 11(Suppl 2):P495 (doi: 10.1186/cc5655) Introduction The number of organ failures in oncologic patients
admitted to the ICU is a good predictor of mortality. We propose
to analyze the association of this variable and quality of life (QOL)
aspects in oncologic patients who survived an ICU admission. S196 Available online http://ccforum.com/supplements/11/S2 Visiting policies in Italian intensive care units: a national
survey A total 54.8% of ICUs surveyed had only one
daily visiting slot, and 44% two. Only 1.2% had more than two
visiting slots. The number of visitors was restricted in 91.8% of
ICUs. The type of visitors (immediate family only) was restricted in
17.5% of ICUs. Children were not permitted to visit in 69.1% of
ICUs and 17.5% had a minimum age limit for visitors. In the case of
a dying patient, 20.6% of ICUs did not alter the visiting policy;
49% extended visiting hours; 44% increased the number of slots;
and 53% allowed more visitors. A gowning procedure was
compulsory for visitors in 95.3% of ICUs. No waiting room was
provided by 25.4% of ICUs. Conclusion On intensive care ward rounds, patients are often not
engaged in conversations or allowed to express their concerns. The majority of patients were not offered reassurance or informed
about the treatment plan. Improved communication skills may help
to lessen patients’ anxiety and unnecessary stress both during their
stay on ICU and following their discharge. Conclusions This is the first survey on visiting policies in Italian
ICUs. Despite the widely-held conviction that there is no sound
scientific basis for restricting visitors in ICUs [1-3], our findings
show a clear tendency in Italian ICUs to apply restricted visiting
policies (concerning visiting hours, number and type of visitors),
which are only partially liberalized when the patient is dying. Our
survey could contribute towards modifying current policies in
favour of opening ICUs that are still ‘closed’ and promoting more
appropriate and attentive care for the patient and his/her family. Hospital volume and outcome following mechanical
ventilation on the intensive care unit S Gopal1, R O’Brien1, J Pooni1, S Macfarlane2
1The Royal Wolverhampton Hospitals NHS Trust, Wolverhampton,
UK; 2ICNARC, Birmingham, UK
Critical Care 2007, 11(Suppl 2):P499 (doi: 10.1186/cc5659) Acknowledgement We thank Gruppo Italiano per la Valutazione
degli Interventi in Terapia Intensiva for their valuable help. Acknowledgement We thank Gruppo Italiano per la Valutazione
degli Interventi in Terapia Intensiva for their valuable help. Introduction
The study was undertaken to determine the
relationship between hospital volume and mortality in mechanically
ventilated adult medical and surgical patients. The regionalisation
of adult critical care services has been suggested by healthcare
providers and health policy-makers as a means of achieving the
ideal balance of providing high-quality care that is both cost-
effective and accessible. Recent studies have had conflicting
results. 1. Burchardi H: Let’s open the door! Intensive Care Med 2002,
8:1371-1372. 1. Burchardi H: Let’s open the door! Intensive Care Med 2002,
8:1371-1372. 2. Berwick DM, et al.: Restricted visiting hours in ICUs: time
to change. JAMA 2004, 292:736-737. 2. Berwick DM, et al.: Restricted visiting hours in ICUs: time
to change. JAMA 2004, 292:736-737. 3. Slota M, et al.: Perspectives on family-centered, flexible
visitation in the intensive care unit setting. Crit Care Med
2003, 31(Suppl):S362-S366. 3. Slota M, et al.: Perspectives on family-centered, flexible
visitation in the intensive care unit setting. Crit Care Med
2003, 31(Suppl):S362-S366. S197 ritical Care March 2007 Vol 11 Suppl 2
27th International Symposium on Intensive Care and Emergency Medicin Figure 1 (abstract P500) Methods The Birmingham and Black Country Critical Care
Network database was retrospectively reviewed over a 10-year
period from 1 April 1996 to 31 March 2006. The database
included 50,686 patient episodes. After exclusion (incomplete
data 9,700 episodes, unventilated patients 19,244 episodes,
mechanical ventilation for less than 24 hours 3,814 episodes,
interhospital transfers 795 episodes) the final cohort included
9,920 adult medical patients and 7,210 surgical patients. Hospitals were grouped into five volume categories to aid inter-
pretation of the results (<100; 100–149; 150–199; 200–249;
≥250 ventilation episodes/year). The odds ratio and 95% confi-
dence intervals for death on the ICU were calculated in relation to
the hospital volume of ventilation. Results For both medical and surgical patients there was no
relationship between the hospital volume of ventilation and death
on the ICU. The odds ratio remained insignificant even after
adjustment for patient demographics, APACHE II score, length of
ICU stay and urgency status. Hospital volume and outcome following mechanical
ventilation on the intensive care unit Medical patients’ adjusted odds ratio
was 0.735 (95% CI 0.604–0.894). Surgical patients’ adjusted
odds ratio was 0.771 (95% CI 0.559–1.064). Conclusion There is no relationship between hospital volume and
ICU mortality in both medical and surgical patients following
mechanical ventilation. The results of this study do not support the
argument for regionalisation of adult critical care services in the
United Kingdom. 35.8 years (24–57); 133 men, 51 women. One hundred and five
students are attending the course in order to improve their
qualification, 87 are studying for the specialist title examination, 58
to work in the ICU and 47 to acquire new knowledge. They
considered their main specialties to be: internal medicine (54),
intensive care (15), surgery (10) and anesthesiology (seven). Sixty-
five percent work in the ICU (12.7% are leaders, 19.5% daily
routine, 86.4% on duty and 6.8% play all three functions), 6% have
the specialist critical care title, 15.7% are associated with the
Brazilian critical care society, 49.45% have medical residence in
another area, 36.4% have other postgraduations. They self-
considered around grade 6 for cognitive aspects, procedural skills
and competence and near grade 8 for communication and
relationship (see Figure 1). Cardiopulmonary resuscitation,
mechanical ventilation, haemodynamics and neurointensivism are
the most desirable subjects. P501 Data completeness in the Finnish Intensive Care Quality
Consortium database
P Mussalo1, J Tenhunen2
1Intensium Ltd, Kuopio, Finland; 2Tampere University Hospital,
Tampere, Finland
Critical Care 2007, 11(Suppl 2):P501 (doi: 10.1186/cc5661) Continuous education in intensive care for physicians in
Brazil: for whom and their needs R Goldwasser1, C David1, D Costa2, C Piras3, P Mello4,
G Macedo5, A Barros6
1Hospital Universitario-Universidade Federal do Rio de Janeiro,
Brazil; 2Hospital Universitario, Cuiaba, Brazil; 3SOESTI, Vitoria,
Brazil; 4SOTIPI, Terezina, Brazil; 5SOTIERJ, Vassouras, Brazil;
6SOTIPE, Recife, Brazil
Critical Care 2007, 11(Suppl 2):P500 (doi: 10.1186/cc5660) Introduction The postgraduation course had been developed by
the Brazilian Critical Care Society (AMIB) to be applied to
physicians from all regions of Brazil since 2004. The importance of
this 360-hour course is to provide continuous education and to
train abilities to make decisions and start treatment. Also, for those
who are in ICU practice, to qualify for application of specialist
examination. The main objective of this study is to identify who are
the doctors that are looking for this course. Conclusions Doctors are mainly from the fourth decade, want to
improve their qualification, and are usually working in ICUs. The
low number of specialists who works in ICU is a reality and there is
a need to expand it. The self-evaluation points to problems with
knowledge and ability; however, communications and relationships
were well adjusted. The diversity of data will assist the AMIB to
provide continuous education and qualify doctors to attend the
demand of intensivists in Brazil. g
Methods An opinion poll was collected from the students on the
first day of the class course approaching the following aspects: Methods An opinion poll was collected from the students on the
first day of the class course approaching the following aspects:
1. Profile. P500 Continuous education in intensive care for physicians in
Brazil: for whom and their needs Data completeness in the Finnish Intensive Care Quality
Consortium database Table 1 (abstract P502)
Causes of all incidents (irrespective of patient outcome) auses of all incidents (irrespective of patient outcome) Methods We assessed data completeness of a Finnish ICU quality
benchmarking database from 1998 to March 2006 containing
93,964 admission records. The data completeness was defined as
a ratio of available and required data at ICU admission level. We
evaluated the dataset and selected 19 most significant admission
scheme variables to be included in completeness ratio calculations. Results The majority of data (77.5%) was collected with the
manual system and the remaining 22.5% with an integration
software. The mean admission data completeness ratio (CR)
increased from 85.3% at 1998 to 97.9% at 2005 (P = 0.01). Between the ICUs, the mean CR varied from 91.6% to 99.6%
(P = 0.01). The mean CR of the data collected with the IVT was
98.7% and with the manual system was 95.1% (P = 0.01). The
rate of 100% complete records per patient was 48.7% and it
increased from 0.0% in 1998 to 71% in 2005. Results The majority of data (77.5%) was collected with the
manual system and the remaining 22.5% with an integration
software. The mean admission data completeness ratio (CR)
increased from 85.3% at 1998 to 97.9% at 2005 (P = 0.01). Between the ICUs, the mean CR varied from 91.6% to 99.6%
(P = 0.01). The mean CR of the data collected with the IVT was
98.7% and with the manual system was 95.1% (P = 0.01). The
rate of 100% complete records per patient was 48.7% and it
increased from 0.0% in 1998 to 71% in 2005. potential or actual harm was perceived in five (15%) of the
incidents. Fifty-three per cent of events were reported by senior
house officer grade and 47% of incidents were reported by a
specialist registrar. Only one incident was reported by a nurse on
the team. Conclusion Data completeness in the FICQC has improved during
the study period, although there is still significant variation between
ICUs. Improved data completeness and decreased proportion of
missing data are most likely due to the increasingly common use of
CIS and automated data collection. We conclude that
measuring/reporting the amount of missing data is mandatory
when data collection and data management procedures for
benchmarking are being developed. Conclusions Interhospital transport of critically ill patients can
pose important risks. P503 Maximisation of heart and lung donation in a neurosurgical
intensive care unit Maximisation of heart and lung donation in a neurosurgical
intensive care unit S Aerdts, J Hofstra
Isala Klinieken, Zwolle, The Netherlands
Critical Care 2007, 11(Suppl 2):P503 (doi: 10.1186/cc5663) S Aerdts, J Hofstra
Isala Klinieken, Zwolle, The Netherlands
Critical Care 2007, 11(Suppl 2):P503 (doi: 10.1186/cc5663) Introduction In this study we created a database to analyse the
incidence and types of critical incidents that occurred during the
interhospital transfer of critically ill patients. The transfer of critically
ill patients presents important risks and the safety of patients has
been shown to be facilitated by the development of standard
equipment and specialist teams [1]. The West of Scotland Shock
team is a designated regional transfer service based in Glasgow. We are involved in the interhospital transfer of patients and not
primary retrieval. A recent study looking at critical incidents during
the intrahospital transport of the critically ill highlighted the risks
posed, and recommended the monitoring of incidents in order to
aid the continuous improvement in patient safety [2]. No similar
study has been carried out looking at the interhospital transport of
the critically ill patient. Critical Care 2007, 11(Suppl 2):P503 (doi: 10.1186/c Introduction The number of heart-beating donors in The Netherlands
is decreasing. This decrease is only partially compensated for by
an increase of nonheart-beating donations, resulting in an
increasing shortage of donor organs, especially of donor hearts
and lungs. In 2005 compared with 2004 the number of patients
waiting for a donor heart increased from 38 to 50 (32%). In lung
donation the increase was 37% (from 79 to 108). One approach
to reduce this shortage is to maximize the number of organs per
donor by optimisation of donor treatment in the ICU. We are involved in the interhospital transfer of patients and not
primary retrieval. A recent study looking at critical incidents during
the intrahospital transport of the critically ill highlighted the risks
posed, and recommended the monitoring of incidents in order to
aid the continuous improvement in patient safety [2]. No similar
study has been carried out looking at the interhospital transport of
the critically ill patient. Methods We investigated the possibilities for improvement of
donor management in our ICU by a retrospective study in 37 heart-
beating organ donors hospitalised in our ICU from 1993 to 2005. P502 2. Beckmann U, Gillies D, Berenholtz S, et al.: Incidents relat-
ing to the intra-hospital transfer of critically ill patients. Intensive Care Med 2004, 30:1579-1585. References References Analysis of critical incidents during the interhospital
transport of critically ill patients Analysis of critical incidents during the interhospital
transport of critically ill patients P Doherty, B Digby
Western Infirmary, Glasgow, UK
Critical Care 2007, 11(Suppl 2):P502 (doi: 10.1186/cc5662) References 1. Faculty of Intensive Care and Australasian College for Emer-
gency Medicine: Minimum Standards for the Transport of the
Critically Ill Patient; 2003 [http://www.acem.org.au/media/
policies_and_guidelines/min_standard_crit_ill.pdf] References
1. Arts D, et al.: Intensive Care Med 2002, 28:656-659. 2. Afessa B, et al.: Intensive Care Med 2005, 31:1537-1543. Data completeness in the Finnish Intensive Care Quality
Consortium database 2. He/she is attending the course in order to: prepare for the
specialist critical care examination (), improve qualification (),
work at an ICU (), any other reason if they do not deal with
critical care patients (). P Mussalo1, J Tenhunen2
1Intensium Ltd, Kuopio, Finland; 2Tampere University Hospital,
Tampere, Finland
Critical Care 2007, 11(Suppl 2):P501 (doi: 10.1186/cc5661) 3. If he/she works at an ICU: how long (years) and the role (duty,
routine or leader). 4. Partners of AMIB (yes) (no); if they have specialist title
recognized by the AMIB (yes) (no). Introduction Benchmarking has been an essential part of intensive
care medicine in Finland since 1994. At present, web-based
quality/performance reports are shared with the 24 members of the
Finnish Intensive Care Quality Consortium (FICQC). Thirteen ICUs
collect FICQC data manually and 11 ICUs utilize data collection
software (IVT) integrated with the Clinical Information System
(CIS). In recent literature, the completeness of data between
centralized medical benchmarking registries varies widely [1,2]. We hypothesized that: (1) the completeness of data in FICQC has Introduction Benchmarking has been an essential part of intensive
care medicine in Finland since 1994. At present, web-based
quality/performance reports are shared with the 24 members of the
Finnish Intensive Care Quality Consortium (FICQC). Thirteen ICUs
collect FICQC data manually and 11 ICUs utilize data collection
software (IVT) integrated with the Clinical Information System
(CIS). In recent literature, the completeness of data between
centralized medical benchmarking registries varies widely [1,2]. We hypothesized that: (1) the completeness of data in FICQC has 5. If he/she has other postgraduation or residency program. ( 6. Self-evaluation related to the critical patient knowledge (scales
from 1 to 9, considering 9 the highest grade). 7. Interest in the subjects of intensive care medicine (scales from
1 to 9). Results From 2004 to 2005 the AMIB started eight
postgraduation courses in different regions of Brazil; 250 students
were enrolled; 184 had answered the survey. The average age was S198 Available online http://ccforum.com/supplements/11/S2 Table 1 (abstract P502)
Causes of all incidents (irrespective of patient outcome)
Communication problem
10 (29%)
Organisational delay
7 (21%)
Lack of staff
2 (6%)
Equipment failure
9 (26%)
Poor preparation of patient
5 (15%)
Staff injury
1 (3%) increased over the years and (2) the variation between the different
units still exists. Data completeness in the Finnish Intensive Care Quality
Consortium database In our study no actual patient harm occurred
although most incidents had the potential to cause harm. The
majority of incidents were caused by system-based factors. This
database has allowed us to perform continuous service
development and education of staff. P504 Medical practices during the last 48 hours of life in
children admitted to seven Brazilian Pediatric intensive
care units P Lago, J Piva, P Garcia
PUCRS, Porto Alegre, Brazil
Critical Care 2007, 11(Suppl 2):P504 (doi: 10.1186/cc5664) y
g
Results A total of 137 physicians and critical care nurses
completed the survey. The average age was 34 years and 58%
were males. ‘Brain death’ was defined as an ‘irreversible cessation
of brainstem function’ by 85% of respondents; 77% relying on
clinical examination, 49.6% consulting neurophysicians and 28.3%
ordering further testing to confirm the diagnosis. Withdrawal of life
support is practiced by 83.2%; most frequently in the setting of
absent brainstem and cortical functioning (74.3%), followed by
acute, progressive multiorgan failure (39.8%). Physicians are more
likely (P
value 0.000) to withdraw mechanical ventilation,
compared with nurses who would withdraw vasopressors (P value
0.006). The primary physician is the most frequent caregiver
(60.2%) to start a discussion on withdrawal of life support, with
72.6% respondents consulting the Hospital Ethics Committee. Only 13.3% respondents never withdraw life support; 28.3%
considered it their responsibility to ‘sustain life at all costs’ and only
8% gave religious beliefs as a reason. Only 56.6% favored organ
harvest for transplantation from cadavers, while 64.6% supported
harvest from brain dead individuals. Nurses were significantly more
likely to support organ harvest for transplant from heart-beating,
brain dead individuals (P value 0.025) than cadavers (P value
0.000). Introduction During the last decades life support limitation (LSL)
practices have been offered more frequently in Latin American
pediatric intensive care units (PICUs). We hypothesize that,
depending on the Brazilian region, the incidence of LSL and the
medical management may differ. Objective To evaluate the incidence of LSL practices and the
medical management during the last 48 hours of life of children
admitted to seven PICUs located in regions of Brazil. Methods A multicenter, observational and retrospective chart
review study. The medical chart of all deaths occurring between
January 2003 and December 2004 in seven Brazilian PICUs
located in Porto Alegre (two), Sao Paulo (two) and Salvador
(three) were evaluated. Two pediatric intensive care residents of
each service filled a standard protocol searching for: demographic
data, mode of death (full reanimation, nonreanimation orders or
withdrawn treatment) and medical management during the last 48
hours of life. Student’s t test, analysis of variance, chi-square test
and relative risk were used for comparing the data. End-of-life care in the critically ill: a description of
knowledge, attitudes and practices of physicians and
nurses from Karachi, Pakistan The primary physician is the most frequent caregiver
(60.2%) to start a discussion on withdrawal of life support, with
72.6% respondents consulting the Hospital Ethics Committee. Only 13.3% respondents never withdraw life support; 28.3%
considered it their responsibility to ‘sustain life at all costs’ and only
8% gave religious beliefs as a reason. Only 56.6% favored organ
harvest for transplantation from cadavers, while 64.6% supported
harvest from brain dead individuals. Nurses were significantly more
likely to support organ harvest for transplant from heart-beating,
brain dead individuals (P value 0.025) than cadavers (P value
0.000). Methods We carried out a cross-sectional survey of clinicians
working at three hospitals in Karachi (one private, university
hospital, one mixed public and private, tertiary care hospital and
one large government-funded hospital). A 13-question instrument
was developed to assess recognition of end-of-life in the ICU,
knowledge of commonly used terms to describe limitations of care,
and attitudes and practices towards withdrawal and limitation of
life-support measures and organ harvest for transplantation. After
measuring the frequencies for presentation of the data, differences
between the three respondent subgroups were compared using a
chi-square analysis. Fisher’s exact test was used where the
individual cell count was <5. A one-way analysis of variance was
used to compare differences in age and years of practice. A two-
sided P value of <0.05 was considered statistically significant. End-of-life care in the critically ill: a description of
knowledge, attitudes and practices of physicians and
nurses from Karachi, Pakistan End-of-life care in the critically ill: a description of
knowledge, attitudes and practices of physicians and
nurses from Karachi, Pakistan N Salahuddin, A Ahmed, S Shafquat
Aga Khan University & Hospital, Karachi, Pakistan
Critical Care 2007, 11(Suppl 2):P505 (doi: 10.1186/cc5665) Introduction As the numbers of people admitted to ICUs are
increasing, physicians are faced with obligations beyond
attempting to reverse illness and include providing quality end-of-
life care. Barriers to this include inadequate understanding of the
dying patient and withdrawal or limitation of care. The objectives of
this study were to document the comprehensions of physicians
and nurses dealing with these situations. Conclusion On the basis of this retrospective study we conclude
that donor management in our ICU can be improved. A
management protocol with special attention for treatment of
disturbance in cardiac and pulmonary function caused by
sympathic overstimulation might considerably increase the
amount of hearts and lungs donated, contributing to a decrease
in organ shortage. g
Methods We carried out a cross-sectional survey of clinicians
working at three hospitals in Karachi (one private, university
hospital, one mixed public and private, tertiary care hospital and
one large government-funded hospital). A 13-question instrument
was developed to assess recognition of end-of-life in the ICU,
knowledge of commonly used terms to describe limitations of care,
and attitudes and practices towards withdrawal and limitation of
life-support measures and organ harvest for transplantation. After
measuring the frequencies for presentation of the data, differences
between the three respondent subgroups were compared using a
chi-square analysis. Fisher’s exact test was used where the
individual cell count was <5. A one-way analysis of variance was
used to compare differences in age and years of practice. A two-
sided P value of <0.05 was considered statistically significant. Results A total of 137 physicians and critical care nurses
completed the survey. The average age was 34 years and 58%
were males. ‘Brain death’ was defined as an ‘irreversible cessation
of brainstem function’ by 85% of respondents; 77% relying on
clinical examination, 49.6% consulting neurophysicians and 28.3%
ordering further testing to confirm the diagnosis. Withdrawal of life
support is practiced by 83.2%; most frequently in the setting of
absent brainstem and cortical functioning (74.3%), followed by
acute, progressive multiorgan failure (39.8%). Physicians are more
likely (P
value 0.000) to withdraw mechanical ventilation,
compared with nurses who would withdraw vasopressors (P value
0.006). P503 There was no protocol for the treatment of organ donors in our
institution. Methods The study was a cross-sectional analysis of critical
incidents occurring during interhospital transport that were reported
to the West of Scotland Shock Team critical incident database set
up in September 2005. The information obtained was categorised
into: (a) where the incident took place, (b) type of incident, (c)
written description of events, (d) outcome (potential or actual harm
to the patient) and (e) designation of the staff member reporting
the incident. Results The heart was donated in 18 of 37 patients (49%). Lung
donation was possible in only eight of 37 donors (22%). Most
hearts and lungs were rejected for transplantation for valid
reasons. In some patients there was room for improvement: in two
of the three cases where hemodynamic instability impeded heart
and lung donation (one dying from subarachnoidal bleeding and
one from ischemic cerebral infarction), hemodynamic instability
was closely associated with the moment of cerebral death. In three
further patients heart donation was not carried out because of wall
movement abnormality or electrocardiogram abnormalities. None of Results A total of 199 transfers were performed over the 6-month
period. Thirty-four critical incidents were reported. Twenty-four
(70%) incidents took place before, seven (21%) during and three
(9%) after transfer. No patients sustained actual harm, 29 (85%)
were perceived by the reporter to have suffered potential harm and
the most common cause of this were delays in the transfer. No S199 ritical Care March 2007 Vol 11 Suppl 2
27th International Symposium on Intensive Care and Emergency Medicin P505 them had previous cardiac disease. All three had disturbances in
cardiac rhythm closely related to the occurrence of cerebral death. Two of these three patients also developed neurogenic pulmonary
edema. We speculate that in all five patients the instability leading
to the decision not to perform heart and lung donation was caused
by excessive sympathic stimulation at the time of cerebral death
leading to impaired myocardial function and neurogenic pulmonary
edema. These disturbances may be reversible within a few hours. Inotropic therapy, judicious fluid administration guided by close
hemodynamic monitoring together with a trial of treatment with
triple hormonal therapy (corticosteroid, vasopressin and thyroid
hormone) might have improved cardiac and pulmonary function,
rendering heart and lung donation possible. P505
End-of-life care in the critically ill: a description of
knowledge, attitudes and practices of physicians and
nurses from Karachi, Pakistan
N Salahuddin, A Ahmed, S Shafquat
Aga Khan University & Hospital, Karachi, Pakistan
Critical Care 2007, 11(Suppl 2):P505 (doi: 10.1186/cc5665) P504 Results There were 561 deaths, 36 being excluded that died with
less than 24 hours, 61 with brain death and 36 missing charts. Full
cardiopulmonary reanimation was offered to 56.5%, with
differences between the northeast and southeast regions (P <
0.001). Higher age (P = 0.02) and long length of PICU stay were
associated with nonreanimation orders. The plan for LSL was
recorded in a clear manner in just 52.7%. No respiratory support
was observed in 14 dying children. For 66% patients with do-not-
resuscitate orders the inotrope drugs were maintained or
increased in the last 48 hours. Conclusion
There are deficiencies and disparities in the
understandings of physicians and nurses on the recognition and
management of end-of-life in the ICU. Conclusions The incidence of LSV has increased among the
Brazilian PICUs with a difference between the regions. The
nonreanimation order is still the most common practice with scarce
initiative for withdrawn life support. S200 P506 Methods We identified original research articles on critical care in
three high impact factor journals (N Engl J Med, JAMA and The
Lancet) published from 2001 to 2005. A list of the countries where
data
collection
occurred
was
extracted. Eight
countries
contributed to ≥10 studies. A collaborator in each country was
asked to provide baseline critical care information for their country
from 2005, or as close to that date as possible. World Resources in Critical Care Study: a survey of critical
care research and resources in eight countries H Wunsch1, D Harrison2, O Collange3, N de Keizer4, R Fowler5,
E Hoste6, A Kersten7, W Linde-Zwirble8, A Sandiumenge9, D
Angus8, K Rowan2
1Columbia University, New York, USA; 2ICNARC, London, UK;
3Strasbourg University Hospital, Strasbourg, France; 4University of
Amsterdam, The Netherlands; 5Sunnybrook Health Sciences
Center, Toronto, Canada; 6Ghent University Hospital, Ghent,
Belgium; 7University Hospital Aachen, Germany; 8University of
Pittsburgh, Pittsburgh, PA, USA; 9University Hospital Joan XXIII,
Tarragona, Spain
Critical Care 2007, 11(Suppl 2):P506 (doi: 10.1186/cc5666) H Wunsch1, D Harrison2, O Collange3, N de Keizer4, R Fowler5,
E Hoste6, A Kersten7, W Linde-Zwirble8, A Sandiumenge9, D
Angus8, K Rowan2
1Columbia University, New York, USA; 2ICNARC, London, UK;
3Strasbourg University Hospital, Strasbourg, France; 4University of
Amsterdam, The Netherlands; 5Sunnybrook Health Sciences
Center, Toronto, Canada; 6Ghent University Hospital, Ghent,
Belgium; 7University Hospital Aachen, Germany; 8University of
Pittsburgh, Pittsburgh, PA, USA; 9University Hospital Joan XXIII,
Tarragona, Spain
Critical Care 2007, 11(Suppl 2):P506 (doi: 10.1186/cc5666) H Wunsch1, D Harrison2, O Collange3, N de Keizer4, R Fowler5,
E Hoste6, A Kersten7, W Linde-Zwirble8, A Sandiumenge9, D
Angus8, K Rowan2 Results Sixty-two studies involving data from 51 countries were
identified. Eight countries contributed data to ≥10 studies during
this time period: the USA (26 studies), France (18), the United
Kingdom (14), Canada (13), Belgium (12), Germany (10), The
Netherlands (10) and Spain (10). Relevant data on baseline
hospital and critical care resources for the eight countries
identified are presented in Figure 1 (data from Canada not
available). Adult ICU beds ranged from 3.3/100,000 population in
the United Kingdom to 24.6 in Germany, and represented a range
of 1.4% of all acute care hospital beds in the United Kingdom to
11.0% of all beds in the USA. P506 1Columbia University, New York, USA; 2ICNARC, London, UK;
3Strasbourg University Hospital, Strasbourg, France; 4University of
Amsterdam, The Netherlands; 5Sunnybrook Health Sciences
Center, Toronto, Canada; 6Ghent University Hospital, Ghent,
Belgium; 7University Hospital Aachen, Germany; 8University of
Pittsburgh, Pittsburgh, PA, USA; 9University Hospital Joan XXIII,
Tarragona, Spain
Critical Care 2007, 11(Suppl 2):P506 (doi: 10.1186/cc5666) Introduction Critical care research involves data from many
countries, but critical care resources in these countries are
unknown. We hypothesized that there are large differences in
critical care resources between countries. Conclusions Many countries contribute substantially to critical
care research. However, the underlying critical care resources vary
dramatically among these countries. Figure 1 (abstract P506)
Baseline critical care resources in eight countries. *Extrapolated from survey data, not full national data. Figure 1 (abstract P506) S201
|
https://openalex.org/W4394581823
|
https://www.researchsquare.com/article/rs-4222544/latest.pdf
|
English
| null |
Adherence to Clinic Appointments and Medication Among Patients Accessing Mental Health Clinics in Lilongwe, Malawi
|
Research Square (Research Square)
| 2,024
|
cc-by
| 4,902
|
Adherence to Clinic Appointments and Medication
Among Patients Accessing Mental Health Clinics in
Lilongwe, Malawi Paul Mekani Paul Mekani Abstract Background: Individuals who are nonadherent to treatment have higher rates of symptom recurrence,
higher rates of hospital readmission and poorer quality of life. Nkhoma Mission Hospital (NMH) in the
central region of Malawi has been integrating mental health within the existing services to ensure that the
services are accessible to people. The purpose of the study was to investigate the prevalence and factors
of nonadherence to appointments and medication among patients with mental illness. Design and methods: A cross-sectional analytical study was conducted at Nkhoma Mission Hospital. A
survey approach and total population sampling were used. The MARS score was used to assess
medication adherence. Associations of alcohol use, insight, and stigma with medication adherence were
established using the AUDIT, BIRCHWOOD and ISMI scales, respectively. Results: The prevalence of nonadherence to clinic appointments and medication was 64% (n=58) and
46.2%, respectively. Females were 4.7 times more likely to miss clinic appointments than males were (B
=-1.555, Exp (B)=0.221, p=0.029), Protestant Christians were 5 times more likely to miss clinic
appointments (B = 5.176, p=0.034), clients who were not married were 15 times more likely not to adhere
to clinic appointments (B=2.722, Exp(B)=25.12, p=0.002), and clients who visited a mobile clinic were
more likely to miss appointments (B =-1.762, Exp (B)=0.172, p=0.020). Patients who had been on
medication for less than 2 years had significantly lower adherence to medication (B=-1.631, t=-2.053,
p=0.043); patients whose occupation involved farming had lower adherence to medication (B=-1.541,
t=-2.057, p=0.043); and psychotic patients had greater adherence to medication than nonpsychotic
patients did (B=1.753, t=2.041, p=0.044). Conclusion: It is important to address the factors that influence nonadherence to clinic appointments and
medication to avoid relapse. Conclusion: It is important to address the factors that influence nonadherence to clinic appointments and
medication to avoid relapse. Research Article License:
This work is licensed under a Creative Commons Attribution 4.0 International
License. Read Full License Additional Declarations: The authors declare no competing interests. Additional Declarations: The authors declare no competing interests. Additional Declarations: The authors declare no competing interests. Page 1/16 Page 1/16 Page 1/16 INTRODUCTION Globally, more than 1 billion people were affected by mental and addictive disorders as of 2016; these
disorders were responsible for 7% of all the global burden of disease, as measured by disability-adjusted
life years (DALYs) (Rehm & Shield, 2019). By 2017, approximately 792 million people had a mental
disorder, which was 10.7% of the global population, with depression and anxiety being the most common
mental disorders (Coronado-v & Museros-sos, 2020). The prevalence of common mental disorders in some African countries is as follows: 33% in Ethiopia,
24% in Tanzania and 25–26% in Zimbabwe (Udedi, 2016). The prevalence of common mental disorders in some African countries is as follows: 33% in Ethiopia,
24% in Tanzania and 25–26% in Zimbabwe (Udedi, 2016). The World Health Organization (WHO) describes medication nonadherence as “a case in which a person’s
behavior in taking medication does not correspond with agreed recommendations from health personnel”
(Semahegn et al., 2020). In contrast, nonadherence was defined as a failure to follow instructions and Page 2/16 advice from service providers (Shah et al., 2019). Nonadherent patients are reported to be 70% more likely
to be admitted to the hospital (Ljungdalh, 2017). The prevalence of nonadherence to mental diseases ranges from 70 to 80%, and for individuals with
depression alone or bipolar disorder, it is between 26.5% and 70% (Alpak et al., 2015). This wide range is
mostly due to a lack of agreement among investigators on the appropriate methodology or criteria for
assessing adherence (e.g., quantitative vs qualitative research, direct measurement of blood or urine
parameters vs indirect measurements, patient self-reports vs clinician reports) (Garcia et al, 2016). Studies on treatment adherence conducted in patients with mental disorders and missing data during
patient follow-up have reported up to 10–55% nonadherence (Alpak et al., 2015). Although considerable
research has been devoted to evaluating adherence to medication for physical conditions, little attention
has been given to researching the prevalence of and factors connected to adherence to mental health
appointments and medication. However, a study conducted in Malawi in 2017 revealed that the
prevalence of noncompliance with antipsychotic medication among patients with mental disorders was
43.9% (Myaba, 2017). The Nkhoma Mission Hospital has been integrating mental health within the existing general services in
support of the PHC delivery model to ensure that services are accessible to where people are accessible
(Mekani & Myaba, 2020). Study setting This study was carried out at Nkhoma Mission Hospital, a general mission hospital with 250 beds in
Lilongwe District, Malawi. The hospital is a referral facility for ten government and mission health centers
(primary health facilities). The hospital runs an outpatient (static) clinic and 13 outreach clinics with 858
patients. NMH was chosen as the study setting because it is one of the first General Mission Hospitals to
initiate the integration of mental health care in the country. Study design The study used a cross-sectional analytical quantitative approach. INTRODUCTION Some patients reported missing appointments and medication despite the
existence of outreach clinics. Therefore, this study sought to address this gap by investigating the
prevalence and factors associated with nonadherence to clinic appointments and mental health
treatment among patients accessing outreach and static clinics in Malawi. Sample size and sampling technique This study used a census approach in which the entire population of patients with a confirmed clinical
diagnosis of a mental disorder on AXIS I based on the Diagnostic Statistical Manual for Mental Disorders
Version IV (DSM IV) was included. There were 111 patients with a diagnosis of mental illness, and all of
them were requested to participate in the study. Statistical analysis The data were analyzed using Statistical Product and Service Solution (SPSS) version 23. Descriptive
statistics were calculated for all the variables collected. Means with standard deviations were used to
describe continuous variables, and counts and percentages were used for categorical data. The analysis
of the data involved describing the frequency of demographic information (gender, diagnosis, religion,
and district). Pearson’s chi-square test was performed to determine whether there was an association
between adherence to clinic appointments and any of the demographic characteristics, environmental-
related factors or medical factors. Multiple regression analysis was also conducted to identify factors that influence adherence to
medication. A multivariate logistic regression model was used to check for factors that could significantly
predict whether a patient was likely to adhere to clinic appointments. All factors that had p values less
than 0.05 were considered to have a significant effect on adherence to medication. For those factors that
were found to be significant predictors, odds ratios (ORs) were calculated at the 95% confidence intervals
(CIs) Data collection tools and measurements Adherence to clinic appointments and medication was assessed through interviewer-administered
questionnaires consisting of measures assessing adherence to clinic appointments and medication. The
Medication Adherence Rating Scale (MARS) was used to assess adherence to medication. Associations Page 3/16 Page 3/16 of alcohol use, insight, and stigma with medication adherence were established using the AUDIT scale,
BIRCHWOOD scale and internalized stigma of mental illness (ISMI) scale, respectively. The questionnaire
was pretested with 13 patients with mental illness at the Bwaila Psychiatric Clinic. Ethical consideration and clearance The study was approved by the Africa University Research Ethics Committee and the National Health
Sciences Research Committee of Malawi (approval number 2727). Permission to conduct the study was
also sought and granted by the relevant authorities of Nkhoma Mission Hospital. The respondents were
also informed that their participation in the study was voluntary. Each respondent signed a written
consent form. Sociodemographic characteristics of the study participants The final sample consisted of 91 participants, representing 81.9% of the total sample. Initially, 111
participants were planned to participate. The majority of the participants were male (56%, n = 51) and
single (39.6%, n = 36%). Male participants were 32 years old on average (SD = 9.03) and were younger
than female participants were 35 years old on average (SD = 9.72) (Table 2). Page 4/16 Page 4/16 Table 1: Sociodemographic characteristics of the participants Sociodemographic Characteristics
Sex of respondent
Male (n=51)
Female(n=40)
Pearson Chi-square
Catholic (n=9)
7
2
Religion
Protestant (n=64)
32
32
Islam (n=2)
0
2
8.815*
None (n=16)
12
4
Education level
None (n=16)
7
9
7.349
Primary (n=59)
30
29
Secondary (n=14)
12
2
Tertiary (n=2)
2
0
Main occupation
Farmer (n=72)
36
36
8.028
Trader/Business(n=4)
4
0
Casual laborer (n=11)
7
4
Student (n=2)
2
0
Other (n=2)
2
0
Age
Minimum
18
19
18
Maximum
73
80
80
Mean
38
44
40
Standard deviation
13
12
13
Prevalence of Nonadherence to Clinic Appointment
This study showed that 64% (n = 58) of the respondents were nonadherent to clinic appointments, 22% (n
= 20) missed a one-month appointment and 32% (n = 29) missed more than 2 months (see Fig. 1). Factors associated with nonadherence to clinic
appointments Factors associated with nonadherence to clinic
appointments The findings showed that sociodemographic characteristics and clinical factors were not significantly
associated with nonadherence to clinic appointments. Page 5/16 Page 5/16 Table 2
Factors associated with adherence to clinical appointments
Categories
Adherent
(%)
Nonadherent
(%)
Pearson Chi-
square
Demographic factors
Sex
Male (n = 51)
39
61
0.437
Female (n = 40)
33
67
Education level
None (n = 16)
31
69
0.366
Primary (n = 59)
37
63
Secondary (n = 14)
36
64
Tertiary (n = 2)
50
50
Marital status
Never married (n = 36)
20
80
9.317
Married (n = 20)
50
50
Separated (n = 2)
0
100
Divorced (n = 27)
48
54
Widowed (n = 6)
50
50
Religion
Catholic (n = 9)
56
44
4.116
Protestant (n = 64)
30
70
Islam (n = 2)
50
50
None (n = 16)
50
50
Main occupation
Farmer (n = 72)
35
65
7.217
Trader/Business (n = 4)
0
100
Casual laborer (n = 11)
64
36
Student (n = 2)
0
100
Other (n = 2)
50
50
Clinical factors
Diagnosis of
patient
Psychosis (n = 75)
40
60
7.354
Depression (n = 3)
33
66
Substance use disorder (n
= 8)
0
100 Table 2 Demographic factors Page 6/16 Categories
Adherent
(%)
Nonadherent
(%)
Pearson Chi-
square
Demographic factors
Alcohol use disorder (n =
2)
0
100
Bipolar (n = 3)
67
33
Medication type
Haloperidol (n = 40)
28
72
2.494
Risperidone (n = 5)
40
60
Chlorpromazine (n = 31)
45
55
Modecate (n = 7)
43
57
Carbamazepine(n = 5)
40
60
Other (n = 3)
33
67
Period on
medication
3–6 Months (n = 3)
33
67
3.404
7–12 months (n = 5)
0
100
13–24 months (n = 10)
30
70
> 24 months (n = 73)
40
40 Categories Demographic factors Reasons for nonadherence to clinic appointments There were multiple options for the participants to choose from as reasons for nonadherence to clinic
appointments. The most frequently mentioned reasons were “I do not have a mental illness” (44%) and “transport problems” (44%) (see Fig. 2). Factors Influencing Nonadherence to Clinic Appointments Factors Influencing Nonadherence to Clinic Appointments The factors in the model accounted for 40.2% of the variance in adherence to medical appointments. The
model was significant, indicating that it was good at predicting whether a client would adhere to clinic
appointments. Compared with male clients, female clients were 4.7 times more likely to miss clinic appointments (B=
-1.555, Exp(B) = 0.221, p = 0.029). Participants were 5 times more likely than those of other religions or those who did not belong to any
religion to miss clinic appointments (B = 1.644, Exp(B) = 5.176, p = 0.034). Participants were 5 times more likely than those of other religions or those who did not belong to any
religion to miss clinic appointments (B = 1.644, Exp(B) = 5.176, p = 0.034). Marital status significantly predicts whether a client will adhere. Clients who had never been married were
15 times more likely not to adhere to clinic appointments than were clients who were married (B = 2.722,
Exp(B) = 25.12, p = 0.002). Page 7/16 Page 7/16 Page 7/16 Clients attending a mobile clinic were 5.8 times more likely not to adhere than were those attending a
static clinic (B= -1.762, Exp(B) = 0.172, p = 0.020). Clients attending a mobile clinic were 5.8 times more likely not to adhere than were those attending a
static clinic (B= -1.762, Exp(B) = 0.172, p = 0.020). Age of client, diagnosis and duration of medication did not significantly predict whether a client would
adhere to clinic appointments (Table 3). Page 8/16
Table 3
Multivariate analysis of factors affecting clinic appointments
Characteristic
B
S.E. Sig. Odds
Ratio
95C.I. C.I. for Odds
Ratio
Lower
Upper
Sex (Female)
Male
-1.555*
0.712
0.029
0.211
0.052
0.853
Age
0.035
0.025
0.162
1.036
0.986
1.088
Religion (None)
0.098
Catholic
-0.273
1.183
0.817
0.761
0.075
7.732
Protestant
1.644*
0.776
0.034
5.176
1.132
23.673
Muslim
-20.766
14011.92
0.999
0
0
. Insight score The mean score for insight was 8.75 (SD = 2.5). The majority of the participants (48; 52.8%) had poor
insight into their illness, while 43 (47.3%) had good insight. AUDIT score The mean score for the Alcohol Use Disorder Identification Test (AUDIT) was 2.2 (SD = 5.9). Seventeen
participants indicated that they use alcohol. Of these, 9 (52.9%) had a score of 9 or above, indicating
harmful drinking. ISMI score The mean score for internalized stigma of mental illness (ISMI) was 2.6 (SD = 0.6). For the majority of the
participants, 57 (62.6%) had a score of 2.5, indicating that they had internalized stigma about their
mental illness. R 2 = .402 (Nagelkerke). ; Model χ2 (12) = 31.631***; *p < .05, **p < 0.01, ***p < .001 R 2 = .402 (Nagelkerke). ; Model χ2 (12) = 31.631***; *p < .05, **p < 0.01, ***p < .001. Reasons for nonadherence to clinic appointments Marital status (Married)
0.005
Never married
2.722**
0.919
0.003
15.211
2.512
92.117
Once married but now single
-0.197
0.704
0.780
0.821
0.207
3.263
Clinic type (Mobile)
Static
-1.762*
0.758
0.020
0.172
0.039
0.759
Duration on medication (> 2
years)
0.843
< 1 year
-0.514
0.879
0.559
0.598
0.107
3.347
1–2 years
21.999
14011.92
0.999
3.58E +
09
0
. Diagnosis type (Nonpsychotic)
Psychotic
0.909
0.947
0.337
2.483
0.388
15.894
District (Dedza)
Lilongwe
-1.621
0.958
0.091
0.198
0.03
1.293
Constant
-0.936
1.609
0.561
0.392 Prevalence of nonadherence to medication The mean MARS score was 7.1 (SD = 0.99), and the median score was 9. Using a median score of 8 as a
cutoff point for nonadherence to medication according to the Medication Adherence Rating Scale
(MARS), 46.2% (n = 42) of the participants were nonadherent to medication (Owie et al., 2018). Results on Factors Affecting Adherence to Medication Marital status, medication, diagnosis of patient, alcohol and insight explained a significant amount
(24.8%) of the variation in medication adherence (F (6, 90) = 4.629, p < 0.001). The results also showed
that patients who had been on medication for less than two years had significantly lower adherence to
medication than patients who had been on medication for more than two years. Patients whose main occupation was farming had lower adherence to medication than did those whose
occupation was other (B = -1.541, t = -2.057, p = 0.043). Finally, patients with psychotic disorders had
greater adherence to medication than did nonpsychotic patients (B = 1.753, t = 2.041, p = 0.044) (see
Table 4). Page 9/16 Table 4 Table 4 Table 4
Factors affecting medication adherence
Independent Variables
B
Std. Error
β
t-statistic
VIF
Constant
9.464
1.829
5.174
Marital status = married
1.164
0.722
0.156
1.613
1.051
Duration on medication = Less than 2 years
-1.631
0.794
-0.211
-2.053*
1.177
Occupation = Farmer
-1.541
0.749
-0.203
-2.057*
1.091
Diagnosis = Psychotic
1.753
0.859
0.216
2.041*
1.256
Alcohol
-0.061
0.052
-0.115
-1.159
1.091
Insight measure
-0.268
0.152
-0.177
-1.759
1.131
R2
0.248
F for R2 change
4.629**
Durbin-Watson
1.517
he dependent variable was adherence to medication (MARS). Significant at p < 0.05 ** P < 0.01 B = model coefficient; β = standardized model coefficient B = model coefficient; β = standardized model coefficient DISCUSSION In general, 64% of the respondents were nonadherent to clinic appointments, 22% of the respondents
missed 2 months of clinic appointments, 10% missed 2 months, and 32% missed more than 2 months of
clinic appointments. A similar study conducted in South Africa revealed that 46.2% of participants
attending outpatient mental health appointments had missed their appointment at one point (Ramlucken
& Sibiya, 2018). Individuals who frequently missed clinic appointments may have reduced their judgment
and understanding of the need for continued follow-up care. The prevalence of nonadherence to medication was 46.2%, which is slightly greater than that reported in
a study conducted in Mzimba, Malawi, among patients with a diagnosis of schizophrenia (44%) (Myaba,
2017). The high rate of nonadherence to medication is consistent with the findings of several studies. For
example, a review of 46 studies conducted in Asia, Europe, Africa and North America revealed that the
prevalence of nonadherence to treatment ranged from 48–57% (Semahegn et al., 2020). These findings
show that poor adherence to medication is common among patients with mental illness. In this study, female clients were 4.7 times more likely not to adhere to clinic appointments than male
clients were. This study agrees with the findings of a study in India's Kolkata Hospital, which revealed that
women were 2.7 times more likely than men to be nonadherent (Banerjee & Varma, 2013). However, a Page 10/16 Page 10/16 study from Nigeria indicated that men were 3.3 times more likely than women to fail to adhere to
treatment (Ibrahim et al., 2015). Sociocultural factors may be responsible for the disparity in the reported
findings. Women have many roles, including as homemakers, professionals, wives, mothers, and
caregivers, which may add to their failure to adhere to the suggested regimen. Protestants were more likely not to adhere than were those who did not belong to any religion. This study
is consistent with a study performed at a psychiatric clinic in Nigeria that found that Christians were more
likely to default to treatment than non-Christians were (Adeponle et al., 2007). Because of their religious
views, some individuals may refuse medical treatment, particularly for mental illness. Some people may
be swayed by spiritual leaders to prioritize spiritual healing above physical care (Borras et al., 2007). On
the other hand, believing that God will heal them may prevent them from adhering to clinic appointments
and medication. DISCUSSION In addition, patients may receive combined traditional therapies. Usually, the pathway to
care in most communities is from traditional healers or spiritual leaders to hospitals and back and forth,
which could contribute to nonadherence to appointments. For example, the findings of a study performed
in Malawi showed that the majority of patients believe that mental illness is caused by witchcraft, and
seeking alternative treatment from traditional healers is not uncommon even among Christians (Mekani &
Myaba, 2020). Respondents who were single and living alone were significantly more likely to miss their first
appointment. These findings are consistent with those of a Malaysian Outpatient Psychiatric Clinic study,
which showed that being alone was connected to missing appointments (Bahagia et al., 2020). Single
patients have less social support and are more prone to missed appointments. Furthermore, living alone
deprives individuals of necessary emotional and social support, as well as the ability to bring patients to
the clinic when they are ill or for follow-up care visits. Clients attending a mobile clinic were more likely not to adhere than were clients attending a static clinic. There is a scarcity of data on studies assessing adherence to outreach clinics. Most studies have shown
that there are many benefits of outreach clinics. Participants who attended mobile clinics were within a
short distance within the community. According to a study conducted in Nigeria, respondents who lived
fewer than 20 kilometers from the hospital were substantially less likely to be clinic defaulters than were
those who lived more than 50 kilometers away (Adelufosi et al., 2013). It is possible that some patients
travel long distances to the clinic, which might explain why they were not adherent to their clinic
appointment. However, further investigations are needed to determine the reasons for nonadherence
among the beneficiaries of outreach clinics. Patients who had been on medication for less than two years had significantly lower adherence to
medication than patients who had been on medication for more than two years. The findings of this
study are similar to those of a study conducted in Quebec, which revealed that nonadherent patients were
more likely to refuse treatment within the first 6 months after initiation (Rabinovitch et al., 2009). Limitations There was no prospective follow-up of clients who missed appointments or medications. The other
limitation is the use of the Medication Adherence Rating Scale (MARS), which is a more subjective
measure of medication adherence than objective measurements. However, the most applied
measurement in adherence studies is subjective, with almost 75% of the existing studies using
information taken from patients, their family members or service providers (Ljungdalh, 2017). DISCUSSION This
finding is inconsistent with that of a study performed at Emmanuel Psychiatric Hospital in central
Ethiopia, which revealed that a long treatment duration was associated with nonadherence among Page 11/16 patients with schizophrenia (Tareke, Tesfaye, Amare, Belete, Abate, et al., 2018). Another study in
Malaysia revealed that clients who had been in the clinic for less than 36 months were more likely to
default to treatment (Bahagia et al., 2020). The results of this study could be indicative of early stages of
treatment, when difficulties such as treatment engagement and acceptance are still being ironed out with
the patient, as the patient might still be in denial. This might indicate a lack of knowledge on the
importance of adhering to medication. Patients whose main occupation was farming had lower adherence to medication than patients whose
main occupation was not farming. Most related studies have evaluated the association between
occupation and nonadherence and have shown that occupation status is strongly associated with
medication adherence. However, no specific studies have examined the association between farming and
adherence. Although farming is a source of income, it may make patients busy, leading to nonadherence. Similar studies have shown that being busy is a reason for nonadherence to medication. Being a farmer
is so involved that one is busy. For example, a study performed in Ethiopia showed that 17.7% of patients
with schizophrenia were busy, which is one of the common reasons for nonadherence to medication
(Mamo, E.S. Gelaw, B.K. Tegenge, 2016). The study revealed that psychotic patients have greater adherence to medication than nonpsychotic
patients. This study is inconsistent with many other studies that have shown that patients with a
diagnosis of psychosis have poor medication adherence. This finding is consistent with that of a study
performed in Ethiopia, which showed that patients who were using psychoactive substances after the
initiation of treatment were nearly twice as likely to be nonadherent to antipsychotic medication than
were those who had no history of substance use (Tareke, Tesfaye, Amare, Belete, & Abate, 2018). This
study differs from a study performed in Europe that showed that patients with bipolar disorder had poor
adherence to medication due to poor insight (Novick et al., 2015) Conclusion It is important to address factors that influence nonadherence to clinic appointments to prevent relapse
and improve overall quality of life. References Page 12/16 1. Adelufosi, A. O., Ogunwale, A., Adeponle, A. B., & Abayomi, O. (2013). Pattern of attendance and
predictors of default among Nigerian outpatients with schizophrenia. 283–287. 2. Adeponle, A. B., Obembe, A. O., Suleiman, G. T., & Adeyemi, O. S. (2007). Missed first appointments:
Prevalence and associated factors in first-time attendees at an outpatient psychiatric clinic in
Nigeria. Mental Health, Religion and Culture, 10(6), 609–620. https://doi.org/10.1080/13674670601054024 3. Alpak, G., Aksoy, I., Demir, B., Unal, A., Virit, O., Bulbul, F., & Savas, H. A. (2015). Original
Paper/Araştırma Missed Appointments and Medication Noncompliance Among Consecutive
Psychiatric Patients. January. https://doi.org/10.5455/jmood.20151110015147 4. Bahagia, H., Kinta, U., Health, M., & River, H. S. (2020). Sociodemographic and Clinical Factors
Associated with Defaulting Outpatient Appointments in a Psychiatric Clinic , Malaysia. MJP Online
Early. 5. Banerjee, S., & Varma, R. P. (2013). Factors affecting nonadherence among patients diagnosed with
unipolar depression in a psychiatric department of a tertiary hospital in Kolkata, India. Depression
Research and Treatment, 2013. https://doi.org/10.1155/2013/809542 6. Coronado-v, V., & Museros-sos, D. (2020). Mental Health Patients ’ Expectations about the Non-
Medical Care They Receive in Primary Care : 1–9. 6. Coronado-v, V., & Museros-sos, D. (2020). Mental Health Patients ’ Expectations about the Non-
Medical Care They Receive in Primary Care : 1–9. 7. Ibrahim, A. W., Yahya, S., Pindar, S. K., Wakil, M. A., Garkuwa, A., & Sale, S. (2015). Prevalence and
predictors of suboptimal medication adherence among patients with severe mental illnesses in a
tertiary psychiatric facility in maiduguri, northeastern nigeria. Pan African Medical Journal, 21, 1–11. https://doi.org/10.11604/pamj.2015.21.39.6664 7. Ibrahim, A. W., Yahya, S., Pindar, S. K., Wakil, M. A., Garkuwa, A., & Sale, S. (2015). Prevalence and
predictors of suboptimal medication adherence among patients with severe mental illnesses in a
tertiary psychiatric facility in maiduguri, northeastern nigeria. Pan African Medical Journal, 21, 1–11. https://doi.org/10.11604/pamj.2015.21.39.6664 8. Ljungdalh, P. M. (2017). Nonadherence to pharmacological treatment in schizophrenia and
schizophrenia spectrum disorders - An updated systematic literature review. 31(4). 8. Ljungdalh, P. M. (2017). Nonadherence to pharmacological treatment in schizophrenia and
schizophrenia spectrum disorders - An updated systematic literature review. 31(4). 9. Mamo, E.S. Gelaw, B.K. Tegenge, G. T. (2016). Advances in Pharmacoepidemiology & Drug Safety
Medication Adherence among Patients with Schizophrenia Treated with. 5(2), 1–6. https://doi.org/10.4172/2167-1052 9. Mamo, E.S. Gelaw, B.K. Tegenge, G. T. (2016). Advances in Pharmacoepidemiology & Drug Safety
Medication Adherence among Patients with Schizophrenia Treated with. 5(2), 1–6. 54(1), 28–35. https://doi.org/10.1177/070674370905400106 54(1), 28–35. https://doi.org/10.1177/070674370905400106 54(1), 28–35. https://doi.org/10.1177/070674370905400106 15. Ramlucken, L., & Sibiya, M. N. (2018). Frequency and reasons for missed appointments of outpatient
mental health care users in the uMgungundlovu District. Curationis, 41(1), 1–4. https://doi.org/10.4102/curationis.v41i1.1835 16. Rehm, J., & Shield, K. D. (2019). Global Burden of Disease and the Impact of Mental and Addictive
Disorders. In Current Psychiatry Reports (Vol. 21, Issue 2). Current Medicine Group LLC 1. https://doi.org/10.1007/s11920-019-0997-0 17. Semahegn, A., Torpey, K., Manu, A., Assefa, N., Tesfaye, G., & Ankomah, A. (2020). Psychotropic
medication nonadherence and its associated factors among patients with major psychiatric
disorders: A systematic review and meta-analysis. Systematic Reviews, 9(1), 1–18. https://doi.org/10.1186/s13643-020-1274-3 18. Shah, C., Patel, K., Amin, N., & Shah, C. (2019). Study of various factors affecting compliance in
schizophrenia: A single center experience in India. Archives of Psychiatry and Psychotherapy, 21(3),
41–52. https://doi.org/10.12740/APP/105489 19. Tareke, M., Tesfaye, S., Amare, D., Belete, T., & Abate, A. (2018). Antipsychotic medication
nonadherence among schizophrenia patients in Central Ethiopia. South African Journal of
Psychiatry, 24(1). https://doi.org/10.4102/sajpsychiatry.v24i0.1124 20. Tareke, M., Tesfaye, S., Amare, D., Belete, T., Abate, A., Science, H., Dar, B., Referral, F. H., & Unit, P. (2018). Antipsychotic medication nonadherence among schizophrenia patients in Central Ethiopia. South African Journal of Psychiatry ISSN: (Online) 2078-6786, (Print) 1608-9685, https://do, 1–6. 21. Udedi, M. (2016). Improving Access to Mental Health Services in Malawi. August. https://doi.org/10.13140/RG.2.1.3996.9524 References https://doi.org/10.4172/2167-1052 10. Mekani, P., & Myaba, J. (2020). Studies in Spiritual Care. 11. Myaba, J. (2017). The Prevalence and Predictors of Antipsychotic Medication Nonadherence among
Clients with Psychotic Disorders in Mzimba, Malawi . University of Cape Town. 11. Myaba, J. (2017). The Prevalence and Predictors of Antipsychotic Medication Nonadherence among
Clients with Psychotic Disorders in Mzimba, Malawi . University of Cape Town. 12. Novick, D., Montgomery, W., Treuer, T., Aguado, J., Kraemer, S., & Haro, J. M. (2015). Relationship of
insight with medication adherence and the impact on outcomes in patients with schizophrenia and
bipolar disorder: Results from a 1-year European outpatient observational study. BMC Psychiatry,
15(1), 1–8. https://doi.org/10.1186/s12888-015-0560-4 12. Novick, D., Montgomery, W., Treuer, T., Aguado, J., Kraemer, S., & Haro, J. M. (2015). Relationship of
insight with medication adherence and the impact on outcomes in patients with schizophrenia and
bipolar disorder: Results from a 1-year European outpatient observational study. BMC Psychiatry,
15(1), 1–8. https://doi.org/10.1186/s12888-015-0560-4 13. Owie, G. O., Olotu, S. O., & James, B. O. (2018). Reliability and validity of the medication adherence
rating scale in a cohort of patients with schizophrenia from Nigeria. Trends in Psychiatry and
Psychotherapy, 40(2), 85–92. https://doi.org/10.1590/2237-6089-2017-0077 13. Owie, G. O., Olotu, S. O., & James, B. O. (2018). Reliability and validity of the medication adherence
rating scale in a cohort of patients with schizophrenia from Nigeria. Trends in Psychiatry and
Psychotherapy, 40(2), 85–92. https://doi.org/10.1590/2237-6089-2017-0077 14. Rabinovitch, M., Béchard-Evans, L., Schmitz, N., Joober, R., & Malla, A. (2009). Early predictors of
nonadherence to antipsychotic therapy in first-episode psychosis. Canadian Journal of Psychiatry, 14. Rabinovitch, M., Béchard-Evans, L., Schmitz, N., Joober, R., & Malla, A. (2009). Early predictors of
nonadherence to antipsychotic therapy in first-episode psychosis. Canadian Journal of Psychiatry, Page 13/16 Page 13/16 Figures Page 14/16 Page 14/16 Figure 1
Number of missed clinic appointments Figure 1 Number of missed clinic appointments Page 15/16 Page 15/16 Figure 2
Reasons for nonadherence to clinic appointments Figure 2 Reasons for nonadherence to clinic appointments Page 16/16
|
https://openalex.org/W2775152656
|
https://hal.archives-ouvertes.fr/hal-01886441/file/journal.pone.0189201.pdf
|
English
| null |
Discovery of carbamate degrading enzymes by functional metagenomics
|
PloS one
| 2,017
|
cc-by
| 12,760
|
Discovery of carbamate degrading enzymes by functional
metagenomics Lisa Ufarté, Elisabeth Laville, Sophie Duquesne, Diego Morgavi, Patrick
Robe, Christophe Klopp, Angeline Rizzo, Sandra Pizzut-Serin, Gabrielle
Potocki-Veronese To cite this version: Lisa Ufarté, Elisabeth Laville, Sophie Duquesne, Diego Morgavi, Patrick Robe, et al.. Discovery
of carbamate degrading enzymes by functional metagenomics. PLoS ONE, 2017, 12 (12), 21 p. 10.1371/journal.pone.0189201. hal-01886441 Distributed under a Creative Commons Attribution 4.0 International License HAL Id: hal-01886441
https://hal.science/hal-01886441v1
Submitted on 28 May 2019 L’archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d’enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés. HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers. Distributed under a Creative Commons Attribution 4.0 International License RESEARCH ARTICLE Editor: Seon-Woo Lee, Dong-A University,
REPUBLIC OF KOREA Editor: Seon-Woo Lee, Dong-A University,
REPUBLIC OF KOREA
Received: March 30, 2017
Accepted: November 21, 2017
Published: December 14, 2017
Copyright: © 2017 Ufarte´ et al. This is an open
access article distributed under the terms of the
Creative Commons Attribution License, which
permits unrestricted use, distribution, and
reproduction in any medium, provided the original
author and source are credited. Received: March 30, 2017
Accepted: November 21, 2017
Published: December 14, 2017 Discovery of carbamate degrading enzymes
by functional metagenomics Lisa Ufarte´1, Elisabeth Laville1, Sophie Duquesne1, Diego Morgavi2, Patrick Robe3,
Christophe Klopp4, Angeline Rizzo1, Sandra Pizzut-Serin1, Gabrielle Potocki-Veronese1* 1 LISBP, Universite´ de Toulouse, CNRS, INRA, INSA, Toulouse, France, 2 UMRH, INRA, Vetagro Sup,
France, 3 LibraGen S.A., Toulouse, France, 4 Plateforme Bio-informatique Toulouse Genopole, UBIA INRA,
Castanet-Tolosan, France * veronese@insa-toulouse.fr * veronese@insa-toulouse.fr a1111111111
a1111111111
a1111111111
a1111111111
a1111111111 a1111111111
a1111111111
a1111111111
a1111111111
a1111111111 Abstract Bioremediation of pollutants is a major concern worldwide, leading to the research of new
processes to break down and recycle xenobiotics and environment contaminating polymers. Among them, carbamates have a very broad spectrum of uses, such as toxinogenic pesti-
cides or elastomers. In this study, we mined the bovine rumen microbiome for carbamate
degrading enzymes. We isolated 26 hit clones exhibiting esterase activity, and were able to
degrade at least one of the targeted polyurethane and pesticide carbamate compounds. The most active clone was deeply characterized. In addition to Impranil, this clone was
active on Tween 20, pNP-acetate, butyrate and palmitate, and on the insecticide fenobu-
carb. Sequencing and sub-cloning of the best target revealed a novel carboxyl-ester hydro-
lase belonging to the lipolytic family IV, named CE_Ubrb. This study highlights the potential
of highly diverse microbiota such as the ruminal one for the discovery of promiscuous
enzymes, whose versatility could be exploited for industrial uses. OPEN ACCESS Citation: Ufarte´ L, Laville E, Duquesne S, Morgavi
D, Robe P, Klopp C, et al. (2017) Discovery of
carbamate degrading enzymes by functional
metagenomics. PLoS ONE 12(12): e0189201. https://doi.org/10.1371/journal.pone.0189201 Editor: Seon-Woo Lee, Dong-A University,
REPUBLIC OF KOREA Editor: Seon-Woo Lee, Dong-A University,
REPUBLIC OF KOREA Discovery of new carbamate degrading enzymes hematopoietic system, liver etc.) [4]. As such, environmental cleanup and wastewater treat-
ment became a high priority, more than 10,000 tons of carbamates being used per year world-
wide in the agriculture sector (data obtained from the Food and Agriculture Organization of
the United Nations, http://faostat3.fao.org/ and from [5]. Ministry of Education and Research provided
support in the form of salaries for [LU]. INRA
provided support in the form of salaries for [SPS],
[GPV] and [EL]. The high throughput screening
work was carried out at the Laboratory for
BioSystems & Process Engineering (Toulouse,
France) with the equipment of the ICEO facility,
dedicated to the screening and the discovery of
original enzymes. ICEO is supported by grants
from the Re´gion Midi-Pyre´ne´es, the European
Regional Development Fund and the Institut
National de la Recherche Agronomique (INRA). One of the authors, Patrick Robe [PR], is employed
by the commercial company LibraGen. LibraGen
provided support in the form of salaries for [PR],
but did not have any additional role in the study
design, data collection and analysis, decision to
publish, or preparation of the manuscript. The
specific roles of [PR] are articulated in the ’author
contributions’ section. The elimination of many lipophilic environmental pollutants is based on their conversion
to water soluble compounds and further microbial metabolisation. The first step in the meta-
bolic degradation of pesticide carbamates is their hydrolysis [1,6] catalysed by carboxyl ester
hydrolases (EC 3.1.1). These enzymes are part of the wide group of ester hydrolases (EC 3.1)
catalysing the hydrolysis of carboxylesters (EC 3.1.1), thioesters (EC 3.1.2), phosphoric (EC
3.1.4/5/7/8) and sulfuric (EC 3.1.6) esters. Carboxylesterases from various bacteria were previ-
ously reported to hydrolyse carbamates: Blastobacter [7], Arthrobacter [8], Pseudomonas [9],
Achromobacter [10] and Micrococcus genera [11]. Some of them display important homologies
with eukaryotic carbamate-acting carboxylesterases [8,12]. Besides phytosanitary products, another type of carbamates, namely polyurethanes (PUs),
causes important environmental problems. These polymers are found in many industrial
products: coatings, furniture, paints, synthetic skin, construction materials, elastomers, and
even implantable biomedical devices [13,14]. Gradually, they have replaced other polymers for
many reasons: chlorinated rubber because of safety reasons; latex rubber because of the lower
density and higher flexibility of PUs; plastics (such as PVC for automotive application for ex-
ample) because of their resistance to water, oils and solvents,etc. [15]. Polyurethanes accounts
for 6 to 7% of the total mass of plastic generated worldwide, with over half of the total global
market for coating applications [14]. Polyurethane worldwide production thus represents 15
Mt per year. The major use of PUs in Europe is packaging, and while recycling has increased
in the last few years, the most important way to dispose PUs is through landfilling [16]. Impra-
nil1DLN, the specific PU used in this study, is a anionic aliphatic polyester-PU produced by
Bayer Corporation for use in textile, leather and aircraft fabric coating [14]. Competing interests: LibraGen provided support
in the form of salaries for author [PR], but did not
have any additional role in the study design, data
collection and analysis, decision to publish, or
preparation of the manuscript. There are no
patents, products in development or marketed
products to declare. This does not alter our
adherence to all the PLOS ONE policies on sharing
data and materials. The specific roles of this author
are articulated in the ’author contributions’ section. PU biodegradation results from the activity of two main classes of enzymes [15,17]: ester-
ases (such as cholesterol esterases) and proteases (such as papain) that were shown to hydro-
lyse carbaryl and 4-nitrophenyl N-methyl-carbamates [18–20]. Other kinds of enzymes such
as ureases [21,22], urethanases [23,24], along with enzymes named impranilases, were shown
to degrade PUs. Moreover, PU degrading bacteria are numerous, mostly from the phyla Firmi-
cutes, Actinobacteria, and Proteobacteria, although the enzymes involved in these processes
have not all been identified to date [20]. It was shown, however, that PUs are barely used as
carbon or nitrogen sources for microorganisms in strict anaerobic conditions [25]. On the
other hand, in aerobic conditions, only one bacterial strain, assigned to the Comamonas genus,
has been shown to use polyester PU as carbon and nitrogen source [26]. Despite these advances in the understanding of carbamate enzymatic degradation, there are
still very few biological routes identified for the breakdown and recycling of carbamate-based
xenobiotics and polymers. In particular, the carbamate degrading potential of the uncultivated
bacterial fraction, which represents between 70 and 99% of most microbial ecosystems, is
underexplored. Only one study indeed allowed the discovery of an esterase from an unculti-
vated soil bacterium [27], capable of degrading poly(diethylene glycol adipate, a component of
polyester polyurethanes. 1. Introduction Copyright: © 2017 Ufarte´ et al. This is an open
access article distributed under the terms of the
Creative Commons Attribution License, which
permits unrestricted use, distribution, and
reproduction in any medium, provided the original
author and source are credited. Carbamates are N-substituted esters of carbamic acid. They are organic compounds with gen-
eral formula R1-NR2-(C = O)O-R3, used in agriculture as pesticides (where R1 is a methyl,
benzimidazole and aromatic moiety, respectively). The synthesis and commercialisation of
carbamate pesticides have been in progress since the 1950’s. Nowadays, the most employed
pesticides are organophosphorus compounds, carbamates and pyrethroids [1]. Data Availability Statement: Nucleotide sequence
data are available in the ENA browser (http://www. ebi.ac.uk/ena/data/view/LT674540-LT674549)
under the accession number(s) LT674540 to
LT674547. Carbamate pesticides have been in use in different kinds of crops all over the world. Their
use increased along with organophosphorus, to replace organochlorine pesticides. However,
some carbamate compounds and derivatives have an acute toxicity for mammals and aquatic
organisms. Carbamates, just like the well-known toxic organophosphorus compounds, are
inhibitors of acetylcholinesterase and therefore cause very similar symptoms. Some of them,
containing aromatic moieties, are also suspected carcinogens and mutagens since they break
down to aniline based derivatives, which were shown to be carcinogenic for humans [2,3]. For
example, methyl carbamates are considered non genotoxic because of the inability of the
methyl group to undergo metabolic degradation to an epoxide, while ethyl carbamates are
considered as multispecies carcinogens causing malignancies in different tissues (lung, Funding: We confirm that this research was
funded by the French Ministry of Education and
Research (Ministère de l’Enseignement supe´rieur
et de la Recherche), the INRA metaprogramme
M2E (project Metascreen), and the European
Union’s framework programme Horizon 2020
(LEITBIO-2015-685474, Metafluidics). The French PLOS ONE | https://doi.org/10.1371/journal.pone.0189201
December 14, 2017 1 / 21 PLOS ONE | https://doi.org/10.1371/journal.pone.0189201
December 14, 2017 2.1. Screening of the bovine rumen metagenomic library The bovine rumen metagenomic library consisted of 19,968 Escherichia coli fosmid clones,
each clone comprising a 30–40 kb DNA insert. The library covers around 700 Mbp of metage-
nomic DNA, which corresponds to the equivalent of more than one hundred bacterial
genomes. The library was first screened for the presence of chosen enzymatic activities: both esterases
and proteases were searched for, since they were previously reported to cleave the carbamate
linkage. The ability of a clone to degrade Tween 20 (polyethylene glycol sorbitan monolaurate,
an ester with C12 chain length), revealed the presence of esterases and lipases, also renamed
non lipolytic esterases and lipolytic esterases, respectively, according to the classification of
Ben Ali et al. [34], whereas the ability to degrade AZCL-casein indicated protease activity. The screen on Tween 20 resulted in 26 positive clones, corresponding to a hit yield of
0.13%. This value is in the same range of those obtained from other activity-based metage-
nomics studies targeted on the bovine rumen microbiome. Indeed, [35] found 11 esterases
from the rumen metagenome (hit yield 0.08%) by using α-naphtyl acetate, a short chain C2
naphtyl ester, as the screening substrate. In another study, [32] found 9 positive clones (hit
yield 0.04%) on tributyrin, a C4 chain triglyceride. The high hit yield obtained in the present
study indicates that Tween20 is an appropriate substrate to explore the functional diversity of
bacterial carboxylesterases. The screen on AZCL-casein did not allow the detection of any positive clone, contrarily to
what we previously observed in the same screening conditions with other metagenomic librar-
ies issued from various composts (unpublished results). A secondary screening of the 26 hit
clones was performed on two different kinds of substrates: Impranil, a commercial polyester
polyurethane, and pNP chromogenic esters of various chain lengths (C2, C4 and C16) to dis-
criminate and quantify lipolytic versus non lipolytic carboxylesterase activities. Impranil degradation was screened by using both positive selection on mineral medium
containing the PU as sole carbon source, and by searching for clones, grown on rich medium,
showing a polymer degradation halo [19]. Among the 26 clones obtained in total after primary
screening, 22 positive clones were obtained on the rich medium supplemented with Impranil. Thirteen of them were also positive on the mineral medium containing Impranil as sole carbon
source. In addition, to our knowledge, no metagenome was mined for activi-
ties of cleavage of the carbamate linkage of pesticides [28]. The bovine rumen metagenome was chosen for this study because of its great functional
and microbial diversity [29], and because of its richness in esterases, including carbohydrate-
esterases [29,30] and lipases [31,32]. In this dense ecosystem, these enzymes are involved both
in the metabolisation of lipids and of plant cell wall components, since carbohydrate-esterases
catalyze the de-O or -N-acylation of substituted hemicelulloses and pectins [33]. PLOS ONE | https://doi.org/10.1371/journal.pone.0189201
December 14, 2017 2 / 21 Discovery of new carbamate degrading enzymes Here we report the discovery, by using a multi-step activity-based metagenomics strategy
targeting the bovine rumen microbiome, of new esterases capable of hydrolysing two different
structures of carbamates, more specifically Impranil and fenobucarb. PLOS ONE | https://doi.org/10.1371/journal.pone.0189201
December 14, 2017 2.1. Screening of the bovine rumen metagenomic library They correspond to those harbouring the largest Impranil degradation halo on the rich
medium, due either to high recombinant gene expression and/or to high enzyme efficiency
and/or even to secretion which may happen, even rarely, in E. coli. Furthermore, of the 22
clones active on Impranil, 5 were not active on the chromogenic esters, 2 were active on pNPA
only, 3 on pNPB only, 10 on both pNPA and pNPB, and 2 on pNPA, pNPB and pNPP, the lat-
ter substrate being specific to lipolytic carboxylesterases [36]. Of the remaining 4 clones that
were not active on Impranil, 2 were not active on the chromogenic esters, 1 was active on both
pNPA and pNPB, and 1 on pNPA, pNPB and pNPP. These results highlight the diversity of substrate specificities of ruminal bacterial esterases. Screening using different substrates allowed the clustering of hit clones based on their func-
tional diversity (S1 Table). From the 22 clones highly active on Impranil, 8 were chosen for fur-
ther sequencing in order to identify novel enzymes active on carbamates. In order to explore
the largest sequence and functional diversity as possible, the clones to be sequenced were PLOS ONE | https://doi.org/10.1371/journal.pone.0189201
December 14, 2017 3 / 21 Discovery of new carbamate degrading enzymes selected because i) they were all able to degrade Impranil, ii) they belonged to various func-
tional clusters, especially to those which contain the highest number of clones, or the most
multispecific clones. Among them, clone 44I12 was one of the most efficient to break down
Impranil, as it produced the largest degradation halos. This clone was active on Impranil with
both assays. This characteristic is particularly important since it shows the ability of the clone
to use Impranil as a carbon source, since recent studies have spread some doubts on the speci-
ficity of the screening methods based on the observation of a degradation halo on solid media
for the discovery of Impranil degrading enzymes and strains [14]. Clone 44I12 was also active
against all 3 tested pNP-esters and it was selected for in depth characterization of its activity on
carbamates of various structures (S1 Fig). 2.2. Polyurethane degradation In order to further investigate the action of clone 44I12 on polyurethane, the concentrated
cytoplasmic extract was incubated in the presence of Impranil. After one day of reaction at
30˚C and pH 7.0, the medium became compact and viscous (Fig 1), and finally a solid aggre-
gate was obtained. We compared these observations with those of [14], who used various com-
mercial enzymes to degrade Impranil: an esterase from Pseudomonas fluorescens with a broad
substrate specificity (from lysophospholipase to amidase activity), Savinase™, a commercial ser-
ine-type protease originally produced by Bacillus sp., and a triacylglycerol lipase from Pseudo-
monas sp.. Biffinger et al. [14] observed that 2 days incubation at 30˚C of Impranil with the
esterase and lipase resulted in a decrease of the reaction medium opacity without aggregate
formation, whereas Impranil aggregated when incubated with protease. In the present work,
however, this effect on Impranil could not be attributed to proteolytic activity, since no prote-
ase activity was detected by testing clone 44I12 on Hide Remazol Blue, AZO- and AZCL-casein
(data not shown). In order to analyse the molecular mass distribution of the Impranil substrate and reaction
products, MALDI-TOF analyses were performed on reaction media before and after reaction. The spectra obtained with clone 44I12 (Fig 2) presented significant differences before and
after reaction. A different molar mass distribution was observed, with the appearance of peaks
at m/z 682.4, 683.4 and 782.4 after incubation. This was not the case when Impranil was incu-
bated with the negative biotic control, ie the E. coli strain Epi100 carrying the empty pCC1FOS
fosmid (S2 Fig). The spectra are in this case very similar before and after incubation. In addi-
tion, the spectrum obtained in the same analysis conditions with Impranil resuspended in
THF (S2 Fig) indicates a regular molar mass distribution which is very different than that
obtained with the biotic samples, which logically contain a lot of impurities. Unfortunately, it Fig 1. Reaction media of 44I12 cytoplasmic extract incubated with Impranil at 30˚C and pH 7.0 during
24h. Negative control: E. coli host strain Epi100 transformed with the empty pCC1FOS fosmid. For 44I12, the
reaction medium, in and out of the tube, is showed, since a solid aggregate could be obtained. https://doi.org/10.1371/journal.pone.0189201.g001 Fig 1. Reaction media of 44I12 cytoplasmic extract incubated with Impranil at 30˚C and pH 7.0 during
24h. Negative control: E. 2.2. Polyurethane degradation coli host strain Epi100 transformed with the empty pCC1FOS fosmid. For 44I12, the
reaction medium, in and out of the tube, is showed, since a solid aggregate could be obtained. https://doi.org/10.1371/journal.pone.0189201.g001 Fig 1. Reaction media of 44I12 cytoplasmic extract incubated with Impranil at 30˚C and pH 7.0 during
24h. Negative control: E. coli host strain Epi100 transformed with the empty pCC1FOS fosmid. For 44I12, the
reaction medium, in and out of the tube, is showed, since a solid aggregate could be obtained. https://doi.org/10.1371/journal.pone.0189201.g001 4 / 21 PLOS ONE | https://doi.org/10.1371/journal.pone.0189201
December 14, 2017 Discovery of new carbamate degrading enzymes Fig 2. MALDI-TOF spectra of the reaction medium containing Impranil and the enzymatic extract of clone 44I12 at the beginning (A) and after 24h
(B) of reaction. The red rectangle shows the new peaks observed after reaction. https://doi org/10 1371/journal pone 0189201 g002 Fig 2. MALDI-TOF spectra of the reaction medium containing Impranil and the enzymatic extract of clone 44I12 at the beginning (A) and after 24h
(B) of reaction. The red rectangle shows the new peaks observed after reaction. Fig 2. MALDI-TOF spectra of the reaction medium containing Impranil and the enzymatic extract of clone 44I12 at the beginning (A) and after 24h
(B) of reaction. The red rectangle shows the new peaks observed after reaction. https://doi.org/10.1371/journal.pone.0189201.g002 https://doi.org/10.1371/journal.pone.0189201.g002 https://doi.org/10.1371/journal.pone.0189201.g002 is still impossible to relate the molar mass distribution to a specific polymeric structure, since
there is no known structure of Impranil [19], even if a hypothetical one has been proposed by
Biffinger et al. [14]. According to this hypothetical structure, the predominant new peaks gen-
erated by clone 44I12 could correspond to the following degradation products: the one at m/z
682.4-is the closest in size to C36H68O8N2 with an atom of Na, with 683.4 a possible isotope;
the one at 782.4 could be the motif C36H66O8N2 with an atom of I but nothing seems to match
with only additions of Na+ or I-. These peaks were not observed on the spectra obtained after
incubation of clone 44I12 with two other polyurethanes (namely poly[4-(2,2-dicyanovinyl)-N-
bis(hydroxyethyl)aniline-alt-(4,4’-methylenebis(phenylisocyanate)))]urethane and poly[4-
(2,2-dicyanovinyl)-N-bis(hydroxyethyl)aniline-alt-(isophroronediisocyanate)]urethane), on
which 44I12 was not active (S3 Fig). This indicates that the peaks at m/z 682.4, 683.4 and 782.4
are specific to clone 44I12 action on Impranil, and not to a modification of a compound con-
tained in the cytoplasmic extract. PLOS ONE | https://doi.org/10.1371/journal.pone.0189201
December 14, 2017 2.2. Polyurethane degradation These results constitute a definite proof, along with those of
screening, that the enzymes produced by clone 44I12 impact the structure of the commercial
polyurethane Impranil. is still impossible to relate the molar mass distribution to a specific polymeric structure, since
there is no known structure of Impranil [19], even if a hypothetical one has been proposed by
Biffinger et al. [14]. According to this hypothetical structure, the predominant new peaks gen-
erated by clone 44I12 could correspond to the following degradation products: the one at m/z
682.4-is the closest in size to C36H68O8N2 with an atom of Na, with 683.4 a possible isotope;
the one at 782.4 could be the motif C36H66O8N2 with an atom of I but nothing seems to match
with only additions of Na+ or I-. These peaks were not observed on the spectra obtained after
incubation of clone 44I12 with two other polyurethanes (namely poly[4-(2,2-dicyanovinyl)-N-
bis(hydroxyethyl)aniline-alt-(4,4’-methylenebis(phenylisocyanate)))]urethane and poly[4-
(2,2-dicyanovinyl)-N-bis(hydroxyethyl)aniline-alt-(isophroronediisocyanate)]urethane), on
which 44I12 was not active (S3 Fig). This indicates that the peaks at m/z 682.4, 683.4 and 782.4
are specific to clone 44I12 action on Impranil, and not to a modification of a compound con-
tained in the cytoplasmic extract. These results constitute a definite proof, along with those of
screening, that the enzymes produced by clone 44I12 impact the structure of the commercial
polyurethane Impranil. 5 / 21 PLOS ONE | https://doi.org/10.1371/journal.pone.0189201
December 14, 2017 Discovery of new carbamate degrading enzymes 2.3. Pesticide carbamate degradation Clone 44I12 was then tested on fenobucarb, fenoxycarb, and prosulfocarb, three synthetic car-
bamate pesticides of known structures (S1 Fig). Fenobucarb is an insecticide with a high
potential for bio-concentration, used in many rice growing countries worldwide. Fenoxycarb
is also an insecticide, but of which bioaccumulation potential is moderate. Finally, prosulfo-
carb is an herbicide which is very persistent in water and sediments [37]. The cytoplasmic extract of clone 44I12 was incubated during three days at 30˚C with these
3 compounds independently, and reaction media were analysed by LC-MS. Nothing signifi-
cant was observed for the reactions on fenoxycarb and prosulfocarb, while the UV profile of
the reaction medium with fenobucarb was significantly changed after reaction (Fig 3). The
fenobucarb peak at retention time 6.4 min decreased by 33 ± 4% after reaction (against only by
3% after incubation with the cellular extracts of the E. coli strain Epi100 carrying the empty
pCC1FOS fosmid, as shown in S4 Fig), at the expense of a second peak with a retention time of
7.7 min. This peak, which is present in very little amount on the commercial fenobucarb UV
profile, corresponds to the degradation product 2-sec-butylphenol [38], which was checked
with a commercial standard. Moreover, mass spectrum analysis allowed us to confirm that the
peak at 6.4 min corresponds to fenobucarb (m/z 207) while the peak at 7.7 min presents MS
peaks at masses (m/z 150 and 121) that correspond to 2-sec-butylphenol. Reference masses
were taken from the work of [3], who studied fenobucarb degradation using membrane anodic
Fenton treatment. These results demonstrate that clone 44I12 is able to degrade fenobucarb by
cleaving the ester link, releasing a product (2-sec-butylphenol) which is less toxic than fenobu-
carb itself [39]. Nevertheless, clone 44I12 is unable to degrade fenoxycarb and prosulfocarb. This observation was already noted by Kim et al. [38], who discovered bacterial strains from
the genera Sphingobium and Novosphingobium, which are able to degrade fenobucarb and car-
baryl, but not other carbamates like fenoxycarb. PLOS ONE | https://doi.org/10.1371/journal.pone.0189201
December 14, 2017 Discovery of new carbamate degrading enzymes Fig 3. A. HPLC analysis from the reaction of fenobucarb with 44I12 enzymatic extract at the beginning of the reaction (blue) and after 24 h of reaction (red). B. Convertion of fenobucarb to 2–sec-butylphenol. htt
//d i
/10 1371/j
l
0189201 003 Fig 3. A. HPLC analysis from the reaction of fenobucarb with 44I12 enzymatic extract at the beginning of the reaction (blue) and after 24 h of reaction (red). B Convertion of fenobucarb to 2–sec-butylphenol Fig 3. A. HPLC analysis from the reaction of fenobucarb with 44I12 enzymatic extract at the beginning of the reaction (blue) and after 24 h of reaction (red). B. Convertion of fenobucarb to 2–sec-butylphenol. n of fenobucarb with 44I12 enzymatic extract at the beginning of the reaction (blue) and after 24 h of reaction (red). ylphenol Fig 3. A. HPLC analysis from the reaction of fenobucarb with 44I12 enzymatic extract at the beginning of the reacti
B. Convertion of fenobucarb to 2–sec-butylphenol. https://doi.org/10.1371/journal.pone.0189201.g003 the putative protease encoding genes were not properly expressed in E. coli, or, if well
expressed, that these enzymes are unable to break down the particular structure of the sub-
strates used in this study. the putative protease encoding genes were not properly expressed in E. coli, or, if well
expressed, that these enzymes are unable to break down the particular structure of the sub-
strates used in this study. According to Gabor et al., [43], E. coli is predicted to readily express around 40% of envi-
ronmental genes, with strong variations depending on source organisms. And as previously
shown, metagenomic genes cloned into fosmids are spuriously transcribed in E. coli thanks to
E. coli promoter sequences that are randomly distributed along the metagenomic DNA insert
[44]. Here, expression of the genes annotated as putative esterases or proteases was checked by
SDS-PAGE analysis of the cytoplasmic extracts of the 8 sequenced clones. For all clones, we
visualized one or several proteins overproduced compared to the negative control. For clones
25I16, 44I12, 50E19 and 50I3, the size of one of these proteins corresponds to that of the puta-
tive esterases identified by functional annotation (S6 Fig, Table 1). Without being a proof of
their function, these results strengthen the value of the functional annotation. They also dem-
onstrate again the potential of E. 2.4. Sequence analysis The metagenomic DNA inserts of the 8 hit clones chosen as previously described in this paper
were sequenced. For each clone, the largest contig ranged in size between 21 and 38 kbp and
had between 21 and 35 predicted ORFs. Two clones present a high redundancy (25I16 and
50E19), their sequence overlapping between ORF 5 and ORF 29 of 25I16 and ORF1 and
ORF25 of 50E19. Such sequence redundancy frequently occurs between sequences issued
from activity-based screening approaches due to the high selection pressure imposed by this
strategy [40,41]. gy
The taxonomic annotation of the largest contigs (Table 1) indicates that all sequences are
issued from bacteria of which the genome has not been sequenced yet. Contigs were all
assigned to Firmicutes, which is the dominant phylum in the bovine rumen microbiota [42]. The clone sequences were then mined for genes annotated as encoding putative esterases,
ureases or proteases that could be responsible for the screened activities. We have not detected
any potential target in small contigs, which contained a maximum of 1 or 2 ORFs. The RAST
annotation of the largest contigs allowed us to identify at least one gene predicted to encode an
esterase or a protease for each clone. These annotations were confirmed by BLASTP compari-
son of the ORF sequences to the NR database. In addition, the BLASTP analysis revealed other
genes encoding putative esterases or proteases that were annotated by RAST as ‘hypothetical
proteins’. Among the 8 sequenced hit clones, 5 contain at least two genes encoding putative
enzymes that may act synergistically on the targeted substrates. All together, we found 9 differ-
ent putative esterase and 6 putative protease sequences (Table 1, Fig 4 and S5 Fig). The fact
that no protease activity was found after primary and secondary screening indicates either that PLOS ONE | https://doi.org/10.1371/journal.pone.0189201
December 14, 2017 6 / 21 PLOS ONE | https://doi.org/10.1371/journal.pone.0189201
December 14, 2017 coli to express metagenomic genes issued from bacteria that
are very distant from Proteobacteria. PLOS ONE | https://doi.org/10.1371/journal.pone.0189201
December 14, 2017 7 / 21 Discovery of new carbamate degrading enzymes Table 1. ORFs of interest from the sequenced clones, annotated as putative esterases or proteases. Clone ID and
accession
number
Substrates
Taxonomic
annotation(Phylum/
Class/Genus)
ORFs of interest
(accession number)
RAST annotation
Best BLAST hit against
the NCBI NR database
(accession number)
Sequence coverage,
sequence identity
Best BLAST hit with a
functional annotation
13M17LT674547
Tween 20,
Impranil (both
media)
Firmicutes/Clostridia/
Thermacetogenium
SIP63269.1
Hypothetical protein
hypothetical protein
[Ruminococcus callidus]
(WP_021683508.1) Cov. 99%, Id. 53%
metallopeptidase
[Anaerostipes hadrus]
(WP_044924108.1) Cov. 98%, Id. 52%
SIP63282.1
Esterase/lipase
hypothetical protein
[Butyrivibrio fibrisolvens]
(WP_051216853.1) Cov. 100%, Id. 73%
esterase [Clostridiales
bacterium S7-1-4]
(WP_034547640.1) Cov. 99%, Id. 39%
25I16LT674546
Tween 20,
Impranil (both
media),
pNPA, pNPB
Firmicutes/Clostridia/
Clostridium
SIP63246.1
Hypothetical protein
putative
transglutaminase/
protease [uncultured
bacterium Contig1767]
(AHF23837.1) Cov. 100%, Id. 100%
putative
transglutaminase/
protease [uncultured
bacterium Contig1767]
(AHF23837.1) Cov. 100%, Id. 100%
SIP63257.1
Putative esterase
putative esterase
[uncultured bacterium
Contig1767]
(AHF23826.1) Cov. 100%, Id. 99%
putative esterase
[uncultured bacterium
Contig1767]
(AHF23826.1) Cov. 100%, Id. 99%
SIP63261.1*
Hypothetical protein
hypothetical protein
[Lachnospiraceae
bacterium C6A11]
(WP_035628054.1) Cov. 99%, Id. 46%
diguanylate
phosphodiesterase
[Butyrivibrio
proteoclasticus]
(WP_013280495.1) Cov. 99%, Id. 28%
29D17LT674545
Tween 20,
Impranil(both
media),
pNPA, pNPB
Firmicutes
SIP63220.1
Esterase/lipase
esterase [Lactobacillus
reuteri]
(WP_003670556.1) Cov. 97%, Id. 50%
esterase [Lactobacillus
reuteri]
(WP_003670556.1) Cov. 97%, Id. 50%
SIP63224.1
Hypothetical protein
hypothetical protein
[Erysipelotrichaceae
bacterium NK3D112]
(WP_051665678.1) Cov. 97%, Id. 52%
peptidase family M20/
M25/M40 [Firmicutes
bacterium CAG:129]
(CCZ45637.1) Cov. 96%,
Id. 49%
37F15LT674544
Tween 20,
Impranil (rich
medium),
pNPA, pNPB
Firmicutes/Clostridia/
Subdoligranulum
SIP63187.1
putative alpha-dextrin
endo-1, 6-alpha-
glucosidase
carbohydrate esterase
[Streptococcus henryi]
(WP_026183046.1) Cov. 100%, Id. 49%
carbohydrate esterase
[Streptococcus henryi]
(WP_026183046.1) Cov. 100%, Id. 49%
SIP63194.1
Esterase/lipase-like
protein
esterase [Lactobacillus
reuteri]
(WP_003666275.1) Cov. 96%, Id. 50%
esterase [Lactobacillus
reuteri]
(WP_003666275.1) Cov. 96%, Id. 50%
39F1LT674543
Tween 20,
Impranil (both
media),
pNPA, pNPB
Firmicutes/
Erysipelotrichia/
Holdemania
SIP63165.1
FIG004556:
membrane
metalloprotease
m50 family membrane
metalloprotease
[Faecalibacterium sp. CAG:74] (CDE51946.1)
Cov. 99%, Id. 46%
m50 family membrane
metalloprotease
[Faecalibacterium sp. CAG:74] (CDE51946.1)
Cov. 99%, Id. 46%
SIP63179.1
Predicted metal-
dependant
phosphoesterase
PHP domain-containing
protein [Clostridiales
bacterium],
WP_084096767.1, Cov. 97%, Id.54%
predicted metal-
dependent
phosphoesterases (PHP
family) [Ruminococcus
sp. CAG:379],
CDD54255.1, Cov.96%,
Id. 46%
44I12LT674542
Tween 20,
Impranil (both
media),
pNPA, pNPB,
pNPP
Firmicutes/Bacili/
Thermobacillus
SIP63154.1*CE_Ubrb
probable lipase/
esterase
hypothetical protein
[[Clostridium]
stercorarium]
(WP_015360182.1)Cov. 95%, Id. 46%
esterase [Lactobacillus
vaginalis]
(WP_003717503.1) Cov. 95%, Id. 43%
(Continued) (Continued) PLOS ONE | https://doi.org/10.1371/journal.pone.0189201
December 14, 2017 8 / 21 56%
*ORFs encoding putative proteins of theorical molecular weight corresponding to overproduced proteins in fosmid clones, as observed by SDS-PAGE
analysis of cytoplasmic extracts (S6 Fig)
https://doi.org/10.1371/journal.pone.0189201.t001
Fig 4. Graphical representation of the metagenomic sequence of clone 44I12, and RAST annotation of the identified ORFs. Red arrow: CE_Ubrb
encoding gene. https://doi.org/10.1371/journal.pone.0189201.g004 The sequence of clone 44I12 was further analysed. It contains no ORF annotated as prote-
ase, and only one ORF (SIP63154.1) annotated by the RAST server as a probable lipase/ester-
ase. The BLASTP analysis of all the other hypothetical proteins did not allow us to identify
*ORFs encoding putative proteins of theorical molecular weight corresponding to overproduced proteins in fosmid clones, as observed by SDS-PAGE
analysis of cytoplasmic extracts (S6 Fig)
https://doi.org/10.1371/journal.pone.0189201.t001 *ORFs encoding putative proteins of theorical molecular weight corresponding to overproduced proteins in fosmid clones, as observed by SDS-PAGE
analysis of cytoplasmic extracts (S6 Fig) *ORFs encoding putative proteins of theorical molecular weight corresponding to overproduced proteins in fosmid clones, as observed by SDS-PAGE
analysis of cytoplasmic extracts (S6 Fig)
https://doi.org/10.1371/journal.pone.0189201.t001 The sequence of clone 44I12 was further analysed. It contains no ORF annotated as prote-
ase, and only one ORF (SIP63154.1) annotated by the RAST server as a probable lipase/ester-
ase. The BLASTP analysis of all the other hypothetical proteins did not allow us to identify
*ORFs encoding putative proteins of theorical molecular weight corresponding to overproduced proteins in fosmid clones, as observed by SDS-PAGE
analysis of cytoplasmic extracts (S6 Fig)
https://doi.org/10.1371/journal.pone.0189201.t001 *ORFs encoding putative proteins of theorical molecular weight corresponding to overproduced proteins in fosmid clones, as observed by SDS-PAGE
analysis of cytoplasmic extracts (S6 Fig) heorical molecular weight corresponding to overproduced proteins in fosmid clones, as observed by SDS-PAGE
i ) The sequence of clone 44I12 was further analysed. It contains no ORF annotated as prote-
ase, and only one ORF (SIP63154.1) annotated by the RAST server as a probable lipase/ester-
ase. The BLASTP analysis of all the other hypothetical proteins did not allow us to identify Fig 4. Graphical representation of the metagenomic sequence of clone 44I12, and RAST annotation of the identified ORFs. Red arrow: CE_Ubrb
encoding gene. the metagenomic sequence of clone 44I12, and RAST annotation of the identified ORFs. Red arrow: CE_Ubrb Fig 4. Graphical representation of the metagenomic sequence of clone 44I12, and RAST annotation of the identified ORFs. Red arrow: CE_Ubrb
encoding gene Fig 4. Discovery of new carbamate degrading enzymes Table 1. (Continued)
Clone ID and
accession
number
Substrates
Taxonomic
annotation(Phylum/
Class/Genus)
ORFs of interest
(accession number)
RAST annotation
Best BLAST hit against
the NCBI NR database
(accession number)
Sequence coverage,
sequence identity
Best BLAST hit with a
functional annotation
50E19
LT674541
Tween 20,
Impranil (both
media),
pNPA, pNPB
Firmicutes/Clostridia/
Clostridium
SIP63132.1
Putative esterase
putative esterase
[uncultured bacterium
Contig1767]
(AHF23826.1) Cov. 100%, Id. 99%
putative esterase
[uncultured bacterium
Contig1767]
(AHF23826.1) Cov. 100%, Id. 99%
SIP63121.1
Hypothetical protein
putative
transglutaminase/
protease [uncultured
bacterium Contig1767]
(AHF23837.1) Cov. 100%, Id. 100%
putative
transglutaminase/
protease [uncultured
bacterium Contig1767]
(AHF23837.1) Cov. 100%, Id. 100%
SIP63136.1*
Hypothetical protein
hypothetical protein
[Lachnospiraceae
bacterium C6A11]
(WP_035628054.1) Cov. 99%, Id. 46%
diguanylate
phosphodiesterase
[Butyrivibrio
proteoclasticus]
(WP_013280495.1) Cov. 99%, Id. 28%
50I3LT674540
Tween 20,
Impranil (rich
medium),
pNPA, pNPB
Firmicutes/Bacili/
Bacillus
SIP63105.1*
N-acetylglucosamine-
6-phosphate
deacetylase (EC
3.5.1.25)
n-acetylglucosamine-
6-phosphate deacetylase
[Ruminococcus sp. CAG:382] (CDD02602.1)
Cov. 99%, Id. 55%
n-acetylglucosamine-
6-phosphate deacetylase
[Ruminococcus sp. CAG:382] (CDD02602.1)
Cov. 99%, Id. 55%
SIP63109.1
Putative esterase
hypothetical protein
[Hungatella hathewayi]
(WP_006780815.1)Cov. 96%, Id. 57%
tributyrin esterase
[Clostridiales bacterium
VE202-28]
(WP_025484029.1) Cov. 96%, Id. 56%
*ORFs encoding putative proteins of theorical molecular weight corresponding to overproduced proteins in fosmid clones, as observed by SDS-PAGE
analysis of cytoplasmic extracts (S6 Fig) The sequence of clone 44I12 was further analysed. It contains no ORF annotated as prote-
ase, and only one ORF (SIP63154.1) annotated by the RAST server as a probable lipase/ester-
ase. The BLASTP analysis of all the other hypothetical proteins did not allow us to identify
pNPA, pNPB
(AHF23826.1) Cov. 100%, Id. 99%
(AHF23826.1) Cov. 100%, Id. 99%
SIP63121.1
Hypothetical protein
putative
transglutaminase/
protease [uncultured
bacterium Contig1767]
(AHF23837.1) Cov. 100%, Id. 100%
putative
transglutaminase/
protease [uncultured
bacterium Contig1767]
(AHF23837.1) Cov. 100%, Id. 100%
SIP63136.1*
Hypothetical protein
hypothetical protein
[Lachnospiraceae
bacterium C6A11]
(WP_035628054.1) Cov. 99%, Id. 46%
diguanylate
phosphodiesterase
[Butyrivibrio
proteoclasticus]
(WP_013280495.1) Cov. 99%, Id. 28%
50I3LT674540
Tween 20,
Impranil (rich
medium),
pNPA, pNPB
Firmicutes/Bacili/
Bacillus
SIP63105.1*
N-acetylglucosamine-
6-phosphate
deacetylase (EC
3.5.1.25)
n-acetylglucosamine-
6-phosphate deacetylase
[Ruminococcus sp. CAG:382] (CDD02602.1)
Cov. 99%, Id. 55%
n-acetylglucosamine-
6-phosphate deacetylase
[Ruminococcus sp. CAG:382] (CDD02602.1)
Cov. 99%, Id. 55%
SIP63109.1
Putative esterase
hypothetical protein
[Hungatella hathewayi]
(WP_006780815.1)Cov. 96%, Id. 57%
tributyrin esterase
[Clostridiales bacterium
VE202-28]
(WP_025484029.1) Cov. 96%, Id. Graphical representation of the metagenomic sequence of clone 44I12, and RAST annotation of the identified ORFs. Red arrow: CE_Ubrb
encoding gene. https://doi.org/10.1371/journal.pone.0189201.g004 PLOS ONE | https://doi.org/10.1371/journal.pone.0189201
December 14, 2017 9 / 21 Discovery of new carbamate degrading enzymes another putative esterase. We therefore hypothesized that this gene was responsible for the
activities of clone 44I12. In order to prove it, we subcloned this gene individually in the overex-
pression vector pET55. The predicted molecular weight of the recombinant protein fused to a
N-terminal Strep-tag and to a C-terminal (His)6 tag is 36,4 kDa, against 32,5 kDa for the native
protein produced by the 44I12 fosmid clone. The SDS-PAGE analysis of the cytoplasmic pro-
teins of the E. coli BL21star (DE3) strain transformed with this plasmid highlighted the over-
production of the full-size recombinant protein, at a slightly higher level than that produced
by the 44I12 fosmid clone (S7 Fig). Moreover, in agreement with these results, the level of
esterase activity of the plasmid clone on pNP-esters (5.26, 2.45 and 0.032 U/mL of cytoplasmic
extract for pNPA, pNPB and pNPP, respectively) was on average 1.3 times higher than that
produced in the same conditions by the fosmid clone. These results confirm that the protein
with accession number SIP63154.1 is an esterase. We named it CE_Ubrb (“carboxyl-esterase
from an uncultured bovine ruminal bacterium”). Its best characterized homolog is the esterase
LC-Est2 from an uncultured bacterium, discovered from a leaf-branch compost metagenome
[45]. LC-Est2 shares 32% identity on 94% of sequence length with CE_Ubrb, and is active on
tributyrin, a substrate specific to esterases and lipases. This is in accordance with our results,
CE_Ubrb being active on all pNP esters tested. LC-Est2 has never been tested on carbamates,
to our knowledge. Six other characterised enzymes were found among the 5,662 sequences of the NCBI NR
database presenting more than 25% identity with CE_Ubrb. These characterised enzymes are
named lipases/esterases, or lipolytic enzymes. All of them are part of the serine hydrolase fam-
ily, containing the GXSXG consensus sequence, and take part in prokaryotic and eukaryotic
lipolysis (Table 2). According to Arpigny et Jaeger [51], bacterial lipolytic enzymes can be classified in eight
families, depending on the conserved sequence motif and their biological properties. https://doi.org/10.1371/journal.pone.0189201.t002 Against
the ESTHER database [52], which clusters in 4 blocks more than 30.000 manually curated pro-
teins displaying an α/β-hydrolase fold, the best CE_Ubrb BLAST hit was found to be Lactoba-
cillus reuteri 100–23 HSL (EDX41824.1), sharing 44% of identity over 99% coverage. This
putative enzyme, which is still not characterised, is a member of the HSL-like family from
block H, which corresponds to family IV of the classification of lipolytic enzymes [51]. This
family is composed of many esterases from distantly related prokaryotes [53,54]. These
enzymes are remarkably similar to mammalian hormone-sensitive lipases (HSL), containing Table 2. Characteristics of the characterised enzymes with more than 25% identity with CE_Ubrb. Accession
number
Annotation and substrate specificity
Sequence identity Coverage
Taxonomic origin
Reference
AIT56388
esterase LC-Est2 : tributyrin
32%
95%
Uncultured
bacterium
[45]
AFG17170
EstJ : tributyrin, p-nitrophenyl esters (C2-4-6-8-10-12-14)
29%
89%
Uncultured
bacterium
[46]
ACF04196
lipase/esterase : tributyrin,p-nitrophenylbutyrate/ caprylate/
laurate
28%
91%
Uncultured
bacterium
[47]
ACL67843
lipolytic enzyme : tributyrin, p-nitrophenylbutyrate
27%
87%
Uncultured
bacterium
[48]
ABQ11272
lipase/esterase : Tributyrin, p-nitrophenylbutyrate
29%
63%
Uncultured
bacterium
[49]
AAS77245
lipase/esterase : Tributyrin, p-nitrophenylbutyrate
27%
65%
Uncultured
bacterium
[50]
AAS77242
lipase/esterase : Tributyrin, p-nitrophenylbutyrate
26%
63%
Uncultured
bacterium
[50]
htt
//d i
/10 1371/j
l
0189201 t002 haracteristics of the characterised enzymes with more than 25% identity with CE_Ubrb. PLOS ONE | https://doi.org/10.1371/journal.pone.0189201
December 14, 2017 PLOS ONE | https://doi.org/10.1371/journal.pone.0189201
December 14, 2017 10 / 21 Discovery of new carbamate degrading enzymes the serine, aspartic acid and histidine catalytic residues, along with a G that is involved in
hydrogen bonding interaction, stabilizing an oxyanion hole formed during enzymatic reaction
and promoting the catalysis [55]. All these residues are conserved in the CE_Ubrb sequence
(S8 Fig). Bacterial HSL supposedly show activity only towards short fatty acid chain length
substrates (tributyrin, vinyl propionate) [56] compared to mammalian HSL that have a broad
substrate specificity (olive oil, short chain esters, trioctanoin, etc.) The CE_Ubrb activity pro-
file shows a closer similarity to mammalian HSL than to bacterial ones, our target being active
on short chain esters but also on Impranil and its long motif. Finally, the ESTHER database
also mentions the affiliation of these HSL-like family to the block H, containing, among others,
plant carboxylesterases and bacterial tannases. It also contains kynurenine-formamidases, a
pattern found in the sequence of CE_Ubrb using the InterProScan software. PLOS ONE | https://doi.org/10.1371/journal.pone.0189201
December 14, 2017 3.1. Chemicals Impranil DLN was supplied by Bayer Corporation (Germany). Poly[4-(2,2-dicyanovinyl)-N-
bis(hydroxyethyl)aniline-alt-(4,4’-methylenebis(phenylisocyanate)))]urethane and poly[4-
(2,2-dicyanovinyl)-N-bis(hydroxyethyl)aniline-alt-(isophroronediisocyanate)]urethane were
purchased from Sigma Aldrich (France). Tween 20, Pefabloc, para-nitrophenyl acetate (pNPA), para-nitrophenyl butyrate (pNPB),
para-nitrophenyl palmitate (pNPP), para-nitrophenol (pNP), tetrahydrofuran (THF), 2-sec-
butylphenol, (2-Butan-2-ylphenyl), N-methylcarbamate (fenobucarb), Ethyl 2-(4-phenoxyphe-
noxy)ethylcarbamate (fenoxycarb) and S-Benzyl dipropylthiocarbamate (prosulfocarb) were
purchased from Sigma Aldrich (France). AZCL-xylan (XYL), AZCL-casein (CAS), AZCL-Barley β-glucan (BGLU), AZO-CM Cellu-
lose (CMC), AZO-Carob Galactomannan (GM) were purchased from Megazyme (Ireland). Lysonase™Bioprocessing Reagent was purchased from Novagen (France). 3.2. Metagenomic DNA sampling and library construction Rumen contents were obtained from two non-producing, rumen-cannulated Holstein dairy
cows. Cows were housed at the Herbipole experimental unit (INRA, Theix). Procedures on
animals complied to national standards fixed by the legislation on animal care (Certificate of
Authorization to Experiment on Living Animals, No. 004495, Ministry of Agriculture, France). They were adapted during 7 weeks to a diet of 80% wheat straw, 12% concentrate and 8% beet-
root molasses. Feeding was ad libitum once a day in the morning. Rumen contents were taken
before feeding from various parts of the rumen and manually homogenized. The metagenomic library was constructed from the mix of rumen samples from both cows. Enriched bacterial fractions were recovered separately from the two rumen samples by a den-
sity gradient technique using Nycodenz as previously described [57]. The cell pellets were sus-
pended in a 50 mM Tris (pH 8), 100 mM EDTA buffer, mixed in equal weight parts and then
incorporated in low-melt-point agarose before a gentle enzymatic lysis as previously described
[40]. Fragments sizing between 30 and 40 kb were isolated and cloned into pCC1FOS fosmid
(Epicentre Technologies). EPI100 E. coli cells were then transfected to obtain a library of
19,968 clones from the rumen samples. Recombinant clones were transferred to 384-well
microtiter plates containing Luria Bertani (LB) medium, supplemented with 12.5 mg/L chlor-
amphenicol and 8% (w/v) glycerol. After 22 hours of growth at 37˚C without shaking, the
plates were stored at -80˚C. According to the
tree we created with sequences from the first 8 lipolytic families described in Arpigny et Jaeger
(Fig 5), it is also clear that the CE_Ubrb sequence clusters with all family IV members, in Fig 5. Phylogenetic tree of sequences characteristic of the first 8 lipolytic families described by Arpigny et Jaeger [51], along with the
characterized CE_Ubrb blast hits against the NCBI-NR database and the first blast hits against the ESTHER database. In red: biochemically
characterized enzymes. Fig 5. Phylogenetic tree of sequences characteristic of the first 8 lipolytic families described by Arpigny et
characterized CE_Ubrb blast hits against the NCBI-NR database and the first blast hits against the ESTHER
characterized enzymes. Fig 5. Phylogenetic tree of sequences characteristic of the first 8 lipolytic families described by Arpigny et Jaeger [51], along with the
characterized CE_Ubrb blast hits against the NCBI-NR database and the first blast hits against the ESTHER database. In red: biochemically
characterized enzymes. Fig 5. Phylogenetic tree of sequences characteristic of the first 8 lipolytic families described by Arpigny et Jaeger [51], along with the
characterized CE_Ubrb blast hits against the NCBI-NR database and the first blast hits against the ESTHER database. In red: biochemically
characterized enzymes. https://doi.org/10.1371/journal.pone.0189201.g005 https://doi.org/10.1371/journal.pone.0189201.g005 PLOS ONE | https://doi.org/10.1371/journal.pone.0189201
December 14, 2017 11 / 21 Discovery of new carbamate degrading enzymes particular the 6 of the 7 characterized best blast hits listed in Table 2. However, surprisingly,
Lc-Est2 (which, according to Okano et al. [45], would belong to the family I-6) also clusters in
the family IV branch, even if it is more distantly related to family IV members than CE_Ubrb
itself. Anyway, no significant homology can be found between CE_Ubrb and family VII mem-
bers, while all other carbamate degrading enzymes identified to date exclusively belong to fam-
ily VII [55]. 3.4. Secondary screening The hit clones isolated from primary screening were then assayed to determine their ability to
degrade Impranil, using two different solid media. The solid selective medium contained 3 g/L Impranil as sole carbon source and a minimal
medium composed of salts (3.6 g/L Na2HPO4, H2O; 0.62 g/L KH2PO4; 0.11 g/L NaCl; 0.42 g/
L NH4Cl), 2 mM MgSO4, 0.03 mM CaCl2, other salts (15 mg/L Na2EDTA, 2H2O; 4.5 mg/L
ZnSO4, 7H2O; 0.3 mg/L CoCl2, 6H2O; 1 mg/L MnCl2, 4H2O; 1 mg/L H3BO3; 0.4 mg/L
Na2MoO4, 2H2O; 3 mg/L FeSO4, 7H2O; 0.3 mg/L CuSO4, 5H2O), leucine 0.04 g/L and thia-
mine hypochloride 0.1 g/L and supplemented with 12.5 mg/L chloramphenicol. The assay
plates were incubated at 37˚C for up to 3 weeks or until growth was observed. The rich Impranil containing medium was constituted by solid LB medium supplemented
with 12.5 mg/L chloramphenicol and with 3 g/L of Impranil in suspension. The assay plates
were incubated at 37˚C for up to 3 weeks, or until apparition of a degradation halo, signifying
the presence of a positive clone. After clone isolation on solid LB medium and validation of their activity on the Tween20
screening medium, the hit clones obtained after primary screening were also grown in micro-
plates containing 200μL of LB medium supplemented with 12.5 mg/L chloramphenicol for pre-
culture, at 37˚C overnight. These pre-cultures were used to inoculate cultures in deep well
micro-plates containing 1.6 mL of LB liquid medium supplemented with 12.5 mg/L chloram-
phenicol, which were subsequently incubated overnight at 37˚C. Cells were pelleted by centrifu-
gation at 1,760 x g for 30 minutes at 4˚C. Each pellet was re-suspended in 250 μL of lysis buffer
(100 mM HEPES pH 7.5, 1 mM pefabloc and 666.7 μl/L lysonase), and incubated at 600 rpm
(shaking throw 25 mm) for one hour at 37˚C in a Multitron Pro shaker (INFORS HT) with a
freeze/thaw cycle at -80˚C in order to perform cell lysis. Cellular extracts were isolated by centri-
fugation at 1,760 x g for 30 minutes at 4˚C, and stored at 4˚C for less than 24 h before use. Carboxylesterase activity of the cytoplasmic extracts was quantified by monitoring the
hydrolysis of pNP esters into the corresponding acid and p-nitrophenol. Assays were performed
in 96-well microtiter plates on pNPA, pNPB and pNPP at 1 mM final concentration. paraNitro-
phenol was used for standard curve. 3.4. Secondary screening For pNPA and pNPB, 195 μL of cellular extract were mixed
with 5μL of substrate dissolved at 40 mM in 2-methyl-2-butanol (2M2B). For pNPP, 175μL of
cellular extract were mixed with 25μL of substrate dissolved at 8 mM in isopropanol. Enzymatic
activity was determined by following the absorbance increase at 405 nm during 30 min at 30˚C,
in a microplate spectrophotometer (BioTek™Eon™Microplate Spectrophotometers, Colmar,
France). A fosmid clone was considered as positive on one of these pNP-substrates if its activity
was at least of 5.10−3 U/mL of cell extract in these screening conditions. 3.3. Primary high-throughput screening of the metagenomic library The library was gridded on 22 cm x 22 cm trays containing solid agar medium supplemented
with 12.5 mg/L chloramphenicol, using an automated microplate gridder (K2, KBiosystem,
Basildon, UK), which allowed to perform 140,000 assays in 2 days. PLOS ONE | https://doi.org/10.1371/journal.pone.0189201
December 14, 2017 12 / 21 Discovery of new carbamate degrading enzymes Carboxylesterase screening medium was constituted by solid LB medium supplemented
with 12.5 mg/L chloramphenicol and with 1% (w/v) final concentration of Tween 20. The
assay plates were incubated during 3 days at 37˚C until apparition of a powdery halo, signify-
ing the presence of a positive clone. Protease activity screening medium was LB medium supplemented with 12.5 mg/L chlor-
amphenicol and with 0.2% (w/v) final concentration of AZCL-casein. Protease screening plates
were incubated during 3 weeks at 37˚C, in order to observe the eventual apparition of a blue
halo around the hit clones. 3.5. Sequencing and data analysis Fosmid DNA of the positive clones was extracted with the NucleoBond Xtra Midi kit from
Macherey-Nagel (France) following supplier recommendations. Fosmids were then PLOS ONE | https://doi.org/10.1371/journal.pone.0189201
December 14, 2017 13 / 21 Discovery of new carbamate degrading enzymes individually labelled to avoid any further miscontigation [58], and sequenced with the MiSeq
technology, at the Genotoul platform (http://get.genotoul.fr/). For each clone, a random selec-
tion of reads was performed to obtain a mean depth coverage of 40 x. Read assembly was car-
ried out using Masurca (http://www.genome.umd.edu/masurca.html). Contigs were cleaned
from the vector pCC1FOS sequence using Crossmatch (http://bozeman.mbt.washington.edu/
phredphrapconsed.html). ORF detection and functional annotation was performed using the
RAST software [59]. Sequences sizing between 21 and 38 kbp, which correspond to the largest
contig obtained for each clone, were deposited in the European Nucleotide Archive (http://
www.ebi.ac.uk/ena) under accession numbers LT674540-LT674547 (Table 1). The RAST annotation of the carboxylesterase encoding genes was confirmed by BLASTP
analysis of the predicted ORFs against the NCBI non-redundant protein sequences database
(E-value 10−8, identity 35%, query length coverage 50%, the same cut-off parameters as
in [40]). Further sequence analysis was performed with other BLASTP analysis against the
ESTerases and alpha/beta-Hydrolase Enzymes and Relatives database (ESTHER) [52]. The
protein signature was detected using the InterProscan software [60]. Sequence alignments
leading to the creation of the phylogenetic tree along with the tree itself were designed using
the MEGA6 software [61]. The sequences used were chosen from different publications, cited
in the text. A distance matrix was generated from the multiple sequence alignment using the
BLOSUM62 amino acid residue substitution matrix. The output result file was subjected to
hierarchical clustering using the Ward’s method [62]. The multiple alignment of CE_Ubrb
sequence with those of its characterized homologs and with members of the lipolytic family IV
was generated with Clustal Omega. Taxonomic assignation of the metagenomic sequences was determined according to Phylo-
Pythias analysis [63] (http://phylopythias.bifo.helmholtz-hzi.de, Model type Generic 2013–800
Genera) of the nucleotide sequence of the largest contigs. Same results were obtained with
minimum slice at 3 and 50%. PLOS ONE | https://doi.org/10.1371/journal.pone.0189201
December 14, 2017 3.6. Characterization of enzymatic activities 3.6.1. Carbamate and polyurethane degradation reactions. The positive clones were
grown in tubes containing 3 mL of LB medium supplemented with 12.5 mg/L chlorampheni-
col for preliminary culture, at 37˚C overnight. These cultures were used to inoculate 20 mL
cultures grown in LB medium supplemented with 12.5 mg/L chloramphenicol at 37˚C, with
orbital shaking at 120 rpm (shaking throw 25 mm). After 24 h, cells were harvested by cen-
trifuging for 5 min at 12,857 x g, and re-suspended in activity buffer (PBS pH 7.0) to obtain a
final OD600nm of 80. Cell lysis was done using sonication. Cell debris were centrifuged at
12,857 x g for 10 min and the cytoplasmic extracts were filtered with a 0.20 μm Minisart RC4
syringe filter (Sartorius). Quantification of total proteins present in the cytoplasmic extracts
was carried out using the Bradford method [64]. The samples were diluted by five, and 20μL of
these dilutions were mixed with 200 μL of Bradford reagent. After 20 minutes, the OD was
measured at 595 nm. The standard used was BSA. Overproduction of recombinant proteins was visualized by SDS-PAGE analysis of the cyto-
plasmic extracts using Any kDTM Mini-PROTEAN_ TGXTM Precast Gel (Bio-Rad). After
migration, proteins were stained with the PageBlue Protein Staining Solution (Thermo Scien-
tific) according to the manufacturer’s recommendations. Enzymatic reactions were carried out
at 30˚C in hemolysis tubes, containing 500 μL of cytoplasmic extract, mixed with 500 μL of the
substrate suspended or solubilized in the activity buffer (PBS pH 7.0) to obtain a final concen-
tration of 6 g/L for the Impranil dispersion, or 2 g/L fenoxycarb, fenobucarb or prosulfocarb
(for structures see S1 Fig). 14 / 21 PLOS ONE | https://doi.org/10.1371/journal.pone.0189201
December 14, 2017 Discovery of new carbamate degrading enzymes The reaction progress was followed by taking samples at 0 and 24h of incubation for LC-
MS and Maldi-Toff analyses. Samples were incubated at 95˚C for 5 minutes to stop the reac-
tion for the small carbamates. Impranil reactions were directly frozen at—80˚C to stop the
reaction, in order to avoid polymer chain reorganization that could have impacted the results. 3.6.2. Matrix assisted laser desorption/ionization–time-of-flight (MALDI-TOF) mass
spectrometry. Samples were lyophilised before being re-suspended in 400 μL of THF. 3.6. Characterization of enzymatic activities A cone of 60 V was used, and the probe temperature was set at 450˚C. Fourty
percents of the sample went through the RI detector, 60% to the mass spectrometer. The Chro-
meleon software was used for data acquisition and analysis. The LC system was hyphenated with a mass spectrophotometer (MSQ PLUS, Thermo Sci-
entific) operated in positive mode and equipped with an electrospray ionisation (ESI) source
for 30 min with a scan time of 0.10 seconds over the range m/z 100–1,500 with nitrogen (N2)
as drying gas. A cone of 60 V was used, and the probe temperature was set at 450˚C. Fourty
percents of the sample went through the RI detector, 60% to the mass spectrometer. The Chro-
meleon software was used for data acquisition and analysis. PLOS ONE | https://doi.org/10.1371/journal.pone.0189201
December 14, 2017 3.6. Characterization of enzymatic activities Sam-
ples were then analyzed onto a commercial MALDI-TOF mass spectrometer MALDI-TOF
Micro Mx (Waters), Laser N2 (337 nm), acceleration voltage 12 kV, reflectron mode, dithranol
matrix and NaI salts, in the linear and positive mode for a range of m/z 200–1,200. Spectra
were acquired automatically using a standard procedure at the Service Commun de Spectro-
me´trie de Masse at Universite´ Paul Sabatier in Toulouse, France. 3.6.3. High performance liquid chromatography–mass spectrometry. As in other
papers describing carbamate-pesticide degradation [38], we used a LC-18 column and UV
detection to quantify carbamate concentration in the samples. LC-18 (octadecyl) are general-
purpose hydrophobic alkyl phases that give good peak shape for a variety of compounds, and
we checked that the method was quantitative for fenobucarb, fenoxycarb and prosulfocarb by
using standard curves prepared from known compound concentrations. Samples were dissolved in 1.5 volumes of acetonitrile, in order to recover a ratio of 60% ace-
tonitrile, 40% water. Analyses were performed on a HPLC system (Ultimate 3000, Dionex)
with in line degasser. LC of small carbamate samples was performed on a SUPELCOSIL™LC-
18 HPLC Column 5 μm particle size (250× 4.6 mm) equipped with a SUPELCOSIL™LC-18
Supelguard™Cartridge 5 μm particle size (20 × 4.0 mm) pre-column. The mobile phase (60%
acetonitrile-40% water) was pumped at a flow rate of 1 mL/min, and UV detection was carried
out at 205 nm, 210 nm and 235 nm for fenobucarb, prosulfocarb and fenoxycarb, respectively. Samples were dissolved in 1.5 volumes of acetonitrile, in order to recover a ratio of 60% ace-
tonitrile, 40% water. Analyses were performed on a HPLC system (Ultimate 3000, Dionex)
with in line degasser. LC of small carbamate samples was performed on a SUPELCOSIL™LC-
18 HPLC Column 5 μm particle size (250× 4.6 mm) equipped with a SUPELCOSIL™LC-18
Supelguard™Cartridge 5 μm particle size (20 × 4.0 mm) pre-column. The mobile phase (60%
acetonitrile-40% water) was pumped at a flow rate of 1 mL/min, and UV detection was carried
out at 205 nm, 210 nm and 235 nm for fenobucarb, prosulfocarb and fenoxycarb, respectively. The LC system was hyphenated with a mass spectrophotometer (MSQ PLUS, Thermo Sci-
entific) operated in positive mode and equipped with an electrospray ionisation (ESI) source
for 30 min with a scan time of 0.10 seconds over the range m/z 100–1,500 with nitrogen (N2)
as drying gas. 4. Conclusion This work is the first metagenomic study targeting the discovery of fenobucarb and polyure-
thane degrading activities. One of the carbamate degrading metagenomic clone we isolated
produces a new lipolytic family IV carboxylesterase named CE_Ubrb. This original enzyme is
very distantly related to all the known carbamate degrading enzymes, which belong to the fam-
ily VII. The diversity of the sequences we predicted, or proved, to encode carboxylesterases,
highlights the interest of complex microbiomes for the mining of promiscuous enzymes of bio-
technological interest. Thanks to their flexible substrate specificity, these enzymes could
indeed be used to break down man-made contaminating compounds in soil, water and other
environments. Supporting information pp
g
S1 Table. Functional profiles of the hit metagenomic clones, and name of the sequenced
clones. (DOC)
S1 Fig. Structure of Tween 20 and of the carbamates used in this study. (TIF)
S2 Fig. A—MALDI-TOF spectrum of Impranil re-suspended in THF. B—MALDI-TOF spec-
tra of the reaction medium containing Impranil and the enzymatic extract of E. coli strain
Epi100 carrying the empty pCC1FOS fosmid at the beginning (B-1) and after 24h (B-2) of
reaction. (PDF)
S3 Fig. A—MALDI-TOF spectra of the reaction medium containing poly[4-(2,2-dicyanovi-
nyl)-N-bis(hydroxyethyl)aniline-alt-(4,4’-methylenebis(phenylisocyanate)))]urethane and the
enzymatic extract of clone 44I12 at the beginning (A-1) and after 24h (A-2) of reaction; B—
MALDI-TOF spectra of the reaction medium containing poly[4-(2,2-dicyanovinyl)-N-bis
(hydroxyethyl)aniline-alt-(isophroronediisocyanate)]urethane and the enzymatic extract of
clone 44I12 at the beginning (B-1) and after 24h (B-2) of reaction. (PDF)
S4 Fig. HPLC analysis of the reaction medium containing fenobucarb and the enzymatic
extract of E. coli strain Epi100 carrying the empty pCC1FOS fosmid at the beginning
(blue) and after 24 h of incubation (red). (TIF) S1 Table. Functional profiles of the hit metagenomic clones, and name of the sequenced
clones. 3.7. Sub-cloning of the CE_Ubrb encoding gene and validation of
carboxylesterase activity First, the CE-Ubrb encoding gene (accession number SIP63154.1) was PCR-amplified from
one single colony of the Escherichia coli metagenomic fosmid clone 44I12 by using the Clo-
neAmpTM kit (Gibco BRL) and the primers forward 5’-CACCATGAGCATTCGCGTCATA
CCG-3’ and reverse 5’-ATCATTTTCGAATCCCTCCGTATTTCTTGC -3’. After PCR (one
denaturation step at 98˚ C for 30 s; 30 cycles composed of a denaturation step at 98˚C for 10
sec, an hybridization step at 55˚C for 15 sec, an elongation step at 72˚C for 30 sec; and a final
elongation step at 72˚C for 3 min), the PCR product was purified from agarose gel using the
GenElute gel extraction kit (Sigma-Aldrich). The PCR product was then cloned into the pENTR/D-TOPO vector (Invitrogen) according
to the manufacturer’s recommendations. After E.coli OneShot TOP10 transformation, the
plasmid was extracted using the QIAGEN Plasmid Purification kit and the construct was
checked by Sanger sequencing. By using recombination according to the manufacturer’s rec-
ommendations, the CE-Ubrb encoding gene was then cloned into the pET55 destination vec-
tor (Novagen), yielding fusion of the recombinant protein to a N-terminal Strep-tag and to a
C-terminal (His)6 tag. PLOS ONE | https://doi.org/10.1371/journal.pone.0189201
December 14, 2017 15 / 21 Discovery of new carbamate degrading enzymes E. coli BL21 star (DE3) cells (Invitrogen) harboring the CE-Ubrb encoding plasmid were
cultured in Erlenmeyer flasks at 28˚C for 24 h in 200 ml ZYM-5052 autoinduction medium
[65] supplemented with 100 mg/L ampicillin, inoculated at A600 nm 0.05. For comparison,
the EPI100 E. coli cells transformed with the 44I12 fosmid were cultured in the same condi-
tions, except that the culture medium was LB supplemented with 12.5 mg/L chloramphenicol. For both plasmid and fosmid clones, cells were harvested by centrifuging for 5 min at 12,857 x
g, and re-suspended in activity buffer (100 mM Hepes, pH 7.5) to obtain a final OD600nm of 80. Cell lysis was done using sonication. Cell debris were centrifuged at 12,857 x g for 10 min and
the cytoplasmic extracts were filtered with a 0.20 μm Minisart RC4 syringe filter (Sartorius). Carboxylesterase activity of the cytoplasmic extracts was quantified by monitoring the hydro-
lysis of pNP-esters into the corresponding acid and p-nitrophenol after dilution of the cyto-
plasmic extracts by 100 times in activity buffer for pNPA and pNPB, and by 10 times for pNPP. S1 Fig. Structure of Tween 20 and of the carbamates used in this study.
(TIF) S2 Fig. A—MALDI-TOF spectrum of Impranil re-suspended in THF. B—MALDI-TOF spec-
tra of the reaction medium containing Impranil and the enzymatic extract of E. coli strain
Epi100 carrying the empty pCC1FOS fosmid at the beginning (B-1) and after 24h (B-2) of
reaction. (PDF) S2 Fig. A—MALDI-TOF spectrum of Impranil re-suspended in THF. B—MALDI-TOF spec-
tra of the reaction medium containing Impranil and the enzymatic extract of E. coli strain
Epi100 carrying the empty pCC1FOS fosmid at the beginning (B-1) and after 24h (B-2) of
reaction. (PDF) S3 Fig. A—MALDI-TOF spectra of the reaction medium containing poly[4-(2,2-dicyanovi-
nyl)-N-bis(hydroxyethyl)aniline-alt-(4,4’-methylenebis(phenylisocyanate)))]urethane and the
enzymatic extract of clone 44I12 at the beginning (A-1) and after 24h (A-2) of reaction; B—
MALDI-TOF spectra of the reaction medium containing poly[4-(2,2-dicyanovinyl)-N-bis
(hydroxyethyl)aniline-alt-(isophroronediisocyanate)]urethane and the enzymatic extract of
clone 44I12 at the beginning (B-1) and after 24h (B-2) of reaction. (PDF) S3 Fig. A—MALDI-TOF spectra of the reaction medium containing poly[4-(2,2-dicyanovi-
nyl)-N-bis(hydroxyethyl)aniline-alt-(4,4’-methylenebis(phenylisocyanate)))]urethane and the
enzymatic extract of clone 44I12 at the beginning (A-1) and after 24h (A-2) of reaction; B—
MALDI-TOF spectra of the reaction medium containing poly[4-(2,2-dicyanovinyl)-N-bis
(hydroxyethyl)aniline-alt-(isophroronediisocyanate)]urethane and the enzymatic extract of
clone 44I12 at the beginning (B-1) and after 24h (B-2) of reaction. (PDF) S4 Fig. HPLC analysis of the reaction medium containing fenobucarb and the enzymatic
extract of E. coli strain Epi100 carrying the empty pCC1FOS fosmid at the beginning
(blue) and after 24 h of incubation (red). (TIF) 16 / 21 PLOS ONE | https://doi.org/10.1371/journal.pone.0189201
December 14, 2017 Discovery of new carbamate degrading enzymes S5 Fig. Graphical representation of the metagenomic sequences of clones 13M17, 25I16,
29D17, 37F15, 39F1, 50E19 and 50I3, and RAST annotation of the identified ORFs. Red
arrows: ORFs encoding putative esterases or proteases, based on RAST annotation or on
results of BLAST comparison with the NCBI NR database. (PDF) S6 Fig. SDS-PAGE analysis of the cytoplasmic extracts of the 8 sequenced fosmid clones,
highlighting overproduction of proteins of molecular weight similar to that of the putative
esterases SIP63261.1 (72,8 kDa, clone 25I16), SIP63154.1 (CE_Ubrb, 32,4 kDa, clone
44I12), SIP63136.1 (72,8 kDa, clone 50E19) and SIP63105.1 (41,4 Kda, clone 50I3), com-
pared to the negative control (E. coli strain Epi100 carrying the empty pCC1FOS fosmid). (TIF) S7 Fig. SDS-PAGE analysis of the cytoplasmic extracts of the E. coli clones producing or
not CE-Ubrb. Acknowledgments This research was funded by the French Ministry of Education and Research (Ministère de
l’Enseignement supe´rieur et de la Recherche), the INRA metaprogramme M2E (project
Metascreen), and the European Union’s framework programme Horizon 2020 (LEIT-BIO-
2015-685474, Metafluidics). The high throughput screening work was carried out at the Laboratory for BioSystems & Pro-
cess Engineering (Toulouse, France) with the equipment of the ICEO facility, dedicated to the
screening and the discovery of new and original enzymes. ICEO is supported by grants from the
Re´gion Midi-Pyre´ne´es, the European Regional Development Fund and the Institut National de la
Recherche Agronomique (INRA). We cordially thank Nelly Monties for technical support. S1 Fig. Structure of Tween 20 and of the carbamates used in this study.
(TIF) A: equivalent volumes of cytoplasmic extracts were deposited in each line; B:
equivalent amounts of total cytoplasmic proteins were deposited in each line. Lines 1 and 7: E. coli BL21 star (DE3), lines 2 and 8: E. coli BL21 star (DE3) transformed with the pET55_-
CE_Ubrb plasmid, lines 3 and 9: E. coli BL21 star (DE3) transformed by the pET53_CE_Ubrb
plasmid, lines 4 and 10: E. coli strain Epi100 carrying the 44I12 fosmid, lines 5 and 11: E. coli
strain Epi100 carrying the empty pCC1FOS fosmid. (TIF) S8 Fig. Multiple alignment of CE_Ubrb sequence with those of its characterized homologs
listed in Table 2, and with members of the lipolytic family IV cited in [46]. The amino acids
highlighted in red are catalytic amino acids, the green ones the oxyanion hole and the blue
ones the GXSXG consensus sequence. “” is for single, fully conserved residue, “:” shows the
conservation between groups of residues bearing strongly similar properties, and “.” between
groups of weakly similar properties. (PDF) Project administration: Gabrielle Potocki-Veronese. Project administration: Gabrielle Potocki-Veronese. Project administration: Gabrielle Potocki-Veronese. Resources: Lisa Ufarte´, Elisabeth Laville, Diego Morgavi, Patrick Robe. Software: Elisabeth Laville, Christophe Klopp. Supervision: Gabrielle Potocki-Veronese. Validation: Lisa Ufarte´, Gabrielle Potocki-Veronese. Visualization: Lisa Ufarte´, Elisabeth Laville, Gabrielle Potocki-Veronese. Writing – original draft: Lisa Ufarte´, Elisabeth Laville, Patrick Robe. Writing – review & editing: Sophie Duquesne, Gabrielle Potocki-Veronese. References 1. Sogorb MA, Vilanova E. Enzymes involved in the detoxification of organophosphorus, carbamate and
pyrethroid insecticides through hydrolysis. Toxicol Lett. 2002 Mar; 128(1):215–228. 2. Nunes G., Barcelo´ D. Analysis of carbamate insecticides in foodstuffs using chromatography and immu-
noassay techniques. TrAC Trends Anal Chem. 1999 Feb; 18(2):99–107. 3. Wang Q, Lemley AT. Competitive Degradation and Detoxification of Carbamate Insecticides by Mem-
brane Anodic Fenton Treatment. J Agric Food Chem. 2003 Aug; 51(18):5382–5390. https://doi.org/10. 1021/jf034311f PMID: 12926887 4. Bemis JC, Labash C, Avlasevich SL, Carlson K, Berg A, Torous DK, et al. Rat Pig-a mutation assay
responds to the genotoxic carcinogen ethyl carbamate but not the non-genotoxic carcinogen methyl
carbamate. Mutagenesis. 2015 May; 30(3):343–347. https://doi.org/10.1093/mutage/geu084 PMID:
25833916 5. Grube A, Donaldson D, Kiely T, Wu L. Pesticides Industry Sales and Usage 2006 and 2007 Market Esti-
mates. 2011. Available from: http://news.agropages.com/UserFiles/Report/Pdf/20120708204254971d. pdf 6. Smith MJ, Bucher G. Tools to study the degradation and loss of the N-phenyl carbamate chlorpropham
—A comprehensive review. Environ Int. 2012 Nov; 49:38–50. https://doi.org/10.1016/j.envint.2012.08. 005 PMID: 22982221 7. Hayatsu M, Nagata T. Purification and Characterization of Carbaryl Hydrolase from Blastobacter sp. Strain M501. Appl Environ Microbiol. 1993 Jul; 59(7):2121–5. PMID: 16348989 8. Pohlenz HD, Boidol W, Schu¨ttke I, Streber WR. Purification and properties of an Arthrobacter oxydans
P52 carbamate hydrolase specific for the herbicide phenmedipham and nucleotide sequence of the cor-
responding gene. J Bacteriol. 1992 Oct; 174(20):6600–6607. PMID: 1400211 9. Mulbry WW, Eaton RW. Purification and characterization of the N-methylcarbamate hydrolase from
Pseudomonas strain CRL-OK. Appl Environ Microbiol. 1991 Dec; 57(12):3679–3682. PMID: 1785941 10. Karns JS, Tomasek PH. Carbofuran hydrolase—purification and properties. J Agric Food Chem. 1991
May; 39(5):1004–1008. 11. Doddamani HP, Ninnekar HZ. Biodegradation of Carbaryl by a Micrococcus Species. Curr Microbiol. 2001 Jan; 43(1):69–73. https://doi.org/10.1007/s002840010262 PMID: 11375667 12. Russell RJ, Scott C, Jackson CJ, Pandey R, Pandey G, Taylor MC, et al. The evolution of new enzyme
function: lessons from xenobiotic metabolizing bacteria versus insecticide-resistant insects: Evolution
of new enzyme function. Evol Appl. 2011 Mar; 4(2):225–48. https://doi.org/10.1111/j.1752-4571.2010. 00175.x PMID: 25567970 13. Rahimi A, Mashak A. Review on rubbers in medicine: natural, silicone and polyurethane rubbers. Plast
Rubber Compos. 2013 Jul; 42(6):223–30. 14. Biffinger JC, Barlow DE, Cockrell AL, Cusick KD, Hervey WJ, Fitzgerald LA, et al. The applicability of
Impranil®DLN for gauging the biodegradation of polyurethanes. Polym Degrad Stab. 2015 Oct;
120:178–85. 15. Howard GT. Biodegradation of polyurethane: a review. Int Biodeterior Biodegrad. Author Contributions Conceptualization: Sophie Duquesne, Diego Morgavi, Gabrielle Potocki-Veronese. p
p
q
g
g
Data curation: Lisa Ufarte´, Elisabeth Laville, Gabrielle Potocki-Veronese. Formal analysis: Lisa Ufarte´, Elisabeth Laville, Christophe Klopp. Funding acquisition: Diego Morgavi, Gabrielle Potocki-Veronese. Investigation: Lisa Ufarte´, Patrick Robe. 17 / 21 PLOS ONE | https://doi.org/10.1371/journal.pone.0189201
December 14, 2017 Discovery of new carbamate degrading enzymes Methodology: Lisa Ufarte´, Sophie Duquesne, Patrick Robe, Angeline Rizzo, Sandra Pizzut-
Serin, Gabrielle Potocki-Veronese. Project administration: Gabrielle Potocki-Veronese. Resources: Lisa Ufarte´, Elisabeth Laville, Diego Morgavi, Patrick Robe. Software: Elisabeth Laville, Christophe Klopp. Supervision: Gabrielle Potocki-Veronese. Validation: Lisa Ufarte´, Gabrielle Potocki-Veronese. Visualization: Lisa Ufarte´, Elisabeth Laville, Gabrielle Potocki-Veronese. Writing – original draft: Lisa Ufarte´, Elisabeth Laville, Patrick Robe. Writing – review & editing: Sophie Duquesne, Gabrielle Potocki-Veronese. Methodology: Lisa Ufarte´, Sophie Duquesne, Patrick Robe, Angeline Rizzo, Sandra Pizzut-
Serin, Gabrielle Potocki-Veronese. Methodology: Lisa Ufarte´, Sophie Duquesne, Patrick Robe, Angeline Rizzo, Sandra Pizzut-
Serin, Gabrielle Potocki-Veronese. Methodology: Lisa Ufarte´, Sophie Duquesne, Patrick Robe, Angeline Rizzo, Sandra Pizzut-
Serin, Gabrielle Potocki-Veronese. References 2002 Jun; 49(4):245–
52. 18 / 21 PLOS ONE | https://doi.org/10.1371/journal.pone.0189201
December 14, 2017 Discovery of new carbamate degrading enzymes 16. PlasticsEurope. Plastics–the Facts 2014/2015 An analysis of European plastics production, demand
and waste data. 2015. Available from: http://www.plasticseurope.org/documents/document/
20150227150049-final_plastics_the_facts_2014_2015_260215.pdf 17. Loredo-Treviño A, Gutie´rrez-Sa´nchez G, Rodrı´guez-Herrera R, Aguilar CN. Microbial Enzymes
Involved in Polyurethane Biodegradation: A Review. J Polym Environ. 2012 Mar; 20(1):258–265. 18. Kuhr RJ, Dorough HW. Carbamate insecticides: chemistry, biochemistry, and toxicology. Cleveland:
CRC Press; 1976. 19. Howard GT, Blake RC. Growth of Pseudomonas fluorescens on a polyester–polyurethane and the puri-
fication and characterization of a polyurethanase–protease enzyme. Int Biodeterior Biodegrad. 1998
Nov; 42(4):213–220. 20. Cregut M, Bedas M, Durand M-J, Thouand G. New insights into polyurethane biodegradation and realis-
tic prospects for the development of a sustainable waste recycling process. Biotechnol Adv. 2013 Dec;
31(8):1634–1647. https://doi.org/10.1016/j.biotechadv.2013.08.011 PMID: 23978675 21. Phua SK, Castillo E, Anderson JM, Hiltner A. Biodegradation of a polyurethane in vitro. J Biomed Mater
Res. 1987 Feb; 21(2):231–246. https://doi.org/10.1002/jbm.820210207 PMID: 3818683 22. Nakajima-Kambe T, Shigeno-Akutsu Y, Nomura N, Onuma F, Nakahara T. Microbial degradation of
polyurethane, polyester polyurethanes and polyether polyurethanes. Appl Microbiol Biotechnol. 1999
Feb; 51(2):134–140. PMID: 10091317 23. Engelhardt G, Wallno¨fer PR, Plapp R. Purification and properties of an aryl acylamidase of Bacillus
sphaericus, catalyzing the hydrolysis of various phenylamide herbicides and fungicides. Appl Microbiol. 1973 Nov; 26(5):709–718. PMID: 4762392 24. Zhao CJ, Kobashi K. Purification and characterization of iron-containing urethanase from Bacillus liche-
niformis. Biol Pharm Bull. 1994 Jun; 17(6):773–778. PMID: 7951136 25. Urgun-Demirtas M, Singh D, Pagilla K. Laboratory investigation of biodegradability of a polyurethane
foam under anaerobic conditions. Polym Degrad Stab. 2007 Aug; 92(8):1599–1610. 26. Nakajima-Kambe T, Onuma F, Kimpara N, Nakahara T. Isolation and characterization of a bacterium
which utilizes polyester polyurethane as a sole carbon and nitrogen source. FEMS Microbiol Lett. 1995
Jun; 129(1):39–42. https://doi.org/10.1016/0378-1097(95)00131-N PMID: 7781989 27. Kang C-H, Oh K-H, Lee M-H, Oh T-K, Kim B, Yoon J-. A novel family VII esterase with industrial poten-
tial from compost metagenomic library. Microb Cell Factories. 2011; 10(1):41. 28. Ufarte´ L, Laville E´ , Duquesne S, Potocki-Veronese G. Metagenomics for the discovery of pollutant
degrading enzymes. Biotechnol Adv. 2015 Oct; 33(8):1845–1854. https://doi.org/10.1016/j.biotechadv. 2015.10.009 PMID: 26526541 29. Wang L, Hatem A, Catalyurek UV, Morrison M, Yu Z. Metagenomic insights into the carbohydrate-
active enzymes carried by the microorganisms adhering to solid digesta in the rumen of cows. PloS
One. PLOS ONE | https://doi.org/10.1371/journal.pone.0189201
December 14, 2017 References 2013; 8(11):e78507. https://doi.org/10.1371/journal.pone.0078507 PMID: 24223817 30. Brulc JM, Antonopoulos DA, Berg Miller ME, Wilson MK, Yannarell AC, Dinsdale EA, et al. Gene-centric
metagenomics of the fiber-adherent bovine rumen microbiome reveals forage specific glycoside hydro-
lases. Proc Natl Acad Sci. 2009 Feb; 106(6):1948–1953. https://doi.org/10.1073/pnas.0806191105
PMID: 19181843 31. Liu K, Wang J, Bu D, Zhao S, McSweeney C, Yu P, et al. Isolation and biochemical characterization of
two lipases from a metagenomic library of China Holstein cow rumen. Biochem Biophys Res Commun. 2009 Aug; 385(4):605–611. https://doi.org/10.1016/j.bbrc.2009.05.110 PMID: 19486892 32. Prive´ F, Newbold CJ, Kaderbhai NN, Girdwood SG, Golyshina OV, Golyshin PN, et al. Isolation and
characterization of novel lipases/esterases from a bovine rumen metagenome. Appl Microbiol Biotech-
nol. 2015 Jul; 99(13):5475–5485. https://doi.org/10.1007/s00253-014-6355-6 PMID: 25575887 33. Faulds CB. What can feruloyl esterases do for us? Phytochem Rev. 2010 Mar; 9(1):121–132. 34. Ben Ali Y, Verger R, Abousalham A. Lipases or Esterases: Does It Really Matter? Toward a New Bio-
Physico-Chemical Classification. In: Sandoval G, editor. Lipases and Phospholipases. Totowa, NJ:
Humana Press; 2012. p. 31–51. 35. Ferrer M, Golyshina OV, Chernikova TN, Khachane AN, Reyes-Duarte D, Santos VAPMD, et al. Novel
hydrolase diversity retrieved from a metagenome library of bovine rumen microflora: Enzymatic diver-
sity from bovine rumen metagenome. Environ Microbiol. 2005 Sep; 7(12):1996–2010. https://doi.org/
10.1111/j.1462-2920.2005.00920.x PMID: 16309396 36. Kim Y-J, Choi G-S, Kim S-B, Yoon G-S, Kim Y-S, Ryu Y-W. Screening and characterization of a novel
esterase from a metagenomic library. Protein Expr Purif. 2006 Feb; 45(2):315–323. https://doi.org/10. 1016/j.pep.2005.06.008 PMID: 16061395 19 / 21 PLOS ONE | https://doi.org/10.1371/journal.pone.0189201
December 14, 2017 Discovery of new carbamate degrading enzymes 37. University of Hertfordshire. The Pesticide Properties DataBase (PPDB) developed by the Agriculture &
Environment Research Unit (AERU). 2013. Available from: http://sitem.herts.ac.uk/aeru/ppdb/en/index. htm 37. University of Hertfordshire. The Pesticide Properties DataBase (PPDB) developed by the Agriculture &
Environment Research Unit (AERU). 2013. Available from: http://sitem.herts.ac.uk/aeru/ppdb/en/index. htm 38. Kim I, Kim D-U, Kim N-H, Ka J-O. Isolation and characterization of fenobucarb-degrading bacteria from
rice paddy soils. Biodegradation. 2014 Jun; 25(3):383–394. https://doi.org/10.1007/s10532-013-9667-9
PMID: 24197220 39. U.S. National Library of Medicine. ChemIDplus Advanced—Chemical information with searchable syno-
nyms, structures, and formulas]. 2014. Available from: http://chem.sis.nlm.nih.gov/chemidplus/ 40. Tasse L, Bercovici J, Pizzut-Serin S, Robe P, Tap J, Klopp C, et al. Functional metagenomics to mine
the human gut microbiome for dietary fiber catabolic enzymes. Genome Res. 2010 Sep; 20(11):1605–
1612. https://doi.org/10.1101/gr.108332.110 PMID: 20841432 41. References Cecchini DA, Laville E, Laguerre S, Robe P, Leclerc M, Dore´ J, et al. Functional Metagenomics Reveals
Novel Pathways of Prebiotic Breakdown by Human Gut Bacteria. Smidt H, editor. PLoS ONE. 2013
Sep; 8(9):e72766. https://doi.org/10.1371/journal.pone.0072766 PMID: 24066026 42. Peng S, Yin J, Liu X, Jia B, Chang Z, Lu H, et al. First insights into the microbial diversity in the omasum
and reticulum of bovine using Illumina sequencing. J Appl Genet. 2015 Aug; 56(3):393–401. https://doi. org/10.1007/s13353-014-0258-1 PMID: 25604266 43. Gabor EM, Alkema WBL, Janssen DB. Quantifying the accessibility of the metagenome by random
expression cloning techniques. Environ Microbiol. 2004 Sep; 6(9):879–886. https://doi.org/10.1111/j. 1462-2920.2004.00640.x PMID: 15305913 44. Tauzin AS, Laville E, Xiao Y, Nouaille S, Le Bourgeois P, Heux S, et al. Functional characterization of a
gene locus from an uncultured gut Bacteroides conferring xylo-oligosaccharides utilization to Escheri-
chia coli. Mol Microbiol. 2016 Sep; 102(4):579–592 https://doi.org/10.1111/mmi.13480 PMID:
27573446 45. Okano H, Hong X, Kanaya E, Angkawidjaja C, Kanaya S. Structural and biochemical characterization
of a metagenome-derived esterase with a long N-terminal extension: Characterization of Metagenome-
Derived Esterase. Protein Sci. 2015 Jan; 24(1):93–104. https://doi.org/10.1002/pro.2591 PMID:
25348365 46. Choi J-E, Kwon M-A, Na HY, Hahm D-H, Song JK. Isolation and characterization of a metagenome-
derived thermoalkaliphilic esterase with high stability over a broad pH range. Extremophiles. 2013 Nov;
17(6):1013–1021. https://doi.org/10.1007/s00792-013-0583-z PMID: 24030484 47. Rashamuse K, Ronneburg T, Hennessy F, Visser D, van Heerden E, Piater L, et al. Discovery of a novel
carboxylesterase through functional screening of a pre-enriched environmental library. J Appl Microbiol. 2009 May; 106(5):1532–1539. https://doi.org/10.1111/j.1365-2672.2008.04114.x PMID: 19226392 48. Hu Y, Fu C, Huang Y, Yin Y, Cheng G, Lei F, et al. Novel lipolytic genes from the microbial metagenomic
library of the South China Sea marine sediment. FEMS Microbiol Ecol. 2010 May; 72(2):228–237. https://doi.org/10.1111/j.1574-6941.2010.00851.x PMID: 20337707 49. Hong KS, Lim HK, Chung EJ, Park EJ, Lee MH, Kim J-C, et al. Selection and characterization of forest
soil metagenome genes encoding lipolytic enzymes. J Microbiol Biotechnol. 2007 Oct; 17(10):1655–
1660. PMID: 18156781 50. Lee S-W, Won K, Lim HK, Kim J-C, Choi GJ, Cho KY. Screening for novel lipolytic enzymes from uncul-
tured soil microorganisms. Appl Microbiol Biotechnol. 2004 Sep; 65(6):720–726. https://doi.org/10. 1007/s00253-004-1722-3 PMID: 15365646 51. Arpigny JL, Jaeger KE. Bacterial lipolytic enzymes: classification and properties. Biochem J. 1999 Oct;
343(1):177–183. 52. Lenfant N, Hotelier T, Velluet E, Bourne Y, Marchot P, Chatonnet A. References ESTHER, the database of the α/β-
hydrolase fold superfamily of proteins: tools to explore diversity of functions. Nucleic Acids Res. 2013
Jan; 41(Database issue):423–429. 53. Jeon JH, Lee HS, Kim JT, Kim S-J, Choi SH, Kang SG, et al. Identification of a new subfamily of salt-tol-
erant esterases from a metagenomic library of tidal flat sediment. Appl Microbiol Biotechnol. 2012 Jan;
93(2):623–631. https://doi.org/10.1007/s00253-011-3433-x PMID: 21720822 54. Li P-Y, Ji P, Li C-Y, Zhang Y, Wang G-L, Zhang X-Y, et al. Structural Basis for Dimerization and Cataly-
sis of a Novel Esterase from the GTSAG Motif Subfamily of the Bacterial Hormone-sensitive Lipase
Family. J Biol Chem. 2014 Jul; 289(27):19031–19041. https://doi.org/10.1074/jbc.M114.574913 PMID:
24867954 55. Hausmann S, Jaeger K-E. Lipolytic Enzymes from Bacteria. In: Timmis KN, editor. Handbook of Hydro-
carbon and Lipid Microbiology. Berlin, Heidelberg: Springer Berlin Heidelberg; 2010. p. 1099–1126. 56. Chahinian H, Ali Y, Abousalham A, Petry S, Mandrich L, Manco G, et al. Substrate specificity and kinetic
properties of enzymes belonging to the hormone-sensitive lipase family: Comparison with non-lipolytic PLOS ONE | https://doi.org/10.1371/journal.pone.0189201
December 14, 2017 20 / 21 Discovery of new carbamate degrading enzymes and lipolytic carboxylesterases. Biochim Biophys Acta BBA—Mol Cell Biol Lipids. 2005 Dec; 1738
(1):29–36. and lipolytic carboxylesterases. Biochim Biophys Acta BBA—Mol Cell Biol Lipids. 2005 Dec; 1738
(1):29–36. 57. Courtois S, Cappellano CM, Ball M, Francou FX, Normand P, Helynck G, et al. Recombinant environ-
mental libraries provide access to microbial diversity for drug discovery from natural products. Appl Env
Microbiol. 2003; 69:49–55. 58. Lam KN, Hall MW, Engel K, Vey G, Cheng J, Neufeld JD, et al. Evaluation of a Pooled Strategy for
High-Throughput Sequencing of Cosmid Clones from Metagenomic Libraries. Cloeckaert A, editor. PLoS ONE. 2014 Jun; 9(6):e98968. https://doi.org/10.1371/journal.pone.0098968 PMID: 24911009 59. Aziz RK, Bartels D, Best AA, DeJongh M, Disz T, Edwards RA, et al. The RAST Server: rapid annota-
tions using subsystems technology. BMC Genomics. 2008; 9(1):75. 60. Jones P, Binns D, Chang H-Y, Fraser M, Li W, McAnulla C, et al. InterProScan 5: genome-scale protein
function classification. Bioinformatics. 2014 May; 30(9):1236–1240. https://doi.org/10.1093/
bioinformatics/btu031 PMID: 24451626 61. Tamura K, Stecher G, Peterson D, Filipski A, Kumar S. MEGA6: Molecular Evolutionary Genetics Anal-
ysis version 6.0. Mol Biol Evol. 2013 Dec; 30(12):2725–2729. https://doi.org/10.1093/molbev/mst197
PMID: 24132122 62. Huson DH, Scornavacca C. Dendroscope 3: An Interactive Tool for Rooted Phylogenetic Trees and
Networks. Syst Biol. 2012 Dec; 61(6):1061–1067. https://doi.org/10.1093/sysbio/sys062 PMID:
22780991 63. PLOS ONE | https://doi.org/10.1371/journal.pone.0189201
December 14, 2017 References Patil KR, Roune L, McHardy AC. The PhyloPythiaS web server for taxonomic assignment of metagen-
ome sequences. Highlander SK, editor. PLoS ONE. 2012 Jun; 7(6), e38581. https://doi.org/10.1371/
journal.pone.0038581 PMID: 22745671 64. Kruger NJ. The Bradford method for protein quantitation. In: Walker J.M., editor. Methods in Molecular
Biology, Humana Press. Basic protein and peptide protocols.1994;32:9–15. 65. Studier FW. Protein production by auto-induction in high-density shaking cultures. Protein Expr Purif. 2005 May; 41(1):207–234. PMID: 15915565 21 / 21
|
https://openalex.org/W2063589808
|
https://europepmc.org/articles/pmc3108176?pdf=render
|
English
| null |
Species Identification of Marine Fishes in China with DNA Barcoding
|
Evidence-based complementary and alternative medicine
| 2,011
|
cc-by
| 5,987
|
Hindawi Publishing Corporation
Evidence-Based Complementary and Alternative Medicine
Volume 2011, Article ID 978253, 10 pages
doi:10.1155/2011/978253 Hindawi Publishing Corporation
Evidence-Based Complementary and Alternative Medicine
Volume 2011, Article ID 978253, 10 pages
doi:10.1155/2011/978253 Hindawi Publishing Corporation
Evidence-Based Complementary and Alternative Medicine
Volume 2011, Article ID 978253, 10 pages
doi:10.1155/2011/978253 Hindawi Publishing Corporation
Evidence-Based Complementary and Alternative Medicine
Volume 2011, Article ID 978253, 10 pages
doi:10.1155/2011/978253 1. Introduction across phylogenetically distant animal groups [12, 13]. To
date, some published papers explicitly address that COI bar-
codes effectively discriminate different species for a variety
of organisms [14–23]. However, several scientists express
concerns that species identification based on variations of
single mitochondrial gene fragment may remain incorrect
or ambiguous assignments, particularly in cases of possible
mitochondrial polyphyly or paraphyly [24, 25]. In the
current study, we test the efficacy of DNA barcoding in
marine fishes of China. The sea area of China is part of the
Indo-West Pacific Ocean, which is regarded as the center
of the world’s marine biodiversity [26]. Highly species-rich
biotas are particularly attractive to test the reliability and
efficiency of DNA barcoding. Fishes are important animal protein sources for human
beings, and they are frequently used in complementary and
alternative medicine/traditional medicine (CAM/TM). The
delimitation and recognition of fish species is not only of
interest for taxonomy and systematics, but also a requirement
in management of fisheries, authentication of food products,
and identification of CAM/TM materials [1–3]. Due to the complexity and limitations of morphological
characters used in traditional taxonomy, several PCR-based
methods of genotype analysis have been developed for the
identification of fish species, particularly for eggs, larvae, and
commercial products. Sequence analysis of species-specific
DNA fragments (often mitochondrial or ribosomal genes)
and multiplex PCR of species-conserved DNA fragments
are efficient for fish species identification [4–10]. However,
these molecular methods are limited to particular known
species and are not easily applicable to a wide range of
taxa. Therefore, Hebert et al. advocated using a standard
DNA sequence that is DNA barcoding to identify species
and uncover biological diversity [11, 12]. For many animal
taxa, sequence divergences within the 5′ region of the
mitochondrial cytochrome oxidase subunit I (COI) gene
were much greater between species than within them, and
this in turn suggests that the approach is widely applicable Junbin Zhang College of Fisheries and Life Science, Shanghai Ocean University, Shanghai 201306, China Correspondence should be addressed to Junbin Zhang, jbzhang30@163.com Received 10 December 2010; Accepted 27 February 2011 Copyright © 2011 Junbin Zhang. This is an open access article distributed under the Creative Commons A
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is DNA barcoding is a molecular method that uses a short standardized DNA sequence as a species identification tool. In this study,
the standard 652 base-pair region of the mitochondrial cytochrome oxidase subunit I gene (COI) was sequenced in marine fish
specimens captured in China. The average genetic distance was 50-fold higher between species than within species, as Kimura two
parameter (K2P) genetic distances averaged 15.742% among congeners and only 0.319% for intraspecific individuals. There are no
overlaps of pairwise genetic variations between conspecific and interspecific comparisons apart from the genera Pampus in which
the introgressive hybridization was detected. High efficiency of species identification was demonstrated in the present study by
DNA barcoding. Due to the incidence of cryptic species, an assumed threshold is suggested to expedite discovering of new species
and biodiversity, especially involving biotas of few studies. Research Article
Species Identification of Marine Fishes in China
with DNA Barcoding Junbin Zhang FishF2 t1: ∗5′-TGTAAAACGACGGCCAGTCGACT-
AATCATAAAGATATCGGCAC-3′.
VF2 t1: ∗5′-TGTAAAACGACGGCCAGTCAACCA-
ACCACAAAGACATTGGCAC-3′.
FishR2 t1: ∗∗5′-CAGGAAACAGCTATGACACTTC-
AGGGTGACCGAAGAATCAGAA-3′.
FR1d t1: ∗∗5′-CAGGAAACAGCTATGACACCTCA-
GGGTGTCCGAARAAYCARAA-3′.
∗The M13F primer sequence is underlined;
∗∗the
M13R primer sequence is underlined. The thermocycling protocol used was 1 min at 95◦C and
35 cycles of 30 sec at 94◦C, 40 sec at 50◦C, and 1 min at 72◦C,
with a final extension at 72◦C for 10 min. Sequecing PCR and
sequencing followed above procedure. DNA sequences were aligned with SEQSCAPE v.2.5
software (Applied Biosystems, Inc.). Sequence divergences
were calculated using the Kimura two parameter (K2P)
distance model [29], and unrooted NJ trees based on K2P
distances were created in MEGA software [30]. In the chosen
taxonomic group, phylogenetic analysis was carried out in
PAUP 4.010b using the maximum parsimony (MP) method,
with 1,000 replications of the full heuristic search. PCR reactions were carried out in 96-well plates using
Mastercycler Eppendorf gradient thermal cyclers (Brink-
mann Instruments, Inc.). The reaction mixture of 825 µl
water, 125 µl 10× buffer, 62.5 µl MgCl2 (25 mM), 6.25 µl
dNTP (10 mM), 6.25 µl each primer (0.01 mM), and 6.25 µl
Taq DNA polymerase (5 U/µl) was prepared for 96 wells of
each plate, in which each well contained 10.5 µl mixture and
2 µl genomic DNA. Thermocycling comprised an initial step
of 2 min at 95◦C and 35 cycles of 30 sec at 94◦C, 40 sec at
52◦C, and 1 min at 72◦C, with a final extension at 72◦C for
10 min. Amplicons were visualized on 2% agarose E-Gel 96-
well system (Invitrogen). PCR products were amplified again
with the primers M13F (5′-TGTAAAACGACGGCCAGT-3′)
and M13R (5′-CAGGAAACAGCTATGAC-3′), respectively,
using the BigDye Terminator v.3.1 Cycle Sequencing Kit
(Applied Biosystems, Inc.). Thermocycling conditions were
as follows: an initial step of 2 min at 96◦C and 35 cycles of
30 sec at 96◦C, 15 sec at 55◦C, and 4 min at 60◦C. Sequencing
was performed on an ABI 3730 capillary sequencer according
to manufacturer’s instructions. p
The following categories of K2P distances were calcu-
lated: intraspecific distances (S), interspecies within the con-
gener (G), and interspecies from different genus but within
intrafamily (F). These values were plotted using the boxplot
representation of R. Boxplots [31] in SPSS 11.5 software
(SPSS Inc., Chicago, IL, USA). Only for families containing
2 or more genera, separate boxplot was constructed for the
sake of comparisons among taxonomic categories. Boxplots
describe median (central bar), interquartile range (IQR:
between upper (Q3) and low (Q1) quartile), values lying
within 1.5× IQR beneath Q1 or 1.5× above Q3 (“whiskers”),
and extreme values (outliers). FishF2 t1: ∗5′-TGTAAAACGACGGCCAGTCGACT-
AATCATAAAGATATCGGCAC-3′.
VF2 t1: ∗5′-TGTAAAACGACGGCCAGTCAACCA-
ACCACAAAGACATTGGCAC-3′.
FishR2 t1: ∗∗5′-CAGGAAACAGCTATGACACTTC-
AGGGTGACCGAAGAATCAGAA-3′.
FR1d t1: ∗∗5′-CAGGAAACAGCTATGACACCTCA-
GGGTGTCCGAARAAYCARAA-3′.
∗The M13F primer sequence is underlined;
∗∗the
M13R primer sequence is underlined. Mann-Whitney tests were
performed between S, G, and F distributions to estimate the
overlap among taxonomic ranks. 2. Material and Methods The majority of fish specimens were captured with the drawl
net at 20 localities along the coast of China (collection
information available at http://www.barcodinglife.org/). A
total of 329 specimens from one hundred species of fish
were collected. Vouchers were deposited in the South China
Sea Institute of Oceanography, Chinese Academy of Sciences,
and all specimens were preserved in 70% ethanol. Tissue
samples were dissected from the dorsal muscle, and genomic
DNA was extracted according to the standard Barcode of Life 2 2 Evidence-Based Complementary and Alternative Medicine 3. Results A total of 329 specimens were analyzed, from which 321
sequences (all >500 bp) belonging to 121 species (another
species was identified to the genus level) were ultimately obt-
ained (GenBank accession numbers: EF607296-EF607616). These species cover the majority of fishes living in the coast-
line of the South China Sea. All sequences were aligned with
a consensus length of 652 bp, and no insertions, deletions,
or stop codons were observed in any sequence. However,
multiple haplotypes were detected for some species. For specimens that failed to yield sequences using the
primer combinations above, a second round of PCR using
the alternative C VF1LFt1/ C VR1LRt1 primer combination
was carried out. C VF1LFt1 consisted of four primers (VF1
t1/VF1d t1/LepF1 t1/VFli t1), and C VR1LRt1 also compri-
sed four primers (VR1 t1/VR1d t1/LepR1 t1/VRli t1) [28]. FishF2 t1: ∗5′-TGTAAAACGACGGCCAGTCGACT-
AATCATAAAGATATCGGCAC-3′. FishF2 t1: ∗5′-TGTAAAACGACGGCCAGTCGACT-
AATCATAAAGATATCGGCAC-3′. VF2 t1: ∗5′-TGTAAAACGACGGCCAGTCAACCA-
ACCACAAAGACATTGGCAC-3′. FishR2 t1: ∗∗5′-CAGGAAACAGCTATGACACTTC-
AGGGTGACCGAAGAATCAGAA-3′. FR1d t1: ∗∗5′-CAGGAAACAGCTATGACACCTCA-
GGGTGTCCGAARAAYCARAA-3′. ∗The M13F primer sequence is underlined;
∗∗the
M13R primer sequence is underlined. VF1 t1: ∗5′-TGTAAAACGACGGCCAGTTCTCAA-
CCAACCACAAAGACATTGG-3′. Except for Acentrogobius caninus, Scomber japonicus,
Terapon jarbua, Upeneus sulphureus, Elops hawaiensis, Gym-
nothorax pseudothyrsoideus, Dendrophysa russelii, and Pen-
nahia anea (which reached the maximum value of 2.02%),
intraspecific genetic distances were generally below 1%, and
some decreased to zero (between some intraspecific individ-
uals of Thryssa setirostris, Parapercis ommatura, Scatophagus
argus, etc.). VR1d t1: ∗∗5′-CAGGAAACAGCTATGACTAGACT-
TCTGGGTGGCCAAAGAATCA-3′. protocol [27]. Firstly, fragments of the 5′ region of the mito-
chondrial COI gene were PCR-amplified using C FishF1t1/
C FishR1t1 primer cocktails [28]. The cocktail C FishF1t1
contained two primers (FishF2 t1/VF2 t1), and C FishR1t1
also contained two primers (FishR2 t1/ FR1d t1). All PCR
primers were tailed with M13 sequences to facilitate sequenc-
ing of products. The nucleotide sequences of the primers
were VF1d t1: ∗5′-TGTAAAACGACGGCCAGTTCTCA-
ACCAACCACAARGAYATYGG-3′. VF1d t1: ∗5′-TGTAAAACGACGGCCAGTTCTCA-
ACCAACCACAARGAYATYGG-3′. LepF1 t1:
∗5′-TGTAAAACGACGGCCAGTATTCA-
ACCAATCATAAAGATATTGG-3′. p.anea
P.argenteus versus P.cinereus
S
G
F
−10
k2P genetic distance (%)
0
10
20
30
40 S GF S GF S GF S GF S GF S GF S GF S GF S GF S GF
−10
k2P genetic distance (%)
0
10
20
30
40
Muraenesocidae
Monacanthidae
Cynoglossidae
Synodontidae
Mullidae
Leiognathidae
Scombrbidae
Carangidae
Engraulidae
Clupeidae
Figure 2: Boxplot distributions of S, G, and F. Intra-species (S),
i
i
i
i
(G)
d i
b S GF S GF S GF S GF S GF S GF S GF S GF S GF S GF
−10
k2P genetic distance (%)
0
10
20
30
40
Muraenesocidae
Monacanthidae
Cynoglossidae
Synodontidae
Mullidae
Leiognathidae
Scombrbidae
Carangidae
Engraulidae
Clupeidae
Figure 2: Boxplot distributions of S, G, and F. Intra-species (S),
interspecies among congeneric species (G), and intergenera but
intrafamily (F) K2P distances for different families. F Figure 1: Box plots of K2P distances. IQR: interval into which
the “central” 50% of the data fall. Black bar in the box indicates
the median. Circle: “mild outlier” and asterisks: “extreme outliers”. Extreme outliers are discussed in the text. Figure 2: Boxplot distributions of S, G, and F. Intra-species (S),
interspecies among congeneric species (G), and intergenera but
intrafamily (F) K2P distances for different families. divergences among congeneric species are above 10%. There
are no overlaps between intraspecific and congeneric K2P
distances within the same family (Figure 3). the average genetic distance among congeneric species is
nearly 50-fold higher than that among individuals within
species. For the higher taxonomic ranks (family, order, and
class), mean pairwise genetic distances increased gradually
and reached 20.199%, 24.656%, and 25.225%, respectively
(Table 1). Standard errors for K2P genetic distances were
small, and values of the mean and median were close
within different taxonomic ranks (Table 1). This indicates
fluctuations of K2P genetic distances tend to be convergent
(Figures 1 and 2). At the species level, all COI sequences clustered in
monophyletic species units. At the family level, there were
paraphyletic clusters for three families (Carangidae, Gobi-
idae, and Ariidae) (Figure 3), though over 98% of specimens
fell into the expected division of families. Intrafamily K2P
distances (F) were generally higher than congeneric (G)
distances, which were definitely higher than intraspecific
(S) distances (Table 1, all Mann-Whitney tests were highly
significant, P value <10−6). However, overlaps between F
and G distances were observed in Clupeidae, Carangidae,
Mullidae, and Muraenesocidae. LepF1 t1:
∗5′-TGTAAAACGACGGCCAGTATTCA-
ACCAATCATAAAGATATTGG-3′. In the unrooted NJ (neighbour-joining) tree (Figure 3),
three specimens of Pampus argentenus were grouped together
and contained within the cluster of Pampus cinereus. These
Pampus argentenus specimens were collected in the same site
offthe west coast of the South China Sea, and were difficult
to identify because of their complex morphological char-
acteristics (available at http://www.barcodinglife.org/). They
possessed combined characteristics of Pampus cinereus and
Pampus argentenus: the asymmetrical tail of Pampus cinereus
and silver color of Pampus argentenus. If the suspicious
congeneric K2P distances in the genera Pampus are excluded
(the extreme outliers in Figure 1), the pairwise genetic LepF1 t1:
∗5′-TGTAAAACGACGGCCAGTATTCA-
ACCAATCATAAAGATATTGG-3′. LepF1 t1:
∗5′-TGTAAAACGACGGCCAGTATTCA-
ACCAATCATAAAGATATTGG-3′. VFli t1: ∗5′-TGTAAAACGACGGCCAGTTCTCAA-
CCAACCAIAAIGAIATIGG-3′. The mean intraspecies K2P (Kimura two-parameter)
distance was 0.319%; the distance increased sharply to
15.742% among individuals of congeneric species. Overall, VR1 t1:
∗∗5
′-CAGGAAACAGCTATGACTAGACT-
TCTGGGTGGCCRAARAAYCA-3′. Evidence-Based Complementary and Alternative Medicine 3 Table 1: Genetic divergences (percentage, K2P distance) within various taxonomic levels. Data are based on
122 species. Table 1: Genetic divergences (percentage, K2P distance) within various taxonomic levels. Data are based on 321 sequences (>500 bp) from
122 species. Comparisons within
Taxa
Number of comparisons
Mean
Median
Minimum
Maximum
s.e.#
Species
121
453
0.319
0.150
0
2.021∗
0.018
Genus
85
397
15.742
16.490
0.154∗∗
25.189
0.292
Family
55
848
20.199
19.850
11.532
34.333
0.134
Order
15
17881
24.656
—
12.923
39.627
0.024
Class
2
29262
25.225
—
15.730
40.800
0.016
∗Pennahia anea; ∗∗Pampus argenteus versus Pampus cinereus. #Standard error. Table 1: Genetic divergences (percentage, K2P distance) within various taxonomic levels. Data are based on 321 sequences (>500 bp) from
122 species. p.anea
P.argenteus versus P.cinereus
S
G
F
−10
k2P genetic distance (%)
0
10
20
30
40
Figure 1: Box plots of K2P distances. IQR: interval into which
the “central” 50% of the data fall. Black bar in the box indicates
the median. Circle: “mild outlier” and asterisks: “extreme outliers”. Extreme outliers are discussed in the text. S GF S GF S GF S GF S GF S GF S GF S GF S GF S GF
−10
k2P genetic distance (%)
0
10
20
30
40
Muraenesocidae
Monacanthidae
Cynoglossidae
Synodontidae
Mullidae
Leiognathidae
Scombrbidae
Carangidae
Engraulidae
Clupeidae
Figure 2: Boxplot distributions of S, G, and F. Intra-species (S),
interspecies among congeneric species (G), and intergenera but
intrafamily (F) K2P distances for different families. p.anea
P.argenteus versus P.cinereus
S
G
F
−10
k2P genetic distance (%)
0
10
20
30
40
Figure 1: Box plots of K2P distances. IQR: interval into which
the “central” 50% of the data fall. Black bar in the box indicates
the median. Circle: “mild outlier” and asterisks: “extreme outliers”. Extreme outliers are discussed in the text. 4. Discussion In morphological taxonomy, characters are delimited usually
without any explicit criteria for character selection or coding,
and morphological data sets have the potential to be quite
arbitrary. For example, morphologists do not generally
report their criteria for including or excluding characters, Evidence-Based Complementary and Alternative Medicine 4 Evidence-Based Complementary and Alternative Medicine 5% Harpadon nehereus|FSCS326 06|FSCS 113 st 1|Synodon
Fistularia commersonii|FSCS214-06|FSCS 81-l-1|Fistulariidae
Fistularia commersonii|FSCS215-06|FSCS 81-l-2|Fistulariidae
Arnoglossus polyspilus|FSCS116-06|FSCS 52-w-1|Bothidae
Arnoglossus polyspilus|FSCS117-06|FSCS 52-w-2|Bothidae
Arnoglossus polyspilus|FSCS118-06|FSCS 52-w-3|Bothidae
Chirocentrus nudus|FSCS175-06|FSCS 26-l-1|Chirocentr
Chirocentrus nudus|FSCS058-06|FSCS 26-W-3|Chirocen
Chirocentrus nudus|FSCS057-06|FSCS 26-W-2|Chirocen
Chirocentrus nudus|FSCS056-06|FSCS 26-W-1|Chirocen
Chirocentrus dorab|FSCS176-06|FSCS 26-l-2|Chirocent
Thryssa setirostris|FSCS158-06|FSCS 8-l-1|Engraulidae
Thryssa setirostris|FSCS014-06|FSCS 8-w-1|Engraulidae
Thryssa setirostris|FSCS018-06|FSCS 9-w-4|Engraulidae
Thryssa kammalensis|FSCS159-06|FSCS 9-l-1|Engraulidae
Thryssa kammalensis|FSCS160-06|FSCS 9-l-2|Engraulidae
Thryssa kammalensis|FSCS240-06|FSCS 9-yz-1|Engraulidae
Thryssa kammalensis|FSCS017-06|FSCS 9-w-3|Engraulidae
Thryssa kammalensis|FSCS015-06|FSCS 9-w-1|Engraulidae
Thryssa kammalensis|FSCS241-06|FSCS 9-yz-2|Engraulidae
Thryssa kammalensis|FSCS161-06|FSCS 9-l-3|Engraulidae
Thryssa hamiltonii|FSCS016-06|FSCS 9-w-2|Engraulidae
Thryssa hamiltonii|FSCS019-06|FSCS 9-w-5|Engraulidae
Engraulis japonicus|FSCS263-06|FSCS 17-z-1|Engraulidae
Engraulis japonicus|FSCS266-06|FSCS 17-z-4|Engraulidae
Engraulis japonicus|FSCS267-06|FSCS 17-z-5|Engraulidae
Anchoviella sp.|FSCS265-06|FSCS 17-z-3|Engraulidae
Dussumieria elopsoides|FSCS262-06|FSCS 16-z-1|Clupeidae
Dussumieria elopsoides|FSCS035-06|FSCS 16-W-1|Clupeidae
Dussumieria elopsoides|FSCS036-06|FSCS 16-W-2|Clupeidae
Sardinella sp.|FSCS287-06|FSCS 94-z-2|Clupeidae
Sardinella melanura|FSCS168-06|FSCS 18-l-1|Clupeidae
Sardinella melanura|FSCS268-06|FSCS 18-z-1|Clupeidae
Sardinella melanura|FSCS269-06|FSCS 18-z-2|Clupeidae
Sardinella melanura|FSCS169-06|FSCS 18-l-2|Clupeidae
Sardinella melanura|FSCS235-06|FSCS 107-l-1|Clupeidae
Sardinella jussieu|FSCS271-06|FSCS 18-z-4|Clupeidae
Sardinella jussieu|FSCS272-06|FSCS 18-z-5|Clupeidae
Amblygaster clupeoides|FSCS286-06|FSCS 94-z-1|Clupeidae
Sardinella aurita|FSCS327-06|FSCS 114-st-1|Clupeidae
Sardinella aurita|FSCS328-06|FSCS 114-st-2|Clupeidae
Sardinella aurita|FSCS329-06|FSCS 114-st-3|Clupeidae
Upeneus tragula|FSCS279-06|FSCS 78-z-1|Mullidae
Upeneus tragula|FSCS207-06|FSCS 78-l-1|Mullidae
Upeneus tragula|FSCS208-06|FSCS 78-l-2|Mullidae
Upeneus tragula|FSCS209-06|FSCS 78-l-3|Mullidae
Upeneus subvittatus|FSCS130-06|FSCS 56-w-5|Mullidae
Upeneus japonicus|FSCS126-06|FSCS 56-w-1|Mullidae
Upeneus japonicus|FSCS128-06|FSCS 56-w-3|Mullidae
Upeneus japonicus|FSCS127-06|FSCS 56-w-2|Mullidae
Upeneus japonicus|FSCS129-06|FSCS 56-w-4|Mullidae
Upeneus japonicus|FSCS245-06|FSCS 56-yz-1|Mullidae
Upeneus sulphureus|FSCS171-06|FSCS 22-l-1|Mullidae
Upeneus sulphureus|FSCS045-06|FSCS 22-W-1|Mullidae
Upeneus sulphureus|FSCS046-06|FSCS 22-W-2|Mullidae
Parupeneus ciliatus|FSCS210-06|FSCS 79-l-1|Mullidae
Parupeneus ciliatus|FSCS211-06|FSCS 79-l-2|Mullidae
Trichiurus lepturus|FSCS155-06|FSCS 3-l-1|Trichiuridae
Trichiurus lepturus|FSCS156-06|FSCS 3-l-2|Trichiuridae
Lepturacanthus savala|FSCS290-06|FSCS 3-b-1|Trichiuridae
Lepturacanthus savala|FSCS007-06|FSCS 3-w-1|Trichiuridae
Scomber sp.|FSCS093-06|FSCS 38-W-5|Scombridae
Scomber japonicus|FSCS092-06|FSCS 38-W-4|Scombridae
Scomber japonicus|FSCS181-06|FSCS 38-l-2|Scombridae
Scomber japonicus|FSCS089-06|FSCS 38-W-1|Scombridae
Scomber japonicus|FSCS309-06|FSCS 38-sz-1|Scombridae
Scomber japonicus|FSCS091-06|FSCS 38-W-3|Scombridae
Scomber japonicus|FSCS180-06|FSCS 38-l-1|Scombridae
Scomber japonicus|FSCS090-06|FSCS 38-W-2|Scombridae
Scomberomorus guttatus|FSCS249-06|FSCS 86-yz-2|Scombridae
Scomberomorus guttatus|FSCS298-06|FSCS 86-b-1|Scombridae
Scomberomorus guttatus|FSCS228-06|FSCS 86-l-2|Scombridae
Scomberomorus commerson|FSCS248-06|FSCS 86-yz-1|Scombridae
Johnius belangerii|FSCS200-06|FSCS 76-l-1|Sciaenidae
Johnius belangerii|FSCS201-06|FSCS 76-l-2|Sciaenidae
Johnius belangerii|FSCS297-06|FSCS 76-b-1|Sciaenidae
Dendrophysa russelii|FSCS068-06|FSCS 29-W-1|Sciaenidae
Dendrophysa russelii|FSCS072-06|FSCS 29-W-5|Sciaenidae
Dendrophysa russelii|FSCS069-06|FSCS 29-W-2|Sciaenidae
Dendrophysa russelii|FSCS070-06|FSCS 29-W-3|Sciaenidae
Dendrophysa russelii|FSCS071-06|FSCS 29-W-4|Sciaenidae Harpadon nehereus|FSCS326 06|FSCS 113 st 1|Synodontidae
Fistularia commersonii|FSCS214-06|FSCS 81-l-1|Fistulariidae
Fistularia commersonii|FSCS215-06|FSCS 81-l-2|Fistulariidae
Arnoglossus polyspilus|FSCS116-06|FSCS 52-w-1|Bothidae
Arnoglossus polyspilus|FSCS117-06|FSCS 52-w-2|Bothidae
Arnoglossus polyspilus|FSCS118-06|FSCS 52-w-3|Bothidae
Chirocentrus nudus|FSCS175-06|FSCS 26-l-1|Chirocentridae
Chirocentrus nudus|FSCS058-06|FSCS 26-W-3|Chirocentridae
Chirocentrus nudus|FSCS057-06|FSCS 26-W-2|Chirocentridae
Chirocentrus nudus|FSCS056-06|FSCS 26-W-1|Chirocentridae
Chirocentrus dorab|FSCS176-06|FSCS 26-l-2|Chirocentridae
Thryssa setirostris|FSCS158-06|FSCS 8-l-1|Engraulidae
Thryssa setirostris|FSCS014-06|FSCS 8-w-1|Engraulidae
Thryssa setirostris|FSCS018-06|FSCS 9-w-4|Engraulidae
Thryssa kammalensis|FSCS159-06|FSCS 9-l-1|Engraulidae
Thryssa kammalensis|FSCS160-06|FSCS 9-l-2|Engraulidae
Thryssa kammalensis|FSCS240-06|FSCS 9-yz-1|Engraulidae
Thryssa kammalensis|FSCS017-06|FSCS 9-w-3|Engraulidae
Thryssa kammalensis|FSCS015-06|FSCS 9-w-1|Engraulidae
Thryssa kammalensis|FSCS241-06|FSCS 9-yz-2|Engraulidae
Thryssa kammalensis|FSCS161-06|FSCS 9-l-3|Engraulidae
Thryssa hamiltonii|FSCS016-06|FSCS 9-w-2|Engraulidae
Thryssa hamiltonii|FSCS019-06|FSCS 9-w-5|Engraulidae
Engraulis japonicus|FSCS263-06|FSCS 17-z-1|Engraulidae
Engraulis japonicus|FSCS266-06|FSCS 17-z-4|Engraulidae
Engraulis japonicus|FSCS267-06|FSCS 17-z-5|Engraulidae
Anchoviella sp.|FSCS265-06|FSCS 17-z-3|Engraulidae
Dussumieria elopsoides|FSCS262-06|FSCS 16-z-1|Clupeidae
Dussumieria elopsoides|FSCS035-06|FSCS 16-W-1|Clupeidae
Dussumieria elopsoides|FSCS036-06|FSCS 16-W-2|Clupeidae
Sardinella sp.|FSCS287-06|FSCS 94-z-2|Clupeidae
Sardinella melanura|FSCS168-06|FSCS 18-l-1|Clupeidae
Sardinella melanura|FSCS268-06|FSCS 18-z-1|Clupeidae
Sardinella melanura|FSCS269-06|FSCS 18-z-2|Clupeidae
Sardinella melanura|FSCS169-06|FSCS 18-l-2|Clupeidae
Sardinella melanura|FSCS235-06|FSCS 107-l-1|Clupeidae
Sardinella jussieu|FSCS271-06|FSCS 18-z-4|Clupeidae
Sardinella jussieu|FSCS272-06|FSCS 18-z-5|Clupeidae
Amblygaster clupeoides|FSCS286-06|FSCS 94-z-1|Clupeidae
Sardinella aurita|FSCS327-06|FSCS 114-st-1|Clupeidae
Sardinella aurita|FSCS328-06|FSCS 114-st-2|Clupeidae
Sardinella aurita|FSCS329-06|FSCS 114-st-3|Clupeidae
Upeneus tragula|FSCS279-06|FSCS 78-z-1|Mullidae
Upeneus tragula|FSCS207-06|FSCS 78-l-1|Mullidae
Upeneus tragula|FSCS208-06|FSCS 78-l-2|Mullidae
Upeneus tragula|FSCS209-06|FSCS 78-l-3|Mullidae
Upeneus subvittatus|FSCS130-06|FSCS 56-w-5|Mullidae
Upeneus japonicus|FSCS126-06|FSCS 56-w-1|Mullidae
Upeneus japonicus|FSCS128-06|FSCS 56-w-3|Mullidae
Upeneus japonicus|FSCS127-06|FSCS 56-w-2|Mullidae
Upeneus japonicus|FSCS129-06|FSCS 56-w-4|Mullidae
Upeneus japonicus|FSCS245-06|FSCS 56-yz-1|Mullidae
Upeneus sulphureus|FSCS171-06|FSCS 22-l-1|Mullidae
Upeneus sulphureus|FSCS045-06|FSCS 22-W-1|Mullidae
Upeneus sulphureus|FSCS046-06|FSCS 22-W-2|Mullidae
Parupeneus ciliatus|FSCS210-06|FSCS 79-l-1|Mullidae
Parupeneus ciliatus|FSCS211-06|FSCS 79-l-2|Mullidae
Trichiurus lepturus|FSCS155-06|FSCS 3-l-1|Trichiuridae
Trichiurus lepturus|FSCS156-06|FSCS 3-l-2|Trichiuridae
Lepturacanthus savala|FSCS290-06|FSCS 3-b-1|Trichiuridae
Lepturacanthus savala|FSCS007-06|FSCS 3-w-1|Trichiuridae
Scomber sp.|FSCS093-06|FSCS 38-W-5|Scombridae
Scomber japonicus|FSCS092-06|FSCS 38-W-4|Scombridae
Scomber japonicus|FSCS181-06|FSCS 38-l-2|Scombridae
Scomber japonicus|FSCS089-06|FSCS 38-W-1|Scombridae
Scomber japonicus|FSCS309-06|FSCS 38-sz-1|Scombridae
Scomber japonicus|FSCS091-06|FSCS 38-W-3|Scombridae
Scomber japonicus|FSCS180-06|FSCS 38-l-1|Scombridae
Scomber japonicus|FSCS090-06|FSCS 38-W-2|Scombridae
Scomberomorus guttatus|FSCS249-06|FSCS 86-yz-2|Scombridae
Scomberomorus guttatus|FSCS298-06|FSCS 86-b-1|Scombridae
Scomberomorus guttatus|FSCS228-06|FSCS 86-l-2|Scombridae
Scomberomorus commerson|FSCS248-06|FSCS 86-yz-1|Scombridae
Johnius belangerii|FSCS200-06|FSCS 76-l-1|Sciaenidae
Johnius belangerii|FSCS201-06|FSCS 76-l-2|Sciaenidae
Johnius belangerii|FSCS297-06|FSCS 76-b-1|Sciaenidae
Dendrophysa russelii|FSCS068-06|FSCS 29-W-1|Sciaenidae
Dendrophysa russelii|FSCS072-06|FSCS 29-W-5|Sciaenidae
Dendrophysa russelii|FSCS069-06|FSCS 29-W-2|Sciaenidae
Dendrophysa russelii|FSCS070-06|FSCS 29-W-3|Sciaenidae
Dendrophysa russelii|FSCS071-06|FSCS 29-W-4|Sciaenidae
(a) (a)
Figure 3: Continued. Evidence-Based Complementary and Alternative Medicine (a) Figure 3: Continued. Evidence-Based Complementary and Alternative Medicine Evidence-Based Complementary and Alternative Medicine 5 Terapon jarbua|FSCS121-06|FSCS 54-w-2|Terapontidae
Terapon jarbua|FSCS123-06|FSCS 54-w-4|Terapontidae
Terapon jarbua|FSCS244-06|FSCS 54-yz-1|Terapontidae
Gerres oblongus|FSCS223-06|FSCS 84-l-2|Gerreidae
Gerres limbatus|FSCS232-06|FSCS 92-l-2|Gerreidae
Gerres limbatus|FSCS231-06|FSCS 92-l-1|Gerreidae
Gerres limbatus|FSCS282-06|FSCS 92-z-1|Gerreidae
Gerres limbatus|FSCS283-06|FSCS 92-z-2|Gerreidae
Gerres limbatus|FSCS250-06|FSCS 92-yz-1|Gerreidae
Thamnaconus tessellatus|FSCS185-06|FSCS 46-l-1|Monacanthid
Thamnaconus tessellatus|FSCS278-06|FSCS 46-z-1|Monacant
Paramonacanthus sulcatus|FSCS101-06|FSCS 45-w-1|Monaca
Paramonacanthus sulcatus|FSCS102-06|FSCS 45-w-2|Monaca
Paramonacanthus sulcatus|FSCS183-06|FSCS 45-l-1|Monacan
Paramonacanthus sulcatus|FSCS103-06|FSCS 45-w-3|Monacan
Paramonacanthus sulcatus|FSCS105-06|FSCS 46-w-2|Monacan
Paramonacanthus sulcatus|FSCS106-06|FSCS 46-w-3|Monacan
Paramonacanthus sulcatus|FSCS243-06|FSCS 45-yz-1|Monacan
Paramonacanthus sulcatus|FSCS184-06|FSCS 45-l-2|Monacant
Paramonacanthus sulcatus|FSCS104-06|FSCS 46-w-1|Monacan
Thamnaconus septentrionalis|FSCS107-06|FSCS 47-w-1|Mona
Thamnaconus septentrionalis|FSCS108-06|FSCS 47-w-2|Mona
Thamnaconus septentrionalis|FSCS186-06|FSCS 47-l-1|Monac
Thalassoma lunare|FSCS198-06|FSCS 72-l-1|Labridae
Scomberoides tol|FSCS063-06|FSCS 28-W-1|Carangidae
Scomberoides tol|FSCS064-06|FSCS 28-W-2|Carangidae
Scomberoides tol|FSCS065-06|FSCS 28-W-3|Carangidae
Scomberoides tol|FSCS067-06|FSCS 28-W-5|Carangidae
Scomberoides tol|FSCS066-06|FSCS 28-W-4|Carangidae
Drepane punctata|FSCS239-06|FSCS 116-l-1|Drepaneidae
Sillago sihama|FSCS196-06|FSCS 70-l-1|Sillaginidae
Sillago sihama|FSCS197-06|FSCS 70-l-2|Sillaginidae
Sillago sihama|FSCS246-06|FSCS 70-yz-1|Sillaginidae
Sillago sihama|FSCS247-06|FSCS 70-yz-2|Sillaginidae
Sillago maculata|FSCS081-06|FSCS 34-W-1|Sillaginidae
Selaroides leptolepis|FSCS087-06|FSCS 36-W-5|Carangidae
Selaroides leptolepis|FSCS083-06|FSCS 36-W-1|Carangidae
Selaroides leptolepis|FSCS084-06|FSCS 36-W-2|Carangidae
Selaroides leptolepis|FSCS085-06|FSCS 36-W-3|Carangidae
Selaroides leptolepis|FSCS086-06|FSCS 36-W-4|Carangidae
Selaroides leptolepis|FSCS179-06|FSCS 36-l-1|Carangidae
Carangoides malabaricus|FSCS012-06|FSCS 7-w-1|Carangidae
Carangoides malabaricus|FSCS013-06|FSCS 7-w-2|Carangidae
Carangoides hedlandensis|FSCS096-06|FSCS 41-w-1|Carangida
Carangoides hedlandensis|FSCS097-06|FSCS 41-w-2|Carangida
Atule mate|FSCS194-06|FSCS 69-l-1|Carangidae
Atule mate|FSCS195-06|FSCS 69-l-2|Carangidae
Atule mate|FSCS296-06|FSCS 69-b-1|Carangidae
Atule sp.|FSCS257-06|FSCS 111-yz-1|Carangidae
Alepes djedaba|FSCS088-06|FSCS 37-W-1|Carangidae
Alepes djedaba|FSCS261-06|FSCS 15-z-2|Carangidae
Alepes djedaba|FSCS292-06|FSCS 15-b-1|Carangidae
Alepes djedaba|FSCS167-06|FSCS 15-l-2|Carangidae
Alepes djedaba|FSCS166-06|FSCS 15-l-1|Carangidae
Alepes djedaba|FSCS260-06|FSCS 15-z-1|Carangidae
Rachycentron canadum|FSCS095-06|FSCS 40-W-1|Rac
Lactarius lactarius|FSCS157-06|FSCS 6-l-1|Russulaceae
Lactarius lactarius|FSCS010-06|FSCS 6-w-1|Russulaceae
Lactarius lactarius|FSCS011-06|FSCS 6-w-2|Russulaceae
Cynoglossus sp.|FSCS111-06|FSCS 49-w-2|Cynoglo
Cynoglossus puncticeps|FSCS110-06|FSCS 49-w-1|Cy
Cynoglossus puncticeps|FSCS112-06|FSCS 49-w-3|Cy
Cynoglossus bilineatus|FSCS114-06|FSCS 51-w-
Cynoglossus bilineatus|FSCS125-06|FSCS 55-w-
Cynoglossus bilineatus|FSCS115-06|FSCS 51-w
Polydactylus sextarius|FSCS305-06|FSCS 100-b-1|Poly
Paraplagusia japonica|FSCS113-06|FSCS 50-w-1|Cyno
Brachirus orientalis|FSCS009-06|FSCS 5-w-1|Soleidae
Mene maculata|FSCS001-06|FSCS 1-w-1|Menidae
Mene maculata|FSCS002-06|FSCS 1-w-2|Menidae
Mene maculata|FSCS003-06|FSCS 1-w-3|Menidae
Mene maculata|FSCS004-06|FSCS 1-w-4|Menidae
Pardachirus pavoninus|FSCS253-06|FSCS 103-yz-1|Soleid
Pardachirus pavoninus|FSCS255-06|FSCS 105-yz-1|Solei
Epinephelus sexfasciatus|FSCS098-06|FSCS 42-w-1|Se
Zebrias quagga|FSCS109-06|FSCS 48-w-1|Soleidae
Lagocephalus spadiceus|FSCS302-06|FSCS 98-b-1|Tetraodontid
Saurida sp.|FSCS277-06|FSCS 44-z-1|Synodontidae
Saurida elongata|FSCS100-06|FSCS 44-w-1|Synodontidae
Harpadon nehereus|FSCS307-06|FSCS 113-b-1|Synodo
Harpadon nehereus|FSCS326-06|FSCS 113-st-1|Synodo
Fistularia commersonii|FSCS214-06|FSCS 81-l-1|Fistulariid
Fistularia commersonii|FSCS215-06|FSCS 81-l-2|Fistularii
(b)
Figure 3: Continued. (b) Figure 3: Continued. 6 Evidence-Based Complementary and Alternative Medicine Evidence-Based Complementary and Alternative Medicine Evidence-Based Complementary and Alternative Medicine 6 Oxyconger leptognathus|FSCS145-06|FSCS 63-w-2|Muraenesocidae
Oxyconger leptognathus|FSCS146-06|FSCS 63-w-3|Muraenesocidae
Muraenesox cinereus|FSCS234-06|FSCS 95-l-2|Muraenesocidae
Muraenesox cinereus|FSCS288-06|FSCS 95-z-1|Muraenesocidae
Elops hawaiensis|FSCS062-06|FSCS 27-W-4|Elopidae
Elops hawaiensis|FSCS059-06|FSCS 27-W-1|Elopidae
Elops hawaiensis|FSCS060-06|FSCS 27-W-2|Elopidae
Elops hawaiensis|FSCS061-06|FSCS 27-W-3|Elopidae
Apogon taeniatus|FSCS191-06|FSCS 67-l-1|Apogonidae
Apogon taeniatus|FSCS192-06|FSCS 67-l-2|Apogonidae
Apogon quadrifasciatus|FSCS149-06|FSCS 66-w-1|Apogonidae
Apogon quadrifasciatus|FSCS150-06|FSCS 66-w-2|Apogonidae
Apogon quadrifasciatus|FSCS295-06|FSCS 66-b-1|Apogonidae
Apogon quadrifasciatus|FSCS256-06|FSCS 109-yz-1|Apogonidae
Apogon fuscus|FSCS190-06|FSCS 66-l-1|Apogonidae
Apogon erythrinus|FSCS193-06|FSCS 68-l-1|Apogonidae
Repomucenus richardsonii|FSCS136-06|FSCS 60-w-1|Callionymidae
Repomucenus richardsonii|FSCS137-06|FSCS 60-w-2|Callionymidae
Repomucenus richardsonii|FSCS139-06|FSCS 60-w-4|Callionymidae
Repomucenus richardsonii|FSCS138-06|FSCS 60-w-3|Callionymidae
Bathycallionymus kaianus|FSCS310-06|FSCS 60-sz-1|Callionymidae
Priacanthus macracanthus|FSCS321-06|FSCS 110-st-1|Priacanthidae
Priacanthus macracanthus|FSCS322-06|FSCS 110-st-2|Priacanthidae
Acentrogobius caninus|FSCS170-06|FSCS 19-l-1|Gobiidae
Acentrogobius caninus|FSCS039-06|FSCS 19-W-3|Gobiidae
Acentrogobius caninus|FSCS273-06|FSCS 19-z-1|Gobiidae
Acentrogobius caninus|FSCS274-06|FSCS 19-z-2|Gobiidae
Acentrogobius caninus|FSCS038-06|FSCS 19-W-2|Gobiidae
Acentrogobius caninus|FSCS037-06|FSCS 19-W-1|Gobiidae
Hypodytes indicus|FSCS131-06|FSCS 57-w-1|Congiopodidae
Parapercis ommatura|FSCS040-06|FSCS 20-W-1|Pinguipedidae
Parapercis ommatura|FSCS043-06|FSCS 20-W-4|Pinguipedidae
Parapercis ommatura|FSCS041-06|FSCS 20-W-2|Pinguipedidae
Parapercis ommatura|FSCS042-06|FSCS 20-W-3|Pinguipedidae
Glossogobius aureus|FSCS082-06|FSCS 35-W-1|Gobiidae
Sphyraena pinguis|FSCS099-06|FSCS 43-w-1|Sphyraenidae
Sphyraena helleri|FSCS182-06|FSCS 43-l-1|Sphyraenidae
Kumococius rodericensis|FSCS132-06|FSCS 58-w-1|Platycephalidae
Kumococius rodericensis|FSCS134-06|FSCS 58-w-3|Platycephalidae
Kumococius rodericensis|FSCS133-06|FSCS 58-w-2|Platycephalidae
Seriola dumerili|FSCS218-06|FSCS 83-l-1|Carangidae
Seriola dumerili|FSCS221-06|FSCS 83-l-4|Carangidae
Seriola dumerili|FSCS219-06|FSCS 83-l-2|Carangidae
Seriola dumerili|FSCS220-06|FSCS 83-l-3|Carangidae
Lutjanus fulvus|FSCS229-06|FSCS 88-l-1|Lutjanidae
Pomadasys hasta|FSCS174-06|FSCS 24-l-1|Haemulidae
Pomadasys hasta|FSCS051-06|FSCS 24-W-3|Haemulidae
Pomadasys hasta|FSCS049-06|FSCS 24-W-1|Haemulidae
Pomadasys hasta|FSCS050-06|FSCS 24-W-2|Haemulidae
Pomadasys hasta|FSCS052-06|FSCS 24-W-4|Haemulidae
Parapristipoma sp.|FSCS216-06|FSCS 82-l-1|Haemulidae
Parapristipoma sp.|FSCS217-06|FSCS 82-l-2|Haemulidae
Hemiramphus far|FSCS177-06|FSCS 31-l-1|Hemiramphidae
Hemiramphus dussumieri|FSCS076-06|FSCS 31-W-1|Hemiramphidae
Hemiramphus dussumieri|FSCS077-06|FSCS 31-W-2|Hemiramphidae
Acanthopagrus schlegelii schlegelii|FSCS143-06|FSCS 62-w-1|Sparidae
Acanthopagrus berda|FSCS078-06|FSCS 32-W-1|Sparidae
Acanthopagrus latus|FSCS178-06|FSCS 32-l-1|Sparidae
Acanthopagrus latus|FSCS308-06|FSCS 32-sz-1|Sparidae
Hypoatherina valenciennei|FSCS151-06|FSCS 80-w-1|Atherinidae
Hypoatherina valenciennei|FSCS152-06|FSCS 80-w-2|Atherinidae
Hypoatherina valenciennei|FSCS212-06|FSCS 80-l-1|Atherinidae
Hypoatherina valenciennei|FSCS213-06|FSCS 80-l-2|Atherinidae
Platycephalus indicus|FSCS135-06|FSCS 59-w-1|Platycephalidae
Gerres filamentosus|FSCS254-06|FSCS 104-yz-1|Gerreidae
Gerres filamentosus|FSCS312-06|FSCS 104-sz-1|Gerreidae
Gerres filamentosus|FSCS222-06|FSCS 84-l-1|Gerreidae
Valamugil cunnesius|FSCS251-06|FSCS 99-yz-1|Mugilidae
Mugil cephalus|FSCS303-06|FSCS 99-b-1|Mugilidae
Mugil cephalus|FSCS304-06|FSCS 99-b-2|Mugilidae
Siganus argenteus|FSCS311-06|FSCS 89-sz-1|Siganidae
Siganus argenteus|FSCS319-06|FSCS 89-st-1|Siganidae
Siganus argenteus|FSCS230-06|FSCS 89-l-1|Siganidae
Siganus argenteus|FSCS317-06|FSCS 13-st-1|Siganidae
Terapon theraps|FSCS318-06|FSCS 54-st-1|Terapontidae
Terapon jarbua|FSCS119-06|FSCS 53-w-1|Terapontidae
Terapon jarbua|FSCS122-06|FSCS 54-w-3|Terapontidae
Terapon jarbua|FSCS293-06|FSCS 54-b-1|Terapontidae
Terapon jarbua|FSCS294-06|FSCS 54-b-2|Terapontidae
Terapon jarbua|FSCS120-06|FSCS 54-w-1|Terapontidae
Terapon jarbua|FSCS121-06|FSCS 54-w-2|Terapontidae
Terapon jarbua|FSCS123-06|FSCS 54-w-4|Terapontidae
Terapon
jarbua|FSCS244-06|FSCS
54-yz-1|Terapontidae
Oxyconger leptognathus|FSCS144-06|FSCS 62-w-1|Muraenesocidae
(c)
Figure 3: Continued. Figure 3: Neighbor-joining (NJ) tree of COI sequences. Scale: 5% K2P distance. The first numbers following species names are the process
IDs, and the latter are the sample IDs. References [1] R. S. Rasmussen, M. T. Morrissey, and P. D. N. Hebert,
“DNA barcoding of commercially important salmon and trout
species (oncorhynchus and salmo ) from North America,”
Journal of Agricultural and Food Chemistry, vol. 57, no. 18, pp. 8379–8385, 2009. [2] B. C. Victor, R. Hanner, M. Shivji, J. Hyde, and C. Cal-
dow, “Identification of the larval and juvenile stages of the
Cubera Snapper, Lutjanus cyanoptems , using DNA barcoding,”
Zootaxa, no. 2215, pp. 24–36, 2009. Biological mechanisms, water dynamics, or historical
events may cause deep genetic structuring of populations
in marine species [26, 39]. Many explanations for genetic
population structuring on local and regional scales involve
behaviors such as the adoption of pelagic early life stages
and movement over broad geographic ranges, and these
factors are theoretically associated with gene flow [40–42]. For many marine fishes, there is a lack of phylogeographic
structure among populations [43, 44]; in this study, for
individuals from long distance localities, some intraspecific
genetic variations reduced to zero within families Carangi-
dae, Sciaenidae, and Mullidae. However, some pairwise
K2P distances exceeded 1.00% within the coastal species
such as Acentrogobius caninus, Scomber japonicus, Terapon
jarbua, Upeneus sulphureus, Elops hawaiensis, Gymnothorax
pseudothyrsoideus, and Dendrophysa russelii. It implied that
biological mechanisms were responsible for the fluctuation
of intraspecific genetic divergences in marine fishes. [3] B. Patwardhan, D. Warude, P. Pushpangadan, and N. Bhatt,
“Ayurveda and traditional Chinese medicine: a comparative
overview,” Evidence-Based Complementary and Alternative
Medicine, vol. 2, no. 4, pp. 465–473, 2005. [4] S. E. Bartlett and W. S. Davidson, “Identification of Thunnus
tuna species by the polymerase chain reaction and direct
sequence analysis of their mitochondrial cytochrome b genes,”
Canadian Journal of Fisheries and Aquatic Sciences, vol. 48, pp. 309–317, 1991. [5] A. Rocha-Olivares, “Multiplex haplotype-specific PCR: a new
approach for species identification of the early life stages of
rockfishes of the species-rich genus Sebastes Cuvier,” Journal
of Experimental Marine Biology and Ecology, vol. 231, no. 2,
pp. 279–290, 1998. [6] A. J. Gharrett, A. K. Gray, and J. Heifetz, “Identification
of rockfish (Sebastes spp.) by restriction site analysis of the
mitochondrial ND-3/ND-4 and 12S/16S rRNA gene regions,”
Fishery Bulletin, vol. 99, no. 1, pp. 49–62, 2001. Evidence-Based Complementary and Alternative Medicine (c) Evidence-Based Complementary and Alternative Medicine 7 7 Pennahia anea|FSCS291-06|FSCS 11-b-1|Sciaenidae
Pennahia anea|FSCS313-06|FSCS 11-st-1|Sciaenidae
Chrysochir aureus|FSCS148-06|FSCS 65-w-1|Sciaenidae
Otolithes ruber|FSCS252-06|FSCS 101-yz-1|Sciaenidae
Otolithes ruber|FSCS306-06|FSCS 101-b-1|Sciaenidae
Arius leiotetocephalus|FSCS284-06|FSCS 93-z-1|Ariidae
Arius leiotetocephalus|FSCS285-06|FSCS 93-z-2|Ariidae
Abudefduf septemfasciatus|FSCS199-06|FSCS 74-l-1|Pomacentridae
Takifugu oblongus|FSCS094-06|FSCS 39-W-1|Tetradontidae
Arius thalassinus|FSCS202-06|FSCS 77-l-1|Ariidae
Arius thalassinus|FSCS205-06|FSCS 77-l-4|Ariidae
Arius thalassinus|FSCS206-06|FSCS 77-l-5|Ariidae
Arius thalassinus|FSCS204-06|FSCS 77-l-3|Ariidae
Scorpaenopsis vittapinna|FSCS224-06|FSCS 85-l-1|Scorpaenidae
Scorpaenopsis vittapinna|FSCS226-06|FSCS 85-l-3|Scorpaenidae
Scorpaenopsis vittapinna|FSCS225-06|FSCS 85-l-2|Scorpaenidae
Pampus cinereus|FSCS289-06|FSCS 112-z-1|Stromateidae
Pampus cinereus|FSCS073-06|FSCS 30-W-1|Stromateidae
Pampus argenteus|FSCS140-06|FSCS 61-w-1|Stromateidae
Pampus argenteus|FSCS141-06|FSCS 61-w-2|Stromateidae
Pampus argenteus|FSCS142-06|FSCS 61-w-3|Stromateidae
Pampus cinereus|FSCS075-06|FSCS 30-W-3|Stromateidae
Pampus cinereus|FSCS325-06|FSCS 112-st-3|Stromateidae
Pampus cinereus|FSCS324-06|FSCS 112-st-2|Stromateidae
Pampus cinereus|FSCS323-06|FSCS 112-st-1|Stromateidae
Pampus argenteus|FSCS074-06|FSCS 30-W-2|Stromateidae
Gymnothorax pseudothyrsoideus|FSCS147-06|FSCS 64-w-1|Muraeni
Gymnothorax pseudothyrsoideus|FSCS189-06|FSCS 64-l-2|Muraenidae
Gymnothorax pseudothyrsoideus|FSCS188-06|FSCS 64-l-1|Muraenidae
Favonigobius gymnauchen|FSCS044-06|FSCS 21-W-1|Gobiidae
Etmopterus lucifer|FSCS162-06|FSCS 9-l-4|Squalidae
Etmopterus lucifer|FSCS238-06|FSCS 115-l-3|Squalidae
Etmopterus lucifer|FSCS237-06|FSCS 115-l-2|Squalidae
Etmopterus lucifer|FSCS236-06|FSCS 115-l-1|Squalidae
Dasyatis zugei|FSCS008-06|FSCS 4-w-1|Dasyatididae
Strongylura strongylura|FSCS153-06|FSCS 2-l-1|Belonidae
Strongylura strongylura|FSCS154-06|FSCS 2-l-2|Belonidae
Strongylura strongylura|FSCS187-06|FSCS 59-l-1|Belonidae
Strongylura leiura|FSCS005-06|FSCS 2-w-1|Belonidae
Strongylura leiura|FSCS006-06|FSCS 2-w-2|Belonidae
Strongylura sp.|FSCS300-06|FSCS 96-b-2|Belonidae
Scatophagus argus|FSCS299-06|FSCS 96-b-1|Scatophagidae
Scatophagus argus|FSCS053-06|FSCS 25-W-1|Scatophagidae
Scatophagus argus|FSCS054-06|FSCS 25-W-2|Scatophagidae
Scatophagus argus|FSCS055-06|FSCS 25-W-3|Scatophagidae
Escualosa thoracata|FSCS258-06|FSCS 10-z-1|Clupeidae
Escualosa thoracata|FSCS259-06|FSCS 10-z-2|Clupeidae
Escualosa thoracata|FSCS020-06|FSCS 10-w-1|Clupeidae
Escualosa thoracata|FSCS024-06|FSCS 10-w-5|Clupeidae
Escualosa thoracata|FSCS021-06|FSCS 10-w-2|Clupeidae
Escualosa thoracata|FSCS022-06|FSCS 10-w-3|Clupeidae
Secutor ruconius|FSCS314-06|FSCS 12-st-1|Leiognathidae
Secutor ruconius|FSCS026-06|FSCS 12-W-1|Leiognathidae
Secutor ruconius|FSCS027-06|FSCS 12-W-2|Leiognathidae
Secutor insidiator|FSCS315-06|FSCS 12-st-2|Leiognathidae
Secutor insidiator|FSCS316-06|FSCS 12-st-3|Leiognathidae
Leiognathus nuchalis|FSCS275-06|FSCS 23-z-1|Leiognathidae
Leiognathus nuchalis|FSCS276-06|FSCS 23-z-2|Leiognathidae
Leiognathus bindus|FSCS172-06|FSCS 23-l-1|Leiognathidae
Leiognathus bindus|FSCS173-06|FSCS 23-l-2|Leiognathidae
Leiognathus bindus|FSCS242-06|FSCS 23-yz-1|Leiognathidae
Leiognathus bindus|FSCS031-06|FSCS 14-W-1|Leiognathidae
Leiognathus bindus|FSCS034-06|FSCS 14-W-4|Leiognathidae
Leiognathus bindus|FSCS033-06|FSCS 14-W-3|Leiognathidae
Leiognathus bindus|FSCS032-06|FSCS 14-W-2|Leiognathidae
Leiognathus leuciscus|FSCS163-06|FSCS 13-l-1|Leiognathidae
Leiognathus leuciscus|FSCS164-06|FSCS 13-l-2|Leiognathidae
Leiognathus leuciscus|FSCS165-06|FSCS 13-l-3|Leiognathidae
Leiognathus leuciscus|FSCS029-06|FSCS 13-W-2|Leiognathidae
Leiognathus leuciscus|FSCS030-06|FSCS 13-W-3|Leiognathidae
Leiognathus leuciscus|FSCS028-06|FSCS 13-W-1|Leiognathidae
Leiognathus brevirostris|FSCS047-06|FSCS 23-W-1|Leiognathidae
Leiognathus brevirostris|FSCS048-06|FSCS 23-W-2|Leiognathidae
Lethrinus lentjan|FSCS280-06|FSCS 91-z-1|Lethrinidae
Lethrinus lentjan|FSCS281-06|FSCS 91-z-2|Lethrinidae
Hirundichthys rondeletii|FSCS079-06|FSCS 33-W-1|Exocoetidae
Hirundichthys rondeletii|FSCS080-06|FSCS 33-W-2|Exocoetidae
Oxyconger sp.|FSCS233-06|FSCS 95-l-1|Muraenesocidae
Oxyconger sp.|FSCS320-06|FSCS 95-st-1|Muraenesocidae
Oxyconger leptognathus|FSCS144-06|FSCS 63-w-1|Muraenesocidae
Oxyconger leptognathus|FSCS145-06|FSCS 63-w-2|Muraenesocidae
Oxyconger leptognathus|FSCS146-06|FSCS 63-w-3|Muraenesocidae (d) Figure 3: Neighbor-joining (NJ) tree of COI sequences. Scale: 5% K2P distance. The first numbers following species names are the process
IDs, and the latter are the sample IDs. Evidence-Based Complementary and Alternative Medicine Evidence-Based Complementary and Alternative Medicine 8 and when criteria are given, they vary considerably among
studies [32]. Thus, it is not surprising that there are so many
synonyms for organisms [33], and an objective, rigorous
species delimitation according to explicit criteria is therefore
necessary for many taxonomic studies [34]. While DNA
barcoding provides taxonomic identification for a specimen,
the accuracy of such an assignment depends on whether
species are monophyletic with respect to sequence variations
of the COI gene. That is, individuals of a given species
are more closely related to all other conspecifics than to
any member of other species. Evidence-Based Complementary and Alternative Medicine Except for the hybridized
specimens in the genus Pampus, there are no overlaps
between genetic variations of S and G (Figure 1). cannot set a threshold of the genetic variation in species
delimitation, we find ourselves sunk in the dilemma facing
new or cryptic species. On the one hand, the morphological
taxonomy cannot give a definite identification. On the
other hand, we cannot claim that it may be a new species
based on molecular analysis without the species delimitation. An assumed threshold is helpful to expedite discovery of
new species and biodiversity, especially in dealing with
little-studied biotas, although a single, uniform threshold
for species delimitation seems arbitrary because rates of
molecular evolution vary widely within and among lineages
[24, 25, 48]. The factors responsible for deviations from taxonomic
monophyly may be varied and complex [35]; one potential
cause of species-level polyphyly is the occasional mat-
ing between distinct species, resulting in hybrid offspring
carrying a mixture of genes from both parent species. Furthermore, mitochondrial genes are generally subjected
to introgression more frequently than nuclear ones, and
introgression also leads to phylogenetic paraphyly [35–
38], like the hybridization between Pampus argentenus and
Pampus cinereus in this study. In such cases, combinations
of morphological and genotypic data are needed for species
assignment of hybrids. Acknowledgments Thanks are due to Chinese National Funding U0633007 and
40776089 and CAS Founding KZCX2-YW-213. Thanks are due to Chinese National Funding U0633007 and
40776089 and CAS Founding KZCX2-YW-213. References p
g
g
The neighbor-joining method was originally employed in
this study for species identification, but some phylogenetic
information was also revealed by the dendrogram, and over
98% of specimens were allocated into different families with-
out polyphyly/paraphyly in the NJ tree (Figure 3). However,
DNA barcoding is independent of the way the taxonomy has
been built, and it cannot be regarded as the “taxonomic” tag
[45]. DNA barcoding is no substitute for taxonomy Ebach
and Holdrege [46], and a great deal of work is needed
to bring about the reconciliation between traditional and
molecular taxonomy. It is unfeasible to build the phylogeny
of fishes only based on mitochondrial DNA fragments. Polyphyly/paraphyly in the NJ tree probably results from
“bad taxonomy” when named species fail to identify the
genetic limits of separate evolutionary entities, particularly
for perplexing taxa involving cryptic species [47]. If we [7] B. Horstkotte and H. Rehbein, “Fish species identification by
means of restriction fragment length polymorphism and high-
performance liquid chromatography,” Journal of Food Science,
vol. 68, no. 9, pp. 2658–2666, 2003. [8] C. J. Noell, S. Donnellan, R. Foster, and L. Haigh, “Molecular
discrimination of garfish Hyporhamphus (Beloniformes) lar-
vae in southern Australian waters,” Marine Biotechnology, vol. 3, no. 6, pp. 509–514, 2001. [9] J. Zhang, L. Huang, and H. Huo, “Larval identification of
Lutjanus Bloch in Nansha coral reefs by AFLP molecular
method,” Journal of Experimental Marine Biology and Ecology,
vol. 298, no. 1, pp. 3–20, 2004. [10] G. Comi, L. Iacumin, K. Rantsiou, C. Cantoni, and L. Cocolin,
“Molecular methods for the differentiation of species used in Evidence-Based Complementary and Alternative Medicine 9 Evidence-Based Complementary and Alternative Medicine production of cod-fish can detect commercial frauds,” Food
Control, vol. 16, no. 1, pp. 37–42, 2005. [26] P. H. Barber, S. R. Palumbi, M. V. Erdmann, and M. K. Moosa,
“Biogeography: a marine Wallace’s line?” Nature, vol. 406, no. 6797, pp. 692–693, 2000. [11] P. D. N. Hebert, A. Cywinska, S. L. Ball, and J. R. DeWaard,
“Biological identifications through DNA barcodes,” Proceed-
ings of the Royal Society B: Biological Sciences, vol. 270, no. 1512, pp. 313–321, 2003. [27] N. V. Ivanova, J. R. DeWaard, and P. D. N. Hebert, “An inex-
pensive, automation-friendly protocol for recovering high-
quality DNA,” Molecular Ecology Notes, vol. 6, no. 4, pp. 998–
1002, 2006. [12] P. D. N. Hebert, E. H. Penton, J. M. Burns, D. H. References Aspden, “MtDNA
barcode identification of fish larvae in the southern Great
Barrier Reef, Australia,” Scientia Marina, vol. 70, no. 2, pp. 7–
12, 2006. [35] D. J. Funk and K. E. Omland, “Species-level paraphyly and
polyphyly: frequency, causes, and consequences, with insights
from animal mitochondrial DNA,” Annual Review of Ecology,
Evolution, and Systematics, vol. 34, pp. 397–423, 2003. [18] N. Hubert, R. Hanner, E. Holm et al., “Identifying Canadian
freshwater fishes through DNA barcodes,” PLoS ONE, vol. 3,
no. 6, article e2490, 2008. [36] J. Arnold, “Cytonuclear disequilibria in hybrid zones,” Annual
Review of Ecology and Systematics, vol. 24, pp. 521–554, 1993. [19] M. Vences, M. Thomas, R. M. Bonett, and D. R. Vieites,
“Deciphering amphibian diversity through DNA barcoding:
chances and challenges,” Philosophical Transactions of the Royal
Society B: Biological Sciences, vol. 360, no. 1462, pp. 1859–1868,
2005. [37] T. G. Barraclough and S. Nee, “Phylogenetics and speciation,”
Trends in Ecology and Evolution, vol. 16, no. 7, pp. 391–399,
2001. [38] P. Alexandrino, R. Faria, D. Linhares et al., “Interspecific
differentiation and intraspecific substructure in two closely
related clupeids with extensive hybridization, Alosa alosa and
Alosa fallax,” Journal of Fish Biology, vol. 69, pp. 242–259, 2006. [20] M. Vences, M. Thomas, A. van der Meijden, Y. Chiari, and D. R. Vieites, “Comparative performance of the 16S rRNA gene
in DNA barcoding of amphibians,” Frontiers in Zoology, vol. 2,
article 5, 2005. [39] J. S. Nelson, R. J. Hoddell, L. M. Chou, W. K. Chan, and V. P. E. Phang, “Phylogeographic structure of false clownfish,
Amphiprion ocellaris, explained by sea level changes on the
Sunda shelf,” Marine Biology, vol. 137, no. 4, pp. 727–736,
2000. [21] M. Aliabadian, M. Kaboli, V. Nijman, and M. Vences, “Molec-
ular identification of birds: performance of distance-based
DNA barcoding in three genes to delimit parapatric species,”
PLoS ONE, vol. 4, no. 1, article e4119, 2009. [40] S. F. Chenoweth and J. M. Hughes, “Genetic population struc-
ture of the catadromous perciform: Macquaria novemaculeata
(Percichthyidae),” Journal of Fish Biology, vol. 50, no. 4, pp. 721–733, 1997. [22] V. Nijman and M. Aliabadian, “Performance of distance-based
DNA barcoding in the molecular identification of Primates,”
Comptes Rendus—Biologies, vol. 333, no. 1, pp. 11–16, 2010. [23] S. J. Scheffer, M. L. Lewis, and R. C. Joshi, “DNA barcoding
applied to invasive leafminers (Diptera: Agromyzidae) in the
Philippines,” Annals of the Entomological Society of America,
vol. 99, no. References Janzen, and
W. Hallwachs, “Ten species in one: DNA barcoding reveals
cryptic species in the neotropical skipper butterfly Astraptes
fulgerator,” Proceedings of the National Academy of Sciences of
the United States of America, vol. 101, no. 41, pp. 14812–14817,
2004. [28] N. V. Ivanova, T. S. Zemlak, R. H. Hanner, and P. D. N. Hebert, “Universal primer cocktails for fish DNA barcoding,”
Molecular Ecology Notes, vol. 7, no. 4, pp. 544–548, 2007. [29] M. Kimura, “A simple method for estimating evolutionary
rates of base substitutions through comparative studies of
nucleotide sequences,” Journal of Molecular Evolution, vol. 16,
no. 2, pp. 111–120, 1980. [13] M. Hajibabaei, D. H. Janzen, J. M. Burns, W. Hallwachs, and
P. D. N. Hebert, “DNA barcodes distinguish species of tropical
Lepidoptera,” Proceedings of the National Academy of Sciences
of the United States of America, vol. 103, no. 4, pp. 968–971,
2006. [30] S. Kumar, K. Tamura, and M. Nei, “MEGA3: integrated
software for molecular evolutionary genetics analysis and
sequence alignment,” Briefings in Bioinformatics, vol. 5, no. 2,
pp. 150–163, 2004. [14] D. M. Lambert, A. Baker, L. Huynen, O. Haddrath, P. D. N. Hebert, and C. D. Millar, “Is a large-scale DNA-based
inventory of ancient life possible?” Journal of Heredity, vol. 96,
no. 3, pp. 279–284, 2005. [31] J. W. Tuckey, Exploratory Data Analysis, Addison–Wesley,
Boston, Mass, USA, 1977. [32] J. J. Wiens, Phylogenetic Analysis of Morphological Data,
Smithsonian Institution Press, Washington, DC, USA, 2000. [15] M. H. Greenstone, D. L. Rowley, U. Heimbach, J. G. Lundgren,
R. S. Pfannenstiel, and S. A. Rehner, “Barcoding generalist
predators by polymerase chain reaction: carabids and spiders,”
Molecular Ecology, vol. 14, no. 10, pp. 3247–3266, 2005. [33] J. K¨ohler, K. Munn, A. R¨uegg, A. Skusa, and B. Smith,
“Quality control for terms and definitions in ontologies and
taxonomies,” BMC Bioinformatics, vol. 7, article 212, 2006. [16] R. D. Ward, T. S. Zemlak, B. H. Innes, P. R. Last, and P. D. N. Hebert, “DNA barcoding Australia’s fish species,” Philosophical
Transactions of the Royal Society B: Biological Sciences, vol. 360,
no. 1462, pp. 1847–1857, 2005. [34] M. Pfenninger, M. Cordellier, and B. Streit, “Comparing
the efficacy of morphologic and DNA-based taxonomy in
the freshwater gastropod genus Radix (Basommatophora,
Pulmonata),” BMC Evolutionary Biology, vol. 6, article 100,
2006. [17] G. G. Pegg, B. Sinclair, L. Briskey, and W. J. References 2, pp. 204–210, 2006. [41] C. L. Dudgeon, N. Gust, and D. Blair, “No apparent genetic
basis to demographic differences in scarid fishes across
continental shelf of the great barrier reef,” Marine Biology, vol. 137, no. 5-6, pp. 1059–1066, 2000. [42] G. Bernardi, S. J. Holbrook, and R. J. Schmitt, “Gene flow at
three spatial scales in a coral reef fish, the three-spot dascyllus,
Dascyllus trimaculatus,” Marine Biology, vol. 138, no. 3, pp. 457–465, 2001. [24] K. W. Will and D. Rubinoff, “Myth of the molecule: DNA bar-
codes for species cannot replace morphology for identification
and classification,” Cladistics, vol. 20, no. 1, pp. 47–55, 2004. [25] R. DeSalle, M. G. Egan, and M. Siddall, “The unholy
trinity: taxonomy, species delimitation and DNA barcoding,”
Philosophical Transactions of the Royal Society B: Biological
Sciences, vol. 360, no. 1462, pp. 1905–1916, 2005. [43] S. R. Palumbi, “Genetic divergence, reproductive isolation,
and marine speciation,” Annual Review of Ecology and System-
atics, vol. 25, pp. 547–572, 1994. Evidence-Based Complementary and Alternative Medicine Evidence-Based Complementary and Alternative Medicine Evidence-Based Complementary and Alternative Medicine 10 [44] M. E. Hellberg, R. S. Burton, J. E. Neigel, and S. R. Palu-
mbi, “Genetic assessment of connectivity among marine
populations,” Bulletin of Marine Science, vol. 70, no. 1, pp. 273–290, 2002. [45] T. Lef´ebure, C. J. Douady, M. Gouy, and J. Gibert, “Rela-
tionship between morphological taxonomy and molecular
divergence within Crustacea: proposal of a molecular thresh-
old to help species delimitation,” Molecular Phylogenetics and
Evolution, vol. 40, no. 2, pp. 435–447, 2006. [46] M. C. Ebach and C. Holdrege, “DNA barcoding is no
substitute for taxonomy,” Nature, vol. 434, no. 7034, p. 697,
2005. [47] C. C. Nice and A. M. Shapiro, “Patterns of morphological,
biochemical, and molecular evolution in the Oeneis chryxus
complex (Lepidoptera: Satyridae): a test of historical biogeo-
graphical hypotheses,” Molecular Phylogenetics and Evolution,
vol. 20, no. 1, pp. 111–123, 2001. [48] E. Zuckerkandl and L. Pauling, “Evolutionary divergence and
convergence in proteins,” in Evolving Genes and Proteins, V. Bryson and H. J. Vogel, Eds., pp. 97–166, Academic Press, New
York, NY, USA, 1965.
|
https://openalex.org/W4390505569
|
https://jurnal.fk.uisu.ac.id/index.php/stm/article/download/406/383
|
Indonesian
| null |
MORFOLOGI MAKROSKOPIS DAN MIKROSKOPIS SCOLEX TAENIA ASIATICA SIMALUNGUN
|
Jurnal Kedokteran STM (Sains dan Teknologi Medik)
| 2,024
|
cc-by-sa
| 3,330
|
A B S T R A K Taeniasis adalah masalah kesehatan yang disebabkan oleh Taenia saginata, Taenia
solium, dan Taenia asiatica, biasanya terjadi setelah memakan daging sapi, babi
atau jeroan babi yang terkontaminasi dengan metacestode Taenia. Taeniasis di
Indonesia telah dilaporkan ada di Papua, Bali, Samosir dan Simalungun. Di
Indonesia, Taenia asiatica ditemukan di Samosir dan Simalungun. Tradisi di
Simalungun adalah memakan hidangan yang disebut dengan “Hinasumba”, yang
terdiri atas hati dan daging babi yang mentah dan “Naiholat” yang terdiri atas
daging babi yang dimasak kurang matang. Tujuan penelitian adalah untuk
mengetahui gambaran mikroskopis dan makroskopis scolex Taenia asiatica
Simalungun. Metode penelitian ini adalah observasi spesimen parasitologi, dengan
jumlah sampel 3 spesimen, dan diambil dengan teknik Simple Random Sampling. Sampel penelitian ini adalah scolex Taenia asiatica dari koleksi Umar Zein. Hasil
penelitian secara mikroskopis ditemukan 4 oral suckers (batil isap) dan tidak
terdapat rostellum, tidak terdapat hooklet dan juga tidak terdapat apical pit, tetapi
ditemukannya “snout” di setiap sampel. Pemeriksaan morfologi scolex Taenia
asiatica Simalungun secara makroskopis tidak bisa dilakukan karena terlalu kecil
untuk dilihat dengan mata telanjang. Dari pemeriksaan morfologinya,
memungkinkan bahwa Taenia asiatica Simalungun ini merupakan sub-spesies
baru dari Taenia asiatica. Kata Kunci
Taenia asiatica, Morfologi,
Scolex, Simalungun
Korespondensi
Tel. 082167256100
Email:
mahdayuantin@gmail.com Kata Kunci
Taenia asiatica, Morfologi,
Scolex, Simalungun
Korespondensi
Tel. 082167256100
Email:
mahdayuantin@gmail.com Mahda Yuantin,a Umar Zein b aMahasiswa Fakultas Kedokteran Universitas Islam Sumatera Utara, Jl. STM No. 77, Medan, Indonesia
bDosen Fakultas Kedokteran Universitas Islam Sumatera Utara, Jl. STM No. 77, Medan, Indonesia Histori Artikel
Diterima:
18 Juli 2023
Revisi:
18 November 2023
Terbit:
01 Januari 2024 Volume VII No I Tahun 2024 Volume VII No I Tahun 2024 Online: https://jurnal.fk.uisu.ac.id/index.php/stm
Jurnal Kedokteran STM (Sains dan Teknologi Medik)
ISSN 2614-610X (Print) | ISSN 2614-8218 (Online) PENDAHULUAN saginata. Taenia solium sangat langka di Taiwan
dengan hanya 5 kasus yang dilaporkan dari tahun
1957 hingga 1970 oleh Hsieh di Taiwan selatan. Baru pada tahun 1966, ketika Huang dan rekan-
rekannya pertama kali mengusulkan bahwa
cacing pita Taenia yang menginfeksi penduduk
asli Taiwan dengan prevalensi yang begitu tinggi
mungkin tidak sama dengan Taenia saginata
klasik. Mereka mengamati bahwa penduduk asli
tidak memiliki akses ke daging sapi, dan sumber
protein hewani utama mereka terutama berasal
dari babi hutan dan binatang buruan lainnya.3 Taeniasis adalah masalah kesehatan
yang disebabkan oleh Taenia saginata, Taenia
solium, dan Taenia asiatica, biasanya terjadi
setelah memakan daging sapi, babi atau jeroan
babi yang terkontaminasi dengan metacestode
yang merupakan tahap larva dari parasit spesies
Taenia.1 WHO telah mengkategorikan Taeniasis
dan sistiserkosis sebagai Neglected Tropical
Disease (NTD) atau Neglected Zoonotic Disease
(NZD).2 Taenia asiatica dianggap sebagai
spesies
saudara
dari
Taenia
saginata
berdasarkan filogeni molekuler dengan kedua
spesies yang secara morfologinya itu mirip. Namun, memiliki siklus hidup yang berbeda dan
hospes perantara yang berbeda pula, dimana
untuk
Taenia
asiatica
adalah
babi
dan
sebaliknya, hospes perantara untuk Taenia
saginata adalah sapi.1 Dr. Ping-Chin Fan merupakan seorang
parasitolog
Taiwan,
melakukan
penelitian
tentang Taenia Taiwan ini pada akhir tahun
1980-an dan awal 1990-an. Melalui studi
observasional dan eksperimental, ia dan timnya
mengamati morfologi dan meneliti epidemiologi
Taiwan Taenia, yang berbeda dari Taenia
saginata.4 Dilakukan juga studi eksperimental di
Korea Selatan (Pulau Jeju-do), Indonesia (Pulau
Samosir), Thailand (Chiang Mai), Filipina, dan
Myanmar juga menunjukkan morfologi yang
sama sehingga membuat para peneliti untuk
mengubah nama Taenia Taiwan menjadi Taenia
Asia, yang menunjukkan distribusi geografisnya
yang lebih beragam.3 Pada awal tahun 1990-an,
sekelompok parasitolog Korea yang dipimpin
oleh Dr. Kee Seon Eom, melakukan berbagai
eksperimen pada spesimen Taenia Asia yang
berasal dari Korea. Mereka mengamati bahwa
kista Taenia Asia berkembang dalam jeroan
babi, membuat mereka mengusulkan nama
Cysticercus viscerotropica. Pada tahun 1993,
mereka mengemukakan spesies baru, yaitu
Taenia asiatica.4 Laporan pertama taeniasis berada di
Taiwan yang diteliti oleh Oi pada tahun 1915,
ketika ia menemukan 2 kasus positif dalam
survei parasitologi tinja dari 301 orang yang
terdiri dari tahanan, pelajar, dan pasien di
Taichung, Taiwan tengah. Kemudian. Pada
tahun 1928, Yokogawa dan rekan-rekannya
melaporkan bahwa dari 812 penduduk asli yang
disurvei di Hsinchu, 163 orang ditemukan
mengeluarkan telur Taenia. A B S T R A C T Taeniasis is a health problem caused by Taenia saginata, Taenia solium, and
Taenia asiatica, usually after eating beef, pork or pig viscera contaminated with
Taenia metacestode. Taeniasis in Indonesia has been reported in Papua, Bali,
Samosir and Simalungun. In Indonesia, Taenia asiatica is found in Samosir and
Simalungun. The tradition in Simalungun is to eat dishes called “Hinasumba” and
“Naiholat” which consists of undercooked pork and raw pork liver. This study
aims to determine the morphology of Taenia asiatica Simalungun scolex
macroscopically and microscopically. This study used the observation of
parasitological specimens, with 3 specimens, and was taken using Simple Random
Sampling technique. The samples are Taenia asiatica scolex from the collection of
Umar Zein. The results of microscopic study found 4 oral suckers and no rostellum,
no hooklet and no apical pit, but “snout” was found in each sample. Macroscopic
examination of Taenia asiatica Simalungun scolex could not be done because it
was too small to be seen with the naked eye. The result concludes it is possible that
Taenia asiatica Simalungun is a new subspecies of Taenia asiatica. Mahda Yuantin
33 33 33 Mahda Yuantin Mahda Yuantin Jurnal Kedokteran STM
Volume VII No. I Tahun 2024 Jurnal Kedokteran STM
Volume VII No. I Tahun 2024 Taeniasis di Indonesia telah dilaporkan
ada di Papua dan Bali dimana ditemukan Taenia
solium, di Bali dimana juga ditemukan Taenia
saginata
dan
pulau
Samosir
dimana
ditemukannya Taenia asiatica.5 Taeniasis yang
disebabkan oleh Taenia asiatica telah dilaporkan
secara eksklusif pada penduduk Pulau Samosir
yang terletak di Danau Toba, Kecamatan
Samosir, Provinsi Sumatera Utara. Penduduk
Sumatera Utara sebagian besar terdiri dari
berbagai suku Batak. Dari penelitian yang telah
dilakukan pada 250 orang, Ditemukan 16 cabang
uterus di masing-masing proglotid gravid yang
dikumpulkan dari sampel feses, menunjukkan
bahwa spesies yang menginfeksi di daerah
tersebut adalah Taenia asiatica (dengan cabang
uterus sekitar 11–32) atau Taenia saginata
(dengan cabang uterus sekitar 14–32), tetapi
bukan Taenia solium (dengan cabang uterus
sekitar 5–11).1 pelanggan yang mengunjungi restoran yang
memasak hati babi setengah matang adalah laki-
laki. Tak satupun dari karier cacing pita
melaporkan memakan daging sapi setengah
matang. Oleh karena itu, dari penelitian yang
dilakukan, diduga bahwa sumber infeksi
merupakan dari babi di daerah tersebut.1 Ada studi terbaru yang melaporkan
bahwa Taenia asiatica ini ditemukan di daerah
endemik yang baru yang sebelumnya tidak
teridentifikasi, yaitu di Simalungun. Tradisi di
Simalungun adalah memakan hidangan yang
disebut dengan “Hinasumba”, yang terdiri atas
hati dan daging babi yang mentah dan “Naiholat”
yang terdiri atas daging babi yang dimasak
kurang matang. Ditemukan bahwa beberapa
bagian dari cacing pita yang ditemukan di
Simalungun itu memiliki bagian yang tidak
ditemukan pada ketiga spesies Taenia yang
diketahui.6 Peneliti tertarik untuk meneliti
bagian scolex dari Taenia asiatica Simalungun
ini secara makroskopis dan mikroskopis dengan
tujuan untuk mengetahui gambarannya yang
dapat membantu mendiagnosis pasti spesies
Taenia sehingga dapat memberikan terapi yang
tepat. Berdasarkan penelitian tersebut, semua
pembawa cacing pita dikonfirmasi beragama
Kristen (100%) dan sebagian besar karier adalah
laki-laki dan petani sawit. Semua karier yang
terkonfirmasi memiliki riwayat menularkan
proglotid dalam 6 bulan terakhir. Karier termuda
adalah seorang anak laki-laki berusia 12 tahun,
dan yang tertua adalah seorang pria berusia 70
tahun. Semua karier (100%) melaporkan makan
daging babi mentah atau daging babi yang tidak
dimasak dengan benar sebagai bagian dari
hidangan tradisional. Dalam budaya Batak,
merupakan suatu tradisi untuk menyajikan
potongan hati babi yang kurang matang kepada
pemimpin
keluarga
(laki-laki)
sebagai
kehormatan di setiap pesta pernikahan atau
budaya. Ditemukan juga bahwa hampir semua PENDAHULUAN Baru pada tahun
1952, ketika Huang dan rekan melaporkan
bahwa 20,5% penduduk asli yang disurvei di
Wulai, Taipei, 16,3% di Lotung, Ilan, dan 9,7%
di
Nan-ao,
Ilan,
masing-masing
positif
mengeluarkan telur Taenia. Sejak itu, sekitar 20
laporan tentang prevalensi taeniasis pada
manusia di Taiwan pada tahun 1960-an dengan
asumsi bahwa penyebabnya adalah Taenia 34 Mahda Yuantin Mahda Yuantin Pemeriksaan Secara Makroskopis Scolex Taenia asiatica Simalungun
tidak bisa dilihat secara makroskopik karena
terlalu kecil untuk dilihat dengan mata
telanjang. METODE Metode penelitian yang digunakan adalah
metode
penelitian
observasi
spesimen
parasitologi. Dimana penelitian ini nantinya
akan
mendeskripsikan
atau
menguraikan
morfologi
dari
scolex
Taenia
asiatica
Simalungun
secara
makroskopis
dan
mikroskopis. Penelitian ini dilakukan di Klinik
Penyakit Tropik dan Infeksi dr. Umar Zein yang
berlokasi di Jalan Denai No. 269, Tegal Sari 35 Mahda Yuantin Mahda Yuantin Jurnal Kedokteran STM
Volume VII No. I Tahun 2024 Mandala II, Kecamatan Medan Denai, Kota
Medan,
Sumatera
Utara. Sampel
dalam
penelitian ini diambil dari koleksi scolex Taenia
asiatica Simalungun milik dr. Umar Zein yang
berada di Klinik Penyakit Tropik dan Infeksi dr. Umar Zein. Jumlah sampel pada penelitian ini
sebanyak 3 sampel. Pengambilan sampel pada
penelitian ini menggunakan teknik random
sampling. Dalam melakukan pemeriksaan,
terlebih dahulu sampel tinja diencerkan dengan
NaCl dan disaring untuk melihat material-
material kecil yang dicurigai sebagai scolex
Taenia asiatica, lalu dilakukan pemeriksaan
melalui mikroskop untuk melihat morfologinya. Data yang diperoleh dianalisis secara deskriptif,
yaitu dengan cara mendeskripsikan scolex
Taenia asiatica, jumlah oral sucker-nya dan
terdapatnya rostellum pada scolex Taenia
asiatica. Penelitian ini telah mendapatkan Mandala II, Kecamatan Medan Denai, Kota
Medan,
Sumatera
Utara. Sampel
dalam
penelitian ini diambil dari koleksi scolex Taenia
asiatica Simalungun milik dr. Umar Zein yang
berada di Klinik Penyakit Tropik dan Infeksi dr. Umar Zein. Jumlah sampel pada penelitian ini
sebanyak 3 sampel. Pengambilan sampel pada
penelitian ini menggunakan teknik random
sampling. Dalam melakukan pemeriksaan,
terlebih dahulu sampel tinja diencerkan dengan
NaCl dan disaring untuk melihat material-
material kecil yang dicurigai sebagai scolex
Taenia asiatica, lalu dilakukan pemeriksaan
melalui mikroskop untuk melihat morfologinya. Data yang diperoleh dianalisis secara deskriptif,
yaitu dengan cara mendeskripsikan scolex
Taenia asiatica, jumlah oral sucker-nya dan
terdapatnya rostellum pada scolex Taenia
asiatica. Penelitian ini telah mendapatkan persetujuan
dari
Komite
Etik
Penelitian
Kesehatan
FK
UISU
No.231/EC/KEPK. UISU/III/2022. persetujuan
dari
Komite
Etik
Penelitian
Kesehatan
FK
UISU
No.231/EC/KEPK. UISU/III/2022. Jurnal Kedokteran STM
Volume VII No. I Tahun 2024 Pemeriksaan Secara Mikroskopis Scolex Taenia asiatica Simalungun
dengan Mikroskop Elektron (Zein, Lim and
Sardjono, 2021)
Hasil Pemeriksaan Mikroskopis:
-
Rostellum: ditemukan
-
Hooklet: tidak ditemukan
-
Apical pit: ditemukan
Gambar 5. Scolex Taenia asiatica (Eom and Rim,
1993)
Hasil Pemeriksaan Mikroskopis:
-
Rostellum: ditemukan
-
Hooklet: ditemukan
-
Apical pit: tidak ditemukan
Gambar 6. Scolex Taenia solium
Hasil Pemeriksaan Mikroskopis:
-
Rostellum: tidak ditemukan
-
Hooklet: tidak ditemukan
-
Apical pit: tidak ditemukan
Gambar 7. Scolex Taenia saginata (Zein, 2014)
DISKUSI
Cacing
pita
yang
diketahui
menyebabkan infeksi zoonosis yaitu Taeniasis
pada manusia adalah Taenia solium, Taenia
saginata, dan Taenia asiatica.10 Ketiga spesies
Taenia memiliki gejala klinis yang mirip. Umumnya
keluhan-keluhan
fisik
jarang
ditemukan. Gejala yang sering ditemukan
adalah keluarnya potongan-potongan proglotid
melalui
anus
sehingga
diperlukannya
penegakan diagnosis yang pasti dengan cara Hasil Pemeriksaan Mikroskopis:
-
Rostellum: ditemukan
-
Hooklet: ditemukan
-
Apical pit: tidak ditemukan Gambaran scolex berdasarkan referensi lain Gambaran scolex berdasarkan referensi lain Hasil Pemeriksaan Mikroskopis:
-
Rostellum: tidak ditemukan
-
Hooklet: tidak ditemukan
-
Apical pit: “snout” Gambar 6. Scolex Taenia solium Hasil Pemeriksaan Mikroskopis:
-
Rostellum: tidak ditemukan
-
Hooklet: tidak ditemukan
-
Apical pit: tidak ditemukan
Gambar 7. Scolex Taenia saginata (Zein, 2014) Gambar 4. Scolex Taenia asiatica Simalungun
dengan Mikroskop Elektron (Zein, Lim and
Sardjono, 2021) Gambar 4. Scolex Taenia asiatica Simalungun
dengan Mikroskop Elektron (Zein, Lim and
Sardjono, 2021) Hasil Pemeriksaan Mikroskopis:
-
Rostellum: ditemukan
-
Hooklet: tidak ditemukan
-
Apical pit: ditemukan
Gambar 5. Scolex Taenia asiatica (Eom and Rim,
1993) Hasil Pemeriksaan Mikroskopis:
-
Rostellum: tidak ditemukan
-
Hooklet: tidak ditemukan
-
Apical pit: tidak ditemukan Gambar 7. Scolex Taenia saginata (Zein, 2014) Pemeriksaan Secara Mikroskopis Berdasarkan gambar di bawah, didapati
pada pemeriksaan mikroskopik scolex Taenia
asiatica Simalungun, ketiga scolex tersebut
terdapat 4 oral suckers (batil isap) dan tidak
terdapat rostellum, tidak terdapat hooklet dan
juga tidak terdapat apical pit. Pada ketiga
sampel scolex Taenia asiatica Simalungun
yang diteliti didapatkan bagian “snout”. Hasil Pemeriksaan Mikroskopis:
-
Rostellum: tidak ditemukan
-
Hooklet: tidak ditemukan
-
Apical pit: “snout”
Gambar 1. Scolex Taenia asiatica Simalungun 1 Hasil Pemeriksaan Mikroskopis:
-
Rostellum: tidak ditemukan
-
Hooklet: tidak ditemukan
-
Apical pit: “snout” Gambar 1. Scolex Taenia asiatica Simalungun 1 36
Mahda Yuantin Mahda Yuantin 36 Jurnal Kedokteran STM
Volume VII No. I Tahun 2024 Sampel 2
Hasil Pemeriksaan Mikroskopis:
-
Rostellum: tidak ditemukan
-
Hooklet: tidak ditemukan
-
Apical pit: “snout”
Gambar 2 Scolex Taenia asiatica Simalungun 2 Sampel 2
Hasil Pemeriksaan Mikroskopis:
-
Rostellum: tidak ditemukan
-
Hooklet: tidak ditemukan
-
Apical pit: “snout”
Gambar 2 Scolex Taenia asiatica Simalungun 2 Sampel 2 Hasil Pemeriksaan Mikroskopis:
-
Rostellum: tidak ditemukan
-
Hooklet: tidak ditemukan
-
Apical pit: “snout” Gambar 2 Scolex Taenia asiatica Simalungun 2 Sampel 3 p
Hasil Pemeriksaan Mikroskopis:
-
Rostellum: tidak ditemukan
-
Hooklet: tidak ditemukan
-
Apical pit: “snout”
Gambar 3. Scolex Taenia asiatica Simalungun 3 Hasil Pemeriksaan Mikroskopis:
-
Rostellum: tidak ditemukan
-
Hooklet: tidak ditemukan
-
Apical pit: “snout”
Gambar 3. Scolex Taenia asiatica Simalungun 3 Hasil Pemeriksaan Mikroskopis:
-
Rostellum: tidak ditemukan
-
Hooklet: tidak ditemukan
-
Apical pit: “snout” Gambar 3. Scolex Taenia asiatica Simalungun 3 37 Mahda Yuantin 37 Jurnal Kedokteran STM
Volume VII No. I Tahun 2024 Jurnal Kedokteran STM
Volume VII No. I Tahun 2024 Jurnal Kedokteran STM
Volume VII No. I Tahun 2024
Gambaran scolex berdasarkan referensi lain
Hasil Pemeriksaan Mikroskopis:
-
Rostellum: tidak ditemukan
-
Hooklet: tidak ditemukan
-
Apical pit: “snout”
Gambar 4. Scolex Taenia asiatica Simalungun
dengan Mikroskop Elektron (Zein, Lim and
Sardjono, 2021)
Hasil Pemeriksaan Mikroskopis:
-
Rostellum: ditemukan
-
Hooklet: ditemukan
-
Apical pit: tidak ditemukan
Gambar 6. Scolex Taenia solium
Hasil Pemeriksaan Mikroskopis:
-
Rostellum: tidak ditemukan
-
Hooklet: tidak ditemukan
-
Apical pit: tidak ditemukan
Gambar 7. Scolex Taenia saginata (Zein, 2014) Gambaran scolex berdasarkan referensi lain
Hasil Pemeriksaan Mikroskopis:
-
Rostellum: tidak ditemukan
-
Hooklet: tidak ditemukan
-
Apical pit: “snout”
Gambar 4. DISKUSI Cacing
pita
yang
diketahui
menyebabkan infeksi zoonosis yaitu Taeniasis
pada manusia adalah Taenia solium, Taenia
saginata, dan Taenia asiatica.10 Ketiga spesies
Taenia memiliki gejala klinis yang mirip. Umumnya
keluhan-keluhan
fisik
jarang
ditemukan. Gejala yang sering ditemukan
adalah keluarnya potongan-potongan proglotid
melalui
anus
sehingga
diperlukannya
penegakan diagnosis yang pasti dengan cara Gambar 5. Scolex Taenia asiatica (Eom and Rim,
1993) 38 Mahda Yuantin Mahda Yuantin Jurnal Kedokteran STM
Volume VII No. I Tahun 2024 yang dilakukan oleh Umar Zein dkk. pada
tahun 2019 bahwa masih terdapat daerah
endemis taeniasis di Sumatera Utara yang
sebelumnya belum teridentifikasi. Daerah yang
dipilih untuk studi dan intervensi sebelumnya,
terutama Pulau Samosir itu mudah diakses dan
memiliki status sosial ekonomi yang lebih
tinggi, dan tampaknya masyarakat miskin di
daerah perkebunan kelapa sawit besar mungkin
diabaikan ketika merancang program. Oleh
karena itu, diperlukan studi yang ekstensif dan
dirancang dengan baik untuk mengklarifikasi
spesies penyebab taeniasis dan untuk lebih
memahami morfologi dan epidemiologi parasit
sehingga program pengendalian Taenia yang
tepat dapat diluncurkan.1 pemeriksaan
morfologi
sehingga
dapat
memberikan terapi yang tepat.11 Taenia
asiatica dikatakan unik karena memiliki
morfologi yang mirip dengan Taenia saginata
dan memiliki siklus hidup yang mirip dengan
Taenia solium dikarenakan babi merupakan
hospes perantaranya.10 Taeniasis yang disebabkan oleh
Taenia solium dan Taenia saginata di
Indonesia banyak ditemukan di Bali, taeniasis
yang disebabkan oleh Taenia solium di
Indonesia banyak ditemukan di Papua dan
taeniasis yang disebabkan oleh Taenia asiatica
di Indonesia banyak ditemukan di Sumatera
Utara, terutama di pulau Samosir.2 Kasus
Taeniasis tidak hanya dapat muncul di daerah
yang telah terpapar, namun dapat juga muncul
di berbagai daerah lain dengan probabilitas
yang tinggi dikarenakan adanya perjalanan
antar daerah yang dilakukan oleh orang yang
terinfeksi. Untuk mengurangi resiko adanya
perkembangan kasus di daerah lain, dapat
dilakukan penegakan diagnosis lebih awal dan
pemeriksaan morfologi yang lebih spesifik.5 Dari penelitian yang telah dilakukan
oleh peneliti, hasil penelitian yang didapatkan
oleh peneliti itu berbeda dengan hasil
penelitian dari peneliti lain. DAFTAR REFERENSI 1. Zein U, Siregar S, Janis I, et al. Identification of a previously unidentified
endemic region for taeniasis in North
Sumatra,
Indonesia. Acta
Trop. 2019;189(October 2018):114-116. doi:10. 1016/j.actatropica.2018.10.004 Hasil penelitian yang didapat oleh
peneliti didukung oleh hasil penelitian yang
dilakukan oleh Umar Zein dkk. pada tahun 2019
dimana pada scolex Taenia asiatica Simalungun
tidak
terdapat
rostellum,
melainkan
ditemukannya bagian “snout” pada bagian
puncak dari scolex Taenia asiatica Simalungun,
yang kemungkinan berfungsi sebagai indra
penciuman dan organ vakum. Bagian ini tidak
ditemukan pada tiga jenis spesies Taenia yang
ada.6 2. Sandi S. Kajian Aspek Epidemiologi
Taeniasis dan Sistiserkosis di Papua. J
Penyakit Bersumber Binatang. 2015;1(2):1-
14. doi:10.22435/jpbb.v1i2.4032.1-14 3. Ooi HK, Ho CM, Chung WC. Historical
overview of Taenia asiatica in Taiwan. Korean J Parasitol. 2013;51(1):31-36. doi:10.3347/kjp.2013.51.1.31 4. Ale A, Victor B, Praet N, et al. Epidemiology and genetic diversity of
Taenia asiatica: A systematic review. Parasites and Vectors. 2014;7(1):1-11. doi:10.1186/1756-3305-7-45 5. Wandra T, Swastika K, Dharmawan NS, et
al. The present situation and towards the
prevention
and
control
of
neurocysticercosis on the tropical island,
Bali, Indonesia. Parasites and Vectors. 2015;8(1):1-11. doi:10.1186/s13071-015-
0755-z DISKUSI Hasil penelitian
Eom dan Rim pada tahun 1993 dari Korea
Selatan diperoleh bahwa pada scolex Taenia
asiatica terdapat rostellum yang menonjol
(cuspidal rostellum), tetapi tidak terdapat
hooklet di sekitar rostellum tersebut, tidak
seperti Taenia solium yang memiliki hooklet
pada rostellum-nya dan Taenia saginata yang
tidak memiliki rostellum dan hooklet pada
scolex-nya.12 Penelitian yang dilakukan oleh
Parija dan Ponnambath pada tahun 2013
memperoleh hasil dimana pada scolex Taenia
asiatica itu memiliki rostellum dan apical pit
dan tidak terdapat hooklet.10 Hasil penelitian
yang diperoleh oleh Flisser pada tahun 2013
adalah scolex Taenia asiatica itu memiliki 2
baris
hooklet
yang
belum
sempurna
(rudimentary hooklet).13 Menurut Bakta pada Terdapat
studi
terbaru
yang
menunjukan bahwa Taenia asiatica juga
ditemukan
di
daerah
endemik
yang
sebelumnya belum teridentifikasi yaitu di Silau
Kahean, Simalungun. Tradisi yang terdapat di
Simalungun kemungkinan menjadi salah satu
penyebab munculnya kasus infeksi Taenia
asiatica. Tradisi tersebut berupa kebiasaan
masyarakat Simalungun memakan hidangan
yang disebut “Hinasumba”, yang terdiri atas
hati dan daging babi yang mentah dan
“Naiholat” yang terdiri atas daging babi yang
dimasak kurang matang.6 Dari data penelitian 39 Mahda Yuantin Mahda Yuantin Jurnal Kedokteran STM
Volume VII No. I Tahun 2024 Jurnal Kedokteran STM
Volume VII No. I Tahun 2024 tahun 2017 Taenia asiatica memiliki gambaran
morfologi yang sangat mirip dengan Taenia
saginata, tetapi mempunyai alat isap yang
rudimenter
dengan
rostellum
telanjang/
rostellum tanpa pengait.14 asiatica Simalungun ini dengan spesies Taenia
yang lainnya. KESIMPULAN Berdasarkan hasil penelitian yang diperoleh,
dapat
disimpulkan
bahwa
pemeriksaan
morfologi scolex Taenia asiatica Simalungun
secara makroskopis tidak bisa dilakukan karena
scolex-nya terlalu kecil untuk dilihat dengan
mata telanjang. Dari pemeriksaan morfologi
scolex Taenia asiatica Simalungun secara
mikroskopis, tidak ditemukannya rostellum dan
hooklet pada setiap scolex-nya, melainkan
ditemukannya bagian “snout”. Dari pemeriksaan
morfologi tersebut, memungkinkan bahwa
Taenia asiatica Simalungun ini merupakan sub-
spesies baru dari Taenia asiatica. 6. Zein U, Siregar S, Habib H, Janis I, Pane
AH, Sardjono TW. Human Tapeworm from
Simalungun, Indonesia. Acta Med Indones. 2019;51(2):177-178. 7. Zein U, Lim H, Sardjono TW. Morphology
of Taenia Asiatica Simalungun , Indonesia. 2021;75(5):382-385. doi:10.5455/medarh.2021.75.382-385 8. Eom
KS,
Rim
HJ. Morphologic
descriptions of Taenia asiatica sp. n. Korean
J Parasitol. 1993;31(1):1-6. doi:10.3347/
kjp.1993.31.1.1 9. Zein U. Taeniasis saginata. In: Atlas Dan
Kasus-Kasus Infeksi Parasit. Vol 1. USU;
2014:1-9. Jurnal Kedokteran STM
Volume VII No. I Tahun 2024 SARAN 10. Parija S, Ponnambath D. Laboratory
diagnosis of Taenia asiatica in humans and
animals. Trop Parasitol. 2013;3(2):120. doi:10.4103/2229-5070.122127 Perlu dilakukannya pemeriksaan morfologi
secara mikroskopik yang lebih lanjut dengan
sampel yang lebih besar dan ditambah dengan
pemeriksaan
molekuler
dan
pemeriksaan
serologi untuk membantu membedakan Taenia 11. OIE. Cysticercosis
and
Coenurosis
Taeniasis , Cysticercosis and Coenurosis. 2020;(March):1-15. 12. Eom KS, Rim HJ, Jeon HK. Taenia
Asiatica: Historical Overview of Taeniasis 40 Mahda Yuantin Jurnal Kedokteran STM
Volume VII No. I Tahun 2024 Jurnal Kedokteran STM
Volume VII No. I Tahun 2024 and
Cysticercosis
with
Molecular
Characterization. Vol 108. 1st ed. Elsevier
Ltd.;
2020. doi:10.1016/bs.apar.2019. 12.004 13. Flisser A. State of the art of Taenia solium
as compared to Taenia asiatica. Korean J
Parasitol. 2013;51(1):43-49. doi:10.3347/
kjp.2013.51.1.43 14. Bakta IM. Taeniasis. In: Setiati S, Alwi I,
Sudoyo AW, Simadibrata M, Setiyohadi B,
Syam AF, eds. Buku Ajar Ilmu Penyakit
Dalam. Edisi
6. Interna
Publishing;
2017:783-788. 41 Mahda Yuantin Mahda Yuantin
|
W4245905777.txt
|
https://www.qeios.com/read/A62TJ9/pdf
| null |
Q-Value
|
Definitions
| 2,020
|
cc-by
| 54
|
Qeios · Definition, February 7, 2020
Ope n Pe e r Re v ie w on Qe ios
Q-Value
National Cancer Institute
Source
National Cancer Institute. Q-Value. NCI T hesaurus. Code C64217.
T he minimum False Discovery Rate (FDR) value required for a test to be considered
significant.
Qeios ID: A62TJ9 · https://doi.org/10.32388/A62TJ9
1/1
|
|
https://openalex.org/W3210234523
|
https://europepmc.org/articles/pmc8569237?pdf=render
|
English
| null |
Chaos May Prevail Without Filial Piety: A Cross-Cultural Study on Filial Piety, the Dark Triad, and Moral Disengagement
|
Frontiers in psychology
| 2,021
|
cc-by
| 9,188
|
Chaos May Prevail Without Filial
Piety: A Cross-Cultural Study on Filial
Piety, the Dark Triad, and Moral
Disengagement Xiuqing Qiao1, Yiqing Lv1, Aamer Aldbyani1,2, Qingke Guo1,4*, Tianyi Zhang3* and
Minghang Cai1* 1 School of Psychology, Shandong Normal University, Jinan, China, 2 Department of Educational and Psychological Science,
Thamar University, Dhamar, Yemen, 3 Department of Psychological Counseling, Shandong Xinkang Prison, Jinan, China,
4 Guangxi University and College Key Laboratory of Cognitive Neuroscience and Applied Psychology, Guangxi Normal
University, Guilin, China Keywords: dual filial piety model (DFPM), dark triad (DT), moral disengagement, narcissism, Machiavellianism,
psychopathy, culture Edited by: Edited by:
Chee-Seng Tan,
Universiti Tunku Abdul Rahman,
Malaysia In traditional Chinese society, filial piety (FP) served as the philosophical foundation of
social governance, without which chaos would prevail. It indicates that the function
of FP is not limited to family. FP can predict attitudes and behaviors in other social
contexts. This study examined the relationship between FP and moral disengagement,
and the mediating roles of the dark triad personality, and cultural differences regarding
these mechanisms. An online self-report survey was conducted in two different culture
groups- university students from China (N = 400, 37% male, Mage = 20.41, SD
age = 2.52) and Islamic countries who are studying in China (N = 378, 59.25% male,
Mage = 24.29, SD age = 4.77). Correlation analysis showed that authoritarian FP was
positively associated with moral disengagement among students from China and Islamic
countries, while reciprocal FP only negatively correlated with moral disengagement
among Chinese students. Moreover, reciprocal FP directly and negatively affected moral
disengagement, and did so indirectly through the mediating role of Machiavellianism. However, authoritarian FP directly and positively influenced moral disengagement,
and did so indirectly through the buffering role of narcissism. These two parallel
mediating models are not affected by culture. Though FP varies from culture to
culture, reciprocal FP and authoritarian FP play critical roles in influencing personality
and moral development. Reciprocal FP reduces moral disengagement directly and
indirectly by weakening Machiavellianism. The role of authoritarian FP is conflicting. It can
strengthen moral disengagement, but may also weaken it by deterring the development
of the narcissistic personality. The findings enlighten us to view authoritarian FP
dialectically. These two parallel mediating models are not affected by culture, indicating
the applicability of DFPM in other societies. Future studies are encouraged to involve
participants from more divergent countries and cultural backgrounds. In traditional Chinese society, filial piety (FP) served as the philosophical foundation of
social governance, without which chaos would prevail. It indicates that the function
of FP is not limited to family. FP can predict attitudes and behaviors in other social
contexts. This study examined the relationship between FP and moral disengagement,
and the mediating roles of the dark triad personality, and cultural differences regarding
these mechanisms. Reviewed by: Reviewed by:
Kai Li Chung,
University of Reading Malaysia,
Malaysia
Vlad Burtaverde,
University of Bucharest, Romania
Xiaoyue Fan,
Jiangsu Normal University, China *Correspondence:
Qingke Guo
guoqingke@163.com
Tianyi Zhang
daywalkerzty@sina.com
Minghang Cai
727162136@qq.com Specialty section:
This article was submitted to
Cultural Psychology,
a section of the journal
Frontiers in Psychology
Received: 08 July 2021
Accepted: 28 September 2021
Published: 22 October 2021
Citation:
Qiao X, Lv Y, Aldbyani A, Guo Q,
Zhang T and Cai M (2021) Chaos
May Prevail Without Filial Piety:
A Cross-Cultural Study on Filial Piety,
the Dark Triad, and Moral
Disengagement. Front. Psychol. 12:738128. doi: 10.3389/fpsyg.2021.738128 Specialty section:
This article was submitted to
Cultural Psychology,
a section of the journal
Frontiers in Psychology Received: 08 July 2021
Accepted: 28 September 2021
Published: 22 October 2021 ORIGINAL RESEARCH
published: 22 October 2021
doi: 10.3389/fpsyg.2021.738128 Edited by: An online self-report survey was conducted in two different culture
groups- university students from China (N = 400, 37% male, Mage = 20.41, SD
age = 2.52) and Islamic countries who are studying in China (N = 378, 59.25% male,
Mage = 24.29, SD age = 4.77). Correlation analysis showed that authoritarian FP was
positively associated with moral disengagement among students from China and Islamic
countries, while reciprocal FP only negatively correlated with moral disengagement
among Chinese students. Moreover, reciprocal FP directly and negatively affected moral
disengagement, and did so indirectly through the mediating role of Machiavellianism. However, authoritarian FP directly and positively influenced moral disengagement,
and did so indirectly through the buffering role of narcissism. These two parallel
mediating models are not affected by culture. Though FP varies from culture to
culture, reciprocal FP and authoritarian FP play critical roles in influencing personality
and moral development. Reciprocal FP reduces moral disengagement directly and
indirectly by weakening Machiavellianism. The role of authoritarian FP is conflicting. It can
strengthen moral disengagement, but may also weaken it by deterring the development
of the narcissistic personality. The findings enlighten us to view authoritarian FP
dialectically. These two parallel mediating models are not affected by culture, indicating
the applicability of DFPM in other societies. Future studies are encouraged to involve
participants from more divergent countries and cultural backgrounds. INTRODUCTION The current study was designed to
explore the link between filial piety and moral disengagement and
the mediating roles of dark triad personality traits. Additionally,
this study examined the universality of the function of filial piety
by comparing students from China and Islamic countries. g g
In
traditional
China,
disrespect
to
parents
is
labeled
as immoral because being filial is compulsory. Filial piety
emphasizes children’s responsibility to parents (Bedford and
Yeh, 2019; Wei and Liu, 2020), which can be manifested in
children’s moral cognition (showing deference and obedience
to parents and give priority to interests of the family over
that of one’s own), moral emotion (showing love, gratitude,
respect to parents), and moral conduct (caring for parents and
family elders, providing material support). Filial beliefs can
influence children’s interpersonal relationships and social roles
even after entering adulthood and beyond (Yeh and Bedford,
2019). Empirical studies indicated that the two types of filial piety
beliefs have different effects on young adults’ psychological and
social adaptation (Chen, 2015). RFP showed a positive effect in
enhancing interpersonal relationships, decreasing parent-child
conflicts, and increasing academic achievement (Chen and Ho,
2012; Zhou et al., 2020); AFP is significantly associated with
maladaptive emotions and behaviors (Yeh, 2006). A recent
study found that the parenting style featured by higher levels
of rejection, over-protection, and lower level of emotional
warmth (all of these overlaps with AFP essentially) has a
role in promoting cyber-aggression of postgraduate students
in universities through the mediating of moral disengagement
(Zhang et al., 2021). On the contrary, secure parental attachment and high-quality
family function, closely associated with RFP, can inhibit moral
disengagement (Bao et al., 2015; Mazzone and Camodeca, 2019). Based on the above theorizing, we proposed that AFP and RFP
have opposite effects on individuals’ moral disengagement. It
should be noted that Chinese filial piety overlaps with family
ethics or values in other cultures and filial piety can be regarded
as a universal dual mechanism of parent-child interaction beyond
ethical norms root in Confucian culture (Bedford and Yeh,
2019, 2021). This laid the foundation for cross-cultural studies
of the functions of FP. Consistent with this proposition, the
relationships between filial piety and psychological outcomes
found in non-Confucian-influenced societies (Bergelson et al.,
2015; Toro et al., 2019) replicate those revealed by studies
conducted in Chinese societies (2016; Chen, 2015; Zhou et al.,
2020). INTRODUCTION and moral decision-making (Bedford and Yeh, 2019). As
the primary moral agency, parent-children interaction can
significantly influence the development of moral disengagement
(Campaert et al., 2018). Correspondingly, previous literature
shows that inductive discipline and adequate monitoring can
reduce children’s moral disengagement, while harsh parenting
may lead to greater moral disengagement (Ball et al., 2017;
Campaert et al., 2018). Surprisingly, few empirical studies have so
far directly investigated the relationship between filial piety and
moral disengagement. Morality is the foundation of Confucianism. In traditional China,
filial piety (FP) plays a primary role in shaping an individual’s
moral development. “One cannot successfully pursue the ethical
life outside of fulfilling certain familial and social obligation”
(Ivanhoe, 2000, p. 17; Yeh, 2006). However, few empirical
studies have so far explored the direct relationship between
filial piety and moral development. Previous research considers
filial piety as the root of Confucian beliefs. The universality
of filial piety’s function in other cultures has seldom been
investigated. For example, “pietas” in Latin and “sawab” in
Islam both mean filial piety to parents and are regarded as
one of the most important virtues. Extant literature on filial
piety focused on its influences on care giving behavior and
aging policy in Confucian-influenced countries, but neglected its
role in influencing individuals’ psycho-social functioning (Chen
et al., 2016; Bedford and Yeh, 2020). Recently some researchers
called for expanding the scope of filial piety studies, both in the
research fields and in applications in other cultural backgrounds
(Tan et al., 2019; Zhou et al., 2020; Bedford and Yeh, 2021). Yeh and Bedford (2003) have proposed a revised dual filial
piety model (DFPM), shifting the focus of conceptualization of
filial piety from cultural norms to the inherent structure of the
relationship between parents and children. DFPM focuses on
two aspects of parent-child interaction in daily life, authoritarian
filial piety (AFP) and reciprocal filial piety (RFP). RFP reflects
the egalitarian interaction between parents and children based
on mutual love and emotional warmth (Chen and Ho, 2012);
AFP reflects the social norms requiring children to satisfy their
parental demands and is driven by a need for group identification
or social belonging (Yeh et al., 2013; Chen et al., 2016; Yeh and
Bedford, 2019). The DFPM stresses that the dual mechanisms
underlying parent-child relations are universal and not specific to
one cultural context, providing a theoretical foundation for filial
piety in non-Chinese societies. INTRODUCTION These findings suggest that filial piety can be seen as a
universal construct, even if its effects on psychological outcomes
differ across cultures (Bedford and Yeh, 2019). Therefore, we
supposed that the FP-MD association has cross-cultural stability. Accordingly, this study proposes the following hypotheses: Citation: October 2021 | Volume 12 | Article 738128 1 Frontiers in Psychology | www.frontiersin.org Filial Piety and Moral Disengagement Qiao et al. Participants and Procedures g g
In the DFPM, RFP, and AFP co-exist within an individual,
influencing the development of personality (Bedford and
Yeh, 2019). RFP, originated from secure attachment style in
parent-child bonds, adequate parental care, and appropriate
discipline, can prevent children from manipulating others
(Machiavellianism), being self-centered (Narcissism), and acting
in the absence of guilt (Psychopathy, see Jonason et al., 2014; Liu
et al., 2019). According to life history theory, negative early life
experiences, such as harsh parenting and unpredictable parental
behavior, may result in pathological personality development
(e.g., exploitation, manipulation; Csathó and Birkás, 2018). AFP,
which emphasizes obedience and obligations, is more likely to
originate from families featured by harsh parenting (Bedford and
Yeh, 2019). This suggests that high AFP individuals tend to adapt
a fast life history strategy conducive to dark triad personality,
while high RFP individuals tend to do the opposite (Jonason
et al., 2017; Csathó and Birkás, 2018). Therefore, we propose that
filial piety beliefs play essential roles in the development of dark
triad personality that is closely associated with unethical decision
making (Jonason et al., 2014; Frankenhuis et al., 2016; Csathó
and Birkás, 2018; Mazzone and Camodeca, 2019; Abdollahi
et al., 2020; Li et al., 2020). Specifically, dark triad traits play
mediating roles in the relationship between filial piety and
moral disengagement. Participants and Procedures
A total of 807 university students from three countries (China,
Indonesia, and Yemen) were recruited. They were required to
complete the measures of the dark triad personality, filial piety
beliefs, and moral disengagement online. To Indonesia and
Yemen students, the English versions of these measures were
administrated. To Chinese participants, the Chinese versions
were administrated. Participants had informed of the voluntary
nature of the investigation and were encouraged to complete all
items honestly. Participants were also told that their scores would
be kept anonymously and confidentially. Participants were also
asked to report their demographic characteristics (e.g., gender,
age, family economic status). Participants who omitted at least
one questionnaire item, who were Indonesians or Yemenis but
reported non-Muslim faith, and who were Chinese but reported
religious faith were excluded (16 Chinese participants were
excluded on account of their religious beliefs). Finally, we had
778 valid cases (96.41% were valid in total). The Relationship Between Filial Piety
and Moral Disengagement and Its
Cross-Cultural Universality People sometimes engage in immoral conduct that violates
the ethical principles they stick to. However, some people
may be psychologically convinced that ethical standards do
not apply to themselves or that their destructive behaviors are
morally acceptable in a particular situation. This self-defending
or self-serving social cognition process is conceptualized as
moral disengagement (MD) by Bandura (Bandura, 1999; Moore,
2015). According to Bandura’s theory of moral agency, moral
disengagement is a socialization process embedded within
specific cultural contexts (Bandura, 2016, p7). This suggests that
filial piety belief, as a variable integrating the roles of individuals,
society, and cultural norms, can greatly influence moral cognition H1a: RFP is negatively correlated with moral disengagement in
both Chinese and Islamic cultures. October 2021 | Volume 12 | Article 738128 Frontiers in Psychology | www.frontiersin.org 2 Filial Piety and Moral Disengagement Qiao et al. H1b: AFP is positively correlated with moral disengagement in
both Chinese and Islamic cultures. H1b: AFP is positively correlated with moral disengagement in
both Chinese and Islamic cultures. and AFP are related but distinct constructs, we proposed the
following hypotheses: H2a. The three dark triad traits serve as parallel mediators in
the associations between RFP and moral disengagement. The Dark Triad as Mediators g g
H2b. The three dark triad traits serve as parallel mediators in
the associations between AFP and moral disengagement. The term dark triad refers to the constellation of three traits:
Machiavellianism, Narcissism, and Psychopathy (Paulhus and
Williams, 2002). Machiavellianism can be characterized by a
cynical disregard for morality, lack of empathy, and focusing
on personal interest and ambition. To maximize personal gain,
Machiavellians often manipulate and exploit others (Muris
et al., 2017). Narcissism is characterized by a grandiose
sense of self-value and a strong need for appreciation and
admiration. Narcissists are self-centered and often consider
themselves deserving of special treatment (Muris et al., 2017). Psychopathy can be characterized by aloofness, an absence
of empathy, remorse or guilt, poor behavioral control, and
irresponsibility (Muris et al., 2017). Finally, the dark triad reflects
a non-communal, manipulative, exploitative, and self-focused
approach to interpersonal relations (Furnham et al., 2013; Miller
et al., 2019). The above features suggest that people high in
Machiavellianism and psychopathy are more likely to cross moral
boundaries to engage in unethical behavior than those scoring
low in Machiavellianism and psychopathy (Sijtsema et al., 2019). Individuals high in narcissism may be prone to commit moral
transgression because their own interests have been given priority
over the interests of others (Egan et al., 2015). Therefore, the dark
triad can be considered as an antecedent of moral disengagement. The Current Study Previous studies have mainly focused on parenting styles and
parent-child interactions on children’s moral disengagement. There is a literature gap in how filial piety influences moral
disengagement. The current study explored whether the dark
triad personality mediated the relations between filial piety
beliefs and moral disengagement. In addition, we planned to
explore whether the above mediation models show cross-cultural
stability. There are many similarities and dissimilarities between
Chinese culture and Islamic culture (Khalaila, 2010). To our
knowledge, no previous studies have compared the mechanism
of moral disengagement between the two cultural groups. Therefore, we try to use culture background as a moderating
variable to explore whether the above mediation models are
different in these two cultural groups. Figure 1 illustrates the
conceptual model. Participants and Procedures Of the total number
of participants, 400 were students from China (Nfemale = 253,
Mage = 20.41, SD age = 2.52), 378 were international students in
China from Islamic countries, Indonesia, and Yemen (Indonesia,
N = 250, Nfemale = 125, Mage = 22.13, SD age = 2.61 and Yemen,
N = 128, Nfemale = 29, Mage = 28.51, SD age = 5.20). After
the administration, participants were thanked and paid 20 yuan
for compensation. As previous literature has suggested, three components of
the dark triad may influence moral development in different
ways (Egan et al., 2015; Sijtsema et al., 2019; Abdollahi et al.,
2020; Kay and Saucier, 2020). We propose that the three dark
triad traits serve as multiple parallel mediators in the filial piety-
moral disengagement relation. Meanwhile, considering that RFP Frontiers in Psychology | www.frontiersin.org Correlations Among Research Variables Correlations Among Research Variables
Pearson correlation analysis was conducted to estimate the
relationships among research variables. The results (Table 1)
showed that AFP was positively correlated with MD among
participants from both China (r = 0.34, p < 0.00) and
Islamic countries (r = 0.25, p < 0.001), while RFP only Dark Triad The 12-item Dirty Dozen scale (DD; Jonason and Webster, 2010)
measured participants’ dark triad traits. Each item was rated on October 2021 | Volume 12 | Article 738128 Frontiers in Psychology | www.frontiersin.org 3 Qiao et al. Filial Piety and Moral Disengagement FIGURE 1 | The proposed moderation effects of culture in the mediation models. FIGURE 1 | The proposed moderation effects of culture in the mediation models. young adults (Wang et al., 2017). For brevity, only the total
score of MDS was used in this study. Participants are instructed
to rate each item using a 5-point scale (1 = strongly disagree;
5 = strongly agree). In this study, α coefficients were 0.95 (Chinese
participants) and 0.93 (Islamic participants). a 5-point Likert-type scale ranging from 1 (strongly disagree)
to 5 (strongly agree). Example items of three subscales are “I
tend to manipulate others to get my way” (Machiavellianism),
“I tend to lack remorse” (Psychopathy), and “I tend to want
others to admire me” (Narcissism). In the Chinese population,
DD has showed good reliability and validity (Geng et al., 2015). In this study, Cronbach’s alpha of the three subscales were 0.72
(Machiavellianism), 0.74 (Psychopathy), and 0.75 (Narcissism)
among Chinese participants, and 0.89 (Machiavellianism), 0.88
(Psychopathy), and 0.87 (Narcissism) among participants from
Islamic countries. Control Variables Considering the correlation between gender, age, socioeconomic
status, and moral disengagement in previous studies (Bandura,
2016; Alexandra et al., 2021; p. 290; Charalampous et al.,
2021), gender, age, and monthly family income were used as
control variables to enhance the validity of research findings. The participants were asked to report their monthly family
income using a scale with 6 response options, namely, 1000–
1999¥, 2000–2999¥, 3000–3999¥, 4000–4999¥, 5000–5999¥,
and ≥6000¥. Filial Beliefs Filial beliefs, including reciprocal filial and authoritarian filial
beliefs, were measured by the Filial Piety Scale (FPS; Yeh and
Bedford, 2003; Chen, 2014). FPS consists of 16 items, each
uses a 6-point scale ranging from 1 (extremely unimportant) to
6 (extremely important). The reciprocal filial belief dimension
(e.g., be frequently concerned about my parents’ general well-
being) and the authoritarian filial belief dimension (e.g., taken
my parents’ suggestions even when I do not agree with them)
each includes eight items. The total scores of all items of each
dimension were taken to represent the levels of filial beliefs. FPS has shown acceptable reliability and validity in previous
research among Chinese samples (Yeh et al., 2013). In this study,
Cronbach’s alpha for reciprocal and authoritarian filial beliefs
were 0.88 and 0.61 among Chinese participants, and 0.89 and 0.80
among Islamic participants. Frontiers in Psychology | www.frontiersin.org RESULTS Harman’s single factor test was conducted to identify common
method bias (Podsakoffet al., 2003). All three scales were
subjected to exploratory factor analysis, yielding 10 factors
with eigenvalue over one, with the first unrotated factor
accounting for 25.00% of the total variance, suggesting that the
relations among research variables may not be contaminated by
common method bias. Moral Disengagement The 32-item Moral Disengagement Scale (MDS; Bandura et al.,
1996) was used to assess eight moral disengagement tactics (e.g.,
telling small lies is permitted because no one is hurt). The
Chinese version of MDS shows good reliability and validity in October 2021 | Volume 12 | Article 738128 Frontiers in Psychology | www.frontiersin.org Filial Piety and Moral Disengagement Qiao et al. TABLE 1 | Descriptive statistics and Pearson correlations among research variables. 1
2
3
4
5
6
1 R.F.P
−
−0.14***
−0.36***
−0.02
−0.26***
−0.52***
2 A.F.P
0.63***
−
0.17**
−0.10*
−0.00
0.34***
3 Machiavellianism
−0.15**
0.10
−
0.44***
0.64***
0.45***
4 Psychopathy
0.08
0.16**
0.19***
−
0.58***
0.24***
5 Narcissism
−0.17**
0.09
0.75***
0.23***
−
0.41***
6 M.D. −0.07
0.25***
0.63***
0.24***
0.52***
−
Mean (SD)Islamic
39.00 (7.03)
33.29 (7.01)
8.79 (4.10)
12.47 (3.90)
8.85 (3.96)
88.92 (19.98)
Mean (SD)China
39.00 (6.57)
25.20 (5.07)
13.06 (4.49)
18.20 (4.71)
14.03 (5.16)
70.27 (22.05)
F(1, 776)
0.01
342.29***
190.27***
340.60***
245.27***
152.40***
R.F.P., Reciprocal filial piety, A.F.P., Authoritarian filial piety, M.D., Moral Disengagement. The upper right part of the diagonal of the table is the results of the Chinese sample, and the lower left part is the results of the Islamic sample. NChinese = 400,
NIslamic = 378. ***p < 0.001, **p < 0.01, *p < 0.05. TABLE 1 | Descriptive statistics and Pearson correlations among research variables. Figure 2 (Model 1), RFP had a significant negative direct effect
on moral disengagement (b = −0.19, SE = 0.11, p < 0.01,
95%CI = [−0.87, −0.44]). And the total mediation effect of
the dark triad between RFP and moral disengagement was
significant (b = −0.07, SE = 0.01, 95%CI = [−0.10, −0.05]). More specifically, the mediation effect via Machiavellianism was
significant (b = −0.06, SE = 0.01, 95%CI = [−0.09 −0.03]),
the mediation effects via psychopathy and narcissism were
not significant considering that a2 (R.F.P.→Psychopathy), b2
(Psychopathy→M.D.), and b3 (Narcissiam→M.D.) in Table 2
were not significant (ps > 0.05). This suggested that RFP had
a direct effect and Machiavellianism played a mediating role in
the whole model. Figure 2 (Model 1), RFP had a significant negative direct effect
on moral disengagement (b = −0.19, SE = 0.11, p < 0.01,
95%CI = [−0.87, −0.44]). And the total mediation effect of
the dark triad between RFP and moral disengagement was
significant (b = −0.07, SE = 0.01, 95%CI = [−0.10, −0.05]). Moral Disengagement More specifically, the mediation effect via Machiavellianism was
significant (b = −0.06, SE = 0.01, 95%CI = [−0.09 −0.03]),
the mediation effects via psychopathy and narcissism were
not significant considering that a2 (R.F.P.→Psychopathy), b2
(Psychopathy→M.D.), and b3 (Narcissiam→M.D.) in Table 2
were not significant (ps > 0.05). This suggested that RFP had
a direct effect and Machiavellianism played a mediating role in
the whole model. negatively correlated with MD among Chinese participants
(r = −0.52, p < 0.001). So far, H1a is partially supported
and H1b is completely supported. Besides, three dark triad
traits, Machiavellianism, Psychopathy, and Narcissism, were all
positively associated with MD, regardless the participants were
Chinese (r = 0.45, 0.24, 0.41, ps < 0.001) or Muslims (r = 0.63,
0.24, and 0.52, ps < 0.001). negatively correlated with MD among Chinese participants
(r = −0.52, p < 0.001). So far, H1a is partially supported
and H1b is completely supported. Besides, three dark triad
traits, Machiavellianism, Psychopathy, and Narcissism, were all
positively associated with MD, regardless the participants were
Chinese (r = 0.45, 0.24, 0.41, ps < 0.001) or Muslims (r = 0.63,
0.24, and 0.52, ps < 0.001). R.F.P., Reciprocal filial piety, M.D., Moral Disengagement. The Relationship Between Filial Piety
Belief and Moral Disengagement:
Across-Cultural Comparison
The Mediation Effects of the Dark Triad The Mediation Effects of the Dark Triad
Model 4 (a template for mediation analysis) of PROCESS macro
for SPSS (Hayes, 2012) was used to examine the indirect effect
of filial piety on moral disengage-ment through three dark triad
traits (H2a and H2b). Gender, age, and monthly family income
were entered as control variables. As shown in Table 2 and Model 2 estimated the parallel mediation of dark triad
between AFP and moral disengagement (Table 3 and Figure 2). Results showed that AFP had positive direct effect on moral
disengagement (b = 0.40, SE = 0.10, 95%CI = [1.06, 1.46]) and
the total mediation effect was significant (b = −0.03, SE = 0.01, TABLE 2 | Mediation models of reciprocal filial beliefs (N = 778). Model 1
b
SE
t
95% CI
R.F.P.→Machiavellianism(a1)
−0.22
0.02
−6.80***
[−0.20, −0.11]
R.F.P.→Psychopathy(a2)
0.02
0.03
0.53
[−0.04, 0.06]
R.F.P.→Narcissism(a3)
−0.18
0.03
−5.56***
[−0.19, −0.09]
Machiavellianism→M.D. (b1)
0.26
0.23
5.40***
[0.79, 1.70]
Psychopathy →M.D.(b2)
−0.07
0.18
−1.68
[−0.67, 0.05]
Narcissism→M.D.(b3)
0.07
0.22
1.34
[−0.13, 0.73]
R.F.P.→M, D. (c′)
−0.19
0.11
−5.95***
[−0.87, −0.44]
Age
0.11
0.19
3.41***
[0.26, 0.97]
Gender
−0.18
1.49
−5.67***
[−11.37, −5.22]
Monthly family income
−0.28
0.43
−8.50***
[−4.55, −2.84]
Mediation effects
Total
−0.07
0.01
[−0.10, −0.05]
R.F.P.→Machiavellianism→M.D. −0.06
0.01
[−0.09, −0.03]
R.F.P.→Psychopathy→M.D. −0.01
0.01
[−0.08, 0.01]
R.F.P.→Narcissism→M.D. −0.001
−0.003
[−0.01, 0.004]
R.F.P., Reciprocal filial piety, M.D., Moral Disengagement. ***p < 0 001; Bootstrap = 5 000 October 2021 | Volume 12 | Article 738128 5 Frontiers in Psychology | www.frontiersin.org Qiao et al. Filial Piety and Moral Disengagement FIGURE 2 | The parallel mediation models of dark triad traits. N = 778, ***p < 0.001; Bootstrap = 5,000. FIGURE 2 | The parallel mediation models of dark triad traits. N = 778, ***p < 0.001; Bootstrap = 5,000. FIGURE 2 | The parallel mediation models of dark triad traits. N = 778, ***p < 0.001; Bootstrap = 5,000. (the index of moderation mediation) contained zero, suggesting
that the mediation path of filial piety- dark triad traits-moral
disengagement did not differ across the two samples. 95%CI = −0.06, −0.01]), among them, only the mediation
effect of narcissism was significant (b = −0.02, SE = 0.01,
95%CI = −0.04, −0.01]). DISCUSSION China
−0.01
0.03
[−0.07, 0.04]
0.06
0.04
[−0.01, 0.14]
Islamic
0.046
0.02
[0.006, 0.103]
A.F.P.→Narcissism→M.D. China
−0.03
0.06
[−0.16, 0.10]
0.05
0.07
[−0.08, 0.19]
Islamic
0.054
0.02
[0.009, 0.099]
R.F.P., Reciprocal filial piety, A.F.P., Authoritarian filial piety, M.D., Moral Disengagement; NChinese = 400, NIslamic = 378. Both models were controlled for age, gender, and monthly family income. TABLE 3 | Mediation models of authoritarian filial beliefs (N = 778). Model 2
b
SE
t
95% CI
A.F.P.→Machiavellianism (a1)
−0.06
0.02
−1.74
[17.45, 22.89]
A.F.P.→Psychopathy (a2)
−0.15
0.03
−4.16***
[−0.16, −0.06]
A.F.P.→Narcissism(a3)
−0.15
0.03
−4.16***
[−0.16, −0.06]
Machiavellianism→M.D. (b1)
0.27
0.21
6.05**
[0.87, 1.71]
Psychopathy →M.D. (b2)
−0.07
0.17
−1.80
[−0.63, 0.03]
Narcissism→M.D. (b3)
0.16
0.21
3.31***
[0.28, 1.10]
A.F.P.→M.D. (c’)
0.40
0.10
12.41***
[1.06, 1.46]
Age
0.08
0.17
2.59**
[0.11, 0.77]
Gender
−0.12
1.41
−4.18***
[−8.63, −3.11]
Monthly family income
−0.17
0.42
−5.29***
[−3.07, −1.41]
Mediation effects
Total
−0.03
0.01
[−0.06, −0.01]
A.F.P.→Machiavellianism→M.D. −0.02
0.02
[−0.04, 0.004]
A.F.P.→Psychopathy→M.D. 0.01
0.01
[−0.00, 0.03]
A.F.P.→Narcissism→M.D. −0.02
0.01
[−0.04, −0.01]
A.F.P., Authoritarian filial piety, M.D., Moral Disengagement. ***p < 0.001, **p < 0.01; Bootstrap = 5,000. TABLE 3 | Mediation models of authoritarian filial beliefs (N = 778). TABLE 4 | Culture differences in the mediation effect. Effect
SE
95%CI
INDEX
SE
95%CI
Model 3
R.F.P.→Machiavellianism→M.D. China
−0.17
0.08
[−0.34, −0.03]
−0.03
0.11
[−0.24, 0.19]
Islamic
−0.20
0.07
[−0.35, −0.07]
R.F.P.→Psychopathy→M.D. China
−0.01
0.01
[−0.04, 0.03]
0.04
0.02
[−0.01, 0.09]
Islamic
0.03
0.02
[−0.00, 0.07]
R.F.P.→Narcissism→M.D. China
−0.13
0.05
[−0.24, −0.04]
0.09
0.06
[−0.02, 0.21]
Islamic
−0.04
0.03
[−0.11, 0.01]
Model 4
A.F.P.→Machiavellianism→M.D. China
0.12
0.07
[0.01, 0.29]
−0.01
0.10
[−0.20, 0.18]
Islamic
0.12
0.06
[−0.005, 0.26]
A.F.P.→Psychopathy→M.D. China
−0.01
0.03
[−0.07, 0.04]
0.06
0.04
[−0.01, 0.14]
Islamic
0.046
0.02
[0.006, 0.103]
A.F.P.→Narcissism→M.D. China
−0.03
0.06
[−0.16, 0.10]
0.05
0.07
[−0.08, 0.19]
Islamic
0.054
0.02
[0.009, 0.099]
R.F.P., Reciprocal filial piety, A.F.P., Authoritarian filial piety, M.D., Moral Disengagement; NChinese = 400, NIslamic = 378. Both models were controlled for age, gender, and monthly family income. TABLE 4 | Culture differences in the mediation effect. R.F.P., Reciprocal filial piety, A.F.P., Authoritarian filial piety, M.D., Moral Disengagement; NChinese = 400, NIslamic = 378. Both models were controlled for age, gender, and monthly family income. with moral disengagement in both two cultural groups. This
confirms that AFP can generally be seen as an unfavorable
family obligation belief regarding individual moral socialization
(Yeh, 2003). DISCUSSION So far, this study has tested the mediating role of the dark
triad. To further explore the possible differences in the mediating
models, Model 59 of PROCESS macro for SPSS was adopted,
using culture as a common moderator (Hayes, 2015). Gender, age,
and monthly family income were entered as control variables. The index of moderated mediation was presented in Table 4. Results showed that all 95% bootstrap confidence intervals For thousands of years, filial piety has been regarded as the
moral foundation for interpersonal relationships in China
and
other
Confucianism-influenced
East
Asian
countries
(Bedford and Yeh, 2019). Little
empirical
research
has
investigated whether and how filial piety influences individuals’
moral disengagement. More specifically, questions about the For thousands of years, filial piety has been regarded as the
moral foundation for interpersonal relationships in China
and
other
Confucianism-influenced
East
Asian
countries
(Bedford and Yeh, 2019). Little
empirical
research
has
investigated whether and how filial piety influences individuals’
moral disengagement. More specifically, questions about the October 2021 | Volume 12 | Article 738128 Frontiers in Psychology | www.frontiersin.org 6 Filial Piety and Moral Disengagement Qiao et al. TABLE 3 | Mediation models of authoritarian filial beliefs (N = 778). Model 2
b
SE
t
95% CI
A.F.P.→Machiavellianism (a1)
−0.06
0.02
−1.74
[17.45, 22.89]
A.F.P.→Psychopathy (a2)
−0.15
0.03
−4.16***
[−0.16, −0.06]
A.F.P.→Narcissism(a3)
−0.15
0.03
−4.16***
[−0.16, −0.06]
Machiavellianism→M.D. (b1)
0.27
0.21
6.05**
[0.87, 1.71]
Psychopathy →M.D. (b2)
−0.07
0.17
−1.80
[−0.63, 0.03]
Narcissism→M.D. (b3)
0.16
0.21
3.31***
[0.28, 1.10]
A.F.P.→M.D. (c’)
0.40
0.10
12.41***
[1.06, 1.46]
Age
0.08
0.17
2.59**
[0.11, 0.77]
Gender
−0.12
1.41
−4.18***
[−8.63, −3.11]
Monthly family income
−0.17
0.42
−5.29***
[−3.07, −1.41]
Mediation effects
Total
−0.03
0.01
[−0.06, −0.01]
A.F.P.→Machiavellianism→M.D. −0.02
0.02
[−0.04, 0.004]
A.F.P.→Psychopathy→M.D. 0.01
0.01
[−0.00, 0.03]
A.F.P.→Narcissism→M.D. −0.02
0.01
[−0.04, −0.01]
A.F.P., Authoritarian filial piety, M.D., Moral Disengagement. ***p < 0.001, **p < 0.01; Bootstrap = 5,000. TABLE 4 | Culture differences in the mediation effect. Effect
SE
95%CI
INDEX
SE
95%CI
Model 3
R.F.P.→Machiavellianism→M.D. China
−0.17
0.08
[−0.34, −0.03]
−0.03
0.11
[−0.24, 0.19]
Islamic
−0.20
0.07
[−0.35, −0.07]
R.F.P.→Psychopathy→M.D. China
−0.01
0.01
[−0.04, 0.03]
0.04
0.02
[−0.01, 0.09]
Islamic
0.03
0.02
[−0.00, 0.07]
R.F.P.→Narcissism→M.D. China
−0.13
0.05
[−0.24, −0.04]
0.09
0.06
[−0.02, 0.21]
Islamic
−0.04
0.03
[−0.11, 0.01]
Model 4
A.F.P.→Machiavellianism→M.D. China
0.12
0.07
[0.01, 0.29]
−0.01
0.10
[−0.20, 0.18]
Islamic
0.12
0.06
[−0.005, 0.26]
A.F.P.→Psychopathy→M.D. Frontiers in Psychology | www.frontiersin.org DISCUSSION Specifically, in this study, narcissism is not only positively
related to moral disengagement but also played a mediating
role between AFP and moral disengagement. This can be
accounted for by cultural differences between the Eastern
and Western societies. Most of the previous studies are
conducted in Western individualistic societies, where there is
a popularity of cultural products eliciting narcissism, such as
song lyrics, reality television and advertisements (Twenge and
Campbell, 2009), narcissism is accepted and even encouraged
in such situations. Therefore, the different findings on the
relation between narcissism and moral disengagement can
be accounted for by how strongly the individualistic value
is endorsed across cultures. High individualistic individuals
tended to make internal attributions when they were asked to
explain social events (Oyserman et al., 2002). They tend to
assume social responsibilities rather than shirk them. However,
in societies that attach great importance to collective goals,
such as Islamic countries and China, narcissism is more
strongly indicative of selfishness and irresponsibility thus has a
stronger relationship with moral disengagement. Nevertheless,
these comparable findings in Chinese and Muslim participants
illustrate that filial piety is rooted in parent-child interactions
rather than behavioral norms shaped by culture (Bedford
and Yeh, 2019). Moreover, these findings suggest that family
obligation beliefs continued to affect on moral cognition, The insignificant moderation effect of culture indicates
that the association of filial piety and moral disengagement
via the dark triad is justifiable among Chinese and Muslim
participants. First,
as
a
contextualized
personality,
filial
piety can profoundly affect personality development, which
in turn influences moral cognition and behavior even in
adulthood. Moreover, this provides empirical support for
DFPM, which posits that filial piety should be conceptualized
mainly in terms of parent-child relationships but not only
culture
norms
(Bedford
and
Yeh,
2019). Therefore,
the
function of filial piety is comparable in China and non-
Confucian-influenced countries. As Bedford and Yeh (2021)
demonstrated, DFPM can be used as the framework to
understand inter-generational and inter-personal relationships
in different cultures. Some interesting findings in this study are noteworthy. More
specifically, the endorsement of AFP in the Chinese sample is
significantly lower than that in the Islamic sample. There are
three reasons to explain this difference. Firstly, previous literature
has observed a decrease of AFP in modern Chinese societies
with industrialization and urbanization (Yeh and Bedford,
2003). Second, past cross-culture studies supported a stronger
endorsement of filial duty among Muslims. DISCUSSION But the negative association of RFP and moral
disengagement is only significant in the Chinese sample. One
of the possible explanations is that, in Confucian societies,
parent-child interactions are more important in children’s
moral development; while in Islam, moral norms are laid
down by Allah Almighty but not human beings (Naeem
and Shah, 2013). This can partly explain why the positive
effects of RFP on moral responsibility are absent among
Muslim participants. mediating mechanisms (i.e., how AFP or RFP predicts moral
disengagement) and the universality of this relationship in
other cultural contexts remain largely unanswered. Therefore,
in this study, we constructed two moderated mediation
models to address these questions. The results showed that
RFP
reduced
moral
disengagement
directly
and
did
so
indirectly by weakening Machiavellianism. The role of AFP
is complicated, which has a direct strengthening effect on
moral disengagement but can weaken it by suppressing the
narcissistic personality. Furthermore, these two mediation
models
were
not
significantly
different
across
different
cultural groups. Besides, there were many interesting findings
regarding the function of filial piety in different cultural
groups in this study. Based on previous findings that the dark triad traits are
predictors of moral disengagement (Sijtsema et al., 2019), and
poor parent-child relationships contribute to the development
of the dark triad (Jonason et al., 2014), this study introduced
the dark triad traits as the mediating mechanisms in the g
p
y
We first examined the relationship between AFP/RFP and
moral disengagement in China and Islamic countries separately. As expected, AFP is significantly and positively associated October 2021 | Volume 12 | Article 738128 Frontiers in Psychology | www.frontiersin.org 7 Filial Piety and Moral Disengagement Qiao et al. link of filial piety and moral disengagement. The two parallel
mediation models indicated that individuals with higher levels
of RFP, who emphasized personal choices and authentic
love to parents (Yeh and Bedford, 2004), are less likely
to manipulate others or disregard personal moral standards. AFP, which advocates personal sacrifice and suppression of
individual needs to fulfill obligations to parents (Yeh and
Bedford, 2004), may be responsible for a higher level of moral
disengagement. High-level AFP often represents strict parental
demands and a disadvantaged position of children in the
family hierarchy (Bedford and Yeh, 2019). In such a raising
environment, children are more inclined to shirk responsibility
to avoid punishment from parents. DISCUSSION When external forces
mainly control one’s behaviors, it is impossible to require an
individual to take responsibility for his/her behaviors (Bandura,
2016). Surprisingly, we found that AFP could reduce moral
disengagement by inhibiting the development of narcissism,
suggesting that AFP is not entirely negative, as past findings
have suggested (Yeh and Bedford, 2004). AFP means that
duties to families come before the interests of an individual. One must suppress personal needs and make sacrifices to
enhance the well-being of the whole family. Therefore, a
filial individual is less likely to show characteristics of high
narcissism, such as “I tend to expect special favors from
others.” in two culture groups. Among Chinese participants AFP and
RFP were negatively correlated. This can be interpreted as the
effect of modernization and industrialization, which considerably
changed Chinese people’s values and beliefs. More and more
Chinese people endorse RFP but refuse AFP (Yeh et al., 2013). That is, they yearn for mutual affection and intimacy (RFP)
in parent-child relationships and oppose traditional teachings
requiring individuals to suppress their needs for the sake of
collective interests. Among Muslim participants, however, AFP
and RFP were positively correlated. This may reflect the fact that
discipline and psychosocial well-being of the children are both
highly valued in Islamic cultures. Children are strictly disciplined
(AFP) to cultivate obedience to parents and God; meanwhile,
the Qur’an, the holy book of Muslims, also requires parents
to ensure the development of good psychosocial functioning of
their children, which needs a positive parent-child interaction
(RFP). This suggests that AFP and RFP are closely connected
in Islamic countries (see Oweis et al., 2012; Riany et al.,
2017). 2017). It is noteworthy that all the dark triad traits were significantly
higher, but moral disengagement was significantly lower in
Chinese relative to Muslim participants. This is consistent
with
Jonason
et
al. (2020)
who
found
that
narcissism,
Machiavellianism, and psychopathy of China (4.41, 2.83, and
2.55) were generally higher than Egypt (4.14, 2.13, and 2.43),
and Indonesia (3.72, 2.66, and 2.80), two Muslim countries. We have no evidence regarding the difference in moral
disengagement scores between Chinese and Muslim students
and its cultural implications. We hope future studies can
address this issue. Another unexpected finding inconsistent with
previous studies (e.g., Egan et al., 2015; Sijtsema et al., 2019)
is that narcissism significantly affected moral disengagement. Frontiers in Psychology | www.frontiersin.org Bandura, A. (2016). Moral Disengagement: How People Do Harm and Live With
Themselves. New York, NY: Worth publishers.
Bandura, A., Barbaranelli, C., Caprara, G. V., and Pastorelli, C. (1996). Mechanisms
of moral disengagement in the exercise of moral agency. J. Pers. Soc. Psychol. 71,
364–374. doi: 10.1037/0022-3514.71.2.364
Bao, Z., Zhang, W., Lai, X., Sun, W., and Wang, Y. (2015). Parental attachment and
Chinese adolescents’ delinquency: the mediating role of moral disengagement.
J. Adolesc. 44, 37–47. doi: 10.1016/j.adolescence.2015.06.002
Bedford, O., and Yeh, K.-H. (eds) (2020). “History of chinese indigenous
psychology,” in Oxford Research Encyclopedia of Psychology, (Oxford: Oxford
University Press). doi: 10.1093/acrefore/9780190236557.013.660
Bedford, O., and Yeh, K.-H. (2019). The history and the future of the psychology
of filial piety: Chinese norms to contextualized personality construct. Front.
Psychol. 10:100. doi: 10.3389/fpsyg.2019.00100 ETHICS STATEMENT In many societies, filial obligations imposed on females
are quite different from those on males (Brasher, 2021). This
suggests that the effects of filial obligations on psychosocial
outcomes may be conditioned by gender (Duguet et al., 2016;
Wang et al., 2016; Szabó and Jones, 2019). However, this
study has not addressed the moderating role of gender in the
relationships among research variables because it is beyond our
research scope. Finally, filial piety was operationalized in this
study as a contextualized personality trait (namely a continuous
variable) but not personality type (namely a categorical variable). According to Yeh and Bedford (2004), there are four filial piety
types (high reciprocal-low authoritarian; low reciprocal-high
authoritarian; low on both, and high on both). Future studies are
encouraged to use a larger sample size to explore whether these The studies involving human participants were reviewed and
approved by the Institutional Review Board (IRB) at Shandong
Normal University. Written informed consent for participation
was not required for this study in accordance with the national
legislation and the institutional requirements. DISCUSSION For example, Duguet
et al. (2016) found that the Muslims show a stronger willingness
to host elderly parents than Europeans. Third, previous research
has found that filial piety beliefs in Arabic cultures involve seven
components (i.e., sacrifice, obligation, respect, face-saving, repay,
intergenerational exchange, family unity), most of which fit the
definition of AFP (Khalaila, 2010). Therefore, it is plausible that
the international students from Islamic countries scored higher
in AFP than Chinese college students. In addition, we found
opposite results regarding the correlations between AFP and RFP October 2021 | Volume 12 | Article 738128 Frontiers in Psychology | www.frontiersin.org 8 Filial Piety and Moral Disengagement Qiao et al. emotions, and behaviors even after the children enter adulthood
and beyond (Wei and Liu, 2020). emotions, and behaviors even after the children enter adulthood
and beyond (Wei and Liu, 2020). four filial piety types are differently associated with personality
and moral development. In so doing, the interaction between RFP
and AFP may be revealed more clearly. CONCLUSION Several limitations should be addressed. Filial piety originates
from parent-child interaction and can be indicated by children’s
perception of family obligation and duty to host the elderly
parents (Schwartz et al., 2010). It can be considered as a family
environmental factor that can shape personality development. Previous literature has explored a broad range of psychosocial
outcomes of the dark triad personality, but few studies have
investigated its antecedent (Furnham et al., 2013). This study
found that RFP can prevent the development of Machiavellianism
and narcissism regardless of cultural contexts. However, no
conclusion can be drawn on which filial piety belief can
prevent psychopathy. Future research may consider conducting
replication studies or using a longitudinal design to confirm
the stability of these relationships. This study revealed culturally
universal and specific aspects of filial piety beliefs. Relevant
findings should be treated with caution because this study
involved only young adults from Chinese and Islamic societies
who are well educated. For instance, a study found that the
two dimensions of filial piety are significantly related to age
among participants ranging from 20 to 69 years old (Yeh et al.,
2013). Furthermore, nationally representative samples with more
divergent cultural backgrounds are expected to be included
in future studies. Using samples from Chinese and Islamic cultures, we introduced
filial piety as an antecedent of the dark triad personality and
moral disengagement. Results supported the direct positive effect
of RFP on reducing moral disengagement and the mediating
effect of Machiavellianism. In contrast, the role of AFP is
conflicting. It directly strengthens moral disengagement and
concurrently weakens moral disengagement by suppressing
Narcissistic personality, enlightening us to view AFP dialectically. In addition, due to that, the effects of filial piety on moral
disengagement were considerably consistent across two cultural
groups, the applicability of DFPM was empirically supported to a
large extent. Future studies are encouraged to involve participants
from more divergent countries and cultural backgrounds. AUTHOR CONTRIBUTIONS XQ and QG designed the research and wrote the manuscript. YL,
TZ, MC, and AA collected and analyzed the data. All authors
listed have made a substantial, direct and intellectual contribution
to the work, and approved it for publication. DATA AVAILABILITY STATEMENT The raw data supporting the conclusions of this article will be
made available by the authors, without undue reservation. Bandura, A., Barbaranelli, C., Caprara, G. V., and Pastorelli, C. (1996). Mechanisms
of moral disengagement in the exercise of moral agency. J. Pers. Soc. Psychol. 71,
364–374. doi: 10.1037/0022-3514.71.2.364 Bandura, A. (2016). Moral Disengagement: How People Do Harm and Live With
Themselves. New York, NY: Worth publishers. REFERENCES Cyberbullying, psychopathic traits, moral disengagement, and school climate:
the role of self-reported psychopathic levels and gender. Educ. Psychol. 41,
282–301. doi: 10.1080/01443410.2020.1742874 Mazzone, A., and Camodeca, M. (2019). Bullying and moral disengagement in
early adolescence: do personality and family functioning matter? J. Child Fam. Stud. 28, 2120–2130. doi: 10.1007/s10826-019-01431-7 Chen, B.-W. (2015). Exploring detraditionalization through gender reflexivity in
late modernity: the negotiation of family/filial responsibilities among Taiwanese
(younger) professional men. Fam. Relation. Soc. 4, 449–464. doi: 10.1332/
204674314X14048129064262 Miller, J. D., Vize, C., Crowe, M. L., and Lynam, D. R. (2019). A critical appraisal
of the dark-triad literature and suggestions for moving forward. Curr. Direct. Psychol. Sci. 28, 353–360. doi: 10.1177/0963721419838233 Moore, C. (2015). Moral disengagement. Curr. Opin. Psychol. 6, 199–204. doi:
10.1016/j.copsyc.2015.07.018 Chen, W.-W. (2014). The relationship between perceived parenting style, filial
piety, and life satisfaction in Hong Kong. J. Fam. Psychol. 28:308. doi: 10.1037/
a0036819 Muris, P., Merckelbach, H., Otgaar, H., and Meijer, E. (2017). The malevolent side
of human nature: a meta-analysis and critical review of the literature on the
dark triad (narcissism, Machiavellianism, and psychopathy). Perspect. Psychol. Sci. 12, 183–204. doi: 10.1177/1745691616666070 Chen, W.-W., and Ho, H.-Z. (2012). The relation between perceived parental
involvement and academic achievement: the roles of Taiwanese students’
academic beliefs and filial piety. Int. J. Psychol. 47, 315–324. doi: 10.1080/
00207594.2011.630004 Naeem, M., and Shah, M. M. (2013). “Filial piety in confucianism and Islam (A
Comparative Study),” in Proceedings of the International Conference on Qur’an
and Hadith Studies (ICQHS 2017), (Paris: Atlantis Press). Chen, W.-W., Wu, C.-W., and Yeh, K.-H. (2016). How parenting and filial piety
influence happiness, parent–child relationships and quality of family life in
Taiwanese adult children. J. Fam. Stud. 22, 80–96. doi: 10.1080/13229400.2015. 1027154 Oweis, A., Gharaibeh, M., Maaitah, R., Gharaibeh, H., and Obeisat, S. (2012). Parenting from a Jordanian perspective: findings from a qualitative
study. J. Nurs. Scholarsh. 44, 242–248. doi: 10.1111/j.1547-5069.2012. 01455.x Csathó, Á, and Birkás, B. (2018). Early-life stressors, personality development,
and fast life strategies: an evolutionary perspective on malevolent personality
features. Front. Psychol. 9:305. doi: 10.3389/fpsyg.2018.00305 Oyserman, D., Coon, H. M., and Kemmelmeier, M. (2002). Rethinking
individualism and collectivism: evaluation of theoretical assumptions and
meta-analyses. Psychol. Bull. 128, 3–72. doi: 10.1037/0033-2909.128.1.3 Duguet, A., Masmoudi, T., Duchier, J., Rwabihama, J., and Maatoug, S. (2016). Access to care in france for elderly immigrants from North Africa: influence
of socio-cultural factors (the matc Survey). Eur. J. REFERENCES Abdollahi, A., Hashemi, F., Faraji, H. R., Hosseinian, S., and Allen, K. A. (2020). Moral disengagement: mediator between moral perfectionism and
machiavellian behavior among undergraduates? Psychol. Rep. [Epub ahead of
print]. doi: 10.1177/0033294120964067 Alexandra, M., Holman, A.-C., and Elenescu, A.-G. (2021). The dark web of
machiavellianism and psychopathy: moral disengagement in IT organizations. Eur. J. Psychol. [Epub ahead of print]. Ball, C. L., Smetana, J. G., Sturge-Apple, M. L., Suor, J. H., and Skibo, M. A. (2017). Moral development in context: associations of neighborhood and maternal
discipline with preschoolers’ moral judgments. Dev. Psychol. 53, 1881–1894. doi: 10.1037/dev0000378 Bandura, A. (1999). Social cognitive theory of personality. Handb. Pers. 2, 154–196. October 2021 | Volume 12 | Article 738128 Frontiers in Psychology | www.frontiersin.org 9 Filial Piety and Moral Disengagement Qiao et al. Bedford, O., and Yeh, K.-H. (2021). Evolution of the conceptualization of filial
piety in the global context: from skin to skeleton. Front. Psychol. 12:995. doi:
10.3389/fpsyg.2021.570547 Kay, C. S., and Saucier, G. (2020). Deviating from the social consensus: relations
among the Dark Triad, moral normativity, and general social normativity. Pers. Individ. Diff. 159:109889. doi: 10.1016/j.paid.2020.109889 ff
j
Khalaila, R. (2010). Development and evaluation of the Arabic filial piety scale. Res. Soc. Work Pract. 20, 356–367. doi: 10.1177/1049731510369495 yg
Bergelson, Y. P., Kurman, J., and Roer-Strier, D. (2015). Immigrant’s emotional
reactions to filial responsibilities and related psychological outcomes. Int. J. Bergelson, Y. P., Kurman, J., and Roer-Strier, D. (2015). Immigrant’s emotional
reactions to filial responsibilities and related psychological outcomes. Int. J. Intercult. Relat. 45, 104–115. doi: 10.1016/j.ijintrel.2015.02.002 Intercult. Relat. 45, 104–115. doi: 10.1016/j.ijintrel.2015.02.002 Li, R., Yao, M., Chen, Y., and Liu, H. (2020). Parent autonomy support
and psychological control, dark triad, and subjective well-being of chinese
adolescents: synergy of variable-and person-centered approaches. J. Early
Adolesc. 40, 966–995. doi: 10.1177/0272431619880335 Brasher, M. S. (2021). Filial norms, altruism, and reciprocity: financial support
to older parents in china. J. Population Ageing [Epub ahead of print]. doi:
10.1007/s12062-020-09316-0 Campaert, K., Nocentini, A., and Menesini, E. (2018). The role of poor parenting
and parental approval for children’s moral disengagement. J. Child Fam. Stud. 27, 2656–2667. doi: 10.1007/s10826-018-1097-1 Liu, G., Meng, Y., Pan, Y., Ma, Y., and Zhang, D. (2019). Mediating effect of
dark triad personality traits on the relationship between parental emotional
warmth and aggression. J. Interpers. Violence [Epub ahead of print]. doi: 10. 1177/0886260519877950 Charalampous, K., Ioannou, M., Georgiou, S., and Stavrinides, P. (2021). REFERENCES Health Law 23, 470–480. doi: 10.1163/15718093-12341431 Paulhus, D. L., and Williams, K. M. (2002). The dark triad of personality:
narcissism, machiavellianism, and psychopathy. J. Res. Pers. 36, 556–563. doi:
10.1016/S0092-6566(02)00505-6 Egan, V., Hughes, N., and Palmer, E. J. (2015). Moral disengagement, the dark
triad, and unethical consumer attitudes. Pers. Individ. Diff. 76, 123–128. doi:
10.1016/j.paid.2014.11.054 Podsakoff, P. M., MacKenzie, S. B., Lee, J.-Y., and Podsakoff, N. P. (2003). Common
method biases in behavioral research: a critical review of the literature and
recommended remedies. J. Appl. Psychol. 88, 879–903. doi: 10.1037/0021-9010. 88.5.879 Frankenhuis, W. E., Panchanathan, K., and Nettle, D. (2016). Cognition in harsh
and unpredictable environments. Curr. Opin. Psychol. 7, 76–80. doi: 10.1016/j. copsyc.2015.08.011 Riany, Y. E., Meredith, P., and Cuskelly, M. (2017). Understanding the influence
of traditional cultural values on Indonesian parenting. Marriage Fam. Rev. 53,
207–226. doi: 10.1080/01494929.2016.1157561 p y
Furnham, A., Richards, S. C., and Paulhus, D. L. (2013). The Dark Triad of
personality: a 10 year review. Soc. Pers. Psychol. Compass 7, 199–216. doi:
10.1111/spc3.12018 Schwartz, S. J., Weisskirch, R. S., Hurley, E. A., Zamboanga, B. L., Park, I. J.,
Kim, S. Y., et al. (2010). Communalism, familism, and filial piety: are they
birds of a collectivist feather? Cult. Divers. Ethn. Minority Psychol. 16, 548–560. doi: 10.1037/a0021370 Geng, Y., Sun, Q., Huang, J., Zhu, Y., and Han, X. (2015). Dirty dozen and short
dark triad: a Chinese validation of two brief measures of the dark triad. Chinese
J. Clin. Psychol. 23, 246–250. Sijtsema, J. J., Garofalo, C., Jansen, K., and Klimstra, T. A. (2019). Disengaging from
evil: longitudinal associations between the dark triad, moral disengagement,
and antisocial behavior in adolescence. J. Abnorm. Child Psychol. 47, 1351–1365. doi: 10.1007/s10802-019-00519-4 Hayes, A. F. (2012). PROCESS: A Versatile Computational Tool for Observed
Variable Mediation, Moderation, and Conditional Process Modeling. Lawrence,
KS: University of Kansas. Szabó, E., and Jones, D. N. (2019). Gender differences moderate Machiavellianism
and impulsivity: implications for Dark Triad research. Pers. Individ. Diff. 141,
160–165. doi: 10.1016/j.paid.2019.01.008 Hayes, A. F. (2015). An index and test of linear moderated mediation. Multiv. Behav. Res. 50, 1–22. doi: 10.1080/00273171.2014.962683 Ivanhoe, P. J. (2000). Confucian Moral Self Cultivation. Indianapolis, IN: Hackett
Publishing. Tan, S. A., Nainee, S., and Tan, C. S. (2019). REFERENCES doi: 10.3389/fpsyg.2021.621878 y
y
p yg
Zhou, J., Guo, Q., and Xu, R. (2020). Reciprocal filial piety facilitates academic
success via autonomy: generalizing findings in chinese society to a global
context. Front. Psychol. 11:69. doi: 10.3389/fpsyg.2020.00069 Zhou, J., Guo, Q., and Xu, R. (2020). Reciprocal filial piety facilitates academic
success via autonomy: generalizing findings in chinese society to a global
context. Front. Psychol. 11:69. doi: 10.3389/fpsyg.2020.00069 Wei, H., and Liu, M. (2020). Loving your parents and treating others well: the
effect of filial piety on cyberbullying perpetration and its functional mechanism
among Chinese graduate students. J. Interpers. Violence [Epub ahead of print]. doi: 10.1177/0886260520978182 Conflict of Interest: The authors declare that the research was conducted in the
absence of any commercial or financial relationships that could be construed as a
potential conflict of interest. Yeh, K.-H. (2003). The beneficial and harmful effects of filial piety: an integrative
analysis. Prog. Asian Soc. Psychol. 42, 67–82. Yeh, K.-H. (2006). The impact of filial piety on the problem behaviours of culturally
Chinese adolescents. J. Psychol. Chinese Soc. 7, 237–257. Publisher’s Note: All claims expressed in this article are solely those of the authors
and do not necessarily represent those of their affiliated organizations, or those of
the publisher, the editors and the reviewers. Any product that may be evaluated in
this article, or claim that may be made by its manufacturer, is not guaranteed or
endorsed by the publisher. Yeh, K. H., and Bedford, O. (2003). A test of the dual filial piety model. Asian J. Soc. Psychol. 6, 215–228. doi: 10.1046/j.1467-839X.2003.00122.x Yeh, K.-H., and Bedford, O. (2004). Filial belief and parent-child conflict. Int. J. Psychol. 39, 132–144. doi: 10.1080/00207590344000312 Yeh, K.-H., and Bedford, O. (2019). “The psychology of filial piety and moral
decision-making in Chinese people,” in The Oxford Handbook of Moral
Development: An Interdisciplinary Perspective, ed. L. A. Jensen (Oxford: Oxford
University Press). doi: 10.1093/oxfordhb/9780190676049.013.21 Copyright © 2021 Qiao, Lv, Aldbyani, Guo, Zhang and Cai. This is an open-access
article distributed under the terms of the Creative Commons Attribution License
(CC BY). The use, distribution or reproduction in other forums is permitted, provided
the original author(s) and the copyright owner(s) are credited and that the original
publication in this journal is cited, in accordance with accepted academic practice. No
use, distribution or reproduction is permitted which does not comply with these terms. Yeh, K.-H., Yi, C.-C., Tsao, W.-C., and Wan, P.-S. REFERENCES “Filial piety and life satisfaction among
malaysian adolescents in a multi-ethnic, collectivist society,” in Proceedings of
the 2nd International Conference on Intervention and Applied Psychology (ICIAP
2018), (Paris: Atlantis Press). doi: 10.2991/iciap-18.2019.12 Jonason, P. K., Foster, J. D., Egorova, M. S., Parshikova, O., Csathó, Á, Oshio, A.,
et al. (2017). The dark triad traits from a life history perspective in six countries. Front. Psychol. 8:1476. doi: 10.3389/fpsyg.2017.01476 2018), (Paris: Atlantis Press). doi: 10.2991/iciap-18.2019.12 Jonason, P. K., Lyons, M., and Bethell, E. (2014). The making of darth vader:
parent–child care and the dark triad. Pers. Individ. Diff. 67, 30–34. doi: 10.1016/
j.paid.2013.10.006 Toro, R. I., Schofield, T. J., Calderon-Tena, C. O., and Farver, J. M. (2019). Filial responsibilities, familism, and depressive symptoms among Latino young
adults. Emerg. Adulthood 7, 370–377. doi: 10.1177/2167696818782773 Twenge, J. M., and Campbell, W. K. (2009). The Narcissism Epidemic: Living in the
Age of Entitlement. New York, NY: Simon and Schuster. Jonason, P. K., and Webster, G. D. (2010). The dirty dozen: a concise measure of
the dark triad. Psychol. Assess. 22, 420–432. doi: 10.1037/a0019265 Age of Entitlement. New York, NY: Simon and Schuster. Jonason, P. K., ˙Zemojtel-Piotrowska, M., Piotrowski, J., Sedikides, C., Campbell, Jonason, P. K., ˙Zemojtel-Piotrowska, M., Piotrowski, J., Sedikides, C., Campbell,
W. K., Gebauer, J. E., et al. (2020). Country-level correlates of the dark triad Wang, X., Lei, L., Liu, D., and Hu, H. (2016). Moderating effects of moral reasoning
and gender on the relation between moral disengagement and cyberbullying in
adolescents. Pers. Individ. Diff. 98, 244–249. doi: 10.1016/j.paid.2016.04.056 Jonason, P. K., ˙Zemojtel-Piotrowska, M., Piotrowski, J., Sedikides, C., Campbell,
W. K., Gebauer, J. E., et al. (2020). Country-level correlates of the dark triad
traits in 49 countries. J. Pers. 88, 1252–1267. doi: 10.1111/jopy.12569 W. K., Gebauer, J. E., et al. (2020). Country-level correlates of the dark triad
traits in 49 countries. J. Pers. 88, 1252–1267. doi: 10.1111/jopy.12569 October 2021 | Volume 12 | Article 738128 Frontiers in Psychology | www.frontiersin.org 10 Qiao et al. Filial Piety and Moral Disengagement Wang, X., Yang, L., Yang, J., Wang, P., and Lei, L. (2017). Trait anger and
cyberbullying among young adults: a moderated mediation model of moral
disengagement and moral identity. Comput. Hum. Behav. 73, 519–526. doi:
10.1016/j.chb.2017.03.073 Zhang, Y., Chen, C., Teng, Z., and Guo, C. (2021). Parenting style and cyber-
aggression in Chinese youth: the role of moral disengagement and moral
identity. Front. Psychol. 12:377. Frontiers in Psychology | www.frontiersin.org October 2021 | Volume 12 | Article 738128 REFERENCES (2013). Filial piety in
contemporary Chinese societies: a comparative study of Taiwan, Hong Kong,
and China. Int. Sociol. 28, 277–296. doi: 10.1177/0268580913484345 October 2021 | Volume 12 | Article 738128 Frontiers in Psychology | www.frontiersin.org 11
|
https://openalex.org/W2785518238
|
http://jurnalpuitika.fib.unand.ac.id/index.php/jurnalpuitika/article/download/50/36
|
Indonesian
| null |
RELEVANSI GAMBAR DAN TUTURAN PADA KOMIK SHIN KOBOCHAN TINJAUAN PRAGMATIK
|
Puitika
| 2,017
|
cc-by-sa
| 5,789
|
ISSN 0854-871X Jurnal Puitika Volume 13 No. 1, April 2017 ISSN 0854-871X Jurnal Puitika Volume 13 No. 1, April 2017 Abstract This article discusses the relevance between the image and the
speech in Japanese. This study is a qualitative research that discusses
and explains the relevance between the image and the speech in strip
comic. The aims of this research to analyze the relevance between the
image and the speech that triggered the formation of story in strip
comic. The data of this study are taken from “Shin Kobochan” strip
comic by Masashi Ueda volume 28, 29 and 30, published in 2014 by
Houbunsha. The theories employed in this study are Sperber and
Wilson’s relevance theory, which aims to see the relevance between
the speech and the images in the form of humor utterances, Danesi
and Peron’s iconicity theory, Pierce’s theory of semiosis process,
which aim to interpret the images and Grice’s implicatures theory
which aims to reveal the implicit meaning of the utterances. The
results show that Images showing the speaker and hearer performing
certain activity are required in the process of understanding the
whole humor, so that the communicated meaning and the message
can be found. Key words: relevance, image, utterance, icons, and semiosis RELEVANSI GAMBAR DAN TUTURAN PADA KOMIK SHIN KOBOCHAN
TINJAUAN PRAGMATIK Idrus
Prodi Sastra Jepang, Fakultas Ilmu Budaya, Universitas Andalas
Email: idrus_unand@hotmail.com Abstrak Artikel ini membahas relevansi gambar dan tuturan bahasa
Jepang. Penelitian ini merupakan penelitian kualitatif yang
membahas dan memaparkan kaitan gambar dan tuturan dalam
komik strip bahasa Jepang. Tujuan penelitian ialah untuk
menganalisis relevansi gambar dan tuturan yang membentuk cerita
pada komik strip, dengan menganalisis makna gambar dan tuturan
yang mengandung implikatur pada komik strip dalam membentuk
cerita. Data penelitian ini ialah komik strip Shin Kobochan karya
Masashi Ueda jilid 28, 29, dan 30 yang diterbitkan pada tahun 2014
oleh penerbit Houbunsha. Teori yang dipakai ialah teori Relevansi
Sperber dan Wilson untuk melihat relevansi gambar dan tuturan,
ikonisitas Danesi dan Peron, serta teori proses semiosis Pierce
untuk memaknai gambar dan teori implikatur Grice untuk 32 ISSN 0854-871X Jurnal Puitika Volume 13 No. 1, April 2017 ISSN 0854-871X Jurnal Puitika Volume 13 No. 1, April 2017 mengungkapkan
makna
tersirat
tuturan. Hasil
penelitan
menunjukkan bahwa gambar memliki peran penting dalam
membentuk cerita. Gambar menampilkan penutur dan mitra tutur
melakukan suatu aktivitas tertentu yang mendukung jalan cerita
komik. Pendahuluan Scott Mccloud (1993:20) mendefinisikan komik sebagai gambar-gambar
atau lambang-lambang yang tersusun dalam urutan tertentu untuk
menyampaikan informasi dan mencapai tanggapan estetis dari pembacanya. Komik menggunakan dua alat komunikasi utama, yaitu gambar-gambar dan
kata-kata (Eisner, 1985:13). Fungsi dasar komik ialah untuk menyampaikan ide
dan atau cerita melalui kata-kata dan gambar yang dilibatkan dalam
pergerakan gambar-gambar tertentu melalui ruang (Eisner, 1985:38). Komik
juga menggunakan sekumpulan gambar berulang dan simbol-simbol yang
sudah dikenal (Eisner, 1985:8). Salah satu bentuk komik ialah komik strip yang dapat ditemukan di
koran-koran atau majalah. Komik strip yang dimuat di koran-koran atau
majalah tersebut digabungkan menjadi buku disebut buku komik (comic book)
yang secara umum lebih dikenal dengan sebutan komik (comic) saja. Pada
awalnya komik strip ditemukan dalam media cetak, tetapi pada era modern ini
komik strip juga sudah ditemukan di dunia maya dalam bentuk komik digital. Komik strip yang paling populer di Amerika Serikat berjudul Peanuts
yang diciptakan Charles Schults. Komik strip ini telah diterjemahkan ke dalam
24 bahasa dengan tokoh-tokohnya adalah Charlie Brown; saudara perempuan
Charlie, yaitu Sally, anjing dan burung Charlie yang dinamainya Snoopy dan
Woodstock, serta teman-teman Charlie, yaitu Lucy, Linus, Schroeder,
Peppermint Patty, dan Marcie (Danesi, 2004:158). Di Jepang, ada komik strip
Kobochan, Kariagenkun yang dikarang oleh Masashi Ueda. Komik strip Kobochan merupakan salah satu komik bergenre humor
yang populer di Jepang. Komik strip ini pertama kali dimuat di harian Yomiuri
Shinbun pada tahun 1982. Versi buku komik (comic book) yang dalam bahasa
Jepang disebut tankoubon diterbikan oleh penerbit Soyosha, lalu komik
Kobochan versi baru diterbitkan oleh penerbit Houbunsha dengan judul Shin
Kobochan. Tokoh-tokoh utama yang menjadi penutur dalam komik ini ialah
Kobo Tabata, Sanae Tabata, Koji Tabata, Miho Tabata, Iwao Yamakawa, dan
Mine Yamakawa. Komik ini bercerita tentang kehidupan sehari-hari keluarga
Kobo yang terdiri atas tiga generasi yang terdiri atas kakek-nenek, orang tua,
dan anak-anak yang sudah jarang dapat ditemukan saat ini. Cerita dalam komik strip Shin Kobochan ini mengangkat tema-tema
yang sederhana dengan cara yang tidak sederhana karena diperlukan 33 ISSN 0854-871X Jurnal Puitika Volume 13 No. 1, April 2017 pemahaman dan pembacaan yang berulang-ulang untuk dapat memahami
ceritanya. Masalah dikaji secara mendalam sehingga dapat memperluas
wawasan pembaca. Dalam hal ini, kekuatan komik strip Kobochan terletak pada
tuturan tokoh yang diungkapkan secara implisit menggunakan implikatur
percakapan. Pendahuluan Pada penelitian ini, dipilih komik sebagai objek karena di dalam komik
kita dapat melihat diri kita sebagaimana yang dikemukakan oleh Mccloud
(1993,36) bahwa ketika kamu masuk dalam dunia kartun, kamu akan melihat
dirimu sendiri. Gambar pada komik berupa gambar abstrak yang dapat diisi
sendiri oleh pembaca. Hal ini juga dipercayai sebagai penyebab utama
anak-anak ‘tergila-gila’ pada komik. Duncan dan Smith (2009:13—17)
menjelaskan empat alasan perlunya komik diteliti, yaitu (1) komik merupakan
bentuk komunikasi yang unik dan potensial karena komik menyampaikan
suatu cerita dan melibatkan pembaca dengan cara-cara yang tidak dapat ditiru
oleh bentuk seni lain (novel atau film), (2) komik merupakan bentuk karya
sastra baru karena kata-kata dan gambar dibaca sebagai teks yang terintegrasi,
(3) komik memiliki sejarah yang panjang, dan (4) komik merupakan media
komunikasi yang potensial karena apa pun dapat dilakukan menggunakan
kata-kata dan gambar. Dalam kehidupan manusia, bahasa digunakan sebagai alat komunikasi
untuk memaparkan keinginan, pikiran, hasrat, dan maksud kepada mitra tutur
untuk memenuhi tujuan tertentu. Dalam penelitian ini, makna hal-hal tersebut
diperoleh dengan memaknai bahasa, dalam hal ini tuturan, yang digunakan di
dalam komik strip Shin Kobochan. Cerita pada komik strip Shin Kobochan tidak
hanya digulirkan dengan teks (tuturan), tetapi juga dengan gambar. Tuturan
dan gambar tersebut dipisahkan oleh panel-panel. Oleh karenanya, untuk
memahami cerita secara keseluruhan diperlukan analisis keterpaduan gambar
dan tuturan pada komik tersebut. Berdasarkan latar belakang di atas, peneliti menganggap perlu adanya
penelitian untuk mengetahui relevansi gambar dan tuturan pada komik. Pada
penelitian ini, gambar dan tuturan-tuturan dalam komik strip Shin Kobochan
dianalisis untuk mengungkapkan makna tersirat percakapan tokoh-tokohnya. Gambar dalam komik strip Shin Kobochan dianalisis untuk pengungkapan
makna tersirat sebagai konteks tuturan para penutur. Pengungkapan makna
tersirat percakapan itu bertujuan untuk menemukan kaitan setiap tuturan yang
membentuk cerita.Hasil penelitian ini bermanfaat dalam mengetahui dan
memahami, serta memaknai makna tersirat percakapan pada komik strip
bahasa Jepang. Teori Relevansi Teori Relevansi yang berkaitan dengan komunikasi menurut Sperber dan
Wilson
(1995:158)
berbunyi,
“Every
act
of
ostensive
communication
communicates a presumption of its own optimal relevance”. ‘Setiap tindakan 34 ISSN 0854-871X Jurnal Puitika Volume 13 No. 1, April 2017 komunikasi
ostensif
mengomunikasikan
anggapan
tentang
relevansi
optimalnya sendiri’. Sperber dan Wilson (1995:194—195) dalam Teori Relevansi
menuntun petutur dengan menjelaskan langkah-langkah yang harus dilakukan
untuk mengidentifikasi maksud penutur, yaitu: a. merumuskan hipotesis yang cocok mengenai asumsi kontekstual yang
dimaksud (dalam teori relevansi disebut premis yang diimplikasikan); a. merumuskan hipotesis yang cocok mengenai asumsi kontekstual yang
dimaksud (dalam teori relevansi disebut premis yang diimplikasikan); b. merumuskan hipotesis yang cocok mengenai implikasi kontekstual yang
dimaksud
(dalam
teori
relevansi
disebut
kesimpulan
yang
diimplikasikan). Sperber dan Wilson (1995:108) juga mengemukakan bahwa suatu
implikasi kontekstual ialah informasi baru dalam arti bahwa informasi tersebut
tidak diambil dari persediaan asumsi-asumsi yang ada. Dengan demikian, hal
ini bukan hanya informasi baru karena juga bukan suatu implikasi analitis
ataupun sintetis dari informasi yang baru disajikan. Hal ini merupakan suatu
sintetis dari informasi lama dan baru, suatu hasil interaksi antara keduanya. Proses Semiosis Prinsip dasar pemikiran Peirce ialah tanda bersifat representatif, yaitu
tanda merupakan sesuatu yang mewakili sesuatu yang lain. Pemaknaan tanda
terjadi dalam proses yang disebut proses semiosis. Peirce (dalam Nth,
1995:39—47) menggambarkan bahwa proses itu dimulai dengan masuknya
unsur tanda yang berada di luar ke dalam indera manusia, yaitu representamen
atau ground. Jika proses penginderaan sudah terjadi, proses selanjutnya di
dalam kognisi manusia ialah pengacuan pada apa yang disebutnya objek, yakni
hal yang diwakili oleh representamen. Proses selanjutnya ialah interpretan,
yaitu saat kita memberikan penafsiran berkaitan dengan situasi tempat kita
berada. Interpretan mempengaruhi perilaku kita dalam situasi tertentu. Peirce (dalam Merrell, 2001:28) menjelaskan proses pemaknaan tanda
mengikuti hubungan antara representamen (R), objek (O), dan interpretan (I). Proses pemaknaan tanda dari representamen, objek, dan interpretan yang
disebut semiosis itu terjadi dengan sangat cepat dalam pikiran manusia. Karena
sebenarnya yang diindera ialah representamen yang seringkali disebut tanda. Lebih jelas lagi mengenai proses semiosis, dapat dilihat pada bagan di bawah
ini. O 1
O2
R 1
I 1 = R 2
I 2 = R3
Keterangan: R : representamen
O : objek I: interpretan
Bagan Proses Semiosis
(Sumber: Hoed 2011:157)
Merujuk pada teori Peirce, tanda-tanda dalam gambar dapat dilihat dari
enis tanda yang digolongkan dalam semiotik. Teori Proses Semiosis dipakai
untuk menganalisis makna tanda yang pada penelitian ini berbentuk ikon. O 1
O2
R 1
I 1 = R 2
I 2 = R3
Keterangan: R : representamen
O : objek I: interpretan
Bagan Proses Semiosis
(Sumber: Hoed 2011:157) O 1 Bagan Proses Semiosis
(Sumber: Hoed 2011:157) Bagan Proses Semiosis
(Sumber: Hoed 2011:157) Merujuk pada teori Peirce, tanda-tanda dalam gambar dapat dilihat dari
jenis tanda yang digolongkan dalam semiotik. Teori Proses Semiosis dipakai
untuk menganalisis makna tanda yang pada penelitian ini berbentuk ikon. Merujuk pada teori Peirce, tanda-tanda dalam gambar dapat dilihat dari
jenis tanda yang digolongkan dalam semiotik. Teori Proses Semiosis dipakai
untuk menganalisis makna tanda yang pada penelitian ini berbentuk ikon. Ikonisitas Ikon merupakan tanda yang tercipta sebagai referen melalui berbagai
bentuk, seperti replikasi, simulasi, imitasi, dan kemiripan (Danesi dan Peron
1999:85). Ikonisitas melimpah ruah dalam semua wilayah representasi manusia. Potret, peta, angka romasi, seperti I, II, dan II merupakan wujud ikonis yang
dirancang atau diciptakan agar mirip dengan sumber acuannya secara visual. Parfum adalah ikon penciuman yang meniru wangi alamiah. Zat tambahan
makanan kimiawi adalah ikon pengecap yang menstimulasi rasa makanan
alamiah. Berdasarkan definisi ikon yang dikemukakan Danesi dan Peron di atas,
dapat diketahui bahwa gambar-gambar pada komik merupakan salah satu
bentuk ikon. Tokoh orang atau binatang digambarkan menyerupai manusia
atau binatang yang sesungguhnya. Properti atau benda-benda yang ada di
dalamnya juga dibuat dengan mengacu pada bentuk yang sesungguhnya di
dunia nyata. Dialog dan onomatope yang terdapat pada komik juga merupakan
representasi dari tuturan para tokoh atau penggambaran keadaan yang menjadi
setting cerita. Danesi (2004:29) menyatakan bahwa ikon ini memiliki fungsi
komunikasi ketika interaksi vokal tidak memungkinkan atau terbatas. Ikon
pada komik menurut Mccloud (1994:27) merupakan segala bentuk gambar yang
digunakan untuk merepresentasikan orang, tempat, benda, atau ide. Gambar-gambar pada komik dibentuk melalui penyederhanaan dengan tidak
terlalu banyak menghilangkan detil-detilnya karena pengarang fokus pada
detil-detil tertentu. Ikonisitas digunakan untuk menganalisis data ikonis untuk mendukung
analisis data tuturan. Hasil analisis data ikonis ini ialah makna perilaku atau
makna ekspresi atau gambar yang terdapat pada komik strip. 35 ISSN 0854-871X Jurnal Puitika Volume 13 No. 1, April 2017 Teori Implikatur Implikatur merupakan suatu komponen makna dari penutur yang
menjadi bagian dari aspek yang dimaksudkan dalam suatu tuturan tanpa
menjadi apa yang disebutkan (Horn dan Ward, 2006:3). Grice (1975:43—45)
membedakan dua macam implikatur, yaitu implikatur konvensional dan
implikatur nonkonvensional (implikatur percakapan). Implikatur konvensional
adalah implikatur yang diperoleh langsung dari makna kata dan bukan dari
prinsip percakapan. Implikatur nonkonvensional atau impilkatur percakapan
adalah implikasi pragmatis yang tersirat dalam suatu percakapan. Implikasi
pragmatis berbeda dari fungsi pragmatis yang disajikan secara eksplisit oleh
tuturan. Dalam tuturan percakapan, terimplikasi suatu maksud atau tersirat
fungsi pragmatis yang dinamakan implikatur percakapan. Grice juga 36 ISSN 0854-871X Jurnal Puitika Volume 13 No. 1, April 2017 membedakan implikatur percakapan atas implikatur percakapan khusus yang
berlaku pada konteks tertentu dan implikatur percakapan umum yang berlaku
pada semua konteks. Teori implikatur ini digunakan dalam proses pemahaman tuturan yang
tidak selalu mudah dan sederhana karena proses pemahaman melibatkan unsur
bahasa dan luar bahasa, yaitu konteks dan situasi. Hal ini disebabkan oleh
fungsi komunikasi yang tidak hanya upaya penyampaian pesan atau informasi. Metode Penelitian Penelitian yang berjudul “Relevansi Gambar dan Tuturan pada Komik
Shin Kobochan Tinjauan Pragmatik” ini merupakan penelitian yang
dilaksanakan dengan metode kualitatif. Creswell (2003:74) menyatakan bahwa
penelitian kualitatif paling tepat digunakan dalam memahami serta
mengeksplorasi suatu konsep atau fenomena. Data pada penelitian ini ialah komik strip Kobochan karya Masashi Ueda
yang dimuat setiap hari di harian Yomiuri Shinbun mulai dari tahun 1982
sampai saat ini (Thompson, 2007). Akan tetapi, yang digunakan pada penelitian
ini ialah komik strip Kobochan yang sudah digabungkan dalam bentuk buku
komik, yaitu Shin Kobochan jilid 28, 29, dan 30 yang diterbitkan masing-masing
bulan Februari, Juli, dan November 2014 oleh penerbit Houbunsha. Setiap jilid
terdiri atas 126 cerita sehingga jumlah data dari ketiga komik ini ialah 378 cerita. Dengan demikian, dapat dikatakan komik strip Shin Kobochan jilid 28, 29, dan
30 tersebut merupakan cerita kehidupan keluarga Kobochan selama lebih
kurang setahun. Teknik pengumpulan data menggunakan metode simak. Menyimak
merupakan langkah awal yang dilakukan dengan membaca dan mempelajari
dengan seksama objek yang diteliti, yaitu humor pada komik strip Shin
Kobochan. Data diambil secara utuh, lalu difotokopi dan dipindai untuk dapat
diolah. Data yang terjaring dari sumber data selanjutnya diolah. Pengolahan
data diawali dengan penerjemahan data menggunakan teknik terjemahan
bebas dengan tujuan untuk mempermudah memahami cerita. Uraian tahapan analisis data penelitian ini dilakukan melalui
tahapan-tahapan di bawah ini: 1) Gambar yang terdapat pada masing-masing strip dianalisis maknanya
sehingga didapatkan makna gambar. 1) Gambar yang terdapat pada masing-masing strip dianalisis maknanya
sehingga didapatkan makna gambar. ungkapan implikatur tuturan dan teks lain yang terdapat pada komik. 2) Pengungkapan implikatur tuturan dan teks lain yang terdapat pada komik. 3) Analisis relevansi gambar dan tuturan untuk mengetahui dan memahami
cerita komik. Analisis Relevansi Gambar dan Tuturan pada Komik Shin Kobochan Analisis Relevansi Gambar dan Tuturan pada Komik Shin Kobochan Analisis Relevansi Gambar dan Tuturan pada Komik Shin Kobochan
Berikut ini dianalisis relevansi gambar dan tuturan pada Komik Shin
Kobochan. Berikut ini dianalisis relevansi gambar dan tuturan pada Komik Shin
Kobochan. 37 ISSN 0854-871X Jurnal Puitika Volume 13 No. 1, April 2017 Data 1
Miho: Aku saja yang melakukan!! Kakek: Kamu anak 3 tahun yang ingin
mengerjakan apa pun ya. (ting tong)
Kakek: Terima kasih. Kakek: Mau coba dorong? Kakek: Masih belum paham soal hanko ya? Data 1
Miho: Aku saja yang melakukan!! Kakek: Kamu anak 3 tahun yang ingin
mengerjakan apa pun ya. (ting tong)
Kakek: Terima kasih. Kakek: Mau coba dorong? Kakek: Masih belum paham soal hanko ya? Analisis gambar yang terdapat pada setiap strip data di atas ialah:
objek
representamen
Miho berkeinginan
melakukan
bermacam hal
sendiri. Interpretan
Strip 1
Miho membuka/
menutup botol. Miho mandiri. Strip 2
Kakek memegang
paket. Seseorang
mengirimkan paket
kepada kakek. Kakek menerima
paket. Strip 3
Miho di belakang
kakek. Miho mengikuti
kakek. Miho ingin
menerima paket. Strip 4
Badan kakek miring. Tangan Miho
mengarah ke depan. Miho mendorong
kakek. Miho ingin mandiri dengan melakukan bermacam hal sendirian. Ketika
kakek menerima paket yang dikirimkan seseorang kepadanya, Miho pun ingin
menerima paket dengan mengikuti kakek di belakang. Miho mendorong kakek
ketika disuruh membubuhkan hanko pada surat tanda terima. Data 1 Kakek: Mau coba dorong? Analisis gambar yang terdapat pada setiap strip data di atas ialah:
objek
representamen
Miho berkeinginan
melakukan
bermacam hal
sendiri. Interpretan
Strip 1
Miho membuka/
menutup botol. Miho mandiri. Strip 2
Kakek memegang
paket. Seseorang
mengirimkan paket
kepada kakek. Kakek menerima
paket. Strip 3
Miho di belakang
kakek. Miho mengikuti
kakek. Miho ingin
menerima paket. Strip 4
Badan kakek miring. Tangan Miho
mengarah ke depan. Miho mendorong
kakek. Analisis gambar yang terdapat pada setiap strip data di atas ialah:
objek
representamen
Miho berkeinginan
melakukan
bermacam hal
sendiri. Interpretan
Strip 1
Miho membuka/
menutup botol. Miho mandiri. Strip 2
Kakek memegang
paket. Seseorang
mengirimkan paket
kepada kakek. Kakek menerima
paket. Strip 3
Miho di belakang
kakek. Miho mengikuti
kakek. Miho ingin
menerima paket. Strip 4
Badan kakek miring. Tangan Miho
mengarah ke depan. Miho mendorong
kakek. Miho ingin mandiri dengan melakukan bermacam hal sendirian. Ketika
kakek menerima paket yang dikirimkan seseorang kepadanya, Miho pun ingin
menerima paket dengan mengikuti kakek di belakang. Miho mendorong kakek
ketika disuruh membubuhkan hanko pada surat tanda terima. Miho ingin mandiri dengan melakukan bermacam hal sendirian. 1 「
お
,押す」osu dalam bahasa Jepang dapat berarti mendorong/menekan atau
membubuhkan. Analisis Relevansi Gambar dan Tuturan pada Komik Shin Kobochan 1, April 2017 (2) Kakek:
ごくろうさま
gokurousama
‘Terima kasih.’ (2) Kakek:
ごくろうさま
gokurousama
‘Terima kasih.’ Analisis Relevansi Gambar dan Tuturan pada Komik Shin Kobochan Ketika
kakek menerima paket yang dikirimkan seseorang kepadanya, Miho pun ingin
menerima paket dengan mengikuti kakek di belakang. Miho mendorong kakek
ketika disuruh membubuhkan hanko pada surat tanda terima. 38 ISSN 0854-871X Jurnal Puitika Volume 13 No. 1, April 2017 Analisis tuturan-tuturan yang terdapat pada setiap strip data di atas:
strip 1
(1) (a) Miho : あたしがやるの!! atashi ga yaru no!! ‘Aku saja yang melakukan!!’
(b) Kakek:
なんでもやりたがる三歳児
さんさいじ
nan demo yaritagaru sansaiji
‘Kamu anak 3 tahun yang mau mengerjakan apa
pun ya.’ Analisis tuturan-tuturan yang terdapat pada setiap strip data di atas:
strip 1 Analisis tuturan-tuturan yang terdapat pada setiap strip data di atas:
strip 1 (1) (c)
ピンポーン
pin pong
‘ting tong’ Pada tuturan (1a)「あたしがやるの!!」‘Aku saja yang melakukan!’, Miho
mengatakan bahwa dia ingin membuka/menutup botol sendiri tanpa bantuan
kakek atau nenek. Penggunaan shuujoshi 「の」‘no’ menunjukkan besarnya
tekad Miho untuk membuka atau menutup tutup botol tanpa bantuan orang
lain. Hal ini juga diperkuat oleh tuturan kakek (1b) 「なんでもやりたがる
三歳児
さんさいじ
」‘Kamu anak 3 tahun yang mau mengerjakan apa pun ya’. Implikasi
kontekstual dari tuturan ini ialah bukan hanya membuka atau menutup botol,
Miho juga berkeinginan mencoba melakukan hal-hal lain. Teks (1c) 「ピンポー
ン」‘ting tong’ merupakan onomatope untuk bunyi bel. Asumsi kontekstual dari
bel yang berbunyi ialah seseorang yang menekan bel sehingga ada bel berbunyi. Implikasi kontekstual yang dilibatkan ialah ada seseorang yang mau bertamu
ke rumah. Orang tersebut menekan bel sebab ada maksud ingin bertemu
dengan pemilik rumah karena suatu keperluan tertentu. Pada tuturan (1a)「あたしがやるの!!」‘Aku saja yang melakukan!’, Miho
mengatakan bahwa dia ingin membuka/menutup botol sendiri tanpa bantuan
kakek atau nenek. Penggunaan shuujoshi 「の」‘no’ menunjukkan besarnya
tekad Miho untuk membuka atau menutup tutup botol tanpa bantuan orang
lain. Hal ini juga diperkuat oleh tuturan kakek (1b) 「なんでもやりたがる
さんさいじ lain. Hal ini juga diperkuat oleh tuturan kakek (1b) 「なんでもやりたがる
三歳児
さんさいじ
」‘Kamu anak 3 tahun yang mau mengerjakan apa pun ya’. Implikasi
kontekstual dari tuturan ini ialah bukan hanya membuka atau menutup botol,
Miho juga berkeinginan mencoba melakukan hal-hal lain. Teks (1c) 「ピンポー
ン」‘ting tong’ merupakan onomatope untuk bunyi bel. Asumsi kontekstual dari
bel yang berbunyi ialah seseorang yang menekan bel sehingga ada bel berbunyi. Implikasi kontekstual yang dilibatkan ialah ada seseorang yang mau bertamu
ke rumah. Orang tersebut menekan bel sebab ada maksud ingin bertemu
dengan pemilik rumah karena suatu keperluan tertentu. strip 2 39 39 ISSN 0854-871X Jurnal Puitika Volume 13 No. (2) Kakek: Pada strip 2 ini, kakek mengatakan (2)「ごくろうさま」‘Terima kasih’
kepada petugas pos. Tuturan ini mengandung implikasi ‘Saya berterima kasih
karena Anda sudah bekerja keras sehingga kiriman ini dapat sampai di sini
(alamat/tujuan)’. Dengan kata lain, petugas pos sudah melakukan perbuatan
jasa, yaitu membawakan kiriman dari alamat pengirim ke alamat tujuan
pengiriman. strip 3
(3) Kakek:
押
お
して1みるか? oshite miru ka? ‘Mau coba tekan?’ (3) Kakek:
押
お
して1みるか? oshite miru ka? ‘Mau coba tekan?’ (3) Kakek:
押
お
して1みるか? oshite miru ka? ‘Mau coba tekan?’ Asumsi kontekstual dari menerima kiriman ialah memberikan
pernyataan sudah meneriman kiriman. Surat pernyataan menerima kiriman
pada strip 3 ini dapat dilihat masih tertempel di atas kiriman tersebut yang
mesti ditanda-tangani atau distempel dengan hanko/inkan. Kakek menawari
Miho untuk membubuhkan 「ハンコ」hanko ‘stempel’ pada surat pernyataan
menerima kiriman dengan mengatakan (3)「押
お
してみるか?」‘Mau coba dorong?’
karena kakek mengetahui bahwa pada strip 1 Miho berkeinginan melakukan
bermacam-macam hal. Keberadaan Miho yang selalu mengikuti kakek di
belakang kakek menguatkan asumsi Miho ingin membubuhkan stempel. Asumsi kontekstual dari menerima kiriman ialah memberikan
pernyataan sudah meneriman kiriman. Surat pernyataan menerima kiriman
pada strip 3 ini dapat dilihat masih tertempel di atas kiriman tersebut yang
mesti ditanda-tangani atau distempel dengan hanko/inkan. Kakek menawari
Miho untuk membubuhkan 「ハンコ」hanko ‘stempel’ pada surat pernyataan menerima kiriman dengan mengatakan (3)「押
お
してみるか?」‘Mau coba dorong?’
karena kakek mengetahui bahwa pada strip 1 Miho berkeinginan melakukan
bermacam-macam hal. Keberadaan Miho yang selalu mengikuti kakek di
belakang kakek menguatkan asumsi Miho ingin membubuhkan stempel. strip 4
(4) Kakek:
ハンコはまだ理解
りかい
してないのね
hanko wa mada rikai shite nai no ne
‘Masih belum paham soal hanko/inkan (stempel) ya?’ strip 4 hanko wa mada rikai shite nai no ne ‘Masih belum paham soal hanko/inkan (stempel) ya?’ 40 ISSN 0854-871X Jurnal Puitika Volume 13 No. 1, April 2017 2 「ハンコ」hanko merupakan stempel pengganti tanda tangan dalam budaya Jepang. ISSN 0854-871X Jurnal Puitika Volume 13 No. 1, April 2017 Pada strip 4 ini, terdapat gambar Miho mendorong kakek yang
memegang hanko/inkan2. Merespon tindakan Miho ini, kakek berkata (4)「ハン
コはまだ理解
りかい
してないのね」‘Masih belum paham soal hanko/inkan (stempel)
ya?’ Asumsi kontekstual 「押
お
す」osu menurut Miho ialah mendorong kakek
sehingga tanpa pikir panjang Miho langsung mendorong tubuh kakek dari
belakang. Sementara itu, asumsi kontekstual 「押
お
す」osu menurut kakek ialah
Miho memegang hanko/inkan dengan tangannya lalu membubuhkan
hanko/inkan tersebut pada surat pernyataan. Relevansi gambar pada pada strip 1 memperlihatkan bahwa Miho tidak
mau dibantu dalam hal membuka/menutup tutup botol yang menunjukkan
bahwa Miho dapat melakukan apa pun. Pada strip 4, terdapat gambar badan
kakek yang miring karena Miho mendorong Kakek agar hanko/inkan di tangan
kakek menempel pada surat pernyataan. Relevansi gambar pada strip 4 ini
menunjukkan bahwa Miho tidak mengetahui cara membubuhkan hanko/inkan. Kakek mengharapkan hanko/inkan di tangan kakek diambil oleh Miho lalu
ditempelkan ke surat pernyataan. Data 2 Data 2 Analisis gambar yang terdapat pada setiap strip pada data di atas adalah:
objek
representamen
Bunyi benturan stick
golf dengan bola. Interpretan
Strip 1
Onomatope: コン
Pukulan papa tepat. Strip 2
Onomatope: パチパ
チパチ
Kobo dan Miho
bertepuk tangan. Papa hebat. Strip 3
Papa mengambil
bola. Bola masuk ke
dalam lubang. Papa hebat. 2 「ハンコ」hanko merupakan stempel pengganti tanda tangan dalam budaya Jepang
Tung
Papa : Kalau di rumah
masuk berkali-kali ya
Plok plok plok
Papa : Ini kalau di
lapangan golf dilihat
orang-orang makanya
nggak masuk. Kobo : Ayo papa, latihan,
latihan. Tung
Papa : Kalau di rumah
masuk berkali-kali ya
Plok plok plok
Papa : Ini kalau di
lapangan golf dilihat
orang-orang makanya
nggak masuk. Kobo : Ayo papa, latihan,
latihan. Papa : Kalau di rumah
masuk berkali-kali ya
Plok plok plok Papa : Kalau di rumah
masuk berkali-kali ya
Plok plok plok Kobo : Ayo papa, latihan,
latihan. Analisis gambar yang terdapat pada setiap strip pada data di atas adalah:
objek
representamen
Bunyi benturan stick
golf dengan bola. Interpretan
Strip 1
Onomatope: コン
Pukulan papa tepat. Strip 2
Onomatope: パチパ
チパチ
Kobo dan Miho
bertepuk tangan. Papa hebat. Strip 3
Papa mengambil
bola. Bola masuk ke
dalam lubang. Papa hebat. 2 「ハンコ」hanko merupakan stempel pengganti tanda tangan dalam budaya Jepang 41 ISSN 0854-871X Jurnal Puitika Volume 13 No. 1, April 2017 Ayunan stick golf papa tepat memukul bola sehingga bola masuk ke
dalam lubang. Melihat hal ini, Kobo dan Miho memberi apresiasi terhadap
kehebatan papa tersebut. ISSN 0854-871X Jurnal Puitika Volume 13 No. 1, April 2017 Namun, papa tidak mau latihan bermain golf di
depan gerbang rumah. Papa malu kalau nanti ayunan stick golfnya tidak dapat
memasukkan bola. Analisis tuturan-tuturan yang terdapat pada setiap strip data di atas:
strip 1 Analisis tuturan-tuturan yang terdapat pada setiap strip data di atas:
strip 1
(1) コン
kon
‘tung’ Pada strip 1 ini terdapat gambar Kobo dan Miho yang melihat papa
sedang latihan golf di rumah. Bunyi (1)「コン」‘tung’ merupakan onomatope
tiruan bunyi pukulan atau benturan stick golf ke bola golf. Asumsi kontekstual
dari gambar papa yang latihan golf ini ialah latihan golf dapat dilakukan di
rumah menggunakan alat bantu latihan golf tertentu. strip 2
(2) (a) Papa:
うちだといくらでも入
はい
るんだよね
uchi da to ikura demo hairu n da yo ne
‘Kalau di rumah masuk berkali-kali ya.’ (2) (a) Papa:
うちだといくらでも入
はい
るんだよね
uchi da to ikura demo hairu n da yo ne
‘Kalau di rumah masuk berkali-kali ya.’ (b) パチパチパチ
pochi pochi pochi
‘plok plok plok’ Papa mengatakan tuturan (2a) 「うちだといくらでも入
はい
るんだよね」
‘Kalau di rumah masuk berkali-kali ya’. Implikasi kontekstual dari tuturan papa
ini ialah papa mau memperlihatkan bahwa dirinya mahir bermain golf karena
setiap kali memukul bola golf selalu dapat masuk ke lubangnya. Kemahiran 42 ISSN 0854-871X Jurnal Puitika Volume 13 No. 1, April 2017 papa memasukkan bola golf ini mendapatkan tepuk tangan/applause dari Kobo
dan Miho. Bunyi tepuk tangan Kobo dan Miho dinyatakan dengan dengan
onomatope (2b)「パチパチパチ」‘plok plok plok’. strip 3
(3) Papa:
これがゴルフ場
じょう
でみんなに見
み
られてると入
はい
らないんだ
kore ga gorufujou de wa minna ni mirareru to hairanai n da
‘Ini kalau di lapangan golf dilihat orang-orang makanya nggak
masuk.’ strip 3
これがゴルフ場
じょう
でみんなに見
み
られてると入
はい (3) Papa: p
kore ga gorufujou de wa minna ni mirareru to hairanai n da
‘Ini kalau di lapangan golf dilihat orang-orang makanya nggak
masuk.’ Tuturan pada strip 3 ini merupakan alasan kenapa papa tidak dapat
memasukkan bola di lapangan golf, yaitu (3)「これがゴルフ場
じょう
でみんなに見
み
ら
れてると入
はい
らないんだ」‘Ini kalau di lapangan golf dilihat orang-orang makanya
nggak masuk’. Asumsi kontekstual dari tuturan ini ialah papa grogi kalau
dilihat oleh orang. Padahal, itu hanya alasan yang dibuat-buat untuk menutupi
ketidakmahiran papa dalam bermain golf. Implikasi kontekstualnya ialah papa
perlu latihan sehingga semakin mahir. Berdasarkan tuturan papa tersebut, papa
harus latihan di hadapan banyak orang agar terbiasa dengan suasana
diperhatikan oleh orang-orang. ISSN 0854-871X Jurnal Puitika Volume 13 No. 1, April 2017 strip 4
(4) Kobo:
ホラパパー練習練習
れんしゅうれんしゅう
hora papa- renshuu renshuu
‘Ayo papa latihan latihan ’ strip 4 (4) Kobo:
ホラパパー練習練習
れんしゅうれんしゅう
hora papa- renshuu renshuu ‘Ayo papa, latihan, latihan.’
れん Pada strip 4, Kobo menyuruh papa 「練習
れんしゅう
」‘latihan’ dengan mengatakan (4
れんしゅうれんしゅう Pada strip 4, Kobo menyuruh papa 「練習
れんしゅう
」‘latihan’ dengan mengatakan (4)
「ホラパパー練習練習
れんしゅうれんしゅう
」‘Ayo papa, latihan, latihan’. Berdasarkan gambar,
dapat diketahui bahwa Kobo memindahkan alat latihan golf papa ke depan
「練習
れんしゅう pintu gerbang rumah, lalu menyuruh papa 「練習
れんしゅう
」‘latihan’ di sana. Kobo
berasumsi bahwa rasa grogi yang menyebabkan papa tidak dapat memasukkan
れんしゅう pintu gerbang rumah, lalu menyuruh papa 「練習」‘latihan’ di sana. Kobo
berasumsi bahwa rasa grogi yang menyebabkan papa tidak dapat memasukkan
れんしゅう dapat dihilangkan dengan latihan. Asumsi kontekstual 「練習
れ
ゅう
」‘latihan’ di
depan gerbang rumah dilihat oleh orang-orang yang lewat. Penggambaran dapat dihilangkan dengan latihan. Asumsi kontekstual 「練習」‘latihan’ di
depan gerbang rumah dilihat oleh orang-orang yang lewat. Penggambaran 43 ISSN 0854-871X Jurnal Puitika Volume 13 No. 1, April 2017 ISSN 0854-871X Jurnal Puitika Volume 13 No. 1, April 2017 orang-orang yang lewat di depan rumah ini yang tidak detil menunjukkan
bahwa
orang-orang
itu
bukanlah
orang-orang
yang
dikenal. Lalu,
penggambaran papa yang tertutup tembok rumah menggoyangkan tangan
menandakan tidak mau 「練習
れんしゅう
」‘latihan’ diperhatikan/dilihat orang-orang
yang lewat di jalan depan rumah. Implikasi kontekstualnya ialah latihan di
depan rumah memalukan. Relevansi papa yang berada di balik dinding pagar berkaitan papa malu
dilihat orang ketika main golf yang dapat dilihat dari gambar papa yang
bersembunyi di balik pagar rumah dan menolak 「練習
れんしゅう
」‘latihan’ golf dengan
melambaikan tangannya pada strip 4. Padahal, Kobo ingin papa latihan
bermain dilihat banyak orang sehingga tidak grogi lagi sehingga di permainan
golf yang sesungguhnya dapat memasukkan bola golf ke lubangnya dengan
baik. Data 3
Miho : Miho yang kerjakan. Mama : Nggak boleh, nggak boleh. Miho : Miho yang kerjakan. Mama : Mana bisa. (nguuung)
Miho : Aku mau membantu pekerjaan
mama! Aku pulang. Kobo : (Kamu) Disuruh melihat apa aku
benar-benar mengerjakan PR? Kobo
:
Pekerjaan
yang
sangat
membosankan ya. Analisis gambar yang terdapat pada setiap strip pada data di atas adalah:
objek
representamen
Menyetrika perlu
keahlian. Interpretan
Strip 1
Mama menyetrika. Miho tidak
diizinkan
menyetrika. Strip 2
Mama
membersihkan
Mengoperasikan
vacuum cleaner pelu
Miho tidak
diperbolehkan Data 3
Miho : Miho yang kerjakan. Mama : Nggak boleh, nggak boleh. Miho : Miho yang kerjakan. ISSN 0854-871X Jurnal Puitika Volume 13 No. 1, April 2017 Mama : Mana bisa. (nguuung)
Miho : Aku mau membantu pekerjaan
mama! Aku pulang. Kobo : (Kamu) Disuruh melihat apa aku
benar-benar mengerjakan PR? Kobo
:
Pekerjaan
yang
sangat
membosankan ya. Data 3 y
g
j
Mama : Nggak boleh, nggak boleh. Miho : Miho yang kerjakan. Mama : Mana bisa. (nguuung) Analisis gambar yang terdapat pada setiap strip pada data di atas adalah:
objek
representamen
Menyetrika perlu
keahlian. Interpretan
Strip 1
Mama menyetrika. Miho tidak
diizinkan
menyetrika. Strip 2
Mama
membersihkan
Mengoperasikan
vacuum cleaner pelu
Miho tidak
diperbolehkan Analisis gambar yang terdapat pada setiap strip pada data di atas adalah:
objek
representamen
Menyetrika perlu
keahlian. Interpretan
Strip 1
Mama menyetrika. Miho tidak
diizinkan
menyetrika. Strip 2
Mama
membersihkan
Mengoperasikan
vacuum cleaner pelu
Miho tidak
diperbolehkan 44 ISSN 0854-871X Jurnal Puitika Volume 13 No. 1, April 2017 rumah dengan
vacuum cleaner. kekuatan. mengoperasikan
vaccum cleaner. Strip 3
Alis Miho naik
ketika berbicara
Miho serius. Miho benar-benar
ingin membantu
mama. Strip 4
Miho berpangku
tangan mengawasi
Kobo. Miho tidak
melakukan apa-apa. Miho bosan. Miho tidak diizinkan menyetrika pakaian karena untuk menyetrika
pakaian itu diperlukan keahlian. Keahlian yang dibutuhkan itu berkaitan
dengan kemampuan mengatur panas setrika sesuai dengan bahan pakaian dan
cara melipat pakaian. Miho juga tidak diperbolehkan mengoperasikan vacuum
cleaner untuk membersihkan rumah karena untuk mengoperasikan vacuum
cleaner diperlukan kekuatan karena mesin vacuum cleaner itu besar dan berat. Meskipun begitu, Miho tetap ingin membantu mama sehingga ketika disuruh
mengerjakan sesuatu yang ditugaskan mama Miho merasa bosan. Analisis tuturan-tuturan yang terdapat pada setiap strip data di atas:
strip 1 Analisis tuturan-tuturan yang terdapat pada setiap strip data di atas:
strip 1 Analisis tuturan-tuturan yang terdapat pada setiap strip data di atas:
strip 1 Analisis tuturan-tuturan yang terdapat pada setiap strip data di atas:
t i (1) (a) Miho: ミホがやる
miho ga yaru
‘Miho yang kerjakan.’ Pada strip 1, Miho mengatakan (1a) 「ミホがやる」 ‘Miho yang
mengerjakan’ ketika melihat mama menyetrika pakaian. Mama melarang
dengan menjawab (1b)「だめだめ」’Nggak boleh, nggak boleh’. Asumsi
kontekstual dari setrika yang menyala ialah panas. Panasnya setrika
digambarkan dengan garis bergelombang yang menunjukkan hawa panas yang
berbahaya karena dapat menyebabkan luka bakar. 45 ISSN 0854-871X Jurnal Puitika Volume 13 No. ISSN 0854-871X Jurnal Puitika Volume 13 No. 1, April 2017 てつだいしたいの！」‘Aku mau membantu pekerjaan mama’. Implikasi
kontekstual dari tuturan ini ialah Miho sangat serius ingin membantu mama. Keinginannya membantu Mama yang kuat ditandai dengan penggunaan
shuujoshi「の」/no di akhir kalimat yang fungsinya 「…聞
き
き手
て
に軽
かる
く念
ねん
を押
お
し
ながら…」 ‘menekankan keinginan pada penutur’ (Kamus Elektronik Kojien
edisi ke-6, 2009). Hal ini diperkuat lagi dengan gambar ekspresi serius pada
wajah Miho dan mulutnya yang terbuka lebar ketika menyampaikan tuturan
(3a). Tuturan (3b)「ただいまー」‘aku pulang’ berimplikasi bahwa ada anggota
keluarga rumah ini yang pulang. strip 4 (4) (a) Kobo:
宿題
しゅくだい
ちゃんとやるか見
み
てるって? shukudai chanto yaru ka mite ru tte? ‘(Kamu) Disuruh melihat apakah aku benar-benar
mengerjakan PR?’ (4) (a) Kobo:
宿題
しゅくだい
ちゃんとやるか見
み
てるって? shukudai chanto yaru ka mite ru tte? ‘(Kamu) Disuruh melihat apakah aku benar-benar
mengerjakan PR?’ ISSN 0854-871X Jurnal Puitika Volume 13 No. 1, April 2017 1, April 2017 (2) (a) Miho: ホがやる
miho ga yaru
‘Miho yang kerjakan.’
(b) Mama: むりよ
muri yo
‘Mana bisa.’
(c) グォー
guo-
‘nguong’ Selanjutnya pada strip 2, ketika melihat mama membersihkan rumah
dengan vacuum cleaner, Miho kembali mengatakan (2a)「ミホがやる」 ‘Miho
yang mengerjakan’. Mama merespon dengan mengatakan (2b) 「むりよ」’Kamu
nggak bisa’. Asumsi kontektual yang dilibatkan berkaitan dengan vacuum
cleaner ialah untuk menggunakan mesin vacuum cleaner ini diperlukan
kekuatan tubuh. Kekuatan tubuh diperlukan untuk mengendalikan mesin
vaccum cleaner yang bergetar yang digambar dengan adanya 2 garis pada
tangkai vacuum cleaner dan tangan mama. Kondisi vacuum cleaner yang sedang
menyala digambarkan onomatope (2c)「グォー」‘nguong’ sebagai tiruan bunyi
mesin yang sedang bekerja. strip 3
(3) (a) Miho : ママのしごとのおてつだいしたいの! mama no shigoto no otetsudai shitai no! ‘Aku mau membantu pekerjaan mama!’ strip 3 (3) (a) Miho : ママのしごとのおてつだいしたいの! mama no shigoto no otetsudai shitai no! ‘Aku mau membantu pekerjaan mama!’ (b) ただいまー
tadaima-
‘Aku pulang.’ Setelah berkali-kali dilarang membantu, di strip 3 Miho menegaskan
ingin membantu pekerjaan mama dengan mengatakan (3a)「ママのしごとのお 46 ISSN 0854-871X Jurnal Puitika Volume 13 No. 1, April 2017 Penutup Gambar pada komik memiliki peran sebagai pelengkap informasi yang
tidak disampaikan melalui tuturan. Ekspresi wajah atau aktivitas yang
dilakukan tokoh-tokoh cerita menjadi informasi yang nonverbal yang
melengkapi informasi yang dikemukakan melalui tuturan. Mengetahui makna
gambar mempermudah dalam menginterpretasi tuturan. Dalam proses
penarikan kesimpulan, untuk menemukan pesan yang dikomunikasikan
ekspresi wajah dan aktivitas tokoh-tokoh cerita, harus diperhatikan karena
tidak dapat dipisahkan dari tuturan. (b) K: 最高
さいこう
につまらないしごとだな
saikou ni tsumaranai shigoto da na
‘Pekerjaan yang sangat membosankan.’
し
くだ Pada strip 4, Kobo berkata (4a)「宿題
しゅくだい
ちゃんとやるか見
み
てるって?」
‘Disuruh melihat apa aku serius mengerjakan PR?’. Asumsi kontekstual yang
dilibatkan pada Kobo seorang anak SD kelas 3 ialah adanya PR yang harus
dikerjakan di rumah. Implikasi kontekstual dari disuruhnya Miho mengawasi
Kobo ialah Kobo tidak serius mengerjakan PR sehingga perlu diawasi/dijaga. さ
う Selanjutnya, Kobo mengatakan (4b)「最高
さいこう
につまらないしごとだな」‘Pekerjaan
yang sangat membosankan’ melihat Miho yang mengawasinya mengerjakan PR. Tuturan ini merupakan sindiran yang disampaikan Kobo kepada Miho. Asumsi
kontekstual dari kata 「しごと」‘bekerja’ ialah menggerakkan badan dan
mengeluarkan tenaga untuk melakukan sesuatu. Pekerjaan yang diperintahkan
mama kepada Miho ialah melihat Kobo mengerjakan PR. Asumsi kontekstual
dari pekerjaan mengawasi ialah diam memperhatikan orang yang diawasi
secara terus-menerus. Implikasi kontekstualnya ialah Miho bekerja, tetapi tidak
melakukan apa-apa. Relevansi gambar dengan tuturan pada cerita ini ialah Miho melakukan
pekerjaan sebagai pengawas. Dengan menjadi pengawas, Miho tidak perlu
melakukan apa-apa. Miho cukup berpangku tangan/menyilangkan tangannya 47 ISSN 0854-871X Jurnal Puitika Volume 13 No. 1, April 2017 di dada pada strip 4 sambil memperhatikan Kobo mengerjakan PR yang
dianggap Kobo itu merupakan hal yang membosankan. di dada pada strip 4 sambil memperhatikan Kobo mengerjakan PR yang
dianggap Kobo itu merupakan hal yang membosankan. DAFTAR PUSTAKA Danesi, M. 2004. Messages, Signs, and Meanings: A Basic Textbook in Semiotics
and Communication Theory. Toronto: Canadian Scholars’ Press Inc. Danesi, M., & Perron, P. 1999. Analyzing Culture: An Introduction & Handbook. Indiana: Indiana University Press. Eisner, W. 1985. Comic and Sequential Art. Florida: Poorhouse Press. Grice, H. P. 1975. "Logic and Conversation" dalam P. Cole, & J. Morgon, Syntax
and Semantics. New York: Academic Press. Hoed, B. H. 2011. Semiotik dan Dinamika Sosial Budaya. Jakarta: Komunitas
Bambu. Horn, L. R., & Ward, G. 2006. The Handbook of Pragmatics. Malden, Oxford
and Victoria: Balckwell Publishing. McCloud, S. 1993. Understanding Comic The Invicible Art. New York: Kitcheng
Sink Press. Merrel, F. 2001. Charles Sanders Peirce's Concept of the Sign. dalam P. Cobley,
Routledge Companion to Semiotics and Linguistics. London and New York:
Routledge. Nöth, W. 1995. Handbook of Semiotics. Bloomington and Indianapolis: Indiana
University Press. Sperber, D., & Wilson, D. 1986. Relevance: Communication and Cognition. Oxford UK and Cambridge USA: Blackwell. Thompson, J. 2007. Manga The Complete Guide. New York: Del Rey of Random
House Inc . 48
|
https://openalex.org/W2114934638
|
https://researchonline.lshtm.ac.uk/id/eprint/4654123/1/ctr0027-E669.pdf
|
English
| null |
Early changes in scores of chronic damage on transplant kidney protocol biopsies reflect donor characteristics, but not future graft function
|
Clinical transplantation/Clinical transplantation.
| 2,013
|
cc-by
| 7,571
|
© 2013 The Authors. Clinical Transplantation Published by John Wiley & Sons Ltd
Clinical Transplantation © 2013 The Authors. Clinical Transplantation Published by John Wiley & Sons Ltd
Clinical Transplantation Clin Transplant 2013: 27: E669–E678 DOI: 10.1111/ctr.12251 Clinical Transplantation Ben Caplina, Kristin Veigheya,
Arundathi Mahenderanb, Miriam
Manookb, Joanne Henryb,
Dorothea Nitschc, Mark Harberb,
Peter Dupontb, David C. Wheelera,
Gareth Jonesb, Bimbi Fernandob,
Alexander J. Howied and Peter
Veitchb Ben Caplina, Kristin Veigheya,
Arundathi Mahenderanb, Miriam
Manookb, Joanne Henryb,
Dorothea Nitschc, Mark Harberb,
Peter Dupontb, David C. Wheelera,
Gareth Jonesb, Bimbi Fernandob,
Alexander J. Howied and Peter
Veitchb Abstract: The amount of irreversible injury on renal allograft biopsy
predicts function, but little is known about the early evolution of this
damage. In a single-center cohort, we examined the relationship between
donor-, recipient-, and transplantation-associated factors and change in a
morphometric index of chronic damage (ICD) between protocol biopsies
performed at implantation and at 2–3 months. We then investigated
whether early delta ICD predicted subsequent biochemical outcomes. We
found little evidence to support differences between the study group, who
had undergone serial biopsies, and a contemporaneous control group,
who had not. In allografts with serial biopsies (n = 162), there was an
increase in ICD between implantation (median: 2%, IQR:0–8) and 2–
3 months post-transplant (median 8% IQR:4–15; p < 0.0001). Donation
from younger or live donors was independently associated with smaller
early post-transplant increases in ICD. There was no evidence for a
difference in delta ICD between donation after cardiac death vs. donation after brain death, nor association with length of cold ischemia. After adjustment for GFR at the time of the second biopsy, delta ICD
after three months did not predict allograft function at one yr. These
findings suggest that graft damage develops shortly after transplantation
and reflects donor factors, but does not predict future biochemical
outcomes. aCentre for Nephrology, UCL Medical School,
bRenal and Transplant Unit, Royal Free
London NHS Foundation Trust, cDepartment of
Non-Communicable Disease Epidemiology,
Faculty of Epidemiology and Population
Health, London School of Hygiene and
Tropical Medicine and dDepartment of
Pathology, University College London,
London, UK Key words: chronic allograft injury – chronic
damage index – digital image analysis –
protocol biopsy – renal transplantation Corresponding author: Kristin Veighey, Centre
for Nephrology, UCL Medical School, London, Tel.: +44 (0)20 7472 6457; fax: +44 (0)20 7317 8591; e-mail: k.veighey@ucl.ac.uk Conflict of interest: The authors declare that
they have no conflict of interest relevant to the
work presented in this manuscript. We have
had no involvements that might raise the
question of bias in the work reported or in the
conclusions, implications, or opinions stated. This is an open access article under the terms
of the Creative Commons Attribution License,
which permits use, distribution and
reproduction in any medium, provided the
original work is properly cited. Early changes in scores of chronic damage
on transplant kidney protocol biopsies
reflect donor characteristics, but not future
graft function Caplin B, Veighey K, Mahenderan A, Manook M, Henry J, Nitsch D,
Harber M, Dupont P, Wheeler DC, Jones G, Fernando B, Howie AJ,
Veitch P. Early changes in scores of chronic damage on transplant
kidney protocol biopsies reflect donor characteristics, but not future
graft function. Caplin et al. Maintenance therapy (com-
menced five d prior to the transplant in recipients
of live donor kidneys) consisted of (i) tacrolimus
adjusted to maintain a trough level of 9–12 lg/L
for the first three months and then 6–9 lg/L
(except in cases of delayed graft function where
target trough levels are 6–9 lg/L until graft func-
tion is established); (ii) mycophenolate mofetil 1 g
bd
reduced
to
750 mg
bd
after
one month;
(iii) prednisolone 20 mg daily for one wk and
10 mg daily for one wk followed by steroid with-
drawal. Acute cellular rejection was treated with
pulsed methylprednisolone and continuation of
oral steroids with the addition of antithymocyte
globulin (ATG) in resistant cases. Acute vascular
rejection was treated with the addition of plasma
exchange where there was an identifiable donor-
specific antibody, plus rituximab in resistant cases. Patients underwent a preemptive CMV surveil-
lance strategy (except for those enrolled in a clini-
cal trial or considered high risk), receiving antiviral
therapy only where routine samples revealed CMV
antigen levels >1250 copies/mL. p
Although previous studies have examined clini-
cal predictors of chronic damage at a single time
point or over many years, little is understood
about the factors surrounding transplantation that
are associated with the early evolution of such
damage, that is, the relationship between clinical
variables and changes in measures of chronic
damage during the first post-transplant months. This is an issue of particular importance in kidneys
from “extended criteria” donors (ECD) or dona-
tion following cardiac death (DCD) as these
allografts are likely to have significant levels of
pre-existing chronic damage in the former case and
suffer increased warm ischemic injury in the latter. The use of a quantitative approach to assess dam-
age, made possible by the use of digital analysis
systems, has been explored in an investigation of
recipients of live donor transplants (8) or kidneys
donated following brain death (DBD) (9), but the
risk factors for the early evolution of chronic
damage on protocol biopsy of single-organ kidney
transplants from a cohort receiving kidneys of
differing donor types remain unclear. Using protocol biopsies performed as a part of
routine clinical care, the aim of this study was to
examine donor and recipient factors associated
with changes in a morphometric measure of
chronic damage over the first three post-transplant
months. Caplin et al. Improvements in the outcomes of kidney trans-
plantation have mainly been confined to preven-
tion of early graft loss. Over the last 20 yr, the
slopes of allograft survival curves from one yr
post-transplant have
remained almost
parallel
(1, 2). Furthermore, due to the chronic undersup-
ply of donor organs, there has been a recent move
toward the use of “extended criteria” donors and
donation
after
cardiac
death
(DCD)
with
consequent concerns surrounding the long-term
outcomes for recipients of these kidneys. ber 31, 2010, underwent protocol biopsies as part
of their routine clinical care. The unit policy is for
protocol biopsies to be performed at three time
points: 30 min following allograft implantation
(PB0), 6–12 wk post-transplantation (PB1), and
one yr post-transplantation. Only data from the
first two are described here, as uptake of the one-yr
biopsy is low (n = 72, 29%) and likely to be heav-
ily influenced by clinical factors; that is, those
patients with a well-functioning graft are likely to
forego this biopsy. All patients undergoing biopsy
gave informed consent as to the clinical risks and
benefits of the program. The following were con-
sidered contraindication to protocol biopsy: high
bleeding risk, pregnancy, and indicated biopsy
within the last 14 d. Improvements in the outcomes of kidney trans-
plantation have mainly been confined to preven-
tion of early graft loss. Over the last 20 yr, the
slopes of allograft survival curves from one yr
post-transplant have
remained almost
parallel
(1, 2). Furthermore, due to the chronic undersup-
ply of donor organs, there has been a recent move
toward the use of “extended criteria” donors and
donation
after
cardiac
death
(DCD)
with
consequent concerns surrounding the long-term
outcomes for recipients of these kidneys. The total amount of irreversible histological
damage on protocol biopsies at early time points,
as estimated by Banffcriteria for chronic damage
(3–5) or as measured morphometrically (6, 7), is a
predictor of longer-term graft outcomes, and this
damage appears to be established early post-trans-
plantation. The
immunosuppressive
protocol
was
unchanged for the duration of this study. Induc-
tion therapy consisted of basiliximab (days 0 and
4), methylprednisolone, tacrolimus, and myco-
phenolate mofetil. Ben Caplina, Kristin Veigheya,
Arundathi Mahenderanb, Miriam
Manookb, Joanne Henryb,
Dorothea Nitschc, Mark Harberb,
Peter Dupontb, David C. Wheelera,
Gareth Jonesb, Bimbi Fernandob,
Alexander J. Howied and Peter
Veitchb [The copyright line for this article was changed
on 8 August 2014 after original online
publication.] Accepted for publication 27 August 2013 E669 E669 Caplin et al. We then investigated whether the early
change in this same measure was a useful predictor
of graft function at one yr. Protocol biopsies were performed by senior
clinicians, under direct vision at implantation or
live
ultrasound
guidance
post-transplantation. Samples were obtained using either 16-gauge nee-
dles (at implantation) or 18-gauge biopsy needles
(post-transplant) and were examined using a dis-
secting microscope at the bedside to confirm ade-
quate
sampling. Biopsies
were
formalin-fixed,
paraffin-embedded, and serially sectioned before
staining using conventional techniques. The mor-
phometric measure, called the index of chronic
damage (ICD), was determined in sections from
PB0 to PB1 (ICD0 and ICD1, respectively) as pre- Patients and Methods In this cohort study, adult recipients of solitary
renal allografts under the care of the Royal Free
London NHS Foundation Trust (RFLNHSFT),
transplanted between February 1, 2008, and Octo- E670 E670 NHSBT definitions were
used for mismatch level (10). Donor serum creati-
nine concentration from admission was used where
available; otherwise, first available creatinine was
obtained. Recipient data were retrieved from elec-
tronic hospital records. Rejection was defined as
per Banffcriteria on indication biopsies prior to
PB1 or on that protocol biopsy (or on biopsies at
less than three months for the group not undergoing
PB1). BK nephropathy was defined by the presence
of virus detected by an immunoperoxidase method. The number of indicated biopsies was the total
number of biopsy attempts prior to the first post-
transplant biopsy (or in the first three months for
those not undergoing PB1). Serum creatinine val-
ues were obtained from day 56 and day 365 (or the
nearest available measurement subsequent to these
dates) post-transplant eGFR calculated by the 4-
variable MDRD equation (11). All analyses were
performed by allograft, so two patients who both
received a second transplant during the study per-
iod were represented twice although sensitivity
analysis excluding these second grafts did not alter
any of the main findings. As not all patients transplanted in the study per-
iod had undergone serial protocol biopsies, we
examined whether there were differences between
the group who had undergone such biopsies and
the group who had not using the chi-squared test
(Fisher’s exact test for cells with small numbers)
and t-test (Wilcoxon rank-sum test for nonpara-
metric variables). Then, in a sensitivity analysis, we
examined whether inclusion in the biopsy group
was
associated
with
differences
in
eGFR
at
eight wks or cumulative incidence of rejection over
the follow-up period, after matching using a pro-
pensity score based on donor and recipient charac-
teristics. To investigate whether delta ICD might predict
future outcome, we then examined whether this
same measurement (as an explanatory variable)
was associated with biochemical measures of kid-
ney function. First, we examined the relationship
between delta ICD quartile and quartile of GFR at
biopsy. Then, to test the usefulness of the measure
as a predictor of future function, we examined the
association between delta ICD quartile and the
change in eGFR between the time of PB1 and one-
yr post-transplant (eGFR at day 365 after adjust-
ment for eGFR at day 56). We went on to examine the associations between
ICD and clinical variables. E670 Early change in ICD reflects donor factors viously described (7). Briefly, on a computerized
image, the area of renal cortex excluding renal cap-
sule was measured in arbitrary units. Areas of
chronic damage, identified by global sclerosis of
glomeruli, tubular atrophy, interstitial fibrosis,
and/or occluded vessels, were also quantified. The
amount of damage was expressed as a percentage
of cortical area to the nearest integer. nonparametric
variables)
and
chi-squared
test
(Fisher’s exact test for cells with small numbers). The change in ICD between paired samples was
examined using the Wilcoxon rank-sum test. For multivariate analysis, we did not group
ECD and DBD donors separately, firstly to avoid
small cell numbers and also so we could examine
clinical factors that would lead to the definition of
a
donor
as
ECD
(donor
serum
creatinine
>133 lMol/L;
intracerebral
hemorrhage,
ICH;
donor age) in both DBD and DCD groups. To
identify independent predictors of ICD0 and delta
ICD, we used a logistic regression models and
included exposure variables where we hypothesized
an impact on ICD. For baseline chronic damage,
these were donor type (live, DCD, or donation
after brain death [DBD]), age, sex, ethnic group,
donor
serum
creatinine>133 lMol/L,
ICH,
diabetes mellitus (DM), and cold ischemic time
(CIT; deceased donors only). For change in
chronic damage, these were as above plus recipient
factors: mismatch level, age, sex, ethnic group, pre-
vious transplantation, primary disease, DM, BK
nephropathy, and rejection. Adjustment was made
for the timing of PB1, but otherwise variables were
retained in the models only where there was an
improvement in model fit as demonstrated by a
reduction in the 2 log-likelihood ratio. We also
performed a restricted analysis excluding donors
dying from ICH. Following fitting of the ordinal
logistic model, the proportional odds assumption
was tested for each of the variables in the model
individually. Where this was violated, as in the
model of ICD0, a multinomial logistic approach
was used, and relative risk ratios were reported for
each category. Predicted odds ratios or relative risk
ratios were compared with observed values for
both multivariable models. A further sensitivity
analysis examining change in chronic damage was
carried out using a linear regression model with log
ICD1 adjusted for log ICD0, and although model
fit was poor, the main conclusions, as identified
using
the
logistical
modeling
approach,
were
unchanged. Donor data were retrieved from NHS Blood and
Transplant (NHSBT). E670 ICD scores were posi-
tively skewed at all time points so to examine pre-
dictors of ICD0, and change in ICD (ICD1-ICD0;
delta ICD) scores was divided into equal frequency
tertiles and quartiles, respectively. Univariable
associations between clinical variables and ICD0
or delta ICD were examined using analysis of vari-
ance (ANOVA) (Kruskal–Wallis [K-W] test for E671 E671 Cohort Two hundred and sixty seven patients under fol-
low-up at the renal transplant unit RFLNHSFT
underwent 269 kidney-alone transplants between
February 1, 2008, and October 31, 2010. Six
patients were transplanted elsewhere, so no ICD0
was
available. A
further
17
allografts
were
excluded from further analysis due to nephrectomy
(n = 8), loss to follow-up (n = 2), recipient death
(n = 5), and contraindication to protocol biopsy
(n = 2). Either ICD0 (n = 45) or ICD1 (n = 61) or
both were not available on a further 81 allografts
due to patient refusal (n = 5), multiple recent indi-
cated biopsies (n = 2), or undocumented reasons. Delta ICD was available for 162 allografts, and
along with three allografts with biopsies that were
technically inadequate, this group (n = 165) was
compared with those who did not undergo both
protocol biopsies (n = 81). The “6–12 wks” post-
transplant protocol biopsies were performed a
median of 56 d (IQR 48–72) following transplanta-
tion. There was a higher prevalence of female
donors, and there were an increased number of
indicated biopsies in the group who did not
undergo serial biopsies, but there were no other
differences observed between the groups (Table 1). Specifically, there were no differences seen in CIT,
the prevalence of different donor types, eGFR, or
biopsy proven rejection. In a sensitivity analysis,
using propensity score matching, no significant dif-
ferences were seen in eGFR at eight wk or the
cumulative incidence of rejection between those
undergoing protocol biopsies and those who did
not (data not shown). Predictors of Change in ICD Overall (including allografts where delta ICD was
not available, n = 188), median ICD1 was 8%
(IQR: 4–15). Restricting the analysis to those sub-
jects for whom delta ICD was available, there was
a small but highly significant increase between
biopsies (median increase, 4%; IQR: 1–9). Box and
whisker plots of ICD0 and ICD1 stratified by
donor type are shown in Fig. 1. A negative delta
ICD was observed in 25 of the 162 allografts. Univariable associations between clinical vari-
ables and quartile of delta ICD are presented in
Table 4. Transplant type (Fig. 2) and history of
donor ICH along with recipient and donor age
were the only clinical variables associated with
delta ICD. Kidneys transplanted from live donors
showed little change in ICD over time, while kid-
neys from DCD donors were more prevalent in the
higher quartiles of delta ICD. Mean donor age was
higher across increasing quartiles of delta ICD
(p < 0.01 for a trend). Borderline relationships
were found with donor serum creatinine concentra-
tion, donor ethnic group, previous transplantation,
donor DM, and mismatch level, although the
power to detect associations for the latter explana-
tory variables was limited due to small numbers. Donor age and donor type were the only vari-
ables independently associated with quartile of
delta ICD on multivariable analysis using an ordi-
nal logistic regression model (Table 5). Increasing
donor age was independently associated with
increased odds of a higher quartile delta ICD with
an OR of 1.29 (95% CI: 1.06–1.57) for each decade
over 48 yr. Receiving a kidney from a live donor
was independently associated with lower odds of a
higher delta ICD quartile with an OR of 0.40 (95%
CI: 0.20–0.80) compared with the reference group
of DBD. There was no significant increase in odds
associated with receiving a kidney from a DCD vs. DBD (OR 1.30; 95% CI: 0.62–2.73). Exclusion of
donors dying from ICH did attenuate the differ-
ences in OR between live and DBD donors, sug- Caplin et al. Summary
statistics
are
presented
as
means standard deviation (or medians with in-
terquartile range for non-normally distributed
variables). Statistical significance was accepted as
p < 0.05. This was a descriptive study, and there-
fore, no power calculations were performed. Data
were analyzed in Stata 11 (Stata Corp LP, College
Station, TX, USA). higher donor age and donation following cardiac
death (Table 3). However other donor variables,
including donor ethnic group, were not associated
with tertile of ICD0 in the adjusted model. Fur-
thermore, other than age, inclusion of factors that
would lead to a donor being defined as “extended
criteria” (ICH, serum creatinine >133 lMol/L,
hypertension) did not alter the relative risk ratios. Most (six of nine) of the donors with DM were in
the highest ICD0 tertile, but as overall numbers
were small, this variable was not included in the
multivariable model. Predictors of ICD on implantation biopsy Overall (including allografts where delta ICD was
not available), median ICD0 was 2% (IQR 0–7). On univariable analysis, donor age, transplant
type, and donor ethnic group were associated with
tertile of ICD0 (Table 2). On multinomial logistic
regression, there was a higher relative risk ratio of
ICD0 falling in tertile two and three with both E672 Table 1. Description of the study cohort and comparison between the groups of allografts for which serial biopsies were not and were per-
formed
Early change in ICD reflects donor factors Early change in ICD reflects donor factors Table 1. Predictors of ICD on implantation biopsy Description of the study cohort and comparison between the groups of allografts for which serial biopsies were not and were per-
formed formed
All allografts n = 246
Allografts without serial
biopsies n = 81
Allografts
with
serial
biopsies n = 165
p-Value
Recipient age
Years, mean, SD
49.4
13.8
47.5
15.3
50.2
13.1
NS
Recipient sex
Female n,%
114
46.3
38
46.9
76
46.1
NS
Recipient ethnic group
Asian n,%
51
20.7
19
23.5
32
19.4
NS
Black n,%
54
22.0
13
16.1
41
24.9
Chin/oth/ns n,%
34
13.8
9
11.1
25
15.2
White n,%
107
43.5
40
49.4
67
40.6
Recipient primary disease
Cystic n,%
20
8.1
8
9.9
12
7.3
NS
DM n,%
27
11.0
11
13.6
16
9.7
Dysplastic/reflux n,%
10
4.1
4
4.9
6
3.6
Glomerular n,%
48
19.5
17
21.0
31
18.8
Vasc/isch/hyp n,%
27
11.0
9
11.1
18
10.9
Other n,%
74
30.1
23
28.4
51
30.9
Unknown n,%
40
16.3
9
11.1
31
18.8
Recipient DM
n,%
35
14.2
10
12.4
25
15.2
NS
Previous transplant
n,%
25
11.0
12
14.8
15
9.1
NS
Donor age
Years, mean, SD
48.0
15.8
47.3
16.3
48.3
15.5
NS
Donor sex
Female n,%
102
43.0
39
54.2
63
38.2
0.02a
Donor ethnic group
Asian n,%
19
8.0
6
8.3
13
7.9
NS
Black n,%
17
7.2
5
6.9
12
7.3
Chin/oth/ns n,%
5
2.1
0
0.0
5
3.0
White n,%
196
82.7
61
84.7
135
81.8
Donor creatinine
lMol/L, geo mean, SD
78.3
1.5
75.1
1.5
79.0
1.5
NS
Donor DM
n,%
10
4.2
3
4.2
7
4.3
NS
Donor weight
Kilograms, mean, SD
78.4
16.7
77.6
16.4
78.7
16.8
NS
Donor type
ECD, n,%
64
26.0
42
25.5
22
27.2
NS
DBD, n,%
17
6.9
11
6.7
56
7.4
DCD, n,%
71
28.9
20
24.7
51
30.9
Live, n,%
94
38.2
33
40.7
61
37.0
Mismatch level
1, n,%
19
8.0
4
5.6
15
9.1
NS
2, n,%
52
21.9
14
19.4
38
23.0
3, n,%
137
57.8
44
61.1
93
56.4
4, n,%
29
12.2
10
13.9
19
11.5
CIT (deceased donor only)
Hours, mean, SD
16.1
4.5
16.4
4.1
16.0
4.6
NS
Indicated biopsies
n, median, IQR
1
0–2
1.5
1–2.5
0
0–2
0.004b
Rejection
n,%
24
9.8
7
8.6
17
10.3
NS
BK virus
n,%
3
1.3
1
1.4
2
1.2
NS
Recipient eGFR at day 56
mL/min/1.73 m2 median (IQR)
47.3
35.6- 59.7
50.1
35.7–65.4
46.4
33.8–57.6
NS
Rejection and indicative biopsies were counted up to the time of first post-transplant protocol biopsy in the group with protocol biopsies and to 12 wks in
the group not undergoing a biopsy at this time point. Rejection and indicative biopsies were counted up to the time of first post-transplant protocol biopsy in the group with protocol biopsies and to 12 wks in
the group not undergoing a biopsy at this time point. Percentages represent column percentage. Numbers of deceased donors with CIT data: total 129; 38
and 91 in each group, respectively.
CIT, cold ischemic time; DM, diabetes mellitus; dysplastic, dysplastic kidneys; vasc/isch/hyp, renal disease classified as renovascular or due to chronic
renal ischemia; ECD, extended criteria donor; DBD, donation after brain death (excluding ECD); DCD, donor after cardiac death; DBD, donor after brain
death; SD, standard deviation.
aBy chi-squared.
bBy Wilcoxon rank-sum test. Predictors of ICD on implantation biopsy Percentages represent column percentage. Numbers of deceased donors with CIT data: total 129; 38
and 91 in each group, respectively. CIT, cold ischemic time; DM, diabetes mellitus; dysplastic, dysplastic kidneys; vasc/isch/hyp, renal disease classified as renovascular or due to chronic
renal ischemia; ECD, extended criteria donor; DBD, donation after brain death (excluding ECD); DCD, donor after cardiac death; DBD, donor after brain
death; SD, standard deviation. aB
hi
d bBy Wilcoxon rank-sum test. E673 Caplin et al. Caplin et al. Table 2. Clinical variables stratified by ICD tertile at implantation Table 2. Clinical variables stratified by ICD tertile at implantation
ICD on implantation biopsy
p-Value
Zero n = 72
Moderate n = 68
High n = 78
ICD
%, median, range
0
0–0
2
1–4
9
5–46
Donor age
Years, mean, SD
41.3
14.6
46.3
14.5
57.6
11.1
<0.001c
Donor sex
Female n,%
35
48.6
28
41.2
28
36.8
NS
Donor ethnic group
Asian n,%
8
11.1
9
13.2
1
1.3
0.02d
Black n,%
6
8.3
3
4.4
5
6.6
Chin/oth/ns n,%
2
2.8
3
4.4
0
0.0
White n,%
56
77.8
53
77.9
70
92.1
Donor creatinine
lMol/L, geo mean, SD
75.9
1.4
77.2
1.5
79.6
1.4
NS
Donor DM
n,%
2
2.8
1
1.5
6
8.1
NS
Donor weight
Kilograms, mean, SD
77.7
19.5
78.1
14.2
81.5
13.0
NS
Donor ICH
n,%
22
30.6
17
25.0
26
33.3
NS
Donor type
DBD n,%
29
40.3
15
22.1
27
34.6
0.001a
DCD n,%
11
15.3
21
30.9
33
42.3
Live n,%
32
44.4
32
47.1
18
23.1
CIT (DCD and DBD only)
Hours, mean, SD
16.1
4.7
16.2
5.5
16.1
4.4
NS
Numbers of deceased donors with CIT data: total 115; 35, 32, and 48 in each group, respectively. Abbreviations and characters as Table 1. CIT, cold ischemic time; DBD, donated after brain death; DCD, donation after cardiac death; DM, diabetes mellitus; ICD, index of chronic damage; ICH,
intracerebral hemorrhage
cBy analysis of variance (ANOVA). dBy Fisher’s exact test. Numbers of deceased donors with CIT data: total 115; 35, 32, and 48 in each group, respectively. Abbreviations and characters as Table 1. CIT, cold ischemic time; DBD, donated after brain death; DCD, donation after cardiac death; DM, diabetes mellitus; ICD, index of chronic damage; ICH,
intracerebral hemorrhage
cBy analysis of variance (ANOVA). dBy Fisher’s exact test. ****
Fig. 1. onors with CIT data: total 115; 35, 32, and 48 in each group, respectively. Abbreviations and characters as Table 1. ;
,
,
g
p,
p
y
CIT, cold ischemic time; DBD, donated after brain death; DCD, donation after cardiac death; DM, diabetes mellitus; ICD, index of chronic damage; ICH,
intracerebral hemorrhage
cBy analysis of variance (ANOVA).
dB Fi h
’
t t
t DBD, donated after brain death; DCD, donation after cardiac death; DM, diabetes mellitus; ICD, index of chronic damage; IC
e Predictors of ICD on implantation biopsy Index of chronic damage (ICD) at implantation and
first protocol biopsy. Box and whisker plot of ICD scores at
implantation (PB0) and ‘6–12 wk’ biopsy (PB1) stratified by
donor type. Centre bar: median; Boxes: 25th and 75th centiles;
Whiskers: upper and lower adjacent values; Dots: outliers. ****p < 0.001 by Wilcoxon signed-rank test. Includes allo-
grafts only where serial ICD was available. **** Table 3. Multinomial logistic regression model of ICD at baseline
Risk ratio relative to lowest tertile ICD0
Middle
Highest
RRR
95% CI
RRR
95% CI
Donor type
DBD
Reference
Reference
DCD
3.71
1.40
9.82
3.96
1.49
10.51
Live
1.93
0.87
4.33
0.77
0.31
4.32
Donor age
Per decade
>48 yrs
1.29
1.01
1.64
2.47
1.82
3.36
Generalized logistic regression model used as proportional odds
assumption violated for the above variables across tertiles of ICD0. ICD0, ICD at implantation biopsy; RRR, relative risk ratio; CI, confidence
interval; DBD, donation after brain death; DCD, donation after cardiac
death; ICD, index of chronic damage. Table 3. Multinomial logistic regression model of ICD at baseline Generalized logistic regression model used as proportional odds
assumption violated for the above variables across tertiles of ICD0. ICD0, ICD at implantation biopsy; RRR, relative risk ratio; CI, confidence
interval; DBD, donation after brain death; DCD, donation after cardiac
death; ICD, index of chronic damage. Fig. 1. Index of chronic damage (ICD) at implantation and
first protocol biopsy. Box and whisker plot of ICD scores at
implantation (PB0) and ‘6–12 wk’ biopsy (PB1) stratified by
donor type. Centre bar: median; Boxes: 25th and 75th centiles;
Whiskers: upper and lower adjacent values; Dots: outliers. ****p < 0.001 by Wilcoxon signed-rank test. Includes allo-
grafts only where serial ICD was available. gesting that this may be one factor responsible for
the differences seen in delta ICD between donor
types (Table 5). Although the prevalence of donor
DM appeared higher in the higher quartiles of
delta ICD, again low numbers mean that this vari- able was not included in the final model. Other
donor-, recipient-, and transplant-associated vari-
ables did not improve model fit. In particular, no E674 Early change in ICD reflects donor factors Table 4. Predictors of ICD on implantation biopsy Clinical variables stratified by quartile of delta ICD on serial protocol biopsies
Quartile of delta ICD
p-Value
1 (n = 36)
2 (n = 36)
3 (n = 45)
4 (n = 45)
Delta ICD
%, Median, range
2
11 to 0
2
1 to 3
5
4 to 8
13
9 to 44
Recipient age
Years, mean, SD
52.4
11.5
47
14.5
47.2
13.4
54.1
12.1
0.023c
Recipient sex
Female n,%
19
52.8
11
30.6
21
46.7
22
48.9
NS
Recipient ethnic group
Asian n,%
5
13.9
6
16.7
11
24.4
8
17.8
NS
Black n,%
7
19.4
5
13.9
11
24.4
17
37.8
Chin/oth/ns n,%
6
16.7
10
27.8
5
11.1
4
8.9
White n,%
18
50.0
15
41.7
18
40.0
16
35.6
Recipient primary disease
Cystic n,%
2
5.6
3
8.3
3
6.7
4
8.9
NS
Dm n,%
3
8.3
4
11.1
5
11.1
3
6.7
Dysplastic/reflux n,%
1
2.8
2
5.6
2
4.4
1
2.2
Glomerular n,%
9
25.0
8
22.2
7
15.6
6
13.3
Vasc/isch/hyp n,%
4
11.1
2
5.6
2
4.4
10
22.2
Other n,%
14
38.9
10
27.8
14
31.1
12
26.7
Unknown n,%
3
8.3
7
19.4
12
26.7
9
20.0
Recipient DM
n,%
6
16.7
5
13.9
7
15.6
6
13.3
NS
Previous transplant
n,%
5
13.9
2
5.6
7
15.6
1
2.2
0.10d
Donor age
Years, mean, SD
44.3
17.3
46.6
16.0
48.2
12.5
53.4
13.9
0.043c
Donor sex
Female n,%
15
41.7
15
41.7
18
40.0
13
28.9
NS
Donor ethnic group
Asian n,%
3
8.3
7
19.4
3
6.7
0
0.0
NS
Black n,%
3
8.3
3
8.3
2
4.4
4
8.9
Chin/oth/ns n,%
1
2.8
1
2.8
1
2.2
2
4.4
White n,%
29
80.6
25
69.4
39
86.7
39
86.7
Donor creatinine
lMol/L, geo mean, SD
72.4
1.4
84.2
1.4
75.3
1.3
86.3
1.6
0.10c
Donor DM
n,%
0
0
0
0
2
4.4
4
9.1
0.10d
Donor weight
Kilograms, mean, SD
77.4
17.4
78.5
16.3
79.7
17.1
80.4
14.7
NS
Donor type
ECD n,%
5
13.9
6
16.7
12
26.7
18
40.0
<0.001d
DBD n,%
6
22.2
3
8.3
1
2.2
0
0
DCD n,%
8
22.2
6
16.7
15
33.3
21
46.7
Live n,%
17
47.2
21
58.3
17
37.8
6
13.3
Donor ICH
n,%
5
13.9
6
16.7
16
35.5
19
42.2
0.009a
Mismatch level
1 n,%
4
11.1
2
5.6
7
15.6
2
4.4
0.11d
2 n,%
8
22.2
10
27.8
10
22.2
9
20.0
3 n,%
19
52.8
19
52.8
28
62.2
26
57.8
4 n,%
5
13.9
5
13.9
0
0.0
8
17.8
CIT (DCD and DBD only)
Hours, mean, SD
16.1
5.3
15.8
4.5
15.5
3.8
16.0
5.1
NS
Rejection
n,%
5
13.9
5
13.9
6
13.3
7
15.5
NS
BK virus
n,%
0
0
1
2.9
0
0
1
2.2
NS
Recipient eGFR at day 56
mL/min/1.73 m2 median (IQR)
51.9
30.7–61.2
50.9
43.7–60.7
46.8
40.5–57.0
37.8
28.0–50.0
<0.001e
Recipient eGFR at day 365
mL/min/1.73 m2 median (IQR)
52.2
40.9–73.8
52.6
40.9–73.8
51.9
41.6–59.1
45.1
35.0–52.1
0.04e
Numbers of deceased donors with CIT data: total 88; 15, 14, 27, and 32 in each group, respectively. Discussion In this study, we describe the clinical associations
of early changes in chronic damage on protocol
biopsies performed as a part of a routine clinical
care. Although several other studies have examined
the prevalence of chronic damage in routine biopsy
samples, to our knowledge, this is the first one to
examine early change in ICD outside a clinical trial,
in a cohort including transplants from donors after
cardiac and brain death, as well as live donors. Fig. 2. Prevalence of donor types amongst quartiles of delta
index of chronic damage (ICD). Unadjusted for other clinical
variables. ***p < 0.005. Table 5. Multivariable ordinal logistic regression model of delta ICD
quartile on serial protocol biopsies Table 5. Multivariable ordinal logistic regression model of delta ICD
quartile on serial protocol biopsies
All donors n = 162
Donors with COD ICH
excluded n = 116
OR
95% CI
OR
95% CI
Donor type
DBD
Reference
Reference
DCD
1.30
0.62
2.73
2.90
1.00
8.39
Live
0.40
0.20
0.80
0.78
0.30
1.95
Donor age
Per decade
>48 yrs
1.29
1.05
1.57
1.33
1.05
1.60
Adjusted for timing of second biopsy (days since transplant). Model
meets proportional odds assumptions. COD, cause of death, OR, odds ratio; CI, confidence interval; DBD, dona-
tion after brain death; DCD, donation after cardiac death; ICD, index of
chronic damage; ICH, intracerebral hemorrhage. As with all studies of this type, a major concern
is whether patients undergoing protocol biopsies
are representative of the cohort of transplant
patients as a whole. Therefore, we compared clini-
cal variables in the group undergoing both proto-
col biopsies with the group undergoing only one or
neither. We could only detect differences in donor
sex and number of indicated biopsies. The higher
number of indicated biopsies in the group not
undergoing protocol biopsies may reflect causation
(i.e., patients do not undergo protocol biopsies
after a recent indication biopsy) or reverse causa-
tion (i.e., clinicians are more likely to refer for
biopsy where there has not been a recent protocol
biopsy). Reassuringly rates of biopsy proven rejec-
tion were no different, suggesting that our analysis
of change in ICD is not restricted to a selected
group of patients in this context. The reasons
underlying lower numbers of female donors in the
protocol biopsy group are less clear, but it could
be that there are differences in transplant course in
recipients of kidneys from female donors (12). Predictors of ICD on implantation biopsy Rejection was defined by a histologically proven epi-
sode of rejection prior to the protocol biopsy. Number of allografts with one-yr creatinine: 127. Abbreviations and characters as Tables 1 and 2. CIT, cold ischemic time; DBD, donation after brain death; DCD, donation after cardiac death; DM, diabetes mellitus; ECD, extended criteria donor; ICD,
index of chronic damage; ICH, intracerebral hemorrhage. eBy Kruskal Wallis test
a y c a ge
C
e ects do o
acto s Table 4. Clinical variables stratified by quartile of delta ICD on serial protocol biopsies E675 Caplin et al. Fig. 2. Prevalence of donor types amongst quartiles of delta
index of chronic damage (ICD). Unadjusted for other clinical
variables. ***p < 0.005. associated with the change in eGFR between day
56 and day 365. We found no association between
delta ICD and change in kidney function between
first post-transplant protocol biopsy and one yr
post-transplant (quartile of eGFR at day 365
adjusted for quartile of eGFR at day 56; p = 0.74). Addition of potential confounders to the model
(rejection, recipient factors) did not alter the lack
of association. Discussion Overall, these findings suggest that the cohort in
whom we examined delta ICD is broadly reflective
of the transplant population followed up at our
institution during the same time period. Early change in ICD reflects donor factors kidneys from live donors and DBD after adjust-
ment for donor age. Others have reported associa-
tions
between
early
changes
in
fibrosis
and
diabetes, rejection, and kidneys from male donors
(9). We observed trends with the first two of these
risk factors and delta ICD in our cohort, but may
have been underpowered to detect significant asso-
ciations. Furthermore, kidneys from female donors
made up less than 30% of those allografts in the
highest delta ICD quartile compared with more
than 40% in the lowest three quartiles; however,
this association did not reach statistical signifi-
cance using our approach. consistent with the worse medium-term outcomes
observed in kidneys transplanted from such donors
(14). Our cohort included too few donors with DM
to draw adequate conclusions as to any association
between this risk factor and delta ICD; however,
with the increasing use of diabetic donors, this
aspect of donor selection would merit further inves-
tigation. We examined associations between delta ICD
(as the explanatory variable) and eGFR, both at
the time of second biopsy and at one yr. Unsur-
prisingly, delta ICD was associated with eGFR at
both time points. These finding are similar to those
reported by Servais and colleagues (9). However,
change in ICD between implantation and first
post-transplantation biopsy was not additionally
informative of biochemical outcome at one yr (a
surrogate for graft loss (2)) over and above an
eGFR measured at the time of the latter biopsy. This analysis does have potential for confounding
as clinicians were aware of ICD scores and may
have altered patient management accordingly, and
the small numbers of transplants lost in the period
between first post-transplant biopsy and end of fol-
low-up mean that we are unable to examine hard
outcomes such as graft failure. However, these
findings do suggest that although early change in
chronic damage reflects past insults, this measure is
unlikely to provide useful information (above rou-
tine biochemical measures) on the future trans-
plant course as judged by change from eight-wk to
one-yr eGFR. Younger donor age and live donation were
independently associated with reduced odds of
higher delta ICD. As age is known risk factor for
failure to recover from acute kidney injury (13), it
might be expected to impact on recovery from
transplantation-associated
ischemia–reperfusion
injury. In one similar study, a similar association
was found on univariable testing (9). Early change in ICD reflects donor factors Another
recent study did not observe a similar association
with donor age (8); this may be because this inves-
tigation was restricted to live donors, where the
increase in ICD is not marked, limiting the power
to detect any relationship. Although live donors
are often younger than DBD or DCD, the associ-
ation of live donation with lower delta ICD was
independent of donor age. Overall, there was a small, but highly significant
increase in ICD between biopsies. This increase in
chronic damage in our cohort appears consistent
with what has been reported in other studies [(8),
(9)]. This early increase in chronic damage suggests
that the process of transplantation itself leads not
only to an acute kidney injury, but also to irrevers-
ible damage detectable at 2–3 months. Almost 16% of serial protocol biopsies demon-
strated a negative delta ICD. Areas of chronic
damage are not thought to recover, so these values
are unlikely to represent true changes. A similar
finding has been reported elsewhere (15), and as
interobserver variability and intra-observer vari-
ability in the reporting of ICD have been found to
be low (7), negative scores are likely to reflect sam-
pling variation. This implies that although poten-
tially a useful research tool, for an individual, even
serial ICD measurements are likely to be of limited
utility except perhaps for very high values (7). Despite differences in ICD at implantation, there
was no evidence for a difference in delta ICD
between DBD and DCD after adjustment for donor
age, suggesting that although kidneys from DCD in
our cohort may have higher levels of chronic dam-
age prior to transplantation, the post-transplant
progression of this damage is similar between these
two donor types. We also found no evidence that
either CIT (within the range of CIT seen in deceased
donors) or early acute rejection was associated with
delta ICD. It is impossible to confidently separate
the impact of CIT from donor type in a study of this
design, but these data suggest that there may be
non-ischemic mediators of the association between
live donors and lower delta ICD. The attenuation
of the differences between live and DBD donors
after exclusion of donors dying from ICH may
implicate this cause of donor death in aggravated
transplantation-associated allograft injury and is In addition to those mentioned above, our study
has several other weaknesses. associations were seen between episodes of rejec-
tion or length of CIT (in deceased donors only)
and delta ICD. Associations between delta ICD and biochemical
measures of kidney function There was a strong association between delta ICD
and eGFR at day 56 (Table 4). There was also an
association between delta ICD and quartile of
eGFR at day 365 on multivariate testing (adjusted
for episodes of rejection, recipient age, ethnic
group, sex, and diabetes) when biochemical kidney
function at the time of second biopsy was not
included in the model. To test whether early fibro-
sis would be a useful predictor of future allograft
function, we examined whether this measure was Donor age was independently associated with
ICD0 underlining the well-recognized importance
of this variable in considering the suitability of
organs for transplantation. Furthermore, DCD
kidneys had a higher baseline ICD independent of
age, which may reflect a difference in the underly-
ing clinical characteristics of donors of kidneys of
these types accepted at our institution. No differ-
ences in baseline ICD were observed between E676 Early change in ICD reflects donor factors Authors’ contributions 9. SERVAIS A, MEAS-YEDID V, NO€EL LH et al. Interstitial
fibrosis evolution on early sequential screening renal allo-
graft biopsies using quantitative image analysis. Am J
Transplant 2011: 11: 1456. BC designed the study, collected, and analyzed
data and wrote the manuscript. AM, KV, MM,
and JH collected data; DN contributed to the
analysis; PD and DCW contributed to the interpre-
tation of the data and writing of the manuscript. MH and BF contributed to the concept and design
of the study, performed the protocol biopsies, and
helped write the manuscript along with GJ who
also collected data; AJH performed the ICD mea-
surements and helped write the manuscript; PV
conceived the project, performed the biopsies, and
acted as a guarantor for the manuscript. All
authors have reviewed and accepted the final
version of the manuscript. 10. NHS BLOOD
AND TRANSPLANT, ORGAN DONATION
AND
TRANSPLANTATION. Patient selection and allocation poli-
cies. Kidney transplantation: organ allocation. 2013. Available at: http://www.odt.nhs.uk/pdf/kidney_allocation_
policy.pdf 11. LEVEY AS, CORESH J, GREENE T et al. Using standardized
serum creatinine values in the modification of diet in renal
disease study equation for estimating glomerular filtration
rate. Ann Intern Med 2006: 145: 247. 12. KAYLER LK, RASMUSSEN CS, DYKSTRA DM et al. Gender
imbalance and outcomes in living donor renal transplanta-
tion in the United States. Am J Transplant 2003: 3: 452. 13. SCHMITT R, COCA S, KANBAY M, TINETTI ME, CANTLEY
LG, PARIKH CR. Recovery of kidney function after acute
kidney injury in the elderly: a systematic review and meta-
analysis. Am J Kidney Dis 2008: 52: 262. Caplin et al. knowledge, this is the largest study examining
changes in ICD in recipients of kidneys from unse-
lected donors, it is possible that it was underpow-
ered to detect all the important relationships of
delta ICD. However, with more than 50 trans-
plants of each donor type, we would expect to
identify most clinically relevant associations. 2. HARIHARAN S, MCBRIDE MA, CHERIKH WS, TOLLERIS CB,
BRESNAHAN BA, JOHNSON CP. Post-transplant renal func-
tion in the first year predicts long-term kidney transplant
survival. Kidney Int 2002: 62: 311. 3. NANKIVELL BJ, BORROWS RJ, FUNG CL, O’CONNELL PJ,
ALLEN RD, CHAPMAN JR. The natural history of chronic
allograft nephropathy. N Engl J Med 2003: 349: 2326. 4. COSIO FG, GRANDE JP, WADEI H, LARSON TS, GRIFFIN
MD, STEGALL MD. Predicting subsequent decline in kid-
ney allograft function from early surveillance biopsies. Am
J Transplant 2005: 5: 2464. In summary, this study demonstrated an early,
small, but measurable increase in irreversible dam-
age in allograft kidneys over the first three months
following transplantation. This increase in chronic
damage was associated with donor age. Further-
more, transplantation from a live donor was asso-
ciated with a smaller increase in ICD. The routine
clinical value of measurement of chronic damage is
unclear due to both the potential for sampling vari-
ation and the observation that the early increase in
histological damage appears to reflect past insults,
but not future course as judged by biochemical
change in function over the following nine months. p
5. COSIO FG, GRANDE JP, LARSON TS et al. Kidney allograft
fibrosis and atrophy early after living donor transplanta-
tion. Am J Transplant 2005: 5: 1130. 6. YILMAZ S, TOMLANOVICH S, MATHEW T et al. Protocol core
needle biopsy and histologic Chronic Allograft Damage
Index (CADI) as surrogate end point for long-term graft
survival in multicenter studies. J Am Soc Nephrol 2003:
14: 773. 7. HOWIE AJ, FERREIRA MA, LIPKIN GW, ADU D. Measure-
ment of chronic damage in the donor kidney and graft sur-
vival. [Miscellaneous article]. Transplantation 2004: 77:
1058. 8. MIURA Y, SATOH S, SAITO M et al. Factors increasing
quantitative interstitial fibrosis from 0 hr to 1 year in liv-
ing kidney transplant patients receiving tacrolimus. Trans-
plantation 2011: 91: 78. Early change in ICD reflects donor factors Although we exam-
ined, and found little evidence for, differences
between the group undergoing protocol biopsies
and those who did not, we cannot exclude the pos-
sibility that we have examined a selected group of
patients. All our patients were from a single center,
and therefore, our conclusions may not be general-
izable. Furthermore, we did not examine our biop-
sies for inflammation in scarred areas, a finding
that has been reported to be a useful predictor of
adverse graft outcomes (4). Although, to our E677 1. U.S. DEPARTMENT
OF HEALTH
AND HUMAN SERVICES,
H.R.a.S.A.,
Healthcare
Systems
Bureau,
Division
of
Transplantation, Rockville, MD., Annual Report of the
U.S. Organ Procurement and Transplantation Network
and the Scientific Registry of Transplant Recipients:
Transplant Data 1999–2008. 2009. References 14. BUSSON M, BENOIT G, N’DOYE P, HORS J. Analysis of
cadaver donor criteria on the kidney transplant survival
rate in 5,129 transplantations. J Urol 1995: 154(2 Pt 1):
356. 1. U.S. DEPARTMENT
OF HEALTH
AND HUMAN SERVICES,
H.R.a.S.A.,
Healthcare
Systems
Bureau,
Division
of
Transplantation, Rockville, MD., Annual Report of the
U.S. Organ Procurement and Transplantation Network
and the Scientific Registry of Transplant Recipients:
Transplant Data 1999–2008. 2009. 15. STEGALL MD, PARK WD, LARSON TS et al. The histology
of solitary renal allografts at 1 and 5 years after transplan-
tation. Am J Transplant 2011; 11: 698. E678
|
https://openalex.org/W2956669133
|
https://epub.ub.uni-muenchen.de/79601/1/fpsyt-10-00458.pdf
|
English
| null |
Low-Grade Inflammation as a Predictor of Antidepressant and Anti-Inflammatory Therapy Response in MDD Patients: A Systematic Review of the Literature in Combination With an Analysis of Experimental Data Collected in the EU-MOODINFLAME Consortium
|
Frontiers in psychiatry
| 2,019
|
cc-by
| 13,869
|
ORIGINAL RESEARCH
doi: 10.3389/fpsyt.2019.00458
published: 09 July 2019 Edited by:
Iris E. Sommer,
University Medical Center Graniger,
Netherlands Edited by:
Iris E. Sommer,
University Medical Center Graniger,
Netherlands Reviewed by:
Eva E. Redei,
Northwestern University,
United States
Jennifer C. Felger,
Emory University,
United States Gara Arteaga-Henríquez 1,2,3†, Maria S. Simon 1†, Bianka Burger 4, Elif Weidinger 1,
Annemarie Wijkhuijs 5, Volker Arolt 6, Tom K. Birkenhager 7, Richard Musil 1,
Norbert Müller 1,4‡ and Hemmo A. Drexhage 2‡* 1 Department of Psychiatry and Psychotherapy, University Hospital, Ludwig-Maximilian-University, Munich,
Germany, 2 Department of Immunology, Erasmus Medical Center, Rotterdam, Netherlands, 3 Psychiatry,
Mental Health and Addictions Group, Vall d’Hebron Research Institute (VHIR), Barcelona, Spain, 4 Marion von Tessin
Memory-Center, Munich, Germany, 5 RMS, Rotterdam, Netherlands, 6 Department of Psychiatry and Psychotherapy,
University Hospital of Muenster, Muenster, Germany, 7Department of Psychiatry, Erasmus Medical Center,
Rotterdam, Netherlands *Correspondence:
Hemmo A. Drexhage
h.drexhage@erasmusmc.nl *Correspondence:
Hemmo A. Drexhage
h.drexhage@erasmusmc.nl ‡These authors share last authorship. Low-grade inflammation plays a role not only in the pathogenesis of major depressive
disorder (MDD) but probably also in the poor responsiveness to regular antidepressants. There are also indications that anti-inflammatory agents improve the outcomes of
antidepressants. Specialty section:
This article was submitted to
Molecular Psychiatry,
a section of the journal
Frontiers in Psychiatry
Received: 03 December 2018
Accepted: 11 June 2019
Published: 09 July 2019 Specialty section:
This article was submitted to
Molecular Psychiatry,
a section of the journal
Frontiers in Psychiatry Aim: To study whether the presence of low-grade inflammation predicts the outcome of
antidepressants, anti-inflammatory agents, or combinations thereof. Received: 03 December 2018
Accepted: 11 June 2019
Published: 09 July 2019 Methods: We carried out a systematic review of the literature on the prediction capability
of the serum levels of inflammatory compounds and/or the inflammatory state of
circulating leukocytes for the outcome of antidepressant/anti-inflammatory treatment in
MDD. We compared outcomes of the review with original data (collected in two limited
trials carried out in the EU project MOODINFLAME) on the prediction capability of the
inflammatory state of monocytes (as measured by inflammatory gene expression) for the
outcome of venlafaxine, imipramine, or sertraline treatment, the latter with and without
celecoxib added. July 2019 | Volume 10 | Article 458 INTRODUCTION Since most of the antidepressant drugs have—next to
their neurotransmission modulatory effects—also immune
modulating capacities (28, 29), it is thought that the
inflammatory state of patients might play a role in non-
responsiveness. To enforce the mood-regulating effects of
antidepressants, and being aware of the notion that low-
grade inflammation plays a role, various studies have been
undertaken to use anti-inflammatory agents as add-ons to
regular antidepressant therapies. In this way, acetylsalicylic
acid (i.e., aspirin, a COX1 and COX2 inhibitor), selective
COX-2 inhibitors (e.g., celecoxib), minocycline (a tetracyclin
with anti-inflammatory effects), and anti-TNF monoclonal
antibodies (e.g., infliximab) have been used experimentally
(30–33). Besides these anti-inflammatory agents, agents such
as cholesterol-lowering fish oil (eicosapentaenoic acid) and
anti-oxidative n-acetylcysteine have also been used (33, 34). These agents also have anti-inflammatory actions, since both
the cholesterol metabolism and the anti-oxidative machinery
are linked to inflammation (35, 36). Though it seems that anti-
inflammatory agents did show limited beneficial effects in
most of the reported studies (30–34), there is still doubt on
the real validity of such interventions, particularly due to the
paucity and preliminary character of the studies, while there is
also the feeling that such anti-inflammatory agents might only
work in a proportion of patients. It is well accepted that immune dysregulation plays an
important role in the pathogenesis of at least a proportion
of patients with major depressive disorder (MDD) (1–16). Genetic defects and/or polymorphisms, childhood trauma,
and chronic stress are all capable of eliciting such immune
dysregulations (17–19). In the last decades, special interest
has been raised for the role of low-grade inflammation in
the immune system dysregulation of MDD. Low-grade
inflammation is characterized by an increase in the level of
circulating pro-inflammatory compounds, such as acute phase
proteins [e.g., C-reactive protein (CRP)] and cytokines [e.g.,
interleukin (IL)-6], and/or by a pro-inflammatory activity of
circulating or tissue resident immune cells (20–23). A wide range of medications is currently available
for the treatment of MDD. First-line agents are the well-
known serotonin reuptake inhibitors (SSRIs; e.g., sertraline,
escitalopram, or citalopram), which show a predominantly
serotonergic action (24). First-line agents are also the
serotonin-noradrenaline reuptake inhibitors (SNRIs), which
show a predominantly serotonergic action at low doses and
a combined serotonergic–noradrenergic action at moderate
to high doses (25). Citation: Arteaga-Henríquez G, Simon MS,
Burger B, Weidinger E, Wijkhuijs A,
Arolt V, Birkenhager TK, Musil R,
Müller N and Drexhage HA
(2019) Low-Grade Inflammation
as a Predictor of Antidepressant
and Anti-Inflammatory Therapy
Response in MDD Patients: A
Systematic Review of the Literature
in Combination With an Analysis of
Experimental Data Collected in the
EU-MOODINFLAME Consortium. Front. Psychiatry 10:458. doi: 10.3389/fpsyt.2019.00458 Results: Collectively, the literature and original data showed that: 1) raised serum
levels of pro-inflammatory compounds (in particular of CRP/IL-6) characterize an
inflammatory form of MDD with poor responsiveness to predominately serotonergic
agents, but a better responsiveness to antidepressant regimens with a) (add-on) July 2019 | Volume 10 | Article 458 Frontiers in Psychiatry | www.frontiersin.org 1 Arteaga-Henriquez et al. Prediction of Anti-Depressive/Anti-Inflammatory Therapy Response in MDD noradrenergic, dopaminergic, or glutamatergic action or b) (add-on) anti-inflammatory
agents such as infliximab, minocycline, or eicosapentaenoic acid, showing—next
to anti-inflammatory—dopaminergic or lipid corrective action; 2) these successful
anti-inflammatory (add-on) agents, when used in patients with low serum levels of
CRP/IL-6, decreased response rates in comparison to placebo. Add-on aspirin, in
contrast, improved responsiveness in such “non-inflammatory” patients; 3) patients
with increased inflammatory gene expression in circulating leukocytes had a poor
responsiveness to serotonergic/noradrenergic agents. Conclusions: The presence of inflammation in patients with MDD heralds a poor
outcome of first-line antidepressant therapies. Immediate step-ups to dopaminergic
or glutamatergic regimens or to (add-on) anti-inflammatory agents are most likely
indicated. However, at present, insufficient data exist to design protocols with reliable
inflammation parameter cutoff points to guide such therapies, the more since detrimental
outcomes are possible of anti-inflammatory agents in “non-inflamed” patients. Keywords: major depression, inflammation, antidepressant therapy, anti-inflammatory therapy, therapy prediction INTRODUCTION Tricyclic antidepressants (TCAs) show
a similar mechanism of action as SNRIs regarding the dual
serotonergic-noradrenergic action, but because of more side
effects, they are actually used as second-line agents. Third-
line agents are drugs with a predominantly noradrenergic/
dopaminergic action, such as mirtazapine or bupropion, or
agents with other mechanisms of action, such as ketamine
[i.e., an N-methyl-d-aspartate (NMDA) receptor antagonist,
elevating glutamate levels]. Despite this wide range of
medications, response rates to treatment are still insufficient,
with about half of the patients not responding adequately to an
installed treatment (26, 27). Collectively, the abovementioned notions lead to the view
that there is a need for a personalized medicine approach to
select patients who, in particular, will respond to first-line
agents and those needing immediate step-up therapies to
drugs other than the first-line drugs and/or an add-on of a
first-line agent with an anti-inflammatory agent. In such
an approach, it is the question whether a pre-existent state
of enhanced low-grade inflammation (present in around
one-third of patients) (37) indeed plays a role in non-
responsiveness to antidepressants and whether such a state July 2019 | Volume 10 | Article 458 Frontiers in Psychiatry | www.frontiersin.org 2 Prediction of Anti-Depressive/Anti-Inflammatory Therapy Response in MDD Arteaga-Henriquez et al. is capable of predicting the outcome of the abovementioned
antidepressant therapy regimens. agents. To make comparisons possible, we indicate in the
result section (Table 1C, marked with B and C) which
studies included bipolar depressed patients, and we discuss
in the Discussion section putative differences stemming
from this inclusion. For this report, we have carried out a systematic review
searching for the relevant literature on the prediction capability
of soluble inflammatory compounds/cytokines in serum/plasma/
CSF and/or the inflammatory state of circulating leukocytes for
the outcome of antidepressant/anti-inflammatory treatments
in MDD. We combined the outcomes of the systematic review
with experimental data collected in the EU-MOODINFLAME
consortium on the prediction capability of the inflammatory
state of circulating monocytes (as measured by inflammatory
gene expression). Two EU-MOODINFLAME trials could be
evaluated, a trial carried out on patients with MDD collected at
the Rotterdam site and treated in first line with venlafaxine or
imipramine (38), and a small trial carried out on patients with
MDD collected at the Munich site and treated with sertraline plus
add-on celecoxib or placebo. INTRODUCTION (4) the absence of severe somatic diseases (especially
inflammation-related); l
(5) the assessment of immune biomarkers;i (6) the use of first-line or other antidepressant agents or the
use of an anti-inflammatory agent added to antidepressant
treatment or alone; (7) the assessment of symptom reduction with standardized
measure [e.g., Hamilton Rating Scale for Depression
(HAMD), Montgomery–Asberg Depression Rating Scale
(MADRS), Beck’s depression inventory (BDI)] and (MADRS), Beck’s depression inventory (BDI)] and (8) the analysis of responder and non-responder subgroups. By reading the abstracts, methods, and results sections
and applying the inclusion criteria and by removing
duplicate records, 36 studies were selected. Further exclusion
criteria were: Search Strategy for Systematic Review (1) no predictive information provided;l (2) use of parameters that are not inflammatory biomarkers in a
narrower sense [e.g., serotonin and kynurenine metabolites,
brain-derived neurotrophic factor (BDNF), calcium-binding
protein B (S100B), macrophage-derived chemokine (MDC),
platelet-derived growth factor (PDGF), and Eotaxin-1/
CCL11]; (3) genetic studies were excluded except for leukocyte gene
expression level studies;l (4) the use of agents whose anti-inflammatory mechanisms
are not direct and even questionable (e.g., l-methylfolate,
pioglitazone, modafinil). y
The following search terms were used: (mdd OR major
depressive disorder OR depression) AND (inflammation) AND
(therapy OR treatment OR antidepressant drugs OR sertraline OR
venlafaxine OR escitalopram OR citalopram OR tricyclic OR ssri
OR snri) AND (biomarker OR cytokines OR il-6 OR t cells OR nk
cells OR th17 OR leukocytes OR macrophages OR crp OR genes)
AND (response OR prediction), (mood disorder OR depression
OR bipolar) AND (anti-inflammatory OR inflammation) AND
(therapy OR treatment OR medication OR drugs OR add-on
OR adjunct OR anti TNF OR infliximab OR CRP OR aspirin
OR ASA OR acetyl salicylic acid OR minocycline OR omega 3
fatty acids OR NAC OR acetylcysteine OR cox 2 inhibitor OR
celecoxib) AND (biomarker OR cytokines OR macrophages OR
t cells OR NK cells OR leukocytes OR CRP OR genes). By applying these exclusion criteria, we finally included 24
reports in the systematic review. With the purpose of providing a comprehensive presentation,
we decided to split the remaining studies into studies concerning
circulating inflammatory compounds/cytokines (n = 19, see
Tables 1A–C) and gene expression in circulating leukocytes
(n = 5; see Table 2). For detailed information about the study
selection, see Figure 1. MATERIALS AND METHODS Search Strategy for Systematic Review
We conducted a systematic literature search in the PubMed/
MEDLINE and Web of Science databases to identify immune-
inflammatory predictors for treatment response to antidepressants,
anti-inflammatory agents, and/or their combination with anti-
inflammatory agents (or anti-inflammatory agents alone) in
MDD from inception (for anti-inflammatory) and from 2008
(for antidepressant) until August 16, 2018. To find additional
relevant studies, citation lists of included articles were tracked in
Google Scholar (39) or citation lists of topic-related reviews and
meta-analyses were checked. The last author of a significant paper
concerning celecoxib and an expert in the field (NM) was also
contacted and asked of awareness of any additional studies. Experimental Clinical Studies Details on the inclusion and exclusion criteria, as well as on the
clinical instruments and characteristics of patients, have been
published before (38, 64). In short, in- and outpatients were
recruited from the Departments of Psychiatry at the Erasmus
Medical Centre (ErasmusMC) in Rotterdam (The Netherlands)
and at the University Hospital of the Ludwig Maximilian
University (LMU) in Munich (Germany). All patients were
diagnosed according to the Diagnostic and Statistical Manual
of Mental Disorders, Text Revision (DSM-IV-TR) (65) and
confirmed by using the Structured Clinical Interview for
DSM-IV Axis I Disorders (SCID-I) (66). Included were patients
with a minimum score of 17 (Rotterdam) or 22 (Munich) on y
g
The initial search of 7,047 studies resulted in 174
relevant studies selected by title. Inclusion criteria for further
selection were: (1) publications written in the English language; (2) human clinical trials; (3) the diagnosis of MDD. Because of the paucity of studies in
unipolar depression, both unipolar and bipolar depression
were included for the studies on (add-on) anti-inflammatory July 2019 | Volume 10 | Article 458 Frontiers in Psychiatry | www.frontiersin.org 3 Prediction of Anti-Depressive/Anti-Inflammatory Therapy Response in MDD Arteaga-Henriquez et al. FIGURE 1 | Flow diagram of the systematic research. See materials and methods section for further explanation. FIGURE 1 | Flow diagram of the systematic research. See materials and methods section for further explanation. including schizophrenia, psychotic disorders, mood disorders,
anxiety disorders, or substance-related disorders according to
DSM-IV criteria; the absence of usage of psychiatric drugs; and
the absence of severe medical illness. HC had to be in self-
proclaimed good health and free of any obvious medical illness
for at least 2 weeks prior to the blood withdrawal, including
acute infections and allergic reactions. the Hamilton Rating Scale for Depression (HAMD, 17-item-
version) (67). Studies had been approved by the ethics committee of
the medical faculty at the LMU, Munich (Germany), and the
medical ethics committee of the ErasmusMC, Rotterdam (the
Netherlands). The study was conducted in compliance with
standards of Good Clinical Practice (CGP), assuring that the
rights, safety, and well-being of patients were protected in
accordance with the principles that have their origin in the
Declaration of Helsinki (June 1964, last amendment Fortaleza
2013). Additionally, the relevant national and European
regulations were adhered, too. After study procedures
had been fully explained, all subjects provided written
informed consent. Treatment Protocols Being both double-blind studies, subjects, investigators, and
study staff had been blinded to the treatment assignment for the
duration of the study. Venlafaxine/Imipramine Study (Rotterdam) Prior to the start of antidepressants, patients with MDD underwent
a wash-out period for at least 1 week. The use of benzodiazepines
was allowed up to a maximum daily dose of 3 mg lorazepam
or the corresponding equivalent. Subsequently, patients were
randomly assigned to a 7-week monotherapy with either the
serotonin-norepinephrine reuptake inhibitor (SNRI) venlafaxine Sertraline Plus Placebo/Celecoxib Study (Munich) Sertraline Plus Placebo/Celecoxib Study (Munich)
Prior to the start of treatment, patients with MDD underwent
a washout period for 3 days. The use of lorazepam or zopiclon
was allowed in this period and also during the study, up to a
maximum daily dose of 3 or 15 mg, respectively. Subsequently,
patients were randomly assigned in a 1:1 ratio to a 6-week
therapy with either the selective serotonin reuptake inhibitor
(SSRI) sertraline plus placebo, or with sertraline plus the
selective COX-2 inhibitor celecoxib. The dose of sertraline
was flexible and ranged between 50 and 100 mg/day. A daily
dose higher than 100 mg was not recommended, but in the
expectation of more clinical benefit, a daily dose of 150 mg
sertraline was allowed. The daily dose of celecoxib was 400 mg
(200 mg in the morning and 200 mg in the evening). Patients
from the placebo group received two identical capsules
(morning and evening). As in the Rotterdam cohort, response
to treatment was defined as ≥50% reduction of the initial
HAM-D score. y
Based on several previous studies on mood disorders (21, 64,
69), we decided to include in our panel the most consistently
abnormally expressed inflammatory genes in the studies. Therefore,
relative to the housekeeping gene ABL1, the expression of a total of
up to 49 genes was determined (also because of the maximum of fill
ports in the Taqman assay) and expression values were calculated
using the comparative threshold cycle (CT) method [see, for
technical details, Refs. (21, 64, 69)]. The mentioned earlier studies
also carried out a hierarchical clustering of these genes and found
two main distinct clusters of gene expression. The first cluster is
found consistently in virtually all of our monocyte inflammatory
gene expression studies (also besides disease conditions such as
mood disorders), and this cluster is composed of well-known
pro-inflammatory cytokines and chemokines and important
enzymes or transcription factors to produce these compounds. For
the calculation of the “positivity of this inflammatory compound
cluster”, we took the expression level of the top 10 genes [the most
consistently overexpressed genes in all our studies thus far; see Ref. (64)] of this cluster into consideration, i.e., IL1β, CCL20, EREG,
IL6, TNFAIP3, CXCL2, PDE4B, ATF3, PTX3, and IL1A. These
genes accounted for 70–99% of the inflammatory cluster response. For each of the 10 genes, we determined a range of the HC gene
expression (using the 2−ΔCt values). Numbers of Patients With MDD and HC Only patients and HC with full data regarding the expression
levels of all key genes for monocyte inflammatory activation could
be used for the present study. The Rotterdam sample therefore
consisted of 34 MDD patients and 45 HC. Of the patient group,
14 patients were treated with venlafaxine and 20 patients were
treated with imipramine. The Munich sample consisted therefore
of 35 MDD patients and 42 HC. Of the patient group, 19 patients
were treated with sertraline plus placebo, and 16 patients were
treated with sertraline plus celecoxib. Blood Collection Blood was collected in sodium-heparin tubes (36 ml) for immune
cell preparation just prior to treatment. From the heparinized
blood, peripheral blood mononuclear cell (PBMC) suspensions
were prepared by low-density gradient centrifugation via Ficoll-
Paque PLUS (GE Healthcare, Uppsala, Sweden) within 8 h to
avoid erythrophagy-related activation of the monocytes. PBMCs
were frozen in 10% dimethylsulfoxide and stored in liquid
nitrogen. This enabled us to test immune cells of patients and
controls together at a later stage. Tests were done at ErasmusMC. Monocyte Inflammatory Gene Expression
CD14+ monocytes were isolated from aliquots of the frozen and
thawed PBMCs by a magnetic cell sorting system (auto MACS
Pro, Miltenyi Biotec, B.V., Bergisch Gladbach, Germany). The
average viability was 86.3 ± 10.4 (Trypan blue staining) and
the purity of monocytes was 95.1 ± 3.0% (flow cytometry). RNA was isolated from the purified monocytes using RNA
easy mini kit according to the manufacturer’s instructions
(Qiagen, Hilden, Germany). On average, monocytes cell yield Frontiers in Psychiatry | www.frontiersin.org Healthy Controls Healthy controls (HCs) were recruited from the same
communities (Rotterdam and Munich). Details on the HC can
be found in Refs. (64) and (68). In short, the inclusion criteria
for HC were the absence of major DSM-IV-TR Axis I disorders July 2019 | Volume 10 | Article 458 Frontiers in Psychiatry | www.frontiersin.org 4 Prediction of Anti-Depressive/Anti-Inflammatory Therapy Response in MDD Arteaga-Henriquez et al. (mean daily dose 371 mg, range dose of 300–375 mg/day) or
with the TCA imipramine (mean dose 206 mg, range dose of
50–450 mg/day). The duration of the treatment trial was 7 weeks
to ensure that patients treated with imipramine had adequate
plasma levels for at least 4 weeks. Response to treatment was
defined as ≥50% reduction of the initial HAM-D score. after isolation was 2.0 ± 1.6 × 106/subject and the quantity of
RNA in monocytes was 3.2 ± 1.8 μg. One microgram of RNA
was reverse-transcribed using the cDNA high capacity reverse
transcription kit (Applied Biosystems, Foster City, CA, USA). qPCR was performed using Taqman Arrays, format 48 (Applied
Biosystems), according to the manufacturer’s protocol and
validated against the single RT-qPCR method. Per fill port,
400 ng of cDNA (converted from total RNA) was loaded. PCR
amplification was performed using an Applied Biosystems
Prism 7900HT sequence detection system with TaqMan Array
block. Thermal cycler conditions were 2 min at 50°C, 10 min at
94.5°C, 30 s at 97°C, and 1 min at 59.7°C for 40 cycles. Sertraline Plus Placebo/Celecoxib Study (Munich) The range was defined by the
mean of the values for that gene in HC monocytes ± 1 standard
deviation (SD). Then, we used this range as a standard of comparison
for the MDD patients’ gene expression. We decided to refer to a
patient’s top gene as upregulated, if the patient’s gene expression
was higher than HC’s mean plus 1×SD, or downregulated when
it was lower than HC’s mean minus 1×SD. This was done for all
10 above given genes. Then, we declared the monocyte population
of a given patient as “pro-inflammatory positive” if 6 of these 10
top inflammatory genes (or more) were upregulated. These data
are given in Table 3 in the Results section. Similar calculations/
algorithms for monocyte inflammatory positivity have been used
by us before (21, 69–71). Further methodological details of the
calculation can be found in these publications. Original Q-PCR
data have been uploaded and can be retrieved via the GEO
repository ref number GSE132315: http://www.ncbi.nlm.nih.gov/
geo/query/acc.cgi?acc=GSE132315 Systematic Review Data on the
Usefulness of Circulating Serum
Inflammatory Compounds Tables 1A, 1B, and 1C show the data of the systematic review
of the 19 selected articles (see the section Search Strategy
for Systematic Review) regarding the predictive capability
of inflammatory state [assessed by serum/plasma immune
compounds (mainly CRP and cytokines) (only one study used
CSF)] in patients with MDD for the response rates to various
classes of antidepressant drugs and to anti-inflammatory agents
added to an antidepressant regimen (except for one study, in
which the anti-inflammatory agent was used as monotherapy)
(52). For comprehensibility, we have grouped the outcomes in
Table 1 according to the regimen used. Taken together, predominantly serotonergic agents showed,
in general, insufficient response rates in those patients with signs
of moderate to high inflammation as measured by circulating
inflammatory compounds.h l
The review also delivered that, in such conditions of moderate
to high signs of inflammation, drugs with another mechanism
of action than primarily serotonergic do show an effect. Using
nortriptyline, mirtazapine, or ketamine alone, or combinations
of an SSRI with nortriptyline or bupropion resulted, in 5 out of 5
studies, in improved responses rates (40, 41, 49–51) as compared
to the patients with low inflammatory markers (Table 1B). Table 1A shows that, in three out of three studies (40–
42), antidepressants with a predominant serotonergic action
[i.e., escitalopram (SSRI)] induced a better response in patients
with low inflammatory markers as compared to patients with
high inflammatory markers in the same study. On the contrary,
when inflammatory markers were high, five out of seven of the l
y
Similar beneficial effects existed for combinations of
antidepressant drugs with anti-inflammatory agents. Table 1C TABLE 1A | Predominantly serotonergic action: higher response rates in low inflammatory state vs. moderate–high inflammatory state (prior to treatment). Statistics Statistical analyses were performed using IBM SPSS v.21 for
Mac. Continuous sample characteristics are reported as mean
(± standard deviation). Group comparisons (e.g., MDD vs. HC,
responders vs. non-responders) were analyzed using analysis of July 2019 | Volume 10 | Article 458 Frontiers in Psychiatry | www.frontiersin.org 5 Prediction of Anti-Depressive/Anti-Inflammatory Therapy Response in MDD Arteaga-Henriquez et al. studies (40, 45–48) showed that drugs with a predominant
serotonergic action (i.e., SSRIs, SNRIs, and TCAs) induced
reduced response rates as compared to patients with low
inflammatory markers in the same study. Cutoff points for low
and high levels were defined for CRP in the reviewed studies
at 1 mg/L; for IL-6 and TNFα, values depended on the actual
sensitivity of the assay used in the report. Two studies formed
an exception. Manoharan et al. (44) did not find any effect of
pre-selection of the inflammatory state. However, this study
was special in that treatment duration was of only 6 weeks, and
patients had a relatively low to moderate depression severity
(HAMD score ≥ 13). The other study (43) showed the opposite
message (i.e., an improved response to SSRIs in patients with
a high inflammatory state as compared to a low inflammatory
state). This study was special, in that many patients were treated
with paroxetine (SSRIs), which—apart from its serotonergic
action—also exerts a considerable dopaminergic action (72). variance (ANOVA) tests for continuous data (e.g., age) and using
Pearson’s chi-square (χ²) tests for categorical data (e.g., gender). For
group comparisons of positivity of monocyte gene expression (e.g.,
MDD vs. HC, responders/non-responders vs. HC, responders vs. non-responders), Pearson’s chi-square (χ²) tests were applied, too. All hypotheses were tested with α ≤ 0.05 (two-sided). SSRI, selective serotonin reuptake inhibitors; SNRI, serotonin-norepinephrine reuptake inhibitor; TCA, tricyclic antidepressant; TNFα, tumor necrosis factor alpha; IL, interleukin;
CSF, cerebrospinal fluid; CRP, C-reactive protein; m–h, moderate–high; IS, inflammatory state.
*p ≤ 0.05, **p ≤ 0.01, ***p ≤ 0.001.
aImprovement on Montgomery–Asberg Depression Rating Scale (MADRS) score 3 points higher with nortriptyline when CRP ≥ 1 mg/L and 3 points higher with escitalopram when
CRP < 1 mg/L. SSRI, selective serotonin reuptake inhibitors; SNRI, serotonin-norepinephrine reuptake inhibitor; TCA, tricyclic antidepressant; TNFα, tumor necrosis factor alpha; IL, interleukin;
CSF, cerebrospinal fluid; CRP, C-reactive protein; m–h, moderate–high; IS, inflammatory state.
*p ≤ 0.05, **p ≤ 0.01, ***p ≤ 0.001. *p ≤ 0.05, **p ≤ 0.01, ***p ≤ 0.001.
aImprovement on Montgomery–Asberg Depression Rating Scale (MADRS) score 3 points higher with nortriptyline when CRP ≥ 1 mg/L and 3 points higher with escitalopram when
CRP < 1 mg/L. Systematic Review Data on the
Usefulness of Circulating Serum
Inflammatory Compounds INFLAMMATORY STATE
STUDY
DRUG
INFLAMMATORY TEST
RESPONSE
LOW
Jha et al., 2017 (40)
Escitalopram (SSRI) + Placebo
CRP < 1 mg/L
Higher response rates compared
to m–h IS *
Uher et al., 2014a (41)
Escitalopram (SSRI)
CRP < 1 mg/L
Higher response rates compared
to m–h IS ***
Eller et al., 2008 (42)
Escitalopram (SSRI)
TNFα
Higher response rates compared
to m–h IS *
MODERATE–HIGH
Yoshimura et al., 2013 (43)
Paroxetine, Sertraline (SSRI)
IL-6
Higher response rates compared
to low IS *
Manoharan et al., 2016 (44)
Fluoxetine (SSRI)
IL-6
No associations between
biomarker values and response
rates
Jha et al., 2017 (40)
Escitalopram (SSRI) + Placebo
CRP ≥ 1 mg/L
Lower response rate compared
to low IS *
Chang et al., 2012 (45)
Fluoxetine (SSRI), Venlafaxine (SNRI)
CRP ≥ 1 mg/L
Lower response rate compared
to low IS *
Haroon et al., 2018 (46)
SSRIs, SNRIs, TCA
CRP, IL-6, TNFα, sTNF-R2
Lower response rate compared
to low IS *
Yoshimura et al., 2009 (47)
Paroxetine, Sertraline, Fluvoxamine,
Milnacipran (SSRI, SSNRI)
IL-6
Lower response rate compared
to low IS *
Martinez et al., 2012 (48)
Venlafaxine (SNRI)
TNFα (CSF)
Lower response rate compared
to low IS *
SSRI, selective serotonin reuptake inhibitors; SNRI, serotonin-norepinephrine reuptake inhibitor; TCA, tricyclic antidepressant; TNFα, tumor necrosis factor alpha; IL, interleukin;
CSF, cerebrospinal fluid; CRP, C-reactive protein; m–h, moderate–high; IS, inflammatory state. *p ≤ 0.05, **p ≤ 0.01, ***p ≤ 0.001. aImprovement on Montgomery–Asberg Depression Rating Scale (MADRS) score 3 points higher with nortriptyline when CRP ≥ 1 mg/L and 3 points higher with escitalopram when
CRP < 1 mg/L. p ≤ 0.05, p ≤ 0.01,
p ≤ 0.001. aImprovement on Montgomery–Asberg Depression Rating Scale (MADRS) score 3 points higher with nortriptyline when CRP ≥ 1 mg/L and 3 points higher with escitalopram when
CRP < 1 mg/L. July 2019 | Volume 10 | Article 458 Frontiers in Psychiatry | www.frontiersin.org 6 Prediction of Anti-Depressive/Anti-Inflammatory Therapy Response in MDD Arteaga-Henriquez et al. TABLE 1B | Predominantly noradrenergic, predominantly dopaminergic, and glutamatergic action: higher response rates in moderate–high inflammatory state vs. low
inflammatory state (prior to treatment). Systematic Review Data on the
Usefulness of Circulating Serum
Inflammatory Compounds INFLAMMATORY STATE
STUDY
DRUG
INFLAMMATORY TEST
RESPONSE
LOW
Jha et al., 2017 (40)
Escitalopram (SSRI) + Bupropion (NDRI)
CRP < 1 mg/L
Lower response rate compared to
m–h IS *
MODERATE–HIGH
Jha et al.,2 017 (40)
Escitalopram (SSRI) + Bupropion (NDRI)
CRP ≥ 1 mg/L
Higher response rates compared
to low IS *
Uher et al., 2014a (41)
Nortriptyline (TCA)
CRP ≥ 1 mg/L
Higher response rates compared to
low IS ***
Harley et al., 2010 (49)
Fluoxetine (SSRI) + Nortriptyline (TCA)
CRP ≥ 1 mg/L
Higher response rates compared to
low IS ***
Yang et al., 2015 (50)
Ketamine (NMDA Receptor Antagonist)
IL-6
Higher response rates compared to
low IS ***
Gupta et al., 2016 (51)
Mirtazapine (NaSSA)
TNFα
Higher response rates compared
to low IS *
SSRI, selective serotonin reuptake inhibitors; NDRI, norepinephrine dopamine reuptake inhibitor; TCA, tricyclic antidepressant; NaSSA, noradrenergic and specific serotonergic
antidepressant; TNFα, tumor necrosis factor alpha; IL, interleukin; CRP, C-reactive protein; m–h, moderate–high; IS, inflammatory state. *p ≤ 0.05, **p ≤ 0.01, ***p ≤ 0.001. aImprovement on Montgomery–Asberg Depression Rating Scale (MADRS) score 3 points higher with nortriptyline when CRP ≥ 1 mg/L and 3 points higher with escitalopram when
CRP < 1 mg/L. TABLE 1B | Predominantly noradrenergic, predominantly dopaminergic, and glutamatergic action: higher response rates in moderate–high inflammatory state vs. low
inflammatory state (prior to treatment). SSRI, selective serotonin reuptake inhibitors; NDRI, norepinephrine dopamine reuptake inhibitor; TCA, tricyclic antidepressant; NaSSA, noradrenergic and specific serotonergic
antidepressant; TNFα, tumor necrosis factor alpha; IL, interleukin; CRP, C-reactive protein; m–h, moderate–high; IS, inflammatory state. *p ≤ 0.05, **p ≤ 0.01, ***p ≤ 0.001. aImprovement on Montgomery–Asberg Depression Rating Scale (MADRS) score 3 points higher with nortriptyline when CRP ≥ 1 mg/L and 3 points higher with escitalopram when TABLE 1C | Anti-inflammatory agents (added to an antidepressant regimen, except for one study): lower response rates in low inf
versus placebo and higher response rates in moderate–high inflammatory state versus low inflammatory state (prior to treatment). versus placebo and higher response rates in moderate–high inflammatory state versus low inflammatory state (prior to treatment). TNFα, tumor necrosis factor alpha; IL, interleukin; CRP, C-reactive protein; m–h, moderate–high; IS, inflammatory state.
*p ≤ 0.05, **p ≤ 0.01, ***p ≤ 0.001, reported effects without significance were not tested for significance but showed a clear descriptive trend and were therefore considered
noteworthy.
bMixed sample with MDD and bipolar depressed patients, cBipolar depressed sample (type I/II and unspecified), dPersonal communication. Systematic Review Data on Gene
Expression in Circulating Leukocytes It must be mentioned that the study of Savitz et al. (54) only
noted such improving effect with minocycline; aspirin had no
such effect in their study. Aspirin did work in their “non-inflamed”
patients, yet had no effect or even a reduced effect in patients with
high signs of inflammation, depending on the inflammatory serum
marker used to determine the state of low-grade inflammation
(CRP or IL-6, see Table 1C). The study of Savitz was also special
in that both unipolar and bipolar depressed patients were included. p
g
y
Table 2 shows the studies we selected that dealt with the gene
message for pro-inflammatory cytokine production in the
circulating leukocyte pool prior to treatment and predictive for
treatment outcome. We found five relevant articles. i
In 2013, Powell et al. (59) described a significantly increased
baseline expression of TNF in escitalopram non-responders (n =
21) compared to responders (n = 25) taken from the GENDEP
study. In the same year, Cattaneo et al. (61) reported on data
of the GENDEP study and found higher baseline mRNA levels
for IL1β, macrophage inhibiting factor (MIF), and TNF in
antidepressant (escitalopram or nortriptyline) non-responders
compared to responders, the three cytokine expressions together
explaining 46% of the variance of treatment response.i Table 1C additionally shows that there are also two out of
three studies (57, 58) that showed that in the case of add-on
n-acetyl cysteine, it was of no use to stratify the patients in low-
or high-grade inflammation prior to therapy. Two of the studies
of add-on n-acetyl cysteine (one showing and one not showing an
effect of prior determination of the inflammatory state) involved
both unipolar and bipolar depressed patients.l Belzeaux et al. (63) identified an algorithm of four mRNAs,
including two cytokine genes (TNF and IL1β, together with PPT1
and HIST1H1E) to be predictive of the treatment response in MDD. However, the weakness of their study was that a whole scale of
antidepressants was used, while numbers of patients and HC were
limited (16 vs. 13). Guilloux et al. (60) predicted non-remission
following escitalopram treatment in MDD with an accuracy of
79.4% using a 13-gene model including four genes associated with
immune and inflammatory activation (however, TNF was not
part of the 13 genes). Mediation of cell proliferation was another
important function of the remaining genes, but not exclusively. In 2016, Cattaneo et al. Systematic Review Data on the
Usefulness of Circulating Serum
Inflammatory Compounds INFLAMMATORY STATE
STUDY
DRUG
INFLAMMATORY TEST
RESPONSE
LOW
Rapaport et al., 2016
(52)
Monotherapy
eicosapentaenoic acid (EPA)
e.g., IL-1ra, hs-CRP
Lower response rate compared
to placebo of low inflammatory
state *
Raison et al., 2013b (53)
Infliximab (anti-TNFα)
CRP ≤ 5mg/L
Lower response rate compared
to placebo of low inflammatory
state **
Savitz et al., 2018c (54)
Minocycline
IL-6
Lower response rate compared
to placebo of low inflammatory
state d
Savitz et al., 2018c (54)
Aspirin (NSAID)
IL-6
Higher response rates compared
to m–h IS d
MODERATE–HIGH
Rapaport et al., 2016
(52)
Monotherapy
eicosapentaenoic acid (EPA)
e.g., IL-1ra, hs-CRP
Higher response rates compared
to low IS *
Raison et al., 2013b (53)
Infliximab (anti-TNFα)
CRP > 5mg/L, TNFα, sTNFR I and II
Higher response rates compared
to low IS **
Savitz et al., 2018c (54)
Minocycline
IL-6
Higher response rates compared
to low IS **d
Husain et al., 2017 (55)
Minocycline
CRP > 5 mg/L
Higher response rates compared
to low IS
Porcu et al., 2018c (56)
N-acetylcysteine
CRP > 5 mg/L
Higher response rates compared
to low IS *
Hasebe et al., 2017 (57)
N-acetylcysteine
IL-6
No associations between
biomarker values and response rates
Panizzutti et al., 2018c (58)
N-acetylcysteine
CRP, IL-6, TNFα, BDNF, IL-8, IL-10
No associations between
biomarker values and response
rates
Savitz et al., 2018c (54)
Aspirin (NSAID)
CRP
No associations between
biomarker values and response
rates
Savitz et al., 2018c (54)
Aspirin (NSAID)
IL-6
Lower response rate compared
to low IS d
TNFα, tumor necrosis factor alpha; IL, interleukin; CRP, C-reactive protein; m–h, moderate–high; IS, inflammatory state. *p ≤ 0.05, **p ≤ 0.01, ***p ≤ 0.001, reported effects without significance were not tested for significance but showed a clear descriptive trend and were therefore considered
noteworthy. bMixed sample with MDD and bipolar depressed patients, cBipolar depressed sample (type I/II and unspecified), dPersonal communication. July 2019 | Volume 10 | Article 458 Frontiers in Psychiatry | www.frontiersin.org 7 Prediction of Anti-Depressive/Anti-Inflammatory Therapy Response in MDD Arteaga-Henriquez et al. high that the use of the effective anti-inflammatory agents (such
as infliximab, minocycline, and fish oil) in states of moderate–
high inflammation actually has an opposite effect than expected
in such patients, namely, a reduced responsiveness. shows that five out of seven studies (52–56) found a significant
improvement of an (add-on) anti-inflammatory therapy, when
patients with high signs were compared to patients with low signs
of inflammation. Systematic Review Data on the
Usefulness of Circulating Serum
Inflammatory Compounds The anti-inflammatory agents used in these
studies were infliximab, minocycline, n-acetylcysteine, and fish
oil (the latter as monotherapy, and compared to placebo). Systematic Review Data on Gene
Expression in Circulating Leukocytes
Table 2 shows the studies we selected that dealt with the gene
message for pro-inflammatory cytokine production in the
circulating leukocyte pool prior to treatment and predictive for
treatment outcome. We found five relevant articles.i Systematic Review Data on Gene
Expression in Circulating Leukocytes (62) took the data of the GENDEP study
further and reported that absolute values of the message for IL1β
and MIF together could predict non-responsiveness to escitalopram
or nortriptyline in over 99%. These outcomes were confirmed in an
independent, naturalistic replication sample. It was remarkable that when an add-on anti-inflammatory
agent was given to patients with low signs of inflammation,
reduced responses were obtained as compared to patients with
high signs of inflammation and even to placebo (two out of three
of such studies) (53, 54). Also, when fish oil (an agent with both
lipid-correcting and anti-inflammatory properties) was given as a
monotherapy to patients with a low inflammatory state, reduced
responses were seen as compared to placebo (52) (Table 1C). As mentioned above, add-on aspirin did induce an increased
response in patients with low signs of inflammation in the study
of Savitz et al. (54). Taking these literature data together, it is difficult to draw a
simple conclusion on the usefulness of a prior measurement of
serum inflammatory markers for the determination of the effect
of (add-on) anti-inflammatory agents. There is a clear trend
that (add-on) anti-inflammatory agents, such as infliximab,
minocycline, and fish oil are effective if inflammatory markers
are clearly present, but this does not apply to aspirin and
n-acetylcysteine. However, it is also safe to say that special
caution must be given when there is an absence of circulating
inflammatory markers in patients with MDD: the chances are Taken together, it is clear that non-responsiveness to an
SSRI or to a TCA (nortriptyline) can likely be predicted by
determining the expression level of combinations of important
immune genes (IL1β, MIF, TNF, and CD3) in preparations of
circulating leukocytes of patients with MDD. TABLE 2 | The predictive capability of inflammatory state prior to therapy measured by circulating leukocyte gene expression for the response to various antidepressant
regimens in MDD. Experimental Data on Inflammation-Related
Gene Expression in Circulating Monocytes
as a Predictor of Treatment Response compared to the respective HC. Taking all patients from the four
study groups together, 25 of the 69 (36%) patients with MDD had
circulating monocytes with a pro-inflammatory gene signature,
while only 9 of 87 (10%) HC had such monocyte signature (p <
0.05). This observation is in accord with earlier observations that
monocytes of part of the patients with MDD show signs of a high
inflammatory state (21). Prior to treatment, we could test 34 patients with MDD [mean
age: 52.2 (±9.9) years, 59% females, collected at the ErasmusMC,
Rotterdam] for inflammatory gene expression in their circulating
monocytes. As a control group, we tested 45 HC of comparable
age [mean age: 49.1 (±9.4) years] and gender (44% females). Of
the 34 patients, 14 were treated with venlafaxine and 20 were
treated with imipramine. An overall response rate of 11% was
found in this trial, with 11/34 patients responding to treatment. The difference between the response rates for both treatment
arms were not statistically significant, i.e., a response rate of 36%
(5/14) for patients treated with venlafaxine and of 30% (6/20)
for patients treated with imipramine. Vermeiden et al. (38) have
reported extensively on this study and described that in the
entire group of patients (n = 85), 45% of the patients responded
to this first line of drug treatment (measured as 50% HAM-D
reduction).h l
y
For the purpose of this study, we divided the total patient group
in those with a negative monocyte inflammatory gene score and
those with a positive score. The data in Table 3 show that in the
response rates in three out of four patient groups, patients with a
positive inflammatory gene score had a lower response rate than
those without a positive score. This, however, did not apply to
the sertraline plus placebo group, and also significant differences
were not reached in any of the groups. The phenomenon of better
responsiveness in “non-inflamed” MDD patients could also be
seen in the total MDD patient group; patients with a positive
inflammatory gene score had a lower response rate than patients
without a positive inflammatory gene score (i.e., 44% vs. 59%);
however, a statistical significance was not reached in the total
group of patients. Experimental Data on Inflammation-Related
Gene Expression in Circulating Monocytes
as a Predictor of Treatment Response The other series of patients involved 35 patients with MDD
[mean age: 41.4 (±10.8) years, 46.7% females, collected at the
LMU, Munich] and 42 HC of comparable age [mean age: 37.9
(±11.9) years] and gender (61.9% females). Of the 35 patients,
19 were treated with sertraline plus placebo and 16 were treated
with sertraline plus celecoxib. A high overall response rate was
found in this trial, i.e., 26/35 (74.3%) of patients responded to
treatment. The difference between the response rates for both
treatment arms was not statistically significant, i.e., a response
rate of 68.4% (13/19) for patients treated with sertraline plus
placebo and 81.3% (13/16) for patients treated with sertraline
plus celecoxib. Systematic Review Data on Gene
Expression in Circulating Leukocytes ANTIDEPRESSANT AGENT
GENE TRANSCRIPT
EFFECT
STUDY
Escitalopram (SSRI)
TNF
Higher levels in non-responders
Powell et al., 2013 (59)
Escitalopram (SSRI)
13-gene model, including immune/inflammatory
genes (CD3D, CD97, IFITM3, and GZMA)
Predicting non-remission with 79.4% accuracy
Guilloux et al., 2015 (60)
Escitalopram(SSRI) or Nortriptyline (TCA)
IL1β, TNF, and MIF (relative mRNA values)
Higher levels in non-responders
Cattaneo et al., 2013 (61)
Escitalopram (SSRI) or Nortriptyline (TCA)
IL1β and MIF (absolute mRNA values)
Algorithm predictive of non-response with
probability of over 99%
Cattaneo et al., 2016 (62)
Antidepressant treatment, not specified
IL1β, TNF, PPT1, and HIST1H1E
Algorithm predictive of treatment response
Belzeaux et al., 2012 (63)
SSRI, selective serotonin reuptake inhibitors; TCA, tricyclic antidepressant; TNF, tumor necrosis factor; IL, interleukin; CD, cluster of differentiation; mRNA, messenger ribonucleic
acid; PPT1, palmitoyl-protein thioesterase 1; HIST1H1E, histone cluster 1 H1 family member E; MIF, macrophage inhibition factor; IFITM3, interferon-inducible transmembrane
protein 3; GZMA, granzyme A. TABLE 2 | The predictive capability of inflammatory state prior to therapy measured by circulating leukocyte gene expression for the response to various antidepressant
regimens in MDD. ANTIDEPRESSANT AGENT
GENE TRANSCRIPT
EFFECT
STUDY
Escitalopram (SSRI)
TNF
Higher levels in non-responders
Powell et al., 2013 (59)
Escitalopram (SSRI)
13-gene model, including immune/inflammatory
genes (CD3D, CD97, IFITM3, and GZMA)
Predicting non-remission with 79.4% accuracy
Guilloux et al., 2015 (60)
Escitalopram(SSRI) or Nortriptyline (TCA)
IL1β, TNF, and MIF (relative mRNA values)
Higher levels in non-responders
Cattaneo et al., 2013 (61)
Escitalopram (SSRI) or Nortriptyline (TCA)
IL1β and MIF (absolute mRNA values)
Algorithm predictive of non-response with
probability of over 99%
Cattaneo et al., 2016 (62)
Antidepressant treatment, not specified
IL1β, TNF, PPT1, and HIST1H1E
Algorithm predictive of treatment response
Belzeaux et al., 2012 (63)
SSRI, selective serotonin reuptake inhibitors; TCA, tricyclic antidepressant; TNF, tumor necrosis factor; IL, interleukin; CD, cluster of differentiation; mRNA, messenger ribonucleic
acid; PPT1, palmitoyl-protein thioesterase 1; HIST1H1E, histone cluster 1 H1 family member E; MIF, macrophage inhibition factor; IFITM3, interferon-inducible transmembrane
protein 3; GZMA, granzyme A. July 2019 | Volume 10 | Article 458 Frontiers in Psychiatry | www.frontiersin.org Frontiers in Psychiatry | www.frontiersin.org 8 Prediction of Anti-Depressive/Anti-Inflammatory Therapy Response in MDD Arteaga-Henriquez et al. The Predictive Capability of the
Inflammatory State for Anti-Depressive
and Anti-Inflammatory Treatment and
Potential Mechanisms Collectively, we deduce from these data that MDD patients
with an activated inflammatory state (as measured by moderate
to high circulating levels of, e.g., CRP, TNF-α, and IL-6, or a
high gene expression of, e.g., IL1β, TNF, and MIF in circulating
leukocytes) need more than a monotherapy with a predominantly
serotonergic agent to improve clinically in a satisfactory way. An
option then seems to be an immediate step up to agents with also
a strong dopaminergic or glutamatergic action.h Importantly, low-grade inflammation has been shown to
influence not only brain development and function but also
neurotransmission, with excellent reviews on the inhibitory
effects of pro-inflammatory cytokines, such as IL-1β and TNF-
α, on the synaptic availability of monoamines and BDNF, while
the same cytokines have been shown to increase extracellular
glutamate, all important molecular determinants in MDD
pathogenesis and response to treatment (15).h The reason for a better response to dopaminergic or
glutamatergic drugs in the case of signs of enhanced inflammation
can only be speculated on. It is possible that these drugs are
needed because they also have clear anti-inflammatory actions,
counteracting the detrimental effects of the high inflammatory
state on the signs and symptoms of depression. There is ample
evidence that dopamine and ketamine can reduce the production
of pro-inflammatory cytokines and enhance that of anti-
inflammatory cytokines (82, 83). On the other hand, the pro-
inflammatory state itself may lead to an altered neurotransmitter
metabolism, necessitating more than a primarily serotonin
reuptake inhibition, but also an intervention in the dopamine
or glutamate metabolism. Pro-inflammatory cytokines have
been reported to activate neuronal mitogen-activated protein
kinase (MAPK) pathways, increasing monoamine transporter
expression and activity in general, which leads to an increased pre-
synaptic reuptake of not only serotonin but also other neuroactive
amines (84, 85). Furthermore, the state of enhanced inflammation
is thought to lead to an enhanced tryptophan breakdown via the
kynurenine pathway, resulting in various neuroactive compounds,
among which NMDA agonists and antagonists, aggravating
glutamatergic neurotransmitter imbalances (86, 87). This might
also necessitate more than only a serotonin reuptake inhibition to
be effective. The Predictive Capability of the
Inflammatory State for Anti-Depressive
and Anti-Inflammatory Treatment and
Potential Mechanisms of microglia and/or of myeloid cells in the periphery (i.e.,
monocytes) have been documented in a considerable (≈30–40%)
proportion of patients with MDD (20, 73, 74). Moreover, imaging
and histological techniques have shown microglial activation in
the hippocampus of depressed patients (75). measurement of circulating inflammatory compounds in
serum/plasma; a high inflammatory gene expression might
typify a state of “stronger/other” inflammation in MDD
needing a treatment with drugs beyond the serotonergic and
noradrenergic drugs. In other studies, we have also noted that
inflammatory gene expression in circulating cells does not
correlate one to one with the circulating protein gene product
in serum/plasma (81). We explained this phenomenon by
assuming that resident cells, such as the endothelial cells and
resident macrophages in the tissues, also contribute to the level
of circulating inflammatory compounds.l By producing an array of neurotrophic factors, pro- and
anti-inflammatory cytokines (e.g., IL-6), as well as axon
guidance molecules, non-inflammatory activated microglia
has been implicated both in white matter integrity and in
the adequate development and function of important stress-
regulating systems in the healthy brain (76, 77). On the contrary,
inflammatory activated microglia (and/or a transfer of peripheral
pro-inflammatory cytokines to the brain) is thought to hamper
the normal development, growth, and synaptic function of
stress-regulating systems and brain connections important
for mood regulation, such as the white matter tracts between
the forebrain and the limbic system. To illustrate this, raised
serum pro-inflammatory cytokine levels have been associated in
mood disorder patients with increased activation of threat- and
anxiety-related neuro-circuits (78), reduced neural responses to
negative stimuli in frontal brain regions involved in cognitive
and emotional functions (79), and compromised integrity of
myelin sheaths in cortico-limbic networks involved in mood
regulation (80).l l
Although the data of our experiments on inflammatory
gene expression levels in circulating monocytes (a subset of the
circulating leukocytes) did not deliver statistically significant
results, they were, by and large, in agreement with the above-
described findings for the gene expression in all circulating
leukocytes and showed that patients with “inflammatory”
monocytes showed reduced response rates to predominantly
serotonergic drug interventions and patients with “non-
inflammatory” monocytes showed higher response rates to these
type of agents. The Predictive Capability of the
Inflammatory State for Anti-Depressive
and Anti-Inflammatory Treatment and
Potential Mechanisms The data of the systematic review and experimental monocyte
data, as presented in this study, collectively point in the
direction that the state of so-called low-grade inflammation
does play a role in the outcome of antidepressant therapy of
patients with MDD. We determined with an already published algorithm [see the
Section Monocyte Inflammatory Gene Expression and Ref. (45)]
the inflammatory state of the monocytes using the top 10 cluster
1 inflammatory genes (IL1β, CCL20, EREG, IL6, TNFAIP3,
CXCL2, PDE4B, ATF3, PTX3, and IL1A). We controlled the patient
monocyte tests with the outcomes of the same tests carried out in
HC. Table 3 shows that, in each study group, a significant larger
proportion of patients had—prior to therapy—circulating
monocytes with a positive inflammatory gene signature as Low-grade inflammation is characterized by an increase in
the serum level of pro-inflammatory compounds (e.g., CRP,
IL-1 β, IL-6, and TNF-α) and/or an activation state of circulating
or tissue resident immune cells, including the brain microglia. Both an increase in pro-inflammatory compounds in the blood
of patients with MDD and a pro-inflammatory activation TABLE 3 | Proportions of patients with a positive inflammatory gene signature of circulating monocytes prior to therapy measured in total and by response. Predominantly serotonergic agents
HC
MDD
Inflammatory negatives
Inflammatory positives
Positive
Positive
Responders
Non-responders
Responders
Non-responders
Sertraline plus Placebo (SSRI)
5/42 (12%)
7/19 (37%)
8/12 (67%)
4/12 (33%)
5/7 (71%)
2/7 (29%)
Sertraline plus Celecoxib (COX-2 inhibitor)
idem
3/16 (19%)
11/13 (85%)
2/13 (15%)
2/3 (67%)
1/3 (33%)
Venlafaxine (SNRI)
2/22 (9%)
6/14 (43%)
3/8 (38%)
5/8 (62%)
2/6 (33%)
4/6 (66%)
Imipramine (TCA)
2/23 (9%)
9/20 (45%)
4/11 (36%)
7/11 (64%)
2/9 (22%)
7/9 (78%)
SUM
9/87 (10%)
25/69 (36%)*
26/44 (59%)*
18/44 (41%)*
11/25 (44%)*
14/25 (56%)*
SSRI, selective serotonin reuptake inhibitors; SNRI, sertraline–noradrenaline reuptake inhibitors; TCA, tricyclic antidepressant; COX-2, cyclooxygenase 2; HC, healthy controls; MDD,
major depressive disorder. *p ≤ 0.05 compared to HC. Positivity was defined by an upregulation of 6 (or more) of the 10 cluster 1 genes. Original Q-PCR data have been uploaded and can be retrieved via the GEO repository ref number GSE132315: http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE132315 July 2019 | Volume 10 | Article 458 Frontiers in Psychiatry | www.frontiersin.org 9 Prediction of Anti-Depressive/Anti-Inflammatory Therapy Response in MDD Arteaga-Henriquez et al. Frontiers in Psychiatry | www.frontiersin.org The Predictive Capability of the
Inflammatory State for Anti-Depressive
and Anti-Inflammatory Treatment and
Potential Mechanisms The data from the here presented systematic review on
circulating inflammatory compounds indicate that patients
with MDD with an activated inflammatory state (as measured
by, e.g., moderate to high levels of circulating CRP, IL-6, and/or
TNF-α) show reduced response rates to antidepressant regimens
with a primarily serotonergic action (e.g., escitalopram),
while showing improved response rates to antidepressant
regimens with a primarily noradrenergic (e.g., nortriptyline),
dopaminergic (e.g., bupropion, mirtazapine), or glutamatergic
action (i.e., ketamine). The systematic review data on the inflammatory
gene expression in circulating leukocytes confirmed this
phenomenon, showing that patients with a high gene
expression level of IL1β, TNF, and/or MIF did not respond
well to interventions with an SSRI in comparison to MDD
patients with a low expression of these genes. However, gene
data in circulating leukocytes disagreed with the data reported
for circulating inflammatory compounds regarding TCA. While the primarily noradrenergic TCA nortriptyline did not
give a satisfactory response in patients with MDD with a high
gene expression level in circulating leukocytes (see Table 2),
nortriptyline did in patients with high levels of circulating
inflammatory compounds (see Table 1B).l f
A step up to dopaminergic and glutamatergic antidepressants
was more effective in “inflammatory” MDD patients than in “non-
inflammatory” patients, and a combination of an antidepressant
with an anti-inflammatory agent increased the response rates in Apparently, inflammatory gene expression in leukocytes
does not measure the same level of inflammation than the July 2019 | Volume 10 | Article 458 10 Prediction of Anti-Depressive/Anti-Inflammatory Therapy Response in MDD Arteaga-Henriquez et al. (52–54) indicated that “non-inflammatory” MDD patients
showed a reduced response rate as compared to even placebo to
the effective (add-on) intervention with an anti-inflammatory
agent. In other words, the addition of the anti-inflammatory
drugs effective in “inflammatory” patients was detrimental,
and the anti-inflammatory drugs inhibited the effect of the
antidepressants or delayed natural recovery. Such an outcome of
an anti-inflammatory regimen is counterintuitive, if one assumes
that inflammation contributes to depressive symptomatology
(see before). The authors of one of the papers describing this
phenomenon (53) explain their finding, that perhaps a small
activation of the inflammatory system is needed for mental
well-being and that both an extreme low and an extreme high
activity of the inflammatory response system is disadvantageous
for mental health. In other words, there would be an optimal
set point for the inflammatory state of an individual for mental
health. The Predictive Capability of the
Inflammatory State for Anti-Depressive
and Anti-Inflammatory Treatment and
Potential Mechanisms Downregulating this optimal state with an effective anti-
inflammatory agent would, in such a view, be counterproductive
and would open the way for the development of depressive
symptoms. these “inflammatory” patients with MDD as compared to “non-
inflammatory” MDD patients. Though the reviewed literature
data are scarce, the best prediction results seem to be obtained
for infliximab (anti-TNF-α agent), minocycline (tetracycline),
and eicosapentaenoic acid (fish oil). For n-acetylcysteine, the
inflammatory state did show conjectural prediction effects,
while for aspirin (acetylsalicylic acid), a reduced response was
actually seen in “inflammatory” patients as compared to “non-
inflammatory” patients.hl l
The strength or character of the anti-inflammatory agents
may have played a role in this variation of predictability of
the state of inflammation for the (add-on) anti-inflammatory
agents. Both anti-TNF agents and minocycline are in clinical
practice and are considered stronger anti-inflammatory drugs
than n-acetylcysteine and aspirin. However, for fish oil, a high
inflammatory state was also predictive for a better effect in
MDD patients, while fish oil is considered a relatively weak
anti-inflammatory agent. Interestingly, fish oil exerts its anti-
inflammatory effects via changing the “bad” pro-inflammatory
lipid state of individuals (88), and perhaps the high state of
inflammation in MDD patients is primarily driven by a bad lipid
profile, which is then best corrected by fish oil.f Another explanation is that there exists a form of MDD that
is non-immune and characterized by absent serological markers
of immune activation. As indicated, (add-on) aspirin has a
beneficial effect in patients and it can be hypothesized that it is
in particular the neuro-modulating effect (anti-glutamatergic) of
aspirin that induces this effect. ii
Also, direct or indirect neurotransmitter effects of the
anti-inflammatory agents may have played a role in the
success or failure to predict their improved responsiveness
in “inflammatory” MDD patients. Interestingly, two of the
three add-on anti-inflammatory agents (minocycline and
fish oil) that worked better in “inflammatory” than in “non-
inflammatory” patients possess dopaminergic activities (89,
90). N-acetylcysteine, of which it is conjectural whether it
works better as add-on in “inflammatory” than in “non-
inflammatory” MDD patients, influences both dopamine
and glutamate levels in the brain (91). Add-on aspirin, in
contrast, had fewer effects in “inflammatory” MDD patients
as compared to “non-inflammatory” patients; interestingly,
aspirin has anti-glutamatergic actions (92, 93). The Predictive Capability of the
Inflammatory State for Anti-Depressive
and Anti-Inflammatory Treatment and
Potential Mechanisms These varying
neuro-modulating actions of anti-inflammatory drugs make
complex interactions in the neuro-immune network possible,
inducing varying outcomes of combinations of antidepressants
and anti-inflammatory agents. Of note also is that three of
the reviewed studies of add-on anti-inflammatory agents
had included bipolar depressed patients (54, 56, 58). This
applies in particular to the study on aspirin (54), in which
a reducing effect was found in “inflammatory” versus “non-
inflammatory” patients. Intrinsic differences between bipolar
and unipolar depression, such as differences in the immune
and the glutamate state (94–98), may have played a role here. f
Based on this literature review, what appears to be the
best and easiest assay system to measure the inflammatory
state of MDD patients? The systematic review data on the
gene expression level of cytokines in circulating leukocytes
showed that two of the leukocyte gene expression studies
resulted in very good accuracy rates of prediction of non-
responsiveness, and algorithms could be developed, which
showed high accuracies from 75% to even a 100% to predict
non-responsiveness to an SSRI/TCA drug intervention (60,
62). Apparently, high levels of inflammatory cytokine gene
message in circulating leukocytes are a precise sign of poor
(treatment) outcome, and perhaps even better than high levels
of inflammatory compounds/cytokines in serum/plasma. Nevertheless, it is technically less demanding to measure
inflammatory compounds/cytokines in serum/plasma than
to perform a gene expression assay in circulating leukocytes. Regarding the inflammatory markers best to be measured in
serum/plasma to determine a raised inflammatory state in
patients with MDD, it is worthy to note that the most consistent
effects were found in our literature analysis with circulating
CRP and/or IL-6 levels. These inflammatory compounds were
tested in a large proportion of the here reviewed studies on
serum inflammatory compounds (15/19), and outcomes and
conclusions were congruent between these studies regarding
these two inflammation markers. Despite the above-listed uncertainties, it is nevertheless tempting
to postulate—based on the outcomes of the literature review—
that when MDD patients are “inflammatory”, (add-on) anti-
inflammatory drugs are also an option to improve responsiveness
and then the best results are probably obtained when anti-
inflammatory agents are potent, influence lipid metabolism, and/or
influence primarily dopaminergic synaptic transmission. l
Circulating TNF-α was measured in only six studies; hence,
sufficient information on the validity of this parameter is lacking. Frontiers in Psychiatry | www.frontiersin.org July 2019 | Volume 10 | Article 458 The Predictive Capability of the
Inflammatory State for Anti-Depressive
and Anti-Inflammatory Treatment and
Potential Mechanisms Importantly, one of the studies showed that circulating TNF-α
levels were not in agreement with the general rule, finding that a
high TNF-α level was not predictive of a decreased responsiveness
to an SSRI/SNRI (while a high IL-6 level in the same study was) l
Regarding the use of (add-on) anti-inflammatory agents,
another important message emerges from our systematic
review of the literature. Interestingly, three out of four reports July 2019 | Volume 10 | Article 458 11 Prediction of Anti-Depressive/Anti-Inflammatory Therapy Response in MDD Arteaga-Henriquez et al. drug protocols with reliable cutoff points for inflammatory
parameters to guide therapy regimens. (43). Other circulating inflammatory compounds (e.g., IL-8,
IL-10, and IL-1) have also been tested in the here reported
studies, but in only very few studies, and therefore data cannot
be reliably evaluated. They nevertheless showed the general trend
for serum/plasma factors that, in a state of inflammation, more
than a monotherapy with a predominantly serotonergic agent
might be needed. (43). Other circulating inflammatory compounds (e.g., IL-8,
IL-10, and IL-1) have also been tested in the here reported
studies, but in only very few studies, and therefore data cannot
be reliably evaluated. They nevertheless showed the general trend
for serum/plasma factors that, in a state of inflammation, more
than a monotherapy with a predominantly serotonergic agent
might be needed. Despite this limitation, a few generalizations can nevertheless
be made from our study regarding inflammation as a predictor. Of the inflammation parameters, the serum CRP and IL-6
seem to be the most promising parameters for further clinical
development. They are relatively easy to determine and, thus,
useful in clinical studies. Using these parameters, a state of
raised inflammation (as evidenced by raised serum CRP and
IL-6 levels) characterizes a form of MDD with a relatively poor
outcome and a non-responsiveness to agents with a predominant
serotonergic action. Such cases might need a faster step-up to
drug regimens with agents with dopaminergic (e.g., mirtazapine
and bupropion) or glutamatergic (e.g., ketamine) effects,
or a combination of a first-line antidepressant with an anti-
inflammatory agent such as infliximab, minocycline, or fish oil
(but not aspirin), most of them showing dopaminergic action. Varying anti-inflammatory properties of antidepressants as well
as varying neuro-modulatory effects of anti-inflammatory agents
(and/or complex interactions thereof) may play a role in the
therapeutic success or failure of the step-ups. ETHICS STATEMENT These studies were carried in compliance with standards of
CGP, assuring that the rights, safety, and well-being of patients
were protected in accordance with the principles that have their
origin in the Declaration of Helsinki (June 1964, last amendment
Fortaleza 2013). Additionally, the relevant national and European
regulations were adhered, too. After study procedures had been
fully explained, all subjects provided written informed consent. Limitations In this article, we only focused on inflammation parameters
as determinants for the outcome of treatment. The various
other determinants important for treatment outcome have
recently been reviewed by Perlman et al. (99). The authors
described not only that inflammation-related determinants are
important but also that a whole array of genetic, endocrine,
neuroimaging,
sociodemographic,
and
symptom-based
predictors turn out to influence outcome. However, due to
heterogeneous sample sizes, effect sizes, publication biases,
and methodological disparities across reviews, Perlman
et al. (99) concluded that they could not accurately assess the
strength and directionality of the predictors, and the authors
therefore highlighted the importance of large-scale research
initiatives and the use of clinically easily accessible biomarkers,
as well as the need for replication studies of current findings. Clearly, we support such view and underscore the notion that
our review data are also affected by the heterogeneous sample
sizes, effect sizes, publication biases, and methodological
disparities and that the data do not yet give a clear-cut picture. Also, our own experimental data on monocyte gene expression
were underpowered and too limited to obtain clear-cut results
and significances. Thus, clearly more studies are needed
using standardized add-on anti-inflammatory treatments to
standardized single antidepressant medications to develop
a clearer picture of the actual response rates in immune and
otherwise stratified patients with MDD. A word of caution is needed regarding the regimens using
as add-on the successful anti-inflammatory agents infliximab,
minocycline, and fish oil: There must indeed be laboratory signs
of inflammation (i.e., raised serum levels of CRP or IL-6) for this
addition to be effective. If not, even response rates lower than the
non-add-on situation might be obtained. AUTHOR CONTRIBUTIONS GA and MS designed the strategy of the present review. BB and
EW collected part of the study cohort, GA, AW and HD evaluated
the data. GAH and MS wrote the first draft of the paper, HD and
NM contributed with supervision and expert advice and critically
revised the draft. All other authors contributed to the manuscript
revision and approved the submitted version. The Predictive Capability of the
Inflammatory State for Anti-Depressive
and Anti-Inflammatory Treatment and
Potential Mechanisms Collectively, it seems that for predicting responsiveness to
regular antidepressants, the avenue exploring the usefulness of
serum/plasma CRP and IL-6 determination is the easiest and
clinically the most feasible and promising approach. High levels
of CRP/IL-6 would indicate that treatment with a serotonergic
drug is not effective enough. However, the data reviewed here
also indicate that the gene expression in circulating leukocytes
cannot be neglected as a predicting parameter due to the reported
high levels of accuracy to predict non-responsiveness to SSRI/
SNRI and TCA therapy. Conclusionsh There are excellent recent reviews on the discovered signs of low-
grade inflammation in psychiatric patients that have transformed
our understanding of neuropsychiatric diseases and urge for
new diagnostic and therapeutic criteria in the emerging field
of immuno-psychiatry (100). There are, however, at present,
insufficient data and reliable concepts on the inflammation
pathogenesis of MDD to design clinically applicable treatment REFERENCES J Affect Disord (2005) 88(2):167–
73. doi: 10.1016/j.jad.2005.07.008 6. Irwin MR, Miller AH. Depressive disorders and immunity: 20 years of
progress and discovery. Brain Behav Immun (2007) 21(4):374–83. doi:
10.1016/j.bbi.2007.01.010 24. Pundiak TM, Case BG, Peselow ED, Mulcare L. Discontinuation of
maintenance selective serotonin reuptake inhibitor monotherapy after
5 years of stable response: a naturalistic study. J Clin Psychiatry (2008)
69(11):1811–7. doi: 10.4088/JCP.v69n1117 7. Dantzer R, O’Connor JC, Freund GG, Johnson RW, Kelley KW. From
inflammation to sickness and depression: when the immune system
subjugates the brain. Nat Rev Neurosci (2008) 9(1):46–56. doi: 10.1038/
nrn2297 25. Dell’Osso B, Palazzo MC, Oldani L, Altamura AC. The noradrenergic
action in antidepressant treatments: pharmacological and clinical
aspects. CNS Neurosci Ther (2011) 17(6):723–32. doi: 10.1111/j.1755-5949.
2010.00217.x 8. Howren MB, Lamkin DM, Suls J. Associations of depression with C-reactive
protein, IL-1, and IL-6: a meta-analysis. Psychosom Med (2009) 71(2):171–
86. doi: 10.1097/PSY.0b013e3181907c1b 26. Furukawa TA, Salanti G, Atkinson LZ, Leucht S, Ruhe HG, Turner EH,
et al. Comparative efficacy and acceptability of first-generation and second-
generation antidepressants in the acute treatment of major depression:
protocol for a network meta-analysis. BMJ Open (2016) 6(7):e010919. doi:
10.1136/bmjopen-2015-010919 9. Miller AH. Depression and immunity: a role for T cells? Brain Behav Immun
(2010) 24(1):1–8. doi: 10.1016/j.bbi.2009.09.009 10. Dowlati Y, Herrmann N, Swardfager W, Liu H, Sham L, Reim EK, et al. A meta-analysis of cytokines in major depression. Biol Psychiatry (2010)
67(5):446–57. doi: 10.1016/j.biopsych.2009.09.033 27. Cipriani A, Furukawa TA, Salanti G, Geddes JR, Higgins JP, Churchill R, et al. Comparative efficacy and acceptability of 12 new-generation antidepressants:
a multiple-treatments meta-analysis. Lancet (2009) 373(9665):746–58. doi:
10.1016/S0140-6736(09)60046-5 11. Drexhage RC, Weigelt K, van Beveren N, Cohen D, Versnel MA, Nolen WA, et
al. Immune and neuroimmune alterations in mood disorders and schizophrenia. Int Rev Neurobiol (2011) 101:169–201. doi: 10.1016/B978-0-12-387718-5.00007-9i 28. Frick LR, Rapanelli M. Antidepressants: influence on cancer and immunity? Life Sci (2013) 92(1):525–32. doi: 10.1016/j.lfs.2013.01.020hl 12. Eyre HA, Stuart MJ, Baune BT. A phase-specific neuroimmune model of
clinical depression. Prog Neuropsychopharmacol Biol Psychiatry (2014)
54:265–74. doi: 10.1016/j.pnpbp.2014.06.011 29. Gałecki P, Mossakowska-Wójcik J, Talarowska M. The anti-inflammatory
mechanism of antidepressants—SSRIs, SNRIs. Prog Neuropsychopharmacol
Biol Psychiatry (2018) 80(Pt C):291–94. doi: 10.1016/j.pnpbp.2017.03.016 13. Müller N. Immunology of major depression. NIM (2014) 21(2–3):123–30. doi: 10.1159/000356540 30. Fond G, Hamdani N, Kapczinski F, Boukouaci W, Drancourt N, Dargel A,
et al. FUNDING This study was financially supported by the EU via the
MOODINFLAME project (EU-FP7-HEALTH-F2-2008-222963),
the PSYCHAID (EU-FP7-PEOPLE-2009-IAPP-MarieCurie-
286334), and the MOODSTRATIFICATION project (H2020- July 2019 | Volume 10 | Article 458 Frontiers in Psychiatry | www.frontiersin.org 12 Arteaga-Henriquez et al. Prediction of Anti-Depressive/Anti-Inflammatory Therapy Response in MDD ACKNOWLEDGMENTS EU.3.1.1., GA754740). NM and GA were additionally supported
by the foundation “Immunität und Seele.” The funders had no
role in study design, data collection, analysis and interpretation
of data, the writing of the report, and the decision to submit the
paper for publication. We would like to acknowledge the excellent technical assistance
of Harm de Wit, Thomas Hoogenboezem, and Angelique van
Rijswijk. Mu Myint collected much of the material in Munich. REFERENCES 19. Poletti S, de Wit H, Mazza E, Wijkhuijs AJM, Locatelli C, Aggio V, et al. Th17 cells correlate positively to the structural and functional integrity of the
brain in bipolar depression and healthy controls. Brain Behav Immun (2017)
61:317–25. doi: 10.1016/j.bbi.2016.12.020 1. Müller N, Hofschuster E, Ackenheil M, Mempel W, Eckstein R. Investigations
of the cellular immunity during depression and the free interval: evidence
for an immune activation in affective psychosis. Prog Neuropsychopharmacol
Biol Psychiatry (1993) 17(5):713–30. doi: 10.1016/0278-5846(93)90055-W 1. Müller N, Hofschuster E, Ackenheil M, Mempel W, Eckstein R. Investigations
of the cellular immunity during depression and the free interval: evidence
for an immune activation in affective psychosis. Prog Neuropsychopharmacol
Biol Psychiatry (1993) 17(5):713–30. doi: 10.1016/0278-5846(93)90055-W 20. Beumer W, Gibney SM, Drexhage RC, Pont-Lezica L, Doorduin J, Klein HC,
et al. The immune theory of psychiatric diseases: a key role for activated
microglia and circulating monocytes. J Leukoc Biol (2012) 92(5):959–75. doi:
10.1189/jlb.0212100 2. Connor TJ, Leonard BE. Depression, stress and immunological activation:
the role of cytokines in depressive disorders. Life Sci (1998) 62(7):583–606. doi: 10.1016/S0024-3205(97)00990-9 2. Connor TJ, Leonard BE. Depression, stress and immunological activation:
the role of cytokines in depressive disorders. Life Sci (1998) 62(7):583–606. doi: 10.1016/S0024-3205(97)00990-9 21. Grosse L, Carvalho LA, Wijkhuijs AJM, Bellingrath S, Ruland T, Ambrée O, et al. Clinical characteristics of inflammation-associated depression: monocyte
gene expression is age-related in major depressive disorder. Brain Behav
Immun (2015) 44:48–56. doi: 10.1016/j.bbi.2014.08.004 3. Anisman H, Merali Z. Anhedonic and anxiogenic effects of cytokine exposure. Adv Exp Med Biol (1999) 461:199–233. doi: 10.1007/978-0-585-37970-8_12 3. Anisman H, Merali Z. Anhedonic and anxiogenic effects of cytokine exposure. Adv Exp Med Biol (1999) 461:199–233. doi: 10.1007/978-0-585-37970-8_12 4. Mikova O, Yakimova R, Bosmans E, Kenis G, Maes M. Increased serum
tumor necrosis factor alpha concentrations in major depression and multiple
sclerosis. Eur Neuropsychopharmacol (2001) 11(3):203–8. doi: 10.1016/
S0924-977X(01)00081-5 22. Gałecki P, Talarowska M. Inflammatory theory of depression. Psychiatr Pol
(2018) 52(3):437–47. doi: 10.12740/PP/76863 23. Medina-Rodriguez EM, Lowell JA, Worthen RJ, Syed SA, Beurel E. Involvement of innate and adaptive immune systems alterations in the
pathophysiology and treatment of depression. Front Neurosci (2018) 12. doi:
10.3389/fnins.2018.00547 5. Myint A-M, Leonard BE, Steinbusch HWM, Kim Y-K. Th1, Th2, and Th3
cytokine alterations in major depression. J Affect Disord (2005) 88(2):167–
73. doi: 10.1016/j.jad.2005.07.008 5. Myint A-M, Leonard BE, Steinbusch HWM, Kim Y-K. Th1, Th2, and Th3
cytokine alterations in major depression. REFERENCES Effectiveness and tolerance of anti-inflammatory drugs’ add-on therapy
in major mental disorders: a systematic qualitative review. Acta Psychiatrica
Scandinavica (2014) 123(3):163–79. doi: 10.1111/acps.12211 14. Haapakoski R, Mathieu J, Ebmeier KP, Alenius H, Kivimäki M. Cumulative
meta-analysis of interleukins 6 and 1β, tumour necrosis factor α and
C-reactive protein in patients with major depressive disorder. Brain Behav
Immun (2015) 49:206–15. doi: 10.1016/j.bbi.2015.06.001hl 31. Müller N. Immunological aspects of the treatment of depression and
schizophrenia. Dialogues Clin Neurosci (2017) 19:1.l 15. Miller AH, Raison CL. The role of inflammation in depression: from
evolutionary imperative to modern treatment target. Nat Rev Immunol
(2016) 16(1):22–34. doi: 10.1038/nri.2015.5 32. Husain MI, Strawbridge R, Stokes PR, Young AH. Anti-inflammatory
treatments
for
mood
disorders:
systematic
review
and
meta-
analysis. J
Psychopharmacol
(Oxford)
(2017)
31(9):1137–48. doi:
10.1177/0269881117725711 16. Grosse L, Hoogenboezem T, Ambrée O, Bellingrath S, Jörgens S, de Wit HJ,
et al. Deficiencies of the T and natural killer cell system in major depressive
disorder: T regulatory cell defects are associated with inflammatory
monocyte activation. Brain Behav Immun (2016) 54:38–44. doi: 10.1016/j. bbi.2015.12.003 33. Adzic M, Brkic Z, Mitic M, Francija E, Jovicic MJ, Radulovic J, et al. Therapeutic strategies for treatment of inflammation-related depression. Curr
Neuropharmacol (2018) 16(2):176–209. doi: 10.2174/1570159X15666170828
163048 17. Gibney SM, Drexhage HA. Evidence for a dysregulated immune system
in the etiology of psychiatric disorders. J Neuroimmune Pharmacol (2013)
8(4):900–20. doi: 10.1007/s11481-013-9462-8l 34. Fernandes BS, Dean OM, Dodd S, Malhi GS, Berk M. Acetylcysteine in
depressive symptoms and functionality: a systematic review and meta-
analysis. J Clin Psychiatry (2016) 77(4):e457-66. doi: 10.4088/JCP.15r09984l 18. Bergink V, Gibney SM, Drexhage HA. Autoimmunity, inflammation, and
psychosis: a search for peripheral markers. Biol Psychiatry (2014) 75(4):324–
31. doi: 10.1016/j.biopsych.2013.09.037 35. Tall AR, Yvan-Charvet L. Cholesterol, inflammation and innate immunity. Nat Rev Immunol (2015) 15(2):104–16. doi: 10.1038/nri3793 July 2019 | Volume 10 | Article 458 Frontiers in Psychiatry | www.frontiersin.org 13 Arteaga-Henriquez et al. Prediction of Anti-Depressive/Anti-Inflammatory Therapy Response in MDD 36. Palacio JR, Markert UR, Martínez P. Anti-inflammatory properties of
N-acetylcysteine on lipopolysaccharide-activated macrophages. Inflamm Res
(2011) 60(7):695–704. doi: 10.1007/s00011-011-0323-8 54. Savitz JB, Teague TK, Misaki M, Macaluso M, Wurfel BE, Meyer M, et al. Treatment of bipolar depression with minocycline and/or aspirin: an adaptive,
2×2 double-blind, randomized, placebo-controlled, phase IIA clinical trial. Transl Psychiatry (2018) 8(1):27. doi: 10.1038/s41398-017-0073-7 37. Raison CL, Miller AH. Is depression an inflammatory disorder? Curr
Psychiatry Rep (2011) 13(6):467–75. doi: 10.1007/s11920-011-0232-0 55. REFERENCES Husain MI, Chaudhry IB, Husain N, Khoso AB, Rahman RR, Hamirani
MM, et al. Minocycline as an adjunct for treatment-resistant depressive
symptoms: a pilot randomised placebo-controlled trial. J Psychopharmacol
(2017) 31(9):1166–75. doi: 10.1177/0269881117724352 38. Vermeiden M, Mulder PG, van den Broek WW, Bruijn JA. Birkenhäger TK. A double-blind randomized study comparing plasma level-targeted dose
imipramine and high-dose venlafaxine in depressed inpatients. J Psychiatr
Res (2013) 47(10):1337–42. doi: 10.1016/j.jpsychires.2013.05.029h 56. Porcu M, Urbano MR, Verri WA, Barbosa DS, Baracat M, Vargas HO, et al. Effects of adjunctive N-acetylcysteine on depressive symptoms: modulation
by baseline high-sensitivity C-reactive protein. Psychiatry Res (2018)
263:268–74. doi: 10.1016/j.psychres.2018.02.056 Res (2013) 47(10):1337–42. doi: 10.1016/j.jpsychires.2013.05.029h 39. Bakkalbasi N, Bauer K, Glover J, Wang L. Three options for citation tracking:
Google Scholar, Scopus and Web of Science. Biomed Digit Libr (2006) 3:7. doi: 10.1186/1742-5581-3-7 57. Hasebe K, Gray L, Bortolasci C, Panizzutti B, Mohebbi M, Kidnapillai S,
et al. Adjunctive N-acetylcysteine in depression: exploration of interleukin-6,
C-reactive protein and brain-derived neurotrophic factor. Acta Neuropsychiatrica
(2017) 29(6):337–46. doi: 10.1017/neu.2017.2 40. Jha MK, Minhajuddin A, Gadad B, Greer T, Grannemann B, Soyombo A, et al. Can C-reactive protein inform antidepressant medication selection in depressed
outpatients? Findings from the CO-MED trial. Psychoneuroendocrinology
(2017) 78:105–13. doi: 10.1016/j.psyneuen.2017.01.023l 58. Panizzutti B, Bortolasci C, Hasebe K, Kidnapillai S, Gray L, Walder K, et al. Mediator effects of parameters of inflammation and neurogenesis from a
N-acetyl cysteine clinical-trial for bipolar depression. Acta Neuropsychiatrica
(2018) 30(6):334–41. doi: 10.1017/neu.2018.13f 41. Uher R, Tansey KE, Dew T, Maier W, Mors O, Hauser J, et al. An inflammatory
biomarker as a differential predictor of outcome of depression treatment
with escitalopram and nortriptyline. Am J Psychiatry (2014) 171(12):1278–
86. doi: 10.1176/appi.ajp.2014.14010094l 42. Eller T, Vasar V, Shlik J, Maron E. Pro-inflammatory cytokines and
treatment response to escitalopram in major depressive disorder. Prog
Neuropsychopharmacol Biol Psychiatry (2008) 32(2):445–50. doi: 10.1016/j. pnpbp.2007.09.015 59. Powell TR, Schalkwyk LC, Heffernan AL, Breen G, Lawrence T, Price T, et al. Tumor necrosis factor and its targets in the inflammatory cytokine pathway
are identified as putative transcriptomic biomarkers for escitalopram
response. Eur Neuropsychopharmacol (2013) 23(9):1105–14. doi: 10.1016/j. euroneuro.2012.09.009 43. Yoshimura R, Hori H, Ikenouchi-Sugita A, Umene-Nakano W, Katsuki A,
Atake K, et al. Plasma levels of interleukin-6 and selective serotonin reuptake
inhibitor response in patients with major depressive disorder: IL-6 and SSRI
response. Hum Psychopharmacol (2013) 28(5):466–70. doi: 10.1002/hup.2333 60. REFERENCES Guilloux J-P, Bassi S, Ding Y, Walsh C, Turecki G, Tseng G, et al. Testing the
predictive value of peripheral gene expression for nonremission following
citalopram treatment for major depression. Neuropsychopharmacology
(2015) 40(3):701–10. doi: 10.1038/npp.2014.226 44. Manoharan A, Rajkumar RP, Shewade DG, Sundaram R, Muthuramalingam A,
Paul A. Evaluation of interleukin-6 and serotonin as biomarkers to predict
response to fluoxetine. Hum Psychopharmacol (2016) 31(3):178–84. doi:
10.1002/hup.2525 61. Cattaneo A, Gennarelli M, Uher R, Breen G, Farmer A, Aitchison KJ, et al. Candidate genes expression profile associated with antidepressants response
in the GENDEP study: differentiating between baseline “predictors” and
longitudinal “targets”. Neuropsychopharmacology (2013) 38(3):377–85. doi:
10.1038/npp.2012.191 45. Chang HH, Lee IH, Gean PW, Lee S-Y, Chi MH, Yang YK, et al. Treatment
response and cognitive impairment in major depression: association with
C-reactive protein. Brain Behav Immun (2012) 26(1):90–5. doi: 10.1016/j. bbi.2011.07.239 62. Cattaneo A, Ferrari C, Uher R, Bocchio-Chiavetto L, Riva MA,
Pariante CM. Absolute measurements of macrophage migration inhibitory
factor and interleukin-1-β mRNA levels accurately predict treatment
response in depressed patients. Int J Neuropsychopharmacol (2016)
19(10):pyw045. doi: 10.1093/ijnp/pyw045 46. Haroon E, Daguanno AW, Woolwine BJ, Goldsmith DR, Baer WM,
Wommack EC, et al. Antidepressant treatment resistance is associated with
increased inflammatory markers in patients with major depressive disorder. Psychoneuroendocrinology (2018) 95:43–9. doi: 10.1016/j.psyneuen.2018.05.026 63. Belzeaux R, Bergon A, Jeanjean V, Loriod B, Formisano-Tréziny C,
Verrier L, et al. Responder and nonresponder patients exhibit different
peripheral transcriptional signatures during major depressive episode. Transl Psychiatry (2012) 2(11):e185. doi: 10.1038/tp.2012.112 47. Yoshimura R, Hori H, Ikenouchi-Sugita A, Umene-Nakano W, Ueda N,
Nakamura J. Higher plasma interleukin-6 (IL-6) level is associated with
SSRI- or SNRI-refractory depression. Prog Neuropsychopharmacol Biol
Psychiatry (2009) 33(4):722–6. doi: 10.1016/j.pnpbp.2009.03.020l 64. Carvalho LA, Bergink V, Sumaski L, Wijkhuijs J, Hoogendijk WJ,
Birkenhager TK, et al. Inflammatory activation is associated with a reduced
glucocorticoid receptor alpha/beta expression ratio in monocytes of
inpatients with melancholic major depressive disorder. Transl Psychiatry
(2014) 4(1):e344. doi: 10.1038/tp.2013.118 48. Martinez JM, Garakani A, Yehuda R, Gorman JM. Proinflammatory and
“resiliency” proteins in the CSF of patients with major depression. Depress
Anxiety (2012) 29(1):32–8. doi: 10.1002/da.20876 49. Harley J, Luty S, Carter J, Mulder R, Joyce P. Elevated C-reactive protein in
depression: a predictor of good long-term outcome with antidepressants and
poor outcome with psychotherapy. J Psychopharmacol (2010) 24(4):625–6. doi: 10.1177/0269881109102770 65. American Psychiatric Association. Diagnostic and statistical manual of
mental disorders (4th ed., text rev). REFERENCES Snijders G, Schiweck C, Mesman E, Grosse L, De Wit H, Nolen WA, et al. A dynamic course of T cell defects in individuals at risk for mood disorders. Brain Behav Immun (2016) 58:11–7. doi: 10.1016/j.bbi.2016.05.007f 89. Du Y, Ma Z, Lin S, Dodel RC, Gao F, Bales KR, et al. Minocycline prevents
nigrostriatal dopaminergic neurodegeneration in the MPTP model of
Parkinson’s disease. Proc Natl Acad Sci (2001) 98(25):14669–74. doi: 10.1073/
pnas.251341998 72. Nakayama K. Effect of paroxetine on extracellular serotonin and dopamine
levels in the prefrontal cortex. Naunyn Schmiedebergs Arch Pharmacol (2002)
365(2):102–5. doi: 10.1007/s00210-001-0497-7 90. Shin SS, Dixon CE. Oral fish oil restores striatal dopamine release after
traumatic brain injury. Neurosci Lett (2011) 496(3):168–71. doi: 10.1016/j. neulet.2011.04.009 73. Köhler CA, Freitas TH, Maes M, de Andrade NQ, Liu CS, Fernandes BS,
et al. Peripheral cytokine and chemokine alterations in depression: a meta-
analysis of 82 studies. Acta Psychiatr Scand (2017) 135(5):373–87. doi:
10.1111/acps.12698 91. Berk M, Malhi GS, Gray LJ, Dean OM. The promise of N-acetylcysteine in
neuropsychiatry. Trends Pharmacol Sci (2013) 34(3):167–77. doi: 10.1016/j. tips.2013.01.001 p
74. Hanisch UW. Microglia as a source and target of cytokines. Glia (2002)
40(2):140–55. doi: 10.1002/glia.10161i 92. De Cristóbal J, Moro MA, Dávalos A, Castillo J, Leza JC, Camarero J, et al. Neuroprotective effect of aspirin by inhibition of glutamate release after
permanent focal cerebral ischaemia in rats. J Neurochem (2001) 79(2):456–9. doi: 10.1046/j.1471-4159.2001.00600.x 75. Czéh B, Nagy SA. Clinical findings documenting cellular and molecular
abnormalities of glia in depressive disorders. Front Mol Neurosci (2018)
11(56):1–16. doi: 10.3389/fnmol.2018.00056 76. Sato K. Effects of microglia on neurogenesis. Glia (2015) 63(8):1394–1405. doi: 10.1002/glia.22858 93. De Cristóbal J, Cárdenas A, Lizasoain I, Leza JC, Fernández-Tomé P, Lorenzo P,
et al. Inhibition of glutamate release via recovery of ATP levels accounts
for a neuroprotective effect of aspirin in rat cortical neurons exposed to
oxygen-glucose deprivation. Stroke (2002) 33(1):261–7. doi: 10.1161/
hs0102.101299 77. Hökfelt T, Stanic D, Sanford SD, Gatlin JC, Nilsson I, Paratcha G, et al. NPY
and its involvement in axon guidance, neurogenesis, and feeding. Nutrition
(2008) 24(9):860–68. doi: 10.1016/j.nut.2008.06.010 j
78. Slavich GM, Way BM, Eisenberger NI, Taylor SE. Neural sensitivity to social
rejection is associated with inflammatory responses to social stress. Proc Natl
Acad Sci USA (2010) 107(33):14817–22. doi: 10.1073/pnas.1009164107 94. Becking K, Haarman BCM, Grosse L, Nolen WA, Claes S, Arolt V, et al. REFERENCES The
circulating levels of CD4+ t helper cells are higher in bipolar disorder as
compared to major depressive disorder. J Neuroimmunol (2018) 319:28–36. doi: 10.1016/j.jneuroim.2018.03.004 79. Poletti S, Leone G, Hoogenboezem TA, Ghiglino D, Vai B, de Wit H, et al. Markers of neuroinflammation influence measures of cortical thickness
in bipolar depression. Psychiatry Res Neuroimaging (2019) 285:64–6. doi:
10.1016/j.pscychresns.2019.01.009 95. Dager SR, Friedman SD, Parow A, Demopulos C, Stoll AL, Lyoo IK, et al. Brain metabolic alterations in medication-free patients with bipolar disorder. Arch Gen Psychiatry (2004) 61(5):450–8. doi: 10.1001/archpsyc.61.5.450 80. Benedetti F, Poletti S, Hoogenboezem TA, Mazza E, Ambree O, de Wit H,
et al. Inflammatory cytokines influence measures of white matter integrity in
bipolar disorder. J Affect Disord (2016) 202:1–9. doi: 10.1016/j.jad.2016.05.047 96. Yüksel C, Öngür D. Magnetic resonance spectroscopy studies of glutamate-
related abnormalities in mood disorders. Biol Psychiatry (2010) 68(9):785–
94. doi: 10.1016/j.biopsych.2010.06.016 97. Gigante AD, Bond DJ, Lafer B, Lam RW, Young LT, Yatam LN. Brain
glutamate levels measured by magnetic resonance spectroscopy in patients
with bipolar disorder: a meta-analysis. Bipolar Disord (2012) 14(5):478–87. doi: 10.1111/j.1399-5618.2012.01033.x f
81. Baldeón Rojas L, Weigelt K, de Wit H, Ozcan B, van Oudenaren A,
Sempértegui F, et al. Study on inflammation-related genes and microRNAs,
with special emphasis on the vascular repair factor HGF and miR-574-3p,
in monocytes and serum of patients with T2D. Diabetol Metab Syndr (2016)
8(6):1–12. doi: 10.1186/s13098-015-0113-5 98. Jun C, Choi Y, Lim SM, Bae S, Hong YS, Kim JE, et al. Disturbance of the
glutamatergic system in mood disorders. Exp Neurobiol (2014) 23(1):28–35. doi: 10.5607/en.2014.23.1.28 82. Beck G, Brinkkoetter P, Hanusch C, Schulte J, van Ackern K, van der Woude FJ,
et al. Clinical review: immunomodulatory effects of dopamine in general
inflammation. Crit Care (2004) 8(6):485–91. doi: 10.1186/cc2879hlf 99. Perlman K, Benrimoh D, Israel S, Rollins C, Brown E, Tunteng J-F, et al. A systematic meta-review of predictors of antidepressant treatment outcome
in major depressive disorder. J Affect Disord (2019) 243:503–15. doi:
10.1016/j.jad.2018.09.067 l
83. Loix S, KocK MD, Henin P. The anti-inflammatory effects of ketamine: state
of the art. Acta Anaesthesiol Belg (2011) 62(1):47–58.. 84. Zhu C-B, Blakely RD, Hewlett WA. The proinflammatory cytokines
interleukin-1beta and tumor necrosis factor-alpha activate serotonin
transporters. Neuropsychopharmacology (2006) 31(10):2121–31. doi:
10.1038/sj.npp.1301029 100. Pape K, Tamouza R, Leboyer M, Zipp F. Immunoneuropsychiatry—Novel
perspectives on brain disorders. Nat Rev Neurol (2019) 15(6):317–28. doi:
10.1038/s41582-019-0174-4 85. REFERENCES Washington, DC: American Psychiatric
Association (2000). 66. First MB, Spitzer RL, Gibbon M, Williams JBW. Structured Clinical Interview
for DSM-IV Axis I disorders (SCID I). New York: Biometric Research
Department (1997). 50. Yang J, Wang N, Yang C, Shi J, Yu H, Hashimoto K. Serum interleukin-6
is a predictive biomarker for ketamine’s antidepressant effect in treatment-
resistant patients with major depression. Biol Psychiatry (2015) 77(3):e19–
e20. doi: 10.1016/j.biopsych.2014.06.021f 67. Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry
(1960) 23:56–62. doi: 10.1037/t04100-000 51. Gupta R, Gupta K, Tripathi AK, Bhatia MS, Gupta LK. Effect of mirtazapine
treatment on serum levels of brain-derived neurotrophic factor and tumor
necrosis factor-α in patients of major depressive disorder with severe
depression. Pharmacology (2016) 97(3–4):184–8. doi: 10.1159/000444220 68. Müller N, Krause D, Barth R, Myint AM, Weidinger E, Zill P, et al. Childhood
adversity and current stress are related to pro- and anti-inflammatory cytokines
in major depression. J Affect Disord (2019) 253:270–76. doi: 10.1016/j. jad.2019.04.088 52. Rapaport MH, Nierenberg AA, Schettler PJ, Kinkead B, Cardoos A, Walker R,
et al. Inflammation as a predictive biomarker for response to omega-3 fatty
acids in major depressive disorder: a proof of concept study. Mol Psychiatry
(2016) 21(1):71–9. doi: 10.1038/mp.2015.22 69. Vogels RJ, Koenders MA, van Rossum EF, Spijker AT. Drexhage HA. T Cell Deficits and overexpression of hepatocyte growth factor in anti-
inflammatory circulating monocytes of middle-aged patients with bipolar
disorder characterized by a high prevalence of the metabolic syndrome. Front Psychiatry (2017) 8(34):1–11. doi: 10.3389/fpsyt.2017.00034 53. Raison CL, Rutherford RE, Woolwine BJ, Shuo C, Schettler P, Drake DF,
et al. A randomized controlled trial of the tumor necrosis factor antagonist
infliximab for treatment-resistant depression. JAMA Psychiatry (2013)
70(1):31–41. doi: 10.1001/2013.jamapsychiatry.4 70. Mesman E, Hillegers MH, Ambree O, Arolt V, Nolen WA, Drexhage HA. Monocyte activation, brain-derived neurotrophic factor (BDNF), and S100B July 2019 | Volume 10 | Article 458 Frontiers in Psychiatry | www.frontiersin.org 14 Arteaga-Henriquez et al. Prediction of Anti-Depressive/Anti-Inflammatory Therapy Response in MDD in bipolar offspring: a follow-up study from adolescence into adulthood. Bipolar Disord (2015) 17(1):39–49. doi: 10.1111/bdi.12231 in bipolar offspring: a follow-up study from adolescence into adulthood. Bipolar Disord (2015) 17(1):39–49. doi: 10.1111/bdi.12231 88. Brooks JD, Norris PC, Dennis EA. Effects of omega-3 fatty acids on lipid
metabolism and signaling using lipidomic analyses. FASEB J (2010) 24:475.1-
475.1. doi: 10.1096/fasebj.24.1_supplement.475.1 71. REFERENCES Zhu C-B, Lindler KM, Owens AW, Daws LC, Blakely RD, Hewlett
WA. Interleukin-1 receptor activation by systemic lipopolysaccharide
induces behavioral despair linked to MAPK regulation of CNS serotonin
transporters. Neuropsychopharmacology (2010) 35(13):2510–20. doi:
10.1038/npp.2010.116 Conflict of Interest Statement: The authors declare that the research was
conducted in the absence of any commercial or financial relationships that could
be construed as a potential conflict of interest. 86. Müller N, Schwarz MJ. The immune-mediated alteration of serotonin and
glutamate: towards an integrated view of depression. Mol Psychiatry (2007)
12(11):988–1000. doi: 10.1038/sj.mp.4002006 Copyright © 2019 Arteaga-Henríquez, Simon, Burger, Weidinger, Wijkhuijs, Arolt,
Birkenhager, Musil, Müller and Drexhage. This is an open-access article distributed
under the terms of the Creative Commons Attribution License (CC BY). The use,
distribution or reproduction in other forums is permitted, provided the original
author(s) and the copyright owner(s) are credited and that the original publication
in this journal is cited, in accordance with accepted academic practice. No use,
distribution or reproduction is permitted which does not comply with these terms. 87. Walker FR. A critical review of the mechanism of action for the selective
serotonin reuptake inhibitors: do these drugs possess anti-inflammatory
properties and how relevant is this in the treatment of depression? Neuropharmacology (2013) 67:304–17. doi: 10.1016/j.neuropharm.2012.10.002 July 2019 | Volume 10 | Article 458 Frontiers in Psychiatry | www.frontiersin.org 15
|
https://openalex.org/W4213247922
|
https://zenodo.org/record/6061369/files/ZDIT11021.pdf
|
Kirghiz, Kyrgyz
| null |
QADIMGI MESOPOTAMIYAGA OID MANBALAR VA ISTORIOGRAFIYA
|
Zenodo (CERN European Organization for Nuclear Research)
| 2,022
|
cc-by
| 2,384
|
ISTORIOGRAFIYA
Jumaboyeva Nilufar Soyibjon qizi, Bo’riqulova Madinabonu Baxriddin qizi
Denov Tadbirkorlik va pedagogika institutining talabalari ISTORIOGRAFIYA
Jumaboyeva Nilufar Soyibjon qizi, Bo’riqulova Madinabonu Baxriddin qizi
Denov Tadbirkorlik va pedagogika institutining talabalari Annotatsiya:
Ushbu
maqolada
Mesopotamiyaga
oid
manbalar
va
istoriografiyalar ,xo’jaliklari, aholisi, ijtimoiy-iqtisodiy hayoti haqida ma’lumot
berilgan. Kalit so’zlar: manba,Gerodot,Sinaxerib,Axikar,”Tarix kutubxonasi” it so’zlar: manba,Gerodot,Sinaxerib,Axikar,”Tarix kutubxonasi” 46
Qadimgi Mesopotamiya tarixiga doir manbalar uch asosiy guruhga bo’linadi: 1)
qadimgi Sharq yozuvi yodgorliklari, 2) moddiy madaniyat yodgorliklari va 3)
antik zamon avtorlarining ma’lumotlari. Qadimgi Sharq hujjatlari tarixchi uchun
hammadan ko’ra ko’proq ahamiyatga ega, chunki bu hujjatlarda tarixning
ijtimoiy-iqtisodiy faktlari, siyosiy hodisalar qayd etilgan, ularda o’sha davrdagi
madaniyatning tarakqiyot darajasi aks etgan. Mesopotamiya xalqlarining
xo’jaligi, texnikasi va turmushi qay darajada taraqqiy qilganligini ko’rsatuvchi
moddiy madaniyat yodgorliklari ham katta ahamiyatga ega. Antik zamon
avtorlari qoldirgan ma’lumotlar bularga qaraganda kamroq ahamiyatga ega. Lekin ishonchli va to’la manbalarga ega bo’lgan hozirgi zamon tekshiruvchisi
antik zamon avtorlarini e’tibordan chetda qoldirmasligi kerak. 1 Antik dunyo
avtorlari qadimgi Sharq madaniyatining so’nggi asrlarida yashaganlar. Ular ko’p
voqyealarni shaxsan ko’rganlar, ko’p narsalarnn o’sha vaqtlarda mavjud bo’lib,
keyinchalik yo’qolib ketgan manbalardan bilganlar. Qadimgi Sharq yozuvining
asl yodgorliklari antik zamon avtorlari bergan ma’lumotlarning ko’pi to’g’ri
ekanligini tasdiqlmadi. Nihoyat, antik zamon avtorlari madaniy taraqqiyot
darajasi jihatidan qadimgi Sharq dunyosnning namoyandalariga qaraganda
ancha yuqori turganlar. Lekin hozirgi zamon tarixchisi grek va Rim
yozuvchilarining asarlarini tanqidiy urganib, undan extiyotlik bilan foydalanishi
keraq Antik dunyo avtorlari bergan ma’lumotlarni qadimgi Sharq hujjatlari va
yodgorliklariga hamma
vaqt taqqoslab
ko’rish
zarur. Hozirgi
zamon
tekshiruvchisi qadimgi zamondagi har bir yozuvchining xususan har bir
tarixchining tendensiyasi va uning dunyoqarash xususiyatini nazarda tutishi
kerak. Nihoyat, antik zamon avtori tarixni qanchalik zamonbop qilib hikoya
qilganligini ham nazarda tutish zarur. Qadimgi Sharq haqida yozgan grek
tarixchilari orasida Gerodot ayrim o’rin tutadi, uni haqli ravishda «tarix otasi»
deb ataydilar. Gerodot (eramizdan av. 480— 425 yillarda) o’zining katta asarini
grek-fors urushlari tarixiga bag’ishlagan. Gerodot ellinlarning daxshatli
dushmani bo’lgan Eron davlatini mumkin qadar batafsil ta’riflashga harakat Qadimgi Mesopotamiya tarixiga doir manbalar uch asosiy guruhga bo’linadi: 1)
qadimgi Sharq yozuvi yodgorliklari, 2) moddiy madaniyat yodgorliklari va 3)
antik zamon avtorlarining ma’lumotlari. Qadimgi Sharq hujjatlari tarixchi uchun
hammadan ko’ra ko’proq ahamiyatga ega, chunki bu hujjatlarda tarixning
ijtimoiy-iqtisodiy faktlari, siyosiy hodisalar qayd etilgan, ularda o’sha davrdagi
madaniyatning tarakqiyot darajasi aks etgan. Mesopotamiya xalqlarining
xo’jaligi, texnikasi va turmushi qay darajada taraqqiy qilganligini ko’rsatuvchi
moddiy madaniyat yodgorliklari ham katta ahamiyatga ega. Antik zamon
avtorlari qoldirgan ma’lumotlar bularga qaraganda kamroq ahamiyatga ega. Lekin ishonchli va to’la manbalarga ega bo’lgan hozirgi zamon tekshiruvchisi
antik zamon avtorlarini e’tibordan chetda qoldirmasligi kerak. «Zamonaviy dunyoda innovatsion tadqiqotlar: Nazariya
va amaliyot» nomli ilmiy, masofaviy, onlayn konferensiya «Zamonaviy dunyoda innovatsion tadqiqotlar: Nazariya
va amaliyot» nomli ilmiy, masofaviy, onlayn konferensiya ISTORIOGRAFIYA
Jumaboyeva Nilufar Soyibjon qizi, Bo’riqulova Madinabonu Baxriddin qizi
Denov Tadbirkorlik va pedagogika institutining talabalari Gerodot ayniqsa Semiramida va
Nntokridaning binokorlik ishlarini, Kayxisrovnnng Bobilni olgani, Eron shohi
Doro xukmronlik qilgan vaqtida bobilliklar ko’targan qo’zg’olon, osur podshosi
Sinaxeribning Misrga qo’shin tortib borganini mufassal tasvirlagan. Georodot o’z
hikoyalarida qadimgi mif (afsona) va xalq ertaklaridan keng foydalanib,
ko’pincha ularni tarixda bo’lgan voqyealar deb tushuntirgan. Chunonchi,
Geraklidlar avlodidan chiqqan Belning ugli Ninni Gerodot osur podsholiginnng
asoschisi deb hisoblagan. Lekin Gerodot asarlarini sinchiklab, tanqidiy ko’z bilan
1 Ko’rsatilgan asar 9 analiz qilgan hozirgi zamon tarixchisi u yozib qoldirgan
faktlarning ko’pidan foydalanishi mumkin. Gerodot qadimgi Sharq xalqlarining
madaniyatiga yuksak baxo bergan va qadimgi Sharq antik dunyoga ta’sir
ko’rsatganligini ta’kidlab o’tgan. Gerodot quyosh soatlari va kunning 12 qismga
bo’linishi haqida gapirib, ellinlar «bularning hammasini bobilliklardan olganlar»
d
di E
i d
l i V
i
ikki
hi
id
t
’il
Kt
i
K id ki «Zamonaviy dunyoda innovatsion tadqiqotlar: Nazariya
va amaliyot» nomli ilmiy, masofaviy, onlayn konferensiya «Zamonaviy dunyoda innovatsion tadqiqotlar: Nazariya
va amaliyot» nomli ilmiy, masofaviy, onlayn konferensiya `
va amaliyot» nomli ilmiy, masofaviy, onlayn konfere
qilib, Eron despotiyasi sostaviga kirgan mamlakatlarning tabiiy sharoitlari,
xalqlarning urf-odatlari, diniy e’tiqodlari, madaniyati va tarixini mufassal bayon
etgan. Gerodot o’z asarini yozishda, asosan, kohinlar va yo’l boshlovchilarning
hikoyalaridan, shuningdek Sharq mamlakatlariga qilgan sayohati vaqtida o’zi
qurgan narsalaridan foydalangan. Gerodot qadimgi Sharq tillarini bilmasa ham
va o’zi foydalangan manbalarga jiddiy tanqidiy ko’z bilan qaray olmagan bo’lsa
ham, biz uning asarida ilmiy tanqidning dastlabki kurtaklarini ko’ramiz. Avtor
Eron va Misr to’g’risida mufassal gapirib, Mesopotamiya ustida ozroq to’xtalgan. Chunki u Osuriya tarixiga bag’ishlab maxsus asar yozmoqchi bo’lgan, ammo yoza
olmagan. Gerodot hamma vaqt mamlakatning tarixi va madaniyatini har
taraflama yoritishga harakat qilib, Mesopotamiyaning tabiiy sharoitlari
to’g’risida gapirganida. u yerdagi sun’iy sug’orishga, foydali o’simliklardan
foydalanish va ularni o’stirishga, shuningdek tuproqning unumdorligiga alohida
ahamiyat bergan. U tuproq unumdorligining ahamiyatiga juda ortiqcha baho
bergan. Gerodot Mesopotamiya xalqlarining turmushi va urf-odatlari haqida
gapirib, kemasozliq suv transporti va savdo xaqida hikoya qilgan. Odamlarning
kiyim-kechagi, ovkati, davolash usullari, uylanishdagi rasm-odatlar va ko’mish
marosimlarini tasvirlagan. Mesopotamiyaning asosiy shahri bo’lmish Bobilni
ayniqsa batafsil tasvirlagan hamda bu shaharni «mamlakatning eng mashxur va
juda ham mustaxkam shaxri» deb hisoblagan. Mesopotamiyaning siyosiy tarixi
haqida Gerodot bergan ma’lumotlar juda ham qisqa bo’lib, unda tasodifiy va
qisman afsonaviy hodisalar tasvir etilgan. Gerodot ayniqsa Semiramida va
Nntokridaning binokorlik ishlarini, Kayxisrovnnng Bobilni olgani, Eron shohi
Doro xukmronlik qilgan vaqtida bobilliklar ko’targan qo’zg’olon, osur podshosi
Sinaxeribning Misrga qo’shin tortib borganini mufassal tasvirlagan. ISTORIOGRAFIYA
Jumaboyeva Nilufar Soyibjon qizi, Bo’riqulova Madinabonu Baxriddin qizi
Denov Tadbirkorlik va pedagogika institutining talabalari 1 Antik dunyo
avtorlari qadimgi Sharq madaniyatining so’nggi asrlarida yashaganlar. Ular ko’p
voqyealarni shaxsan ko’rganlar, ko’p narsalarnn o’sha vaqtlarda mavjud bo’lib,
keyinchalik yo’qolib ketgan manbalardan bilganlar. Qadimgi Sharq yozuvining
asl yodgorliklari antik zamon avtorlari bergan ma’lumotlarning ko’pi to’g’ri
ekanligini tasdiqlmadi. Nihoyat, antik zamon avtorlari madaniy taraqqiyot
darajasi jihatidan qadimgi Sharq dunyosnning namoyandalariga qaraganda
ancha yuqori turganlar. Lekin hozirgi zamon tarixchisi grek va Rim
yozuvchilarining asarlarini tanqidiy urganib, undan extiyotlik bilan foydalanishi
keraq Antik dunyo avtorlari bergan ma’lumotlarni qadimgi Sharq hujjatlari va
yodgorliklariga hamma
vaqt taqqoslab
ko’rish
zarur. Hozirgi
zamon
tekshiruvchisi qadimgi zamondagi har bir yozuvchining xususan har bir
tarixchining tendensiyasi va uning dunyoqarash xususiyatini nazarda tutishi
kerak. Nihoyat, antik zamon avtori tarixni qanchalik zamonbop qilib hikoya
qilganligini ham nazarda tutish zarur. Qadimgi Sharq haqida yozgan grek
tarixchilari orasida Gerodot ayrim o’rin tutadi, uni haqli ravishda «tarix otasi»
deb ataydilar. Gerodot (eramizdan av. 480— 425 yillarda) o’zining katta asarini
grek-fors urushlari tarixiga bag’ishlagan. Gerodot ellinlarning daxshatli
dushmani bo’lgan Eron davlatini mumkin qadar batafsil ta’riflashga harakat 46 «Zamonaviy dunyoda innovatsion tadqiqotlar: Nazariya
va amaliyot» nomli ilmiy, masofaviy, onlayn konferensiya `
«Zamonaviy dunyoda innovatsion tadqiqotlar: Naza
va amaliyot» nomli ilmiy, masofaviy, onlayn konfere
qilib, Eron despotiyasi sostaviga kirgan mamlakatlarning tabiiy sharoitlari,
xalqlarning urf-odatlari, diniy e’tiqodlari, madaniyati va tarixini mufassal bayon
etgan. Gerodot o’z asarini yozishda, asosan, kohinlar va yo’l boshlovchilarning
hikoyalaridan, shuningdek Sharq mamlakatlariga qilgan sayohati vaqtida o’zi
qurgan narsalaridan foydalangan. Gerodot qadimgi Sharq tillarini bilmasa ham
va o’zi foydalangan manbalarga jiddiy tanqidiy ko’z bilan qaray olmagan bo’lsa
ham, biz uning asarida ilmiy tanqidning dastlabki kurtaklarini ko’ramiz. Avtor
Eron va Misr to’g’risida mufassal gapirib, Mesopotamiya ustida ozroq to’xtalgan. Chunki u Osuriya tarixiga bag’ishlab maxsus asar yozmoqchi bo’lgan, ammo yoza
olmagan. Gerodot hamma vaqt mamlakatning tarixi va madaniyatini har
taraflama yoritishga harakat qilib, Mesopotamiyaning tabiiy sharoitlari
to’g’risida gapirganida. u yerdagi sun’iy sug’orishga, foydali o’simliklardan
foydalanish va ularni o’stirishga, shuningdek tuproqning unumdorligiga alohida
ahamiyat bergan. U tuproq unumdorligining ahamiyatiga juda ortiqcha baho
bergan. Gerodot Mesopotamiya xalqlarining turmushi va urf-odatlari haqida
gapirib, kemasozliq suv transporti va savdo xaqida hikoya qilgan. Odamlarning
kiyim-kechagi, ovkati, davolash usullari, uylanishdagi rasm-odatlar va ko’mish
marosimlarini tasvirlagan. Mesopotamiyaning asosiy shahri bo’lmish Bobilni
ayniqsa batafsil tasvirlagan hamda bu shaharni «mamlakatning eng mashxur va
juda ham mustaxkam shaxri» deb hisoblagan. Mesopotamiyaning siyosiy tarixi
haqida Gerodot bergan ma’lumotlar juda ham qisqa bo’lib, unda tasodifiy va
qisman afsonaviy hodisalar tasvir etilgan. ISTORIOGRAFIYA
Jumaboyeva Nilufar Soyibjon qizi, Bo’riqulova Madinabonu Baxriddin qizi
Denov Tadbirkorlik va pedagogika institutining talabalari Strabon asarida Bobil va undagi Xaldeya astronomlari
observatoriyasnning ajoyib ta’rifi, shuningdek Nin va Semiramida haqida antik
davr tarixshunosligida keng o’rin olgan afsonalar kabi tarixiy afsonalar saqlanib
qolgan. Shuning uchun ham bu afsonalarning avloddan-avlodga kelganligi
ajablanarli emas. O’rta asr tarixchilari bu afsonalarni, antik zamon tarixchilari
yozib qoldirgan oz-moz ma’lumotlar bilan birga, yangi davr boshlarida qadimgi
Sharq olamining allaqachonlar unutilgan xalqlari madaniyatiga qaytadan
qiziqish uyg’otgan olimlarga meros qilib o’tkazganlar Old Osiyoning qadimgi «Zamonaviy dunyoda innovatsion tadqiqotlar: Nazariya
va amaliyot» nomli ilmiy, masofaviy, onlayn konferensiya `
va amaliyot» nomli ilmiy, masofaviy, onlayn konfere
podsholigiga asos solgan Nin bilan Semiramid haqidagi afsonalarni kiritgan. Bu
barcha afsonalar Sharq rivoyatlari bilan ancha keyin vujudga kelgan grek
naqllarining xilma-xil aralashmasi bo’lib ketgan. Ammo Ktesiy ba’zi hollarda
ishonchliroq manbalardan, jumladan podsholar pergamentlaradan foydalangan
bo’lishi mumkin. Ktesiy Eron shohi Artakserksning saroy tabibi bo’lgan, shu
tufayli u Suzadagi shoh arxivlariga kirib, bu pergamentlarni o’rganish
imkoniyatiga ega bo’lgan. Ktesiy asari bizning zamongacha saqlanmagan. Uning
asaridan olingan ayrim parchalar Diodor asarida saqlanib qolgan. 1 Eramizdan
avvalgi I asrda yashagan Diodor «Tarix kutubxonasi» degan asarida o’zidan oldin
o’tgan tarixchilarning turli asarlaridan, xususan Gerodot bilan Ktesiy asarlaridan
keng foydalangan. Diodor osur podsholigining asoschilari Nin va Semiramidning
afsonaviy hayot va faoliyatlariny ayniqsa mufassal tasvirlagan. Diodor asaridagi
Bobil tasviri, jumladan Bobilni qazish vaqtida topilgan Bobil saroylarining
devorlaridagi nafis suratlarning tasviri birmuncha kiziqarlidir. Nihoyat, Xaldeya
astrologiyasi va astronomiyasinnng Diodor asarida saqlanib qolgan tasviri ham
diqqatga sazovordir. Eramizdan avvalgi I asrning oxiri va eramizning I asri
boshlarida yashagan Strabonning «Geografiya»sida kadimgi Mesopotamiyaning
tarixi
haqida
ma’lumotlar
saqlanib
qolgan. Strabon
o’z
asarida
Mesopotamiyaning tabiiy sharoitini tasvirlagan hamda Dajla va Frotning vaqt-
vaqti bilan bo’lib turadigan toshqiniga va sun’iy sug’orish tarmoqlari tashkil
qilishning zarurligiga e’tibor bergan. Strabonning ko’pgina kuzatishlari
anchagina qiziqarli bo’lsa-da, lekin uning tasvirlarida juda mubolag’a qilib
yuborilgan joylar ham bor. Masalan, Strabon Mesopotamiya yerlarinnng
unumdorligini va xurmo daraxtinnng xo’jalikda keng ishlatilishini haddan
tashqari bo’rttirib ko’rsatgan. Strabon bobilliklarning urf-odat va kiyim-
kechaklarini, uylanishdagi rasm-odatlar va ko’mish marosimlarini batafsil
tasvirlagan. Strabon o’zining bu hikoyalarida ko’p narsalarni tasvirlashda
Gerodotga ergashgan. Strabon asarida Bobil va undagi Xaldeya astronomlari
observatoriyasnning ajoyib ta’rifi, shuningdek Nin va Semiramida haqida antik
davr tarixshunosligida keng o’rin olgan afsonalar kabi tarixiy afsonalar saqlanib
qolgan. Shuning uchun ham bu afsonalarning avloddan-avlodga kelganligi
ajablanarli emas. O’rta asr tarixchilari bu afsonalarni, antik zamon tarixchilari
yozib qoldirgan oz-moz ma’lumotlar bilan birga, yangi davr boshlarida qadimgi
Sharq olamining allaqachonlar unutilgan xalqlari madaniyatiga qaytadan
qiziqish uyg’otgan olimlarga meros qilib o’tkazganlar. ISTORIOGRAFIYA
Jumaboyeva Nilufar Soyibjon qizi, Bo’riqulova Madinabonu Baxriddin qizi
Denov Tadbirkorlik va pedagogika institutining talabalari Georodot o’z
hikoyalarida qadimgi mif (afsona) va xalq ertaklaridan keng foydalanib,
ko’pincha ularni tarixda bo’lgan voqyealar deb tushuntirgan. Chunonchi,
Geraklidlar avlodidan chiqqan Belning ugli Ninni Gerodot osur podsholiginnng
asoschisi deb hisoblagan. Lekin Gerodot asarlarini sinchiklab, tanqidiy ko’z bilan
1 Ko’rsatilgan asar 9 analiz qilgan hozirgi zamon tarixchisi u yozib qoldirgan
faktlarning ko’pidan foydalanishi mumkin. Gerodot qadimgi Sharq xalqlarining
madaniyatiga yuksak baxo bergan va qadimgi Sharq antik dunyoga ta’sir
ko’rsatganligini ta’kidlab o’tgan. Gerodot quyosh soatlari va kunning 12 qismga
bo’linishi haqida gapirib, ellinlar «bularning hammasini bobilliklardan olganlar»
deydi. Eramizdan avvalgi V asrning ikkinchi yarmida tug’ilgan Ktesiy Knidskiy
yozib qoldirgan ma’lumotlar ilmiy jihatdan kamrok ahamiyatga ega. Ktesiy
Osuriya tarixiga bag’ishlangan ocherkiga ko’pgina xalq afsonalarini kiritgan,
masalan Sinaxerib va Asarxaddonnnng vaziri dono Axikar haqidagi Osuriya 47 «Zamonaviy dunyoda innovatsion tadqiqotlar: Nazariya
va amaliyot» nomli ilmiy, masofaviy, onlayn konferensiya `
«Zamonaviy dunyoda innovatsion tadqiqotlar: Naza
va amaliyot» nomli ilmiy, masofaviy, onlayn konfere
podsholigiga asos solgan Nin bilan Semiramid haqidagi afsonalarni kiritgan. Bu
barcha afsonalar Sharq rivoyatlari bilan ancha keyin vujudga kelgan grek
naqllarining xilma-xil aralashmasi bo’lib ketgan. Ammo Ktesiy ba’zi hollarda
ishonchliroq manbalardan, jumladan podsholar pergamentlaradan foydalangan
bo’lishi mumkin. Ktesiy Eron shohi Artakserksning saroy tabibi bo’lgan, shu
tufayli u Suzadagi shoh arxivlariga kirib, bu pergamentlarni o’rganish
imkoniyatiga ega bo’lgan. Ktesiy asari bizning zamongacha saqlanmagan. Uning
asaridan olingan ayrim parchalar Diodor asarida saqlanib qolgan. 1 Eramizdan
avvalgi I asrda yashagan Diodor «Tarix kutubxonasi» degan asarida o’zidan oldin
o’tgan tarixchilarning turli asarlaridan, xususan Gerodot bilan Ktesiy asarlaridan
keng foydalangan. Diodor osur podsholigining asoschilari Nin va Semiramidning
afsonaviy hayot va faoliyatlariny ayniqsa mufassal tasvirlagan. Diodor asaridagi
Bobil tasviri, jumladan Bobilni qazish vaqtida topilgan Bobil saroylarining
devorlaridagi nafis suratlarning tasviri birmuncha kiziqarlidir. Nihoyat, Xaldeya
astrologiyasi va astronomiyasinnng Diodor asarida saqlanib qolgan tasviri ham
diqqatga sazovordir. Eramizdan avvalgi I asrning oxiri va eramizning I asri
boshlarida yashagan Strabonning «Geografiya»sida kadimgi Mesopotamiyaning
tarixi
haqida
ma’lumotlar
saqlanib
qolgan. Strabon
o’z
asarida
Mesopotamiyaning tabiiy sharoitini tasvirlagan hamda Dajla va Frotning vaqt-
vaqti bilan bo’lib turadigan toshqiniga va sun’iy sug’orish tarmoqlari tashkil
qilishning zarurligiga e’tibor bergan. Strabonning ko’pgina kuzatishlari
anchagina qiziqarli bo’lsa-da, lekin uning tasvirlarida juda mubolag’a qilib
yuborilgan joylar ham bor. Masalan, Strabon Mesopotamiya yerlarinnng
unumdorligini va xurmo daraxtinnng xo’jalikda keng ishlatilishini haddan
tashqari bo’rttirib ko’rsatgan. Strabon bobilliklarning urf-odat va kiyim-
kechaklarini, uylanishdagi rasm-odatlar va ko’mish marosimlarini batafsil
tasvirlagan. Strabon o’zining bu hikoyalarida ko’p narsalarni tasvirlashda
Gerodotga ergashgan. ISTORIOGRAFIYA
Jumaboyeva Nilufar Soyibjon qizi, Bo’riqulova Madinabonu Baxriddin qizi
Denov Tadbirkorlik va pedagogika institutining talabalari Old Osiyoning qadimgi
xalqlari to’g’risida yozgan antik tarixchilar orasida eramizdan avvalgi IV—III
asrlarda yashagan bobillik Beros alohida o’rin tutadi. U Bobildagi Marduk
ib d t
i i
k hi i b ’l
i
b bli ib d t
i l
id
f
d l
i h 48 «Zamonaviy dunyoda innovatsion tadqiqotlar: Nazariya
va amaliyot» nomli ilmiy, masofaviy, onlayn konferensiya «Zamonaviy dunyoda innovatsion tadqiqotlar: Nazariya
va amaliyot» nomli ilmiy, masofaviy, onlayn konferensiya imkoniyatiga ega bo’lgan, bu hol esa uning ishinn yengillashtirgan. Aleksandr
Makedonskiy va dastlabki Salavkalarnnng zamondoshi Beros grek madaniyatiga
daxldor bo’lgan, Bobil tarixi hamda madaniyatini u o’sha zamonning bilimdon
kishisi nuqtai nazaridan ta’riflab bera olgan. Shunnng uchun Beros grek tilida
Bobil tarixi va mifologiyasi ocherkidan iborat katta tarixiy asar yarata olgan. Berosning asari uch kitobdan iborat. «Donishmandlik» deb atalgan birinchi
kitobda Bobil miflari bayon etilgan. Ikkinchi kitobda afsonalardagi dunyo to’foni
dazridan tortib to shox Pulning (ya’ni osur podshosi Tiglatpalasar III ning)
podsholik qilish davrigacha bo’lgan Mesopotamiya tarixi bayon qilingan. Uchinchi kitobda Mesopotamiya tarixining Aleksandr Makedonskiy o’limigacha
bo’lgan davri tasvirlangan. Xulosa: Xulosa: Afsuski Berosning asari to’la saqlanib qolmagan. Beros asarining Iosif Flaviy va
boshqa yozuvchilarning asarlarida keltirilgan parchalari va qitatalarigina 11
bizning zamongacha yetib kelgan. Bu parchalar ibtidoiy zamonlar, to’fon davri,
patriarxlar, Sinaxerib va Navuxodonosor haqidagi qissalardan iborat. Foydanilgan adabiyotlar ro’yxati: 1. Авдиев В.И. Вавилонская религия. Б.С.Е, Т.6 М-1951. 2. Авдиев В.И. Қадимги шарқ тарихи. Т -1964. 3. Бартольд В.В. Восточно –иранский вопрос. М-1922. 4. Большая советская Энциклопедия. Изд.2. Т.З М-1952. 5. Винклер Г. Вавилонская культура. под ред. Никольского. 6. Волков И.М. Законы Вавилонского царя Хаммурапи. М-1941. 7. Дяконов И.М Государственный строй древнейшего Шумера. –«Вестник
древней истории» 1952 N 2. 8. История древнего востока. Под.ред. Кузищина В.И. М.,1979. 9. Косидовский Венон. Когда солнце было богом. М., 1968. 10.Липин Л.А.,
Белов А. Глиняные книги. Л., 1956. 9. Косидовский Венон. Когда солнце было богом. М., 1968. 10.Липин Л.А.,
Белов А. Глиняные книги. Л., 1956. Белов А. Глиняные книги. Л., 1956. 49 49
|
https://openalex.org/W4235535728
|
https://bmccancer.biomedcentral.com/track/pdf/10.1186/s12885-020-07465-1
|
English
| null |
Artificial neural networks improve LDCT lung cancer screening: A comparative validation study
|
Research Square (Research Square)
| 2,020
|
cc-by
| 6,618
|
Hsu et al. BMC Cancer (2020) 20:1023
https://doi.org/10.1186/s12885-020-07465-1 Hsu et al. BMC Cancer (2020) 20:1023
https://doi.org/10.1186/s12885-020-07465-1 Open Access Artificial neural networks improve LDCT
lung cancer screening: a comparative
validation study Yin-Chen Hsu1,2, Yuan-Hsiung Tsai1,2, Hsu-Huei Weng1,2, Li-Sheng Hsu1,2,3, Ying-Huang Tsai2,4,5,6,7,8,
Yu-Ching Lin2,6,7,8, Ming-Szu Hung2,6,7,8, Yu-Hung Fang2,6,7,8 and Chien-Wei Chen1,2,9,10* Abstract Background: This study proposes a prediction model for the automatic assessment of lung cancer risk based on an
artificial neural network (ANN) with a data-driven approach to the low-dose computed tomography (LDCT)
standardized structure report. Methods: This comparative validation study analysed a prospective cohort from Chiayi Chang Gung Memorial
Hospital, Taiwan. In total, 836 asymptomatic patients who had undergone LDCT scans between February 2017 and
August 2018 were included, comprising 27 lung cancer cases and 809 controls. A derivation cohort of 602
participants (19 lung cancer cases and 583 controls) was collected to construct the ANN prediction model. A
comparative validation of the ANN and Lung-RADS was conducted with a prospective cohort of 234 participants (8
lung cancer cases and 226 controls). The areas under the curves (AUCs) of the receiver operating characteristic
(ROC) curves were used to compare the prediction models. Results: At the cut-off of category 3, the Lung-RADS had a sensitivity of 12.5%, specificity of 96.0%, positive
predictive value of 10.0%, and negative predictive value of 96.9%. At its optimal cut-off value, the ANN had a
sensitivity of 75.0%, specificity of 85.0%, positive predictive value of 15.0%, and negative predictive value of 99.0%. The area under the ROC curve was 0.764 for the Lung-RADS and 0.873 for the ANN (P = 0.01). The two most
important predictors used by the ANN for predicting lung cancer were the documented sizes of partially solid
nodules and ground-glass nodules. Conclusions: Compared to the Lung-RADS, the ANN provided better sensitivity for the detection of lung cancer in
an Asian population. In addition, the ANN provided a more refined discriminative ability than the Lung-RADS for
lung cancer risk stratification with population-specific demographic characteristics. When lung nodules are detected
and documented in a standardized structured report, ANNs may better provide important insights for lung cancer
prediction than conventional rule-based criteria. Keywords: Early detection of cancer, Receiver operating characteristic (ROC) curves, Sensitivity and specificity,
Machine learning, Data visualization * Correspondence: chienwei33@gmail.com Development of the ANN Development of the ANN
Each baseline LDCT report consists of a description of
the intra- and extra-pulmonary findings, and a Lung-
RADS risk category. The reports were designed to aid
lung cancer screening. Using data scraping techniques,
22 input features were automatically extracted from the
descriptive parts of the baseline LDCT reports and used
to develop the ANN. Four of the inputs constituted clin-
ical information or LDCT parameters. Another seven in-
puts pertained to nodule patterns and sizes based on the
Lung-RADS standardized lexicon. The remaining inputs
were extra-pulmonary interpretations, which consisted
of 11 descriptive features. These inputs were in binary
form (0 or 1). The Lung-RADS classification was not in-
cluded among the input features. Table 1 lists all 22 in-
put features, and shows the distribution of the baseline
Lung-RADS categories in the derivation and validation
cohorts. This study aims to propose a reporting system based
on an ANN with a data-driven approach to the LDCT
standardized structured report. We further explore de-
terminants for predicting lung cancer in this study
population. © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License,
which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give
appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if
changes were made. The images or other third party material in this article are included in the article's Creative Commons
licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons
licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain
permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the
data made available in this article, unless otherwise stated in a credit line to the data. Hsu et al. BMC Cancer (2020) 20:1023 Hsu et al. BMC Cancer (2020) 20:1023 Page 2 of 9 Page 2 of 9 Background had at least 1 year of follow-up after the LDCT baseline
scan. The diagnosis of lung cancer was confirmed based
on surgical resection or lung biopsy and was recorded in
a hospital-based cancer registry. Patients who had con-
firmed lung cancer prior to the index date of July 30,
2019 were classified as lung cancer patients (category 1);
all other patients were classified as controls (category 0). Figure 1 shows the flowchart of the study. ac g ou d
Lung cancer is the leading cause of cancer mortality
worldwide [1]. The National Lung Screening Trial
(NLST) showed that low-dose computed tomography
(LDCT) screening could reduce lung cancer mortality by
20% compared to chest X-ray (CXR) [2]. With the in-
creasing use of LDCT for lung cancer screening, the
American College of Radiology (ACR) introduced the
Lung Imaging Screening Reporting and Data System
(Lung-RADS), which assigns groups for screening popu-
lations [3]. Aimed at high-risk smokers in the USA, the
validity of the Lung-RADS remains unclear in areas with
a high prevalence of non-smoking-related lung cancer,
such as China, Taiwan, and Japan [4]. In Taiwan, more
than 95% of lung cancer patients are non-smokers, most
of whom have adenocarcinoma [5, 6]. Given the wide
range of lung cancer demographics in Asia, the imple-
mentation of the Lung-RADS is not yet universal [7]. To
address ambiguity, medical institutions have developed
various structured reporting systems [8]. However, there
is no current evidence showing explicit superiority for
any reporting system in assessing lung cancer risks. LDCT image acquisition and interpretation All LDCT scans were performed with a 64-slice multide-
tector computed tomography (CT) (Somatom Sensation
64; Siemens Healthcare, Erlangen, Germany) in a low-
dose setting without contrast enhancement (volumetric
CT dose index ≤2.0 mGy for a standard patient). The
scan parameters were 120 kVp, 25 effective mAs, soft-
tissue kernel (B30f), and 3 mm slice thickness. All equip-
ment specifications and acquisition parameters followed
the recommendations of the ACR Society of Thoracic
Radiology Practice Parameters for the Performance and
Reporting of Lung Cancer Screening Thoracic CT [12]. Each LDCT baseline scan was reported by one thoracic
radiologist with 7 years of experience. The standardized
structured reports described the size, shape, location,
and texture of the lung nodules, as well as other inciden-
tal findings. The density of each lung nodule was re-
ported according to the definition from the Fleischner
Society guidelines [13, 14]. The size of each lung nodule
was measured on lung windows and recorded as recom-
mended by the Lung-RADS. The artificial neural network (ANN) is a field of artifi-
cial intelligence technology characterized by simulating
biological neural systems based on mathematical theor-
ies [9]. ANNs modify their behaviour by adjusting the
weights between hidden units until the output correctly
converges to the ground truth, and they are particularly
adept at classification problems with different input data
[10]. With the ability to analyse complex nonlinear rela-
tionships between predictors and diseases, well-trained
ANNs make predictions with greater accuracy than con-
ventional rule-based criteria [11]. Study design and participants The Institutional Review Board of Chang Gung Medical
Foundation approved this case-control study. From Feb-
ruary 2017 through August 2018, a total of 836 consecu-
tive asymptomatic participants who underwent both
CXR and LDCT at Chiayi Chang Gung Memorial Hos-
pital, Taiwan, for lung cancer screening were prospect-
ively enrolled. The inclusion criteria were age between
40 and 80 years old and willingness to participate in
follow-up imaging or diagnostic workup. Subjects were
excluded if a pulmonary nodule was detected on CXR,
or if they had a known medical history of any malignant
disease. Serial imaging reports, basic patient information,
and demographic data were obtained. Each participant Feed-forward neural networks based on the back-
propagation algorithm were constructed using Keras ver-
sion 2.2.4 [15], a high-level neural network application
programming interface that can simplify the ANN con-
struction
process. The
inputs
for
the
ANN
were Hsu et al. BMC Cancer (2020) 20:1023 Page 3 of 9 Fig. 1 Flow diagram normalized such that they fell between 0 and 1. The ANN
consisted of the first two hidden layers, followed by a
dropout layer to prevent over-fitting and a dense layer as
the output layer [16]. There were 10 hidden units in each
of the first two hidden layers and a rectified linear unit
was used as the activation function. We also tested net-
works including different numbers of hidden units in each
layer; none of these proved superior to the 10-unit net-
work. Figure 2 shows the structure of the ANN. An adap-
tive learning rate optimizer based on the adaptive
moment estimation method was used to facilitate conver-
gence [17]. The network weights were randomly initialized
between −1 and 1. The learning rate was 0.001 and the
dropout rate of the dropout layer was set to 0.1. The out-
put layer eventually generated a number between 0 and 1
using the sigmoidal activation function. The predictive
performance of the models was monitored during training
to optimize the hyperparameters. divided into three equal parts. At each cycle, one of the
three parts was selected as the test set and removed
from the dataset, while the remaining cases were used as
the training set of the ANN. This process was repeated
until the entire dataset had been used once as the test
set. Finally, the ANN was validated with the prospective
validation cohort. Statistical analyses
l
l Statistical
analyses
were
performed
using
MedCalc
18.9.1 (MedCalc Software, Ostend, Belgium). Observed
distributions were tested against the hypothesized nor-
mal distribution (Kolmogorov–Smirnov test). Data are
reported as the mean ± standard deviation or number
(%) unless otherwise indicated. To determine and com-
pare the performance of the Lung-RADS and ANN, the
sensitivity and specificity of the lung cancer classification
at different thresholds were analysed based on the re-
sults of area under the receiver operating characteristic
(ROC) curve analyses. The optimal diagnostic thresholds
of the ROC curves were determined using maximized
Youden’s [21] index. ROC curves were compared using
the method described by DeLong et al. [22]. The sensi-
tivity,
specificity,
positive
predictive
value
(PPV), Study design and participants To investigate the determining factors for predicting
lung cancer, we applied a permutation feature import-
ance method proposed by Leo Breiman [20]. The per-
mutation feature importance for each feature used in the
ANN was evaluated with the validation cohort, and the
performance metric was AUC. At each iteration, one of
the features was randomly shuffled, and the permutation
feature importance score was calculated to show how
much the performance metric decreased. Therefore, a
high score revealed a feature with a great contribution to
the discriminative ability of the model. The dataset used in this study is unbalanced, but
ANNs are sensitive to such datasets. Due to the iterative
nature of the training, ANNs are prone to converge to
the majority class. Thus, to achieve a cost-sensitive
neural network, we used the class weighting approach;
this assigns error weights to samples based on their class
[18]. A 2:1 class weight ratio between lung cancer cases
(category 1) and controls (category 0) was used in the
ANN. We also explored networks with other class
weight ratios (5:1, 10:1, 20:1, 25:1, 29:1 and 35:1). How-
ever, in terms of sensitivity, specificity and AUC, none of
which performed significantly better than the setting
with a 2:1 class weight ratio. Validation and risk group identification In the training process, the ANN was internally validated
via “three-fold cross-validation” [19]. The dataset was Hsu et al. Validation and risk group identification BMC Cancer (2020) 20:1023 Page 4 of 9 Table 1 Clinical descriptors of the derivation and validation cohorts at the baseline
Derivation cohort (N = 602)
Validation cohort (N = 234)
P b
Cancer (N = 19)
Control c (N = 583)
Cancer (N = 8)
Control c (N = 226)
Sex a
Male
7 (36.84%)
236 (40.48%)
2 (25.00%)
111 (49.12%)
0.038
Female
12 (63.16%)
347 (59.52%)
6 (75.00%)
115 (50.88%)
Age (y) a
64.89 ± 7.53
61.87 ± 6.42
57.63 ± 8.73
61.05 ± 7.88
0.053
LDCT parameters
Dose (mSv) a
1.95 ± 0.64
1.46 ± 0.24
1.78 ± 0.45
1.49 ± 0.26
0.161
DLP (mGy.cm) a
75.53 ± 32.54
49.17 ± 11.08
64.50 ± 24.43
50.77 ± 10.72
0.206
Pattern of nodules
Nodules of interest a
2.42 (1–7)
1.11 (0–32)
1.88 (1–7)
1.29 (0–8)
0.330
Number of involved lobes a
1.68 (1–3)
0.75 (0–5)
1.38 (1–4)
0.99 (0–5)
0.007
Size of nodules (mm)
Solid nodule a
10.01 (0–136.00)
1.49 (0–19.80)
0.63 (0–5.00)
1.80 (0–36.75)
1.000
PS nodule a
3.89 (0–20.40)
0.38 (0–11.95)
1.77 (0–4.90)
0.54 (0–7.30)
0.498
GGN a
8.87 (0–31.00)
0.58 (0–23.30)
4.56 (0–10.30)
0.24 (0–9.05)
0.038
Calcified nodule a
0.00 (0)
0.39 (0–19.25)
0.86 (0–6.90)
0.55 (0–7.05)
0.100
Fat-containing nodule a
0.00 (0)
0.05 (0–28.15)
0.00 (0)
0.00 (0)
0.506
Intra-pulmonary findings
Linear atelectasis a
10 (52.63%)
431 (73.93%)
2 (25.00%)
108 (47.79%)
< 0.001
Plate-like atelectasis a
5 (26.32%)
73 (12.52%)
0 (0.00%)
19 (8.41%)
0.050
Plate-like GGN a
2 (10.53%)
143 (24.53%)
1 (12.50%)
39 (17.26%)
0.029
Bronchiectasis a
0 (0.00%)
39 (6.69%)
1 (12.50%)
8 (3.54%)
0.143
Emphysema a
1 (5.26%)
51 (8.75%)
2 (25.00%)
28 (12.39%)
0.068
Fibrotic change a
2 (10.53%)
154 (26.42%)
0 (0.00%)
42 (18.58%)
0.015
Extra-pulmonary findings
Mediastinal tumour a
4 (21.05%)
30 (5.15%)
1 (12.50%)
8 (3.54%)
0.290
Thyroid nodule a
1 (5.26%)
19 (3.26%)
0 (0.00%)
2 (0.88%)
0.045
Adrenal nodule a
1 (5.26%)
5 (0.86%)
0 (0.00%)
0 (0.00%)
0.125
Hepatic nodule a
1 (5.26%)
67 (11.49%)
0 (0.00%)
20 (8.85%)
0.245
Renal nodule a
0 (0.00%)
16 (2.74%)
0 (0.00%)
10 (4.42%)
0.229
Lung-RADS
Category 1
0 (0.00%)
323 (55.40%)
0 (0.00%)
115 (50.89%)
0.240
Category 2
6 (31.58%)
222 (38.08%)
7 (87.50%)
102 (45.13%)
0.021
Category 3
5 (26.32%)
31 (5.32%)
1 (12.50%)
6 (2.65%)
0.080
Category 4
8 (42.10%)
7 (1.20%)
0 (0.00%)
3 (1.33%)
0.279
a The 22 input features for developing the ANN
b Comparison of the derivation cohort and validation cohort, P-values less than 0.05 indicated statistical significance
c Participant who did not have confirmed lung cancer prior to the index date were labelled as control
BMI body mass index; DLP dose length product; GGN ground-glass nodule; PS nodule, part-solid nodule
The values are given as the mean ± SD, range or n (%) The 22 input features for developing the ANN
b Comparison of the derivation cohort and validation cohort, P-values less than 0.05 indicated statistical significance
c Participant who did not have confirmed lung cancer prior to the index date were labelled as control
BMI body mass index; DLP dose length product; GGN ground-glass nodule; PS nodule, part-solid nodule
The values are given as the mean ± SD, range or n (%) negative predictive value (NPV), positive likelihood ratio
(LR+), and negative likelihood ratio (LR–) of each model
for lung cancer diagnosis were calculated [23]. Validation and risk group identification In all
analyses, P < 0.05 was considered to indicate statistical
significance. Results Results
Demographic and clinical characteristics
The study cohort included a total of 836 consecutive
asymptomatic participants who had undergone LDCT
for lung cancer screening (27 lung cancer cases and 809 Demographic and clinical characteristics The study cohort included a total of 836 consecutive
asymptomatic participants who had undergone LDCT
for lung cancer screening (27 lung cancer cases and 809 Hsu et al. BMC Cancer (2020) 20:1023 Page 5 of 9 Hsu et al. BMC Cancer Fig. 2 Structure of an ANN Fig. 2 Structure of an ANN controls) at our institution. Between February 2017 and
February 2018, 602 participants were included in the
derivation cohort. Among the participants in the deriv-
ation cohort, 29 subjects underwent surgical resection or
biopsy for tissue sampling. Nineteen of those subjects
were diagnosed with lung cancer (adenocarcinoma in
situ, n = 3; minimally invasive adenocarcinoma, n = 1; in-
vasive adenocarcinoma, n = 14; small cell carcinoma, n =
1), and the remaining ten had benign lesions (pneumo-
nia, n = 5; pulmonary fibrosis, n = 4; and pulmonary
hamartoma, n = 1). Between March and August 2018,
234 participants were included in the validation cohort. Nine of these subjects underwent tissue sampling, eight
of whom were diagnosed with lung cancer (adenocarcin-
oma in situ, n = 3; invasive adenocarcinoma, n = 4; small
cell carcinoma, n = 1); the remaining subjects had benign
lesions (pulmonary fibrosis, n = 1). Despite the adoption
of identical inclusion criteria, there were several signifi-
cant differences in demographic features between the
training and validation cohorts. The full demographic
and clinical descriptions of each cohort at the baseline
are presented in Table 1. the 19 lung cancer participants (3.16%) included 6 with
category 2, 5 with category 3, and 8 with category 4;
none had category 1. For the validation cohort (n = 234),
the distribution of baseline Lung-RADS categories was
as follows: category 1 (49.14%), category 2 (46.58%), cat-
egory 3 (3.00%), and category 4 (1.28%). Among the sub-
jects in this cohort, the 8 lung cancer participants
(3.42%) included 7 with category 2 and 1 with category
3; none had category 1 or category 4. Performance of prediction models the non-cancer cases were correctly identified by both
the Lung-RADS and ANN (specificity: 96.0 and 85.0%,
respectively), but more lung cancer cases were correctly
identified by the ANN (sensitivity: 12.5 and 75.0%, re-
spectively). Figure 3 presents the ROC curves and AUCs
for assessing the overall validity of both tools. There was
a significant difference between the AUCs of the Lung-
RADS and ANN (AUC 0.764 vs. 0.873, respectively, P =
0.013). Table 3 presents the sensitivity, specificity, PPV,
NPV, LR+, and LR−of the two risk assessment tools. For Lung-RADS, a positive predictive value of 10.0%
(95% CI: 1.6 to 43.7%) and negative predictive value of
96.9% (95% CI: 96.0 to 97.6%) were calculated at the
cut-off point of category 3. For the ANN, a positive pre-
dictive value of 15.0% (95% CI: 9.6 to 22.6%) and nega-
tive predictive value of 99.0% (95% CI: 96.7 to 99.7%)
were calculated at the optimal cut-off value. The likeli-
hood ratios confirm that the results according to both
lung cancer risk classification tools differ from those ac-
cording to chance. AUC area under the curve; CI confidence interval; LR+ positive likelihood ratio;
LR−negative likelihood ratio; NPV negative predictive value; PPV positive
predictive value Performance of prediction models BMC Cancer (2020) 20:1023 Page 6 of 9 Table 2 Contingency table for the Lung-RADS and ANN models
(n = 234)
Scale/
model
Lung-RADS
ANN
No
Yes
Sum
No
Yes
Sum
Control a
217
9
226
192
34
226
Lung cancer
7
1
8
2
6
8
Sum
224
10
234
194
40
234
a Participant who did not have confirmed lung cancer prior to the index date
were labelled as control Table 2 Contingency table for the Lung-RADS and ANN models
(n = 234) Table 3 Performance analysis for the Lung-RADS and ANN
models (n = 234)
Scale/model
Lung-RADS
ANN
Cut-off
Category 3
> 0.012
AUC (95% CI)
0.764 (0.705, 0.817)
0.873 (0.823, 0.913)
Classification accuracy (%)
93.16
84.62
Sensitivity (95% CI)
12.50 (0.3, 52.7)
75.00 (34.9, 96.8)
Specificity (95% CI)
96.02 (92.6, 98.2)
84.96 (79.6, 89.4)
PPV (95% CI)
10.0 (1.6, 43.7)
15.0 (9.6, 22.6)
NPV (95% CI)
96.9 (96.0, 97.6)
99.0 (96.7, 99.7)
LR+ (95% CI)
3.14 (0.5, 21.9)
4.99 (3.0, 8.3)
LR- (95% CI)
0.91 (0.7, 1.2)
0.29 (0.1, 1.0)
AUC area under the curve; CI confidence interval; LR+ positive likelihood ratio;
LR−negative likelihood ratio; NPV negative predictive value; PPV positive
predictive value Table 3 Performance analysis for the Lung-RADS and ANN
models (n = 234) the non-cancer cases were correctly identified by both
the Lung-RADS and ANN (specificity: 96.0 and 85.0%,
respectively), but more lung cancer cases were correctly
identified by the ANN (sensitivity: 12.5 and 75.0%, re-
spectively). Figure 3 presents the ROC curves and AUCs
for assessing the overall validity of both tools. There was
a significant difference between the AUCs of the Lung-
RADS and ANN (AUC 0.764 vs. 0.873, respectively, P =
0.013). Table 3 presents the sensitivity, specificity, PPV,
NPV, LR+, and LR−of the two risk assessment tools. For Lung-RADS, a positive predictive value of 10.0%
(95% CI: 1.6 to 43.7%) and negative predictive value of
96.9% (95% CI: 96.0 to 97.6%) were calculated at the
cut-off point of category 3. For the ANN, a positive pre-
dictive value of 15.0% (95% CI: 9.6 to 22.6%) and nega-
tive predictive value of 99.0% (95% CI: 96.7 to 99.7%)
were calculated at the optimal cut-off value. The likeli-
hood ratios confirm that the results according to both
lung cancer risk classification tools differ from those ac-
cording to chance. Feature importance and risk group identification Figure 4 shows a plot visualizing permutation feature
importance scores of the ANN. In this plot, the rows
correspond to the 22 input items of the ANN. The per-
mutation feature importance scores for each feature
used in the ANN are calculated and ranked. The items
towards the top are the most important features and
those towards the bottom matter least. Accordingly,
ground-glass nodules (GGNs) and partially solid nodules
were important predictors of lung cancer. Performance of prediction models Using the training set, both the ANN and Lung-RADS
showed good discriminative ability with respect to lung
cancer risk stratification in the derivation cohort (AUC
0.90 vs. 0.91, respectively, no significant difference). For
the Lung-RADS, a sensitivity of 68.4% (95% confidence
interval [CI]: 43.4 to 87.4%) and specificity of 93.5%
(95% CI: 91.2 to 95.3%) were calculated at the cut-off
point of category 3, which adhered to the original defin-
ition of a positive LDCT scan. For the ANN, a sensitivity
of 73.7% (95% CI: 48.8 to 90.9%) and specificity of 94.7%
(95% CI: 92.5 to 96.4%) were calculated at the optimal
cut-off value. For the derivation cohort (n = 602), the distribution of
baseline Lung-RADS categories was as follows: category
1 (53.66%), category 2 (37.87%), category 3 (5.98%), and
category 4 (2.49%). Among the subjects in this cohort, Both models were prospectively validated using the
validation cohort. Table 2 presents the contingency re-
sults of both lung cancer assessment models. Most of Hsu et al. Discussion When the Lung-RADS was applied, these
patients were classified as category 2 and may have been
falsely reassured by the “negative” screening results and
thus did not return for follow-up scans. Among the 5 of
8 lung cancer cases in the validation cohort, the ANN
could identify all (100%) of these patients who had pul-
monary lesions and initially presented with GGNs < 20
mm, which were finally confirmed as adenocarcinoma. In several studies performed in Asian cohorts, the ma-
jority of lung cancer patients were non-smokers with
pulmonary adenocarcinoma spectrum lesions, which
typically presented as pure GGNs or partially solid nod-
ules [33, 34]. The current literature shows that larger
GGNs (variable cut-off, range 10.5 ~ 15.0 mm) tend to
be more aggressive or appear as invasive pulmonary
adenocarcinoma [35, 36]. This is a particular concern in
Asian populations, where it would be important to re-
port these GGNs and develop corresponding algorithms
with follow-up strategies. Therefore, the ANN poten-
tially assimilates population-specific demographic char-
acteristics and provides important insights that improve
the efficacy of lung cancer screening programmes. Fig. 4 The plot visualizing permutation feature importance scores of
the ANN model for lung cancer risk using artificial intelligence algo-
rithms, such as ANNs. Andoni et al. demonstrated the ability of a two-layer
neural network to use low-order polynomials [29]. Sev-
eral studies have used various models to assess the risk
of various types of cancer. The results showed that ANN
generally achieved better performance than other algo-
rithms [30, 31]. As a preliminary step, we tried to fit the
training dataset to several types of models, including
ANN, support vector machines, decision trees, naive
Bayes classifiers, and linear discriminant classifiers. The
ANN showed the best performance, which was compar-
able to that of Lung-RADS. Therefore, an ANN was
used in this study. There were several limitations to this study. First, clas-
sification models based on machine learning tend to be
unstable in small datasets. However, both models in this
study were externally validated using a prospective co-
hort. Second, the PPVs and NPVs were influenced by
the prevalence of disease within the study population. The prevalence of lung cancer was estimated to be ap-
proximately 3%, as mentioned above, and is therefore ar-
bitrary to some extent. Finally, the follow-up period was
relatively short. Discussion In lung cancer screening, LDCT is used to detect pul-
monary nodules and evaluate their size and morphology. Most pulmonary nodules are small (< 5 mm in diameter)
and benign, and their morphology is variable [24]. Across the lung cancer screening literature, the major
challenge faced by this diagnostic imaging modality is
the difficulty of defining a “positive scan [25, 26].” The
false-positive rate of the Lung-RADS has increased due
to the large degree of variation in lung cancer demo-
graphics between populations, thus limiting the reliabil-
ity of this tool [27]. In addition, application of the
unitary criteria without appropriate validation may result
in false-positive results, overdiagnosis, and unnecessary
costs [28]. In this study, the Lung-RADS predicted lung
cancer risks for the validation cohort with an AUC of
0.76, which indicated suboptimal decisive power to as-
sess lung cancer risks in the population. The principles
of the Lung-RADS are uniformity of radiology interpret-
ation, risk assessment, and nodule management in
LDCT lung cancer screening programmes, and although
the clinical presentations of lung cancer are likely to vary
greatly between populations, some of these imaging find-
ings are not assessed. One possible remedy for this obs-
tacle is the development of a validated prediction model Fig. 3 ROC curves for the Lung-RADS and ANN model Fig. 3 ROC curves for the Lung-RADS and ANN model Hsu et al. BMC Cancer (2020) 20:1023 Page 7 of 9 Page 7 of 9 Fig. 4 The plot visualizing permutation feature importance scores of
the ANN model shown that well-trained ANNs are capable of making ac-
curate predictions for various types of cancer, they have
been considered as “black boxes” due to their complexity
[30–32]. In this study, efforts were made to determine
what the ANN had learnt using the permutation import-
ance estimation method. According to the ranking of
permutation feature importance, GGNs and partially
solid nodules were important predictors of lung cancer. This study also sought to address the heterogeneity of
lung cancer risk assessments in populations containing a
high percentage of non-smoking-related lung cancers. Among the subjects in this study, more than one-third
of the confirmed lung cancer lesions presented with
GGNs < 20 mm (5 of 19 lung cancer cases in the deriv-
ation cohort and 5 of 8 lung cancer cases in the valid-
ation cohort). Discussion A large-scale prospective study with
long-term follow-up is required to confirm the benefits
of using an ANNs as an element of LDCT lung cancer
screening programme. In this study, the ANN took many risk factors into ac-
count, and it predicted lung cancer risks for the valid-
ation cohort with an AUC of 0.87. Compared to the
Lung-RADS, ANNs may be more robust in the predic-
tion of lung cancer. Additionally, the standardized struc-
tured reports in this study involved the use of lung
nodule descriptions from the Lung-RADS lexicon sug-
gested by the ACR. As these input features can be easily
identified and are generally assessed by radiologists, the
ANN-based
LDCT
reporting
system
is
both
cost-
effective and user-friendly. Funding
Thi
k This work was supported by Chang Gung Memorial Hospital. (Contract Nos. PMRPG6F0021 and CMRPG6H0651). The funding body did not play any role
in design, in the collection, analysis, and interpretation of data; in the writing
of the manuscript; and in the decision to submit the manuscript for
publication. 10. Baker JA, Kornguth PJ, Lo JY, Williford ME, Floyd CE Jr. Breast cancer:
prediction with artificial neural network based on BI-RADS standardized
lexicon. Radiology. 1995;196:817–22. 10. Baker JA, Kornguth PJ, Lo JY, Williford ME, Floyd CE Jr. Breast cancer:
prediction with artificial neural network based on BI-RADS standardized
lexicon. Radiology. 1995;196:817–22. 11. Weng SF, Reps J, Kai J, Garibaldi JM, Qureshi N. Can machine-learning
improve cardiovascular risk prediction using routine clinical data? PLoS One
2017;12:e0174944. 11. Weng SF, Reps J, Kai J, Garibaldi JM, Qureshi N. Can machine-learning
improve cardiovascular risk prediction using routine clinical data? PLoS One. 2017;12:e0174944. Acknowledgements
W
k
l d
S
i 6. Ha SY, Choi SJ, Cho JH, Choi HJ, Lee J, Jung K, et al. Lung cancer in never-
smoker Asian females is driven by oncogenic mutations, most often
involving EGFR. Oncotarget. 2015;6:5465–74. We acknowledge Springer Nature Author Service for editing this manuscript. Authors’ contributions 7. Carter BW, Lichtenberger JP 3rd, Wu CC, Munden RF. Screening for lung
Cancer: lexicon for communicating with health care providers. AJR Am J
Roentgenol. 2018;210:473–9. Y-CH conceptualized the study, performed analysis and wrote the main
manuscript text. C-WC assisted with the writing of the manuscript and pre-
pared all figures. Yu-HT oversaw the project. L-SH and H-HW assisted with
study design and statistical analysis. Yi-HT, Y-CL, M-SH and Y-HF assisted with
collection of patients’ meta data and interpretation. All authors read and ap-
proved the final manuscript. 8. Hsu HT, Tang EK, Wu MT, Wu CC, Liang CH, Chen CS, et al. Modified lung-
RADS improves performance of screening LDCT in a population with high
prevalence of non-smoking-related lung Cancer. Acad Radiol. 2018;25:1240–
51. 8. Hsu HT, Tang EK, Wu MT, Wu CC, Liang CH, Chen CS, et al. Modified lung-
RADS improves performance of screening LDCT in a population with high
prevalence of non-smoking-related lung Cancer. Acad Radiol. 2018;25:1240–
51. 9. Bishop CM. Neural networks for pattern recognition. New York: Oxford
University Press; 1995. p. 482. 9. Bishop CM. Neural networks for pattern recognition. New York: Oxford
University Press; 1995. p. 482. Availability of data and materials
h d
d
d
l
d d 12. Kazerooni EA, Austin JH, Black WC, Dyer DS, Hazelton TR, Leung AN, et al. ACR–STR practice parameter for the performance and reporting of lung
cancer screening thoracic computed tomography (CT): 2014 (resolution 4). J
Thorac Imaging. 2014;29:310–6. The datasets used and/or analyzed during the current study are available
from the corresponding author on reasonable request. Abbreviations ACR: American College of Radiology; ANN: Artificial neural network;
AUC: Area under the curve; GGN: Ground-glass nodule; CXR: Chest X-ray;
LDCT: Low-dose computed tomography; Lung-RADS: Lung CT Screening
Reporting and Data System; NLST: National Lung Screening Trial;
NPV: Negative predictive value; PPV: Positive predictive value; ROC: Receiver
operating characteristic NPV: Negative predictive value; PPV: Positive predictive value; ROC: Receiver
operating characteristic NPV: Negative predictive value; PPV: Positive predictive value; ROC: Receiver
operating characteristic 5. Chen KY, Chang CH, Yu CJ, Kuo SH, Yang PC. Distribution according to
histologic type and outcome by gender and age group in Taiwanese
patients with lung carcinoma. Cancer. 2005;103:2566–74. Consent for publication
Not applicable. 15. Chollet F. Keras: GitHub; https://github.com/fchollet/keras%7D%7D; 2015. 15. Chollet F. Keras: GitHub; https://github.com/fchollet/keras%7D%7D; 2015. 16. Srivastava N, Hinton G, Krizhevsky A, Sutskever I, Salakhutdinov R. Dropout: a
simple way to prevent neural networks from overfitting. J Mach Learn Res. 2014;15:1929–58. References 1. American Cancer Society. Cancer Facts & Figures 2018. Atlanta: American
Cancer Society; 2018. 1. American Cancer Society. Cancer Facts & Figures 2018. Atlanta: American
Cancer Society; 2018. 2. National Lung Screening Trial Research Team, Aberle DR, Adams AM, Berg
CD, Black WC, Clapp JD, et al. Reduced lung-cancer mortality with low-dose
computed tomographic screening. N Engl J Med. 2011;365:395–409. 2. National Lung Screening Trial Research Team, Aberle DR, Adams AM, Berg
CD, Black WC, Clapp JD, et al. Reduced lung-cancer mortality with low-dose
computed tomographic screening. N Engl J Med. 2011;365:395–409. 2. National Lung Screening Trial Research Team, Aberle DR, Adams AM, Berg
CD, Black WC, Clapp JD, et al. Reduced lung-cancer mortality with low-dose
computed tomographic screening. N Engl J Med. 2011;365:395–409. 3. Lung CT screening reporting and data system (Lung-RADS). American
College of Radiology. 2014. https://www.acr.org/Clinical-Resources/
Reporting-and-Data-Systems/Lung-Rads. Accessed 1 Dec 2018. 3. Lung CT screening reporting and data system (Lung-RADS). American
College of Radiology. 2014. https://www.acr.org/Clinical-Resources/
Reporting-and-Data-Systems/Lung-Rads. Accessed 1 Dec 2018. 4. Detterbeck FC, Marom EM, Arenberg DA, Franklin WA, Nicholson AG, Travis
WD, et al. The IASLC lung cancer staging project: background data and
proposals for the application of TNM staging rules to lung cancer
presenting as multiple nodules with ground glass or lepidic features or a
pneumonic type of involvement in the forthcoming eighth edition of the
TNM classification. J Thorac Oncol. 2016;11:666–80. Ethics approval and consent to participate 13. MacMahon H, Austin JH, Gamsu G, Herold CJ, Jett JR, Naidich DP, et al. Guidelines for management of small pulmonary nodules detected on CT
scans: a statement from the Fleischner society. Radiology. 2005;237:395–400. 13. MacMahon H, Austin JH, Gamsu G, Herold CJ, Jett JR, Naidich DP, et al. Guidelines for management of small pulmonary nodules detected on CT
scans: a statement from the Fleischner society. Radiology. 2005;237:395–400. The study was approved by the Institutional Review Board (IRB) of Chang
Gung Medical Foundation, in accordance with the ethical standards of the
responsible committee on human experimentation (IRB Nos. 201801905B0). Written consents were obtained from study participants. 14. MacMahon H, Naidich DP, Goo JM, Lee KS, Leung ANC, Mayo JR, et al. Guidelines for Management of Incidental Pulmonary Nodules Detected on
CT images: from the Fleischner society 2017. Radiology. 2017;284:228–43. Consent for publication
Not applicable. Competing interests 17. Kingma DP, Ba J. Adam: A method for stochastic optimization. arXiv
preprint arXiv:14126980; 2014. 17. Kingma DP, Ba J. Adam: A method for stochastic optimization. arXiv
preprint arXiv:14126980; 2014. The authors declare that they have no competing interests. Conclusions We also determined predictors of lung cancer; these
factors could be useful for identifying patients at high
risk of lung cancer. Although previous studies have Compared to the Lung-RADS, the ANN may have sub-
stantially improved the sensitivity for the detection of Hsu et al. BMC Cancer (2020) 20:1023 Hsu et al. BMC Cancer (2020) 20:1023 Page 8 of 9 Page 8 of 9 Page 8 of 9 lung cancer in an Asian population. Furthermore, ANNs
have a more refined discriminative ability than the
Lung-RADS for lung cancer risk stratification with
population-specific demographic characteristics. When
lung nodules are detected and documented in a stan-
dardized structured report, ANNs may better provide
important insights for lung cancer prediction than con-
ventional rule-based criteria. The effects of using an
ANN in clinical practice must be examined carefully in
further prospective large cohort studies. Received: 21 April 2020 Accepted: 28 September 2020 Received: 21 April 2020 Accepted: 28 September 2020 Author details
1 18. Kukar M, Kononenko I. Cost-sensitive learning with neural networks. ECAI;
1998. 18. Kukar M, Kononenko I. Cost-sensitive learning with neural networks. ECAI;
1998. 1Department of Diagnostic Radiology, Chang Gung Memorial Hospital Chiayi
Branch, Chiayi, Taiwan. 2Department of Medicine, Chang Gung University
College of Medicine, Taoyuan, Taiwan. 3Department of Biomedical
Engineering, National Cheng Kung University, Tainan, Taiwan. 4Department
of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital,
Linkou, Taiwan. 5Department of Respiratory Therapy, Chang Gung University,
Taoyuan, Taiwan. 6Department of Pulmonary and Critical Care Medicine,
Chang Gung Memorial Hospital Chiayi Branch, Chiayi, Taiwan. 7Department
of Respiratory Care, Chang Gung University of Science and Technology
Chiayi Campus, Chiayi, Taiwan. 8Department of Respiratory Care, Chang
Gung Memorial Hospital Chiayi Branch, Chiayi, Taiwan. 9Institute of Medicine,
Chung Shan Medical University, Taichung, Taiwan. 10Department of Medical
Imaging and Radiology, Shu-Zen Junior College of Medicine and
Management, Kaohsiung, Taiwan. 19. James G, Witten D, Hastie T, Tibshirani R. An introduction to statistical
learning: springer; 2013. 20. Breiman L. Random forests. Mach Learn. 2001;45:5–32. 21. Youden WJ. Index for rating diagnostic tests. Cancer. 1950;3 22. DeLong ER, DeLong DM, Clarke-Pearson DL. Comparing the areas under
two or more correlated receiver operating characteristic curves: a
nonparametric approach. Biometrics. 1988;44:837–45. 23. Sheskin DJ. Handbook of parametric and nonparametric statistical
procedures: crc press; 2003. 23. Sheskin DJ. Handbook of para
procedures: crc press; 2003. 24. van Riel SJ, Sanchez CI, Bankier AA, Naidich DP, Verschakelen J, Scholten ET,
et al. Observer variability for classification of pulmonary nodules on low-
dose CT images and its effect on nodule management. Radiology. 2015;277:
863–71. 24. van Riel SJ, Sanchez CI, Bankier AA, Naidich DP, Verschakelen J, Scholten ET,
et al. Observer variability for classification of pulmonary nodules on low-
dose CT images and its effect on nodule management. Radiology. 2015;277:
863–71. Page 9 of 9 Hsu et al. BMC Cancer (2020) 20:1023 Hsu et al. BMC Cancer (2020) 20:1023 25. Gierada DS, Pilgram TK, Ford M, Fagerstrom RM, Church TR, Nath H, et al. Lung cancer: interobserver agreement on interpretation of pulmonary
findings at low-dose CT screening. Radiology. 2008;246:265–72. 26. Balata H, Evison M, Sharman A, Crosbie P, Booton R. CT screening for lung
cancer: are we ready to implement in Europe? Lung Cancer. 2019;134:25–
33. 27. Author details
1 Haiman CA, Stram DO, Wilkens LR, Pike MC, Kolonel LN, Henderson BE, et al
Ethnic and racial differences in the smoking-related risk of lung cancer. N
Engl J Med. 2006;354:333–42. 28. Patz EF Jr, Pinsky P, Gatsonis C, Sicks JD, Kramer BS, Tammemagi MC, et al. Overdiagnosis in low-dose computed tomography screening for lung
cancer. JAMA Intern Med. 2014;174:269–74. 29. Andoni A, Panigrahy R, Valiant G, Zhang L. Learning polynomials with
neural networks. International conference on machine learning; 2014. 30. Hart GR, Roffman DA, Decker R, Deng J. A multi-parameterized artificial
neural network for lung cancer risk prediction. PLoS One. 2018;13:e0205264. 31. Nakatochi M, Lin Y, Ito H, Hara K, Kinoshita F, Kobayashi Y, et al. Prediction
model for pancreatic cancer risk in the general Japanese population. PLoS
One. 2018;13:e0203386. 32. JVJJoce T. Advantages and disadvantages of using artificial neural networks
versus logistic regression for predicting medical outcomes. J Clin Epidemiol. 1996;49:1225–31. 32. JVJJoce T. Advantages and disadvantages of using artificial neural networks
versus logistic regression for predicting medical outcomes. J Clin Epidemiol
1996;49:1225–31. 33. Sun S, Schiller JH, Gazdar AF. Lung cancer in never smokers—a different
disease. Nat Rev Cancer. 2007;7:778–90. 33. Sun S, Schiller JH, Gazdar AF. Lung cancer in never smokers—a different
disease. Nat Rev Cancer. 2007;7:778–90. 34. Saito S, Espinoza-Mercado F, Liu H, Sata N, Cui X, Soukiasian HJ. Current
status of research and treatment for non-small cell lung cancer in never-
smoking females. Cancer Biol Ther. 2017;18:359–68. 35. Jin X, Zhao SH, Gao J, Wang DJ, Wu J, Wu CC, et al. CT characteristics and
pathological implications of early stage (T1N0M0) lung adenocarcinoma
with pure ground-glass opacity. Eur Radiol. 2015;25:2532–40. 36. Lee HY, Choi YL, Lee KS, Han J, Zo JI, Shim YM, et al. Pure ground-glass
opacity neoplastic lung nodules: histopathology, imaging, and
management. AJR Am J Roentgenol. 2014;202:W224–33. 36. Lee HY, Choi YL, Lee KS, Han J, Zo JI, Shim YM, et al. Pure ground-glass
opacity neoplastic lung nodules: histopathology, imaging, and
management. AJR Am J Roentgenol. 2014;202:W224–33. Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations. Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.
|
https://openalex.org/W2032554204
|
https://zenodo.org/records/2410826/files/article.pdf
|
English
| null |
PRIAPISM COMPLICATING MYELOGENOUS LEUKÆMIA AND NOTED AS THE FIRST SYMPTOM.
|
Lancet
| 1,922
|
public-domain
| 6,009
|
505 505 pressure figures. It is enough that such people regard
their
" nerves " and intimacies of metabolism as
topics of general conversational interest. Freedom
from anxiety, business, domestic and personal, is
therapeutically most important for the subject of the
hypertension which requires treatment. Patients
who brood over their own blood-pressure figures, or
the fact that their doctor has told them that they
" suffer from high blood pressure," are very prone to
become the subjects of a vicious circle in which the
processes revolve the faster the more introspective
the patient becomes. ing on the new species he notes, " A re-examination of
material from the Chinese and Japanese cases, with
specimens collected in Egypt, does not reveal any
constant specific differences."
This does not seem to
advance matters, since there might presumably be two
species of Heterophyes parasitising man in Japan, the
presence of one only of which, in the laboratories of
the London School of Tropical Medicine, has no
obvious bearing on the matter. ing on the new species he notes, " A re-examination of
material from the Chinese and Japanese cases, with
specimens collected in Egypt, does not reveal any
constant specific differences."
This does not seem to
advance matters, since there might presumably be two
species of Heterophyes parasitising man in Japan, the
presence of one only of which, in the laboratories of
the London School of Tropical Medicine, has no
obvious bearing on the matter. obvious bearing on the matter. Since these happenings I have been fortunate enough
to obtain material passed by a Japanese after the
exhibition of 60 gr. of thymol. These flukes varied
greatly in length, particularly in the degree to which
the mobile pre-acetabular portion of the body was
extended. The essentials of their description are
contained in the third column of the accompanying
table. It has been mentioned above that the supposed
specific differences in the case under consideration rest
mainly upon measurements affected by muscular
action. These could only conceivably be the basis of
accurate comparison, could one be satisfied that in
either case the muscles concerned were contracted to
the same degree. Obviously this is impossible. The
last column illustrates the fact, well known but little
appreciated, that the state of relaxation is extra-
ordinarily variable, and that the limits of size, maxi-
mum and minimum, are altered accordingly, and
to so considerable an extent, that to rely upon them
as constituting specific differences seems perhaps as
reasonable as it would be to classify sparrows speci-
fically according to the extent to which their wings
remain spread in rigor mortis. the patient
We wish particularly to thank Sir Humphry
Rolleston for his very kind and constant encourage-
ment in our work at Chelsea, and for the invaluable
advice he has given us in the preparation of our papers
for publication. HETEROPHYES NOCENS
AS A DISTINCT SPECIES OF TREMATODE PARASITE.
BY CLAYTON LANE, M.D. LOND.,
LIEUT.-COLONEL I.M.S. (RETIRED). IN the Journal of Parasitology for December, 1921,
Cort and Yokogawa drew attention to Heterophyes
nocens, Onji and Nishio, 1915, inhabiting the middle
third of the small intestine of man, and whose ova were
found in the stools of 31 out of 168 persons dwelling in
two villages in the Yakaguchi Province of Japan. Its
distinction from the Egyptian Heterophyes heterophyes
was based upon the differences, mainly in measure-
ments, found in the first two columns of the accom-
panying table. The original table was accompanied
by the comment,
" An examination of the table shows
that these two species are distinct." spread
rigor
The number of rodlets on the genital- sucker is
clearly variable, and if measurements suggest any-
thing, it is that they may increase in number with
growth. In any case one has constantly to decide
whether one will consider a branched rodlet as two
or one. Since the symmetry or otherwise of the
intestinal csecal terminations varies with the age of the
fluke, if the illustrations of Cort and Yokogawa are
to be accepted, they quite possibly vary in the adult
under the influence of other factors, and can hardly be
accepted as being of specific value. There remains the
shape of the posterior margin of the very minute
cuticular spines on which the writer expresses no
opinion other than that were he able to detect it, he
would still require proof of its constancy before
admitting that it could be of value as influencing at all
the question of specific difference. p
Table of Measurements of Heterophyes. All the measurements are in millimetres, except for the
ova, where micro-millimetres are implied. p
Table of Measurements of Heterophyes. question
specific
The new evidence affords no grounds for revision of
the judgment that the name Heterophyes nocens must
lapse as a synonym of Heterophyes heterophyes, and
human helminthology be correspondingly simplified. COMPLICATING MYELOGENOUS LEUKÆMIA AND NOTED
AS THE FIRST SYMPTOM. Comment- K2 506 506 short history of each of the 140 cases of priapism he
had found recorded. The number of cases complica-
ting the blood disease was 36, and several not men-
tioned by Blum were added to those occurring between
1906 and 1911. In December, 1914, Hinman in
America stated that there had been up to that time
170 cases of priapism in the literature, 45 of which
had definitely complicated leukaemia. and chloral hyd., gr. xv., increased from four-hourly to two-
hourly. 9/6: Lumbar puncture : fluid clear, limpid under
slight pressure, 2 c.cm. of 5 per cent. novocain injected
intrathecally ;
no improvement. 10/6 : Liq. epispasticus
to lower lumbar region. 13/6 : Corpora cavernosa less hard. Patient complains less of pain. Drowsy, but still miserable
and painfully uncomfortable. 22/6 : Benzol, 3i., in capsules,
with olive oil; omne nocte post cibum. 28/6 : Discontinue
benzol. 12/7: Repeat benzol. 14/7: Penis apparently normal. 5/8 : Discontinue benzol. 6/8 : 0-15 gm. N.A.B. ex. 20 c.cm. distilled water. 9/8: Repeat N.A.B. 12/8: Repeat N.A.B. and chloral hyd., gr. xv., increased from four-hourly to two-
hourly. 9/6: Lumbar puncture : fluid clear, limpid under
slight pressure, 2 c.cm. of 5 per cent. novocain injected
intrathecally ;
no improvement. 10/6 : Liq. epispasticus
to lower lumbar region. 13/6 : Corpora cavernosa less hard. Patient complains less of pain. Drowsy, but still miserable
and painfully uncomfortable. 22/6 : Benzol, 3i., in capsules,
with olive oil; omne nocte post cibum. 28/6 : Discontinue
benzol. 12/7: Repeat benzol. 14/7: Penis apparently normal. 5/8 : Discontinue benzol. 6/8 : 0-15 gm. N.A.B. ex. 20 c.cm. distilled water. 9/8: Repeat N.A.B. 12/8: Repeat N.A.B. short history of each of the 140 cases of priapism he
had found recorded. The number of cases complica-
ting the blood disease was 36, and several not men-
tioned by Blum were added to those occurring between
1906 and 1911. In December, 1914, Hinman in
America stated that there had been up to that time
170 cases of priapism in the literature, 45 of which
had definitely complicated leukaemia. definitely complicated
He does not give the references, and I am only
able to find 39 cases reported by writers whose names
appear in the reference list at the end of this article. Remarks. Here we have an example of priapism constituting
the first symptom of myelogenous leukaemia. The
patient never complained of bleeding from his nose
or gums, nor was blood visible in his stools. The
blood count was high, for, although the count of
2,008,000 on June 30th was almost certainly inaccurate,
later careful counts showed 1,020,000 leucocytes in
1 c.mm. of blood. It is stated that an analogous
condition is sometimes met with in females, and that
prolonged erection of the clitoris, unaccompanied by
sexual excitement, occasionally occurs in leukaemia,. I have not been able to find such a condition reported. Gardner’s case is unique, in that it was of the lympho-
cytic variety, 95 per cent. of the 1,014,000 leucocytes
being small lymphocytes. Otherwise all reported
cases of priapism due to leukaemia present a striking
similarity. Previous attacks are mentioned in a large
number ; sudden onset at night befell 11 victims;
the duration of the priapism in 80 per cent. of the
cases was from 20 to 60 days ; and the period of life
usually affected was between the twentieth and fiftieth
years. In parenthesis, it is interesting to record that
the youngest patient to suffer from priapism was a
congenitally syphilitic babe a few days old, while the
oldest was a man aged 75 years. Pain in all leukeemic
cases was a constant feature ; sexual desire was never
present ; ejaculation was never observed; and coitus
aggravated rather than relieved the symptoms. Urination was always difficult, but usually possible,
and almost without exception only the corpora
cavernosa were involved. y
y
History.-X. Y., a bootmaker aged 31, was admitted to
hospital on June 6th, 1921, complaining of an " erection "
of his penis which had persisted with no alteration for six
days. He had wakened up in the morning and had got out
of bed to pass water. On returning to bed the " erection "
took place and was not accompanied by any sexual desire,
indeed, he had neither had, nor desired any sexual intercourse
with his wife for at least 11 weeks. Similar " erections "
had occurred, under more or less the same circumstances,
four times previously, and on one occasion had persisted for
at least two hours. There was no history of any injury. He had been in Mesopotamia during the war, and had had
malaria once and sand-fly fever twice. Remarks. In September, 1920,
he had " pleurisy " which lasted for two months, and in
April, 1921, he complained of a very sharp pain in his left
leg, which lasted two or three days. He denied ever having
had syphilis or gonorrhoea, and had two healthy children. yp
g
,
y
Condition on .<j!MMssMM.—Patient
looks pale, unintelligent,
and unhealthy, and is obviously in great discomfort. He
lies with an anxious, tired expression, accentuated by his
hare-lip, with his thighs drawn up and with his knees flexed. Besides the great pain and discomfort he complains of a
headache at night. Pain has not been relieved by purging
or local fomentations, and even morphia has failed to give
him sleep. There is no history of loss of weight, or increasing
weakness, or bleedings from any mucous membrane. ea
ess,
bleedings
a y
Examination.-Teeth : Decayed ; pyorrhoea alveolaris. Chest : Glands size of marbles in both axiilse ; otherwise
no appreciable disease. Abdomen : Spleen reaches down to
level of umbilicus and to within Ii in. of mid-line, being firm,
sharply defined, smooth, and not tender. Liver enlarged,
reaches 11 in. below costal margin in nipple line, being
smooth, not tender, with border difficult to palpate. Penis
erected, lying close to the lower abdominal wall and almost
reaching to level of umbilicus ; not turgid ; does not feel
hot; not painful when touched, but only when attempt is
made to move it ; corpora cavernosa board-like, but corpus
spongiosum apparently normal ; ischio-cavernosus muscles
very hard. A rubber catheter passes easily, and the man
can, with some difficulty, pass his water. Prostate not
enlarged ; nothing abnormal found per rectum. Nervous
system : No appreciable disease. Urine : A varying amount
of uric acid and urates. It is worth noticing that in five cases of incomplete
erection, due to fracture of the spine at the level of
the cervical portion of the cord, the corpora cavernosa
alone were affected. On stimulation of the glans penis,
however, a complete erection took place, which
gradually passed into the former state. gradually passed
Priapism is not synonymous with " prolonged
erection " or with satyriasis, but is a condition in
which the penis is erected without there being any
associated sexual excitement. COMPLICATING MYELOGENOUS LEUKÆMIA AND NOTED
AS THE FIRST SYMPTOM. There are probably a few more cases, which, owing to
the war, have not found their way into the " Index
Medicus," but Osler’s statement that " priapism is a
curious symptom which has been present in a large
number of cases " is in the nature of an exaggeration,
seeing that he states that " the disease is not very
rare." 9/8: epeat
12/8:
p
Condition on Further Examination,.-I had the opportunity
of examining the patient in November, 1921. He was paler
and looked decidedly more " ill " than when I saw him last. The strain of a recent journey to the seaside had caused severe
oedema of his scrotum, thighs, and legs. The spleen extended
to the iliac crest on the left side, but not to the mid-line,
while the liver reached to 7 in. below the right costal border,
in the mid-axillary line. He was an invalid and had to
remain on his couch, any exertion causing him palpitation
and shortness of breath. His penis was small, symmetrical,
and gave no evidence of inequality of consistency. He had
found " erection " impossible and he was impotent, being
neither desirous nor capable of consummating the sexual act. I am indebted to Mr. Arthur Cooke for allowing me
to report the following case, admitted to Addenbrooke’s
Hospital under his care when I was house surgeon
there, in June, 1921. By his request the treatment
was undertaken by Dr. Ernest Lloyd Jones. COMPLICATING MYELOGENOUS LEUKÆMIA AND NOTED
AS THE FIRST SYMPTOM. All the measurements are in millimetres, except for the
ova, where micro-millimetres are implied. BY G. W. THEOBALD, M.B., B.CH. CAMB.,
ASSTSTANT MASTER, THE ROTUNDA HOSPITAL, DUBLIN. In criticism it may be noted that the measurements
are those of muscular organs, or of the body as a whole
which is itself to a considerable extent a muscular
structure, and that the degree of muscular contraction
must and does materially alter the shape and size of
both ; that apart from this the upper and lower limits
of the measurements in several cases overlap ; that
in trematodes the spines may vary in shape and size
in different parts of the body, as Ward and Hirsch have
convincingly shown for Paragonimus westermanii,
the lung fluke of man ; and that as regards the
intestinal cseca the illustrations of Cort and Yokogawa
indicate that in artificial infections, which it is claimed
to have been effected, the intestinal caeca in flukes two
days after infection are equal in length. On these
grounds I have placed Heterophyes nocens as a synonym
of Heterophyes heterophyes, in Vol. III. of Byam and
Archibald’s " Practice of Medicine in the Tropics," now
in the press. ALTHOUGH priapism is so well-recognised a complica-
tion of myelogenous leukaemia that von Leube has
laid stress upon its diagnostic value, yet there are
few cases of it on record in the literature. Indeed,
although the condition is mentioned by the writers
on leukaemia in the " Systems of Medicine," compiled
by Allbutt and Rolleston and Osler and McCrae, yet
neither of them had seen a case. In 1880 Peabody
collected 32 cases of persistent priapism not connected
with lesions of the central nervous system ; and of
these only seven were definitely connected with
leucocythaemia. To this number, he suggests, one or
two of the cases recorded before the Virchow-Bennett
controversy of 1845 should possibly be added. Blum
in 1906 read an interesting paper on the subject in
Vienna and discussed its aetiology. He collected 70
cases of priapism, of which 15, including his own case. were due to leukaemia. Scheuer in 1911 made a very
comprehensive survey of the condition, and gave a press. The next step taken in the matter was that of
Leiper in a brief helminthological review in the
Tropical Diseases Bulletin for June, 1922. epileptic
3. General Conditions.-(a) Intoxications as caused
by alcohol, cantharides, and other aphrodisiac drugs ;
(b) infectious diseases (cases reported by Lyssa) ;
(c) constitutional and blood diseases.
Although
diabetes is frequently cited as a cause of priapism,
Blum was unable to find a single case recorded. It i&
in this subdivision that leukaemia comes. changes
circulation e.g.,
2. Nervous Conditions.-(a) Organic, such as early
tabes and G.P.I. ;
(b) functional, including the
" priapismus amatorius " of Darwin, and the so-called
" epileptic " cases. Normal Penile Erection. considerably. It is suggested that the dilatation is caused by con-
traction of the longitudinal fibres of the arteries
innervated by the nervi erigentes, and that contraction
is due to the circular fibres. It seems almost necessary
by this hypothesis to assume that the penile arteries
are always, except for brief and occasional periods, in
" tone." The relation of hormatones to this problem
is not yet investigated, but we do know that sexual
precocity accompanies adenoma of the adrenals, and
that adrenalin has a very marked effect on some portion
of the " nerve-endings
" to plain muscle. We can at
least say, though much work still requires to be done,
that a " balance " between the various factors is
normally maintained, and that this balance is tem-
porarily upset in tumescence. In many diseases, such
as gout, tabes, G.P.I., diabetes and leukaemia, the
later stages are associated with a diminution of sexual
desire. Whatever may be the various factors con-
cerned, whether chemical, or nervous, or both, we may
term the condition an abnormal male " menopause."
It is not unnatural to assume that in this change the
" balance " is upset-and not always evenly-causing
dilatation of the penile arteries and erection. Indeed,
the wonder is that it does not occur more often. With such a hypothesis there is no reason why
sexual excitement should accompany this phenomenon,
or why the corpus spongiosum should be affected. In 11 cases on record, after the priapism had dis-
appeared, ejaculation occurred before the power of
erection returned, which strongly suggests that different
nerve paths are concerned in the two acts. The
probability is that in normal events the corpus
spongiosum is not affected until ejaculation takes
place, and therefore the usual remark in the recorded
cases of priapism " that only the corpora cavernosa
were affected " is only what one would expect if the
condition were simply due to a temporary alteration
of the blood-supply to the organ. The " board-like "
contraction of the ischio-cavernosus muscles may be
accounted for by supposing a condition of cramp, or
by assuming that the contraction is secondary to the
erection-secondary, that is to say, either to the
actual mechanical stretching of the penis or to the asso-
ciated nerve impulses. Normal Penile Erection. With this explanation it is not
altogether inexplicable that priapism should occur
from injury, sexual excess, nervous diseases, old age,
aphrodisiac drugs, gout, leukaemia, new growth of
the penis, urethritis, nasal abnormalities, cerebral
tumours, and other pathological conditions, but except
in the case of new growth or injury of the penis the
cause is almost certainly " nervous." In order to understand the various factors in the
causation of priapism, it is necessary to know the
mechanism of normal penile erection. This is very
complicated and not yet fully worked out. Most of
the information given here is derived from Nagel’s
or Schafer’s physiology, and the credit for the work is
chiefly due to Eckhard. The nerves concerned are
those from the lumbar and sacral regions of the cord. From the lower lumbar region a sympathetic communi-
cation goes to the sacral ganglia, from which grey
rami communicantes proceed to the pudic nerves. A few fibres from this region join the hypogastric
nerve, and joining the pelvic plexus, cause, when
stimulated, a strong contraction of the penile arteries. The sacral nerves may also be divided into two groups
- visceral and somatic. The former are the nervi
erigentes, and they cause, when stimulated, a dilata-
tion of the penile arteries and an inhibition of the
plain muscle which they supply-i.e., the anal canal
and lower portion of the rectum. The somatic fibres
supply the ischio- and bulbo-cavernosus and the
constrictor urethrae muscles. The organs such as the
bladder and vesiculae seminales receive their supply
from the third, fourth, and fifth lumbar nerves through
the mesenteric ganglion. This mechanism, therefore,
may be set in motion either through impulses from
above or from peripheral stimulation. It has been
shown that in a dog the whole of the lumbar and the
upper part of the sacral regions of the cord can be
destroyed, without destroying the local sexual reflex
action caused by stimulation of the glans penis. We
also know that in some types of inversion-e.g.,
fetichism-central inhibition prevents any response
to normal local sexual stimulation. Moreover, as we
should expect, violent stimulation of the other areas
supplied by the nervi erigentes, such as the lower
portion of the rectum, by the process of " overflow of
stimuli," may cause erection of the penis. Theories of Explanation of Priapism. p
p
There have been two theories advanced in explana-
tion of this condition. The one, due to Salzen, suggests
that it is due to pressure on some part of the course
of the nervi erigentes, either by the more than
normally viscid blood, or by the enlarged lymphatic
glands. The other, subscribed to by Ward, Weber,
Blum, and others, is that the condition is due to
thrombosis in the corpora cavernosa. Objections
raised to the first theory are :
(1) That it seems
incredible that such nervous stimulation could persist
for so many weeks ; (2) that the erection is not
accompanied by the usual psychic phenomena ; and
(3) the corpus spongiosum has, in all recorded cases,
remained more or less normal, and the corpora
cavernosa alone have been involved. The latter two
objections are not really valid, as will be shown further
on.T To the second theory the following objections are
brought forward:
(1) In many of the cases the
priapism has been preceded by shorter periods of
erection. In the case I am recording, such erections
had occurred four times, and had lasted at least two
hours on one occasion. (2) If all the blood in both
corpora cavernosa were thrombosed, one would expect
pain, tenderness, and turgidity of the organ, and
possibly suppuration and local gangrene. (3) It is
unusual that this thrombosis should occur only in the
penis, and not in other parts of the body. Remarks. They also showed that there was a
latent period of two and a quarter seconds after the
stimulation, before the erection took place ; that the
penis when erected contained from 8 to 15 times the
normal quantity of blood ; and that shortly after
erection the pressure in the penile veins rose very
considerably. connexion are the five recorded cases of priapism in
association with nasal polypi, and the case of sperma-
torrhoea following submucous resection referred to
by Ellis. Clearly any conditions that normally cause
erection may abnormally cause priapism. The corpora
cavernosa are sponge-like bodies lined by the same
type of epithelium as the capillaries, and supported
and surrounded by a fibrous investment which sends
off trabeculae into their substance. The spaces so
formed have free communication with one another,
and are, to a certain extent, comparable with tortuous
veins. The arteries which supply them are the arteria
dorsalis penis and the cavernous branches of the pudic
arteries, the latter being much the more important. These arteries divide into the helicine arteries of
Muller, and into capillaries, both varieties ending in
the sponge-like spaces. The blood is drained away
by venules entering the dorsal vein at different posi-
tions, but chiefly by veins entering the pudic plexus. Eckhard showed that erection was actually caused by
dilatation of the penile arteries, and could not be
caused by ligature of the penile veins. Francois and
Frank obtained erection in dogs by stimulating the
nervi erigentes, and detumescence by stimulating the
pudendic nerve. They also showed that there was a
latent period of two and a quarter seconds after the
stimulation, before the erection took place ; that the
penis when erected contained from 8 to 15 times the
normal quantity of blood ; and that shortly after
erection the pressure in the penile veins rose very
considerably. Remarks. It may be caused by
many conditions, and I will give the classification
which Blum suggested, rather than the more complete
one of Scheuer. R.B.C. = Red blood cells. W.B.C. = White blood cells. 1. Local Conditions in the Penis.-(a) Of an inflam-
matory nature--e.g., periurethritis and urethritis
(gonococcal) ; (b) new growth ; (c) injury ; (d) result
of changes in the circulation-e.g., thrombosis. changes
circulation e.g.,
2. Nervous Conditions.-(a) Organic, such as early
tabes and G.P.I. ;
(b) functional, including the
" priapismus amatorius " of Darwin, and the so-called
" epileptic " cases. epileptic
3. General Conditions.-(a) Intoxications as caused
by alcohol, cantharides, and other aphrodisiac drugs ;
(b) infectious diseases (cases reported by Lyssa) ;
(c) constitutional and blood diseases. Although
diabetes is frequently cited as a cause of priapism,
Blum was unable to find a single case recorded. It i&
in this subdivision that leukaemia comes. Treatment. Treatment. 6/6/21 : Deep C]EICI, anaesthesia (no improvement) ;
pot. brom., gr. Ix. ; chloral hyd., gr. xxx. 7/6 : Three
leaches to penis (bleeding continued freely, with fomentation,
for seven days). Atropin, gr. 1/50 ; pot. brom., gr. xxx., 507 507 connexion are the five recorded cases of priapism in
association with nasal polypi, and the case of sperma-
torrhoea following submucous resection referred to
by Ellis. Clearly any conditions that normally cause
erection may abnormally cause priapism. The corpora
cavernosa are sponge-like bodies lined by the same
type of epithelium as the capillaries, and supported
and surrounded by a fibrous investment which sends
off trabeculae into their substance. The spaces so
formed have free communication with one another,
and are, to a certain extent, comparable with tortuous
veins. The arteries which supply them are the arteria
dorsalis penis and the cavernous branches of the pudic
arteries, the latter being much the more important. These arteries divide into the helicine arteries of
Muller, and into capillaries, both varieties ending in
the sponge-like spaces. The blood is drained away
by venules entering the dorsal vein at different posi-
tions, but chiefly by veins entering the pudic plexus. Eckhard showed that erection was actually caused by
dilatation of the penile arteries, and could not be
caused by ligature of the penile veins. Francois and
Frank obtained erection in dogs by stimulating the
nervi erigentes, and detumescence by stimulating the
pudendic nerve. AN UNUSUAL EFFECT OF NOVARSENOBILLON. and the condition cleared up. In conclusion, it seems probable that priapism,
malignant and traumatic cases excepted, is always due
to " nervous " causes, and does not usually persist for
more than ten days. The condition is favourable to
thrombosis, and partial or complete thrombosis may
take place, particularly in those cases in which the
blood is considerably altered, as in leukaemia. The
evidence is not at all convincing that anything like
a complete thrombosis usually takes place, even in the
leukaemic cases. The treatment recommended by
Hinman in the leukaemic cases and in others where
thrombosis is feared is free -incision. The incision
should be made on the dorsal aspect of the penis and
on its proximal half, mid-way between the mid-line and
the outer side. The incision should be deep enough
to remove all the " thick grumous material."
This
operation relieves the condition immediately, and does
not preclude the possibility of normal erection after
recovery has taken place, although sexual intercourse
may be prevented by the consequent abnormal curva-
ture of the erected organ. This treatment undoubtedly
saves a lot of suffering, and in the leukaemic cases may
be justified, seeing that over 50 per cent. of the cases
become impotent. Short of surgical interference, which
must be carried out with very special aseptic precau-
tions, no local treatment is of any avail, as the great
number of suggested remedies so adequately testify. Benzol did seem to act beneficially in the Addenbrooke’s
case and certainly reduced the number of white as well
as of red blood corpuscles. Hypnotics in large doses
are required ; otherwise treatment on general lines,
with especial attention to the bowels, is the only course
open to the physician. BY MARY O’BRIEN BEADON, M.B., B.S.LOND. (From the Victoria Hospital, Triplicane, Madras.) THE following is a brief note on a hitherto unre-
ported effect of N.A.B. In this hospital we have been
in the habit of giving N.A.B. regularly for the past
six to eight months, and the technique used is that
which I saw in the out-patient department of the
Lock Hospital, London-i.e., the solution is made
with sterile normal saline, and injected by means of a
syringe into the selected vein. AN UNUSUAL EFFECT OF NOVARSENOBILLON. We have occasionally
had trouble in getting into the vein, as the average
Indian woman’s veins appear to be very small and
fine, but in no case had we noticed the effect which I
am about to report, even though some of the solution
found its way into the tissues. way
We advise out-patients having injections to take a
purgative the day before, to have a very light break-
fast, to keep as quiet as possible -all day after the
injection, and to report their condition next day. All
N.A.B. injections are given in the morning, usually in
pairs-i.e., the contents of a 0-9 g. phial are dissolved
in 20 c.cm. sterile saline, and 10 c.cm. given to two
patients, who are ready waiting while the drug is being
dissolved. The untoward effect was first noticed in
the case of injections given on May 24th. j
g
y
In two cases injected on this date the veins were large and
easily entered, and the injections were given as usual. There
was no apparent ill-effect at the time of injection, but on the
next day an area about the size of the palm of the hand,
situated in front of the elbow where the injection had been
made, was found to be dark brown and vesicating. It looked
as if the part had been burnt with chloroform. In one case References.—Adams: Inaug. Diss., Bonn, 1894. Blum : Wiener
klin. Woch., 1906, xix., p. 1133-1139. Carpenter. A.: THE
LANCET, 1880, ii., p. 173. Duckworth: Trans. Clin. Soc., London,
1892, vol. xxv., p. 97. Dujon (2nd case): Revue de Chirurg.,
1910, p. 1189. Edes : Boston Med. Jour., 1871, Bd. lxxxv. Eisenstädler: Wiener med. Wochenschr., 1907, No. 15. Ellis,
Havelock: Psychology of Sex. Favera, Dalla: Monatsch. f. prakt. Dermat., Hamb., 1908, xlvii., 13-21. Gardner, G. :
Tr. Amer. Ass. Genit. Ur. Surg., N.Y., 1915, x., 1-3. Goebel (1st case):
Mitt. aus den Grenzgeb. d. Med. u. Chir., 1904, Bd. xiii. Gunckel:
Amer. Med. Philadelphia, 1906, xi., p. 27. Guttmann: Berl. klin. Wochenschr., 1891, No. 46. Haillot and Viardin
:
Bullet. Méd., 1904, No. 72. Hinman: Annals of Surgery, December,
1914. Jadioux: Gaz. des Hôpitaux, Paris, 1845, p. 626. Kast :
Zeitsch. f. klin. Med., 1895, Bd. xxviii., p. 79. Kétle: Orvosi
Hetilap, 1883, No. 9. Klemme: Inaug. Diss., Cassel. 1863 ;
Schmidt’s Jahrbücher, 1866, Bd. cxxxi., p. 173. Koschel :
Ref. Berl. klin. Factors Influencing Erection. Sexual selection is a very complicated and difficult
physiological and psychological study. Havelock
Ellis makes it clear that in it are concerned the senses
of touch, smell, sight, and hearing, and he shows that
they are all capable of exerting an influence on sexual
excitement. Truly catholic, then, must be the nervous
paths which influence the nervi erigentes. Added to
this the memory, the storehouse of the impressions
of the senses, is, in the absence of other stimuli, capable
of causing sexual tumescence. Of great interest in this 508 508 Markow: New York Med. Jour., 1885. Mathias: Allgem.
Med.
Zentralzeit., 1876, Nos. 97-98.
Müller:
Deutsche
Zeitschrift f. Nervenheilk., 21, 1902. Nagel: Physiology, Bd. ii.,
p. 69. Neidhardt: Allgem. Med. Zentralzeitung, 1876, p. 682.
Osler: Principles and Pract. of Med., p. 743. Peabody: New
York Med. Jour., 1880, vol. xxxi., p. 463.
Rokitansky:
Lehrbuch der Pathol. Anat., Bd. iii., p. 407.
Salzer: Berl.
klin. Wochenschr., 1879, No. 11, p. 152.
Schener Archiv f.
Derm. u. Syph., 1911, 109, p. 449.
Schulze (2 cases): Deutsche
Arch. f. klin. Med. Bd. liii. Stanjeck: Inaug. Diss., Leipzig, 1909.
Steuber: Diss. Berlin, 1889. Stevens, W. M.: THE LANCET, 1905,
i., p. 153.
Sticker: Zeit. f. klin. Med., 1888, Bd. xiv., p. 80.
Stimson: New York Med. Jour., 1885, t. xli., p. 676. Vorster
(1st case): Deutsche Zeitschr. f. Chir., 1888, p. 173. Ward, A.H.:
THE LANCET, London, 1897, vol. i., p. 1143. Weber: Edinburgh
Medical Journal, September, 1898. Weinerek : Cas6pis Lakini
eeskych v. Praze, 1907.
Wetherell: Med. Rec., New York,
1880, t. xviii., p. 192. Clinical Notes
:
MEDICAL, SURGICAL, OBSTETRICAL,
AND THERAPEUTICAL. The three main factors concerned in causing throm-
bosis are : (1) Slowing of the blood-stream and eddies ;
(2) injury to the epithelium of the blood-vessels ;
(3) alteration in the physical and chemical condition
of the blood. In leukaemia there are marked chemical
and physical changes in the blood, and the viscosity
is very materially altered. In the Addenbrooke’s
case there were roughly 500,000 myelocytes per c.mm. of blood. The cross diameter of a myelocyte is about
12 /, while that of an ordinary capillary is from
6-8 /t. Considering these’ facts, and the abnormal
pressure and quantity of blood in the penis, the con-
ditions would be favourable to thrombosis. There
was, however, no fluctuation detected at any time,
and certainly the blood drawn off by the leeches,
assuming it came from the corpora cavernosa, gave no
suggestion of thrombotic changes. In Blum’s case a
small area of fluctuation was detected and a small
quantity of altered blood was aspirated. Goebel and
Kast each had a case in which they were able to detect
after death signs of thrombosis, both macroscopically
and microscopically. Weber and Dyce Duckworth
and others believed thrombosis to have occurred in
their cases, but offer no reasons or suggestive evidence. Hinman states that in his case about 2 oz. of thick
grumous blood-clot was removed, and claims that in
all cases in which incision and drainage had been tried
similar material had been removed. On the other hand,
Lewis simply ligatured the dorsal artery of the penis,
and the condition cleared up. A CASE OF
IMPACTION OF THE PHARYNX BY A WATCH.
BY PHILIP E. HILL, M.R.C.S., L.S.A.,
MEDICAL OFFICER OF HEALTH, CRICKHOWELL R.D.C., BRECONSHIRE. A CASE OF
IMPACTION OF THE PHARYNX BY A WATCH. BY PHILIP E. HILL, M.R.C.S., L.S.A.,
MEDICAL OFFICER OF HEALTH, CRICKHOWELL R.D.C., BRECONSHIRE. THE following case of a watch impacted in the
pharynx during an attack of acute delirious mania in
a patient suffering from pneumonia merits record. patient suffering
pneumonia
On May 31st I was urgently called to a man, aged 32,
suffering from pneumonia, who had swallowed a watch. On
my arrival I found him controlled by two men. He was
cyanosed, struggling violently, and in great distress. I
passed my finger down the pharynx and felt the watch lying
transversely and hooked my finger into the bow, but owing
to the patient’s violence it was impossible to dislodge it. I
then passed a pair of curved forceps with the same result,
when suddenly the heart failed and he fell back dead. suddenly
Had this man been sane it is doubtful if he could
have succeeded in wilfully destroying himself by thus
mechanically blocking up his throat. A NOTE ON
AN UNUSUAL EFFECT OF NOVARSENOBILLON. BY MARY O’BRIEN BEADON, M.B., B.S.LOND. (From the Victoria Hospital, Triplicane, Madras.) A NOTE ON
AN UNUSUAL EFFECT OF NOVARSENOBILLON. A NOTE ON
AN UNUSUAL EFFECT OF NOVARSENOBILLON. AN UNUSUAL EFFECT OF NOVARSENOBILLON. Woch., 1908, No. 18, p. 896. Knust : Med. Klin., 1907, iii., 45. Leube : Spec. Diagnose, Leipzig, 1895,
p. 312. Lonquet (2 cases): Progrès Médical, 1875, p. 447. (Continued at foot of next column.)
|
W1995529826.txt
|
https://zenodo.org/records/1926308/files/article.pdf
|
de
|
Review of Beitrag zur Lehre des intermittierenden Lichtreizes der gesunden und der kranken Retina.
|
Psychological bulletin
| 1,905
|
public-domain
| 1,299
|
314
VISION,
greater for blue than for green, and for green than for red. In the
absence of initial determinations, it is impossible to state the total
amount of increase, but Loeser conjectures that in the optimal stage of
dark-adaptation, color-sensitivity is 500 or 600 times greater than in
light-adaptation. Loeser does not agree with previous investigators
who have found that the adaptive change of sensitivity is in a constant
direction. On the contrary, he holds that the optimal stage is reached
relatively early, and that a decrease of sensitivity then ensues. He
suggests that this change of direction may be due to the heightened
sensitivity of the rods which may be assumed to contribute a whitishness to the color sensation; and he points out that there is an approximate coincidence between the point of time at which the color-limen
begins to rise, and that at which Piper found the brightness-limen to
begin its rapid descent. This view receives support from the fact that
there was scarcely any diminution of sensitivity in the case of the red
stimulus.
In the opinion of the reviewer, Loeser*s experiments do not furnish
indubitable evidence of the presence in dark-adaptation of a diminution of sensitivity. His numerical results lack uniformity; different
determinations of the same limen (presumably by the same observer)
vary by as much as 45 per cent., and when the limina of different
observers are plotted, one finds curves which have little in common
with each other. These facts lead one to suspect the influence of a
factor which has not been taken into account. Loeser's description of
his procedure is unfortunately too meager to furnish a definite clue to
the solution of the difficulty. It seems probable, however, that there
may have been a progressive change of chromatic adaptation during
each series of experiments. At any rate, determinations of color-limina must, in the nature of the case, be less reliable when made serially
than when each is the product of a separate sitting.
J. W. BAIRD.
JOHNS HOPKINS UNIVBRSXTY.
Beitrag zur Lehre des intermittierenden Lichtreizes der gesunden
und der kranken Retina. £ . P. BRAUNSTEIN. Zeitschrift fur
Psychol. und Physiol. der Sinn., XXXIII., 171-206, 341-288.
Braunstein's problem is to find the rate of succession of retinal
stimuli that is necessary for the production of a single sensory image.
Upon the determination of this rate depend greater accuracy in
medical diagnosis and the answers to many questions concerning
after-images and other visual phenomena. The solution of this
problem has often been attempted, but the results have been con-
PSYCHOLOGICAL LITERATURE.
215
, tradictory. The author makes an effort to discover the causes of
l their divergence.
'
In most of his experiments, the observer looks through an opening
; in a sheet of black cardboard or through a small tube at a rotating
1 disk. This disk is made up of two, four, eight, or more alternating
. black and white sectors. Each revolution of the disk is recorded on
I the drum of a kymograph. This record is accompanied by a time
curve. The moment the increase of their speed makes the sectors
blend into an even gray, the observer breaks the electric circuit, by
means of which the entire group of apparatus is propelled.
According to Braunstein, those who have found that increase of
illumination hinders blending, and, therefore, requires a more rapid
rate, have failed to see that greater intensities of light heighten the
contrasts between the two stimuli. If the stimuli are such that their
contrasts remain unchanged when the illumination is increased, a
slower rate will produce fusion. He demonstrates this by means of a
disk, A, one half of which is gray and the other half white; and
another disk, B, one half of which is gray and the other half black.
The gray in both cases is the same as that which would be produced
by rotating a disk composed of the white and the black semicircles.
Let the illumination of the white = ir and of the black = o. The
illumination of A = (1 + i)/2i o r ii a n d of B = (o •+• -£)/2, or J.
Therefore, A is illuminated three times as much as B. Nevertheless,
A blends with a slower rate of rotation than B.
The results depend, also, upon whether the eye has become accustomed to the intensity of light used in the experiment. He finds that
the fovea requires a more rapid rate of succession for fusion after a
half hour's perfect rest in a dark room.
When the sectors are increased in number, more stimuli per second are necessary. But the required rate of succession, he discovers,
remains more nearly the same the narrower the opening through
which the disk is seen. Diminishing the width of this opening makes
it less and less possible for the eye to follow the rotation of the sectors.
This is interpreted to mean that the increase of the rate with the
greater number of sectors is due, chiefly, if not entirely, to the greater
ease with which the eye can fixate and follow an object that makes a
small retinal image.
Braunstein asserts that all other investigators have overlooked
the fact that unless the eye is in a perfectly healthy condition, its
discriminative power is impaired. Hence, fusion takes place with a
slower rate of stimulation. He arrives at this conclusion through
8l6
HEARING.
the comparison of results from a large number of normal and defective eyes.
C. HOMER B E A N .
UNIVERSITY OF CHICAGO.
HEARING.
Studies in Pitch Discrimination.
GUY MONTHOSE WHIPPLE.
Amer. J. of Psychol., 1903, XIV., 289-309. Commemoration
Number.
This paper is a further working out of a problem treated by Dr.
Whipple in two earlier papers, /. «., the process of pitch memory
and pitch discrimination as conditioned by individual observers and
by varying time intervals. The first test was made on a young woman
with some musical training, who at the age of twelve had discovered
in herself the gift of absolute pitch. Her parents were unmusical but
they came of musical families, so it is inferred that this gift may be
an inherited musical Anlage^ somewhat perfected by practice. This
subject was not an experienced introspectionist. The results of the
experiment were as follows: (1) Relatively accurate judgments of
pitch can be made of instrumental or vocal music, the latter being
more difficult. (2) Judgments are always direct, rapid, and in
terms of visual-motor imagery, and referred to the piano key-board.
(3) With no error greater than a tone, usually only a half-tone,
under best experimental conditions, the piano notes were correctly
identified ninety-two times in one hundred. ( 4 ) Accuracy of recognition is diminished if the clang-color of the notes is unfamiliar,
i. e., more correct judgments were made if the subject's own piano
were used. (5) The octave in which a note lies is never mistaken.
(6) Recognition is most accurate in the once and twice accented
octaves. (?) With but fair ability to recognize the pitch of notes,
this subject (vs. the generalization of Abraham) was able to image
and reproduce assigned pitches very correctly. (8) Subject's sensible discrimination is no better than that of a trained musical observer, and is not aided by absolute pitch memory. (9) Kampfe's
method of modification of right and wrong cases was found to be the
only satisfactory one with an observer of subjective type, *'. «., one
whose judgments are easily modified by suggestion.
The subject in the second series of tests was a good introspectionist,
a woman of almost no musical ability although fond of music. Dr.
Whipple summarizes these tests of discrimination as follows:
" We have found that a typical unmusical observer, when placed
|
|
https://openalex.org/W3186880585
|
https://repozitorij.ffzg.unizg.hr/islandora/object/ffzg:4328/datastream/PDF/download
|
Croatian
| null |
Psihijatrijski diskurs u hrvatskom društvu na prijelazu iz devetnaestoga u dvadeseto stoljeće
| null | 2,021
|
cc-by
| 115,272
|
Psihijatrijski diskurs u hrvatskom društvu na prijelazu
iz devetnaestoga u dvadeseto stoljeće Drača, Vinko Vinko Drača
Psihijatrijski diskurs u hrvatskom društvu na
prijelazu iz devetnaestoga u dvadeseto
stoljeće Vinko Drača DOKTORSKI RAD University of Zagreb
Faculty of Humanities and Social Sciences University of Zagreb
Faculty of Humanities and Social Sciences Vinko Drača Psychiatric Discourse in Croatian Society at
the turn of the 19th and 20th century Doctoral Dissertation Zahvale Pri pisanju ove disertacije otisnuo sam se prema teritoriju koji mi je dotad bio nepoznat i
snalaženje na tom puto bilo bi mnogo teže bez pomoći brojnih divnih ljudi . Prvo trebam
spomenuti svoje strpljive mentorice, profesorice Idu Ograjšek Gorenjak i Željku Matijašević. One
su strpljivo iščitavale moj tekst, imale strpljenja za moje uporne pravopisne pogreške, ispravljale
francuska i njemačka imena koja bih uporno pogrešno pisao, pronalazile mi članke i knjige koje
su mi uvelike pomogle pri istraživanju, te mi pomogle da dobijem pristup arhivu bez kojeg bi
ovaj rad bio nemoguć. Na marljivom angažmanu i podršci zahvaljujem i ostalim profesorima s
Poslijediplomskog studija moderne i suvremene hrvatske povijesti u europskom i svjetskom
kontekstu: brojni od Vas su mi dali savjet, otvorili vrata, ili me upoznali s nekom informacijom
koja mi je koristila u radu. Posebne zahvale upućujem ljudima iz Klinike za psihijatriju Vrapče:
pokojnom ravnatelju Vladi Jukiću koji nažalost nije dočekao obranu ovog rada i arhivaru Zlatku
Stanišaku koji mi je pravio društvu u arhivu Klinike tijekom dugih i usamljenih jutara. Pri
istraživanju ovog rada veliku pomoć i podršku pružili su znanstvenice i znanstvenice koji se bave
sličnom tematikom i koji su uvijek bili spremni dati savjet na okruglim stolovima i
konferencijama. Veliko hvala Luci Malatestiju, Heike Karge, Ani Antić, Filipu Čeču, Vanniju
D'Alessiu, Franku Doti i Jeleni Seferović. Naš zajednički rad na projektu proučavanja povijesti
psihijatrije u Srednjoj i Jugoistočnoj Europi obogatio je moj metodološki pristup i natjerao me da
si postavim uzbudljiva pitanja koja si inače ne bih postavio. Zahvaljujem i članovima i članicama
komisije za obranu teme doktorskog rada. Oni su postavili pitanja koja su me usmjerila i učinila
ovaj rad potpunijim. Ekipa iz Centra za ženske studije, na čijim sam skupovima gostovao iz
godine u godinu, pokazala je izniman interes za temu ove disertacije i pomogla brojnim
sugestijama i savjetima. U samoj završnici pisanja rada, na ljetnoj školi u Dubrovniku, upoznao
sam brojne mlade znanstvenike i znanstvenice koji su mi otvorili nove perspektive u razmatranju
mog vlastitog polja, iako su se bavili drugačijim temama. Topao i srdačan pozdrav Nataliji Lago,
mojoj „borboleti“ koja je dala osoban pečat zadnjim poglavljima ove disertacije, i ostalima iz
Global Humanities Institutea koje neću navoditi poimence jer bi lista bila odviše duga- svi ste
učinili moje istraživačke dane zabavnijima i bogatijima. Zahvale Zahvaljujem svima koji su dali savjet ma
kako minoran bio, mojim prijateljima Žutom koji je slušao o mojoj disertaciji za mnogih dugih
večeri, Snowy koja je pronašla najbolji soundtrack za pisanje doktorata i fantastičnoj Vlatki Košir koja mi je prije gotovo deset godina posudila knjigu Thomasa Szassa i zainteresirala me za
propitivanje pojma duševne bolesti. Naravno, ništa ne bi bilo moguće bez moje obitelji koja je
uvijek bila tu da pruži emotivnu i financijsku podršku. koja mi je prije gotovo deset godina posudila knjigu Thomasa Szassa i zainteresirala me za
propitivanje pojma duševne bolesti. Naravno, ništa ne bi bilo moguće bez moje obitelji koja je
uvijek bila tu da pruži emotivnu i financijsku podršku. Sažetak Rad analizira povijest psihijatrijskog diskursa u hrvatskom društvu na prijelazu iz devetnaestog u
dvadeseto stoljeće. Razdoblje obuhvaćeno radom počinje 1879. godine, osnutkom Kraljevskog i
zemaljskog zavoda za umobolne u Stenjevcu, kao prve psihijatrijske institucije u hrvatskom
dijelu Austro-Ugarske Monarhije, a završava 1918. godine. Teorijski i metodološki pristup bazira
se na konstruktivističkoj školi povijesti psihijatrije, koja smatra da je medicinski pogled na um i
duševno zdravlje bio uvelike obilježen povijesnim kontekstom, institucionalnim praksama
psihijatrije i dominantnim emotivnim režimima društva. Pri analizi izvora koristi se metodološki
aparat povijesti emocija i kulturne povijesti psihijatrije. Psihijatrijski diskurs bio je neodvojiv od
psihijatrijske prakse i razvijao se u stalnoj komunikaciji između psihijatara i štićenika
psihijatrijskih zavoda, te psihijatara i ostalih društvenih institucija i pojedinaca: pravosudnih
organa, organa lokalne administrativne vlasti, obitelji štićenika i drugih liječnika. Izvori za opis i
analizu ove mreže odnosa su psihijatrijski članci i knjige, te povijesti bolesti štićenika sačuvane u
arhivu Klinike za psihijatriju Vrapče. Na temelju navedenih izvora analizira se razvoj i nastanak
hrvatske psihijatrije u kontekstu europskih intelektualnih kretanja druge polovice devetnaestog
stoljeća, naročito s obzirom na u to vrijeme prevladavajuće evolucionističke i somaticističke
teorije te narative o degeneraciji i primitivizmu, usko povezane sa znanstvenim rasizmom. Opisuju se uvjeti života štićenika i terapeutske metode primjenjivane u zavodu. Osobita pažnja
posvećuje se mjestu roda, seksualnosti, straha i sukoba u psihijatrijskom diskursu. Diskursi oko
tih pojmova čine bitan dio narativa o duševnoj bolesti u devetnaestom stoljeću, a psihijatrijski
pristup tim konceptima analizira se gustim opisom niza povijesti bolesti. Pri analizi istaknuto se
mjesto nastoji dati upravo glasovima štićenika i štićenica. Proučavanje njihovih iskaza bilo je
ključno za formiranje psihijatrijskog znanja, iako se onodobna psihijatrija prema njihovom
govoru ponašala ambivalentno. S jedne strane, isti je bio pomno zapisivan, s druge strane kao
„govor luđaka“ bio je delegitimiran, te je štićenicima i štićenicama oduzeto bilo kakvo pravo
objašnjavanja i tumačenja vlastitih simptoma. Summary Thesis analyzes history of psychiatric discourse in Croatian society at the turn of the nineteenth
and twentieth century. The time period covered by this research starts in 1879, the year Royal and
Land Asylum for the Insane in Stenjevec was opened as the first psychiatric institution in
Croatian part of Austria-Hungary and it ends in 1918. Theoretical and methodological approach
is based upon the constructivist school of history of psychiatry which assumes that medical
perspectives of mind and mental health were necessarily informed by specific historical context,
institutional practices of psychiatry and dominant emotional regimes present in society. p
p y
y
g
p
y
In the analysis of sources methodological apparatus of the history of emotions and the cultural
history of psychiatry was used. Psychiatric discourse was inseparable from psychiatric practice
and developed in constant communication between psychiatrists and inmates of psychiatric
institutions, and psychiatrists and other social institutions and individuals: judicial authorities,
local administrative authorities, families of inmates and other physicians. Sources for the
description and analysis of this network of relationships are psychiatric articles and books, as
well as the patient histories kept in the archives of the Vrapče Psychiatric Clinic. Based on these
sources, the development and emergence of Croatian psychiatry in the context of European
intellectual movements of the second half of the nineteenth century is analyzed, especially given
the prevailing evolutionary and somaticist theories and narratives of degeneration and
primitivism, closely related to scientific racism. The living conditions of the asylum inmates and
the therapeutic methods applied in the institution are described. Particular attention is paid to the
place of gender, sexuality, fear, and conflict in psychiatric discourse. Discourses around these
concepts form an essential part of the narrative of mental illness in the nineteenth century, and the
psychiatric approach to these concepts is analyzed by a dense description of a series of medical
histories. In the analysis, a prominent place is given to voices of the inmates. The medical study
of their statements was crucial for the formation of psychiatric knowledge, although psychiatry at
the time treated their speech ambivalently. On the one hand, it was carefully written down, on the
other hand, it was delegitimized as "madman's speech", and the inmates were deprived of any
right to explain and interpret their own symptoms. 1.Uvod............................................................................................................................................14
2.Historiografija psihijatrije: teorije, metode i izvori.....................................................................20
2.1. Summary Povijest psihijatrije između „vigovske” povijesti i društvenog konstruktivizma....................20
2.2.Povijesti bolesti i glas psihijatrijskih pacijenata: metodologija istraživanja psihijatrije..........26
3. Europska psihijatrija u devetnaestom stoljeću............................................................................34
3.1. „Moral treatment” i začeci psihijatrije.....................................................................................34
3.2.Terapeutski pesimizam i degeneracija......................................................................................43
3.3. Od Griesingera do Kräpelina: njemačka neuropsihijatrija na prijelazu stoljeća.....................50
4. Kraljevski i zemaljski zavod za umobolne u Stenjevcu.............................................................58
4.1.Osnutak i izgradnja zavoda za umobolne u Stenjevcu.............................................................58
4.2. Liječnici Kraljevskog i zemaljskog zavoda za umobolne u Stenjevcu....................................62
4.3 Štićenici stenjevačkog zavoda..................................................................................................68
4.4. Život u Zavodu za umobolne...................................................................................................78
4.5. Terapeutske metode i terapijski pesimizam.............................................................................89
5.Rod i seksualnost.......................................................................................................................107
5.1.Rodne uloge i seksualnost u emotivnom režimu građanstva kasnog devetnaestog stoljeća. .107
5.2. Spektakl histerije u Stenjevcu................................................................................................114
5.3. Tijelo van kontrole: „Rittermeisterov satni mehanizam” i „viloviti” notar iz Veliševca“.....133
5.4. Nevidljivost sifilisa: progresivna paraliza u Stenjevcu.........................................................138
5.5. Seksualna nastranost, primitivizam i „moral insanity”: Seksualnost, moral i ludilo na
prijelazu stoljeća...........................................................................................................................146
6.Strah u Stenjevcu.......................................................................................................................157
6.1. Strah i anksioznost u kulturi devetnaestog stoljeća...............................................................157
6.2.Strah i anksioznost u psihijatriji devetnaestog stoljeća..........................................................167
6.3. Strah od neimaštine................................................................................................................174
6.4. Strah od natprirodnog............................................................................................................183
6.5. Strah od nasilja......................................................................................................................189
6.6.Paranoidne mreže i strah od moći države...............................................................................200
7. Bijes, nasilje i sukobi................................................................................................................210 7.1. Bijes, nasilje i sukobi u psihijatriji devetnaestog stoljeća.....................................................210
7.2. Sukobi unutar obitelji............................................................................................................215
7.3.Dječaci s revolverima: nasilničko ponašanje adolescenata....................................................230
7.4. Epileptičari i gorući štagljevi: sukobi unutar ruralnih zajednica...........................................249
7.5. Anarhisti i atentatori: politički sukobi u psihijatriji 19. stoljeća............................................263
Zaključak......................................................................................................................................279
Bibliografija..................................................................................................................................298
Životopis.......................................................................................................................................310 Za Tenu
jer svaki je pogled odraz u krhotinama vječnosti. Volim te, djevojko! Za Tenu
jer svaki je pogled odraz u krhotinama vječnosti. Volim te, djevojko! 1.Uvod Klinika za psihijatriju Vrapče danas se proteže kroz ogroman kompleks zgrada i obuhvaća
raznovrsne medicinske i pomoćne zgrade: od centralnog neoklasicističkog zdanja čiji „dvokrilni”
plan još odaje tragove devetnaestoljetnog Kirkbrideovog dizajna, do moderne bijele zgrade u
kojoj je smješten arhiv bolnice. Dok sam provodio istraživanje za ovu disertaciju često sam bio
iznenađen uklopljenošću kompleksa u okoliš i odsutnošću bilo kakvog osjećaja izolacije kakav
ljudi obično povezuju s psihijatrijskim institucijama - u prostor bolnice se ulazilo nesmetano
(postojala je čak i „prečica” koja je vodila do rupe u ogradi koju sam koristio da bih brže došao
do najbliže trgovine), pacijenti su zajedno s osobljem, učenicima i učenicima obližnje škole za
medicinske sestre i slučajnim posjetiteljima šetali prostranim perivojima. Bolnica je s obje strane
ograde bila okružena kućama tipičnima za predgrađe poput Vrapča i jedino što bi nekom
neupućenom moglo odati dojam da se radi o psihijatrijskoj bolnici, bile su rešetke na prozorima
ponekih zgrada. U periodu obuhvaćenom ovom disertacijom, bolnica je pružala daleko drugačiju sliku. Tada se
zvala Kraljevski i zemaljski zavod za umobolne u Stenjevcu. Njezin dugogodišnji ravnatelj, Ivo
Žirovčić jednom je napisao da je naziv osobito nepogodan jer asocira na stenjanje, a bio je
neprikladan jer sama bolnica nije zapravo bila u naselju Stenjevec nego je dobila to ime zbog
blizine željezničke stanice koja je nosila to ime. Nalazila se u izoliranom ruralnom kraju,
okružena poljima i vinogradima. Tlo je bilo močvarno, nije bilo učinkovitog načina odvođenja
kanalizacijskih voda, a zadah koji se tijekom ljeta širio oko prostora bolnica je bio neizdrživ. Izolacija mjesta je bila tolika da su ravnatelj, kućni liječnici i osoblje bili prisiljeni živjeti u
samom krugu bolnice, a umrli kojih je zbog generalne onemoćalosti štićenika, kao i epidemija,
bio nemali broj, sahranjivani su na obližnjem bolničkom groblju. Radilo se o mjestu koje je bilo
daleko zatvorenije i izoliranije nego što su to današnje psihijatrijske klinike: perspektiva ljudi koji
su u njemu završili bila je mračna: ako i nisu umrli, na njima je ostajala stigma duševnog
bolesnika. Nisu se mogli nadati izlječenju, niti tretmanu koji bi učinio njihovu bolest lakšom. Liječnici su imali težak zadatak skrbi za stotine i tisuće onih koje je društvo odbacilo; bili su to 11 ljudi koji su odabrali granu medicine koja na raspolaganju još nije imala učinkovite metode
liječenja. 1.Uvod Njihov rad se uglavnom svodio na kontroliranje nemirnih štićenika, nekad pomoću
vlastitog autoriteta i lijekova za smirenje nekad poprilično brutalnim metodama poput vezivanja
ili umatanja u plahte i na produženje života onih koji su patili od kroničnih ili infektivnih bolesti. Kao prva i najveća psihijatrijska institucija Stenjevec je bio mjesto na kojem se formirala
hrvatska psihijatrija. Iako su liječnici u godinama kojima se ovaj rad bavi bili obrazovani na
sveučilištima u današnjoj Češkoj, Austriji i Njemačkoj, njihovi pogledi na duševnu bolest bili su
formirani kliničkim iskustvom stenjevačkog zavoda. Njihovi pacijenti bili su ljudi tragičnih
sudbina čiji život je često bio obilježen neimaštinom, odbacivanjem, sukobima s okolinom i
marginalnim položajem u zajednici. Povijesti bolesti sačuvane u Arhivu Klinike za psihijatriju
Vrapče u velikom broju slučajeva su jedini zapisi koji govore o njihovim životnim iskustvima. U
njima štićenici neposredno ili posredno progovaraju o iskustvu osoba čiji je život bio obilježen
dijagnozom „umobolje” ili „ludila” u Hrvatskoj na prijelazu stoljeća. Njihov govor i govor
liječnika koji su u kontaktu s medicinskom zajednicom i javnošću razvijali psihijatrijsku
disciplinu, njeno znanje i diskurs i etablirali svoj pogled na pojedinca i društvo u cjelini čine
osnovu ove disertacije. Od šezdesetih godina dvadesetog stoljeća psihijatrija je predmet historiografskog istraživanja. Unutar povijesti psihijatrije javile su se različite struje i pristupi. No, psihijatrija se također
gotovo isključivo istraživala iz pozicije liječnika. Glas psihijatrijskih pacijenata predstavlja
rijetko korišten, vrijedan ali i metodološki problematičan izvor. Za glavne hipoteze ovog rada ključno je upravo mjesto glasa štićenika u formiranju
psihijatrijskog diskursa. Hipoteze koje ću istraživati u ovom radu su: 1. Psihijatrijski diskurs u Hrvatskoj formirao se pod utjecajem europske (osobito njemačke i
austrijske) biološke psihijatrije, te na temelju spoznaja formiranih u interakciji psihijatara
Kraljevskog i zemaljskog zavoda za umobolne u Stenjevcu i njihovih štićenika. 1. Psihijatrijski diskurs u Hrvatskoj formirao se pod utjecajem europske (osobito njemačke i
austrijske) biološke psihijatrije, te na temelju spoznaja formiranih u interakciji psihijatara austrijske) biološke psihijatrije, te na temelju spoznaja formiranih u interakciji psihijatara
Kraljevskog i zemaljskog zavoda za umobolne u Stenjevcu i njihovih štićenika. Kraljevskog i zemaljskog zavoda za umobolne u Stenjevcu i njihovih štićenika. 12 2. Stavovi hrvatskih psihijatara o rodu i seksualnosti odražavaju patrijarhalnu i seksualno
konzervativnu kulturu građanstva. 2. Stavovi hrvatskih psihijatara o rodu i seksualnosti odražavaju patrijarhalnu i seksualno
konzervativnu kulturu građanstva. 2. Stavovi hrvatskih psihijatara o rodu i seksualnosti odražavaju patrijarhalnu i seksualno
konzervativnu kulturu građanstva. 3. 1.Uvod Mjesto straha i strepnje u psihijatrijskom diskursu devetnaestog stoljeća je izuzetno
problematično: strah i strepnja zauzimaju bitno mjesto u emotivnom režimu onog doba,
no biološki fokus psihijatrije rezultira potcjenjivanjem njihovog utjecaja u etiologiji
duševnih bolesti. 4. Psihijatrija se u devetnaestom stoljeću predstavlja kao grana medicine koja nastoji
izliječiti duševne bolesti znanstvenim i humanim pristupom. No, postoji i druga
percepcija psihijatrije- kao sredstva biopolitičkog nadzora koje ima bitnu ulogu u
suzbijanju društvene devijacije. Suprotstavljenost tih dvaju poimanja izražava se na
osobito vidljiv način u odnosu psihijatrije prema različitim oblicima nasilnih konflikata:
od sukoba unutar obitelji i adolescentskog nasilja, do političkih sukoba. Prvu od pretpostavki istražit ću kroz proučavanje odnosa između intelektualnih utjecaja europske
psihijatrije na teoretska razmatranja i kliničku praksu stenjevačkih psihijatara i njihovih refleksija
o životu i ponašanju štićenika zavoda. Dualitet tih utjecaja vidljiv je u primjeni koncepata
proizišlih iz europske psihijatrije poput borderlandsa i degeneracije na procese dijagnosticiranja i
liječenja zavodskih pacijenata i ponekad na kontekst hrvatskog društva prijelaza stoljeća u cjelini. S druge strane, interakcija liječnika i štićenika, često obilježena izrazitom asimetrijom moći i
epistemičkim nasiljem, sama je rezultirala proširenjem psihijatrijskih znanja. Govor štićenika,
njihova tijela i njihove životne prilike bile su podvrgnute kliničkom zoru i poslužile su kao
elementi konstrukcije diskursa o ludilu koji je objedinjavao postojeće društvene kontradikcije s
eugeničkim i moralističkim nazorima društvenih elita. Druga teza temelji se na pretpostavci da su psihijatri kao profesionalci koji su pripadali
građanskom sloju i predstavljali stavove intelektualnih i društvenih elita, imali izrazito
konzervativno poimanje seksualnosti i roda, oblikovano patrijarhalnom građanskom kulturom
devetnaestog stoljeća i biološkim i medicinskim teorijama koje su prikazivale ženska tijela na
način koji je u fokus stavljao njihovu reproduktivnu funkciju. Pri tome će u psihijatriji izražena
biti dihotomija između „feminine“ histerije i maskuline „progresivne paralize“. Tim bolestima 13 pridavani su orođeni uzroci: histerija je imala uzrok u „inferiornom“ živčanom sustavu žena, dok
se progresivna paraliza nije dovodila u vezu sa spolno prenosivim sifilisom, već se njen uzrok
tražio u „iscrpljenosti“ produktivne građanske klase. Treća hipoteza vezana je uz mjesto straha i strepnje (anksioznosti) unutar psihijatrijskog
diskursa. Iako sami pacijenti često spominju strah i strepnju, zbog naglaska koji psiijatrija
prijelaza stoljeća stavlja na biologiju, hereditet i degeneraciju dovela do činjenice te se emocije
rijetko smatraju važnima u etiologiji duševnih bolesti. 1.Uvod S druge strane, diskurs psihijatrije će biti
informiran strahovima i strepnjama društvenih elita vezanim uz društvene promjene koje je donio
modernitet, što će biti vidljivo u nekim od ključnih medicinskih tekstova nastalih u drugoj
polovici devetnaestog stoljeća. Praksa psihijatrije, često će biti vezana i uz strah od duševno bolesnih pojedinaca kao osoba koje
remete javni mir i društveni poredak. S tom percpecijom je povezana posljednja hipoteza u kojoj
se nastoji ispitati odnos između dvije različite društvene uloge psihijatrije. Psihijatrija se u
devetnaestom stoljeću nastojala predstaviti kao nova grana medicine koja je nudila inovativan
znanstveno utemeljen terapeutski pristup liječenju duševnih oboljenja. No s druge strane, postoji
percepcija psihijatrije kao sredstva društvene kontrole, institucije koja bi trebala biopolitičkim
metodama i izolacijom suzbiti društvenu devijaciju. Kompleksan odnos psihijatrije prema
društvenim sukobima zasniva se na stalnoj napetosti između tih društvenih uloga. Naravno, te
uloge nisu uvijek bile suprotstavljene, no u periodu kojim se ovaj rad bavi, posvemašnji
terapeutski pesimizam dovest će do percepcije stenjevačkog zavoda kao institucije kojoj je
primarna svrha izolacija društveno devijantnih pojedinaca, usprkos činjenici da se i sami
psihijatri često opiru takvim pogledima na vlastitu struku. U prvom poglavlju nastojati pozabaviti različitim pristupima povijesnog istraživanja psihijatrije i
metodološkim problemima medicinskih izvora. Budući da je psihijatrija u Hrvatskoj uvijek
nastojala ići u korak s europskim razvojem discipline, u drugom poglavlju će biti sažeto prikazan
razvoj europske psihijatrije u dugom devetnaestom stoljeću. U prikazu bit će navedene glavne
postavke moral treatmenta, opisat će se terapeutski pesimizam i kriza psihijatrije koja se javlja od
sredine devetnaestog stoljeća, a posebna pažnja bit će posvećena njemačkoj neuropsihijatriji kao 14 intelektualnoj tradiciji koja je bila u najintenzivnijem dodiru s hrvatskom psihijatrijom. Na
početku trećeg poglavlja govorim o izgradnji Kraljevskog i zemaljskog zavoda za umobolne u
Stenjevcu, te dajem kratak životopis liječnika koji su bili ravnateljima zavoda između 1879. i
1918.. godine. Nakon poglavlja o liječnicima slijedi duži prikaz socijalne strukture štićenika
zavoda. Osim boravka u zavodu i njihovog društvenog položaja, za stanje i govor štićenika bitna
su i njihova individualna iskustva prije dolaska u zavod, koja također nastojim opisati. U
poglavlju ću ocrtati i teške uvjete života u zavodu. 1.Uvod Budući da je Kraljevski i zemaljski zavod za
umobolne u Stenjevcu osnovan u trenutku kad je moral treatment ustupao mjesto pesimizmu
prijelaza stoljeća, jedna od teza koju ću istražiti u prva dva poglavlja bit će da je hrvatska
psihijatrija od samih početaka obilježena ispreplitanjem humane misije zavoda kao mjesta skrbi
za duševno bolesne i sve veće percepcije duševnih bolesti kao znaka nepovratne degeneracije. Zavod je praktički od svog osnutka bio mjestom čija je terapeutska uloga dovedena u pitanje u
samom psihijatrijskom diskursu, a visoka smrtnost i niska stopa izlječenja doprinijeli su tome da
je zavod sve češće bio mjestom na koje su upućivani pojedinci u čije se šanse izlječenja nije
vjerovalo. Četvrti dio disertacije govori o rodu i seksualnosti. Rod i seksualnost su, kako je
devetnaesto stoljeće odmicalo, dobivali sve izraženiju ulogu u medicinskim i psihijatrijskim
diskursima. Slijedeći četiri diskursa o seksualnosti koja je u prvom dijelu svoje Povijesti
seksualnosti istaknuo Michael Foucault (diskurs o „histerizaciji” ženskih tijela, maltuzijanskoj
kontroli populacije, seksualnoj nastranosti i masturbaciji) i pridodavši im diskurs o
„primitivizmu” i „moralnoj izopačenosti” ruralne populacije, narativ „tijela izvan kontrole” koji
se pojavljivao kod pojedinih štićenica i diskurs o „nevidljivosti sifilisa” u poglavlju opisujem
kakvu su ulogu patrijarhalno poimanje roda i konzervativno poimanje seksualnosti imali u
psihijatriji Banske Hrvatske. U petom poglavlju, prelazim na strah i anksioznost. Te emocije bile
su bitan dio emotivnih režima u zapadnoj kulturi, a o istima već postoje brojne historiografske
studije. Psihijatrijski pogled na strah promatra se kroz proučavanje takozvanih „društvenih
strahova” vezanih uz degeneraciju i strepnju pred propašću europske kulture i načinu na koji su
se isti reflektirali u medicini i psihijatriji. Zatim se prelazi na strahove samih štićenika i kroz
brojne studije slučaja analiziraju se strah od neimaštine, strah od natprirodnog, strah od nasilja i
strah od moći državnog sustava represije nad pojedincima. Analizom tih strahova nastoji se 15 ustanoviti kakva je bila uloga straha i strepnje u emotivnim režimima devetnaestog stoljeća. Posljednje poglavlje problematizira nasilje, agresiju i sukobe. Na početku tog poglavlja
promatram sukobe i nasilje unutar obitelji i ulogu koju je psihijatrija imala u posredovanju i
medijaciji tih sukoba te objašnjavanju uzroka i posljedica tog nasilja. Zatim govorim o sve
izraženijem problemu adolescentske delinkvencije. Prepoznavanje i konstruiranje adolescenta
kao osobe u specifičnom životnom razdoblju i formiranje „mladenačkog identiteta” postavilo je
nove izazove pred društvene institucije koje su dolazile u doticaj s mladima. 1 Micale i Porter, 1994: 4-5. 1.Uvod Psihijatrija je
specifično reagirala na te izazove: prvo se javilo prepoznavanje i zasebno tretiranje psihičkih
poremećaja u djetinjstvu i adolescenciji, zatim konstrukcija hebefrenije i dementiae praecox kao
„mladenačkog ludila” koje se dovodilo u usku vezu s adolescencijom kad se ličnost pojedinca
integrira i na posljetku pokušajem šire društvene kampanje koja je objedinjavala zahtjev za
psihijatrijskim obrazovanjem liječnika koji rade s djecom i eugeniku. Osim problematike obitelji
i adolescenata (kroz koju se istovremeno propituje i kompleksan međuodnos privatne sfere,
psihijatrije i društva) prelazim na analizu sukoba i nasilja u ruralnim zajednicama. U toj se analizi
osvrćem na postupnu medikalizaciju nasilnih sukoba koji su prije bili promatrani kroz kulturno ili
društveno očište. Na posljetku, analizirat ću pojedine slučajeve politički motiviranog nasilja. Politički motivirano nasilje je u devetnaestom stoljeću zahtijevalo izuzetno kompleksan
angažman psihijatara jer je istovremeno postojala potreba da se ovaj ekstreman oblik društvene
devijacije prikaže i kao medicinski problem i kao moralnu i zakonsku transgresiju. U okviru
pravnog sustava, te su dvije kategorije u devetnaestom stoljeću bile isključive, a psihijatri su ih
često nastojali premostiti. 16 ,
2 Ibid: 5. 2 Ibid: 5. 2 Ibid: 5. 1 Micale i Porter, 1994: 4-5. Micale i Porter, 1994: 4-5.
Ibid: 5. 2.1. Povijest psihijatrije između „vigovske” povijesti i društvenog konstruktivizma 2.1. Povijest psihijatrije između „vigovske” povijesti i društvenog konstruktivizma
Prve zapisane povijesti znanstvenih i medicinskih disciplina imale su praktičnu ulogu pregleda
dosadašnjih spoznaja ostvarenih unutar nekog znanstvenog polja. Zato nije neobično da su prve
zapisane povijesti psihijatrije pisali upravo sami psihijatri kako bi pomogli doprinijeti daljnjem
napretku psihijatrijskog znanja. Prve „povijesti psihijatrije” bile su objavljene kao povijest
pojedinih psihijatrijskih institucija ili biografije zaslužnih liječnika. Fokusirale su se uglavnom na
usku institucionalnu i intelektualnu historiju, a povijest psihijatrije predstavljale su kao povijest
linearnog napretka i poboljšanja skrbi za duševno oboljele. Osim već spomenute uloge
psihijatrijskih povijesti kao kataloga dosadašnjih postignuća te povijesne studije imale su i drugu
svrhu, sličnu onoj koju se pridaje povijesti znanstvenih disciplina uopće. Stvaranjem kontinuiteta
između „velikih umova” iz prošlosti discipline i suvremenih radnika ostvaruje se inicijacija
mlađih učenjaka u disciplinu.1 Za povjesničare psihijatrije, položaj „velikih umova” najčešće su
zauzimali pioniri suvremene medicinske psihijatrije poput Phillipea Pinela i Jean-Étiennea
Dominiquea Esquirola, te učenjaci za koje se smatralo da su unaprijedili disciplinu poput Emila
Kräpelina i Henryja Maudsleyja. Hrvatski povjesničari psihijatrije će za svog „velikana” uzimati
doktora Ivana Žirovčića, u svoje vrijeme poprilično kontroverznog ravnatelja Kraljevskog i
zemaljskog zavoda za umobolne u Stenjevcu. U slučaju psihijatrije kao relativno nove i u svojim
počecima često marginalizirane i osporavane medicinske discipline te su povijesti također imale
svrhu uspostavljanja epistemološkog integriteta pokazujući napredak psihijatrijske misli kao
evolucijski put prema sve „znanstvenijim” i učinkovitijim dijagnostičkim, i terapeutskim
metodama, čime sama disciplina u očima intelektualne javnosti dobiva znanstveni kredibilitet.2 Put psihijatrije u tim povijestima uvijek se bio prikazan na sličan način: od praznovjernog straha
pred ludilom, preko sve učinkovitijih i humanijih tretmana duševno oboljelih. Samim time,
slijedio je uvriježeni prosvjetiteljski narativ o pobjedi znanosti nad praznovjerjem, medicine nad
1 Mi
l i P
1994 4 5 17 bolestima i razuma nad strahom i predrasudama. Fokus istraživanja bio je na intelektualnoj
povijesti, često ignorirajući utjecaj društvenih, političkih i ekonomskih faktora na razvoj
psihijatrije. Takav pristup kasnije je prozvan vigovskom historijom psihijatrije. Naziv „vigovska
historija” (whig history) preuzet je iz knjige britanskog povjesničara Herberta Butterfielda The
Whig Interpretation of History iz 1931. godine. Butterfield je u svojoj knjizi kritizirao tendenciju
onodobnih britanskih povjesničara da trenutno stanje vide kao neku vrstu „vrhunca razvitka” ili
„ideala”. ,
4 Micale i Porter, 1994: 6. 3 Butterfield, 1965:12-13. 5 Ibid: 7. 5 Ibid: 7. 2.1. Povijest psihijatrije između „vigovske” povijesti i društvenog konstruktivizma Za Butterfielda, vigovska historija ima sljedeće karakteristike: promatra prošlost
referirajući se na sadašnjost, često svrstava povijesne aktere i ideje u kampove „pokretača
progresa” i „nazadnih”, u prošlim događajima vidi uzroke ili anticipaciju sadašnje situacije i
prosuđuje prošle događaje na temelju njihovih percipiranih konačnih posljedica.3 „Vigovske” povijesti psihijatrije doživjele su svoj vrhunac u tridesetim, četrdesetim i pedesetim
godinama dvadesetog stoljeća. Jedna od najistaknutijih takvih studija bila je djelo
psihoanalitičara i ruskog emigranta Gregoryja Zilboorga A History of Medical Psychology
(Povijest medicinske psihologije).4 Zilborgova studija predstavlja freudovsku psihoanalizu kao
vrhunac psihijatrijskog i psihološkog znanja i poistovjećuje napredak psihijatrije s napretkom
humanizma.5 U tim godinama, svjetlo dana ugledale su brojne slične studije uglavnom fokusirane
na razvoj nacionalnih psihijatrija i povijest pojedinih institucija, a uglavnom su nastajale u
zemljama engleskog govornog područja. Navedena struja unutar povijesti psihijatrije bila je
otporna na promjene paradigmi i pristupa unutar historijske znanosti. To se vidi i na primjeru
knjige Edwarda Shortera A history of psychiatry: from the era of the asylum to the age of Prozac
iz 1996. godine. U toj opsežnoj intelektualnoj historiji europske i američke psihijatrije, Shorter
podređuje cjelopkupnu intelektualnu misao psihijatrije suvremenim dosezima farmakološke
psihijatrije. Shorter će isticati upravo somaticističku struju, od Maudsleyja, preko Kräpelina i
Alzheimera do pojave prvih antipsihotika kao kontinuiran niz intelektualnog razvoja medicinske
discipline koji je rezultirao uspješnim i humanim tretmanom duševnih bolesti kakav postoji
danas. Tradicije koje pretpostavljaju drugačiju etiologiju i terapeutske metode poput psihoanalize, 18 „moral treatmenta” i reformskog pokreta psihijatara poput Lainga i Basaglie, Shorter će smatrati
svojevrsnim epistemološkim „slijepim ulicama” koje u najboljem slučaju nisu doprinijele razvoju
psihijatrije, a u najgorem su ga unazadile. Shorter time slijedi i teleološki pristup i tendencioznost
ranijih „vigovskih” povjesničara, eksplicitno odbacivši konstruktivističku struju i ne osvrćući se
na rodne i post-kolonijalne studije psihijatrije. U Hrvatskoj, primjer „vigovskog”
historiografskog djela je doktorska disertacija liječnika Lavoslava Glesingera Povijest psihijatrije
u Hrvatskoj objavljena 1959. godine u kojoj Glesinger ustanovljuje godinu osnivanja
„Kraljevskog i zemaljskog zavoda za umobolne u Stenjevcu” kao početak psihijatrije u
Hrvatskoj. Sličan pristup nalazi se i u brojnim spomenicama Klinike za psihijatriju Vrapče, koje
daju kronološki pregled razvoja bolnice od njezinih teškoćama ispunjenih početaka do trenutnog
stanja. Takve spomenice objavljivali su brojni ravnatelji bolnice od Rudolfa Hercega koji je svoju
spomenicu povodom pet desetljeća rada objavio 1933. godine do Vlade Jukića koji je povijesti
Klinike za psihijatriju Vrapče posvetio priličan broj publikacija. 2.1. Povijest psihijatrije između „vigovske” povijesti i društvenog konstruktivizma U šezdesetim godinama prošlog stoljeća brojne su društvene i humanističke znanosti doživjele
teorijsku i metodološku transformaciju pod utjecajem epistemoloških spoznaja strukturalizma,
poststrukturalizma i postmodernističke filozofije. Spoznaje društvenih i prirodnih znanosti, do
tada promatrane kao dio nepromjenjive istine otkrivane sve savršenijim metodološkim aparatom
neprekidno napredujućih znanstvenih disciplina počinju se gledati kao produkt određenih
konstelacija moći u društvu. Medicina i psihijatrija se također počinju promatrati kao discipline
na čiji su razvoj utjecale specifične društvene i političke okolnosti, a u slučaju psihijatrije, izrazita
se pažnja počela posvećivati modernizacijskim procesima, naročito onima povezanima uz jačanje
državne moći. Aspekti državne moći povezani s kontrolom populacije i borbom protiv javnog
nemorala, zločina i epidemija objedinjavali su policijski represivni aparat i politike javnog
zdravlja. Smjer povijesti psihijatrije koji se formirao tih godina najčešće se naziva „socijalnim
revizionizmom” ili „socijalnim konstruktivizmom”. „Velika revizija” koja se u povijesti
psihijatrije dogodila šezdesetih godina najčešće se povezuje s četirima djelima koja su dovela u
pitanje shvaćanje duševne bolesti kao neupitne medicinske činjenice. Navedene knjige su Azili
Ervinga Goffmana, Mit o duševnoj bolesti Thomasa Szassa, Povijest ludila u doba klasicizma 19 Michela Foucaulta i „Podjeljeno Ja” Ronalda D. Lainga.6 U Azilima Goffman je opisao proces
„institucionalizacije” duševno oboljelih u psihijatrijskim ustanovama. Proces institucionalizacije
za Goffmana znači usvajanje određenih obrazaca ponašanja uslijed prilagodbe na
depersonalizaciju koja je posljedica života u totalnoj instituciji poput psihijatrijskog zavoda. Ti
obrasci ponašanja su isti obrasci ponašanja prepoznati kao simptomi kroničnih duševnih bolesti. U skladu s time, Goffman je zaključio da sam sustav zatočenja i izolacije duševno oboljelih
proizvodi elemente stanja percipiranog kao ludilo ili duševna bolest. Thomas Szasz pak dovodi u
pitanje samu duševnu bolest kao medicinsku činjenicu: budući da je bolest identična s
patološkom promjenom na tijelu, a promjene na ličnosti je nemoguće kontinuirano opažati,
duševna bolest je zabluda proizvedena kako bi se određeni oblici ponašanja koji prkose
društvenim normama mogli regulirati, nadzirati i suzbijati. Povijest psihijatrije je, za Szasza,
povijest legitimiranja zablude koja je formirana kao sredstvo opresije nad osobama koje je
društvo izoliralo kao „drugačije” ili „opasne”. Robert David Laing bio je škotski psihijatar koji je
napao epistemološke temelje psihijatrije tvrdnjom da se biološka patologija ne može uvjerljivo
dijagnosticirati na temelju ponašanja, a Michel Foucault je u Povijesti ludila potpuno obrnuo
„vigovski” narativ napretka postavivši tezu o „Velikom zatočenju”. 6 Ibid. 2.1. Povijest psihijatrije između „vigovske” povijesti i društvenog konstruktivizma Za Foucaulta, pojava
moderne medicinske psihijatrije početkom devetnaestog stoljeća predstavlja kulminaciju
uspostave sve rafiniranijih metoda kontrole nad tijelima pojedinaca: bilo da se radilo o duševno
bolesnima, kriminalcima, alkoholičarima, oboljelima od zaraznih bolesti ili siromašnima i
prosjacima. „Veliko zatočenje” povijesni je proces koji koincidira s početkom postupnog
uvođenja sve učinkovitijih mjera državnog nadzora nad teritorijem i populacijom krajem
sedamnaestog i početkom osamnaestog stoljeća, a sastoji se u osnivanju posebnih institucija za
izolaciju i zatočenje pojedinaca koji su zbog svog ponašanja bili shvaćeni kao prijetnja
postojećem poretku. Prvi socijalni revizionisti nisu bili povjesničari (Laing i Szasz su bili liječnici, Foucault je bio
filozof, a Goffman sociolog) i njihova su ključna djela bila temeljena na uskom fondu prilično
površno interpretiranih izvora. No njihov rad inspirirao je niz povijesnih analiza od kasnih 6 Ibid. 20 šezdesetih godina do danas. Prve metodološki sustavnije historijske studije revizionističkog
smjera objavili su Ida Macalpine i Richard Hunter, majka i sin koji su kao trenirani
psihoanalitičari pristupili historijskoj analizi duševnih oboljenja povijesnih ličnosti poput „ludog”
engleskog kralja Georgea III. i Daniela Schrebera, suca koji je objavio memoarski zapis vlastite
duševne bolesti i boravka u psihijatrijskoj instituciji, a u povijesnoj studiji zavoda za siromašne u
Colney Hatchu, istražili su utjecaj ekonomskih faktora i socijalnih politika na razvoj psihijatrije. Ubrzo su uslijedili drugi važni tekstovi: njemački povjesničar i psihijatar Klaus Doerner objavio
je 1969. studiju Luđaci i građanstvo u kojoj analizira vezu između uspona građanske klase u
kasnom sedamnaestom stoljeću i razvoja psihijatrije, a britanski sociolog Andrew Scull je od
sedamdesetih godina prošlog stoljeća nadalje objavio niz dobro potkrijepljenih studija koje
predstavljaju ključan doprinos za socijalnu povijest angloameričke psihijatrije. Najveći doprinos
historiografiji psihijatrije dao je britanski povjesničar znanosti i medicine Roy Porter. 7 Ibid: 12. 2.1. Povijest psihijatrije između „vigovske” povijesti i društvenog konstruktivizma U svojim
knjigama Anatomy of Madness, A Social History of Madness: Stories of the Insane (1987), Mind-
Forg'd Manacles: A History of Madness in England from the Restoration to the Regency (1987),
Madness: A Brief History (2002) i posthumno objavljenom Madmen: A Social History of
Madhouses, Mad-Doctors and Lunatics (2006) Porter čini svojevrstan odmak kako od
„vigovske” historije tako i od „socijalnih revizionista” priznajući važnost i jednih i drugih, ali i
jednima i drugima zamjerajući suviše suženu perspektivu usmjerenu više na tendenciozno
potkrepljivanje vlastitih stavova o mjestu psihijatrije u društvu nego na sustavnu historiografsku
analizu.7 Osim pristupa povijesti psihijatrije koji su nužno „vigovski” ili „revizionistički” od kasnih
šezdesetih do danas pojavio se niz studija povijesti psihijatrije u kojima autori i autorice
analiziraju ulogu psihijatrije u različitim povijesnim procesima: od kolonijalizma, rasizma i
dekolonizacije, borbe žena za rodnu ravnopravnost, te uloge psihijatrije u društvima koja prolaze
ubrzane procese modernizacije. Za povijest psihijatrije iz rodne perspektive naročito je bitan rad
britanske povjesničarke književnosti i znanstvenice na polju kulturnih studija Elaine Showalter,
koja je u knjizi The female malady: women, madness, and English culture, 1830-1980 (1985) 21 istaknula ulogu koju su psihijatrijske dijagnoze poput histerije, „shellshocka”(granatnog šoka) i
shizofrenije imale pri perpetuiranju postojećih rodnih stereotipa i patrijarhalnih odnosa moći u
društvu. Na sličan se način poviješću histerije u antičkoj medicini bavila antička povjesničarka
Helen King. Karipski psihijatar Frantz Fanon koji će kasnije biti prepoznat kao jedan od
utemeljitelja postkolonijalne misli, svoja je istraživanja pedesetih godina temeljio na svojoj
psihijatrijskoj praksi, te se bavio specifičnom psihopatologijom kolonijalizma. Nakon Fanona
javio se niz istraživača kolonijalne psihijatrije. Od bitnih studija na polju kolonijalne psihijatrije
valja istaknuti rad američkog povjesničara Jonathana Sadowskog koji je u svojoj knjizi Imperial
Bedlam Institutions of Madness in Colonial Southwest Nigeria (1999) problematizirao odnos
psihijatrije i kolonijalne politike u britanskom imperijalnom kontekstu devetnaestog stoljeća. Za povijest psihijatrije na području Hrvatske, izrazito je bitan rad povjesničara koji proučavaju
razvoj psihijatrije u društvima koja prolaze modernizacijsku transformaciju iz pretežno ruralnih
društava u industrijalizirana društva obilježena kapitalističkim odnosima proizvodnje. Američka
povjesničarka Ann Goldberg 1999. godine objavila je studiju pod nazivom Sex, Religion, and the
Making of Modern Madness: the Eberbach Asylum and German Society, 1815-1849 u kojoj
analizira način na koji su psihijatrijske dijagnoze poput religiozne manije i nimfomanije u ranoj
njemačkoj psihijatriji konstruirane putem „kliničkog zora” u promatranju ruralnih praksi vezanih
uz religioznost i seksualnost. g,
9 Meyer, 2017: 177. 8 Goldberg, 1999: 6. g,
9 Meyer, 2017: 177. 10 Arbex, 2013: 23. 2.1. Povijest psihijatrije između „vigovske” povijesti i društvenog konstruktivizma Golberg pokazuje kako su kulturno i ideološki informirane
percepcije ponašanja štićenika i štićenica ruralnog porijekla od strane obrazovanih liječnika koji
su pripadali građanskoj klasi ili aristokraciji i percipirali se kao nositelji prosvjetiteljstva i
modernizacije, bili ključni za nastajanje dijagnostičkih kategorija moderne psihijatrije.8
Povjesničarka Manuella Meyer u svojim studijama istražuje ulogu psihijatara kao aktera
političkih procesa modernizacije u Brazilu u devetnaestom stoljeću i prvoj polovici dvadesetog
stoljeća, naročito njihovu ulogu u formiranju Brazila kao moderne nacije-države.9 Tamniju ulogu
modernizacijskih procesa u Brazilu istražila je novinarka i aktivistica za ljudska prava Daniela
Arbex. U svojoj knjizi Holocausto Brasileiro opisala je tragičnu sudbinu štićenika psihijatrijske
kolonije Barbacena u kojoj je od prijelaza stoljeća do 1980. uslijed neljudskih uvjeta života i 22 zlostavljanja preminulo 60 000 ljudi. Više od osamdeset posto štićenika nije imalo medicinsku
dijagnozu duševne bolesti, već su pripadali širokoj kategoriji „nepoželjnih” i društveno
devijantnih osoba.10 Pristupi koji promatraju psihijatriju u širem kontekstu modernizacijskih procesa u središtu su
istraživačkih pristupa povjesničara i povjesničarki koji su proučavali povijest psihijatrije na
području bivše Jugoslavije. Jedna od najrelevantnijih studija na tom polju je knjiga Therapeutic
Fascism. Experiencing the violence of Nazi New Order in Yugoslavia,(2017) srpske povjesničarke
Ane Antić, koja živi i radi u Velikoj Britaniji. Antić je na temelju povijesti bolesti i stručne
psihijatrijske literature istražila ulogu koju su psihijatri imali u turbulentom političkom razdoblju
neposredno prije, za vrijeme i neposredno nakon Drugog svjetskog rata. Njemačka povjesničarka
Heike Karge je u svojim radovima istraživala ulogu psihijatrije u konstrukciji socijalnih
kategorija u Srednjoj i Jugoistočnoj Europi. Od hrvatskih istraživača treba spomenuti rad Marina
Kuhara i Stele Fatović-Ferenčić koji su u nizu članaka objavljenih u domaćim i međunarodnim
publikacijama analizirali formiranje distinktivnih kategorija duševne bolesti kroz mrežu
interakcija psihijatrije i pravosuđa u Banskoj Hrvatskoj. U ovom radu nastojim slijediti pristupe koji smještaju psihijatrijski diskurs u širi društveni
kontekst i promatrati odnos psihijatrije prema različitim aspektima društva fin de sieclea poput
rodnih uloga i seksualnosti, odnosa privatne i javne sfere, strahova koji su često postajali
elementom političkog života i nasilja. Moj rad, kao i brojni od radova koje sam upravo naveo
oslanja se na povijest bolesti kao specifičan izvor za povijest psihijatrijskog diskursa i
psihijatrijske prakse. Iz tog razloga, potrebno je detaljno problematizirati povijest bolesti kao
nesvakidašnji tip arhivskog izvora u historijskim istraživanjima. ti bolesti i glas psihijatrijskih pacijenata: metodologija istraživanja psihijatrije Prilikom proučavanja psihijatrijskog diskursa u Hrvatskoj i istraživanja kako se isti formirao pod
utjecajem terapijskih i izolacijskih praksi stenjevačkog zavoda (te kako je diskurs pomogao
formirati proučavane prakse) bilo je potrebno detaljno opisati polje medicine i psihijatrije u
Europi i hrvatskom dijelu Austro-Ugarske monarhije. Za opisivanje intelektualnog horizonta 23 hrvatskih psihijatara i ostalih liječnika koji su na više ili manje neposredan način sudjelovali u
radu zavoda za umobolne, primarno su poslužili članci i izvještaji objavljeni u Liječničkom
vjesniku, glasilu Hrvatskog liječničkog zbora koje je počelo izlaziti 1877. godine i nastavilo do
danas izlaziti na mjesečnoj bazi. Pri iščitavanju Liječničkog vjesnika nastojao sam što je moguće
vjernije opisati razvoj određenih medicinskih ideja i diskurzivnih koncepata unutar liječničke
struke. Budući da su priloge Liječničkog vjesnika pisali i čitali liječnici, isti daju vjernu sliku
formiranja i širenja medicinskog znanja unutar same struke. Pritom valja naglasiti da razvoj
medicinskog znanja u stručnom miljeu ne treba doživljavati u smislu jednosmjernog progresa već
kao niz rasprava unutar liječničke zajednice koje su oblikovane kako obrazovanjem koje su
liječnici stekli na inozemnim sveučilištima, tako i njihovom svakodnevnom praksom i susretima s
pacijentima, te njihovim osobnim uvjerenjima. Način formiranja tih znanja može se pobliže
objasniti pojmovima polja, habitusa i doktrine, koje je uveo francuski sociolog Pierre Bourdieu. U bourdieuvskom smislu, polje u kojem su locirani liječnici kao akteri koji razvijaju psihijatrijske
koncepte i prakse odgovara prostorima javnog djelovanja medicinske profesije. Njihov habitus
čine njihove prakse i dispozicije koje oni kao agenti društvenog djelovanja zauzimaju. Te prakse
istovremeno su pomogle strukturirati društveni kontekst medicine i psihijatrije u Hrvatskoj na
prijelazu stoljeća, ali i formirale određenu (auto)percepciju mjesta psihijatrije u
društvu.11Intelektualni položaj samih psihijatara bit će na prijelazu stoljeća obilježen njihovom
stalnom borbom za socijalni kapital unutar medicinske profesije i društva u cjelini, a društveni
položaj psihijatara kao pripadnika obrazovane društvene elite koja je pripadala plemstvu ili
građanskom sloju, a koji ipak djeluje na dvostrukim marginama: Austro-Ugarskog Carstva i
marginama medicinske profesije oblikovao je njihova uvjerenja i vrijednosti. Te vrijednosti koje
Bourdieau naziva „doxa” ili doktrina utjecale su na njihovo intelektualno i institucionalno
djelovanje i u velikoj mjeri formirale sam psihijatrijski diskurs. S tim na umu, nastojao sam
članke objavljene u Liječničkom vjesniku čitati kao primjer javnog djelovanja psihijatara na polju
medicine s ciljem legitimacije hrvatske psihijatrije kao moderne medicinske discipline koja
nastoji izboriti svoje mjesto unutar polja hrvatske medicine koje se na prijelazu stoljeća još uvijek
tek počinje formirati. 11 Bourdieu, 1996: 171. 11 Bourdieu, 1996: 171. ti bolesti i glas psihijatrijskih pacijenata: metodologija istraživanja psihijatrije Istinsko formiranje i etabliranje moderne medicine na ovim prostorima 24 dogodit će se tek nakon Prvog svjetskog rata osnivanjem Medicinskog fakulteta i kasnijim
formiranjem Škole narodnog zdravlja putem koje su hrvatski liječnici počeli aktivnije sudjelovati
u formiranju zdravstvenih politika. Od posebnog su značaja bila i zdravstvena izvješća
Kraljevskog i zemaljskog zavoda za umobolne u Stenjevcu koja su u prvim desetljećima rada
psihijatri objavljivali u Liječničkom vjesniku, a koja su osigurala podatke brojnosti, socijalnoj
strukturi i smrtnosti štićenika, a koje sam nastojao prikazati i grafički. Pored članaka objavljenih u Liječničkom vjesniku kao izvor za poučavanje psihijatrije služit će i
stručni tekstovi europskih i američkih psihijatara. Radi se o radovima objavljenim u stručnim
publikacijama i medicinskim priručnicima. Proučavanje tekstova inozemnih (uglavnom
austrijskih, njemačkih, francuskih i britanskih) psihijatara daje detaljan pregled razvoja i transfera
pojedinih termina i koncepata u psihijatrijskoj znanosti. To se naročito odnosi na dijagnostičke
kategorije, etiologiju duševnih bolesti i terapeutske pristupe. Svaki od koncepata opisanih u
tekstovima hrvatskih psihijatara i primijenjenih u praksi zavoda, legitimiran je pozivanjem na
određene psihijatrijske autoritete što pokazuje kako je hrvatska psihijatrija bile uvelike formirana
pod utjecajem spoznaja europskih psihijatara i neurologa. Istraživanje psihijatrijskih priručnika
napisanih na stranom jeziku (u vremenu obuhvaćenom ovim istraživanjem ne postoje takvi
priručnici na hrvatskom jeziku) omogućava smještanje psihijatrije u širi europski kontekst i odaje
transformaciju i primjenu koncepata europske psihijatrije u diskursu i praksi hrvatskih psihijatara. Osim komunikacije psihijatara sa psihijatrijskom zajednicom izvan Hrvatske i s drugim
liječnicima, bitno je pratiti i emotivni režim obrazovanih društvenih elita pripadali. Osim
sekundarne literature o kulturnoj povijesti emocija u kasnom devetnaestom i ranom dvadesetom
stoljeća, poslužio sam se književnim djelima koja su nastajala ili bila čitana u Hrvatskoj za
vrijeme ili neposredno nakon i prije proučavanog razdoblja. Smatram kako je književnost, kao
jedan od bitnih medija kroz koji su obrazovani slojevi formirali svoj stav o emotivnosti i
međuljudskim odnosima značajan izvor za objašnjavanje emotivnog režima razdoblja u kojem je
pisana riječ još uvijek dominantni oblik društvene komunikacije. 25 Medicinski i književno-umjetnički tekstovi formiraju vanjski pogled na emocije, psihu i duševnu
bolest no psihijatrijski diskurs se primarno formira unutar heterotopije zavoda i bolnica za
duševne bolesti. Sama klinička praksa obilježena je aktivnom interakcijom liječnika i pacijenta. 13 Ibid: 140. 14 Lunbeck, 1995: 133-134. 12 Foucault, 2003: 135. 13 Ibid: 140. ti bolesti i glas psihijatrijskih pacijenata: metodologija istraživanja psihijatrije I
dok stručna medicinska literatura raspravlja i opisuje medicinske koncepte, praksa podvrgavanja
tijela pacijenta „medicinskom zoru” koji strukturira, grupira i klasificira osobine uočene na
tijelima pacijenata u definitivne označitelje „zdravog” i „patološkog” događa se u izoliranom
prostoru klinike koji je prilagođen isključivo toj vrsti proizvodnje znanja. Prostor psihijatrijskog
zavoda i prostor stručnog medicinskog teksta odgovaraju dvama prostorima čije je postojanje
Foucault pretpostavio činu kliničke opservacije: prostoru bolnice i prostoru podučavanja12. Mjesto zavoda mjesto je gdje kategorije psihijatrijskog znanja bivaju strukturirane i opisane kroz
procese izmjene kliničkog govora i kliničkog zora, uspostavom korelacije između njih i konačno,
opisom patologije koju zor otkriva na tijelima i u riječima psihijatrijskih štićenika.13 Povijest bolesti je jedan od konačnih artefakata znanja koji nastaje tim procesom, mjesto gdje se
tijela štićenika transformiraju u objekte psihijatrijskog znanja ključnog za formiranje svakog
diskursa. U Klinici za Psihijatriju Vrapče, svaka povijest bolesti organizirana je kao jedinstvo
liječničkih kliničkih opservacija i govora štićenika. Kliničke opservacije počinju od prve stranice
na kojoj su doneseni osnovni podaci o svakom štićeniku ─ ime i prezime, dob, vjerska
pripadnost, zanimanje, mjesto stanovanja, datum dolaska u zavod (eventualni raniji boravak u
zavodu se također bilježi), dijagnoza, pretpostavljeni uzrok bolesti, dodatne bilješke, te datum i
okolnosti izlaska iz zavoda. U slučaju smrti naveden je i uzrok smrti štićenika. Nakon osnovnih
podataka opisanih na prvoj stranici, prelazi se na nekoliko stranica gusto ispisanih kliničkih
bilješki o ponašanju i zdravstvenom stanju štićenika. Te bilješke počinju biti pisane od prvog
dana dolaska u zavod kad se štićenika podvrgava detaljnom tjelesnom pregledu i intervjuu s
liječnikom. Time se sustav konstantnog kliničkog nadzora uspostavlja kao dominantni okvir
unutar kojeg nastaje dokument o štićenikovom boravku u zavodu.14 Iako je sam proces
promatranja u stručnim tekstovima prezentiran kao objektivan i informiran postojećim 26 medicinskim i znanstvenim kategorijama, povijesti bolesti odaju njegovu subjektivnu prirodu. Kao što je u svom ranijem istraživanju prepoznala Ana Antić, kategorije na osnovu kojih se
dijagnosticira duševno zdravlje štićenika bile su u velikoj mjeri kulturno i društveno uvjetovane.15
Od štićenika se tako očekivalo da poznaju trenutnu političku situaciju, rješavaju matematičke
zadatke, odgovaraju na pitanja o vlastitim vjerskim i moralnim načelima (idu li u crkvu, znaju li
molitve, daju svoj stav o pitanjima poput: je li u redu krasti i treba li supruga slušati svog muža)16. Brojni opisi ponašanja i izgleda štićenika i štićenica su izrazito subjektivni i daleko od egzaktnih
znanstvenih i medicinskih kategorija. 15 Antić, 2016: 31.
16 Arhiv Klinike za psihijatriju Vrapče, povijesti bolesti. U daljnjem tekstu koristim kraticu KPV.
17 KPV, 1895: 2630.
18 KPV, 1895: 1737.
19 KPV, 1914: 6787.
20 KPV, 1914: 9053. 15 Antić, 2016: 31. 20 KPV, 1914: 9053. 19 KPV, 1914: 6787. 15 Antić, 2016: 31.
16 Arhiv Klinike za psihijatriju Vrapče, povijesti bolesti. U daljnjem tekstu koristim kraticu KPV
17 KPV 1895: 2630 ti bolesti i glas psihijatrijskih pacijenata: metodologija istraživanja psihijatrije Tako se u povijestima bolesti nalaze opisi poput: „Izraz lica
inteligentan, pogled erotičan”,17 „nesnošljiva ženska”,18 „Smiješi se kao seoska guska.”,19 „Jedna
od najužasavajućih katatoničnih prikaza.”20 Pored bilješki povijest bolesti sadrži i obaveznu
liječničku svjedodžbu na temelju koje je štićenik primljen u zavod, a koja sadrži opservacije
mjesnog ili kotarskog liječnika ili liječnika zaposlenih u nekoj od općih bolnica. Bilješke
kotarskih liječnika uglavnom sadrže iste podatke kao i naslovne stranice povijesti bolesti, no
često daju detaljniji pregled anamneze štićenika ─ prethodne bolesti kao i informaciju o
eventualnim bolestima članova obitelji. Uz liječničku svjedodžbu pojedine povijesti bolesti
sadrže i pisma samih štićenika, njihovih članova obitelji, prijatelja i poznanika, poslodavaca te
ponekad predstavnika lokalne vlasti. Za razumijevanje povijesti bolesti nužno je, osim liječničkih i bolničarskih primjedbi prepoznati i
govor samih štićenika kao konstitutivni element izvora. Glasovi štićenika javlja se u tri oblika:
posredovan glas, djelomično posredovan glas i neposredan glas. Potpuno posredovan glas javlja
se kada se govor štićenika prenosi u trećem licu od strane psihijatara i bolničara. U primjerima
takvog posredovanja rijetko dobivamo riječi koje je štićenik direktno koristio, a iskazi štićenika
uglavnom su reducirani na informacije koje je osoba koja je zapisivala govor smatrala bitnima. U
nekim slučajevima, navedene su pojedine riječi štićenika unutar prepričanog iskaza, uglavnom
kako bi ih se osobito istaknulo na primjer, u slučaju sluškinje Tereze G: 27 „Kasnije služila u Mariboru, Zagrebu i Grazu. Nije nigdje dugo zadržala (sic!), jer je žestoke
ćudi i lako se svadila a sve je to kriv rittmajstor, mladi Perger u Gracu. On ju progoni, sluša,
zna njezine misli, ona mora govoriti ono , što on misli, može njezino tijelo micati kako hoće i
to sve pomoću nekakvog hoeraparata. On joj napravio „Schuttelfrost” poslije kog je morala
mnogo urinirati.”21 „Kasnije služila u Mariboru, Zagrebu i Grazu. Nije nigdje dugo zadržala (sic!), jer je žestoke
ćudi i lako se svadila a sve je to kriv rittmajstor, mladi Perger u Gracu. On ju progoni, sluša,
zna njezine misli, ona mora govoriti ono , što on misli, može njezino tijelo micati kako hoće i
to sve pomoću nekakvog hoeraparata. On joj napravio „Schuttelfrost” poslije kog je morala
mnogo urinirati.”21 Iako je cijeli Terezin govor zapisan u neupravnom govoru, s opisom njezinih deluzija u trećem
licu, osoba koja je zapisivala njezin iskaz istaknula je njemačku riječ „Schuttelfrost” (nazeb) kao
frazu koju uglavnom germanofona Tereza koristi. 23 Antić, 2016: 37. 22 KPV, 1911: 7840. 21 KPV, 1911: 5604.
22 KPV, 1911: 7840.
23 Antić, 2016: 37. ti bolesti i glas psihijatrijskih pacijenata: metodologija istraživanja psihijatrije Slično je i u povijesti bolesti seljakinje Jane L.:
„Tužila se zatim, da joj hoće neko oči izvaditi, da joj ispanu svaki čas „gadne riječi, tako da je i
sad izbacila dvije gadne riječi.”22. Nakon prepričavanja Janinih strahova i pritužbi, fraza „gadne
riječi” odijeljena je navodnicima i označena kao izvorni navod štićenice, te ju se zatim nastavilo
koristiti kroz povijest bolesti. Upotreba navodnika, kao što je navela i Ana Antić, osim
odjeljivanja izvornog i prepričanog govora štićenika odaje i eksplicitnu asimetriju moći između
štićenika i liječnika. Pozivajući se na Bahtinov koncept lingvističkih zona, Antić je primijetila da
govor pacijenata često zauzima prostor medicinskog dokumenta i pokušava nametnuti
štićenikovu perspektivu njegovog vlastitog mentalnog stanja i okolnosti u kojima se našao.23
Navodnici, kao direktna intervencija označuju liječnikovo distanciranje od štićenikovih riječi i
ekspliciraju ih kao simptom. Govor štićenika postaje iskaz podvrgnut kliničkom nadzora koji ima
ulogu potvrđivanja štićenikove duševne bolesti. Navodnicima su često istaknute upravo
neuobičajene fraze ili krivo upotrijebljeni iskazi kao vid dodatnog naglašavanja da ih koristi
upravo sam štićenik. Djelomično posredovan glas štićenika također je zapisan od strane bolničara ili liječnika, ali su
iskazi preneseni u prvom licu, često i na dijalektu štićenika, ponegdje odijeljeni navodnicima, a
ponegdje ne. Taj je govor najčešće uokviren izjavom koja jasno obilježava iskaz kao štićenikov
poput „kaže da” ili „govori: ”. Često je djelomično posredovan glas dodatno ilustriran izjavom o
emotivnom stanju štićenika na primjer: 21 KPV, 1911: 5604. 22 KPV, 1911: 7840. 23 Antić, 2016: 37. 28 „Kod vizite se vrlo plaši, boji se kad mu bolničar stoji iza glave, svi moraju stajati pred njim, do
nogu kreveta; iznenada zaplače i vikne: Nemojte mi stavljati prisilne maske na lice.”24 U povijestima bolesti štićenici neposredno progovaraju kroz pisma koja su pisali liječnicima,
obitelji ili predstavnicima vlasti. Takva pisma su brojna i napisana su rukom štićenika. Iako tu
glas štićenika dolazi cjelovito uobličen od strane štićenika, treba imati na umu da je i tu prisutna
selekcija od strane liječnika. Radi se isključivo o pismima koja nisu odaslana na adrese na koje su
ih štićenici namjeravali odaslati i sačuvana su kao dio povijesti bolesti upravo jer su ih liječnici
smatrali artefaktom patologije štićenika. Pisma priložena povijestima bolesti nisu izmijenjena, ali
su kontekstualizirana unutar narativa kroz koji su štićenici zavoda konstruirani kao osobe
„abnormalnog” i „poremećenog” uma. 24 KPV, 1909:7130. ,
26 De Young,2015: 447. ti bolesti i glas psihijatrijskih pacijenata: metodologija istraživanja psihijatrije Glas štićenika, je čak i kad progovara neposredno unutar
zavoda uvijek podložan intervenciji kliničkog zora, koji se u konkretnom primjeru sačuvanih
pisama javlja u formi moći selekcije: liječnik odlučuje koji će od iskaza biti zabilježeni, a koji
ignorirani, koje izjave postaju dijelom štićenikove povijesti, a koje su predane zaboravu. Komunikacija unutar zavoda isključivo je jednodimenzionalna i locirana je isključivo između
medicinskih koncepata normalnog i patološkog. Iskazi koji su zabilježeni, zabilježeni su upravo
kao elementi kliničke slike, bez osvrta na sve druge dimenzije tih iskaza, a naročito one koje bi
mogle predstaviti autentičan pogled štićenika na njihovo vlastito duševno stanje. Povijest bolesti
je izvor u kojem je glas štićenika neprekidno podvrgnut epistemičkom nasilju liječnika i u
potpunosti stavljen u subalternu i marginalnu poziciju iz koje može progovarati jedino unutar
kategorija propisanih samom svrhom zavoda kao mjesta pripisivanja ili potvrđivanja stigme
ludila. U ovom radu nastojim povijesti bolesti, stručne medicinske tekstove i književne tekstove
podvrgnuti geertzovskom gustom opisu i prikazati poglede tek nastajuće hrvatske psihijatrije na
seksualnost, strah i nasilje. Rad se trudi zahvatiti sve razine manifestacije psihijatrijskog diskursa:
od najširih intelektualnih debata unutar europske i američke psihijatrije, preko postupnog razvoja 29 psihijatrijske misli u kontekstu hrvatske medicine, do bliskih susreta liječnika i štićenika, te
naposljetku, interakcije medicine i društva kroz način na koji je psihijatrija prenosila kategorije
formirane unutar zavoda na društvo u cjelini. Pritom ću pokušati neprestano imati na umu da
govoreći o hrvatskim psihijatrima i štićenicima za koje su se, nekad manje a nekad više uspješno
skrbili, prenosim priču s trostrukih margina u kojoj stručnjaci stasali u polju marginalne grane
medicinske profesije, svakodnevno komuniciraju s marginaliziranim članovima društva koje se
nalazilo na marginama Austro-Ugarskog Carstva. 30 30 25 Foucault, 2002: 10. 27 Ibid. g,
27 Ibid. ,
29 Glesinger, 2012: 20. 3.1. „Moral treatment” i začeci psihijatrije Usprkos smjeloj tvrdnji Michaela Foucaulta o osamnaestom i devetnaestom stoljeću kao vremenu
u kojem dolazi do „Velikog utamničenja” duševno bolesnih25, pomnije proučavanje tog vremena
otkriva stalnu diskurzivnu borbu između raznih intelektualnih disciplina koje su htjele imati
autoritet nad tumačenjem pojava povezanih sa unutarnjim životom čovjeka. U toj borbi, psihijatri
i ravnatelji zavoda u kojima se „zatočivalo” ljude s psihičkim tegobama nisu uvijek imali glavnu
riječ: vjerski autoriteti, pučka medicina, privatne i državne inicijative, te brojne intelektualne
struje unutar medicine, psihologije i filozofske antropologije sebi su pridržavali pravo
objašnjavanja ljudske psihe te nudili različite oblike tretmana onoga što su u različitim epohama
nazivali „ludilom”, „umoboljom” psychozom” ili „psihopatologijom”. Činjenica da je dugo
devetnaesto stoljeće u povijesti psihijatrije na simboličan način prikazano poznatom slikom na
kojoj francuski „otac psihijatrije” Philippea Pinela koji u pariškoj klinici Salpetriere skida okove
sa štićenika zapravo više odražava suženu sliku koju su o tom vremenu imali i povijesničari
institucija poput Gruba i Shortera i socijalni konstruktivisti poput Foucaulta i Goffmana. Devetnaesto stoljeće obiluje raznolikim i konfliktnim odgovorima na problem uzroka ludila. No
ipak, do kraja stoljeća, psihijatrija se, najprije u građanskim krugovima, a potom i šire postepeno
nametala kao jedina disciplina koja može pružiti odgovore na pitanje uzroka duševnih bolesti i
tretmana duševno oboljelih. „Moral Treatment”je pojam koji je skovao Phillipe Pinel i koji bi na hrvatski bilo najumjesnije
prevesti kao „psihološki tretman” budući da riječ „moral” ovdje konotira misli, strasti, emocije,
sentimente i afekte pacijenata, ukratko njihovu psihu26. Pod tim imenom najčešće se
podrazumjeva niz „predmedicinskih”27 terapeutskih metoda liječenja duševnih bolesti poput
terapeutske arhitekture, terapije radom i izolacijom te principa „non-restrainta”, to jest ukidanja
starih mehaničkih načina sputavanja štićenika. Iako je definicija pojma „moral treatment” pomalo 31 nejasna i neodređena, na temelju preskriptivnih opisa psihijatrijskih institucija koji često bili
pisani i objavljivani od kraja osamnaestog do sredine devetnaestog stoljeća možemo odrediti
četiri osnovna trenda „moral treatmenta” kao razdoblja u povijesti psihijatrije: 1. Odustajanje od različitih fizioloških terapija poput klistira, purgativa, abrazivnih terapija i
puštanja krvi, 1. Odustajanje od različitih fizioloških terapija poput klistira, purgativa, abrazivnih terapija i
puštanja krvi, 2. Etiologija duševnih bolesti se temelji na emocionalnim uzrocima. Prema tome i terapije imaju
za svoj cilj discipliniranje pacijentovih emocija nasuprot discipliniranju fizičkog tijela. 2. Etiologija duševnih bolesti se temelji na emocionalnim uzrocima. Prema tome i terapije imaju
za svoj cilj discipliniranje pacijentovih emocija nasuprot discipliniranju fizičkog tijela. 3. 28 Foucault, 2002: 9. ,
29 Glesinger, 2012: 20. 3.1. „Moral treatment” i začeci psihijatrije Svrha institucija za duševno oboljele je primarno terapeutska te se smatra se da arhitektura
institucija ima blagotvorni utjecaj na zdravlje oboljele osobe. 3. Svrha institucija za duševno oboljele je primarno terapeutska te se smatra se da arhitektura
institucija ima blagotvorni utjecaj na zdravlje oboljele osobe. 4. Postoji trend ukidanja dosadašnjih metoda sputavanja duševno oboljelih (tzv. „non-restraint”
princip). Taj trend ne rezultira potpunim prestankom same prakse sputavanja nemirnih bolesnika
već uglavnom uvođenjem „humanijih” mehanizama sputavanja poput „luđačkih košulja” ili
stezulja i soba za izolaciju s mekim zidovima. Te metode su humanije utoliko što je deklarativna
ideja iza njihove implementacije sprečavanje namjernog ili slučajnog samoozljeđivanja, a ne
isključivo ograničenje slobode kretanja štićenika. Razvoj institucionalne brige za duševno oboljele zapravo ne počinje s Pinelom i s praksom
„moral treatmenta”. No, načini na koje je ludilo kao društvena pojava bilo percipirano tretirano
prije nastanka institucionalne psihijatrije bili su temom brojnih debata među povjesničarima
psihijatrije. S jedne strane stoji slabo potkrijepljena teza Michaela Foucaulta o vremenu kad je
život duševno bolesnim bio obilježen lutanjem28. S druge strane, psihijatri devetneatog stoljeća
često ističu primjere ranijeg okrutnog postupanja s duševno oboljelima, te navode da su se
opsjednutost demonima, natprirodno djelovanje vještica i vukodlaka i uroci smatrali uzrokom
ludila.29 Čini se da su se iskustva duševno bolesnih u ranom novom vijeku, uvelike razlikovala
kao što su se razlikovale i paradigme ludila- medicinske metode stajale su uz bok religijskim i
magijskim pogledima na ludilo i terapeutskim riznicama pučke medicine. Stoga „moral 32 treatment” ipak predstavlja prvi pokušaj standardizacije psihijatrijske skrbi u širem europskom
kontekstu. U protopsihijatrijskim metodama koje favoriziraju liječnici prije „moral treatmenta” mogu se još
uvijek naći kontinuiteti humoralne medicine, koja svoje intelektualne korijene vuče iz antike. Humoralna medicina, temelji se na uvjerenju da četiri tjelesne tekućine: krv, sluz te crna i žuta
žuč upravljaju ritmovima razvoja i promjenama koje se odvijaju unutar ljudskog tijela.30
Promjene u ravnoteži između tih tjelesnih sokova također nalaze odraz u karakternim crtama
čovjeka, te mogu izazvati napade ludila. Na primjer, prevelike količine krvi i žute žuči mogu
dovesti do manije, dok prevelike količine crne žuči dovode do melankolije i depresije. 31 Takvo
viđenje duševnih bolesti dovelo je do česte primjene terapija baziranih na izlučivanju određenih
tjelesnih tekućina poput puštanja krvi, sredstava za čišćenje poput klistira i emetika u tretiranju
duševnih bolesti. 30 Porter, 2002:37. ,
31 Ibid:41. 32 Pinel, 1806:99. ,
31 Ibid:41. 3.1. „Moral treatment” i začeci psihijatrije Sa pojavom „moral treatmenta” na kraju osamnaestog i početku devetnaestog
stoljeća, ta se sredstva se rijeđe upotrebljavaju u zavodima- zamijenjuju ih režimi prehrane,
psihološke metode liječenja poput liječenja strahom i hidroterapija koja sve više dobija na
popularnosti kako se ugled kupališne medicine širi međi višim slojevima. Metode liječenja koje
Philippe Pinel ističe u svom slavnom psihijatrijskom udžbeniku Traité médico-philosophique sur
l'aliénation mentale; ou la manie (Medicinsko-filozofski traktat o duševnom otuđenju ili maniji)
ponajviše proizlaze iz karaktera same institucije u kojoj se liječenje odvija. Pinel je preuzeo
zavod u Bicetreu pokraj Pariza 1795. godine, nakon iskustva rada u brojnim privatnim
liječilištima u Francuskoj. Potaknut humanističkim načelima prosvjetiteljstva i užasnut kaosom
Francuske revolucije i terorom i nasiljem koji su uslijedili nakon nje, Pinel se trudio istaknuti
važnost nadzora i reda u instituciji za liječenje duševnih oboljenja. Pinel tako kaže da su
najvažnije karakteristike ravnatelja „velika pronicljivost, neumorna predanost, trajna i neumorna
pozornost koja se pridaje svakom pojedinačnom slučaju”.32 Sam unutarnji ustroj institucije i
uloga ravnatelja kao figure autoriteta koja nadzire svaki aspekt života u instituciji i uspostavlja
nepobitan gotovo očinski autoritet nad pacijentima i pomoćnim osobljem bivaju istaknuti kao 33 ključni u Pinelovom udžbeniku dok se bogatstvo ranonovovjekovne farmakopeje i kirurških
metoda ne spominju. U isto vrijeme kao Pinel, liječnici poput britanskog kvekera Williama Tukea
i firentinskog upravitelja bolnice Svetog Bonifacija Vincenza Chiarugija počinju posvećivati sve
više pažnje ustroju same institucije i autoritetu liječnika, napuštajući dotadašnje neučinkovite
metode liječenja zasnovane na humoralnoj medicini. Primjena novih terapeutskih metoda neodvojiva je od promjene paradigme vezane uz etiologiju
duševnih bolesti. Krajem osamnaestog i devetnaestog stoljeća vode se brojne rasprave o tome je
li duševna bolest posljedica patoloških promjena na mozgu ili se radi o primarno afektivnom
poremećaju čiji su uzroci psihološke prirode. U pozadini tih prijepora, nalaze se zapravo
filozofsko-antropološka rasprave o samom ustroju čovjekova uma i njegove ličnosti, koje svoje
korijene vuku iz filozofije klasičnog njemačkog idealizma i njezinog suprotstavljanja
mehanicizmu prosvjetiteljstva. Naime sredinom devetnaestog stoljeća, dolazi do sukoba oko
definiranje odnosa tijela i uma između „somaticističke škole” kojoj su pribadali brojni liječnici i
platonističke škole koju su uglavnom predstavljali filozofski antropolozi. Somaticisti,
inspirarirani Descartesom su smatrali da um i tijelo jasno odvojeni pojmovi, pri čemu um sam ne
može oboljeti. Samim time, duševne bolesti moraju biti samo simptomi tjelesnih oboljenja koja
sprečavaju da um obavlja svoje više funkcije. 33 Verwey, 1985: 21. 33 Verwey, 1985: 21. 3.1. „Moral treatment” i začeci psihijatrije Druga škola, inspirirana platonističkim
koncepcijama, prema kojima je duša predstavlja istinskog čovjeka dok je tijelo samo njezina
sjena.33 Samim time, duševne bolesti su uistinu bolesti duše, koje nastaju zbog grešnog života ili
jake emotivne patnje. Većina pobornika „moral treatmenta” među europskim psihijatrima
odabrala je upravo afekt kao uzrok psihičkih poremećaja i time se svrstala uz „platonističku”,
monističku struju. O tome detaljno govori Pinelovo čitanje povijesti bolesti pacijenata bolnice
Bicetreu i njegovo objašnjenje uzroka ludila. Pinel uzrok ludila vidi u velikim duševnim potresima: na primjer, jedan od Pinelovih pacijenata
je svećenik za kojeg Pinel navodi da je poludio zbog progona katolicizma nakon Francuske 34 Revolucije.34 Slične poglede na uzrok duševnih bolesti imaju i ostali pobornici „moral
treatmenta” u ranom devetnaestom stoljeću- talijanski liječnik i reformator skrbi za duševno
oboljele, Vincenzio Chiarugi, smatrao je da za ispravan tretman duševnih bolesti nužno objediniti
neurološku perspektivu sa dušom, duhom i umom jer se ljudski život, za Chiarugija sastoji u
reciprocitetu između spiritualnog i materijalnog35. Kod najizrazitijeg britanskog predstavnika rane
zavodske psihijatrije Williama Tukea također se naglašava simpatička i recipročna veza između
tijela i uma, te se napuštaju agresivni fiziološki tretmani poput puštanja krvi.36 Umjesto njih, Tuke
u svojoj instituciji „The Retreat” u Yorku, kombinira blagotvoran utjecaj rustikalne arhitekture,
rutiniranog života, ispravne prehrane, rada i tjelovježbe.37 Općenito gledano pri etiologiji
duševnih poremećaja i praktičnom pristupu liječenju istih na psihu i tijelo se gledalo kao jednu
neodvojivu cijelinu. Samim time, psihijatrija se etablira kao distinktivna intelektualna disciplina
koja se uzima „ludilo” za svoje područje proučavanja, dok ju teoretska pretpostavka
međuovisnosti psihe i tijela spojena s primarno terapeutskim ciljem konačno približavaju
medicini i udaljuju od alternativnih filozofsko antropoloških izvorišta, kojima će se ponovno
vratiti tek početkom dvadesetog stoljeća u okviru psihoanalize. Treće bitno obilježje „moral treatmenta” vezuje psihijatriju za terapeutsku ustanovu zavoda. Psihijatrijski zavod, na engleskom govornom području često nazvan „asylum” će se tek kasnije
preobraziti u psihijatrijsku bolnicu ili psihijatrijsku kliniku. To ispreplitanje psihijatrijske prakse i
institucijskog konteksta najvidljivije je u terapeutskoj arhitekturi i velikoj pažnji posvećenoj
unutarnjem institucionalnom ustroju zavoda. 34 Pinel, 1806: 61. 37 Ibid: 2-3. 36 Kibria i Metcalfe, 2014: 3. 38 Yanni, 2007: 29-30. 35 Gerrard, 1977, 383. 37 Ibid: 2-3. 34 Pinel, 1806: 61.
3 G
d 19
383 3.1. „Moral treatment” i začeci psihijatrije Neki od ključnih elemenata terapeutske arhitekture -
izolacija od društva, dnevna rutina i uklanjanje mehaničkih sredstava sputavanja vuku porijeklo
iz malih privatnih klinika u kojima su se, prije uspostave prvih velikih zavoda, liječili imućniji
pripadnici plemstva i građanstva.38 Te privatne klinike, usko su se vezivale uz kupališnu kulturu
ranog devetnaestog stoljeća iuz blagotvorno djelovanje izolacije, nudile su obilje fizioloških
lijekova za probleme „napetih živaca” i „poremećene ravnoteže tjelesnih sokova”. Omasovljenje 35 institucionalizacije osoba s duševnim poteškoćama stvara potrebu za inovativnim arhitektonskim
rješenjima koja će objediniti potrebu za efikasnim nadzorom, disciplinu i blagotvorno djelovanje
krajolika. Prvo takvo rješenje je takozvani linearni ili Kirkbrideov plan (nazvan tako po
američkom reformatoru brige za mentalno zdravlje i ravnatelju psihijatrijske institucije u
Pennsylvaniji). Linearni plan zamišlja psihijatrijsku instituciju kao zgradu u obliku širokog slova
U ili W sa odvojenim krilima za mirne i nemirne štićenike, prostranim hodnicima i sobama
smještenim s jedne strane kako bi se olakšao nadzor. 39 Osim soba za štićenike, večina planova
predviđa i stanove u kojima, u sklopu zavoda žive ravnatelj, glavni liječnik i ostali bitni
zaposlenici. Time se osigurava kontinuiran nadzor ravnatelja i njemu podređenog osoblja nad
čitavim zavodom, a i riješava se problem koji bi predstavljalo putovanje liječnika iz grada u često
izolirani zavod. Najviše psihijatrijskih institucija izgrađenih u devetnaestom stoljeću, izgrađeno
je po Kirkbridgeovom planu . U drugoj polovici devetanestog stoljeća, razvijen je i alternativni paviljonski plan kojeg su
prvenstveno osmislili američki liječnici inspirirani primjerom belgijskog grada Ghaela u kojem je
svećenstvo vodilo skrb za duševno oboljele još od 13. stoljeća.40 Separatni, paviljonski ili
„cottage” plan se zasniva na organizaciji prostora institucije oko niza odvojenih paviljona u
kojima bi štićenici imali relativni mir i slobodu kretanja, a koji bi bili razmješteni oko središnje
zgrade u kojoj se nalaze stanovi ravnatelja i liječnika. Taj je model do neke mjere korišten i u
Stenjevcu, ali se javio u vrijeme kad je paradigma „terapeutske arhitekture” već polako bivala
napuštana u ozračju terapeutskog pesimizma fin de sieclea. Model terapeutske arhitekture je nerazdvojno vezan uz uvjerenje da fizička izolacija i smještaj u
pastoralnom okruženju blagotvorno djeluju na duševno zdravlje. Opis idealne lokacije za smještaj
zavoda dao je otac francuske forenzičke medicine François-Emmanuel Fodéré u svom
šestotomnom djelu Traité de médecine légale et d'hygiène publique ou de police de santé iz 1813. godine:„Htio bih da se takvi domovi grade u svetim šumama, na nepristupačnim i izoliranim
mjestima. 39 Ibid: 39-40. 40 Ibid : 84. 41 Foucault, 2006: 2. 40 Ibid : 84. 39 Ibid: 39-40. 45 Kibria i Metcalfe, 2014: 4. 44 Ibid. 43 Showalter, 1985: 35. 42 Pinel, 1806: 59-60. 44 Ibid. ,
46 Pinel, 1806: 68. 46 Pinel, 1806: 68. 3.1. „Moral treatment” i začeci psihijatrije U svetim gajevima usred velike divljine...”41 Važnost izolacije i pastoralnog karaktera
mjesta na kojem bi se zavodi trebali graditi je ovdje pojačana i sakralizirana opetovanim 36 dodavanjem pridjeva „sveti”. Imena zavoda poput Tukeovog „Retreata” (utočočište, odmorište,
mjesto na koje se osoba povlači) su također ostavljala dojam zavoda kao izdvojenog prostora,
heterotopije isključivo posvećene liječenju, na koju ne bi trebao djelovati širi društveni kontekst. Istovremeno, opetovano se ističe kako je liječenje nemoguće izvan tog izdvojenog svijeta te da je
za oporavak nužna dobro regulirana instuticija zatvorenog zavodskog tipa, čiji ravnatelj može
uspostaviti potpunu kontrolu nad režimom štićenikovog oporavka.42 Ovaj režim autoritarne kontrole ravnatelja nad cjelokupnim životom unutar institucije, drugi je
bitan element „moral treatmenta”. Ustroj psihijatrijatrijske institucije takav je da daje apsolutni
„očinski” autoritet upravitelju ludnice. Arhitektonski planovi poput Kirkbrideovog su pružali
mogućnost da se stari sustav „mehaničkog sputavanja” često kritiziran kao okrutan ili primitivan
zamijeni struktuiranim sustavom nadzora štićenikovog okoliša.43 Pored toga, bilo je bitno da
psihijatrijske institucije odaju dojam „domaćinstva” a ne institucije posvećene nadzoru, tako da
su rešetke na prozorima i pojačana vrata zamijenjeni inovacijama poput dvostrukih staklenih
okana i običnim vratima koja su se mogla otvarati samo s vanjske strane.44 Arhitektura je, samim
time zapravo služila kao panoptikonski instrument disciplinarne moći koja je, zaodjevena u
diskurs „moralnog autoriteta” liječnika koji blagim, ali nepokolebljivim značajem vraća razum
štićenicima, zapravo učinjena terapeutskom osnovom „moral treatmenta”. S liječničkim autoretitom i principom humanog postupanja povezano je i napuštanje mehaničkih
instrumenata sputavanja poput metalnih okova i lanaca u zavodima koji su uveli moral treatment
kao terapeutski princip. William Tuke je tako naglašavao da se mehanički načini kontrole trebaju
izbjegavati kad god je to mogući i zamijenjivati kombinacijom blagog postupanja i izazivanja
straha od autoriteta kod štićenika.45 Pinel u svom traktatu ističe da se za smirivanje nemirnih
štićenika trebaju koristiti jedino „stezulje, fizička nadmoć i izolacija na ograničeno vrijeme” dok
bolničarima ne smije nipošto biti dopušteno da udaraju štićenike.46 Za Pinela je, kao i za Tukea,
najbitnije bilo održavanje i upravljanje strahom kod njegovih štićenika, koji za njega mora biti 37 povezan s osjećajem poštovanja kako bi bio potpuno učinkovit.47 Može se zapravo reći da „moral
treatment” kao psihološki i emotivni tretman predstavlja obrat s kontrole tijela putem mehaničkih
sprava za vezanje prema kontroli emocija. Međutim, kontrola emocija nije mogla biti odvojena
od nametanja režima „terapeutske arhitekture” i nadzornikovog suverenog vladanja izdvojenim
prostorom institucije na sama tijela štićenika. 48 Shorter, 1996: 56-57. ,
49 Ibid: 50. 47 Ibid: 67. 49 Ibid: 50. ,
49 Ibid: 50. 47 Ibid: 67.
48 Shorter, 1996: 56-57. 3.1. „Moral treatment” i začeci psihijatrije Čini se da se radi o foucaultovskom principu
zaodjevanja direktne sile u diskurs autoriteta koji rezultira kapilarnim širenjem ultimativne
disciplinarne moći kroz cjelokupnu instituciju. Kraj dominacije „moral treatmenta” kao paradigme u tretmanu duševnih oboljenja povezan je s
činjenicom da je utopiju izoliranih, pastoralnih utočišta za oboljele bilo nemoguće provesti u
društvu koje je zahtijevalo sve veći opseg institucionalizacije društveno devijantnih osoba. Jedan
od uzroka tog fenomena je velika epidemija progresivne paralize ili kasnog cerebralnog stadija
sifilisa koji je postajao sve rašireniji među muškarcima srednje klase, a kako su modernizacijski
procesi uzimali maha širio se i na radničke i zemljoradničke slojeve.48 Drugi dominantni uzrok
bila je sve veća promjena koncepta obitelji, kao primarno afektivne intimne zajednice.49
Formiranje takve zajednice zahtijevalo je novi, specifični emotivni režim koji je imao manje
tolerancije za devijacije duševno bolesnih. Taj je režim rezultirao izolacijom svih onih koji su
prezentirali oblike ponašanja koji u njemu nisu imali mjesto ili us bili smatrani odviše
disruptivnima za takvu, građansku sliku obitelji. Treći uzrok bio je donekle iatrogenetski. Naime,
osnivanje sve većeg broja zavoda koji su izolirali osobe s psihičkim poteškoćama, potiče državu i
lokalne zajednice da koriste te zavode za uklanjanja sve većeg broja devijantnih pojedinaca iz
društva. Osobe sklone konfliktima, agresivne osobe, pojedinci skloni skitnji, epileptičari, osobe s
poteškoćama u razvoju, ljudi mentalno onemoćali zbog starosti i alkoholičari postaju predmetom
psihijatrijske skrbi i bivaju sve češće upućivani u psihijatrijske institucije, često unatoč otporu
samih ravnatelja tih institucija. Prenapučenost i povećanje broja neizlječivih štićenika dovest će
do svojevrsnog terapeutskog pesimizma koji će, već pred kraj devetnaestog stoljeća rezultirati
ponovnom okretanju somaticističkoj psihijatriji, naročito u kontekstu njemačke i austro-ugarske
sveučilišne i zavodske psihijatrije. Pridržavanje određenih temeljnih principa moral treatmenta 38 poput ideje o apsolutnoj nužnosti institucije i nepobitnog autoriteta njenog ravnatelja će se
usprkos tome, zadržati u psihijatriji sve do pokreta za reformu psihijatrije koji se počinje polako
pojavljivati od šezdesetih godina dvadesetog stoljeća. poput ideje o apsolutnoj nužnosti institucije i nepobitnog autoriteta njenog ravnatelja će se
usprkos tome, zadržati u psihijatriji sve do pokreta za reformu psihijatrije koji se počinje polako
pojavljivati od šezdesetih godina dvadesetog stoljeća. 39 39 ,
52 Scull, 2014: 54-54.
Č 52 Scull, 2014: 54-54.
53 Izraz „hram Čovječnosti” stoji na ploči koja je postavljena na ulazu u današnju Kliniku za Psihijatriju Vrapče.
Njegov je autor navodno ban Ivan Mažuranić. 51 Showalter, 1985: 101. 50 https://historicengland.org.uk/research/inclusive-heritage/disability-history/1832-1914/daily-life-in-the-asylum/.
51 Showalter, 1985: 101. 53 Izraz „hram Čovječnosti” stoji na ploči koja je postavljena na ulazu u današnju Kliniku za Psi
Njegov je autor navodno ban Ivan Mažuranić. ,
52 Scull, 2014: 54-54. 1 Showalter, 1985: 101.
2 Scull, 2014: 54-54.
3 Izraz hram Čovječnosti” stoji na ploči koja je postavljena na ulazu u današnju Kliniku za Psihija 51 Showalter, 1985: 101.
52 Scull, 2014: 54-54.
Č ,
55 Scull, 2014: 55. 54 Matoš, 1990: 215. 3.2.Terapeutski pesimizam i degeneracija Sredinu devetnaestog stoljeća obilježava nagli uspon psihijatrijskog zavoda kao institucije u
Europi i Sjedinjenim Američkim Državama. Broj psihijatrijskih institucija je u stalnom porastu, i
dok su u Sjedinjenim Državama i Engleskoj one uglavnom vezane uz privatnu inicijativu, ili
inicijativu lokalnih vlasti, u Francuskoj, Rusiji i Srednjoj Europi inicijative za njihovim
osnivanjem je uglavnom državna. Kao što je spomenuto u prethodnom poglavlju, legitimacija
institucije kao terapeutskog sredstva, u nekim je slučajeva imala iatrogenički efekt na samu
praksu- sve veći broj ljudi koji nisu nalazili svoje mjesto u modernizirajućim društvima
devetnaestog stoljeća bivalo predano na skrb u psihijatrijske institucije i broj štićenika je rastao iz
godine u godinu. Istovremeno, financijsko stanje institucija i njihova infrastruktura nisu mogle
pratiti taj brzi rast i zavodi diljem Europe su se sve češće odavali sliku zapuštenosti,
prenapučenosti i užasnih higijenskih uvjeta, te su bili u izrazito lošem stanju. Otvaranje Conley
Hatcha, velikog zavoda za siromašne štićenike u engleskom Middlesexu pratila je atmosfera
viktorijanskog progresa i optimizma- zavod je 1851 u godine velike izložbe otvorio Princ Albert,
kraljevski suprug kraljice Victorije50. Već šest godina kasnije, grandiozno historicističko zdanje se
raspadalo: cijeli dijelovi zida i stropa su se urušavali, broj štićenika je neprekidno rastao a država
nije mogla osiguravati sredstva za njegovo održavanje51. Broj „recidivista”- štićenika koji su se
nakon navodnog izlječenja vraćali u nabujali sustav psihijatrijske skrbi je istovremeno sve više
rastao, što je narušilo kredibilitet početnih tvrdnji psihijatrijskih upravitelja koji su se hvalili
velikim brojem uspješno izliječenih štićenika. U isto vrijeme, sami zavodi su došli na loš glas kao
„muzeji ludila”. Poznati pisac Charles Dickens, obišao je britanske zavode za psihijatrijsko
oboljele i svojim uobičajeno slikovitim stilom pisao o letargičnoj i beznadnoj atmosferi kojom su
odisali tadašnji zavodi.52 Na sličan se način mijenja i percepcija stenjevačkog zavoda. Iako je
zavod na početku hvaljen kao „hram čovječnosti”53 Matoš ga 1910 u jednom putopisu iz zbirke
Naši ljudi i krajevi ocrtava u slikama koje referiraju na najstrašnije prizore iz klasične
književnosti: 50 https://historicengland.org.uk/research/inclusive-heritage/disability-history/1832-1914/daily-life-in-the-asylum/. 51 Showalter, 1985: 101. 52 S
ll 2014 54 54 52 Scull, 2014: 54-54. 53 Izraz „hram Čovječnosti” stoji na ploči koja je postavljena na ulazu u današnju Kliniku za Psihijatriju Vrapče. Njegov je autor navodno ban Ivan Mažuranić. 40 „Tamne, užasne spirale Danteova pakla tri koraka od Zagreba! 3.2.Terapeutski pesimizam i degeneracija U nasmijanom zatišju Zagrebačke
gore, pri blagoj idili ubave savske ravnice, na podnožju vinorodnih brežuljaka i župnih sela-
mračno poglavlje iz najmračnijeg Dostojevskoga, zelene mrtve oči iz zakutka Poeove vinske
fantazije, oči mutne i nijeme iz haotičnih raskrša gdje se križa sedam putova razuma, gdje duva
zagonetni vjetar iz čudnog, iz onoga svijeta, nagomilavajući u žutoj kući, u ludnici, svoje jesenje
lišće mrtvih, usahnulih, obezdušenih života”54 Znakovito je da Matoš mračne i potresne slike stenjevačkog zavoda stavlja u kontrast s
pastoralnom pitomošću okolnog krajolika. Krajolik i okoliš gube svoju terapeutsku ulogu i
prisutni su tek kako bi stilski naglasili patnju i pesimizam koja vlada unutar skučenog i
beznadnog prostora „žute kuće”. Osim široke kampanje pisaca i novinara i sami pacijenti su počeli opisivati svoja stravična
iskustva u psihijatrijskim institucijama. Žanr protestne literature pacijenata koji su pisale ugledne
autorice i aktivistkinje poput Elizabeth Packard u Sjedinjenim Američkim Državama i Louise
Lowe u Ujedinjenom Kraljevstvu govorio je o lakoći s kojom su liječnici i predstavnici lokalne
vlasti upućivali pacijenta, (a pogotovo pacijentice) u psihijatrijske institucije.55 Porast pesimizma
je u Europi koincidirao s rastućom popularnosti Darwinove teorije evolucije i prirodne selekcije u
znanstvenim i medicinskim krugovima. Charles Darwin je svoju knjigu Porijeklo vrsta objavio
1859. godine. Budući da su i ranije psihijatri poput Pinela, Esquirola i Morela isticali važnost
herediteta kao jednog od faktora koji mogu pridonijeti duševnoj bolesti, ideje o prirodnoj
selekciji brzo su se u europskoj psihijatriji aktualizirale u vidu zabrinutosti zbog hereditarnog
tereta psihičke nestabilnosti, histerije i napetih živaca koji pritišće cijele generacije Europljana. Ubrzo su se kroz psihijatrijsku literaturu počele širiti turobne i pesimistične teorije o degeneraciji
koje su gotovo preko noći zamijenile pastoralno-prosvjetiteljski optimizam ranih pobornika. Začetnik teorija o degeneraciji bio je francuski psihijatar Benedict Morel, veliki dijagnostički
inovator koji je, između ostalih i prije Kräpelina prepoznao konceptualizirao „dementiu praecox”
kao zasebni poremećaj. Morel je bio ravnatelj zavoda za duševno oboljele u komuni Saint Yon na 41 sjeveru Francuske. Kao intelektualac, Morel je stasao u za francusko društvo turbulentnim
tridesetim i četrdesetim godinama devetnaestog stoljeća i pokazivao je velik interes za društvene
probleme poput siromaštva, kriminala i alkoholizma, kao i za religijsku antropologiju. 57 Morel, 1860: II. 56 Morel, 1857: 6. 58 Ibid: III-IV. 56 Morel, 1857: 6.
57 Morel, 1860: II.
58 Ibid: III-IV. 3.2.Terapeutski pesimizam i degeneracija U svom
djelu Traité des dégénérescences physiques, intellectuelles et morales (Traktat o fizičkoj,
intelektualnoj i moralnoj degeneraciji) objavljenom u Parizu 1857.godine Morel je prikazao
dvanaest portreta svojih pacijenata i pacijentica na kojima su navodno uočljivi dokazi trajne i
nepromjenjive fizičke, mentalne i moralne degeneracije.56 U svojoj sljedećoj knjizi iz 1860. godine Traité des maladies mentales (Traktat o mentalnoj bolesti) Morel je jasnije elaborirao
samu degeneraciju kao proces „patološke devijacije od idealnog tipa ljudskog bića kakvo je
stvorio Bog, proces koji je počeo s Adamom i Evom. Dok je dio čovječanstva bio zdrav i
prilagodljiv, dio je bio sve više nesposoban za društvenu djelotnast i prenosio je te svoje
karakteristike na potomstvo”.57 Degeneracija se, po Morelu manifestirala kao duševna bolest i
kao prisustvo vidljivih tjelesnih „stigmi” poput urođenih deformacija i „nepravilnog” oblika
lubanje. Na stvaranje navedenih hereditarnih osobina utjecale su uglavnom životne navike poput
nemorala i alkoholizma, kao i određene tjelesne bolesti, a proces se pogoršavao iz generacije u
generaciju te ga je bilo moguće usporiti ili zaustaviti jedino eugeničkim mjerama.58 Morel je u
nastavku studije dao novu klasifikaciju duševnih bolesti koja je bila uže vezana uz njihovu
etiologiju (za Pinela i ranije psihijatre od etiologije je bila bitnija kvaliteta simptoma, što je
vidljivo i u nazivima kategorija poput „manije”, „melankolije”, „monomanije” i „manije bez
delirija”). Morel duševne bolesti dijeli na: 1. „Ludila radi intoksikacije” („Folies par intoxication”) kao mentalne bolesti u kojima su fizičke,
intelektualne i moralne funkcije pojedinca trajno narušene često konzumacijom alkohola ili
drugog opojnog sredstva. 2. „Histerična, hipohondrična i epileptička ludila” koja imaju uzrok u nervnoj konstituciji
pojedinca. 2. „Histerična, hipohondrična i epileptička ludila” koja imaju uzrok u nervnoj konstituciji
pojedinca. 3. „Bolesti bez vidljivog uzroka” 42 Za Morela ipak hereditet leži u korijenu svih duševnih bolesti bez obzira na to što se smatralo
njihovim direktnim povodom.59 U nastavku knjige Morel će, za razliku od ranijih autora koji su
većinu prostora posvećivali liječenju najveći dio knjige posvetiti spekulaciji o različitim uzrocima
ludila- od obrazovanja i načina života, bolesti mozga i krvožilnog sustava, menstruacije, trudnoće
i dojenja do religijskih i političkih uzroka, ali će se pri opisivanju svakog od njih ponovno vraćati
na hereditarne dispozicije i isticati važnost eugeničkih mjera. 60 Showalter, 1985: 113. 62 Maudsley, 1870: 116. 59 Ibid V-VI. 59 Ibid V-VI. y
64 Maudsley, 1870: 55-56. y
63 Maudsley, 1874: 276. 61 Ibid: 103. 61 Ibid: 103. 3.2.Terapeutski pesimizam i degeneracija Eugenika i hereditet su naročito veliku podršku dobili među britanskim psihijatrima, među
kojima je prednjačio ambiciozni Henry Maudsley, urednik časopisa Journal for Medical Science i
jedan od prvih psihijatara koji je uspio steći značajan imetak od svog psihijatrijskog poziva.60
Maudsley je, prije svega bio izrazito plodan i dobar pisac koji je pisao o psihijatrijskim tegobama
stilom pristupačnim velikom dijelu građanske klase. Postavka koja je u korijenu njegovog
pogleda na psihu čovjeka je hijerarhijski ustroj mentalnih, intelektualnih i emocionalnih
karakteristika od instinkta divljaka do rafinirane perceptivnosti civiliziranih elita.61Prema
Maudsleyu, postoji jasna linija napretka „od senzacije, preko strasti, emocije i razuma do najviše
faze, dobro oblikovane volje”.62 Za psihijatre koji su, poput Maudsleya prigrlili darvinističke
principe, ludilo je atavizam ili regresija na niže stupnje inelektualnog ili duševnog razvoja i zato
ju Maudsley, poput Morela često dovodi u vezu s određenim tjelesnim karakteristikama ili
osobinama ličnosti. U drugom izdanju svoje knjige „Responsibility in Mental disease” koje je
objavljeno 1870. godine Maudsley ističe: „Ne bi bilo pretjerano reći da malobrojni polude bez da
pokažu, više ili manje očito po svom hodu, manirama, gestama, načinima mišljenja osjećanja ili
ponašanja da imaju neku vrst predispozicija prema ludilu”.63 U ranijoj knjizi Body and Mind
Maudsley preciznije opisuje znakove koji upućuju na predispoziciju za duševne bolesti
„nepravilan i asimetričan oblik glave, nedostatak harmonije i pravilnosti u tjelesnim obilježjima,
deformacija ušnih školjki, tikovi, govorne mane, neobičnosti u očima ili sklonost igrama
riječima”.64 43 Uvođenje evolucionističke hijerarhije mentalnih osobina i sve veće pretvaranje mentalnog
zdravlja u pitanje javne rasprave (čemu su široko citirani pisci poput Maudsleya uvelike
doprinijeli) dovelo je do prodora dva nova i povezana pojma u diskursu o psihijatriji. Prvi od tih
pojmova je pojam, „borderlandsa” a drugi je degeneracija. Degeneracija u smislu u kojem ju je
shvaćao i opisao Morel postat će jedan od dominantnih strahova europske i američke srednje
klase. On će biti ponovno aktualiziran u eugeničkom pokretu i u jednoj značajnoj mjeri
biologiziranoj slici društva u autoritarnim fašističkim režimima prve polovice dvadesetog
stoljeća. Za razliku od pogleda na duševnu bolest kao na prolazno stanje uzrokovano afektima, psihijatri
darvinističke psihijatrije vidjeli su psihičke poremećaje kao na neku vrstu urođenog hereditarnog
tereta kojem je podvrgnut velik broj ljudi. Prostor duševne slabosti, histeričnog karaktera i
ekscentričnosti počeo se smatrati graničnim prostorom između mentalnog zdravlja,
predstavljenog Muadsleyevim, tipično viktorijanskim poimanjem čvrste i dobro formirane volje i
ludila. 3.2.Terapeutski pesimizam i degeneracija Pojam „borderlandsa” u psihijatriju je uveo britanski liječnik Andew Wynter koji je u
svom domu u Chadwicku primao imućne pacijente i liječio ih od duševnih bolesti. Kao načitan
provincijski intelektualac redovno je pisao priloge za mnoge časopise i bavio se širokim
rasponom tema, a za života je postao poznat po tome što je često uspoređivao ljudsko društvo s
društvom pčela. Wynterova knjiga The Borderlands of Insanity and other Allied Papers
objavljena je 1875. godine i izvršila je velik utjecaj na psihijatriju, pa i na kulturu fin de sieclea. Prvi esej u Wynterovoj knjizi „The Borderlands of Insanity” govori o duševnoj bolesti kao o
pojavi koja je u većem dijelu populacije latentna. Na takvu percepciju duševne bolesti utjecala je
već ranije spomenuta epidemija progresivne paralize, odnesno neurosifilisa. Karakter progresivne
paralize kao oboljenja koje se manifestira iznenada, pogađa uglavnom muškarce građanske klase
starije od 35 godina i ima za posljedicu naglo i progresivno propadanje psihičkih i tjelesnih
funkcija, bio je velik šok i neobjašnjiva zagonetka za liječnike kasnog devetnaestog stoljeća koji
su se i sami najčešće nalazili u navedenoj društvenoj skupini. Wynter navodi primjere pacijenata
kod kojih su simptomi bolesti dugo bili neprimjetni da bi se onda pojavili sasvim iznenada u
trenucima kad je pacijent bio na vrhuncu života. Dapače, Wynter ističe da je duševno propadanje 44 već počelo u trenutku kad se pacijent još kreće u društvu i brine o svojim poslovima i nitko osim
liječnika ne primjećuje da je „propao kroz rupu na mostu i da se nikad više neće kretati u
zaposlenim prebivalištima ljudi”.65 Wynter je manje jasan kad govori o uzrocima progresivne
paralize. Tako će progresivnu paralizu dovesti u vezu s „omekšanjem mozga” (vjerojatno bolest
koju će mnogi drugi autori nazivati neurastenijom), navodeći užurban i napet tempo života koji
od „mladića zahtijeva da za zvanje službenika prođe ispit rigorozniji od onog koji se nekad
zahtijevao za sveučilišno zvanje”, 66ozlijede glave u djetinjstvu, poremećaje krvotoka i
neizostavni hereditet kao moguće uzroke. „Latentna iscrpljenost mozga” za Wyntera postaje
problem epidemijskih proporcija, pa tako Wynter govori o „generaciji koja je sistematski
prenapregnula svoje mozgove.”67 U skladu s već formiranim pretpostavkama darvinističke
psihijatrije, hereditet je presudan faktor u slabljenju mentalne snage generacije. Djeca duševno
bolesnih često prelaze u granično područje ludila iako sama nemaju nikakvu uočljivu duševnu
bolest. 68 Ibid: 42. 67 Ibid: 36. 65 Wynter, 1877: 25 (kao izvor koristim drugo, nadopunjeno izdanje Wynterove knjige kojoj je doprinio Joseph
Mortimer Granville.
66 Ibid: 6. 66 Ibid: 6. 69 Ibid: 215. 69 Ibid: 215. 70 Woolf, Virginia prema Blom, 2008: 341. 46 3.2.Terapeutski pesimizam i degeneracija Kod njih se uglavnom mogu uočiti „stigme” o kojima su još ranije govorili Morel i
Maudsley: „neuralgije, epilepsije ili koreje” ili pak u moralnom pogledu „ekstremna sklonost
strastima, sklonost okrutnostima, krađa, laganje i ostali poroci u kojima je volja nadvladana
impulsom. ”68 Matoš je prilikom svog posjeta Stenjevcu također koristio odrazio mišljenje o postojanju
graničnog prostora između duševnog zdravlja i duševne bolesti: „Pritajena ludost, abnormalnost, sakrivena pod nervozama i neuropatijama svakog modernog
čovjeka, budi se kod tog kontakta kolektivne ludosti: srodnost s tim nesretnicima biva sve
očiglednija i imperativnija i strah, neopisiv strah vas uhvati da tkogod ludu, prikrivenog luđaka u
vama ne primjeti...”69 Matoš, kao i Wynter i Maudsley vidi ludilo skriveno ispred naoko banalnih duševnih procesa
karakterističnih za njegove suvremenike. I sam susret s duševno oboljelima dovoljan je da
„izvuče” iz čovjeka latentno ludilo. 65 Wynter, 1877: 25 (kao izvor koristim drugo, nadopunjeno izdanje Wynterove knjige kojoj je doprinio Joseph
Mortimer Granville. 66 Ibid: 6 45 Ideja povezana s predodžbom da se čitave generacije mogu nalaziti na samoj granici ludila je sve
češća percepcija čitavog društva kao bolesnog organizma opterećenog teretom užurbanog života
čija volja postupno slabi i koji postepeno degenerira. U takvim idejama ne moguće je ne vidjeti
rastuću zbunjenost i anksioznost koju su muškarci viših slojeva osjećali pri susretu sa svijetom
koji se mijenja i unutar kojeg su se pastoralne i ladanjske utopije toliko česte u književnosti i
slikarstvu ranog predviktorijanskog i viktorijanskog doba sve više pokazivale kao nezreli
eskapizam elita koja su odbijale prihvatiti stvarnost sve ubrzanijih modernizacijskih procesa. Povezanost diskursa o degeneraciji s moralističkim i konzervativnim viđenjem čovjeka bilo je
prisutno još i u Morelovoj apokalitpičnoj viziji konstantnog pada iz blagodati Rajskog vrta u
današnji svijet u kojem su ludilo, siromaštvo i kriminal sve rašireniji.Uistinu, kako je stoljeće
odmicalo, sve se veći dio modernih pojava, poput emancipacije žena i novih modernističkih
smjerova u kulturi opisivao upravo diskursom degeneracije, a takav narativ služio je kao
alternativa onim narativima koji su u problemima vidjeli primarno društvene uzroke. No,
činjenice nisu bile tako jednostrane. Eugenički pokret je supostojao s brojnim socijalno
angažiranim pokretima upravo jer je darvinistički diskurs dao snažan znanstveni legitimitet teoriji
o hereditarnim uzrocima društvenih problema. Bilo je pretjerano očekivati da onodobni europski
intelektualci prihvate bilo koji svjetonazor koji nije pristupao emocijama i duševnim procesima
strogo hijerarhijski, stavivši čvrstu volju kao (auto)percipiranu karakteristiku obrazovanog
bijelog muškarca na sam vrh piramide mentalne evolucije. 3.2.Terapeutski pesimizam i degeneracija Degeneracija postaje jedan od
najbitnijih dijelova slagalice koje čine sliku intelektualnog horizonta građanske klase na prijelazu
stoljeća. Virginia Woolf u svojim dnevnicima iz 1915 daje sljedeći opis londonskih invalida ili
siromaha: Ideja povezana s predodžbom da se čitave generacije mogu nalaziti na samoj granici ludila je sve
češća percepcija čitavog društva kao bolesnog organizma opterećenog teretom užurbanog života
čija volja postupno slabi i koji postepeno degenerira. U takvim idejama ne moguće je ne vidjeti
rastuću zbunjenost i anksioznost koju su muškarci viših slojeva osjećali pri susretu sa svijetom
koji se mijenja i unutar kojeg su se pastoralne i ladanjske utopije toliko česte u književnosti i
slikarstvu ranog predviktorijanskog i viktorijanskog doba sve više pokazivale kao nezreli
eskapizam elita koja su odbijale prihvatiti stvarnost sve ubrzanijih modernizacijskih procesa. Povezanost diskursa o degeneraciji s moralističkim i konzervativnim viđenjem čovjeka bilo je
prisutno još i u Morelovoj apokalitpičnoj viziji konstantnog pada iz blagodati Rajskog vrta u
današnji svijet u kojem su ludilo, siromaštvo i kriminal sve rašireniji.Uistinu, kako je stoljeće
odmicalo, sve se veći dio modernih pojava, poput emancipacije žena i novih modernističkih
smjerova u kulturi opisivao upravo diskursom degeneracije, a takav narativ služio je kao
alternativa onim narativima koji su u problemima vidjeli primarno društvene uzroke. No,
činjenice nisu bile tako jednostrane. Eugenički pokret je supostojao s brojnim socijalno
angažiranim pokretima upravo jer je darvinistički diskurs dao snažan znanstveni legitimitet teoriji
o hereditarnim uzrocima društvenih problema. Bilo je pretjerano očekivati da onodobni europski
intelektualci prihvate bilo koji svjetonazor koji nije pristupao emocijama i duševnim procesima
strogo hijerarhijski, stavivši čvrstu volju kao (auto)percipiranu karakteristiku obrazovanog
bijelog muškarca na sam vrh piramide mentalne evolucije. Degeneracija postaje jedan od
najbitnijih dijelova slagalice koje čine sliku intelektualnog horizonta građanske klase na prijelazu
stoljeća. Virginia Woolf u svojim dnevnicima iz 1915 daje sljedeći opis londonskih invalida ili
siromaha: „ Na obali smo sreli i prošli kraj dugog reda imbecila. Prvi je bio visok mladić, dovoljno
neobičan da bi ga se pogledalo dvaput, ali ne više od tog; drugi se meškoljio i gledao u stranu;
tada se moglo primjetiti da je svaki od ljudi u tom dugom redu, bijedno, nesposobno teturajuće
idiotsko stvorenje, bez čela i brade s cerekom imbecila ili divljim sumnjičavim pogledom. Bilo je
užasno. Sigurno bi ih trebalo pobiti.”70 46 Do početka dvadesetog stoljeća, degeneracija će uglavnom biti identificirana kao uzrok
društvenih problema, a eugeničke mjere preporučane kao poželjno, efikasno i humano riješenje
istih. 3.2.Terapeutski pesimizam i degeneracija Prvi Međunarodni Eugenički Kongres održan 1912. godine u Londonu na kojem se okupila
znanstvena i politička krema kasnog devetnaestog stoljeća (od Alexandera Grahama Bella do
mladog Winstona Churchilla)71 bio je dokaz široke prihvaćenosti socijalnog darvinizma kao
društvenog svjetonazora. Bez previše pretjerivanja moglo se reći da je viktorijanski zavod za
duševno oboljele, u vremenu svoje intelektualne i terapeutske krize, uistinu postao ključni
argument u prilog tvrdnji da moderno društvo postaje sve bolesnije i sve brže posrće pod teretom
raširenog poroka i ludila. Rastući broj štićenika u tim „muzejima ludila” opetovano je služio kao
statistički uvjerljiv i emotivno snažan dokaz teorija o „borderlandsu” i degeneraciji, a
neizlječivost većine štićenika i visoka smrtnost dovela do sve beznandnije i očajnije perspektive
za europsku psihijatriju. 71 Blom, 2008: 334. 3.3. Od Griesingera do Kräpelina: njemačka neuropsihijatrija na prijelazu stoljeća Teraupetski pesimizam zavodske psihijatrije uspio je poljuljati vjeru liječnika u moral treatment i
blagotvorno djelovanje zavodske arhitekture i „non restraint” principa, ali nipošto nije umanjio
interes za proučavanje ljudske psihe. Paradigme darvinističkih psihijatara poputa Maudsleya
skrenule su pažnju liječnika prema biološkim uzrocima ludila. Da bi se došlo do bioloških uzroka
bolesti poput progresivne paralize i epilepsije, seciralo se mozgove preminulih zavodskih
pacijenata i mikroskopski ispitivalo uzorke cerebrospinalnog likvora, a da bi se otkrilo „stigme”
koje bi mogle ukazivati na hereditarne predispozicije provodila su se antropometrijska mjerenja i
bilježilo se svako odstupanje. Psihijatrija prijelaza stoljeća nije više samo bila psihijatrija zavoda,
već i psihijatrija laboratorija. Kultura sveučilišne laboratorijske psihijatrija najbolje se razvila u
Njemačkoj i Austro-Ugarskoj, zemljama koje su posjedovala jak državni sustav zdravstvene skrbi
(brojne su ga Njemačke države imale od prve polovice devetnaestog stoljeća, a u Austro-
Ugarskoj je nastajao u dva „apsolutistička” vala, za vrijeme prosvjećenog apsolutizma Josipa
Drugog i neoapsolutizma Franje Josipa I.). U Njemačkoj je razvoj psihijatrije bio povezan sa
sustavom cijenjenih sveučilišta od kojih su neka, poput badenskog i wurtemberškog imala i 47 međunarodnu reputaciju.72 Decentraliziran sustav sveučilišta u malim njemačkim državicama
povezan s činjenicom da su sva ta sveučilišta pripadala istom jezičnom području rezultirao je u
isto vrijeme i natjecanjem za prestiž i intenzivnom razmijenom ideja između raznih intelektualnih
škola i krugova. Čini se da je takav ustroj osobito pogodovao razvoju psihologije i psihijatrije. Već i samo neurološko i psihijatrijatrijsko nazivlje od Nisslove mrlje do Kräpelinove dihotomije
govori o ogromnom doprinosu kojeg su austrijski i njemački liječnici dali psihijatrijskoj
dijagnostici i metodologiji, a većina tih spoznaja razvila se u devetnaestom stoljeću. Između
1850. i 1914. austrijski su i njemački sveučilišni i zavodski liječnici i psiholozi razvili niz novih
teorija o psihi i duševnim bolestima i otkrili mnogobrojne procese vezane uz način rada i
patologiju ljudskog mozga. Wilhelm Griesinger je 1845. godine objavio jedan od najšire
korištenih psihijatrijskih udžbenika (još veću primjenu doživjelo je prošireno drugo izdanje iz
1861.). Austrijski liječnik Theodor Hermann Meynert je otkrio karminsko bojilo koje je
omogućilo efektnije mikroskopiranje moždanih stanica.73 Wilhelm Wundt je 1879. u Leipzigu
osnovao prvi psihološki laboratorij, Sigmund Freud je na prijelazu stoljeća utemeljio
psihoanalizu, a Alois Alzheimer je 1911. 74 Draaisma, 2009: 217. 72 Shorter, 1996: 35. ,
75 Verwey, 1985: 19. 73 Shorter, 1996: 77. 3.3. Od Griesingera do Kräpelina: njemačka neuropsihijatrija na prijelazu stoljeća otkrio da je teška degenerativna bolest mozga koja
danas nosi njegovo ime uzrokovana specifičnim lezijama mozgovnog tkiva.74 Druga polovica
devetnaestog stoljeća bila je razdoblje kad se intelektualna središta proučavanja mozga i psihe
sele iz rustikalnih psihijatrijskih ustanova Francuske i Velike Britanije u njemačka sveučilišta i
austrijske laboratorije. Na samom početku devetnaestog stoljeća, duševne su bolesti u Njemačkoj filozofskoj zajednici
tema intenzivne rasprave između psihicističke i somaticističke škole. Psihicisti su svog
najuglednijih saveznika našli u leipziškom teologu i liječniku Johannu Christianu Augustu
Heinrothu koji je u svom djelu Störungen des Seelenlebens (Poremećaji duševnog života) iznio
vlastitu teoriju etiologije dušenih bolesti. Po Heinrothu, duševne bolesti imaju uzrok u
„zamračenju duše koja dolazi u dodir sa zlom izvana” 75. Heinroth dakle, daje primat duševnom 48 nad tjelesnom, te čak ide toliko daleko da je odbacio izraz „duševne bolesti” tvrdeći da duša ne
može biti bolesna i u svojim djelima koristio izraz „duševni poremećaj.”76 Poziciju suprotnu Heinrothu veoma je rano počeo isticati Carl Wigand Maximilian Jacobi,
upravitelj zavoda za duševno oboljele u Salzburgu i Siegburgu, koji se kratko vrijeme obrazovao
u inozemstvu i uveo ideje Tukea i Pinela u srednjoeuropsku psihijatriju. Jacobi je u prvoj polovici
devetnaestog stoljeća bio poznat po ekstremnom somaticizmu, tvrdeći da je duševna bolest
zapravo samo simptom somatskog poremećaja koji može nastati bilo gdje u tijelu: u mozgu,
probavnim organima, koži ili bilo kojem drugom organu.77 Jacobi otpočekta odbacuje
spiritualističko objašnjenje, polazeći od kartezijanskog principa odvojenosti tijela i duše, poput
Heinrotha tvrdeći da duša kao savršena spiritualna esencija čovjeka ne može biti bolesna.78
Jacobijev ugled i činjenica da su u njegovim dvama zavodima radili brojni njemački i austrijski
liječnici koji su kasnije stekli značajan utjecaj učvrstili su somaticističku školu u Njemačkoj i
Austro-Ugarskoj psihijatriji. Bernhard von Gudden, Jacobijev asistent i kasniji profesor
psihijatrije na Munchenskom sveučilištu u svoje je učenike ubrajao Augustea Henrija Forela i
Emila Kräpelina, a skončao je u jezeru Starnberg na dno kojeg ga je 1886. povukao njegov
posljednji i najslavniji pacijent, bavarski kralj Ludwig II. Jacobi je vjerovao u organske uzroke duševnih bolesti i optimistično držao da se liječenjem
izvornog tjelesnog oboljenja može izliječiti i psihički poremećaj. Kako je medicina otkrivala
nove i bolje dijagnostičke instrumente, ljudski je mozak postao sve češćim predmetom
proučavanja na njemačkim sveučilištima. 76 Ibid: 16.
77 Ibid: 27.
78 Ibid: 28. 79 Shorter, 1996: 75. 82 Shorter, 1996: 101. 81 Draaisma, 2009: 204. 80 Ibid. 83 Ibid. 83 Ibid. 80 Ibid. 80 Ibid. 85 Greenfeld, 2013: 118. 84 Ibid: 105. 3.3. Od Griesingera do Kräpelina: njemačka neuropsihijatrija na prijelazu stoljeća Jedan od liječnika koji će dati najveći doprinos
proučavanju neuroloških uzroka duševnih bolesti bio je Wilhelm Griesinger, psihijatar i internist
koji je tijekom bogate i burne karijere bio upraviteljem brojnih psihijatrijskih zavoda. Osim već
spomenutog udžbenika, Griesinger je već kao mladi liječnik postao poznat po svojim
nastojanjima da približi psihijatriju granama somatske medicine. Bolnicu Charite u Berlinu, gdje
je 1865. godine imenovan za ravnatelja podjelio je u dva dijela: onaj na kojem su bili smješteni 49 pacijenti s običnim živčanim poteškoćama i onaj na kojem su bili pacijenti sa živčanim
poteškoćama koji su pokazivali primarno psihijatrijske simptome.79 Pored toga, Griesinger je
redovito držao predavanja i demonstracije simptoma duševnih oboljenja studentima, te obrazovao
psihijatrijske pripravnike na način da su usvajali znanje ostalih medicinskih disciplina, tražeći od
njih da, na primjer, obavljaju komplicirane porode.80 Te metode služile su približavanju
psihijatrije, koja se u Griesingerovo vrijeme još uvijek nalazila između antropološko-filozofske i
medicinske discipline medicini i stvaranju reputacije psihijatra kao liječnika, a ne pukog
ravnatelja institucije koja služi izolaciji društveno neprilagođenih pojedinaca. Drugo izdanje
Griesningerovog udžbenika Pathologie und Therapie der psychischen Krankheiten (Patologija i
terapija duševnih bolesti) bit će najraširenije primjenjivana stručna knjiga iz područja psihijatrije
sve do objavljivanja knjige Lehrbuch der Psychiatrie koju je 1893. objavio njemački psihijatar
Emil Kräpelin, osoba koja je uz Freuda najviše obilježila razvoj psihijatrije u dvadesetom
stoljeću. Kräpelin je rođen na sjeveru Njemačke ali je već 1878. došao u München, gdje je sedamdesetih
godina psihijatrija doživljavala procvat. U Münchenu amo je boravio i radio poznati predstavnik
biološke psihijatrije Bernhard von Gudden i njegov kolega Frank Nissl. Obojica su razvili
inovativne metode seciranja i bojenja mozga. Von Gudden je izumio mikrotom, cilindričnu
spravu za pripravljanje mikroskopskih preparata od mozgovnog tkiva, dok je Nissl usavršio
Meynertovu metodu bojenja, koristeći plavu boju umjesto karmina, što je tehnika koja je danas
poznata kao Nisslova mrlja.81 Kräpelin ipak nije mogao sudjelovati u mikroskopskom
proučavanju mozga radi vlastitih problema s vidom, te se zbog toga posvetio proučavanju
ponašanja pacijenata82 (kasnije će, za provođenje mikroskopskih analiza angažirati Aloisa
Alzheimera, koji će na svoju ruku otkriti patološke promjene koje dovode do Alzheimerove
bolesti). Smatrao je da mu proučavanje eksperimentalne psihologije može pomoći pri
dijagnosticiranju duševnih bolesti; stoga 1882. napušta Munchen i odlazi u Leipzig raditi u
psihološkom laboratoriju Wilhelma Wundta.83 50 Nakon usavršavanja u leipziškom psihologijskom laboratoriju i kratkog angažmana na sveučilištu
u estonskom gradu Dorpatu, Kräpelin 1890. 84 Ibid: 105.
85 Greenfeld, 2013: 118. 84 Ibid: 105. 3.3. Od Griesingera do Kräpelina: njemačka neuropsihijatrija na prijelazu stoljeća postaje ravnateljem sveučilišne klinike u
Heidelbergu, gdje dovodi Nissla i Alzheimera. Zahvaljujući ovom medicinskom timu koji je
pokrivao različite discipline unutar neuropsihijatrijske struke (Nissl je bio stručnjak za anatomiju,
Alzheimer vrstan neurolog, a Kräpelin je imao nova znanja iz područja eksperimentalne
psihologije), sveučilište u Heidelbergu postalo je centrom proučavanja duševnih oboljenja, a
rezultat tih proučavanja bio je Kräpelinov Udžbenik psihijatrije (Lehrbuch der Psychiatrie) iz
1893. godine. Kräpelinov udžbenik je sjajan dijagnostički i klinički priručnik koji će biti
pretečom kasnijih dijagnostičkih priručnika poput Dijagnostičko-statističkog priručnika. Udžbenik daje detaljan opis i pregled psihijatrijskih simptoma, a zatim klasificira duševne bolesti
s obzirom na njihov uzrok i na karakteristične pravilnosti u simptomima koji se pojavljuju
tijekom dužeg vremena. To predstavlja odmak u odnosu na dosadašnju psihijatrijsku praksu koja
je bolesti klasificirala s obzirom na jedan dominantan simptom koji se unutar bolesti javlja. Novost je i Kräpelinovo razgraničenje između manično-depresivnog ludila i dementie praecox
(Kräpelin navodno nije znao da je Morel upotrijebio isti naziv za tu bolest)84. Time je okončana
unitarna teorija duševne bolesti koja je ranije bila na snazi, a koja je pretpostavljala da su sve
duševne bolesti zapravo samo različite manifestacije jednog oboljenja nazivanog „manijom” ili
„ludilom”. Uz taj bitan doprinos, „dementia praecox” je dobila vlastiti dijagnostički naziv i set
dijagnostičkih kriterija. Može se, donekle reći da su ranije klasifikacije bile prilagođene
specifičnim potrebama ravnatelja psihijatrijskih institucija- kategorije poput „manie”,
„melancholie” i „dementie” omogućavale su ravnateljima da predvide hoće li štićenici biti mirni
ili nemirni, te ima li nade za njihovo izlječenje i eventualno otpuštanje iz zavoda. Kräpelin je, s
druge strane esencijalizirao pojedina psihijatrijska oboljenja na temelju simptomskih uzoraka i
samim time stvorio jasne i neodvojive kategorije „abnormalnog uma”. Manično-depresivno
ludilo će biti primarno afektivno oboljenje, dok će se na „dementiu praecox” gledati kao na
postupno slabljenje intelekta koje počinje u mladoj životnoj dobi.85 Čini se da je Kräpelinu bilo
stalo do toga da jasno razdvoji afektivnu i intelektualnu sferu čovjekovog mentalnog života i da
svakoj od njih pripiše zasebnu kategoriju poremećaja. Također, naziv „dementia” koji je Kräpelin 51 dao toj novoj bolesti implicira degeneraciju intelekta, što upućuje na to da je bolest degenerativne
prirode i neizlječiva (slično kao što je Alzheimerova bolest na početku bila nazivana
Alzheimerovom demencijom, dok se za progresivnu paralizu koristio naziv „dementia
paralytica”). 87 Kräpelin, 1902: 170. 86 Ibid: 119. 89 Ibid: 158-159. 88 Ibid: 155. 90 Ibid: 167. 3.3. Od Griesingera do Kräpelina: njemačka neuropsihijatrija na prijelazu stoljeća Švicarski psihijatar Eugen Bleuer, blizak psihoanalitičarima nije dijelio to mišljenje
i istu je bolest nazvao shizofrenijom što upućuje na njen disocijativni, a ne degenerativni
karakter.86 Što se tiče etiologije, Kräpelin je dementiu praecox smatro oboljenjem koje je u tri četvrtine
slučajeva uzrokovano defektivnim hereditetom dok je ostatak slučajeva uzrokovan tifusnom
groznicom i ozlijedama glave. Bolesnici često još u djetinjstvu pokazuju poneke predispozicije
poput sklonosti samoći i prekomjernom uživanju alkohola te pretjeranoj pobožnosti.87 „Dementia
praecox” se za Kräpelina manifestira slabljenem gotovo svih mentalnih funkcija od opažanja koje
je ometano halucinacijama88 do propadanja moralnih i emocionalnih karakteristika.89 Kräpelin
naglašava emocionalno propadanje oboljelih od „dementie praecox” ističući da oboljeli u kasnoj
fazi bolesti „žive prazan život, bez briga i strepnji i bez razmišljanja o budućnosti”.90 Uzroke
manično- depresivnog ludila Kräpelin također vidi u hereditetu, ali smatra rod bitnom
predispozicijom- ističe da bolest pretežno pogađa žene, a često počinje za vrijeme trudnoće.91
Druga ključna razlika je tok bolesti. Manično-depresivno ludilo ne rezultira trajnom
degeneracijom psihičkih funkcija, već obično dolazi do poboljšanja u roku od nekoliko dana do
nekoliko tjedana za manični oblik poremećaja 92 i nekoliko mjeseci za depresivni oblik.93
Naravno Kräpelin ističe da se napadi manije i depresije najčešće ponavljaju kroz čitav život
pacijenta, naročito kod žena za vrijeme klimakterija,94 ali nema progresivnog pogoršanja stanja,
niti propadanja intelektualnih ili emocionalnih sposobnosti. 52 Iako su Kräpelinova znanstvena metodologija bila više psihologijska nego tradicionalno
somaticistička, Kräpelin se i dalje pridržava načela socijalnog darvinizma koja su bila
ukorijenjena u onodobnoj psihijatriji. Premda je manje pažnje posvetio traženju somatskih
znakova, a više opisivanju psihološke simptomatologije, Kräpelin će nebrojeno puta u svojoj
knjizi istaknuti važnost herediteta, tvrdeći da je hereditarna degeneriranost osobito važan faktor
kod javljanja pojedinih kompulzivnih misli.95Također, Kräpelin je bio ogrezao u beznandni
terapeutski pesimizam i nije pristupao svojim pacijentima kao ljudima koje se uopće isplati
pokušavati liječiti. Veliki pomor štićenika psihijatrijskih institucija u Njemačkoj za vrijeme i
nakon Prvog svjetskog rata, uzrokovan glađu i epidemijom španjolske gripe Kräpelin je nazvao
olakšavanjem ekonomskog tereta koji su za zdravstveni sustav predstavljali neizlječivi pacijenti.96
Uopće, čini se da je njemačka psihijatrija bila osobito sklona teoriji degeneracije i obilježavanju
određenih kategorija ljudi kao duševno manje vrijednih. U osvit rastuće borbe za ravnopravnost
spolova, neki od stavova njemačkih psihijatara poprimali su osobito reakcionaran karakter. Studija leipziškog psihijatra Paula Juliusa Mobiusa objavljena 1900. godine pod naslovom
Fiziološka mentalna zaostalost žena odiše diskursom koji za ono doba možemo smatrati izrazito
mizoginim. ,
98 Beddies i Mueller, 2006: 101. 97 Lifton, 1986: 80. 96 Ibid: 260. 96 Ibid: 260. 99 Ibid: 94-95. ,
101 Glesinger, Lavoslav prema Fatović- Ferenčić i Pećina, 2012. :80. 102 Barle, 1904.: 370. 102 Barle, 1904.: 370. 100 Ulčnik, 1957.: 302. 104 Glesinger, 2012: 80. 103 Ibid. 3.3. Od Griesingera do Kräpelina: njemačka neuropsihijatrija na prijelazu stoljeća Konzervativna klima u društvu i sveopći antropološki i terapeutski pesimizam doveli
su do sve intenzivnijeg zagovaranja eugeničkih mjera. Posljedice takve klime u njemačkoj i
austrijskoj psihijatrijskog zajednici rezultirale su dvama događajima u dvadesetom stoljeću Prvi
je rođenje psihoanalize kao svojevrsnog novog pravca koji je obećavao određene uspjehe u
tretmanu neuroza. Drugi, daleko tragičniji bio je manjak otpora nacističkom programu masovne
eutanazije duševno bolesnih osoba i invalida među psihijatrima. Tek šačica liječnika,
najpoznatijih od kojih je bio bavarski neurolog Hans Gerhard Creutzfeldt odlučila je pokušati
spasiti svoje štićenike.97 Naravno, može se reći da je strah od kazne bio bitan faktor, ali ostaju
činjenice da su i prije dolaska nacista na vlast među psihijatrima postojali brojni zagovornici
mjera poput akcije T4, te da nijedan od malobrojnih psihijatara koji su se usprotivili
eutanazijskim mjerama nije bio ozbiljno kažnjen.98 Njemački psihijatar Alfred Hoche u brošuri 53 Uništenje života koji nije vrijedan življenja objavljenoj još 1920. godine dao je i konkretnu
teoretsku podlogu za tu zločinačku akciju.99 Premda će svi ravnatelji Zavoda za umobolne u Stenjevcu u devetnaestom stoljeću studirali na
austrijskim i njemačkim sveučilištima, čini se da eugeničke ideje ovdje nisu uzele tolikog maha
kao u Njemačkoj i Austriji. Teorije o degenaraciji su u Hrvatskoj bile marginalne i u potpunosti
su potisnute u drugi plan za vrijeme međuratnog pokreta socijalne medicine, a psihijatrija je os
svojih početaka u devetnaestom stoljeću imala određenu humanu i socijalnu komponentu koja u
Austriji i Njemačkoj nije bila zastupljena u značajnijoj mjeri. 54 104 Glesinger, 2012: 80. 102 Barle, 1904.: 370.
103 Ibid. 102 Barle, 1904.: 370.
103 Ibid.
104 Glesinger 2012: 80 103 Ibid. 01 Glesinger, Lavoslav prema Fatović Ferenčić i Pećina, 2012. :80.
02 Barle, 1904.: 370.
03 Ibid 104 Glesinger, 2012: 80. 100 Ulčnik, 1957.: 302.
101 Gl
i
L
l
F t
ić F
čić i P ći
2012 80 4.1.Osnutak i izgradnja zavoda za umobolne u Stenjevcu Psihijatrija u Hrvatskoj je u devetnaestom stoljeću još uvijek bila u povojima. Nisu postojale
institucije gdje bi se empirijskim metodama mogli proučavati razvoj i etiologija psihičkih
poremećaja što je rezultiralo činjenicom da su se psihijatri morali obučavati u inozemstvu. Također, medicinska bibliografija vezana uz psihijatrijske poremećaje bila je oskudna i nije bila
dostupna većini liječnika. Sam Ugarski dio Monarhije zaostajao je za austrijskim dijelom u
izgradnji zavodskih institucija - zavod Lipótmező u Budimpešti osnovan je tek 1868. godine. Hrvatski Sabor je 1840. godine zaključio da se iz županijske zaklade izgradi „luđački dom”, no
došlo je samo do osnutka odjela za umobolne u zagrebačkoj Bolnici Milosrdne braće.100Pitanje
osnutka zavoda za Hrvatsku i Slavoniju ponovno je pokrenuto pedesetih godina 19. stoljeća. Tadašnje carsko i kraljevstvo ministarstvo unutrašnjih poslova priznalo je 1853. godine potrebu
podizanja takvog zavoda101. Međutim, kaotična unutarnjepolitička i vanjskopolitička situacija u
kojoj se tadašnja Habsburška Monarhija nalazila u prednagodbenim godinama doveli su do toga
da je to pitanje ponovno pokrenuto tek sredinom 1860-ih godina. Glavni zagovornik osnutka novog zavoda postao je protomedicus Josip Kalazancije Schlosser
koji je u to vrijeme bio na funkciji zemaljskog praliječnika i namjesničkog savjetnika102 . Schlosser, koji je bio jedan od uglednijih liječnika sredine devetnaestog stoljeća, rođen je u
Moravskoj, a obrazovao se u Beču i Italiji. Dugi niz godina radio je kao kupališni liječnik u
Varaždinskim Toplicama, a 1867. proglašen je vitezom i dobio je plemićki predikat „Klekovski”. 103 Godine 1865. podnio je namjesničkom vijeću „Osnovu o podignuću i ustrojstvu zemaljske
ludnice”104. Schlosser u svojem izvješću ističe kako „Takozvana ludnica kod milosrdne braće u
Zagrebu nije nikakvo liječilište ili vidalište, već samo prosto čuvalište kao i prehranilište za takve 55 bolesnike, koji se smatraju da bi po naravi svoje bolesti ili sami sebi ili pako drugima opasni
bili”105. Schlosser ističe ključne uvjete koje novi zavod treba ispunjavati kako bi poslužio
terapeutskoj svrsi koja mu je u okviru tada dominantne „moral treatment” paradigme. Schlosserovi uvjeti su bili u skladu s naglaskom koji je psihijatrija kasnog devetnaestog stoljeća
stavljala na arhitektonske i higijenske karakteristike zavodskih građevina, kao i na njihovu
opskrbu. Opskrba se temeljila na korištenju terapijskog rada štićenika u svrhu što veće
samoodrživosti zavoda u pogledu hrane. Po Schlosseru, zavod nije smio biti dijelom opće
bolnice, već treba biti samostalan. Također, zavod treba imati i vrt i gospodarstvo zbog
„pribavljanje hrane i uposlenja bolesnika”. 106 Ibid: 80-81. 105 Ibid:73. 107 Ibid. 107 Ibid. 4.1.Osnutak i izgradnja zavoda za umobolne u Stenjevcu Po mogućnosti trebalo je iskoristiti postojeću zgradu
koja ne bi bila previše daleko od grada jer niti jedan liječnik ne bi htio ići stanovati tamo. Zavod
ne treba služiti pukom zatvaranju luđaka već i liječenju, treba biti dovoljno prostran da odgovara
broju duševnih bolesnika u trojednoj kraljevini. Neizliječeni bolesnici bi se mogli ostaviti u
Bolnici milosrdne braće dok bi se izlječivi trebali odijeliti po bolesti i po spolu. Schlosser je
procijenio ukupni broj bolesnika u trojednoj kraljevini na 100 duševnih bolesnika, među kojima
je 20 „nečišćenaka, pozlobica i goropadnika” koji moraju biti smješteni u posebne ćelijice
udaljene od ostalih bolesnika. U tim ćelijama vrata moraju biti bez kvake a namještaj treba biti
pričvršćen za pod. Zahodi u ćelijama se moraju prazniti izvana, a mirni bolesnici bi trebali biti
smješteni u manjim ili većim grupama. Dimenzije prostorija, koje moraju biti svijetle i zračne su
točno navedene. Zavod bi se sastojao od 87 prostorija, dok gospodarstvo treba obuhvaćati 14 do
16 jutara.106 Namjesničko je vijeće izradilo troškove i nacrt, te odlučilo da će troškove gradnje snositi
zemaljska konkureciona zaklada. Troškovi su trebali iznositi 132 539 forinti i 55 novčića, čemu
je dodano 6000 forinti za nabavu zemljišta te 42 920 forinti za unutrašnje uređenje.107 Nakon
rasprave u državnom ministarstvu u Beču i sugestija koje je dao, ravnatelj bečkog zavoda i
liječnik meksičke carice Carlote Josef Gottfried Riedel prijedlog je vraćen Hrvatskom Saboru. 56 Sabor je u sljedeća dva zasjedanja raspravljao o uključenju vojnog erara u financiranje izgradnje
zavoda, budući da je isti trebao pokrivati potrebe Vojne Krajine108. Rasprave o izgradnji zavoda
su trenutno odgođene 1870. zbog teške financijske situacije i razvojačenja bjelovarske vojne
krajine109 da bi bila nastavljena 17. 8. 1872. od strane Dr. Franje Kviringa. Franjo Kviring bio je zastupnik Strossmayerove Narodne stranke iz virovitičkog kotara.110 On je
naveden kao potpisnik „Osnove zakona o ustrojenju javne ludnice za obseg kraljevina Hrvatske i
Slavonije od 23. 12. 1873”. Konačni tekst tog nacrta imao je samo 4 stavka: prvi je odredio
„javnu ludnicu” kao zemaljski zavod i istaknuo da se ista treba podići u Zagrebu. Drugi je
govorio da će trošak snositi građanska i vojna Hrvatska i Slavonija po razmjeru broja pučanstva. Treći govori da će građanska Hrvatska i Slavonija namirivati svoj prinosak iz bolničkih zaklada,
a četvrti imenuje bana kao izvršitelja zakona. 114 Liječnički vjesnik, (u daljnjim bilješkama, LV.) 1880:32. 115 Glesinger, 2012: 68. 108 Ulčnik, 1957: 302.
109 Glesinger, 2012: 82.
110 Horvat, 1936: 39.
111 Glesinger, 2012: 83.
112 U originalu: “Landesnervenklinik Sigmund Freud”.
113 Ibid.
114 Liječnički vjesnik, (u daljnjim bilješkama, LV.) 1880:32.
115 Glesinger 2012: 68 g ,
112 U originalu: “Landesnervenklinik Sigmund Freud”. 108 Ulčnik, 1957: 302. 4.1.Osnutak i izgradnja zavoda za umobolne u Stenjevcu 111 Nakon donošenja zakonskog prijedloga
ustanovljeno je da će kao prototip za gradnju zavoda poslužiti zavod „Feldhof” u Grazu (danas
„Državna klinika za živčane poteškoće „Sigmund Freud”112). Komisija sačinjena od doktora
Schlossera, tajnika zdravstvenog odsjeka zemaljske vlade Antuna Schwarza i vojnog liječnika
Stjepana Mađareviča koji je zastupao vojni erar upućena je u ljeti 1874. godine u Graz kako bi
proučila ustroj Feldhofa.113 Antun Schwarz bio je još jedan liječnik obrazovan u Beču koji je služio kao željeznički liječnik u
Požunu i rudarski liječnik u Banatu, te županijski liječnik u Križevcima i Varaždinu, pokrenuo je
Liječnički vjesnik te je radio na osmišljavanju hrvatske liječničke terminologije.114 Od 1875
objavljivao je u Liječničkom vjesniku detaljne zdravstvene izvještaje u kojima je davao podatke i
o broju duševnih bolesnika.115 Usprkos svojoj mladosti, uživao je znatan ugled u hrvatskim
liječničkim krugovima. Treći član delegacije Madjarević, imao je u tom trenutku već dvadeset 57 godina iskustva kao vojni liječnik. Upravo će se Antun Schwarz u kasnijim godinama najviše
zauzimati za izgrađu zagrebačkog zavoda. Zemaljska vlada je 1877. nakon prvotnog pokušaja da
se zavod izgradi na zemljištu koje je donirao veleposjednik Pongrac kupila od zagrebačkog
kaptola jeftino močvarno zemljište pod imenom Jačkovina.116 Izbor zemljišta biti će izvorom
brojnih problema za zavod: močvarno tlo će pogodovati širenju raznih bolesti i redovno zračenje
prostorija će biti otežano zbog toga što je zavod bio smješten u udolini. Gradnja je povjerena
mladom arhitektu Kuni Weidmannu koji je uzore, osim u gradačkom tražio i u bečkom i
budimpeštanskom zavodu. Glavna zgrada bila je izgrađena u neorenesansnom stilu s dvokatnim
središnjim dijelom i nešto nižim, jednokatnim krilima. Pisarnica, liječnikov stan i stan glavne
sestre su bili smješteni u središnjem dijelu, dok su se bolesničke sobe bile smještene na sjevernoj
strani hodnika (slika 1). Smještanje soba samo s jedne strane hodnika omogućavalo je liječniku ili
bolničarima da promatraju bolesnike bez da im ikad budu okrenuti leđima. Kao što sam naveo u
prethodnom poglavlju takav se,plan izgradnje zavoda u devetnaestom se stoljeću nazivao
linearnim ili Kirkbridgeovim planom po prvom ravnatelju Pennsylvania Hospital for the Insane
Thomas Story Kirkbridgeu koji je 1854. godine napisao studiju On the Construction,
Organization, and General Arrangements of Hospitals for the Insane with Some Remarks on
Insanity and Its Treatment117. 120 LV, br. 3, 1894: 44-45. 119 Yanni, 2007:84. 116 Ibid: 84.
117 Yanni, 2007: 38.
118 LV 5, 1879: 80.
119 Yanni, 2007:84.
120 LV, br. 3, 1894: 44-45. 117 Yanni, 2007: 38. 118 LV 5, 1879: 80. 116 Ibid: 84. 121 Glesinger, 2012: 85. g ,
122 LV, 1877: 199. 4.1.Osnutak i izgradnja zavoda za umobolne u Stenjevcu Iako se pri izradi nacrta glavne zgrade Kuno Waidmann držao
linearnog plana, sam je zavod osim glavne zgrade imao još osam manjih paviljona ili, kako ih je
članak u Liječničkom vjesniku nazvao „nuszgrada”118 čime se približio drugoj vrsti plana zvanoj
paviljonski ili separatni plan. Paviljonski plan gradnje zavoda postaje sve češći u drugoj polovici
devetnaestog stoljeća i njegovo glavno obilježje je niz odvojenih paviljona, u Velikoj Britaniji i
SAD-u često zamišljenih kao rustikalne kućice, u kojima bi bolesnici trebali živjeti jednostavnim
životom uz bavljenje poljoprivredom119. Sam Waidmann je na svom predavanju pred skupštinom
zbora liječnika hvalio paviljonski stil120, a dograđivanja koja su vršena kasnije, naročito za
vrijeme dok je zavodom upravljao dr. Ivo Žirovčić kojem je bilo izuzetno važno biti u toku sa
svjetskim medicinskim trendovima išla su u daljnjem smjeru pretvaranja Zavoda za umobolne u 58 Stenjevcu u ustanovu paviljonskog tipa. Stenjevački paviljoni bili su povezani natkrivenim
hodnicima koji su olakšavali premještanje bolesnika s odjela na odjel. No glavni problem zavoda
bio je u tome što se već od početka pokazao premalenim za potrebe kojima je trebao služiti. Izgradnja je trajala gotovo dvije godine i već nakon svečanog otvorenja 16. studenog 1879. prevezeni su bolesnici iz Bolnice milosrdne braće fijakerima u novu bolnicu121. Usprkos
naputcima koji su davani prilikom originalnih rasprava o svrsi zavoda, među bolesnicima je bilo
mnogo već umirućih i neizlječivih, oboljelih od poteškoća u razvoju, staračke demencije ili
progresivne paralize. U uvjetima prenapučenosti, epidemije su počele harati i zavod je nažalost
ubrzo postao mjestom umiranja. g ,
122 LV, 1877: 199. 4.2. Liječnici Kraljevskog i zemaljskog zavoda za umobolne u Stenjevcu j
j
g
j
g
j
U razdoblju kojim se ovaj rad bavi zavod je promijenio tri ravnatelja i velik broj kućnih i
pomoćnih liječnika. Budući da u hrvatskom dijelu Austro-Ugarske nije bilo medicinskog
fakulteta na kojem bi ti liječnici mogli dobiti potrebno obrazovanje većina se školovala u
inozemstvu, te su sa stranih sveučilišta donosili nove spoznaje o psihi i duševnim oboljenjima. Te
spoznaje bile su uglavnom primjenjivane u Stenjevcu samo u onoj mjeri koliko je to kontekst
Stenjevca kao nove i financijski slabo stojeće institucije dopuštao. Njihov praktični rad u
Stenjevcu mijenjao je i proširivao neke isključivo akademske medicinske spoznaje i rezultirao
formiranjem praktične zavodske psihijatrije koja je trebala odgovarati specifičnim potrebama
društva Banske Hrvatske. Prvi ravnatelj Zavoda bio je Ivan (Jan) Rohaček (1843.-1898.). Rohaček je prije imenovanja za
ravnatelja zavoda bio sekundarni liječnik na ludničkom odjelu u Kosmonosyju u Češkoj, no
1877. preselio se u kaznionicu u Lepoglavi, gdje djeluje kao privremeni kućni liječnik.122 Moguće
je da ga je za ravnatelja predložio Dr. Ante Schwarz koji se zanimao za izgradnju zemaljskog
zavoda i bio upoznat s medicinskom službom u Lepoglavskoj kaznionici- pisao je o
zdravstvenom stanju u Lepoglavi iste godine kad je Rohaček ondje zaposlen. Rohačeka su, zbog
njegovog ranijeg iskustva smatrali velikim stručnjakom za psihijatriju, a da je uživao nesumnjiv 59 ugled kao psihijatar dokazuje i činjenica da mu je nuđenu prestižno mjesto kućnog liječnika u
Pragu koje je iz nepoznatih razloga odbio.123 Nema puno podataka o njegovom obrazovanju prije
zaposlenja u Kosmonosyju, no po njegovim izvješćima i ustroju Stenjevca u njegovo vrijeme,
čini se da je imao određeni oblik psihijatrijskog obrazovanja. Kao kaznionički liječnik, mnogo je
polagao na forenzičku psihijatriju i psihijatrijska vještačenja optuženik u Stenjevcu se počinju
provoditi od samog osnivanja institucije. Rohaček je također uveo većinu terapeutskih i
dijagnostičkih praksi koje su se primjenjivale u Stenjevcu. Njegova stručnost bila je predmetom
kontroverze u dvadesetom stoljeću, kad su psihijatri Herceg i Bazala tvrdili da je Rohaček bio
samo kaznionički liječnik bez specijalističke naobrazbe i da je njegovo imenovanje dokaz
marginalnog mjesta psihijatrije u medicini devetnaestog stoljeća, dok je Zvonimir Sučić tvrdio da
je Rohaček imao potrebne kvalifikacije za taj položaj.124 Rohaček je umirovljen 1894. nakon čega se vratio u Češku kako bi se tamo posvetio privatnoj
praksi. Između 1894. i 1896. Zavodom je privremeno upravljao Ivo Žirovčić, koji će kasnije
postati najdugovječnijim i najzaslužnijim ravnateljem Stenjevca. 126 LV, 1897: 432. 127 Ibid. 128 Dujić, 2012: 142. 123 LV, 1878: 130.
124 LV, 1954: 709.
125 LV, 1896: 175.
126 LV, 1897: 432.
127 Ibid.
128 Dujić, 2012: 142. 4.2. Liječnici Kraljevskog i zemaljskog zavoda za umobolne u Stenjevcu Nakon tog kratkog
interregnuma, za ravnatelja je imenovan još jedan liječnik iz Češke Ivan (Jan) Šimsa (1865.-
1945.). Ivan Šimsa je doveden od strane tadašnjeg bana Dragutina Khuena Hedervaryja i ban ga
je direktno imenovao izvanrednim članom zemaljskog zdravstvenog vijeća125. Šimsa preuzima
zavod u pomalo kaotičnom stanju- zbog financijske neodrživosti zavod je 1894. prešao u zakup
samostana reda časnih sestara svetog Vinka Paulskog, a odmah po dolasku Šimsa iz nekog
razloga mijenja cjelokupno osoblje zavoda.126 Šimsa je prije zaposlenja u Stenjevcu bio liječnik u
zavodu za umobolne u Dobžany u Češkoj, a bio je na glasu kao neurolog i stručnjak za
mikroskopsku analizu tkiva. Njegov interes ostavio je traga i u Stenjevačkom zavodu gdje je
naručio skupu opremu za mikroskopske i bakteriološke testove.127 Osim toga, Šimsa je počeo
mikroskopski testirati vodu koja je štićenicima služila za piće kako bi spriječio eventualne
epidemije, a naročit interes pokazao je za detaljne obdukcije umrlih štićenika.128 Nalazi obdukcija 60 prilagani su povijestima bolesti jedino u vrijeme Šimsinog kratkotrajnog, ali plodnog upravljanja
zavodom. Šimsa je bio uvjereni zagovornik apstinencije od alkoholnih pića, a zahvaljujući
detaljnom mikroskopskom proučavanju mozga preminulih štićenika počeo je naslućivati ezu
između progresivne paralize i tercijarnog sifilisa. Odbacivao je teorije po kojima do progresivne
paralize dovodi prenapregnutost živaca, već je kao presudne faktore koji dovodi do razvitka
progresivne paralize nakon prvotne infekcije sifilisom navodio hereditet i alkoholizam.129 Iako se
teorija o povezanosti sifilisa i progresivne paralize javila već sredinom devetnaestog stoljeća,
nepobitno ju je dokazao tek Hideyo Noguchi 1913. godine. Kraft- Ebbing, jedan od glavnih
autoriteta među psihijatrima u Austro-Ugarskoj smatrao je da je sifilis uzrokom progresivne
paralize u manjem broju slučajeva dok je primarni uzrok progresivne paralize nalazio u
duševnom naporu koji je iscrpljivao živčani sustav muškaraca građanskog sloja. Šimsa se nije
slagao s Kraft-Ebbingom i tražio je uzroke epidemije progresivne paralize u alkoholizmu i
prostituciji kao socijalnim faktorima koji se mogu ispraviti društveno angažiranima djelovanjem
liječnika. Šimsa je naročito osuđivao zaradu koju od alkohola ostvaruju ”države i obćine” dok
epidemija alkoholizma ima dugoročne i dalekosežne posljedice po čitavo društvo.130 Šimsa je otišao u mirovinu početkom 1901. 132 Wanger, 2011. 130 Ibid. 129 Šimsa, 1898: 2. 131 LV, 1901: 363. 129 Šimsa, 1898: 2.
130 Ibid.
131 LV, 1901: 363.
132 W
2011 4.2. Liječnici Kraljevskog i zemaljskog zavoda za umobolne u Stenjevcu godine ,a nakon umirovljenja otvorio je privatni
sanatorij za liječenje živčanih i duševnih bolesti u Krču u Češkoj.131Nakon umirovljenja nastavio
je pisati brojne članke i knjige u kojima je isticao štetnosti alkoholizma i zalagao se za potpunu
apstinenciju od alkoholnih pića, a postao je poznat po istraživanju glasina o duhovima i pisanju o
spiritizmu.132 Ivan Žirovčić (1855.-1940.) bio je drugi i četvrti ravnatelj Stenjevca i ostao je zapamćen kao
jedan od najuspješnijih i najcjenjenijih ravnatelja Zavoda, a često ga se spominje i kao „oca
hrvatske psihijatrije”. Rođen u Križancu, u Hrvatskom Zagorju u plemićkoj obitelji, nakon studija
medicine u Beču svoju je karijeru počeo kao kupališni liječnik u Lipiku, zatim podžupanijski
liječnik u Pisarovini i Severinu i okružni liječnik u Ogulinu. Nakon odlaska Ivana Rohačeka, Dr. 61 Viktor Struppi je zamolio Žirovčića da preuzme zavod, na što Žirovčić nakon kraćeg nagovaranja
i specijalizacije u gradačkom zavodu Feldhof pristaje. 133 Viktor Struppi je zamolio Žirovčića da preuzme zavod, na što Žirovčić nakon kraćeg nagovaranja
i specijalizacije u gradačkom zavodu Feldhof pristaje. 133 Za vrijeme studija u Beču, Žirovčić upoznao s Theodorom Meynertom, koji je u mladom
liječniku probudio interes za psihijatriju. U vrijeme kad je Žirovčić studirao u Beču, kod
Meynerta su studirali i Sigmund Freud i Josef Breuer. Ta cijela generacija psihijatara će, uz
Richarda von Krafta- Ebbinga koji je kasnije radio kao liječnik u Feldhofu pretvoriti Austro-
Ugarsku monarhiju u jedan od najproduktivnijih centara psihijatrijske i psihoanalitičke misli. Žirovčić preuzima Stenjevec 1894. kao prvi specijalizirani psihijatar ne njegovom čelu i odmah
biva razočaran zatečenim stanjem. Zavod je prešao u zakup milosrdnih sestara, bio je slabo
financiran, infrastruktura nije bila zadovoljavajuća a adinistrativnom i liječničkom osoblju je
nedostajalo stručnosti i iskustva. Iz tih razloga Žirovčić dolazi u sukob s Hedervarijevom
zemaljskom vladom i biva prijevremeno umirovljen 1896. godine.134 U vrijeme svog prvog mandata Žirovčić nije stigao provesti reformu zavoda željenom opsegu, no
utvrdio je vlastitu klasifikaciju duševnih bolesti koja se oslanjala na Meynertovu. Prije Žirovčića
nije bilo usustavljene klasifikacije duševnih oboljenja u Stenjevcu, što je otežavalo upravljanje
Zavodom. Žirovčić je klasifikaciju temeljio na tada modernim načelima austrijske biološke
psihijatrije te uvodi i „neurasthenične ili konstitucionalne psihoze”. 133 Lopašić, 1925: 230. 136 Ibid: 66-67. 135 Žirovčić, 1895a: 67. 134 Ibid. 136 Ibid: 66-67. 134 Ibid.
Ž 4.2. Liječnici Kraljevskog i zemaljskog zavoda za umobolne u Stenjevcu 135 Radi se o duševnim
slabostima koje su uvjetovane hereditarnim slabljenjem duševne konstitucije, a ljudi koje pate od
istih predstavljaju ”graničnu skupinu” (u skladu s Maudsleyevim pojmom „borderlandsa”)
herditarno opterećenih pojedinaca koje „riedko vidjamo u ludnicah, jer imaju dosta inteligencije,
da se mogu održati usried čovječanskoga družtva” ali slabost njihovog živčanog ustroja ih navodi
na impulzivno djelovanje koje ih „dovadjaju... ...često pred kriminalni forum.”136 Žirovčića je, nakon prvog neuspješnog mandata naslijedio Jan Šimsa, koji ubrzo dolazi u istu
vrstu sukoba sa zemaljskom vladom. Žirovčić se 1901., nakon Šimsine ostavke vraća iz
prijevremene mirovine kako bi nastavio upravljati zavodom. Njegov odnos sa zemaljskom 62 vladom bio je uvijek pomalo napet, posebno iz razloga što je Žirovčić intenzivirao svoje javno
djelovanje. Članci koje je pisao u Liječničkom vjesniku i ostali javni istupi, imali su intenciju
podizanja ugleda psihijatrije kao struke i samim time, vjerojatno, poticanja večeg izdvajanja za
psihijatrijske zavode. Također, Žirovčić posreduje između medicine i pravosudnog sustava kao
psihijatrijski vještak. Iako su se psihijatrijska vještačenja u Stenjevcu provodila od samog osnutka
Zavoda, Žirovčić ih prvi nastoji publicirati. Kroz njihovu publikaciju, Žirovčić često debatira s
uvriježenim pravosudnim i medicinskim pojmovima poput „ubrojivosti” ili „moral insanity”. Najveća kontroverza vezana uz Žirovčićev rad dogodila se 1912. kad je pozvan da provede
psihijatrijsko vještačenje nad Lukom Jukićem, atentatorom na kraljevskog povjerenika Slavka
Cuvaja. Žirovčić je bio pod iznimnim pritiskom javnosti i svojih kolega da proglasi Jukića
neuračunjivim.137 No, Žirovčićevo vještačenje proglasilo je Jukića ubrojivim što je omogućilo da
isti bude osuđen na smrt. Osim Jukićevog, Žirovčić vodi vještačenje u nizu politički nabijenih
sudskih slučajeva, poput slučaja I.M. studenta koji je 1909. uništio portret bana Khuena
Hedervaryja i Josipa Vugrina koji je 1907. izvršio atentat na brdovečkog župnika, koji je bio
politički motiviran. U zaključku tog vještačenja, Žirovčić se ne libi izricanja vlastitih političkih
sudova, pa premda osuđuje čin umorstva i atmosferu nasilja koju raspiruje stranački tisak,
također ističe da „ljute rane našeg naroda, koje su Josipa Vugrina potaknule na čin osvete,
žalibože nisu tlapnja”138 Predan forenzičkoj antropologiji i željan dati psihijatriji znanstveni i
pozitivistički pečat Žirovčić nije bježao od ovakvih, kontroverznih slučajeva. U mirovinu je
morao otići 1919. nakon što ga je nemirni štićenik prilikom vizite oslijepio udarcem u glavu139. Nakon umirovljenja, ostatak života provodi u okolini Stenjevca, često sudjelujući u raspravama
psihijatrijskog društva i s mnogo interesa prateći nova medicinska otkrića na polju psihijatrije. p
138 Žirovčić, 1907: 33. 137 Lopašić, 1925: 231.
Ž ,
139 Lopašić, 1925: 231. 4.2. Liječnici Kraljevskog i zemaljskog zavoda za umobolne u Stenjevcu Mnogi stenjevački psihijatri, poput Dragutina Forenbachera, Armanda Vinskog i Milana
Lončareka istakli su se kao poznati psihijatri iako nikad nisu bili ravnateljima zavoda. Zanimanje
zavodskog liječnika u devetnaestom stoljeću nije bilo prestižno niti omiljeno, zbog čega mnogi
od njih, usprkos nedvojbenoj stručnosti nisu birali ostali u Stenjevcu. Teški uvjeti života u 63 zavodu, sveprožimajući pesimizam i bezizglednost i velika smrtnost pacijenata odbijali su
liječnike od psihijatrije uopće, a naročito od stenjevačkog zavoda, koji je imao reputaciju loše
izgrađene, provincijske bolnice u koju se nedovoljno ulaže. zavodu, sveprožimajući pesimizam i bezizglednost i velika smrtnost pacijenata odbijali su
liječnike od psihijatrije uopće, a naročito od stenjevačkog zavoda, koji je imao reputaciju loše
izgrađene, provincijske bolnice u koju se nedovoljno ulaže. 64 64 140 LV, 1883:86-87. ,
141 Ibid. ,
141 Ibid. ,
141 Ibid. ,
141 Ibid. 145 Rohaček, 1885:50. 4.3.1.Socijalna struktura štićenika zavoda za umobolne u Stenjevcu Budući da je većina stanovnika Hrvatske krajem devetnaestog stoljeća živjela na selu, najveći dio
štićenika zavoda također je došao iz ruralnih sredina. Uz to, imućniji građani i plemići bili su u
boljoj prilici osigurati kućnu njegu ili skrb u nekom od inozemnih zavoda, dok su siromašniji
štićenici bili sprovođeni u Stenjevac, gdje su samo bolesnici prvog razreda plaćali vlastitu
obskrninu, dok su oni drugog i trećeg razreda, djelomično ili u cijelosti bili smješteni u Stenjevac
na teret grada. U izvješću koje pokriva godine od 1879. do 1882. kao zanimanje većine štićenika navedeno je
„poljodjelci” (166 odnosno 48.25 %) zatim „zanatnici” odnosno obrtnici (36 odnosno 10.46%)
dok težaci i sluge zajedno čine 61 štićenika odnosno 14. 8 %. Mali je broj štićenika iz građanskih
zanimanja. U zavodu je tek troje učitelja, po jedan liječnik i ljekarnik, dok je supruga činovnika
među štićenicama bilo deset a samih činovnika sedam140. Osim zanimanja, indikativan je i omjer
broja štićenika koji je dolazio iz gradova naspram broju koji je dolazio sa sela. Isto rano izvješće
navodi da je iz gradova ukupno došao četrdeset i jedan štićenik, iz podžupanija Hrvatske i
Slavonije 232, iz nekadašnje Vojne Krajine 57 a ostalih (iz drugih zemalja AU, iz Bosne i iz
Italije) trinaest.141 Takav trend se nastavlja sve do 1918. godine. Većina štićenika ostaju poljodjelci iz ruralnih
sredina, sluge služavke i težaci, što oslikava populaciju Stenjevca kao siromašnu, uglavnom
slabije obrazovanu i naviklu na težak fizički rad. Također, brojnost seoskog stanovništva u
zavodima za umobolne, nije bila isključivo hrvatski fenomen. Britanski statističari sredine ,
141 Ibid. 65 devetnaestog stoljeća su također zaključili da većina duševno bolesnih dolazi za sela,142 što je
navelo i Maudsleyja da zaključi da je „ludila najviše tamo gdje ima najmanje ideja, gdje su
osjećaji najjednostavniji i žudnje i način života najprostiji.”143 Kontinuirano je malo prosjaka i
lutalica, što bi moglo ići u prilog Shorterovoj tezi o institucionalizaciji kao posljedici promjena u
poimanju obiteljskog života i porodične svakodnevice krajem 19. stoljeća.144 142 Showalter, 2001: 108.
143 Maudsley, 1895: 30.
144 Shorter, 1997: 51.
145 Rohaček, 1885:50.
146 Ibid.
147 Showalter, 2001: 52. 146 Ibid. 142 Showalter, 2001: 108. 144 Shorter, 1997: 51. 143 Maudsley, 1895: 30. 147 Showalter, 2001: 52. 146 Ibid. 153 Ibid: 59. 148 Ibid.
149 Rohaček, 1888.: 68.
150 LV, br. 6. 1883. str. 86.
151 Rohaček, 1886:66.
152 Shorter,1997:54.
153 Ibid: 59.
154 Forenbacher, 1892: 2-3. 154 Forenbacher, 1892: 2-3. 152 Shorter,1997:54. 149 Rohaček, 1888.: 68. 150 LV, br. 6. 1883. str. 86. 148 Ibid. 151 Rohaček, 1886:66. Graf 1: Bolesnici po zanimanju 1884. godine145 Graf 1: Bolesnici po zanimanju 1884. godine145 U ranim su godinama muškarci znatno brojniji od žena- u prvih pet godina (od 1879. do 1884.)
oni uvijek čine više od polovice štićenika zavoda.146 Te brojke se na prvi pogled čine
suprotstsavljene podacima koje navodi E. Showalter, prema kojima žene prevladavaju među
štićenicama zavoda za umobolne u devetnaestom stoljeću147. No, nakon 1883. godine omjeri
između pacijenata i pacijentica postaju takvi da se može zaključiti kako je ludilo i u Stenjevcu 66 bilo „ženskom boljkom”. Napokon, 1885. godine je prvi put u Stenjevački zavod primljeno više
žena nego muškaraca.148 Ubrzo nakon, toga 1887. u zavodu opet ima znatno više muškaraca nego
žena, no budući da su muškarci odlazili iz zavoda i umirali u većoj mjeri nego žene, krajem
godine broj štićenika i štićenica je po prvi put bio izjednačen 146 muškaraca i 146 žena.149 Izvori ukazuju na još nekoliko aspekata onodobnog poimanja ludila kod kojih je rod štićenika
igrao veliku ulogu i koji objašnjavaju kako trend postepenog izjednačavanja broja muškaraca i
žena u zavodu za umobolne, tako i percepciju Elaine Showalter o vezi između ženske
seksualnosti i ponašanja koje je prkosilo društveno uvriježenim normama i broja
institucionaliziranih žena. Najočitiji primjer toga su dijagnoze i uzroci bolesti. U prvim
izvješćima muškarci brojem prevladavaju u gotovo svim dijagnozama, samo je kod slučajeva
„melancholie” i „epilepsie” broj žena i muškaraca podjednak. 150 S vremenom, raste broj žena s
dijagnozama „manie”, „melancholie” i „anoie”, a u 1885. žene su brojnije u svim dijagnostičkim
kategorijama osim „vesanie”, „paralysys” i „epilepsie”.151 Ove brojke govore da je veći broj
muškaraca, nego žena smještenih u Stenjevcu bolovao od „progresivne paralize” odnosno
terminalnog krajnjeg stadija sifilisa koji je u drugoj polovici devetnaestog stoljeća u Europi
poprimao epidemijske razmjere.152 Druga pojava koja je u devetnaestom stoljeću poprimala
epidemijske razmjere bio je alkoholizam, koji uzrokuje niz psihičkih poremećaja i koji je
uglavnom pogađao muškarce, budući da je socijalno opijanje bilo muška aktivnost. Bolji
standardi života i nove destilacijske tehnologije omogućili su veliku dostupnost jeftinog alkohola
što je povećalo potrošnju alkoholnih pića diljem Europe.153 Može se pretpostaviti i da jedan dio
muškaraca koji je u zavodu bio s dijagnozom druge bolesti također možda bolovao od
progresivne paralize u početnoj fazi koja je karakterizirana tek rastresenošću, omaglicama i
povremenim promjenama raspoloženja154. 155 Rohaček, 1885:50. 155 Rohaček, 1885:50. 156 Rohaček, 1889:149. 157 Ibid. 157 Ibid. Graf 1: Bolesnici po zanimanju 1884. godine145 Tako je Maudsley u svojoj raspravi „Sex and Education” istakao kako „žene
koje prolaze istu vrstu obrazovanja kao muškarci to čine pod cijenu velikih poteškoća i patnje
koja ih na kraju čini nesposobnima za obavljanje prirodnih funkcija njihovog spola”161 Drugi
podatak kojeg se može izvući iz uzroka bolesti je činjenica da su liječnici vidjeli oskudicu kao
dominantan uzrok bolesti. Čini se da su štićenici i štićenice u Stenjevac dolazili iz života koji je
bio obilježen teškim egzistencijalnim uvjetima, neimaštinom i nedovoljnom prehranom. Budući
da Rohaček nekoliko godina za redom pretpostavlja da je neimaština uzrok bolesti kod većine
štićenika kod kojih se ne može naći drugačiji, jasan povod njihovog ludila, razumno je zaključiti
da je siromaštvo bilo najuočljivija i najodredljivija karakteristika stenjevačkog pacijenta. Rana
percepcija veze između siromaštva i ludila dat će zapisima stenjevačkih psihijatara distinktivan
socijalno angažirani ton. Neki uzroci ludila pak govore o ranjivom položaju žena i o patrijarhalnim predrasudama vezanim
za ustroj ženskog uma. Tako se među uzrocima ludila kod žena navode: „razmažen odgoj”159,
„mensess cessantes”, „excessus in Venere”, „duševni napor” i „čitanje romana”160. To ide u prilog
dominantnoj paradigmi koja gleda na žene kao na bića čije su djelovanje i zdravlje upravljane
njihovim reproduktivnim funkcijama i kod kojih težak intelektualni napor može prouzročiti
duševno oboljenje. Tako je Maudsley u svojoj raspravi „Sex and Education” istakao kako „žene
koje prolaze istu vrstu obrazovanja kao muškarci to čine pod cijenu velikih poteškoća i patnje
koja ih na kraju čini nesposobnima za obavljanje prirodnih funkcija njihovog spola”161 Drugi
podatak kojeg se može izvući iz uzroka bolesti je činjenica da su liječnici vidjeli oskudicu kao
dominantan uzrok bolesti. Čini se da su štićenici i štićenice u Stenjevac dolazili iz života koji je
bio obilježen teškim egzistencijalnim uvjetima, neimaštinom i nedovoljnom prehranom. Budući
da Rohaček nekoliko godina za redom pretpostavlja da je neimaština uzrok bolesti kod većine
štićenika kod kojih se ne može naći drugačiji, jasan povod njihovog ludila, razumno je zaključiti
da je siromaštvo bilo najuočljivija i najodredljivija karakteristika stenjevačkog pacijenta. Rana
percepcija veze između siromaštva i ludila dat će zapisima stenjevačkih psihijatara distinktivan
socijalno angažirani ton. Traženje uzroka ludilu u teškim životnim uvjetima i neimaštini je bila jedinstvena pojava za
europsku psihijatriju prijelaza stoljeća, koja je bila previše opterećena seksualnošću i
hereditetom. Tako je uvid u tešku svakodnevicu socijalno depriviranog stanovništva utjecao na
formiranje socijalne struje u hrvatskoj psihijatriji. Graf 1: Bolesnici po zanimanju 1884. godine145 Obzirom na to da je progresivna paraliza najčešće 67 završavala smrću, podatak koji govori da se nakon „otpada” broj muškaraca i žena izjednačava
može ukazivati na činjenicu da veći broj muškaraca u Stenjevcu znači veći broj onih koji su u
Stenjevec došli zbog neuroloških tegoba prouzročenih terminalnim sifilisom. Kada se dakle, od
ukupnog broja štićenika odbiju oni s degenerativnim procesima na mozgu poput sifilitičara i
epileptičara, ostaje nam zbilja veči broj žena koje su u Stenjevac primane bez vidljive neurološke
patologije. One su uglavnom bile tu zbog poremećaja vezanih za emocije i izražavanje istih
(melacholiu i maniju). Od toga broja zasigurno je velik broj onih čiji je način ponašanja i
nošenja s emocijama bio predmetom diskurzivnih modela patologizacije, selektivne diskurzivne
prakse koja je na temelju kriterija društvene prihvatljivosti određene načine ponašanja označavala
stigmom patologije, što ide u prilog tezama Elaine Showalter. Graf 2 : Dijagnoze (muškarci) u 1884. godini155 Graf 2 : Dijagnoze (muškarci) u 1884. godini155 68 Ovisnost stigme patologije o rodu vidi se iz pretpostavljenih uzroka bolesti. U prvih deset godina
zavoda, izvješća navode brojne uzroke bolesti koji su specifični za žene. „Spirituosas” (pijanstvo)
je u tim ranim izvješćima gotovo isključivo „muški” uzrok duševnog poremećaja. Kod žena
prevladava „affectus” ili, kako je Rohaček to preveo na hrvatski „silno ganuće srdca”156. Kod
muškaraca su tri vodeća uzroka oboljenja pijanstvo, affectus i nasljedni elementi (hereditas), dok
su kod žena to affectus, nasljedni elementi i ponekad glavobolja a ponegdje porod. Valja istaknuti
da Rohaček zapravo za većinu štićenika ne zna navesti uzrok oboljenja no uvijek pretpostavi da Graf 3: Dijagnoze (žene) u 1884. godini157 Graf 3: Dijagnoze (žene) u 1884. godini157 69 je kod muškaraca riječ o oskudici, a kod žena o oskudici i s njom povezanom slabokrvnosti158 je kod muškaraca riječ o oskudici, a kod žena o oskudici i s njom povezanom slabokrvnosti158 Neki uzroci ludila pak govore o ranjivom položaju žena i o patrijarhalnim predrasudama vezanim
za ustroj ženskog uma. Tako se među uzrocima ludila kod žena navode: „razmažen odgoj”159,
„mensess cessantes”, „excessus in Venere”, „duševni napor” i „čitanje romana”160. To ide u prilog
dominantnoj paradigmi koja gleda na žene kao na bića čije su djelovanje i zdravlje upravljane
njihovim reproduktivnim funkcijama i kod kojih težak intelektualni napor može prouzročiti
duševno oboljenje. ,
161 Maudsley, 1884: 17. 158 Ibid. 160 Rohaček, 1887: 69. 158 Ibid.
159 Ibid.
160 Rohaček, 1887: 69.
161 Maudsley, 1884: 17. Graf 1: Bolesnici po zanimanju 1884. godine145 No pod pritiscima terapeutskog pesimizma i
forenzičko-eugeničkog fokusa mainstream psihijatrije, ta će se struja uspjeti u potpunosti
aktualizirati tek nakon Drugog svjetskog rata. 70 ,
164 Žirovčić. 1904: 312-313. 4.3.2. Iskustva štićenika prije dolaska u Stenjevac Teško je sa sigurnošću reći kakva su bila iskustva štićenika prije dolaska u Stenjevac. Zapisi
psihijatara i povijesti bolesti govore o životu koji je bio ispunjen zlostavljanjem, praznovjernim
predmedicinskim praksama liječenja duševne bolesti i nasiljem. Psihijatar Rudolf Herceg u
jednom od svojih zapisa govori ovako o položaju duševnih bolesnika: „U našim krajevima bila je teška sudbina tih jadnika još koncem prošlog stoljeća kad se
duševne bolesne viđalo po cestama,gdje se izlažu ruglu djece i neozbiljnih ljudi, a samo opasni
ili akutno oboljeli sklanjali su se u bolnicu Reda milosrdne braće na Jelačićevom trgu u
Zagrebu. Odjel broj 13 u dvorištu te bolnice bio je dugi niz godina onaj zloglasni broj, koji je u
toj bolnici značio naročitu nevolju i nesreću.”162 Članci liječnika i povijesti bolesti često govore o okrutnom postupanju rodbine, seoskih vlasti, pa
čak i liječnika i bolničara zaposlenih u bolnici Milosrdne braće koji su nerijetko neprimjereno
liječili, zatvarali i tukli bolesnike. Članak Ive Žirovčiča, dugogodišnjeg i veoma uspješnog
ravnatelja Zavoda za umobolne u Stenjevcu, objavljen u Liječničkom vjesniku iz 1904. govori u
slučaju mlade seljakinje Minke P. koja je osumnjičena zbog umorstva suprugova brata
gluhonijemog Franje P. jer je nekoliko dana prije Franjine pogibije (koja je kasnije Žirovčićevim
tumačenjem objašnjena kao bizarna nesreća) bila u stanju koje bi suvremena psihijatrija označila
kao psihotičnu epizodu, odnosno akutnu psihozu. U članku se kroz iskaze brojnih svjedoka
(redarstvenika i suseljana) govori o postupku suprugove obitelji prema Minki. Liječnici koji su
pregledali Minku su tako našli „tragove vezivanja i na leđima dugoljaste ogrebotine.”163 Žirovčić,
književno obrazovan i vjerojatno svjestan da psihijatrijska vještačenja privlače pažnju javnosti i
čine, inače zapostavljenu, zavodsku psihijatriju vidljivijom prepričava ovaj slučaj u maniri gothic
romana i ističe još jedan prilično bizaran detalj. Naime, svjedoci govore kako je suprugova obitelj
Minku golu zavezala lancem za stup od žrvnja, ističući pritom da je zavezana lancem jer je
„dretu” kojom su je prvotno razvezali bila razgrizla.164 Članci liječnika i povijesti bolesti često govore o okrutnom postupanju rodbine, seoskih vlasti, pa
čak i liječnika i bolničara zaposlenih u bolnici Milosrdne braće koji su nerijetko neprimjereno
liječili, zatvarali i tukli bolesnike. Članak Ive Žirovčiča, dugogodišnjeg i veoma uspješnog
ravnatelja Zavoda za umobolne u Stenjevcu, objavljen u Liječničkom vjesniku iz 1904. govori u
slučaju mlade seljakinje Minke P. koja je osumnjičena zbog umorstva suprugova brata
gluhonijemog Franje P. g
163 Žirovčić, 1904: 309. 162 Herceg, 1933: 6. 4.3.2. Iskustva štićenika prije dolaska u Stenjevac jer je nekoliko dana prije Franjine pogibije (koja je kasnije Žirovčićevim
tumačenjem objašnjena kao bizarna nesreća) bila u stanju koje bi suvremena psihijatrija označila
kao psihotičnu epizodu, odnosno akutnu psihozu. U članku se kroz iskaze brojnih svjedoka
(redarstvenika i suseljana) govori o postupku suprugove obitelji prema Minki. Liječnici koji su
pregledali Minku su tako našli „tragove vezivanja i na leđima dugoljaste ogrebotine.”163 Žirovčić, književno obrazovan i vjerojatno svjestan da psihijatrijska vještačenja privlače pažnju javnosti i
čine, inače zapostavljenu, zavodsku psihijatriju vidljivijom prepričava ovaj slučaj u maniri gothic
romana i ističe još jedan prilično bizaran detalj. Naime, svjedoci govore kako je suprugova obitelj
Minku golu zavezala lancem za stup od žrvnja, ističući pritom da je zavezana lancem jer je
„dretu” kojom su je prvotno razvezali bila razgrizla.164 71 Pomalo makabričan opis postupanja seljaka s bolesnom Minkom, koji zauzima ključno mjesto u
članku čiji je predmet psihijatrijsko vještačenje. Njegova uloga je povezivanje senzacionalističke
privlačnosti slike mlade žene privezane nage za stup sa željenom predodžbom o psihijatriji kao
čovječnoj disciplini koja uistinu liječi one prema kojima se iz straha i praznovjerja neljudski
postupa. Možda upravo zbog toga zapisi o zlostavljanju duševnih bolesnika uvijek zauzimaju
prominentno mjesto u stenjevačkim povijestima bolesti. Dapače, često se upravo u tim zapisima
makabrizam psihijatrijskog diskursa, koji je često bio usmjeravan prema štićenicima okreće
prema van i postaje kritičan prema nekim štetnim i nehumanim praksama. Među praksama koje bivaju kritizirane u tim zapisima na udaru se nalaze mnoge metode liječenja
koje spadaju u narodnu medicinu, a koje liječnici smatraju pogubnima za tjelesno i duševno
zdravlje. Povijest bolesti stanovite Jele S. lončareve supruge koja je u zavod primljena 1881. kazuje da je povod bolesti: „neumjestan odgoj, obćenje s babami koje joj glavu napunjavahu
raznimi praznovjernim pričami...”165 Bolesnica je za vrijeme boravka pokazivala izražen strah od
čarolija i imala noćne more. Liječnik koji je pisao izvješće na temelju koga je bolesnica primljena
u bolnicu pravi jasnu razliku između postupanja s bolesnicom u zavodu i „pučkih lijekova”
kojima su pribjegavali njeni ukućani: „Lječenje u bolnici od 14. veljače se sastojalo samo u tome što se je nastojalo mirnim
pristupom, otklonjenjem svakog razdraživanja umobolnu umiriti, a ljekarie dobiala je kad kada
prema potrebi... Kod kuće postupaše s njom protivno zdravom umu, iztjerivaše iz nje vraga,
držaše molitve nad njom, kadiše ju meni nepoznatim tvorinami. 165 KPV, 1881: 312. ,
166 Ibid. ,
166 Ibid. ,
166 Ibid. ,
166 Ibid. 165 KPV, 1881: 312. 165 KPV, 1881: 312. 4.3.2. Iskustva štićenika prije dolaska u Stenjevac Taj postupak ju je do najvećeg
stepena razdraženosti doveo.”166 Osim egzorcizama i sličnih postupaka koji su rezultat folklornih vjerovanja o duševnoj bolesti
kao „opsjednutosti” ili posljedici crne magije brojni su primjeri koji govore o tome kako se
bolesnike otvoreno zlostavljalo prije dolaska u zavod. Tako je Obrada S. mladića iz Sošana
sklonog lutanju bio zlostavljao njegov otac: „Dosele u ogradi čvrstoj u štali pod kućom, iz koje 72 nije nikud mogao. Isprva ga je otac tukao, a kad je vidio da je bolestnik zbilja lud i pogibeljan,
zatvorio ga u štalu i nikad ga više nije pustio slobodna, inače je s njim dobro postupao”167 nije nikud mogao. Isprva ga je otac tukao, a kad je vidio da je bolestnik zbilja lud i pogibeljan,
zatvorio ga u štalu i nikad ga više nije pustio slobodna, inače je s njim dobro postupao”167
Ovdje je zanimljiv izbor riječi. Usprkos tome što ga je otac tukao i zatvarao u štalu ispod kuće,
povijest bolesti svejedno navodi da je „inače s njim (sic!) dobro postupao” što implicira da su
stenjevački liječnici i bolničari u svojoj praksi susretali slučajeve mnogo goreg zlostavljanja od
ovog. Osim rodbine, kao zlostavljači se navode i bolničari sa već kritiziranog odjela 13 bolnice
Reda milosrdne braće. Bolesnica Marta V., seljanka iz Dubrave kod Ogulina koja je u bolnicu
Milosrdne braće primljena u trudnoći tako svjedoči da je žalosna jer su ju „kod braće vezali i
zlostavljali”168. Djevojka seljačkog porijekla iz Plaškog koja je odvedena kod milosrdne braće jer
se s roditeljima sukobila zbog nedozvoljene ljubavne veze govori kako je u bolnici bila
zlostavljanja i dobivala injekcije, a njen nalaz prilikom pregleda govori kako je „(njena) koža
udarana na više mjesta ogrebena i modričava.”169 Činjenica da je bolesnica otpuštena kao zdrava
tek mjesec dana nakon primitka u zavod također baca zanimljivo svjetlo na ovaj slučaj. Jedno od najdramatičnijih svjedočanstava o zlostavljanju u bolnici Reda Milosrdne braće dolazi
iz bolničkog kartona Ane V. sluškinje iz Mihovljana koja je jedno vrijeme radila u zagrebačkoj
bolnici kao sluškinja. Nakon što je optužila jednog liječnika za zlostavljanje, poglavarstvo ju je
predalo u istu bolnicu radi motrenja. 170 KPV, 1895: 1066. 167 KPV, 1895: 2537.
168 KPV, 1911: 8104.
169 KPV, 1911: 8138.
170 KPV, 1895: 1066. 169 KPV, 1911: 8138. 4.3.2. Iskustva štićenika prije dolaska u Stenjevac Nakon što je upućena u Stenjevac, jedna od povijesti bolesti
donosi njen glas: „...uvek se tuži da su joj u zagrebačkoj bolnici liječnici najprije s rukami njezino djevičanstvo
uzeli, a kašnje kad su ju postavili za bolničarku napastovali su ju fratri te su ju svi hteli
silovati , a jednomu je i zbilja pošlo za rukom. Od to doba jerbo se je prestrašila i zasramila
nema mira niti pokoja...”170 Iako bi ponašanje Ane V. u Zavodu današnji psihijatri vjerojatno tumačili kao posljedicu neke
vrste traume uzrokovane seksualnim zlostavljanjem, stenjevački su liječnici bili odlučni u
zaključku da ona nije bila silovana. Usprkos njihovoj nesklonosti da povjeruju takvim tvrdnjama
svojih štićenika, psihijatri su temeljito bilježili sve što je moglo ukazivati na neku vrst okrutnog
postupanja prema duševno oboljelima. Jednoj povijesti bolesti je tako priloženo pismo Ivana B. 167 KPV, 1895: 2537. 168 KPV, 1911: 8104. 169 KPV, 1911: 8138. 170 KPV, 1895: 1066. 73 pravnika iz Vrblja kod Nove Gradiške koji je 1915. četiri godine nakon što je bio
institucionaliziran, optužio liječnika Kostu Mladenovića da ga je poslao u Stenjevec zbog
političkih sukoba. U pismu, (koje vjerojatno zbog ratnih okolnosti u kojima je napisano obiluje
antisrpskim sentimentom) Ivan B. govori kako se : „...čuvajući livadu od susjeda koji su pasli i štetu činili te se po noći tvorno grozili, fićukali itd. nahladio i pao u groznicu. Isti su nešto od neukosti svoje nasilno izveli puštanje krvi po
Mikolcu iz Gunjavaca, pravoslavne vjere (srpske) uz crkvenu molitvu sa zamotanom rukom po
nekoj crnoj postavi. Na to me rođaci dovezoše u bolnicu u Novu Gradišku. Službujući liječnik,
dr. Kosta Mladenović, grko-istočne vjere dao me po sluzi Jovanu pravoslavne vjere (srpske)
zatvarati u samici rujna 1911 u mrežu. Taj je i drugi vikom kroz zid (da se ne opaze),
grožnjom, pogrdama, provociranim neosnovanim pitanjima prema svojim intencijama nastojali
provocirati nekakvi hrvatski proces radi nemira smjerajući onamo da stave vjernost prema hrv. kralju u dvojbu i ocrne te naškode, i nepoštujući kat. Vjeru i hrv. junake. To je sve dojavljeno g. dr. K. Mladenoviću, koji je i sam sugestijama i sl. bolest da se poveća htio te sve u (srpstva)
političku korist izrabio. ,
172 Herceg, 1933: 159. 171 KPV, 1911: 8232. 4.3.2. Iskustva štićenika prije dolaska u Stenjevac Kad sam prinužden otvorio nekoliko puta mrežu iznutra bacili me u
smradnu sobu pred bolnicom, koja se nije zračila, niti se prozor otvarao – a niti sam vode dobio
za umivanje.”171 Iako su od samog slučaja prošle četiri godine, ravnatelj Ivo Žirovčić, kojem je pismo bilo
upućeno ga je sačuvao u kartonu nekadašnjeg štićenika, što govori o tome da se ovakvim
slučajevima pridavala velika važnost. Članak dr. Rudolfa Hercega, objavljen u monografiji „Stenjevec - državna bolnica za duševne
bolesti 1879.-1933” koji nosi naslov „Prijava bolesnika u bolnicu”, iako datiran mnogo kasnije od
navedenog razdoblja obiluje sličnim primjerima nasilnog i često brutalnog odvođenja ljudi u
bolnicu, kao i primjerima liječničke aljkavosti pri izdavanju uputnica. Herceg navodi da su se
slučajevi nasilnog postupanja prema bolesnicima i u 1930-ima događali svakodnevno.172 Herceg
iznosi primjere seljaka koji su svezali bolesnika za kola „debelim konopom, a voze se već šest 74 sati” i općinskog pandura koji štapom tjera bolesnika svezanog u stezulju.173 Nasilno postupanje s
psihički oboljelima od strane općinskih vlasti, obitelji i susjeda je dakle i u 19. i u 20. stoljeću
bila svakodnevica pred kojom liječnici nisu pokazivali veliko zgražanje i čuđenje, iako su takve
postupke naravno osuđivali svakom prilikom. 175 Showalter, 2001: 106 107.
176 Prvi je bio kaznionički liječnik, prije nego što je postao ravnateljem Stenjevca, drugi je pokazivao veliki interes
za sudska vještačenja i o tome redovito objavljivao članke u Liječničkom vjesniku. 173 Ibid. ,
175 Showalter, 2001: 106-107. 174 Jukić, 2015: 11. 4.4.1. Dolazak u zavod Prvo iskustvo štićenika nakon prijema u bolnicu bio je prvi pregled koje je ostalo zabilježeno u
povijestima bolesti bio je pregled u pisarnici tijekom kojeg bi liječnik pisao takozvani „status
praesens”. „Status praesens” je bio zapis o trenutnom tjelesnom i duševnom stanju bolesnika
prilikom prijema u bolnicu. Taj pregled i izvještaj su bili ključni za postavljanje dijagnoze, te su
pomogli odrediti na koji će od odjela bolesnik biti smješten. Pregled bi se događao na dan
prijema, ili najkasnije dan ili dva nakon prijema u zavod, što je vjerojatno ovisilo o tome je li
liječnik bio dostupan u trenutku kad bi štićenika doveli. Pacijent bi bio doveden u jednu od
pisarnica gdje bi ga jedan od kućnih liječnika ili ravnatelj pregledali.Sve pisarnice nalazile su se u
prizemlju glavne zgrade.174 Pri tom pregledu, velika se pažnja posvećivala određenim tjelesnim
karakteristikama za koje se smatralo stigmama hereditarne degeneracije. Takvi detalji bili su
deformacije usta, ušiju, lica i zubala175 a stenjevački ravnatelji Ivan Rohaček i Ivo Žirovčić su kao
specijalisti za forenzičku psihijatriju 176 pokazivali izniman interes za socio-darvinističke teorije
autora poput Maudsleyja i Mobiusa i kriminalnu antropologiju Cesarea Lombrosa. Zapisi s prvih
pregleda redovito daju opis zubala, ušiju, oblika lubanje (nekad s točnim mjerama, nekad bez),
prisutnost određenih neuroloških znakova koji bi mogli upućivati na progresivnu paralizu poput
stanja zjenica i provjere refleksa. Pregledani bi bili i otkucaji srca i disanje, a kod žena bi se
posebna pažnja posvetila obliku grudi i spolnih organa. Pregled već spomenute Minke obiluje
hereditarnim znakovima: „...žena sitna, srednje ugojena. Lubanja nepravilnog oblika objam 510
duljina 175 širina 140 mm…Ušesa vrlo malena, izobličena, nejednaka, lievo veće, desno 75 manje… Nos malen, tubast, sedlast u korenu nizak i širok. Desni ustni kut niži. Zubi zdravi, sitni,
rašljasti.“177. Poneki opisi obiluju nekim motivima u kojima se razaznaju natruhe devetnaestoljetnog
znanstvenog rasizma. Povijest bolesti Katarine F., žene krčmara iz Apatina posebnu je pažnju
posvetilo njezinom židovskom porijeklu, a opis tjelesnih karakteristika je, neuobičajeno krenuo u
smjeru navođenja određenih tjelesnih osobina koja su bile opisivane kao atavističke. Također,
neke od njenih tjelesnih karakteristika opisivane su jezikom rasnih atavizama, na primjer oblik
usta koja su opisana kao „laloke na van svedene davajuć licu izraz majmuna”178. Nakon tjelesnog pregleda uslijedio je intervju u kojem je liječnik utvrđivao duševno stanje
štićenika. 178 KPV, 1879. 246. ,
179 Žirovčić, 1906: 221. 177 Žirovčić, 1904: 56. 177 Žirovčić, 1904: 56.
178 KPV, 1879. 246.
179 Žirovčić, 1906: 221. 4.4.1. Dolazak u zavod Taj intervju imao je neka opća mjesta: štićenika se pitalo zašto je ovdje, pokušalo se od
njega saznati podatke iz obiteljske povijesti, naročito uzroke smrti drugih članova obitelji i je li
itko drugi iz obitelji bio duševno bolestan. Također, pribjegavalo se testovima pismenosti i
provjeravalo razlikuju li štićenici pojedine novčanice, znaju li molitve, imena mjeseci i dane u
tjednu, te rješavati jednostavnije matematičke zadatke. Iz zapisa je, doduše, nejasno u kojoj su
mjeri liječnici pogreške u zbrajanju i neznanje specifičnih molitvi pripisivali duševnoj bolesti ili
neobrazovanosti štićenika. S obzirom na dobro poznatu Maudsleyevu paradigmu o ludilu kao
posljedici „siromaštva ideja” moguće je da su izvodili eventualnu vezu između duševne bolesti i
nedostatka obrazovanja. Primjer takve provjere znanja možemo vidjeti u objavljenom vještačenju
Gjure Gjankovića. Gjuro Gjanković bio je 22. veljače predan u Zavod za umobolne u Stenjevcu
radi psihijatrijskog vještačenja, jer je iz osvete zapalio štalu svog očuha. Prilikom razgovora u
liječničkoj pisarni morao je riješiti sljedeći zadatak: „Ako imaš 20 krajcara, pa kupiš za 3 krajcara
pakl duhana, koliko ti još ostane novaca ? Ne odgovara-veli, da on kupuje pakl po 4 krajcara. Dakle 4, pa koliko ti onda ostane od 20 krajcara? Nakon dugog razmišljanja veli: ostane 10
krajcara. Kako to? Ja kupim još šibica i papirića.179 76 U slučajevima citiranima u Liječničkom vjesniku navedeno je obilje ovakvih zadataka.neuspjeh
pri rješavanju ovakvih zadataka najčešće se smatrao simptomom duševne zaostalosti ili oboljenja. Pritom se nije uzimala u obzir činjenica da su takvi zadaci prikladniji i razumljiviji obrazovanim
ljudima, dapače, iz gornjeg primjera vidimo da Gjuro uopće ne razumije očekivanja koja liječnik
postavlja pred njega ovim matematičkim problemom: on uporno govori iz vlastitog iskustva jer je
dosadašnji razgovor bio o njegovim iskustvima. Dapače on ne pokazuje nemoć da riješi
matematički račun, već ga kontekstualizira u vlastito konkretno iskustvo. Žirovčić na temelju
njegove nemogućnosti, zaključuje da je Gjuro „mladić vrlo ograničenih umnih sposobnosti”180 Osim provjere herediteta, životnih navika i duševnih sposobnosti, liječnici nekad pokazuju
detaljan interes za poneke simptome duševnih bolesti, naročito za sadržaj halucinacija i deluzija. Pritom s osobitom pažnjom bilježe sve što, prema onodobnim konvencijama može upućivati na
abnormalnu seksualnost, te na onaj oblik deluzija koje bi današnja psihijatrija nazvala bizarnim
deluzijama. Tako u slučaju kranjskog sluge Antona P. koji je 30. listopada 1910. doveden u
Stenjevec s dijagnozom „manije” Žirovčić pokazuje izražen interes za njegovo vjerovanje u
„mure” (vjerojatno dijalektalni oblik „more” čestog čudovišta u narodnim predajama). 180 Ibid.
181 KPV, 1911: 7947. 180 Ibid. 4.4.1. Dolazak u zavod U
povijesti bolesti nalazimo sljedeći zapis: „Pripovieda da se kod kuće napio rakije i onda smeo. On se je htio liečiti jer ga je njeka
„mura sisala”. Najprije je htio muru oterati tako da na molitveniku spava, pa je uzeo molitvenik
pod jastuk, što je i pomoglo, nu onda je oćutio boli u želudcu, uzeo je paprike, a nato se i dobro
napio rakije. Onako zmotan otišao je u trafiku da kupi duhana i to onoga za 4 novčića „crveni
neki iz Srbije u Mađarskoj i koji je određen za županiju zagrebačku.” To se je ljudima činilo
smešno, pa su ga prijavili...Šta je to „muria?” To ni ja neznam, ali ima više ljudi koje murija
(sic) sisa nu oni se toga ne mogu otresti, ali ja sam ipak došal na to kak se more oterati,”... „Što
je dakle sa murom?” „Neće ništa da otom danas razgovara već onako opet smeteno peć
gledati”... „Obećao da će sve napisati o onoj muri” ...„Predao pismo gdje opisuje svoju bolest o
„muri””181 77 Nakon početnog pregleda u pisarni štićenik biva upućen na jedan od zavodskih odjela. Sama
politika odjela u zavodu je izrazito bitna jer se pomoću njih razvrstavalo štićenike u strogo
definirane kategorije. Svaka kategorija imala je određeno mjesto u arhitektonskom rasporedu
zavoda, vlastiti set pravila, te vlastite uvjete života. Te kategorije određivale su vrstu i blizinu
kontrole te način primjene psihijatrijske moći na tijela pacijenata raspoređena u prostor zavoda:
možemo čak reći da su tijela štićenika kao objekti disciplinskog nadzora bila ukalupljivana u
arhitekturu zavoda koja je u velikoj mjeri služila uspostavljanju i perpetuiranju kontrole nad
tijelima. Nakon početnog pregleda u pisarni štićenik biva upućen na jedan od zavodskih odjela. Sama
politika odjela u zavodu je izrazito bitna jer se pomoću njih razvrstavalo štićenike u strogo
definirane kategorije. Svaka kategorija imala je određeno mjesto u arhitektonskom rasporedu
zavoda, vlastiti set pravila, te vlastite uvjete života. Te kategorije određivale su vrstu i blizinu
kontrole te način primjene psihijatrijske moći na tijela pacijenata raspoređena u prostor zavoda:
možemo čak reći da su tijela štićenika kao objekti disciplinskog nadzora bila ukalupljivana u
arhitekturu zavoda koja je u velikoj mjeri služila uspostavljanju i perpetuiranju kontrole nad
tijelima. g,
183 Foucault, 2003: 242. 182 De Young, 2015: 485-486 g,
183 Foucault, 2003: 242. 182 De Young, 2015: 485-486. 4.4.2. Sustav odjela u Zavodu za umobolne u Stenjevcu i uvjeti života Kao što je spomenuto u poglavlju o izgradnji zavoda, Zavod za umobolne u Stenjevcu u svom je
nacrtu zamišljen kao prijelazni tip između Kirkbrideovog linearnog i paviljonskog plana. Oba
plana odražavala su tipičnu onodobnu paradigmu o povoljnom terapeutskom utjecaju pažljivo
strukturiranog prostora zavoda. U Kirkbrideovom planu „terapeutske arhitekture” odjeli su imali
ključno mjesto: pacijenti koji su povoljno reagirali na režim institucije bili bi premještani na
odjele na kojima su uvjeti života bili bolji, a najbolji su bili rezervirani za one koji su se ponašali
u skladu s pravilima. Tako su u zavodima široko shvaćene dijagnoze (u slučaju Stenjevca
„mirni”, „siloviti”, „nečisti” itd.) uzurpirale identitet štićenika, a uniformnost kategorija je
apsorbirala individualnost182 i medicinsku praksu brige o pacijentima kao pojedinačnim
slučajevima. Primjer odjela najbolje pokazuje kako su devetnaestoljetni zavodi za umobolne
služili kao svojevrsne heterotopije biomoći. Biomoć se ovdje uzima u smislu kako ju je definirao
Michel Foucault, kao kategorija upravljanja koja dijeli populaciju na uniformne kategorije čijim
se tijelima upravlja preko specifičnih disciplinarnih aparatusa.183 S obzirom na česte epidemije
koje su pogađale Stenjevec, svrstavanje na određeni odjel moglo je doslovno značiti razliku
između života i smrti. U povijestima bolesti, odjeli su designirani brojem, i ponekad popratnim slovom prema čemu se
može zaključiti da ih je bilo dvanaest. Iako nigdje nije točno navedeno koji od odjela je čemu
služio, zna se da su muškarci bili smješteni na zapadnoj strani bolnice, a žene na istočnoj. U
182 De Young, 2015: 485-486. 78 glavnoj zgradi, u istočnom su krilu bile „mirne“ i „polumirne“ žene, a u zapadnom „mirni“ i
„polumirni“ muškarci184. U udaljenijim paviljonima smještenim sjeverno od glavne zgrade,
nalazile su se „nečiste” (inkontinentne) i „silovite” žene i „nečisti” i „siloviti” muškarci185, a
istočno od glavne zgrade izgrađena je 1895 „nemoćnica” za one bolesnike koji su bili teško
bolesni ili invalidni186. Kasnijim nadogradnjama, sjeverno od glavne zgrade su bila izrađena još
dva „radnička” paviljona u kojima su bili smješteni bolesnici koji su radom doprinosili
gospodarstvu bolnice.187 Budući da su stanovi ravnatelja, liječnika i glavne sestre, bili smješteni u
glavnoj zgradi, kao i većina prostora namijenjenih slobodnom vremenu bolesnika, bolesnici koji
su bili klasificirani kao „mirni“ su imali bolji pristup liječničkoj skrbi i priliku za druženje s
drugim bolesnicima, dok su „siloviti” i „nečisti” smješteni u najdaljem dijelu bolnice, udaljeni od
ceste, glavne zgrade bili osuđeni na svojevrsnu izolaciju. 184 KPV, “Izgradnja i razvoj bolnice”, 2014: 28-29.
185 Ibid 34 dnja i razvoj bolnice”, 2014: 28-29. 4.4.2. Sustav odjela u Zavodu za umobolne u Stenjevcu i uvjeti života Osim poštivanja zavodskih pravila i
higijene, čini se da je i socijalni status štićenika imao utjecaj na raspored odjela. Plan glavne
zgrade tako predviđa zasebne sobe za bolesnike „klasiste“ koji sami snose troškove liječenja188, a
ravnatelj dr. Ivo Žirovčić je u jednom članku nazvao odjel IVa, odjelom „za mirne bolestnike
naobraženijih slojeva.”189 U izvorima postoje brojni primjeri korištenja premještanja s odjela na
odjel radi discipliniranja štićenika. Štićenica Lena Glueck, je tako „Sbog ogovaranja, laganja i
zadirkivanja, nesloge premještena s V na I razdjel”190. Također, nekad izvor implicira da je
premještanje na bolji odjel rezultiralo promjenom stanja štićenika na bolje, a ne obrnuto. Povijest
bolesti švelje Marice P. navodi da je ista premještena s odjela III na odjel II, nakon čega se
počela ponašati „čisto i pametno”191. Sami štićenici često traže da ih se premjesti na odjele na kojima su uvjeti života bolji. Razdjeli za
„nečiste” i „silovite” često su bili prenapučeni jer su zgrade u kojima su se nalazili bile manje,
miris je bio neugodan, vjerojatno su bili slabije grijani i štićenici su bili izloženi napadima
bolesnika koji su bili u uznemirenom stanju ili su se iz drugih razloga ponašali agresivno. 79 Štićenik Jakob F. je, prema dijagnozi postavljenoj u Stenjevcu, bolovao od progresivne paralize,
bolesti koja je često rezultirala nasilnim ispadima. Smješten na odjel za „silovite“, uspio je u dva
dana dvaput ozlijediti istog štićenika, prvi put ga udarivši vrčem po glavi i „razbivši mu glavu na
četiri strane“.192 Dva dana kasnije ga je „udario peharom,” te mu zadao „tri velike rane na
glavi.”193 Bolesnica Filomena B., smještena na prvi odjel, žalila se i tražila premještaj „na drugi
razdjel, da joj se dade bolje jelo. Tuži se da ju čapaju, da će joj sve vlasi potrgati.”194 Zahvaljujući prenapučenosti odjela za „silovite” i „nečiste” kvaliteta života bila je niska, a
smrtnost na tim odjelima je bila neuobičajeno visoka. Na odjel za „nečiste” su često smještani
štićenici koji su bolovali od dizenterije ili tuberkoloze. Zaraze su širile brzo i bile su primarni
uzrok pomora bolesnika. Zavod je bio sagrađen na močvarnom tlu i „...po svojem položaju niže
od nadolazećeg potoka Vrapčaka, gušio (se) u nečisti i smradu jer otoka iz zavoda nije bilo”195. Ogroman broj oboljelih od zaraznih bolesti, osobito tuberkoloze, naveo je 1910. poznatog
liječnika Frana Oriovčanina Gundruma da kritizira ravnateljstvo zavoda i u članku upita koliko se
umrlih od tuberkuloze zarazilo u samom zavodu196. 192 KPV, 1880: 32.
193 Ibid.
194 KPV, 1895: 2657.
195 Herceg, 1933: 11.
196 Gundrum, 1910: 152. g,
196 Gundrum, 1910: 152. 192 KPV, 1880: 32. 4.4.2. Sustav odjela u Zavodu za umobolne u Stenjevcu i uvjeti života Problemi kanalizacije i opskrbe pitkom vodom bili su prisutni od same izgradnje zavoda. Zahodske su jame bile izgrađene od opeke i propuštale su, a odvodni kanali vodili su u otvorenu,
jamu ispred zavoda koja je bila obrasla raslinjem i užasno je zaudarala. Svi apeli ravnatelja
zavoda da se taj ogromni higijenski problem riješi, bili su ignorirani. Situacija je, donekle
poboljšana 1900 godine kada je iskopan kanal. koji je trebao odvoditi kanalizaciju u Savu. No
budući da je jama bila smještena niže od korita Save, za napajanje kanala bila je potrebna pumpa
koja se često kvarila. Usto, kanal je bio otvoren i prolazio je kroz cijeli zavod, šireći smrad i
zaraze što je 1901 godine uzrokovalo veliku epidemiju tifusa i dizenterije tijekom koje je umrlo 80 230 štićenika.197 Velike i smrtonosne epidemije tifusa i crnih boginja pogodile su zavod i 1916. godine, i bile su znatno pogoršane neadekvatnom prehranom štićenika uslijed ratnih uvjeta.198 Opskrba vodom vršena je pomoću deset metara dubokog bunara iskopanog u blizini glavne
zgrade. Voda se iz njega, pomoću pumpi, izvlačila u spremnik koji se nalazio na tavanu glavne
zgrade, odakle je vodovodnim cijevima raspoređivan po zavodu. S obzirom na činjenicu da je
kanalizacija bila otvorena, a bunar plitak, voda je često bila onečišćena, a ljeti je bunar znao i
presušiti, ostavljajući zavod bez pitke vode.199 Dovođenje vode u odjele udaljene od glavne
zgrade otvorenim vodovodnim cijevima moglo je postati opasno za štićenike. Zabilježena su
barem dva slučaja u kojima su štićenici umrli od ozbiljnih opeklina prilikom kupelji jer se dovod
hladne vode zimi zaledio što prezaposleno bolničko osoblje nije primijetilo. Žirovčić spominje
slučaj štićenika oboljelog od progresivne paralize koje, je vruća voda oparila kožu i koji je
nekoliko sati nakon toga umro200, a identičan incident dogodio se i Katarini K., podvornikovoj
supruzi koja je 1914. umrla u zavodu od posljedica opeklina: „Jutros ju je bolničarka metnula u
kupelji otvoriv obje pipe, kao obično, od vrućeg i mrzlog vodovoda, a nije opazila da mrzla voda
neteče (ona se je od velike studeni vani smrzla) i opržila joj obje noge.)”201 Osim vodovoda i kanalizacije, problematični su bili i ventilacija i zagrijavanje zavoda. Po jednom
od ranih izvještaja za zagrijavanje i ventilaciju bila je zadužena bečka tvrtka Holdorrf i Bruckner. ,
202 Činjenica da zavod još krajem devetnaestog stoljeća koristi zastarjelu Reaumurovu skalu vjerojatno upućuje na
stare mjerne instrumente.
203 LV, 1880: 29-30. 201 KPV, 1914: 8505. 197 Herceg, 1933: 11.
198 Ibid: 12-13.
199 Ibid: 11-12.
200 Žirovčič, 1896b: 282.
201 KPV, 1914: 8505.
202 Činjenica da zavod još krajem devetnaestog stoljeća koristi zastarjelu Reaumurovu skalu vjerojatno upućuje na
stare mjerne instrumente.
203 LV, 1880: 29-30. 204 KPV, 1879: 48.
205 KPV, 1880: 219.
206 Yanni,2007: 32.
207 Ibid: 31.
208 Herceg, 1933:7.
209 KPV,1914: 8715. 209 KPV,1914: 8715. 208 Herceg, 1933:7. 4.4.2. Sustav odjela u Zavodu za umobolne u Stenjevcu i uvjeti života Po nalazu prve inspekcije prostorije u glavnoj zgradi i zgradama za „silovite“ i „nečiste“ su bile
ugrijane na 17-18 stupnjeva po Reaumurovoj skali (oko 25 stupnjeva celzijevih)202, a zrak se
mijenjao jedan i pol puta po satu. Prema istom izvješću, zrak se u prostorijama za „nečiste” i
„silovite” mijenjao do sedam puta u satu. Uz to navedeno je da se glavna zgrada grijala
„kaloriferima osebujne konštrukcije.” a ostale zgrade „pećima nasipnjačama”.203 Iako ovaj 81 izvještaj zaključuje da je stanje grijanja i ventilacije u zavodu zadovoljavajuće, povijesti bolesti
bilježe brojne pritužbe štićenika. Jana B. seljakinja iz Sušinovca, koja je 1879. dovezena u
Stenjevec s ludničkog odjela bolnice Milosrdne braće opetovano je tražila da ju vrate u „Zagreb
u špital” jer ovdje ne zrače204. Osobito je zanimljiv slučaj težaka Miška M. koji je u zimi 1880. odlučio provaliti u zavodsku mrtvačnicu kako bi skinuo odjeću s trupla jednog od štićenika jer
mu je bilo suviše hladno.205 Problem ventilacije i grijanja u zavodu vjerojatno dijelom vuče
porijeklo iz osebujne arhitekture, sa sobama raspoređenim samo duž jedne strane hodnika kako bi
se bolničarima i liječnicima olakšao nadzor štićenika i otežao eventualan bijeg. Iz tih razloga je i
broj vrata i prozora u zavodima za umobolne bio daleko manji od onog u ostalim bolnicama.206
Teškoćama s ventilacijom pridonio je i izbor zemljišta.Iako je praksa devetnaestog stoljeća
nalagala da se bolnice grade na ugodnim lokacijama koje osiguravaju cirkulaciju svježeg zraka i
daleko su od zagađenih gradova207, stenjevački je zavod bio izgrađen na niskom, isušenom
močvarnom tlu (prije izgradnje zavoda tamo je bio ribnjak u kojem su se lovile divlje patke)208,
bez mogućnosti učinkovitog odvoda otpadnih voda. Uz to, tlo je vjerojatno bilo vlažno što je
zavod činilo izrazito energetski neučinkovitim. izvještaj zaključuje da je stanje grijanja i ventilacije u zavodu zadovoljavajuće, povijesti bolesti
bilježe brojne pritužbe štićenika. Jana B. seljakinja iz Sušinovca, koja je 1879. dovezena u
Stenjevec s ludničkog odjela bolnice Milosrdne braće opetovano je tražila da ju vrate u „Zagreb
u špital” jer ovdje ne zrače204. Osobito je zanimljiv slučaj težaka Miška M. koji je u zimi 1880. odlučio provaliti u zavodsku mrtvačnicu kako bi skinuo odjeću s trupla jednog od štićenika jer
mu je bilo suviše hladno.205 Problem ventilacije i grijanja u zavodu vjerojatno dijelom vuče
porijeklo iz osebujne arhitekture, sa sobama raspoređenim samo duž jedne strane hodnika kako bi
se bolničarima i liječnicima olakšao nadzor štićenika i otežao eventualan bijeg. 207 Ibid: 31. ,
211 Kuljženko, 1931: 675. 210 Forenbacher, 1892: 6. 212 Ibid. 213 Ibid. 4.4.2. Sustav odjela u Zavodu za umobolne u Stenjevcu i uvjeti života Iz tih razloga je i
broj vrata i prozora u zavodima za umobolne bio daleko manji od onog u ostalim bolnicama.206 Visoka smrtnost pacijenata u Stenjevcu ostala je zabrinjavajuća kroz cijelo devetnaesto stoljeće,
rijetko padajući ispod 10% a dosežući preko 25% u godinama Prvog svjetskog rata (vidi grafove
4 i 5). U brojnim povijestima bolesti navodi se kako je rodbina štićenika priložila novac za
brzojave koje je ravnatelj trebao odaslati u slučaju njegove ili njezine smrti.209 Takva praksa
postaje sve učestalija kako vrijeme odmiče i svjedoči o činjenici da se Zavod za umobolne u
Stenjevcu sve više počelo smatrati institucijom iz koje se bolesnici rijetko vraćaju živi. Visoka
smrtnost je vjerojatno utjecala na sve veći terapeutski pesimizam stenjevačkih psihijatara koji se
kako vrijeme odmiče sve više suočavaju s neuspjesima „moral treatmenta”. Već 1892. u jednom 82 predavanju dugogodišnjeg zavodskog kućnog liječnika Dragutina Forenbachera odjekuje
pesimizam europskih psihijatara koji sve češće govore o degeneraciji zapadne civilizacije: „Tisućljetni hrast koji je prkosio stoljetnim vjetrovom i olujam počinje klonuti... ...Dok je svijet
bio u muževnoj dobi, nije se svačega bojao, jer mu ustroj bijaše čvršći i žilaviji. Sad smo
marasmični, odtud i snaga i jakost svakog upliva na nas.”210 Graf 4 (smrtnost bolesnika u zavodu 1879.-1918.)211 Graf 4 (smrtnost bolesnika u zavodu 1879.-1918.)211 83 Graf 5 : Smrtnost bolesnika izražena u postocima212 Graf 5 : Smrtnost bolesnika izražena u postocima212 212 Ibid. 84 Graf: 6 Broj bolesnika u zavodu 1879.-1918.213 Graf: 6 Broj bolesnika u zavodu 1879.-1918.213 213 Ibid. 85 214 Žirovčić, 1897: 320. 4.5. Terapeutske metode i terapijski pesimizam Nakon uspona „moral treatmenta” sredinom devetnaestog stoljeća, druga polovica stoljeća
rezultirala je svojevremenim terapeutskim pesimizmom u liječenju duševnih bolesti. Teze o
postepenoj degeneraciji rase koje su iznijeli Morel i kasnije Maudsley, bile su rezultat rasta broja
duševnih bolesnika u zavodima diljem Europe. Taj rast je bio uvjetovan brojnim faktorima, ali
ono što je bilo presudno za gubitak vjere u izlječivost duševnih oboljenja bio je velik broj
recidivista- ljudi koji su jednom bili otpušteni iz zavoda kao izliječeni, da bi se opet vratili u
zavod nekoliko godina kasnije. Ipak, ravnatelji stenjevačkog zavoda u proučavanom razdoblju
inzistiraju na terapeutskoj ulozi zavoda. Žirovčić u svom članku pod naslovom: „O postupku s
duševno bolestnimi” koji je izašao u Liječničkom vjesniku 1897.u dva dijela vrlo decidirano
ističe:„Govoreći o liečenju duševno bolestnik, moramo si ponajprije staviti načelno pitanje: može
li se u obće duševni bolestnik izliečiti, ili još bolje, može li duševno oboljeli čovjek ozdraviti?Na
takvo pitanje možemo odlučno odgovoriti: da.”214 U Stenjevcu su se uistinu koristile brojne terapijske metode, neke od njih iz razloga što su
tadašnji psihijatri zbilja vjerovali u njihovu učinkovitost, a neke su bile korištene isključivo kako
bi disciplinirale i olakšale nadzor bolesnika. Iz onodobnih izvora možemo izlučiti sljedeće
metode liječenja: a) odmor u krevetu
b) radna terapija
c) „fiksiranje” i ostali oblici autoritarnog podvrgavanja volji liječnika
d) sredstva za sputavanje i osamljivanje
e) rana psihofarmakološka terapija
f) hipnotizam
g) prehrana
h) hidroterapija a) odmor u krevetu
b) radna terapija
c) „fiksiranje” i ostali oblici autoritarnog podvrgavanja volji liječnika
d) sredstva za sputavanje i osamljivanje
e) rana psihofarmakološka terapija
f) hipnotizam
g) prehrana
h) hidroterapija c) „fiksiranje” i ostali oblici autoritarnog podvrgavanja volji liječnika 86 215 De Young, 2015: 19.
216 Ibid, 20.
217 Žirovčić, 1897: 322.
218 Ibid, 355.
219 De Young, 2015: 19.
220 Ibid.
221 KPV, 1911:6295. 219 De Young, 2015: 19. 220 Ibid. 218 Ibid, 355. 216 Ibid, 20. 215 De Young, 2015: 19. 4.5.1.Odmor u krevetu Terapiju krevetom u europsku su psihijatriju uveli njemački psihijatri. Sredinom devetnaestog
stoljeća izrazitim zagovornikom ove terapije bio je Wilhelm Griesinger,215 njemački liječnik i
sveučilišni profesor, kojeg su stenjevački psihijatri često citirali. S obzirom na činjenicu da su
stenjevački psihijatri bili obrazovani u austrijskim i njemačkim zavodima i na Griesingerov
utjecaj, odmor u krevetu je bio jedno od glavnih terapeutskih sredstava koje se primjenjivalo u
Stenjevcu. Držanje bolesnika u krevetima je u zavodima devetnaestog stoljeća imalo trostruku
svrhu. Prva svrha bila je povezana s poznatom psihijatrijskom paradigmom o „prenapregnutosti
živčanog sustava” kao uzroku duševne bolesti. Prema tome bilo je važno izolirati štićenika od
vanjskih podražaja kako bi mu se um odmorio.216 Slično rezonira i Žirovčić koji tvrdi da i sama
ludnica, zapravo, kod duševno oboljelih igra onu ulogu koju kod tjelesno oboljelih igra
bolesnička postelja.217 Također, Žirovčić je smatrao da je ležanje u krevetu za duševno oboljele
velika blagodat i da melankolični, histerični i neurastenični bolesnici vole ležati u krevetu dok
manične i nemirne treba na to privoliti silom, te je propisivao da je korisno da i nemiran bolesnik
leži u krevetu makar ga tamo trebalo i fizički zadržati.218 Drugi razlog zbog kojeg se pribjegavalo
smještanju bolesnika u krevet bilo je olakšavanje nadzora. Liječnik je mogao pratiti ponašanje,
tjelesnu temperaturu i puls219, a štićeniku je u geografiji zavoda bilo fiksirano lako pamtljivo
mjesto na kojem je provodio većinu vremena, što je olakšavalo ograničavanje kretanja i
sprječavalo mogućnost bijega. Pored toga, svrha propisivanja ostanka u krevetu bila je i u tome
da se što vjernije pokuša replicirati kontekst bolnice i odnosi koji su vladali u istoj. Ako je
štićeniku propisano mirovanje u krevetu, onda postaje očito da je on uistinu bolestan, što ga
navodi da lakše prihvati liječnikov autoritet.220 U Stenjevcu, štićenike bi se smještalo u krevete odmah po dolasku na određeni odjel. Često bi u
krevetu odležali po nekoliko dana221 prije nego što bi ih se pustilo u šetnju ili na rad. Odbijanje 87 ležanja u krevetu shvaćalo se kao znak agitacije i kao simptom bolesti pa su se natuknice poput
„izlazi više puta iz kreveta”222 u povijestima bolesti pojavljivale kako bi potkrijepile dijagnozu
duševne bolesti. No jednako tako se kao simptom navodi odbijanje ustajanja iz kreveta, što je u
skladu s vjerovanjem da bi pretjerivanje u upotrebi „krevetne terapije” moglo rezultirati
razvijanjem takozvanog „poriva za ležanjem” tj. bolesnikovog odbijanja da ikad napusti
krevet223. 4.5.1.Odmor u krevetu Prisilno smještanje u krevet se koristilo jedino kod bolesnika koji su bili agitirani, dok
se dugotrajno ostajanje deprimiranih bolesnika u krevetu nastojali obeshrabriti. g
224 Herceg, 1933: 12. 225 Ibid. 223 De Young, 2015: 21. 222 KPV, 1911: 8067. 226 Žirovčić, 1897: 359. g
225 Ibid. 4.5.2. Radna terapija Stenjevački zavod je otpočetka predviđao korištenje bolesnika za rad, ponajviše za rad u
poljoprivredi. Prilikom gradnje dvanaest i pol jutara zavodskog zemljišta je odvojeno za potrebe
zavodskog poljodjelstva.224 Radni kapaciteti zavoda uvelike su prošireni za vrijeme uprave
ravnatelja Ive Žirovčića kad je zavodskom gospodarstvu pridodano deset krava, četiri konja i
pedeset svinja, a osnovane su krojačka, postolarska, stolarska i tapetarska radionica. U svim tim
radionicama su rad bolesnika nadzirali od zavoda plaćeni strukovni namještenici.225 U psihijatrijskoj literaturi devetnaestog stoljeća, naročito u zapisima sljedbenika „moral
treatment” terapije ima puno primjera u kojima se ističe povoljan utjecaj fizičkog rada na psihu,
no takav je rad imao i svoje veoma opipljivo ekonomsko opravdanje. Rad štićenika činio je zavod
djelomično samoodrživim i manje ovisnim o državnim donacijama. Takav sentiment odražava i
Žirovčić kad kaže da je primarna svrha rada „da se bolesnici čine donekle korisnima i da
doprinose smanjenju troškova zavoda” te da „ne padaju na teret obitelji niti državi.”226 Jedan od
kriterija potrebnih da bi se štićenika smatralo izliječenim bila je spremnost istoga da radi na
poljoprivrednom imanju ili u jednoj od radionica. Muškarci su naravno češće bili zaduženi za
poljoprivredni rad, dok su žene uglavnom radile u krojačkoj radionici. Osim tih terapijskih
poslova, štićenici su također pomagali nositi ugljen za loženje u podrum zavoda, a za jednu od 88 štićenica je navedeno kako je barem tri godine radila kao sluškinja u stanu ravnatelja Šimse,
usprkos nekom sukobu kojeg je imala s ravnateljevom suprugom.227 Sami štićenici nisu uvijek shvaćali prirodu rada u zavodu. Neki od njih su tražili da budu što prije
pušteni na rad kako bi se osjećali korisnima. No mnogi od njih pokazuju otvoren otpor radu. Mara G. seljakinja iz Hercegovca je tako bolničarima rekla da ne želi ovdje raditi već „da je se
pusti kući pa će onda kući raditi”228. Postolarski pomoćnik Tomo G. koji je u Stenjevac doveden 1907. s dijagnozom „Paranoia
confusa” također nije shvaćao terapijski karakter rada. Čim je prispio u zavod tražio je da ga se
pusti kako bi izvan zavoda mogao „sebi zanatom steći kruh.”229 Nakon što je počeo raditi u
zavodskoj postolarskoj radionici počeo se tužiti kako „ne zna računa i nema svoje knjige”230. Nakon toga često pokušava pobjeći i napada bolničare tražeći da mu se plati za rad koji je obavio
u zavodu ili da ga se pusti da nastavi pošteno zarađivati kao postolarski pomoćnik. 227 KPV, 1911: 3401.
228 KPV, 1895:2216.
229 KPV, 1911: 6905.
230 Ibid. 230 Ibid. ,
229 KPV, 1911: 6905. ,
230 Ibid. ,
230 Ibid. 228 KPV, 1895:2216. 4.5.2. Radna terapija Radna terapija je u zavodu korištena dvadesetom stoljeća, a primjenjuje se i danas. Zanimljivo je
da je o korištenu rada u terapijske svrhe malo napisano u literaturi koja se bavi poviješću
psihijatrije, dok je isti imao bitnu ulogu u svakodnevici zavoda te je činio jednu od osnovnih
terapijskih praksi „moral treatmenta”. Povezanost duševnog zdravlja sa spremnošću za rad
zapravo odražava ulogu koji je građanski moral imao u diskursu devetnaestoljetne psihijatrije. U
svjetonazoru građanske klase visoko su vrednovani rad i produktivnost. Zavodi za umobolne nam
mogu, sa svojim radionicama, poljoprivrednim gospodarstvima i detaljno vođenim financijskim
knjigama, poslužiti kao sjajan primjer povezanosti psihijatrijske skrbi i razvijajućeg kapitalizma
te načina na koji je radna etika građanstva utjecala na medicinsko poimanje mentalnog zdravlja i
prirode psihičkih poremećaja. 89 ,
232 Žirovčić, 1905a: 280. 231 Foucault, 2006: 4. 232 Žirovčić, 1905a: 280. 4.5.3. „Fiksiranje” i ostali oblici autoritarnog podvrgavanja volji liječnika Ako slijedimo Foucaultovu paradigmu koja odnos moći gleda kao na mehanizam koji smješta
tijela u prostor, oblikuje ih i definira onda u mreži odnosa moći koji čine psihijatriju
najistaknutiju ulogu ima tijelo liječnika. Upravo je liječnik onaj nadzornik na vrhu Benthamova
panoptikona koji može kapilarno proširiti svoju moć čitavim zavodom i kao produžetak čije moći
zapravo zavod funkcionira. Posluživši se tekstom francuskom „moral treatment” psihijatra Jean
Ettienea Dominiquea Esquirola iz 1818 Foucault je ovako opisao pojavu liječnika: „Uopće, jedan od prvih uvjeta uspjeha u našoj profesiji je odlična, to jest muževna i plemenita
pojava- ista je neophodna kako bi se impresioniralo luđake. Tamna kosa, ili kosa osijedila od
godina, žive oči, udovi i prsa koji odaju snagu i zdravlja, istaknute crte lice i jak i izražajan glas
su prizori koji u pravilu imaju jak efekt na pojedince koji misle da su superiorni svima
ostalima“.231” Liječnik prvenstveno funkcionira kao impozantno tijelo koje je odraz autoriteta i moći. Naravno,
ako za trenutak stavimo Foucaultov „body politics” sa strane vidjet ćemo da je moć liječnika (a
osobito ravnatelja zavoda) prisutna i na mnoge druge načine. Upravo ravnatelj vodi brigu o
administraciji zavoda, zapošljava i otpušta osoblje, odjeli s pacijentima koji pokazuju najviše
poštovanja za zavodske propise su mu fizički najbliži te kao autoritet za teme duševnog zdravlja i
ludila zapravo oblikuje društveni diskurs o psihi. No u direktnom odnosu s pacijentom, zbog
razlike u obrazovanju i miljeu mora premostiti određen kulturni jaz. Taj jaz proizlazi i iz
emotivnog stanja pacijenta i njegovog stanja svijesti. Liječnik mora funkcionirati kao simbol
autoriteta, slika koja će bez mnogo riječi i argumentacije pokazati kako je upravo u njoj izvor
psihijatrijske moći. Takav pristup se smatrao nužnim jer su u svojoj nemoći i nedostatku
razumijevanja duševni bolesnici bili dugo smatrani „nepotpunim ljudima”, ili kako ih je Ivo
Žirovčić to jednom opisao „individualnostima manje vrijednosti”232 te je prema njima trebalo
postupati kao s djecom. I Eleaine Showalter je također, u analogiji koja povezuje viktorijansku
ludnicu s obiteljskim domom ravnatelju ludnice dala ulogu supruga i oca, a štićenicima ulogu
djece koju strog, ali pravedan otac odgaja i vraća na pravi put. U opisima zavoda iz 90 viktorijanskog perioda isti se često opisuju kao škole ili obdaništa233 Iz toga možemo zaključiti da
je uspješnost psihijatrijskog liječenja ovisila o stalnom potvrđivanju liječnikova autoriteta nad
pacijentima. Jedan od najdirektnijih i „najtjelesnijih” načina reaktualizacije tog specifičnog
odnosa moći bilo je takozvano „fiksiranje”. ,
234 Foucault, 1989: 129-130. 233 Showalter, 2001: 28. ,
234 Foucault, 1989: 129-130. 233 Showalter, 2001: 28. 4.5.3. „Fiksiranje” i ostali oblici autoritarnog podvrgavanja volji liječnika Fiksiranje je zapravo čin kojim liječnik „hvata” štićenikov pogled i dugotrajnim i autoritativnim
gledanjem utvrđuje svoju moć nad pacijentom. Upravo je fiksiranje ključni instrument
Foucaltovog „kliničkog zora” koji razdvaja pacijentovo tijelo od njegove individualnosti i
pretvara pacijenta u objekt medicinske dijagnoze.234 Za potpunu aktualizaciju psihijatrovog
autoriteta bitno je pacijentovo pokoravanje kliničkom zoru - pacijent mora prihvatiti
objektifikaciju i činjenicu da će njegovo tijelo za liječnike postati tek skup simptoma, svojevrsni
tekst bolesti preko, kojeg će se narativ njegovih kretnji, riječi i izraza lica prevoditi u medicinski
diskurs o duševnoj bolesti. Fiksiranje je prema tome, primjena kliničkog pogleda kojim se
primarno fiksira pacijentov položaj u odnosu liječnik-pacijent. Pacijent postaje onaj kojeg se
promatra, kojeg se ima pravo promatrati i sve što se sa štićenikom dogodi od dolaska u zavod do
njegovog izlaska iz zavoda bit će obilježeno tim promatranjem. Liječnik postaje onaj kojem
pacijent mora predati pravo na tumačenje njegovih postupaka. Pacijentova perspektiva postaje
bitna za daljnji razvoj njegove bolesti jedino ako ju liječnikov autoritet odobri, a tada jedino kao
simptom ludila. Duševna bolest tako postaje ne samo stanje pacijenta već i njegov identitet. Fiksiranje se u člancima stenjevačkih liječnika spominje zajedno s pojmom sugestije. Pojam
sugestije za psihijatre predstavlja nametanje vlastite moći pacijentu. To je epistemička moć je da
se tumači stvarnost: pacijent je bolestan ne zbog eventualne nelagode koju sam osjeća već upravo
zato što liječnik vidi bolest u njegovom tijelu. Prihvaćanje te sugestije bolesti, prihvaćanje
vlastitih stavova i osjećaja kao morbidnih prvi je korak prema ozdravljenju. Pritom valja
„sugestiju” razlikovati od suvremenog pojma „talking cure” prisutnog u psihoterapiji jer su
psihijatri devetnaestog stoljeća sami veoma rezolutni u odbacivanju ideje bilo kakvog govora s
psihički oboljelima kao s razumnim bićima. Žirovčić tako piše da „nastojiš li ludu čovjeku iz 91 glave izbiti njegove tlapnje i lude misli, na krivom si putu, nikad nećeš uspjeti”. 235 Žirovčić kao
glavno sredstvo psihijatrijskog liječenja, u humanističkoj maniri, navodi „duševni postupak”
pribjegavši sljedećoj analogiji kako bi istakao „roditeljsku” ulogu psihijatra u zavodu:„...kao što
odgojitelj duševnim utjecajem djeluje na razvijajuću se dušu dojenčeta, tako će i psychiater
djelovati na bolestnu dušu luđaka.”236 Pri fiksiranju pacijenta izrazito se važnom smatrala uspostava očnog kontakta. 235 Žirovčić, 1897: 232.
236 Ibid, 356.
237 De Young, 2015: 258.
238 KPV, 1911: 7946.
239 KPV, 1895: 2621.
240 KPV, 1911: 7789.
241 KPV, 1914: 5731.
242 KPV, 1911: 7281.
243 KPV, 1895: 2589.
244 Foucault, 2006: 305.
245 KPV, 1914: 5731.
246 KPV, 1910: 7579. 4.5.3. „Fiksiranje” i ostali oblici autoritarnog podvrgavanja volji liječnika O važnosti
pogleda kao instrumenta uspostavljanja dominacije govori i osnivač moderne psihijatrije Pinel
koji je opisao Willisa, liječnika kralja Georgea II kao čovjeka čiji je pogled dopirao u samo srce
pacijenta i koji je uz pomoć tog pogleda samog mogao uspostaviti autoritet nad pacijentom.237
Spremnost štićenika da uspostavi kontakt pogledom i tako bude „fiksiran” u svoju ulogu tijela
izloženog kliničkom zoru ima važnu ulogu u povijestima bolesti. Pogled štićenika opisuje se na
različite načine- bolničarima i liječnicima je tako važno kamo gledaju („Zagledala se u neku
točku”238 „gleda obično okolo”239) i kako gledaju („gleda plaho”240, „gleda ljutito”241) i
izbjegavaju li očni kontakt („neće ni da pogleda u lice”242, „ne može je se fiksirati”243). Pri fiksiranju pacijenta izrazito se važnom smatrala uspostava očnog kontakta. O važnosti
pogleda kao instrumenta uspostavljanja dominacije govori i osnivač moderne psihijatrije Pinel
koji je opisao Willisa, liječnika kralja Georgea II kao čovjeka čiji je pogled dopirao u samo srce
pacijenta i koji je uz pomoć tog pogleda samog mogao uspostaviti autoritet nad pacijentom.237 Pored bolničara i liječnika, štićenici također često naslućuju važnost „kliničkog zora” i razvijaju
taktike otpora prema istom. Foucault je histeriju objasnio kao otpor vrsti autoriteta koja se temelji
na pretvaranju tijela u predstavu simptoma koji zbunjuju klinički pogled liječnika svojom
nekonzistentnošću, naglim pojavljivanjem i nestajanjem i neuhvatljivom etiologijom.244 Povijesti
bolesti bilježe brojne suptilne i manje suptilne načine opiranja liječnikovom pogledu. Štićenice,
naročito često skrivaju lice rukama ili u jastuk245 ili direktno prigovaraju liječnicima zbog toga što
ih intenzivno gledaju („što me gledate kao da me hoćete pojesti”)246. Možda je i čin razodijevanja 92 kojem su brojni štićenici i štićenice pribjegavali imao ulogu tjeranja liječnika da odvrate pogled
od pacijenata. U svakom slučaju, fiksiranje je često primjenjivano, ali je rijetko o njemu pisano. Štićenici su ga svejedno, prepoznavali kao instrument kontrole i svjesno ili podsvjesno mu se
opirali. g
248 Žirovčić, 1897: 323. 247 De Young, 2015: 357. 249 LV, 1880: 30. ,
250 Žirovčić, 1897: 356. 249 LV, 1880: 30. 4.5.4.Sredstva za sputavanje i osamljivanje Terapijski princip „moral treatmenta” u anglo-saksonskoj je literaturi poznat i kao „non-restraint
princip” jer je uklanjanje mehaničkih mehanizama sputavanja pacijenata navodio kao svojevrsni
civilizacijski doseg. Usprkos tome, mehanička sredstva obuzdavanja štićenika još se uvijek
koriste u stenjevačkom i u drugim zavodima i njihovo korištenje se ne taji, već se prema istome
odnosi kao prema nužnom zlu koje je potrebno kako bi se osigurala sigurnost pacijenata. Među
sredstva mehaničkog obuzdavanja u Stenjevcu se koristi stavljanje pacijenta u izolaciju s
ograničenom mogućnošću kretanja („osamljivanje”) i razne vrste sprava za vezanje štićenika
(stezulje, užad, mrežasti krevet). Izolacija kao terapeutsko sredstvo je nešto što stoji iza same ideje zavoda kao institucije. Osamljena lokacija zavoda u pretežno ruralnom području247 i izdvajanje duševno bolenih osoba
kako od njihovih obitelji, tako od drugih već izoliranih grupa (poput zatvorenika ili kronično
oboljelih od tjelesnih bolesti)248 su prakse koje devetnaestoljetna psihijatrija neprestano ponavlja
kao presudne za izlječenje duševnih bolesti. Unutar zavoda, izolacija se provodi tako da se
štićenika smjesti u posebnu prostoriju (u Stenjvcu su ju zvali „samica” ili „soba za osamljivanje”)
čime se onemogućio kontakt štićenika sa ostalim štićenicima. Izolacijska soba u Stenjevcu je bila
dobro prozračivana i grijana249 s ležajem od konjske dlake, trave ili drvenih vlakana u koju su
štićenici stavljani goli 250 koji je osiguravao osamljenu osobu od slučajnih ozljeda. Štićenike se u
nju smještalo ako bi bili nemirni ili ulazili u fizičke sukobe s drugim štićenicima. 93 Od sredstava mehaničkog obuzdavanja najčešće su korištene stezulje i mrežasti kreveti. Stezulja
je korištena veoma često, kad bi štićenik bio agitiran i kad bi ga trebalo prisilno hraniti jer je
odbijao hranu (kao u slučaju pjesnika Vladimira Vidrića, koji je prisilno hranjen u stezulji jer je
vjerovao da je hrana otrovana251). Iako se „moral treatment” pokret hvalio svojim non-restraint
principom, proponenti istog su primjenjivali i preporučivali sredstva sa mehaničko sputavanje
duševno bolesnih, pa je čak i Pinel bio pobornik korištenja stezulje.252 Žirovčić opravdava
korištenje stezulje tvrdeći da „ona teoritično nije dozvoljena, dok se u praksi ne može vazda
izbjeći” 253i da bi ju se puno rjeđe koristilo kad bi bolničko osoblje bilo obučenije. 251 Župić, 1937: 343.
252 De Young, 2015: 451.
253 Žirovčić, 1897: 356.
254 KPV, 1880: 208.
255 De Young, 2015: 423.
256 KPV, 1914: 9095.
257 Goldberg, 2002: 7-8.
258 KPV, 1890: 1355.
259 De Young, 2015: 412. g
258 KPV, 1890: 1355. 259 De Young, 2015: 412. ,
254 KPV, 1880: 208. 253 Žirovčić, 1897: 356. 255 De Young, 2015: 423. 257 Goldberg, 2002: 7-8. 252 De Young, 2015: 451.
Ž 256 KPV, 1914: 9095. 251 Župić, 1937: 343. 4.5.4.Sredstva za sputavanje i osamljivanje No, korištenje
stezulje nije mnogo doprinosilo smirivanju bolesnika- povijest bolesti nekih od njih pokazuje da
su bili puno nemirniji u stezulji, dok bi im se ponašanje popravilo čim bi liječnici ili bolničari
uklonili stezulju.254 Zanimljivo je da Žirovčić u člancima ne spominje korištenje mrežastih
kreveta, koji su krajem devetnaestog stoljeća bili često kritizirani kao nehumani,255 dok povijesti
bolesti pokazuju da su se koristili prilično učestalo256. Prešućivanje pojedinih disciplinskih mjera,
ukazuje na činjenicu da se Žirovčić ipak nije htio previše izložiti osudi javnosti. Uzrok tome
može biti činjenica da su zavodi za umobolne u Njemačkoj bili izloženi žestokim kritikama zbog
sudske afere koju je potaknuo jedan gostioničar i antipsihijatrijski aktivist koji je razotkrio brojne
slučajeve okrutnog postupanja prema bolesnicima u jednom zavodu kraj Mariaberga.257 Osim
stezulja i mrežastih kreveta, povijesti bolesti upućuju na barem jedan slučaj u kojem se štićenica,
tužila da ju „vežu na križ”258. Opis tog postupka možda upućuje na primjenu takozvanog „križnog
položaja”. Tu praksu vezanja razvio je početkom devetnaestog stoljeća berlinski psihijatar Ernst
Horn. Osobu se uz pomoć užeta veže u stojeći položaj dok su joj ruke sapete rukavima stezulje i
privezane za zid iznad njezine glave259. Sama praksa je bila česta u njemačkim zavodima u
devetnaestom stoljeću, ali ponovno, jedini spomen nečeg što može indicirati na primjenu te vrste 94 sputavanja u Stenjevcu je govor jedne od pacijentica, koja se možda nije ni referirala na nešto što
se dogodilo u stenjevačkom zavodu. 260 Ibid, 83.
261 Žirovčić, 1897: 355.
262 KPV, 1881: bez broja.
263 Žirovčić, 1897: 355.
264 Goodman, 1970: 121-122. ,
264 Goodman, 1970: 121-122. j
263 Žirovčić, 1897: 355. 262 KPV, 1881: bez broja. 4.5.5. Rana psihofarmakološka terapija Budući da su gotovo svi lijekovi koji se u na prijelazu stoljeća koriste u Stenjevcu hipnotici, ranu
psihofarmakološku terapiju je teško gledati odvojeno od terapije smještanjem u krevet. Širokoj
primjeni hipnotika doprinijelo je i to što je u ondašnjoj medicini san imao izrazito istaknutu
ulogu, te se smatralo da je dobar san i uredan režim spavanja ključ zdravog života. Terapeutsko
djelovanje sna spominju još antički liječnici i u povijesti medicine se povoljno djelovanje istog na
organizam drugo podrazumijevalo. Ipak, unutar psihijatrijskih zavoda su prenapučenost, loši
životni uvjeti, velika buka i smrad i agitirani štićenici kojih je bio velik broj doveli do ponovnog
opetovanog isticanja važnosti sna za psihičko i fizičko zdravlje.260 Vrtoglav rast broja štićenika u
zavodima se dogodio u isto vrijeme kad i otkriće ranih sedativa i narkotika koji su ubrzo našli
široku primjenu pri uspavljivanju agitiranih štićenika i pomaganju onima koji su mučili od
nesanice ili anksioznosti. Iako Žirovčić nije smatrao hipnotike idealnim rješenjem, u svom se
članku složio da je san izazvan hipnoticima bolji od nikakvog sna, iako se njegova blagotvornost
ne da usporediti s potonjim.261 Od specifičnih lijekova u Stenjevcu se ranih godina često rabi
kloral-hidrat, sedativ sintetiziran 1869, kojeg stenjevački liječnici navode pod imenom
„chloral”262, a koji se tamo rabio za uspavljivanje onih štićenika koji zbog uzbuđenosti nisu mogli
spavati.263 Osim „chlorala”, u Stenjevcu se kao hipnotici koriste i trional i sulfonal, koji ubrzo
potiskuju kloral-hidrat. Također, barbiturat Veronal se u povijestima bolesti počinje spominjati
ubrzo nakon što ga se 1904. počelo distribuirati. Drugi lijek koji je još od početka osamdesetih godina devetnaestog stoljeća uživao široku
primjenu u hrvatskoj psihijatriji bio je kalijev bromid, kojeg hrvatski liječnici zovu bromkalij. Otkad je prvi put primijenjen 1857. godine za uspješno suzbijanje epileptičnih napadaja264,
bromkalij se smatralo jednim od najuspješnijih psihofarmakoloških preparata. Činjenica da 95 kalijev bromid ima i jaka sedativna svojstva i da ga je relativno lako dozirati i dati štićenicama
učinila je kalijev bromid najpopularnijim psihofarmakom kasnog devetnaestog stoljeća. 4.5.5. Rana psihofarmakološka terapija U
Stenjevcu se primjenjuje od samih početaka rada zavoda i propisuje ga se u velikom boju
dijagnoza- osim kod epileptičara daje ga se štićenicima kojima je dijagnosticirana melankolija
(zabilježeno je da je jedna od melankoličnih štićenica nakon terapije bromkalijem postala
veselija)265 i onima koji haluciniraju266, A Žirovčić ga hvali kao naročito učinkovit lijek pri
liječenju „hysteričnih, epileptičnih, neurastheničnih bolestnika, kao i sexualno-hypochondrične
senzacije.”267 Ako izuzmemo epileptičare, kalijev bromid je također disproporcionalno propisivan
štićenicama zbog uvjerenja da djeluje smirujuće na ženske reproduktivne žlijezde. Za smirivanje nemirnih bolesnika i onih koji su imale bolove, široko se koristi morfij što nije
nimalo iznenađujuće, budući da su morfij i ostali derivati opijuma temeljni anelgetici ondašnje
medicine koji i izvan zavoda imaju široku farmakološku primjenu. Iako ga Žirovčić tek ovlaš
spominje (možda upravo i zbog sveprisutnosti morfija) povijesti bolesti bilježe da se pojedine
pacijente tretiralo „velikim injekcijama morfija”.268 Čini se, ipak da je korištenje morfija s
vremenom postajalo sve rijeđe. U anelgetskoj i sedativnoj upotrebi ga je u velikom broju
slučajeva zamijenio hioscin, alkaloid dobiven iz bunike kojeg je 1880 sintetizirao njemački
znanstvenik Albert Ladenburg. Žirovčić hioscin, zajedno s njegovom podvrstom, duboisinom,
uglavnom preporuča za smirivanje nemirnih štićenika i onih koji su u delirantnom stanju.269 Za smirivanje nemirnih bolesnika i onih koji su imale bolove, široko se koristi morfij što nije
nimalo iznenađujuće, budući da su morfij i ostali derivati opijuma temeljni anelgetici ondašnje
medicine koji i izvan zavoda imaju široku farmakološku primjenu. Iako ga Žirovčić tek ovlaš
spominje (možda upravo i zbog sveprisutnosti morfija) povijesti bolesti bilježe da se pojedine
pacijente tretiralo „velikim injekcijama morfija”.268 Čini se, ipak da je korištenje morfija s
vremenom postajalo sve rijeđe. U anelgetskoj i sedativnoj upotrebi ga je u velikom broju
slučajeva zamijenio hioscin, alkaloid dobiven iz bunike kojeg je 1880 sintetizirao njemački
znanstvenik Albert Ladenburg. Žirovčić hioscin, zajedno s njegovom podvrstom, duboisinom,
uglavnom preporuča za smirivanje nemirnih štićenika i onih koji su u delirantnom stanju.269
Većina lijekova koja se koristi u Stenjevcu, sintetizirana je u Njemačkoj i najveću je primjenu
doživjela upravo tamo. Također, zavod je relativno brzo dobivao nove psihofarmake i počinjao ih
redovito koristiti. Svrha većine lijekova (s mogućim izuzetkom kalijeva bromida) nije bila
izliječenje duševne bolesti, pa čak niti ublažavanje simptoma (ako izuzmemo neispavanost) koji
su mučili štićenike već smirivanje nemirnih štićenika. Većina lijekova koja se koristi u Stenjevcu, sintetizirana je u Njemačkoj i najveću je primjenu
doživjela upravo tamo. 265 KPV, 1880: 257.
266 KPV: 1911: 6295.
267 Žirovčić, 1897: 355.
268 KPV, 1881: bez broja.
269 Žirovčić, 1897:355. ,
j
269 Žirovčić, 1897:355. 268 KPV, 1881: bez broja. 265 KPV, 1880: 257. 4.5.5. Rana psihofarmakološka terapija Također, zavod je relativno brzo dobivao nove psihofarmake i počinjao ih
redovito koristiti. Svrha većine lijekova (s mogućim izuzetkom kalijeva bromida) nije bila
izliječenje duševne bolesti, pa čak niti ublažavanje simptoma (ako izuzmemo neispavanost) koji
su mučili štićenike već smirivanje nemirnih štićenika. 96 ,
273 Scull, 2015: 278. 270 Scull, 2015: 181. 270 Scull, 2015: 181.
271 Ibid,182.
272 Braid, 1853: 16.
273 Scull, 2015: 278. 272 Braid, 1853: 16. 271 Ibid,182. 4.5.6 Hipnotizam Slika psihijatra kao hipnotizera koji liječi psihičke tegobe uz pomoć smirujućeg glasa, sugestije i
buđenja potisnutih sjećanja mnogo je starija od Sigmunda Freuda. Prvo povezivanje psihijatrije i
hipnoze ima svoje korijenjene u mesmerizmu ili „animalnom magnetizmu” pseudomedicinskoj
metodi koja je u 18. stoljeću postala izrazito raširena u mondenim krugovima plemstva i
imućnijeg građanstva. Mesmerizam je dobio ime po Franzu Antonu Mesmeru (1734-1815),
bečkom liječniku koji je tvrdio da je otkrio „životinjski magnetizam”- novu fluidnu silu koja
protječe kroz ljudska tijela.270 Mesmer je tvrdio kako se na tu silu može utjecati, bilo pomoću
magnetiziranih štapova, bilo pomoću vještine mesmerista.271 Naravno, ideja nevidljive sile je bila
u skladu s tadašnjim svjetonazorom elita u kojem su se misticizam i znanost često prožimali i
nadopunjavali. Mesmerove će ideje u devetnaestom stoljeću preuzeti i propagirati škotski liječnik
James Braid, koji će ih povezati sa činjenicom da dug i fokusiran pogled u jednu točku „paralizira
živčane centre u osjetilima i izbacuje živčani sustav iz ravnoteže, time uzrokujući sugestibilno
stanje koje je nazvao hipnozom”.272 Braid je odbacio dosadašnje pretpostavke da se kod hipnoze
radi o bilokakvom „životinjskom magnetizmu” i istakao da se radi o stanju koje je slično snu i
koje izaziva prenapregnutost živčanog sustava usred usredotočivanja. Braid je time
poznanstvenio hipnozu i iako njegova terapeutska metoda nikad nije doživjela širu legitimaciju
unutar medicine, ona ipak postaje praksom koju se sada primarno vezuje uz profesionalne
liječnike i to uz specifičnu vrstu liječnika, takozvanog „liječnika za živce”. Liječnici za živce su
uglavnom radili u privatnoj praksi, te liječili bogatije klijente koji su zbog velike stigme koju je
duševna bolest nosila izbjegavali obraćanje psihijatrima. Također, smatralo se da hipnoza može
biti koristim sredstvom anestezije pri kirurškim zahvatima, no otkriće kemijskih sredstava za
narkozu je učinilo takvu primjenu hipnoze nepotrebnom. Veliki terapeutski autoritet hipnozi je
dao Charcot koji ju je koristio prilikom svojih javnih demonstracija slučajeva histerije.273
Charcotovi eksperimenti krajem 1870-ih i početkom 1880-ih postaju široko poznati u europskoj
medicinskoj zajednici i tada raste interes za hipnozu među hrvatskim liječnicima. Psihijatri nisu
jedini koji prednjače u tome- liječnik Niko Selak, koji je radio kao općinski liječnik u Jelsi je 97 napisao jednu od najsustavnijih rasprava o hipnozi. U raspravi objavljenoj u Liječničkom vjesniku
1890. i 1891. Niko Selak se poziva na Charcota kad tvrdi da je hipnoza zapravo „na umjetni
način stvorena neurosa”274 i naširoko govori o njenim terapeutskim primjenama u anesteziji i pri
liječenju epileptičkih grčeva275. 274 Selak, 1891: 9.
275 Ibid, 10-11.
276 Forenbacher, 1886: 160.
277 KPV, 1895: 1435.
278 KPV, 1890: 2337. ,
278 KPV, 1890: 2337. 274 Selak, 1891: 9. 4.5.6 Hipnotizam Prije Selaka o hipnotizmu je pisao i stenjevački kućni liječnik
Dragutin Forenbacher koji govori o uspješnom liječenju „hystero-epileptične žene”
kombinacijom hipnoze i terapije kalijevim bromidom276 I Forenbacher i Selak nalaze potrebnim
iznijeti argumente za znanstveno utemeljenje hipnoze, što pokazuje da je ista kao terapeutska
metoda bila osporavana u medicinskim krugovima. Također, liječnici koji pišu o hipnozi nastoje
ju odvojiti od teorija o „animalnom magnetizmu” i tako prisvojiti medicini pravo na znanstveno
tumačenje hipnotičkih fenomena. S obzirom na prisustvo spiritizma u građanskim krugovima
kasnog devetnaestog stoljeća, medicinska struka se vjerojatno morala stalno boriti protiv
uvriježenih okultističkih predodžbi o hipnozi. Hipnoza se u Stenjevcu primjenjivala najviše tijekom vala interesa za hipnozu kojeg su među
psihijatrima izazvali Charcotovi eksperimenti i to ponajviše na štićenicima kojima su
dijagnosticirane histerija i epilepsija Sobarica Kornelija H. Primljena je u Zavod 1889 s
dijagnozom „hystero-epilepsije” čiji su glavni simptomi čini se bili „razvratan i raskalašen život”,
„strah od muškaraca” i „glavobolje i omaglice”. Po dolasku nije htjela odgovarati na pitanja
liječnika, no nakon što je hipnotizirana, počela je surađivati, a uz pomoć hipnoze su joj se
„odsugerirale” glavobolja i omaglica, te osjećaj tjeskobe.277 Osim histeričnih pacijentica, hipnoza
je primjenjivana i kod epileptičara, gdje liječnici i bolničari često navode njenu uspješnost.278
Početkom dvadesetog stoljeća čini se da se u terapeutski učinak hipnoze prestaje vjerovati te se
ista prestaje primjenjivati u stenjevačkom zavodu. 98 279 Rohaček, 1889:149.
280 Herceg, 1933: 12.
281 Žirovčić, 1897: 353.
282 LV, 1883: 101.
283 Rohaček, 1889: 150.
284 De Young, 2015: 147. 280 Herceg, 1933: 12. ,
284 De Young, 2015: 147. 279 Rohaček, 1889:149. ,
282 LV, 1883: 101. ,
283 Rohaček, 1889: 150. 281 Žirovčić, 1897: 353. 4.5.7. Prehrana Već je rečeno kako je u ranim danima stenjevačkog zavoda kao najčešći uzrok duševne bolesti
bila navođena „bijeda” ili „slabokrvnost zbog bijede”279. Nalaženje uzroka bolesti u materijalnoj
bijedi i važnost koju su uravnoteženoj i obilnoj prehrani pripisivali ravnatelji zavoda u kojima se
razvio „moral treatment” su rezultirale u činjenici da se u Stenjevcu posebna pažnja posvećivala
prehrani štićenika. Važnost zdrave, redovite i obilne prehrane bazirane na obilju ugljikohidrata i
bjelančevina je često isticana kako u inozemnoj, tako i u hrvatskoj psihijatrijskoj literaturi. Naravno, opskrba hranom je često bila otežana, a za vrijeme Prvog Svjetskog Rata, stenjevačkim
je zavodom zavladala glad.280 Važnost prehrane u Stenjevcu nazire se u kako u godišnjim izvješćima, tako i u člancima
liječnika. Ivo Žirovčić u svom članku o postupanju s duševno oboljelima govori kako hrana u
psihijatrijskim zavodima mora biti obilna zdrava i raznolika.281 U godišnjim izvješćima često se
detaljno navode troškovi hrane i „poboljšica” u prehrani štićenika. Izvješće za 1882. godinu tako
javlja da su se „bolestnikom tielesno propalim pružale u okviru jestvenika sve moguće
poboljšice: u jutro ili mlieko ili kava u 10 satih ili goveđa ili vinska juha, na obied ili pečenka ili
tiestenina.. a za južinu dobivalo je samo nekoliko bolestnikah kavu sa žemljom”282 Prema
izvješću za 1887. i 1888. na hranu bolesnika trošilo se dnevno 25.77 novčića, a za bolesnike koji
rade još se dodatno trošilo na duhan, vino i kavu te za „poboljšice” u vidu grožđa i voća.283 Iako se alkoholizam smatrao čestim uzrokom duševnih oboljenja, mnogi onodobni psihijatri
smatrali su da u umjerenim količinama može djelovati blagotvorno. To je gledište u psihijatriji
zastupao i poznati britanski liječnik Joseph Mason Cox, koji je smatrao da umjerene količine
alkohola pomažu kod liječenja melankolije.284 Slično misli i Žirovčić koji tvrdi da manje količine 99 alkohola ne mogu štetiti bolesniku iako nisu nužne za njegov oporavak. 285 Drugačiji je bio stav
njegovog prethodnika na mjestu ravnatelja zavoda, Ivana Šimse koji je bio žestoki protivnik
alkoholizma i pobornik potpune zabrane alkoholnih pića. Nakon Šimsina odlaska iz Stenjevca u
zavodu su se alkoholna pića mogla slobodno konzumirati. Vladimir Vidrić je, već anegdotalno,
prije smrti nazdravljao šampanjcem286 a zidarski pomoćnik Filip P. je tijekom 1910. 4.5.7. Prehrana godine
redovito dobivao alkoholna pića kao nagradu za zidarske poslove koje je obavljao u Zavodu, iako
je u Stenjevac primljen s dijagnozom alkoholizma.287 Budući da su mnogi od zavodskih štićenika prije dolaska u zavod živjeli u stanju egzistencijalne
oskudice koja je nedvojbeno mnogima utjecala na psihičko stanje, nije isključeno da je redovita
prehrana jedan od faktora koji je najvidljivije utjecao na poboljšanje stanje štićenika. Samim
time, razumljiva je terapeutska važnost koju su zavodski liječnici davali zdravoj i obilnoj
prehrani. Važnost prehrane postala je još izraženija kad se uzme u obzir da je prenapučeni Zavod
stalno bio na rubu oskudice i gladi. Većina planova o postepenoj sammodrživosti zavoda padala
je u vodu jer velik broj štićenika nije bio sposoban ni motiviran za radnu terapiju. Uz to vođenje
poljoprivrednog gospodarstva zahtijevalo je osobit tip znanja i iskustva kakvo ravnatelji zavoda,
obrazovani kao liječnici, nisu imali. Samim time, može se reći da je prehranjivanje štićenika, i
posljedično, prehrana općenito, postala neka vrsta opsesije zavodskih liječnika, zbog čega je
učestalo figurirala u njihovim studijama o skrbi za duševno oboljele. 286 Župić, 1937: 344. p ,
287 KPV, 1911: 6807. 285 Žirovčić, 1897:353. 285 Žirovčić, 1897:353.
286 Župić, 1937: 344.
287 KPV, 1911: 6807. 291 Lockheart Robertson, 1861: 267. 288 De Young, 2015: 307. 289 Ibid , 2015: 250. 293 Žirovčić, 1897: 356. 292 Ibid: 266. 292 Ibid: 266. 290 Žirovčić, 1897: 356. 290 Žirovčić, 1897: 356. 293 Žirovčić, 1897: 356. 4.5.8.Hidroterapija Primjena vode kao sredstva liječenja duševnih tegoba starija je od pojave zavodske psihijatrije i
svoja izvorišta vjerojatno ima u tradiciji toplica i ljekovitih kupki. Ljekovita svojstva vode
poznata su još od antike, a krajem osamnaestog i početkom devetnaestog stoljeća, takozvana
„kupališna medicina” postaje neka vrst trenda među plemstvom i građanskim elitama. Prve
terapije vodom u psihijatrijskim zavodima zapravo su služile plašenju štićenika. Naime, vjerovalo 100 se da jak i intenzivan strah može prenuti duševno oboljelu osobu i uzrokovati njeno ozdravljenje
što se nazivalo „salutornim strahom”.288 Prvi tip hidroterapije u modernoj medicini popularizirao
je Vincent Priessnitz početkom devetnaestog stoljeća. Priessnitz nije bio obrazovani liječnik, već
nadriliječnik ruralnog porijekla. Ipak njegova terapija vodom je postala izrazito popularna nakon
što je otvorio vlastitu kliniku za hidroterapiju i tvrdi da je uz pomoć vode zacijelio vlastite
prijelome rebara nakon nesreće s kolima.289 Među njegovim pacijentima bili su brojni pripadnici
društvenih elita, koji su u hidroterapeutskim metodama poput kupki tražili lijek za brojne živčane
teškoće. Njegov uspjeh pri primjeni hidroterapije ohrabrio je i brojne ravnatelje zavoda za
umobolne da, s većim ili manjim uspjehom, počnu primjenjivati hidroterapijske metode. Ravnatelji Stenjevca bili su uvjereni u ljekovita svojstva vode. Hidroterapija se u Stenjevcu
primjenjivala na dva načina: zamatanjem pacijenata u plahte i kupkama. Ravnatelj Žirovčić bio je
protiv nekih intenzivnijih tehnika koje su se primjenjivale u europskim umobolnicama,
smatrajući da one samo dodatno agitiraju pacijente.290 Primjena plahti na nemirnim pacijentima bila je jedna od tehnika koju je u praksu uveo Priessnitz
u svome liječilištu. Sredinom 19. stoljeća ju je u psihijatrijske institucije donio C. Lockheart
Robinson, ravnatelj umobolnice u Sussexu, koji je dao detaljan opis postupka: „Plahta od vodootpornog platna se položi preko madraca, a preko nje se stavi pokrivač. Obična
plahta se tada natopi vodom i rasprostre preko pokrivača. Pacijent se položi na plahtu koja se
brzo omota oko njega tako da mu i ruke budu umotane. Plahta je učvršćena oko tijela i preko
nje su položena još tri ili četiri pokrivača. Ispočetka pacijent malo drhti, no to ubrzo prolazi
kako se plahta zagrijava i kako krv dolazi na površinu tijela.”291 U članku u kojem opisuje tretman, Robertson ističe sedativna svojstva hladne vode292, a
Žirovčić postupak umatanja štićenika u plahte direktno uspoređuje s navlačenjem stezulje
nemirnom pacijentu.293 Čini se da su Priessnitzove hidroterapijske metode zadobile
disciplinirajući značaj kad ih se počelo primjenjivati unutar zavoda. 294 KPV, 1911: 7367.
295 KPV, 1914: 8715.
296 Ibid.
297 Rohaček, 1885: 60.
298 LV, 1883: 100-101. 4.5.8.Hidroterapija U psihijatrijskim 101 tekstovima ima malo pozivanja na blagotvorno djelovanje vode na liječenje duševnih oboljenja
već se primjena iste svodi na smirivanje nemirnih štićenika, što pokazuje velik odmak od
značaja koju je hidroterapija imala u folklornoj i kupališnoj medicini. Priessnitzova vjera u
čudotvorno djelovanje vode je pokleknula pred terapeutskim pesimizmom institucionalne
prakse; ono što je ostalo bila je primjena vode za sputavanje i umirivanje štićenika. Povijesti bolesti često svjedoče o disciplinskoj primjeni zamatanja u plahte i povremenoj upotrebi
kupelji. Gjuri Ž. su tako 1909. plahte određene kroz tri dana, nakon što je skupini pacijenata koji
su kartali oteo i bacio karte tvrdeći da slike na kartama prikazuju njegove rođake.294. Činjenica da
su mu plahte određene „kroz sljedeća tri dana” upućuje na to da takav tretman nije bio viđen kao
medicinski postupak terapije već kao disciplinski postupak kažnjavanja- zbog nemirnog
ponašanja štićenik će „dobivati plahte” bez obzira na eventualno poboljšanje njegovog duševnog
stanja. Marija S. koju je u Stenjevec smjestio suprug nakon što ga je odlučila napustiti također je bivala
zamatana u plahte, a u povijesti bolesti je navedeno da od plahti ima „silni rešpekt”295. Plahte su
na njoj primjenjivane u trajanju od dva sata svaki put kad bi bila nemirna i suprotstavljala se
bolničarima. Kasnije se navodi da je i prijetnja umatanjem u hladne plahte bila dovoljna da se
štićenica smiri.296 Osim navedenih terapijskih metoda jedno rano izvješće spominje primjenu elektroterapije, iako
ne pojašnjava u kojem se obliku ona tada primjenjivala.297 Nekim štićenicima davale su se i
tinkture željeza, vjerojatno kao dodatak prehrani, budući da se anemija usred neimaštine smatrala
jednim od glavnih uzroka duševne bolesti u zavodu298. U skladu s „moral treatmentom” velika se
pažnja pridavala slobodnom vremenu štićenika: zavod za umobolne je već nekoliko godina nakon
svog utemeljenja imao malu knjižnicu koja je prikupljena donacijama, kuglana te gusle, biljar i 294 KPV, 1911: 7367. 295 KPV, 1914: 8715. 296 Ibid. 297 Rohaček, 1885: 60. 298 LV, 1883: 100-101. 102 glasovir za „uglednije bolestnike” te tamburice za one iz „seljačkog stališa”299. Štićenici su
dobivali novine i časopise300, a vrijeme su kratili i kartanjem.301 Povijesti bolesti govore o određenom terapeutskom pesimizmu koji je vladao u Stenjevcu. Nema
pokušaja sustavne terapije niti dugotrajnog liječnikovog bavljenja pojedinačnim pacijentima. Pokušaji dijagnosticiranja konkretnih patoloških promjena na mozgu putem autopsija prestaju, a
sva gore navedena terapijska sredstva zapravo postaju disciplinska sredstva koja su trebala
omogućiti dobro vladanje štićenika. 299 Rohaček, 1885: 62.
300 KPV, 1911: 7842.
301 KPV, 1911: 7367. ,
300 KPV, 1911: 7842. 299 Rohaček, 1885: 62.
300 KPV, 1911: 7842. y
303 Ibid, 120-121. 302 Reddy, 2002: 145. ,
304 Ibid, 145. 5.Rod i seksualnost 5.Rod i seksualnost 304 Ibid, 145. 4.5.8.Hidroterapija Postupak prema štićenicima kako vrijeme odmiče, a broj
istih raste sve manje dobiva obilježje trajnog izlječenja, a sve više određenog oblika palijativne
skrbi povezane sa strogom disciplinom. Nejasno je je li svrha te discipline imala ulogu
podvrgavanja štićenika neospornog liječničkom autoritetu ili se jednostavno radilo o posljedici
prenapučenosti i nedostatka materijalnih i ljudskih resursa u Zavodu, što je dovelo do fokusa na
discipliniranje kako bi se jednostavno Zavod učinilo funkcionalnim unjegovoj ulozi mjesta na
kojem su se čuvali oni pojedinci koje je njihova okolina okarakterizirala opasnima za sebe i
druge. 103 304 Ibid, 145. y,
303 Ibid, 120-121. ,
304 Ibid, 145. 5.1.Rodne uloge i seksualnost u emotivnom režimu građanstva kasnog devetnaestog stoljeća 5.1.Rodne uloge i seksualnost u emotivnom režimu građanstva kasnog devetnaestog stoljeća
Pogledi psihijatara i štićenika na rod i seksualnost često su se razlikovali zbog toga što su
psihijatri bili pripadnici obrazovanih građanskih slojeva dok su štićenici Zavoda u Stenjevcu
najčešće bili osobe bez formalnog obrazovanja koje su dolazile iz ruralnih područja. Na kraju
devetnaestog stoljeća etički i filozofski nazori građanskih slojeva o seksualnosti, romantičnoj
ljubavi i rodnim ulogama bili su naturalizirani u načinu života, umjetnosti i znanosti. Odstupanja
od istih često su se gledala kroz prizmu moralnih devijacija ili duševne bolesti. Prije nego što se
objasni kako se unutar psihijatrije formirao diskurs o ljudskoj seksualnosti i rodu, potrebno je
promotriti koje su mjesto seksualnost, rod, tjelesnost i ljubav zauzimali unutar emotivnog režima
građanske klase, kojoj su psihijatri pripadali. Pojam emotivnog režima shvaćam u smislu u kojem ga je opisao William Reddy kao „skup
normativnih emocija i praksi, rituala i emotiva koji ih izražavaju i preko kojih se isti uče“ 302. Emotiv je Reddy definirao kao komunikacijski iskaz o emocijama, koji ima i deskriptivnu i
performativnu komponentu, budući da u isto vrijeme opisuje emocije i kroz aktivan iskaz nam
omogućuje da reflektiramo o istima303 Po Reddyju, emotivni režim je u temelju svakog
uspješnog političkog režima.304 Pristup institucijama u okviru kojih su formirani diskurzivni
elementi emocionalnog režima koji su se odnosili na tretman roda i seksualnosti bio je područje
djelovanja obrazovanih muškaraca iz građanskih ili aristokratskih slojeva. Same te institucije
nastajale su u okviru modernizacijskih procesa karakterističnih za devetnaestoljetna europska
društva. Odnos seksualnosti i psihijatrije zrcali predodžbe o odnosu između tijela i duše, odnosno tijela i
uma koje se intenzivno razvijaju od 17. stoljeća nadalje pod utjecajem razvoja svijesti o
„individualnom sebstvu”. Pod utjecajem reformacije i izmijenjenog odnosa prema religioznosti,
te pojave tiska i brže komunikacije ideja, razni filozofski, teološki i pučko-kulturni oblici odnosa 104 između duše i tijela kojima se opisivao čovjekov identitet se sve više formiraju kao modeli
dihotomije uma i tijela među kojima postoje različite vrste međuodnosa. Kartezijanska premisa
koja je definirala um kao izvor sebstva („self”) imala je dvije važne posljedice za poimanje
identiteta i poimanje roda. Prva je zamišljala sebstvo kao univerzaliziranu misleću strukturu,
povezanu s tijelom, ali ipak pojmovno odijeljenu od istog305. 305 Laqueur, 1990: 55. 305 Laqueur, 1990: 55.
306 Ibid,152.
307 Scull, 2009: 49.
308 Porter, 2003: 45.
309 Ibid. 308 Porter, 2003: 45. 306 Ibid,152. 307 Scull, 2009: 49. 309 Ibid. 5.1.Rodne uloge i seksualnost u emotivnom režimu građanstva kasnog devetnaestog stoljeća Druga bitna odrednica je da su se
rodne razlike počele uglavnom shvaćati kao tjelesne razlike - rod tako prestaje biti shvaćen
aristotelovski kao razlika između muškog djelatnog uzroka i ženskog materijalnog principa i
njegova se osnova počinje tražiti u biološkim razlikama muškaraca i žena306. Unutar
međuovisnosti uma i tijela, tijelo je još uvijek donekle shvaćano sekundarnim ili animalnim dok
je um, u svojim različitim koncepcijama od „racia” do „volje” smatran onime što razlikuje
čovjeka od životinje i stavlja ga na hijerarhijski povlašteno mjesto u prirodnom poretku. Unutar
tog poretka emocije su doživjele različit tretman - neke od njih poput melankolične tuge (u
književnom i intelektualnom diskursu devetnaestog stoljeća nazivana „spleen”) su pozitivno
predstavljane kao izraz duševne i intelektualne rafiniranosti307 dok su druge, poput bijesa, straha i
seksualne žudnje bile odrazom niže „životinjske” strane čovjeka. Ljubav je od početka bila
kognitizirana kroz antitetičke pojmove: tjelesna ljubav („eros” ili „cupidas”) bila je
suprotstavljena duhovnoj ljubavi („agape” ili „caritas”)308. Ista je distinkcija od samih svojih
početaka bila prožeta patrijarhalnim diskursom. U ranom novom vijeku tijelo je tradicionalno
predstavljano kroz lik senzualne Eve, a duša i kasnije razum identificirani su s Adamom. 309
Ukorijenjena slika čovjeka u obrazovanoj građanskoj kulturi tako je podrazumijevala uniju ili
„brak” ženske, putene tjelesnosti i maskulinog razuma i ta se arhetipska slika preslikavala na
kulturne i intelektualne koncepcije roda i seksualnosti. Također se dvojna „eros-agape” ljubav u
okviru građanske kulture kasnog osamnaestog i ranog devetnaestog stoljeća objedinjuje u pojmu
romantične ljubavi. Glavni aspekti romantične ljubavi kako se ona shvaća u zapadnom modernitetu su želja da se
djeluje u skladu s dobrobiti voljene osobe, želja da se provode vrijeme u neposrednoj blizini 105 voljene osobe i želja za fizičkim kontaktom i seksualnim odnosom s voljenom osobom.310 U tim
aspektima ujedinjeni su fizički i duhovni/intelektualni aspekti ljubavi, a rituali poput udvaranja,
sastanaka, darivanja, zaruka, pisanja ljubavne poezije i ljubavnih pisama (pisma su najčešće
posredovana) i vjenčanja vezali su romantičnu ljubav uz ideju obitelji kao afektivne zajednice. Podjela između javne i privatne sfere koja je karakterizirala građansko društvu je još jedan važan
aspekt u shvaćanju emocija i seksualnosti u devetnaestom stoljeću. Nastanak i razvoj javne sfere
kao prostora vidljivog društvenog djelovanja vezan je uz konstrukciju i elaboraciju posebnog
područja proizvodne i komercijalne djelatnosti. 313 Davidoff, 2003: 16, 310 Reddy, 2002: 107. 312 Davidoff, 1998, 93. 311 Davidoff, 2003: 15. 310 Reddy, 2002: 107.
311 Davidoff, 2003: 15.
312 Davidoff, 1998, 93.
313 Davidoff, 2003: 16, 314 Ibid, 19. 5.1.Rodne uloge i seksualnost u emotivnom režimu građanstva kasnog devetnaestog stoljeća Koncepti privređivanja kako bi se preživjelo i
ideja „profesije“ kao aspekta osobnog identiteta u velikoj su mjeri proizvodi devetnaestog
stoljeća.311 Leonore Davidoff pokazuje kako je u devetnaestom stoljeću ideja maskulinog
idenititeta bila usko povezana s posjedovanjem vlastitog rada kojim se ulazi u javni svijet
kapitalističke proizvodnje. Takvo poimanje proširilo se i na niže slojeve manualnih radnika koji
ju prihvaćaju kako bi kompenzirali za unižen položaj koji je manualni rad zauzimao. Odnos
prema radu i otuđenje istog u velikoj je mjeri utjecao na proširenje javne sfere i vezanost iste za
svijet profesionalaca. Žene su u tradicionalnim obiteljima bile podređene muškarcima i takav im
je odnos prema radu bio zapriječen.312U devetnaestom stoljeću javna sfera obuhvaća čitav niz
formi i funkcija: znanstvenu, religijsku, kulturnu, političku i ekonomsku.“313 S druge strane,
područje obiteljskog doma postaje povezivano s atmosferom intimnosti, afektivne obiteljske
zajednice i privatnosti. Budući da su žene u području javne sfere tradicionalno zauzimale
marginalno mjesto (s mogućom iznimkom žena iz radničkih slojeva koje su bile djelomično
prisutne u javnoj sferi proizvodnje dobara) muškarci su dominirali javnom sferom dok je ženama
bila prepuštena skrb o kućanstvu. Pored toga, muškarci su imali privilegiranu poziciju i mogli su
premošćivati javnu i privatnu sferu. Izvan obiteljskog doma bila su im dostupna brojna mjesta
poput klubova, kavana i bordela gdje su mogli uživati u više ili manje privatnim aktivnostima. Također, kao gospodar doma o čijem radu za plaću ovisi financijska obstojnost kućanstva,
muškarac je imao realnu moć nad domom kao prostorom artikulacije privatnog. S druge strane,
žene srednjih i viših društvenih slojeva bile su okružene mrežom neformalnih zabrana i 106 psiholoških barijere koje su ih sprečavale da djeluju izvan prostora vlastitog doma, pa čak i da ga
napuštaju bez pratnje.314 Takva demarkacija društvenog prostora utjecala je i na poimanje
emotivnosti i seksualnosti i učinila patrijarhat dominantnim aspektom emotivnog režima
građanske klase, dok je sam emotivni režim dodatno učvršćivao patrijarhalne društvene odnose. Pripisivanje kvaliteta senzualnosti i emotivnosti ženama, također je smjestila seksualnost i
emotivnost u područje privatne sfere i tako dodatno učvrstili semantičke asocijacije vezane uz
pojam ženstvenosti. Prema tome, možemo zaključiti da shvaćanje roda i seksualnosti unutar emotivnog režima
građanskih slojeva ima sljedećih elemente: 1. Ljubav između muškaraca i žena konceptualizira se kroz emotive i rituale romantične ljubavi
2. Odnos razuma i tijela je hijerarhiziran, pri čemu se razum identificira s muškarcima a tijelo sa
ženama. 1. 5.1.Rodne uloge i seksualnost u emotivnom režimu građanstva kasnog devetnaestog stoljeća Ljubav između muškaraca i žena konceptualizira se kroz emotive i rituale romantične ljubavi
2. Odnos razuma i tijela je hijerarhiziran, pri čemu se razum identificira s muškarcima a tijelo sa
ženama. 3. Postoji jasna podjela između javne i privatne sfere u kojoj javna sfera kao prostor političkog i
društvenog djelovanja pripada muškarcima. Seksualnost i tjelesnost pripadaju privatnoj sferi gdje
ih se regulira pomoću patrijarhalnih moralnih normi. 4. Postoje određene heterotopije seksualnosti, mjesta unutar kojih se seksualne prakse mogu
prakticirati na način suprotstavljen uobičajenim moralnim normama. Okviri društvene
prihvatljivosti ispoljavanja seksualnosti su mnogo manje rigidni za muškarce, gdje je seksualna
transgresija društveno institucionalizirana kroz kulturu bordela. Ženska seksualnost ostaje
svedena na žensku reproduktivnu ulogu i posve potisnuta iz javne sfere, a emocije vezane uz istu
bivaju ili moralno osuđivane ili patologizirane kao znak duševnih bolesti ili mentalne devijacije. Primjeri ovakvog emotivnog režima u životu građanske klase u Hrvatskoj devetnaestog stoljeća
su brojni, a nalazimo ih u intelektualnim i književnim publikacijama i u svakodnevici građanskog
društva. Udvaranje i odnosi između mladića i djevojaka bili su u građanskom društvu strogo
ritualizirani. Iskra Iveljić navodi brojne primjere iz bontona pisanih krajem devetnaestog i
početkom dvadesetog stoljeća. Pravila pristojnog ponašanja su tako nalagala suzdržavanje od bilo
kakvih tjelesnih kontakata čak i između zaručnika:„Zaručnici su morali izbjegavati da budu sami, 314 Ibid, 19. 107 morali su voditi pristojnu konverzaciju, što je značilo da nisu mogli razgovarati o svojim
osjećajima, a tjelesni su dodiri morali biti vrlo čedni.”315 Nekad se i iz samih proskribiranih ponašanja mogu nazrijeti prakse u koje su se zaljubljeni
upuštali. Djevojkama je tako bilo zabranjeno pisati ljubavna pisma, a ako su ih primile morale su
ih odmah predati roditeljima316 no to nije sprječavalo intenzivnu razmjenu ljubavnih pisama koja
obiluju izrazima karakterističnim za koncept romantične ljubavi. Pismo Vladimira Deželića
njegovoj zaručnici Tonki tako obiluje izrazima poput „angjeo...ideal...nada...ljubav” i
reminiscencijama na njihova druženja uz glasovir gdje mu je Tonka šaptala „Tvoja...samo
tvoja”317. Roman Mala Revolucionarka Marije Jurić Zagorke, čija je radnja smještena u vrijeme
banovanja Khuena Hedervaryja, obiluje opisima ritualiziranog udvaranja. Djevojkama Nadi i
Zlati obožavatelji tajno upućuju pisma preko posluge318 ili ih bacaju na prozor pretvarajući se da
šeću ulicom pored njihove kuće. Takav ritual njihova starija rođakinja Elza naziva „Fenster
promenadom“.319 Identifikacija razuma s muškošću, a tjelesnosti s femininošću je česta u kulturi devetnaestog
stoljeća te je prisutna u svim intelektualnim krugovima. 315 Iveljić, 2007: 321. g
320 Porter, 2003: 216-217. 315 Iveljić, 2007: 321.
316 Ibid.
317 Ibid.
318 Zagorka, 1988: 18.
319 Zagorka, 1988: 21-22.
320 Porter, 2003: 216-217.
321 Iveljić, 2007: 320. 321 Iveljić, 2007: 320. g
,
319 Zagorka, 1988: 21-22. 317 Ibid. 316 Ibid. 318 Zagorka, 1988: 18. 5.1.Rodne uloge i seksualnost u emotivnom režimu građanstva kasnog devetnaestog stoljeća Čak i rane feministkinja poput Mary
Wollstonecraft kao problem ističu opsesiju djevojaka vlastitim tijelom što ih čini putenima i
taštima, „životinjama jedino prikladnim za seraglio”. Mary Wollstonecraft smatra taj trend
posljedicom lošeg odgoja koji naglašava brigu o fizičkom izgledu nauštrb duhovnog razvoja320. Povezivanje žena s putenošću i seksualnošću vidljivo je i u opsesivnoj kontroli kojima je društvo
nastojalo podvrgnuti njihova tijela - od restriktivnih korzeta do strogog pravila kojima se
propisivalo prihvatljivo tjelesno držanje i hod. Djevojkama je tako bilo zabranjeno „zibati se,
obijesno poskakivati i oholo se previjati.”321 Ukratko, bilo kakvo privlačenje pažnje na tijelo žene
bilo je osuđivano, osim u onim primjerima kad je ono bilo pod strogom kontrolom i u službi
muškog pogleda kao u primjerima bordela ili u medicinskom spektaklu histerije o kojem će
kasnije biti riječi. Proces histerizacije ženskih tijela, koji je od početka prisutan u psihijatriji
devetnaestog stoljeća (a intenzivirat će se šezdesetih i sedamdesetih godina devetnaestog stoljeća 108 u Charcotovom spektaklu histerije) ima u korijenu upravo semantičko povezivanja žene s
tjelesnim, a tjelesnog sa seksualnim. Histerizacija ženskih tijela koja je, prema Foucaultu,
trodijelni proces kojim su ženska tijela analizirana kao „sustavi iskonski zasićeni seksualnošću”
bio je integriran u sferu medicinskih praksi, te na kraju stavljen u organsku komunikaciju s
društvenim tijelom, obiteljskim prostorom i brigom o potomstvu.322 Histerizaciju možemo
shvatiti i kao pokušaj legitimiranja antičkog aristotelovskog shvaćanja žene kao materijalnog
principa u diskursu medicine. Ako je, naime, suvremena znanstvena i politička paradigma
iziskivala biološku uvjetovanost razlika između spolova, patrijarhalna je ideologija morala naći
legitimiranje rodne nejednakosti u tijelima. Bujanje javne sfere krajem osamnaestog i početkom
devetnaestog stoljeća neprestano je dovodilo pitanje rodne ravnopravnosti na dnevni red, a
modernizacija društva činila je stare transcendentalne izvore razlikovanja među rodovima sve
manje uvjerljivima323. Zbog toga su rodne razlike morale iznaći svoju legitimaciju u biologiji i
medicini, a histeričnost ženskog tijela je „otkrivena” kao strukturni temelj konstruirane biološke
nejednakosti i „manje duševne vrijednosti” žena. Iako se ideja formirala na znanstvenom polju
neuropsihijatrijske znanosti, već na prijelazu stoljeća hiperseksualizirana histerična junakinja
napustila je medicinsku sferu i postala dijelom uvriježenog društvenog imaginarija kojim se
prikazivalo žene. To dokazuju brojni primjeri iz književnosti; Ksaver Šandor Gjalski tako u svom
romanu Đurđica Agićeva objavljenom 1889. j
325 Kovačić.2015: 66. 322 Foucault, 1998: 104.
323 Laqueur, 1990: 152.
324 Gjalski, 1964: 28-29.
325 Kovačić.2015: 66.
326 Ibid, 235. 323 Laqueur, 1990: 152. 324 Gjalski, 1964: 28-29. 326 Ibid, 235. 322 Foucault, 1998: 104. 326 Ibid, 235. 5.1.Rodne uloge i seksualnost u emotivnom režimu građanstva kasnog devetnaestog stoljeća opisuje ushit zbog pedagoškog zvanja svoje
junakinje istaknuto somatizirajući njezine misli i emocije:„Nešto snažno, mlado i jedro sijevnulo
bi joj u taki tren dušom, a nježno nad poslom prignuto tijelo čisto bi uvis poraslo.”324 Ne samo da u trenutku ushita Đurđica reagira svojim čitavim „nježnim” tijelom nego su i njezini
dojmovi opisani epitetima kakvima se najčešće opisuju tijela (snažno, mlado, jedro). Ante
Kovačić je svoju fatalnu Lauru definirao događajima iz prošlosti koji su svi redom seksualne
prirode: začeta je silovanjem325, upušta se u incestnu vezu s ocem, sama je žrtva silovanja, a svoju
motivaciju crpi iz libidne strasti za muškarcima. Na kraju do svoje osvete dolazi seksualnim
sakaćenjem Ivičine supruge Anice.326 Ljudmila Borković iz Propalih dvora Janka Leskovara je
pak književni lik junakinja na čije je emotivno stanje pod stalnim utjecajem muškaraca iz njezine 109 neposredne okoline, a njezine svakodnevne kretnje poput popravljanja ukosnice opisane su kao
da odišu senzualnošću. 327 Naravno, muški likovi u hrvatskoj prozi prijelaza stoljeća će najčešće u
svojim akcijama biti vođeni razumom, ili barem čuvstvima i uvjerenjima koja pokazuju njihove
mentalne snage ili slabosti, dok je kod junakinja aspekt tjelesnog opetovano naglašavan. Postupno uklanjanje tjelesnog iz javne sfere proces je koji je kao dio „civilizacijskog procesa”
opisao sociolog Norbert Elias. On na temelju izvora iz ranog novog vijeka bilježi sve veće
sužavanje emotivne granice srama i sve više restrikcija vezanih uz odnos prema tijelu i
seksualnosti. Tako od šesnaestog stoljeća nadalje golotinja u javnosti postaje sve manje
prihvatljiva i raste razina društvenih inhibicija vezanih uz javno prikazivanje seksualnosti.328
Naravno, kao što je Foucault istaknuo, devetnaesto stoljeće ne odlikuje isključivo potiskivanje
seksualnosti iz javne u privatnu sferu već i proizvodnja raznih hijerarhiziranih diskursa o
seksualnosti.329 Na prijelazu stoljeća se javlja proliferacija znanstvenih i medicinskih djela koja
tematiziraju seksualnost od Krafft-Ebingove Psychopatia sexualis (1886) do Freudovih Tri eseja
o teoriji seksualnosti (1905). Pored proliferacije znanstvenih diskursa, u određenim kontekstima
seksualna transgresija poprima obilježja javnog spektakla: suđenje transvestitima iz visokog
društva Ernestu Stelli Boultonu i Fredericku Fanny Parku probudilo je širok interes londonskog
tiska i zainteresirane javnosti koja je iz tjedna u tjedan popunjavala sudnicu.330 Sličan interes
pobudilo je i suđenje piscu Oscaru Wildeu. Seksualnost je tako u javnoj sferi postala prisutna ili
kao znanstveni diskurs ili kao karnevalski spektakl transgresije. Uz marginalizaciju seksualnosti
javila se i marginalizacija žena koje bivaju isključene iz rastuće sfere političke javnosti. 328 Elias, 2000: 138-139. 327 Leskovar, 1993:207. 327 Leskovar, 1993:207.
328 Elias, 2000: 138-139.
329 Foucault, 1998: 30.
330 Kaplan, 2005: 89.
331 Iveljić, 2007: 321.
332 Ibid, 320.
333 Ibid, 290. 329 Foucault, 1998: 30. 330 Kaplan, 2005: 89. 331 Iveljić, 2007: 321. 333 Ibid, 290. 5.1.Rodne uloge i seksualnost u emotivnom režimu građanstva kasnog devetnaestog stoljeća Dok
muškarci i adolescenti vrijeme provode u kavanama diskutirajući o politici,331 pisci bontona
preporučuju da se takve teme izbjegavaju pred ženama jer bi to moglo „povrijediti njihovu
tankoćutnost”.332 Iako žene u devetnaestom stoljeću sve više javno i politički djeluju, njihovo
javno djelovanje, kad nije ograničeno na prostor dobrotvornog rada333 smatra se transgresijom
koju se ponekad ismijava i moralno osuđuje, a ponekad se smatra znakom duševne bolesti. 110 Također, prostor bordela postaje prostor nesmetanog prakticiranja muške seksualnosti. Zagrebačke gradske vlasti u devetnaestom su stoljeću tako blagonaklono gledale na svijet bordela
i krčmi koji se pružao današnjom Tkalčićevom ulicom i Kožarskom ulicom.334 Rad „bludilišta”
bio je reguliran posebnim gradskim propisima, ali ona nisu bila na udaru formalnih zabrana. Nalazila su se na mjestu doticaja privatne i javne sfere i tvorila su određenu vrstu heterotopije za
slobodno iskazivanje seksualnosti. Polujavni karakter bordela i razvratnih krčmi jedan je od
primjera koji najbolje ilustriraju asimetrične poglede građanskog društva na seksualnost. Iako
relegirana na privatnu sferu, o istoj se sve više govori kao o rubnom prostoru javne sfere,
prostoru koji se nastoji iskoristiti za afirmaciju i legitimaciju patrijarhalnog poretka. Taj pogled
prenijet će se i na psihijatriju: seksualno će u psihijatriji biti isključivo prisutno kao ilustracija
tjelesnog i „seksualne” prirode ženskog spola ili kao spektakl „devijantne” seksualnosti kojem je
cilj potvrditi teorije o moralnoj i duševnoj degeneraciji društva. ,
335 Borossa, 2003: 19. ,
336 Scull, 2009: 82. 334 Ibid, 319. 334 Ibid, 319. 5.2. Spektakl histerije u Stenjevcu Pariški psihijatrijski zavod Salpêtrière postao je u drugoj polovici devetnaestog stoljeća
prostorom seksualiziranog spektakla histerije. Neuropsihijatar Jean-Martin Charcot povezao je
vlastiti znanstveni interes za traženje tjelesnog uzroka histerije s talentom za javne nastupe i
organizirao medicinske demonstracije na kojima je javnost mogla uživati u prizorima seksualno
nesputanog i erotiziranog ponašanja Charcotovih štićenica. Neke od njih, poput Louise Augustine
Gleizes i „kraljice histerika” Marie Blanche Wittman postale su slavne zbog svojih izvedbi a sam
Charcot uživao je u pariškom tisku komičnu i grandioznu titulu „Napoleona neuroza” .335 Charcot je svoju praksu temeljio na bogatoj medicinskoj tradicija „liječnika za živce”
sedamnaestog i osamnaestog stoljeća. Ti liječnici su uglavnom bili praktičari koji su tretirali
bogate slojeve plemstva i građanstva. Njihov novi uvid u histeriju ogledao se u tome da se uzrok
iste prestao vezivati uz maternicu, te ga se počelo tražiti u „slabosti nervne konstitucije.”336
Dijagnostički i etiološki temelji histerije prvi su put detaljno opisani u sedamnaestom i
osamnaestom stoljeću (sam termin vuče porijeklo iz antičke medicine). U devetnaestom stoljeću
histerija postaje sveprisutna u medicinskom govoru i javnom diskursu - zavodi za umobolne ju
bilježe kao dijagnozu, simptom ili uzrok oboljenja. Sanatoriji, toplice i lječilišta u medicinskim se 111 časopisima reklamiraju kao mjesta koja nude obilje raznih tretmana za histerične poteškoće.337
Charcot dolazi na vrhuncu tog vala medicinskog i laičkog interesa za histeriju i pokreće trend
intenzivnog istraživanja i eksperimentalnog tretiranja histerije koje će na kraju kulminirati u
psihoanalitičkom obratu koji je stavio histeriju u središte novog psihodinamskog modela ličnosti. Charcota je bitno spomenuti i zbog njegove uloge u konstruiranju histerije kao poremećaja. Njegovo tendenciozno čitanje ranijih medicinskih tekstova i „histeriziranje” povijesnih fenomena
poput vjerskih ekstaza i zaposjednutosti demonima pomoglo je u prepoznavanju histerije kao
poremećaja koji je bio oduvijek prisutan. Uz stvaranje kontinuiteta između nejasnih dijagnoza
poput Galenovog „gušenja maternice” i histerije kakvu su opisali liječnici osamnaestog stoljeća,
Charcot je uveo standardiziran set simptoma koji za tu dotad prilično različito opisivanu
protejsku bolest. Time Charcotov spektakl histerije dobiva novo značenje- nije se samo radilo o demonstraciji
histeričnih simptoma pred auditorijem pariške javnosti već su Charcot, njegovi asistenti i njegove
štićenice kroz te nastupe zajedno konstruirali novi diskurs o histeriji koji je istovremeno bio
zagrnut aurom erotike i medicinskim autoritetom. Time je histerizacija ženskih tijela o kojoj
govori Foucault zapravo konačno institucionalizirana u psihijatrijskom diskursu. ,
338 Showalter, 1993: 335. 337 Porter,1993: 228. ,
339 Ibid, 336. 339 Ibid, 336. ,
339 Ibid, 336. 5.2. Spektakl histerije u Stenjevcu Dragutin Forenbacher „objavljuje svoje predavanje o
liječenju hystero-epileptične žene bromkalijem i hipnozom”.344 Radilo se o njegovoj privatnoj
pacijentici dvadesetogodišnjoj Ružici K. koja nije bila štićenica zavoda. Sam članak opisuje
jedino prvu od četiriju Charcotovih faza histeričnog napadaja, a fokusira se više na hipnozu kao
metodu liječenja nego na samu histeriju, iz čega se može zaključiti da je histerija sama po sebi
bila dobro poznata hrvatskim liječnicima. Čini se da Forenbacher, u skladu s organicističkom
tradicijom, nalazi hereditet uzrokom histerije, opisujući Ružičinu majku kao „veoma
neurastheničnu bolujuć od histerije”.345 Forenbacher će kasnije i demonstrirati jedan slučaj Po Charcotu, histerija ima četiri prepoznatljiva stadija koja se uvijek javljaju u pravilnom slijedu
jedan za drugim. Prvi je bio takozvani epileptoidni period u kojem bi pacijentica pretrpjela
konvulzivni napadaj sličan epileptičnom. Njega je slijedio „period previjanja i grandioznih
pokreta” u kojima bi pacijentica činila dramatične poze, od kojih je najpoznatija bila poza
nazvana „arc de cercle” u kojoj bi se pacijentica savila unatrag tako da su joj samo vrh glave i
pete doticale pod340. Charcot je tvrdio da može izazvati taj stadij pritiskom u predjelu jajnika, na
mjestu koje je nazivao „histeriogenom zonom”341 i nazivao je te poze „klaunizmima”
(clownisme)342. Treća faza sastojala se u usvajanju takozvanih „attitudes passionelles” u kojima bi
pacijentice prikazivale poze nalik „razapinjanju” ili „erotskoj ekstazi”. Nakon te faze slijedila bi
faza karakterizirana halucinacijama i sumanutim mislima, nakon koje bi napadaj prošao.343 Hrvatski su se liječnici pri svojim opisima histerije često oslanjali na Charcota, a najraniji
izvještaji o histeriji opisani u Liječničkom vjesniku datiraju iz osamdesetih godina devetnaestog
stoljeća. Budući da je to vrijeme Charcotove najveće aktivnosti, one svjedoče o činjenici da su
Charcotove demonstracije bile poznate liječnicima diljem Europe. Izvješće iz zavoda u Stenjevcu
koje potpisuje doktor Rohaček a koje datira iz 1885. i koje pokriva prvih šest godina rada zavoda
ne spominje histeriju kao mogući uzrok bolesti ili dijagnozu. No već iduće godine u Liječničkom
vjesniku kućni liječnik u Stenjevcu dr. Dragutin Forenbacher „objavljuje svoje predavanje o
liječenju hystero-epileptične žene bromkalijem i hipnozom”.344 Radilo se o njegovoj privatnoj
pacijentici dvadesetogodišnjoj Ružici K. koja nije bila štićenica zavoda. Sam članak opisuje
jedino prvu od četiriju Charcotovih faza histeričnog napadaja, a fokusira se više na hipnozu kao
metodu liječenja nego na samu histeriju, iz čega se može zaključiti da je histerija sama po sebi
bila dobro poznata hrvatskim liječnicima. 344 Forenbacher, 1886: 158. 340 Scull, 2009:124. 5.2. Spektakl histerije u Stenjevcu Charcot je,
doduše, prepoznavao histeriju kod muškaraca i to najčešće kod manualnih radnika nižeg socio-
ekonomskog statusa,338 no to ne znači da sama histerija u Charcotovim demonstracijama nije
imala rodni karakter. Kao prvo, Charcot je smatrao da histerija kod muškaraca ima drugačiji
uzrok nego histerija kod žena. Kod žena, histerija je bila uzrokovana njihovom krhkom
emocionalnom prirodom i nemogućnošću žena da kontroliraju svoje emocije, dok je uzroke
muške histerije Charcot tražio u fizičkoj traumi živčanog sustava zadobivenoj radom,
alkoholizmom ili seksualnim ekscesima. Prema tome, kako Elaine Showalter tvrdi: „histerične
žene su patile od ekscesa vezanih uz feminina ponašanja, a histerični muškarci od ekscesa
vezanih uz maskulina ponašanja.”339 Također, nizak socio-ekonomski status Charcotovih
muškaraca implicirao je njihovu drugotnost, a traženje uzroka u alkoholu i seksualnom razvratu
projiciralo je građanske moralističke predrasude o načinu života radničkih slojeva. Može se 112 također reći da Charcotov tretman muških pacijenata nije imao obilježje seksualiziranog
spektakla, kao što je to slučaj s njegovim „kraljicama histerije”. Po Charcotu, histerija ima četiri prepoznatljiva stadija koja se uvijek javljaju u pravilnom slijedu
jedan za drugim. Prvi je bio takozvani epileptoidni period u kojem bi pacijentica pretrpjela
konvulzivni napadaj sličan epileptičnom. Njega je slijedio „period previjanja i grandioznih
pokreta” u kojima bi pacijentica činila dramatične poze, od kojih je najpoznatija bila poza
nazvana „arc de cercle” u kojoj bi se pacijentica savila unatrag tako da su joj samo vrh glave i
pete doticale pod340. Charcot je tvrdio da može izazvati taj stadij pritiskom u predjelu jajnika, na
mjestu koje je nazivao „histeriogenom zonom”341 i nazivao je te poze „klaunizmima”
(clownisme)342. Treća faza sastojala se u usvajanju takozvanih „attitudes passionelles” u kojima bi
pacijentice prikazivale poze nalik „razapinjanju” ili „erotskoj ekstazi”. Nakon te faze slijedila bi
faza karakterizirana halucinacijama i sumanutim mislima, nakon koje bi napadaj prošao.343
Hrvatski su se liječnici pri svojim opisima histerije često oslanjali na Charcota, a najraniji
izvještaji o histeriji opisani u Liječničkom vjesniku datiraju iz osamdesetih godina devetnaestog
stoljeća. Budući da je to vrijeme Charcotove najveće aktivnosti, one svjedoče o činjenici da su
Charcotove demonstracije bile poznate liječnicima diljem Europe. Izvješće iz zavoda u Stenjevcu
koje potpisuje doktor Rohaček a koje datira iz 1885. i koje pokriva prvih šest godina rada zavoda
ne spominje histeriju kao mogući uzrok bolesti ili dijagnozu. No već iduće godine u Liječničkom
vjesniku kućni liječnik u Stenjevcu dr. 343 Ibid. 341 Showalter, 1993: 334 . 342 Scull, 2009: 124. 345 Ibid. 345 Ibid. 343 Ibid. 350 Selak, 1890: 170.
351 Na primjer oglas iz LV, 1888. str. 48 ili Stojanović, 1888: 140.
Ž p
j
g
,
j
,
352 Žirovčić, 1905a: 275. 353 Ibid, 275-276. p
j
g
352 Žirovčić, 1905a: 275. 351 Na primjer oglas iz LV, 1888. str. 48 ili Stojanović, 1888: 140. 353 Ibid, 275-276. 350 Selak, 1890: 170. 349 Ibid.
350 Selak, 1890: 170.
351 N
i j
l
i LV 1888
48 ili S j
ić 1888 140 5.2. Spektakl histerije u Stenjevcu I premda je histerija
zabilježena i kod muškaraca, Žirovčić ju ovdje opisuje kao poglavito žensku bolest koja upravo
zbog toga vuče ime od riječi za maternicu.352 Žirovčić, u svom povezivanju histerije s rodom
odlazi još korak dalje od Charcota i europskih psihijatara i navodi kako je histerija „zbirka
ženskih slabosti u pojačanom i iskrivljenom obliku: nestalnost, hirovitost, razdražljivost,
samoljublje, taština, lažljivost, okrutnost, podlost, ujedljivost, himbenost, nepromišljenost,
lakovjernost, uporna tvrdoglavost, kićenost, raznježenost i boležljivost.”353 Također, umjesto
Charcotovog preciznog opisa četiriju distinktivnih faza histerije i niza diferencijalnih simptoma 114 114 (poput „globusa hystericusa”, osjećaja gušenja u grlu koji je svojstven ranim fazama histeričnog
napadaja)354, Žirovčić u maniri starije medicinske tradicije ponovno opisuje histeriju kao
protejsku bolest koju je moguće prepoznati na temelju bilo kojeg seta simptoma, pa tako kaže da
„ne ima bolestnoga pojava koji se ne bi mogao u obliku hysteričnom prikazati.”355 Čini se da je,
nasuprot Charchotu i nekim drugim hrvatskim liječnicima Žirovčić bio uvjeren da od histerije
oboljevaju jedino žene. Čak i kad govori o epidemijama masovne histerije, on isključivo govori o
ženama kao akterima takvih pojava: (poput „globusa hystericusa”, osjećaja gušenja u grlu koji je svojstven ranim fazama histeričnog
napadaja)354, Žirovčić u maniri starije medicinske tradicije ponovno opisuje histeriju kao
protejsku bolest koju je moguće prepoznati na temelju bilo kojeg seta simptoma, pa tako kaže da
„ne ima bolestnoga pojava koji se ne bi mogao u obliku hysteričnom prikazati.”355 Čini se da je, „Hysterične osobe vrlo su podatne društvenom uplivisanju, one su sugestibilne. Jedna hysterična
osoba može množinu ženskih svojim vladanjem zaraziti, na oponašanje potaknuti; tako nastaju
čitave hysterične epidemije”356 Žirovčić se također osvrće na izgled i ponašanje histeričnih žena. One se odlikuju „ako ne baš
ljepotom, to nekim osobito zamamljivim čarom svoga bića kojim umiju okolinu za sebe
pridobiti”357. Nadalje, one su sklone spletkarenju i fantazijama i raznašanju najnejerojatnijih laži
koje prenose „polusvjesno” brkajući ono što su čule čitale ili sanjale sa stvarnim događajima. Kao
takve one često pobuđuje sažaljenje i zanimanje ljudi i senzaciju.358 Za Žirovčića ključno je obilježje histerije prenaglašenost pojedinih crta ličnosti koje on smatra
obilježjima ženskog karaktera. Dapače, u skladu s tada poznatim nazorima o „graničkom
području” u kojem egzistiraju hereditarne klice duševnih bolesti, Žirovčić pretpostavlja mnogo
različitih stupnjeva histerije: „...počam od obične ženske ćutljivosti, strašljivosti, plačljivosti...pa
sve do teškog hysteričnog izopačenja i do hysteričnih psihoza”359. 5.2. Spektakl histerije u Stenjevcu Čini se da Forenbacher, u skladu s organicističkom
tradicijom, nalazi hereditet uzrokom histerije, opisujući Ružičinu majku kao „veoma
neurastheničnu bolujuć od histerije”.345 Forenbacher će kasnije i demonstrirati jedan slučaj 113 „hystero-epilepsije” na javnom predavanju. 346Općinki liječnik iz Jaske Niko Selak pak sljedeće
godine daje detaljan opis slučaja histerične rodilje koju je također liječio hypnozom: „Arc de
cercle bio je na dlaku spodoban onome što se vidi na slikah iz Saltpêtrière, pak i za takozvani
Clownismus nikad boljeg primjera nisam vidio.”347 Izbor termina i direktna referenca na Charcotove javne pokuse, kao i izbor hipnoze kao metode
liječenjan govore o tome kako se predodžba o histeriji u hrvatskoj medicini formirala pod
utjecajem Charcota. Ona će biti opisivana sličnim terminima i biti tretirana pod utjecajem
devetnaestostoljetnih nazora o rodu, te na identičan i podjednako spektakularan način. Dapače,
Selak na kraju izlaganja kaže da se nada da će moći predstaviti svoju pacijenticu drugim
liječnicima i na njoj „na umjetan način izazvati iste grčeve upiranjem ili trenjem po kojoj
histeriogenoj zoni”348. Također, Selak kao provincijski liječnik svjedoči da je „za vrijeme
službovanja kod dra Mullera vidio više od 50 histeričnih žena“, što ponovno dokazuje dobro
poznavanje charcotovske histerije u hrvatskoj medicinskoj zajednici.349 Selak će i u ostalim
svojim člancima pokazivati izniman interes za histeriju, a napisat će i poduži tekst o hipnozi kao
metodi liječenja.350Zanimljivo je da se na stranicama Liječničkog vjesnika javljaju brojni oglasi
koji reklamiraju ljekovite vode i kupališta kao sredstvo za liječenje histerije.351 Osobit stav o
histeriji izražava Ivan Žirovčić. Žirovčić se upušta u definiranje histerije na kraju svoje studije
slučaja Ane Schier koja će biti prikazana u nastavku ovog poglavlja. 354 Scull, 2009: 14. 355 Žirovčić, 1905a: 276. 356 Ibid. 356 Ibid. 357 Ibid. 358 Ibid.
359 Ibid. 5.2. Spektakl histerije u Stenjevcu Ako je histerija prisutna u
nekim običnim, tradicionalno „ženskim” duševnim osobinama koje su kod žena histeričnog
karaktera jednostavno prenaglašene, onda Žirovčić zapravo podrazumijeva da svaka žena u sebi
nosi klicu histerije. Sam histerija kao duševno oboljenje je zapravo samo prenaglašenost
femininih crta karaktera. Takvo gledanje na rod poistovjećuje femininost s duševnom patologijom
podrazumijevajući maskulini um kao idealnu sliku duševnog zdravlja. 115 Primjeri iz Stenjevca pokazuju kako je takvo poimanje histerije prenošeno i na tijela štićenica
kojima nije bila postavljena dijagnoza histerije. U stenjevačkom zavodu postojale su brojne
dijagnoze povezane s histerijom. U povijestima bolesti se, uz histeriju, tako nalaze „hysterička
smetenost”, „hystero-epilepsija”, „hysterica”, „paranoia hysterica”, „exaltatio hysterica”,
„psychosis hysterica” i „mania hysterica”. Histerija je prepoznata isključivo kod štićenica zavoda
i ne navode se slučajevi Charcotove „muške histerije”. Ipak postoji jedan slučaj histerije kod
muškarca nastale uslijed fiziološke traume naveden u Liječničkom vjesniku koji nije tretiran u
zavodu.360 Jednom osamnaestogodišnjem štićeniku iz Odre, dijagnoza „hysterije” izmijenjena je u
epilepsiju361. Liječnici su u teoriji i u praksi dopuštali postojanje histerije kod muškaraca, ali
jedino bi žene sa sličnim dijagnozama bile institucionalizirane. . Ana B., neudana švelja iz
Mitrovice primljena je s dijagnozom „exaltatio hysterice” u ožujku 1895. Dijagnoza, dana u
liječničkoj svjedodžbi je ubrzo izmijenjena u „amentiu”. Za štićenicu je rečeno kako je pri
prijemu „dočekala liječnike afektirano obučena, ista takova u kretnjama i govoru, odmah se
predstavi i poče pripovijedati da je ona zapravo iz plemićke madjarske obitelji, ona je rodjena
grof. Bačani362, ona da je nezakonito dijete madjarskog grofa Bačanija i sudbina dovela ju u kuću
učitelja B....izraz lica inteligentan, pogled erotičan. Kod istraživanja postaje vrlo erotična.”363. Liječnici su iz liječničke svjedodžbe dobili informaciju o štićenici kao „histeričnoj”. Nakon toga
opis u „statusu preasensu” započinje neuobičajeno slikovitim izrazom: štićenica je liječnike
„dočekala” čime se implicira njena podređenost i određena vrst žudnje za maskulinom figurom
liječnika. Odmah zatim opisuje se njena odjeća (kao da se specifično, „afektirano” odjenula za
liječnike) i njene kretnje i govor, koji narira njezino imaginarno porijeklo kao „grofice Bačani”. Također, liječnik se ne uspjeva dugo zadržati na opisu Aninog lica bez da naglasi „erotičnost”
njezinog pogleda. Opisi stanja štićenika i štićenica pri prijemu u zavod bili su, kako smo ranije
vidjeli, zaodjeveni u diskurs kojim se nastojala postići objektivnost i znanstveni karakter. U
slučaju „histerizirane” Ane B. on se posve fokusira na njezin „afektiran” i „erotičan” izgled. 361 KPV, 1894: 1995.
362 Pravo prezime štićenice, koje izostavljam iz etičkih razloga nije Bačani. ,
361 KPV, 1894: 1995. 363 KPV, 1895: 2630. p
363 KPV, 1895: 2630. 360 Selak, 1888: 169. 61 KPV, 1894: 1995.
62 Pravo prezime štićenice koje izostavljam iz etičkih razloga nije Bačani 5.2. Spektakl histerije u Stenjevcu Kao
što se može vidjeti, opisi histeričnih štićenica štićenica bili su izrazito seksualizirani Klinički zor liječnika ovdje ne traži hereditarne, tjelesne stigme i ne zamara se navođenjem
točnih mjera obujma glave, već traži stigme izražene ženske seksualnosti. Sličan tretman 116 erotizacije ženskih tijela nalazimo i u drugim povijestima bolesti štićenica. Seljakinja Mara, s
dijagnozom „hysterične smetenosti” će tako u svojoj liječničkoj svjedodžbi biti opisana samo
jednom riječju „erotična” a stenjevačka povijest bolesti će istaknuti kako joj je „uvijek spolno
druženje na pameti.” Bilješka nakon te će reći da smatra „izvanjski svijet neprijateljskim,
navlastito u pogledu spolnih napada.”364 Bilješka u opisu Kornelije, sobarice iz Petrinje, navodit
će kako je štićenica „pomalo slaboumna, a k tome nagnuće imala na razkošni i bludni život. Bijaše i služavka i sobarica samo da po volji može ljubakati se.”365Kristinea H., pučka učiteljica
iz Siska, u Stenjevcu je proboravila punih četrnaest godina, od 1897. do svoje smrti u 1911. Prvotna dijagnoza bila je „hysteria”, no kasnije joj je dijagnoza promijenjena u „Dementiu
secundariu” što je naziv koji se koristio za neizlječive duševne bolesti koje nastaju kao posljedice
neizlječene ranije duševne bolesti. Kao uzrok bolesti navodio se njezin „naporan školski rad”
zbog kojeg je oboljela na živce.366 Uspostavivši vezu između intelektualnog zanimanja štićenice i
njene bolesti, liječnik ju je upitao „je li možda imala kakav ljubavni odnošaj”367 te zabilježio
njezinu reakciju koja se sastojala od pokrivanja lica rukama i crvenjenja. Tijekom dugogodišnjeg
boravka u bolnici mnogo je pažnje posvećeno Kristininim histeričnim napadajima u kojima je
nasilna i trga odjeću sa sebe.368 No, na pojedinim mjestima se opet nalaze seksualizirani opisi
dani u kratkim rečenicama: „Namiguje liečnikom. Počinje drhtati. Kaže da više nije djevica.” Jedan od najbolje dokumentiranih slučajeva histerije bio je slučaj Terezije H. „udovice trgovca i
ubogarke” koja je u Stenjevcu boravila dvaput: prvi put od 8. rujna 1908. do 4.srpnja 1910. i
drugi put od 2. kolovoza 1910. do 3. kolovoza 1911. Oba puta, majka ju je odvela kući nakon
poboljšanja u stanju. U toj opsežnoj povijesti bolesti nalazimo priču žene iznimno zainteresirane
za aktualna burna politička zbivanja, a povijest bolesti sadrži i njezin autentični neposredovani
glas u pismima koja je slala članu zagrebačkog poglavarstva Zlatku Hotkiću, Slavku Cuvaju i
gradonačelniku Milanu Amrušu. 369 Showalter, 1993: 329. 366 KPV, 1897: 3071. 367 Ibid. 368 Ibid. 5.2. Spektakl histerije u Stenjevcu Također, povijest bolesti sadrži sve najistaknutije primjere
psihijatrijskog diskursa o histeriji: žensku seksualnost koja se probija u „mušku” sferu političkog,
te uvriježenu predodžbu histerične pacijentice kao žene koja se iscrpljuje intelektualnim radom,
emocionalno je nestabilna, ali ju odaje buntovnost i silovitost karaktera369 117 Terezija je u Stenjevac dovedena na preporuku liječnika iz Virja gdje je boravila kod majke,
nakon suprugove smrti. Čini se da je tridesetogodišnja Tereza bila iz skromne, ruralne sredine i
da je njezin brak sa zagrebačkim trgovcem predstavljao znatan uspon na društvenoj ljestvici, dok
je njegova smrt i povratak u sredinu u kojoj je odrasla shvaćen traumatično. Kotarski liječnik je,
poštujući propisanu proceduru za pisanje liječničkih uputnica opisao njeno Terezijino ponašanje
prije primanja u zavod, naročito se osvrnuvši na njezino obrazovanje: „Ona potiče od seljačkog stališa, svršila samo 4 razreda pučke škole, a odkad se udala počela
se je po gradjanski nositi, novine i svakojačke knjige čitati. Ona je bila od djetinjstva uvjek
zdrava, menstruirala je u 14 godini, a udala se u 17 godini za jednoga trgovca. Ona je bila već
onda eksaltirana, utvarala si da ona nije za seljaka, već za gospodina. Nakon smrti supruga
htjela se je više gospode udati, koji nisu na nju ni izdaleka mislili, a ona je komu god pisala
ljubavne listove, makar nije dobila nikad odgovora. Već godinu dana pripovjeda ona okolo da
će ju najprvi čovjek Bosne i Hercegovine dr. Ivica Elegović ženiti. Osim toga piše ona već
dulje vremena našem obć. načelniku g. Andriji Ljubiću ljubavne listove da se hoće za njega
udati, a potpiše jedanput Tereziju Elegović. Drugi put Tereziju Ljubić. Susjedi kažu da se ona u
sobi gola svuče zove dečke, da ju gledaju, drugiput pak obuče se u bijelo odijelo, a bježi okolo
po ulicama ili pako ide u crkvu, istupi gore k oltaru i pogleda u narod, kao da je ona
svećenik.”370 Charcot je histeriju proučavao u kliničkom kontekstu. Često je podvrgavao svoje štićenice
hipnozi i sugestiji kako bi pred publikom demonstrirale teatralno i seksualizirano ponašanje. Njegov znanstveni rad bio je obilježen nastojanjem da svede gomilu raznolikih simptoma i
duševnih stanja (od ponašanja svojih štićenica, do povijesnih primjera vjerske ekstaze na
renesansnim slikama) na univerzalno prepoznatljiv sindrom hystero-epilepsije.371 Nasuprot tome,
Terezijino je ponašanje bilo promatrano u kontekstu njezine svakodnevice, i ona nije mogla
producirati jasno razlučiv niz simptoma. ,
371 Scull, 2009: 124-125. 370 KPV, 1911: 7845. ,
371 Scull, 2009: 124-125. 5.2. Spektakl histerije u Stenjevcu Kako bi uklopio duševno stanje svoje pacijentice u
predodžbu histerične osobe kotarski liječnik poseže za selektivnim opisom njenog ponašanja
kako su mu ga prenijeli njezini susjedi i obitelj. Terezija je tako opisana kao žena koja se želi
(ponovno) udajom izdići iznad svog statusa što je bilo u skladu s opisom histerije kao bolesti koja
naročito pogađa pretjerano ambiciozne žene. Također vidljive su deluzije, koje je Charcot opisao 118 kao jednu od faza histerije. Liječnik pridaje pažnju i bijelom odijelu i „istupanju naprijed” u
crkvi, što je možda čitano kao simptom histerične ekstaze. Znakovito je kako su glasine o
Terezijinom ekshibicionističkom ponašanju stavljene odmah pokraj njezinog istupa u crkvi, što
navodi na zaključak da je liječnik možda htio tvoriti vezu između simptoma vjerske i erotske
ekstaze. Osim opisa ponašanja, kotarski liječnik prenosi i Terezijine riječi: Osim opisa ponašanja, kotarski liječnik prenosi i Terezijine riječi: „Kod pregledbe ponaša se ona preko mjere exaltirano. Brblja mnogo, brzo i nesavjestno, traži
od načelnika oružanu silu, detektive i vojsku da tjeraju njezinu djecu u školu, jer njezin sin
neće da ide u školu, a ima pameti kao dr. Kršnjavi, a postat će inšpektor leptira i žaba. Ako se
njezinom zahtjevu udovoljiti neće obratiti će se na brata dra Amruša koji hoće već u našoj
obćini red obnašati. Obćina će se razpustiti kako i ruska duma, a nastat če revolucija. Dr. Ivica
Frank je prvi i najljepši čovjek u Hrvatskoj a tko nije za njega taj će glavom nastradati.”372. Frank je prvi i najljepši čovjek u Hrvatskoj a tko nije za njega taj će glavom nastradati.”372. Prije navođenja njezinog govora, liječnik ih na retoričkoj razini diskvalificira kao „...brzo i
nesavjesno brbljanje” naglasivši pritom „exaltiranost” njezina ponašanja. Time su njezine riječi
određene kao emotivne čime ih se, unutar emotivnog režima obilježenog pozitivnom
normativizacijom racionalnosti diskvalificira, a samo emotivno raspoloženje štićenice određeno
je kao „prekomjerno”. Osim toga, diskvalificirajući Terezijin govor kao „brbljanje”, liječnik daje
jasan subjektivan komentar izrečenog i oduzima njezinim riječima ikakvu istinsku važnost. No,
navođenje tog govora nije sasvim nevažno, inače bi on bio izostavljen. Terezijine riječi su
upisane u klinički odnos moći i prisvojene od strane liječnika kao demonstracija bizarnosti
njezinih kognitivnih procesa. Opisan kao besmisleno brbljanje njezin iskaz nije više samo niz
slikovitih pritužbi na ponašanje vlastitog djeteta ili hiperboličan izraz frustracije političkom
situacijom. ,
373 Antić, 2017: 69. 372 KPV, 1911: 7845. 5.2. Spektakl histerije u Stenjevcu On zadobiva klinički značaj, kao simptom patološkog duševnog stanja i retoričko
sredstvo za dodatnu legitimaciju asimetrija moći upisanih u odnos Terezije i liječnika. Ana Antić
je u svojoj analizi međuratne i ratne psihijatrije u Jugoslaviji pokazala kako su slične diskurzivne
prakse diskvalifikacije govora štićenika služile kako bi potvrdili organicističke i determinističke
modele duševne bolesti, te naglašavale razliku između obrazovanih i racionalnih psihijatara i
njihovih „primitivnih” i „degeneriranih” štićenika i štićenica373 ,
373 Antić, 2017: 69. 119 Po dolasku u Stenjevac, Terezija je pregledana gdje je njen način govora opisan sličnim izrazima:
„Po prijemu mirna, prilikom pregleda živahna Nije nikad čula da je tko u familiji bio lud, ali
joj je mati grozna baba, grđa nego ruska revolucija. Ona ima sa majkom proces radi grunta.Sve
to ona pripovjeda vrlo brzo, oštro, afektirano, preokreće očima, drži se zanosno. U svom
pripovjedanju prepliće ideje progonstva i veličine. Ljudi su joj neprijatelji, načelnik u Virju ju
je proglasio umobolnom, a on je hoće ženiti. Već njezin pokojni suprug joj je rekao, samo ti
čitaj romane i odgajaj djecu na taj način onda ćeš doći u sanatorij gdje će te 4 liečnika
izpitivati.”374 Stenjevačka povijest bolesti prepoznaje zanosno držanje kao simptom bolesti, a znakovito je da
se navodi prenošenje riječi Terezijinog pokojnog supruga, gdje Terezija sama misli kako je u
zavod (ona ga naziva sanatorijem, koristeći riječ koja je u 19. stoljeću obično označavala elitniju,
privatnu ustanovu) dospjela radi svojih neuobičajenih životnih navika. U Stenjevcu se puno
pažnje posvećivalo Terezijnom čitanju političke literature. Tri dana nakon prijema navodi se kako
Terezija želi čitati „Hrvatsko pravo, Napried i Nastićevu brošuru” koja je poslužila kao dokaz na
veleizdajničkom procesu. Čini se da će Terezijin interes za politiku i njezina ljubavna opsesija
Josipom Frankom postati središtem psihijatrijskog narativa o njezinoj bolesti. Također, često će
se isticati njezina želja da se ponaša na način nesvojstven njezinom društvenom položaju. Na
primjer, u jednoj se bilješci navodi kako upotrebljava brojne tehničke izraze „iskrivljene i na
krivom mjestu.”375 Prolaskom vremena, tako njezine maštarije o moći postaju elaboriranije, dok opisi liječnika
naglašavaju njihovu teatralnost i seksualiziranost. Čini se da je Terezija opsjednuta brojnim
moćnim muškarcima iz političkog života: „Ne radi ništa – već šeće kao paunica po razdjelu ili vrtu- čita samo novine, traži ih svaki dan i
ljuti se, da će umrijeti ili poluditi, ako neće svaki dan dobiti novina. Jer ona mora čuti, što radi
njezin premoćni Rauch i veleučeni dr. 374 KPV, 1911: 7845. ,
375 Ibid. ,
375 Ibid. ,
375 Ibid. 374 KPV, 1911: 7845. 374 KPV, 1911: 7845. 375 Ibid. 5.2. Spektakl histerije u Stenjevcu Josip Frank. Frank, Ivica Elegović i ban su je posjetili i
ona je određena za hrvatsku kraljicu. Ona je njihova žrtva i samo je ovdje u zatočju- ali tad će 120 još slavnije izaći iz tog zatvora kao kraljica- biti će okrunjena zlatnom krunom, stanovat će u
zlatnom dvoru s kraljem Rauchom- a uz nju će biti uvijek Ivica Frank i Elegović.”376 još slavnije izaći iz tog zatvora kao kraljica- biti će okrunjena zlatnom krunom, stanovat će u
zlatnom dvoru s kraljem Rauchom- a uz nju će biti uvijek Ivica Frank i Elegović.”376
Njezino ponašanje prema liječnicima se često opisuje kao „erotično”. Terezija često traži od još slavnije izaći iz tog zatvora kao kraljica- biti će okrunjena zlatnom krunom, stanovat će u
zlatnom dvoru s kraljem Rauchom- a uz nju će biti uvijek Ivica Frank i Elegović.”376
Njezino ponašanje prema liječnicima se često opisuje kao „erotično”. Terezija često traži od
liječnika bolju hranu te se „mazi i vješa po liječnicima”. Opisi njezinog fizičkog izgleda su
također česti i u njima ju se opisuje kao „liepu žensku koja se osebujno i gizdavo oblači”. 377 Ne
dobije li što želi, niže uvrede koje imaju distinktivno politički karakter i odražavaju opsege
političke polarizacije hrvatskog društva na prijelazu stoljeća: Njezino ponašanje prema liječnicima se često opisuje kao „erotično”. Terezija često traži od
liječnika bolju hranu te se „mazi i vješa po liječnicima”. Opisi njezinog fizičkog izgleda su
također česti i u njima ju se opisuje kao „liepu žensku koja se osebujno i gizdavo oblači”. 377 Ne
dobije li što želi, niže uvrede koje imaju distinktivno politički karakter i odražavaju opsege
političke polarizacije hrvatskog društva na prijelazu stoljeća: „Ako joj se želje ne ispune, uzruja se žestoko, stane vikati, a znade biti i veoma prosta. Tad
psuje veoma frivolno kralja, veli on nije kralj, jer nezna niti hrvatski- već će biti Rauch uz
Franka svemoćni kralj ujedinjene Hrvatske. Psuje Pokretaše, Slavoljube na najgrublji način, jer
će oni prodati Hrvatsku. Ona bi ih još više povješala-nego će ih biti povješano. Piše uzastopce
listove čas milom Rauchu – prevažnom Franku - Elegoviću ili Ivici Franku itd. - sadržaj tih
listova je obično zahtjev da se odavde oslobodi ili nada u budući ljepši život kao kraljica. Katkad je čudi, što se njezini spasitelji za nju tako slabo brinu. Tad svali svoj gniev i na
njih.”378 Čini se da liječnici udovoljavaju Terezijinoj želji za novinama. 376 Ibid.
377 Ibid.
378 Ibid. 376 Ibid.
377 Ibid.
378 Ibid.
121 5.2. Spektakl histerije u Stenjevcu Bilješka nakon njezinog izljeva
bijesa govori o Terezijinom živahnom interesu za veleizdajnički proces. Također, čini se da
liječnici, barem na razini opisa pristaju na njezinu igru - u kasnijim zabilješkama prestaju se na
nju referirati kao na „bolesnicu” i nazivaju ju „kraljicom”. Ta ironična kvalifikacija narušava
dosadašnji prividno objektivni ton povijesti bolesti i dodatno literarizira već ionako romantizirani
opis njezinog ponašanja. Kao da svrha povijesti bolesti više nije u kliničkom opisu simptoma već
u senzacionalističkom praćenju Terezinih ekscentričnosti. Kako se radilo o internom dokumentu
kojeg su koristili jedino bolničari i liječnici, tituliranje dobiva obilježje svojevrsne interne šale. Moglo bi se čak reći da je tom promjenom Tereza uistinu pretvorena u „kraljicu” Stenjevca, te se
odlučuje povlađivati njezinoj fantaziji. No nedugo nakon te promjene u odnosu Terezija čini i
politički zaokret: „Kad je saznala da je Rauch pao - bila je isprva neutješiva-plakala... Sad će se Hrvatska sva
povlašiti- prokleti pokretaši će domovinu izdati itd. Za čas ali okrenula list – neće više čitati
Hrvatskog Prava već traži Pokret- jer su to pravi ljudi. Rauch, Frank su je i onako zaboravili, 121 ma da je ona njihova žrtva. Želi im da propadnu. „Kraljica” se gubi vječno u politici, svojom
osobom se bavi i traži slobodu. Ne radi ništa već se samo cifra.”379 U povijesti bolesti se ne navodi čime je ovaj preokret motiviran, no čini se da ga je sama štićenica
argumentirala činjenicom da joj aktualni politički moćnici nisu pružili pomoć koju je od njih
očekivala i na koju je apelirala u pismima. Ubrzo nakon Terezijinog odricanja lojalnosti Josipu
Franku i njegovoj Čistoj Stranci Prava, nastupa poboljšanje njezinog duševnog stanja. Često se
raspitkuje za političku situaciju, navodeći da nije čitala novine zadnjih mjesec dana, a u jednom
trenutku pita liječnika „kad će je već jednoć tatica velmožni pustiti kući. Ne može već živiti
medju ovima jopcima”. Zanimljiv je izbor riječi koji Terezija koristi obraćajući se liječniku kao
„velmožnom tatici”. Čini se da je, pred kraj svog boravka prestala maštati o zaštiti moćnih
političara i prihvatila zavodskog ravnatelja kao „velmožnog” oca potčinivši se njegovoj
simboličkoj patrijarhalnoj moći Puštena je kući kao poboljšana, a u zavod se htjela vratiti već
nakon mjesec dana. Čini se da je razlog povratku bio osjećaj odbačenosti od okoline. 5.2. Spektakl histerije u Stenjevcu Terezija se
pojavila u „svojoj svijetloj visokoj opravi” i „veličanstvenom držanju”.380 Njen drugi boravak
uglavnom dokumentira njezinu nemogućnost nošenja sa stigmom koju je iskusila zbog svog
boravka u zavodu i nekadašnjeg ponašanja. Terezija, ovaj put prilično suosjećajnog liječnika
naziva „taticom” i govori kako „tko je jednom bio u ludnici za njeg nije da ide van među ovaj
zlobni svijet.”381 Iako se stidi svog ponašanja čini se da, kad je sama nastavlja živjeti fantaziju o
političkoj moći: „Kad je liečnik nagovorio odgovarala je uvijek vrlo promišljeno, birano a kad bi joj čovjek
spomenuo njezinu ljepotu, gizdavost ili nazvao ju ”kraljicom” tada je obično uvrijeđeno odbila,
no kad je bila sama a mislila da je se ne motri tad se vidilo kako sama sobom govori, kako se
smješka, klanja, prima deputacije i kako dostojanstveno prolazi mahnuvši kadšto blagohotno
rukom nekoj umišljenoj valjda osobi.”382 Godinu dana nakon povratka u zavod, Terezija H. je otpuštena kao poboljšana. Povijest bolesti
sadrži i tri njena nikad odaslana pisma napisana tijekom 1908. i 1909. godine kad su njene
fantazije o Rauchu i Josipu Franku bile najintenzivnije, Prvo je naslovljeno na Zlatka Hotkića,
senatora kod zagrebačkog poglavarstva. U navedenom pismu Terezija moli novac za opravu i
svoju zamolbu ilustrira pomalo bizarnim obećanjem koji se tiče njezinog angažmana: 122 „Stoga molim da mi naručite kod Božičevića 1 opravu crnu, finu i crne cipele kod (nečitljivo)
tvornice i bledi šešir kod Bratiček ili Klompfa i biti će dosta za te stvari 100 forinti.Dajem vam
na znanje da se u buduće neću baviti politikom i zaljubljivanjem nego pragmatikom i
uredbami ustavnih reformih koje su u Hrvatskoj na žalosti jako zamršene. Budem se posvetila
žurnalistici i programu Programu Spasitelja Monarhije Privatnomu i Putovanju na automobili i
mislim da će ovo biti najbolje i uvjeravam samu sebe da će mi svirati Sirena na Margiti. Ovaj
Sanatorium skrivio mi je Frankov doktor više nemam nikakve političke mozgovne opne samo
mladu grešku na srcu političkomu.”383 Čini se da je tijekom boravka u zavodu Tereza sama počela procjenjivati svoj interes za politiku
kao simptom bolesti. Njezino drugo pismo adresirano je na tadašnjeg podbana Slavka Cuvaja i
gradonačelnika Milana Amruša. Ono se uglavnom sastoji od Terezijinih zahtjeva, pa tako traži da
podban Cuvaj prenese Rauchu da Terezija potrebuje opravu, šešir, nakit cipele i donje rublje. 384 Ibid. 383 Ibid.
384 Ibid.
385 Ibid. 5.2. Spektakl histerije u Stenjevcu Također, Terezija u tom pismu naglašava kako smatra svoje zatočenje u Stenjevcu oblikom
političkog progona i uspoređuje se sa Zrinskim i Frankopanom:„Ja sam ovdje za velike i ozbiljne
stvari za domovinu, nisam za insulte nego za mučenike Zrinjski i Frankopane i moga tatu Pavicu
Raucha.”384 U drugom, kraćem pismu upućenom Pavlu Rauchu, Terezija moli bana da ju izvede iz Stenjevca i
traži „ekipažu, adjutanta i banska kola da ju isprate u Zagreb.”385 Povijest bolesti Terezije H. Govori o ženi koja je zahvaljujući svom braku s trgovcem doživjela
određeni uspon na društvenoj ljestvici. Nakon udaje živjela je u Zagrebu i tako mogla biti
neposrednim svjedokom političkih previranja s prijelaza stoljeća. Povratkom u Virje izgubila je
financijsku sigurnost i vezu s političkim životom, te se vratila u okolinu s kojom je bila u sukobu. Njezina pisma i izjave koje su liječnici zapisali pokazuju da je Terezija žudjela za zaštitom
moćnog muškarca, vjerojatno misleći da bi time povratila ekonomsku sigurnost. Sve njezine
fantazije vrte se oko političke moći, pa se čak i njezino „erotično ponašanje prema liječnicima”
može gledati kao ponašanje motivirano istim željama. Dok je Terezija maštala o životu u kojem
se upravo ona nalazi u središtu pažnje poznatih političkih ličnosti, slučaj Ane Schier, koja se u
Stenjevcu našla zbog sudskog vještačenja, našao je odjek u javnosti. 123 Slučaj je objavljen kao studija u sedmom broju Liječničkog vjesnika iz 1905. godine pod
naslovom Hysterična žena pred sudom radi klevetanja. Njegova zanimljivost leži upravo u
činjenici da u njemu vodeći hrvatski psihijatar kraja devetnaestog stoljeća, doktor Ivan Žirovčić,
iznosi svoje poglede na histeriju. Također, dok je sukob između Terezije i njezine okoline tek
površno ocrtan u liječničkoj svjedodžbi, Žirovčić detaljno dokumentira sudski slučaj koji se
vodio protiv Ane Schier. Priča o Ani Schier, rođenoj Škert počela je nakon smrti njezinog oca Josipa Škerta. Josip Škert je
bio umirovljeni šumar koji je u Donjem Miholjcu živio skromno. Prije umirovljenja, radio je na
kao revirni šumar na posjedu plemićke obitelji von Prandau u Poganovcima386. Imao je više
odrasle djece koja su se odselila od njega, tako da mu je kućanstvo vodila Otilija Magnani uz
pomoć svoje kćeri Marije. Ana Schier, u to vrijeme stara trideset i sedam godina je živjela u
Budimpešti kao krojačica, netom razvedena od svog supruga, trgovca Karola Schiera387. Njegova
najstarija kći, Terezija udala se 1884. 386 Milošević, 2016: 42.
387 Budapest Főváros Levéltára.1906. Civil law cases: HU BFL - VII.2.c - 1906 - V.0530: 1- 7.
388 Ži
čić 1905
274 386 Milošević, 2016: 42. p
388 Žirovčić, 1905a: 274. 389 Ibid, 271. 390 Ibid. 388 Žirovčić, 1905a: 274.
389 Ibid, 271.
390 Ibid p
388 Žirovčić, 1905a: 274. 386 Milošević, 2016: 42. 391 Ibid. 87 Budapest Főváros Levéltára.1906. Civil law cases: HU BFL - VII.2.c - 1906 - V.0530: 1- 7.
88 Žirovčić, 1905a: 274. ,
389 Ibid, 271. 388 Žirovčić, 1905a: 274. 5.2. Spektakl histerije u Stenjevcu za književnika (tada učitelja na posjedu baruna Prandau)
Janka Leskovara kojemu je Ana Schier kasnije pisala iz Stenjevca moleći ga da se zauzme za
nju388. Škert je umro 27. lipnja 1901. od srčanog udara u sedamdesetoj godini. Ubrzo nakon toga,
Ana Schier je optužila Otiliju i Mariju Magnani da su otele njezinom ocu štedioničku knjižicu
nakon što su ga otrovale arsenom koji su nabavile od poštanskog činovnika Ljudevita Wuchse,
Marijinog zaručnika.389 Nakon početka istrage, Ana Schier iznosi jednu za drugom sve
senzacionalnije optužbe, pa tako između ostalog optužuje kotarskog suca da je uništio oporuku J. Škerta, krivotvorio isprave i zatajio zakonite nasljednike i općinskog liječnika Božidara Katušića
da je „dao prije vremena zakopati mrtvo tijelo Josipa Škerta da se time prikrije otrovanje.”390
Ubrzo je tijelo Josipa Škerta ekshumirano, no novine su pisale kako je „ekshumacija Škertovog
trupla bila samo komedija” i da je „podmetnuta druga lješina.”391 Istraga protiv Otilije i Marije
Magnani je ubrzo obustavljena, ali su njih dvije i Wuchsa počele dobivati anonimna prijeteća 124 pisma, a zbog glasina koje su u dalje objavljivane u novinama, Wuchsi je prijetilo otpuštanje s
mjesta poštanskog činovnika.392 Svi koje je Ana Schier optuživala, podigli su protiv nje tužbu zbog „zločinstva potvore”393 i
Schier je odvedena u istražni zatvor u Osijeku. Od tamo je 12. rujna 1904. upućena na
psihijatrijsko vještačenje u Kraljevski i zemaljski zavod za umobolne u Stenjevcu.394 Kao glavni
razlog provođenja psihijatrijskog vještačenja nad Anom Schier navedena je tvrdnja da njezine
optužbe „ne stoje”. To je prilično čudno, budući da su druga forenzička vještačenja koja su se
vršila u Stenjevcu uglavnom bila potaknuta bizarnim karakterom zločina ili čudnim ponašanjem
optuženog prije ili nakon zločina. Žirovčić pak, kao kriterij navodi samu neistinitost optužbi koje
je Ana Schier iznijela. Prilikom prijema u Stenjevec, Schier je bila u sedmom mjesecu trudnoće. Pri utvrđivanju statusa preasensa liječnici su detaljno opisivali njezinu trudnoću, ali i tražili
karakteristične hereditarne stigme koje bi ukazivale na duševnu bolest. Tako se, u skladu s
uvjerenjima psihijatara somaticističke škole poput Maudsleyja osobita pažnja ukazuje obliku
ušiju i nosa Ane Schier. Za uši se kaže da su „malene, nejednake i deformirane”395, a za nos da je
„malen i šiljast”396. Također, mjeri se obujam njezine lubanje, i navodi se nedostatak refleksa
mekog nepca. U bolnici se Ana Schier ponaša mirno, svaljujući svoje tegobe na političke prilike
u Hrvatskoj i prepričavajući svoj slučaj ostalim bolesnicama. Posjećuje ju budimpeštanski
novinar Paul Engelman. 5.2. Spektakl histerije u Stenjevcu Engelmanov odnos s Anom Schier je podosta nejasan - pred liječnicima
Engelman tako tvrdi da je Schier „umobolna pravdašica” dok u pismu koje piše nekoliko dana
poslije pokazuje simpatiju za nju i njezin slučaj. Engelman joj piše da ne odustaje od krojačkog
zanata u kojem je umjetnica i da se i njemu dogodio sličan politički progon kad su ga uhapsili
kao socijaldemokrata.397 Prvog listopada Žirovčić u zavodskoj pisarnici provodi razgovor s Anom
Schier u kojem ona govori o svojim teškim obiteljskim prilikama. Ana je imala elementarno
obrazovanje: išla je 4 godine u školu u Josipovcu, a nakon toga ju je otac podučavao kod kuće. Otac je navodno bio grub čovjek koji je zlostavljao svoju suprugu i varao ju s nekom seljakinjom
Simeonom Lazić koju Ana Schier slikovito opisuje kao „mužaču”398 zbog čega ga je majka Ane 125 Schier napustila i otišla živjeti u Osijek kao nadničarka. Ana je vodila kućanstvo i upravo ona je
1884. dovela u kuću Otiliju Magnani koja je tada bila, prema Aninim riječima 24 godine stara
neznatna, nelijepa, lijena i neuredna osoba sklona skitnji.399 Ana opisuje kako se njezin otac ubrzo
upustio u vezu s Otilijom Magnani, govori kako je otac imao štednu knjižicu, te kako se Otilia
Magnani nije slagala s njezinim mlađim sestrama. Sukobi u kućanstvu su jednom gotovo završili
nasilno- navodno su mlađe sestre Julija i Aurelija „htjele ubiti Otiliju revolverom koji su uzeli s
očeva stola, a Ana im je revolver otela”400. Osim života u krugu obitelji, Ani Schier je i kasniji
bračni život bio obilježen teškoćama i sukobima. Za svog supruga govori da je najveći „zlotvor i
lopov” te da je odlučio pomagati Otiliju Magnani. Nakon opisivanja svojih bračnih prilika i obiteljske povijesti, Ana Schier opisuje sam trenutak
očeve smrti i opetuje optužbe o trovanju. Prema njenom objašnjenju, otac joj je iznenada dobio
„herzkrampf” i postao žut i crn. Liječnici i ljekarnici kojima se obratila, učvrstili su ju u uvjerenju
da je njen otac otrovan arsenom. Uz mišljenje liječnika, Schier tvrdi da ju je na zaključak o
trovanju navelo i vlastito iskustvo. Naime, Schier je u Budimpešti učila retušerski zanat kod
fotografa Strelitzkog i tamo svjedočila slučajnom otrovanju skupine djevojaka arsenom. Ana
Schier je tvrdila da su djevojke pokazale iste simptome.401 Ana Schier također ponavlja i elaborira
optužbe protiv suca i liječnika: govori kako je i dalje uvjerena da je umjesto njezinog oca
ekshumiran drugi leš. 399 Ibid.
400 Ibid.
401 Ibid.
402 Ibid. 5.2. Spektakl histerije u Stenjevcu Čini se da je Ana Schier bila prisutna u trenutku ekshumacije i da je u
jednom trenutku prišla samom lešu i gurnula mu ruku u usta kako bi mu prebrojila zube. Prebrojavši zube lešu, ustanovila je da ih je tijelo na ekshumaciji imalo samo četiri, dok ih je
njezin otac imao više. Ovdje se prvi put u članku detaljno oslikava pomalo makabričan i
neuobičajen prizor: Ana Schier gura lešu prste u usta, ne pokazajući nikakav osjećaj straha,
gađenja ili bilo kakve druge averzije koju bi devetnaestoljetno društvo očekivalo od žene. Taj
trenutak predstavlja jednu prilično jasnu transgresiju u okviru emotivnog režima devetnaestog
stoljeća. Iako taj postupak nije naveden kao razlog predavanja Ane Schier na vještačenje u
Stenjevec, kasnije će biti apostrofiran kao važan za dijagnozu histerije koju je Žirovčić postavio u
svom vještačkom mišljenju. Uz broj zubi, Ana Schier navodi kako je ime njezinog oca na lijesu
izgledalo „friško priljepljeno”402. Nakon prepričavanja ekshumacije, Ana iznosi optužbe na račun 126 kotarskog suca i okružnog liječnika. Za suca tako kaže da je „opak čovjek, pijanica, kartaš i
ženskar” te implicira da bi zbog tih svojih navika lako mogao primiti mito. Doktora Katušića
optužila je da je „pijanica i da javno tuče svoju ženu”.403 U konkretnom slučaju Ane Schier, Žirovčić je odlučio posve zanemariti njezin iskaz. Umjesto
toga, u njegovom mišljenju je ključna važnost dana iskazu njezina supruga koji je u ono vrijeme
živio s Anom Schier. Prema njegovom iskazu Ana Schier je „divlja, hladnokrvna, lažljiva, gruba,
lijena, pravdalica, razkošna, razuzdana”404. Žirovčić suprugove riječi potvrđuje nekritički
konstatiravši da „taj opis odgovara vladanju Ane Schier, koja se upornom tvrdoglavošću pravda
za lažnu stvar, koja bezobzirnim bijesom ujeda poštenje svakoga, koji joj pravdanjem na put
dodje te hladnokrvno čeprka prstom po ekshumiranoj lješini svog oca.”405 U svojoj dijagnozi Žirovčić se, kao i liječnik koji je preporučio smještanje Terezije H. u
Stenjevec oslanja na iskaz supruga, posve zanemarivši govor štićenice. Iako je Ana Schier
napustila supruga, živjela u lošim odnosima s istim i zatrudnjela s drugim muškarcem, suprugovo
se mišljenje uzima kao nepristran sud o njezinom karakteru. Kroz očište te prosudbe se gledaju
kasniji javni istupi Ane Schier i postavlja medicinska dijagnoza. Zanimljivo je, da u svom opisu
histeričnog karaktera i Aninog ponašanja Žirovčić često imenuje brojne emocije i time ih zapravo
vrijednosno smješta unutar psihijatrijskog diskursa o rodu. 403 Ibid.
404 Ibid.
405 Ibid. 403 Ibid.
404 Ibid. 5.2. Spektakl histerije u Stenjevcu Tako su „ženska ćutljivost, strašljivost
i plačljivost” zapravo najmanje intenzivna obilježja histerije dok se „bezobziran bijes” i
„hladnokrvnost” kasnije navode kao dokazi da je upravo Ana Schier histerična. Svraćanje pažnje
na emocije, davanje rodnog karaktera istima i prepoznavanje „abnormalnosti” određenih emocija
na temelju unaprijed stvorenih pretpostavki o ženskoj psihi zapravo čini histeriju poremećajem
koji služi kao kod za žensku izvedbu emocija. To naročito vrijedi za slučajeve poput onog Ane
Schier gdje su emocije poput bijesa zbog nepravde postale prisutne u javnom prostoru, te čak
pobudile suosjećajnu reakciju pojedinih dijelova javnosti. Na kraju krajeva, angažman
budimpeštanskog socijaldemokratskog tiska i politizacija slučaja su vjerojatno potakli kod
Žirovčića reakciju koja je kroz medikalizaciju emotivnog stanja Ane Schier, trebala delegitimirati 127 javni odjek njezinih riječi. Zbog toga se vjerojatno upustio u objašnjavanje fenomena masovne
histerije i pridao histeričnim ženama neku sugestivnu i zavodljivu moć nad drugim ljudima. U svom zaključku Žirovčić je još jednom pojasnio rezultate svog forenzičkog vještačenja. Tako
ističe da je „um Ane Schier oslabljen uslijed hysteričnog živčanog rastrojenja”406. Zanimljivo je i
da su njezine ranije pritužbe na fiziološke teškoće, čak i one koje su mogle biti pripisane trudnoći
poput nadutosti i bolova u nogama i leđima pripisane histeričnom živčanom ustroju, kao i
„nećutljivost ždrijelne i nepčane sluznice” i „labilitet krvnocijevnog aparata, po čem ona lako
blijedne i rumeni”. Naravno, kao ključni znak njezinog „histeričnog ustroja” navedene su njezine
karakterne crte: sklonost „laganju, spletkarenju, tužakanju, pravdanju i pogrđivanju tuđeg
poštenja.”407 Uz to, Žirovčić je smatrao da Ana Schier pati od histerije višeg stupnja jer se
histerija kod nje manifestirala i „izopačenjem karaktera.”408 Usprkos činjenici da ju je
okarakterizirao kao teško duševno bolesnu ženu, Žirovčić ju ipak ne proglašava neubrojivom. Argumentaciju za svoj zaključak on nalazi u pravnoj definiciji neubrojivosti prema kojoj se
kaznene odgovornosti za zločin oslobađa ona osoba koja je u trenutku počinjenja bila: „a) sasvim
bez porabe razuma“, ili b) u stanju ludovanja“ ili „u ćutilnoj smetnji.“409 Budući da je Ana Schier više puta ponovila svoje optužbe i ustrajala u njima, bila dovoljno
prisebna da nastupa pred sudom i javno djeluje i budući da njezine optužba nisu bile posljedica
halucinacija i sumanutih misli, Žirovčić ju nije mogao proglasiti neubrojivom. Ipak zaključio je
kako je Ana Schier, „kao ženska hysterična, afektivna, umno ograničena, individualnost manje
vrijednosti.”410 Iz slučajeva Ane Schier i Terezije H. 406 Ibid, 278. 410 Ibid, 280. 409 Ibid, 279-280. 406 Ibid, 278.
407 Ibid.
408 Ibid.
409 Ibid, 279-280.
410 Ibid, 280. 5.2. Spektakl histerije u Stenjevcu možemo vidjeti kakva je bila percepcija histerije unutar
Stenjevca i u kojoj mjeri se ona razlikovala od Charcotovog spektakla. S jedne strane, štićenice
kojima je dijagnosticirana histerija su uistinu histerizirane i erotizirane u kliničkom kontekstu u
smislu da su njihove duševne tegobe somatizirane i vezane uz njihov rod i njihovu seksualnost. Tako su i afektivnost Ane Schier i njezine fizičke tegobe i njezina javna eksponiranost i upornost 128 u suprotstavljanju moćnim muškim figurama poput liječnika i suca za Žirovčića dokaz njezinog
histeričnog karaktera. Isto se može reći i za ponašanje Terezije H. U njoj stenjevački liječnici ne
vide ženu koja se, shrvana i traumatizirana nakon smrti supruga i povratka majci u sredinu s
kojom je bila u sukobu, predaje maštarijama o zaštiti moćnih ljudi i sudjelovanju u političkom
životu, nego ju isključivo gledaju kroz prizmu njezinog erotičnog ponašanja, ponegdje ju čak
pretvarajući u romantizirani objekt vlastite žudnje. Također, stenjevački liječnici su imali velike
teškoće u repliciranju spektakularnih Charcotovih simptoma u kliničkom kontekstu. Zbog toga,
histerija ponovno postaje ekskluzivno ženskom protejskom bolešću. Njezin uzrok se, pod
utjecajem predstavnika njemačke somatičke medicine sad usko vezuje uz nižu duševnu vrijednost
žena. Simptomi histerije se uglavnom traže u javnom pokazivanju određenih emocija, i u
ustrajnosti u suprotstavljanju autoritetima. Znakovito je kako u slučaju Ane Schier, doktor
Žirovčić snažnim riječima spominje Aninu spremnost da pogrdi tuđe poštenje i koliko spremno u
obranu uzima općinskog liječnika, kotarskog suca i poštanskog činovnika Wuchsu. Čini se da mu
se sama ideja žene niskog obrazovanja i po ondašnjim moralnim normama upitnog seksualnog
morala koja iznosi optužbe za korupciju protiv muškaraca građanske klase činila izrazito
izopačenom i nepojmljivom. Duševne bolesti kod žena su se u psihijatrijskoj literaturi često povezivale s intelektualnim
naporom: Maudsley je tako često isticao da obrazovanje uništava reproduktivne organe i
mozgove žena411. Bolest Ane B. će kao uzrok navesti: „tjelesno prenaprezanje napornim radom
uz slabu konstituciju; a duševno čitanjem zamršenih i za nju nerazumljivih stvari”412. Podatke o
njezinim čitalačkim navikama liječnici su dobili iz njenih izjava i pisama u kojima je spominjala
čitanje Schopenhauera, Goethea, Darwina i Shakespearea.413 Iako njezina pisma pokazuju
zavidnu razinu obrazovanja s obzirom na njezin socioekonomski status i zanimanje, liječnici ipak
tvrde da su knjige koje je čitala za nju bile nerazumljive. Sličan stav nalazimo kod supruga
stenjevačke štićenice Terezije H. koja je strastveno pratila političke prilike i čitala dnevni tisak. Iskazi Terezije H. i Ane Schier se također odbacuju od strane liječnika. ,
412 KPV, 1895: 2630. 411 Showalter, 1995: 124-125. ,
413 Ibid. ,
412 KPV, 1895: 2630. ,
412 KPV, 1895: 2630. ,
413 Ibid. 411 Showalter, 1995: 124-125. 5.2. Spektakl histerije u Stenjevcu Terezijin će biti opisan
kao „brbljanje” dok će Žirovčić ismijavati izjavu Ane Schier da je prepoznala simptome trovanja 129 arsenom, iako je ona, za jednog laika dobro opisala karakteristične znakove otrovanja,
uključujući i diskoloraciju lica,414 te se u zaključku neće niti jednom referirati na njezin iskaz. Daleko veći značaj bit će dan izjavi njezinog supruga, čiju prosudbu karaktera Ane Schier,
Žirovčić bez propitkivanja prihvaća kao objektivnu. Možemo reći da su „histerične” štićenice u
Stenjevcu bile tretirane kao osobe čija je transgresija emotivnog režima i rodnih normi
promatrana kao dokaz njihove „niže duševne vrijednosti” koja je proistjecala iz njihovih
karakteristično ženskih karakternih crta. Kao takvima, u pravilo im je oduzeto pravo na vlastiti
glas, a čak i u slučajevima poput onog Ane Schier kad bi javno istupale i dobile podršku javnosti,
sama ta podrška bila je pripisivana njihovoj „histeričnoj zavodljivosti”. Promjenjiv karakter
histerije, njezina uska povezanost s rodom i njezin spektakularan i erotiziran karakter rezultirali
su potpunom objektifikacijom štićenica s tom dijagnozom u kojoj je njihovo duševno oboljenje
posve dominiralo slikom o njima. Sve što bi izrekle ili učinile, dojam koji bi ostavile na druge,
njihove tjelesne karakteristike i emocije koje bi iskazale, moglo se gledati kroz prizmu histerije
koja je ujedno predstavljala i hiperseksualiziranu i reduciranu sliku ženskosti. 5.3. Tijelo van kontrole: „Rittermeisterov satni mehanizam” i „viloviti” notar iz Veliševca“
Brojni su slučajevi u kojima se štićenice žale da su izgubile kontrolu nad vlastitim tijelom. Takvi
se slučajevi mogu povezati s rodnom nejednakošću i supresijom seksualnosti. Kao što smo već
ranije spomenuli u dijelu rada o životu štićenika i štićenica prije dolaska u zavod, seksualno i
drugo zlostavljanje od strane muškaraca, nevolje u braku i podređen položaj u društvu obilježili
su iskustvo brojnih štićenica. Budući da je ženska seksualnost u devetnaestom stoljeću bila strogo
regulirana društvenim normama, brojni simptomi o kojima štićenice Stenjevca govore tokom
svog boravka i koji su ostali zabilježeni u povijestima bolesti vezani su uz seksualnost i kontrolu. U deluziji Tereze D., četrdeset i četverogodišnje sluškinje iz Bjelovara, ženska seksualnost
postaje dio kompliciranog tehnološkog mehanizma kontrole u kojem se susreću Terezina
subalterna i marginalna pozicija sluškinje, fantazije o”strojevima kontrole” i anksioznosti
modernog doba. Tereza D. primljena je u Stenjevac 1903. iz klinike u Grazu. U zavodu je boravila do svoje smrti
od upale žučnog mjehura 1911. godine. Dijagnoza koja joj je postavljena glasila je „paranoia”
414 Drača, 2017: 47. 420 Tausk, 1992: 186. 415 KPV, 1911: 5604. 419 Haslan, 1810. 416 Ibid. 418 Ibid. 418 Ibid. 5.2. Spektakl histerije u Stenjevcu 130 dok je kao uzrok naveden „klimakterij”.415 Tereza je, prema status preasensu, bila služavka u
Zagrebu, Mariboru i Grazu no nigdje se nije dugo zadržala zbog vlastite svadljivosti. Za svoju
svadljivost okrivljavala je muškarca za čiju obitelj je radila nekog mladog Pergera iz Graza kojeg
je nazivala „rittmeisterom”, naziv koji označava časnički čin u austrijskoj konjici. Terezina
povijest bolesti bilježi različite sumanute misli i halucinacije vezane uz Pergera. Naime, Tereza je
bila uvjerena da ju mladi Perger kontrolira preko nekog uređaja koji je nazivala „hoeraparatom”
što je njemačka riječ za satni mehanizam. Pomoću navedenog hoeraparata, Perger je mogao na
daljinu pomicati njezino tijelo i komunicirati sa njim telepatski bez da ju itko drugi čuje, što je
Tereza, koja u komunikaciji s liječnicima redovito govori njemački, nazivala „Das ist ein
Sprachen in Gedanken” („To je govorenje u mislima”). Tereza vjeruje da joj je „rittermeister”
pomoću svog satnog mehanizma prouzrokovao „Schuttelfrost” (nazeb) nakon kojeg je morala
učestalo mokriti 416 Pergerov utjecaj na Terezu imao je i snažne seksualne elemente. Tereza
optužuje Pergera da joj je „napravio da je morala rukom na spolovilo”417. S vremenom, utjecaj
„rittmeistera” postaje sve veći i Tereza se često žali kako on gospodari njezinim mislima i kako
joj nalaže što treba govoriti ili učiniti. Učestalo tvrdi kako „rittermeister” plaća njezino
uzdržavanje u zavodu i kako također plaća boravak i „koštu” ostalim štićenicama, što ju čini
ljubomornom. U jednom od kasnijih napada bijesa, Tereza će reći da „rittermeister” uzdržava
cijeli zavod i da živi u vili u blizini zavoda.418 Halucinacija o tehnološki naprednom stroju koji kontrolira tijelo i misli jedna je od češćih pojava
u povijesti. Tako je James Matthews, trgovac čajem i štićenik londonske klinike Bedlam, 1798. tvrdio da ga francuski agenti kontroliraju pomoću pneumatskih strojeva za proizvodnju misli i
osjećaja. Matthews je svom liječniku dao čak i precizne skice tih strojeva koji su „tkali” emocije
iz zraka, nalik tada novim parnim tkalačkim strojevima.419 Bečki psihoanalitičar Viktor Tausk
nazvat će tu vrstu deluzije „strojem za kontrolu” (eng. „influencing machine“) i opisao pet
različitih efekta koje pacijenta pripisuju tim strojevima: projiciranje slika, proizvodnja ili
„otimanje” misli”, upravljanje motornim funkcijama tijela, proizvodnja senzacija u tijelu i
proizvodnja patoloških procesa u tijelu.420 Kod Tereze vidimo da stroj ima četiri od pet tih
415 KPV, 1911: 5604. 418 Ibid. 131 funkcija. j
422 Fugier i Perrot, 1990: 235-236. 421 Fuchs i Hirjak, 2010: 100-101. g
,
423 Harris, 1997: 452. 424 Ibid, 463. j
422 Fugier i Perrot, 1990: 235-236.
i g
,
423 Harris, 1997: 452. j
,
422 Fugier i Perrot, 1990: 235-236. g
,
423 Harris, 1997: 452. g
,
423 Harris, 1997: 452. 421 Fuchs i Hirjak, 2010: 100-101. 422 Fugier i Perrot, 1990: 235-236.
423 Harris 1997: 452 5.2. Spektakl histerije u Stenjevcu Psihijatri Hirjak i Fuchs su našli uzroke prevalentnosti takvih deluzija u nekim
karakteristikama modernih tehnologija poput činjenice da moderne tehnologije imaju skrivene
efekte, da čine prostorne i vremenske granice propusnijima, mogu stvoriti dojam drugačijih
realnosti te reificiraju tijela.421 Premda se ne može poreći da je Terezina fantazija o „hoeraparatu”
mogla imati izvore u strepnjama vezanim uz tehnologiju, moguće je da ona odražava i neke od
strepnji vezanih za njezin položaj kao služavke. Prvo što saznajemo o „rittermeisteru” Pergeru je
da se radi o članu gradačke porodice za koju je Tereza radila. Sluškinje su zbog teške financijske
situacije često bile prisiljene osiguravati sredstva za svoju materijalnu egzistenciju radom u
drugim gradovima, daleko od svojih obitelji. Pritom su kao stranac koji je svjedočio obiteljskoj
intimi bile u izrazito nepovoljnom položaju. Njihova individualnost često je bila negirana do te
mjere da su prilikom dolaska u službu morale usvojiti druga imena, a njihova privatnost, prostor
za život, intima i seksualnost su često bile pod kontrolom njihovih poslodavaca.422 Kontrola nad
tijelom, mislima i seksualnošću povezana s idejama o financijskoj ovisnosti cijelog zavoda o
„rittermeisteru” na gotovo jezovit način odražava financijsku ovisnost sluškinja i reifikaciju
njihovih tijela i individualnosti u okviru patrijarhalnih kućanstava. Dok su primjeri tehnološke kontrole podosta rijetki, jer mnogi štićenici dolaze iz ruralnih krajeva,
gdje moderna tehnologija još nije dio svakodnevnog iskustva, štićenice često artikuliraju
predodžbe o gubitku kontrole nad vlastitim mislima i tijelom kroz iskustvo opsjednutosti. Opsjednutost od strane nekih nadnaravnih entiteta dio je folklornih vjerovanja u brojnim
zajednicama, a u devetnaestom stoljeću za isti fenomen postaju zainteresirani i psihijatri. Jedan
od najpoznatijih primjera kolektivne opsjednutosti dogodio se u zajednici migrantskih radnika u
mjestu Morzine koje je tada bilo dio okruga Chablai u Francuskoj, pedesetih i šezdesetih godina
devetnaestog stoljeća. Opsjednutost je bila povezana s ukazanjima Djevice Marije, koja je ubrzo
počela i zaposjedati lokalne žene i djevojke. 5.2. Spektakl histerije u Stenjevcu Slučaj je privukao izrazitu pažnju javnosti i
psihijatrijske struke, a masovna opsjednutost je navodno poprimila takve razmjere da je morala
intervenirati i vojska.423 Za slučaj je indikativna činjenica da su zaposjednute bile samo žene koje
su govorile u nekoj vrsti transa i preuzimale identitet muškaraca, najčešće lovaca i ostalih ljudi
koji nisu pripadali njihovoj zajednici, već su tek povremeno dolazili u kontakt sa selom.424 Ann 132 Goldberg je u svojoj studiji „Sex, Religion, and the Making of Modern Madness: The Eberbach
Asylum and German Society, 1815-1849.” povezala slučajeve zaposjedanja sa sukobom između
predmodernih koncepcija sebstva koje postoji u stalnoj interakciji sa zajednicom i natprirodnim
svijetom i moderne koncepcije integriranog sebstva kojim upravlja razum.425Iako stenjevačke
povijesti bolesti ne govore o slučajevima grupne opsjednutosti, neke od njih prenose slučajeve
žena koje su tvrdile da su zaposjednute i u tom se stanju često ponašale sablažnjivo. Ono što je
naročito značajno u tim slučajevima je jezik kojim su štićenice govorile o vlastitom stanju
zaposjednutosti- kao da je neka nadnaravna sila, opisana gotovo isključivo u muškom rodu,
uspostavila kontrolu nad njihovim tijelima protiv njihove volje. Seljakinja iz Čazme, Jaga Š., koja je bila u Stenjevcu između 1891. i 1895.godine, kad je
otpuštena kao poboljšana predstavlja još jedan primjer zaposjedanja. Njena dijagnoza glasila je
„hysteria”. Prilikom boravka u zavodu tvrdila je da ima „vraga u želucu”426. U trenucima kad bi
ju vrag preuzeo, govorila bi o sebi u muškom rodu, i otvoreno pokazivala bijes vikanjem,
udaranjem rukama i nogama, lupanjem glavom u zid i bacanjem po podu. Liječnik je u povijesti
bolesti identificirao mirna („melankolična”) i „manijakalna” stanja. U skladu sa Charcotovim
eksperimentima, manijakalno bi stanje kod Jage nastupilo nakon pritiska na histerogenu točku. Zanimljivo je da taj podatak iznosi sama štićenica: „pokazuje na maternicu, veleć kad je tamo
prime da joj leti jezik i govor, tako da se nije kadra da izdrži, a da neviče i nepjeva”427 Usprkos ovako izraženom bogohulnom ponašanju u stanjima kad ”iz nje nije govorio vrag” Jaga
se ponašala mirno i pobožno: „Govori u muškom spolu, kao da tobože to vrag govori:smrdi crkva, kvragu neka ide krunica,
ja mrzim boga, ja vrag okrećem k crkvi rit, ja mrzim majku božju itd. Kad se je već naderala i
nabacala te nadrečila tad lupi sobom u zemlju i leže kao mrtva. g,
426 KPV, 1895: 1882. 427 Ibid. 425 Goldberg, 1999: 81. 428 Ibid. ,
427 Ibid. ,
427 Ibid. 5.2. Spektakl histerije u Stenjevcu U svojem ludovanju, oponaša i
lavež psa, tvrdeć da to vrag u njoj laje.”428 Jaga je u svojim „melankoličnim” stanjima bila svjesna činjenice da ponekad ne može
kontrolirati vlastito tijelo i izjavila je kako se osjeća prisiljenom da se ponaša bogohulno. Govorila je da se mora valjati i bacati po zemlji kad god vrag u njoj zaviče, a u povijesti bolesti 133 se naglašavao kontrast između njezinih dvaju duševnih stanja i njezin osjećaj gubitka kontrole
nad vlastitim tijelom:„Čudnovato je to da u stadiju manijakalnom veli da ima vraga u sebi, da je
sama vrag, te pljuje na križ i otčenaše i kune. U melankoličnom stanju moli boga, ljubi križeve i
otčenaše i pripovjeda da se nemože u manijakalnom stanju uzdržati da ne pljuje na križ.”429
Bizarniji oblik gubitka kontrole nad vlastitim tijelom iskusila je Dora G., seljakinja iz Pokupskog
kraj Turopolja, koja je 1895. godine bila u Stenjevcu nešto više od mjesec dana prije nego što ju
je neizlječenu odveo suprug. Dora je u Stenjevec primljena 27. srpnja, no njezine su poteškoće
počele mnogo ranije, još od zime, ili kako je sama Dora izjavila „od božićne nedjelje”.430 Iako je
Dora kratko boravila u Stenjevcu, tamošnji liječnici su detaljno zabilježili njezino svjedočanstvo. Dora je ispričala kako su u njoj: se naglašavao kontrast između njezinih dvaju duševnih stanja i njezin osjećaj gubitka kontrole
nad vlastitim tijelom:„Čudnovato je to da u stadiju manijakalnom veli da ima vraga u sebi, da je
sama vrag, te pljuje na križ i otčenaše i kune. U melankoličnom stanju moli boga, ljubi križeve i
otčenaše i pripovjeda da se nemože u manijakalnom stanju uzdržati da ne pljuje na križ.”429 Bizarniji oblik gubitka kontrole nad vlastitim tijelom iskusila je Dora G., seljakinja iz Pokupskog
kraj Turopolja, koja je 1895. godine bila u Stenjevcu nešto više od mjesec dana prije nego što ju
je neizlječenu odveo suprug. Dora je u Stenjevec primljena 27. srpnja, no njezine su poteškoće
počele mnogo ranije, još od zime, ili kako je sama Dora izjavila „od božićne nedjelje”.430 Iako je
Dora kratko boravila u Stenjevcu, tamošnji liječnici su detaljno zabilježili njezino svjedočanstvo. Dora je ispričala kako su u njoj: „...slike pokupskog bilježnika i jedne vile iz Veliševca koje iz nje govore. Boji i plaši se po
noći, malo spava. Pokupska obćina izgubila jednu šumu krivnjom bilježnika i ona je putila
ljude da idu u Zagreb fiškalu radi te šume... 433 Pocs, 2018: 260. 430 KPV, 1895: 2702. 432 Ibid. 429 Ibid. 431 Ibid. 5.2. Spektakl histerije u Stenjevcu misli da je zato bolestna, što je ljude putila proti
bilježniku, koji da je vilovit”431 Dora je iskustvo gubitka kontrole nad vlastitim tijelom gledala kroz prizmu sukoba s bilježnikom,
kojem je pak pridavala natprirodne moći. U liječničkoj svjedodžbi Dora kotarskom liječniku
govori kako ju „slike” veliševačkog bilježnika i njegove supruge vile sve više obuzimaju: „U njoj su vilovske slike...Ona ništa ne govori nego ta slika govori.…Traži medicinu da bi se
ovu sliku moglo iz nje protjerati, ona nema ni uma ni razuma, sve joj je oteto, srdce i
jezik...Raste joj novi nos. Slika promjenjuje obraze njezine. Govori o sebi u trećoj osobi…
Slika sve pojeda, G. jede a on u njoj sve pojede. Sve je njezino, oko, ruka, noga, glava, lice. Jezik je njezin ali su se slike naturile na njega” 432 Čini se da je Dora svoj gubitak kontrole gledala kroz prizmu folklornih vjerovanja o vilama. O
tome svjedoči pomalo morbidna slika u kojoj joj vile mijenjaju lice. Naime, jedan skup
vjerovanja u vile, zabilježen u Srednjoj i Jugoistočnoj Europi, govori o vilama koje zaposjedaju
tijelo osoba koje im se zamjere te im „restruktuiraju” tijelo i um. Pritom vile često mijenjaju
dijelove lice zaposjednute osobe ili joj oduzimaju udove ili dijelove lica.433 134 Iskustvo strane kontrole nad mislima i tijelom o kojem često pričaju štićenice zavoda za
umobolne u Stenjevcu može se dakako, isključivo gledati kao psihotični ili disocijativni simptom,
no u svjedočanstvima o kontroli nazire se nekoliko razina rodne opresije. Iza različito
artikuliranih osjećaja gubitka vlasti nad osobnim mislima i tijelima često stoje ljudske sudbine
koje govore o vlastitoj depersonalizaciji, gubitku identiteta ili sukobu s autoritetom koji je, kao u
slučaju „rittermeistera” ili bilježnika, posjedovao stvarnu ekonomsku ili administrativnu moć nad
štićenicama. Također, narativ o kontroli ženskih tijela se proteže i na svakodnevicu života u
zavodu: dok su štićenice umišljale da njihova tijela kontroliraju natprirodnim moćima ili
naprednom tehnologijom, liječnici i bolničari su, uz pomoć njihove rodbine i administrativnih
vlasti ostvarivali stvarnu tehnološku moć nad njihovim tijelima. Njihova tijela su tako bila
smještena u sustav odjela arhitektonski osmišljen s ciljem učinkovitije kontrole, vezana u stezulje
ili omatana u plahte i podvrgnuta terapijskom radu ili umirujućim psihoaktivnim sredstvima. Strogi emotivni režimi i nadzor seksualnosti podvrgavali su njihovu tjelesnost i njihov unutarnji
život sofisticiranim oblicima društvenog nadzora. 5.2. Spektakl histerije u Stenjevcu Samim time može se reći da je žensko iskustvo
na prijelazu stoljeća, a naročito iskustvo „histeriziranih” štićenica zavoda za umobolne bilo u
mnogome iskustvo prisilne kontrole nad njihovima tijelima i osjećajima. 434 Maudsley, 1873. prema Krafft- Ebing, 2011: 24. y,
p
g,
435 Krafft- Ebing, 2011: 24. y
p
g
435 Krafft- Ebing, 2011: 24. y,
p
435 Krafft- Ebing, 2011: 24. 434 Maudsley, 1873. prema Krafft- Ebing, 2011: 24. 5.4. Nevidljivost sifilisa: progresivna paraliza u Stenjevcu Uska isprepletenost morala i seksualnosti bila je naglašeno prisutna u psihijatriji druge polovine
devetnaestog stoljeća. Maudsley je tako, oslanjajući se na Darwina, svojevremeno proglasio
seksualni nagon izvorom društvenog poretka434. Richard von Krafft-Ebing, kojeg mnogi smatraju
začetnikom moderne seksologije je nadovezujući se na Maudsleyja istom neraskidivom vrpcom
povezao seksualnost, religiju, etiku i estetiku ustvrdivši da je „seksualni osjećaj korijen svake
etike i bez sumnje, esteticizma i religije”.435 Seksualnost u devetnaestom stoljeću postaje sve
vidljivija u javnom prostoru, a njezina prisutnost kao dio medicinskih, društveno-reformskih ili
moralističkih rasprava ju čini političkim pitanjem. Eugenički pokret, koji je nastao sredinom
devetnaestog stoljeća i jačao sve do kraja Drugog svjetskog rata, pretvara seksualnost u bojno
polje na kojem se vodi ključna bitka za opstanak „zapadne civilizacije” ili čak, ljudske vrste. Povećana vidljivost seksualnosti, koju Foucault naziva „multiplikacijom diskursa o 135 seksualnosti”436 nije zaobišla ni psihijatriju. Unutar psihijatrije nastao je diskurs o seksualnosti
usko vezan uz moralistički koncept degeneracije. Taj je diskurs pretendirao na znanstvenost i
nastojao se legitimirati somatičkom neurologijom, a njegova je primarna svrha bila naturalizacija
uvriježenih rodnih predodžbi i koncepcija o seksualnosti. U hrvatskoj psihijatriji se diskurs o
seksualnosti uglavnom razvijao oko triju točaka: progresivne paralize, „seksualne perverzije” i
„moral insanityja”. Dok je progresivna paraliza bila posljedicom zaraze seksualno prenosivim
sifilisom, „moral insanity” je bila dijagnoza kojom su se opisivali različiti oblici ponašanja koje
se smatralo devijantnim, uključujući i određene seksualne prakse. Seksualne perverzije nisu
pripisivane nijednoj pojedinoj bolesti, ali su često spominjane u člancima ili povijestima bolesti. Njihovo spominjanje u kontekstu duševnih oboljenja, često je davalo tim dokumentima koji su
pretendirali na vlastitu znanstvenost izraženu moralističku notu. Uopće, sve tri točke
psihijatrijskog diskurse povlačile su za sobom jake moralističke konotacije i predstavljaju
jedinstven primjer dodirivanja i ispreplitanja predznanstvenog pojma grijeha s medicinskim
pojmom patologije. Progresivna paraliza bila je neizlječiva i terminalna bolest koja je prema Shorteru, bila jedan od
uzroka naglog porasta broja štićenika u psihijatrijskim zavodima437. Iako je pogađala i muškarce i
žene, bila je češća među muškarcima. Bolest je bila posljedicom tercijarnog stadija infekcije
sifilisnom spirohetom (Treponema Pallidum), uzročnikom sifilisa. Prema najuvjerljivijoj teoriji ,
sifilis se u Europu proširio s Hispanole, odakle su ga donijeli mornari ekspedicije Kristofora
Kolumba.438 Među prvim narativima o sifilisu bili su iskazi koji su odisali rasističkim osjećajem
moralne superiornosti europskih kolonijalnih osvajača. ,
438 Hayden, 2003: 25. 436 Foucault, 1998: 53. y
,
439 Spongberg, 1997: 18. 437 Shorter, 1997:56. 5.4. Nevidljivost sifilisa: progresivna paraliza u Stenjevcu Madridski plemić Ferdinand de Oviedo
tvrdi da je zaraza nastala zbog općenja s nemoralnim ženama Hispanole koje su „poznate po
nečistoći, indolenciji, često jedu crve, pauke, zmije i šišmiše i vrste guštera koje su otrovne za
sve osim za urođenike.”439Kroz cijeli rani novi vijek, povezan sa smrtnim grijehom bludnosti,
sifilis je među kršćanima bio smatran kaznom za moralno posrnuće. U devetnaestom stoljeću,
sifilis i progresivna paraliza navođeni su kao jedan od dokaza u prilog eugeničkih teorija
hereditarne degeneracije kojima su europski psihijatri bili osobito skloni. Između kršćanskog
morala i upozorenja o propasti društva zbog „naslijeđenog grijeha” sifilis i progresivna paraliza 136 bili su usko vezani uz moralistički i konzervativni pogled na seksualnost. Britanska
povjesničarka umjetnosti Monika Pietrzak-Franger pokazala je da su pogledi na sifilis u znanosti
i kulturi devetnaestog stoljeća bili obilježeni stalnom napetošću između njegove vidljivosti i
nevidljivosti.440 Ta napetost odlikuje i poglede psihijatrije na sifilis i progresivnu paralizu: iako se
sifilis relativno često javlja kao uzrok duševnih bolesti i premda povijesti bolesti redovito bilježe
slučajeve ranije infekcije sifilisom, psihijatri još uvijek ne prave eksplicitnu vezu između sifilisa i
progresivne paralize. To poricanje eksplicitnih veza između tih dvaju čestih oboljenja postaje još
paradoksalnije kad se uzme u obzir da je Alfred Fournier još 1879. dokazao vezu između tih
dvaju bolesti.441 Europski psihijatri su odbacivali takvu ideju zbog uvjerenja da bacil sifilisa ne
može proći krvno-moždanu barijeru. 442 Drugi uzrok neprihvaćanja Fournierovog otkrića bio je u
činjenici da je između zaraze sifilisom i pojave progresivne paralize slijedio period latencije za
vrijeme kojeg su se simptomi zaraze pojavljivali sporadično i često bivali otpisani kao znakovi
lošeg zdravlja, hipohondrije ili neurasteničnog oboljenja. Treći razlog odbijanja veze između
sifilisa i progresivne paralize bio je u činjenici da su psihijatri često bili neskloni iznalaženju
jasne etiologije duševnih bolesti. Ranije smo pokazali da je upravo postojanje mutnog graničnog
prostora između duševnog zdravlja i ludila bilo jedno od općih mjesta psihijatrije druge polovice
devetnaestog stoljeća. Upravo zbog takve percepcije duševnog oboljenja, psihijatri su bili skloni
progresivnu paralizu pripisivati brojnim labavo definiranim uzrocima koji su uključivali
„naprezanje mozga2, alkoholizam i nemoralan život. Uz to, predmoderna dihotomija ludila i
razuma bila je još uvijek dominantan način gledanja na duševne bolesti. Umjesto jasne
povezanosti konkretnih uzroka i definitivne dijagnoze, na pojedina se duševna oboljenja više
gledalo kao na različite manifestacije iste bolesti-ludila dok su svi različiti uzroci mogli u većoj
ili manjoj mjeri biti svedeni pod krovni pojam degeneracije. y
,
442 Ibid, 40. 440 Pietrzak- Franger, 2017: 1. 443 Pietrzak- Franger, 2017: 5. g
441 Hayden, 2003: 39. y
,
442 Ibid, 40. 441 Hayden, 2003: 39. 5.4. Nevidljivost sifilisa: progresivna paraliza u Stenjevcu Sifilis je napadao različite organe i tjelesne sustave, izazivajući jako širok spektar simptoma, što
je navelo britanskog kirurga i venerologa Jonathana Hutchinsona da ga nazove „Velikim
Imitatorom”443. Percepcija sifilisa kao bolesti „imitatora” činila ga je u neku ruku muškim
ekvivalentom protejskoj histeriji. Naravno, paralele između sifilisa i histerije tu ne prestaju. Javni
diskurs o sifilisu bio je bremenit moralističkim poimanjem seksualnosti, kao i diskurs o histeriji. 137 Dok je histerija predstavljala erotizirani spektakl ženske nezapriječene seksualnosti, sifilis je
predstavljao gotički spektakl strave i užasa i služio kao opomena usmjerena protiv preslobodnog
seksualnog ponašanja, predstavljajući svojevrsni „tamni odraz” histerije. Dok je histerija bila
medicinski konstrukt koji je novim, znanstvenim rječnikom artikulirao i naturalizirao
konzervativnu podjelu rodnih uloga, sifilis je bio stvarna bolest sakrivena iza slojeva ideoloških i
moralističkih narativa o degeneraciji. Histerija je bila prikazivana i promatrana, dok je sifilis bio
potiskivan. Dok je histerija predstavljala erotizirani spektakl ženske nezapriječene seksualnosti, sifilis je
predstavljao gotički spektakl strave i užasa i služio kao opomena usmjerena protiv preslobodnog
seksualnog ponašanja, predstavljajući svojevrsni „tamni odraz” histerije. Dok je histerija bila
medicinski konstrukt koji je novim, znanstvenim rječnikom artikulirao i naturalizirao
konzervativnu podjelu rodnih uloga, sifilis je bio stvarna bolest sakrivena iza slojeva ideoloških i
moralističkih narativa o degeneraciji. Histerija je bila prikazivana i promatrana, dok je sifilis bio
potiskivan. Odnos sifilisa, moralnih nazora i degeneracije bio je mnogostruk i kompleksan. Dijete zaraženo
kongenitalnim sifilisom (naslijeđenim od zaraženih roditelja) postalo je u devetnaestom stoljeću
jednom od najsnažnijih ideologema kojim su se podjednako služili zagovornici eugeničkih
teorija, feminističke autorice i umjetnici pesimističnog pogleda na svijet. Na slici Naslijeđe
Edwarda Muncha iz 1903. godine referira se kršćanski motiv „Madone s djetetom”, no majka na
Munchovoj slici drži dijete prekriveno sifiličnim lezijama.444 Prizor predstavlja sumorno
upozorenje o budućim generacijama koje nose bolest kao teret naslijeđa modernizacije. Dok je na
Munchovoj slici muškarac odsutan, u zapisima feminističkih autorica upravo on snosi glavnu
krivnju za rasnu degeneraciju i slabljenje budućih naraštaja. „Nove žene” i feministkinje poput
Emmeline Pankhurst naglašavale su prijetnju hereditarnog sifilisa kako bi legitimirale vlastiti
pristup medicinskom znanju, koje su u devetnaestom stoljeću isključivo posjedovali muškarci.445
Hrvatska feministička književnica i prevoditeljica Vilma Vukelić također navodi spolne bolesti
kao posljedicu rodne nejednakosti i dogovorenih brakova pri čemu naročito ističe žene kao žrtve. 447 Hayden, 2003: 138. 444 Ibid, 233-234. 446 Vukelić, 2003: 365. 444 Ibid, 233-234.
445 Ibid, 282.
446 Vukelić, 2003: 365.
447 Hayden 2003: 138 445 Ibid, 282. 5.4. Nevidljivost sifilisa: progresivna paraliza u Stenjevcu Spominje svoju sestričnu koju je nametnuti suprug već u prvoj bračnoj noći zarazio spolnom
bolešću od koje je patila cijeli život.446 Sam sifilis je bio bolest od čijeg se spomena u građanskim
krugovima najčešće zaziralo. Van Gogh, Nietzsche i Maupassant su pokazivali simptome
progresivne paralize, a posljednja dvojica su i umrla od posljedica iste.Vincent Van Gogh i njegov
brat Theo će tako u svojim pismima izbjegavati direktno spomenuti zarazu, služeći se umjesto
toga brojnim eufemizmima.447 Također Elizabeth Förster-Nietzsche, sestra filozofa Friedricha
Nietzschea dugo se trudila da ospori dijagnozu sifilisa koju su brojni liječnici i biografi postavili 138 njezinom bratu.448 No neki su smatrali šutnju o sifilisu znakom licemjerja građanske kulture. Buntovni francuski književnik Guy de Maupassant prilično euforičnim tonom izražava prezir
prema tajenju sifilisa u pismu prijatelju gdje slikovito opisuje trenutak u kojem je doznao da je
zaražen sifilisom: „Imam lues! Napokon! Prava stvar! Ne prezira vrijedni triper, ne crkvenjačku podagru, ne
buržujsku klamidiju, niti grahoraste izrasline - ne, ne, veliki lues od kojeg je umro Francois I. Veličanstveni lues, jednostavno; elegantni sifilis...Imam lues i ponosim se time, grom i pakao i
dovraga s buržujima. Aleluja, imam lues i ne trebam se više brinuti da ću se zaraziti pa ševim
uličarke i kurve i kažem im: Imam lues. Njih je strah, a ja se smijem!”449 „Imam lues! Napokon! Prava stvar! Ne prezira vrijedni triper, ne crkvenjačku podagru, ne
buržujsku klamidiju, niti grahoraste izrasline - ne, ne, veliki lues od kojeg je umro Francois I. Veličanstveni lues, jednostavno; elegantni sifilis...Imam lues i ponosim se time, grom i pakao i
dovraga s buržujima. Aleluja, imam lues i ne trebam se više brinuti da ću se zaraziti pa ševim
uličarke i kurve i kažem im: Imam lues. Njih je strah, a ja se smijem!”449
Od iste bolesti su umrle ili barem patile brojne poznate ličnosti iz kulturnog i političkog života
Hrvatske u devetnaestom stoljeću, poput bana Josipa Jelačića Bužimskog, Augustina
Harambašića, Vladimira Vidrića i Frane Supila. Progresivna paraliza bila je jedna od
prevladavajućih dijagnoza među stenjevačkim štićenicima - tu je dijagnozu 1909. imalo 60 od
262 štićenike, što ju je činilo drugom dijagnozom iza široko definirane „amentie”450. Izuzetna
raširenost i velika smrtnost te socijalni značaj bolesti koja je najčešće pogađala muškarce
srednjeg i višeg sloja u dobi od 30 do 50 godina rano je probudila interes zavodskih liječnika za
uzroke i tretman progresivne paralize. 450 Žirovčić prema Gundrum, 1910: 152. U prijašnjim izvještajima se dijagnoza progresivne paralize naziva
drugačije- Rohačekovi izvještaji iz 1883. i 1885 ju nazivaju „Alienatio mentis cum paralysis”. Ta definicija
nužno nije identična s onom progresivne paralize, ali njezina učestalost je slična onoj iz 1910 Od nje je 1893.
patilo 51 od 344 štićenika a 1895 47 od 409 štićenika koji su te godine primljeni u Stenjevac. uss avs y
o e , 005: 0.
čić prema Gundrum, 1910: 152. U prijašnjim izvještajima se dijagnoza progresivne paralize naziva ,
p j
j
j
j
j g
p
g
p
ohačekovi izvještaji iz 1883. i 1885 ju nazivaju „Alienatio mentis cum paralysis”. Ta definicija 448 Ibid, 2003: 152. 449 Bogousslavsky i Boller, 2005: 10. j
p
g
p
j
j
j
51 od 344 štićenika a 1895 47 od 409 štićenika koji su te godine primljeni u Stenjevac. čić prema Gundrum, 1910: 152. U prijašnjim izvještajima se dijagnoza progresivne paralize naziva
ije- Rohačekovi izvještaji iz 1883. i 1885 ju nazivaju „Alienatio mentis cum paralysis”. Ta definicij drugačije- Rohačekovi izvještaji iz 1883. i 1885 ju nazivaju „Alienatio mentis cum paralysis . Ta definicija
nužno nije identična s onom progresivne paralize, ali njezina učestalost je slična onoj iz 1910 Od nje je 1893.
patilo 51 od 344 štićenika a 1895 47 od 409 štićenika koji su te godine primljeni u Stenjevac. j
j
j
j
p
y
j
entična s onom progresivne paralize, ali njezina učestalost je slična onoj iz 1910 Od nje je 1893. 449 Bogousslavsky i Boller, 2005: 10.
Ž 52.
ky i Boller, 2005: 10. 5.4. Nevidljivost sifilisa: progresivna paraliza u Stenjevcu Od iste bolesti su umrle ili barem patile brojne poznate ličnosti iz kulturnog i političkog života
Hrvatske u devetnaestom stoljeću, poput bana Josipa Jelačića Bužimskog, Augustina
Harambašića, Vladimira Vidrića i Frane Supila. Progresivna paraliza bila je jedna od
prevladavajućih dijagnoza među stenjevačkim štićenicima - tu je dijagnozu 1909. imalo 60 od
262 štićenike, što ju je činilo drugom dijagnozom iza široko definirane „amentie”450. Izuzetna
raširenost i velika smrtnost te socijalni značaj bolesti koja je najčešće pogađala muškarce
srednjeg i višeg sloja u dobi od 30 do 50 godina rano je probudila interes zavodskih liječnika za
uzroke i tretman progresivne paralize. U Hrvatskoj medicinskoj publicistici je jedan od prvih članaka o progresivnoj paralizi bio
članak stenjevačkog kućnog liječnika Dragutina Forenbachera „O progresivnoj paralizi“
objavljen u prvom i drugom broju Liječničkog vjesnika iz 1892. godine. Forenbacher nikad nije
postao ravnateljem Zavoda u Stenjevcu, ali je u ranim godinama postojanja zavoda upravo on
najviše pisao o duševnim bolestima. Njegov članak o progresivnoj paralizi zanimljiv je upravo iz
razloga što je dvije godine ranije u Liječničkom vjesniku objavio opsežan članak o paološkim
promjenama na mozgu nastalim uslijed sifilisa Syphilis u moždjanih (Lues cerebri). Indikativno
je da Forenbacher navodi sličan set simptoma za progresivnu paralizu i za bolest koju je nazvao
cerebralnim luesom. Kao simptome moždanog luesa Forenbacher tako navodi glavobolje,
vrtoglavice i kljenuti te niz duševnih simptoma, od naglih promjene raspoloženja, umora i smetnji 139 mišljenja i pamćenja, promjene ličnosti do konačnog propadanja duševnih funkcija koje je
Forenbacher znakovito nazvao ”pseudoparalizom”.451 Kod progresivne paralize Forenbacher
navodi isti skup simptoma - omaglice, vrtoglavice, klijenuti promjena raspoloženja i promjena
ličnosti.452 No dok u članku u „lues cerebri” Forenbacher više govori o histološkim nalazima
dobivenih obdukcijom oboljelih i tjelesnim simptomima, kod progresivne paralize su znakovi
duševnog propadanja opisani prilično detaljno, a sam članak završava dvama kazuističkim
prilozima.453 Po tome se vidi da Forenbacher „luesu cerebri” pristupa kao primarno somatičkom
oboljenju, dok u progresivnoj paralizi vidi duševnu bolest. Forenbacher također otvoreno
osporava sifilis kao uzrok progresivne paralize, smještajući ga radije među faktore koji mogu
doprinijeti bržem razvoju bolesti: „Sve, što moždjane direktno vriedja kao: trauma i insolacija, nadalje intoksikacije alkoholom, a
navlastito Syphilis imadu se smatrati važni faktori za causalni momenat paralize. Osobito mi je
naglasit to o syphilisu, naravno ne u onom smislu, kao da on nefaljeno i direktno prouzročuje
paralizu. 451 Forenbacher, 1890: 74-75. 452 Forenbacher, 1892: 4-5. 454 Ibid, 5. 453 Ibid, 21-22. ,
453 Ibid, 21-22. 455 Ibid. 454 Ibid, 5. 5.4. Nevidljivost sifilisa: progresivna paraliza u Stenjevcu Excessus in Venere, ako moždjane i oslabljuje, nemože se sam po sebi uzeti kao
veoma težući faktor.”454 Sam sifilis je tako naveden kao jedan od mogućih popratnih faktora koji oslabljuju mozak. Nije
jasno doprinosi li razvitku paralize sam sifilis ili slobodne seksualne navike koje Forenbacher
naziva „excessus in Venere”, a koje su povezane i sa spolnim bolestima i s razvitkom duševnih
bolesti (sam pojam „excessus in Venere” često će se sam po sebi javljati kao uzrok duševnih
oboljenja). Sukladno svojoj percepciji progresivne paralize kao primarno duševnog oboljenja
Forenbacher će i njezin uzrok smjestiti u mutnu sferu interakcije mentalnog i tjelesnog. Za
Forenbachera su tako primarni uzroci progresivne paralize „afekti kao briga, skrb, borba za
obstanak duševno preobterećuje” (sic).455 Dok je „ženska” histerija bila posljedicom konstitutivne
slabosti ženskog mozga i živčanog sustava, uzroci „muške” „dementie paralytice” su radikalno
drugačiji. Naime muškarci su „izvrženiji od žena borbi za opstanak i duševnom naporu”. Kako je
stres modernog života sve veći tako i raste broj oboljelih od te bolesti u inteligentnom dijelu
pučanstva. Kasnije u članku Forenbacher povlači direktnu paralelu između progresivne paralize i
neurastenije, bolesti za koju se u 19. stoljeću smatralo posljedicom brzog i neumoljivog tempa 140 modernog života.456 Znakovito je da se Forenbacher u svom članku ne zadržava na pisanju o
progresivnoj paralizi, već se upušta u digresiju o modernitetu kao znaku nestajanja „muževne
snage” čovječanstva. Forenbacher će čovječanstvo prispodobiti s tisućljetnim hrastom koji
počinje klonuti od starosti, a želju za brzim tehnološkim napretkom istaknut će kao još jedan
simptom neurastenične slabosti: „Naš viek baš teži zatim, da si sve prilagodi, izmišlja svašta, da si osladi svoj boravak; čezne za
novostmi, žudi za promjenom: već mu neudovoljuje ni željeznica, pa teži zatim, da nebom
zaplovi!Nepotiče li baš ta čežnja za promjenami, za izumi iz patoložke razpoloživosti živčane,
drugimi riečmi: nije li sve to plod današnje nevrastenije?”457 Ivan Žirovčić će u svojoj podjeli duševnih bolesti nazvati progresivnu paralizu, odnosno
„dementiu paralyticu” „bolešću u kojoj se pojavljuju sve moguće duševne abnormalnosti” a
njezinim uzrocima smatrat će „alcoholismus, lues, i prekomjerno naprezanje moždjana.”
odbacivši hereditet kao faktor.458 Žirovčić, za razliku od Forenbachera neće negirati sifilis kao
mogući uzrok progresivne paralize već će ga, uz alkoholizam pridodati „prekomjernom
naprezanju moždjana”. Čini se da Žirovčić i Forenbacher imaju različite poglede na progresivnu paralizu: Forenbacher je
sklon previdjeti vezu između sifilisa i progresivne paralize jer smatra muškarce koji uglavnom
obolijevaju od progresivne paralize moralnim stupovima društva. 458 Žirovčić, 1895a: 90-91. 459 Forenbacher, 1892: 5. 461 Šimsa, 1898: 1. 460 Žirovčić, 1898: 412. 457 Ibid, 6-7. 456 Ibid, 6. 5.4. Nevidljivost sifilisa: progresivna paraliza u Stenjevcu Kao najčešće pacijente
Forenbacher navodi „vojne časnike, činovnike i bersijance”, a pojavu bolesti kod potonjih
povezuje s krahovima burze459. Zbog toga mu je prirodnije pretpostaviti da oni obolijevaju zbog
brige i duševnog napora nego zbog vlastitih nemoralnih navika ili neodgovornog seksualnog
ponašanja. Žirovčić je skloniji tražiti različite uzroke progresivne paralize i povezivati ih sa
životnim navikama bolesnika. U svom kasnijem članku iz 1898. godine Žirovčić će iznijeti slučaj
bankara koji je umro od progresivne paralize i njegovu će bolest pripisati prenaprezanju uslijed
napornog rada da se uspostavi bankovni integritet460 Kao što sam već ranije naveo, češki
psihijatar Jan Šimsa koji je kratko vrijeme bio ravnatelj stenjevačkog zavoda vršio je detaljne
obdukcije štićenika oboljelih od progresivne paralize i našao kod mnogih dokaz cerebralnog
sifilisa461 zbog čega se suprotstavio dominantnom stavu austro-ugarskih psihijatara da je temeljni 141 uzrok progresivne paralize duševni napor uzrokovan modernim tempom života koji je zastupao
Krafft-Ebing.462 Čini se da Šimsini nalazi ipak nisu našli širi odjek u stenjevačkoj praksi: povijesti
bolesti ne uspostavljaju jasnu vezu između sifilisa i progresivne paralize. Uzroci progresivne paralize navođeni u povijestima bolesti će biti raznoliki, od „affectusa” i
alkoholizma do luesa, „neimaštine” i „raspuštenog života” no ono što će im biti zajedničko je da
će isti biti iščitavani iz životnih navika oboljelih. Stjepanu K., umirovljenom činovniku solarskih
ureda će tako u povijesti bolesti pisati da je dementia paralytica uzrokovana „spirituosom”463
(alkoholizmom) dok se Mariji H. ženi mlinarskog radnika iz Garčina u Banatu uzrok bolesti traži
u uzrujavanju zbog predstojeće sudske parnice.464 Povijesti bolesti često ističu seksualne navike
štićenika oboljelih od „dementia paralytica”, no u podjednakoj se mjeri fokusiraju na stres ili na
naporan rad. Čini se da je postojala tendencija da se sifilis, alkoholizam i nemoralan život prije pretpostavljaju
kao uzroci oboljenja kod štićenika i štićenica iz nižih društvenih slojeva. Razloge tome možemo
naći kako u činjenici da su liječnici, i sami pripadnici građanskog sloja imali predrasude o nižim
slojevima kao nemoralnima tako i u činjenici da su građanske obitelji bile sklonije skrivati
alkoholizam i sifilis. Tako će kćerku seljanke Roze S. iz Sigetca kod Koprivnice liječnik ispitivati
o majčinim seksualnim navikama: „Na pitanje da li je majka i sama sprovadjala nemoralan život,
nije dala točnog odgovora; iz nećkanja njezinog opazilo se, da je to bilo moguće, jer je želja
kćerke da joj majka čim prije umre.”465Iako je Rozu S. ,
466 Ibid. 462 Ibid, 2.
463 KPV, 1895: 2288.
464 KPV, 1911: 7972.
465 KPV, 1911: 8213.
466 Ibid 465 KPV, 1911: 8213. 466 Ibid. 5.4. Nevidljivost sifilisa: progresivna paraliza u Stenjevcu suprug zarazio luesom, uzrok progresivne
paralize je ipak tražen u njezinim vlastitim tobožnjim seksualnim ekscesima.466 Napetost između
vidljivosti i nevidljivosti sifilisa koje je definirala ambivalentan odnos devetnaestoljetnog društva
prema toj bolesti se tako odražava i u teorijskim i kliničkim osvrtima stenjevačkih psihijatara na
„dementia paralytica”. Sifilis se tako uvijek spominje u kontekstu te raširene bolesti ali ga se
uporno odbija prepoznati uzrokom iste. Također, iako se eventualni dokazi infekcije sifilisom kod
građana zanemaruju, stenjevački opisi dementia paralytica kod štićenika iz nižih društvenih
slojeva često vrve referencama na isti. Možemo reći da je progresivna paraliza bila bolest čija se
seksualno prenosiva priroda potiskivala zbog predodžbi liječnika o građanstvu kao visoko 142 moralnoj klasi koja se odlikuje napornim radom zbog kojeg često žrtvuje vlastito duševno
zdravlje. ,
468 KPV, 1895: 2640. 467 LV, 1883: 101. 468 KPV, 1895: 2640. 5.5. Seksualna nastranost, primitivizam i „moral insanity”: Seksualnost, moral i ludilo na
prijelazu stoljeća Govor o seksualnosti u kontekstu patologizacije određenih seksualnih praksi bit će česta tema
stenjevačkih liječnika, a naročito će izraženi biti opisi seksualnih nastranosti u forenzičko-
psihijatrijskim člancima u Liječničkom vjesniku. U prvim povijestima bolesti seksualnost
štićenika se rijetko spominje, no sedam godina nakon otvaranja zavoda, austrijski psihijatar
Richard von Krafft-Ebing objavljuje svoje seminalno djelo Psychopatia sexualis: forenzičko-
kliničke studije. Hrvatski zavodski liječnici bili su pod izrazitim utjecajem austrijske psihijatrijske
škole, a kako se njihov suvremenik Krafft Ebing intenzivno bavio seksualnošću, tako joj se i
Stenjevcu počela pridavati izrazita važnost. Može se vidjeti kako nakon objavljivanja
„Psychopatie sexualis“ stenjevački liječnici pokazuju sve više interesa za seksualno ponašanje
svojih štićenika. O tome da je sam Krafft-Ebing bio jedan od većih intelektualnih autoriteta među
stenjevačkim liječnicima govori i činjenica da se u liječničkom izvješću iz 1883. spominje kako
se kalijev bromid kao sredstvo za liječenje epilepsije koristio u skladu s uputom dobivenoj od
Krafft-Ebinga u Grazu.467 Samim time, moguće je da stenjevački liječnici nisu samo čitali Krafft-
Ebingova djela, već i osobno dobivali upute od njega. Pojedine povijesti bolesti govore i o tome
da su se u Stenjevcu liječili i neki od Krafft- Ebingovih pacijenata između ostalih i trgovac iz
Virovitice, Jakob Konig, kojem je Krafft Ebing postavio dijagnozu „Einfersuchtswahn”
(„ljubomorno ludilo”), a u Stenjevcu su ga liječili od „neurasthenije.”468 „Psychopatia sexualis” donosi detaljnu klasifikaciju poremećaja vezanih uz seksualnost, sa
sažetim studijama slučaja iz prakse različitih psihijatara, ili iz sudske povijesti. U samoj knjizi
nigdje nije objašnjeno zašto su upravo ti slučajevi najrelevantniji, a sami dokazi „devijantnosti”
opisanih seksualnih praksi ili sklonosti ukorijenjeni su u Krafft-Ebingovom konzervativnom
shvaćanju ljudske seksualnosti. Iako je za Krafft-Ebinga seksualnost izvor religijskih i estetskih
osjećaja, njegovo shvaćanje zdrave seksualnosti je izuzetno suženo i odnosi se samo na seksualni
nagon koji je usmjeren prema produžetku vrste i čije su funkcije kod ljudi nužno vezane s 143 idejama „morala, sublimnog i ljepote”.469 Uska isprepletenost morala i estetike sa seksualnošću je
u neku ruku misao vodilja cijele Psychopatia sexualis, a emotivne i seksualne prakse koje Krafft-
Ebing uzima kao osnovu zdrave seksualnosti u potpunosti su informirane konzervativnim
moralnim nazorima i emotivnim režimom građanskih slojeva. Krafft- Ebing će tako smatrati
seksualnost neodvojivom od koncepta romantične monogamne ljubavi. 469 Krafft- Ebing, 2011: 24. 473 Krafft-Ebing, 2011: 31. 475 Krafft-Ebing, 2011: 55. g
470 Ibid, 28. 472 Ibid. 471 Ibid, 30. 470 Ibid, 28. 474 Ibid. 471 Ibid, 30. 472 Ibid. g
470 Ibid, 28. 474 Ibid. 5.5. Seksualna nastranost, primitivizam i „moral insanity”: Seksualnost, moral i ludilo na
prijelazu stoljeća Ljubav je za Krafft-
Ebinga primani element seksualne naklonosti,470 a istinsku ljubav Krafft- Ebing definira kao
„prepoznavanje moralnih i mentalnih kvaliteta voljene osobe.”471 No Krafft- Ebing ju također
odvaja od puke sentimentalnosti i zamišlja ju kao spoj građanske etike i senzualnosti.472
Psychopatia sexualis također pretpostavlja tradicionalno patrijarhalno poimanje rodnih uloga. Za
Krafft- Ebinga muškarci imaju jači spolni nagon, agresivni su, a njihova ljubav je izraženo
senzualna i usmjerena na fizički izgled. No kod muškarca seksualni poriv ne ispunjava čitavo
psihu i „nakon što osvoji nagradu njegovu ljubav zasjenjuju drugi životni i društveni interesi.”473
Žena pak, „ako je mentalno i fizički normalna ima malo senzualne žudnje” i „muškarac koji
izbjegava žene i žena koja traži muškarce su anomalije”. Žene moraju ostati seksualno pasivne jer
to „od njih zahtjeva njihov seksualni ustroj, a u tome joj pomažu pravila dobrog odgoja”.474
Konzervativno poimanje seksualnosti i rodnih uloga od početka će obojiti Krafft-Ebingovi
klasifikaciju seksualnih poremećaja i njegovu selekciju slučajeva na primjeru kojih je te pokušaje
objašnjavao. Po Krafft-Ebingu, seksualni se poremećaji dijele na periferne neuroze, spinalne
neuroze i cerebralne neuroze. Periferne neuroze odnose se na neuralgije, gubitak osjeta i
preosjetljivost koji su vezani uz patologiju perifernih živaca, sredstava za izlučivanje ili organa za
pokretanje. Kao jedini primjer spinalnih neuroza Krafft-Ebing navodi jedino „bolesti centra za
erekciju”475 dok je najveći prostor posvećen upravo cerebralnim neurozama koje Krafft-Ebing
dijeli na sljedeći način:1. Paradoksija ili pojava seksualnog nagona neusklađene s fiziološkim
razvojem seksualnih organa (u studijama slučaja naglasak će biti uglavnom na izraženoj
seksualnosti osoba starije životne dobi)2. Anestezija ili psihički uvjetovano odsustvo spolnog 144 nagona.3. Hiperestezija ili preintenzivan spolni nagon 4. Parestezija ili uzbuđivanje seksualnog
nagona uslijed neadekvatnim podražajima476 Poimanja „zdrave” spolnosti ukorijenjena u građanskom moralu bit će ključne za određivanje
toga što Krafft-Ebing u Psychopatia sexualis shvaća kao normalan intenzitet seksualnog nagona i
adekvatan podražaj za pobuđivanje spolnog nagona. Krafft-Ebing ilustrira hiperesteziju pomoću
slučaja preuzetog od francuskog psihijatra Valentina Magnana koji govori o „mladoj ženi, kćeri
luđaka, majci troje djece... koja je jednog dana otvoreno rekla svom suprugu da je zaljubljena u
jednog mladića”477. Sam Krafft-Ebing navodi kako je sam tretirao još pet slučajeva „patološke
ljubavi udanih žena prema mlađim muškarcima”.478 Krafft- Ebing je očito smatrao da seksualno i
emotivno pasivna uloga žene znači da će duševno i tjelesno zdrava žena pokazivati seksualnu
privlačnost jedino prema vlastitom suprugu. 479 Krafft-Ebing, 2011: 31. g,
480 Ibid, 25. 480 Ibid, 25. 478 Ibid. 477 Ibid, 73. g
480 Ibid, 25. 5.5. Seksualna nastranost, primitivizam i „moral insanity”: Seksualnost, moral i ludilo na
prijelazu stoljeća Uz to, jedino je spolni nagon koji može rezultirati
reprodukcijom smatran zdravim, tako da su svi oblici muške i ženske homoseksualnosti obrađeni
u poglavlju o parestezijama. I muška i ženska tijela su kod Krafft-Ebinga neodvojiva od patrijarhalnih moralnih nazora o
ustroju društva. Krajnji produkt takvog diskursa je bio dvojak: s jedne strane seksualnost je
moralizirana, s druge strane građanski moral (a samim tim i emotivni režim građanske klase) je
naturaliziran time što ga se zaogrnulo u auru medicinskog i znanstvenog autoriteta. Krafft-Ebing
je eksplicitan u svojoj eticizaciji tjelesnosti ponegdje direktno nalazeći dokaze svojih nazora o
seksualnosti u društvenim institucijama. Kad Krafft-Ebing govori o ženskoj seksualnosti kao u
većoj mjeri pasivnoj i spiritualnoj nego senzualnoj, ta je kvalifikacija argumentirana tvrdnjom da
bi u suprotnom: „brak i obiteljski život bili prazne riječi”. 479 Naturalizacija takve slike svijeta
dodatno je potkrijepljena eurocentričnim opisom odnosa među spolovima u različitim kulturama. Pojednostavljen i ahistoričan prikaz seksualnosti unutar okvira europske kulture obilježene
antičkim nasljeđem i kršćanstvom Krafft-Ebing ističe kao najviši civilizacijski doseg. S druge
strane, seksualne prakse i bračni običaji drugih kultura su arogantno otpisani kao „tretiranje žena
kao rasplodnih životinja”.480 Moralistički pogled Krafft-Ebinga na ljudsku seksualnost uklapa 145 psihijatrijsku seksologiju devetnaestog stoljeća u proces izdvajanja seksualnosti kao zasebnog
instinkta koji će odmah po svom izdvajanju putem različitih diskurzivnih praksi biti podvrgnut
društvenoj kontroli. Pritom su, kako je u svojoj studiji istaknuo Michel Foucault bitni objekti
koji služe kao loci kontrole upravo pojedina tijela: tijelo žene koje se histerizira, tijelo
masturbirajućeg adolescenta koje se podvrgava pedagoškom nazoru, maltuzijanski par koji je
podvrgnut demografskoj biopolitici i perverzna odrasla osoba koju se nastoji kontrolirati putem
medicinske seksologije.481 Psihijatrija je u određenoj mjeri stvarala svoj diskurs oko navedenih
lokusa. Diskurzivna histerizacija ženskih tijela je redovno provođena u psihijatrijskoj zavodskoj
praksi. Masturbacija je u nekim slučajevima smatrana simptomom duševne bolesti, nekad u formi
masturbatornog ludila kao duševna bolest sama po sebi, a ponegdje kao njezin uzrok, no psihijatri
su je općenito često isticali u povijestima bolesti. Maltuzijanski par čije je razmnožavanje
podređeno opstanku vrste će postati ključnim objektom psihijatrijske eugenike, a nastrana
odrasla osoba bit će utemeljenjem diskursa o moralnoj ludosti. U okvirima hrvatske psihijatrije navedeni aspekti medicinske biopolitike su imali još jedan važan
socijalni element. Naime, stenjevački psihijatri su se uglavnom bavili pacijentima ruralnom
porijekla čije se obrazovanje i imovinski status razlikovao od onog samih liječnika. 481 Foucault, 1998: 105. ,
482 Guči, 1880: 1. 482 Guči, 1880: 1. 481 Foucault, 1998: 105. 5.5. Seksualna nastranost, primitivizam i „moral insanity”: Seksualnost, moral i ludilo na
prijelazu stoljeća Taj dodir
visoke građanske kulture s ruralnim stanovništvom čija je egzistencija često bila obilježena
neimaštinom i predmodernim poimanjem vlastite tjelesnosti i seksualnosti proizvest će dodatne
diskurzivne forme u okviru kojih će hrvatski psihijatri govoriti o seksualnosti. Njihov govor o
seksualnosti neće se isključivo usredotočiti na pesimistične opise patologija modernog
neurasteničnog i histeričnog pojedinca (iako će i oni biti prisutni) nego će, pod utjecajem
konkretnih iskustava iz kliničke prakse, krenuti u smjeru povezivanja patološke seksualnosti i
percipiranog primitivizma štićenika. Samim time stenjevački će liječnici na sebe preuzeti
svojevrsnu „civilizirajuću” zadaću u okviru koje će borba protiv duševne bolesti biti neodvojiva
od borbe protiv primitivizma. U tome naravno neće biti usamljeni: jedan od prvih tekstova u Liječničkom vjesniku koji se bavi
problemima bračnih običaja u Hrvatskoj doći će iz pera sisačkog liječnika Ante Gučija. Guči je
na mjesečnoj skupštini Zbora liječnika 27. listopada 1879. održao izlaganje pod naslovom Kako
se može preranoj ženidbi u Posavini na put stati482. Izlaganje je objavljeno u prvom i drugom
broju Liječničkog vjesnika iz 1880. godine. Iako se radi o izvještaju provincijskog liječnika koji 146 se bavi problematikom iz svog kraja, u njemu se mogu nazrijeti pogledi medicinara na neke
običaje koji su bili prisutni u kulturi hrvatskog sela. Osim toga, predavanje je zanimljivo i kao
dokaz ranih početaka angažmana hrvatskih liječnika na polju socijalne reforme. Ta će tendencija
doživjeti svoj vrhunac i punu aktualizaciju za vrijeme djelovanja Škole narodnog zdravlja i
doktora Andrije Štampara, ali Gučijevo izlaganje pokazuje da su nastojanja u smjeru
prosvjećivanja ruralnog stanovništva vukla korijen duboko iz devetnaestog stoljeća. U svom
predavanju Guči povezuje ranu ženidbu u posavskom kraju (uglavnom u dobi od petnaest do
dvadeset godina) s potrebom siromašnih zadružnih kućanstava za radnom snagom koju im
nevjesta pruža. Zaključuje da su uzroci „rane ženidbe” to što su Posavci „baš od maloće i baš radi
preranih ženidaba lijeni, da im se ako dobiju ma kakovu problematičnu radnu silu više neće
raditi” zatim to što je narod „veoma malo neobražen” i „da još nisu dorasli” te u tome da postoje
sebični, bezdušni i lakomi ljudi koji narod potiču na ranu ženidbu iz tobožnjih patriotskih
razloga483. Predodžbe o bračnim i ljubavnim običajima na selu su se od početka razvijale u paternalističkom
tonu. Uzrok nekih nedvojbeno štetnih praksi liječnici devetnaestog stoljeća ne vide u teškim
socijalnim prilikama, već u neobrazovanosti nedoraslosti i moralnoj inferiornosti ruralnog
stanovništva. 483 Ibid, 19.
484 Ibid, 4.
485 Ibid, 6.
486 Ibid.
487 Ibid,7-8. 487 Ibid,7-8. 483 Ibid, 19. 5.5. Seksualna nastranost, primitivizam i „moral insanity”: Seksualnost, moral i ludilo na
prijelazu stoljeća Sami razlozi zbog kojih Guči smatra ranu ženidbu štetnom su kombinacija
medicinskih, moralističkih i eugeničkih tvrdnji kakva inače karakterizira medicinski govor o
seksualnosti na prijelazu stoljeća: rano upuštanje u spolne odnose tako „škodi zdravlju muža i
žene i priječi potpuni razvitak njihovih „tjelesnih i duševnih moći”, 484, djeca iz takvih brakova
nisu „tjelesno ni moralno dozrela”485, postoji rizik od neplodnosti,486 takva ženidba promiče
nećudorednost, pobačaj i u takvim brakovima u pravilu nema ljubavi.487 Iako Gučijev angažman
iskreno ide u smjeru poboljšavanja kvalitete života na posavskom selu, njegova percepcija
seoskog života i seksualnih praksi ide u smjeru moralne osude ruralnog stanovništva. Često
nalaženje uzroka problema u moralnim manjkavostima ruralnog stanovništva i njihovim
seksualnim praksama stvorit će kod dijela hrvatskih liječnika jasnu dihotomiju između
„civilizacije” predstavljene medicinom i građanskim moralom i „primitivizma” i nemorala koji
postaje jedna od glavnih karakteristika njihovih pacijenata. Stavovi stenjevačkih psihijatara u 147 velikoj su mjeri reflektirali moralističke stavove šire medicinske zajednice. Zbog toga su često
povezivali devijantnu seksualnost s urođenim primitivizmom i moralnom „uniženošću”
stenjevačkih štićenika488. Nazori o „primitivizmu” štićenika iz ruralnih krajeva često se javljaju u prikazima Žirovčićevih
psihijatrijskih vještačenja. Minku, mladu ženu iz „jednog od najsiromašnijih krajeva naše zemlje”
489koja je bila na psihijatrijskom vještačenju jer je bila optužena da je ugušila brata svog supruga
Žirovčić opisuje na način koji prispodobljuje njezin fizički izgled i duševno stanje sa siromašnim
podnebljem iz kojeg je potekla: „Minka P. mlada je seljačka žena, kratka i nesumjerna tiela,
nepodobne glave, „mongoloidnoga” tipa. Duševni njezin razvitak na nizkom je stepenu, nu
odgovara sriedi, u kojoj je odrasla...”490 Ideje o povezanosti primitivizma i određenih duševnih oboljenja dugo će opstojati u hrvatskoj
psihijatriji. U međuratnom razdoblju, a još naglašenije u prvim godinama socijalističke
Jugoslavije psihijatri će sebe percipirati kao prosvjetitelje koji imaju bitnu ulogu u oblikovanju
umova nacije. No istovremeno gledanje vlastitih štićenike kroz očište „primitivizma” dovelo je
do određene epistemološke i terapeutske krize. Opetovano su se nalazili u situaciji da ne
razumiju ljude kojima bi trebali pomoći, što je mnoge vodilo u novi pesimizam i dvojbe oko toga
postoji li u njihovim pacijentima išta nalik intelektu491. To je, naravno doprinijelo pomalo
dehumanizirajućem diskursu o duševno oboljelim ljudima- On nikad nije dosegao isti opseg kao
u Njemačkoj ili u brojnim kolonijalnim psihijatrijskim kontekstima, ali je svejedno ponekad
izbijao na površinu. Psihijatri će patološki seksualni nagon ponekad dovoditi i u vezu s pojmom „moral insanityja”. Dragutin Forenbacher je 1893. 488 Takav stav neće biti vidljiv samo u odnosu prema seksualnosti. Primjerice,, stenjevački psihijatri često ističu
raširenost alkoholizma u ruralnim krajevima i povezanost tog problema s duševnim oboljenjima. No jedino će
Jan Šimsa proširiti svoju kritiku na društvene probleme koji uzrokuju alkoholizam, dok će za Žirovčića isti biti
tek još jedan simptom moralnog posrnuća “primitivnih” nižih slojeva.
Ž j
j
p
489 Žirovčić, 1904: 309. ,
490 Žirovčić, 1904: 311. ,
491 Antić, 2017: 241. j
j
p
g p
p
j
489 Žirovčić, 1904: 309. 89 Žirovčić, 1904: 309.
90 Ži
čić 1904 311 5.5. Seksualna nastranost, primitivizam i „moral insanity”: Seksualnost, moral i ludilo na
prijelazu stoljeća u Liječničkom vjesniku objavio rad O takozvanoj moralnoj ludosti
(moral insanity) osobitim obzirom na patološki spolni nagon (s gledišta psychiatrijsko-pravna). Iz Forenbacherovog se članka može iščitati da je na njegove stavove o seksualnosti uvelike
utjecao Krafft-Ebing- dapače, oko trećine članka zauzima sažimanje glavnih ideja i primjera 148 iznesenih u Psychopatiji sexualis. Kao i za Krafft – Ebinga i za Forenbachera je seksualnost izvor
estetskih osjećaja, ali je ”nered u spolnom nagonu” uzrokom brojnih psihoza i neuroza.492Članak
odražava tada veoma aktualne rasprave o prirodi kriminalnog ponašanja koje su često dijelile
pravnike i psihijatre. U trenutku kad se psihijatrija krajem osamnaestog stoljeća počela etablirati
kao grana medicine, počeli su prijepori o tome jesu li izuzetno nasilni i brutalni zločini zapravo
simptom duševne bolesti i pripadaju li počinitelji istih u djelokrug rada kaznenog prava ili
psihijatrije. Te rasprave rasplamsale bi se svaki put kad bi neki novi nasilni zločin ili
senzacionalni sudski slučaj privukao pažnju javnog mnijenja. Početkom devedesetih godina
devetnaestog stoljeća, jedan od povoda buđenju interesa za forenzičku psihijatriju i patološku
seksualnost bila su ubojstva prostitutki u londonskoj četvrti Whitechapel počinjena između 1888. i 1891. Umorstva oko kojih je stvoren mit o Jacku Rasparaču isticala su se osobitom brutalnošću,
nedostatkom motiva i činjenicom da je ubojica, usprkos angažiranom radu londonske policije
ostao neuhvatljiv. Iz tih razloga su umorstva, u sjećanju javnosti bila događaj bez presedana493, a
ulogu u njegovoj ozloglašenosti igralo je i sve ”žutije” novinarstvo koje je u nedostatku jasnih
informacije širilo glasine i rasplitalo nevjerojatne teorije o umorstvima. Forenbacher se u članku
direktno referira na zločine Jacka Rasparača od kojih je posljednji počinjeno manje od dvije
godine prije objavljivanja članka494. Poremećaje seksualnog nagona Forenbacher smatra
podvrstom moralne ludosti. Moralna ludost ili „moral insanity” je kojeg je u psihijatriju uveo
Bénédict Morel, a kasnije su ga usavršili Henry Maudsley i Cesare Lombroso.495
U hrvatskoj psihijatriji pojam „moral insanity” bio je usko vezan uz devijantnu seksualnost, a
k
i i
k k bi
i
blik d
ij k ji
h
ć
j di d š k ji
č
i U hrvatskoj psihijatriji pojam „moral insanity” bio je usko vezan uz devijantnu seksualnost, a
koristio se kako bi opisao „oblik degeneracije koji zahvaća onaj dio duše koji zovemo čuvstvom i
koji rezultira potpunim gubitkom etičkih i moralnih sudova”496. Po Forenbacherovom mišljenju,
takvi pojedinci su: „...tupi na sve što je liepo, dobro, plemenito i uzvišeno. Oni ne mogu da shvate ili prosude
etičke pojmove. 496 Forenbacher, 1893: 50. 493 Sugden, 2006: 71. 492 Forenbacher, 1893: 67-68. 497 Ibid, 49-50. 494 Forenbacher, 1893: 68. 495 Čeč et al., 2017: 224-225. 492 Forenbacher, 1893: 67-68.
493 Sugden, 2006: 71.
494 Forenbacher, 1893: 68.
495 Čeč et al., 2017: 224-225.
496 Forenbacher, 1893: 50.
497 Ibid, 49-50. 5.5. Seksualna nastranost, primitivizam i „moral insanity”: Seksualnost, moral i ludilo na
prijelazu stoljeća Jer ne poznadu ništa plemenita, ne imađu srdca ni za braću, ni za roditelje, niti
znadu, što je to ljubav domovine, što li sućut prema bližnjemu nevoljniku. Oni ne mogu da
dublje proniknu u zakon, da mu ođkriju njegovu etičnu i estetičnu stranu, pače sam zakon nije
im drugo, već samo zapriekom, da ne čine zlo.” 497 149 Žirovčić definira „moral insanity” na sličan način kao i Forenbacher. I za njega postoji čitava
skupina ljudi koji su „nemoralni porijeklom”.498 Znakovito je da Žirovčić u svojoj eksplikaciji
„moral insanity” istu ne shvaća bolešću, već urođenim defektom koji je neizlječiv, pa se prema
tome protivi smještanju istih u zavodu. Naime, Žirovčić ipak poima zavod kao lječilište, a
„moralni idioti” nisu bolesni i ne mogu se izliječiti a uz to su „trajna neprilika i spačka za druge
bolestnike”.499Stoga su takvi bolesnici u Stenjevcu izuzetno rijetki. Dokumentirana je povijest bolesti nekog Petra G. pisara iz Orlovca koji je u Stenjevcu bio u tri
navrata između 1883. i 1895. godine, pri čemu je prvi put otpušten kao oporavljen nakon dvije
godine boravka, dok je drugi put uspio pobjeći nakon samo mjesec dana. No jedino dijagnoza iz
njegovog prvog boravka, 1883 glasi „moral insanity”. Pri kasnijim prijemima Rohaček i Žirovčić
su mu postavili dijagnoze „vesania” i „imbecilitas”500. Petar je prvi put primljen u Stenjevac
nakon što se pokušao ubiti iz revolvera zbog nesretne ljubavi.501 Pisma njegove sestre, zapisi
liječnika iz novogradiške bolnice i bolnice milosrdne braće gdje se prije liječio se mogu čitati kao
katalog Petrovih seksualnih ekscesa i konflikata s obitelji. Izvješće iz novogradiške bolnice ga
opisuje na način kako su se stereotipno prikazivali „rođeni zločinci”:„...od rane mladosti naginje
piću, gine za ženskim spolom, vodi razvratan život, sanjari o ženidbi, utuvio si je u glavu nečiste
misli, godi mu ako ga tko potiče na zlo, tjera u potaji onaniju i ponašanje mu je u opće
nevaljalo”502 U cijeloj povijesti bolesti gotovo uopće se ne spominje njegov posao, niti simptomi koji ne bi bili
povezani sa seksualnim ponašanjem. Čak i sam štićenik stavlja vlastite seksualne navike u fokus
kad piše svoj životopis koji je priložen povijesti bolesti. Životopis je prilično nečitljiv i
nekoherentan, pun opscenih pjesmica i epizoda koje uključuju zabavljanje s prostitutkama. Liječnikov komentar iz dvanaestog siječnja 1884. govori gotovo isključivo o Petrovom gubitku
etičkih nazora. 498 Žirovčić, 1896a: 203. ,
500 KPV, 1895: 2678. 499 Ibid, 205. 501 Ibid. ,
501 Ibid. 502 Ibid. ,
500 KPV, 1895: 2678. 502 Ibid. 502 Ibid. 499 Ibid, 205. 5.5. Seksualna nastranost, primitivizam i „moral insanity”: Seksualnost, moral i ludilo na
prijelazu stoljeća Njegove homoseksualne sklonosti pomalo su osebujno opisane kao „gubitak
ćudorednosti genitalne sfere.” „Pojmovi u obće čisti, inteligencija nije potamnila, pače vidja se velika oštroumnost, ali samo u
zlih poslovih, te njegova umobolja ide samo na način pokvarene ćudorednosti. Ukoren s činih
opisanih u anamnezi, nije se niti najmanje pokazao pokaljan, pače se nekom prilikom izrazi da 150 bi svog otca za 10 forinti ubio, isto tako nije ga sram ukrasti te pozvat kako je pokrao nekog
putnika, odvrati smiešeći se „kad je imao novaca” te dodaje da bi više bio imao bio bu mu sve
uzeo. Bolestnik pripovjeda nadalje da je bio kadetom /što je veoma dvojbeno/ te nekom
prilikom svojem majoru sabljom /koju inače kadeti ne nose/ uho odsjeko, jer je tobože major
njemu bio prije čelo posieko...”Kako je daleko moralno propao dokazuje to činjenica, što veli
danas da bi sakupio četu poput Kovačevića /harambaša u Hercegovini/ te mu se ne bi smililo ni
živa čovjeka rezati. I čudnorednost genitalne sfere sasvim izgubljena, te nekoliko puta na
nekojih bolestnicih pederastiju izveo bez ikakva srama.”503 Brojne druge povijesti bolesti redovito spominju seksualne navike štićenika i štićenica. Ranije je
spomenuta neodređena „erotičnost” kojom su se opisivale pojedine štićenice. Osim takvih
nedefiniranih pojmova, puno se pažnje posvećuje masturbaciji i homoseksualnim odnosima
između štićenika. Kod Pavla B. dvadeset i jednogodišnjeg učenika trgovačke škole iz Osijeka
koji je u Stenjevcu proboravio skoro tri godine prije nego što je 1911. godine umro od
tuberkuloze, isticala se njegova sklonost masturbiranju. Dijagnoza mu je glasila „Dementia
juvenilis” što se može čitati kao pomalo neobična varijanta Kräpelinove „Dementiae praecox”
Pavao je već ranije bio u privatnom sanatoriju dr. Gluecka u Budimpešti „radi nervoznosti i što je
rado onanirao”504, a opisan je kao „žestoki masturbant”505. Zanimljivo je da je Pavao i sam
pretpostavljao da su njegove nikad detaljno opisane duševne tegobe uzrokovane masturbiranjem,
barem je tako naveo u pismu koje je adresirao na liječnika: „Ovim hoću da opišem moju bolest radi koje sam ovdje u Zagrebu u bolnici. Prvi početak moje
bolesti jeste što sam se naučio onanirati, te se od toga poslije dugog već onaniziranja koje je
trajalo tri godine nisam mogao predomisliti da je to za mene vrlo vel. zahtjev da se od toga
odučim te da to više ne radim ili barem da to rijetko radim. 504 KPV, 1911: 7281. ,
505 Ibid. 503 Ibid. 505 Ibid. 503 Ibid. 5.5. Seksualna nastranost, primitivizam i „moral insanity”: Seksualnost, moral i ludilo na
prijelazu stoljeća Ja sam to započeo jedanput raditi te
sam se od toga posve odučio i onda sam poslije nekog vremena opet radio te se meni to činilo
uvijek težje i sa većim zaprekama spojeno da se od toga odučim. Ja sam poslije to tako radio da
nisam znao pošto sam to uvijek prije zaspanja na krevetu obavio kada sam već polak ili sasvim
spavao dali se od toga mogu odučiti ili ne. Ja sam od toga imao te poslijedice da sam u opće
postao trom da mislim i poslije sam već postao trom da se dignem iz kreveta u jutro i da se
obučem poslije sam se već sasvim zanemario u svemu te sam već i teško nastojao iz moje 151 školske knjige učiti. Ja sam poslije već i nesigurno išao, a glavno je od svega da sam se i u
karakteru promijenio. Ja se ne ćutim sada ako prizivam istinu u opće bolestan niti je meni sada
više teško misliti, ja sam sada uopće u tom bolestan što sam kod kuće bio vrlo uzrujan i što sam
ja dijelom kodkuće demoralizirao i radi čega su mene uvijek psovali čemu je bio taj razlog što
du dvojica kodkuće mislili da ja sve krivo radim i držali su me da ja tako hoću biti što sam slab
na umu. Ja hoću još konačno reći da si nisam mogao ni kod kuće ni u školi pribaviti moj mir
kako sam htjeo. Sada sebi da preduzmem da ću se drugačije držati vladati itd. te da ću se mirno
vladati kao što se vide ljudi kod kuće na šetanju u društvu, na zabavi i.t.d. Pošto to držim da ću
to učiniti.”506 Pavlovo pismo možemo čitati kao svojevrsnu ispovjest liječniku u kojem štićenik konačno
priznaje da njegova „nemogućnost da si pribavi mir” potjeće od njegovog seksualnog ponašanja. Pored tromosti i „uzrujanosti” i teškoća u učenju, Pavao kao jedinu tegobu zapravo navodi
sukobe s vlastitom obitelji zbog vlastitog „demoraliziranja”. 507 Neumann, 1975: 9-10. ,
508 Ibid, 11. 506 Ibid. 506 Ibid. 508 Ibid, 11. 506 Ibid.
507 Neumann, 1975: 9-10. ,
508 Ibid, 11. 5.5. Seksualna nastranost, primitivizam i „moral insanity”: Seksualnost, moral i ludilo na
prijelazu stoljeća Pritisak na obitelji da reguliraju seksualno ponašanje djece i adolescenata počinje još u
osamnaestom stoljeću, a unutar građanskih obitelji vidljiv je sve veći trend usvajanja
psihijatrijskog diskursa kojim se masturbacija prije isključivo gledana kao grešna i nemoralna
sada počela gledati kao patološka pojava.507 Sam Pavao posve usvaja gledište koje su psihijatri
zastupali o masturbaciji kao praksi koja dovodi do lijenosti i nepoštovanja prema roditeljima508,
vjerojatno u nadi kako će njegovo uviđanje vlastite pogreške dovesti do njegova puštanja iz
institucije. U povijesti bolesti Petra G. vidljivo je kako je njegovo nemoralno ponašanje dovedeno
u vezu s homoseksualnim sklonostima. Seksualnost koja nije odgovarala uvriježenim društvenim
normama je stavljena uz bok Petrovoj sklonosti prema krađi i njegovim izjavama o vlastitoj
sklonosti nasilju. Seksualni nagon je, u skladu s Krafft-Ebingovim pretpostavkama, za
Stenjevačke psihijatre imao veliku važnost. Njegova će „abnormalnost“ zbog toga služiti kao
eksplanatorni model za ostale moralne transgresije štićenika s „moral insanityjem“. Seksualnost je u psihijatrijskom diskursu bila mjesto na kojem su predmoderni moralistički
nazori upisani u patrijarhalne strukture građanskog društva dobivali svoj znanstveni legitimitet i 152 medicinsku potvrdu. Psihijatri Zavoda u Stenjevcu su posvećivali iznimno veliku pažnju
seksualnim praksama svojih štićenika: njihova seksualnost je pomno kontrolirana, istraživana i
bilježena i smatrala se bitnim elementom u etiologiji njihovih duševnih poremećaja. Mogla je biti
korištena kao simptom poremećaja ili kao dokaz njihove „niže duševne vrijednosti”. Usprkos
formalnom somaticizmu psihijatrije na prijelazu stoljeća, samim fiziološkim funkcijama vezanim
za seksualnost pridavalo se malo pažnje. Iako su pojmovi poput „histeriogenih zona” i „slabljenja
nervne konstitucije uslijed masturbacije” bili relativno često spominjani, nije bilo pokušaja da se
za njih nađe somatsko opravdanje. Oni su prožimali diskurs u kojem je seksualnost bila
prezentirana kao pomalo burleskni, a često i makabrični spektakl u kojem su se zrcalile brojne
anksioznosti građanske klase kojoj su liječnici pripadali. Degeneracija, užurbani tempo života,
modernitet, emancipacija žena, sifilis i „primitivizam” borili su se za mjesto u pomalo
konfuznom pokušaju da se artikulira vlastito traumatično iskustvo svijeta suočenog sa svim
proturječnostima modernizacije u okviru kojeg supostoje tradicionalne strukture i grčevita želja
za promjenom. 153 509 Farge i Revel, 1999:12. ,
511 Petrungaro, 2011: 68. 510 Ibid, 124. g
,
512 Ibid,49. 510 Ibid, 124. g
512 Ibid,49. 6.1. Strah i anksioznost u kulturi devetnaestog stoljeća U proljeće 1750. godine diljem Pariza izbile su pobune potaknute policijskim mjerama hapšenja
mladih skitnica. Tijekom dvodnevnih pobuna, bijesni građani ubili su gradskog pozornika
poznatog po imenu Labbe, razbijali prozore i vrata, kamenovali javne institucije i pljačkali
lokalne trgovine.509 Pobune su u jednoj mjeri bile motivirane strahom da će policija početi otimati
gradsku djecu. Jedna od glasina koja je kružila govorila je o „gubavom princu“ kojem policajci
dovode djecu kako bi ih ubijao i kupao se u njihovoj krvi. Princ je navodno vjerovao da takve
krvave kupke liječe njegovu bolest.510 Slična bizarna manifestacija masovnog straha dogodila se gotovo stoljeće i pol kasnije u selima u
okolici Karlovca, prilikom buna 1897. godine. Iako su uzroci buna bili brojni i kompleksni
(nezadovoljstvo teškim ekonomskim i društvenim prilikama u kojima su se ta sela našla nakon
pripojenja nekadašnje Vojne Krajine Banskoj Hrvatskoj), u njima je važnu ulogu imao strah
potaknut raznolikim glasinama. Selima su kružile glasine o tome da će morati plaćati porez na
sunce511 i da će vladina „mađaronska“ stranka ukinuti brakove i vjenčanja.512 Strah je potaknuo
eskalaciju nasilja koja je vrhunac doživjela u selu Sjeničak pokraj Karlovca gdje su brutalno
ubijena trojica vladinih službenika. Povijest je puna ovakvih epidemija nasilja potaknutih strahom od neke realne, preuveličane ili
umišljene prijetnje. Ti primjeri svjedoče o bitnoj ulozi koju je strah igrao u životu zajednica i o
tome da, kad govorimo o strahu ne govorimo samo o individualnoj emociji ili afektu već o pojavi
koja često ima konkretne društvene manifestacije. Feministička teoretičarka Sarah Ahmed u
svojoj studiji politike emocija govori o strahu kao emociji koja konfigurira javni i tjelesni prostor. Strah omogućuje određenim tijelima da se sigurno kreću kroz javni prostor istovremeno
ograničavajući taj isti prostor drugim tijelima. Tijela kojima strah omogućuje slobodno kretanje
kroz javni prostor zamišljena su kao tijela koja valja štititi od onih tijela koja se čitaju kao izvor
opasnosti. Efektivno, strah pretvara prostore u teritorije. Psihijatrija je u devetnaestom stoljeću
pristupala strahu kao osobnom afektu te nije obraćala puno pažnje na društvene komponente 154 straha, no u okviru suvremene historiografije strah se rijetko promatra kao puka manifestacija
kognitivnih procesa odvojena od kulturnog i društvenog okružja.ž Jedan od terminoloških prijepora u pristupu povijesti straha je njegova povezanost s pojmom
anksioznosti. 517 Laplanche i Pontalis, 1992: 30-31. 513 Delimo, 2003: 35. 516 Ibid. p
,
518 Ibid, 434-435. 514 Ibid, 38. 515 Rachman, 2004: 3. 516 Ibid. p
518 Ibid, 434-435. 518 Ibid, 434-435. 514 Ibid, 38. 515 Rachman, 2004: 3. 516 Ibid.
517 Laplanche i Pontalis, 1992: 30-31. ,
515 Rachman, 2004: 3. 6.1. Strah i anksioznost u kulturi devetnaestog stoljeća Jedan od najčuvenijih povjesničara straha Jean Delumeau definira strah kao osjećaj
zapanjenosti kojem često prethodi iznenađenje izazvano uviđanjem neke opasnosti koja prijeteći
nadire i koja ugrožava naš opstanak.513 Anksioznost se pak manifestira kao bolno iščekivanje pred
nekom opasnošću koja nije jasno identificirana; ona je opći osjećaj nesigurnosti.514 Klinički
psiholog Stanley Rachman, jedan od vodećih stručnjaka na polju anksioznih poremećaja radi
sličnu distinkciju. I strah i anksioznost su mješavina osjećaja napetosti i osjećaja neugodne
anticipacije. No strah je, prema Rachmanu, emotivna reakcija na specifičnu percipiranu opasnost,
na prijetnju koju je moguće identificirati. Fokusiran je, epizodan i prestaje (ili mu barem
intenzitet slabi) kad se ukloni izvor percipirane opasnosti. U tom smislu strah je ovisan o
vanjskom percipiranom događaju ili podražaju.515 Anksioznost se razlikuje od straha po tome što osoba koja osjeća anksioznost ne može sa
sigurnošću identificirati izvor svoje unutarnje napetosti ili prirodu anticipirane katastrofe. U
svojem najčišćem obliku, anksioznost je raspršena, nedostaje joj objekt, ona je neugodna i
trajna.516 Upravo zbog svoje fluidnosti i neodređenosti svog objekta, anksioznost je pobuđivala
velik interes psihoanalitičara. Inhibicije i potiskivanje nagona igraju bitnu ulogu u
psihoanalitičkim pogledima na psihu čovjeka. Prema tome, pojava nagonske napetosti i
anticipacije kojoj nedostaje jasno definiran objekt ili gdje se objekt percipirane opasnosti ne može
racionalno objasniti (npr. fobija spram konja, malog Hansa) bio je bitan za psihoanalitičku
koncepciju neuroza. Sigmund Freud se opširno bavio anksioznošću i u toku svoje karijere razvio
je dva psihoanalitička modela anksioznosti. U prvim spisima, Freud strepnju promatra kao
„posljedicu nagomilane i neispražnjene libidalne napetosti“:517 U svom kasnijem djelu „Zapreka,
simptom i strepnja“ Freud je znanto proširio svoju prvotnu definiciju strepnje i vezao ju uz pojam
„signala strepnje“. Signalom strepnje Freud naziva mehanizam što ga pokreće ego kad je suočen
s opasnošću, kako bi se zaštitio pred prejakim dotokom podražaja.518 155 Od psihoanalitičkih teorija strepnje treba još spomenuti i onu koju je iznio francuski
psihoanalitičar, Jacques Lacan. Lacanov pogled na aksioznost jedinstven je u tome jer je suprotno
uvriježenoj percepciji, Lacan ustvrdio da anksioznost ima objekt. Objekt anksioznosti za Lacana
je „objekt a“. U Lacanovom sustavu, objekt a je onaj objekt kojeg se nikad ne može doseći, jer je
on izvorom žudnje, a ne objektom prema kojem žudnja stremi. 521 Delimo, 2003: 23. 519 Evans, 1996: 125.
520 Ibid, 11-12.
521 Delimo, 2003: 23.
522 Ibid 274 ,
522 Ibid, 274. 522 Ibid, 274. 519 Evans, 1996: 125. 520 Ibid, 11-12. 6.1. Strah i anksioznost u kulturi devetnaestog stoljeća 519Kao takav, objekt a, se ne može
simbolički izraziti, to jest nema svoje mjesto u Simboličkom - sustavu lingvističkih i kulturnih
označitelja pomoću kojih se strukturiraju odnosi Imaginarnog.520 Klinička psihologija i psihoanaliza, kao i Delumeau, imaju tendenciju gledati na strah i
anksioznost kao prirodne emocije ili afekte s korijenom u neurobiološkom ili psihodinamskom
ustroju ljudi. No, pri proučavanju emocija ne smije se izgubiti iz vida činjenica da su iste često
određene kulturnim i povijesnim kontekstom. Delumeau kroz svoj rad primjećuje nekoliko
društvenih promjena koje se tiču straha. Tako ističe kako je kroz povijest strah promatran kao
emocija koja priliči jedino nižim društvenim slojevima, pritom se pozivajući na niz izvora od
Vergilija do Montaignea521. Kroz Rani novi vijek, Delumeau čini sličnu distinkciju između straha
neobrazovanog i ruralnog stanovništva (ono se češće plaši prirodnih pojava, vojnika i razbojnika,
divljih zvijeri, čarolija i hodajućih mrtvaca) i „sofisticiranijih” strahova obrazovanih. Strahovi
obrazovanih ili kako ih Delumeau naziva strahovi „vladajuće kulture“ su eshatološke prirode i
proizlaze iz kršćanske teologije i strepnji povezanih s religijskim i političkim krizama.522
Percepcija i izražavanje straha i anksioznosti su u dugom devetnaestom stoljeću također
poprimili nekoliko transformacija. U europskom i sjevernoameričkom kontekstu te
transformacije su uglavnom bile potaknute modernizacijom i načinom na koje su različiti
umjetnički i znanstveni trendovi ulazili u javni diskurs. Kulturne transformacije vezane uz strah i
anksioznost u devetnaestom stoljeću možemo podijeliti u tri grupe: a) Različiti pozitivni i negativni pogledi na strah u umjetnosti i filozofiji koji sežu od
prosvjetiteljske glorifikacije razuma i odbacivanja iracionalnog, preko romantičarske estetizacije
emocija i straha, do medikalizacije straha i formiranja pojma traume na samom kraju dugog 156 devetnaestog stoljeća. Ti trendovi često supostoje u društvu i stvaraju pluralizam kulturnih
perspektiva straha unutar kompleksnih emotivnih režima devetnaestog stoljeća. devetnaestog stoljeća. Ti trendovi često supostoje u društvu i stvaraju pluralizam kulturnih
perspektiva straha unutar kompleksnih emotivnih režima devetnaestog stoljeća. b) Pojava novih objekta strahova poput straha od živog pokopa ili strahova vezanih uz utjecaj devetnaestog stoljeća. Ti trendovi često supostoje u društvu i stvaraju pluralizam kulturnih
perspektiva straha unutar kompleksnih emotivnih režima devetnaestog stoljeća. b) Pojava novih objekta strahova poput straha od živog pokopa ili strahova vezanih uz utjecaj
razvoja tehnologija poput željeznice. b) Pojava novih objekta strahova poput straha od živog pokopa ili strahova vezanih uz utjecaj
razvoja tehnologija poput željeznice. b) Pojava novih objekta strahova poput straha od živog pokopa ili strahova vezanih uz utjecaj
razvoja tehnologija poput željeznice. 524 Tackett, 2015: 124. 523 Reddy, 2004: 216. 526 Reddy, 20014: 217. 525 Ibid. 525 Ibid. 6.1. Strah i anksioznost u kulturi devetnaestog stoljeća c) Sve veća prisutnost anksioznosti u političkim, filozofskim i znanstvenim narativima, poput
narativa o degeneraciji. U tim narativima, anksioznost nije otvorena iskazana kao emocija, već
potisnuta i izražena diskursom koji joj daje auru znanstvene objektivnosti. U kasnom osamnaestom stoljeću, razum i emocije nisu smatrani suprotstavljenim pojmovima. Sentiment kojeg se moglo odrediti kao „zdravog” i „prirodnog” smatran je izvorom vrline.523
Ipak, nasilje Francuske revolucije i kasnijih napoleonskih ratova dovelo je do skepticizma prema
strastima. Nazivi pojedinih ključnih događaja koji su prethodili Francuskoj revoluciji ili slijedili
neposredno poslije nje („Veliki strah” ne selima ili „Vladavina Terora” koju su jakobinski vođe
zazivali u pozitivnom smislu) doveli su strah u središte govora o politici. Još od ljeta 1789. glasine o zavjerama su kružile među pariškom populacijom, često dopirući i do novih političkih
elita.524 Strasti i sentimenti su se pokazali politički opasnim konceptima koji imaju potencijala
ugroziti javnu sigurnost i politički poredak. Radi toga su se u emotivnom režimu elita, „prirodni
sentimenti” sve više zamjenjivani konceptom vrlina. Vrlina se počinje promatrati kao prirodni
izdanak volje koja je vođena razumom i usmjerena prema obuzdavanju strasti.525 U novom
emotivnom režimu koji je nastojao podrediti emocije vladavini razuma, strah će biti osobito
negativno kogniziran (pitati kako prevesti „cognized emotion) jer se važnost počela pridavati
osobnim kvalitetama među kojima su principijelnost i hrabrost bile veoma važne zauzimale
istaknuto mjesto.526 S druge strane emocije su počele zauzimati jedno od središnjih mjesta u poetici romantizma. Gotički romani osamnaestog stoljeća poput Hoffmanovih Đavoljih eliksira i Misterija Udolfa
Ann Radcliffe tretiraju emociju straha na znatno drugačiji način od sentimentalizma kasnog
osamnaestog stoljeća i kasnije etike vrlina. Unutar estetika gotičkog romana osjećaj strave se
invocira preko niza narativnih tropa i umjetničkih postupaka. Izazivanje straha i sličnih
intenzivnih emocija usko vezuje estetiku uz emotivnost. Naravno, može se reći da je strah koji 157 prevladava u romantičarskim književnim djelima predstavljen kao nešto inherentno iracionalno i
prema tome predstavlja mračni zrcalni odraz prirodi čovjeka određenoj vrlinom i razumom. U
Đavoljim Eliksirima strast, žudnja i strah personificirani su kao mračni dvojnik (doppelgänger)
Medardu, talentiranom i staloženom redovniku koji je prije kušanja đavoljih eliksira predstavljen
kao primjer kršćanske vrline. U romanu Frankenstein ili novi Prometej Mary Shelley, znanstvena
znatiželja Waltona i Frankensteina stoji u kontrastu s ispočetka djetinje nevinom, a kasnije
destruktivnom i osvetoljubivom prirodom Frankensteinove odbačene kreacije. Frankensteinovo
čudovište postaje objekt straha i svojevrsna „tamna slika“ znanstvenog optimizma
prosvjetiteljstva. 527 Shelley, 1994: 55. y
528 Ibid, 7. y,
528 Ibid, 7. y,
528 Ibid, 7. 527 Shelley, 1994: 55. 6.1. Strah i anksioznost u kulturi devetnaestog stoljeća Trenutak nastanka Frankensteina kako je opisan u autoričinom uvodu iz 1831. godine svjedoči o određenoj fikcionalizaciji same geneze teksta. Frankenstein kao i samo
čudovište,527 nastaje za olujne noći na obalama Ženevskog jezera kao produkt natjecanja između
Mary Shelley, Lorda Byrona i Percyja Shelleya u pisanju i pričanju stravičnih priča.528 Sama
atmosfera nastanka književnog djela morala je biti u skladu s atmosferom jeze kojom je djelo
prožeto. Primjera stravičnih priča imamo i u hrvatskoj književnosti sredine i kraja 19. stoljeća. Poimanje
straha kao emocije koja je usko vezana uz nasilno, primalno i iracionalno, ali koja također nosi
određenu privlačnost bit će prisutno u umjetnosti kroz čitavo devetnaesto stoljeće. U većini tih
djela strah je nužno vezan uz određene likove koji su percipirani kao ontološki i imagološki
Drugi. Primjerice, u Jorgovanićevoj kratkoj priči „Stella Raiva” protagonist počinje osjećati jezu
pri susretu s naslovnom junakinjom, egzotičnom indijskom opernom pjevačicom. Strah obuzme
junaka u trenutku kad mu Stella Raiva” strastveno obeća da će mu se „u ponoć razgaliti”. Jorgovanić opisuje trenutak jeze: „Stella se sruši natrag na divan i zadubi lice u jastuk. Jeza me prođe po svem tijelu, i misli tol
sablastive i grozne zakružiše mojom glavom. Što je toj ženi, je li poludjela? pitah se ja. Zašto mi
baš o ponoći hoće razgaliti srce, kad je tomu sada vremena i zgode? Pogledam na sat - bilo je
jedanaest sati. Imao sam dakle još jednu uru čekati. Uzmem roman sa ormara i stanem ga čitati,
ali čitam deset i više puta jednu te istu izreku a da ne znam štosam čitao. Čujem kako mi srce
jako bije, kako mi se kosa na glavi podiže... upravo onako kao da sam slutio da nismo nas dvoje y,
528 Ibid, 7. 158 sami u toj tihanoj sobici, već da je još netko s nama al ne stvor od mesa i krvi, već duh,
sablast...”529 Pokazuje se da je protagonistov osjećaj jeze i neodređene sablasne prisutnosti u prostoriji dolazio
od lubanje nekadašnjeg zaručnika koju je Stella Raiva sačuvala kao fetiš.530 Ne samo da je
sentimentalnost junakinje time prikazana kao groteskna, već je i sam strah egzotiziran – njegov je
objekt u dvostrukom onostranom- onom koje je onkraj smrti i onom koje je onkraj dominantnog
kulturnog poimanja emocija. 529 Jorgovanić, 2002: 316. 533 Lerner i Micale, 2001: 39-40. 532 Ibid, 81-84. 532 Ibid, 81-84. 531 Blankini, 1906: 79. 531 Blankini, 1906: 79. 530 Ibid. 531 Blankini, 1906: 79. 530 Ibid. 6.1. Strah i anksioznost u kulturi devetnaestog stoljeća Usprkos prevladavajućem poimanju književnosti kao objektivnog i ponegdje čak znanstvenog
prikaza društva u realizmu, mnogi su istaknuti predstavnici realizma poput Honoréa de Balzaca i
Guya de Maupassanta također pisali priče strave i užasa. Kulturni fenomeni kasnog devetnaestog
stoljeća poput spiritualizma i opsesije znanstvenim proučavanjem paranormalnog predstavljat će
svojevrsno proširenje te tendencije na polje znanosti. Književnost prijelaza stoljeća bila je
obilježena estetikom moderne. Moderna je često tematizirala psihološka stanja, pritom se
nerijetko služeći i tada aktualnim teorijama iz područja medicine i parapsihologije. Zbog toga ne
čudi da se strah, kao bitan motiv književnosti često javlja i u djelima modernističkih pisaca poput
A. G. Matoša. Osnovni narativni motiv Matoševe modernističke kratke priče „Camao” je zazorni
papagaj koji predstavlja projekciju negativnih osjećaja glavnih likova. Budući da je u središtu
radnje Camaa ljubavna afera Kamenskog i Fanny, papagaj možda služi kao mjesto projekcije niza
tjeskobnih emocija vezanih za seksualnu transgresiju glavnih likova. Izvan književnosti kraj stoljeća dolazi i sve veću medikalizaciju strahu preko pojma traume. Prve
natruhe traumatskog poremećaja vezane su uz pojavu nazvanu „railway spine”. „Railway spine”
je bio naziv za niz psiholoških simptoma prisutnih kod ljudi koji su preživjeli nesreće vlakova, a
koji nisu pokazivali vidljive ozlijede. Simptomi „railway spinea” su bili raznoliki. Članak u
Liječničkom vjesniku iz 1906. godine opisuje devetnaest slučajeva „railway spinea” kod hrvatskih
radnika u kamenolomu Illis kod Chicaga koji su preživjeli sudar vlakova.531 U sažeto opisanim Izvan književnosti kraj stoljeća dolazi i sve veću medikalizaciju strahu preko pojma traume. Prve
natruhe traumatskog poremećaja vezane su uz pojavu nazvanu „railway spine”. „Railway spine”
je bio naziv za niz psiholoških simptoma prisutnih kod ljudi koji su preživjeli nesreće vlakova, a
koji nisu pokazivali vidljive ozlijede. Simptomi „railway spinea” su bili raznoliki. Članak u
Liječničkom vjesniku iz 1906. godine opisuje devetnaest slučajeva „railway spinea” kod hrvatskih
radnika u kamenolomu Illis kod Chicaga koji su preživjeli sudar vlakova.531 U sažeto opisanim
slučajevima navedeni su simptomi poput omaglice, šuma u ušima, psihijatrijskih simptoma,
afazije i bolova po cijelom tijelu.532 Poremećaj je prvi put opisan u engleskom listu „Lancet“
1862. godine.533 Od trenutka kad je opisan, vodile su se debate oko njegove etiologije: dok su 159 pojedinci pripisivali simptome mikroskopskim oštećenjima leđne moždine, javila su se i
tumačenja koja su pretpostavljala efekt psihičke traume kao uzrok simptoma. Među onima koji
naglašavaju moguće psihološke uzroke „railway spinea“ je i stenjevački psihijatar Dragutin
Forenbacher. 534 LV, 1892: 163. 536 Ibid 33. 537 Blankini 1906: 79. 534 LV, 1892: 163.
535 Ibid, 34.
536 Ibid 33.
537 Blankini 1906: 79. 535 Ibid, 34. 6.1. Strah i anksioznost u kulturi devetnaestog stoljeća Forenbacher u jednom predavanju o „traumatičnim psychozama i nevrozama“ rekao
da navedene psihičke poteškoće često nastaju nakon ozljeda centralnog živčanog sustava. No za
njihov nastanak, prema Forenbacheru, nije nužna direktna ozljeda mozga ili leđne moždine već je
dovoljan i takozvani „psychički shock“ 534Traumatične posljedice straha će biti dodatno
medikalizirane u praksi Sigmunda Freuda i Eugena Bleulera, a vrhunac medicinskom bavljenja
traumom uslijedit će nakon masovne pojave „shellshocka” u rovovima Prvog svjetskog rata. Devetnaesto stoljeće svjedoči i pojavi brojnih novih strahova. Već spomenuti „railway spine“ kao
traumatski poremećaj ne može se odvojiti od stravičnih, novih nesreća koje su pratile pojavu
brzih vlakova i širenje željeznice kao dominantnog prijevoznog sredstva. Lerner i Micale tako
drže „railway spine“ odrazom šire društvene traume koju je izazvala pojava željeznice kao brzog
masovnog načina prijevoza. Iako su ljudi već bili upoznatim s masovnim i tragičnim nesrećama
na moru, one su se u pravilu događale daleko od očiju javnosti i u okolišu koji je odavno bio
poznat kao opasan i nepredvidiv. Željezničke su se nesreće događale u okolici prostora na kojima
su ljudi živjeli i radili, a njihove žrtve nisu bile mornari ili putnici u daleke krajeve, već ljudi koji
su željeznicom putovali svakodnevno na posao, tržnicu ili odmor.535Kako su vlakovi postajali brži
a broj ljudi koji se služio željezničkim prijevozom veći, povećavao se i broj nesreća i žrtava. 536
Velikoj smrtnosti sigurno je doprinijela i neusklađenost brzog tehnološkog razvoja željezničkog
transporta s donošenjem adekvatnih sigurnosnih propisa na željeznicama. O kolektivnoj traumi
koju su za društvo predstavljale nesreće na željeznici svjedoče i brojne folk-pjesme iz
devetnaestog stoljeća koje tematiziraju željezničke nesreće poput pjesama „Wreck of Old 97“ i
„Casey Jones“. I Blankinijev ranije spomenuti članak o „railway spineu“ kod hrvatskih radnika
ne propušta spomenuti loše sigurnosne uvjete na američkim željeznicama. Za vlak na kojem se
nesreća dogodila se tako govori da je jurio „amerikanskom brzinom i neopreznošću“537, a autor u
posebnoj bilješci navodi niz podataka o rekordnim brzinama američkih lokomotiva, doveden u 160 vezu s rekordnim brojem poginulih u željezničkim nesrećama.538 Pored željezničkih nesreća, još
je jedan strah postao izrazito raširen u devetnaestom stoljeću. Devetnaesto stoljeće je promijenilo odnos prema umiranju i smrti. Smrt osobe u vlastitom domu
i u okruženju obitelji sve je više ustupala mjesto smrti u bolnici ili barem u prisutnosti liječnika. Povezanost liječnika uz proces umiranja stvorio je dvije vrste novih strahova vezanih uz smrt. 539 Bourke, 2011. 538 Ibid. ,
540 Ibid 540 Ibid ,
540 Ibid 538 Ibid. 539 Bourke, 2011. 6.1. Strah i anksioznost u kulturi devetnaestog stoljeća Ti
su se strahovi pridružili ranijim strahovima od kazne u zagrobnom životu, a sekularizacijom
građanskom društva su ih počeli sve učestalije zauzimati njihovo mjesto kao primarni. Jedna
vrsta straha bila je naročito prisutna kod siromašnijih, a radilo se o strahu od posthumne
disekcije. Zakon o anatomiji prošao je u Britanskom parlamentu 1832. godine i omogućio je
anatomima da iskoriste tijela osoba umrlih u ubožnicama i domovima za siromašne u svrhu
akademskog poučavanja anatomije. Usprkos činjenici da je relativno malen broj siromašnih
uistinu završio na autopsijskim stolovima, senzacionalistički je tisak bio pun opisa užasa
autopsijske dvorane kao mjesta gdje mladi liječnici komadaju leševe bez ikakvog poštovanja za
dostojanstvo preminulih.539 Medikalizacija smrti dovela je i do straha od mogućnosti živog pokopa. Glasine o ljudima koji su
se probudili iz duboke nesvjestice, samo da bi doživjeli pravu, užasnu smrt u lijesu su zahvatile
europsku javnost i dovele do izuma „sigurnih ljesova“ opremljenih zvoncem, ili kasnije
telefonskom vezom s uredom čuvara groblja. Zastupnici javnih kampanja protiv preuranjenog
pokapanja tvrdili su da su skupili stotine svjedočanstava ljudi koji su preživjeli taj postupak. Istraživanje provedeno na 1200 ekshumiranih trupala u New Yorku tijekom 1860-ih i 1870-ih
pokazalo je da je tak strah barem djelomično bio ukorijenjen u stvarnosti: šest leševa je navodno
pokazivalo znakove preranog pokopa.540 Ipak, opseg straha i anti-medicinski podtekst narativa o
preranom pokopu pokazuje da su izvori te panike vjerojatno u društvenoj nelagodi vezanoj uz
depersonalizaciju procesa umiranja i uz nov status liječnika kao znanstvenog autoriteta koji
proglašava smrt. Ideja znanstvenog i objektivnog medijatora između života i smrti bila je u
suprotnosti s ranijim idealiziranim i sentimentalnim prikazima umiranja kao produhovljenog i
intimnog procesa. 161 Dok su različite vrste straha i jeze krajem stoljeća posve preseljene u sferu umjetnosti ili
medicine, anksioznost je sve više postajala diskursom kroz koji se promatrala, spoznavala i
opisivala stvarnost. Različite političke i društvene tenzije koje su obilježile fin de siècle, davale se
svakom govoru o društvu pomalo nervoznu i napetu notu. Pred kraj stoljeća i najkonzervativnijim društvenim slojevima postalo je jasno da se vremena
mijenjaju, a imperativ promjene donosio je nesigurnost i strepnju pred neizvjesnom budućnošću. Ta budućnost se često činila mračnom, a svijet se promatrao kao neprekidna borba pojedinaca,
država, nacija i rasa za opstanak. Jedan od dominantnih ideoloških narativa bila je teorija
degeneracije koja je potekla upravo iz medicinskih krugova. 541 Blom, 2008: 185. 6.1. Strah i anksioznost u kulturi devetnaestog stoljeća Već sam spomenuo Benedicta
Morela i utjecaj koji je njegovo djelo imalo na somaticističku psihijatriju utemeljenu na
lamarkističkim teorijama herediteta. Prema kraju stoljeća teorije o degeneraciji postaju sve
prisutnije izvan psihijatrijskih krugova i postaju očište kroz koje se promatra društvo u cjelini. Osoba koja je možda najzaslužnija za širenje pojma degeneracije izvan medicine bio je Max
Nordau. Nordauova knjiga O degeneraciji, posvećena talijanskom utemeljitelju kriminalne
antropologije Cesareu Lombrosu, proširila je medicinski pojam degeneracije na polje čitave
kulture prijelaza stoljeća. Nordau je i sam bio liječnik, a kao mađarski Židov koji je živio u
Parizu za vrijeme neslavne antisemitizmom obilježene Dreyfussove afere postao je zabrinut za
budućnost Zapadne kulture. Nordau je vjerojatno i val antisemitizma smatrao izrazom propasti
kulture, a napetosti modernizacije nastojao je iskazati diskursom tada suvremene medicine.541 Knjiga je postala europski bestseler i bitno je utjecala na dominantna poimanja moderniteta u
kulturi prijelaza stoljeća. Jedna od ideja knjige - Nordauov intelektualni protest protiv
antisemitizma i iskaz želje za emancipacijom europskih Židova je pao u drugi plan pred
distopijskim vizijama suvremene kultura kojima je knjiga obilovala, a iz kojih izbija strepnja za
budućnost građanskih društava Zapadne Europe. Stil Degeneracije Maxa Nordaua varira između
duhovitosti i mračnih slutnji. Nordau vidi fin de siècle kao „emancipaciju od tradicionalne
discipline, koja teoretski još vlada. Za naviklog na obilje to znači nesputanu putenost, za uvelo
srce egoista prezir prema bližnjem...sve u svemu kraj uvriježenog poretka koji je zadovoljavao 162 logiku, okovao nemoral i u svakoj umjetnosti uzgojio nešto lijepo.”542 Na stranicama
Degeneracije pažnju privlače motivi koji odaju anksioznost kao stil kojim se propadanje
tradicionalnog i rađanje novog opisuje. Oblaci gore „čudnim prekrasnim sjajem koji se mogao
godinama vidjeti nakon erupcije Krakatoe, dok se zemljom provlače turobne duboke sjene,
obgrljavajući sve u misterioznu tamu koja uništava svu sigurnost i svaka se mogućnost čini
relevantnim. Oblici gube svoje obrise i rastaču se u lebdećoj magli.543 Nordau slika stvarnost
nakon implicirane katastrofe prispodobive erupciji vulkana, stvarnost koja i sama postaje fluidna
poput anksioznosti. Stvarnost je stalno postojanje bez mogućnosti ukotvljenja u sigurnostima
tradicionalnog života. Kriza tradicionalnih vrijednosti za Nordaua je vidljiva osobito na polju
estetike, koju on čini se usko povezuje s moralom. Koristeći se pojmovima degeneracije i
„borderlandsa” kako su opisani kod Maudsleyja, Morela i ostalih psihijatara druge polovice
devetnaestog stoljeća, Nordau opisuje kulturne predstavnike moderniteta kao degenerirane
histerike i neurastenike. Brojnima od njih Nordau dijagnosticira „moral insanity” u blažem
opsegu. 542 Nordau, 2016: 12. 545 Blom, 2008: 181. 546 Ibid, 164. 547 Tattersall, 2014: 19. 546 Ibid, 164. 543 Ibid, 13. 544 Ibid, 24. 544 Ibid, 24. 543 Ibid, 13. 6.1. Strah i anksioznost u kulturi devetnaestog stoljeća Oni ne čine kriminalna djela, ali žele „filozofskim floskulama dokazati da su dobro i zlo,
vrlina i porok arbitrarne distinkcije.”544 Naravno, progovarajući o kulturnim fenomenima
medicinskim diskursom, Nordau zaogrće moralističku kritiku moderniteta aurom objektivnosti. Anksioznost neće prožimati samo diskurs o degeneraciji bit će vidljiva i u diplomaciji kraja
devetnaestog stoljeća. U Velikoj Britaniji počinje se sumnjati u premoć vojske i mornarice i raste
strah od potencijalnih njemačkih špijuna tako da čak i konobari njemačkog porijekla i stranci s
čudnim naglaskom bivaju sumnjivi.545 U Francuskoj afera Dreyfuss rezultira antisemitizmom i
ksenofobijom kod monarhista i konzervativaca. Na lijevoj strani političkog spektra, anksioznost
je vezana uz vojsku koju se promatra kao utočište reakcionarnih snaga i unutarnji neprijatelj
političkog poretka.546 U svijetu znanosti, anksioznost izazivaju spoznaje suvremene
termodinamike o mogućem „toplinskom kraju svemira” postupnom gubitku sunčeve topline.547
Bilo da se radilo o termodinamici, medicini ili rastućim političkim napetostima, anksioznost se na
prijelazu stoljeća činila samorazumljivim pogledom na svijet obrazovanih elita. Možda upravo 163 zbog normalizacije anksioznosti kroz brojne znanstvene i političke diskurse, tradicionalna
psihijatrija je nije prepoznala kao mogući uzrok brojnih psihičkih poteškoća. p
549 Horwitz i Wakefield, 2012: 80-81. 548 Plamper, 2012: 96. 550 Ibid, 83. 548 Plamper, 2012: 96. 552 Pinel, 1806: 141. 551 Pinel, 1806: 114. ,
551 Pinel, 1806: 114. ,
550 Ibid, 83. 550 Ibid, 83. 551 Pinel, 1806: 114. 550 Ibid, 83.
551 Pinel, 1806: 114. 6.2.Strah i anksioznost u psihijatriji devetnaestog stoljeća Psihijatrija devetnaestog stoljeća kontinuirano spominje strah u opisima simptoma duševnih
bolesti i u dijagnozama. S druge strane anksioznost je odsutna iz njezinog diskursa, a tamo gdje
se spominje, ona je opisana kao skup fizioloških simptoma koji prate strah, a ne kao zasebna
emocija. Ako odlučimo koristiti podjelu antropologa Roberta Levyja između hiperkogniziranih
emocija (emocije koje se u nekom društvu smatraju relevantnima) i hipokogniziranih emocija
(one koje nisu društveno relevantne)548, možemo reći da je unutar psihijatrije strah
hiperkogniziran, a anksioznost hipokognizirana. Takav stav prema anskioznosti djelomice potiče
od činjenice što klasična medicina dugo vremena nije pravila vidljivu razliku između straha i
anksioznosti. Hipokrat je opisao anksioznost kod nekoliko individualnih slučajeva melankolije,
ali ju nije jasno razlučio od straha. Kod Hipokratovog sljedbenika, Andreasa od Charystosa
anksioznost je također opisana kao „panphobia” ili „strah od svega.549 Kasniji pisci medicinskih djela poput Roberta Burtona i Nicholasa Robinsona govore o
neutemeljenim strahovima, ponekad opisujući anksioznost kao simptom melankolije, ali ju ne
odvajajući od straha.550 Phillipe Pinel, jedan od utemeljitelja moral treatment pristupa i
suvremene psihijatrije također hiperkognizira strah i često ističe važnost istog kod patoloških
psihičkih stanja. Pinel je često vidio uzroke duševnih oboljenja u snažnim i potresnim emotivnim
stanjima. Spominjući moguće vrste psihičkih podražaja koji mogu dovesti do duševnog oboljenja,
Pinel će tako istaknuti kako „...u Bicêtreu možemo naći brojne svećenike i redovnike, kao i ljude
sa sela, užasnute do tog stanja (duševne bolesti), anticipacijom mučenja u paklu.551 Također, u
svom opisu melankolije, Pinel ističe kako „svaki uzrok straha i užasa može proizvesti osjetljivost
na te emocije i potkopavši duševnu snagu, uzrokovati opasnu slabost i smrt”552 Pinel se, kao
liječnik inspiriran idejama francuskog Prosvjetiteljstva, često referira na specifično religijsku
komponentu straha kao mogućeg uzroka duševnog oboljenja. Tako navodi slučaj redovnika koji 164 je „doveden do stanja ludila religijskim entuzijazmom tvrdio da ga je Bogorodica u snu
nagovorila da ubije svog poznanika.”553 Kasnijim razvojem psihijatrije strah nije izgubio svoju važnu ulogu u razvoju pojedinih
poremećaja. Emil Kräpelin će, kao kasni predstavnik njemačke biologijske psihijatrije istaknuti
strah kao najperzistentniju emociju u morbidnim stanjima.554 No, Kräpelin će obratiti pažnju i na
anksioznost. Naime, Kräpelin ističe da je u morbidnim stanjima strah isprva bez objekta i da se
pacijent boji bez da nalazi uzrok svom strahu i shvaća da je njegov strah neopravdan.555 Kräpelin
takav strah neće definirati kao anksioznost i istaknut će ga kao isključivo morbidnu i patološku
pojavu. 554 Kräpelin, 1902: 50. 553 Ibid, 142. 558 Ibid, 65. 555 Ibid. 557 Ibid, 50-51. 556 Ibid. 555 Ibid. 553 Ibid, 142. 558 Ibid, 65. 556 Ibid. 6.2.Strah i anksioznost u psihijatriji devetnaestog stoljeća Uz to, Kräpelin će opisati dva tipa manifestacije straha: anksiozno uzbuđenje i anksioznu
napetost. Anksiozno uzbuđenje se manifestira intenzivnom reakcijom i pripremom na obranu ili
bijeg. Anksiozna napetost je manje intenzivno stanje straha koje pokazuje remisije, naročito
noću.556 Prema tome, kod Kräpelina se pojam „anksioznosti” javlja tek kod opisa specifičnih
manifestacija straha u morbidnim stanjima, a ono što se danas u psihološkoj, psihijatrijskoj i
psihoanalitičkoj literaturi naziva anksioznošću, Kräpelin opisuje jednostavno kao patološki strah
bez objekta. Kao pobornik teorija o „borderlandsu” Kräpelin spominje konstantnu bojažljivost i
kukavičluk kao neke od najčešćih znakova „konstitutivnog psihopatskog stanja.”557 Za Kräpelina
ti aspekti ličnosti odaju „naslijeđene osebujnosti” koje u konačnici mogu rezultirati
kompulzivnim strahovima, odnosno fobijama. Kräpelin će kasnije strah povezati s kompulzivnim
radnjama, koja također smatra znakom konstitutivnog psihopatskog stanja558 kao jednog od
elemenata hereditarne degeneracije. Osim straha kao uzroka ili simptoma bolesti, psihijatrija devetnaestog stoljeća prepoznaje i
terapijski efekt straha. Terapija „ljekovitim strahom” bila je utemeljena u percepciji duševno
oboljelih kao ljudi kojima dominira gotovo animalni instinkt kojeg se može suzbiti jedino
strogom disciplinom. Načini kako se u povijesti historiografije strah koristio u terapijske svrhe
bili su raznoliki. Najčešće su se koristile verbalne prijetnje, ponegdje i fizičko kažnjavanje. Pacijente se također naglo uranjalo u hladnu vodu, što je oblik terapije koji je naročito hvalio 165 Phillipe Pinel zbog učinkovitosti tog načina pri prekidanju „lanca deliroznih ideja”.559 Joseph
Guislain, belgijski liječnik koji će kasnije postati ravnateljem zavoda za duševno bolesne u
Ghentu 1821 godine je u tu svrhu projektirao posebnu napravu koju je nazvao „kineskim
hramom”. Kineski hram se sastojao od metalne konstrukcije situirane na mostu položenom preko
jezerca. U trenutku kad bi se pacijent našao unutar konstrukcije, sustav kolotura i poluga naglo bi
spustio cijeli taj dio mosta u jezero, zajedno s pacijentom.560 Taj elaborirani mehanizam
projektiran je s namjerom (kako je rekao sam Guislainu) da u štićenicima izazove strah od
utapanja na siguran način. Guislan ističe da je na umu imao dva cilja: „učiniti liječnika
pacijentovim gospodarom i spriječiti slučajno utapljanje pacijenta”.561 Naglo uranjanje štićenika u
vodu s ciljem postizanja straha i kontrole zadržalo se u duševnim bolnicama kroz cijelo
devetnaesto stoljeće, o čemu svjedoče zapisnici brojnih istraga u britanskim i američkim
zavodima krajem devetnaestog stoljeća. U njima se zaranjanje glave u hladnu vodu navodi kao
čest oblik zlostavljanja kojem su štićenici bili izloženi.562 U njemačkim zavodima početka
devetnaestog stoljeća strah se ponekad postizao izuzetno maštovitim sredstvima. 561 Guislain, 1826: 166. 560 De Young, 2015: 323. 562 De Young, 2015: 323-324. 563 Ibid, 326-327. 564 Reil, 1803: 205. 559 Pinel, 1806: 265. g
563 Ibid, 326-327. 559 Pinel, 1806: 265.
560 De Young, 2015: 323.
561 Guislain, 1826: 166.
562 De Young, 2015: 323-324.
563 Ibid, 326-327.
564 Reil 1803: 205 6.2.Strah i anksioznost u psihijatriji devetnaestog stoljeća Poznati
njemački liječnik Johann Christian Reil je u knjizi objavljenoj 1803. godine „Rapsodije o
korištenju psiholoških terapija za mentalno oboljele” tvrdio da se duševna bolest može izliječiti
tako da se kod oboljelog izazovu osjećaji straha, gađenja ili bijesa. Uz manje nekonvencionalne
tretmane poput šibanja bolesnika koprivama, škakljanja i žigosanja pacijenata rastopljenim
voskom ili užarenim željezom,563 Reil je predložio osebujnu napravu koju je nazvao „mačji
klavir” (Katzenklavier). Svrha te naprave bila je u ispunjavanju štićenika strahom kako bi se oni
mogli bolje fokusirati na svijet oko sebe. „Mačji klavir” se sastojao od naprave unutar koje bi bile
sputane mačke: „(mačke) bi zatim bile poredane jedna do druge s repovima nategnutima prema van. Ploča s
tipkama, na dnu kojih bi bili naoštreni čavli bi se položila preko repova. Mačka bi nakon
udarca u tipku proizvela zvuk. Fuga odsvirana na tom instrumentu ─ kada je bolesna osoba
smještena tako da ne može propustiti izraz na licima mačaka niti zvuk tih životinja- morala bi
privesti i Lotovu ženu iz njezinog zaluđenog stanju u stanje u kojem je svjesna okoline”564 166 Nije poznato je li ova metoda ikad primijenjena u njemačkim zavodima, no Reil je još za života
slovio kao jedan od najutjecajnijih predstavnika „moral treatmenta” u njemačkim zemljama i
mnoge od njegovih manje ekscentričnih terapija su bile primjenjivane u prvoj polovici
devetnaestog stoljeća.565 Hrvatski psihijatri, oslanjajući se na tradiciju somaticističke psihijatrije
tretiraju strah primarno kao simptom duševnog oboljenja, a tek u rijetkim slučajevima kao njegov
uzrok. Bolesti uz koje su se strah i anksioznost naročito povezivale bile su melankolija, paranoja i
neurastenija. Melankolija je još od antike usko povezana s emocijama straha i tjeskobe. U klasifikaciji Ive
Žirovčića iz 1895. godine, melankolija se upravo često opisuje kao afektivni poremećaj za kojeg
su ključne emocije tuge i strah. Strah je kod melankolika povezan s osjećajem neke umišljenje
krivnje. Kod Žirovčića,”Melankolik traži uzrok svojoj boli uviek samo u svojoj vlastitoj krivnji,
on sebe obtužuje, sebe potvara, da se je ogriešio, da je počinio zlo djelo, unesrećio svoju obitelj,
cielo čovječanstvo; on sebe ponizuje, drži se nevriednim, da se s njim prijazno postupa, da mu se
daje jesti, njega bi trebalo uništiti, objesiti, baciti na djubre; on pati od straha i užasa, savjest ga
peče svejedno, kao daje sbilja šta zla počinio...”566 „Strah” i „užas” kao emocije od kojih melankolik pati pojavit će se i u kasnijem članku u kojem
Žirovčić opisuje neke temeljne simptome duševnih bolesti. 565 De Young, 2015: 282. g,
566 Žirovčić, 1895a: 4. ,
567 Žirovčić, 1896b: 252. 6.2.Strah i anksioznost u psihijatriji devetnaestog stoljeća Članak Ive Žirovčića iz studenog
1896. navodi bolesti kod kojih se mogu javiti patološke emocije. Strah, tjeskoba, užas i očajnost
su opet navedeni kao osjećaji jako izraženi kod melankolika, a u manjem stupnju kod
neurastenika.567 Neurastenija je bolest karakteristična za ubrzani tempo života koju je prvi opisao američki
psihijatar E. H. Van Duesen, a slavnom ju je učinio njujorški neurolog George Beard. Sama
neurastenija bila je još jedna od svojevrsnih „protejskih bolesti” devetnaestoljetne psihijatrije. Od
1869. kad je prvi put opisana do polaganog prestanka korištenja dijagnoze u međuratnom
razdoblju prošla je brojne etiološke transformacije i opisivana je kao skup različitih simptoma. U
kliničkim opisima neurastenije se često eksplicitno spominjao strah, a implicitno anksioznost. Zbog toga možemo reći da je povijest neurastenije bitna za daljnje razumijevanje straha i
anksioznosti u psihijatriji prijelaza stoljeća. E.H. Van Duesen bio je ravnatelj psihijatrijskog
zavoda u Kalamazoou u državi Michigan. Van Duesen je neurasteniju uočio kod mladih supruga 167 siromašnih farmera, a kao njene uzroke vidio je monoton život, intelektualno nepoticajno okružje
brige za kućanstvo i razdvojenost od roditeljskog doma.568 Rani simptomi te bolesti za Van
Duesena su nalikovali simptomima malarije, a sastojali su se od gubitka apetita, pospanosti,
čudne boje urina, gubitak snage u mišićima, razdražljivosti i neuralgija.569 No, Van Duesen je
svojoj bolesti pridodao još brojne somatske i psihičke simptome. Opis između ostalog navodi
nepovjerljivost, promjene raspoloženja, paranoidne ideje, glavobolje, prestanak mjesečnice,
probavne smetnje, iscrpljenost, poremećaje rada srca. Anksioznost i strah se ne spominju
eksplicitno u opisu bolesti, ali primjeri psiholoških simptoma su uvijek povezani s određenom
tjeskobom. „Nepovjerenje” neurasteničnih žena je tako povezano sa zebnjom nad različitim
aspektima života: „Ako je bolesnica osoba dubokih religijskih uvjerenja... ...javlja se nepovjerenje u Božja
obećanja, morbidni pogledi na osobne odnose s crkvom i društvom-ono što se nepravilno naziva
„religiozno melankolijom. Ako je stjecanje imetka i posjedovanje velikog zemljišta njezin životni
cilj, muči ju strah od siromaštva.... Ako su bračni odnosi bili bliski i ispunjeni nježnošću, muči
je ljubomora.”570 Van Duesen je neurasteniju prepoznao kod svojih siromašnih ruralnih pacijentica. Promatrao ju je
u odnosu prema malariji i ukazivao na distinktivno psihološku prirodu neurastenije. George
Beard je svoj prikaz neurastenije dao nekoliko mjeseci kasnije i njegov će opis simptoma i uzroka
te bolesti imati daleko veći utjecaj na psihijatre od Van Duesenovog. 568 Van Deusen, 1869: 447. ,
570 Ibid, 450-451. ,
571 Beard, 1869: 217. 569 Ibid, 448-450. 6.2.Strah i anksioznost u psihijatriji devetnaestog stoljeća Beard se u svom predavanju
o neurasteniji održanom pred njujorškom udrugom urednika medicinskih časopisa ne poziva na
Van Duesena i govori kako u trenutnim medicinskim traktatima trenutno ne postoji poglavlje ili
rad o neurasteniji. Čini se da je pojam neurastenije ipak bio korišten u medicinskoj praksi i prije
Bearda i Van Duesena jer Beard navodi kako je pojam „živčane iscrpljenosti” već poznat u dijelu
medicinske literature.571 Ono u čemu se sastoji najznačajniji Beardov doprinos ideji „živčane iscrpljenosti” je činjenica da
je od iste učinio bolest modernog doba povezavši strahove pacijenata sa stresnim utjecajima
užurbanog urbanog života na pojedinca. Primarni uzrok neurastenije za Bearda nije socijalna
izolacija na farmama pograničnog i ruralnog Michigana, već moderna civilizacija. Među glavne
osobine kojima se moderna civilizacija razlikuje od „drevnih” civilizacija Beard ubraja parni 168 stroj, periodični tisak, telegraf, znanost i duševnu aktivnost žena.572 Sekundarni i tercijarni faktori
uzroci neurastenije su klima, institucije, osobne navike i prekomjerno prepuštanje porivima i
strastima.573 Užurbani način života i modernizacija za Bearda su odlike američkog života i zbog
toga je neurastenija prepoznata kao „američka bolest”. Živčano oboljenje postalo je svojevrstan
odraz nacionalnog identiteta i dokaz razvijenosti Sjedinjenih Američkih Država u odnosu na
Europu- naročito u odnosu na Veliku Britaniju koju Beard direktno spominje u knjizi koja je
popratila njegovo predavanje,574 U spomenutoj knjizi, prikladno nazvanoj American Nervousness
Beard opisuje tjelesni ustroj ljudi koji se značajno razlikuje od Van Duesenovog: oni su
profinjenog ustroja, tanke nježne kose i kože, malih kostiju, izduženih udova i slabe
muskulature.575 Takav tjelesni ustroj Beard prepoznaje kao dominantan u Sjedinjenim Američkim
Državama kao opis onog sloja ljudi koji svojim radom „tjera zemlju naprijed”. Pritom Beard pod
radom podrazumijeva isključivo intelektualni rad576 koji za sobom donosi slabljenje živčanog
sustava i mnogobrojne psihosomatske tegobe, strahove i nervozno raspoloženje. Hrvatski psihijatri nisu prepoznali mnogo slučajeva neurastenije, ali su opsežno pisali o njoj. Također, može se reći da je u okvirima hrvatske psihijatrije neurastenija dodatno somatizirana i
povezana sa hereditetom. Za Žirovčića će neurastenične osobe nužno biti „hereditarno obterećene
individue”577. p
577 Žirovčić, 1895a: 67. 575 Beard, 1869: 23. 576 Campbell, 2007 :162. 578 Ibid, 66. 572 Ibid, vi.
573 Ibid.
574 Beard, 1860 vii.
575 Beard, 1869: 23.
576 Campbell, 2007 :162.
577 Žirovčić, 1895a: 67.
578 Ibid, 66. 578 Ibid, 66. 574 Beard, 1860 vii. 572 Ibid, vi. 6.2.Strah i anksioznost u psihijatriji devetnaestog stoljeća Neurastenija je, uz melankoliju također definirana strahovima i fobijama, te
osjećajem strepnje i nelagode koji bismo danas možda prepoznali kao anksioznost: „Ovamo spadaju nadalje razne fobije: bolestnik se plaši visokih, visećih, gibajućih se predmeta,
otvorenoga prostora, samoće, množtva ljudi; žaca sedirnuti kvaku na vratih, pak ako je to morao
učiniti, pere si neprestano rake, kao da se je nečim zamrljao...boji se preći preko mosta, jer bi
sebe ili koga drugoga morao u vodu baciti; strah ga hvata, neće li se ovo ili ono dogoditi, neće li
sviet propasti itd.”578 Osim što je kod Žirovčića neurastenija povezana s hereditetom i što je karakterizirana kao
„konstitutivna psihoza” pojedinaca sklonih strepnjama, kompulzijama i fobijama, ona gubi svoju
vezu s napornim mentalnim radom, već se počinje vezivati i uz moralna posrtanja. Kod
hereditarnih neurastenika se tako pojavljuju razni „duševni defekti” između ostalih i lažljivost i 169 „protivno spolno osjećanje”. Nadalje, oni su nepostojani i nepouzdani.579 Žirovčić uz hereditarnu
neurasteniju opisuje i stečenu neurasteniju koja se odlikuje sličnim simptomima kao i hereditarna. „Plahost” i „strašljivost” se pojavljuju i kod jedne i kod druge bolesti.580 Melankolija i neurastenija su jedine bolesti u čijem opisu Žirovčić spominje strah. U nekim
povijestima bolesti strah se navodi kao mogući uzrok psihičkog poremećaja. Premda je hrvatska
psihijatrija bila somaticistička u svom shvaćanju etiologije duševnih bolesti, rana izvješća su
navodila „affectus” kao jedan od kontinuirano najčešćih uzroka oboljenja. „Affectus” će
prevladavati kao uzrok mentalne bolesti kod žena koje su u devetnaestoljetnoj medicini smatrane
podložnije djelovanju snažnih osjećaja jer ih se smatralo osobama krhkijeg „živčanog ustroja”. Liječnička svjedodžba bolesti lončarove supruge Jele S. povezuje početak njezine bolesti sa
strahom od „čarolija”: „26 prosinca pr. g. da se je probudila kao preplašena, okol sebe gledala
zatim poče pripovjedati o strašnih sanjah i čarolijah pa kad joj ne htjedoše vjerovati razgnjevi se i
poče sve oko sebe parati i tući”581 Seljak Pavao T., tvrdio je da se razbolio služeći vojsku kad je „je jedne noći, dok je bio na svojoj
patroli, došao u stražarnicu k njemu čovjek, legao uz njega i opet ustao. Od tada ga lovi
strah.”582. Liječnička svjedodžba također govori kako je uzrok Pavlovog oboljenja bio strah, ali
navodi znatno drugačiji kontekst. Prema liječničkom izvješću Pavla je veliki strah uhvatio zbog
nekih trgovačkih ugovora koje je nosio svom ocu.583 Seljanka Zlata Š. 582 KPV, 1895: 2685. 581 KPV, 1881: 319. 583 Ibid. 580 Ibid, 67. 579 Ibid.
580 Ibid, 67.
581 KPV, 1881: 319.
582 KPV, 1895: 2685.
583 Ibid.
584 KPV, 1910: 7771. 6.2.Strah i anksioznost u psihijatriji devetnaestog stoljeća se, prema izjavi koju je
liječnicima dao njezin suprug, uplašila i razboljela kad im je susjed s kojim su bili u zavadi
otrovao kokoši.584 Strah se kao uzrok bolesti najčešće navodi kod štićenica ili muškaraca nižeg socio-ekonomskog
statusa, no kao što će analiza slučajeva u ovom poglavlju pokazati, svjedočanstva o strahu kao
uzroku bolesti se često ignoriraju jer nisu u skladu sa dominantno somaticističkom etiologijom
kojom se psihijatrija vodi. Objekti straha i njihov konkretan odnos s izbijanjem bolesti bili su
raznovrsni: osim uzroka bolesti, štićenici osjećaju razne strahove i strepnje vezane uz različite
aspekte svoje svakodnevice. U nastavku nastojat ću opisati četiri temeljne manifestacije straha ili tjeskobe u povijestima
bolesti stenjevačkih štićenika. Radi se o strahu od neimaštine, strahu od natprirodnog, strahu od 170 nasilja, te paranoidnim strahovima vezanim uz politiku i opresivnu moć države. Na temelju
navedenih manifestacija, nastojat ću razlučiti kakvu su ulogu strah i strepnja imali u
psihijatrijskom diskursu. Od naročite će važnosti biti distinkcija između emotivnih stanja koja su
se smatrala normalnima i onih koja su se doživljavala kao patološka, bilo da ih se promatralo kao
distinktivni simptom duševnog oboljenja ili ih se dovodilo u vezu s pojavom duševne bolesti. Osim toga, strah i anksioznost štićenika su bili povezani sa njihovim iskustvom, sustavom
mišljenja i vjerovanja i svakodnevicom, a nerijetko su se u njima javljali strahovi i strepnje
potaknuti širom društvenom i političkom situacijom. ,
586 KPV, 1880: 29. 585 Rohaček, 1889: 149. ,
586 KPV, 1880: 29. 6.3. Strah od neimaštine Čini se da je htio biti
primljen u službu kao zavodski sluga „jer ne zna kako će kod kuće živjeti”.587 Nikolin strah za
vlastiti život povezan je s gubitkom stoke od koje je ranije preživljavao. Druga “bosanska
bjegunica”, Sava R. također često govori o gladi i teškim uvjetima života pred kojima je
pobjegla, jednom čak plačući jer je „izbljuvala lijepi ručak koji su joj liječnici dali.”588
Osim bosanskih bjegunaca, strah od siromaštva je gotovo stalno prisutan i kod ruralnih štićenika. Prilično često ga izražavaju štićenici kojima je dijagnosticirana „melancholia” a koji su bili sa
sela. Može se uočiti da je sama „melancholia” (uz „maniu”) češće bila dijagnosticirana
štićenicama iz ruralnih krajeva, nego onima iz gradova. Budući da su se u Žirovčićevoj
klasifikacija „melancholia” i „mania” smatrale „afektivnim psihozama”589 i da su afekti u okviru
emotivnog režima građanske klase zauzimali hijerarhijski niži položaj od razuma ili „etičkih i
estetičkih čuvstava” to može odražavati percepciju siromašnog seoskog stanovništva kao
„primitivnijeg” i sklonijem emocijama. Osim bosanskih bjegunaca, strah od siromaštva je gotovo stalno prisutan i kod ruralnih štićenika. Prilično često ga izražavaju štićenici kojima je dijagnosticirana „melancholia” a koji su bili sa
sela. Može se uočiti da je sama „melancholia” (uz „maniu”) češće bila dijagnosticirana
štićenicama iz ruralnih krajeva, nego onima iz gradova. Budući da su se u Žirovčićevoj
klasifikacija „melancholia” i „mania” smatrale „afektivnim psihozama”589 i da su afekti u okviru
emotivnog režima građanske klase zauzimali hijerarhijski niži položaj od razuma ili „etičkih i
estetičkih čuvstava” to može odražavati percepciju siromašnog seoskog stanovništva kao
„primitivnijeg” i sklonijem emocijama. Osim bosanskih bjegunaca, strah od siromaštva je gotovo stalno prisutan i kod ruralnih štićenika. Prilično često ga izražavaju štićenici kojima je dijagnosticirana „melancholia” a koji su bili sa
sela. Može se uočiti da je sama „melancholia” (uz „maniu”) češće bila dijagnosticirana
štićenicama iz ruralnih krajeva, nego onima iz gradova. Budući da su se u Žirovčićevoj
klasifikacija „melancholia” i „mania” smatrale „afektivnim psihozama”589 i da su afekti u okviru
emotivnog režima građanske klase zauzimali hijerarhijski niži položaj od razuma ili „etičkih i
estetičkih čuvstava” to može odražavati percepciju siromašnog seoskog stanovništva kao
„primitivnijeg” i sklonijem emocijama. Udovici iz Grane. Mari Š. Dijagnoza „melancholie” kasnije je pretvorena u „anoiu”. Mara je
boravila u Stenjevcu 1881. godine, a tamo je i preminula od tuberkuloze krajem iste godine. Kao
uzrok Marine bolesti naveden je „prestanak mjesečnice”. 6.3. Strah od neimaštine Liječnici i bolničari stenjevačkog zavoda bili su svjesni da velik broj njihovih štićenika vodi život
na rubu oskudice ili se direktno bori za preživljavanje. Prvi ravnatelj zavoda Ivan Rohaček je
usprkos dominiranju somaticističkih teorija u jednom od godišnjih izvješća pretpostavio da je kod
većine štićenika uzrok oboljenja siromaštvo i s njime povezana slabokrvnost.585 Većina liječnika,
osobito onih koji su imali iskustvo rada u ruralnim krajevima Hrvatske je svjesna nepovoljnih
utjecaja siromaštve i bijede na zdravlje stanovništva. Siromaštvo i bijeda su rašireni, naročito kod
pojedinaca koji iz različitih razloga ne mogu računati na materijalnu podršku najbližih. Štićenici
u Stenjevcu često opisuju teške uvjete života i osjećaj strepnje koje su isti u njima izazivali. Očekivano, takvi opisu dominiraju u povijestima bolesti seljaka i sitnih obrtnika, te nadničara. Na samom početku rada Stenjevca pojedini bolesnici su zavedeni kao „bosanski bjegunci”. Radilo se, vjerojatno o ruralnoj populaciji Bosne koja je izbjegla nakon intervencije Austro-
Ugarske vojske u Bosni 1878. godine. Intervencija, nakon koje je uslijedila Austro-Ugarska
okupacija Bosne, bila je praćena otporom lokalnog stanovništva, a nasilje okupacije je utjecalo i
na civile. Točan broj ljudi koji su izbjegli iz Bosne nakon okupacije i pobuna koje su uslijedile
nakon iste u razdoblju između 1879. i 1882. godine nije istražen, no dio stenjevačkih povijesti
bolesti govori o egzistencijalnoj nesigurnosti i strahu od ekstremne bijede koju su izbjeglice
osjećali. Bosanski bjegunac Nikola K. primljen je u zavod 15. studenog 1879. i boravio je u
zavodu do 13. lipnja 1880. godine. U zavodu mu nije postavljena nikakva dijagnoza, a opis
njegovog psihičkog stanja kaže da je „prilikom bijega iz Bosne izgubio svoju marvu i od toga
vremena počeo bolovati”586. U zavodu, Nikola je miran i staložen, vrijedno obavlja sve poslove 171 no opetovano je zabilježena njegova strepnja nad vlastitom budućnošću. Čini se da je htio biti
primljen u službu kao zavodski sluga „jer ne zna kako će kod kuće živjeti”.587 Nikolin strah za
vlastiti život povezan je s gubitkom stoke od koje je ranije preživljavao. Druga “bosanska
bjegunica”, Sava R. također često govori o gladi i teškim uvjetima života pred kojima je
pobjegla, jednom čak plačući jer je „izbljuvala lijepi ručak koji su joj liječnici dali.”588 no opetovano je zabilježena njegova strepnja nad vlastitom budućnošću. 590 KPV, 1881: 309. 591 Ibid. 587 Ibid.
588 KPV, 1881: 116.
589 Žirovčić, 1895a: 20.
590 KPV, 1881: 309.
591 Ibid.
592 Ibid.
172 589 Žirovčić, 1895a: 20. 592 Ibid. 6.3. Strah od neimaštine Bolest se manifestirala time što je Mara
„prvo zapuštala posao, zatim se klatarila po noći, vikala psovala i trgala odielo”590. U kući je
ležala, raskuštrane kose,motreći oštrim pogledom svoju okolinu i pokrivena starim pokrivačem te
često pjevala, vikala i psovala. 591 Prema izjavama koje daje u zavodu, Mara je uglavnom zdvajala
oko udaje za nekog „dimnjačara, bogca” pred kojom je strahovala. Mara je nekoliko puta dala do
znanja da će se morati udati za „bogca” ili će izgubiti kuću te da će i ona biti „bogec”. U jednoj
od izjava koju je dala liječnicima 21. travnja 1881, Mara tumači svoju bolest kao posljedicu
straha od ponovne udaje za nekog siromašnog: „Mora bogca uzeti, a ona ga neće... Bogca se boji od lanjske godine, prem ga vidjela nije: kad
ju iznenada strah spopadne tako pa poče bježati po kući. Inače više-manje na pitanja uredno
odgovara, no sve misli joj se oko bogca i kuće vrte. Takve bogce čuje ona na sve strane koji joj
dovikuju: „i ti buš bogec, bogec i ti.592” 172 Kod nekih štićenika bolest se pojavila u trenutku kad su im se dogodile velike ekonomske
poteškoće, bilo zbog neke nesreće ili zbog dugova. Seljanka Mara K. razboljela se nakon što su
joj kuća i marva izgorjele u požaru. Nakon toga je često palila vatru u kući i u strahu zvala
seljane da ju idu gasiti.593 Druga seljakinja, po imenu Kata K. primljena je u Stenjevec 20. kolovoza 1880. godine s dijagnozom „melancholie”. Jedini simptom njezine bolesti koji se
provlači kroz povijest bolesti je strah od nekog povjerenstva koje će joj prodati kuću zbog
duga.594 U povijesti bolesti je ostala zabilježena i njezina slikovita izjava da su ju službeni organi,
načelnik i panduri „u pakao upisivali”595. Bara D. iz Dražica udala se prema izjavi općinskog
liječnika „iz bogate kuće za bogeca”596. Suprug ju je doveo liječniku i opisao okolnosti nastanka
njezine bolesti: Kod nekih štićenika bolest se pojavila u trenutku kad su im se dogodile velike ekonomske
poteškoće, bilo zbog neke nesreće ili zbog dugova. Seljanka Mara K. razboljela se nakon što su
joj kuća i marva izgorjele u požaru. Nakon toga je često palila vatru u kući i u strahu zvala
seljane da ju idu gasiti.593 Druga seljakinja, po imenu Kata K. primljena je u Stenjevec 20. kolovoza 1880. godine s dijagnozom „melancholie”. 594 KPV, 1880: 257. 593 KPV, 1880: bez broja. 593 KPV, 1880: bez broja.
594 KPV, 1880: 257.
595 Ibid.
596 KPV, 1881: 250.
597 Ibid.
598 Ibid.
599 KPV, 1880: bez broja. 595 Ibid. 599 KPV, 1880: bez broja. 597 Ibid. 596 KPV, 1881: 250. 6.3. Strah od neimaštine Jedini simptom njezine bolesti koji se
provlači kroz povijest bolesti je strah od nekog povjerenstva koje će joj prodati kuću zbog
duga.594 U povijesti bolesti je ostala zabilježena i njezina slikovita izjava da su ju službeni organi,
načelnik i panduri „u pakao upisivali”595. Bara D. iz Dražica udala se prema izjavi općinskog
liječnika „iz bogate kuće za bogeca”596. Suprug ju je doveo liječniku i opisao okolnosti nastanka
njezine bolesti: „Ovog proljeća hranila je ona 2 kom. svinjah što ih je kupila bila kako se čini, istom namjerom
da ih dobro uhrani i onda prodade. Nu na jednom- bez poznatog razloga krepalo je joj oba ona
dva svinjčeta. Ovaj gubitak dojmio se nje tako silno da je ona, koja je do sada uvijek nabožna
bila- mislila da je to očito kaštiga božja. To se vidi iz njenih rieči polog kojih smo svi mi
grešni, te za griehe naše bogu se moliti moramo. „597 Čini se da je gubitak svinja bio izrazito traumatičan za Baru: nakon ugibanja svinja često je
„Čislom u ruci oplakivala svoje krepane svinje, išla bi po selu čislom i Bogu se molila i
nabožne pjesme pjevala...”598 U zavodu se Bara ponaša mirno, često izražavajući naklonost
prema svom suprugu te ne pokazuje strah zbog financijskog gubitka koje je smrt svinja
predstavljala. Zanimljivo je i da Barina povijest bolesti sadrži zanimljivu dijagnozu „Mania
religiosa ex amissis suibus” (religiozna manija zbog gubitka svinja”. Kosta F. iz Opatovca je pak
zapao u beznađe i strepnju jer se bojao da neće moći financijski opstati nakon što mu je sin
unovačen. Odlazak odraslog djeteta u vojsku je vjerojatno značio gubitak radne snage na zemlji
i neizvjesniju budućnost za čitavu Kostinu obitelj. Kosta je nakon sinovljevog unovačenja bio
neutješan: ”...bojao se da će žena i djeca od glada morat poginuti, zadržavao se većinom na dvorištu gor i
dol hodeć, psovao domare”599. Liječnik koji je preporučio njegovo smještanje u zavod pričao je 173 173 s njegovim ukućanima i susjedina koji su svjedočili da Kosta „jede samo suhi kruh i uklanja se
vlastima”. 600 Došavši u Stenjevec, Kosta opetovano očituje svoju zabrinutost za preživljavanje
svoje obitelji govoreći kako „...će svi u kući od gladi poginuti, da niti hleba niti druga sredstva
u kući nema, raditi ne može i to je zlo što uslijed toga mora sve propasti. 6.3. Strah od neimaštine Upitan zašto da ne
radi odgovorio je razjaren da on raditi u stanju nije jer ništa nema i jer je sve propalo”601
Odnos liječnika zavoda prema traumatičnim posljedicama siromaštva nalazimo artikuliran u dva
slučaja koji uključuju štićenice dovedene u Stenjevac na psihijatrijsko vještačenje zbog umorstva
vlastite djece. Obje su tvrdile da su počinile umorstva kako bi spasile djecu mučne smrti od
gladi. Slučajevi su se dogodili s razmakom od dvadeset i sedam godina, no nalazi vještačenja
koje su napisali Drago Forenbacher i Ivan Žirovčić odaju slične poglede na emotivne posljedice
siromaštva. Prvi slučaj odnosi se na Baru O. tridesetgodišnju seljanku iz Podgarja kod Virovitice
koja je optužena da je „zaklala kamom troje svoje djece” pa nakon toga pokušala počiniti
samoubojstvo. 602 O uvjetima njezinog života doznaje se uglavnom od nje same i od rođaka i
susjeda. Bara je navodno bila zlostavljana od strane svog supruga koji ju je „tukao i
proganjao,”603 a kad je uhapšena priznala je da je ubila djecu jer „joj je djece žao bilo da se ne
muče i ne trpe glad, pa da je bila voljna i sama s djecom umrieti.”604 U Stenjevec je dovedena 10. s njegovim ukućanima i susjedina koji su svjedočili da Kosta „jede samo suhi kruh i uklanja se
vlastima”. 600 Došavši u Stenjevec, Kosta opetovano očituje svoju zabrinutost za preživljavanje
svoje obitelji govoreći kako „...će svi u kući od gladi poginuti, da niti hleba niti druga sredstva
u kući nema, raditi ne može i to je zlo što uslijed toga mora sve propasti. Upitan zašto da ne
radi odgovorio je razjaren da on raditi u stanju nije jer ništa nema i jer je sve propalo”601 Odnos liječnika zavoda prema traumatičnim posljedicama siromaštva nalazimo artikuliran u dva
slučaja koji uključuju štićenice dovedene u Stenjevac na psihijatrijsko vještačenje zbog umorstva
vlastite djece. Obje su tvrdile da su počinile umorstva kako bi spasile djecu mučne smrti od
gladi. Slučajevi su se dogodili s razmakom od dvadeset i sedam godina, no nalazi vještačenja
koje su napisali Drago Forenbacher i Ivan Žirovčić odaju slične poglede na emotivne posljedice
siromaštva. Prvi slučaj odnosi se na Baru O. tridesetgodišnju seljanku iz Podgarja kod Virovitice
koja je optužena da je „zaklala kamom troje svoje djece” pa nakon toga pokušala počiniti
samoubojstvo. 602 O uvjetima njezinog života doznaje se uglavnom od nje same i od rođaka i
susjeda. 602 KPV, 1890: 1626. 600 Ibid. 6.3. Strah od neimaštine Bari je dijagnosticirao „Dementiu” ali ju na više mjesta
spominje kao „melankolika”:„U melancholika nadodju momenti da takav bolesnik gonjen nekom
nevoljom silom nadvlada pasivnost te prijeđe u pravo bjesnilo uništavajuć sve što mu ruku
dođe.”608 U svom mišljenju, Forenbacher potpuno ignorira bilo kakav mogući utjecaj emocija (makar i
sasvim patoloških) na Barin zločin. Bari je dijagnosticirao „Dementiu” ali ju na više mjesta
spominje kao „melankolika”:„U melancholika nadodju momenti da takav bolesnik gonjen nekom
nevoljom silom nadvlada pasivnost te prijeđe u pravo bjesnilo uništavajuć sve što mu ruku
dođe.”608 U svom mišljenju, Forenbacher potpuno ignorira bilo kakav mogući utjecaj emocija (makar i
sasvim patoloških) na Barin zločin. Bari je dijagnosticirao „Dementiu” ali ju na više mjesta
spominje kao „melankolika”:„U melancholika nadodju momenti da takav bolesnik gonjen nekom
nevoljom silom nadvlada pasivnost te prijeđe u pravo bjesnilo uništavajuć sve što mu ruku
dođe.”608 Iako se u većini opisa melankolije spominju tuga i strah/anskioznost kao dominantne emocije,
jedina emocija koju Forenbacher indirektno spominje je „bjesnilo” (moguće je, također da se tim
pojmom prije opisuje stanje svijesti nego emocija). U stanje „bjesnila” melankolik dolazi tako da
ga na to nagoni „neka nevoljna sila.” Forenbacher tako udaljuje moguće motivacije za nasilan čin
od konkretnih životnih uvjeta Bare O., te ih apstrahira na razinu neodređenih „nevoljnih” sila
koje utječu na postupanje melankolika. Dvadeset i osam godina kasnije, u jeku Prvog svjetskog
rata, Ivan Žirovčić je u članku objavljenom u Liječničkom vjesniku opisao drugi slučaj umorstva
djece motiviranog neimaštinom. Radilo se o psihijatrijskom vještačenju R. D. tridesetogodišnje
muslimanke koja je živjela u Misurićima kraj Maglaja, gradića u središnjoj Bosni. Maglajska
srednjovjekovna utvrda i šumom obrasle planine oko nje se često pojavljuju na austrijskim
orijentalističkim razglednicama prijelaza stoljeća, koje su gradu pridavale auru pastoralne
egzotike. No, već u godinama prije okupacije Bosne i Hercegovine, Maglajska je utvrda bila
zapuštena i urušavala se, a stanovništvo Maglaja i okolnih mjesta često je bilo na rubu
neimaštine. Izbijanjem Prvog svjetskog rata, zavladale su nestašice hrane koje će biti jednim od
uzroka tragedije o kojoj Žirovčić piše. R. D. i njezin suprug Salko su bili siromašni, a susjedi su
R. opisivali kao marljivu kućanicu i brižnu majku koja je do trenutka tragedije bila duševno
zdrava.609 Njezin suprug je bio unovačen, a ona i kćeri ostale su same i živjele su u iznimnoj
neimaštini. R. i najstarija kćer, jedanaestogodišnja Šaha, morale su privređivati za hranu. U
srpnju 1917 R. 609 Žirovčić, 1918: 336. ,
610 Ibid: 333. 6.3. Strah od neimaštine Bara je navodno bila zlostavljana od strane svog supruga koji ju je „tukao i
proganjao,”603 a kad je uhapšena priznala je da je ubila djecu jer „joj je djece žao bilo da se ne
muče i ne trpe glad, pa da je bila voljna i sama s djecom umrieti.”604 U Stenjevec je dovedena 10. lipnja 1890. godine. Kao što je to često bio običaj u vrijeme upravljanja ravnatelja Rohačeka,
njeno psihijatrijsko vještačenje na sebe je preuzeo Dragutin Forenbacher. U Stenjevcu nema puno
zapisa o Barinom ponašanju budući da je nakon dva mjeseca preminula od tuberkuloze. Čini se
da Bara u nekoliko navrata navodi različite motive za umorstvo svoje djece. Tako prvo odbija reći
razloge koji su ju nagnali na zločin i „... bezbrižno, skoro smijuć se veli da je i sebe htjela
ubiti”605 Dva dana kasnije u nastavku razgovora s liječnikom Bara tvrdi da je ubila djecu jer „su
ljudi sumnjičavi, da neimade djecu sa svojim mnogo starijim mužem nego s drugim,”606 U svom
konačnom mišljenju Forenbacher je specifično išao opovrgavati siromaštvo kao mogući motiv
zločina. Naime, Forenbacheru se čini da teško ekonomsko stanje ne može biti motiv takvog
zločina jer je glad toliko učestala, a umorstva i samoubojstva nisu čest au toj populaciji:„Da se je lipnja 1890. godine. Kao što je to često bio običaj u vrijeme upravljanja ravnatelja Rohačeka,
njeno psihijatrijsko vještačenje na sebe je preuzeo Dragutin Forenbacher. U Stenjevcu nema puno
zapisa o Barinom ponašanju budući da je nakon dva mjeseca preminula od tuberkuloze. Čini se
da Bara u nekoliko navrata navodi različite motive za umorstvo svoje djece. Tako prvo odbija reći
razloge koji su ju nagnali na zločin i „... bezbrižno, skoro smijuć se veli da je i sebe htjela
ubiti”605 Dva dana kasnije u nastavku razgovora s liječnikom Bara tvrdi da je ubila djecu jer „su
ljudi sumnjičavi, da neimade djecu sa svojim mnogo starijim mužem nego s drugim,”606 U svom 174 motrenica zbilja toliko mučila i da je glad trpjela, to nije istina; druge žene bog zna koliko trpe pa
ne ubijaju sebe i djecu. Taj čin neima dakle razloge u izvanjskom svietu”607 motrenica zbilja toliko mučila i da je glad trpjela, to nije istina; druge žene bog zna koliko trpe pa
ne ubijaju sebe i djecu. Taj čin neima dakle razloge u izvanjskom svietu”607
U svom mišljenju, Forenbacher potpuno ignorira bilo kakav mogući utjecaj emocija (makar i
sasvim patoloških) na Barin zločin. 608 Ibid. 610 Ibid: 333. 608 Ibid. 607 Ibid. 6.3. Strah od neimaštine je utopila dvije mlađe kćeri, sedmogodišnju Ajku i četverogodišnju Nailu u Bosni,
negdje uz cestu od Maglaja prema Doboju.610 Prvo je utopila Nailu zaronivši joj glavu pod vodu. Ajka je uspjela pobjeći i izići do obale, ali su je prolaznici vratili majci misleći da je upala u
vodu slučajno. Nakon toga ju je R. odvela do obližnjeg potoka Jelovca i tamo joj držala glavu 175 pod malenim vodopadom dok nije izdahnula. Poslije svog čina, pričekala je najstariju kćerku koja
se nalazila u gradu i s njom odnijela djecu kući, predstavivši svima njihove smrti kao nesretan
slučaj. No, netko je posumnjao u njezinu priču i nakon što su lokalne vlasti povele istragu R. je
priznala zločin.611 Nakon uhićenja R. je bila podvrgnuta višestrukim psihijatrijskim vještačenjima tijekom kojih je
više puta navodila kako je ubila djecu jer je patila i gladovala pa je odlučila ubiti i sebe i djecu. Psihijatrijski vještaci u Tuzli i Sarajevu susreli su se s istim problemom s kojim se ranije susreo
Dragutin Forenbacher: može li strah od smrti od gladi nadvladati majčinski instinkt (kojeg
psihijatri poput Krafft-Ebinga ističu kao najjači prirodni poriv kod žena) i nagna ženu na
umorstvo vlastite djece. U horizontu devetnaestoljetne psihijatrije, potvrdan bi odgovor na to
pitanje podrazumijevao određeno duševnu abnormalnost, a s obzirom na prevladavajuću
somaticističku paradigmu, ta je abnormalnost morala proizlaziti iz tjelesnog ustroja žene. S druge
strane, psihijatre je zbunjivala promišljenost i planiranje čina, koji su opet bili u neskladu s
emotivnim stanjem koje us primjećivali kod R.. Prvo forenzičko mišljenje iz 25. kolovoza 1917. koje su dali vještaci suda u Tuzli, odaje njihovu zbunjenost i zdvojnost u slučaju R.D.: „Nedvojbeno, u slučaju postoji proračunatost i određen logičan odnos prema činjenicama. S
druge strane, osoba je manjkavih duševnih kvaliteta, budući da pati od određenog stupnja
melankolije. Dvojbeno je, je li čin počinjen u trenutku melankoličnog napada, u neubrojivom
stanju budući da glad kao motiv ne može objasniti počinjene djela”612 R. je upućena na daljnje vještačenje u zemaljsku bolnicu u Sarajevu, a tamošnji su vještaci dali
dva različita nalaza. U prvom koje je datirano 13. 11. 1917. nije nađen konkretno duševno
oboljenje pod utjecajem kojeg je R. D. mogla počiniti zločin već se navodi da je ubila djecu „pod
uplivom velike bijede, koja ju je dovela do zdvojnosti”613. No, kako je istraga napredovali,
Sarajevski su vještaci promijenili svoj stav. 611 Ibid.
612 Ibid: 333-334 original: »Es liegt demnach auch eine Berechnung und gewisse logische Erwagung der Tatsachen
zweifellos vor; anderseits aber ist die Untersuchte nicht von einwandfreier geistiger Qualitat, da zweifellos ein
gewisser Grad von Melancholie vorhanden ist. Es ist aber für uns zw eifelhaft, ob diese Tat wirklich im
Zeitpunkt eines melancholischen Raptus vollbracht wurde, in einem Zustande, der Zurechnungsfähigkeit
ausschliessen würde, da das Motiv Hunger die vollbrach te Tat nicht erklären kann”, preveo autor
613 Ibid: 334. ausschliessen würde, da das Motiv Hunger die vollbrach te Tat nicht erklären k
613 Ibid: 334. 6.3. Strah od neimaštine Čini se da je presudno za njihov sud bilo otkriće neke
hrane koje ju je R. imala kod kuće. Njihovo izmijenjeno mišljenje od prvog ožujka 1918. kvalificiralo je R. kao duševno zaostalu: 176 „...duševna labilnost i defekti R. D. su patološke naravi, označuju se kao slaboumnost, i
kvalificiraju je, kao da je sasvim bez uma: to proizlazi iz opstojnosti na raspravi ustanovljene,
da je u nje u kući nadjeno dovoljno hrane za nju i za djecu za više dana, te oskudica ne može
dovoljno motivirati njezin čin; njezina prevrtljivost u iskazivanju, nestalnost reprodukcije i
defekti rasudjivanja očituju se naročito time, što je potvrdjivala iskaze svjedoka, koji su
protuslovili njezinim čas prije navedenim izjavama. U ostalom kažu vještaci, izmedju duševne
tuposti i patološke slaboumnosti ne može se povući točna granica...” Njezina je bolest
navedena kao „urođena slaboumnost”.614 Budući da su i dalje postojale dvojbe oko R-inog psihičkog stanja u trenutku počinjena umorstva
upućena je u Kraljevski i zemaljski zavod za umobolne u Stenjevcu. U zavodu je R. letargična i
mirna. Pri dolasku zabilježena je njezina iznimna pothranjenost, koja je možda i uzrokovala
njezino gotovo katatonično ponašanje. Kad je primljena u zavod R. je težila 49 kilograma na
visinu od 167 centimetara i iz zapisa se vidi da je ustala iz kreveta i čak počela raditi na
zavodskom poljoprivrednom dobru nakon što je dobila na težini.615 U iskazu koji je dala doktoru Žirovčiću, R. opisuje tešku oskudicu koja je vladala u Maglaju. Iako
je težačkim poslom mogla zaslužiti novac, čini se da u cijelom gradu nije bilo hrane na prodaju. Imućniji koji su imali hrane, nisu je htjeli prodavati jer su „od njih nosili u Carevinu” (vjerojatno
rekvirirali hranu za vojne potrebe) pa su se i sami bojali gladi.616 R. i kćeri su preživljavale od
voća koje bi kupile za zasluženi novac i od „gebira” (sljedovanja) koji su se sastojali od tri četvrt
kilograma brašna tjedno i suhih šljiva. Uz to, R. je kuhala bilje koje je raslo kraj puteva. 617 Kad
govori o svom zločinu, Žirovčić bilježi da se R. kaje i „gorko i dugo plače” čim ju se pita o djeci
ili o umorstvima.618 Žirovčić, kao i drugi vještaci primjećuje da se R. ne sjeća točno detalja svog
čina, te da o njemu govori šturo i kroz plač. Nakon tromjesečnog vještačenja, Žirovčić donosi
zaključak kojim pokušava objediniti utjecaj neimaštine i somaticističke i rodno determinističke
pretpostavke psihijatrijske misli. 614 Ibid.
615 Ibid.
616 Žirovčić, 1918: 335.
617 Ibid.
618 Ibid.
619 Žirovčić, 1918: 337. 619 Žirovčić, 1918: 337. 614 Ibid. 618 Ibid. 617 Ibid. 620 Ibid. 621 Ibid: 338. 620 Ibid. 620 Ibid. 621 Ibid: 338. 621 Ibid: 338. 6.3. Strah od neimaštine Naime, Žirovčić nalazi da je R. D. histeričnog duševnog ustroja
što potkrepljuje smanjenim osjetom za bol i izostankom refleksa u ždrijelu.619 Izostanak osjeta na
bol, Žirovčić čak dovodi u asocijativnu vezu s nedostatkom majčinskog instinkta u nastojanju da 177 177 prikaže R. kao patološki bešćutnu osobu,usprkos njezinim intenzivnim emotivnim reakcijama na
događaj: „Za ovršenje tako okrutnoga posla mora se pretpostaviti sasvim vanredno duševno
raspoloženje, po gotovo, kad to još mati na vlastitom svojem djetetu ovršuje, mora se za taj
posao pretpostaviti posvemašnja duševna bešćutnost (anaesthesia psychica), koja ne može biti
svojstvena zdravom duševnom stanju matere, prije toga neporočne i koja tupa praznina ćudi
odgovara onoj kožnoj bešćutnosti (anaesthesia cutanea), što su je liječnici vremenito našli kod
R., „620 Žirovčić histerijom objašnjava i nekonzistentnost u različitim verzijama događaja koje je R. D. ispričala: „Mišljenje histerično bolesnih biva često tako maglovito i nejasno i sa činjenicama neskladno,
da je teško razabrati hotimičnu lažljivost od one lažne reprodukcije, za koju sam pripovijedač
pravo ne zna, što je istina, što nije, To pomućeno duševno stanje histeričnih naziva se
sumračnim stanjem (Dammerzustand, intenebratio hysterica), a to može biti raznoga stepena,
kao što je sumrak u prelazu iz dnevnog svjetla u noćnu tminu raznog stepena jasnoće: tako
može biti za histeričnu osobu u stanju duševnog sumraka doživljeni dogodjaj sasvim nepoznat,
ako joj je svijest bila sasvim potamnjena, ali pojedinosti dogadjaja mogu osvanuti u sjećanju,
ako duševni sumrak nije bio potpun.”621 Vidimo da Žirovčić pomiruje proturječne pozicije vještaka smještajući R. D. na granično
područje između svjesnog postupanja i neke vrsti privremene histerične zbunjenosti. Kao ni u
slučaju Ane Schier kojeg sam opisao u prethodnom poglavlju, ni ovdje histerija nema ništa
zajedničkog sa Charchotovim jasnim opisom neuroloških simptoma. To jest, histerija nema ulogu
dijagnoze konkretnog oboljenja, već medicinskog eksplanatornog modela za ponašanje koje
transgresira kulturno dominantnu percepciju roda. No ako Žirovčić i smatra da je histerija
stvorila preduvjete za abnormalno duševno stanje R. D., on ipak ne ignorira utjecaj gladi i
nestašice. Zbog toga će, za razliku od Forenbachera ipak priznati da je neimaština mogla utjecati
na umorstvo. Žirovčić će istaknuti kako prisutnost hrane u kući R.D. ne znači da ona prilikom
počinjenja zločina, ipak nije bila pothranjena. No, kao somaticistički psihijatar, Žirovčić neće
tražiti uzroke u stresu kojim je nestašica mogla utjecati na psihu R. D. 622 Ibid: 336-337. 624 Ibid, 2003: 337.
625 U ruralnim djelovima Hrvatske posljednji sudski slučaj na kojem se osobu optuživalo za korištenje crne magije
datira iz 1996 (slučaj Štefice Balaško iz Kunovec Brega kraj Koprivnice) . Slični primjeri vjerojatno se i danas
mogu naći diljem svijeta, kako među urbanom tako i među ruralnom populacijom. Čini se da je vjera u okultno,
barem što se tiče svakodnevnog folklora, preživjela usprkos modernizaciji društva.
626
l
2008 211 624 Ibid, 2003: 337. 6.3. Strah od neimaštine Umjesto toga pribjeći će 178 eksplanatornom modelu koju objedinjuje suvremene spoznaje o ljudskom metabolizmu i
anakrone pretpostavke humoralne medicine: „Jedno je lokalni glad, čuvstvo praznine želuca, koje traži, da se želudac napuni; tomu gladu
dade se časovito udovoljiti i takvom tvarju, koja ima malo ili ništa hranbenih vrijednosti, kao
što je i R. u nuždi kuhala koprive i neko zelje, nemajući brašna. Drugo je opći glad organizma,
u kojem svaka stanica ćuti nedostatak materijala za tvarnu izmjenu u svojoj životnoj
djelatnosti, to je kronični glad, koji neminovno dovodi do stradanja i propasti organizma. Gladovanje znatno mijenja izlučivanje životnih sokova, koji bitno djeluju na moždjansku
djelatnost. Prastara medicina osnovala je na mješavini 'tjelesnih sokova glavna četiri
temperamenta: sanguinični (sanguis krv), flegmatični (flegma=sluz), holerični (hole=žuč) i
melanholični (crna žuč), Kod stanovitih obolenja poremeti se sekrecija i ekskrecija sokova na
štetu organizma, na pr. kad bolesni bubrezi ne izlučuju mokraćevinu, te ona prelazi u krv i
djeluje na moždjane tako otrovno, da bolesnik zapane u smrtonosan delir.” 622 Ono što je zajedničko ovim dvama psihijatrijskim vještačenjima je činjenica da je utjecaj
siromaštva na psihičko i emotivne stanje pojedinca neprepoznat kod stenjevačkih liječnika:
Forenbacher će, zaobišavši emocije govoriti o nekoj sili koja utječe na volju dok će Žirovčić
postupke optužene tumačiti kroz biokemijske modele i diskurs histerije. Za stenjevačke liječnike
neimaština će ostati vidljiva kroz svoje materijalne manifestacije: anemiju, neuhranjenost, loše
higijenske uvjete, ili kroz diskurs o moralnoj i duševnoj inferiornosti siromašnih. Anksioznost i
strepnja zbog svakodnevnog egzistiranja na rubu oskudice i očaj zbog dugotrajne nemogućnosti
da se pobjegne od gladi nisu imali mjesto u psihijatrijskom diskursu orijentiranom na tijelo. Upravo iz tog razloga, o strahu od siromaštva doznajemo uglavnom iz govora štićenika i njihovih
poznanika- čak ni u onim slučajevima duševnog oboljenja gdje je „affectus” naveden kao uzrok
duševne bolesti, taj afekt nije doveden u vezu s teškim imovinskim prilikama. Osim fokusa
psihijatre na tjelesnu etiologiju duševnih bolesti tima je sigurno i doprinio stav da je siromaštvo
pojava na koju su ljudi nižih društvenih slojeva trebali naviknuti kao na stalno stanje svoje
egzistencije. 179 623 Delimo, 2003: 129. 626 Blom, 2008: 211. 628 KPV, 1881: 319. 627 Ibid: 214. 6.4. Strah od natprirodnog U Delumeauvoj studiji Strah na Zapadu natprirodno kao objekt straha zauzima izraženo mjesto
kako u strahovima ruralne populacije, tako u strahovima elita. Folklor je bogat pričama o
mrtvacima koji se vraćaju iz grobova, vješticama, vukodlacima i sličnim natprirodnim
čudovištima. Delumeau spominje strahove od zlih duhova ljudi koji su umrli nasilnom ili
prijevremenom smrću, ponajviše od duhova utopljenika i pobačene i nekrštene djece.623
Obrazovane elite osjećaju strepnju pred krajem svijeta i strahuju od Strašnog Suda, Sotone i
njegovih demona. Rani novi vijek obiluje književnim, teološkim i filozofskim djelima koja
govore o prisutnosti Sotone i njegovih slugu ─ vještica, čarobnjaka i demona na svijetu.624 U
devetnaestom stoljeću su i folklorna čudovišta i eshatološka strepnja i dalje prisutni. Na selu je
još uvijek rašireno vjerovanje u nadnaravna bića i magiju625, a brojni elementi pučke religioznosti
pronose strahove od demona i kraja svijeta i među ruralnu populaciju. Među obrazovanim
elitama šire se novi oblici ezoteričnih vjerovanja poput spiritizma i teozofije. Helena Blavatsky
već 1870-ih godina predstavlja britanskim, američkim i njemačkim intelektualnim elitama
osebujnu mješavinu spiritizma i indijske filozofije a do 1911. godine njezino teozofijskodruštvo u
Londonu već ima 16 000 članova.626 U Njemačkoj, kao i u Austro-Ugarskoj Monarhiji slična
vjerovanja širi Rudolf Steiner, koji će svoju antropozofsku školu udaljiti od budističkih uzora i
približiti ju katolicizmu, Hegelovoj filozofiji i rasnim teorijama.627 Stenjevački štićenici često izražavaju strahove od natprirodnog i vjerovanja vezana za isto su
prisutna u njihovim deluzijama. Ranije sam spomenuo slučajeve poput onog lončareve supruge
Jele kojoj su „babe napunjavale glavu raznimi prazovjernimi pričami628”. Jelina bolest pojavila se
pod direktnim utjecajem strašnih priča koje je navodno čula. Naime, prema liječničkoj
svjedodžbi, Jela se oko šestog prosinca 1880 „probudila kao preplašena” gledajući oko sebe i
počela pričati o „strašnih sanjah i čarolijah” i reagirala je bijesno i agresivno kad joj nisu htjeli 180 vjerovati.629 Slična vjerovanja u natprirodno spominjala su se i u slučajevima zaposjedanja i
percipiranog gubitka kontrole nad vlastitim tijelom koje sam obradio u prethodnom poglavlju. Kao i štićenice čije sam priče iznio u spomenutom poglavlju, brojni štićenici pripisuju svoju
bolest najrazličitijim natprirodnim uplivima. Seljakinja Milka P., stara 21 godinu ponašala se
nemirno i mahala zamišljenom zastavom vičući: „Ne dajmo se, mi smo Hrvati, naša je zastava
crveno-bijelo-plava a ne zelena. Apcug Mađari.”630. 629 Ibid.
630 KPV, 1911: 8031.
631 Ibid.
632 KPV, 1914: 8933.
633 KPV, 1911: 8060.
634 KPV, 1911: 8003.
635 Ibid. 634 KPV, 1911: 8003. 6.4. Strah od natprirodnog Nakon što je dovedena u Stenjevec gdje joj je
dijagnosticirana „mania” objasnila je liječnicima svoju bolest kroz prizmu folklornih vjerovanja o
vješticima i raskrižjima rekavši „da su je coprnice pomotale kad je išla na križanje, tam da je bio
jedan veliki vol koji se pretvorio u kravu.”631Vještica se bojala i seljakinja Boja M. iz Gračaca
koja nije mogla spavati strahujući „od vještica koje vidi pred sobom.632 Uz vještice, bitno mjestu
u imaginariju pučkih čudovišta zauzimaju i duhovi kojih se brojni štićenici boje ili im pripisuje
simptome svojih tjelesnih i duševnih oboljenja. Josip L. iz Brestovače krivio je „zlog duha” za
niz tegoba koje je osjećao: od zubobolje i impotencije do vlastitih psihičkih teškoća: „Pripovjeda
da je u njemu zao duh kojega je u njeg stavio gospodin Isus Krist. Taj mu duh prkosi i radi žena,
drži mu žilu i ne da da mu se napne, a pamet mu je već 4 mjeseca okrenuta.”633 Strah od „zlog
duha” ponekad je povezan s osjećajem krivnje zbog grešnog života. Pepa D. iz Varaždina, stara
40 godina, radila je u Zagrebu kao služavka kad su je počele mučiti misli o oženjenom
podvorniku u kojeg se zaljubila. Mislila je da njezin ljubavnik podvornik ne želi ostaviti ženu
zbog nje jer je „vodila zločest život” pa je pokušala samoubojstvo pijenjem lizola pomiješanog s
terpentinom i petrolejem.634 U Stenjevcu nije mogla spavati i bila je u velikom strahu. Kad ju je
liječnik upitao čega se boji, odgovorila je da se osjeća „nesretnom progonjenom od zlog duha jer
da je jako griešna”.635 Bolničarka je također pričala da je Pepa jučer dobila maramu, ali ju je
bacila u zahod pričajući kako je u marami „nečastivi duh”. Vjerovanje u „nečiste duhove” nije
ograničeno isključivo na štićenike lošijeg socijalnog statusa. Josipa Klemm, supruga tvorničkog
nadzornika iz Turopolja također je bila u strahu od duhova koje je halucinirala prilikom
suprugove posjete. Pojavu tih duhova također je povezala s grijehom i otvoreno je rekla da ih se
boji:„...pripovieda, da je jučer kod nje bio njezin suprug obučen u žensko odielo a oko njega je 181 bilo mnogo grieha: zlih duhova- vidila je to, kad je išla spavati, pa sad ju je velik strah od tih
duhova.”636 Jozefina je primljena u Stenjevec 1905. godine, na preporuku općinskog liječnika Neumanna. U
Stenjevcu će ostati sve do svoje smrti od tuberkuloze u veljači 1914. godine.637 Sama stenjevačka
povijest bolesti Jozefine T. 637 KPV, 1914: 6482. 636 KPV, 1914: 8471. 639 Žirovčić, 1895: 249. 638 Ibid. 638 Ibid. 6.4. Strah od natprirodnog ne obiluje mnogobrojnim detaljima, ali joj je priložena liječnička
svjedodžba koju je potpisao općinski liječnik Julijo Neumann kojoj se kao glavni simptom
Jozefinine bolesti navodi velika želja za čistoćom i kompuzivno pranje uz deluzije vjerskog i
ljubavnog sadržaja. Povijesti bolesti je priloženo i pismo njezinog brata koji prepričava početak
njezine bolesti: „Što se tiče uzroka, mislim ovo: Zaljubila se, drugarice je draškale pa tim i povećale ljubav. Ljubljeni nije odvraćao, bar nije pokazivao ničim i oženio se. Otac je nagle ćudi, višeput
nesmiljen prema majci; osim toga čula za nj sestra svašta pripovjedati, što je na nju silno
djelovalo i moralo nužno djelovati- i to je jedan veliki uzrok. Nadalje bila je oklevetana od
drugarica, rodjakinja još k tomu, pa se to nje silno dojmilo i posljedica je bila da ih je zamrzila, a
jer smo mi govorili da baš nije tako, kako ona misli, zato je izgubila u nas povjerenje sve po redu
nije nas trpjela; na koncu nikoga nije trpjela do jedne časne sestre u bolnici pakračkoj. Utješiti se
nije dala i bolest je rasla još više i više. Ovi su znaci bili ustrajni. Isprva vidjela je duhove,
mrtvace, plašila se, poslije je to prestalo.”638 Kad psihijatri spominju strah od natprirodnog oni ga ne gledaju isključivo kao simptom neke
duševne patologije, iako u jednom dijelu društva nedvojbeno postoji i takva percepcija. U
sudskom spisu Jove Ljubojevića, seljaka koji je optužen za umorstvo vlastite supruge navode se
izjave brojnih svjedoka koji govore o tome da je Ljubojević išao kod vračara i vjerovao da je
začaran. No Žirovčić, u svom mišljenju Ljubojevićeva vjerovanja ne pripisuje duševnoj bolesti
već „seljačkom praznovjerju”.639 U navedenim slučajevima strah od natprirodnog nema centralno mjesto u duševnom svijetu
navedenih štićenika već se javlja usputno, kao reakcija na specifičnu halucinaciju ili deluziju, ili
kao štićenikovo objašnjenje vlastitih tjelesnih ili duševnih tegoba. U nekim slučajevima,
vjerovanja u natprirodno i strah od istih će biti neki od središnjih elemenata štićenikovog
psihičkog stanja i okolina štićenika će im pristupati mnogo sustavnije nego što je to slučaj kod 182 štićenika gdje se strah javlja samo kao izolirana epizoda ili pojedinačan i kratkotrajan simptom. Vrste prepoznatih oboljenja u kojima strah od natprirodnog često zauzima središnje mjesto je
oboljenje koje se u prvim godinama rada Zavoda naziva religioznom manijom ili religijskom
paranojom. j
642 KPV, primjer obrasca liječničke svjedodžbe. ,
641 Matijašević.2006:84. , p
j
j
j
643 KPV, 1911: 8073. 640 Freud, 2010: 2418. p
j
643 KPV, 1911: 8073. 640 Freud, 2010: 2418. 6.4. Strah od natprirodnog Dijagnoza će se u kasnijim zapisima javljati sve rjeđe, vjerojatno zbog Žirovčićeve
nesklonosti klasifikacijama bolesti koje uzimaju u obzir sadržaj emocija bolesnika. Pri pisanju
svoje klasifikacije, Žirovčić se ugledao na Meynerta i klasificirao bolesti prema aspektu uma koji
je prepoznao kao poremećen (afekt, mišljenje, etička čuvstva ili cjelokupna duševna konstitucija)
i pretpostavljenom uzroku. Iako je takvom klasifikacijom religijski sadržaj strahova učinjen manje eksplicitnim, strahovi
povezani s religijskim koncepcijama grijeha, božje kazne i pakla nastavljaju biti dokumentirani u
povijestima bolesti. Jedan od najpoznatijih slučajeva paranoje s religijskim elementima bio je
slučaj suca Daniela Paula Schrebera. Slučaj je postao slavan jer je Schreber odlučio objaviti
detaljan prikaz vlastite bolesti koji je poslije zainteresirao i Sigmunda Freuda. Freud je na temelju
Schreberovog svjedočanstva formirao vlastiti stav o tom dobro dokumentiranom slučaju,
povezavši Schreberov strah s njegovim latentnim homoseksualnim željama prema njegovom
liječniku doktoru Flechsigu.640 Osim toga, Freud gleda na Schreberov sustav kozmoloških
deluzija kao na pokušaj samoizlječenja od žudnje koja je kod Schrebera stvarala anksioznost. Schreber se u svojoj deluziji, zamišlja kao „božju ženu“ doktora Flechsiga, čime Schreber
nadilazi protivljenje homoseksualnoj pobudi koje je kod njega proizvelo unutarnji sukob.641
Stenjevački primijeri strahova vezanih uz religiozna vjerovanja štićenika su jednako brojni kao i
oni vezani uz folklorna čudovišta. Nacrt svjedodžbe koju su općinski liječnici koristila za
upućivanje bolesnika u Stenjevac predviđao je pitanja o vjerskim navikama osobe: ide li redovito
u crkvu, psuje li ili „bogohuli” i ponaša li se „ćudoredno”.642 Ponegdje religiozni strahovi bivaju
obojeni osebujnim shvaćanjem koncepata preuzetih iz katoličkog nauka. Magda B. seljanka iz
Letinca pokraj Brinja primljena je u Stenjevec u stanju velike tjelesne iscrpljenosti od koje je i
preminula nakon šest dana 18. travnja 1911. godine.643 Za vrijeme boravka u Stenjevcu bolničari
bilježe njezine riječi u kojima Magda izražava strah od nečeg što naziva „limba”. Čini se da
bolničari ne razumiju na što Magda točno misli, niti su odviše zainteresirani za govor starice na 183 samrti kojoj nisu ni postavili dijagnozu. Magda govori da se „limba” nalazi na zemlji ili u zraku i
da je se ona boji i moli joj se. U liječničkom izvješću Magda govori o „limbi” kao o kazni:
„Ona ovu rieč često opetuje. Izgleda kao da joj daje značenje njekakove kazne. Uvijek je u
njekom strahu. Hoće da plače i plaštljivim glasom govori: Zabadava je- zabadava plakati sada. Sad je već zavezano... 644 Ibid.
645 KPV, 1911: 7708.
646 KPV, 1880: 57.
647 KPV, 1895: 2327.
648 KPV, 1895: 2711.
649 Župić, 1937: 344. ,
649 Župić, 1937: 344. 6.4. Strah od natprirodnog Molim se bogu, ali najviše limbi...644 Moguće je da je Magda na samrti govorila liječnicima o svom strahu od Čistilišta, te da je Magda
personificirala Čistilište. Naravno, budući da je Magda smatrana duševno bolesnom i da je
postojao velik jaz u obrazovanju i statusu između nje i liječnika, oni su na njezine izjave o
„limbi” jednostavno gledali kao na besmislicu. U brojnim izjavama štićenika, centralno mjesto
njihovih strahova zauzima vrag kao natprirodna prisutnost utjelovljena u stvarnim neprijateljima
iz njihove okoline. Prosjakinja Franjica C. iz okolice Delnica, koju su u Stenjevec sproveli
redarstvenici je vidjela vraga upravo u njima. Franjica je došla u Stenjevec u velikom strahu i
„vidjela vraga u svakom i svakog se plašila, naročito redara u koje se vrag pretvorio i koji ju
tjeraju po općinskim zatvorima”. 645 Štićenici često optužuju vragove sa svoje tjelesne tegobe. Posjednik Martin B. tako govori da su tri vraga došla u njega i da mu izazivaju tegobe u udovima
i trbuhu.646 Ilinka Dj. iz Leskovca tvrdila je da u sebi ima vraga koji joj ne da jesti 647, Roza M. iz
Ogulina je tvrdila da joj vrag „neda gutati jer joj na grlo navaljuje” i da joj „kuca po svim
žilama”648. Na puno slikovitiji način je svoje tjelesne tegobe opisao pjesnik Vladimir Vidrić koji
se liječnicima požalio da ga „čop tunje po trbuhu peha”649 (ujeda ga velika tuna koja mu je u
trbuhu). Iako se vjerojatno radi o slikovitim opisima tjelesnih tegoba, koja su ponekad bila
povezana s pučkim vjerovanjima o natprirodnom uzroku bolesti, liječnici i bolničari ih predano
bilježe kao i sve ostale oblike vjerovanja u natprirodno koje bolesnici izražavaju. U stenjevačkim povijestima bolesti i ranijim liječničkim izvješćima strahovi od natprirodnog
zauzimaju daleko značajnije mjesto nego strahovi od siromaštva. Liječnici ih temeljito zapisuju,
ponekad tražeći od štićenika da dodatno pojasne svoja vjerovanja. Primjer intervjua sa Spasojem
S., nadničarom iz Đakova pokazuje kako liječnici potiču govor o neobičnim i bizarnim
vjerovanjima kod štićenika. Spasoje je doveden u Stenjevec 1911. godine i u Stenjevcu je ostao 184 samo četrnaest dana prije premještaja u Pakrac. U liječničkom izvješću stoji da ga je brat dao u
bolnicu jer „razbija i prijeti polovici sela ubojstvom”650. Općinski liječnik u Đakovu podvrgava
Spasoja detaljnom ispitivanju u kojem naročitu ulogu igraju Spasojeva neobična vjerovanja
vezana uz crne mačke i pse, i religijske prizore: „Da li ste čuli ili opažali štogod osobita u toj kući? 650 KPV, 1911: 8120. ,
651 Ibid. ,
651 Ibid. 651 Ibid. 6.4. Strah od natprirodnog Jest, jednu noć došla neka velika šarena
mačka, krijesile joj se oči, išla oko moje glave dva puta, čupkala me po nogama i tražila
mlijeka, zacvilila i nestalo je. Možda ste još nešto čuli ili viđali? Opet došla crna mačka,
prevraćala moje cipele, neznam što je ćela i uvijek mi cipele razvrnute, a ja znam kako sam ih
ostavio...i opet neki veliki crni pas, neznam što je ćeo, možda kosti tražiti...(to kaže s
porugom)Jednoč sam sanjao, ali nisam spavao, a nešto kraj mene prođe, šušne zvizne i sađe nad
mene, a ja kažem, da ću u dubine morske, a ono pod mene, a ja kažem da ću u visine nebeske-a
tad to krilima mane, pravo sam čuo krila, popiša se i odleti...Šta izvađate iz toga? Ne odgovara. Jednoč sam sanjao: Vidim Frušku goru ili kako je zovu, s jedne joj strane ženska u bijelom
odijelu, s druge ikona, križ, na vršku zlatna kruna, oko nje andjeli. To govori bolestnik osobito
tajanstveno zadovoljnim licem...Jeste još što čuli i vidjevali? U toj kući ustalo rano ujutro malo dijete, neznam čije i šta je ćelo, došlo do mene, otišlo, išlo se
umivati, otišlo napolje, a oni rekli: oće se jačati ─ a bilo je četiri sata. Vidio sam bijelu ženu-bila
je gola, išla prema meni i ja sam bio gol, ona mi kaže: odi na desno, a ja ću na lievo- a ja podjem
na lijevo a ona na desno ode. I ljetos se nješto javljalo, došlo u cipelama.”651 Liječnik u razgovoru sa Spasojem pokazuje interes za njegove riječi u trenutku kad Spasoje
počne govoriti o crnim mačkama, životinjama koje su tradicionalno vezivane uz okultizam i
čarolije. Iz kasnijih liječnikovih primjedbi daje se iščitati da Spasoje neke od svojih crtica o
natprirodnim događajima i snovima „govori s porugom” i „sa zadovoljnim izrazom lica” kao da
ga zabavlja liječnikov interes za pučka praznovjerja (u Stenjevcu, Spasoje nijednom ne spominje
praznovjerne priče o ženama u bijelom i crnim mačkama). U zapisima iz Stenjevca svako se spominjanje natprirodnog ili straha od vještica, vragova ili
sličnih bića gleda u kontekstu patološkog. Pritom se ne razlikuju vjerovanja koja potječu iz
folklora, slikoviti opisi koji se utječu religijskom ili magijskom imaginariju i opisi halucinacija i
deluzija. Elementi natprirodnog, bilo da se radi o elementima pučke predaje ili kršćanske ,
651 Ibid. 185 religioznosti podjednako su zastupljeni kod štićenika svih zanimanja i svake razine obrazovanja. 6.4. Strah od natprirodnog U slučaju bića koja u predaji imaju ulogu čudovišta vjerovanje u natprirodno je isključivo vezano
uz osjećaj straha ili strepnje pred kaznom u zagrobnom životu. Taj strah bio je izvorom patnje za
mnoge stenjevačke štićenike, a često je javno iskazivanje tog straha bilo uzrokom njihove
hospitalizacije. Spominjanje religioznih navika u obrascu liječničke svjedodžbe kao dokumenta
na osnovu kojeg se primalo štićenike u Stenjevec pokazuje da se u okviru psihijatrije formiralo
poimanje religioznosti koje se smatralo „normalnim”. Iako konkretne vjerske navike koje se
smatraju „normalnim” izražavanjem vjerskih osjećaja nisu nigdje eksplicirane, strah od
natprirodnog nije bio u skladu s koncepcijama religioznog iskustva prevladavajućima u okviru
kulture obrazovanog građanstva. Te koncepcije su strahu od božanskog pretpostavljale izgradnju
odnosa s Bogom temeljenog na racionalnom poimanju vjere i tradicionalnom građanskom
moralu. Manifestacije pučke religioznosti koje su konfesionalnom nauku pristupale na emotivniji
i mističniji način, te ju povezivale s različitim magijskim praksama i eklektičnim vjerovanjima
dočekivane su s nerazumijevanjem ili bivale otpisivane kao znak praznovjerja, a u nekim
slučajevima i patologije. 6.5. Strah od nasilja Povezanost nasilja i duševne bolesti predmet je brojnih rasprava u psihijatriji devetnaestog
stoljeća. Od samih početaka psihijatrije vode se rasprave o tome spadaju li nasilni zločini u
domenu psihijatrije ili se njima treba baviti represivni i pravosudni aparat. S druge strane,
štićenici psihijatrijskih institucija često su bili izloženi nasilju okoline prije dolaska u zavode,
nerijetko su bili žrtvama nasilja od strane bolničara ili drugih štićenika i često su izražavala strah
od nasilja, bilo da je objekt tog straha bilo nešto izvan same institucije ili su čin
institucionalizacije shvaćali kao čin nasilja koji je uvod u daljnje nasilje. Analiza straha od nasilja
počivat će na dijakronijskom opisu svih navedenih strahova. Odnos prema strahu i nasilju
oblikovan je u podjednakoj mjeri iskustvima i emocijama štićenika kao i iskustvima i emocijama
liječnika. Zbog činjenica da su liječnici živjeli u samom krugu psihijatrijske institucije njihov
strah od nasilja je mogao utjecati na emotivnu atmosferu koja je vladala u okviru zavoda, čak i
ako nije bio ekspliciran. Ivan Žirovčić u svom članku „O postupku s duševno bolestnimi” naglašava razliku između
postupanja s bolesnicima u predmedicinskim društvima i postupanja u modernim psihijatrijskim
institucijama. Žirovčić izdvaja dva načina na koje se duševno oboljele tretiralo prije pojave 186 moderne psihijatrije od kojih su oba vezana uz strah od duševno oboljele osobe. Prvi je
strahopoštovanje pred duševno oboljelim kao pred „mudracem ili prorokom” koje, prema
Žirovčiću obilježava tretman bolesnika kod „nekih primitivnih naroda”652. Nasuprot toma postoji
izdvajanje bolesnika iz društva motivirano strahom kojeg Žirovčić smatra praznovjernim i
povezuje s vjerovanjem u nadnaravni uzrok duševne bolesti. Povijesni strah od duševno oboljelih
Žirovčić dočarava opisom nekadašnjih ludnica koja postaju mjesta na kojima su zatočeni ljudi od
kojih društvo strahuje i koje smatra nepoželjnima: „Ludnice prošlih vremena bile su tamnice, u kojih su umobolnici u debelih zidinah, iza
željeznimi rešetkami, često još okovani i prikovani, u skrajnoj biedi čamili i, prepušteni
nemilosrdnosti surovih stražara, jadno pogibali, a nikomu nije bilo na kraj pameti, da bi
nesretni umobolnik kraj milosrdnijega i razumnijega postupka možda još mogao ozdraviti ili
bar donekle opet dospjeti do čovječanskoga dostojanstva”653 Naravno, Žirovčić predstavlja psihijatriju kao humanu disciplinu koja je vođena razumnim i
znanstvenim poimanjem duševne bolesti kao bolesti organizma. Samim time i suvremeni će
zavodi biti opisani kao mjesta humanosti u kojima je strah ustupio mjesto razumu i milosrđu. 652 Žirovčić, 1897: 320. ,
653 Ibid: 322. 654 Ibid: 322-333. ,
653 Ibid: 322. 654 Ibid: 322-333. 6.5. Strah od nasilja No,
Žirovčić je svjestan toga da je javno poimanje psihijatrijskih institucija i dalje obilježeno
strahom: „Pa ipak lebdi nad timi dvorovi najplemenitijega ljudskoga milosrdja prokletstvo stare
surovosti, jer se još i dandanas mnogi ljudi žacaju svoje bolestnike u ludnicu predati, bojeći se
zlostavljanja, silovita postupka i potajnih mučila, bez česa si ne mogu pomišljati liečenje
umobolnika. Javno mnienje je neobično osjetljivo u pogledu ludnica, pa ako se gdjekad u njih
dogodi kojemu bolestniku nesreća, eto krike i vike po svih novinah, eto strke pozvanih i
nepozvanih, da njuškaju, prisluškuju, pretjeravaju, izvraćaju i sumnjiče; a ne pomišljaju, koliko
se nesreća odvraća i spriečuje svaki dan u ludnicah. gdje je u mnogobrojnih bolestnih dušah
nagomilano toliko užasnih strasti i razvratne napetosti, koja elementarnom silom provaljuje
proti vanjštini i vlastitom omraženomu životu, a da se takova nagla i časovita provala
bezrazumne uzbudjenosti kadkada niti najpomnijom pozornošću zapriečiti ne da ; ne
pomišljaju, koliko je pogibelji, nesreće i štete odklonjeno od ljudskoga družtva, ako se
umobolnici za vremena smjeste u ludnicu.„654 187 Iako Žirovčić nastupa s pozicije modernog i znanstvenog poimanja ludila, njegov diskurs još
uvijek odaje strah od nekih manifestacija duševne bolesti. Kad govori o unutarnjem svijetu
duševno oboljelih, Žirovčić napušta objektivni diskurs i počinje se služiti emotivima. U
„dušama” psihički bolesnih su nagomilane „užasne strasti” i „razvratna napetost,” a njihova je
uzbuđenost „bezrazumna” i događa se u provalama. Na početku članka Žirovčić će predstaviti
duševnu bolest kao znanstveno spoznatljiv proces kojeg je moguće razumjeti u okvirima
somatičke medicine i prirodnih znanosti, da bi čim počne legitimirati nesreće koje se događaju i u
modernim institucijama počeo govoriti o štićenicima kao osobama čije strasti mogu izazvati užas
i čiji se postupci i motivacija često nalaze onkraj razuma. Uređene psihijatrijske institucije su
temelj terapijskog autoriteta na kojeg se Žirovčić poziva, no Žirovčić će ih u istom članku
predstaviti i kao sigurnosnu mjeru protiv nasilja duševno oboljelih:”Radi pogibelji, koja od
poremećena razuma, čuvstva i volje duševnoga bolestnika prieti,. 655 Ibid: 333. 656 Ibid: 324. 6.5. Strah od nasilja a za dobro i korist bolestnika
samoga najshodnije jest, da se preda u ludnicu, koja je za liečenje i njegovanje umobolnika
valjano uredjena...”655 Usprkos činjenici da Žirovčić ističe neke duševno oboljele kao opasne za
društvo, njegov članak također osuđuje predrasude i stigmatizaciju duševno oboljelih potaknutu
strahom: „Ljudi ne samo da se nekako instinktivno žacaju ludnice, već bolestnika, koji je bio u ludnici,
te iz nje, makar zdrav, izašao, žalibože susretaju i motre nekom plahošću, kao da je na njemu
ostala neka sramotna ljaga, dočim boravak u bolnici nikoga ne sramoti. Ovakove predsude
spadaju, poput mnogih drugih, u slabosti, nepravednosti i nedosliednosti, u ljudske mane, s
kojim! se baš mi liečnici obilno imamo boriti, te s koje borbe uviek ne izlazimo pobjednici”656
Čini se da psihijatri devetnaestog stoljeća ne dovode u vezu strah koji dio javnosti osjeća prema
duševno oboljelima i diskurs koji psihijatri ponekad koriste, a koji također povremeno izražava
strah i djeluje dehumanizirajuće. Takav stav bit će iskazan i u predavanju koje je Žirovčić u
ožujku 1898. godine održao na skupštini zbora liječnika. Predavanje nosi naslov „Ludjačka
umorstva, nazvana 'la folie rouge'”. Naslov je zanimljiv jer se u njemu Žirovčić spominje „la folie
rouge” „(crveno ludilo)” kao naziv za nasilne zločine duševno oboljelih osoba. Taj termin se
inače ne spominje u onodobnoj psihijatrijskoj literaturi i Žirovčićevo predavanje je jedini trag
korištenja te fraze na koji sam uspio naći. Nije jasno odakle ga Žirovčić preuzima, on se na
početku predavanja poziva na novinske izvještaje o umorstvima, tako da je moguće da se u dijelu 188 tiska koristio taj termin. Žirovčić predavanje počinje osporavanjem u javnosti uvriježene
percepcije da su djela duševno oboljelih djela bez jasnog motiva, te govori da su čak i
„najgrozniji čini” duševno bolesnih motivirani mišljenjem i osjećajima, jedino su kod njih
mišljenje i osjećaji nezdravi.657 U nastavku predavanja, Žirovčić će nabrajati koja sve duševna
oboljenja mogu pogodovati počinjenju zločina. Pri tom počinje od „poremećenog” spolnog
nagona za koji kao primjer ističe „londonskog Jacka-rasparača”658 čiji su zločini pobuđivali
ogroman interes javnosti u devedesetim godinama devetnaestog stoljeća. 657 Žirovčić, 1898: 226. 659 Ibid: 227. 658 Ibid. 661 Ibid: 228. 660 Ibid. 662 Ibid: 232. 658 Ibid. 6.5. Strah od nasilja Ubrzo nakon toga
slijedi opis pogubnog utjecaja alkohola u kojem će prevladavati emotivi straha: „Patholožko pijano stanje i alkoholni delir čine čovjeka groznim strašilom, bjesnećim
razornikom, koji nožem i sjekirom, a osobito puškom, navaljuje na tudji život, budi da se baci
proti umišljenim, u snatrenju vidjenim i čuvenim napadačem, budi da si naprosto strašna
unutarnja živčana napetost probije provalu djelotvornom mišićnom trzavicom.”659 Uz alkoholičare, kao predmet straha su predstavljeni i epileptičari- epileptičar tako „počinja u
ludilu strašan pokolj” o epilepsiji se govori kao o „sablasti” a ako je „mišićnu trzavicu
epileptičara strašno vidjeti, delir epileptičara je strašan sadržajem”.660 Osobe koje pate od
epilepsije opisane su nizom epiteta koji ih tretira kao emotivno i duševno nestabilne, moralno
manjkave i gotovo isključivo opasne za društvo: „ ...epileptičari odavaju i u svojem karakteru
silovitu ćud, ujedljivu razdražljivost, prkositu zakopčanost, tiransku nesnošljivost, naginju na
tmasto religiozno snatrenje, te se iztiču okorjelim egoizmom. Tako ustrojene individualnosti
imaju sve uvjete, da budu ljudskomu družtvu pogibeljne.”661 Žirovčić kasnije govori da i ostale
duševne bolesti, od manije, melankolije i paranoje pa do neurastenije i histerije također mogu biti
uzrokom ubojstava. Predavanja vodi prema zaključku kako je za sprečavanje zločina koje
počinjavaju duševno oboljeli potrebna bolja i suvremenija psihijatrijska skrb, valjano uređeni
zavodi za duševno oboljele i bolji rad upravnih i redarstvenih organa u nadziranju onih duševno
bolesnih koji se nalaze izvan zavoda.662 Iz ovih članaka može se zaključiti da je psihijatrijski diskurs vezan za strah od duševno oboljelih
kao potencijalno nasilnih ljudi dvojak. Psihijatri se s jedne strane percipiraju kao nositelji
naprednih i humanih znanstvenih ideja koji trebaju legitimirati svoj položaj unutar medicine i
657 Žirovčić, 1898: 226. 189 unutar javnih politika. Legitimacija tog položaja ovisi o percepciji ludila kao medicinskog stanja
koje ima uzroke u somatskim promjenama. Samim time, oni se suprostavljaju „praznovjernom”
strahu od duševno oboljelih i njihovoj stigmatizaciji. S druge strane, način na koji se duševno
oboljeli opisuju često obiluju iskazima straha koji su tek na površini skriveni iza objektivnosti i
racionalnosti znanstvenog diskursa. Takav naizgled paradoksalan stav je vjerojatno posljedica
negativnog kogniziranja straha unutar emotivnog režima građanske klase. Budući da se strah
smatra nelegetimnim, njegove se manifestacije nastoji gurnuti u drugi plan ona kada se nastoji
tvrdnjama dati znanstveni legitimitet. U slučaju da su psihijatri bili nesvjesni toga da je njihov
strah vidljiv u formulacijama kojima su opisivali duševno oboljele, radi se o potiskivanju emocija
kako bi se postigao dojam znanstvene objektivnosti. 663 Ahmed, 2014: 65. 6.5. Strah od nasilja S druge strane, moguće je da je imagem
duševno bolesne osobe bio svjesno konstruiran tako da ih se predstavi kao istovremeno osobe
koje trebaju medicinsku skrb i osobe opasne za društvo. Takvim naoko kontradiktornim
imagemom „luđaka” u kojem se spajaju figura čudovišta i figura žrtve legitimira se psihijatriju
kao granu medicine koja štiti društvo od o nereguliranog ponašanja duševno oboljelih. Za razliku od psihijatara, štićenici Stenjevca nemaju problema s izražavanjem svog stvarnog ili
imaginarnog straha od nasilja, a u okviru institucije tim se „snažno” artikuliranim strahovima
pridaje daleko veća pažnja nego „slabo” artikuliranim strahovima psihijatara i šire javnosti. Ponekad je strah od nasilja samo usputan i ima karakteristiku instinktivnog, i intenzivnog
visceralnog straha kojim se anticipira nešto što će osobi naškoditi ili ju tjelesno ozlijediti.663
Primjeri takvog straha su brojni i oni se naročito često susreću kod štićenika kojima su
dijagnosticirane takozvane „afektivne psihoze” - manija i melankolija. Angjelia R. iz Ogulina
razboljela se u ljeto 1911. godine (dijagnosticirana joj je „melancholia”) i u Stenjevcu neprestano
govori o vlastitim strahovima: „14. 6. Bolesnica hoda okolo i gleda kao da se koga plaši i kaže da će izgorjeti i da će ju netko
ubiti, svaki čas traži jesti, a kad joj se dade, onda neće, već sve razbaciva, navečer se neda
nikako u postelju. 5.7. Nemirna, neprestano traži, da bi se objesila ili izgorjela ili da bi ju tko htjeo ubiti. Moli da
ju odvedemo tamo, gdje ima vukova, da ju požderu; plačući prosi, da joj ne produljimo života. 190 12.8. Neprestano hallucinira, vidi kako selo gori, plače da su joj djeca izgorjela, posvema
smetena hida neprestance okolo, po noći nemirna, mora biti u samici, premještena sa IX b na
XI.”664 Angjelijino stanje straha i smetenosti trajat će sve do njezine smrti od enteritisa u kolovozu 1911. godine. Instinktivni strahovi od nasilja različito identificiraju mogućeg počinitelja nasilja. Manda
K. iz Jasenovca užasno se bojala vlastitog oca, a strah je bio potaknut epizodom u kojoj je njezin
otac tukao konje: „Pred osam dana poplašili se konji njezinom ocu, on ih je toga radi nemilosrdno tukao i vikao
na njih-ona ga išla miriti, a otac se izdere na nju, da ga pusti na miru. Neka žena koja je bila
prisutna, upozorila je bolesnicu, neka se oca rad kani, jer je u istoj zgodi htio njezin otac majci
odrezati sjekirom ruku, jer ga išla uzrujanoga miriti. 667 Freud, 2010: 2147. 666 KPV, 1911: 7840. 665 KPV, 1914: 7886. 6.5. Strah od nasilja U svojim zbrkanim pismima, Mijo izražava strah da ga
stanovnici te kuće žele tući jer je odbio brak s nekom djevojkom. Od bana je zahtijevao da se svi
iz navedene kuće, (uključujući i kućevlasnika i njegovu obitelj) isele jer zbog straha od njih više
ne može nikud ići. Uz to, traži da svatko tko mu bude prijetio bude smrtno kažnjen, te da mu ban
da garanciju da ga nitko ne može privoljeti na ženidbu s tom djevojkom jer će se on „radije
utopiti u Savi nego ženiti.”668 Gradsko poglavarstvo je na Mijina opetovana pisma reagiralo tako
da je odredilo konzilij liječnika koji će ga pregledati. Liječnički konzilij uputio je Miju u
Stenjevac. Mijo je u Stenjevcu bio u dva navrata- prvi put od 13. lipnja 1905. do 17. kolovoza
1905. kad je otpušten kao poboljšan, drugi put je doveden od majke 7. veljače 1906., a ostao je u
Stenjevcu do svoje smrti od tuberkuloze pet godina kasnije, ponašajući se uglavnom mirno. Miji
je postavljena dijanoza „imbecilitas originario” (urođena slaboumnost) kojoj je kao uzrok
postavljena jednostavno „degeneracija”. Ipak kako Miju u pisanju ne odaje ispodprosječno
obrazovanje niti teškoće u intelektualnom razvoju, vjerojatno su liječnici postavili navedenu
dijagnozu kako bi naznačili da se Mijo nalazi na Maudsleyevom „borderlandu” između duševno
oboljelih i zdravih pojedinaca. Iz iskaza koji je Mijo dao čini se da se Mijo na čudan način
osjećao neku vrst obaveze prema nekoj neimenovanoj djevojci iz susjedstva kojoj je pisao i
možda udvarao. Nakon što je odlučio da se ne želi oženiti njome, primijetio je da ga „seljaci”
motre i žele tući. Ljudi s navedenog kućnog broja su ga više puta zvali da ide sa njima šetati „na
ciglanu ili u Maksimir”. 669 Mijo je bio uvjeren da ti pozivi znače da ga oni žele tući jer je bio
siguran da ga oni mrze jer ne želi oženiti spomenutu djevojku. Mijo osjeća kao da je po
obrazovanju i statusu iznad svojih susjeda- opisuje ih kao „seljake”, a sve njegove misli vrte se Primjer straha od nasilja nalazimo kod stenjevačkog štićenika Mije P.. Mijo P. bio je sin sitne
trgovkinje iz Zagreba koji je sa svojom majkom živio na Maksimirskoj cesti. Tijekom 1905. i
1906. godine napisao niz pisama banu Teodoru Pejačeviću potaknut strahom od susjeda koji su
živjeli u kući na broju sedamdeset. 668 KPV, 1911: 6403. ,
669 Ibid. 6.5. Strah od nasilja Od toga se bolesnica toliko uplašila i od
osam dana stala vikati, plašiti se, da će je ko ubiti, vikala o sjekiri, puškama itd.”665 Jana L. iz Vidovca smatrala bojala se da će biti izložena izrazito brutalnom nasilju kao kazni za
grijehe. Gotovo čitava Janina povijest bolesti se sastoji od njezinih grafičkih opisa vojski i
„kanona” i kazni kojima će biti izložena:„Danas se uzrujala – u velikom strahu plače i viče, da
mora pobjeći, jer već cijelu noć pucaju kanoni za njom, da ju ubije, a ovi da joj hoćaju oči
iskopati i glavu sjeći, da joj srce izvade i njezino tijelo da na komade sasjeku i onda viče: a joj,
joj, kaj bude z mene”666 Takvi strahovi su jednostavno artikulirani i kod njih se ne preciziraju motivi zbog kojih bi netko
htio nauditi osobi koja se boji. S druge strane, postoje štićenici čiji su strahovi od nasilja često
elaborirani i imaju elemente cjelovitih i kompleksnih narativa fokusiranih na opasnost od
percipiranih neprijatelja. Objektu straha je tu često prilično jasno definiran, a štićenici mu
pripisuju namjeru i motiv, te izražavaju opsesivan strah za vlastitu sigurnost i sigurnost svojih
najbližih. U takvim slučajevima strah često opsjeda štićenike i čitav njihov pogled na svijet biva
oblikovan odnosom prema prijetnjama i iznalaženjem načina kako ih izbjeći. Sigmund Freud je
analizirajući povijest bolesti i terapiju svog slavnog pacijenta „Čovjeka Štakora” osjećaj stalne
strepnje pred nasiljem povezao s njegovim potisnutim agresivnim i/ili seksualnim impulsima. Kod „Čovjeka-štakora” često se radilo o agresivnim mislima usmjerenima prema ljudima za koje
je vjerovao da stoje na putu između njega i djevojke koja mu se sviđala.667Na kraju, „Čovjek- 191 štakor“ je, kako bi zaštitio svoj ego od nasilnih misli, iznašao čitav niz opsesivnih
hiperracionalizacija i hiperintelektualizacija koje su ga trebale zaštiti od nasilnih kompulzija. Iako
je upitno može li se Freudova analiza specifičnog slučaja primijeniti i na emotivna iskustva
stenjevačkih štićenika, seksualne i nasilne fantazije su često bitan dio njihovih strahova i često
bivaju više ili manje otvoreno artikulirane u njihovim svjedočanstvima. Primjer straha od nasilja nalazimo kod stenjevačkog štićenika Mije P.. Mijo P. bio je sin sitne
trgovkinje iz Zagreba koji je sa svojom majkom živio na Maksimirskoj cesti. Tijekom 1905. i
1906. godine napisao niz pisama banu Teodoru Pejačeviću potaknut strahom od susjeda koji su
živjeli u kući na broju sedamdeset. 6.5. Strah od nasilja U svojim zbrkanim pismima, Mijo izražava strah da ga
stanovnici te kuće žele tući jer je odbio brak s nekom djevojkom. Od bana je zahtijevao da se svi
iz navedene kuće, (uključujući i kućevlasnika i njegovu obitelj) isele jer zbog straha od njih više
ne može nikud ići. Uz to, traži da svatko tko mu bude prijetio bude smrtno kažnjen, te da mu ban
da garanciju da ga nitko ne može privoljeti na ženidbu s tom djevojkom jer će se on „radije
utopiti u Savi nego ženiti.”668 Gradsko poglavarstvo je na Mijina opetovana pisma reagiralo tako
da je odredilo konzilij liječnika koji će ga pregledati. Liječnički konzilij uputio je Miju u
Stenjevac. Mijo je u Stenjevcu bio u dva navrata- prvi put od 13. lipnja 1905. do 17. kolovoza
1905. kad je otpušten kao poboljšan, drugi put je doveden od majke 7. veljače 1906., a ostao je u
Stenjevcu do svoje smrti od tuberkuloze pet godina kasnije, ponašajući se uglavnom mirno. Miji
je postavljena dijanoza „imbecilitas originario” (urođena slaboumnost) kojoj je kao uzrok
postavljena jednostavno „degeneracija”. Ipak kako Miju u pisanju ne odaje ispodprosječno
obrazovanje niti teškoće u intelektualnom razvoju, vjerojatno su liječnici postavili navedenu
dijagnozu kako bi naznačili da se Mijo nalazi na Maudsleyevom „borderlandu” između duševno
oboljelih i zdravih pojedinaca. Iz iskaza koji je Mijo dao čini se da se Mijo na čudan način
osjećao neku vrst obaveze prema nekoj neimenovanoj djevojci iz susjedstva kojoj je pisao i
možda udvarao. Nakon što je odlučio da se ne želi oženiti njome, primijetio je da ga „seljaci”
motre i žele tući. Ljudi s navedenog kućnog broja su ga više puta zvali da ide sa njima šetati „na
ciglanu ili u Maksimir”. 669 Mijo je bio uvjeren da ti pozivi znače da ga oni žele tući jer je bio
siguran da ga oni mrze jer ne želi oženiti spomenutu djevojku. Mijo osjeća kao da je po
obrazovanju i statusu iznad svojih susjeda- opisuje ih kao „seljake”, a sve njegove misli vrte se 192 oko ženidbe iako nigdje ne navodi je li djevojka kojom je opsjednut uopće u bilo kakvoj vezi s
ljudima koji mu navodno žele nauditi. U Mijinim opsesivnim mislima nije teško vidjeti
svojevrsnu patološku opsesiju tom djevojkom, iako iz oskudne povijesti bolesti ne možemo točno
razabrati prirodu njihovog ranijeg odnosa. 672 Ibid: 34. 670 Ibid.
671 Žirovčić, 1911: 33. 672 Ibid: 34. 673 Ibid. 673 Ibid. 670 Ibid. 6.5. Strah od nasilja U jednom od svojih pisama banu Pejačeviću Mijo
odaje i opseg svojih elaboriranih iluzija i svoju percepciju vlastitih susjeda kao „primitivnih”: „Na Maksimirskoj cesti u Zagrebu – gdje je naobraženje na vrlo niskom stepenu- tamo mu
ljudi ne daju mira, groze mu se, htjeli su ga tući, a možda i ubiti, imali su bičeve i željezne
štange za njega u pripravi, što je na svoje oči vidio. Inače je takodje sa svih strana čuo, kako se
njegovi neprijatelji dogovaraju, da će ga tući.”670 Jedini uzrok psihičkih poteškoća Mije P. liječnici su vidjeli u „hereditarnoj degeneraciji”.i čini se
da , nakon potvrde da je zbilja psihički bolestan, nisu posvećivali nikakvu pažnju niti njemu niti
njegovim elaboriranim strahovima. Nekoliko godina kasnije prilikom psihijatrijsko-forenzičkog vještačenja makedonskog radnika
Stojana Blažova s kraja 1909. i početka 1910. godine, Žirovčić će u svojem stručnom mišljenju
povezati hereditet, tjelesnu slabost i predrasude o „primitivizmu”. Stojan Blažov uhapšen je na
željezničkoj stanici u Zaprešiću nakon što je iz revolvera ustrijelio dvojicu putnika. U iskazu pred
sudom izjavio je kako se vraćao kući s rada u Sjedinjenim Državama. Na austrijskoj granici u
vlak je ušla grupa ljudi, po govoru Hrvata ili Srba koja se počela došaptavati i pogledavati prema
njima. Kad su u Zidanom mostu trebali presjedati u drugi vlak, neznanci su ga slijedili. Pri
dolasku u Zagreb postalo je „njihovo dogovaranje već tako opasno, da je on bio prisiljen njihovoj
navali predusresti: stoga je izpalio u svakoga od poginule dvojice po dva hitca, a onda je hotio
sebi u čelo, ali je taj hitac zatajio” 671. Budući da se na sudu činilo da njegov postupak nije imao
jasnog motive, Stojan Blažov je predan na vještačenje u Stenjevec. U zavodu se Blažov ponašao
mirno. Uglavnom je provodio vrijeme čitajući i družeći se s „inteligentnijim” štićenicima
zavoda.672 Pri ispitivanju detaljno je govorio o svom teškom životu, koji je od mladosti bio
ispunjen nasiljem i strahom. Odrastao je u mjestu Gorno Vodno nedaleko Skopja i u ranoj
mladosti (prilikom ispitivanja bio je star trideset i dvije godine) je izgubio oca i majku zbog
bolesti, a mlađeg brata u bizarnoj nesreći s vatrenim oružjem.673 Sam se uzdržavao i završio
preparandiju no nije mogao naći službu kao učitelj jer se protivio „turskom nasilju”. Prije studija 193 u preparandiji, imao je kraći živčani slom od kojeg se oporavljao kod kuće. 6.5. Strah od nasilja Zbog toga je otišao u
Bugarsku gdje je radio kao nadcestar u Ruščuku (danas Ruse u Bugarskoj). Pri povratku u
Makedoniju, išao je kraćim putem kroz Srbiju gdje su ga srpski policajci uhapsili kao špijuna i
izgladnjivali u zatvoru, te je pušten tek na intervenciju otomanskih vlasti u Makedoniji. Tada je
počeo sumnjati da ga njegovi neprijatelji iz Makedonije denunciraju iz političkih razloga i
odlučio otići u Ameriku. Mukotrpno je radio kao nadničar, tvornički radnik i građevinski radnik
u Virginiji, a tamo se konstantno bojao da mu netko ne ukrade teško zarađen novac. Zaradivši
oko 1500 kruna, odlučio se sa dvojicom sunarodnjaka vratiti u Makedoniju. Put je bio iscrpljujuć,
vlakovi tijekom cijelog puta pretrpani ljudima, a Blažov se tijekom prekooceanske plovidbe
razbolio od neke groznice. Također, čini se da su i Blažov i njegovi makedonski suputnici proveli
cijeli put u strahu da ih netko ne okrade: skanjivali su se kupovati hranu i izlaziti iz vlaka na
postajama u inozemstvu da netko ne vidi kako imaju novaca i orobi ih, pa su u četiri dana jeli
samo dvaput. Također, budući da od Engleske do Zidanog mosta nisu izlazili iz željezničkih
vagona, bili su izrazito dezorijentirani, tako da je Blažov od svih mjesta na kojima je vlak stajao
zapamtio samo Le Havre u Francuskoj.674 Također, među radnicima u Sjedinjenim Državama
kružila je priča o ubojstvu hrvatskih povratnika iz Amerike koje se navodno dogodilo negdje u
Engleskoj kad su neki prevaranti „prodali Hrvatom smrdljiva mesa , koje oni nisu htjeli uzeti
odatle proizašle svadje i osvete”675 Blažovljev strah se intenzivirao nakon prelaska austrijske granice kad su u njegov kupe ušli ljudi
koji su govorili nekim slavenskim jezikom. Velik dio Blaževljevog straha upravo je došao iz
činjenice da su to bili prvi suputnici čiji je jezik mogao bar djelomično razumjeti i interpretirati u
svjetlu svojih strahova. 674 Ibid.
675 Ibid.
676 Ibid: 35.
677 Ibid: 36.
678 Ibid. 6.5. Strah od nasilja Jedan od tek pridošlih putnika počeo je tako ispitivati Blažova o tome
koliko ima novaca.676 Drugi je pak prilikom ručka u vagon-restoranu govorio nešto o nagovaranju
nekog da pije pivo, što je Blažov protumačio kao njihovu namjeru da opiju stražara na stanici.677
Ubrzo nakon toga, jedan od kasnije ubijenih putnika rekao je da „popiju pivo sad jer kasnije neće
biti raspoloženi, što je Blažov shvatio kao „neće biti raspoloženi nakon što ga ubiju.”678
Blažovljev strah je dosegao vrhunac kad je vlak počeo izlaziti iz Zaprešića i kad su se putnici
počeli razgovarati o nekom „aktu koji moraju obaviti sad jer smo ovdje svi naši”. Jedan od 194 putnika spomenuo je da u kupeu ima i Bugara na što je njegov sugovornik opsovao majku
Bugarima. Nakon toga je jedan od Hrvata ustao i približio se Blaževu, a Blažev je u strahu
izvadio revolver i počeo pucati, ustrijelivši dvojcu putnika. Nakon toga je pokušao počiniti
samoubojstvo, ali mu je revolver zapeo, pa je pobjegao u pisarnu na željezničkoj stanici i prijavio
se vlastima.679 Blažev je kasnije shvatio da je njegov strah bio neopravdan i izrazio žaljenje zbog zločina,680 no
rekao je da je prilikom putovanja pretpostavljao da pravi motiv njegovih ubojica leži u tragičnoj
pogibiji njegovog brata. Naime, Blažev je vjerovao da njegov sumještanin koji je slučajno
ustrijelio njegovog brata strahuje od moguće krvne osvete pa je unajmio grupu ljudi da ga ubiju
na putu.681 Životna priča Stojana Blaževa obiluje primjerima nasilja koje mu se događalo- od smrti brata
ustrijeljenog u igri puškom, preko političkog nasilja u Makedoniji na prijelazu stoljeća, do
brutalnog i opasnog života fizičkog radnika u SAD-u. U svojoj priči Blažev prenosi iskustvo
osobe koja se nikad i nigdje nije mogla opustiti i čije su dotadašnja iskustva često uključivala
nenadane primjere ekstremnog nasilja, poput njegovog uhićenja na srpsko-bugarskoj granici gdje
je prošao ponižavanje, zatočenje, izgladnjivanje i mučenje.682 Žirovčić njegovu bolest opisuje kao
„progonstveni obman” ili „paranoia persecutoria”.683 „Progonstveni obman” Žirovčić definira kao
stanje u kojem „kritika razuma iščezava i varave zamjetbe djeluju na bolesnika poput realne
istine” i u kojem su navedene varke neprijateljskog sadržaja. Žirovčić, očekivano, gleda na stanje
Stojana Blaževa kroz prizmu herediteta i metaboličkih procesa, što je dijagnostički okvir koji
često primjenjuje. Pri pregledu Stojana Blaževa Žirovčić nije uočio vidljive „stigme” hereditarne
degeneracije. 679 Ibid.
680 Ibid: 35.
681 Ibid: 36.
682 Ibid.
683 Ibid: 37.
684 Ibid: 38.
685 Ibid: 37. 686 Ibid.
687 Ibid: 38. 6.6.Paranoidne mreže i strah od moći države Neki od štićenika demonstriraju strah od suptilnijeg strukturalnog nasilja, a to je nasilje
represivnog aparata države. Iako su reakcije psihijatara na te strahove iste kao i reakcije na ostale
strahove od nasilja, njihovi emotivni i narativni mehanizmi kojima se štićenici služe su ipak
specifični i odražavaju jednu vrstu jedinstvenog pogleda na institucionalnu moć države odozdo,
koja dolazi s margina modernizirajućeg društva. Jedan od posljedica procesa modernizacije,
prisutan od Ranog novog vijeka naovamo svakako je jačanje državne administrativne moći i
širenja njezinog represivnog i nadzirućeg aparata. U devetnaestom stoljeću taj represivni državni
upliv biva naročito izražen na polju borbe protiv zločina i poroka koja predstavlja državu kao
zaštitnika moralnog poretka.688 Ti aparati nadzora nisu samo simptomi porasta anksioznosti u
društvu nego i sami mogu potaknuti osjećaj anksioznosti i otuđenosti istovremenom
impersonalnošću i sveobuhvatnošću vlastitog utjecaja na ljudska tijela i na prostor kojim se ta
tijela kreću. Delumeau navodi jedan rani primjer takvog mehanizma nadzora kad, parafrazirajući
Montaignea govori o sustavu dvostrukih vrata na ulazu u grad Augsburg u 16. stoljeću: „Putnici se najprije nađu pred jednim vratima koja prvi stražar, čija se odaja nalazi na sto
koraka odatle, otvara sa svoga mesta pomoću gvozdenog lanca, koji zaobilazno i s mnogo
zaokreta povlači jedan- također gvozdeni- klin. Pošto se prekorači prag, vrata se najednom
ponovno zatvaraju. Posetilac zatim prelazi most iznad gradskog šanca i stiže na malu zaravan,
gde pokazuje svoje isprave i daje adresu na kojoj će boraviti u Ausburgu. Stražar onda zvonom
obaveštava kolegu koji okreće oprugu smeštenu u prokopu blizu njegovu odaje. Ova opruga
otvara najprije jednu pregradu- takođe gvozdenu- zatim pomoću velikog točka, diže pokretni
most a da se od svih tih pokreta ne može ništa opaziti: jer oni se obavljaju kroz otvore u zidu i
vrata, i sve se najednom ponovno zatvara uz veliku buku. Na drugoj strani pokretnog mosta
otvaraju se jedna ogromna vrata od drveta ali okovana s više velikih gvozdenih šina. Stranac
stupa u odaju gde se najednom nađe zatvoren sam u mraku. Ali druga vrata, slična prethodnim,
propuštaju ga u sledeću odaju u kojoj ovoga puta ima svetla i u sredini koje, obešena na
lancum visi jedna gvozdena posuda. U nju on stavlja novac kojim plaća ulaz. Drugi vratar
povlači lanac, uzima novac koji je posetilac ostavio i proverava njegov iznos. Ukoliko ovaj ne
odgovara utvrđenoj tarifi, vratar će ga ostaviti da dreždi do ujutro. 6.5. Strah od nasilja Zbog toga kao dokaz hereditarnog upliva, Žirovčić ističe njegovo ranije oboljenje
o kojem ga je izvijestila Blaževljeva tetka.684 Osim herediteta Žirovčić ističe da su pojavi bolesti
pridonijeli i mnogi vanjski utjecaji koji su uglavnom djelovali na Blaževljev metabolizam: težak
rad u Americi, zagušljiv zrak na pretrpanom parobrodu, nedostatak sna od straha i nepovoljnog
tjelesnog položaja i izostanak hrane.685 Iako Žirovčić navodi stres kao mogući uzrok Blaževljevog 195 mentalnog sloma, on je u potpunosti fokusiran na utjecaje stresa na tijelo jer svi navedeni faktori
„kvare svježost krvi koja hrani mozdjane”686. Pritom pridavanje krvi neodređene kvalitete poput
„svježosti” ponovno podsjeća na relikt humoralne medicine. Zanimljivo je da Žirovčić spominje i
okolnosti Blažovljevog odrastanja, ali ne kako bi objasnio njegov intenzivan strah, već kako bi
objasnio njegovu nasilnu reakciju, potkrijepljenu prilično orijentalističkom slikom samog
Blažova. Blažov je „ ...rodjen i odgojen usred divlje borbe raznih plemena med sobom i protiv
turske sile, vičan oružju, pogibelji, krvoproliću i doma i u Americi, gdje si ljudi ne samo laktom,
već i revolverom prokrčuju put...”687. Prema tome, opasna sredina u kojoj je Blažov odrastao nije
imala utjecaj na njegovu psihu koliko na njegove navike - zbog svog porijekla Blažov je
posjedovao revolver i bio ga spreman upotrijebiti ga u stanju duševne rastrojenosti izazvane
kombinacijom hereditarnih i metaboličkih faktora. Stenjevački liječnici imaju ambivalentan odnos prema strahu od nasilja i kad je u pitanju nasilje
duševnih bolesnika i kad je u pitanju strah samih štićenika od nasilja. Čini se da im je taj strah
bitan jedino kao simptom, a i u tom smislu su najbitnije vanjske manifestacije te emocije koje se
mogu promatrati medicinski. Među njima, najbitnije im je je li strah od nasilja manifestiran na
način koji bi odavao duševno oboljenje, na primjer vrištanjem ili nasilnom reakcijom poput one
Blažova. Osim toga, liječnici pokazuju interes za objekt tog straha, ali se čini da sam objekt za
njih nema dijagnostičku vrijednost, prvenstveno zato što u njihovoj dijagnostička tradiciji sama
kvaliteta emocije nema toliku vrijednost kao njezina prisutnost ili odsutnost i intenzitet i način
pokazivanja emocije. Kod straha od nasilja pritom nije bilo bitno je li on bio opravdan ili ne u
kontekstu štićenikovog životnog iskustva, iako je kod strahova navedenih u povijestima bolesti
veza s pojedinim epizodama iz života štićenika očita. 196 688 Osterhammel, 2014: 622. 688 Osterhammel, 2014: 622. ,
690 Fuchs i Hirjak, 2010: 100-101. j
,
691 Foucault, 2003: 242. 689 Delimo, 2003: 19-20. j
,
691 Foucault, 2003: 242. 6.6.Paranoidne mreže i strah od moći države Ali ukoliko je zadovoljan,
onda mu na isti način otvara jedna velika vrata slična ostalima, koja se zatvaraju čim se 197 prekorače i posetilac se nađe u gradu...ispod odaja uređen je veliki podrum za boravak pet
stotina naoružanih ljudi, zajedno s njihovim konjima pripravnih na svako iznenađenje. Ako bi
zatrebalo, šalju se u rat „bez znanja običnog sveta u gradu.”689 Delumeau ovaj mehanizam navodi kao dokaz činjenice da su vlasti Ausburga u 16. stoljeću bile u
iznimnom strahu, no ono što je još bitnije je da uređaj sam može izazvati anksioznost kod nekog
tko se susreće sa njegovim djelovanjem. Impersonalnost mehanizma (posjetitelju je otežana ili
čak onemogućena mogućnost komunikacije lice u lice s vratarima, I ne dobiva priliku za dužu
komunikaciju s istima), netransparentnost njegovog djelovanja (sam mehanizam pomoću kojeg se
vrata otvaraju i zatvaraju je nemoguće opaziti s mjesta s kojeg posjetitelj stoji, i oni koji njime
upravljaju su jednako skriveni od pogleda, a umjesto govorom komuniciraju signalima zvona),
efekt koji isti ima na osjetila (izmjena osvijetljenih i tamnih prostora, signali zvonom, čekrci i
zveket željeznih lanaca) i apsolutnost njegove moći (operator mehanizma može u bilo kojem
trenutku ostaviti posjetitelja pred vratima) mogu stvoriti osjećaj bespomoćnosti kod onih koji su
izloženi toj demonstraciji moći. Administrativna moć koja upravlja gradom dobiva efekt
neljudskosti i neumoljivosti- ona je skrivena iza rigidnog željeza i drva koje otvara i zatvara
prostor u skladu s njezinim teško protumačivima signalima, a jedini način da ju se privoli na
popuštanje je dokazivanje identiteta i pogađanje točne „tarife”. Može se reći da i sama državna
moć posjeduje sve karakteristike modernih tehnologija koje su Hirjak i Fuchs doveli u vezu s
deluzijama Tauskovih „strojeva za kontrolu” 690. Tehnologije moderne državno-administrativne kontrole imaju skrivene efekte - bilo da se radi o
mehanizmu upravljanja gradskim vratima ili mehanizmu birokratskog aparata nepropusnog za
nekog neupućnog u birokraciju. One mogu činiti prostorne i vremenske granice propusnima ili
nepropusnima pomoću funkcija sigurnosnog ograničavanja prostora i skupljanja podataka o
prošlom životu građana. Kroz legalistički i birokratsko-administrativni diskurs mogu stvoriti
dojam drugačijih „virtualnih” realnosti (danas bi takve realnosti, pod utjecajem „Procesa” i
„Dvorca” vjerojatno nazvali kafkanesknim). Na kraju, oni reificiraju tijela i populaciju kao
objekte nad kojima se vrši nadzor s ciljem ostvarivanja njihove pune produktivnosti, u čemu je i
Michael Foucault vidio suštinu biopolitike.691 198 Od vremena prosvijećenog apsolutizma na području Banske Hrvatske se formiraju različiti
moderni elementi državne kontrole. ,
693 Žirovčić, 1896: 33. 692 KPV,1911: 3096. 694 Ibid. ,
694 Ibid. 6.6.Paranoidne mreže i strah od moći države Dio stanovništva te mehanizme smatra nasilnima- to naročito
vrijedi za područje nekadašnje Vojne Krajine gdje je stavljanje tih prostora pod bansku upravu
često bila povezivano s gubitkom tradicionalnih privilegija. U mnogim slučajevima
neprijateljstvo prema elementima državne kontrole rezultira i konspirativnim narativima, poput
već spomenutog „poreza na sunce” ili želje države da uspostavi moć nad brakovima i rađanjem
djece. Teorije zavjere stenjevačkih štićenika gotovo su uvijek očito bizarne i patološke. Njihov
sadržaj je često osebujan i nestvaran, ali one također svjedoče o osjećaju anksioznosti povezanom
s već navedenim karakteristikama moderne državne moći i njezinim utjecajem na sudbine ljudi. U vremenu afere Dreyfuss i ponovne aktualizacije antisemitskih predrasuda brojne stenjevačke
teorije zavjere uključuju Židove kao agente tajnog društva koje vrši nadzor nad štićenicima. Služavka iz Desinića kod Pregrade je tako za svoju hospitalizaciju krivila zavjeru Židova koji su
je otpremili u Stenjevec jer „zna mnoge tajne o njima.”692 Paranoidne misle krajiškog pisara i
„stražmeštra” poznatog kao M.M, koji je bio na psihijatrijskom vještačenju u Stenjevcu nakon što
se predao sudu tvrdivši da je pokušao ustrijeliti svog oca također se vezuju uz Židove i Slobodne
Zidare. Tvrdnje koje je M.M iznio tijekom vještačenja daju persekutornu sliku moderne državne
birokracije i percepciju efekata koje je tak aparat imao na neke od pojedinaca na području Vojne
Krajine. Žirovčić u svom detaljnom prikazu slučaja M.M. ne navodi ime grada u kojem su se navedeni
događaji odvili, jedino ističući da se radi o području nekadašenje Vojne Krajine. Otac M.M bio je
umirovljeni krajiški kapetan, a M.M je pokušao ići njegovim stopama. Pohađao je vojničke
zavode iz kojih je „radi slaba napretka i raznih nepodopština istjeran”. Nakon toga je neko
vrijeme bio vojnik i stražmeštar, radio u pisarnama, okušao se u poljoprivredi te dvaput završio
na sudu: prvi put zbog pronevjere, drugi put zbog javnog nasilja. U vrijeme prije dolaska u
Stenjevec postao je „besposlica i skitalica” koji je dugi niz godina bio u zavadi s vlastitim ocem. Okrivljivao je oca da je „zatro zadružni imetak” i tražio od njega da mu kupi poljoprivredno
zemljište na kojem bi M.M. mogao živjeti i raditi.693 Otac mu je više puta posuđivao novac koji bi
M. M. brzo potrošio, te je često prijetio da će zapaliti očevu kuću, zbog čega su se i otac i
suseljani žalili poglavarstvu.694 Jednog jutra M.M. je došao u oružničku vojarnu i prijavio se da je 694 Ibid. 6.6.Paranoidne mreže i strah od moći države 199 pokušao ubiti oca ispalivši u njega četiri hica iz revolvera. Kao motiv svom činu na sudu je naveo
„da je kanio otca ubiti, jer je zatro njihov imetak, jer živi u zajednici s drugimi, koje uzdržava, a
njemu neće da kupi posjeda.” 695 Prilikom ispitivanja, ponašao se „smušeno” i više puta dao
oduška svome bijesu vrijeđajući sud, zbog čega je naređeno psihijatrijsko vještačenje.696Prilikom
vještačenja, M.M se izdvaja od ostalih štićenika i provodi dane šećući zavodskim perivojem. Ne
želi raditi već govori da bi „jedino na svom vlastitom posjedu poljodjelstvo tjerao, jer to je
njegovo pravo zvanje, a da toga nema, kriv je otac, koji je njihov zadružni imetak zatro.”697 Ne
želi ni čitati knjige iz zavodske knjižnice već tvrdi da želi čitati „nešto uzvišenijega,
filozofičnog”698. Njegovo ponašanje odaje distancu prema samoj instituciji: pozdravlja liječnika
vojnički, te tvrdi da ne spada u Stenjevec, jer „nije lud on već njegov otac”699. Iz početka, slučaj
se doima kao obični imovinsko-obiteljski sukob, možda potenciran procesom propadanja zadruga
u krajiškim krajevima. Kasnije, u razgovoru s liječnikom pored frustracije ocem M.M. postepeno
otkriva progonstvene ideje koje odaju sve veći strah od neke zavjere protiv njega. Na pitanje je li
zbilja želio ubiti svog oca, M. M. govori kako je isprva uistinu smatrao oca glavnim krivcem za
svoju nesreću, no kasnije ga je počeo držati za agenta državne urote protiv njega: „Da Vam pravo kažem, jesam zaista bio nakanio otca ubiti, jer sam sudio, da je on kriv svemu. Nu doduše sad sam druge misli, nije on baš sve kriv, es muss der Hacken anderwärts wo
liegen. Ja vidim, da se neki lov tjera na me, to sam reko već kod suda, a mislim, da se je otac
sasvim prodao državi ili kralju, ili tako nešto sličnoga.”700 Žirovčić detaljno intervjuira M.M. o njegovim paranoidnim mislima i ubrzo postaje jasno da
M.M. gradi svoj progonstveni narativ oko tri epizode koje smatra ključnim dokazima zavjere
protiv sebe. Prva je njegov odnos s ocem za kojeg kaže da je prodao zadružni imetak i prevario
ga za njegov dio te se sad seli iz kuće u kuću ovisno o tome „kako je zgodno za njegove
kombinacije” te živi s „prostom selskom flundrom”701. M. M. tvrdi da je dokaz zavjere protiv
njega i činjenica da njegovo ime nije zapisano u matične knjige, zbog čega navodno nije mogao
ostvariti pravo na svoj dio novca od prodaje posjeda. 697 Ibid: 34. 695 Ibid.
696 Ibid.
697 Ibid: 34.
698 Ibid.
699 Ibid.
700 Ibid.
701 Ibid.
200 6.6.Paranoidne mreže i strah od moći države Također sam pokušaj umorstva oca se
izjalovio zato što su meci, čini se bili dijelom zavjere- M. M. ih, na svojoj mješavini hrvatskog i 200 njemačkog naziva „politische patronen”.702 M.M smatra da je njegova namjera da počini
umorstvo moralna i taj svoj stav obrazlaže kroz distinkciju „božjeg” i „madjarskog” zakona: njemačkog naziva „politische patronen”.702 M.M smatra da je njegova namjera da počini
umorstvo moralna i taj svoj stav obrazlaže kroz distinkciju „božjeg” i „madjarskog” zakona: njemačkog naziva „politische patronen”.702 M.M smatra da je njegova namjera da počini
umorstvo moralna i taj svoj stav obrazlaže kroz distinkciju „božjeg” i „madjarskog” zakona:
„Razlaže, kako se čovjek od životinje razlikuje time, što životinja nemora svojim potomkom ništa njemačkog naziva „politische patronen”.702 M.M smatra da je njegova namjera da počini
umorstvo moralna i taj svoj stav obrazlaže kroz distinkciju „božjeg” i „madjarskog” zakona:
„Razlaže, kako se čovjek od životinje razlikuje time, što životinja nemora svojim potomkom ništa
ostaviti, dočim čovjek mora. Nije to dovoljno, da samo odgoji djecu, to je ‘samo po magjarskom
naravogojnom sistemu’, kako je to negdje čitao. On da će raditi samo po božjem zakonu, a božji
zakon se neprotivi tomu, da on otca ubije”703 Drugi događaj na koji se M.M. stalno poziva je tučnjava u kojoj je nastradao od nekih nepoznatih
ljudi. M.M. tom napadu pridaje veliki značaj i zaodjeva ga u svoj jezik zavjere nazivajući ga
„Sophienaffaire” i navodeći „ da i to spada u kombinacije”704. Naime, u noći 24 svibnja uoči
dana Svete Sofije napalo ga je na ulici jedanaest ljudi, te su ga istukli tako da je morao biti
prevezen u bolnicu u Zagrebu. Kasnije M. M. govori da je motiv tog napada na njega bio u tome
da ga se „napravi besvjesnim” što su njegovi napadači navodno i uspjeli.705 Treći element progona u M.-ovom narativu je postojanje čitave mreže državnih službenika koji
ga prisluškivaju, uhode i sabotiraju. M. M. govori o nizu zbrkanih događaja koji dokazuju da su
se neki „Herrenklubovi” i „Freimauern” urotili protiv njega i ciljano ga progone. M. M. upliće
državu, Slobodne Zidare i Židove u fantastične zavjere kojima je cilj upravljanje svijetom, a
upitan od Žirovčića da definira tko su „Freimauern” o kojima stalno govori, M.M izjavljuje da se
ta kvalifikacija odnosi na svakog obrazovanog državnog službenika. 706 Ibid: 36. 702 Ibid.
703 Ibid: 36.
704 Ibid: 35.
705 Ibid.
706 Ibid: 36. 704 Ibid: 35. 705 Ibid. 6.6.Paranoidne mreže i strah od moći države On se od Slobodnih Zidara
čak trudio ostvariti materijalnu korist jer je bio uvjeren da ga oni mogu učiniti plemićem, a neki
„doktor T.” ga je navodno pozvao da im se pridruži : „K tomu ja računam u kratko svakoga naobraženoga službenika, baš radi tih stvari, što se proti
meni radi. To je ono isto, što se zove Freimaurerorden. Oni si neka svietom vrte koliko hoće,
ali meni neka dadu mira. Doktor T. mi je rekao: Wollen Sie nicht beitreten zum
Freimauerorden? Ja dobro pazim i razglabam rieči, pa ako se toliko za me zanimaju, bješe im
meni pomoći, da budem grof. Pa nebi ja samo za se radio, ja nisam kao židov, premda židovi
imaju pravo: Geld regiert die Welt”706 M.M. prepričava čitav niz događaja koji dokazuju upliv Židova i Slobodnih Zidara u njegov
svakodnevni život poput epizode kad su mu oružnici jednom došli s namjerom da mu zaplijene 201 revolver:„...jedan od te dvojice da je bio pravi oružnik, a drugi ne, već je samo bio preobučen,
‘kao kad Talijan jopca preobuče.’ Zapitan, što bi to moglo značiti, da preobučeni ljudi k njemu
dolaze, veli, da se svašta dogadja, da se živi ljudi proglase mrtvimi, da si imena promiene”707
Osim toga, M.M. navodi da su ga pratili neki Židovi „iz Beča i Pešte” koji su se predstavljali kao
braća, „iako nisu bili slični” te da je jednom napisao opširno pismo caru ali se čitav „Postwessen
preokrenuo bio kako bi se njegova pošiljka izgubila.”708 U pismu koje je namjeravao poslati ocu, M.M. tvrdi kako su i on i otac žrtve te tajanstvene
organizacije:„To tebe u mrežah držeće maurersko družtvo se je u mojoj osobi prevarilo malo
neugodno ali neka se tješe sa tobom skupa, jer bi bili bolje uradili, da su ma koju inu sektu
producirali, jer ja neću - ne velim nemogu biti ma igdje t. z. varoškim bikom”709 Slične formulacije M.M. ponavlja u svojim pismima Žirovčiću, a Žirovčić ih sve otpisuje kao
„nerazumljivu smjesu navoda”710. Žirovčić M.-a smatra paranoikom koji pati od „misli
samouveličanja” i „progonstvenih misli”711. No, ono što je znakovito je da Žirovčić, ni u ovoj
studiji slučaja ni u svom opisu paranoje kojeg je objavio godinu dana ranije ne povezuje paranoju
sa strahom ili tjeskobom. 712 Žirovčić, 1895a: 44. 713 Resnik, 1998: 30. 711 Ibid: 59. 711 Ibid: 59. 709 Ibid: 57. 707 Ibid: 35.
708 Ibid.
709 Ibid: 57.
710 Ibid.
711 Ibid: 59.
712 Žirovčić, 1895a: 44.
713 Resnik, 1998: 30. 710 Ibid. 6.6.Paranoidne mreže i strah od moći države Dapače, čini se da je se, za Žirovčića, suština paranoje sastoji u
osjetilnim varkama, a ne u strahu od umišljenih progonitelja: „Glavni sadržaj i glavno obilježje paranoične bolesti jesu varke ćutila i varke mišljenja, a
subjekt, oko kojega se sve te varke kao gusta mreža pletu, jest vlastiti ego bolestnika. Svaki
dodir bolestnika sa vanjskim svietom shvaća se krivo i sve se tumači u odnošaju prema
vlastitoj osobnosti u dvima pravcima, u pravcu oštećivanja i pravcu uzvisivanja vlastite
osobe...Prema tim mislim reagira on budi afektom tuge, budi veselja, a obično se nalazi u
trajnom stanju uzrujanosti, razdražljivosti ”712 U ovom opisu paranoje možemo naći tragove koncepcije paranoje koju je kasnije iznio
argentinski psihoanalitičar Salomon Resnik. Resnik je istakao da osoba koja pati od paranoidnih
ideja zapravo konstruira vlastiti „svijet progonstva” tako da projicira osjećaje krivnje, straha i
anksioznosti prema van i trudi se funkcionirati po pravilima svijeta oblikovanog projekcijama tih
emocija.713 Znakovito je da su upravo ti osjećaji posve izostavljeni iz Žirovčićevog opisa 202 202 paranoje, a zamjenjuju ih tuga, veselje i uzrujanost, odnosno razdražljivosti. Razlog tome je
možda upravo u činjenici da su strah i anksioznost projicirani i mogu se iščitati iz paranoikovog
opisa stvarnosti, više nego iz njegovog ponašanja. Budući da se govor duševno oboljelih u
postojećoj praksi smatrao „besmislenim” nije se posvećivala pažnja samom značenju paranoidnih
konstrukcija i tjeskobi koja se često nalazila iza istih. U paranoidnim idejama M.M. bitnu ulogu
igraju agenti i službe države: oružnici, poštanski ured, popisi stanovništva i etička opreka između
„božjeg” i „mađarskog” zakona. Kroz svoj paranoidni svijet M.M. zapravo konstruira sliku
državne vlasti kao agenta koji djeluje protiv njega i koji je kriv za njegovo teško financijsko
stanje. Zakon po kojem je M.M. stalno progonjen je upravo „mađarski” a agenti koji ga
prisluškuju i prate su iz „Beča i Pešte”. Osim toga, M.M. koristi izraz „politische” u negativnom
smislu kao oznaku za nešto što sudjeluje u zavjeri. Samim time, može se reći da M.M. vidi izvor
svoje projicirane anksioznosti u administrativnom sustavu kojem je Vojna Krajina bila
podvrgnuta nakon pripojenja Banskoj Hrvatskoj. Administrativni sustav mađarskog dijela Austro-
ugarske monarhije razlikovao se od administrativnog i pravnog sustava Vojne Krajine i bio je
primarno birokratiziran, nasuprot militiziranom sustavu koji je tamo prevladavao ranije.714 Stav o
tome kako mađarski i bečki birokrati žele osiromašiti i eksploatirati stanovništvo Vojne Krajine
bio je prisutan nakon ukidanja krajiške administracije,715 a kod M.M. 714 Buczinski, 1994: 79.
715 Pavličević, 1980: 36.
716 Žirovčić, 1909: 291.
717 Žirovčić, 1909: 289. ,
717 Žirovčić, 1909: 289. 6.6.Paranoidne mreže i strah od moći države nalazimo tragove te mržnje
prema državnoj birokraciji i straha od države. Naravno, M-ov strah je svakako patološki, ali se i
dalje radi o implicitno kulturnoj i političkoj percepciji države kao „mreže” tajanstvenih društava
u kojima se M. kao društveno neprilagođena osoba nesklona disciplini, nije najbolje snalazio i
pred kojima je svakako strepio. Salomon Resnik kao bitne osjećaje kod paranoje uz strah i anksioznost spominje i krivnju. Sudski slučaj zagrebačkog studenta filozofije I. M.-a postavit će krivnju i strah kao emocije kroz
koje će se definirati odnos pojedinca i državnog represivnog aparata. I. M. je bio siromašan
student koji je živio s bratom i dvjema sestrama u podrumskoj sobici u Zagrebu. 716 Još kao dijete bio je veoma inteligentan i marljiv, završio je školu s odličnim ocjenama, kao i učiteljsku
preparandiju i upisao Filozofski fakultet. Živio je veoma umjereno i provodio dane u čitanju
knjiga i novina717, no neki od njegovih kolega primijetili su da je „uobražen” i često zanesen zbog 203 čega je bio izložen podsmjehu.718 U zavodu se našao nakon što je 30. kolovoza 1907. priznao
redarstveniku da je tjedan dana ranije izrezao komad platna iz portreta bivšeg bana Khuena
Hedervaryja koji se nalazio u dvorani zgrade Odjela za bogoštovlje i nastavu Kraljevske i
zemaljske vlade. Na čin vandaliziranja slike ga je potakla teška politička situacija u zemlji: činilo
mu se da je „čudno, da se vani viče na omraženoga bana, a gore se pred njegovom slikom
klanjaju te je smatrao da će mnoge obradovati njegov čin kao osveta za željezničku pragmatiku
kojom se u Hrvatskoj „ozakonjuje mađarski jezik”.719 Prilikom ispitivanja na sudu, I.M. je često
govorio o progonu od strane detektiva, te je predan na vještačenje u Stenjevec.720 Prilikom
vještačenja u Stenjevcu I.M. navodi kako su detektivi već drugi dan poslije počinjenja njegova
čina znali da je on krivac. Na tu misao ga je potaknuo događaj na Zrinjevcu gdje se I.M. odmarao
sjedeći na klupi: „Na Zrinjskom trgu pridje k njemu neki čovjek, pjevkajuć sjedne kraj njega na klupu i upusti
se s njim u razgovor. Na to dodje još jedan čovjek sa ženskom izpod ruke, guraju se kao pijani
i upuste se takodjer s njim u razgovor. Te ljude drži on za detektive, koji su došli k njemu, da u
njom pobude grižnju savjesti. Onaj, koji je prvi k njemu sjeo. 722 Ibid: 291. 723 Ibid. 6.6.Paranoidne mreže i strah od moći države hotio je predobiti onu ženu, koja
je došla sa svojim mužem, žena htjela i nehtjela, borila se sama sa sobom, savjest ju grizla i
jedva se je otela nevjeri. O tom je I. M. razmišljao i došao do zaključka, da ne postoji samo
materijalna sila, već da ima i duševna sila, koja moćno upliva na čovjeka, te je i tu ženu
sačuvala od nevjere, a njega prisilila, da se sam oda. Takvom silom uplivisanja osobito
razpolažu detektivi.”721 U temelju svih paranoidnih primisli koje I.M. prenosi psihijatrima nalazit će se ista ideja:
detektivi posjeduju tajnu duševnu silu koja kod ljudi može probuditi grižnju savjest, pa ju je
probudila i kod njega. I.M. osjeća strah pred liječnicima i štićenicima zavoda- smatra ih
prerušenim detektivima koji glume da su duševno bolesni ili liječnici, te njihove riječi i geste
tumači u ključu za svakodnevne stvari (poput oblika medaljona na crtežu govoreći da „nešto
znače”.722 U njegovim paranoidnim mislima opet se javlja moć države jer vjeruje da ga okoliš
nekako osobito motri i podpaža, da mu hoće nametnuti svoje političko osvjedočenje; to
uplivisanje jest „kameralizam”723. 204 I kod I.M.-a ko kod M.M.-a vidljiv je izrazit strah od zavjere, a glavni objekti tog straha su akteri
države. Dok M. M.-u državni činovnici uspijevaju naškoditi pomoću asimetrije političke moći,
detektivi kojih se boji I. M. posjeduju „duševnu silu”. Tu duševnu silu obrazovani I.M. poistovjećuje sa „kameralizmom” - ekonomskom politikom jačanja državne blagajne koja je
karakterizirala pruski i austrijski apsolutizam 18. stoljeća. Način na koji I.M. projicira strah od
države podsjeća na proces internalizacije savjesti koji je Ann Goldberg opisala u svojoj studiji
psihijatrijskog zavoda u Eberbachu. Prema Ann Goldberg modernizacijski procesi su pomoću
disciplinirajućih institucija poput škola, zatvora i psihijatrijskih zavoda promijenili naše poimanje
osjećaja krivnje. Ono prestaje biti definirano unutar brojnih društvenih odnosa (ili čak odnosa
čovjeka s božanskim) i kroz psihološki mehanizam savjesti postaje dijelom integrirane ličnosti
pojedinca upravljanog autonomnim razumom.724 I.M. projicira svoj osjećaj krivnje (ponovno ga
eksternalizirajući) i zbog toga stalno živi u strahu od detektiva koji mu telepatskim silama nastoje
utjecati na misli. Zanimljivo je također da kroz svoju definiciju „kameralizma” I.M. stvara
svjesnu ili podsvjesnu poveznicu između sustava disciplinskog nadzora i jačanja centralizirane
države orijentirane prema ekonomiji, što je jedna od ključnih postavki u Nadzoru i kazni Michela
Foucaulta.725 Žirovčić ne prepoznaje strah ni kod I.M.-a ni kod M.M.-a. I.M. g,
725 Foucault, 1977: 215. 724 Goldberg, 1999: 81. ,
726 Žirovčić, 1909: 290. 727 Haslam, 1996: 167. 6.6.Paranoidne mreže i strah od moći države pokazuje strah puno
otvorenije od M.M.-a koji ga skriva iza hvalisanja i agresivnog ponašanja. I.M. ne može spavati,
nemiran je, i prema samom Žirovčiću, pokazuje simptome neurastenije.726 No za Žirovčićevu
dijagnozu paranoje, puno su bitniji iskazi njegovih kolega o tobožnjoj I.-ovoj uobraženosti. Može se reći da je strah ekstremno hipokogniziran u iskazima štićenika koji ga projiciraju u sliku
progonstvenog svijeta- kao emocija uopće nije spomenut, a ključ paranoje traži se u
usredotočenosti paranoika na sebe samog. Kompleksne slike državne moći kao prijeteće i
nerazumljive tako u psihijatrijskom diskursu neće biti povezivane sa strahovima koji nastaju
uslijed nesigurne i burne političke situacije prijelaza stoljeća i sve veće „politizacije” društva u
Banskoj Hrvatskoj. Kao i kod ostalih primjera koje sam naveo u ovom poglavlju strah postaje
vidljiv tek u glasu samih štićenika. Sudeći po njihovom glasu, strah i strepnja štićenika često
imaju korijene u njihovoj svakodnevici. Strah od siromaštva reakcija je na stalno stanje oskudice
kojem su pojedini štićenici bili izloženi. Strah od natprirodnog potječe od duboko ukorjenjenih 205 pučkih vjerovanja ili je izraz pojačanog interesa za okultno na prijelazu stoljeća. Strahovi od
nasilja i od državne kontrole potaknuti su fizičkim ili strukturalnim nasiljem s kojim su se
štićenici suočavali. No, niti sadržaj strahova štićenika, niti njihova svakodnevica nisu u fokusu
dijagnostičkog procesa stenjevačkih psihijatara. Strah je medikiliziran i odvojen od životne
svakodnevice i kulturne pozadine štićenika koji o njemu govore. No, dok psihijatri nastoje
negirati samu emociju straha i tjeskobe u slučajevima straha štićenika od političkih zavjera i
progona, govor štićenika ipak ponekad otkriva iskrivljenu, ali vidljivo politiziranu sliku
navedenih emocija. Na sličan će se način u narativima štićenika politizirati, a u tumačenjima
pojedinih liječnika medikalizirati problemi agresije i nasilja o kojima ću govoriti u sljedećem
poglavlju. 206 206 728 Ibid. ,
728 Ibid. 7.1. Bijes, nasilje i sukobi u psihijatriji devetnaestog stoljeća Na ranim likovnim prikazima duševno oboljele osobe često su prikazane u stanju destruktivnog
bijesa. Figure manije i melankolije, prikazane iznad londonskog Bedlama stoljećima su bile
tradicionalan način zamišljanja i prikazivanja duševnih bolesti. Uz melankoliju se vezivao osjećaj
potištenosti, tuge i ponekad, iskrivljena percepcijaustvarnosti poput one kod Cervantesovog Don
Quijotea i Shakespearovog Kralja Leara”. Na spomenutoj Cibberovoj statui iz 1676. godine,
Melankolija leži ispružena sa zamišljenim izrazom lica, zadubljena u vlastite misli. Manija je
sapeta čvrstim čeličnim lancima, mišići su joj napeti, a dok se pokušava osloboditi na licu joj je
izraz gotovo animalnog bijesa. Studija Fione Haslam From Hogarth to Rowlandson: Medicine in
Art in Eighteenth-century Britain pokazuje kako su se slike melankolije i manije razvijale na
medicinskim ilustracijama i u umjetničkim prikazima ludila kroz osamnaesto stoljeće. Dok su
prikazi melankolije često imali romantičan i pomalo tragičan sentiment, manija je u kontekstu sve
prisutnijeg racionalističkog poimanja čovjeka kao „bića razuma” služila kao zastrašujući prikaz
destruktivnih impulsa nesputanih razumom. Prije nego što su se kompleksniji medicinski pogledi
na duševnu bolest proširili među obrazovanim slojevima, „bjesneći manijak” u lancima (uz
tragično-donkihotovsku figuru siromaha koji je umislio da je kralj) je najčešći prikaz kojim se
kodira duševno oboljenje.727 Takav pogled odgovara prosvjetiteljskim percepcijama duševno
oboljelog kao osobe koja je izgubila „razum” ili joj su joj racionalne odlike nedostupne. Budući
da je razum karakteristika koja u prosvjetiteljskim poimanjima razlikuje čovjeka od životinje,
ludilo se dovodi u vezu s „nižim” instinktivnijim aspektima ljudske prirode.728 Nagonsko i
„životinjsko” u čovjeku se često manifestira kao nekontrolirani bijes. Takva percepcija bijesa
govori o prevalentno negativnoj hiperkognizaciji bijesa u europskoj kulturi. Bijes je
hiperkogniziran iz razloga jer je usko povezan s nasiljem, pa je samim time u emotivnim
režimima morao biti podvrgnut raznim oblicima društvene kontrole. Jedan od najranijih primjera
književno umjetničke hiperkognizacije bijesa nalazi se u Homerovoj Ilijadi. Već u početnim 207 stihovima Homer kao temeljnu temu svog epa ne određuje ratničke podvige i prikaze junaštva (na
kraju, samo osvajanje Troje nije nikad prikazano u Ilijadi) već upravo bijes ili srdžbu (μῆνις):
„Srdžbu mi, boginjo, pjevaj Ahileja, Peleju sina,Pogubnu, kojano zada Ahejcima tisuću jada,”729
Svađa Ahileja i Agammemnona rezultira pogibijom za ahejsku vojsku upravo zato što Ahilej,
potaknut Ateninim savjetom odabire određen način pokazivanja vlastite srdžbe. ,
730 Dennen, 2005:18. 729 Homer, 2003 :3. 729 Homer, 2003 :3.
730 Dennen, 2005:18. 7.1. Bijes, nasilje i sukobi u psihijatriji devetnaestog stoljeća Ahilej odlučuje
susprezati svoje emocije upravo kad mu boginja vojne strategije Atena kaže da će pokazavši bijes
odbijanjem ratovanja, a ne direktnim fizičkim sukobom dobiti daleko veću satisfakciju za svoj
povrijeđeni osjećaj časti. Primjer „Ilijade” pokazuje da je kognizacije bijesa vezana uz osudu
direktnih iskazivanja te emocije i uz što učinkovitiju kontrolu gnjevnih impulsa prisutna još od
Starog Vijeka. Norbert Elias je kroz svoju studiju „Civilizacijskog procesa” detaljno prikazao modele
postepenog podvrgavanja nasilnog ponašanja društvenoj kontroli. Upravo Eliasovi primjeri dobro
ocrtavaju povezanost između emotiva kao čina iskazivanja emocije u određenom socijalnom
kontekstu i unutarnjeg kogniziranja same emocije. Formalni i neformalni oblici kontrole
agresivnog ponašanja, vezali su bijes uz nasilje te ga učinili emocijom koju je društveno
neprihvatljivo pokazivati. Pojavom racionalističke koncepcije ljudskog uma, bijes je sveden na
instinktivnu emociju čije otvoreno iskazivanje služi kao dokaz slabljenja racionalnih
mehanizama. Pitanje bijesa i agresije predstavljalo je neodgovoren problem za psihologe, psihijatre i
psihoanalitičare. Jedan od najranih prijepora u psihoanalizi je upravo mjesto agresivnosti unutar
psihodinamičkih koncepcija ličnosti. Freud, za kojeg su dugo vremena bili ključni seksualni
nagon i nagon za samoodržanjem, na početku nije pridavao važnost agresivnim implusima niti
emociji bijesa, za razliku od svog suvremenika Alfreda Adlera koji je agresiju smatrao biološkim
nagonom i postulirao „agresivni poriv” unutar svoje teorije o kompleksu inferiornosti.730 Kasnije
će Freud početi shvaćati agresiju kao jednu od manifestacija „thanatosa” ili nagona smrti. Za
razumijevanje kasnih Freudovih pogleda na agresiju, bitno je njegovo djelo Nelagoda u kulturi iz
1930. godine.U Nelagodi u kulturi Freud će zaključiti da je postojanje destruktivnih agresivnih
nagona koji bi rezultirali nasiljem da nisu inhibirani, pretpostavka za postojanje društvenih
inhibicija i samim time, za postojanje uređenih društava. Za Freuda, ljudi nisu dobrohotna bića, 208 sposobna braniti se od opasnosti već su obdareni agresivnošću kao jednim od svojih urođenih
nagona. Ta sklonost agresiji je stalna prijetnja za ljudsko društvo, a društvo, kako bi izbjeglo
dezintegraciji mora postaviti restrikcije protiv seksualnih sloboda i agresivnog ponašanja. Kao
jednu od ključnih restrikcija, Freud vidi zapovjed o „ljubljenju bližnjega svoga ka samog sebe”. Freud tvrdi da taj naputak, ne bi imao razloga postojati da ljudi po svojoj prirodi nisu podložni
agresivnom nagonu.731 Kao mladi psihoanalitičar s izraženim interesom za forenzičku psihijatriju,
Jacques Lacan se bavio uzrocima nasilja. Lacan se u svom članku „Motivi paranoičnog zločina:
zločin sestara Papin” bavi zločinom sestara Christine i Lee Papin koje su 1933. 731 Freud, 2010: 4504-4505. 733 Fromm, 1974: 187. 732 Fazerkaš, 2016: 95. 734 Ibid: 218. 734 Ibid: 218. 734 Ibid: 218. 7.1. Bijes, nasilje i sukobi u psihijatriji devetnaestog stoljeća u Le Mansu na
osobito brutalan način ubile svoju gazdaricu i njezinu kćer. U analizi zločina Lacan ističe vezu
između agresivnog nagona i paranoidne psihoze pri čemu agresivni nagon služi kao baza
paranoidnog delirija i koji se u činu umorstva manifestira putem kompromisa s integriranim
društvenim zahtjevima koji maskiraju istinski motiv zločina.732 Jedan od najtemeljitijih analiza agresije i agresivnosti dao je Erich Fromm, psihoanalitičar i
filozof koji je bio jedan od predstavnika „Frankfurtske škole”. U Anatomiji ljudske
destruktivnosti Fromm je podijelio agresiju na benignu i malignu. Oblici agresije koje je Fromm
odredio kao benigne nastali su kao posljedica evolucijskog razvoja ljudske vrste, a javljaju se kao
odgovor na prijetnju jedinki. Često se javlja i kod ljudi i kod životinja i nikad nije spontana i
eskalirajuća, već obrambena i reaktivna, a za cilj ima otklanjanje prijetnje. 733 Benignu agresiju,
Fromm je dalje podijelio na pseudoagresiju (agresivni postupci koji mogu naškoditi nekome, ali
im to nije primarna svrha) i obrambenu agresiju koja nastaje kao reakcija na stvarnu ili umišljenju
opasnost. Malignu agresiju za Fromma predstavljaju postupci koji su svojstveni samo čovjeku i
ne javljaju se u životinjskom svijetu. Ona je uvijek destruktivna i jedan je od mogućih odgovora
na specifične psihičke potrebe ukorjenjene u ljudskom bivanju i nastaje uslijed različitih oblika
interakcije društvenih okolnosti s tim potrebama.734 Fromm je malignu agresiju vidio kao
manifestaciju dva različita oblika destruktivnosti: prvu je nazvao spontanom destruktivnošću koju
dalje dijeli na osvetničku i ekstatičku. Druga je destruktivnost ona koja proizlazi iz specifične
strukture ličnosti. Za Fromma postoje dvije vrste destruktivnosti koje mogu biti utkane u
strukturu ličnosti: sadizam i nekrofilija. Sadizam za Fromma znači seksualnu ili aseksualnu želju 209 za nanošenjem boli drugima, a nekrofilija užitak u smrti i uništavanju. Razvoj ranih
psihoanalitičkih pogleda na bijes i agresiju odaje jednu važnu karakteristiku promatranja
agresivnih i „destruktivnih” emocija: one često nisu ni opisivane ili doživljavane kao emocije već
ih se konceptualiziralo kao „nagone”, „instinkte” ili „porive”. Time se naglašavala njihova
iracionalna, primalna, „niža” priroda što govori o njihovoj negativnoj percepciji unutar emotivnih
režima. No, s razvojom psihoanalitičkih teorija pogled na bijes i agresiju postaje daleko
kompleksniji i u njega se nastoje uključiti kako sukobi unutar pojedinca tako i šire društvene
dimenzije koje mogu povoljno djelovati na razvoj agresije, tako da će postfrojdovska
psihoanaliza obilovati analizama agresivnosti i narcisističkog bijesa. 735 Macalpine i Hunter, 1966: 69. g,
737 Pinel, 1806: 188 u engleskom prijevodu s početka devetnaestog stoljeća nije bilo moguće otvoreno istaknuti da
se radi o još vladajućem engleskom monarhu.
738 Ibid 19 736 De Young, 2015: 245. p
736 De Young, 2015: 245. j
j
g
738 Ibid:19. 7.1. Bijes, nasilje i sukobi u psihijatriji devetnaestog stoljeća U godinama kad se moderna europska psihijatrija tek počela formirati veliku je pažnju privukla
bolest Georgea III, „ludog kralja” Velike Britanije i protopsihijatrijski tretman kojem je bolesnog
kralja podvrgao njegov liječnik Francis Willis. Novija istraživanja bolesti Kralja Georgea III
navode da je bolovao od porfirije, nasljedne bolesti metabolizma koja između ostalog uzrokuje
promjene raspoloženja i psihozu735. Kraljevi ispadi nekontroliranog bijesa i Willisova sposobnost
ublažavanja istih, izvršili su velik utjecaj na terapeutske metode „moral treatmenta” i na poimanje
ludila u devetnaestoljetnoj psihijatriji. Willis je smirivao kraljeve ispade bijesa kombinacijom
tehnike „fiksiranja” (navodno je Willisov pogled bio toliko čvrst da je prilikom jednog sastanka
natjerao vođu opozicije Edmunda Bourkea da obori oči pred njim)736 i nametanjem neupitnog
liječničkog autoriteta. Primjer tog tretmana je učvrstio percepciju liječnikovog autoriteta kao
važnog elementa unutar „moral treatmenta”. Willisove terapeutske metode bile su toliko utjecajne
da ih Phillipe Pinel navodi kao uzor postupanja prema duševnim bolesnicima ustvrdivši da je
Willisova metoda izolacije kralja Georgea i njegovo nametanje vlastitog autoriteta, dodatno
potpomognuto dvojicom „snažnih pomoćnika” dovela do „sigurnog i trajnog izlječenja.737 U
istom dijelu, Pinel stvara vezu između bijesa i manije koje će se psihijatri držati kroz cijelo
devetnaesto stoljeće. Pinel piše: „Onaj koji je poistovjetio ljutnju s bijesom ili prolaznim ludilom
(ira furor brevis est) je izrekao tvrdnju čiju smo istinitost više ili manje skloni potvrditi
proporcionalno s opsegom našeg znanja o ludilu. Paroksizmi ludila su uglavnom tek pobješnjele
emocije koje traju duže od svog uobičajenog trajanja...”738Za Pinela su sama kvaliteta, valencija, 210 210 osjećaj ili cilj emocija nebitni u razlici između prihvatljivog izražavanja emocija i luđačkog
paroksizma: paroksizam manijaka je određen time što traje duže nego što je uobičajeno bez
slabljenja intenziteta. Kao primjer emocije koju je već i poslovično teško odvojiti od ludila, Pinel
ističe upravo bijes. No, u kasnijoj psihijatriji oštro poistovjećivanje ludila s bijesom nestaje. Za Žirovčića tako bijes
kao konkretna emocija nije bitan simptom duševnog oboljenja već on u svojim pojavama govori
o veselom i turobnom raspoloženju, razdražljivosti i osjećaju straha 739, dok maniju poistovjećuje
s veselim raspoloženjem.740 Takva distinkcija neće biti izražena u kliničkoj praksi: brojni
štićenici kojima će se dijagnosticirati „mania” pokazivat će znakove bijesa i agresivnog
ponašanja, a ono će biti prisutno i kod većine drugih duševnih oboljenja. Tako su prvi simptomi
bolesti književnika Ante Kovačića, koji je 1883. umro u Stenjevcu s dijagnozom „manije” bili
obilježeni upravo velikom agitacijom i bijesnim ponašanjem. 739 Žirovčić, 1896b: 252. 740 Žirovčić, 1895a: 4. p ,
742 Žirovčić, 1898: 228-229. 743 Jones, 2016: 116. 741 Župić, 1937: 345. 7.1. Bijes, nasilje i sukobi u psihijatriji devetnaestog stoljeća U iduća četiri dijela, pisat ću o sukobima unutar obitelji, devijantnom
ponašanju adolescenata, sukobima unutar ruralnih zajednica i o političkom nasilju te ću, na
temelju povijesti bolesti i forenzičkih vještačenja nastojati ustanoviti na koji je način psihijatrijski
diskurs progovarao o tim sukobima, suočen s govorom štićenika. U navedenim primjerima
psihijatri će morati napustiti isključivo medicinski pogled na bijes i agresiju i preuzeti ulogu
medijatora u konfliktnim situacijama, konstantno nastojeći razlučiti „devijantno” i „patološko”
iskazivanje bijesa i agresije od uobičajenih oblika nasilja manifestiranih u konfliktnim
situacijama Ono što je karakteristika bijesa i agresije je činjenica da se javljaju u konfliktnim situacijama, te
da služi kao emotivni način razrješenja određenog sukoba. Somatiziranje agresije kakvo je
predložio Lombroso, izmjestilo je bijes i agresiju iz konteksta sukoba u kojima se oni javljaju. Stvarnost sukoba u nekoj društvenoj sredini, bilo da se radi o obitelji, široj zajednici ili čitavom
društvu postaje nevidljiva u psihijatrijskim čitanjima zločina i agresije. Način na koji se sukob
percipira, bit će usmjeren na osobu za koju je ustanovljeno da je akter agresije pri čemu se njezin
bijes čita isključivo kao simptom uz sve ostale dijagnostičke faktore koje psihijatrijski pogled
smatra bitnima za identificiranje duševno oboljelog ili hereditarno degeneriranog pojedinca:
tjelesne „stigmate”, obiteljska povijest ludila ili devijantnog ponašanja i slično. Medikalizacijom
bijesa i agresivnog ponašanja i biologizacijom zločina čine se nevidljivima brojni partikularni
događaji koji su doveli do svake nekontrolirane provale bijesa ili nasilnog akta. Ipak, stenjevačke
povijesti bolesti sukreirali su i sami štićenici kroz svoj neposredan ili posredovan govor. U tom
govoru, možemo naći različite narative fizičkog, psihičkog i emotivnog nasilja koje se događalo u
obiteljima, malim zajednicama i u širem društvu. Dok se psihijatri bave obuzdavanjem
destruktivnih emocija štićenika i dok traže neurološki izvor njihovih tegoba, štićenici često
govore o brojnim sukobima, mikroagresijama i frustracijama koje su obilježavale njihov
svakodnevni život. U iduća četiri dijela, pisat ću o sukobima unutar obitelji, devijantnom
ponašanju adolescenata, sukobima unutar ruralnih zajednica i o političkom nasilju te ću, na
temelju povijesti bolesti i forenzičkih vještačenja nastojati ustanoviti na koji je način psihijatrijski
diskurs progovarao o tim sukobima, suočen s govorom štićenika. U navedenim primjerima
psihijatri će morati napustiti isključivo medicinski pogled na bijes i agresiju i preuzeti ulogu
medijatora u konfliktnim situacijama, konstantno nastojeći razlučiti „devijantno” i „patološko”
iskazivanje bijesa i agresije od uobičajenih oblika nasilja manifestiranih u konfliktnim
situacijama 7.1. Bijes, nasilje i sukobi u psihijatriji devetnaestog stoljeća Prema povijesti bolesti ona je
počela „nespavanjem, vikanjem, skakanjem, uništavanjem stvari... Bio je tako bijesan da su ga
vezana u zavod doveli.”741 O agresivnom i za društvo opasnom ponašanju brojnih štićenika,
Žirovčić je pisao u svom članku „Ludjačka umorstva nazvana la folie rouge” iz 1898. godine. U
tom članku, kako je istaknuto u prošlom poglavlju, Žirovčić govori o sklonosti duševnih
bolesnika prema počinjenju nasilja i pritom osobito ističe epileptičare, alkoholičare i „hereditarno
opterećene pojedince”742. Čini se da se, sa somatizacijom etiologije duševnih bolesti u psihijatriji,
važnost bijesa kao emocije smanjuje. No ono što ostaje je percepcija duševno bolesnih osoba kao
pojedinaca sklonih agresiji. On je vidljiva i u Žirovčićevim člancima, i u povijestima bolesti i u
pojedinim teorijama „kriminalne antropologije” poput one koje je razvio talijanski kriminolog
Cesare Lombroso. Lombrosove teorije tražile su uzrok kriminalnog ponašanja pojedinaca u
psihijatrijskim teorijama degeneracije743, te su imale velik utjecaj na njemačku forenzičku
psihijatriju i posljedično, na poimanje kriminalnog i agresivnog ponašanja kod stenjevačkih
liječnika. 211 211 Ono što je karakteristika bijesa i agresije je činjenica da se javljaju u konfliktnim situacijama, te
da služi kao emotivni način razrješenja određenog sukoba. Somatiziranje agresije kakvo je
predložio Lombroso, izmjestilo je bijes i agresiju iz konteksta sukoba u kojima se oni javljaju. Stvarnost sukoba u nekoj društvenoj sredini, bilo da se radi o obitelji, široj zajednici ili čitavom
društvu postaje nevidljiva u psihijatrijskim čitanjima zločina i agresije. Način na koji se sukob
percipira, bit će usmjeren na osobu za koju je ustanovljeno da je akter agresije pri čemu se njezin
bijes čita isključivo kao simptom uz sve ostale dijagnostičke faktore koje psihijatrijski pogled
smatra bitnima za identificiranje duševno oboljelog ili hereditarno degeneriranog pojedinca:
tjelesne „stigmate”, obiteljska povijest ludila ili devijantnog ponašanja i slično. Medikalizacijom
bijesa i agresivnog ponašanja i biologizacijom zločina čine se nevidljivima brojni partikularni
događaji koji su doveli do svake nekontrolirane provale bijesa ili nasilnog akta. Ipak, stenjevačke
povijesti bolesti sukreirali su i sami štićenici kroz svoj neposredan ili posredovan govor. U tom
govoru, možemo naći različite narative fizičkog, psihičkog i emotivnog nasilja koje se događalo u
obiteljima, malim zajednicama i u širem društvu. Dok se psihijatri bave obuzdavanjem
destruktivnih emocija štićenika i dok traže neurološki izvor njihovih tegoba, štićenici često
govore o brojnim sukobima, mikroagresijama i frustracijama koje su obilježavale njihov
svakodnevni život. 7.2. Sukobi unutar obitelji Usponom građanske klase u osamnaestom i devetnaestom stoljeću, pojavljuje se nova koncepcija
obitelji. Unutar emotivnog režima građanstva, javni prostor kao sfera kojom dominiraju
muškarci, sve više postaje prostorom racionalnog djelovanja. S druge strane, obitelj se doživljava
kao afektivna i emotivna zajednica. Shorter navodi da je shvaćanje obitelji kao prvenstveno
emotivne zajednice u suprotnosti s ranijim shvaćanjem obitelji kao zajednice utemeljene na 212 odnosima vlasništva i rodoslovlja.744 Obitelj kao mjesto emotivne sigurnosti povezuje se s
percepcijom oca i supruga kao „patera familiasa“ čija je moć unutar zidova obiteljskog doma
neupitna. Marija Jambrišak je 1921. godine opisala obitelj kao emotivnu zajednicu koja
prvenstveno služi za zadovoljavanje emotivnih potreba muškarca: „U onom času kad je muž prekoračio kućni prag- u drugom je svijetu. U svojoj porodici neka
strese sa sebe prašinu vanjsku, neka ostavi pred kućom dnevne brige…“ Obiteljski život ono
njega savija „bedem koji odbija navalu vanjskih misli i briga i dnevnih napora, on sjedi u njemu i
podaje se cijelom dušom novim radostima drugog porodičnog svijeta.“745 Jambrešak također implicira da unutar te zajednice većinu emotivnog rada treba obavljati žena
izjavivši da je „muž glava, a žena srce kuće“746. Jasno je da u okviru građanskog emotivnog
režima, obiteljski dom mora služiti kao protuteža muškarčevim zahtjevnim zadaćama u javnom
životu.747 Od supruge se zahtijevalo da podredi svoj društveni život emotivnim potrebama
supruga. Građanski slojevi i plemstvo sve su češće uređivali svoje obiteljske odnose tako da da
odgovaraju ideji obitelji kao takvog emotivnog utočišta. Jambrešak također implicira da unutar te zajednice većinu emotivnog rada treba obavljati žena
izjavivši da je „muž glava, a žena srce kuće“746. Jasno je da u okviru građanskog emotivnog
režima, obiteljski dom mora služiti kao protuteža muškarčevim zahtjevnim zadaćama u javnom
životu.747 Od supruge se zahtijevalo da podredi svoj društveni život emotivnim potrebama
supruga. Građanski slojevi i plemstvo sve su češće uređivali svoje obiteljske odnose tako da da
odgovaraju ideji obitelji kao takvog emotivnog utočišta. Zanimljivo je da je Edward Shorter, kao jedan od uzroka porasta broja štićenika u zavodima
devetnaestog stoljeća, naveo upravo takvu promjenu u poimanju obitelji. Naime, ako se obitelj
počela poimati kao sentimentalna i emotivna zajednica, prisutnost osoba s duševnim
poteškoćama bila je disruptivna za „mir porodičnog svijeta”. 744 Shorter, 1997: 50. 746 Ibid: 340. 745 Iveljić, 2009: 339-340. 747 Ibid. 748 Shorter, 1997: 50. 746 Ibid: 340. 7.2. Sukobi unutar obitelji Dok se ranije za takve osobe
nastojalo skrbiti u krugu obitelji, one su sad percipirane kao osobe koje narušavaju emotivnu
ravnotežu, te ih se zbog tog narušavanja nastojalo smjestiti u zavode, čak i u slučajevima kad za
to nije bilo stvarne potrebe.748 Tako je interniranje u zavodu postalo jedan od načina za rješavanje
potencijalno konfliktnih situacija u krugu obiteljskog doma. U trenutku kad se obitelj odluči na
institucionalizaciju jednog od svojih članova, psihijatrijski diskurs postaje jedan od diskursa
unutar kojeg se postavljaju emotivni sukobi, a liječnici, kroz komunikaciju sa štićenikom i
njegovom obitelji, jedni od posrednika i arbitara sukoba. To se često događa u trenucima kad su
se pojedinci u krugu obitelji počeli ponašati toliko nasilno da je njihovo interniranje bilo jedinim 213 213 načinom da obitelj ostane sigurna. Po povratku u Ozalj iz Zagreba, akvarelistica Slava Raškaj je
plašila čitavu svoju obitelj svojim nasilnim ispadima bijesa za vrijeme kojih je uništavala
pokućstvo i nekoliko puta na jeziku gluhih saopćila majci da ju želi ubiti. Čini se da je i sam
boravak u krugu obitelji poticao agresivno ponašanje Slave Raškaj, budući da je u zavodu
njezino ponašanje opisano kao mirno. Već po dolasku u zavod samo je tiho, na njemačkom
odgovarala liječnicima da se osjeća dobro.749 S druge strane, ideja obitelji kao emotivne zajednice ukorijenjena u građanskim slojevima
prijelaza stoljeća, još se uvijek ponegdje prožima s drugom koncepcijom obitelji koja
prvenstveno zamišlja obiteljski dom kao kućanstvo. U sudskim zapisnicima koje je analizirala
Eliza Earle Ferguson, a koji se tiču pariških obitelji radničke klase s prijelaza stoljeća, najčešća
riječ koja se koristi za domaćinsku zajednicu nije „familie” (obitelj) već „ménage” (kućanstvo).750
Kućanstvo, uz emotivni i simbolički, podrazumijeva i ekonomski aspekt te zajednice jer
obuhvaća i zajednički dom i predmete koji se u istom nalaze. Može se reći da krajem stoljeća,
aspekti obitelji kao „kućanstva” supostoje s aspektima obitelji kao središta emotivnog života. To
znači da u životu većine obitelji, privatna sfera emocija i javna sfera sudjelovanja na tržištu rada i
zarađivanja nisu bile strogo odvojene. I uistinu, i u slučajevima koje je istražila Eliza Ferguson i u
brojnim stenjevačkim povijestima bolesti, (a nasuprot relativno oštroj razdjelnici koju favorizira
Shorter) u sukobima unutar obitelji često se isprepliću emotivno i ekonomsko, a ponekad ih
postaje teško jasno razdvojiti. 749 KPV, 1906: 5364 Činjenica da u razgovoru s liječnicima (koji možda ne znaju znakovni jezik gluhih) Slava
Raškaj uspijeva artikulirano vokalizirati nekoliko riječi dovodi u pitanje uobičajene prikaze te slikarice kao
gluhonijeme. g
j
750 Ferguson, 2010: 56. g
,
751 KPV, 1911:8135. gluhonijeme.
750 Ferguson, 2010: 56. g
j
750 Ferguson, 2010: 56. g
,
751 KPV, 1911:8135. 7.2. Sukobi unutar obitelji U obrazloženjima u kojima se traži smještanje štićenika u zavod,
ekonomski aspekt postaje daleko važniji od emotivnog, što se vidi po činjenici da se smještanje u
zavod često opravdava činjenicom da obitelj nema financijskih sredstava ili vremena da skrbi za
disruptivnog člana obitelji. Tako su ostarjelog ratara Imbru K. njegovi ukućani predali liječničkoj
skrbi, ne jer je narušavao emotivni sklad obitelji, već jer im je, zbog prirode poljodjelskog rada
bilo teško „čuvati”. Sin je Imbru preuzeo nakon 28 dana boravka u zavodu i odveo ga kući,
vjerojatno zbog toga što je završetkom žetve prestalo vrijeme intenzivnih radova.751 Iako je Imbra
bio star, nemoćan i psihički nestabilan, čini se da je njegovo interniranje u zavodu bilo potaknuto 214 specifičnim ekonomskim potrebama kućanstva, a da je vraćen kući jer ga se ipak doživljavalo
dijelom emotivne zajednice. Ispreplitanje ekonomskog i emotivnog, uz posredovanje različitih medicinskih diskursa kako bi
se razriješio obiteljski sukob vidimo na kompleksnom slučaju Darinke Dj., supruge liječnika iz
Sarajeva koja je bila u zavodu od 1903. do svoje smrti od tuberkuloze 1914. Darinka je dovedena
u Stenjevec iz Vakufske bolnice u Sarajevu. U Vakufsku je bolnicu, Darinka dospjela iz zavoda u
Grazu, gdje su se pojavili prvi simptomi njezine bolesti. Bolest joj je prvo dijagnosticirana kao
„amentia” a zatim kao „dementia secundaria”. Njezino duševno stanje prilikom prijema u bolnicu
u Sarajevu bilo je izuzetno teško. Unos u povijesti bolesti iz Vakuf-Spitala u Sarajevu iz 30. listopada 1902. govori da je njezino pamćenje bilo ”...sasvim iščeznulo, djelimice falsificirano
uslijed tlapnja i smetenosti.”752 Upravo činjenica da se Darinka, čini se nije mogla sjetiti
posljednih dana svog boravka izvan bolnice je bila razlog kasnijeg višegodišnjih optuživanja
između Darinkine obitelji i njezinog supruga liječnika. Darinkina obitelj je optužila njezinog
supruga, Damjana, da je uzrokovao njezinu psihičku bolest zlostavljanjem, dok je Damjan oštrim
riječima predstavio Darinkinu obitelj kao hereditarno opterećenu i sklonu seksualnim
nastranostima. Damjan Dj. je bio perspektivan student medicine u Grazu, no kako sam priznaje u
pismu Ivanu Žirovčiću, imao je financijskih poteškoća.753 U studijima ga je na početku uzdržavao
brat. Zaruke s Darinkom iz imućne obitelji Ć. donijele su mu znatnu financijsku korist- dobio je
2500 forinti po sklapanju braka, a obećano mu je još toliko nakon što završi studij medicine. Damjan je tvrdio da je prvih 2500 forinti uložio u zemaljsku banku u Sarajevu na Darinkino
ime.754 Bračni par se, nakon vjenčanja 1900. 752 KPV, 1914: 5731. 753 Ibid. ,
753 Ibid.
754 Ibid.
755 Ibid.
756 Ibid. 7.2. Sukobi unutar obitelji godine, uputio u Graz, gdje je Damjan završavao
studije i gdje se Darinka razboljela. Povijest bolesti iz Vakuf-Spitala ističe da je Darinka, usprkos
hereditetu s očeve i majčine strane („otac podat piću, majka je nakon poroda bolovala od „akutne
duševne bolesti”) bila zdrava do udaje za Damjana Dj.. 755 Prvi znakovi koji su upućivale da nešto
nije u redu bila su Darinkina pisma koja je slala braći iz Graza. U njima je, navodno tvrdila da je
„je vrlo nesretna i ucviljena, da je muž zapušćuje, da joj se grozi kako će je pustiti, da se nje u
javnosti stidi, jer da nije lijepa, da novac troši, da ona plače dan i noć itd.”756. Sarajevski liječnici Damjan je tvrdio da je prvih 2500 forinti uložio u zemaljsku banku u Sarajevu na Darinkino
ime.754 Bračni par se, nakon vjenčanja 1900. godine, uputio u Graz, gdje je Damjan završavao
studije i gdje se Darinka razboljela. Povijest bolesti iz Vakuf-Spitala ističe da je Darinka, usprkos
hereditetu s očeve i majčine strane („otac podat piću, majka je nakon poroda bolovala od „akutne
duševne bolesti”) bila zdrava do udaje za Damjana Dj.. 755 Prvi znakovi koji su upućivale da nešto
nije u redu bila su Darinkina pisma koja je slala braći iz Graza. U njima je, navodno tvrdila da je
„je vrlo nesretna i ucviljena, da je muž zapušćuje, da joj se grozi kako će je pustiti, da se nje u
javnosti stidi, jer da nije lijepa, da novac troši, da ona plače dan i noć itd.”756. Sarajevski liječnici 215 istakli su da se Darinka jako bojala supruga, te je molila braću „da joj mužu ne kažu, kako se je
tužila na njega, jer bi je on ubio”757. Na kraju je svom bratu, upravitelju manastira Obrena Vasilju
Ć. poslala telegram u kojem govori kako je doznala da joj suprug ima izvanbračno dijete u Grazu
i „kako ju kani pustiti”.758 Istovremeno s Darinkinim telegramima, telegrame Darinkinoj obitelji
šalje i Damjan. U njima Damjan opisuje stanje svoje žene koristeći medicinske termine: tvrdi da
Darinka „oboljela na histeriji” i da ima „Heimweh” (nedostaje joj dom).759 Brat je došao po nju i
odveo ju u Cilj, gdje joj se „uzrujanost njezina tako pogoršala, da su telegrafirali po muža u Graz,
da je odvede natrag.” Provela je nekoliko tjedana u Grazu, nakon čega je premještena u Sarajevo. p
761 KPV, 1914: 5731. ,
762 Ibid. 760 Spector, 2016: 53. 762 Ibid. 757 Ibid.
758 Ibid.
759 Ibid.
760 Spector, 2016: 53.
761 KPV, 1914: 5731.
762 Ibid. 7.2. Sukobi unutar obitelji Damjanovo opsivanje Darinkinog stanja kao „Heimwecha” osobito je indikativno ako se uzme u
obzir da su tih godina psihijatri heidelberške škole poput Karla Wilmannsa, povezivali osjećaj
nostalgije za domom kod žena i djevojaka s degeneracijom i sklonošću kriminalu.760 Tijekom boravka u Sarajevu, liječnici ističu da su dominantne emocije kod Darinke „žalost i
strah” a zapisan Darinkin govor odaje dezorijentiranost i zbunjenost, no znakovito je da Darinka
često spominje novac i optužuje nekog neodređenog da joj je „pomiješao um”:
”Zašto vi ne jedete? Nema tko platiti, ovo nije plaćeno. Pomeli mi moj mozak, pa ništa neznam, što radim. Tko Vam je pomeo mozak? Nema tko platiti, ovo nije plaćeno. Pomeli mi moj mozak, pa ništa neznam, što radim. Tko Vam je pomeo mozak? 26.9. Dajte me molim Vas pustite da idem služiti, nemam samo nego 2 Kr. 26.9. Dajte me molim Vas pustite da idem služiti, nemam samo nego 2 Kr. 27.9. Govor mi se prevrće u mozgu kao da sam poludila... 27.9. Govor mi se prevrće u mozgu kao da sam poludila... 30.10. Što se ovo od mene radi- gdje su mi novci ko će ovo za mene platiti”761
Nakon gotovo godine dana boravka u sarajevskoj bolnici, Darinka je 25. svibnja 1903. dovedena
u Stenjevec. U stenjevačkom zavodu njezino je stanje izuzetno teško i čini se da je izgubila svaki
dodir sa stvarnošću. Prema povijesti bolesti „vlada se nemirno i bezobrazno, pjeva vesele
poskočice, pleše i smije se bez razloga.”762 Tijekom godina stanje joj je nepromijenjeno, jedino se
može pratiti njezino fizičko propadanje. Zapis s kraja 1907. tako govori:„Izgubila skoro sve zube 216 često veoma uzrujana, silovita, erotična, tako da je morala često biti osamljena. Po noći često
veoma nemirna. Nečista, neuredna. Sasvim glupa i tupa.”763 U tom stanju, stenjevački liječnici nisu mogli dati jasno mišljenje o uzrocima njezine bolesti, niti
o tome igraju li neobične obiteljske prilike i nesretan brak ikakvu ulogu u njima. No, Damjanova
uloga u Darinkinoj bolesti nije prestala zanimati njezinu obitelj, koja se obratila vlastima. Kancelarija Dobro-bosanska poslala je 1907. godine zahtjev za Žirovčićevim stručnim
mišljenjem o bolesti Darinke Dj. Zahtjev je sadržavao četiri pitanja: Može li se dokazati da je Darinka Dj. rodj. Ć., sa amencijom nasljedno obterećena? „1. Može li se dokazati da je Darinka Dj. rodj. Ć., sa amencijom nasljedno obter 2.Što je mogao biti razlog da je bolest u nje odmah prvijeh nedjelja poslie stupanja u brak
izbila? 3. 763 Ibid.
764 Ibid.
765 Ibid. 7.2. Sukobi unutar obitelji Da li se ista žali na muža? 4.Može li se, i kada, bolest njene na bolje, i u kojoj mjeri okrenuti, da bi za bračni život
sposobna bila?”764 Žirovčićev odgovor na upit Dobro-bosanske kancelarije je bio neuobičajen za hrvatsku
psihijatriju prijelaza stoljeća. Kod prvog pitanja Žirovčić nije posegnuo za uvriježenim
pretpostavkama o hereditarnoj etiologiji duševnih bolesti već je bio neodređen. U svom šturom
odgovoru, Žirovčić daje do znanja da ne može utvrditi hereditet kao uzrok Darinkine bolesti: „Mnogostručno iskustvo uči da duševne bolesti ne prelaze na potomstvo baš u istoj formi
bolesti kakva je bila u roditelja nego da se u potomstvu pojavljuju najrazličitiji oblici duševnog
ili živčanog oboljenja, manjkavosti i tromosti duševnog i tjelesnog razvitka, a da i ne moraju
hereditarno obterećeni potpmci duševno oboljeti Tako nalazimo u obitelji Ć. u oca
alkoholizam, u matere akutnu porodjajnu psihozu; a od njihovog potomstva samo je kći
duševno obolila u dvadesetoj godini života, dočim od braće jedan brat ima poteškoću govora, a
drugi je obtužen radi nećudoredna čina, što kod obojice još ne znači duševnu bolest. Ne može
se dakle dokazati, da je Darinka sa amencijom nasljedno obterećena, nego se može uztvrditi, da
je ona od oca alkoholičara i prolazno umobolne matere nasliedila sklonost na duševno
oboljenje. Oboljenje je moglo i sasvim izostati ili pod uplivom osobitih životni prilik
buknuti.”765 Jedna od takvih životnih prilika za Žirovčića je i ulazak u brak jer 217 „”Sam brak i bračne dužnosti ne mogu biti dostatnim motivom za navalu duševne bolesti, ali
nesretan brak, otrovan bezobzirnim vriedjanjem i ponižavanjem mlade supruge po njezinom
suprugu, kojega je ona uza sve to ljubila, te je moralo njezinu duševnost duboko potresti i to je
bio povod da je duševna bolest kod nje tako silno izbila.”766 „”Sam brak i bračne dužnosti ne mogu biti dostatnim motivom za navalu duševne bolesti, ali
nesretan brak, otrovan bezobzirnim vriedjanjem i ponižavanjem mlade supruge po njezinom
suprugu, kojega je ona uza sve to ljubila, te je moralo njezinu duševnost duboko potresti i to je
bio povod da je duševna bolest kod nje tako silno izbila.”766 Iako će kasnije Žirovčić reći da se Darinka tijekom boravka u zavodu „nije žalila na muža” te da
„je izgubila moć bistra sjećanja i sve nježnije sveze što ju čuvstveno spajahu sa svietom u
njezinoj su duševnosti raskinute. 7.2. Sukobi unutar obitelji Odlomci rastrganih uspomena, koji bi se u njezinom
neobuzdanom snatrenju i pojavljivali nebi imali nikakve vriednosti, da se na njih gleda kao na
njezino mišljenje iz doba mladobračnog života.”767 istaknut će i da Darinka nije i vjerojatno neće
biti sposobna za bračni život radi „opasnosti za svoje potomstvo”, 768 ali će kao uzrok njezine
bolesti navesti „affectus (nesretan brak”769. U svom mišljenju, Žirovčić govori o Darinki znatno manje dehumanizirajućim rječnikom nego
što ga koristi kad govori o nekim drugim stenjevačkim štićenicima. Kad govori o „raskidanju
nježnijih veza” Žirovčić na trenutak čak djeluje sentimentalno i u njegovom se govoru može
naslutiti suosjećanje. Usprkos svom kliničkom somatizmu, čini se da je Žirovčić kroz iskustvo
interakcije s Darinkom, u njoj prepoznao žrtvu nasilja u braku, te na pomalo nekarakterističan
način, odredio traumu zlostavljanja kao uzrok njezine bolesti. Glas o takvom Žirovčićevom
mišljenju se proširio u krugu tada još uvijek malene medicinske zajednice, i preko prijatelja koji
nije imenovan, došao do Damjana Dj. koji je reagirao ljutitim pismom Žirovčiću. Pismo je
zanimljivo jer Damjan, da bi se obranio od optužbi za zlostavljanje koje „Darinkina porodica
trubi po cijeloj Bosni i Hercegovini”770 poseže za medicinskim diskursom. U uvodnom dijelu
objašnjava optužbe protiv sebe da je Darinku u Grazu „zaključao, nije joj dao ništa jesti, a on
otišao i lumpovao po cio dan i noć.771 U nastavku, Damjan se upušta u akademsku raspravu i
objašnjava Žirovčiću etiološke postavke koje iznosi Emil Kräpelin. Tako Damjan citira da po
Kräpelinu „ kod 60-70% pa čak i do 90% duševnih bolesnika dispozicija ima glavnu ulogu”772 te 218 da je „trauma vrlo rijedak etiološki momenat u duševnim bolestima” i da „strah, gladovanje,
brige, itd. mogu užasno biti jake, pa ipak da ne proizvedu duševnu bolest u zdravom mozgu”773. Zanimljivo je da Damjan navodi medicinsku poziciju kojoj se Žirovčić inače priklanjao u nekim
slučajevima spomenutim u prethodnom poglavlju. Također, u čitavom pismu Damjan nigdje
eksplicitno ne negira optužbe o izgladnjivanju, već se brani činjenicom da one ne bi izazvale
duševnu bolesti da Darinka nije imala hereditarne dispozicije. Nakon takve obrane, Damjan drugi
dio svog pisma u medicinskoj tradiciji naslovljuje” anamneza”. U tom dijelu Damjan navodi
gomilu anegdotskih dokaza o alkoholizmu, kriminalu i seksualnim nastranostima Darinkine
obitelji. Nijedan član obitelji nije pošteđen Damjan „dijagnoza” koje ih predstavljaju kao duševno
poremećene ili „degenerirane”. 773 Ibid.
774 Ibid.
775 Ibid.
776 Ibid.
777 Ibid.
219 7.2. Sukobi unutar obitelji Darinkin djed i otac su bili „potatori”, a poziva se i na predrasude
o Bosancima kao alkoholičarima kad kaže da je poznato „Kakvu je ulogu igrala a i danas igra po
Bosni kod srednjeg i nižeg staleža: šljivovica a kod bogatijeg: mastika.”774 Ujaci i tetke su također Zanimljivo je da Damjan navodi medicinsku poziciju kojoj se Žirovčić inače priklanjao u nekim
slučajevima spomenutim u prethodnom poglavlju. Također, u čitavom pismu Damjan nigdje
eksplicitno ne negira optužbe o izgladnjivanju, već se brani činjenicom da one ne bi izazvale
duševnu bolesti da Darinka nije imala hereditarne dispozicije. Nakon takve obrane, Damjan drugi
dio svog pisma u medicinskoj tradiciji naslovljuje” anamneza”. U tom dijelu Damjan navodi
gomilu anegdotskih dokaza o alkoholizmu, kriminalu i seksualnim nastranostima Darinkine
obitelji. Nijedan član obitelji nije pošteđen Damjan „dijagnoza” koje ih predstavljaju kao duševno
poremećene ili „degenerirane”. Darinkin djed i otac su bili „potatori”, a poziva se i na predrasude
o Bosancima kao alkoholičarima kad kaže da je poznato „Kakvu je ulogu igrala a i danas igra po
Bosni kod srednjeg i nižeg staleža: šljivovica a kod bogatijeg: mastika.”774 Ujaci i tetke su također
ubojice, alkoholičari ili priglupi, majka joj je pijanica, a brat joj je „pederast” koji „ne poznaje
nikakvog roda osim matere i sestre. On je svaki svoj rod kojitovao – sve što mu je došlo pod
ruku”775. Također navodi da sva Darinkina braća mucaju i govori kako je Darinka uvijek bila
„dosta ograničena”776. Na kraju svog pisma o odnosima svoje supruge i njene braće govori gotovo
pornografski, a priznaje da je Darinku oženio zbog svoje financijske koristi i činjenice da tada
„nije imao pojma o psihijatriji”777. Žirovčić je pismo sačuvao, ali se čini da ono nije utjecalo na
njegovo ranije izrečeno mišljenje o Darinkinoj bolesti. Bosni kod srednjeg i nižeg staleža: šljivovica a kod bogatijeg: mastika. Ujaci i tetke su također
ubojice, alkoholičari ili priglupi, majka joj je pijanica, a brat joj je „pederast” koji „ne poznaje
nikakvog roda osim matere i sestre. On je svaki svoj rod kojitovao – sve što mu je došlo pod
ruku”775. Također navodi da sva Darinkina braća mucaju i govori kako je Darinka uvijek bila
„dosta ograničena”776. Na kraju svog pisma o odnosima svoje supruge i njene braće govori gotovo
pornografski, a priznaje da je Darinku oženio zbog svoje financijske koristi i činjenice da tada
„nije imao pojma o psihijatriji”777. 7.2. Sukobi unutar obitelji Žirovčić je pismo sačuvao, ali se čini da ono nije utjecalo na
njegovo ranije izrečeno mišljenje o Darinkinoj bolesti. Slučaj Darinke Dj. pokazuje način na koji su psihijatri ponekad bili prisiljeni posredovati u
slučajevima zlostavljanja u braku, te kako je Žirovčić, potaknut konkretnim kliničkim iskustvom
i empatijom prema žrtvi, bio u stanju izaći iz okvira uvriježenih prevladavajućih psihijatrijskih
teorija. Žirovčićevo svrstavanje na stranu Darinke kao žrtve, suprotno tada aktualnim spoznajama
i optužba koju je u svom mišljenju iznio protiv kolege liječnika, govore kako su interakcije
između štićenika i psihijatara ponekad mogle probuditi i suosjećanje i osnažiti psihijatre za
ostvarivanje uvida u stanje štićenika koji su bili ispred svog vremena. Darinkin slučaj pokazuje 219 dva suprotstavljena pogleda na duševnu bolest. Ono što je osobito zanimljivo je da Žirovčić
zastupa gledište koje u psihijatriji onog vremena nije bilo često: da je trauma nasilja u obitelji
uzrokovala teško Darinkino mentalno stanje. Pritom se Žirovčić ne poziva na medicinske
autoritete već isključivo na vlastito promatranje pacijentice. Damjan Dj. koji doduše nije
psihijatar, zastupa stav koji je bio daleko učestaliji u psihijatriji devetnaestog stoljeća, negira
mogućnost da nasilje u braku uopće može biti uzrokom duševnog oboljenja. U svojoj redukciji
uzroka Darinkinog oboljenja na hereditet, Damjan se oslanja na medicinske autoritete onog
vremena. Činjenica da upravo Žirovčić odstupa od somaticističkog redukcionizma kako bi
naglasio mogućnost da se Darinka razboljela zbog toga jer je bila zlostavljanja u braku, pokazuje
da su stenjevački psihijatri često u praksi prepoznavali traumatične posljedice sukoba u obitelji i
nasilja u braku. U nekim sukobima s kojima su se liječnici u Stenjevcu susretali, ekonomsko, afektivno i
seksualno se isprepliću na nevjerojatne načine tvoreći rašomonsku sliku obiteljskih i bračnih
odnosa u vremenu modernizacije. Takav je slučaj Jakoba K., trgovca židovskog porijekla iz
Virovitice koji je prebačen u Stenjevec 1895. nakon što se liječio prvo kod Richarda von Krafft-
Ebinga, zatim u privatnoj klinici doktora Wilhelma Svetlina u Beču i u budimpeštanskom zavodu
za umobolne. Zavodski liječnici trebali su procjeniti je li Jakobova supruga imala aferu s
njegovim šogorom i poslodavcem Josipom Takačem ili su optužbe za nevjeru bile Jakobova
deluzija. Jakob je svoj sukob za suprugom i Josipom Takačem detaljno opisao u razgovoru sa
Žirovčićem i u kasnijem pismu upućenom Žirovčiću, koje je poslao tridesetog travnja, nakon
nešto više od mjesec dana boravka u Stenjevcu. 778 KPV, 1895: 2640. ,
779 Ibid. ,
779 Ibid. 7.2. Sukobi unutar obitelji Prema Jakobu, nevolje u njegovom braku počele
su kad ga je Takač nagovorio da dođe u Banja Luku i uloži novac u njegovu kožarsku tvornicu. Prema Jakovljevom mišljenju tada su Takač i njegov partner počeli manipulirati njegovom ženom
i „izprepletali oko njega mreže, da ga na taj način dovabe u Banja Luku, da mogu tjerati svoje
bezsramne orgije”778. Tijekom razgovora, Jakob optužuje ženu za flert i seksualnu nevjeru i
izražava izrazito neprijateljstvo prema njoj. Vidio je nju i Takača kako se „srdačno pozdravljaju,
diraju nogama ispod stola, sluškinje su ih ogovarale, a na posljetku mu je supruga navodno sama
priznala aferu.”Osim toga, Jakov je vidio dokaz nevjere u supruginom uljepšavanju.779 „Bijesan i 220 ljubomoran, Jakob je počeo „svoju ženu i T.-a psovati, a napokon je i samu ženu otjerao njezinoj
majci.”780 Iako je Jakov bio neprijateljski raspoložen prema svojoj supruzi i Takaču, čini se da je Takač
uspio postići znatan utjecaj nad Jakovom. Takač je tako smirio Jakova i uvjerio ga da potraže
hipnotizera kako bi hipnotizirali Jakovljevu suprugu, kako bi ona pod hipnozom izjavila da nije
prevarila svog supruga. U tu svrhu, Jakov i Josip Takač su 1894. godine posjetili Stenjevec, no
prema Jakovljevoj izjavi liječnik je odbio hipnotizirati njegovu suprugu. Nakon toga, Takač je
ustvrdio da je Jakov „uzrujanih živaca” i odveo ga Krafft-Ebingu u Beč. Krafft-Ebing je Jakovu
dijagnosticirao „Einfensuchtswahn” (ljubomorno ludilo). Krafft-Ebing ga je uputio na liječenje u
Svetlinov zavod. Jakov je tvrdio da je prije prijema u zavod Takaču predao na čuvanje svotu od
6000 forinti koju mu ovaj do danas nije vratio.781 Čini se da je Jakov istovremeno sumnjičio ženu
za aferu i s druge strane polagao veliko povjerenje u njezinog navodnog ljubavnika Takača. Dopustio mu je da ga ovaj vodi po zavodima i da mu ostavi popriličnu svotu novca bez
priznanice jer „neće me valjda prevariti”.782 Jakovljev iskaz odaje čudnu dinamiku međusobnih
odnosa unutar građanske obitelji te se na trenutak ne može jasno razlučiti pati li Jakov od
umišljaja ili je Takač zapravo umješni manipulator koji mu je razorio obitelj i financijski ga
upropastio. Žirovčić je Jakovu dijagnosticirao „neurastheniju” te ga nakon nešto više od tri
mjeseca boravka u zavodu otpustio kao poboljšanog. U zavodu Jakov govori da se radi o zavjeri
njegove supruge, njezinog brata psihijatra kojeg ne spominje imenom i Takača „s ciljem da ga
smjeste u ludnicu i da mu supruga bude u boljem položaja pri brakorazvodnoj parnici.”783. 780 Ibid.
781 Ibid.
782 Ibid.
783 Ibid. 7.2. Sukobi unutar obitelji Žirovčić ne komentira takve optužbe, no njegova nevoljkost da na duže vrijeme zadrži Jakova u
zavodu odaje da možda nije vjerovao da je Jakov ozbiljno bolestan. Zanimljivost Jakovljevog slučaja je u mjestu koje psihijatrijski diskurs i diskurs o seksualnosti
zauzima u ovom obiteljskom sukobu. Takač, optužen za zavođenje Jakovljeve žene predlaže
hipnozu kao pouzdan način za utvrđivanje istine o bračnoj nevjeri, a Jakov prihvaća tu metodu
bez previše sumnje. Kod Krafft-Ebinga, Jakovljeva ljubomora je patologizirana u osobitu vrstu
poremećaja, kojem je emocija u samom imenu i koji dotad nije bio jasno opisan u psihijatrijskoj 221 praksi. I samo ime Krafft-Ebingove dijagnoze, nije tipično za austrijsku i njemačku psihijatrijsku
tradiciju. U Stenjevcu, Jakov se služi psihijatrijskim diskursom kako bi dokazao da nije
poremećen. Jakov svoj razgovor s liječnicima počinje negirajući obiteljsku anamnezu koju im je
prenio brat njegove žene psihijatar koji je opisao njegovog oca kao alkoholičara, i izjavio da mu
se bratić ubio a sestra bila gluhonijema: „Detaljno opisuje svog oca koji ”nije bio potator” tvrdi da brat njegove žene laže o tome. Govori
o bratiću koji se ubio u Beču, te opravdava njegov čin (”čini mi se da je imao sifilis i bojao se od
revolvera pa smo se čudili da se ubio”) i sestri koja je umrla kao gluhonijema”784 Jakov je, dakle upućen o narativ o hereditetu kao uzroku duševne bolesti i trudi se opovrgnuti ga. I Jakov i Takač se zapravo upuštaju u vlastito, laičko tumačenje Jakovljeva stanja putem
aproprijacije diskursa psihijatrijske struke, a nekonzistentne i neuobičajene dijagnoze i
oklijevanje psihijatara da jasno zauzmu stav o sukobu, upućuje na činjenicu da ni psihijatri nisu
mogli rasplesti mrežu optužbi koju su Jakov, njegova supruga i njezin brat ispleli jedni oko
drugih. Osim psihijatrijskog diskursa, Jakov otvoreno progovara o vlastitom poimanju
seksualnosti i njegove riječi pružaju rijedak uvid u stavove građanstva o seksualnosti. Jakov
spominje kako je otvoreno govorio sa suprugom o seksu i kako mu je ona spomenula da se
upustila u čin analnog seksa s Takačem: „Žena mu je, jednom, posle svršenog coitusa... ...počela
pričati kako je Josip Takač š njom na zahodu po dva puta i to per buzora puteno obćio i kako njoj
to ništa škodilo nije...”785 S jedne strane, Jakovljevo ponašanje granični s patološkom ljubomorom, no s druge ne zna je li
njegovo ponašanje posljedica kombinacije neobičnog odnosa sa šogorom Takačem i suprugom
koja se vjerojatno nije ponašala u skladu s Jakovljevim patrijarhalnim nazorima. 784 Ibid. 785 Ibid. 784 Ibid. 7.2. Sukobi unutar obitelji Znakovito je da
Žirovčić, nigdje nije opisao Jakova kao nekog tko umišlja supruginu aferu. I nakon boravka u
Stenjevcu, Jakov je ustrajao u tvrdnji da ga je supruga prevarila, a istog je mišljenja bila i
Jakovljeva strana obitelji. Slučaj Jakova K. govori da su se građani na laički način služili
psihijatrijskim diskursom pri objašnjavanju sukoba unutar obitelji. Sve strane u iznijetom
obiteljskom sukobu ga objašnjavaju medicinskim pojmovima i pozivaju se na psihijatrijski skup
znanja o psihi, seksualnosti i emocijama. Psihijatrima je dana uloga posrednika koji trebaju
objasniti i razrješiti sukob i utvrditi istinu o mogućoj nevjeri Jakovljeve supruge. Od psihijatrije 222 se traži znanstvena i objektivna procjena i validacija emocija oko kojih nastaje sukob: ona treba
razdvojiti opravdanu ljubomoru od patološke, stvarnu seksualnu transgresiju od umišljene,
zamišljenu nepravdu od stvarnog iznevjeravanja povjerenja. Može se reći da pojedine građanske
obitelji vide psihijatriju kao validaciju emotivnog režima. Sukobi unutar obitelji u nekim su stenjevačkim zapisima završavali tragično. Manda M.,
nadničarka iz Aljmaša, boravila je u Stenjevcu u pet navrata između 1885. i 1914. godine, kad je
umrla od „bronchopneumonie”786. Njezina povijest bolest sadrži intenzivnu komunikaciju između
Mande, stenjevačkih ravnatelja i Mandinih ukućana koji su od nje živjeli u strahu. Spirala nasilja
u ovom Aljmaškom kućanstvu doživjela je vrhunac 1888. godine kad je probola svog supruga
Marijana nožem.787 Mandin život je od djetinjstva bio težak: liječničko izvješće s kraja 1888. godine, upućuje da joj je otac bio „potator” a da je ona rođena kao nedonošče u 7 mjesecu
trudnoće, te da je patila od „hydrocephalus”. „Hydrocephalus” ili „vodena glava” je medicinsko
stanje koje je moglo upućivati na neki oblik neurološkog oštećenja. Manda je prvi put u
Stenjevcu boravila od 29.9. 1885. do 23. 5. 1886. uz jedan kratkotrajan pokušaj bijega nakon
kojeg je vraćena u Stenjevec. U zavod ju je doveo njezin suprug Marijan s kojim je imala i dijete. 786 KPV, 1914: 6573. 787 Ibid. 788 Ibid. 788 Ibid.
789 Ibid. 787 Ibid. 7.2. Sukobi unutar obitelji On je općinskom liječniku kako već deset godina živi u strahu od nje: „Po pričanju Marijana Mariančevića jeste isti opazio još prije 10 godina da njegova žena
Manda nije duševno posve zdrava, a to je zaključio stoga što je u to doba začela mnogo
govoriti, u govoru skakati od jedne stvari čak na desetu, pritom je postala svadljivom, nije dala
niti mužu niti komšiluku mira, svakoga uzimala u pretres, osobno ga grdila najgadnijim
riečima, te s te svoje mane postala je upravo strašilo cieloga sokaka, a zatim bi posao svoj
zanemarila, a povremeno i nasilnom postajala tako da joj je muž morao mlogu noć van kuće
probaviti od straha.” 788 Dok liječničko izvješće, pozivajući se na suprugov iskaz od Mande pravi svojevrsni objekt straha
od nasilja, „strašilo cijelog sokaka” Manda u stenjevačkom zavodu daje vlastito objašnjenje svog
ponašanja: „Ne taji ni sama da joj u glavi nekoliko dužicah manjka, nu dodaje da se više čini
ludom nego jest, jer se u društvu takvom ne može pametno vladati.”789 223 Manda dakle govori da se „više čini ludom nego jest” jer joj njezina okolina onemogućuje
pametno vladanje. U svom prvom iskazu, Manda ne navodi čime ju njezina okolina potiče da se
ponaša na način svojstven duševno bolesnoj osobi. U samom zavodu izrazito je nemirna i dolazi
u sukob sa zavodskim osobljem: „U bolnici bijaše obično nasilna i nesnosljiva. Neima toga što bi joj godilo, ili joj u volju
učinilo. Psuje bolničarke groznimi psovkami i pogrdami, baca jelo na tlo, svojom pogani maže
sobu, viče pri tom što ju grlo nosi s čega promukne, ili opet nariče kao nad mrtvacem, drugi
put pak časak boga moli, a svrši psovkama na boga, treći put opet skače i igra.” Povijest bolesti uz opis ponašanja koje je više-manje opće mjesto u kartonima nemirnih štićenika,
naglašeno spominje Mandino nezadovoljstvo, time zapravo implicirajući da je njezino ekstremno
ponašanje oblik bunta protiv nečega, a o buntovnosti govori i činjenica da je jednom pobjegla iz
zavoda. Njezina prvotna dijagnoza glasila je „Periodična mahnitost uz benavost”790 iz čega se vidi
da su ju liječnici smatrali duševno zaostalom osobom sklonom napadajima bijesa. Manda je u Stenjevcu drugi put završila nakon što je 14. prosinca 1888. ubila muža nožem
tijekom svađe. 790 Ibid.
791 Ibid.
792 Ibid.
793 Ibid. 7.2. Sukobi unutar obitelji Liječničko izvješće govori da je Marijana „...u svadji nožem u lievu stranu leđa
duboko probola, tako da mu je slezenu ozliedila uslied čega je silni izliev krvi u trbušnu šupljinu
nastupio tako da je za kratko vrieme umro”791. Dijagnoza je ovog puta glasila „periodična
mahnitost” a u stenjevačkoj se povijesti bolesti po prvi put spominje „slabljenje etičkih i
estetičkih čuvstava” što je u devetnaestom stoljeću bio jedan od ključnih elemenata
psihijatrijskog narativa o degeneraciji: „Opaža se neko pomanjkanje ili umanjenje estetičnoga i etičnoga čuvstva- pripovjeda ko
sasvim bezazlen događaj s mužem, te lahke duše- tako rekuć smijuć se- opetuje kako je muža
ubola, te joj ga nije žao. U tom pokazuje i slaboumnost jer slabije kombinira i sudi, djetinjasta
je i jogunasta.”792 Osim liječnikovog mišljenja, povijest bolesti iz 1889. donosi i Mandin glas spominjući kako ona
često ponavlja frazu „Manda luda, ne imade suda”793 i donoseći njezino opravdanje za umorstvo
supruga:„Veli da muža ne bi bila niti ubila da ju nije dražio riečim ”luda Manda” pače i tukao kad 224 bi se napio. Ići će svojoj kući, gdje je čeka njezino diete koje sada pazi neki Kovač, koji stanuje u
kući i uživa zemljište njezino.”794 Štićenici koji su počinili zločin u neuračunljivom stanju su najčešće mogli računati na doživotni
boravak u Stenjevcu: pritisak javnosti da se „opasni luđaci” barem na ovaj način liše slobode, bio
je prevelik da bi psihijatri riskirali ugled vlastite profesije puštajući potencijalno opasne štićenike
na slobodu. Zato je jako neobično da je Manda, nakon godine dana boravka u Stenjevcu 1.svibnja
1890. otpuštena kao poboljšana. Povijest bolesti često govori o Mandi kao o „djetinjastoj i
slaboumnoj” te im se usprkos svojem zločinu, Manda ne čini opasnom. Tri godine kasnije, 9. svibnja 1893. Mandu će ponovno prebaciti u Stenjevec iz beogradske
bolnice. U beogradskoj je bolnici završila nakon što je, u posjetu rođacima oboljela od neke očne
bolesti. Tamo je ubrzo postala nasilna i fizički napadala bolesnice i bolničarke. Izvješće iz
beogradske bolnice navodi kao njezinu dijagnozu „Manie reigne chez une dégénérée” 795
(hereditarnu maniju zbog degeneracije) uzrokovanu alkoholnim pićima. Povijest bolesti ne
donosi detalje incidenta koji je doveo do Mandine hospitalizacije, no čini se da se i ovaj put
radilo o nekom sukobu u krugu njezine obitelji, jer je ta okolnost istaknuta i u stenjevačkoj
povijesti bolesti i u liječničkom izvješću iz Beograda. Ni u jednom od dva medicinska kartona
nema spomena bilo kakve očne bolesti. 794 Ibid.
795 Ibid 7.2. Sukobi unutar obitelji Manda je pobjegla iz Stenjevca 23. prosinca 1893. godine. Ubrzo je uhvaćena i 15. siječnja 1894. vraćena u Stenjevec. Njezino ponašanje ponovno
varira između djetinjastog i izrazito nasilnog. Često traži burmut i cigare od liječnika i bolničarki,
ali zabilježen je i incident prilikom kojeg je „držalo od drvene žlice turila jednoj bolesnici u
vaginu i ozledila ju, tako da je ova krvarila”796 . Doduše, iako zapis iz povijesti bolesti tumači taj
čin kao nasilan, nije isključeno da se možda radilo o seksualnom činu koji je slučajno završio
ozljedom. Ponovno je pobjegla trećeg kolovoza 1895. godine. Ponovno je dovedena u Stenjevec
23. veljače 1906. godine. Nakon što je provela gotovo deset godina u bijegu, Manda se vratila
kako bi od pastorke (kćeri pokojnog supruga iz ranijeg braka) tražila pravo na kuću. Uz Mandinu
povijest bolesti priloženo je i pastorkino pismo koje upozorava na Mandinu umješnost u bježanju
iz zavoda izražava realan strah pred njom: 225 ”Dana 23 ovoga otpravljena jest odavde luđakinja Manda Marijančević na liečenje k slavnom
naslovu. Ista bijaše prije 10 godina sa istom bolesti na liečenju u pomenutom zavodu iz koga je
umakla posakrivce. Toga radi dolazim oniže potpisata slavnu upravu zamoliti da na itu paziti
dade da ne umakne, a u slučaju da bi ista iz zavoda umakla molim da mene slavna uprava
odmah o tome obavijesti: radi tog da mogu oko moje kuće postaviti dati stražu i pažnju jer ona
u svome ludilu bi mogla kuću da zapali ili inu nedaću da napravi.”797 S druge strane, čini se da je Mandino blago djetinjasto ponašanje također nestalo. Ona se ponaša
nasilno, te otvoreno prijeti pastorki ubojstvom. Ipak, liječnik koji je napisao uputnicu za prijem u
Stenjevec nastoji prikazati sukob Mande i njezine pastorke donekle objektivno: „Bolesnica je momentarno mirna, vrlo živahno gestikulira i razgovara, smije se, mnogo
pripovjeda, psuje svoju pastorku i njenog priležnika koji da ju žele baciti iz kuće van (nešto je
uistinu na stvari, jer se ona sa pastorkom ne slaže, svojata kuću za se, a pastorka tvrdi da joj
pripada samo 4. dio). Muž je bio padavičar i pijanac, često ju tukao po glavi. Kad je htio
prodati zemlju, došlo je do raspre i tom prilikom do ubojstva. Čin je ispočetka tajila.”Od tri
nedjelje je sasma nemirna, grozi se da će zaklati pastorku, zapaliti kuću etc. Konflikt je u kući
navodno nastao jer je zadnje vrieme pastorka uzela k sebi svog ljubavnika. 797 Ibid. 797 Ibid.
798 Ibid. 798 Ibid. 7.2. Sukobi unutar obitelji Navodno rado pije,
slabo spava, čista je, jede dobro.”798 Mandina dijagnoza će sad u skladu s novom, “meynertovskom” klasifikacijom, koju je uveo Ivo
Žirovčić, glasiti „Mania hysterica”, a povijest bolesti više neće sadržavati bilo kakve reference na
Mandinu djetinjastu i duševno zaostalu prirodu, umjesto toga ju prikazujući kao potencijalno
opasnu ženu sklonu nasilnim ispadima i alkoholu. Manda će u Stenjevcu dočekati smrt od
„bronchopneumonie” 13. 4. 1914. Slučaj Mande M. je ilustrativan jer pokazuje na koje su načine psihijatrijske institucije
posredovale prilikom sukoba unutar obitelji. S jedne strane, prilikom ranog Mandinog boravka u
Stenjevcu, psihijatri i bolničari iskazuju ambivalentne stavove između percipiranja Mande kao
nasilne duševno oboljele osobe i duševno zaostale žrtve suprugovog zlostavljanja. Nakon
opetovanog Mandinog nasilničkog ponašanja i brojnih bjegova, njihova se percepcija Mande
mijenja. Nema više govora o „periodičkim” napadajima ludila- Mandi je dijagnosticirana
histerična manija, bolest svrstana u konstitutivne i degenerativne neuroze. Ta je dijagnoza nosila i 226 daleko značajnije moralističke implikacije od jednostavne urođene slaboumnosti. Ostaje nejasno
je li Manda na početku glumila bezopasnu osobu kako bi izbjegla kaznu za umorstvo i lakše
pobjegla ili su liječnici počeli čitati njezino djetinjasto ponašanje kao oblik „histeričnog”
ponašanja, a ne kao simptom urođenih mentalnih poteškoća. Sukobi u obitelji stavljali su stenjevačke psihijatre u prilično nezavidan položaj. Priče o
muževima i ženama koji predstavljaju svoje supružnike kao psihički bolesne kako bi došli do
financijske koristi ili olakšali ljubavnu aferu kružile su u tisku i popularnim romanima poput
„Nevine u ludnici” tijekom čitavog devetnaestog stoljeća Uz to, dugotrajne posljedice
emocionalnog zlostavljanja i „gaslighting” nisu bili prepoznati unutar devetnaestoljetne
psihijatrije. Psihijatri su morali stjecati uvide u privatni život štićenika, uzimati u obzir
kompleksnost njihovih obiteljskih odnosa i često se hvatati u koštac s oblicima nasilja koji nisu
bili objašnjivi unutar tadašnjih somaticističkih paradigmi. U nekima od slučajeva, poput onog
Darinke Djokić, psihijatri ipak priznaju posljedice tih oblika nasilja na duševno zdravlje. U
drugim slučajevima, poput onog Jakova K., često pridaju veliku pažnju glasu štićenika kako bi
bili sigurni da oni sami ne postaju sredstvo manipulacije u obiteljskom sukobu. Napokon, u
nekim slučajevima poput Mandinog, psihijatri su svjedočili psihičkom i fizičkom nasilju unutar
obitelji koje je trajalo desetljećima i znanje o kojem je često informiralo njihove dijagnoze. Može
se reći da je susret psihijatrije s obiteljskim odnosima uvelike redefinirao i psihijatriju i poimanje
obitelji, te doveo do često nejasnih ispreplitanja intimne sfere obiteljskog i javne sfere
zdravstvenog. 799 Iveljić, 2007: 318. 7.3.Dječaci s revolverima: nasilničko ponašanje adolescenata Uz promjenu poimanja obitelji, psihijatri i liječnici na prijelazu stoljeća počinju u povećanoj
mjeri obraćati pozornost na djecu i adolescente zasebnu dobnu skupinu koja ima vlastite potrebe,
ali i čije je ponašanje također potrebno regulirati i o njemu skrbiti. Adolescencija je u Europi i
Sjedinjenim Državama prepoznata kao zasebno životno razdoblje tek u drugoj polovini
devetnaestog stoljeća, a u Austro-Ugarskoj Monarhiji, Allgemeines Buergerlich Gestzbuch nije
tretirao osobe starije od četrnaest godina i mlađe od 24 godine kao punoljetne799. Prije
prepoznavanja adolescencije, kojem je ponajviše doprinio američki psiholog Stuart Hall, pojam je 227 često bio obuhvaćen elastičnim definicijama djetinjstva koje su isto nekad protezale i do tridesete
godine života.800 Mnogi povjesničari adolescencije usko vezuju adolescenciju s procesima urbanizacije i
modernizacije. John i Virginia Demos, tako postuliraju da su ruralne obitelji bile karakterizirane
unutarnjom kohezijom između dobnih skupina: i djeca i odrasli dijelili su sličnu vrst poslova,
imali slične oblike razonode, kretali se unutar istog kruga ljudi i imali slična očekivanja u
pogledu budućnosti.801 U modernim gradovima, djeca nisu imala ekonomsku ulogu unutar obitelji
kakvu su imala na selu. Ako su radila, kao u slučaju dječjeg tvorničkog rada, njihov posao bio je
drugačiji od onog njihovih roditelja, Također, na poslu, ulici i u školama, kretali su se u društvu
svojih vršnjaka. Ti faktori doveli su do određenog „diskontinuiteta među generacijama” koji je
učinio adolescenciju kao razdoblje fizičkog i psihičkog razvoja uočljivom.802 Povjesničar
adolescencije Jon Savage, također dovodi prepoznavanje adolescencije koje se događa u
devetnaestom stoljeća u vezu s modernizacijskim procesima. Savage naglašava ulogu političkih i
ekonomskih promjena s kraja osamnaestog stoljeća na poimanje mladosti u Zapadnom svijetu. Prema Savageu adolescencija je konstruirana iz niza društvenih procesa koji su nepovratno
promijenili svakodnevicu mladih i njihovo mjesto u društvu. Industrijska revolucija je potaknula
preseljene stanovništva sa sela u gradove, stvorivši urbano društvo temeljeno na materijalizmu,
konzumerizmu i masovnoj proizvodnji, te zauvijek mijenjajući tradicionalne strukture rada,
susjedstva i obiteljskog života. Ti procesi odvijali su se kroz čitavo dugo devetnaesto stoljeće i
događali su se istovremeno s prodorom sve većeg broja egalitarnih političkih ideja i povećanjem
pismenosti.803 Svijet adolescenata, naročito onih koji su dolazili iz ekonomski depriviranih društvenih slojeva
bio je ispunjen nasiljem. Tjelesno kažnjavanje djece bilo je široko rasprostranjeno i smatrano je
prihvatljivim oblikom discipliniranja, te se događalo u mnogim domovima i školama. Život u
siromaštvu, često je navodio mlade na koketiranje s raznim oblicima kriminalnog i devijantnog
ponašanja. 800 Shuttleworth, 2010 :20. 801 Demos i Demos, 1969: 636. 802 Ibid: 637. 802 Ibid: 637. 802 Ibid: 637. 803 Savage, 2007:4-5. 801 Demos i Demos, 1969: 636. 805 Schecter, 2000: 91. 804 Ibid: 29. ,
806 Ibid: 86-87. 806 Ibid: 86-87. ,
806 Ibid: 86-87. 7.3.Dječaci s revolverima: nasilničko ponašanje adolescenata Mnogo izraženiji doticaj sa čitavim spektrom političkih ideja, povezan s rubnim
položajem mladih, ograničenjima koje je nametalo tradicionalno društvo i egzistencijalnom
nesigurnošću poticao je adolescente prema buntovnom ponašanju i često prema političkom
ekstremizmu. Problem adolescentske delinkvencije i sve vidljivijeg nasilja među mladima brzo je 228 privukao pažnju široke javnosti. Psihijatri su, kao stručnjaci za različite oblike devijantnog
ponašanja također sudjelovali u pokušajima da se novi društveni problem adolescentskog nasilja
objasni kroz medicinski diskurs. Prepoznavanje adolescencije i društvenih problema vezanih uz istu u medicinskim i pravnim
krugovima rezultiralo je različitim teorijama o uzrocima devijantnog ponašanja adolescenata. Ekstremni primjeri adolescentskih zločina poput onog Jesseja Pomeroya, petnaestogodišnjaka iz
Bostona koji je otimao, mučio i ubijao djecu iz susjedstva i Anne Marie-Boeglin,
sedamnaestogodišnjakinje iz Stettina koja je otrovala svog oca i dvojicu braće plijenili su pažnju
tiska željnog senzacije, ali i psihijatara koji su odlučili sudjelovati u nastojanjima da se
delinkvenciju objasni i disciplinira. Za psihijatre, devijantno ponašanje adolescenata bilo je društveni i medicinski problem. Taj je
problem sagledavan u skladu s moralističkim pogledima devetnaestoljetnih liječnika na duševnu
bolest, kao i s biološkom paradigmom engleske i njemačke psihijatrije koja je povezala pojam
„borderlandsa” s načelom herediteta kao primarne etiologije . Također, slučajevi adolescentskog
nasilja bili su u skladu s eugeničkim postavkama psihijatara poput Nordaua koji su govorili o
postupnoj degeneraciji populacije. Nordau je u svojoj knjizi Degeneracija moralističkim
diskursom eksplicitno istaknuo utjecaju nove generacije književnika poput Baudelairea,
Nietzschea i Wildea kao pisce koji slave individualnost, opisujući Wildea kao „patološku
aberaciju rasnog instinkta”804 Devijantno ponašanje mladih bilo je u okviru tih narativa uglavnom
izolirano od društvenih okolnosti, te je u njemu često tražen dokaz hereditarnog slabljenja mladih
generacija. Ipak, ponegdje se naglašavala uloga siromaštva i utjecaj pogubne literature na mlade. U slučaju Jesseja Pomeroya, mnogo je pažnje posvećeno njegovoj strasti prema šund romanima
koji su šezdesetih i sedamdesetih godina 19. stoljeća kao široko dostupan način razonode
doživjeli izrazitu popularnost među mladima, naročito onima iz urbanih radničkih slojeva.805 No
jednaka pažnja posvećena je i veličini i obliku Pomeroyjeve lubanje i činjenice da mu je jedno
oko bilo deformirano što su novinari koji su pratili slučaj smatrali sigurnom stigmom hereditarne
degeneracije koja je obilježila Pomeroya kao rođenog zločinca.806 806 Ibid: 86-87. 229 Psihijatrijski narativi o nasilnom ponašanju adolescenata bili su dijelom medicinskog diskursa o
duševnim oboljenjima djece i mladih koji se u psihijatriji počeo razvijati od sredine devetnaestog
stoljeća. 808 Esquirol, 1845: 34. 807 Shuttleworth,2010: 20. q
,
809 Ibid: 372. q
809 Ibid: 372. ,
808 Esquirol, 1845: 34. q
,
809 Ibid: 372. 7.3.Dječaci s revolverima: nasilničko ponašanje adolescenata U prvoj polovici devetnaestog stoljeća, psihijatri se nisu mogli usuglasiti mogu li djeca,
budući da još nisu razvila „racionalnost odraslih” uopće patiti od ludila.807 Iako Haslam, Esquirol
i Morel spominju primjere djece i adolescenata koji pate od psihičkih poteškoća navedeni
slučajevi su često bili anegdotalni i psihijatri se njima nisu bavili na sustavan način niti ih
promatrali odvojeno od duševno oboljelih odraslih. Pogledi na dob i ludilo često su bili
nesistematični i kontradiktorni: Esquirol tako navodi da se u djetinjstvu može pojaviti jedino
mentalna zaostalost, a da je pubertet, kao „razdoblje menstruacije i naglog rasta” životna dob kad
se prvi put javljaju simptomi duševnih bolesti.808 Ipak Equirol u nastavku svoje studije donosi
slučajeve sedmogodišnjih djevojčica oboljelih od „umorstvene manije” prikazavši ih u poglavlju
o monomanijama809. Esquirol i ostali psihijatri prve polovine devetnaestog stoljeća uglavnog
naglašavaju utjecaj lošeg odgoja na razvoj psihičkih poremećaja kod djece. Prvi stručni članak koji se bavi ludilom u djetinjstvu i adolescenciji bio je tekst Jamesa Crichtona
Brownea „Psychical Diseases of Early Life” (Duševne bolesti u ranoj životnoj dobi”). Browne će
se kasnije proslaviti kao jedan od vodećih britanskih neuropsihijatara i dati ime Browneovom
znaku, dijagnostičkom znaku za rano prepoznavanje progresivne paralize. Članak je rezultat
predavanja koje je devetnaestogodišnji student medicine Browne održao pred edinburškim
Kraljevskim medicinskim društvom. Objavljen je u The British Journal of Psychiatry 1860. godine. Browne je, uz Maudsleya bio jedan od studenata mlade generacije britanskih psihijatara
koja se počela okretati dalje od terapeutskih postavki „moral treatmenta” i okretati se
Darwinovim teorijama i somatizmu. Browne radi oštar otklon od dosadašnjih psihijatara koji su
se bavili duševnim bolestima u ranoj dobi. Prvi se njima bavi kao zasebnom problematikom i
odmiče se od odgoja kao glavnog faktora u razvoju duševnih oboljenja, naglašavajući umjesto
toga biološke pretpostavke ludila. Rad Crichtona Brownea zanimljiva je mješavina vjerovanja
preuzetih od antičkih autora ili iz narodne medicine, prevladavajućih pretpostavki „moral
treatmenta” i novih teorija o degeneraciji inspiriranih psihijatrima poput Morela. Zaokret prema
pomalo ekstremnom somaticizmu vidljiv je već od prvih stranica predavanja Crichtona Brownea. Ono počinje karakterizacijom čovjeka kao skupa hereditarnih utjecaja koji se realiziraju od 230 trenutka sjedinjenja spermatozoida i jajašca. 813 Maudsley, 1867: 262. 812 Ibid: 294. 810 Browne, 1860: 285. 814 Ibid: 266. y
814 Ibid: 266. 811 Ibid: 290. 812 Ibid: 294. 7.3.Dječaci s revolverima: nasilničko ponašanje adolescenata Spolne stanice, smatra Crichton prenose potomstvu
stečene sklonosti i slabosti predaka prema određenim bolestima, no one ne prenose samo
potencijal za razvoj djeteta u određenom smjeru već i „najsitnije i osobite posebnosti i
neobičnosti, kako tjelesne tako i mentalne koje karakteriziraju roditelje.810 U skladu sa svojim
biološkim i hereditarnim determinizmom, Browne će tako zaključiti da je ludilo prisutno već in
utero od samog trenutka začeća embrija. Osim hereditarnih utjecaja Browne naglašava sklonost
roditelja ovisnostima i seksualnim porocima kao faktor koji može utjecati na razvoj duševnih
oboljenja kod djece, navodeći neumjerenost u hrani, alkoholizam, masturbaciju i razvratan život
te duševna uzbuđenja.811 No uz te štetne uplive, Browne govori o djelovanju snažnih
emocionalnih utisaka na majku tijekom trudnoće vjerovanje direktno preuzeto antičke i pučke
medicine. Između ostalog, Browne navodi vjerovanje da žena koja je vidjela epileptičara tijekom
napadaja može roditi dijete koje će i samo patiti od epilepsije, te da blage i produhovljene crte
lica koji imaju žene u katoličkim zemljama imaju uzrok u satima koje njihove trudne majke
provedu u molitvi pred slikama Bogorodice.”812 Stavljanje takvih vjerovanja uz bok primjerima
koji govore o štetnom utjecaju alkohola na razvoj embrija svjedoče o sudjelovanju brojnih
epistemičkih lanaca znanja u formiranju psihijatrijskog diskursa. Za razliku od Esquirola, Browne
prepoznaje kod djece svaku duševnu bolest koju je moguće pronaći kod odraslih. Browneov suvremenik Henry Maudsley bio je nešto oprezniji u svojem shvaćanju duševnih
oboljenja djece, iako je dijelio Browneov ekstremni somaticizam. Maudsley je drugo poglavlje
svoje knjige The Physiology and Pathology of mind (Fiziologija i patologija uma) čije je prvo
izdanje objavljeno 1867. godine posvetio „ludilu u ranoj životnoj dobi”. U tom poglavlju
Maudsley opisuje mnogobrojne vrste psihičkih i neuroloških poremećaja ranog i kasnog
djetinjstva, počevši od konvulzivnih poremećaja kod novorođenčadi813 i noćnih strahova.814
Posebnu pažnju Maudsley posvećuje određenim poremećajima vezanim uz nasilne porive kod
djece. Budući da smatra dječji mozak nedovoljno formiranim za razvoj kompleksnih psihičkih
poremećaja, Maudsley ističe da su neki od najčešćih poremećaja „monomanije ili djelomična
idejna ludila”. Monomanije nastaju djelovanjem neke sumanute misli usađene u djetetov um na
centar za kretanje djeteta tjerajući ga na počinjenje nasilnih čina. Tim nasilnim porivima dijete se 231 ne može oduprijeti, a oni ga mogu natjerati na počinjenje ubojstava, krađa, paleža i
samoubojstava.815 Od naročitog su interesa za Maudsleya duševni poremećaji kod djece nazvani
afektivnim ludilima. 815 Ibid: 273.
816 Ibid: 281.
817 Ibid.
818 Ibid: 288.
819 Ibid.
820 Ibid: 291.
821 Ibid: 270. 7.3.Dječaci s revolverima: nasilničko ponašanje adolescenata Afektivna ludila direktno su povezana s devijantnim ponašanjem u
djetinjstvu i kasnije u adolescenciji, a Maudsley ih dijeli na dvije skupine: poremećaji nekog
temeljnog instinkta i „sistemska moralna perverzija koju laici često smatraju običnom zloćom”816
Prvu skupinu je nazvao instinktivnom podvrstom afektivnog ludila,a drugu pravim moralnim
ludilom („moral insanity proper”).817 U te dvije skupine Maudsley je svrstao niz devijantnih
ponašanja kod djece i adolescenata: od poriva da se fizički naudi ili čak ubiju vlastiti roditelji do
seksualiziranih ponašanja djece. „Moral insanity proper” za Maudsleya podrazumijeva
preuranjenu sklonost izraženoj zloći koja je od malena prepoznata kao neprirodna.818 I jedan i
drugi poremećaj Maudsley smatra posljedicom hereditarnog tereta koji su „degenerirani” roditelji
prenijeli djeci.819 Maudsley također opisuje takvu djecu na izrazito dehumanizirajući način
govoreći o njima kao o morbidnim podvrstama ljudi koji nemaju niti instinkte životinja niti
razum i svjesne aspiracije čovjeka.820 ne može oduprijeti, a oni ga mogu natjerati na počinjenje ubojstava, krađa, paleža i
samoubojstava.815 Od naročitog su interesa za Maudsleya duševni poremećaji kod djece nazvani
afektivnim ludilima. Afektivna ludila direktno su povezana s devijantnim ponašanjem u
djetinjstvu i kasnije u adolescenciji, a Maudsley ih dijeli na dvije skupine: poremećaji nekog
temeljnog instinkta i „sistemska moralna perverzija koju laici često smatraju običnom zloćom”816 Maudsley, kao ni ostali njegovi suvremenici ne spominje adolescenciju kao zasebno razdoblje. Njegove ideje o dječjem mozgu kao nedovoljno razvijenom te, uglavnom upravljanom porivima
kojima se ne može učinkovito oduprijeti utjecat će na percepciju mladih štićenika u
psihijatrijskim zavodima. Maudsleyeva eksplicitno postavljena veza iza moralnog ludila i ostalih
hereditarnih stigmi obilježit će velik dio psihijatrijskog narativa o adolescentima koji su počinili
zločine. Na kraju, iako Maudsley spominje moguć utjecaj odgoja na dječju psihu, navodeći
primjer djeteta koje je tijekom noćnih strahova haluciniralo vraga jer su mu „punili glavu
budalastim i opasnim idejama o vragu i paklu”821 njegovo gledište na razvoj duševnih bolesti u
mladoj dobi je naglašeno somaticističko i primarno prikazano kroz vokabular živčanih impulsa,
nervnih stanica i nesvjesnih pokreta kojima je nemoguće odoljeti. Utjecaj te vrste somatizma
očitovao se u načinu na koji su psihijatri pisali o svojim mladim štićenicima. Psihijatrijski diskurs 232 o mladim štićenicima će često pojašnjavati njihove postupke kroz očište poriva, previđajući
mogućnost samostalnog izbora. Velik prilog bavljenju duševnim problemima u adolescentskoj dobi dala su dvojica njemačkih
psihijatara Karl Kahlbaum i njegov asistent i učenik Ewald Hecker. Kahlbaum je početkom
sedamdesetih godina 19. ,
823 Hecker, 2009: 97. 824 Ibid. 822 Noll, 2011: 59 ,
824 Ibid. 7.3.Dječaci s revolverima: nasilničko ponašanje adolescenata stoljeća bio na poziciji ravnatelja psihijatrijskog zavoda u Goerlitzu u
Gornjoj Lužici, gdje je Hecker služio kao kućni liječnik822. Njihov glavni doprinos bio je u
opisivanju specifične duševne bolesti koja je primarno pogađala adolescente, a koju je Hecker u
članku iz 1871. godine nazvao hebefrenijom (hebephrenia, prema Hebi, starogrčkoj božici
mladosti). Hebefrenija je za Heckera bolest koja se javlja na samom kraju puberteta. Hecker ju
dovodi u vezu s procesima formiranja identiteta pojedinca u pubertetu. Hecker slikovitim
rječnikom opisuje tjelesne i duševne transformacije koje dijete prolazi u pubertetu: „...čitav niz mračnih imaginacija budi u duši mladog muškarca ili žene...Novo stvaralačko „ja”
želi aktivno prodrijeti u staro, ali ne nalazi dovoljno mjesta u postojećim oblicima. Tijelo i duša
se rastežu i šire u nezgrapnim pokušajima da se prilagode novim osjećajima i idejama... To je
doba kad se najnaglašenije suprotnosti dotiču i pojavljuju jedne kraj drugih u neuravnoteženoj
maniri. Entuzijastična ozbiljnost i sklonost ekstravagantnim idejama i zrelim razgovorima
miješa se sa specifičnom duhovitošću i sklonošću prizemnim i frivolnim šalama. Zajedno s
nježnim osjetima i osjećajima javlja se grubost i surovost...Tek krajem tog razdoblja,oko
osamnaeste i devetnaeste godine događa se skupljanje i sjedinjavanje i počinje se formirati
određeni oblik, još uvijek neodređen i krhak.” 823 Heckler osvještava postojanje i važnost adolescencije kao prijelaznog razdoblja u kojem se
formira ličnost odrasle osobe. Upravo graničnost i nedefiniranost tih godina čini adolescente
osobito sklonima hebefreniji specifičnom obliku duševnog oboljenja, koji se među ostalim
manifestira i konfliktnošću i nekontroliranim ispadima bijesa i nasilja. Hebefrenija pogađa mlade
ljude baš u trenutku kad se njihova „nova ličnost” počinje konsolidirati, djelujući destruktivno na
istu i razarajući njenu još uvijek krhku strukturu824. Slike uništenja i kaosa kojima Hecker opisuje
pubertet i hebefreniju zrcale se u destruktivnom ponašanju svojih pacijenata čije je slučajeve
donio u nastavku članka: jedan od njih je pokazivao znakove agitacije, udarajući djecu i 233 životinje825, drugi je bio „ljut na sve oko sebe, psovao, vikao i bjesnio bez razloga, te je jednom
čak fizički napao svog oca826. Također, Hecker na temelju pisama pacijenata pokazuje
nekoherentnost ponašanja koja karakterizira hebefreničare. Hebefreniju Hecker promatra
paraleleno s progresivnom paralizom jer u njima vidi dva oblika jasno prepoznatljive, neizlječive
duševne bolesti u kojima je postepno slabljenje duševnih i intelektualnih sposobnosti bolesnika
prisutno od samog početka.827. Obje bolesti počinju naglim promjenama afektivnih stanja i
slijede progresiju od manije, preko melankolije do zatupljivanja i konačnog propadanja svih
psihičkih funkcija. 829 Kräpelin, 1902: 153, 828 . Ibid: 98. 830 Ibid. 7.3.Dječaci s revolverima: nasilničko ponašanje adolescenata Ono što ih razlikuje je činjenica da se hebefrenija javlja u adolescenciji dok je
progresivna paraliza bolest zrelije životne dobi, i činjenica da hebefreniju prema Heckeru
karakterizira djetinjasto i nezrelo ponašanje i „površnost osjećaja”828 Na Heckerov klinički opis hebefrenie kao specifičnog oblika progresivne bolesti adolescenata,
nadovezat će se Emil Kräpelin, utjecajni njemački psihijatar. Kräpelin je u svom udžbeniku
kliničke psihijatrije prepoznao hebefreniju kao jedan od tipova njegove dementiae praecox, uz
katatonični i paranoidni tip. Kräpelin je samu dementia praecox smatrao bolešću mlađe životne
dobi tvrdeći da bolesnici mlađi od dvadeset i pet godina čine više od šezdeset posto pacijenata,
dok je među oboljelima od hebefreničnog tipa dementiae praecox udio bolesnika mlađih od
dvadeset i pet godina gotovo tri četvrtine.829 Kräpelin povezuje dementia praecox u širem smislu s
„autointoksikacijom” tijela tijekom puberteta,830 time zapravo pretpostavivši njezine metaboličke
uzroke, a među simptomima hebefreničnog tipa te bolesti su uz halucinacije i deluzije i afektivne
promjene i devijantno ponašanje. Osobe koje boluju od hebefrenije tako između ostalog „gube
svoju uobičajenu energiju, povlače se u sebe, postaju stidljive i osamljuju se, ili su pak
razdražljive, svojeglave i nepažljive, ne mare za sve svoje obaveze, često odlaze u krevet gdje
ostaju tjednima, ne mare ni za kakav posao. Često lutaju, osobito noću ili se upuštaju u
promiskuitetne seksualne odnose.”831 S druge strane, njihova bolest može rezultirati i agresivnim
ponašanjem od kojeg Kräpelin spominje paljenje kuća i razbijanjem prozora.832 Ukratko
Kräpelinova slika hebefrenije pokriva mnoštvo emotivnih stanja i ponašanja, od seksualnog 234 promiskuiteta do izrazite pobožnosti, od nedostatka energije do izrazite aktivnosti i kompulzivne
potrebe za kretanjem koja hebefreničara tjera na skitnju, od depresivnih stanja do nezrelog
duhovitog ponašanja i agresivnosti. Kao i kod Heckera, tijek bolesti je degenerativan i šanse
oporavka su male. Stenjevački psihijatri često liječe adolescente, ali rijetko raspravljaju o životnom razdoblju
adolescencije kao životnoj dobi od posebnog interesa. Žirovčićeva klasifikacija, oslanjajući se na
Meynerta, a ne na Kräpelina ne spominje dementia praecox. Na stranicama Liječničkog vjesnika,
bolest se spominje u popisu inventara nabave za knjižnicu Zbora liječnika iz 1903. godine kad se
spominje naručivanje knjige marburškog psihijatra Maximiliana Jahrmaerkera Zur frage der
Dementia praecox.833 Žirovčić nudi svoj pogled na hebefreniju i dementia praecox u dvjema
psihijatrijskim vještačenjima iz 1906. i 1908. godine. U prvom vještačenju Žirovčić prikazuje
slučaj 30-godišnjaka koji je ubio svog rođaka. 834 Žirovčić, 1906: 163. 835 Ibid. 833 Schwarz, 1903. 76. ,
835 Ibid. 836 Ibid: 163-164. 836 Ibid: 163-164. 836 Ibid: 163-164. 7.3.Dječaci s revolverima: nasilničko ponašanje adolescenata Zaključivši da okrivljenik boluje od hebefrenije,
Žirovčić prikazuje hebefreniju kao prijetvornu bolest koju je teško dijagnosticirati na početku
njezinog razvoja jer su njezini znakovi suviše suptilni i često ih se smatra izrazima „...zloće,
pokvarenosti jer se očituju činima odpornosti, često i škodljivosti”834. Žirovčić kao još jedan od
simptoma hebefrenije navodi sklonost neuobičajenim raspoloženjima i naoko bezrazložnim
ponašanjima:„S jedne je strane neka potpuna pasivnost i neki nepojmljivi negativizam,
posvemašnja nehajnost za sve , što se naokolo sbiva, mlitava bezvoljnost, tupost ćudi,
nepomičnost, mrtva šutnja; s druge opet strane iznenadna provala sasvim nesmislenih,
bezrazložnih, protuslovnih čina.”835 Pri opisu hebefrenije, Žirovčić ne govori o halucinacijama i deluzijama kao što to čini Kräpelin,
niti nagovještava potencijalne uzroke. Navodi da je „mladenačka psychoza” poznata pod raznim
imenima: „hebephrenia, dementia primaria – simplex- praecox i imbecilitas, glavna karakteristika
je „u polaganom otupljenju intelektualnih i estetičnih svojstvi sve do raznih stepena duševne
propasti.836 U drugom slučaju iz veljače 1908. godine, Žirovčić opisuje hebefreniju na sličan
način, kao bolest koja se razvija u mladosti ili čak još u djetinjstvu te njezin naziv prevodi kao
„mladenačku neumnost”. Simptomi su opet različita neuobičajena ponašanja i emotivna stanja:
„nepromišljenost i neposrednost, sklonost na izvanjski neosnovana zloraspoloženja ćudi i na lude, 235 blesave čine.”837 Ponovno, Žirovčić ističe da ova bolest najčešće završava potpunim propadanjem
duševnih funkcija. Istaknutim naglašavanjem emotivnih promjena i devijantnog ponašanja kao
simptoma hebefrenije, psihijatri su otvorili put medikalizaciji adolescencije. Sukobi između
adolescenata i roditeljskog ili učiteljskog autoriteta, kao i poneka emotivna stanja poput
„povlačenja u sebe” ili nagla i učestale promjene raspoloženja, mogla su biti čitana kao prvi znaci
uznapredovale duševne bolesti. Neposredno prije Prvog svjetskog rata, kad se pojam
adolescencije već počeo koristiti u psihološkoj literaturi u Sjedinjenim Državama, psihijatri u
Austro-Ugarskoj monarhiji počinju pokazivati izrazito zanimanje za problem adolescentske i
dječje delikvencije. Taj se trend odražava i u medicinskim publikacijama u hrvatskom dijelu
Monarhije, gdje Liječnički vjesnik u svibnju 1913. godine donosi prijevod članka češkog
neuropsihijatra i proponenta eugenike, Ladislava Raškovca „Potreba skrbi za mladež duševno
pogrješnu i ugroženu”. Raškovčev članak pisan je iz perspektive neuropsihijatra koji je studirao
kod Charcota u Parizu i koji je pomno pratio trendove europske psihijatrije i želio ih proširiti
među liječnicima u Austro-Ugarskoj i odaje sve veću zabrinutost zbog mnogobrojnih socijalnih
problema vezanih uz mlade, naročito mlade u urbanim sredinama. Potpisan je prezimenom
prevoditelja, doktora Machaceka. ,
838 Machacek, 1913: 251. 837 Žirovčić, 1908: 45. 7.3.Dječaci s revolverima: nasilničko ponašanje adolescenata Među mladima su, prema Raškovcu, naročito rašireni problemi
„zločinstva, prostitucije i samoubojstva” a uzrok tih problema Raškovec vidi u raširenosti
mnogobrojnih karakternih nedostataka među mladima: „Bolesna zavist, tvrdoglavost, lijenost,
ravnodušnost i rasipnost što priječe odgoj i ustrojenje vlastite eksistencije”. 838 No, sami
karakterni nedostaci ne proizlaze primarno iz odgoja, niti su posljedica socijalnih i ekonomskih
kriza u kojima se društvo nalazi. Čini se da je Raškovčev članak prvenstveno bio zamišljen kao
apel društvenim institucijama da počnu promatrati problem maloljetničkih zločina i
samoubojstava iz medicinske i eugeničke perspektive. Nakon što je naveo pojave koje laici često
smatraju uzrokom delinkvencije među mladima, poput petparačkih romana i moralne krize
društva, Raškovec odlučuje medikalizirati problem ukazujući na opasnost degeneracije. Klicu
degeneracije nose i na prvi pogled duševno zdravi ljudi: „Na oko lagana bolesna živčana i duševna stanja gmaze po tijelu društva kao plazeći čir, te
učine više štete i kvara nego patentirane i svim jasne i dobro poznate duševne bolesti. Nije tu
potrebno na široko raspredati, da su mi na misli defekti nepregledne čete nervoznih od 236 rodjenja, na fobije, opsesije, inhibicije naginjujući, bića slabe volje, bolesnog emotiviteta,
spolnih pretjeranaca, ćudoredno i čuvstveno izopačenih i anestetičkih, degeneriranih.”839 Kao način spriječavanja sve raširenije degeneracije i delinkvencije mladih koja proizlazi iz iste,
Raškovec predlaže obrazovanje školskih liječnika u neurologiji i psihijatriji kako bi mogli na
vrijeme prepoznati pojedinci koji su „duševno i živčano bolesna i degenerirani” i kako bi im se
na vrijeme mogla pružiti psihijatrijska skrb,840 zatim izgradnju zavoda za duševno oboljelo
djecu, obrazovanjem ljudi koja se svodi na podizanje „ćudoredne razine ljudstva koja utišava
strast za nasladama” i borbu protiv alkoholizma i sifilisa.”841 Raškovec svoju borbu protiv
devijantnog ponašanja mladih zasniva na istoj mješavini konzervativnih moralističkih ideja i
biološkog determinizma uvriježenog u psihijatriji. To ispreplitanje najočitije je u njegovom
objašnjenju uzroka degeneracije iz „nesređene i nesavladive čežnje za pustim nasladama” i „iz
pomanjkanja pravog poznanja i odgoja”.842 Pojam adolescencije nije primjenjivan u stručnoj psihijatrijskoj literaturi, no promjene ponašanja
i emotivnih stanja u pubertetu su percipirane od strane psihijatara. Emotivna stanja koja nisu
bila u skladu s dominantnim emotivnim režimom i devijantno ponašanje mladih postepeno su
vezivani uz hebefreniju, specifičnu duševnu bolest koja je opisivana kao bolest koja se
manifestira brojnim i raznolikim simptomima. 841 Ibid: 256-257. 842 Ibid: 256. 7.3.Dječaci s revolverima: nasilničko ponašanje adolescenata Također, narativ o degeneraciji bio je naročito
primjenjiv na adolescente- oni su bili najmlađi naraštaj i osobe promatrane u razdoblju tjelesnog i
duševnog razvoja i njihove psihičke tegobe gledane su kao posljedica moralnog posrnuća društva
i biološkog slabljenja rase. U skladu s takvim stavovima, nije iznenađujuće da je velik broj štićenika mlađih od dvadeset pet
godina došao u Stenjevec nakon sukoba s roditeljima ili zakonom i da su psihijatri posvetili
mnogo pažnje potencijalnim znakovima degeneracije na njihovim tijelima i neobičnim
emotivnim stanjima koja se mogla upućivati na hebephreniu ili dementia praecox. U jednom od
najranijih detaljnije opisanih slučajeva hebefrenije, bolest je u povijesti bolesti nazvana „mania
hebephrenica” a štićenica je bila osamnaestogodišnja kći posebnice iz Bjelovara. Njezina majka 237 dovela ju je kotarskom liječniku i opisala njezino stanje kao uzrokovano prekomjernim čitanjem i
zaljubljenošću: „Čitala je dan i noć... ...knjige najraznorodnijega sadržaja. Istim veseljem kojim je čitala
kakovu znanstvenu medicinsku ili prirodoslovnu knjigu zadubila bi se i u kakav god njemački
”Schund roman”. Od tri tjedna počela je pisati pjesme jer se je po navodu majke zaljubila te ju
ovo potonje tako uzrujalo, da je počela nesuvisno govoriti, sablazljivo se ponašati i vikati bez
razloga na svoju okolinu.”843 Liječničko izvješće također ističe da ju majka ne smatra duševno bolesnom već samo
zaljubljenom. Štićenica je ubrzo otpuštena kući kao neizlječena.844 Drugačiji tip neobičnog i konfliktnog ponašanja doveo je u Stenjevec Srećka O., bivšeg realca iz
Tršća. Srećko O. doveden je u Stenjevec tri puta između 1906. i 1911. godine, svaki put primljen
s dijagnozom amentia hebephrenica„ otpušten kao poboljšan. Umjesto neposrednog nasilnog
ponašanja, Srećka je u konflikt s roditeljima dovela njegova pasivnost, introvertiranost i
zanemarivanje obrazovanja kakvo su za njega predvidjeli njegovi roditelji. Najviše detalja o
pojavi njegove bolesti doznajemo iz pisma njegova brata u kojem se navodi da se Srećko stalno
žali: „(da) već nije 14 dana jeo ništa, da je slab, propao, da ga progonimo, netrpimo da mu ne damo
ništa jesti. Potajno naručuje liekove, ocu majci otima iz ruku novac, a ako mu se što ma i u
najljepšoj formi predbaci, odmah se razdraži tako žestoko, da se prieti vješanjem, strieljanjem
i.t.d. Zatvara se u svojoj sobi, bavi se bezsmislicama, stenografirajući,, matematikom i
sličnim.”845 U zavodu Srećko se uglavnom ponaša apatično i odbija hranu. 845 KPV, 1911: 7948. 843 KPV, 1904: bez broja. 846 Ibid. 844 Ibid. 846 Ibid. 844 Ibid. 845 KPV, 1911: 7948. 7.3.Dječaci s revolverima: nasilničko ponašanje adolescenata Na pitanje zašto je u zavodu
odgovara da mu se „brat grozio da će ga tući pa ga je stoga poslušao i dao se ovamo dovesti”846
Nasuprot poimanju hebefrenije kao neizlječive bolesti koja rezultira postupnim gubljenjem
duševnih funkcija, o čemu pišu i europski i stenjevački psihijatri velik broj mladih ljudi kojima je
ista dijagnosticirana, otpuštan je iz zavoda brzo, nakon nekoliko mjeseci. Anton P., gimnazijalac iz Požege, primljen je u Stenjevec nakon što su se njegovi roditelji žalili
liječniku da je sklon lutanju i da pati od halucinacija. No u povijesti bolesti se halucinacije na
spominju. Sam Anton ih negira u razgovoru s liječnikom, te daje nejasnu izjavu „samo ranije
843 KPV, 1904: bez broja. 844 Ibid 238 imao je ružne, vidio zmije, osobe malene, sitne koje se samo poskliznu.”847 No bijesna pisma koja
je Anton slao roditeljima ukazuju na činjenicu da je između njih postojao neki sukob. U dvjema
pismima priloženima povijesti bolesti Antonov ton djeluje konfuzno i ogorčeno. Anton opetovano
zahtjeva da mu roditelji kažu što žele i očekuju od njega: „U ostalom, ja hoću da znam točno i potpuno što hoćete, a onda dalje što bilo od mene, meni je
svejedno, prije ili poslije smrti se ne bojim, a to vam je dosta. Zato dođite, što prije, jer što
kasnije, bit će ljući sud među nama. Hoću da znam zašto živim i zašto vi sada živite. Koliko je
vama do života, ne znam ali meni vrlo malo, te bi bilo čudo da bi se preokrenulo, jer mi je sve
dodijalo. Ovdje sam malo ozdravio, nisam gledao baš to oko vas, što me je najviše mučilo, pa
vas molim da me sada odavde izbavite.”848 Iako Anton nigdje ne eksplicira detalje svog sukoba s roditeljima, iz tona pisma se može
zaključiti da ih krivi za svoje teško duševno stanje i da se, u neku ruku istovremeno osjeća
napušteno od njih i nemoćnim ispuniti očekivanja koja su postavili pred njega. Anton je, kad je
bio primljen u Stenjevac imao dvadeset i dvije godine, i zakonski je još uvijek bio u skrbi svojih
roditelja, bez zanimanja i vlastitih sredstava za život, a sama obiteljska situacija mu je
nedvojbeno izazivala emotivnu patnju, na što upućuju njegove izjave da mu je dosta života. Iako
mu je dijagnosticirana hebefrenije koju se smatralo neizlječivom, Anton je otpušten kao zdrav
nakon tri mjeseca boravka u zavodu. Marica A. 847 KPV, 1911: 7989. 849 KPV, 1911:7701. 848 Ibid. 850 Ibid. 850 Ibid. 848 Ibid. 7.3.Dječaci s revolverima: nasilničko ponašanje adolescenata osamnaestogodišnja sluškinja iz Vaganca upućena je u Stenjevec iz bolnice Sestara
Milosrdnica u Zagrebu gdje se na veneričnom odjelu liječila od upale maternice i konjuktivitisa. Za vrijeme liječenja počela se ponašati konfliktno, bila je „neposlušna, svađala se s drugim
bolesnicama i tražila muško društvo, pače posjećivala muškaračke sobe”849. Liječnik iz bolnice
Sestara Milosrdnica u svjedodžbi daje zanimljivo objašnjenje svoje odluke da uputi Maricu u
Stenjevec. Odlučio se za taj korak nakon što nespecificirane „disciplinarne kazne” nisu
djelovale. Marica je prvo premještena na psihijatrijski odjel, gdje je postala još uzrujanija, nakon
čega je upućena u zavod. 850 Takvo postupanje implicira da su neki liječnici gledali na
psihijatrijski zavod kao na instituciju koja može poslužiti „discipliniranju” devijantnih pojedinaca
koji nastavljaju prkositi autoritetu usprkos kaznama. U Stenjevcu se Marica ponašala primjerno,
te nije dolazila u sukob s drugim štićenicama niti s liječnicima. Povijest bolest navodi kako se
847 KPV 1911: 7989 239 „sasvim razbistrila, smirila, postala uljudna, prijazna, pozdravlja liječnike sa: klanjam se, daje im
ruke, umiljava im se, traži pudera, ponaša se prema njima erotično, ali pristojno.”851 Prilikom
razgovora s liječnikom Marica je na pitanje zna li čitati ili pisati „spremno i razumno” odgovorila
da ne zna „jer je nitko nije za mlada učio, a sad je već kasno – ljubiti je ali već mlada naučila.” 852
Marica je puštena kući kao zdrava nakon godinu dana boravka u zavodu, a iz zapisa se da
zaključiti da su liječnici zaključili da je ozdravila jer se ponašala staloženo i jer je bila marljiva
prilikom rada u kuhinji koji joj je dodijeljen u svrhu terapije. „sasvim razbistrila, smirila, postala uljudna, prijazna, pozdravlja liječnike sa: klanjam se, daje im
ruke, umiljava im se, traži pudera, ponaša se prema njima erotično, ali pristojno.”851 Prilikom
razgovora s liječnikom Marica je na pitanje zna li čitati ili pisati „spremno i razumno” odgovorila
da ne zna „jer je nitko nije za mlada učio, a sad je već kasno – ljubiti je ali već mlada naučila.” 852 Marica je puštena kući kao zdrava nakon godinu dana boravka u zavodu, a iz zapisa se da
zaključiti da su liječnici zaključili da je ozdravila jer se ponašala staloženo i jer je bila marljiva
prilikom rada u kuhinji koji joj je dodijeljen u svrhu terapije. 851 Ibid.
852 Ibid. 851 Ibid. 852 Ibid. 7.3.Dječaci s revolverima: nasilničko ponašanje adolescenata Romantične emocije i seksualnost mladih djevojaka se često nalaze u žarištu medicinskog
pogleda stenjevačkih liječnika koji u povijestima bolesti naročito bilježe govor o seksualnim i
romantičnim iskustvima i primjere ponašanja koja interpretiraju kao „erotična”. Ako je agresivno
ponašanje štićenice navedeno kao povod njezinu smještanju u Stenjevec, stvara se asocijativna
veza između tek probuđene ženske seksualnosti i agresije. Kao jedan od osnovnih simptoma
hebefrenije i dementia praecox kod muškaraca prepoznavana je njihova pasivnost i povlačenje u
sebe, što govori o činjenici da je diskurs o tim bolestima unutar hrvatske psihijatrije bio izrazito
orođen: patološkom se smatralo aktivno pokazivanje seksualnosti kod djevojaka i introvertiranost
kod dječaka. Stenjevački liječnici čini se, nisu shvaćali hebefreniju i dementia praecox kao
neizlječive, već su, čini se imali stav da je moguće zavodskim liječenjem disciplinirati
„devijantne” emocije mladih štićenika i uklopiti ih u postojeći emotivni režim. Takav stav
rezultirao je otpuštanjem tih štićenika kao „poboljšanih” ili „ozdravljenih” u trenutku kad je
njihovo ponašanje u zavodu počelo odavati „zdrav” stav prema emocijama. S obzirom na sve češću karakterizaciju mladenačkog nasilja kao društvenog problema kojim se
psihijatri trebaju ozbiljnije pozabaviti posebno su zanimljivi slučajevi adolescenata koji su došli u
sukob sa zakonom. Takvi slučajevi davali su priliku Žirovčiću, kao najistaknutijem forenzičkom
psihijatru u Banskoj Hrvatskoj da izrazi svoje stavove o problemu adolescentskog nasilja. Jedan
od ekstremnijih slučajeva „zločinačke mladeži” kojima se Žirovčić morao baviti bio je onaj
Rudolfa Stanića, šesnaestogodišnjeg pisarskog vježbenika iz Osijeka koji je bio optužen da je u
Sesvetama ubio kočijaš koji ga je povezao. Rudolf Stanić služio je kod odvjetnika Reina u
Osijeku. Otac mu je bio siromašni bilježnik koji je služio kod gospodarskog društva u Osijeku
nakon što je bio suspendiran iz općinske službe. Svojom mjesečnom plaćom od devedeset kruna, 240 uzdržavao je petoro djece i svoju suprugu. Rudolfova majka prošla je kroz deset porođaja (samo
petoro djece je preživjelo) u trenutku kad se protiv Rudolfa vodio sudski proces bila je ponovno
trudna. Liječnički vještaci koji su ju pregledali ustanovili su da „je tjelesno slaba i u sedmom
mjesecu trudna, da liječnicima na pozdrav ne odzdravlja, tuži se na veliku slabost, jedva na
nogama stoji, ne može jesti ni spavati, da je već 4 godine veoma uzrujana i često ne zna što
govori.”853 Rudolfov otac opisuje svog sina kao dobro odgojenog dječaka koji doduše „nije imao
volje za nauku” kad je pohađao realku u Osijeku, te je ponavljao prvi i drugi razred. 853 Žirovčić, 1907a: 93. 854 Ibid: 94. 855 Ibid: 93. 855 Ibid: 93. 855 Ibid: 93. 854 Ibid: 94. 7.3.Dječaci s revolverima: nasilničko ponašanje adolescenata Nakon toga
otac ga je dao u službu trgovcu u Glini, gdje ga je njegov poslodavac hvalio u pismima, a zatim
kao pisara odvjetniku doktoru Reinu. Otac je također naveo da Rudolf nije pokazivao nikakve
znakove duševnog oboljenja, te da ga je tukao kad bi izostajao iz škole, a bio je fizički kažnjavan
i u školi prije nego što je odustao od iste.854 Odvjetnik Rein navodi da je Rudolf marljivo radio i
dobro se ponašao jedino „nije pazio na vanjsko lice napisanog”. Rudolfovi postupci od prvog
lipnja 1906. morali su iznenaditi sve koji su poznavali mladića. Rudolf je tad preuzeo od Reina
svotu od 310 forinti kako bi ju predao na poštu, no Rudolf je ukrao novac i pobjegao iz Osijeka, k
Brodu na Savi. Svom ocu je napisao zbrkano pismo u kojem se opravdava kako je novac izgubio,
i u strahu od kazne pokušao pobjeći pišući:„bježao sam do iza dolnjeg grada, gdje sam skočio u
Dravu, plivati nijesam znao i ugušio sam se”855 U Brodu se Rudolf očito obskbio za dulji bijeg od
kuće: kupio je odjeću, duhan, sat s lancem, batinu i revolver.856 Nakon toga otišao je u Glinu, a
zatim u Zagreb gdje je živio u hotelu, rasipavao novce i udvarao se djevojkama po
gostionicama.857 Petog lipnja Rudolf je sjeo u fijaker i naredio kočijašu da vozi prema Sesvetama,
gdje ga je ustrijelio iz revolvera. Ranivši kočijaša odvezao je fijaker i konje do Sv. Ivana Zeline
gdje je tvrdio da su njega i kočijaša napali razbojnici i da im je jedva umakao. Uhapšen je
sutradan, a pri saslušanju je isprva tvrdio da je htio počiniti samoubojstvo, a kočijaš mu je pri tom
smetao pa ga je ubio, da bi na kraju rekao da je ubio kočijaša da ukrade fijaker i konje i proda ih. Na glavnoj raspravi 20. rujna njegov branitelj je predložio psihijatrijsko vještačenje, čemu je sud 241 Po dolasku u Stenjevec, Rudolf je podvrgnut uobičajenom pregledu, a Žirovčić je pomno
zabilježio pojedine fizičke stigme koje bi mogle upućivati na degeneraciju u skladu s uputama
Maudsleyja i Lombrosa: „Lubanja strebasta, široka, objam 57 ctm. Čelo nizko, uzko, koso. Ušesa nejednaka, desno
nešto veće. Zjenice veoma široke, okrugle, jednake,reagiraju spremno na svjetlo i
akomodaciju. Nos ovelik, debeo, tubast. Zubi zdravi - sluznica ždrijela malko zažarena. Ustroji
disanja i krvokruženja u redu. 861 Ibid: 94-95. 862 Ibid: 95. 859 Ibid: 94. 860 Ibid. 861 Ibid: 94-95.
862 Ibid: 95. 861 Ibid: 94 95.
862 Ibid: 95. 7.3.Dječaci s revolverima: nasilničko ponašanje adolescenata Desno mudo manje od lijevoga, sasvim drobno, kao omanji
orah, kao da je poslije bludobolne upale atrofiralo.”859 U zavodu se Rudolf ponekad ponaša mirno, a ponekad podrugljivo, očito nastojeći isprovocirati
liječnike i bolničare. Kako vrijeme odmiče, postaje sve razdražljiviji pa jednom prilikom govori
„da mu dodijalo, da ima nož, zaklao bi kojega liječnika. Njemu nije stalo za ljudski život, ako
sada dobije i deset godina, pa kad bude izašao, bit će mu tek 27 godina, i onda će svjet čuti, što će
on sve raditi.”860 Pri razgovoru naglašava da su ga često fizički kažnjavali u „realci” a na pitanje od odlasku u
krčme se „grohotom smije i kaže da je išao. Na pitanje o tome kakve je knjige čitao govori da je
čitao „Svašta, romane, dozvoljene i zabranjene, najradje povijest.” S velikim užitkom govori o
nekom zabranjenom romanu kojeg je čitao: „Naslova se ne sjeća, a da su zabranjeni, to je na koricama bilo debelo pisano, za to je išao tu
knjigu kupiti. Bila je to njemačka knjiga s nekakvim židovskim, jako smiješnim naslovom. Bilo je tu pisano proti vjeri i popovima, da Isus nije nikada eksistirao, to da su samo izmislili. Od onda je zamrzio popove, nije išo u crkvu i nije se Bogu molio.”861 Povremeno se čini očitim kako šesnaestogodišnji Rudolf čak i pretjerano naglašava svoju
sklonost nasilju, nekonvencionalnim vjerovanjima i hrabrost u opasnim situacijama, kao kad kaže
bolničaru da je onu večer kad je ubio fijakerista: „... u Zagrebu došao u jedan bordel, tamo da su
ga napali neki soldati s bajunetama, on je pucao iz revolvera, nastala galama, on pobjego i na
Jelačićevu trgu skočio u fijaker — pa je kočijaša u srditosti ubio!”862 Upravo su Rudolfova
hvalisanja, njegov fizički izgled i njegovo vlastito naglašavanje nedostatka empatije prema
ljudima (koje je Žirovčić uzeo za dokaz njegove „moralne nezdravosti”) bili kriteriji koji su
stenjevačkim psihijatrima omogućili da Rudolfa svrstaju u Lombrosov tip „rođenog zločinca”. 242 Rudolfova službena dijagnoza bila je „moral insanity” koji Žirovičić pojašnjava analogijom
između etičkog osjećaja i sluha za glazbu i poistovjećuje s određenim stupnjem degeneracije:
„kao što ima ljudi, koji neshvaćaju harmonije zvukova , te ne mogu pojmiti ljepote ne samo
kakvog umjetnog glasbotvora, već niti najjednostavnije pjesme, tako može biti ljudi bez
obdarenosti za altruističo ćućenje i moralno pojimanje. 863 Ibid: 96.
864 Ibid: 98.
865 Ibid: 97. 863 Ibid: 96.
864 Ibid: 98.
865 Ibid: 97. 7.3.Dječaci s revolverima: nasilničko ponašanje adolescenata Redovito potiču moralno nezdravi ljudi
od predaka, koji su bili duševno ili živčano bolestni, ili pijanice, ili su inače imali u svojem
biću nešto stranoga , neobičnoga; oni se svojom duševnošću , a često i obličjem odstranjuju od
poprečnoga tipa čovjeka- stoga se nazivaju „degeneriranima “ iliti „ izrodjenima “863 Za Žirovčića su Rudolfova navodna hladnokrvnost, odsustvo suosjećanja prema kočijašu i
sklonost laganju, te njegova nepromišljenost, svojstvena moralno nezdravim ljudima dokaz da
Rudolf spada u „manje vrijedne ličnosti”864. Žirovčić se osvrće i na izjave Rudolfovog oca i
drugih ljudi koji su poznavali Rudolfa koji govore o njemu kao o djetetu koje se nije isticalo
svojom zloćom. Žirovčić misli da ti ljudi ublažuju Rudolfovu zločinačku prirodu, ali i
pretpostavlja da je pojava devijantnog ponašanja povezana s njegovim ulaskom u pubertet:
„Moguće ipak, da je sve to u njemu spremljeno i pritajeno bilo, pa je tek u šestnaestoj godini
izbilo, jer je spolna dozrelost u moralnih idiota obično doba, u kojem se njihov defekt začne
pojavljati nemoralnim činima”.865 Žirovčić se također odmiče od strogo somaticističkog pogleda i
dopušta mogućnost da su uz „degeneriran i moralno manjkav ustroj” i teške obiteljske okolnosti
mogle nagnati Rudolfa na počinjenje nasilnog zločina. No pod teške okolnosti Rudolfova
odrastanja, Žirovčić ne ubraja ni siromaštvo ni tjelesno kažnjavanje kojem je bio redovito izložen
i u školi i kod kuće, a koje sam Rudolf često spominje. Umjesto toga, Žirovčić stavlja naglasak
na duševnu bolest njegove majke i njezinu nesposobnost da na adekvatan način vodi kućanstvo:
M
ć j d kl
d R d lf S
ić
ij
l š
ž j
k
j
d
l d
l či „Moguće je dakle, da Rudolfa Stanića nije samo loše možgjansko ustrojstvo dovelo do zločina,
nego i loš odgoj. 867 Žirovčić, 1910: 250. 872 Ibid: 251. 868 Ibid. 866 Ibid. 866 Ibid.
867 Žirovčić, 1910: 250. 868 Ibid. 7.3.Dječaci s revolverima: nasilničko ponašanje adolescenata Ktomu bilo je prilike u obiteljskim odnošajima maloga činovnika, slabo
plaćenoga, koji mijenja mjesta, koji je suspendiran radineke nepravilnosti, gdje kućanstvom
rukovodi i s obitelju upravlja slabašna umobolna žena, koja radja već jedanaesto dijete, mada
joj svaki porodjaj sve više zdravlje ruši, a u svijet stavlja kržljavo pokoljenje-što je doduše u 243 dogmatičnom smislu snošljivo s moralom , ali po prirodnom shvaćanju jamačno nevaljano i
nemoralno”866 Žirovčić se ne osvrće na teške socijalne i ekonomske prilike, na činjenicu da je Rudolf morao
raditi odgovoran posao kako bi pomogao prehraniti obitelj niti na sveprisutno tjelesno
kažnjavanje koje je od malena izlagalo mlade nasilju, već promatra okolnosti Rudolfova
odrastanja iz direktno patrijarhalne perspektive, ističući ulogu majke kao osnove obiteljskog
doma i njezin angažman kao preduvjet zdravog duševnog razvoja djece. Osim toga, Žirovčićeva
poruka o rađanju potencijalno „kržljavog” potomstva upućuje na činjenicu da on vidi rješenje
problema maloljetničkog nasilja u eugeničkim i moralističkim kategorijama. Rudolfovo vještačenje može se usporediti sa slučajem drugog „dječaka s revolverom”
osamnaestogodišnjeg Gjure Molnara. Gjuro Molnar je boravio u Stenjevcu od 15. studenog 1908. do 12. siječnja 1909. 867 Molnar je, kao i Rudolf odrastao u teškim uvjetima, bez majke, uz oca
alkoholičara koji je propio njihov posjed i otišao služiti kao vincilir u Cabunu. Uz to ga je njegov
brat često tukao. 868 Pobjegavši od kuće, Gjuro je počeo preživljavati od krađe, a u Stenjevec je
doveden nakon što je ranio Antuna Matičevića iz revolvera. Sam događaj je bio bizaran: nakon
što je ustrijelio Matičevića u ruku, Gjuro je odbio novac kojeg mu je ovaj ponudio te mu ispričao
svoju životnu priču rekavši mu da se ne slaže s ocem te je zbog toga pobjegao u šumu i odlučio
ubiti nekoga, pa sebe.869 Žirovčić je i Molnara svrstao među degenerirane „osobe manje vrijednosti” opisavši ga kao
mladića čija „pojava odaje već vanjštinom čovjeka nerazvijena, umno ograničena, izobličena,
degenerirana.”870 Molnaru Žirovčić nije dijagnosticirao moral insanity nego je samo zaključio da
je Molnar „manje razvijen, imbecil nižeg stepena.”871 I iako Žirovčić spominje teške okolnosti
okrivljenikovog života, ipak ih ne dovodi u vezu sa psihičkim stanjem Gjure Molnara prije
počinjenja čina, već se fokusira na njegovu „moralnu tupost”. 874 Savage,2007: 46. 873 Ibid: 253. 873 b d: 53.
874 Savage,2007: 46. 873 Ibid: 253. 7.3.Dječaci s revolverima: nasilničko ponašanje adolescenata Dok se Rudolf hvalio svojim
nedostatkom kajanja, Molnar govori da mu je žao što je pucao na Matičevića i opravdava se
pijanstvom.872 No Žirovčić se ne osvrće posebno na tu njegovu izjavu, pretpostavljajući da je 244 Molnar na svom stupnju duševnog razvoja nesposoban razviti osjećaj krivnje.873 I u slučaju
Rudolfa i Gjure Molnara Žirovčić ne pripisuje zločin niti jednoj duševnoj bolesti, otpisujući
eksplicitno hebefreniju u navedenim primjerima. Umjesto toga, Žirovčić na osnovu njihove
vanjštine, neprilagođenog ponašanja i samih njihovih pojedinačnih nasilnih djela, promatra
dvojicu maloljetnih delikvenata kao „degenerirane” pojedince. Oni na temelju vlastitog porijekla
i intelektualnog ustroja imaju sklonost nasilju i zločinačkom životu - Rudolf jer ne može pojmiti
moralne nazore, Gjuro jer ne posjeduje mentalni kapacitet da uistinu suosjeća s drugima, niti je
sposoban kontrolirati vlastite porive. Žirovčić prepoznaje da je njihovo teško odrastanje,
ispunjeno bijedom i nasiljem moglo doprinijeti konkretnom razvoju situacije koji ih je doveo na
krivu stranu zakona, ali mu odriče ulogu u formiranju njihove ličnosti. Ako uzmemo prilike odrastanja mladih, siromašnih ljudi u gradovima prijelaza stoljeća, fenomen
ovakvog nasilničkog ponašanja postaje puno razumljiviji. Na kraju, Rudolfov i Gjurin zločin su
motivirani imovinskom dobiti, loše isplanirani i izvedeni od strane mladića koji su odrastali u
uvjetima siromaštva i bili fizički zlostavljani. Za mnoge od mladića koji su se našli u Stenjevcu,
odrastanje je bilo iskustvo obilježeno nesigurnošću i brutalnošću, a adolescencija je, kao najava
odrastanja značila nove izazove. Nasilje je ponekad bilo izraz želje da se pobjegne iz siromaštva,
a ponekad kao u slučaju agresivnog napada na sve društvene tabue u izljevima hvalisavog bijesa
kojima u zavodu pribjegava Rudolf Stanić želja da dobiju osjećaj moći nad zajednicom gradeći
sliku sebe kao opasnih i beskrupuloznih, bijesnih mladih ljudi na sličan način na koji su to činile
adolescentske bande u većim gradovima poput pariških „Apaša”.874 Psihijatri na nasilje mladih
gledaju iz moralističke i biološke perspektive, promatrajući sve veću učestalost delinkvencije kao
krajnju posljedicu degeneracije. Najmlađa generacija tako dobiva ulogu žrtve „grijeha otaca” i
primjeri njezina problematičnog ponašanja postaju upozorenje za čitavo društvo koje se nastoji
usmjeriti kako prema aktivnijim mjerama socijalne medicine, tako i prema eugenici. Problem prisutan unutar obiteljskog doma su i oni neprilagođeni i buntovni adolescenti čije
emocije nisu u skladu s emotivnim režimom građanstva. U Stenjevcu je hebefrenija imala upravo
ulogu objašnjavanja neobičnih emotivnih stanja pojedinih adolescentskih pacijenata. 7.3.Dječaci s revolverima: nasilničko ponašanje adolescenata No iz
primjera štićenika kojima je dijagnosticirana hebefrenija, vidimo da je njezina klinička slika bila 245 mnogo drugačijom od opisa danog u stručnim medicinskim tekstovima: češće od degenerativne
bolesti koja završava potpunim duševnim propadanjem, vidimo sukobe između emotivnih režima
roditelja i adolescenata te nemogućnost njihove međusobne komunikacije. Hebefreničari često
bivaju vraćeni u okrilje obitelji kao zdravi, tek ponekad demonstrirajući u okružju zavoda
konfliktno ponašanje na koje su se žalili ljudi iz njihove okoline. Mnoge od psihijatrijskih
dijagnoza vezanih uz ponašanje adolescenata proizlaze iz činjenice da se adolescencija kao
zasebno razdoblje obilježeno i vlastitim poimanjem sebstva tek počela razvijati i biti prepoznata. Fenomen adolescencije je uz razvojno-psihološku imao i snažnu društvenu i kulturnu
komponentu, koja je izmicala onodobnim znanstvenicima a naročito psihijatrima sklonima
percipirati svijet iz medicinsko-biološke i ponekad moralističke perspektive. 876 Ibid: 5. 875 Goffman, 1963: 4. 877 Ibid: 138. 877 Ibid: 138. ,
876 Ibid: 5. 876 Ibid: 5. 7.4. Epileptičari i gorući štagljevi: sukobi unutar ruralnih zajednica Za ruralne zajednice, prisustvo osobe s duševnim poteškoćama bilo je izvor stalnog straha. Čak i
u doba moderniteta, svakodnevica seoskog života bila je obilježena ustaljenim ciklusima
poljoprivrednih radova i godišnjih svetkovina. Veličina zajednice i način života unutar nje
rezultirali su mrežom međuljudskih odnosa gdje su ljudi dobro poznavali jedni druge. Obiteljska
povijest, životne prilike zdravlje i financijsko stanje nisu se mogli tajiti i definirali su međusobnu
komunikaciju suseljana. Kanadski sociolog Erving Goffman opisao je društvenu ulogu tih osoba
kao trajno obilježenu stigmom mentalne bolesti. Za Goffmana, mentalne poteškoće spadaju u
kategoriju stigme karakternih mana zajedno sa kriminalnom prošlošću, ovisnošću, alkoholizmom,
homoseksualnošću, nezaposlenošću, suicidalnim ponašanjem i radikalnim političkim
stavovima.875 Kao i sve ostale stigme, stigme karakternih mana rezultiraju time da pojedinac koji bi inače bio
prihvaćen u socijalnoj interakciji, privlači pažnju nekom svojom karakteristikom koja odvraća
ljude koji s njime komuniciraju od njega i zasjenjuje sva ostala svojstva koje pojedinac
posjeduje876. Bitno obilježje Goffmanova gledanja na stigmu je upravo činjenica da je kvaliteta
percipiranih osobina sekundarna u odnosu na sam okvir društvene interakcije ─ odnos i definicije
„normalnog” i „devijantnog” upravo se formiraju kroz proces socijalnih interakcija.877 U tom
smislu su socijalni kontakti unutar malih zajednica u kojima se većina interakcija odvija licem u
lice bili veoma bitni za formiranje koncepata devijacije. 246 Širenjem utjecaja medicine, sve je veći opseg devijantnih ponašanja bio medikaliziran, a liječnici
i osobito psihijatri našli su se u poziciji medijatora kojima su se zajednice uklanjale kad bi unutar
njih izbio sukob. Osobe koje se ne ponašaju u skladu s uobičajenim obrascima ponašanja nosile
su stalnu stigmu, a ako bi u bilo kojem trenutku ušle u direktan sukob sa zajednicom, zajednica bi
se počela zalagati za njihovo uklanjanje iz društva ─ naročito ako te osobe nisu mogle računati na
podršku vlastitih obitelji. Budući da su na selu ljudi živjeli jedni blizu drugih, međusobno
pomagali jedni drugima pri radovima i često bili povezani ženidbenim ili ekonomskim vezama,
seoska zajednica posjedovala je učinkovit mehanizam kolektivnog nadzora i discipliniranja. „Devijantne” pojedince bilo je izrazito lako prepoznati, društveno ih izolirati i kolektivnim
apeliranjem na medicinski, policijski ili administrativni autoritet osigurati njihovo uklanjanje iz
zajednice. U ruralnim zajednicama sukobi su često rezultirali počinjenjem imovinske štete. Imovina, u
obliku gospodarskih zgrada ili poljoprirednih dobara bi bila zapaljena ili na neki drugi način
uništena. 878 Schulte, 1994: 26. 878 Schulte, 1994: 26. 7.4. Epileptičari i gorući štagljevi: sukobi unutar ruralnih zajednica Svjedočanstva seljana predstavnicima vlasti ili liječnicima obiluju spominjanjem
imovinske štete koju je devijantni pojedinac nanio ili bi mogao nanijeti svojim susjedima i
suseljanima. Sprječavanje imovinske štete najčešće se ističe kao razlog zbog kojeg se tražilo
institucionaliziranje nasilnih pojedinaca. Strah od imovinske štete i sklonost da se istu nanosi u
konfliktnim situacijama Regina Schulte je objasnila činjenicom da je napad na imovinu pojedinca
u ruralnim zajednicama predstavljao mnogo više od uništavanja materijalnih objekata. Identitet
ratara ili stočara bio je usko vezan uz njegovu sposobnost da preživljava i stječe imovinsku korist
pomoću zemlje i stoke i poljoprivrednih oruđa koje mu omogućavaju bavljenje istom. Samim
time, može se reći da je udar na seljakovu imovinu predstavljao napad na jedan od ključnih
elemenata njegovog identiteta. Nadalje, dramatičan čin paleža ili sličnog uništavanja imovine bio
je izrazito javan i obilježavao je napadača i žrtvu pred cijelom zajednicom, čineći sukob
vidljivim.878 Upravo zbog toga, prisutnost osobe koja je spremna počiniti palež ili sličan
destruktivan čin bila je pogubna za koheziju i identitet zajednice i predstavljala je snažan
argument za traženje pomoći psihijatara. 247 Primjeri štićenika koji su počinili imovinsku štetu ili ju prijetili počiniti bili su disproporcionalno
brojni u povijestima bolesti od samog osnutka institucije. Slučaj Augustina M., ratara iz Krasice i
jednog od prvih štićenika zavoda, slučaj pokazuje da se u slučajevima sukoba u manjim
zajednicama, nije odmah posezalo za smještanjem osobe u zavod. Primjeri štićenika koji su počinili imovinsku štetu ili ju prijetili počiniti bili su disproporcionalno
brojni u povijestima bolesti od samog osnutka institucije. Slučaj Augustina M., ratara iz Krasice i
jednog od prvih štićenika zavoda, slučaj pokazuje da se u slučajevima sukoba u manjim
zajednicama, nije odmah posezalo za smještanjem osobe u zavod. Prema svjedočanstvima seljaka, Augustin se četrnaest godina ponašao čudno i nasilno no oni su
se obratili vlastima tek kad im je njegovo destruktivno ponašanje nanijelo veliku materijalnu
štetu: prema izvještaju poglavarstva Augustin je postao „osobito rječit i brbljav te pokušavao sve
korisno utamaniti i uništiti”879. Augustin je prvo smješten u pritvor, no budući da je od tamo uspio
uništiti zid i pobjeći, poslalo ga se u stenjevački zavod. Takav razvoj pokazuje da su sukobi na
selu mogli su trajati godinama prije nego što se zatražila intervencija izvanjskih autoriteta. Također, čini se da je ključnu su ključnu ulogu u smještanju Augustina u Stenjevec imale vlasti
riječke podžupanije. 879 KPV, 1880-1881: 48. ,
880 Ibid. 7.4. Epileptičari i gorući štagljevi: sukobi unutar ruralnih zajednica Liječnička svjedodžba je izrazito štura i sadrži samo sažet opis
Augustinovog fizičkog stanja i ranije preboljelih bolesti uz kratku napomenu da je kod njega
„opažena (je) monomania, da sve što mu pod ruku dođe hoće zatrti i uništiti.” Načelnikov dopis
sadrži opis pritužbi suseljana i sve korake koje je podžupanijsko poglavarstvo poduzelo, sa
posebnim osvrtom na imovinsko stanje njegove obitelji. Takav razvoj situacije govori da se, u
trenutku kad je sukob eskalirao, prvo tražilo od obitelji da se pobrine za nasilnog pojedinca, a
onda su se poduzeli pravni koraci, da bi se naposljetku pokušalo problem riješiti pomoću
internacije u psihijatrijski zavod. Suseljani su ga odlučili predati poglavarstvu nakon što je
razbijao prozore i pčelinjake te zapalio pastirske kolibe u šumi. Poglavarstvo ga je držalu u
pritvoru, no on je u pritvoru uspio provaliti zid.880 Dopis načelnika riječke podžupanije
poglavarstva priložen povijesti bolesti donosi svjedočanstva suseljana od Augustinovom
agresivnom ponašanju i ističe da njegova obitelj u ”slaboj kući uz siromaštvo i nejaku djecu ne
može najmiti potrebnog čovjeka za čuvanje”881. Augustin u Stenjevcu tvrdi da je „krsnik” (ime za
iscjelitelja u Primorju) rođen u „kapici” (vjerojatno pučki izraz za amnionsku membranu koja u
rijetkim slučajevima može prekriti lice i glavu novorođenčeta) nekoliko puta iskazuje svoju
nevinost i tvrdi da su optužbe protiv njega „djelo zlih ljudi koji su me optužili krivo.”882 248 Zanimljiva je i kompleksna dijagnoza koja je Augustinu izrečena u zavodu: „Mania destructionis
in vero similiter epileptico”883 ─ uništavalačka manija zapravo nalik epilepsiji. Činjenica da su
stenjevački liječnici usporedili Augustinovo oboljenje s epilepsijom, iako ni liječničko izvješće ni
povijest bolesti ne spominju epileptične napadaje upućuje na osobit oblik stigme koja je
pripisivana epileptičarima, a koja ih je dovodila u vezu s nasiljem i paležom. Također, povezanost
epilepsije s određenim oblicima kriminalnog ponašanja bilo je prisutno i u tadašnjoj forenzičkoj
psihijatriji. Cesare Lombroso, čiji su rani radovi svakako bili poznati stenjevačkim liječnicima,
tvrdio je da „svi urođeni zločinci pate od prikrivenog vida epilepsije koja se klinički ne
manifestira epileptičkim napadajima već pervazivnim poremećajem ličnosti.884 U četvrtom izdanju svoje opširne studije zločinačkog ponašanja L'uomo delinquente (Zločinac)
objavljenoj 1889. godine, Lombroso postulira nekoliko razina povezanosti između epilepsije i
zločinačkog ponašanja. Prva razina su fiziološke sličnosti između „rođenih zločinaca” i
epileptičara. Lombroso u iste uvrštava asimetriju lubanje, nedostatak osjetljivosti na dodir i
ljevorukost, osobine, prema Lombrosu, natprosječno česte kod zločinaca i epileptičara.885. Lombroso naglašava prikriven karakter epileptičara. 885 Lombroso, 2006: 248-250. 885 Lombroso, 2006: 248-250. 883 Ibid.
884 Fatović-Ferenčić i Kuhar, 2017: 461. ,
886 Ibid: 250-251. ,
885 Lombroso, 2006: 248-250. 884 Fatović-Ferenčić i Kuhar, 2017: 461. 886 Ibid: 250-251. 883 Ibid.
884 Fatović-Ferenčić i Kuhar, 2017: 461.
885 Lombroso, 2006: 248-250.
886 Ibid: 250-251. ,
886 Ibid: 250-251. ,
886 Ibid: 250-251. 887 Ibid: 257. 883 Ibid.
884 Fatović-Ferenčić i Kuhar, 2017: 461. 7.4. Epileptičari i gorući štagljevi: sukobi unutar ruralnih zajednica Karakteristika „zločinca-epileptičara” koju
Lombroso konstantno naglašava je njegova sklonost ekstremnim emocijama i prikriven karakter
njegove bolesti. Epileptičar tako „u trenutku kad dođe u sukob sa zakonom pokazuje lucidnost
zbog koje se često doima kao da lažira svoju epilepsiju, a to stanje može trajati satima, danima ili
tjednima”.886 Ono na čemu Lombroso u najvećoj mjeri temelji vezu između epilepsije i zločina
navodna je sklonost epileptičara bezrazložnom nasilju. To je naročito vidljivo u njegovoj
definiciji „skrivene epilepsije”. Prema Lombrosu, glavna karakteristika skrivene epilepsije su
„nagle, nepredvidive provale nasilnog ponašanja. Ti „psihološki ekvivalenti fizičkog epileptičkog
napadaja su obilježeni nepredvidivošću i razornim bijesom koji pretvaraju uobičajeno ponašanje
epileptičara u kratkotrajnu karikaturu zločinačkog ponašanja.”887 Definiranjem „skrivene epilepsije” kao egzaktnog psihijatrijskog fenomena, epilepsija time
prestaje biti isključivo bolest koja je zbog svojih dramatičnih i intenzivnih simptoma bila lako
prepoznatljiva i laicima. Ona postaje zajedničkom dijagnozom za mnoštvo teško objašnjivih
nasilničkih ponašanja. Budući da se primarni uzroci epilepsije traže u hereditetu, ona postaje još 249 jedno stanje koje se prepoznaje kao posljedica degeneracije, granična pojava koja se može dugo
skrivati kod naoko zdravih pojedinaca samo da bi se iznenada manifestirala provalom
destruktivnog bijesa. Lombrosova „epilepsija urođenih zločinaca” i oboljenja koja su se manifestirala epileptoformnim
napadima bila su isprepletena u medicinskim i laičkim narativima. Stenjevački kućni liječnik
Dragutin Forenbacher u svom je članku o „moral insanity” proširio Lombrosovu teoriju i doveo
svaki tip epilepsije u vezu s nekim oblikom „moralne degeneracije” ustvrdivši sljedeće: „Već u
mladosti padavičavca, pa ma se još i nepokazali pravi znakovi padavice pokazuje se pokvarena
ćud, kašnje biva toga i više”888. Dakle, uz činjenicu da se kriminalce koji su počinjali paleže i bili
skloni sukobima smatralo epileptičarima također su i osobe koje su patile od epileptičkih napada
bile su često smatrane opasnima. Stav hrvatskih psihijatara o epilepsiji dijelili su i mnogi laici, a
osobe koje su patile od epilepsije bile su često percipirane kao opasne za zajednicu koja je tražila
njihovo zatvaranje u zavode. U liječničkim izvještajima bolesnika s epileptičkim napadima,
gotovo se kao pravilo spominje opasnost od paleža. Dora K. četrdesetogodišnja seljakinja iz
Novigrada koja je redovito imala epileptične napadaje bila je u Stenjevcu od 1890. godine do
1895. kad je umrla od „nepoznatih uzroka” za vrijeme jednog napadaja. 888 Forenbacher, 1893: 50-51. ,
889 KPV, 1895: 1737. ,
889 KPV, 1895: 1737. 7.4. Epileptičari i gorući štagljevi: sukobi unutar ruralnih zajednica Njezina liječnička
svjedodžba traži njezino zatvaranje u zavod je je ”opasna za društvo čovječje naginjući na
podmetanje vatre”889 iako se nigdje u njezinoj dokumentaciji ne spominje da je podmetnula požar
ili se na bilo koji način ponašala nasilno. U liječničkom izvješću Gjoke A., seljaka iz Ostrova,
liječnik dovodi u usku vezu njegovu epilepsiju, sklonost alkoholu i konfliktno ponašanje. Izvješću su pridodana izjava anonimnog suseljana koji svjedoči o Gjokinom nasilničkom
ponašanju: „Bolesnik je nađen na ulici, sav usplahiren, izbuljenih očiju, iz usta mu curi pjena, govori bez
smisla, držeći u obje ruke po jedan oveći kamen. Svi ljudi žene i djeca bježe od njega. Na
pitanje podpisanoga, kojeg on od bolesti oca i brata poznaje; koga traži odgovara:
˛'Neprijatelje, koga on može odma umlatiti.' Zatim je prešao preko ulice i ušao u jednu kuću,
gde je pre nekoliko meseci bila birtija V. M.-a, koji mu je u odbrani glavu razbio, te je tamo sve
prozore i kuhinjske sudove razlupao, ukućani se svi odavno razbjegli; posle toga je jurišao na 250 crkvu, gde se je služilo večernje, zatim je otišao u birtiju, gde je počeo piti, preteći se birtašici
da će je ubiti ako mu neda piće.”890 I u Gjokinom slučaju svjedoci spominju raniji sukob pri kojem je Gjoka čak i pretrpio ozljedu
glave, što upućuje na činjenicu da je Gjoka duže vrijeme bio izvor problema za Ostrovljane. Budući da je Gjoka opisan kao epileptičar liječnik se mora osvrnuti na vezu te pretpostavljenu
vezu te bolesti s podmetanjem požara zaključivši svoje izvješće jednostavnom primjedbom „Dali
je palikuća ne može se doznati.”891 U slučaju Petra S., seljaka iz Starog Čiča priroda bolesti problematičnog pojedinca postala je
predmetom prijepora između predstavnika zadruge kojoj je Petar pripadao i stenjevačkih
liječnika. Petar je u Stenjevcu bio u pet navrata između 1890. i 1911. kada je umro od
tuberkuloze. Svaki njegov boravak trajao je nekoliko mjeseci i postavljan mu je niz dijagnoza od
„acutne hallucinatorne bezumnosti” preko „manie periodice”, „epilepsie” i „psychose” periodice
do „amentie periodice catatonice”. Nakon svakog boravka bio je otpušten s napomenom
„poboljšan” ili „izlječen”. U Stenjevačkoj povijesti bolesti je redovito opisan kao „smeten” i
primijećeno je da često govori o religiji.892 No, činjenica da Petra otpuštaju iz bolnice izaziva
negodovanje drugih članova njegove zadruge koji redovito pišu pisma upraviteljima Stenjevca,
tražeći da se Petra tamo stalno zadrži. 890 KPV, 1911: 8086. 890 KPV, 1911: 8086.
891 Ibid.
892 KPV, 1911: 4356.
893 Ibid 891 Ibid. 893 Ibid. 893 Ibid. 893 Ibid. 892 KPV, 1911: 4356. 7.4. Epileptičari i gorući štagljevi: sukobi unutar ruralnih zajednica U pismima, zadrugari opetovano opisuju Petra kao
opasnog i opetovano ističu strah od požara kao primarni razlog zbog kojeg bi Petra trebalo
zatvoriti: „Mi smo svi celo selo jedan drugoga blizu sa zgradami a svoje staine slamom pokrivamo,
drugo, nas im a u zadrugi Sobolski osim Petra 13 dušah ili osoba mi po običaju svi u jednu
sobe stanujemu i spavamo, što bog da čuvaj da on dođe van što bi mogel štete počiniti u jedne
noći kada društvo po zaspava on je pogibeljan i radi ubojstva i radi požarne propasti, molim
lipo meni kao molitelju bilo bi mi jako drago da moj Petar dodje kući zdrav i bistra uma...ali
ako bi on obstrelan na pogibel, bolje da bude tamo gdje je kao što su i drugi koji su
pogibeljni.”893 251 Pismo zadrugara iz 1892, također spominje Petrovu pokojnu „ludu majku”894 i ističe element
herediteta, kojeg liječnici u njegovom slučaju ne spominju. Gjuro K. dvadesetšestogodišnji seljak iz Kozarevca patio je čitav život od epileptičnih napadaja. Poslan je u Stenjevec 1903. godine, a obaveznoj i šturoj liječničkoj svjedožbi priložena su pisma
župnika i njegovog oca. Njegov otac piše da ga je dvaput uhvatio kako pokušava potpaliti štagalj,
a župnik navodi kako je prijetio da će potpaliti i kuću. Gjuro negira sve ove navode, a iako nije
pokazivao znakove agresivnog ponašanja niti opsesije vatrom, ipak je zadržan u Stenjevcu punih
osam godina, sve do 1911.895 Slučajevi navedenih štićenika pokazuju da je uklanjanje problematičnog člana zajednice u
psihijatrijski zavod često bila aktivnost oko koje su se angažirale osobe koje su smatrane
autoritetima u zajednici poput župnika i predstavnika zadruge. Također, liječnici nisu uvijek bili
pretjerano skloni medikalizirati sukobe unutar zajednice, često u povijestima bolesti dajući glas
štićenicima i zapisujući njihovo poricanje optužbi. S druge strane, sukobi između zajednice i
stigmatiziranih pojedinaca često su bili dugotrajni, a poticaj za obraćanje vlastima najčešće je bila
nenadana eskalacija nasilja i trenutak u kojem pojedinci iz ekonomskih ili nekih drugih razloga
više nisu mogli računati na potporu svojih obitelji. Eskalaciji nasilja ipak je često prethodio
dugotrajan period u kojem bi stigmatizirani pojedinac svakodnevno trpio zlostavljanje i izolaciju
od strane svojih sumještana. Samim time, njihovo je nasilje često bilo tek dramatična reakcija na
situaciju koja se činila nepodnošljivom. Takav razvoj možemo pratiti u oba slučaja paleža koje je Dragutin Forenbacher opisao u članku
naslovljenom „Dva slučaja paleža, kao prilog k psychiatricko-sudbenoj praksi”. 895 KPV, 1911: 5598. ,
896 Forenbacher, 1888: 85. 894 Ibid. 894 Ibid. 252 7.4. Epileptičari i gorući štagljevi: sukobi unutar ruralnih zajednica Članak je izišao
u dva broja Liječničkog vjesnika iz 1888. godine. Foenbacher u članku opisuje forenzička
vještačenja dvojice muškaraca iz Bjelovarske županije, gdje se po Forenbacheru „palež osobito
često počinja.”896 Počinitelji paleža o kojima Forenbacher piše su muškarac koji je patio od
epilepsije i drugi koji je opisan kao osoba s poteškoćama u intelektualnom razvoju. Glavni motiv
njihovih zločina bila je osveta za zlostavljanje koje su pretrpjeli od strane suseljana. Prvi
počinitelj bio je S.G. dvadesetogodišnji seljak iz Severina. Prema Forenbacherovoj kliničkoj slici
S.B. nije polazio školu, pa nije znao ni čitati ni pisati, već četiri godine patio je od epileptičnih 252 napadaja koji su ga spopadali jednom mjesečno. Pored toga opisivan je kao miroljubiv i pošten
čovjek.897 S. B. je, prema rezultatima istrage zapalio kuću svog kuma, nakon što ga je ovaj iz
nepoznatih razloga nekoliko puta udario po ramenu. Forenbacher u svojoj sažetoj analizi
izbjegava zločin paleža i emociju bijesa kojom je S. B. reagirao nakon ničim izazvanog napada
dovesti u direktnu vezu s S. B. - ovom epilepsijom. S.B.-ov odvjetnik bazirao je obranu pred
sudom na činjenici da je njegov branjenik patio od napadaja. Forenbacher jednostavno ističe da je
palež „bio motiviran srčbom i osvetom, a izveden je u psycholožkom načelu”.898 Emociju
„srdžbe” Forenbacher spominje na nekoliko mjesta u tekstu ističući da je ovakvo njezino
iskazivanje i osveta putem paleža sasvim očekivana za ruralnu sredinu u kojoj je S. B. živio: „U
toj srčbi, a u namisli na osvetu, obtuženik namah ju i izvede; — izvede na način, koji je u onoga
diela našega naroda i najobičniji, naime paležem”.899 Drugi slučaj, čiji je prikaz nažalost nedovršen u Liječničkom vjesniku tiče se S.J. -a, koji nije
patio od padavice, ali je prikazan kao odgojno zapušten čovjek s poteškoćama u razvoju. Prema
Forenbacherovoj anamnezi, majka se nije brinula za njega, udavši se ponovno nakon očeve smrti
te nije naučio govoriti ni hodati do pete godine. Općinsko poglavarstvo opisalo ga je kao
„razuzdana i nećudoredna čovjeka” 900. Forenbacher u svom vještačenju naglašava da je S. J. često trpio porugu i nepravedan tretman od strane suseljana: opisivali su ga kao „budalu
nesposobnu za ikakav rad osim čobanstva” lijenog i nesposobnog čovjeka sklonog ispadima
bijesa kojeg su seoska djeca zadirkivala rugalicom „brusnica i šogor”.901 S.J. je uhapšen nakon što
je zapalio štagalj svog bivšeg gazde J.M.-a nakon što mu je ovaj odbio dati plaću, a u požaru je
poginulo i dvoje J. 900 Ibid: 148. 902 Ibid. 903 Ibid: 149-150. 901 Ibid. 7.4. Epileptičari i gorući štagljevi: sukobi unutar ruralnih zajednica M.- ove malodobne djece koja su spavala u štaglju. Budući da je cilj
vještačenja bilo prosuditi je li S.J. u trenutku kad je počinio čin paleža (i potencijalno, umorstva)
bio smanjeno ubrojiv, Forenbacher mnogo vremena posvećuje postupcima J. M.-a i ostalih
seljaka koji su mogli nagnati okrivljenika na čin osvete. S. J.-a su nagovarali da u ponoć nosi križ
na groblje kako bi dokazao kako se ne boji sablasti902, J.M. ga je naveo da umjesto njega preuzme
krivnju za štetu počinjenu u šumi i odleži u zatvoru, često ga zapošljavali da im obavlja razne
poslove nalazeći izlike da mu ne plate, tvrdeći da su svinje koje je čuvao počinile štetu. 903 Sam S. 253 J. Je istakao da ga je štagalj zapalio iz osvete jer mu J.M. nije platio za mjesec dana rada, te ga
nastavio zadirkivati.904 Iako su okrivljenici pokazivali znakove duševnog oboljenja, Forenbacher
u navedenim slučajevima prepoznaje sukobe koji su se događali u seoskim zajednicama kao
motiv zločina i ističe učestalost paleža u sličnim sukobima. J. Je istakao da ga je štagalj zapalio iz osvete jer mu J.M. nije platio za mjesec dana rada, te ga
nastavio zadirkivati.904 Iako su okrivljenici pokazivali znakove duševnog oboljenja, Forenbacher
u navedenim slučajevima prepoznaje sukobe koji su se događali u seoskim zajednicama kao
motiv zločina i ističe učestalost paleža u sličnim sukobima. Najdetaljnije opisan slučaj paleža u forenzičkoj praksi stenjevačkih liječnika onaj je Save
Dragosavljevića, pedesetsedmogodišnjaka iz Dugog Sela. Sava Dragosavljević doveden je u
zavod 24. listopada 1902. godine iz pritvora Kraljevskog sudbenog stola u Zagrebu gdje je bio
pod optužbom da je 18. 905 Žirovčić, 1908: 231. 904 Ibid: 150.
Ž 906 Ibid. 904 Ibid: 150.
905 Žirovčić, 1908: 231.
906 Ibid.
907 Ibid.
908 Ibid.
909 Ibid: 233.
910 Ibid: 232.
911 Ibid: 231. 7.4. Epileptičari i gorući štagljevi: sukobi unutar ruralnih zajednica lipnja iste godine zapalio kuću Milke Dragosavljević i Vuje
Dragosavljevića, te pokušao zapaliti kuću Nikole Dragosavljevića.905 Prema izjavama očevidaca
Sava je Milkinu kuću zapalio potpalivši slamnati krov šibicom dok je Nikolinu kuću pokušao
zapaliti na osobito bizaran način: ušao je u kuću i bacao rukama žeravicu na krov dok ga
domaćica Petra Dragosavljević i njezina kćer Milica nisu otjerale.906 Seljani su ga pronašli
mokrog u jednoj šikari, prema svjedočenju jednog od seljaka: „s pjenom u ustima, držeći mokre
žigice u ruci od kojih su se glavice pušile; on je bulaznio i svakojake gluposti govorio”907 Seljaci
su grubo postupali s dezorijentiranim Savom: vukli su ga pod ruku, tjerali da hoda preko brvna i
prijetili mu da će ga baciti u vatru908 a zatim su ga svezali i ostavili pred zgarištem jedne od kuća
cijelu noć tako da mu je „kiša u usta padala”909 da bi ga tek ujutro predali oružnicima. Sava je,
prema izjavi suda već ranije dolazio u sukob i sa zakonom i sa seljanima. Prvi put je osuđen na
osam dana zatvora 1890. godine zbog sprečavanja pljenidbe. Prema Savinoj izjavi danoj
liječniku, pokušali su greškom plijeniti svinju njegove žene zbog štete u šumi koju je počinio
Savin pokojni brat. Drugi put se 1896. posvađao sa susjedom i potukao se sa njim te bio osuđen
na tri dana zatvora. Suseljani su ga također sumnjičili da je prije nekoliko godina zapalio kuću
Stevana Radosavljevića910. Također, općinska svjedodžba opisivala je Savu kao „zlobnog i
opakog čovjeka silovitog vladanja.”911 904 Ibid: 150. 905 Žirovčić, 1908: 231. 906 Ibid. 907 Ibid. 908 Ibid. 909 Ibid: 233. 910 Ibid: 232. 911 Ibid: 231. 254 Kao što je bio slučaj i s ostalim štićenicima poslanima u Stenjevec nakon nekog nasilnog čina i
kod Save je prisutna duga povijest sukoba sa zajednicom u kojoj je živio. Poput većine ostalih,
Sava se u Zavodu ponaša mirno i ne pokazuje sklonost nasilnom ponašanju ni ispadima bijesa. Prema Žirovčićevom kazivanju mirno govori svoju verziju događaja: cijeli dan je okapao zemlju,
išao je obići svoju kćer Jelicu koja je bila sa stokom na paši. Čuo je povike o vatri, potrčao prema
selu i putem pao u lokvu vode. Srela su ga trojica suseljana, prijetili mu da će ga baciti u vatru i
zavezali ga. 914 Ibid: 231-232. 915 Ibid: 233. 912 Ibid: 232.
913 Ibid: 233.
914 Ibid: 231-232. 913 Ibid: 233. 7.4. Epileptičari i gorući štagljevi: sukobi unutar ruralnih zajednica Negira da je ikad bio duševno bolestan, a naročito se čudi izjavi da je bacao žeravicu
golim rukama na kriv, izjavivši: „ta ne bi ni najbedastiji ovdje toga učinio, a gdje bi ja koji nisam
bedast.”912 Također, tijekom ispitivanja ističe se da niti jedan svjedok nije prisegao da je sa
sigurnošću vidio Savu kako pali kući, osim Petre Dragosavljević.913 Ivan Žirovčić je dobio dojam
da je Sava Dragosavljević miran i zdrav čovjek bez simptoma bilo kakvih duševnih bolesti i
epilepsije. Budući da nikad nije bježao od natruha senzacionalizma kad je pisao o slučajevima iz
svoje forenzičko-psihijatrijske prakse, naslovio je svoj članak „Zagonetan palež”. Usprkos
povijesti sukoba između Save i suseljana i sudske presude u kojoj je stajalo da je Sava sposoban
za čine nasilja, Žirovčić se ipak odlučuje njegov čin objasniti epileptičnim napadajem ─ čini se
jedinim u Savinom životu. Pritom Žirovčić daje opis epilepsije koji se uvelike oslanjao na
Lombrosove poglede. Žirovčić velik značaj za dijagnozu epilepsije pridaje hereditarnim stigmama poput asimetrije
lubanje („Lubanja napadno malena, opseg 540, širina 153, duljina 183 mm, nepravilna, čelo
nisko, tjeme verugasto, zatiljnica izbočena)914 pritom uopće ne spominjući osjetljivost na dodir,
niti ruku koju Dragosavljević preferira. Također, Žirovčić potvrđuje da Dragosavljević nije imao
niti jedan epileptični napadaj za vrijeme boravka u zavodu, iako je čitava dva mjeseca bio „dan i
noć pod paskom bolničarskog osoblja.”915 Prepoznavanje uobičajenih hereditarnih stigmi bilo
tjelesnih (asimetričnost lubanje) ili psiholoških (neuobičajeno miran ili „silovit” karakter,) i
nedostatak jasnog motiva kod Žirovčića će imati daleko veći značaj za prepoznavanje epilepsije
od prisutnosti epileptičnih napada u ranijoj anamnezi Uz pasku bolničara, liječnici su, ozbiljno
shvaćali psihijatrijska vještačenja i prema Žirovčićevoj izjavi posjećivali su Dragosavljevića
dvaput dnevno pomno bilježeći i prateći njegovo ponašanje i duševno stanje. Opisali su ga kao 255 razumnog, mirnog, strpljivog i bistrog čovjeka.916 Takav opis je bio prilično daleko od osobe
kakvom je Dragosavljević prikazan u općinskoj svjedodžbi- silovit i nasilan čovjek već dvaput
pritvaran zbog buntovnog ponašanja i tučnjava. No, Žirovčić sljedeći Lombrosa, zaključuje da
Dragosavljevićev miran i staložen karakter prikriva oblik epilepsije koji se manifestira
neobjašnjivim ispadima nasilja. Za Žirovčića, inače sklonog demistifikaciji duševnih bolesti,
„bitnost epileptične bolesti još je neotkrita tajna”917. 919 Žirovčić, 1908: 234. ,
920 Ibid: 235. 918 Ibid: 233-234. 920 Ibid: 235. 917 Ibid: 234. 916 Ibid. 918 Ibid: 233-234. 7.4. Epileptičari i gorući štagljevi: sukobi unutar ruralnih zajednica Žirovčić epilepsiju dijeli na najčešći tip u
kojem bolesnici „padaju i doskora se tresu u grčevitoj trzavici mišićja” zatim „epileptičnu
absentiu” koja se manifestira samo kratkotrajnim gubitkom svijesti, „epileptični
somnambulizam” u kojem ljudi „dospiju u stanje trajne duševne omračenosti”, ali su i dalje
sposobni obavljati kompleksne radnje, hodati i govoriti, te „epileptični delir”918, stanje kojim će
Žirovčić tumačiti Dragosavljevićeve postupke. Žirovčić daje slikovit opis „epileptičnog delira” i objašnjava povezanost istog s nasiljem:
„...tu probijaju u duševnosti patnika strašne tlapnje, halucinacije i iluzije na koje on odvraća
otporom i groznim činima; tu se dakle na mjesto običnih epileptičkih grčeva pojavlja silna
trzavica u obliku sporedjenih kompliciranih čina, a kako je sadržaj epileptičnih tlapnji obično
zastrašujući, to ide reakcija snatrećeg epileptika ponajviše u smjeru uništavanja, ubijanja,
mrcvarenja, paljenja, osobito paljenja! Epileptici imadu često priviđenja crvene boje, a buduć
oni tako često ubijaju i pale, to se misli da u njih između crvenih halucinacija, predstava crvene
krvi, crvene vatre i konačnih silovitih čina opstoji neki asocijativni uzročni savez”919 Za Žirovčićevo shvaćanje epilepsije je ključno da se manifestira nekim oblikom „trzavice”- bilo
grčenjem mišića tijekom epileptičnog napada ili grčevitim nasilnim djelima, koje Žirovčić,
zanimljivo, dovodi u vezu s halucinacijama „crvene boje” stvarajući asocijativnu vezu između
poriva za podmetanjem požara i iskustava osoba koje pate od epilepsije. Žirovčić također
postulira da se taj specifičan oblik epilepsije može manifestirati samo jedanput u životu „jer
takvih slučajeva ima zabilježeno u kazuistici kriminalne psihopatologije”920 Žirovčićeva
dijagnoza rezultirala je prekidom sudskog procesa protiv Save Dragosavljevića koji je proveo još
pet godina života u zavodu, prije nego što je kao zdrav otpušten kući. Za vrijeme svog boravka, 256 ponašao se mirno i razumno, pišući kući da bi se raspitao o svojoj obitelji i nastojeći brinuti o
svom gospodarstvu iz zavoda.921 Sukobi u ruralnim zajednicama ponekad su rezultirali i umorstvom ili pokušajem umorstva. Slučaj Tome Mihalića iz Kajgane kod Garešnice, koji je 29. studenog 1909. predan u Stenjevac
na motrenje nakon što je pokušao iz revolvera ubiti svog suseljana Filipa Rietkovića daje tragičnu
sliku dugotrajnog sukoba u zajednici koja je rezultirala jednim umorstvom i jednim pokušajem
ubojstva. Tomo Mihalić, bio je rodom iz Klokočevca, a doselio je u Kajganu 1904. godine kad je otkupio
posjed ženine braće, nekih Malekovića iz Kajgane. Kao pridošlica od početka se nije snašao u
Kajgani i bio je umiješan u brojne sudske rasprave: 1905. 922 Žirovčić, 1912: 151. 921 Ibid.
Ž 923 Ibid. 926 Ibid: 152. 925 Ibid: 153. 924 Ibid. 921 Ibid.
Ž 7.4. Epileptičari i gorući štagljevi: sukobi unutar ruralnih zajednica godine je udario i ozlijedio Petra
Malekovića jer je potonji „zatjerao race u njegovu travu”922. Dvije godine kasnije pretukao je Evu
Gojak šakama jer ga je „potvorila da je ukrao luka,” zbog čega je također osuđen na dva dana
zatvora, a 1908. osuđen je na tri dana jer je „ćušnuo Maru Aržek koja je htjela otjerati svoju
svinju „koju je on pritvorio jer ju je našao pod svojoj jabukom u kvaru”923. Osim toga opisao je
stanovnike Kajgane kao „nesnosljive i svadljive ljude”924 koji su mu bili zavidni na njegovom
bogatstvu. Očito je Mihalić radi ženidbene veze uspio povoljno kupiti dobro zemljište koje su
mnogi Kajgančani vjerojatno htjeli za sebe. Nasilje je eskaliralo nakon što je bio svjedok u
sudskom procesu protiv grupe ljudi koji su ubili jednog duševno bolesnog čovjeka, motivirani
strahom od njega. U spisu nam je dostupna jedino Mihalićeva verzija događaja. Mihalić navodi
da se Miško Gjurović, „slabouman čovjek” vratio iz Lepoglave gdje je služio zatvorsku kaznu
radi umorstva. Seljaci su ga optuživali da krade i bili u strahu od njega. Na kraju su ga
dvanaestorica seljaka namamili u jednu kuću gdje su ga „zlostavljali” dok nije podlegao
ozljedama925 Mihalić se pojavio kao svjedok na suđenju toj dvanaestorici čime je navukao na sebe
bijes suseljana. Trojica seljaka umiješana u incident navodno su sačekala Mihalića kad se vraćao
iz krčme te su ga isprebijali dok nije izgubio svijest. Sutradan ih je prijavio sucu u Garešnici. No
njegova tužba je odbačena jer svjedoci koje je imenovao nisu pristupili prvom ročištu, a s drugog
je bio odsutan sam Mihalić.926 Filip Rietković, na kojeg je Mihalić ispalio tri hitca iz revolvera, 257 bio je jedan od trojice seljaka koji su sudjelovali u napadu na Miška Gjurovića i koji su bili
oslobođeni krivnje. 7.4. Epileptičari i gorući štagljevi: sukobi unutar ruralnih zajednica Mihalić se branio da nije htio ustrijeliti Rietkovića već samo izazvati sudski
postupak „da njihova stara raspra opet dođe na sud” jer se osjećao oštećenim time što Rietković i
druga dvojica napadača nisu bili osuđeni prvi put.927 Mihalić je naime bio uvjeren da su mu u
tučnjavi nanesene ozbiljne i potencijalno smrtonosne ozlijede, iako su liječnici tvrdili da je
potpuno zdrav.928 Osjećao je veliki revolt zbog nespremnosti svjedoka da se pojave na suđenju i
zbog sudske odluke da odbaci njegovu tužbu, te se ustrajno žalio liječnicima i bolničarima na
nepravdu koja mu je nanesena .929 Nakon što je bio optužen za pokušaj ubojstva, Mihalić je postao još više razočaran u pravosudni
sustav, bijesan što su njegove pritužbe ignorirane i što ga se navođenjem prethodnih presuda
izrečenih protiv njega nastojalo opisati kao konfliktnu i nasilnu osobu. Svoj bijes je izrazio
tijekom razgovora s liječnikom u Stenjevcu i Žirovčić je pomno zabilježio njegove emocije: „Pri tom dolazi u afekt zacrveni se u licu, govori glasno i uzvišenim tonom, ljuti se, zašto ga nisu
odmah poslali ovamo, kako je branitelj predložio, vriedjalo ga je, kad mu je sudac čitao njegove
prijašnje kazne, a to su bile sitnice, zatvor je bio pretvoren u globu, i on ju je platio, pa o tom nije
trebalo više govoriti.”930 Upravo je njegovo ustrajanje u tvrdnjama da je ozbiljno ozlijeđen i da će „Pri tom dolazi u afekt zacrveni se u licu, govori glasno i uzvišenim tonom, ljuti se, zašto ga nisu
odmah poslali ovamo, kako je branitelj predložio, vriedjalo ga je, kad mu je sudac čitao njegove
prijašnje kazne, a to su bile sitnice, zatvor je bio pretvoren u globu, i on ju je platio, pa o tom nije
trebalo više govoriti.”930 Upravo je njegovo ustrajanje u tvrdnjama da je ozbiljno ozlijeđen i da će
uskoro umrijeti bilo razlogom zbog kojeg je Mihalić upućen na forenzičko vještačenje u
Stenjevec. Žirovčić je zaključio da Mihalić pati od bolesti koju je nazvao paranoia
hypochondrica ─ vrsta paranoje koju karakteriziraju patološke misli o vlastitom oboljenju931. Njegovu želju da nastavi tražiti zadovoljštinu pred sudom, čak i pod cijenu toga da bude optužen
za pokušaj umorstva, Žirovčić je objasnio drugim paranoidnim poremećajem natruhe kojega su se
počele javljati kod Mihalića ─ paranoiom querulans ─ „pravdaškom ludošću” 932vrstom
poremećaja karakteriziranom stalnom željom oboljelog da se upušta u parnice i obraća se
sudovima. 927 Ibid: 154.
928 Ibid: 157.
929 Ibid: 155.
930 Ibid.
931 Ibid: 157.
932 Ibid: 158. 7.4. Epileptičari i gorući štagljevi: sukobi unutar ruralnih zajednica Istovremeno, liječnici su se našli u situaciji da odgovaraju na potrebe širih zajednica
koje su od njih zahtijevale zatvaranje devijantnih i nasilnih pojedinaca iza zidova psihijatrijskih
zavoda. To je značilo da zavodi nisu više mogli biti isključivo prostorom skrbi za duševno
oboljele, kakvima su zamišljeni u danima „moral treatmenta” već su u sve većoj mjeri služili
institucionaliziranju devijantnih pojedinaca. Slično se dogodilo u sudskim slučajevima, kad je
prosudba od strane psihijatra značila smještanje optuženog u zatvor ili zavod. Psihijatrija se, kroz
proces medicinskog reguliranja slučajeva nasilja, polako preobražavala u instituciju društvenog
nadzora. Uz pomoć vlastitog epistemičkog autoriteta psihijatri su, arbitrirajući i opisujući nasilje
pojedinca prema drugim pojedincima i zajednice prema pojedincu, konstruirali ruralnu zajednicu
konflikta i stigmatiziranog epileptičnog ili paranoičnog pojedinca. Psihijatrijski diskurs
postepeno je zamjenjivao raznolike i polifone glasove bijesa i osvete unificirajućim narativima
somaticističke psihijatrije i kriminalne antropologije. Ti narativi postat će naročito važni kad
devijantni pojedinci postanu nositeljima devijantnih političkih ideja i kad njihov bijes postane
usmjeren na postojeći politički poredak. Uloga psihijatrije kao institucije društvenog nadzora
doći će u prvi plan kad psihijatri dobiju ulogu u sukobima koji su imali politički karakter. 7.4. Epileptičari i gorući štagljevi: sukobi unutar ruralnih zajednica Za razliku od Forenbacherovih ranijih vještačenja, vidimo da Žirovčić u Dragosavljevićevom i
Mihalićevom slučaju ignorira specifičnu pozadinu sukoba između optuženika i ljudi iz njihove
životne sredine svodeći razloge njihovih dijela isključivo na njihovu biološki determiniranu 258 duševnu bolest. U Dragosavljevićevom slučaju bolest je zagonetni oblik epilepsije, „delir” koji se
kod njega manifestirao samo jednom, nestao jednako naglo kao što se i pojavio i natjerao ga na
čin paleža. Kod Mihalića, radilo se u uznapredovaloj paranoji koji ga je navodila da traži sudsku
zadovoljštinu. Iako oba slučaja daju poprilično detaljnu povijest sukoba između optuženika i
drugih ljudi iz njihove sredine (Mihalićev slučaj čak govori o ranijem ekstremnom nasilju grupe
stanovnika Kajgane prema duševno oboljeloj osobi) Žirovčić ne spominje osvetu ili bijes niti se
osvrće na moguće motive počinjenih djela gledajući nasilje i bijes primarno kroz prizmu
somaticističke psihijatrije. U slučajevima sukoba u ruralnim sredinama, psihijatrijski je diskurs često bio preuziman i
korišten od laika članova zajednice, nositelja administrativne vlasti i crkvenog autoriteta. S druge
strane, psihijatri su ga koristili kako bi legitimirali svoju poziciju medicinskih radnika i na naoko
objektivan te znanstveno utemeljen način pokušali objasniti brojne slučajeve nasilja. Uključivanje psihijatrije u sukobe između neprilagođenih pojedinaca i zajednice često je dovodilo
do prodora psihijatrijskih ideja, poput onih o hereditetu i povezanosti između epilepsije i
nasilničkog ponašanja u zajednice i nudilo prihvatljiv okvir za promatranje i klasificiranje oblika
ponašanja koje se smatralo devijantnima. Psihijatri su ponekad, ponajviše inspirirani idejama
Cesarea Lombrosa o povezanošću epilepsije i neobjašnjivih nasilnih zločina. No u nekim
slučajevima, stenjevački su liječnici, komunicirajući s kotarskim i općinskim liječnicima,
lokalnim vlastima i autoritetima poput poglavara zadruge, župnika i sudova, uistinu ulazili u
međuljudske odnose unutar zajednica, nastojeći razlučiti medicinske uzroke devijantnog
ponašanje od društvenih devijacija koje bi rezultirale nasiljem. Naravno ti su odnosi često
tumačeni na izrazito moralistički način, u skladu s uvriježenim pogledom na selo kao prostor u
kojem vladaju alkoholizam i „primitivne strasti”, bez naročitog osvrta na društveni kontekst
bijesa i agresije. Također, u skladu s poimanjem psihijatrije kao grane medicine čija je svrha
liječenje ljudi, psihijatri nisu bili skloni smještanju devijantnih štićenika u zavode, tim više što su
isti često bili nemirni i nasilni, te je u lošim uvjetima u kojima je Zavod za umobolne u Stenjevcu
djelovao za njih bilo teško skrbiti. 259 Komunikacija između šire javnosti i zavodskih liječnika stavila je i dodatan pritisak na same
liječnike. 7.5. Anarhisti i atentatori: politički sukobi u psihijatriji 19. stoljeća Do kraja devetnaestog stoljeća mnoge nove i radikalne političke ideje prodrle su do šire javnosti. Neki od uzroka njihova širenja su u sve većoj prometnoj povezanosti, urbanizaciji i porastu
pismenosti i raširenosti političkog tiska usprkos prisustvu cenzure u većini europskih zemalja. Politika prestaje biti „regnum arcana” i ne odvija se više u dvorovima i ministarskim kabinetima
kako je to bio slučaj ranije, već se polako preljeva u javnost. I dok su javne manifestacije
političke moći poput trijumfa i krunidbi već tisućljećima služile za njezinu legitimaciju u dugom
devetnaestom stoljeću sve vidljivijima postaju i javne manifestacije političkog otpora: agitacija,
pamfleti, štrajkovi, demonstracije pa sve do jedne od najdramatičnijih: političkog atentata. Modernizacija utječe na formiranje brojnih novih ideja o političkom uređenju društva, no ona
također mijenja emotivne režime i poglede na identitet. Pojedinac koji se formira u okviru
modernizirajućih društava također prolazi transformaciju i u svojim se idejama, emocijama,
obrascima ponašanja i svakodnevnom životu često nalazi između „tradicionalnog čovjeka” i
individualca modernog doba. U svojoj studiji političkog i religijskog ekstremizma u Ujedinjenom
Kraljevstvu viktorijanskog doba, engleski povjesničar književnosti Clive Bloom nazvao je 260 devetnaesto stoljeće stoljećem u kojem su „nerealizirano sebstvo i nerealizirana država, oboje s
naizgled beskrajnim potencijalom, u jednakoj mjeri postojali unutar glava ljudi i u vanjskom
svijetu i kad su revolucionari smatrali da utjelovljuju budućnost ili ju donose svjedočeći
Evanđelje politike koju su prigrlili.”933 U takvim okolnostima izljevi političkog bijesa i političkog nasilja postali su sve učestaliji. Revolucionari spremni na nasilje, često su legitimizirali svoje akte iznoseći nove političke ideje,
nepoznate velikom dijelu javnosti. Nakon što bi bili optuženi za nasilne zločine, često su dolazili
pod povećalo psihijatrije, koja je već u svojim počecima nastojala proširiti svoj autoritet i na
tumačenje i potencijalno liječenje zločinačkog ponašanja. Jedno od najranijih suđenja
atentatorima, bilo je suđenje Jamesu Hadfieldu, članu milenarističke sekte, koji je 1800. godine
pucao na kralja Georgea III. Na njemu još nisu svjedočili psihijatri, ali su dvoje kirurga i liječnik
za kojeg je sud utvrdio da je „stručan u pogledu ludila” utvrdili da je Hardfield pucao na kralja u
stanju pomućenog uma, što je dovelo do oslobađajuće presude.934 Psihijatri su imali presudnu
ulogu 1840. i 1843. godine prilikom suđenja Edwardu Oxfordu, osamnaestogodišnjaku koji je
pokušao ubiti kraljicu Viktoriju i Danielu M'Naghtenu koji je ustrijelio Edwarda Drummonda,
premijerovog tajnika. 934 Jones, 2016: 64. 933 Bloom,2013: 3. ,
935 Ibid: 73. ,
935 Ibid: 73. ,
934 Jones, 2016: 64. 935 Ibid: 73. 7.5. Anarhisti i atentatori: politički sukobi u psihijatriji 19. stoljeća Na Oxfordovom suđenju sudjelovao je John Connolly, jedan od vodećih
autoriteta na polju „moral treatmenta” u Velikoj Britaniji sredinom stoljeća, dok su vještaci na
M'Naghtenovom bili ugledni liječnici iz psihijatrijskih zavoda u Londonu i Glasgowu Edward
Thomas Monro i William Hutchinson.935 Obojica okrivljenika oslobođena su optužbi zbog vlastite
neubrojivosti u trenutku počinjenja kaznenog djela. Ovi slučajevi, doveli su do ispreplitanja
političkog, pravnog i medicinskog polja, a činjenica da su atentatori čija su djela prijetila
državnom poretku izbjegli smrtnu kaznu intervencijom psihijatara legitimirali su ulogu
psihijatrijskih vještaka u sudskim procesima i naveli pravnike da pokušaju formulirati što je
moguće jasniju definiciju pravne ubrojivosti. Štićenici koji su na neki način došli u sukob s vlastima i izražavali bijes prema institucijama moći
bili su prisutni u Stenjevcu od otvaranja institucije. Jedna od najranijih povijesti bolesti je ona
učiteljice pletenja Klementine B. preuzete iz Bolnice milosrdne braće koja je 1876. javno prijetila 261 pred zgradom gradsko-delegiranog kotarskog suda u Zagrebu. Sačuvano je i njezino liječničko
izvješće iz gradske bolnice u kojem je opisan Klementinin čin: „Proljećem i lietom o.g. vidjevala se obično pred večer i to u Ilici, na Jelačićevom i Zrinskom
trgu visoka žena, blieda i suha,živahna i nestalna pogleda vazda jednako vrlo neukusno i
previše nakićeno i ureseno odjevena, vazda sama, lagano hodajući, svakoga koga sretne
začuđeno gledajući,katkada se smješeć, kadkada namrgodiv lice, u jednoj ruci suncobran u
drugoj rubac i lepeza, kod muzike vazda glavom kimajući po taktu glazbe: to bijaše
Klementina B., učiteljica koja jedva umije svoje ime potpisati- nu kojoj to ne bijaše predmet
poduke-ona nauča plesti čarape... Dan kad je privedoše ovamo u zavod šetala se vrlo brzo po
Markovom trgu pred delegovanim sudom mašući u ruki s velikim kuhinjskim nožem grozeći
se š njim naprama raznim kućama najčešće naprama navedenom sudu.”936 Liječnik koji je sastavio izvješće o Klementininom ponašanju u njezinom slučaju radi stilski
otklon od uobičajenog načina pisanja liječničkih izvješća i prepričava njezin napad na delegirani
sud na romantiziran i pomalo podrugljiv način. Može se reći da liječnik, u određenoj mjeri, čak
literarizira događaj o kojem piše, ubacujući u njega izrazito subjektivne detalje poput „živahna i
nestalna pogleda” ili izraza njezinog lica te ubacivši ime pacijentice tek u sredinu odlomka kao da
mu je cilj graditi neki oblik dramske napetosti unutar forme medicinskog dokumenta. Klementina
progovara o svom postupku na samom kraju izvješća. 936 KPV, 1879-1880: 162. ,
937 Ibid. ,
937 Ibid. 7.5. Anarhisti i atentatori: politički sukobi u psihijatriji 19. stoljeća Nažalost, njezin je iskaz dosta štur a govor
posredovan:„..bila je vrlo nemirna, uzrujana, da s nožem nije nikog raniti ni ubiti htjela, već da je
htjela samo predstojniku delegovanog suda, kaj misli da ona hrabra nije, pokazati htjela da je ona
vrlo hrabra nu da mu nije ništa učiniti htjela.”937 Točan razlog Klementininog nezadovoljstva predstojnikom suda nije zanimao liječnike. U
Stenjevcu Klementini je originalna dijagnoza „hysteria” prepravljena u „Vesaniu”. Otpuštena je
1880. godine. Taj slučaj jedan je od rijetkih slučajeva gdje se politički sukob navodi kao jedan od
povoda institucionalizacije, a sudeći po povijestima bolesti politika se ne javlja često u govoru
štićenika (izuzetak su štićenici s teškim deluzijama koji tvrde da su političke figure). Jedan od
najintrigantnijih slučajeva intervencije psihijatrije u političke procese počet će 1897. prvim
dolaskom Miloša Krpana u Stenjevec. Miloš Krpan bio je pučki učitelj u selu Dubovik kraj
Slavonskog Broda, a rođen je 1862. u mjestu Lipe kraj Gospića kao dijete siromašnih roditelja sa 262 sela.938 Usprkos skromnom porijeklu i formalnom obrazovanju koje se sastojalo samo od
učiteljske preparandije u Petrinje, Krpan je kao autodidakt stekao široko obrazovanje iz povijesti
i filozofije, a u mladosti je uspio proputovati Palestinu, Egipad, SAD, Kanadu, Njemačku,
Francusku, Belgiju i Englesku formiravši se kao čovjek širokih političkih pogleda koji je imao
poznanstva diljem Europe. Njegovi politički nazori bili su poprilično kompleksni: hvalio je Antu
Starčevića, nazivajući ga „sjajnim meteorom”939 deklarirao se kao anarhist i socijalist, bio izrazito
anti-klerikalno nastrojen te je bio načelnik općine Podvinje na listi Komunističke partije
Jugoslavije 1920. godine. U Stenjevac je prvi put dospio nakon što je seoski starješina Đuro
Ostojić prijavio gradskom poglavarstvu u Brodu na Savi da „Miloš Krpan, socijalist na bunu diže
seljake i čudne skupove s njima održava”940. Prilikom istrage, na školskom tavanu pronađeni su
Krpanovi subverzivni spisi. Krpan je uhićen i optužen „radi zločina pokušanog zavođenja na
veleizdaju, uvrede članova C. i Kr. kuće ometanja javnog mira i ometanja vjerozakona.”941 sela.938 Usprkos skromnom porijeklu i formalnom obrazovanju koje se sastojalo samo od
učiteljske preparandije u Petrinje, Krpan je kao autodidakt stekao široko obrazovanje iz povijesti
i filozofije, a u mladosti je uspio proputovati Palestinu, Egipad, SAD, Kanadu, Njemačku,
Francusku, Belgiju i Englesku formiravši se kao čovjek širokih političkih pogleda koji je imao
poznanstva diljem Europe. 940 KPV, 1899: 3745. 938 Pejić, 2016: 143. 939 Ibid: 142. 941 Ibid. 941 Ibid. 7.5. Anarhisti i atentatori: politički sukobi u psihijatriji 19. stoljeća Njegovi politički nazori bili su poprilično kompleksni: hvalio je Antu
Starčevića, nazivajući ga „sjajnim meteorom”939 deklarirao se kao anarhist i socijalist, bio izrazito
anti-klerikalno nastrojen te je bio načelnik općine Podvinje na listi Komunističke partije
Jugoslavije 1920. godine. U Stenjevac je prvi put dospio nakon što je seoski starješina Đuro
Ostojić prijavio gradskom poglavarstvu u Brodu na Savi da „Miloš Krpan, socijalist na bunu diže
seljake i čudne skupove s njima održava”940. Prilikom istrage, na školskom tavanu pronađeni su
Krpanovi subverzivni spisi. Krpan je uhićen i optužen „radi zločina pokušanog zavođenja na
veleizdaju, uvrede članova C. i Kr. kuće ometanja javnog mira i ometanja vjerozakona.”941
Optužnica je temeljenja na zaplijenjenim spisima koje je Krpan namjeravao objediniti u knjigu
pod naslovom „Liepa naša Domovina” koju bi ilegalno distribuirao među lokalnim obrazovanim
ljudima. Među inkriminiranim ulomcima iz Krpanove nikad objavljene knjige je izjava kako je
dužnost „svih ljudi srca i razuma da se late na obranu svoje zasužnjene braće noža, puške,
bodeža, dinamita da ruše tirane, crkve i prestolja”942 te uvrede izrečene na račun carice Marije
Terezije koja je „dielila spajiluke svojim razkalašenim priležnicima ali mantijaši i zavedena
prostačina i danas vapi za vladom majke carice jer je ona popovske Werkstatte zidala.”943 U
optužnim spisima Krpan se nekoliko puta naziva socijalistom i anarhistom, predstavljajući
program anarhizma kao internacionalan i vođen čovjekoljubljem: „Anarhizam ne poznaje vjere,
narodnosti, zemlje, za njega je mjerodavna oplemenjena savjest, zajednička mater zemaljska
kruglja i njezina djeca ravnopravno i radino čovječanstvo...”944 Sudski vještaci su na zahtjev Krpanovog odvjetnika Josipa Franka pregledali Krpana i iako su
prilikom istrage prosudili da je „Miloš Krpan svojih djela svjestan, da je ubrojiv i za svoje riječi i
djela odgovoran, no da se u njega razvila neka vrst megalomanije, koja je često preteča ozbiljne 263 duševne bolesti.”945 No, na samoj sudskoj raspravi vještak dr. Isidor Schliek je promijenio svoj
iskaz i donio mišljenje prema kojem Miloš Krpan nije ubrojiv.946 Krpan je na temelju tog
mišljenja oslobođen optužbe. Ubrzo nakon oslobađajuće presude Krpan je postao jedan od
rijetkih štićenika koji su sami zatražili smještanje u Stenjevec navodeći kao razlog da je „iz
razlaganja sudbenog vještaka dra Schlieka pri sudbenoj raspravi, te iz obrazloženja osude
razabrao da su se u njegovom životu pojavili znakovi koji se mogu tumačiti kao početak duševne
bolesti, ali koji se mogu, po izjavi dr. 945 Ibid.
946 Ibid.
947 Ibid.
948 Ibid.
949 Ibid.
950 Ibid.
951 Ibid.
264 7.5. Anarhisti i atentatori: politički sukobi u psihijatriji 19. stoljeća Schlichta „mirnim životom i dobrom njegom izliečiti”
pridodavši da „osjeća neku nervoznost.”947 Krpan u Stenjevcu iznenađuje liječnike svojim uglađenim ponašanjem i naobrazbom, kakvu čini
se nisu očekivali od pučkog učitelja. Ipak, zapažaju na njemu određenu aroganciju i sklonost
buntovnom razmišljanju. U statusu praesens, Krpan je opisan na sljedeći način: Krpan u Stenjevcu iznenađuje liječnike svojim uglađenim ponašanjem i naobrazbom, kakvu čini
se nisu očekivali od pučkog učitelja. Ipak, zapažaju na njemu određenu aroganciju i sklonost
buntovnom razmišljanju. U statusu praesens, Krpan je opisan na sljedeći način:
„...miran, čist i dobro orientiran...govori mnogo kad ga se nagovori, ali sasvim logično i vrlo
rječito...Akoprem je vrlo učtiv naspram liječnikom to se može opaziti da se drži bez dvojbe ako
ne pametnijim to ipak isto tako pametnim i učenim kao što su oni. Ako što pripovieda to radi
uvjek u nekom poučavajućem i odrešitom tonu, koji izključuje svaki protuslov te pokazuje
kako je duboko i nepokolebivo uvjeren u istinitost svega što kaže.”948 „...miran, čist i dobro orientiran...govori mnogo kad ga se nagovori, ali sasvim logično i vrlo
rječito...Akoprem je vrlo učtiv naspram liječnikom to se može opaziti da se drži bez dvojbe ako
ne pametnijim to ipak isto tako pametnim i učenim kao što su oni. Ako što pripovieda to radi
uvjek u nekom poučavajućem i odrešitom tonu, koji izključuje svaki protuslov te pokazuje
kako je duboko i nepokolebivo uvjeren u istinitost svega što kaže.”948 U zavodu su Krpana zamolili da napiše svoj životopis što je on, sa zadovoljstvom učinio. Životopis je bio naslovljen „Kaplja u moru ili iz života jednog nazovi-luđaka, napisao Krpan,
Motto: empiričkom filozofijom za vječnim idealima.”949 U tom spisu, Krpan zaogrće svoju
životnu priču u pomalo mesijansku auru kakvu je kod predvodnika novih političkih pokreta
devetnaestog stoljeća opazio i Bloom. Navodi da je kao dječak jednom na paši čitao djela Vase
Pelagića kad su ga srela dva „učenjaka evropskog glasa” koje je fascinirao svojom duhovitošću
tako da su rekli da će „ovaj dječak jednom biti slavan muž”.950 U mladosti se zainteresirao za
čitanje filozofskih djela, te je živio „kao pustinjak kloneći se svieta i njegovih bučnih bachanalia,
jer je vidio da je sviet odviše sebičan i zloban”951. 7.5. Anarhisti i atentatori: politički sukobi u psihijatriji 19. stoljeća Odlučio je posvetiti život zalaganju za 264 siromašne i od tog je trenutka njegov život bio nalik „ladji na uzburkanom moru” i uvijek su ga
proganjali „izprazni, sebični, okrutni, glupi, ljudi današnjeg društva, koji misle da će pomoću
tamnice i ludnice održati svoje nakaradne odnošaje.”952 Liječnici su, na temelju spisa priloženih optužnici i autobiografije zaključili da Krpan boluje od
„paranoie originarie”. Nalaz iz zavoda pojašnjava Krpanovu dijagnozu: „Ne ćemo ustvrditi da je on ludjak kakvoga si obično lajci (sic) predstavljaju već mislimo pod
imenom paranoika čovjeka koji već od djetinjstva gaji na jednoj strani misli progonjenja a na
drugoj misli precjenjivanja svoje osobe. Duševni abnormalitet takvog čovjeka netreba biti
napadan njegovoj okolici, dapače taj čovjek može biti radi svojih ideja i nazora smatran vrlo
učenim i ženialnim čovjekuljobom i borcem za poboljšanje ljudskih prilika.”953 Za stenjevačke vještake spoznavanje društvene stvarnosti putem observacije i knjiga te kasnija
borba za poboljšanje uvjeta života ljudi i usvajanje novih i revolucionarnih ideja bila je očekivana
posljedica razvoja Krpanove paranoje: „Ovakvi ljudi osjećaju se još od svoje mladosti pozvanima da postanu nešto velikoga. Najprije
promatraju narav, odnošaje ljudske, uče i čitaju vrlo mnogo, postaju nezadovoljni sa
postojećima odnošajima svojima i drugih ljudi, te hoće da svojim izvanrednim požrtvovnim
radom i plamtećim govorom poboljšaju stanje ljudsko u smislu svojih novih ideja.”954 U daljnjem tekstu medikaliziran je svaki element političkog i međuljudskog djelovanja Miloša
Krpana: učtiv i pomalo nadmen govor i ponašanje postaju znakom da se Krpan drži boljim od
većine drugih ljudi, njegovo pozivanje na kontakte s inozemnim učenjacima je ismijano kao
pretjerivanje, a prepoznavanja svećenika i državnih službenika kao neprijatelja svojih ideja kao
znak progonstvenih ideja.955 „Paranoia originaria” okarakterizirana je kao oblik neizlječivog i
kroničnog ludila, koji se još nije manifestirao do kraja i koji će Krpana prije ili kasnije dovesti u
sukob sa zakonom ili ćega dovesti do konačnog ludila. Pažnja je posvećena i opasnosti koja može
doći od daljnjeg širenja Krpanovih ideja. U mnijenju je istaknuto kako u Krpanu postoji
„neodoljiv nagon da svoje socijalističke ideje i svoje osebujne filozofične i znanstvene nazore u
govoru i pismu raširuje”956 . Taj nagon liječnici su smatrali opasni zbog njegovog zvanja kao 265 pučkog učitelja, te su bili zabrinuti da bi Krpan mogao djeci koju podučava „u srdca usaditi
sjeme mržnje prema postojećem zakonom i društvenim odnošajem. 961 Pejić, 2016: 150. 7.5. Anarhisti i atentatori: politički sukobi u psihijatriji 19. stoljeća Kratko rečeno, mislimo da bi
uzgajao moderne pesimiste.”957 Krpan je nakon nešto više od mjesec dana boravka u zavodu pušten kući na revers, na zahtjev
Terezije Krpan, njegove supruge. Liječnici su se očito bojali da će dalje dolaziti u sukob s
vlastima i Terezija Krpan je morala potpisati očitovanje u kojem stoji da će „osobito paziti da on
nikakvih spisa na sudove i novine nešalje”.958 To je jedan od rijetkih slučajeve u kojima se
liječničkom preporukom nastojalo ograničiti javno djelovanje otpuštenog štićenika. Usprkos
reversu, Krpan će u Stenjevcu završiti još jedanput 1898. godine, nakon što je optužen zbog
uvrede vjerozakona jer je svom zamjeniku na mjestu pučkog učitelja u Duboviku u svađi opsovao
Uskrs.959 Vještačko mišljenje uglavnom ponavlja prijašnje zaključke o Krpanovoj duševnoj
bolesti samo što se ovaj put njegovo stanje dodatno medikalizira time mu se pretpostavljeni uzrok
nalazi u činjenici da Krpan „potječe iz hereditarno obterećene porodice” te da je „već u mladosti
imao za svoje doba abnormalne nagone da, naime, marljivim čitanjem i velikim znanjem nadkrili
svoje drugove”.960 Neuobičajeni stavovi Miloša Krpana, zbog kojih je opetovano dolazio u sukob
s okolinom somatizirani su kao posljedica herediteta, a njegova želja da se obrazovanjem izdigne
iz svoje siromašne sredine i omogući si bolji život je tumačeno kao početni simptom paranoičnog
poremećaja. Krpan je ponovno otpušten na revers u travnju 1899. godine. Nakon otpusta,
umirovljen je kao učitelj i sudeći po njegovoj kasnijoj biografiji (između ostalog, osnovao je
međunarodnu anarhističku komunu u okolici Dubovika i nakon Prvog Svjetskog Rata se
pridružio Komunističkoj partiji Jugoslavije)961 nastavio je s političkim radom, uspješno izbjegavši
kazneni progon i novu hospitalizaciju. U oba navrata u kojima se Krpan našao u Stenjevcu, liječnici su ključnima za dijagnozu smatrali
dva aspekta njegove ličnosti: njegovu percipiranu intelektualnu nadmoć nad okolinom i osjećaj
da je progonjen od strane vlasti. No Krpanovi stavovi i ponašanje bili su u mnogočemu tipični za
svijet političkih revolucionara 19. stoljeća karakteriziran milenarizmom i slijepim vjerovanjem u
ostvarenje političke utopije kroz zalaganje grupe „osvještenih” pojedinaca. Čak su i njegovo 266 „uzvisujuće” ponašanje i „podučavajući” način govora tipični za osobu neuobičajeno širokog
obrazovanja u odnosu na svoju sredinu i koja je na sebe preuzela ulogu agitatora i širitelja
naprednih ideja u siromašnoj ruralnoj sredini. Godine na prijelazu devetnaestog u dvadeseto stoljeće, značile su i radikalizaciju političke
situacije u Banskoj Hrvatskoj. 962 KPV, 1911: 7551. 964 KPV, 1911: 8021. 963 Ibid. 965 Ibid. 965 Ibid. 7.5. Anarhisti i atentatori: politički sukobi u psihijatriji 19. stoljeća Formiranje Hrvatsko-srpske koalicije i njezin otpor uvođenju
mađarskog jezika na željeznicama rezultirali su političkim previranjima, čestim smjenjivanjima i
ostavkama banova. Sukob između bana Pavla Raucha i Hrvatskog Sabora rezultirao je
raspuštanjem Sabora. Otpor brojnih zastupnika i političkih stranaka budimpeštanskoj i bečkoj
vladi doveo je do suspenzije ustava 1912. Pored postojećih napetosti, krajem devetnaestog
stoljeća prošireno je izborno pravo, čime dnevna politika postaje sve važnijim pitanjem interesa
za šire slojeve. Samim time, politička pitanja su sve prisutnija u javnom govoru. Zaoštravanjem političke situacije i politizacijom javne sfere iskazi štićenika u zavodu postaju sve
politiziraniji. Ivan B., kočijaš iz Ličkog Osika, primljen u Stenjevac 1909. godine sa dijagnozom
„paranoie” patio je od progonstvenih ideja vezanih uz svoj glas na izborima za Sabor. Ivan je
mislio da ga progone jer je glasao za dr. Banjačevića i „jako vikao i klicao Banjačeviću i
Hrvatskoj”962. Po dolasku u Zemun da ga progone „seljaci, gospoda, popovi i Mađari” koji su ga
zbog njegovih uvjerenja htjeli zatvoriti, a njegov strah od uhićenja je pojačavalo to što su djeca
na ulici vikala „ključ” i „mislio je da se to tiče njega.”963 Neki štićenici koji su bili u Stenjevcu
duže vremena počinju iskazivati strahove ili misli progonstva vezane uz političku situaciju, dok
su iste prije toga imale drugačiji karakter. Kosta S., magistar farmacije iz Stare Pazove bio je šest
puta institucionaliziran u Stenjevcu između 1901. i 1910. u više navrata bježeći iz zavoda, sve
dok 1911. nakon posljednjeg bijega nije nestao iz bolničkih spisa. U početku, Kostine se
sumanute misli uglavnom tiču odnosa unutar obitelji. U pismu poslanom liječnicima prilikom
Kostinog dolaska u zavod, njegov brat kaže kako Kosta ima „fiksu ideju da ja oću njega da
prevarim”,964 a sam Kosta piše duga pisma u kojima objašnjava kako ima pravo na svoj dio očeve
imovine koji mu njegov brat želi na prevaru oduzeti pa ga je zato smjestio u zavod. 965 Sedmog
prosinca 1901. Kosta daje liječnicima detaljan opis svog progonstvenog svijeta u kojem glavnu
962 KPV 1911 7551 267 ulogu uistinu ima njegova obitelj koja ga navodno progoni i uskraćuje mu nasljedstvo,
smještajući ga zdravog u „ludnice”966. Nakon zaoštravanja odnosa između Austro-Ugarske i
Srbije nakon Svibanjskog prevrata i rasta međuetničkih napetosti nakon prosvjeda zbog članka
„Srbi i Hrvati” u „Srbobranu” 1903. godine, Kostini strahovi sve više postaju vezani uz političke
sukobe. Sredinom 1904. 966 Ibid.
967 Ibid.
968 Ibid 967 Ibid. 966 Ibid.
967 Ibid.
968 Ibid. 966 Ibid. 7.5. Anarhisti i atentatori: politički sukobi u psihijatriji 19. stoljeća će tako optužiti ravnatelja Žirovčića da ga progoni jer je on (Kosta)
Srbin, a tri godine kasnije opet se žalio ga da u zavodu proganjaju zbog njegove narodnosti i
tražio kaznu za liječnike, Hrvate koji s njim loše postupaju.967 Osim toga, Kosta se pokušao i
politički angažirati pisanjem pisama koja je adresirao vođama svim političkih stranaka i
ministarstvu obrane. U pismu ministarstvu obrane, Kosta „savjetuje kruni da trži s Racima jer će
pomoću njihovom najlakše Madjare otjerati u Mongolsku”.968 U tim politički burnim godinama početka dvadesetog stoljeća, Ivan Žirovčić je, kao već etablirani
forenzički psihijatar često pozivan da pruži stručno mišljenje u procesima protiv pojedinaca koji
su počinili zločine političkog karaktera. Jedan od takvih slučajeva, onaj studenta I. M. koji je
oštetio portret bana Karola Khuena Hedérváryja donio sam u prethodnom poglavlju. Daleko su
ozbiljniji bili slučajevi nasilnih politički motiviranih zločina, kakav je bio onaj Josipa Vugrina,
bolničara iz Bolnice milosrdne braće koji je 1. prosinca 1905. godine hicima iz revolvera ranio
brdovečkog župnika Matiju Penića. Vugrin tijekom slučaja iznosi tri različita motiva zločina. dmah nakon pokušaja ubojstva Vugrin je govorio seljanima da je pucao je na župnika jer ga je
župnik „opsovao fakinom” dok je nakon uhićenja počeo pričati „da je župnika htjeo naumice
ustrijeliti i tako iz Brdovca maknuti, jer je župnik „Obzoraš“ i s narodom zlo postupa, a on, Josip
Vugrin, je župniku politički protivnik, čita i drži si „Hrvatsko Pravo“, koje je toga župnika grdilo,
i to je Vugrina tako podjarilo, da je odlučio osvetiti se župniku, pa je u tu svrhu pod izlikom
kućne diobe uzeo dopust i oboružan revolverom, pošao u Brdovec. Odvjetnik Josip Frank
zatražio je psihijatrijsko vještačenje i usprkos žučnim prosvjedima, Vugrin je doveden u
Stenjevec. U zavodu se Vugrin ponaša mirno, no u pismima Franku i dalje inzistira da nije
bolestan. Tada iznosi i treći motiv svog zločina „Kaže, da nije to baš bilo povodom njegovog atentata, već da je župnik u selu omražen,jer je za
poslijednje bune narod huckao, narod je životom nastradao, a župnik se je narodu iznevjerio, 268 on je nemilosrdan, siromacima se ruga, u crkvi narod psuje, težake plaća s 3 seksera i još im
kod plaćanja prezirno novac pod noge baca. On kaže, da se danas u Brdovcu nebi ni jedan
župljan našao, koji ne bi rekao : šteta, da Vugrin nije župnika do mrtva ubio... 969 Žirovčić, 1907: 29. 971 Ibid: 31. 970 Ibid: 30. 972 Ibid: 33. 972 Ibid: 33. 970 Ibid: 30.
971 Ibid: 31 7.5. Anarhisti i atentatori: politički sukobi u psihijatriji 19. stoljeća To ga je
potaknulo, da se on za druge žrtvuje.”969 Vugrin i dalje ostaje pri tvrdnji da su motivi zločina bili političke prirode, jedino ga sad ne
povezuje sa stranačkom situacijom već se predstavlja kao zaštitnik siromašnih seljaka u njihovom
navodnom sukobu za župnikom. Uvidom u anamnezu koju je u Stenjevac dostavio Josip Frank, dobiva se slika Josipa Vugrina kao
ekscentričnog čovjeka sklonog laganju i nasilnim ispadima: prilikom služenja vojske pokušao je
bajunetom probosti stražmeštra koji ga je kaznio zbog kartanja, drugi bolničari su ga u bolnici
Milosrdne braće zvali „nori” ili „smušeni”, a sukobljavao se i s liječnicima i tukao bolesnike.970 Uvidom u anamnezu koju je u Stenjevac dostavio Josip Frank, dobiva se slika Josipa Vugrina kao
ekscentričnog čovjeka sklonog laganju i nasilnim ispadima: prilikom služenja vojske pokušao je
bajunetom probosti stražmeštra koji ga je kaznio zbog kartanja, drugi bolničari su ga u bolnici
Milosrdne braće zvali „nori” ili „smušeni”, a sukobljavao se i s liječnicima i tukao bolesnike.970
Često se pravio važan pretjerujući u korištenju stručnih izraza koje je uz to i krivo izgovarao te je
mnogo pio.971 Na osnovi činjenice da se, osim stalnog laganja, kod Vugrina ne pojavljuju znakovi
duševne bolesti, Žirovčić će zaključiti da Vugrin nije duševno bolestan „nego da ima u njega
nezdravih svojstava i duševnih nedostataka, što čini njegovu duševnu ličnost manje vrijednom i
sklonijom na protusocijalne čine”972. Žirovčić neće tražiti uzrok Vugrinovog zločina u nekom
određenom duševnom poremećaju pa čak niti u Vugrinovom pijanstvu, već će ga zaključak o
mogućim motivima napada temeljiti na svojem poimanju nižih slojeva. Kao što sam već
spomenuo u jednom od prethodnih poglavlja, mnogi liječnici obrazovani u inozemstvu,
uključujući i Žirovčića, promatrali su siromašne seljake kao „primitivne” osobe koje su duševno,
tjelesno i moralno manje vrijedne od osoba građanskih slojeva. Za Žirovčića će stoga biti
prirodno da širenje političkih ideja među širokim masama može reagirati samo eksplozijom
nasilja i u podužem odlomku predstavlja Vugrinov atentat na župnika kao dokaz primitivizma
ruralnog stanovništva i nesposobnosti istog za razumijevanje i bavljenje politikom. „Pita se ponajprije, može li mu se zaista vjerovati, da je on nakanio usmrtiti župnika iz mržnje
kao političkog protivnika. 975 Jutarnji List, 1912., br. 84: 1. 973 Ibid: 32. 974 Ibid. 974 Ibid. 973 Ibid: 32. 7.5. Anarhisti i atentatori: politički sukobi u psihijatriji 19. stoljeća Vjerodostojnost toga razloga ne da se poreći, ako se uvaži, kako
žestoko se razplamćuju strančarske strasti, te bijesna buka bezobzirne i za kulturu sramotne
lično-strančarske borbe iz sabornica i novinstva odjekuje čak u seljačkim kolibama, gdje 269 doduše ne može pobuditi razumijevanje, ali može uzbuditi surove nagone neuka puka.”973 Uz
Vugrinovo primitivno porijeklo, Žirovčić smatra i da je kraj (okolica Zaprešića) iz koje Vugrin
potječe također formirala njegov karakter učinivši ga nasilnom i moralno manjkavom osobom. Pritom se poziva na povijest prijašnjih zločina u tom kraju. Navodna krvava povijest tog kraja i
njegova zaostalost i primitivizam nisu mogli u Vugrina „odgojiti osobitu plemenštinu, niti
zatomiti divlju okrutnost čovjeka- životinje.974” Za razliku od Krpana kojeg je duševna bolest nagnala na usvajanje radikalnih ideja, kod Vugrina
se čak ni ne može govoriti o političkom radikalizmu, već jednostavno o niskim strastima koji
proizlaze iz lošeg porijekla i odrastanja u sredini koju Žirovčić smatra osobito primitivnom. Za
Vugrina, politička borba može biti jedino shvaćena kao nagonsko nasilje. Rođen na selu, bio je
predodređen za život primitivizma, a selidbom u grad zarazio se političkim idejama i postao
svojevrsna himera- čovjek životinja. Prema tome, čini se da Žirovčić misli da neobrazovano
ruralno stanovništvo, sklono nasilju i zlodjelima, od političke borbe može usvojiti jedino nasilne
emocije osvetničkog bijesa i okrutnosti. Najpoznatiji slučaj političkog nasilja u kojem je Žirovčić sudjelovao (i koji će gotovo zapečatiti
njegovu karijeru forenzičkog vještaka) bio je slučaj Luke Jukića, člana napredne omladine koji je
8. lipnja 1912. pokušao ubiti bana i kraljevskog povjerenika Slavka Cuvaja. Atentat je bio
neuspješan- Jukić je promašio Cuvaja i smrtno ranio njegovog savjetnika Ivu Hervoića. Javnost
je bila zaprepaštena Jukićevim činom i ubrzo su se pojavile teorije o njegovoj neuračunljivosti u
trenutku počinjenja zločina. Izvještaj o atentatu koji je sljedećeg dana izišao u Jutarnjem listu
indirektno dovodi u vezu sam čin atentata s atipičnim mentalnim stanjem: „Sasvim ljudski osjećaj
javlja se pri tom: osjećaj da je samo fanatična zasljepljenost mogla u duši atentatora proizvesti
psihološku dispoziciju pod kojom je počinio svoje zločinstvo.”975 Vještaci Ivan Žirovčić, tadašnji ravnatelj zavoda za umobolne u Stenjevcu i Artur Lang, primarni
liječnik istog zavoda mogli su pregledati Jukića i Neidharta u njihovim ćelijama tijekom suđenja i
promatrati njihovo ponašanje za vrijeme sudskih rasprava. S obzirom na ugled koji je Žirovčić
već tada uživao, njegovo svjedočenje je moglo osloboditi Jukića smrtne kazne. 976 Jutarnji list, 1912., br. 134: 3. 977 Ibid. 977 Ibid.
978 Ibid 978 Ibid. 977 Ibid.
978 Ibid.
979 Ibid. 7.5. Anarhisti i atentatori: politički sukobi u psihijatriji 19. stoljeća Pozivanje na 270 Jukićevu neuračunljivost bila je osnova njegove obrane, a u prilog toj tezi išli su Jukićevi
emotivni ispadi bijesa u sudnici, kao i činjenica da je 1910. godine bio otpušten iz vojske zbog
duševne bolesti navedene pod kompliciranim nazivom: „Reizbare Schwaeche des Nervensystem
als ausdruck einer psychopatischen Veranlagung gekennzeichnet durch andauerende
Verstimmung durch Verworrenheit zustaenden zunehmende Abmagerung. Degenerationszeichen:
Pupillendifferenz, angewachsene Ohrlaeppchen”(Razdražljiva slabost živčanog sustava kao izraz
psihopatske predispozicije, koja se manifestira uznemirenošću i zbunjenošću i gubitkom težine. Znakovi degeneracije: različite zjenice, velike ušne školjke).976 Osim toga, Jukić je imao
obiteljsku povijest duševnih bolesti i bolesti živčanog sustava i s očeve i s majčine strane, a i
sestra mu je bila štićenica stenjevačkog zavoda. U izvješću vojnog liječnika je također stajalo da
je bolest bila posljedica herediteta i da nije nastupila tijekom vojne službe.977 Žirovčić i Lang su iznijeli rezultate svog vještačenja pred sudom. Žirovčić je prvi iznio svoje
mišljenje, već na početku odredivši Luku Jukića kao „teško hereditarno obterećenog čovjeka”.978
No, prije iznošenja mišljenja o Jukićevom duševnom zdravlju, Žirovčić govori o povezanosti
političkih zločina i duševne bolesti, govori da je percepcija atentatora kao duševno bolesnog
uvriježena u javnosti te priznaje da se i njemu samom isprva činilo da bi počinitelj mogao biti
„kakav lud čovjek” te spominje tri vrsta duševne bolesti koje su mu pale na um: „umobolnik”
koji odjednom „bez svakog razmišljanja prasne nekim silovitim činom” hebefreni kojima „poput
djece padne kakva god opasna ludorija u glavu” i „paranoici koji žive pod dojmom kakve
utuvljene obmane koja ih goni na silovite čine”979 Žirovčićevi dotadašnji članci bili su objavljeni
u stručnom časopisu i bili namijenjeni liječnicima koji su imali osnovna znanja o duševnoj
bolesti. Govoreći pred sudom u svjedočenju koje je preko tiska bilo preneseno široj javnosti,
Žirovčić iznosi sažetu definiciju duševno bolesnog pojedinca: „Umobolan čovjek goji u svojoj duši svoj posebni umišljeni svijet, koji s vanjskim realnim
svijetom nije u skladu, a bolesnik ipak dojmove svojega sobstvenoga mišljenja stavlja u
vanjski svijet kao realnu činjenicu, te dolazi tom bludnjom s realnim svijetom u opreku i u
sukob. On proteže ne sebe ono što ga se nimalo ne tiče, utvara si neprijateljstva i progonstva te
na ti reagira otporom: ili sebe preuveličava ludom obmanom, umišljajući sebi osobitu kakvu
976 Jutarnji list, 1912., br. 134: 3. 977 Ibid 271 važnost, uvijek je vlastiti njegov ja ono središte s kojega proizlazi i na koje se vraća sve
njegovo mišljenje... 982 Jutarnji list, 1912., br. 134: 4. 985 Jutarnji list, 1912., br. 134: 5. j
983 Ibid. 984 Ibid. 984 Ibid. 981 Ibid. 983 Ibid. 981 Ibid.
982 Jutarnji list, 1912., br. 134: 4. 980 Ibid. 983 Ibid.
984 Ibid.
985 J
ji li
1912 b 134 5 7.5. Anarhisti i atentatori: politički sukobi u psihijatriji 19. stoljeća ”980 Ova definicija ludila iznosi podsjeća na definiciju paranoje koju je sam Žirovčić opisao 1895. godine i na način na koji je opisana Krpanova duševna bolest petnaest godina ranije. Žirovčić je
isključio iz definicije „umobolje”, sve bolesti temeljene na patološkim raspoloženjima, epilepsiju
i hebefreniju koje je prije uključivao i naglasio trenutak nesklada sa stvarnošću i usmjerenost
duševno oboljelog na sebe samoga. Nakon toga, Žirovčić je zaključio svoje vještačenje
mišljenjem u korist optužbe, izjavivši da Jukićev čin nije proizišao iz njegovog sukoba s realnim
svijetom. Umjesto toga Jukić je „gojio plemenite težnje” poput kulturnog i političkog sjedinjenja
svog naroda i samostalnosti i slobode domovine, a na sam čin atentata natjerala ga je „njegova
divlja ćud uzbuđena „burnim vremenima”.981 Raniju dijagnozu duševne bolesti koju su postavili
vojni liječnici Žirovčić dovodi u pitanje, definirajući je kao slabost živčanog sustava koja može
rezultirati duševnim oboljenjem, a ne kao samu duševnu bolest. Vladimir Prebeg odlučio se na agresivno unakrsno ispitivanje Ive Žirovčića, prvo dovevši u
pitanje njegovu nepristranost i upitavši ga je li vladin činovnik na što je Žirovčić odgovorio da
jest, ali da je u svojoj znanosti nepristran i da svoje mišljenje daje u najboljoj savjesti.982 No, u
nastavku ispitivanja, Žirovčić počinje djelovati nesigurno. Tako ga Prebeg navodi da prizna kako
nije podrobno pregledao optuženog: nije provjerio boluje li Jukić od sifilisa, onanira li, te je
ustvrdio da stigme degeneracije, za koje je priznao da su uočljive na Jukići nisu presudne za
dokazivanje duševne bolesti.983 Time je Žirovčić naizgled napravio odmak od somaticističkog
determinizma i moralističkog poimanja duševne bolesti i opetovano isticao da je Jukićev čin bio
promišljena reakcija na političku situaciju u zemlji. Žirovčić također nije mogao na
zadovoljavajući način objasniti Jukićevo ponašanje i poneke bizarne tvrdnje poput one da mu
raste nova kost ispod jezika a na Prebegove upite je odgovarao uglavnom kratkim rečenicama.984
Nakon Žirovčića, svjedočio je Lang. Čini se da je on ipak detaljnije pregledao okrivljenika,
provjerio mu fizičko stanje i reflekse i utvrdio osjetljivost kože na dodir i bol.985 Lang je potvrdio
Žirovčićev sud o Jukićevoj stanju i zaključio da je Luka Jukić „exogeno i endogeno nervozan Nakon Žirovčića, svjedočio je Lang. ,
988 Fatović-Ferenčić i Kuhar, 2019:15-16. 986 Jutarnji list, 1912., br. 134: 6. 989 Ibid: 17. j
987 Thaller, 1933: 470. j
987 Thaller, 1933: 470. 986 Jutarnji list, 1912., br. 134: 6. 986 Jutarnji list, 1912., br. 134: 6. 989 Ibid: 17. 7.5. Anarhisti i atentatori: politički sukobi u psihijatriji 19. stoljeća Čini se da je on ipak detaljnije pregledao okrivljenika,
provjerio mu fizičko stanje i reflekse i utvrdio osjetljivost kože na dodir i bol.985 Lang je potvrdio
Žirovčićev sud o Jukićevoj stanju i zaključio da je Luka Jukić „exogeno i endogeno nervozan 272 čovjek nu da ne spada u ni jednu meni u psihijatriji poznatih duševnih bolesti”.986 Ostatak
njegovog svjedočenja bio je više manje istovjetan Žirovčićevom. Obrana neuračunljivošću nije
urodila plodom i Luka Jukić je osuđen na smrtnu kaznu koja je kasnije preinačena u doživotni
zatvor. Iz zatvora je izišao nakon uspostavljanja Kraljevine SHS. Zbog svog svjedočenja,
Žirovčić je bio žestoko kritiziran od strane Liječničkog zbora koji se ogradio od njegovog
vještačenja.987 Članovi Liječničkog zbora ubrzo su bili kažnjeni od strane Slavka Cuvaja, a
Žirovčić je dao odgovor u Narodnim novinama u kojem je istaknuo svoje razočaranje zbog
osude udruženja u čijem je časopisu proteklih devetnaest godina objavljivao psihijatrijska
vještačenja.988 Uloga koju je Žirovčić igrao u smrtnoj presudi Jukiću s kojim je veliki dio pro-jugoslavenski
orijentiranih članova Liječničkog Zbora vjerojatno simpatizirao i kasnije kazne izrečene
pojedinim liječnicima zauvijek su narušile Žirovčićeve odnose s kolegama. Nakon sukoba s
Liječničkim Zborom, Žirovčić će u Liječničkom vjesniku objaviti samo još jedno vještačenje
godinu dana prije svog prijevremenog umirovljenja. Žirovčićevo vještačenje Luke Jukića bilo je
u suprotnosti s brojnim njegovim dotadašnjim zaključcima, a njegov nastup je odavao dojam
nesigurnosti što je navelo brojne suvremenike i povjesničare poput Josipa Horvata i Stjepana
Sirovice da zaključe da je Žirovčić učinio ustupak vlastima.989 Ipak, ako se Žirovčićevo iskaz
usporedi s njegovom analizom atentata koji je počinio Josip Vugrin, primjećuje se da je Žirovčić
smatrao da je burna politička situacija u državi kadra navesti ljude niskog porijekla i upitnog
obrazovanja na nasilje bez da pojedini nasilni postupci imaju svoje uzroke u nekoj određenoj
duševnoj bolesti. Žirovčić je nedvojbeno osjećao veliki pritisak, budući da ga je ban Khuen
Héderváry već jednom smijenio s mjesta ravnatelja Stenjevca, zbog daleko banalnijeg sukoba s
vlastima. Kao dugogodišnji i predani ravnatelj, posvetio je čitavu svoju karijeru napredovanju
zavoda i imao je motivaciju ponuditi sudu mišljenje koje neće kompromitirati njegov položaj. Na
kraju, njegova nesigurnost je mogla potjecati od činjenice da nije dobio priliku pregledati Luku
Jukića u samom zavodu kako je to obično činio i da je njegovo vrijeme s osumnjičenikom bilo
ograničeno. 273 Slučaj atentata na kraljevskog namjesnika Cuvaja dokaz je recepcije psihijatrijskih ideja u
javnosti krajem devetnaestog stoljeća. 7.5. Anarhisti i atentatori: politički sukobi u psihijatriji 19. stoljeća Branitelji, pisci novinskih članaka, okrivljenici i liječnici
daju vlastita tumačenja odnosa između duševne bolesti, političkog radikalizma i nasilnih
postupaka. Može se reći da se političko i medicinsko isprepliću od početka do kraja Jukićevog
slučaja: onodobni intelektualci poput Antona Gustava Matoša i kasniji povjesničari poput Josipa
Horvata se ne mogu osvrnuti na atentat bez da se upuste u dijalog s psihijatrijom, ili pribjegnu
davanju medicinskog mišljenja o Jukićevom stanju. S druge strane, način na koji je Žirovčić kao
najugledniji psihijatar u Banskoj Hrvatkoj tog vremena bio izložen profesionalnim i političkim
napadima govori kako su slučajevi „političkih bolesnika” mogli imati dalekosežne posljedice na
karijeru liječnika. Psihijatri su morali balansirati između ugleda vlastite discipline kao grane
medicine koja donosi objektivan i znanstveni sud o društveno važnim pitanjima i političkih
pritisaka kojima su se izlagali davanjem mišljenja u slučajevima poput Jukićevog. Na posljetku,
Žirovčić je nakon svog svjedočenja bio izložen napadima upravo zbog sumnje da nije djelovao
kao medicinski stručnjak već kao državni službenik, dok se Jukićev slučaj nastavljao opisivati
psihijatrijskim diskursom korištenim od strane laika. Slučajevi nasilja, bilo da se radilo o obiteljskom nasilju, adolescentskom nasilju, konfliktima u
ruralnim zajednicama ili političkim sukobima uvijek su dovodili psihijatre u težak položaj. S
jedne strane, psihijatri koji su pokazivali interes za forenzičku psihijatriju imali su jasnu namjeru
da legitimiraju novu medicinsku granu iznoseći svoj vlastiti medicinski sud o nasilju i zločinu,
najčešće utemeljene u biološkom determinizmu Lombrosove kriminalne antropologije. No uz tu
je tendenciju uvijek postojala svijest o tome da nasilje često ima kompleksne uzroke koji nisu
svodivi isključivo na biologiju. Također, čak i onda kad bi psihijatri nedvojbeno opisali
konfliktne štićenike kao „rođene zločince” ili „duševno manje vrijedne ličnosti” kao što je to bio
slučaj s Rudolfom Stanićem i Josipom Vugrinom, često su oklijevali proglasiti ih duševno
bolesnima, odabirući umjesto toga granične pojmove „primitivizma” ili „moral insanityja”. Njihov pristup se često razlikovao od slučaja do slučaja, pa je tako Miloš Krpan proglašen
neuračunljivim zbog same nepokolebljive uvjerenosti u vlastite političke ideja, dok je Luka Jukić
proglašen zdravim upravo zbog toga što je počinio zločin motiviran jasnom političkom idejom. Psihijatrijski tretman slučajeva nasilja, naročito kad je isto imalo političku dimenziju probudilo je
interes javnosti za psihijatriju i politiziralo ju na mnogo eksplicitniji način nego što je to bio 274 slučaj s drugim problemima kojima se psihijatrija bavila, jer je za razliku od emocija ili
seksualnosti, nasilje gotovo uvijek smatrano problemom od javnog interesa. 275 275 Zaključak Ideja o osnivanju Kraljevskog i zemaljskog zavoda za umobolne u Stenjevcu rodila se u trenutku
kad je nedostatak institucije za duševno oboljele u tadašnjoj Banskoj Hrvatskoj prepoznat kao
ozbiljan društveni problem. „Ludnički odjeli” koji su postojali u ostalim zemaljskim bolnicama
nisu više bili adekvatni za zbrinjavanje sve većeg broja duševno bolesnih, a uostalom,
funkcionirali su više kao ustanove palijativne skrbi. Još sredinom stoljeća, postojalo je čvrsto
uvjerenje da izgradnja specijaliziranih zavoda koje vode specijalizirani zavodski psihijatr. iRješavanje tog problema motiviralo je liječnike i saborske zastupnike no put od prvih diskusija
do izgradnje takve institucije bio je izrazito dugotrajan. Na kraju, zavod je otvorio svoja vrata
1879. godine, u doba kad je zavodska psihijatrija u Europi već bila preplavljena duhom
terapeutskog pesimizma- zavodi su bili zapušteni i prenapučeni i nije se činilo izvjesnim da će se
liječnici koji su njima upravljali pronaći način učinkovitog tretmana za duševne bolesti. Sam
zavod, od svojih se početaka morao boriti s logističkim i ekonomskim problemima- zemljište je
bilo neadekvatno i močvarno, što je pogodovalo širenju epidemija, broj štićenika je rastao, i već
od prvih godina premašivao kapacitete zavoda, planovi o samoodrživosti zavoda su bili osuđeni
na propast jer je većina štićenika bila nesposobna za rad zbog teškog tjelesnog i psihičkog stanja,
a osoblje nije imalo iskustva u upravljanju poljoprivrednim zemljištem. U drugom desetljeću
postojanja zavoda, te su probleme pratile i poteškoće s nadležnošću i vlasništvom nad zavodskim
zemljištem i sukobi ravnatelja sa zemaljskim vlastima. Iz tih razloga terapeutski pesimizam je bio
jedan od elemenata koji su formirali intelektualnu klimu u kojoj su Rohaček, Forenbacher,
Žirovčić i ostali djelovali. Imenovanje kaznioničkog liječnika Jana Rohačeka prvim ravnateljem zavoda u Stenjevcu od
početka je usmjerilo hrvatske psihijatre prema forenzičkoj psihijatriji. Uz tada suvremene i naoko
revolucionarne teorije Ceserea Lombrosoa i Richarda von Kraffta Ebinga, usmjerenost
forenzičkoj psihijatriji čvrsto je povezala percepciju duševne bolesti sa društveno devijantnim
ponašanjem i seksualnim praksama koje su još ranije bile opisane kao nemoralne. Kako se bližio
kraj devetnaestog stoljeća, ideje o „degeneraciji”, popularizirane od strane europskih psihijatara i
konzervativnih filozofa koji su usvojili ideologiju „znanstvenog rasizma” proširile su se i među 276 hrvatskim liječnicima, a kroz književnost i pisanje brojnih socijalnih reformatora prodrle su i u
širu javnost. Obrazovanje liječnika na austrijskim, češkim i njemačkim sveučilištima upoznalo ih
je s tada aktualnim somaticizmom i biološkim determinizmom. Zaključak Susret sa štićenicima od kojih je
većina bila siromašna i ruralnog porijekla, doveo je do povezivanja ideja o „degeneraciji“ s
predrasudama o ruralnom stanovništvu kao primitivnom i manje inteligentnom. Intelektualni
horizont hrvatske psihijatrije prijelaza stoljeća bio je oblikovan terapeutskim pesimizmom
prožetim s ostacima paradigme moral treatmenta. Naslijeđe moral treatmenta je osobito vidljivo
u preživljanju velikog broja terapijskih metoda, poput radne terapije, važnosti ispravne prehrane,
izolacije i liječnikovog neupitnog autoriteta. No dominantna obilježja psihijatrijskog diskursa u
Hrvatskoj i dalje su biološki determinizam i somaticistička etiologija duševne bolesti, teorije o
degeneraciji i tendencija k diskurzivnoj i praktičnoj medikalizaciji brojnih ponašanja smatranih
društveno i/ili moralno devijantnima. Svakodnevna praksa hrvatske psihijatrije, značila je s druge
strane, stalnu borbu liječnika za preživljavanje štićenika koji su bili držani u teškim životnim
uvjetima, prenapučenost, epidemije, nedostatak stručnog osoblja, konstantnu komunikaciju sa
štićenicima i više ili manje pomno bilježenje njihovog govora. U tim bilješkama, koje su činile
osnovni dio svake povijesti bolesti vidi se sukob koji je obilježio hrvatsku psihijatriju. Radi se o
sukobu između teorijski formulirane »normalnosti« utemeljene u emotivnom režimu i
patrijarhalnom moralu građanskih slojeva i traumatične svakodnevice marginaliziranih štićenika,
sukob između modernističkog utopijskog sna moderne medicine i nemogućnosti komunikacije
između intelektualnih elita i marginaliziranih pojedinaca. Narativi bolesnika, skupljeni iz pisama
i zapisanih izjava susreću diskurs liječnika koji se trude zadržati epistemičku hegemoniju i
legitimirati svoju društvenu ulogu medicinske discipline koja može objasniti i disciplinirati svijet
devijantnih praksi i atipičnih emotivnih stanja. Dolazi do otpora- štićenici se trude izraziti svoju
perspektivu i objasniti svoje okruženje i svoj unutarnji svijet vlastitim riječima. Pravo na govor,
na iskazivanje istine i definiranje vlastite ličnosti postaje predmet stalne borbe. Neki od štićenika
uživaju u nadmudrivanju liječnika, pokazujući im otvoreno da ne mogu prosuditi njihovu
poziciju. Neki usvajaju psihijatrijski diskurs, objašnjavaju svoje simptome na naoko stručan
način. Štićenici, bilo da su umrli u zavodu, pobjegli iz njega ili su ih liječnici odlučili pustiti,
često ulažu izuzetan trud u pričanje vlastitih priča, iskazuju emocije riječima i postupcima, šalju
pisma ili nude svoju verziju stvarnosti liječnicima na razmatranje, poneki među njima, kao Miloš
Krpan pišu vlastite biografije u kojima iznose poglede na svijet zbog kojih su zatočeni. 277 S druge strane, brojne društvene institucije počinju komunicirati sa zavodom i uključuju ga u
brojne mreže društvenih odnosa. Zaključak Pravosudni organi, obitelji štićenika i predstavnici lokalnih
administrativnih vlasti percipiraju zavod kao odgovor na probleme s kojima se susreću, bilo da se
radilo o nasilju, moralnoj krizi ili društvenim anksioznostima. Odvjetnici i suci traže
psihijatrijsko vještačenje klijenata. Tisak piše o pojedinim štićenicima kao nepravedno
zatvorenima i proširuje u javnosti sliku psihijatrijskih zavoda kao stravičnih simbola društvene
nepravde. Liječnici, često djelujući na intervenciju obitelji ili lokalne vlasti, šalju u zavod osobe
čije je ponašanje godinama predstavljalo problem za njihovu okolinu. Sami psihijatri nastoje
etablirati društvenu poziciju psihijatrije kao discipline koja će pronaći znanstveni odgovor na
probleme društva i pomoći brojnim ljudima kojima duševne poteškoće uništavaju živote. No,
njihova znanost je ukorjenjena u svjetonazoru građanske klase i njezinom konzervativnom
pogledu seksualnost, emocije i politiku. Ona pati od napetosti između deklarativnog slavljenja
moderninteta i anksioznosti pred svijetom koji se ubrzano mijenja. Psihijatri smatraju da je
racionalni muškarac europske više srednje klase ideal duševnog zdravlja i gledaju na štićenike i
štićenice kroz tu, uvelike ideologiziranu sliku. No, kao dio rubne i mlade grane medicine,
provodeći vlastiti život izolirani u zavodima u siromašnoj zemlji u kojoj je zemaljska vlast
zanemarivala zdravstvenu i socijalnu politiku, vodeći bitku s nedostatkom stručnog osoblja,
epidemijama kolere, tuberkuloze i tifusa, liječnici i sami predstavljaju grupu koja se često nalazi
u sukobu sa širim društvom. Povijest Kraljevskog i zemaljskog zavoda za umobolne u Stenjevcu može biti opisana kroz
kompleksnu mrežu odnosa između tih triju aktera. Prvi vrh trokuta čine pojedini štićenici, njihove
emocija, traumatična iskustava i životne priča. Drugi vrh su liječnici, koji kroz prizmu
psihijatrijskih znanja i vlastitih moralnih nazora interpretiraju ponašanje štićenika i obilježavajući
pojedina ponašanja kao „poremećena” normaliziraju pojedine norme ponašanja i načine
iskazivanja emocija. Treći kut trokuta čini javnost, predstavljena u glasovima članova obitelji,
pravosudnih organa, književnika, kotarskih liječnika i predstavnika političke vlasti. Niz
pojedinačnih slučajeva opisanih u ranijim poglavljima pruža nam uvid u mjesto koje su rod,
seksualnost, strah, anksioznost, politika i nasilje zauzimali u tom trokutu i koje su se episteme
međusobno susretale u diskurzivnoj mreži odnosa. 278 Pitanja roda i seksualnosti, kako je Foucault pokazao u svojoj „Povijesti seksualnosti”, u
građanskoj kulturi devetnaestog stoljeća postaju važna u smislu njihovog medicinskog i
znanstvenog proučavanja. Kao što smo vidjeli na primjeru studije Richarda von Krafft-Ebinga
znanstveno proučavanje seksualnosti i roda išlo je ruku pod ruku s normativiziranjem postojećih
patrijarhalnih i moralističkih pogleda na rodne uloge i ljudsku seksualnost. Zaključak Psihijatrijska praksa u
zavodu obiluje primjerima specifično patrijarhalnih i konzervativnih pogleda na rod i
seksualnost. Ženska tijela su erotizirana kako prilikom pregleda po dolasku u zavod, tako i kroz
interpretaciju njihovih emocija i ponašanja kao „erotičnih” što je epitet kojim liječnici gotovo
nikad ne opisuju muškarce. Etiologija psiholoških simptoma pacijentica bila je percipirana kroz
klinički pogled koji je stavljao naglasak na njihov reproduktivni sustav i percipiranu mentalnu
„ranjivost”. Tijela štićenica i dalje su bila gledana kroz predmedicinko očište koje je u središte
stavljalo reproduktivni sustav i mapiralo njihova tijela kao fluidna, karakterizirana permanentnom
nestalnošću osjeta, emocija i motiva. Javno istupanje žena, interes za politiku i čitanje, te učestalo
suprostavljanje muškim autoritetima smatrani su simptomima duševnih poremećaja (ponajviše
histerije), a čitanje knjiga se ponekad smatralo uzrokom duševne bolesti. Što se psihijatrijskih
dijagnoza tiče, liječnici su i dalje smatrali žene osjećajnijima i podložnijima tjelesnim utjecajima
na psihu. Iz tog razloga, češće im se pripisivalo takozvane „afektivne psihoze” dovođene u vezu s
intenzivnim emotivnim stanjima poput „manije” i „melankolije”, a rjeđe poremećaje povezane s
pogrešnom primjenom logičkih i „racionalnih” kognitivnih postupaka poput paranoje. Kod
uzroka bolesti kod žena, često se ignoriraju specifičnosti njihovog svakodnevnog života i
ishodište problema se somatizira i smješta u reproduktivni sustav što dovodi do navođenja,
menstruacije i dismenoreje kao uzroka bolesti. Prema tome, može se reći da povijesti bolesti
govore u prilog tezi o histerizaciji ženskih tijela, koju je postavio Michel Foucault, a koji su
prepoznali brojni povjesničari i povjesničarke devetanestoljetne medicine. Same štićenice, kroz svoje iskaze i simptome, često govore o teškim životnim situacijama koje su
obilježavale svakodnevicu brojnih žena i djevojaka u devetnaestom stoljeću. Ana Schier će tako
direktno govoriti o teškoćama kojima su izložene žene koje pokušavaju ostvariti neko pravo
preko suda, a koje pritom nemaju podršku muškaraca. Brojne štićenice su udovice ili napuštene
od muževa i odbačene od obitelji i djeluju u ruralnim patrijarhalnim društvima, te se često zbog 279 strukturalne opresije kojima su bile izložene ne mogu izboriti za svoj glas. Brojne svjedoče i o
seksualnom, emotivnom i fizičkom zlostavljanju od strane svojih muževa, obitelji, pa i drugih
muških osoba na poziciji društvene moći poput bolničara ili liječnika. U većini analiziranih
slučajeva, psihijatri nisu uzimali ta svjedočanstva ozbiljno, a govor štićenica je uvijek bio
bilježen isključivo kao demonstracija njihovih simptoma i nije bio uziman u obzir kao
dijagnostički ili terapeutski relevantan. Zaključak Hrvatski liječnici su bili rano i dobro upoznati sa Charcotovom definicijom i kliničkim opisom
histerije i neki od njih, poput Nike Selaka su ekstenzivno pisali o histeriji kod svojih pacijentica i
pacijenata. Iako su stenjevački liječnici bili upoznati sa Charcotovim radom, njihov klinički
tretman histerije bio je mnogo drugačiji i opet je od histerije učinio „protejsku bolest” fluidnih
simptoma. Također, histerija je, u skladu s njezinim opisom koji daju njemački klinički psihijatri
poput Kräpelina, bila više odlikom duševnog i tjelesnog ustroja samih žena, stanje koje je
zapravo inherentno ženama i koje se samo u određenim okolnostima manifestira u obliku
„histerične psihoze” ili „histeričnog ludila” (histerrisches Irrensein). Prema tome, narativ histerije
bio je stalno prisutan u percepciji štićenica, čak im nije postavljena specifična dijagnoza histerije. Kad je histerija dijagnosticirana, u većini slučajeva koje sam imao priliku analizirati povezivana
je s transgresijom emotivnih režima i kršenjem normi ponašanja vezanih za rodne uloge. Unutar
emotivnog režima građanstva, žene su ohrabrivane i odgajane da pokazuju „nježne” i „pasivne”
emocije dugog trajanja i niskog intenziteta poput majčinske ljubavi, a njihova temeljna uloga
sastojala se u afektivnoj brizi za privatnu sferu. Pokazivanje intenzivnih emocija poput izrazite
seksualne strasti i bijesa ili njihovo djelovanje u javnoj sferi na način koji otvoreno prkosi
muškim autoritetima bio je smatran transgresijom, koja je bila dovoljnom za dijagnozu histerije. Hrvatski liječnici su bili rano i dobro upoznati sa Charcotovom definicijom i kliničkim opisom
histerije i neki od njih, poput Nike Selaka su ekstenzivno pisali o histeriji kod svojih pacijentica i
pacijenata. Iako su stenjevački liječnici bili upoznati sa Charcotovim radom, njihov klinički
tretman histerije bio je mnogo drugačiji i opet je od histerije učinio „protejsku bolest” fluidnih
simptoma. Također, histerija je, u skladu s njezinim opisom koji daju njemački klinički psihijatri
poput Kräpelina, bila više odlikom duševnog i tjelesnog ustroja samih žena, stanje koje je
zapravo inherentno ženama i koje se samo u određenim okolnostima manifestira u obliku
„histerične psihoze” ili „histeričnog ludila” (histerrisches Irrensein). Prema tome, narativ histerije
bio je stalno prisutan u percepciji štićenica, čak im nije postavljena specifična dijagnoza histerije. Kad je histerija dijagnosticirana, u većini slučajeva koje sam imao priliku analizirati povezivana
je s transgresijom emotivnih režima i kršenjem normi ponašanja vezanih za rodne uloge. Zaključak Unutar
emotivnog režima građanstva, žene su ohrabrivane i odgajane da pokazuju „nježne” i „pasivne”
emocije dugog trajanja i niskog intenziteta poput majčinske ljubavi, a njihova temeljna uloga
sastojala se u afektivnoj brizi za privatnu sferu. Pokazivanje intenzivnih emocija poput izrazite
seksualne strasti i bijesa ili njihovo djelovanje u javnoj sferi na način koji otvoreno prkosi
muškim autoritetima bio je smatran transgresijom, koja je bila dovoljnom za dijagnozu histerije. Možemo dakle reći da se histerija u praksi hrvatske psihijatrije rjeđe doživljava kao precizno
definiran i opisan skup psiholoških i neuroloških simptoma kao kod Charcota, a više kao trajno
emotivno i fizičko stanje žena koje mora biti strogo regulirano odgojem i koje žene čini
nesposobnima za javno, političko i intelektualno djelovanje („osobe niže duševne vrijednosti” po
Žirovčiću). To stanje ponekad može dovesti do brojnih manifestacija duševne bolesti. U prilog
činjenici da je histerija kod stenjevačkih psihijatara bila strogo povezana uz konzervativno
poimanje rodnih uloga u građanskom društvu govori i odsutnost „histeričnih” muškaraca u praksi
a oda iako s ih opisali i Charcot i neki hr atski liječnici Možemo dakle reći da se histerija u praksi hrvatske psihijatrije rjeđe doživljava kao precizno
definiran i opisan skup psiholoških i neuroloških simptoma kao kod Charcota, a više kao trajno
emotivno i fizičko stanje žena koje mora biti strogo regulirano odgojem i koje žene čini
nesposobnima za javno, političko i intelektualno djelovanje („osobe niže duševne vrijednosti” po
Žirovčiću). To stanje ponekad može dovesti do brojnih manifestacija duševne bolesti. U prilog
činjenici da je histerija kod stenjevačkih psihijatara bila strogo povezana uz konzervativno
poimanje rodnih uloga u građanskom društvu govori i odsutnost „histeričnih” muškaraca u praksi
zavoda, iako su ih opisali i Charcot i neki hrvatski liječnici. 280 Osim svjedočanstava o zlostavljanju, štićenice ponekad spominju deluzije vezane uz
zaposjedanje ili strojeve kontrole. U tim slučajevima žene gube kontrolu nad vlastitim tijelom, pa
čak i tjelesni integritet . Među tim slučajevima osobito su važni oni kod kojih je osoba koja vrši
kontrolu muškarac na poziciji moći. Takvi slučajevi govore o depersonalizaciji i gubitku
identiteta do kojeg dolazi u situacijama izrazite nejednakosti moći između štićenica i muškaraca. Njihovom analizom i uzimanjem glasa štićenica i njihovih emocija u obzir mogu se povući jasne
paralele o zrcaljenju stvarne administrativne i financijske moći koju su spomenuti muškarci imali
nad navedenim ženama u njihovim fantazijama o magijskoj i tehnološkoj kontroli. Zaključak Kompleksnost problematike roda i seksualnosti u hrvatskoj psihijatriji devetnaestog stoljeća
nazire se u tretmanu jedne tipično „muške” bolesti - „dementiae paralytice” ili progresivne
paralize, degenerativne bolesti živčanog sustava koja se razvija u tercijarnom stadiju sifilisa. Ta
tada neizlječiva bolest već je od sredine devetnaestog stoljeća dovođena u vezu sa sifilisom, a
muškarci oboljeli od nje činili su velik udio populacije europskih zavoda za duševno oboljele. Kompleksnost problematike roda i seksualnosti u hrvatskoj psihijatriji devetnaestog stoljeća
nazire se u tretmanu jedne tipično „muške” bolesti - „dementiae paralytice” ili progresivne
paralize, degenerativne bolesti živčanog sustava koja se razvija u tercijarnom stadiju sifilisa. Ta
tada neizlječiva bolest već je od sredine devetnaestog stoljeća dovođena u vezu sa sifilisom, a
muškarci oboljeli od nje činili su velik udio populacije europskih zavoda za duševno oboljele. No, velik dio europskih i hrvatskih psihijatara osporavao je vezu između zaraze sifilisom i
progresivne paralize. Među stenjevačkim psihijatrima, izuzetak je bio kratkotrajni ravnatelj Ivan
(Jan) Šimsa koji je pomoću obdukcija pacijenata oboljelih od progresivne paralize utvrdio
postojanje veze između sifilisa i kasnijih patoloških promjena na mozgu koje dovode do pojave te
degenerativne bolesti. Drugi psihijatri poput Forenbachera i Žirovčića, tražili su uzroke
progresivne paralize u nemoralnom životu, alkoholizmu i iscrpljenosti. Sifilis je ponekad
prepoznat kao uzrok progresivne paralize kod nižih društvenih slojeva, zajedno sa alkoholizmom
i nemoralnim životom, dok se kod oboljelih muškaraca iz građanskog sloja bolest pripisivala
iscrpljenošću uslijed napornog rada. Takvi pogledi na progresivnu paralizu odražavali su
uvjerenje brojnih onodobnih liječnika o seljacima i siromašnim radnicima kao nemoralnima,
raskalašenima i sklonima alkoholu i građanstvu kao klasi koja žrtvuje svoje zdravlje naporno
radeći i stječući. Moralističko poimanje seksualnosti kod psihijatara manifestira se i u psihijatrijskim definicijama
seksualnih patologija. Začetnikom psihijatrijskog proučavanja seksualnosti smatra se Richard von
Krafft-Ebing, čiji je rad ostavio značajan trag na poimanje seksualnosti kod stenjevačkih 281 liječnika. Gotovo svi bitniji autori koji su radili u stenjevačkom zavodu se često pozivaju na
Krafft-Ebingovu „Psychopatiu sexualis”. U tom djelu Krafft-Ebing, bez da je za svoje tvrdnje
pružio ikakve uvjerljive dokaze biologizira postojeće rodne uloge i seksualne norme, dajući im
medicinski autoritet. Seksualne prakse poput homoseksualnosti i masturbacije koje su prije bile
smatrane grijehom i moralnim prijestup sad su dobile značaj patologije i medicinske devijacije. Pod utjecajem vijesti o senzacionalnim zločinima poput londonskih ubojstava Jacka Trbosjeka,
naročita se pažnja posvećuje vezama između devijantne seksualnosti i ostalih oblika društveno
devijantnog ponašanja poput krađa i nasilja. Zaključak Seksualnost štićenika u stenjevačkom zavodu bila je
pomno bilježena, praćena, regulirana i nadzirana, a navodno devijantne seksualne prakse
smatrane su dokazom duševne bolesti ili hereditarne manjkavosti štićenika. Iz ponekih pisama
štićenika vidljivo je da i poneki bolje obrazovani štićenici sami usvajaju medikalizirani diskurs o
seksualnosti. Osim nadzora koji se događa unutar Stenjevca, pokušaji discipliniranja ljudskih tijela i
moralističko-medicinskog ograničavanja seksualnosti bit će prisutni u liječničkim pokušajima da
utječu na bračne i seksualne navike šire populacije povezujući navodni „primitivizam” hrvatskih
seljaka sa njihovom lijenošću i intelektualnom zaostalošću, a njihove seksualne prakse poput
ranih brakova smatrane su uzrocima moralne i društvene degeneracije. Prema tome, može se reći
da su tendencija da se patrijarhalno poimanje rodnih uloga, tradicionalni pogledi na ljudsku
seksualnost legitimiziraju kroz psihijatriju i medicinu bila je prisutna u hrvatskoj psihijatriji od
samih njezinih početaka. Ona je išla ruku pod ruku s percepcijom građanske klase kao
intelektualno, moralno, tjelesno i duševno nadmoćne ruralnoj populaciji iz čijih je redova dolazila
većina štićenika, a sve je to nedvojbeno utjecalo na način kako su se navedene ideje, ogrnute
aurom znanstvene objektivnosti, širile i još čvršće ukorjenjivale u društvu Banske Hrvatske. Uz rod i seksualnost, brojne povijesti bolesti tematiziraju strah. Isti se doduše, mnogo manje
javlja u stručnim člancima stenjevačkih psihijatara, no emocije straha i anksioznosti su opisane
kao simptomi određenih duševnih bolesti ili uzroci istih. Poimanje straha kao uzroka duševnog
oboljenja preuzeto je još iz zapisa Phillipea Pinela. Teorije o degeneraciji i radikalno
somaticističko shvaćanje etiologije duševnih bolesti koje prevladava od sredine devetnaestog
stoljeća gurnule su strah i anksioznost u drugi plan, te se isti u medicinskoj literaturi spominje 282 isključivo kao simptomi duševne bolesti. No, iako je eksplicitno spominjanje straha i
anksioznosti u medicinskoj literaturi rijetkost, to ipak ne znači da opisi degeneracije kao
postepenog i neizbježnog propadanja zapadne civilizacije uslijed nasljednog fizičkog, duševnog i
moralnog slabljenja populacije ne odišu tim emocijama. U djelima poput O Degeneraciji Maxa
Nordaua vidi se kako je strepnja koja je na prijelazu stoljeća obuzimala obrazovane elite bila u
velikoj mjeri prisutna i u psihijatriji. Dio psihijatrijskog pogleda na društvo bio je obilježen
strahom od posljedica sve većeg širenja hereditarnih karakteristika koje su liječnici smatrali
patološkima. To je značilo sve veći broj ljudi koji su se nalazili u prostoru ocrtanom kao
„borderlands” granično područje između ludila i ideala duševnog zdravlja, a takva je perspektiva
u atmosferi sve raširenijeg terapeutskog pesimizma rezultirala mračnom slikom budućeg društva. Zaključak Uz to, anksioznost, strepnja i strah sve su više činili dio svakodnevne emotivne kulture
društvenih elita, bilo da se radilo o pitanjima diplomacije, ekonomije, posljedica tehnološkog
razvoja ili politike. Uz somaticizam, njihova sveopća prisutnost u javnom diskursu, učinila ih je
relativno nevidljivim u kliničkim opisima duševnih oboljenja. Tek Freudovim odbacivanjem
somaticističke etiologije, teorija o degeneraciji i prepoznavanjem „neurotičnih” elemenata u
temeljima građanskog društva i europske kulture u cjelini, strah i anksioznost postaju eksplicitno
prepoznati kao emocije bitne za prepoznavanje uzroka određenih duševnih poteškoća. U Stenjevcu štićenici demonstriraju strah od neimaštine, natprirodnog, nasilja i moći države. Strah od siromaštva i strepnja pred gladovanjem često se javljaju kod štićenika i štićenica koji
pripadaju najsiromašnijim društvenim grupama. Naročito se svojom brojnošću ističu siromašni
seljaci koji su često živjeli na rubu oskudice, a prvi ravnatelj Zavoda Ivan Rohaček čak je naveo
siromaštvo i slabokrvnost uslijed neadekvatne prehrane kao vjerojatan uzrok bolesti većine
štićenika. Štićenici koji u iskazuju strah od siromaštva i strepnju za vlastito preživljavanje
najčešće imaju dijagnoze melankolije i manije. Te dijagnoze su u pravilu prevladavale kod siromašnog ruralnog stanovništva. Definicija tih
bolesti kao „afektivnih psihoza” uklapala se u dominantni emotivni režim građanske klase koji je
smatrao siromašnije slojeve sklonijima emotivnim uplivima, a same emocije držao inferiornima
razumu. Osim seljaka, u prvim godinama postojanja stenjevačkog zavoda siromaštvo je čest
motiv u povijestima bolesti štićenika identificiranih kao „bosanski bjegunci”- izbjeglice iz
ruralnih krajeva Bosne i Hercegovine koji su pobjegli u Bansku Hrvatsku pred valovima nasilja 283 nakon austrougarske okupacije 1878. godine. U kasnijim godinama, veza između straha za
vlastitu egzistenciju u uvjetima teške neimaštine i duševne bolesti se gubi iz povijesti bolesti i
uzroci bolesti se sve više traže u fiziologiji štićenika i štićenica. Ta tendencija je vidljiva na
primjeru dvaju žena koje su ubile svoju djecu i tvrdile da su učinile taj zločin strahujući od gladi. U oba slučaja, psihijatri koji su trebali dati svoje stručno mišljenje o sposobnosti rasuđivanja tih
žena nalaze motivaciju za taj zločin izvan materijalnih okolnosti okrivljenica. U oba slučaja
okrivljenice su govorile o teškoj neimaštini kao motivu umorstva, no psihijatri su odlučili
ignorirati takvo objašnjenje. Ni neimaština kod Žirovčića nije promatrana kao stanje koje može
izazvati traumatičnu strepnju, već isključivo kao stanje u kojem neadekvatna prehrana uzrokuje
fiziološke promjene i slabi živčani sustav. Zaključak Premda psihijatri nisu uzimali strah od siromaštva u obzir, česta prisutnost istog u govoru
štićenika nam približava povezanost emotivnog svijeta štićenika sa njihovom teškom borbom za
materijalnu sigurnost. Isto vrijedi i za brojne primjere straha od natprirodnog koji se javlja u
povijestima bolesti štićenika. Strah od natprirodnog uglavnom se manifestira kao strah od bića iz
pučke predaje: sablasti, „muri”, vila, „coprnjica”. Ponekad, kao u slučaju seljakinje Magde,
religiozni koncepti poput Čistilišta su personificirani i o njima se govori kao o bićima. Strah od
vraga, kojeg se krivi za životne poteškoće, utjelovljuje u neprijateljima i kome se pripisuje
uzrokovanje bolova i tjelesnih poteškoća je također učestalo. Štićenici često govore o svojim
strahovima od natprirodnog i njihovi strahovi govore o širokoj rasprostranjenosti vjerovanja u
magiju, fantastična stvorenja i bogatoj pučkoj religioznosti. Sami liječnici pokazuju izražen
interes za te strahove, potičući štićenike da govore o svojim vjerovanjima. U nekim slučajevima,
liječnici ne shvaćaju vjerovanja u fantastična bića i natprirodne pojave znakom duševne bolesti,
već ih jednostavno pripisuju praznovjerju i nedostatku obrazovanja. Ipak, religijske navike
štićenika jedna su od rubrika istaknutih u Liječničkoj svjedodžbi. interes liječnika za religiozne
navika štićenika odaje posebnu dimenziju odnosa između religiozih vjerovanja i psihijatrije. Psihijatri su smatrali vjerski život štićenika važnim pokazataljem njihovog mentalnog zdravlja. Definicija „normalnog” religioznog ponašanja nije nigdje eksplicirana, no vjerovanja istaknuta
kao neuobičajena u liječničkim svjedodžbama i povijestima bolesti pokazuju da je ideja
religioznosti koju su psihijatri i drugi liječnici percipirali kao „normalnu” imala svoj izvor u
građanskom poimanju religioznosti kao racionalnog razumijevanja vjere i tradicionalnom moralu, 284 dok su rituali i vjerovanja prožeti mnogo emotivnijim i sinkretičnim doživljajem božanskog
kakav je karakterizirao pučku religioznost u konteksu promatranja u psihijatrijskom zavodu
mogli puno lakše biti shvaćeni kao znak patologije. Strah od nasilja česta je tema u stručnoj psihijatrijskoj literaturi devetnaestoj stoljeća. Strah od
nasilja u izvorima ima dva lica: s jedne strane možemo pratiti emotive vezane uz strah psihijatara
i javnosti od nasilja duševno oboljelih, dok s druge strane možemo pratiti govor samih duševno
oboljelih koji izražavaju strah od stvarnog ili zamišljenog nasilja. Psihijatri su često pisali o
strahu od duševno oboljelih koji je još uvijek bio prisutan u javnosti i o percepciji duševno
oboljelih kao nasilnih. Deklarativno, opovrgavali su taj strah nalazeći njegove izvore u
predmedicinskom praznovjernom stavu prema duševnim oboljenjima. Ipak neki od stručnih
radova implicitno koriste taj strah i predstavljaju psihijatriju kao instituciju koja štiti društvo od
nasilnog ponašanja štićenika. Zaključak Također, usprkos konstantnom ekspliciranju stava o ljudskoj psihi
kao podrućju koje se može spoznati na objektivan i znanstven način, porivi i emocije duševno
oboljelih se često opisuju makabričnim slikama čija upotreba odaje strah ili strepnju. Psihijatrija
prijelaza stoljeća je obilježena ambivalentim stavom prema samim duševno oboljelima: s jedne
strane, liječnici poimaju duševno oboljenje kao bolest i nastoje se izboriti za human tretman
duševno oboljelih i za suzbijanje stigme. No, sami evociraju strah o ludila prisutan u javnosti
kako bi naglasili društvenu važnost psihijatrije, a njihovi slikoviti opisi duševnih stanja odaju
određen strah i nerazumijevanje duševnih oboljenja, ponekad dehumanizirajući duševno oboljele. Sami štićenici često iskazuju strah od nasilja, bilo kao jednostavnu visceralnu reakciju kojom se
anticipira moguća opasnost po njih, bilo kao elaboriran strah od jasno definiranih osoba koje rade
protiv njih i žele im nauditi. Bez obzira na samu prirodu straha, psihijatri ne obraćaju mnogo
pažnje na sam objekt straha koliko na njegovu prisutnost ili odsutnost (prisutnost straha se uvijek
gleda kao mogući znak duševne patologije) i na način pokazivanja emocije straha. Također, za
psihijatre nije previše bitno je li strah bio opravdan prijašnjim životnim iskustvima štićenika. Posebna vrsta straha od nasilja koja se javlja kod određenog broja štićenika je strah od
strukturalnog nasilja državnog aparata. Štićenici koji ističu takav strah odaju kognitivni fenomen
koji je Solomon Resnik nazvao „konstrukcijom progonstvenog svijeta”. Progonstveni svijet
štićenika obilježen je izrazito „politiziranom” slikom stvarnosti u kojoj se događaji iz njihove 285 svakodnevice tumače kroz prizmu malicioznog djelovanja državne administracije, tajnih društava
i agenata državne represije. Sami psihijatri u tim slučajevima ne pokazuju previše interesa za
strah koji štićenici manje i više eksplicitno pokazuju, a iako im često dijagnosticiraju paranoju,
sam strah nije dio kliničkog opisa paranoje koji je Žirovčić dao u svojoj „Razdjelbi duševnih
bolesti” iz 1895. godine. Iako mu psihijatri nisu pridavali osobito značenje, strah štićenika od
državnog aparata i sa njime povezanog nadzora svjedoči o anksioznosti koju su mnogi osjećali
pred povećanjem moći državnih institucija i većom prisutnošću birokratskih i represivnih
elemenata tradicionalnog nadzora u svakodnevnom životu ljudi. Najintenzivnija prisutnost psihijatrijskog diskursa u javnosti povezana je s agresijom, konfliktima
i slučajevima nasilja. Kad se radilo o nasilnim zločinima, psihijatri su bili u intenzivnom kontaktu
s pravosudnim institucijama i objavljivanjem svojih vještačenja nastojali etablirati psihijatriju kao
društvenu institucija koja može objasniti fenomen društvene devijacije kroz prizmu medicine. Zaključak Osim s pravosuđem, psihijatri su u svojoj svakodnevnoj praksi susretali sa članovima obitelji
štićenika, članovima zajednice u kojoj su štićenici živjeli i predstavnicima administrativnih vlasti,
te drugim liječnicima. Njihova društvena uloga dovodila je do činjenice da su u mnogobrojnim
sukobima bili percipirani kao institucionalni autoritet od kojeg se očekuje medicinsko rješenje
konflikta. Rješenje koje se od psihijatara najčešće zahtjevalo bilo je uklanjanje problematičnog
pojedinca iz zajednice. U slučajevima obiteljskih sukoba i sukoba u ruralnim zajednicama
psihijatri često iskazuju ambivalentne stavove. Tako stenjevački psihijatri često ne prihvaćaju sud
članova obitelji i zajednice o tome da problematični pojedinci nužno predstavljaju opasnost i
iziskuju hospitalizaciju. U slučajevima nekih duševno oboljelih štićenika, psihijatri poput
Žirovčića su spremni napraviti odmak od somaticizma i prepostati zlostavljanje u obitelji kao
uzrok duševnog oboljenja. Sukobi unutar obitelji predstavljaju i jedinstven slučaj ulaska
psihijatrije kao javne institucije u obitelj koja se u građanskom društvu smatrala privatnom
sferom. Svaki put kad se nasilje i konflikti pojave u psihijatrijskim zapisima, svjedočimo interakciji
psihijatrije sa društvom u cjelini, a psihijatri su u tim slučajevima prisiljeni zauzeti ulogu
institucije društvene kontrole devijacije. Tu kontrolu psihijatri artikuliraju kroz medicinski
diskurs. Nekad je epistemički okvir spoznavanja duševne devijacije zaogrnut u narative novih 286 duševnih bolesti, poput hebefrenije koja se koristi za objašnjavanje burnih emocija i buntovnih
postupaka adolescenata ili širokog shvaćanja pojma epilepsije kojom se objašnjavaju slučajevi
paleža u ruralnim zajednicama. Drugi put radi se o konstrukciji granične kategorije „osoba niže
duševne vrijednosti” bilo da se radilo o „osobama hereditarno oslabljene nervne konstitucije”,
„moralnim idiotima” ili Lombrosovim „rođenim zločincima”. U bilo kojem od navedenih
slučajeva, psihijatrija nudi spremno objašnjenje društveno devijantnog ponašanja u medicini. U
prvim godinama postojanja stenjevačkog zavoda, neki liječnici poput
Forenbachera nastoje
objasniti pojedine nasilne čine kulturnim i društvenim praksama, no kako vrijeme odmiče,
agresivnost i nasilje se sve češće objašnjavaju biološkim uzrocima. Čak i u slučajevima kad
psihijatri ne prepoznaju jasnu duševnu patologiju kod osobe koja je počinila neki čin nasilja, na
počinitelje se primjenjuje diskurs degeneracije kojim se objašnjava njihova sklonost nasilnom
ponašanju. Psihijatrijski diskurs na prijelazu stoljeća u početku razdoblja kojim se ovaj rad bavi nema
hegemoniju u objašnjavanju psihe čovjeka. Bio je samo jedan od mnogih diskursa kojima su se
objašnjavali kognitivni procesi poput emocija ili seksualne privlačnosti. Zaključak Na kraju krajeva, budući
da je za razvoj psihijatrijskog znanja bila potrebna heterotopija psihijatrijski zavoda, u prvim
desetljećima posTojanja Zavoda za umobolne u Stenjevcu, psihijatrijski diskurs je i sam u stadiju
formiranja- dijagnoze, uzroci bolesti, etiologija i terapijske metode su u eksperimentalnoj fazi. Psihijatrijski diskurs na prijelazu stoljeća u početku razdoblja kojim se ovaj rad bavi nema
hegemoniju u objašnjavanju psihe čovjeka. Bio je samo jedan od mnogih diskursa kojima su se
objašnjavali kognitivni procesi poput emocija ili seksualne privlačnosti. Na kraju krajeva, budući
da je za razvoj psihijatrijskog znanja bila potrebna heterotopija psihijatrijski zavoda, u prvim
desetljećima posTojanja Zavoda za umobolne u Stenjevcu, psihijatrijski diskurs je i sam u stadiju
formiranja- dijagnoze, uzroci bolesti, etiologija i terapijske metode su u eksperimentalnoj fazi. Možemo identificirati dvije kategorije dokumenata kojima psihijatri oblikuju vlastiti diskurs. U
prvu kategoriju spadaju interni dokumenti namijenjeni samim psihijatrima poput povijesti bolesti
i stručne literature. Njihov glavni cilj je pronalaženje medicinskog objašnjenja za određene
oblike devijantnog ponašanja koji su se ono vrijeme opisivali pojmom ludila. Objašnjenje je
značilo klasifikaciju, pronalaženje uzroka, detaljan opis simptoma i tek u rijetkim slučajevima
moguće metode liječenja. Putem proizvodnje i diseminacije internih diskursa o duševnim
bolestima stvarao se set kliničkih znanja o ljudskom mozgu, kognitivnim procesima i
ponašanjima. Ta znanja bila su isključivo medicinska znanja, koja su postepeno reducirala
emocije i ponašanje na njihove biološke uzroke. Takva redukcija ne znači da su emocije i
ponašanja bili jednostavno opisani kao patološki ili normalni. Psihijatri su već od sredine stoljeća
baratali pojmovima „borderlandsa” i degeneracije te su predviđali čitav niz kategorija ljudi koji
su bili smješteni između duševnog zdravlja i patologije, a prema njihovoj slici modernog društva, Možemo identificirati dvije kategorije dokumenata kojima psihijatri oblikuju vlastiti diskurs. U
prvu kategoriju spadaju interni dokumenti namijenjeni samim psihijatrima poput povijesti bolesti
i stručne literature. Njihov glavni cilj je pronalaženje medicinskog objašnjenja za određene
oblike devijantnog ponašanja koji su se ono vrijeme opisivali pojmom ludila. Objašnjenje je
značilo klasifikaciju, pronalaženje uzroka, detaljan opis simptoma i tek u rijetkim slučajevima
moguće metode liječenja. Putem proizvodnje i diseminacije internih diskursa o duševnim
bolestima stvarao se set kliničkih znanja o ljudskom mozgu, kognitivnim procesima i
ponašanjima. Ta znanja bila su isključivo medicinska znanja, koja su postepeno reducirala
emocije i ponašanje na njihove biološke uzroke. Takva redukcija ne znači da su emocije i
ponašanja bili jednostavno opisani kao patološki ili normalni. Zaključak Psihijatri su već od sredine stoljeća
baratali pojmovima „borderlandsa” i degeneracije te su predviđali čitav niz kategorija ljudi koji
su bili smješteni između duševnog zdravlja i patologije, a prema njihovoj slici modernog društva, 287 u tu je kategoriju spadala većina ljudi. Hoće li neki ljudi podleći duševnoj bolesti ili ne, nije
ovisilo isključivo o hereditetu već i o njihovim životnim uvjetima. Tako su psihijatri predviđali
alkoholizam, masturbaciju, pretjerano upuštanje u spolne odnose, venerične bolesti, iscrpljenosti,
zapušten odgoj, određene emocije i siromaštvo kao moguće uzroke duševnih bolesti. Takav
pogled nužno je dalo psihijatrijskom diskursu moralističku komponentu, dok joj je zagovaranje
somaticističke etiologije i biološkog determinizma dalo eugeničku komponentu. Psihijatri pritom
zagovaraju moralne nazore i način života obrazovane građanske klase. Interni diskurs psihijatrije nastaje u bliskoj interakciji sa štićenicima. Odnos psihijatara i štićenika
je ambivalentan. S jedne strane obilježen je ekstremnom asimetrijom moći: psihijatri su ugledni i
obrazovani članovi društvene elite, štićenici već prije dolaska u zavod nose stigmu duševne
bolesti i uz to je u Stenjevcu većina njih bila teškog imovinskog stanja, neobrazovana i pripadala
je ruralnoj populaciji. Nad štićenicima se provodi epistemičko nasilje: njihova svjedočanstva i
glas iako često sustavno i temeljito zapisana nemaju nikakvu težinu u dijagnostičkom procesu i
terapiji. Psihijatri imaju potpunu moć što se tiče objašnjavanja simptoma štićenika, njihove
klasifikacije unutar dijagnostičkog sustava i internog „arhitektonskog” sustava odjela u zavodu,
načinom na koji se sa njima postupa unutar samog zavoda i njihovim eventualnim otpuštanjem iz
zavoda. S druge strane, njihovom govoru i ponašanju u kliničkom kontekstu posvećena je izrazita
pažnja- njihove riječi su zapisane, pisma koja šalju i primaju su sačuvana, a sa njima se
opetovano razgovaralo i tražilo se pojašnjenje njihovih emotivnih stanja i postupaka. Razlog
istovremenom ignoriranju i bilježenju glasova štićenika bio je upravo u činjenici da je zapisivanje
govora duševno oboljelih osoba bilo čin stvaranje kataloga simptoma što je bio ključan korak u
formiranju prvih dijagnostičkih priručnika na temelju kojih us psihijatri klasificirali i razvrstavali
duševno oboljele. S druge strane, podvrgavanje svakog čina duševno oboljele osobe kliničkom
zoru pretvorilo je svaki čin koji je bio u suprotnosti s građanskim moralom ili emotivnim
režimom u potencijalni simptom duševne bolesti, što je imalo presudnu ulogu u trenucima kad su
psihijatri progovarali o društvenim problemima poput adolescentskog ili političkog nasilja. Vanjski psihijatrijski diskurs bio je diskurs kojim je psihijatrija komunicirala s ostatkom
medicinske zajednice, društvenih institucija i šire javnosti, uključujući i štićenike i njihove
porodice. Zaključak Taj diskurs služio je prvenstveno etabliranju psihijatrije kao društveno važne discipline 288 i medicinske grane koja doprinosi zdravlju društva u cjelini. No, budući da psihijatrija nije mogla
ponuditi učinkovitu terapeutsku metoda koja bi dovela do liječenja ili prevencije duševnih
bolesti, postepeno se sve više pretvarala u instituciju društvenog nadzora. Psihijatrijski zavod
prestao je biti mjestom liječenja i postao mjestom zatočenja i izolacije društveno devijantnih
pojedinaca. Sami psihijatri su se borili protiv takve percepcije psihijatrijskih zavoda i stigme koju
je ista značila i za njih i za njihove štićenike, no njihov entuzijazam brzo je ugašen u atmosferi
terapeutskog pesimizma i teških uvjeta rada u prenapučenim zavodima u kojima nije bilo
dovoljno osoblja, hrane, odjeće ni medicinskih potrepština. Sami štićenici u zavodima su bili
protiv svoje volje, a tamo su u najboljem slučaju mogli dobiti samo palijativnu skrb. Dapače,
budući da su u zavodu epidemije bile veoma učestale, moguće je da je institucionalizacija
zapravo smanjila njihove šanse preživljavanja. Bijegovi iz zavoda su česti, primjeri štićenika koji
svojevoljno dolaze u zavod rijetki (mnogi od istih biraju zavod suočeni s alternativom zatvora), a
komunikacija štićenika i psihijatara obilježena epistemičkim i institucionalnim nasiljem i
dehumanizacijom s jedne strane i primjerima otpora s druge strane. Najvidljivija posljedica
kontakta psihijatrije sa širom javnošću vidi se u postepenom širenju medicinskih pogleda na
ljudsku psihu u književnosti, tisku, kriminologiji, sociologiji i antropologiji. Medicinske ideje o
emocijama, društvenoj devijaciji i ljudskom umu do kraja Prvog svjetskog rata biti će potpuno
ukorjenjene u hrvatskom građanskom društvu, usprkos postojanju alternativnih pogleda na iste. Govor štićenika i štićenica koji sami počinju progovarati o svojim emocijama i duševnom stanju
medicinskim diskursom samo je jedna od posljedica tog širenja. Početkom dvadesetog stoljeća psihijatrija počinje sve više biti percipirana kao jedina disciplina
koja uživa znanstveni autoritet u pogledu dijagnosticiranja, traženja uzroka duševnih bolesti i
njihovog tretiranja. Doba terapeutskog pesimizma, tko će prestati ubrzo nakon Prvog svjetskog
rata, kad će iznalaženje novih terapeutskih metoda poput terapije groznicom koju je tijekom
ratnih godina razvio bečki psihijatar Julius Wagner-Jauregg. Terapija inokulacijom malarijom
inducirala je dugotrajne remisije kod oboljelih od progresivne paralize te produžila životni vijek
i poboljšala kvalitetu života oboljelih od te teške i neizlječive bolesti. Wagner-Jauregg će zbog
tog svog otkrića postati prvi psihijatar dobitnik Nobelove nagrade za medicinu, a njegovo otkriće
će početi doba eksperimentiranja s raznolikim terapijama u zavodskoj medicini. 990 Bourke, 2003. 120-121. Zaključak Sami zavodi se
pretvaraju u prave istraživačke klinike u kojima se vrše laboratorijski testovi i gdje se aktivno 289 iskušavaju brojne terapije, od hormonalnih terapija, terapija induciranom komom do
elektrokonvulzivne terapije i psihokirurgije koje se javljaju u osvit Drugog svjetskog rata. Novi
optimizam liječnika, psihijatrijski termini i načini govora o ljudskom umu postaju sve prisutniji u
javnosti. Govor o psihopatologiji izišao je iz psihijatrijskih klinika i ušao u svakodnevni govor
ljudi, a likovi psihijatara i duševno oboljelih počinju se sve češće pojavljivati u književnosti i
filmu. Joanna Bourke primijetila je kako je od 1930-ih godina, govor o strahu u memoarima
nekadašnjih vojnika prestao biti tumačen kao izraz pukog instinkta za samoodržanjem i postao
prožet psihijatrijskim i psihoanalitičkim diskursom.990 Psihijatrija će tako prestati biti
marginalnom disciplinom koja se bavi ljudima odbačenima od društva i postat će disciplinom čije
će ideje sve više oblikovati javni diskurs prodirući u ostale institucije društva i pojavljujući se u
ostalim znanstvenim disciplinama. U dvadesetom stoljeću, ta će recepcija psihijatrijskih ideja imati dvije veoma izražene dimenzije
koje će većinu vremena biti suprotstavljene. Jedna se sastojala u transformaciji diskursa o
degeneraciji u eugeniku i znanstveni rasizam koji će u razdoblju između dva svjetska rata postati
dominantnom idejom u brojnim europskim društvima, a u nekim politikama ostavit će trag sve do
danas. Eugenika i znanstveni rasizam, kao trendovi naročito prihvaćeni u njemačkoj psihijatriji (i
u jednoj mjeru u psihijatriji Sjedinjenih Američkih Država) ostat će mrlja na povijesti psihijatrije,
jer će u konačnici dovesti do teške dehumanizacije duševno oboljelih. Najtragičnija posljedica te
dehumanizacije bio je organizirani projekt ubijanja duševno oboljelih u nacističkoj Njemačkoj,
zloglasna akcija T4 koja upravo zbog sveprisutnosti eugenike u psihijatrijskim krugovima nije
naišla na značajan otpor psihijatara. Tijekom akcije T4 ubijeno je oko 300 000 duševno oboljelih
koji su proglašeni „životima nevrijednim življenja.” Utjecaj znanstvenog rasizma bio je očit i u
drugoj velikoj psihijatrijskoj tragediji dvadesetog stoljeća, tragediji psihijatrijske kolonije u
Barbaceni u brazilskoj pokrajini Minas Gerais gdje je zbog zlostavljanja i zanemarivanja od
1903. do 1980. godine umrlo više od 60 000 štićenika od kojih je većina bila Afro-Brazilskog
porijekla. Utjecaji eugeničkog i rasističkog nasljeđa na psihijatriju izazivaju kontroverze i danas,
kao što je vidljivo na primjeru nedavnih kontroverzi oko dijagnoze Aspergerova sindroma. Prvi
klinički opisi kasnih 1930-ih godina odražavali su percepciju mentalnog zdravlja ukorijenjenu u 990 Bourke, 2003. 120-121. j
p g
j
j
Asperger’s Children: The Origins of Autism in Nazi Vienna objavljenoj 2018. godine. p g
g
f
j
j
j
g
992 Amaddeo, Barbui i Tansella, 2012: 315 991 Kontroverze u vezi s nacističkim nasljeđem Aspergerova sindroma detaljno je istražila Edith Sheffer u knjizi
Asperger’s Children: The Origins of Autism in Nazi Vienna objavljenoj 2018. godine. 991 Kontroverze u vezi s nacističkim nasljeđem Aspergerova sindroma detaljno je istražila Edith Sh 991 Kontroverze u vezi s nacističkim nasljeđem Aspergerova sindroma detaljno je istražila Edith Sheffer u knjizi
Asperger’s Children: The Origins of Autism in Nazi Vienna objavljenoj 2018. godine. p g
g
f
992 Amaddeo, Barbui i Tansella, 2012: 315 Zaključak 290 nacističkog poimanju „normalnosti”, a Hans Asperger po kojem je sindrom dobio ime, bio je
strastven podržavatelj nacističkih mjera i programa eutanazije duševno oboljelih991. No, odnos psihijatrije i društva nije rezultirao isključivo shvaćanjem psihijatrije kao biopolitičkog
sredstva duševne kontrole čija je uloga uklanjanje „društvenih patologija” pod svaku cijenu. Već
u vremenu između dva rata psihijatrija se pomalo počinje fokusirati na kulturne i interpersonalne
aspekte duševnih bolesti. Kao reakcija na dehumanizirajući pokret eugenike, sve veći broj
psihijatara počinje uviđati važnost zalaganja za destigmatizaciju i dostojanstven tretman
duševnih bolesnika, kako unutar duševnih bolnica, tako i u širem društvu. Nakon Drugog
svjetskog rata, užasni uvjeti u brojnim psihijatrijskim klinikama dospjevaju u medije i počinju
rezultirati pozivima na sveobuhvatnu reformu psihijatrije. Neki liječnici, poput Thomasa Szassa
i Ronalda D. Lainga odabrali su radikalan smjer propitivanja samog koncepta duševne bolesti kao
medicinske činjenice. Njihovi radovi su i danas važan doprinos kritičkom promatranju
psihijatrije, no najopipljiviji rezultat postigao je samozatajni talijanski psihijatar Franco Basaglia. Basaglia je tijekom šezdesetih godina dvadesetog stoljeća radio kao psihijatar u Gorici i Trstu,
gdje je počeo implementirati svoj projekt postupne deinstitucionalizacije i reforme psihijatrijskih
klinika: prestao je s praksom vezivanja pacijenata i ukinuo sobe za izolaciju. Kroz svoju udrugu
„Demokratska psihijatrija” izborio se za takozvani „Zakon 180”. Donesen 1978. godine, zakon je
stavio izvan zakona prisilnu hospitalizacijue u psihijatrijskim bolnicama, zabranio izgradnju
novih psihijatrijskih bolnica i potaknuo osnivanje odjela za liječenje duševnih bolesnika u općim
bolnicama na kojima se oboljeli mogu liječiti uz pristanak. Time je talijanska psihijatrija prestala
biti povezana za institucije bazirane na izolaciji duševno oboljelih i stvorila je uvjete za tretiranje
takvih bolesnika u općim bolnicama i komunalnim centrima mentalnog zdravlja. Posljedice
zakona bile su dalekosežne- trideset godina nakon psihijatrijske reforme Italija je imala manje
psihijatrijskih kreveta od ostalih europskih zemalja, manje populacije je uzimalo
psihofarmakološke lijekove a broj od 18 hospitalizacija na 100 000 stanovnika, zabilježen 2004. godine među najnižima je u Europi.992 Italija je postala primjer zemlje koja već desetljećima
provodi uspješan model mentalnog zdravlja baziran na pristupu duševno oboljelima koji smanjuje
njihovu patnju, istovremenu štiteći njihovu slobodu izbora i dostojanstvo. 291 Kraj terapeutskog pesimizma koji je nova generacija psihijatara donijela nije nužno značio kraj
poimanja psihijatrije kao sredstva društvene kontrole, ali je pružio realnu alternativu. Psihijatrija
se njime oslobodila iz mračnih zidova „muzeja ludila” i postala mjestom ne samo diskursa o
društvenoj degeneraciji i patologiji, već uistinu diskursa o duševnom zdravlju. 993 Scull, 2015: 382. Zaključak No, veća
društvena uloga psihijatrije rezultirala je i nekim izazovima sa kojima se i psihijatrija i društvo
tek trebaju suočiti. Kako je psihijatrija postajala priznata znanost tako se širila njezina moć da
objasni različita psihička i emotivna stanja unutar vlastitih medicinskih okvira. Medicinski
diskurs kojim se počelo govoriti o emocijama, često može dovesti do zanemarivanja njihovih
interpersonalnih, društvenih, kulturnih, pa i političkih aspekata.Dva ključna događaja iz sredine
dvadesetog stoljeća pomogli su psihijatriji da nametne novo medicinsko poimanje psihe. Prvi od
tih događaja bila je standardizacija psihijatrijskih dijagnoza kroz Međunarodnu Klasifikaciju
Bolesti (ICD) koju je 1949. donijela Svjetska Zdravstvena Organizacija i Dijagnostički i
Statistički Priručnik Mentalnih Poremećaja (DSM) čije je prvo izdanje tiskano 1952. godine. Standardizacija i klasifikacija psihijatrijskih dijagnoza omogućila je njihovu primjenu na velik
broj različitih ponašanja i simptoma. Uz to, u kasnijim izdanjima ovih priručnika, broj dijagnoza
neprestano raste: prvi DSM razlikovao je 106 dijagnoza, a trenutno je na snazi peta verzija koja
ih prepoznaje preko 400. Ostaje li otvoreno pitanje odražava li povećanje broja dijagnoza
rafiniraniji dijagnostički i klasifikacijski aparat suvremene psihijatrije ili se radi o sve većoj
medikalizaciji ljudskih ponašanja i emotivnih i duševnih stanja. Druga velika povijesna promjena
bilo je otkriće djelotvornih psihofarmaka poput klorpromazina sintetiziranog 1950. godine i
brojnih antipsihotika i sredstava koja inhibiraju i utječu na raspoloženje. Uspon
psihofarmakologije od sredine stoljeća do danas, pružio je psihijatriji novi način terapije koji je
bio lako provodiv i koji je nedvojbeno pomogao daljnjoj legitimaciji psihijatrije kao medicinske
discipline jer je nalikovao terapeutskim pristupima ostalih medicinskih grana.993 Uspon
psihofarmaka dao je vjetar u jedra novoj somaticističkoj paradigmi, koja ovaj put nije bila
bazirana na degeneraciji i eugeničkim temeljima, već na diskursu o neurotransmiterima i
neuravnoteženoj kemiji mozga. Ono čime će se svako društveno-humanističko istraživanje
psihijatrije morati pozabaviti su veliki profiti koje psihofarmakološko liječenje duševnih bolesti
donosi globalnoj farmaceutskoj industriji. Kao što je istaknuo Andrew Scull, antipsihotici i 292 antidepresivi se, otkad su se našli na tržištu, nalaze među najprofitabilnijim farmaceutskim
pripravcima.994 To nije zbog toga što predstavljaju neku vrst „psihijatrijskog penicilina”995-
njihovo djelovanje više je palijativno nego kurativno i tretman psihifarmacima rijetko rezultira
potpunim izliječenjem. Upravo je njihova nepotpuna učinkovitost ono što ih čini profitabilnima
jer ih duševno oboljeli moraju uzimati dugi niz godina kako bi olakšali simptome vlastitih
oboljenja. 994 Scull, 2015: 402. ,
995 Ibid: 401. ,
995 Ibid: 401. Zaključak Jedan od najvažnijih zaključaka ovog istraživanja je da su psihijatriji devetnaestog
stoljeća (uključujući i liječnike Kraljevskog i zemaljskog zavoda za umobolne u Stenjevcu
kojima se ovaj rad bavi) često bili rastrgani između humane želja da ublaže patnju, uloge agenata
koji kontroliraju društvenu devijaciju koja im je bila pripisivana i nemogućnosti da uspostave
komunikaciju s vlastitim pacijentima radi vlastitih predrasuda, te emotivnog režima i morala u
koji je oblikovao njihov pogled na psihu. Ta rastrganost rezultirala je u sustavu mentalnog
zdravlja koji je djelovao izrazito represivno, a najčešće se pokazao neuspješnim u onome što je
smatrao svojom zadaćom: pomaganju osobama sa duševnim tegobama. Ono što će se nametati
kao pitanje onima koji proučavaju i koji će proučavati psihijatriju naših dana je utjecaj globalnog
farmaceutskog tržišta na kurativnu ulogu psihijatrije. U kojoj je mjeri znanstvena psihijatrija
danas sposobna djelovati kurativno, a u kojoj mjeri doprinosi medikalizaciji interpersonalnih i
društvenih problema koji bi se možda mogli bolje riješiti intervencijama koje uključuju promjenu
cjelokupnih društvenih stavova o mentalnom zdravlju? Ova disertacija prati povijest stenjevačkog zavoda do 1918. godine, godine obilježene brojnim
povijesnim diskontinuitetima od kraja Prvog svjetskog rata i uspostave novog političkog i
društvenog poretka u Europi, do kraja Austro-ugarske monarhije u sklopu čijeg sustava
mentalnog zdravlja je zavod dotad djelovao. Prestanak terapeutskog pesimizma odrazio se i u
hrvatskoj psihijatriji. Mjesto njezinog razvoja koje više neće biti samo zavodi za umobolne već
će, kao dio širokog pokreta socijalne medicine u obje jugoslavenske države borba duševno
zdravlje populacije biti vođena u čitavoj javnosti. Autoritet psihijatrije kao znanstvene i
medicinske grane, potvrđuje se i u Hrvatskoj, osobito nakon što je 1921. studentima Medicinskog
fakulteta Sveučilišta u Zagrebu omogućena specijalizacija iz neuropsihijatrije. Time se uistinu
počinju razvijati specifična psihijatrijska misao u Hrvatskoj koja usprkos osnutku drugih klinika
postaje usko vezana uz stenjevački zavod kao središnju instituciju. Sam zavod ubrzo mijenja ima 293 u „Bolnica za duševne bolesti Stenjevec”, i ta promjena također odražava novu percepciju
institucije, kao mjesta čija je uloga eksplicitnije terapijska nego što je to bila dotad. Pritom će u
konkretnom jugoslavenskom slučaju, glasovi koji su se zalagali za somaticizam i eugeniku
postajati sve tiši. Fokus koji su zagovornici socijalne medicine stavljali na prosvjećivanje ruralne
populacije nije mogao dugo supostojati sa starim pogledima na stanovništvo sela kao na
primitivno i nepovratno degenerirano. Hrvatska psihijatrija će, kroz kontakt s javnošću i
postepenu politizaciju, s vremenom sve više poprimati socijalni karakter. Izvori: Arhiv Klinike za Psihijatriju Vrapče, povijesti bolesti. Budapest Főváros Levéltára.1906. Civil law cases: (VII.2.c - 1906 - V.0530: 1- 7). Bibliografija Bibliografija Zaključak Naravno, tome su
uvelike doprinijela medicinska otkrića poput Salvarsana i inzulinske terapije, kao i obrazovanje
čitave nove generacije psihijatara poput Rudolfa Hercega, Stanislava Župića i Dezidera Julijusa
koji su bili spremni eksperimentirati i zbog činjenice da su imali intenzivniji dodir s a većim
spektrom medicinskih znanja i terapeutskih perspektiva. Upravo će Dezider Julijus, nekoliko
mjeseci prije vlastite tragične smrti (počinio je samoubojstvo 1953. godine nakon što je na
sastanku lokalne partijske organizacije optužen za teško kršenje zakona u vođenju bolnice)
donijeti iz Švicarske prve uzorke klorpromazina čime je započeo psihofarmakološku fazu u
hrvatskoj psihijatriji. Način na koji su se suvremeni trendovi u intelektualnoj povijesti psihijatrije
uklopili u nove kulturne i političke kontekste hrvatskog društva u dvadesetom stoljeću, trebat će
proučavati u skladu s napetošću između psihijatrije kao medicinske discipline i psihijatrije kao
sredstva društvene kontrole devijantnih ponašanja i emocija koje je obilježilo čitavu njezinu
povijest. 294 294 Bibliografija
Izvori:
Arhivsko gradivo:
Arhiv Klinike za Psihijatriju Vrapče, povijesti bolesti. Budapest Főváros Levéltára.1906. Civil law cases: (VII.2.c - 1906 - V.0530: 1- 7). Tisak:
Jutarnji list. Godište:1912. Liječnički vjesnik .Godišta:1875.-1952. Stručni članci i medicinske knjige toga vremena: Beard, George. 1869. „Neurasthenia or nervous exhaustion.” The Boston Medical and
Surgical Journal, br. 13, str. 217-221. Blankini, Anthony. 1906. „19 slučajeva railway spine.” Liječnički vjesnik, br. 31. str. 79-96. Braid, James. 1853. Neurohypnology or The Rationale of Nervous Sleep Considered in
Relation with Animal Magnetism. J.Churchill, London. Browne, J. Crichton. 1860. „Psychical Diseases of Early Life”. Journal of Mental Science, br. 33, str. 284-320. Esquirol, Jean-Étienne Dominique. 1845. Mental Maladies: Treatise on Insanity. Lea and
Blanchard, Philadelphia. Forenbacher, Dragutin. 1886. „Slučaj hypnotizma u hystero-epileptične žene”. Liječnički
vjesnik, br.10, str. 158- 160. Forenbacher, Dragutin. 1888. „Dva slučaja paleža, kao prilog k psychiatricko-sudbenoj
praksi”. Liječnički vjesnik, br. 6, str. 84-87. 295 nbacher, Dragutin. 1892. „O progresivnoj paralizi”. Liječnički vjesnik,.br. 1, str.1-7. Guči, Ante. 1880. „Kako se može preranoj ženitbi u Posavini na put stati”. Liječnički vjesnik,. br. 1, str. 1-9 i br. 2, str. 17-23. Guislan, Joseph. 1826. Traité sur l'Aliénation Mentale Et sur les Hospices des Aliénés. J. Van
Der Hayt et fils, Amsterdam. Gundrum, Fran. 1910. „Dr. Ivo Žirovčić: Zdravstveno izvješće kr. zemalj. zavoda za
umobolne u Stenjevcu za godinu 1908.“ Liječnički vjesnik, br. 3., str. 151-154. Haslam, John. 1810. Illustrations of madness: exhibiting a singular case of insanity and a no
less remarkable difference in medical opinion ... with a description of the tortures experienced
[by the patient, James Tilly Matthews, in hallucinations]. G. Hayden for Rivingtons, etc.,
London. Heckler, Eward. 2009. „Hebephrenia: A Contribution to Clinical Psychiatry.” History of
Psychiatry, vol. 20, br. 1-2., str. 87–106, str. 233–248. „Iz povijesti bolnice Vrapče: Izgradnja i razvoj bolnice”. 2014. Brošura Klinike za Psihijatriju
Vrapče. Kräpelin, Emil. 1902. Clinical Psychiatry: A Textbook for Students and Physicians Abstracted
and Adapted from the Sixth German Edition of Kräpelin's Lehrbuch der Psychiatrie. The
Macmillan Company, New York. Kräpelin, Emil. 1992. „Psychiatrische Randbemerkungen zur Zeitgeschichte”. History of
Psychiatry, br. 10, str, 256-269. Krafft-Ebing, Richard von. 2011. Psychopatia sexualis: The Classic Study of Deviant Sex. Arcade Publishing, New York. Kuljženko, Aleksej. 1931. „Medicinska statistika državnog zavoda za duševno bolesne u
Stenjevcu za godinu 1930.” Liječnički vjesnik, br. 8, str. 673.-708. Lockheart-Robertson, Charles. 1861. „On the Sedative Action of the Cold Wet Sheet in the
reatment of Recent Mania, with cases: A contribution to the curative treatment of Mental
Disease.” Journal of Mental Science, br. 38, str. 265-277. Lombroso, Cesare. 2006. Criminal man. Duke University Press, Durham & London. Lopašić, Radoslav. 1925. „Ivan Žirovčić (1855.-1925)”. Machacek, Franjo. 1913. „Iz slavenske medicinske literature. Prof. dr. Lad. Haškovec: Boj s
detskou zločinnosti, prostituci a sebevraždou.” Liječnički Vjesnik, br.6. str.251-257. Stručni članci i medicinske knjige toga vremena: Liječnički vjesnik, br. 9, str. 230-232. Machacek, Franjo. 1913. „Iz slavenske medicinske literature. Prof. dr. Lad. Haškovec: Boj s
detskou zločinnosti, prostituci a sebevraždou.” Liječnički Vjesnik, br.6. str.251-257. 296 Maudsley, Henry. 1867. The Physiology and Pathology of the Mind. D. Appleton and
Company, New York. Maudsley, Henry. 1870. Body and Mind. Macmillan, London. Maudsley, Henry. 1874. Responsibility in Mental Disease. Kegan Paul, London. Morel, Benedict Augustin. 1857. Traité des dégénérescences physiques, intellectuelles et
morales.” Baillière, Pariz. Morel, Benedict Augustin. 1860. Traité des maladies mentales. Masson, Pariz. Nordau, Max. 2016. Degeneration. Popular edition, London. Pinel, Phillipe. 1806. A Treatise on Insanity: In which are Contained the Principles of a New
and More Practical Nosology of Maniacal Disorders Than Has Yet Been Offered to the
Public. W. Todd, Sheffield. Reil, Johann Christian. 1803. Rhapsodieen über die Anwendung der psychischen Curmethode
auf Geisteszerrüttungen. Halle. Rohaček, Ivan. 1885. „Liečničko izvješće kr. Zem. Zavoda za umobolne u Stenjevcu”. Liječnički vjesnik, br.4, str. 49-63. Rohaček, Ivan. 1889. „Kr. zemaljski zavod za umobolne u Stenjevcu godine 1887. i 1888”. Liječnički vjesnik, br. 10, str. 147-149. Schwarz, Dragutin. 1903. „Knjižnica”. Liječnički vjesnik, br.2, str. 76. Selak, Niko. 1887. „Kraniotomija u hypnosi”. Liječnički vjesnik, br.8. str. 114-117. Selak, Niko. 1888. „Hemianaesthesia uslijed psyhičnog uzdrmanja padom u zdenac”. Liječnički vjesnik, br. 11, str. 167-170 . Selak, Niko. 1891. „Hypnotizam ili Braidizam”. Liječnički vjesnik,. br.1 str. 9-12. Stojanović, Gjuro. 1888. „Kupalište Neuhaus u južnoj Štajerskoj”. Liječnički vjesnik, br.9, str. 137-142. Šimsa, Ivan. 1898. „Syphilis cerebri”. Liječnički vjesnik, br. 1, str. 1-7. Thaller, Lujo. 1933. „Teodor Wickerhauser”. Liječnički vjesnik , br. 10, str. 466-471. Van Deusen, Edwin Holmes.1869. „Observations on a form of nervous prostation
(neurasthenia) culminating in insanity”. Journal of Insanity, br. 4, str. 445-461. 297 Wynter, Andrew. 1877. The Borderlands of Insanity and other papers. The Strand, London. Žirovčić, Ivan. 1895. „Casus Ljuboević . Kriminalno - psyholožka crtica”. Liječnički vjesnik,
br. 12 , str. 234-251. Žirovčić, Ivan. 1895a.“O nazivlju i razdielbi duševnih bolesti”. Liječnički vjesnik, br. 4, str. 66-69. Žirovčić Ivan. 1896. „Crtica iz kriminalne psychologije”. Liječnički vjesnik, br.2-3, str. 33-60. Žirovčić, Ivan. 1896a. „Moralna izkvarenost i duševna bolest”. Liječnički vjesnik, br. 9, str. 201-206. Žirovčić, Ivan. 1896b. „O nekojih temeljnih pojavih duševnoga bolovanja”. Liječnički vjesnik,
br.11-12, str. 249-292. Žirovčić, Ivan. 1897. „O postupku s duševno bolestnimi”. Liječnički vjesnik, br. 10, str. 318-
324 i br. 11, str. 353-360. Žirovčić, Ivan. 1898. „Ludjačka umorstva nazvana ”la folie rouge”. Liječnički vjesnik,. Stručni članci i medicinske knjige toga vremena: br. 7,
str. 225-232. Žirovčić, Ivan. 1904. „II. Sudbeni slučaj, u kojem je mlada seljačka žena osumnjičena, da je
zadušila brata svoga supruga”. Liječnički vjesnik, br.10, str. 309-316. Žirovčić, Ivan. 1905. „III. Slučaj bluda učitelja sa školskim djevojčicama”. Liječnički vjesnik,
br.4, str. 120-128. Žirovčić, Ivan. 1905a. „Hysterična žena pred sudom radi klevetanja“. Liječnički vjesnik, br. 7,
str.271-280. Žirovčić, Ivan. 1906. „VI. Slaboumnik palikuća”. Liječnički vjesnik, br.6, str. 219-223. Žirovčić, Ivan. 1906a. .„Ubojstvo u pomućenom duševnom stanju”. Liječnički vjesnik, br.5,
str. 161-164. Žirovčić, Ivan. 1907. „X. Zvekast napadač”. Liječnički vjesnik, br.2, str. 27-33. Žirovčić, Ivan. 1907a. „Dječak ubojica”. Liječnički vjesnik, br. 4. str. 93-98. Žirovčić, Ivan. 1908. „Zagonetan palež.”. Liječnički vjesnik, br.8, str. 231-235. Žirovčić, Ivan. 1910. „Benav dječak igra se razbojnika”. Liječnički vjesnik, br. 7, str. 249-254. Žirovčić, Ivan. 1911. „Zločin u progonstvenom obmanu”. Liječnički vjesnik, br. 2, str. 33-38. 298 Žirovčić, Ivan. 1912. „Napadač iz obmana”. Liječnički vjesnik, br.4, str. 152-158. Žirovčić, Ivan. 1918. „Potopila rodjenu djecu od gladi”. Liječnički vjesnik, br. 11, str. 333-
338. Župić, Stanislav. 1937 „O bolesti Harambašića, Vidrića i Kovačića”. Liječnički vjesnik, br. 8,
str. 341-346. Književna djela: Književna djela: Gjalski, Ksaver Šandor. 1964. Đurđica Agićeva. Branko Đonović, Beograd. Homer. 2003. Ilijada. Nakladni Zavod Matice Hrvatske, Zagreb. Jorgovanić, Rikard. 2002. „Stella Raiva”. U Rikard Jorgovanić: Izabrana djela, ur. Miroslav
Šicel. Matica Hrvatska, Zagreb. Kovačić,
Ante. 2015. U
registraturi. elektire.škole.hr. Preuzeto
s:
http://gimnazija-sb.com/portal/wp-content/uploads/2015/02/kovacica_uregistraturi.pdf, 13. rujna 2018. Leskovar, Janko. 1993. Sabrana djela I. Boris Krizmanič, Pregrada. Leskovar, Janko. 1993. Sabrana djela I. Boris Krizmanič, Pregrada. Matoš, Antun Gustav. 1990. Vidici i Putovi. Naši ljudi i krajevi .Tiskara Rijeka, Rijeka. Shelley, Mary. 1994. Frankenstein or, The modern Prometheus: the 1918 text. Oxford
University Press, New York. Vukelić, Vilma. 2003. Tragovi prošlosti. Zagreb: Nakladni zavod Matice Hrvatske. iteratura: Literatura: Ahmed, Sara. 2014. Cultural Politics of Emotion. Edinburgh University Press, Edinburgh. Ammadeo, Francesco, Corrado Barbui i Michele Tansella. 2012. „State of psychiatry in Italy
35 years after psychiatric reform. A critical appraisal of national and local data.” International
Review of Psychiatry, br.4, str. 314–320. Antić, Ana. 2017. Therapeutic Fascism. Experiencing the violence of Nazi New Order in
Yugoslavia. Oxford University Press, Oxford. Arbex, Daniela. 2013. Holocausto brasileiro: vida, genocidio e 60 mil mortes no maior
hospicio do Brasil. Geração Editorial, Sao Paulo. Ahmed, Sara. 2014. Cultural Politics of Emotion. Edinburgh University Press, Edinburgh. Ammadeo, Francesco, Corrado Barbui i Michele Tansella. 2012. „State of psychiatry in Italy
35 years after psychiatric reform. A critical appraisal of national and local data.” International
Review of Psychiatry, br.4, str. 314–320. Antić, Ana. 2017. Therapeutic Fascism. Experiencing the violence of Nazi New Order in
Yugoslavia. Oxford University Press, Oxford. Arbex, Daniela. 2013. Holocausto brasileiro: vida, genocidio e 60 mil mortes no maior
hospicio do Brasil. Geração Editorial, Sao Paulo. 299 Beddies, Thomas Müller. 2006. „The Destruction of 'Life Unworthy of Living' in National
Socialist Germany”. International Journal of Mental Health, vol. 35, br.3, str 94-104. Blom, Philipp. 2008. The Vertigo Years: Europe 1900-1914. Basic Books, New York. Bloom, Clive. 2013. Victoria's Madmen: Revolution and Alienation. Palgrave Macmillan,
Basinstoke. Bogousslavsky, Julien i Francois Boller. 2005. Neurological Disorders in Famous Artists. Karger, Basel. Borossa, Julia. 2003. Histerija, Ideje u psihoanalizi. Jesenski i Turk, Zagreb. Bourdieu, Pierre. 1996. Distinction: a social critique of the judgement of taste. Harvard
University Press, Cambridge. Bourke, Joanna. 2005. Fear: A Cultural History. Kindle Edition. Bourke, Joanna. 2005. Fear: A Cultural History. Kindle Edition. Bourke, Joanna. 2003. „Fear and Anxiety: Writing about Emotion in Modern History”. History Workshop Journal, br. 55, str. 111-133. Buczynski, Alexander. 1994. „Organizacija policije i pravosuđa u Vojnoj krajini”. Povijesni
prilozi br. 13., str. 77-109. Butterfield, Herbert. 1965. The Whig Interpretation of History. Norton and Company, New
York. Campbell, Brad. 2007. „The making of 'American': race and nation in neurasthenic
discourse.” History of Psychiatry, br.2., str 157-178. Čeč, Filip, Vani D'Alessio i Heike Karge. 2017. ”Crime and Madness on the Opposite Shores
of the Adriatic: Moral Insanity in Italian and Croatian Psychiatric Discourses”. Acta Medica
Historica Adriatica, br. 2, str. 219-252. Davidoff, Leonore. 1998. „Adam spoke first and named the orders of the World': Masculine
and Feminine Domains in History and Sociology”. U Gender and History in Western Europe,. De Young, Mary. 2015. Encyclopedia of asylum therapeutics, 1750-1950s. McFarland &
Company, Jefferson, North Carolina. Foucault, Micheal. 1977. Discipline and Punish: The Birth of the Prison. Vintage Books,
New York. Literatura: ur. Robert Shoemker i Mary Wincester, str. 85-104. Arnold, London, New York, Sydney,
Auckland. Davidoff, Leonore. 2003. „Gender and the Great Divide:Public and Private in British Gender
History.” Journal of Women's History. br. 1, str. 11-27. De Young, Mary. 2015. Encyclopedia of asylum therapeutics, 1750-1950s. McFarland &
Company, Jefferson, North Carolina. 300 300 Delimo, Žan. 2003. Strah na Zapadu (od XIV do XVIII veka). Izdavačka k
Stojadinovića, Sremski Karlovci. Delimo, Žan. 2003. Strah na Zapadu (od XIV do XVIII veka). Izdavačka knjižarnica Zorana
Stojadinovića, Sremski Karlovci. Demos, John i Virginia Demos. 1969. „Adolescence in historical perspective”. Journal of
Marriage and Family, vol. 31, broj 4, str. 632-638, Dennen, Johann. . 2005. „Theories of Aggression: Psychoanalytic theories of aggression“. Default journal, preuzeto s https://core.ac.uk/download/pdf/148195139.pdf, 15. studenog
2019. godine, Draaisma, Douwe. 2009. Disturbances of the Mind. Cambridge University Press, Cambridge. Drača, Vinko. 2017. „'Stenjevačka Ofelija' Ana Schier: rod i duševna bolest u Hrvatskoj na
prijelazu stoljeća“. U Kamen na cesti: granice, opresija i imperativ solidarnosti, ur. Lada
Čale Feldman, Lidija Dujić, Maša Grdešić, Renata Jambrešić Kirin, Anita Dremel, Nataša
Medved. Centar za Ženske Studije, Zagreb. Dujić, Emanuela. 2012. „Povijest kliničkog laboratorija u psihijatrijskoj bolnici Vrapče”. U
Ludnica i lučbarnica. Razvoj laboratorija u psihijatrijskoj bolnici, ur. Stella Fatović-Ferenčić
i Marko Pećina, HAZU, Zagreb. Elias, Norbert. 2000. The Civilizing Process: Sociogenetic and Psychogenetic Investigations. Blackwell Publishing, Oxford. Evans, Dylan. 1996. An Introductory Dictionary of Lacanian Psychoanalysis. Verso, London. Farge Arlette i Jacques Revel. 1999. The vanishing children of Paris: rumor and politics
before the French Revolution. Harvard University Press, Cambridge. Fatović-Ferenčić, Stela i Marin Kuhar. „'A Tortured Nation Gave Birth to a Lunatic': The
Construction of Insanity in the 1912 Terrorist Act in Croatia.” Social History of Medicine,
članak hkz043. https://doi.org/10.1093/shm/hkz043 (objavljeno 19.7. 2019.,). Fatović-Ferenčić, Stela i Marin Kuhar. 2017. „They accused me of strangling her: epilepsy
and violence debate in Croatia at the end of the nineteenth and the beginning of the twentieth
centuries”. History of Psychiatry, vol. 28, br. 4, str. 460-472. Fazerkaš, Ana. 2016. „Diskurzivne tvorbe zločina: Papin-Lacan-Genet”. Književna smotra:
Časopis za svjetsku književnost, vol.48, br. 179 (1), str. 81-98. Ferguson, Eliza Earle. 2010. Gender and Justice, Violence, Intimacy and Community in fin de
siecle Paris. The Johnson University Press, Baltimore Foucault, Micheal. 1977. Discipline and Punish: The Birth of the Prison. Vintage Books,
New York. 301 Foucault, Michel. 1989. The Birth of the Clinic: An archeology of medical perception. Gilman, Sander L., Helen King, Roy Porter, G. S. Rousseau, i Elaine Showalter. 1993.
Hysteria Beyond Freud. University of California Press, Berkley. Literatura: Routledge, London. Foucault, Michel. 1998. The History of Sexuality: Volume one. The Will to Knowledge. Penguin Books, New York. Foucault, Michel. 2002. Madness and civilization: a history of insanity in the age of reason. Routledge, London i New York. Foucault, Michel. 2003. Society Must Be Defended Lectures at the Collège de France 1975–
1976. Palgrave Macmillan, New York. Foucault, Michel. 2006. Psychiatric Power: Lectures at the College de France 1973-1974. Palgrave Macmillan, New York. Freud, Sigmund. 2000. „Opća znanost o neurozama”. U Uvod u psihoanalizu,. Stari Grad,
Zagreb. Freud, Sigmund. 2010. „Civilization and its Discontents.” U Freud-Complete Works, ur. Ivan
Smith. Str. 4462-4532. E-pub
edition,
preuzeto
s
https://www.valas.fr/IMG/pdf/Freud_Complete_Works.pdf 9. rujna, 2018. Freud, Sigmund. 2010. „Notes Upon A Case of Obsessional Neurosis”. U Freud-Complete
Works, ur. IvanSmith, str. 2125- 2194. E-pub edition, preuzeto s
https://www valas fr/IMG/pdf/Freud Complete Works pdf
9 rujna 2018 Freud, Sigmund. 2010. „Notes Upon A Case of Obsessional Neurosis . U Freud-Complete
Works, ur. IvanSmith, str. 2125- 2194. E-pub edition, preuzeto s
https://www.valas.fr/IMG/pdf/Freud_Complete_Works.pdf .9. rujna, 2018. https://www.valas.fr/IMG/pdf/Freud_Complete_Works.pdf .9. rujna, 2018. Freud, Sigmund. 2010. „Psycho-Analytic Notes on an Autobiographical Account of a Case of
Paranoia”. U Freud- Complete Works, ur. Ivan Smith, U Freud-Complete Works, ur. Ivan
Smith,
str. 2385-2448. E-pub
edition,
preuzeto
s
https://www.valas.fr/IMG/pdf/Freud_Complete_Works.pdf. 9. rujna, 2018. Fromm, Erich. 1973. The Anatomy of Human Destructivness. Holt, Rheinhart and Winston,
New York, Chicago i San Francisco. Fuchs, Thomas i Dusan Hirjak. 2009. „Delusions of Technical Alien Control: A
Phenomenological Description of Three Cases”. Psychopathology, br.2, str. 96-103. Fugier, Anne-Martin i Michelle Perrot,. 1990. „The Actors ”. U A History of Private Life IV:
From the Fires of Revolution to the Great War, ur. Michelle Perrot, The Belknap Press of
Harvard University Press, Cambridge Massachusetts, London, England, str. 95-261. Gerrard, Donald L. 1997. „Chiarugi and Pinel Considered: Soul's brain/person's mind”. Journal of the History of the Behavioral Sciences, vol. 33, br. 4, str 381-403. Gilman, Sander L., Helen King, Roy Porter, G. S. Rousseau, i Elaine Showalter. 1993. Hysteria Beyond Freud. University of California Press, Berkley. 302 Glesinger, Lavoslav. 2012. „Povijest psihijatrije u Hrvatskoj- pretisak doktorske disertacije”. U Ludnica i lučbarnica. Razvoj laboratorija u psihijatrijskoj bolnici, ur. Stella Fatović-
Ferenčić i Marko Pećina, HAZU, Zagreb, str. 18-88. Goffman, Ervin. 1963. Stigma: notes on the management of spoiled identity. Prentice Hall,
Inc. Englewood Cliffs. Goldberg, Ann. 1999. Literatura: Sex, Religion, and the Making of Modern Madness: The Eberbach
Asylum and Germany Society, 1815-1849. Oxford University Press, New York. Goldberg, Ann. 2002. „The Mellage Trial and the Politics of Insane Asylums in Wilhelmine
Germany”. The Journal of Modern History, br. 74, str. 1-32. Goodman, Gilman. 1970. The Biological Basis of Therapeutics. Macmillan, London. Greenfeld, Liah. 2013. Mind Modernity Madness: The Impact of Culture on Human
Experience. Harvard University Press, Cambridge and London. Haslam, Fiona. 1996. From Hogarth to Rowlandson: Medicine in Art in Eighteenth-century
Britain. Liverpool University Press, Liverpool. Harris, Ruth. 1997. „Possession on the Borders: The 'Mal de Morzine' in Nineteenth-Century
France.” The Journal of Modern History, br.3, str. 451-478. Hayden, Deborah. 2003. Pox: Genius, Madness and the Mysteries of Syphilis. Basic Books,
New York. Herceg, Rudolf. 1933. „Zavod za umobolne 'Stenjevec' od 1879. do 1933.“ U Stenjevec-
državna bolnica za duševne bolesti 1879.-1933.Spomenica povodom pet decenija rada, str. 6-
30. Društvo za socijalnu pomoć duševnim bolesnicima u Stenjevcu, Zagreb, Horwitz, Allan i Jerome Wakefield. 2012. All We Have to Fear: Psychiatry’s Transformation
of Natural Anxieties into Mental Disorders. Oxford University Press, New York. Iveljić, Iskra. 2007. Očevi i sinovi : privredna elita Zagreba u drugoj polovici 19. stoljeća. Leykam International, Zagreb. Jones, David W. 2016. Disordered Personalities and Crime: An analysis of the history of the
moral insanity. Routledge, London i New York. Jukić, Vlado. 2015. Izgradnja, dogradnje i adaptacije zgrada i drugih infrastrukturnih
objekata bolnice 'Vrapče' od 1877. do 2014. godine – iz povijesti Bolnice Vrapče. Medicinska
naklada Zagreb, Zagreb. Kaplan, Morris B. 2005. Sodom on the Themes. Sex, Love and Scandal in Wilde Times. Cornell University, Ithaca. 303 Kibria, Ayisha A. i Neil H. Metcalfe. 2016. „A biography of William Tuke (1732–1822):
Founder of the modern mental asylum.”Journal of Medical Biography, br. 3, str. 384-388. Laqueur, Thomas Walter. 2003. Making Sex: Body and Gender from Greeks to Freud. Harvard University Press, Cambridge, Massatchusetts i London, Engleska. Lerner, Paul i Mark Micale. 2001. Traumatic Pasts: History, Psychiatry, and Trauma in the
Modern Age, 1870–1930. Cambridge University Press, Cambridge. Lifton, Robert Jay. 1986. The Nazi Doctors: Medical Killing and the Psychology of Genocide. Basic Books, New York. Lunbeck, Elisabeth. 1994. The Psychiatric Persuasion: Knowledge, Gender and Power in
Modern America. Princeton University Press, Princeton. Macalpine, Ida i Richard Hunter. 1966. „'The Insanity ' of King George III: a Classic Case of
Porphyria”. Literatura: British Journal of Medicine, br.1, str. 65-71. Matijašević, Željka. 2006. Strukturiranje nesvjesnog: Freud i Lacan. Biblioteka Sintagma,
Zagreb. Meyer, Manuella. 2017. Reasoning against Madness Psychiatry and the State in Rio de
Janeiro, 1830–1944. University of Rochester Press, Rochester. Micale, Mark i Porter, Roy. 1994. Discovering the History of Psychiatry. Oxford University
Press, Oxford i New York. Milošević, Dragan. 2016. Vlastelinstva i seljački posjedi u Slavoniji od 1699.-1848.- 1945. godine- povijesna, ekonomska i društvena analiza, preuzeto s https://www.zupa-
valpovo.com/dokumenti/kronologija/Vlastelinstva_1699-1945.pdf, 7. rujna 2018. godine. Neumann, Roderick. 1975. „Masturbation, Madness, and the Modern Concepts of Childhood
and Adolescence”. Journal of Social History, br.3, str. 1-27. Noll, Richard. 2011. American Madness: The Rise and Fall of Dementia Praecox. Harvard
University Press, Cambridge Massatchussets, London, England. Osterhammel, Jürgen. 2009. The Transformation of the World: A Global History of the
Nineteenth Century. Princeton University Press, Princeton. Pavličević, Dragutin. 1980. Narodni pokret 1883. u Hrvatskoj. Sveučilišna zaklada, Zagreb. Pejić, Luka. 2016. Historija klasičnog anarhizma u Hrvatskoj. Fragmenti Subverzije. DAF,
Zagreb. 304 Petrungaro, Stefano. 2011. Kamenje i puške: društveni protest na hrvatskom selu krajem XIX. stoljeća. Srednja Europa, Zagreb. Pietrzak-Franger, Monika. 2017. Syphilis in Victorian Literature and Culture: Medicine
Knowledge and the Spectacle of Victorian Invisibility. Palgrave MacMillan, London. Plamper, Jan. 2012. The History of emotions: An Introduction. Oxford UniversityPress,
Oxford. Pocs, Eva. 2018. „Small Gods, Small Demons: Remnants of an Archaic Fairy Cult in Central
and South-Eastern Europe“. U Fairies, Demons and Natural Spirits: 'Small Gods' at the
Margins of Christendom, ur. Michael Gostling, str. 255-277. Palgrave MacMillan, London. Porter, Roy. 2003. Flesh in the Age of Reason. Penguin Books, London. Porter, Roy. 2002. Madness: A Brief History. Oxford University Press, Oxford. Rachman, Stanley. 2004. Anxiety. Psychology Press, New York. Reddy, William. 2002. The Navigation of Feeling: A Framework for the History of Emotions. Cambridge University Press, Cambridge. Resnik, Solomon. 1998. „Being in a persecutory world: the construction of a world model and
its distortions”. U Even paranoids have enemies – new perspectives on paranoia and
persecution. ur. Joseph H. Berke, Stella Pierides, Andrea Sabbadini i Stanley Schneider, str. 16-36. Routledge, London. Savage, Joe. 2007. Teenage: The Creation of Youth 1875-1945. Chatto & Windus, London. Schecter, Harold. 2000. Fiend: The Shocking True Story of America's Youngest Serial Killer. Pocket Books, New York. Schulte, Regina. 1994. The Village in Court: Arson, infanticide, and poaching in the court
records of Upper Bavaria, 1848-1910. Yanni, Carla. 2007. The Architecture of Madness: Insane Asylums in the United States.
Minnesota University Press, Minneapolis. Literatura: Press Syndicate of the University of Cambridge,
Cambridge. Scull, Andrew. 2014. Cultural Sociology of Mental Illness: An A-to-Z Guide. University of
California, San Diego. Scull, Andrew. 2009. Hysteria: the Biography. Oxford University Press, Oxford. Scull, Andrew. 2015. Madness in Civilization: Cultural History of Insanity from the Bible to
Freud, from the Madhouse to Modern Medicine. Princeton University Press, Princeton. Shorter, Edward. 1997. A history of psychiatry: from the era of the asylum to the age of
Prozac. John Wiley and Sons New York. 305 Showalter, Elaine. 2001. The female malady: women, madness, and English culture, 1830-
1980. Virago Press. London. Shuttleworth, Sally. 2010. The Mind of a child.Child development in literature, science, and
medicine 1840-1900. Oxford University Press, Oxford. Spector, Scott. 2016. Violent Sensations: Sex, Crime, and Utopia in Vienna and Berlin, 1860-
1914. University of Chicago Press, Chicago. Spongberg, Mary. 1997. Feminizing Venereal Disease: The Body of the Prostitute in
Nineteenth- Century Medical Discourse. New York University Publishing, New York. Sugden, Philip. 2006. The Complete History of Jack The Ripper. Constable and Robinson ltd.,
London. Tackett, Timothy. 2015. The Coming of the Terror in the French Revolution. Harvard
University Press, Cambridge. Tattersall, Mason. 2014. „Thermal Degeneration: Thermodynamics and the Heat-Death of the
Universe in Victorian Science, Philosophy, and Culture.” U Decadence, Degeneration, and
the End- studies in European fin de siecle, ur. Marja Härmänmaa i Christopher Nissen, str. 17-
35. St. Martin's Press, New York. Tausk, Viktor. 1992. „On the Origin of the 'Influencing Machine' in Schizophrenia”. The
Journal of Psychotherapy Practice and Research, br. 2 , str. 184-206. Verwey, Gerlof. 1985. Psychiatry in an Anthropological and Biomedical Context:
Philosophical Presuppositions and Implications of German Psychiatry,1820-1870. D. Reidel
Publishing Company, Dodrecht,Boston, Lancaster. Wagner, Karel. 2011. Psychiatrie a fenomén zvaný Poltergeis. https://karelwagner.blog.idnes.cz/blog.aspx?c=229735, 23. travnja 2018. Yanni, Carla. 2007. The Architecture of Madness: Insane Asylums in the United States. Minnesota University Press, Minneapolis. 306 306 Životopis Vinko Drača rođen je 1989. godine u Zagrebu Završio je preddiplomski studij novinarstva na
Fakultetu političkih znanosti i diplomski studij povijesti na Filozofskom fakultetu u Zagrebu. Upisao je doktorski studij na studiju Moderne i suvremene hrvatske povijesti u europskom i
svjetskom kontekstu na Filozofskom fakultetu u Zagrebu gdje je primarno istraživao povijest
duševnih bolesti. Sudjelovao je na brojnim međunarodnim znanstvenim skupovima u Zagrebu
(„Zagorkini dani 2016.“ i „Zagorkini dani 2017.“. Desničini susreti 2017. i 2018. godine),
Beogradu („Migrations in Visual Culture“, „Creating Memories in Early Modern and Modern Art
and Literature“) i Ljubljani („Selfologija“ „Simbozij“). Teme iz povijesti psihijatrije predstavio je
na kongresu „RI-seminario” u Rijeci, međunarodnoj radionici „Managing Maladjustment in the
Modern World. Perspectives from Southeastern Europe” te na ljetnoj konferenciji ASEEES-a u
Zagrebu 2019. Sudjelovao je na ljetnoj školi GHI u Dubrovniku, „Cultural trauma and Crisis of
Democracy” u srpnju 2019. godine.Bio je organizatorom međunarodne doktorandske
konferencije „Revolutions and Upheavals in History“ i član organizacijskog odbora ISHA-ine
konferencije „(Re)making Europe“. Radove jeobjavljivao u časopisima „Historijski zbornik“ i
„Radovi zavoda za hrvatsku povijest Filozofskog Fakulteta u Zagrebu“ te u zbornicima
navedenih skupova. i 307
|
https://openalex.org/W3177300599
|
https://tema.sbmac.org.br/tema/article/download/1494/1049
|
English
| null |
Fractional Derivatives Applied to Epidemiology
|
Trends in Computational and Applied Mathematics
| 2,021
|
cc-by
| 10,999
|
*Corresponding author: Sandro Rodrigues Mazorche – E-mail: sandro.mazorche@ufjf.edu.br
1Instituto de Ciˆencias Exatas, Departamento de Matem´atica, Universidade Federal de Juiz de Fora (UFJF), Juiz de Fora,
MG, Brazil – E-mail: nzmonteiro@ice.ufjf.br https://orcid.org/0000-0002-0556-2462
2Instituto de Ciˆencias Exatas, Departamento de Matem´atica, Universidade Federal de Juiz de Fora (UFJF), Juiz de Fora,
MG, Brazil E-mail: sandro.mazorche@ufjf.edu.br https://orcid.org/0000-0002-6863-3723 Received on July 31, 2020 / Accepted on December 17, 2020 Received on July 31, 2020 / Accepted on December 17, 2020 ABSTRACT. We seek investigate the use of fractional derivatives, both analytically and through simula-
tions. We present some models and perform investigations about them, starting with the classic model and
the basic definitions to discuss difficulties in constructing a non-artificial fractional model. Also, we analyze
the COVID-19 pandemic using a fractional epidemiological SIR model carefully constructed and present
numerical results using MATLAB. Keywords: SIR model, Fractional Derivatives, COVID-19. N. ZERAICK MONTEIRO1 and S. RODRIGUES MAZORCHE2* Received on July 31, 2020 / Accepted on December 17, 2020 in Computational and
Applied Mathematics
Trends
Trends in Computational and Applied Mathematics, 22, N. 2 (2021), 157-177
Sociedade Brasileira de Matem´atica Aplicada e Computacional
Online version ISSN 2676-0029
www.scielo.br/tcam
doi: 10.5540/tcam.2021.022.02.00157 in Computational and
Applied Mathematics
Trends
Trends in Computational and Applied Mathematics, 22, N. 2 (2021), 157-177
Sociedade Brasileira de Matem´atica Aplicada e Computacional
Online version ISSN 2676-0029
www.scielo.br/tcam
doi: 10.5540/tcam.2021.022.02.00157 Trends in Computational and Applied Mathematics, 22, N. 2 (2021), 157-177
Sociedade Brasileira de Matem´atica Aplicada e Computacional
Online version ISSN 2676-0029
www.scielo.br/tcam
doi: 10.5540/tcam.2021.022.02.00157 Trends in Computational and Applied Mathematics, 22, N. 2 (2021), 157-177
Sociedade Brasileira de Matem´atica Aplicada e Computacional
Online version ISSN 2676-0029
www.scielo.br/tcam
doi: 10.5540/tcam.2021.022.02.00157 in Computational and
Applied Mathematics
Trends 1
INTRODUCTION Throughout history, epidemics have devastated a large percentage of humanity. Important ques-
tions can be worked out through mathematical modeling: mathematicians study their evolution
and try to elucidate essential questions, such as when the peak of the disease is expected and how
many people will be infected in total. The coronavirus disease 2019 (COVID-19) is a respiratory disease that spreads from person
to person. As of July 28, 2020, the reported cases of COVID-19 on the planet exceeded 16
million [25]. Person-to-person spread is thought to occur mainly via respiratory droplets, as the
spread of influenza [22]. This suggests that the use of the epidemiological model SIR (Susceptible
- Infected - Removed) is reasonable for understanding the spread of COVID-19. As fractional calculus has proven to be a faithful tool in capturing the dynamics of the physical
process of many scientific objects, being its most striking features the memory effect, here we
revisit much of the mathematical and epidemiological theory in order to improve understanding
of fractional models. The tool has already been used to model the dynamics of the new coro-
navirus in interesting works, such as [21, 31]. In this work, we are concerned with the precise FRACTIONAL DERIVATIVES APPLIED TO EPIDEMIOLOGY 158 construction of a fractional model following the seminal ideas of the SIR model creators. We an-
alyze problems and difficulties that occur when simply replacing derivatives of whole order with
derivatives of fractional orders and correcting the dimension artificially, such as, for example, the
unexplained change in the total population. It was in Angstmann, Henry & McGann [5] that we
found solid steps that could explain why and where fractional derivatives can arise, paying atten-
tion to the precise definition of each parameter and the dimensioning. We revisited the authors’
work and, in addition to starting the discussion of the reproduction number for their model, we
applied the model to the data of the Brazilian and Italian COVID-19 pandemic. We intend that the work will attract readers’ attention to the care with the use of fractional
derivatives, presenting a non-artificial construction for an epidemiological model and its appli-
cation. For this aim, in Chapter 2 we offer a re-presentation of the classic SIR model proposed
by Kermack & McKendrick in 1927 [20], continuing with special attention to the case of con-
stant parameters and the definition of the number of reproduction of an infectious disease. 2
THE SIR MODEL In 1927, the SIR (Susceptible-Infected-Removed) model was introduced in a remarkable way
in a work proposed by Kermack & McKendrick [20]. The authors concluded that, although the
causative agent does not lose its infectiousness and the population is not entirely infected, the
end of an epidemic may result from a special relationship between population density, infectivity
and rates of recovery and death. We present below a brief adaptation of this work. 1
INTRODUCTION In
Chapter 3, we offer fractional calculus preliminaries and establish difficulties in defining the
fractional model. In Chapter 4, we present a physical derivation of a fractional model, follow-
ing the steps of Angstmann, Henry & McGann [5], where they use the probabilistic language of
the Continuous-Time Random Walks (CTRW) and the Riemann-Liouville fractional derivative. Finally, in Chapter 5 we display several numerical results. 2.1
General Theory Initially, we uniformly discretize time considering ∆T = 1 and we assume that people are infected
only when passing from one interval to another, not during the interval itself. We denote the
number of infected at time t who have been infected for θ intervals by vt,θ . The total number
of infected at time t is therefore It = ∑t
θ=0 vt,θ . The notation vt is also used to indicate the rate
of new infections in time t . In general, vt = vt,0
∆T , except at the origin, when a population of
infectious I0 , regardless of the model to be developed, is inserted into the total population. Thus,
v0,0 = v0∆T +I0 . If ψ(θ) = ψθ denotes the rate of removal of the infectious compartment at the age of infection
θ (that is, the sum of recovery and death rates), so the number removed from each θ−group is
given by ψθvt,θ = vt,θ −vt+1,θ+1
∆T
. Therefore, it follows that vt,θ = vt−1,θ−1(1 −ψ(θ −1)∆T). Proceeding, we obtain vt,θ = vt−θ,0 Bθ,
(2.1) (2.1) Trends Comput. Appl. Math., 22, N. 2 (2021) Trends Comput. Appl. Math., 22, N. 2 (2021) N. ZERAICK MONTEIRO and S. RODRIGUES MAZORCHE 159 where Bθ = (1−ψ(θ −1)∆T)(1−ψ(θ −2)∆T)···(1−ψ(0)∆T). It is important to note that, in
order not to overload the notation, we write time t +1 , θ −2 , etc., instead of t +∆T , θ −2∆T
and so on. Now, if φ(θ) = φθ denotes the infectivity rate of an infected person who has been infected for θ
stages, the rate of new infected vt should be equal to St ∑t
0 φθvt,θ, where St denotes the number
of people not yet infected/ immunized at time t. Clearly, St = N −
t
∑
0
vt∆T −I0,
(2.2) (2.2) where N is the total population. If Rt denotes the number of removed (by recovery or death),
then, disregarding vital dynamics processes, St +It +Rt = N. We have It =
t
∑
0
vt,θ =
t
∑
0
Bθvt−θ∆T +BtI0. (2.3) (2.3) Also note that, from Eq. 2.1, we have Also note that, from Eq. 2.1
General Theory 2.1, we have vt = St
t
∑
1
φtvt,θ = St
t
∑
1
Aθvt−θ∆T +AtI0
,
(2.4) (2.4) where we define Aθ = φθBθ and assume φ0 = 0 , that is, a person is not infective at the moment
of the infection. By other hand, for t > 0 , we have vt = St −St+1
∆T
. Therefore, it follows from Eq. 2.4 that St −St+1
∆T
= St
t
∑
1
Aθvt−θ∆T +AtI0
. (2.5) (2.5) Finally, we note that Finally, we note that Rt+1 −Rt
∆T
=
t
∑
1
Cθvt−θ∆T +CtI0
,
(2.6) (2.6) where we define Cθ = ψθBθ . where we define Cθ = ψθBθ . where we define Cθ = ψθBθ . where we define Cθ = ψθBθ . Allowing ∆T →0, we get the relationship vt = −dSt/dt and the three equations that define the
SIR model
dS
Z t
Allowing ∆T →0, we get the relationship vt = −dSt/dt and the three equations that define the
SIR model dSt
dt = −St
Z t
0 Aθvt−θdθ +AtI0
;
(2.7)
It =
Z t
0 Bθvt−θdθ +BtI0;
(2.8)
dRt
dt =
Z t
0 Cθvt−θdθ +CtI0,
(2.9) (2.7) (2.8) (2.9) where we have, by the property of the product integral [32], Bθ = exp
−
R θ
0 ψ(a)da
. It is
observed that the upper limit t must be divided by the unit of time considered, becoming scalar. where we have, by the property of the product integral [32], Bθ = exp
−
R θ
0 ψ(a)da
. It is
observed that the upper limit t must be divided by the unit of time considered, becoming scalar. The reader will be able to verify that dSt +dIt +dRt
dt
= 0 , which means that the population is
kept constant, regardless of the functions ψ,φ . where we have, by the property of the product integral [32], Bθ = exp
−
R θ
0 ψ(a)da
. It is where we have, by the property of the product integral [32], Bθ = exp
−
R θ
0 ψ(a)da
. It is
observed that the upper limit t must be divided by the unit of time considered, becoming scalar. 2.2
Constant rates β
, that is, if N β
γ ≤1 . In fact, in this case W0
−S0βe−Nβ/γ
γ
≈W0
−Nβ
γ
e−Nβ/γ
= −Nβ/γ
e R∞≈0 . The constant N β
γ is equivalent, in this model, to the so-called basic reproduction 2.1
General Theory The reader will be able to verify that dSt +dIt +dRt
dt
= 0 , which means that the population is
kept constant, regardless of the functions ψ,φ . Trends Comput. Appl. Math., 22, N. 2 (2021) 160 FRACTIONAL DERIVATIVES APPLIED TO EPIDEMIOLOGY 2
Constant rates 2.2
Constant rates The analysis of the case in which the φ,ψ rates are constants β,γ, respectively, provides insights
for understanding epidemics. In this case, the system 2.7 - 2.9 becomes, omitting the t index for
simplicity
dS dS
dt = −βSI;
(2.10)
dI
dt = βSI −γI;
(2.11)
dR
dt = γI. (2.12) dS
dt = −βSI;
(2.10)
dI
dt = βSI −γI;
(2.11)
dR
dt = γI. (2.12) (2.10) (2.11) (2.12) So dR/dt = γ(N −S −R) . In addition, dS/dR = −(β/γ)S , a separable equation that leads to
the result log(S0/S) = (β/γ)R . Therefore, S = S0 exp(−(β/γ)R) , following that So dR/dt = γ(N −S −R) . In addition, dS/dR = −(β/γ)S , a separable equation that leads to
the result log(S0/S) = (β/γ)R . Therefore, S = S0 exp(−(β/γ)R) , following that dR
dt = γ(N −S0 exp(−(β/γ)R)−R). (2.13) (2.13) From Eq. 2.13, we can obtain the total number of infected throughout the course of the disease
by studying dR∞/dt = 0 , which is equivalent to N −S0 exp(−(β/γ)R∞)−R∞= 0 . Considering
S0 ̸= 0 , we get R∞= N + γ
β W0
−S0βe−Nβ/γ
γ
,
(2.14) (2.14) where W0 represents the principal branch of the Lambert W function [9], not used by the classical
authors [20]. We note that if the disease is early, S0 ≈N and the epidemic does not occur if N ≤γ
β β
, that is, if N β
γ ≤1 . In fact, in this case W0
−S0βe−Nβ/γ
γ
≈W0
−Nβ
γ
e−Nβ/γ
= −Nβ/γ
e R∞≈0 . The constant N β
γ is equivalent, in this model, to the so-called basic reproduction
number, to be presented in the next section. It is possible to obtain some other results for small
epidemics, which are not of interest to us here, but have been studied in the main reference [20]. β
, that is, if N β
γ ≤1 . In fact, in this case W0
−S0βe−Nβ/γ
γ
≈W0
−Nβ
γ
e−Nβ/γ
= −Nβ/γ
e R∞≈0 . The constant N β
γ is equivalent, in this model, to the so-called basic reproduction
number, to be presented in the next section. It is possible to obtain some other results for small
epidemics, which are not of interest to us here, but have been studied in the main reference [20]. 3
APPLICATIONS OF FRACTIONAL DERIVATIVES TO SIR TYPE MODELS Currently, fractional calculus has proven to be a faithful tool in capturing the dynamics of the
physical process of many scientific objects, such as biological or ecological phenomenas and
control systems [34]. One of its most striking features is the memory effect. Over the years,
varied fractional operators have been defined with different focuses and applications. Although it
is not used in this work, we highlight the recent introduction of the ψ-Hilfer fractional derivative,
a fractional derivative with respect to a function ψ which incorporates a large class of fractional
derivatives as particular cases [10,11,12]. The fractional calculus has already been used to model the dynamics of the new coronavirus in
interesting works, such as [21,31]. Here, we related the memory effect to potential laws regard-
ing the infectiousness (transmission) of the infected patient and the removal rate. That is, the
longer infected, the less infectious and the more likely he will be removed from the infectious
compartment. This effect is important and is not captured by classic models. We intend to study
the orders of derivatives that best reproduce the data of the pandemic considering the variation
in infectivity and removal rate. It is important to mention that the memory effect decreases when
the fractional orders tend to 1 [33]. 2.3
The Basic Reproduction Number The reproduction number ℜreflects how infectious a disease is in a given context. This constant
is often confused with the basic reproduction number, ℜ0, which represents the reproduction
number when there is no immunity or deliberate intervention in the transmission of the disease. On the other hand, ℜis the effective reproductive number and is modified both by the decreasing
of susceptible population and by the implementation of interventions and the infectivity changes
that the virus may suffer. Under conditions of homogeneous population, ℜis defined as the
average number of infections that a single individual can generate during his infectious period [7]. In traditional models, epidemics of an infection cannot occur when the ℜ0 is less than 1 and
established outbreaks will disappear if interventions or depletion of the susceptible part of the
population are sufficient to keep ℜbelow 1. Also according to [7], it is important to keep in mind Trends Comput. Appl. Math., 22, N. 2 (2021) 161 N. ZERAICK MONTEIRO and S. RODRIGUES MAZORCHE that the ℜ0 of an infection depends on the population analyzed, because the rates of contact
between people may differ due to differences in population density and culture. The ℜat a given
time can also vary from place to place, as communities may differ in their levels of immunity
and intervention. 3.1
Preliminaries of Fractional Calculus The Mittag-Leffler functions are of important use in the theory of fractional calculus. We present
the following definition [8]: Definition 1. (Two and Three-parameter Mittag–Leffler function) Let z ∈C, with α,β,ρ ∈C
three-parameters such that Re(α) > 0, Re(β) > 0,Re(ρ) > 0. We define the three-parameter
Mittag–Leffler function via the power series Eρ
α,β(z) =
∞
∑
k=0
(ρ)k
Γ(αk +β)
zk
k!,
(3.1) (3.1) where (ρ)k is the Pochhammer symbol. Particularly, when ρ = 1, we have the two-parameter
Mittag–Leffler function, denoted simply by Eα,β(z). Note that this function generalizes the
exponential function, being equal to the exponential when α = β = 1. The following results are worth: The following results are worth: Proposition 1. The Laplace transform of the function tβ−1Eρ
α,β(atα) is given by: Proposition 1. The Laplace transform of the function tβ−1Eρ
α,β(atα) is given by: L [tβ−1Eρ
α,β(atα)](s) = s−β(1−as−α)−ρ,
(3.2) (3.2) Trends Comput. Appl. Math., 22, N. 2 (2021) Trends Comput. Appl. Math., 22, N. 2 (2021) 162 FRACTIONAL DERIVATIVES APPLIED TO EPIDEMIOLOGY where Re(s) > 0 and |as−α| < 1. Proposition 2. (Three-parameter Mittag-Leffler function derivative) The following identity is
valid:
dk dk
dxk Eρ
α,β(z) = (ρ)kEρ+k
α,β+αk(z). (3.3) (3.3) The proofs of the propositions can be found at [8]. Below we consider [a,b] ⊂R,α > 0, a
function f ∈Lp[a,b], p ≥1, and n −1 < α < n, with n ∈N. Also, Γ is the gamma function. finition 2. The Riemann-Liouville fractional integral of order α is defined for t ∈[a,b] by aJα
t f(t) =
1
Γ(α)
Z t
a (t −θ)α−1 f(θ)dθ. (3.4) (3.4) Proposition 3. (Fractional integral of the three-parameter Mittag-Leffler function [8]) We have
the following identity: 0Jν
t [tβ−1Eρ
α,β(atα)] = tν+β−1Eρ
α,ν+β(atα). (3.5) (3.5) Definition 3. The Riemann-Liouville fractional derivative of order α is defined for t ∈[a,b] by: Definition 3. The Riemann-Liouville fractional derivative of order α is defined for t ∈[a,b] by: R−L
a
Dα
t f(t) =
1
Γ(n−α)
dn
dtn
Z t
a (t −θ)n−α−1 f(θ)dθ . (3.6) (3.6) In other words, In other words, R−L
a
Dα
t f(t) = Dn[aJn−α
t
f(t)],
(3.7) (3.7) with Dn representing the integer order derivative. with Dn representing the integer order derivative. with Dn representing the integer order derivative. Definition 4. The Caputo fractional derivative of order α is defined for t ∈[a,b] by: Definition 4. The Caputo fractional derivative of order α is defined for t ∈[a,b] by: C
a Dα
t f(t) =
1
Γ(n−α)
Z t
a (t −θ)n−α−1 dn
dθ n f(θ)dθ . (3.8) (3.8) In other words, In other words, C
a Dα
t f(t) = aJn−α
t
[Dn f(t)]. (3.9) (3.9) The
Riemann-Liouville
fractional
integral
is
the
inverse
to
the
right
of
both
the
Riemann-Liouville and the Caputo fractional derivatives [26], that is, C
a Dα
t aJα
t f(t) = R−L
a
Dα
t aJα
t f(t) = f(t). (3.10) (3.10) Trends Comput. Appl. Math., 22, N. 2 (2021) 163 N. ZERAICK MONTEIRO and S. RODRIGUES MAZORCHE The Definition 2 can be seen as an application of the Laplace transform and the Convolution
Theorem. In what follows, we use the notation Jα for 0Jα
t . Using Laplace transform properties,
we can write, to n ∈N, L {(Jn f)(t)} = s−nL { f(t)}. Therefore, it is reasonable to assume that,
for fractional α, it also holds: (Jα f)(t) = L −1
s−αL { f(t)}
. (3.11) (3.11) Considering p(t) = tα−1, we have L {p(t)} = s−αΓ(α). Therefore, by the convolution equation
and by the linearity of the transform: Considering p(t) = tα−1, we have L {p(t)} = s−αΓ(α). Therefore, by the convolution equation
and by the linearity of the transform: (Jα f)(t) =
1
Γ(α)L −1{L {p(t)}L {f(t)}} =
1
Γ(α)(p∗f) =
1
Γ(α)
Z t
0 (t −θ)α−1 f(θ)dθ,
(3.12) (3.12) as in Definition 2. Is important to note that when the fractional order tends to the integer order,
the fractional derivative tends to the same result as the ordinary derivative. This is known by
backward compatibility and this property for the Gr¨unwald–Letnikov, Riemann–Liouville and
Caputo fractional derivatives can be seen on [27]. 3.2
Difficulties in Defining the Fractional Model different type of that of order 1/2, in the same way that, in classical physics, the rate of order 1,
velocity, is different from that corresponding to the order 2, the acceleration. Other authors (eg. [2, 19]) correct the dimension by multiplying time constants or raising the
parameters to α. In this last case, the fractional SIR model could be written as follows y,
p
g
,
Other authors (eg. [2, 19]) correct the dimension by multiplying time constants or raising the
parameters to α. In this last case, the fractional SIR model could be written as follows Other authors (eg. [2, 19]) correct the dimension by multiplying time constants or raising the
parameters to α. In this last case, the fractional SIR model could be written as follows DαS(t) = −β αI(t)S(t)
(3.16)
DαI(t) = β αI(t)S(t)−γαI(t)
(3.17)
DαR(t) = γαI(t). (3.18) (3.16) (3.18) Finally, we read authors (eg. [1,15,16,17]) who, intending to extend the fractional models, seek
a system with multiple orders, which, if on the one hand is of great mathematical interest, on the
other hand makes the analysis even more complicated. More than the parameter definitions and
the dimensional difficulty, the relationship between different orders can influence the total mass
or population. The article [13] demonstrates, in a simple two-compartment system, that the use of
different fractional orders without proper care leads to the violation of mass balance. The authors
defend, in an article of the same year [14], that, both in the context of the pharmacokinetics then
considered and in analog systems, an outgoing mass flow defined as a fractional order rate cannot
appear as an inflow into another compartment, with a different fractional order, without violating
the mass balance. Finally, we read authors (eg. [1,15,16,17]) who, intending to extend the fractional models, seek
a system with multiple orders, which, if on the one hand is of great mathematical interest, on the
other hand makes the analysis even more complicated. More than the parameter definitions and
the dimensional difficulty, the relationship between different orders can influence the total mass
or population. The article [13] demonstrates, in a simple two-compartment system, that the use of
different fractional orders without proper care leads to the violation of mass balance. 3.2
Difficulties in Defining the Fractional Model We studied some models in which authors generalize classic first order ODE’s by replacing the
integer derivative on the left side with fractional derivatives, usually the Caputo one, once it
allows conventional initial conditions and its derivative of a constant is bounded (specifically,
equal to 0) [28]. We found that these models can produce very good estimates, as well as inter-
esting equations from a mathematical point of view. However, we are interested in the following
question: does the change in the order of derivatives automatically establish consistent models,
with respect to the definition of parameters, units and balance? In 2010, an interesting article was
published [13] proving that, in general, this cannot happen. In the literature on the use of fractional derivatives in SIR-type models, we find some more
common versions. Based on the model 2.10 - 2.12 or its various extensions, some authors (eg. [3, 30]) replace the derivative on the left side with the Caputo fractional derivative of order α,
keeping the same parameters as the model with an integer derivative. For example, for the SIR
model, it is considered DαS(t) = −βI(t)S(t)
(3.13)
DαI(t) = βI(t)S(t)−γI(t)
(3.14)
DαR(t) = γI(t),
(3.15) (3.13) (3.15) when β and γ are positive constants defined as in the system 2.10-2.12. The first difficulty noted
with this definition concerns units. We note that Dα f(t) has unit [time]−α. Therefore, the right
side of the equation must have this unit. Just abolishing the units does not solve the problem. According to [13], the units actually help to reveal the issue: a 1 order rate, for example, is a Trends Comput. Appl. Math., 22, N. 2 (2021) FRACTIONAL DERIVATIVES APPLIED TO EPIDEMIOLOGY 164 different type of that of order 1/2, in the same way that, in classical physics, the rate of order 1,
velocity, is different from that corresponding to the order 2, the acceleration. Other authors (eg. [2, 19]) correct the dimension by multiplying time constants or raising the different type of that of order 1/2, in the same way that, in classical physics, the rate of order 1,
velocity, is different from that corresponding to the order 2, the acceleration. different type of that of order 1/2, in the same way that, in classical physics, the rate of order 1,
velocity, is different from that corresponding to the order 2, the acceleration. 3.2
Difficulties in Defining the Fractional Model The authors
defend, in an article of the same year [14], that, both in the context of the pharmacokinetics then
considered and in analog systems, an outgoing mass flow defined as a fractional order rate cannot
appear as an inflow into another compartment, with a different fractional order, without violating
the mass balance. We will analyze the relationship between orders and the total population N of the fractional SIR
model defined as Dα1S(t) = −β1I(t)S(t)
(3.19)
Dα2I(t) = β2I(t)S(t)−γ2I(t)
(3.20)
Dα3R(t) = γ3I(t). (3.21) (3.19) (3.21) The fractional derivative is in Caputo sense and α1,α2,α3 ∈(0,1], as most of the authors we had
access considered. We define the parameters in some way that balances the units, for instance,
βi = β αi and γi = γαi for i ∈{1,2,3}. Applying Laplace transform and performing operations on
the equations 3.19 - 3.21, we obtain The fractional derivative is in Caputo sense and α1,α2,α3 ∈(0,1], as most of the authors we had
access considered. We define the parameters in some way that balances the units, for instance,
βi = β αi and γi = γαi for i ∈{1,2,3}. Applying Laplace transform and performing operations on
the equations 3.19 - 3.21, we obtain L {S+I +R} = S0 +I0 +R0
s
+
β2
sα2 −β1
sα1
L {SI}+
γ3
sα3 −γ2
sα2
L {I}. (3.22) (3.22) Applying the inverse transform, we finally write Applying the inverse transform, we finally write N = N0 +
β2tα2−1
Γ(α2) −β1tα1−1
Γ(α1)
∗SI +
γ3tα3−1
Γ(α3) −γ2tα2−1
Γ(α2)
∗I,
(3.23) (3.23) that is, N
= N0 +
Z t
0
β2(t −θ)α2−1
Γ(α2)
−β1(t −θ)α1−1
Γ(α1)
S(θ)I(θ)dθ
+
Z t
0
γ3(t −θ)α3−1
Γ(α3)
−γ2(t −θ)α2−1
Γ(α2)
I(θ)dθ
. (3.24) (3.24) Trends Comput. Appl. Math., 22, N. 2 (2021) 165 N. ZERAICK MONTEIRO and S. RODRIGUES MAZORCHE Note that, if α1 = α2 = α3, the integrals in Eq. 3.24 become nulls, that is, the population remains
constant, but the same may not be true in other cases. For example, if α1 < α2 < α3, the popula-
tion goes up to large t. Conversely, if α1 > α2 > α3, the population decreases to large t. The big
problem is not to change the population, which can happen due to vital dynamics, migration etc.,
but to justify the change. 3.2
Difficulties in Defining the Fractional Model This indicates that the
ℜ0 of the SIR model, classically given by the constant N β
γ , is not trivial on the fractional case. Finally, we note that Eq. 3.19, 3.20 and 3.21 have different parameters. This indicates that the
ℜ0 of the SIR model, classically given by the constant N β
γ , is not trivial on the fractional case. 3.2
Difficulties in Defining the Fractional Model In this case, without migration or dynamics, people could not disappear
or appear as illustrated in the Fig. 1-2. Note that, if α1 = α2 = α3, the integrals in Eq. 3.24 become nulls, that is, the population remains
constant, but the same may not be true in other cases. For example, if α1 < α2 < α3, the popula-
tion goes up to large t. Conversely, if α1 > α2 > α3, the population decreases to large t. The big
problem is not to change the population, which can happen due to vital dynamics, migration etc.,
but to justify the change. In this case, without migration or dynamics, people could not disappear
or appear as illustrated in the Fig. 1-2. 0
50
100
150
200
t in days
0
1
2
3
4
S(t)(gray) , I(t)(black) , R(t)(-.)
N(t)=S(t)+I(t)+R(t) (--), N0 (:)
#10 8
C.I.: S0=210147124 ; I0=1 ; R0=0
Parameters:
-=1/N0 ;
.=0.15
,1= 0.5 ;
,2=0.6 ;
,3=0.65
Figure 2: The R compart. exceed N0. 0
50
100
150
200
t in days
0
0.5
1
1.5
2
2.5
S(t)(gray) , I(t)(black) , R(t)(-.)
N(t)=S(t)+I(t)+R(t) (--), N0 (:)
#10 8
C.I.: S0=210147124 ; I0=1 ; R0=0
Parameters:
-=1.3/N0 ;
.=0.3
,1= 0.55 ;
,2=0.6 ;
,3=0.5
Figure 1: Oscilation of N(t). 0
50
100
150
200
t in days
0
1
2
3
4
S(t)(gray) , I(t)(black) , R(t)(-.)
N(t)=S(t)+I(t)+R(t) (--), N0 (:)
#10 8
C.I.: S0=210147124 ; I0=1 ; R0=0
Parameters:
-=1/N0 ;
.=0.15
,1= 0.5 ;
,2=0.6 ;
,3=0.65
Figure 2: The R compart. exceed N0. Finally, we note that Eq. 3.19, 3.20 and 3.21 have different parameters. This indicates that the
ℜof the SIR model classically given by the constant N β is not trivial on the fractional case 0
50
100
150
200
t in days
0
1
2
3
4
S(t)(gray) , I(t)(black) , R(t)(-.)
N(t)=S(t)+I(t)+R(t) (--), N0 (:)
#10 8
C.I.: S0=210147124 ; I0=1 ; R0=0
Parameters:
-=1/N0 ;
.=0.15
,1= 0.5 ;
,2=0.6 ;
,3=0.65 0
50
100
150
200
t in days
0
0.5
1
1.5
2
2.5
S(t)(gray) , I(t)(black) , R(t)(-.)
N(t)=S(t)+I(t)+R(t) (--), N0 (:)
#10 8
C.I.: S0=210147124 ; I0=1 ; R0=0
Parameters:
-=1.3/N0 ;
.=0.3
,1= 0.55 ;
,2=0.6 ;
,3=0.5 Figure 2: The R compart. exceed N0. Figure 1: Oscilation of N(t). Finally, we note that Eq. 3.19, 3.20 and 3.21 have different parameters. 4.1
Model Derivation Consider an individual infected since the time t′. If there are S(t) susceptible in time t, this in-
fected person has a probability S(t)/N that his contact is susceptible, considering the population
homogeneous. Therefore, in the period of t to t +∆T, the expected number of new infections per
infected individual is given by σ(t,t′)S(t)
N ∆T. The transmission rate per infectious individual
σ(t,t′) depends both on the age of the infection, t −t′, and on the present time, t, which, among
others, influences the amount of contacts of the infectious. The probability that an individual infected at the moment t′ is still infected at the moment t is
given by the survival function Φ(t,t′). Therefore, the flux of individuals to the I compartment at
time t is recursively given by q+(I,t) =
Z t
−∞σ(t,t′)S(t)
N Φ(t,t′)q+(I,t′)dt′. (4.1) (4.1) The initial condition is obtained by the number of individuals infected at the time 0 and con-
sidering the time in which each individual has become infected. This is given by the function
i(−t′,0) which represents the number of individuals who are still infectious at time 0 and who
were originally infected at some point earlier t′ < 0. Then q+(I,t′) = i(−t′,0)/Φ(0,t′) for t′ < 0. For simplicity, we consider i(−t,0) = i0δ(−t), where δ(t) is the Dirac delta function. So, The initial condition is obtained by the number of individuals infected at the time 0 and con-
sidering the time in which each individual has become infected. This is given by the function
i(−t′,0) which represents the number of individuals who are still infectious at time 0 and who
were originally infected at some point earlier t′ < 0. Then q+(I,t′) = i(−t′,0)/Φ(0,t′) for t′ < 0. For simplicity, we consider i(−t,0) = i0δ(−t), where δ(t) is the Dirac delta function. So, q+(I,t) =
Z t
0 σ(t,t′)S(t)
N Φ(t,t′)q+(I,t′)dt′ +i0σ(t,0)S(t)
N Φ(t,0). (4.2) (4.2) The infection rate σ(t,t′) is assumed to be a function of both the current time (due, for example,
to containment measures), having an extrinsic infectivity ω, and the age of infection t −t′, having
an intrinsic infectivity ρ. So we can write The infection rate σ(t,t′) is assumed to be a function of both the current time (due, for example,
to containment measures), having an extrinsic infectivity ω, and the age of infection t −t′, having
an intrinsic infectivity ρ. 4
DERIVATION OF THE FRACTIONAL MODEL In the previous section, we presented fractional models commonly used by authors in the field
and made some considerations. Still other questions arise: can we replace the entire order with
fractional orders on the left based on some mathematical theorem? If there are two different
orders (say, coming from potential laws on infectiousness and recovery/removal), these should be
considered in the equations of which compartments among the three or four used? In addition to
the adequacy of the units, is there an epidemiological explanation for multiplying time constants
or raising the parameters to the order used? We have not yet obtained precise justifications,
although we have verified, through published works and simulations that we carry out, that these
models are capable of representing reality with a good degree of precision. As already mentioned, we believe that the emergence of fractional derivatives in models similar
to the original comes from considering the functions of infectiousness and removal derived from
potential laws. Next, we present a physical derivation of a fractional model, following the steps of
Angstmann, Henry & McGann [5], where they use the probabilistic language of the Continuous-
Time Random Walks (CTRW). Trends Comput. Appl. Math., 22, N. 2 (2021) FRACTIONAL DERIVATIVES APPLIED TO EPIDEMIOLOGY 166 4.1
Model Derivation So we can write σ(t,t′) = ω(t)ρ(t −t′). (4.3) (4.3) Assuming that the natural death and the removal of an infected individual are independent
processes, we can write the survival function as Φ(t,t′) = φ(t −t′)θ(t,t′),
(4.4) (4.4) where φ(t −t′) is the probability that an individual infected since t′ has not yet recovered or been
killed by the disease at time t. Also, θ(t,t′) is the probability that an infected individual since t′
has not yet died of natural death (that is, independent of the disease) until time t. The θ function
is constructed similarly to the B function in Section 2.1, given by θ(t,t′) = e−
R t
t′ γ(u)du,
(4.5) (4.5) where γ is the death rate. Notice that where γ is the death rate. Notice that θ(t,t′) = θ(t,u)θ(u,t′), ∀t′ < u < t. (4.6) (4.6) Trends Comput. Appl. Math., 22, N. 2 (2021) Trends Comput. Appl. Math., 22, N. 2 (2021) Trends Comput. Appl. Math., 22, N. 2 (2021) 167 N. ZERAICK MONTEIRO and S. RODRIGUES MAZORCHE
167 Individuals in the I compartment at time t must have entered this compartment at some time
before and remained in it until t. Therefore, we can express the number of infected individuals
as follows:
Z t Individuals in the I compartment at time t must have entered this compartment at some time
before and remained in it until t. Therefore, we can express the number of infected individuals
as follows:
Z t I(t) = I0(t)+
Z t
0 Φ(t,t′)q+(I,t′)dt′. (4.7) (4.7) The I0(t) function provides the number of individuals who were infected at 0 and remain
infectious at t. This function can be written as follows: The I0(t) function provides the number of individuals who were infected at 0 and remain
infectious at t. This function can be written as follows: I0(t) =
Z 0
−∞
Φ(t,t′)
Φ(0,t′)i(−t′,0)dt′ = Φ(t,0)
Φ(0,0)i0 = Φ(t,0)i0. (4.8) (4.8) With this information we can build the principal equations of the model. We start by deriving Eq. 4.7 through the Leibniz Rule, obtaining dI(t)
dt
= q+(I,t)−
Z t
0 ψ(t −t′)θ(t,t′)q+(I,t′)dt′
−γ(t)
Z t
0 φ(t −t′)θ(t,t′)q+(I,t′)dt′ + dI0(t)
dt
,
(4.9) (4.9) where ψ(t) = −dφ(t)
dt
. This ψ has an important relationship with the continuous random variable
X that provides the time of removal of the individual from the infectious compartment. Trends Comput. Appl. Math., 22, N. 2 (2021) 4.1
Model Derivation The
cumulative distribution of X, namely F defined by F(t) = P(X ≤t), is such that F(t) = 1−φ(t). Therefore, the probability density function of X is ψ(t) = −dφ(t)
dt
. where ψ(t) = −dφ(t)
dt
. This ψ has an important relationship with the continuous random variable
X that provides the time of removal of the individual from the infectious compartment. The
cumulative distribution of X, namely F defined by F(t) = P(X ≤t), is such that F(t) = 1−φ(t). Therefore, the probability density function of X is ψ(t) = −dφ(t)
dt
. Using Eq. 4.2 - 4.7, Eq. 4.9 can be rewritten as Using Eq. 4.2 - 4.7, Eq. 4.9 can be rewritten as dI(t)
dt
= ω(t)S(t)
N
Z t
0 ρ(t −t′)Φ(t,t′)q+(I,t′)dt′ +ρ(t)Φ(t,0)i0
−
Z t
0 ψ(t −t′)θ(t,t′)q+(I,t′)dt′ −i0ψ(t)θ(t,0)−γ(t)I(t)
. (4.10) (4.10) In what follows, we will remove the dependency of q+(I,t′) from Eq. 4.10 by defining infectivity
and recovery memory kernels. We will henceforth consider i0 = 1 for simplicity. We can rewrite
Eq. 4.7 as I(t)
θ(t,0) −φ(t) =
Z t
0 φ(t −t′)q+(I,t′)
θ(t′,0) dt′. (4.11) (4.11) The right side is now in convolution form. Taking the Laplace transform, we get L
I(t)
θ(t,0) −φ(t)
= L {φ(t)}L
q+(I,t)
θ(t,0)
. (4.12) (4.12) The first integral of Eq. 4.10 is the product of θ(t,0) with an integral that can be rewritten using
the Laplace transform in the form L {ρ(t)φ(t)}L
q+(I,t)
θ(t,0)
. We can write, by Eq. 4.12, L {ρ(t)φ(t)}L
q+(I,t)
θ(t,0)
= L {ρ(t)φ(t)}
L {φ(t)}
L
I(t)
θ(t,0) −φ(t)
= L
Z t
0 KI(t −t′)
I(t′)
θ(t′,0)
dt′ −ρ(t)φ(t)
,
(4.13) (4.13) Trends Comput. Appl. Math., 22, N. 2 (2021) Trends Comput. Appl. Math., 22, N. 2 (2021) FRACTIONAL DERIVATIVES APPLIED TO EPIDEMIOLOGY 168 where we define the infectivity memory kernel by: where we define the infectivity memory kernel by: KI(t) = L −1
L {ρ(t)φ(t)}
L {φ(t)}
. (4.14) (4.14) Similarly, the second integral of Eq. 4.10 is the product of θ(t,0) with an integral that can be
rewritten using Laplace transform in the form Similarly, the second integral of Eq. Trends Comput. Appl. Math., 22, N. 2 (2021) 4.1
Model Derivation ZERAICK MONTEIRO and S. RODRIGUES MAZORCHE
169 169 It is not difficult to prove that Eα,α
−
t
τ
α
= αE2
α,1+α
−
t
τ
α
. Thus, by Eq. 3.3, the
correspondent survival function is α
−
t
τ
α
= αE2
α,1+α
−
t
τ
α
. Thus, by Eq. 3.3, the It is not difficult to prove that Eα,α
−
t
τ
α
= αE2
α,1+α
−
t
τ
α
. Thus, by Eq. 3.3, the
correspondent survival function is φ(t) = Eα,1
−
t
τ
α
. (4.22) (4.22) Using Eq. 3.2, we can calculate the Laplace transform of the recovery memory kernel with
Mittag-Leffler distribution, obtaining Using Eq. 3.2, we can calculate the Laplace transform of the recovery memory kernel with
Mittag-Leffler distribution, obtaining L {KR(t)} = L {ψ(t)}
L {φ(t)} = s1−ατ−α. (4.23) (4.23) On the other hand, we have L {R−L
0
D1−α
t
f(t)} = s1−αL { f(t)} −0 Jα f(t) |t=0+. We consider
here 0Jα f(t) |t=0+= 0, as in [4]. Hereafter, for simplicity, we write D1−α in place of R−L
0
D1−α. From these considerations, a convolution with the recovery memory kernel can be written as On the other hand, we have L {R−L
0
D1−α
t
f(t)} = s1−αL { f(t)} −0 Jα f(t) |t=0+. We consider
here 0Jα f(t) |t=0+= 0, as in [4]. Hereafter, for simplicity, we write D1−α in place of R−L
0
D1−α. From these considerations, a convolution with the recovery memory kernel can be written as Z t
0 KR(t −t′) I(t′)
θ(t′,0)dt′ = τ−αD1−α
I(t)
θ(t,0)
. (4.24) (4.24) A fractional derivative can also be incorporated into the infectivity memory kernel. Note that Eq. 4.14 has a Laplace transform similar to Eq. 4.23 and it is interesting to consider A fractional derivative can also be incorporated into the infectivity memory kernel. Note that Eq. 4.14 has a Laplace transform similar to Eq. 4.23 and it is interesting to consider ρ(t) =
1
φ(t)
tβ−1
τβ Eα,β
−
t
τ
α
. (4.25) (4.25) As ρ(t) ≥0 is required, we must have 0 < α ≤β ≤1. Using Eq. 4.25, we obtain the Laplace
transform of the infectivity kernel: As ρ(t) ≥0 is required, we must have 0 < α ≤β ≤1. Using Eq. 4.1
Model Derivation 4.10 is the product of θ(t,0) with an integral that can be
rewritten using Laplace transform in the form L {ψ(t)}L
q+(I,t)
θ(t,0)
= L {ψ(t)}
L {φ(t)} L
I(t)
θ(t,0) −φ(t)
= L
Z t
0 KR(t −t′)
I(t′)
θ(t′,0)
dt′ −ψ(t)
,
(4.15) (4.15) where we define the recovery memory kernel by where we define the recovery memory kernel by KR(t) = L −1
L {ψ(t)}
L {φ(t)}
. (4.16) (4.16) Replacing Eq. 4.13 and 4.15 in Eq. 4.10, we get dI(t)
dt
= ω(t)S(t)
N
θ(t,0)
Z t
0 KI(t −t′)
I(t′)
θ(t′,0)
dt′ −θ(t,0)ρ(t)φ(t)+ρ(t)Φ(t,0)
−θ(t,0)
Z t
0 KR(t −t′)
I(t′)
θ(t′,0)
dt′ +θ(t,0)ψ(t)−ψ(t)θ(t,0)−γ(t)I(t)
. (4 17) (4.17) (4.17)
(
)
(4.17) (4.17)
Fi
ll
i
lif th
t f
ti
f
th SIR
d l (4.17)
Finally, we simplify the set of equations for the SIR model: Finally, we simplify the set of equations for the SIR model: we simplify the set of equations for the SIR model: dS(t)
dt
= γ(t)N −ω(t)S(t)
N θ(t,0)
Z t
0 KI(t −t′) I(t′)
θ(t′,0)t′dt′ −γ(t)S(t);
(4.18) dS(t)
dt
= γ(t)N −ω(t)S(t)
N θ(t,0)
Z t
0 KI(t −t′) I(t′)
θ(t′,0)t′dt′ −γ(t)S(t);
(4.18)
dI(t)
dt
= ω(t)S(t)
N θ(t,0)
Z t
0 KI(t −t′) I(t′)
θ(t′,0)t′dt′
−θ(t,0)
Z t
0 KR(t −t′) I(t′)
θ(t′,0)dt′ −γ(t)I(t);
(4.19)
dR(t)
dt
= θ(t,0)
Z t
0 KR(t −t′) I(t′)
θ(t′,0)dt′ −γ(t)R(t),
(4.20) (4.18) (4.19) (4.20) where we consider the same rate γ(t) of natural mortality in each compartment, with the birth
rate equal to that. In this case the population remains constant. We incorporate fractional derivatives into the model by choosing ψ(t) with potential law and
ρ(t) related to the choice of ψ(t). In particular, we use the Mittag-Leffler function, according to
Definition 1: ψ(t) = tα−1
τα Eα,α
−
t
τ
α
,
(4.21) (4.21) for 0 < α ≤1, where τ is a scale parameter. The asymptotic expansion of the Mittag-Leffler
function [6] allows to affirm that ψ(t) = O(t−1−α) for t →∞. for 0 < α ≤1, where τ is a scale parameter. The asymptotic expansion of the Mittag-Leffler
function [6] allows to affirm that ψ(t) = O(t−1−α) for t →∞. Trends Comput. Appl. Math., 22, N. 2 (2021) Trends Comput. Appl. Math., 22, N. 2 (2021) N. Trends Comput. Appl. Math., 22, N. 2 (2021) 4.1
Model Derivation 4.25, we obtain the Laplace
transform of the infectivity kernel: L {KI(t)} = s1−βτ−β,
(4.26) (4.26) following that Z t
0 KI(t −t′) I(t′)
θ(t′,0)dt′ = τ−βD1−β
I(t)
θ(t,0)
. (4.27) (4.27) Replacing Eq. 4.24 and 4.27 in the model 4.18 - 4.20, we obtain a fractional SIR model: dS(t)
dt
= γ(t)N −ω(t)S(t)θ(t,0)
Nτβ
D1−β
I(t)
θ(t,0)
−γ(t)S(t);
(4.28)
dI(t)
dt
= ω(t)S(t)θ(t,0)
Nτβ
D1−β
I(t)
θ(t,0)
−θ(t,0)
τα
D1−α
I(t)
θ(t,0)
−γ(t)I(t);
(4.29)
dR(t)
dt
= θ(t,0)
τα
D1−α
I(t)
θ(t,0)
−γ(t)R(t). (4.30) (4.28) (4.29) (4.30) Note that if α = β = 1 and γ(t) ≡γ,ω(t) ≡ω are considered constant, we get the model 2.10 -
2.12, added only by the vital dynamics: Note that if α = β = 1 and γ(t) ≡γ,ω(t) ≡ω are considered constant, we get the model 2.10 -
2.12, added only by the vital dynamics: dS(t)
dt
= γN −ωS(t)I(t)
Nτ
−γS(t);
(4.31) (4.31) Trends Comput. Appl. Math., 22, N. 2 (2021) Trends Comput. Appl. Math., 22, N. 2 (2021) 170
FRACTIONAL DERIVATIVES APPLIED TO EPIDEMIOLOGY 170 dI(t)
dt
= ωS(t)I(t)
Nτ
−1
τ I(t)−γI(t);
(4.32)
dR(t)
dt
= 1
τ I(t)−γR(t). (4.33) (4.32) dR(t)
dt
= 1
τ I(t)−γR(t). (4.33) (4.33) Finally, note that the probability distribution F(t) = 1 −φ(t) is a Mittag-Leffler distribution
F(t;α,τ) = 1 −Eα
−
t
τ
α
. If α = β = 1, we have an exponential distribution and the
expectation (first moment) of the random variable X exists, with τ being exactly the average
recovery time. F(t;α,τ)
1
Eα
τ
. If α
β
1, we have an exponential distribution and the
expectation (first moment) of the random variable X exists, with τ being exactly the average
recovery time.
expectation (first moment) of the random variable X exists, with τ being exactly the average
recovery time. 4.1.1
The Reproduction Number The effective reproduction number ℜ(t′) at time t′ can be understood as the expected number of
individuals that will be infected by an individual infected since t′. So, we can calculate ℜ(t′) =
Z ∞
t′ σ(t,t′)S(t)
N Φ(t,t′)dt =
Z ∞
t′ ω(t)ρ(t −t′)φ(t −t′)θ(t,t′)S(t)
N dt. (4.34) (4.34) If we consider that during the infeccious period of the individual we have S(t)
N
≈S(t′)
N , we obtain
from Eq. 4.25 ℜ(t′) = S(t′)
N
Z ∞
t′ ω(t)θ(t,t′)(t −t′)β−1
τβ
Eα,β
−
(t −t′)
τ
α
dt. (4.35) (4.35) As an example, we consider γ(t) ≡γ > 0 and an exponential decay of ω over time: ω(t) =
ω ·e−t/a. So, ω(t)θ(t,t′) = ω ·e−(γ+1/a)(t−t′)e−t′/a. (4.36) (4.36) Therefore, ℜ(t′) = S(t′)ω
Nτ
e−t′/a
Z ∞
t′ e−(γ+1/a)(t−t′)
(t −t′)
τ
β−1
Eα,β
−
(t −t′)
τ
α
dt. (4.37) (4.37) We simplify it by changing t := t −t′. Verifying that the integral is in the form of a Laplace
Transform, we use Eq. 3.2, finally obtaining We simplify it by changing t := t −t′. Verifying that the integral is in the form of a Laplace
Transform, we use Eq. 3.2, finally obtaining ℜ(t′) = S(t′)ω
Nτβ e−t′/a
(γ +1/a)α−β
(γ +1/a)α +τ−α . (4.38) (4.38) Particularly, if S0 ≈N, Particularly, if S0 ≈N, ℜ0 =
ω(γ +1/a)α−β
τβ(γ +1/a)α +τβ−α . (4.39) (4.39) Trends Comput. Appl. Math., 22, N. 2 (2021) 171 N. ZERAICK MONTEIRO and S. RODRIGUES MAZORCHE
171 We note that if a →∞, then ω(t) ≈ω for every t and the expression of ℜ0 becomes the expression
given by [5] for the case ω(t) ≡ω constant, ℜ0 =
ωγα−β
τβγα +τβ−α . (4.40) (4.40) It is interesting to note that, in fractional order simulations with different orders or variable ω,
the peak of infectious may no longer occurs when ℜ(t′) = 1. Moreover, it is very important to
states that the approximation S(t)
N
≈S(t′)
N
is really crude and should be explored in our future
works. 5
APPLICATIONS TO THE COVID-19 PANDEMIC We constructed a slightly modification of the L1-scheme [24] to discretize the fractional SIR
model 4.28-4.30. Then, according to available data from the COVID-19 pandemic on Brazil and
Italy, we apply through MATLAB the Least Squares Method using the FDIPA [18] algorithm in
order to minimize the function f(ω,τ) = ||AI −I||2 + ||AR −R||2, where AI is a vector formed
by the data of the infected being monitored and, AR, by the data of those removed (recovered +
deaths). 5.1
Discretization of the fractional order derivative The fractional order 1 −α is assumed in the range [0,1). The time interval [0,t] is discretized
as 0 = t0 < t1 < ··· < tn = t, where the time steps ∆T have the same size. Since we wanted to
compare the model to the daily data, we choose each time step with size ∆T = 1. In particular,
ti = i∆T = i (unit [time]) for all i ∈{0,1,··· ,n}, so we performed the following discretization
for the Riemann-Liouville derivative, with unit [time]1−α D1−α f(tj) =
1
Γ(α +1)
d
dtj
Z tj
0 (tj −θ)α−1 f(θ)dθ
≃
1
Γ(α +1)
j−1
∑
k=0
f(k)[(j −k +1)α −2( j −k)α +(j −k −1)α]+ f( j)
=
1
Γ(α +1)
j−1
∑
k=0
[f(k +1)−f(k)][(j −k)α −( j −k −1)α]+ f(0)[(j +1)α −jα]
. (5.1) (5.1) 5.3
Results Initially we fixed α = β = 1 and ω(t) ≡ω, considering a classic SIR model with constant
parameters. The results are obtained in Fig. 3 (comparison between model and real data) and
Fig. 4 (projection of the peak of infection). The data was updated until 07/25/2020 and the ℜ
showed is the effective reproduction number on this date with the approximations 4.37-4.38. 0
50
100
150
t in days -26-Feb-2020 to 25-Jul-2020
0
0.5
1
1.5
2
2.5
3
3.5
4
AI(t) (*) , I(t)(-)
AR(t) (o), R(t)(--)
#10 6
COVID-19. Brazil. Model X Real data
<=1.4199
Figure 3: Model X Real data. 0
100
200
300
400
t in days -26-Feb-2020 to 20-Feb-2021
0
2
4
6
8
10
12
I(t) , R(t)(--)
#10 7
COVID-19. Brazil. I.C.: S0=210147124; I0=1; R0=0
Parameters:
!=1.4583 ;
==4.5434 ;
.=6.08e-05
<0=1.4579 ;
,=1 ; -=1
Highest Peak of Infection
12004863 ,
30-Aug-2020
5.71%. Figure 4: Projection of the peak. We observed that, even though ℜ0 is small, the I and R curves do not tend to equilibrium as fast 0
50
100
150
t in days -26-Feb-2020 to 25-Jul-2020
0
0.5
1
1.5
2
2.5
3
3.5
4
AI(t) (*) , I(t)(-)
AR(t) (o), R(t)(--)
#10 6
COVID-19. Brazil. Model X Real data
<=1.4199
Figure 3: Model X Real data. COVID-19. Brazil. Model X Real data COVID-19. Brazil. Model X Real data 0
100
200
300
400
t in days -26-Feb-2020 to 20-Feb-2021
0
2
4
6
8
10
12
I(t) , R(t)(--)
#10 7
COVID-19. Brazil. I.C.: S0=210147124; I0=1; R0=0
Parameters:
!=1.4583 ;
==4.5434 ;
.=6.08e-05
<0=1.4579 ;
,=1 ; -=1
Highest Peak of Infection
12004863 ,
30-Aug-2020
5.71%. Figure 4: Projection of the peak. Figure 4: Projection of the peak. Figure 3: Model X Real data. We observed that, even though ℜ0 is small, the I and R curves do not tend to equilibrium as fast
as the real curves. We believe that this is due to the fact that we disregard the laws of infection
and recovery and, above all, because we take constant ω. Next, in Fig.5-10, we consider ω with exponential decay, a = 70 and different orders α,β. We
emphasize that, as α decreases, the right tail of the I compartment becomes heavier. 5.2
Parameters In the 4.28 - 4.30 system, the parameter ω(t) is related to contagion, being strongly affected by
government measures, such as quarantine, as well as hygiene and readaptation measures in times
of pandemic, both social and physical. Thus, we consider three situations in the simulations: 1)
Constant value ω(t) ≡ω, as considered in most models; 2) Exponential decay in value over time:
ω(t) = ω · e−t/a; 3) Exponential decay with oscillations, representing relaxation and periodic
hardening of the containment measures: ω(t) = ω ·e−t/a ·cos2(tπ/b). Trends Comput. Appl. Math., 22, N. 2 (2021) 172 FRACTIONAL DERIVATIVES APPLIED TO EPIDEMIOLOGY The Brazilian population is given by N = 210147125 inhabitants and the initial stage by
(S,I,R) = (N −1,1,0). As said, applying the Least Squares Method through the FDIPA algo-
rithm we seek to minimize the function f(ω,τ) = ||AI −I||2 + ||AR −R||2. It is noted that the
absence of data about recovered in the first two months of the Brasilian pandemic prejudices the
model. 5.3
Results 0
50
100
150
t in days -26-Feb-2020 to 25-Jul-2020
0
2
4
6
8
10
12
14
16
18
AI(t) (*) , I(t)(-)
AR(t) (o), R(t)(--)
#10 5
COVID-19. Brazil. Model X Real data
<=0.65557
Fi
5 M d l X R
l d
0
100
200
300
400
t in days -26-Feb-2020 to 20-Feb-2021
0
0.5
1
1.5
2
2.5
3
I(t) , R(t)(--)
#10 6
COVID-19. Brazil. I.C.: S0=210147124; I0=1; R0=0
Parameters:
!=7.3832 ;
==21.4948 ;
.=6.08e-05
<0=5.643 ;
,=1 ; -=1
Highest Peak of Infection
605191 ,
16-Jul-2020
0.29%. Fi
6 P
j
i
f h
k 0
100
200
300
400
t in days -26-Feb-2020 to 20-Feb-2021
0
0.5
1
1.5
2
2.5
3
I(t) , R(t)(--)
#10 6
COVID-19. Brazil. I.C.: S0=210147124; I0=1; R0=0
Parameters:
!=7.3832 ;
==21.4948 ;
.=6.08e-05
<0=5.643 ;
,=1 ; -=1
Highest Peak of Infection
605191 ,
16-Jul-2020
0.29%. 0
50
100
150
t in days -26-Feb-2020 to 25-Jul-2020
0
2
4
6
8
10
12
14
16
18
AI(t) (*) , I(t)(-)
AR(t) (o), R(t)(--)
#10 5
COVID-19. Brazil. Model X Real data
<=0.65557 COVID-19. Brazil. Model X Real data Figure 6: Projection of the peak. Figure 5: Model X Real data. 0
50
100
150
t in days -26-Feb-2020 to 25-Jul-2020
0
2
4
6
8
10
12
14
16
18
AI(t) (*) , I(t)(-)
AR(t) (o), R(t)(--)
#10 5
COVID-19. Brazil. Model X Real data
<=0.64375
Figure 7: Model X Real data 0
100
200
300
400
t in days -26-Feb-2020 to 20-Feb-2021
0
0.5
1
1.5
2
2.5
3
I(t) , R(t)(--)
#10 6
COVID-19. Brazil. I.C.: S0=210147124; I0=1; R0=0
Parameters:
!=7.88 ;
==26.6617 ;
.=6.08e-05
<0=5.5451 ;
,=0.9 ;
-=0.9
Highest Peak of Infection
764441 ,
20-Jul-2020
0.36%. Figure 8: Projection of the peak. Figure 8: Projection of the peak. Figure 7: Model X Real data. 0
50
100
150
t in days -26-Feb-2020 to 25-Jul-2020
0
2
4
6
8
10
12
14
16
18
AI(t) (*) , I(t)(-)
AR(t) (o), R(t)(--)
#10 5
COVID-19. Brazil. Model X Real data
<=0.6738
Figure 9: Model X Real data. 0
100
200
300
400
t in days 26 Feb 2020 to 20 Feb 2021
0
0.5
1
1.5
2
2.5
3
3.5
I(t) , R(t)(--)
#10 6
COVID-19. Brazil. 5.3
Results In Fig.11
and Fig.12, we take an oscilating exponential decay for ω, with a = 140,b = 110 and orders
α = 0.8,β = 0.9. In this test we approximate the ℜ0 as in the last case, but we do not calculate
the ℜ. Finally, we used the orders α = 0.9,β = 0.95 to carry out a test in relation to the Italian pandemic,
which has the important characteristic of having its curve of infected individuals declining since
the last week of April. The results of the comparisons between the models and the actual data [23]
are shown in Fig. 13 and 14. For Italy, we use a = 40 and γ = 2.92·10−5 [35]. The available data
has visible outliers. Trends Comput. Appl. Math., 22, N. 2 (2021) 173 N. ZERAICK MONTEIRO and S. RODRIGUES MAZORCHE
173 0
50
100
150
t in days -26-Feb-2020 to 25-Jul-2020
0
2
4
6
8
10
12
14
16
18
AI(t) (*) , I(t)(-)
AR(t) (o), R(t)(--)
#10 5
COVID-19. Brazil. Model X Real data
<=0.65557
Figure 5: Model X Real data. 0
100
200
300
400
t in days -26-Feb-2020 to 20-Feb-2021
0
0.5
1
1.5
2
2.5
3
I(t) , R(t)(--)
#10 6
COVID-19. Brazil. I.C.: S0=210147124; I0=1; R0=0
Parameters:
!=7.3832 ;
==21.4948 ;
.=6.08e-05
<0=5.643 ;
,=1 ; -=1
Highest Peak of Infection
605191 ,
16-Jul-2020
0.29%. Figure 6: Projection of the peak. 0
50
100
150
t in days -26-Feb-2020 to 25-Jul-2020
0
2
4
6
8
10
12
14
16
18
AI(t) (*) , I(t)(-)
AR(t) (o), R(t)(--)
#10 5
COVID-19. Brazil. Model X Real data
<=0.64375
Figure 7: Model X Real data. 0
100
200
300
400
t in days -26-Feb-2020 to 20-Feb-2021
0
0.5
1
1.5
2
2.5
3
I(t) , R(t)(--)
#10 6
COVID-19. Brazil. I.C.: S0=210147124; I0=1; R0=0
Parameters:
!=7.88 ;
==26.6617 ;
.=6.08e-05
<0=5.5451 ;
,=0.9 ;
-=0.9
Highest Peak of Infection
764441 ,
20-Jul-2020
0.36%. Figure 8: Projection of the peak. 6
8
10
12
14
16
18
(t) (*) , I(t)(-)
R(t) (o), R(t)(--)
#10 5
COVID-19. Brazil. Model X Real data
<=0.6738
1.5
2
2.5
3
3.5
, R(t)(--)
#10 6
COVID-19. Brazil. I.C.: S0=210147124; I0=1; R0=0
Parameters:
!=5.8311 ;
==15.7123 ;
.=6.08e-05
<0=5.8081 ;
,=0.7 ;
-=0.9
Highest Peak of Infection
669451 ,
27-Jul-2020
0.32%. 174
FRACTIONAL DERIVATIVES APPLIED TO EPIDEMIOLOGY 0
50
100
150
t in days -26-Feb-2020 to 25-Jul-2020
0
0.5
1
1.5
2
AI(t) (*) , I(t)(-)
AR(t) (o), R(t)(--)
#10 6
COVID-19. Brazil. Model X Real data
Figure 11: Model X Real data. 0
100
200
300
400
500
t in days -26-Feb-2020 to 10-Jul-2021
0
1
2
3
4
5
I(t) , R(t)(--)
#10 6
COVID-19. Brazil. I.C.: S0=210147124; I0=1; R0=0
Parameters:
!=5.6941 ;
==10.6744 ;
.=6.08e-05
<0=6.5216 ;
,=0.8 ;
-=0.9
Highest Peak of Infection
731162 ,
16-Jul-2020
0.35%. Figure 12: Projection of the peak. 0
50
100
150
200
t in days -31-Jan-2020 to 25-Jul-2020
0
0.5
1
1.5
2
2.5
3
3.5
4
AI(t) (*) , I(t)(-)
AR(t) (o), R(t)(--)
#10 5
COVID-19. Italy. Model X Real data
<=0.067192
Figure 13: Model X Real data. 0
50
100
150
200
250
t in days -31-Jan-2020 to 07-Oct-2020
0
1
2
3
4
I(t) , R(t)(--)
#10 5
COVID-19. Italy. I.C.: S0=60461825; I0=2; R0=0
Parameters:
!=8.359 ;
==18.478 ;
.=2.92e-05
<0=5.7934 ;
,=0.9 ;
-=0.95
Highest Peak of Infection
110202 ,
28-Apr-2020
0.18%. Figure 14: Projection. 0
100
200
300
400
500
t in days -26-Feb-2020 to 10-Jul-2021
0
1
2
3
4
5
I(t) , R(t)(--)
#10 6
COVID-19. Brazil. I.C.: S0=210147124; I0=1; R0=0
Parameters:
!=5.6941 ;
==10.6744 ;
.=6.08e-05
<0=6.5216 ;
,=0.8 ;
-=0.9
Highest Peak of Infection
731162 ,
16-Jul-2020
0.35%. 0
50
100
150
t in days -26-Feb-2020 to 25-Jul-2020
0
0.5
1
1.5
2
AI(t) (*) , I(t)(-)
AR(t) (o), R(t)(--)
#10 6
COVID-19. Brazil. Model X Real data COVID-19. Brazil. Model X Real data Figure 12: Projection of the peak. 0
50
100
150
200
250
t in days -31-Jan-2020 to 07-Oct-2020
0
1
2
3
4
I(t) , R(t)(--)
#10 5
COVID-19. Italy. I.C.: S0=60461825; I0=2; R0=0
Parameters:
!=8.359 ;
==18.478 ;
.=2.92e-05
<0=5.7934 ;
,=0.9 ;
-=0.95
Highest Peak of Infection
110202 ,
28-Apr-2020
0.18%. 0
50
100
150
200
t in days -31-Jan-2020 to 25-Jul-2020
0
0.5
1
1.5
2
2.5
3
3.5
4
AI(t) (*) , I(t)(-)
AR(t) (o), R(t)(--)
#10 5
COVID-19. Italy. Model X Real data
<=0.067192 Figure 13: Model X Real data. Figure 14: Projection. Figure 14: Projection. 5.3
Results I.C.: S0=210147124; I0=1; R0=0
Parameters:
!=5.8311 ;
==15.7123 ;
.=6.08e-05
<0=5.8081 ;
,=0.7 ;
-=0.9
Highest Peak of Infection
669451 ,
27-Jul-2020
0.32%. Figure 10: Projection of the peak. Figure 9: Model X Real data. Trends Comput. Appl. Math., 22, N. 2 (2021) 174
FRACTIONAL DERIVATIVES APPLIED TO EPIDEMIOLOGY 174 Acknowledgments We appreciate the support of the Coordenac¸˜ao de Aperfeic¸oamento de Pessoal de N´ıvel Superior
- Brasil (CAPES) - Financing Code 001. We appreciate the support of the Coordenac¸˜ao de Aperfeic¸oamento de Pessoal de N´ıvel Superior
- Brasil (CAPES) - Financing Code 001. 6
DISCUSSION AND CONCLUSIONS Moreover,
we intend to discuss equilibrium points and better calculations for the reproduction number. A
better understanding in this area can be useful not only for epidemiology, but also for the other
applied areas in which fractional derivatives are used, such as thermoelasticity and diffusion. 6
DISCUSSION AND CONCLUSIONS We investigated the use of fractional derivatives, both analytically and through simulations. We
present models and perform investigations about them, discussing difficulties and differences
between classic and fractional models. Also, we analyzed the COVID-19 pandemic using a frac-
tional epidemiological SIR model carefully built and performed a numerical solution using dis-
cretization and implementation in MATLAB. We observed that, among others effects, the use of
fractional orders allows us accentuate the asymmetry of the curve (slow decline). This effect is
being observed in the real data of many countries [29]. We reiterate that the work is not in disagreement with any research cited. On the contrary, we
respect the models obtained by the literature review, believing that they contribute with equations
of great interest to Mathematics. Also, it is possible that some authors write their equations as
mentioned in section 3.2 for reasons that we do not perceive or that are in literature that we do Trends Comput. Appl. Math., 22, N. 2 (2021) 175 N. ZERAICK MONTEIRO and S. RODRIGUES MAZORCHE not access. Our goal is only to present questions and calculations that we believe to be of both
pure and applied interest, as the definition of parameters and the units and population balances. We emphasize that the choice of the Riemann-Liouville fractional derivative was due to the
application that arose during the construction of the model, with attention to Eq.4.23. In the
future we want to extend the mathematical discussion on the parameters effects (including the
cases when α is close to 0, what corresponds to too heavy right tail on I compartment), more
accurate discretizations and also on the use of different types of fractional operators. Moreover,
we intend to discuss equilibrium points and better calculations for the reproduction number. A
better understanding in this area can be useful not only for epidemiology, but also for the other
applied areas in which fractional derivatives are used, such as thermoelasticity and diffusion. We emphasize that the choice of the Riemann-Liouville fractional derivative was due to the
application that arose during the construction of the model, with attention to Eq.4.23. In the
future we want to extend the mathematical discussion on the parameters effects (including the
cases when α is close to 0, what corresponds to too heavy right tail on I compartment), more
accurate discretizations and also on the use of different types of fractional operators. REFERENCES [1] A. Ahmad et al. Dynamical behavior of SIR epidemic model with non-integer time fractional
derivatives: A mathematical analysis. Int. J. Adv. Appl. Sci, 5(1) (2018), 123–129. [2] R. Almeida. Analysis of a fractional SEIR model with treatment. Applied Mathematics Letters, 84
(2018), 56–62. [3] I. Ameen. “Fractional Calculus: Numerical Methods and SIR Models”. Ph.D. thesis, University of
Padova, Padova, Italy (2017). PhD thesis. [4] C.N. Angstmann, B.I. Henry & A.V. McGann. A fractional-order infectivity SIR model. Physica A:
Statistical Mechanics and its Applications, 452 (2016), 86–93. [5] C.N. Angstmann, B.I. Henry & A.V. McGann. A fractional-order infectivity and recovery SIR model. Fractal and Fractional, 1(1) (2017), 11. [6] H. Bateman. “Higher transcendental functions”, volume 3. McGraw-Hill Book Company (1953). [7] N.G. Becker et al. Using mathematical models to assess responses to an outbreak of an emerged viral
respiratory disease. In “Final Report to the Australian Government Department of Health and Ageing. National Centre for Epidemiology and Population Health, Australian National University” (2006). [8] E. Capelas de Oliveira. “Solved Exercises in Fractional Calculus”. Springer (2019). [9] R.M. Corless et al. On the Lambert W function. Advances in Computational mathematics, 5(1) (1996),
329–359. [10] J.V. da Costa Sousa & E. Capelas de Oliveira. On the ψ-Hilfer fractional derivative. Communications
in Nonlinear Science and Numerical Simulation, 60 (2018), 72–91. Trends Comput. Appl. Math., 22, N. 2 (2021) FRACTIONAL DERIVATIVES APPLIED TO EPIDEMIOLOGY 176 [11] J.V. da Costa Sousa & E. Capelas de Oliveira. Leibniz type rule: ψ-Hilfer fractional operator. Communications in Nonlinear Science and Numerical Simulation, 77 (2019), 305–311. [12] J.V. da Costa Sousa, G. Frederico & E. Capelas de Oliveira. ψ-Hilfer pseudo-fractional operator: new
results about fractional calculus (2020). [13] A. Dokoumetzidis, R. Magin & P. Macheras. A commentary on fractionalization of multi-
compartmental models. Journal of pharmacokinetics and pharmacodynamics, 37(2) (2010),
203–207. [14] A. Dokoumetzidis, R. Magin & P. Macheras. Fractional kinetics in multi-compartmental systems. Journal of pharmacokinetics and pharmacodynamics, 37(5) (2010), 507–524. [15] M. Farman et al. Dynamical Behavior of Hepatitis B Fractional-order Model with Modeling and
Simulation. Journal of Biochemical Technology, 10(3) (2019), 11. [16] A.C.F.N. Gomes & A. de Cezaro. Modelo SIRC fracion´ario com m´ultiplas ordens para influenza. Scientia Plena, 15(4) (2019). [17] S. Hasan et al. Solution of fractional SIR epidemic model using residual power series method. Applied
Mathematics and Information Sciences, 13(2) (2019), 153–161. [18] J. Herskovits. Feasible direction interior-point technique for nonlinear optimization. Trends Comput. Appl. Math., 22, N. 2 (2021) REFERENCES Journal of
optimization theory and applications, 99(1) (1998), 121–146. [19] M.R. Islam, A. Peace, D. Medina & T. Oraby. Integer versus fractional order seir deterministic and
stochastic models of measles. International Journal of Environmental Research and Public Health,
17(6) (2020), 2014. [20] W.O. Kermack & A.G. McKendrick. Contributions to the mathematical theory of epidemics–I. 1927. (1991). [21] M.A. Khan & A. Atangana. Modeling the dynamics of novel coronavirus (2019-nCov) with fractional
derivative. Alexandria Engineering Journal, (2020). [22] K. McIntosh, M.S. Hirsch & A. Bloom. Coronavirus disease 2019 (COVID-19). UpToDate Hirsch
MS Bloom, 5 (2020). [23] Microsoft/Bing. COVID-19-Data
(2020). URL
https://raw.githubusercontent.com/
microsoft/Bing-COVID-19-Data/master/data/Bing-COVID19-Data.csv. [Online; accessed
29-July-2020]. [24] K. Oldham & J. Spanier. “The fractional calculus theory and applications of differentiation and
integration to arbitrary order”. Elsevier (1974). [25] W.H. Organization & N. Authorities. “Coronavirus disease 2019 (COVID-19): situation report, 190”. World Health Organization (2020). [26] M. Ortigueira & J. Machado. Fractional definite integral. Fractal and Fractional, 1(1) (2017), 2. [27] M.D. Ortigueira & J.T. Machado. What is a fractional derivative? Journal of computational Physics,
293 (2015), 4–13. Trends Comput. Appl. Math., 22, N. 2 (2021) 177 N. ZERAICK MONTEIRO and S. RODRIGUES MAZORCHE
177 [28] I. Podlubny. “Fractional differential equations: an introduction to fractional derivatives, fractional
differential equations, to methods of their solution and some of their applications”. Elsevier (1998). [29] R. Ranjan. Estimating the final epidemic size for Covid-19 outbreak using improved epidemiological
models. medRxiv, (2020). [30] D. Rostamy & E. Mottaghi. Numerical solution and stability analysis of a nonlinear vaccination model
with historical effects. Hacettepe Journal of Mathematics and Statistics, 47(6) (2017), 1478–1494. [31] A.S. Shaikh, I.N. Shaikh & K.S. Nisar. “A mathematical model of covid-19 using fractional derivative:
Outbreak in india with dynamics of transmission and control”. Preprints (2020). 32] A. Slav´ık. “Product integration, its history and applications”. Matfyzpress Prague (2007). [33] H. Sun, W. Chen, H. Wei & Y. Chen. A comparative study of constant-order and variable-order frac-
tional models in characterizing memory property of systems. The European Physical Journal Special
Topics, 193(1) (2011), 185. [34] K. Wang & J. Huang. High order fast algorithm for the Caputo fractional derivative. arXiv preprint
arXiv:1705.06101, (2017). [35] Wikipedia contributors. Demographics of Italy – Wikipedia, The Free Encyclopedia (2020). URL
https://en.wikipedia.org/w/index.php?title=Demographics_of_Italy&oldid=
969810317. [Online; accessed 29-July-2020]. Trends Comput. Appl. Math., 22, N. 2 (2021)
|
https://openalex.org/W4362550443
|
https://aacr.figshare.com/articles/journal_contribution/Supplementary_Figure_Legends_from_A_Novel_Therapeutic_Strategy_Targeting_the_Mesenchymal_Phenotype_of_Malignant_Pleural_Mesothelioma_by_Suppressing_LSD1/22526165/1/files/39989036.pdf
|
English
| null |
Supplementary Figure Legends from A Novel Therapeutic Strategy Targeting the Mesenchymal Phenotype of Malignant Pleural Mesothelioma by Suppressing LSD1
| null | 2,023
|
cc-by
| 894
|
Supplementary Figure Legends Supplementary Figure S1. TGFβ1 treatment in MPM cells. (A) Microscopic images
of ACC-MESO-4 cells following TGFβ1 treatment for 0, 24, 48, and 72 h. Scale bar = 20
μm. (B) E-cadherin, Zo-1, vimentin, and actin (loading control) protein expression in
ACC-MESO-4 cells incubated with or without TGFβ1 (1, 5, or 10 ng/mL) for 24 or 48 h. Supplementary Figure S2. Snail-1 induces a mesenchymal phenotype in MPM cell (A) Microscopic images of Y-MESO-25 ER-Snail-16SA and empty vector cells following
4-OHT exposure for 0 and 72 h. Scale bar = 20 μm. (B) Snail, E-cadherin, fibronectin,
vimentin, and GAPDH (loading control) protein expression in Y-MESO-25 ER-Snail-
16SA and empty vector control cells following 4-OHT exposure for 72 and 96 h. (C)
Wound healing assay in Y-MESO-25 ER-Snail-16SA and empty vector cells treated with
4-OHT for 48 h. Cells were imaged 0 and 24 h after a scratch wound was made on the
cell surface. Left: Representative images. Scale bar = 200 μm. Right: Quantification of
wound healing area. Data represent the mean SD of three independent experiments: *p
< 0.05, two-tailed unpaired Student’s t-test. (D) IC50 for CDDP in Y-MESO-25 ER- Snail-
16SA and empty vector cells following 4-OHT exposure for 72 h with or without CDDP. Data represent the mean SD of three independent experiments: *p < 0.05, two-tailed 1 1 unpaired Student’s t-test. Supplementary Figure S3. LSD1 suppression attenuated the mesenchymal
phenotype. (A) Microscopic images of Y-MESO-8A cells infected with shNT or shLSD1
(#1 and #2). Scale bar = 20 μm. (B) LSD1, E-cadherin, fibronectin, vimentin, and
GAPDH (loading control) protein expression in Y-MESO-8A cells infected with shNT or
shLSD1 (#1 and #2). (C) Wound healing assay in Y-MESO-8A cells infected with shNT
or shLSD1 (#1 and #2). Cells were imaged 0 and 18 h after a scratch wound was made
on the cell surface. Left: Representative images. Scale bar = 200 μm. Right:
Quantification of wound healing area. Data represent the mean SD of three independent
experiments: *p < 0.05, two-tailed unpaired Student’s t-test. (D) Left: Chemosensitivity
assay in Y-MESO-8A cells infected with shNT or shLSD1 in the presence or absence of
CDDP. Right: IC50 for CDDP. Data represent the mean SD of three independent
experiments: *p < 0.05, two-tailed unpaired Student’s t-test. (E) Cleaved caspase 3 and
GAPDH (loading control) protein expression in Y-MESO-8A cells infected with shNT or
shLSD1 (#1 and #2) following CDDP exposure for 48 h. (F) The percentage of apoptotic
cells determined using Annexin V staining in Y-MESO-8A cells infected with shNT or
shLSD1 (#1 and #2) following CDDP exposure for 48 h. Data represent the mean SD 2 2 of three independent experiments: *p < 0.05, two-tailed unpaired Student’s t test. Supplementary Figure S2. Snail-1 induces a mesenchymal phenotype in MPM cell (G)
Left: Chemosensitivity assay in ACC-MESO-4 cells treated with or without S2101 in the
presence or absence of CDDP. Right: IC50 for CDDP. Data represent the mean SD from
three independent experiments: *p < 0.05, two-tailed unpaired Student’s t-test. Supplementary Figure S4. MFGE8 regulates the FAK pathway. (A) LSD1, p-FAK,
FAK, p-AKT, AKT, and GAPDH (loading control) protein expression in Y-MESO-8A
cells infected with shNT and shLSD1 following CDDP exposure for 48 h. (B) Snail, p-
FAK, FAK, p-AKT, AKT, and GAPDH (loading control) protein expression in ACC-
MESO-4 ER-Snail-16SA cells treated with or without 4-OHT following CDDP exposure
for 48 h. (C) Schematic representation of up- and down-regulated genes common to both
shLSD1 #1- and #2-treated ACC-MESO-1 cells. 335 genes were commonly down-
regulated and 244 were commonly up-regulated. Comparison with chromatin
accessibility data identified 13 down-regulated genes and 10 up-regulated genes as
candidate direct targets of LSD1. (D) MFGE8 mRNA expression in Y-MESO-8A cells
infected with shNT or shLSD1 (#1 and #2). Data represent the mean SD of three
independent experiments: *p < 0.05, two-tailed unpaired Student’s t-test. upplementary Figure S4. MFGE8 regulates the FAK pathway. (A) LSD1, p-FAK, 3 3 Supplementary Figure S5. Role of MFGE8 in MPM. (A) MFGE8 (left), ITGB3
(middle), and ITGB5 (right) mRNA expression in 62 epithelial and 25
sarcomatoid/biphasic MPM samples from TCGA cohort: *p < 0.05, two-tailed unpaired
Student’s t-test. (B) ELISA quantification of serum MFGE8 in 22 epithelial and 10
sarcomatoid/biphasic MPM samples. (C) Comparison of OS in patients with high and
low MFGE8 expression from TCGA cohort. (D) MFGE8, E-cadherin, vimentin, and
GAPDH (loading control) protein expression in ACC-MESO-4 cells infected with pLV-
MFGE8 and control vector. (E) LSD1, MFGE8, Snail, integrin β3, and GAPDH (loading
control) protein expression in Y-MESO-8A cells infected with shNT or shLSD1 (#1 and
#2). (F) MFGE8 and GAPDH (loading control) protein expression in ACC-MESO-4 ER-
Snail-16SA and Y-MESO-25 ER-Snail-16SA cells following 4-OHT exposure. (G) Integrin
β3 and GAPDH (loading control) protein expression in ACC-MESO-4 ER-Snail-16SA, Y-
MESO-25 ER-Snail-16SA, and empty vector control cells treated with 4-OHT. Supplementary Figure S6. Restoring MFGE8 abolishes apoptosis by re-activating
the FAK-AKT pathway. (A) p-FAK, FAK, p-AKT, AKT, cleaved caspase 3, and
GAPDH (loading control) protein expression in Y-MESO-8A cells infected with shNT or
shLSD1 (#1 and #2) with CDDP in the presence or absence of rhMFGE8 for 48 h. (B) 4 LSD1, p-FAK, FAK, p-AKT, AKT, cleaved caspase 3, and GAPDH (loading control)
protein expression in MFGE8-overexpressing Y-MESO-8A cells infected with shNT or
shLSD1 (#1 and #2) treated with CDDP. 5
|
https://openalex.org/W2054620820
|
http://pei-pusat.org/jurnal/index.php/jei/article/download/59/pdf1
|
English
| null |
The effect of DMSO on ITS2 amplification in the molecular identification of Anopheles farauti Laveran (Diptera: Culicidae), from a colony established in the laboratory
|
Jurnal Entomologi Indonesia
| 2,013
|
cc-by
| 3,041
|
*Penulis korespondensi: Ign. Joko Suyono. Departemen Biologi, Fakultas Matematika dan Ilmu Pengetahuan Alam,
Universitas Cenderawasih, Jalan Kamp Walker Waena, Jayapura 99358
Tel: +6281328886652, Faks: 0967-571115, Email: ignetds@yahoo.com ABSTRACT Sibling species identification is very important in the understanding of malaria epidemiology. Morphological criteria are usually used in the identification of anopheline species, but this fails when
sibling or cryptic species occur. Analysis by PCR-RFLP of rDNA ITS2 is currently the most reliable
and sensitive method for distinguishing between members of the Anopheles punctulatus group. The
objective of this study was to investigate the effect of DMSO concentration on ITS2 amplification of
An. farauti from the colony maintained at BATAN Jakarta using PCR-RFLP based on the rDNA ITS2. The results showed that the addition of 6 % and 7 % DMSO produced ITS2 amplification products in
the size 750 bp. DMSO could be used in PCR to relieve secondary structures when amplifying high
GC templates. Molecular identification of An. farauti is found to be Anopheles farauti sensu stricto. Key words: molecular identification, sibling species, PCR-RFLP, rDNA ITS2, secondary structure September 2013, Vol. 10 No. 2, 93-97
Online version: http://journal.ipb.ac.id/index.php/entomologi
DOI: 10.5994/jei.10.2.93 Jurnal Entomologi Indonesia
Indonesian Journal of Entomology
ISSN: 1829-7722 Jurnal Entomologi Indonesia
Indonesian Journal of Entomology
ISSN: 1829-7722 September 2013, Vol. 10 No. 2, 93-97
Online version: http://journal.ipb.ac.id/index.php/entomologi
DOI: 10.5994/jei.10.2.93 Ign. Joko Suyono1,2*, Jesmandt Situmorang2, R.C. Hidayat Soesilohadi2,
Rarastoeti Pratiwi2 Ign. Joko Suyono1,2*, Jesmandt Situmorang2, R.C. Hidayat Soesilohadi2,
Rarastoeti Pratiwi2 1Departemen Biologi, Fakultas Matematika dan Ilmu Pengetahuan Alam,
Universitas Cenderawasih, Jalan Kamp Walker Waena, Jayapura 99358
2Fakultas Biologi, Universitas Gadjah Mada
Jalan Teknika Selatan, Yogyakarta 55281 INTRODUCTION used in the amplification reaction to eliminate the
DNA secondary structure (Beebe & Saul 1995). But there is limited discussion on DMSO function
and no information is given about how to run this
experiment. The main malaria vectors in the southwest
Pacific islands of Moluccas, Papua, Papua New
Guinea, the Bismarck Archipelago, the Solomon
and Vanuatu are the members of the Anopheles
punctulatus group. The species belong to this group
originally are An. farauti, An. koliensis and An. punctulatus. These species could be differentiated
morphologically based on the pale scales of the
proboscis. The proboscis of An. farauti entirely
dark scaled except for a narrow light ring at
extreme apex. An. koliensis with a ventral patch
of white scales on the apical third of the proboscis
and variable size, and An. punctulatus with the
apical half of the proboscis almost entirely white
scaled (Rozebbom & Knigh 1946 cit Beebe et al. 2000a). Crossmating, cytogenetic, DNA probe
and allozyme analyses now identified 12 species
within Anopheles punctulatus group: Anopheles
farauti 1–7 (An. farauti complex), An. punctulatus,
An. koliensis, An. clowi, An. rennellensis and An. species near punctulatus (Beebe et al. 2000a;
Beebe et al. 2000b; Schmidt et al. 2003). Mosquito colonies maintained at The National
Agency of Atomic Energy (BATAN) Jakarta were
obtained from The Naval Medical Research Unit 2
(NAMRU 2) Jakarta. Especially for this An. farauti
colony which was maintained at BATAN, the name
was based on its morphological identification,
therefore the exact name of this sibling species
remains unclear. In the former study conducted
by Benet et al. (2004) reported that specimens
that were identified morphologically as An. farauti
were consisted of An. farauti sensu stricto, An. farauti 4, An. farauti 2, An. koliensis and An. punctulatus by PCR-RFLP analysis, therefore is
very important to identify the An. farauti colony
from BATAN. The aim of this study is to investigate the effect
of DMSO concentration on ITS2 amplification in
the identification of An. farauti complex species
from the colony maintained at BATAN Jakarta
using PCR-RFLP. Identification of An. punctulatus group
commonly based on the proboscis morphology
and sector spot on the costa is proving to be quite
unreliable in differentiating them, making field
studies on their biology and behavior of each of
the members of the group difficult. Sample preparation An. farauti was obtained from a colony
maintained at BATAN Jakarta. Mosquitoes were
preserved in vials and kept dry in tins containing
silica gel for molecular identification using PCR-
RFLP. The investigation was performed from July
to September 2010 at the Laboratory of Genetic
Engineering of Research Center for Biotechnology,
University of Gadjah Mada Yogyakarta. The ITS2 region of An. punctulatus group has
rapid evolution compared with the coding region. This conserved sequence especially 3’ to the 5.8
rDNA and 5’ to the 28S rDNA can pair and form
stable stem loops. Due to this strong secondary
structure, 10% dimethyl sulfoxide (DMSO) was ABSTRAK Identifikasi spesies sibling sangat penting untuk mempelajari epidemiologi malaria. Ciri
morfologi secara umum digunakan dalam identifikasi spesies Anopheles, namun tidak sesuai ketika
digunakan untuk spesies sibling dan spesies kriptik. Analisis dengan menggunakan PCR-RFLP dari
ITS2 rDNA pada saat ini merupakan metode yang paling cocok dan sensitif untuk membedakan
spesies Anopheles punctulatus group. Tujuan penelitian ini adalah untuk mengetahui pengaruh
konsentrasi DMSO terhadap amplifikasi ITS2 dalam mengidentifikasi An. farauti dari koloni di
BATAN Jakarta dengan PCR-RFLP berdasarkan ITS2 rDNA. Hasil penelitian menunjukkan bahwa
penambahan DMSO dengan konsentrasi 6% dan 7% menghasilkan produk amplifikasi ITS2 dengan
ukuran 750 pb. DMSO dapat digunakan dalam PCR untuk mencegah terbentuknya struktur sekunder 93 Suyono et al.: Effect of DMSO on ITS2 amplification ketika mengamplifikasi template dengan kandungan GC yang tinggi. Identifikasi molekular An. farauti dengan
menggunakan PCR-RFLP merupakan Anopheles farauti sensu stricto. ketika mengamplifikasi template dengan kandungan GC yang tinggi. Identifikasi molekular An. farauti dengan
menggunakan PCR-RFLP merupakan Anopheles farauti sensu stricto. Kata kunci: identifikasi molekular, spesies sibling, PCR-RFLP, ITS2 rDNA, struktur sekunder Kata kunci: identifikasi molekular, spesies sibling, PCR-RFLP, ITS2 rDNA, struktur sekunder Kata kunci: identifikasi molekular, spesies sibling, PCR-RFLP, ITS2 rDNA, struktur sekunder INTRODUCTION Analysis by
polymerase chain reaction-restriction fragment
length
polymorphism
(PCR-RFLP)
of
the
ribosomal DNA (rDNA) internal transcribed
spacer 2 (ITS2) is currently the most reliable
and sensitive method for distinguishing between
members of the group. It is based on specific
banding pattern for each of the sibling species
(Beebe & Saul 1995; Benet et al. 2004). Product digestion and visualization The ITS2 products were subjected to
electrophoresis on a 1.5% agarose gel containing
0.5 µg/ml of ethidium bromide and visualized on
an ultraviolet transilluminator. The PCR products
were then digested with five units of Msp I (final
volume 20 µl) and the resulting products resolved
by electrophoresis on a 2% agarose gel containing
0.5 µg/ml of ethidium bromide and visualized on
an ultraviolet transilluminator. The patterns of
bands were compared to known patterns for An. punctulatus group (Beebe & Saul 1995). Figure 2. Polymerase chain reaction-restriction frag
ment length polymorphism pattern for in
ternal transcribed spacer 2 of Anopheles
farauti from BATAN separated on a 2%
agarose gel. M: 100 bp marker; 1-2: An. farauti sensu stricto; 3: Undigested ITS2
amplification product. 6% DMSO was
used in the PCR reaction. bp= basepairs. Figure 2. Polymerase chain reaction-restriction frag
ment length polymorphism pattern for in
ternal transcribed spacer 2 of Anopheles
farauti from BATAN separated on a 2%
agarose gel. M: 100 bp marker; 1-2: An. farauti sensu stricto; 3: Undigested ITS2
amplification product. 6% DMSO was
used in the PCR reaction. bp= basepairs. PCR for effect of DMSO on ITS2 amplification PCR for effect of DMSO on ITS2 amplification
DNA template of 3 µl was added directly to
PCR mixture in final reaction volume of 25 µl
that contained 50 mM KCl, 10 mM Tris-HCL,
pH 8.3, 2.5 mM MgCl2, 0.2 mM dNTP, various
concentrations (4%, 6%, 7%, 8% and 10%) of
DMSO, 1.25 unit of Taq polymerase and 0.6 µM
of each primer. The internal transcribed spacer
2 (ITS2) was amplified using forward primer
ITS2A,
5’-TGTGAACTGCAGGACACAT-3’
and reverse primer ITS2B, 5’-TATAGCTTAAA
TTCAGGGGGT-3’ (Beebe & Saul 1995). A
Perkin-Elmer type GeneAmp System 2400
thermocycler was used for all reactions with
following parameters: an initial denaturation
at 94 °C for five minutes, and then 35 cycles at
94 °C for one minute, 53 °C for one minute, and
72 °C for two minutes, followed by a final extention
of 7 minutes at 72 °C. The ITS2 products were
subjected to electrophoresis on a 1.5% agarose
gel containing 0.5 µg/ml of ethidium bromide and
visualized on an ultraviolet transilluminator. The
ITS2 amplification results with optimum DMSO
(6%) then was used for subsequent enzyme
reaction analysis. M
1
2
3
4
5 Figure 1. Determination of optimum DMSO
concentration of ITS2 from Anopheles
farauti. M: 100 bp marker; 1: 4%
DMSO; 2: 6% DMSO; 3: 7% DMSO;
4: 8% DMSO; 5: 10% DMSO. bp=
basepairs. Figure 1. Determination of optimum DMSO
concentration of ITS2 from Anopheles
farauti. M: 100 bp marker; 1: 4%
DMSO; 2: 6% DMSO; 3: 7% DMSO;
4: 8% DMSO; 5: 10% DMSO. bp=
basepairs. Figure 1. Determination of optimum DMSO
concentration of ITS2 from Anopheles
farauti. M: 100 bp marker; 1: 4%
DMSO; 2: 6% DMSO; 3: 7% DMSO;
4: 8% DMSO; 5: 10% DMSO. bp=
basepairs. Figure 2. Polymerase chain reaction-restriction frag
ment length polymorphism pattern for in
ternal transcribed spacer 2 of Anopheles
farauti from BATAN separated on a 2%
agarose gel. M: 100 bp marker; 1-2: An. farauti sensu stricto; 3: Undigested ITS2
amplification product. 6% DMSO was
used in the PCR reaction. bp= basepairs. 500 bp
100 bp
1000 bp
M
1
2
3 500 bp
100 bp
000 bp
M
1
2
3 500 bp
100 bp
1000 bp
M
1
2
3 DNA extraction The DNA was extracted by following the
procedure described in Li et al. (2005). Each
of
mosquito
specimens
were
individually
homogenized in 50 µl of TE buffer consisting
of 10 mM Tris-HCl, 1mM EDTA, pH 8. These 94 Jurnal Entomologi Indonesia, September 2013, Vol. 10, No. 2, 93-97 ITS2 product. Figure 1 shows that amplification of
ITS2 had DMSO optima in 6% and 7%. tubes were incubated at 100 °C for 10 minutes
and centrifuged at 9,500 rpm for 10 minutes. Supernatant was transferred to new tube and stored
at -20 °C for further use. DNA from individual mosquitoes was used as
a template for PCR amplification of the ITS2 after
35 cycles delivered products of approximately
750 bp (Figure 2 lane 3). Species-specific banding
patterns were generated from an Msp I digestion
using one-fifth of the PCR mixture and could be
visualized on a 2% agarose gel containing ethidium
bromide. All the above samples produced bands
at ≈ 300, 190, and 150-bp. (Figure 2 lane 1-2). RESULTS AND DISCUSSION Various concentration of DMSO (4%, 6%,
7%, 8% and 10%) were investigated to define
conditions resulting consistent amplification of 95 Suyono et al.: Effect of DMSO on ITS2 amplification complex, An. funestus group and An. minimus
group could be amplified without addition of
DMSO in PCR (Djadid et al. 2007; Garros et al. 2004; Van Bortel et al. 2000), because the ITS2
from these species has slightly low GC content,
e.g. the ITS2 of An. maculipennis complex has a
GC content of 49.33-54.76% (Djadid et al. 2007). Therefore, the finding in this experiment may be
applied by researcher who will do research on the
An. punctulatus group. Molecular identification of An. farauti from the
colony maintained at BATAN Jakarta using PCR-
RFLP is An. farauti sensu stricto (formerly An. farauti No.1), confirming the PCR-RFLP result by
Beebe & Saul (1995). Molecular identification of An. farauti from the
colony maintained at BATAN Jakarta using PCR-
RFLP is An. farauti sensu stricto (formerly An. farauti No.1), confirming the PCR-RFLP result by
Beebe & Saul (1995). Amplification of ITS2 occurred at 6 % and 7% of
DMSO. The PCR products of ITS2 approximately
750 bp size. The PCR product of ITS2 also was
detected at 10% DMSO with faint band. This
result showed that the apparent inhibitory effect
of increasing DMSO concentrations in PCR is
presumably due to the inactivation of Tag DNA
polymerase (Gelfand 1989), so that more enzymes
were required. In this study, 6% DMSO can be
used to amplify PCR products ITS2 required 1.25
U Tag polymerase, but another study by Beebe &
Saul (1995) showed that used 10% DMSO for ITS2
amplification was required more Tag polymerase
enzyme concentration (2.5 U). PCR-RFLP analysis based on the ITS2 region
of the rDNA is successfully applied to mosquito
colony from BATAN, although that technique has
been modified by Suyono et al. (2011). Molecular
identification result is An. farauti sensu stricto
(formerly An. farauti 1) which belongs to An. farauti complex included in An. punctulatus group. Sibling species within An. farauti complex are
very similar and can only be rediably differentiated
by allozyme and DNA-based technology (Folley
et al. 1993 cit Mueller et al. 2002; Beebe & Saul
1995). At present there is no reliable way of
morphollogically identifying any of the members
of An. punctulatus group and identification using
proboscis morphology should be approached with
great caution (Beebe et al. 2000a). RESULTS AND DISCUSSION y
(
)
DMSO is an organosulfur compound with a
high polarity and high dielectric constant, that is
used in PCR to facilitate strand separation of double
helix DNA by altering its melting characteristics,
especially acts by disrupting inter and intrastrand
re-annealing and then to disrupt secondary
structure formation in the DNA template (Simon
et al. 2009; Jansen et al. 2010). This is particularly
useful in templates with high GC content, because
the increased hydrogen bond strength increases the
difficulty of denaturing the template and causes
intermolecular secondary structures to form more
readily, which can compete with primer annealing
(Chakrabarti & Schutt 2001). Thus the addition of
DMSO can greatly improve yields and specificities
of PCR priming reactions. DMSO concentration is an important factor
in the PCR reaction to amplify ITS2 of An. punctulatus group. DMSO could be used in PCR
to relieve secondary structures when amplifying
high GC templates. Molecular identification of
An. farauti from the colony maintained at BATAN
Jakarta using PCR-RFLP of ITS2 revealed to be
Anopheles farauti sensu stricto (formerly An. farauti 1). The effect of DMSO that we observed in this
study may be related in part to the destabilizing
influence of DMSO on dsDNA. The presence of a
high GC ratio would stabilize dsDNA in both PCR
products and intramolecular secondary structures,
and could inhibit the PCR. Moreover Bower et al. (2009) reported that the GC ratio ITS2 from An. punctulatus group varied between 64-71.3%. The
5’ end of ITS2 usually has multiple tandem copies
of G-C rich repeat (63.5-73%), 109-188 bp that
folds into a conserved stem structure. REFERENCES Gelfand DH. 1989. Thermus aquaticus DNA
polymerase. In: Erlich HA, Gibbs R, Kazazian
HH. (Eds.),
Current
Communications
in
Molecular
Biology:
Polymerase
Chain
Reactions. pp. 11-17. New York: Cold Spring
Harbor Laboratory, Cold Spring Harbor. Beebe NW, Cooper RD, Morrison DA, Ellis JT. 2000a. A phylogenetic study of Anopheles
punctulatus group of malaria vectors comparing
rDNA sequence alignments derived from the
mitochondrial and nuclear small ribosomal
subunits. Molecular Phylogenetics and Evolution
17:430-436. doi:
http://dx.doi.org/10.1006/
mpev.2000.0853. Jansen MA, Fukushima M, Davis RW. 2010. DMSO
and Betanine greatly improve amplification of
GC-rich construct in de novo synthesis. PLoS
ONE 5:e11024. doi: http://dx.doi.org/10.1371/
journal.pone.0011024. Beebe NW, Cooper RD, Morrison DA, Ellis JT. 2000b. Subset partitioning of the ribosomal DNA
small subunit and its effect on the phylogeny
of the Anopheles punctulatus group. Insect
Molecular Biology 9:515-520. doi: http://dx.doi. org/10.1046/j.1365-2583.2000.00211.x. Li C, Lee JS, Groebner JL, Kim HC, Klein TA,
O’Guinn ML, Wilkerson RC. 2005. A newly
recognized in Anopheles Hyrcanus Group and
molecular identification of related species from
the Republic South Korea (Diptera: Culicidae). Zootaxa 939:1-8. Beebe NW, Saul A. 1995. Discrimination of all
members of the Anopheles punctulatus complex
by
polymerase
chain
reaction-restriction
fragment
length
polymorphism
analysis. American Journal of Tropical Medicine and
Hygiene 53:478-481. Mueller I, Taime J, Ibam E, Kundi J, Lagog M,
Bockarie M and Reeder JC. 2002. Complex
patterns of malaria epidemiology in the highland
region of Papua New Guinea. Papua New Guinea
Medical Journal 45:200-205. Schmidt ER, Foley DH, Bugoro H, Bryan JH. 2003. A morphological study of the Anopheles
punctulatus group (Diptera: Culicidae) in the
Solomon Islands, with a description of Anopheles
(Cellia) irenicus Schmidt, sp.n. Bulletin of
Entomological Research 93:515-526. doi: http://
dx.doi.org/10.1079/BER2003267. Benet A, Mai V, Bockarie V, Lagog M, Zimmerman
P, Alpers MP, Reeder JC, Bockarie MJ. 2004. Polymerase chain reaction diagnosis and the
changing pattern of vector ecology and malaria
transmission dynamic in Papua New Guinea. American Journal of Tropical Medicine and
Hygiene 71:277-284. Simon LS, Grierson LM, Naseer Z, Bookman AA,
Shainhouse JZ. 2009. Efficacy and safety of
topical diclofenac containing dimethyl sulfoxide
(DMSO) compared with those of topical placebo,
DMSO vehicle and oral diclofenac for knee
osteoarthritis. Pain 143:238-245. doi: http://
dx.doi.org/10.1016/j.pain.2009.03.008. Bower JE, Cooper RD, Beebe NW. 2009. Internal
repetition and intravidual variation in the rDNA
ITS1 of the Anopheles punctulatus Group
(Diptera: Culicidae) multiple unit and rate
turnover. Journal of Molecular Evolution. 68:66-
79. ACKNOWLEGMENTS We appreciate the assistance of Drs Nigel
W. Beebe and Michael J. Bangs for their advice
and suggestion to this research. We also like to
thank Mr. Tony Ruwaedi for technical work in
the laboratory and Mr. Ali Rahayu for providing
us with mosquito’s laboratory colony in BATAN. This study was a part of the research project funded
by DGHE Republic of Indonesia. The ITS2 from several anophelines, e.g. sibling species of the members of An. maculipennis 96 Jurnal Entomologi Indonesia, September 2013, Vol. 10, No. 2, 93-97 REFERENCES doi: http://dx.doi.org/10.1007/s00239-008-
9188-z Suyono IJ, Rarastoeti, Hidayat RC, Situmorang J. 2011. Pengembangan PCR-RFLP berdasarkan
ITS2 rDNA untuk identifikasi spesies sibling
anggota Anopheles punctulatus group dari
Papua. Vektora 3:44-53. Chakrabarti R, Schutt CE. 2001. The enhancement
of PCR amplification by low molecular-weight
sulfones. Gene 274:293-298. doi: http://dx.doi. org/10.1016/S0378-1119(01)00621-7. Djadid ND, Gholizadeh S, Tafsiri E, Romi R, Gordeev
M, Zakeri S. 2007. Molecular identification of
Paleartic members of Anopheles maculipennis in
northern Iran. Malaria Journal 6:6. doi: http://
dx.doi.org/10.1186/1475-2875-6-6. Van Bortel W, Trung HD, Roelants P, Harbach RE,
Backeljau T, Coosemans M. 2000. Molecular
identification of Anopheles minimus s.l. beyond
distinguishing the members of the species
complex. Insect Molecular Biology 9:335-
340. doi: http://dx.doi.org/10.1046/j.1365-
2583.2000.00192.x. Garros C, Koekemoer LL, Coetzee M, Coosemans
M, Manguin S. 2004. A single multiplex assay to
identify major malaria vectors within the African
Anopheles funestus group and the oriental An. minimus groups. American Journal of Tropical
Medicine and Hygiene 70:583-590. 97
|
https://openalex.org/W3087997050
|
https://link.springer.com/content/pdf/10.1007/s40747-020-00189-6.pdf
|
English
| null |
A comparative study of social group optimization with a few recent optimization algorithms
|
Complex & intelligent systems
| 2,020
|
cc-by
| 27,346
|
Complex & Intelligent Systems (2021) 7:249–295
https://doi.org/10.1007/s40747-020-00189-6 Complex & Intelligent Systems (2021) 7:249–295
https://doi.org/10.1007/s40747-020-00189-6 ORIGINAL ARTICLE ORIGINAL ARTICLE Abstract From the past few decades, the popularity of meta-heuristic optimization algorithms is growing compared to deterministic
search optimization algorithms in solving global optimization problems. This has led to the development of several optimiza-
tion algorithms to solve complex optimization problems. But none of the algorithms can solve all optimization problems
equally well. As a result, the researchers focus on either improving exiting meta-heuristic optimization algorithms or intro-
ducing new algorithms. The social group optimization (SGO) Algorithm is a meta-heuristic optimization algorithm that was
proposed in the year 2016 for solving global optimization problems. In the literature, SGO is shown to perform well as
compared to other optimization algorithms. This paper attempts to compare the performance of the SGO algorithm with
other optimization algorithms proposed between 2017 and 2019. These algorithms are tested through several experiments,
including multiple classical benchmark functions, CEC special session functions, and six classical engineering problems etc. Optimization results prove that the SGO algorithm is extremely competitive as compared to other algorithms. Keywords Meta-heuristic · Benchmark functions · Optimization algorithms · Fitness evaluations Abbreviations the search in some promising areas. Flexibility and gradient-
free approaches are the two main characteristics that make
meta-heuristic strategies exceedingly popular for optimiza-
tion researchers. From 1960s till date, several meta-heuristic
optimization algorithms have been proposed. According to
no-free-lunch (NFL) [1] theorem for optimization, none
of the algorithms could solve all classes of optimization
problems. This motivated many researchers to design new
algorithms or modify/hybridize existing algorithms to solve
different problems or provide competitive results, as com-
pared to the current algorithms. Pop_size
Population size
Max_FEs Maximum number of function evaluations
Fes
Function evaluations
RS test
Wilcoxon’s rank-sum test A comparative study of social group optimization with a few recent
optimization algorithms Anima Naik1 · Suresh Chandra Satapathy2 Received: 22 January 2020 / Accepted: 17 August 2020 / Published online: 23 September 2020
© The Author(s) 2020 2
School of Computer Engineering, KIIT Deemed To Be
University, Bhubaneswar, Odisha, India 1
Department of CSE, KL University, Hyderabad, Telangana,
India B Anima Naik
animanaik@klh.edu.in
Suresh Chandra Satapathy
suresh.satapathyfcs@kiit.ac.in
1
Department of CSE, KL University, Hyderabad, Telangana,
India
2
School of Computer Engineering, KIIT Deemed To Be
University, Bhubaneswar, Odisha, India Introduction The meta-heuristic optimization algorithm is a practical
approach for solving global optimization problems. It is
mainly based on simulating nature and artificial intelligence
tools, invokes exploration and exploitation search procedures
to diversify the search all over the search space and intensify Meta-heuristic algorithms can be classified into mainly
four categories: (a) evolutionary-based algorithm, (b) swarm
intelligence-based algorithm, (c) human-based algorithm,
and (d) physics and chemistry-based algorithm. Evolution-
ary algorithms mimic concepts of evolution in nature. The
genetic algorithm (GA) [2] is the best example of an evolu-
tionary algorithm that simulates the concepts of Darwinian
theory of evolution. After that several other evolutionary
algorithms have been proposed such as evolutionary strat-
egy (ES) [3], and evolutionary programming (EP) [4], gene
expression programming (GEP) [5, 6], genetic programming
(GP) [7], covariance matrix adaptation evolution strategy B Anima Naik
animanaik@klh.edu.in
Suresh Chandra Satapathy
suresh.satapathyfcs@kiit.ac.in 123 123 Complex & Intelligent Systems (2021) 7:249–295 250 CMA-ES) [8], differential evolution (DE) [9], biogeography-
based optimization (BBO) algorithm [10]. cycle algorithm(WCA) [74]. Spiral optimization (SO) [75],
river formation dynamics (RFD) [76], sine cosine algorithm
(SCA) [77], multi verse optimizer (MVO) [78], lightning
attachment procedure optimization (LAPO) [79], golden
ratio optimization method (GROM) [80]. Swarm intelligence algorithms mimic the intelligence of
swarms. Each swarm consists of a group of creatures. So,
these algorithms originate from the collective behaviour of
a group of creatures in the swarm. Many swarm intelligence
algorithms are seen in the literature. These are particle swarm
optimization (PSO) [11] inspired by bird flocking, ant colony
optimization (ACO) [12] inspired by Ants behaviour while
collecting food, artificial bee colony (ABC) [13] mimicked
by Honey bee for collecting nectar, etc. Additionally, there
are many more algorithms such as bacterial foraging(BF)
[14], bat algorithm (BA) [15], firefly algorithm (FFA) [16],
krill herb (KB) [17], cuckoo search (CS) [18], monkey search
(MS) [19], bee colony optimization (BCO) [20], cat swarm
[21], wolf search (WS) [22], ant lion optimizer (ALO) [23],
grey wolf optimization (GWO) [24], whale-optimization
algorithm (WOA) [25], crow search algorithm (CSA) [26],
Salp swarm algorithm (SSA) [27], grasshopper optimiza-
tion algorithm (GOA) [28], butterfly optimization algorithm
(BOA) [29], squirrel search algorithm (SSA) [30], Harris
Hawks optimization (HHO) [31]. p
Meta-heuristic algorithms are extensively recognized as
effective approaches for solving large-scale optimization
problems (LOPs). These algorithms provide effective tools
with essential applications in business, engineering, eco-
nomics, and science. Introduction Recently, many researchers of meta-
heuristic algorithm have paid their attention to the solution
of large-scale optimization problems [81]. However, the stan-
dard metaheuristic algorithms for solving LOPs suffer from
a main deficiency which is the curse of dimensionality, i.e.,
the performance of algorithms deteriorates when dimen-
sion of problems increases. There are two major reasons for
the performance deterioration of these algorithms: Firstly,
increasing size of the problem dimension increases its land-
scape complexity and characteristic alteration. Secondly, the
search space exponentially increases with the problem size;
so, an optimization algorithm must be able to explore the
entire search space efficiently; which is not a trivial task. It
is motivating to consider these reasons and difficulties while
proposing new approaches of tackling LOPs [82]. The exist-
ing algorithms for LOPs can be mainly classified into the
following two categories [83]: (1) the cooperative coevo-
lution methods for LOPs, (2) the methods with learning
strategies for LOPs. Since several real-world applications
are considered as optimization of a large number of vari-
ables, various meta-heuristic algorithms have been proposed
to handle the large-scale optimization problems [84–89]. Human based algorithms are mainly inspired by behav-
iors of human. Some of the popular algorithms are
teaching–learning-based optimization (TLBO) [32], har-
mony search (HS) [33], Tabu (Taboo) search (TS) [34–36],
group search optimizer (GSO) [37, 38], imperialist compet-
itive algorithm (ICA) [39], league championship algorithm
(LCA) [40], firework algorithm [41], colliding bodies opti-
mization (CBO) [42], interior search algorithm (ISA) [43],
mine blast algorithm (MBA) [44], soccer league competi-
tion (SLC) algorithm [45], seeker optimization algorithm
(SOA) [46], social-based algorithm (SBA) [47], exchange
market algorithm (EMA) [48], and group counselling opti-
mization (GCO) algorithm [49, 50], social emotional opti-
mization (SEO) [51], ideology algorithm (IA) [52], social
learning optimization (SLO) [53], social group optimization
(SGO) [54, 55], election algorithm (EA) [56], cultural evo-
lution algorithm (CEA) [57], cohort intelligence (CI) [58],
anarchic society optimization (ASO) [59], volleyball premier
league algorithm (VPL) [60], socio evolution and learning
optimization algorithm (SELO) [61]. In the real world, it is common to face an optimization
problem with more than three objectives. Such problems
are called many-objective optimization problems (MaOPs)
that pose great challenges to the area of evolutionary com-
putation. The failure of conventional Pareto based multi-
objective evolutionary algorithms in dealing with MaOPs
motivates various new approaches. Deb et al. 123 Introduction [90] sug-
gest a reference-point-based many-objective evolutionary
algorithm following NSGA-II framework that emphasizes
population members that are nondominated, yet close to a
set of supplied reference points. This approach is applied
to several many-objective test problems and gets satisfac-
tory results to all problems [90]. Lin et al. propose a
balanceable fitness estimation method and a novel velocity
update equation to compose a novel multi-objective particle
swarm optimization algorithm to address the (MaOPs) [91]. Achieving a balance between convergence and diversity in
many-objective optimization is a great challenge. Liu et al. suggest an evolutionary algorithm based on a region search
strategy that enhances the diversity of the population with-
out losing convergence [92]. A hybrid evolutionary algorithm
based on knee points and reference vector adaptation strate- Physical and chemical based algorithms are inspired by
physical rules and chemical reactions of the universe. Some
popular algorithms are simulated annealing (SA) [62], grav-
itational local search (GLSA) [63], big-bang big-crunch
(BBBC) [64], gravitational search algorithm (GSA) [65],
charged system search (CSS) [66], central force optimiza-
tion (CFO) [67], artificial chemical reaction optimization
algorithm (ACROA) [68], black hole (BH) algorithm [69],
ray optimization (RO) [70] algorithm, small-world optimiza-
tion algorithm (SWOA) [71], galaxy-based-search algorithm
(GbSA) [72], curved space optimization (CSO) [73], water 123 251 Complex & Intelligent Systems (2021) 7:249–295 gies (KnRVEA) is proposed to improve the convergence of
solution where a novel knee adaptation strategy is introduced
to adjust the distribution of knee points [93]. A new differ-
ential evolution algorithm (NSDE-R) capable of efficiently
solving many-objective optimization problems, where the
algorithms make use of reference points evenly distributed
through the objective function space to preserve diversity
and aid in multi-criteria-decision making was thus proposed
[94]. Generally, the methods proposed for solving MaOPs
can be roughly classified into three categories [95]. These
are (1) multi/many-objective optimization algorithms based
on dominance relationships. (2) multi/many-objective opti-
mization algorithms based on decomposition strategy and
(3) indicator-based evolutionary algorithms. The applica-
tion of many-objective optimization can be demonstrated
in stormwater management project selection, encouraging
decision-maker buy-in [96]. Additionally, the application
can also be seen in mixed-model disassembly line balanc-
ing along with multi-robotic workstation [97]. that were developed from 2017 to 2019. The GOA algorithm
mimics the behavior of grasshopper swarms and their social
interaction. Applications of the GOA algorithm are elabo-
rated in papers [110–115]. Introduction The SSA algorithm is inspired by
the swarming behavior of salps when navigating and foraging
in oceans. In [116–121], applications of SSA are highlighted. The LAPO algorithm is based on the concepts of the light-
ning attachment procedure. The application of LAPO is seen
in paper [122–125]. The GROM algorithm is inspired by the
golden ratio of plant and animal growth. The BOA algorithm
mimics the food search and mating behavior of butterflies. The SSOA algorithm imitates dynamic foraging behavior of
southern flying squirrels and their efficient way of locomo-
tion. The HHO algorithm is based on cooperative behavior
and the chasing style of Harris’ hawks in nature. The VPL
algorithm is inspired by competition and interaction among
volleyball teams during a season. It also mimics the coaching
process during a volleyball match. The SELO algorithm is
inspired by the social learning behavior of humans organized
as families in a societal setup. Many real-world optimization problems are challeng-
ing because the evaluation of solutions is computationally
expensive. For those expensive problems, there are three
kinds of models utilized in the meta-heuristic algorithms,
i.e., the global model, the local model, and the surrogate
ensembles [98]. Surrogate-assisted evolutionary algorithms
are promising approaches to tackle this kind of prob-
lems. They use efficient computational models, known as
surrogates, for approximating the fitness function in evolu-
tionary algorithms. These are found successful applications
not only in solving computationally expensive single or
multi-objective optimization problems but also in address-
ing dynamic optimization problems, constrained optimiza-
tion problems, and multi-modal optimization problems. Surrogate models have shown to be effective in assist-
ing meta-heuristic algorithms for solving computationally
expensive complex optimization problems. Examples of
some surrogate-assisted optimization algorithms for expen-
sive optimization problems can be found in [99–103]. In this paper, we have compared the performance of
those nine algorithms developed between 2017 and 2019, to
SGO, which exhibit similar characteristics. These algorithms
are tested through several experiments using many classical
benchmark functions, CEC special session functions, and
six classical engineering design problems. The results of the
experiments are tabulated, and inferences are drawn in con-
clusion. The remaining paper is organized as follows: In "Prelim-
inaries of SGO, SSA, GOA, LAPO, GROM, BOA, SSOA,
VPL, HHO, and SELO", all algorithms are briefly summa-
rized. In "Simulation and experimental results", simulation
and experimental results are discussed, and the paper con-
cludes with "Conclusion". Preliminaries of SGO, SSA, GOA, LAPO,
GROM, BOA, SSOA, VPL, HHO, and SELO In the year 2017–2019, some of the popular meta-heuristic
algorithms were proposed. Those are Salp swarm algorithm
(SSA), grasshopper optimization algorithm (GOA), light-
ning attachment procedure optimization (LAPO), golden
ratio optimization method (GROM), butterfly optimization
algorithm (BOA), squirrel search optimization algorithm
(SSOA), Harris Hawks optimization (HHO), volleyball pre-
mier league algorithm (VPL), socio evolution and learning
optimization algorithm (SELO). SGO algorithm was pro-
posed in the year of 2016 by Satapathy et.al. The SGO
algorithm is based on the social behavior of humans for solv-
ing a global optimization problem. Applications of the SGO
algorithm are discussed in papers [104–109]. In this work,
the authors plan to have an exhaustive comparative analy-
sis with SGO, their own proposed algorithm, and algorithms 123 Algorithm: SGO Algorithm Start Assume the N person
(i = 1,2,………,N) in D-dimensional search space,
Randomly distribute the entire persons in the group throughout the search space during
initialization process. Compute fitness value
for each person
based on the problem under concern Step 1: Find the best person ‘gbest’ in the group
[minvalue, index]=min
gbest= (index,:)
for solving the minimization problem Step 3: Initiate acquiring phase to further update knowledge of a person by randomly choosing a person from
the group and following the ‘gbest’. Step 3: Initiate acquiring phase to further update knowledge of a person by randomly choosing a person from
the group and following the ‘gbest’. Step 4: if
all persons have approximately similar to fitness values or reach termination criterion
then
terminate the search and display the optimized result for the chosen problem
else
goto step 2. endif Step 4: if
all persons have approximately similar to fitness values or reach termination criterion
then
terminate the search and display the optimized result for the chosen problem
else
goto step 2. endif fixed dimensional and composite benchmark functions. In
the second experiment, BOA is compared with the SGO
algorithm using thirty classical benchmark functions. In the
third experiment, SSOA is compared with the SGO algorithm
using twenty-six classical benchmark functions, and seven
functions are taken from the CEC 2014 special session. In
the fourth experiment, VPL is compared with the SGO algo-
rithm using twenty-three classical benchmark functions. In
the fifth experiment, SELO is compared with the SGO algo-
rithm using fifty classical benchmark functions. In the sixth
experiment, HHO, SSA, and GOA algorithms are compared
with the SGO algorithm using twenty-nine classical bench-
mark functions. The selections of the batch of algorithms
are made based on the benchmark functions experiments
which have been made by reference papers and the avail-
ability of results. In the seventh experiment, all algorithms
are compared with each other by considering six classical
engineering problems. SSA, GOA, LAPO, GROM, BOA, SSOA, VPL, HHO
and SELO algorithms Preliminaries of the above-listed algorithms can be found in
the literature. The SSA can be referred to in [27]; the basic
of GOA is in [28], BOA is well described in [29]. The basic
of SSOA is in [30]. The basic of HHO is in [31], and basic of
VPL is in [60]. SELO, LAPO, and GROM can be followed
in [61, 79, 80], respectively. Social group optimization (SGO) algorithm The SGO algorithm is based on the social behavior of human
to solve complex problems. Each person represents a candi-
date solution empowered with some information (i.e., traits)
and has an ability to solve a problem. The human traits repre-
sent the dimension of the person, which in turn represents the
number of design variables of the problem. This optimiza-
tion algorithm goes through two-phase: improving phase
and acquiring phase. In the improving phase, an individual’s
knowledge (solution) level is improved based on the best
individual influence. In the acquiring phase, the individual’s
knowledge (solution) level is improved by mutual interac-
tion between individuals and the person who has the highest 123 123 252 Complex & Intelligent Systems (2021) 7:249–295 conducted with all nine algorithms with SGO. In the first
experiment, the LAPO and GROM algorithms are compared
with the SGO algorithm by considering twenty-nine bench-
mark functions in a combination of unimodal, multimodal, knowledge level, as well as the ability to solve the problem
under consideration. However, for a detailed description of
SGO, anyone’s paper can be referred to [54, 55]. Algorithm
1 details the flow of SGO. 123 123 Simulation and experimental results We have carried out an extensive comparison of SGO with
the other nine algorithms. Individually, six experiments have
been conducted batch-wise, on selecting a few algorithms out
of nine algorithms; they are compared with SGO. Finally,
in the last experiment, an overall comparison analysis is 123 123 Complex & Intelligent Systems (2021) 7:249–295 253 Fig. 1 Figure of benchmark functions Fig. 1 Figure of benchmark functions performance of algorithms, twenty-nine classical benchmark
functions are considered. Out of which seven are unimodal
benchmark-functions. The unimodal functions (F1–F7) are
suitable for benchmarking the exploitation of algorithms
since they have only one global optimum. Six are multimodal
benchmark-functions and, ten are fixed-dimensional multi-
modal benchmark-functions. Each multimodal function from
F8–F23 has massive numbers of local optima. These func-
tions are considered to examine the exploration capability of
algorithms. There are six composite benchmark functions. The composite benchmark-functions (F24–F29) are consid-
ered from CEC 2005 special session [126]. These benchmark
functions are kept for judging the capability of the algorithm
for the proper balance between exploration and exploitation
search to avoid local optima and are described in Appendix
A with illustrations in Fig. 2. To compare the performance, the SGO algorithm is imple-
mented by us and, the results of all other algorithms are taken
from their respective papers (Fig. 1). “For comparing the speed of the algorithms, the first thing
we require is fair time measurement. The number of itera-
tions or generations cannot be accepted as a time measure
since the algorithms perform the different amount of works
in their inner loops, and they have different population sizes
(pop_sizes). Hence, we choose the number of fitness function
evaluations (FEs) as a measure of computation time instead
of generations or iterations” [54]. Since meta-heuristic algo-
rithms are stochastic in nature, the results of two successive
runs usually do not match. Hence, we have taken different
independent runs (with different seeds of random number
generator) of each algorithm and find out the best function
value, mean function value, and standard deviation and put
in tables in each experiment. For comparing the performance
of algorithms, different tests have been conducted in experi-
ments. In our experiment test functions are solved for two cases,
low dimensional and high dimensional. SGO algorithm is
implemented in MATLAB 2016a. Experiments are con-
ducted on an Intel Core i5, 8 GB RAM, and Windows 10
environment. Simulation and experimental results For the LAPO, results are taken from [79], and
for the GROM algorithm, the results are taken from [80]. 123 Experiment 1 In this experiment, LAPO and GROM algorithms are com-
pared with the SGO algorithm. For comparison of the For low dimensional cases, the common control parameter
such as pop_size is set to 40, maximum iteration is 500, and 123 123 254 Complex & Intelligent Systems (2021) 7:249–295 Fig. 2 a Schematic of the spring; b stress distribution evaluated at the optimum design; and c displacement distribution evaluated at the optimum
design Fig. 2 a Schematic of the spring; b stress distribution evaluated at the optimum design; and c displacement distribution evaluated at the optimum
design Max_FEs is set to 40,000. The other specific parameters for
each algorithm are given below. shown excellent performance in exploitation capability and
convergence characteristic. It has also successfully overcome
to solve all the problems within this category except F5. It is
clear from results that SGO achieves success in finding global
optimum on F1, F2, F3, and F4 within 40,000 max_FEs. For
F1, F2, F3, F4, F6, F7, the performance of SGO is better
than LAPO and GROM algorithm, whereas, for F5, the per-
formance of LAPO and GROM algorithm is far better than
SGO. From Table 1, we find that out of seven unimodal test
functions according to the WRS test, SGO performs superior
to LAPO and GROM in six test functions and worse in one
test function. • SGOsetting:ForSGO,thereisonlyoneparameterCcalled
a self-introspection factor. The value of C is empirically
set to 0.2. • LAPO settings: There is no such specific parameter to set
value. • GROM settings: There is no such specific parameter to set
value. For each benchmark function, algorithms are run 30 times
with different randomly generated populations. Statistical
results in terms of best value, mean value, and correspond-
ing standard deviation are reported in tables. Table 1 is for
unimodal benchmark-functions. Table 2 is for multimodal
benchmark-functions. Table 3 is for fixed dimensional multi-
modal benchmark-functions and, Table 4 is for the composite
benchmark. The multimodal functions test functions F8–F13 are ben-
eficial, while the exploration capability of the optimization
algorithm is considered. Form Table 2, results show that the
SGO algorithm is eligible for solving problems with chal-
lenging search space. In this case, SGO has demonstrated
excellent performance in comparison, and it has reached to
first rank among algorithms. Table 2 shows that SGO has con-
sistently performed better than other algorithms. Experiment 1 SGO has
an excellent performance in exploration, and it successfully
overcomes to solve all the problems within this category. It
is clear from table results that both SGO and GROM achieve
success in finding global optimum on F9 and F11, and for
F10, find equivalent results. From Table 2, we get that out
of six multimodal test functions according to the WRS test,
SGO performs superior to LAPO in all six test functions and
superior to GROM in three test functions and equivalent in
three test functions. For the high dimensional case, the 200-dimensional ver-
sion of unimodal, multimodal functions are solved in two
cases. In case 1, pop_size is taken as 200, and the maximum
iteration is 2000, and the results are given in Table 5. In case
2, pop_size is taken as 40, and the maximum iteration is 500,
and the results are given in Table 6. The idea is to see how
the algorithms behave for high dimensions in a large popu-
lation with more iteration, and relatively small populations
with less iteration. For every benchmark function, the best
results have been put in bold letters in the result table. The fixed-dimensional multimodal functions are designed
to have many local optimal where computation complexity
increases drastically with the increase of the problem size. The results reported from Table 3 for functions F14-F23 indi-
cate that SGO has an excellent exploration capability except
for the shekel family (F21, F22, F23) that SGO has. It is
clear from tabular results that the SGO algorithm achieves
success in finding a global optimum on F14–F20. In con-
trast, GROM achieves success in F16–F19, F21–F23, and
LAPO achieves success in F4, F16, F18, and F19 in find-
ing a globally optimal solution. GROM achieves success in
finding an optimum solution on the shekel family only. The To obtain statistically sound conclusions, Wilcoxon’s
rank-sum (WRS) test at a 0.05 significance level is con-
ducted on experimental results, and the last three rows of
each respective table summarize experimental results. 123 Discussion The unimodal functions have only one global optimum. These functions allow evaluating the exploitation capabil-
ity of the investigated meta-heuristic algorithms. As seen
in Table 1, SGO has gained the best performance, and it
has reached to first rank among other algorithms. SGO has 123 123 Complex & Intelligent Systems (2021) 7:249–295 255 e 1 Unimodal benchmark
tion on 30 repetitions
Functions
LAPO
GROM
SGO
Results
WRS Test
Results
WRS Test
results
F1
Best
1.3406e−15
–
0
−
0
Mean
2.0664e−13
3.1350e−247
0
Std
5.5098e−13
6.5961e−251
0
F2
Best
4.2412e−9
−
2.8836e−53
−
0
Mean
2.2547e−8
1.367e−52
0
Std
1.7473e−8
9.173e−53
0
F3
Best
4.1270e−7
−
0
−
0
Mean
1.1385e−5
3.398e−87
0
Std
3.6624e−5
9.6154e−87
0
F4
Best
2.7951e−7
−
7.155e−145
−
0
Mean
4.3915e−7
1.118e−131
0
Std
1.3825e−7
3.0352e−132
0
F5
Best
19.5667
+
18.46243
+
22.4419
Mean
22.7427
19.12
24.1058
Std
0.6846
0.6160
0.6143
F6
Best
1.3619e−6
−
1.594e−7
−
1.7698e−12
Mean
1.1151e−5
3.9096e−7
4.0337e−08
Std
1.0200e−5
3.573e−7
9.9545e−08
F7
Best
1.3323e−4
−
2.677e−5
−
4.5252e−06
Mean
7.1418e−4
0.000131
3.0393e−05
Std
4.3695e−4
4.7138e−5
1.7084e−05
Total +
01
01
Total −
06
06
Total ≈
00
00
“−”, “+” and “≈” denote that performance of LAPO and GROM is worse, better and similar to SGO,
respectively “−”, “+” and “≈” denote that performance of LAPO and GROM is worse, better and similar to SGO,
respectively results for LAPO on the shekel family are better than the
SGO algorithm. From Table 3, as per WRS test, we find that
out of ten fixed dimensional multimodal test functions, SGO
performs superior to LAPO in two test functions, worse in
three test functions, and equivalent with five tests functions. Again SGO performs superior to GROM in two test func-
tions, worse in three test functions and equivalent with five
test functions. of the algorithms achieve success in finding the global opti-
mal solution. However, LAPO and GROM find a superior
solution than then SGO algorithm in solving F24, F25, and
F28, whereas SGO finds superior solution then LAPO and
GROM in solving F26, F27, and F29 benchmark functions. From Table 4, it is seen that out of six composite test func-
tions according to the WRS test, SGO performs superior to
LAPO and GROM in three test functions, worse in three test
functions. 123 Discussion The composite functions are well enough to judge the
ability to escape from local minima of a meta-heuristics
optimization algorithm. Optimization of composite mathe-
matical functions is a challenging task because only a proper
balance between exploration and exploitation allows local
optima to be avoided. The results in Table 4 show that none In Tables 5 and 6, seven unimodal and six multi-
modal functions are considered for judging high dimensional
parameter optimizations among SGO, LAPO, and GROM
algorithm by considering 200 dimensions. Table 5 is for the
results of pop_size 200 and 2000 iteration, and Table 6 is for 123 Complex & Intelligent Systems (2021) 7:249–295 256 Table 2 Multimodal benchmark
function on 30 repetitions
Functions
LAPO
GROM
SGO
Results
WRS test
Results
WRS test
Results
F8
Best
−1.0613e+4
−
−9467.296
−
−1.0871e+04
Mean
−1.036e+4
−9070.8
−1.0423e+04
Std
1.9994e+3
347.215
949.1964
F9
Best
0
−
0
≈
0
Mean
1.53344
0
0
Std
3.70144
0
0
F10
Best
9.5009e−9
−
8.8817e−16
≈
8.8818e−16
Mean
5.8694e−8
8.8817e−16
8.8818e−16
Std
5.0496e−8
0
0
F11
Best
1.7764e−15
−
0
≈
0
Mean
1.5914e−13
0
0
Std
2.9758e−13
0
0
F12
Best
6.8458e−9
−
3.8742e−9
−
2.4752e−13
Mean
0.0104
9.980e−9
1.8697e−10
Std
0.0311
5.7890e−9
6.1247e−10
F13
Best
5.5452e−7
−
5.2761e−7
−
2.7975e−12
Mean
0.0098
0.003506
0.00043
Std
0.0240
0.006430
0.00067
Total +
00
00
Total −
06
03
Total ≈
00
03
“ −”, “+” and “≈” denote that performance of LAPO and GROM is worse, better and similar to SGO,
respectively “ −”, “+” and “≈” denote that performance of LAPO and GROM is worse, better and similar to SGO,
respectively and superior to GROM in ten test functions and equivalent
with three test functions out thirteen test functions. the results of pop_size 40 and iterations 500. It is clear from
both tables that SGO achieves success in finding global opti-
mum on F1, F2, F3, F4, F9, and F11 in both cases. GROM
achieves success in finding global optimum on F9 and F11
in both cases. GROM and SGO find equivalent results on
F10 for both cases. SGO algorithm finds better results than
GROMonF1–F8,F12,andF13inbothcases.Inthefirstcase,
the LAPO algorithm achieves success on finding global opti-
mum for F9 and F11, it finds equivalent results as of SGO for
F10, and worse results on F1–F8, F12 and F13 compared to
SGO. Discussion However, SGO algorithm finds superior results com-
pared to LAPO for all benchmark functions F1-F13 in the
second case. Hence, from Table 5 we summarize that as per
the WRS test, SGO performs superior to LAPO and GROM
in ten test functions and equivalent on three tests out of thir-
teen test functions. And from the Table 6, as per the WRS test,
SGO performs superior to LAPO in all thirteen test functions the results of pop_size 40 and iterations 500. It is clear from
both tables that SGO achieves success in finding global opti-
mum on F1, F2, F3, F4, F9, and F11 in both cases. GROM
achieves success in finding global optimum on F9 and F11
in both cases. GROM and SGO find equivalent results on
F10 for both cases. SGO algorithm finds better results than
GROMonF1–F8,F12,andF13inbothcases.Inthefirstcase,
the LAPO algorithm achieves success on finding global opti-
mum for F9 and F11, it finds equivalent results as of SGO for
F10, and worse results on F1–F8, F12 and F13 compared to
SGO. However, SGO algorithm finds superior results com-
pared to LAPO for all benchmark functions F1-F13 in the
second case. Hence, from Table 5 we summarize that as per
the WRS test, SGO performs superior to LAPO and GROM
in ten test functions and equivalent on three tests out of thir-
teen test functions. And from the Table 6, as per the WRS test,
SGO performs superior to LAPO in all thirteen test functions Experiment 2 In this experiment, BOA (butterfly optimization algorithm)
[29] is compared with the SGO algorithm. For comparison
of the performance of algorithms, 30 classical benchmark
functions are considered. These benchmark functions are
described in appendix B. These functions are chosen from the
benchmark set proposed in [127, 128] to determine various
features of the algorithm, such as fast convergence, attain-
ment of a large number of local minima points, ability to
jump out of local optima and avoid premature convergence. BOA results are taken from paper [29], and for results of
the SGO algorithm, the codes are implemented in MATLAB
2016a. Experiments are conducted on an Intel Core i5, 8 GB
RAM, and Windows 10 environment. Experiment 2 123 Complex & Intelligent Systems (2021) 7:249–295 257 Functions
LAPO
GROM
SGO
Results
WRS test
Results
WRS test
Results
F14
Best
0.9980
≈
0.998
−
0.9980
Mean
0.9980
1.1964
0.9980
Std
5.7495e−8
0.5952
0
F15
Best
3.0749e−4
≈
3.0749e−4
≈
3.0749e−04
Mean
5.5811e−4
5.5811e−4
3.0749e−04
Std
2.2495e−4
2.83762e−19
2.1112e−15
F16
Best
−1.0316
≈
−1.0316
≈
−1.0316
Mean
−1.0316
−1.0316
−1.0316
Std
1.4460e−7
3.315148e−7
6.7752e−16
F17
Best
0.3979
−
0.397887
≈
0.3979
Mean
0.3983
0.39788
0.3979
Std
4.8405e−4
6.678e−7
0
F18
Best
3.0000
≈
2.999
≈
3.0000
Mean
3.0000
2.999
3.0000
Std
7.5626e−16
7.02166e−16
5.2804e−16
F19
Best
−3.8628
≈
−3.8627
≈
−3.8628
Mean
−3.8628
−3.862
−3.8628
Std
8.5422e−16
8.88178e−16
2.6712e−16
F20
Best
−3.3220
−
−3.3219
−
−3.3220
Mean
−3.2729
−3.29821
−3.3220
Std
0.0571
0.0475558
1.3897e−15
F21
Best
−10.1532
+
−10.153
+
−10.1532
Mean
−9.6960
−10.1531
−5.0552
Std
0.8042
7.944109e−16
1.0300e−15
F22
Best
−10.4029
+
−10.402
+
−10.4029
Mean
−10.1728
−10.402
−5.2648
Std
0.6905
1.4862e−15
0.9704
F23
Best
−10.5364
+
−10.536
+
−10.5364
Mean
−10.2295
−10.53
−5.3087
Std
0.6352
1.776e−15
0.9873
Total +
03
03
Total −
02
02
Total ≈
05
05
“−”, “+” and “≈” denote that performance of LAPO and GROM is worse, better and similar to SGO respec-
i
l Table 3 Fixed-dimensional
multimodal benchmark function
on 30 repetitions “−”, “+” and “≈” denote that performance of LAPO and GROM is worse, better and similar to SGO respec-
tively Complex & Intelligent Systems (2021) 7:249–295 258 Table 4 Composite benchmark
function on 30 repetitions
Functions
LAPO
GROM
SGO
Results
WRS test
Results
WRS test
Results
F24
Best
0
+
1.3254e−29
+
0
Mean
7.7214e−23
4.9821e−21
90.0000
Std
4.2143e−23
9.8425e−25
73.7865
F25
Best
2.7340
+
1.85201
+
5.8786
Mean
29.87214
23.75416
96.5807
Std
32.23484
19.4826
91.6926
F26
Best
116.0883
−
124.5176
−
6.9055
Mean
175.86457
165.9840
109.6482
Std
90.15781
38.4128
102.0611
F27
Best
265.2541
−
211.48966
−
100
Mean
312.145
263.7109
164.8116
Std
67.9681
48.9548
76.3725
F28
Best
0
+
0
+
18.4288
Mean
45.8928
34.41452
122.2605
Std
56.4218
29.4751
70.4767
F29
Best
500.000
−
440.9783
−
4.4439
Mean
544.8186
495.41875
93.0821
Std
119.6597
98.4126
113.6061
Total +
03
03
Total −
03
03
Total ≈
00
00
“−”, “+” and “≈” denote that performance of LAPO and GROM is worse, better and similar to SGO respec-
tively “−”, “+” and “≈” denote that performance of LAPO and GROM is worse, better and similar to SGO respec-
tively • BOA settings: Modular modality c is 0.01, and power
exponent a is increased from 0.1 to 0.3 throughout iter-
ations, p 0.8. 123 Experiment 2 These parameters are set as reported by
authors in paper [29]. For the BOA algorithm, according to parameter setting
in its paper [29], the common control parameter such as
pop_size and maximum iterations are 50 and 10,000, respec-
tively. But for the SGO algorithm, we have taken the same
pop_size, but maximum iteration is reduced to 500. This is
due to our observation of the fast convergence characteristic
of SGO. Max_FEs is set to 50,000 (2×50×500 50,000). It is due to two times fitness calculation in one iteration for
one particle in population. In this experiment, we have done
two tests. In one test, we have set common control parame-
ters the same as above, and in other, we have set pop_size is
ten and maximum iteration 500. So Max_FEs is set to 10,000
(2×10×500 10,000). The other specific parameters for
each algorithm are given below. For each benchmark function, algorithms are run 30 times
with different randomly generated populations. Statistical
results in terms of mean value, standard-deviation value,
the best value, median value, and worse value are reported
in tables. Table 9 provides results for test 1 with 50,000
max_FEs, and Table 10 presents results for test 2 with 10,000
max_FEs. For every benchmark function, the best results are
boldfaced. To obtain statistically sound conclusions, Wilcoxon’s
rank-sum test at a 0.05 significance level is conducted on
experimental results of Tables 9, 10 and put in Table 11. The
comparison results in terms of best value also are given in • SGO setting: For SGO, there is only one parameter C
called a self-introspection factor. The value of C is empir-
ically set to 0.2. • SGO setting: For SGO, there is only one parameter C
called a self-introspection factor. The value of C is empir-
ically set to 0.2. Experiment 2 123 Complex & Intelligent Systems (2021) 7:249–295 259 Functions
LAPO
GROM
SGO
Results
WRS test
Results
WRS test
Results
F1
Best
3.7643e−29
−
4.0197e−283
−
0
Mean
8.1296e−29
5.0162e−283
0
Std
3.2204e−29
0
0
F2
Best
1.4339e−15
−
1.1623e−156
−
0
Mean
1.8098e−15
1.6258e−156
0
Std
2.7520e−16
3.2777e−157
0
F3
Best
0.4160
−
1.2908e−207
−
0
Mean
2.6872
1.7886e−191
0
Std
3.5371
0
0
F4
Best
2.0925e−10
−
6.8726e−122
−
0
Mean
7.2703e−10
7.808e−122
0
Std
3.3558e−10
7.3555e−123
0
F5
Best
192.6322
−
189.62
−
183.7878
Mean
193.0862
190.04
187.0531
Std
0.3316
0.30596
1.3745
F6
Best
0.0283
−
0.14347
−
3.0886e−09
Mean
0.0412
0.203
1.4761e−05
Std
0.0072
0.064899
3.7908e−05
F7
Best
2.8619e−5
−
1.9492e−5
−
9.1045e−07
Mean
1.8284e−4
5.4613e−5
3.8285e−06
Std
1.3097e−4
1.1139e−6
1.9758e−06
F8
Best
−5.617e4
−
−55,179
−
−7.1398e+04
Mean
−5.5361e4
−53,752
−6.4767e+04
Std
527.2355
1010.1
5.9902e+03
F9
Best
0
≈
0
≈
0
Mean
0
0
0
Std
0
0
0
F10
Best
8.8817e−16
≈
8.8817e−16
≈
8.8817e−16
Mean
8.8817e−16
8.8817e−16
8.8817e−16
Std
0
0
0
F11
Best
0
≈
0
≈
0
Mean
0
0
0
Std
0
0
0
F12
Best
8.64884e−5
−
1.4254e−5
−
4.1243e−11 Table 5 Result 200 dimensional
with population size 200 and
2000 iterations Complex & Intelligent Systems (2021) 7:249–295 260 Table 5 continued Table 5 continued
Functions
LAPO
GROM
SGO
Results
WRS test
Results
WRS test
Results
Mean
1.1944e−4
5.3593e−5
4.2072e−07
Std
2.2692e−5
7.2927e−5
1.3192e−06
F13
Best
0.071735
−
0.09547
−
3.8861e−10
Mean
0.1748
1.0157
0.0030
Std
0.0712
1.4678
0.0049
Total +
00
00
Total −
10
10
Total ≈
03
03
“−”, “+” and “≈” denote that performance of LAPO and GROM is worse, better and similar to SGO,
respectively
Table 11. The last three rows of Table 11 summarize experi-
l
l
the BOA algorithm in nine functions and equivalent results in
19 f
i
f 29 b
h
k f
i
S
l i Table 11. The last three rows of Table 11 summarize experi-
mental results. the BOA algorithm in nine functions and equivalent results in
19 functions out of 29 benchmark functions. So only in one
case, SGO finds worse results than BOA. For test 2, i.e., from
Tables 10 and 11, the SGO algorithm performs better than
the BOA algorithm in nine functions and equivalent results
in 18 functions out of 29 benchmark functions. Discussion In Tables 9 and 10, for the function F22, in the place of
best value, worse value, and median value, we have put star
‘*’ because we think that these values are wrongly put in the
paper [29]. For the function F28, the minimum function value
isgivenas−1500[29].ButtheBOAalgorithmfindslessthan
that −1500 and hence a confusion arises on the minimum
value. Toavoidanyconflicts, wehaveexcludedthis result and
have put ‘*’ in Table 11. From Table 11, we see that except
for the F5 function, both Tables 9 and 10 show equivalent
results. From Tables 9 and 10, it is clear that SGO algorithm
reaches global optimum for 22 benchmark functions such as
F1–F4, F6, F8, F11–F13, F15–F24, F26, F27, F29 whereas
BOA reaches to global optimum for 18 benchmark functions
such as F1–F4, F6, F11–F13, F15–F17, F19, F21–F24, F27,
F29. SGO also shows its dominating performance in most
functions and satisfactory results in 10 functions such as F7,
F8, F9, F10, F14, F18, F20, F25, F26, and F30. For function
F26, i.e., shekel 4.5, the BOA algorithm finds superior results
than the SGO algorithm. Special attention should be paid to
the noisy (quartic) problems as these challenges frequently
occur in real-world applications. SGO provided a significant
performance boost on this noisy problem and gave an equiv-
alent solution in comparison to BOA, but the best result is
better than BOA’s best result. It is shown in Table 9. Besides
optimization accuracy, convergence speed is quite essential
to an optimizer. In this experiment, Table 9 provided the
results on 50,000 max_FES with 500 iterations as the ter-
mination criterion. Table 10 provided the results on 10,000
max_FES with 500 iterations as the termination, whereas for
BOA 10,000 iterations as the termination criterion. From the above experiment and results in discussion, it
is found that SGO outperformed than BOA, and the con-
vergence is much fast as it is evident from the maximum
numbers of FEs and iterations. Experiment 2 So only in
two cases, the SGO algorithm finds worse results than the
BOA algorithm. Similarly, when we compare the results by
considering the best results, we find that SGO performs best
in ten functions and equally well for 18 functions than BOA
in both tests. 123 Experiment 3 In this experiment, SSOA (squirrel search optimization
algorithm) [30] is compared with the SGO algorithm. For
comparison of performances of both the algorithms, 33
benchmark functions are considered. Out of these, 26 func-
tions are classical benchmark functions, and seven are taken
from CEC 2014 special session [129]. These benchmark
functions are described in Appendix C. These benchmark
functions are also described in the paper [30] and taken
from [130, 131]. Out of these 26 classical benchmark func-
tions, four are unimodal separable benchmark functions,
eight are unimodal non-separable benchmark functions, six
are multimodal separable benchmark functions, and eight are
multimodal non-separable benchmark functions. We have directly derived results of SSOA from [30], and
for results of the SGO algorithm, the codes are implemented
inMATLAB2016a.ExperimentsareconductedonIntelCore
i5, 8 GB RAM, and Windows 10 environment. Experiment 3 According to parameter settings of SSOA in its respective
paper [30], the common control parameter such as pop_size ForTest1,i.e.,fromTables9and11,accordingtotheWRS
test, it is clear that the SGO algorithm finds better results than Complex & Intelligent Systems (2021) 7:249–295 261 Functions
LAPO
GROM
SGO
Results
WRS test
Results
WRS test
Results
F1
Best
1.0288e−12
−
3.1809e−65
−
0
Mean
1.8090e−9
5.3021e−65
0
Std
6.1216e−9
1.6155e−65
0
F2
Best
2.0087e−7
−
3.7697e−36
−
0
Mean
3.5023e−6
5.2158e−36
0
Std
4.3034e−6
1.0254e−36
0
F3
Best
0.9660
−
1.1586e−62
−
0
Mean
6.7051
2.8633e−57
0
Std
5.7391
2.553e−57
0
F4
Best
9.8895e−6
−
3.8682e−30
−
0
Mean
2.4845e−5
4.0382e−30
0
Std
1.4955e−5
1.4237e−31
0
F5
Best
196.3227
−
195.44
−
194.5407
Mean
197.3273
197.6
195.2793
Std
0.5454
0.55796
0.4570
F6
Best
13.7919
−
16.756
−
0.0345
Mean
16.5038
17.942
0.2781
Std
1.3669
1.1032
0.1591
F7
Best
3.5309e−4
−
1.7976e−4
−
5.1821e−07
Mean
0.0010
2.8908e−4
2.6497e−06
Std
4.5410e−4
1.1115e−4
1.5043e−05
F8
Best
−1.5279e4
−
−15,765
−
−6.5602e+04
Mean
−1.324e4
−15,167
−5.4946e+04
Std
815.8747
430.67
5.4972e+03
F9
Best
4.5475e−13
−
0
≈
0
Mean
9.2776e−10
0
0
Std
3.6949e−10
0
0
F10
Best
7.6647e−8
−
8.8818e−16
≈
8.8818e−16
Mean
4.2081e−6
8.8818e−16
8.8818e−16
Std
2.8691e−6
0
0
F11
Best
2.8019e−12
−
0
≈
0
Mean
5.6723e−10
0
0
Std
2.8363e−10
0
0
F12
Best
0.0995
−
0.15496
−
4.0511e−04 Table 6 Result 200 dimensional
with population size 40 and 500
iterations Complex & Intelligent Systems (2021) 7:249–295 262 Table 6 continued Table 6 continued
Functions
LAPO
GROM
SGO
Results
WRS test
Results
WRS test
Results
Mean
0.0149
0.1663
0.0025
Std
0.1178
0.00805
0.0020
F13
Best
12.7156
−
12.803
−
0.0177
Mean
1.9412
12.822
0.3140
Std
15.7881
0.024253
0.3987
Total +
00
00
Total −
13
10
Total ≈
00
03
“ −”, “+” and “≈” denote that performance of LAPO and GROM is worse, better and similar to SGO,
respectively “ −”, “+” and “≈” denote that performance of LAPO and GROM is worse, better and similar to SGO,
respectively Table 7 Overall algorithms comparison on Wilcoxon’s rank-sum test using Tables 1, 2, 3 and 4
Functions
Unimodal
Multimodal
Fixed dimensional
Composite
Overall in LAPO
Overall in
GROM
LAPO
GROM
LAPO
GROM
LAPO
GROM
LAPO
GROM
Total +
01
01
00
00
03
03
03
03
7
07
Total −
06
06
06
03
02
02
03
03
17
14
Total ≈
00
00
00
03
05
05
00
00
05
08
Total
07
07
06
06
10
10
06
06
29
29
07
06
10
06
29
Table 8 Overall algorithms comparison of Wilcoxon’s rank-sum test using Tables 5 and 6
Functions
Test of 200 dimensional
with pop_size 200 and
maximum iteration 2000
Test of 200 dimensional
with pop_size 40 and
maximum iteration 500
Overall in LAPO
Overall in
GROM
LAPO
GROM
LAPO
GROM
Total +
00
00
00
00
00
00
Total −
10
10
13
10
23
20
Total ≈
03
03
00
03
03
06
Total
13
13
13
13
26
26
13
13
26 ithms comparison on Wilcoxon’s rank-sum test using Tables 1, 2, 3 and 4 Table 7 Overall algorithms comparison on Wilcoxon’s rank-sum test using Tables 1, 2, 3 and 4 Table 7 Overall algorithms comparison on Wilcoxon’s rank-sum test using Tables 1, 2, 3 and 4 Table 8 Overall algorithms comparison of Wilcoxon’s rank-sum test using Tables 5 and 6
Functions
Test of 200 dimensional
with pop_size 200 and
maximum iteration 2000
Test of 200 dimensional
with pop_size 40 and
maximum iteration 500
Overall in LAPO
Overall in
GROM
LAPO
GROM
LAPO
GROM
Total +
00
00
00
00
00
00
Total −
10
10
13
10
23
20
Total ≈
03
03
00
03
03
06
Total
13
13
13
13
26
26
13
13
26 able 8 Overall algorithms comparison of Wilcoxon’s rank-sum test using Tables 5 and 6 • SGO setting: For SGO, there is only one parameter C
called a self-introspection factor. 123 Experiment 3 The value of C is empir-
ically set to 0.2. is 50, and the maximum iteration is 500. For seven CEC2014
benchmark functions, pop_size is 50, and the maximum iter-
ation is 6000. So max_FEs is 300,000. So for the SGO
algorithm, we have taken pop_size is 25, and the maximum
iteration is 500. Hence max_FEs are 25,000(2×25×500
25,000, two is due to two-time fitness calculation in one
iteration for one particle in population) for classical bench-
mark functions, and pop_size is 50, and maximum iteration
is 3000. So max_FEs is 300,000 (2×50×3000 300,000)
for CEC2014 benchmark functions. SOA settings: nutritious food resources Nfs 4, gliding
constant Gc 1.9 and predator presence probability Pdp
0.1. Parameters are set as reported by authors in paper [30]. 25,000, two is due to two-time fitness calculation in one
iteration for one particle in population) for classical bench-
mark functions, and pop_size is 50, and maximum iteration
is 3000. So max_FEs is 300,000 (2×50×3000 300,000)
for CEC2014 benchmark functions. For each benchmark function, algorithms are run 30 times
with different randomly generated populations. Statistical
results in terms of mean value, corresponding standard-
deviation, the best value, and worse value are reported in
tables. Table 12 indicates the test results for unimodal sepa-
rable benchmark functions. Table 13 reports the test results
for unimodal non-separable benchmark functions. Table 14 The other specific parameters for each algorithm are given
below. 123 263 Complex & Intelligent Systems (2021) 7:249–295 p
g
y
(
)
Table 9 Comparison on BOA and SGO on 30 independent runs with 50,000 fitness function evaluations
Fun no. Experiment 3 Function Name
Algorithms
Mean
Std
Best
Median
Worse
F1
Sphere
BOA
0
0
0
0
0
SGO
0
0
0
0
0
F2
Beale
BOA
0
0
0
0
0
SGO
0
0
0
0
0
F3
Cigar
BOA
0
0
0
0
0
SGO
0
0
0
0
0
F4
Step
BOA
0
0
0
0
0
SGO
0
0
0
0
0
F5
Quartic function with noise
BOA
3.8917e−05
2.9003e−05
5.8800e−05
3.5850e−05
1.2000e−05
SGO
2.4890e−05
1.0695e−05
4.0050e−06
4.6955e−05
4.2739e−05
F6
Bohachevsky
BOA
0
0
0
0
0
SGO
0
0
0
0
0
F7
Ackley
BOA
1.7183e+00
0
1.7183e+00
1.7183e+00
1.7183e+00
SGO
8.8818e−16
0
8.8818e−16
8.8818e−16
8.8818e−16
F8
Griewank
BOA
1.8472e−19
2.6886e−20
1.6300e−19
1.6300e−19
2.1700e−19
SGO
0
0
0
0
0
F9
Levy
BOA
4.4108e−01
5.7467e−02
2.8900e−01
3.7800e−01
5.7400e−01
SGO
4.5472e−04
2.3885e−04
7.2873e−05
4.7006e−04
8.7819e−04
F10
Michalewiz
BOA
−5.3382
−5.6092
−5.7700
−3.6200
−2.2500
SGO
−9.1418
0.2639
−9.6141
−9.6141
−8.6585
F11
Rastrigin
BOA
0
0
0
0
0
SGO
0
0
0
0
0
F12
Alpine
BOA
0
0
0
0
0
SGO
0
0
0
0
0
F13
Schaffer
BOA
0
0
0
0
0
SGO
0
0
0
0
0
F14
Rosenbrock
BOA
2.8837e+01
3.1281e−02
2.8754e+01
2.8754e+01
2.8927e+01
SGO
23.2241
0.7375
21.7366
23.2401
24.5057
F15
Easom
BOA
−1.0000
0
−1.0000
−1.0000
−1.0000
SGO
−1
0
−1
−1
−1
F16
Shubert
BOA
−1.8673e+02
2.06493e−11
−1.8673e+02
−1.8673e+02
−1.8673e+02
SGO
−186.7309
4.7915e−14
−186.7309
−186.7309
−186.7309
F17
Schwefel 1.2
BOA
0
0
0
0
0
SGO
0
0
0
0
0
F18
Schwefel 2.21
BOA
6.9906e−153
1.4788e−152
3.7983e−155
2.3793e−153
9.7687e−152
SGO
0
0
0
0
0
F19
Schwefel 2.22
BOA
0
0
0
0
0
SGO
0
0
0
0
0
F20
Schwefel 2.26
BOA
−2.2662e+03
4.5626e+02
−2.8790e+03
−2.3458e+03
−1.8373e+03
SGO
−9.3595e+03
1.0556e+03
−1.1721e+04
−9.5886e+03
−7.9691e+03
F21
Booth
BOA
0
0
0
0
0
SGO
0
0
0
0
0
F22
Goldstein price
BOA
3.0000e+00
0.0000e+00
0.0000e+00*
0.0000e+00*
0.0000e+00*
SGO
3.0000
0
3.0000
3.0000
3.0000
F23
Matyas
BOA
0
0
0
0
0
SGO
0
0
0
0
0 mparison on BOA and SGO on 30 independent runs with 50,000 fitness function evaluations 123 Complex & Intelligent Systems (2021) 7:249–295 264 Table 9 continued
Fun no. Experiment 3 Function Name
Algorithms
Mean
Std
Best
Median
Worse
F24
Powell
BOA
0
0
0
0
0
SGO
0
0
0
0
0
F25
Power sum
BOA
2.8400e−02
1.3179e−02
8.9600e−03
2.6800e−02
5.4300e−02
SGO
7.2637e−04
5.4052e−04
5.6591e−05
6.4722e−04
0.0020
F26
Shekel 4.5
BOA
−10.200
0
−10.200
−10.200
−10.200
SGO
−5.3101
1.1399
−10.1532
−5.0552
−5.0552
F27
Sum squares
BOA
0
0
0
0
0
SGO
0
0
0
0
0
F28
Trid
BOA
−2.7500e+07*
5.6500e+07*
−9.6100e+07*
−3.1800e+07*
7.3000e+07*
SGO
−3.6951e+03
340.1588
−4.1038e+03
−3.8835e+03
−3.0904e+03
F29
Zettl
BOA
−3.7900e−03
0
−3.7900e−03
−3.7900e−03
−3.7900e−03
SGO
−3.7900e−03
0
−3.7900e−03
−3.7900e−03
−3.7900e−03
F30
Leon
BOA
1.1527e−06
9.4711e−07
1.0700e−08
6.9200e−07
2.6800e−06
SGO
2.4663e−12
3.3155e−12
1.3378e−13
5.9250e−13
9.5362e−12 reports the test results for multimodal separable benchmark
functions. Table 15 reports the test results for multimodal
non-separable benchmark functions, and Table 16 reports
the test results for CEC2014 functions. For every benchmark
function, the best results are boldfaced. SSOA is found identical to SGO. For F16 and F17, SGO
could not reach the global optimum region but find better
results than the SSOA. It is clear from Table 15 results that the SGO achieves suc-
cess in finding global optimum on multimodal non-separable
functions F19, F20, F21, F22, F23, F25, but the SSOA
achieves success in finding only on F20, F21, F22, and F23. Only for F24 and F26, SGO could not reach the global opti-
mum region. For F24, SSOA finds better results, and for F26,
SGO finds a better result. To obtain statistically sound conclusions, the WRS test at
a 0.05 significance level is conducted on the experimental
results of Tables 12, 13, 14, 15, 16 and reported in Table 17. A comparison of the best results obtained in Tables 12, 13,
14, 15, 16, also published in Table 17. The last three rows of
Table 17 summarize experimental results. It is clear from Table 16 that SGO finds a better solution
in F27, F28, F29, then SSOA, whereas SSOA finds better in
F30 and F31 then SGO, and in F32 and F33, both SGO and
SSOA finds equivalent results. 123 Discussion q
From Table 17, according to the WRS test, we find that
theSGOalgorithmperformssuperiorsolutionsinthreecases,
equivalent solution in one case out of four unimodal separa-
ble benchmark functions than the SSOA algorithm. Out of
eightunimodalnon-separablebenchmarkfunctions,theSGO
algorithm performs superior solutions in six cases, equiv-
alent solution in one case and worse solution in one case
than the SSOA algorithm. Out of six multimodal separable
benchmark functions, the SGO algorithm performs superior
solutions in four cases, an equivalent solution in two cases
than the SSOA algorithm. Out of eight multimodal non-
separable benchmark functions, the SGO algorithm performs
superior solutions in three cases, equivalent solution in four
cases, worse solution in one case than the SSOA algorithm. Out of seven CEC2014 benchmark functions, the SGO algo-
rithm performs superior solutions in three cases, equivalent
solutions in two cases, and worse solutions in two cases than
the SSOA algorithm. It is clear from Table 12 that the SGO achieves success in
finding global optimum on unimodal separable functions F1,
F2, and F3. For F1, the performance of the SSOA is found
identical to the SGO. Only for F4, the SGO could not reach
the global optimum region but find better results than the
SSOA. Table13providesresultsonunimodalnon-separablefunc-
tions. It is clear from the table that the SGO achieves success
in finding global optimum on functions F5, F6, F7, F9, F10,
F11, but the SSOA achieves success in finding global opti-
mum only on F6. For F6 only, the performance of SSOA is
found identical to the SGO. Only for F8 and F12, SGO could
not reach the global optimum region. For the F8 function,
SSOA finds a better result than SGO, and for F12 SGO, find
a better result than SSOA. It is clear from Table 14 that the SGO achieves success in
finding global optimum on multimodal separable functions
F13, F14, F15, F18, but SSOA achieves success in finding
only on F13 and F15. For F13 and F15, the performance of 123 123 265 Complex & Intelligent Systems (2021) 7:249–295 Table 10 Comparison of BOA and SGO on 30 independent runs with 10,000 fitness function evaluations
Fun no. Discussion Function name
Algorithms
Mean
Std
Best
Median
Worse
F1
Sphere
BOA
0
0
0
0
0
SGO
0
0
0
0
0
F2
Beale
BOA
0
0
0
0
0
SGO
0
0
0
0
0
F3
Cigar
BOA
0
0
0
0
0
SGO
0
0
0
0
0
F4
Step
BOA
0
0
0
0
0
SGO
0
0
0
0
0
F5
Quartic function with noise
BOA
3.8917e−05
2.9003e−05
5.8800e−05
3.5850e−05
1.2000e−05
SGO
1.0432e−04
7.9660e−05
8.1471e−06
8.8846e−05
3.1340e−04
F6
Bohachevsky
BOA
0
0
0
0
0
SGO
0
0
0
0
0
F7
Ackley
BOA
1.7183e+00
0
1.7183e+00
1.7183e+00
1.7183e+00
SGO
8.8818e−16
0
8.8818e−16
8.8818e−16
8.8818e−16
F8
Griewank
BOA
1.8472e−19
2.6886e−20
1.6300e−19
1.6300e−19
2.1700e−19
SGO
0
0
0
0
0
F9
Levy
BOA
4.4108e−01
5.7467e−02
2.8900e−01
3.7800e−01
5.7400e−01
SGO
0.0016
7.9751e−04
4.5448e−04
0.0013
0.0032
F10
Michalewiz
BOA
−5.3382
−5.6092
−5.7700
−3.6200
−2.2500
SGO
−8.1452
0.6628
−9.3669
−8.1402
−6.8557
F11
Rastrigin
BOA
0
0
0
0
0
SGO
0
0
0
0
0
F12
Alpine
BOA
0
0
0
0
0
SGO
0
0
0
0
0
F13
Schaffer
BOA
0
0
0
0
0
SGO
0
0
0
0
0
F14
Rosenbrock
BOA
2.8837e+01
3.1281e−02
2.8754e+01
2.8754e+01
2.8927e+01
SGO
28.3809
0.3189
27.6996
28.4405
28.7686
F15
Easom
BOA
−1.0000
0
−1.0000
−1.0000
−1.0000
SGO
−1
0
−1
−1
−1
F16
Shubert
BOA
−1.8673e+02
2.06493e−11
−1.8673e+02
−1.8673e+02
−1.8673e+02
SGO
−186.7309
4.7915e−11
−186.7309
−186.7309
−186.7309
F17
Schwefel 1.2
BOA
0
0
0
0
0
SGO
0
0
0
0
0
F18
Schwefel 2.21
BOA
6.9906e−153
1.4788e−152
3.7983e−155
2.3793e−153
9.7687e−152
SGO
0
0
0
0
0
F19
Schwefel 2.22
BOA
0
0
0
0
0
SGO
0
0
0
0
0
F20
Schwefel 2.26
BOA
−2.2662e+03
4.5626e+02
−2.8790e+03
−2.3458e+03
−1.8373e+03
SGO
−6.9949e+03
1.0556e+03
−9.3437e+03
−0.6536e+03
−5.6009e+03
F21
Booth
BOA
0
0
0
0
0
SGO
0
0
0
0
0
F22
Goldstein price
BOA
3.0000
0
3.0000
3.0000
3.0000
SGO
3.0000
0
3.0000
3.0000
3.0000
F23
Matyas
BOA
0
0
0
0
0
SGO
0
0
0
0
0 mparison of BOA and SGO on 30 independent runs with 10,000 fitness function evaluations 123 Complex & Intelligent Systems (2021) 7:249–295 266 Table 10 continued
Fun no. Parameters are set as reported by authors in paper [60]. For each benchmark-function, algorithms are run 30 times
with different randomly generated populations. Statistical
results in terms of mean value, corresponding standard-
deviation, the best value, and worse value are reported in
tables. Table 18 reports the test results for unimodal bench-
mark functions. The test results for multimodal benchmark
functions are reported in Table 19. Table 20 reports the test
result for fixed dimensional multimodal benchmark func-
tions. For every benchmark function, the best results are
boldfaced. 123 Discussion Function name
Algorithms
Mean
Std
Best
Median
Worse
F24
Powell
BOA
0
0
0
0
0
SGO
0
0
0
0
0
F25
Power sum
BOA
2.8400e−02
1.3179e−02
8.9600e−03
2.6800e−02
5.4300e−02
SGO
0.0012
0.0014
3.5053e−05
3.0905e−04
0.0045
F26
Shekel 4.5
BOA
−10.2000
0
−10.2000
−10.2000
−10.2000
SGO
−5.3101
1.1399
−10.1532
−5.0552
-5.0552
F27
Sum squares
BOA
0
0
0
0
0
SGO
0
0
0
0
0
F28
Trid
BOA
−2.7500e+07*
5.6500e+07*
−9.6100e+07*
−3.1800e+07*
7.3000e+07*
SGO
−286.1084
448.9151
−1.4262e+03
−99.4426
–24.0904
F29
Zettl
BOA
−3.7900e−03
0
−3.7900e−03
−3.7900e−03
−3.7900e−03
SGO
−3.7912e−03
1.3348e−18
−3.7912e−03
−3.7912e−03
−3.7912e−03
F30
Leon
BOA
1.1527e−06
9.4711e−07
1.0700e−08
6.9200e−07
2.6800e−06
SGO
2.4663e−09
3.3155e−07
1.3378e−12
5.9250e−09
9.5362e−7 According to parameter settings of the VPL algorithm in
its respective paper [60], the common control parameter, such
as max_FEs, is 100,000. So, for the SGO algorithm, common
control parameters such as pop_size are set to 50, and maxi-
mum iteration is set to 1000. So max_FEs is 2 × 50 × 1000
100,000. The other specific parameters for each algorithm
are given below. While comparing in terms of best solution value between
SGO and SSOA algorithm, then the SGO algorithm performs
better in three cases and similar to SSOA algorithm in one
case, out of four unimodal separable benchmark functions. The SGO algorithm is better performing in six cases, one case
being similar, and one case giving worse solution than SSOA
algorithm out of eight unimodal non-separable benchmark
functions. The SGO algorithm is better in two cases and simi-
lar to the SSOA algorithm in four cases, out of six multimodal
separable benchmark functions. The SGO algorithm is bet-
ter in one case, similar in six cases and gives worse solution
than SSOA algorithm in one case, out of eight multimodal
non-separable benchmark function. The SGO algorithm is
better in three cases and gives similar solution with SSOA
algorithm in four cases, out of seven CEC2014 benchmark
functions. • SGO setting: For SGO, there is only one parameter C
called a self-introspection factor. The value of C is empir-
ically set to 0.2. • VPL setting: For VPL L 60, PC 0.5, rate of promoted
δPr 0.05, δst 0.54, N 10, and β 7. • SGO setting: For SGO, there is only one parameter C
called a self-introspection factor. The value of C is empir-
ically set to 0.2. Discussion • VPL setting: For VPL L 60, PC 0.5, rate of promoted
δPr 0.05, δst 0.54, N 10, and β 7. • VPL setting: For VPL L 60, PC 0.5, rate of promoted
δPr 0.05, δst 0.54, N 10, and β 7. Parameters are set as reported by authors in paper [60]. Experiment 4 According to Table 18, SGO has gained the best perfor-
mance and consistently performed better than VPL algo- 123 Complex & Intelligent Systems (2021) 7:249–295 267 ult
OA
function
Function Name
Wilcoxon rank
test result using
Table 9
Comparison of
best result of
Table 9
Wilcoxon rank
test result using
Table 10
Comparison of
best result of
Table 10
F1
Sphere
≈
Same
≈
Same
F2
Beale
≈
Same
≈
Same
F3
Cigar
≈
Same
≈
Same
F4
Step
≈
Same
≈
Same
F5
Quartic function
with noise
≈
Best
+
Best
F6
Bohachevsky
≈
Same
≈
Same
F7
Ackley
−
Best
−
Best
F8
Griewank
−
Best
−
Best
F9
Levy
−
Best
−
Best
F10
Michalewiz
−
Best
−
Best
F11
Rastrigin
≈
Same
≈
Same
F12
Alpine
≈
Same
≈
Same
F13
Schaffer
≈
Same
≈
Same
F14
Rosenbrock
−
Best
−
Best
F15
Easom
≈
Same
≈
Same
F16
Shubert
≈
Same
≈
Same
F17
Schwefel 1.2
≈
Same
≈
Same
F18
Schwefel 2.21
−
Best
−
Best
F19
Schwefel 2.22
≈
Same
≈
Same
F20
Schwefel 2.26
−
Best
−
Best
F21
Booth
≈
Same
≈
Same
F22
Goldstein price
≈
Same
≈
Same
F23
Matyas
≈
Same
≈
Same
F24
Powell
≈
Same
≈
Same
F25
Power sum
−
Best
−
Best
F26
Shekel 4.5
+
Worse
+
Worse
F27
Sum squares
≈
Same
≈
Same
F28
Trid
∗
*
∗
*
F29
Zettl
≈
Same
≈
Same
F30
Leon
−
Best
−
Best
Total +
01
1, worse
02
1, worse
Total −
09
10, best
09
10, best
Total ≈
19
18, same
18
18, same
“−”, “+” and “≈” denote that performance of BOA is worse, better and similar to SGO respectively Table 11 Wilcoxon rank test
result and the comparison result
on the best value between BOA
and SGO Table 11 Wilcoxon rank test
result and the comparison result
on the best value between BOA
and SGO
function
Function Name
Wilcoxon rank
test result using
Table 9
Comparison of
best result of
Table 9
Wilcoxon rank
test result using
Table 10
Comparison o
best result of
Table 10
F1
Sphere
≈
Same
≈
Same
F2
Beale
≈
Same
≈
Same
F3
Cigar
≈
Same
≈
Same
F4
Step
≈
Same
≈
Same
F5
Quartic function
with noise
≈
Best
+
Best
F6
Bohachevsky
≈
Same
≈
Same
F7
Ackley
−
Best
−
Best
F8
Griewank
−
Best
−
Best
F9
Levy
−
Best
−
Best
F10
Michalewiz
−
Best
−
Best
F11
Rastrigin
≈
Same
≈
Same
F12
Alpine
≈
Same
≈
Same
F13
Schaffer
≈
Same
≈
Same
F14
Rosenbrock
−
Best
−
Best
F15
Easom
≈
Same
≈
Same
F16
Shubert
≈
Same
≈
Same
F17
Schwefel 1.2
≈
Same
≈
Same
F18
Schwefel 2.21
−
Best
−
Best
F19
Schwefel 2.22
≈
Same
≈
Same
F20
Schwefel 2.26
−
Best
−
Best
F21
Booth
≈
Same
≈
Same
F22
Goldstein price
≈
Same
≈
Same
F23
Matyas
≈
Same
≈
Same
F24
Powell
≈
Same
≈
Same
F25
Power sum
−
Best
−
Best
F26
Shekel 4.5
+
Worse
+
Worse
F27
Sum squares
≈
Same
≈
Same
F28
Trid
∗
*
∗
*
F29
Zettl
≈
Same
≈
Same
F30
Leon
−
Best
−
Best
Total +
01
1, worse
02
1, worse
Total −
09
10, best
09
10, best
Total ≈
19
18, same
18
18, same
“−”, “+” and “≈” denote that performance of BOA is worse, better and similar to SGO respectively
Table 12 Comparison on SSOA
and SGO on 30 independent
runs on unimodal separable
benchmark functions
Function no. Experiment 4 In this experiment, the VPL (volleyball premier league)
algorithm [60] is compared with the SGO algorithm. For per-
formance comparison of algorithms, 23 classical benchmark-
functions are considered. Out of which seven are uni-
modal benchmark-functions, six are multimodal benchmark-
functions, ten are fixed-dimension multimodal benchmark-
functions. These benchmark-functions are described in
Appendix A. To obtain statistically sound conclusions, the WRS test at
a 0.05 significance level is conducted on the experimental
results of Tables 18, 19, 20 and reported in their respective
tables. Also, comparisons on the best results are obtained and
are given in the respective table also. The last three rows of
tables summarize experimental results. We have directly derived results of the VPL algorithm
from [60], and for results of the SGO algorithm, the codes
are implemented in MATLAB 2016a. Experiments are con-
ducted on an Intel Core i5, 8 GB memory laptop in Windows
10 environment. Table 11 Wilcoxon rank test
result and the comparison result
on the best value between BOA
and SGO Experiment 4 Function name
Algorithms
Best
Worse
Mean
Std
F1
Step
SSOA
0
0
0
0
SGO
0
0
0
0
F2
Sphere
SSOA
7.9225e−20
5.7411e−07
4.1689e−08
1.4356e−
SGO
0
0
0
0
F3
Sumsquares
SSOA
2.0052e−28
2.3194e−06
1.5201e−07
4.6741e−
SGO
0
0
0
0
F4
Quartic
SSOA
3.0998e−02
9.9258e−01
5.0192e−01
2.9565e−
SGO
2.5878e−06
8.2220e−05
3.6441e−05
2.5849e− “−”, “+” and “≈” denote that performance of BOA is worse, better and similar to SGO respectively SOA
t
Function no. Function name
Algorithms
Best
Worse
Mean
Std
F1
Step
SSOA
0
0
0
0
SGO
0
0
0
0
F2
Sphere
SSOA
7.9225e−20
5.7411e−07
4.1689e−08
1.4356e−07
SGO
0
0
0
0
F3
Sumsquares
SSOA
2.0052e−28
2.3194e−06
1.5201e−07
4.6741e−07
SGO
0
0
0
0
F4
Quartic
SSOA
3.0998e−02
9.9258e−01
5.0192e−01
2.9565e−01
SGO
2.5878e−06
8.2220e−05
3.6441e−05
2.5849e−05 123 Complex & Intelligent Systems (2021) 7:249–295 268 Table 13 Comparison on SSOA
and SGO on 30 independent
runs on unimodal nonseparable
benchmark functions
Function no. Function name
Algorithms
Best
Worse
Mean
Std
F5
Beale
SSOA
2.1832e−29
2.7633e−20
9.5584e−22
5.0400e−21
SGO
0
0
0
0
F6
Easom
SSOA
−1
−1
−1
0
SGO
−1
−1
−1
0
F7
Matyas
SSOA
1.5111e−29
2.0707e−24
1.542e−25
4.7571e−25
SGO
0
0
0
0
F8
Colville
SSOA
8.5561e−21
2.4871e−08
1.4309e−09
4.6907e−09
SGO
4.2541e−11
6.9093e−05
8.4402e−06
1.8988e−05
F9
Zakharov
SSOA
1.9954e−23
1.5225e−07
5.2215e−09
2.7772e−08
SGO
0
0
0
0
F10
Schwefel 2.22
SSOA
2.2266e−08
7.1423e−03
5.1849e−04
1.4144e−03
SGO
0
0
0
0
F11
Schwefel 1.2
SSOA
6.6803e−18
3.4907e−04
1.6925e−05
6.6811e−05
SGO
0
0
0
0
F12
Dixon-Price
SSOA
1.8308e−01
6.6951e−01
2.2412e−01
1.2107e−01
SGO
3.3801e−04
0.1258
0.0946
0.0731
Table 14 Comparison on SSOA
and SGO on 30 independent
runs on multimodal separable
benchmark-functions
Function no. Function name
Algorithms
Best
Worse
Mean
Std
F13
Bohachevsky1
SSOA
0
0
0
0
SGO
0
0
0
0
F14
Booth
SSOA
1.2622e−29
8.1255e−24
9.5859e−25
1.7996e−24
SGO
0
0
0
0
F15
Michalewicz2
SSOA
−1.8013
−1.8013
−1.8013
1.0275e−15
SGO
−1.8013
−1.8013
−1.8013
6.8344e−16
F16
Michalewicz5
SSOA
−4.6877
−3.5563
−4.3479
3.2785e−01
SGO
−4.6877
−4.4948
−4.5862
0.0848
F17
Michalewicz10
SSOA
−9.4806
−5.9146
−7.5900
9.9570e−01
SGO
−9.5515
−8.4770
−9.0513
0.3087
F18
Rastrigin
SSOA
0
7.6657e−06
4.9059e−07
1.5057e−06
SGO
0
0
0
0 In Table 19, there is ‘*’ mark in the first row with the result
oftheVPLalgorithmtosaythattheresultmaybeputwrongly
as the minimum value of the F8 function is −12,569.487. Experiment 4 But we get less than that in the paper and hence a confusion
arising on the minimum value. To avoid any conflicts, we
have excluded this result and have put ‘*’ in Table 19. So,
for comparison, we have considered only five multimodal
functions. The multimodal functions are beneficial, while
the exploration capability of the optimization algorithm is
considered. Form Table 19, results show that the SGO algo-
rithm is eligible for solving problems with challenging search
space. The table shows that SGO has consistently performed
better than VPL algorithms. SGO has an excellent perfor-
mance in exploration and convergence, and it successfully
overcomes to solve all the problems within this category. It
is clear from table results that both SGO and VPL achieve rithms. SGO has an excellent performance in exploitation
and convergence then VPL, and it successfully overcomes to
solve all the problems within this category. It is clear from the
results that SGO achieves success in finding global optimum
on F1–F4. For F5, F6, and F7, the performance of SGO is
better than VPL. From Table 18, we find that in all the cases of unimodal
benchmark functions according to the WRS test, the SGO
algorithm shows better performance than the VPL algorithm. Similarly, comparison on best results obtained by algorithms,
we find that the SGO algorithm gets either the best result
than the VPL algorithm or similar result with the VLP algo-
rithm. From the table, it is evident that the SGO algorithm
outperforms in solving unimodal benchmark functions in
comparison to VPL algorithms. 123 Complex & Intelligent Systems (2021) 7:249–295 269 Table 15 Comparison on SSOA
and SGO on 30 independent
runs on multimodal
nonseparable functions
Function no. Experiment 4 Function
name
Algorithms
Best
Worse
Mean
Std
F19
Schaffer
SSOA
0
9.7159e−03
9.7159e−04
2.9646e−03
SGO
0
0
0
0
F20
Six Hump
Camel
Back
SSOA
−1.03163
−1.03163
−1.03163
4.5168e−16
SGO
−1.03163
−1.03163
−1.03163
0
F21
Boachevsky2
SSOA
0
0
0
0
SGO
0
0
0
0
F22
Boachevsky3
SSOA
0
0
0
0
SGO
0
0
0
0
F23
Shubert
SSOA
−186.73
−186.73
−186.73
2.6389e−14
SGO
−186.73
−186.73
−186.73
1.6722e−15
F24
Rosenbrock
SSOA
3.9637e−19
2.8475e+01
9.4919e−01
5.1988e+00
SGO
25.4955
26.6390
26.1690
0.3605
F25
Griewank
SSOA
0
4.1375e−05
3.435e−06
9.6702e−06
SGO
0
0
0
0
F26
Ackley
SSOA
2.2418e−10
2.5867e−03
1.3915e−04
4.8513e−04
SGO
−
8.8818e−16
−
8.8818e−16
−
8.8818e−16
0
Table 16 Comparison on SSOA
and SGO on 30 independent
runs on CEC 2014
benchmark-functions with 30
dimension
Function no. Function name
Algorithms
Best
Worse
Mean
Std
F27
CEC1
SSOA
9.1044e+04
1.7503e+06
8.1899e+05
4.0164e+05
SGO
3.7329e+04
3.6134e+05
1.5721e+05
9.9594e+04
F28
CEC2
SSOA
2.1599e+02
2.8185e+04
1.0049e+04
9.8268e+03
SGO
200.0005
635.8838
331.9643
119.1971
F29
CEC4
SSOA
4.0000e+02
5.4414e+02
4.5717e+02
3.9877e+01
SGO
400.0035
463.4008
402.8456
11.5184
F30
CEC17
SSOA
7.0506e+03
6.0131e+04
2.6151e+04
1.5238e+04
SGO
5.9331e+03
8.3743e+04
3.2450e+04
1.9765e+04
F31
CEC23
SSOA
2.500e+03
2.500e+03
2.500e+03
8.4083e−10
SGO
2500
2.6152e+03
2.5576e+03
58.6071
F32
CEC24
SSOA
2.600e+03
2.600e+03
2.600e+03
8.3747e−02
SGO
2600
2600
2600
0
F33
CEC125
SSOA
2.700e+03
2.700e+03
2.700e+03
4.8285e−11
SGO
2700
2700
2700
0
success in finding global optimum on F9 and F1 For F10
ing multimodal benchmark functions in comparison to VPL success in finding global optimum on F9 and F1. For F10,
both SGO and VPL get equivalent results. For F12 and F13,
the SGO algorithm finds better results than the VPL algo-
rithm. According to the WRS test from Table 19, we find
that in two out of five cases, SGO algorithm shows better
performance than the VPL algorithm and similar in three
out of five cases with the VPL algorithm. Similarly, com-
parison on best results obtained by algorithms, we get that
the SGO algorithm either gets the best result than the VPL
algorithm or similar result to the VPL algorithm. Hence, we
find that the SGO algorithm shows best performance in solv- ing multimodal benchmark functions in comparison to VPL
algorithms. ing multimodal benchmark functions in comparison to VPL
algorithms. Experiment 4 In Table 20, there is ‘*’ mark with the result of the VPL
algorithm to say that there, the result might be put wrongly
as the minimum value of the F15 function is 3.0749e−04. But we get different values in the paper and hence a confu-
sion arising on minimum value. To avoid any conflicts, we
have excluded this result and have put ‘*’ in Table 20. The
fixed-dimensional multimodal functions are designed to have
many local optimal where computation complexity increases
drastically with the problem size. The results reported from 123 Complex & Intelligent Systems (2021) 7:249–295 270 Table 17 Wilcoxon rank test result and comparison result on best value between SSOA and SGO
Function
no. Wilcoxon
test
Comparison
on best
Function
no. Wilcoxon
test
Comparison
on best
Function
no. Wilcoxon
test
Comparison
on best
Function
no. Wilcoxon
test
Comparison
on best
Function
no. Wilcoxon
test
Comparison
on best
F1
≈
Same
F5
−
Best
F13
≈
Same
F19
−
Same
F27
−
Best
F2
−
Best
F6
≈
Same
F14
−
Best
F20
≈
Same
F28
−
Best
F3
−
Best
F7
−
Best
F15
≈
Same
F21
≈
Same
F29
−
Same
F4
−
Best
F8
+
Worse
F16
−
Same
F22
≈
Same
F30
+
Best
F9
−
Best
F17
−
Best
F23
≈
Same
F31
+
Same
F10
−
Best
F18
−
Same
F24
+
Worse
F32
≈
Same
F11
−
Best
F25
−
Same
F33
≈
Same
F12
−
Best
F26
−
Best
T −
03
S 1
06
S 1
04
S 4
03
S 6
03
S 4
T +
00
B 3
01
B 6
00
B 2
01
B 1
02
B 3
T ≈
01
W 0
01
W 1
02
W 0
04
W 1
02
W 0
“ −”, “+” “≈” denote that performance of SSOA is worse, better and similar to SGO respectively and same, best, and worse are similar, better and worse solutions of SGO then
SSOA algorithm in term of the best result Table 17 Wilcoxon rank test result and comparison result on best value between SSOA and SGO “ −”, “+” “≈” denote that performance of SSOA is worse, better and similar to SGO respectively and same, best, and worse are similar, b
SSOA algorithm in term of the best result Table 18 Result of unimodal benchmark functions
Function no. Experiment 4 Algorithms
Best
Comparison on best result
Worse
Mean
Std
WRS test
F1
VPL
0.00e+00
Same
2.34e−130
7.81e−132
4.20e−131
−
SGO
0.00e+00
0.00e+00
0.00e+00
0.00e+00
F2
VPL
1.12e−102
Best
2.85e−89
1.13e−90
5.13e−90
−
SGO
0.00e+00
0.00e+00
0.00e+00
0.00e+00
F3
VPL
1.93e−33
Best
1.53e−02
8.16e−04
2.85e−03
−
SGO
0.00e+00
0.00e+00
0.00e+00
0.00e+00
F4
VPL
0.00e+00
Same
1.63e−28
1.54e−29
3.96e−29
−
SGO
0.00e+00
0.00e+00
0.00e+00
0.00e+00
F5
VPL
2.58e+01
Best
2.67e+01
2.62e+01
2.76e−01
−
SGO
17.8419
21.6899
20.4626
1.0124
F6
VPL
1.82e−05
Best
2.34e−03
4.09e−04
5.33e−04
−
SGO
1.0720e−26
2.9247e−18
1.3337e−19
5.4652e−19
F7
VPL
4.67e−05
Best
4.81e−03
1.93e−03
1.36e−03
−
SGO
1.6238e−07
2.3695e−05
9.9687e−06
7.6441e−06
Total no of the best
05
Total +
00
Total no. of worse
00
Total −
00
Total no. of the same
02
Total ≈
07
“ −”, “+”,“≈” denote performance of VPL is worse, better and similar to SGO respectively and same, best, and worse are the similar, better, and
worse solutions of SGO then SSA algorithm in terms of the best result Table 18 Result of unimodal benchmark functions “ −”, “+”,“≈” denote performance of VPL is worse, better and similar to SGO respectively and same, best, and worse are the similar, better, and
worse solutions of SGO then SSA algorithm in terms of the best result algorithm or similar result with the VLP algorithm except for
two cases. Hence, we can see that the VPL algorithm shows
best performance in solving fixed dimensional multimodal
benchmark functions in comparison to SGO algorithms. Table 20 shows that the SGO algorithm achieves success in
finding global optimum on F14, F15, F16, F17, F18, and F19. In contrast, VPL reaches optimal solution only for F14,
F16, F17, and F18. For shekel family, i.e., for F21, F22 and
F23 VPL finds better result than SGO algorithm. From Table
20, according to the WRS, we find that out of ten cases, SGO
algorithm shows better performance in three cases and sim-
ilar performance in four cases than the VPL algorithm In
contrast, the VPL algorithm shows its better performance in
threecasesoutoftenthantheSGOalgorithm.Similarly,com-
parison on best results obtained by algorithms, we find that
the SGO algorithm either gets the best result than the VPL 123 Experiment 5 In this experiment, SELO (socio evolution and learning
optimization) [61] algorithm is compared with the SGO algo-
rithm. For comparison of the performance of algorithms, a
set of 50 benchmark functions are considered. These set of
test functions include problems of varying complexity levels, 123 Complex & Intelligent Systems (2021) 7:249–295 271 Table 19 Result of multimodal benchmark functions
Function no. Algorithms
Best
Comparison on best result
Worse
Mean
Std
WRS test
F8
VPL
−1.19e+112*
–
−7.38e+90*
−4.68e+110*
2.15e+111*
–
SGO
−1.1385e+04
−7.7527e+03
−9.0646e+03
1.0705e+03
F9
VPL
0.00e+00
Same
0.00e+00
0.00e+00
0.00e+00
≈
SGO
0.00e+00
0.00e+00
0.00e+00
0.00e+00
F10
VPL
8.88e−16
Same
8.88e−16
8.88e−16
9.86e−32
≈
SGO
8.8818e−16
8.8818e−16
8.8818e−16
0.00e+00
F11
VPL
0.00e+00
Same
0.00e+00
0.00e+00
0.00e+00
≈
SGO
0.00e+00
0.00e+00
0.00e+00
0.00e+00
F12
VPL
1.11e−06
Best
6.56e−05
2.58e−05
1.74e−05
−
SGO
3.6451e−26
5.6154e−23
7.3910e−24
1.3826e−23
F13
VPL
2.63e−05
Best
2.31e−03
4.18e−04
4.84e−04
−
SGO
2.5068e−25
0.0110
6.8145e−12
2.2671e−08
Total no of the best
02
Total +
01
Total no. of worse
01
Total −
02
Total no. of the same
03
Total ≈
03
“ −”, “+”, “≈” denote performance of VPL is worse, better, and similar to SGO respectively and same, best and worse are the similar, better and
worse solution of SGO then VPL algorithm in term of the best result Table 19 Result of multimodal benchmark functions “ −”, “+”, “≈” denote performance of VPL is worse, better, and similar to SGO respectively and same, best and worse are the similar, better and
worse solution of SGO then VPL algorithm in term of the best result Table 20 Results on fixed-dimensional benchmark functions
Function no. “−”, “+”, “≈” denote performance of VPL is worse, better and similar to SGO respectively and same, best and worse are the similar, better and
worse solution of SGO then VPL algorithm in term of the best result Experiment 5 Also, the range, formula-
tion, characteristics, and dimensions of these problems and
listed in paper [61]. In Table 21, there is ‘*’ mark with the result of the
SELO algorithm for the function F14 and F26 to say that
there the result might be put wrongly as the minimum value
of F14 function is −1, and minimum value for F26 is
−1.801303410098554. To avoid any conflicts, we have
excluded this result and have put ‘*’ in Table 21. From Table
21, according to the WRS test, we find that in 19 cases out of
50 cases SGO(1) algorithm shows better performance than
the SELO algorithm and similar to 24 cases out of 50 cases
with the SELO algorithm. In contrast, the SELO algorithm
shows its better performance in 7 cases out of 50 than the
SGO (1) algorithm. Similarly, we find that in 19 cases out of
50 cases SGO (2) algorithm shows better performance than
SELO algorithm and similar with 20 cases out of 50 cases
withSELOalgorithm.Incontrast,theSELOalgorithmshows
its better performance in eleven cases out of 50 than the SGO
(2) algorithm. We have directly derived results of the SELO algorithm
from [61], and for results of the SGO algorithm, the codes
are implemented in MATLAB 2016a. Experiments are con-
ducted on an Intel-Core-i5, 8 GB memory laptop in Windows
10 environment. According to parameter settings of the SELO algorithm
in its respective paper [61], the common control parameter,
such as a maximum number of iterations, is 70,000. In this
experiment for each function, the SGO algorithm is tested
twice. So, in the first test, we have considered pop_size 50,
and the maximum iteration is 250. Hence Max_FEs is (2
× 50 × 250 25,000), and in the second test, we have
found pop_size is 20, and the maximum iteration is 50, so
maximum Max_FEs is (2 × 20 × 50 2,000). The other
specific parameters for each algorithm are given below. Hence, we find that the SGO algorithm shows superior
performance than the SELO algorithm in this experiment. However, max_FEs for SGO is much less than max_FEs for
SELO algorithm, i.e. (25,000 FEs in SGO(1)<70,000 itera-
tions) and (2000 FEs in SGO(2)<70,000 iterations). So we
can claim that the SGO algorithm outperformed than SELO
algorithm in Experiment 5. • SGO setting: For SGO, there is only one parameter C
called a self-introspection factor. Experiment 6 In this experiment, HHO (Harris hawks optimization) [31],
SSA (Salp swarm algorithm) [27], GOA (grasshopper opti-
misation algorithm) [28] and SGO (Social Group optimiza-
tion) [54] algorithm are compared together. For comparison
oftheperformanceofalgorithms,asetof29benchmarkfunc-
tions are considered. Details of these benchmark functions
are given in experiment 1. For each benchmark-function, algorithms are run 30 times
with different randomly generated populations. Statistical
results in terms of mean value, corresponding standard devi-
ation, and best value are reported in Table 21. The table
reports the results corresponding to SGO(1) with (2×50×
250) Max_FEs and results corresponding to SGO(2) with
(2×20×50) Max_FEs. In this experiment values below 1
E−16 are considered to be zero. For every benchmark func-
tion, the best results are boldfaced. We have directly derived results of the HHO algo-
rithm from [31], and the results of the SGO algorithm,
SSA algorithm, and GOA algorithm, the codes are imple-
mented in MATLAB 2016a. The source code for the SSA
algorithm and GOA algorithm is taken from https://www. alimirjalili.com/SSA.html and https://www.alimirjalili.com/
GOA.html, respectively. Experiments are conducted on an
Intel-Core−i5, 8 GB memory laptop in Windows 10 envi-
ronment. To obtain statistically sound conclusions, the WRS test at
a 0.05 significance level is conducted on experimental results
of Table 21 for both SGO(1) and SGO(2) and reported in the
same table. The last three rows of the table summarize results. Experiment 5 The value of C is empir-
ically set to 0.2. • For SELO initial number of families created M 03, num-
ber of parents in each family p 02, number of children in
each family 03, parent_follow_probability rp 0.999,
follow_prob_ownparent 0.999,peer_follow_probability
rk 0.1, follow_prob_factor _otherkids 0.9991 and
sampling interval reduction factor r 0.95000 to 0.99995. Parameters are set as reported by authors in paper [61]. Experiment 5 Algorithms
Best
Comparison on best result
Worse
Mean
Std
WRS test
F14
VPL
9.98e−01
Same
9.98e−01
9.98e−01
2.32e−13
≈
SGO
0.9980
0.9980
0.9980
5,3418e−15
F15
VPL
2.45e−05*
Best
1.82e−03
1.25e−03
3.08e−04
−
SGO
3.0749e−04
3.0749e−04
3.0749e−04
1.2533e−19
F16
VPL
−1.03e+00
Same
−1.03e+00
−1.03e+00
2.56e−06
≈
SGO
−1.0316
−1.0316
−1.0316
6.7752e−16
F17
VPL
3.98e−01
Same
3.98e−01
3.98e−01
2.69e−06
≈
SGO
0.3979
0.3979
0.3979
4.1563e−15
F18
VPL
3.00e+00
Same
3.00e+00
3.00e+00
7.58e−05
≈
SGO
3.0000
3.0000
3.0000
2.1377e−15
F19
VPL
−3.85e+00
Best
−3.49e+00
−3.77e+00
9.37e−02
−
SGO
−3.8628
−3.8628
−3.8628
2.7101e−15
F20
VPL
−3.32e+00
Same
−3.20e+00
−3.28e+00
5.41e−02
−
SGO
−3.3220
−3.2031
−3.3061
0.0411
F21
VPL
−1.02e+01
Same
−5.06e+00
−9.30e+00
1.90e+00
+
SGO
−10.1532
−5.0552
−8.9012
2.0231
F22
VPL
−1.04e+01
Same
−5.09e+00
−8.99e+00
2.35e+00
+
SGO
−10.4029
−5.2648
−8.2761
2.9251
F23
VPL
−1.05e+01
Same
−3.57e+00
−9.40e+00
2.28e+00
+
SGO
−10.5364
−5.3087
−7.0231
2.4619
Total no of the best
02
Total +
03
Total no. of worse
00
Total −
03
Total no. of same
08
Total ≈
04
“−”, “+”, “≈” denote performance of VPL is worse, better and similar to SGO respectively and same, best and worse are the similar, better and
worse solution of SGO then VPL algorithm in term of the best result Table 20 Results on fixed-dimensional benchmark functions “−”, “+”, “≈” denote performance of VPL is worse, better and similar to SGO respectively and same, best and worse are the similar, better and
worse solution of SGO then VPL algorithm in term of the best result 123 Complex & Intelligent Systems (2021) 7:249–295 272 optimum for functions F2, F19, F20, F21, F26. For function
F3, F4, F6, F12, F13, F14, F19, F21, F22, F27, F28, F29,
F36, F37, F48, F49, SGO finds better results than SELO
algorithm. For F23, F24, F31, F34, F39, F40, F41 function
SELO finds better results than SGO algorithm. optimum for functions F2, F19, F20, F21, F26. For function
F3, F4, F6, F12, F13, F14, F19, F21, F22, F27, F28, F29,
F36, F37, F48, F49, SGO finds better results than SELO
algorithm. For F23, F24, F31, F34, F39, F40, F41 function
SELO finds better results than SGO algorithm. such as unimodal, multimodal, separable, and non-separable
[132–134]. All benchmark test problems are divided into
four categories, such as unimodal separable (US), multi-
modal separable (MS), unimodal non-separable (UN), and
multimodal non-separable (MN). 123 Discussion According to parameter settings of the HHO algorithm
in its respective paper [31], the common control parameter,
such as a maximum number of iterations is 500, and Pop_size
is 30. So, for the GOA algorithm and SSA algorithm, the
maximum number of iteration and pop_size is set to 500 According Table 21, SGO algorithm achieves success in find-
ing global optimum on F1, F5, F11, F14–F18, F25, F30, F33,
F35, F36, F37, F38, F42–F47, F50 functions and near-global 123 273 Complex & Intelligent Systems (2021) 7:249–295 Table 21 Comparison on SELO and SGO on 30 repetitions
Fun no. Function name
Algorithms
Mean
WRS t
F1
Foxholes
SELO
0.9980038538690870
SGO(1)
0.998003837794450
≈
SGO(2)
0.998003837794450
≈
F2
Goldstein-Price
SELO
3.0013971187248700
SGO(1)
2.999999999999922
≈
SGO(2)
2.999999999999932
≈
F3
Penalized
SELO
0.2899597890213580
SGO(1)
6.626245443150890e−08
−
SGO(2)
0.010200028675921
−
F4
Penalizd2
SELO
2.3720510573781100
SGO(1)
2.877561733141524e−06
−
SGO(2)
0.085954598316699
−
F5
Ackley
SELO
0.0000000000000000
SGO(1)
0
≈
SGO(2)
0
≈
F6
Beale
SELO
0.0000997928359263
SGO(1)
4.368615398517635e−13
−
SGO(2)
1.895031504568669e−06
−
F7
Bonachevsky1
SELO
0.0000000000000000
SGO(1)
0.0000000000000000
≈
SGO(2)
0.0000000000000000
≈
F8
Bonachevsky2
SELO
0.0000000000000000
SGO(1)
0.0000000000000000
≈
SGO(2)
0.0000000000000000
≈
F9
Bonachevsky3
SELO
0.0000000000000000
SGO(1)
0.0000000000000000
≈
SGO(2)
0.0000000000000000
≈
F10
Booth
SELO
0.0000000000000000
SGO(1)
0.0000000000000000
≈
SGO(2)
0.0000000000000000
≈
F11
Branin
SELO
0.3978943993817670
SGO(1)
0.397887357729738
≈
SGO(2)
0.397887357747411
≈
F12
Colville
SELO
3.6688019971758100
SGO(1)
1.507864423649453e−04
≈
SGO(2)
0.882361880633636
≈
F13
Dixon-Price
SELO
0.9737369841168760
SGO(1)
0.666666670526110
−
SGO(2)
0.676421575540618
−
F14
Easom
SELO
0.0000000000000000*
SGO(1)
−1
−
SGO(2)
−1
−
F15
Fletcher
SELO
0.0000000000000000
SGO(1)
0.0000000000000000
≈
SGO(2)
2.150797382901120e−06
+
F16
Fletcher
SELO
0.0000000000000000
SGO(1)
0.0000000000000000
≈
SGO(2)
2.467632725158199e−05
+
F17
Fletcher
SELO
0.0000000000000000
SGO(1)
0.0000000000000000
≈ Table 21 Comparison on SELO and SGO on 30 repetitions
Fun no. 123 Discussion Function name
Algorithms
Mean
WRS t
SGO(2)
3.080801090891568e−05
+
F18
Griewank
SELO
0.0000000000000000
SGO(1)
0
≈
SGO(2)
0
≈
F19
Hartman3
SELO
−2.2922815000937700
SGO(1)
−3.862782147820754
−
SGO(2)
−3.862782147820719
−
F20
Hartman6
SELO
−1.1719158908829300
SGO(1)
−3.322368011415514
−
SGO(2)
−3.322364207472817
−
F21
Kowalik
SELO
0.0003493601571991
SGO(1)
3.076983923252769e−04
−
SGO(2)
3.077095661972494e−04
−
F22
Langermann2
SELO
−1.0835400071766800
SGO(1)
−1.811847812568286
−
SGO(2)
−1.805545479911096
−
F23
Langermann5
SELO
−1.4999998390866700
SGO(1)
−1.0966771227191070
+
SGO(2)
−1.096643509059383
+
F24
Langermann10
SELO
−1.4999991427332700
SGO(1)
−0.758576555648690
+
SGO(2)
−0.336386278772926
+
F25
Matyas
SELO
0.0000000000000000
SGO(1)
0
≈
SGO(2)
0
≈
F26
Michalewicz2
SELO
−1.8166465888521900*
SGO(1)
−1.801303410098554
−
SGO(2)
−1.801303410098554
−
F27
Michalewicz5
SELO
−3.3591408962129900
SGO(1)
−4.630088626421673
−
SGO(2)
−4.470327732745007
−
F28
Michalewicz10
SELO
−3.9793838974626000
SGO(1)
−9.006441111102800
−
SGO(2)
−9.000011111102800
−
F29
Perm
SELO
2.0169277899221400
SGO(1)
0.118539980853471
−
SGO(2)
1.561978679351149
−
F30
Powell
SELO
0.0000000000000000
SGO(1)
0
≈
SGO(2)
0
≈
F31
Powersum
SELO
0.0000000000000000
SGO(1)
0.006946315911962
+
SGO(2)
0.098635720687768
+
F32
Quartic
SELO
0.0000989055208389
SGO(1)
2.4890e−05
≈
SGO(2)
5.600438682972288e−04
≈
F33
Rastrigin
SELO
0.0000000000000000
SGO(1)
0
≈
SGO(2)
0
≈
F34
Rosenbrock
SELO
0.0000000000000000
SGO(1)
25.035766221298609
+ Table 21 continued
Fun no. Discussion Function name
Algorithms
Mean
WRS test
Std
Best
F1
Foxholes
SELO
0.9980038538690870
0.0000013769725269
0.9980038383022720
SGO(1)
0.998003837794450
≈
0
0.998003837794450
SGO(2)
0.998003837794450
≈
0
0.998003837794450
F2
Goldstein-Price
SELO
3.0013971187248700
0.0018936009191261
3.0000021202023800
SGO(1)
2.999999999999922
≈
0
2.999999999999922
SGO(2)
2.999999999999932
≈
0
2.999999999999922
F3
Penalized
SELO
0.2899597890213580
0.0159272187796787
0.2497905224307240
SGO(1)
6.626245443150890e−08
−
7.52597822238106e−08
3.058821148321699e−09
SGO(2)
0.010200028675921
−
0.009202450188521
0.001628725501707
F4
Penalizd2
SELO
2.3720510573781100
0.1531241868389090
2.0664368584658500
SGO(1)
2.877561733141524e−06
−
5.85184409308598e−06
7.490617403906734e−08
SGO(2)
0.085954598316699
−
0.054697463554651
0.014253156952674
F5
Ackley
SELO
0.0000000000000000
0.0000000000000000
0.0000000000000000
SGO(1)
0
≈
0
0
SGO(2)
0
≈
0
0
F6
Beale
SELO
0.0000997928359263
0.0001311815541321
0.0000007530509495
SGO(1)
4.368615398517635e−13
−
5.28892784615697e−13
0
SGO(2)
1.895031504568669e−06
−
2.60630701264704e−06
1.104986488459038e−08
F7
Bonachevsky1
SELO
0.0000000000000000
0.0000000000000000
0.0000000000000000
SGO(1)
0.0000000000000000
≈
0.0000000000000000
0.0000000000000000
SGO(2)
0.0000000000000000
≈
0.0000000000000000
0.0000000000000000
F8
Bonachevsky2
SELO
0.0000000000000000
0.0000000000000000
0.0000000000000000
SGO(1)
0.0000000000000000
≈
0.0000000000000000
0.0000000000000000
SGO(2)
0.0000000000000000
≈
0.0000000000000000
0.0000000000000000
F9
Bonachevsky3
SELO
0.0000000000000000
0.0000000000000001
0.0000000000000000
SGO(1)
0.0000000000000000
≈
0.0000000000000000
0.0000000000000000
SGO(2)
0.0000000000000000
≈
0.0000000000000000
0.0000000000000000
F10
Booth
SELO
0.0000000000000000
0.0000000000000000
0.0000000000000000
SGO(1)
0.0000000000000000
≈
0.0000000000000000
0.0000000000000000
SGO(2)
0.0000000000000000
≈
0.0000000000000000
0.0000000000000000
F11
Branin
SELO
0.3978943993817670
0.0003536060523484
0.3978822494361650
SGO(1)
0.397887357729738
≈
0
0.397887357729738
SGO(2)
0.397887357747411
≈
5.5627150160592e−11
0.397887357729738
F12
Colville
SELO
3.6688019971758100
1.7577708967227600
0.8388908577815620
SGO(1)
1.507864423649453e−04
≈
2.96207622896498e−04
5.829850050174075e−10
SGO(2)
0.882361880633636
≈
1.387258853940873
1.154167980463728e−04
F13
Dixon-Price
SELO
0.9737369841168760
0.0054869670667257
0.9541730938494050
SGO(1)
0.666666670526110
−
5.3066451465398e−09
0.666666666666667
SGO(2)
0.676421575540618
−
0.003921661696013
0.671115588054493
F14
Easom
SELO
0.0000000000000000*
0.1083854312160620
0.5936514558196160*
SGO(1)
−1
−
0
−1
SGO(2)
−1
−
0
−1
F15
Fletcher
SELO
0.0000000000000000
0.0000000000000000
0.0000000000000000
SGO(1)
0.0000000000000000
≈
0.0000000000000000
0.0000000000000000
SGO(2)
2.150797382901120e−06
+
7.05840633570035e−05
3.013791380954771e−09
F16
Fletcher
SELO
0.0000000000000000
0.0000000000000000
0.0000000000000000
SGO(1)
0.0000000000000000
≈
0.0000000000000000
0.0000000000000000
SGO(2)
2.467632725158199e−05
+
5.2319588043272e−04
2.980057177690114e−09
F17
Fletcher
SELO
0.0000000000000000
0.0000000000000000
0.0000000000000000
SGO(1)
0.0000000000000000
≈
0.0000000000000000
0.0000000000000000 1 Comparison on SELO and SGO on 30 repetitions Std
Best
0.0000013769725269
0.9980038383022720
0
0.998003837794450
0
0.998003837794450
0.0018936009191261
3.0000021202023800
0
2.999999999999922
0
2.999999999999922
0.0159272187796787
0.2497905224307240
7.52597822238106e−08
3.058821148321699e−09
0.009202450188521
0.001628725501707
0.1531241868389090
2.0664368584658500
5.85184409308598e−06
7.490617403906734e−08
0.054697463554651
0.014253156952674
0.0000000000000000
0.0000000000000000
0
0
0
0
0.0001311815541321
0.0000007530509495
5.28892784615697e−13
0
2.60630701264704e−06
1.104986488459038e−08
0.0000000000000000
0.0000000000000000
0.0000000000000000
0.0000000000000000
0.0000000000000000
0.0000000000000000
0.0000000000000000
0.0000000000000000
0.0000000000000000
0.0000000000000000
0.0000000000000000
0.0000000000000000
0.0000000000000001
0.0000000000000000
0.0000000000000000
0.0000000000000000
0.0000000000000000
0.0000000000000000
0.0000000000000000
0.0000000000000000
0.0000000000000000
0.0000000000000000
0.0000000000000000
0.0000000000000000
0.0003536060523484
0.3978822494361650
0
0.397887357729738
5.5627150160592e−11
0.397887357729738
1.7577708967227600
0.8388908577815620
2.96207622896498e−04
5.829850050174075e−10
1.387258853940873
1.154167980463728e−04
0.0054869670667257
0.9541730938494050
5.3066451465398e−09
0.666666666666667
0.003921661696013
0.671115588054493
0.1083854312160620
0.5936514558196160*
0
−1
0
−1
0.0000000000000000
0.0000000000000000
0.0000000000000000
0.0000000000000000
7.05840633570035e−05
3.013791380954771e−09
0.0000000000000000
0.0000000000000000
0.0000000000000000
0.0000000000000000
5.2319588043272e−04
2.980057177690114e−09
0.0000000000000000
0.0000000000000000
0.0000000000000000
0.0000000000000000 Complex & Intelligent Systems (2021) 7:249–295 274 Table 21 continued
Fun no. Discussion Function name
Algorithms
Mean
WRS test
Std
Best
SGO(2)
3.080801090891568e−05
+
6.0194808128832e−05
0.274919045293553e−09
F18
Griewank
SELO
0.0000000000000000
0.0000000000000000
0.0000000000000000
SGO(1)
0
≈
0
0
SGO(2)
0
≈
0
0
F19
Hartman3
SELO
−2.2922815000937700
0.5795350381767260
−3.5841184056629400
SGO(1)
−3.862782147820754
−
0
−3.862782147820756
SGO(2)
−3.862782147820719
−
6.5228542918761e−14
−3.862782147820755
F20
Hartman6
SELO
−1.1719158908829300
0.0003690446342091
−1.1727699585993300
SGO(1)
−3.322368011415514
−
0
−3.322368011415516
SGO(2)
−3.322364207472817
−
0.026555990240542
−3.322367990993992
F21
Kowalik
SELO
0.0003493601571991
0.0000226057336871
0.0003226283751593
SGO(1)
3.076983923252769e−04
−
5.61846636883800e−07
3.074859878057995e−04
SGO(2)
3.077095661972494e−04
−
1.0500275462894e−04
3.076322880214414e−04
F22
Langermann2
SELO
−1.0835400071766800
0.5277882902242550
−2.1933014645645000
SGO(1)
−1.811847812568286
−
0.005275898770057
−1.816046503083688
SGO(2)
−1.805545479911096
−
0.043450476166699
−1.816031587779646
F23
Langermann5
SELO
−1.4999998390866700
0.0000000818646069
−1.4999999590992100
SGO(1)
−1.0966771227191070
+
0.169499381875222
−1.096711632260348
SGO(2)
−1.096643509059383
+
0.252772872708808
−1.096671357897672
F24
Langermann10
SELO
−1.4999991427332700
0.0000003717669841
−1.4999999303979900
SGO(1)
−0.758576555648690
+
0.298898483760396
−1.096671262010903
SGO(2)
−0.336386278772926
+
0.222342169689975
−1.096613119161391
F25
Matyas
SELO
0.0000000000000000
0.0000000000000000
0.0000000000000000
SGO(1)
0
≈
0
0
SGO(2)
0
≈
0
0
F26
Michalewicz2
SELO
−1.8166465888521900*
0.0072804985619476
−1.8106292157333700*
SGO(1)
−1.801303410098554
−
6.83438873551149e−16
−1.801303410098554
SGO(2)
−1.801303410098554
−
9.42055475210266e−16
−1.801303410098554
F27
Michalewicz5
SELO
−3.3591408962129900
0.2009584117455920
−3.9631157953194900
SGO(1)
−4.630088626421673
−
0.065864489928322
−4.687658179088150
SGO(2)
−4.470327732745007
−
0.185850086498683
−4.687327806500385
F28
Michalewicz10
SELO
−3.9793838974626000
0.0005104314209355
−3.9806353395021300
SGO(1)
−9.006441111102800
−
0.311393097467809
−9.443832461708885
SGO(2)
−9.000011111102800
−
0.216734109908823
−9.22441111102800
F29
Perm
SELO
2.0169277899221400
1.2374893392409200
0.3208703882956150
SGO(1)
0.118539980853471
−
0.177190100467076
8.561870933468390e−04
SGO(2)
1.561978679351149
−
1.880078781358827
0.100091999152719
F30
Powell
SELO
0.0000000000000000
0.0000000000000000
0.0000000000000000
SGO(1)
0
≈
0
0
SGO(2)
0
≈
0
0
F31
Powersum
SELO
0.0000000000000000
0.0000000000000000
0.0000000000000000
SGO(1)
0.006946315911962
+
0.007668016054973
2.606821962241941e−04
SGO(2)
0.098635720687768
+
0.084418253336401
0.010937757009189
F32
Quartic
SELO
0.0000989055208389
0.0000521772789680
0.0000104209894311
SGO(1)
2.4890e−05
≈
1.0695e−05
4.0050e−06
SGO(2)
5.600438682972288e−04
≈
3.86799368671367e−04
7.704746295587896e−05
F33
Rastrigin
SELO
0.0000000000000000
0.0000000000000000
0.0000000000000000
SGO(1)
0
≈
0
0
SGO(2)
0
≈
0
0
F34
Rosenbrock
SELO
0.0000000000000000
0.0000000000000000
0.0000000000000000
SGO(1)
25.035766221298609
+
0.611250805204646
23.907706666327510 Complex & Intelligent Systems (2021) 7:249–295 275 Table 21 continued
Fun no. Discussion Function name
Algorithms
Mean
WRS t
SGO(2)
28.429285971794421
+
F35
Schaffer
SELO
0.0000000000000000
SGO(1)
0
≈
SGO(2)
0.002428978248610
+
F36
Schwefel
SELO
−0.3402784042291390
SGO(1)
−
8.461065358958511e+03
−
SGO(2)
−
5.205982653292700e+03
−
F37
Schwefel 1.2
SELO
0.0000000000000009
SGO(1)
0
−
SGO(2)
0
−
F38
Schwefel 2.22
SELO
0.000000000000000
SGO(1)
0
≈
SGO(2)
0
≈
F39
Shekel10
SELO
−10.536281667618100
SGO(1)
−8.128589453290765
+
SGO(2)
−7.893427865009119
+
F40
Shekel5
SELO
−10.1531669871808000
SGO(1)
−7.05529877773245551
+
SGO(2)
−5.98564390999007122
+
F41
Shekel17
SELO
−10.4028748144797000
SGO(1)
−8.2648567899765433
+
SGO(2)
−6.98877811908877666
+
F42
Shubert
SELO
−
186.7153981691330000
SGO(1)
−
1.867309088310239e+02
−
SGO(2)
−
1.867309025071344e+02
−
F43
Six ump camelback
SELO
−1.0303924506027700
SGO(1)
−1.031628453489878
−
SGO(2)
−1.031628453489878
−
F44
Sphere2
SELO
0.000000000000000
SGO(1)
0
≈
SGO(2)
0
≈
F45
Step2
SELO
0.0000000000000010
SGO(1)
0
−
SGO(2)
0
−
F46
Stepint
SELO
0.0000000000000000
SGO(1)
0
≈
SGO(2)
0
≈
F47
Sumsquares
SELO
0.0000000000000000
SGO(1)
0
≈
SGO(2)
0
≈
F48
Trid6
SELO
−46.672022811734100
SGO(1)
−50.000000000000128
−
SGO(2)
−49.271240785282032
−
F49
Trid10
SELO
−162.571266865506000
SGO(1)
−
2.099999999933476e+02
− Table 21 continued
Fun no. 123 Discussion Function name
Algorithms
Mean
WRS test
Std
Best
SGO(2)
28.429285971794421
+
0.148799583491346
28.038832676808092
F35
Schaffer
SELO
0.0000000000000000
0.0000000000000000
0.0000000000000000
SGO(1)
0
≈
0
0
SGO(2)
0.002428978248610
+
0.004316407618997
0
F36
Schwefel
SELO
−0.3402784042291390
3.2212919091274600
−0.0325083488969540
SGO(1)
−
8.461065358958511e+03
−
1.51802365024271e+03
−
1.114791885433872e+04
SGO(2)
−
5.205982653292700e+03
−
1.06445694628382e+03
−
8.685216618435348e+03
F37
Schwefel 1.2
SELO
0.0000000000000009
0.0000000000000001
0.0000000000000007
SGO(1)
0
−
0
0
SGO(2)
0
−
0
0
F38
Schwefel 2.22
SELO
0.000000000000000
0.000000000000000
0.000000000000000
SGO(1)
0
≈
0
0
SGO(2)
0
≈
0
0
F39
Shekel10
SELO
−10.536281667618100
0.0000481237097736
−10.5363928369535000
SGO(1)
−8.128589453290765
+
3.74659045343333e−04
−10.5363989876543000
SGO(2)
−7.893427865009119
+
3.39874357819912
−9.06579934232111154
F40
Shekel5
SELO
−10.1531669871808000
0.0000172333322304
−10.1531973132210000
SGO(1)
−7.05529877773245551
+
9.03368988843222e−03
−
10.15329067674322995
SGO(2)
−5.98564390999007122
+
3.9067544443900010
−8.95647808884321001
F41
Shekel17
SELO
−10.4028748144797000
0.0000478046191696
−10.4029869270437000
SGO(1)
−8.2648567899765433
+
0.970478900654556
−10.402989342189900
SGO(2)
−6.98877811908877666
+
3.897656789000011
−9.9009015643335678
F42
Shubert
SELO
−
186.7153981691330000
0.0190762312882078
−
186.7363874875390000
SGO(1)
−
1.867309088310239e+02
−
2.35095908427784e−14
−
1.867309088310239e+02
SGO(2)
−
1.867309025071344e+02
−
2.79033681398514e−05
−
1.867309088310239e+02
F43
Six ump camelback
SELO
−1.0303924506027700
0.0025133845110030
−1.0314918740874000
SGO(1)
−1.031628453489878
−
1.4408156546143e−16
−1.031628453489878
SGO(2)
−1.031628453489878
−
1.44081565461429e−16
−1.031628453489878
F44
Sphere2
SELO
0.000000000000000
0.000000000000000
0.000000000000000
SGO(1)
0
≈
0
0
SGO(2)
0
≈
0
0
F45
Step2
SELO
0.0000000000000010
0.0000000000000001
0.0000000000000006
SGO(1)
0
−
0
0
SGO(2)
0
−
0
0
F46
Stepint
SELO
0.0000000000000000
0.0000000000000000
0.0000000000000000
SGO(1)
0
≈
0
0
SGO(2)
0
≈
0
0
F47
Sumsquares
SELO
0.0000000000000000
0.0000000000000000
0.0000000000000000
SGO(1)
0
≈
0
0
SGO(2)
0
≈
0
0
F48
Trid6
SELO
−46.672022811734100
1.1721159591339900
−48.933141750726300
SGO(1)
−50.000000000000128
−
2.3509590842779e−14
−50.000000000000171
SGO(2)
−49.271240785282032
−
0.976855025960445
−49.999991413401290
F49
Trid10
SELO
−162.571266865506000
−162.571266865506000
−162.922114827822000
SGO(1)
−
2 099999999933476
02
−
1.2523636396815e−08
−
2 100000000000009
02 t
Std
Best
0.148799583491346
28.038832676808092
0.0000000000000000
0.0000000000000000
0
0
0.004316407618997
0
3.2212919091274600
−0.0325083488969540
1.51802365024271e+03
−
1.114791885433872e+04
1.06445694628382e+03
−
8.685216618435348e+03
0.0000000000000001
0.0000000000000007
0
0
0
0
0.000000000000000
0.000000000000000
0
0
0
0
0.0000481237097736
−10.5363928369535000
3.74659045343333e−04
−10.5363989876543000
3.39874357819912
−9.06579934232111154
0.0000172333322304
−10.1531973132210000
9.03368988843222e−03
−
10.15329067674322995
3.9067544443900010
−8.95647808884321001
0.0000478046191696
−10.4029869270437000
0.970478900654556
−10.402989342189900
3.897656789000011
−9.9009015643335678
0.0190762312882078
−
186.7363874875390000
2.35095908427784e−14
−
1.867309088310239e+02
2.79033681398514e−05
−
1.867309088310239e+02
0.0025133845110030
−1.0314918740874000
1.4408156546143e−16
−1.031628453489878
1.44081565461429e−16
−1.031628453489878
0.000000000000000
0.000000000000000
0
0
0
0
0.0000000000000001
0.0000000000000006
0
0
0
0
0.0000000000000000
0.0000000000000000
0
0
0
0
0.0000000000000000
0.0000000000000000
0
0
0
0
1.1721159591339900
−48.933141750726300
2.3509590842779e−14
−50.000000000000171
0.976855025960445
−49.999991413401290
−162.571266865506000
−162.922114827822000
1.2523636396815e−08
−
2.100000000000009e+02 123 Complex & Intelligent Systems (2021) 7:249–295 276 Table 21 continued
Fun no. Discussion Function name
Algorithms
Mean
WRS test
Std
Best
SGO(2)
−
2.021218477684638e+02
−
1.27911440793196007
−
2.04763477684638e+02
F50
Zakharov
SELO
0.0000000000000000
0.0000000000000000
0.0000000000000000
SGO(1)
0
≈
0
0
SGO(2)
0
≈
0
0
Total + for SGO(1)
07
Total + for SGO(2)
11
Total −for SGO(1)
19
Total −for SGO(2)
19
Total ≈for SGO(1)
24
Total ≈for SGO(2)
20
“−”, “+”, “≈” denote performance of SELO is worse, better and similar to SGO respectively and 30, respectively. For the SGO algorithm, the maximum
number iteration is set to 250.and pop_size is set 30. Hence
max_FEs for SGO (2×30×250) are the same with other
algorithms. The other specific parameters for each algorithm
are given below. algorithms. It is clear from the results that SGO achieves
success in finding global optimum on F1, F3, F9, and F11. HHO algorithm makes success in finding global optimum
for the function F9 and F11. For F5, F6, F8, F12, F13, the
performance of HHO is better than SSA, GOA, and SGO,
whereas, for F1, F2, F3, F4, F7, the performance of SGO is
better than HHO, SSA, and GOA. For F19, F10, and F11,
both HHO and SGO find equivalent solutions. • SGO setting: For SGO, there is only one parameter C
called a self-introspection factor. The value of C is empir-
ically set 0.2. From Table 22, according to the WRS test, we find that
the SGO algorithm performs superior to the HHO algo-
rithm in five cases, equivalent with four cases out of 13 in
30-dimensional functions. Similarly, the SGO algorithm per-
forms superior to the SSA algorithm in 12 cases and from
the GOA algorithm in 13 cases out of 13. In contrast, the
HHO algorithm performs superior to the SGO algorithm
in four cases, and the SSA algorithm performs superior to
SGO in one case. Hence it is seen that the SGO algorithm is
outperforming than HHO, SSA, and GOA algorithm in solv-
ing 30-dimensional benchmark functions. From Table 23,
according to the WRS test, we find that the SGO algorithm
performs superior to the HHO algorithm in five cases, equiv-
alent with three cases out of 13 in 100-dimensional functions. Discussion • SSA settings: For SSA, there is a parameter c1 2 ×
e−( 4
L )2
, where L max_iteration 500 as in [27] • GOA settings: For GOA, cmax=1, cmin 0.00004 for find-
ing value of c cmax −l × ((cmax −cmin)/Max_iter),
Max_iter 500 as in [28] • HHO setting: referred to paper [31]. In this experiment, all algorithms are utilized to tackle
scalable unimodal and multimodal F1–F13 test cases with
30, 100, 500, and 1000 dimensions. For each benchmark-
function, algorithms are run 30 times with different ran-
domly generated populations. Statistical results in terms of
mean value, corresponding standard-deviation are reported
in tables. Table 22 reports the result for 30 dimensions. Table
23 reports the result for 100 dimensions. Table 24 reports the
result for 500 dimensions. Table 25 reports the result for 1000
dimensions, and Table 26 reports the result for fixed dimen-
sional multimodal and composite benchmark functions. For
every benchmark function, the best results are boldfaced. Similarly, the SGO algorithm performs superior to the
SSA algorithm in 13 cases and from the GOA algorithm in
13 cases out of 13. In contrast, the HHO algorithm performs
superior to the SGO algorithm in five cases. Hence it is seen
that both SGO and HHO algorithms are performing equiv-
alent performance, and both SGO and HHO algorithms are
outperforming than SSA and GOA algorithm in solving 100-
dimensional benchmark functions. From Table 24, according
to the WRS test, we find that the SGO algorithm performs
superior to the HHO algorithm in five cases, equivalent with
three cases out of 13 in 500-dimensional functions. Similarly,
the SGO algorithm performs superior to the SSA algorithm
in 13 cases and from the GOA algorithm in 13 cases out
of 13. In contrast, the HHO algorithm performs superior to
the SGO algorithm in five cases. Hence it is seen that the
SGO algorithm is performing equivalent performance with
the HHO algorithm and outperforming than SSA and GOA
algorithm in solving 500-dimensional benchmark functions. To obtain statistically sound conclusions, the WRS test at
a 0.05 significance level is conducted on experimental results
of Tables 22, 23, 24, 25 and 26 and reported in their respective
tables. The last three rows of each respective table summarize
experimental results. 123 Discussion According to Tables 22, 23, 24 and 25, SGO has gained the
bestperformanceandconsistentlyperformedbetterthanSSA
and GOA algorithms. 123 “−”, “+”, “≈” denote that performance of HHO, SSA and GOA are worse, better and similar to SGO
respectively Table 23 Comparison result on
HHO, SSA, GOA and SGO on
3O repetitions on 100 dimension 123 “−”, “+” and “≈” denote that performance of HHO, SSA, and GOA are worse, better and similar to SGO
respectively Discussion SGO has an excellent performance in
exploitation as well as an exploration than SSA and GOA Complex & Intelligent Systems (2021) 7:249–295 277 Functions
HHO
SSA
GOA
SGO
Results
WRS test
Results
WRS test
Results
WRS test
Results
F1
Mean
3.95e−97
−
2.6663e−07
−
32.1323
−
0
Std
1.72e−96
3.3145e−07
25.0649
0
F2
Mean
1.56e−51
−
2.7193
−
9.6642
−
4.1502e−173
Std
6.98e−51
1.9372
4.7732
0
F3
Mean
1.92e−6
−
1.3772e+03
−
2.7763e+03
−
0
Std
1.05e−62
663.1158
979.5025
0
F4
Mean
1.02e−47
−
11.3980
−
13.3983
−
1.5744e−173
Std
5.01e−47
3.1804
1.8694
0
F5
Mean
1.32e−02
+
311.3904
−
4.6817e+03
−
26.4532
Std
1.87e−02
469.2823
2.9084e+03
0.5254
F6
Mean
1.15e−04
≈
2.1058e−07
+
26.9521
−
1.5225e−04
Std
1.56e−04
3.8546e−07
12.3120
0.0081
F7
Mean
1.40e−04
−
0.1738
−
0.0405
−
7.5202e−05
Std
1.07e−04
0.0768
0.0106
5.2364e−05
F8
Mean
−1.25e+04
+
−
7.4013e+03
−
−
7.3496e+03
−
−
8.4145e+03
Std
1.47e+02
639.3972
479.3866
1.0912e+03
F9
Mean
0.00e+00
≈
54.2915
−
81.0099
−
0
Std
0.00e+00
22.3942
22.1101
0
F10
Mean
8.88e−16
≈
2.4587
−
4.6578
−
8.8818e−16
Std
4.01e−31
0.8542
0.7395
0
F11
Mean
0.00e+00
≈
0.0195
−
1.0406
−
0
Std
0.00e+00
0.0167
0.1348
0
F12
Mean
2.08e−06
+
6.1578
−
7.4999
−
9.3737e−05
Std
1.19e−05
2.2550
3.3588
2.1044e−04
F13
Mean
1.57e−04
+
12.0079
−
49.1074
−
3.3322e−04
Std
2.15e−04
15.4045
14.0232
2.3423e−03
Total +
04
01
00
Total −
05
12
13
Total ≈
04
00
00
“−”, “+”, “≈” denote that performance of HHO, SSA and GOA are worse, better and similar to SGO Complex & Intelligent Systems (2021) 7:249–295 278 Functions
HHO
SSA
GOA
SGO
Results
WRS test
results
WRS test
Results
WRS test
Results
F1
Mean
1.91e−94
−
1.3120e+03
−
1.1420e+04
−
0
Std
8.66e−94
368.2236
1.2257e+03
0
F2
Mean
9.98e−52
−
46.1574
−
91.9275
−
6.1579e−173
Std
2.66e−51
7.0802
9.9197
0
F3
Mean
1.84e−59
−
5.4964e+04
−
6.2409e+04
−
0
Std
1.01e−58
3.0366e+04
1.0232e+04
0
F4
Mean
8.76e−47
−
28.6121
−
30.7976
−
1.7327e−173
Std
4.79e−46
3.1910
3.7461
0
F5
Mean
2.36e−02
+
1.5948e+05
−
3.9104e+06
−
96.7537
Std
2.99e−02
7.3288e+04
1.1528e+06
0.4560
F6
Mean
5.12e−04
+
1.4014e+03
−
1.1686e+04
−
0.0285
Std
6.77e−04
421.3000
1.5398e+03
0.1388
F7
Mean
1.85e−04
−
2.6735
−
0.6814
−
7.1811e−05
Std
4.06e−04
0.5435
0.1922
5.0044e−05
F8
Mean
−4.19e+04
+
−
2.1568e+04
−
−
1.7308e+04
−
−
2.4282e+04
Std
2.82e+00
1.5894e+03
2.4081e+03
4.7056e+03
F9
Mean
0.00e+00
≈
232.0861
−
404.9512
−
0
Std
0.00e+00
43.8589
39.2338
0
F10
Mean
8.88e−16
≈
9.9830
−
13.3441
−
8.8818e−16
Std
4.01e−31
1.0140
0.7088
0
F11
Mean
0.00e+00
≈
15.0274
−
101.8061
−
0
Std
0.00e+00
4.5248
10.9556
0
F12
Mean
4.23e−06
+
33.1875
−
7.6639e+03
−
2.2716e−04
Std
5.25e−06
11.1185
8.7399e+03
0.0018
F13
Mean
9.13e−05
+
7.9763e+03
−
2.6647e+06
−
0.0230
Std
1.26e−04
1.3000e+04
2.1350e+06
1.7442
Total +
05
00
00
Total −
05
13
13
Total ≈
03
00
00
“−”, “+”, “≈” denote that performance of HHO, SSA and GOA are worse, better and similar to SGO 123 123 Complex & Intelligent Systems (2021) 7:249–295 279 Functions
HHO
SSA
GOA
SGO
Results
WRS test
Results
WRS test
Results
WRS test
Results
F1
Mean
1.46e−92
−
9.4569e+04
−
8.7478e+04
−
0
Std
8.01e−92
6.2059e+03
4.3559e+03
0
F2
Mean
7.87e−49
−
530.3178
−
500.1891
−
4.2194e−172
Std
3.11e−48
19.8194
10.6519
0
F3
Mean
6.54e−37
−
1.4517e+06
−
4.5669e+14
−
0
Std
3.58e−36
6.2641e+05
2.9900e+14
0
F4
Mean
1.29e−47
−
40.1866
−
32.9244
−
1.7939e−173
Std
4.11e−47
2.7635
41.9023
0
F5
Mean
3.10e−01
+
3.6217e+07
−
7.6774e+07
−
493.9169
Std
3.73e−01
4.2649e+06
6.9429e+06
0.3720
F6
Mean
2.94e−03
+
9.3480e+04
−
1.3352e+05
−
4.6227
Std
3.98e−03
7.0249e+03
8.7871e+03
2.4453
F7
Mean
2.51e−04
−
276.0543
−
117.6845
−
9.3814e−05
Std
2.43e−04
45.7197
267.8912
5.8056e−05
F8
Mean
−2.09e+05
+
−
5.9853e+04
−
−
4.7092e+04
−
−
8.2593e+04
Std
2.84e+01
4.2282e+03
2.9012e+04
2.2958e+04
F9
Mean
0.00e+00
≈
3.1838e+03
−
4.8912e+03
−
0
Std
0.00e+00
119.4264
2.7615e+03
0
F10
Mean
8.88e−16
≈
14.2634
−
891.2316
−
8.8818e−16
Std
4.01e−31
0.2265
262.5149
0
F11
Mean
0.00e+00
≈
854.4929
−
13.0011
−
0
Std
0.00e+00
66.3466
0.9623
0
F12
Mean
1.41e−06
+
1.3346e+06
−
1.8308e+07
−
8.5429e−04
Std
1.48e−06
8.0189e+05
4.5409e+06
0.0113
F13
Mean
3.44e−04
+
3.6253e+07
−
9.6599e+07
0.3790
Std
4.75e−04
9.4885e+06
2.9012e+06
19.2315
Total +
05
00
00
Total −
05
13
13
Total ≈
03
00
00
“−”, “+” and “≈” denote that performance of HHO, SSA, and GOA are worse, better and similar to SGO Complex & Intelligent Systems (2021) 7:249–295 280 Functions
HHO
SSA
GOA
SGO
Results
WRS test
Results
WRS test
Results
WRS test
Results
F1
Mean
1.06e−94
−
2.3895e+05
−
4.6729e+05
−
0
Std
4.97e−94
1.0130e+04
3.9023e+04
0
F2
Mean
2.52e−50
−
1.1980e+03
−
978.7342
−
8.8515e−172
Std
5.02e−50
25.9659
23.3419
0
F3
Mean
1.79e−17
−
5.5065e+06
−
4.8911e+16
−
0
Std
9.81e−17
2.1001e+06
2.0211e+16
0
F4
Mean
1.43e−46
−
46.0339
−
61.5621
−
1.8015e−173
Std
7.74e−46
2.2454
10.9793
0
F5
Mean
5.73e−01
+
1.2061e+08
−
2.0374e+08
−
989.8076
Std
1.40e+00
1.0872e+07
1.8934e+07
0.9994
F6
Mean
3.61e−03
+
2.2885e+05
−
2.9168e+05
−
10.8339
Std
5.38e−03
9.0680e+03
5.8715e+03
6.4262
F7
Mean
1.41e−04
−
1.7908e+03
−
680.8912
−
7.5620e−05
Std
1.63e−04
178.7950
92.1475
4.7538e−05
F8
Mean
−4.19e+05
+
−
8.7049e+04
−
−
6.4190e+04
−
−
1.5102e+05
Std
1.03e+02
9.3834e+03
3.5412e+03
4.7114e+04
F9
Mean
0.00e+00
≈
7.5972e+03
−
7.0342e+03
−
0
Std
0.00e+00
205.0048
3.7534e+03
0
F10
Mean
8.88e−16
≈
14.5380
−
3.6790e+03
−
8.8818e−16
Std
4.01e−31
0.1588
1.1832e+03
0
F11
Mean
0.00e+00
≈
2.1056e+03
−
13.9612
−
0
Std
0.00e+00
102.3777
0.4812
0
F12
Mean
1.02e−06
+
1.1915e+07
−
3.8182e+07
−
0.0022
Std
1.16e−06
3.2836e+06
1.9756e+07
0.0078
F13
Mean
8.41e−04
+
1.4035e+08
−
3.5707e+08
−
2.0727
Std
8.41e−04
1.9003e+07
6.4523e+07
42.0966
Total +
05
00
00
Total −
05
13
13
Total ≈
03
00
00
“−”, “+” and “≈” denote that performance of HHO, SSA, and GOA are worse, better and similar to SGO Table 25 Comparison result on
HHO, SSA, GOA, and SGO on
3O repetitions on 1000
dimension 123 123 Complex & Intelligent Systems (2021) 7:249–295 281 Functions
HHO
Results
WRS tes
F14
Mean
9.98e−01
≈
Std
9.23e−01
F15
Mean
3.10e−04
≈
Std
1.97e−04
F16
Mean
−1.03e+00
≈
Std
6.78e−16
F17
Mean
3.98e−01
≈
Std
2.54e−06
F18
Mean
3.00e+00
≈
Std
0.00e+00
F19
Mean
−3.86e+00
≈
Std
2.44e−03
F20
Mean
−3.322
≈
Std
0.137406
F21
Mean
−10.1451
+
Std
0.885673
F22
Mean
−10.4015
+
Std
1.352375
F23
Mean
−10.5364
+
Std
0.927655
F24
Mean
396.8256
−
Std
79.58214
F25
Mean
910
−
Std
0
F26
Mean
910
−
Std
0
F27
Mean
910
−
Std
0
F28
Mean
860.8925
−
Std
0.651222 Functions
HHO
SSA
GOA
SGO
Results
WRS test
Results
WRS test
Results
WRS test
Results
F14
Mean
9.98e−01
≈
1.0643
−
0.9980
≈
0.9980
Std
9.23e−01
0.2567
1.5701e−16
3.4303e−08
F15
Mean
3.10e−04
≈
9.1497e−04
≈
0.0086
−
3.1049e−04
Std
1.97e−04
2.8876e−04
0.0101
2.3310e−05
F16
Mean
−1.03e+00
≈
−1.0316
≈
−1.0316
≈
−1.0316
Std
6.78e−16
2.4267e−14
1.5289e−13
6.7752e−16
F17
Mean
3.98e−01
≈
0.3979
≈
0.3979
≈
0.3979
Std
2.54e−06
2.6978e−04
3.8926e−13
4.5168e−16
F18
Mean
3.00e+00
≈
3.0000
≈
3.0000
≈
3.0000
Std
0.00e+00
2.2603e−13
3.2446e−12
1.5003e−15
F19
Mean
−3.86e+00
≈
−3.8628
≈
−3.8589
−
−3.8628
Std
2.44e−03
2.3584e−11
0.0084
2.2584e−16
F20
Mean
−3.322
≈
−3.2222
−
−3.2729
−
−3.3220
Std
0.137406
0.0521
0.0673
0.0363
F21
Mean
−10.1451
+
−6.8073
−
−6.1441
−
−7.0552
Std
0.885673
3.3663
3.7934
9.0336e−03
F22
Mean
−10.4015
+
−7.5677
−
−6.2905
−
−8.2648
Std
1.352375
3.6407
3.8768
0.9704
F23
Mean
−10.5364
+
−8.4837
−
−4.2256
−
−8.1285
Std
0.927655
3.5235
3.5349
3.7465
F24
Mean
396.8256
−
20.0000
+
180.0000
−
56.6667
Std
79.58214
44.7214
148.3240
67.8911
F25
Mean
910
−
35.0843
+
378.5491
−
99.9197
Std
0
43.9729
113.3010
90.4498
F26
Mean
910
−
202.1367
+
342.4062
−
228.5903
Std
0
83.0302
157.5014
46.0290
F27
Mean
910
−
320.4287
+
286.0073
+
457.9925
Std
0
33.0710
139.0947
110.2783
F28
Mean
860.8925
−
25.2016
+
199.6790
−
59.3325
Std
0.651222
41.8286
120.4731
70.9304 Table 26 Comparison result on
HHO, SSA, GOA and SGO on
3O repetitions on
fixed-dimensional and
composite benchmark functions 282 Complex & Intelligent Systems (2021) 7:249–295 Table 26 continued Table 26 continued
Functions
HHO
SSA
GOA
SGO
Results
WRS test
Results
WRS test
Results
WRS test
Results
F29
Mean
558.9653
−
582.7280
−
206.6856
+
486.6667
Std
5.112352
179.4161
90.5928
73.0297
Total +
03
05
02
Total −
06
06
10
Total ≈
07
05
04
“−”, “+” and “≈” denote that performance of HHO, SSA, and GOA are worse, better and similar to SGO
respectively From Table 25, according to Wilcoxon’s rank-sum test, we
find that the SGO algorithm performs superior to the HHO
algorithm in five cases, equivalent with three cases out of 13
in 1000 dimensional functions. Discussion Similarly, the SGO algorithm
performs superior to the SSA algorithm in 13 cases and from
the GOA algorithm in 13 cases out of 13, whereas the HHO
algorithm performs superior to the SGO algorithm in five
cases. It is seen that the SGO algorithm is performing equiva-
lent performance with the HHO algorithm and outperforming
than SSA and GOA algorithm in solving 1000-dimensional
benchmark functions. the SSA algorithm performs superior to SGO in five cases,
and the GOA algorithm performs superior to SGO in two
cases. Hence it is seen that the SGO algorithm is outper-
forming performance than HHO, SSA and GOA algorithm
in solving ten fixed dimensional multimodal and six com-
posite benchmark functions. Tension/compression spring design problem The objective of this test problem is to minimize the weight
of tension/compression spring shown in Fig. 2 [135, 136]. The optimum design must satisfy constraints on shear stress,
surge frequency, and deflection. There are three design vari-
ables: wire diameter (d), mean coil diameter (D), and many
active coils (N). The formulated optimization problem is
given in Appendix D. The composite functions are well enough to judge the
ability to escape from local minima of meta-heuristics opti-
mization algorithms. The results from Table 26, it is clear
that the SSA algorithm finds a superior solution for F24,
F25, F26, and F28, and for F27 and F29, GOA finds supe-
rior solution than other algorithms. The performance of the
HHO algorithm for solving composite benchmark functions
is worse than other algorithms. The optimization result of all algorithms for the compres-
sion spring design problem is given in Table 27. The result of
LAPO algorithm is reported from paper [79], for GROM the
result is reported from [80], for BOA the result is reported
from [29], for VPL the result is reported from [60], for HHO
the result is reported from [31], for SSA the result is taken
reported from [27] and result for SGO is found by us. “NA”
stands for an experiment that is not conducted for that algo-
rithm. The best result is represented in boldface. From the
table, we find that the BOA algorithm outperforms than all
other algorithms. From Table 26, according to the WRS test, we find that
the SGO algorithm performs superior to the HHO algorithm
in six cases, equivalent with seven cases out of 16 benchmark
functions. Similarly, the SGO algorithm performs superior to
the SSA algorithm in six cases, equivalent with five cases out
of 16 benchmark functions. SGO algorithm performs supe-
rior to the GOA algorithm in ten cases, equivalent with four
casesoutof16benchmarkfunctions.WhereastheHHOalgo-
rithm performs superior to the SGO algorithm in three cases, Experiment 7: on classical engineering problem In this experiment, we have applied all the algorithms such
as LAPO, GROM, BOA, SSA, VPL, HHO, SELO, SSOA,
GOA, and SGO algorithm for solving classical engineering
problems. Here we have considered six classical engineering
problems. These are. The fixed-dimensional multimodal functions are designed
to have many local optimal where computation complex-
ity increases drastically with the problem size. The results
reported from Table 26, it is clear that the SGO algorithm
achieves success in finding an optimal solution for func-
tions F14, F16, F17, F18, F19, and F20. Similarly, the GOA
algorithm makes success in finding an optimal solution for
functions F14, F16, F17, and F18. SSA algorithm finds suc-
cess for function F16–F19. HHO algorithm finds success for
function F14, F16–F20, F22–F23. For the shekel family, the
HHO algorithm finds superior solutions than SSA, GOA, and
SGO algorithm. 123 Cantilever beam design problem In this problem, the goal is to minimize the weight of a
cantilever beam with hollow square blocks. There are five
squares of which the first block is fixed, and the fifth one bur-
dens a vertical load, box girders, and lengths of those girders
are design parameters for this problem. This cantilever beam
design is shown in Fig. 5 [78]. The formulated optimization
problem is defined in Appendix D. The welded beam design problem There are four optimization variables: the thick-
ness of the weld (h), length of clamped bar (l), the height
of the bar (t), and thickness of the bar (b). The formulated
optimization problem is given in Appendix D. Optimization constraints are on shear stress (τ), and bending
stress in the beam (θ), buckling load (Pc), end deflection of
beam (δ). There are four optimization variables: the thick-
ness of the weld (h), length of clamped bar (l), the height
of the bar (t), and thickness of the bar (b). The formulated
optimization problem is given in Appendix D. The optimization result of algorithms for the pressure ves-
sel design problem is given in Table 29. The result of the
LAPO algorithm is reported from paper [79], for the GROM
the result is reported from [80], for the VPL the result is
reported from [60], for HHO the result is reported from [31]
andresultforSGOisfoundbyus.A“NA”standfortheexper-
iment is not conducted for that algorithm. The best result is
represented in boldface. From table, we find that the SGO
algorithm outperforms all other algorithms. The optimization result of all algorithms for Welded beam
design problem is given in Table 28. The result of LAPO
algorithm is reported from paper [79], for GROM the result
is reported from [80], for BOA the result is reported from
[29], for VPL the result is reported from [60], for HHO the
result is reported from [31], for SSA the result is reported
from [27]. The result for SGO is found by us. “NA” stands
for an experiment that is not conducted for that algorithm. The best result is represented in boldface. From the table,
we find that the SGO algorithm outperforms than all other
algorithms. The welded beam design problem The objective of this test problem is to minimize the fab-
rication cost of the welded beam shown in Fig. 3 [137]. 123 Complex & Intelligent Systems (2021) 7:249–295 283 Table 27 Comparison of
tension/compression spring
design problem
Algorithm
Optimum variables
Optimum weight
d
D
N
SGO
0.05167575
0.3563976
11.3077598
0.0126652
LAPO
0.0519038638
0.361890902
11.28885
0.01265722
GROM
0.0517271517
0.357630345
11.2361437
0.01265809
BOA
0.051343
0.334871
12.922700
0.0119656
SSOA
NA
VPL
0.0501910! 0.331680! 12.834269! 0.0123947! HHO
0.051796393
0.359305355
11.138859
0.012665443
SELO
NA
SSA
0.051207
0.345215
12.004032
0.0126763
GOA
NA
Fig. 3 Welded beam design problem: a schematic of the weld; b stress distribution evaluated at the optimum design; c displacement distribution at
the optimum design Table 27 Comparison of
tension/compression spring
design problem
Algorithm
Optimum variables
Optimum weight
d
D
N
SGO
0.05167575
0.3563976
11.3077598
0.0126652
LAPO
0.0519038638
0.361890902
11.28885
0.01265722
GROM
0.0517271517
0.357630345
11.2361437
0.01265809
BOA
0.051343
0.334871
12.922700
0.0119656
SSOA
NA
VPL
0.0501910! 0.331680! 12.834269! 0.0123947! HHO
0.051796393
0.359305355
11.138859
0.012665443
SELO
NA
SSA
0.051207
0.345215
12.004032
0.0126763
GOA
NA Table 27 Comparison of
tension/compression spring
design problem
Algorithm
Optimum variables
Optimum weight
d
D
N
SGO
0.05167575
0.3563976
11.3077598
0.0126652
LAPO
0.0519038638
0.361890902
11.28885
0.01265722
GROM
0.0517271517
0.357630345
11.2361437
0.01265809
BOA
0.051343
0.334871
12.922700
0.0119656
SSOA
NA
VPL
0.0501910! 0.331680! 12.834269! 0.0123947! HHO
0.051796393
0.359305355
11.138859
0.012665443
SELO
NA
SSA
0.051207
0.345215
12.004032
0.0126763
GOA
NA Fig. 3 Welded beam design problem: a schematic of the weld; b stress distribution evaluated at the optimum design; c displacement distribution at
the optimum design problem: a schematic of the weld; b stress distribution evaluated at the optimum design; c displacement distribution at Fig. 3 Welded beam design problem: a schematic of the weld; b stress distribution evaluated at the optimum design; c displacement distribution at
the optimum design Fig. 3 Welded beam design problem: a schematic of the weld; b stress distribution evaluated at the optimum design; c displacement distribution at
the optimum design variables: the thickness of the shell (Ts), the thickness of the
head (Th), inner radius (R), length of the cylindrical section
without considering head (L). The formulated optimization
problem is given in Appendix D. Optimization constraints are on shear stress (τ), and bending
stress in the beam (θ), buckling load (Pc), end deflection of
beam (δ). Pressure vessel design problem This problem goal is to minimize the total cost (material,
forming, and welding) of cylindrical pressure vessels shown
in Fig. 4 [25]. Both ends of the vessel are capped while the
head has a hemispherical shape. There are four optimization 123 Complex & Intelligent Systems (2021) 7:249–295 284 Table 28 Comparison of Welded beam design problem
Algorithm
Variables
Optimum cost
h
l
t
b
SGO
0.21542798
0.21542796
7.41442256
0.21542797
1.5921491
LAPO
0.205528028615
3.394773587424
9.076635213428
0.2055309791245
1.71960676580
GROM
0.205530838237860
3.39469488081047
9.07663928640037
0.20553083824796
1.7196019906343
BOA
0.1736
2.9690
8.7637
0.2188
1.6644
SSOA
NA
VPL
0.215235! 6.898945! 8.815033! 0.216253! 2.264711! HHO
0.204039
3.531061
9.027463
0.206147
1.73199057
SELO
NA
SSA
0.2057
3.4714
9.0366
0.2057
1.72491
GOA
NA
Fig. 4 Pressure vessel design problem: a schematic of the vessel; b stress distribution evaluated at the optimum design; and c displacement
distribution evaluated at the optimum design Table 28 Comparison of Welded beam design problem
Algorithm
Variables
Optimum cost
h
l
t
b
SGO
0.21542798
0.21542796
7.41442256
0.21542797
1.5921491
LAPO
0.205528028615
3.394773587424
9.076635213428
0.2055309791245
1.71960676580
GROM
0.205530838237860
3.39469488081047
9.07663928640037
0.20553083824796
1.7196019906343
BOA
0.1736
2.9690
8.7637
0.2188
1.6644
SSOA
NA
VPL
0.215235! 6.898945! 8.815033! 0.216253! 2.264711! HHO
0.204039
3.531061
9.027463
0.206147
1.73199057
SELO
NA
SSA
0.2057
3.4714
9.0366
0.2057
1.72491
GOA
NA Table 28 Comparison of Welded beam design problem
Algorithm
Variables
Optimum cost
h
l
t
b
SGO
0.21542798
0.21542796
7.41442256
0.21542797
1.5921491
LAPO
0.205528028615
3.394773587424
9.076635213428
0.2055309791245
1.71960676580
GROM
0.205530838237860
3.39469488081047
9.07663928640037
0.20553083824796
1.7196019906343
BOA
0.1736
2.9690
8.7637
0.2188
1.6644
SSOA
NA
VPL
0.215235! 6.898945! 8.815033! 0.216253! 2.264711! HHO
0.204039
3.531061
9.027463
0.206147
1.73199057
SELO
NA
SSA
0.2057
3.4714
9.0366
0.2057
1.72491
GOA
NA
Fig. 4 Pressure vessel design problem: a schematic of the vessel; b stress distribution evaluated at the optimum design; and c displacement
distribution evaluated at the optimum design Table 28 Comparison of Welded beam design problem Fig. Three-bar truss design problem The objective of Gear train design problem is to minimize
gear ratio where gear ratio is calculated as by Eq. 1: Here the objective is to design a truss with a minimum weight
that does not violate constraints. A most important issue in
designing truss is constraints that include stress, deflection,
and buckling constraints. Figure 7 [78] shows the structural
parameters of this problem. The formulated design problem
is given in Appendix D. We can see that the objective func-
tion is quite simple, but it is subject to several challenging
constraints. This truss design problems are prevalent in the
literature of meta-heuristics [138, 139] Pressure vessel design problem 4 Pressure vessel design problem: a schematic of the vessel; b stress distribution evaluated at the optimum design; and c displacement
distribution evaluated at the optimum design Table 29 Comparison of pressure vessel design problem
Algorithm
Optimum variables
Optimum cost
Ts
Th
R
L
SGO
1.258846989
0
65.22523267
10.00000000
2611.921927
LAPO
0.786283665
0.39160673845
40.758736322
194.296457539
5916.1935786
GROM
0.778168641372626
0.384649162633450
40.3196187241064
200
5885.33277364205
BOA
NA
SSOA
NA
VPL
0.815200
0.426500
42.0912541
176.742314
6044.9565
HHO
0.81758383
0.4072927
42.09174576
176.7196352
6000.46259
SELO
NA
SSA
NA
GOA
NA
Fig.5 Cantilever beam design
123 Table 29 Comparison of pressure vessel design problem
Algorithm
Optimum variables
Optimum cost
Ts
Th
R
L
SGO
1.258846989
0
65.22523267
10.00000000
2611.921927
LAPO
0.786283665
0.39160673845
40.758736322
194.296457539
5916.1935786
GROM
0.778168641372626
0.384649162633450
40.3196187241064
200
5885.33277364205
BOA
NA
SSOA
NA
VPL
0.815200
0.426500
42.0912541
176.742314
6044.9565
HHO
0.81758383
0.4072927
42.09174576
176.7196352
6000.46259
SELO
NA
SSA
NA
GOA
NA Table 29 Comparison of pressure vessel design problem
Algorithm
Optimum variables
Optimum cost
Ts
Th
R
L
SGO
1.258846989
0
65.22523267
10.00000000
2611.921927
LAPO
0.786283665
0.39160673845
40.758736322
194.296457539
5916.1935786
GROM
0.778168641372626
0.384649162633450
40.3196187241064
200
5885.33277364205
BOA
NA
SSOA
NA
VPL
0.815200
0.426500
42.0912541
176.742314
6044.9565
HHO
0.81758383
0.4072927
42.09174576
176.7196352
6000.46259
SELO
NA
SSA
NA
GOA
NA
Fig.5 Cantilever beam design
123 Table 29 Comparison of pressure vessel design problem Fig.5 Cantilever beam design Fig.5 Cantilever beam design 123 Complex & Intelligent Systems (2021) 7:249–295 285 Table 30 Results for cantilever beam design problem
Algorithm
Optimal values for variables
Optimum weight
x1
x2
x3
x4
x5
SGO
6.01605811183
5.30964910182
4.4941343030
3.50169590256
2.152122757
1.3365206094
LAPO
6.01243634
5.314870556
4.4959135494
3.4993942765
2.151154796
1.336521415
GROM
6.015401113310
5.30998470907
4.49536712598
3.50063527673
2.152272871848
1.33652066668
BOA
NA
SSOA
NA
VPL
NA
HHO
NA
SELO
NA
SSA
6.015134526133
5.30930467605
4.4950067163
3.5014262863
2.15278790
1.3399563910
GOA
6.011674
5.31297
4.48307
. 3.50279
2.16333
1.33996
Fig. 6 Gear train design Table 30 Results for cantilever beam design problem
Algorithm
Optimal values for variables
Optimum weight
x1
x2
x3
x4
x5
SGO
6.01605811183
5.30964910182
4.4941343030
3.50169590256
2.152122757
1.3365206094
LAPO
6.01243634
5.314870556
4.4959135494
3.4993942765
2.151154796
1.336521415
GROM
6.015401113310
5.30998470907
4.49536712598
3.50063527673
2.152272871848
1.33652066668
BOA
NA
SSOA
NA
VPL
NA
HHO
NA
SELO
NA
SSA
6.015134526133
5.30930467605
4.4950067163
3.5014262863
2.15278790
1.3399563910
GOA
6.011674
5.31297
4.48307
. 3.50279
2.16333
1.33996 Table 30 Results for cantilever beam design problem Fig. 6 Gear train design design is shown in Fig. 6 [78]. The formulated optimization
problem is defined in Appendix D. The optimization result of algorithms for cantilever beam
design problem is given in Table 30. The result of LAPO
algorithm is reported from paper [79], for GROM the result
is reported from [80], for VPL the result is taken from [60],
for SSA the result is reported from [27], for GOA the result is
reported from [28] and result for SGO is found by us. “NA”
stands for the experiment are not conducted for that particular
algorithm. The best result is represented in boldface. From
the Table, we get that the SGO algorithm outperforms than
all other algorithms. The optimization result of algorithms for the gear train
design problem is given in Table 31. The result of the LAPO
algorithm is reported from paper [79]. For GROM, the result
is reported from [80], for BOA, the result is reported from
[28], the result for SGO is found by us. “NA” stands for the
experiment is not conducted for that particular algorithm. The best result is represented by boldface. From the table,
we get that all the algorithms perform equally. 123 Overall conclusion Table 31 Comparison results for gear train design problem
Algorithm
Variables
Optimum gear
nA
nB
nC
nD
SGO
43
16
19
49
2.7008571488865e−12
LAPO
49
16
19
43
2.700857E−12
GROM
43
16
19
49
2.7008571E−12
BOA
43
16
19
49
2.7008571E−12
SSOA
NA
VPL
NA
HHO
NA
SELO
NA
SSA
NA
GOA
NA This section applies all the algorithms such as LAPO,
GROM, BOA, SSA, VPL, HHO, SELO, SSOA, GOA, and
SGO algorithm for solving benchmark functions as well as
classical engineering problems. From the above experiments,
we conclude that the performance of the SGO algorithm
is worse than other algorithms while solving Rosenbrock’s
benchmark function, shekel family benchmark function, i.e.,
shekel 2, shekel 5, and shekel 7. While solving composite
benchmark functions, SSA (Salp swarm algorithm) is supe-
rior, and the HHO algorithm is worse than other algorithms. On solving high dimensional and classical engineering prob-
lems, the SGO algorithm is superior to other algorithms. Fig. 7 Three-bar-truss design Fig. 7 Three-bar-truss design Gear ratio angular velocity of output shaft
angular velocity of input shaft .
(1) (1) This problem has four parameters. The parameters of this
problem are discrete with an increment size of 1 since they
define teeth of the gears (nA, nB, nC, nD). These constraints
are only limited to the ranges of the variables. This Gear train 123 Complex & Intelligent Systems (2021) 7:249–295 286 Table 31 Comparison results for gear train design problem
Algorithm
Variables
Optimum gear
nA
nB
nC
nD
SGO
43
16
19
49
2.7008571488865e−12
LAPO
49
16
19
43
2.700857E−12
GROM
43
16
19
49
2.7008571E−12
BOA
43
16
19
49
2.7008571E−12
SSOA
NA
VPL
NA
HHO
NA
SELO
NA
SSA
NA
GOA
NA
Fig. 7 Three-bar-truss design Table 31 Comparison results for gear train design problem
Algorithm
Variables
Optimum gear
nA
nB
nC
nD
SGO
43
16
19
49
2.7008571488865e−12
LAPO
49
16
19
43
2.700857E−12
GROM
43
16
19
49
2.7008571E−12
BOA
43
16
19
49
2.7008571E−12
SSOA
NA
VPL
NA
HHO
NA
SELO
NA
SSA
NA
GOA
NA Conclusion In this paper, we have considered ten algorithms SGO,
LAPO, GROM, BOA, SSOA, VPL, HHO, SELO, GOA,
and SSA those are proposed in the year 2017–2019 except
SGO as SGO is proposed in the year of 2016, and have con-
ducted seven experiments by considering a different type of
problems such as mathematical classical optimization prob-
lems, CEC global optimization problems, and six classical
engineering design problems. We have seen that the SGO
algorithm has shown its superior performance in compar-
ison to all other algorithms in solving problems in each
experiment. Still, while addressing Rosenbrock benchmark
function and shekel family benchmark function, i.e., shekel
2, shekel 5, and shekel 7, the performance of SGO is not so
well in comparison to other algorithms. One of the best things
we see in SGO is that the performance does not deteriorate
as the dimension of the problem increases, and at the same
time, it can find an optimum result in less fitness evaluation. As further research, we improve the performance of the SGO
algorithm by balancing between exploration and exploitation
search so that it can find the optimal solution of benchmark
function like shekel family and other. Also, we compare SGO performance with newly proposed optimization algorithms,
solving the problem of large-scale optimizations and multi-
objective optimizations. Conclusion As we know, meta-heuristic optimization algorithms are
more popular than deterministic search optimization algo-
rithms in solving global optimization problems, and several
optimization algorithms are proposed to solve global opti-
mization problems. The exploration search and exploitation
search are two important factors related to meta-heuristic
optimization methods. These two factors are in contrast with
each other. In other words, focusing too much on local search,
i.e., exploitation may result in getting stuck in local optimum
points, and too much focusing on global search, i.e., explo-
ration, may cause the low quality of the final best answer. So an algorithm should be in the form that it can balance
in between and find out an optimal solution to the prob-
lem. Free-Lunch theorem for optimization says that none of
the optimization algorithms can solve all optimization prob-
lems and makes this area of research open. So, researchers
improve/adapt the current algorithms for solving different
problems or propose new algorithms for providing competi-
tive results compared to the existing algorithms. As a result, Fig. 7 Three-bar-truss design The optimization result of algorithms for the three-bar-
truss design problem is given in Table 32. The result for the
HHO algorithm is reported from paper [31], for SSA, the
result is reported from [27], for GOA, the result is reported
from [28], the result for SGO is found by us. “NA” stands for
the experiment are not conducted for that algorithm. The best
result is represented in boldface. From the Table, we get that
the SGO algorithm outperforms than all other algorithms. Table 32 Results of the
three-bar truss design problem
Algorithm
Variables
Optimal weight
x1
x2
SGO
0.788674579690751
0.408249860015748
263.8958433810869
LAPO
NA
GROM
NA
BOA
NA
SSOA
NA
VPL
NA
HHO
0.788662816
0.408283133832900
263.8958434
SELO
SSA
0.788665414258065
0.408275784444547
263.8958434
GOA
0.788897555578973
0.407619570115153
263.895881496069
123 Algorithm
Variables
Optimal weight
x1
x2
SGO
0.788674579690751
0.408249860015748
263.8958433810869
LAPO
NA
GROM
NA
BOA
NA
SSOA
NA
VPL
NA
HHO
0.788662816
0.408283133832900
263.8958434
SELO
SSA
0.788665414258065
0.408275784444547
263.8958434
GOA
0.788897555578973
0.407619570115153
263.895881496069 Complex & Intelligent Systems (2021) 7:249–295 287 a number of optimization algorithms have been proposed
from a few decades to till date. It is difficult to compare all
algorithms or challenging to say, which is the best because
none of the algorithms can solve all optimization prob-
lems. Compliance with ethical standards Conflict of interest Authors declares that they have no conflict of inter-
est on publication of this paper Open Access This article is licensed under a Creative Commons
Attribution 4.0 International License, which permits use, sharing, adap-
tation, distribution and reproduction in any medium or format, as
long as you give appropriate credit to the original author(s) and the
source, provide a link to the Creative Commons licence, and indi-
cate if changes were made. The images or other third party material
in this article are included in the article’s Creative Commons licence,
unless indicated otherwise in a credit line to the material. If material
is not included in the article’s Creative Commons licence and your
intended use is not permitted by statutory regulation or exceeds the
permitteduse,youwillneedtoobtainpermissiondirectlyfromthecopy-
right holder. To view a copy of this licence, visit http://creativecomm
ons.org/licenses/by/4.0/. Table 33 Unimodal benchmark
functions Appendix A See Tables 33, 34, 35, and 36. Appendix A 10]
−10.1532
F22(x) −7
i1 [(X −ai)(X −ai)T + ci]−1
4
[0. 10]
−10.4028
F23(x) −10
i1 [(X −ai)(X −ai)T + ci]−1
4
[0. 10]
−10.5363 Functions
Dim
Range
fmin
F24(C F1)
f1, f2, f3,…, f10 Sphere function
[σ1, σ2, σ3, . . . . . . , σ10] [1,1,1,…,11]
[λ1, λ2, λ3 . . . . . . , λ10] [ 5
100, 5
100, 5
100,…, 5
100]
30
[−5, 5]
0
F25(C F2)
f1, f2, f3,…, f10 Griewank’s function
[σ1, σ2, σ3, . . . . . . , σ10] [1,1,1,…,1]
[λ1, λ2, λ3 . . . . . . , λ10] [ 5
100, 5
100, 5
100,…, 5
100]
30
[−5, 5]
0
F26(C F3)
f1, f2, f3,…, f10 Griewank’s Function
[σ1, σ2, σ3, . . . . . . , σ10] [1,1,1,…,1]
[λ1, λ2, λ3 . . . . . . , λ10] [1,1,1,…,1]
30
[−5, 5]
0
F27(C F4)
f1, f2 Ackley’s function, f3, f4 Rastrgin’s function, f5, f6 Weierstrass
function, f7, f8 Griewank’s function, f9, f10 Sphere function
[σ1, σ2, σ3, . . . . . . , σ10] [1,1,1,…,1]
[λ1, λ2, λ3 . . . . . . , λ10] [ 5
32, 5
32,1,1, 5
0.5,
5
0.5,
5
100,
5
100, 5
100,
5
100]
30
[−5, 5]
0
F28(C F5)
f1, f2 Rastrigin’s function, f3, f4 Weierstrass function, f5, f6 Griewank’s
function, f7, f8 Ackley’s function, f9, f10 Sphere function
[σ1, σ2, σ3, . . . . . . , σ10] [1,1,1,…,1]
[λ1, λ2, λ3 . . . . . . , λ10] [ 1
5, 1
5, 5
0.5,
5
0.5,
5
100,
5
100, 5
32,
5
32,
5
100,
5
100]
30
[−5, 5]
0
F29(C F6)
f1, f2 Rastrigin’s function, f3, f4 Weierstrass function, f5, f6
Griewank’s function, f7, f8 Ackley’s function, f9, f10 sphere function
[σ1, σ2, σ3, . . . . . . , σ10] [0.1,0.2,0.3,0.4,0.5,0.6,0.7,0.8,0.9,1]
[λ1, λ2, λ3 . . . . . . Appendix A Table 33 Unimodal benchmark
functions
Function
Dim
Range
fmin
F1(x) n
i1 x2
i
30
[−100, 100]
0
F2(x) n
i1|xi| + n
i−1|xi|
30
[−10, 10]
0
F3(x) n
i1
i
j1 x j
2
30
[−100,1 00]
0
F4(x) maxi{|xi|, 1 ≤i ≤n}
30
[−100, 100]
0
F5(x) n−1
i1 [100
xi+1 −x2
i
2 + (xi −1)2]
30
[−30, 30]
0
F6(x) n
i1 ([xi + 0.5])2
30
[−100, 100]
0
F7(x) n
i1 ix4
i + random[0, 1)
30
[−1.28, 1.28]
0
Table 34 Multi-modal benchmark functions
Function
Dim
Range
fmin
F8(x) n
i1 −xisin(√|xi|)
30
[−500, 500]
0
F9(x) n
i1[x2
i −10cos(2πxi) + 10]
30
[−5.12, 5.12]
0
F10(x) −20exp(−0.2
1
n
n
i1 x2
i ) −exp( 1
n
n
i1 cos(2πxi))+20 + e
30
[−32, 32]
0
F11(x)
1
4000
n
i1 x2
i −n
i1 cos
xi
√
i
+ 1
30
[−600, 600]
0
F12(x)
30
[−50, 50]
0
F12(x) π
n {10sin(πyi)+n−1
i1 (yi −1)2
1 + 10sin2(πyi+1)
+ (yn −1)2} + n
i1 u(xi, 10, 100, 4)
yi 1 + xi +1
4 u(xi, a, k, m)
⎧
⎨
⎩
k(xi −a)mxi > a
0 −a < xi < a
k(−xi −a)mxi < −a
F13(x)=0.1{sin2(3πx1) + n
i1 (xi −1)2[1 + sin2(3πxi+1)] + (xn −1)2[1 + sin2(2πxn)]} + n
i1 u(xi,
5, 100, 4)
30
[−50, 50]
0
123 Table 33 Unimodal benchmark
functions
Function
Dim
Range
fmin
F1(x) n
i1 x2
i
30
[−100, 100]
0
F2(x) n
i1|xi| + n
i−1|xi|
30
[−10, 10]
0
F3(x) n
i1
i
j1 x j
2
30
[−100,1 00]
0
F4(x) maxi{|xi|, 1 ≤i ≤n}
30
[−100, 100]
0
F5(x) n−1
i1 [100
xi+1 −x2
i
2 + (xi −1)2]
30
[−30, 30]
0
F6(x) n
i1 ([xi + 0.5])2
30
[−100, 100]
0
F7(x) n
i1 ix4
i + random[0, 1)
30
[−1.28, 1.28]
0 Table 34 Multi-modal benchmark functions Table 34 Multi-modal benchmark functions
Function
Dim
Range
fmin
F8(x) n
i1 −xisin(√|xi|)
30
[−500, 500]
0
F9(x) n
i1[x2
i −10cos(2πxi) + 10]
30
[−5.12, 5.12]
0
F10(x) −20exp(−0.2
1
n
n
i1 x2
i ) −exp( 1
n
n
i1 cos(2πxi))+20 + e
30
[−32, 32]
0
F11(x)
1
4000
n
i1 x2
i −n
i1 cos
xi
√
i
+ 1
30
[−600, 600]
0
F12(x)
30
[−50, 50]
0
F12(x) π
n {10sin(πyi)+n−1
i1 (yi −1)2
1 + 10sin2(πyi+1)
+ (yn −1)2} + n
i1 u(xi, 10, 100, 4)
yi 1 + xi +1
4 u(xi, a, k, m)
⎧
⎨
⎩
k(xi −a)mxi > a
0 −a < xi < a
k(−xi −a)mxi < −a
F13(x)=0.1{sin2(3πx1) + n
i1 (xi −1)2[1 + sin2(3πxi+1)] + (xn −1)2[1 + sin2(2πxn)]} + n
i1 u(xi,
5, 100, 4)
30
[−50, 50]
0 Complex & Intelligent Systems (2021) 7:249–295 288 Table 35 Fixed –dimensional
multimodal benchmark
functions Function
Dim
Range
fmin
F14(x)
1
500 + 25
j1
1
j+2
i1 (xi −ai j)6
−1
2
−[65, 65]
1
F15(x) 11
i1 [ai −x1(b2
i +bi x2)
b2
i +bi x3+x4 ]
2
4
[−5, 5]
0.00030
F16(x) 4x2
1 −2.1x4
1 + 1
3 x6
1 + x1x2 −4x2
2 + 4x4
2
2
[−5, 5]
−1.0316
F17(x) (x2 −5.1
4π2 x2
1 + 5
π x1 −6)
2 + 10
1 −
1
8π
cosx1 + 10
2
[−5, 5]
0.398
F18(x) [1 + (x1 + x2 + 1)2(19 −14x1 + 3x2
1 −14x2+6x1x2+3x2
2)]
X[30+(2x1 −3x2)2x(18–32x1+12x2
1+48x2 −36x1x2 + 27x2
2)]
2
[−2, 2]
3
F19(x) −4
i1 c1exp(−3
j1 ai j(x j −pi j)2)
3
[1, 3]
−3.86
F20(x) −4
i1 c1exp(−6
j1 ai j(x j −pi j)2)
6
[0, 1]
−3.32
F21(x) −5
i1 [(X −ai)(X −ai)T + ci]−1
4
[0. 123 Table 36 Composite functions Table 36 Composite functions Appendix A , λ10] [0.1× 1
5, 0.2× 1
5, 0.3× 5
0.5, 0.4 ×
5
0.5, 0.5 ×
5
100,
0.6 ×
5
100, 0.7 ×
5
32, 0.8 ×
5
32, 0.9 ×
5
100, 1 ×
5
100]
30
[−5, 5]
0 123 Complex & Intelligent Systems (2021) 7:249–295 289 rk functions used in butterfly optimization algorithm
Benchmark functions
Type
Formula
Dim
range
fmin
Sphere
M.S
f (x) D
i1 x2
i
30
[−100, 100]
0
Beale
U.N
f (x) (1.5 −x1 + x1x2)2 + (2.25 −x1 + x1x2
2)2 + (2.625 −x1 + x1x3
2)2
2
[−4.5, 4.5]
0
Cigar
U.N
f (x) x2
1+106 D
i2 x2
i
30
[−100, 100]
0
Step
U.S
f (x) D
i1 (
xi + 0.5
)2
30
[−100, 100]
0
Quartic function with no ise
U.S
f (x) D
i1 ix4
i + random(0, 1)
30
[−1.28, 1.28]
0
Bohachevsky
M.N
f (x) x2
1 + 2x2
2 −0.3cos(3πx1) −0.4cos(4πx2)+0.7
2
[−100, 100]
0
Ackley
M.N
(x) −20 exp
−0.2
1
D
D
i1 x2
i
−20 + e
30
[−32, 32]
0
Griewank
M.N
f (x)
1
4000
D
iexp
1n
D
i1 cos
2×pi×xi
+1 x2
i −D
i1 cos( xi
√
i ) + 1
30
[−600, 600]
0
Levy
M.S
f (x) sin2(3πx1) + (x1 −1)2
1 + sin2(3x2)
+ (x1 −1)2
1 + sin2(2πx2)
2
[−10, 10]
0
Michalewiz
M.S
f (x) −D
i1 sin(xi )(sin(ix2
i /π))2m, m 10
10
[0, pi]
−0.966015
Rastrigin
M.S
f (x) D
i1[x2
i −10cos
2πxi
+ 10]
30
[−5.12 ,5.12]
Alpine
M.S
f (x) D
i1
xi sin
xi
+ 0.1xi
30
[−10, 10]
0
Schaffer
M.N
f (x)
sin2
x2
1+x2
2
−0.5
(1+0.001(x2
1+x2
2))2
2
[−100, 100]
0
Rosenbrock
U.N
f (x) D−1
i1 [100
xi+1 −x2
i
2
+ (xi −1)2]
30
[−10,10]
0
Easom
M.S
f (x) −cos(x1)cos(x2)exp(−(x1 −π)2 −(x2 −π)2)
2
[−100, 100]
−1
Shubert
M.S
f (x) (5
i1 icos((i + 1)x1 + i))(5
i1 icos((i + 1)x2 + i))
2
[−10, 10]
−186.7309
Schwefel 1.2
U.N
f (x) D
i1 (i
j1 x j )2
30
[−10, 10]
0
Schwefel 2.21
U.S
f (x) max
i
{
xi
, 1 ≤i ≤D}
30
[−10, 10]
0
Schwefel 2.22
U.N
f (x) D
i1
xi
+ D
i1
xi
30
[−10, 10]
0
Schwefel 2.26
M.S
f (x) D
i1[xi sin(
xi
)]
30
[−500, 500]
−418.982XD
Booth
U.N
f (x) (x1 + 2x2 −7)2 + (2x1 + x2 −5)2
2
[−10, 10]
0
Goldstein price
M.N
[1 + (x1 + x2 + 1)2(19 −14x1 + 3x2
1 −14x2+6 x1x2+ 3 x2
2)]
X[30+(2x1 −3x2)2 x(18–32 x1+12 x2
1+48 x2 −36x1x2 + 27x2
2)]
2
[−2, 2]
3
Matyas
U.N
f (x) 0.26
x2
1 + x2
2
−0.48x1x2
2
[−10, 10]
0
Powell
U.N
f (x) D/4
i1 (x4i−3 + 10x4i−2)2 + 5(x4i−1 −x4i )2 + (x4i−2 −x4i−1)4
+10(x4i−3 −x4i )4
24
[−4, 5]
0
Power sum
M.N
f (x) D
k1 [
D
i1 xk
i
−bk]
2
4
[0, D]
0
Shekel 4.5
M.N
f (x) −5
i1 [
x −ai
x −ai
T + ci ]
−1
4
[0, 10]
−10.1532
Sum square
U.S
f (x) D
i1 ix2
i
30
[−10, 10]
0
Trid
M.N
f (x) D
i1 (xi −1)2 −D
i2 xi xi−1
30
[−D2, −D2]
−1500
Zettl
U.N
f (x) (x2
1 + x2
2 −2x1)2 + 0.25x1
2
[−1, 5]
0.00379
leon
U.N
f (x) 100(x2 −x3
1)2 + (1 −x1)2
2
[−1.2, 1.2]
0
i
d l S
bl
N
bl
Di
di
i 123 123 Complex & Intelligent Systems (2021) 7:249–295 290 Appendix C See Tables 38, 39, 40, 41 and 42. Tension/compression spring design problem g6(X) 0.125 −x1 ≤0
g7(X) 6000 −F ≤0 g6(X) 0.125 −x1 ≤0 Min f (x1, x2, x3) (x3 + 2)x2
1x2
Subject to: Min f (x1, x2, x3) (x3 + 2)x2
1x2
Subject to: g1(X) 1 −
x2
2x3
71785x4
1
≤0
g2(X)
x2(4x2 −x1)
12566x3
1(x2 −x1) +
1
5108x2
1
−1 ≤0
g3(X) 1 −140.45x1
x2
2x3
≤0
g4(X) 2(x2 + x1)
3
−1 ≤0 where the variables satisfy 0.1 ≤x1, x4 ≤2.0 and 0.1 ≤x2,
x3 ≤10. where the variables satisfy 0.1 ≤x1, x4 ≤2.0 and 0.1 ≤x2,
x3 ≤10. ρ 50400/x2
3x4 ρ 50400/x2
3x4 ρ 50400/x2
3x4 Q 6000(14 + x2/2)
D 1
2
x2
2 + (x1 + x3)2β QD
J
J
√
2x1x2 (x2
2/6+(x1 + x3)2/2) where the variables satisfy 0.05 ≤x1 ≤2, 0.25 ≤x2 ≤1.3
and where the variables satisfy 0.05 ≤x1 ≤2, 0.25 ≤x2 ≤1.3
and where the variables satisfy 0.05 ≤x1 ≤2, 0.25 ≤x2 ≤1.3
and and δ 65856/3000x3
3x4α 6000/(
√
2x1x2) δ 65856/3000x3
3x4α 6000/(
√
2x1x2) δ 65856/3000x3
3x4α 6000/(
√
2x1x2)
τ
α2 + αβx2
D
+ β2
F 0.61423 ×106 x3
4 x3
6 (1 −x3
√30/48
28
) 2 ≤x3 ≤15. τ
α2 + αβx2
D
+ β2 Appendix D Appendix D
Welded beam design problem
Min
f (x1, x2, x3, x4)
1.10471x2
1x2 + 0.04811x3x4
(14.0 + x2)
Subject to:
g1(X) x1 −x4 ≤0
g2(X) δ −0.25 ≤0
Pressure vessel design problem
Min
f (x1, x2, x3, x4)
0.6224x1x2x3
+
1.7881x2x2
3+3.1661 x4x2
1+19.84 x3x2
1
Subject to:
g1(X) −x1 + 0.0193x3 ≤0
g2(X) −x2 + 0.0954x3 ≤0
g3(X) −πx2
3x4 −4
3πx2
3 + 1296000 ≤0 Min
f (x1, x2, x3, x4)
1.10471x2
1x2 + 0.04811x3x4
(14.0 + x2) Min
f (x1, x2, x3, x4)
1.10471x2
1x2 + 0.04811x3x4
(14.0 + x2) g1(X) −x1 + 0.0193x3 ≤0
g2(X) −x2 + 0.0954x3 ≤0
g3(X) −πx2
3x4 −4
3πx2
3 + 1296000 ≤0
g4(X) x4 −240 ≤0 Subject to: g1(X) x1 −x4 ≤0
g2(X) δ −0.25 ≤0
g3(X) τ −13600 ≤0
g4(X) ρ −30000 ≤0 where the variables satisfy 0 ≤x1, x2 ≤100 and 10 ≤x3,
x4 ≤200. g5(X) 0.10471x2
1 + 0.04811x3x4(14.0 + x2) −5 ≤0 Appendix C Table 38 Unimodal separable function
Function
Name
Formulae
Dim
Range
fmin
F1
Step
Description in Appendix B
F2
Sphere
Description in Appendix B
F3
Sum squares
Description in Appendix B
F4
Quartic
Description in Appendix B
Table 39 Unimodal nonseparable function
Function
Name
Formulae
Dim
Range
fmin
F5
Beale
Description in Appendix B
F6
Easom
Description in Appendix B
F7
Matyas
Description in Appendix B
F8
Colville
f (x) 100(x2
1 −x2)2 + (x1 −1)2+(x3 −1)2+90 (x2
3 −x4)2+10.1 (x2 −1)2+
(x2 −1)(x4 −1)
4
[−10, 10]
0
F9
Zakharov
f (x) D
i1 x2
i + (D
i1 0.5ixi)
2 + (D
i1 0.5ixi)
4
10
[−5, 10]
0
F10
Schwefel 2.22
Description in Appendix B
F11
Schwefel 1.2
Description in Appendix B
F12
Dixon-Price
f (x) (x1 −1)2 + D
i2 i(2x2
i −xi −1)2
30
[−10, 10]
0
Table 40 Multimodal separable function
Function
Name
Formulae
Dim
Range
fmin
F13
Bohachevsky1
Description in Appendix B
F14
Booth
Description in Appendix B
F15
Michalewicz2
f (x) −D
i1 sin(xi)(sin(ix2
i /π))2m, m 10
2
[0, π]
−1.8013
F16
Michalewicz5
f (x) −D
i1 sin(xi)(sin(ix2
i /π))2m, m 10
5
[0, π]
−4.6877
F17
Michalewicz10
f (x) −D
i1 sin(xi)(sin(ix2
i /π))2m, m 10
10
[0, π]
−9.6602
F18
Rastrigin
Description in Appendix B
Table 41 Multimodal nonseparable function
Function
Name
Formulae
Dim
Range
fmin
F19
Schaffer
Description in Appendix B
F20
Six Hump Camel Back
f (x) 4 x2
1 −2.1x4
1 + 1
3 x6
1 + x1x2 −4x2
2 + 4x4
2
2
[−5, 5]
−186.73
F21
Boachevsky2
f (x) x2
1 + 2x2
2 −0.3cos(3πx1) × cos(4πx2) + 0.3
2
[−100, 100]
0
F22
Boachevsky3
f (x) x2
1 + 2x2
2 −0.3cos((3πx1) + (4πx2))+
0.3
2
[−100, 100]
0
F23
Shubert
Description in Appendix B
F24
Rosenbrock
Description in Appendix B
F25
Griewank
Description in Appendix B
F26
Ackley
Description in Appendix B Table 38 Unimodal separable function Table 39 Unimodal nonseparable function
Function
Name
Formulae
Dim
Range
fmin
F5
Beale
Description in Appendix B
F6
Easom
Description in Appendix B
F7
Matyas
Description in Appendix B
F8
Colville
f (x) 100(x2
1 −x2)2 + (x1 −1)2+(x3 −1)2+90 (x2
3 −x4)2+10.1 (x2 −1)2+
(x2 −1)(x4 −1)
4
[−10, 10]
0
F9
Zakharov
f (x) D
i1 x2
i + (D
i1 0.5ixi)
2 + (D
i1 0.5ixi)
4
10
[−5, 10]
0
F10
Schwefel 2.22
Description in Appendix B
F11
Schwefel 1.2
Description in Appendix B
F12
Dixon-Price
f (x) (x1 −1)2 + D
i2 i(2x2
i −xi −1)2
30
[−10, 10]
0 Table 39 Unimodal nonseparable function Table 40 Multimodal separable function
Function
Name
Formulae
Dim
Range
fmin
F13
Bohachevsky1
Description in Appendix B
F14
Booth
Description in Appendix B
F15
Michalewicz2
f (x) −D
i1 sin(xi)(sin(ix2
i /π))2m, m 10
2
[0, π]
−1.8013
F16
Michalewicz5
f (x) −D
i1 sin(xi)(sin(ix2
i /π))2m, m 10
5
[0, π]
−4.6877
F17
Michalewicz10
f (x) −D
i1 sin(xi)(sin(ix2
i /π))2m, m 10
10
[0, π]
−9.6602
F18
Rastrigin
Description in Appendix B Table 40 Multimodal separable function Table 41 Multimodal nonseparable function
Function
Name
Formulae
Dim
Range
fmin
F19
Schaffer
Description in Appendix B
F20
Six Hump Camel Back
f (x) 4 x2
1 −2.1x4
1 + 1
3 x6
1 + x1x2 −4x2
2 + 4x4
2
2
[−5, 5]
−186.73
F21
Boachevsky2
f (x) x2
1 + 2x2
2 −0.3cos(3πx1) × cos(4πx2) + 0.3
2
[−100, 100]
0
F22
Boachevsky3
f (x) x2
1 + 2x2
2 −0.3cos((3πx1) + (4πx2))+
0.3
2
[−100, 100]
0
F23
Shubert
Description in Appendix B
F24
Rosenbrock
Description in Appendix B
F25
Griewank
Description in Appendix B
F26
Ackley
Description in Appendix B Table 41 Multimodal nonseparable function 123 Complex & Intelligent Systems (2021) 7:249–295 291 Table 42 Brief description of
CEC 2014 benchmark functions
Function
Name
Dim
Range
fmin
F27
Rotated high conditional elliptic function (CEC1)
30
[−100, 100]
100
F28
Rotated bent cigar function (CEC2)
30
[−100, 100]
200
F29
Shifted and rotated Rosenbrock’s function (CEC4)
30
[−100, 100]
400
F30
Hybrid function 1 (CEC17)
30
[−100, 100]
1700
F31
Composition function 1 (CEC23)
30
[−100, 100]
2300
F32
Composition function 2 (CEC24)
30
[−100, 100]
2400
F33
Composition function 3 (CEC25)
30
[−100, 100]
2500 Pressure vessel design problem References 26. Alireza A (2016) A novel metaheuristic method for solving
constrainedengineeringoptimizationproblems:crowsearchalgo-
rithm. Comput Struct 169:1–12 1. Wolpert DH, Macready WG (1997) No free lunch theorems for
optimization. Evol Comput IEEE Trans 1:67–82 1. Wolpert DH, Macready WG (1997) No free lunch theorems for
optimization. Evol Comput IEEE Trans 1:67–82 27. Mirjalili S, Gandomi AH, Mirjalili SZ, Faris SH,Mirjalili SM
(2017)Salp swarm algorithm: a bio-inspired optimizer for engi-
neering design problems. Adv Eng Soft 1–29 2. Goldberg DE, Holland JH (1988) Genetic algorithms and machine
learning. Mach Learn 3:95–99 2. Goldberg DE, Holland JH (1988) Genetic algorithms and machine
learning. Mach Learn 3:95–99 3. Rechenberg I (1973) Evolution strategy: optimization of tech-
nical systems through biological evolution, vol 104. Fromman
Holzboog, Stuttgart, pp 15–16 28. Saremi S, Mirjalili S, Lewis A (2017) Grasshopper optimization
algorithm: theory and application. Adv Eng Softw 105:30–47 29. Arora S, Singh S (2019) Butterfly optimization algorithm: a
novel approach for global optimization. Soft Comput 23:715–734. https://doi.org/10.1007/s00500-018-3102-4 4. Yao X, Liu Y, Lin G (1999) Evolutionary programming made
faster. Evol Comput IEEE Trans 3:82–102 30. Jain M, Singh V, Rani A (2019) A novel nature-inspired algo-
rithm for optimization: squirrel search algorithm. Swarm Evolut
Comput 44:148–175 5. Ferreira C (2001) Gene expression programming: a new adaptive
algorithm for solving problems. Complex Syst 13(2):87–129 6. Ferreira C (2006) Gene expression programming: mathematical
modeling by an artificial intelligence. Springer, Berlin (ISBN 3-
540-32796-7) p
31. Heidari AA, Mirjalili S, Faris H, Aljarah I, Mafarja M, Chen H
(2019) Harris hawks optimization: algorithm and applications. Future Gener Comput Syst 97:849–872. https://doi.org/10.1016/
j.future.2019.02.028 7. Koza JR, Rice JP (1992) Genetic programming: the movie. MIT
Press, Cambridge 8. Hansen N, Kern S (2004) Evaluating the CMA evolution strategy
on multimodal test functions. Springer, Berlin, pp 282–291 32. Rao RV, Savsani VJ, Vakharia DP (2011) Teaching–learning-
based optimization: a novel method for constrained mechanical
design optimization problems. Comput Aided Des 43:303–315 9. Storn R, Price K (1997) Differential evolution—a simple and effi-
cient heuristic for global optimization over continuous spaces. J
Glob Optim 11:341–359 33. Geem ZW, Kim JH, Loganathan GV (2001) A new heuristic opti-
mization algorithm: harmony search. Simulation 76:60–68 10. Simon D (2008) Biogeography-based optimization. Evol Comput
IEEE Trans 12:702–713 34. Fogel D (2009) Artificial intelligence through simulated evolu-
tion. Wiley-IEEE Press 11. Kennedy J, Eberhart R (1995) Particle swarm optimization. Gear train design problem Min f (x1, x2, x3, x4)=(
1
6.931 −x3x2
x1x4 )
2
Variable range 12 ≤x1, x2, x3, x4 ≤60 Min f (x1, x2, x3, x4)=(
1
6.931 −x3x2
x1x4 )
2
Variable range 12 ≤x1, x2, x3, x4 ≤60 F 0.61423 ×106 x3
4 x3
6 (1 −x3
√30/48
28
) 292 Complex & Intelligent Systems (2021) 7:249–295 Three-bar truss design problem 14. Kevin MP (2002) Biomimicry of bacterial foraging for distributed
optimization and control. Control Syst IEEE 22(3):52–67 Min f (x1, x2)
2
√
2x1 + x2
× l
Subject to: Min f (x1, x2)
2
√
2x1 + x2
× l
Subject to: 15. Yang XS (2010) A new metaheuristic bat-inspired algorithm. In: Proceedings of the workshop on nature inspired cooperative
strategies for optimization (NICSO 2010). Springer, pp 65–74 Min f (x1, x2)
2
√
2x1 + x2
× l Subject to: 16. Yang XS (2010) Firefly algorithm, stochastic test functions and
design optimization. Int J Bio-Inspired Comput 2:78–84 g1(X)
√
2x1 + x2
√
2x2
1 + 2x1x2
P −σ ≤0
g2(X)
x2
√
2x2
1 + 2x1x2
P −σ ≤0
g3(X)
1
√
2x2
1 + 2x1x2
P −σ ≤0 17. Gandomi AH, Alavi AH (2012) Krill Herd: a new bio-inspired
optimization algorithm. Commun Nonlinear Sci Numer Simul
17(12):4831–4845 18. Yang XS, Deb S (2009) Cuckoo search via Lévy flights. In: Pro-
ceedings of the world congress on nature & biologically inspired
computing, NaBIC 2009, pp 210–214 19. Mucherino A, Seref O (2007) Monkey search: a novel meta-
heuristic search for global optimization. In: AIP conference
proceedings, p 162 Variable range 0 ≤x1, x2 ≤1
Where l 100 cm. P 2 KN/cm2σ 2KN/cm2 Variable range 0 ≤x1, x2 ≤1 20. Duˇsan T, Dell’Orco M (2005) Bee colony optimization—a coop-
erative learning approach to complex transportation problems. In
Advanced OR and AI methods in transportation: proceedings of
16th Mini–EURO conference and 10th meeting of EWGT, pp
51–60 Where l 100 cm. P 2 KN/cm2σ 2KN/cm2 Cantilever beam design problem 21. Chu SA, Tsai PW, Pan JS (2006) Cat swarm optimization. Lecture
Notes in Computer Science (including subseries Lecture Notes in
Artificial Intelligence and Lecture Notes in Bioinformatics), 4099
LNAI 2006, pp 854–858 Min f (x1, x2, x3, x4, x5) 0.6224(x1 + x2 + x3 + x4 + x5)
Subject to: g1(X) 61
x3
1
+ 27
x3
2
+ 19
x3
3
+ 7
x3
4
+ 1
x3
5
−1 ≤0 22. Tang R, Fong S, Yang XS, Deb S (2012) Wolf search algorithm
with ephemeral memory. Dig Inf Manag (ICDIM) 2012:165–172 23. Mirjalili S (2015) The ant lion optimizer. Adv Eng Softw
83:80–98. https://doi.org/10.1016/j.advengsoft.2015.01.010 Variable range 0.01 ≤x1, x2, x3, x4, x5 ≤100. Variable range 0.01 ≤x1, x2, x3, x4, x5 ≤100. 24. Mirjalili S, Mirjalili SM, Lewis A (2014) Grey wolf optimizer. Adv Eng Softw 69:46–61 25. Mirjalili S, Lewis A (2016) The whale optimization algorithm. Adv Eng Softw 95:51–67 123 References In:
Proceedings of the 1995 IEEE international conference on neural
networks, pp 1942–1948 35. Glover F (1989) Tabu search—part I. ORSA J Comput 1:190–206 36. Glover F (1990) Tabu search—part II. ORSA J Comput 2:4–32 37. He S, Wu Q, Saunders J (2006) A novel group search optimizer
inspired by animal behavioural ecology. In: Proceedings of the
2006 IEEE congress on evolutionary computation, CEC 2006, pp
1272–1278 12. Dorigo M, Birattari M, Stutzle T (2006) Ant colony optimization. IEEE Comput Intell 1:28–39 13. Basturk B, Karaboga D (2006) An artificial bee colony (ABC)
algorithm for numeric function optimization. In: Proceedings of
the IEEE swarm intelligence symposium, pp 12–14 123 123 Complex & Intelligent Systems (2021) 7:249–295 293 38. He S, Wu QH, Saunders J (2009) Group search optimizer: an
optimization algorithm inspired by animal searching behavior. IEEE Trans EvolComput13:973–90 59. Javid AA (2011) Anarchic society optimization: a human-inspired
method. In: Evolutionary computation, CE 2011 IEEE congress,
IEEE, New Orleans, pp 2586–2592 p
39. Atashpaz GE, Lucas C (2007) Imperialist competitive algorithm:
an algorithm for optimization inspired by imperialistic competi-
tion. In: Proceedings of the 2007 IEEE congress on evolutionary
computation, CEC 2007, pp 4661–4667 60. Moghdani R, Salimifard K (2018) Volleyball premier league algo-
rithm. Appl Soft Comput 64:161–185 61. Kumar M, Kulkarni AJ, Satapathy SC (2018) Socio evolution
& learning optimization algorithm: a socio-inspired optimization
methodology. Future Gener Comput Syst 81:252–272. https://doi. org/10.1016/j.future.2017.10.052 40. Kashan AH (2009) League championship algorithm: a new algo-
rithm for numerical function optimization. In: Proceedings of the
international conference on soft computing and pattern recogni-
tion, SOCPAR’09, pp 43–48 62. Kirkpatrick S, Gelatt CD, Vecchi MP (1983) Optimization by
simulated annealing. Science 220:671–680 41. Tan Y, Zhu Y (2010) Fireworks algorithm for optimization. Advances in swarm intelligence. Springer, Berlin, pp 355–364 63. Webster B, Bernhard PJ (2003) A local search optimization algo-
rithm based on natural principles of gravitation. In: Proceedings of
the 2003 international conference on information and knowledge
engineering (IKE’03), pp 255–261 42. KavehA(2014)Collidingbodiesoptimization.Advancesinmeta-
heuristic algorithms for optimal design of structures. Springer,
Berlin, pp 195–232 64. ErolOK,EksinI(2006)Anewoptimizationmethod:bigbang–big
crunch. Adv Eng Softw 37:106–111 43. Gandomi AH (2014) Interior search algorithm (ISA): a novel
approach for global optimization. ISA Trans 53(4):1168–1183. https://doi.org/10.1016/j.isatra.2014.03.018 65. Rashedi E, Nezamabadi-Pour H, Saryazdi S (2009) GSA: a grav-
itational search algorithm. Inf Sci 179:2232–2248 p
g
j
44. References Sadollah A, Bahreininejad A, Eskandar H, Hamdi M (2013) Mine
blast algorithm: a new population-based algorithm for solving
constrained engineering optimization problems. Appl Soft Com-
put 13:2592–2612 66. Kaveh A, Talatahari S (2010) A novel heuristic optimization
method: charged system search. Acta Mech 213:267–289 67. Formato RA (2007) Central force optimization: a new meta-
heuristic with applications in applied electromagnetics. Prog
Electromagn Res 77:425–491 45. Moosavian N, Roodsari BK (2014) Soccer league competition
algorithm: a new method for solving systems of nonlinear equa-
tions. Int J Intell Sci 4(1):7–16. https://doi.org/10.4236/ijis.2014. 41002 68. Alatas B (2011) ACROA: artificial chemical reaction opti-
mization algorithm for global optimization. Expert Syst Appl
38:13170–13180 46. Dai C, Zhu Y, Chen W (2007) Seeker optimization algorithm. Computational intelligence and security. Springer, Berlin, pp
167–176 69. Hatamlou A (2013) Black hole: a new heuristic optimization
approach for data clustering. Inf Sci 222:175–184 70. Kaveh A, Khayatazad M (2012) A new meta-heuristic method:
ray optimization. Comput Struct 112:283–294 47. Ramezani F, LotfiS (2013) Social-based algorithm (SBA). Appl
Soft Comput 13:2837–2856 71. Du H, Wu X, Zhuang J (2006) Small-world optimization algo-
rithm for function optimization. Advances in natural computation. Springer, Berlin, pp 264–273 48. Ghorbani N, Babaei E (2014) Exchange market algorithm. Appl
Soft Comput 19:177–187 49. Eita MA, Fahmy MM (2014) Group counseling optimization. Appl Soft Comput 22:585–604 72. Shah-Hosseini H (2011) Principal components analysis by the
galaxy-based search algorithm: a novel metaheuristic for contin-
uous optimization. Int J Comput Sci Eng 6:132–140. https://doi. org/10.1504/IJCSE.2011.041221 50. Eita MA, Fahmy MM (2010) Group counseling optimization: a
novel approach. In: Research and development in intelligent sys-
tems XXVI. Springer, London, pp 195–208 73. Moghaddam FF, Moghaddam RF, Cheriet M (2012) Curved space
optimization: a random search based on general relativity theory. arXiv: 1208.2214 51. Xu Y, Cui Z, Zeng J (2010) Social emotional optimization
algorithm for nonlinear constrained optimization problems. In:
Swarm, evolutionary, and memetic computing. Springer, pp
583–590 74. Eskandar H, Sadollah A, Bahreininejad A, Hamdi M (2012) Water
cycle algorithm—a novel metaheuristic optimization method for
solving constrained engineering optimization problems. Comput
Struct. https://doi.org/10.1016/j.compstruc.2012.07.010 52. Huan TT, Kulkarni AJ, Kanesan J (2017) Ideology algorithm:
a socio-inspired optimizationmethodology. Neural Comput Appl
28:845–876. https://doi.org/10.1007/s00521-016-2379-4 p
g
j
p
75. Tamura K, Yasuda K (2011) Spiral dynamics inspired optimiza-
tion. J Adv Comput Intell Intell Inform 15(8):1116–1122 53. References Wang H, Liang M, Sun C, Zhang G, Xie L (2020) Multiple-
strategy learning particle swarm optimization for large-scale
optimization problems. Complex Intell Syst. https://doi.org/10. 1007/s40747-020-00148-1 84. Gu Q, Li X, Jiang S (2019) Hybrid genetic grey wolf algorithm
for large-scale global optimization. Complexity. https://doi.org/1
0.1155/2019/2653512 103. Wan K, He C, Camacho A, Shang K, Cheng R, Ishibuchi H (2018)
A hybrid surrogate-assisted evolutionary algorithm for com-
putationally expensive many-objective optimization. In: IEEE
congress on evolutionary computation (CEC), Wellington, pp
2018–2025 85. Hadi AA, Mohamed AW, Jambi KM (2019) LSHADE-SPA
memetic framework for solving large-scale optimization prob-
lems. Complex Intell Syst 5:25–40. https://doi.org/10.1007/s407
47-018-0086-8 104. Dey N, Rajinikanth V, Ashour A, Tavares JM (2018) Social
group Optimization supported segmentation and evaluation of
skin melanoma images. Symmetry 10(2):51 86. Qiao W, Yang Z (2019) Solving large-scale function optimization
problem by using a new metaheuristic algorithm based on quan-
tum Dolphin swarm algorithm. IEEE Access 7:138972–138989 105. Rajinikanth V, Satapathy SC (2018) Segmentation of ischemic
stroke lesion in brain MRI based on social group optimization
and Fuzzy–Tsallis entropy. Arab J Sci Eng 43(8):4365–4378 87. Wen L, Jianjun J, Ximing L, Mingzhu T (2018) Inspired grey wolf
optimizer for solving large-scale function optimization problems. Appl Math Model 60:112–126. https://doi.org/10.1016/j.apm.20
18.03.005 106. Madhavi G, Harika V (2018) Implementation of social group opti-
mization to economic load dispatch problem. Int J Appl Eng Res
13:11195–11200 88. Ran C, Jin Y (2014) A competitive swarm optimizer for large
scale optimization. IEEE Trans Cybern 45(2):191–204 107. Monisha R, Mrinalini R, Britto MN (2019) Social group opti-
mization and Shannon’s function-based RGB image multi-level
thresholding. Smart Intell Comput Appl 105:123–132 89. Ran C, Jin Y (2015) A social learning particle swarm optimization
algorithm for scalable optimization. Inf Sci 291:43–60 108. Praveen SP, Rao KT, Janakiramaiah B (2018) Effective allocation
ofresourcesandtaskschedulingincloudenvironmentusingsocial
group optimization. Arab J Sci Technol 43(8):4265–4272 90. Deb K, Jain H (2014) An evolutionary many-objective optimiza-
tion algorithm using reference-point-based nondominated sorting
approach. Part I: solving problems with box constraints. IEEE
Trans Evol Comput 18:577–601 109. Rao KT (2018) Client-awareness resource allotment and job
scheduling in heterogeneous cloud by using social group opti-
mization. Int J Nat Comput Res. https://doi.org/10.4018/IJNCR. 2018010102 91. Lin Q, Liu S, Zhu Q (2018) Particle swarm optimization with
a balanceable fitness estimation for manyobjective optimization
problems. IEEE Trans Evol Comput 22(4):32–46 110. References Liu ZZ, Chu DH, Song C, Xue X, Lu BY (2016) Social learn-
ing optimization (SLO) algorithm paradigm and its application in
QoS-aware cloud service composition. Inf Sci 326:315–333 76. Rabanal P, Rodríguez I, Rubio F (2007) Using river formation
dynamics to design heuristic algorithms. In: Unconventional com-
putation. UC 2007. Lecture notes in computer science, vol 4618. Springer, Berlin, pp 163–177. https://doi.org/https://doi.org/10.1
007/978-3-540-73554-0_16 54. Satapathy SC, Naik A (2016) Social group optimization (SGO):
a new population evolutionary optimization technique. Complex
Intel Syst 2(3):173–203 55. Naik A, Satapathy SC, Ashour AS, Dey N (2018) Social group
optimization for global optimization of multimodal functions and
data clustering problems. Neural Comput Appl 30(1):271–287 77. Mirjalili S (2016) SCA: a sine cosine algorithm for solving opti-
mization problems. Knowl Based Syst 96:120–133 78. Mirjalili S, Mirjalili SM, Hatamlou A (2016) Multi-verse opti-
mizer: a nature-inspired algorithm for global optimization. Neural
Comput Appl 27:495–513. https://doi.org/10.1007/s00521-015-1
870-7 56. Emami H, Derakhshan F (2015) Election algorithm: a new socio-
politically inspired strategy. AI Commun 28(3):591–603 57. Kuo HC, Lin CH (2013) Cultural evolution algorithm for
global optimizations and its applications. J Appl Res Technol
11(4):510–522 79. Nematollahi AF, Rahiminejad A, Vahidi B (2017) A novel
physical based meta-heuristic optimization method known as
lightning attachment procedure optimization. Appl Soft Comput
59:596–621. https://doi.org/10.1016/j.asoc.2017.06.033 58. Kulkarni AJ, Durugkar IP, Kumar M (2013) Cohort intelligence:
a self supervised learning behavior. In: Systems, man, and cyber-
netics, SMC, IEEE international conference, IEEE, Manchester,
pp 1396–1400 80. Nematollahi AF, Rahiminejad A, Vahidi B (2020) A novel meta-
heuristicoptimizationmethodbasedongoldenratioinnature.Soft
Comput 24:1117–1151. https://doi.org/10.1007/s00500-019-039
49-w 123 294 Complex & Intelligent Systems (2021) 7:249–295 100. Wang H, Jin Y, Doherty J (2017) Committee-based active learning
for surrogate-assisted particle swarm optimization of expensive
problems. IEEE Trans Cybern 9:2664–2677 81. Omidvar MN, Li X, Tang K (2015) Designing benchmark prob-
lemsforlarge-scalecontinuousoptimization.InfSci316:419–436 82. Tang K, Li X, Suganthan PN, Yang Z, Weise T (2010) Benchmark
functions for the CEC 2010 special session and competition on
large-scale global optimization. Technical report, University of
Science and Technology of China y
101. Haibo Y, Ying T, Jianchao Z, Chaoli S, Yaochu J (2018) Surrogate-
assisted hierarchical particle swarm optimization. Inf Sci. https://
doi.org/10.1016/j.ins.2018.04.062 102. Sun C, Ding J, Zeng J (2018) A fitness approximation assisted
competitive swarm optimizer for large scale expensive optimiza-
tion problems. Memet Comput 10:123–134. https://doi.org/10.10
07/s12293-016-0199-9 83. References Mafarja M, Aljarah I, Heidari AA, Abdelaziz I, Hammouri FH
(2018) Evolutionary population dynamics and grasshopper opti-
mization approaches for feature selection problems. Knowl Based
Syst 145:25–45 92. LiuY QH, Zhang Z, Yao L, Wang C, Mo L, Ouyang S, Li J (2019)
A region search evolutionary algorithm for many-objective opti-
mization. Inf Sci 488:19–40. https://doi.org/10.1016/j.ins.2019.0
3.016 111. Heidari AA, Faris H, Aljarah I (2019) An efficient hybrid multi-
layer perceptron neural network with grasshopper optimization. SoftComput23:7941–7958.https://doi.org/10.1007/s00500-018-
3424-2 93. Dhiman G, Kumar V (2019) KnRVEA: a hybrid evolutionary
algorithm based on knee points and reference vector adap-
tation strategies for many-objective optimization. Appl Intell
49:2434–2460. https://doi.org/10.1007/s10489-018-1365-1 112. Jie L, Huiling C, Qian Z (2018) An improved grasshopper opti-
mization algorithm with application to financial stress prediction. Appl Math Model 64:654–668 p
g
94. Reddy SR, Dulikravich GS (2019) Many-objective differential
evolution optimization based on reference points: NSDE-R. Struct
Multidisc Optim 60:1455–1473. https://doi.org/10.1007/s00158-
019-02272-0 pp
113. Arora S, Anand P (2019) Chaotic grasshopper optimiza-
tion algorithm for global optimization. Neural Comput Appl
31:4385–4405. https://doi.org/10.1007/s00521-018-3343-2 95. Qin S, Sun C, Zhang G, He X, Tan Y (2020) A modified particle
swarm optimization based on decomposition with different ideal
points for many-objective optimization problems. Complex Intell
Syst. https://doi.org/10.1007/s40747-020-00134-7 114. Aljarah I, Al-Zoubi AM, Faris H (2018) Simultaneous feature
selection and support vector machine optimization using the
grasshopper optimization algorithm. Cogn Comput 10:478–495. https://doi.org/10.1007/s12559-017-9542-9 96. Matteo MD, Maier HR, Dandy GC (2019) Many-objective port-
folio optimization approach for stormwater management project
selection encouraging decision-maker buy-in. Environ Model
Softw 111:340–355 115. Mafarja M, Aljarah I, Faris H, Hammouri AI, Al-Zoubi AM,
Mirjalili S (2019) Binary grasshopper optimisation algorithm
approaches for feature selection problems. Expert Syst Appl
117:267–286 97. Fang Y, Liu Q, Li M, Laili Y, Pham DT (2019) Evolution-
ary many-objective optimization for mixed-model disassembly
line balancing with multi-robotic workstations. Eur J Oper Res
276(1):160–174. https://doi.org/10.1016/j.ejor.2018.12.035 116. Faris H, Mafarja MM, Heidari AA, Ibrahim AI, Mirjalili S,
Fujita H (2018) An efficient binary Salp swarm algorithm with
crossover scheme for feature selection problems. Knowl Based
Syst 154:43–67 98. Sun C, Jin Y, Zeng J, Yu Y (2015) A two-layer surrogate-
assisted particle swarm optimization algorithm. Soft Comput
19(6):1461–1475. https://doi.org/10.1007/s00500-014-1283-z 117. Abbassi R, Abbassi A, Heidari AA, Mirjalili S (2019) An efficient
Salp swarm-inspired algorithm for parameters identification of
photovoltaic cell models. Energy Convers Manag 179:362–372 99. References Sun C, Jin Y, Cheng R, Ding J, Zeng J (2017) Surrogate-assisted
cooperative swarm optimization of high-dimensional expensive
problems. IEEE Trans Evol Comput 21(4):644–660 118. Sayed GI, Khoriba G, Haggag MH (2018) A novel chaotic salp
swarm algorithm for global optimization and feature selection. 123 123 Complex & Intelligent Systems (2021) 7:249–295 295 Appl Intell 48:3462–3481. https://doi.org/10.1007/s10489-018-1
158-6 129. Liang JJ, Qu BY, Suganthan PN (2013) Problem definitions and
evaluation criteria for the CEC 2014 special session and competi-
tion on single objective. Technical Report 201311, Computational
IntelligenceLaboratory,ZhengzhouUniversity,ZhengzhouChina
and Technical Report, Nanyang Technological University, Singa-
pore Real-Parameter Numerical Optimization 119. Attia A, Fergany E (2018) Extracting optimal parameters of
PEM fuel cells using Salp swarm optimizer. Renew Energy
119:641–648 120. Ibrahim RA, Ewees AA, Oliva D (2019) Improved Salp swarm
algorithm based on particle swarm optimization for feature selec-
tion. J Ambient Intell Human Comput 10:3155–3169. https://doi. org/10.1007/s12652-018-1031-9 130. Cheng MY, Prayogo D (2014) Symbiotic organisms search: a new
metaheuristic optimization algorithm. Comput Struct 139:98–112 131. Cheng MY, Lien LC (2012) Hybrid artificial intelligence-based
PBA for benchmark functions and facility Layout design opti-
mization. J Comput Civ Eng 26(5):612–624 121. Ibrahim A, Ahmed A, Hussein S, Hassanien AE (2018) Fish
image segmentation using Salp swarm algorithm. In: The inter-
national conference on advanced machine learning technologies
and applications. AMLTA 2018. Advances in intelligent systems
and computing. Springer, p 723 132. Karaboga D, Basturk B (2008) On the performance of artificial
bee colony (ABC) algorithm. Appl Soft Comput 8(1):687–697 133. Krink T, Filipic B, Fogel GB (2004) Noisy optimization problem-
s—a particular challenge for differential evolution? In: Congress
on evolutionary computation, CEC2004, IEEE, vol 1, pp 332–339 122. Nematollahi FA, Rahiminejad A, Vahidi B (2019) A novel
multi-objective optimization algorithm based on lightning attach-
ment procedure optimization algorithm. Appl Soft Comput
75:404–427. https://doi.org/10.1016/j.asoc.2018.11.032 134. Surjanovic S, Bingham D (2017) British Columbia, 2015. https://www.sfu.ca/~ssurjano/optimization.html. Accessed
15
Jan 2017 p
g
j
123. Shuang S, Zhiwei Y, Lingyu Y, Jun S, Ruoxi W (2018) Wrap-
per feature selection based on lightning attachment procedure
optimization and support vector machine for intrusion detec-
tion. In: 2018 IEEE 4th international symposium on wireless
systems within the international conferences on intelligent data
acquisition and advanced computing systems (IDAACS-SWS). https://doi.org/https://doi.org/10.1109/IDAACS-SWS 8525742 135. Arora JS (2004) Introduction to optimum design. Academic Press. 136. Belegundu AD (1983) Study of mathematical programming meth-
ods for structural optimization. Publisher’s Note Springer Nature remains neutral with regard to juris-
dictional claims in published maps and institutional affiliations. References Diss Abstr Int Part B Sci Eng
43:1983 137. Coello CA (2000) Use of a self-adaptive penalty approach for
engineering optimization problems. Comput Ind 41:113–127 124. Zheng T, Luo W (2019) An enhanced lightning attachment pro-
cedure optimization with quasi-opposition-based learning and
dimensional search strategies. Comput Intell Neurosci. https://
doi.org/10.1155/2019/1589303 138. Sadollah A, Bahreininejad A, Eskandar H, Hamdi M (2013) Mine
blast algorithm: a newpopulationbasedalgorithmforsolvingcon-
strained engineering optimization problems. Appl Soft Comput
13:2592–2612 125. Mahrous AT, Kamel S, Jurado F, Ebeed M (2020) Optimal
power flow solution incorporating a simplified UPFC model using
lightning attachment procedure optimization. Electr Energy Syst
30(1):e12170 139. Gandomi AH, Yang XS, Alavi AH (2013) Cuckoo search algo-
rithm: metaheuristic approach to solve structural optimization
problems. Eng Comput 29:17–35 126. Suganthan PN, Hansen N, Liang JJ, Deb K, Chen YP, Auger A,
Tiwari S (2005) Problem definitions and evaluation criteria for the
cec 2005 special session on real-parameter optimization. Tech-
nical Report, Nanyang Technological University, Singapore and
KanGAL Report Number 2005005 (Kanpur Genetic Algorithms
Laboratory, IIT Kanpur) Publisher’s Note Springer Nature remains neutral with regard to juris-
dictional claims in published maps and institutional affiliations. 127. Yao X, Liu Y, Lin G (1999) Evolutionary programming made
faster. Evolut Comput IEEE Trans 3(2):82–102 128. LiangJJ,QuBY,SuganthanPN,Hernández-DíazAG(2013)Prob-
lem definitions and evaluation criteria for theCEC2013 special
session on real-parameter optimization. Computational Intelli-
gence Laboratory, Zhengzhou University, Zhengzhou, China and
Nanyang Technological University, Singapore, Technical Report
12, pp 3–18 123
|
https://openalex.org/W2663746340
|
https://hipatiapress.com/hpjournals/index.php/hse/article/download/2663/pdf, https://www.redalyc.org/pdf/3170/317051453004.pdf, https://research.rug.nl/files/49082246/Promoting_school_efficiency.pdf, https://pure.rug.nl/ws/files/49082246/Promoting_school_efficiency.pdf, https://dialnet.unirioja.es/descarga/articulo/6071245.pdf
|
es
|
Promoting school efficiency: Dutch school doctors and the meaning of child health (1930-1970)
|
Historia social y de la educación
| 2,017
|
cc-by
| 8,488
|
Instructions for authors, subscriptions and further details:
http://hse.hipatiapress.com
Promoting school efficiency: Dutch school doctors and the
meaning of child health (1930-1970)
Nelleke Bakker1
1) University of Groningen (Netherlands)
Date of publication: June 23rd, 2017
Edition period: June 2017 – October 2017
To cite this article:.Bakker, N. (2017). Promoting school efficiency: Dutch
school doctors and the meaning of child health (1930-1970). Social and
Education History 6(2), 196-219. doi:10.17583/hse.2017.2663
To link this article: http://dx.doi.org/10.17583/hse.2017.2663
PLEASE SCROLL DOWN FOR ARTICLE
The terms and conditions of use are related to the Open Journal System and
to Creative Commons Attribution License (CC-BY).
HSE – Social and Education History Vol. 6 No. 2 June 2017 pp. 196219
Promoting School Efficiency: Dutch
School Doctors and the Meaning of
Child Health (1930-1970)
Nelleke Bakker
University of Groningen
(Netherlands)
Abstract
_________________________________________________________________
This paper explores the meaning of child health, as applied by Dutch school doctors
between 1930 and 1970, and the way it reflected the rapidly improving standard of
living and the increasing importance of mental health following World War II. It
focuses on both the national discourse and school doctors’ daily activities. For the
latter, the countryside of the province of Groningen has been studied. Despite
assertions that their profession subscribed to a new, positive and inclusive concept
of health, as introduced by the World Health Organization in 1948, the Groningen
school doctors continued to use a negative concept of a “healthy” schoolchild until
well after World War II: a child who was not bothered by diseases or infirmities or
any other “abnormalities.” They clung to the original aim of school medical
inspection: the promotion of the school’s efficiency through the reduction of
possible threats to pupils’ learning capacity. In the postwar years, school doctors
more often associated these threats with an unfavorable school climate. Overly large
classes and heavy academic loads were thought to lead to “mental overburdening.”
Thus, school doctors changed their concept of health by linking physical and mental
health so that it became more inclusive
_________________________________________________________________
Key words: school hygiene, school doctors, child health, school medical inspection
2017 Hipatia Press
ISSN: 2014-3567
DOI: 10.17583/hse.2017.2663
HSE – Social and Education History Vol. 6 No. 2 June 2017 pp. 196219
Promoviendo la Eficiencia Escolar:
Medicos Escolares Holandeses y el
Significado de la Salud Infantil (1930-1970)
Nelleke Bakker
University of Groningen
(Netherlands)
Resumen
_________________________________________________________________
Este trabajo explora el significado de la salud infantil, aplicado por los médicos escolares
holandeses entre 1930 y 1970, y la forma en que ello reflejó el rápido aumento del nivel de
vida y la creciente importancia de la salud mental después de la Segunda Guerra Mundial.
Este se centra tanto en el discurso nacional como en las actividades diarias de los médicos
escolares. En relación a este último, se ha estudiado la zona rural de la provincia de
Groningen. A pesar de las afirmaciones de que su profesión se había adherido a un concepto
nuevo, positivo e inclusivo de la salud, introducido por la Organización Mundial de la Salud
en 1948, los médicos escolares de Groningen continuaron utilizando un concepto negativo de
escolares «sanos» hasta mucho después de la Segunda Guerra Mundial: un niño o niña que no
había estado afectado por enfermedades o dolencias o cualquier otra "anormalidad". Estos se
aferraban al objetivo original de la inspección médica escolar: la promoción de la eficiencia
escolar mediante la reducción de las posibles amenazas a la capacidad de aprendizaje del
alumnado. En los años de la posguerra, los médicos escolares a menudo asociaban estas
amenazas con un clima escolar desfavorable. Las clases excesivamente grandes y las fuertes
cargas académicas se consideraron factores que conducían a la "sobrecarga mental." Por lo
tanto, los doctores escolares cambiaron su concepto de la salud al vincular salud física a salud
mental
para
que
este
fuera
más
inclusivo.
_________________________________________________________________
Palabras clave: higiene escolar, médicos de escuela, salud infantil, inspección
médica escolar
2017 Hipatia Press
ISSN: 2014-3567
DOI: 10.17583/hse.2017.2663
198 Bakker – Promoting school efficiency
I
n the developed world, child health became a public concern at the
end of the nineteenth century. School medical inspection was one of
the flowers that grew from the seeds spread by public hygiene
campaigns addressing the living conditions of the poor. It marked the
transition from a focus on the environment to a direct concern with the
individual. As such it was a component of a new welfare state policy that
became urgent as a consequence of compulsory education, which brought
about the incorporation of children from home environments that lacked
basic hygienic provisions. The first municipal institutions providing hygienic
care for schoolchildren were created in the 1870s and 1880s in cities in
Europe (Hendrick, 2003). Brussels pioneered in 1874; other Belgian and
German cities followed soon afterwards (Velle, 1990). The international
character of the child-hygiene movement is demonstrated by the first
international conferences on school hygiene in 1904 (Nuremberg) and 1906
(London and Paris) (Barona, 2008). In 1906 the British Medical Journal
reported that school medical officers had been appointed in cities in at least
twenty different countries, including Spain, Argentina, Chile, and the
Netherlands. In some countries, such as England and Wales in 1907 and
Spain in 1911, the state stimulated the development of school hygiene by
legislation that enforced the establishment of municipal school medical
inspection in the larger centers (Harris, 1995; Moreno Martínez, 2006).
The establishment of school medical services was first of all motivated
by the wish to protect children against infectious diseases. The risk of
contamination was one of the dark sides of compulsory schooling. In
crowded classrooms, bacilli could circulate freely. School medical
inspection was meant to combat this danger. A second reason is the one
particularly emphasized by authors discussing the establishment of school
medical inspection in the English-speaking world. They point to the fear of
physical deterioration and degeneration of the white race, a fear that
manifested itself around 1900 in Britain. It was inspired by the decline in its
international supremacy and was concretized in the Interdepartmental
Committee on Physical Deterioration, whose report (1904) paved the way
for the introduction of free school meals for undernourished children in 1906
and school medical inspection in 1907, and indirectly for the introduction of
physical education in British schools as a means to promote national fitness
and efficiency (Harris, 1995).
HSE – Social and Education History, 6(1)199
In the early decades of the twentieth century, tuberculosis was the
greatest child-killer in the Western world. Thus, school hygiene became part
of the international anti-tuberculosis campaign, which inspired a set of
welfare provisions for children, from health camps to open air schools. Each
of these interventions linked up the social and the medical, in that the
hygienic mood was fostered by a child-saving ethos that focused on the
poor. Undernourished, pale, and sickly children were categorized as
“pretubercular.” According to the experts, they were probably contaminated
with the bacillus but “not yet ill,” a condition that might deteriorate but was
likely to improve by means of more nourishing food and health-promoting
conditions. Poor children’s ascribed predisposition to the disease stimulated
public interest in nutrition as being essential to optimum health, necessary
for fighting infectious diseases, as well as activism to combat poor
nourishment, excessive (school)-work, lack of hygiene, and poor living
conditions. The anti-tuberculosis campaign accelerated at the time of the
First World War and slowed down shortly before the Second, when the
number of victims fell rapidly because of the improved health and nutritional
condition of the population (Connolly, 2004; Barona, 2008). Only in the
countryside did hygiene lag behind and need to be spearheaded in future
public hygiene campaigns, according to a series of reports (1931-1933)
produced by the League of Nations Health Committee. In the 1920s,
hygienists had revealed the backwardness and relatively high pathogenicity
of rural areas (Barona, 2005).
To date, studies in the history of school medical services have focused
either on their establishment and early years (Hendrick, 1992; Parker, 1998),
on the development of the national institution (Harris, 1995; De Beer, 2008),
or on their contribution to the “modernization” of education (Moreno
Martínez, 2006). They seldom extend beyond the interwar period and
usually take for granted that school doctors’ work focused on children’s
physical health. Across the West, school doctors’ assignments have included
the prevention of the spread of contagious diseases, vaccination, periodic
health examinations of pupils and teachers, the promotion of hygienic school
buildings and furniture, the prevention of health-threatening timetables, and
the dissemination of hygiene knowledge among teachers, parents, and
pupils. While in some countries, like England and Wales (Harris, 1995),
school doctors also treated a child’s ailments, in other countries, such as
200 Bakker – Promoting school efficiency
Spain (Moreno Martínez, 2006) and the Netherlands (De Beer, 2008), their
assignment was limited to prevention. Everywhere, school doctors were
expected to identify the health problems of individual children, like
defective vision and hardness of hearing, as early as possible in order to
prevent learning problems. When special provisions were available,
“feebleminded” children were referred to special schools or classes, and
“pretuberculous” children to open air schools and health camps.
Although the establishment of child guidance clinics from the 1920s
onwards made mental health an increasingly important issue in education
(Cohen, 1999), this is not discussed by historians of school medical
inspection. Studies on the history of psychology, on the other hand, consider
schooling an important domain where psychologists could practice testing
and family guidance, and determine the limits of normality. They emphasize
their contribution to disciplining and normalizing childhood and the family
(Rose, 1985; Gleason, 1999; Turmel, 2008). These studies suggest a natural
inclusion of children’s mental health in school hygiene as part of a social
policy that supported the developing welfare state of the mid-twentieth
century. This is likely to have happened after the World Health Organization
(WHO) exchanged a “negative” concept of health, “the absence of disease
and infirmity,” for a positive and inclusive one, “a state of complete
physical, mental and social wellbeing,” in 1948. This new concept of health
was also at the heart of the Technical Report of the WHO’s Expert
Committee on School Health Services (WHO, 1951).
This shift in focus may be related to the improved physical health of
pupils, especially in the cities, because of postwar prosperity (Schuyt &
Taverne, 2004). Did this apply to Dutch schoolchildren and, if so, in what
respects did their health improve and what was considered an
”improvement”? Did school doctors shift their attention away from
governing children’s bodies toward a more inclusive concept of health and
wellbeing? And did they shift their interpretation of health from the absence
of certain unfavorable physical conditions to the presence of physical and
mental conditions that were considered favorable for a child’s intellectual,
emotional and social wellbeing?
The Netherlands is one of the few developed countries that did not
legislate the aims and conditions of school medical inspection until the
1980s. This implies that Dutch school doctors were relatively free to choose
HSE – Social and Education History, 6(1)201
their own focuses of attention and interpretations of child health. This paper
will explore the meaning of child health, as it was applied by Dutch school
doctors, and the way it reflected the rapidly improving standard of living and
the increasing importance of mental health after World War II. The focus
will be on both the national and a regional level. As to the former, the
analysis will encompass the discourse on standards of health and ways to
promote it. The absence of a legal basis for school medical inspection
implies that data about schoolchildren’s health, collected by school doctors,
was largely incomparable and that national data was almost nonexistent. As
regards school doctors’ daily activities and the concept of health that was
applied in their work, the research must, therefore, focus on the local or
regional level, and use archival sources. To this end, the countryside of the
northern province of Groningen – a relatively poor and underdeveloped,
agrarian-industrial area – has been chosen, since there is a unique and
complete set of annual reports and an archive of the district school doctors
available covering the mid-twentieth century (1930-1970). In this rural area,
improvement of physical child health is not likely to have occurred at the
same time and on the same level as in the more prosperous, urbanized
regions in the west of the country. First, the paper will discuss the discourse
and practice of Dutch school doctors up to the 1940s. Next, it will focus on
the changes in the concept of health that became manifest in the postwar
years of rapid economic growth and prosperity.
Prevention of School Diseases: School Hygiene up to the 1940s
In the Netherlands, the first school doctors were appointed in 1904 as public
health officers in seven cities. Four years later, school medical inspection
was available in 49 cities. The city of Groningen first appointed a school
doctor in 1908. In 1929, 48% of all Dutch primary pupils were under
hygienic supervision, mostly in cities. Private religious schools were free to
use or not use the service, whereas public schools participated automatically.
The service was free for all schools, and, if a school participated, parents
were free to refuse to have their child examined. The first countryside
district school doctors were appointed in 1927 in a very poor and
underdeveloped peat-producing region in the province of Drenthe, just south
of Groningen (De Beer, 2008). This inspired the province of Groningen to
202 Bakker – Promoting school efficiency
support their municipalities in forming “groups” that could appoint a school
doctor collectively. Between 1930 and 1933 four groups appointed a district
school doctor, which made the province a champion of district services.
In 1942, during the German occupation, all Dutch municipalities
were obliged to appoint school doctors. After the war, the Dutch government
continued to subsidize the establishment of school medical services. As a
result the number of participating municipalities grew rapidly, covering 80%
of the country in 1947. Full coverage was not reached until 1965, when the
last municipality joined a district service (De Beer, 2008). In the province of
Groningen this point had been reached earlier, in 1943, when all 65
municipalities participated in one of its seven district services. Because
schools were not obliged to make use of the service, this did not imply that
all children were monitored by a school doctor, but for the most part they
were. The acceptance of the service was high, even among religious parents
who used to be afraid of state regulation of their private, religious schools –
though not of state financing for these schools. School doctors in the
province of Groningen continued to emphasize that their service covered all
or almost all schools in their district. At first this involved mostly primary
schools and schools for extended primary education. As elsewhere in the
country, nursery and secondary schools were included in the services only
after World War II.
The instructions for school doctors of the pioneering cities show that the
prevention of diseases that could be transferred and caught at school, the socalled “school diseases,” was the prime objective of these new civil servants.
Common to these instructions, which served as models for other cities, is the
focus on examining for illnesses that might “harm a pupil’s fitness for
education,” “impede or obstruct teaching,” or “endanger other pupils.”
Reading these instructions makes clear that keeping the schools safe from
contagious diseases, along with preventing deterioration of infected ears and
eyes, were the main objectives (Bakker & De Beer, 2009). As in neighboring
Belgium and Germany, Dutch school doctors’ work was strictly
preventative. Unlike their British colleagues, they were not allowed to treat
children’s ailments, and, therefore, did not run clinics of their own. They
were to refer a sick child to his or her family doctor or to a specialized clinic
for treatment.
HSE – Social and Education History, 6(1)203
The focus on the prevention of “school diseases” in the assignment given
to Dutch school doctors reflects the reasons local communities were willing
to pay for the service. These and their negative impact on school efficiency
had played a key role in the public debate that preceded the appointment of
the first school doctors. The introduction of compulsory education in 1901
had reinforced the case of those who argued that schools ought to be a safe
place. A state that forced children to attend school had the moral duty to
minimize health risks at school, many politicians and hygienists argued.
Child labor before and after school hours, and its detrimental effects on child
health and national fitness – a major argument for the introduction of the
school medical service in England and Wales (Hendrick, 1992) – did not
play a significant role in the Dutch discourse. Religious groups were of the
opinion that only parents had the authority to decide whether a child should
attend school or work, a conviction that had made them vote against
compulsory education in Parliament. The same aversion to state interference
made representatives of Christian parties usually oppose the appointment of
school doctors in their local councils. Any mention of the health-threatening
effects of child labor on the periphery of the school day was avoided by local
hygiene activists, so as not to arouse extra opposition to the establishment of
a school medical service. The same seems to be true of problems of
malnutrition and the lack of fitness of poor children (Bakker & De Beer,
2009), which enabled the medical profession in England and Wales to justify
its claims that the health of schoolchildren should be monitored (Harris,
1995).
Throughout the period under study, a precarious balance had to be kept
between the two halves of the Dutch population: liberals and social
democrats, on the one hand, and denominational groups, on the other.
Education was heavily contested. As a result, even non-religious groups
refrained from attempts to extend state regulation in education, the state’s
full financial responsibility for all schools from 1920 aside. The
precariousness of this balance explains also why eugenic objectives,
referring to national fitness, scarcely played any role as a moving force in
the history of Dutch school medical inspection. Protagonists of school
hygiene were not driven by fear of physical deterioration or degeneration of
the Dutch population.
204 Bakker – Promoting school efficiency
In the interwar years the national discourse on school medical inspection
focused on the fight against infectious diseases such as diphtheria, measles,
scarlet fever, and tuberculosis. School doctors were disappointed that the
Christian parties had managed to remove the obligatory vaccination of
schoolchildren against smallpox from the new Contagious Diseases Act
(1928). They likewise resented these parties’ refusal to extend their power to
close a school and ban infected children in case of a school epidemic. School
doctors’ options, when faced with such a threat, continued to depend on
local regulations. Tuberculosis screening of all pupils by means of a Pirquet
patch test was discussed as a possible extension of the school doctors’
assignment, but it was practiced by only a minority of the school medical
services. A positive reaction to the test indicated tubercle infection only, not
the stage, the severity (active or latent), or the contagiousness. Nevertheless,
over the years the scale of testing of complete school populations increased,
especially during the 1930s. At the same time the percentage of children
with a positive Pirquet reaction decreased rapidly. In the city of Groningen it
fell from 65% of all eleven-year-old pupils in 1915 to 14% of all fourthgraders (aged ten to eleven) in 1937. The same is true of the number of
deaths from tuberculosis, including children and adolescents (Bakker, 2010).
In their annual reports the district school doctors of the Groningen
countryside mostly paid attention to the results of the routine health
examination of pupils. They conceived of this as their most important task.
As elsewhere in the Netherlands, each year they subjected about half of the
pupils of the supervised schools to a medical check-up. This involved all
pupils in the first grade (aged six to seven), in the final grade (aged eleven to
fourteen), and of one of the grades in between, so that every pupil was fully
examined at least three times. A small number of pupils was examined more
closely because they were sickly and missed school often, or because the
teacher suspected that they were suffering from a particular, possibly
contagious, disease. Where it was suspected that a child was suffering from
tuberculosis, referral was made to an out-patient clinic, where specialized
doctors could further examine the child. By the 1930s, such cases were
already very rare. Extra visits were paid to schools that experienced early
signs of an epidemic of scarlet fever or diphtheria, which could be contained
by hygienic intervention, such as banning infected children from the school
HSE – Social and Education History, 6(1)205
and vaccination of children who had not yet caught the disease. Referrals to
a general practitioner for treatment were frequently made.
One of the main focuses of attention of the health examination was the
child’s “nourishment status,” which was established on the basis of the
child’s physical appearance. In 1937, a survey by the national Inspection for
Child Hygiene among school doctors showed that, despite the economic
crisis, the majority of the Dutch children were “well” (49%) or “sufficiently”
(32%) fed, and that only a small minority was “insufficiently” fed (7%). The
Groningen school doctors participated in this survey. It turned out that, in
the city, the children were more often “well” fed (64%) than the average
Dutch child. In the countryside districts, however, they were more often
“insufficiently” fed (12% on average) (“Verslag over de jaren 1936 en
1937…,” 1938, p. 765), a finding that confirmed the international concern in
the 1930s about the health of the population in the countryside. A
comparison of the nourishment status of poor schoolchildren over time can
be made only for a few working-class neighborhoods in Amsterdam. In
1936, despite large-scale unemployment, it turned out to have improved
considerably compared to 1916 and 1920, although poor children continued
to trail behind those from more well-to-do neighborhoods (“Onderzoek…,”
1936).
Malnutrition could be remedied in two ways. First, poor relief could
provide for extra meals through the school. However, school doctors were
not allowed to select the children who qualified for these meals, since the
churches dominated this work. A doctor’s assessment of a child’s
nourishment status was only one of the criteria for admission. Instead,
doctors’ contribution focused on the effect of these meals in anthropometric
terms. They measured the increase in weight and height of every child who
was accepted into a program. In the Groningen countryside districts, the
results were positive almost without exception (Verslag …1935, n.d.;
Verslag …1936, n.d.). Second, pale and undernourished children could be
sent to a “health colony” for six weeks. These “colonies” were located on the
coast or in the woods and were organized by philanthropic societies, many
of which were church-related. Throughout the year they received large
groups of “weak” children, who were “treated” with heavy meals of porridge
and stew, physical education, and walking tours. School doctors selected the
206 Bakker – Promoting school efficiency
children, and they strongly advocated this work, which – like other public
health interventions – grew rapidly during the 1930s (Bakker, 2007).
Apart from nourishment, the routine health examination of the Groningen
district school doctors focused on children’s eyes, ears, teeth, chest, throat,
spine, posture, limbs, skin, and the cleanliness of their hair and head.
Altogether, there were eleven items of physical health and one related to
emotional wellbeing, bed-wetting, which was believed to be an expression of
distress at the time. The doctors found a large part of the pupils had
“abnormalities,” 46% in 1930. School doctors were proud to be able to
report so many health deficiencies. Some added that nine out of ten of the
ones “discovered” had not been known beforehand (Verslag …Veendam …
1932, n.d.). In their view, this confirmed the importance of their work.
In the 1930s the Groningen district school doctors most often found
problems with children’s posture and their spines. Scoliosis, a deformation
of the spine, was frequently diagnosed. It was believed at the time that this
was caused by sitting at a school desk that was the wrong size or sitting
slantwise, in addition to a lack of exercise. In 1935, in two districts 16% of
the pupils on average were diagnosed with scoliosis. Another 14% suffered
from other kinds of posture problems (Verslag … 1935, n.d.). This high
frequency explains the constant concern of the school doctors about school
desks, which goes back to the mid-nineteenth century (Moreno Martínez,
2006). During the economic crisis of the 1930s, Groningen countryside
schools still used to buy only a few different sizes of desks, whereas
prevention of scoliosis required that each child sit at a desk of the right size,
doctors insisted.
School doctors conceived of themselves as hygienic educators of the
working class. That is why mothers were supposed to accompany their child
during the health examination. The doctors’ message of cleanliness and due
amounts of fresh air, exercise, rest, and healthy food was supported by a
small booklet, edited and distributed by the national society of school
doctors. It was meant to rule out “wrong ideas” and promote bathing,
swimming, a weekly change of underwear, and daily hair and tooth brushing
as “modern” hygienic child care (Van Voorthuijsen, 1931). From the late
1930s on, the first signs are noticeable that the profession’s concept of
hygiene was beginning to broaden from the physical health and cleanliness
of the child’s body and clothes to embrace aspects of mental health as well.
HSE – Social and Education History, 6(1)207
These involved children’s emotional wellbeing. Doctors’ broadening interest
is reflected in their response to questions frequently asked by mothers about
how to handle their “difficult” or “nervous” children. It is no coincidence
that this occurred at the time when child-rearing advice was medicalized, in
the sense that it presented a “normal” child as mentally healthy and happy
rather than virtuous and took psychiatric theory as its intellectual foundation
(Bakker, 2006). This added to the authority of doctors in matters of childrearing. At the same time, the one-sided physical orientation of school
doctors’ education was being criticized more often as inadequate to handling
these problems.
A Broader Concept of Health: the Postwar Years
In the 1950s and 1960s, Dutch school medical inspection extended into two
rapidly growing parts of the educational system, nursery and secondary
schooling. As a consequence, the number of pupils under supervision
increased rapidly. In the Groningen countryside districts, it grew for example
from 16,706 pupils, supervised by three school doctors in 1940 (5,569 pupils
per doctor), to 66,948 pupils, supervised by nine school doctors in 1960
(7,439 pupils per doctor). One of the consequences was that instead of half
of the pupils of the supervised schools, no more than one third could be
examined annually. On the other hand, from the 1950s onwards, a child as a
rule was fully examined five times during his/her school career: once in
kindergarten, three times in the primary school, and another time in an
extended primary school or in one of the secondary schools of the Groningen
countryside (Bakker, 2015).
The national organization of school doctors was an early adopter of the
positive and inclusive concept of health presented by the WHO in 1948. As
early as the late 1940s, they invited speakers to their meetings to discuss
topics like mental health, readiness for school, and behavioral problems and
their causes (“Sectie Schoolgeneeskunde…,” 1947; De Vries, 1949) From
that time on, educational programs for school doctors included child
psychology and child-rearing as new subjects. Nevertheless, in 1952, at a
national conference on the future of school medical inspection, the
profession was seriously criticized for not innovating their work. Scientists
criticized school doctors’ routines involving searching for and registering
208 Bakker – Promoting school efficiency
“abnormalities” in children, regardless of whether or not these had already
been identified by parents or a general practitioner. By continuing to focus
on numbers of “abnormalities,” school doctors contributed data to medical
statistics, but they did not approach child health “positively,” and by sticking
to the prevention of physical illness, they ignored the increasingly important
“psychosocial problems” children experienced, critics pointed out. The onesided focus on physical ill-health had outlived itself as a consequence of
decreasing infant and child mortality and morbidity, along with a higher
standard of living, a professor of social medicine claimed. He blamed school
doctors for not having changed the nature of their work in 45 years: “mass
screening of the school population aiming to find abnormalities”
(“Nederlands Congres,” 1952, p. 74). Some critics were of the opinion that
mental health had become even more important since physical child health
had improved significantly in the immediate postwar years (Buma, 1954).
During the 1950s, these accusations were often repeated by medical experts,
confirming the low status of school doctors within the medical profession –
a condition that seems to have been the major cause of the rapid
feminization of school medical inspection in the post-war years (De Beer,
2008).
School doctors defended themselves by pointing to their one-sided
education as physicians. They declared that they were willing to
professionalize by means of courses on mental health, and emphasized their
role as intermediaries between parents, teachers, and the growing number of
specialized professionals, such as speech therapists, to whom they could
refer. They did not want to give up their traditional approach, but they were
willing to include aspects of mental health in their routine examinations. The
school doctors’ organization concluded the ongoing debate in 1960 with a
report that re-established the old approach on a somewhat different basis.
The concept of health was adapted to encompass the promotion of the
optimal health of each individual child and the inclusion of psychosocial
aspects of development, such as a young child’s “readiness for schooling.”
The routine health examination, preferably five times during a child’s school
career, remained the main instrument, school doctors asserted (“Rapport der
Commissie,” 1960).
Not only did the numbers of pupils under their supervision and the
number of routine examinations increase, new tasks were also added to the
HSE – Social and Education History, 6(1)209
school doctors’ assignment. Though it was not prescribed, tuberculosis
screening of all pupils became standard practice after the war. In 1957, two
thirds of school doctors conducted tuberculosis screening. However, the
number of children this mass screening found to be infected was very low,
approached zero in the 1960s, which in turn inspired criticism. The minutes
of the committees that supervised the work of the Groningen countryside
district school doctors show that a single case of a “discovery” of an infected
child could silence this critique for years (Minutes SPG, 1930-1970). This
explains why the tuberculosis screening continued for so long, up until 1970
in the Groningen districts. From 1952 onwards, moreover, a national
vaccination program for babies was started. Initially it was limited to
diphtheria, but soon other illnesses were added: whooping cough, tetanus
and polio. School doctors took the revaccination of schoolchildren upon
themselves. This program quickly turned out to be very effective (De Beer,
2008).
At the same time, school doctors’ reports and their routine health
examinations were also extended. From 1948 onwards, the national
Inspector for Child Hygiene limited the freedom of school doctors to report
in their own way, requiring information on a list of items in their annual
reports. The national results were published between 1952 and 1958. They
encompassed the years 1948-1955 (Verslagen en Mededelingen, 19521958). School doctors did continue to report in different ways, but with time
their reports became more homogeneous and more detailed with regard to
children’s “abnormalities.” From the late 1940s onwards, with regard to
eyesight, for example, all Groningen district school doctors recorded the
numbers of children suffering from squint and color-blindness, in addition to
the number of children with weak eyesight or eye diseases. From the 1960s
onwards, they started to differentiate between weak-sighted children who
already wore glasses and “newly found” cases. Around 1960, vaccination
levels and referrals to special care, such as remedial physical education and
speech therapy, became more important in the doctor’s annual reports than
the numbers of “abnormalities” found. This shift in focus followed the
reports of the national Inspector for Child Hygiene, who stopped collecting
numbers of schoolchildren’s health deficiencies in the late 1950s, a decision
that was not followed by the Groningen district doctors until 1971. By
210 Bakker – Promoting school efficiency
adding brief summaries of collective concerns to their reports, these doctors
displayed their most disquieting worries from the early 1950s.
The routine health examination itself developed from the relatively
simple check-up of a child’s basic bodily functions (eyes, ears, throat, teeth,
posture, and spine), cleanliness (of the skin and hair), and nourishment status
in the 1930s, to a much more extensive examination in the 1960s, focusing
particularly on “abnormalities” in the functioning of all senses and organs,
including the central nervous system. In 1960, the Groningen district school
doctors reported on an average number of 23 aspects of child health, from
“general physical condition” (which replaced the “nourishment status”) and
“eyes” to referrals to a general practitioner, more than twice as many aspects
as had been covered in 1940 (Verslag …1940, n.d.; Verslag … 1960, n.d.).
As to the results of the examinations, throughout the 1950s and 1960s the
numbers of children found “with abnormalities” by the Groningen district
school doctors were some 30% higher than in 1930 (60%-68% percent as
against 46%). In 1955, 68% of the pupils examined showed “abnormalities”
(versus 63% in the country as a whole) (Verslag …1955, n.d.; Verslagen en
Mededelingen, 1958). Children’s sight and hearing, in particular, were found
to be deficient more often, and their posture and their teeth more often in bad
shape: results that are consistent with the national Dutch and the English
data available (Harris, 1995). The higher level of “abnormalities” was not
only caused by the more detailed list of items the doctors now had to use in
their postwar examinations, but also by improved screening for visual and
hearing deficiencies, the growing proportion among those examined of
secondary pupils (who needed glasses much more often than elementary
pupils), and the introduction of school dentists.
Still, a tendency toward an overall improvement in the physical condition
of the pupils can be discerned. The proportion of Groningen countryside
schoolchildren whose general physical condition was insufficient fell from
29% in 1935 to 14% in 1950 (versus 5% in the country as a whole), and only
4% in 1960. More hygienic housing, better living conditions, and betterinformed parents seem to be responsible for a reduction of the number of
“unclean heads” and diseases of the skin, such as scabies and eczema. The
1950s saw a spectacular drop in the number of children suffering from
rickets, from 12% to 3% of those examined, which is probably related to a
richer and more varied diet and more frequent check-ups for babies and
HSE – Social and Education History, 6(1)211
toddlers at the infant health bureaus. The prosperous 1960s are likely to have
witnessed the effects of more frequent physical education classes and the
general availability of remedial physical education, to which school doctors
could refer, since posture problems and scoliosis virtually disappeared
(Bakker, 2015; Schuyt & Taverne, 2004).
Dutch school doctors had been pleased when the wartime German
government had made it impossible for schools to avoid teaching physical
education for lack of a gym. Throughout the 1950s, the Groningen district
school doctors continued to complain about the quality of the
accommodations where the lessons in physical education were taught: they
were too small, too dirty, or too dark. Sometimes lessons took place outside
in the mud. In the early 1960s, these complaints just about ceased, since
even country schools were provided with gyms. From that point on, school
doctors pleaded for more hours of physical education, preferably one hour a
day. They ascribed an additional value to physical education as a means to
improve the school’s effectiveness. Children, they maintained, would learn
more if they were physically healthy and energetic. Physical education
would contribute to pupils’ “mental and physical” fitness and prevent moral
“degeneration”. The same was said of recess outdoors: instead of one
morning break, two were advised.
From the 1930s and especially in the post-war years, villages in the
Groningen countryside had built outdoor swimming pools. Primary schools
organized swimming lessons for their pupils in the middle grades. The
ability to swim saved lives in a country full of ditches and canals and it
promoted schoolchildren’s physical and mental health, school doctors
claimed. Like other sports it could compensate for too many hours of
academic work. That is why school doctors welcomed the initiative and
hoped that these lessons would soon become available for all children.
Predictably, they took upon themselves the new assignment of examining all
candidates for swimming lessons, focusing on children’s ears, throat, and
heart. The examples of physical education and swimming illustrate how
school doctors succeeded in linking up physical and mental health.
In the early 1950s the Groningen district school doctors started to pay
tribute to the new, positive and inclusive concept of health. They made clear
in their reports that they conceived of their work as pivotal in promoting
this. The province had to wait relatively long, until 1960, before a child
212 Bakker – Promoting school efficiency
guidance clinic was established in the city of Groningen. Up to that point,
there had been a mobile consultation clinic for parents and children
experiencing child-rearing problems. The clinic held consulting hours once a
week at four different places in the province. That did not satisfy the
increasing need for the psychiatric treatment of “difficult” children, but even
after the child guidance clinic was established, referrals of countryside
children to this urban clinic and to the university clinic for child-psychiatry
remained very rare. Despite school doctors’ admitted lack of psychological
expertise, most child-rearing problems were taken care of during their own
consulting hours, which were held at least once a month in the district
centers. For testing they could refer a child to the Youth Department of the
Provincial Psychiatric Service (Jeugd Psychiatrische Dienst, JPD). Referrals,
which can be found from 1947 onwards, mostly concerned cases of learning
problems (Bakker, 2015).
What kind of child-rearing problems were the district school doctors
confronted with in their consultations? It is likely that these were the same
problems they discussed in their reports: bed-wetting, speech problems, and
mental retardation. Each of these was included in the Inspector’s list to be
used in the routine health examination. Together, these three items
comprised the bulk of school medical service’s interest in mental health. As
compared to the physical ailments, these “abnormalities” particularly
involved young children. Over time, bed-wetting was found more often
(from 3.8% of the pupils examined in 1950 to 6.5% in 1970) (Verslag
…1950, n.d.; Verslag …1970, n.d.). This does not indicate a growing
problem but the vanishing of a taboo. Mothers gradually became less
inhibited to discuss the problem and seek a solution. Although bed-wetting
was not discussed often in their reports, it is clear that the doctors were
aware of the complexity of the problem and convinced that it was connected
to psychosocial background. During the 1950s, school doctors echoed the
national discourse by considering wed-wetting a “neurotic disorder,” a
symptom of mental ill-health, or an effect of “mental overburdening” of a
child. They agreed that bed-wetting was a hard-to-combat ailment, for which
the right therapy had not yet been found. Only in very serious cases did
doctors refer a bed-wetting child to the psychiatric service or the child
guidance clinic.
HSE – Social and Education History, 6(1)213
Speech problems like stammering and stuttering were likewise found
more often in the 1950s, but slightly less often in the 1960s. References to
speech therapy by trained professionals were made from the early 1950s
when the municipalities were first compensated for the expense. It is likely
that both the rise and the subsequent fall in the number of speech
impediments that were identified were an effect of the availability of speech
therapists. School doctors were aware of the possibility of an emotional
background to speech problems, since they differentiated between
impairments with and without a physiological cause and classified almost all
of them in the latter category. Repeatedly school doctors called stammering
a “neurotic” disorder, for which “mental overburdening” and a one-sided
intellectual school climate might be responsible. Treatment, therefore,
needed to be psychotherapeutic. In 1953 the district school doctors estimated
that 8% to 10% of the schoolchildren needed speech therapy (Verslag
…1953, n.d.). They themselves took responsibility for the selection.
Mental retardation was by far the most important non-physical issue for
school doctors of the Groningen countryside. “Backwardness” was an
“abnormality” on the list of items of the national Inspector for Child
Hygiene, but it was used only to estimate the need for special schools for
“feebleminded” children in districts that could not yet avail themselves of
such a school and there was no national standard indicating the limits of this
category. Between 1939 and 1954 in the province of Groningen every
countryside district center established at least one special school for these
children, except for two towns near the city of Groningen; they continued to
use the city’s special schools. School doctors were responsible for the
selection of pupils for these schools. They administered IQ-tests to children
who continued to lag behind, even after having repeated a grade once or
twice, and they sat on admission committees. Soon, school doctors
manifested themselves as crusaders in a campaign to fight countryside
parents’ resistance to having a child attend a special school. They took pains
to combat what they conceived of as parental ignorance and prejudice, such
as the idea that children would not learn anything at such a school or would
be better off in a classroom with normally endowed children (Verslag
…1956, n.d., Verslag …1963, n.d.). Moreover, they actively promoted
separate schooling for the “feebleminded” as a blessing for both the children
concerned, and the pupils and teachers of the regular schools.
214 Bakker – Promoting school efficiency
A new kind of special school for children with learning and behavioral
problems (leer- en opvoedingsmoeilijkheden, LOM) but a normal IQ,
introduced in 1949, did not reach the Groningen countryside districts before
the mid-1960s. There, the first LOM-schools were established in 1965 and
1967 (Verslag …1965, n.d., Verslag …1967, n.d.). The timing was due to a
collective plea on the part of district school doctors in 1964, arguing that
such schools were badly needed in the countryside. It occurred after more
than ten years of lobbying by individual school doctors to have specific
learning disabilities, such as “word blindness,” recognized as qualifying for
special didactic support and a mental health risk in case of continued
disregard for these children’s special needs (Verslag …1964, n.d.). These
learning problems were sometimes referred to as an effect from the large
size of school classes or of uniform mass teaching, causing “emotional
conflict,” “neurotic reactions,” and inhibitions in children, as well as “mental
overburdening” (Verslag …1953, n.d.).
Conclusion
Despite assertions that their profession subscribed to the WHO’s new,
positive, and inclusive concept of health, in their daily activities Dutch
school doctors continued to use a negative concept of a “healthy”
schoolchild until well after World War II. A healthy schoolchild was a child
who was not bothered by diseases or infirmities or any other
“abnormalities.” The child was not only fit enough to attend school and not
pose a threat to the health of other pupils, but the child’s senses –
particularly vision and hearing – had to function well enough so as to meet
the increasingly strict norms that were determined by rapidly improving
screening techniques for visual and hearing deficiencies. These stricter
standards partly explain the fact that the numbers of “abnormalities” found
by school doctors in their routine health examinations increased instead of
decreased after the war, and that improvement of schoolchildren’s physical
health cannot be inferred from these numbers.
Nevertheless, schoolchildren’s health did improve in the post-war period,
even in the relatively poor countryside of the province of Groningen.
Diseases of the skin and “unclean heads” became rare, a development for
which more hygienic housing and living conditions seem to be responsible.
HSE – Social and Education History, 6(1)215
A richer and more varied diet, together with more frequent check-ups for
infants and toddlers, may explain the sharp decrease of rickets in the 1950s.
Scoliosis almost disappeared in the 1960s, a likely consequence of more
frequent physical education and the general availability of remedial physical
education, to which a school doctor could refer before serious harm to the
spine could develop.
School doctors’ screening and routine health examinations themselves,
however, did not necessarily contribute to better health, as the example of
mass tuberculosis screening shows; it was introduced when it was no longer
necessary. The availability of speech therapy and the inclusion of speech
problems in the Inspector’s list show that screening could produce
“abnormalities.” The increase in dental deficiencies in the 1950s, when
school dental care was introduced, is another example.
These examples make clear that school doctors clung to the original aim
of school medical inspection: the promotion of the school’s efficiency by
reducing possible threats to pupils’ learning capacity. In the postwar years
these threats were more often considered to be rooted in an unfavorable
school climate, where large classes and heavy academic loads led to “mental
overburdening.” Despite their admitted lack of psychological expertise,
school doctors’ concept of health became more inclusive when they linked
physical and mental health, as the promotion of physical education,
swimming, and outdoor recess show. Their additional value did not have to
promote national fitness but needed to compensate for too many hours of
learning and of sitting still.
References
Bakker, N. (2006). Child Guidance and Mental Health in the Netherlands.
Paedagogica Historica, 42(6), 769-791. doi:
10.1080/00309230600929534
Bakker, N. (2007). Sunshine as Medicine: Health Colonies and the
Medicalization of Childhood in the Netherlands c. 1900-1960. History of
Education, 36(6), 659-679. doi:10.1080/00467600701619663
216 Bakker – Promoting school efficiency
Bakker, N. (2010). Fresh air and good food: children and the antituberculosis campaign in the Netherlands c.1900-1940. History of
Education, 39(3), 343-361. doi: 10.1080/00467600903173386
Bakker, N. (2015). De gezondheid van het kind en het veranderend
perspectief van de Groningse plattelandsschoolarts (1930-1970).
Studium, 8(1), 18-38. doi: 10.18352/studium.10076
Bakker, N. & De Beer, F. (2009). The dangers of schooling. The
introduction of school medical inspection in the Netherlands (c.1900).
History of Education, 38(4), 505-524. doi: 10.1080/00467600801969224
Barona, J.L. (2005). The European Conference of Rural Health (Geneva,
1931) and the Spanish Administration. In J.L. Barona & S. Cherry (Eds.),
Health and Medicine in Rural Europe (1850-1945) (pp. 127-146).
València: SEC University of València.
Barona, J.L. (2008). Nutrition and Health. The International Context During
the Inter-war Crisis. Social History of Medicine, 21(1), 87-105. doi:
10.1080/00467600801969224
Buma, J.T. (1954). De sociale kinderhygiëne in Nederland. Haar
organisatie en haar toekomst. Assen: Van Gorcum.
Cohen, S. (1999). Challenging Orthodoxies. Toward a New Cultural History
of Education. New York etc., Peter Lang.
Connolly, C. (2004). Pale, poor and “pretubercular” children: a history of
pediatric antituberculosis efforts in France, Germany and the United
States, 1899-1929. Nursing Inquiry, 11, 139-147. doi: 10.1111/j.14401800.2004.00225.x
De Beer, F. (2008). Witte jassen in de school. De schoolarts in Nederland
ca. 1895-1965. Assen: Van Gorcum.
De Vries, D. (1949). Het schoolkind met afwijkend gedrag. Verslag van de
vergadering van de Sectie Schoolgeneeskunde. Tijdschrift voor Sociale
Geneeskunde, 27, 363-364.
Gleason, M. (1999). Normalising the Ideal. Psychology, Schooling and the
Family in Postwar Canada. Toronto: University of Toronto Press.
Harris, B. (1995). The Health of the Schoolchild. A History of the School
Medical Service in England and Wales. Buckingham: Open University
Press.
HSE – Social and Education History, 6(1)217
Hendrick, H. (1992). Child labour, medical capital, and the School Medical
Service, c. 1890-1918. In R. Cooter (Ed.), In the Name of the Child:
Health and Welfare 1880-1940 (pp. 45-71). London: Routledge.
Hendrick, H. (2003). Child Welfare. Historical Dimensions, Contemporary
Debate. Bristol: Policy Press.
Moreno Martínez, P.L. (2006). The Hygienist Movement and the
Modernization of Education in Spain. Paedagogica Historica, 42(5),
793-815. doi: 10.1080/00309230600929542
Nederlands Congres voor Schoolgeneeskunde (1952). Tijdschrift voor
Sociale Geneeskunde, 31, 59-130.
Onderzoek naar den voedingstoestand van schoolkinderen te Amsterdam
1936 (1936). Tijdschrift voor Sociale Geneeskunde, 14,177-184.
Parker, D. (1998). A convenient dispensary: elementary education and the
influence of the school medical service 1907-39. History of Education,
27(1), 59-83. doi: 10.1080/0046760980270105
Rapport der Commissie “Taak en werkwijze van de schoolarts” (1960).
Tijdschrift voor Sociale Geneeskunde, 38, 431-446.
Rose, N. (1985). The Psychological Complex. Psychology, politics, and
society in England, 1869-1939. London: Routledge and Kegan Paul.
Schuyt, C.J.M. & Taverne, E. (2004). 1950. Prosperity and Welfare. Dutch
Culture in a European Perspective. Assen: Van Gorcum.
Sectie Schoolgeneeskunde A.N.V.v.S.G. (1947). Verslag van de vergadering
op 18-1-1947. Tijdschrift voor Sociale Geneeskunde, 25, 77-80.
Turmel, A. (2008). A Historical Sociology of Childhood. Developmental
Thinking, Categorization and Graphic Visualization. Cambridge
University Press: Cambridge etc.
Velle, K. (1990). Medische schoolinspectie, gezondheidsvoorlichting en
seksuele opvoeding in België in de 19de en 20ste eeuw. Pedagogisch
Tijdschrift, 15, 64-75.
Verslag over de jaren 1936 en 1937 van den Geneeskundig en
Pharmaceutisch Hoofdinspecteur van de Volksgezondheid (1938).
Verslagen en Mededelingen betreffende de Volksgezondheid, 677-955.
Verslag van den Schoolartsendienst in de groep Veendam over het jaar 1932
(n.d.). Veendam: Keizer.
Verslag van den Schoolartsendienst in de groepen Appingedam, Hoogezand,
Veendam en Winschoten over het jaar 1935 (n.d.). Sappemeer.
218 Bakker – Promoting school efficiency
Idem 1936.
Verslag van den Schoolartsendienst in de groepen Appingedam, Hoogezand
en Veendam over het jaar 1940 (n.d.). Groningen.
Verslag van de Schoolartsendienst in de groepen Appingedam, Hoogezand,
Veendam, Vlagtwedde, Winschoten, Winsum en Zuidhorn over het jaar
1950 (n.d.). Groningen.
Idem 1953.
Idem 1955.
Idem 1956.
Verslag van de Schoolartsendienst in de groepen Appingedam, Bedum,
Hoogezand-Sappemeer, Veendam, Vlagtwedde, Winschoten, Winsum en
Zuidhorn over het jaar 1960 (n.d.). Groningen.
Idem 1963.
Idem 1964.
Idem 1965.
Idem 1967.
Idem 1970.
Verslagen en Mededelingen betreffende de Volksgezondheid (VMbV) 19521958 (1955-1962). ’s- Gravenhage: Hoofdinspecteur van de
Volksgezondheid.
World Health Organization (WHO) Expert Committee on School Health
Services (1951). World Health Organization Technical Report Series no.
30. Geneva: WHO.
Archival sources
Minutes of the Meetings of the Committees of the School Doctors Service of
the Province of Groningen (Schoolartsendienst Provincie Groningen, SPG,
1930-1970). Archive SPG (no. 1236, boxes I-V). Groningen Archives,
Groningen.
Van Voorthuijsen, A. (19315). Nu uw kind op school gaat. Archive ANVSG
(box 1). International Institute for Social History, Amsterdam.
HSE – Social and Education History, 6(1)219
Nelleke Bakker: Associate professor of History of Education, Department
of Education. University of Groningen (Netherlands).
Orcid ID: http://orcid.org/0000-0001-9425-1844
Contact Address: p.c.m.bakker@rug.nl
|
|
https://openalex.org/W2073750827
|
http://www.scirp.org/journal/PaperDownload.aspx?paperID=52106
|
English
| null |
The Jeans Equation Generalization for the Rotating Universe
|
International journal of astronomy and astrophysics
| 2,014
|
cc-by
| 3,899
|
Keywords Keywords Jeans Equations, Rotating Universe Jeans Equations, Rotating Universe The Jeans Equation Generalization for the
Rotating Universe Leonid M. Chechin, Aigerim T. Ibraimova
Astrophysical Institute Named After V.G. Fessenkov, Almaty, Kazakhstan
Email: chechin-lm@mail.ru, b_e_n_t_o_s@mail.ru How to cite this paper: Chechin, L.M. and Ibraimova, A.T. (2014) The Jeans Equation Generalization for the Rotating Universe.
International Journal of Astronomy and Astrophysics, 4, 614-619. http://dx.doi.org/10.4236/ijaa.2014.44056 national Journal of Astronomy and Astrophysics, 2014, 4, 614-619
shed Online December 2014 in SciRes. http://www.scirp.org/journal/ijaa
//dx.doi.org/10.4236/ijaa.2014.44056
The Jeans Equation Generalization for the
Rotating Universe
Leonid M. Chechin, Aigerim T. Ibraimova
Astrophysical Institute Named After V.G. Fessenkov, Almaty, Kazakhstan
Email: chechin-lm@mail.ru, b_e_n_t_o_s@mail.ru
Received 23 September 2014; revised 20 October 2014; accepted 15 November 2014
Academic Editor: Luigi Maxmilian Caligiuri, University of Calabria, Italy
Copyright © 2014 by authors and Scientific Research Publishing Inc.
This work is licensed under the Creative Commons Attribution International License (CC BY).
http://creativecommons.org/licenses/by/4.0/
Abstract
The generalization of Jeans equation in expanding and rotating Universe is given. We found the
generalized frequency of baryonic substrate oscillations in the rotating Universe. In doing this,
two cases were considered: the generalized wave vector coincides with the Jeans wave vector and
second case, when the generalized wave vector tends to zero.
Keywords
Jeans Equations, Rotating Universe national Journal of Astronomy and Astrophysics, 2014, 4, 614-619
shed Online December 2014 in SciRes. http://www.scirp.org/journal/ijaa
//dx.doi.org/10.4236/ijaa.2014.44056
The Jeans Equation Generalization for the
Rotating Universe
Leonid M. Chechin, Aigerim T. Ibraimova
Astrophysical Institute Named After V.G. Fessenkov, Almaty, Kazakhstan
Email: chechin-lm@mail.ru, b_e_n_t_o_s@mail.ru
Received 23 September 2014; revised 20 October 2014; accepted 15 November 2014
Academic Editor: Luigi Maxmilian Caligiuri, University of Calabria, Italy
Copyright © 2014 by authors and Scientific Research Publishing Inc. This work is licensed under the Creative Commons Attribution International License (CC BY). http://creativecommons.org/licenses/by/4.0/
Abstract
The generalization of Jeans equation in expanding and rotating Universe is given. We found the
generalized frequency of baryonic substrate oscillations in the rotating Universe. In doing this,
two cases were considered: the generalized wave vector coincides with the Jeans wave vector and
second case, when the generalized wave vector tends to zero. Keywords
Jeans Equations, Rotating Universe International Journal of Astronomy and Astrophysics, 2014, 4, 614-619
Published Online December 2014 in SciRes. http://www.scirp.org/journal/ijaa
http://dx.doi.org/10.4236/ijaa.2014.44056 Abstract The generalization of Jeans equation in expanding and rotating Universe is given. We found the
generalized frequency of baryonic substrate oscillations in the rotating Universe. In doing this,
two cases were considered: the generalized wave vector coincides with the Jeans wave vector and
second case, when the generalized wave vector tends to zero. Keywords 1. Introduction In these cases, the constrained Poisson equation may be even more com-
plicated due to the presence of extra scalar(s) in non-local or string-inspired gravity. Dark matter density profiles from the Jeans equation were considered in article [10]. They make a simple
analytical study of radial profiles of dark matter structures, with special attention to the question of the central
radial density profile. Recent numerical dark matter simulations show that the phase-space-like density profile
ε
ρ σ
, is well fitted locally with a simple power law with ε of the order 2 - 3. They shown that when the
radial density profile is an exact power law
~ r β
ρ
−, the spherically symmetric and isotropic Jeans equations
only admit the solutions where the density power slope is in the range 1
3
β
≤
≤
. In [11], it was considered dark matter angular momentum profile from the Jeans equation. Authors studied the
form of the spherical Jeans equation when one includes angular momentum, and find that bulk motion leads to
the introduction of extra term, which includes the average rotational velocity. They present a new connection
between the radial profiles of the angular momentum and the velocity anisotropy, which is also in fair agreement
with numerical findings. Finally they have shown how the spin parameter λ increases as a function of radius. And last, stellar dynamics in the galactic centre—proper motions and anisotropy—was examined in [12]. Au-
thors proposed a new analysis of the stellar dynamics in the Galactic centre, based on improved sky and line-
of-sight velocities for more than one hundred stars in the central few arcseconds from the black hole candidate
SgrA*. They explicitly include velocity anisotropy in estimating the central mass distribution. They also show
how Leonard-Merritt and Bahcall-Tremainemass estimates give systematic offsets in the inferred mass of the
central object when applied to finite concentric rings for power law clusters. Corrected Leonard-Merritt pro-
jected mass estimators and Jeans equation modeling confirm previous conclusions (from isotropic models) that a
compact central concentration (central density
12.6
3
10
pc
M
−
≥
) is present and dominates the potential between
0.01 and 1 pc. Depending on the modeling method used the derived central mass ranges between 2.6 and
6
3.3 10 M
×
for
8.0
R
=
kpc. 1. Introduction It is well known that discovery of cosmic vacuum radically changed main cosmological models [1]. By cosmic
vacuum concept, it is possible to describe the basic properties of the Universe—expansion, accelerated expan-
sion, epochs of evolution, etc. Cosmic vacuum actively influences on the process of large-scale objects formation in the Universe, also (see,
for example [2]). Moreover, cosmic vacuum (or dark energy) is the reason of Universe rotation. One of the first articles devoted
to this problem searching was done by Ellis and Olive [3]. They pointed out that an inflationary episode in the
very early Universe could solve the rotation problem and thus make the Mach principle redundant as an expla-
nation. Earlier such possibility was proposed by Gamov [4]. In our article [5] we found that Universe rotates by action of cosmic vacuum with angular velocity
~
V
Ω
V
Gρ
. Some other characteristics of the rotating Universe—coordinates of “axis of evil”, anisotropy of the
deceleration parameter—were theoretically described in [6]. How to cite this paper: Chechin, L.M. and Ibraimova, A.T. (2014) The Jeans Equation Generalization for the Rotating Universe. International Journal of Astronomy and Astrophysics, 4, 614-619. http://dx.doi.org/10.4236/ijaa.2014.44056 L. M. Chechin, A. T. Ibraimova The Universe rotation, in its turn, can plays significant role for describing physical processes that are elapsing
in it. Talk about the Universe rotation’s influence on the process of galaxy creation. It’s well-known that classical approach to study the origin of galaxies is basing on Jeans equations [7]. Al-
though this equation was derived for the classical cosmology, it hasn’t lost their relevance up to the present time. Lower we’ll enumerate some of modern articles devoted to such equation usage. So, the Jeans equation generalization for the dark energy with nonstationary equation of state and its applica-
tion to study the antigravitational instability of cosmic substrate in the Newtonian cosmology was done in article
[8]. Further, in [9] a system at equilibrium by time—independent distribution function
(
)
0
,
f
x υ and two solu-
tions of the modified Poisson and collisionless Boltzmann equations were described by Jeans equation. They
were analyzed the Jeans instability mechanism, adopted for star formation, considering the Newtonian approxi-
mation of
( )
f R -gravity. ( )
Moreover, the approach developed in this work admits direct generalizations for other modified Gauss-Bon-
net theory, string-inspired gravity, etc. 2. The Jeans Equation Generalization for the Rotating Universe As we said above the problem of stability the homogeneous distribution matter mathematically was formulated
and solved in the framework of small perturbations theory at first by Jeans. He took into account two factors:
gravity that tend to conserve a substance dividing into separate bunches, and pressure that have a tendency to
smooth the appeared nonhomogeneities. pp
g
Recall the equations of hydrodynamics and gravitation in the Newtonian approximation for an ideal gas - (
)
(
)
div
0,
1
grad
grad
grad
0,
divgrad
4π
. t
u
P
t
G
ρ
ρ
φ
ρ
φ
φ
ρ
∂
+
=
∂
∂
+
+
+
=
∂
∆
=
=
u
u
u
(1) (1) where ρ —density, u —velocity, φ —gravitational potential. Consider that unperturbed state is a stationary
gas (
)
0
0
=
u
, that is uniformly distributed in space (
)
0
const
ρ
ρ
=
=
. Its pressure is constantly everywhere where ρ —density, u —velocity, φ —gravitational potential. Consider that unperturbed state is a stationary
gas (
)
0
0
=
u
, that is uniformly distributed in space (
)
0
const
ρ
ρ
=
=
. Its pressure is constantly everywhere 615 L. M. Chechin, A. T. Ibraimova (
)
(
)
0
const
P
P ρ
=
=
. And last assumption is— grad
0
φ =
. (
)
(
)
0
const
P
P ρ
=
=
. And last assumption is— grad
0
φ =
. (
)
(
)
To obtain a solution for the perturbations it is necessary use the method of decomposing an arbitrary pertur-
bation on the system of orthogonal functions, and examining the time evolution of the perturbations’ compo-
nents. 2. The Jeans Equation Generalization for the Rotating Universe Following [7], the perturbed solution is searched in the form of a plane wave with wave vector k — (
)
( )
(
)
(
)
( )
(
)
( )
(
)
0
0
2
0
0
0
0
,
1
e
,
,
0
,
e
,
,
e
,
e
,
i
i
i
i
t
t
u
t
t
t
t
f t
P
P
P
P
b
ρ
ρ
δ
υ
φ
φ
ρ
ρ
ρ δ
ρ
=
+
=
+
=
=
+
∂
=
+
−
=
+
∂
kx
kx
kx
kx
x
x
x
ω
x
(2) (2) where b —adiabatic velocity of sound. y
Substituting these expressions into equations of hydrodynamics, we will consider only terms that are linear
with respect to δ , ω , f . As a result we get the system of linear homogeneous equations 2
2
0
d
0,
d
d
0,
d
4π
. i
t
i f
i b
t
k f
G
δ
ω
δ
ρ δ
+
=
+
+
=
= −
kω
k
k
(3) (3) In monograph [7], that we’ll widely used later on, it is shown that the system (3), be generalized to the case of
an expanding Universe reduces to the next differential equation of the second order (
)
2
2
0
2
4π
0
H
b k
G
δ
δ
ρ
δ
+
+
−
=
(4) (4) where
0
ρ is the baryonic matter density, H -Hubble constant. Naturally that under conditions
0
H =
and
0
const
ρ =
,
const
=
k
,
const
=
b
Equation (4) reduces to Jeans classical equation 2
2
0
4π
0
G
b k
δ
ρ δ
δ
−
+
=
(5) 2
2
0
4π
0
G
b k
δ
ρ δ
δ
−
+
=
(5) The aim of our work is a further generalization of Equation (4) for the case of rotating Universe. For doing
this, it is necessary take into account that rotation of the Universe changes Hubble “constant”. In fact, this question was considered in our paper [13]. 2. The Jeans Equation Generalization for the Rotating Universe Its explicit
form is given by the following formula where ϖ is the generalized oscillations’ frequency of baryonic substrate in the rotating Universe. Its explicit
form is given by the following formula (
)
2
2
2
0
1,2
2
2
2
2
4π
1
1
1
1
1
b k
G
H
H
H
H
ρ
ϖ
−
Ω
=
+
−±
−
Ω
+
(10) (10) For searching these frequencies we’ll impose the general condition existence For searching these frequencies we’ll impose the general condition existence 2
2
0
2
2
4π
1
b k
G
H
ρ
−
+ Ω
(11) (11) that allows simplify expression (10) by decomposing it into the Taylor series. Thus, the generalized oscillation
frequency of baryonic substrate in the rotating Universe takes on the form that allows simplify expression (10) by decomposing it into the Taylor series. 2. The Jeans Equation Generalization for the Rotating Universe There it was shown that the rate of Universe expansion
in direction perpendicular to the axis of rotation becomes larger than in the parallel direction. Therefore, the
value of Hubble “constant” in perpendicular axis of rotation, is associated with the standard value H by the
following relation 2
2
1
H
H
H
⊥
Ω
=
+
(6) (6) In expression (6), Ω represents the angular velocity of the Universe, which in its vacuum model is
~
V
V
Gρ
Ω
[5]. Replacing H
H⊥
→
in (4) and taking into account expression (6), we get the generalized
Jeans equation for the case of expanding and rotating Universe (
)
2
2
2
0
2
2
1
4π
0
H
b k
G
H
δ
δ
ρ
δ
Ω
+
+
+
−
=
(7) (7) This equation is the basis of our following searching. In doing this its second term plays the role of “friction”
force. And this force, as it clear from physical consideration, increases “friction” at the centrifugal force pres-
ence. Beside, next searching of the generalized Jeans equation relates to the vacuum-dominated epoch that ex-
actly allows consider the baryonic mass density as approximately invariable parameter. 616 Concerning third term of Equation (7) we mark that its standard physical interpretation is the Hook-like force. 3. Solutions of the Generalized Jeans Equations 3. Solutions of the Generalized Jeans Equations quation (7) we set the standard designation For solving Equation (7) we set the standard designation For solving Equation (7) we set the standard designation For solving Equation (7) we set the standard designation (8) 2
2
2
0
4π
b k
G
ω
ρ
=
−
(8) for oscillations’ frequency of baryonic substrate. So, equation (7) be accompanied with (8) is an ordinary diffe-
rential equation of the second order with constant coefficients. Its general solution is as follows for oscillations’ frequency of baryonic substrate. So, equation (7) be accompanied with (8) is an ordinary diffe-
rential equation of the second order with constant coefficients. Its general solution is as follows ( )
1,2
0
1,2
exp
t
t
δ
δ
ϖ
=
(9) (9) where ϖ is the generalized oscillations’ frequency of baryonic substrate in the rotating Universe. 2. The Jeans Equation Generalization for the Rotating Universe Thus, the generalized oscillation
frequency of baryonic substrate in the rotating Universe takes on the form ( )
(
)
2
2
2
0
1,2
2
2
2
4π
1
1 1
2
b k
G
t
H
H
H
ρ
ϖ
−
Ω
≈
+
−± −
+ Ω
(12) (12) (
)
2
2
1
0
1
4π
2
b k
G
H
ϖ
ρ
= −
−
(13) (13) Hence, from (13) we find the standard critical value of Jeans vector module Hence, from (13) we find the standard critical value of Jeans vector module 0
1
4π
Jk
G
b
ρ
=
(14) 0
1
4π
Jk
G
b
ρ
=
(14) (14) The second frequency becomes more complicated and equals to
The second frequency becomes more complicated and equals to The second frequency becomes more complicated and equals to The second frequency becomes more complicated and equals to 2
2
2
0
2
2
2
2
2
4π
1
2
2
1
b k
G
H
H
H
H
ρ
ϖ
−
Ω
=
+
−−
Ω
+
(15) (15) Now let discuss the generalized length of Jeans basing on (15). For doing this, in accordance with [7], it is
necessary equate to zero the oscillation frequency of baryonic substrate. So, taking into account (14), we get the
generalized Jeans vector module from (15) 2
2
0
1
2
1
π
J
H
k
k
Gρ
+
Ω
=
⋅
−
(16) (16) It is clear that the generalized wave vector module k may coincide with the Jeans wave vector
Jk as well
tends to zero. 617 L. M. Chechin, A. T. Ibraimova L. M. Chechin, A. T. Ibraimova 4. Conclusions 4. Conclusions As the result we can make the following conclusions. As the result we can make the following conclusions. 1) In the framework of Big Bang model, the inflationary stage of the Universe evolution was described by
condition
V
ρ
ρ
=
and
0
0
ρ =
. Consequently, rotation of the Universe as whole is determined by cosmic va-
cuum and it was considered in our paper [5]. 1) In the framework of Big Bang model, the inflationary stage of the Universe evolution was described by
condition
V
ρ
ρ
=
and
0
0
ρ =
. Consequently, rotation of the Universe as whole is determined by cosmic va-
cuum and it was considered in our paper [5]. 2) In the case of cosmic vacuum neglecting (
)
0 ,
V
ρ →
, its angular velocity coincides practically (the factor
2 ) with the previous Liapunov result [15]. However, to obtain sizes of protogalactic cloud’s fragments that are
equal to Jeans length (18), it is necessary to consider the rotation effect. 2) In the case of cosmic vacuum neglecting (
)
0 ,
V
ρ →
, its angular velocity coincides practically (the factor
2 ) with the previous Liapunov result [15]. However, to obtain sizes of protogalactic cloud’s fragments that are
equal to Jeans length (18), it is necessary to consider the rotation effect. 3) Rotation of the Universe, as it clears from general physical considerations, is an external factor that can
produce the wave disturbances in protogalactic substrate. However, in some cases the rotation doesn’t leads to
such wave existence (see expression (20)). Unfortunately, such types of astronomical observations based on the
well-known deep sky surveys (HDF, CDF, GOODS, etc.) do not give the possibility of this effect detection. 3) Rotation of the Universe, as it clears from general physical considerations, is an external factor that can
produce the wave disturbances in protogalactic substrate. However, in some cases the rotation doesn’t leads to
such wave existence (see expression (20)). Unfortunately, such types of astronomical observations based on the
well-known deep sky surveys (HDF, CDF, GOODS, etc.) do not give the possibility of this effect detection. Acknowledgements The authors express their deep gratitude to JSC “National Centre of Space Research and Technology” for the
support of this research in the budget program 055 subprogram 101 “Grant funding of scientific research”. We also thank our reviewers whose remarks made our article physically more transparent. The authors express their deep gratitude to JSC “National Centre of Space Research and Techn
support of this research in the budget program 055 subprogram 101 “Grant funding of scientific re p
p g
p
gy
support of this research in the budget program 055 subprogram 101 “Grant funding of scientific research”. We also thank our reviewers whose remarks made our article physically more transparent. We also thank our reviewers whose remarks made our article physically more transparent. 3.2. Case II: k
0
→ Now consider the case when generalized wave vector module tends to zero that corresponds to the absence of
wave perturbations in baryonic matter density. In this case 2
2
0
1
2
1
0
π
H
Gρ
+
Ω
−
→
(19) (19) Hence, we find the corresponding angular velocity of the Universe Ω
(
)
2
8
G
Ω
(20) Hence, we find the corresponding angular velocity of the Universe Ω Hence, we find the corresponding angular velocity of the Universe Ω
(
)
0
2 π
8
cr
V
G ρ
ρ
Ω
≈
−
(20) (
)
0
2 π
8
cr
V
G ρ
ρ
Ω
≈
−
(20 (20) This formula indicates that at matter dominated epoch (
)
0
V
ρ
ρ
>
there is no perturbations in baryonic mat-
ter though the Universe rotates, and demonstrates the complicated relation between these phenomena. 3.1. Case I:
J
k
k
= First case relates to condition when generalized wave vector’s module coincides with the Jeans wave vector
module, i.e. J
k
k
=
. From (16) we have 2
2
0
1
2
1
1
π
H
Gρ
+
Ω
−
= (17) (17) Hence, with the value of Hubble constant [14], we find the angular velocity of the Universe Ω (
)
0
2 π
4
V
G ρ
ρ
Ω=
+
. (18) (18) From this expression we see that angular velocity depends both on the baryonic mass density as well as va-
cuum mass density. 3.2. Case II: k
0
→ [1]
Byrd, G.G., Chernin, A.D. and Valtonen, M.J. (2007) Cosmology: Foundations and Frontiers. URSS, Moscow.
[2]
Chernin, A.D. (2006) Cosmic Vacuum and Galaxy Formation. Astronomical and Astrophysical Transactions, 25, 205-
211. http://dx.doi.org/10.1080/10556790600938743
[3]
Ellis, J. and Olive, K.A. (1983) Inflation Can Solve the Rotation Problem. Nature, 303, 679-681. [3]
Ellis, J. and Olive, K.A. (1983) Inflation Can Solve the Rotation Problem. Nature, 303, 679-681. References [3]
Ellis, J. and Olive, K.A. (1983) Inflation Can Solve the Rotation Problem. Nature, 303, 679-681. 618 L. M. Chechin, A. T. Ibraimova http://dx.doi.org/10.1038/303679a0 [4]
Gamov, G. (1946) Rotating Universe. Nature, 158, 549. http://dx.doi.org/10.1038/158549a0 [5]
Chechin, L.M. (2010) The Cosmic Vacuum and the Rotation of Galaxies. Astronomy Reports, 54, 719-723. http://dx.doi.org/10.1134/S1063772910080044 [6]
Chechin, L.M. (2013) On the Modern Status of the Universe Rotation Problem. Journal of Modern Physics, 4, 126-
132. http://dx.doi.org/10.4236/jmp.2013.48A012 [7]
Zel’dovich, Ya.B. and Novikov, I.D. (1983) Structure and Evolution of the Universe, Relativistic Astrophysics. Uni-
versity of Chicago Press, Chicago. [8]
Chechin, L.M. (2006) Antigravitational Instability of Cosmic Substrate in the Newtonian Cosmology. Chinese Physics
Letters, 23, 2344-2347. http://dx.doi.org/10.1088/0256-307X/23/8/104 [9]
Capozziello, S., Laurientis, M., Martino, I., et al. (2000) Jeans Analysis of Self-Gravitating Systems in f(R) Gravity. arXiv:astro-ph/0001428v1 [10] Hansen, S.H. (2004) Dark Matter Density Profiles from the Jeans Equation. arXiv:astro-ph/0405371v2 [11] Kasper, B.S., Hansen, S.H., An, J.H., et al. (2009) Dark Matter Angular Momentum Profile from the Jeans Equation. ArXiv:0901.0928v3[astro-ph.Co] [12] Genzel, R., Pichon, C., Eckart, A., et al. (2009) Stellar Dynamics in the Galactic Centre: Proper Motions and Aniso-
tropy. ArXiv:astro-ph/0001428v1 [13] Chechin, L.M. and Ibraimova, A.T. (2013) Friedmann Equations in the Rotating Frame of Reference. The Bulletin of
the National Academy of Sciences of the Republic of Kazakhstan, 15-19 (in Russian). [14] Zel’dovich, Ya.B., Sazhin, M.V. and Dolgov, A.D. (1990) Early Universe Cosmology. Moscow State University, Mos-
cow. [15] Chandrasekhar, S. (1969) Ellipsoidal Figures of Equilibrium. Yale University Press, Dover.
|
https://openalex.org/W4361876272
|
https://figshare.com/articles/journal_contribution/Figure_S3_from_TRPM2_Mediates_Neutrophil_Killing_of_Disseminated_Tumor_Cells/22419333/1/files/39865473.pdf
|
Latin
| null |
Figure S1 from TRPM2 Mediates Neutrophil Killing of Disseminated Tumor Cells
| null | 2,023
|
cc-by
| 909
|
0
20
40
60
80
0.0
0.2
0.4
0.6
0.8
1.0
205708_s_at
Time (months)
Probability
Expression
low
high
Number at risk
25
21
17
7
0
low
18
16
14
6
1
high
HR = 0.19 (0.02 − 1.54)
logrank P = 0.082
0
50
100
150
200
250
300
0.0
0.2
0.4
0.6
0.8
1.0
205708_s_at
Time (months)
Probability
Expression
low
high
Number at risk
668
489
246
70
11
0
0
low
1078
751
346
95
16
2
0
high
HR = 1.1 (0.9 − 1.34)
logrank P = 0.35
0
50
100
150
200
0.0
0.2
0.4
0.6
0.8
1.0
205708_s_at
Time (months)
Probability
Expression
low
high
Number at risk
153
74
27
10
1
low
79
54
23
9
2
high
HR = 0.48 (0.26 − 0.89)
logrank P = 0.017
0
50
100
150
200
0.0
0.2
0.4
0.6
0.8
1.0
205708_s_at
Time (months)
Probability
Expression
low
high
Number at risk
44
19
10
3
0
low
75
42
19
8
2
high
HR = 0.7 (0.37 − 1.31)
logrank P = 0.27
0
50
100
150
200
250
300
0.0
0.2
0.4
0.6
0.8
1.0
205708_s_at
Time (months)
Probability
Expression
low
high
Number at risk
265
233
122
37
6
0
0
low
700
541
269
73
10
1
0
high
HR = 1.18 (0.86 − 1.64)
logrank P = 0.31
0
50
100
150
200
250
0.0
0.2
0.4
0.6
0.8
1.0
205708_s_at
Time (months)
Probability
Expression
low
high
Number at risk
127
90
51
8
2
0
low
303
187
71
17
4
1
high
HR = 1.32 (0.89 − 1.95)
logrank P = 0.17
Basal (232 patients)
HER2+ (119 patients)
TNBC (43 patients)
All (1746 patients)
Luminal A (965 patients)
Luminal B (430 patients) 0
20
40
60
80
0.0
0.2
0.4
0.6
0.8
1.0
205708_s_at
Time (months)
Probability
Expression
low
high
Number at risk
25
21
17
7
0
low
18
16
14
6
1
high
HR = 0.19 (0.02 − 1.54)
logrank P = 0.082
0
50
100
150
200
250
300
0.0
0.2
0.4
0.6
0.8
1.0
205708_s_at
Time (months)
Probability
Expression
low
high
Number at risk
668
489
246
70
11
0
0
low
1078
751
346
95
16
2
0
high
HR = 1.1 (0.9 − 1.34)
logrank P = 0.35
0
50
100
150
200
0.0
0.2
0.4
0.6
0.8
1.0
205708_s_at
Time (months)
Probability
Expression
low
high
Number at risk
153
74
27
10
1
low
79
54
23
9
2
high
HR = 0.48 (0.26 − 0.89)
logrank P = 0.017
0
50
100
150
200
0.0
0.2
0.4
0.6
0.8
1.0
205708_s_at
Time (months)
Probability
Expression
low
high
Number at risk
44
19
10
3
0
low
75
42
19
8
2
high
HR = 0.7 (0.37 − 1.31)
logrank P = 0.27
0
50
100
150
200
250
300
0.0
0.2
0.4
0.6
0.8
1.0
205708_s_at
Time (months)
Probability
Expression
low
high
Number at risk
265
233
122
37
6
0
0
low
700
541
269
73
10
1
0
high
HR = 1.18 (0.86 − 1.64)
logrank P = 0.31
0
50
100
150
200
250
0.0
0.2
0.4
0.6
0.8
1.0
205708_s_at
Time (months)
Probability
Expression
low
high
Number at risk
127
90
51
8
2
0
low
303
187
71
17
4
1
high
HR = 1.32 (0.89 − 1.95)
logrank P = 0.17
Basal (232 patients)
HER2+ (119 patients)
TNBC (43 patients)
All (1746 patients)
Luminal A (965 patients)
Luminal B (430 patients) 0
50
100
150
200
250
0.0
0.2
0.4
0.6
0.8
1.0
205708_s_at
Time (months)
Probability
Expression
low
high
Number at risk
127
90
51
8
2
0
low
303
187
71
17
4
1
high
HR = 1.32 (0.89 − 1.95)
logrank P = 0.17
Luminal B (430 patients) 0
50
100
150
200
250
300
0.0
0.2
0.4
0.6
0.8
1.0
205708_s_at
Time (months)
Probability
Expression
low
high
Number at risk
265
233
122
37
6
0
0
low
700
541
269
73
10
1
0
high
HR = 1.18 (0.86 − 1.64)
logrank P = 0.31
Luminal A (965 patients) 0
50
100
150
200
250
300
0.0
0.2
0.4
0.6
0.8
1.0
205708_s_at
Time (months)
Probability
Expression
low
high
Number at risk
HR = 1.1 (0.9 − 1.34)
logrank P = 0.35
All (1746 patients) 205708_s_at
Luminal A (965 patients) 205708_s_at
Luminal A (965 patients) 205708_s_at
Luminal B (430 patients) 205708_s_at
Luminal B (430 patients) 205708_s_at
All (1746 patients) 205708_s_at
All (1746 patients) 0
50
100
150
200
0.0
0.2
0.4
0.6
0.8
1.0
205708_s_at
Time (months)
Probability
Expression
low
high
Number at risk
153
74
27
10
1
low
79
54
23
9
2
high
HR = 0.48 (0.26 − 0.89)
logrank P = 0.017
Basal (232 patients) 0
20
40
60
80
0.0
0.2
0.4
0.6
0.8
1.0
205708_s_at
Time (months)
Probability
Expression
low
high
Number at risk
25
21
17
7
0
low
18
16
14
6
1
high
HR = 0.19 (0.02 − 1.54)
logrank P = 0.082
TNBC (43 patients) 0
50
100
150
200
0.0
0.2
0.4
0.6
0.8
1.0
205708_s_at
Time (months)
Probability
Expression
low
high
Number at risk
44
19
10
3
0
low
75
42
19
8
2
high
HR = 0.7 (0.37 − 1.31)
logrank P = 0.27
HER2+ (119 patients) 205708_s_at
Basal (232 patients) 205708_s_at
HER2+ (119 patients) 205708_s_at
TNBC (43 patients) 205708_s_at
TNBC (43 patients) Figure S3
|
https://openalex.org/W4395463185
|
https://pusdikra-publishing.com/index.php/jisc/article/download/1825/1581
|
Indonesian
| null |
Pengaruh Mobile Banking Service dan Customer Perceived Value Melalui Customer Satisfaction Terhadap Customer Loyality
|
Journal of Management, Economic and Accounting
| 2,024
|
cc-by-sa
| 3,310
|
Pengaruh Mobile Banking Service dan Customer Perceived Value Melalui
Customer Satisfaction Terhadap Customer Loyality (Bank Syariah Mandiri
Kantor Cabang Pembantu Krian) Pengaruh Mobile Banking Service dan Customer Perceived Value Melalui
Customer Satisfaction Terhadap Customer Loyality (Bank Syariah Mandiri
Kantor Cabang Pembantu Krian) Djowan Naly Novy1, Lu’lu’il Maknuun2, Rahman Yusri Aftian3
1,2,3 Universitas Kh Abdul Chalim Mojokerto, Indonesia
Corresponding Author : Djowannalynov@gmail.com
ABSTRACT Djowan Naly Novy1, Lu’lu’il Maknuun2, Rahman Yusri Aftian3
1,2,3 Universitas Kh Abdul Chalim Mojokerto, Indonesia
Corresponding Author : Djowannalynov@gmail.com
ABSTRACT Tujuan dari adanya penelitian ini yaitu untuk mengetahui pengaruh mobile
banking dan nilai pelanggan melalui kepuasan nasabah terhadap loyalitas
nasabah. Pendekatan
yang
yaitu
pendekatan
kuantitatif
yang
menggunakan data primer. Populasi dalam penelitian ini adalah nasabah
Bank Syariah Mandiri KCP Krian yang menggunakan mobile banking. Sampel penelitian diambil dengan menggunakan metode Nonpropability
Sampling. Analisis data dalam penelitian ini menggunakan menggunakan
tools Smart PLS 3. Hasil penelitian menunjukkan bahwa terdapat pengaruh
positif signifikan mobile banking service terhadap kepuasan nasabah. Terdapat pengaruh positif signifikan nilai pelanggan terhadap kepuasan
nasabah. Terdapat pengaruh positif signifikan kepuasan nasabah terhadap
loyalitas nasabah. Tidak terdapat pengaruh positif signifikan mobile banking
service terhadap loyalitas nasabah, namun terdapat hubungan tidak
langsung mobile banking service terhadap loyalitas melalui kepuasan
nasabah. Terdapat pengaruh positif signifikan nilai pelanggan terhadap
loyalitas nasabah, serta terdapat hubungan tidak langsung mobile banking
service terhadap loyalitas melalui kepuasan nasabah. Mobile Banking Service, Nilai Pelanggan, Kepuasan Nasabah, Loyalitas Nasabah
This work is licensed under a
Creative Commons Attribution-ShareAlike 4.0 International License Mobile Banking Service, Nilai Pelanggan, Kepuasan Nasabah, Loyalitas Nasabah Mobile Banking Service, Nilai Pelanggan, Kepuasan Nasabah, Loyalitas Nasabah Journal of Management, Economic and Accounting (JMEA)
Volume 2, Issue 4, November 2023
Journal Homepage:
https://pusdikra-publishing.com/index.php/jisc Keywords This work is licensed under a PENDAHULUAN Pada era modern saat ini teknologi berkembang dengan sangat pesat,
Pesatnya kemajuan teknologi di era ini tentunya sangat membantu masyarakat
dala memenuhi kebutuhannya. Teknologi dapat membantu masyarakat dalam
berbagai pekerjaan salah satunya dalam bidang perbankan yaitu dalam layanan
perbankan. Penggunaaan teknologi dalam layanan perbankan tentunya akan
meningkatkan efektivitas dan efisiensi pengguna layanan tersebut. (Miswan
Ansori, 2019, 32) Perkembangan teknologi ini juga didorong dengan meningkatnya jumlah
pengguna Smartphone dan tingginya tingkat penetrasi internet. Peningkatan dan
perkembangan teknologi internet berkembang terus menurus dan bertumbuh
dengan masif. Berdasarkan penelitian yang dilakukan We Are Social, pada bulan 12 Journal of Management, Economic and Accounting (JMEA)
Volume 2, Issue 4, November 2023
Page 12-20 Januari tahun 2020 lalu, terjadi peningkatan pengguna internet, ada kenaikan
sekitar 17% dari tahun sebelumnya, pada tahun 2020 disebutkan terdapat 175,4
juta pengguna internet di Indonesia dari total populasi penduduk indonesia
272,1 juta jiwa, dapat diartikan 64% atau setengah penduduk Indonesia telah
menggunakan internet. (Perusahaan Media Social asal Inggris 2020) (
gg
)
Gambar 1. Jenis Perangkat Yang Digunakan
Sumber: We Are Social
96%
94%
21%
66%
23%
16% 5.10%
JENIS PERANGKAT YANG
DIGUNAKAN Gambar 1. Jenis Perangkat Yang Digunakan Jenis Perangkat Yang Digunakan %
94%
JENIS PERANGKAT YANG
DIGUNAKAN Sumber: We Are Social Dapat dilihat dari informasi yang dipaparkan dalam gambar 1.1
persentase pengguna Mobile Smartphone sebesar 96%, Smartphone 94%, Non-
Smartphone Mobile Phone 21%, Laptop dan komputer 66%, Table 23%, Konsol
game 16 %, dan virtual reality device 5,1%. Penguna Mobile smartphone dan
smartphone jauh lebih banyak dari penguna perangkat-perangkat lainnya. Masyarakat Indonesia hampir semua membutuhkan jasa perbankan,
seperti menabung, transfer uang, dan pembiayaan. Namun, seiring dengan
perkembangan teknologi, hal ini juga berdampak kepada kebiasaan masyarakat
dalam bertransaksi. Metode konvensional (manual) seperti nasabah harus
datang ke bank untuk bertransaksi sudah tidak diminati lagi, karena di era ini
metode konvensional dianggap tidak efisien dan efektif. Kemajuan teknologi ini
bersifat multiplier (pengganda), yang memiliki arti kemajuan tersebut berdampak
pula bagi bidang-bidang lainnya, salah satunya yaitu bidang sistem
pembayaran. (Ujang Sumarwan, 2011, 346) Masyarakat saat ini mempunyai mobilitas yang lebih tinggi, Cashless
merupakan salah satu kegiatan yang digemari masyarakat pada saat ini, cashless
adalah pengunaan bentuk pembayaran secara nir tunai atau digital, Hal ini
dirasa cukup efektif dan efisien, salah satu transaksi pembayaran yang berbasis
digital contohnya pembayaran QR Pay lewat aplikasi mobile banking. (Elshabyta,
2018) Perbankan perlu melakukan penyesuaian terhadap kebiasaan masyarakat
tersebut jika tidak, cepat atau lambat akan tertinggal dari lembaga keuangan
yang lain. Perbankan perlu meningkatkan dan menciptakan produk serta 13 Journal of Management, Economic and Accounting (JMEA)
Volume 2, Issue 4, November 2023
Page 12-20 layanan yang lebih murah, lebih baik, dan lebih cepat. Menurut Maryanto
Supriyono kemajuan pesat yang terjadi dalam bidang teknologi, memiliki
dampak yang sangat besar terhadap pelayanan jasa perbankan dalam hal
teknologi atau elektronik. (Maryanto Supriyono, 2011, 65). layanan yang lebih murah, lebih baik, dan lebih cepat. Menurut Maryanto
Supriyono kemajuan pesat yang terjadi dalam bidang teknologi, memiliki
dampak yang sangat besar terhadap pelayanan jasa perbankan dalam hal
teknologi atau elektronik. (Maryanto Supriyono, 2011, 65). Untuk menghadapi tantangan ini, Bank Syariah Mandiri memperkuat daya
saingnya melalui upaya peningkatan layanan digital dengan meluncurkan New
Mandiri Syariah Mobile Banking, Mobile Banking adalah layanan transaksi
keuangan dengan memanfaatkan teknologi smarthphone atau perangkat Mobile
yang sumber dananya berasal dari tabungan atau rekening masing-masing
nasabah yang ada di bank. New Mandiri Syariah Mobile Banking merupakan
layanan perbankan yang berbasis teknologi seluler atau ponsel yang diharapkan
dapat memberikan kemudahan untuk melakukan berbagai kegiatan transaksi
perbankan dimanapun dan kapanpun. %
94%
JENIS PERANGKAT YANG
DIGUNAKAN Keunggulan baru layanan New Mandiri
Syariah Mobile Banking yaitu penambahan fitur-fitur ibadah seperti Ziswaf
(Zakat, Infaq Sedekah, dan wakaf) Waktu sholat, arah kiblat, dan masjid terdekat. (Anual Report, Bank Syariah
Mandiri, 2018) Menurut Ahmad Syafii (Direktur IT dan Operational Mandiri
Syariah) yang dikutip dari Republika.co.id Bank Mandiri Syariah akan terus
berinovasi untuk mengembangkan dan meningkatkan layanan digital, khusunya
Mobile Banking. Hal ini bertujuan agar nasabah merasakan kemudahan dalam
menggunakan layanan dan transaksi yang disediakan Bank Syariah Mandiri. Saat ini terdapat 72 fitur pada Mandiri Syariah Mobile Banking yang dapat
memudahkan nasabah dalam bertransaksi. Ahmad Syafii juga menjelaskan
bahwa sampai bulan September 2019 penguna Mandiri Syariah Mobile Banking
mencapai 973 ribu akun dengan jumlah transaksi 2,29 juta transaksi. Hadirnya Mobile Banking sebagai layanan yang ditawarkan perbankan akan
mempermudah masyarakat dalam bertransaksi. Layanan Mobile Banking ini
adalah perpaduan dan gabungan antara sistem informasi dan teknologi untuk
menunjang aktivitas perbankan tanpa harus nasabah mengunjungi kantor. Pelayanan inipun tidak terbatas waktunya, dapat melakukan transaksi selama 24
jam setiap harinya, dan dapat diakses menggunakan perangkat Mobile
smartphone. Intensitas dan interaksi pengguna dengan sistem menunjukkan
bahwa sistem tersebut dapat memberikan kemudahan dalam bertransaksi. (Andri daisy rahmad, 2017, 38) Pengunaan Mobile banking Service ini akan berpengaruh terhadap tingkat
loyalitas nasabah. Apabila nasabah mersakan puas dalam melakukan transaksi
menggunakan Mobile banking maka tingkat loyalitasnya nasabah pun akan
meningkat dan jika nasabah merasa puas maka mereka akan berbicara baik dan
merekomendasikan mobile banking service kepada orang lain, hal ini didukung 14 Journal of Management, Economic and Accounting (JMEA)
Volume 2, Issue 4, November 2023
Page 12-20 oleh penelitian yang dilakukan oleh Fajar Akbar yang menjelaskan terdapat
pengaruh signifikan antara kepuasan pengguna Mobile banking terhadap
loyalitas nasabah. Perbankan juga perlu memperhatikan pemasaran dengan mengedepankan
nilai dari nasabah, meyakinkan nasabah bahwa produk yang ditawarkan akan
memberikan manfaat kepada nasabah sehingga dengan adanya keyakinan
seperti itu maka akan timbul emotional Value pada diri nasabah. Menurut Palilati
yang dikutip oleh Kusnul Customer Perceived Value adalah persepsi tentang nilai
yang diperoleh dari produk yang terdiri atas manfaat, nilai pelayanan yang
terdiri dari kecepatan pelayanan, keprofesionalan karyawan, kenyamanan,
hubungan interaktif, dan informasi yang diberikan, serta cita perusahaan. (Kusnul Azizah, 2019, 23) Dalam hal ini jika bank dapat menciptakan ikatan emotional yang baik
dengan memenuhi harapan pelanggan dan menambahkan nilai atas produk atau
jasa yang mereka butuhkan maka pelanggan akan merasa puas dan senang
sehingga hal tersebut dapat meningkatkan loyalitas nasabah. %
94%
JENIS PERANGKAT YANG
DIGUNAKAN Namun ditemukan
hasil yang berbeda dalam penelitian yang dilakukan oleh Soliha dan Solechah
dalam penelitian tersebut ditemukan bahwa nilai pelanggan tidak berpengaruh
secara langsung terhadap loyalitas namun berpengaruh secara positif dan
signifikan terhadap loyalitas. Perbankan perlu meningkatkan
kinerjanya dengan meningkatkan
efektifitas dan efesiensi layanannya serta kualitas layanan pada nasabah, ini
semua dilakukan demi terciptanya kepuasan nasabah. Kepuasan nasabah
merupakan sebuah kunci keberhasilan dari suatu bank sebagai perusahaan yang
bergerak dibidang jasa, kepuasan dan ketidakpuasan nasabah adalah bentuk
respon pelanggan terhadap evaluasi dari ketidaksesuaian apa yang dirasakan
antara harapan sebelumnya dengan kinerja aktual yang dirasakan setelah suatu
layanan atau produk digunakan. Pelayanan yang diberikan kepada nasabah
mempunyai pengaruh kepada kinerja usaha bank, jika nasabah puas maka akan
memberikan pengaruh yang positif, dan jika nasabah tidak puas maka akan
memberikan dampak yang negatif. Menurut Kotler dan Keller yang dikutip oleh
Noviana seorang pelanggan yang tingkat kepuasannya tinggi akan berbicara
baik tentang produk tersebut, tidak memperhatikan produk-produk dari merek
pesaing, kurang sensitif terhadap harga, akan melakukan pembelian atau
pengunaan ulang. Dengan terciptanya kepuasan bagi nasabah memberikan dampak positif
pada meningkatnya loyalitas nasabah, loyalitas nasabah adalah nilai yang
terbentuk dari sudut pandang nasabah yang mampu memberikan nilai terhadap
layanan yang ditawarkan oleh perbankan dimana kualitas tersebut membentuk 15 Journal of Management, Economic and Accounting (JMEA)
Volume 2, Issue 4, November 2023
Page 12-20 suatu citra yang baik. Loyalitas adalah sebuah komitmen nasabah untuk
bertahan dan berlangganan untuk melakukan penggunaan jasa atau pembelian
produk bank yang terpilih secara konsiten dalam jangka waktu yang panjang
serta tidak goyah dengan usaha-usaha pemasaran bank pesaing. Loyalitas
nasabah merupakan sebuah kunci sukses suatu usaha dalam menjalin hubungan
jangka panjang antara nasabah dengan bank untuk menjamin kelangsungan
usaha bank. (Nur Azilah, 2016, 25) Semakin nasabah merasa ekspektasinya terpenuhi maka akan semakin
tinggi tingkat loyalitas nasabah, namun hal tersebut berbeda dengan hasil
penelitian yang dilakukan oleh Rohmiyatun dimana kepuasan berpengaruh
positif dan tetapi tidak signifikan terhadap loyalitas nasabah, yaitu bahwa
semakin tinggi tingkat kepuasan nasabah tidak membuat nasabah semakin setia
dengan perusahaan. Sesuai dengan latar belakang tersebut peneliti tertarik untuk melakukan
penelitian mengenai “Pengaruh Mobile Banking Service dan Customer Perceived
Value melalui Customer Satisfaction terhadap Customer Loyality” METODE PENELITIAN Pendekatan yang yaitu pendekatan kuantitatif yang menggunakan data
primer. Populasi dalam penelitian ini adalah nasabah Bank Syariah Mandiri KCP
Krian yang menggunakan mobile banking. Sampel penelitian diambil dengan
menggunakan metode Nonpropability Sampling. Analisis data dalam penelitian ini
menggunakan menggunakan tools Smart PLS 3. HASIL DAN PEMBAHASAN Pada Sub bab ini akan dipaparkan interpretasi hasil analisis yang telah
dilakukan. Berikut pemaparan hasil sebagaimana yang telah diajukan pada
pertanyaan dan hipotesis sebelumnya: Terdapat pengaruh positif signifikan Mobile Banking Service kepada
Customer Satisfaction Sebagaimana hasil yang diperoleh dari analisis struktural
model pada pengujian t-test dengan nilai 10. 263 menunjukkan H1 diterima yang
dapat diartikan variable mobile banking memiliki pengaruh terhadap Customer
Satisfaction. Kemudian didukung oleh nilai path coefficient 0.715 yang
menunjukkan bahwa hipotesis yang menghubungkan mobile banking ->
kepuasan nasabah memiliki pengaruh yang signifikan secara positif. Hal
tersebut menunjukan bahwa mobile banking yang meliputi system avability,
privacy, trust, site aesthentic, performance, reliability, dan feature mempunyai
pengaruh signifikan terhadap kepuasan nasabah berupa overall customer
satisfaction, confirmation of expectations, repurchase intent, dan wilingness to 16 Journal of Management, Economic and Accounting (JMEA)
Volume 2, Issue 4, November 2023
Page 12-20 recomended. Dan jika dilihat dari nilai effect sizenya 0,089 menunjukkan bahwa
mobile banking -> kepuasan nasabah berpengaruh besar. Hasil dari penelitian
yang telah dilakukan ini sesuai dengan beberapa penelitian terdahulu yang
dilakukan oleh Yogi Yuliansyah (Yogi Yuliansyah, 2017) dan Yeni Anda (Yeni
Anda Dewi, 2019) yang menyatakan bahwa mobile banking berpengaruh positif
signifikan terhadap kepuasan nasabah, hal tersebut menjelaskan bahwa semakin
baik kualitas produk dan kualitas layanan mobile banking maka akan semakin
meningkatkan kepuasan nasabah. Terdapat pengaruh positif signifikan Customer Perceived Value terhadap
Customer Satisfaction Sebagaimana hasil yang diperoleh dari analisis struktural
model pada pengujian t-test dengan nilai 2.274 menunjukkan H2 diterima yang
berarti customer perceived value memiliki pengaruh terhadap Customer Satisfaction. Terdapat pengaruh positif signifikan Customer Perceived Value terhadap
Customer Satisfaction Sebagaimana hasil yang diperoleh dari analisis struktural
model pada pengujian t-test dengan nilai 2.274 menunjukkan H2 diterima yang
berarti customer perceived value memiliki pengaruh terhadap Customer Satisfaction. Hal ini didukung oleh nilai path coefficient 0.188 yang dapat diartikan bahwa
hipotesis yang menghubungkan nilai pelanggan -> kepuasan nasabah memiliki
pengaruh yang signifikan secara positif. Ini menunjukkan bahwa nilai pelanggan
yang meliputi emotional value, social value, dan performance value mempunyai
pengaruh signifikan terhadap kepuasan nasabah berupa overall customer
satisfaction, confirmation of expectations, repurchase intent, dan wilingness to
recomended. Dan jika dilihat dari nilai effect sizenya 0,062 menunjukkan bahwa
nilai pelanggan -> kepuasan nasabah memiliki pengaruh kecil. HASIL DAN PEMBAHASAN Hasil dari
penelitian yang telah dilakukan ini sesuai dengan beberapa penelitian terdahulu
yang dilakukan oleh Yeri Restika, Ginanjar Ramadhan, dan Kusnul Azizah
(Kusnul Azizah, 2017) yang menyatakan bahwa nilai pelanggan berpengaruh
positif signifikan terhadap kepuasan nasabah, hal tersebut menjelaskan bahwa
semakin baik penilaian nasabah terhadap produk atau layanan yang diberikan
bank maka akan semakin mendorong atau meningkatkan kepuasan nasabah. Terdapat pengaruh positif signifikan Customer Satisfaction terhadap
Customer Loyality Berdasarkan hasil yang diperoleh dari analisis struktural model
pada pengujian t-test dengan nilai 7.127 menunjukkan H3 diterima yang berarti
customer satisfaction berpengaruh terhadap Customer loyality. Hal tersebut juga
diperkuat dengan nilai path coefficient 0.748 yang dapat diartikan hipotesis yang
menghubungkan kepuasan nasabah -> loyalitas nasabah mempunyai pengaruh
positif signifikan. Hal tersebut mengambarkan bahwa kepuasan nasabah yang
terdiri dari overall customer satisfaction, confirmation of expectations, repurchase
intent, dan wilingness to recomended mempunyai pengaruh signifikan terhadap
loyalitas nasabah berupa pembelian secara teratur, membeli produk dan jasa
lain, merekomendasikan word of mouth hal-hal yang positif dan tidak tertarik
dengan pemasaran pesaing. Dan jika dilihat dari nilai effect sizenya 0,484
mengambarkan bahwa kepuasan nasabah -> loyalitas nasabah mempunyai 17 Journal of Management, Economic and Accounting (JMEA)
Volume 2, Issue 4, November 2023
Page 12-20 pengaruh kecil. Hasil dari research yang telah dilakukan ini sesuai dengan
beberapa penelitian terdahulu oleh Avin Christy, Noviana Landy (Kusnul
Azizah, 2019), dan A’syiroh (A’Syiroh, 2017) yang menyatakan bahwa kepuasan
nasabah mempunyai pengaruh terhadap loyalitas nasabah. Kepuasan nasabah
memainkan peranan penting dalam menciptakan dan retensi loyalitas. Terdapat pengaruh positif signifikan Mobile Banking Service terhadap
Customer Loyality Berdasarkan hasil yang diperoleh dari analisis struktural model
pada pengujian t-test dengan nilai 0.914 menunjukkan H4 ditolak yang berarti
mobile banking berpengaruh terhadap Customer loyality. Hal tersebut didukung
oleh nilai path coefficient -0.103 berhubungan dengan hasil hipotesis mobile banking
-> loyalitas nasabah dan berpengaruh negatif. Hal tersebut menunjukan bahwa
mobile banking yang meliputi system avability, privacy, trust, site aesthentic,
performance, reliability, dan feature tidak berpengaruh signifikan terhadap
loyalitas nasabah berupa pembelian dengan teratur, membeli produk dan jasa
lain, merekomendasikan word of mouth hal-hal yang positif dan tidak tertarik
dengan pemasaran pesaing. Dan hal tersebut diperkuat oleh nilai effect sizenya
0,008 menunjukkan bahwa mobile banking -> loyalitas nasabah tidak memiliki
pengaruh. KESIMPULAN Berdasakan hasil dan pembahasan mengenai pengaruh mobile banking
service dan customer perceived value melalui customer satisfaction terhadap customer
loyality, dalam hal ini maka dapat disimpulkan bahwa: 1) Terdapat pengaruh positif signifikan Mobile Banking Service terhadap
Customer Satisfaction. 1) Terdapat pengaruh positif signifikan Mobile Banking Service terhadap
Customer Satisfaction. 2) Terdapat pengaruh positif signifikan Customer Perceived Value terhadap
Customer Satisfaction. 3) Terdapat pengaruh positif signifikan Customer Satisfaction terhadap
Customer Loyality. 4) Tidak terdapat pengaruh positif signifikan Mobile Banking Service terhadap
Customer Loyality, namun terdapat pengaruh tidak langsung antara mobile
banking service terhadap customer loyality melalui variabel kepuasan
nasabah. 5) Terdapat pengaruh positif signifikan Customer Perceived Value terhadap
Customer Loyality dan terdapat pengaruh secara tidak langsung antara
customer perceived value terhadap customer loyality melalui kepuasan
nasabah. 5) Terdapat pengaruh positif signifikan Customer Perceived Value terhadap
Customer Loyality dan terdapat pengaruh secara tidak langsung antara
customer perceived value terhadap customer loyality melalui kepuasan
nasabah. HASIL DAN PEMBAHASAN Namun setelah dilakukan uji specific indirect effect dengan
menggunakan variabel kepuasan nasabah sebagai variabel intervening atau
variabel yang memediasi antara mobile banking dan loyalitas nasabah didapatkan
hasil yang signifikan kepuasan sebagai variabel intervening memediasi
sempurna (full mediation) hubungan antara variabel mobile banking dan variabel
loyalitas nasabah yaitu dari yang sebelumnya mobile banking tidak memiliki
pengaruh terhadap loyalitas, berubah menjadi memiliki pengaruh dengan
hubungan yang tidak langsung melalui kepuasan nasabah. Hasil dari research
yang telah dilakukan ini sinkron dengan penelitian terdahulu yang dilakukan
oleh Fajar Akbar dan Niken (Fajar Akbar dan Niken, 2015) yang menyatakan
bahwa semakin nasabah merasakan kepuasan dalam menggunalakan layanan
mobile banking maka akan semakin tinggi tingkat loyalitas nasabah. Terdapat pengaruh positif signifikan Customer Perceived Value terhadap
Customer Loyality Berdasarkan hasil yang diperoleh dari analisis struktural model
pada pengujian t-test dengan nilai 2.108 menunjukkan H5 diterima yang berarti
customer perceived value berpengaruh untuk Customer loyality. Dimana hal
tersebut juga diperkuat oleh nilai path coefficient 0.231 yang dapat menunjukkan
bahwa hipotesis yang menghubungkan nilai pelanggan -> loyalitas nasabah
memiliki pengaruh positif signifikan. Hal tersebut mengartikan bahwa nilai
pelanggan yang meliputi emotional value, social value, dan performance value
mempunyai pengaruh signifikan terhadap loyalitas nasabah berupa pembelian
secara teratur, membeli produk dan jasa lain, merekomendasikan word of mouth 18 Journal of Management, Economic and Accounting (JMEA)
Volume 2, Issue 4, November 2023
Page 12-20 hal-hal yang positif dan tidak tertarik dengan pemasaran pesaing. Nilai effect
sizenya 0,076 menunjukkan bahwa nilai pelanggan -> loyalitas nasabah memiliki
pengaruh kecil. Selanjutnya setelah dilakukan uji specific indirect effect dengan
menggunakan variabel kepuasan nasabah sebagai variabel intervening atau
variabel yang memediasi antara nilai pelanggan dan loyalitas nasabah
didapatkan hasil yang signifikan kepuasan sebagai variabel intervening
memediasi sebagian (partial mediation) hubungan antara variabel nilai pelanggan
dan variabel loyalitas nasabah. Hasil dari penelitian yang telah dilakukan ini
sinkron dengan research terdahulu yang dilakukan oleh Muhammad Nur Fauzi
(Muhammad Nur Fauzi, 2018) dan Faranita Amelia (Faranita Amalia dan Keni,
2019) yang menyatakan bahwa semakin tinggi dimensi value yang diperoleh oleh
nasabah maka akan semakin tinggi kepuasan nasabah, sehingga loyalitas
nasabah akan terbangun sesuai dengan value yang didapat. Andri daisy rahmad, “Pengaruh Kemudahan Dan Kepercayaan Terhadap Sms
Banking”, Jurnal Administrasi Bisnis (JAB), Vol. 43 No.1, 2017, 38 DAFTAR PUSTAKA A’Syiroh “Pengaruh Customer Value Terhadap Loyalitas Nasabah bank
Tabungan Negara(BTN) Syariah KCP Ciputat”, (Skripsi UIN Syarif
Hidayatullah, 2017) Andri daisy rahmad, “Pengaruh Kemudahan Dan Kepercayaan Terhadap Sms
Banking”, Jurnal Administrasi Bisnis (JAB), Vol. 43 No.1, 2017, 38 19 Journal of Management, Economic and Accounting (JMEA)
Volume 2, Issue 4, November 2023
Page 12-20 Anual Report, Bank Syariah Mandiri, 2018 Anual Report, Bank Syariah Mandiri, 2018 Avin Christy , “Pengaruh Kepuasan Nasabah dan Loyalitas Nasabah Terhadap
Word Of Mouth Pada PT. Bank Mandiri Bandar Lampung”, (Tesis UNILA,
2017) Elshabyta, “Fintech dan Cashless Society: Sebuah Revolusi Pendongkrak
Ekonomi Kerakyatan”, Essay Booklet The Transformative Power Of Fintech
UGM, 2018 Fajar Akbar dan Niken, “Analisis Pengaruh Kualitas Layanan Mobile Banking
Terhadap Kepuasan dan Loyalitas Nasabah Pada Pengguna Layanan BRI
Mobile BRI Kantor Cabang Cirebon”, Jurnal Pengembangan Teknologi
Informasi dan Ilmu Komputer , Vol. 3 No 5 (2015) Faranita Amalia dan Keni, “Pengaruh Customer Perceived Value, Customer
Satisfaction, Dan Product Innovation Terhadap Customer Loyalty (Studi
Kasus Rebranding All New Sour Sally)”, Jurnal Manajemen Bisnis dan
Kewirausahaan , Vol. 3 No 1 (2019) Kusnul Azizah, “Pengaruh Nilai Pelanggan, Loyalitas Pelanggan, dan Lokasi
Terhadap Kepuasan Nasabah di BNI Syariah”, (Skripsi IAIN Tulung
Agung, 2019), 5 Maryanto Supriyono, Buku Pintar Perbankan (Yogyakarta: Andi Offset, 2011), 65 Maryanto Supriyono, Buku Pintar Perbankan (Yogyakarta: Andi Offset, 2011), 65
Mi
A
i ”P
k
b
D
D
k Fi
i l T
h
l
(Fi t
h) Miswan Ansori,”Perkembangan Dan Dampak Financial Technology (Fintech)
Terhadap Industri Keuangan Syariah Di Jawa Tengah”, Jurnal studi
Keislaman, Volume 5 nomor 1 (1 April 2019), 32 Muhammad Nur Fauzi “Pengaruh Nilai Pelanggan, Kepuasan Nasabah, Kualitas
Pelayanan, dan Relationship Marketing Terhadap Loyalitas Nasabah”,
(Skripsi UIN Syarif Hidayatullah, 2018) Nur Azilah, “Analisis Faktor-faktor Yang Mempengaruhi Kepuasan dan
Loyalitas Nasabah”, (Skripsi UIN Syarif Hidayatullah, 2016), 25
P
h
M di S
i l
l I
i Perusahaan Media Social asal Inggris Ujang Sumarwan, Perilaku Konsumen: Teori Dan Penerapannya Dalam Pemasaran,
(Bogor: Ghalia Indonesia, 2011), 346 Yeni Anda Dewi, “Pengaruh Kualitas Layanan Dan Produk Mobile Banking
Terhadap Kepuasan Nasabah Pada BRI Syariah KCP Ponorogo”, (Skripsi
IAIN Ponorogo 2019) Yogi Yuliansyah, “Analisis Pengaruh Layanan Mobile Banking Terhadap
Kepuasan Nasabah Pada Bank Syariah Mandiri Kantor cabang Pembantu
Kaliurang Yogyakarta”, (Skripsi UIN Syarif Hidayatullah, 2017)
Zakat, Infaq Sedekah, dan wakaf. 20
|
https://openalex.org/W3137973845
|
https://link.springer.com/content/pdf/10.1007/JHEP06(2021)003.pdf
|
English
| null |
Measurements of W+W−+ ≥ 1 jet production cross-sections in pp collisions at $$ \sqrt{s} $$ = 13 TeV with the ATLAS detector
|
The Journal of high energy physics/The journal of high energy physics
| 2,021
|
cc-by
| 40,667
|
Received: March 19, 2021
Accepted: May 12, 2021
Published: June 1, 2021 Received: March 19, 2021
Accepted: May 12, 2021
Published: June 1, 2021 Measurements of W +W −+ ≥1 jet production
cross-sections in pp collisions at √s = 13 TeV with
the ATLAS detector JHEP06(2021)003 The ATLAS collaboration E-mail: atlas.publications@cern.ch E-mail: atlas.publications@cern.ch T
28
B t¯t background estimate
31
The ATLAS collaboration
42 Contents
1
Introduction
1
2
The ATLAS detector
4
3
Data and Monte Carlo samples
4
4
Event reconstruction and selection
6
5
Background estimate
8
5.1
Top-quark background
8
5.2
Drell-Yan background
10
5.3
Backgrounds with non-prompt or misidentified leptons
11
5.4
Other backgrounds
12
5.5
Selected WW candidate events
12
6
Fiducial and differential cross-section determination
15
7
Uncertainties
16
8
Results
19
8.1
Comparison with theoretical predictions
19
8.2
Effective field theory interpretation
21
9
Conclusion
27
A Measurement at high plead. lep. T
28
B t¯t background estimate
31
The ATLAS collaboration
42 Contents
1
Introduction
1
2
The ATLAS detector
4
3
Data and Monte Carlo samples
4
4
Event reconstruction and selection
6
5
Background estimate
8
5.1
Top-quark background
8
5.2
Drell-Yan background
10
5.3
Backgrounds with non-prompt or misidentified leptons
11
5.4
Other backgrounds
12
5.5
Selected WW candidate events
12
6
Fiducial and differential cross-section determination
15
7
Uncertainties
16
8
Results
19
8.1
Comparison with theoretical predictions
19
8.2
Effective field theory interpretation
21
9
Conclusion
27
A Measurement at high plead. lep. T
28
B t¯t background estimate
31
The ATLAS collaboration
42 JHEP06(2021)003 B t¯t background estimate E-mail: atlas.publications@cern.ch Abstract: Fiducial and differential cross-section measurements of W +W −production in
association with at least one hadronic jet are presented. These measurements are sensitive
to the properties of electroweak-boson self-interactions and provide a test of perturbative
quantum chromodynamics and the electroweak theory. The analysis is performed using
proton-proton collision data collected at √s = 13 TeV with the ATLAS experiment, corre-
sponding to an integrated luminosity of 139 fb−1. Events are selected with exactly one op-
positely charged electron-muon pair and at least one hadronic jet with a transverse momen-
tum of pT > 30 GeV and a pseudorapidity of |η| < 4.5. After subtracting the background
contributions and correcting for detector effects, the jet-inclusive W +W −+ ≥1 jet fiducial
cross-section and W +W −+ jets differential cross-sections with respect to several kinematic
variables are measured. These measurements include leptonic quantities, such as the lepton
transverse momenta and the transverse mass of the W +W −system, as well as jet-related
observables such as the leading jet transverse momentum and the jet multiplicity. Limits on
anomalous triple-gauge-boson couplings are obtained in a phase space where interference
between the Standard Model amplitude and the anomalous amplitude is enhanced. Keywords: Hadron-Hadron scattering (experiments) ArXiv ePrint: 2103.10319 https://doi.org/10.1007/JHEP06(2021)003 Open Access, Copyright CERN,
for the benefit of the ATLAS Collaboration. Article funded by SCOAP3. Contents
1
Introduction
1
2
The ATLAS detector
4
3
Data and Monte Carlo samples
4
4
Event reconstruction and selection
6
5
Background estimate
8
5.1
Top-quark background
8
5.2
Drell-Yan background
10
5.3
Backgrounds with non-prompt or misidentified leptons
11
5.4
Other backgrounds
12
5.5
Selected WW candidate events
12
6
Fiducial and differential cross-section determination
15
7
Uncertainties
16
8
Results
19
8.1
Comparison with theoretical predictions
19
8.2
Effective field theory interpretation
21
9
Conclusion
27
A Measurement at high plead. lep. 1
Introduction The measurement of W-boson pair (WW) production cross-sections is an important test
of the Standard Model (SM). WW production at hadron colliders is sensitive to the prop-
erties of electroweak-boson self-interactions and provides a test of perturbative quantum
chromodynamics (QCD) and the electroweak (EW) theory. It also constitutes a large back-
ground in the measurement of Higgs boson production as well as in searches for physics
beyond the SM. Inclusive and fiducial WW production cross-sections have been measured
in proton-proton (pp) collisions at √s = 7 TeV [1, 2], 8 TeV [3–5] and 13 TeV [6–8], as well – 1 – as in e+e−collisions at LEP [9] and in p¯p collisions at Tevatron [10–12]. However, to reduce
backgrounds, the measurements of inclusive cross-sections typically require that the WW
pair is produced without additional jet activity, or at most with one additional jet. The
production of WW+jets has therefore not been studied in detail. This article presents results of measurements of fiducial and differential cross-sections
for a WW pair produced in association with one or more jets. For the first time at the
LHC, differential measurements are performed in a jet-inclusive phase space. This measure-
ment complements previous results as the combination of measurements with and without
jets improves the precision of the inclusive WW cross-section due to an anti-correlation
of important systematic uncertainties, for example the jet energy scale uncertainty, as
demonstrated in previous measurements from ATLAS [5] and CMS [8]. JHEP06(2021)003 The analysis of one-jet topologies can also improve searches for anomalous triple-gauge-
boson couplings (aTGCs), due to the increased interference between the SM amplitude
and the anomalous amplitude [13]. The impact of the QW aTGC operator, as defined in
ref. [14], increases rapidly with energy, making a measurement at the energies probed by
the LHC important. However, at high centre-of-mass energy, the SM amplitude and the
anomalous amplitude are dominated by different helicity configurations, so their interfer-
ence is suppressed, which reduces the impact of the operator. The reduced sensitivity to
the interference also poses a problem for the validity of the effective field theory inter-
pretation, as contributions that are quadratic in the dimension-six amplitude, which are
expected to be subdominant in the EFT expansion, become large. Requiring hard jets in
addition to the diboson pair allows different helicity configurations and, thus, reduces the
interference-suppression [13]. 1Even though different partonic initial states contribute to both processes, the notation gg →WW
is used to identify the loop-induced gluon-gluon fusion channel while q¯q →WW describes the dominant
production mode. 2ATLAS uses a right-handed coordinate system with its origin at the nominal interaction point (IP) in
the centre of the detector and the z-axis along the beam pipe. The x-axis points from the IP to the centre
of the LHC ring, and the y-axis points upwards. Cylindrical coordinates (r, φ) are used in the transverse
plane, φ being the azimuthal angle around the z-axis. The rapidity is defined as y = 1
2 ln E+pz
E−pz while the
pseudorapidity is defined in terms of the polar angle θ as η = −ln tan(θ/2). Angular distance is measured
in units of ∆R ≡
p
(∆η)2 + (∆φ)2. 1
Introduction In pp collisions, two leading processes contribute to WW production: q¯q →WW in
the t- and s-channel, and loop-induced gluon-gluon fusion processes gg →WW. Beyond
leading order in perturbation theory and in particular for WW+jets production, additional
partonic initial states can contribute to both processes.1
Representative diagrams for
WW+jet production are shown in figure 1. In this analysis, the resonant gg →H →WW
production is included in the signal definition and simulation, although the process is
strongly suppressed via kinematic selection requirements. The measurement of WW →e±νµ∓ν production cross-sections at √s = 13 TeV is
performed, using pp collision data recorded by the ATLAS experiment in 2015–2018, cor-
responding to an integrated luminosity of 139 fb−1. The number of events due to top-quark
pair production (t¯t), the largest background for this measurement, is reduced by rejecting
events containing jets from b-hadron decays (b-jets). However, the t¯t background is still
sizeable due to the requirement that events contain at least one jet, and a data-driven
method is required to reduce its contribution to systematic uncertainties in the measure-
ment. This is achieved by simultaneously measuring the number of t¯t events and the
efficiency of identifying b-jets in these events. The procedure reduces the impact of system-
atic uncertainties associated with the modelling of t¯t events and the b-tagging efficiency – 2 – W −
W +
q′
q′′
q
g
W −
W +
q
q
Z/γ∗
g
W −
W +
g
g
q
q′
g
Figure 1. Feynman diagrams for the production of a W +W −boson pair in association with a jet. W −
W +
g
g
q
q′
g Figure 1. Feynman diagrams for the production of a W +W −boson pair in association with a je JHEP06(2021)003 calibration, and provides a precise and accurate estimate of the background up to partonic
centre-of-mass energies of the order of 1 TeV and for up to five jets. The measurement is performed in a fiducial phase space close to the geometric and
kinematic acceptance of the experimental analysis. The cross-section of WW production
is measured differentially as a function of: • the transverse momentum2 of the leading lepton, plead. lep. T
, • the transverse momentum of the sub-leading lepton, psub-lead. lep. T
, • the transverse momentum of the leading jet, plead. p
3The transverse mass is defined as mT,eµ =
p
(ET,eµ + Emiss
T
)2 −(⃗pT,eµ + ⃗p miss
T
)2, where ET,eµ =
p
|⃗pT,eµ|2 + m2eµ and Emiss
T
is the magnitude of the missing transverse momentum. 1
Introduction jet
T
, • the jet multiplicity, • the invariant mass of the lepton pair, meµ, • the transverse momentum of the lepton pair, pT,eµ, • the scalar sum of all jet transverse momenta, HT, • the scalar sum of all jet and lepton transverse momenta, ST, • the transverse mass of the dilepton system and the missing transverse momentum,3
mT,eµ, • the rapidity of the dilepton system, yeµ, • the azimuthal separation of the two leptons, ∆φ(e, µ), and • cos θ∗= | tanh(∆η(e, µ)/2)| , which is sensitive to the spin structure of the W-boson
pair [15]. • cos θ∗= | tanh(∆η(e, µ)/2)| , which is sensitive to the spin structure of the W-boson
pair [15]. – 3 – These observables comprehensively characterize W-boson kinematics and jet produc-
tion in WW events. To facilitate an anomalous coupling interpretation that is less plagued
by the aforementioned interference suppression, the differential cross sections as a function
of meµ and ∆φ(e, µ) are also measured for plead. jet
T
> 200 GeV, where the jet pT threshold
is chosen as a compromise between increased interference and good measurement precision. Additional measurements with plead. lep. T
> 200 GeV are presented in appendix A. 2
The ATLAS detector The ATLAS experiment [16] at the LHC [17] is a multipurpose particle detector with a
forward-backward symmetric cylindrical geometry and a near 4π coverage in solid angle. It consists of an inner tracking detector surrounded by a thin superconducting solenoid
providing a 2 T axial magnetic field, electromagnetic and hadron calorimeters, and a muon
spectrometer with three large superconducting toroidal magnets with eight coils each. JHEP06(2021)003 The inner tracking detector covers the pseudorapidity range |η| < 2.5. It consists of
a high-granularity silicon pixel detector, including the insertable B-layer installed before
Run 2 [18, 19], followed by the silicon microstrip tracker. The silicon detectors are comple-
mented by a transition radiation tracking detector, enabling extended track reconstruction
within |η| < 2.0. Lead/liquid-argon (LAr) sampling calorimeters provide electromagnetic (EM) energy
measurements with high granularity. A steel/scintillator-tile hadron calorimeter covers
the central pseudorapidity range (|η| < 1.7). The endcap and forward regions are in-
strumented with copper/LAr and tungsten/LAr calorimeters for EM and hadronic energy
measurements up to |η| = 4.9. The muon spectrometer surrounds the calorimeters and is based on three large air-core
toroidal superconducting magnets with eight coils each. The field integral of the toroids
ranges between 2.0 and 6.0 Tm. across most of the detector. The muon spectrometer
includes a system of precision tracking chambers and fast detectors for triggering. Events are selected using a two-level trigger system. The first-level trigger is imple-
mented in hardware and uses a subset of the detector information to accept events at a rate
of about 100 kHz. The level-1 trigger is followed by a software-based trigger that reduces
the accepted event rate to 1 kHz on average depending on the data-taking conditions. 3
Data and Monte Carlo samples The analysis uses data collected in proton-proton collisions at a centre-of-mass energy of
13 TeV from 2015 to 2018. After applying data quality criteria [20], the dataset corresponds
to 139 fb−1, with an uncertainty of 1.7% [21], obtained using the LUCID-2 detector [22]
for the primary luminosity measurements. Monte Carlo (MC) simulated event samples are used to correct the signal yield for
detector effects and to estimate background contributions. All samples were passed through
a full simulation of the ATLAS detector [23], based on Geant4 [24]. Table 1 lists the
configuration for the nominal MC simulation used in the analysis. – 4 – Signal events were modelled using the Sherpa 2.2.2 [25] generator at next-to-leading
order (NLO) accuracy in QCD for up to one additional parton, and leading-order (LO)
accuracy for two to three additional parton emissions for q¯q initial states. The matrix ele-
ment calculation of gg →WW production, which includes off-shell effects and Higgs boson
contributions, incorporates up to one additional parton emission at LO. It was matched
and merged with the Sherpa parton shower based on Catani-Seymour dipole [26, 27] us-
ing the MEPS@NLO prescription [28–31]. The virtual QCD corrections were provided by
the OpenLoops library [32, 33]. The NNPDF3.0NNLO set of parton distribution func-
tions (PDF) was used [34], along with the dedicated set of tuned parton-shower parameters
developed by the Sherpa authors. JHEP06(2021)003 To assess the uncertainty in the matrix element calculation and the parton shower
modelling, alternative events for q¯q
→WW production were generated using the
Powheg-Box v2 [35–38] generator at NLO accuracy in QCD. Events were interfaced to
Pythia 8.186 [39] for the modelling of the parton shower, hadronization, and underlying
event, with parameter values set according to the AZNLO set of tuned parameters [40]. The
CT10nlo set PDF [41] was used for the hard-scattering processes, whereas the CTEQ6L1
PDF set [42] was used for the parton shower. The events were normalized to the next-to-
next-to-leading order (NNLO) cross-section [43]. For the gg →WW initial state, which
makes up only 5% of the signal, no alternative simulation is used. The production of t¯t and single-top Wt events was modelled using the Powheg-
Box v2 [35–37, 44] generator at NLO with the NNPDF3.0NLO [34] PDF. 4The hdamp parameter is a resummation damping factor and one of the parameters that control the
matching of Powheg matrix elements to the parton shower and thus effectively regulates the high-pT
radiation against which the t¯t system recoils. 3
Data and Monte Carlo samples The events
were interfaced to Pythia 8.230 [45] to model the parton shower, hadronization, and
underlying event, with the A14 set of tuned parameters [46] and using the NNPDF2.3LO
set of PDFs [47]. For t¯t event generation, the hdamp parameter4 was set to 1.5mtop [48]. The
diagram-removal scheme [49] was employed to handle the interference between the Wt and
t¯t production processes [48]. Alternative samples were generated to assess the uncertainties
in the top-background modelling. The uncertainty due to initial-state radiation and higher-
order QCD effects was estimated by simultaneous variations of the hdamp parameter and the
renormalization and factorization scales, and by choosing the Var3c up/down variants of the
A14 set of tuned parameters as described in ref. [50]. The impact of final-state radiation was
evaluated with weights that account for the effect of varying the renormalisation scale for
final-state parton-shower emissions up or down by a factor two. To assess the dependence
on the t¯t-Wt overlap removal scheme, the diagram-subtraction scheme [49] was employed as
an alternative to the diagram-removal scheme. The uncertainty due to the parton shower
and hadronization model was evaluated by comparing the nominal sample of events with an
event sample generated by Powheg-Box v2 and interfaced to Herwig 7.04 [51, 52], using
the H7UE set of tuned parameters [52] and the MMHT2014LO PDF set [53]. To assess the
uncertainty in the matching of NLO matrix elements to the parton shower, the nominal
sample was compared with a sample generated by MadGraph5_aMC@NLO 2.6.2 [54] at
NLO in QCD using the five-flavour scheme and the NNPDF2.3NLO PDF set. The events – 5 – were interfaced with Pythia 8, as for the nominal sample. The t¯t sample was normalized
to the cross-section prediction at NNLO QCD. in QCD including the resummation of next-
to-next-to-leading logarithmic (NNLL) soft-gluon terms calculated using Top++2.0 [55–
61]. The inclusive cross-section for single-top Wt was corrected to the theory prediction
calculated at NLO in QCD with NNLL soft-gluon corrections [62, 63]. The background due to Z/γ∗+jets production was simulated with the Sherpa 2.2.1
generator using NLO-accurate matrix elements for up to two jets, and LO-accurate matrix
elements for three and four jets calculated with the Comix [26] and OpenLoops libraries. They were matched with the Sherpa parton shower [27] using the MEPS@NLO prescrip-
tion [28–31] and the set of tuned parameters developed by the Sherpa authors. 3
Data and Monte Carlo samples The
NNPDF3.0NNLO set of PDFs was used, and the samples were normalised to a NNLO
prediction [64]. To assess the uncertainties in modelling the Z+jets process, an alternative
sample was simulated using LO-accurate matrix elements with up to four final-state partons
with MadGraph5_aMC@NLO 2.2.2, with the NNPDF2.3LO set of PDFs. Events were
interfaced to Pythia 8.186 using the A14 set of tuned parameters. The overlap between
matrix-element and parton-shower emissions was removed using the CKKW-L merging
procedure [65, 66]. The inclusive cross-section of both the nominal simulation and the
alternative simulation was corrected to the theory prediction calculated at NNLO in QCD. JHEP06(2021)003 The production of WZ, ZZ, V γ (with V = W, Z) and triboson (V V V , on-shell) final
states was simulated with the Sherpa 2.2.2 and Sherpa 2.2.8 generators using Open-
Loops at NLO QCD accuracy for up to one additional parton and LO accuracy for two to
three additional parton emissions, matched and merged with the Sherpa parton shower. The V Z simulation includes V γ∗contributions for m(ℓℓ) > 4 GeV. Samples were generated
using the NNPDF3.0NNLO PDF set and normalized to the cross-section calculated by the
event generator. Alternative samples for diboson backgrounds with WZ or ZZ production
were generated in the same way as the nominal signal sample: the default Sherpa sim-
ulation was exchanged for Powheg + Pythia 8, using NLO-accurate matrix elements. The Powheg diboson cross-section was scaled to NNLO [67–70], while the cross-section
calculated by Sherpa was found to be in good agreement with the NNLO value. Samples generated with Powheg-Box or MadGraph5_aMC@NLO used the Evt-
Gen 1.2.0 or 1.6.0 program [71] to model the decay of bottom and charm hadrons. The
effect of multiple interactions in the same and neighbouring bunch crossings (pile-up) was
modelled by overlaying the hard-scattering event with simulated inelastic pp events gen-
erated with Pythia 8.186 using the NNPDF2.3LO set of PDFs and the A3 set of tuned
parameters [72]. 4
Event reconstruction and selection Candidate WW events are selected by requiring exactly one isolated electron and one
isolated muon with opposite charges. Events with two isolated leptons of the same flavour
are not considered in the analysis due to the higher background from Drell-Yan events. Events were recorded by either single-electron or single-muon triggers [74, 75]. The
minimum pT threshold varied during data-taking between 24 GeV and 26 GeV for electrons, – 6 – Process
Generator
Parton shower
Matrix element O(αS)
Normalization
q¯q →WW
Sherpa 2.2.2
Sherpa
NLO (0–1 jet), LO (2–3 jets)
Generator†
gg →WW
Sherpa 2.2.2
Sherpa
LO (0–1 jet)
Generator
t¯t
Powheg-Box v2
Pythia 8
NLO
NNLO+NNLL
Wt
Powheg-Box v2
Pythia 8
NLO
NLO+NNLL
Z+jets
Sherpa 2.2.1
Sherpa
NLO (0–2 jets), LO (3–4 jets)
NNLO
WZ,ZZ
Sherpa 2.2.2
Sherpa
NLO (0–1 jet), LO (2–3 jets)
Generator†
Wγ,Zγ
Sherpa 2.2.8
Sherpa
NLO (0–1 jet), LO (2–3 jets)
Generator†
V V V
Sherpa 2.2.2
Sherpa
NLO (0–1 jet), LO (2–3 jets)
Generator†
†: the cross-section calculated by Sherpa is found to be in good agreement with the NNLO result [67–70, 73]. JHEP06(2021)003 Table 1. Summary of the nominal Monte Carlo simulated samples used in the analysis. The
gg →WW simulation includes Higgs boson contributions. The last two columns give the order
in αS of the matrix element calculation and the overall cross-section normalization. All nominal
MC samples use the NNPDF3.0 PDF set. The samples generated with Sherpa use the default
set of tuned parton-shower parameters, while for the Powheg-Box samples the A14 set of tuned
parameters and the NNPDF2.3LO PDF set are used for the parton shower. Table 1. Summary of the nominal Monte Carlo simulated samples used in the analysis. The
gg →WW simulation includes Higgs boson contributions. The last two columns give the order
in αS of the matrix element calculation and the overall cross-section normalization. All nominal
MC samples use the NNPDF3.0 PDF set. The samples generated with Sherpa use the default
set of tuned parton-shower parameters, while for the Powheg-Box samples the A14 set of tuned
parameters and the NNPDF2.3LO PDF set are used for the parton shower. and between 20 GeV and 26 GeV for muons, both requiring ‘loose’ to ‘medium’ isolation
criteria. Triggers with higher pT thresholds and looser isolation requirements are also used
to increase the efficiency. 4
Event reconstruction and selection The trigger selection efficiency is more than 99% for signal events
fulfilling all other selection requirements, which are detailed below. and between 20 GeV and 26 GeV for muons, both requiring ‘loose’ to ‘medium’ isolation
criteria. Triggers with higher pT thresholds and looser isolation requirements are also used
to increase the efficiency. The trigger selection efficiency is more than 99% for signal events
fulfilling all other selection requirements, which are detailed below. Candidate events are required to have at least one vertex having at least two associated
tracks with pT > 400 MeV. The vertex with the highest P p2
T of the associated tracks is
taken as the primary vertex. Electrons are reconstructed from energy deposits in the calorimeter that are matched
to tracks [76]. Electron candidates are required to fulfil the ‘tight’ likelihood-based identifi-
cation criteria as defined in ref. [76]. Furthermore, they are required to have ET > 27 GeV
and |η| < 2.47, excluding the transition region between barrel and endcap regions,
1.37 < |η| < 1.52. Muon candidates are reconstructed by combining a track in the inner detector (ID)
with a track in the muon spectrometer [77]. Muons are required to have pT > 27 GeV and
|η| < 2.5 and to satisfy the Medium identification selection, as defined in ref. [77]. Leptons are required to be compatible with the primary vertex by imposing require-
ments on the impact parameters of associated tracks. The transverse impact parameter
significance, d0/σd0 is required to satisfy |d0/σd0| < 5 (3) for electrons (muons). The longi-
tudinal impact parameter z0 must satisfy |z0 ·sin θ| < 0.5 mm, where θ is the polar angle of
the track. Additionally, leptons are required to be isolated using information from the ID
tracks and energy clusters in the calorimeters in a cone around the lepton. The Gradient
working point is used for electrons [76], while for muons the Tight_FixedRad working point
is used, which is similar to the Tight selection defined in ref. [78] but with altered criteria
at muon pT > 50 GeV in order to increase the background rejection. The electron or muon
trigger object is required to match the respective reconstructed lepton. – 7 – Jets are reconstructed using the anti-kt algorithm [79] with a radius parameter of
R = 0.4 using particle-flow objects [80]. They are required to have pT > 30 GeV and
|η| < 4.5. 4
Event reconstruction and selection To suppress jets that originate from pile-up, a jet-vertex tagger [81] is applied
to jets with pT < 60 GeV and |η| < 2.4. Jet energy scale and resolution are corrected with
η- and pT dependent scale factors [82]. Jets with pT > 20 GeV and |η| < 2.5 containing
decay products of a b-hadron are identified using the DL1r b-tagging algorithm [83, 84] at
the 85% efficiency working point. The missing transverse momentum, with magnitude Emiss
T
, is computed as the negative
of the vectorial sum of the transverse momenta of tracks associated with jets and muons,
as well as tracks in the ID that are not associated with any other component. The pT of
the electron track is replaced by the calibrated transverse momentum of the reconstructed
electron [85]. JHEP06(2021)003 In order to resolve the overlap between particles reconstructed as multiple physics
objects in the detector, non-b-tagged jets are removed if they overlap, within ∆R < 0.2,
with an electron, or with a muon if the jet has less than three associated tracks with
pT > 500 MeV and satisfies pµ
T/pjet
T > 0.5, and the ratio of the muon pT to the sum of the
track pT associated with the jet is greater than 0.7. Electrons or muons overlapping within
∆R < 0.4 with any jet, including b-tagged jets, after the former selection are removed. Events having at least one jet, but no b-tagged jets, are selected for the analysis. To
reduce the Drell-Yan backgrounds, dominated by Z+jets events with Z →τ +τ −decays,
the invariant mass of the electron-muon pair is required to be meµ > 85 GeV. This require-
ment also reduces the contribution of resonant gg →H →WW production. Events with
additional leptons with pT > 10 GeV and satisfying Loose isolation and LooseLH (Loose)
identification requirements for electrons (muons), are vetoed to reduce backgrounds due to
WZ and ZZ production. Additionally, the subsets of events with high leading-jet trans-
verse momentum, plead. jet
T
> 200 GeV, are analysed in detail, to investigate the reduced
interference-suppression in the aTGC interpretation. Table 2 gives a summary of the lep-
ton, jet and event selection requirements used to define the signal region. 5
Background estimate The top-quark background, from either t¯t or single-top Wt production, comprises about
60% of the events passing the event selection and about 90% of the total background. Addi-
tional backgrounds considered are Z+jets production, events with non-prompt or misiden-
tified leptons, diboson production (WZ, Wγ, ZZ, and Zγ), and triboson production. 5.1
Top-quark background An estimate of the t¯t background is obtained using a data-driven technique, while the
single-top Wt background is estimated using simulation and is found to contribute about
16% of the top-quark background. Following the procedure used in a measurement of the
t¯t cross-section [86], two control regions requiring exactly one and exactly two b-tagged
jets are defined. All other selection criteria are the same as in the signal region. These
regions are dominated by t¯t events and can be used to infer the number of t¯t events in – 8 – Selection
Criteria
Lepton pT
> 27 GeV
Lepton η
|η| < 2.47 and not 1.37 < |η| < 1.52 (electron)
|η| < 2.5 (muon)
Lepton identification
TightLH (electron), Medium (muon)
Lepton isolation
Gradient (electron), Tight_FixedRad (muon)
Lepton impact parameter
|d0/σd0| < 5, 3 (electron, muon)
|z0 · sin θ| < 0.5 mm
Jet selection
pT > 30 GeV, |η| < 4.5
b-jet selection
pT > 20 GeV, |η| < 2.5, DL1r (85% eff. WP)
Lepton selection
1 electron and 1 muon of opposite charge,
no additional lepton with pT > 10 GeV, Loose isolation,
and LooseLH (electron) / Loose (muon) identification
Number of jets
≥1
Number of b-jets
0
meµ
> 85 GeV
High plead. jet
T
selection
plead. jet
T
> 200 GeV
Table 2. Summary of the object and event selection criteria. JHEP06(2021)003 Table 2. Summary of the object and event selection criteria. the signal region with minimal dependence on the selection and b-tagging efficiencies. The
contribution of non-t¯t events in the 1-b-jet and 2-b-jet control regions is 13% and 4% of the
expected events, respectively, of which 90% can be attributed to single-top Wt production. The numbers of t¯t events in the two control regions as well as in the signal region are the signal region with minimal dependence on the selection and b-tagging efficiencies. The
contribution of non-t¯t events in the 1-b-jet and 2-b-jet control regions is 13% and 4% of the
expected events, respectively, of which 90% can be attributed to single-top Wt production. contribution of non-t¯t events in the 1-b-jet and 2-b-jet control regions is 13% and 4% of the
expected events, respectively, of which 90% can be attributed to single-top Wt production. 5.1
Top-quark background The numbers of t¯t events in the two control regions, as well as in the signal region, are
given by The numbers of t¯t events in the two control regions, as well as in the signal region, are
given by Nt¯t
1b = N1b −Nothers
1b
= Lσt¯tεeµ · 2εb (1 −Cbεb) ,
(5.1)
Nt¯t
2b = N2b −Nothers
2b
= Lσt¯tεeµ · Cbε2
b ,
(5.2)
Nt¯t
0b = Lσt¯tεeµ ·
1 −2εb + Cbε2
b
,
(5.3) (5.1) (5.3) where Nib and Nothers
ib
are, respectively, the number of selected events in data and the num-
ber of non-t¯t events, estimated using simulation, with exactly i b-tagged jets. The term
Lσt¯tεeµ is the product of the integrated luminosity, the t¯t cross-section, and the general
selection efficiency, and εb is the efficiency of selecting a b-jet in a t¯t event. The correction
factor Cb = εbb/ε2
b accounts for correlation effects between selecting one and two b-jets. It
is determined from t¯t simulation as Cb = 4 · Nt¯t
MCNt¯t
2b,MC/
Nt¯t
1b,MC + 2 · Nt¯t
2b,MC
2, and typ-
ically has values close to unity. The b-jet selection efficiency, εb, accounts for the efficiency
of the b-tagging algorithm and also for the acceptance of b-jets. Using eqs. (5.1)–(5.3), the – 9 – number of t¯t events in the signal region can be expressed as Nt¯t
0b = Cb
4
Nt¯t
1b + 2Nt¯t
2b
2
Nt¯t
2b
−Nt¯t
1b −Nt¯t
2b , which depends only on Nib and Nothers
ib
(i = 1, 2), as well as Cb. The t¯t background estimate
is performed in each analysis bin, i.e. for the fiducial selection as well as in each individual
bin for the differential measurements. Because b-tagged jets are selected with a lower pT
threshold than regular jets, this method also works for events with exactly one regular jet. As the t¯t background estimate is largely based on observed yields in data control
regions and the only input from t¯t simulation is the correlation factor Cb, this method
strongly reduces experimental and theoretical uncertainties in the t¯t background, and,
thus, lowers the total uncertainty in the background by a factor of approximately five. 5.1
Top-quark background In
regions of phase space where, for a large fraction of events, one or both b-jets are outside the
detector acceptance, the reliance on t¯t simulation for the extrapolation into the signal region
increases. In such cases, the t¯t estimate remains valid because modelling uncertainties cover
rate and shape differences between data and simulation for b-jet kinematic distributions in
the control region. Uncertainties in the single-top Wt production rate that are independent
of the b-jet multiplicity, such as the cross-section uncertainty, partially cancel out because
single-top Wt is the dominant background to t¯t in the t¯t control regions. A variation
leading to a larger Wt prediction in the control regions reduces the t¯t estimate, so if the
same variation also leads to a larger Wt prediction in the signal region, the overall effect
on the combined top background is reduced. The total uncertainty in the top background
in the signal region is 2.8%. JHEP06(2021)003 The top background estimate is validated in a top-enriched subset of the signal re-
gion which requires mℓj < 140 GeV and ∆φ(e, µ) < π/2 in addition to the normal event
selection. Here mℓj is the invariant mass of the leading jet and the closest lepton. This
region is approximately 70% pure in top events and shows good agreement between the
data and the combined signal and background prediction, which uses the data-driven top
background estimate. The level of agreement of the prediction with the observed events
in the control regions and the top-enriched selection is summarized in table 3. Figure 2
shows the distributions of the plead. lep. T
and the jet multiplicity, confirming the accurate
modelling of lepton and jet-related properties in events without b-jets. 5.3
Backgrounds with non-prompt or misidentified leptons To suppress contamination from W+jets events in this
sample, the sum of Emiss
T
and the transverse mass of the lepton and Emiss
T
system is required
to be smaller than 50 GeV. The approach used closely follows the one applied in ref. [88]. Systematic uncertainties in the composition of the different sources of fake leptons are
estimated by varying the selection of the data sample in which the extrapolation factors
are determined. The variations include selecting events with a b-jet recoiling against the
lepton candidate, as well as changing the Emiss
T
requirements to increase the fake-lepton
contributions. The normalization of the prompt-lepton background in the control region
used for the extrapolation factor determination is varied by 10%, which covers the largest
discrepancies between simulation and data observed in a dedicated validation region. An
additional 25% uncertainty in the fake-lepton background normalization covers a potential
mismodelling of the identification efficiency of prompt leptons that fail the tight, but fulfil
the looser, lepton identification requirements. The uncertainty in the signal contamination
in the control region, which is subtracted using simulation, is determined from the typical
size of the largest deviations between the measured and predicted differential cross-sections,
which is 20%. The total relative uncertainty in the fake-lepton background is about 40%. In order to validate the estimate of the fake-lepton backgrounds, the opposite-charge
requirement of the signal region selection is inverted, and events with an electron-muon
pair of the same charge are selected. As many processes leading to fake leptons are charge
symmetric, while most Standard Model processes are not, this selection increases the con-
tribution of W+jets events to about 25%. The modelling of the fake-lepton backgrounds Systematic uncertainties in the composition of the different sources of fake leptons are
estimated by varying the selection of the data sample in which the extrapolation factors
are determined. The variations include selecting events with a b-jet recoiling against the
lepton candidate, as well as changing the Emiss
T
requirements to increase the fake-lepton
contributions. The normalization of the prompt-lepton background in the control region
used for the extrapolation factor determination is varied by 10%, which covers the largest
discrepancies between simulation and data observed in a dedicated validation region. An
additional 25% uncertainty in the fake-lepton background normalization covers a potential
mismodelling of the identification efficiency of prompt leptons that fail the tight, but fulfil
the looser, lepton identification requirements. 5.2
Drell-Yan background The Drell-Yan Z+jets background is estimated using MC simulation. The meµ > 85 GeV
requirement strongly suppresses this background by a factor of about nine. The contri-
bution of this background to the selected events in the signal region is about 3%, almost
entirely due to Z/γ∗→τ +τ −+jets events. The Z+jets estimate is checked in a validation region requiring a dilepton invariant
mass between 45 GeV and 80 GeV and either pT,eµ < 30 GeV or Emiss
T
< 20 GeV, in addition
to the b-jet veto and the requirement of at least one jet with pT > 30 GeV and |η| < 4.5. The Z+jets purity of this region is 75% and good modelling of the data is observed, as – 10 – shown in table 3. Figure 2 shows the distribution of the dilepton invariant mass meµ in the
validation region, which features the resonant Z →ττ distribution over a rising background
of top events. In addition to the theoretical uncertainty in the Z+jets cross-section of 5% [87], un-
certainties are estimated by comparing the nominal MC simulation with events simulated
by MadGraph5_aMC@NLO. This uncertainty estimate was found to bracket the effect
of scale uncertainties. In the signal region, the total uncertainty in the Z+jets background
is about 30%. 5.3
Backgrounds with non-prompt or misidentified leptons JHEP06(2021)003 Reducible backgrounds from events with non-prompt or misidentified leptons are called
fake-lepton backgrounds or ‘fakes’. Fake leptons correspond to leptons from heavy-flavour
hadron decays and jets misidentified as electrons. Fake-lepton events stem mainly from
W+jets production and contribute about 3% of the selected events. Top backgrounds with
one prompt lepton contribute about 10% of the fake-lepton backgrounds. Fake-lepton backgrounds are estimated using a data-driven technique. A control region
is defined, where one of the two lepton candidates fails the nominal selection with respect to
the impact parameters and isolation criteria, but instead fulfils a looser set of requirements
designed to increase the contribution of fake leptons. The fake-lepton background in the
signal region is, then, obtained by scaling the number of data events in this control region
by an extrapolation factor, after subtracting processes with two prompt leptons using
simulation. The extrapolation factor is determined in a data sample that is dominated by
fake leptons, and it depends on the pT, |η|, and flavour of the lepton. The data sample is
selected by requiring events with a dijet-like topology with one lepton candidate recoiling
against a jet, with |∆φ(ℓ, j)| > 2.8. To suppress contamination from W+jets events in this
sample, the sum of Emiss
T
and the transverse mass of the lepton and Emiss
T
system is required
to be smaller than 50 GeV. The approach used closely follows the one applied in ref. [88]. Fake-lepton backgrounds are estimated using a data-driven technique. A control region
is defined, where one of the two lepton candidates fails the nominal selection with respect to
the impact parameters and isolation criteria, but instead fulfils a looser set of requirements
designed to increase the contribution of fake leptons. The fake-lepton background in the
signal region is, then, obtained by scaling the number of data events in this control region
by an extrapolation factor, after subtracting processes with two prompt leptons using
simulation. The extrapolation factor is determined in a data sample that is dominated by
fake leptons, and it depends on the pT, |η|, and flavour of the lepton. The data sample is
selected by requiring events with a dijet-like topology with one lepton candidate recoiling
against a jet, with |∆φ(ℓ, j)| > 2.8. 5.4
Other backgrounds Backgrounds from WZ, ZZ, Wγ and Zγ production are estimated from simulation, and
are found to contribute about 3% of the total selected events, dominated by WZ events,
which are observed to be well described by the nominal Sherpa simulation in ref. [89]. Uncertainties are derived by comparing the nominal simulation with events simulated by
Powheg + Pythia 8. The difference in generator predictions was found to be larger
than the impact of scale uncertainties in the Sherpa simulation, and thus the assigned
uncertainty is the conservative option. Additionally, the uncertainty in the diboson cross-
section of 10% [90, 91] is included. JHEP06(2021)003 The V Z (WZ and ZZ) prediction is validated in events containing a third lepton
having pT ≥10 GeV that must satisfy loosened identification criteria. The invariant mass
of the resulting same-flavour opposite-charge pair of leptons is required to be between
80 GeV and 100 GeV, close to the Z boson mass. These selections gives a very pure sample
of diboson events, and the prediction is in good agreement with the data, as seen in figure 2
and table 3. In figure 2 the Emiss
T
distribution in the V Z validation region shows separation
between ZZ and WZ events. V γ (Wγ and Zγ) events enter the signal region as backgrounds when the photon
is reconstructed and selected as an electron candidate. To validate estimates of these
backgrounds, the electron identification requirements are changed such that contributions
from photon conversions increase. As the electron candidates reconstructed from photon
conversion are charge symmetric, both opposite-charge and same-charge candidates are
selected with respect to the selected muon. For the V γ validation region the pT distribution
of the electron candidates is shown in figure 2. It is dominated by electrons from photon
conversion. Good agreement with the observed data in the validation regions is found. Based on MC simulations, it is estimated that the triboson background contributes
less than 0.1% of the inclusive selected events and at most 0.5% of the selected events in a
single bin and is thus neglected in the analysis. 5.3
Backgrounds with non-prompt or misidentified leptons The uncertainty in the signal contamination
in the control region, which is subtracted using simulation, is determined from the typical
size of the largest deviations between the measured and predicted differential cross-sections,
which is 20%. The total relative uncertainty in the fake-lepton background is about 40%. In order to validate the estimate of the fake-lepton backgrounds, the opposite-charge
requirement of the signal region selection is inverted, and events with an electron-muon
pair of the same charge are selected. As many processes leading to fake leptons are charge
symmetric, while most Standard Model processes are not, this selection increases the con-
tribution of W+jets events to about 25%. The modelling of the fake-lepton backgrounds – 11 – can be validated despite the relatively low purity since the dominant diboson background
in this region is known with a precision of about 10%. Reasonable agreement of the pre-
diction with the data is observed, as is shown in figure 2 in the psub-lead. lep. T
distribution,
and in table 3 comparing the numbers of observed and predicted events. 5.5
Selected W W candidate events *: without WW modelling uncertainties
ATLAS
-1
= 13 TeV, 139 fb
s
Top enriched
45
50
55
60
65
70
75
80
[GeV]
µ
e
m
0.8
0.9
1
1.1
1.2
Data/SM
0
100
200
300
400
500
600
700
800
Events / GeV
Data
Drell-Yan
Top
WW
γ
WZ,ZZ,V
syst. ⊕
Stat. ATLAS
-1
= 13 TeV, 139 fb
s
Drell-Yan VR
2
10
[GeV]
T
p
Electron candidate
0.8
0.9
1
1.1
1.2
Data/SM
30
40
60
80
2
10
×
3
0
10
20
30
40
50
60
Events / GeV
Data
γ
V
W+jets
Drell-Yan
Top
WW
syst. ⊕
Stat. ATLAS
-1
= 13 TeV, 139 fb
s
VR
γ
V JHEP06(2021)003
2
10
[GeV]
lead. lep. T
p
0.8
0.9
1
1.1
1.2
Data/SM
30
40
60
80
2
10
×
3
0
20
40
60
80
100
120
140
160
180
Events / GeV
Data
Top
WW
Fakes
γ
WZ,ZZ,V
Drell-Yan
*
syst. ⊕
Stat. *: without WW modelling uncertainties
ATLAS
-1
= 13 TeV, 139 fb
s
Top enriched
1
2
3
4
5
> 30 GeV)
T
p
Number of jets (
0.8
0.9
1
1.1
1.2
Data/SM
0
500
1000
1500
2000
2500
3000
3500
4000
4500
Events
Data
Top
WW
Fakes
γ
WZ,ZZ,V
Drell-Yan
*
syst. ⊕
Stat. *: without WW modelling uncertainties
ATLAS
-1
= 13 TeV, 139 fb
s
Top enriched
2
10
[GeV]
sub-lead. lep. T
p
0.8
0.9
1
1.1
1.2
Data/SM
30
40
60
80
2
10
×
2
0
20
40
60
80
100
120
140
160
180
200
Events / GeV
Data
Fakes
γ
WZ,ZZ,V
WW
Top
Drell-Yan
syst. ⊕
Stat. ATLAS
-1
= 13 TeV, 139 fb
s
Same-sign VR
45
50
55
60
65
70
75
80
[GeV]
µ
e
m
0.8
0.9
1
1.1
1.2
Data/SM
0
100
200
300
400
500
600
700
800
Events / GeV
Data
Drell-Yan
Top
WW
γ
WZ,ZZ,V
syst. ⊕
Stat. ATLAS
-1
= 13 TeV, 139 fb
s
Drell-Yan VR
0
20
40
60
80
100
120
140
[GeV]
miss
T
E
0.8
0.9
1
1.1
1.2
Data/SM
0
20
40
60
80
100
120
Events / GeV
Data
WZ
ZZ
Others
syst. ⊕
Stat. 5.5
Selected W W candidate events Table 4 lists the number of selected WW candidate events, as well as the breakdown of
the background predictions. Details of the systematic uncertainties are given in section 7. Figure 3 shows selected distributions at detector level in the final analysis binning and
compares the observed data with the signal prediction and the background estimate. Rea-
sonable agreement between data and expectations is observed for both the event yields and
the shapes of the distributions. For the nominal signal model, small excesses are seen in
the predictions at low plead. lep. T
, as well as at low meµ in the high-plead. jet
T
selection (both
in figure 3). These are, however, covered by the theory uncertainties of the signal, which
are not included in the error bands in this figure. – 12 – JHEP06(2021)003
1
2
3
4
5
> 30 GeV)
T
p
Number of jets (
0.8
0.9
1
1.1
1.2
Data/SM
0
500
1000
1500
2000
2500
3000
3500
4000
4500
Events
Data
Top
WW
Fakes
γ
WZ,ZZ,V
Drell-Yan
*
syst. ⊕
Stat. *: without WW modelling uncertainties
ATLAS
-1
= 13 TeV, 139 fb
s
Top enriched
45
50
55
60
65
70
75
80
[GeV]
µ
e
m
0.8
0.9
1
1.1
1.2
Data/SM
0
100
200
300
400
500
600
700
800
Events / GeV
Data
Drell-Yan
Top
WW
γ
WZ,ZZ,V
syst. ⊕
Stat. ATLAS
-1
= 13 TeV, 139 fb
s
Drell-Yan VR
2
10
[GeV]
T
p
Electron candidate
0.8
0.9
1
1.1
1.2
Data/SM
30
40
60
80
2
10
×
3
0
10
20
30
40
50
60
Events / GeV
Data
γ
V
W+jets
Drell-Yan
Top
WW
syst. ⊕
Stat. ATLAS
-1
= 13 TeV, 139 fb
s
VR
γ
V
. (top left) and the jet multiplicity (top
same-sign validation region (VR) (middle
miss
T
in the V Z VR (bottom left), and the
ptons (bottom right). The last bin contains
her with the predictions for the signal and
the top-enriched region is estimated using
her regions the nominal MC prediction is
e total prediction. The uncertainty bands
cluding theory uncertainties on the signal. 1
2
3
4
5
> 30 GeV)
T
p
Number of jets (
0.8
0.9
1
1.1
1.2
Data/SM
0
500
1000
1500
2000
2500
3000
3500
4000
4500
Events
Data
Top
WW
Fakes
γ
WZ,ZZ,V
Drell-Yan
*
syst. ⊕
Stat. 5.5
Selected W W candidate events Detector-level distributions o
right) in the top-enriched region, the psub-
T
left), the meµ in the Drell-Yan VR (middl
electron candidate pT in the V γ VR with op
overflow events Data are shown as black 1
2
3
4
5
> 30 GeV)
T
p
Number of jets (
0.8
0.9
1
1.1
1.2
Data/SM
0
500
1000
1500
2000
2500
3000
3500
4000
4500
Events
Data
Top
WW
Fakes
γ
WZ,ZZ,V
Drell-Yan
*
syst. ⊕
Stat. *: without WW modelling uncertainties
ATLAS
-1
= 13 TeV, 139 fb
s
Top enriched 2
10
[GeV]
lead. lep. T
p
0.8
0.9
1
1.1
1.2
Data/SM
30
40
60
80
2
10
×
3
0
20
40
60
80
100
120
140
160
180
Events / GeV
Data
Top
WW
Fakes
γ
WZ,ZZ,V
Drell-Yan
*
syst. ⊕
Stat. *: without WW modelling uncertainties
ATLAS
-1
= 13 TeV, 139 fb
s
Top enriched
2
10
[GeV]
sub-lead. lep. T
p
0.8
0.9
1
1.1
1.2
Data/SM
30
40
60
80
2
10
×
2
0
20
40
60
80
100
120
140
160
180
200
Events / GeV
Data
Fakes
γ
WZ,ZZ,V
WW
Top
Drell-Yan
syst. ⊕
Stat. ATLAS
-1
= 13 TeV, 139 fb
s
Same-sign VR
0
20
40
60
80
100
120
140
[GeV]
miss
T
E
0.8
0.9
1
1.1
1.2
Data/SM
0
20
40
60
80
100
120
Events / GeV
Data
WZ
ZZ
Others
syst. ⊕
Stat. ATLAS
-1
= 13 TeV, 139 fb
s
VZ VR 1
2
3
4
5
> 30 GeV)
T
p
Number of jets (
0.8
0.9
1
1.1
1.2
Data/SM
0
500
1000
1500
2000
2500
3000
3500
4000
4500
Events
Data
Top
WW
Fakes
γ
WZ,ZZ,V
Drell-Yan
*
syst. ⊕
Stat. *: without WW modelling uncertainties
ATLAS
-1
= 13 TeV, 139 fb
s
Top enriched
45
50
55
60
65
70
75
80
[GeV]
µ
e
m
0.8
0.9
1
1.1
1.2
Data/SM
0
100
200
300
400
500
600
700
800
Events / GeV
Data
Drell-Yan
Top
WW
γ
WZ,ZZ,V
syst. ⊕
Stat. ATLAS
-1
= 13 TeV, 139 fb
s
Drell-Yan VR 2
10
[GeV]
lead. lep. 5.5
Selected W W candidate events ATLAS
-1
= 13 TeV, 139 fb
s
VZ VR
2
10
[GeV]
T
p
Electron candidate
0.8
0.9
1
1.1
1.2
Data/SM
30
40
60
80
2
10
×
3
0
10
20
30
40
50
60
Events / GeV
Data
γ
V
W+jets
Drell-Yan
Top
WW
syst. ⊕
Stat. ATLAS
-1
= 13 TeV, 139 fb
s
VR
γ
V
Figure 2. Detector-level distributions of the plead. lep. T
(top left) and the jet multiplicity (top
right) in the top-enriched region, the psub-lead. lep. T
in the same-sign validation region (VR) (middle
left), the meµ in the Drell-Yan VR (middle right), the Emiss
T
in the V Z VR (bottom left), and the
electron candidate pT in the V γ VR with opposite-sign leptons (bottom right). The last bin contains
overflow events. Data are shown as black markers, together with the predictions for the signal and
background production processes. The top background in the top-enriched region is estimated using
the data-driven method explained in the text; in all other regions the nominal MC prediction is
used. The lower panels show the ratio of the data to the total prediction. The uncertainty bands
shown include statistical and systematic uncertainties, excluding theory uncertainties on the signal. 2
10
[GeV]
lead. lep. T
p
0.8
0.9
1
1.1
1.2
Data/SM
30
40
60
80
2
10
×
3
0
20
40
60
80
100
120
140
160
180
Events / GeV
Data
Top
WW
Fakes
γ
WZ,ZZ,V
Drell-Yan
*
syst. ⊕
Stat. *: without WW modelling uncertainties
ATLAS
-1
= 13 TeV, 139 fb
s
Top enriched
2
10
[GeV]
sub-lead. lep. T
p
0.8
0.9
1
1.1
1.2
Data/SM
30
40
60
80
2
10
×
2
0
20
40
60
80
100
120
140
160
180
200
Events / GeV
Data
Fakes
γ
WZ,ZZ,V
WW
Top
Drell-Yan
syst. ⊕
Stat. ATLAS
-1
= 13 TeV, 139 fb
s
Same-sign VR
0
20
40
60
80
100
120
140
[GeV]
miss
T
E
0.8
0.9
1
1.1
1.2
Data/SM
0
20
40
60
80
100
120
Events / GeV
Data
WZ
ZZ
Others
syst. ⊕
Stat. ATLAS
-1
= 13 TeV, 139 fb
s
VZ VR
Figure 2. 5.5
Selected W W candidate events jet
T
p
0.8
0.9
1
1.1
1.2
Data/SM
1
10
2
10
3
10
4
10
Events / GeV
Data
WW
Top
Drell-Yan
Fakes
γ
WZ,ZZ,V
*
syst. ⊕
Stat. *: without WW modelling uncertainties
ATLAS
-1
= 13 TeV, 139 fb
s
-veto
b
|<4.5),
η
1 jet (30 GeV,|
≥
,
±
µ
±
e 2
10
3
10
[GeV]
lead. lep. T
p
0.8
0.9
1
1.1
1.2
Data/SM
1
−
10
1
10
2
10
3
10
4
10
Events / GeV
Data
WW
Top
Drell-Yan
Fakes
γ
WZ,ZZ,V
*
syst. ⊕
Stat. *: without WW modelling uncertainties
ATLAS
-1
= 13 TeV, 139 fb
s
-veto
b
|<4.5),
η
1 jet (30 GeV,|
≥
,
±
µ
±
e Data/SM Data/SM JHEP06(2021)003 T
2
10
3
10
[GeV]
µ
T,e
m
0.8
0.9
1
1.1
1.2
Data/SM
1
10
2
10
3
10
Events / GeV
Data
WW
Top
Drell-Yan
Fakes
γ
WZ,ZZ,V
*
syst. ⊕
Stat. *: without WW modelling uncertainties
ATLAS
-1
= 13 TeV, 139 fb
s
-veto
b
|<4.5),
η
1 jet (30 GeV,|
≥
,
±
µ
±
e Events Data/SM Data/SM 2
10
3
10
[GeV]
µ
e
m
0.8
0.9
1
1.1
1.2
Data/SM
1
−
10
1
10
2
10
Events / GeV
Data
WW
Top
Drell-Yan
Fakes
γ
WZ,ZZ,V
*
syst. ⊕
Stat. *: without WW modelling uncertainties
ATLAS
-1
= 13 TeV, 139 fb
s
-veto
b
|<4.5),
η
1 jet (30 GeV,|
≥
,
±
µ
±
e
> 200 GeV
lead. jet
T
p 0
0.5
1
1.5
2
2.5
3
)|
µ
(e,
φ
∆|
0.8
0.9
1
1.1
1.2
Data/SM
0
1000
2000
3000
4000
5000
Events
Data
WW
Top
Drell-Yan
Fakes
γ
WZ,ZZ,V
*
syst. ⊕
Stat. *: without WW modelling uncertainties
ATLAS
-1
= 13 TeV, 139 fb
s
-veto
b
|<4.5),
η
1 jet (30 GeV,|
≥
,
±
µ
±
e
> 200 GeV
lead. jet
T
p 10
[GeV]
µ
e
m Figure 3. Signal region detector-level distributions of the plead. lep. T
(top left), the plead. jet
T
(top
right), the jet multiplicity (middle left), the mT,eµ (middle right), and, for events with plead. jet
T
>
200 GeV, the ∆φ(e, µ) (bottom left) and meµ (bottom right). 5.5
Selected W W candidate events *: without WW modelling uncertainties
ATLAS
-1
= 13 TeV, 139 fb
s
-veto
b
|<4.5),
η
1 jet (30 GeV,|
≥
,
±
µ
±
e
> 200 GeV
lead. jet
T
p
2
10
3
10
[GeV]
µ
e
m
0.8
0.9
1
1.1
1.2
Data/SM
1
−
10
1
10
2
10
Events / GeV
Data
WW
Top
Drell-Yan
Fakes
γ
WZ,ZZ,V
*
syst. ⊕
Stat. *: without WW modelling uncertainties
ATLAS
-1
= 13 TeV, 139 fb
s
-veto
b
|<4.5),
η
1 jet (30 GeV,|
≥
,
±
µ
±
e
> 200 GeV
lead. jet
T
p
Figure 3. Signal region detector-level distributions of the plead. lep. T
(top left), the plead. jet
T
(top
right), the jet multiplicity (middle left), the mT,eµ (middle right), and, for events with plead. jet
T
>
200 GeV, the ∆φ(e, µ) (bottom left) and meµ (bottom right). Data are shown as black markers
together with the predictions for the signal and background production processes. The last bin
contains overflow events. The lower panels show the ratio of the data to the total prediction. The uncertainty bands shown include statistical and systematic uncertainties, excluding theory
uncertainties on the signal. JHEP06(2021)003
2
10
3
10
[GeV]
lead. jet
T
p
0.8
0.9
1
1.1
1.2
Data/SM
1
10
2
10
3
10
4
10
Events / GeV
Data
WW
Top
Drell-Yan
Fakes
γ
WZ,ZZ,V
*
syst. ⊕
Stat. *: without WW modelling uncertainties
ATLAS
-1
= 13 TeV, 139 fb
s
-veto
b
|<4.5),
η
1 jet (30 GeV,|
≥
,
±
µ
±
e
2
10
3
10
[GeV]
µ
T,e
m
0.8
0.9
1
1.1
1.2
Data/SM
1
10
2
10
3
10
Events / GeV
Data
WW
Top
Drell-Yan
Fakes
γ
WZ,ZZ,V
*
syst. ⊕
Stat. *: without WW modelling uncertainties
ATLAS
-1
= 13 TeV, 139 fb
s
-veto
b
|<4.5),
η
1 jet (30 GeV,|
≥
,
±
µ
±
e
2
10
3
10
[GeV]
µ
e
m
0.8
0.9
1
1.1
1.2
Data/SM
1
−
10
1
10
2
10
Events / GeV
Data
WW
Top
Drell-Yan
Fakes
γ
WZ,ZZ,V
*
syst. ⊕
Stat. *: without WW modelling uncertainties
ATLAS
-1
= 13 TeV, 139 fb
s
-veto
b
|<4.5),
η
1 jet (30 GeV,|
≥
,
±
µ
±
e
> 200 GeV
lead. jet
T
p
of the plead. lep. 5.5
Selected W W candidate events *: without WW modelling uncertainties
ATLAS
-1
= 13 TeV, 139 fb
s
-veto
b
|<4.5),
η
1 jet (30 GeV,|
≥
,
±
µ
±
e
2
10
3
10
[GeV]
µ
e
m
0.8
0.9
1
1.1
1.2
Data/SM
1
−
10
1
10
2
10
Events / GeV
Data
WW
Top
Drell-Yan
Fakes
γ
WZ,ZZ,V
*
syst. ⊕
Stat. *: without WW modelling uncertainties
ATLAS
-1
= 13 TeV, 139 fb
s
-veto
b
|<4.5),
η
1 jet (30 GeV,|
≥
,
±
µ
±
e
> 200 GeV
lead. jet
T
p JHEP06(2021)003
2
10
3
10
[GeV]
lead. lep. T
p
0.8
0.9
1
1.1
1.2
Data/SM
1
−
10
1
10
2
10
3
10
4
10
Events / GeV
Data
WW
Top
Drell-Yan
Fakes
γ
WZ,ZZ,V
*
syst. ⊕
Stat. *: without WW modelling uncertainties
ATLAS
-1
= 13 TeV, 139 fb
s
-veto
b
|<4.5),
η
1 jet (30 GeV,|
≥
,
±
µ
±
e
2
10
3
10
[GeV]
lead. jet
T
p
0.8
0.9
1
1.1
1.2
Data/SM
1
10
2
10
3
10
4
10
Events / GeV
Data
WW
Top
Drell-Yan
Fakes
γ
WZ,ZZ,V
*
syst. ⊕
Stat. *: without WW modelling uncertainties
ATLAS
-1
= 13 TeV, 139 fb
s
-veto
b
|<4.5),
η
1 jet (30 GeV,|
≥
,
±
µ
±
e
1
2
3
4
5
> 30 GeV)
T
p
Number of jets (
0.8
0.9
1
1.1
1.2
Data/SM
0
10
20
30
40
50
60
3
10
×
Events
Data
WW
Top
Drell-Yan
Fakes
γ
WZ,ZZ,V
*
syst. ⊕
Stat. *: without WW modelling uncertainties
ATLAS
-1
= 13 TeV, 139 fb
s
-veto
b
|<4.5),
η
1 jet (30 GeV,|
≥
,
±
µ
±
e
2
10
3
10
[GeV]
µ
T,e
m
0.8
0.9
1
1.1
1.2
Data/SM
1
10
2
10
3
10
Events / GeV
Data
WW
Top
Drell-Yan
Fakes
γ
WZ,ZZ,V
*
syst. ⊕
Stat. *: without WW modelling uncertainties
ATLAS
-1
= 13 TeV, 139 fb
s
-veto
b
|<4.5),
η
1 jet (30 GeV,|
≥
,
±
µ
±
e
0
0.5
1
1.5
2
2.5
3
)|
µ
(e,
φ
∆|
0.8
0.9
1
1.1
1.2
Data/SM
0
1000
2000
3000
4000
5000
Events
Data
WW
Top
Drell-Yan
Fakes
γ
WZ,ZZ,V
*
syst. ⊕
Stat. 5.5
Selected W W candidate events *: without WW modelling uncertainties
ATLAS
-1
= 13 TeV, 139 fb
s
-veto
b
|<4.5),
η
1 jet (30 GeV,|
≥
,
±
µ
±
e 2
10
3
10
[GeV]
lead. lep. T
p
0.8
0.9
1
1.1
1.2
Data/SM
1
−
10
1
10
2
10
3
10
4
10
Events / GeV
Data
WW
Top
Drell-Yan
Fakes
γ
WZ,ZZ,V
*
syst. ⊕
Stat. *: without WW modelling uncertainties
ATLAS
-1
= 13 TeV, 139 fb
s
-veto
b
|<4.5),
η
1 jet (30 GeV,|
≥
,
±
µ
±
e
1
2
3
4
5
> 30 GeV)
T
p
Number of jets (
0.8
0.9
1
1.1
1.2
Data/SM
0
10
20
30
40
50
60
3
10
×
Events
Data
WW
Top
Drell-Yan
Fakes
γ
WZ,ZZ,V
*
syst. ⊕
Stat. *: without WW modelling uncertainties
ATLAS
-1
= 13 TeV, 139 fb
s
-veto
b
|<4.5),
η
1 jet (30 GeV,|
≥
,
±
µ
±
e
0
0.5
1
1.5
2
2.5
3
)|
µ
(e,
φ
∆|
0.8
0.9
1
1.1
1.2
Data/SM
0
1000
2000
3000
4000
5000
Events
Data
WW
Top
Drell-Yan
Fakes
γ
WZ,ZZ,V
*
syst. ⊕
Stat. *: without WW modelling uncertainties
ATLAS
-1
= 13 TeV, 139 fb
s
-veto
b
|<4.5),
η
1 jet (30 GeV,|
≥
,
±
µ
±
e
> 200 GeV
lead. jet
T
p 2
10
3
10
[GeV]
lead. lep. T
p
0.8
0.9
1
1.1
1.2
Data/SM
1
−
10
1
10
2
10
3
10
4
10
Events / GeV
Data
WW
Top
Drell-Yan
Fakes
γ
WZ,ZZ,V
*
syst. ⊕
Stat. *: without WW modelling uncertainties
ATLAS
-1
= 13 TeV, 139 fb
s
-veto
b
|<4.5),
η
1 jet (30 GeV,|
≥
,
±
µ
±
e
1
2
3
4
5
> 30 GeV)
T
p
Number of jets (
0.8
0.9
1
1.1
1.2
Data/SM
0
10
20
30
40
50
60
3
10
×
Events
Data
WW
Top
Drell-Yan
Fakes
γ
WZ,ZZ,V
*
syst. ⊕
Stat. *: without WW modelling uncertainties
ATLAS
-1
= 13 TeV, 139 fb
s
-veto
b
|<4.5),
η
1 jet (30 GeV,|
≥
,
±
µ
±
e 2
10
3
10
[GeV]
lead. 5.5
Selected W W candidate events T
p
0.8
0.9
1
1.1
1.2
Data/SM
30
40
60
80
2
10
×
3
0
20
40
60
80
100
120
140
160
180
Events / GeV
Data
Top
WW
Fakes
γ
WZ,ZZ,V
Drell-Yan
*
syst. ⊕
Stat. *: without WW modelling uncertainties
ATLAS
-1
= 13 TeV, 139 fb
s
Top enriched JHEP06(2021)003 Data/SM Data/SM µ
2
10
[GeV]
T
p
Electron candidate
0.8
0.9
1
1.1
1.2
Data/SM
30
40
60
80
2
10
×
3
0
10
20
30
40
50
60
Events / GeV
Data
γ
V
W+jets
Drell-Yan
Top
WW
syst. ⊕
Stat. ATLAS
-1
= 13 TeV, 139 fb
s
VR
γ
V Events / GeV Data/SM Figure 2. Detector-level distributions of the plead. lep. T
(top left) and the jet multiplicity (top
right) in the top-enriched region, the psub-lead. lep. T
in the same-sign validation region (VR) (middle
left), the meµ in the Drell-Yan VR (middle right), the Emiss
T
in the V Z VR (bottom left), and the
electron candidate pT in the V γ VR with opposite-sign leptons (bottom right). The last bin contains
overflow events. Data are shown as black markers, together with the predictions for the signal and
background production processes. The top background in the top-enriched region is estimated using
the data-driven method explained in the text; in all other regions the nominal MC prediction is
used. The lower panels show the ratio of the data to the total prediction. The uncertainty bands
shown include statistical and systematic uncertainties, excluding theory uncertainties on the signal. – 13 – JHEP06(2021)003
2
10
3
10
[GeV]
lead. jet
T
p
0.8
0.9
1
1.1
1.2
Data/SM
1
10
2
10
3
10
4
10
Events / GeV
Data
WW
Top
Drell-Yan
Fakes
γ
WZ,ZZ,V
*
syst. ⊕
Stat. *: without WW modelling uncertainties
ATLAS
-1
= 13 TeV, 139 fb
s
-veto
b
|<4.5),
η
1 jet (30 GeV,|
≥
,
±
µ
±
e
2
10
3
10
[GeV]
µ
T,e
m
0.8
0.9
1
1.1
1.2
Data/SM
1
10
2
10
3
10
Events / GeV
Data
WW
Top
Drell-Yan
Fakes
γ
WZ,ZZ,V
*
syst. ⊕
Stat. 5.5
Selected W W candidate events T
(top left), the plead. jet
T
(top
ddle right), and, for events with plead. jet
T
>
m right). Data are shown as black markers
ground production processes. The last bin
ratio of the data to the total prediction. systematic uncertainties, excluding theory 2
10
3
10
[GeV]
lead. lep. T
p
0.8
0.9
1
1.1
1.2
Data/SM
1
−
10
1
10
2
10
3
10
4
10
Events / GeV
Data
WW
Top
Drell-Yan
Fakes
γ
WZ,ZZ,V
*
syst. ⊕
Stat. *: without WW modelling uncertainties
ATLAS
-1
= 13 TeV, 139 fb
s
-veto
b
|<4.5),
η
1 jet (30 GeV,|
≥
,
±
µ
±
e
1
2
3
4
5
> 30 GeV)
T
p
Number of jets (
0.8
0.9
1
1.1
1.2
Data/SM
0
10
20
30
40
50
60
3
10
×
Events
Data
WW
Top
Drell-Yan
Fakes
γ
WZ,ZZ,V
*
syst. ⊕
Stat. *: without WW modelling uncertainties
ATLAS
-1
= 13 TeV, 139 fb
s
-veto
b
|<4.5),
η
1 jet (30 GeV,|
≥
,
±
µ
±
e
0
0.5
1
1.5
2
2.5
3
)|
µ
(e,
φ
∆|
0.8
0.9
1
1.1
1.2
Data/SM
0
1000
2000
3000
4000
5000
Events
Data
WW
Top
Drell-Yan
Fakes
γ
WZ,ZZ,V
*
syst. ⊕
Stat. *: without WW modelling uncertainties
ATLAS
-1
= 13 TeV, 139 fb
s
-veto
b
|<4.5),
η
1 jet (30 GeV,|
≥
,
±
µ
±
e
> 200 GeV
lead. jet
T
p
Figure 3. Signal region detector-level d
right), the jet multiplicity (middle left), t
200 GeV, the ∆φ(e, µ) (bottom left) and
together with the predictions for the sign
contains overflow events. The lower pan
The uncertainty bands shown include st
uncertainties on the signal. 2
10
3
10
[GeV]
lead. jet
T
p
0.8
0.9
1
1.1
1.2
Data/SM
1
10
2
10
3
10
4
10
Events / GeV
Data
WW
Top
Drell-Yan
Fakes
γ
WZ,ZZ,V
*
syst. ⊕
Stat. *: without WW modelling uncertainties
ATLAS
-1
= 13 TeV, 139 fb
s
-veto
b
|<4.5),
η
1 jet (30 GeV,|
≥
,
±
µ
±
e
2
10
3
10
[GeV]
µ
T e
m
0.8
0.9
1
1.1
1.2
Data/SM
1
10
2
10
3
10
Events / GeV
Data
WW
Top
Drell-Yan
Fakes
γ
WZ,ZZ,V
*
syst. ⊕
Stat. 5.5
Selected W W candidate events The individual uncertainties are correlated, and do not add up in quadrature to the
total uncertainty. Table 4. Selected WW candidate events, together with the signal prediction and the background
estimates. The uncertainties include statistical and systematic contributions, excluding theory
uncertainties on the signal. The fractions in percent give the relative contribution to the total SM
prediction. The individual uncertainties are correlated, and do not add up in quadrature to the
total uncertainty. 5.5
Selected W W candidate events Data are shown as black markers
together with the predictions for the signal and background production processes. The last bin
contains overflow events. The lower panels show the ratio of the data to the total prediction. The uncertainty bands shown include statistical and systematic uncertainties, excluding theory
uncertainties on the signal. – 14 – Region
Observed
Predicted ± Error
Purity
t¯t CR 1b
260 971
268 000 ± 19 000
87%
t¯t CR 2b
257 777
267 000 ± 21 000
96%
Top enriched
7167
7000 ±
1000
72%
Same-sign VR
5095
5000 ±
600
25%
Drell-Yan VR
11 824
13 000 ±
1600
74%
V Z VR
14 770
14 000 ±
1900
94%
V γ VR (OS)
2720
2670 ±
240
63%
V γ VR (SS)
2401
2250 ±
240
76% JHEP06(2021)003 Table 3. Summary of the observed and predicted events in the background control regions (CR)
and validation regions (VR), and in the top-background enriched selection. The uncertainty in the
prediction includes statistical and systematic effects, excluding theory uncertainties on the signal. The purity column gives the purity of the target process, relative to the total prediction. The t¯t
prediction in the two t¯t control regions is from simulation, while in the top-enriched region the
data-driven estimate is used. Signal region
plead. jet
T
> 200 GeV
Data
89 239
5825
Total SM
91 600 ± 2500
5980 ± 150
WW
28 100 ± 1200
31%
2480 ± 60
42%
Total bkg. 63 500 ± 1800
69%
3500 ± 140
58%
Top
55 800 ± 1500
61%
3030 ± 110
51%
Drell-Yan
2200 ± 700
2%
66 ±
9
1%
Fake leptons
2700 ± 1100
3%
140 ± 70
2%
WZ, ZZ, V γ
2800 ± 500
3%
270 ± 70
4% Table 4. Selected WW candidate events, together with the signal prediction and the background
estimates. The uncertainties include statistical and systematic contributions, excluding theory
uncertainties on the signal. The fractions in percent give the relative contribution to the total SM
prediction. The individual uncertainties are correlated, and do not add up in quadrature to the
total uncertainty. Table 4. Selected WW candidate events, together with the signal prediction and the background
estimates. The uncertainties include statistical and systematic contributions, excluding theory
uncertainties on the signal. The fractions in percent give the relative contribution to the total SM
prediction. 6
Fiducial and differential cross-section determination The WW+jets cross-section is evaluated in the fiducial phase space of the WW →e±νµ∓ν
decay channel as defined in table 5. In simulated events, electrons and muons are required
to originate directly from the hard interaction and not from τ-lepton or hadron decays. The
momenta of photons emitted in a cone of size ∆R = 0.1 around the lepton direction that
do not originate from hadron decays are added to the lepton momentum to form ‘dressed’ – 15 – leptons. Stable final-state particles,5 excluding prompt leptons and the associated photons,
are clustered into particle-level jets using the anti-kt algorithm with radius parameter R
= 0.4. The missing transverse momentum is defined at particle level as the transverse
component of the vectorial sum of the neutrino momenta. The nominal definition of the
particle-level fiducial phase space does not include a veto on b-jets. Alternative results that
include a veto on particle-level b-jets6 with pT > 20 GeV are provided in HEPData.7 The fiducial cross-section is obtained as follows: The fiducial cross-section is obtained as follows: σfid = Nobs −Nbkg
C × L
, JHEP06(2021)003 where L is the integrated luminosity, Nobs is the observed number of events, Nbkg is the es-
timated number of background events and C accounts for detector inefficiencies, resolution
effects, and contributions from τ-lepton decays. C is calculated as the number of simulated
signal events passing the reconstruction-level event selection divided by the events in the
fiducial phase space. Its numerical value is C = 0.747 ± 0.061 and its uncertainty is dom-
inated by uncertainties in jet energy scale, jet energy resolution, and pile-up modelling. The fraction of WW events passing the event selection but containing at least one lepton
from τ-lepton decays is 9%. The differential cross-sections are determined using an iterative Bayesian unfolding
method [93, 94]. The unfolding procedure corrects for migrations between bins in the
distributions during the reconstruction of the events, and applies fiducial as well as recon-
struction efficiency corrections. The fiducial corrections take into account events that are
reconstructed in the signal region, but originate from outside the fiducial region; the recon-
struction efficiency corrects for events inside the fiducial region that are not reconstructed
in the signal region due to detector inefficiencies. Tests with MC simulation demonstrate
that the method is successful in retrieving the true distribution in the fiducial region from
the reconstructed distribution in the signal region. 6
Fiducial and differential cross-section determination To reduce bias due to the assumed true
distribution, the method can be applied iteratively, at the cost of an increased statistical
uncertainty. Two iterations are used to unfold the HT, ST, and plead. jet
T
distributions and
the exclusive jet multiplicity, which are subject to large modelling uncertainties. For the
remaining distributions, either the result is independent of the number of iterations, or the
modelling uncertainty is not reduced and the statistical uncertainties increase. For these
cases, only one unfolding iteration is performed. 6At particle level, b-jets are defined by ghost-association [92], wherein b-hadrons are included in the jet
clustering as infinitely soft particles (ghosts). Jets with b-hadron ghosts among their constituents are b-jets.
7https://www.hepdata.net/record/100511. 5Particles are considered stable if their decay length cτ is greater than 1 cm.
6 7https://www.hepdata.net/record/100511. 7
Uncertainties Systematic uncertainties in the WW+jets cross-section measurements arise from experi-
mental sources, the background determination, the procedures used to correct for detector
effects, and theoretical uncertainties in the signal modelling. 6At particle level, b-jets are defined by ghost-association [92], wherein b-hadrons are included in the jet
clustering as infinitely soft particles (ghosts). Jets with b-hadron ghosts among their constituents are b-jets. 7https://www.hepdata.net/record/100511. – 16 – Fiducial selection requirements
pℓ
T
>
27 GeV
|ηℓ|
<
2.5
meµ
>
85 GeV
pj
T
>
30 GeV
|yj|
<
4.5
Table 5. Definition of the WW →eµ+jets fiducial phase space, where pℓ
T (ηℓ) refers to the
transverse momentum (pseudorapidity) of charged leptons and pj
T (yj) to the transverse momentum
(rapidity) of jets. Fiducial selection requirements
pℓ
T
>
27 GeV
|ηℓ|
<
2.5
meµ
>
85 GeV
pj
T
>
30 GeV
|yj|
<
4.5
Table 5. Definition of the WW →eµ+jets fiducial phase space, where pℓ
T (ηℓ) refers to the
transverse momentum (pseudorapidity) of charged leptons and pj
T (yj) to the transverse momentum
(rapidity) of jets. Table 5. Definition of the WW →eµ+jets fiducial phase space, where pℓ
T (ηℓ) refers to the
transverse momentum (pseudorapidity) of charged leptons and pj
T (yj) to the transverse momentum
(rapidity) of jets. Table 5. Definition of the WW →eµ+jets fiducial phase space, where pℓ
T (ηℓ) refers to the
transverse momentum (pseudorapidity) of charged leptons and pj
T (yj) to the transverse momentum
(rapidity) of jets. JHEP06(2021)003 The dominant experimental systematic uncertainties arise in the calibration of the
jet energy scale and resolution and the calibration of the b-tagging efficiency and mis-tag
rates. Experimental uncertainties also encompass uncertainties in the calibration of lepton
trigger, reconstruction, identification and isolation efficiencies, the calibration of the lepton
momentum or energy scale and resolution, and the modelling of pile-up. All experimental
uncertainties are evaluated by varying the respective calibrations, and propagating their
effects through the analysis, affecting both the background estimates and the unfolding of
detector effects. Systematic uncertainties in the estimate of fake leptons are derived by changing the
selection used to estimate the weights, in order to change the composition of the sources
of fake leptons. Additionally, the subtraction of the prompt-lepton sources in the control
region is varied, and the statistical uncertainties of the weights are propagated. 7
Uncertainties “Other Systemat-
ics” includes modelling and total cross-section uncertainties in the remaining backgrounds, lepton-
related uncertainties as well as uncertainties due to pile-up reweighting and the signal modelling in
the unfolding, while “Statistical Uncertainty” is the combined statistical uncertainty in the signal
region, from control regions, and from MC simulations. Relative Uncertainty [%] 2
10
[GeV]
lead. lep. T
p
0
5
10
15
20
25
30
35
Relative Uncertainty [%]
Total Uncertainty
Jet Calibration
Top Modelling
Fake Lepton Backgr. Other Systematics
Statistical Uncertainty
ATLAS
-1
= 13 TeV, 139 fb
s
j
ν
±
µ
ν
±
e
→
pp 2
10
[GeV]
lead. jet
T
p
0
5
10
15
20
25
30
35
Relative Uncertainty [%]
Total Uncertainty
Jet Calibration
Top Modelling
Fake Lepton Backgr. Other Systematics
Statistical Uncertainty
ATLAS
-1
= 13 TeV, 139 fb
s
j
ν
±
µ
ν
±
e
→
pp JHEP06(2021)003 Figure 4. Relative size of uncertainties for the unfolded plead. lep. T
and plead. jet
T
distributions. “Jet
Calibration” uncertainties encompass jet energy scale and resolution uncertainties while “Top Mod-
elling” encompasses all t¯t and single-top modelling uncertainties. “Fake Lepton Backgr.” is the
uncertainty in the non-prompt-lepton estimate from the fake-factor method. “Other Systemat-
ics” includes modelling and total cross-section uncertainties in the remaining backgrounds, lepton-
related uncertainties as well as uncertainties due to pile-up reweighting and the signal modelling in
the unfolding, while “Statistical Uncertainty” is the combined statistical uncertainty in the signal
region, from control regions, and from MC simulations. Uncertainties in the unfolding procedure due to the theoretical modelling of the signal
are evaluated by repeating the unfolding procedure with alternative signal simulations. The uncertainty due to missing higher-order QCD corrections is evaluated by varying the
renormalization and factorization scales. The uncertainty due to the choice of generator
for the hard interaction, the parton shower model and the underlying-event modelling
is estimated using the alternative simulation of q¯q →WW production, from Powheg-
Box v2, interfaced to Pythia 8.186. For the uncertainty estimation, the alternative model
is first reweighted to the nominal model, so that uncertainties due to disagreement in the
predicted shape of distributions can be ignored, and only the difference in the prediction
of the migration matrix and fiducial and efficiency corrections are taken into account. 7
Uncertainties More
details on the uncertainties affecting the fake-lepton estimate can be found in section 5. The estimate of the top background is affected by the statistical uncertainty of the
number of events in the control region, and by uncertainties in the modelling of t¯t and
single-top Wt events, such as the uncertainty in the matrix element calculation, the parton
shower modelling, the QCD scale choices, the initial- and final-state radiation and the inter-
ference between t¯t and single-top Wt events. These are evaluated by using the alternative
simulations described in section 3 and propagating the results through the top background
estimate. The effect of the PDF uncertainty on the top background was evaluated, but
found to be negligible. The uncertainty in minor backgrounds is estimated by varying their total cross-section
within its uncertainty and by using alternative simulations, as described in section 5. The
difference between nominal and alternative simulations covers PDF uncertainties, missing
higher-order QCD corrections, and the parton shower model. The bias introduced by using distributions generated by the nominal signal simulation
as a prior in the unfolding is estimated by reweighting these distributions at generator level
with a smooth function such that, after including simulated detector effects, they closely
resemble the background-subtracted data. This reweighted detector-level prediction is
unfolded using the nominal unfolding set-up. The unfolding procedure is able to very
accurately recover the generator-level distribution, so this uncertainty source is negligible. – 17 – 2
10
[GeV]
lead. lep. T
p
0
5
10
15
20
25
30
35
Relative Uncertainty [%]
Total Uncertainty
Jet Calibration
Top Modelling
Fake Lepton Backgr. Other Systematics
Statistical Uncertainty
ATLAS
-1
= 13 TeV, 139 fb
s
j
ν
±
µ
ν
±
e
→
pp
2
10
[GeV]
lead. jet
T
p
0
5
10
15
20
25
30
35
Relative Uncertainty [%]
Total Uncertainty
Jet Calibration
Top Modelling
Fake Lepton Backgr. Other Systematics
Statistical Uncertainty
ATLAS
-1
= 13 TeV, 139 fb
s
j
ν
±
µ
ν
±
e
→
pp
Figure 4. Relative size of uncertainties for the unfolded plead. lep. T
and plead. jet
T
distributions. “Jet
Calibration” uncertainties encompass jet energy scale and resolution uncertainties while “Top Mod-
elling” encompasses all t¯t and single-top modelling uncertainties. “Fake Lepton Backgr.” is the
uncertainty in the non-prompt-lepton estimate from the fake-factor method. 8
Results The measured fiducial cross-section for WW+jets production, with WW →e±νµ∓ν, at
√s = 13 TeV, for the phase space defined in table 5 is The measured fiducial cross-section for WW+jets production, with WW →e±νµ∓ν, at
√s = 13 TeV, for the phase space defined in table 5 is σfid = 258 ± 4 (stat.) ± 25 (syst.) fb, with a total uncertainty of 10%. In figure 5, the measured result is compared with various
predictions for WW+jets production, and good agreement is found. Differential fiducial
cross-sections are presented in figures 6 to 8. Figure 9 displays distributions in a phase
space that additionally requires a jet with a transverse momentum of at least 200 GeV. with a total uncertainty of 10%. In figure 5, the measured result is compared with various
predictions for WW+jets production, and good agreement is found. Differential fiducial
cross-sections are presented in figures 6 to 8. Figure 9 displays distributions in a phase
space that additionally requires a jet with a transverse momentum of at least 200 GeV. 7
Uncertainties Statistical uncertainties are evaluated by creating pseudo data samples that are obtained
by varying the data within their Poisson uncertainties in each bin and then propagating
these varied samples through the unfolding. The statistical uncertainties of the background
estimates, which include statistical uncertainties in MC predictions and due to the control
regions used in estimating the top and fake-lepton backgrounds, are evaluated using the
same method. If not stated otherwise, ‘statistical uncertainties’ refers to the combined
statistical uncertainties from signal and control regions. Table 6 gives a breakdown of the uncertainties in the fiducial cross-section measure-
ments, and figure 4 displays the uncertainties as a function of the unfolded plead. lep. T
and
plead. jet
T
distributions. Jet-related uncertainties generally decrease with plead. jet
T
and with
correlated quantities such as plead. lep. T
, while statistical uncertainties increase at high en-
ergy. This leads to a minimum of the total uncertainty for intermediate values of plead. jet
T
and plead. lep. T
. – 18 – Uncertainty source
Relative effect
Total uncertainty
10%
Signal region statistical uncertainty
1.1%
Data-driven background and MC statistics
1.2%
Jet calibration
6.3%
Top modelling
4.5%
Fake-lepton background
4.3%
Signal modelling
2.7%
Other background
2.3%
Flavour tagging
2.3%
Luminosity
1.9%
Other systematic uncertainties
0.6% JHEP06(2021)003 Table 6. Breakdown of the uncertainties in the measured fiducial cross-section. “Jet calibration”
uncertainties encompass jet energy scale and resolution uncertainties, “Top modelling” and “Signal
modelling” are uncertainties in the theoretical modelling of the respective processes, “Fake-lepton
background” is the uncertainty in the fake-lepton estimate while “Other background” is the uncer-
tainty due to minor prompt-lepton backgrounds, “Flavour tagging” is all uncertainties in flavour
tagging efficiency and mis-tag rate, and “Luminosity” is the uncertainty in the measurement of
the integrated luminosity. All systematic uncertainties belonging to none of the above categories
are included in “Other systematic uncertainties”. Statistical uncertainties arise in both the signal
region and control region used for the data-driven top and fake-lepton estimates and also from
backgrounds that are estimated using MC simulations. 8.1
Comparison with theoretical predictions 100
150
200
250
300
Integrated fiducial cross-section [fb]
Data
25 (syst) fb
±
4 (stat)
±
258
MATRIX 2.0 nNNLO
18 (scale) fb
±
2 (PDF)
±
279
NLO EW
⊗
MATRIX 2.0 nNNLO
18 (scale) fb
±
2 (PDF)
±
278
Sherpa 2.2.2 (0-1j@NLO, 2-3j@LO)*
44 (scale) fb
±
3 (PDF)
±
277
MG5_aMC + Pythia8 FxFx (0-1j@NLO)*
16 (scale) fb
±
3 (PDF)
±
263
Powheg MiNLO + Pythia8 (0-1j@NLO)*
21 (scale) fb
±
3 (PDF)
±
254
WW
→
* + Sherpa & OpenLoops gg
ATLAS
-1
= 13 TeV, 139 fb
s
j
ν
±
µ
ν
±
e
→
pp
Data
Stat. Unc. Tot. Unc. Predictions JHEP06(2021)003 Figure 5. Comparison of the measured fiducial WW+jets cross-section with various theoretical
predictions. Theoretical predictions are indicated as points with inner (outer) error bars denoting
PDF (PDF+scale) uncertainties. The central value of the measured cross-section is indicated by a
vertical line with the narrow band showing the statistical uncertainty and the wider band the total
uncertainty including statistical and systematic uncertainties. The result is compared with a fixed-
order parton-level prediction from MATRIX 2.0 that is accurate to NNLO (NLO) for q¯q →WW
(gg →WW) production, and a prediction that additionally accounts for EW corrections to WW +
jet production, which have been calculated with Sherpa 2.2.2 + OpenLoops. It is also compared
with predictions from Sherpa 2.2.2, MadGraph5_aMC@NLO + Pythia 8 with FxFx merging,
and Powheg MiNLO + Pythia 8, which are all supplemented by a Sherpa 2.2.2 + OpenLoops
gg →WW LO+PS prediction. also compared with a prediction that combines the QCD corrections from MATRIX with
NLO EW corrections to WW+jets production that were generated with Sherpa 2.2.2 +
OpenLoops [25, 100–102]. Photon-induced contributions are included as an additive cor-
rection, while the EW correction to q¯q →WW is taken into account multiplicatively. The
latter correction decreases the cross-section by 4%, while the former leads to an increase of
4%. The importance of both corrections increases with energy. The difference between an
additive and multiplicative combination scheme for QCD and EW corrections is typically
of the order 1% but can be as large as 10% in the highest HT and ST bins. 8.1
Comparison with theoretical predictions The measurement is compared to the theory predictions listed in table 7. The measured
fiducial cross-section is compatible with the prediction of 279 ± 2 (pdf) +20
−16 (scale) fb
from MATRIX [32, 33, 43, 73, 95–99], which is accurate to NNLO (NLO) for q¯q →
WW (gg →WW) production, denoted nNNLO, but only NLO (LO) accurate for
q¯q →WW (gg →WW) production in association with a jet. For this prediction, the
NNPDF3.1NNLO parton distribution function is used, while renormalization and factor-
ization scales are set to mW . In figure 5, the measured integrated fiducial cross-section is – 19 – 100
150
200
250
300
Integrated fiducial cross-section [fb]
Data
25 (syst) fb
±
4 (stat)
±
258
MATRIX 2.0 nNNLO
18 (scale) fb
±
2 (PDF)
±
279
NLO EW
⊗
MATRIX 2.0 nNNLO
18 (scale) fb
±
2 (PDF)
±
278
Sherpa 2.2.2 (0-1j@NLO, 2-3j@LO)*
44 (scale) fb
±
3 (PDF)
±
277
MG5_aMC + Pythia8 FxFx (0-1j@NLO)*
16 (scale) fb
±
3 (PDF)
±
263
Powheg MiNLO + Pythia8 (0-1j@NLO)*
21 (scale) fb
±
3 (PDF)
±
254
WW
→
* + Sherpa & OpenLoops gg
ATLAS
-1
= 13 TeV, 139 fb
s
j
ν
±
µ
ν
±
e
→
pp
Data
Stat. Unc. Tot. Unc. Predictions
Figure 5. Comparison of the measured fiducial WW+jets cross-section with various theoretical
predictions. Theoretical predictions are indicated as points with inner (outer) error bars denoting
PDF (PDF+scale) uncertainties. The central value of the measured cross-section is indicated by a
vertical line with the narrow band showing the statistical uncertainty and the wider band the total
uncertainty including statistical and systematic uncertainties. The result is compared with a fixed-
order parton-level prediction from MATRIX 2.0 that is accurate to NNLO (NLO) for q¯q →WW
(gg →WW) production, and a prediction that additionally accounts for EW corrections to WW +
jet production, which have been calculated with Sherpa 2.2.2 + OpenLoops. It is also compared
with predictions from Sherpa 2.2.2, MadGraph5_aMC@NLO + Pythia 8 with FxFx merging,
and Powheg MiNLO + Pythia 8, which are all supplemented by a Sherpa 2.2.2 + OpenLoops
gg →WW LO+PS prediction. 8.1
Comparison with theoretical predictions Also displayed in figure 5 are the nominal q¯q →WW Sherpa 2.2.2 prediction, a pre-
diction from MadGraph 2.3.3 using FxFx merging [103] and interfaced to Pythia 8.212,
and a Powheg MiNLO [104] prediction interfaced to Pythia 8.244. All three calculations
are NLO-accurate for WW production with one jet and use the NNPDF3.0 PDF set. The
effects of scale uncertainties for all predictions are estimated by varying the factorization
and renormalization scales of the hard process. The effects of scale uncertainties on the
Sherpa 2.2.2 prediction are large in comparison with the other generators as this calcula-
tion includes leading-order matrix elements with up to three jets, which are strongly affected – 20 – Process
Generator
Parton shower
PDF
Matrix element O(αS)
q¯q →WW
MATRIX 2.0
—
NNPDF3.1
NNLO
gg →WW
MATRIX 2.0
—
NNPDF3.1
NLO
q¯q →WW
Sherpa 2.2.2
Sherpa
NNPDF3.0
NLO (0–1 jet), LO (2–3 jets)
q¯q →WW
Powheg MiNLO
Pythia 8
NNPDF3.0
NLO (0–1 jet)
q¯q →WW
MadGraph 2.3.3
Pythia 8
NNPDF3.0
NLO (0–1 jet)
gg →WW
Sherpa 2.2.2 + OpenLoops
Sherpa
NNPDF3.0
LO (0–1 jet)
Table 7. Summary of the theoretical predictions that are compared with the measured cross-
sections. The samples generated with Sherpa use the default parton-shower tune, while for those
using Pythia 8 the A14 tune and the NNPDF2.3LO PDF set are used for the parton shower. Table 7. Summary of the theoretical predictions that are compared with the measured cross-
sections. The samples generated with Sherpa use the default parton-shower tune, while for those
using Pythia 8 the A14 tune and the NNPDF2.3LO PDF set are used for the parton shower. JHEP06(2021)003 by scale variations. Both predictions are supplemented by the Sherpa 2.2.2 + OpenLoops
simulation of gg →WW, which is normalized to the total NLO QCD cross-section [99]. The measured distributions in figures 6–9 are also compared with the predictions de-
scribed above. Within uncertainties, all predictions give an excellent description of the
observed data. For the nominal Sherpa 2.2.2 prediction, values of χ2 divided by the
number of degrees of freedom are below one, except for the meµ distribution measured for
plead. jet
T
> 200 GeV, for which the value is 1.4. Comparisons of the remaining predictions
with the data yield similar χ2 values, except for the jet multiplicity, HT, and ST distribu-
tions, where, for the highest multiplicities and energies, small discrepancies exist between
data and predictions. 8.2
Effective field theory interpretation Many new-physics models that introduce new states at a high energy scale (Λ) can be
described, at lower energy scales, by operators with mass dimensions larger than four in
an effective field theory (EFT) framework. The higher-dimensional operators of the lowest
order that can generate anomalous triple-gauge-boson couplings (aTGC) are of dimension
six. The QW dimension-six operator, as defined in ref. [14], is of particular interest for an
analysis of diboson production because it can only be measured in processes affected by
modifications of the gauge-boson self-couplings. Its effect increases rapidly with the centre-
of-mass energy, making a measurement at the energies probed by the LHC important. However, the interference of the SM and anomalous amplitudes, and, thus, the observable
consequences of the operator, decrease with increasing energy due to the different helicities
of the dominant contributions to the two amplitudes [105, 106]. As a consequence, the
square of the anomalous dimension-six amplitude, which is quadratic in the ratio of the
Wilson coefficient, cW , to Λ2, dominates, while, in general, the interference of dimension-
six operators with the SM is expected to be larger, as it is linear in cW /Λ2 and, thus,
less suppressed by Λ. The interference-suppression weakens the limits on cW that can be
achieved by a measurement of diboson production and also poses a problem for the validity
of an interpretation in a dimension-six model, since other terms of order Λ−4, for example
those due to dimension-eight operators, are neglected. Requiring a hard jet in addition
to the diboson pair alters the relative contributions of different helicity configurations and
reduces the suppression of the interference of SM and anomalous amplitudes [13]. – 21 – 2
−
10
1
−
10
1
10
2
10
[fb/GeV]
lead. lep. T
p
/d
σ
d
1
10
2
10
3
10
4
10
[fb]
σ
∆
Data and Stat. Uncertainty
Total Uncertainty
Sherpa 2.2.2 *
MG5_aMC+Pythia8 FxFx *
MiNLO+Pythia8 *
NLO EW
⊗
MATRIX nNNLO
WW
→
* plus Sherpa+OL gg
ATLAS
-1
= 13 TeV, 139 fb
s
j
ν
±
µ
ν
±
e
→
pp
[GeV]
lead. lep. T
p
0.6
0.8
1
1.2
1.4
Prediction/Data
30
40 50 60
2
10
2
10
×
2
2
10
×
3
2
10
×
4.5
≥
2
−
10
1
−
10
1
10
2
10
[fb/GeV]
sub-lead. lep. 8.2
Effective field theory interpretation T
p
/d
σ
d
1
10
2
10
3
10
4
10
[fb]
σ
∆
Data and Stat. Uncertainty
Total Uncertainty
Sherpa 2.2.2 *
MG5_aMC+Pythia8 FxFx *
MiNLO+Pythia8 *
NLO EW
⊗
MATRIX nNNLO
WW
→
* plus Sherpa+OL gg
ATLAS
-1
= 13 TeV, 139 fb
s
j
ν
±
µ
ν
±
e
→
pp
[GeV]
sub-lead. lep. T
p
0.6
0.8
1
1.2
1.4
Prediction/Data
30
40
50
60 70 80
2
10
2
10
×
2
≥
1
−
10
1
10
[fb/GeV]
lead. jet
T
p
/d
σ
d
10
2
10
3
10
[fb]
σ
∆
Data and Stat. Uncertainty
Total Uncertainty
Sherpa 2.2.2 *
MG5_aMC+Pythia8 FxFx *
MiNLO+Pythia8 *
NLO EW
⊗
MATRIX nNNLO
WW
→
* plus Sherpa+OL gg
ATLAS
-1
= 13 TeV, 139 fb
s
j
ν
±
µ
ν
±
e
→
pp
[GeV]
lead. jet
T
p
0.6
0.8
1
1.2
1.4
Prediction/Data
40
50 60
2
10
2
10
×
2
2
10
×
3
2
10
×
4.5
≥
1
−
10
1
10
[fb/GeV]
T
H
/d
σ
d
10
2
10
3
10
[fb]
σ
∆
Data and Stat. Uncertainty
Total Uncertainty
Sherpa 2.2.2 *
MG5_aMC+Pythia8 FxFx *
MiNLO+Pythia8 *
NLO EW
⊗
MATRIX nNNLO
WW
→
* plus Sherpa+OL gg
ATLAS
-1
= 13 TeV, 139 fb
s
j
ν
±
µ
ν
±
e
→
pp
[GeV]
T
H
0.6
0.8
1
1.2
1.4
Prediction/Data
40 50 60
2
10
2
10
×
2
2
10
×
3
2
10
×
5
≥
Figure 6. Measured fiducial cross-sections of WW+jets production for (from left to right and top
to bottom): plead. lep. T
, psub-lead. lep. T
, plead. jet
T
, and HT. The last bin of each distribution is inclusive
in the measured observable and the corresponding integrated cross-section is indicated by the right-
hand-side axis. The measured cross-section values are shown as points with error bars giving the
statistical uncertainty and solid bands indicating the size of the total uncertainty. 8.2
Effective field theory interpretation The results
are compared with the NNLO prediction with extra NLO EW corrections and NLO corrections
for gg →WW production (denoted MATRIX ⊗NLO EW) as well as NLO+PS predictions from
Sherpa 2.2.2, MadGraph5_aMC@NLO + Pythia 8 with FxFx merging, and Powheg MiNLO
+ Pythia 8 for q¯q initial states, combined with Sherpa + OpenLoops (LO+PS) for the gg
initial state. The Sherpa 2.2.2 + OpenLoops prediction is normalized to the total cross-section
calculated at NLO in QCD. Theoretical predictions are indicated as markers with vertical lines
denoting PDF and scale uncertainties. 2
−
10
1
−
10
1
10
2
10
[fb/GeV]
lead. lep. T
p
/d
σ
d
1
10
2
10
3
10
4
10
[fb]
σ
∆
Data and Stat. Uncertainty
Total Uncertainty
Sherpa 2.2.2 *
MG5_aMC+Pythia8 FxFx *
MiNLO+Pythia8 *
NLO EW
⊗
MATRIX nNNLO
WW
→
* plus Sherpa+OL gg
ATLAS
-1
= 13 TeV, 139 fb
s
j
ν
±
µ
ν
±
e
→
pp
[GeV]
lead. lep. T
p
0.6
0.8
1
1.2
1.4
Prediction/Data
30
40 50 60
2
10
2
10
×
2
2
10
×
3
2
10
×
4.5
≥
1
−
10
1
10
[fb/GeV]
lead. jet
T
p
/d
σ
d
10
2
10
3
10
[fb]
σ
∆
Data and Stat. Uncertainty
Total Uncertainty
Sherpa 2.2.2 *
MG5_aMC+Pythia8 FxFx *
MiNLO+Pythia8 *
NLO EW
⊗
MATRIX nNNLO
WW
→
* plus Sherpa+OL gg
ATLAS
-1
= 13 TeV, 139 fb
s
j
ν
±
µ
ν
±
e
→
pp
[GeV]
lead. jet
T
p
0.6
0.8
1
1.2
1.4
Prediction/Data
40
50 60
2
10
2
10
×
2
2
10
×
3
2
10
×
4.5
≥ 2
−
10
1
−
10
1
10
2
10
[fb/GeV]
sub-lead. lep. T
p
/d
σ
d
1
10
2
10
3
10
4
10
[fb]
σ
∆
Data and Stat. Uncertainty
Total Uncertainty
Sherpa 2.2.2 *
MG5_aMC+Pythia8 FxFx *
MiNLO+Pythia8 *
NLO EW
⊗
MATRIX nNNLO
WW
→
* plus Sherpa+OL gg
ATLAS
-1
= 13 TeV, 139 fb
s
j
ν
±
µ
ν
±
e
→
pp
[GeV]
sub-lead. lep. 8.2
Effective field theory interpretation T
p
0.6
0.8
1
1.2
1.4
Prediction/Data
30
40
50
60 70 80
2
10
2
10
×
2
≥
1
−
10
1
10
[fb/GeV]
T
H
/d
σ
d
10
2
10
3
10
[fb]
σ
∆
Data and Stat. Uncertainty
Total Uncertainty
Sherpa 2.2.2 *
MG5_aMC+Pythia8 FxFx *
MiNLO+Pythia8 *
NLO EW
⊗
MATRIX nNNLO
WW
→
* plus Sherpa+OL gg
ATLAS
-1
= 13 TeV, 139 fb
s
j
ν
±
µ
ν
±
e
→
pp
[GeV]
T
H
0.6
0.8
1
1.2
1.4
Prediction/Data
40 50 60
2
10
2
10
×
2
2
10
×
3
2
10
×
5
≥ JHEP06(2021)003 3
[fb]
σ
∆ Figure 6. Measured fiducial cross-sections of WW+jets production for (from left to right and top
to bottom): plead. lep. T
, psub-lead. lep. T
, plead. jet
T
, and HT. The last bin of each distribution is inclusive
in the measured observable and the corresponding integrated cross-section is indicated by the right-
hand-side axis. The measured cross-section values are shown as points with error bars giving the
statistical uncertainty and solid bands indicating the size of the total uncertainty. The results
are compared with the NNLO prediction with extra NLO EW corrections and NLO corrections
for gg →WW production (denoted MATRIX ⊗NLO EW) as well as NLO+PS predictions from
Sherpa 2.2.2, MadGraph5_aMC@NLO + Pythia 8 with FxFx merging, and Powheg MiNLO
+ Pythia 8 for q¯q initial states, combined with Sherpa + OpenLoops (LO+PS) for the gg
initial state. The Sherpa 2.2.2 + OpenLoops prediction is normalized to the total cross-section
calculated at NLO in QCD. Theoretical predictions are indicated as markers with vertical lines
denoting PDF and scale uncertainties. – 22 – 1
−
10
1
10
[fb/GeV]
T
S
/d
σ
d
10
2
10
3
10
[fb]
σ
∆
Data and Stat. Uncertainty
Total Uncertainty
Sherpa 2.2.2 *
MG5_aMC+Pythia8 FxFx *
MiNLO+Pythia8 *
NLO EW
⊗
MATRIX nNNLO
WW
→
* plus Sherpa+OL gg
ATLAS
-1
= 13 TeV, 139 fb
s
j
ν
±
µ
ν
±
e
→
pp
[GeV]
T
S
0.6
0.8
1
1.2
1.4
Prediction/Data
2
10
2
10
×
9
≥
2
10
×
2
2
10
×
3
2
−
10
1
−
10
1
10
[fb/GeV]
µ
T,e
m
/d
σ
d
1
10
2
10
3
10
[fb]
σ
∆
Data and Stat. 8.2
Effective field theory interpretation Uncertainty
Total Uncertainty
Sherpa 2.2.2 *
MG5_aMC+Pythia8 FxFx *
MiNLO+Pythia8 *
NLO EW
⊗
MATRIX nNNLO
WW
→
* plus Sherpa+OL gg
ATLAS
-1
= 13 TeV, 139 fb
s
j
ν
±
µ
ν
±
e
→
pp
[GeV]
µ
T,e
m
0.6
0.8
1
1.2
1.4
Prediction/Data
2
10
2
10
×
8
≥
2
10
×
2
2
10
×
3
1
−
10
1
10
[fb/GeV]
µ
e
m
/d
σ
d
10
2
10
3
10
[fb]
σ
∆
Data and Stat. Uncertainty
Total Uncertainty
Sherpa 2.2.2 *
MG5_aMC+Pythia8 FxFx *
MiNLO+Pythia8 *
NLO EW
⊗
MATRIX nNNLO
WW
→
* plus Sherpa+OL gg
ATLAS
-1
= 13 TeV, 139 fb
s
j
ν
±
µ
ν
±
e
→
pp
[GeV]
µ
e
m
0.6
0.8
1
1.2
1.4
Prediction/Data
90
2
10
2
10
×
2
2
10
×
3
2
10
×
4
≥
1
−
10
1
10
2
10
[fb/GeV]
µ
T,e
p
/d
σ
d
10
2
10
3
10
4
10
[fb]
σ
∆
Data and Stat. Uncertainty
Total Uncertainty
Sherpa 2.2.2 *
MG5_aMC+Pythia8 FxFx *
MiNLO+Pythia8 *
NLO EW
⊗
MATRIX nNNLO
WW
→
* plus Sherpa+OL gg
ATLAS
-1
= 13 TeV, 139 fb
s
j
ν
±
µ
ν
±
e
→
pp
[GeV]
µ
T,e
p
0.6
0.8
1
1.2
1.4
Prediction/Data
20
30
40 50 60
2
10
2
10
×
2
2
10
×
3
≥
0
Figure 7. Measured fiducial cross-sections of WW+jets production for (from left to right and
top to bottom): ST, mT,eµ, meµ, and pT,eµ. The last bin of each distribution is inclusive in the
measured observable and the corresponding integrated cross-section is indicated by the right-hand-
side axis. The measured cross-section values are shown as points with error bars giving the statistical
uncertainty and solid bands indicating the size of the total uncertainty. The results are compared
with the NNLO prediction with extra NLO EW corrections and NLO corrections for gg →WW
production (denoted MATRIX ⊗NLO EW) as well as NLO+PS predictions from Sherpa 2.2.2,
MadGraph5_aMC@NLO + Pythia 8 with FxFx merging, and Powheg MiNLO + Pythia 8
for q¯q initial states, combined with Sherpa + OpenLoops (LO+PS) for the gg initial state. The
Sherpa 2.2.2 + OpenLoops prediction is normalized to the total cross-section calculated at NLO
in QCD. 8.2
Effective field theory interpretation Theoretical predictions are indicated as markers with vertical lines denoting PDF and
scale uncertainties. 1
−
10
1
10
[fb/GeV]
T
S
/d
σ
d
10
2
10
3
10
[fb]
σ
∆
Data and Stat. Uncertainty
Total Uncertainty
Sherpa 2.2.2 *
MG5_aMC+Pythia8 FxFx *
MiNLO+Pythia8 *
NLO EW
⊗
MATRIX nNNLO
WW
→
* plus Sherpa+OL gg
ATLAS
-1
= 13 TeV, 139 fb
s
j
ν
±
µ
ν
±
e
→
pp
[GeV]
T
S
0.6
0.8
1
1.2
1.4
Prediction/Data
2
10
2
10
×
9
≥
2
10
×
2
2
10
×
3 2
−
10
1
−
10
1
10
[fb/GeV]
µ
T,e
m
/d
σ
d
1
10
2
10
3
10
[fb]
σ
∆
Data and Stat. Uncertainty
Total Uncertainty
Sherpa 2.2.2 *
MG5_aMC+Pythia8 FxFx *
MiNLO+Pythia8 *
NLO EW
⊗
MATRIX nNNLO
WW
→
* plus Sherpa+OL gg
ATLAS
-1
= 13 TeV, 139 fb
s
j
ν
±
µ
ν
±
e
→
pp
[GeV]
µ
T,e
m
0.6
0.8
1
1.2
1.4
Prediction/Data
2
10
2
10
×
8
≥
2
10
×
2
2
10
×
3
1
−
10
1
10
2
10
[fb/GeV]
µ
T,e
p
/d
σ
d
10
2
10
3
10
4
10
[fb]
σ
∆
Data and Stat. Uncertainty
Total Uncertainty
Sherpa 2.2.2 *
MG5_aMC+Pythia8 FxFx *
MiNLO+Pythia8 *
NLO EW
⊗
MATRIX nNNLO
WW
→
* plus Sherpa+OL gg
ATLAS
-1
= 13 TeV, 139 fb
s
j
ν
±
µ
ν
±
e
→
pp
[GeV]
µ
T,e
p
0.6
0.8
1
1.2
1.4
Prediction/Data
20
30
40 50 60
2
10
2
10
×
2
2
10
×
3
≥
0 1
−
10
1
10
[fb/GeV]
T
S
/d
σ
d
10
2
10
3
10
[fb]
σ
∆
Data and Stat. Uncertainty
Total Uncertainty
Sherpa 2.2.2 *
MG5_aMC+Pythia8 FxFx *
MiNLO+Pythia8 *
NLO EW
⊗
MATRIX nNNLO
WW
→
* plus Sherpa+OL gg
ATLAS
-1
= 13 TeV, 139 fb
s
j
ν
±
µ
ν
±
e
→
pp
[GeV]
T
S
0.6
0.8
1
1.2
1.4
Prediction/Data
2
10
2
10
×
9
≥
2
10
×
2
2
10
×
3
1
−
10
1
10
[fb/GeV]
µ
e
m
/d
σ
d
10
2
10
3
10
[fb]
σ
∆
Data and Stat. 8.2
Effective field theory interpretation Uncertainty
Total Uncertainty
Sherpa 2.2.2 *
MG5_aMC+Pythia8 FxFx *
MiNLO+Pythia8 *
NLO EW
⊗
MATRIX nNNLO
WW
→
* plus Sherpa+OL gg
ATLAS
-1
= 13 TeV, 139 fb
s
j
ν
±
µ
ν
±
e
→
pp
[GeV]
µ
e
m
0.6
0.8
1
1.2
1.4
Prediction/Data
90
2
10
2
10
×
2
2
10
×
3
2
10
×
4
≥ JHEP06(2021)003 Figure 7. Measured fiducial cross-sections of WW+jets production for (from left to right and
top to bottom): ST, mT,eµ, meµ, and pT,eµ. The last bin of each distribution is inclusive in the
measured observable and the corresponding integrated cross-section is indicated by the right-hand-
side axis. The measured cross-section values are shown as points with error bars giving the statistical
uncertainty and solid bands indicating the size of the total uncertainty. The results are compared
with the NNLO prediction with extra NLO EW corrections and NLO corrections for gg →WW
production (denoted MATRIX ⊗NLO EW) as well as NLO+PS predictions from Sherpa 2.2.2,
MadGraph5_aMC@NLO + Pythia 8 with FxFx merging, and Powheg MiNLO + Pythia 8
for q¯q initial states, combined with Sherpa + OpenLoops (LO+PS) for the gg initial state. The
Sherpa 2.2.2 + OpenLoops prediction is normalized to the total cross-section calculated at NLO
in QCD. Theoretical predictions are indicated as markers with vertical lines denoting PDF and
scale uncertainties. – 23 – 50
100
150
200
250
300
350
400
| [fb]
µ
e
φ
∆
/d|
σ
d
[fb]
σ
∆
Data and Stat. Uncertainty
Total Uncertainty
Sherpa 2.2.2 *
MG5_aMC+Pythia8 FxFx *
MiNLO+Pythia8 *
NLO EW
⊗
MATRIX nNNLO
WW
→
* plus Sherpa+OL gg
ATLAS
-1
= 13 TeV, 139 fb
s
j
ν
±
µ
ν
±
e
→
pp
0
0.5
1
1.5
2
2.5
3
|
µ
e
φ
∆|
0.6
0.8
1
1.2
1.4
Prediction/Data
50
100
150
200
250
300
[fb]
µ
e
y
/d
σ
d
[fb]
σ
∆
Data and Stat. 8.2
Effective field theory interpretation Uncertainty
Total Uncertainty
Sherpa 2.2.2 *
MG5_aMC+Pythia8 FxFx *
MiNLO+Pythia8 *
NLO EW
⊗
MATRIX nNNLO
WW
→
* plus Sherpa+OL gg
ATLAS
-1
= 13 TeV, 139 fb
s
j
ν
±
µ
ν
±
e
→
pp
0
0.5
1
1.5
2
2.5
3
|
µ
e
φ
∆|
0.6
0.8
1
1.2
1.4
Prediction/Data
100
200
300
400
500
600
700
*) [fb]
θ
/dcos(
σ
d
Data and Stat. Uncertainty
Total Uncertainty
Sherpa 2.2.2 *
MG5_aMC+Pythia8 FxFx *
MiNLO+Pythia8 *
NLO EW
⊗
MATRIX nNNLO
WW
→
* plus Sherpa+OL gg
ATLAS
-1
= 13 TeV, 139 fb
s
j
ν
±
µ
ν
±
e
→
pp
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
*)
θ
cos(
0.6
0.8
1
1.2
1.4
Prediction/Data 50
100
150
200
250
300
[fb]
µ
e
y
/d
σ
d
Data and Stat. Uncertainty
Total Uncertainty
Sherpa 2.2.2 *
MG5_aMC+Pythia8 FxFx *
MiNLO+Pythia8 *
NLO EW
⊗
MATRIX nNNLO
WW
→
* plus Sherpa+OL gg
ATLAS
-1
= 13 TeV, 139 fb
s
j
ν
±
µ
ν
±
e
→
pp
0
0.5
1
1.5
2
2.5
µ
e
y
0.6
0.8
1
1.2
1.4
Prediction/Data
10
2
10
3
10
[fb]
σ
Data and Stat. Uncertainty
Total Uncertainty
Sherpa 2.2.2 *
MG5_aMC+Pythia8 FxFx *
MiNLO+Pythia8 *
NLO EW
⊗
MATRIX nNNLO
WW
→
* plus Sherpa+OL gg
ATLAS
-1
= 13 TeV, 139 fb
s
j
ν
±
µ
ν
±
e
→
pp
1
2
3
4
5
≥
> 30 GeV)
T
p
Number of jets (
0.5
1
1.5
Prediction/Data JHEP06(2021)003 100
200
300
400
500
600
700
*) [fb]
θ
/dcos(
σ
d
Data and Stat. Uncertainty
Total Uncertainty
Sherpa 2.2.2 *
MG5_aMC+Pythia8 FxFx *
MiNLO+Pythia8 *
NLO EW
⊗
MATRIX nNNLO
WW
→
* plus Sherpa+OL gg
ATLAS
-1
= 13 TeV, 139 fb
s
j
ν
±
µ
ν
±
e
→
pp
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
*)
θ
cos(
0.6
0.8
1
1.2
1.4
Prediction/Data Figure 8. Measured fiducial cross-sections of WW+jets production for (from left to right and top
to bottom): ∆φ(e, µ), yeµ, cos θ∗, and the exclusive jet multiplicity. The measured cross-section val-
ues are shown as points with error bars giving the statistical uncertainty and solid bands indicating
the size of the total uncertainty. 8.2
Effective field theory interpretation Uncertainty
Total Uncertainty
Sherpa 2.2.2 *
MG5_aMC+Pythia8 FxFx *
MiNLO+Pythia8 *
NLO EW
⊗
MATRIX nNNLO
WW
→
* plus Sherpa+OL gg
ATLAS
-1
= 13 TeV, 139 fb
s
j
ν
±
µ
ν
±
e
→
pp
0
0.5
1
1.5
2
2.5
µ
e
y
0.6
0.8
1
1.2
1.4
Prediction/Data
100
200
300
400
500
600
700
*) [fb]
θ
/dcos(
σ
d
[fb]
σ
∆
Data and Stat. Uncertainty
Total Uncertainty
Sherpa 2.2.2 *
MG5_aMC+Pythia8 FxFx *
MiNLO+Pythia8 *
NLO EW
⊗
MATRIX nNNLO
WW
→
* plus Sherpa+OL gg
ATLAS
-1
= 13 TeV, 139 fb
s
j
ν
±
µ
ν
±
e
→
pp
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
*)
θ
cos(
0.6
0.8
1
1.2
1.4
Prediction/Data
10
2
10
3
10
[fb]
σ
[fb]
σ
∆
Data and Stat. Uncertainty
Total Uncertainty
Sherpa 2.2.2 *
MG5_aMC+Pythia8 FxFx *
MiNLO+Pythia8 *
NLO EW
⊗
MATRIX nNNLO
WW
→
* plus Sherpa+OL gg
ATLAS
-1
= 13 TeV, 139 fb
s
j
ν
±
µ
ν
±
e
→
pp
1
2
3
4
5
≥
> 30 GeV)
T
p
Number of jets (
0.5
1
1.5
Prediction/Data
Figure 8. Measured fiducial cross-sections of WW+jets production for (from left to right and top
to bottom): ∆φ(e, µ), yeµ, cos θ∗, and the exclusive jet multiplicity. The measured cross-section val-
ues are shown as points with error bars giving the statistical uncertainty and solid bands indicating
the size of the total uncertainty. The results are compared with the NNLO prediction with extra
NLO EW corrections and NLO corrections for gg →WW production (denoted MATRIX ⊗NLO
EW) as well as NLO+PS predictions from Sherpa 2.2.2, MadGraph5_aMC@NLO + Pythia 8
with FxFx merging, and Powheg MiNLO + Pythia 8 for q¯q initial states, combined with Sherpa
+ OpenLoops (LO+PS) for the gg initial state. The Sherpa 2.2.2 + OpenLoops prediction is
normalized to the total cross-section calculated at NLO in QCD. Theoretical predictions are indi-
cated as markers with vertical lines denoting PDF and scale uncertainties.The MATRIX prediction
is not defined for more than two jet emissions. 50
100
150
200
250
300
350
400
| [fb]
µ
e
φ
∆
/d|
σ
d
Data and Stat. 8.2
Effective field theory interpretation The results are compared with the NNLO prediction with extra
NLO EW corrections and NLO corrections for gg →WW production (denoted MATRIX ⊗NLO
EW) as well as NLO+PS predictions from Sherpa 2.2.2, MadGraph5_aMC@NLO + Pythia 8
with FxFx merging, and Powheg MiNLO + Pythia 8 for q¯q initial states, combined with Sherpa
+ OpenLoops (LO+PS) for the gg initial state. The Sherpa 2.2.2 + OpenLoops prediction is
normalized to the total cross-section calculated at NLO in QCD. Theoretical predictions are indi-
cated as markers with vertical lines denoting PDF and scale uncertainties.The MATRIX prediction
is not defined for more than two jet emissions. – 24 – 1
−
10
1
[fb/GeV]
µ
e
m
/d
σ
d
10
2
10
[fb]
σ
∆
Data and Stat. Uncertainty
Total Uncertainty
Sherpa 2.2.2 *
MG5_aMC+Pythia8 FxFx *
MiNLO+Pythia8 *
NLO EW
⊗
MATRIX nNNLO
WW
→
* plus Sherpa+OL gg
ATLAS
-1
= 13 TeV, 139 fb
s
j
ν
±
µ
ν
±
e
→
pp
> 200 GeV
lead. jet
T
p
[GeV]
µ
e
m
0.6
0.8
1
1.2
1.4
Prediction/Data
90
2
10
2
10
×
2
2
10
×
3
2
10
×
4
≥
2
4
6
8
10
12
14
16
18
20
22
| [fb]
µ
e
φ
∆
/d|
σ
d
[fb]
σ
∆
Data and Stat. Uncertainty
Total Uncertainty
Sherpa 2.2.2 *
MG5_aMC+Pythia8 FxFx *
MiNLO+Pythia8 *
NLO EW
⊗
MATRIX nNNLO
WW
→
* plus Sherpa+OL gg
ATLAS
-1
= 13 TeV, 139 fb
s
j
ν
±
µ
ν
±
e
→
pp
> 200 GeV
lead. jet
T
p
0
0.5
1
1.5
2
2.5
3
|
µ
e
φ
∆|
0.6
0.8
1
1.2
1.4
Prediction/Data
Figure 9. Measured fiducial cross-sections of WW+jets production for meµ (left) and ∆φ(e, µ)
(right) in the fiducial phase space requiring plead. jet
T
> 200 GeV. The last bin of the meµ distribu-
tion is inclusive and the corresponding integrated cross-section is indicated by the right-hand-side
axis. The measured cross-section values are shown as points with error bars giving the statistical
uncertainty and solid bands indicating the size of the total uncertainty. 8.2
Effective field theory interpretation The results are compared
with the NNLO prediction with extra NLO EW corrections and NLO corrections for gg →WW
production (denoted MATRIX ⊗NLO EW) as well as NLO+PS predictions from Sherpa 2.2.2,
MadGraph5_aMC@NLO + Pythia 8 with FxFx merging, and Powheg MiNLO + Pythia 8
for q¯q initial states, combined with Sherpa + OpenLoops (LO+PS) for the gg initial state. The
Sherpa 2.2.2 + OpenLoops prediction is normalized to the total cross-section calculated at NLO
in QCD. Theoretical predictions are indicated as markers with vertical lines denoting PDF and
scale uncertainties. 1
−
10
1
[fb/GeV]
µ
e
m
/d
σ
d
10
2
10
[fb]
σ
∆
Data and Stat. Uncertainty
Total Uncertainty
Sherpa 2.2.2 *
MG5_aMC+Pythia8 FxFx *
MiNLO+Pythia8 *
NLO EW
⊗
MATRIX nNNLO
WW
→
* plus Sherpa+OL gg
ATLAS
-1
= 13 TeV, 139 fb
s
j
ν
±
µ
ν
±
e
→
pp
> 200 GeV
lead. jet
T
p
[GeV]
µ
e
m
0.6
0.8
1
1.2
1.4
Prediction/Data
90
2
10
2
10
×
2
2
10
×
3
2
10
×
4
≥ 2
4
6
8
10
12
14
16
18
20
22
| [fb]
µ
e
φ
∆
/d|
σ
d
[fb]
σ
∆
Data and Stat. Uncertainty
Total Uncertainty
Sherpa 2.2.2 *
MG5_aMC+Pythia8 FxFx *
MiNLO+Pythia8 *
NLO EW
⊗
MATRIX nNNLO
WW
→
* plus Sherpa+OL gg
ATLAS
-1
= 13 TeV, 139 fb
s
j
ν
±
µ
ν
±
e
→
pp
> 200 GeV
lead. jet
T
p
0
0.5
1
1.5
2
2.5
3
|
µ
e
φ
∆|
0.6
0.8
1
1.2
1.4
Prediction/Data JHEP06(2021)003 Figure 9. Measured fiducial cross-sections of WW+jets production for meµ (left) and ∆φ(e, µ)
(right) in the fiducial phase space requiring plead. jet
T
> 200 GeV. The last bin of the meµ distribu-
tion is inclusive and the corresponding integrated cross-section is indicated by the right-hand-side
axis. The measured cross-section values are shown as points with error bars giving the statistical
uncertainty and solid bands indicating the size of the total uncertainty. 8.2
Effective field theory interpretation The results are compared
with the NNLO prediction with extra NLO EW corrections and NLO corrections for gg →WW
production (denoted MATRIX ⊗NLO EW) as well as NLO+PS predictions from Sherpa 2.2.2,
MadGraph5_aMC@NLO + Pythia 8 with FxFx merging, and Powheg MiNLO + Pythia 8
for q¯q initial states, combined with Sherpa + OpenLoops (LO+PS) for the gg initial state. The
Sherpa 2.2.2 + OpenLoops prediction is normalized to the total cross-section calculated at NLO
in QCD. Theoretical predictions are indicated as markers with vertical lines denoting PDF and
scale uncertainties. Constraints on the Wilson coefficient, cW , are determined using the unfolded meµ
cross-section, which is the measured distribution most sensitive to the interference of the
QW operator with the SM. The fit is performed both for jet pT > 30 GeV and for jet
pT > 200 GeV. The latter selection is used to enhance the effect of the interference term
per the above discussion. Templates of the distributions representing the pure SM contribution, the new-physics
contribution, and the interference between the SM and the new-physics contributions at LO
are prepared using MadGraph5_aMC@NLO 2.7.2 [107], interfaced to Pythia 8.244 [45],
with the A14 tune [46], for parton showering, and hadronization. Events with zero or one
jet are simulated in MadGraph5_aMC@NLO and the overlap between matrix-element
and parton-shower emissions is removed using the CKKW-L merging procedure [65, 66]. Agreement of the MadGraph5_aMC@NLO prediction with the baseline Sherpa 2.2.2
generator is ensured by applying a bin-wise correction, determined as the ratio of the SM
predictions from Sherpa and MadGraph5_aMC@NLO. It is assumed that the relative
scale-induced uncertainties of the Sherpa prediction are also applicable, differentially in
meµ, to the prediction that includes the effect of dimension-six operators. The predic-
tion and the measured cross-section are, then, used to construct a likelihood function. – 25 – Jet pT
Linear only
68% CI obs. 95% CI obs. 68% CI exp. 95% CI exp. > 30 GeV
yes
[–1.64, 2.86]
[–3.85, 4.97]
[–2.30, 2.27]
[–4.53, 4.41]
> 30 GeV
no
[–0.20, 0.20]
[–0.33, 0.33]
[–0.28, 0.27]
[–0.39, 0.38]
> 200 GeV
yes
[–0.29, 1.84]
[–1.37, 2.81]
[–1.12, 1.09]
[–2.24, 2.10]
> 200 GeV
no
[–0.43, 0.46]
[–0.60, 0.58]
[–0.38, 0.33]
[–0.53, 0.48]
Table 8. 8.2
Effective field theory interpretation Observed and expected confidence intervals (CI) for cW for a linearized and a quadratic
EFT fit of meµ, when requiring either jet pT > 30 GeV or jet pT > 200 GeV. The new-physics scale
Λ is set to 1 TeV. Table 8. Observed and expected confidence intervals (CI) for cW for a linearized and a quadratic
EFT fit of meµ, when requiring either jet pT > 30 GeV or jet pT > 200 GeV. The new-physics scale
Λ is set to 1 TeV. JHEP06(2021)003 Measurement uncertainties are modelled using a multivariate Gaussian distribution, while
QCD scale and PDF uncertainties affecting the theory prediction are considered as nui-
sance parameters, constrained with a Gaussian distribution. Two nuisance parameters are
introduced to model the scale uncertainty affecting the predicted meµ distribution so that
its effect is not fully correlated between bins. The first (second) parameter models the
full effect of the scale uncertainty in the first (last) bin of the distribution. The effect de-
creases linearly with log(meµ) such that the parameter has no effect in the last (first) bin. The decorrelation of scale-uncertainty effects increases the width of confidence intervals
by up to 40% relative to a model in which the scale-uncertainty effects are assumed to be
fully correlated between bins of meµ. Confidence intervals for cW are derived using Wilk’s
theorem [108], assuming that the profile likelihood test statistic is χ2 distributed [109]. Observed and expected 95% confidence intervals for the EFT coefficients are summa-
rized in table 8. They are presented both for a fit that takes into account only linear terms
in the cross-section parameterization and for a fit that also takes into account quadratic
terms due to the square of the dimension-six amplitude. For jet pT > 200 GeV, limits in
the linearized EFT expansion are improved relative to a pT > 30 GeV requirement, and
the impact of the quadratic term is reduced. As expected, the analysis of the phase space
characterized by a high-pT jet increases the experimental sensitivity to effects proportional
to cW /Λ2 due to the reduced suppression of the interference between the SM amplitude
and the dimension-six amplitude. However, pure dimension-six contributions, which are
O(Λ−4), are still dominant in this phase space, and the EFT expansion in Λ−1 does not
converge quickly. 9
Conclusion The cross-section for the production of W-boson pairs decaying into e±νeµ∓νµ final states
in pp collisions at √s = 13 TeV is measured in a fiducial phase space that requires the
presence of at least one hadronic jet with transverse momentum of at least 30 GeV, pro-
viding jet-inclusive measurements in WW events. The measurement is performed with
data recorded by the ATLAS experiment at the LHC between 2015 and 2018 that cor-
respond to an integrated luminosity of 139 fb−1. The measured fiducial cross-section,
σfid = 258 ± 4 (stat) ± 25 (syst) fb, is found to be consistent with theoretical predictions. With a total uncertainty of 10%, this result represents a precise measurement of WW
production in association with jets at the LHC that probes a previously unexplored event
topology. Differential cross-sections for WW+jets production are measured as a function of
the kinematics of the final-state charged leptons, jets, and missing transverse momentum,
and are compared with predictions from perturbative QCD calculations. The data agree
well with predictions in all differential distributions, up to the highest measured trans-
verse momenta and for up to five jets. Dimension six operators that produce anomalous
triple-gauge-boson interactions are studied in a phase space that benefits from enhanced
interference between the Standard Model amplitude and the anomalous amplitude. JHEP06(2021)003 8.2
Effective field theory interpretation The limits are, thus, not valid in a general SM EFT scenario that includes
additional Λ−4 contributions due to dimension-eight operators. The presented constraints on cW , obtained accounting for quadratic terms, are weaker
than those obtained by the ATLAS measurement of WW events with no associated jets [7]. There, a dataset corresponding to only 36 fb−1 was analysed and the results constrain
cW /Λ2 to a 95% confidence interval with a width of 0.5/TeV2. Limits obtained from this
measurement when only including linear terms are improved relative to the previous mea-
surement, for which the corresponding confidence interval has a width of 11/TeV2. The lim-
its from such a linear fit are, however, an order of magnitude weaker than those obtained by
the ATLAS analysis of electroweak production of dijets in association with a Z boson [110]. – 26 – Acknowledgments We thank CERN for the very successful operation of the LHC, as well as the support staff
from our institutions without whom ATLAS could not be operated efficiently. We acknowledge the support of ANPCyT, Argentina; YerPhI, Armenia; ARC, Aus-
tralia; BMWFW and FWF, Austria; ANAS, Azerbaijan; SSTC, Belarus; CNPq and
FAPESP, Brazil; NSERC, NRC and CFI, Canada; CERN; ANID, Chile; CAS, MOST
and NSFC, China; COLCIENCIAS, Colombia; MSMT CR, MPO CR and VSC CR, Czech
Republic; DNRF and DNSRC, Denmark; IN2P3-CNRS and CEA-DRF/IRFU, France;
SRNSFG, Georgia; BMBF, HGF and MPG, Germany; GSRT, Greece; RGC and Hong
Kong SAR, China; ISF and Benoziyo Center, Israel; INFN, Italy; MEXT and JSPS, Japan;
CNRST, Morocco; NWO, Netherlands; RCN, Norway; MNiSW and NCN, Poland; FCT,
Portugal; MNE/IFA, Romania; JINR; MES of Russia and NRC KI, Russian Federation;
MESTD, Serbia; MSSR, Slovakia; ARRS and MIZŠ, Slovenia; DST/NRF, South Africa;
MICINN, Spain; SRC and Wallenberg Foundation, Sweden; SERI, SNSF and Cantons of
Bern and Geneva, Switzerland; MOST, Taiwan; TAEK, Turkey; STFC, United Kingdom;
DOE and NSF, United States of America. In addition, individual groups and members have
received support from BCKDF, CANARIE, Compute Canada, CRC and IVADO, Canada;
Beijing Municipal Science & Technology Commission, China; COST, ERC, ERDF, Hori-
zon 2020 and Marie Skłodowska-Curie Actions, European Union; Investissements d’Avenir
Labex, Investissements d’Avenir Idex and ANR, France; DFG and AvH Foundation, Ger-
many; Herakleitos, Thales and Aristeia programmes co-financed by EU-ESF and the Greek
NSRF, Greece; BSF-NSF and GIF, Israel; La Caixa Banking Foundation, CERCA Pro-
gramme Generalitat de Catalunya and PROMETEO and GenT Programmes Generalitat
Valenciana, Spain; Göran Gustafssons Stiftelse, Sweden; The Royal Society and Lever-
hulme Trust, United Kingdom. – 27 – plead. lep. T
> 200 GeV
Data
3873
Total SM
3960 ± 120
WW
1740 ± 50
44%
Total bkg. 2210 ± 110
56%
Top
1920 ± 90
49%
Drell-Yan
42 ±
6
1%
Fake leptons
70 ± 40
2%
WZ, ZZ, V γ
180 ± 40
4%
Table 9. Selected WW candidate events, together with the signal prediction and the background
estimates for plead. lep. T
> 200 GeV. The uncertainties include statistical and systematic contribu-
tions. The fractions in percent give the relative contribution to the total SM prediction. JHEP06(2021)003 Table 9. Selected WW candidate events, together with the signal prediction and the background
estimates for plead. lep. T
> 200 GeV. The uncertainties include statistical and systematic contribu-
tions. Acknowledgments The fractions in percent give the relative contribution to the total SM prediction. Table 9. Selected WW candidate events, together with the signal prediction and the background
estimates for plead. lep. T
> 200 GeV. The uncertainties include statistical and systematic contribu-
tions. The fractions in percent give the relative contribution to the total SM prediction. The crucial computing support from all WLCG partners is acknowledged gratefully,
in particular from CERN, the ATLAS Tier-1 facilities at TRIUMF (Canada), NDGF
(Denmark, Norway, Sweden), CC-IN2P3 (France), KIT/GridKA (Germany), INFN-CNAF
(Italy), NL-T1 (Netherlands), PIC (Spain), ASGC (Taiwan), RAL (U.K.) and BNL
(U.S.A.), the Tier-2 facilities worldwide and large non-WLCG resource providers. Ma-
jor contributors of computing resources are listed in ref. [112]. A
Measurement at high plead. lep.
T At high vector-boson pT, predictions for inclusive WW events suffer from so-called ‘giant
K-factors’, which correspond to large higher-order corrections for QCD and electroweak ef-
fects [111]. These come in part from event topologies similar to those in W+jets production
with the additional emission of a real W boson from a hard jet. In order to study kinematic configurations that are expected to be strongly affected
by higher-order EW and QCD corrections, a sample of events is selected with the re-
quirement that plead. lep. T
> 200 GeV. This selects event topologies that generally have a
high-pT W boson accompanied by a lower-pT W boson. Here the cross-section is measured
differentially in the azimuthal separation between the sub-leading lepton and the leading
jet, ∆φ(sub-lead. lep., jet), and their η–φ separation ∆R(sub-lead. lep., jet), as well as in
the ratio of the lepton transverse momenta, psub-lead. lep. T
/plead. lep. T
, and the ratio of the
sub-leading lepton and leading jet transverse momenta, psub-lead. lep. T
/plead. jet
T
. Table 9 lists the selected WW candidate events in this region, as well as the breakdown
of the background estimates. Figure 10 shows the measured distributions at detector level
in the final analysis binning, comparing the observed data with the signal prediction and
the background estimate. The unfolded distributions are shown in figure 11. In general, the predictions are in
good agreement with the measurement. – 28 – 2
−
10
1
−
10
1
lead. jet
T
p
/
sub-lead. lep. T
p
0.8
0.9
1
1.1
1.2
Data/SM
0
1000
2000
3000
4000
5000
6000
7000
8000
Events
Data
WW
Top
Drell-Yan
Fakes
γ
WZ,ZZ,V
*
syst. ⊕
Stat. *: without WW modelling uncertainties
ATLAS
-1
= 13 TeV, 139 fb
s
-veto
b
|<4.5),
η
1 jet (30 GeV,|
≥
,
±
µ
±
e
> 200 GeV
lead. lep. T
p
0
0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9
1
lead. lep. T
p
/
sub-lead. lep. T
p
0.8
0.9
1
1.1
1.2
Data/SM
0
2
4
6
8
10
12
3
10
×
Events
Data
WW
Top
Drell-Yan
Fakes
γ
WZ,ZZ,V
*
syst. ⊕
Stat. *: without WW modelling uncertainties
ATLAS
-1
= 13 TeV, 139 fb
s
-veto
b
|<4.5),
η
1 jet (30 GeV,|
≥
,
±
µ
±
e
> 200 GeV
lead. lep. A
Measurement at high plead. lep.
T T
p 0
0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9
1
lead. lep. T
p
/
sub-lead. lep. T
p
0.8
0.9
1
1.1
1.2
Data/SM
0
2
4
6
8
10
12
3
10
×
Events
Data
WW
Top
Drell-Yan
Fakes
γ
WZ,ZZ,V
*
syst. ⊕
Stat. *: without WW modelling uncertainties
ATLAS
-1
= 13 TeV, 139 fb
s
-veto
b
|<4.5),
η
1 jet (30 GeV,|
≥
,
±
µ
±
e
> 200 GeV
lead. lep. T
p 2
−
10
1
−
10
1
lead. jet
T
p
/
sub-lead. lep. T
p
0.8
0.9
1
1.1
1.2
Data/SM
0
1000
2000
3000
4000
5000
6000
7000
8000
Events
Data
WW
Top
Drell-Yan
Fakes
γ
WZ,ZZ,V
*
syst. ⊕
Stat. *: without WW modelling uncertainties
ATLAS
-1
= 13 TeV, 139 fb
s
-veto
b
|<4.5),
η
1 jet (30 GeV,|
≥
,
±
µ
±
e
> 200 GeV
lead. lep. T
p
0.5
1
1.5
2
2.5
3
3.5
4
4.5
5
(sub-lead. lep., lead. jet)
R
∆
0.8
0.9
1
1.1
1.2
Data/SM
0
200
400
600
800
1000
1200
1400
1600
1800
2000
Events
Data
WW
Top
Drell-Yan
Fakes
γ
WZ,ZZ,V
*
syst. ⊕
Stat. *: without WW modelling uncertainties
ATLAS
-1
= 13 TeV, 139 fb
s
-veto
b
|<4.5),
η
1 jet (30 GeV,|
≥
,
±
µ
±
e
> 200 GeV
lead. lep. T
p 2
−
10
1
−
10
1
lead. jet
T
p
/
sub-lead. lep. T
p
0.8
0.9
1
1.1
1.2
Data/SM
0
1000
2000
3000
4000
5000
6000
7000
8000
Events
Data
WW
Top
Drell-Yan
Fakes
γ
WZ,ZZ,V
*
syst. ⊕
Stat. *: without WW modelling uncertainties
ATLAS
-1
= 13 TeV, 139 fb
s
-veto
b
|<4.5),
η
1 jet (30 GeV,|
≥
,
±
µ
±
e
> 200 GeV
lead. lep. T
p Events JHEP06(2021)003 Data/SM Data/SM Data/SM Figure 10. Signal region detector-level distributions, requiring plead. lep. T
>
200 GeV, of
psub-lead. lep. T
/plead. jet
T
(top left), psub-lead. lep. T
/plead. lep. T
(top right), ∆R(sub-lead. lep., jet) (bottom
left) and ∆φ(sub-lead. lep., jet) (bottom right). Data are shown as black markers together with
the predictions for the signal and background production processes. The last bin contains overflow
events. The lower panels show the ratio of the data to the total prediction. A
Measurement at high plead. lep.
T T
p
0.5
1
1.5
2
2.5
3
3.5
4
4.5
5
(sub-lead. lep., lead. jet)
R
∆
0.8
0.9
1
1.1
1.2
Data/SM
0
200
400
600
800
1000
1200
1400
1600
1800
2000
Events
Data
WW
Top
Drell-Yan
Fakes
γ
WZ,ZZ,V
*
syst. ⊕
Stat. *: without WW modelling uncertainties
ATLAS
-1
= 13 TeV, 139 fb
s
-veto
b
|<4.5),
η
1 jet (30 GeV,|
≥
,
±
µ
±
e
> 200 GeV
lead. lep. T
p
0
0.5
1
1.5
2
2.5
3
(sub-lead. lep., lead. jet)|
φ
∆|
0.8
0.9
1
1.1
1.2
Data/SM
0
500
1000
1500
2000
2500
Events
Data
WW
Top
Drell-Yan
Fakes
γ
WZ,ZZ,V
*
syst. ⊕
Stat. *: without WW modelling uncertainties
ATLAS
-1
= 13 TeV, 139 fb
s
-veto
b
|<4.5),
η
1 jet (30 GeV,|
≥
,
±
µ
±
e
> 200 GeV
lead. lep. T
p
Figure 10. Signal region detector-level distributions, requiring plead. lep. T
>
200 GeV, of
psub-lead. lep. T
/plead. jet
T
(top left), psub-lead. lep. T
/plead. lep. T
(top right), ∆R(sub-lead. lep., jet) (bottom
left) and ∆φ(sub-lead. lep., jet) (bottom right). Data are shown as black markers together with
the predictions for the signal and background production processes. The last bin contains overflow
events. The lower panels show the ratio of the data to the total prediction. The uncertainty bands
shown include statistical and systematic uncertainties, excluding theory uncertainties on the signal. 0
0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9
1
lead. lep. T
p
/
sub-lead. lep. T
p
0.8
0.9
1
1.1
1.2
Data/SM
0
2
4
6
8
10
12
3
10
×
Events
Data
WW
Top
Drell-Yan
Fakes
γ
WZ,ZZ,V
*
syst. ⊕
Stat. *: without WW modelling uncertainties
ATLAS
-1
= 13 TeV, 139 fb
s
-veto
b
|<4.5),
η
1 jet (30 GeV,|
≥
,
±
µ
±
e
> 200 GeV
lead. lep. T
p
0
0.5
1
1.5
2
2.5
3
(sub-lead. lep., lead. jet)|
φ
∆|
0.8
0.9
1
1.1
1.2
Data/SM
0
500
1000
1500
2000
2500
Events
Data
WW
Top
Drell-Yan
Fakes
γ
WZ,ZZ,V
*
syst. ⊕
Stat. *: without WW modelling uncertainties
ATLAS
-1
= 13 TeV, 139 fb
s
-veto
b
|<4.5),
η
1 jet (30 GeV,|
≥
,
±
µ
±
e
> 200 GeV
lead. lep. A
Measurement at high plead. lep.
T The uncertainty bands
shown include statistical and systematic uncertainties, excluding theory uncertainties on the signal. – 29 – 2
4
6
8
10
12
14
(sub-lead lep.,lead. jet) [fb]
φ
∆
/d
σ
d
[fb]
σ
∆
Data and Stat. Uncertainty
Total Uncertainty
Sherpa 2.2.2 *
MG5_aMC+Pythia8 FxFx *
MiNLO+Pythia8 *
NLO EW
⊗
MATRIX nNNLO
WW
→
* plus Sherpa+OL gg
ATLAS
-1
= 13 TeV, 139 fb
s
j
ν
±
µ
ν
±
e
→
pp
> 200 GeV
lead. lep. T
p
0
0.5
1
1.5
2
2.5
3
(sub-lead lep.,lead. jet)
φ
∆
0.6
0.8
1
1.2
1.4
Prediction/Data
2
4
6
8
10
12
) [fb]
(sub-lead lep.,lead. jet}
R
∆
/d
σ
d
[fb]
σ
∆
Data and Stat. Uncertainty
Total Uncertainty
Sherpa 2.2.2 *
MG5_aMC+Pythia8 FxFx *
MiNLO+Pythia8 *
NLO EW
⊗
MATRIX nNNLO
WW
→
* plus Sherpa+OL gg
ATLAS
-1
= 13 TeV, 139 fb
s
j
ν
±
µ
ν
±
e
→
pp
> 200 GeV
lead. lep. T
p
0.5
1
1.5
2
2.5
3
3.5
4
4.5
5
)
(sub-lead lep.,lead. jet}
R
∆
0.6
0.8
1
1.2
1.4
Prediction/Data
10
20
30
40
50
60
70
80
) [fb]
lead lep. T
p
/
sub-lead lep. T
p
/d(
σ
d
[fb]
σ
∆
Data and Stat. Uncertainty
Total Uncertainty
Sherpa 2.2.2 *
MG5_aMC+Pythia8 FxFx *
MiNLO+Pythia8 *
NLO EW
⊗
MATRIX nNNLO
WW
→
* plus Sherpa+OL gg
ATLAS
-1
= 13 TeV, 139 fb
s
j
ν
±
µ
ν
±
e
→
pp
> 200 GeV
lead. lep. T
p
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
lead lep. T
p
/
sub-lead lep. T
p
0.6
0.8
1
1.2
1.4
Prediction/Data
1
10
2
10
3
10
) [fb]
lead jet
T
p
/
sub-lead lep. T
p
/d(
σ
d
[fb]
σ
∆
Data and Stat. Uncertainty
Total Uncertainty
Sherpa 2.2.2 *
MG5_aMC+Pythia8 FxFx *
MiNLO+Pythia8 *
NLO EW
⊗
MATRIX nNNLO
WW
→
* plus Sherpa+OL gg
ATLAS
-1
= 13 TeV, 139 fb
s
j
ν
±
µ
ν
±
e
→
pp
> 200 GeV
lead. lep. T
p
2
−
10
2
−
10
×
2
1
−
10
1
−
10
×
2
1
2
3 4 5
lead jet
T
p
/
sub-lead lep. A
Measurement at high plead. lep.
T T
p
0.6
0.8
1
1.2
1.4
Prediction/Data
Figure 11. Measured fiducial cross-sections of WW+jets production for (from left to right
and top to bottom):
∆φ(sub-lead. lep., jet), ∆R(sub-lead. lep., jet), psub-lead. lep. T
/plead. lep. T
, and
psub-lead. lep. T
/plead. jet
T
in the fiducial phase space requiring plead. lep. T
> 200 GeV. The measured cross-
section values are shown as points with error bars giving the statistical uncertainty and solid bands
indicating the size of the total uncertainty. The results are compared with the NNLO prediction
with extra NLO EW corrections and NLO corrections for gg →WW production (denoted MATRIX
⊗NLO EW) as well as NLO+PS predictions from Sherpa 2.2.2, MadGraph5_aMC@NLO +
Pythia 8 with FxFx merging, and Powheg MiNLO + Pythia 8 for q¯q initial states, combined
with Sherpa + OpenLoops (LO+PS) for the gg initial state. The Sherpa 2.2.2 + OpenLoops
prediction is normalized to the total cross-section calculated at NLO in QCD. Theoretical predic-
tions are indicated as markers with vertical lines denoting PDF and scale uncertainties. 2
4
6
8
10
12
14
(sub-lead lep.,lead. jet) [fb]
φ
∆
/d
σ
d
Data and Stat. Uncertainty
Total Uncertainty
Sherpa 2.2.2 *
MG5_aMC+Pythia8 FxFx *
MiNLO+Pythia8 *
NLO EW
⊗
MATRIX nNNLO
WW
→
* plus Sherpa+OL gg
ATLAS
-1
= 13 TeV, 139 fb
s
j
ν
±
µ
ν
±
e
→
pp
> 200 GeV
lead. lep. T
p
0
0.5
1
1.5
2
2.5
3
(sub-lead lep.,lead. jet)
φ
∆
0.6
0.8
1
1.2
1.4
Prediction/Data
10
20
30
40
50
60
70
80
) [fb]
lead lep. T
p
/
sub-lead lep. T
p
/d(
σ
d
Data and Stat. Uncertainty
Total Uncertainty
Sherpa 2.2.2 *
MG5_aMC+Pythia8 FxFx *
MiNLO+Pythia8 *
NLO EW
⊗
MATRIX nNNLO
WW
→
* plus Sherpa+OL gg
ATLAS
-1
= 13 TeV, 139 fb
s
j
ν
±
µ
ν
±
e
→
pp
> 200 GeV
lead. lep. T
p
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
lead lep. T
p
/
sub-lead lep. T
p
0.6
0.8
1
1.2
1.4
Prediction/Data ) [fb]
(sub-lead lep.,lead. jet}
R
∆
/d
σ
d 2
4
6
8
10
12
) [fb]
(sub-lead lep.,lead. jet}
R
∆
/d
σ
d
Data and Stat. A
Measurement at high plead. lep.
T Uncertainty
Total Uncertainty
Sherpa 2.2.2 *
MG5_aMC+Pythia8 FxFx *
MiNLO+Pythia8 *
NLO EW
⊗
MATRIX nNNLO
WW
→
* plus Sherpa+OL gg
ATLAS
-1
= 13 TeV, 139 fb
s
j
ν
±
µ
ν
±
e
→
pp
> 200 GeV
lead. lep. T
p
0.5
1
1.5
2
2.5
3
3.5
4
4.5
5
)
(sub-lead lep.,lead. jet}
R
∆
0.6
0.8
1
1.2
1.4
Prediction/Data
1
10
2
10
3
10
) [fb]
lead jet
T
p
/
sub-lead lep. T
p
/d(
σ
d
Data and Stat. Uncertainty
Total Uncertainty
Sherpa 2.2.2 *
MG5_aMC+Pythia8 FxFx *
MiNLO+Pythia8 *
NLO EW
⊗
MATRIX nNNLO
WW
→
* plus Sherpa+OL gg
ATLAS
-1
= 13 TeV, 139 fb
s
j
ν
±
µ
ν
±
e
→
pp
> 200 GeV
lead. lep. T
p
2
−
10
2
−
10
×
2
1
−
10
1
−
10
×
2
1
2
3 4 5
lead jet
T
p
/
sub-lead lep. T
p
0.6
0.8
1
1.2
1.4
Prediction/Data (sub-lead lep.,lead. jet) [fb]
φ
∆
/d
σ
d 2
4
6
8
10
12
) [fb]
(sub-lead lep.,lead. jet}
R
∆
/d
σ
d
Data and Stat. Uncertainty
Total Uncertainty
Sherpa 2.2.2 *
MG5_aMC+Pythia8 FxFx *
MiNLO+Pythia8 *
NLO EW
⊗
MATRIX nNNLO
WW
→
* plus Sherpa+OL gg
ATLAS
-1
= 13 TeV, 139 fb
s
j
ν
±
µ
ν
±
e
→
pp
> 200 GeV
lead. lep. T
p
0.5
1
1.5
2
2.5
3
3.5
4
4.5
5
)
(sub-lead lep.,lead. jet}
R
∆
0.6
0.8
1
1.2
1.4
Prediction/Data JHEP06(2021)003 )
(
p
j
}
1
10
2
10
3
10
) [fb]
lead jet
T
p
/
sub-lead lep. T
p
/d(
σ
d
Data and Stat. Uncertainty
Total Uncertainty
Sherpa 2.2.2 *
MG5_aMC+Pythia8 FxFx *
MiNLO+Pythia8 *
NLO EW
⊗
MATRIX nNNLO
WW
→
* plus Sherpa+OL gg
ATLAS
-1
= 13 TeV, 139 fb
s
j
ν
±
µ
ν
±
e
→
pp
> 200 GeV
lead. lep. T
p
2
−
10
2
−
10
×
2
1
−
10
1
−
10
×
2
1
2
3 4 5
lead jet
T
p
/
sub-lead lep. T
p
0.6
0.8
1
1.2
1.4
Prediction/Data 10
20
30
40
50
60
70
80
) [fb]
lead lep. T
p
/
sub-lead lep. A
Measurement at high plead. lep.
T T
p
/d(
σ
d
Data and Stat. Uncertainty
Total Uncertainty
Sherpa 2.2.2 *
MG5_aMC+Pythia8 FxFx *
MiNLO+Pythia8 *
NLO EW
⊗
MATRIX nNNLO
WW
→
* plus Sherpa+OL gg
ATLAS
-1
= 13 TeV, 139 fb
s
j
ν
±
µ
ν
±
e
→
pp
> 200 GeV
lead. lep. T
p
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
lead lep. T
p
/
sub-lead lep. T
p
0.6
0.8
1
1.2
1.4
Prediction/Data Figure 11. Measured fiducial cross-sections of WW+jets production for (from left to right
and top to bottom):
∆φ(sub-lead. lep., jet), ∆R(sub-lead. lep., jet), psub-lead. lep. T
/plead. lep. T
, and
psub-lead. lep. T
/plead. jet
T
in the fiducial phase space requiring plead. lep. T
> 200 GeV. The measured cross-
section values are shown as points with error bars giving the statistical uncertainty and solid bands
indicating the size of the total uncertainty. The results are compared with the NNLO prediction
with extra NLO EW corrections and NLO corrections for gg →WW production (denoted MATRIX
⊗NLO EW) as well as NLO+PS predictions from Sherpa 2.2.2, MadGraph5_aMC@NLO +
Pythia 8 with FxFx merging, and Powheg MiNLO + Pythia 8 for q¯q initial states, combined
with Sherpa + OpenLoops (LO+PS) for the gg initial state. The Sherpa 2.2.2 + OpenLoops
prediction is normalized to the total cross-section calculated at NLO in QCD. Theoretical predic-
tions are indicated as markers with vertical lines denoting PDF and scale uncertainties. – 30 – B
t¯t background estimate Figure 12 shows the plead. lep. T
and jet multiplicity distributions in the two t¯t control regions,
which require exactly one and exactly two b-jets, respectively. The b-jet correlation factor
Cb for the two distributions is shown in figure 13. Figure 14 shows the meµ distribution for
plead. jet
T
> 200 GeV in the two control regions and for the top-enriched selection, together
with the b-jet correlation factor Cb. The excess of events predicted at high plead. lep. T
, in
comparison with data, is corrected for by the data-driven estimate, and no discrepancy
is seen in the top-enriched selection, as shown in figure 2 in the main body. The jet
multiplicity is well modelled up to five selected jets. JHEP06(2021)003 – 31 – JHEP06(2021)003
2
10
[GeV]
lead. lep. T
p
0.8
0.9
1
1.1
1.2
Data/SM
30
40
60
80
3
10
×
3
0
1000
2000
3000
4000
5000
Events / GeV
Data
(MC)
tt
Single top Wt
Others
syst. ⊕
Stat. ATLAS
-1
= 13 TeV, 139 fb
s
-jet
b
CR 1
tt
1
2
3
4
5
> 30 GeV)
T
p
Number of jets (
0.8
0.9
1
1.1
1.2
Data/SM
0
20
40
60
80
100
120
3
10
×
Events
Data
(MC)
tt
Single top Wt
Others
syst. ⊕
Stat. ATLAS
-1
= 13 TeV, 139 fb
s
-jet
b
CR 1
tt
2
10
[GeV]
lead. lep. T
p
0.8
0.9
1
1.1
1.2
Data/SM
30
40
60
80
3
10
×
3
0
1000
2000
3000
4000
5000
Events / GeV
Data
(MC)
tt
Single top Wt
Others
syst. ⊕
Stat. ATLAS
-1
= 13 TeV, 139 fb
s
-jets
b
CR 2
tt
1
2
3
4
5
> 30 GeV)
T
p
Number of jets (
0.8
0.9
1
1.1
1.2
Data/SM
0
20
40
60
80
100
120
140
3
10
×
Events
Data
(MC)
tt
Single top Wt
Others
syst. ⊕
Stat. ATLAS
-1
= 13 TeV, 139 fb
s
-jets
b
CR 2
tt
Figure 12. Detector-level distributions of the plead. lep. T
(left) and the jet multiplicity (right) in
the t¯t control regions with one b-jet (left) and two b-jets (right). Data are shown together with
the predictions for t¯t, single-top Wt and other production processes from simulation. The last bin
contains overflow events. B
t¯t background estimate The lower panels show the ratio of the data to the total prediction. The
uncertainties shown include statistical and systematic uncertainties. 1
2
3
4
5
> 30 GeV)
T
p
Number of jets (
0.8
0.9
1
1.1
1.2
Data/SM
0
20
40
60
80
100
120
3
10
×
Events
Data
(MC)
tt
Single top Wt
Others
syst. ⊕
Stat. ATLAS
-1
= 13 TeV, 139 fb
s
-jet
b
CR 1
tt 1
2
3
4
5
> 30 GeV)
T
p
Number of jets (
0.8
0.9
1
1.1
1.2
Data/SM
0
20
40
60
80
100
120
3
10
×
Events
Data
(MC)
tt
Single top Wt
Others
syst. ⊕
Stat. ATLAS
-1
= 13 TeV, 139 fb
s
-jet
b
CR 1
tt
1
2
3
4
5
> 30 GeV)
T
p
Number of jets (
0.8
0.9
1
1.1
1.2
Data/SM
0
20
40
60
80
100
120
140
3
10
×
Events
Data
(MC)
tt
Single top Wt
Others
syst. ⊕
Stat. ATLAS
-1
= 13 TeV, 139 fb
s
-jets
b
CR 2
tt 2
10
[GeV]
lead. lep. T
p
0.8
0.9
1
1.1
1.2
Data/SM
30
40
60
80
3
10
×
3
0
1000
2000
3000
4000
5000
Events / GeV
Data
(MC)
tt
Single top Wt
Others
syst. ⊕
Stat. ATLAS
-1
= 13 TeV, 139 fb
s
-jet
b
CR 1
tt
2
10
[GeV]
lead. lep. T
p
0.8
0.9
1
1.1
1.2
Data/SM
30
40
60
80
3
10
×
3
0
1000
2000
3000
4000
5000
Events / GeV
Data
(MC)
tt
Single top Wt
Others
syst. ⊕
Stat. ATLAS
-1
= 13 TeV, 139 fb
s
-jets
b
CR 2
tt 2
10
[GeV]
lead. lep. T
p
0.8
0.9
1
1.1
1.2
Data/SM
30
40
60
80
3
10
×
3
0
1000
2000
3000
4000
5000
Events / GeV
Data
(MC)
tt
Single top Wt
Others
syst. ⊕
Stat. ATLAS
-1
= 13 TeV, 139 fb
s
-jet
b
CR 1
tt Events JHEP06(2021)003 Data/SM Data/SM )
T
p
j
(
1
2
3
4
5
> 30 GeV)
T
p
Number of jets (
0.8
0.9
1
1.1
1.2
Data/SM
0
20
40
60
80
100
120
140
3
10
×
Events
Data
(MC)
tt
Single top Wt
Others
syst. ⊕
Stat. B
t¯t background estimate ATLAS
-1
= 13 TeV, 139 fb
s
-jets
b
CR 2
tt T
2
10
[GeV]
lead. lep. T
p
0.8
0.9
1
1.1
1.2
Data/SM
30
40
60
80
3
10
×
3
0
1000
2000
3000
4000
5000
Events / GeV
Data
(MC)
tt
Single top Wt
Others
syst. ⊕
Stat. ATLAS
-1
= 13 TeV, 139 fb
s
-jets
b
CR 2
tt Data/SM Figure 12. Detector-level distributions of the plead. lep. T
(left) and the jet multiplicity (right) in
the t¯t control regions with one b-jet (left) and two b-jets (right). Data are shown together with
the predictions for t¯t, single-top Wt and other production processes from simulation. The last bin
contains overflow events. The lower panels show the ratio of the data to the total prediction. The
uncertainties shown include statistical and systematic uncertainties. – 32 – JHEP06(2021)003 2
10
3
10
[GeV]
T
Leading lepton p
0.95
0.96
0.97
0.98
0.99
1
1.01
1.02
1.03
b
b-jet correlation C
Simulation
ATLAS
1
2
3
4
5
Jet multiplicity (30 GeV)
0.75
0.8
0.85
0.9
0.95
1
1.05
b
b-jet correlation C
Simulation
ATLAS
Figure 13. Distribution of the b-jet correlation factor Cb as a function of the plead. lep. T
(left) and
the jet multiplicity (right), as determined from the nominal t¯t simulation. The uncertainties shown
include MC statistical and systematic uncertainties. 2
10
3
10
[GeV]
T
Leading lepton p
0.95
0.96
0.97
0.98
0.99
1
1.01
1.02
1.03
b
b-jet correlation C
Simulation
ATLAS 1
2
3
4
5
Jet multiplicity (30 GeV)
0.75
0.8
0.85
0.9
0.95
1
1.05
b
b-jet correlation C
Simulation
ATLAS Figure 13. Distribution of the b-jet correlation factor Cb as a function of the plead. lep. T
(left) and
the jet multiplicity (right), as determined from the nominal t¯t simulation. The uncertainties shown
include MC statistical and systematic uncertainties. – 33 – 2
10
3
10
[GeV]
µ
e
m
0.8
0.9
1
1.1
1.2
Data/SM
0
1000
2000
3000
4000
5000
6000
7000
Events / bin
Data
(MC)
tt
Single top Wt
Others
syst. ⊕
Stat. ATLAS
-1
= 13 TeV, 139 fb
s
> 200 GeV
lead. B
t¯t background estimate jet
T
p
-jet,
b
CR 1
tt
2
10
3
10
[GeV]
µ
e
m
0.8
0.9
1
1.1
1.2
Data/SM
0
2
4
6
8
10
3
10
×
Events / bin
Data
(MC)
tt
Single top Wt
Others
syst. ⊕
Stat. ATLAS
-1
= 13 TeV, 139 fb
s
> 200 GeV
lead. jet
T
p
-jets,
b
CR 2
tt
2
10
3
10
[GeV]
µ
e
m
0.8
1
1.2
Data/SM
0
5
10
15
20
25
30
Events / bin
Data
Top
WW
Fakes
γ
WZ,ZZ,V
Drell-Yan
*
syst. ⊕
Stat. *: without WW modelling uncertainties
ATLAS
-1
= 13 TeV, 139 fb
s
> 200 GeV
lead. jet
T
p
Top enriched,
2
10
3
10
[GeV]
µ
e
m
0.95
0.96
0.97
0.98
0.99
1
1.01
1.02
1.03
b
b-jet correlation C
Simulation
ATLAS
Figure 14. Detector-level distributions of the dilepton invariant mass meµ for plead. jet
T
> 200 GeV
in the one b-tag and two b-tag control regions as well as the top-enriched region, together with the
b-jet correlation factor Cb. The lower panels in the plots of detector-level distributions show the
ratio of the data to the total prediction. The uncertainties shown include statistical and systematic
uncertainties, for both the distributions and the correlation factor. 2
10
3
10
[GeV]
µ
e
m
0.8
0.9
1
1.1
1.2
Data/SM
0
2
4
6
8
10
3
10
×
Events / bin
Data
(MC)
tt
Single top Wt
Others
syst. ⊕
Stat. ATLAS
-1
= 13 TeV, 139 fb
s
> 200 GeV
lead. jet
T
p
-jets,
b
CR 2
tt
2
10
3
10
[GeV]
µ
e
m
0.95
0.96
0.97
0.98
0.99
1
1.01
1.02
1.03
b
b-jet correlation C
Simulation
ATLAS 2
10
3
10
[GeV]
µ
e
m
0.8
0.9
1
1.1
1.2
Data/SM
0
1000
2000
3000
4000
5000
6000
7000
Events / bin
Data
(MC)
tt
Single top Wt
Others
syst. ⊕
Stat. ATLAS
-1
= 13 TeV, 139 fb
s
> 200 GeV
lead. jet
T
p
-jet,
b
CR 1
tt
2
10
3
10
[GeV]
µ
e
m
0.8
1
1.2
Data/SM
0
5
10
15
20
25
30
Events / bin
Data
Top
WW
Fakes
γ
WZ,ZZ,V
Drell-Yan
*
syst. ⊕
Stat. *: without WW modelling uncertainties
ATLAS
-1
= 13 TeV, 139 fb
s
> 200 GeV
lead. B
t¯t background estimate jet
T
p
Top enriched,
Fi
14
D t
t
l
l di t ib ti
f t 2
10
3
10
[GeV]
µ
e
m
0.8
0.9
1
1.1
1.2
Data/SM
0
2
4
6
8
10
3
10
×
Events / bin
Data
(MC)
tt
Single top Wt
Others
syst. ⊕
Stat. ATLAS
-1
= 13 TeV, 139 fb
s
> 200 GeV
lead. jet
T
p
-jets,
b
CR 2
tt 2
10
3
10
[GeV]
µ
e
m
0.8
0.9
1
1.1
1.2
Data/SM
0
1000
2000
3000
4000
5000
6000
7000
Events / bin
Data
(MC)
tt
Single top Wt
Others
syst. ⊕
Stat. ATLAS
-1
= 13 TeV, 139 fb
s
> 200 GeV
lead. jet
T
p
-jet,
b
CR 1
tt Events / bin JHEP06(2021)003 Data/SM Data/SM 2
10
3
10
[GeV]
µ
e
m
0.8
1
1.2
Data/SM
0
5
10
15
20
25
30
Events / bin
Data
Top
WW
Fakes
γ
WZ,ZZ,V
Drell-Yan
*
syst. ⊕
Stat. *: without WW modelling uncertainties
ATLAS
-1
= 13 TeV, 139 fb
s
> 200 GeV
lead. jet
T
p
Top enriched, 2
10
3
10
[GeV]
µ
e
m
0.95
0.96
0.97
0.98
0.99
1
1.01
1.02
1.03
b
b-jet correlation C
Simulation
ATLAS Figure 14. Detector-level distributions of the dilepton invariant mass meµ for plead. jet
T
> 200 GeV
in the one b-tag and two b-tag control regions as well as the top-enriched region, together with the
b-jet correlation factor Cb. The lower panels in the plots of detector-level distributions show the
ratio of the data to the total prediction. The uncertainties shown include statistical and systematic
uncertainties, for both the distributions and the correlation factor. – 34 – Open Access. This article is distributed under the terms of the Creative Commons
Attribution License (CC-BY 4.0), which permits any use, distribution and reproduction in
any medium, provided the original author(s) and source are credited. Open Access. This article is distributed under the terms of the Creative Commons
Attribution License (CC-BY 4.0), which permits any use, distribution and reproduction in
any medium, provided the original author(s) and source are credited. References [1] ATLAS collaboration, Measurement of W +W −production in pp collisions at √s = 7 TeV
with the ATLAS detector and limits on anomalous WWZ and WWγ couplings, Phys. Rev. D 87 (2013) 112001 [Erratum ibid. 88 (2013) 079906] [arXiv:1210.2979] [INSPIRE]. [2] CMS collaboration, Measurement of the W +W −cross section in pp collisions at
√s = 7 TeV and limits on anomalous WWγ and WWZ couplings, Eur. Phys. J. C 73
(2013) 2610 [arXiv:1306.1126] [INSPIRE]. JHEP06(2021)003 [3] ATLAS collaboration, Measurement of total and differential W +W −production cross
sections in proton-proton collisions at √s = 8 TeV with the ATLAS detector and limits on
anomalous triple-gauge-boson couplings, JHEP 09 (2016) 029 [arXiv:1603.01702]
[INSPIRE]. [3] ATLAS collaboration, Measurement of total and differential W +W −production cross
sections in proton-proton collisions at √s = 8 TeV with the ATLAS detector and limits on
anomalous triple-gauge-boson couplings, JHEP 09 (2016) 029 [arXiv:1603.01702]
[INSPIRE]. [4] CMS collaboration, Measurement of the W +W −cross section in pp collisions at
√s = 8 TeV and limits on anomalous gauge couplings, Eur. Phys. J. C 76 (2016) 401
[arXiv:1507.03268] [INSPIRE]. [4] CMS collaboration, Measurement of the W +W −cross section in pp collisions at
√s = 8 TeV and limits on anomalous gauge couplings, Eur. Phys. J. C 76 (2016) 401
[arXiv:1507.03268] [INSPIRE]. [5] ATLAS collaboration, Measurement of W +W −production in association with one jet in
proton-proton collisions at √s = 8 TeV with the ATLAS detector, Phys. Lett. B 763 (2016)
114 [arXiv:1608.03086] [INSPIRE]. [5] ATLAS collaboration, Measurement of W +W −production in association with one jet in
proton-proton collisions at √s = 8 TeV with the ATLAS detector, Phys. Lett. B 763 (2016)
114 [arXiv:1608.03086] [INSPIRE]. [6] ATLAS collaboration, Measurement of the W +W −production cross section in pp
collisions at a centre-of-mass energy of √s = 13 TeV with the ATLAS experiment, Phys. Lett. B 773 (2017) 354 [arXiv:1702.04519] [INSPIRE]. [7] ATLAS collaboration, Measurement of fiducial and differential W +W −production
cross-sections at √s = 13 TeV with the ATLAS detector, Eur. Phys. J. C 79 (2019) 884
[arXiv:1905.04242] [INSPIRE]. [8] CMS collaboration, W +W −boson pair production in proton-proton collisions at
√s = 13 TeV, Phys. Rev. D 102 (2020) 092001 [arXiv:2009.00119] [INSPIRE]. [9] ALEPH, DELPHI, L3, OPAL and LEP Electroweak collaboration, Electroweak
measurements in electron-positron collisions at W-boson-pair energies at LEP, Phys. Rept. 532 (2013) 119 [arXiv:1302.3415] [INSPIRE]. References [10] CDF collaboration, Observation of W +W −production in ¯pp collisions at √s = 1.8 TeV,
Phys. Rev. Lett. 78 (1997) 4536 [INSPIRE]. [11] CDF collaboration, Measurement of the W +W −production cross section and search for
anomalous WWγ and WWZ couplings in p¯p collisions at √s = 1.96 TeV, Phys. Rev. Lett. 104 (2010) 201801 [arXiv:0912.4500] [INSPIRE]. [12] D0 collaboration, Measurement of the WW production cross section with dilepton final
states in p¯p collisions at √s = 1.96 TeV and limits on anomalous trilinear gauge couplings,
Phys. Rev. Lett. 103 (2009) 191801 [arXiv:0904.0673] [INSPIRE]. [13] A. Azatov, J. Elias-Miro, Y. Reyimuaji and E. Venturini, Novel measurements of anomalous
triple gauge couplings for the LHC, JHEP 10 (2017) 027 [arXiv:1707.08060] [INSPIRE]. – 35 – [14] B. Grzadkowski, M. Iskrzynski, M. Misiak and J. Rosiek, Dimension-six terms in the
Standard Model Lagrangian, JHEP 10 (2010) 085 [arXiv:1008.4884] [INSPIRE]. [15] A.J. Barr, Measuring slepton spin at the LHC, JHEP 02 (2006) 042 [hep-ph/0511115]
[INSPIRE]. [16] ATLAS collaboration, The ATLAS experiment at the CERN Large Hadron Collider, 2008
JINST 3 S08003 [INSPIRE]. [17] L. Evans and P. Bryant eds., LHC machine, 2008 JINST 3 S08001 [INSPIRE]. [18] ATLAS collaboration, ATLAS Insertable B-Layer technical design report, Tech. Rep. CERN-LHCC-2010-013, CERN, Geneva, Switzerland (2010) [ATLAS-TDR-19]. JHEP06(2021)003 JHEP06(2021)003 [19] ATLAS IBL collaboration, Production and integration of the ATLAS Insertable B-Layer,
2018 JINST 13 T05008 [arXiv:1803.00844] [INSPIRE]. [20] ATLAS collaboration, ATLAS data quality operations and performance for 2015–2018
data-taking, 2020 JINST 15 P04003 [arXiv:1911.04632] [INSPIRE]. [21] ATLAS collaboration, Luminosity determination in pp collisions at √s = 13 TeV using the
ATLAS detector at the LHC, Tech. Rep. ATLAS-CONF-2019-021, CERN, Geneva,
Switzerland (2019). [22] G. Avoni et al., The new LUCID-2 detector for luminosity measurement and monitoring in
ATLAS, 2018 JINST 13 P07017 [INSPIRE]. [23] ATLAS collaboration, The ATLAS simulation infrastructure, Eur. Phys. J. C 70 (2010)
823 [arXiv:1005.4568] [INSPIRE]. [24] GEANT4 collaboration, GEANT4 — a simulation toolkit, Nucl. Instrum. Meth. A 506
(2003) 250 [INSPIRE]. [25] Sherpa collaboration, Event generation with Sherpa 2.2, SciPost Phys. 7 (2019) 034
[arXiv:1905.09127] [INSPIRE]. [26] T. Gleisberg and S. Höche, Comix, a new matrix element generator, JHEP 12 (2008) 039
[arXiv:0808.3674] [INSPIRE]. [27] S. Schumann and F. Krauss, A parton shower algorithm based on Catani-Seymour dipole
factorisation, JHEP 03 (2008) 038 [arXiv:0709.1027] [INSPIRE]. [28] S. Höche, F. Krauss, M. Schönherr and F. References Siegert, A critical appraisal of NLO+PS
matching methods, JHEP 09 (2012) 049 [arXiv:1111.1220] [INSPIRE]. [29] S. Höche, F. Krauss, M. Schönherr and F. Siegert, QCD matrix elements + parton showers:
the NLO case, JHEP 04 (2013) 027 [arXiv:1207.5030] [INSPIRE]. [30] S. Catani, F. Krauss, R. Kuhn and B.R. Webber, QCD matrix elements + parton showers,
JHEP 11 (2001) 063 [hep-ph/0109231] [INSPIRE]. [31] S. Höche, F. Krauss, S. Schumann and F. Siegert, QCD matrix elements and truncated
showers, JHEP 05 (2009) 053 [arXiv:0903.1219] [INSPIRE]. [32] F. Cascioli, P. Maierhöfer and S. Pozzorini, Scattering amplitudes with open loops, Phys. Rev. Lett. 108 (2012) 111601 [arXiv:1111.5206] [INSPIRE]. [33] A. Denner, S. Dittmaier and L. Hofer, Collier: a fortran-based Complex One-Loop LIbrary
in Extended Regularizations, Comput. Phys. Commun. 212 (2017) 220 [arXiv:1604.06792]
[INSPIRE]. – 36 – [34] NNPDF collaboration, Parton distributions for the LHC run II, JHEP 04 (2015) 040
[arXiv:1410.8849] [INSPIRE]. [35] P. Nason, A new method for combining NLO QCD with shower Monte Carlo algorithms,
JHEP 11 (2004) 040 [hep-ph/0409146] [INSPIRE]. [36] S. Frixione, P. Nason and C. Oleari, Matching NLO QCD computations with parton shower
simulations: the POWHEG method, JHEP 11 (2007) 070 [arXiv:0709.2092] [INSPIRE]. [37] S. Alioli, P. Nason, C. Oleari and E. Re, A general framework for implementing NLO
calculations in shower Monte Carlo programs: the POWHEG BOX, JHEP 06 (2010) 043
[arXiv:1002.2581] [INSPIRE]. JHEP06(2021)003 JHEP06(2021)003 [38] P. Nason and G. Zanderighi, W +W −, WZ and ZZ production in the POWHEG-BOX-V2,
Eur. Phys. J. C 74 (2014) 2702 [arXiv:1311.1365] [INSPIRE]. [39] T. Sjöstrand, S. Mrenna and P.Z. Skands, A brief introduction to PYTHIA 8.1, Comput. Phys. Commun. 178 (2008) 852 [arXiv:0710.3820] [INSPIRE]. [40] ATLAS collaboration, Measurement of the Z/γ∗boson transverse momentum distribution
in pp collisions at √s = 7 TeV with the ATLAS detector, JHEP 09 (2014) 145
[arXiv:1406.3660] [INSPIRE]. [41] H.-L. Lai et al., New parton distributions for collider physics, Phys. Rev. D 82 (2010)
074024 [arXiv:1007.2241] [INSPIRE]. [42] J. Pumplin, D.R. Stump, J. Huston, H.L. Lai, P.M. Nadolsky and W.K. Tung, New
generation of parton distributions with uncertainties from global QCD analysis, JHEP 07
(2002) 012 [hep-ph/0201195] [INSPIRE]. [43] T. Gehrmann et al., W +W −production at hadron colliders in next to next to leading order
QCD, Phys. Rev. Lett. 113 (2014) 212001 [arXiv:1408.5243] [INSPIRE]. [44] S. Frixione, P. Nason and G. [51] M. Bähr et al., HERWIG++ physics and manual, Eur. Phys. J. C 58 (2008) 639
[arXiv:0803.0883] [INSPIRE]. References Ridolfi, A positive-weight next-to-leading-order Monte Carlo
for heavy flavour hadroproduction, JHEP 09 (2007) 126 [arXiv:0707.3088] [INSPIRE]. [45] T. Sjöstrand et al., An introduction to PYTHIA 8.2, Comput. Phys. Commun. 191 (2015)
159 [arXiv:1410.3012] [INSPIRE]. [46] ATLAS collaboration, ATLAS PYTHIA 8 tunes to 7 TeV data, Tech. Rep. ATL-PHYS-PUB-2014-021, CERN, Geneva, Switzerland (2014). [47] R.D. Ball et al., Parton distributions with LHC data, Nucl. Phys. B 867 (2013) 244
[arXiv:1207.1303] [INSPIRE]. [48] ATLAS collaboration, Studies on top-quark Monte Carlo modelling for Top2016, Tech. Rep. ATL-PHYS-PUB-2016-020, CERN, Geneva, Switzerland (2016). [49] S. Frixione, E. Laenen, P. Motylinski, B.R. Webber and C.D. White, Single-top
hadroproduction in association with a W boson, JHEP 07 (2008) 029 [arXiv:0805.3067]
[INSPIRE]. [50] ATLAS collaboration, Studies on top-quark Monte Carlo modelling with Sherpa and
MG5_aMC@NLO, Tech. Rep. ATL-PHYS-PUB-2017-007, CERN, Geneva, Switzerland
(2017). [51] M. Bähr et al., HERWIG++ physics and manual, Eur. Phys. J. C 58 (2008) 639
[arXiv:0803.0883] [INSPIRE]. – 37 – [52] J. Bellm et al., HERWIG 7.0/HERWIG++ 3.0 release note, Eur. Phys. J. C 76 (2016) 196
[arXiv:1512.01178] [INSPIRE]. [53] L.A. Harland-Lang, A.D. Martin, P. Motylinski and R.S. Thorne, Parton distributions in
the LHC era: MMHT 2014 PDFs, Eur. Phys. J. C 75 (2015) 204 [arXiv:1412.3989]
[INSPIRE]. [54] J. Alwall et al., The automated computation of tree-level and next-to-leading order
differential cross sections, and their matching to parton shower simulations, JHEP 07
(2014) 079 [arXiv:1405.0301] [INSPIRE]. [55] M. Beneke, P. Falgari, S. Klein and C. Schwinn, Hadronic top-quark pair production with
NNLL threshold resummation, Nucl. Phys. B 855 (2012) 695 [arXiv:1109.1536] [INSPIRE] JHEP06(2021)003 JHEP06(2021)003 [56] M. Cacciari, M. Czakon, M. Mangano, A. Mitov and P. Nason, Top-pair production at
hadron colliders with next-to-next-to-leading logarithmic soft-gluon resummation, Phys. Lett. B 710 (2012) 612 [arXiv:1111.5869] [INSPIRE]. [57] P. Bärnreuther, M. Czakon and A. Mitov, Percent level precision physics at the Tevatron:
first genuine NNLO QCD corrections to q¯q →t¯t + X, Phys. Rev. Lett. 109 (2012) 132001
[arXiv:1204.5201] [INSPIRE]. [58] M. Czakon and A. Mitov, NNLO corrections to top-pair production at hadron colliders: the
all-fermionic scattering channels, JHEP 12 (2012) 054 [arXiv:1207.0236] [INSPIRE]. [59] M. Czakon and A. Mitov, NNLO corrections to top pair production at hadron colliders: the
quark-gluon reaction, JHEP 01 (2013) 080 [arXiv:1210.6832] [INSPIRE]. [60] M. Czakon, P. Fiedler and A. Mitov, Total top-quark pair-production cross section at hadron
colliders through O(α4
S), Phys. Rev. Lett. 110 (2013) 252004 [arXiv:1303.6254] [INSPIRE]. [61] M. References Czakon and A. Mitov, Top++: a program for the calculation of the top-pair
cross-section at hadron colliders, Comput. Phys. Commun. 185 (2014) 2930
[arXiv:1112.5675] [INSPIRE]. [62] N. Kidonakis, Two-loop soft anomalous dimensions for single top quark associated
production with a W −or H−, Phys. Rev. D 82 (2010) 054018 [arXiv:1005.4451]
[INSPIRE]. [63] N. Kidonakis, Top quark production, in Helmholtz international summer school on physics
of heavy quarks and hadrons, DESY-PROC-2013-03, (2013) [arXiv:1311.0283] [INSPIRE]. [64] C. Anastasiou, L.J. Dixon, K. Melnikov and F. Petriello, High precision QCD at hadron
colliders: electroweak gauge boson rapidity distributions at NNLO, Phys. Rev. D 69 (2004)
094008 [hep-ph/0312266] [INSPIRE]. [65] L. Lönnblad, Correcting the color dipole cascade model with fixed order matrix elements,
JHEP 05 (2002) 046 [hep-ph/0112284] [INSPIRE]. [66] L. Lönnblad and S. Prestel, Matching tree-level matrix elements with interleaved showers,
JHEP 03 (2012) 019 [arXiv:1109.4829] [INSPIRE]. [67] M. Grazzini, S. Kallweit, D. Rathlev and M. Wiesemann, W ±Z production at hadron
colliders in NNLO QCD, Phys. Lett. B 761 (2016) 179 [arXiv:1604.08576] [INSPIRE]. [68] M. Grazzini, S. Kallweit, D. Rathlev and M. Wiesemann, W ±Z production at the LHC:
fiducial cross sections and distributions in NNLO QCD, JHEP 05 (2017) 139
[arXiv:1703.09065] [INSPIRE]. – 38 – [69] M. Grazzini, S. Kallweit and D. Rathlev, ZZ production at the LHC: fiducial cross sections
and distributions in NNLO QCD, Phys. Lett. B 750 (2015) 407 [arXiv:1507.06257]
[INSPIRE]. [70] F. Cascioli et al., ZZ production at hadron colliders in NNLO QCD, Phys. Lett. B 735
(2014) 311 [arXiv:1405.2219] [INSPIRE]. [71] D.J. Lange, The EvtGen particle decay simulation package, Nucl. Instrum. Meth. A 462
(2001) 152 [INSPIRE]. [72] ATLAS collaboration, The PYTHIA 8 A3 tune description of ATLAS minimum bias and
inelastic measurements incorporating the Donnachie-Landshoffdiffractive model, Tech. Rep. ATL-PHYS-PUB-2016-017, CERN, Geneva, Switzerland (2016). JHEP06(2021)003 [73] M. Grazzini, S. Kallweit, S. Pozzorini, D. Rathlev and M. Wiesemann, W +W −production
at the LHC: fiducial cross sections and distributions in NNLO QCD, JHEP 08 (2016) 140
[arXiv:1605.02716] [INSPIRE]. [74] ATLAS collaboration, Performance of electron and photon triggers in ATLAS during LHC
run 2, Eur. Phys. J. C 80 (2020) 47 [arXiv:1909.00761] [INSPIRE]. [75] ATLAS collaboration, Performance of the ATLAS muon triggers in run 2, 2020 JINST 15
P09015 [arXiv:2004.13447] [INSPIRE]. [76] ATLAS collaboration, Electron and photon performance measurements with the ATLAS
detector using the 2015–2017 LHC proton-proton collision data, 2019 JINST 14 P12006
[arXiv:1908.00005] [INSPIRE]. References [77] ATLAS collaboration, Muon reconstruction and identification efficiency in ATLAS using
the full run 2 pp collision data set at √s = 13 TeV, arXiv:2012.00578 [INSPIRE]. [78] ATLAS collaboration, Muon reconstruction performance of the ATLAS detector in
proton-proton collision data at √s = 13 TeV, Eur. Phys. J. C 76 (2016) 292
[arXiv:1603.05598] [INSPIRE]. [79] M. Cacciari, G.P. Salam and G. Soyez, The anti-kt jet clustering algorithm, JHEP 04
(2008) 063 [arXiv:0802.1189] [INSPIRE]. [80] ATLAS collaboration, Jet reconstruction and performance using particle flow with the
ATLAS detector, Eur. Phys. J. C 77 (2017) 466 [arXiv:1703.10485] [INSPIRE]. [81] ATLAS collaboration, Performance of pile-up mitigation techniques for jets in pp collisions
at √s = 8 TeV using the ATLAS detector, Eur. Phys. J. C 76 (2016) 581
[arXiv:1510.03823] [INSPIRE]. [82] ATLAS collaboration, Jet energy scale and resolution measured in proton-proton collisions
at √s = 13 TeV with the ATLAS detector, arXiv:2007.02645 [INSPIRE]. [83] ATLAS collaboration, Optimisation and performance studies of the ATLAS b-tagging
algorithms for the 2017–18 LHC run, Tech. Rep. ATL-PHYS-PUB-2017-013, CERN,
Geneva, Switzerland (2017). [84] ATLAS collaboration, ATLAS b-jet identification performance and efficiency measurement
with t¯t events in pp collisions at √s = 13 TeV, Eur. Phys. J. C 79 (2019) 970
[arXiv:1907.05120] [INSPIRE]. – 39 – [85] ATLAS collaboration, Performance of missing transverse momentum reconstruction with
the ATLAS detector using proton-proton collisions at √s = 13 TeV, Eur. Phys. J. C 78
(2018) 903 [arXiv:1802.08168] [INSPIRE]. [86] ATLAS collaboration, Measurement of the t¯t production cross-section and lepton
differential distributions in eµ dilepton events from pp collisions at √s = 13 TeV with the
ATLAS detector, Eur. Phys. J. C 80 (2020) 528 [arXiv:1910.08819] [INSPIRE]. [87] ATLAS collaboration, Measurement of W ± and Z-boson production cross sections in pp
collisions at √s = 13 TeV with the ATLAS detector, Phys. Lett. B 759 (2016) 601
[arXiv:1603.09222] [INSPIRE]. JHEP06(2021)003 [88] ATLAS collaboration, Observation of electroweak production of a same-sign W boson pair
in association with two jets in pp collisions at √s = 13 TeV with the ATLAS detector, Phys. Rev. Lett. 123 (2019) 161801 [arXiv:1906.03203] [INSPIRE]. [89] ATLAS collaboration, Measurement of W ±Z production cross sections and gauge boson
polarisation in pp collisions at √s = 13 TeV with the ATLAS detector, Eur. Phys. J. C 79
(2019) 535 [arXiv:1902.05759] [INSPIRE]. [90] ATLAS collaboration, Multi-boson simulation for 13 TeV ATLAS analyses, Tech. Rep. ATL-PHYS-PUB-2016-002, CERN, Geneva, Switzerland (2016). [91] M. References Grazzini, S. Kallweit and D. Rathlev, Wγ and Zγ production at the LHC in NNLO
QCD, JHEP 07 (2015) 085 [arXiv:1504.01330] [INSPIRE]. [92] M. Cacciari and G.P. Salam, Pileup subtraction using jet areas, Phys. Lett. B 659 (2008)
119 [arXiv:0707.1378] [INSPIRE]. [93] G. D’Agostini, A multidimensional unfolding method based on Bayes’ theorem, Nucl. Instrum. Meth. A 362 (1995) 487 [INSPIRE]. [94] G. D’Agostini, Improved iterative Bayesian unfolding, in Alliance workshop on unfolding
and data correction, (2010) [arXiv:1010.0632] [INSPIRE]. [95] S. Catani and M. Grazzini, An NNLO subtraction formalism in hadron collisions and its
application to Higgs boson production at the LHC, Phys. Rev. Lett. 98 (2007) 222002
[hep-ph/0703012] [INSPIRE]. [96] S. Catani, L. Cieri, D. de Florian, G. Ferrera and M. Grazzini, Vector boson production at
hadron colliders: hard-collinear coefficients at the NNLO, Eur. Phys. J. C 72 (2012) 2195
[arXiv:1209.0158] [INSPIRE]. [97] T. Gehrmann, A. von Manteuffel and L. Tancredi, The two-loop helicity amplitudes for
q¯q′ →V1V2 →4 leptons, JHEP 09 (2015) 128 [arXiv:1503.04812] [INSPIRE]. [98] M. Grazzini, S. Kallweit and M. Wiesemann, Fully differential NNLO computations with
MATRIX, Eur. Phys. J. C 78 (2018) 537 [arXiv:1711.06631] [INSPIRE]. [99] M. Grazzini, S. Kallweit, M. Wiesemann and J.Y. Yook, W +W −production at the LHC:
NLO QCD corrections to the loop-induced gluon fusion channel, Phys. Lett. B 804 (2020)
135399 [arXiv:2002.01877] [INSPIRE]. [100] S. Kallweit, J.M. Lindert, P. Maierhöfer, S. Pozzorini and M. Schönherr, NLO electroweak
automation and precise predictions for W + multijet production at the LHC, JHEP 04
(2015) 012 [arXiv:1412.5157] [INSPIRE]. – 40 – [101] M. Schönherr, An automated subtraction of NLO EW infrared divergences, Eur. Phys. J. C
78 (2018) 119 [arXiv:1712.07975] [INSPIRE]. [102] F. Buccioni et al., OpenLoops 2, Eur. Phys. J. C 79 (2019) 866 [arXiv:1907.13071]
[INSPIRE]. [103] R. Frederix and S. Frixione, Merging meets matching in MC@NLO, JHEP 12 (2012) 061
[arXiv:1209.6215] [INSPIRE]. [104] K. Hamilton, T. Melia, P.F. Monni, E. Re and G. Zanderighi, Merging WW and WW +
jet with MINLO, JHEP 09 (2016) 057 [arXiv:1606.07062] [INSPIRE]. [105] A. Azatov, R. Contino, C.S. Machado and F. Riva, Helicity selection rules and
noninterference for BSM amplitudes, Phys. Rev. D 95 (2017) 065014 [arXiv:1607.05236]
[INSPIRE]. JHEP06(2021)003 JHEP06(2021)003 [106] A. Falkowski, M. Gonzalez-Alonso, A. Greljo, D. Marzocca and M. Son, Anomalous triple
gauge couplings in the effective field theory approach at the LHC, JHEP 02 (2017) 115
[arXiv:1609.06312] [INSPIRE]. [107] J. Alwall, M. References Herquet, F. Maltoni, O. Mattelaer and T. Stelzer, MadGraph 5: going beyond,
JHEP 06 (2011) 128 [arXiv:1106.0522] [INSPIRE]. [108] S.S. Wilks, The large-sample distribution of the likelihood ratio for testing composite
hypotheses, Annals Math. Statist. 9 (1938) 60 [INSPIRE]. [109] G. Cowan, K. Cranmer, E. Gross and O. Vitells, Asymptotic formulae for likelihood-based
tests of new physics, Eur. Phys. J. C 71 (2011) 1554 [Erratum ibid. 73 (2013) 2501]
[arXiv:1007.1727] [INSPIRE]. [110] ATLAS collaboration, Differential cross-section measurements for the electroweak
production of dijets in association with a Z boson in proton-proton collisions at ATLAS,
Eur. Phys. J. C 81 (2021) 163 [arXiv:2006.15458] [INSPIRE]. [111] M. Grazzini, S. Kallweit, J.M. Lindert, S. Pozzorini and M. Wiesemann, NNLO QCD +
NLO EW with Matrix+OpenLoops: precise predictions for vector-boson pair production,
JHEP 02 (2020) 087 [arXiv:1912.00068] [INSPIRE]. [112] ATLAS collaboration, ATLAS computing acknowledgements, Tech. Rep. ATL-SOFT-PUB-2020-001, CERN, Geneva, Switzerland (2020). – 41 – The ATLAS collaboration The ATLAS collaboration G. Aad101, B. Abbott127, D.C. Abbott102, A. Abed Abud36, K. Abeling53, D.K. Abhayasinghe93, Aad101, B. Abbott127, D.C. Abbott102, A. Abed Abud36, K. Abeling53, D.K. Abhayasinghe93,
H. Abidi29, O.S. AbouZeid40, N.L. Abraham155, H. Abramowicz160, H. Abreu159, Y. Abulaiti6, A.C. Abusleme Hoffman145a, B.S. Acharya66a,66b,p, B. Achkar53, L. Adam99, C. Adam Bourdarios5, L. Adamczyk83a, L. Adamek165, J. Adelman120, A. Adiguzel12c,ad,
S. Adorni54, T. Adye142, A.A. Affolder144, Y. Afik159, C. Agapopoulou64, M.N. Agaras38, A. Aggarwal118, C. Agheorghiesei27c, J.A. Aguilar-Saavedra138f,138a,ac, A. Ahmad36, gg
g
g
g
F. Ahmadov79, W.S. Ahmed103, X. Ai46, G. Aielli73a,73b, S. Akatsuka85, M. Akbiyik99, T.P.A. Åkesson96, E. Akilli54, A.V. Akimov110, K. Al Khoury39, G.L. Alberghi23b,23a, JHEP06(2021)003 JHEP06(2021)003 J. Albert174, M.J. Alconada Verzini160, S. Alderweireldt36, M. Aleksa36, I.N. Aleksandrov79, Alexa27b, T. Alexopoulos10, A. Alfonsi119, F. Alfonsi23b,23a, M. Alhroob127, B. Ali140, S. Ali157 Aliev164, G. Alimonti68a, C. Allaire36, B.M.M. Allbrooke155, P.P. Allport21, A. Aloisio69a,69b, Alonso88, C. Alpigiani147, E. Alunno Camelia73a,73b, M. Alvarez Estevez98, M.G. Alviggi69a,69b,
A
l C
i h 80b A A
bl
103 L A
b
133 C A
l
36 D A
id i105 S.P. Amor Dos Santos138a, S. Amoroso46, C.S. Amrouche54, C. Anastopoulos148, N. Andari143,
T A d
11 J K A d
20 S Y A d
45a 45b A A d
68a 68b V A d
i61a S. Angelidakis9, A. Angerami39, A.V. Anisenkov121b,121a, A. Annovi71a, C. Antel54, S. Angelidakis9, A. Angerami39, A.V. Anisenkov121b,121a, A. Annovi71a, C. Antel54, L. Asquith155, J. Assahsah35e, K. Assamagan29, R. Astalos28a, R.J. Atkin33a, M. Atkinson171,
N B Atlay19 H Atmani64 P A Atmasiddha105 K Augsten140 V A Austrup180 G Avolio36 P. Bagnaia72a,72b, M. Bahmani84, H. Bahrasemani151, A.J. Bailey172, V.R. Bailey171, P. Bagnaia72a,72b, M. Bahmani84, H. Bahrasemani151, A.J. Bailey172, V.R. Bailey171, J.T. Baines142, C. Bakalis10, O.K. Baker181, P.J. Bakker119, E. Bakos16, D. Bakshi Gupta8, J.T. Baines142, C. Bakalis10, O.K. Baker181, P.J. Bakker119, E. Bakos16, D. Bakshi Gupta8, S. Balaji156, R. Balasubramanian119, E.M. Baldin121b,121a, P. Balek178, E. Ballabene68a,68b, Balaji156, R. Balasubramanian119, E.M. Baldin121b,121a, P. Balek178, E. Ballabene68a,68b, K.N. Barends33 , T. Barillari
, M-S. Barisits36, J. Barkeloo 30, T. Barklow 5 , B.M. Barnett
R.M. Barnett18, Z. Barnovska-Blenessy60a, A. Baroncelli60a, G. Barone29, A.J. Barr133,
L. Barranco Navarro45a,45b, F. Barreiro98, J. Barreiro Guimarães da Costa15a, U. Barron160,
S. Barsov136, F. Bartels61a, R. Bartoldus152, G. Bartolini101, A.E. Barton89, P. Bartos28a,
A. Basalaev46, A. Basan99, I. Bashta74a,74b, A. Bassalat64,ah, M.J. Basso165, C.R. Basson100, S. Barsov136, F. Bartels61a, R. Bartoldus152, G. Bartolini101, A.E. Barton89, P. The ATLAS collaboration Bartos28a, Bauer143,∗, P. Bauer24, H.S. Bawa31, A. Bayirli12c, J.B. Beacham49, T. Beau134, H. Beauchemin168, F. Becherer52, P. Bechtle24, H.P. Beck20,r, K. Becker176, C. Becot46, P.H. Beauchemin168, F. Becherer52, P. Bechtle24, H.P. Beck20,r, K. Becker176, C. Becot46, A.J. Beddall12a, V.A. Bednyakov79, C.P. Bee154, T.A. Beermann180, M. Begalli80b, M. Begel J. Beddall12a, V.A. Bednyakov79, C.P. Bee154, T.A. Beermann180, M. Begalli80b, M. Begel29 Behera154, J.K. Behr46, J.F. Beirer53,36, F. Beisiegel24, M. Belfkir5, G. Bella160, A. Behera154, J.K. Behr46, J.F. Beirer53,36, F. Beisiegel24, M. Belfkir5, G. Bella160, Bellagamba23b, A. Bellerive34, P. Bellos21, K. Beloborodov121b,121a, K. Belotskiy111, L. Bellagamba23b, A. Bellerive34, P. Bellos21, K. Beloborodov121b,121a, K. Belotskiy111, N.L. Belyaev111, D. Benchekroun35a, Y. Benhammou160, D.P. Benjamin6, M. Benoit29, L. Belyaev111, D. Benchekroun35a, Y. Benhammou160, D.P. Benjamin6, M. Benoit29, J.R. Bensinger26, S. Bentvelsen119, L. Beresford133, M. Beretta51, D. Berge19, R. Bensinger26, S. Bentvelsen119, L. Beresford133, M. Beretta51, D. Berge19, Bergeaas Kuutmann170, N. Berger5, B. Bergmann140, L.J. Bergsten26, J. Beringer18, E. Bergeaas Kuutmann170, N. Berger5, B. Bergmann140, L.J. Bergsten26, J. Beringer18, S. Bhatta154, D.S. Bhattacharya175, P. Bhattarai26, V.S. Bhopatkar6, R. Bi137, R.M. Bianchi137 S. Bhatta154, D.S. Bhattacharya175, P. Bhattarai26, V.S. Bhopatkar6, R. Bi137, R.M. Bianchi137, – 42 – Biebel113, R. Bielski36, K. Bierwagen99, N.V. Biesuz71a,71b, M. Biglietti74a, T.R.V. Billoud140, O. Biebel113, R. Bielski36, K. Bierwagen99, N.V. Biesuz71a,71b, M. Biglietti74a, T.R.V. Billoud ,
,
g
,
,
g
,
,
M. Bindi53, A. Bingul12d, C. Bini72a,72b, S. Biondi23b,23a, C.J. Birch-sykes100, G.A. Bird21,142, ,
,
g
,
,
g
,
M. Bindi53, A. Bingul12d, C. Bini72a,72b, S. Biondi23b,23a, C.J. Birch-sykes100, G.A. Bird21,14 ,
,
g
,
,
g
,
,
Bindi53, A. Bingul12d, C. Bini72a,72b, S. Biondi23b,23a, C.J. Birch-sykes100, G.A. Bird21,142, ,
g
,
,
,
y
,
Birman178, T. Bisanz36, J.P. Biswal3, D. Biswas179,k, A. Bitadze100, C. Bittrich48, ,
g
,
,
,
y
,
M. Birman178, T. Bisanz36, J.P. Biswal3, D. Biswas179,k, A. Bitadze100, C. Bittrich48, Bjørke132, T. Blazek28a, I. Bloch46, C. Blocker26, A. Blue57, U. Blumenschein92, K. Bjørke132, T. Blazek28a, I. Bloch46, C. Blocker26, A. Blue57, U. Blumenschein92, G.J. Bobbink119, V.S. Bobrovnikov121b,121a, D. Bogavac14, A.G. Bogdanchikov121b,121 G.J. Bobbink119, V.S. Bobrovnikov121b,121a, D. Bogavac14, A.G. Bogdanchikov121b,12 C. Bohm45a, V. Boisvert93, P. Bokan46, T. Bold83a, M. Bomben134, M. Bona92, C. Bohm45a, V. Boisvert93, P. Bokan46, T. Bold83a, M. Bomben134, M. Bona92, M. Boonekamp143, C.D. Booth93, A.G. Borbély57, H.M. Borecka-Bielska109, L.S. Borgn Boonekamp143, C.D. Booth93, A.G. Borbély57, H.M. Borecka-Bielska109, L.S. Borgna94, p
,
,
y
,
,
g
,
G. The ATLAS collaboration Borissov89, D. Bortoletto133, D. Boscherini23b, M. Bosman14, J.D. Bossio Sola103, G. Borissov89, D. Bortoletto133, D. Boscherini23b, M. Bosman14, J.D. Bossio Sola103, A. Boveia126, J. Boyd36, D. Boye29, I.R. Boyko79, A.J. Bozson93, J. Bracinik21, N. Brahimi60d,6 A. Boveia126, J. Boyd36, D. Boye29, I.R. Boyko79, A.J. Bozson93, J. Bracinik21, N. Brahimi60d,60c Brandt180, O. Brandt32, F. Braren46, B. Brau102, J.E. Brau130, W.D. Breaden Madden57, G. Brandt180, O. Brandt32, F. Braren46, B. Brau102, J.E. Brau130, W.D. Breaden Madden JHEP06(2021)003 JHEP06(2021)003 K. Brendlinger46, R. Brener159, L. Brenner36, R. Brenner170, S. Bressler178, B. Brickwedde K. Brendlinger46, R. Brener159, L. Brenner36, R. Brenner170, S. Bressler178, B. Brickwedde99 D.L. Briglin21, D. Britton57, D. Britzger114, I. Brock24, R. Brock106, G. Brooijmans39, L. Briglin21, D. Britton57, D. Britzger114, I. Brock24, R. Brock106, G. Brooijmans39, W.K. Brooks145d, E. Brost29, P.A. Bruckman de Renstrom84, B. Brüers46, D. Bruncko28b .K. Brooks145d, E. Brost29, P.A. Bruckman de Renstrom84, B. Brüers46, D. Bruncko28b, Bruni23b, G. Bruni23b, M. Bruschi23b, N. Bruscino72a,72b, L. Bryngemark152, T. Buanes17, A. Bruni23b, G. Bruni23b, M. Bruschi23b, N. Bruscino72a,72b, L. Bryngemark152, T. Buane Buat154, P. Buchholz150, A.G. Buckley57, I.A. Budagov79, M.K. Bugge132, O. Bulekov111, Q. Buat154, P. Buchholz150, A.G. Buckley57, I.A. Budagov79, M.K. Bugge132, O. Bulekov A. Bullard59, T.J. Burch120, S. Burdin90, C.D. Burgard46, A.M. Burger128, B. Burghgrave8, T.P. Burr46, C.D. Burton11, J.C. Burzynski102, V. Büscher99, E. Buschmann53, P.J. Bussey57, J.T.P. Burr46, C.D. Burton11, J.C. Burzynski102, V. Büscher99, E. Buschmann53, P.J. Bussey J.M. Butler25, C.M. Buttar57, J.M. Butterworth94, W. Buttinger142, C.J. Buxo Vazquez106, M. Butler25, C.M. Buttar57, J.M. Butterworth94, W. Buttinger142, C.J. Buxo Vazquez106, A.R. Buzykaev121b,121a, G. Cabras23b,23a, S. Cabrera Urbán172, D. Caforio56, H. Cai137, R. Buzykaev121b,121a, G. Cabras23b,23a, S. Cabrera Urbán172, D. Caforio56, H. Cai137, M.M. Cairo152, O. Cakir4a, N. Calace36, P. Calafiura18, G. Calderini134, P. Calfayan65, V.M.M. Cairo152, O. Cakir4a, N. Calace36, P. Calafiura18, G. Calderini134, P. Calfayan65, Callea57, L.P. Caloba80b, A. Caltabiano73a,73b, S. Calvente Lopez98, D. Calvet38, S. Calvet38, G. Callea57, L.P. Caloba80b, A. Caltabiano73a,73b, S. Calvente Lopez98, D. Calvet38, S. Calvet38 T.P. Calvet101, M. Calvetti71a,71b, R. Camacho Toro134, S. Camarda36, D. Camarero Munoz98, T.P. Calvet101, M. Calvetti71a,71b, R. Camacho Toro134, S. Camarda36, D. Camarero Munoz98, A. Camplani40, V. Canale69a,69b, A. Canesse103, M. Cano Bret77, J. Cantero128, Y. Cao171, A. Camplani40, V. Canale69a,69b, A. Canesse103, M. Cano Bret77, J. Cantero128, Y. Cao171, B.T. Carlson137, E.M. Carlson174,166a, L. Carminati68a,68b, M. Carnesale72a,72b, B.T. Carlson137, E.M. Carlson174,166a, L. Carminati68a,68b, M. Carnesale72a,72b, M.D. Carney152, S. Caron118, E. Carquin145d, S. Carrá46, G. Carratta23b,23a, J.W.S. The ATLAS collaboration Carter165, R.M.D. Carney152, S. Caron118, E. Carquin145d, S. Carrá46, G. Carratta23b,23a, J.W.S. C T.M. Carter50, D. Casadei33c, M.P. Casado14,h, A.F. Casha165, E.G. Castiglia181, F.L. Castillo172, L. Castillo Garcia14, V. Castillo Gimenez172, N.F. Castro138a,138e, A. Catinaccio36, J.R. Catmore132, A. Cattai36, V. Cavaliere29, N. Cavalli23b,23a, V. Cavasinni71a,71b, E. Celeb F. Celli133, K. Cerny129, A.S. Cerqueira80a, A. Cerri155, L. Cerrito73a,73b, F. Cerutti18, A. Cervelli23b,23a, S.A. Cetin12b, Z. Chadi35a, D. Chakraborty120, M. Chala138f, J. Chan179, W.S. Chan119, W.Y. Chan90, J.D. Chapman32, B. Chargeishvili158b, D.G. Charlton21, T.P. Charman92, M. Chatterjee20, C.C. Chau34, S. Chekanov6, S.V. Chekulaev166a, G.A. Chelkov79,af, B. Chen78, C. Chen60a, C.H. Chen78, H. Chen15c, H. Chen29, J. Chen60a, J. Chen39, J. Chen26, S. Chen135, S.J. Chen15c, X. Chen15b, Y. Chen60a, Y-H. Chen46, C.L. Cheng179, H.C. Cheng62a, H.J. Cheng15a, A. Cheplakov79, E. Cheremushkina46, R. Cherkaoui El Moursli35f, E. Cheu7, K. Cheung63, L. Chevalier143, V. Chiarella51, G. Chiarelli71a, G. Chiodini67a, A.S. Chisholm21, A. Chitan27b, I. Chiu162, Y.H. Chiu174, ,
,
,
,
,
L.D. Christopher33f, M.C. Chu62a, X. Chu15a,15d, J. Chudoba139, J.J. Chwastowski84, D. Cieri114
K.M. Ciesla84, V. Cindro91, I.A. Cioară27b, A. Ciocio18, F. Cirotto69a,69b, Z.H. Citron178,l,
M. Citterio68a, D.A. Ciubotaru27b, B.M. Ciungu165, A. Clark54, P.J. Clark50, S.E. Clawson100,
C. Clement45a,45b, L. Clissa23b,23a, Y. Coadou101, M. Cobal66a,66c, A. Coccaro55b, J. Cochran78, L.D. Christopher33f, M.C. Chu62a, X. Chu15a,15d, J. Chudoba139, J.J. Chwastowski84, D. Cieri1 ,
,
,
,
,
,
M. Citterio68a, D.A. Ciubotaru27b, B.M. Ciungu165, A. Clark54, P.J. Clark50, S.E. Clawson100,
C. Clement45a,45b, L. Clissa23b,23a, Y. Coadou101, M. Cobal66a,66c, A. Coccaro55b, J. Cochran78,
R. Coelho Lopes De Sa102, S. Coelli68a, H. Cohen160, A.E.C. Coimbra36, B. Cole39, J. Collot58,
P. Conde Muiño138a,138h, S.H. Connell33c, I.A. Connelly57, E.I. Conroy133, F. Conventi69a,al,
A.M. Cooper-Sarkar133, F. Cormier173, L.D. Corpe94, M. Corradi72a,72b, E.E. Corrigan96, – 43 – F. Corriveau103,aa, M.J. Costa172, F. Costanza5, D. Costanzo148, B.M. Cote126, G. Cowan93, ,
,
,
,
,
J.W. Cowley32, J. Crane100, K. Cranmer124, R.A. Creager135, S. Crépé-Renaudin58, y
,
,
,
g
,
p
,
F. Crescioli134, M. Cristinziani150, M. Cristoforetti75a,75b,b, V. Croft168, G. Crosetti41b,41a, ,
,
,
,
,
A. Cueto5, T. Cuhadar Donszelmann169, H. Cui15a,15d, A.R. Cukierman152, W.R. Cunningha ,
,
y
,
g
,
J.V. Da Fonseca Pinto80b, C. Da Via100, W. Dabrowski83a, T. Dado47, S. Dahbi33f, T. Dai105, y
M.F. Daneri30, M. Danninger151, V. Dao36, G. Darbo55b, A. Dattagupta130, S. D’Auria68a,68b, M.F. Daneri30, M. Danninger151, V. Dao36, G. Darbo55b, A. Dattagupta130, S. D’Auria68a,68b, R. De Asmundis69a, M. The ATLAS collaboration De Beurs119, S. De Castro23b,23a, N. De Groot118, P. de Jong119, R. De Asmundis69a, M. De Beurs119, S. De Castro23b,23a, N. De Groot118, P. de Jong119, H. De la Torre106, A. De Maria15c, D. De Pedis72a, A. De Salvo72a, U. De Sanctis73a,73b, De la Torre106, A. De Maria15c, D. De Pedis72a, A. De Salvo72a, U. De Sanctis73a,73b, JHEP06(2021)003 JHEP06(2021)003 M. De Santis73a,73b, A. De Santo155, J.B. De Vivie De Regie58, D.V. Dedovich79, J. Degen De Santis73a,73b, A. De Santo155, J.B. De Vivie De Regie58, D.V. Dedovich79, J. Degens119, M. Deiana42, J. Del Peso98, Y. Delabat Diaz46, F. Deliot143, C.M. Delitzsch7, A.M. Deiana42, J. Del Peso98, Y. Delabat Diaz46, F. Deliot143, C.M. Delitzsch7, Della Pietra69a,69b, D. Della Volpe54, A. Dell’Acqua36, L. Dell’Asta73a,73b, M. Delmastro5, M. Della Pietra69a,69b, D. Della Volpe54, A. Dell’Acqua36, L. Dell’Asta73a,73b, M. Delmastro5,
58
181
79
109
122
12 M. Della Pietra69a,69b, D. Della Volpe54, A. Dell’Acqua36, L. Dell’Asta73a,73b, M. P.A. Delsart58, S. Demers181, M. Demichev79, G. Demontigny109, S.P. Denisov122, L A. Delsart58, S. Demers181, M. Demichev79, G. Demontigny109, S.P. Denisov122, L. D’Eramo120, D. Derendarz84, J.E. Derkaoui35e, F. Derue134, P. Dervan90, K. Desch24, K. Dette165 Derendarz84, J.E. Derkaoui35e, F. Derue134, P. Dervan90, K. Desch24, K. Dette165, ,
,
,
,
,
,
C. Deutsch24, P.O. Deviveiros36, F.A. Di Bello72a,72b, A. Di Ciaccio73a,73b, L. Di Ciaccio5 ,
,
,
,
,
,
Deutsch24, P.O. Deviveiros36, F.A. Di Bello72a,72b, A. Di Ciaccio73a,73b, L. Di Ciaccio5, C. Di Donato69a,69b, A. Di Girolamo36, G. Di Gregorio71a,71b, A. Di Luca75a,75b Di Donato69a,69b, A. Di Girolamo36, G. Di Gregorio71a,71b, A. Di Luca75a,75b, B. Di Micco74a,74b, R. Di Nardo74a,74b, C. Diaconu101, F.A. Dias119, T. Dias Do Vale138a, Di Micco74a,74b, R. Di Nardo74a,74b, C. Diaconu101, F.A. Dias119, T. Dias Do Vale138a, A. Diaz145a, F.G. Diaz Capriles24, J. Dickinson18, M. Didenko164, E.B. Diehl105, J. Dietrich19, M.A. Diaz145a, F.G. Diaz Capriles24, J. Dickinson18, M. Didenko164, E.B. Diehl105, J. Dietri S. Díez Cornell46, C. Diez Pardos150, A. Dimitrievska18, W. Ding15b, J. Dingfelder24, Díez Cornell46, C. Diez Pardos150, A. Dimitrievska18, W. Ding15b, J. Dingfelder24, S.J. Dittmeier61b, F. Dittus36, F. Djama101, T. Djobava158b, J.I. Djuvsland17, M.A.B. Do M. Dobre27b, D. Dodsworth26, C. Doglioni96, J. Dolejsi141, Z. Dolezal141, M. Donadelli80c, M. Dobre27b, D. Dodsworth26, C. Doglioni96, J. Dolejsi141, Z. Dolezal141, M. Donadelli80c, B. Dong60c, J. Donini38, A. D’onofrio15c, M. D’Onofrio90, J. Dopke142, A. Doria69a, M.T. D A.T. Doyle57, E. Drechsler151, E. Dreyer151, T. Dreyer53, A.S. Drobac168, D. Du60b, A.T. Doyle57, E. Francavilla71a,71b, S. Francescato72a,72b, M. Franchini23b,23a, S. Franchino61a, D. Francis36, The ATLAS collaboration Drechsler151, E. Dreyer151, T. Dreyer53, A.S. Drobac168, D. Du60b, A.T. Doyle
, E. Drechsler
, E. Dreyer
, T. Dreyer
, A.S. Drobac
, D. Du
,
T.A. du Pree119, Y. Duan60d, F. Dubinin110, M. Dubovsky28a, A. Dubreuil54, E. Duchovn G. Duckeck113, O.A. Ducu36,27b, D. Duda114, A. Dudarev36, A.C. Dudder99, M. D’uffizi100, G. Duckeck113, O.A. Ducu36,27b, D. Duda114, A. Dudarev36, A.C. Dudder99, M. D’uffizi100, L. Duflot64, M. Dührssen36, C. Dülsen180, M. Dumancic178, A.E. Dumitriu27b, M. Dunford61a, S. Dungs47, A. Duperrin101, H. Duran Yildiz4a, M. Düren56, A. Durglishvili158b, B. Dutta46, D. Duvnjak1, G.I. Dyckes135, M. Dyndal83a, S. Dysch100, B.S. Dziedzic84, B. Eckerova28a, M.G. Eggleston49, E. Egidio Purcino De Souza80b, L.F. Ehrke54, T. Eifert8, G. Eigen17, K. Einsweiler18, T. Ekelof170, H. El Jarrari35f, A. El Moussaouy35a, V. Ellajosyula170, Einsweiler18, T. Ekelof170, H. El Jarrari35f, A. El Moussaouy35a, V. Ellajosyula170, M. Ellert170, F. Ellinghaus180, A.A. Elliot92, N. Ellis36, J. Elmsheuser29, M. Elsing36, 170, F. Ellinghaus180, A.A. Elliot92, N. Ellis36, J. Elmsheuser29, M. Elsing36, Emeliyanov142, A. Emerman39, Y. Enari162, J. Erdmann47, A. Ereditato20, P.A. Erland84, D. Emeliyanov142, A. Emerman39, Y. Enari162, J. Erdmann47, A. Ereditato20, P.A. Erland8 Errenst180, M. Escalier64, C. Escobar172, O. Estrada Pastor172, E. Etzion160, G. Evans138a, M. Errenst180, M. Escalier64, C. Escobar172, O. Estrada Pastor172, E. Etzion160, G. Evans13 H. Evans65, M.O. Evans155, A. Ezhilov136, F. Fabbri57, L. Fabbri23b,23a, V. Fabiani118,
G. Facini176, R.M. Fakhrutdinov122, S. Falciano72a, P.J. Falke24, S. Falke36, J. Faltova141,
Y. Fan15a, Y. Fang15a, Y. Fang15a, G. Fanourakis44, M. Fanti68a,68b, M. Faraj60c, A. Farbin8,
A. Farilla74a, E.M. Farina70a,70b, T. Farooque106, S.M. Farrington50, P. Farthouat36, F. Fassi35f,
D. Fassouliotis9, M. Faucci Giannelli73a,73b, W.J. Fawcett32, L. Fayard64, O.L. Fedin136,q,
A. Fehr20, M. Feickert171, L. Feligioni101, A. Fell148, C. Feng60b, M. Feng49, M.J. Fenton169,
A.B. Fenyuk122, S.W. Ferguson43, J. Ferrando46, A. Ferrari170, P. Ferrari119, R. Ferrari70a,
D. Ferrere54, C. Ferretti105, F. Fiedler99, A. Filipčič91, F. Filthaut118, K.D. Finelli25,
M.C.N. Fiolhais138a,138c,a, L. Fiorini172, F. Fischer113, J. Fischer99, W.C. Fisher106, T. Fitschen21,
I. Fleck150, P. Fleischmann105, T. Flick180, B.M. Flierl113, L. Flores135, L.R. Flores Castillo62a,
F.M. Follega75a,75b, N. Fomin17, J.H. Foo165, G.T. Forcolin75a,75b, B.C. Forland65, A. Formica143,
F.A. Förster14, A.C. Forti100, E. Fortin101, M.G. Foti133, D. Fournier64, H. Fox89,
P. Francavilla71a,71b, S. Francescato72a,72b, M. Franchini23b,23a, S. Franchino61a, D. Francis36, H. Evans65, M.O. Evans155, A. Ezhilov136, F. Fabbri57, L. Fabbri23b,23a, V. Fabiani118, Evans65, M.O. Evans155, A. Ezhilov136, F. Fabbri57, L. Fabbri23b,23a, V. Fabiani118, G. Facini
, R.M. Fakhrutdinov
, S. Falciano
, P.J. The ATLAS collaboration Falke
, S. Falke
, J. Faltova
,
Y. Fan15a, Y. Fang15a, Y. Fang15a, G. Fanourakis44, M. Fanti68a,68b, M. Faraj60c, A. Farbin8,
A. Farilla74a, E.M. Farina70a,70b, T. Farooque106, S.M. Farrington50, P. Farthouat36, F. Fassi35f,
D. Fassouliotis9, M. Faucci Giannelli73a,73b, W.J. Fawcett32, L. Fayard64, O.L. Fedin136,q,
A. Fehr20, M. Feickert171, L. Feligioni101, A. Fell148, C. Feng60b, M. Feng49, M.J. Fenton169,
A.B. Fenyuk122, S.W. Ferguson43, J. Ferrando46, A. Ferrari170, P. Ferrari119, R. Ferrari70a,
D. Ferrere54, C. Ferretti105, F. Fiedler99, A. Filipčič91, F. Filthaut118, K.D. Finelli25,
M.C.N. Fiolhais138a,138c,a, L. Fiorini172, F. Fischer113, J. Fischer99, W.C. Fisher106, T. Fitschen21,
I. Fleck150, P. Fleischmann105, T. Flick180, B.M. Flierl113, L. Flores135, L.R. Flores Castillo62a,
F.M. Follega75a,75b, N. Fomin17, J.H. Foo165, G.T. Forcolin75a,75b, B.C. Forland65, A. Formica143,
F.A. Förster14, A.C. Forti100, E. Fortin101, M.G. Foti133, D. Fournier64, H. Fox89,
P. Francavilla71a,71b, S. Francescato72a,72b, M. Franchini23b,23a, S. Franchino61a, D. Francis36, D. Fassouliotis9, M. Faucci Giannelli73a,73b, W.J. Fawcett32, L. Fayard64, O.L. Fedin136,q, – 44 – L. Franco5, L. Franconi20, M. Franklin59, G. Frattari72a,72b, P.M. Freeman21, B. Freund109, ,
,
,
,
,
,
W.S. Freund80b, E.M. Freundlich47, D.C. Frizzell127, D. Froidevaux36, J.A. Frost133, Y. Fu60 ,
,
,
,
,
,
Freund80b, E.M. Freundlich47, D.C. Frizzell127, D. Froidevaux36, J.A. Frost133, Y. Fu60a, ,
,
,
,
,
M. Fujimoto125, E. Fullana Torregrosa172, T. Fusayasu115, J. Fuster172, A. Gabrielli23b,23a, ,
,
,
,
,
ujimoto125, E. Fullana Torregrosa172, T. Fusayasu115, J. Fuster172, A. Gabrielli23b,23a, A. Gabrielli36, P. Gadow46, G. Gagliardi55b,55a, L.G. Gagnon18, G.E. Gallardo133, E.J. Gall A. Gabrielli36, P. Gadow46, G. Gagliardi55b,55a, L.G. Gagnon18, G.E. Gallardo133, E.J. Gallas133, B.J. Gallop142, R. Gamboa Goni92, K.K. Gan126, S. Ganguly178, J. Gao60a, Y. Gao50, J. Gallop142, R. Gamboa Goni92, K.K. Gan126, S. Ganguly178, J. Gao60a, Y. Gao50, Y.S. Gao31,n, F.M. Garay Walls145a, C. García172, J.E. García Navarro172, J.A. García Pascual15a, Y.S. Gao31,n, F.M. Garay Walls145a, C. García172, J.E. García Navarro172, J.A. García Pascual15a Garcia-Sciveres18, R.W. Gardner37, D. Garg77, S. Gargiulo52, C.A. Garner165, V. Garonne132, ,
,
g
,
g
,
,
S.J. Gasiorowski147, P. Gaspar80b, G. Gaudio70a, P. Gauzzi72a,72b, I.L. Gavrilenko110, S.J. Gasiorowski147, P. Gaspar80b, G. Gaudio70a, P. Gauzzi72a,72b, I.L. Gavrilenko110, C.N.P. Gee142, J. Geisen96, M. Geisen99, C. Gemme55b, M.H. Genest58, C. Geng105, C.N.P. Gee142, J. Geisen96, M. Geisen99, C. Gemme55b, M.H. Genest58, C. Geng105, JHEP06(2021)003 JHEP06(2021)003 M. Ghasemi Bostanabad174, M. Ghneimat150, A. Ghosh169, A. Ghosh77, B. Giacobbe23b, M. Ghasemi Bostanabad174, M. Ghneimat150, A. Ghosh169, A. Ghosh77, B. Giacobbe23b, S. Giagu72a,72b, N. The ATLAS collaboration Giangiacomi165, P. Giannetti71a, A. Giannini69a,69b, S.M. Gibson93, Giagu72a,72b, N. Giangiacomi165, P. Giannetti71a, A. Giannini69a,69b, S.M. Gibson93, M. Gignac144, D.T. Gil83b, B.J. Gilbert39, D. Gillberg34, G. Gilles180, N.E.K. Gillwald46, M. Gignac144, D.T. Gil83b, B.J. Gilbert39, D. Gillberg34, G. Gilles180, N.E.K. Gillwald46 D.M. Gingrich3,ak, M.P. Giordani66a,66c, P.F. Giraud143, G. Giugliarelli66a,66c, D. Giugni68a D.M. Gingrich3,ak, M.P. Giordani66a,66c, P.F. Giraud143, G. Giugliarelli66a,66c, D. Giugn F. Giuli73a,73b, S. Gkaitatzis161, I. Gkialas9,i, E.L. Gkougkousis14, P. Gkountoumis10, Giuli73a,73b, S. Gkaitatzis161, I. Gkialas9,i, E.L. Gkougkousis14, P. Gkountoumis10, dilin112, C. Glasman98, G.R. Gledhill130, M. Glisic130, I. Gnesi41b,d, M. Goblirsch-Kolb26, L.K. Gladilin112, C. Glasman98, G.R. Gledhill130, M. Glisic130, I. Gnesi41b,d, M. Goblirsch-Kolb
D Godin109 S Goldfarb104 T Golling54 D Golubkov122 A Gomes138a,138b L.K. Gladilin112, C. Glasman98, G.R. Gledhill130, M. Glisic130, I. Gnesi41b,d, M. Gob
D. Godin109, S. Goldfarb104, T. Golling54, D. Golubkov122, A. Gomes138a,138b, L.K. Gladilin112, C. Glasman98, G.R. Gledhill130, M. Glisic130, I. Gnesi41b,d, M. Gobl
D. Godin109, S. Goldfarb104, T. Golling54, D. Golubkov122, A. Gomes138a,138b, ,
,
,
,
,
Godin109, S. Goldfarb104, T. Golling54, D. Golubkov122, A. Gomes138a,138b, g
Goncalves Gama53, R. Gonçalo138a,138c, G. Gonella130, L. Gonella21, A. Gongadze79, R. Goncalves Gama53, R. Gonçalo138a,138c, G. Gonella130, L. Gonella21, A. Gongadze79, Gonnella21, J.L. Gonski39, S. González de la Hoz172, S. Gonzalez Fernandez14, F. Gonnella21, J.L. Gonski39, S. González de la Hoz172, S. Gonzalez Fernandez14, R. Gonzalez Lopez90, C. Gonzalez Renteria18, R. Gonzalez Suarez170, S. Gonzalez-Sevilla54, Gonzalez Lopez90, C. Gonzalez Renteria18, R. Gonzalez Suarez170, S. Gonzalez-Sevilla54, G.R. Gonzalvo Rodriguez172, R.Y. González Andana145a, L. Goossens36, N.A. Gorasia21, P.A. Gorbounov123, H.A. Gordon29, B. Gorini36, E. Gorini67a,67b, A. Gorišek91, A.T. Gos P.A. Gorbounov123, H.A. Gordon29, B. Gorini36, E. Gorini67a,67b, A. Gorišek91, A.T. Goshaw49, M.I. Gostkin79, C.A. Gottardo118, M. Gouighri35b, V. Goumarre46, A.G. Goussiou147, N. Govender33c, C. Goy5, I. Grabowska-Bold83a, K. Graham34, E. Gramstad132, S. Grancagnolo19, N. Govender33c, C. Goy5, I. Grabowska-Bold83a, K. Graham34, E. Gramstad132, S. Grancagnolo19, I.M. Gregor46, P. Grenier152, K. Grevtsov46, C. Grieco14, N.A. Grieser127, A.A. Grillo144, I.M. Gregor46, P. Grenier152, K. Grevtsov46, C. Grieco14, N.A. Grieser127, A.A. Grillo144, K. Grimm31,m, S. Grinstein14,x, J.-F. Grivaz64, S. Groh99, E. Gross178, J. Grosse-Knetter53, m31,m, S. Grinstein14,x, J.-F. Grivaz64, S. Groh99, E. Gross178, J. Grosse-Knetter53, Z.J. Grout94, C. Grud105, A. Grummer117, J.C. Grundy133, L. Guan105, W. Guan179, ut94, C. Grud105, A. Grummer117, J.C. Grundy133, L. Guan105, W. Guan179, els173, J. Guenther36, J.G.R. Guerrero Rojas172, F. Guescini114, D. Guest19, R. Gugel99, C. Gubbels173, J. Guenther36, J.G.R. Guerrero Rojas172, F. Guescini114, D. Guest19, R. A. The ATLAS collaboration Guida46, T. Guillemin5, S. Guindon36, J. Guo60c, L. Guo64, Y. Guo105, R. Gupta46, 46, T. Guillemin5, S. Guindon36, J. Guo60c, L. Guo64, Y. Guo105, R. Gupta46, z24, G. Gustavino127, M. Guth52, P. Gutierrez127, L.F. Gutierrez Zagazeta135, S. Gurbuz24, G. Gustavino127, M. Guth52, P. Gutierrez127, L.F. Gutierrez Zagazeta135, Gutschow94, C. Guyot143, C. Gwenlan133, C.B. Gwilliam90, E.S. Haaland132, A. Haas124, C. Gutschow94, C. Guyot143, C. Gwenlan133, C.B. Gwilliam90, E.S. Haaland132, A. Haas M.H. Habedank19, C. Haber18, H.K. Hadavand8, A. Hadef99, M. Haleem175, J. Haley128, H. Habedank19, C. Haber18, H.K. Hadavand8, A. Hadef99, M. Haleem175, J. Haley128, J.J. Hall148, G. Halladjian106, G.D. Hallewell101, L. Halser20, K. Hamano174, H. Hamdao J. Hall148, G. Halladjian106, G.D. Hallewell101, L. Halser20, K. Hamano174, H. Hamdaoui35f, Hamer24, G.N. Hamity50, K. Han60a, L. Han15c, L. Han60a, S. Han18, Y.F. Han165, M. Hamer24, G.N. Hamity50, K. Han60a, L. Han15c, L. Han60a, S. Han18, Y.F. Han165, Hanagaki81,v, M. Hance144, M.D. Hank37, R. Hankache100, E. Hansen96, J.B. Hansen40, K. Hanagaki81,v, M. Hance144, M.D. Hank37, R. Hankache100, E. Hansen96, J.B. Hansen D. Hansen40, M.C. Hansen24, P.H. Hansen40, E.C. Hanson100, K. Hara167, T. Harenberg180, Harkusha107, Y.T. Harris133, P.F. Harrison176, N.M. Hartman152, N.M. Hartmann113, Y. Hasegawa149, A. Hasib50, S. Hassani143, S. Haug20, R. Hauser106, M. Havranek140, Y. Hasegawa149, A. Hasib50, S. Hassani143, S. Haug20, R. Hauser106, M. Havranek140, C.P. Hays133, J.M. Hays92, H.S. Hayward90, S.J. Haywood142, F. He60a, Y. He163, Y. He134, C.P. Hays133, J.M. Hays92, H.S. Hayward90, S.J. Haywood142, F. He60a, Y. He163, Y. He134, – 45 – S. Higashino81, E. Higón-Rodriguez172, K. Hildebrand37, K.K. Hill29, K.H. Hiller46, S.J. Hillier21,
M. Hils48, I. Hinchliffe18, F. Hinterkeuser24, M. Hirose131, S. Hirose167, D. Hirschbuehl180, Higashino81, E. Higón-Rodriguez172, K. Hildebrand37, K.K. Hill29, K.H. Hiller46, S.J. Hillier21, S. Higashino81, E. Higón-Rodriguez172, K. Hildebrand37, K.K. Hill29, K.H. Hiller46, S.J. Hillier2 S. Higashino81, E. Higón-Rodriguez172, K. Hildebrand37, K.K. Hill29, K.H. Hiller46, S.J. Hillier21,
M Hils48 I Hinchliffe18 F Hinterkeuser24 M Hirose131 S Hirose167 D Hirschbuehl180 g
g
g
M. Hils48, I. Hinchliffe18, F. Hinterkeuser24, M. Hirose131, S. Hirose167, D. Hirschbuehl18 ,
,
,
,
,
B. Hiti91, O. Hladik139, J. Hobbs154, R. Hobincu27e, N. Hod178, M.C. Hodgkinson148, ,
,
,
,
,
Hiti91, O. Hladik139, J. Hobbs154, R. Hobincu27e, N. Hod178, M.C. Hodgkinson148, H. Hodkinson32, A. Hoecker36, J. Hofer46, D. Hohn52, T. Holm24, T.R. Holmes37, B.H. Hodkinson32, A. Hoecker36, J. Hofer46, D. Hohn52, T. Holm24, T.R. Holmes37, M. Holzbock114, L.B.A.H. Hommels32, B.P. Honan100, T.M. Hong137, J.C. Honig52, A. B.H. The ATLAS collaboration Hooberman171, W.H. Hopkins6, Y. Horii116, P. Horn48, L.A. Horyn37, S. Hou157, ,
y
,
y
,
y
,
y
,
,
S.-C. Hsu147, Q. Hu39, S. Hu60c, Y.F. Hu15a,15d,am, D.P. Huang94, X. Huang15c, Y. Huang60a, JHEP06(2021)003 JHEP06(2021)003 K.W. Janas83a, G. Jarlskog96, A.E. Jaspan90, N. Javadov79,ab, T. Javůrek36, M. Javurkova102, F. Jeanneau143, L. Jeanty130, J. Jejelava158a, P. Jenni52,e, S. Jézéquel5, J. Jia154, Z. Jia15c, Y. Jiang60a, S. Jiggins52, F.A. Jimenez Morales38, J. Jimenez Pena114, S. Jin15c, A. Jinaru27b, ,
,
,
,
,
,
R.W.L. Jones89, T.J. Jones90, J. Jovicevic36, X. Ju18, J.J. Junggeburth114, A. Juste Rozas14, ,
,
g
,
g
,
,
E. Kajomovitz159, C.W. Kalderon29, A. Kaluza99, A. Kamenshchikov122, M. Kaneda j
N.J. Kang144, S. Kang78, Y. Kano116, J. Kanzaki81, D. Kar33f, K. Karava133, M.J. Kareem166b, N.J. Kang144, S. Kang78, Y. Kano116, J. Kanzaki81, D. Kar33f, K. Karava133, M.J. Kareem166b,
I. Karkanias161, S.N. Karpov79, Z.M. Karpova79, V. Kartvelishvili89, A.N. Karyukhin122, g
,
g
,
,
,
,
,
,
I. Karkanias161, S.N. Karpov79, Z.M. Karpova79, V. Kartvelishvili89, A.N. Karyukhin122, g
T. Kawamoto143, G. Kawamura53, E.F. Kay174, F.I. Kaya168, S. Kazakos14, V.F. Kazanin121b,121a, Y. Ke154, J.M. Keaveney33a, R. Keeler174, J.S. Keller34, D. Kelsey155, n121b,121a, Y. Ke154, J.M. Keaveney33a, R. Keeler174, J.S. Keller34, D. Kelsey155, J.J. Kempster21, J. Kendrick21, K.E. Kennedy39, O. Kepka139, S. Kersten180, B.P. Kerševan S. Ketabchi Haghighat165, F. Khalil-Zada13, M. Khandoga134, A. Khanov128, S. Ketabchi Haghighat
, F. Khalil-Zada
, M. Khandoga
, A. Khanov
,
A.G. Kharlamov121b,121a, T. Kharlamova121b,121a, E.E. Khoda173, T.J. Khoo19, G. Khoriau hramov79, J. Khubua158b, S. Kido82, M. Kiehn36, A. Kilgallon130, E. Kim163, Y.K. Kim37, E. Khramov79, J. Khubua158b, S. Kido82, M. Kiehn36, A. Kilgallon130, E. Kim163, Y.K. Kim N. Kimura94, A. Kirchhoff53, D. Kirchmeier48, J. Kirk142, A.E. Kiryunin114, T. Kishimoto mura94, A. Kirchhoff53, D. Kirchmeier48, J. Kirk142, A.E. Kiryunin114, T. Kishimoto162, ,
,
,
,
y
,
,
D.P. Kisliuk165, V. Kitali46, C. Kitsaki10, O. Kivernyk24, T. Klapdor-Kleingrothaus52, D.P. Kisliuk165, V. Kitali46, C. Kitsaki10, O. Kivernyk24, T. Klapdor-Kleingrothaus52, Kisliuk165, V. Kitali46, C. Kitsaki10, O. Kivernyk24, T. Klapdor-Kleingrothaus52, M. Klassen61a, C. Klein34, L. Klein175, M.H. Klein105, M. Klein90, U. Klein90, P. Klimek36, Klassen61a, C. Klein34, L. Klein175, M.H. Klein105, M. Klein90, U. Klein90, P. Klimek36, A. Klimentov29, F. Klimpel36, T. Klingl24, T. Klioutchnikova36, F.F. Klitzner113, P. Kluit119, A. Klimentov29, F. Klimpel36, T. Klingl24, T. Klioutchnikova36, F.F. Klitzner113, P. Kluit119,
S. Kluth114, E. Kneringer76, T.M. Knight165, A. Knue52, D. Kobayashi87, M. Kobel48,
M. The ATLAS collaboration Kocian152, T. Kodama162, P. Kodys141, D.M. Koeck155, P.T. Koenig24, T. Koffas34,
N.M. Köhler36, M. Kolb143, I. Koletsou5, T. Komarek129, K. Köneke52, A.X.Y. Kong1,
T. Kono125, V. Konstantinides94, N. Konstantinidis94, B. Konya96, R. Kopeliansky65,
S. Koperny83a, K. Korcyl84, K. Kordas161, G. Koren160, A. Korn94, S. Korn53, I. Korolkov14,
E.V. Korolkova148, N. Korotkova112, O. Kortner114, S. Kortner114, V.V. Kostyukhin148,164,
A. Kotsokechagia64, A. Kotwal49, A. Koulouris9, A. Kourkoumeli-Charalampidi70a,70b,
C. Kourkoumelis9, E. Kourlitis6, R. Kowalewski174, W. Kozanecki143, A.S. Kozhin122,
V.A. Kramarenko112, G. Kramberger91, D. Krasnopevtsev60a, M.W. Krasny134,
A. Krasznahorkay36, J.A. Kremer99, J. Kretzschmar90, K. Kreul19, P. Krieger165, F. Krieter113,
S. Krishnamurthy102, A. Krishnan61b, M. Krivos141, K. Krizka18, K. Kroeninger47, H. Kroha114,
J. Kroll139, J. Kroll135, K.S. Krowpman106, U. Kruchonak79, H. Krüger24, N. Krumnack78, ,
p
,
g
,
,
,
,
S. Kluth114, E. Kneringer76, T.M. Knight165, A. Knue52, D. Kobayashi87, M. Kobel48,
M. Kocian152, T. Kodama162, P. Kodys141, D.M. Koeck155, P.T. Koenig24, T. Koffas34,
N.M. Köhler36, M. Kolb143, I. Koletsou5, T. Komarek129, K. Köneke52, A.X.Y. Kong1,
T. Kono125, V. Konstantinides94, N. Konstantinidis94, B. Konya96, R. Kopeliansky65,
S. Koperny83a, K. Korcyl84, K. Kordas161, G. Koren160, A. Korn94, S. Korn53, I. Korolkov14,
E.V. Korolkova148, N. Korotkova112, O. Kortner114, S. Kortner114, V.V. Kostyukhin148,164,
A. Kotsokechagia64, A. Kotwal49, A. Koulouris9, A. Kourkoumeli-Charalampidi70a,70b,
C. Kourkoumelis9, E. Kourlitis6, R. Kowalewski174, W. Kozanecki143, A.S. Kozhin122,
V.A. Kramarenko112, G. Kramberger91, D. Krasnopevtsev60a, M.W. Krasny134,
A. Krasznahorkay36, J.A. Kremer99, J. Kretzschmar90, K. Kreul19, P. Krieger165, F. Krieter113,
S. Krishnamurthy102, A. Krishnan61b, M. Krivos141, K. Krizka18, K. Kroeninger47, H. Kroha114,
J. Kroll139, J. Kroll135, K.S. Krowpman106, U. Kruchonak79, H. Krüger24, N. Krumnack78, – 46 – C. Kruse49, J.A. Krzysiak84, A. Kubota163, O. Kuchinskaia164, S. Kuday4b, D. Kuechler46, M.C. Kruse49, J.A. Krzysiak84, A. Kubota163, O. Kuchinskaia164, S. Kuday4b, D. Kuechle ,
y
,
,
,
y
,
,
J.T. Kuechler46, S. Kuehn36, T. Kuhl46, V. Kukhtin79, Y. Kulchitsky107,ae, S. Kuleshov145b, y
y
J.T. Kuechler46, S. Kuehn36, T. Kuhl46, V. Kukhtin79, Y. Kulchitsky107,ae, S. Kuleshov1 ,
,
,
,
y
,
M. Kumar33f, N. Kumari101, M. Kuna58, A. Kupco139, T. Kupfer47, O. Kuprash52, ,
,
,
,
y
,
M. Kumar33f, N. Kumari101, M. Kuna58, A. Kupco139, T. Kupfer47, O. Kuprash52, Kurashige82, L.L. Kurchaninov166a, Y.A. Kurochkin107, A. Kurova111, M.G. Kurth15a,15d, H. Kurashige82, L.L. Kurchaninov166a, Y.A. Kurochkin107, A. Kurova111, M.G. Kurth S. Kuwertz36, M. Kuze163, A.K. Kvam147, J. Kvita129, T. Kwan103, C. Lacasta172, E.S. Kuwertz36, M. Kuze163, A.K. Kvam147, J. Kvita129, T. Kwan103, C. Lacasta172, F. The ATLAS collaboration Melini159, B.R. Mellado Garcia33f, T. Megy38, S. Mehlhase113, A. Mehta90, B. Meirose43, D. Melini159, B.R. Mellado Garcia33f, F. Meloni46, A. Melzer24, E.D. Mendes Gouveia138a,138e, A.M. Mendes Jacques Da Costa21, Meloni46, A. Melzer24, E.D. Mendes Gouveia138a,138e, A.M. Mendes Jacques Da Costa21, H.Y. Meng165, L. Meng36, S. Menke114, E. Meoni41b,41a, S.A.M. Merkt137, C. Merlassino133, g
,
g
,
,
,
,
,
P. Mermod54, L. Merola69a,69b, C. Meroni68a, G. Merz105, O. Meshkov112,110, J.K.R. Meshrek J. Metcalfe6, A.S. Mete6, C. Meyer65, J-P. Meyer143, M. Michetti19, R.P. Middleton142, J. Metcalfe6, A.S. Mete6, C. Meyer65, J-P. Meyer143, M. Michetti19, R.P. Middleton142, j
g
C.D. Milke42, D.W. Miller37, L.S. Miller34, A. Milov178, D.A. Milstead45a,45b, A.A. Minaenko122 JHEP06(2021)003 JHEP06(2021)003 Y. Mino85, L.M. Mir14, M. Miralles Lopez172, M. Mironova133, T. Mitani177, V.A. Mitsou1 M. Mittal60c, O. Miu165, P.S. Miyagawa92, Y. Miyazaki87, A. Mizukami81, J.U. Mjörnmark96 T. Mkrtchyan61a, M. Mlynarikova120, T. Moa45a,45b, S. Mobius53, K. Mochizuki109, P. Moder46, P. Mogg113, S. Mohapatra39, G. Mokgatitswane33f, B. Mondal150, S. Mondal140, K. Mönig46, E. Monnier101, A. Montalbano151, J. Montejo Berlingen36, M. Montella94, F. Monticelli88, Morange64, A.L. Moreira De Carvalho138a, M. Moreno Llácer172, C. Moreno Martinez14, N. Morange64, A.L. Moreira De Carvalho138a, M. Moreno Llácer172, C. Moreno Martinez14, Morettini55b, M. Morgenstern159, S. Morgenstern176, D. Mori151, M. Morii59, M. Morinaga177, V. Morisbak132, A.K. Morley36, A.P. Morris94, L. Morvaj36, P. Moschovakos36, B. Moser119, Morisbak132, A.K. Morley36, A.P. Morris94, L. Morvaj36, P. Moschovakos36, B. Moser119, M. Mosidze158b, T. Moskalets52, P. Moskvitina118, J. Moss31,o, E.J.W. Moyse102, S. Muanza Mosidze158b, T. Moskalets52, P. Moskvitina118, J. Moss31,o, E.J.W. Moyse102, S. Muanza101,
137
89
96
135
68
68b M. Mosidze
, T. Moskalets
, P. Moskvitina
, J. Moss
, E.J.W. Moyse
, S. Muanza
,
J. Mueller137, D. Muenstermann89, G.A. Mullier96, J.J. Mullin135, D.P. Mungo68a,68b, J. Mueller137, D. Muenstermann89, G.A. Mullier96, J.J. Mullin135, D.P. Mungo68a,68b, Mueller137, D. Muenstermann89, G.A. Mullier96, J.J. Mullin135, D.P. Mungo68a,68b, J.L. Munoz Martinez14, F.J. Munoz Sanchez100, M. Murin100, P. Murin28b, W.J. Murray176,142,
A. Murrone68a,68b, J.M. Muse127, M. Muškinja18, C. Mwewa29, A.G. Myagkov122,af, J.L. Munoz Martinez
, F.J. Munoz Sanchez
, M. Murin
, P. Murin
, W.J. Murray
,
A. Murrone68a,68b, J.M. Muse127, M. Muškinja18, C. Mwewa29, A.G. Myagkov122,af, ,
,
,
,
y
,
A. Murrone68a,68b, J.M. Muse127, M. Muškinja18, C. Mwewa29, A.G. Myagkov122,af, j
y g
A. Myers137, G. Myers65, J. Myers130, M. Myska140, B.P. Nachman18, O. Nackenhorst47, A.A. Myers137, G. Myers65, J. Myers130, M. Myska140, B.P. Nachman18, O. Nackenhorst47, A.Nag Nag48, K. The ATLAS collaboration Lacava72a,72b, D.P.J. Lack100, H. Lacker19, D. Lacour134, E. Ladygin79, R. Lafaye5, F. Lacava72a,72b, D.P.J. Lack100, H. Lacker19, D. Lacour134, E. Ladygin79, R. Lafaye5, B. Laforge134, T. Lagouri145c, S. Lai53, I.K. Lakomiec83a, N. Lalloue58, J.E. Lambert127, S. Lammers65, W. Lampl7, C. Lampoudis161, E. Lançon29, U. Landgraf52, M.P.J. Landon92, S. Lammers65, W. Lampl7, C. Lampoudis161, E. Lançon29, U. Landgraf52, M.P.J. Landon92, A. Lanza70a, A. Lapertosa55b,55a, J.F. Laporte143, T. Lari68a, F. Lasagni Manghi23b,23a, JHEP06(2021)003 JHEP06(2021)003 F. Ledroit-Guillon58, A.C.A. Lee94, C.A. Lee29, G.R. Lee17, L. Lee59, S.C. Lee157, S. Lee78,
L.L. Leeuw33c, B. Lefebvre166a, H.P. Lefebvre93, M. Lefebvre174, C. Leggett18, K. Lehmann151, C.E. Leitgeb113, R. Leitner141, K.J.C. Leney42, T. Lenz24, S. Leone71a, C. Leonidopoulos50, E. Leitgeb113, R. Leitner141, K.J.C. Leney42, T. Lenz24, S. Leone71a, C. Leonidopoulos50, Leopold134, C. Leroy109, R. Les106, C.G. Lester32, M. Levchenko136, J. Levêque5, D. Levin105, A. Leopold134, C. Leroy109, R. Les106, C.G. Lester32, M. Levchenko136, J. Levêque5, D. Levi L.J. Levinson178, D.J. Lewis21, B. Li15b, B. Li105, C-Q. Li60c,60d, F. Li60c, H. Li60a, H. Li60b, ,
,
,
,
Q
,
,
,
,
J. Li60c, K. Li147, L. Li60c, M. Li15a,15d, Q.Y. Li60a, S. Li60d,60c,c, X. Li46, Y. Li46, Z. Li60b, ,
,
,
,
Q
,
,
,
,
Li60c, K. Li147, L. Li60c, M. Li15a,15d, Q.Y. Li60a, S. Li60d,60c,c, X. Li46, Y. Li46, Z. Li60b, Z. Li133, Z. Li103, Z. Li90, Z. Liang15a, M. Liberatore46, B. Liberti73a, K. Lie62c, C.Y. Lin32, Li133, Z. Li103, Z. Li90, Z. Liang15a, M. Liberatore46, B. Liberti73a, K. Lie62c, C.Y. Lin32, K. Lin106, R.A. Linck65, R.E. Lindley7, J.H. Lindon21, A. Linss46, A.L. Lionti54, E. Lipeles13 J. Maeda82, T. Maeno29, M. Maerker48, V. Magerl52, J. Magro66a,66c, D.J. Mahon39, g
g
C. Maidantchik80b, A. Maio138a,138b,138d, K. Maj83a, O. Majersky28a, S. Majewski130, g
g
C. Maidantchik80b, A. Maio138a,138b,138d, K. Maj83a, O. Majersky28a, S. Majewski130, N. Makovec64, B. Malaescu134, Pa. Malecki84, V.P. Maleev136, F. Malek58, D. Malito41b,41a, – 47 – G. McCarthy114, W.P. McCormack18, E.F. McDonald104, A.E. McDougall119, T.G. McCarthy114, W.P. McCormack18, E.F. McDonald104, A.E. McDougall119, y
,
,
,
g
,
A. Mcfayden155, G. Mchedlidze158b, M.A. McKay42, K.D. McLean174, S.J. McMahon142, y
g
J.A. Mcfayden155, G. Mchedlidze158b, M.A. McKay42, K.D. McLean174, S.J. McMahon142 y
,
,
y
,
,
,
P.C. McNamara104, R.A. McPherson174,aa, J.E. Mdhluli33f, Z.A. Meadows102, S. Meehan36, y
,
,
y
,
,
,
C. McNamara104, R.A. McPherson174,aa, J.E. Mdhluli33f, Z.A. Meadows102, S. Meehan36, Megy38, S. Mehlhase113, A. Mehta90, B. Meirose43, D. The ATLAS collaboration Nagai133, K. Nagano81, J.L. Nagle29, E. Nagy101, A.M. Nairz36, A.Nag Nag48, K. Nagai133, K. Nagano81, J.L. Nagle29, E. Nagy101, A.M. Nairz36, R. Narayan42, I. Naryshkin136, M. Naseri34, T. Naumann46, G. Navarro22a, J. Navarro-Gonzalez172, P.Y. Nechaeva110, F. Nechansky46, T.J. Neep21, A. Negri70a,70b, ,
,
y
,
p
,
g
,
M. Negrini23b, C. Nellist118, C. Nelson103, K. Nelson105, M.E. Nelson45a,45b, S. Nemecek139, – 48 – P. Pani46, G. Panizzo66a,66c, L. Paolozzi54, C. Papadatos109, S. Parajuli42, A. Paramonov6, ,
,
,
p
,
j
,
,
C. Paraskevopoulos10, D. Paredes Hernandez62b, S.R. Paredes Saenz133, B. Parida178, p
,
,
,
,
T.H. Park165, A.J. Parker31, M.A. Parker32, F. Parodi55b,55a, E.W. Parrish120, J.A. Parsons3 U. Parzefall52, L. Pascual Dominguez134, V.R. Pascuzzi18, J.M.P. Pasner144, F. Pasquali119, E. Pasqualucci72a, S. Passaggio55b, F. Pastore93, P. Pasuwan45a,45b, J.R. Pater100, A. Pathak17 J. Patton90, T. Pauly36, J. Pearkes152, M. Pedersen132, L. Pedraza Diaz118, R. Pedro138a, ,
y
,
,
,
,
,
T. Peiffer53, S.V. Peleganchuk121b,121a, O. Penc139, C. Peng62b, H. Peng60a, M. Penzin164, g
g
g
B.S. Peralva80a, M.M. Perego64, A.P. Pereira Peixoto138a, L. Pereira Sanchez45a,45b, S. Perrella36, A. Perrevoort119, K. Peters46, R.F.Y. Peters100, B.A. Petersen36, T.C. Petersen40, E. Petit101, V. Petousis140, C. Petridou161, P. Petroff64, F. Petrucci74a,74b, M. Pettee181, JHEP06(2021)003 JHEP06(2021)003 N.E. Pettersson102, K. Petukhova141, A. Peyaud143, R. Pezoa145d, L. Pezzotti70a,70b, G. Pezzullo181, T. Pham104, P.W. Phillips142, M.W. Phipps171, G. Piacquadio154, E. Pianori F. Piazza68a,68b, A. Picazio102, R. Piegaia30, D. Pietreanu27b, J.E. Pilcher37, A.D. Pilkington100, F. Piazza68a,68b, A. Picazio102, R. Piegaia30, D. Pietreanu27b, J.E. Pilcher37, A.D. Pilkington100,
M. Pinamonti66a,66c, J.L. Pinfold3, C. Pitman Donaldson94, D.A. Pizzi34, L. Pizzimento73a,73b, M. Pinamonti66a,66c, J.L. Pinfold3, C. Pitman Donaldson94, D.A. Pizzi34, L. Pizzimento73a,73 Podberezko121b,121a, R. Poettgen96, R. Poggi54, L. Poggioli134, I. Pogrebnyak106, D. Pohl24, ,
g
,
gg
,
gg
,
g
y
,
,
Pokharel53, G. Polesello70a, A. Poley151,166a, A. Policicchio72a,72b, R. Polifka141, A. Polini23b, I. Pokharel53, G. Polesello70a, A. Poley151,166a, A. Policicchio72a,72b, R. Polifka141, A. Polini2 C.S. Pollard46, Z.B. Pollock126, V. Polychronakos29, D. Ponomarenko111, L. Pontecorvo36, S. Pollard46, Z.B. Pollock126, V. Polychronakos29, D. Ponomarenko111, L. Pontecorvo36, S. Popa27a, G.A. Popeneciu27d, L. Portales5, D.M. Portillo Quintero58, S. Pospisil140, P. Postolache27c, K. Potamianos133, I.N. Potrap79, C.J. Potter32, H. Potti11, T. Poulsen46, J. Poveda172, T.D. Powell148, G. Pownall46, M.E. Pozo Astigarraga36, A. Prades Ibanez172, P. Pralavorio101, M.M. Prapa44, S. Prell78, D. Price100, M. Primavera67a, M.A. Principe Martin98, M.L. Proffitt147, N. Proklova111, K. Prokofiev62c, F. Prokoshin79, S. Protopopescu29, J. Proudfoot6, M. The ATLAS collaboration Przybycien83a, D. Pudzha136, P. Puzo64, D. Pyatiizbyantseva111, J. Qian105, G. Rahal97, J.A. Raine54, S. Rajagopalan29, K. Ran15a,15d, D.F. Rassloff61a, D.M. Rauch46, S. Rave99, B. Ravina57, I. Ravinovich178, M. Raymond36, A.L. Read132, N.P. Readioff148, y
M. Reale67a,67b, D.M. Rebuzzi70a,70b, G. Redlinger29, K. Reeves43, D. Reikher160, A. Reiss99, A. Rej150, C. Rembser36, A. Renardi46, M. Renda27b, M.B. Rendel114, A.G. Rennie57, S. Resconi68a, E.D. Resseguie18, S. Rettie94, B. Reynolds126, E. Reynolds21, S. Resconi68a, E.D. Resseguie18, S. Rettie94, B. Reynolds126, E. Reynolds21, M. Rezaei Estabragh180, O.L. Rezanova121b,121a, P. Reznicek141, E. Ricci75a,75b, R. Richter114, S. Richter46, E. Richter-Was83b, M. Ridel134, P. Rieck114, O. Rifki46, M. Rijssenbeek154, A. Rimoldi70a,70b, M. Rimoldi46, L. Rinaldi23b, T.T. Rinn171, M.P. Rinnagel113, G. Ripellin I. Riu14, P. Rivadeneira46, J.C. Rivera Vergara174, F. Rizatdinova128, E. Rizvi92, C. Rizzi54, S.H. Robertson103,aa, M. Robin46, D. Robinson32, C.M. Robles Gajardo145d, ,
,
,
j
,
M. Robles Manzano99, A. Robson57, A. Rocchi73a,73b, C. Roda71a,71b, S. Rodriguez Bosca172,
A. Rodriguez Rodriguez52, A.M. Rodríguez Vera166b, S. Roe36, J. Roggel180, O. Røhne132,
R.A. Rojas145d, B. Roland52, C.P.A. Roland65, J. Roloff29, A. Romaniouk111, M. Romano23b,23a,
N. Rompotis90, M. Ronzani124, L. Roos134, S. Rosati72a, G. Rosin102, B.J. Rosser135, E. Rossi165,
E. Rossi5, E. Rossi69a,69b, L.P. Rossi55b, L. Rossini46, R. Rosten126, M. Rotaru27b, B. Rottler52,
D. Rousseau64, D. Rousso32, G. Rovelli70a,70b, A. Roy11, A. Rozanov101, Y. Rozen159, X. Ruan33f,
A.J. Ruby90, T.A. Ruggeri1, F. Rühr52, A. Ruiz-Martinez172, A. Rummler36, Z. Rurikova52,
N.A. Rusakovich79, H.L. Russell36, L. Rustige38, J.P. Rutherfoord7, E.M. Rüttinger148,
M. Rybar141, E.B. Rye132, A. Ryzhov122, J.A. Sabater Iglesias46, P. Sabatini172, L. Sabetta72a,72b,
H.F-W. Sadrozinski144, R. Sadykov79, F. Safai Tehrani72a, B. Safarzadeh Samani155,
M. Safdari152, P. Saha120, S. Saha103, M. Sahinsoy114, A. Sahu180, M. Saimpert36, M. Saito162,
T. Saito162, D. Salamani54, G. Salamanna74a,74b, A. Salnikov152, J. Salt172, A. Salvador Salas14, M. Robles Manzano99, A. Robson57, A. Rocchi73a,73b, C. Roda71a,71b, S. Rodriguez Bosca172 A. Rodriguez Rodriguez52, A.M. Rodríguez Vera166b, S. Roe36, J. Roggel180, O. Røhne132, N. Rompotis90, M. Ronzani124, L. Roos134, S. Rosati72a, G. Rosin102, B.J. Rosser135, E. Rossi165, N. Rompotis90, M. Ronzani124, L. Roos134, S. Rosati72a, G. Rosin102, B.J. Rosser135, E. Rossi165,
E. Rossi5, E. Rossi69a,69b, L.P. Rossi55b, L. Rossini46, R. Rosten126, M. Rotaru27b, B. Rottler52,
D. Rousseau64, D. Rousso32, G. Rovelli70a,70b, A. Roy11, A. Rozanov101, Y. Rozen159, X. Ruan33f,
A.J. Ruby90, T.A. Ruggeri1, F. Rühr52, A. Ruiz-Martinez172, A. Rummler36, Z. Rurikova52,
N.A. Rusakovich79, H.L. Russell36, L. Rustige38, J.P. Rutherfoord7, E.M. Rüttinger148,
M. Rybar141, E.B. Rye132, A. Ryzhov122, J.A. The ATLAS collaboration Sabater Iglesias46, P. Sabatini172, L. Sabetta72a,72b,
H.F-W. Sadrozinski144, R. Sadykov79, F. Safai Tehrani72a, B. Safarzadeh Samani155,
M. Safdari152, P. Saha120, S. Saha103, M. Sahinsoy114, A. Sahu180, M. Saimpert36, M. Saito162,
T. Saito162, D. Salamani54, G. Salamanna74a,74b, A. Salnikov152, J. Salt172, A. Salvador Salas14, D. Rousseau64, D. Rousso32, G. Rovelli70a,70b, A. Roy11, A. Rozanov101, Y. Rozen159, X. Ruan33f, A.J. Ruby
, T.A. Ruggeri , F. Rühr
, A. Ruiz Martinez
, A. Rummler
, Z. Rurikova
,
N.A. Rusakovich79, H.L. Russell36, L. Rustige38, J.P. Rutherfoord7, E.M. Rüttinger148,
M. Rybar141, E.B. Rye132, A. Ryzhov122, J.A. Sabater Iglesias46, P. Sabatini172, L. Sabetta72a,72b,
H.F-W. Sadrozinski144, R. Sadykov79, F. Safai Tehrani72a, B. Safarzadeh Samani155,
M. Safdari152, P. Saha120, S. Saha103, M. Sahinsoy114, A. Sahu180, M. Saimpert36, M. Saito162,
T. Saito162, D. Salamani54, G. Salamanna74a,74b, A. Salnikov152, J. Salt172, A. Salvador Salas14, – 49 – D. Salvatore41b,41a, F. Salvatore155, A. Salzburger36, D. Sammel52, D. Sampsonidis161, Salvatore41b,41a, F. Salvatore155, A. Salzburger36, D. Sammel52, D. Sampsonidis161, ,
,
g
,
,
p
,
D. Sampsonidou60d,60c, J. Sánchez172, A. Sanchez Pineda66a,36,66c, H. Sandaker132, C.O. S ,
,
g
,
,
p
,
idou60d,60c, J. Sánchez172, A. Sanchez Pineda66a,36,66c, H. Sandaker132, C.O. Sander46, p
,
,
,
,
I.G. Sanderswood89, M. Sandhoff180, C. Sandoval22b, D.P.C. Sankey142, M. Sannino55b,55a G. Sanderswood89, M. Sandhoff180, C. Sandoval22b, D.P.C. Sankey142, M. Sannino55b,55a, y
Y. Sano116, A. Sansoni51, C. Santoni38, H. Santos138a,138b, S.N. Santpur18, A. Santra178, Sano116, A. Sansoni51, C. Santoni38, H. Santos138a,138b, S.N. Santpur18, A. Santra178, K.A. Saoucha148, A. Sapronov79, J.G. Saraiva138a,138d, O. Sasaki81, K. Sato167, C. Sauer61b A. Saoucha148, A. Sapronov79, J.G. Saraiva138a,138d, O. Sasaki81, K. Sato167, C. Sauer61b, F. Sauerburger52, E. Sauvan5, P. Savard165,ak, R. Sawada162, C. Sawyer142, L. Sawyer95, Sauerburger52, E. Sauvan5, P. Savard165,ak, R. Sawada162, C. Sawyer142, L. Sawyer95, I. Sayago Galvan172, C. Sbarra23b, A. Sbrizzi66a,66c, T. Scanlon94, J. Schaarschmidt147, I. Sayago Galvan172, C. Sbarra23b, A. Sbrizzi66a,66c, T. Scanlon94, J. Schaarschmidt147, y g
,
,
,
,
,
P. Schacht114, D. Schaefer37, L. Schaefer135, U. Schäfer99, A.C. Schaffer64, D. Schaile113, P. Schacht114, D. Schaefer37, L. Schaefer135, U. Schäfer99, A.C. Schaffer64, D. Schaile113, g
g
g
y
D. Scheirich141, F. Schenck19, M. Schernau169, C. Schiavi55b,55a, L.K. Schildgen24, D. Scheirich141, F. Schenck19, M. Schernau169, C. Schiavi55b,55a, L.K. Schildgen24, Z.M. Schillaci26, E.J. Schioppa67a,67b, M. Schioppa41b,41a, B. Schlag99, K.E. Schleicher52, Z.M. Schillaci26, E.J. Schioppa67a,67b, M. Schioppa41b,41a, B. Schlag99, K.E. Schleic JHEP06(2021)003 JHEP06(2021)003 S. Schlenker36, K. Schmieden99, C. Schmitt99, S. Schmitt46, L. Schoeffel143, A. The ATLAS collaboration Schoening61b, P.G. Scholer52, E. Schopf133, M. Schott99, J. Schovancova36, S. Schramm54, F. Schroeder180, A. Schulte99, H-C. Schultz-Coulon61a, M. Schumacher52, B.A. Schumm144, Ph. Schune143, A. Schwartzman152, T.A. Schwarz105, Ph. Schwemling143, R. Schwienhorst106, A. Sciandra144, G. Sciolla26, F. Scuri71a, F. Scutti104, C.D. Sebastiani90, K. Sedlaczek47, P. Seema19, G. Sciolla26, F. Scuri71a, F. Scutti104, C.D. Sebastiani90, K. Sedlaczek47, P. Seema19, S.C. Seidel117, A. Seiden144, B.D. Seidlitz29, T. Seiss37, C. Seitz46, J.M. Seixas80b, S.C. Seidel117, A. Seiden144, B.D. Seidlitz29, T. Seiss37, C. Seitz46, J.M. Seixas80b, G. Sekhniaidze69a, S.J. Sekula42, L.P. Selem5, N. Semprini-Cesari23b,23a, S. Sen49, C. Serfon29, Serin64, L. Serkin66a,66b, M. Sessa60a, H. Severini127, S. Sevova152, F. Sforza55b,55a, A. Sfyrla54, E. Shabalina53, J.D. Shahinian135, N.W. Shaikh45a,45b, D. Shaked Renous178, L.Y. Shan15a, M. Shapiro18, A. Sharma36, A.S. Sharma1, S. Sharma46, P.B. Shatalov123, K. Shaw155, M. Shapiro18, A. Sharma36, A.S. Sharma1, S. Sharma46, P.B. Shatalov123, K. Shaw155, S.M. Shaw100, M. Shehade178, Y. Shen127, P. Sherwood94, L. Shi94, C.O. Shimmin181, S.M. Shaw100, M. Shehade178, Y. Shen127, P. Sherwood94, L. Shi94, C.O. Shimmin181, Y. Shimogama177, M. Shimojima115, J.D. Shinner93, I.P.J. Shipsey133, S. Shirabe163, E.M. Shrif33f, M.J. Shroff174, E. Shulga178, P. Sicho139, A.M. Sickles171, E. Sideras Haddad33f E.M. Shrif33f, M.J. Shroff174, E. Shulga178, P. Sicho139, A.M. Sickles171, E. Sideras Haddad33f S.B. Silverstein45a, S. Simion64, R. Simoniello36, S. Simsek12b, P. Sinervo165, V. Sinetckii112, S.B. Silverstein45a, S. Simion64, R. Simoniello36, S. Simsek12b, P. Sinervo165, V. Sinetckii112, S. Singh151, S. Sinha33f, M. Sioli23b,23a, I. Siral130, S.Yu. Sivoklokov112, J. Sjölin45a,45b, A Singh151, S. Sinha33f, M. Sioli23b,23a, I. Siral130, S.Yu. Sivoklokov112, J. Sjölin45a,45b, A. Skaf53, E. Skorda96, P. Skubic127, M. Slawinska84, K. Sliwa168, V. Smakhtin178, B.H. Smart142, E. Skorda96, P. Skubic127, M. Slawinska84, K. Sliwa168, V. Smakhtin178, B.H. Smart142, J. Smiesko141, S.Yu. Smirnov111, Y. Smirnov111, L.N. Smirnova112,s, O. Smirnova96, E.A. Smiesko141, S.Yu. Smirnov111, Y. Smirnov111, L.N. Smirnova112,s, O. Smirnova96, E.A. Smith37, H.A. Smith133, M. Smizanska89, K. Smolek140, A. Smykiewicz84, A.A. Snesarev110, H.L. A. Smith133, M. Smizanska89, K. Smolek140, A. Smykiewicz84, A.A. Snesarev110, H.L. Snoek119, M. Snyder130, S. Snyder29, R. Sobie174,aa, A. Soffer160, A. Søgaard50, F. Sohns53, I.M. Snyder130, S. Snyder29, R. Sobie174,aa, A. Soffer160, A. Søgaard50, F. Sohns53, A. Solans Sanchez36, E.Yu. Soldatov111, U. Soldevila172, A.A. Solodkov122, S. Solomon52, C.A. Solans Sanchez36, E.Yu. Soldatov111, U. Soldevila172, A.A. Solodkov122, S. Solomo A. Soloshenko79, O.V. Solovyanov122, V. Solovyev136, P. Sommer148, H. Son168, A. Sonay14, A. Soloshenko79, O.V. Solovyanov122, V. Solovyev136, P. Sommer148, H. Son168, A. Sona W.Y. Song166b, A. Sopczak140, A.L. Sopio94, F. Sopkova28b, S. The ATLAS collaboration Tam62b, N.M. Tamir160, E.P. Takeva50, Y. Takubo81, M. Talby101, A.A. Talyshev121b,121a, K.C. Tam62b, N.M. Tamir J. Tanaka162, R. Tanaka64, S. Tapia Araya171, S. Tapprogge99, A. Tarek Abouelfadl Mohamed10 S. Tarem159, K. Tariq60b, G. Tarna27b,f, G.F. Tartarelli68a, P. Tas141, M. Tasevsky139, y
E. Tassi41b,41a, G. Tateno162, Y. Tayalati35f, G.N. Taylor104, W. Taylor166b, H. Teagle90, y
y
y
g
A.S. Tee89, R. Teixeira De Lima152, P. Teixeira-Dias93, H. Ten Kate36, J.J. Teoh119, A.S. Tee89, R. Teixeira De Lima152, P. Teixeira-Dias93, H. Ten Kate36 A.S. Tee89, R. Teixeira De Lima152, P. Teixeira-Dias93, H. Ten Kate36, J.J. Teoh119, ,
,
,
,
,
,
T. Theveneaux-Pelzer19, D.W. Thomas93, J.P. Thomas21, E.A. Thompson46, P.D. Thompson21, JHEP06(2021)003 JHEP06(2021)003 S. Timoshenko111, P. Tipton181, S. Tisserant101, S.H. Tlou33f, A. Tnourji38, K. Todome23b,23a, E. Tolley126, R. Tombs32, M. Tomoto81,116, L. Tompkins152, P. Tornambe102, E. Torrence130, H. Torres48, E. Torró Pastor172, M. Toscani30, C. Tosciri37, J. Toth101,z, D.R. Tovey148, A. Traeet17, C.J. Treado124, T. Trefzger175, A. Tricoli29, I.M. Trigger166a, S. Trincaz-Duv A. Trischuk173, W. Trischuk165, B. Trocmé58, A. Trofymov64, C. Troncon68a, F. Trovato155, y
Truong33c, M. Trzebinski84, A. Trzupek84, F. Tsai154, A. Tsiamis161, P.V. Tsiareshka107,ae, A. Tsirigotis161,w, V. Tsiskaridze154, E.G. Tskhadadze158a, M. Tsopoulou161, I.I. Tsukerman123, Tsirigotis161,w, V. Tsiskaridze154, E.G. Tskhadadze158a, M. Tsopoulou161, I.I. Tsukerman123, V. Tsulaia18, S. Tsuno81, O. Tsur159, D. Tsybychev154, Y. Tu62b, A. Tudorache27b, Tsulaia18, S. Tsuno81, O. Tsur159, D. Tsybychev154, Y. Tu62b, A. Tudorache27b, V. Tudorache27b, A.N. Tuna36, S. Turchikhin79, D. Turgeman178, I. Turk Cakir4b,u, R V. Tudorache27b, A.N. Tuna36, S. Turchikhin79, D. Turgeman178, I. Turk Cakir4b,u, R.J. Turner21, R. Turra68a, P.M. Tuts39, S. Tzamarias161, P. Tzanis10, E. Tzovara99, K. Uchida162, Turra68a, P.M. Tuts39, S. Tzamarias161, P. Tzanis10, E. Tzovara99, K. Uchida162, F. Ukegawa167, G. Unal36, M. Unal11, A. Undrus29, G. Unel169, F.C. Ungaro104, K. Uno F. Ukegawa167, G. Unal36, M. Unal11, A. Undrus29, G. Unel169, F.C. Ungaro104, K. Uno162, J. Urban28b, P. Urquijo104, G. Usai8, R. Ushioda163, Z. Uysal12d, V. Vacek140, B. Vachon103,
K.O.H. Vadla132, T. Vafeiadis36, C. Valderanis113, E. Valdes Santurio45a,45b, M. Valente166a, j
y
K.O.H. Vadla132, T. Vafeiadis36, C. Valderanis113, E. Valdes Santurio45a,45b, M. Valente166a, T.R. Van Daalen14, P. Van Gemmeren6, S. Van Stroud94, I. Van Vulpen119, M. Vanadia73a,73b, T.R. Van Daalen14, P. Van Gemmeren6, S. Van Stroud94, I. Van Vulpen119, M. Vanadia73a,73b, W. Vandelli36, M. Vandenbroucke143, E.R. Vandewall128, D. Vannicola72a,72b, L. Vannoli55b,55a, R. Vari72a, E.W. Varnes7, C. Varni55b,55a, T. Varol157, D. Varouchas64, K.E. Varvell156, M.E. Vasile27b, L. Vaslin38, G.A. Vasquez174, F. Vazeille38, D. The ATLAS collaboration Sottocornola70a,70b, W.Y. Song166b, A. Sopczak140, A.L. Sopio94, F. Sopkova28b, S. Sottocornola70a,70b, R. Soualah66a,66c, A.M. Soukharev121b,121a, Z. Soumaimi35f, D. South46, S. Spagnolo67a,67b, M. Spalla114, M. Spangenberg176, F. Spanò93, D. Sperlich52, T.M. Spieker61a, G. Spigo36, p
,
p
g
g
,
p
,
p
,
p
,
p g
,
M. Spina155, D.P. Spiteri57, M. Spousta141, A. Stabile68a,68b, B.L. Stamas120, R. Stamen61a, M. Stamenkovic119, A. Stampekis21, E. Stanecka84, B. Stanislaus133, M.M. Stanitzki46, M. Stankaityte133, B. Stapf46, E.A. Starchenko122, G.H. Stark144, J. Stark101, D.M. Starko166b M. Stankaityte133, B. Stapf46, E.A. Starchenko122, G.H. Stark144, J. Stark101, D.M. Starko166b, M. Stankaityte133, B. Stapf46, E.A. Starchenko122, G.H. Stark144, J. Stark101, D.M. Starko166b,
P. Staroba139, P. Starovoitov61a, S. Stärz103, R. Staszewski84, G. Stavropoulos44, P. Steinberg29,
A.L. Steinhebel130, B. Stelzer151,166a, H.J. Stelzer137, O. Stelzer-Chilton166a, H. Stenzel56,
T.J. Stevenson155, G.A. Stewart36, M.C. Stockton36, G. Stoicea27b, M. Stolarski138a,
S. Stonjek114, A. Straessner48, J. Strandberg153, S. Strandberg45a,45b, M. Strauss127,
T. Strebler101, P. Strizenec28b, R. Ströhmer175, D.M. Strom130, L.R. Strom46, R. Stroynowski42,
A. Strubig45a,45b, S.A. Stucci29, B. Stugu17, J. Stupak127, N.A. Styles46, D. Su152, S. Su60a,
W. Su60d,147,60c, X. Su60a, N.B. Suarez137, K. Sugizaki162, V.V. Sulin110, M.J. Sullivan90,
D.M.S. Sultan54, S. Sultansoy4c, T. Sumida85, S. Sun105, S. Sun179, X. Sun100, C.J.E. Suster156, P. Staroba139, P. Starovoitov61a, S. Stärz103, R. Staszewski84, G. Stavropoulos44, P. Steinberg29,
A.L. Steinhebel130, B. Stelzer151,166a, H.J. Stelzer137, O. Stelzer-Chilton166a, H. Stenzel56,
T.J. Stevenson155, G.A. Stewart36, M.C. Stockton36, G. Stoicea27b, M. Stolarski138a,
S. Stonjek114, A. Straessner48, J. Strandberg153, S. Strandberg45a,45b, M. Strauss127,
T. Strebler101, P. Strizenec28b, R. Ströhmer175, D.M. Strom130, L.R. Strom46, R. Stroynowski42,
A St
bi 45a 45b S A St
i29 B St
17 J St
k127 N A St l
46 D S 152 S S 60a P. Staroba
, P. Starovoitov
, S. Stärz
, R. Staszewski
, G. Stavropoulos
, P. Steinberg
,
A.L. Steinhebel130, B. Stelzer151,166a, H.J. Stelzer137, O. Stelzer-Chilton166a, H. Stenzel56,
T J St
155 G A St
t36 M C St
kt
36 G St i
27b M St l
ki138a – 50 – M.R. Sutton155, M. Svatos139, M. Swiatlowski166a, S.P. Swift2, T. Swirski175, A. Sydorenko99 ,
,
,
,
,
y
I. Sykora28a, M. Sykora141, T. Sykora141, D. Ta99, K. Tackmann46,y, A. Taffard169, y
,
y
,
y
,
,
,
,
R. Tafirout166a, E. Tagiev122, R.H.M. Taibah134, R. Takashima86, K. Takeda82, T. Takeshita ,
g
,
,
,
,
,
P. Takeva50, Y. Takubo81, M. Talby101, A.A. Talyshev121b,121a, K.C. The ATLAS collaboration Zheng105, D. Zhong171, B. Zhou105, C. Zhou179, H. Zhou7,
M. Zhou154, N. Zhou60c, Y. Zhou7, C.G. Zhu60b, C. Zhu15a,15d, H.L. Zhu60a, H. Zhu15a, J. Zhu105,
Y. Zhu60a, X. Zhuang15a, K. Zhukov110, V. Zhulanov121b,121a, D. Zieminska65, N.I. Zimine79,
S. Zimmermann52,∗, Z. Zinonos114, M. Ziolkowski150, L. Živković16, A. Zoccoli23b,23a, K. Zoch53,
T.G. Zorbas148, R. Zou37, W. Zou39 and L. Zwalinski36 M. Weirich99, C. Weiser52, P.S. Wells36, T. Wenaus29, B. Wendland47, T. Wengler36, S. Wenig36 M. Weirich99, C. Weiser52, P.S. Wells36, T. Wenaus29, B. Wendland47, T. Wengler36, S. Wenig36,
N. Wermes24, M. Wessels61a, T.D. Weston20, K. Whalen130, A.M. Wharton89, A.S. White59,
A. White8, M.J. White1, D. Whiteson169, W. Wiedenmann179, C. Wiel48, M. Wielers142,
N. Wieseotte99, C. Wiglesworth40, L.A.M. Wiik-Fuchs52, H.G. Wilkens36, L.J. Wilkins93,
D.M. Williams39, H.H. Williams135, S. Williams32, S. Willocq102, P.J. Windischhofer133,
I. Wingerter-Seez5, F. Winklmeier130, B.T. Winter52, M. Wittgen152, M. Wobisch95, A. Wolf99,
R. Wölker133, J. Wollrath52, M.W. Wolter84, H. Wolters138a,138c, V.W.S. Wong173,
A.F. Wongel46, N.L. Woods144, S.D. Worm46, B.K. Wosiek84, K.W. Woźniak84, K. Wraight57,
J. Wu15a,15d, S.L. Wu179, X. Wu54, Y. Wu60a, Z. Wu143, J. Wuerzinger133, T.R. Wyatt100,
B.M. Wynne50, S. Xella40, J. Xiang62c, X. Xiao105, X. Xie60a, I. Xiotidis155, D. Xu15a, H. Xu60a,
H. Xu60a, L. Xu60a, R. Xu135, W. Xu105, Y. Xu15b, Z. Xu60b, Z. Xu152, B. Yabsley156,
S. Yacoob33a, D.P. Yallup94, N. Yamaguchi87, Y. Yamaguchi163, M. Yamatani162, H. Yamauchi167,
T. Yamazaki18, Y. Yamazaki82, J. Yan60c, Z. Yan25, H.J. Yang60c,60d, H.T. Yang18, S. Yang60a,
T. Yang62c, X. Yang60a, X. Yang15a, Y. Yang162, Z. Yang105,60a, W-M. Yao18, Y.C. Yap46,
H. Ye15c, J. Ye42, S. Ye29, I. Yeletskikh79, M.R. Yexley89, P. Yin39, K. Yorita177, K. Yoshihara78,
C.J.S. Young36, C. Young152, R. Yuan60b,j, X. Yue61a, M. Zaazoua35f, B. Zabinski84,
G. Zacharis10, E. Zaffaroni54, J. Zahreddine101, A.M. Zaitsev122,af, T. Zakareishvili158b,
N. Zakharchuk34, S. Zambito36, D. Zanzi52, S.V. Zeißner47, C. Zeitnitz180, G. Zemaityte133,
J.C. Zeng171, O. Zenin122, T. Ženiš28a, S. Zenz92, S. Zerradi35a, D. Zerwas64, M. Zgubič133,
B. Zhang15c, D.F. Zhang15b, G. Zhang15b, J. Zhang6, K. Zhang15a, L. Zhang15c, M. Zhang171,
R. Zhang179, S. Zhang105, X. Zhang60c, X. Zhang60b, Z. Zhang64, P. Zhao49, Y. Zhao144,
Z. Zhao60a, A. Zhemchugov79, Z. Zheng105, D. Zhong171, B. Zhou105, C. Zhou179, H. Zhou7,
M. Zhou154, N. Zhou60c, Y. Zhou7, C.G. Zhu60b, C. Zhu15a,15d, H.L. Zhu60a, H. Zhu15a, J. Zhu105,
Y. Zhu60a, X. Zhuang15a, K. Zhukov110, V. Zhulanov121b,121a, D. Zieminska65, N.I. Zimine79,
S. Zimmermann52,∗, Z. Zinonos114, M. Ziolkowski150, L. Živković16, A. Zoccoli23b,23a, K. Zoch53,
T.G. Zorbas148, R. The ATLAS collaboration Vazquez Furelos14, T. Vazquez Schroeder36, J. Veatch53, V. Vecchio100, M.J. Veen119, L.M. Veloce165, F. Veloso138a,138c, S. Veneziano72a, A. Ventura67a,67b, A. Verbytskyi114, M. Verducci71a,71b, C. Vergis24, M. Verissimo De Araujo80b, W. Verkerke119, A.T. Vermeulen119, J.C. Vermeulen119 Vergis24, M. Verissimo De Araujo80b, W. Verkerke119, A.T. Vermeulen119, J.C. Vermeulen119, Vernieri152, P.J. Verschuuren93, M.L. Vesterbacka124, M.C. Vetterli151,ak, N. Viaux Maira145d, C. Vernieri152, P.J. Verschuuren93, M.L. Vesterbacka124, M.C. Vetterli151,ak, N. Viaux Maira Vickey148, O.E. Vickey Boeriu148, G.H.A. Viehhauser133, L. Vigani61b, M. Villa23b,23a, Villaplana Perez172, E.M. Villhauer50, E. Vilucchi51, M.G. Vincter34, G.S. Virdee21, M. Villaplana Perez172, E.M. Villhauer50, E. Vilucchi51, M.G. Vincter34, G.S. Virdee21, M. Vreeswijk119, N.K. Vu101, R. Vuillermet36, I. Vukotic37, S. Wada167, C. Wagner102, M. Vreeswijk119, N.K. Vu101, R. Vuillermet36, I. Vukotic37, S. Wada167, C. Wagner102, – 51 – M. Weirich99, C. Weiser52, P.S. Wells36, T. Wenaus29, B. Wendland47, T. Wengler36, S. Wenig36,
N. Wermes24, M. Wessels61a, T.D. Weston20, K. Whalen130, A.M. Wharton89, A.S. White59,
A. White8, M.J. White1, D. Whiteson169, W. Wiedenmann179, C. Wiel48, M. Wielers142,
N. Wieseotte99, C. Wiglesworth40, L.A.M. Wiik-Fuchs52, H.G. Wilkens36, L.J. Wilkins93,
D.M. Williams39, H.H. Williams135, S. Williams32, S. Willocq102, P.J. Windischhofer133,
I. Wingerter-Seez5, F. Winklmeier130, B.T. Winter52, M. Wittgen152, M. Wobisch95, A. Wolf99,
R. Wölker133, J. Wollrath52, M.W. Wolter84, H. Wolters138a,138c, V.W.S. Wong173,
A.F. Wongel46, N.L. Woods144, S.D. Worm46, B.K. Wosiek84, K.W. Woźniak84, K. Wraight57,
J. Wu15a,15d, S.L. Wu179, X. Wu54, Y. Wu60a, Z. Wu143, J. Wuerzinger133, T.R. Wyatt100,
B.M. Wynne50, S. Xella40, J. Xiang62c, X. Xiao105, X. Xie60a, I. Xiotidis155, D. Xu15a, H. Xu60a,
H. Xu60a, L. Xu60a, R. Xu135, W. Xu105, Y. Xu15b, Z. Xu60b, Z. Xu152, B. Yabsley156,
S. Yacoob33a, D.P. Yallup94, N. Yamaguchi87, Y. Yamaguchi163, M. Yamatani162, H. Yamauchi167,
T. Yamazaki18, Y. Yamazaki82, J. Yan60c, Z. Yan25, H.J. Yang60c,60d, H.T. Yang18, S. Yang60a,
T. Yang62c, X. Yang60a, X. Yang15a, Y. Yang162, Z. Yang105,60a, W-M. Yao18, Y.C. Yap46,
H. Ye15c, J. Ye42, S. Ye29, I. Yeletskikh79, M.R. Yexley89, P. Yin39, K. Yorita177, K. Yoshihara78,
C.J.S. Young36, C. Young152, R. Yuan60b,j, X. Yue61a, M. Zaazoua35f, B. Zabinski84,
G. Zacharis10, E. Zaffaroni54, J. Zahreddine101, A.M. Zaitsev122,af, T. Zakareishvili158b,
N. Zakharchuk34, S. Zambito36, D. Zanzi52, S.V. Zeißner47, C. Zeitnitz180, G. Zemaityte133,
J.C. Zeng171, O. Zenin122, T. Ženiš28a, S. Zenz92, S. Zerradi35a, D. Zerwas64, M. Zgubič133,
B. Zhang15c, D.F. Zhang15b, G. Zhang15b, J. Zhang6, K. Zhang15a, L. Zhang15c, M. Zhang171,
R. Zhang179, S. Zhang105, X. Zhang60c, X. Zhang60b, Z. Zhang64, P. Zhao49, Y. Zhao144,
Z. Zhao60a, A. Zhemchugov79, Z. The ATLAS collaboration Zou37, W. Zou39 and L. Zwalinski36 g
N. Wermes24, M. Wessels61a, T.D. Weston20, K. Whalen130, A.M. Wharton89, A.S. White59 ,
,
,
,
,
A. White8, M.J. White1, D. Whiteson169, W. Wiedenmann179, C. Wiel48, M. Wielers142, JHEP06(2021)003 1 Department of Physics, University of Adelaide, Adelaide; Australia 1 Department of Physics, University of Adelaide, Adelaide; Australia 2 Physics Department, SUNY Albany, Albany NY; United States of America 2 Physics Department, SUNY Albany, Albany NY; United States of America (a)Department of Physics, Ankara University, Ankara;(b)Istanbul Aydin University, Application and 4
(a)Department of Physics, Ankara University, Ankara;(b)Istanbul Aydin University, Application
Research Center for Advanced Studies, Istanbul;(c)Division of Physics, TOBB University of 4
(a)Department of Physics, Ankara University, Ankara;(b)Istanbul Aydin University, Application and
Research Center for Advanced Studies, Istanbul;(c)Division of Physics, TOBB University of
Economics and Technology, Ankara; Turkey 4
(a)Department of Physics, Ankara University, Ankara;(b)Istanbul Aydin University, Application and
Research Center for Advanced Studies, Istanbul;(c)Division of Physics, TOBB University of
Economics and Technology, Ankara; Turkey Economics and Technology, Ankara; Turkey 5 LAPP, Univ. Savoie Mont Blanc, CNRS/IN2P3, Annecy; France 5 LAPP, Univ. Savoie Mont Blanc, CNRS/IN2P3, Annecy; France 5 LAPP, Univ. The ATLAS collaboration Physikalisches Institut, Justus-Liebig-Universität Giessen, Giessen; Germany 57 SUPA — School of Physics and Astronomy, University of Glasgow, Glasgow; United Kingdom 58 LPSC, Université Grenoble Alpes, CNRS/IN2P3, Grenoble INP, Grenoble; France 59 Laboratory for Particle Physics and Cosmology, Harvard University, Cambridge MA; United States
of America JHEP06(2021)003 JHEP06(2021)003 60
(a)Department of Modern Physics and State Key Laboratory of Particle Detection and Electronics,
University of Science and Technology of China, Hefei;(b)Institute of Frontier and Interdisciplinary
Science and Key Laboratory of Particle Physics and Particle Irradiation (MOE), Shandong
University, Qingdao;(c)School of Physics and Astronomy, Shanghai Jiao Tong University, Key
Laboratory for Particle Astrophysics and Cosmology (MOE), SKLPPC, Shanghai;(d)Tsung-Dao Lee
Institute, Shanghai; China 60
(a)Department of Modern Physics and State Key Laboratory of Particle Detection and Electronics,
University of Science and Technology of China, Hefei;(b)Institute of Frontier and Interdisciplinary Science and Key Laboratory of Particle Physics and Particle Irradiation (MOE), Shandong University, Qingdao;(c)School of Physics and Astronomy, Shanghai Jiao Tong University, Key Laboratory for Particle Astrophysics and Cosmology (MOE), SKLPPC, Shanghai;(d)Tsung-Dao Lee
Institute, Shanghai; China ,
g
;
61
(a)Kirchhoff-Institut für Physik, Ruprecht-Karls-Universität Heidelberg, Heid
Institut, Ruprecht-Karls-Universität Heidelberg, Heidelberg; Germany ,
g
;
61
(a)Kirchhoff-Institut für Physik, Ruprecht-Karls-Universität Heidelberg, Heidelberg;(b)Physikalisches 61
(a)Kirchhoff-Institut für Physik, Ruprecht-Karls-Universität Heidelberg, Heidelberg;(b)Physikali
Institut Ruprecht Karls Universität Heidelberg Heidelberg; Germany Institut, Ruprecht-Karls-Universität Heidelberg, Heidelberg; Germany 62
(a)Department of Physics, Chinese University of Hong Kong, Shatin, N.T., Hong
Kong;(b)Department of Physics, University of Hong Kong, Hong Kong;(c)Department of Physics
and Institute for Advanced Study, Hong Kong University of Science and Technology, Clear Water
Bay, Kowloon, Hong Kong; China ment of Physics, University of Hong Kong, Hong Kon 63 Department of Physics, National Tsing Hua University, Hsinchu; Taiwan 64 IJCLab, Université Paris-Saclay, CNRS/IN2P3, 91405, Orsay; France Lab, Université Paris-Saclay, CNRS/IN2P3, 91405, 65 Department of Physics, Indiana University, Bloomington IN; United States of America
( )
( )
( ) 66
(a)INFN Gruppo Collegato di Udine, Sezione di Trieste, Udine;(b)ICTP, Trieste;(c)Dipartime 66
(a)INFN Gruppo Collegato di Udine, Sezione di Trieste, Udine;(b)ICTP, Trieste;(c)Dipart
Politecnico di Ingegneria e Architettura, Università di Udine, Udine; Italy ( )INFN Gruppo Collegato di Udine, Sezione di Trieste, Udine;( )ICTP, Tr
Politecnico di Ingegneria e Architettura, Università di Udine, Udine; Italy Politecnico di Ingegneria e Architettura, Università di Udine, Udine; Italy 67
(a)INFN Sezione di Lecce;(b)Dipartimento di Matematica e Fisica, Università del Salento, Lecce;
Italy 69
(a)INFN Sezione di Napoli;(b)Dipartimento di Fisica, Università di Napoli, Napo 70
(a)INFN Sezione di Pavia;(b)Dipartimento di Fisica, Università di Pavia, Pavia; Italy 71
(a)INFN Sezione di Pisa;(b)Dipartimento di Fisica E. The ATLAS collaboration Savoie Mont Blanc, CNRS/IN2P 6 High Energy Physics Division, Argonne National Laboratory, Argonne IL; United States of America 7 Department of Physics, University of Arizona, Tucson AZ; United States of America 9 Physics Department, National and Kapodistrian University of Athens, Athens; Gree 9 Physics Department, National and Kapodistrian University of Athens, Athens; Greece 10 Physics Department, National Technical University of Athens, Zografou; Greece 10 Physics Department, National Technical University of Athens, Zografou; Greece 11 Department of Physics, University of Texas at Austin, Austin TX; United States of America 12
(a)Bahcesehir University, Faculty of Engineering and Natural Sciences, Istanbul;(b)Istanbul Bilgi
University, Faculty of Engineering and Natural Sciences, Istanbul;(c)Department of Physics,
Bogazici University, Istanbul;(d)Department of Physics Engineering, Gaziantep University,
Gaziantep; Turkey 12
(a)Bahcesehir University, Faculty of Engineering and Natural Sciences, Istanbul;(b)Istanbul Bilgi
University, Faculty of Engineering and Natural Sciences, Istanbul;(c)Department of Physics,
Bogazici University, Istanbul;(d)Department of Physics Engineering, Gaziantep University,
Gaziantep; Turkey 13 Institute of Physics, Azerbaijan Academy of Sciences, Baku; Azerbaijan
4 13 Institute of Physics, Azerbaijan Academy of Sciences, Baku; Azerbaijan 14 Institut de Física d’Altes Energies (IFAE), Barcelona Institute of Science and Technology,
Barcelona; Spain 14 Institut de Física d’Altes Energies (IFAE), Barcelona Institute of Science and Technology,
Barcelona; Spain 15
(a)Institute of High Energy Physics, Chinese Academy of Sciences, Beijing;(b)Physics Department,
Tsinghua University, Beijing;(c)Department of Physics, Nanjing University, Nanjing;(d)University
of Chinese Academy of Science (UCAS), Beijing; China 15
(a)Institute of High Energy Physics, Chinese Academy of Sciences, Beijing;(b)Physics Department,
Tsinghua University, Beijing;(c)Department of Physics, Nanjing University, Nanjing;(d)University
of Chinese Academy of Science (UCAS), Beijing; China – 52 – 16 Institute of Physics, University of Belgrade, Belgrade; Serbia 17 Department for Physics and Technology, University of Bergen, Bergen; Norway 18 Physics Division, Lawrence Berkeley National Laboratory and University of California, Berkeley
CA; United States of America ;
f
19 Institut für Physik, Humboldt Universität zu Berlin, Berlin; Germany 20 Albert Einstein Center for Fundamental Physics and Laboratory for High Energy Physics,
University of Bern, Bern; Switzerland 21 School of Physics and Astronomy, University of Birmingham, Birmingham; United Kingdom
( ) 21 School of Physics and Astronomy, Univ 22
(a)Facultad de Ciencias y Centro de Investigaciónes, Universidad Antonio Nariño,
Bogotá;(b)Departamento de Física, Universidad Nacional de Colombia, Bogotá, Colombia; Colom
( )
( ) 23
(a)INFN Bologna and Universita’ di Bologna, Dipartimento di Fisica;(b)INFN Sezione di Bologna;
Italy JHEP06(2021)003 24 Physikalisches Institut, Universität Bonn, Bonn; Germany hysikalisches Institut, Universität Bonn, Bonn; Germ 25 Department of Physics, Boston University, Boston MA; United States of America 26 Department of Physics, Brandeis University, Waltham MA; United States of Amer 27
(a)Transilvania University of Brasov, Brasov;(b)Horia Hulubei National Institute of Physics and
Nuclear Engineering, Bucharest;(c)Department of Physics, Alexandru Ioan Cuza University of Iasi,
Iasi;(d)National Institute for Research and Development of Isotopic and Molecular Technologies,
Physics Department, Cluj-Napoca;(e)University Politehnica Bucharest, Bucharest;(f)West
University in Timisoara, Timisoara; Romania University in Timisoara, Timisoara; Romania 28
(a)Faculty of Mathematics, Physics and Informatics, Comenius University,
Bratislava;(b)Department of Subnuclear Physics, Institute of Experimental Physics of the Slovak
Academy of Sciences, Kosice; Slovak Republic 29 Physics Department, Brookhaven National Laboratory, Upton NY; United States of America 30 Departamento de Física, Universidad de Buenos Aires, Buenos Aires; Argentina 31 California State University, CA; United States of America 32 Cavendish Laboratory, University of Cambridge, Cambridg
( ) 32 Cavendish Laboratory, University of Cambridge, Cambridge; United Kingdom 33
(a)Department of Physics, University of Cape Town, Cape Town;(b)iThemba Labs, Western
Cape;(c)Department of Mechanical Engineering Science, University of Johannesburg,
Johannesburg;(d)National Institute of Physics, University of the Philippines Diliman;(e)University
of South Africa, Department of Physics, Pretoria;(f)School of Physics, University of the
Witwatersrand, Johannesburg; South Africa Witwatersrand, Johannesburg; South Africa 34 Department of Physics, Carleton University, O 35
(a)Faculté des Sciences Ain Chock, Réseau Universitaire de Physique des Hautes Energies —
Université Hassan II, Casablanca;(b)Faculté des Sciences, Université Ibn-Tofail, Kénitra;(c)Faculté
des Sciences Semlalia, Université Cadi Ayyad, LPHEA-Marrakech;(d)Moroccan Foundation for
Advanced Science Innovation and Research (MAScIR), Rabat;(e)LPMR, Faculté des Sciences,
Université Mohamed Premier, Oujda;(f)Faculté des sciences, Université Mohammed V, Rabat;
Morocco 36 CERN, Geneva; Switzerland 37 Enrico Fermi Institute, University of Chicago, Chicago IL; United States of Am 38 LPC, Université Clermont Auvergne, CNRS/IN2P3, Clermont-Ferrand; France Nevis Laboratory, Columbia University, Irvington NY; United States of America 39 Nevis Laboratory, Columbia University, Irvington NY; United States of America 40 Niels Bohr Institute, University of Copenhagen, Copenhagen; Denmark
41
( )
(b) 40 Niels Bohr Institute, University of Copenhagen, Copenhagen; Denmark , U
y
f C p
g
, C p
g
;
41
(a)Dipartimento di Fisica, Università della Calabria, Rende;(b)INFN Gruppo Collegato di Cosenza,
Laboratori Nazionali di Frascati; Italy 41
(a)Dipartimento di Fisica, Università della Calabria, Rende;(b)INFN Gruppo Collegato di Cosenza,
Laboratori Nazionali di Frascati; Italy Physics Department, Southern Methodist Universit 42 Physics Department, Southern Methodist University, Dallas TX; United States of America 43 Physics Department, University of Texas at Dallas, Richardson TX; United States National Centre for Scientific Research “Demokritos”, Agia Paraskevi; Greece 44 National Centre for Scientific Research “Demokritos”, Agia Paraskevi; Greece (a)Department of Physics, Stockholm University;(b)Oskar Klein Centre, Stockholm; Sweden 45
(a)Department of Physics, Stockholm University;(b)Oskar Klein Centre, Stockho Deutsches Elektronen-Synchrotron DESY, Hamburg and Zeuthen; Germany 46 Deutsches Elektronen-Synchrotron DESY, Hamburg and Zeuthen; Germany Lehrstuhl für Experimentelle Physik IV, Technische Universität Dortmund, Dortmund; Germany 47 Lehrstuhl für Experimentelle Physik IV, Technische Universität Dortmund, Dortmund; Germany – 53 – 48 Institut für Kern- und Teilchenphysik, Technische Universität Dresden, Dresden; Germany f
p y
,
,
;
y
49 Department of Physics Duke University Durham NC; United States of America 49 Department of Physics, Duke University, Durham NC; United States of America 50 SUPA — School of Physics and Astronomy, University of Edinburgh, Edinburgh; United Kingdom 50 SUPA — School of Physics and Astronomy, University of Edinburgh, Edinburgh; United Kingdom
51 INFN e Laboratori Nazionali di Frascati, Frascati; Italy f
y
y,
y
f
g ,
g ;
g
51 INFN e Laboratori Nazionali di Frascati, Frascati; Italy NFN e Laboratori Nazionali di Frascati, Frascati; Ital ,
;
y
52 Physikalisches Institut, Albert-Ludwigs-Universität Freiburg, Freiburg; Germany hysikalisches Institut, Albert-Ludwigs-Universität Fre 53 II. The ATLAS collaboration Physikalisches Institut, Georg-August-Universität Göttingen, Göttingen; Germany 54 Département de Physique Nucléaire et Corpusculaire, Université de Genève, Genève; Switzerlan 55
(a)Dipartimento di Fisica, Università di Genova, Genova;(b)INFN Sezione di Genova; Italy 56 II. The ATLAS collaboration Fermi, Università di Pisa, Pisa; Italy 72
(a)INFN Sezione di Roma;(b)Dipartimento di Fisica, Sapienza Università di Roma, Roma; Italy
( )
( ) 73
(a)INFN Sezione di Roma Tor Vergata;(b)Dipartimento di Fisica, Università di Roma Tor Vergata,
Roma; Italy 74
(a)INFN Sezione di Roma Tre;(b)Dipartimento di Matematica e Fisica, Università Roma Tre,
Roma; Italy 75
(a)INFN-TIFPA;(b)Università degli Studi di Trento, Trento; Italy 76 Institut für Astro- und Teilchenphysik, Leopold-Franzens-Universität, Innsbruck; Austria 77 University of Iowa, Iowa City IA; United States of America 78 Department of Physics and Astronomy, Iowa State University, Ames IA; United States of America
79 78 Department of Physics and Astronomy, Iowa State University, Ames IA; epartment of Physics and Astronomy, Iowa State Un 79 Joint Institute for Nuclear Research, Dubna; Russia 80
(a)Departamento de Engenharia Elétrica, Universidade Federal de Juiz de Fora (UFJF), Juiz de
Fora;(b)Universidade Federal do Rio De Janeiro COPPE/EE/IF, Rio de Janeiro;(c)Instituto de
Física, Universidade de São Paulo, São Paulo; Brazil Física, Universidade de São Paulo, São Paulo; Brazil 81 KEK, High Energy Accelerator Research Organization, Tsukuba; Japan 82 Graduate School of Science, Kobe University, Kobe; Japan 83
(a)AGH University of Science and Technology, Faculty of Physics and Applied Computer Science,
Krakow;(b)Marian Smoluchowski Institute of Physics, Jagiellonian University, Krakow; Poland – 54 – 84 Institute of Nuclear Physics Polish Academy of Sciences, Krakow; Poland 85 Faculty of Science, Kyoto University, Kyoto; Japan 86 Kyoto University of Education, Kyoto; Japan 87 Research Center for Advanced Particle Physics and Department of Physics, Kyushu University,
Fukuoka; Japan 88 Instituto de Física La Plata, Universidad Nacional de La Plata and CONICET, La Plata; Argent 89 Physics Department, Lancaster University, Lancaster; United Kingdom 90 Oliver Lodge Laboratory, University of Liverpool, Liverpool; United Kingdom 91 Department of Experimental Particle Physics, Jožef Stefan Institute and Department o
University of Ljubljana, Ljubljana; Slovenia 91 Department of Experimental Particle Physics, Jo 91 Department of Experimental Particle Physics, Jožef Stefan Institute and Department of Physics, of Experimental Particle Physics, Jožef Stefan Instit University of Ljubljana, Ljubljana; Slovenia University of Ljubljana, Ljubljana; Slovenia 92 School of Physics and Astronomy, Queen Mary University of London, Lo 92 School of Physics and Astronomy, Queen Mary University of London, London; United Kingdom partment of Physics, Royal Holloway University of Lo JHEP06(2021)003 JHEP06(2021)003 p
f
y
,
y
y
y
f
,
g
;
g
94 Department of Physics and Astronomy, University College London, London; United Kingdom
95 94 Department of Physics and Astronomy, University College London, London; United Kingdo 95 Louisiana Tech University, Ruston LA; United States of America 96 Fysiska institutionen, Lunds universitet, Lund; Sweden 97 Centre de Calcul de l’Institut National de Physique Nucléaire et de Physique des Particules
(IN2P3), Villeurbanne; France 98 Departamento de Física Teorica C-15 and CIAFF, Universidad Autónoma de Madrid, Madrid;
Spain 99 Institut für Physik, Universität Mainz, Mainz; Germany Institut für Physik, Universität Mainz, Mainz; Germ 100 School of Physics and Astronomy, University of Manchester, Manchester; United Kingdom 100 School of Physics and Astronomy, University of Manchester, Man 101 CPPM, Aix-Marseille Université, CNRS/IN2P3, Marseille; France 102 Department of Physics, University of Massachusetts, Amherst MA; United States of America 102 Department of Physics, University of Massachusetts, Amherst MA; U 103 Department of Physics, McGill University, Montreal QC; Canada 104 School of Physics, University of Melbourne, Victoria; Australia 105 Department of Physics, University of Michigan, Ann Arbor MI; United States of America
106 106 Department of Physics and Astronomy, Michigan State University, East Lansing MI; United States
of America 107 B.I. The ATLAS collaboration Stepanov Institute of Physics, National Academy of Sciences of Belarus, Minsk; Belarus
108 R
h I
tit t
f
N
l
P
bl
f B
l
i
St t
U i
it
Mi
k B l 107 B.I. Stepanov Institute of Physics, National Academy of Sciences of Belarus, Minsk; Belarus 108 Research Institute for Nuclear Problems of Byelorussian State University, Minsk; Belarus 109 Group of Particle Physics, University of Montreal, Montreal QC; Canada 110 P.N. Lebedev Physical Institute of the Russian Academy of Sciences, Moscow; Russia 111 National Research Nuclear University MEPhI, Moscow; Russia
112 111 National Research Nuclear University MEPhI, Moscow; Russia Research Nuclear University MEPhI, Moscow; Russi 112 D.V. Skobeltsyn Institute of Nuclear Physics, M.V. Lomonosov Moscow State University, Moscow;
Russia 113 Fakultät für Physik, Ludwig-Maximilians-Universität München, München; Germany 114 Max-Planck-Institut für Physik (Werner-Heisenberg-Institut), München; Germany 115 Nagasaki Institute of Applied Science, Nagasaki; Japan 116 Graduate School of Science and Kobayashi-Maskawa Institute, Nagoya University, Nagoya; Japan
117 Department of Physics and Astronomy University of New Mexico Albuquerque NM United States 116 Graduate School of Science and Kobayashi-Maskawa Institute, Nagoya University, Nagoya; Japan
117 Department of Physics and Astronomy, University of New Mexico, Albuquerque NM; United States f
y
,
g y
y,
g y ;
p
117 Department of Physics and Astronomy, University of New Mexico, Albuquerque NM; United States
of America 118 Institute for Mathematics, Astrophysics and Particle Physics, Radboud University/Nikhef,
Nijmegen; Netherlands 119 Nikhef National Institute for Subatomic Physics and University of Amsterdam, Amsterdam;
Netherlands 120 Department of Physics, Northern Illinois University, DeKalb IL; United States of America
121
(a)Budker Institute of Nuclear Physics and NSU, SB RAS, Novosibirsk;(b)Novosibirsk State
University Novosibirsk; Russia 122 Institute for High Energy Physics of the National Research Centre Kurchatov Institute, Protvino;
Russia 123 Institute for Theoretical and Experimental Physics named by A.I. Alikhanov of National Research
Centre “Kurchatov Institute”, Moscow; Russia – 55 – 124 Department of Physics, New York University, New York NY; United States of America 125 Ochanomizu University, Otsuka, Bunkyo-ku, Tokyo; Japan 126 Ohio State University, Columbus OH; United States of America 127 Homer L. The ATLAS collaboration Dodge Department of Physics and Astronomy, University of Oklahoma, Norman OK;
United States of America 128 Department of Physics, Oklahoma State University, Stillwater OK; United States of America 129 Palacký University, RCPTM, Joint Laboratory of Optics, Olomouc; Czech Republic 130 Institute for Fundamental Science, University of Oregon, Eugene, OR; United States of A 131 Graduate School of Science, Osaka University, Osaka; Japan 132 Department of Physics, University of Oslo, Oslo; Norway 133 Department of Physics, Oxford University, Oxford; United Kingdom JHEP06(2021)003 JHEP06(2021)003 /
135 Department of Physics University of Pennsylvania Philadelphia PA; United Sta 135 Department of Physics, University of Pennsylvania, Philadelphia PA; United States of America 136 Konstantinov Nuclear Physics Institute of National Research Centre “Kurchatov Institute”, PNPI
St. The ATLAS collaboration Petersburg; Russia 137 Department of Physics and Astronomy, University of Pittsburgh, Pittsburgh PA; United States of
America 138
(a)Laboratório de Instrumentação e Física Experimental de Partículas — LIP,
Lisboa;(b)Departamento de Física, Faculdade de Ciências, Universidade de Lisboa,
Lisboa;(c)Departamento de Física, Universidade de Coimbra, Coimbra;(d)Centro de Física Nuclear
da Universidade de Lisboa, Lisboa;(e)Departamento de Física, Universidade do Minho,
Braga;(f)Departamento de Física Teórica y del Cosmos, Universidad de Granada, Granada
(Spain);(g)Dep Física and CEFITEC of Faculdade de Ciências e Tecnologia, Universidade Nova d
Lisboa, Caparica;(h)Instituto Superior Técnico, Universidade de Lisboa, Lisboa; Portugal partamento de Física, Faculdade de Ciências, Univer Lisboa, Caparica;(h)Instituto Superior Técnico, Universidade de Lisboa, Lisboa; Portugal 139 Institute of Physics of the Czech Academy of Sciences, Prague; Czech Republic 140 Czech Technical University in Prague, Prague; Czech Republic 141 Charles University, Faculty of Mathematics and Physics, Prague; Czech Republic
142 University, Faculty of Mathematics and Physics, Prag 142 Particle Physics Department, Rutherford Appleton Laboratory, Didcot; United Kingdom 143 IRFU, CEA, Université Paris-Saclay, Gif-sur-Yvette; France 144 Santa Cruz Institute for Particle Physics, University of California Santa Cruz, Santa Cruz CA;
United States of America 145
(a)Departamento de Física, Pontificia Universidad Católica de Chile, Santiago;(b)Universidad
Andres Bello, Department of Physics, Santiago;(c)Instituto de Alta Investigación, Universidad de
Tarapacá;(d)Departamento de Física, Universidad Técnica Federico Santa María, Valparaíso; Chile 145
(a)Departamento de Física, Pontificia Universidad Católica de Chile, Santiago;(b)Universidad
Andres Bello, Department of Physics, Santiago;(c)Instituto de Alta Investigación, Universidad de Andres Bello, Department of Physics, Santiago;(c)Instituto de Alta Investigación, Universidad de
Tarapacá;(d)Departamento de Física, Universidad Técnica Federico Santa María, Valparaíso; Chile Tarapacá;(d)Departamento de Física, Universidad Técnica Federico Santa María, Valparaíso; 146 Universidade Federal de São João del Rei (UFSJ), São João del Rei; Brazil 147 Department of Physics, University of Washington, Seattle WA; United States of America Department of Physics and Astronomy, University of Sheffield, Sheffield; United Kingdom 148 Department of Physics and Astronomy, University of Sheffield, Sheffield; United Kingdom ment of Physics and Astronomy, University of Sheffie 149 Department of Physics, Shinshu University, Nagano; Japan 150 Department Physik, Universität Siegen, Siegen; Germany 152 SLAC National Accelerator Laboratory, Stanford CA; United States of Ame 152 SLAC National Accelerator Laboratory, Stanford CA; United States of America 153 Physics Department, Royal Institute of Technology, Stockholm; Sweden 154 Departments of Physics and Astronomy, Stony Brook University, Stony Brook NY; United States of
America 154 Departments of Physics and Astronomy, Stony Brook University, Stony Brook NY; United States
America 155 Department of Physics and Astronomy, University of Sussex, Brighton; United Kingdom
156 156 School of Physics, University of Sydney, Sydney; Australia 157 Institute of Physics, Academia Sinica, Taipei; Taiwan 158
(a)E. The ATLAS collaboration Javakhishvili Tbilisi St
Energy Physics Institute, Tbilisi State University, Tbilisi; Georgia f
y
,
Energy Physics Institute, Tbilisi State University, Tbilisi; Georgia 159 Department of Physics, Technion, Israel Institute of Technology, Haifa; Israel 160 Raymond and Beverly Sackler School of Physics and Astronomy, Tel Aviv University, Tel Aviv;
Israel – 56 – 161 Department of Physics, Aristotle University of Thessaloniki, Thessaloniki; Greece 162 International Center for Elementary Particle Physics and Department of Physics, University of
Tokyo, Tokyo; Japan 163 Department of Physics, Tokyo Institute of Technology, Tokyo; Japan 164 Tomsk State University, Tomsk; Russia 165 Department of Physics, University of Toronto, Toronto ON; Canada 165 Department of Physics, University of Toronto, Toronto ON; Canada 166
(a)TRIUMF, Vancouver BC;(b)Department of Physics and Astronomy, York University, Toronto
ON; Canada 167 Division of Physics and Tomonaga Center for the History of the Universe, Faculty of Pure and
Applied Sciences, University of Tsukuba, Tsukuba; Japan 168 Department of Physics and Astronomy, Tufts University, Medford MA; United States of America 169 Department of Physics and Astronomy, University of California Irvine, Irvine CA; United States of
America JHEP06(2021)003 JHEP06(2021)003 170 Department of Physics and Astronomy, University of Uppsala, Uppsala; Sweden 171 Department of Physics, University of Illinois, Urbana IL; United States of America 172 Instituto de Física Corpuscular (IFIC), Centro Mixto Universidad de Valencia — CSIC, Valencia;
Spain 173 Department of Physics, University of British Columbia, Vancouver BC; Canada 175 Fakultät für Physik und Astronomie, Julius-Maximilians-Universität Würzburg, Würzburg; German 176 Department of Physics, University of Warwick, Coventry; United Kingdom 176 Department of Physics, University of Warwick, Coventry; United Kingdom 177 Waseda University, Tokyo; Japan 177 Waseda University, Tokyo; Japan 178 Department of Particle Physics and Astrophysics, Weizmann Institute of Science, Rehovot; Israel 179 Department of Physics, University of Wisconsin, Madison WI; United States of America 180 Fakultät für Mathematik und Naturwissenschaften, Fachgruppe Physik, Bergische Universität
Wuppertal, Wuppertal; Germany 180 Fakultät für Mathematik und Naturwissenschaften, Fachgruppe Physik, Bergische Universität
Wuppertal, Wuppertal; Germany 181 Department of Physics, Yale University, New Haven CT; United States of America 181 Department of Physics, Yale University, New Haven CT; United States of America a Also at Borough of Manhattan Community College, City University of New York, New York NY;
United States of America a Also at Borough of Manhattan Community College, City University of New York, New York NY;
United States of America b Also at Bruno Kessler Foundation, Trento; Italy b Also at Bruno Kessler Foundation, Trento; Italy c Also at Center for High Energy Physics, Peking University; China c Also at Center for High Energy Physics, Peking University; China d Also at Centro Studi e Ricerche Enrico Fermi; Italy d Also at Centro Studi e Ricerche Enrico Fermi; Italy e Also at CERN, Geneva; Switzerland f Also at CPPM, Aix-Marseille Université, CNRS/IN2P3, Marseille; France f Also at CPPM, Aix-Marseille Université, CNRS/IN2P3, Marseille; France g Also at Département de Physique Nucléaire et Corpusculaire, Université de Genève, Genève;
Switzerland h Also at Departament de Fisica de la Universitat Autonoma de Barcelona, Barcelona; Spain i Also at Department of Financial and Management Engineering, University of the Aegean, Chios;
Greece j Also at Department of Physics and Astronomy, Michigan State University, East Lansing MI;
United States of America k Also at Department of Physics and Astronomy, University of Louisville, Louisville, KY; United
States of America l Also at Department of Physics, Ben Gurion University of the Negev, Beer Sheva; Israel m Also at Department of Physics, California State University, East Bay; United States of America n Also at Department of Physics, California State University, Fresno; United States of America o Also at Department of Physics, California State University, Sacramento; United States of America p Also at Department of Physics, King’s College London, London; United Kingdom q Also at Department of Physics, St. The ATLAS collaboration Andronikashvili Institute of Physics, Iv. Javakhishvili Tbilisi State University, Tbilisi;(b)High
Energy Physics Institute Tbilisi State University Tbilisi; Georgia 158
(a)E. Andronikashvili Institute of Physics, Iv. Javakhishvili Tbilisi State University, Tbilisi;(b)High 158
(a)E. Andronikashvili Institute of Physics, Iv. Javakhishvili Tbilisi State University, Tbilisi;(b)High 158
(a)E. Andronikashvili Institute of Physics, Iv. The ATLAS collaboration Petersburg State Polytechnical University, St. Petersburg;
Russia r Also at Department of Physics, University of Fribourg, Fribourg; Switzerland s Also at Faculty of Physics, M.V. Lomonosov Moscow State University, Moscow; Russia – 57 – t Also at Faculty of Physics, Sofia University, ‘St. Kliment Ohridski’, Sofia; Bulgaria t Also at Faculty of Physics, Sofia University, ‘St. Kliment Ohridski’, Sofia; Bulgaria u Also at Giresun University, Faculty of Engineering, Giresun; Turkey u Also at Giresun University, Faculty of Engineering, Giresun; Turkey v Also at Graduate School of Science, Osaka University, Osaka; Japan v Also at Graduate School of Science, Osaka University, Osaka; Japan Also at Hellenic Open University, Patras; Greece Also at Institucio Catalana de Recerca i Estudis Av y Also at Institut für Experimentalphysik, Universität Hamburg, Hamburg; Germany z Also at Institute for Particle and Nuclear Physics, Wigner Research Centre for Physics, Budapes
Hungary Hungary aa Also at Institute of Particle Physics (IPP); Canada ab Also at Institute of Physics, Azerbaijan Academy of Sciences, Baku; Azerbaijan ab Also at Institute of Physics, Azerbaijan Academy of Sciences, Baku; Azerbaijan ac Also at Instituto de Fisica Teorica, IFT-UAM/CSIC, Madrid; Spain ac Also at Instituto de Fisica Teorica, IFT-UAM/CSIC, Madrid; Spain JHEP06(2021)003 ae Also at Joint Institute for Nuclear Research, Dubna; Russia ae Also at Joint Institute for Nuclear Research, Dubna; Russia af Also at Moscow Institute of Physics and Technology State University, Dolgoprudny; Russia af Also at Moscow Institute of Physics and Technology State University, Dolgoprudny; Russi ag Also at National Research Nuclear University MEPhI, Moscow; Russia ag Also at National Research Nuclear University MEPhI, Moscow; Russia ah Also at Physics Department, An-Najah National University, Nablus; Palestine ah Also at Physics Department, An-Najah National University, Nablus; Palestine ai Also at Physikalisches Institut, Albert-Ludwigs-Universität Freiburg, Freiburg; Germany ai Also at Physikalisches Institut, Albert-Ludwigs-Universität Freiburg, Freiburg; German aj Also at The City College of New York, New York NY; United States of America aj Also at The City College of New York, New aj Also at The City College of New York, New York NY; United States of America ak Also at TRIUMF, Vancouver BC; Canada al Also at Universita di Napoli Parthenope, Napoli; Italy al Also at Universita di Napoli Parthenope, Napoli; Italy am Also at University of Chinese Academy of Sciences (UCAS), Beijing; China am Also at University of Chinese Academy of Sciences (UCAS), Beijing; China y
f
y
f
(
),
j
g;
∗Deceased ∗Deceased ∗Deceased – 58 –
|
https://openalex.org/W2947436003
|
https://europepmc.org/articles/pmc6509857?pdf=render
|
English
| null |
Colorectal cancer screening in newly insured Medicaid members: a review of concurrent federal and state policies
|
BMC health services research
| 2,019
|
cc-by
| 6,142
|
O’Leary et al. BMC Health Services Research (2019) 19:298
https://doi.org/10.1186/s12913-019-4113-2 O’Leary et al. BMC Health Services Research (2019) 19:298
https://doi.org/10.1186/s12913-019-4113-2 (2019) 19:298 O’Leary et al. BMC Health Services Research
https://doi.org/10.1186/s12913-019-4113-2 Open Access © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Abstract Background: Colorectal cancer (CRC) screening is underutilized by Medicaid enrollees and the uninsured. Multiple
national and state policies were enacted from 2010 to 2014 to increase access to Medicaid and to promote CRC
screening among Medicaid enrollees. We aimed to determine the impact of these policies on screening initiation
among newly enrolled Oregon Medicaid beneficiaries age-eligible for CRC screening. Methods: We identified national and state policies affecting Medicaid coverage and preventive services in Oregon
during 2010–2014. We used Oregon Medicaid claims data from 2010 to 2015 to conduct a cohort analysis of
enrollees who turned 50 and became age-eligible for CRC screening (a prevention milestone, and an age at which
guideline-concordant screening can be assessed within a single year) during each year from 2010 to 2014. We
calculated risk ratios to assess whether first year of Medicaid enrollment and/or year turned 50 was associated with
CRC screening initiation. Results: We identified 14,576 Oregon Medicaid enrollees who turned 50 during 2010–2014; 2429 (17%) completed
CRC screening within 12 months after turning 50. Individuals newly enrolled in Medicaid in 2013 or 2014 were 1.58
and 1.31 times more likely, respectively, to initiate CRC screening than those enrolled by 2010. A primary care visit
in the calendar year, having one or more chronic conditions, and being Hispanic was also associated with CRC
screening initiation. Discussion: The increased uptake of CRC screening in 2013 and 2014 is associated with the timing of policies such
as Medicaid expansion, enhanced federal matching for preventive services offered to Medicaid enrollees without
cost sharing, and formation of Medicaid accountable care organizations, which included CRC screening as an
incentivized quality metric. Keywords: Colorectal Cancer, Health Policy, Health Promotion, Medicaid, Screening CRC-specific deaths could be prevented by implementing
interventions to improve timely screening, follow-up and
treatment, and risk-factor modifications
[3]. Multiple
screening modalities, including colonoscopy and stool tests,
are effective in reducing morbidity and mortality from CRC
and are recommended for average-risk adults ages 50–75
by the U.S. Preventive Services Task Force [2]. Yet, screen-
ing rates remain relatively low, especially among adults
newly age-eligible for CRC screening. In 2014, just 60.8% of
all adults ages 50–64 were up-to-date with CRC screening
nationally (median), compared to 76.1% of adults age 65
and older [4]. CRC screening initiation and up-to-date rates Colorectal cancer screening in newly
insured Medicaid members: a review of
concurrent federal and state policies Meghan C. O’Leary1*
, Kristen Hassmiller Lich1, Yifan Gu2, Stephanie B. Wheeler1,3,4, Gloria D. Coronado5,
Sarah E. Bartelmann6, Bonnie K. Lind2,7, Maria E. Mayorga8 and Melinda M. Davis7,9,10 Background Colorectal cancer (CRC) is the fourth most common type
of cancer in the United States. Approximately 135,000
cases are newly diagnosed each year, representing 8% of
all new cancer cases [1]. CRC is also the second leading
cause of cancer-related deaths, accounting for an esti-
mated 50,000 deaths annually [1, 2]. Over half of these * Correspondence: mcoleary@live.unc.edu
1Department of Health Policy & Management, Gillings School of Global
Public Health, University of North Carolina at Chapel Hill, 1105E
McGavran-Greenberg Hall, Chapel Hill, NC 27599, USA
Full list of author information is available at the end of the article * Correspondence: mcoleary@live.unc.edu
1Department of Health Policy & Management, Gillings School of Global
Public Health, University of North Carolina at Chapel Hill, 1105E
McGavran-Greenberg Hall, Chapel Hill, NC 27599, USA
Full list of author information is available at the end of the article Methods have also been consistently lower for Medicaid enrollees
and the uninsured, as compared to the privately insured
[5–7]. For example, in 2013, up-to-date rates across demo-
graphic groups, except for Hispanics, the only group in
which this finding was reversed, were 6–17 percentage
points lower among U.S. Medicaid enrollees ages 50–64
than the privately insured in the same age group [5]. We conducted a policy review and retrospective claims
analysis
to
understand
incident
CRC
screening
in
Oregon between 2010 and 2014 within the Medicaid
population. First, we reviewed the literature to identify
national and Oregon-specific policies implemented be-
tween 2010 and 2014 aimed at either increasing access
to Medicaid coverage or improving CRC screening
among Medicaid enrollees. Second, we consulted with
policy experts to ensure that our list of policies was
comprehensive and accurate. Figure 1 summarizes rele-
vant policy changes such as, at the national level, the en-
actment of the Affordable Care Act (ACA) in 2010 and
increased Medicaid matching rates for states offering
preventive services with no cost sharing in 2013 [8–19]. Oregon policy changes included the enrollment of Me-
dicaid members into coordinated care organizations
(CCOs, a type of accountable care organization) in 2012,
the measurement of CRC screening as a CCO quality in-
centive beginning in 2013, and the expansion of the
state’s Medicaid program in 2014. The objective of this paper is to assess associations be-
tween the timing of national and state policies and inci-
dent CRC screening behaviors among newly enrolled
Medicaid beneficiaries turning 50 between 2010 and 2014. We focus specifically on CRC screening in Oregon be-
cause screening rates in this state closely resemble na-
tional rates; Oregon data for 2014 show that 60.8% of
adults ages 50–64 (vs. 60.8% nationally) and 78.4% of
adults 65 and older (vs. 76.1% nationally) were up-to-date
on CRC screening [4]. In addition, Oregon enacted mul-
tiple policies designed to increase access to insurance and
preventive services during these years, providing an op-
portunity to compare incident screening annually in the
context of health policy changes. We first develop a time-
line of state and federal policy changes related to Medicaid
coverage and preventive services during the study period. Methods We then explore changes in CRC screening initiation, de-
fined as screening within 12 months after an enrollee
turned 50 years old, based on year enrolled in Medicaid
and year becoming age eligible (i.e., turned 50). Screening
initiation was studied because it is an important preven-
tion milestone, and an age at which screening in a single
year can be assessed for guideline concordance. We then obtained Oregon Medicaid claims data from
2010 to 2015 (Additional file 1: Figure S1) to determine if
there was a differential impact of first gaining Medicaid
coverage and/or becoming age-eligible for CRC screening
in any given year that may be associated with the
respective policy changes. For this sample, we included in-
dividuals who turned age 50 from 2010 to 2014 and were
continuously enrolled in Medicaid for at least 11 of 12
months following their 50th birthday. Page 2 of 7 Page 2 of 7 O’Leary et al. BMC Health Services Research (2019) 19:298 O’Leary et al. BMC Health Services Research (2019) 19:298 O’Leary et al. BMC Health Services Research (2019) 19:298 Methods Of these
individuals, 2429 (17%) completed any form of CRC
screening within 12 months after their 50th birthday. enrollees with a birthday during the last quarter of each
study year to assess CRC screening initiation over a
12-month period consistently across all study years, given
the transition from ICD-9 to ICD-10 codes in October
2015. We also excluded enrollees with a history of CRC,
colectomy, or end-stage renal disease (Additional file 1:
Table S1); those who passed away during the study period;
and those dually eligible for Medicaid and Medicare be-
cause their patterns of care are different than those in-
sured solely by Medicaid [7] and because we lacked access
to Medicare claims. g
y
Table 2 presents risk ratios (RR) to identify how much
more likely Medicaid enrollees were to initiate CRC
screening within 12 months after turning 50 based on
demographics, geographic characteristics, health status,
healthcare utilization, year turned 50, and year enrolled
in Medicaid. Newly age-eligible Medicaid enrollees who
had a PCP visit were significantly more likely to get
screened than those without a visit (RR: 5.38; 95% CI =
4.33, 6.70). Enrollees with one or more chronic condi-
tions were 1.66 times more likely to initiate screening
within 12 months than those without (95% CI = 1.45,
1.91). Compared to those who first enrolled in 2010,
those who first enrolled in Medicaid in 2013 were 1.58
times as likely to get screened (95% CI = 1.20, 2.09), and
first time enrollees in 2014 were 1.31 times as likely to
get screened (95% CI = 1.15, 1.49). Although the RR was
higher in 2013 relative to 2014, the absolute number of
individuals who enrolled in Medicaid in 2014 was con-
siderably higher than in 2013. In terms of race and eth-
nicity, Hispanics were 1.16 times as likely to initiate
CRC screening as white enrollees (95% CI = 1.00, 1.34). Sex, rural/urban residence, distance from an endoscopy
facility, year turned 50, and turning 50 and enrolling in
Medicaid in the same year prior to Medicaid expansion
were not statistically significant. Our primary outcome was any indication of CRC screen-
ing with colonoscopy, sigmoidoscopy, or stool testing within
12 months after turning 50 (Additional file 1: Table S2). Using
claims
data
alone,
it
is
difficult
to
identify
guideline-concordant CRC screening due to the multiple
ways in which people can become up-to-date on screening
(e.g. Methods We excluded Federal
Policies
Oregon
Policies
March 23, 2010
Patient Protection and
Affordable Care Act
signed into law8
January 1, 2013
States qualify for one
percentage point
increase in Medicaid
match rate if preventive
services offered with no
cost sharing9
May 17, 2013
Federal notification of
Medicaid “Fast Track”
option allowing states
to begin identifying
residents who may be
eligible under
expansion10
January 1, 2014
Medicaid
enrollment under
expansion becomes
active10
March 2008
First of 8 Medicaid lottery
drawings for enrolling
uninsured residents ages
19-64 with incomes <100%
FPL who did not meet
categorical eligibility12
February 1, 1994
Oregon Health Plan
Section 1115 Medicaid
demonstration waiver
approved11
September 2008
Last of 8 Medicaid
lottery drawings,
ultimately selecting
35,000 of 85,000
individuals on the wait
list to apply, 30% of
whom were enrolled12
2011
Medicaid lottery
waiting list is re-
opened with 14
additional drawings
held from February
2012-November
201314
July 5, 2012
Amendment to
Medicaid waiver to
reduce spending
growth and improve
quality and access
by enrolling
members in CCOs15-16
October 16, 2012
17 quality measures
and targets (including
CRC screening) for
CCOs finalized by
Metrics and Scoring
Committee17
January 2013
Measurement
period for
incentivized
CCO quality
metrics began18
November 15, 2013
One of 5 states with
Medicaid “Fast
Track” enrollment
option approved10
January 1,
2014
Medicaid
income eligibility
threshold
increased
from 100% to
138% FPL10
June 30, 2014
Annual incentives
up to 2% of CCO’s
aggregate monthly
capitation rates
paid for 2013
quality metrics18-19
2008
2009
2010
2011
2012
2013
2014
June 26, 2009
House Bill 2009 enacted,
which created Oregon’s
Patient-Centered Primary
Care Home Program13
Fig. 1 Timeline of Medicaid expansion and preventive services coverage in Oregon and nationally Page 3 of 7 O’Leary et al. BMC Health Services Research (2019) 19:298 O’Leary et al. BMC Health Services Research (2019) 19:298 Page 3 of 7 CRC screening (Table 1). Eligible enrollees included urban
(57%) and rural (43%) residents, 56% were female, 72%
were white, and 10% were Hispanic. Most (78%) enrollees
lived within 5 miles of the nearest endoscopy facility. Three-quarters (78%) of the enrollees visited their PCP
during the index year, and 73% had a chronic condition. One in four (26%) individuals enrolled in Medicaid for the
first time in 2014; 60% first enrolled by 2010. The year
2014 was when most (44%) enrollees turned 50. Methods colonoscopy 10 years ago, stool testing in the past year)
as well as fluctuations in coverage for Medicaid enrollees
over time (e.g., screening completed while a patient is pri-
vately insured will not appear in Medicaid claims). Therefore,
we focused on this newly age-eligible Medicaid population
who turned 50 during the study window to minimize the
chance of any missed CRC screenings in our dataset. Finally, we used a log Poisson model to assess whether
eligible Medicaid enrollees were more likely to initiate CRC
screening within 12 months after their 50th birthday in re-
sponse to national and/or state policy changes within the
year that they turned 50 (e.g., ACA Medicaid expansion). In this way, turning 50 in a particular policy year is a form
of random assignment. We report screening rates for years
2011, 2012, 2013, and 2014, with 2010 serving as the refer-
ence group for this analysis. In addition, we consider differ-
ences in CRC screening among these 50-year-old enrollees
as a result of policy changes in the same year in which they
first enrolled in Medicaid. We defined new enrollment in
Medicaid as having no enrollment from 2005 until the year
an individual turned 50. All analyses controlled for poten-
tial covariates, including sex, race/ethnicity, geography, dis-
tance to endoscopy facility, having a chronic condition,
visiting a primary care provider (PCP), and enrolling in Me-
dicaid and turning 50 in the same year. Similar to prior
studies, distance to endoscopy facility was calculated using
zip code centroids to determine the closest distance from
the member’s residence to the nearest endoscopy facility
[6], and PCP visit was defined as any visit with a primary
care procedure code in the calendar year [20]. Analyses
were conducted using R, version 3.4.4. We assessed statis-
tical significance using an alpha level of 0.05 and report
95% confidence intervals (CI). Discussion In this analysis, we explored the potential impact of na-
tional and state policies on the likelihood of CRC
screening initiation in newly age-eligible Medicaid enrol-
lees between 2010 and 2014 in Oregon. Compared to
2010, we found a statistically significant increase in CRC
screening initiation among individuals who first enrolled
in Medicaid in either 2013 or 2014. These results mirror
national CRC screening trends, in which CRC screening
plateaued from 2010 to 2013, followed by an increase
from 2013 to 2015 [21]. Mapping these trends onto state
and federal policy changes provides an opportunity to
understand how health policy may drive screening initi-
ation behaviors. Results The uptake in CRC screening among those who first
enrolled in 2013 and 2014 is associated with the enact-
ment of multiple policies intended to increase Medicaid A total of 14,576 Oregon Medicaid enrollees turned 50
between 2010 and 2014 and were newly age-eligible for O’Leary et al. BMC Health Services Research (2019) 19:298 Page 4 of 7 Page 4 of 7 Table 1 Characteristics of Oregon Medicaid enrollees who
turned age 50 in 2010–2014
Characteristic
Total Population (%,
N)
Completed CRC Screening
Within 12 Months After 50th
Birthday (%, N)
Total (N)
Sex
14,576
2429
Male
44.4 (6479)
42.0 (1019)
Female
55.6 (8097)
58.0 (1410)
Race/Ethnicity
White
71.8 (10,469)
71.4 (1735)
Hispanic
10.3 (1497)
9.1 (220)
African
American
3.9 (568)
5.2 (127)
Other/
Unknown
14.0 (2042)
14.3 (347)
Geography
Rural
43.0 (6274)
39.9 (969)
Urban
57.0 (8302)
60.1 (1460)
Distance to endoscopy facility
> 5 miles
22.4 (3263)
20.4 (496)
≤5 miles
77.6 (11,313)
79.6 (1933)
Chronic condition
No
26.7 (3888)
11.0 (268)
Yes
73.3 (10,688)
89.0 (2161)
Primary care provider visit
No
21.9 (3186)
4.0 (98)
Yes
78.1 (11,390)
96.0 (2331)
Year turned 50
2010
10.5 (1529)
9.5 (231)
2011
15.3 (2230)
15.4 (373)
2012
15.6 (2276)
16.0 (388)
2013
14.4 (2095)
14.1 (342)
2014
44.2 (6446)
45.1 (1095)
Year first enrolled in Medicaid
2010 or earlier
59.9 (8738)
58.6 (1423)
2011
8.8 (1289)
8.7 (212)
2012
3.6 (527)
3.6 (87)
2013
1.9 (277)
2.6 (64)
2014
25.7 (3745)
26.5 (643) program in 2014, and the decision to participate in “fast
track” enrollment in which the state could start to iden-
tify and begin outreach in 2013 to residents who would
become newly eligible for coverage through Medicaid
expansion, provided more state residents with access to
coverage [10]. The larger increase in the number of new
enrollees screened in 2014 compared to 2013, along with
the finding that the year in which individuals turn 50 is
not statistically significant, point to differences in CRC
screening behaviors among those newly enrolled through
Medicaid expansion compared to those newly enrolled
in prior years. p
y
While prior research [23, 24] demonstrates that insur-
ance access is an important predictor of CRC screening,
we also observed differences in CRC screening initiation
based on patient characteristics. This suggests that, in
addition to increased coverage, certain groups may need
more assistance in completing recommended preventive
care. Results In addition, an ongoing Oregon statewide public
health campaign intended to promote CRC screening, ini-
tially piloted in 2011, also provides dedicated resources to
Table 2 Relative risk of completing CRC screening among
Oregon Medicaid enrollees who turned age 50 in 2010–2014
within 12 months after 50th birthday
Characteristic
Risk Ratio
(95% CI)
P-value
Sex
Male
Reference
Female
1.03 (0.95–1.11)
.548
Race/Ethnicity
White
Reference
Hispanic
1.16 (1.00–1.34)
.044
African American
1.19 (0.98–1.43)
.075
Other/Unknown
1.10 (0.98–1.24)
.121
Geography
Rural
Reference
Urban
1.08 (0.96–1.22)
.190
Distance to endoscopy facility
> 5 miles
Reference
≤5 miles
1.05 (0.94–1.19)
.391
Chronic condition
No
Reference
Yes
1.66 (1.45–1.91)
<.0001
Primary care provider visit
No
Reference
Yes
5.38 (4.33–6.69)
<.0001
Year turned 50
2010
Reference
2011
1.13 (0.96–1.34)
.143
2012
1.12 (0.95–1.33)
.163
2013
1.05 (0.88–1.24)
.610
2014
1.11 (0.94–1.31)
.207
Year first enrolled in Medicaid
2010 or earlier
Reference
2011
1.05 (0.90–1.24)
.509
2012
1.11 (0.88–1.41)
.369
2013
1.58 (1.20–2.09)
.001
2014
1.31 (1.15–1.49)
<.0001
Turned 50 and first enrolled in Medicaid in same year (2010–2013)
No
Reference
Yes
0.98 (0.77–1.25)
.871 CRC screening among Hispanics may also reflect the trend
in increased use of fecal testing during the study period in
Oregon [20]; notably, fecal testing has been shown to be an
effective and acceptable screening modality among His-
panics [37, 38]. Nevertheless, there is a continued need for
targeted policies to reduce disparities in preventive care. There are several strengths of this analysis. We de-
veloped a comprehensive timeline of federal and
Oregon-specific
health
policy
changes
during
the
study window that had the potential to influence CRC
screening patterns. We also identified opportunities to
improve CRC screening among Medicaid beneficiaries,
a population with known disparities in use of recom-
mended preventive services as well as CRC outcomes. p
This analysis includes some limitations. First, we an-
ticipate that CRC screening initiation is underestimated
based on our use of claims data alone; however, claims
analyses provide a validated method of identifying screen-
ing patterns over multiple years without the potential
biases (e.g. recall bias) associated with self-reported data
collection [39, 40]. Second, the impact of the evaluated
health policies may also be muted because we do not
know the percentage of unscreened individuals who initi-
ated screening soon after the 12-month window, and it
may take longer to see the effects of Medicaid expansion
on preventive screening rates. Results Within our population, PCP visits and the presence
of chronic conditions were the biggest determinants of
CRC screening within 12 months. Individuals who visit
their PCP or who have a chronic condition may be more
actively engaged in their health and more likely to get
screened than those who have not seen their PCP in the
calendar year or who do not have a chronic condition [6,
25, 26]. Given efforts to promote CRC screening through
policy in Oregon, providers may have been more likely
to recommend screening during the study window. Clinics and facilities may also have increased the use of
various screening modalities beyond colonoscopy to
achieve the CCO quality metric [20, 27]. For example,
following the development of Oregon’s Patient-Centered
Primary Care Home Program (PCPCH), Oregon PCPs
were focused on improving their delivery of preventive
care and PCPCHs received training related to their care
delivery and metric-specific efforts [13]. In contrast, Me-
dicaid enrollees who were assigned to a CCO and pro-
vider but did not establish care right away likely did not
receive a recommendation for CRC screening. Add-
itional resources and population outreach strategies may
be needed to meet the growing demand of newly en-
rolled Medicaid members. The CRC screening rate was also higher among His-
panics – a pattern that has mixed prior evidence. While na-
tional CRC screening rates are lower among Hispanics
compared to non-Hispanic whites [28, 29], research has
shown relatively high CRC screening rates among His-
panics who are insured or English-speaking [30–33]. More-
over, Hispanics who are included in mailed FIT outreach
programs are found to have higher FIT completion rates
than non-Hispanic whites [34]. In Oregon, the strategies
employed by CCOs to improve equity, such as the use of
community health workers, have improved primary care
use and screening uptake among racial and ethnic groups enrollment and coverage of preventive services within
this population during this timeframe. Both federal and
state
policies
during
this
period
incentivized
CRC
screenings. For example, in 2012 Oregon assigned Me-
dicaid members into newly formed CCOs [22], in which
CRC screening began to be measured as a quality metric
in 2013 with gradually increasing financial incentives
[18, 19]. Meanwhile, the expansion of Oregon’s Medicaid Page 5 of 7 Page 5 of 7 O’Leary et al. BMC Health Services Research (2019) 19:298 [35]. Competing interests From November 2014 – August 2015, Gloria Coronado served as a co-
Investigator on an industry-funded study, funded by EpiGenomics, to evalu-
ate patient adherence to an experimental blood test for colorectal cancer. From September 2017 – June 2018, Gloria Coronado served as the Principal
Investigator on an industry-funded study, funded by Quidel Corporation, to
compare the clinical performance of an experimental FIT to an FDA-
approved FIT. Stephanie Wheeler receives unrelated grant funding to her in-
stitution from Pfizer. All other authors report no competing interests. References 1. National Cancer Institute Surveillance, Epidemiology, and End Results
Program. Cancer stat facts: colorectal cancer Available from: https://seer. cancer.gov/statfacts/html/colorect.html. 1. National Cancer Institute Surveillance, Epidemiology, and End Results
Program. Cancer stat facts: colorectal cancer Available from: https://seer. cancer.gov/statfacts/html/colorect.html. 2. US Preventive Services Task Force. Screening for colorectal cancer: US
Preventive Services Task Force recommendation statement. JAMA. 2016;
315(23):2564–75. https://doi.org/10.1001/jama.2016.5989. 3. Vogelaar I, van Ballegooijen M, Schrag D, Boer R, Winawer SJ, Habberma JD,
et al. How much can current interventions reduce colorectal cancer
morbidity in the U.S.? Mortality projections for scenarios of risk-factor
modification, screening, and treatment. Cancer. 2006;107(7):1624–33. https://
doi.org/10.1002/cncr.22115. g
p
g
UH3CA188640. The funding organizations did not have a role in the design
of the study; collection, analysis, and interpretation of data, or writing of the
manuscript. The content provided is solely the responsibility of the authors
and does not necessarily represent the official views of the funders. 4. American Cancer Society. Colorectal Cancer Facts & Figures 2017–2019. Atlanta: American Cancer Society; 2017. 5. Medicaid and CHIP Payment and Access Commission. Access in brief:
use of cervical, breast, and colon cancer tests among adult Medicaid
enrollees. 2016. Available from: https://www.macpac.gov/wp-content/
uploads/2016/11/Use-of-Cervical-Breast-and-Colon-Cancer-Tests-among-
Adult-Medicaid-Enrollees.pdf. Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations. Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations. Abbreviations ACA: Affordable Care Act; CCO: Coordinated Care Organization;
CI: Confidence Interval; CPT: Current Procedural Terminology; CRC: Colorectal
Cancer; FIT: Fecal Immunochemical Test; HCPCS: Healthcare Common
Procedure Coding System; ICD-10: International Classification of Diseases,
Tenth Edition; ICD-9: International Classification of Diseases, Ninth Edition;
PCP: Primary Care Provider; PCPCH: Patient-Centered Primary Care Home
Program; RR: Risk Ratio Results In addition, the year 2010 is
somewhat different than the other study years because it
included individuals who first enrolled in 2010 and those
who enrolled in prior years. Finally, while our data point
to a cumulative positive effect of the related health pol-
icies, we are unable to separate out the individual impact
of specific policy interventions or assess causality. Despite
these limitations, this analysis provides a snapshot of CRC
screening uptake among a vulnerable population during a
period characterized by numerous policy changes. Continued
assessment
of
CRC
screening
rates
among
individuals
new
to
Medicaid
and
newly
turned 50 could be helpful in identifying longer-term
trends of national and state policies. Since 2014, new
statewide policies have gone into effect in Oregon
that further promote CRC screening across insurers. These policies include House Bill 4085, which elimi-
nates cost sharing for recommended CRC screening
tests,
inclusive
of
the
removal
of
polyps
during
screening [41], and House Bill 2560, which provides
coverage of diagnostic colonoscopies following an
abnormal fecal test result among adults at least 50
years of age.42 It will be important to evaluate the
impact of these and future policy efforts to facilitate
CRC screening in the larger state population and
among Medicaid enrollees. Findings may also inform
other states that are exploring opportunities to im-
prove CRC prevention by expanding access to Me-
dicaid and incentivizing screening. [35]. In addition, an ongoing Oregon statewide public
health campaign intended to promote CRC screening, ini-
tially piloted in 2011, also provides dedicated resources to
reach Spanish-speaking residents as well as other vulner-
able groups, including African Americans, Native Ameri-
cans, and rural communities [36]. Although this study did
not assess differences in screening modality, the higher Page 6 of 7 O’Leary et al. BMC Health Services Research (2019) 19:298 O’Leary et al. BMC Health Services Research (2019) 19:298 Page 6 of 7 Availability of data and materials The datasets generated and/or analyzed during the current study are
available from the Oregon Health Authority but restrictions apply to the
availability of these data, which were used under license for the current
study and so are not publicly available. Data are, however, available from the
authors upon reasonable request and within permission of Oregon Health
Authority. 6. Davis MM, Renfro S, Pham R, Hassmiller Lich K, Shannon J, Coronado GD, et
al. Geographic and Population-Level Disparities in Colorectal Cancer Testing:
A Multilevel Analysis of Medicaid and Commercial Claims Data. Prev Med. 2017;101(8):44–52. https://doi.org/10.1016/j.ypmed.2017.05.001. 6. Davis MM, Renfro S, Pham R, Hassmiller Lich K, Shannon J, Coronado GD, et
al. Geographic and Population-Level Disparities in Colorectal Cancer Testing:
A Multilevel Analysis of Medicaid and Commercial Claims Data. Prev Med. 2017;101(8):44–52. https://doi.org/10.1016/j.ypmed.2017.05.001. Consent for publication
Not applicable. Consent for publication
Not applicable. Funding This study was supported, in part, by Cooperative Agreement Numbers U48-
DP005017 (University of North Carolina at Chapel Hill) and U48-DP005006
(Oregon Health & Science University) from the Centers for Disease Control
and Prevention (CDC) Prevention Research Centers (PRC) Program and the
National Cancer Institute (NCI), as part of the Cancer Prevention and Control
Research Network (CPCRN). Melinda Davis was supported by an Agency for
Healthcare Research & Quality patient-centered outcomes research (PCOR)
K12 award (Award # K12 HS022981 01, PI: Jeanne-Marie Guise) and an NCI
K07 award (1K07CA211971-01A1, PI: Davis). Gloria Coronado was supported
in part by the National Cancer Institute of the National Institutes of Health
Common Fund, through Cooperative Agreements UH2AT007782/ Author details
1 Additional file 1: Figure S1. Inclusion and exclusion criteria. Table S1. Billing codes indicating CRC screening procedures. Table S2. Billing
codes indicating exclusion criteria (DOCX 34 kb) 1Department of Health Policy & Management, Gillings School of Global
Public Health, University of North Carolina at Chapel Hill, 1105E
McGavran-Greenberg Hall, Chapel Hill, NC 27599, USA. 2Center for Health
Systems Effectiveness, Oregon Health & Science University, Portland, OR, USA. 3Lineberger Comprehensive Cancer Center, University of North Carolina at
Chapel Hill, Chapel Hill, NC, USA. 4Center for Health Promotion & Disease
Prevention, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. 5Kaiser Permanente Center for Health Research, Portland, OR, USA. 6Center
for Outcomes Research and Education, Portland, OR, USA. 7OHSU-PSU School
of Public Health, Oregon Health & Science University, Portland, OR, USA. 8Edward P. Fitts Department of Industrial and Systems Engineering, North
Carolina State University, Raleigh, NC, USA. 9Department of Family Medicine,
Oregon Health & Science University, Portland, OR, USA. 10Oregon Rural
Practice-based Research Network, Oregon Health & Science University,
Portland, OR, USA. Conclusions Ethics approval and consent to participate Ethics approval and consent to participate This study was approved by the Institutional Review Board at the Oregon
Health & Science University, the site where all analyses for this study were
conducted, with a waiver of informed consent (IRB #8865). We observed higher CRC screening initiation in newly
age-eligible Oregon Medicaid enrollees during a time
period when insurance expansion and policies to pro-
mote preventive service use were implemented. Being
newly enrolled in Medicaid in 2013 and 2014 was sig-
nificantly associated with increased CRC screening ini-
tiation. In this insured population, PCP visits and
presence of a chronic condition were particularly strong
indicators for CRC screening. Our findings show that
recent state and national health promotion policies ap-
pear to have supported CRC screening among Medicaid
enrollees. Such policies, combined with facilitators at
the practice- and patient-levels, are important for pro-
moting CRC screening uptake. Acknowledgements Received: 14 February 2019 Accepted: 22 April 2019 Received: 14 February 2019 Accepted: 22 April 2019 Authors’ contributions 7. Wheeler SB, Kuo T, Goyal RK, Meyer AM, Hassmiller Lich K, Gillen EM, et al. Regional variation in colorectal cancer testing and geographic availability of
care in a publicly insured population. Health Place. 2014;29:114–23. https://
doi.org/10.1016/j.healthplace.2014.07.001. 7. Wheeler SB, Kuo T, Goyal RK, Meyer AM, Hassmiller Lich K, Gillen EM, et al. Regional variation in colorectal cancer testing and geographic availability of
care in a publicly insured population. Health Place. 2014;29:114–23. https://
doi.org/10.1016/j.healthplace.2014.07.001. MO, KL, SW, MM, and MD made substantial contributions to the study
conception and analytic approach. YG and BL analyzed the data. MO, KL, SW,
GC, SB, and MD helped with data interpretation. MO, KL, and MD drafted the
manuscript. All authors critically reviewed, edited, and approved the final
manuscript. 8. The Patient Protection and Affordable Care Act. H.R. 3590. Available from: https://
www.gpo.gov/fdsys/pkg/BILLS-111hr3590enr/pdf/BILLS-111hr3590enr.pdf. Page 7 of 7 Page 7 of 7 O’Leary et al. BMC Health Services Research (2019) 19:298 O’Leary et al. BMC Health Services Research (2019) 19:298 9. The Henry J. Kaiser Family Foundation. Kaiser Commission on Medicaid and
the uninsured: coverage of preventive services for adults in Medicaid. 2012. Available from: https://www.kff.org/health-reform/issue-brief/coverage-of-
preventive-services-for-adults-in/. 9. The Henry J. Kaiser Family Foundation. Kaiser Commission on Medicaid and
the uninsured: coverage of preventive services for adults in Medicaid. 2012. Available from: https://www.kff.org/health-reform/issue-brief/coverage-of-
preventive-services-for-adults-in/. 29. White A, Thompson TD, White MC, Sabatino SA, de Moor J, Doria-Rose PV,
et al. Cancer screening test use – United States, 2015. MMWR Morb Mortal
Wkly Rep. 2017;66:201–6. https://doi.org/10.15585/mmwr.mm6608a1. 30. Liss DT, Baker DW. Understanding current racial/ethnic disparities in
colorectal cancer screening in the United States: the contribution of
socioeconomic status and access to care. Am J Prev Med. 2014;46(3):228–
36. https://doi.org/10.1016/j.amepre.2013.10.023. 10. The Henry J. Kaiser Family Foundation. Fast track to coverage: facilitating
enrollment of eligible people into the Medicaid expansion. 2013. Available
from: https://www.kff.org/medicaid/issue-brief/fast-track-to-coverage-
facilitating-enrollment-of-eligible-people-into-the-medicaid-expansion/. 10. The Henry J. Kaiser Family Foundation. Fast track to coverage: facilitating
enrollment of eligible people into the Medicaid expansion. 2013. Available
from: https://www.kff.org/medicaid/issue-brief/fast-track-to-coverage-
facilitating-enrollment-of-eligible-people-into-the-medicaid-expansion/. 31. Savas LS, Vernon SW, Atkinson JS, Fernandez ME. Effect of acculturation and
access to care on colorectal cancer screening in low-income Latinos. J Immigr
Minor Health. 2015;17(3):696–703. https://doi.org/10.1007/s10903-014-0061-4. 11. Special Terms and Conditions for Oregon Section 1115 Medicaid Demonstration
amended July 5, 2012: 9–12, 172–173. Available from: https://www.oregon.gov/
oha/HSD/Medicaid-Policy/1115Waiver/CURRENT%20WAIVER%20-%207-5-
2012%20to%206-30-2017%20(Eff.%206-13-2015).pdf. 32. Diaz JA, Roberts MB, Goldman RE, Weitzen S, Eaton CB. Authors’ contributions Effect of
language on colorectal cancer screening among Latinos and non-
Latinos. Cancer Epidemiol Biomark Prev. 2008;17(8):2169–73. https://doi. org/10.1158/1055-9965.EPI-07-2692. 12. Finkelstein A, Taubman S, Wright B, Bernstein M, Gruber J, Newhouse JP, et
al. The Oregon health insurance experiment: evidence from the first year. Q
J Econ. 2012;127(3):1057–106. PMID: 23293397. 33. Coronado GD, Rivelli JS, Fuoco MJ, Vollmer WM, Petrik AF, Keast E, et al. Effect of reminding patients to complete fecal immunochemical testing: a
comparative effectiveness study of automated and live approaches. J Gen
Intern Med. 2018;33(1):72–8. 13. Oregon Health Authority. Patient-Centered Primary Care Home Program. 2015. Available from: https://www.oregon.gov/oha/HPA/dsi-pcpch/
Documents/2014-2015%20PCPCH%20Program%20Annual%20Report.pdf. 34. McConnell KJ, Charlesworth CJ, Meath THA, George RM, Kim H. Oregon’s
emphasis on equity shows signs of early success for Black and American
Indian Medicaid enrollees. Health Aff (Millwood). 2018;37(3):386–93. https://
doi.org/10.1377/hlthaff.2017.1282. 14. Wright BJ, Conlin AK, Allen HL, Tsui J, Carlson MJ, Li HF. What does
Medicaid expansion mean for cancer screening and prevention? Results
from a randomized trial on the impacts of acquiring Medicaid coverage. Cancer. 2016;122(5):791–7. https://doi.org/10.1002/cncr.29802. 35. Oregon Health Authority. “The cancer you can prevent.” Available from:
http://thecanceryoucanprevent.org/about-this-campaign/. 15. McConnell KJ, Renfro S, Lindrooth RC, Cohen DJ, Wallace NT, Chernew ME. Oregon’s Medicaid reform and transition to global budgets were associated
with reductions in expenditures. Health Aff (Millwood). 2017;36(3):451–9. https://doi.org/10.1377/hlthaff.2016.1298. 36. Baker DW, Brown T, Buchanan DR, Weil J, Balsley K, Ranalli L, et al. Comparative effectiveness of a multifaceted intervention to improve
adherence to annual colorectal cancer screening in community health
centers: a randomized clinical trial. JAMA Intern Med. 2014;174(8):1235–41. https://doi.org/10.1001/jamainternmed.2014.2352. 16. Coronado GD, Petrik AF, Bartelmann SE, Coyner LA, Coury J. Health
policy to promote colorectal cancer screening: improving access and
aligning federal and state incentives. Clin Res (Alex). 2015;29(1):50–5. https://doi.org/10.14524/CR-14-0044. 37. Loi CXA, Tyson DM, Chavarria EA, Gutierrez L, Klasko L, Davis S, et al. ‘Simple
and easy:’ providers’ and latinos’ perceptions of the fecal immunochemical
test (FIT) for colorectal cancer screening. Ethn Health. 2018:1–16. https://doi. org/10.1080/13557858.2017.1418298. p
g
17. Oregon Metrics and Scoring Committee. Meeting minutes, vol. 16; 2012. l h
h
h
l h
f 18. Oregon Health Authority. Oregon’s health system transformation: 2013
performance report. 2014. Available from: http://www.oregon.gov/oha/HPA/
ANALYTICS-MTX/documents/cco-metrics-2013-final-report.pdf. 38. Dodou D, de Winter JCF. Agreement between self-reported and registered
colorectal cancer screening: a meta-analysis. Eur J Cancer Care (Engl). 2015;
24(33):286–98. https://doi.org/10.1111/ecc.12204. 19. Oregon Health Authority. Oregon’s health system transformation: 2014
performance report. 2015. Authors’ contributions Available from: http://www.oregon.gov/oha/HPA/
ANALYTICS-MTX/Documents/CCO-Metrics-2014-Final-Report.pdf. 39. Schenck AP, Klabunde CN, Warren JL, Peacock S, Davis WW, Hawley ST, et
al. Data sources for measuring colorectal endoscopy use among Medicare
enrollees. Cancer Epidemiol Biomark Prev. 2007;16(10):2118–27. https://doi. org/10.1158/1055-9965.EPI-07-0123. 20. Davis MM, Shafer P, Renfro S, Lich KH, Shannon J, Coronado GD, et al. Does a
transition to accountable care in Medicaid shift the modality of colorectal cancer
testing? BMC Health Serv Res. 2019;19:54. https://doi.org/10.1186/s12913-018-3864-5. 40. 77th Oregon Legislative Assembly - 2014 Regular Session. Enrolled House
Bill 4085 (HB 4085-Intro). https://olis.leg.state.or.us/liz/2014R1/Downloads/
MeasureDocument/HB4085. 21. de Moor JS, Cohen RA, Shapiro JA, Nadel MR, Sabatino SA, Yabroff KA, et al. Colorectal cancer screening in the United States: trends from 2008 to 2015
and variation by health insurance coverage. Prev Med. 2018;112:199–206. https://doi.org/10.1016/j.ypmed.2018.05.001. 41. 78th Oregon Legislative Assembly - 2015 Regular Session. House Bill 2560. https://olis.leg.state.or.us/liz/2015R1/Downloads/MeasureDocument/HB2560/
Introduced. 22. Stock R, Goldberg B, editors. Health reform policy to practice: Oregon’s path to a
sustainable health system, a study in innovation. London: Academic Press; 2017. 23. Petrik AF, Le T, Keast E, Rivelli J, Bigler K, Green B, et al. Predictors of
colorectal cancer screening prior to implementation of a large pragmatic
trial in federally qualified health centers. J Community Health. 2018;43(1):
128–36. https://doi.org/10.1007/s10900-017-0395-7. 24. Zhao G, Okoro CA, Li J, Town M. Health insurance status and clinical cancer
screenings among U.S. adults. Am J Prev Med. 2018;54(1):e11–9. https://doi. org/10.1016/j.amepre.2017.08.024. 24. Zhao G, Okoro CA, Li J, Town M. Health insurance status and clinical cancer
screenings among U.S. adults. Am J Prev Med. 2018;54(1):e11–9. https://doi. org/10.1016/j.amepre.2017.08.024. 25. Halm EA, Beaber EF, McLerran D, Chubak J, Corley DA, Rutter CM, et al. Association between primary care visits and colorectal cancer screening
outcomes in the era of population health outreach. J Gen Intern Med. 2016;
31(10):1190–7. https://doi.org/10.1007/s11606-016-3760-9. 26. Wang H, Qiu F, Gregg A, Chen B, Kim J, Young L, et al. Barriers and
facilitators of colorectal cancer screening for patients of rural accountable
care organization clinics: a multilevel analysis. J Rural Health. 2017;34(2):202–
12. https://doi.org/10.1111/jrh.12248. 27. Davis MM, Gunn R, Pham R, Wiser A, Hassmiller Lich K, Wheeler SB, Coronado GC. Key collaborative factors when Medicaid accountable care organizations work
with primary care clinics to improve colorectal cancer screening: Relationships,
data, and quality improvement infrastructure. Prevent Chronic Dis. In Press. 28. Authors’ contributions QuickStats: colorectal cancer screening among adults aged 50–75 years,
by race/ethnicity – National Health Interview Survey, United States,
2000–2015. MMWR Morb Mortal Wkly Rep. 2016;65:1042. doi: https://doi. org/10.15585/mmwr.mm6538a6. 28. QuickStats: colorectal cancer screening among adults aged 50–75 years,
by race/ethnicity – National Health Interview Survey, United States,
2000–2015. MMWR Morb Mortal Wkly Rep. 2016;65:1042. doi: https://doi. org/10.15585/mmwr.mm6538a6.
|
https://openalex.org/W3180948935
|
https://cardiab.biomedcentral.com/counter/pdf/10.1186/s12933-021-01338-y
|
English
| null |
Improving statin treatment strategies to reduce LDL-cholesterol: factors associated with targets’ attainment in subjects with and without type 2 diabetes
|
Cardiovascular diabetology
| 2,021
|
cc-by
| 10,481
|
Morieri et al. Cardiovasc Diabetol (2021) 20:144
https://doi.org/10.1186/s12933-021-01338-y Morieri et al. Cardiovasc Diabetol (2021) 20:144
https://doi.org/10.1186/s12933-021-01338-y Cardiovascular Diabetology ORIGINAL INVESTIGATION
Improving statin treatment strategies
to reduce LDL‑cholesterol: factors associated
with targets’ attainment in subjects
with and without type 2 diabetes
Mario Luca Morieri1,4* , Valentina Perrone2, Chiara Veronesi2, Luca Degli Esposti2, Margherita Andretta3,
Mario Plebani1, Gian Paolo Fadini1,4, Saula Vigili de Kreutzenberg1,4 and Angelo Avogaro1,4
Open Access © The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which
permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the
original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or
other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line
to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory
regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this
licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativeco
mmons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Improving statin treatment strategies
to reduce LDL‑cholesterol: factors associated
with targets’ attainment in subjects
with and without type 2 diabetes Mario Luca Morieri1,4* , Valentina Perrone2, Chiara Veronesi2, Luca Degli Esposti2, Margherita Andretta3,
Mario Plebani1, Gian Paolo Fadini1,4, Saula Vigili de Kreutzenberg1,4 and Angelo Avogaro1,4 Abstract Background: This cross-sectional study aimed to identify actionable factors to improve LDL-cholesterol target
achievement and overcome underuse of lipid-lowering treatments in high- or very-high-cardiovascular risk patients. Methods: We evaluated healthcare records of 934,332 subjects from North-Italy, including subjects with avail-
able lipid profile and being on statin treatments up to December 2018. A 6-month-period defined adherence with
proportion-of-days-covered ≥ 80%. Treatment was classified as high-intensity-statin (HIS) + ezetimibe, HIS-alone, non-
HIS (NHIS) + ezetimibe or NHIS alone. Results: We included 27,374 subjects without and 10,459 with diabetes. Among these, 30% and 36% were on sec-
ondary prevention, respectively. Adherence was high (78–100%) and increased with treatment intensity and in sec-
ondary prevention. Treatment intensity increased in secondary prevention, but only 42% were on HIS. 2019-guidelines
LDL-cholesterol targets were achieved in few patients and more often among those with diabetes (7.4% vs. 10.7%,
p < 0.001). Patients in secondary prevention had mean LDL-cholesterol levels aligned slightly above 70 mg/dl (range
between 68 and 73 mg/dl and between 73 and 85 mg/dl in patients with and without diabetes, respectively). Moreo-
ver, the differences in mean LDL-cholesterol levels observed across patients using treatments with well-stablished
different LDL-lowering effect were null or much smaller than expected (HIS vs. NHIS from − 3 to − 11%, p < 0.001,
HIS + ezetimibe vs. HIS—from − 4 to + 5% n.s.). These findings, given the observational design of the study, might
suggest that a “treat to absolute LDL-cholesterol levels” approach (e.g., targeting LDLc of 70 mg/dl) was mainly used
by physicians rather than an approach to also achieve the recommended 50% reduction in LDL-cholesterol levels. Our
analyses suggested that female sex, younger age, higher HDL-c, and elevated triglycerides are those factors delaying
prescription of statin treatments, both in patients with and without diabetes and in those on secondary prevention. Conclusions: Among patients on statin treatment and high adherence, only a small proportion of patients achieved
LDL-cholesterol targets. Late initiation of high-intensity treatments, particularly among those with misperceived low-
risk (e.g., female subjects or those with high HDL-cholesterol), appears as pivotal factors needing to be modified to
improve CVD prevention. *Correspondence: morieri.ml@gmail.com
1 Department of Medicine, University of Padova, Via Giustiniani 2,
35128 Padua, Italy
Full list of author information is available at the end of the article Introduction although a significant correlation is observed between
adherence and plasma LDLc [13], the probability of goal
achievement appears, and lipid management appears far
from perfect [14]. Mainly routine care data have shown
high off-target prevalence and little change in LDLc over
time [9, 15–17]. Off-target values are persistent in diabe-
tes mellitus, which is considered an equivalent of CV dis-
ease, also in primary prevention [11, 18]. Cardiovascular disease (CVD) is the leading cause of
mortality and morbidity in patients with type 2 diabetes
mellitus. In these patients, dyslipidemia is a major car-
diovascular risk factor. As such, the 3-hydroxy-3-meth-
ylglutaryl coenzyme A (HMG-CoA) reductase inhibitors
(statins) are the best therapy for low-density lipoprotein
cholesterol (LDLc) reduction. Several trials have shown
significant CV risk reduction through LDLc lowering
in patients with diabetes, supporting its causal role in
atherogenesis, as also demonstrated in genetic studies
[1]. Statin therapy is considered essential both in pri-
mary and secondary prevention of CVD in diabetes. Tri-
als have shown that statin therapy is beneficial for people
with diabetes even if they do not already have manifest
coronary heart disease or high cholesterol concentra-
tions [2]. In the Health Protection Study (HPS), alloca-
tion to 40 mg simvastatin daily reduced the rate of first
major vascular events by about a quarter in the diabetic
patients included in that study [3]. Key observations pro-
vide evidence that, in patients with type 2 diabetes, the
benefit of statin therapy confers protection at consider-
ably low LDLc levels of less than 1.8 mmol/l (< 70 mg/dl)
[4]. Additional trials and metanalyses have highlighted
a benefit by further reducing LDL cholesterol down to
55 mg/dl [5, 6]. This concept has been incorporated in
most of the recent guidelines, which now recommend
the initiation of statin treatment on the LDL choles-
terol target levels and the CV risk profile of the patient
[7]. Most of the patients referring to diabetes clinics suf-
fer from type 2 diabetes and have an average duration of
the disease > 10 years, at least 90% have high blood pres-
sure. More than 60% are on statin treatment [8]: there-
fore, according to the 2019 ESC/EASD Guidelines, most
of them fall into either high or very high-risk categories
for which LDLc levels < 70 mg/dl and 55 mg/dl, respec-
tively, are recommended. © The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which
permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the
original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or
other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line
to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory
regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this
licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativeco
mmons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Morieri et al. Cardiovasc Diabetol (2021) 20:144 Page 2 of 12 Morieri et al. Cardiovasc Diabetol Keywords: Cardiovascular prevention, Statins, PCSK9, Ezetimibe, Gender, HDL Introduction With the same class of recom-
mendation and level of evidence, guidelines underscore
the importance of LDLc reduction of at least 50%. These
more stringent goals make the attainment of LDLc tar-
gets among diabetic patients even more problematic. In the PINNACLE registry, patients with comorbidi-
ties were less likely to have LDLc at target, particularly
those with diabetes [9]. Overall, systematic reviews and
national-or multinational surveys indicate that a substan-
tial proportion of patients at high risk are exposed to an
unacceptably high concentration of LDLc [10]. Previous
studies have highlighted the difficulties to reach lipid tar-
gets, especially in patients with type 2 diabetes [11, 12], However, comparisons between LDLc targets as a
function of the type of statin treatment, adherence, prior
cardiovascular event in patients with and without diabe-
tes are lacking. Furthermore, the prevalence of off-target
values, in light of the new recommended LDLc target for
very high-risk patients, is unknown. Therefore, in light of these considerations, we per-
formed a retrospective, cross-sectional study, intending
to gain a snapshot of lipid levels of two different popu-
lations, with and without diabetes, in the light of a pre-
vious cardiovascular event. More specifically, we wished
to: (1) determine the proportion of patients, on different
types of statin treatments, at target for LDLc; (2) analyze
the differences between patients without and with diabe-
tes; (3) quantify the impact of prior events; (4) identify
the determinants of LDLc attainment and quantify their
contribution. Data source To accomplish our aims, we have obtained: (1) Admin-
istrative data of the Padova Regional Health System Dis-
trict; (2) Central Laboratory data from the University
Hospital of Padova using anonymized claims data. For
the administrative data, we have integrated four primary
sources: (a) subject-specific and co-payment exemption
data from the regional registry of healthcare beneficiar-
ies, which records each citizen’s reference local health-
care unit, start and end of the residency in the Veneto
Region, and their exemption from co-payment (due to ill-
ness or income); (b) prescription medicine data including
the Anatomical-Therapeutic Chemical (ATC) code and
detailed pharmacy-claim with information on the dose
of the package dispensed to the patients; (c) hospitaliza-
tion-related diagnoses at hospital discharge, and proce-
dures during the hospital stay, recorded using ICD-9-CM
codes; (d) visits in outpatient clinics at a university-affili-
ated tertiary care center [19]. For the present analysis, all the data used were pre-
viously anonymized as per the law concerning their
research and governance purposes. As requested by the Morieri et al. Cardiovasc Diabetol (2021) 20:144 Page 3 of 12 local Institutional Review Board, the researchers only
accessed a non-identifiable dataset. local Institutional Review Board, the researchers only
accessed a non-identifiable dataset. disease before the index date if the diagnosis code, either
principal or secondary, was identified with the follow-
ing ICD-9 codes: 430, 431, 432, 433, 434, 435, 436, 437,
438. Patients were defined as having coronary heart dis-
ease (CHD) before the index date if the diagnosis code,
either principal or secondary, was identified with the fol-
lowing ICD-9-CM codes: 414 or procedure codes 00.55,
00.61–00.66, 36.03, 36.06–36.07, 36.1. Patients were
defined as having coronary heart disease before the index
date if the diagnosis code, either principal or secondary,
was identified with the following ICD-9 codes: 443.9. We have classified as hypertensive patients who had in
the year before the index date at least two prescriptions
of antihypertensive medication (ATC codes: C03, C07,
C08, C09). In the present analysis, the following statin
treatments have been categorized into high-intensity
statin (HIS) treatments: Atorvastatin 40 mg and 80 mg,
Rosuvastatin 20 mg, and 40 mg, Atorvastatin + Ezetimibe
40/10 and 80/10 mg, Rosuvastatin + Ezetimibe 20/10
and 40/10 mg. Other statin treatments have been cat-
egorized as non-high-intensity statin (NHIS) treatments. Data source We stratified patients in the following group of increas-
ing LDL-c lowering effect: NHIS, NHIS + ezetimibe, HIS,
HIS + ezetimibe. Risk level identification and LDLc targets
h
d
h We have categorized patients with or without diabetes
according to the presence/absence of previous cardio-
vascular events. The current LDLc target in patients with
very high cardiovascular risk (including those with or
without diabetes with prior history of the cardiovascu-
lar event) requires both the following criteria: more than
50% reduction from baseline LDLc levels and achieve-
ment of absolute LDLc levels < 55 mg/dl. We also evalu-
ated the less stringent goal of absolute LDLc < 70 mg/dl
(OR 50% reduction from baseline) since these were rec-
ommended by the guidelines available at the time when
these data were collected (i.e., according to EAS/ESC
2016 Guidelines) [21]. According to EAS/ESC guide-
lines, we considered only HIS and HIS + ezetimibe as
treatments allowing to reduce LDLc levels of at least 50%
from pre-treatment levels [21, 22]. Study populationh The enrolment period started on the first of January 2014
and ended 31 December 2018, which corresponds to the
end of data availability. All the subjects included in the
present analysis had at least one routine laboratory lipid
analysis report: total cholesterol, LDLc, and HDL cho-
lesterol, between 1/01/2014 and 31/12/2018 from the
Laboratory of the University Hospital of Padova and a
concomitant statin treatment (Atorvastatin—ATC code
C10AA01, Lovastatin—ATC code C10AA02, Pravas-
tatin—ATC code C10AA03, Fluvastatin—ATC code
C10AA04, Atorvastatin—ATC code C10AA05, Rosuvas-
tatin—ATC code C10AA07, Simvastatin + Ezetimibe—
ATC code C10BA02, Atovarvastatin + Ezetimibe—ATC
code C10BA05, Rosuvastatin + Ezetimibe—ATC code
C10BA06).The index date for each patient included in the
study was defined as the last LDLc determination date
within the enrolment period. The index date can occur
during the enrolment period and marked the moment
from which no other LDLc determination was observed
until the end of data availability. Additional clinical data available for the present analy-
sis were: triglycerides, creatinine, and glycated hemo-
globin (HbA1c). The patients included in the current
analysis had at least one determination of these param-
eters within the year before the index date. Non-HDL
cholesterol is defined as the total cholesterol value minus
HDL cholesterol value. The estimated glomerular filtra-
tion rate was calculated according to the Chronic Kidney
Disease Epidemiology Collaboration (CKD-EPI). Adherence assessment
dh Adherence to statin treatment has been estimated
6 months before the index date using the proportion of
days covered (PDC) method [20], i.e., the ratio between
the number of days of medication supplied (according
to pharmacy-claim) and days of observation before the
index date, multiplied by 100. Patients were considered
adherent to statin treatment if they had a PDC of ≥ 80%. Patients had the diagnosis of diabetes and were iden-
tified as such if they had a hospital diagnosis code ICD-
9-CM 250 or at least two prescriptions of antidiabetic
medication (ATC code A10) in the 12 months before the
index date. Exclusion criteria were all patients treated
with monoclonal antibodies against Proprotein con-
vertase subtilisin/Kexin type 9 (PCSK9i) (ATC codes
C10AX13, C10AX14) before the index date. Main characteristics, statin/ezetimibe treatment,
and adherence. Among the 934,332 citizens assisted by the Euganea
Veneto Regional Health Service, 241,712 had at least
one lipid determination between January 1st, 2014 and
December 31st, 2018 (Additional file 1: Figure S1B), and
37,883 (16%) of these were on statin therapy (72% with-
out diabetes and 28% with diabetes). The prevalence
of cardiovascular events was higher among patients
with diabetes than that without diabetes (36% vs. 30%
p < 0.0001). LDL and non‑HDL levels across different treatments
As reported in Tables 2 and 3, patients with prior events,
either with or without diabetes, had lower LDLc and
non-HDLc concentrations across a different combina-
tion of treatments. Moreover, irrespective of the type of
therapy and previous cardiovascular events, the LDLc
and Non-HDLc concentrations were significantly lower
in patients with diabetes (all p for comparison between
groups < 0.01), except for those with the previous event
treated with HIS + ezetimibe where LDLc were similar
(p = 0.8). p
Overall, as shown in Table 1, most of the patients
were treated with NHIS (81%) and only 19% with
HIS, and 9% of subjects were on concomitant treat-
ment with ezetimibe (7% on NHIS + ezetimibe and
2% on HIS + ezetimibe). The proportion of women
on statin treatment was overall 47%, and it was pro-
gressively reduced with the increasing intensity of
lipid-lowering treatments (from 51% on NHIS to 30%
in HIS + ezetimibe, p < 0.001 for trend; all between-
groups comparison were statistically significant after
Bonferroni correction, except HIS vs HIS + ezetimibe). The prevalence of diabetes was similar across differ-
ent treatment groups, while as expected, prevalence of
CVD was progressively higher with increasing intensity
of treatments. The eGFR in patients with or without
diabetes was lower in those with a prior event (Tables 2
and 3). Patients with diabetes were on reasonably Notably, both in subjects with and without diabetes,
when we compared those treated with HIS with those
treated with NHIS, we found, on average, only minor dif-
ferences in LDLc concentration (w/o diabetes: − 8% to
− 11%; diabetes: − 3% to − 8%, all p < 0.05). These were
indeed markedly lower than the 28% reduction expected
on average when shifting from NHIS to HIS (as reported
by dyslipidemia guidelines) [22]. Even more strikingly,
we found no significant differences (with the paradoxi-
cal trend towards higher levels) between-subjects on
HIS + ezetimibe vs. CV event assessment As shown in Additional file 1: Figure S1A, cardiovascular
events were identified starting from 10/01/2010 based on
the first six diagnosis codes and admission time reported
in the hospital discharge claims database, that is, by map-
ping ICD-9-CM codes to the appropriate outcomes: diag-
nosis codes 410–414 to infarction, 430–438 to stroke,
390–459 to hospitalization for cardiovascular causes;
procedure codes 00.55, 00.61–00.66, 36.03, 36.06–36.07,
36.1, 38.48, 39.50, 39.52, 39.71, and 39.90 to revasculari-
zation. Patients were defined as having cerebrovascular Morieri et al. Cardiovasc Diabetol (2021) 20:144 Page 4 of 12 Statistical analysis good metabolic control as testified by HbA1c levels,
and a significant proportion of them was on insulin
treatment. Continuous data are presented as means ± standard
deviation and categorical variables as numbers and per-
centages. The analysis of variance (ANOVA) test and
the chi-square test were used to compare continuous
variables and categorical variables, respectively. The rela-
tionship between diabetes and the probability of achiev-
ing LDLc targets among secondary prevention subjects
was reported as relative risk (relative risk with 95% CI). Logistic models were performed to analyze predictors
of the LDL cholesterol < 70 mg/dl in patients with and
without diabetes. Models were adjusted for prespecified
covariates: age, gender, HDLc, triglycerides, estimated
glomerular filtration rate (eGFR), presence of previ-
ous cardiovascular events, type of statin treatment, and
adherence to statin therapy. These analyses were con-
ducted on a complete-case dataset. Effect sizes were
reported as odds ratios (OR) and 95% confidence inter-
vals (CI). The results were considered statistically signifi-
cant when the p-value was < 0.05. All statistical analyses
were performed using STATA SE software version 12.1
(StataCorp LP, College Station, Texas). As reported in Tables 2 and 3, treatment with HIS
(either alone or with Ezetimibe) was fourfold higher
in those with an event compared to those without an
event, both in patients with and without diabetes (8.5%
vs. 37.0% and 8.4% vs. 43.7%, respectively). However,
the addition of Ezetimibe among patients with previ-
ous events (as graphically depicted in Fig. 1) was mostly
prescribed in combination with NHIS and only in a few
cases with HIS (NHIS/HIS ratio significantly greater
in the ezetimibe group). Conversely, among subjects
in primary prevention, NHIS/HIS ratio was similar
between subjects with/without Ezetimibe, but Ezetimibe
was mainly used in combination with low dose statin
(i.e., simvastatin 10 or 20 mg in more the two-third of
patients). In both populations, with and without diabe-
tes, the treatment adherence was significantly higher in
those with a previous event and increased with increas-
ing treatment intensity [being higher among those sub-
jects on high-intensity statins + Ezetimibe, as reported in
Tables 2 and 3, were, beyond the significant ANOVA test,
between-group comparison showed that the adherence
was consistently significantly higher in patients treated
with HIS + ezetimbe as compared to those on NHIS (all
p < 0.05 after Bonferroni correction)]. Main characteristics, statin/ezetimibe treatment,
and adherence. HIS (w/o diabetes: − 4 to + 5%; dia-
betes + 7% to + 10% n.s.), as compared to the 30% reduc-
tion expected from RCTs and reported in guidelines [22]. Morieri et al. Cardiovasc Diabetol (2021) 20:144 Page 5 of 12 Table 1 General characteristics of the population included in the study
Data reported as mean (S.D.) or as n (%). Opinion 05/2014 on “Anonymisation Techniques” drafted by the “European Commission Article 29 Working Party”, the
analyses involving less than three patients were not reported, as potentially reconductable to single individuals. Therefore, results referred to ≤ 3 patients were
reported as NI (not issuable)
NHIS
NHIS + Eze
HIS
HIS + Eze
p value*
N = 27,795 (74%)
N = 2815 (7%)
N = 6578 (17%)
N = 645 (2%)
Age in years mean (S.D.)
72.6 (11)
69.4 (11)
71.7 (11)
66.9 (11)
< 0.001
Female n (%)
14,145 (51)
1202 (43)
2157 (33)
196 (30)
< 0.001
Age < 80 years n (%)
20,695 (75)
2411 (86)
5026 (76)
597 (93)
< 0.001
Hypertension n (%)
21,712 (78)
2296 (82)
5789 (88)
579 (90)
< 0.001
Diabetes n (%)
7718 (28)
772 (27)
1821 (28)
148 (23)
N.S
GFR (ml/min/1.73 m2) mean (S.D.)
89.9 (31)
85.1 (30)
89.4 (32)
91.9 (31)
< 0.001
HbA1c (mmol/mol) mean (S.D.)
47.6 (13)
46.6 (12)
46.2 (13)
45.0 (12)
< 0.001
CVD n (%)
2592 (9)
573 (20)
1816 (28)
287 (45)
< 0.001
Cerebrovascular disease n (%)
2355 (9)
257 (9)
1838 (28)
72 (11)
< 0.001
Peripheral vascular disease n (%)
12 (0)
N.I
N.I
0 (0)
N.S
Total-chol (mg/ml) mean (S.D.)a
167.8 (39)
162.4 (42)
145.1 (39)
145.3 (41)
< 0.001
LDL-chol (mg/dl) mean (S.D.)a
94.1 (32)
88.1 (35)
78.8 (31)
79.6 (35)
< 0.001
HDL-chol (mg/dl) mean (S.D.)a
52.8 (16)
51.8 (15)
46.8 (15)
47.3 (13)
< 0.001
Triglycerides (mg/dl) mean (S.D.)a
98.7 (62)
103.9 (69)
89.9 (64)
82.1 (52)
< 0.001
Non-HDL-chol (mg/dl) mean (S.D.)a
115.0 (35)
110.6 (39)
98.3 (35)
98 (39)
< 0.001
ACEi/ARB n (%)
17,097 (62)
1793 (64)
4570 (70)
472 (73)
< 0.001
Beta blockers n (%)
8923 (32)
1223 (43)
3482 (53)
435 (67)
< 0.001
CCB n (%)
6690 (24)
677 (24)
1716 (26)
138 (21)
< 0.01
Treat. LDLc and non‑HDLc levels according to the event site patients with cerebrovascular disease, significantly lower
concentrations were observed in patients with diabe-
tes only in those on NHIS and HIS treatment. Also, in
these patients, a gradient toward significantly lower lev-
els according to statin intensity was observed only in
patients without diabetes. Similar results were found when the population was
stratified according to the event site (Additional file 1:
Figure S2): in those with a previous CHD event, both
the LDLc and the non-HDLc concentrations were sig-
nificantly lower in patients with diabetes (71 ± 26 vs. 82 ± 29 mg/dl, p < 0.0001 for NHIS, 65 ± 24 vs. 79 ± 29
for NHIS + ezetimibe, 68 ± 27 vs. 77 ± 25 for HIS) than
in those without diabetes except for the HIS + ezetimibe
group. Similar results were seen for the non-HDLc. While in patients without diabetes, there were consist-
ently lower concentrations according to statin inten-
sity, this was not observed in patients with diabetes. In Main characteristics, statin/ezetimibe treatment,
and adherence. Diabetes n (%)
7373 (27)
728 (26)
1665 (25)
134 (21)
< 0.01
Fibrates n (%)
185 (0.7)
31 (1.1)
50 (0.8)
5 (0.8)
N.S
Simvastatin n (%)
10,350 (37.2)
44 (1.6)
0 (0.0)
0 (0.0)
Lovastatin n (%)
840 (3.0)
30 (1.1)
0 (0.0)
0 (0.0)
Pravastatin n (%)
1297 (4.7)
44 (1.6)
0 (0.0)
0 (0.0)
Fluvastatin n (%)
256 (0.9)
5 (0.2)
0 (0.0)
0 (0.0)
Atorvastatin n (%)
12,003 (43.2)
205 (7.3)
5864 (89.0)
516 (80.0)
Rosuvastatin n (%)
3049 (11.0)
116 (4.1)
712 (11.0)
113 (17.5)
Simvastatin + Ezetimibe n (%)
0 (0.0)
2363 (83.9)
0 (0.0)
0 (0.0)
Rosuvastatin + Ezetimibe n (%)
0 (0.0)
8 (0.3)
N.I
16 (2.5) Table 1 General characteristics of the population included in the study HIS high-intensity statins, NHIS non-HIS, Eze ezetimibe * ANOVA P value for differences between groups (i.e., if < 0.05 not all group are equivalent) a Analyses performed on patients with at least one detection before index Patients at target As shown in Fig. 2A, among subject with prior events,
only two-thirds of subjects achieved the 2016-recom-
mended targets. This proportion dropped to one out of
ten subjects when the 2019-guidelines recommended
target were considered (LDLc of < 55 mg/dl and on Morieri et al. Cardiovasc Diabetol (2021) 20:144 Page 6 of 12 Table 2 Characteristics of patients without diabetes according to concomitant events. Opinion 05/2014 on “Anonymisation Techniques” drafted by the “European Commission Article 29 Working Party”, the analyses involving less than three patients were
not reported, as potentially reconductable to single individuals. Therefore, results referred to ≤ 3 patients were reported as NI (not issuable)
CHD coronary heart disease, PAD peripheral artery disease, ACEi angiotensin converting-enzyme inhibitors, ARBs angiotensin II receptor blocker, CCB calcium channel
blockers
* ANOVA P value for differences between groups (i.e., if < 0.05 not all group are equivalent)
a Analyses performed on patients with at least one detection before index
1. No-diabetes w/o event
2. No-diabetes with event
NHIS
NHIS + Eze
HIS
HIS + Eze
p value*
NHIS
NHIS + Eze
HIS
HIS + Eze
p value*
Nr. Patients at target 39% and 16%,
respectively, all p < 0.001). Similar differences were con-
firmed in all different categories of treatments. treatment allowing at least 50% reduction from base-
line LDLc levels, i.e., HIS and HIS + ezetimibe). Subjects
with diabetes were more likely to achieve these targets
(for 2019 targets: 7.4% and 10.7%, for patients with and
without diabetes, respectively; relative risk: 1.44, 95% CI
1.28–1.62, p < 0.001). Moreover, as shown in Fig. 2 panel
B, the overall proportion of patients with diabetes achiev-
ing < 70 mg/dl or < 55 mg/dl of LDLc was higher than
those without diabetes (55% and 29% vs. 39% and 16%,
respectively, all p < 0.001). Similar differences were con-
firmed in all different categories of treatments. Patients at target patients
16,131 (85)
1305 (7)
1492 (8)
123 (1)
3946 (47)
738 (9)
3265 (39)
374 (5)
Adherent
12,586 (78)
1091 (84)
1213 (81)
112 (91)
< 0.001
3186 (81)
660 (89)
2767 (85)
356 (95)
< 0.001
Total-chol (mg/dl)a
180.3 (37)
178.5 (43)
168.7 (43)
170.1 (46)
< 0.001
152.6 (39)
150.2 (36)
139.1 (33)
136.6 (33)
< 0.001
LDL-chol (mg/dl)a
103.8 (31)
100.8 (36)
95.6 (36)
100 (42)
< 0.001
84.5 (31)
79.5 (28)
75.4 (27)
72.7 (26)
< 0.001
HDL-chol (mg/dl)a
56.2 (16)
55.6 (15)
52.7 (16)
52.5 (14)
< 0.001
49 (16)
50.6 (15)
46.5 (14)
47.2 (13)
< 0.001
Triglycerides (mg/dl)a
97.6 (58)
102.9 (65)
97.2 (66)
85.1 (47)
0.001
86.4 (59)
92.4 (65)
78.7 (54)
74 (48)
< 0.001
NON-HDL-chol (mg/dl)a
124.1 (34)
122.8 (42)
116 (40)
117.6 (45)
< 0.001
103.6 (35)
99.6 (33)
92.6 (30)
89.4 (31)
< 0.001
GFR (ml/min/1.73 m2)a
91.8 (26)
89.6 (25)
95.2 (31)
93.4 (44)
< 0.001
80.4 (34)
80.3 (30)
89.6 (30)
92.3 (23)
< 0.001
HbA1c (mmol/mol)a
41 (8)
40.8 (6)
41.3 (7)
40.7 (6)
N.S
40 (7)
39.7 (5)
39.6 (6)
40.6 (8)
N.S
CHD
1672 (42)
398 (54)
1197 (37)
215 (58)
< 0.001
Cerebrovascular disease
1565 (40)
171 (23)
1307 (40)
44 (12)
< 0.001
PAD
4 (0)
N.I
N.I
0 (0)
N.S
ACEi/ARB
9001 (56)
710 (54)
906 (61)
77 (63)
0.001
2608 (66)
520 (71)
2269 (70)
278 (74)
< 0.001
Beta blockers
4178 (26)
359 (28)
539 (36)
51 (42)
< 0.001
2041 (52)
491 (67)
1914 (59)
277 (74)
< 0.001
CCB
3183 (20)
248 (19)
296 (20)
16 (13)
N.S
1096 (28)
183 (25)
782 (24)
72 (19)
< 0.001
Fibrates
83 (1)
7 (1)
12 (1)
N.I
N.S
16 (0)
7 (1)
9 (0)
N.I
N.S Table 2 Characteristics of patients without diabetes according to concomitant events. 2. No-diabetes with event treatment allowing at least 50% reduction from base-
line LDLc levels, i.e., HIS and HIS + ezetimibe). Subjects
with diabetes were more likely to achieve these targets
(for 2019 targets: 7.4% and 10.7%, for patients with and
without diabetes, respectively; relative risk: 1.44, 95% CI
1.28–1.62, p < 0.001). Moreover, as shown in Fig. 2 panel
B, the overall proportion of patients with diabetes achiev-
ing < 70 mg/dl or < 55 mg/dl of LDLc was higher than
those without diabetes (55% and 29% vs. Discussionh The recent ESC/EASD Guidelines on diabetes, pre-dia-
betes, and cardiovascular diseases [7] but also the ESC/
EAS Guidelines on the management of dyslipidaemias
[22], endorse with a class I of recommendations, and a B
level of evidence, that the target of LDLc, in patients with
and without type 2 diabetes at very high CV risk, should
be < 55 mg/dL (< 1.4 mmol/L) and at least 50% reduction
from baseline [7]. Based on this premise, the key-findings
of the present study were that among patients currently
treated with statins: (1) Despite the overall high adher-
ence to treatment in our population, only a small propor-
tion of patients with a previous event achieve the target
defined by these two criteria; (2) Few patients are treated
with HIS, or with statin-ezetimibe combined treatment,
and prescription of statins follow mainly a “treat to abso-
lute” LDLc targets rather than achieving relative (%)
reduction from pre-treatment LDLc levels; (3) Female
sex, younger age, higher HDLc and triglycerides (all inde-
pendently associated with lower probability of achieving
LDLc targets both in patients with and without diabetes
regardless of adherence, the intensity of treatments and
presence of a prior event) are factors associated with
unjustifiably delayed initiation of statin treatment only
for higher LDLc levels; (4) Despite being still far from the Factor associated with absolute LDLc target attainment
Finally, after accounting for prior CVD events and dif-
ferent types of statin treatments, we evaluated which
factors were associated with a higher or lower probabil-
ity of having LDLc levels < 70 mg/dl. As shown in Fig. 3,
both in patients with and without diabetes, subjects with
higher adherence were more likely to achieve this tar-
get. Conversely, female subjects, younger subject, those
with higher HDL-cholesterol or triglycerides were inde-
pendently associated with a lower probability of being
at LDLc < than 70 mg/dl. Among patients with diabetes,
also lower eGFR was marginally but significantly associ-
ated with a higher probability of being at LDLc target. Morieri et al. Cardiovasc Diabetol (2021) 20:144 Page 7 of 12 Page 7 of 12 Table 3 Characteristics of patients with diabetes according to concomitant events
Opinion 05/2014 on “Anonymisation Techniques” drafted by the “European Commission Article 29 Working Party”, the analyses involving less than three patients were
not reported, as potentially reconductable to single individuals. Discussionh Therefore, results referred to ≤ 3 patients were reported as NI (not issuable)
CHD coronary heart disease, PAD peripheral artery disease, ACEi angiotensin converting-enzyme inhibitors, ARBs angiotensin II receptor blocker, CCB calcium channel
blockers
* ANOVA P value for differences between groups (i.e., if < 0.05 not all group are equivalent)
a Analyses performed on patients with at least one detection before index
3. Diabetes w/o event
4. Diabetes with event
NHIS
NHIS + Eze
HIS
HIS + Eze
p value*
NHIS
NHIS + Eze
HIS
HIS + Eze
p value*
Nr. Discussionh Diabetes with event Opinion 05/2014 on “Anonymisation Techniques” drafted by the “European Commission Article 29 Working Party”, the analyses involving less than three patients were
not reported, as potentially reconductable to single individuals. Therefore, results referred to ≤ 3 patients were reported as NI (not issuable) Opinion 05/2014 on Anonymisation Techniques drafted by the European Commission Article 29 Working Party , the analyses involving less than three patients were
not reported, as potentially reconductable to single individuals. Therefore, results referred to ≤ 3 patients were reported as NI (not issuable)
CHD coronary heart disease, PAD peripheral artery disease, ACEi angiotensin converting-enzyme inhibitors, ARBs angiotensin II receptor blocker, CCB calcium channel
blockers
* ANOVA P value for differences between groups (i.e., if < 0.05 not all group are equivalent)
a Analyses performed on patients with at least one detection before index intrinsically related to LDLc levels as reported in mul-
tiple studies [11, 25–27], it likely explains only a minor
part of the low-achievement of LDLc targets in high-risk
patients. recommended target, patients with diabetes have a sig-
nificantly lower lipid values irrespective of statin treat-
ments, prior event and its location, compared to patients
without diabetes. Second, as reported by others, our data suggest that
the low-achievement of targets is strongly related, espe-
cially in patients with a prior event, by the underuse of
HIS, either alone or in combination with Ezetimibe, both
in patients with and without diabetes [14, 23, 28–30]. Our data, however, allow providing more details on rea-
sons and factors requiring modification to implement the
2019-guidelines recommendation. These findings allow conveying some novel and impor-
tant messages to address and tackle the widely and con-
tinuously reported issue of low achievement of LDLc
targets among patients with high or very high cardiovas-
cular risk [10, 23, 24]. First, our study selected a population enriched of sub-
jects with high adherence (by study design only subjects
actively on statin treatments and collecting the medica-
tion from the pharmacy in the 6 months before lipid pro-
file assessment were included). Indeed, the proportion
of subjects with high adherence ranged between 78 and
100% and was progressively higher in those with a prior
event or on higher intensity treatment. However, despite
this, we found that only a small proportion achieved
the 2016-targets and less than one out of ten subjects
achieved the 2019-targets. Discussionh patients n (%)
5661 (85)
447 (7)
532 (8)
33 (1)
2057 (54)
325 (9)
1289 (34)
115 (3)
Adherent n (%)
4777 (84)
404 (90)
461 (87)
33 (100)
< 0.001
1677 (82)
294 (91)
1085 (84)
106 (92)
< 0.001
Total-chol (mg/dl)a
154.2 (34)
153.7 (37)
149.8 (37)
155.3 (48)
N.S
138.8 (37)
136.9 (34)
130.5 (35)
136.6 (44)
< 0.001
LDL-chol (mg/dl)a
81.7 (27)
79.6 (30)
79.2 (29)
87.5 (39)
N.S
73.1 (28)
68.8 (27)
67.6 (27)
72.1 (36)
< 0.001
HDL-chol (mg/dl)a
49.5 (15)
48.7 (14)
46.4 (14)
43 (9)
< 0.001
42.6 (14)
43.7 (14)
41.1 (13)
41.5 (12)
< 0.01
Triglycerides (mg/dl)a
108.9 (70)
122.5 (79)
114.3 (74)
109.2 (65)
< 0.001
100.7 (68)
106.6 (71)
97.6 (71)
96 (61)
N.S
NON-HDL-chol (mg/dl)a
104.7 (32)
105 (35)
103.4 (34)
112.3 (48)
N.S
96.2 (34)
93.2 (31)
89.4 (33)
95.1 (43)
< 0.001
GFR (ml/min/1.73 m2)a
94.7 (33)
92.5 (31)
93.8 (32)
98.7 (29)
N.S
75.2 (37)
71.8 (37)
82 (36)
86.5 (40)
< 0.001
HbA1c (mmol/mol)a
55.7 (13)
56.4 (13)
55.8 (13)
56 (15)
N.S
55.1 (14)
54.4 (14)
56.2 (15)
56.9 (14)
N.S
CHD
920 (45)
175 (54)
619 (48)
72 (63)
< 0.001
Cerebrovascular disease
790 (38)
86 (27)
531 (41)
28 (24)
< 0.001
PAD
8 (0)
N.I
N.I
0 (0)
N.S
ACEi/ARB
3986 (70)
320 (72)
395 (74)
26 (79)
N.S
1502 (73)
243 (75)
1000 (78)
91 (79)
< 0.05
Beta blockers
1588 (28)
152 (34)
213 (40)
16 (49)
< 0.001
1116 (54)
221 (68)
816 (63)
91 (79)
< 0.001
CCB
1669 (30)
127 (28)
147 (28)
7 (21)
N.S
742 (36)
119 (37)
491 (38)
43 (37)
N.S
Fibrates
64 (1)
12 (3)
14 (3)
0 (0)
< 0.01
22 (1)
5 (2)
15 (1)
N.I
N.S
Insulin
1366 (24)
136 (30)
154 (29)
9 (27)
< 0.01
823 (40)
144 (44)
498 (39)
49 (43)
N.S
Metformin
3724 (66)
258 (58)
333 (63)
25 (76)
< 0.01
906 (44)
132 (41)
643 (50)
59 (51)
= 0.001
Sulfonylureas
1131 (20)
88 (20)
100 (19)
N.I
N.S
290 (14)
39 (12)
174 (14)
11 (10)
N.S
DPP-4
300 (5)
36 (8)
25 (5)
N.I
N.S
171 (8)
29 (9)
89 (7)
7 (6)
N.S
GLP-1
160 (3)
17 (4)
17 (3)
N.I
N.S
29 (1)
8 (3)
26 (2)
5 (4)
N.S
SLGT2
69 (1)
12 (3)
11 (2)
0 (0)
< 0.05
24 (1)
6 (2)
17 (1)
6 (5)
< 0.01 Table 3 Characteristics of patients with diabetes according to concomitant events 4. Discussionh Conversely,
moderate intensity statin are more likely used in those
subjects with lower LDL at baseline (e.g., before treat-
ment LDLc ≈ 100 mmg/dl, with after treatment levels
≈ 70 mg/dl). Altogether, these results suggest that most
of the patients are treated following a “treat to absolute
LDLc targets” approach. In support of this, one can note
that the mean LDLc levels of subjects with diabetes and
a prior event are aligned around 70 mg/dl, and this is
explainable with 2016-guidelines targets (valid at the time
when these data were collected) requiring for those on
secondary prevention an absolute LDLc < 70 mg/dl OR at
least a 50% reduction from untreated levels. Conversely,
recent guidelines beyond reducing the absolute LDLc
targets clarified that both criteria (at least 50% reduc-
tion from untreated levels) must be achieved, regardless
of baseline LDLc levels (for all patients with high or very
high cardiovascular risk). A modification strongly sup-
ported by the established log-linear relationship between
LDLc reduction and reduction of cardiovascular risk [1]. Therefore, our data highlights the importance of modi-
fying physician prescription patterns towards a “treat to
absolute targets AND a relative change in LDLc levels”. of CV events in patients with diabetes by one third [14]. Positive attainment should require a more robust
adhesion to statin treatment and the optimization of
their dosing also in patients on ezetimibe therapy. This
is graphically depicted in Fig. 2, in which is clear that
across different treatments, most of the patients with a
previous event in both groups, without and with diabe-
tes, were eligible for a maximum tolerated dose of sta-
tin plus Ezetimibe. Second, we show that only a small
proportion of patients in the two groups were on high
intensity statin plus Ezetimibe. Conversely, consider-
ing: (1) the current treatment used by patietns, (2) the
observed LDL-c levels, and (3) the expected reduction
in LDLc from intensification of lipid-lowering treat-
ments, it is possible to estimate that in this large popu-
lation based study ≈ 40% of patients (with and without
diabetes) on secondary CVD prevention would be able
to achieve the 55 mg/dl targets if treated with a com-
bination of HIS + Ezetimibe. HIS alone would be suf-
ficient to achieve the target only in 40% and 22% of
patients with and without diabetes, respectively. Discussionh Therefore, while adherence is Notably, after the stratification of subjects according
to the presence of diabetes and prior event, there were
only small or minor differences in the observed mean
LDLc levels across groups of subjects exposed to treat-
ments having different lipid-lowering intensity (e.g., HIS
vs. NHIS or HIS + ezetimibe vs. HIS alone). Such results
might appeared counterintuitive if one consider the well-
established efficacy of these treatments (consistently Morieri et al. Cardiovasc Diabetol (2021) 20:144 Page 8 of 12 Fig. 1 Proportion of patients (in %) on each single molecule and dosage according to presence or absence of diabetes and recorded cardiovascular
events. Area under the blue area (i.e. statin alone) is 100%, sum of pink area (i.e., statin + ezetimibe) is 100%, in each of the four panel Fig. 1 Proportion of patients (in %) on each single molecule and dosage according to presence or absence of diabetes and recorded cardiovascular
events. Area under the blue area (i.e. statin alone) is 100%, sum of pink area (i.e., statin + ezetimibe) is 100%, in each of the four panel Fig. 2 Patients with event achieving guidelines recommended targets. Error Bar represents 95% CI; § for p < 0.001 Diabetes vs. w/o Diabetes at
< 55 mg/dl and * for p < 0.001 Diabetes vs. w/o Diabetes at < 70 mg/dl Fig. 2 Patients with event achieving guidelines recommended targets. Error Bar represents 95% CI; § for p < 0.001 Diabetes vs. w/o Diabetes at
< 55 mg/dl and * for p < 0.001 Diabetes vs. w/o Diabetes at < 70 mg/dl should be interpreted in the context of a cross-sectional
observational study. Indeed the expected differences
between HIS vs. NHIS or HIS + ezetimibe vs. HIS alone observed in randomized clinical trials regardless of most
of the clinical characteristics of patients, including the
presence of diabetes) [22, 31, 32]. However, our findings should be interpreted in the context of a cross-sectional
observational study. Indeed the expected differences
between HIS vs. NHIS or HIS + ezetimibe vs. HIS alone Morieri et al. Cardiovasc Diabetol (2021) 20:144 Page 9 of 12 Fig. Discussionh 3 Factors associated with LDL-c levels < 70 mg/dl in patients without and with diabetes (model adjusted by age, sex, prior history of
cardiovascular events, adherence, statin treatment intensity, HDL-c, triglycerides, eGFR) treatments are valid if the patients have similar before-
treatment LDLc levels, that is hardly to imagine in real-
world setting. In this context, one should consider an
indication bias as a possible explanation, i.e. the possi-
bility that the most intensive treatment (allowing ≥ 50%
reduction) are more likely used among those with higher
LDL-c at baseline (e.g., before treatment LDLc ≈ 140
leading to after treatment levels ≈ 70 mg/dl). Conversely,
moderate intensity statin are more likely used in those
subjects with lower LDL at baseline (e.g., before treat-
ment LDLc ≈ 100 mmg/dl, with after treatment levels
≈ 70 mg/dl). Altogether, these results suggest that most
of the patients are treated following a “treat to absolute
LDLc targets” approach. In support of this, one can note
that the mean LDLc levels of subjects with diabetes and
a prior event are aligned around 70 mg/dl, and this is
explainable with 2016-guidelines targets (valid at the time
when these data were collected) requiring for those on
secondary prevention an absolute LDLc < 70 mg/dl OR at
least a 50% reduction from untreated levels. Conversely,
recent guidelines beyond reducing the absolute LDLc
targets clarified that both criteria (at least 50% reduc-
tion from untreated levels) must be achieved, regardless
of baseline LDLc levels (for all patients with high or very
high cardiovascular risk). A modification strongly sup-
ported by the established log-linear relationship between
LDLc reduction and reduction of cardiovascular risk [1]. Therefore, our data highlights the importance of modi-
fying physician prescription patterns towards a “treat to
absolute targets AND a relative change in LDLc levels”. diabetes and would reduce, over 10 years, the number
of CV events in patients with diabetes by one third [14]. treatments are valid if the patients have similar before-
treatment LDLc levels, that is hardly to imagine in real-
world setting. In this context, one should consider an
indication bias as a possible explanation, i.e. the possi-
bility that the most intensive treatment (allowing ≥ 50%
reduction) are more likely used among those with higher
LDL-c at baseline (e.g., before treatment LDLc ≈ 140
leading to after treatment levels ≈ 70 mg/dl). Discussionh Nota-
bly, the addition of PCSK9 inhibitors on top of HIS
and ezetimibe, would be needed to achieve the targets
in another 18% and 34% of patients with and without
diabetes, respectively. Unfortunately, we were unable
to quantify those who were statin intolerant: however,
as many as 15% of individuals with a clinical indication
for statin therapy are unable to take it because of some
degree of intolerance [33]. Therefore, the proportion
of subjects needing PCSK9-inhibitors treatment might
be even larger after accounting for those patients being
intolerant or with reduced tolerance to statins. In support of this recommendation, we have indeed
recently reported how their implementation would
have a dramatic impact on the cardiovascular burden in Page 10 of 12 Morieri et al. Cardiovasc Diabetol (2021) 20:144 Morieri et al. Cardiovasc Diabetol (2021) 20:144 Third, for the same reasons described above (cross-
sectional design of the study and expected independent
response to statins regardless of patient characteristics)
our data suggest that female sex, lower age, high HDLc
levels, and more elevated triglycerides are factors likely
associated with delayed initiation of statin treatments
and only in case of higher baseline LDLc levels.h observed in previous studies [40], and, when compared
with patients with CAD, patients with the stroke earlier
are less likely for patients to have LDLc < 100 or < 70 mg/
dl. This observation has a particular relevance also in the
light of the finding that intensive treatment reduces cer-
ebrovascular events [41], and after the observation that
in patients with an ischemic stroke or TIA, and LDLc
level of < 70 mg/dl had a lower risk of subsequent cardio-
vascular events than those with an LDLc between 90 and
110 mg/dl [42].h These analyses, given the cross-sectional and observa-
tional setting of real-world study, should be interpret as
associations and cannot confirm any causal relationship. Moreover we were not able to consider other impor-
tant cardiovascular risk factors such as smoking habits
and blood pressure controls. However, the underuse of
lipid-lowering treatment in female subjects has also been
reported in other studies [14, 25], and here we confirmed
that it is independent of adherence. One possible expla-
nation might be the misperceived CVD risk of female
subjects. While historically considered “protected” from
CVD, this protection is progressively reduced or lost with
aging and among those on secondary prevention and,
particularly, among those with diabetes [34]. Discussionh Therefore,
increasing LDLc lowering treatment in female patients
represents a pivotal factor in improving cardiovascu-
lar prevention strategies. Similarly, the known inverse
association between HDLc and CVD risk might cause
physicians to underestimated the importance of reduc-
ing LDLc in patients with relatively high HDLc. We also
found that hypertriglyceridemia was inversely associated
with the achievement of low LDLc levels. However, while
selected patients might have cardiovascular benefit from
TG-lowering approaches [35, 36], it must be stressed that
LDLc targets are the first goal to be achieved in patients
with mild-hypertriglyceridemia and only after that other
treatments to reduce TG-rich lipoprotein should be initi-
ated (e.g., fenofibrate or omega-3 eicosapentaenoic acid)
[22]. Fourth, in patients with diabetes, we have observed
significantly lower lipid values and a higher proportion
of patients at target, both < 70 mg/dl and at < 55 mg/dl
LDLc. This observation has already been reported in a
real-world setting in Netherland [30], and from an exten-
sive, national, administrative claims database in United
States [37, 38]; the presence of diabetes has been reported
as an independent predictor of achieving LDLc goal [39]. In the present study, we add some exciting observations,
i.e., patients with diabetes had significantly lower LDLc
and non-HDLc concentrations independently of the site
of a prior event.i The lower LDLc levels also observed in primary pre-
vention suggest that patients with diabetes are treated
earlier and at lower LDLc levels than patients with dia-
betes. The specific Italian diabetic clinic organization
can partly justify this observation: attending the dia-
betic clinic is associated with a significant 30% decrease
in mortality [43] and a significant 17% reduction in CV
mortality. We have recently shown that for patients with
type 2 diabetes attending a specialist outpatient clinic,
intensive complication screening is followed by better
long-term cardiovascular outcomes [8]. g
This study has limitations and strengths. First, its
cross-sectional nature does not provide any informa-
tion on each treatment’s role on incident events, nor
we provide information on those with more than one
event who would be eligible to even lower LDLc tar-
gets. Second, we could not evaluate the role of two
important risk factors for CVD such as smoking habit
and blood pressure control. Author details
1 In conclusion, the present study demonstrates that
among patients currently on statin treatment and with
relatively high adherence to treatment, the propor-
tion of patients at LDLc target is very low, also among
those on secondary prevention. We identified, both
in patients with and without diabetes, the late initia-
tion of high-intensity treatments, particularly among
those with misperceived low risk (e.g., female subjects
or those with high HDLc), as possible pivotal factors
needing to be modified to improve CVD prevention. 1 Department of Medicine, University of Padova, Via Giustiniani 2, 35128 Padua,
Italy. 2 CliCon S.R.L. Health Economics & Outcomes Research, Bologna, Italy. 3 Assistenza Farmaceutica Territoriale, Azienda ULSS 8 Berica, Vicenza, Italy. 4 University Hospital of Padova , Padova, Italy. Received: 10 May 2021 Accepted: 6 July 2021 Received: 10 May 2021 Accepted: 6 July 2021 Discussionh While in patients in sec-
ondary prevention these would have not changed the
LDL-cholesterol targets, this information would have
improved risk stratification in patients on primary
prevention (and therefore the identification of the
appropriate LDL-cholesterol targets). Although this
information are typically not available in large admin-
istrative databases, physician should nonetheless aim to
a comprehensive control of patients’ cardiovascular risk
and target them. Third, it should be outlined that, since
our study is based on laboratory information collected
from the Central Laboratory of the University Hospi-
tal of Padova, a possible hospital-bias might be pre-
sent. Before generalizing these results to other setting,
one should consider that usually patients with a higher
clinical complexity are referred to third level hospital
laboratory (as inpatient or as outpatient). Nonetheless
it is remarkable that we were able to initially evaluate
≈ 26% of the entire population of the Padua province
(934,332 subjects) having at least one determination of
lipid profile in this laboratory. Fourth, we were not able
to evaluate the actual adherence of intake of pills from
patients given the large observational population-based
study, however the PDC measure is considered as one
of the most reliable method to measure adherence in Furthermore, the level of LDLc was significantly lower
among those with CVD compared to those with cerebro-
vascular disease. However, it must be acknowledged that
the significance is present only in the groups of treat-
ment with the highest numerosity. A lower achieve-
ment of LDLc in patients with stroke has been already Morieri et al. Cardiovasc Diabetol (2021) 20:144 Page 11 of 12 Page 11 of 12 Abbreviations
ATC A
l 2. Colhoun HM, Betteridge DJ, Durrington PN, Hitman GA, Neil HA,
Livingstone SJ, et al. Primary prevention of cardiovascular disease with
atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes
Study (CARDS): multicentre randomised placebo-controlled trial. Lancet. 2004;364(9435):685–96. ATC: Anatomical-therapeutic chemical; CHD: Coronary heart disease; CVD:
Cardiovascular disease; eGFR: Estimated glomerular filtration rate; HDL: High
density lipoprotein; HIS: High-intensity-statin.; LDL: Low dense lipoprotein;
NHIS: Non-high-intensity-statin.; PDC: Proportion of days covered. 3. Collins R, Armitage J, Parish S, Sleigh P, Peto R, Heart Protection Study
Collaborative G. MRC/BHF heart protection study of cholesterol-lowering
with simvastatin in 5963 people with diabetes: a randomised placebo-
controlled trial. Lancet. 2003;361(9374):2005–16. Funding Funding
This study was supported by an unconditional Grant from Amgen Italia S.p.a. 9. Spinler SA, Cziraky MJ, Willey VJ, Tang F, Maddox TM, Thomas T, et al. Frequency of attainment of low-density lipoprotein cholesterol and
non-high-density lipoprotein cholesterol goals in cardiovascular clinical
practice (from the National Cardiovascular Data Registry PINNACLE Regis-
try). Am J Cardiol. 2015;116(4):547–53. 9. Spinler SA, Cziraky MJ, Willey VJ, Tang F, Maddox TM, Thomas T, et al. Frequency of attainment of low-density lipoprotein cholesterol and
non-high-density lipoprotein cholesterol goals in cardiovascular clinical
practice (from the National Cardiovascular Data Registry PINNACLE Regis-
try). Am J Cardiol. 2015;116(4):547–53. Availability of data and materials The data underlying this article were provided by CliCon by permission. Data
will be shared on request to the corresponding author with the permission of
CliCon. 10. Bruckert E, Parhofer KG, Gonzalez-Juanatey JR, Nordestgaard B, Arca M,
Giovas P, et al. Proportion of high-risk/very high-risk patients in Europe
with low-density lipoprotein cholesterol at target according to European
guidelines: a systematic review. Adv Ther. 2020;37(5):1724–36. 10. Bruckert E, Parhofer KG, Gonzalez-Juanatey JR, Nordestgaard B, Arca M,
Giovas P, et al. Proportion of high-risk/very high-risk patients in Europe
with low-density lipoprotein cholesterol at target according to European
guidelines: a systematic review. Adv Ther. 2020;37(5):1724–36. Competing interests chronic therapies and is expected to reflect the actual
pill intake [44]. The strengths of this study are the high
number of subjects included, the comparison in two
different populations of two other lipid targets, the pro-
portion of adherence evaluated form pharmacy-claim
data, and detailed information on statin dosage. MLM received Grant support, lecture or consultant fees from Lilly, Merck
Sharp & Dome, Mylan, Servier, Amryt and SLAPharma. AA received research
grants, lecture or advisory board fees from Merck Sharp & Dome, AstraZeneca,
Novartis, Boeringher-Ingelheim, Sanofi, Mediolanum, Janssen, Novo Nordisk,
Lilly, Servier, Neopharmed Gentili, and Takeda. Authors’ contributions 7. Cosentino F, Grant PJ, Aboyans V, Bailey CJ, Ceriello A, Delgado V,
et al. 2019 ESC guidelines on diabetes, pre-diabetes, and cardiovas-
cular diseases developed in collaboration with the EASD. Eur Heart J. 2020;41(2):255–323. 7. Cosentino F, Grant PJ, Aboyans V, Bailey CJ, Ceriello A, Delgado V,
et al. 2019 ESC guidelines on diabetes, pre-diabetes, and cardiovas-
cular diseases developed in collaboration with the EASD. Eur Heart J. 2020;41(2):255–323. All authors provided substantial contribution to the manuscript Study design:
MLM, AA, LDE, MA, MP, VP; Data collection and analysis and interpretation:
MLM, CV, AA, VP; Manuscript writing: MLM, CV, VP, LDE, AA. Data interpretation
and critical revision of the manuscript: SDK, GPF, LDE, MA. All authors read and
approved the final manuscript. 8. Morieri ML, Longato E, Mazzucato M, Di Camillo B, Cocchiglia A, Gubian L,
et al. Improved long-term cardiovascular outcomes after intensive versus
standard screening of diabetic complications: an observational study. Cardiovasc Diabetol. 2019;18(1):117. 8. Morieri ML, Longato E, Mazzucato M, Di Camillo B, Cocchiglia A, Gubian L,
et al. Improved long-term cardiovascular outcomes after intensive versus
standard screening of diabetic complications: an observational study. Cardiovasc Diabetol. 2019;18(1):117. References 1. Ference BA, Ginsberg HN, Graham I, Ray KK, Packard CJ, Bruckert E, et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus
statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J. 2017;38(32):2459–72. Supplementary Information The online version contains supplementary material available at https://doi.
org/10.1186/s12933-021-01338-y. The online version contains supplementary material available at https://doi.
org/10.1186/s12933-021-01338-y. 4. Briel M, Nordmann AJ, Bucher HC. Statin therapy for prevention and treat-
ment of acute and chronic cardiovascular disease: update on recent trials
and metaanalyses. Curr Opin Lipidol. 2005;16(6):601–5. Additional file 1: Figure S1. Study flow-chart and design. Figure S2. LDL-cholesterol levels in patients with events according to event site and
lipid-lowering treatments. y
5. Cannon CP, Blazing MA, Giugliano RP, McCagg A, White JA, Theroux P,
et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372(25):2387–97. 6. Ray KK, Colhoun HM, Szarek M, Baccara-Dinet M, Bhatt DL, Bittner VA,
et al. Effects of alirocumab on cardiovascular and metabolic outcomes
after acute coronary syndrome in patients with or without diabetes: a
prespecified analysis of the ODYSSEY OUTCOMES randomised controlled
trial. Lancet Diabetes Endocrinol. 2019;7(8):618–28. Ethics approval and consent to participate 11. Alwhaibi M, Altoaimi M, AlRuthia Y, Meraya AM, Balkhi B, Aldemerdash A,
et al. Adherence to statin therapy and attainment of LDL cholesterol goal
among patients with type 2 diabetes and dyslipidemia. Patient Prefer
Adherence. 2019;13:2111–8. The study protocol conforms to the ethical guidelines of the 1975 Declara-
tion of Helsinki. The study used anonymous data and, based on National and
International regulations, a waiver was applied to the requirement for patients’
informed consent. 12. de Vries FM, Voorham J, Hak E, Denig P. Prescribing patterns, adherence
and LDL-cholesterol response of type 2 diabetes patients initiating statin
on low-dose versus standard-dose treatment: a descriptive study. Int J
Clin Pract. 2016;70(6):482–92. 12. de Vries FM, Voorham J, Hak E, Denig P. Prescribing patterns, adherence
and LDL-cholesterol response of type 2 diabetes patients initiating statin
on low-dose versus standard-dose treatment: a descriptive study. Int J
Clin Pract. 2016;70(6):482–92. Consent for publication
Not applicable. Bhatt DL, Steg PG, Miller M, Brinton EA, Jacobson TA, Ketchum SB, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceri-
demia. N Engl J Med. 2019;380(1):11–22. 18. Yang YS, Yang BR, Kim MS, Hwang Y, Choi SH. Low-density lipoprotein
cholesterol goal attainment rates in high-risk patients with cardiovascular
diseases and diabetes mellitus in Korea: a retrospective cohort study. Lipids Health Dis. 2020;19(1):5. 36. Morieri ML, Shah HS, Sjaarda J, Lenzini PA, Campbell H, Motsinger-Reif
AA, et al. PPARA polymorphism influences the cardiovascular benefit of
fenofibrate in type 2 diabetes: findings from ACCORD-lipid. Diabetes. 2020;69(4):771–83. 19. Longato E, Di Camillo B, Sparacino G, Saccavini C, Avogaro A, Fadini GP. Diabetes diagnosis from administrative claims and estimation of the
true prevalence of diabetes among 4.2 million individuals of the Veneto
region (North East Italy). Nutr Metab Cardiovasc Dis. 2020;30(1):84–91. 37. Friedman HS, Rajagopalan S, Barnes JP, Roseman H. Combination therapy
with ezetimibe/simvastatin versus statin monotherapy for low-density
lipoprotein cholesterol reduction and goal attainment in a real-world
clinical setting. Clin Ther. 2011;33(2):212–24. 20. Farmer KC. Methods for measuring and monitoring medication
regimen adherence in clinical trials and clinical practice. Clin Ther. 1999;21(6):1074–90 (discussion 3). 38. Lee YH, Hong N, Lee CJ, Park SH, Lee BW, Cha BS, et al. Differential
association of ezetimibe-simvastatin combination with major adverse
cardiovascular events in patients with or without diabetes: a retrospec-
tive propensity score-matched cohort study. Sci Rep. 2018;8(1):11925. 21. Catapano AL, Graham I, De Backer G, Wiklund O, Chapman MJ, Drexel H,
et al. 2016 ESC/EAS guidelines for the management of dyslipidaemias. Eur Heart J. 2016;37(39):2999–3058. 22. Mach F, Baigent C, Catapano AL, Koskinas KC, Casula M, Badimon L, et al. 2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid
modification to reduce cardiovascular risk. Eur Heart J. 2020;41(1):111–88. 39. Hajahmadi Pourrafsanjani M, Khayati Shal E, Khezrpour S. Risk factors
associated with failure to achieve the low density lipoprotein cholesterol
therapeutic target in patients with acute coronary syndrome: a longi-
tudinal, single centre investigation. High Blood Press Cardiovasc Prev. 2019;26(1):37–43. 23. Arca M, Ansell D, Averna M, Fanelli F, Gorcyca K, Iorga SR, et al. Statin
utilization and lipid goal attainment in high or very-high cardiovascu-
lar risk patients: insights from Italian general practice. Atherosclerosis. 2018;271:120–7. 40. Presta V, Figliuzzi I, Miceli F, Coluccia R, Fogacci F, Cicero AFG, et al. Consent for publication
Not applicable. Consent for publication
Not applicable. Consent for publication
Not applicable. Page 12 of 12 Page 12 of 12 Page 12 of 12 Morieri et al. Cardiovasc Diabetol (2021) 20:144 Morieri et al. Cardiovasc Diabetol (2021) 20:144 13. Parris ES, Lawrence DB, Mohn LA, Long LB. Adherence to statin therapy
and LDL cholesterol goal attainment by patients with diabetes and
dyslipidemia. Diabetes Care. 2005;28(3):595–9. 30. Kuiper JG, Sanchez RJ, Houben E, Heintjes EM, Penning-van Beest FJA,
Khan I, et al. Use of lipid-modifying therapy and LDL-C goal attainment
in a high-cardiovascular-risk population in the Netherlands. Clin Ther. 2017;39(4):819-27.e1. 14. Morieri ML, Avogaro A, Fadini GP. Cholesterol lowering therapies and
achievement of targets for primary and secondary cardiovascular preven-
tion in type 2 diabetes: unmet needs in a large population of outpatients
at specialist clinics. Cardiovasc Diabetol. 2020;19(1):190. 31. Leiter LA, Betteridge DJ, Farnier M, Guyton JR, Lin J, Shah A, et al. Lipid-altering efficacy and safety profile of combination therapy with
ezetimibe/statin vs. statin monotherapy in patients with and without
diabetes: an analysis of pooled data from 27 clinical trials. Diabetes Obes
Metab. 2011;13(7):615–28. 15. Groenhof TKJ, Kofink D, Bots ML, Nathoe HM, Hoefer IE, Van Solinge WW,
et al. Low-density lipoprotein cholesterol target attainment in patients
with established cardiovascular disease: analysis of routine care data. JMIR Med Inform. 2020;8(4): e16400. 32. Cholesterol Treatment Trialists C, Kearney PM, Blackwell L, Collins R, Keech
A, Simes J, et al. Efficacy of cholesterol-lowering therapy in 18,686 people
with diabetes in 14 randomised trials of statins: a meta-analysis. Lancet. 2008;371(9607):117–25. 16. Garcia-Gil M, Blanch J, Comas-Cufi M, Daunis-i-Estadella J, Bolibar B,
Marti R, et al. Patterns of statin use and cholesterol goal attainment in a
high-risk cardiovascular population: a retrospective study of primary care
electronic medical records. J Clin Lipidol. 2016;10(1):134–42. 33. Riaz H, Khan AR, Khan MS, Rehman KA, Alansari SAR, Gheyath B, et al. Meta-analysis of placebo-controlled randomized controlled trials on the
prevalence of statin intolerance. Am J Cardiol. 2017;120(5):774–81. 17. Bongard V, Dallongeville J, Arveiler D, Ruidavets JB, Amouyel P, Wagner
A, et al. Attainment of low-density lipoprotein cholesterol target
in the French general population according to levels of cardiovas-
cular risk: insights from the MONA LISA study. Arch Cardiovasc Dis. 2013;106(2):93–102. 34. Kautzky-Willer A, Harreiter J, Pacini G. Sex and gender differences in risk,
pathophysiology and complications of type 2 diabetes mellitus. Endocr
Rev. 2016;37(3):278–316. 35. Consent for publication
Not applicable. Achievement of low density lipoprotein (LDL) cholesterol targets in pri-
mary and secondary prevention: analysis of a large real practice database
in Italy. Atherosclerosis. 2019;285:40–8. 24. Allahyari A, Jernberg T, Lautsch D, Lundman P, Hagstrom E, Schubert J,
et al. LDL-cholesterol target attainment according to the 2011 and 2016
ESC/EAS dyslipidaemia guidelines in patients with a recent myocardial
infarction—nationwide cohort study, 2013–2017. Eur Heart J Qual Care
Clin Outcomes. 2020. https://doi.org/10.1093/ehjqcco/qcaa016. 41. de Vries FM, Kolthof J, Postma MJ, Denig P, Hak E. Efficacy of standard and
intensive statin treatment for the secondary prevention of cardiovascular
and cerebrovascular events in diabetes patients: a meta-analysis. PLoS
ONE. 2014;9(11): e111247. 25. Guglielmi V, Bellia A, Pecchioli S, Della-Morte D, Parretti D, Cricelli I, et al. Effectiveness of adherence to lipid lowering therapy on LDL-cholesterol
in patients with very high cardiovascular risk: a real-world evidence study
in primary care. Atherosclerosis. 2017;263:36–41. 42. Amarenco P, Kim JS, Labreuche J, Charles H, Abtan J, Bejot Y, et al. A
comparison of two LDL cholesterol targets after ischemic stroke. N Engl J
Med. 2020;382(1):9. 26. Karalis DG, Wild RA, Maki KC, Gaskins R, Jacobson TA, Sponseller CA, et al. Gender differences in side effects and attitudes regarding statin use in
the Understanding Statin Use in America and Gaps in Patient Education
(USAGE) study. J Clin Lipidol. 2016;10(4):833–41. 43. Bonora E, Monami M, Bruno G, Zoppini G, Mannucci E. Attending diabe-
tes clinics is associated with a lower all-cause mortality. A meta-analysis
of observational studies performed in Italy. Nutr Metab Cardiovasc Dis. 2018;28(5):431–5. y
27. Chi MD, Vansomphone SS, Liu IL, Cheetham C, Green KR, Scott RD, et al. Adherence to statins and LDL-cholesterol goal attainment. Am J Manag
Care. 2014;20(4):e105-12. 44. Raebel MA, Schmittdiel J, Karter AJ, Konieczny JL, Steiner JF. Standardizing
terminology and definitions of medication adherence and persistence
in research employing electronic databases. Med Care. 2013;51(8 Suppl
3):S11-21. 28. Eid WE, Sapp EH, McCreless T, Nolan JR, Flerlage E. Prevalence and
characteristics of patients with primary severe hypercholesterolemia in a
multidisciplinary healthcare system. Am J Cardiol. 2020. https://doi.org/
10.1016/j.amjcard.2020.07.008. Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in pub-
lished maps and institutional affiliations. 29. Froylan DM, Esteban JG, Carlos PR, Aida XM, Ma Rocio MA, Horacio OA,
et al. Prevalence of poor lipid control in patients with premature coronary
artery disease. Nutr Metab Cardiovasc Dis. 2020. https://doi.org/10.1016/j.
numecd.2020.04.030.
|
https://openalex.org/W4390707227
|
https://www.nature.com/articles/s41467-023-44326-4.pdf
|
English
| null |
Temperature and quantum anharmonic lattice effects on stability and superconductivity in lutetium trihydride
|
Nature communications
| 2,024
|
cc-by
| 7,247
|
Temperature and quantum anharmonic
lattice effects on stability and
superconductivity in lutetium trihydride Roman Lucrezi
1, Pedro P. Ferreira
1,2, Markus Aichhorn
1 &
Christoph Heil
1 Received: 13 June 2023
Accepted: 8 December 2023
Check for updates In this work, we resolve conflicting experimental and theoretical findings
related to the dynamical stability and superconducting properties of
Fm3m-LuH3, which was recently suggested as the parent phase harboring
room-temperature superconductivity at near-ambient pressures. Including
temperature and quantum anharmonic lattice effects in our calculations, we
demonstrate that the theoretically predicted structural instability of the Fm3m
phase near ambient pressures is suppressed for temperatures above 200 K. We
provide a p–T phase diagram for stability up to pressures of 6 GPa, where the
required temperature for stability is reduced to T > 80 K. We also determine
the superconducting critical temperature Tc of Fm3m-LuH3 within the Migdal-
Eliashberg formalism, using temperature- and quantum-anharmonically-
corrected phonon dispersions, finding that the expected Tc for electron-
phonon mediated superconductivity is in the range of 50–60 K, i.e., well below
the temperatures required to stabilize the lattice. When considering moderate
doping based on rigidly shifting the Fermi level, Tc decreases for both hole and
electron doping. Our results thus provide evidence that any observed room-
temperature superconductivity in pure or doped Fm3m-LuH3, if confirmed,
cannot be explained by a conventional electron-phonon mediated pairing
mechanism. The scientific community’s interest in lutetium hydrides has been
reignited overnight following Dasenbrock-Gammon et al. recent
announcement of a room-temperature superconductor (RTS) at
almost ambient pressure in the Lu-N-H system1. If this result would be
confirmed, it could mark the discovery of a new, revolutionary class of
lowest-pressure, highest-Tc hydrides, paving the way for a plethora of
technological advancements in fields ranging from medicine to
quantum computing2–9. the authors due to the bright red color of the samples, remains
unknown given the inability of conventional spectroscopy methods in
measuring defect densities and fractional occupations of light ele-
ments such as H or N. The main phase reported in ref. 1 to be superconducting is sug-
gested to be LuH3−δNϵ with Fm3m face-centered cubic (fcc) space-
group (SG), based on the obtained diffraction patterns and compar-
isons
with
known
lutetium
hydrides10–13. A
minor,
non-
superconducting phase B was also identified in all the obtained sam-
ples and assigned to a Fm3m-LuH2 structure1. Although the proposed RTS phase has been characterized using
several different experimental techniques in ref. Article https://doi.org/10.1038/s41467-023-44326-4 1Institute of Theoretical and Computational Physics, Graz University of Technology, NAWI Graz 8010 Graz, Austria. 2Universidade de São Paulo, Escola de
Engenharia de Lorena, DEMAR, 12612-550 Lorena, Brazil.
e-mail: christoph.heil@tugraz.at Article doping with N, as suggested in ref. 1, could also impact the super-
conducting properties. the experimental findings and gaining a better understanding of the
proposed superconducting phase14–23. A few theoretical studies have
also been made available24–29, identifying the most likely phases that
match the experimental data and investigating the possibility of
achieving RTS in the Lu-N-H system within the electron-phonon (el-ph)
coupling mechanism. the experimental findings and gaining a better understanding of the
proposed superconducting phase14–23. A few theoretical studies have
also been made available24–29, identifying the most likely phases that
match the experimental data and investigating the possibility of
achieving RTS in the Lu-N-H system within the electron-phonon (el-ph)
coupling mechanism. With this work, we want to clarify the conflicting experimental and
theoretical findings related to the stability of Fm3m-LuH3 and provide
an accurate description of its superconducting properties to under-
stand if RTS at near-ambient pressure is attainable in this phase. Compellingly, by the inclusion of quantum ionic effects and anhar-
monicity within the framework of the stochastic self-consistent har-
monic approximation (SSCHA)41, we show that the Fm3m-LuH3 phase
can be stabilized at temperatures above 200 K for pressures of 1 GPa
and we also provide a p–T phase diagram for stability up to 6 GPa. Moreover, by utilizing the Migdal-Eliashberg formalism42,43, we predict
a Tc of approx. 50–60 K at a pressure of 2.8 GPa, and also probe the
effects of small doping on Tc, providing evidence that any observed
room-temperature superconductivity in pure or moderately doped
Fm3m-LuH3, if present at all, cannot be explained by a conventional el-
ph pairing mechanism. Independent crystal structure prediction studies have demon-
strated that both the LuH2 and LuH3 compositions are thermo-
dynamically stable in the Lu-N-H ternary phase diagram24–26,28. While
these theoretical
works
have
confirmed
the
presence of
the
Fm3m-LuH2 phase on the convex hull, they have also revealed that for
LuH3 the cubic Fm3m phase is not the thermodynamically most stable
one close to ambient pressure24–26,28. In addition, phonon calculations
for Fm3m-LuH3 within the commonly employed harmonic approx-
imation suggest that this phase is dynamically highly unstable due to
the presence of several imaginary modes in the vibrational spectra
present in the whole extent of the Brillouin zone (BZ)24,25,29. The two Fm3m phases of LuH2 and LuH3, even though the latter is
supposedly dynamically unstable, are of significant importance. Temperature and quantum anharmonic lattice effects on
stability y
As mentioned above, the phonon dispersion of Fm3m-LuH3 (hereafter,
we omit the Fm3m notation when referring to Fm3m-LuH2 or
Fm3m-LuH3) at ambient pressures within the harmonic approximation
exhibits several imaginary phonon modes throughout the whole BZ,
shown in Fig. 1a as dashed black lines. This could either indicate a
genuine structural instability of the phase or an inadequate theoretical
description of the physical system. To resolve this issue, we have cal-
culated the vibrational properties incorporating quantum ionic,
anharmonic, and temperature effects on the same footing, as imple-
mented in SSCHA41. The self-consistent harmonic approximation
method effectively maps the full anharmonic and interacting lattice
onto an auxiliary harmonic system. The actual system’s ground state is
then obtained by minimizing the free energy of the auxiliary harmonic
system44–47. This minimization is performed stochastically via Monte
Carlo summation and sampling over several consecutive ensembles
arbitrarily populated by many structures.Within the density-functional
theory (DFT) framework, each structure denotes a supercell with dis-
placed atomic positions, where the supercell dimension determines
the density of phonon wave vectors in the BZ37. Further information is
available in the Method section, Supplementary Method 1, and
refs. 32,36,39,41,48–50. On the other hand, it has been predicted recently thatFm3m-LuH2
has a negligibly low Tc
24, while Fm3m-LuH3 is predicted to have finite
critical temperatures smaller than 35 K24. It is important to note,
however, that the calculations for the latter have been performed by
neglecting all contributions of the imaginary modes to the el-ph cou-
pling and, therefore, only serve as a rough estimate. To get an accurate description of the physical properties in these
systems, several effects have to be taken into account: (i) As has been
demonstrated for various materials, anharmonicity and the quantum
motion of ions, effects that are neglected in harmonic phonon calcu-
lations within the Born–Oppenheimer approximation, can have sig-
nificant implications for certain materials30,31,31–35. These corrections
can become particularly important for hydrogen-rich compounds35–40,
where the zero-point motion of H atoms can even modify the ground
state structure, and anharmonic effects may significantly change the
energy of high-frequency H vibrations. (ii) Given that the experiments
for the Lu-N-H system have been conducted at elevated temperatures
up to room temperature, including temperature effects may be crucial
for an accurate modeling of the system as well. (iii) Furthermore, Noteworthy, the potential energy surface changes upon including
quantum anharmonic lattice effects. Article On the
one hand, recent studies argue that the actual composition observed in
Dasenbrock-Gammon et al.’s work1 is, in fact, N-doped or pure fcc
LuH2
14,16–18,20. The differentiation here is quite tricky, as LuH2 and LuH3
share the same structural framework with H atoms occupying only
tetrahedral sites or tetrahedral + octahedral sites, respectively. More-
over, their crystal cell volumes at ambient pressure are also quite similar
(V 0
LuH2 = 31:6 Åvs. V 0
LuH3 = 31:3 Å) and they both match the reported XRD
patterns of Dasenbrock-Gammon et al. for the main phase24,25. Temperature and quantum anharmonic
lattice effects on stability and
superconductivity in lutetium trihydride 1, including X-ray
diffraction (XRD), energy-dispersive X-ray, and Raman spectroscopy,
the structural details of the red matter superconductor, as named by Since the initial report by Dasenbrock-Gammon et al.1, several
experimental groups have invested significant efforts into replicating Nature Communications| (2024) 15:441 1 https://doi.org/10.1038/s41467-023-44326-4 Article Temperature and quantum anharmonic lattice effects on
stability For the high-symmetry LuH3, the
only structural degree of freedom is the lattice constant (synony-
mously, the unit cell volume), as all other structural parameters are Fig. 1 | Phonon dispersions as a function of temperature. SSCHA phonon dis-
persion for different temperatures T (solid colored lines). The calculations have
been performed for the structure with a = 5.040 Åand the harmonic phonon
dispersions are indicated by dashed black lines. Panel a shows the entire energy
range and b only the low-energy part. The energy section for the zoomed-in region
in b is indicated by solid black lines between the panels. Fig. 1 | Phonon dispersions as a function of temperature. SSCHA phonon dis-
persion for different temperatures T (solid colored lines). The calculations have
been performed for the structure with a = 5.040 Åand the harmonic phonon dispersions are indicated by dashed black lines. Panel a shows the entire energy
range and b only the low-energy part. The energy section for the zoomed-in region
in b is indicated by solid black lines between the panels. Nature Communications| (2024) 15:441 2 2 https://doi.org/10.1038/s41467-023-44326-4 https://doi.org/10.1038/s41467-023-44326-4 Article Fig. 3 | Phase diagram of stability. p–T phase diagram of stability based on the
lowest-energy phonon mode at K. The markers correspond to the data points
reported in Table 1 and the color profile is obtained by a cubic spline interpolation. Solid lines indicate the contour lines at positive integer frequencies ℏωK (in meV),
and the dashed lines the isochores. The star marks the p–T set for the ME calcu-
lation discussed in the main text. The corresponding dispersions are shown in
Supplementary Fig. 3. https://doi.org/10.1038/s41467-023-44326-4 fixed by symmetry. Effectively, this means that, for a given value of the
lattice constant, one can define an associated pressure within DFT
(pDFT) and within SSCHA (p), the latter also depending on the tem-
perature. The fact that p is, in general, larger than pDFT, can be readily
understood by considering the effects of zero-point motion35. To obtain a p–T phase diagram, we performed several scans as a
function of p and T, described in the following: By performing a SSCHA
calculation for a = 5.040 Åand T = 0 K to compare with the harmonic
calculation, one finds a pressure of p = 2.1 GPa, i.e., very close to the
synthesis pressure reported by ref. Temperature and quantum anharmonic lattice effects on
stability 1, and the stabilization of almost all
imaginary phonon modes; except for two degenerate modes around
the X and the K high-symmetry points, as indicated by the solid blue
lines in Fig. 1. This implies that the imaginary phonon frequencies at
these points in the BZ are, in fact, genuine structural instabilities. Fig. 3 | Phase diagram of stability. p–T phase diagram of stability based on the
lowest-energy phonon mode at K. The markers correspond to the data points
reported in Table 1 and the color profile is obtained by a cubic spline interpolation. Solid lines indicate the contour lines at positive integer frequencies ℏωK (in meV),
and the dashed lines the isochores. The star marks the p–T set for the ME calcu-
lation discussed in the main text. The corresponding dispersions are shown in
Supplementary Fig. 3. Increasing the temperature, that instability is suppressed for
T > 150 K (cf. Fig. 1) and p increases slightly (cf. Table 1). We also
observe that the optical phonon modes for energies above ℏω > 70
meV are barely affected by temperature effects. The same applies to
the acoustic modes, except for regions near the instabilities around X
and K. The optical modes around 40–50 meV harden slightly with
increasing temperature. To investigate how changes in the lattice
constant—or, in other words, the pressure—affect the phonon disper-
sions, we kept the temperature fixed at T = 150 K and performed
SSCHA calculations for four different values of a. The results can be
appreciated in Fig. 2, which shows the acoustic phonon branches in the
low-energy region of the dispersion (for the entire dispersions as a
function of pressure, we refer the reader to Supplementary Fig. 2 in
Supplementary Discussion 1). As expected, the phonon energies
increase with increasing pressure, and the instability is entirely absent
for p = 4.4 GPa at 150 K. K for five different values of the lattice constant a are reproduced. In
addition, we present in Fig. 3 a p–T phase diagram by cubic inter-
polation of the energy of the lowest phonon mode at K, indicated by
circle markers, as a function of p and T. In the following, we base our
predictions about stability on the interpolated contour lines shown in
Fig. 3, if not stated otherwise. Temperature and quantum anharmonic lattice effects on
stability The phonon dispersions shown and discussed in the main text are
based on calculations in 2 × 2 × 2 supercells. The convergence with
respect to the supercell size is shown and discussed in more detail in
Supplementary Discussion 2, and Supplementary Figs. 6–8, and 1451,52. We note in passing that the calculations in higher supercells do not
unambiguously answer the question of dynamic (in)stability in a spe-
cific region in the BZ in a certain pressure range. Hence, we consider
the p–T conditions of dynamical stability in the 2 × 2 × 2 supercells as a
lower limit. To determine more accurately at which temperature LuH3
becomes stable as a function of pressure, we have performed further
SSCHA calculations, whose results we summarize in Table 1. There,
DFT pressures pDFT and pressures p at temperatures of 0, 150, and 300 Table 1 | Lattice constants and pressures
a
pDFT
p(0 K)
p(150 K)
p(300 K)
5.080
−4.0
−0.1
0.2
0.6
5.060
−3.0
1.0
1.3
1.7
5.040
−2.0
2.1
2.3
2.8
5.005
0.0
4.1
4.4
4.9
4.972
2.0
6.2
6.4
6.9
Lattice constant a in Å, DFT pressure pDFT in GPa, and pressure p in GPa within the constant-
volume SSCHA calculations at different temperatures T. Table 1 | Lattice constants and pressures Our results highlight that although quantum anharmonic lattice
effects strongly influence the phonon properties, finite temperatures
are imperative to stabilize the fcc LuH3 phase. In fact, we find that
temperatures of 80 K or higher are required to suppress the structural
instability for pressures up to 6 GPa (cf. Fig. 3). As an aside, we want to
note that during the revision process, we became aware of another
work examining the stability of the Fm3m phase of LuH3 within the
SSCHA formalism53. We want to mention at this point that we did
similar calculations for LuH2, which is dynamically stable already at the
harmonic level, and find that temperature and quantum anharmonic
lattice effects on phonon energies are much smaller there and sub-
ordinate (more details are provided in Supplementary Fig. 13). Lattice constant a in Å, DFT pressure pDFT in GPa, and pressure p in GPa within the constant-
volume SSCHA calculations at different temperatures T. Fig. 2 | Phonon dispersions as a function of pressure. Low-energy part of the
phonon dispersions as a function of pressure p at a fixed temperature (T = 150 K). Temperature and quantum anharmonic lattice effects on
stability The full dispersion relations for all modes are provided in Supplementary Fig. 2. Superconductivity 4–9), high-
Tc SC requires that electrons of H-bonds participate in the el-ph pairing
to harness the high phonon energies of the H vibrations. Having mainly
Lu-d states at the Fermi level is thus quite detrimental to RTS. Fur-
thermore, the low density of electrons at the Fermi level is also dis-
advantageous for achieving the highest-Tc’s4–9. On a more technical
note, the minute sizes of the Fermi surface pockets also mean that
converging any calculation for el-ph interactions and SC is particularly
challenging, as the BZ integrals that have to be evaluated require very
dense k and q wave vector grids. At this point, we want to highlight an important consequence of
our results: Despite the quite sizeable Tc’s in the range of 50–60 K, fcc
LuH3 will not show SC in experiments near ambient pressures, as its
critical temperature for stability is larger than 80 K in this pressure
regime (cf. Fig. 3). In the report of room-temperature SC at near-ambient pressures
by ref. 1, the authors mention that LuH3 could be doped with small
amounts of N. To estimate the effects of changing the number of
electrons on Tc and to see whether room-temperature SC is attainable
in the LuH3 phase with such a doping, we performed additional ME
calculations within the rigid-band approximation. To determine the superconducting properties of LuH3, we
employed the Migdal-Eliashberg formalism42 as implemented in the
EPW code43, which allows the interpolation of the electronic and
vibrational properties onto very dense grids in reciprocal space using
Wannier interpolation. The calculations are performed using the
SSCHA-renormalized dynamical matrices at T = 300 K, the tempera-
ture closest to where ref. 1 report the transition, and choosing a
standard
value
of
μ* = 0.1
for
the
Morel-Anderson
Coulomb
pseudopotential54. (Using
the
corrected
anharmonic
dynamical
matrices is justified as the ions, due to the Fm3m symmetry, are fixed
to the same high-symmetry sites within DFPT and SSCHA.) With this
setup, we want to determine at which temperature LuH3 becomes
superconducting, i.e., at which temperature the superconducting gap
Δ opens. g
The energy shifts ΔE taken into consideration are indicated in
Fig. 4 as dashed horizontal lines: For ΔE = −0.2 eV, which corresponds
to a change in electron numbers by −0.03, we find a decrease of Tc to
about 30 K, which is because the DOS available for pairing is relatively
low in this region. Superconductivity 4b, where we plot
the Fermi surface colored according to the respective H-s orbital
contributions. In addition, the DOS increases steeply around the Fermi
level with increasing energy, with Lu-d bands above and hybridized Lu-
H bands below the Fermi energy. It’s worth mentioning that almost
70% of the H-s states of the hole pocket around Γ originate from H
located at the octahedral sites, which are unoccupied in LuH2,
explaining to some extent the difference in superconducting behavior. To elucidate better the origin of el-ph coupling, we present in
Fig. 5b the wave-vector (q) and mode (ν) resolved el-ph coupling
strength λq,ν, plotted as fat bands onto the phonon dispersion. This
shows clearly that almost all of the contributions to the el-ph coupling
originate from the lowest two optical phonon modes and, to a lesser
extent, from the lower acoustic branch, around L. This corresponds to
the coupling of electrons between the Γ-centered hole pocket and the
electron
pockets
at
L,
i.e.,
to
a
phonon
wave
vector
of
q = (0.5, −0.5, 0.5) ⋅2π/a (cf. Fig. 4 and inset of Fig. 5). The respective
contributions of the phonon modes to the total coupling can also be
appreciated from the provided Eliashberg spectral function α2F(ω) in
Fig. 5, which has most of its weight between 40–60 meV. According to
our calculations, the total el-ph coupling strength λ is about 1.7. of Lu-d orbital character with only little hybridization to H-s states. Consequently, the Fermi surface has three small pockets: one Γ-
centered hole pocket, where a small amount of H-s hybridization with
Lu-d is observed; and two nested electron pockets around L of purely
Lu-d character. This can also be appreciated in Fig. 4b, where we plot
the Fermi surface colored according to the respective H-s orbital
contributions. In addition, the DOS increases steeply around the Fermi
level with increasing energy, with Lu-d bands above and hybridized Lu-
H bands below the Fermi energy. It’s worth mentioning that almost
70% of the H-s states of the hole pocket around Γ originate from H
located at the octahedral sites, which are unoccupied in LuH2,
explaining to some extent the difference in superconducting behavior. These findings have several implications: As for example dis-
cussed in ref. 24 for the Lu-N-H system (or in general in refs. Superconductivity Having demonstrated that LuH3 can become dynamically stable with
the inclusion of temperature and quantum anharmonic lattice effects,
we move on to obtain a detailed picture of the superconducting state,
assuming the pairing is mediated by el-ph interactions. To do so, we
first have to discuss its electronic properties. Unless otherwise
expressed explicitly, all calculations from now on are based on the
Fm3m-LuH3 structure with a = 5.040 Å(corresponding to a pressure p
of 2.8 GPa at room temperature). Additional cases are reported in
Supplementary Table 2. Figure 4a shows the electronic dispersions and (partial) DOS
around the Fermi level, which is the energy region relevant for SC
pairing within the conventional el-ph mechanism (a more zoomed-out
version of this plot is provided in Supplementary Fig. 9). LuH3 is a
metal with three very dispersive bands crossing the Fermi level, mainly Fig. 2 | Phonon dispersions as a function of pressure. Low-energy part of the
phonon dispersions as a function of pressure p at a fixed temperature (T = 150 K). The full dispersion relations for all modes are provided in Supplementary Fig. 2. Nature Communications| (2024) 15:441 Nature Communications| (2024) 15:441 3 https://doi.org/10.1038/s41467-023-44326-4 Article Fig. 4 | Electronic properties. a Electronic dispersions with H contributions indi-
cated as colored markers, (partial) DOS for an energy window around the Fermi
level, and detailed region showing the H contributions to the DOS. The dashed
horizontal lines at −0.2, 0.2, and 0.4 eV indicate the energy shifts used in the rigid-
band approximation calculations (more details in the main text). b Fermi surface
with colors again representing the H contributions. Fig. 4 | Electronic properties. a Electronic dispersions with H contributions indi-
cated as colored markers, (partial) DOS for an energy window around the Fermi
level, and detailed region showing the H contributions to the DOS. The dashed horizontal lines at −0.2, 0.2, and 0.4 eV indicate the energy shifts used in the rigid-
band approximation calculations (more details in the main text). b Fermi surface
with colors again representing the H contributions. of Lu-d orbital character with only little hybridization to H-s states. Consequently, the Fermi surface has three small pockets: one Γ-
centered hole pocket, where a small amount of H-s hybridization with
Lu-d is observed; and two nested electron pockets around L of purely
Lu-d character. This can also be appreciated in Fig. Superconductivity This Tc value refers to the isotropic calculation. In
the anisotropic case, the convergence of the ME equations fails due to
the low density of states at the Fermi energy, where an extremely
dense k-grid is needed to generate explicit points at the Fermi energy. Interestingly, for positive shifts of 0.2 and 0.4 eV (corresponding to
adding 0.12 and 0.33 electrons, respectively), we also observe a
decrease in Tc to less than 30 and 45 K, respectively. Although the DOS
strongly increases for energies above the Fermi level, the H contribu-
tions, in fact, decrease (cf. Fig. 4). As these are crucial to SC in LuH3, the
critical temperatures consequently also decrease. More details for
these calculations are provided in Supplementary Fig. 12 and Supple-
mentary Table 2. We extend our SC analysis to pressures and phononic
temperatures covered in the phase diagram in Fig. 3 and find only
minor changes in Tc. The results are provided in Supplementary
Table 2. Figure 5 summarizes the results of our calculations. Within the
isotropic ME formalism, we obtain a TIME
c
of about 53 K. When solving
the fully anisotropic ME equations, the superconducting critical tem-
perature increases to about TAME
c
= 60 K (see Supplementary Fig. 11). The inset of Fig. 5a shows the Fermi surface colored according to the
values of the anisotropic superconducting gap function Δk at a tem-
perature T = 10 K, demonstrating a rather isotropic distribution of gap
values. Despite the rigid-band approximation providing only a rough
estimate for the dependence of Tc with doping, it should be accurate Nature Communications| (2024) 15:441 4 https://doi.org/10.1038/s41467-023-44326-4 https://doi.org/10.1038/s41467-023-44326-4 Article Fig. 5 | Electron-phonon properties and superconductivity. a Superconducting
gap value Δ as a function of temperature calculated from the isotropic ME equa-
tions. The inset shows the Fermi surface colored according to the k-dependent gap
values Δk from an anisotropic ME calculation. b Phonon dispersion (solid black
lines) as considered in the calculations with the respective wave-vector- and mode-
resolved el-ph coupling strength λq,ν indicated as ochre fat bands, along with the
phonon DOS (solid black line), α2F(ω), and cumulative el-ph coupling strength λ(ω). lines) as considered in the calculations with the respective wave-vector- and mode-
resolved el-ph coupling strength λq,ν indicated as ochre fat bands, along with the
phonon DOS (solid black line), α2F(ω), and cumulative el-ph coupling strength λ(ω). Fig. Discussion To summarize, our results demonstrate that even with employing
quantum anharmonic corrections as implemented in SSCHA, the
proposed Fm3m-LuH3 is dynamically unstable for pressures below 6
GPa at T = 0 K. With the additional incorporation of temperature
effects, however, this phase can be stabilized for T > 200 K at p = 0 GPa
(T > 80 K at p = 6 GPa). While this means that ref. 1 could indeed have
synthesized the Fm3m-LuH3 phase near room-temperature, our cal-
culations for the superconducting properties within the fully aniso-
tropic Migdal-Eliashberg theory, including temperature- and quantum-
anharmonic-corrected phonon dispersions, unambiguously demon-
strate that the expected Tc for an el-ph mediated SC pairing (50–60 K)
is well below the reported room-temperature one; in fact, it is smaller
than the critical temperature of stability in these pressure ranges, and
thus Fm3m-LuH3 would decompose or transition into a different
structure before it has the chance to become a (conventional)
superconductor. Superconductivity 5 | Electron-phonon properties and superconductivity. a Superconducting
gap value Δ as a function of temperature calculated from the isotropic ME equa-
tions. The inset shows the Fermi surface colored according to the k-dependent gap
values Δk from an anisotropic ME calculation. b Phonon dispersion (solid black no contribution of the Lu-f states on the electronic structure around
the Fermi energy, and no noticeable influence on the harmonic pho-
non dispersions, (cf. Supplementary Figs. 15 and 16). enough for small doping levels. A more realistic but computationally
demanding approach would be to incorporate N atoms into the LuH3
structure, which requires dealing with large supercells. Nevertheless,
the very fact that Tc decreases for shifts of the Fermi level in both
doping directions strongly indicates that optimizing the electron
count will not be able to turn LuH3 into a room-temperature super-
conductor at near-ambient pressures. We performed extensive convergence tests on the numerical
parameters and achieved an accuracy of below 1 meV/atom for the
total energy with a 12 × 12 × 12 k-grid, plane-wave cutoff energy of 100
Ry, and a smearing value for the Brillouin zone integration of 0.005 Ry. The unit cell (uc) calculations were carried out in the fcc primitive unit
cell with 4 atoms (lutetium in Wyckoff site 4a, hydrogen in 4b and 8c)
employing a convergence threshold of 10−10 Ry for the total energy in
all electronic self-consistency calculations. For the structure relaxa-
tions, we used a convergence threshold of 10−7 Ry in total energy; all
force components are zero by symmetry. For the DFT calculations in
2 × 2 × 2 supercells, the k-grid was reduced to 6 × 6 × 6 according to the
larger cell dimensions. The harmonic dynamical matrices and the self-
consistent first-order variation of the potential are calculated within
DFPT on a 6 × 6 × 6 q-grid employing a phonon self-convergency
threshold of 10−16. SSCHA calculations The SSCHA calculations are performed in the constant-volume mode
without relaxation, as implemented in the SSCHA python package41. As
all atomic positions are fixed by symmetry, the structure does not
change in the SSCHA minimization procedure. We performed separate
SSCHA calculations in 2 × 2 × 2 supercells for all 12 considered p–T
combinations. The physical quantities converge within a few hundred
random structures, and to further reduce the stochastic noise, we
increase the number of random structures in the last ensemble to
1000. The total energies, forces, and stress tensors for the individual
displaced structures are obtained from DFT calculations, as described
in the corresponding methods section. The SSCHA minimization is
stopped for Kong-Liu ratios below 0.3 and when the ratio between the
free energy gradient with respect to the auxiliary dynamical matrix and
its stochastic error becomes smaller than 10−7. With these settings, the
free energy differences between the last two ensembles for each p–T
case are well below 1 meV/uc, and the pressure differences below 0.1
GPa. The temperature-dependent anharmonic phonon dispersions are
calculated from the positional free-energy Hessians in the bubble
approximation, i.e., without the fourth-order corrections. As shown in
Supplementary Fig. 1 in Supplementary Method 1, the fourth-order
corrections are negligible in LuH3. The largest differences in anhar-
monic phonon dispersions between the last two ensembles are in the
order of 1 meV. The color profile and contour lines in Fig. 3 are based Nature Communications| (2024) 15:441 References 27. Fang, Y.-W., Dangić, Ɖ, Errea, I. Assessing the feasibility of near-
ambient conditions superconductivity in the Lu-N-H system, arXiv
preprint arXiv:2307.10699 (2023). 1. Dasenbrock-Gammon, N. et al. Evidence of near-ambient super-
conductivity in a N-doped lutetium hydride. Nature 615, 244 (2023). 28. Xie, F. et al. Lu-H-N phase diagram from first-principles calculations. Chin. Phys. Lett. 40, 057401 (2023). 2. Mohtadi, R. & Orimo, S.-i The renaissance of hydrides as energy
materials. Nat. Rev. Mater. 2, 1 (2016). 3. Duan, D. et al. Structure and superconductivity of hydrides at high
pressures. Natl Sci. Rev. 4, 121 (2017). 3. Duan, D. et al. Structure and superconductivity of hydrides at high
pressures. Natl Sci. Rev. 4, 121 (2017). 29. Sun, Y., Zhang, F., Wu, S., Antropov, V. & Ho, K.-M. Effect of nitrogen
doping and pressure on the stability of LuH3. Phys. Rev. B 108,
L020101 (2023). 4. Boeri, L. & Bachelet, G. B. Viewpoint: the road to room-temperature
conventional superconductivity. J. Phys. Condens. Matter 31,
234002 (2019). 4. Boeri, L. & Bachelet, G. B. Viewpoint: the road to room-temperature
conventional superconductivity. J. Phys. Condens. Matter 31,
234002 (2019). 30. Errea, I., Rousseau, B. & Bergara, A. Anharmonic stabilization of the
high-pressure simple cubic phase of calcium. Phys. Rev. Lett. 106,
165501 (2011). 5. Pickard, C. J., Errea, I. & Eremets, M. I. Superconducting hydrides
under pressure. Ann. Rev. Condens. Matter Phys. 11, 57 (2020). 31. Leroux, M. et al. Strong anharmonicity induces quantum melting of
charge density wave in 2H-NbSe2 under pressure. Phys. Rev. B 92,
140303 (2015). 6. Flores-Livas, J. A. et al. A perspective on conventional high-
temperature superconductors at high pressure: methods and
materials. Phys. Rep. 856, 1 (2020). 32. Ribeiro, G. A. S. et al. Strong anharmonicity in the phonon spectra of
PbTe and SnTe from first principles. Phys. Rev. B 97, 014306 (2018). 7. Boeri, L. et al. The 2021 room-temperature superconductivity
roadmap. J. Phys. Condens. Matter 34, 183002 (2022). 33. Lucrezi, R. & Heil, C. Superconductivity and strong anharmonicity in
novel Nb–S phases. J. Phys. Condens. Matter 33, 174001 (2021). 8. Hilleke, K. P., Bi, T. & Zurek, E. Materials under high pressure: a
chemical perspective. Appl. Phys. A 128, 441 (2022). 34. Ranalli, L. et al. Temperature-dependent anharmonic phonons in
quantum paraelectric KTaO3 by first principles and machine-
learned force fields. Adv. Quantum Technol. 6, 2200131 (2023). 9. Pickett, W. E. Migdal-Eliashberg calculations 19. Li, Z. et al. Superconductivity above 70 K observed in lutetium
polyhydrides. Sci. China Phys. Mechan. Astron. 66, 267411 (2023). We employed the EPW code package42,43 for the Wannier interpolation
of the el-ph matrix elements onto dense k- and q-grids and the sub-
sequent self-consistent solution of the isotropic and the fully aniso-
tropic Migdal-Eliashberg equations. In particular, we used coarse
6 × 6 × 6 k- and q grids and interpolated onto fine 30 × 30 × 30 reci-
procal grids (see Supplementary Fig. 10), set a Matsubara frequency
cutoff of 1 eV, included electronic states within ± 1 eV around the Fermi
energy, and chose a standard value for the Morel-Anderson pseudo-
potential of μ* = 0.10. The starting projections for the Wannierization
were chosen using the SCDM method63,64 for electronic states in the
range of −15 eV to +5 eV around the Fermi energy. The rigid band shift
is achieved within EPW by setting explicitly the Fermi energy to dif-
ferent values and hence changing the included electronic band
manifold. 20. Xing, X. et al. Observation of non-superconducting phase changes
in nitrogen doped lutetium hydrides. Nat. Commun. 14, 5991 (2023). 21. Wang, N. et al. Percolation-induced resistivity drop in lutetium
dihydride with controllable electrical conductivity over six orders of
magnitude. Sci. China Phys. Mechan. Astron. 66, 297412 (2023). 22. Cai, S. et al. No evidence of superconductivity in a compressed
sample prepared from lutetium foil and H2/N2 gas mixture. Matter
Radiat. Extrem. 8, 048001 (2023). 23. Moulding, O. et al. Pressure-induced formation of cubic lutetium
hydrides derived from trigonal LuH3. Phys. Rev. B 108, 214505
(2023). 24. Ferreira, P. P. et al. Search for ambient superconductivity in the Lu-
N-H system. Nat. Commun. 14, 5367 (2023). 25. Hilleke, K. P. et al. Structure, stability, and superconductivity of
N-doped lutetium hydrides at kbar pressures. Phys. Rev. B 108,
014511 (2023). https://doi.org/10.1038/s41467-023-44326-4 https://doi.org/10.1038/s41467-023-44326-4 15. Ming, X. et al. Absence of near-ambient superconductivity in
LuH2±xNy. Nature 620, 72 (2023). on a cubic spline interpolation of the p −T data points in Table 1 to a
p × T-grid of size 150 × 150. The final positional free energy Hessian
matrices are interpolated to a 6 × 6 × 6 q-grid and used as dynamical
matrices for the Migdal-Eliashberg calculations. We want to stress at
this point again that all data presented in the main text have been
obtained using 2 × 2 × 2 supercells and the ONCV-PBE settings descri-
bed above. Further details and higher supercell calculations are pro-
vided in Supplementary Method 1 and in Supplementary Discussion 2. 16. Shan, P. et al. Pressure-induced color change in the lutetium dihy-
dride LuH2. Chin. Phys. Lett. 40 (2023). 17. Zhang, Y.-J. et al. Pressure induced color change and evolution of
metallic behavior in nitrogen-doped lutetium hydride. Sci. China
Phys. Mechan. Astron. 66, 287411 (2023). 18. Zhao, X. et al. Pressure tuning of optical reflectivity in LuH2. Sci. Bull. 68, 883 (2023). Data availability The authors confirm that the data supporting the findings of this study
are available within the article and its Supplementary Information. Further information is available upon request. 26. Huo, Z. et al. First-principles study on the conventional super-
conductivity of N-doped fcc-LuH3. Matter Radiat. Extrem. 8,
038402 (2023). DF(P)T calculations The electronic and harmonic phonon properties are calculated within
density-functional (perturbation) theory using the plane-wave pseu-
dopotential code Quantum Espresso55. We used the PBE-GGA para-
metrization for the exchange-correlation functional56 in combination
with scalar-relativistic optimized norm-conserving Vanderbilt pseu-
dopotentials (ONCV)57,58, including one valence electron for hydrogen
and 25 valence electrons for Lutetium. We investigated the influence of
employing different types of pseudopotentials59 for our results, which
can be found in Supplementary Discussion 2, Supplementary Table 1,
and Supplementary Figs. 4 and 5. The employed Lu pseudopotential
treats the 4f states explicitly and places them well below the Fermi
energy in LuH3, which is in excellent agreement with other works on
explicit Lu-H-N structures25,27,60,61. We further confirm the 4f energy
range by an all-electron calculation using WIEN2K62. Upon including
on-site Coulomb interactions within DF(P)T + U calculations, we find Nature Communications| (2024) 15:441 5 Article https://doi.org/10.1038/s41467-023-44326-4 https://doi.org/10.1038/s41467-023-44326-4 40. Lucrezi, R., Di Cataldo, S., von der Linden, W., Boeri, L. & Heil, C. In-
silico synthesis of lowest-pressure high-Tc ternary superhydrides. npj Comput. Mater. 8, 119 (2022). 62. Blaha, P. et al. WIEN2k: an APW+lo program for calculating the
properties of solids. J. Chem. Phys. 152, 074101 (2020). 62. Blaha, P. et al. WIEN2k: an APW+lo program for calculating the
properties of solids. J. Chem. Phys. 152, 074101 (2020). 63. Vitale, V. et al. Automated high-throughput wannierisation. npj
Comput. Mater. 6, 66 (2020). 41. Monacelli, L. et al. The stochastic self-consistent harmonic
approximation: calculating vibrational properties of materials with
full quantum and anharmonic effects. J. Phys. Condens. Matter 33,
363001 (2021). 64. Damle, A., Lin, L. & Ying, L. Compressed representation of
Kohn–sham orbitals via selected columns of the density matrix. J. Chem. Theory Comput. 11, 1463 (2015). 42. Margine, E. R. & Giustino, F. Anisotropic migdal-eliashberg theory
using wannier functions. Phys. Rev. B 87, 024505 (2013). Acknowledgements 43. Lee, H. et al. Electron–phonon physics from first principles using
the epw code. npj Comput. Mater. 9, 156 (2023). RL and CH acknowledge the Austrian Science Fund (FWF) and PPF
acknowledges the São Paulo Research Foundation (FAPESP) under
Grants 2020/08258-0 and 2021/13441-1. Calculations were per-
formed on the Vienna Scientific Cluster and on the dcluster of the
Graz University of Technology. This research was funded in part by
the Austrian Science Fund (FWF) P 32144-N36. For the purpose of
open access, the author has applied a CC BY public copyright
licence to any Author Accepted Manuscript version arising from
this submission. 44. Born, M. Die Gültigkeitsgrenze der Theorie der idealen Kristalle und
ihre Überwindung, in Festschrift zur Feier des Zweihundertjährigen
Bestehens der Akademie der Wissenschaften in Göttingen: I. Mathematisch-Physikalische Klasse 1–16 (Springer, 1951). 45. Hooton, D. J. LI. A new treatment of anharmonicity in lattice ther-
modynamics: I. Lond. Edinb. Dublin Philos. Mag. J. Sci. 46, 422 (1955). 46. Koehler, T. R. Theory of the self-consistent harmonic approximation
with application to solid neon. Phys. Rev. Lett. 17, 89 (1966). Additional information Supplementary information The online version contains
supplementary material available at
https://doi.org/10.1038/s41467-023-44326-4. Supplementary information The online version contains
supplementary material available at
https://doi.org/10.1038/s41467-023-44326-4. 50. Aseginolaza, U. et al. Phonon collapse and second-order phase
transition in thermoelectric SnSe. Phys. Rev. Lett. 122, 075901 (2019). 51. Shapeev, A. V. Moment tensor potentials: a class of systematically
improvable interatomic potentials. Multiscale Model. Simul. 14,
1153 (2016). Correspondence and requests for materials should be addressed to
Christoph Heil. Correspondence and requests for materials should be addressed to
Christoph Heil. 52. Gubaev, K., Podryabinkin, E. V., Hart, G. L. & Shapeev, A. V. Accel-
erating high-throughput searches for new alloys with active learn-
ing of interatomic potentials. Comput. Mater. Sci. 156, 148 (2019). Peer review information Nature Communications thanks the anon-
ymous, reviewer(s) for their contribution to the peer review of this work. A peer review file is available. Peer review information Nature Communications thanks the anon-
ymous, reviewer(s) for their contribution to the peer review of this work. A peer review file is available. 53. Dangić, D., Garcia-Goiricelaya, P., Fang, Y.-W., Ibañez Azpiroz, J. &
Errea, I. Ab initio study of the structural, vibrational, and optical
properties of potential parent structures of nitrogen-doped lute-
tium hydride. Phys. Rev. B 108, 064517 (2023). Competing interests 49. Monacelli, L., Errea, I., Calandra, M. & Mauri, F. Pressure and stress
tensor of complex anharmonic crystals within the stochastic self-
consistent harmonic approximation. Phys. Rev.B 98, 024106 (2018). Author contributions 47. Werthamer, N. R. Self-consistent phonon formulation of anharmo-
nic lattice dynamics. Phys. Rev. B 1, 572 (1970). R.L. performed most of the calculations, P.P.F. and M.A. assisted with
additional calculations and figure design, and C.H. supervised the pro-
ject. All authors contributed to the discussion of the results and parti-
cipated in preparing the manuscript. 48. Bianco, R., Errea, I., Paulatto, L., Calandra, M. & Mauri, F. Second-
order structural phase transitions, free energy curvature, and
temperature-dependent anharmonic phonons in the self-consistent
harmonic approximation: theory and stochastic implementation. Phys. Rev. B 96, 014111 (2017). References Colloquium: room temperature superconductivity:
the roles of theory and materials design. Rev. Mod. Phys. 95,
021001 (2023). 35. Lucrezi, R. et al. Quantum lattice dynamics and their importance in
ternary superhydride clathrates. Commun. Phys. 6, 298 (2023). 10. Palasyuk, T. & Tkacz, M. Pressure induced hexagonal to cubic phase
transformation in erbium trihydride. Solid State Commun. 130,
219 (2004). 36. Errea, I., Calandra, M. & Mauri, F. First-principles theory of anhar-
monicity and the inverse isotope effect in superconducting
palladium-hydride compounds. Phys. Rev. Lett. 111, 177002 (2013). 11. Palasyuk, T. & Tkacz, M. Pressure-induced structural phase transi-
tion in rare-earth trihydrides. part i.(GdH3, HoH3, LuH3). Solid State
Commun. 133, 481 (2005). 37. Errea, I., Calandra, M. & Mauri, F. Anharmonic free energies and
phonon dispersions from the stochastic self-consistent harmonic
approximation: Application to platinum and palladium hydrides. Phys. Rev. B 89, 064302 (2014). 12. Song, H. et al. High Tc superconductivity in heavy rare earth
hydrides. Chin. Phys. Lett. 38, 107401 (2021). 13. Shao, M. et al. Superconducting ScH3 and LuH3 at megabar pres-
sures. Inorg. Chem. 60, 15330 (2021). 38. Errea, I. et al. High-pressure hydrogen sulfide from first principles: a
strongly anharmonic phonon-mediated superconductor. Phys. Rev. Lett. 114, 157004 (2015). 14. Liu, M. et al. Parent structures of near-ambient nitrogen-doped
lutetium hydride superconductor. Phys. Rev. B 108,
L020102 (2023). 39. Errea, I. et al. Quantum crystal structure in the 250-kelvin super-
conducting lanthanum hydride. Nature 578, 66 (2020). Nature Communications| (2024) 15:441 6 6 Article https://doi.org/10.1038/s41467-023-44326-4 Reprints and permissions information is available at
http://www.nature.com/reprints 54. Morel, P. & Anderson, P. W. Calculation of the superconducting
state parameters with retarded electron-phonon interaction. Phys. Rev. 125, 1263–1271 (1962). Publisher’s note Springer Nature remains neutral with regard to jur-
isdictional claims in published maps and institutional affiliations. 55. Giannozzi, P. et al. Advanced capabilities for materials modelling
with Quantum ESPRESSO. J. Phys. Condens. Matter. 29,
465901 (2017). Open Access This article is licensed under a Creative Commons
Attribution 4.0 International License, which permits use, sharing,
adaptation, distribution and reproduction in any medium or format, as
long as you give appropriate credit to the original author(s) and the
source, provide a link to the Creative Commons licence, and indicate if
changes were made. The images or other third party material in this
article are included in the article’s Creative Commons licence, unless
indicated otherwise in a credit line to the material. If material is not
included in the article’s Creative Commons licence and your intended
use is not permitted by statutory regulation or exceeds the permitted
use, you will need to obtain permission directly from the copyright
holder. To view a copy of this licence, visit http://creativecommons.org/
licenses/by/4.0/. 56. Perdew, J. P., Burke, K. & Ernzerhof, M. Generalized gradient
approximation made simple. Phys. Rev. Lett. 77, 3865 (1996). 57. Hamann, D. R. Optimized norm-conserving Vanderbilt pseudopo-
tentials. Phys. Rev. B 88, 085117 (2013). 58. Schlipf, M. & Gygi, F. Optimization algorithm for the generation of
ONCV pseudopotentials. Comput. Phys. Commun. 196, 36 (2015). 59. Dal Corso, A. Pseudopotentials periodic table: from H to Pu. Com-
put. Mater. Sci. 95, 337 (2014). 60. Tao, X., Yang, A., Yang, S., Quan, Y. & Zhang, P. Leading compo-
nents and pressure-induced color changes in N-doped lutetium
hydride. Sci. Bull. 68, 1372 (2023). 61. Liang, X. et al. Observation of flat band and van Hove singularity in
non-superconducting nitrogen-doped lutetium hydride. arXiv pre-
print arXiv:2308.16420 (2023). © The Author(s) 2024 7 Nature Communications| (2024) 15:441 7
|
https://openalex.org/W4309183682
|
https://dipot.ulb.ac.be/dspace/bitstream/2013/351526/3/PaG2022.pdf
|
English
| null |
Is Protest Only Negative? Examining the Effect of Emotions and Affective Polarization on Protest Behaviour
|
Politics and governance
| 2,022
|
cc-by
| 10,595
|
Issue This article is part of the issue “Negative Politics: Leader Personality, Negative Campaigning, and the Oppositional
Dynamics of Contemporary Politics” edited by Alessandro Nai (University of Amsterdam), Diego Garzia (University of
Lausanne), Loes Aaldering (Free University Amsterdam), Frederico Ferreira da Silva (University of Lausanne), and Katjana
Gattermann (University of Amsterdam). © 2022 by the author(s); licensee Cogitatio (Lisbon, Portugal). This article is licensed under a Creative Commons Attribu‐
tion 4.0 International License (CC BY). * Corresponding author (luca.bettarelli@ulb.be) Submitted: 26 April 2022 | Accepted: 25 September 2022 | Published: in press Submitted: 26 April 2022 | Accepted: 25 September 2022 | Published: in press Abstract This contribution sheds light on the link between affect and protest behaviors. Using data from a voter survey conducted
around the 2019 elections in Belgium, we examine two dimensions of affect: a vertical one, i.e., negative and positive emo‐
tions towards politics in general, and a horizontal one, i.e., affective polarization towards fellow citizens. Our findings make
three important contributions. First, we identify five distinct classes of respondents depending on their emotions towards
politics (apathetic, angry, hopeful, highly emotional, and average). Second, we demonstrate that the combination of both
anger and hope is more strongly associated with protest action than anger alone. By contrast, apathy, characterized by
an absence of emotions towards politics, is negatively related to protest behavior. Third, we show that affective polariza‐
tion is a key driver of protest behavior per se. We also show that the two dimensions of affect have distinctive effects. Yet they interact: Affective polarization towards political opponents compensates for the absence of emotions towards
politics in general. Keywords affective polarization; Belgium; emotions; protest Politics and Governance, 2022, Volume 10, Issue 4, Pages X–X uca Bettarelli *, Caroline Close, and Emilie van Haute Centre d’Étude de la Vie Politique (CEVIPOL), Université Libre de Bruxelles, Belgium Politics and Governance (ISSN: 2183–2463)
2022, Volume 10, Issue 4, Pages X–X
https://doi.org/10.17645/pag.v10i4.5665 1. Introduction Their
findings echo those of Lerner and Keltner (2001), who
show that discrete emotions having a dissimilar valence
(positive vs. negative), such as anger and hope, or anger
and happiness, can lead to similar risk appraisal, i.e.,
optimistic risk appraisal. Hence, they show that both
anger and hope can be associated with goal‐oriented
behavior. By contrast, some emotions sharing a similar
valence, such as anger and fear, can lead to opposite risk
appraisals—then, fear and anger would have opposite
effects on protest action. simultaneous effect of emotions and affective polariza‐
tion and their interactions. We test these expectations by
looking at the case of Belgium, using the 2019 RepResent
Panel Voter Survey. Theoretically, we bridge the literature from social
movement studies that look at the role of emotions
and affective group ties to the process of identity build‐
ing and collective protest action (Jasper, 1998; Melucci,
1995, p. 45; Polletta & Jasper, 2001), to individual‐level
research from social and political psychology that inves‐
tigates the influence of discrete emotions on how citi‐
zens process information, evaluate politics, and shape
their political preferences and their decision to take
part in political processes, in both the electoral and
non‐electoral arenas (Altomonte et al., 2019; Close &
van Haute, 2020; Marcus, 2000). We also go one step fur‐
ther by not only considering the effect of discrete emo‐
tions separately but also how the combination of various
emotions can affect individual protest behaviors. Our findings make three important empirical contri‐
butions. First, at the descriptive level, a latent class analy‐
sis (LCA) shows that respondents display different “clus‐
ters” of emotions, and we identify five classes of respon‐
dents depending on their emotions towards politics: apa‐
thetic, angry, hopeful, highly emotional, and average. Second, we show that the vertical and horizontal dimen‐
sions of affect are distinctly related to protest behav‐
iors. On the vertical dimension, we demonstrate that the
combination of both anger and hope is more strongly
associated with protest action than anger alone. By con‐
trast, apathy, characterized by an absence of emotions
towards politics, is negatively related to protest behav‐
iors. On the horizontal dimension, we show that affec‐
tive polarization is significantly related to protest behav‐
iors. 1. Introduction cal dimension) and affective polarization towards other
party supporters (horizontal dimension). On the one
hand, we consider the combined role of specific, discrete
negative and positive emotions towards politics in gen‐
eral, tapping into citizens’ emotions towards elites and
institutions (Capelos & Demertzis, 2018; Vasilopoulou
& Wagner, 2017). On the other hand, we look at the
horizontal dimension of affect by investigating the role
of affective polarization, that is, the tendency among
party supporters (the in‐party group) to increasingly dis‐
like or resent supporters of other parties (the out‐party
group), tapping into citizen’s feelings towards other fel‐
low citizens (Iyengar et al., 2019; Wagner, 2021; Ward
& Tavits, 2019). In addition, we further investigate the Contemporary politics has been increasingly character‐
ized by its affective character (Webster & Albertson,
2022). At the same time, conventional forms of polit‐
ical participation are losing ground, and social upris‐
ings which challenge the established political order are
on the rise. In this context, better understanding the
affective drivers of protest behaviors appears crucial. This article explores the connection between affect and
protest participation. More specifically, we examine the role of two dimen‐
sions of affect on individual protest behaviors: spe‐
cific, discrete emotions towards politics in general (verti‐ Politics and Governance, 2022, Volume 10, Issue 4, Pages X–X 1 cratic contexts, where the risk of repression and vio‐
lence is high (Dornschneider, 2020; Nikolayenko, 2022). In democratic contexts, Capelos and Demertzis (2018)
show that, during periods of crisis in Greece, anxious
people reported a low political activity while those who
were angry reported a high degree of participation, espe‐
cially in violent actions. Looking at voting behavior in
the Brexit referendum, Vasilopoulou and Wagner (2017)
show that, while anger was positively associated with
support for the leave option, fear prompted greater mod‐
eration. According to the appraisal‐tendency framework
(Lerner & Keltner, 2001), fear would enhance individu‐
als’ reliance on the evaluation of the situation and would
trigger pessimistic risk estimates and risk‐averse choices
(Valentinoet al., 2008), whereas anger would trigger opti‐
mistic risk estimates and risk‐seeking choices (Lerner &
Keltner, 2001). Individual protest behavior is also asso‐
ciated with positive emotions. Capelos and Demertzis
(2018) again show that during periods of crisis in Greece,
not only angry but also hopeful people reported a high
level of engagement in legal and illegal actions. 1. Introduction We also demonstrate that the two dimensions of
affect interact with each other, with high levels of affec‐
tive polarization compensating for the lack of emotion
towards politics, thus pushing apathetic individuals to
participate in protest behaviors. Yet few of these studies look at the combination or
simultaneous effect of positive and negative emotions
(for exceptions, see Dornschneider, 2020; Landmann &
Rohmann, 2020; Nikolayenko, 2022). One has to look at
social movement theories to find studies dealing with
sets of emotions as crucial elements in the process of
collective identity building and as potential drivers of
collective action (Jasper, 1998; Polletta & Jasper, 2001). Jasper (2014a, p. 211) refers to protest as being the result
of “pairs of positive and negative emotions,” such as
outrage and hope (Castells, 2012); or as the result of
sequences of emotions, such as shame turning into pride
through anger in groups sharing a stigmatized identity
(Britt & Heise, 2000). This literature points to the role of
sets of emotions in creating, nurturing, and potentially
breaking a collective movement. Politics and Governance, 2022, Volume 10, Issue 4, Pages X–X 2.2. Affective Polarization and Protest Next to the vertical dimension of emotions towards
politics, we focus on a second, horizontal dimension
of affect: affective polarization. Initially introduced by
Iyengar et al. (2012), affective polarization refers to the
tendency among party supporters (the in‐party group)
to increasingly dislike or resent supporters of other par‐
ties (the out‐party group). The fast‐growing literature
has mainly focused on measuring, assessing, and explain‐
ing levels of affective polarization across democracies
and over time (see, among others, Bettarelli et al., 2022;
Bettarelli & Van Haute, 2022b; Druckman & Levendusky,
2019; Gidron et al., 2020; Iyengar et al., 2019; Reiljan,
2020; Wagner, 2021). H2: Respondents displaying high levels of affective
polarization will report a higher level of protest par‐
ticipation, while respondents displaying low levels
of affective polarization will report a lower level of
protest participation. In the analysis, we will also consider the combined and
interactive effect of the horizontal and vertical dimen‐
sions of affect, given that the interaction between these
two dimensions remains largely unexplored. In the analysis, we will also consider the combined and
interactive effect of the horizontal and vertical dimen‐
sions of affect, given that the interaction between these
two dimensions remains largely unexplored. Much less is known about the consequences of affec‐
tive polarization. Iyengar et al. (2019) summarize congru‐
ent findings that show that it has negative non‐political
consequences, as it damages social relations and neg‐
atively affects economic behaviors. However, the evi‐
dence is more mixed regarding political consequences. Ward and Tavits (2019) demonstrated that higher lev‐
els of affective polarization create biases in the percep‐
tion of party competition, with voters viewing other
parties as more extreme. Furthermore, Hetherington
and Rudolph (2015) emphasized that it decreases trust
among voters. Affective polarization is also associ‐
ated with resistance to compromise, intolerance, and
advancement of their own group over the collective
good (Mason, 2018). More worryingly, Kingzette et al. (2021) show how affective polarization in the US under‐
mines support for democratic norms. On the other hand,
there is also evidence of the mobilizing power of affec‐
tive polarization. Ward and Tavits (2019) showed that it
enhances the perception that politics has high stakes and
that electoral outcomes and success are highly impor‐
tant. 2.1. Emotions and Protest We for‐
mulate the following hypothesis: appraisal themes (Lerner & Keltner, 2001), their effects
on behavior reinforce each other. Note that we distance
ourselves from most studies that look at respondents’
emotions towards a specific event. Rather, we measure
respondents’ level of emotion when they think about
politics in general, which is connected to the concept of
political resentment vis‐à‐vis the political elites and insti‐
tutions (Capelos & Demertzis, 2018). Consequently, we
expect that: H1: Respondents displaying a combination of high
hope and high anger (“highly emotional” respon‐
dents) will report a higher level of protest participa‐
tion, while respondents displaying low levels of both
hope and anger (apathy) will report a lower level of
protest participation. 2.2. Affective Polarization and Protest Consequently, they show that high levels of affec‐
tive polarization also lead voters to perceive that par‐
ticipation is crucial, and to higher levels of turnout (see
also Harteveld & Wagner, 2022; Wagner, 2021). Others
have shown similar dynamics for ideological polariza‐ 2.1. Emotions and Protest We first investigate the vertical dimension of affect
on protest behavior. Political psychology has examined
the interplay between discrete emotions and individual
protest behaviors (Marcus, 2000), such as signing a peti‐
tion, demonstrating, boycotting (Capelos & Demertzis,
2018), or voting for protest parties (Altomonte et al.,
2019; Marcus et al., 2019; Vasilopoulos et al., 2019). Anger was pinpointed as a crucial driver of protest
action (Gaffney et al., 2018; Salmela & von Scheve,
2017; Vasilopoulos et al., 2019), as it closely relates
to feelings of frustration, indignation (Jasper, 2014b),
or ressentiment (Capelos & Demertzis, 2018). By con‐
trast, studies emphasized that fear and anxiety deter
individuals from engaging in protest, particularly in auto‐ Taking stock of this research, we test how different
types of emotional clusters that respondents disclose
relate to their level of protest participation. Among the
range of emotions, we focus on anger and hope, as they
were shown as central factors for mobilization in previ‐
ous studies. We argue that it is the combination of anger
and hope that is the most likely to prompt participation. In other words, being only angry would be less power‐
ful than being angry and hopeful. Hope—the belief that
things may change—is also necessary. The underlying
mechanism is that because anger and hope have similar Politics and Governance, 2022, Volume 10, Issue 4, Pages X–X 2 tion, which is associated with higher levels of political
interest, political information, and electoral participation
(Abramowitz & Saunders, 2008; Dalton, 2008). However,
these studies focus on electoral participation. What
remains unexplored is whether these findings also apply
to other forms of participation and if affective polariza‐
tion has the same mobilizing power on non‐institutional
participation, especially protest. We expect that it is the
case, and we put forward two types of explanations. First,
as suggested above, affective polarization is connected
to a sense that “something is at stake” and that partic‐
ipating is important. Second, in line with the affective
approach to social movements, affective polarization
could involve negative affect (fear, hate, anger, outrage)
towards political opponents or other societal groups,
which, when shared within the group, can have a mobi‐
lizing effect (Jasper, 2014a, p. 209). At the same time,
positive affect towards other group members (love, com‐
passion, respect, pride) can help create solidarity, keep
the group together, and promote participation. Politics and Governance, 2022, Volume 10, Issue 4, Pages X–X 3.3. Dependent Variable To grasp respondents’ reported participation in protest
actions, we make use of the following question: “There
are different ways to improve things in Belgium or to
be more politically active. How often did you take part
in any of the following actions in the past 12 months?”
(1 = never, 2 = seldom, 3 = sometimes, 4 = often). Nine
types of political action were offered, out of which we
focus on four: (a) signing petitions, (b) participating in
protest or demonstration, (c) boycotting products, and
(d) breaking rules for political reasons. Tables 2 and 3
report descriptive statistics for the above items and the
correlation matrix, respectively. 3.1. Case Selection Descriptive statistics of items of
Variable
Obs
(a) Petitions
7,539
(b) Protest
7,536
(c) Boycotting
7,539
(d) Breaking rules
7,539
Table 3. Correlations matrix among item
Variables
(
(a) Petitions
1.0
(b) Protest
0. (c) Boycotting
0. (d) Breaking rules
0. Politics and Governance, 2022, Volume 10, Is from 5 April to 21 May since this wave included questions
on protest participation. A total of 7,617 individuals were
interviewed. The survey was conducted using computer‐
assisted web interviewing questionnaires and was dis‐
tributed by Kantar TNS to their own online panel. Panel
participants were selected using a quota sample based on
gender, age, education, and region of residency. The final
samples slightly differ from the target population, with an
overrepresentation of higher educated respondents and
the 45–65 age group. Therefore, when we compute vari‐
ables using the RepResent dataset, we use weights for
age, gender, and education. with deep social divisions mediated by consensus at the
elite level. However, the capacity of the elite of the
two main linguistic groups (French and Dutch speak‐
ers) to reach agreements has been challenged in recent
years, as indicated by the length of government forma‐
tion at the federal level (De Winter, 2019). This trans‐
lated into polarizing trends in the ballot box. The 2019
elections saw substantial shifts in party preferences and
the rise of the radical left (PVDA‐PTB, 12 seats in the
Lower Chamber, +10) and radical right parties (VB, which
became the second party in Flanders with 18 seats in the
Lower Chamber, +15) and the continuing decline of the
center, Christian Democratic parties (CD&V, CDH, DéFI). These trends show how Belgium incarnates the under‐
studied and complex character of polarization in multi‐
party settings. 3.1. Case Selection In this article, we focus on Belgium as negative affect and
its political consequences remain understudied in this
setting (with a few exceptions, see Bettarelli & Van Haute,
2022a, 2022b; Close & van Haute, 2020; van Erkel &
Turkenburg, 2020). It is surprising, as Belgium is an ideal
case to better understand the role of emotions and affec‐
tive polarization in multiparty settings. Belgium is a highly fragmented multiparty system. Since the split of traditional party families along the
French–Dutch linguistic divide, Belgium is characterized
by two‐party systems operating separately (Table 1):
Flemish parties compete in Flanders (north of the coun‐
try), whereas Francophone parties compete in Wallonia
(south of the country). We exclude Brussels from our ana‐
lysis due to its complexity (parties from the two language
groups compete on its territory) and data availability (we
do not have data about affective polarization for respon‐
dents from Brussels). Furthermore, the relationship dynamics between
parties have changed over the last decades. Belgium has
long been labeled as a typical consociational democracy Politics and Governance, 2022, Volume 10, Issue 4, Pages X–X 3 Table 1. List of parties with representation in the federal parliament, 2014–2019 and 2019–present. Party Family
Flanders
Wallonia
Christian Democrats
CD&V
CDH
Greens
Groen
Ecolo
Regionalists
N‐VA
DéFI
Liberals
OpenVLD
MR
Social Democrats
sp.a
PS
Radical Right
VB
PP
Radical Left
PVDA
PTB f parties with representation in the federal parliament, 2014–2019 and 2019–present. with deep social divisions mediated by c
elite level. However, the capacity of t
two main linguistic groups (French an
ers) to reach agreements has been chal
years, as indicated by the length of gov
tion at the federal level (De Winter, 20
lated into polarizing trends in the ballo
elections saw substantial shifts in party
the rise of the radical left (PVDA‐PTB,
Lower Chamber, +10) and radical right pa
became the second party in Flanders wit
Lower Chamber, +15) and the continuin
center, Christian Democratic parties (CD
These trends show how Belgium incarn
studied and complex character of polar
party settings. 3.2. Data
Our main data source is the RepResent Pa
2019, conducted by the Excellence of
tium of five research teams at the Unive
Vrije Universiteit Brussel, KU Leuven, Un
Bruxelles, and UCLouvain. It is a rich and
that includes multiple waves (more deta
2020; Walgrave et al., 2022). We are in
first pre‐electoral wave of the survey tha
Table 2. 3.2. Data Our main data source is the RepResent Panel Voter Survey
2019, conducted by the Excellence of Science consor‐
tium of five research teams at the University of Antwerp,
Vrije Universiteit Brussel, KU Leuven, Université Libre de
Bruxelles, and UCLouvain. It is a rich and original dataset
that includes multiple waves (more details in Pilet et al.,
2020; Walgrave et al., 2022). We are interested in the
first pre‐electoral wave of the survey that was conducted Table 2. Descriptive statistics of items of protest participation. Variable
Obs
Mean
SD
Min
Max
(a) Petitions
7,539
1.99
0.987
1
4
(b) Protest
7,536
1.486
0.8
1
4
(c) Boycotting
7,539
1.997
1.101
1
4
(d) Breaking rules
7,539
1.383
0.728
1
4
Table 3. Correlations matrix among items of protest participation. Variables
(a)
(b)
(c)
(d)
(a) Petitions
1.000
—
—
—
(b) Protest
0.515
1.000
—
—
(c) Boycotting
0.532
0.453
1.000
—
(d) Breaking rules
0.396
0.512
0.408
1.000 Table 2. Descriptive statistics of items of protest participation. atively correlated to protest, we ran additional regres‐
sion models with fear as a discrete emotion. Adding fear
did not alter our findings. Note that anger and hope
are weakly correlated (−0.2). We make use of the LCA
to locate respondents into emotional groups. In such a
model, a categorical latent (unobserved) variable is used
to identify the probability of each individual belonging
to a specific emotional category by means of a general‐
ized structural equation model. We obtain the best fit
when our sample is split into five emotional groups (see
Figure 1). In light of these results, we define Group 1
as average, when respondents register average scores
for both hope and anger; Group 2 as apathy, indicat‐
ing individuals with low scores in each emotion cate‐
gory; Groups 3 and 4 as hopeful and angry, respectively,
where the former includes people with high rates of
hope and low rates of anger, while the latter is the other
way round; Group 5 as highly emotional, which includes
individuals showing high rates of both anger and hope. In the empirical analysis, the average will represent the
baseline category. Operationally, we assemble an additive index that
sums the four items (Cronbach’s alpha is equal to 0.8)
to collapse them into a unique indicator of protest. 3.4. Independent Variables 3.4. Independent Variables 3.4.1. Emotions Our
measure
of
respondents’
emotions
towards
politics is captured by thermometer ratings. While
other measurement strategies exist, such as facial or
text/sentiment analysis, or physiological responses
(Schumacher et al., 2022), ratings are best suited for
large survey designs. Furthermore, it matches our choice
of measurement of our second independent variable,
affective polarization (see Section 3.4.2). Using ther‐
mometer ratings for our two independent variables
enhances consistency and comparability, especially since
we are interested in the combination of the two. We used
the following question: “When you think of Belgian pol‐
itics in general, to what extent do you feel each of the
following emotions?” Respondents were offered eight
emotions (anger, bitterness, anxiety, fear, hope, relief,
happiness, and satisfaction), and a scale ranging from
zero (not at all) to 10 (to a great extent). As previous
research pointed to the crucial role of two emotions,
one negative (anger) and one positive (hope), in mobi‐
lizing protesters, we focus on these two specific emo‐
tions. We computed a similar classification of respon‐
dents using all emotions. The number and nature of
the groupings are very similar, although the distinction
between categories is less clear‐cut. Regression results
are also highly similar to the ones presented in this ana‐
lysis. As previous studies showed that fear can be neg‐ Other methods than LCA could have been used to
assess the combined and isolated effect of discrete emo‐
tions, such as interaction effect or principal component
analysis (PCA). By using the interaction effect between
anger and hope, we would capture the “mediating”
effect of one emotion on the other, but we would not
actually catch the effect of having both emotions at the
same time. Interaction tells us if, e.g., the effect of anger
towards politics on protest participation is higher when
the degree of hope increases—which is not our argu‐
ment. Besides, interaction would have implied treating
the two emotions, not as continuous but as discrete vari‐
ables, and then checking all possible combinations of
anger and hope. This latter exercise makes the presen‐
tation of results much more complex. In the end, the
conclusions are highly similar to those when using LCA. 8
6
4
2
0
average
apathy
hopeful
angry
highly emoonal
mean of anger
mean of hope
Figure 1. Distribution of anger and hope across groups (LCA). Figure 1. Distribution of anger and hope across groups (LCA). 3.2. Data The resulting variable varies from 4 to 16; the higher
the index, the more often respondents engage in
protest action. 3.4. Independent Variables 3.4.1. Emotions Politics and Governance, 2022, Volume 10, Issue 4, Pages X–X Politics and Governance, 2022, Volume 10, Issue 4, Pages X–X 5 We also ran a PCA that highlighted two components: one
that negatively correlates anger and hope and one that
positively correlates the two, each explaining approxi‐
mately half of the variation in the data. Each compo‐
nent explains half of the scenarios resulting from the LCA:
The component that positively correlates the two emo‐
tions would contrast the “highly emotional” scenario
with the “apathy” one. As a result, we should have used
both in the same regression, making results qualitatively
similar to LCA but more complex to interpret. political emotions, with a particular focus on highly emo‐
tional people, i.e., those who display high levels of both
anger and hope. In terms of size (Table 4), two groups (average and
negative) account for over 70% of the respondents. Nevertheless, no group contains less than 500 individu‐
als. Note that the overall standard deviation of each emo‐
tion is consistently larger than that within each group,
thus further supporting our modeling choice. Table 5 reports the distribution of protest participa‐
tion by group. It indicates that protest participation is
significantly lower in the apathy group, and larger in the
negative and (mostly) the highly emotional groups, com‐
pared to the average. By contrast, no significant differ‐
ences emerge between the average and positive groups. We have explored these possibilities, but LCA offers
the best tool to explore our research question and test
our hypothesis, both in terms of conceptual message and
clarity of presentation of results. LCA groups observa‐
tions based on a data‐driven process. As a result, it cre‐
ates clear‐cut categories that classify respondents based
on their emotional states and allows them to then link
them to participation in protest action. Conceptually, cat‐
egorization by means of LCA allows one to clearly disen‐
tangle the propensity to participate in protests of differ‐
ent categories of individuals, defined according to their 3.4.2. Affective Polarization Politics and Governance, 2022, Volume 10, Issue 4, Pages X–X 3.4.3. Controls We include standard individual‐level socio‐demographic
variables (gender, age, education) that contribute to
determining political engagement (Brady et al., 1995;
Marien et al., 2010). Gender is a dummy equal to one
for female. Age (“What is your age?”) is a continu‐
ous variable, while education is a five‐category vari‐
able, ranging from none or elementary to university
degree. Income is measured by the following question:
“To what extent are you satisfied with your family’s total
income?” (0–10 scale, with 0 = very unsatisfied and
10 = very satisfied). We include standard individual‐level socio‐demographic
variables (gender, age, education) that contribute to
determining political engagement (Brady et al., 1995;
Marien et al., 2010). Gender is a dummy equal to one
for female. Age (“What is your age?”) is a continu‐
ous variable, while education is a five‐category vari‐
able, ranging from none or elementary to university
degree. Income is measured by the following question:
“To what extent are you satisfied with your family’s total
income?” (0–10 scale, with 0 = very unsatisfied and
10 = very satisfied). y
f
We also control for political attitudes. First, we con‐
trol for respondents’ left–right self‐placement for two
reasons: It allows us to further establish that affec‐
tive polarization and ideological positions are two dis‐
tinct phenomena. Second, it allows us to control for
the specific dynamics of protest in Belgium under the
2014–2019 legislature. The coalition government that
came out of the 2014 elections was exceptional, as it only
included (center‐)right parties (N‐VA, CD&V, OpenVLD,
and MR). Therefore, one can expect that protests were
initiated by the left‐wing opposition. Second, we con‐
trol for the degree of ideological extremeness of respon‐
dents, computed as the difference in absolute value
between the score on the left–right scale of each respon‐
dent and the average score across our sample. The higher
the score; the more ideologically extreme the respon‐
dent. Third, we control for respondents’ satisfaction with
democracy to further establish that emotions towards
politics are distinct from evaluations of the political sys‐
tem. We use the following question: “In politics, people
often talk of ‘left’ or ‘right.’ Can you place your own opin‐
ions on a scale from 0 to 10, with 0 meaning left, 5 the
centre, and 10 the right?” “Overall, how satisfied are you
with the way democracy is working in Belgium?” (1 = very
satisfied; 5 = very unsatisfied). 3.4.2. Affective Polarization The higher the score, the higher the sympathy
towards partisans of the party. Following the distinct
party offer, respondents in Flanders had to indicate their
feelings towards supporters of the seven Dutch‐speaking
parties listed in Table 1, and respondents in Wallonia had
to do the same with the seven French‐speaking parties
listed in Table 1. We make use of the spread‐of‐score
method proposed by Wagner (2021). The index is com‐
puted based on the following equation: institutions); it is rather a general measurement of neg‐
ative affect towards other partisan groups. To measure
affective polarization for each respondent, we also use
thermometer ratings, the most common strategy in the
literature (Iyengar et al., 2019). We make use of the fol‐
lowing question from the RepResent dataset: “Could you
use the scale below to indicate how you feel about the
following groups?” (scale ranging from 0 to 100, 0 to
49 = not very favorable; 50 = neutral; 51 to 100 = favor‐
able). The higher the score, the higher the sympathy
towards partisans of the party. Following the distinct
party offer, respondents in Flanders had to indicate their
feelings towards supporters of the seven Dutch‐speaking
parties listed in Table 1, and respondents in Wallonia had
to do the same with the seven French‐speaking parties
listed in Table 1. We make use of the spread‐of‐score
method proposed by Wagner (2021). The index is com‐
puted based on the following equation: 3.4.3. Controls 3.4.2. Affective Polarization Contrary to our measurement of discrete emotions,
affective polarization does not take into account dif‐
ferent feelings towards politics (political elites and Table 4. Descriptive statistics of anger and hope across groups. N
Mean
SD
Min
Max
Overall
Anger
7,471
5.94
2.69
0
10
Hope
7,469
3.84
2.56
0
10
Average
Anger
3,408
5.35
1.31
2
9
Hope
3,409
4.99
1.18
3
8
Apathy
Anger
523
0.93
1.14
0
4
Hope
523
0.91
1.10
0
3
Hopeful
Anger
612
1.50
1.14
0
4
Hope
612
6.25
1.10
4
10
Angry
Anger
2,019
8.41
1.43
4
10
Hope
2,017
1.28
1.36
0
3
Highly Emotional
Anger
699
8.22
1.19
4
10
Hope
699
7.12
1.58
6
10
Table 5. Descriptive statistics of protest participation split by groups. Categories
N
Mean
SD
Min
Max
p(x,y)
Average
3,405
6.68
2.69
4
16
—
Apathy
521
5.86
2.41
4
15
0.00
Hopeful
610
6.74
2.54
4
16
0.76
Angry
2,093
6.95
2.82
4
16
0.03
Highly emotional
694
8.05
3.41
4
16
0.00
Note: p(x,y) in the last column is the t‐test of equality of means across the baseline category average (x) and other categories (y), under
the assumption of equal variances. Table 4. Descriptive statistics of anger and hope across groups. Table 5. Descriptive statistics of protest participation split by groups. Categories
N
Mean
SD
Min
Max
p(x,y)
Average
3,405
6.68
2.69
4
16
—
Apathy
521
5.86
2.41
4
15
0.00
Hopeful
610
6.74
2.54
4
16
0.76
Angry
2,093
6.95
2.82
4
16
0.03
Highly emotional
694
8.05
3.41
4
16
0.00
Note: p(x,y) in the last column is the t‐test of equality of means across the baseline category average (x) and other categories (y), under
the assumption of equal variances. Politics and Governance, 2022, Volume 10, Issue 4, Pages X–X 6 institutions); it is rather a general measurement of neg‐
ative affect towards other partisan groups. To measure
affective polarization for each respondent, we also use
thermometer ratings, the most common strategy in the
literature (Iyengar et al., 2019). We make use of the fol‐
lowing question from the RepResent dataset: “Could you
use the scale below to indicate how you feel about the
following groups?” (scale ranging from 0 to 100, 0 to
49 = not very favorable; 50 = neutral; 51 to 100 = favor‐
able). 3.4.3. Controls Fourth, we include a vari‐
able measuring the respondents’ degree of interest in
politics on a scale of 0–10, ranging from 0 = not interested
at all to 10 = extremely interested. Spreadi = √
P
∑
p=1
(likeip −likei)
2 where subscripts i and p indicate each survey respon‐
dent and each French‐ or Dutch‐speaking party, respec‐
tively; “like” signifies the like–dislike evaluation towards
a party on a scale from 0 to 100; and “like” is the average
like–dislike score of respondent i. The higher the index,
the higher the degree of affective polarization. Note that
we do not weigh the index for the electoral size of each
party, for two reasons. First, as we use Wave 1 (pre‐
electoral) of the RepResent dataset, we do not have a
good reference time point to weigh each party’s size. Second, we argue that the weighting strategy is appropri‐
ate when using a territorial approach, as the social conse‐
quences of disliking supporters of small or large parties
may differ significantly; however, it is not essential for
individual‐level analyses. The average level of affective polarization among our
population is 19.5, ranging from 0 to 49. In Table 6, we
describe the average level of protest participation for dif‐
ferent intensities of affective polarization (split in per‐
centiles, from <20th to >80th). Results show that partici‐
pation in protest action significantly increases across per‐
centiles, thus indicating a positive correlation between
affective polarization and protest. Finally, we control for the place of residence of each
respondent, as there may exist habits of protest partici‐
pation linked to territories. To do so, we use NUTS‐3 fixed
effects in our regression model. Table 6. Descriptive statistics of protest participation split by percentiles of affective polarization. Mean
SD
Min
Max
AffPol < 20
6.36
2.82
4
16
20 < AffPol < 40
6.57
2.63
4
16
40 < AffPol < 60
6.60
2.59
4
16
60 < AffPol < 80
6.88
2.63
4
16
Affpol > 80
7.33
3.01
4
16
Note: The first column indicates the group under analysis with respect to percentiles of the affective polarization distribution, i.e., 20th,
40th, 60th, and 80th. Table 6. Descriptive statistics of protest participation split by percentiles of affective polarization. Politics and Governance, 2022, Volume 10, Issue 4, Pages X–X 7 emotion (Column 1). 3.4.4. Modelling Strategy In our regression analyses, continuous variables were
standardized using the z‐score, i.e., mean equal to zero
and standard deviation equal to one, to ease the inter‐
pretation of coefficients among variables computed at
different scales. Coefficients were computed using OLS
models, with NUTS‐3 fixed effects. The dependent vari‐
able in the models is the additive index of protest, as
discussed above. We checked the presence of potential
collinearity issues using the Variance Inflation Factor test
and registered a value below two in all models. and registered a value below two in all models. 4. Results
Table 7 presents the results of our regression analyses. First, we introduce the groups of respondents by type of
condition per se to increase participation in protest
action. However, as shown in Figure 1, this could also
result from the fact that levels of hope do not diverge so
much between the average and hopeful groups. Turning
towards the angry group, we see a positive coefficient,
even if it is not statistically significant at any conventional
Table 7. Regression results. (1)
(2)
(3)
(4)
Protest
Protest
Protest
Protest
Affpol (std)
0.362***
0.353***
0.085*
(0.042)
(0.043)
(0.045)
Groups (Emotions)
Average (baseline)
Apathy
−1.142***
−1.04***
−0.528***
(0.136)
(0.146)
(0.139)
Hopeful
−0.128
−.316**
−0.319**
(0.127)
(0.133)
(0.133)
Angry
0.043
−0.042
0.171*
(0.09)
(0.094)
(0.097)
Highly emotional
1.363***
1.016***
0.828***
(0.173)
(0.175)
(0.153)
Gender
−0.13
(0.079)
Age (std)
−0.39***
(0.041)
Education (std)
0.113***
(0.04)
Income (std)
−0.078*
(0.042)
Left_right (std)
−0.254***
(0.042)
Extremeness (std)
0.227***
(0.045)
Satisfaction with democracy (std)
−0.044
(0.048)
Political interest (std)
0.836***
(0.045)
Observations
6,894
5,990
5,829
5,753
R2
0.073
0.049
0.072
0.192
NUTS‐3 dummies
Yes
Yes
Yes
Yes
Notes: Robust standard errors are in parentheses; *** p < 0.01, ** p < 0.05, * p < 0.1. Politics and Governance, 2022, Volume 10, Issue 4, Pages X–X
8 3.4.3. Controls Coefficients associated with these
groups must be interpreted as differences with respect
to the baseline group (average anger and hope). Results
provide very interesting and novel insights. Protest par‐
ticipation, as expected, is significantly lower in the apa‐
thy group compared to the average category. In fact, a
switch from the latter to the former increases protest
participation by over one point. When we consider the
hopeful group, we see that the coefficient is not statisti‐
cally significant. This denotes that being hopeful when
thinking about politics does not represent a sufficient
condition per se to increase participation in protest
action. However, as shown in Figure 1, this could also
result from the fact that levels of hope do not diverge so
much between the average and hopeful groups. Turning
towards the angry group, we see a positive coefficient,
even if it is not statistically significant at any conventional 4. Results In other words, those who
participate in protest action most frequently feel angry
yet hopeful and may believe that political conditions
are likely to improve thanks to collective action. Similar
findings were uncovered using other statistical methods
(interaction effect between discrete emotions and PCA):
(a) Anger per se matters more than hope; (b) the inter‐
action between the two has a positive and significant
effect; (c) protest participation is particularly high among
individuals that show high values of both hope and anger. In addition, if we used LCA categorization based on all
emotions available (listed in Section 3.1.1), again, the
findings are similar. with democracy does not report a significant coefficient;
contrarily, the degree of interest in politics of respon‐
dents turns out to be positively correlated to protest par‐
ticipation, thus indicating that the more the respondents
are interested in politics, the higher the frequency with
which they participate in protest action. As expected, both the magnitude and significance
level of coefficients associated with our variables of inter‐
est have changed due to the introduction of the con‐
trol variables. However, the overall message we can draw
from the analysis remains qualitatively similar. As far as
theemotionalgroupsareconcerned,wecanobservethat
protest participation is significantly larger in the highly
emotional group than in any other category, although
the size of the coefficient is partially reduced. The apa‐
thy group is still characterized by its lower propensity to
protest, even if its associated coefficient reduces in mag‐
nitude with respect to Column 3. Finally, if the hopeful
group behaves consistently with previous findings, the
angry one is now significantly correlated with protest par‐
ticipation, even if the magnitude and significance level
of the coefficient are somewhat weak. However, what
changes the most if compared to previous results is the
effect of the affective polarization index, which is now
one‐fourth of that in Column 3. This is due to the fact
that affective polarization captured the effect of some
of our controls. In order to fully understand the mech‐
anisms driving this result, we re‐estimated the model
in Column 3 by adding one control at a time. We do
not report the results of this exercise in this article for
the sake of brevity, but they are available upon request. We find that only the degree of extremeness and interest
in politics affect our findings regarding affective polariza‐
tion. 4. Results When we include the degree of extremeness, the
coefficient of affective polarization reduces from 0.353
(Column 3) to 0.228 (p‐value 0.00). This (partial) reduc‐
tion can be explained by the fact that extreme voters
may have more extreme (negative) feelings towards sup‐
porters of other parties. However, as shown in Bettarelli
and Van Haute (2022a), affective polarization also oper‐
ates from moderate to extreme voters, thus leaving room
for an independent effect of the affective polarization
index. Contrarily, when Polint is included, the coefficient
of affective polarization drops from 0.353 (column 3) to
0.102 (p‐value 0.18), signaling on one side that people
who show high levels of affective polarization are those
who care the most about politics and, on the other side,
that affective polarization is not only related to affect but
is also greatly connected to cognitive processes. In Columns 3 and 4, we introduce the affective polar‐
ization index, without and with the groups of emo‐
tions, respectively. We do so to test the stability of the
coefficient associated with affective polarization when
included simultaneously with other political and emo‐
tional states. Results reassure us of the independent rela‐
tionship between affective polarization, as its coefficient
does not vary much between the two models. As indi‐
cated by Column 3, all else equal, affective polarization
positively correlates with participation in protest action
(H2 supported). Note that the coefficient associated with
the hopeful group becomes significant (with a negative
sign). This indicates that, even if positive feelings towards
national politics are broadly related to a lower propensity
to protest, there may be a subset of politically hopeful
respondents who engage in protest action because they
dislike (some of) supporters of other parties, thus par‐
tially biasing results in Column 1. Finally, in Column 4, we test if previous results are
robust to the inclusion of the set of controls intro‐
duced in Section 3.3.3. Before commenting on our main
explanatory variables (i.e., emotional groups and affec‐
tive polarization), we observe the behavior of the con‐
trols. The sign and significance level of coefficients
denote that participation in protest action is not linked
to the gender of respondents, while it is higher among
younger respondents with a higher level of education. Moreover, it is lower among well‐off people. 4. Results Table 7 presents the results of our regression analyses. First, we introduce the groups of respondents by type of Table 7. Regression results. (1)
(2)
(3)
(4)
Protest
Protest
Protest
Protest
Affpol (std)
0.362***
0.353***
0.085*
(0.042)
(0.043)
(0.045)
Groups (Emotions)
Average (baseline)
Apathy
−1.142***
−1.04***
−0.528***
(0.136)
(0.146)
(0.139)
Hopeful
−0.128
−.316**
−0.319**
(0.127)
(0.133)
(0.133)
Angry
0.043
−0.042
0.171*
(0.09)
(0.094)
(0.097)
Highly emotional
1.363***
1.016***
0.828***
(0.173)
(0.175)
(0.153)
Gender
−0.13
(0.079)
Age (std)
−0.39***
(0.041)
Education (std)
0.113***
(0.04)
Income (std)
−0.078*
(0.042)
Left_right (std)
−0.254***
(0.042)
Extremeness (std)
0.227***
(0.045)
Satisfaction with democracy (std)
−0.044
(0.048)
Political interest (std)
0.836***
(0.045)
Observations
6,894
5,990
5,829
5,753
R2
0.073
0.049
0.072
0.192
NUTS‐3 dummies
Yes
Yes
Yes
Yes
Notes: Robust standard errors are in parentheses; *** p < 0.01, ** p < 0.05, * p < 0.1. Politics and Governance, 2022, Volume 10, Issue 4, Pages X–X
8 Table 7. Regression results. (1)
(2)
(3)
(4)
Protest
Protest
Protest
Protest
Affpol (std)
0.362***
0.353***
0.085*
(0.042)
(0.043)
(0.045)
Groups (Emotions)
Average (baseline)
Apathy
−1.142***
−1.04***
−0.528***
(0.136)
(0.146)
(0.139)
Hopeful
−0.128
−.316**
−0.319**
(0.127)
(0.133)
(0.133)
Angry
0.043
−0.042
0.171*
(0.09)
(0.094)
(0.097)
Highly emotional
1.363***
1.016***
0.828***
(0.173)
(0.175)
(0.153)
Gender
−0.13
(0.079)
Age (std)
−0.39***
(0.041)
Education (std)
0.113***
(0.04)
Income (std)
−0.078*
(0.042)
Left_right (std)
−0.254***
(0.042)
Extremeness (std)
0.227***
(0.045)
Satisfaction with democracy (std)
−0.044
(0.048)
Political interest (std)
0.836***
(0.045)
Observations
6,894
5,990
5,829
5,753
R2
0.073
0.049
0.072
0.192
NUTS‐3 dummies
Yes
Yes
Yes
Yes
Notes: Robust standard errors are in parentheses; *** p < 0.01, ** p < 0.05, * p < 0.1. Politics and Governance, 2022, Volume 10, Issue 4, Pages X–X
8 8 level. These results indicate that positive or negative
emotions alone do not contribute to increasing the
propensity to engage in protest action. Protest partici‐
pation is significantly larger than in the average group
only for the highly emotional group, with a value of the
coefficient much larger than any other category. In fact,
the difference between apathetic and highly emotional
respondents, those registering the lowest and highest
probability of protest participation, respectively, is over
two points. These results provide a relevant message:
Protest participation is connected to the joint action of
positive (hope) and negative (anger) emotions towards
politics, thus supporting H1. Politics and Governance, 2022, Volume 10, Issue 4, Pages X–X 4. Results If we switch
the attention to political‐related controls, we note that
participation in protest action is also higher among
respondents who position themselves to the left of the
ideological spectrum, or among those who hold more
extreme political views. Finally, the degree of satisfaction In addition to these analyses, we want to explore fur‐
ther how the two dimensions of affect relate to protest
participation. We are interested in how the two dimen‐
sions interact, as their combined impact on protest par‐
ticipation may vary according to the specific combination
of the two. The interaction between these two dimen‐
sions of affect remains largely unexplored, yet it could
provide novel insight concerning the drivers of protest
participation. For instance, affective polarization may 9 operate either as a substitute or a complement of emo‐
tions. In the former scenario, a high degree of affective
polarization would compensate for the lack of emotion
towards politics. Or, in other words, horizontal affects
driving people to participate in protest action predom‐
inate over vertical. Contrarily, if the effect of affective
polarization is stronger when emotions are high, it would
signal that the horizontal and vertical dimensions rein‐
force each other. from ca. −2.6 to +2.7, with higher values corresponding
to higher degrees of both hope and anger (i.e., the highly
emotional category). Figure 2 below shows the mean of
pol_feel by groups of emotions and further corroborates
the validity of the PCA exercise. Next, we run a regression model where we inter‐
act the two variables of interest, namely affective polar‐
ization and pol_feel, together with the standard set of
controls as in Column 4 (Table 7). Figure 3 below plots
the average marginal effects. Results suggest a substi‐
tution dynamic: The effect of affective polarization is
large in magnitude and statistically significant for low lev‐
els of pol_feel (i.e., apathetic respondents). Contrarily,
its impact drastically decreases as much as the pol_feel
index increases, and it becomes not significant for the
highly emotional respondents. To better investigate this interaction and to ease the
interpretation of results, we collapse the categories of
emotions into a unique continuous variable by means
of a PCA involving individuals’ self‐reported degree of
anger and hope. We consider the component that posi‐
tively correlatesthe twoemotions. Politics and Governance, 2022, Volume 10, Issue 4, Pages X–X 5. Discussion and Limitations Our analysis has focused on the specific case of Belgium
inthe 2019 (pre‐)electoralsequence. This raisesthe ques‐
tion of the generalisability of the findings. g
y
g
Belgium is often described as a multipartisan conso‐
ciational democracy characterized by a culture of politi‐
cal compromise and by social concertation (Delwit, 2022;
Deschouwer, 2012). It has consequences on action reper‐
toires. Protest action, especially in the form of mass
demonstrations, is quite common and structured by civil
society organizations such as unions. These organizations
are linked to the state, which is relatively permeable
and open to social movements. Demonstrations are usu‐
ally peaceful and welcome a broad range of citizens—
not exclusively the most extremist or desperate activists. In majoritarian democracies where social movements
and the state operate in a more confrontational rela‐
tionship (such as France or the US), one could expect a
stronger and more isolated effect of anger and a lower
effect of hope, as well as a stronger effect of affective
polarization. Yet while the consociational nature of the
Belgian political system usually produces broad coali‐
tion governments representing most segments of society,
the 2014–2019 government leaned particularly towards
the right end of the spectrum, affecting the capacity of
left‐wing movements (and especially workers’ organiza‐
tions) to influence government policies. This created a cli‐
mate of social unrest. The relationship between left‐wing
self‐placement and protest uncovered in the models par‐
tially reflects that context. Moreover, this context may
have exacerbated the role of negative feelings between
social groups, hence, affective polarization, as well as
distrust and dissatisfaction towards the national govern‐
ment. This specific context tends to offset the specificities
mentioned above and brings our findings closer to what
one could expect in majoritarian democracies, enhancing
the generalizability of our results to other settings. Finally, our study does not examine the mechanisms
linking affective states to protest action. Emotions may
lead to (negative) evaluation or judgment about politics
(see Webster, 2018), and this judgment would lead to
action. In this case, emotions would indirectly influence
protest behavior. But emotions could also derive from a
cognitive appraisal of the situation and could work as a
catalyst for engagement in protest behavior. Regarding
affective polarization, we discussed two mechanisms in
our theoretical section: One connects affective polariza‐
tion to political interest and politicization; another con‐
nects affective polarization to in‐ and out‐group identity‐
building dynamics. 4. Results The resulting variable,
which we refer to as political feelings (pol_feel), ranges 2
1
mean of pol_feel
0
–1
–2
apathy
hopeful
angry
highly emo onal
Figure 2. Mean of pol_feel, by groups. Average marginal effects of Affpol (std) with 95% Cls
–2.6
–0.4
–0.2
0
0.2
0.4
0.6
–1.6
–0.6
0.4
1.4
2.4
Figure 3. Average marginal effect of affective polarization on protest participation when pol_feel increases (i.e., from no
emotions to high emotions). Note: CI stands for Confidence Interval. Politics and Governance, 2022, Volume 10, Issue 4, Pages X–X
10 2
1
mean of pol_feel
0
–1
–2
apathy
hopeful
angry
highly emo onal
Figure 2. Mean of pol_feel, by groups. Figure 2. Mean of pol_feel, by groups. Average marginal effects of Affpol (std) with 95% Cls
–2.6
–0.4
–0.2
0
0.2
0.4
0.6
–1.6
–0.6
0.4
1.4
2.4 Average marginal effects of Affpol (std) with 95% Cls Figure 3. Average marginal effect of affective polarization on protest participation when pol_feel increases (i.e., from no
emotions to high emotions). Note: CI stands for Confidence Interval. Politics and Governance, 2022, Volume 10, Issue 4, Pages X–X 10 Our findings are also limited by the methodology
adopted in the study. Given that all our measurements
are from the same wave of the RepResent survey, the
design prevents us from asserting any causal relation‐
ship between the variables, nor can we be sure about
the direction of any such potential relationship. While
theoretically, we could expect affect to influence polit‐
ical behavior, participation in protest action could also
create or reinforce emotions towards politics, both nega‐
tive and positive, as well as affective polarization. Social
interactions with like‐minded peers in collective action,
for instance, could reinforce affective predispositions,
which are shared within the group, as suggested by
social movement theories. The roots of the emotional
reactions investigated in this article would deserve spe‐
cific attention. To sum up, affective polarization is positively related
to protest participation. Moreover, it acts as a substi‐
tute for apathy and may stimulate protest participa‐
tion among people who do not have strong emotions
towards politics. 5. Discussion and Limitations Yet our empirical strategy does not
allow us to disentangle these underlying mechanisms,
and further research is needed to provide greater insight
in this regard. Our findings nevertheless contribute to
stimulating the debate. Politics and Governance, 2022, Volume 10, Issue 4, Pages X–X 6. Conclusion This article has sought to better understand the role of
affect in protest behaviors. We investigate two dimen‐
sions of affect. On the vertical dimension, we go beyond
the effect of one discrete emotion at a time. Our LCA
distinguishes five categories of citizens based on their
emotions towards politics: apathetic, angry, hopeful,
highly emotional, and average. This is the first impor‐
tant contribution of the article: We show how sets of
positive and negative emotions can combine simultane‐
ously in diverse manners and “produce” types of citi‐
zens who respond emotionally to politics in very differ‐
ent ways. The behavioral consequences of these combi‐
nations deserve further attention. We demonstrate that
protest behaviors are the highest among citizens display‐
ing a combination of high anger and hope, and the lowest
among apathetic citizens who display an absence of posi‐
tive or negative emotions towards politics. This is the sec‐
ond important contribution of the article. We show that
being angry can mobilize protesters but that the combi‐
nation of anger and hope can be even more connected to
protest action than anger alone. Hope—suggesting a pos‐
itive or optimistic appraisal of the future—can be crucial In addition, 2019 was particularly marked by climate
mobilizations, including school strikes and demonstra‐
tions (Wouters et al., 2022). Given the nature and objec‐
tives of these pro‐environmental collective actions, our
findings may overestimate the role of positive emotions
such as hope (Landmann & Rohmann, 2020). However,
our analyses focus on the general population and not
the specific segment of climate activists. Wouters et al. (2022) also show that participants in climate mobiliza‐
tions were younger and less politically experienced than
typical demonstrators. This could partly explain the neg‐
ative relationship we uncover between age and protest,
although it is a common pattern in protest participation
(Marien et al., 2010). Politics and Governance, 2022, Volume 10, Issue 4, Pages X–X 11 identity politics. In S. Stryker, T. J. Owens, & R. W. White (Eds.), Self, identity, and social movements (pp. 252–270). University of Minnesota Press. for political engagement. Yet hope alone does not seem
to activate protest. On the horizontal dimension, we show that protest
behaviors are highest among citizens displaying higher
levels of affective polarization, that is, higher levels of
dislike of political opponents. In this case, negativity is
key. Interestingly, we also show that the two dimensions
are distinct drivers of protest. 6. Conclusion This is the third impor‐
tant contribution of the article: Affect is crucial to better
understand protest behaviors and different dimensions
of affect matter. Capelos, T., & Demertzis, N. (2018). Political action and
resentful affectivity in critical times. Humanity & Soci‐
ety, 42(4), 410–433. Castells, M. (2012). Networks of outrage and hope: Social
movements in the internet age. Polity Press. Close, C., & van Haute, E. (2020). Emotions and vote
choice: An analysis of the 2019 Belgian elections. Pol‐
itics of the Low Countries, 2(3), 353–379. Dalton, R. J. (2008). The quantity and the quality of party
systems: Party system polarization, its measurement,
and its consequences. Comparative Political Studies,
41(7), 899–920. Lastly, we show that the two dimensions of affect
interact. We knew from previous research that affective
polarization has mobilization potential. We now better
understand how this mobilization works: By appealing to
a different dimension of affect, it can mobilize otherwise
apathetic citizens. This is the fourth important contribu‐
tion of the article. Nurturing a dislike of political oppo‐
nents can make up for the absence of emotions towards
politics. This could be a key to better understanding the
dynamics of radical parties and leaders. Delwit, P. (2022). La vie politique en Belgique de 1830 à
nos jours [The political life in Belgium from 1830 to
nowadays]. Editions de l’Université de Bruxelles. Deschouwer, K. (2012). The politics of Belgium: Govern‐
ing a divided society. Red Globe Press. De Winter, L. (2019). Government coalitions as a reflec‐
tion of national politics: The complex case of Belgium. In M. Evans (Ed.), Coalition government as a reflec‐
tion of a nation’s politics and society (pp. 64–85). Routledge. Acknowledgments Bettarelli received funding from the European Union’s
Horizon 2020 research and innovation programme
under the Marie Sklodowska‐Curie Grant Agreement
No. 801505. Van Haute received funding from the
FWO‐FNRS EoS Grant No. 30431006. Dornschneider, S. (2020). Hot contention, cool absten‐
tion: Positive emotions and protest behavior during
the Arab Spring. Oxford University Press. Druckman, J. N., & Levendusky, M. S. (2019). What do
we measure when we measure affective polarization. Public Opinion Quarterly, 83(1), 114–122. Conflict of Interests Gaffney, A. M., Hackett, J. D., Rast, D. E., III, Hohman, Z. P.,
& Jaurique, A. (2018). The state of American protest:
Shared anger and populism. Analyses of Social Issues
and Public Policy, 18(1), 11–33. The authors declare no conflict of interests. References Schumacher, G., Rooduijn, M., & Bakker, B. (2022). Hot
populism? Affective responses to antiestablishment
rhetoric. Political Psychology, 43(5), 851–871. Kingzette, J., Druckman, J. N., Klar, S., Krupnikov, Y., Lev‐
endusky, M. S., & Ryan, J. (2021). How affective polar‐
ization undermines support for democratic norms. Public Opinion Quarterly, 85(2), 663–677. Valentino, N. A., Hutchings, V. L., Banks, A. J., & Davis,
A. K. (2008). Is a worried citizen a good citizen? Emo‐
tions, political information seeking, and learning via
the internet. Political Psychology, 29(2), 247–273. Landmann, H., & Rohmann, A. (2020). Being moved
by protest: Collective efficacy beliefs and injus‐
tice appraisals enhance collective action inten‐
tions for forest protection via positive and nega‐
tive emotions. Journal of Environmental Psychology,
71, Article 101491. https://doi.org/10.1016/j.jenvp. 2020.101491 van Erkel, P., & Turkenburg, E. (2020). Attitudes dif‐
férentes, comportements électoraux différents, sen‐
timents différents? [Different attitudes, different
electoral behaviours, different sentiments?]. In J.‐B. Pilet, P. Baudewyns, K. Deschouwer, A. Kern & J. Lefe‐
vere (Eds.), Les Belges haussent leur voix [The Bel‐
gians raise their voice] (pp. 153–173). Presses Univer‐
sitaires de Louvain. Lerner, J. S., & Keltner, D. (2001). Fear, anger, and risk. Journal of Personality and Social Psychology, 81(1),
146–159. Vasilopoulos, P., Marcus, G. E., Valentino, N. A., & Fou‐
cault, M. (2019). Fear, anger, and voting for the far
right: Evidence from the November 13, 2015 Paris ter‐
ror attacks. Political Psychology, 40(4), 679–704. Marcus, G. E. (2000). Emotions in politics. Annual Review
of Political Science, 3, 221–250. Vasilopoulou, S., & Wagner, M. (2017). Fear, anger and
enthusiasm about the European Union: Effects of
emotional reactions on public preferences towards
European integration. European Union Politics, 18(3),
382–405. Marcus, G. E., Valentino, N. A., Vasilopoulos, P., & Fou‐
cault, M. (2019). Applying the theory of affective
intelligence to support for authoritarian policies and
parties. Political Psychology, 40(S1), 109–139. Marien, S., Hooghe, M., & Quintelier, E. (2010). Inequali‐
ties in non‐institutionalised forms of political partici‐
pation: A multi‐level analysis of 25 countries. Political
Studies, 58(1), 187–213. Wagner, M. (2021). Affective polarization in multiparty
systems. Electoral Studies, 69, Article 102199. Walgrave, S., Celis, K., Deschouwer, K., Marien, S., Pilet,
J.‐B., Rihoux, B., Van Haute, E., Van Ingelgom, V.,
Baudewyns, P., Van Erkel, P., Jennart, I., Lefevere, J.,
& Kern, A. (2022). RepResent longitudinal survey
2019–2021. DANS. https://doi.org/10.17026/dans‐
xf5‐djem Mason, L. (2018). Uncivil agreement: How politics
became our identity. University of Chicago Press. References Gidron, N., Adams, J., & Horne, W. (2020). Ameri‐
can affective polarization in comparative perspective. Cambridge University Press. Abramowitz, A. I., & Saunders, K. L. (2008). Is polarization
a myth? The Journal of Politics, 70(2), 542–555. Altomonte, C., Gennaro, G., & Passarelli, F. (2019). Collec‐
tive emotions and protest vote (CESifo Working Paper
No. 7463). CESifo. Harteveld, E., & Wagner, M. (2022). Does affective
polarisation increase turnout? Evidence from Ger‐
many, the Netherlands and Spain. West European
Politics. Advance online publication. https://doi.org/
10.1080/01402382.2022.2087395 Bettarelli, L., Reiljan, A., & Van Haute, E. (2022). A regional perspective to the study of affective
polarization. European Journal of Political Research. Advance online publication. https://doi.org/
10.1111/1475‐6765.12548 Hetherington, M. J., & Rudolph, T. J. (2015). Why Wash‐
ington won’t work: Polarization, political trust, and
the governing crisis. University of Chicago Press. Iyengar, S., Lelkes, Y., Levendusky, M. S., Malhotra, N.,
& Westwood, S. J. (2019). The origins and conse‐
quences of affective polarization in the United States. Annual Review of Political Science, 22(1), 129–146. Bettarelli, L., & Van Haute, E. (2022a). Affective polariza‐
tion and coalition preferences in times of pandemic. Frontiers in Political Science, 4. https://doi.org/
10.3389/fpos.2022.945161 Bettarelli, L., & Van Haute, E. (2022b). Regional inequali‐
ties as drivers of affective polarization. Regional Stud‐
ies, Regional Science, 9(1), 549–570. https://doi.org/
10.1080/21681376.2022.2117077 Iyengar, S., Sood, G., & Lelkes, Y. (2012). Affect, not ide‐
ology: A social identity perspective on polarization. Public Opinion Quarterly, 76(3), 405–431. Jasper, J. M. (1998). The emotions of protest: Affective
and reactive emotions in and around social move‐
ments. Sociological Forum, 13(3), 397–424. Brady, H. E., Verba, S., & Schlozman, K. L. (1995). Beyond
SES: A resource model of political participation. American Political Science Review, 89(2), 271–294. Brady, H. E., Verba, S., & Schlozman, K. L. (1995). Beyond
SES: A resource model of political participation. American Political Science Review, 89(2), 271–294. Britt, L., & Heise, D. (2000). From shame to pride in Jasper, J. M. (2014a). Constructing indignation: Anger
dynamics in protest movements. Emotion Review, ,
( ),
Britt, L., & Heise, D. (2000). From shame to pride in Politics and Governance, 2022, Volume 10, Issue 4, Pages X–X 12 right‐wing political populism. Social Science Informa‐
tion, 56(4), 567–595. 6(3), 208–213. Jasper, J. M. (2014b). Emotions, sociology and protest. In
C. von Scheve & M. Salmella (Eds.), Collective emo‐
tions: Perspectives from psychology, philosophy, and
sociology (pp. 341–355). Oxford University Press. References Melucci, A. (1995). The process of collective identity. In
H. Johnston & B. Klandermans (Eds.), Social move‐
ments and cutlure (pp. 41–63). Routledge. Nikolayenko, O. (2022). “I am tired of being afraid”: Emo‐
tions and protest participation in Belarus. Interna‐
tional Sociology, 37(1), 78–96. Ward, D., & Tavits, M. (2019). How partisan affect shapes
citizens’ perception of the political world. Electoral
Studies, 60(4), Article 102045. Pilet, J.‐B., Baudewyns, P., Deschouwer, K., Kern, A., &
Lefevere, J. (2020). Les Belges haussent leur voix [The
Belgians raise their voice]. Presses Universitaires de
Louvain. Webster, S. W. (2018). Anger and declining trust in gov‐
ernment in the American electorate. Political Behav‐
ior, 40(4), 933–964. Webster, S. W., & Albertson, B. (2022). Emotion and
politics: Noncognitive psychological biases in public
opinion. Annual Review of Political Science, 25(1),
401–418. Polletta, F., & Jasper, J. M. (2001). Collective identity and
social movements. Annual Review of Sociology, 27,
283–305. Reiljan, A. (2020). “Fear and loathing across party lines”
(also) in Europe: Affective polarisation in European
party systems. European Journal of Political Research,
59(2), 376–396. Wouters, R., De Vydt, M., & Staes, L. (2022). Truly excep‐
tional? Participants in the Belgian 2019 Youth for
Climate protest wave. Politics of the Low Countries. Advance online publication. Salmela, M., & von Scheve, C. (2017). Emotional roots of Salmela, M., & von Scheve, C. (2017). Emotional roots of Salmela, M., & von Scheve, C. (2017). Emotional roots of Politics and Governance, 2022, Volume 10, Issue 4, Pages X–X About the Authors Luca Bettarelli is a Marie‐Curie individual fellow at the Centre d’Étude de la Vie Politique (CEVIPOL,
Université Libre de Bruxelles). He holds a PhD in political economics from the University of Milan‐
Bicocca. He has been a consultant for various international institutions, such as the World Bank
and the International Monetary Fund. He is the editorial manager of the Italian Journal of Regional
Science. His research focuses on the drivers and consequences of political polarization across individ‐
uals and territories. Politics and Governance, 2022, Volume 10, Issue 4, Pages X–X 13 Caroline Close is a professor in the Department of Political Science at the Université Libre de Bruxelles
and a researcher at the Centre d’Étude de la Vie Politique (CEVIPOL). Her research interests include
party politics, political behavior, representation, and democratic innovations. Her work has appeared
in Party Politics, Acta Politica, Parliamentary Affairs, Political Studies, and Representation. Emilie van Haute is a professor at the Université Libre de Bruxelles and a researcher at the Centre
d’Étude de la Vie Politique (CEVIPOL). Her research interests focus on political parties, elections, par‐
ticipation, and representation. Her research has appeared in West European Politics, Party Politics,
Electoral Studies, Political Studies, and European Journal of Political Research. She is co‐editor of Acta
Politica. Caroline Close is a professor in the Department of Political Science at the Université Libre de Bruxelles
and a researcher at the Centre d’Étude de la Vie Politique (CEVIPOL). Her research interests include
party politics, political behavior, representation, and democratic innovations. Her work has appeared
in Party Politics, Acta Politica, Parliamentary Affairs, Political Studies, and Representation. Emilie van Haute is a professor at the Université Libre de Bruxelles and a researcher at the Centre
d’Étude de la Vie Politique (CEVIPOL). Her research interests focus on political parties, elections, par‐
ticipation, and representation. Her research has appeared in West European Politics, Party Politics,
Electoral Studies, Political Studies, and European Journal of Political Research. She is co‐editor of Acta
Politica. 14
|
https://openalex.org/W4220758769
|
https://link.springer.com/content/pdf/10.1007/s10664-022-10141-6.pdf
|
English
| null |
Correction to: Uniform and scalable sampling of highly configurable systems
|
Empirical software engineering
| 2,022
|
cc-by
| 502
|
https://doi.org/10.1007/s10664-022-10141-6
Empirical Software Engineering (2022) 27: 57 https://doi.org/10.1007/s10664-022-10141-6
Empirical Software Engineering (2022) 27: 57 AUTHOR CORRECTION The online version of the original article can be found at https://doi.org/10.1007/s10664-021-10102-5 2
University of Seville, Seville, Spain Correction to: Uniform and scalable sampling of highly
configurable systems Ruben Heradio1
& David Fernandez-Amoros1 & José A. Galindo2 &
David Benavides2 & Don Batory3 Ruben Heradio1
& David Fernandez-Amoros1 & José A. Galindo2 &
David Benavides2 & Don Batory3 # The Author(s) 2022
Published online: 14 March 2022 # The Author(s) 2022
Published online: 14 March 2022 Correction to: Empir Software Eng (2022) 27: 44
https://doi.org/10.1007/s10664-021-10102-5 Correction to: Empir Software Eng (2022) 27: 44
https://doi.org/10.1007/s10664-021-10102-5 The original version of this article, unfortunately, contained mistakes. The title of Section 2.2.3
should be "Method 3: Measure the distance between the theoretical variable probabilities with
the empirical variable frequencies in a sample", and the title of Section 2.2.4 should be
"Method 4: A statistical goodness-of-fit test that compares the theoretical variable probabilities
with the empirical variable frequencies in a sample". The original article has been corrected. The original article has been corrected. 1
Universidad Nacional de Educación a Distancia, Madrid, Spain 3
University of Texas at Austin, Austin, TX, USA The online version of the original article can be found at https://doi.org/10.1007/s10664-021-10102-5
* Ruben Heradio
rheradio@issi.uned.es
David Fernandez-Amoros
david@issi.uned.es
José A. Galindo
jagalindo@us.es
David Benavides
benavides@us.es
Don Batory
batory@cs.utexas.edu
1
Universidad Nacional de Educación a Distancia, Madrid, Spain
2
University of Seville, Seville, Spain
3
University of Texas at Austin, Austin, TX, USA The online version of the original article can be found at https://doi.org/10.1007/s10664-021-10102-5 * Ruben Heradio
rheradio@issi.uned.es
David Fernandez-Amoros
david@issi.uned.es
José A. Galindo
jagalindo@us.es
David Benavides
benavides@us.es
Don Batory
batory@cs.utexas.edu
1
Universidad Nacional de Educación a Distancia, Madrid, Spain
2
University of Seville, Seville, Spain
3
University of Texas at Austin, Austin, TX, USA * Ruben Heradio
rheradio@issi.uned.es David Fernandez-Amoros
david@issi.uned.es 1
Universidad Nacional de Educación a Distancia, Madrid, Spain 1
Universidad Nacional de Educación a Distancia, Madrid, Spain 2
University of Seville, Seville, Spain 2
University of Seville, Seville, Spain 57
Page 2 of 2 Empirical Software Engineering (2022) 27: 57 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which
permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give
appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and
indicate if changes were made. The images or other third party material in this article are included in the article's
Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included
in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or
exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy
of this licence, visit http://creativecommons.org/licenses/by/4.0/. Publisher's note Springer Nature remains neutral with regard to jurisdictional claims in published maps and
institutional affiliations.
|
https://openalex.org/W3112550329
|
https://dergipark.org.tr/en/download/article-file/1364190
|
English
| null |
Effect of BMI on Fundamental Motor Skill Proficiency Among 9 to 10 years-old Turkish Children
|
Uluslararası spor egzersiz ve antrenman bilimi dergisi
| 2,020
|
cc-by
| 4,672
|
Vol 6, Issue 4, 110–116 (2020)
Original Article
http://dergipark.gov.tr/useeabd
Effect of BMI on Fundamental Motor Skill Proficiency Among 9 to 10
years-old Turkish Children
Fatma lker KERKEZ1, Varol TUTAL2
Abstract
Keywords
Aim: To examine the effect of body mass index (BMI) on Fundamental Motor Skill Proficiency
among 9 to 10 years-old Turkish children.
Methods: A total of 214 children (mean age 9.45±0.49) were included in the study (110 girls,
104 boys). Fundamental Motor Skill Proficiency was assessed with the Test of Gross Motor
Development-Second Edition (TGMD-2). Body mass index (BMI) was calculated according to
the formula [kg/height2] after the height and weight measurement for each child and classified
according to The Centers for Disease Control and Prevention Agency (CDC) guidelines.
Results: 72% of the children have a healthy weight, 14.5% were overweight and 13.6% were
obese. The ratio of overweight and obese is higher for boys than for girls. There was a
significant difference between BMI groups in terms of TGMD-2 locomotor subtest scores (p
<0.05), but no significant difference in terms of manipulative subtests. It can be said that being
overweight restricts mobility for Turkish children but does not affect object control skills that
doing the mostly static position.
Conclusion: This study demonstrates inadequate fundamental motor skills proficiency levels
among Turkish 9-10 years old children. Childhood education centers should provide 'planned'
movement programs under the supervision of physical education teachers in order to support
motor skills development and prevent obesity among Turkish children.
Motor Skill Proficiency,
BMI,
9-10 years-old,
children.
Article Info
Received: 26.10.2020
Accepted: 14.12.2020
Online Published: 15.12.2020
DOI:10.18826/useeabd.816482 Vol 6, Issue 4, 110–116 (2020)
Original Article
http://dergipark.gov.tr/useeabd
Effect of BMI on Fundamental Motor Skill Proficiency Among 9 to 10
years-old Turkish Children
Fatma lker KERKEZ1, Varol TUTAL2
Abstract
Keywords
Aim: To examine the effect of body mass index (BMI) on Fundamental Motor Skill Proficiency
among 9 to 10 years-old Turkish children. Methods: A total of 214 children (mean age 9.45±0.49) were included in the study (110 girls,
104 boys). Fundamental Motor Skill Proficiency was assessed with the Test of Gross Motor
Development-Second Edition (TGMD-2). Body mass index (BMI) was calculated according to
the formula [kg/height2] after the height and weight measurement for each child and classified
according to The Centers for Disease Control and Prevention Agency (CDC) guidelines. Results: 72% of the children have a healthy weight, 14.5% were overweight and 13.6% were
obese. The ratio of overweight and obese is higher for boys than for girls. There was a
significant difference between BMI groups in terms of TGMD-2 locomotor subtest scores (p
<0.05), but no significant difference in terms of manipulative subtests. It can be said that being
overweight restricts mobility for Turkish children but does not affect object control skills that
doing the mostly static position. Conclusion: This study demonstrates inadequate fundamental motor skills proficiency levels
among Turkish 9-10 years old children. Childhood education centers should provide 'planned'
movement programs under the supervision of physical education teachers in order to support
motor skills development and prevent obesity among Turkish children. Motor Skill Proficiency,
BMI,
9-10 years-old,
children. Article Info
Received: 26.10.2020
Accepted: 14.12.2020
Online Published: 15.12.2020
DOI:10.18826/useeabd.816482 ffect of BMI on Fundamental Motor Skill Proficiency Among 9 to 10
ears-old Turkish Children Abstract Keywords y
Aim: To examine the effect of body mass index (BMI) on Fundamental Motor Skill Proficiency
among 9 to 10 years-old Turkish children. Motor Skill Proficiency,
BMI, g
y
Methods: A total of 214 children (mean age 9.45±0.49) were included in the study (110 girls,
104 boys). Fundamental Motor Skill Proficiency was assessed with the Test of Gross Motor
Development-Second Edition (TGMD-2). Body mass index (BMI) was calculated according to
the formula [kg/height2] after the height and weight measurement for each child and classified
according to The Centers for Disease Control and Prevention Agency (CDC) guidelines. Results: 72% of the children have a healthy weight, 14.5% were overweight and 13.6% were
obese. The ratio of overweight and obese is higher for boys than for girls. There was a
significant difference between BMI groups in terms of TGMD-2 locomotor subtest scores (p
<0.05), but no significant difference in terms of manipulative subtests. It can be said that being
overweight restricts mobility for Turkish children but does not affect object control skills that
doing the mostly static position. g
y
p
Conclusion: This study demonstrates inadequate fundamental motor skills proficiency levels
among Turkish 9-10 years old children. Childhood education centers should provide 'planned'
movement programs under the supervision of physical education teachers in order to support
motor skills development and prevent obesity among Turkish children. p p
p
1Corresponding author: Faculty of Sports Sciences, Muğla Sıtkı Koçman University, Muğla/Turkey, fatmakerkez@mu.edu.tr ORCID ID:0000-0002-5485-1834
2Faculty of Sports Sciences, Siirt University, Siirt/Turkey, v.tutal@siirt.edu.tr, ORCID ID: 0000-0001-5647-9370 Effect of BMI on Fundamental Motor Skill Proficiency Among 9 to 10
years-old Turkish Children Fatma lker KERKEZ1, Varol TUTAL2 The role and contributions of each authors as in the section of IJSETS Writing Rules “Criteria for Authorship” is reported that: 1. Author: The study designing;
collecting, analyzing and interpretation data and manuscript preparation, 2. Author: The study designing; collecting, analyzing and interpretation data and
manuscript preparation. Fatma lker KERKEZ1, Varol TUTAL2 Fatma lker KERKEZ1, Varol TUTAL2 INTRODUCTION Fundamental motor skills are common motor activities with specific observable models. Most skills
used in sports, dance, physical fitness, and other movement activities are advanced versions of
fundamental motor skills. For example, handball, tennis service or javelin throws are the advanced forms
of basic overhand throwing (Gallahue et al., 2012). The fundamental motor skills are classified
according to their functions as stability (non-locomotor), movement (locomotor) and object control
skills (manipulative). The main factors affecting the acquisition of fundamental motor skills are the
characteristics of the child (age, physical characteristics, gender, ability, interest, motivation),
environmental factors (family, friends, living environment, economic status, etc.) and the requirements
of the task. Although children have the potential to specialize in most FMSs until the age of 6. The
development rate is highly individual and depends on practice opportunities (Gallahue et al., 2012). In
the literature, it is stated that physical activity opportunities are not sufficiently provided for the
development of fundamental motor skills in children (Stodden et al., 2008; Whitehead, 2010). The situation is not different in Turkey. Preschool education is not compulsory in Turkey. The
preschool curriculum published by the Ministry of Education (2019) has motor development
achievements, which are movement (changing position), stability movements, object control
movements, movements that require the use of small muscles, and movements accompanied by music
and rhythm. In the program, it is stated that the movement activity can be used to support the motor
development of the children and to gain the movement skills as well as a transition activity, and also
that the activities should last at least 30 minutes (the first 5 minutes being warming up games, 20 minutes
of repetition of previous activity and new fundamental movement skills and last 5 minutes being cooling
activities) and could take place in the classroom or outdoors in the yard. As can be seen, the program
fails to meet the recommended physical activity level by the World Health Organization (2011) for the
5 to 17 age group both in theory and in practice: the WHO recommends at least 60 minutes of moderate
to severe daily aerobic physical activity for this age group. In the elementary schools, the name of the 110 Int J Sport, Exer & Train Sci, 2020, Vol 6, Issue 4, 110–116 FI. Kerkez, V. Participants Participants of the study were 214 healthy children (110 girls, 104 boys) aged 9 to 10 years (mean age
9.45 ± 0.49 years) who reside in the city center of Malatya province in Turkey. Schools that were
recruited were from various socioeconomic backgrounds. According to Ministiry of Education 2012-
2013 statistics, there was 56.221 primary school students in Malatya. In order to represent the universe,
an average of 400 students were determined as a sample on a voluntary basis and randomly, taking into
account 5% sampling error. In addition to the Ethics Committee approval that was obtained from the
Inonu University (2013-152), consent forms were also obtained from parent and children for the study. 258 of 400 families whose consent forms were sent agreed to participate in the study, 214 children were
reached on the days of measurement. INTRODUCTION Tutal class, which was "Game and Physical Activities" until 2018, has been changed to "Physical Education
and Game" and it is taught by the classroom teacher 5 hours per week for 1st, 2nd, and 3rd graders and
2 hours per week for 4th graders. However, there are findings suggest that the classroom teachers use
the play and physical education classes in order to make up for other classes, that teachers are not
supported by school administrations in terms of materials and location, and that it would be beneficial
to have physical education teachers to teach play and physical activities classes starting from the 1st
grade (Guven & Yıldız, 2014). The effect of insufficient practice opportunities on the fundamental motor skills development
among Turkish children has not been examined in depth. However, there are few studies examining
motor development in general (Boz & Gungor Aytar, 2012; Ersoz, 2012; Ulutas et al., 2017). According to the OECD report (2016) on obesity rates among Turkish adults 28.8% of are obese. Obesity continues to increase despite the efforts of the Turkish Ministry of Health's Healthy Nutrition
and Active Life Program since 2013. "Promoting Physical Activity 2015-2018" project, one of the
projects implemented for this purpose, delivered one million bicycles to schools, universities and
municipalities within 4 years. However, how much these bicycles were used or their impact are yet to
be determined. According to Turkey Nutrition and Health Research (2014) study among children, 8.2%
of 6 to 18 year-old children were obese/overweight (M:9.1%, F:7.3) 14.3% were slightly overweight
(M: 14.2 F: 14.4), 14.9% were thin (M:15.2, F:14.5), and 3.9% were very thin (M: 3.8, F: 4.1). However,
there is no study examining the relationship between BMI and fundamental motor development. The aim of this study was to determine the fundamental motor skill levels of Turkish children aged
9 to 10 according to their BMI groups and to examine their fundamental skill levels according to age
and gender variables with identifying the association between the BMI and the gross motor skill. Measurement Procedures Height measurement: Height was measured barefoot with an accuracy of 0.1 cm, using a standard steel
stadiometer. Weight measurement: Weight was measured barefoot with no metal on the Tanita BC-418 Segmental
Body Analysis System (Tanita Corporation, Tokyo, Japan). BMI: BMI values were calculated taking CDC 2-20 age growth curve table by using the BMC Percentile
Calculation tool for children and adolescents (3): <5 percentile as thin, 5-85. percentile as healthy
weight, 85-95 percentile as overweight, and the >95 as obese. Process All measurements were carried out in the school gyms under the supervision of teachers. First, height
and weight were measured and then locomotor and manipulative tests were recorded on video. After
that, two different experts watched the video recordings and made TGMD-2 test evaluations and
prepared averages. Evaluation of Fundamental Motor Skill Level Evaluation of Fundamental Motor Skill Level
In this study, fundamental motor skill level was evaluated through TGMD-2 test. TGMD-2 was
developed by Ulrich (2000) to evaluate the fundamental motor development of children between the
ages of 3-10, depending on age. TGMD- 2 is a motor assessment tool that requires the observation of
12 motor skills consisting of two subtests: locomotor subtests (running, jumping, galop, jumping,
hopscotch and gliding) and object control subtests (catching, kicking ball, ball bumping, overhand ball
throwing and rounding ball under hand and batting with two hands). Each skill is evaluated according
to three to five performance criteria. If a participant demonstrates the criteria, he / she receives a 1, if
not a 0. It includes the total raw score (0-48 points) of the observed criteria for each subscale. Raw scores
can be converted to percentiles and standard scores, which allows comparison with the scores of their
peers. 111 Int J Sport, Exer & Train Sci, 2020, Vol 6, Issue 4, 110–116 FI. Kerkez, V. Tutal Statistical analysis SPSS 22 package program was used for data analysis and statistical significance was determined as 0.05. The normality test by Shapiro Wilk was used to verify the data distribution. In order to compare
fundamental motor skill raw scores according to age and gender using average and percentile value
descriptive statistical method, the study used t-test for independent groups and one-way Anova test to
compare according to BMI groups. The association between the BMI and the gross motor skill was
analyzed through the Pearson bivariate correlation (rs) overall and by subtests. RESULTS Weight, Height, and Body Mass Index g
,
g
,
y
72% of the children had a healthy weight (M=28.8 kg; BMI=16.1); 14.5% were overweight (M=39.7
kg: BMI=20.3); and 13.6% were obese (M=46.7 kg; BMI=24.3). g
)
(
g
)
In terms of age groups, 9.3% of 9-year-old children were overweight and 16.9% were obese. Whereas for 10-year old children, 20.8% of them were overweight and 9.4% were obese. The ratio of
overweight and obese boys was found to be higher than that of girls. Children's height, weight, and BMI
information were categorized according to their age and gender and are presented in Table 1. Table 1. Descriptive information for boys and girls aged 9-10 years. Gender
Girl (n = 110)
Boy (n = 104)
Age Group
9 years-old
(n = 69)
10 years-old
(n = 41)
Avg. 9 years-old
(n = 49)
10 years-old
(n = 55)
Avg. Variables
X̄ ±SD
X̄ ± SD
X̄ ± SD
X̄ ± SD
X̄ ± SD
X̄ ± SD
Height (cm)
133.3±6.3
136.4±6.6
134.5±6.6
133.2±6.2
137.5±6.8
135.5±6.8
Weight (kg)
31.3±7.4
32.4±5.7
31.7±6.8
33.3±8.5
34.5±8.9
33.9±8.7
BMI
17.4±3.1
17.3±2.3
17.4±2.8
18.6±3.6
18.0±3.5
18.3±3.6
n (%)
n (%) Total n (%)
n (%)
n (%)
Total n (%)
Healthy Weight
55 (50.0)
30 (27.3)
85 (77.3)
32 (30.8)
37 (35.6)
69 (66.3)
Overweight
5 (4.5)
9 (8.2)
14 (12.7)
6 (5.8)
11 (10.6)
17 (16.3)
Obese
9 (8.2)
2 (1.8)
11 (10.0)
11 (10.6)
7 (6.7)
18 (17.3)
*Taking into account the CDC 2-20 age growth curve scale, the BMI levels were calculated as <5. percentile as thin, 5-85. percentile as healthy
weight, 85-95 percentile as overweight, and > 95th percentile as obese using the CDC BMI Percentile Calculation Tool for Children and
Adolescents (CDC, 2019). Avg: Mean, BMI: Body mass index, X̄ : Mean, SD: Standart deviation Table 1. Descriptive information for boys and girls aged 9-10 years. G
d
Gi l (
110) *Taking into account the CDC 2-20 age growth curve scale, the BMI levels were calculated as <5. percentile as thin, 5-85. percentile as healthy
weight, 85-95 percentile as overweight, and > 95th percentile as obese using the CDC BMI Percentile Calculation Tool for Children and
Adolescents (CDC, 2019). Avg: Mean, BMI: Body mass index, X̄ : Mean, SD: Standart deviation BMI- Fundamental Motor Skill Proficiency BMI- Fundamental Motor Skill Proficiency Pearson's bivariate correlational results indicate that BMI showed negative correlation with FMS total
(r=-0.22, p<0.001) and locomotor subtest total (r=-0.24. p<0.001), but the relationship between
manipulative subtest and total score was not significant. When locomotor subtest raw score was compared using one-way analysis of variance, a significant
difference was found among the groups of healthy weight, overweight and obese children [F (6.348) =
91.80, p=0.02]. According to the post hoc test result, the locomotor subtest raw score of obese children
was significantly lower than that of children with healthy weight. Manipulative subtest total score
difference according to BMI groups was not significant [F (2.615)=68.55. p=0.076]. Gross motor test
total score was significantly different among BMI groups [F (6.990)=317.69, p=0.01]. The scores of
healthy children were significantly higher than those of obese children. 112 Int J Sport, Exer & Train Sci, 2020, Vol 6, Issue 4, 110–116 FI. Kerkez, V. Tutal Figure 1. Locomotor and manipulative test raw scores by BMI groups. Figure 1. Locomotor and manipulative test raw scores by BMI groups. Age and Gender - Fundamental Motor Skill Proficiency g
f
y
Locomotor test total score of 10-year-old children (34.2±4.8) was significantly higher than that of
(31.7±3.4) 9-year-old children (t=-5.040, p<0.01). The total score of manipulative subtest of the 10 year-
old children (32.4 ± 4.8) was significantly higher than the 9 year-old children (28.4 ± 4.7) (t=-6.036. p
<0.01). There was no significant difference between boys' (33.0±4.4) and girls' (32.6±3.3) locomotor
subtest scores (t=0.826. p> 0.05). There was a significant difference in the total score of the manipulative
subtest (t=9.911, p<0.01) between boys (33.2±4.5) and girls (27.4±3.9). The fundamental motor skill
levels were categorized according to age and gender and are presented in Table 2. Table 2. Descriptive information on fundamental motor skill levels. Gender
Girls (n=110)
Boys (n=104)
Age Group
9 years-old
(n = 69)
10 years-old
(n = 41)
Avg. 9 years-old
(n = 49)
10 years-old
(n = 55)
Avg. BMI- Fundamental Motor Skill Proficiency Locomotor and Object
control test scores *
X̄ ±SD
X̄ ± SD
X̄ ± SD
X̄ ± SD
X̄ ± SD
X̄ ± SD
Locomotor, total score
31.6±2.7
34.2±3.5
32.6±3.3
31.7±4.2
34.2±4.2
33.0±4.4
Running
6.2±0.9
6.4±0.7
6.3±0.8
6.6±1.1
6.9±0.9
6.7±1.1
Hopping
5.3±1.1
5.8±1.3
5.5±1.2
4.9±1.1
5.5±1.0
5.2±1.1
Galloping
4.8±1.3
5.7±1.4
5.1±1.4
4.4±1.2
4.9±1.4
4.7±1.3
Slide
5.2±0.8
5.6±0.8
5.4±0.8
5.2±1.1
5.8±0.9
5.6±1.1
Leap
4.4±0.6
5.0±0.8
4.6±0.7
4.3±.08
4.8±1.0
4.6±0.9
Horizontal jumping
5.6±0.9
5.5±1.1
5.6±1.0
6.0±1.1
6.1±1.5
6.0±1.3
Object control, total score
26.2±3.5
29.5±3.7
27.4±3.9
31.6±4.2
34.6±4.4
33.2±4.5
Striking a stationary ball
2.4±1.0
2.5±1.1
2.4±1.0
3.2±1.3
3.3±1.4
3.2±1.4
Kick
4.0±1.1
4.7±1.5
4.2±1.3
5.6±1.0
6.6±1.3
6.1±1.3
Overhand throw
3.7±1.9
4.9±1.4
4.2±1.8
5.0±2.0
6.3±1.2
5.7±1.7
Catch
4.7±1.2
5.0±1.2
4.8±1.2
5.2±1.0
5.3±1.1
5.0±1.2
Stationary dribble
5.1±1.5
6.0±1.6
5.4±1.6
6.1±1.3
6.5±1.3
6.3±1.3
Underhand roll
6.0±1.3
6.2±1.5
6.1±1.4
6.3±1.3
6.9±1.2
6.6±1.3 Table 2. Descriptive information on fundamental motor skill levels. DISCUSSION The prevalence of obesity in children is increasing. The negative impact of obesity on health was
described in detail for many years. Although the effect of obesity on mobility of children has been
studied in the international literature for over 30 years, there is no data on the effect of being overweight
and obese on motor efficacy of Turkish children. This study is the first one examining the FMS levels 113 Int J Sport, Exer & Train Sci, 2020, Vol 6, Issue 4, 110–116 FI. Kerkez, V. Tutal of 9 to 10-year-old Turkish children according to BMI groups. The study included 214 children with an
average age of 9.45 ± 0.49 years and evaluated FMS results according to age and gender. of 9 to 10-year-old Turkish children according to BMI groups. The study included 214 children with an
average age of 9.45 ± 0.49 years and evaluated FMS results according to age and gender. FMS results in Turkish children were compared with similar studies using TGMD-2 test. The
locomotor and object control raw scores of Turkish children were found to be lower than the results by
Ré et al. (2018), which for the girls with same age were 35.8±4.3 for locomotor total and 28.8±5.1 for
object control and for boys’ locomotor total was 35.9±4.3 and object control total was 33.0±5.7. On the
other hand, it was found to be higher than the result by Nobre et al. (2016) who found that total locomotor
in girls of the same age was 25.5 and object control was 26 and locomotor total for boys was 25.1 and
object control total was 26.3. When the results were compared with the subtest scores given in Nobre et
al. (2016) individually, it showed that the lowest score of the Turkish children was for ‘striking a
stationary ball test’, which was one of the object control subtests (2.4 ± 1.0 for girls and 3.2 ± 1.4 for
boys). The failure of this subtest stems from the fact that Turkish children had never learned this skill
before since ‘striking a stationary ball’ was not included in any street game or in the school curriculum. On the other hand, hitting, catching, dribbling can be practiced to a certain extent in children's games
and in the “Physical Education and Game” classes in primary schools. In the literature, there are different results about the relationship between BMI and motor skill level. DISCUSSION There are few studies showing that there is no relationship between BMI and fundamental motor skill
level and these studies include preschool population. Catenassi et al. (2007) found no relation between
BMI and motor skills of 4 to 6 year-old children. Likewise, Lin & Yang (2015) reported that the effect
of BMI on locomotor, object control and fundamental motor skill levels of children aged 3 to 7 year-old
was very limited. On the other hand, there are more studies showing that being overweight and obese negatively
affects mobility of children (Saygın & Ceylan, 2017; Poulsen et al., 2015; Cliff et al., 2012; Lopes et
al., 2012; D’hondt et al., 2009; Wearing et al., 2006). Marmeleira et al. (2017) noted that motor competence of children aged 6 to 10 year-old was
negatively associated with body fat and that children with healthy weight displayed better motor
competence than those who were overweight or obese. The results that suggested that the negative
impact of excessive body weight was stronger for locomotor skills including dynamic body movements
than object control skills in steady state and that fine motor skills were comparatively independent of
limitations caused by excess body weight were similar to the results of our study. In their study
investigating the relationship between motor skills and BMI in children aged 5 to 10 years, D'Hondt et
al. (2009) noted that obese children had lower levels of motor skills than their healthy and overweight
peers. Southall, Okely & Steele (2004) reported that the real and perceived physical competence of
overweight children in the sample with an average age of 10.8 years was lower than those with a healthy
weight. Our results show that the situation is similar for Turkish children. Obese children had lower
results than healthy children in locomotor subtests requiring mobility. The limitation of this study is the
low sample numbers and low number of overweight and obese children in the sample. The effect of
excessive weight on mobility should be further explained with studies to be conducted with a larger
sample group. CONCLUSION In conclusion, this study demonstrates inadequate fundamental motor skills proficiency levels among
Turkish 9-10 years old children. Obese children had lower results than healthy children in locomotor
subtests requiring mobility. It can be said that being overweight restricts mobility for Turkish children
but does not affect object control skills that doing the mostly static position. If asked to train successful
athletes in Turkey, motor development and nutrition in children cannot be left just to the attention of
parents. There should be a strong government policy that supports children's participation in planned
movement training from an early age under the supervision of physical education teachers. REFERENCES Boz, M. & Gungor Aytar, A. (2012). The Effect of Fundamental Movement Education on Pre-school
Children’s Movement Skills. Hacettepe University Journal of Education, Special Issue 1: 51-59. Catenassi, F, Marques, Z.I., Bastos, C.B., Basso, L., Vaz Ronque, E.R. & Gerage, A.M. (2007). Relationship between body mass index and gross motor skill in four to six-year-old children. Rev
Bras Med Esporte, 13(4), 203-206. DOİ: 10.1590/S1517-86922007000400003. CDC. (2019). BMI Percentile Calculator for Child and Teen, 2019. Retrieved from
https://www.cdc.gov/healthyweight/bmi/calculator.html on 20 October 2019. Cliff, D.P., Okely, A.D., Morgan, P.J., Jones, R.A., Steele, J.R. & Baur, L.A. (2012). Proficiency
deficiency: Mastery of fundamental movement skills and skill components in overweight and obese
children. Obesity, 20, 1024–33. DOI: 10.3109/17477166.2011.575154. D’hondt, E., Deforche, B., Bourdeaudhuij, I.D. & Lenoir, M. (2009). Relationship Between Motor Skill
and Body Mass Index in 5- to 10-Year-Old Children. Adapted Physical Activity Quarterly, 26, 21-
37. DOI: 10.1123/apaq.26.1.21. Ersoz, Y. (2012). Effect of Multi-Skill Sport Education on Motor Development of Boys aged 7 to 10. Unpublished Sport Physiology Master’s Thesis, Izmir, Turkey, Dokuz Eylül University. Gallahue, D.I., Ozmun, J.C. & Goodway, J.D. (2012). Understanding Motor Development:
Children, Adolescents, Adults Motor (7th ed.). Boston, MA: McGraw-Hill. Guven, O. & Yildiz, O. (2014). Expectations of the Classroom Teachers from Play and Physical
Activities Lesson. Kastamonu Education Journal, 22 (2), 525-538. Lin, S-J. & Yang, S-C. (2015). The Development of Fundamental Movement Skills by Children Aged
Six to Nine. Universal Journal of Educational Research, 2015; 3(12): 1024-1027, DOI:
10.13189/ujer.2015.031211. Lopes, V.P., Stodden. D.F., Bianchi. M.M., Maia. J.A. & Rodrigues. L.P. (2012). Correlation between
BMI and motor coordination in children. Journal of Science and Medicine in Sport, 2012; 15, 38–
43. DOI: 10.1016/j.jsams.2011.07.005. Marmeleira, J., Veiga. G., Cansado. H. & Raimundo. A. (2017). Relationship between motor proficiency
and body composition in 6- to 10-year-old children. Journal of Pediatrics and Child Health, 53,
348–353. DOI:10.1111/jpc.13446. Nobre, G.C., Bandeira, P.F.R. & Valentini, N.C. (2016). The Relationship Between General Perceived
Motor Competence, Perceived Competence Relative to Motor Skill and Actual Motor Competence
in Children. Journal of Physical Education, 27, e2744. DOI: 10.4025/jphyseduc.v27i1.2744. OECD Obesity Update (2016). Retrieved from https://www.oecd.org/health/obesity-update.htm on 20
October 2020. Poulsen, A.A., Desha, L., Ziviani, J., Griffiths, L., Heaslop, A., Khan, A. & Leong, G.M. (2011). Fundamental movement skills and self-concept of children who are overweight. International
Journal of Pediatric Obesity, 6, e464–71. DOI: 10.3109/17477166.2011.575143. Ré, A.H.N., Logan, S.W., Cattuzzo, M.T., Henrique, R.S., Tudela, M.C. ACKNOWLEDGEMENTS The authors report no conflict of interest. A part of this study was presented at the V. INES Science
Technolohy and Innovation Congress (STI 2019) 17 - 21 April 2019 as oral presentation. 114 FI. Kerkez, V. Tutal Int J Sport, Exer & Train Sci, 2020, Vol 6, Issue 4, 110–116 CITATION OF THIS ARTICLE
Kerkez, FI. & Tutal, V. (2020). Effect of BMI on Fundamental Motor Skill Proficiency Among Turkish
Children. International Journal of Sport, Exercise & Training Sciences - IJSETS, 6(4), 110-116.
DOI:10.18826/useeabd.816482. REFERENCES & Stodden, D.F. (2018). Comparison of motor competence levels on two assessments across childhood. Journal of Sports
Sciences, 36:1, 1-6, DOI:10.1080/02640414.2016.1276294. Saygın, Ö., & Ceylan, H. İ. (2017). A Comparison of body mass index and daily step numbers of
secondary school and high school students according to age and gender. Int J Sport Exer & Train
Sci, 3 (4), 142-152. DOI: 10.18826/useeabd.337683 Southall, J., Okely, A. & Steele, J. (2004). Actual and perceived physical competence in overweight and
non-overweight children. Pediatric Exercise Science, 16, 15 – 24. DOI: 10.1123/pes.16.1.15. Stodden, D.F., Goodway, J.D., Langendorfer, S.J., Roberton, M.A., Rudisill, M.E., Garcia, C. & Garcia,
L.E. (2008). A developmental perspective on the role of motor skill competence in physical
activity:
An
emergent
relationship. Quest,
60(2),
290–306. DOI:
10.1080/00336297.2008.10483582. 115 Int J Sport, Exer & Train Sci, 2020, Vol 6, Issue 4, 110–116 FI. Kerkez, V. Tutal The Preschool Curriculum. (2019). Ministry of Education, Ankara, Turkey, 2013. Retrieved from
https://tegm.meb.gov.tr/dosya/okuloncesi/ooproram.pdf on 20 October 2019. Turkey Nutrition and Health Research. (2014). Ministry of Health, Ankara, Turkey, 2014. Hyperlink:
[https://hsgm.saglik.gov.tr/depo/birimler/saglikli-beslenme-hareketli-hayat-
db/Yayinlar/kitaplar/diger-kitaplar/TBSA-Beslenme-Yayini.pdf]. Retrieved on 14 January 2020. Turkey Nutrition and Health Research. (2014). Ministry of Health, Ankara, Turkey, 2014. Hyperlink:
[https://hsgm.saglik.gov.tr/depo/birimler/saglikli-beslenme-hareketli-hayat-
db/Yayinlar/kitaplar/diger-kitaplar/TBSA-Beslenme-Yayini.pdf]. Retrieved on 14 January 2020. [
p
g
g
g
p
g
y
db/Yayinlar/kitaplar/diger-kitaplar/TBSA-Beslenme-Yayini.pdf]. Retrieved on 14 January 2020. Ulrich, D. (2000). Test of gross motor development: second edition Austin, TX: PRO-ED. Ulutas, A., Demir, E. & Yayan, E.H. (2017). Effect of Motor Development Program on Rough and Fine
Motor Development of Five-Six-Year-Old Children. Abant İzzet Baysal University Education
Faculty Journal, 17 (3), 1523-1538. Wearing, S.C., Hennig, E.M., Byrne, N.M., Steele, J.R. & Hills, A.P. (2006). The impact of childhood
obesity on musculoskeletal form. Obesity Reviews, 7: 209–18. DOİ:10.1111/j.1467-
789X.2006.00216.x. Whitehead, M. (2010). Physical literacy: Throughout the life course, Oxon, MD: Routledge. WHO. (2019). Global Recommendations on Physical Activity for Health, 5–17 years old, USA, 2011. Retrieved from https://www.who.int/dietphysicalactivity/factsheet_young_people/en/ CITATION OF THIS ARTICLE
Kerkez, FI. & Tutal, V. (2020). Effect of BMI on Fundamental Motor Skill Proficiency Among Turkish
Children. International Journal of Sport, Exercise & Training Sciences - IJSETS, 6(4), 110-116. DOI:10.18826/useeabd.816482. 116
|
https://openalex.org/W4240110663
|
http://ejournal.uinsaizu.ac.id/index.php/komunika/article/download/108/82
|
Indonesian
| null |
Semiotika: Sebuah Pendekatan dalam Studi Agama
|
Komunika
| 1,970
|
cc-by-sa
| 4,236
|
PENDAHULUAN Suatu komunikasi akan terjadi atau berlangsung jika ada pemahaman makna dalam bahasa yang diungkapkan. Kesamaan bahasa yang dipergunakan itu belum menjamin terjadinya kesamaan makna. Dengan lain perkataan, mengerti
bahasanya saja belum tentu mengerti makna yang dibawakan oleh bahasa itu. Dalam hal ini sebuah pemahaman akan di-
peroleh dengan bahasa dan makna yang dikandung dalam bahasa tersebut.1 Bahasa menjadi sentral dalam diskusi-diskusi
filosofis, dan juga merupakan esensi komunikasi manusia yang berfungsi sebagai ‘pembentuk’ pikiran, instrument interaksi
sosial, sekaligus penebar makna.2Karena signifikansi bahasa itulah dalam perkembangannya, filsafat saat ini sering dikatakan
mengalami “pembalikan ke arah bahasa” (linguistic turn)”. Jika seratus tahun sebelumnya istilah kunci filsafat bergerak di
seputar “akal”, ‘roh’, “pengalaman”, dan “kesadaran”, kini yang dianggap sebagai istilah kunci adalah ‘bahasa’. Namun
demikian gerakan kembali ke bahasa itu sendiri sebenarnya merupakan gejala yang kompleks, mencakup banyak aliran
pemikiran yang tidak bisa begitu saja dimasukkan dalam satu kategori. Di dalamnya bisa disebutkan misalnya semiotik, struk-
turalisme, post-strukturalisme, filsafat bahasa sehari-hari, dan hermeneutic. Dengan menggunakan analisis linguistik, misalnya struktur-struktur yang tersembunyi di balik teks dapat diungkapkan. Dalam perspektif analisis linguistik inilah semiotik diperbincangkan, seperti didefinisikan oleh Eco. Umberto Eco
mengemukakan bahwa semiotika sebagai ilmu tentang tanda, dan juga membahas segala gejala budaya sebagai proses-proses
komunikasi. Asumsi Eco ini akan menjadi teori umum yang dapat digunakan untuk menjelaskan setiap kasus “fungsi tanda”
(sign function).3Makna dalam proses semiotik terjadi di bawah syarat-syarat tertentu, yakni ketika sesuatu yang benar-benar
tersaji pada persepsi orang yang dituju mewakili sesuatu yang lain, yang itu berarti ada signifikansi. Kalangan semiotisi yang
melihat signifikansi ini hampir ada di setiap tempat dan setiap hal (everywhere and everything), mencoba untuk menem-
patkan “tanda” sebagai pusat interaksi manusia, yakni di setiap tindakan komunikasi. *)Penulis adalah Magister Agama (M.Ag.), dosen tetap Jurusan Komunikasi (Dakwah) STAIN Purwokerto. *)Penulis adalah Magister Agama (M.Ag.), dosen tetap Jurusan Komunikasi (Dakwah) STAIN Purwokerto. Abstract: Semiotic is a science about sign in form word, picture, sound and literary work. Semiotic often used as
approach to analyze text, in order to formulate structure and possible meaning, and often used as approach in social
culture matter, literary works and religious texts. In religious texts, we can see Arkoun’s reading on surah al-Fatihah, when basic
assumes offered by Arkoun based on al-Qur’an that according to him have open characteristic by using syntax and
semantic analysis. Netton also using semiotic approach that focused to reveal meaning behind Suhrawardi works. Keywords:
Semiotic, Text, Religion, Language, Arkoun, Netton. Semiotika: Sebuah Pendekatan dalam Studi Agama Khusnul Khotimah *) JURNAL DAKWAH DAN KOMUNIKASI SEKILAS TENTANG SEMIOTIK Semiotika adalah ilmu tentang tanda. Istilah ini diambil dari kata Yunani Semeion yang berarti “tanda”.4 Tanda ada di
mana-mana, bisa berupa kata, gambar, bunyi, struktur karya sastra, struktur film, struktur musik dan sebagainya. Semiotik
juga merupakan suatu ilmu yang mengkaji gejala kebudayaan dengan memahami makna tanda-tanda kehidupan. Ada empat
hal yang mesti diperhatikan dalam semiotik, yaitu tanda (ikon lambang), jenis sistem tanda (bahasa musik, atau gerakan
tubuh), jenis teks dan jenis konteks atau situasi yang mempengaruhi makna tanda (kondisi psikologis, sosial historis dan
kultural).5Semiotik sering digunakan sebagai sebuah pendekatan dalam analisis teks, baik verbal maupun non verbal. Analisis KOMUNIKA
Vol.2 No.2 Jul-Des 2008 pp.277-289 Jurusan Dakwah STAIN Purwokerto ISSN: 1978-126 JURNAL DAKWAH DAN KOMUNIKASI teks dengan pendekatan semiotik berupaya untuk mengidentifikasi beragam tanda dalam sebuah teks dengan maksud untuk
menemukan struktur dan makna-makna yang mungkin. teks dengan pendekatan semiotik berupaya untuk mengidentifikasi beragam tanda dalam sebuah teks dengan maksud untuk
menemukan struktur dan makna-makna yang mungkin. Menurut Bertens, awal mula konsep semiotik diperkenalkan oleh Ferdinand de Saussure, yang mempunyai latar
belakang pendidikan sastra Prancis dari alumnus Universitas Sorbonne, Prancis. Saussure memperkenalkan semiotik melalui
dikotomi sistem tanda: signifieddan signifieratau signified dansignificantyang bersifat atomistis. Konsep ini melihat bahwa
makna muncul ketika ada hubungan yang bersifat asosiasi atau in absentia antara ‘yang ditandai’ (signified) dan ‘yang
menandai’ (signifier). Tanda adalah kesatuan dari suatu bentuk penanda (signifier) dengan sebuah ide atau petanda
(signified). Dengan kata lain, penanda adalah “bunyi yang bermakna” atau “”coretan yang bermakna”. Jadi penanda adalah
aspek material dari bahasa, yaitu apa yang dikatakan atau didengar dan apa yang ditulis atau dibaca. Petanda adalah
gambaran mental, pikiran, atau konsep.6 Pada setiap disiplin ilmu dapat dicari kemungkinan penerapan semiotika. Salah satu cara menafsirkan persoalan
kebudayaan dan sosial supaya esensinya terpekakan ialah dengan meretas dan membedah tanda-tanda yang memaknai
kehidupan, fenomena, dan aktivitas sosial budaya manusia.7 Kebudayaan dan persoalan sosial tidak bisa dipahami atau
ditafsirkan hanya oleh suatu interpretasi karena kebudayaan adalah proses dinamis yang tak mungkin didominasi segelintir
kelompok terkuat saja. Dengan memakai kaca mata semiotik ini yang tercermin dalam tanda-tanda, maka sistem makna
dalam bahasa akan dapat diteropong. Kajian-kajian yang sudah lazim dilakukan di masing-masing bidang pada gulirannya
secara keseluruhan dapat lebih diperkaya dengan menggunakan pendekatan semiotik. MEMAKNAI AGAMAMELALUI SEMIOTIK Sebagai ilmu tentang tanda, pada prinsipnya semiotika dapat diterapkan pada kajian teks keagamaan. Hal ini didasari
antara lain, Pertama, agama sering digambarkan sebagai tanda Allah. Kedua, teks-teks kitab suci agama, termasuk al-Qur’an,
merupakan himpunan tanda-tanda yang menunjukan makna tertentu yang perlu digali dalam proses penafsiran. Ketiga, teks-
teks kitab suci pada umumnya dianggap sebagai himpunan tanda yang menyampaikan pesan atau amanat Ilahi. Keempat,
kajian mengenai agama dapat dianalisis sebagai himpunan tanda. Proses pembentukan ortodoksi, ketertutupan dan
keterbukaan korpus rujukan dalam bidang teologi atau hukum agama, dan sebagainya merupakan persoalan-persoalan yang
muncul di wilayah ini.8 Begitu penting dalam agama, misalnya dalam agama Kristen, persoalan tanda dan signifikansi diperhatikan sejak awal
sejarah gereja. Menurut Eugenio sebagaimana dikutip oleh Meuleman menyebut Aurelius Agustinus sebagai pendiri
semiotika dalam arti yang sebenarnya. Agustinus beranggapan bahwa dunia ciptaan mengandung tanda kehendak Allah. Bertolak dari pendapat itu, dapat dipahami bahwa Agustinus tidak membatasi berfungsinya tanda pada bidang kebahasaan
yang mengandung tanda, lambang, dan parabel dalam teks alkitab tetapi juga pada aspek keagamaan, terutama dalam bidang
liturgi.9 Dalam agama Islam, semiotika juga berperan dalam al-Qur’an. Kata ayat (ayah) terdapat ratusan kali dalam al-Qur’an. Arti dasarnya adalah “tanda”. Sebagimana dalam surat Fussilat:53 yang artinya “Kami akan memperlihatkan kepada mereka
tanda-tanda Kami dalam cakrawala-cakrawala” ditafsirkan sebagai wilayah bumi yang seluas-luasnya, di segala penjuru bumi
dan dalam jiwa mereka sendiri hingga jelas bagi mereka bahwa itu – wahyu yang disampaikan kepada Nabi Muhammad-
adalah benar. Kata “tanda” dalam al-Qur’an juga berkonotasi “bukti”, dan dapat pula bermakna “contoh”. Misalnya pada Surat
Hud: 103, hukuman Allah terhadap Fir’aun dan kaumnya yang sesat- terdapat contoh bagi yang takut akan siksa di
akhirat.Pada prinsipnya al-Qur’an sebagai teks dan seluruh agama Islam merupakan wilayah subur bagi analisis semiotik. Pengalaman agama adalah “pertemuan” yang bersifat “konatif”, yaitu pengalaman yang kita alami secara langsung dan
murni. Dalam pengalaman “konatif”, kita mengalami pertemuan antara “aku” dengan “yang lain” (the other). Dalam
pengalaman ini, fenomenologi bahasa akan menyebutnya bersifat langsung, murni, dan terjadi pada taraf tidak sadar. Ketika
kita mulai menyadari dan mulai berbicara mengenai pengalaman tersebut, masuklah pada aspek “konatif” kepada “bahasa KOMUNIKA
Vol.2 No.2 Jul-Des 2008 pp.277-289 Jurusan Dakwah STAIN Purwokerto ISSN: 1978-126 JURNAL DAKWAH DAN KOMUNIKASI yang bersifat reflektif,” yaitu pengalaman yang sudah diabstraksikan ke dalam pola-pola data indrawi (sense data). MEMAKNAI AGAMAMELALUI SEMIOTIK Fenomena
dan problem inilah kemudian membawa kepada pendekatan semiotik dalam mengungkap pengalaman agama.10 yang bersifat reflektif,” yaitu pengalaman yang sudah diabstraksikan ke dalam pola-pola data indrawi (sense data). Fenomena
dan problem inilah kemudian membawa kepada pendekatan semiotik dalam mengungkap pengalaman agama.10 Ludwig Wittgenstein sebagaimana dikutip oleh Budhy Munawar mengatakan bahwa “kita perlu membawa kembali
kata-kata dari permainan metafisik kepada permainan bahasa sehari-hari”. Menghidupkan kembali realitas mitafisik bisa
dilakukan dengan analisis semiotik yang terkandung dalam bahasa, termasuk bahasa agama.11Bahasa agama memiliki logika
sendiri di mana merupakan sebuah cara berbicara orang beragama mengenai agamanya, oleh karena problem keabsahan
bahasa merupakan keniscayaan yang harus dipahami. Bagaimana kemudian pendekatan semiotik diterapkan dalam rangka studi kebudayaan Islam, produksi teks-teks
keagamaan, dan secara spesifik pemikiran Islam. Tulisan ini akan mengelaborasi, mendeskripsikan dan menganalisis secara
kritis penerapanpemikiran semiotik dalam bidang kajian agama Islam, khususnya seperti yang telah diupayakan oleh Arkoun
dalam pembacaannya terhadap surat al-Fatihah, juga di bidang filsafat dan teologi Islam sebagaimana yang dilakukan Netton
dalam karyanya “Allah Transcendent: Studies in the Structure and Semiotics of Islamics Philosophy, Teology and
Cosmology”.12 JURNAL DAKWAH DAN KOMUNIKASI tindakan (al-hamdu) yang niscaya memiliki pelaku-pengirim. Namun, yang terakhir ini tidak sama dengan pengujar: saya bisa mengujarkan
alhamdu lillahsebagai contoh tata bahasa saja. Tetapi, jika kita beralih dari tataran sintaksis ke semantik, pengujar lebih sulit memisahkan diri dari
pelaku-pengirim. Sesungguhnya, hubungan (antara pengirim dan penerima) ditambah dengan fungsi baru: tindakan pemujian mempranggapkan
secara semantik suatu pelaku-pengirim kebaikan dan suatu aktan penerima itu. Dengan demikian kita sampai pada model aktansial tempat al-lah
adalah aktan pengirim kebaikan, penerima tindakan pemujian; pengujar adalah aktan penerima kebaikan, pengirim tindakan pemujian. Kita
melihat bahwa pengertian aktan memenuhi keperluan untuk menunjukkan sekumpulan fungsi sintaksis dan semantik yang dilaksanakan oleh
‘subjek’ yang sama.16 Arkoun juga menandaskan bahwa analisis mitis dapat membantu untuk menggali kekayaan teks keagamaan yang lebih
bersifat simbolis (konotatif dalam istilah Barthes) daripada denotatif. Arkoun melihat bahwa dalam al-Qur’an ada banyak
simbolisme yang mengungkapkan realitas asli dan universal manusia. Justru aspek itulah yang memudahkan orang dari
berbagai kebudayaan begitu terpikat akan pesan-pesan al-Qur’an. Selama berabad-abad, orang menyatakan bahwa salah satu
kemukjizatan al-Qur’an terletak pada keindahan kesusastraannya. Di sinilah seseorang akan mencari kemukjizatan dalam
simbolisme yang primordial dan universal. Kemukjizatan al-Qur’an, demikian pula surat al-Fatihah menurut Arkoun paling
tidak terdapat empat macam simbolisme: (1) simbolisme tentang kesadaran manusia akan kejahatan dan kesalahan, (2)
simbolisme akan cakrawala eskatologi atau kehidupan yang akan datang, (3) simbolisme tentang kesadaran manusia sebagai
umat, dan (4) simbolisme tentang hidup dan mati.17 b. Catatan Kritis tentang Pendekatan Semiotik Arkoun Upaya Arkoun dalam menggunakan analisis semiotik mempunyai batas-batasnya sendiri. Hal yang penting bahwa
semiotika sampai sekarang mengabaikan sifat khusus dari teks-teks keagamaan, dan para ahli semiotika belum
mengembangkan peralatan analitis khusus untuk teks keagamaan. Teks-teks keagamaan berbeda dengan teks lain karena
berpretensi memberi petanda terakhir (le signifie dernier). Semiotika dalam hal ini kurang memperhatikan aspek dasar itu
dari teks-teks keagamaan. Dengan menyadari keterbatasan itu, Arkoun sacara sadar melampui batas analisis semiotis karena perhatiannya bukan
saja pada teks atau wacana, melainkan pada hubungan antarwacana, kenyataan (realitas), dan persepsi akan wacana dan
realitas oleh manusia yang dimediasi oleh bahasa. Hal tersebut dapat dilihat pada asumsi Arkoun tentang al-Qur’an yang
merupakan korpos berbatas (fini) yang terdiri atas sejumlah ujaran tertentu yang mempunyai bentuk tetap (korpus tersebut
bersifat selesai dari segi bentuk ungkapan dan bentuk isi, tetapi menurutnya al-Qur,an juga merupakan korpus terbuka pada
konteks yang beraneka ragam. Sebagaimana Ungkapan Arkoun yang dikutip oleh Meuleman sebagai berikut: “Qur’an adalah korpus berbatas dan terbuka dari ujaran dalam bahasa Arab dan yang hanya dapat kita dekati melalui teks yang dibekukan
secara grafis setelah abad IV/X. Keseluruhan teks yang dibekukan demikian berfungsi secara bersamaan sebagai karya tulis dan wicara liturgis.”18 Karena itulah, ia meninggalkan bukan hanya wilayah ilmu bahasa struktural, melainkan juga wilayah semiotika secara
umum. Proses interpretasi dalam al-Qur’an pembahasannya tidak terbatas pada analisis sinkronis, melainkan mengutamakan
analisis diakronis, dan itu pun bukan hanya dalam bentuk semiotika yang menganalisis peralihan yang terjadi di dalam satu
teks antara keadaan struktural awal dan keadaan struktural akhir, melainkan sebagai analisis perkembangan teks itu sendiri
dan terutama penafsiran teks dari waktu ke waktu. Arkoun juga tidak hanya memakai anggitankorpus dalam al-qur’an saja,
melainkan pada teks-teks suci yang lain. Di bawah ini merupakan pengamatan Arkoun terhadap teks Qur’an, terdapat 3 unsur
penting mengenai perkembangan penafsiran al-Qur’an. Pertama, menghubungkan proses pembekuan dan penutupan
dalam penafsiran (yaitu pengartian) Qur’an dengan pengalihannya dari bentuk lisan ke bentuk tulisan. Pendirian ini
merumuskan bahwa pencatatan teks Qur’an lebih penting sebagai faktor pembekuan penafsiran dari pada lisan. Kedua,
dalam pemikiran manusia terjadi peralihan antara dua cara pemakaian bahasa. Dalam hal ini dimaksudkan bahwa pemikiran
manusia mengalami peralihan dari kalam kenabian ke wacana pengajaran. Gejala iniberlaku bagi pemikiran manusia secara
umum. Kalam kenabian membicatakan situasi batas kondisi manusia, seperti keberadaan, cinta kasih, hidup, dan mati. a. Arkoun: Analisis Semiotik Surat al-Fatihah JadiAl-lahadalah penerima tetap dari suatu Jurusan Dakwah STAIN Purwokerto KOMUNIKA
Vol.2 No.2 Jul-Des 2008 pp.277-289 KOMUNIKA
Vol.2 No.2 Jul-Des 2008 pp.277-289 ISSN: 1978-126 JURNAL DAKWAH DAN KOMUNIKASI a. Arkoun: Analisis Semiotik Surat al-Fatihah Pendekatan semiotik Arkoun dapat kita temukan terutama dalam bukunya yang berjudul “Berbagai Pembacaan al-
Qur’an”,13 ia menerapkan analisis semiotik terhadap teks al-Qur’an. Pada prinsipnya, setiap pembacaan (qiraah) berurusan
dengan persoalan sebagaimana suatu teks dapat menghasilkan makna (signifikansi). Pemaknaan atau pencarian makna ini
berjalan sejajar dengan upaya manusia mengatasi problem konkret bagi dirinya sendiri (“L’homme est un probleme concret
pour I’homme”), yakni usaha manusia sebagai makhluk yang berpikir (animale rationale) untuk mengetahui tentang hidup,
dunia dan dirinya sendiri. Dengan asumsi dasar itulah Arkoun melakukan pembacaan terhadap surat al-Fatihah. Tujuan Arkoun membaca surat
al-Fatihah adalah untuk memahami makna, agar dengan pemahaman tersebut dapat mengatasi problem absolut, yaitu
manusia itu sendiri. Asumsi dasar lainnya mengatakan bahwa teks yang sedang dibaca adalah suatu korpus (al-Qur’an) yang
bersifat terbuka. Di dalam teks Qur’ani mengatakan sesuatu, mengungkapkan suatu komunikasi, memberikan sesuatu untuk
dipikirkan. Isi komunikasi inilah yang harus terus menerus dieksplorasi ketika membaca suatu teks. Lewat analisisnya terhadap surat al-Fatihah, Arkoun sebenarnya sedang mengusahakan pemahaman yang intensif
bukannya eksentif tentang teks surat al-Fatihah. Usahanya itu, secara garis besar dilakukan lewat dua tahap. Langkah pertama
ia melakukan semacam “intellectual exercise” melalui analisis linguistik kritis. Langkah kedua adalah usaha untuk melakukan
semacam “re-enacment”pengalaman keagamaan, yakni dengan analisis mitis teks surat al-fatihah. Dalam analisis linguistik kritis, Arkoun menganalisis unsur-unsur linguistis seperti determinan (ism ma’rifah), kata ganti
orang (pronominal, dlamir), sistem kata kerja (fi’il), sistem kata benda (ism dan musamma), struktur sintaksis dan prosodie. Fokus analisis Arkoun dalam hal ini terarah pada analisis sintaksis dan semantik. Arkoun melihat bahwa pentingnya linguistik
kritis ini terletak pada kemungkinan untuk “mengungkapkan struktur dalam yang terletak di balik penampakan teks yang
seolah-olah tidak teratur”.14 Analisis ini dilakukan sedemikian rupa sehingga dapat menangkap keseluruhan teks sebagai
sistem hubungan-hubungan internal. Hubungan internal ini dianalisis berdasarkan tanda-tanda bahasa yang ada. Demikianlah teks tidak hanya tampak sebagai kumpulan kata-kata, melainkan tampak sebagai suatu sistem hubungan
internal. Untuk menemukan dan memahami isi komunikasi teks surah al-Fatihah, harus dipahami tidak hanya lewat analisis
linguistik, melainkan juga lewat hubungan-hubungan kritis, yakni analisis mitis.15 Berikut ini merupakan kutipan langsung
Arkoun dalam pembacaannya terhadap surat al-Fatihah sebagaimana dikutip Meuleman: Ungkapan dasar al-hamdu lillahidari sudut pandang sintaksis, klausa tersebut adalah nominal, inkoaktif (mubtada’) dan predikat (khabar). Segala tindakan ditujukan kepada Allah tanpa acuan apapun kepada seorang penutur dan pada waktu. b. Catatan Kritis tentang Pendekatan Semiotik Arkoun Ketiga, bahasa lisan adalah bentuk lebih awal daripada bahasa tulisan.19 KOMUNIKA
Vol.2 No.2 Jul-Des 2008 pp.277-289 Jurusan Dakwah STAIN Purwokerto ISSN: 1978-126 ISSN: 1978-126 JURNAL DAKWAH DAN KOMUNIKASI Pembahasan Arkoun yang melampaui wilayah semiotika tersebut tidak berarti tidak menimbulkan pertanyaan dan
mengandung sejumlah kelemahan antara lain, sebagai berikut. Pertama; persoalan hubungan antara teks dan konteks tidak dibahas oleh semiotika, tetapi justru memusatkan
perhatian pada hubungan “ketandaan” di dalam suatu teks atau sistem tanda lain. Karena alasan itulah, pembahasan linguistik
itu selalu disinergikan dengan pembahasan historis dan antropologis. Kedua, uraiannya seringkali sangat abstrak dan agak samar antara lain karena ia tidak selalu merumuskan istilah dan
anggitan yang digunakannya dengan cara yang jelas atau tetap. Satu contoh adalah penggal-penggal mengenai mitos dan
bebagai bentuk fungsi dan disfungsinya. Ketiga, analisis Arkoun sangat kaya akan rujukan teoritis, tetapi tidak selalu sadar akan ketegangan antara berbagai
acuan itu atau antara unsur tertentu dari sumber rujukannya dan dari pendiriannya sendiri. Hal ini karena pengaruh
pemikiran Derrida yang sangat menonjol terhadap Arkoun.20 JURNAL DAKWAH DAN KOMUNIKASI JURNAL DAKWAH DAN KOMUNIKASI b. Catatan tentang Pendekatan Semiotik Netton Jika melihat hasil yang dicapai dari pendekatan semiotik Netton terhadap pemikiran filsafat dan teologi Islam,
khususnya dalam kasus analisis terhadap pemikiran Suhrawardi, ternyata tidak banyak yang ditawarkan oleh semiotik. Hal ini
dikarenakan dua alasan. Pertama, kita tidak mendapatkan informasi baru menyangkut pengaruh-pengaruh Zoroastrian yang
hadir dalam karya-karya Suhrawardi. Seyyed Hossein Nasr dalam Three Muslim Sages, Avicenna – Suhrawardi – Ibn
‘Arabi27 , telah menemukan adanya pengaruh Zoroastrian dalam Angelology Suhrawardi. Kedua, tidak berbeda dengan
uraian-uraian tradisional tentang filsafat Suhrawardi seperti halnya yang pernah dikerjakan oleh Nasr, tidak ada informasi
baru yang ditemukan dari informasi semiotik Netton atas teks-teks Suhrawardian. Selain itu kritik terhadap pendekatan semiotik, dan linguistik pada umumnya adalah terabaikan dari perspektif historis. Analisis linguistik atas al-Qur’an, misalnya cenderung mengabaikan pertimbangan menyangkut konteks sosio-historis di
mana teks muncul, seperti dalam studi asbab al-nuzul dalam al-Qur’an, atau asbab al-wurud dalam bidang hadis. Namun
demikian, ada juga fenomena analisis linguistik yang menarik dengan ditemukannya – bukan dalam konteks peristiwa-
peristiwa turunnya ayat, melainkan berkenaan dengan perkembangan-perkembangan strukturalnya –istilah-istilah etik yang
ada dalam masyarakat Arab pra-Islam yang terpelihara dalam al-Qur’an.28 PENUTUP Penerapan pendekatan semiotik seperti yang telah dipaparkan di atas mempunyai kelebihan dan kekurangan, terutama
berkenaan dengan bidang kajian teks-teks keagamaan. Manfaat analisis semiotik bahwa pendekatan semiotik memandang
suatu teks sebagai keseluruhan dan sebagai suatu sistem dari hubungan-hubungan intern. Pendekatan dengan cara demikian
memungkinkan untuk memahami banyak aspek dari sebuah teks yang tidak dapat ditangkap atas dasar suatu analisis yang
bertolak dari unsur tertentu yang terpisah dan berdiri sendiri dari teks yang bersangkutan. Kelebihan lain adalah bahwa
pendekatan semiotik membuat kita mendekati teks tanpa interpretasi tertentu sebelumnya atau pra anggapan lain. Namun demikian, ada juga beberapa kelemahan mendasar dari pendekatan ini. Analisis semiotik cenderung
mengabaikan aspek-aspek kesejarahan (konteks sosio historis) terhadap teks. Dengan menekankan pada struktur internal
teks, semiotik melakukan interpretasi secara a-historis. Dalam bidang kajian keagamaan, terutama menyangkut teks-teks
agama, proses semiotik yang tiada berakhir menjadikannya tidak memungkinkan untuk menemukan petanda terakhir
(petanda transendental) yang mutlak bagi agama. Ketiadaan petanda terakhir ini membuat terperangkap dalam lingkaran
semiosis, tanpa mampu menemukan makna terakhir. a. Analisis Semiotik Teosofi Israqi Fokus analisis yang prinsipil menurut Netton adalah dengan mengistilahkan “paradigma pencipta qur’ani”. Istilah ini
merupakan artikulasi dari modelatau ‘wajah’ qur’ani Tuhan. Dengan ini Netton mencoba untuk menghindari dua perangkap
umum yang dapat mengkonstitusikan suatu dasar yang kadangkala tersembunyi, tetapi seringkali tampak dalam kebanyakan
tulisan modern mengenai Islam secara umum, dan teologi serta filsafat Islam abad tengah secara khusus. Gagasan bahwa
adanya Islam ortodok , dan desakan untuk melihat semua hal secara murni serta pengaruh Islam dari luar.21 Salah satu pemikiran Islam yang menjadi objek kajian Netton dengan pendekatan semiotiknya adalah analisis dan
interpretasi terhadap karya-karya Suhrawardi yang berjudul “Suhrawardian Semiosis and the Structure of Reality According
to Ibn al-Arabi”, di mana Netton mencoba untuk melakukan interpretasi semiotk terhadap tradisi Israqi.22 Dalam hal ini
pendekatan semiotik digunakan untuk mengungkap makna-makna tersembunyi dari tanda-tanda dalam teks. Untuk itu
Netton membagi dua macam theologemeyang ia coba identifikasikan dalam karya Suhrawardi. Pertama, adalah theologeme
negatif, semacam pendekatan vianegativeterhadap hakikat Tuhan. Kedua,adalah theologeme positif, seperti “motif cahaya”
(motif of Light).23 Theologeme-theologeme ini dapat ditemukan dalam karya Suharawardi dan menjadi ‘tanda-tanda’ (sign)
yang mengungkapkan suatu konsentrasi cahaya dan kegelapan sebagai dua hal yang saling bertentangan. Cahaya murni (pure
light) berkorespondensi dengan Tuhan, sementara kehadiran cahaya yang tercampur (gelap) berkorespondensi dengan
tingkat eksistensi manusia.24 Menurut Netton, theologeme merupakan tanda yang menunjukan realitas Tuhan, yang merupakan unsur-unsur
Plotinian, Kristian, model-model Qur’ani, atau paradigma-paradigma.25 Hal-hal yang tercakup dalam theologeme seperti
“keesaan Tuhan” (divine unity), “tidak dapat diketahuinya Tuhan” , “aspek yang dapat diketahui Tuhan” (knowable aspect),
“keagungan Tuhan” (God’s Glory), “kosa kata cahaya” (light vocabulary), yakni Tuhan yang diselubungi cahaya,
“pengetahuan Tuhan”, “kebangkitan” (resurrection), dan Allah sebagai “wajib al-wujud”. Theologeme-theologeme lainnya
merupakan theologeme “kesederhanaan” (simplicity) atau theologeme ’transendensi’ seperti “kekekalan (immutability),
“individualitas” (individuality), “tak terdefinisikan” (indefinability), “immaterialitas” (immateriality).26 Dengan mengaplikasikan pendekatan yang diilhami secara semantik guna menemukan makna ‘tanda’ yang
direpresentasikan oleh unsur-unsur luar dalam pemikiran Suhrawardi, Netton menemukan adanya nama Zoroastrian yang
dianggap Suhrawardi sebagai unsur-unsur cahaya ontologisnya. Dengan demikian, Netton menemukan adanya pengaruh-
pengaruh Zoroastrian dalam karya-karya Suhrawardi. KOMUNIKA
Vol.2 No.2 Jul-Des 2008 pp.277-289 KOMUNIKA
Vol.2 No.2 Jul-Des 2008 pp.277-289 Jurusan Dakwah STAIN Purwokerto Jurusan Dakwah STAIN Purwokerto ISSN: 1978-126 ISSN: 1978-126 ISSN: 1978-126 JURNAL DAKWAH DAN KOMUNIKASI 28Toshihiko Izutsu, Etika Beragama dalam Qur’an. Terj. Masurussin Djoely (Jakarta: Pustaka Firdaus, 1995), hal. 111-2. ,
,
,
,
27Seyyed Hossein Nasr, Three Muslim Sages, Avicenna –suhrawardi –Ibn ‘Arabi(Delmar, NY: Caravan Books, 1969), hal. 52-58 27Seyyed Hossein Nasr, Three Muslim Sages, Avicenna –suhrawardi –Ibn ‘Arabi(Delmar, NY: Caravan Books, 1969), hal. 52-58. 28ToshihikoIzutsu,EtikaBeragamadalamQur’an.Terj.MasurussinDjoely(Jakarta:PustakaFirdaus,1995),hal.111-2. 28Toshihiko Izutsu, Etika Beragama dalam Qur’an. Terj. Masurussin Djoely (Jakarta: Pustaka Firdaus, 1995), hal. 111-2. ENDNOTE 3Umberto Eco, A Theory of Semiotics(Bloomington: Indiana University Press, 1976), hal. 33-4. 8 Johan Hendrik Meuleman (Ed.), “Sumbangan dan Batas Semiotika dalam Ilmu Agama”, dalam Tradisi, Kemodernan dan Metamodernisme: 8 Johan Hendrik Meuleman (Ed.), “Sumbangan dan Batas Semiotika dalam Ilmu Agama”, dalam Tradisi, Kemodernan dan Metamodernisme:
MemperbincangkanPemikiranMohammedArkoun(Yogyakarta:LKiS 1996) hal 35-6 Memperbincangkan Pemikiran Mohammed Arkoun(Yogyakarta: LKiS, 1996), hal. 35-6. 9 Eugenio Coseriu, Die Geschichte der Srachphilosophie von der Antike bis zur Gegenwart (Tubingen: TBL, 1970), hal. 123, dikutip oleh Johan
Meuleman. Op.Cit. hal 36. 9 Eugenio Coseriu, Die Geschichte der Srachphilosophie von der Antike bis zur Gegenwart (Tubingen: TBL, 1970), hal. 123, dikutip oleh Johan
Meuleman. Op.Cit. hal 36. 10 Budhi Munawar Rachman, “Bahasa agama dalam Filsafat: Ekspresi Pengalaman Ketersingkapan”, dalam Islam Pluralis, Wacana Kesetaraan
Kaum Beriman(Jakarta: Paramadina, 2001), hal. 4. 10 Budhi Munawar Rachman, “Bahasa agama dalam Filsafat: Ekspresi Pengalaman Ketersingkapan”, dalam Islam Pluralis, Wacana Kesetaraan
Kaum Beriman(Jakarta: Paramadina, 2001), hal. 4. Jurusan Dakwah STAIN Purwokerto JURNAL DAKWAH DAN KOMUNIKASI 11Ibid., hal. 5. 11Ibid., hal. 5. 12Ian R. Netton, Transcendent: Studies in the Structure and Semiotics of Islam:cs Philosophy, Theology and Cosmology (Routledge: Curzon, 1995),
hal. 201-3. 12Ian R. Netton, Transcendent: Studies in the Structure and Semiotics of Islam:cs Philosophy, Theology and Cosmology (Routledge: Curzon, 1995)
h l 2013 13Mohammed Arkoun, Berbagai Pembacaan Qur’an, Terj. Machasin (Jakarta: INIS, 1997). 14Ibid., hal. 103. 15 Analisis mitis ini oleh Arkoun diyakini dapat memberikan pemahaman multi dimensi antarteks. Analisis ini dapat melengkapai analisis-analisis
tradisional yang terfokus pada analisis leksiko-gramatikal, teologis, dan sebagainya. Analisis mitis sebenarnya banyak dilakukan di bidang antropologi
sosial dan budaya untuk mengungkap struktur-struktur mitos dari berbagai kebudayaan. Oleh karena itulah, dalam pembacaan surat al-Fatihah, Arkoun
memberi ruang kepada moment (langkah) antropologis guna mengungkapkan “struktur bahasa mitis yang ada dalam al-Qur’an”. Ibid.,hal.115. Sementara itu, ada berbagai kemungkinan pembacaan teradap mitos ini. Roland Barthes, misalnya, menganalisis mitos sebagai tanda, yang merupakan
gabungan penanda dan petanda pada tataran signifikasi pertama atau denotasi, yang kemudian menjadi penanda dalam suatu “sistem semiotik tingkat
kedua atau konotasi”. Sistem signifikasi kedua itulah yang disebutnya mitos. Untuk penjelasan lebih lanjut mengenai sistem signifikasi ini lihat Rolanda
Barthes, Mythologiest, trans. Jonathan Cape (New York: Hill and Wang, 1983), hal. 120. 16Johan Hendrik Meuleman, Op.Cit., hal. 43. 17Arkoun, Op.Cit., hal. 98. 18Johan Meuleman (Ed.), Op.Cit., hal. 46, Mohammed Arkoun, La pensee arabe(Paris: P.U.F., 1975), hal. 9. 19Ibid hal48 20 Dalam usahanya untuk melampui batas semiotika, Arkoun banyak dipengaruhi Derrida. Arkoun mengambil-alih anggitan “pembongkaran”,
kungkungan logosentris”, serta “yang tak dipikirkan” dan “yang tak terpikirkan” dari Derrida. Teks adalah sebuah sistem dari jejak yang saling menunjukan. Tidak ada suatu asal atau dasar dari jejak di luar teks. Makna justru hanya diciptakan oleh jejak-jejak–atau lebih tepat oleh ke-berbeda-an antara segala
jejak Ibid 54-5 20 Dalam usahanya untuk melampui batas semiotika, Arkoun banyak dipengaruhi Derrida. Arkoun mengambil-alih anggitan “pembongkaran”,
kungkungan logosentris”, serta “yang tak dipikirkan” dan “yang tak terpikirkan” dari Derrida. Teks adalah sebuah sistem dari jejak yang saling menunjukan. Tidak ada suatu asal atau dasar dari jejak di luar teks. Makna justru hanya diciptakan oleh jejak-jejak–atau lebih tepat oleh ke-berbeda-an antara segala
jejak. Ibid., 54-5. 21Netton., Op.Cit., hal. 18. 22Ibid., hal. 280. 23Ibid., hal. 301-2. 24Ibid., hal. 300-1. 25Ibid., hal. 80, 132, 135. 26Ibid., hal. 132, 237, 240, 240. Ibid., hal. 132, 237, 240, 240. 27Seyyed Hossein Nasr, Three Muslim Sages, Avicenna –suhrawardi –Ibn ‘Arabi(Delmar, NY: Caravan Books, 1969), hal. 52-58. DAFTAR PUSTAKA Arkoun, Mohammed.1997. Berbagai Pembacaan Qur’an, terj. Machasin Jakarta: INIS. Arkoun, Mohammed. 1975. La pensee Arabe.Paris: P.U.F. Barthes, Roland. 1983. Mythologiest, trans. Jonathan Cape. New York: Hill and Wang. Coseriu, Eugenio. 1970. Die Geschichte der Srachphilosophie von der Antike bis zur Gegenwart. Tubingen: TBL. Eco, Umberto . 1976. A Theory of Semiotics.Bloomington: Indiana University Press. Eco, Umberto . 1976. A Theory of Semiotics.Bloomington: Indiana University Press. Effendy, Onong Uchjana. 2006. Ilmu Komunikasi,Teori dan Praktek. Bandung: PT Remaja Rosdakarya. Gadamer, Hans George. 1976. Philosopical Hermeneutics. Barkeley: University of California Press. Izutsu, Toshihiko.1995. Etika Beragama dalam Qur’an. Terj. Masurussin Djoely. Jakarta: Pustaka Firdaus. Meuleman, Johan Hendrik (Ed.). 1996. Sumbangan dan Batas Semiotika dalam Ilmu Agama. dalam Tradisi, Kemodernan dan
Metamodernisme:MemperbincangkanPemikiranMohammedArkoun Yogyakarta:LKiS Hendrik (Ed.). 1996. Sumbangan dan Batas Semiotika dalam Ilmu Agama. dalam Tradisi, Kemodernan dan Meuleman, Johan Hendrik (Ed.). 1996. Sumbangan dan Batas Semiotika dalam Ilmu Agama. dalam
Metamodernisme: Memperbincangkan Pemikiran Mohammed Arkoun.Yogyakarta: LKiS. Nasr, Seyyed Hossein. 1969. Three Muslim Sages, Avicenna –Suhrawardi –Ibn ‘Arabi. Delmar, NY: Caravan Books. Nasr, Seyyed Hossein. 1969. Three Muslim Sages, Avicenna –Suhrawardi –Ibn ‘Arabi. Delmar, NY: Caravan Books. Netton, Ian R. 1995. Transcendent: Studies in the Structure and Semiotics of Islam:cs Philosophy, Theology and Cosmology. Routledge:
Curzon. Netton, Ian R. 1995. Transcendent: Studies in the Structure and Semiotics of Islam:cs Philosophy, Theology and Cosmology. Routledge:
Curzon. Rachman, Budhi Munawar. 2001. Bahasa agama dalam Filsafat: Ekspresi Pengalaman Ketersingkapan. dalam Islam Pluralis, Wacana
Kesetaraan Kaum Beriman.Jakarta: Paramadina. Rachman, Budhi Munawar. 2001. Bahasa agama dalam Filsafat: Ekspresi Pengalaman Ketersingkapan. dalam Islam Pluralis, Wacana
Kesetaraan Kaum Beriman.Jakarta: Paramadina. Sidik,
A. Ja’far
M. 2008. “Resensi
Buku
-Membedah
Makna
Budaya
Dengan
Pisau
Semiotik”
dalam Antara. http://www.antara.co.id/arc/0807/31/resensibuku-membedah-makana-kehidupan-dengan-pisau.semiotik.htm. Sidik,
A. Ja’far
M. 2008. “Resensi
Buku
-Membedah
Makna
Budaya
Dengan
Pisau
Semiotik”
dalam Antara. http://www.antara.co.id/arc/0807/31/resensibuku-membedah-makana-kehidupan-dengan-pisau.semiotik.htm. KOMUNIKA
ISSN: 1978-126
Vol.2 No.2 Jul-Des 2008 pp.277-289 Jurusan Dakwah STAIN Purwokerto JURNAL DAKWAH DAN KOMUNIKASI Sudjiman, Panuti dan Aart van Zoest (Ed.). 1996. Serba-serbi Semiotika. Jakarta: Gramedia. Wikipedia Indonesia.2008. Semiotika. http://id.wikipedia.0rg/wiki/Semiotika/0807/31/.htm. KOMUNIKA
Vol.2 No.2 Jul-Des 2008 pp.277-289 KOMUNIKA
Vol.2 No.2 Jul-Des 2008 pp.277-289 Jurusan Dakwah STAIN Purwokerto ISSN: 1978-126 Jurusan Dakwah STAIN Purwokerto ISSN: 1978-126
|
https://openalex.org/W2046374046
|
https://bmcecolevol.biomedcentral.com/counter/pdf/10.1186/1471-2148-7-198
|
English
| null |
Analysis of complete mitochondrial genome sequences increases phylogenetic resolution of bears (Ursidae), a mammalian family that experienced rapid speciation
|
BMC evolutionary biology
| 2,007
|
cc-by
| 9,432
|
BioMed Central BioMed Central BioMed Central BMC Evolutionary Biology 2007, 7:198
doi:10.1186/1471-2148-7-198 BMC Evolutionary Biology 2007, 7:198
doi:10.1186/1471-2148-7-198 This article is available from: http://www.biomedcentral.com/1471-2148/7/198 s article is available from: http://www.biomedcentral.com/147 © 2007 Yu et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0),
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Published: 24 October 2007 Published: 24 October 2007 BMC Evolutionary Biology Open Access p
p
p
Li Yu*†1, Yi-Wei Li†1, Oliver A Ryder3 and Ya-Ping Zhang*2,1 Address: 1Laboratory for Conservation and Utilization of Bio-resource, Yunnan University, Kunming 650091, China, 2State Key Laboratory of
Genetic Resource and Evolution, Kunming Institute of Zoology, Kunming 650223, China and 3Conservation and Research for Endangered Species,
Zoological Society of San Diego, PO Box 551, San Diego, CA 92112, USA Email: Li Yu* - yuli1220@yahoo.com.cn; Yi-Wei Li - azalee713@gmail.com; Oliver A Ryder - oryder@ucsd.edu; Ya-
Ping Zhang* - zhangyp1@263.net.cn * Corresponding authors †Equal contributors * Corresponding authors †Equal contributors Received: 9 February 2007
Accepted: 24 October 2007 Received: 9 February 2007
Accepted: 24 October 2007 Background Finding a valid genetic marker that offers sufficient varia-
tion to distinguish among recently divergent species
posed a major challenge to advancing the understanding
of ursid phylogeny. Previous investigations of phyloge-
netic relationships among the bear species mainly utilized
analysis of portions of a single mitochondrial (mt) gene
or a small number of mt genes [8,10-13]. In general,
mtDNA accumulates mutations at a relatively faster rate
and has a shorter expected coalescence time than other
types of sequence data, e.g. nuclear DNA, thus making it
particularly useful for revealing closely spaced branching
events [14-17]. However, none of the previous mt analy-
ses provided conclusive resolution for this low-level phy-
logeny. Additionally, analyses of different genes within
the mt genome have resulted in inconsistent branching
patterns being reported in the Ursidae (Figure 1A–E). Recently, several lines of evidence have demonstrated that
using sufficiently large amounts of mtDNA sequence data,
e.g. the whole mt genome, is a powerful way to ameliorate
the discordances and poor resolution that plague analyses
based on single genes or segments [16,18-22]. Thus, as a
further step toward the understanding of Ursidae phylog-
eny, it was highly desirable to address this evolutionary
question from a mitogenomic perspective. g
The Ursidae is a major family of the order Carnivora, com-
prising eight species. They are generally classified into
three genera: Ailuropoda (giant panda), Tremarctos (specta-
cled bear), and Ursus (brown, polar, sloth, sun, and Asiatic
and American black bears) [1-3]. Despite the small
number of ursid species, bear phylogeny has long been a
focus of study due to their conservation value, as all bear
genera have been classified as endangered at either the
species or subspecies level. The ultimate recognition of the
giant panda Ailuropoda melanoleuca as the most basal off-
shoot in the bear family, after more than a century of
debate since this species' discovery in 1864, was one of the
most spectacular events in the history of modern phyloge-
netics [4-8]. This achievement also sparked controversy
regarding the relationships among the other members of
Ursidae and the possibility of an extremely recent radia-
tion for genus Ursus [6,8,9] (6 million years ago). Up to
now, only the subsequent divergence of Tremarctos ornatus
(the spectacled bear) to the giant panda, and the sister
grouping of Ursus arctos (the brown bear) and Ursus mar-
itimus (the polar bear) have been unambiguously
accepted. http://www.biomedcentral.com/1471-2148/7/198 http://www.biomedcentral.com/1471-2148/7/198 Abstract Background: Despite the small number of ursid species, bear phylogeny has long been a focus of
study due to their conservation value, as all bear genera have been classified as endangered at either
the species or subspecies level. The Ursidae family represents a typical example of rapid
evolutionary radiation. Previous analyses with a single mitochondrial (mt) gene or a small number
of mt genes either provide weak support or a large unresolved polytomy for ursids. We revisit the
contentious relationships within Ursidae by analyzing complete mt genome sequences and
evaluating the performance of both entire mt genomes and constituent mtDNA genes in recovering
a phylogeny of extremely recent speciation events. Results: This mitochondrial genome-based phylogeny provides strong evidence that the
spectacled bear diverged first, while within the genus Ursus, the sloth bear is the sister taxon of all
the other five ursines. The latter group is divided into the brown bear/polar bear and the two black
bears/sun bear assemblages. These findings resolve the previous conflicts between trees using
partial mt genes. The ability of different categories of mt protein coding genes to recover the
correct phylogeny is concordant with previous analyses for taxa with deep divergence times. This
study provides a robust Ursidae phylogenetic framework for future validation by additional
independent evidence, and also has significant implications for assisting in the resolution of other
similarly difficult phylogenetic investigations. Conclusion: Identification of base composition bias and utilization of the combined data of whole
mitochondrial genome sequences has allowed recovery of a strongly supported phylogeny that is
upheld when using multiple alternative outgroups for the Ursidae, a mammalian family that
underwent a rapid radiation since the mid- to late Pliocene. It remains to be seen if the reliability
of mt genome analysis will hold up in studies of other difficult phylogenetic issues. Although the
whole mitochondrial DNA sequence based phylogeny is robust, it remains in conflict with
phylogenetic relationships suggested by analysis of limited nuclear-encoded data, a situation that
will require gathering more nuclear DNA sequence information. Page 1 of 11
(page number not for citation purposes) (page number not for citation purposes) http://www.biomedcentral.com/1471-2148/7/198 BMC Evolutionary Biology 2007, 7:198 Background All other relationships within the genus Ursus
remained an unresolved polytomy (Figure 1). Long-standing unresolved Ursidae phylogeny (tree in the left) and competing hypotheses proposed based on previous
sequence data (mtA-E and nuA-B)
Figure 1
Long-standing unresolved Ursidae phylogeny (tree in the left) and competing hypotheses proposed based on previous
sequence data (mtA-E and nuA-B). Trees were constructed from (mtA) combined analysis of partial control region, 12SrRNA,
CYTB, tRNAPro, and tRNAThr mt genes [11], (mtB) MP analysis of complete CYTB, tRNAPro, and tRNAThr mt genes [12], (mtC)
NJ analysis of complete CYTB, tRNAPro, and tRNAThr mt genes [12], (mtD) combined analysis of partial control region, CYTB,
ND4, ND5, COII, and 16SrRNA mt genes [8], (mtE) combined analysis of partial control region, 12SrRNA, complete CYTB,
tRNAPro, and tRNAThr mt genes [13], (nuA) combined analysis of interphotoreceptor retinoid binding protein (IRBP) exon1
and transthyretin (TTR) intron 1 nuclear genes [13], and (nuB) combined analysis of four type I sequence-tagged sites (STS) and
IRBP exon 1 nuclear genes [60]. esolved Ursidae phylogeny (tree in the left) and competing hypotheses proposed based on previous
A-E and nuA-B)
esolved Ursidae phylogeny (tree in the left) and competing hypotheses proposed based on previous
A E
d
A B) T
d f
(
A)
bi
d
l
i
f
i l
l
i
12S Long-standing unresolved Ursidae phylogeny (tree in the left) and competing hypotheses proposed based on previous
sequence data (mtA-E and nuA-B)
Figure 1
Long-standing unresolved Ursidae phylogeny (tree in the left) and competing hypotheses proposed based on previous
sequence data (mtA-E and nuA-B). Trees were constructed from (mtA) combined analysis of partial control region, 12SrRNA,
CYTB, tRNAPro, and tRNAThr mt genes [11], (mtB) MP analysis of complete CYTB, tRNAPro, and tRNAThr mt genes [12], (mtC)
NJ analysis of complete CYTB, tRNAPro, and tRNAThr mt genes [12], (mtD) combined analysis of partial control region, CYTB,
ND4, ND5, COII, and 16SrRNA mt genes [8], (mtE) combined analysis of partial control region, 12SrRNA, complete CYTB,
tRNAPro, and tRNAThr mt genes [13], (nuA) combined analysis of interphotoreceptor retinoid binding protein (IRBP) exon1
and transthyretin (TTR) intron 1 nuclear genes [13], and (nuB) combined analysis of four type I sequence-tagged sites (STS) and
IRBP exon 1 nuclear genes [60]. Reconstructing the Phylogenetic Relationships g
y
g
p
The combined data set of 12 protein-coding genes (10882
aligned nucleotide sites; 3534 variable and 1970 parsi-
mony-informative) produced a single most-parsimonious
tree of 5512 steps without MP weighting (Figure 2A). In
this tree, the spectacled bear diverged earliest (MP BS =
100%), followed by the sloth bear (MP BS = 67%). Sister-
group relationships were indicated between the Asiatic
black and the American black bear (MP BS = 86%), as well
as between the brown and the polar bear (MP BS = 100%),
while the sun bear clustered with the two black bears (MP
BS = 65%). Because the giant panda sequence deviates sig-
nificantly from the mean nucleotide frequency on the 3rd
codon position by a 5% chi-square test (p < 0.05), the
phylogenetic analysis was therefore also conducted under
different weighting schemes, including P12 and RY-cod-
ing methods (see Methods). In all cases, an identical
topology to that of unweighted analysis was obtained, but
the close relatedness between the Asian black and Ameri-
can black bears was less well supported (MP BS < 50%;
Figure 2A). Generally, better resolution and stronger boot-
strap supports were obtained from DNA datasets that
included all substitutions than from those subjected to
the weighting. As an alternative attempt to evaluate the
effect of compositional bias on the reconstructed tree, we
reanalyzed the data without the giant panda and used
spectacled bear for rooting. This approach provided a data
set without significant base composition variation (p >
0.05). Interestingly, the resulting tree topology remained
constant but there was a noticeable effect on the nodal
support, where all relationships in the tree were robustly
identified (MP BS > 85%; Figure 2A). Particularly, BS for
the positions of the sloth bear and the sun bear increased
to 90% and 87%, respectively. ML and partitioned Baye-
sian analyses (using distinct models and rates for each Background Page 2 of 11
(page number not for citation purposes) http://www.biomedcentral.com/1471-2148/7/198 http://www.biomedcentral.com/1471-2148/7/198 BMC Evolutionary Biology 2007, 7:198 BMC Evolutionary Biology 2007, 7:198 BMC Evolutionary Biology 2007, 7:198 On the basis of the most comprehensive molecular data
set assembled to date for the Ursidae, the present work
revisits the contentious relationships within genus Ursus
by analyzing complete mt genome sequences from all rep-
resentatives of bears and, for the first time, evaluates the
performance of both entire mt genomes and constituent
mtDNA genes in recovering a phylogenetic tree within a
rapid, recent radiation. The improved reconstruction of
ursid relationships utilizing the entire mt genome also
permitted a refined dating of evolutionary divergence
among these bear species. Our research thus not only gen-
erates a strong Ursidae phylogenetic framework for future
validation using additional evidence but, most signifi-
cantly, provides a model system against which to examine
the usefulness of mt genomes for resolving difficult phyl-
ogenies with rapid species radiation. tRNA dataset (average 5.2%), from 5.0 to 18.9% for the
control region (average 10%), and from 2.2 to 17.0% for
the complete dataset (average 10.7%). http://www.biomedcentral.com/1471-2148/7/198 http://www.biomedcentral.com/1471-2148/7/198 BMC Evolutionary Biology 2007, 7:198 protein gene) of the dataset, whether the giant panda or
the spectacled bear was used as outgroup, showed the
same tree topology as Figure 2A. All nodes in the ML and
Bayesian trees received high BP (≥ 85%) and PP (≥ 0.99)
except for the position of the sloth bear. Tables in Figure
2A illustrate the confidence level of the nodal relation-
ships under all analytical approaches. 50% majority-rule consensus of the two parsimonious
trees (Figure 2B), the two black bears and the sun bear
formed a clade on the ML (ML BS = 62%) and partitioned
Bayesian trees (distinct models and rates for two rRNA
genes; PP = 0.95; Figure 2C), a relationship also supported
in the protein-coding gene analysis. Interestingly, when
stem-loop secondary structures were considered, the sin-
gle most-parsimonious tree (495 steps) based on the loop
region (1283 bp) identified the same topology as Figure
2A. In contrast, 50% majority-rule consensus of three
equally most-parsimonious trees (186 steps) based on the
stem region (1291 bp) recovered a tree topology that dif-
fered in placing the Asiatic black bear as basal to the reset
of Ursus, while joining the American black bear, the sun
bear, and the sloth bear on a common branch (data not
shown). However, nodal supports for most relationships
in the stem and loop trees are below 50%, with the excep-
tion of the earliest branching of the spectacled bear
among the in-group and the close association of the
brown and polar bears (MP BS = 100%). Both of the combined RNA data sets (rRNAs and tRNAs)
demonstrated reduced resolving power for phylogenetic
inference compared to protein-coding gene analysis (Fig-
ure 2B–D). The aligned rRNA sequences (combined 12S
and 16SrRNA genes) were 2574 bp in length, of which
480 nucleotide sites were variable and 222 were parsi-
mony-informative. MP analysis yielded two equally most-
parsimonious trees of 683 steps. One of them is topolog-
ically identical to the protein-coding gene tree shown in
Figure 2A. Although most relationships collapsed on the Phylogenetic trees and nodal supports (groups that received
more than 50% BS or 0
Figure 2
Phylogenetic trees and nodal supports (groups that received
more than 50% BS or 0.6 PP were retained) based on analy-
ses of different subsets of mt genome. http://www.biomedcentral.com/1471-2148/7/198 The tRNA data set (combined 22 tRNA genes) contained
1518 bp of aligned sites, of which 256 were variable and
100 were parsimony-informative. Parsimony analysis
produced a most-parsimonious tree of 341 steps with a
different topology from those of protein-coding and rRNA
gene analyses. According to this tree, the sloth bear was
grouped with the Asiatic black bear, and they are placed as
a clade sister to the lineage leading to the American black
bear and the sun bear. However, in this tree only the basal
position of the spectacled bear, and the close association
of the brown bear and the polar bear, were convincingly
supported (MP BS = 100%; Figure 2D); none of the other
relationships received MP BS larger than 50%. ML and
Bayesian analyses produced a similar tree topology and
nodal support as the MP tree. In the control region of the mt genome, tandem repeated
sequences and ambiguously aligned regions were
excluded, leaving 1008 positions in the phylogenetic anal-
ysis. 316 were variable and 124 were parsimony-informa-
tive. MP reconstruction yielded a most-parsimonious tree
of 463 steps. The striking topological difference from pro-
tein-coding and RNA gene analyses was the positioning of
the sun bear, Asian black bear, and American bears as the
successive sister taxa to the clade consisting of the brown
and polar bears. However, only the branch that separates
the spectacled bear from Ursus and the basal diverging of
the sloth bear within Ursus, and the affinity of the brown
and polar bears, received >50% bootstrap support (Figure
2E). ML and Bayesian analyses of the same data set found
a large unresolved polytomy leading to most bear species,
and only the sister-grouping of the brown and polar bears
was strongly supported (ML BS = 99% and PP = 1.00; Fig-
ure 2F). Sequence Characteristics The general characteristics of eight bear mt genomes are
summarized in Table 1. These complete mt genomes
range from 16,746–17,020 bp in size. Length differences
are largely due to the variation in copy number of tandem
repeated sequences in the conserved sequence block
(CSB) domains of the mt control region. All genomes
share not only 13 protein-coding genes, 22 tRNAs genes,
2 rRNAs, and a control region, but also the same gene
order. The overall average nucleotide composition of bear
mt genomes is A = 30.9%, C = 25.0%, G = 15.6%, and T =
28.5%. The constancy of nucleotide base composition
was examined using the chi-square test with PUZZLE for
different subsets of mt genome (defined in Methods), and
heterogeneous nucleotide composition (p < 0.05) was
observed in the combined protein-coding gene dataset
and the complete dataset (as described below). The K2P
distances [23] among seven ingroup taxa calculated using
MEGA3 [24] range from 2.3 to 19.9% for the protein-cod-
ing dataset (average 12.8%), from 1.2 to 10.1% for the
rRNA dataset (average 6.1%), from 1.3 to 8.7% for the Page 3 of 11
Table 1: General characteristics of eight bear mt genomes
Taxa
Genome Length(bp)
G+C nucleotide content (%)
Genus
Scientific
Name
Sample Source
Accesion No. total
protein
coding
rRNAs
tRNAs
control
region
total
protein-
coding
rRNAs
tRNAs
control
region
Ursus
U. arctos
----
AF303110 [38]
17,020
10,882
2,541
1,511
1,578
40.8
41.5
40.5
35.9
41.6
U. maritimus
----
AF303111 [38]
17,017
10,882
2,542
1,511
1,575
40.8
41.4
40.6
36.2
42.0
U. thibetanus
Yunnan Province,
China
EF196661
(this study)
16,795
10,877
2,548
1,512
1,346
40.7
41.4
40.3
35.9
40.6
U. americanus
----
AF303109 [38]
16,841
10,882
2,545
1,512
1,396
40.4
41.0
40.2
36.4
40.3
U. malayanus
Yunnan Province,
China
EF196664
(this study)
16,783
10,882
2,546
1,512
1,337
40.7
41.4
40.2
35.9
40.2
U. ursinus
San Diego Zoo,
USA
EF196662
(this study)
16,817
10,882
2,545
1,511
1,371
41.6
42.3
40.9
36.9
41.7
Tremarctos
T. ornatus
San Diego Zoo,
USA
EF196665
(this study)
16,766
10,882
2,553
1,510
1,315
41.1
41.9
40.1
35.7
43.0
Ailuropoda
A. melandeuca
Sichuan Province,
China
EF196663
(this study)
16,746
10,880
2,551
1,515
1,286
38.5
38.3
39.0
37.0
41.1 Table 1: General characteristics of eight bear mt genomes Table 1: General characteristics of eight bear mt genomes http://www.biomedcentral.com/1471-2148/7/198 http://www.biomedcentral.com/1471-2148/7/198 BMC Evolutionary Biology 2007, 7:198 To maximize the amount of phylogenetic information, we
also pooled all mt protein-coding genes, RNA genes, and
control regions to form a single data set with a length of
15982 aligned sites for "genome phylogeny" reconstruc-
tion, of which 4586 were variable and 2416 were parsi-
mony-informative. A unique topology exactly identical to
that produced by the combined protein-coding gene anal-
ysis, but with higher statistical nodal supports, was
obtained by all three analytical approaches (Figure 3; 70–
100% BS and 0.85–1.00 PP). The tree topology was not
affected by exclusion of the giant panda sequence (p <
0.05 with PUZZLE) and moreover, by rooting the tree
with the spectacled bear, the supports for most branches
increased to convincing statistical significance (≥ 85 BS
and ≥ 0.95 PP), increasing our confidence in the result. The complete mtDNA genome-based phylogeny of the
Ursidae incorporates the largest amount of phylogeneti-
cally informative sequence-based characters and provides
the most robust tree for this carnivore family in terms of
resolved topology and support for nodes. species in Ursus was either not recovered at all or varied
considerably with little or no nodal support. Among these
single gene trees, only the CYTB and ND5 trees have the
same branching order as that from the combined all gene
analysis (Figure 3). To better assess which grouping in whole-genome phylog-
eny was supported by different parts of the mt genome
(i.e., protein-coding, RNA genes, and control region), we
performed partitioned Bremer support (PBS) analysis and
the result is shown in Figure 5. The partial Bremer index
for each data partition is determined by subtracting the
number of steps for that partition in the most parsimoni-
ous tree from the number of steps for that partition in the
shortest tree lacking the node in question [25]. Partial
decay indices may be either positive or negative for an
individual data partition. PBS analysis indicated that
among the 16 gene partitions examined (Figure 5), the
ND5 gene provides the greatest contribution to the com-
plete gene tree resolution (124/750 = 16.53%) while the
ND3 gene contributes the least (9/750 = 1.30%). From
the results of PBS analysis, we find that all genes allocated
Bremer supports predominately in the traditionally well-
established relationships, i.e., branches 1 and 5 in the tree
(94.93% in total; data not shown). Assessing the Performance of Individual Genes Assessing the Performance of Individual Genes
The determination of complete mt sequences from all
bear species affords the opportunity not only to utilize
these data to estimate the phylogeny of the Ursidae but
also, to examine characteristics of the evolution of mito-
chondrial protein coding and non-coding genes. It is of
interest to evaluate their individual performance in sup-
porting the complete mtDNA-based phylogeny within
such a recent radiation involving specializations to a vari-
ety of habitats and reproductive patterns. For this reason,
unweighted MP analysis was also performed on protein-
coding and rRNA genes individually (Figure 4; only >50%
MP BS are indicated on the branches). The earliest split of
the spectacled bear and the grouping of the brown bear
and polar bear, which are the only two strongly supported
hypotheses in Ursidae phylogeny to date, are observed in
all of these single-gene trees (61–100% and 76–100% MP
BS, respectively) whereas the position of the other bear http://www.biomedcentral.com/1471-2148/7/198 Leaving these two
branches out of the analysis, the ND5 gene still provided
the largest proportion of PBS values (19/40 = 47.50%)
compared to those of the remaining branches (Figure 5). In contrast, the ND1 gene provided the highest conflict
values (-14/40 = -35.00%). Whether branches 1 and 5
were included or not, PBS analyses give the rough appear-
ance of relatively superior performance of ND5, ND4,
CYTB, 16SrRNA, and ND2 genes, and on the other hand,
of the poor utility of ND3, ND4L and ND1 genes. Com-
bined tRNAs, COX2, 12SrRNA genes, and control region
are intermediate (Figure 5). Phylogenet
more than
Figure 2 Phylogenetic trees and nodal supports (groups that received
more than 50% BS or 0
Figure 2
Phylogenetic trees and nodal supports (groups that received
more than 50% BS or 0.6 PP were retained) based on analy-
ses of different subsets of mt genome. y g
pp
(g
p
g
Phylogenetic trees and nodal supports (groups that received
more than 50% BS or 0.6 PP were retained) based on analy-
ses of different subsets of mt genome. Page 4 of 11
(page number not for citation purposes) http://www.biomedcentral.com/1471-2148/7/198 http://www.biomedcentral.com/1471-2148/7/198 Page 5 of 11
(page number not for citation purposes) Dating the Evolutionary Divergences Results of a likelihood ratio test of the molecular-clock
hypothesis for the five data sets, as defined for the phylo-
genetic analysis, are presented in Table 2. The combined
protein-coding data set was used in estimating divergence
times of Ursidae radiation, in view of its relatively good
tree resolution and constant evolutionary rates across all
taxa. By applying a minimum paleonotological date of
separation between the giant panda and the other bear
species of 12 million years ago [26,27] (MYA), which has
also been used as an established reference in all previous
studies of Ursidae [8,12,13], we inferred that the diver-
gence of the spectacled bear from the ursine clade
occurred at 10.91 MYA (95% confidence intervals = 9.93–
11.89 MYA). The six closely related bears in genus Ursus
began their recent radiation from a common ancestor at
6.34 MYA (95% confidence intervals = 5.95–6.73 MYA;
node 5 in Figure 3). Similar thinking applied to the genus Mt genome tree and nodal supports
Figure 3
Mt genome tree and nodal supports. Mt genome tree and nodal supports
Figure 3
Mt genome tree and nodal supports. g
pp
g
Mt genome tree and nodal supports. g
pp
g
Mt genome tree and nodal supports. Page 5 of 11
(page number not for citation purposes) Page 5 of 11
(page number not for citation purposes) http://www.biomedcentral.com/1471-2148/7/198 BMC Evolutionary Biology 2007, 7:198 Phylogenetic trees based on individual mt genes
Figure 4
Phylogenetic trees based on individual mt genes. Only >50% MP BS are indicated on the branches. Phylogenetic trees based on individual mt genes
Figure 4
Phylogenetic trees based on individual mt genes. Only >50% MP BS are indicated on the branches. Phylogenetic trees based on individual mt genes
Figure 4
Phylogenetic trees based on individual mt genes. Only >50% MP BS are indicated on the branches. Ursus suggests a divergence time between the brown and
polar bears and the two black bears/sun bear of 6.13 MYA
(95% confidence intervals = 5.54–6.72 MYA; node 4), and
that between the sun bear and the two black bears of
5.673 MYA (95% confidence intervals = 5.09–6.26 MYA;
node 3). The dating for the divergence between the Asian
black and American black bear was 5.19 MYA (95% con-
fidence intervals = 4.6–5.78 MYA; node 2), and that
between the brown bear and polar bear 1.32 MYA (95%
confidence intervals = 0.93–1.71 MYA; node 1). Dating the Evolutionary Divergences Table 3
shows these divergence time evaluations and also those in
previous studies for comparison. Page 6 of 11
(page number not for citation purposes) Discussion Among mammalian phylogenies, those characterized by
rapid species radiations have long been one of the most
plaguing and challenging problems in species tree recon-
struction [28]. This is the first study utilizing data from
whole mitochondrial genome sequences from ursids, an
approach that allows increased phylogenetic resolution of
the Ursidae family, whose origin can be traced back to the
extremely recent mid-Miocene[6,9] (15–20 MYA). Previ-
ous molecular studies relevant to Ursidae phylogeny pro-
vided either an inconsistent view on the issue or weak
statistical support for discriminating alternative hypothe-
ses (Figure 1). The branching event following the diver-
gence of the spectacled bear has long been a large
unresolved polytomy leading to six Ursus species, of
which only the sister-relationship between the brown
bear and polar bear was unanimously favored. The close
relatedness of brown bear and polar bear, as well as the
paraphyletic association between mtDNA of these two
bears has been upheld in previous studies [29-31]. More
sequences of brown bear and polar bear included in the
future research will help test further the earlier observa-
tions. In sum, the long-standing lack of full resolution
within Ursidae may be primarily due to the low level of
variation harbored in much shorter sequences than those
used in this study. Results of partitioned Bremer support (PBS) analyses to each
node on the mt genome tree and comparisons of phyloge-
netic performance of mt genes among the studies
Figure 5
Results of partitioned Bremer support (PBS) analyses to each
node on the mt genome tree and comparisons of phyloge-
netic performance of mt genes among the studies. Based on the largest available mt data set from Ursidae,
our genome phylogeny provides strong evidence that
within genus Ursus, the sloth bear is the sister taxa of all
the other five ursines, and that the latter group is divided
into the brown bear/polar bear and the two black bears/
sun bear assemblages, upholding and strengthening the
hypothesis drawn by our previous analysis of the five frag-
ments of mtDNA [13] (Figure 1E). Alternative hypotheses
for a mitochondrial sequence based phylogeny are not
supported when the entire mitochondrial DNA sequence
information is utilized. In particular, when nucleotide
base compositional bias introduced by the giant panda
outgroup was removed from our analysis and the specta- Results of
node on th
netic perfo
Figure 5 Results of
node on th
netic perfo
Figure 5 The necessity of including other
unlinked genes for phylogenetic resolution of the Ursidae
is also illustrated by the fact that our recent study on two
nuclear genes, transthyretin (TTR) and interphotoreceptor
retinoid binding protein (IRBP), has united the sloth bear
and the sun bear as sister taxa with high statistical support
[13] (Figure 1 nuA), a relationship not consistent with mt
gene analyses, including the present study. In mt trees, the
sloth bear was mostly placed as the earliest diverging taxa
among the six ursine species [8,11,13, and the present
result], and the sun bear closer to the American black bear
[11], the brown bear/polar bear clade [MP phylogeny in
12; ML phylogeny in 8], or the clade including the two
black bears (NJ phylogeny in 12; 13 and the present
result). Notably, the sister relationship between the Asian
and American black bears, previously proposed on pale-
ontological and morphological grounds [34,35] was rein-
forced by consistent recovery from both our mt genome
and nuclear analysis. Such a grouping has also been
retrieved previously with moderate support by mt analysis
of complete CYTB and 2 tRNAs [12], as well as the addi-
tion of the partial D-loop region [13]. Thus, the place-
ments of the sun bear and the sloth bear represent are the
most obvious discrepancy observed in the mt and nuclear
trees comparisons. Our genome analysis has established a Combined protein-coding genes (10888 aligned sites,
4522 variable and 3245 parsimony-informative) and all
mt genes (15017 aligned sites, 5642 variable and 3926
parsimony-informative; control region was not included
due to alignment difficulty) analyses of the eight bear spe-
cies using available Pinnipedia mt genomes as outgroups
(Accession No. AJ428576, AJ428578 and X63726;
[32,33]) gave an identical tree topology to that obtained
using the giant panda as the outgroup. Support levels for
most branches were similar to those estimated with the
giant panda outgroup except for an increased ML BS (≥
85) and PP (≥ 0.95 PP) of placement of the sloth bear
(Figure 2A and 3). A chi-square test of composition sta-
tionary showed that both Pinnipedia and the giant panda
have deviant base composition with respect to the other
bears (p < 0.05), a circumstance that might have a nega-
tive impact on the branch supports in MP analysis. Results of
node on th
netic perfo
Figure 5 p
pp
(
)
y
g
p
p y g
p
g
g
g
Results of partitioned Bremer support (PBS) analyses to each
node on the mt genome tree and comparisons of phyloge-
netic performance of mt genes among the studies. p
pp
(
)
y
g
p
p y g
p
g
g
g
Results of partitioned Bremer support (PBS) analyses to each
node on the mt genome tree and comparisons of phyloge-
netic performance of mt genes among the studies. Page 6 of 11
(page number not for citation purposes) Page 6 of 11
(page number not for citation purposes) http://www.biomedcentral.com/1471-2148/7/198 BMC Evolutionary Biology 2007, 7:198 Table 2: Results of likelihood ratio test of the molecular-clock hypothesis
combined protein-coding gene
combined rRNAs gene
combined tRNAs gene
control region
combined all gene
Log L without clock
-36253.65
-6614.67
-3682.41
-3351.94
-50256.75
Log L with clock
-36258.55
-6616.48
-3685.10
-3431.73
-30265.12
significance level (p)
0.13
0.73
0.49
<0.01
<0.05 Table 2: Results of likelihood ratio test of the molecular-clock hypothesis represents the most probable explanation of bear evolu-
tion. cled bear was used for rooting, the overall Ursidae rela-
tionships recovered have the largest statistical support in
comparison to all other previously proposed hypotheses. To further examine the sensitivity of our tree topology to
outgroup choice, we selected Pinnipedia. This superfamily
in Carnivora includes the Otariidae, Phocidae, and Odo-
benidae families, members of which have been used as
alternative roots in earlier studies of bears [8,12]. cled bear was used for rooting, the overall Ursidae rela-
tionships recovered have the largest statistical support in
comparison to all other previously proposed hypotheses. To further examine the sensitivity of our tree topology to
outgroup choice, we selected Pinnipedia. This superfamily
in Carnivora includes the Otariidae, Phocidae, and Odo-
benidae families, members of which have been used as
alternative roots in earlier studies of bears [8,12]. Nevertheless, a more in-depth understanding of the Ursi-
dae relationships will definitely benefit from the addition
of independent sequence data, considering that the
genome phylogeny obtained here is based on a single and
haploid linkage unit. Results of
node on th
netic perfo
Figure 5 Thus,
our genome phylogeny was robust with either outgroup,
though the spectacled bear, exhibiting the least phyloge-
netic noise, appears a more favorable outgroup for Ursi-
dae in terms of overall support levels. Taken together, the
present genome result significantly resolved the conflict
between those trees using partial mt genes [8,11-13] and Table 3: Divergence time evaluation of Ursidae family (Mya)
fossil recordsa
protein electrophoresis analysis from
Goldman, Giri and O'Brien (1989) [6]
partial mt gene analysis from
Talbot and Shields (1996) [12]
two nuclear gene analysis from
Yu et al (2004) [13]
mt genome analysis
from this study
T. ornatus separation
5–7
10–15
12–13
6–8
10.91
six Ursine bears (or U. ursinus)
divergence (node 5)
4–6
4–8
5–7
2–5
6.34
five Ursine bears (except U. ursinus) divergence (node 4)
-
-
6
-
6.13
U. malayanus divergence (node 3)
0.2–1 or 5–10
-
5
-
5.67
U. thibetanus – U. americanus split
(node 2)
1–3.5
-
5
-
5.19
U. arctos – U. maritimus split
(node 1)
0.07–0.1
2–3
1–2
1–1.5
1.32
- no divergence time evaluation in the study
a from Kurten 1968 [9]; Thenius 1979 [27]; Kurten and Anderson 1980 [35]; Savage and Russell 1983 [37]; Wayne et al. 1991 [26] Table 3: Divergence time evaluation of Ursidae family (Mya) Page 7 of 11
(page number not for citation purposes)
Table 3: Divergence time evaluation of Ursidae family (Mya)
fossil recordsa
protein electrophoresis analysis from
Goldman, Giri and O'Brien (1989) [6]
partial mt gene analysis from
Talbot and Shields (1996) [12]
two nuclear gene analysis from
Yu et al (2004) [13]
mt genome analysis
from this study
T. ornatus separation
5–7
10–15
12–13
6–8
10.91
six Ursine bears (or U. ursinus)
divergence (node 5)
4–6
4–8
5–7
2–5
6.34
five Ursine bears (except U. ursinus) divergence (node 4)
-
-
6
-
6.13
U. malayanus divergence (node 3)
0.2–1 or 5–10
-
5
-
5.67
U. thibetanus – U. americanus split
(node 2)
1–3.5
-
5
-
5.19
U. arctos – U. maritimus split
(node 1)
0.07–0.1
2–3
1–2
1–1.5
1.32
- no divergence time evaluation in the study
a from Kurten 1968 [9]; Thenius 1979 [27]; Kurten and Anderson 1980 [35]; Savage and Russell 1983 [37]; Wayne et al. - no divergence time evaluation in the study http://www.biomedcentral.com/1471-2148/7/198 BMC Evolutionary Biology 2007, 7:198 very useful benchmark that can be tested with future inde-
pendent evidence. used in previous studies lack sufficiently strong phyloge-
netic signals and provide limited resolving power for
recovering a strongly supported Ursidae phylogeny. As is
seen in Table 3, our estimates of the diversification of the
Ursidae family was more in agreement with those
obtained with partial mt genes analysis [12] and protein
electrophoresis analysis [6] than those obtained with the
fossil record [9,26,35]and nuclear sequence analysis [13],
which are slightly younger than the present results. Our genome analyses provide important insights into not
only Ursidae phylogeny, but also the phylogenetic utility
of different mt genes. Our data add to the well-studied
performance of individual mt genes, mostly protein-cod-
ing genes, for estimating phylogeny of deep divergence
[16,36], we are interested to see their relative efficiencies,
adding mt RNA genes and control region as well, in those
of extremely recent split. Our results suggest that com-
bined mt protein-coding genes are more informative than
the other subsets of mt genes regarding the lower-level
bear relationships resolution. Only by combining all
genes is it possible to reach a fully-resolved tree with mod-
erate to strong support from MP, ML, and Bayesian meth-
ods of analysis. Ranking single genes by their respective
contribution to the total PBS values of the genome tree, as
a rough indicator of phylogenetic utility, reveals that some
genes, such as ND5, ND4, CYTB, ND2, and 16SrRNA are
better indicators of Ursidae evolution than are other
genes, such as ND3, ND4L, and ND1 (Figure 5). Our
results add to previous findings from Zardoya and Meyer
(1996) [16] and Russo, Takezaki, and Nei (1996) [36]
that did not included concatenated tRNAs, 2 rRNAs, and
control regions in the evaluation of phylogenetic perform-
ance, and also agree globally with their conclusions about
the rough classification of 12 mt protein-coding genes
into good, medium, and poor categories. These conclu-
sions are upheld even though significantly different evo-
lutionary time frames between our studies and theirs (i.e.,
distantly related vertebrates) (Figure 5) are involved. In
this sense, general knowledge of phylogenetic values of
the mt genes makes it possible to preselect subsets of mt
genes for different-level phylogenetic questions in the case
of mt genomes unavailable. http://www.biomedcentral.com/1471-2148/7/198 In fact, in some previous
studies, Ursidae phylogenies based on the combined anal-
ysis of a few mt genes have also, to a degree, demonstrated
the potential valuable information as those based on
complete genome analysis [8,12]. Conclusion
d
ifi
i Identification of base composition bias and utilization of
the combined data of whole mitochondrial genome
sequences has allowed recovery of a strongly supported
phylogeny that is upheld when using multiple alternative
outgroups for the Ursidae, a mammalian family that
underwent a rapid radiation since the mid- to late
Pliocene. The suggestion of Delisle and Strobeck (2002) [38] that
application of mitogenomic datasets would be likely to be
useful for distinguishing nodes resulting from rapid radi-
ation episodes such as the ursine speciation events is vali-
dated by these findings. It remains to be seen if the
reliability of mt genome analysis will hold up in studies of
other difficult phylogenetic issues. Although the whole
mitochondrial DNA sequence based phylogeny is robust,
it remains in conflict with phylogenetic relationships sug-
gested by analysis of limited nuclear-encoded data, a situ-
ation that will require gathering more nuclear DNA
sequence information. Results of
node on th
netic perfo
Figure 5 1991 [26] - no divergence time evaluation in the study
a from Kurten 1968 [9]; Thenius 1979 [27]; Kurten and Anderson 1980 [35]; Savage and Russell 1983 [37]; Wayne et al. 1991 [26] no divergence time evaluation in the study
a from Kurten 1968 [9]; Thenius 1979 [27]; Kurten and Anderson 1980 [35]; Savage and Russell 1983 [37]; Wayne et al. 1991 [26] http://www.biomedcentral.com/1471-2148/7/198 Universal p
primers (u
Figure 6 p
[
]
y
g
p
p
p
(
)
p y g
g
g
Universal primers [35] and newly designed species-specific
primers (underlined) used for amplifying Ursidae mt
genomes. Locations of new primers are indicated in brackets
and correspond to nucleotide numbers from the harbor seal
sequence (Accession No. X63726). Eleven mtDNA frag-
ments (mtDNA1-11) covering the entire mt genome are
labeled as described in Delisle and Strobeck (2002) [38]. p
y
g
p
p
p
(
)
p y g
g
g
Universal primers [35] and newly designed species-specific
primers (underlined) used for amplifying Ursidae mt
genomes. Locations of new primers are indicated in brackets
and correspond to nucleotide numbers from the harbor seal
sequence (Accession No. X63726). Eleven mtDNA frag-
ments (mtDNA1-11) covering the entire mt genome are
labeled as described in Delisle and Strobeck (2002) [38]. Universal primers [35] and newly designed species-specific
primers (underlined) used for amplifying Ursidae mt
genomes. Locations of new primers are indicated in brackets
and correspond to nucleotide numbers from the harbor seal
sequence (Accession No. X63726). Eleven mtDNA frag-
ments (mtDNA1-11) covering the entire mt genome are
labeled as described in Delisle and Strobeck (2002) [38]. 95°C hot start (5 min), 10 cycles of 94°C denaturation (1
min), 60–50°C annealing (1 min; °C/cycle), 72°C exten-
sion (1 min), and finally 25 cycles of 94°C denaturation
(1 min), 50°C annealing (1 min), 72°C extension (1
min). The amplified DNA fragments were purified and
sequenced in both directions with an ABI PRISM™ 3700
DNA sequencer following the manufacturer's protocol. Mt sequences obtained were checked carefully to ensure
that they did not include nuclear copies of mtDNA-like
pseudogenes. The exact length of the control region in the
mt genome cannot be determined due to the presence of
long tandem repeated sequences. Newly determined
genomes have been deposited in GenBank under Acces-
sion No. EF19661–EF19665. To avoid potential tree estimation bias introduced by
nucleotide composition [49,50] or saturation, two addi-
tional weighting strategies were applied in the analysis of
combined 12 protein-coding genes: (1) excluding the 3rd
codon positions (P12), and (2) recoding the 3rd codon
position nucleotides to two-state categories, R (purine)
and Y (pyrimidine), (RY-coding). The RY-coding was used
here based on the growing observation that it can greatly
improve consistency in phylogenetic resolution by reduc-
ing bias from differences in nucleotide composition [51-
54]. Universal p
primers (u
Figure 6 In the combined analysis, portions of the 12S rRNA
and 16S rRNA genes were also partitioned into two sepa-
rate subsets according to their secondary structures: single-
strand stems and base-paired loops [55,56]. http://www.biomedcentral.com/1471-2148/7/198 BMC Evolutionary Biology 2007, 7:198 Universal primers [35] and newly designed species-specific
primers (underlined) used for amplifying Ursidae mt genomes
Figure 6
Universal primers [35] and newly designed species-specific
primers (underlined) used for amplifying Ursidae mt
genomes. Locations of new primers are indicated in brackets
and correspond to nucleotide numbers from the harbor seal
sequence (Accession No. X63726). Eleven mtDNA frag-
ments (mtDNA1-11) covering the entire mt genome are
labeled as described in Delisle and Strobeck (2002) [38]. Each of these data sets was subjected to unweighted max-
imum parsimony (MP) and maximum likelihood (ML)
analyses using PAUP *4.0b8 [41]. For MP analyses, we
adopted an exhaustive search algorithm with TBR branch
swapping. For model-based ML analyses, we introduced
hierarchical likelihood ratio tests (hLRT) to compare the
goodness of fit of 56 nucleotide substitution models using
ModelTest version 3.06 [42]. Once an appropriate model
was established, a ML tree was constructed based on this
model of sequence evolution. The reliability of phyloge-
netic relationships was evaluated by bootstrap analysis
[43] for MP and ML trees (BS; 1000 replicates for MP and
100 replicates for ML). In addition, we performed a parti-
tioned Bayesian inference (pBI) analysis [44] for phyloge-
netic reconstruction using MrBayes 3.1 [45], allowing a
separate general time reversible (GTR) + I + Γ model and
set of parameters for each gene partition, with the assump-
tion that the underlying evolutionary process was poten-
tially different across these partitions. Four Metropolis-
coupled Markov chain Monte Carlo (MCMC) analyses
were run for 2 million generations, sampling trees every
100 generations. Robustness for branches in pBI analysis
was assessed by posterior probability (PP). We also con-
ducted partitioned Bremer support analysis (PBS) [46-48]
with TreeRot.v2 [25] to measure the contribution of each
data partition to the total Bremer support for the nodes of
genome-based tree topology. DNA Samples and Sequence Determination DNA Samples and Sequence Determination
The complete mt sequences of three bear species in genus
Ursus, the polar bear (U. maritimus), the brown bear (U. arctos), and the American black bear (U. americanus), have
been determined in previous studies of genome evolution
[38]. Thus, the availability of the other five mt genome
sequences from Ursidae was of considerable interest for
phylogenetic reconstruction. We extracted total DNA
from fresh blood or frozen tissues of the Asiatic black bear
(U. thibetanus), the sloth bear (U. ursinus), the sun bear
(U. malayanus), the spectacled bear (Tremarctos ornatus)
and the giant panda (Ailuropoda melanoleuca) using stand-
ard proteinase K, phenol/chloroform extraction [39]. Ursidae has one of the most extensive fossil records of
extant Carnivora families [9,26,27,35,37]. Given a good
fossil documentation and strongly supported phyloge-
netic relationships from the largest available data set, it is
of interest to draw a comparison between the present
mitogenomic dating results and those from previous pale-
ontological and molecular evidence (Table 3). According
to estimates based on our genome data, all the separation
times within genus Ursus appear to have occurred in the
Late Miocene or Early Pliocene (5–6 MYA), except that in
the Early Pleistocene the most closely related bear species,
the brown and polar bears diverged. The rather recent ori-
gins and rapid succession of these bear lineages are in line
with the observation that most short mtDNA sequences Mt genome sequences were initially amplified with sets of
universal primers (73 in total) described in Delisle and
Strobeck's original study (2002) [38]. In the case of poor
PCR performance with universal primers, 31 additional
species-specific oligonucleotide primers were designed
(underlined in Figure 6). Primer sequence information
was available upon request. A "touch-down" PCR ampli-
fication was carried out using the following parameters: Page 8 of 11
(page number not for citation purposes) Page 8 of 11
(page number not for citation purposes) http://www.biomedcentral.com/1471-2148/7/198 http://www.biomedcentral.com/1471-2148/7/198 References g
f g
f
25. Sorenson MD: TreeRot, version 2. Boston Univ., Boston, MA;
1999. 1. Wayne RK, Benveniste RE, Janczewski DN, O'Brien SJ: Molecular
and biochemical evolution of the Carnivora. In Carnivore Behav-
ior, Ecology, and Evolution Edited by: Gittleman JL. Cornell Univ. Press,
Ithaca; 1989:465-494. 26. Wayne RK, VanValkenburgh B, O'Brien SJ: Molecular distance and
divergence time in carnivores and primates. Mol Biol Evol 1991,
8:297-319. 2. Nowak RM: Walker's Mammals of the World. Johns Hopkins
Press, Baltimore; 1991. 27. Thenius E: Zur systematischen und phylogenetischen Stellung
des Bambusbaren Ailuropoda melanoleuca David (Car-
nivora:Mammalia). Z Sauge tierk 1979, 44:286-305. 3. Kitchener AC: A review of the evolution, systematics, func-
tional morphology, distribution and status of the Ursidae. Int
Zoo News 1994, 242:4-24. )
g
28. Rokas A, Carroll S: Bushes in the tree of life. Plos Biol 2006,
4:1899-1904. 4. O'Brien SJ, Nash WG, Wildt DE, Benveniste RE: A molecular solu-
tion to the riddle of the giant panda's phylogeny. Nature 1985,
317:140-144. 29. Shields GF, Kocher TD: Phylogenetic relationships of North
American ursids based on analysis of mitochondrial DNA. Evolution 1991, 45:218-221. 5. Nash WG, O'Brien SJ: A comparative chromosome banding
analysis of the ursidae and their relationship to other carni-
vores. Cytogene Cell Genet 1987, 45:206-212. 30. Talbot SL, Shields GF: Phylogeography of brown bears (Ursus
arctos) of Alaska and paraphyly within the Ursidae. Mol Phyl-
ogenet Evol 1996, 5:477-494. y g
6. Goldman D, Giri PR, O'Brien SJ: Molecular genetic-distance esti-
mates among the ursidae as indicated by one- and two-
dimensional
protein
electrophoresis. Evolution
1989,
43:282-295. g
31. Shields GF, Adams D, Garner G, Labelle M, Pietsch J, Ramsay M,
Schwartz C, Titus K, Williamson S: Phylogeography of mitochon- 31. Shields GF, Adams D, Garner G, Labelle M, Pietsch J, Ramsay M,
Schwartz C, Titus K, Williamson S: Phylogeography of mitochon-
drial DNA variation in brown bears and polar bears. Mol Phy-
logenet Evol 15:319-326. drial DNA variation in brown bears and polar bears. Mol Phy-
logenet Evol 15:319-326. 7. Hashimoto T, Otaka E, Adachi J, Mizuta K, Hasegawa M: The giant
panda is closer to a bear judged by alpha- and beta-hemo-
globin sequences. J Mol Evol 1993, 36:282-289. g
32. Arnason U, Johnsson E: The complete mitochondrial DNA
sequence of the harbor seal, Phoca vitulina. J Mol Evol 1992,
34:493-505. g
q
J
8. References Waits LP, Sullivan J, O'Brien SJ, Ward RH: Rapid radiation events
in the family ursidae indicated by likelihood phylogenetic
estimation from multiple fragments of mtDNA. Mol Phylo-
genet Evol 1999, 13:82-92. 33. Arnason U, Adegoke JA, Bodin K, Born EW, Esa YB, Gullberg A, Nils-
son M, Short RV, Xu X, Janke A: Mammalian mitogenomic rela-
tionships and the root of the eutherian tree. Proc Natl Acad Sci
USA 2002, 99:8151-8156. g
9. Kurten B: The Pleistocene Mammals of Europe. Aldine, Chi-
cago. III; 1968. 34. Allen GM: "The mammals of China and Mongolia." National
History of Central Asia. Am Must Nat Hist, New York
1938:328-336. g
10. Zhang YP, Ryder OA: Mitochondrial DNA sequence evolution
in the Arctoidea. Proc Natl Acad Sci USA 1993, 90:9557-9561. 35. Kurten B, Anderson E: Pleistocene Mammals of North Amer-
cia. Cornell Univ Press Ithaca; 1980. 11. Zhang YP, Ryder OA: Phylogenetic relationships of bears (the
ursidae) inferred from mitochondrial DNA sequences. Mol
Phylogenet Evol 1994, 3:351-359. 36. Russo CAM, Takezaki N, Masatoshi N: Efficiencies of different
genes and different tree-building methods in recovering a
known vertebrate phylogeny. Mol Biol Evol 1996, 13:525-536. y g
12. Talbot SL, Shields GF: A phylogeny of the bears (ursidae)
inferred from complete sequences of three mitochondrial
genes. Mol Phylogenet Evol 1996, 5:567-575. p y
g
y
37. Savage DE, Russell DE: Mammalian paleofaunas of the world. Addison-Wesley, London; 1983. g
y g
13. Yu L, Li QW, Ryder OA, Zhang YP: Phylogeny of the bears (Ursi-
dae) based on nuclear and mitochondrial genes. Mol Phylo-
genet Evol 2004, 32:480-494. 38. Delisle I, Strobeck C: Conserved primers for rapid sequencing
of the complete mitochondrial genome from carnivores,
applied to three species of bears. Mol Biol Evol 2002, 19:357-361. g
14. Brown WM, George M, Wilson AC: Rapid evolution of animal
mitochondrial DNA. Proc Natl Acad Sci USA 1979, 76:1967-1971. pp
p
39. Sambrook E, Fritsch F, Maniatis T: Molecular Clonging. Cold
Spring Harbor Press, Cold Spring Harbor, NY; 1989. 15. Moore WS: Inferring phylogenies from mtDNA variation:
Mitochondrial gene trees versus nuclear gene trees. Evolution
1995, 49:718-726. p
g
p
g
40. Thompson JD, Gibson TJ, Plewniak F, Jeanmougin F, Higgins DG: The
clustalx windows interface: flexible strategies for multiple
sequence alignment aided by quality analysis tools. Nucleic
Acids Research 1997, 24:4876-4882. 16. Authors' contributions LY and YPZ designed the study. YWL carried out the exper-
iment work. LY performed the analyses. LY, OAR and YPZ
prepared the manuscript. All authors read and approved
the final manuscript. 20. Cao Y, Fujiwara M, Nikaido M, Okada N, Hasegawa M: Interordinal
relationships and timescale of eutherian evolution as
inferred from mitochondrial genome data. Gene 2000,
259:149-158. 21. Miya M, Kawaguchi A, Nishida M: Mitogenomic exploration of
higher teleostean phylogenies: a case study for moderate-
scale evolutionary genomics with 38 newly determined com-
plete mitochondrial DNA sequences. Mol Biol Evol 2001,
18:1993-2009. Acknowledgements g
This work was supported by grants from the State Key Basic Research and
Development Plan (2007CB411600), National Natural Science Foundation
of China (30600067, 30460026, 30621092), and Bureau of Science and
Technology of Yunnan Province, and by a start-up fund from the Yunnan
University. We thank Andrea Johnson at CRES for helpful comments on the
manuscript. This work was supported by grants from the State Key Basic Research and
Development Plan (2007CB411600), National Natural Science Foundation
of China (30600067, 30460026, 30621092), and Bureau of Science and
Technology of Yunnan Province, and by a start-up fund from the Yunnan
University. We thank Andrea Johnson at CRES for helpful comments on the
manuscript. 22. Ingman M, Kaessmann H, Paabo S, Gyllensten U: Mitochondrial
genome variation and the origin of modern humans. Nature
2001, 408:708-713. 23. Kimura M: A simple method for estimating evolutionary rates
of base substitutions through comparative studies of nucle-
otide. J Mol Evol 1980, 16:111-120. J
24. Kumar S, Tamura K, Nei M: MEGA3: Integrated Software for
Molecular Evolutionary Genetics Analysis and Sequence
Alignment. Briefings in Bioinformatics 2004, 5:150-163. Competing interests 18. Cummings MP, Otto SP, Wakeley J: Sampling properties of DNA
sequence data in phylogenetic analysis. Mol Biol Evol 1995,
12:814-822. p
g
The author(s) declares that there are no competing inter-
ests. 19. Cao Y, Adachi J, Janke A, Paabo S, Hasegawa M: Phylogenetic rela-
tionships among eutherian orders estimated from inferred
sequences of mitochondrial proteins: instability of a tree
based on a single gene. J Mol Evol 1994, 39:519-527. http://www.biomedcentral.com/1471-2148/7/198 BMC Evolutionary Biology 2007, 7:198 Sequence Data Analyses The giant panda was used as an outgroup for estimating
phylogenetic relationships within genus Ursus. To exam-
ine if the resulting tree topologies were sensitive to out-
group alteration, we also carried out phylogenetic analysis
with Pinnipedia, a non-ursine superfamily in Carnivora,
for the rooting. The complete mt genome sequences of all extant bear spe-
cies were aligned with program CLUSTAL X [40] and veri-
fied by eye. Five data sets comprising (1) all protein-
coding genes combined except NADH6 gene, (2) 12S and
16S tRNA genes combined, (3) all 22 rRNA genes com-
bined, (4) control region (CR), and (5) all genes com-
bined were analyzed for phylogenetic reconstruction. The
NADH6 gene is excluded from the analyses due to its
anomalous nucleotide composition which can confound
phylogenetic inferences. The molecular clock hypothesis was examined using the
likelihood-ratio test [57] with PUZZLE [58,59]. When
clock-like behavior was not rejected by the test, the diver-
gence times among them were calculated and compared
to previous molecular results and fossil records. Page 9 of 11
(page number not for citation purposes) Page 9 of 11
(page number not for citation purposes) http://www.biomedcentral.com/1471-2148/7/198 BMC Evolutionary Biology 2007, 7:198 http://www.biomedcentral.com/1471-2148/7/198 http://www.biomedcentral.com/1471-2148/7/198 http://www.biomedcentral.com/1471-2148/7/198 43. Felsenstein J: Confidence limits on phylogenies: An approach
using the bootstrap. Evolution 1985, 39:783-791. g
p
44. Larget B, Simon DL: Markov chain Monte Carlo algorithms for
the Bayesian analysis of phylogenetic trees. Mol Biol Evol 1999,
16:750-759. 45. Ronquist F, Huelsenbeck JP: MRBAYES 3: Bayesian phylogenetic
inference
under
mixed
models. Bioinformatics
2003,
19:1572-1574. 46. Bremer K: The limits of amino acid sequence data in
angiosperm phylogenetic r5econstruction. Evolution 1988,
42:795-803. 47. Bremer K: Branch support and tree stability. Cladistics 1994,
10:295-304. 48. Baker RH, DeSalle R: Multiple sources of character information
and the phylogeny of Hawaiian drosophilids. Syst Biol 1997,
46:674-698. 49. Saccone C, Lanave C, Pesole G, Preparata G: Influence of base
composition on quantitative estimates of gene evolution. Methods Enzymol 1990, 183:570-583. y
50. Saccone C, Gissi C, Lanave C, Larizza A, Pesole G, Reyes A: Evolu-
tion of the mitochondrial genetic system: an overview. Gene
2000, 261:153-159. 51. Delsuc F, Phillips MJ, Penny D: Comment on "Hexapod origins:
monophyletic or paraphyletic?". Science 2003, 301:1482. 52. Phillips MJ, Penny D: The root of the mammalian tree inferred
from whole mitochondrial genomes. Mol Phylogenet Evol 2003,
28:171-185. 53. Harrison GL, McLenachan PA, Phillips MJ, Slack KE, Cooper A, Penny
D: Four new avian mitochondrial genomes help get to basic
evolutionary questions in the late cretaceous. Mol Biol Evol
2004, 21:974-983. 54. Gibson AV, Gowri-Shankar P, Higgs G, Rattray M: A comprehen-
sive analysis of mammalian mitochondrial genome base
composition and improved phylogenetic methods. Mol Biol
Evol 2005, 22:251-264. 55. Springer MS, Douzery E: Secondary structure and patterns of
evolution among mammalian mitochondrial 12S rRNA mol-
ecules. J Mol Evol 1996, 43:357-373. J
56. Mears JA, Sharma MR, Gutell RR, McCook AS, Richardson PE,
Caulfield TR, Agrawal RK, Harvey SC: A structural model for t he
large subunit of the mammalian mitochondrial ribosome. J
Mol Biol 2006, 358:193-212. 57. Felsenstein J: Phylogenies from molecular sequences: infer-
ence and reliability. Annu Rev Genet 1988, 22:521-565. y
58. Strimmer K, von Haeseler A: Quartet puzzling: A quartet max-
imum likelihood method for reconstructing tree topologies. Mol Biol Evol 1996, 13:964-969. 59. Schmidt HA, Strimmer K, Vingron M, von Haeseler A: TREE-PUZ-
ZLE: maximum likelihood phylogenetic analysis using quar-
tets and parallel computing. Bioinformatics 2002, 18:502-504. 60. References Zardoya R, Meyer A: Phylogenetic performance of mitochon-
drial protein-coding genes in resolving relationships among
vertebrates. Mol Biol Evol 1996, 13:933-942. 41. Swofford DL: PAUP*: phylogenetic analysis using parsimony
(* and other methods). Version 4.0b8. Sinauer Associates, Sun-
derland, MA; 2001. 17. Springer MS, Debry RW, Douady C, Amrine HM, Madsen O, de Jong
WW, Stanhope MJ: Mitochondrial versus nuclear gene
sequences in deep-level mammalian phylogeny reconstruc-
tion. Mol Biol Evol 2001, 18:132-143. 42. Posada D, Crandall KA: Modeltest: testing the model of DNA
substitution. Bioinformatics 1998, 14:817-818. Page 10 of 11
(page number not for citation purposes) BMC Evolutionary Biology 2007, 7:198 BMC Evolutionary Biology 2007, 7:198 Fulton TL, Strobeck C: Molecular phylogeny of the Arctoidea
(Carnivora): Effect of missing data onsupertree and super-
matrix analyses of multiple gene data sets. Mol Phylogenet Evol
2006, 41:165-181. Publish with BioMed Central and every
scientist can read your work free of charge
"BioMed Central will be the most significant development for
disseminating the results of biomedical research in our lifetime."
Sir Paul Nurse, Cancer Research UK
Your research papers will be:
available free of charge to the entire biomedical community
peer reviewed and published immediately upon acceptance
cited in PubMed and archived on PubMed Central
yours — you keep the copyright
Submit your manuscript here:
http://www.biomedcentral.com/info/publishing_adv.asp
BioMedcentral
Page 11 of 11
(page number not for citation purposes) Publish with BioMed Central and every
scientist can read your work free of charge
"BioMed Central will be the most significant development for
disseminating the results of biomedical research in our lifetime."
Sir Paul Nurse, Cancer Research UK
Your research papers will be:
available free of charge to the entire biomedical community
peer reviewed and published immediately upon acceptance
cited in PubMed and archived on PubMed Central
yours — you keep the copyright
Submit your manuscript here:
http://www.biomedcentral.com/info/publishing_adv.asp
BioMedcentral Publish with BioMed Central and every
scientist can read your work free of charge
"BioMed Central will be the most significant development for
disseminating the results of biomedical research in our lifetime."
Sir Paul Nurse, Cancer Research UK
Your research papers will be:
available free of charge to the entire biomedical community
peer reviewed and published immediately upon acceptance
cited in PubMed and archived on PubMed Central
yours — you keep the copyright
Submit your manuscript here:
http://www.biomedcentral.com/info/publishing_adv.asp
BioMedcentral Publish with BioMed Central and every
scientist can read your work free of charge
|
https://openalex.org/W2956656114
|
https://discovery.ucl.ac.uk/id/eprint/10078034/1/Fraioli2019_Article_SynergisticApplicationOfPulmon.pdf
|
English
| null |
Synergistic application of pulmonary 18F-FDG PET/HRCT and computer-based CT analysis with conventional severity measures to refine current risk stratification in idiopathic pulmonary fibrosis (IPF)
|
European journal of nuclear medicine and molecular imaging
| 2,019
|
cc-by
| 8,402
|
European Journal of Nuclear Medicine and Molecular Imaging
https://doi.org/10.1007/s00259-019-04386-5 European Journal of Nuclear Medicine and Molecular Imaging
https://doi.org/10.1007/s00259-019-04386-5 ORIGINAL ARTICLE Abstract Abstract
Introduction To investigate the combined performance of quantitative CT (qCT) following a computer algorithm analysis
(IMBIO) and 18F-FDG PET/CT to assess survival in patients with idiopathic pulmonary fibrosis (IPF). Methods A total of 113 IPF patients (age 70 ± 9 years) prospectively and consecutively underwent 18F-FDG PET/CT and high-
resolution CT (HRCT) at our institution. During a mean follow-up of 29.6 ± 26 months, 44 (48%) patients died. As part of the
qCT analysis, pattern evaluation of HRCT (using IMBIO software) included the total extent (percentage) of the following
features: normal-appearing lung, hyperlucent lung, parenchymal damage (comprising ground-glass opacification, reticular pat-
tern and honeycombing), and the pulmonary vessels. The maximum (SUVmax) and minimum (SUVmin) standardized uptake
value (SUV) for 18F-FDG uptake in the lungs, and the target-to-background (SUVmax/SUVmin) ratio (TBR) were quantified using
routine region-of-interest (ROI) analysis. Pulmonary functional tests (PFTs) were acquired within 14 days of the PET/CT/HRCT
scan. Kaplan–Meier (KM) survival analysis was used to identify associations with mortality. Results Data from 91 patients were available for comparative analysis. The average ± SD GAP [gender, age, physiology] score
was 4.2 ± 1.7 (range 0–8). The average ± SD SUVmax, SUVmin, and TBR were 3.4 ± 1.4, 0.7 ± 0.2, and 5.6 ± 2.8, respectively. In
all patients, qCT analysis demonstrated a predominantly reticular lung pattern (14.9 ± 12.4%). KM analysis showed that TBR
(p = 0.018) and parenchymal damage assessed by qCT (p = 0.0002) were the best predictors of survival. Adding TBR and qCT to
the GAP score significantly increased the ability to differentiate between high and low risk (p < 0.0001). g
y
y
g
(p
)
DG PET and qCT are independent and synergistic in predicting mortality in patients with IPF. Conclusion 18F-FDG PET and qCT are independent and synergistic in predicting mortality in patients with IPF. Keywords Idiopathicpulmonaryfibrosis .Quantitativecomputeranalysis .Positronemissiontomography .Fluorine-18FDGand
pulmonary vessels Keywords Idiopathicpulmonaryfibrosis .Quantitativecomputeranalysis .Positronemissiontomography .Fluorine-18FDGand
pulmonary vessels This article is part of the Topical Collection on Infection and Inflammation * Francesco Fraioli
fraioli.francesco@gmail.com Synergistic application of pulmonary 18F-FDG PET/HRCT
and computer-based CT analysis with conventional severity
measures to refine current risk stratification in idiopathic pulmonary
fibrosis (IPF) Francesco Fraioli1 & Maria Lyasheva2 & Joanna C. Porter3 & Jamshed Bomanji1 & Robert I. Shortman1 &
Raymond Endozo1 & Simon Wan1 & Linda Bertoletti4 & Maria Machado1 & Balaji Ganeshan1 & Thida Win5 &
Ashley M. Groves1 Francesco Fraioli1 & Maria Lyasheva2 & Joanna C. Porter3 & Jamshed Bomanji1 & Robert I. Shortman1 &
Raymond Endozo1 & Simon Wan1 & Linda Bertoletti4 & Maria Machado1 & Balaji Ganeshan1 & Thida Win5 &
Ashley M. Groves1 Received: 12 February 2019 /Accepted: 30 May 2019
# The Author(s) 2019 Received: 12 February 2019 /Accepted: 30 May 2019
# The Author(s) 2019 1
Institute of Nuclear Medicine, UCL(H) and University College
London Hospital, 235 Euston Rd, London NW1 2BU, UK Introduction * Francesco Fraioli
fraioli.francesco@gmail.com High-resolution CT (HRCT) is the current imaging reference
standard in the investigation of patients with idiopathic pul-
monary fibrosis (IPF), revealing structural details of the entire
lung parenchyma which reflect the characteristic histological
changes. However, HRCT is conventionally a purely structur-
al, qualitative imaging technique and requires dedicated radio-
logical training to assess the severity of disease [1, 2]. Several
computer-based quantitative CT (qCT) methods have been
developed to precisely quantify the extent of disease [3]. However, despite showing a significant correlation with both 1
Institute of Nuclear Medicine, UCL(H) and University College
London Hospital, 235 Euston Rd, London NW1 2BU, UK 1
Institute of Nuclear Medicine, UCL(H) and University College
London Hospital, 235 Euston Rd, London NW1 2BU, UK 2
Department of Oncology, School of Clinical Medicine, University of
Cambridge, Cambridge, UK 2
Department of Oncology, School of Clinical Medicine, University of
Cambridge, Cambridge, UK 3
CITR, UCL and Interstitial Lung Disease Centre, UCLH,
London, UK 3
CITR, UCL and Interstitial Lung Disease Centre, UCLH,
London, UK 4
Imaging Department, University of Rome “Sapienza”, Rome, Italy 5
Respiratory Medicine, Lister Hospital, Stevenage, UK 5
Respiratory Medicine, Lister Hospital, Stevenage, UK Eur J Nucl Med Mol Imaging includes other fibrosing ILDs such as hypersensitivity pneu-
monitis, sarcoidosis, and rheumatoid arthritis. visual score and pulmonary function tests (PFTs), qCT has yet
to provide insight into the mechanisms and activity of fibrosis
and disease progression. The ability to radiologically quantify
the response of individual patients to treatment would be an
important advance given the current lack of end points for
drug trials in IPF [4]. The study was approved by the ethics board (London-
Harrow Research Ethics Committee [REC reference 06/
Q0505/22]), and all patients provided written informed
consent. Positron emission tomography (PET) offers the means for
non-invasive investigation of cellular metabolism in vivo. PET studies in animals have yielded potentially valuable in-
sight into the biology of IPF, with heightened 18F-
fluorodeoxyglucose (18F-FDG) PET signal intensity related
to interstitial lung changes [5, 6]. 18F-FDG pulmonary uptake
on PET has been shown to relate to disease severity as
assessed by quality-of-life measurement, lung volume, and
gas transfer, and more recently it was shown that baseline
objective measures of 18F-FDG uptake on PET predict patient
survival, independent of PFTs [7, 8]. Introduction The follow-up period was defined from the date of scan to
death (all causes) or 9 years, whichever happened first. Repeat
scans were performed when clinically indicated, and not rou-
tinely unless this affected patient management, according to
National Institute for Health and Care Excellence (NICE) IPF
clinical guidelines.Patient survival was confirmed by the use
of patient charts, electronic database, primary health care phy-
sician records, or telephone interview. The GAP index was computed based on four variables:
gender (G), age (A), and two lung physiology (P) parameters,
forced vital capacity (FVC) and transfer factor of the lung for
carbon monoxide (TLCO) [10]. This comprised a model using
continuous predictors (GAP calculator) and a simple point-
scoring system (GAP index), which varies from 0, potentially
indicating a good outcome, to 8, potentially indicating a worse
outcome. Given the need for biomarkers in patients with IPF for risk
stratification and drug development, we investigated the po-
tential synergistic application of pulmonary18F-FDG PETsig-
nal with qCT to predict survival in IPF. We compared this
synergistic approach with the clinical gender-age-physiology
(GAP) scoring system for prognostic accuracy [9]. Based on the GAP index, the three stages identified are as
follows: GAP stage I included GAP index 0, 1, 2, 3; GAP
stage II included GAP index 4, 5; and GAP stage III included
GAP index 6, 7, 8. PET/CT acquisition From January 2008 to December 2017, a total of 113 (93
male, 20 female, mean age 70 ± 8.9 years) prospective and
consecutive patients with IPF underwent 18F-FDG PET/CT/
HRCT at our institution. The entire cohort was previously
reported in a study assessing only FDG PET [8]. In the present
study, a subgroup of that cohort is used for additional analysis
(qCT) to compare and explore the synergistic value of qCT as
compared to the previously reported FDG PET findings. All
patients underwent full clinical assessment and baseline pul-
monary function tests (PFTs). The PET/CT scans were obtained using a 64-slice multidetec-
tor CT scanner (VCT PET/64, GE Healthcare, Chicago, IL,
USA). Three imaging sequences of the thorax were performed
while the patient remained supine on the table throughout. A
CT scan was performed for attenuation correction. With the
patient maintaining the supine position, a chest 18F-FDG PET
emission scan (8 min/bed position) was performed 1 h after
injection of 200 MBq of 18F-FDG. After completion of the PET/CT, with the patient maintain-
ing the same supine position, an HRCT (volumetric 1-mm full
inspiration scan, peak voltage of 120 kVp, tube current mod-
ulation range 30–140 mA, B70 kernel reconstruction) was
performed. All patients were referred from primary and secondary care
to the UCLH NHS-England Specialist Centre for the diagno-
sis and management of interstitial lung diseases (ILDs). The
mean average time from first visit to our tertiary care center
was 15 ± 10 months (4–23 months), and patients displayed a
wide variation in levels of dyspnea when first assessed. Modified PET and qCT score The potential synergistic effect of GAP and imaging-derived
biomarkers (PET and qCT) in prognostication was assessed
creating a novel score based on the GAP index. We propose to
add to the GAP index another factor based on the best predic-
tor for PET (either SUVmax, SUVmin or TBR) according to the
prognostic ability of the biomarker to create a synthetic score
based on the imaging test as previously described [8] (hereaf-
ter called GAP_PET). Similarly, we propose to use the best
biomarker derived from the qCT analysis as an added factor
for a third modified score (hereafter GAP_PET_qCT). According to the best cutoff point previously determined, im-
aging biomarkers were binarized in adverse (coded as 1) or
favorable (coded as 0) biomarkers. This was subsequently
added to the existing GAP index value, resulting in
GAP_PET ranging from 0 to 9 and GAP_PET_qCT ranging
from 0 to 10, as compared to the standard GAP index, which is
from 0 to 8. The new scores redefined the stages as follows:
stage I for GAP_PET as 0–3 and for GAP_PET_qCT as 0–4;
stage II for GAP_PET as 4–6 and for GAP_PET_qCT as 5–7;
and stage III for GAP_PET as 7–9 and for GAP_PET_qCT as
8–10. QCTanalysis on HRCTwas undertaken using IMBIO soft-
ware (the technical features have been described [12] previ-
ously). Briefly, evaluation of HRCT data involved algorithmic
identification and volumetric quantification of every voxel
volume unit into one of the following radiologic parenchymal
features: normal-appearing lung, hyperlucent lung, ground-
glass opacification, reticular pattern, honeycombing, and the
pulmonary vessels. Volumes were then converted into per-
centages using, as reference, the total volume of the lungs as
measured by the software. A synthetic value was created by
adding up ground-glass opacification, reticular pattern, and
honeycombing to express the total burden of disease in the
lung parenchyma. Statistical analysis Statistical analyses were performed using RStudio version
1.1.463 (RStudio Inc., Boston, MA, USA) for Macintosh
based on R version 3.5.1 (R Foundation for Statistical
Computing). Statistical analyses were performed using RStudio version
1.1.463 (RStudio Inc., Boston, MA, USA) for Macintosh
based on R version 3.5.1 (R Foundation for Statistical
Computing). Correlations between the area of highest pulmonary 18F-
FDG uptake (SUVmax), lowest pulmonary 18F-FDG uptake
(SUVmin), TBR, extent of qCT parenchymal patterns, and
individual PFTs were explored with Spearman’s correlation
coefficient and displayed using a correlation matrix; to ac-
count for multiple comparisons, the Bonferroni correction
was applied (p < 0.0042). Image display and processing Patients with symptoms of acute infection and lung malig-
nancy were excluded. Diagnosis of IPF was made on clinical
and radiological grounds following multidisciplinary team
(MDT) review. The MDT comprises specialists including at
least two ILD-trained radiologists, three specialist ILD respi-
ratory physicians, a specialist nurse and a lung pathologist. A
dedicated clinical assessment and investigations were used to
rule out other possible causes of usual interstitial pneumonitis
(UIP) that can give the same radiological picture as IPF. This PET/CT images were analyzed by a dedicated thoracic radi-
ologist and senior PET technologist with more than 10 years
of experience in quantifying pulmonary 18F-FDG PET uptake
in ILD and examining HRCT. All images were loaded onto a dedicated workstation. Using a volumetric region of interest, the area of most intense
pulmonary 18F-FDG uptake was identified and the highest Eur J Nucl Med Mol Imaging In all the analyses that were not corrected for multiple com-
parison, p values <0.05 were considered significant. value (SUVmax) measured. In addition, the region of pulmo-
nary parenchyma considered mostly normal on CT by the
expert thoracic radiologist, with the lowest SUV, was identi-
fied and the SUVmin in this region recorded. The target-to-
background ratio (TBR = SUVmax/SUVmin) was also recorded
as a standard measurement [11]. Results The HRCT was not analyzable by the qCT software in 22
patients. Reasons for failure were motion artifacts in 17 pa-
tients and incorrect reconstruction kernel in 5 patients. Thus,
91 patients with IPF were included and analyzed for this com-
parative FDG PET/qCT study. The survival analysis was performed using the package
‘survminer’ (https://cran.r-project.org/web/packages/
survminer/) and its dependencies. To explore the
relationships of imaging-derived parameters (PET and qCT),
PFTs, and GAP with patient survival, a Kaplan–Meier (KM)
survival analysis was calculated for each of the parameters. Patients that were alive at the time of the follow-up collection
were censored. Initially, the median value was chosen as a
threshold (cutoff) to divide the cohort into two groups accord-
ing to their prognosis (poor and good prognostic groups). Subsequently, optimal cutoffs that best separated the survival
plots were determined (lowest p value). KM curves displaying
patients above and below each threshold were generated to
facilitate the visualization of the survival trend of the two
populations. Subsequently, the parameters that were found to
significantly discriminate between the prognostic groups were
used as input for a multivariate stepwise (forward and back-
ward) Cox regression. The variables to be retained at each step
were determined using the Akaike information criterion. p
q
y
Of the retained patients, 78 (85.7%) were male, and 23
(25.3%) were treated with pirfenidone. At baseline, the aver-
age GAP index was 4.2 ± 1.7 (0–8); 31 patients (34.4%) were
classified as GAP stage I, 38 patients (42.2%) were GAP stage
II, and the remaining 21 patients (23.3%) were classified as
stage III; one patient was excluded from the GAP analysis
because the FVC was unobtainable. Values of FVC, forced
expiratory volume in 1 s (FEV1), total lung capacity (TLC),
carbon monoxide transfer coefficient (KCO), and TLCO are
shown in Table 1. The mean follow-up period was 29.6 ±
26 months (0–109.4); during this time, 47 (51.6%) patients
died. Cause of death was as follows: exacerbation of IPF (17
[37%]), pulmonary embolism (3 [6%]), pneumonia (14
[31%]), heart failure/cor polmonale (6 [12%]), 3 cancer (2
lung and 1 colon [6%]), and 4 unknown (8%). The mean SUVmax was 3.4 ± 1.4 (1.5–10.7), the mean
SUVmin (background lung activity) was 0.7 ± 0.2 (0.3–1.3),
and the mean TBR 5.7 ± 2.8 (2.2–21.4). Results FVC =
forced vital capacity, FEV1 = forced expiratory volume in 1 s, TLC =
total lung capacity, KCO = carbon monoxide transfer coefficient,
TLCO = transfer factor of the lung for carbon monoxide. The GAP index
was obtained as per Ley B, Ryerson CJ, Vittinghoff E, Ryu JH, Tomassetti
S, Lee JS, Poletti V, Buccioli M, Elicker BM, Jones KD, King TE Jr,
Collard HR. A multidimensional index and staging system for idiopathic
pulmonary fibrosis. Ann Intern Med. 2012 May 15;156(10):684-91. doi:
https://doi.org/10.7326/0003-4819-156-10-201,205,150-00004. PubMed
PMID: 22586007) Values are expressed as mean ± standard deviation (range) qCT analysis are shown in Table 2; the predominant pattern
was reticular lung, with an average percentage of 14.9 ±
12.4% (0.3–74.5); on average, 71.8 ± 16% (19.2–94) of lung
parenchyma was deemed normal. The KM analyses were then repeated using the optimal
cutoff as threshold for the groups’ separation. Optimal
cutoff and corresponding median survival are shown in
Table 4. SUVmax and SUVmin were confirmed to be
non-predictive of patient outcome (p = 0.081 and p = Bivariate analysis Correlations between the area with highest pulmonary 18F-
FDG uptake (SUVmax), lowest pulmonary uptake (SUVmin),
TBR, extent of qCT parenchymal patterns, and individual
PFTs are shown in Fig. 1. The imaging-derived parameters
available from the qCT software correlated significantly
among themselves (0.0000 < p < 0.004), acting as internal val-
idation for the software itself. Of the PFTs, only TLC was
correlated with an imaging biomarker (SUVmin); this correla-
tion was negative (r = −0.76; p = 0.0025). Fig. 1 Correlation matrices among the highest pulmonary 18F-FDG
uptake (SUVmax), lowest uptake (SUVmin), TBR, extent of qCT
parenchymal patterns, and GAP index and stage. Correlations were
explored using Spearman’s correlation coefficient; to account for
multiple comparisons, the Bonferroni correction was applied. A value
of 1 indicates complete positive correlation; a value of −1 indicates
complete negative correlation. *Indicates statistical significance Fig. 1 Correlation matrices among the highest pulmonary 18F-FDG
uptake (SUVmax), lowest uptake (SUVmin), TBR, extent of qCT
parenchymal patterns, and GAP index and stage. Correlations were
explored using Spearman’s correlation coefficient; to account for
multiple comparisons, the Bonferroni correction was applied. A value
of 1 indicates complete positive correlation; a value of −1 indicates Results The results of the Eur J Nucl Med Mol Imaging qCT analysis are shown in Table 2; the predominant pattern
Table 1
Pulmonary function tests (PFTs) obtained at baseline
PFTs
Value
FVC
74.9 ± 17.6 (37–122)
FEV1
77.1 ± 16.5 (31.8–129)
TLC
69.9 ± 11.1 (48–91)
KCO
77.8 ± 21.7 (27–135)
TLCO
45.3 ± 14.4 (11–79)
GAP index
4.2 ± 1.7 (0–8)
Figures are expressed as mean ± standard deviation (range). FVC =
forced vital capacity, FEV1 = forced expiratory volume in 1 s, TLC =
total lung capacity, KCO = carbon monoxide transfer coefficient,
TLCO = transfer factor of the lung for carbon monoxide. The GAP index
was obtained as per Ley B, Ryerson CJ, Vittinghoff E, Ryu JH, Tomassetti
S, Lee JS, Poletti V, Buccioli M, Elicker BM, Jones KD, King TE Jr,
Collard HR. A multidimensional index and staging system for idiopathic
pulmonary fibrosis. Ann Intern Med. 2012 May 15;156(10):684-91. doi:
https://doi.org/10.7326/0003-4819-156-10-201,205,150-00004. PubMed
PMID: 22586007)
Table 2
PET values and quantitative CT parameters derived from PET/
CT and HRCT
Parameter
Value
PET
SUVmax
3.4 ± 1.4 (1.5–10.7)
SUVmin
0.7 ± 0.2 (0.3–1.3)
TBR
5.7 ± 2.8 (2.2–21.4)
qCT
Normal parenchyma (%)
71.8 ± 16 (19.2–94)
Normal parenchyma (cm3)
2986.1 ± 1236.6 (83.9–5600)
Hyperlucent (%)
5 ± 6.9 (0.00005–26)
Ground-glass (%)
6.3 ± 8.6 (0.04–50.6)
Reticular (%)
14.9 ± 12.4 (0.3 ± 74.5)
Honeycomb (%)
1.8 ± 2.2 (90–9.3)
Parenchymal damage (%)
23 ± 16.7 (0.8–80.8)
Vessels (%)
3.9 ± 1.6 (0.9–9.8)
Vessels (cm3)
147.5 ± 47.9 (67.1–304.7)
Values are expressed as mean ± standard deviation (range) Table 2
PET values and quantitative CT parameters derived from PET/
CT and HRCT
Parameter
Value
PET
SUVmax
3.4 ± 1.4 (1.5–10.7)
SUVmin
0.7 ± 0.2 (0.3–1.3)
TBR
5.7 ± 2.8 (2.2–21.4)
qCT
Normal parenchyma (%)
71.8 ± 16 (19.2–94)
Normal parenchyma (cm3)
2986.1 ± 1236.6 (83.9–5600)
Hyperlucent (%)
5 ± 6.9 (0.00005–26)
Ground-glass (%)
6.3 ± 8.6 (0.04–50.6)
Reticular (%)
14.9 ± 12.4 (0.3 ± 74.5)
Honeycomb (%)
1.8 ± 2.2 (90–9.3)
Parenchymal damage (%)
23 ± 16.7 (0.8–80.8)
Vessels (%)
3.9 ± 1.6 (0.9–9.8)
Vessels (cm3)
147.5 ± 47.9 (67.1–304.7)
Values are expressed as mean ± standard deviation (range) Figures are expressed as mean ± standard deviation (range). Univariate and multivariate survival analysis The KM analysis was performed for all the clinical variables
(PFTs and GAP) and the imaging-derived biomarkers (PET
and qCT); results are summarized in Table 3. The KM analysis using the median as cutoff value
demonstrated that all the PFTs with the exception of the
TLC (p = 0.21) were able to significantly differentiate pa-
tients according to survival, with the strongest predictor
being the TLCO (p = 0.0004). Of the PET-derived bio-
markers, TBR was a significant predictor of patient sur-
vival (p = 0.019); curves are shown in Fig. 2. The synthet-
ic score generated to express the total burden of paren-
chymal damage evaluated by qCT was significantly pre-
dictive of patient outcome (p = 0.0013); however, the
strongest predictor of patient outcome from the qCT pa-
rameters was the vessel percentage (p = 0.0001; Fig. 3). Fig. 1 Correlation matrices among the highest pulmonary 18F-FDG
uptake (SUVmax), lowest uptake (SUVmin), TBR, extent of qCT
parenchymal patterns, and GAP index and stage. Correlations were
explored using Spearman’s correlation coefficient; to account for
multiple comparisons, the Bonferroni correction was applied. A value
of 1 indicates complete positive correlation; a value of −1 indicates
complete negative correlation. *Indicates statistical significance Fig. 1 Correlation matrices among the highest pulmonary 18F-FDG
uptake (SUVmax), lowest uptake (SUVmin), TBR, extent of qCT
parenchymal patterns, and GAP index and stage. Correlations were
explored using Spearman’s correlation coefficient; to account for
multiple comparisons, the Bonferroni correction was applied. A value
of 1 indicates complete positive correlation; a value of −1 indicates
complete negative correlation. Univariate and multivariate survival analysis *Indicates statistical significance Eur J Nucl Med Mol Imaging Table 3
Results of Kaplan–Meier analysis conducted using the median
values as cutoff to discriminate between the two groups (presence or lack
of event during follow-up)
Parameter
Cutoff
p value
Pulmonary function tests
FVC
74
0.01
FEV1
77
0.036
TLC
69
0.21
KCO
78
0.032
TLCO
46
0.0004
GAP index
4
0.018
PET-derived parameters
SUVmax
3.1
0.33
SUVmin
0.6
0.29
TBR
5
0.019
qCT
Total volume (cm3)
4103.86
0.2
Vessel percentage (%)
3.80
<0.0001
Normal parenchyma (%)
74.56
0.011
Hyperlucent (%)
2.05
0.69
Ground-glass (%)
2.80
0.017
Reticular (%)
11.46
<0.0001
Honeycomb (%)
0.71
0.5
Parenchymal damage (%)
18.94
0.0013
FVC = forced vital capacity, FEV1 = forced expiratory volume in 1 s,
TLC = total lung capacity, KCO = carbon monoxide transfer coefficient,
TLCO = transfer factor of the lung for carbon monoxide Table 3
Results of Kaplan–Meier analysis conducted using the median
values as cutoff to discriminate between the two groups (presence or lack
of event during follow-up) 0.12 respectively). Patients with TBR < 4.8 had a median
survival of 70.6 months as compared to 26.5 months in
patients with TBR > 4.8 at the baseline PET (p = 0.018). The synthetic score of parenchymal damage demonstrated
a slightly better performance than TBR; patients with
values <18.5 had a median survival of 70.6 months as
compared to 22.2 months in patients that presented a
higher burden of parenchymal damage (p = 0.0002). The parameters that significantly predicted outcome with
KM analysis were used as the input for the Cox multivariate
analysis and the Cox forward stepwise regression analysis;
results are shown in Table 5. The stepwise regression con-
firmed that TBR is an independent prognostic predictor (p =
0.01). Moreover, in a model constructed including the qCT
parameters, the forward stepwise Cox regression analysis con-
firmed that the volume of normal parenchyma, the vessels,
and the hyperlucent pattern are independent prognostic indi-
cators (p = 0.03, p = 0.01 and p = 0.01, respectively). Modified GAP score The results of the KM analysis conducted on the incre-
mental scores (GAP_PET and GAP_PET_qCT) obtained
by modifying the GAP score are presented in Fig. 4. The
two incremental scores were all significantly able to pre-
dict patient survival (p < 0.0001); however, their ability to
predict median survival differed (Table 6). Using an opti-
mal cutoff of 6, the GAP_PET showed a median survival
of 43.9 months in patients with a score lower than the
cutoff, and median survival of 11.6 months in patients
above the cutoff. The GAP_PET_qCT score showed an FVC = forced vital capacity, FEV1 = forced expiratory volume in 1 s,
TLC = total lung capacity, KCO = carbon monoxide transfer coefficient,
TLCO = transfer factor of the lung for carbon monoxide FVC = forced vital capacity, FEV1 = forced expiratory volume in 1 s,
TLC = total lung capacity, KCO = carbon monoxide transfer coefficient,
TLCO = transfer factor of the lung for carbon monoxide Fig. 2 Kaplan–Meier plots of survival analysis. Patients were classified
according to their median (a is SUVmax, b is SUVmin, and c is TBR) and
according to the optimal cutoff (d is SUVmax, e is SUVmin, and f is TBR)
values as described in the methods section. The log-rank test
demonstrated a statistically significant worse prognosis in patients with
TBR greater than 5 (median value, p = 0.019, curve c) and 4.8 (optimal
cutoff, p = 0.018, curve f). Using the optimal cutoff for all the parameters
improved the capacity of differentiating between patients with better and
worse prognosis; however, SUVmax (a and d) and SUVmin (b and e) were
not statistically significant TBR greater than 5 (median value, p = 0.019, curve c) and 4.8 (optimal
cutoff, p = 0.018, curve f). Using the optimal cutoff for all the parameters
improved the capacity of differentiating between patients with better and
worse prognosis; however, SUVmax (a and d) and SUVmin (b and e) were
not statistically significant Fig. 2 Kaplan–Meier plots of survival analysis. Patients were classified
according to their median (a is SUVmax, b is SUVmin, and c is TBR) and
according to the optimal cutoff (d is SUVmax, e is SUVmin, and f is TBR)
values as described in the methods section. The log-rank test
demonstrated a statistically significant worse prognosis in patients with Eur J Nucl Med Mol Imaging Fig. 3 Kaplan–Meier plots of survival analysis. Modified GAP score Patients were classified
according to their median (a is parenchymal damage, b is total vessel
percentage) and according to the optimal cutoff (d is parenchymal
damage and e is total vessel percentage) values, as described in the
methods section. The parenchymal damage was obtained by adding up
ground-glass opacification, reticular pattern, and honeycombing to
express the total burden of disease in the lung parenchyma; the total
vessel percentage reflects the percentage of vessels in the lung
parenchyma. The log-rank test demonstrated a statistically significant
worse prognosis in patients with parenchymal damage greater than 18.9
(median value, p = 0.0013, curve a) and 18.5 (optimal cutoff, p = 0.0002,
curve c). Similarly, a vessel percentage greater than 3.8% (median value,
p < 0.0001, curve b) and 3.66% (optimal cutoff, p < 0.0001, curve d)
predicted significantly worse prognosis. Using the optimal cutoff
calculated in R improved the capacity to differentiate between patients
with better and worse prognosis, using both parenchymal damage and
total vessel percentage worse prognosis in patients with parenchymal damage greater than 18.9
(median value, p = 0.0013, curve a) and 18.5 (optimal cutoff, p = 0.0002,
curve c). Similarly, a vessel percentage greater than 3.8% (median value,
p < 0.0001, curve b) and 3.66% (optimal cutoff, p < 0.0001, curve d)
predicted significantly worse prognosis. Using the optimal cutoff
calculated in R improved the capacity to differentiate between patients
with better and worse prognosis, using both parenchymal damage and
total vessel percentage Fig. 3 Kaplan–Meier plots of survival analysis. Patients were classified
according to their median (a is parenchymal damage, b is total vessel
percentage) and according to the optimal cutoff (d is parenchymal
damage and e is total vessel percentage) values, as described in the
methods section. The parenchymal damage was obtained by adding up
ground-glass opacification, reticular pattern, and honeycombing to
express the total burden of disease in the lung parenchyma; the total
vessel percentage reflects the percentage of vessels in the lung
parenchyma. The log-rank test demonstrated a statistically significant patients, where there is a lack of validated biomarkers for risk
stratification and therapeutic intervention. improvement in outcome prediction, particularly in the
worst outcome group, with a median survival of
86.5 months in patients with a score lower than 6, and
median survival of 17.2 months in patients with a score
above the cutoff. Modified GAP score Among the PET parameters, patients with a high TBR had
a worse prognosis, while for the qCT, the percentage of nor-
mal parenchyma and the percentage of vessels (higher % cor-
responding to worse prognosis) were the strongest indepen-
dent imaging biomarkers of survival (Table 4). These findings
confirm data previously reported elsewhere [13]. Discussion This may have
l
i th
li i
l
tti
i d t
i i
t
t
t
Table 4
Median survival obtained from Kaplan–Meier analysis
conducted using the optimal cutoff to discriminate between the two
groups (presence or lack of event during follow-up)
Parameter
Cutoff
Median survival
p value
< Cutoff
> Cutoff
Pulmonary function tests
FVC
72
26.37
86.47
0.0044
FEV1
96.3
35.37
70.6
0.02
TLC
65.6
28.57
86.73
0.027
KCO
50
19.9
46.8
0.00097
TLCO
44.8
23.53
70.60
0.00027
GAP index
4
70.6
19.9
0.00046
PET-derived parameters
SUVmax
2.4
86.73
34.43
0.081
SUVmin
0.6
26.53
67.50
0.12
TBR
4.8
70.60
26.53
0.018
qCT
Total volume (cm3)
4352.77
28.57
80.93
0.011
Vessel percentage (%)
3.66
86.47
19.90
<0.0001
Normal parenchyma (%)
80.20
26.37
86.37
0.00029
Hyperlucent (%)
11.12
46.80
22.23
0.0038
Ground-glass (%)
6.79
67.5
16.3
<0.0001
Reticular (%)
10.96
70.60
26.53
0.004
Honeycomb (%)
4.23
40.80
16.63
0.0022
Parenchymal damage (%)
18.48
70.60
22.23
0.0002
Synthetic scores
GAP + PET
6
43.90
11.56
<0.0001
GAP + PET + qCT
6
86.47
17.23
<0.0001
FVC = forced vital capacity, FEV1 = forced expiratory volume in 1 s,
TLC = total lung capacity, KCO = carbon monoxide transfer coefficient,
TLCO = transfer factor of the lung for carbon monoxide
Table 5
Cox modelling of survivals according to pulmonary function
tests, TBR, and qCT parameters
Parameter
Hazard ratio (95% CI)
p value
Pulmonary function tests
FVC
0.99 (0.90–1.11)
0.997
FEV1
0.99 (0.91–1.07)
0.775
TLC
0.94 (0.86–1.02)
0.155
KCO
0.96 (0.90–1.02)
0.146
TLCO
0.99 (0.87–1.12)
0.849
GAP index
3.77 (1.12–12.69)
0.032
PET-derived parameters
TBR
1.09 (1.00–1.19)
0.043
qCT
Total volume (cm3)
Vessel percentage (%)
2.57 (1.04–6.38)
0.0414
Normal parenchyma (%)
5.22 (4.75–5.73)
0.9202
Hyperlucent (%)
5.12 (4.63–5.67)
0.9211
Ground-glass (%)
4.76 (4.32–5.25)
0.9246
Reticular (%)
4.74 (4.32–5.20)
0.9249
Honeycomb (%)
5.00 (4.57–5.46)
0.9223
Parenchymal damage (%)
1.09 (0.99–1.19)
0.008
FVC = forced vital capacity, FEV1 = forced expiratory volume in 1 s
TLC = total lung capacity, KCO = carbon monoxide transfer coefficient,
TLCO = transfer factor of the lung for carbon monoxide Table 5
Cox modelling of survivals according to pulmonary function
tests, TBR, and qCT parameters
Parameter
Hazard ratio (95% CI)
p value
Pulmonary function tests
FVC
0.99 (0.90–1.11)
0.997
FEV1
0.99 (0.91–1.07)
0.775
TLC
0.94 (0.86–1.02)
0.155
KCO
0.96 (0.90–1.02)
0.146
TLCO
0.99 (0.87–1.12)
0.849
GAP index
3.77 (1.12–12.69)
0.032
PET-derived parameters
TBR
1.09 (1.00–1.19)
0.043
qCT
Total volume (cm3)
Vessel percentage (%)
2.57 (1.04–6.38)
0.0414
Normal parenchyma (%)
5.22 (4.75–5.73)
0.9202
Hyperlucent (%)
5.12 (4.63–5.67)
0.9211
Ground-glass (%)
4.76 (4.32–5.25)
0.9246
Reticular (%)
4.74 (4.32–5.20)
0.9249
Honeycomb (%)
5.00 (4.57–5.46)
0.9223
Parenchymal damage (%)
1.09 (0.99–1.19)
0.008
FVC = forced vital capacity, FEV1 = forced expiratory volume in 1 s
TLC = total lung capacity, KCO = carbon monoxide transfer coefficient,
TLCO = transfer factor of the lung for carbon monoxide Table 4
Median survival obtained from Kaplan–Meier analysis
conducted using the optimal cutoff to discriminate between the two
groups (presence or lack of event during follow-up)
Parameter
Cutoff
Median survival
p value
< Cutoff
> Cutoff
Pulmonary function tests
FVC
72
26.37
86.47
0.0044
FEV1
96.3
35.37
70.6
0.02
TLC
65.6
28.57
86.73
0.027
KCO
50
19.9
46.8
0.00097
TLCO
44.8
23.53
70.60
0.00027
GAP index
4
70.6
19.9
0.00046
PET-derived parameters
SUVmax
2.4
86.73
34.43
0.081
SUVmin
0.6
26.53
67.50
0.12
TBR
4.8
70.60
26.53
0.018
qCT
Total volume (cm3)
4352.77
28.57
80.93
0.011
Vessel percentage (%)
3.66
86.47
19.90
<0.0001
Normal parenchyma (%)
80.20
26.37
86.37
0.00029
Hyperlucent (%)
11.12
46.80
22.23
0.0038
Ground-glass (%)
6.79
67.5
16.3
<0.0001
Reticular (%)
10.96
70.60
26.53
0.004
Honeycomb (%)
4.23
40.80
16.63
0.0022
Parenchymal damage (%)
18.48
70.60
22.23
0.0002
Synthetic scores
GAP + PET
6
43.90
11.56
<0.0001
GAP + PET + qCT
6
86.47
17.23
<0.0001
FVC = forced vital capacity, FEV1 = forced expiratory volume in 1 s,
TLC = total lung capacity, KCO = carbon monoxide transfer coefficient,
TLCO = transfer factor of the lung for carbon monoxide pulmonary 18F-FDG uptake and the extent of morphological
abnormalities on HRCT might help identify subpopulations of
patients that had a poorer outcome [8]. Discussion Using qCT and PET,
we created two modified versions of the GAP score that im-
proved the capacity to classify patients according to their out-
come at the follow-up using baseline tests. This may have
relevance in the clinical setting in determining treatment rec-
ommendations based on a combination of the three indepen-
dent variables (GAP + qCT + PET). FVC = forced vital capacity, FEV1 = forced expiratory volume in 1 s,
TLC = total lung capacity, KCO = carbon monoxide transfer coefficient,
TLCO = transfer factor of the lung for carbon monoxide Further explanations have been also proposed, including
the presence of vascular abnormalities in fibrotic lungs, dem-
onstrated histologically and reminiscent of pulmonary venous
occlusive disease with aberrant capillary duplication. The re-
ported increased vascular volume was found in less affected
areas of the lung and correlated with pulmonary arterial pres-
sure as estimated by transthoracic echocardiography [15]. The synergies between GAP, PET, and qCT are encour-
aging. In GAP stage I, we identified IPF patients with a
worse outcome than the other GAP I patients, and they
may have benefited from treatment. Likewise, there were
patients in GAP stage II and particularly III that showed
lower 18F-FDG uptake and qCT parameters, whose out-
come was more favorable. This may have important clin-
ical implications, as with our data we were able to re-
classify many patients from GAP III into the new modi-
fied GAP I score despite impaired lung function (FVC <
80% predicted), compared to a group of patients with
mildly impaired lung function (FVC > 80% predicted) that
progressed rapidly. Thus, the synergistic use of 18F-FDG
PET and qCT in this context raises the possibility for
more accurate selection of patients that may benefit most
from pirfenidone or nintedanib treatment from a wider
patient population. It is interesting that PET is able to detect subtle metabolic
changes in visually normal or minimally involved lung in
patients with IPF [16]. In this regard, the combined applica-
tion of metabolic, morphological, and quantitative informa-
tion may enable more accurate assessment of early disease,
for example, to determine whether the subtle changes seen on
FDG PETare in fact due to regional increases in blood flow in
areas of limited interstitial lung pathology. Discussion Using qCT and PET,
we created two modified versions of the GAP score that im-
proved the capacity to classify patients according to their out-
come at the follow-up using baseline tests. Discussion This may have important clin-
ical implications, as with our data we were able to re-
classify many patients from GAP III into the new modi-
fied GAP I score despite impaired lung function (FVC <
80% predicted), compared to a group of patients with
mildly impaired lung function (FVC > 80% predicted) that
Table 4
Median survival obtained from Kaplan–Meier analysis
conducted using the optimal cutoff to discriminate between the two
groups (presence or lack of event during follow-up)
Parameter
Cutoff
Median survival
p value
< Cutoff
> Cutoff
Pulmonary function tests
FVC
72
26.37
86.47
0.0044
FEV1
96.3
35.37
70.6
0.02
TLC
65.6
28.57
86.73
0.027
KCO
50
19.9
46.8
0.00097
TLCO
44.8
23.53
70.60
0.00027
GAP index
4
70.6
19.9
0.00046
PET-derived parameters
SUVmax
2.4
86.73
34.43
0.081
SUVmin
0.6
26.53
67.50
0.12
TBR
4.8
70.60
26.53
0.018
qCT
Total volume (cm3)
4352.77
28.57
80.93
0.011
Vessel percentage (%)
3.66
86.47
19.90
<0.0001
Normal parenchyma (%)
80.20
26.37
86.37
0.00029
Hyperlucent (%)
11.12
46.80
22.23
0.0038
Ground-glass (%)
6.79
67.5
16.3
<0.0001
Reticular (%)
10.96
70.60
26.53
0.004
Honeycomb (%)
4.23
40.80
16.63
0.0022
Parenchymal damage (%)
18.48
70.60
22.23
0.0002
Synthetic scores
GAP + PET
6
43.90
11.56
<0.0001
GAP + PET + qCT
6
86.47
17.23
<0.0001
FVC = forced vital capacity, FEV1 = forced expiratory volume in 1 s,
TLC = total lung capacity, KCO = carbon monoxide transfer coefficient,
TLCO = transfer factor of the lung for carbon monoxide
Table 5
Cox modelling of survivals according to pulmonary function
tests, TBR, and qCT parameters
Parameter
Hazard ratio (95% CI)
p value
Pulmonary function tests
FVC
0.99 (0.90–1.11)
0.997
FEV1
0.99 (0.91–1.07)
0.775
TLC
0.94 (0.86–1.02)
0.155
KCO
0.96 (0.90–1.02)
0.146
TLCO
0.99 (0.87–1.12)
0.849
GAP index
3.77 (1.12–12.69)
0.032
PET-derived parameters
TBR
1.09 (1.00–1.19)
0.043
qCT
Total volume (cm3)
Vessel percentage (%)
2.57 (1.04–6.38)
0.0414
Normal parenchyma (%)
5.22 (4.75–5.73)
0.9202
Hyperlucent (%)
5.12 (4.63–5.67)
0.9211
Ground-glass (%)
4.76 (4.32–5.25)
0.9246
Reticular (%)
4.74 (4.32–5.20)
0.9249
Honeycomb (%)
5.00 (4.57–5.46)
0.9223
Parenchymal damage (%)
1.09 (0.99–1.19)
0.008
FVC = forced vital capacity, FEV1 = forced expiratory volume in 1 s
TLC = total lung capacity, KCO = carbon monoxide transfer coefficient,
TLCO = transfer factor of the lung for carbon monoxide pulmonary 18F-FDG uptake and the extent of morphological
abnormalities on HRCT might help identify subpopulations of
patients that had a poorer outcome [8]. Discussion The unexpected signal provided by pulmonary vessel
volume (PVV) in this study has been described but is not
fully comprehensible. Jacob et al. provided three plausible
explanations: 1) blood-flow diversion from advanced fi-
brotic areas to relatively spared lung regions, with aber-
rant dilatation of capacitance vessels resulting in in-
creased PVV; 2) dilatation effect on blood vessels of in-
creased negative pressure during inspiration due to in-
creased lung stiffness in IPF patients; and 3) the effect
of pleuroparenchymal and bronchopulmonary arterial
anastomosis [14]. Our study has shown that in IPF patients, the baseline mea-
sures of FDG PET and several qCT parameters in HRCT are
potential independent biomarkers related to patient survival. Their combined use can have a synergistic effect in the assess-
ment of disease prognosis. These data demonstrate that in IPF
patients, both pulmonary glucose uptake and qCT are inde-
pendent prognostic factors. Moreover, these factors are syner-
gistic and may offer better outcome modeling than current
GAP analysis alone. This is potentially important in IPF Eur J Nucl Med Mol Imaging Further explanations have been also proposed, including
the presence of vascular abnormalities in fibrotic lungs, dem-
onstrated histologically and reminiscent of pulmonary venous
occlusive disease with aberrant capillary duplication. The re-
ported increased vascular volume was found in less affected
areas of the lung and correlated with pulmonary arterial pres-
sure as estimated by transthoracic echocardiography [15]. It is interesting that PET is able to detect subtle metabolic
changes in visually normal or minimally involved lung in
patients with IPF [16]. In this regard, the combined applica-
tion of metabolic, morphological, and quantitative informa-
tion may enable more accurate assessment of early disease,
for example, to determine whether the subtle changes seen on
FDG PETare in fact due to regional increases in blood flow in
pulmonary 18F-FDG uptake and the extent of morphological
abnormalities on HRCT might help identify subpopulations of
patients that had a poorer outcome [8]. Using qCT and PET,
we created two modified versions of the GAP score that im-
proved the capacity to classify patients according to their out-
come at the follow-up using baseline tests. This may have
relevance in the clinical setting in determining treatment rec-
ommendations based on a combination of the three indepen-
dent variables (GAP + qCT + PET). The synergies between GAP, PET, and qCT are encour-
aging. Discussion In GAP stage I, we identified IPF patients with a
worse outcome than the other GAP I patients, and they
may have benefited from treatment. Likewise, there were
patients in GAP stage II and particularly III that showed
lower 18F-FDG uptake and qCT parameters, whose out-
come was more favorable. Discussion When we combined the pulmonary PET uptake, qCT, and
PFT parameters, we found that the combination of these three
independent parameters had the strongest association with
survival. In fact, even in IPF patients with good PFTs, the Eur J Nucl Med Mol Imaging Fig. 4 Kaplan–Meier plots of survival analysis. Patients were classified
according to the optimal cutoff values as described in the methods
section; a represents the GAP index, b is GAP_PET (obtained from the
addition of GAP and TBR), and c is GAP_PET_qCT (obtained adding
the qCT to the GAP_PET); additional details on the synthetic score can be
found in the methods section. The log-rank test demonstrated that all the
scores were statistically significant predictors of survival (p values in
corresponding panel); however, adding information from PET and qCT
improved the ability to differentiate between a better and worse prognosis Fig. 4 Kaplan–Meier plots of survival analysis. Patients were classified
according to the optimal cutoff values as described in the methods
section; a represents the GAP index, b is GAP_PET (obtained from the
addition of GAP and TBR), and c is GAP_PET_qCT (obtained adding
the qCT to the GAP_PET); additional details on the synthetic score can be found in the methods section. The log-rank test demonstrated that all the
scores were statistically significant predictors of survival (p values in
corresponding panel); however, adding information from PET and qCT
improved the ability to differentiate between a better and worse prognosis HRCT is the main diagnostic imaging tool in IPF, but until
recently there have been only limited data on the prognostic
use of this imaging technique. This may be because in many
cases, the morphological appearance does not allow for accu-
rate and reproducible assessment [17]. However, a number of
studies investigating the association between mortality and
different variables, including normal lung, centrilobular em-
physema, and number of vessels, have shown qCT to be su-
perior to visual HRCTscoring [18]. qCT-derived features have
also outperformed visual CT patterns in predicting outcome
across several fibrosing lung diseases other than IPF. may pave the way for more detailed longitudinal studies. However, we recognize that there are limitations: several technical
factors related to qCT and PET need to be improved. Regarding
qCT, several analytical methods have been described (e.g. Discussion seg-
mentation and feature extraction based on lung density [measured
in Hounsfield units]), all heavily influenced by CT dose, slice
thickness, and reconstruction kernels. In our study, slightly differ-
ent HRCTacquisition protocols adopted at the start of our recruit-
ment since 2006 led to the exclusion of some patients due to
different reconstruction methods or scanning protocols. Limitations of PET imaging also need to be recognized,
such as the importance of air and tissue fraction and motion
correction. For example, in the normal lung, previous studies
showed that the uptake distribution without air fraction cor-
rection (AFC) appeared uniform throughout the lung, but on
correcting for the air component, the results for the regional
uptake changed [19, 20]. Also, future studies need to explore
the use of texture heterogeneity analysis as part of the overall/
comprehensive qCTanalysis techniques, which could provide
additional insight into morphological feature extraction [21]. One of the best known software algorithms, CALIPER
(Computer-Aided Lung Informatics for Pathology Evaluation
and Rating), based on lung texture analysis, was developed at
the Biomedical Imaging Resource, Mayo Clinic, Rochester, MN,
USA. This software has been shown to be reproducible and
robust across a wide variety of acquisition and reconstruction
techniques, including low- and ultralow-dose (0.1–0.3 mSv)
CT techniques with both filtered back-projection and iterative
reconstruction. The model proposed in our study is based on
CALIPER and provides a detailed map of lung textures that
are key to identifying ILDs and other fibrotic conditions [18]. Jacob et al. recently reported their application of CALIPER quan-
titative HRCT in IPF patients, showing that stratification using
CALIPER variables and PFTs provided a stronger mortality sig-
nal than stratification using the GAP index alone [13]. We also acknowledge that the imaging was not always
performed at the time of diagnosis, which is a common prob-
lem for imaging studies, as patients often present at later
stages of the disease. We recognize that our combined approach is not feasible
for all patients, as it is time-consuming and is not always
financially justifiable. On the other hand, current therapies
for IPF are expensive and often limited by side effects, and
not all patients may benefit from them. There are no validated The technical protocol we have developed in this study is
novel and uses a low-dose HRCT acquired in breath-hold at the
end of half-dose FDG PET. Conclusion We have shown that high pulmonary uptake of 18F-FDG and
several qCT parameters are associated with mortality in pa-
tients with IPF. These PET and qCT findings can be used
synergistically with PFTs and could help offer a personalized
approach to treatment for individual patients. 9. Ley B, Collard HR, King TE Jr. Clinical course and prediction of
survival in idiopathic pulmonary fibrosis. Am J Respir Crit Care
Med. 2011;183(4):431–40. 10. Ley B, Ryerson CJ, Vittinghoff E, Ryu JH, Tomassetti S, Lee JS,
et al. A multidimensional index and staging system for idiopathic
pulmonary fibrosis. Ann Intern Med. 2012;15:684–91. 11. Chen DL, Schuster DP. Imaging pulmonary inflammation with pos-
itron emission tomography: a biomarker for drug development. Mol
Pharm. 2006;3:488–95. Acknowledgements The authors want to acknowledge the help of Prof. Kris Thielemans and Prof. Brian Hutton for their contribution to the
image reconstruction at the Institute of Nuclear Medicine, London, UK. 12. Jacob J, Hirani N, van Moorsel CHM, Rajagopalan S, Murchison
JT, et al. Predicting outcomes in rheumatoid arthritis related inter-
stitial lung disease. Eur Respir J. 2019;53. We also acknowledge Gabrielle Azzopardi and Dr. Fulvio Zaccagna
for help with the database and patient clinical information. 13. Jacob J, Bartholmai BJ, Rajagopalan S, Kokosi M, Nair A, Karwoski R,
Walsh SL, Wells AU, Hansell DM. Mortality prediction in idiopathic
pulmonary fibrosis: evaluation of computer-based CTanalysis with con-
ventional severity measures. Eur Respir J. 2017;49. Funding This work was performed at UCLH/UCL, which received a
portion of funding from the UK Department of Health’s NIHR
Biomedical Centres (BRC UCLH 2012) funding scheme. 14. Jacob J, Nicholson AG, Wells AU, Hansell DM. Impact of pulmo-
nary vascular volume on mortality in IPF: is it time to reconsider the
role of vasculature in disease pathogenesis and progression? Eur
Respir J. 2017;49(2). Discussion This combined quantitative approach Table 6
Distribution of patients (expressed as n) according to the risk category as defined by GAP index, GAP PET values, and quantitative CT
parameters and their corresponding average survival (expressed in months)
Scoring system
Low risk
Intermediate risk
High risk
Patients (n)
Survival (months)
Patients (n)
Survival (months)
Patients (n)
Survival (months)
GAP index
31
33.3
38
29.3
21
24.4
GAP index + PET
41
35.0
36
27.6
14
19.5
GAP index + PET + qCT
54
36.3
25
21.8
12
16.3 ssed as n) according to the risk category as defined by GAP index, GAP PET values, and quantitative CT
ge survival (expressed in months) Table 6
Distribution of patients (expressed as n) according to the risk category as defined by GAP index, GAP P
parameters and their corresponding average survival (expressed in months) Eur J Nucl Med Mol Imaging 4. Spagnolo P, Maher TM. Clinical trial research in focus: why do so
many clinical trials fail in IPF? Lancet Respir Med. 2017;5:372–4. disease response biomarkers available, and our combined ap-
proach may refine the stratification of this heterogenous group
of patients, as well as speed the assessment of novel therapies,
and enable a personalized approach in selected cases. 5. Jones HA, Cadwallader KA, White JF, Uddin M, Peters AM, Chilvers
ER. Dissociation between respiratory burst activity and deoxyglucose
uptake in human neutrophil granulocytes: implications for interpretation
of 18F-FDG PET images. J Nucl Med. 2002;43:652–7. Finally, although the PETand HRCT acquisition scans can be
done on different scanners and the results of the two techniques
evaluated independently, some newer PET/CT scanners allow
simultaneous HRCT/PET acquisition in breath-hold, reducing
the time for a double scan and limiting ionizing radiation. 6. Wallace WE, Gupta NC, Hubbs AF, Mazza SM, Bishop HA, Keane
MJ, et al. Cis-4-[18F]fluoro-L-proline PET imaging of pulmonary
fibrosis in a rabbit model. J Nucl Med. 2002;43:413–20. 7. Groves AM, Win T, Screaton NJ, Berovic M, Endozo R, Booth H,
et al. Idiopathic pulmonary fibrosis and diffuse parenchymal lung
disease: implications from initial experience with 18F-FDG PET/
CT. J Nucl Med. 2009;50:538–45. 8. Win T, Screaton NJ, Porter JC, Ganeshan B, et al. Pulmonary (18)F-
FDG uptake helps refine current risk stratification in idiopathic
pulmonary fibrosis (IPF). Eur J Nucl Med Mol Imaging. 2018;45(5):806–15. Compliance with ethical standards There is no disclosure
with this paper. Ethical approval
All procedures performed in studies involving human
participants were in accordance with the ethical standards of the institu-
tional and/or national research committee and with the 1964 Helsinki
Declaration and its later amendments or comparable ethical standards. 15. Puxeddu E, Cavalli F, Pezzuto G, et al. Impact of pulmonary vas-
cular volume on mortality in IPF: is it time to reconsider the role of
vasculature in disease pathogenesis and progression? Eur Respir J. 2017;49:1602345. 16. Win T, Thomas BA, Lambrou T, et al. Areas of normal pulmonary
parenchyma on HRCT exhibit increased FDG PET signal in IPF
patients. Eur J Nucl Med Mol Imaging. 2014;41:337–42. Informed consent
Informed consent was obtained from all individual
participants included in the study. 17. McLoud TC. Role of high-resolution computed tomography in id-
iopathic pulmonary fibrosis: the final word? Am J Respir Crit Care
Med. 2005;172:408–9. Open Access This article is distributed under the terms of the Creative
Commons Attribution 4.0 International License (http://
creativecommons.org/licenses/by/4.0/), which permits unrestricted use,
distribution, and reproduction in any medium, provided you give appro-
priate credit to the original author(s) and the source, provide a link to the
Creative Commons license, and indicate if changes were made. 18. Jacob J, Bartholmai BJ, Rajagopalan S, Kokosi M, et al. Automated
quantitative computed tomography versus visual computed tomography
scoring in idiopathic pulmonary fibrosis: validation against pulmonary
function. J Thorac Imaging. 2016;31:304–11. 19. Chen DL, Cheriyan J, Chilvers ER, Choudhury G, et al. Quantification of lung PET images: challenges and opportunities. J Nucl Med. 2017;58:201–7. Publisher’s note Springer Nature remains neutral with regard to
jurisdictional claims in published maps and institutional affiliations. References 20. Holman BF, Cuplov V, Millner L, Hutton BF, et al. Improved cor-
rection for the tissue fraction effect in lung PET/CT imaging. Phys
Med Biol. 2015;60:7387–402. 1. Lynch DA, David GJ, Safrin S, et al. High-resolution computed
tomography in idiopathic pulmonary fibrosis: diagnosis and prog-
nosis. Am J Respir Crit Care Med. 2005;172:488–93. 21. Ganeshan B, Miles KA, Young RC, Chatwin CR. Three-
dimensional selective-scale texture analysis of computed tomogra-
phy pulmonary angiograms. Investig Radiol. 2008;43:382–94. 2. Watadani T, Sakai F, Johkoh T, et al. Interobserver variability in the
CT assessment of honeycombing in the lungs. Radiology. 2013;266:936–44. Publisher’s note Springer Nature remains neutral with regard to
jurisdictional claims in published maps and institutional affiliations. 3. Wu X, Kim GH, Salisbury ML, Barber D, et al. Computed tomographic
biomarkers in idiopathic pulmonary fibrosis. The future of quantitative
analysis. Am J Respir Crit Care Med. 2019;199:12–21.
|
https://openalex.org/W4283818311
|
http://revista.letras.unmsm.edu.pe/index.php/le/article/download/2103/2153, https://revistasinvestigacion.unmsm.edu.pe/index.php/revistaLetras/article/download/20847/18313
|
es
|
Translingüismo como una perspectiva que permite desarrollar literacidad académica en una lengua extranjera en educación superior: una revisión de literatura
|
Letras
| 2,022
|
cc-by
| 8,242
| ERROR: type should be string, got "https://doi.org/10.30920/letras.93.137.7\n\nTranslingualism as an Insight to Develop Academic\nLiteracy in Foreign Language in Tertiary Education:\nA Literature Review\nTranslingüismo como una perspectiva que permite\ndesarrollar literacidad académica en una lengua extranjera\nen educación superior: una revisión de literatura\nAntonio Esquicha Medina\nUniversidad de Talca, Campus Santiago LBI, Santiago de Chile, Chile\nContacto: jesquicha@utalca.cl\nhttps://orcid.org/0000-0002-1339-5799\n\nRESUMEN\n\nABSTRACT\n\nLa literacidad académica en una lengua extranjera es una competencia a desarrollarse hoy en día.\nSin embargo, los enfoques hacia la escritura en una\nsegunda lengua se rigen tradicionalmente por perspectivas monolingües, reforzando la idea de una\ndeseada homogeneidad lingüística que sitúa al hablante nativo como referente. El translingüismo reconoce la variedad de contextos propios del ámbito\neducativo, desafiando el dominio del inglés como\nlengua vehicular en comunidades académicas. El\ntranslingüismo ofrece una comprensión amplia de\ncómo ocurren las prácticas letradas, entendiendo\nel cambio entre una lengua hacia otra como una\nevidencia de un repertorio lingüístico, en lugar de\ninterferencia lingüística. Esta revisión de literatura\npretende describir la contribución del translingüismo en el desarrollo de la literacidad académica en\nel ámbito universitario. Los principales resultados\nobservados en los estudios empíricos revisados\naquí hacen referencia a la importancia de la lengua\nmaterna en el desarrollo de la identidad del escritor,\na las implicancias del translingüismo en los procesos de escritura en segunda lengua, y a las prácticas letradas multimodales y digitales. Se concluye\nque se requieren perspectivas alternativas respecto\na los procesos de literacidad académica para comprender las prácticas letradas en contextos universitarios actuales al escribir en una lengua extranjera.\n\nAcademic literacy in a foreign language is a competence to be developed nowadays. However,\napproaches towards second language writing have\ntraditionally been informed by monolingual perspectives, which reinforce the idea of a desired linguistic homogeneity with the native speaker as a\nreferent. Translanguaging acknowledges the variety of backgrounds in current educational contexts,\nchallenging the dominance of English as a target\nlanguage within academic communities. Translingualism provides an ample comprehension of literacy practices occurring worldwide, where shuttling between codes is considered as evidence of\nlinguistic repertoire instead of language interference. This literature review aims at describing contributions of translingualism to the development of\nacademic literacy at tertiary level. Importance of L1\nin the development of the writer’s identity, implications of translingualism in second language writing\nand multimodality and digital translingual practices are described as the main results reported in\nempirical research. To conclude, alternative insights towards academic literacy seem necessary to\nunderstand current literacy practices at university\nlevel when writing in a foreign language.\n\nPalabras clave: Escritura académica; Prácticas letradas; Translingüismo; Translenguaje; Revisión de\nliteratura.\nRecibido: 28.05.21\n\n86\n\nRevisado: 14.02.22\n\nKeywords: Academic Writing; Literacy Practices;\nTranslingualism; Translanguaging; Literature Review.\n\nAceptado: 07.04.22\n\nLETRAS (Li ma), 93(137), 2022\n\n\fhttps://doi.org/10.30920/letras.93.137.7\n\n1. Introduction\nWriting has traditionally been considered in academic contexts for gatekeeping or evaluation purposes,\nas passing or failing university courses frequently\ndepends on reading and writing academic and disciplinary texts (Lillis, 2001; Thaiss & Myers-Zawacki,\n2006). However, it is also considered as an element\nthat promotes graduation in tertiary education (Fernandez Lamarra & Costa de Paula, 2011). In that context, many universities have incorporated academic\nwriting and foreign language courses to their curricula\nto prepare students for the challenges of this heterogeneous society. However, foreign language learners\npresent difficulty in achieving academic standards\nand a formal register while writing under traditional\nteaching methods (Hyland, 2006). This eclecticism in\nacademic writing makes it necessary to describe literacy practices as they occur these days (Mcgrath &\nKaufhold, 2016).\nWriting in academic genres at university represents a challenge for these students as they were exposed to other literacy practices during their schooling,\nnot related to the disciplinary communities (De Silva,\n2015). In a longitudinal study, Zavala (2017) reported\ncases of two writers who feel their voice was not represented in the tasks assigned by teachers and curriculum. Both describe academic writing as a threat to\ntheir identity as this discourse does not convey natural\ncommunication. Street (2010) also described cases of\nalternative literacy practices in southern Asia that do\nnot align with the formal, clear, precise, concrete and\ntransparent features of academic discourse. Nevertheless, some initiatives have been conducted in tertiary\neducation to integrate academic literacy to communicative approaches in foreign language instruction;\nwhich might have been perceived as epistemologically incompatible in academic writing contexts.\nAn informal style has never been considered\nas appropriate in academic contexts as it enhanced a\nmore subjective interpretation of the writer towards a\ntopic; risking its objectivity, sophistication and intelligibility. Notwithstanding situated approaches aiming to\nfoster academic standards in second-language writers,\ncurrent literacy practices are still regarded as informal\nas they do not fit the impersonal and sophisticated\nlanguage of formal writing (Hyland & Jiang, 2017).\nHowever, an alternative notion of a continuum between formal and informal styles in academic writing\n87\n\nis required (Hyland, 2007). In fact, Hyland and Jiang\n(2017) recognize that informality has entered oral and\nwritten discourse in recent years, following academic\nwriting this tendency and becoming less formal.\nIn this regard, an informal use of a language\nattempts to build a more intimate relationship with\nreaders, where assumptions about a shared context\nand more thorough background knowledge make\ncommunication possible. Therefore, texts that include\nan informal register as a first-person pronoun, colloquial language, verbal phrases, etc., should not be any\nmore now considered as invalid samples of literacies.\nThe following features of writing need to be considered to foster this skill: (1) writing as a collaborative\nactivity, (2) the influence of the learning environment\nand the languages involved, and (3) the need of interaction and activities within a disciplinary discourse\nwhere the learners get familiarized with the genres\nand their purposes (McGrath & Kaufhold, 2016).\nMcGrath and Kaufhold (2016) describe that a\ncommitment towards a ‘bottom-up approach’ is now\nobserved at universities, allowing more pluralistic\npedagogical choices. Strauss (2017) claims that traditional academic writing requirements do not serve the\ninterests of the disciplines or of the students anymore,\nas they cannot make changes to promote proficient\nliteracy in each vocational area. Kaufhold (2015) emphasizes the relevance of students’ involvement in\nthe academic work as voluntary participation of them\nin her study provided evidence of their willingness\nand commitment towards the acquisition of academic writing, being active participants by incorporating\ntheir previous knowledge and learning experiences,\nin order to gain confidence as writers. Therefore, a\nmore thorough insight towards literacy and academic\nwriting is required to comprehend current practices\noccurring in the field of second language writing in\nuniversity contexts.\nThe movement of Academic Literacies emerges\nas a response to legitimize actual literacy practices in\nthe academic community (Lillis & Scott, 2015), trying to offer an alternative and comprehensive understanding of academic writing as a situated social practice, in which communication is the main target. Park\n(2013, p. 344) describes writing as “situated, social\nand political practice offering new writers in English\nan opportunity to find power and legitimacy in a new\nlanguage,” in line with the movement of Academic\nLiteracies, which describes actual written practices\nLETRAS (Li ma), 93(137), 2022\n\n\fhttps://doi.org/10.30920/letras.93.137.7\n\noccurring worldwide. The main contribution of this\napproach towards writing is of a legitimating tool that\nwriters and authors, independently of their cultural\nor linguistic background, use in academia to nurture\nthemselves continuously to become part of such communities.\nOne of the major problems reported in foreign\nlanguage instruction is to communicate accurately\nin the target language (L2). No full-immersion programmes are possible in non-native contexts, where\nlearners rely on their mother tongue (L1) to communicate later in the target language. Doiz, Lasagabaster\nand Sierra (2013, p. 24) describe this linguistic phenomenon as translingualism, defining it as “the adoption of bilingual supportive scaffolding practices”\ntowards language learning. From a Bakhtinian perspective, it refers to a strategy available to writers from\ndiverse linguistic backgrounds that challenges limiting\nand oppressive discourses (Canagarajah, 2018). These\npractices occur more frequently when two or more\ndifferent languages, varieties or people from different\nlinguistic backgrounds interact with each other across\ntime and space (Coronel-Molina & Samuelson, 2016).\nTranslingualism tensions teaching and learning traditions which originate from a monolingual perspective.\nTranslingualism also recognizes the multicultural and\nmultilingual background of L2 learners and writers,\nchallenging the desired linguistic homogeneity in L2\ninstruction (Matsuda, 2006).\nUnder the premise of writing as a means of\nnew knowledge making throughout social interaction,\nideas are never generated in isolation (Park, 2013).\nThis implies a connection of the learners’ world\nknowledge, mostly represented in the L1, with the\nideas and topics presented in the target language (L2)\nin the classroom. Despite the criticism to the use of\nL1 in the foreign language class, mainly by terms of\nL1 interference (May, 2013); some studies have been\nrecently conducted to provide the benefits of traslanguaging, using different languages in pedagogical\ncontexts (Blackledge & Creese, 2010; Canagarajah,\n2013; Garcia & Wei, 2014). Furthermore, incorporating both languages in the classroom can increase\nlearners’ willingness to use their entire linguistic repertoire more actively (Fu & Matuosh, 2015). Thus, using different languages to communicate reflects the\nreality of heterogeneous and multicultural societies,\ncontributing to the integration of language practices\nworldwide (Garcia & Wei, 2014).\n88\n\nConsidering the multilingual and multicultural\nbackgrounds of today’s society, alternative approaches towards academic literacy are required to understand this phenomenon occurring both in first and\nsecond language writing in tertiary education. The\nlatter is of utmost importance as student mobility has\nreshaped university contexts, allowing different languages to coexist. Nevertheless, academic literacy is\nstill governed by monolingual paradigms under the\nhegemony of Written Standard English (Canagarajah, 2011). Translingualism emerges as an approach\nthat challenges monoglossic language ideologies, informing second language writing. This perspective\ncan also contribute to moving beyond the fallacy of\nthe native speaker as the error-free language expert,\nempowering the non-native writer as an effective user\n(Phillipson, 1992).\nThis reconceptualization of academic literacy, however, leads to criticism in foreign language\ninstruction and second language writing. Therefore,\nthis literature review becomes relevant to support and\nframe alternative insights towards academic literacy\nwith empirical evidence, empowering language teachers to make informed pedagogical decisions. Under\ntranslingual perspectives, writing might not anymore\nbe considered a technology that restructures thought\n(Canagarajah, 2018) but also as developing alternate\nmodels in one language. The purpose of this revision\nis to inform the use of different languages, a concept\nknown as translingualism, in academic writing preparation at tertiary level, reported in empirical research\narticles and organized systematically. Therefore, the\nfollowing revision question guides this literature review:\n What translingual practices are reported in empirical research articles as a contribution to the\ndevelopment of academic literacy at tertiary level?\n\nOn that account, a revision of empirical studies was conducted and is described in the methodology section, considering three main aspects found\nthroughout these articles: theoretical foundations towards translingualism, translingual spaces in second\nlanguage writing, pedagogical implications of translingualism and multimodality in translingual practices.\nThe results of the revision and analysis of these articles are included in the third section of this assignment, followed by the discussion.\nLETRAS (Li ma), 93(137), 2022\n\n\fhttps://doi.org/10.30920/letras.93.137.7\n\n2. Methodology\nBibliographical research of articles in indexed journals was conducted in Web of Science and Scopus,\nconsidering the ten recent years, from 2010 to 2020,\nand data-driven sources. Although the topics partially\nrelate to each other, keywords were essential to narrow the search process towards translanguaging in\nsecond language writing and academic literacy. Table\n1 depicts the search criteria and the keywords used in\nthis literature review.\nTable 1. Keywords used in this literature review\nSearch\t\t\t\t\norder\n\nKeywords\n\n1\n\n“translingualism” OR “translanguaging”\n\n2\n\n“academic literacies” AND “translingualism” OR\n“translanguaging”\n\n3\n\n“academic writing” AND “translingualism” OR\n“translinguaging”\n\n4\n\n“second language writing” AND “translingual writing”\n\n5\n\n“academic literacies” AND “translingual writing”\n\n6\n\n“second language writing” AND “higher education”\n\nSource: Own elaboration based on the articles revised for this literature review.\n\nInitially, 23.792 empirical articles were found.\nTherefore, a systematic revision of both titles and abstracts of each of the articles that refer specifically to\n\ntranslingual practices in academic writing in multilingual contexts was conducted, obtaining 622 papers.\nThe inclusion criteria for the articles used in this literature review were: (1) open access, (2) publication\ndate within the ten recent years, (3) written in English,\n(4) findings obtained through empirical research, and\n(5) papers referring to translingual practices informing\nforeign language instruction and academic literacies.\nAll articles referring to multilingualism, bilingualism, second language acquisition, genre pedagogies, as well as book reviews published in indexed\njournals, were excluded as their scope is not closely\nrelated to translingualism. Papers describing academic literacies and translingual practices at school level,\nregarding primary or secondary education; or to specific areas as translation, linguistics, sociology, were\nnot considered in this literature review. Following\nthese criteria, 26 articles informing translanguaging\ntowards academic literacy practices resulted in the\nfinal revision.\nTable 2 describes the 26 articles selected as the\ndata-driven source for this literature review, organized\nupon the contribution of translingualism towards academic writing: Importance of L1 in the development\nof the writer’s identity, implications of translingualism\nin second language writing instruction and multimodality and digital translingual practices into writing.\nThis classification was obtained after a brief revision\nof each article focusing on the empirical results reported and the authors cited in the discussion and\nbibliography; under the scope of the aforementioned\nrevision question.\n\nTable 2. Articles considered in the literature review\nArticle\nMethods\nSample\nAspect of \t\t\n\t\t\t contribution\n\n89\n\n1. Adamson, J. & Coulson, D. (2015). Translanguaging\nin English academic writing preparation. International\nJournal of Pedagogies and Learning, 10(1), 24-37.\n\nQualitative –\ncase study\n\n475 Japanese university Importance of\nL1 – identity\nstudents: questionnaire\ndevelopment\n271 students’ reports\n\n2. Albawardi, A. (2018). The translingual digital practices\nof Saudi females on WhatsApp. Discourse, Context and\nMedia, 25, 68-77.\n\nQualitative\n\n220 WhatsApp chats of 130 Multimodality and\nSaudi university students digital translingual\npractices\nstudying English\n\n3. Anderson, J. (2017). Reimagining English language\nlearners from a translingual perspective. ELT Journal,\n72(1), 26-37.\n\nQuantitative\n\n116 General English, Exam Implications of\nTL in L2 writing\nEnglish and ESP learners\ninstruction\n\nLETRAS (Li ma), 93(137), 2022\n\n\fhttps://doi.org/10.30920/letras.93.137.7\n\n4. Ashraf, H. (2018). Translingual practices and\nmonoglot policy aspirations: a case study of Pakistan’s\nplurilingual classrooms. Current Issues in Language\nPlanning, 19(1), 1-21.\n\nQuantitative\n\nImportance of\n324 students’ responses\nrecorded and transcribed L1 – identity\ndevelopment\n\n5. Canagarajah, S. (2011). Codemeshing in Academic\nWriting: Identifying Teachable Strategies of\nTranslanguaging. The Modern Language Journal, 95(3),\n401-417.\n\nQualitative ethnography\n\n1 graduate student in\na teaching of secondlanguage writing course\n\nImplications of\nTL in L2 writing\ninstruction\n\n6. Canagarajah, S. (2018). Translingual Practice as\nSpatial Repertoires: Expanding the Paradigm beyond\nStructuralist Orientations. Applied Linguistics, 39(1), 31-54.\n\nQualitative\n\n24 Chinese scholars,\n1 Korean and Turkish\ncommunicative practices\n\nImplications of\nTL in L2 writing\ninstruction\n\n7. Caruso, E. (2018). Translanguaging in higher\neducation: Using several languages for the analysis\nof academic content in the teaching and learning\nprocess. CercleS, 8(1), 65-90.\n\nQualitative –\nCase study\n\n15 participants in a\nmultilingual classroom\nat a university course in\nPortugal\n\nImplications of\nTL in L2 writing\ninstruction\n\n8. Cavazos, A. (2017). Translingual oral and written\npractices: Rhetorical resources in multilingual\nwriters’ discourse. International Journal of Bilingualism,\n21(4), 385-401.\n\nQualitative\n\nLanguage practices of\n3 scholars in academic\ngenres.\n\nImportance of\nL1 – identity\ndevelopment\n\n9. De Costa, P., Singh, J., Milu, E., Wang, X., Fraiberg, S.\n& Canagarajah, S. (2017). Pedagogizing Translingual\nPractice: Prospects and Possibilities. Research in the\nTeaching of English, 51(4), 464-473.\n\nQualitative\n\nAutoethnography of\nteaching practices of six\nscholars in translingual\npedagogy\n\nImportance of\nL1 – identity\ndevelopment\n\n10. Flores, N. & Aneja, G. (2017). “Why Needs Hiding?”\nTranslingual (Re) Orientations in TESOL Teacher\nEducation. Research in the Teaching of English, 51(4),\n441-463.\n\nQualitative\n\n36 university TESOL\nstudents’ projects (1st\nphase)\n\nImportance of\nL1 – identity\ndevelopment\n\n11. Gevers, J. (2018). Translingualism revisited:\nLanguage difference and hybridity in L2 writing.\nJournal of Second Language Writing, 40, 73-83.\n\nQualitative\n\n12. Holdway, J. & Hitchcock, C. (2018). Exploring\nideological becoming in professional development\nfor teachers of multilingual learners: Perspectives on\ntranslanguaging in the classroom. Teaching and Teacher\nEducation, 75, 60-70.\n\n90\n\n10 students: focus groups\nand interviews (2nd phase)\n2 first-year students of\nwriting courses taught by\nthe author\n114 teachers participating\nQualitative –\nAction Research in a professional\ndevelopment programme\nCase study\nthrough an online\nplatform: 114 discussions\nand 114 summaries\n\nImplications of\nTL in L2 writing\ninstruction\n\nImplications of\nTL in L2 writing\ninstruction\n\n13. Hopkins, S., Zoghbor, W. & Hassall, PJ. (2020). The\nuse of English and linguistic hybridity among Emirati\nmillennials. World Englishes, 1-15.\n\nMixed-methods\n– Questionnaire,\nobservations and\nclassroom notes\n\n100 Emirati students\nstudying an English\nwriting course in Abu\nDhabi university\n\nImplications of\nTL in L2 writing\ninstruction\n\n14. Kaufhold, K. (2018). Creating translanguaging spaces\nin students’ academic writing practices. Linguistics and\nEducation, 45, 1-9.\n\nQualitative –\ncase study\n\n2 participants in\nlongitudinal case studies\nin Sweden\n\n15. Kiernan, J., Meier, J., & Wang, X. (2017). Translingual\napproaches to reading and writing. International\nAssociation for Research in L1 Education, 17, 1-18.\n\nQualitative\n\n9 students’ reflective\nmemos\n\nImportance of\nL1 – identity\ndevelopment\nImplications of\nTL in L2 writing\ninstruction\n\nLETRAS (Li ma), 93(137), 2022\n\n\fhttps://doi.org/10.30920/letras.93.137.7\n\n16. Kim, S. (2018). “It was kind of a given that we were Qualitative – case\nall multilingual”: Transnational youth identity work study\nin digital translanguaging. Linguistics and Education, 43,\n39-52.\n\n1 participant: 3\ninterviews, 11 recorded\ninformal conversations,\n16 videos, identity map,\nliteracy checklist and\nsocial media activities\n9 compositions of 4th\ngraders and 1 case study\n\n17. Kiramba, L. (2017). Translanguaging in the Writing\nof Emergent Multilinguals. International Multilingual Qualitative\nResearch Journal, 11(2), 115-130.\n\n5 students in an EMI\nprogramme in Business\nStudies at Swedish\nuniversity\n\nMultimodality and\ndigital translingual\npractices\nImportance of\nL1 – identity\ndevelopment\nImportance of\nL1 – identity\ndevelopment\nImportance of\nL1 – identity\ndevelopment\n\n18. Kuteeva, M. (2019). Revisiting the ‘E’ in EMI\nstudents’ perceptions of standard English, lingua Qualitative\nfranca and translingual practices. International Journal\nof Bilingual Education and Bilingualism, 23(3), 287-300.\n\n3 Chinese youths at\nUniversity of London:\ninterviews, observations\nand recordings of social\ninteraction\n\n19. Wei, L. (2011). Moment Analysis and translanguaging\nspace: Discursive construction of identities by Qualitative\nmultilingual Chinese youth in Britain. Journal of\nPragmatics, 43, 1222-1235.\n\nCorpus of ordinary\nMultimodality and\nEnglish utterances\nbetween Chinese users of digital translingual\npractices\nEnglish\n\n20. Wei, L. (2018). Translanguaging as a Practical Theory\nQualitative\nof Language. Applied Linguistics, 39(1), 9-30.\n\n21. Wei, L. & Ho, W. (2018). Learning Language Sans Qualitative\nFrontiers: A Translanguaging View. Annual Review of\nApplied Linguistics, 38, 33-59.\n22. McIntosh, K., Connor, U. & Gokpinar-Shelton, E.\n(2017). What intercultural rhetoric can bring to EAP/\nESP writing studies in an English as a lingua franca Qualitative – case\nworld. Journal of English for Academic Purposes, 29(1), study\n12-20.\n23. Mori, J. & Sanuth, K. (2018). Navigating between\na monolingual utopia and translingual realities:\nExperiences of American learners of Yorùbá as an Qualitative\nAdditional Language. Applied Linguistics, 39(1), 78-98.\n\nImportance of\nL1 – identity\ndevelopment\n\nExchange between a\nChinese-Singaporean\nand a friend, 11\nlearners of Chinese\nTranscript of screen\nImportance of\nrecording of 2 learners\nL1 – identity\ndevelopment\nPost-graduate science and\nImportance of\nengineering students\nL1 – identity\nin a grant proposaldevelopment\nwriting module\n\n6 graduate and 5\nundergraduate\nNigerian students:\nfieldnotes and\ninterviews\n\nImplications of\nTL in L2 writing\ninstruction\n\nMultimodality and\ndigital translingual\n8 first-year students of the practices\nCurriculum Design\nModel at a urban\nuniversity in S. Africa\n\nQualitative - case\n24. Motlhaka, H. & Makalela, L. (2016). Translanguaging study\nin an academic writing class: Implications for a\ndialogic pedagogy. Southern African Linguistics and Qualitative –\nApplied Language Studies, 34(3), 251-260.\nEthnomethodology\n25. Wagner, J. (2018). Multilingual and Multimodal and Conversation Conversation between\n3 non-native English\nAnalysis\nInteractions. Applied Linguistics, 39(1), 99-107.\nspeakers using English\n26. Yanguas, I. (2019). L1 vs L2 synchronous text-based\nto communicate\nQuantitative\ninteraction in computer-mediated L2 writing. System,\n85 intermediate students Implications of\n88, 1-11.\nof Spanish in four\nTL in L2 writing\ndyadic writing groups instruction\nat a US college\nSource: Own elaboration based on the articles revised for this literature review\n\n91\n\nLETRAS (Li ma), 93(137), 2022\n\n\fhttps://doi.org/10.30920/letras.93.137.7\n\norganizes the geographical distribution in terms of the\n3. Results\nTo begin with, a synthesis of bibliometric de- country where the research was conducted.\nscriptors is provided, considering year and country of\npublication, the journal publishing the articles and the\nmethodological design described. The main findings Figure 2. Geographical distribution of the countries\nwhere research was conducted\nof the research articles part of this literature review follow, suggesting translingual practices as an evidence\nof developing academic literacies in second language\ncontexts, specifically regarding writing instruction at\nuniversity level.\nRegarding the year of publication, empirical\narticles conducted between the years 2010 and 2020\nwere considered in the initial stage of this literature\nreview. However, the first research reporting translingual practices in second language writing at tertiary\nlevel was published in 2011. A total of 26 papers were\nidentified within this period, outnumbering years\n2017 and 2018, with seven (27%) and twelve (46%)\npublished articles respectively. Figure 1 illustrates the Source: Own elaboration based on the articles revised for this literature\nreview.\nnumber of articles in each year of publication.\nFigure 1. Number of articles published in each year\n(period 2010-2020)\n\nOn the other hand, British indexed journals concentrate two-thirds of the research articles (65%). US journals published 12% of these papers (N=3), followed by\nthe Netherlands with 8% (N=2). Belgian, South-African, Spanish and Australian journals had each 4% of\nthe articles each (N=1). Figure 3 depicts the geographical distribution in terms of the country of publication,\nwhereas the journals where these research articles\nwere published are described in Table 3.\nFigure 3. Geographical distribution of the countries\nof publication\n\nSource: Own elaboration based on the articles revised for this\nliterature review.\n\nReferring to the geographical distribution of these\nresearch articles, two variables were considered: the\ncountry where the research was conducted and the\ncountry of the publishing journal. Regarding the former, a democratic geographic distribution is observed\nworldwide. Eight articles (32%) report research conducted in Asia, eight (32%) in America, five (20%) in\nEurope and four (16%) in African countries. Besides\nthe US, South Africa, Sweden, China, England and\nSaudi Arabia outline with two articles each. Figure 2\n\n92\n\nSource: Own elaboration based on the articles revised for this\nliterature review.\n\nLETRAS (Li ma), 93(137), 2022\n\n\fhttps://doi.org/10.30920/letras.93.137.7\n\nTable 3. Journals and countries of publication of articles of this literature review\nJournal\n\nCountry of\npublication\n\nN° articles\n\nAfrican Linguistics and Applied Language Studies\n\nSouth Africa\n\n1\n\nAnnual Review of Applied Linguistics\n\nUnited Kingdom\n\n1\n\nApplied Linguistics\n\nUnited Kingdom\n\n4\n\nCercles\n\nSpain\n\n1\n\nCurrent Issues in Language Planning\n\nUnited Kingdom\n\n1\n\nDiscourse, Context and Media\n\nNetherlands\n\n1\n\nELT Journal\n\nUnited Kingdom\n\n1\n\nInternational Association for Research in L1 Education\n\nBelgium\n\n1\n\nInternational Journal of Bilingual Education and\nBilingualism\n\nUnited Kingdom\n\n1\n\nInternational Journal of Bilingualism\n\nUnited Kingdom\n\n1\n\nInternational Journal of Pedagogies and Learning\n\nAustralia\n\n1\n\nInternational Multilingual Research Journal\n\nUnited Kingdom\n\n1\n\nJournal of English for Academic Purposes\n\nUnited Kingdom\n\n1\n\nJournal of Pragmatics\n\nNetherlands\n\n1\n\nJournal of Second Language Writing\n\nUnited Kingdom\n\n1\n\nLinguistics and Education\n\nUnited Kingdom\n\n2\n\nResearch in the Teaching of English\n\nUnited States\n\n2\n\nSystem\n\nUnited Kingdom\n\n1\n\nTeaching and Teacher Education\n\nUnited Kingdom\n\n1\n\nThe Modern Language Journal\n\nUnited States\n\n1\n\nWorld Englishes\n\nUnited Kingdom\n\n1\n\nSource: Own elaboration based on the articles revised for this literature review.\n\nRegarding research methods involved in each\nof the articles part of this revision, 88% (N=23) informed qualitative procedures in their methodological sections, whereas two articles (8%) were conducted under quantitative methods. Only one paper (4%)\nreported mixed-methods research, combining both\nqualitative and quantitative approaches. Figure 4 provides an overview of the research methods considered in this literature review.\n\nFigure 4. Overview of research methods reported\nin this literature review\n\nSource: Own elaboration based on the articles revised for this\nliterature review.\n\n93\n\nLETRAS (Li ma), 93(137), 2022\n\n\fhttps://doi.org/10.30920/letras.93.137.7\n\nFinally, from the 26 articles considered in this\nliterature revision, one referred to ontological and\ntheoretical reflections towards translingualism, from\na poststructuralist perspective (Canagarajah, 2018).\n46% of the articles (12) focused on the importance of\nL1 in the development of the writer’s identity in academic contexts whereas 38% of them (10) discussed\nthe implications of translingualism in second language\nwriting instruction. Finally, four papers (16%) incorporated multimodality and digital translingual practices\ninto writing. This section describes the findings from\nthis literature review to describe translingual writing\nas an insight to comprehend writers’ entire linguistic\nrepertoire.\n3.1. Importance of L1 in the development of\nthe writer’s identity\nTranslingual practices might tension the boundaries\nand conventions of academic literacy, as it challenges\nand resists the hegemony of Written Standard English\n(WSE). Their relation to literacy has led controversy,\nmostly in academic contexts, as they are still informed\nby a monolingual paradigm that emerged from a\ndominant native-speaker ideology that values efficiency in communication, as well as focuses on form and\ngrammar over social practices (Gevers, 2018). Under\nmultilingual and translingual perspectives, writing\nmight not anymore be understood as a technology\nthat restructures thought (Canagarajah, 2018) but as\ndeveloping alternate models in one language. This\nreconceptualization of writing, however, leads to criticism in foreign language instruction and in second\nlanguage writing.\nAccording to Canagarajah (2011), writing implies the active involvement of the author and the target readers in the process itself. Kiernan, Meier and\nWang (2017) argue that writing is an essential skill\nto practice in order to engage in deeper and more\nmeaningful learning, since it “stabilises discourse\nand practice, developing agency.” Kaufhold (2018,\np. 7) describes the simultaneous use of L1 and L2\nas a means to develop fluency in writing. “Not only\ndoes a multilingual orientation more accurately reflect\nthe linguistic reality within the academic community,\nit is also consistent with ‘connected’ online culture”\n(Adamson & Coulson, 2015, p. 27). In fact, Kuteeva\n(2019) describes a case of a US student in a Swedish\nuniversity switching to British linguistic variety only\n94\n\nin academic writing contexts. Multilingual students\ncould benefit from their knowledge and experience\nof academic writing across language codes, focusing both on the construction of the writer’s identity\nand socio-political constraints to multilingual writing\n(Canagarajah, 2011).\nAlthough traditional foreign language instruction promotes communication exclusively in the target language, some pedagogical practices allow the\nuse of L1 in academic writing. For instance, Mori and\nSanuth (2018) report US participants having difficulty\nin learning Yorùbá as a second language in Africa.\nThe desired monolingual utopia, despite being in a\ncountry where Yorùbá was spoken by majority of\npeople, was not possible due to translingual realities.\nAshraf (2018) reports a continuum between English and\nUrdu in Pakistan, recognizing the presence of more\nthan one language in communication and raising language awareness in formal educational settings. Emirati university students use both Arabic and English\nwhen performing university tasks, with predominance\nof the latter due to its academic status in the UAE context (Hopkyns, Zoghbor & Hassall, 2020). Kiramba\n(2017) considers that translingual practices transgress\nmonolingual habitus, especially in countries where\nthe mother tongue is neglected in favour of the colonization language, as the cases previously described.\nTranslingual practices do not only occur in\nenvironments where people cannot communicate in\ntheir mother tongue. Translingualism is also reported\nin developed countries as England, where Wei (2011)\ndescribes the experience of three Chinese students\nin London. They communicated both in English and\nChinese depicting confidence in their own multilingualism, despite the monolingual ideologies predominant in today’s London. Kaufhold (2018) reports experiences with language, Spracherleben, of two Swedish\nstudents writing their dissertations in English. Despite\nstudying in their home country, they declared negotiating and developing their repertoires in academic\nwriting in both languages. Interestingly, one participant claims ownership of the foreign language as English assists her in developing her identity as a scholar.\nAdamson and Coulson (2015) narrate the experience\nof 495 Japanese students in bilingual university contexts. Despite the predominance of English as having\nmore prestige for business and academic purposes,\nthese students declare using their L1 for in-class and\nwriting purposes.\nLETRAS (Li ma), 93(137), 2022\n\n\fhttps://doi.org/10.30920/letras.93.137.7\n\nTo conclude, translanguaging as a creative,\ntransformational and collaborative space can be a\nfruitful pedagogical metaphor for students to explore;\nassisting them to develop a metalanguage and an\nawareness of multicultural repertoire instead of cultural assimilation of the target language. The latter can\nassist them in developing their identities as writers in\nacademic contexts, either in L1 or L2, contributing\nto the meaning-making goal. However, second language writers need to feel confident to negotiate ideologies, meaning and language perspectives in order\nto achieve their communicative purpose. Therefore,\nL1 should not be considered a detriment anymore in\nforeign language learning as it is a mirror of language\nuse in a multicultural society.\n3.2. Implications of translingualism in second-language writing instruction\nMonolingual perspectives based on colonialism and\nmonoglossic language beliefs remain as the guiding\nframework in foreign language instruction (Kiernan,\nMeier & Wang, 2017). Native speaker ideologies continue influencing language teaching marginalising\nnon-native speakers as language teachers and maintaining the privileges of the former in job positions,\ncurricular resources and language assessments (Holdway & Hitchcock, 2018). However, translingualism\nprovides a framework to challenge these ideologies\nand a new understanding of language in multicultural and multilinguistic contexts (Caruso, 2018). Under\na translingual approach, language development is no\nlonger described as attainment of “native-like” proficiency, but as choosing strategies for communication\nin ways that reflect bi/multilingual identities and accommodate their interlocutors, informing their repertoire (Anderson, 2017).\nHowever, translingual practices are not homogeneous as they might vary depending on the language\nuser profile. Anderson (2017) suggests a translingual\ncontinuum to understand language practices in the multicultural classroom settings, providing practical suggestions for language teachers, going from monolingual to highly translingual. In his research, 19.8% of\nthe participants considered to be mainly monolingual,\nas they might be speaking English only in their future professional context; for instance, in Hong Kong\nor the United Kingdom. Regarding translingualism,\n47.4% referred to themselves as partly translingual as\n95\n\nsome might be using English, sometimes monolingually and sometimes more translingually; whereas\n20.7% identified as highly translingual. These results\ndepict that nowadays, more language users identify as\ntranslingual, instead of monolingual.\nNon-native language teachers can find in translingual practices support to develop more positive conceptualisations of their identities. Translingualism can\nalso provide a framework to develop pedagogical approaches for students from multilingual backgrounds\n(Flores & Aneja, 2017; Holdway & Hitchcock, 2018).\nMotlhaka and Makalela (2016), for instance, reported\nlearners using both English and Sesotho to move strategically between different rhetorical conventions in their\nacademic writing stages. Translingual practices also reshape the content of teacher education, breaking down\nthe binary oppositions that characterize this field. This\nmeans reimagining the language classroom as a translingual community, as in Anderson’s study (2017)\nwhere the participants identified themselves as translingual practitioners, avoiding dichotomies between native and non-native speakers. The latter redefines the\nauthenticity of a language speaker (Gevers, 2018).\nTranslingualism does not entail doing and saying whatever speakers want, but a negotiation of all\ncommunicative interactions and shifts of language\nthat students must acquire by following correct rules\nof grammar, and towards treating language as a malleable tool to develop unique rhetoric styles (Caruso, 2018). For instance, her students had the freedom\nof communicating in English, French, Portuguese,\nItalian or Spanish, but using an appropriate register\nand accurately. Translanguaging broadens the understanding of codeswitching as it refers to a more flexible use of resources from more than one language\nwithin a single system, transcending traditional understandings of separate languages. The notion of languages as separate, largely immutable entities is then\nchallenged, including multimodal resources to communicate. Translingual practices involve negotiating\ncode-choice where communication moves along this\ncontinuum, depending on activity, outcome and interlocutors (Caruso, 2018).\nCommunicative competence comes from monolingual perspectives, whereas translingual competence\nrecognizes that code choice might be negotiable and\nfluid, when appropriate; adjusting to the multilingual\nmultimodal terrain of the communicative act (Garcia\nLETRAS (Li ma), 93(137), 2022\n\n\fhttps://doi.org/10.30920/letras.93.137.7\n\ny Klelfgen, 2009). The latter is evidenced nowadays in\nonline and virtual communities, becoming necessary\nto integrate the concept of “semiotic competence”\nwithin translingualism. Technology has restructured\nacademic genres within scholar communities, where\nemails replaced formal letters and instant messaging\nmemorandums. For that reason, the role multimodality plays in academic writing nowadays and how translingualism mediates literacy practices is described in\nthe last section.\n3.3. Multimodality and digital translingual\npractices in writing\nTranslanguaging, as a theory of language, has reshaped academic literacy incorporating the use of\ntechnology and digital media into writing practices.\nWei and Ho (2018), as well as Wagner (2018), describe this phenomenon as a transdisciplinary research\nperspective. Human communication has always been\nmultimodal as people interact through textual, aural,\nlinguistic, spatial and visual resources. Interconnections between language and other cognitive systems\nmake communication a multimodal phenomenon\n(Kim, 2018). Albawardi (2018) reports Saudi women\ncommunicating using multimodal codes in ‘Arabish,’\nan Arabicized English, through WhatsApp. Such digital practices are considered by the author as translingual, where participants engage in fluid language\ninteraction.\nAlthough languaging might be considered multimodal, our understanding of language as a semiotic system is based on Indo-European languages and\nlanguage studied as speech or text (Wagner, 2018).\nTherefore, language was initially described, and\nis understood until now, as an arbitrary of symbols\nand rules, where the resemblance between form and\nmeaning is the norm. However, gesture does influence thinking and speaking, converting languaging\ninto a multimodal phenomenon (Albawardi, 2018).\nImage, writing, layout, speech and moving images\nare examples of different modes, described by Wei\nand Ho (2018) as a “socially and culturally shaped\nresource for meaning-making.” Moreover, Kim (2018)\npresents how language and images converge as one\ncode when communicating is the purpose. Albawardi\n(2018) also suggests that both codes seem necessary\nas an attempt not to give up cultural identities in a\nglobalized community.\n96\n\nTranslanguaging instinct fosters to go beyond\nthe linguistic norms to achieve effective communication, including the multisensory and multimodal\nprocess of language learning and language use (Albawardi, 2018; Kim, 2018). Translanguaging instinct\nhas also implications for language learning, as the acquisition of first and second language in early childhood and adulthood differ in cognitive, semiotic\nsystems that affect linguistic semiosis. Therefore, as\npeople become more involved in complex communicative tasks and demanding environments, they tend\nto combine and exploit a variety of resources to foster\nsocial interactions. This innate capacity of exploiting\nresources is enhanced with experience, becoming\nmore developed through metalinguistic awareness\nin adult learners. The multisensory, multimodal and\nmultilingual nature of human learning and interaction\nis at the centre of translanguaging Instinct.\n4. Discussion\nAs previously suggested, translingual practices could\nbe described as instances where users can integrate\nsocial spaces and linguistic codes that have been\ntraditionally separated through practices in different\nplaces due to monolingual paradigms informing academic literacy (Wei, 2011). These instances make the\nlanguage user go beyond linguistic structures, cognitive and semiotic systems and modalities, as well as\nbringing together different dimensions of the learners’ personal history, experience and environment,\ntheir attitude, belief and ideology, and their cognitive\nand physical capacity (p. 1223). Furthermore, variety\nand continuity of interactions of people from diverse\nbackgrounds using current technology enhance the\nconstruction and reconstruction of social identities,\nconstantly modified through language. However, Wei\n(2018, p. 106) avoids generalizing translingualism as\na theory, reporting it as “a resource to be chosen. In\nfact, he suggests participants’ responsibility for the language used for communication.\nFrom a translingual perspective, not only can\nlearners integrate their knowledge from L1 to L2 easily, like anxiety and lack of confidence in the target\nlanguage decrease, but these literacy practices, of a language course exercise, can be transferred to real situations and the curriculum (Adamson & Coulson, 2015).\nThis aspect is crucial while developing literacy skills at\ntertiary level, where autonomous and long-life learning\nLETRAS (Li ma), 93(137), 2022\n\n\fhttps://doi.org/10.30920/letras.93.137.7\n\nis required. Regarding the use of different languages\nin writing, this reflects our current multicultural society where we might rely on our mother tongue in the\nbrainstorming, planning, organization or editing stages (Motlhaka & Makalela, 2016). Canagarajah (2011)\ndescribes four strategies that multilingual learners use\nwhile translanguaging in academic writing tasks: (1)\nrecontextualization, (2) voice, (3) interactional and (4)\ntextualization. In general terms, translanguaging prioritizes the communicative nature of language over focusing on form. Both the background and learning experience of these learners influence their writing process.\nHowever, they also take ownership of the target language and invite the reader to renegotiate the meaning\nand how the messages are being delivered.\nTranslanguaging also brings a variety of linguistic resources to academic writing in terms of meaning-making in academia (Cavazos, 2017). Switching\nlanguages occurs naturally and is a strategy that multilingual students employ intuitively (Canagarajah, 2018;\nCavazos, 2017; Cumming, 2006; Kiramba, 2017). In\nthis case, learners can display their knowledge about\na specific genre and transfer it to similar genres in different language codes, provided lexico-grammatical\nresources are available. To achieve this, the register\nand the written genre need to be familiar to the audience or readers in the different languages, and accepted by these communities. For instance, research\narticles and thesis are regarded by Kaufhold (2018)\nas a pedagogic genre (Johns & Swales, 2002), whose\nconventions are carefully observed by the academic\ncommunity, independently of language codes. Not\nonly does translingualism make silent voices heard\nthrough writing, but it questions the role of local languages promoting permeability across languages for\nmultilinguals.\nNevertheless, whereas advanced L2 writers\nmay have a proficient level in L2 that allows them\nto experiment with translingual practices without major problems, low-level students might require more\nopportunities to develop proficiency in the target language (Gevers, 2018). Transference of orality-based\ndiscourse to writing could assist learners in expanding their expressive range and challenge restrictive\nconventions through creative innovation. However,\nit can also hinder their developing of proficiency in\nthe target language and a formal register, especially\nin environments where the latter plays a crucial role.\n97\n\nTherefore, L2 writing teachers need to consider the\nliteracies expected of multilingual students in academic and professional communities in order to evaluate\nto what degree L2 students might benefit from incorporating non-standard language patterns into their\nwriting (Gevers, 2018; Kiramba, 2017).\nDeveloping multilingual awareness in language\nteachers might provide them with tools to address\ntheir students’ multilingualism in the L2 classroom;\nlegitimizing both language proficiency and cultural\nbackgrounds of non-native teachers (Flores & Aneja,\n2017). Language diversity should then be seen as a\nresource that can facilitate more effective communication (Mori & Sanuth, 2018). Canagarajah (2013) identified for translingual macrostrategies in second-language writing: (1) invoicing, (2) recontextualization,\n(3) interactional strategies, and (4) entextualization;\nwhich provided these learners with opportunities\nto negotiate meanings by challenging the dominant\nmonoglossic language ideologies. Translingualism require moving alongside this continuum described in order to promote interaction among speakers; adapting\nto the context involved, by means of activity, outcome\nand interlocutors. This insight is referred to as a starting point to empower non-native English-speaking\nteachers in foreign language instruction.\n5. Conclusions\nThe articles revised for this systematic literature review\nlead to conclude that there is limited research informing translingual practices in academic or professional\nwriting contexts, even though different projects have\nbeen conducted in translingualism at school level and\nin teacher training programmes. In fact, 0,96% of the\n23.792 papers describing translingual practices published in indexed journals refer to academic literacy\nat university level. Most articles referring to translanguaging describe classroom experiences where different linguistic codes coexist, mostly based on class\nobservation in secondary education. However, this\nliterature review suggests that more research needs to\nbe conducted for a thorough comprehension of this\nlinguistic phenomenon, occurring worldwide due to\nglobalization and technology.\nCurrent academic contexts privilege native-like\nmonolingual paradigms, which is evidenced in foreign\nlanguage instruction where teachers require learners\nto imitate native speakers of the target language. BeLETRAS (Li ma), 93(137), 2022\n\n\fhttps://doi.org/10.30920/letras.93.137.7\n\nsides influencing L2 teaching and learning processes,\nthis notion excludes actual social practices where different languages interact in different media like social\nnetworking. Not only does this monoglossic ideology\nexclude multilingual practices among speakers, who\nare described as non-proficient users of the target language; but it hinders language development of people aiming to communicate in a variety of codes as\nacademic literacy. The experiences reported in the\nresearch articles reviewed in this study suggest that\ntranslingual literacy practices promote creative and\ncollaborative writing, as well as provide an opportunity to develop written production integrating their linguistic repertoire, which is often constructed in more\nthan one language.\nMoreover, translingualism contributes to developing transversal strategies that enhance interaction among speakers from a diversity of multicultural\nbackgrounds. The latter has an impact on the communicative competences of language learners, who\nuse a variety of linguistic resources available in different languages, not due to incomplete development of\nthe target language but to informed choices between\ndifferent codes. Translanguaging, therefore, has a\npositive impact on the development of the identities\nof language learners, who recognize themselves as\ntranslingual writers with voice in the L2, claiming its\nownership. The idea of a continuum proposed in this literature review challenges academic writing tradition,\n\nrequiring a reconceptualization of literacy practices in\nterms of style, register, use of language, genres and\nmedia; where translingualism aims to describe actual\ncommunication patterns.\nFinally, some limitations emerge from this literature review if considering writing as a process instead of a final product, mostly regarding the drafts\nwhere translingual practices occur. Most studies in\nsecond language writing either focus on the linguistic\ndescription of finished written assignments or suggest\npedagogic models based on monolingual paradigms,\nwhere the learner needs to master a skill using unfamiliar linguistic codes. A translingual insight might\nalso lead to rethink pedagogic and teacher-training practices, as learners might be able to use their\nwhole linguistic repertoire without being labelled as\nnon-proficient users, especially in a globalized society\nwhere a variety of cultures coexist and interact. Future research needs to address writing as a process to\nevidence translingual practices in written communication, mostly as temporary drafts in pre-writing stages.\nTechnology also tensions the traditional notion of L2\nacademic literacy, where multimodal texts outline informed choices of using different codes once multilingual awareness is achieved. This multimodality could\nportray translingual literacies in second language writing, providing a new insight that reflects current academic practices where different languages coexist for\nmeaning-making and communication.\n\nBibliographic references\nAdamson, J., & Coulson, D. (2014). Pathways towards success for novice academic writers\nin a CLIL setting: A study in an Asian EFL context. In R. Al-Mahrooqi, A. Roscoe,\n& V.S. Thakur (Eds.), Teaching writing in EFL/ESL: A fresh look. Hershey, PA: IGI\nGlobal.\nAdamson, J., & Coulson, D. (2015). Translanguaging in English academic writing preparation. International Journal of Pedagogies and Learning, 10(1), 24-37. https://doi.or\ng/10.1080/22040552.2015.1084674\nAlbawardi, A. (2018). The translingual digital practices of Saudi females on Whatsapp. Discourse, Context and Media, 25, 68-77. https://doi.org/10.1016/j.dcm.2018.03.009\nAnderson, J. (2017). Reimagining English language learners from a translingual perspective. ELT Journal, 72(1), 26-37. https://doi.org/10.1093/elt/ccx029\nAshraf, H. (2018). Translingual practices and monoglot policy aspirations: a case study of\nPakistan’s plurilingual classrooms. Current Issues in Language Planning, 19(1), 1-21.\nhttps://doi.org/10.1080/14664208.2017.1281035\nBlackledge, A., & Creese, A. (2010). Translanguaging in the bilingual classroom: A pedagogy for learning and teaching? The Modern Language Journal, 94, 103-105.\nhttps://doi.org/10.1111/j.1540-4781.2009.00986.x\n98\n\nLETRAS (Li ma), 93(137), 2022\n\n\fhttps://doi.org/10.30920/letras.93.137.7\n\nCanagarajah, A. S. (2011). Codemeshing in Academic Writing: Identifying Teachable Strategies of Translanguaging. The Modern Language Journal, 95(3), 401-417. https://\ndoi.org/10.1111/j.1540-4781.2011.01207.x\nCanagarajah, A. S. (2013). Translingual Practice. Routledge. https://doi.\norg/10.4324/9780203120293\nCanagarajah, A. S. (2018). Translingual Practice as Spatial Repertoires: Expanding the Paradigm beyond Structuralist Orientations. Applied Linguistics, 39(1), 31-54. https://\ndoi.org/10.1093/applin/amx041\nCaruso, E. (2018). Translanguaging in higher education: Using several languages for the\nanalysis of academic content in the teaching and learning process. CercleS, 8(1),\n65-90. https://doi.org/10.1515/cercles-2018-0004\nCavazos, A. (2017). Translingual oral and written practices: Rhetorical resources in multilingual writers’ discourse. International Journal of Bilingualism, 21(4), 385-401.\nhttps://doi.org/10.1177/1367006916629225\nCoronel-Molina, S., & Samuelson, B. (2016). Language contact and translingual literacies.\nJournal of Multilingual and Multicultural Development, 38(5), 379-389. https://doi.or\ng/10.1080/01434632.2016.1186681\nCummins, J. (2006). Identity texts: The imaginative construction of self through multiliteracies pedagogy. In O. Garcia, T. Skutnabb-Kangas, & M. Torres-Guzman (Eds),\nImagining multilingual schools: Languages in Education and globcalisation (pp. 5168). Clevedon: Multilingual matters. https://doi.org/10.21832/9781853598968-003\nDe Silva, R. (2015). Writing strategy instruction: Its impact on writing in a second language\nfor academic purposes. Language Teaching Research, 19(3), 301-323. https://doi.\norg/10.1177/1362168814541738\nDoiz, A., Lasagabaster, D., & Sierra, J. M. (2013). Future challenges for English-medium instruction at the tertiary level. In A. Doiz, D. Lasagabaster & J. M. Sierra (Eds.), English\n–medium instruction at universities (pp. 2213-2221). Multilingual Matters. https://\ndoi.org/10.21832/9781847698162\nFernández Lamarra, N., & Costa de Paula, N. (2011). Introducción. In N. Fernández Lamarra\n& N. Costa de Paula (Eds.), La democratización de la educación superior en América\nLatina. Límites y posibilidades (pp. 9-34). Tres de Febrero: EDUNTREF. https://doi.\norg/10.1590/S1414-40772010000200002\nFlores, N., & Aneja, G. (2017). “Why Needs Hiding?” Translingual (Re) Orientations in\nTESOL Teacher Education. Research in the Teaching of English, 51(4), 441-463.\nFu, D., & Matuosh, M. (2015). Focus on literacy. Oxford Key Concepts and Language Classroom Series. Oxford University Press.\nGarcia, O. & Klelfgen, J. (2009). Translanguaging and Literacies. Reading Research Quarterly, 55(4), 1-19. https://doi.org/10.1002/rrq.286\nGarcia, O., &, Wei, L. (2014). Translanguaging. New York: Palgrave Macmillan. https://doi.\norg/10.1057/9781137385765_7\nGevers, J. (2018). Translingualism revisited: Language difference and hybridity in L2 writing. Journal of Second Language Writing, 40, 73-83. https://doi.org/10.1016/j.\njslw.2018.04.003\nHoldway, J., & Hitchcock, C. (2018). Exploring ideological becoming in professional development for teachers of multilingual learners: Perspectives on translanguaging in the\nclassroom. Teaching and Teacher Education, 75, 60-70. https://doi.org/10.1016/j.\ntate.2018.05.015\nHopkins, S., Zoghbor, W. & Hassall, P. J. (2020). The use of English and linguistic hybridity among Emirati millennials. World Englishes, 1-15. https://doi.org/10.1111/\nweng.12506\nHyland, K. (2006). English for academic purposes: an advanced resource book. London:\nRoutledge. https://doi.org/10.4324/9780203006603\nHyland, K. (2007). Genre pedagogy: Language, literacy and L2 writing instruction. Journal of\nSecond Language Writing, 16, 148-164. https://doi.org/10.1016/j.jslw.2007.07.005\nHyland, K., & Jiang, F. (2017). Is academic writing becoming more informal? English for\nSpecific Purposes, 45, 40-51. https://doi.org/10.1016/j.esp.2016.09.001\n\n99\n\nLETRAS (Li ma), 93(137), 2022\n\n\fhttps://doi.org/10.30920/letras.93.137.7\n\nKaufhold, K. (2015). Conventions in postgraduate academic writing: European students’\nnegotiations of prior writing experience at an English speaking university. Journal of English for Academic Purposes, 20, 125-134. https://doi.org/10.1016/j.\njeap.2015.08.007\nKaufhold, K. (2018). Creating translanguaging spaces in students’ academic writing practices. Linguistics and Education, 45, 1-9. https://doi.org/10.1016/j.linged.2018.02.001\nKiernan, J., Meier, J., & Wang, X. (2017). Translingual approaches to reading and writing. International Association for Research in L1 Education, 17, 1-18. https://doi.\norg/10.17239/L1ESLL-2017.17.03.04\nKim, S. (2018). “It was kind of a given that we were all multilingual”: Transnational youth\nidentity work in digital translanguaging. Linguistics and Education, 43, 39-52.\nhttps://doi.org/10.1016/j.linged.2017.10.008\nKiramba, L. (2017). Translanguaging in the Writing of Emergent Multilinguals. International\nMultilingual Research Journal, 11(2), 115-130. https://doi.org/10.1080/19313152.2\n016.1239457\nKuteeva, M. (2019). Revisiting the ‘E’ in EMI students’ perceptions of standard English,\nlingua franca and translingual practices. International Journal of Bilingual Education\nand Bilingualism, 23(3), 287-300. https://doi.org/10.1080/13670050.2019.163739\n5\nLillis, T. (2001). Student writing: Access, regulation, desire. London: Routledge. https://\ndoi.org/10.4324/9780203186268\nLillis, T., & Scott, M. (2015). Defining academic literacies research: issues of epistemology,\nideology and strategy. Journal of Applied Linguistics and Professional Practice, 4(1),\n5-32. https://doi.org/10.1558/japl.v4i1.5\nMatsuda, P. K. (2006). The myth of linguistic homogeneity in US college composition. College English, 68(6), 637-651. https://doi.org/10.2307/25472180\nMay, S. (2013). Disciplinary divides, knowledge construction, and the multilingual turn.\nIn S. May (Ed.), The multilingual turn (pp. 7-31). New York: Routledge. https://doi.\norg/10.4324/9780203113493\nMcgrath, L., & Kaufhold, K. (2016). English for Specific Purposes and Academic Literacies:\neclecticism in academic writing pedagogy. Teaching in Higher Education, 21(8), 933947. https://doi.org/10.1080/13562517.2016.1198762\nMcIntosh, K., Connor, U. & Gokpinar-Shelton, E. (2017). What intercultural rhetoric can bring\nto EAP/ESP writing studies in an English as a lingua franca world. Journal of English\nfor Academic Purposes, 29(1), 12-20. https://doi.org/10.1016/j.jeap.2017.09.001\nMori, J., & Sanuth, K. (2018). Navigating between a monolingual utopia and translingual\nrealities: Experiences of American learners of Yorùbá as an Additional Language.\nApplied Linguistics, 39(1), 78-98. https://doi.org/10.1093/applin/amx042\nMotlhaka, H., & Makalela, L. (2016). Translanguaging in an academic writing class: Implications for a dialogic pedagogy. Southern African Linguistics and Applied Language\nStudies, 34(3), 251-260. https://doi.org/10.2989/16073614.2016.1250356\nPark, G. (2013). ‘Writing is a way of knowing’: writing and identity. ELT Journal, 67(3), 336345. https://doi.org/10.1093/elt/cct012\nPhillipson, R. (1992). Linguistic Imperialism. Oxford University Press.\nStrauss, P. (2017). Caught between two stools? Academic writing in ‘new’ vocational disciplines in higher education. Teaching in Higher Education, 22(8), 925-939. https://\ndoi.org/10.1080/13562517.2017.1319813\nStreet, B. V. (2010). Adopting an ethnographic perspective in research and pedagogy. In\nC. Coffin, T. M. Lillis, & K. O’Halloran (Eds.), Applied Linguistics Methods: A Reader\n(pp. 201-215). Routledge.\nThaiss, C., & Myers Zawacki, T. (2006). Engaged Writers and Dynamic Disciplines: Research on the Academic Writing Life. Boynton, Cook Heinemann.\nWagner, J. (2018). Multilingual and Multimodal Interactions. Applied Linguistics, 39(1), 99107. https://doi.org/10.1093/applin/amx058\nWei, L. (2011). Moment Analysis and translanguaging space: Discursive construction of\nidentities by multilingual Chinese youth in Britain. Journal of Pragmatics, 43, 12221235. https://doi.org/10.1016/j.pragma.2010.07.035\n100\n\nLETRAS (Li ma), 93(137), 2022\n\n\fhttps://doi.org/10.30920/letras.93.137.7\n\nWei, L. (2018). Translanguaging as a Practical Theory of Language. Applied Linguistics,\n39(1), 9-30. https://doi.org/10.1093/applin/amx039\nWei, L. & Ho, W. (2018). Language Learning Sans Frontiers: A Translanguaging View.\nAnnual Review of Applied Linguistics, 38, 33-59. https://doi.org/10.1017/\nS0267190518000053\nYanguas, I. (2019). L1 vs L2 synchronous text-based interaction in computer-mediated L2\nwriting. System, 88, 1-11. https://doi.org/10.1016/j.system.2019.102169\nZavala, V. (2017). Nuevos bilingüismos y viejas categorías en la formación inicial de\ndocentes. Revista Peruana de Investigación Educativa, 1, 61-84. https://doi.\norg/10.34236/rpie.v9i9.58\n\n101\n\nLETRAS (Li ma), 93(137), 2022\n\n\f"
|
|
https://openalex.org/W2613123695
|
https://europepmc.org/articles/pmc5441637?pdf=render
|
English
| null |
The mitochondrial SIR2 related protein 2 (SIR2RP2) impacts Leishmania donovani growth and infectivity
|
PLoS neglected tropical diseases
| 2,017
|
cc-by
| 14,884
|
Conclusion Our data suggests that LdSIR2RP2 possesses NAD+-dependent ADP-ribosyltransferase
activity. However, NAD+-dependent deacetylase and desuccinylase activities were not
detected. The protein localises to the mitochondrion of the promastigotes. Gene deletion
studies showed that ΔLdSIR2RP2 null mutants had restrictive growth phenotype associated
with accumulation of cells in the G2/M phase and compromised mitochondrial functioning. The null mutants had attenuated infectivity. Deletion of LdSIR2RP2 resulted in increased
sensitivity of the parasites to the known SIR2 inhibitors. The sirtuin inhibitors inhibited the
ADP-ribosyltransferase activity of recombinant LdSIR2RP2. In conclusion, sirtuins could be
used as potential new drug targets for visceral leishmaniasis. RESEARCH ARTICLE Editor: Armando Jardim, McGill university,
CANADA Editor: Armando Jardim, McGill university,
CANADA Nimisha Mittal1, Rohini Muthuswami2, Rentala Madhubala1* 1 School of Life Sciences, Jawaharlal Nehru University, New Delhi, India, 2 Chromatin Remodelling
Laboratory, School of Life Sciences, Jawaharlal Nehru University, New Delhi, India * rentala@outlook.com a1111111111
a1111111111
a1111111111
a1111111111
a1111111111 a1111111111
a1111111111
a1111111111
a1111111111
a1111111111 Background Leishmania donovani, a protozoan parasite is the major causative agent of visceral leish-
maniasis. Increased toxicity and resistance to the existing repertoire of drugs has been
reported. Hence, an urgent need exists for identifying newer drugs and drug targets. Previ-
ous reports have shown sirtuins (Silent Information Regulator) from kinetoplastids as prom-
ising drug targets. Leishmania species code for three SIR2 (Silent Information Regulator)
related proteins. Here, we for the first time report the functional characterization of SIR2
related protein 2 (SIR2RP2) of L. donovani. Methodology Recombinant L. donovani SIR2RP2 was expressed in E. coli and purified. The enzymatic
functions of SIR2RP2 were determined. The subcellular localization of LdSIR2RP2 was
done by constructing C-terminal GFP-tagged full-length LdSIR2RP2. Deletion mutants of
LdSIR2RP2 were generated in Leishmania by double targeted gene replacement methodol-
ogy. These null mutants were tested for their proliferation, virulence, cell cycle defects, mito-
chondrial functioning and sensitivity to known SIR2 inhibitors. Received: February 15, 2017
Accepted: April 21, 2017
Published: May 11, 2017 Copyright: © 2017 Mittal et al. This is an open
access article distributed under the terms of the
Creative Commons Attribution License, which
permits unrestricted use, distribution, and
reproduction in any medium, provided the original
author and source are credited. The mitochondrial SIR2 related protein 2
(SIR2RP2) impacts Leishmania donovani
growth and infectivity Nimisha Mittal1, Rohini Muthuswami2, Rentala Madhubala1* OPEN ACCESS Citation: Mittal N, Muthuswami R, Madhubala R
(2017) The mitochondrial SIR2 related protein 2
(SIR2RP2) impacts Leishmania donovani growth
and infectivity. PLoS Negl Trop Dis 11(5):
e0005590. https://doi.org/10.1371/journal. pntd.0005590 Data Availability Statement: All relevant data are
within the paper. Funding: This work was supported by the
University for Potential for Excellence grant (UPE-
II, Project ID -11) from the University Grants
Commission, Government of India and Department
of Science and Technology, Government of India
(DST –PURSE; SLS/RM/DST PURSE/2016-17)
grant to RMa and RMu. RMa is a JC Bose National
Fellow. NM is supported by Council for Scientific
and Industrial Research (CSIR), India. The funders 1 / 25 PLOS Neglected Tropical Diseases | https://doi.org/10.1371/journal.pntd.0005590
May 11, 2017 SIR2 related protein 2 of Leishmania donovani had no role in study design, data collection and
analysis, decision to publish, or preparation of the
manuscript. had no role in study design, data collection and
analysis, decision to publish, or preparation of the
manuscript. Author summary Sirtuins are present in most organisms, including plants, bacteria, and animals. They play
a vital role in promoting an organism’s health and survival. These proteins are involved in
the regulation of several functions in eukaryotic cells, including transcriptional repression,
recombination, cell cycle, cellular responses to DNA-damaging agents, and longevity. Sir-
tuins are known to be involved in regulation of vital cellular processes. Hence, they have
been proposed as promising targets for the development of antiparasitic drugs. Leish-
mania donovani, a protozoan parasite that causes visceral leishmaniasis is known to
express three sirtuins; SIR2RP1, SIR2RP2, and SIR2RP3. We have worked on the func-
tional characterization of the SIR2RP2 protein from L. donovani in this study. We report
that the SIR2RP2 is an NAD+-dependent ADP-ribosyltransferase. This protein is present
in the mitochondrion of the promastigotes and deletion of both copies of the gene caused
reduced growth, compromised mitochondrial functioning and cell cycle arrest in the
transgenic parasites. The transgenic parasites also had reduced infectivity. Deletion of
LdSIR2RP2 resulted in increased sensitivity of the parasites to the known sirtuin inhibi-
tors. Furthermore, the sirtuin inhibitors were found to inhibit the ADP-ribosyltransferase
activity of LdSIR2RP2 thus, indicating that parasitic sirtuins can be exploited as drug tar-
gets for antileishmanial chemotherapy. Competing interests: The authors have declared
that no competing interests exist. Materials All restriction enzymes, DNA-modifying enzymes, and DNA ladders were obtained from New
England Biolabs. Plasmid pETM-41 and TEV protease were kindly provided by Dr Amit
Sharma (ICGEB, New Delhi). Protein markers were obtained from Thermo Fisher Scientific
(USA). Nicotinamide Adenine Dinucleotide [Adenylate-32P] (800Ci/mmol) was purchased
from American Radiolabeled Chemicals (USA). Ni2+-NTA agarose and amylose resin were
purchased from Qiagen and New England Biolabs, respectively. Sirtinol, nicotinamide, cambi-
nol, and Ex-527 were obtained from Sigma-Aldrich (USA). SIRT1 Fluorometric Drug Discov-
ery Kit and SIRT5 Fluorometric Drug Discovery Kit were procured from Enzo Life Sciences
(USA). Other materials used in this study were of analytical grade and were commercially
available. SIR2 related protein 2 of Leishmania donovani of multiple targets within the cell, by deacetylation, ADP-ribosylation and desuccinylation/
demalonylation of specific lysine residues. Parasite sirtuins are distributed in all the phylogenetically defined sirtuin classes [16]. Sir-
tuins of protozoan parasites have both the canonical and atypical activities that contribute to
both conserved and apparently unique functions. T. brucei SIR2RP1, a nuclear protein that co-
localizes with telomeric sequences and mini-chromosomes and has both deacetylase and ADP
ribosylase activity, is known to be involved in DNA repair [13]. T. cruzi lacks SIR2RP2 but
expresses SIR2RP1 and SIR2RP3 that have been found to be essential for the proliferation of
the parasite, host- parasite interplay and differentiation among life cycle stages [17]. Besides
this, TcSIR2RP3 has been studied as a possible target for the treatment of Chagas’ disease [18]. The parasite Leishmania donovani is a protozoan parasite, the major causative agent of vis-
ceral leishmaniasis [19]. The disease is fatal if left untreated. The parasite has a digenetic life
cycle which alternates between mammalian immune cells and gut of insect vector, phleboto-
mine sand flies [20]. The current therapies are inadequate because of the increasing resistance
to the currently used drugs and their serious side effects. Hence, an urgent need exists to
develop new chemotherapeutic targets and agents against Leishmaniasis. Leishmania parasites are known to express three sirtuins; SIR2RP1, SIR2RP2, and SIR2RP3. Out of the three, only SIR2RP1 has been characterized in L. major and L. infantum wherein it
was found to be present in the cytoplasmic granules and indispensable for parasite survival
[21, 22]. It was found to have both NAD+-dependent deacetylase and ADP- ribosyltransferase
activities unrelated to epigenetic silencing. The other two sirtuins, SIR2RP2 and SIR2RP3,
have not yet been characterized. Here, we for the first time report the functional characterization of an SIR2RP2 protein
from L. donovani. SIR2RP2 is an NAD+-dependent ADP-ribosyltransferase. SIR2RP2 local-
izes to the mitochondrion of the promastigotes. Gene deletion mutations were attempted
via targeted gene replacement methodology in order to elucidate the physiological role of
LdSIR2RP2. Deletion of LdSIR2RP2 from the parasite caused compromised mitochondrial
functioning and accumulation of cells in the G2/M phase. The null mutants also had attenu-
ated infectivity. Deletion of LdSIR2RP2 resulted in increased sensitivity of the parasites to
the known sirtuin inhibitors. Introduction Acetylation and deacetylation of proteins have recently emerged as a major post-translational
modification [1]. Initially described for N-terminal tails of histones [2], reversible acetylation
of proteins in the cytoplasm and in the mitochondria, suggest a central role for acetylation in
regulatory mechanisms within and outside the nucleus of the cells [3]. The Silent Information Regulator (SIR2), the founding member of the family of sirtuins,
was originally described as a regulator of transcriptional silencing of mating-type loci, telo-
meres and ribosomal DNA [4], and also involved in the lifespan extension of yeast [5]. Since
their discovery, SIR2-like genes, known as sirtuins, have been studied in most organisms,
including plants, bacteria, and animals, where they play a vital role in promoting an organism’s
health and survival [6]. All sirtuins are characterized by a core domain of ~250 amino acids
that is highly conserved among different organisms [7]. They were first described to have
NAD+-dependent deacetylase activity, that consumes the cofactor nicotinamide adenine dinu-
cleotide (NAD+), yielding nicotinamide, O-acetyl ADP ribose (AADPR), and the deacetylated
substrate [8, 9]. Bacterial and archaeal genomes express one or two sirtuins, but eukaryotes usually have
multiple sirtuins, like yeast has Hst1–4 in addition to Sir2p, and humans have seven sirtuins
named SIRT1–7 [10], showing a discrete pattern of subcellular localization. However, being
present in large number in different cellular compartments, other novel enzymatic activities
for sirtuins have also been described like ADP-ribosyltransferase activity involving the transfer
of a single ADP-ribosyl group from NAD+ to proteins [11] and NAD+-dependent desucciny-
lase and demalonylase activity [12]. ADP-ribosylation activity is known to be present in yeast
SIR2, the human SIRT2, the mouse SIRT6, the Trypanosoma brucei SIR2RP1, Leishmania
infantum SIR2RP1 and the Plasmodium falciparum SIR2 [11, 13–15]. Desuccinylation and
demalonylation activity has only been described for SIRT5 of human [12]. In summary, the
evidence emerging from the literature is that the SIR2 proteins regulate the structure/function 2 / 25 PLOS Neglected Tropical Diseases | https://doi.org/10.1371/journal.pntd.0005590
May 11, 2017 SIR2 related protein 2 of Leishmania donovani penicillin (Sigma-Aldrich, USA), 100 μg/ml streptomycin (Sigma-Aldrich, USA) and 5% heat-
inactivated fetal bovine serum (Biowest). Wild-type (WT) parasites were routinely cultured in
media with no drug supplementations, whereas the genetically manipulated LdSIR2RP2 heterozy-
gotes, in which one allele of LdSIR2RP2 gene has been replaced either with hygromycin phospho-
transferase gene (LdSIR2RP2/HYG) or with neomycin phosphotransferase gene (LdSIR2RP2/NEO)
and null mutants (ΔLdSIR2RP2)were maintained in either 200 μg/ml hygromycin or 300 μg/ml
paromomycin or both respectively. The ΔLdSIR2RP2strain containing pSP72a-zeo-a-LdSIR2RP2
episome (‘add-back’ mutant cell line) was maintained in 800 μg/ml zeocin, 200 μg/ml hygromycin
and 300 μg/ml paromomycin. pSP72a-neo-a-GFP-LdSIR2RP2 transfected parasites were main-
tained in 40 μg/ml G418. For characterising the mutant parasites phenotypically, cells were sub-
cultured without selection antibiotics prior to experiments. The mouse monocyte-macrophage-like cell line J774A.1 obtained from ATCC was cultured
in RPMI 1640 (Sigma-Aldrich, USA) supplemented with 10% FBS and 100 units/ml penicillin
and 100 μg/ml streptomycin at 37˚C in humidified CO2 incubator. Cloning, expression and purification of recombinant LdSIR2RP2 The gene for LdSIR2RP2 was amplified by PCR using a forward primer with a flanking NcoI
restriction site (Forward: 50 AACCATGGCTATGAGGCCGGCGGGGACGATC 30) and a
reverse primer with a flanking KpnI restriction site (Reverse: 50 AAGGTACCCTAGAGTTGA
ATCGTCTTGCGGCGGAAG 30) from L. donovani genomic DNA. The ~ 963 bp amplicon
encompassing the complete ORF of LdSIR2RP2 gene was cloned into a pETM41 expression
vector. The recombinant vector pETM41-LdSIR2RP2 was transformed into Artic-Express DE3
strain. Expression of recombinant LdSIR2RP2 was induced in mid-exponential phase with 0.1
mM IPTG (isopropyl ß D-thiogalactoside) for 24 h at 10˚C. Cells were harvested by centrifuga-
tion at 5,000 rpm for 15 min. The bacterial pellet was resuspended in lysis buffer (20 mM Tris-
HCl pH 7.2, 200 mM NaCl, 10% glycerol, 10 mM beta-mercaptoethanol, 0.1 mg/ml lysozyme,
2 mM phenylmethylsulfonyl fluoride and protease inhibitor cocktail). The cells were lysed by
sonication and cleared by centrifugation at 6,000 rpm for 20 min. The cleared supernatant was
applied to pre-equilibrated amylose beads (NEB), and protein was eluted with buffer contain-
ing 20 mM Tris–HCl pH 7.2, 200 mM NaCl, 10 mM beta-mercaptoethanol and 2 mM maltose. The tag (MBP with His tag) was removed by incubating with TEV protease at 4˚C for 24 h. Multiple sequence alignment and phylogeny Sirtuin sequences of Leishmania and other kinetoplastids were retrieved from TriTrypDB
database [23] and used for sequence analysis. The human sirtuin sequences were obtained
from UniProt [24]. Subcellular localization prediction was made using a web version of WoLF
PSORT [25]. Phylogenetic analysis was performed using MUSCLE [26] and Unrooted soft-
ware. Multiple sequence alignment of these sequences was generated using a standalone ver-
sion of CLUSTALW [27] using default parameters. For analyzing the conserved motif patterns
and subfamily classification of the kinetoplastid sequences, multiple sequence alignment of
only the kinetoplastid sequences was generated. Strains and culture conditions L. donovani Bob (LdBob strain/MHOM/SD/62/1SCL2D) was originally obtained from Dr Ste-
phen Beverley (Washington University, St. Louis, MO). Wild-type promastigotes were cul-
tured at 22˚C in M199 medium (Sigma-Aldrich, USA) supplemented with 100 units/ml 3 / 25 PLOS Neglected Tropical Diseases | https://doi.org/10.1371/journal.pntd.0005590
May 11, 2017 Localisation of LdSIR2RP2 in L. donovani Intracellular localisation of LdSIR2RP2 in L. donovani was detected using pSP72-α-neo-α-GFP-
LdSIR2RP2 transfected promastigotes. For the construction of LdSIR2RP2-GFP fusion con-
struct, the 963 bp ORF of LdSIR2RP2 was amplified from LdBob genomic DNA using sense
primer: 50 AACCATGGCTATGAGGCCGGCGGGGACGATC 30 and antisense primer 50
CTCTAGACTAGAGTTGAATCGTCTTGCGGCGGAAG 30. The restriction sites incorpo-
rated in the primers are underlined. The amplicon was cloned into BamH1 and Xba1 restriction
sites of the vector pSP72-α-neo-α-GFP. Correct orientation and sequence fidelity of the inserts
was verified by nucleotide sequence analysis. The recombinant vector was transfected by elec-
troporation in wild-type L. donovani promastigotes according to the standard protocol [28],
and the transfectants were selected in the presence of 40 μg/ml G418 (Sigma-Aldrich, USA). L. donovani, pSP72-α-neo-α-GFP-LdSIR2RP2 transfected promastigotes were used to
detect the cellular distribution of LdSIR2RP2. Log phase promastigotes were incubated with 1
nM MitoTracker red CMXRos (Molecular Probes) diluted in M199 medium for 20 min at
22˚C in the dark. The cells were then washed with 1 X PBS and immobilised on poly-L-lysine-
coated glass coverslips. Subsequently, the cells were fixed with 4% paraformaldehyde for 30
min, washed and permeabilized in 0.5% Triton X-100-PBS for 5 min. The cellular DNA was
then stained with 1 μg/ml of DAPI (Sigma) for 30 min at RT. The coverslips were mounted on
glass slides for visualisation. The cells were imaged by Andor Spinning Disk Confocal Microscope equipped with iXon
Ultra 897 EMCCD camera at the required fluorescence excitation and emission wavelengths. The raw images were processed using FV10-ASW 1.7 viewer or Image J software. The co-local-
ization analysis was done using JACoP (Image J). SIR2 related protein 2 of Leishmania donovani was measured with excitation at 360 nm and emission at 460 nm using Varioskan Flash Multi-
mode Reader (Thermo Fisher Scientific). The enzymatic activities were calculated by plotting
a standard curve using deacetylated standard available with the kit. was measured with excitation at 360 nm and emission at 460 nm using Varioskan Flash Multi-
mode Reader (Thermo Fisher Scientific). The enzymatic activities were calculated by plotting
a standard curve using deacetylated standard available with the kit. Protein ADP-ribosylation assays were performed as described in [13]. Briefly, the reaction
was carried out in a volume of 20 μl containing 2.5 μg of rLdSIR2RP2, 2.5 μCi of [32P]NAD+
and 5 μg of calf thymus histones (Sigma-Aldrich, USA) or BSA as indicated. The reaction
buffer contained 150 mM NaCl, 10 mM dithiothreitol (DTT), 50 mM Tris-HCl pH 8.8. The
samples were incubated for 2 h at room temperature. The reactions were terminated by the
addition of Laemmli gel loading buffer. The proteins were resolved on a 12% SDS-PAGE gel
and visualized with the help of a PhosphorImager (Fujifilm). For quantitative experiments, the
reaction products were precipitated with 20% (w/v) trichloroacetic acid (TCA), washed and
counted for radioactivity after the addition of scintillation cocktail. The NAD+-dependent lysyl desuccinylase activity was done using a commercially available
SIRT5 Fluorometric Drug Discovery Kit (Enzo Life Sciences). The enzymatic reaction having
2.5 μg of rLdSIR2RP2 was carried out according to the manufacturer’s protocol. Briefly,
recombinant protein was incubated with 50 μM to 1 mM NAD+ and 50 μM fluorogenic pep-
tide for 60 min at 37˚C followed by incubation in the developer for 15 min at 37˚C. The fluo-
rescence was measured with excitation at 360 nm and emission at 460 nm using Varioskan
Flash Multimode Reader (Thermo Fisher Scientific). The enzymatic activities were calculated
by plotting a standard curve using desuccinylated standard available with the kit. Enzyme activity assays The NAD+-dependent deacetylase activity was estimated by using a commercially available
SIRT1 Fluorometric Drug Discovery Kit (Enzo Life Sciences). The enzymatic reaction contain-
ing rLdSIR2RP2 was carried out according to the manufacturer’s protocol. Briefly, the recom-
binant protein was incubated with 50 μM to 1 mM NAD+ and 64 μM fluorogenic peptide for
20 min at 37˚C followed by incubation in the developer for 45 min at 37˚C. The fluorescence 4 / 25 PLOS Neglected Tropical Diseases | https://doi.org/10.1371/journal.pntd.0005590
May 11, 2017 Table 1. Primers used for generation of the Hyg and Neo specific linear replacement cassette fragments.
S.No
L.donovani primers
Primer Sequences
1.
A
5’ TGATGGAGTTGCCAATCCAATTACA 3’
2.
BHYG
5’ GGTGAGTTCAGGCTTTTTCATGAGAAGATAGCAGCTGAAT 3’
3.
CHYG
5’ ATTCAGCTGCTATCTTCTCATGAAAAAGCCTGAACTCACC 3’
4.
DHYG
5’ACGCCAAGTCAAAAAGCGATCCTATTCCTTTGCCCTCGGACGAG 3’
5.
EHYG
5’CTCGTCCGAGGGCAAAGGAATAGGATCGCTTTTTGACTTGGCGT 3’
6.
BNEO
5’CAATCCATCTTGTTCAATCATGAGAAGATAGCAGCTGAAT 3’
7.
CNEO
5’ ATTCAGCTGCTATCTTCTCATGATTGAACAAGATGGATT 3’
8.
DNEO
5’ ACGCCAAGTCAAAAAGCGATCTCAGAAGAACTCGTCAAGAAG 3’
9.
ENEO
5’ CTTCTTGACGAGTTCTTCTGAGATCGCTTTTTGACTTGGCGT 3’
10.
F
5’ CATGAAGCTAAGAAGCAGAAA 3’ Table 1. Primers used for generation of the Hyg and Neo specific linear replacement cassette fragments flanking regions were amplified from LdBob genomic DNA and fused to antibiotic resistance cas-
settes: hygromycin phosphotransferase gene (HYG) or neomycin phosphotransferase gene
(NEO). The 50UTR (907 bp) of L. donovani LdSIR2RP2 was amplified with primers A & BHyg or
primers A & BNeo (Table 1). The NEO gene (795 bp) was amplified from pX63-NEO with prim-
ers CNeo & DNeo. The HYG gene (1012 bp) was amplified from pX63HYG with primers CHyg &
DHyg (Table 1). The 30UTR (967 bp) of L. donovani LdSIR2RP2 was PCR amplified from wild-
type LdBob genomic DNA using primers EHyg or ENeo & antisense primer F (Table 1). The
50UTR of L. donovani LdSIR2RP2 was then ligated to the antibiotic resistance marker genes by
PCR using primers A & DHyg or A & DNeo. Finally, this fragment (50UTR-marker gene) was
fused with 30UTR of LdSIR2RP2 using primers A & F, yielding the fragment, 50UTR-Hyg-30UTR
or 50UTR-Neo-30UTR. To generate the episomal ‘add back’ construct, the full-length LdSIR2RP2 coding sequence
was amplified with primers; Forward: 50 CCCTCTAGAATGAGGCCGGCGGGGACGATC 30
and Reverse: 50CCCAAGCTTCTAGAGTTGAATCGTCTTGCGGCGGAAG 30. This ampli-
fied product was then cloned into the Xba1 and HindIII restriction sites of the pSP72α-zeo-α
vector to get pSP72α-zeo-α-LdSIR2RP2 complementation construct. All the fragments and
constructs were sequenced for confirmation of their correct orientation and sequence fidelity. Molecular constructs for the replacement of LdSIR2RP2 alleles Targeted gene replacement strategy was utilized for the inactivation of LdSIR2RP2 gene in L. donovani. A fusion PCR-based strategy was employed as reported earlier [29]. Briefly, LdSIR2RP2 5 / 25 PLOS Neglected Tropical Diseases | https://doi.org/10.1371/journal.pntd.0005590
May 11, 2017 https://doi.org/10.1371/journal.pntd.0005590.t001 SIR2 related protein 2 of Leishmania donovani Table 1. Primers used for generation of the Hyg and Neo specific linear replacement cassette fragments. S.No
L.donovani primers
Primer Sequences
1. A
5’ TGATGGAGTTGCCAATCCAATTACA 3’
2. BHYG
5’ GGTGAGTTCAGGCTTTTTCATGAGAAGATAGCAGCTGAAT 3’
3. CHYG
5’ ATTCAGCTGCTATCTTCTCATGAAAAAGCCTGAACTCACC 3’
4. DHYG
5’ACGCCAAGTCAAAAAGCGATCCTATTCCTTTGCCCTCGGACGAG 3’
5. EHYG
5’CTCGTCCGAGGGCAAAGGAATAGGATCGCTTTTTGACTTGGCGT 3’
6. BNEO
5’CAATCCATCTTGTTCAATCATGAGAAGATAGCAGCTGAAT 3’
7. CNEO
5’ ATTCAGCTGCTATCTTCTCATGATTGAACAAGATGGATT 3’
8. DNEO
5’ ACGCCAAGTCAAAAAGCGATCTCAGAAGAACTCGTCAAGAAG 3’
9. ENEO
5’ CTTCTTGACGAGTTCTTCTGAGATCGCTTTTTGACTTGGCGT 3’
10. F
5’ CATGAAGCTAAGAAGCAGAAA 3’ Cell cycle analysis 2 x 107 log phase promastigotes of WT, ΔLdSIR2RP2 and ΔLdSIR2RP2/+ were collected, washed
twice with 1X PBS and then fixed in ice-cold 30% PBS/70% (v/v) methanol for 1 h at 4˚C. The
fixed cells were washed twice with ice-cold 1X PBS and then resuspended in 1 ml 1X PBS con-
taining 100 μg/ml RNase and 20 μg/ml propidium iodide (Sigma-Aldrich, USA). The cells were
incubated for 45 min at 37˚C in the dark. The samples were then analysed using BD Biosciences
FACS Calibur system using BD Biosciences CellQuest software. For each sample, data for at least
20,000 events were collected. The resulting distribution of cells was analysed by the Modfit Lt. Software to determine the percentage of cells in G0/G1, S, or G2/M phases of the cell cycle. SIR2 related protein 2 of Leishmania donovani Infectivity assay J774A.1 murine macrophage cell line was plated on poly-L-lysine-coated glass coverslips at a
density of 5 × 105 cells per well in a 6-well flat bottom plate. The adherent cells were infected
with stationary-phase promastigotes, at a ratio of 20:1 for 6 h. Excess non-adherent promasti-
gotes were removed by incubation of the cells for 30 s in 1X phosphate buffer saline (1 X PBS). These were subsequently maintained in RPMI1640 containing 10% FBS at 37˚C with 5% CO2. Intracellular parasite load was visualised by Giemsa staining. Growth curve analysis Growth rate experiments were conducted by inoculating stationary-phase parasites at a density
of 1 × 106 cells/ml in standard M199 medium with 5% FBS in 25 cm2 flasks without particular
selection drug and culturing at 22˚C. The growth rate of each of the cultures was determined
at 24 h intervals by using a Neubauer hemocytometer. Growth studies with each individual
cell line were performed at least three times, and similar results were obtained consistently. https://doi.org/10.1371/journal.pntd.0005590.t002 Generation of genetically manipulated parasites 50UTR-Hyg- 30UTR or 50UTR-Neo-30UTR linear fragments were generated through PCR
amplification. The fragments were gel purified, and about 1–2 micrograms of each fragment
were individually transfected by electroporation in wild-type L. donovani promastigotes
according to the standard protocol [28] Depending on the marker gene, transfectants were
selected either in the presence of 200 μg/ml hygromycin (Sigma-Aldrich, USA) or 300 μg/ml
paromomycin (Sigma-Aldrich, USA). The cells resistant to antibiotic selection were checked
by PCR-based analysis for the correct integration of the replacement cassettes using primers
shown in (Table 2). Thereafter, the second round of transfection was done to knock-out the
other copy of LdSIR2RP2 gene. The genotypes of the LdSIR2RP2 mutants were confirmed by
Southern blotting analysis using standard protocols [30]. The ‘add-back’ line ΔLdSIR2RP2/+ was created from the ΔLdSIR2RP2 null mutants by
transfecting these parasites with pSP72α-zeo-α-LdSIR2RP2 episome. After transfection, these
parasites ΔLdSIR2RP2/+ were selected in 800 μg/ml zeocin, 200 μg/ml hygromycin and
300 μg/ml paromomycin. Further, the genotype of the ‘add-back’ line ΔLdSIR2RP2/+ was con-
firmed by PCR analysis using primers mentioned in (Table 2). PLOS Neglected Tropical Diseases | https://doi.org/10.1371/journal.pntd.0005590
May 11, 2017 6 / 25 SIR2 related protein 2 of Leishmania donovani Results Sequence analysis and phylogeny Inhibitor studies The susceptibility profile of L. donovani wild-type and mutant promastigotes for sirtinol, nico-
tinamide (NAM), Ex-527, and cambinol was determined using MTT [3-(4, 5- dimethylthiazol-
2-yl) -2, 5 diphenyltetrazolium bromide] assay [31]. Briefly, log-phase promastigotes (5×105
cells/well) were seeded in a 96-well flat-bottomed plate and incubated with different drug con-
centrations at 22˚C. DMSO was used as a vehicle control for inhibitors which were dissolved
in DMSO. After 72 h of incubation, 20 μL of MTT (Sigma-Aldrich, USA) (5 mg/ml) was
added to each well, and the plates were further incubated at 37˚C for 3 h. The reaction was ter-
minated by the addition of 50 μL of stopping solution (50% isopropanol and 20% SDS) fol-
lowed by gentle shaking at 37˚C for 30 min to 1 h. The absorbance was measured at 570 nm in
a microplate reader (SpectraMax M2 from Molecular Devices). The susceptibility of wild-type and mutant amastigotes to the above-mentioned inhibitors
was determined by visualisation of intracellular parasite load using Giemsa staining of the
infected J774A.1 murine macrophages, 48 h after treatment with different concentrations of
the drug. The cytotoxicity of inhibitors on J774A.1 murine macrophage cell line was determined by
MTT assay. Briefly, 1 x 104 cells per well were seeded in a 96-well flat-bottomed plate and incu-
bated with different drug concentrations at 37˚C, 5% CO2. DMSO was used as a vehicle con-
trol for inhibitors which were dissolved in DMSO. After 48 h of incubation, the assay was
terminated by adding MTT as mentioned above and the absorbance was measured at 570 nm. The effect of inhibitors on the ADP-ribosyltransferase activity of recombinant LdSIR2RP2
was assessed. Briefly, the assays were carried out with 2.5 μg of recombinant LdSIR2RP2, 5 μg of
calf thymus histones (Sigma), and the respective inhibitors at indicated concentrations. The
reaction mixtures were incubated at 37˚C for 1 h. Thereafter, 2.5 μCi of [32P]NAD+ was added
to the above mixture, and the reactions were allowed to proceed further at room temperature
for 2 h. The reactions were terminated, resolved on 12% SDS gel and visualized as stated above. Measurement of intracellular ATP levels The cellular ATP levels of the parasites were measured using a bioluminescence-based ATP
detection assay kit (BioVision) as per the manufacturer’s protocol. Briefly, 1 × 107 log phase
WT, ΔLdSIR2RP2 and ΔLdSIR2RP2/+ cells were seeded in a 96-well plate and treated with
indicated compounds (5 mM, 2-deoxyD-glucose (2DG) (Sigma-Aldrich, USA) or 10 μM Oli-
gomycin (Oligo) (Sigma-Aldrich, USA). The cells were lysed, substrate solution was added,
and the luminescence intensity was measured in a luminometer (Turners Design, TD 20/20). Percentage cellular ATP levels were plotted in reference to control. Statistical analysis Statistical analysis was done using Graph Pad Prism Version 5.0. Data shown are representa-
tive of at least three independent experiments unless otherwise stated as n values given in the
legend. All the experiments were set in triplicate, and the results are expressed as the mean ± S. D. Student’s t test was employed to assess the statistical significance of differences between a
pair of data sets with a p-value of < 0.05 considered to be significant. Measurement of mitochondrial transmembrane potential (ΔΨm) The mitochondrial transmembrane potential was investigated using MitoTracker Red CMXRos
(Invitrogen). Logarithmically growing promastigotes (1 × 106 cells) were incubated with Mito
Tracker Red CMXRos (100 nM) for 30 minutes. Wild-type cells treated with protonophore car-
bonyl cyanide m-chlorophenyl hydrazone (CCCP) (50 μM) (Sigma-Aldrich, USA), a mitochon-
drial membrane depolarization compound was used as a control. Subsequently, the cells were
washed with 1 X PBS and fixed as mentioned in the above protocol. The samples were then ana-
lysed using FACS, BD Biosciences FACS Calibur system using BD Biosciences CellQuest soft-
ware. The mean fluorescence intensities (MFI) of FL2 channel were used for analysis. For each
sample, data for at least 20,000 events were collected. Table 2. Primers used for the molecular characterization of the genetically manipulated parasites by PCR-based analysis. S.No
L. donovani Primers
Sequences
1. Primer 1
5’ TGTAGAAGTACTCGCCGATAGTGG 3’
2. Primer 2
5’ TTGCTTGCCTTTCAGGAAGGGGAGGTT 3’
3. Primer 3
5’ CGCAGCTATTTACCCGCAGGACAT 3’
4. Primer 4
5’ CCGACTTGTTGTCTTTTCTCGTCTCC 3’
5. Primer 5
5’ ATAGCGTTGG CTACCCGTGATATTGC 3’
6. Primer 6
5’ AACACGGCGGCATCAGAGCAGCCGATTG 3’
7. Primer 7
5’ AAACTCAATGTGGAGAGCGTCGGAA 3’
8. Primer 8
5’ CAGCGCTCCATGAACGATGCGATCGT 3’
9. Zeo F
5’ ATGGCCAAGTTGACCAGTGCCGTTCC 3’
10
Zeo R
5’ TCAGTCCTGCTCCTCGGCCACGAA 3’
https://doi.org/10.1371/journal.pntd.0005590.t002
PLOS Neglected Tropical Diseases | https://doi org/10 1371/journal pntd 0005590
May 11 2017
7 / 25 ers used for the molecular characterization of the genetically manipulated parasites by PCR-based analysis. Table 2. Primers used for the molecular characterization of the genetically manipulated parasites by PC 7 / 25 Further, it is also evident from the phylogeny that class III kinetoplastid sir-
tuins are closely related to HsSIRT5 sirtuin that have been shown to possess both NAD+-depen-
dent deacetylase and the novel desuccinylase/ demalonylase activities [12]. To date, the Class I
homologs of Leishmania [15, 21] and Trypanosoma [13, 17] parasites have been characterized,
and nothing is known about the sirtuins belonging to Class III and Class II subfamilies. The
LdSIR2RP1, LdSIR2RP2, and LdSIR2RP3 encode putative polypeptides of amino acids 373,
320 and 243, respectively. The predicted molecular mass of LdSIR2RP1, LdSIR2RP2 and
LdSIR2RP3 is 41, 35 and 27 kDa, respectively. Of these, the SIR2 Leishmania homolog
LdBPK_260200.1 was predicted to be localized in the cytosol. The other two SIR2 copies on
Chromosome 34 (LdBPK_341900.1) and Chromosome 23 (LdBPK_231450.1) are predicted
to be localized in the mitochondria. All the three Leishmania sirtuins lack the N-terminal
extension present in HsSIRT1 and HsSIRT2 that are required for nucleolar localization [33]
but contain a full catalytic SIR2 domain (Fig 1B). These proteins also have the conserved Zn2+
binding motif (CX2CX20CX2C), although one of the Cys residues is lacking in LdSIR2RP3
(Fig 1B). Multiple sequence alignment of the catalytic region of Leishmania sirtuins with that of
human sirtuins homologs shows the conserved sequence patterns characteristic of the individ-
ual subfamilies of sirtuins (Fig 2). GAG, TQNID and HG motifs, as well as other residues
essential for enzymatic catalysis, are conserved in Leishmania sirtuins. Among the conserved
motifs, the “HG” motif is of interest as mutation of “HG” to “YG” has been shown to convert
the yeast sirtuin into a dominant negative gene with loss in function [7] while it is conserved as
“QG” in microbial sirtuins denoted as SirTM subfamily [34]. Thus, the “HG” motif essential
for sirtuin-mediated ADP-ribosylation and deacetylation is conserved in all the kinetoplastid
sequences suggestive of active sirtuins. Both LdSIR2RP1 and LdSIR2RP2 contain a zinc bind-
ing motif. Overall, LdSIR2RP1 sequence shares 46% sequence identity with its human homo-
log HsSIRT2, while LdSIR2RP2 and LdSIR2RP3 share 39% and 37% sequence identity with
HsSIRT4 and HsSIRT5, respectively. SIR2 related protein 2 of Leishmania donovani while kinetoplastids have Class I, Class II, and Class III sirtuins (Fig 1A). There are three SIR2
related proteins in L. donovani. The SIR2 related proteins of L. donovani (LdBPK_260200.1,
LdBPK_231450.1, and LdBPK_341900.1) are termed as LdSIR2RP1, LdSIR2RP2, and LdSIR2RP3. The phylogenetic analysis of kinetoplastid sequences along with the homologs from human (Fig
1A) suggests a clear branching of the individual sirtuin subfamilies. LdSIR2RP1 belongs to Class I;
LdSIR2RP2 belongs to Class II, and LdSIR2RP3 belongs to Class III, of sirtuins. Class I, kineto-
plastid sequences are related to HsSIRT1, HsSIRT2, and HsSIRT3. Class II kinetoplastid sequences
are closer to HsSIRT4. Further, it is also evident from the phylogeny that class III kinetoplastid sir-
tuins are closely related to HsSIRT5 sirtuin that have been shown to possess both NAD+-depen-
dent deacetylase and the novel desuccinylase/ demalonylase activities [12]. To date, the Class I
homologs of Leishmania [15, 21] and Trypanosoma [13, 17] parasites have been characterized,
and nothing is known about the sirtuins belonging to Class III and Class II subfamilies. The
LdSIR2RP1, LdSIR2RP2, and LdSIR2RP3 encode putative polypeptides of amino acids 373,
320 and 243, respectively. The predicted molecular mass of LdSIR2RP1, LdSIR2RP2 and
LdSIR2RP3 is 41, 35 and 27 kDa, respectively. Of these, the SIR2 Leishmania homolog
LdBPK_260200.1 was predicted to be localized in the cytosol. The other two SIR2 copies on
Chromosome 34 (LdBPK_341900.1) and Chromosome 23 (LdBPK_231450.1) are predicted
to be localized in the mitochondria. All the three Leishmania sirtuins lack the N-terminal
extension present in HsSIRT1 and HsSIRT2 that are required for nucleolar localization [33]
but contain a full catalytic SIR2 domain (Fig 1B). These proteins also have the conserved Zn2+
binding motif (CX2CX20CX2C), although one of the Cys residues is lacking in LdSIR2RP3
(Fig 1B). while kinetoplastids have Class I, Class II, and Class III sirtuins (Fig 1A). There are three SIR2
related proteins in L. donovani. The SIR2 related proteins of L. donovani (LdBPK_260200.1,
LdBPK_231450.1, and LdBPK_341900.1) are termed as LdSIR2RP1, LdSIR2RP2, and LdSIR2RP3. The phylogenetic analysis of kinetoplastid sequences along with the homologs from human (Fig
1A) suggests a clear branching of the individual sirtuin subfamilies. LdSIR2RP1 belongs to Class I;
LdSIR2RP2 belongs to Class II, and LdSIR2RP3 belongs to Class III, of sirtuins. Class I, kineto-
plastid sequences are related to HsSIRT1, HsSIRT2, and HsSIRT3. Class II kinetoplastid sequences
are closer to HsSIRT4. Sequence analysis and phylogeny The eukaryotic sirtuins are classified into four classes: I, II, III and IV, based on the conserved
sequence motif patterns [7]. Humans have seven sirtuins distributed in all the four classes [32] 8 / 25 PLOS Neglected Tropical Diseases | https://doi.org/10.1371/journal.pntd.0005590
May 11, 2017 LdSIR2RP2 of L. donovani is an NAD+- dependent ADP-
ribosyltransferase In order to overexpress the recombinant LdSIR2RP2, the coding sequence of LdSIR2RP2 was
cloned into a pETM41 expression vector possessing an N-terminal maltose binding protein
(MBP) tag. The construct was transformed into Artic-Express DE3 strain and induced as
explained in the Methods section, resulting in expression of MBP-tagged recombinant LdSIR2
RP2 with an estimated molecular size of ~ 77 kDa (Fig 3A). The size of the recombinant pro-
tein correlated with the amino acid composition of the LdSIR2RP2 protein (~ 35 kDa) and
MBP tag (~ 42 kDa). The recombinant MBP-LdSIR2RP2 was affinity purified on a pre-equili-
brated amylose resin column yielding *1 mg of pure protein from 1 litre of bacterial culture. The MBP tag cleavage of the recombinant protein was done by using TEV protease at a w/w
ratio of 1% the amount of fusion protein at 4˚C. The pure recombinant LdSIR2RP2 was
obtained after passing the reaction mixture, first through pre-equilibrated Ni2+-NTA column PLOS Neglected Tropical Diseases | https://doi.org/10.1371/journal.pntd.0005590
May 11, 2017 9 / 25 SIR2 related protein 2 of Leishmania donovani Fig 1. Phylogenetic analysis of Leishmania sirtuins. (A) The unrooted neighbor-joining tree was generated using MUSCLE program
and Unrooted software. The sequences are divided into four sirtuin classes; I, II, III and IV based on the conserved sirtuins core
deacetylase domain. (B). Schematic representation of the predicted L. donovani sirtuins compared with HsSIRT1, HsSIRT2, HsSIRT3,
HsSIRT4, and HsSIRT5. The location of Cys residues that form the Zn2+ -binding motif are indicated (black bars). https://doi.org/10.1371/journal.pntd.0005590.g001
SIR2 related protein 2 of Leishmania donovani
l
d T
i
l Di
| h
//d i
/
/j
l
d
M
/ Fig 1. Phylogenetic analysis of Leishmania sirtuins. (A) The unrooted neighbor-joining tree was generated using MUSCLE program
and Unrooted software. The sequences are divided into four sirtuin classes; I, II, III and IV based on the conserved sirtuins core
deacetylase domain. (B). Schematic representation of the predicted L. donovani sirtuins compared with HsSIRT1, HsSIRT2, HsSIRT3,
HsSIRT4, and HsSIRT5. The location of Cys residues that form the Zn2+ -binding motif are indicated (black bars). https://doi.org/10.1371/journal.pntd.0005590.g001 Fig 1. Phylogenetic analysis of Leishmania sirtuins. (A) The unrooted neighbor-joining tree was generated using MUSCLE program
and Unrooted software. The sequences are divided into four sirtuin classes; I, II, III and IV based on the conserved sirtuins core
deacetylase domain. (B). Schematic representation of the predicted L. SIR2 related protein 2 of Leishmania donovani Fig 2. Sequence analysis. Multiple sequence alignment of Leishmania sirtuins with HsSIRT1, HsSIRT2,
HsSIRT3, HsSIRT4 and HsSIRT5 using Clustal Omega. The conserved GAG, TQNID, and HG motifs are
highlighted in light grey, The Cys residues from the Zn2+-binding domain are shown in dark grey (arrowheads). https://doi.org/10.1371/journal.pntd.0005590.g002 Fig 2. Sequence analysis. Multiple sequence alignment of Leishmania sirtuins with HsSIRT1, HsSIRT2,
HsSIRT3, HsSIRT4 and HsSIRT5 using Clustal Omega. The conserved GAG, TQNID, and HG motifs are
highlighted in light grey, The Cys residues from the Zn2+-binding domain are shown in dark grey (arrowheads
https://doi.org/10.1371/journal.pntd.0005590.g002 https://doi.org/10.1371/journal.pntd.0005590.g002 to remove TEV protease and then through pre-equilibrated amylose resin column to remove
the MBP tag protein (Fig 3A). the MBP tag protein (Fig 3A). Proteins belonging to the SIR2 family exhibit NAD+-dependent deacetylase activity due to
the presence of a well-conserved enzymatic core SIR domain of *250 amino acids [7, 35]. Some members of the SIR2 family are also known to catalyze the transfer of ribose 50-phos-
phate from nicotinic acid mononucleotide to amino acid residues of bovine serum albumin
(BSA), histones or SIR2 proteins themselves [11, 35]. Recently, class III sirtuins have been
reported to have novel enzymatic activities like desuccinylase and demalonylase [12, 36]. Using recombinant LdSIR2RP2, we checked NAD+-dependent deacetylase and/or NAD+-
dependent ADP-ribosyltransferase activity and/or desuccinylase activities. However, the
recombinant protein did not show any detectable deacetylase and desuccinylase activities. Next, to assess whether LdSIR2RP2 is an ADP-ribosyltransferase, [32P]NAD+ as the donor
and bovine serum albumin (BSA) or calf thymus histone as acceptor substrates were used. rLdSIR2RP2 protein was able to catalyze the ADP-ribosylation of calf thymus histones (Fig
3B). However, there was no transfer of ADP-ribose on BSA, suggesting its strong specificity
towards histones. Quantitative analysis of rLdSIR2RP2 done using histones as acceptor protein Proteins belonging to the SIR2 family exhibit NAD+-dependent deacetylase activity due to
the presence of a well-conserved enzymatic core SIR domain of *250 amino acids [7, 35]. Some members of the SIR2 family are also known to catalyze the transfer of ribose 50-phos-
phate from nicotinic acid mononucleotide to amino acid residues of bovine serum albumin
(BSA), histones or SIR2 proteins themselves [11, 35]. Recently, class III sirtuins have been
reported to have novel enzymatic activities like desuccinylase and demalonylase [12, 36]. Using recombinant LdSIR2RP2, we checked NAD+-dependent deacetylase and/or NAD+-
dependent ADP-ribosyltransferase activity and/or desuccinylase activities. LdSIR2RP2 of L. donovani is an NAD+- dependent ADP-
ribosyltransferase donovani sirtuins compared with HsSIRT1, HsSIRT2, HsSIRT3,
HsSIRT4, and HsSIRT5. The location of Cys residues that form the Zn2+ -binding motif are indicated (black bars). https://doi.org/10.1371/journal.pntd.0005590.g001 PLOS Neglected Tropical Diseases | https://doi.org/10.1371/journal.pntd.0005590
May 11, 2017 10 / 25 Ribosyltransferase reactions were performed with 5 μg of histones, 2.5 μg of rLdSIR2RP2 and 2.5 μCi of [32P]NAD+ (standard
reaction) or a double concentration of histone (10 μg, 2X histones), rLdSIR2RP2 (5 μg, 2X rLdSIR2RP2) and [32P]NAD+ (5 μCi, 2X
NAD+). The reaction products were precipitated with 20% TCA, collected, washed and then counted after the addition of
scintillation liquid. Fig 3. Expression, purification and enzymatic characterization of LdSIR2RP2. (A). Lane 1, molecular weight marker; Lane 2,
uninduced cell lysate; Lane 3, induced cell lysate; Lane 5, concentrated eluates showing purified protein; Lane 6, Purified protein
after TEV protease cleavage; Lane 7, LdSIR2RP2 protein without the MBP tag after passing through second amylose column. (B)
(i). In vitro ribosylation reaction of rLdSIR2RP2 (+), was performed using [32P] NAD+ as donor and BSA or calf thymus histones as
acceptor protein. The reaction products were resolved by 12% SDS-PAGE and analyzed by PhosphorImager and Coomassie blue
stain. (B)(ii). Quantitative analysis of the effect of NAD+, histones, and rLdSIR2RP2 on the extent of ribosylation by rLdSIR2RP2. Ribosyltransferase reactions were performed with 5 μg of histones, 2.5 μg of rLdSIR2RP2 and 2.5 μCi of [32P]NAD+ (standard
reaction) or a double concentration of histone (10 μg, 2X histones), rLdSIR2RP2 (5 μg, 2X rLdSIR2RP2) and [32P]NAD+ (5 μCi, 2X
NAD+). The reaction products were precipitated with 20% TCA, collected, washed and then counted after the addition of
scintillation liquid. https://doi.org/10.1371/journal.pntd.0005590.g003 https://doi.org/10.1371/journal.pntd.0005590.g003 showed that a two-fold increase in the number of histones and recombinant protein did not
have any effect on the extent of ADP-ribosylation. However, when the amount of NAD+ was
doubled, there was ~1.5-fold increase in ADP-ribosylation (Fig 3B(ii)), suggesting that NAD+
is the only limiting factor for ADP-ribosylation activity of rLdSIR2RP2. Phylogenetically
LdSIR2RP2 belongs to class II of sirtuin family, of which HsSIRT4 is a prominent member. HsSIRT4 only has NAD+-dependent ADP-ribosyltransferase activity [37]. Thus, it can be
concluded that like its human counterpart, LdSIR2RP2 possessed an NAD+-dependent ADP-
ribosyltransferase activity and lacked measurable NAD+-dependent deacetylase and desucci-
nylase activities. However, this needs to be further validated using stringent purification
methods. However, the
recombinant protein did not show any detectable deacetylase and desuccinylase activities. Next, to assess whether LdSIR2RP2 is an ADP-ribosyltransferase, [32P]NAD+ as the donor
and bovine serum albumin (BSA) or calf thymus histone as acceptor substrates were used. rLdSIR2RP2 protein was able to catalyze the ADP-ribosylation of calf thymus histones (Fig
3B). However, there was no transfer of ADP-ribose on BSA, suggesting its strong specificity
towards histones. Quantitative analysis of rLdSIR2RP2 done using histones as acceptor protein 11 / 25 PLOS Neglected Tropical Diseases | https://doi.org/10.1371/journal.pntd.0005590
May 11, 2017 SIR2 related protein 2 of Leishmania donovani Fig 3. Expression, purification and enzymatic characterization of LdSIR2RP2. (A). Lane 1, molecular weight marker; Lane 2,
uninduced cell lysate; Lane 3, induced cell lysate; Lane 5, concentrated eluates showing purified protein; Lane 6, Purified protein
after TEV protease cleavage; Lane 7, LdSIR2RP2 protein without the MBP tag after passing through second amylose column. (B)
(i). In vitro ribosylation reaction of rLdSIR2RP2 (+), was performed using [32P] NAD+ as donor and BSA or calf thymus histones as
acceptor protein. The reaction products were resolved by 12% SDS-PAGE and analyzed by PhosphorImager and Coomassie blue
stain. (B)(ii). Quantitative analysis of the effect of NAD+, histones, and rLdSIR2RP2 on the extent of ribosylation by rLdSIR2RP2. Ribosyltransferase reactions were performed with 5 μg of histones, 2.5 μg of rLdSIR2RP2 and 2.5 μCi of [32P]NAD+ (standard
reaction) or a double concentration of histone (10 μg, 2X histones), rLdSIR2RP2 (5 μg, 2X rLdSIR2RP2) and [32P]NAD+ (5 μCi, 2X
NAD+). The reaction products were precipitated with 20% TCA, collected, washed and then counted after the addition of
scintillation liquid. Fig 3. Expression, purification and enzymatic characterization of LdSIR2RP2. (A). Lane 1, molecular weight marker; Lane 2,
uninduced cell lysate; Lane 3, induced cell lysate; Lane 5, concentrated eluates showing purified protein; Lane 6, Purified protein
after TEV protease cleavage; Lane 7, LdSIR2RP2 protein without the MBP tag after passing through second amylose column. (B)
(i). In vitro ribosylation reaction of rLdSIR2RP2 (+), was performed using [32P] NAD+ as donor and BSA or calf thymus histones as
acceptor protein. The reaction products were resolved by 12% SDS-PAGE and analyzed by PhosphorImager and Coomassie blue
stain. (B)(ii). Quantitative analysis of the effect of NAD+, histones, and rLdSIR2RP2 on the extent of ribosylation by rLdSIR2RP2. SIR2 related protein 2 of Leishmania donovani parasites transfected with GFP vector alone (without insert) were fixed and analysed by fluo-
rescence microscopy. The GFP fluorescence was visible in approximately 80% of the cells (Fig
4A (i)). The kinetoplast and nuclear DNA in these cells were readily identified by their bright
staining with DAPI. The parasites transfected with the GFP vector alone showed GFP fluores-
cence in the entire promastigotes (Fig 4A). However, the LdSIR2RP2-GFP fusion protein was
found to localise in the mitochondria as seen by the co-localization of the LdSIR2RP2−GFP
with the fluorescence associated to the MitoTracker Red CMXRos that reveals the position of
mitochondria within the promastigotes (Fig 4B). Gene deletion studies of LdSIR2RP2 In order to determine the essentiality and biological function(s) of the mitochondrial sirtuin in
L. donovani, we replaced both the alleles of LdSIR2RP2 gene using classical gene replacement
experiments. Two successive rounds of gene targeting with two dominant selectable markers were under-
taken to inactivate the LdSIR2RP2 gene completely. This was done by the generation of inactiva-
tion cassettes having hygromycin phosphotransferase (HYG) or neomycin phosphotransferase
(NEO) as selection markers along with 50UTR and 30UTR of LdSIR2RP2 gene, as described in the
Methods. Linear replacement cassette fragments were transfected into wild-type L. donovani pro-
mastigotes leading to the generation of heterozygous parasites in which one copy of LdSIR2RP2
gene was replaced with either the hygromycin or neomycin drug resistance gene. Subsequently, another round of gene targeting was done to generate LdSIR2RP2 homozy-
gous null mutant parasites. PCR analysis was done to confirm the recombination events (Fig
5A and 5B). Genomic DNA from the WT parasites was used as a positive control (Fig 5C). Bands corresponding only to the LdSIR2RP2 gene were obtained indicating the specificity of
HYG and NEO primers. The genotype of the heterozygous (LdSIR2RP2/Hyg and LdSIR2RP2/
Neo) and homozygous (ΔLdSIR2RP2) null mutant parasites was further confirmed by South-
ern blot analysis (Fig 5D). y
g
The ‘add-back’ mutant line (ΔLdSIR2RP2/+) was prepared by transfecting pSP72a-zeo-a-
LdSIR2RP2 episome into homozygous null mutant parasites (ΔLdSIR2RP2). PCR analysis was
done to confirm the presence of the episomal plasmid (Fig 5A and 5E). A band of ~ 360 bp
was obtained upon amplification with ZeoF and ZeoR primers, which correspond to Sh ble
gene, that confers Zeocin antibiotic resistance [38], thus confirming the presence of episomal
pSP72a-zeo-a-LdSIR2RP2 in the ‘add-back’ line (ΔLdSIR2RP2/+). LdSIR2RP2 is localized to the mitochondria In-silico analysis performed with PSORTII software indicated a higher probability for a mito-
chondrial localisation of LdSIR2RP2. The subcellular localisation of LdSIR2RP2 was confirmed
using confocal microscopy to evaluate the localisation of C-terminal GFP-tagged full-length
LdSIR2RP2. L. donovani parasites transfected with the LdSIR2RP2-GFP fusion constructs and 12 / 25 PLOS Neglected Tropical Diseases | https://doi.org/10.1371/journal.pntd.0005590
May 11, 2017 LdSIR2RP2 is essential for growth as well as infectivity The growth rate of each of the cell line was determined in order to verify phenotypic alter-
ations in the wild-type and genetically manipulated parasites. This was done by counting pro-
mastigote cells using a hemocytometer for a period of 12 days. The absence of LdSIR2RP2 in
the promastigotes led to a significant decrease in the growth rate of the parasite as compared
to the WT cells (Fig 6A). The doubling time of the ΔLdSIR2RP2 (~ 32 h) was ~ 2.5 fold higher
than the WT cells (~ 12 h). This restrictive growth phenotype was rescued in the promastigotes
expressing episomal LdSIR2RP2 (ΔLdSIR2RP2/+) with doubling time of ~ 14 h. Next, we assessed whether the genetic deficiency of LdSIR2RP2 in L. donovani has an impact
on its ability to infect host cells by performing infectivity assays with stationary-phase promasti-
gotes in the J774A.1 murine macrophage. Microscopic observation of murine macrophages
stained with Giemsa showed that, while WT parasites were capable of ~ 50% infection in murine
macrophages, ΔLdSIR2RP2 parasites had reduced infectivity with only ~ 25% of the macro-
phages infected (Fig 6B). The add-back line (ΔLdSIR2RP2/+) showed infection comparable to 13 / 25 PLOS Neglected Tropical Diseases | https://doi.org/10.1371/journal.pntd.0005590
May 11, 2017 SIR2 related protein 2 of Leishmania donovani Fig 4. Cellular distribution of LdSIR2RP2. (A) Confocal microscopy of wild-type L. donovani transfected with pSP72-α-neo-α-GFP. (i) Large
field vision at 60x (ii) Magnifications of the boxed areas in the top images. Panel 1, wild-type L. donovani stained with MitoTracker Red; Panel
2, wild-type L. donovani expressing GFP protein; Panel 3, wild-type L. donovani stained with DAPI; Panel 4, Merged micrograph; Panel 5,
Phase contrast micrograph. (B) Confocal microscopy of wild-type L. donovani transfected with pSP72-α-neo-α-LdSIR2RP2-GFP. (i) Large field
vision at 60x (ii) Magnifications of the boxed areas in the top images. Panel 1, wild-type L. donovani stained with MitoTracker Red; Panel 2,
wild-type L. donovani expressing LdSIR2RP2-GFP fusion protein; Panel 3, wild-type L. donovani stained with DAPI; Panel 4, Merged
micrograph; Panel 5, Phase contrast micrograph. n, nuclear DNA; k, kinetoplast DNA. Scale bar represents 10 μm. https://doi.org/10.1371/journal.pntd.0005590.g004 Fig 4. Cellular distribution of LdSIR2RP2. (A) Confocal microscopy of wild-type L. donovani transfected with pSP72-α-neo-α-GFP. (i) Large
field vision at 60x (ii) Magnifications of the boxed areas in the top images. Panel 1, wild-type L. donovani stained with MitoTracker Red; Panel
2, wild-type L. PLOS Neglected Tropical Diseases | https://doi.org/10.1371/journal.pntd.0005590
May 11, 2017 LdSIR2RP2 is essential for growth as well as infectivity donovani expressing GFP protein; Panel 3, wild-type L. donovani stained with DAPI; Panel 4, Merged micrograph; Panel 5,
Phase contrast micrograph. (B) Confocal microscopy of wild-type L. donovani transfected with pSP72-α-neo-α-LdSIR2RP2-GFP. (i) Large field
vision at 60x (ii) Magnifications of the boxed areas in the top images. Panel 1, wild-type L. donovani stained with MitoTracker Red; Panel 2,
wild-type L. donovani expressing LdSIR2RP2-GFP fusion protein; Panel 3, wild-type L. donovani stained with DAPI; Panel 4, Merged
micrograph; Panel 5, Phase contrast micrograph. n, nuclear DNA; k, kinetoplast DNA. Scale bar represents 10 μm. https://doi.org/10.1371/journal.pntd.0005590.g004 https://doi.org/10.1371/journal.pntd.0005590.g004 https://doi.org/10.1371/journal.pntd.0005590.g004 that of WT (Fig 6B). Upon comparing the parasite numbers of the WT, ΔLdSIR2RP2, and
ΔLdSIR2RP2/+ in the murine macrophages, it was observed that ΔLdSIR2RP2 mutant parasites
had ~ 50% reduction in the number of amastigotes per macrophages relative to the wild-type
parasites 48 h p.i (Fig 6C). In the ‘add-back’ line (ΔLdSIR2RP2/+) the parasite numbers were
restored to the levels comparable to that of WT. Thus, these observations imply that loss of
LdSIR2RP2 affects the ability of the parasite to infect and sustain robust infection within murine
macrophages. This could be partially attributed to the slow growth phenotype of the null
mutants compared to their wild-type counterparts. Since the ΔLdSIR2RP2 parasites exhibited a restrictive growth phenotype, the possibility of
any cell cycle-related defects, which could have lowered the growth rate of mutant parasites,
was examined. For this, log phase cells of WT, ΔLdSIR2RP2, and ΔLdSIR2RP2/+ parasites were
taken and examined for their DNA content. The null mutants showed an increased G2/M pop-
ulation of cells (~ 40.33%) (p = 0.0001) compared to the WT (23.68%) and ‘add-back lines 14 / 25 PLOS Neglected Tropical Diseases | https://doi.org/10.1371/journal.pntd.0005590
May 11, 2017 SIR2 related protein 2 of Leishmania donovani Fig 5. Generation of deletion mutants of LdSIR2RP2 in L. donovani. (A) Restriction map of the LdSIR2RP2 locus and pSP72α-zeo-α-LdSIR2RP2
along with the location of the primers used for confirmation by PCR analysis. BsrGI restriction enzyme was used to analyse the recombination event. Primer 4 was designed as a forward primer to match the upstream region of LdSIR2RP2 gene, and primers 8, 3 and 6 were designed internally to
LdSIR2RP2, HYG, and NEO coding regions, respectively. LdSIR2RP2 is essential for growth as well as infectivity (C) Genomic DNA from WT parasites was used as a template for PCR analysis with
HYG, NEO and LdSIR2RP2 (WT) gene specific primers. M indicates the DNA molecular size marker in kb. (D) Southern blot analysis of wild-type Bob
(WT), heterozygotes LdSIR2RP2 /NEO, LdSIR2RP2/HYG and ΔLdSIR2RP2 null mutant parasites. An equal amount of genomic DNA was digested with
BsrGI, resolved on a 0.6% agarose gel and hybridised with a LdSIR2RP2 gene specific probe. Molecular weight marker is indicated to the right of the blot. (E) PCR analysis of ΔLdSIR2RP2 parasites transfected with pSP72α-zeo-α-LdSIR2RP2 (ΔLdSIR2RP2/+). The specificity of recombination event was
checked with HYG, NEO, LdSIR2RP2 (WT) and Sh ble (ZeoR) gene specific primers. M indicates the DNA molecular size marker. (17.79%) (Fig 6D). It is possible that the G2/M block in the null mutants may be indirectly
responsible for the slow growth kinetics of ΔLdSIR2RP2 parasites. LdSIR2RP2 is essential for growth as well as infectivity Primer 2 was designed as a reverse primer to match the downstream region of LdSIR2RP2
gene, and primers 7, 1 and 5 were designed as forward primers, internal to LdSIR2RP2, HYG, and NEO coding regions, respectively. Primers ZeoF and
ZeoR were designed as forward and reverse primers for Sh ble gene that codes for Zeocin antibiotic resistance. (B) Genomic DNA from ΔLdSIR2RP2
parasites was used as a template for PCR analysis. The specificity of recombination event was checked with HYG, NEO and LdSIR2RP2 (WT) gene
specific primers. M indicates the DNA molecular size marker in kb. (C) Genomic DNA from WT parasites was used as a template for PCR analysis with
HYG, NEO and LdSIR2RP2 (WT) gene specific primers. M indicates the DNA molecular size marker in kb. (D) Southern blot analysis of wild-type Bob
(WT), heterozygotes LdSIR2RP2 /NEO, LdSIR2RP2/HYG and ΔLdSIR2RP2 null mutant parasites. An equal amount of genomic DNA was digested with
BsrGI, resolved on a 0.6% agarose gel and hybridised with a LdSIR2RP2 gene specific probe. Molecular weight marker is indicated to the right of the blot. (E) PCR analysis of ΔLdSIR2RP2 parasites transfected with pSP72α-zeo-α-LdSIR2RP2 (ΔLdSIR2RP2/+). The specificity of recombination event was
checked with HYG, NEO, LdSIR2RP2 (WT) and Sh ble (ZeoR) gene specific primers. M indicates the DNA molecular size marker. https://doi org/10 1371/journal pntd 0005590 g005 Fig 5. Generation of deletion mutants of LdSIR2RP2 in L. donovani. (A) Restriction map of the LdSIR2RP2 locus and pSP72α-zeo-α-LdSIR2RP2
along with the location of the primers used for confirmation by PCR analysis. BsrGI restriction enzyme was used to analyse the recombination event. Primer 4 was designed as a forward primer to match the upstream region of LdSIR2RP2 gene, and primers 8, 3 and 6 were designed internally to
LdSIR2RP2, HYG, and NEO coding regions, respectively. Primer 2 was designed as a reverse primer to match the downstream region of LdSIR2RP2
gene, and primers 7, 1 and 5 were designed as forward primers, internal to LdSIR2RP2, HYG, and NEO coding regions, respectively. Primers ZeoF and
ZeoR were designed as forward and reverse primers for Sh ble gene that codes for Zeocin antibiotic resistance. (B) Genomic DNA from ΔLdSIR2RP2
parasites was used as a template for PCR analysis. The specificity of recombination event was checked with HYG, NEO and LdSIR2RP2 (WT) gene
specific primers. M indicates the DNA molecular size marker in kb. LdSIR2RP2 is required for mitochondrial function Since LdSIR2RP2 had mitochondrial localization, the effect of LdSIR2RP2 deletion on the func-
tioning of the parasite mitochondria was investigated. Mitochondria utilise oxidation of substrates
to produce membrane potential in the form of a proton gradient across the inner mitochondrial
membrane. Maintenance of this potential is necessary for the generation of ATP by mitochondria
[39]. Hence, the effect of LdSIR2RP2 gene deletion on the mitochondrial transmembrane poten-
tial (ΔCm) was evaluated by using MitoTracker Red. MitoTracker Red is known to accumulate
in energised mitochondria [40]. Relative to wild-type control, ΔLdSIR2RP2 mutants showed
decreased MitoTracker red fluorescence by ~ 48.33% thus indicating reduced ΔCm (Fig 7A). ΔLdSIR2RP2mutants expressing episomal LdSIR2RP2 showed ΔCm comparable to that of the PLOS Neglected Tropical Diseases | https://doi.org/10.1371/journal.pntd.0005590
May 11, 2017 15 / 25 SIR2 related protein 2 of Leishmania donovani Fig 6. Phenotypic characterisation of ΔLdSIR2RP2 null mutant parasites. (A) Growth curve analysis of L. donovani wild-type (WT), LdSIR2RP2
homozygous (ΔLdSIR2RP2) null mutants and LdSIR2RP2 ‘add-back’ mutant (ΔLdSIR2RP2/+). The experiment was repeated thrice independently in
triplicate. The representative data from one experiment is shown. (B) and (C): Comparison of infectivity (B) and parasite load (C) of L. donovani wild-
type (WT), null mutant (ΔLdSIR2RP2) and ‘add-back’ mutant (ΔLdSIR2RP2/+) parasites in J774A.1 murine macrophage cell line. Murine macrophage
cell line J774A.1 was infected with stationary-phase promastigotes at an MOI of 20:1. Cells were stained with Giemsa after 48 h and amastigotes were
enumerated visually. The results represent mean ± SD with n = 3. * p < 0.05; **, p < 0.01, *** p < 0.005 and ns indicates not significant (p > 0.05). (D)
Bar graph depicting the percentage of cells in the G2/M phase of WT, ΔLdSIR2RP2 and ΔLdSIR2RP2/+. The data represents mean ± SD with n = 3. *
p < 0.05; **, p < 0.01, *** p < 0.005 and ns indicates not significant (p > 0.05). Fig 6. Phenotypic characterisation of ΔLdSIR2RP2 null mutant parasites. (A) Growth curve analysis of L. donovani wild-type (WT), LdSIR2RP2
homozygous (ΔLdSIR2RP2) null mutants and LdSIR2RP2 ‘add-back’ mutant (ΔLdSIR2RP2/+). The experiment was repeated thrice independently in
triplicate. The representative data from one experiment is shown. (B) and (C): Comparison of infectivity (B) and parasite load (C) of L. donovani wild-
type (WT), null mutant (ΔLdSIR2RP2) and ‘add-back’ mutant (ΔLdSIR2RP2/+) parasites in J774A.1 murine macrophage cell line. PLOS Neglected Tropical Diseases | https://doi.org/10.1371/journal.pntd.0005590
May 11, 2017 LdSIR2RP2 is required for mitochondrial function Murine macrophage
cell line J774A.1 was infected with stationary-phase promastigotes at an MOI of 20:1. Cells were stained with Giemsa after 48 h and amastigotes were
enumerated visually. The results represent mean ± SD with n = 3. * p < 0.05; **, p < 0.01, *** p < 0.005 and ns indicates not significant (p > 0.05). (D)
Bar graph depicting the percentage of cells in the G2/M phase of WT, ΔLdSIR2RP2 and ΔLdSIR2RP2/+. The data represents mean ± SD with n = 3. *
p < 0.05; **, p < 0.01, *** p < 0.005 and ns indicates not significant (p > 0.05). https://doi.org/10.1371/journal.pntd.0005590.g006 WT control. WT cells treated with 50 μM CCCP were used as positive controls. These cells
showed a decrease in the mean fluorescence intensity values (32.67% of reduction) as compared
to the untreated WT cells. The alterations in the mitochondrial membrane potential are known to affect the levels
of cellular ATP. Since the null mutants exhibited reduced ΔCm, intracellular levels of ATP
were determined. ΔLdSIR2RP2 cells exhibited a significant decline (47%) in cellular ATP
levels when compared to the wild-type controls (Fig 7B). The ATP levels of rescue mutants
(ΔLdSIR2RP2/+) cell were restored to that of the WT cells. The present data indicates the
effect of LdSIR2RP2 deletion on mitochondrial membrane potential and hence, ATP syn-
thesis in the cell. Furthermore, we delineated whether this decline in total cellular ATP levels was due to a
decrease in the mitochondrial or glycolytic ATP synthesis. For this, WT and ΔLdSIR2RP2 par-
asites were treated either with oligomycin, a classical inhibitor of F0-F1-ATP synthase or
2-deoxyD-glucose (2DG), a competing substrate for hexokinase. It was observed that the WT
cells treated with 2DG, exhibited higher ATP levels (85%) in comparison to ΔLdSIR2RP2
(20%) when treated with 2DG (Fig 7C). This implied that the decline in total cellular ATP pool 16 / 25 PLOS Neglected Tropical Diseases | https://doi.org/10.1371/journal.pntd.0005590
May 11, 2017 SIR2 related protein 2 of Leishmania donovani Fig 7. Deletion of LdSIR2RP2 affects mitochondrial functioning in parasites. (A)(i) The mitochondrial membrane potential of WT, ΔLdSIR2RP2,
and ΔLdSIR2RP2/+ cells was monitored using the fluorescent probe MitoTracker Red. Cells were incubated with 100 nM of MitoTracker Red, washed,
fixed and analysed by BD Biosciences FACS Calibur system using BD Biosciences CellQuest software. Uncoupling agent CCCP (50 μM) was used as a
positive control. LdSIR2RP2 is required for mitochondrial function * p < 0.05; **, p < 0.01, *** p < 0.005 and ns indicates
not significant (p > 0.05). Fig 7. Deletion of LdSIR2RP2 affects mitochondrial functioning in parasites. (A)(i) The mitochondrial membrane potential of WT, ΔLdSIR2RP2,
and ΔLdSIR2RP2/+ cells was monitored using the fluorescent probe MitoTracker Red. Cells were incubated with 100 nM of MitoTracker Red, washed,
fixed and analysed by BD Biosciences FACS Calibur system using BD Biosciences CellQuest software. Uncoupling agent CCCP (50 μM) was used as a
positive control. Percent Mean Fluorescence Intensity (MFI), relative to WT control was plotted. (ii) Histograms showing an overlay of mitochondrial
membrane potential of WT, WT treated with CCCP, ΔLdSIR2RP2, and ΔLdSIR2RP2/+ cells. The x-axis shows the log FL-2 channel fluorescence
intensity and the y-axis indicate the cell number. (B) Total cellular ATP levels of WT, ΔLdSIR2RP2, and ΔLdSIR2RP2/+ cells were determined using
ATP/ADP determination kit (BioVision). ATP levels were calculated relative to 100% of the control WT. (C) WT and ΔLdSIR2RP2 cells were incubated
with either M199 medium plus 10 μM Oligomycin to inhibit mitochondrial ATP generation or M199 medium plus 5 mM 2-deoxyD-glucose (2DG), to inhibit
glycolytic ATP generation. Afterwards, cells were washed, and ATP levels were determined using ATP/ADP determination kit (BioVision). ATP levels
were calculated relative to 100% of the control WT. All the results represent mean ± SD with n = 3. * p < 0.05; **, p < 0.01, *** p < 0.005 and ns indicates
not significant (p > 0.05). https://doi.org/10.1371/journal.pntd.0005590.g007 https://doi.org/10.1371/journal.pntd.0005590.g007 in ΔLdSIR2RP2 was due to a reduction in the mitochondrial generated ATP. On the contrary,
when the cells were treated with 10 μM of oligomycin, WT parasites had only 5% ATP levels as
opposed to 22.5% ATP levels in ΔLdSIR2RP2 parasites (Fig 7C), suggesting that the glycolytic
ATP generation is higher in ΔLdSIR2RP2 parasites than the WT parasites. This is in accor-
dance with the observation that when the ability of parasites to generate ATP through mito-
chondrial oxidative phosphorylation is compromised, parasites increase their glycolytic
metabolism to maintain the energy supply [41]. LdSIR2RP2 is required for mitochondrial function Percent Mean Fluorescence Intensity (MFI), relative to WT control was plotted. (ii) Histograms showing an overlay of mitochondrial
membrane potential of WT, WT treated with CCCP, ΔLdSIR2RP2, and ΔLdSIR2RP2/+ cells. The x-axis shows the log FL-2 channel fluorescence
intensity and the y-axis indicate the cell number. (B) Total cellular ATP levels of WT, ΔLdSIR2RP2, and ΔLdSIR2RP2/+ cells were determined using
ATP/ADP determination kit (BioVision). ATP levels were calculated relative to 100% of the control WT. (C) WT and ΔLdSIR2RP2 cells were incubated
with either M199 medium plus 10 μM Oligomycin to inhibit mitochondrial ATP generation or M199 medium plus 5 mM 2-deoxyD-glucose (2DG), to inhibit
glycolytic ATP generation. Afterwards, cells were washed, and ATP levels were determined using ATP/ADP determination kit (BioVision). ATP levels
were calculated relative to 100% of the control WT. All the results represent mean ± SD with n = 3. * p < 0.05; **, p < 0.01, *** p < 0.005 and ns indicates
not significant (p > 0.05). ts mitochondrial functioning in parasites. (A)(i) The mitochondrial membrane potential of WT, ΔLdSIR2RP2, g 7. Deletion of LdSIR2RP2 affects mitochondrial functioning in parasites. (A)(i) The mitochondrial membrane Fig 7. Deletion of LdSIR2RP2 affects mitochondrial functioning in parasites. (A)(i) The mitochondrial membrane potential of WT, ΔLdSIR2RP2,
and ΔLdSIR2RP2/+ cells was monitored using the fluorescent probe MitoTracker Red. Cells were incubated with 100 nM of MitoTracker Red, washed,
fixed and analysed by BD Biosciences FACS Calibur system using BD Biosciences CellQuest software. Uncoupling agent CCCP (50 μM) was used as a
positive control. Percent Mean Fluorescence Intensity (MFI), relative to WT control was plotted. (ii) Histograms showing an overlay of mitochondrial
membrane potential of WT, WT treated with CCCP, ΔLdSIR2RP2, and ΔLdSIR2RP2/+ cells. The x-axis shows the log FL-2 channel fluorescence
intensity and the y-axis indicate the cell number. (B) Total cellular ATP levels of WT, ΔLdSIR2RP2, and ΔLdSIR2RP2/+ cells were determined using
ATP/ADP determination kit (BioVision). ATP levels were calculated relative to 100% of the control WT. (C) WT and ΔLdSIR2RP2 cells were incubated
with either M199 medium plus 10 μM Oligomycin to inhibit mitochondrial ATP generation or M199 medium plus 5 mM 2-deoxyD-glucose (2DG), to inhibit
glycolytic ATP generation. Afterwards, cells were washed, and ATP levels were determined using ATP/ADP determination kit (BioVision). ATP levels
were calculated relative to 100% of the control WT. All the results represent mean ± SD with n = 3. SIR2 related protein 2 of Leishmania donovani (Ex-527) and cambinol, on the growth of WT, ΔLdSIR2RP2, and ΔLdSIR2RP2/+ parasites, was
determined. (Ex-527) and cambinol, on the growth of WT, ΔLdSIR2RP2, and ΔLdSIR2RP2/+ parasites, was
determined. Sirtinol is a naphthol derivative compound and is a known inhibitor of NAD+-dependent
deacetylase activity of sirtuins. Treatment of WT, ΔLdSIR2RP2, and ΔLdSIR2RP2/+ with sirti-
nol inhibited the growth of both the promastigote and the amastigote stage of the parasites in a
concentration-dependent manner. The IC50 of sirtinol for the promastigotes of WT was not
significantly different from that of ΔLdSIR2RP2 (p = 0.08). Similar observation was made in
the case of intracellular amastigotes (p = 0.09) (Fig 8A, Table 3). Nicotinamide (NAM) is a known physiological inhibitor of SIR2 deacetylase activity of
HsSIRT1 and ScSIR2 [43]. Concentrations of NAM as high as 10 mM did not inhibit the
growth of the promastigote stage of WT, ΔLdSIR2RP2 and ΔLdSIR2RP2/+ parasites (Table 3). This could be attributed to the presence of thick lipophosphoglycan layer around the promasti-
gotes that could interfere with the entry of the inhibitor inside the promastigotes. However,
NAM inhibited the proliferation of intracellular amastigotes of WT, ΔLdSIR2RP2, and
ΔLdSIR2RP2/+. The IC50 value of NAM was significantly lower in the case of ΔLdSIR2RP2
than that of WT parasites. The IC50 value of NAM in the rescue mutants (ΔLdSIR2RP2/+) was
comparable to that of the WT parasites (Fig 8B). NAM was also tested for its cytotoxicity to
J774A.1 and was found to inhibit its growth at an IC50 value of 29.21 ± 5.3 mM, which was ~3
fold higher than that observed for the intracellular amastigotes (Table 3). EX-527 is an indole-based sirtuin inhibitor. WT, ΔLdSIR2RP2, and ΔLdSIR2RP2/+, pro-
mastigotes were susceptible to EX-527 inhibition. The IC50 value of EX-527 for null mutants
was ~2 fold lower than that of the WT parasites. The IC50 of EX-527 for ΔLdSIR2RP2/+ was
comparable to that of the WT parasites (Fig 8C, Table 3). EX-527 was found to be a more effec-
tive inhibitor in the case of intracellular amastigotes of all parasitic cell lines (Table 3). The
IC50 value of EX-527 for ΔLdSIR2RP2 was ~2 fold lower than that for the WT intracellular
amastigotes. EX-527 inhibited J774A.1 mouse macrophages at higher concentrations (IC50:
157 ± 4.4 μM) when compared to that observed in the case of the intracellular amastigotes. Cambinol, a potent human SIRT1 and SIRT2 inhibitor [44], inhibited the growth of WT,
ΔLdSIR2RP2, and ΔLdSIR2RP2/+ promastigotes (Fig 8D, Table 3). The IC50 value of cambinol
for ΔLdSIR2RP2 was ~4 fold lower than that of the WT promastigotes. Cambinol inhibited the
growth of WT, ΔLdSIR2RP2 and ΔLdSIR2RP2/+ intracellular amastigotes at the IC50 value of
1.7 ± 0.02 μM, 0.8 ± 0.1 μM and 2.4 ± 0.2 μM, respectively, (Fig 8D, Table 3). The compound
was found to be cytotoxic to the J774A.1 mouse macrophages (IC50: 188 ± 11.6 μM). Our data indicates increased susceptibility of null mutants to all the tested compounds
except sirtinol. This would indicate the possible pleiotropic effect of these inhibitors on the
other two parasitic sirtuins, LdSIR2RP1, and LdSIR2RP3. Earlier studies have also shown that
NAM inhibits recombinant LiSIR2RP1 (15). Furthermore, overexpression of either of these
sirtuins, TcSIR2RP1 and TcSIR2RP3 in T. cruzi protected the parasite from the effect of cambi-
nol and NAM (17). Effect of sirtuin inhibitors on the growth of WT, ΔLdSIR2RP2, and
ΔLdSIR2RP2/+ parasites The structural and biochemical differences between the human and the parasitic sirtuins have led
to exploring sirtuins as potential anti-parasitic therapeutic targets [42]. The effect of sirtuin inhib-
itors: sirtinol, nicotinamide (NAM), 6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide 17 / 25 17 / 25 PLOS Neglected Tropical Diseases | https://doi.org/10.1371/journal.pntd.0005590
May 11, 2017 Effect of sirtuin inhibitors on the activity of recombinant LdSIR2RP2 Concentration as low as 2.5 μM of cambinol inhibited
the ADP-ribosyltransferase activity of LdSIR2RP2. low as 50 μM (Fig 9A). Out of all the four inhibitors, cambinol was the most effective in inhib-
iting the activity of LdSIR2RP2 (Fig 9B). Concentration as low as 2.5 μM of cambinol inhibited
the ADP-ribosyltransferase activity of LdSIR2RP2. Values are expressed as mean ± S.D of experiments performed in triplicates. IC50 values were calculated using 0.1 μM- 200 μM of sirtinol, 0.5 mM– 20 mM
of nicotinamide, 0.01 μM- 400 μM of EX-527 and 0.01 μM- 300 μM of cambinol. The cytotoxicity of the inhibitors to the murine macrophages was determined
using the same concentrations of the inhibitors.
*i di
t
i
ifi
t P
l
d t WT N D
t d t
i
d Effect of sirtuin inhibitors on the activity of recombinant LdSIR2RP2 Assay for the ADP-ribosyltransferase activity of LdSIR2RP2 was further performed in the pres-
ence of sirtinol, NAM, EX-527 and cambinol to test their specificity and investigate the ability
to inhibit the activity of recombinant LdSIR2RP2. A dose-dependent inhibition of the ADP-
ribosyltransferase activity of LdSIR2RP2 was assessed. ADP-ribosylation assays were per-
formed as mentioned in “materials and methods” section with varying concentrations of the
inhibitors. Sirtinol did not result in inhibition of ribosylation of histones at concentrations as
high as 40 μM (Fig 9A). NAM and EX-527 inhibited LdSIR2RP2 activity at concentrations as PLOS Neglected Tropical Diseases | https://doi.org/10.1371/journal.pntd.0005590
May 11, 2017 18 / 25 SIR2 related protein 2 of Leishmania donovani Fig 8. Effect of sirtuin inhibitors on the growth of WT, ΔLdSIR2RP2, and ΔLdSIR2RP2/+ parasites. The leishmanicidal effect of sirtuin inhibitors was
tested on the promastigotes and the intracellular amastigotes of WT, ΔLdSIR2RP2 and ΔLdSIR2RP2/+ strains. The mean IC50 values were calculated for
each inhibitor and are plotted as bar graphs. A, B, C and D: Effect of A, Sirtinol; B, Nicotinamide (NAM); C, Ex-527; and D, Cambinol; on the growth of
promastigotes and intracellular amastigotes. The bar graphs represent mean ± SD with n = 3. * p < 0.05; **, p < 0.01, *** p < 0.005 and ns indicates not
significant (p > 0.05). Fig 8. Effect of sirtuin inhibitors on the growth of WT, ΔLdSIR2RP2, and ΔLdSIR2RP2/+ parasites. The leishmanicidal effect of sirtuin inhibitors was
tested on the promastigotes and the intracellular amastigotes of WT, ΔLdSIR2RP2 and ΔLdSIR2RP2/+ strains. The mean IC50 values were calculated for
each inhibitor and are plotted as bar graphs. A, B, C and D: Effect of A, Sirtinol; B, Nicotinamide (NAM); C, Ex-527; and D, Cambinol; on the growth of
promastigotes and intracellular amastigotes. The bar graphs represent mean ± SD with n = 3. * p < 0.05; **, p < 0.01, *** p < 0.005 and ns indicates not
significant (p > 0.05). https://doi.org/10.1371/journal.pntd.0005590.g008 low as 50 μM (Fig 9A). Out of all the four inhibitors, cambinol was the most effective in inhib-
iting the activity of LdSIR2RP2 (Fig 9B). Concentration as low as 2.5 μM of cambinol inhibited
the ADP-ribosyltransferase activity of LdSIR2RP2. low as 50 μM (Fig 9A). Out of all the four inhibitors, cambinol was the most effective in inhib-
iting the activity of LdSIR2RP2 (Fig 9B). g
*indicates non-significant P value compared to WT. N.D: not determined. https://doi.org/10.1371/journal.pntd.0005590.t003 alue compared to WT. N.D: not determined. *indicates non-significant P value compared to WT. N.D: not determined. SIR2 related protein 2 of Leishmania donovani in the regulation of several functions in eukaryotic cells, including transcriptional repression,
recombination, cell cycle, cellular responses to DNA-damaging agents, microtubule organisa-
tion and longevity. Sirtuins, being central to proper cellular functioning and proliferation,
have been studied in protozoan parasites like Plasmodium and Trypanosomes. The parasitic sir-
tuins have been found to have both conserved and unique functions, which regulate a broad
diversity of cellular processes, thus making them suitable drug targets for anti- parasitic ther-
apy [16]. Three SIR2 homologs were identified in the in silico analysis of Leishmania genome;
SIR2RP1, SIR2RP2, and SIR2RP3. SIR2RP1, a cytosolic sirtuin, is known to be essential for the
infectivity and survival of the parasite and hence an attractive drug target for antileishmanial
chemotherapy [21]. The other two mitochondrial sirtuins of Leishmania have not yet been
characterised. In the present study, we describe the functional role of LdSIR2RP2 in L. donovani. Phyloge-
netic and sequence analysis reveals that LdSIR2RP2 is closer to the human homolog HsSIRT4,
which belongs to class II of the sirtuin family. In the present study, we demonstrate that
LdSIR2RP2 like HsSIRT4 has only NAD+-dependent ADP-ribosyltransferase activity. The pro-
tein was found to localise in the mitochondria of the parasite, similar to HsSIRT4. Although
LdSIR2RP2 was not found to be essential for the survival of the parasite, the null mutants
exhibited delayed growth rate and attenuated infectivity. Cell cycle analysis of the null mutant
parasites revealed a G2/M block which could be a possible reason for the growth defects
observed in the mutant lines. Since, LdSIR2RP2 is a mitochondrial protein, analysis of the
mitochondrial parameters revealed compromised mitochondria with lowered ΔCm and
hence, lesser mitochondrial ATP content of the cell. These phenotypic alterations in the
ΔLdSIR2RP2 parasites were relieved by ectopic expression of LdSIR2RP2 in ΔLdSIR2RP2/+. Thus, deletion of the mitochondrial sirtuin LdSIR2RP2 in Leishmania affects mitochondrial
functioning leading to lowered ATP content of the cells and hence delayed growth kinetics. HsSIRT4 is a mitochondrial ADP-ribosyltransferase that inhibits mitochondrial glutamate
dehydrogenase 1 activity [37]. Overexpression of SIRT4 in mammalian cells causes an increase
in mitochondrial respiration, glycolysis, and glucose oxidation, but with no change in growth
rate or in steady-state ATP concentrations [45]. Mitochondria, the energy provider of the cell,
depends on the universal coenzyme (NAD+) or its phosphorylated counterpart NADP, to
maintain homoeostasis within the cell [46]. Discussion The silent information regulator 2 (SIR2)-like family of NAD+ dependent protein deacetylases
are highly conserved proteins from archaea to higher eukaryotes. These proteins are involved Table 3. Effect of sirtuin inhibitors on the growth of WT, ΔLdSIR2RP2, ΔLdSIR2RP2/+ parasites and murine macrophages J774A.1 cell lines. Inhibitor
Promastigotes
Amastigotes
Murine Macrophages
Wild Type
ΔLdSIR2RP2
ΔLdSIR2RP2/+
Wild Type
ΔLdSIR2RP2
ΔLdSIR2RP2/+
J774A.1
Sirtinol (μM)
10.8 ± 2.5
7.6 ±1.4*
13.9 ± 3.3
5.0 ± 1.5
3.2 ± 0.13*
8.7 ± 3.16
21.6 ± 3.2
NAM (mM)
N.D. N.D. N.D. 8.8 ± 4.4
5.1 ± 2.2
9.2 ± 3.2*
29.2 ± 5.3
EX-527 (μM)
157 ± 3.1
80 ± 2.5
101 ± 2.9
5.7 ± 3.4
2.8 ± 0.2
7.9 ± 2.6
157 ± 4.4
Cambinol (μM)
19.7 ± 4.1
5.1 ± 6.8
15.5 ± 6.4
1.7 ± 0.02
0.7 ± 0.1
2.4 ± 0.2*
188 ± 11.6 f WT, ΔLdSIR2RP2, ΔLdSIR2RP2/+ parasites and murine macrophages J774A.1 cell lines. Table 3. Effect of sirtuin inhibitors on the growth of WT, ΔLdSIR2RP2, ΔLdSIR2RP2/+ parasites and mur Table 3. Effect of sirtuin inhibitors on the growth of WT, ΔLdSIR2RP2, ΔLdSIR2 PLOS Neglected Tropical Diseases | https://doi.org/10.1371/journal.pntd.0005590
May 11, 2017 19 / 25 In addition to participation in redox reactions,
NAD+ acts as a versatile cellular signalling molecule through the generation of ADP-ribose
(ADPR) [47]. The mitochondrial sirtuins SIRT3, SIRT4, and SIRT5 utilise mitochondrial
NAD+ pool to regulate the activity of their targets implicated in the regulation of both glycoly-
sis and cellular oxidative stress [46, 48] via deacetylation and mono- ADP-ribosylation. Mono-ADP-ribosylation of proteins is a phylogenetically ancient, reversible, and cova-
lent posttranslational modification of proteins. Both mono- and poly-ADP-ribosylation of
nuclear and cytosolic proteins are known to regulate various physiological processes, such
as mitosis, cellular differentiation, and proliferation, telomere dynamics, and ageing pro-
grammed necrosis and apoptosis via signalling, chromatin modification and remodelling of
chromatin structure [49]. Apart from this, both, poly and mono-ADP-ribosylation modifi-
cation of mitochondrial proteins is reported to have an effect on the metabolism of this
organelle as well [47]. Recently, the role of mitochondrial sirtuins in parasites has been reported. It was observed
that the overexpression of mitochondrial SIR2RP3 in T. cruzi led to an increase in parasite pro-
liferation, movement, and differentiation. This was due to increased deacetylation of mito-
chondrial targets within the parasite [17]. Similarly, in our study, we observed a slow growth
pattern and reduced infectivity upon deletion of the mitochondrial sirtuin, LdSIR2RP2. The 20 / 25 PLOS Neglected Tropical Diseases | https://doi.org/10.1371/journal.pntd.0005590
May 11, 2017 SIR2 related protein 2 of Leishmania donovani Fig 9. Effect of sirtuin inhibitors (A) Sirtinol, (B) Nicotinamide, (C) EX-527 and (D) cambinol, on the NAD+ dependent ADP-ribosyltransferase activity of
recombinant LdSIR2RP2. ADP-ribosyltransferase assays for rLdSIR2RP2 were set up as mentioned in “materials and methods” section in the presence
of indicated concentrations of each inhibitor. The top panel in each indicates the PhosphorImager visualized image and the bottom panel shows the
segment of the Coomassie-stained gel corresponding to calf thymus histones shown as loading control. htt
//d i
/10 1371/j
l
td 0005590 009 Fig 9. Effect of sirtuin inhibitors (A) Sirtinol, (B) Nicotinamide, (C) EX-527 and (D) cambinol, on the NAD+ dependent ADP-ribosyltransferase activity of
recombinant LdSIR2RP2. ADP-ribosyltransferase assays for rLdSIR2RP2 were set up as mentioned in “materials and methods” section in the presence
of indicated concentrations of each inhibitor. The top panel in each indicates the PhosphorImager visualized image and the bottom panel shows the
segment of the Coomassie-stained gel corresponding to calf thymus histones shown as loading control. Acknowledgments We are grateful to Dr Amit Sharma, International Centre for Genetic Engineering and Bio-
technology, New Delhi, India, for kindly providing pETM-41 expression vector and TEV
protease. SIR2 related protein 2 of Leishmania donovani ADP-ribosyltransferase (15). Furthermore, overexpression of either of these sirtuins, TcSIR2RP1
and TcSIR2RP3 protected the parasite from the effect of cambinol and NAM (17). ADP-ribosyltransferase (15). Furthermore, overexpression of either of these sirtuins, TcSIR2RP1
and TcSIR2RP3 protected the parasite from the effect of cambinol and NAM (17). With increasing drug resistance, toxicity and the cost of the available chemotherapeutic
agents for the treatment of Leishmaniasis, the development of new leishmanicidal drugs and the
search for new targets is required. The peculiar differences between the parasite and mammalian
mitochondria, as well as unique characteristics of parasite mitochondria, makes mitochondrial
proteins as good drug targets. Several new studies involving inhibitors like; Benzophenone-
derived bisphosphonium salts [54], artemisinin [55], chalcones, including licochalcone A [56],
Tafenoquine [57], luteolin and quercetin [58]; indicate the essential role of mitochondrial biol-
ogy in the survival of the parasite. Here, we have attempted to characterise a mitochondrial sirtuin, which is involved in main-
taining the mitochondrial homoeostasis. LdSIR2RP2 deletion resulted in reduced growth and
virulence of the parasite. Known sirtuin inhibitors were able to inhibit the growth of the para-
site. The inhibitors also showed inhibitory effect on the enzymatic activity of recombinant
LdSIR2RP2. However, the pleiotropic effect of these inhibitors on the other two parasitic sir-
tuins, LdSIR2RP1, and LdSIR2RP3, cannot be ruled out. Thus, developing a specific inhibitor
to target LdSIR2RP2 alone or in combination with the available chemotherapeutic agents
could provide a better rationale for the treatment of Leishmaniasis. Conceptualization: RMa. Data curation: RMa NM RMu. Data curation: RMa NM RMu. Formal analysis: NM RMa RMu. Funding acquisition: RMa RMu. Funding acquisition: RMa RMu. Methodology: RMa NM RMu. Project administration: RMa RMu. Project administration: RMa RMu. Software: RMa NM RMu. Supervision: RMa RMu. Supervision: RMa RMu. Validation: RMa RMu NM. Visualization: RMa NM RMu. Writing – original draft: NM RMa. Writing – review & editing: RMa NM RMu. https://doi.org/10.1371/journal.pntd.0005590.g009 null mutants also exhibited compromised mitochondrial functioning and delayed growth
kinetics. In kinetoplasts, actively respiring mitochondria are required for survival of both, the
promastigotes and amastigotes [50, 51]. Thus, it can be speculated that deletion of LdSIR2RP2
might have affected the activity of some of the main mitochondrial proteins which could be
regulated by ADP-ribosylation, thereby affecting mitochondrial functioning in the null
mutants. However, further studies are necessary to identify the specific substrates targeted by
LdSIR2RP2, in order to gain insight into the role of this mitochondrial sirtuin in parasite
biology. Sirtuins are known to be involved in regulation of vital cellular processes. Hence, they have
been proposed as promising targets for the development of anti-parasitic drugs [42, 52, 53]. Here, the efficacy of known sirtuin inhibitors; sirtinol, nicotinamide, Ex-527, and cambinol,
on the growth of the WT and genetically manipulated parasites was determined. Except for sirti-
nol, all the other three inhibitors were more effective in inhibiting the growth of ΔLdSIR2RP2
parasites than the WT. This increased susceptibility of the inhibitors was relieved by ectopic
expression of LdSIR2RP2. The concentrations tested had no significant effect on the host cells,
indicating a selectivity of these inhibitors for the parasitic sirtuins than for the host sirtuins. While
these inhibitors show specificity towards the ADP-ribosyltransferase activity of LdSIR2RP2, we
cannot rule out the off-target effect of these inhibitors on the other two sirtuins. Earlier studies
have demonstrated that NAM inhibits recombinant LiSIR2RP1 which is both a deacetylase and 21 / 25 PLOS Neglected Tropical Diseases | https://doi.org/10.1371/journal.pntd.0005590
May 11, 2017 Author Contributions Conceptualization: RMa. SIR2 related protein 2 of Leishmania donovani 2. Strahl BD, Allis CD. The language of covalent histone modifications. Nature. 2000; 403(6765):41–5. Epub 2000/01/19. https://doi.org/10.1038/47412 PMID: 10638745 3. Norvell A, McMahon SB. Cell biology. Rise of the rival. Science. 2010; 327(5968):964–5. Epub 2010/
02/20. https://doi.org/10.1126/science.1187159 PMID: 20167774 4. Sinclair DA, Guarente L. Extrachromosomal rDNA circles—a cause of aging in yeast. Cell. 1997; 91
(7):1033–42. Epub 1998/01/15. PMID: 9428525 5. Kaeberlein M, McVey M, Guarente L. The SIR2/3/4 complex and SIR2 alone promote longevity in Sac-
charomyces cerevisiae by two different mechanisms. Genes Dev. 1999; 13(19):2570–80. Epub 1999/
10/16. PMID: 10521401 6. Haigis MC, Sinclair DA. Mammalian sirtuins: biological insights and disease relevance. Annu Rev
Pathol. 2010; 5:253–95. Epub 2010/01/19. https://doi.org/10.1146/annurev.pathol.4.110807.092250
PMID: 20078221 7. Frye RA. Phylogenetic classification of prokaryotic and eukaryotic Sir2-like proteins. Biochem Biophys
Res Commun. 2000; 273(2):793–8. Epub 2000/06/30. https://doi.org/10.1006/bbrc.2000.3000 PMID:
10873683 8. Tanny JC, Moazed D. Coupling of histone deacetylation to NAD breakdown by the yeast silencing pro-
tein Sir2: Evidence for acetyl transfer from substrate to an NAD breakdown product. Proc Natl Acad Sci
U S A. 2001; 98(2):415–20. Epub 2001/01/03. https://doi.org/10.1073/pnas.98.2.415 PMID: 11134535 9. Sauve AA, Celic I, Avalos J, Deng H, Boeke JD, Schramm VL. Chemistry of gene silencing: the mecha-
nism of NAD+-dependent deacetylation reactions. Biochemistry (Mosc). 2001; 40(51):15456–63. Epub
2001/12/19. 10. Sauve AA, Wolberger C, Schramm VL, Boeke JD. The biochemistry of sirtuins. Annu Rev Biochem. 2006; 75:435–65. Epub 2006/06/08. https://doi.org/10.1146/annurev.biochem.74.082803.133500
PMID: 16756498 11. Tanny JC, Dowd GJ, Huang J, Hilz H, Moazed D. An enzymatic activity in the yeast Sir2 protein that is
essential for gene silencing. Cell. 1999; 99(7):735–45. Epub 2000/01/05. PMID: 10619427 12. Du J, Zhou Y, Su X, Yu JJ, Khan S, Jiang H, et al. Sirt5 is a NAD-dependent protein lysine demalonylase
and desuccinylase. Science. 2011; 334(6057):806–9. Epub 2011/11/15. https://doi.org/10.1126/
science.1207861 PMID: 22076378 13. Garcia-Salcedo JA, Gijon P, Nolan DP, Tebabi P, Pays E. A chromosomal SIR2 homologue with both
histone NAD-dependent ADP-ribosyltransferase and deacetylase activities is involved in DNA repair in
Trypanosoma brucei. EMBO J. 2003; 22(21):5851–62. Epub 2003/11/01. https://doi.org/10.1093/
emboj/cdg553 PMID: 14592982 14. Liszt G, Ford E, Kurtev M, Guarente L. Mouse Sir2 homolog SIRT6 is a nuclear ADP-ribosyltransferase. J Biol Chem. 2005; 280(22):21313–20. Epub 2005/03/30. https://doi.org/10.1074/jbc.M413296200
PMID: 15795229 15. Tavares J, Ouaissi A, Santarem N, Sereno D, Vergnes B, Sampaio P, et al. References 1. Norris KL, Lee JY, Yao TP. Acetylation goes global: the emergence of acetylation biology. Sci Signal. 2009; 2(97):pe76. Epub 2009/11/19. https://doi.org/10.1126/scisignal.297pe76 PMID: 19920250 22 / 25 PLOS Neglected Tropical Diseases | https://doi.org/10.1371/journal.pntd.0005590
May 11, 2017 SIR2 related protein 2 of Leishmania donovani 22. Vergnes B, Sereno D, Madjidian-Sereno N, Lemesre JL, Ouaissi A. Cytoplasmic SIR2 homologue over-
expression promotes survival of Leishmania parasites by preventing programmed cell death. Gene. 2002; 296(1–2):139–50. Epub 2002/10/18. PMID: 12383511 23. Aslett M, Aurrecoechea C, Berriman M, Brestelli J, Brunk BP, Carrington M, et al. TriTrypDB: a func-
tional genomic resource for the Trypanosomatidae. Nucleic Acids Res. 2010; 38(Database issue):
D457–62. Epub 2009/10/22. https://doi.org/10.1093/nar/gkp851 PMID: 19843604 24. UniProt: a hub for protein information. Nucleic Acids Res. 2015; 43(Database issue):D204–12. Epub
2014/10/29. https://doi.org/10.1093/nar/gku989 PMID: 25348405 25. Horton P, Park KJ, Obayashi T, Fujita N, Harada H, Adams-Collier CJ, et al. WoLF PSORT: protein
localization predictor. Nucleic Acids Res. 2007; 35(Web Server issue):W585–7. Epub 2007/05/23. https://doi.org/10.1093/nar/gkm259 PMID: 17517783 26. Edgar RC. MUSCLE: multiple sequence alignment with high accuracy and high throughput. Nucleic
Acids Res. 2004; 32(5):1792–7. Epub 2004/03/23. https://doi.org/10.1093/nar/gkh340 PMID:
15034147 27. Thompson JD, Higgins DG, Gibson TJ. CLUSTAL W: improving the sensitivity of progressive multiple
sequence alignment through sequence weighting, position-specific gap penalties and weight matrix
choice. Nucleic Acids Res. 1994; 22(22):4673–80. Epub 1994/11/11. PMID: 7984417 28. Kapler GM, Coburn CM, Beverley SM. Stable transfection of the human parasite Leishmania major
delineates a 30-kilobase region sufficient for extrachromosomal replication and expression. Mol Cell
Biol. 1990; 10(3):1084–94. Epub 1990/03/01. PMID: 2304458 29. Darveau A, Pelletier A., and Perreault J. PCR-mediated synthesis of chimeric molecules. Methods in
Neurosciences 1995;(26):77–85. 30. Sambrook J. FEF, Maniatis T. Molecular Cloning: Cold Spring Harbour Laboratory, New York; 1989. 31. Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and
cytotoxicity assays. J Immunol Methods. 1983; 65(1–2):55–63. Epub 1983/12/16. PMID: 6606682 32. Vassilopoulos A, Fritz KS, Petersen DR, Gius D. The human sirtuin family: evolutionary divergences
and functions. Hum Genomics. 2011; 5(5):485–96. Epub 2011/08/03. https://doi.org/10.1186/1479-
7364-5-5-485 PMID: 21807603 33. Cockell MM, Perrod S, Gasser SM. Analysis of Sir2p domains required for rDNA and telomeric silencing
in Saccharomyces cerevisiae. Genetics. 2000; 154(3):1069–83. Epub 2000/04/11. PMID: 10757754 34. Rack JG, Morra R, Barkauskaite E, Kraehenbuehl R, Ariza A, Qu Y, et al. Identification of a Class of
Protein ADP-Ribosylating Sirtuins in Microbial Pathogens. Mol Cell. 2015; 59(2):309–20. Epub 2015/
07/15. https://doi.org/10.1016/j.molcel.2015.06.013 PMID: 26166706 35. Frye RA. Characterization of five human cDNAs with homology to the yeast SIR2 gene: Sir2-like pro-
teins (sirtuins) metabolize NAD and may have protein ADP-ribosyltransferase activity. Biochem Biophys
Res Commun. 1999; 260(1):273–9. The Leishmania infantum
cytosolic SIR2-related protein 1 (LiSIR2RP1) is an NAD+ -dependent deacetylase and ADP-ribosyl-
transferase. Biochem J. 2008; 415(3):377–86. Epub 2008/07/05. https://doi.org/10.1042/BJ20080666
PMID: 18598238 16. Religa AA, Waters AP. Sirtuins of parasitic protozoa: in search of function(s). Mol Biochem Parasitol. 2012; 185(2):71–88. Epub 2012/08/22. https://doi.org/10.1016/j.molbiopara.2012.08.003 PMID:
22906508 17. Ritagliati C, Alonso VL, Manarin R, Cribb P, Serra EC. Overexpression of cytoplasmic TcSIR2RP1 and
mitochondrial TcSIR2RP3 impacts on Trypanosoma cruzi growth and cell invasion. PLoS Negl Trop
Dis. 2015; 9(4):e0003725. Epub 2015/04/16. https://doi.org/10.1371/journal.pntd.0003725 PMID:
25875650 18. Moretti NS, da Silva Augusto L, Clemente TM, Antunes RP, Yoshida N, Torrecilhas AC, et al. Charac-
terization of Trypanosoma cruzi Sirtuins as Possible Drug Targets for Chagas Disease. Antimicrob
Agents Chemother. 2015; 59(8):4669–79. Epub 2015/05/28. https://doi.org/10.1128/AAC.04694-14
PMID: 26014945 19. Chang KP. Cellular and molecular mechanisms of intracellular symbiosis in leishmaniasis. Int Rev Cytol
Suppl. 1983; 14:267–305. Epub 1983/01/01. PMID: 6341275 20. Dostalova A, Volf P. Leishmania development in sand flies: parasite-vector interactions overview. Para-
sit Vectors. 2012; 5:276. Epub 2012/12/05. https://doi.org/10.1186/1756-3305-5-276 PMID: 23206339 21. Vergnes B, Sereno D, Tavares J, Cordeiro-da-Silva A, Vanhille L, Madjidian-Sereno N, et al. Targeted
disruption of cytosolic SIR2 deacetylase discloses its essential role in Leishmania survival and prolifera-
tion. Gene. 2005; 363:85–96. Epub 2005/10/21. https://doi.org/10.1016/j.gene.2005.06.047 PMID:
16236469 23 / 25 PLOS Neglected Tropical Diseases | https://doi.org/10.1371/journal.pntd.0005590
May 11, 2017 SIR2 related protein 2 of Leishmania donovani Chem. 2002; 277(47):45099–107. Epub 2002/09/26. https://doi.org/10.1074/jbc.M205670200 PMID:
12297502 44. Heltweg B, Gatbonton T, Schuler AD, Posakony J, Li H, Goehle S, et al. Antitumor activity of a small-
molecule inhibitor of human silent information regulator 2 enzymes. Cancer Res. 2006; 66(8):4368–77. Epub 2006/04/19. https://doi.org/10.1158/0008-5472.CAN-05-3617 PMID: 16618762 45. de Moura MB, Uppala R, Zhang Y, Van Houten B, Goetzman ES. Overexpression of mitochondrial sir-
tuins alters glycolysis and mitochondrial function in HEK293 cells. PLoS One. 2014; 9(8):e106028. Epub 2014/08/29. https://doi.org/10.1371/journal.pone.0106028 PMID: 25165814 46. Koch-Nolte F, Fischer S, Haag F, Ziegler M. Compartmentation of NAD+-dependent signalling. FEBS
Lett. 2011; 585(11):1651–6. Epub 2011/03/30. https://doi.org/10.1016/j.febslet.2011.03.045 PMID:
21443875 47. Dolle C, Rack JG, Ziegler M. NAD and ADP-ribose metabolism in mitochondria. The FEBS journal. 2013; 280(15):3530–41. Epub 2013/04/27. https://doi.org/10.1111/febs.12304 PMID: 23617329 48. George J, Ahmad N. Mitochondrial Sirtuins in Cancer: Emerging Roles and Therapeutic Potential. Can-
cer Res. 2016; 76(9):2500–6. Epub 2016/05/20. https://doi.org/10.1158/0008-5472.CAN-15-2733
PMID: 27197261 49. Hassa PO, Haenni SS, Elser M, Hottiger MO. Nuclear ADP-ribosylation reactions in mammalian cells:
where are we today and where are we going? Microbiol Mol Biol Rev. 2006; 70(3):789–829. Epub 2006/
09/09. https://doi.org/10.1128/MMBR.00040-05 PMID: 16959969 50. Hart DT, Vickerman K, Coombs GH. Respiration of Leishmania mexicana amastigotes and promasti-
gotes. Mol Biochem Parasitol. 1981; 4(1–2):39–51. Epub 1981/11/01. PMID: 7322186 51. Van Hellemond JJ, Tielens AG. Inhibition of the respiratory chain results in a reversible metabolic arrest
in Leishmania promastigotes. Mol Biochem Parasitol. 1997; 85(1):135–8. Epub 1997/03/01. PMID:
9108556 52. Sacconnay L, Angleviel M, Randazzo GM, Queiroz MM, Queiroz EF, Wolfender JL, et al. Computa-
tional studies on sirtuins from Trypanosoma cruzi: structures, conformations and interactions with phy-
tochemicals. PLoS Negl Trop Dis. 2014; 8(2):e2689. Epub 2014/02/20. https://doi.org/10.1371/journal. pntd.0002689 PMID: 24551254 53. Kaur S, Shivange AV, Roy N. Structural analysis of trypanosomal sirtuin: an insight for selective drug
design. Mol Divers. 2010; 14(1):169–78. Epub 2009/05/01. https://doi.org/10.1007/s11030-009-9147-7
PMID: 19404761 54. Luque-Ortega JR, Reuther P, Rivas L, Dardonville C. New benzophenone-derived bisphosphonium
salts as leishmanicidal leads targeting mitochondria through inhibition of respiratory complex II. J Med
Chem. 2010; 53(4):1788–98. Epub 2010/02/05. https://doi.org/10.1021/jm901677h PMID: 20128602 55. Sen R, Bandyopadhyay S, Dutta A, Mandal G, Ganguly S, Saha P, et al. Artemisinin triggers induction
of cell-cycle arrest and apoptosis in Leishmania donovani promastigotes. J Med Microbiol. 2007; 56(Pt
9):1213–8. Epub 2007/09/01. https://doi.org/10.1099/jmm.0.47364-0 PMID: 17761485 56. Chen M, Zhai L, Christensen SB, Theander TG, Kharazmi A. PLOS Neglected Tropical Diseases | https://doi.org/10.1371/journal.pntd.0005590
May 11, 2017 Epub 1999/06/25. https://doi.org/10.1006/bbrc.1999.0897 PMID:
10381378 36. Peng C, Lu Z, Xie Z, Cheng Z, Chen Y, Tan M, et al. The first identification of lysine malonylation sub-
strates and its regulatory enzyme. Molecular & cellular proteomics: MCP. 2011; 10(12):M111 012658. Epub 2011/09/13. 37. Haigis MC, Mostoslavsky R, Haigis KM, Fahie K, Christodoulou DC, Murphy AJ, et al. SIRT4 inhibits
glutamate dehydrogenase and opposes the effects of calorie restriction in pancreatic beta cells. Cell. 2006; 126(5):941–54. Epub 2006/09/09. https://doi.org/10.1016/j.cell.2006.06.057 PMID: 16959573 38. Bennett RP, Cox CA, Hoeffler JP. Fusion of green fluorescent protein with the Zeocin-resistance marker
allows visual screening and drug selection of transfected eukaryotic cells. Biotechniques. 1998; 24
(3):478–82. Epub 1998/04/04. PMID: 9526661 39. Chen LB. Mitochondrial membrane potential in living cells. Annu Rev Cell Biol. 1988; 4:155–81. Epub
1988/01/01. https://doi.org/10.1146/annurev.cb.04.110188.001103 PMID: 3058159 40. Kholmukhamedov A, Schwartz JM, Lemasters JJ. Isolated mitochondria infusion mitigates ischemia-
reperfusion injury of the liver in rats: mitotracker probes and mitochondrial membrane potential. Shock. 2013; 39(6):543. Epub 2013/05/18. 41. Manzano JI, Carvalho L, Perez-Victoria JM, Castanys S, Gamarro F. Increased glycolytic ATP synthe-
sis is associated with tafenoquine resistance in Leishmania major. Antimicrob Agents Chemother. 2011; 55(3):1045–52. Epub 2011/01/05. PubMed Central PMCID: PMC3067095. https://doi.org/10. 1128/AAC.01545-10 PMID: 21199921 42. Zheng W. Sirtuins as emerging anti-parasitic targets. Eur J Med Chem. 2013; 59:132–40. Epub 2012/
12/12. https://doi.org/10.1016/j.ejmech.2012.11.014 PMID: 23220641 43. Bitterman KJ, Anderson RM, Cohen HY, Latorre-Esteves M, Sinclair DA. Inhibition of silencing and
accelerated aging by nicotinamide, a putative negative regulator of yeast sir2 and human SIRT1. J Biol PLOS Neglected Tropical Diseases | https://doi.org/10.1371/journal.pntd.0005590
May 11, 2017 24 / 25 58.
Mittra B, Saha A, Chowdhury AR, Pal C, Mandal S, Mukhopadhyay S, et al. Luteolin, an abundant die-
tary component is a potent anti-leishmanial agent that acts by inducing topoisomerase II-mediated
kinetoplast DNA cleavage leading to apoptosis. Mol Med. 2000; 6(6):527–41. Epub 2000/09/06. PMID:
10972088 Inhibition of fumarate reductase in Leish-
mania major and L. donovani by chalcones. Antimicrob Agents Chemother. 2001; 45(7):2023–9. Epub
2001/06/16. https://doi.org/10.1128/AAC.45.7.2023-2029.2001 PMID: 11408218 57. Carvalho L, Luque-Ortega JR, Manzano JI, Castanys S, Rivas L, Gamarro F. Tafenoquine, an antiplas-
modial 8-aminoquinoline, targets leishmania respiratory complex III and induces apoptosis. Antimicrob
Agents Chemother. 2010; 54(12):5344–51. Epub 2010/09/15. https://doi.org/10.1128/AAC.00790-10
PMID: 20837758 58. Mittra B, Saha A, Chowdhury AR, Pal C, Mandal S, Mukhopadhyay S, et al. Luteolin, an abundant die-
tary component is a potent anti-leishmanial agent that acts by inducing topoisomerase II-mediated
kinetoplast DNA cleavage leading to apoptosis. Mol Med. 2000; 6(6):527–41. Epub 2000/09/06. PMID:
10972088 25 / 25
|
https://openalex.org/W2590848542
|
https://europepmc.org/articles/pmc5322348?pdf=render
|
English
| null |
Epitope Addition and Ablation via Manipulation of a Dengue Virus Serotype 1 Infectious Clone
|
MSphere
| 2,017
|
cc-by
| 7,821
|
Epitope Addition and Ablation via
Manipulation of a Dengue Virus
Serotype 1 Infectious Clone Emily N. Gallichotte,a Vineet D. Menachery,b Boyd L. Yount, Jr.,b
Douglas G. Widman,b Kenneth H. Dinnon III,a Steven Hartman,b
Aravinda M. de Silva,a Ralph S. Barica,b Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill,
North Carolina, USAa; Department of Epidemiology, Gillings School of Global Public Health, University of North
Carolina, Chapel Hill, North Carolina, USAb ABSTRACT Despite the clinical relevance, dengue virus (DENV) research has been
hampered by the absence of robust reverse genetic systems to manipulate the viral
serotypes for propagation and generation of mutant viruses. In this article, we de-
scribe application of an infectious clone system for DENV serotype 1 (DENV1). Similar
to previous clones in both flaviviruses and coronaviruses, the approach constructs a
panel of contiguous cDNAs that span the DENV genome and can be systematically
and directionally assembled to produce viable, full-length viruses. Comparison of the
virus derived from the infectious clone with the original viral isolate reveals identical
sequence, comparable endpoint titers, and similar focus staining. Both focus-forming
assays and percent infection by flow cytometry revealed overlapping replication lev-
els in two different cell types. Moreover, serotype-specific monoclonal antibodies
(MAbs) bound similarly to infectious clone and the natural isolate. Using the clone,
we were able to insert a DENV4 type-specific epitope recognized by primate MAb
5H2 into envelope (E) protein domain I (EDI) of DENV1 and recover a viable chimeric
recombinant virus. The recombinant DENV1 virus was recognized and neutralized by
the DENV4 type-specific 5H2 MAb. The introduction of the 5H2 epitope ablated two
epitopes on DENV1 EDI recognized by human MAbs (1F4 and 14C10) that strongly
neutralize DENV1. Together, the work demonstrates the utility of the infectious clone
and provides a resource to rapidly manipulate the DENV1 serotype for generation of
recombinant and mutant viruses. Received 20 December 2016 Accepted 2
February 2017 Published 22 February 2017
Citation Gallichotte EN, Menachery VD, Yount
BL, Jr, Widman DG, Dinnon KH, III, Hartman S,
de Silva AM, Baric RS. 2017. Epitope addition
and ablation via manipulation of a dengue
virus serotype 1 infectious clone. mSphere
2:e00380-16. https://doi.org/10.1128/
mSphere.00380-16. E.N.G. and V.D.M. contributed equally to this
work. IMPORTANCE Dengue viruses (DENVs) are significant mosquito-transmitted patho-
gens that cause widespread infection and can lead to severe infection and complica-
tions. January/February 2017
Volume 2
Issue 1
e00380-16 msphere.asm.org
1 RESEARCH ARTICLE RESEARCH ARTICLE
Molecular Biology and Physiology
crossm RESEARCH ARTICLE
Molecular Biology and Physiology
crossm Received 20 December 2016 Accepted 2
February 2017 Published 22 February 2017
Citation Gallichotte EN, Menachery VD, Yount
BL, Jr, Widman DG, Dinnon KH, III, Hartman S,
de Silva AM, Baric RS. 2017. Epitope addition
and ablation via manipulation of a dengue
virus serotype 1 infectious clone. mSphere
2:e00380-16. https://doi.org/10.1128/
mSphere.00380-16. Epitope Addition and Ablation via
Manipulation of a Dengue Virus
Serotype 1 Infectious Clone Here we further characterize a novel and robust DENV serotype 1 (DENV1) in-
fectious clone system that can be used to support basic and applied research. We
demonstrate how the system can be used to probe the antigenic relationships be-
tween strains by creating viable recombinant viruses that display or lack major anti-
body epitopes. The DENV1 clone system and recombinant viruses can be used to
analyze existing vaccine immune responses and inform second-generation bivalent
vaccine designs. KEYWORDS antibody, dengue, epitope, infectious clone D
engue viruses (DENVs) represent a significant threat to human health and the
global economy, causing widespread and frequent epidemics (1, 2). Transmitted
by female mosquitos, the DENV family has four known serotypes that are genetically
and antigenically related. Infection with any one DENV serotype typically produces
asymptomatic or mild disease but induces long-term immunity against that serotype
(3). However, subsequent exposure to a different serotype may result in more-severe D msphere.asm.org
1 January/February 2017
Volume 2
Issue 1
e00380-16 Gallichotte et al. disease characterized by dengue hemorrhagic fever or dengue shock syndrome often
attributed to antibody-dependent enhancement (2, 4). Overall, potential adverse dis-
ease outcomes due to immune cross-reactivity complicates efforts to produce effective
vaccines against the DENV family (5). To study aspects of infection and pathogenesis, a number of reverse genetic
systems have been generated for members of the flavivirus family, which includes
DENV (6, 7). These approaches have provided powerful tools to manipulate the viral
genome and have given insight into viral protein function, virulence determinants, viral
immune evasion, host specificity, and other virus-host interactions (6). Reverse genetic
systems have also facilitated improved research methodologies with the development
of reporter assays as well as the means to produce virus-like particles and live atten-
uated vaccines (8, 9). In addition, infectious clones provide the opportunity to explore
a clonal population of DENV with relatively few mutations versus the “mutant spec-
trum” typically observed in laboratory passaged stocks (10–12). Together, these tools
have been critical in building a foundation to understanding DENV disease and
pathogenesis. Yet, while current systems have been useful, several obstacles remain for DENV
reverse genetic systems (6). Flavivirus clones are difficult to maintain in bacteria and
often result in sequence rearrangements or mutations that reduce expression of toxic
elements from the viral genome. Epitope Addition and Ablation via
Manipulation of a Dengue Virus
Serotype 1 Infectious Clone Several approaches have been employed to improve
propagation, including use of low-copy-number plasmid (6), insertion into bacterial or
yeast artificial chromosomes (13–15), disruption of promoter regions in viral cDNA (16),
as well as microbe-free propagation approaches (17, 18). However, these methods
often diminish yields, produce changes in viral sequence, or require significant extra-
neous effort that reduces the overall utility of the approaches. Importantly, many of
these reverse genetic systems report significant attenuation relative to their control
wild-type (WT) viruses despite similar consensus sequencing (6). Overall, these results
highlight the obstacles for using reverse genetic systems to study DENV disease and
pathogenesis. In this study, we extend our characterization of a dengue virus serotype 1 (DENV1)
infectious clone (19) by comparing and contrasting the growth and antigenic proper-
ties of molecularly cloned recombinant and wild-type DENV1. Importantly, DENV1
derived from the clone maintained equivalent replication and complete antibody
binding fidelity with the wild-type strain. Using the tetrapartite DENV1 molecular clone,
we then inserted a known DENV4 envelope protein domain I (EDI) neutralization
epitope and demonstrated efficient gain of neutralization function. However, by intro-
ducing these changes, we simultaneously ablated two known DENV1 antibody binding
sites and disrupted their binding and neutralization. Together, the results illustrate the
utility of this newly developed infectious clone as a platform to study DENV immunity
by exchanging functional complex epitopes between DENV strains, simultaneously
gaining new neutralization properties to other strains while ablating the primary
neutralizing antigenic sites of DENV1. January/February 2017
Volume 2
Issue 1
e00380-16 RESULTS Design and construction of DENV1 full-length infectious clone. The recombinant
DENV1 infectious clone (rDENV1ic) was synthesized as a panel of four continuous cDNA
segments that span the entire genome (Fig. 1A) (19). Based on sequence from a
laboratory strain of DENV1 West Pac ‘74, each segment is flanked by class IIS restriction
endonuclease sites that cleave palindromic sequences into asymmetric 3-nucleotide
overhangs. These overhangs permit directional assembly of the cleaved fragments to
generate full-length viral cDNA. With the exception of an ablated restriction site (see
Materials and Methods), the sequence directly reconstitutes the wild-type (WT) labo-
ratory strain. The ligated cDNA fragments are then used as a template to produce
full-length viral RNA, which is electroporated into C6/36 mosquito cells. To demonstrate
transfection efficiencies of full-length transcripts, the results of the infectious center
assay indicate low, but stable infection (0.4%) (Fig. 1B). After several days, cell culture msphere.asm.org
2 January/February 2017
Volume 2
Issue 1
e00380-16 FIG 1 DENV1 infectious clone design, characterization, and growth. (A) Structure of DENV1 viral genome and division into the four
subgenomic fragments designated plasmids A (nucleotides [nt] 1 to 2052), B (nt 2053 to 4215), C (nt 4216 to 8563), and D (nt 8564 to
10736). (B) Full-length viral RNA was electroporated into C6/36 cells, and the cells were diluted and added to confluent C6/36 cells. After
incubation, infected cells were stained to determine the initial percentage of electroporated cells capable of producing infectious virus. (C) Peak infectious titers of virus stocks were determined on C6/36 cells. The titers of virus were determined in focus-forming units (FFU)
per milliliter. (D) Immunostaining of DENV1 and rDENV1ic foci in C6/36 cells. (E) C6/36 cells were inoculated at an MOI of 0.01, and every
24 h, supernatant containing virus was harvested, and the titers of the virus were subsequently determined on C6/36 cells. (F and G) C6/36
cells were inoculated at an MOI of 0.01 (F) or 1% of DC-SIGN-expressing U937 (U937DC-SIGN) cells were infected (G), and every 12 h,
the cells were harvested and stained for intracellular viral antigen, and the total percentage of infected cells was calculated. DENV1 Epitope Addition and Disruption DENV1 Epitope Addition and Disruption FIG 1 DENV1 infectious clone design, characterization, and growth. January/February 2017
Volume 2
Issue 1
e00380-16 RESULTS (A) Structure of DENV1 viral genome and division into the four
subgenomic fragments designated plasmids A (nucleotides [nt] 1 to 2052), B (nt 2053 to 4215), C (nt 4216 to 8563), and D (nt 8564 to
10736). (B) Full-length viral RNA was electroporated into C6/36 cells, and the cells were diluted and added to confluent C6/36 cells. After
incubation, infected cells were stained to determine the initial percentage of electroporated cells capable of producing infectious virus. (C) Peak infectious titers of virus stocks were determined on C6/36 cells. The titers of virus were determined in focus-forming units (FFU)
per milliliter. (D) Immunostaining of DENV1 and rDENV1ic foci in C6/36 cells. (E) C6/36 cells were inoculated at an MOI of 0.01, and every
24 h, supernatant containing virus was harvested, and the titers of the virus were subsequently determined on C6/36 cells. (F and G) C6/36
cells were inoculated at an MOI of 0.01 (F) or 1% of DC-SIGN-expressing U937 (U937DC-SIGN) cells were infected (G), and every 12 h,
the cells were harvested and stained for intracellular viral antigen, and the total percentage of infected cells was calculated. supernatant containing progeny rDENV1ic virions is harvested and passaged once on
C6/36 cells to generate working virus stocks. RNA isolated from infected cells was verified relative to the parental wild-type strain
using genome length analysis and finding no differences in the consensus amino acid
sequences. Similarly, endpoint titers from C6/36 cells (Fig. 1C) found no notable
difference between the viruses derived from wild-type DENV1 and rDENV1ic in regard
to replication. In C6/36 cells, both wild-type DENV1- and infectious-clone-derived virus
maintain similar sized foci following infection (Fig. 1D). Together, the results indicate
that no replication deficit nor focus formation deficit was observed between the
wild-type and infectious clone virus. Replication kinetics of rDENV1ic. Some of the previously described reverse ge-
netic systems for DENVs have been hampered by replication attenuation relative to the
wild-type strain despite identical consensus sequences (6). To determine whether
rDENV1ic is attenuated relative to the wild-type virus, growth curves were completed
in C6/36 mosquito cells over a 7-day time course (Fig. 1E). The data indicate that msphere.asm.org
3 January/February 2017
Volume 2
Issue 1
e00380-16 Gallichotte et al. FIG 2 rDENV1ic is bound only by DENV1 serotype-specific antibodies. RESULTS DENV1 and rDENV1ic were analyzed for their ability to
bind DENV1 serotype-specific antibodies 1F4, 14C10, and 1C19.2 (A to C) or DENV2, DENV3, and DENV4 serotype-specific
antibodies 2D22, 5J7, and 5H2 (D to F) in an ELISA virus capture assay. Binding measured by the optical density at 405 nm (OD
405) is shown on the y axes, and the log concentration (in nanograms per microliter) is shown on the x axes. FIG 2 rDENV1ic is bound only by DENV1 serotype-specific antibodies. DENV1 and rDENV1ic were analyzed for their ability to
bind DENV1 serotype-specific antibodies 1F4, 14C10, and 1C19.2 (A to C) or DENV2, DENV3, and DENV4 serotype-specific
antibodies 2D22, 5J7, and 5H2 (D to F) in an ELISA virus capture assay. Binding measured by the optical density at 405 nm (OD
405) is shown on the y axes, and the log concentration (in nanograms per microliter) is shown on the x axes. wild-type DENV1 and rDENV1ic replicate equivalently, peaking in focus-forming units
5 days after infection (Fig. 1E). Percent infection of C6/36 cells also demonstrated no
significant difference between the wild-type and infectious clone with nearly 100%
infection observed 4 days after infection (Fig. 1F). We next examined replication in the
human monocyte-derived U937 cell line stably expressing DC-SIGN (dendritic cell-
specific intercellular adhesion molecule 3-grabbing nonintegrin), a known DENV at-
tachment factor (Fig. 1G); similar to the C6/36 mosquito cell line, we observed no
difference in the replication of the wild-type DENV1 and rDENV1ic in DC-SIGN-
expressing U937 (U937DC-SIGN) cells. These results demonstrate no detectable at-
tenuation of the rDENV1ic clone relative to the wild-type strain in either insect or
human cells. Display of antibody epitopes on rDENV1ic. Antibody binding and neutralization
are critical issues in DENV pathogenesis in humans; as such, the infectious clone and
parental WT strain must display the same surface architecture and epitopes. To
compare the display of antibody epitopes, enzyme-linked immunosorbent assays
(ELISAs) were performed using a panel of DENV1-specific monoclonal antibodies
(MAbs) against rDENV1ic and the parental wild-type strain (see Table S1 in the sup-
plemental material). MAb 1F4, derived from a DENV1-infected patient (20), binds in the
envelope domain I (EDI) region and extends into the EDI and domain II (EDII) hinge
region (21); ELISA with MAb 1F4 produced strong and equivalent binding to both the
wild-type and infectious clone (Fig. 2A). January/February 2017
Volume 2
Issue 1
e00380-16 RESULTS Similarly, the EDI, EDIII, and EDI/II hinge region
is the epitope for MAb 14C10, which also bound similarly between the wild-type DENV1
and rDENV1ic (Fig. 2B). Finally, MAb 1C19.2, an EDIII antibody, also bound similarly to
both wild-type DENV1 and rDENV1ic (Fig. 2C). Together, the results indicate that
rDENV1ic displays the same antibody epitopes as the wild-type control virus. We also tested the binding of DENV serotype 2, 3, and 4 monoclonal antibodies
(Table S1) to rDENV1ic. Beginning with a DENV2-specific antibody, MAb 2D22 (22),
failed to bind to either wild-type DENV1 or rDENV1ic (Fig. 2D). Similarly, MAb 5J7 (23)
also fails to bind to rDENV1ic or wild-type strain while efficiently binding DENV3
(Fig. 2E). Finally, MAb 5H2, an EDI antibody specific to DENV4, showed no binding to
either DENV1 iteration (Fig. 2F). Together, combined with DENV1 monoclonal data, the
results indicate that rDENV1ic has the same surface architecture and epitopes as the
wild-type strain. msphere.asm.org
4 DENV1 Epitope Addition and Disruption FIG 3 rDENV1ic maintains fidelity to DENV1 serotype-specific antibodies in a focus reduction neutralization test. Neutralization of
DENV1 and rDENV1ic by monoclonal antibodies was measured in a C6/36 focus reduction neutralization test (FRNT) using DENV1
serotype-specific MAbs 1F4, 14C10, and 1C19.2 (A to C) and DENV2, DENV3, and DENV4 serotype-specific MAbs 2D22, 5J7, and 5H2
(D to F). FIG 3 rDENV1ic maintains fidelity to DENV1 serotype-specific antibodies in a focus reduction neutralization test. Neutralization of
DENV1 and rDENV1ic by monoclonal antibodies was measured in a C6/36 focus reduction neutralization test (FRNT) using DENV1
serotype-specific MAbs 1F4, 14C10, and 1C19.2 (A to C) and DENV2, DENV3, and DENV4 serotype-specific MAbs 2D22, 5J7, and 5H2
(D to F). Antibody neutralization of rDENV1ic. While observing equivalent antibody bind-
ing between rDENV1ic and wild-type virus by ELISA, neutralization is an even more
sensitive functional assay to compare viruses. Small changes in binding conformation
may induce enhancement versus neutralization; as such, these assays must be
equivalent between the infectious clone and the wild-type virus to justify the use
of rDENVic for vaccine and immunogenicity studies. Using a focus reduction
neutralization test (FRNT), we examined the ability of well-defined MAbs to block
virus infectivity. For all three DENV1 monoclonal antibodies (1F4, 14C10, and
1C19.2), percent neutralization was nearly identical between the wild-type DENV1
and rDENV1ic (Fig. 3A to C). RESULTS Similar to ELISA results, monoclonal antibodies against
the other DENV serotypes were unable to neutralize either the clone or wild-type virus
(Fig. 3D to F). Extending studies to a U937DC-SIGN flow-based neutralization assay,
percent infection results revealed overlapping neutralization of rDENV1ic and wild-type
DENV1 following DENV1 monoclonal antibody incubations (Fig. S1A to C). In addition,
none of the other DENV serotype-specific antibodies provides any significant reduction
in viral infection (Fig. S1D to F). Together, the results match the ELISA data and indicate
antibody neutralization fidelity between the infectious clone and wild-type viruses in
two independent neutralization assays. Gain of DENV4 monoclonal binding and neutralization. To use the rDENVic to
study antibody responses to specific epitopes, we generated a DENV1 mutant virus that
incorporates the DENV4 5H2 epitope into the DENV1 backbone virus. 5H2 is a DENV4
type-specific and strongly neutralizing MAb isolated from a nonhuman primate in-
fected with DENV4 (24, 25). A high-resolution structure of 5H2 bound to DENV4 E
protein has led to the identification of 17 residues within EDI that interact with the
antibody (Table 1) (24, 25). Of these 17 amino acids, five are conserved between DENV1
and DENV4. The remaining 12 residues in DENV1 were replaced with those from DENV4,
by manipulating plasmid A of the DENV1 infectious clone (rDENV1ic-5H2-epitope
[rDENV1ic-EDI]) (Fig. 4A) (Table 1). The DENV4 MAb 5H2 bound and neutralized the
rDENV1ic-EDI virus (Fig. 4B and C). As the parental clone and wild-type DENV1 were not
recognized by 5H2 (Fig. 4B and C), these results confirm successful transfer of a
conformational epitope from DENV4 into DENV1. msphere.asm.org
5 January/February 2017
Volume 2
Issue 1
e00380-16 Gallichotte et al. TABLE 1 Virus amino acid sequences and MAb epitopesa aAmino acid sequences for wild-type rDENV1ic, rDENV4ic are shown with chimeric rDENV1ic-EDI residues highlighted in orange (DENV4 amino acids
transplanted into the DENV1 backbone sequence). rDENV1ic-EDI virus that was recovered contained an additional mutation (light orange) unrelated to the
transplanted 5H2 epitope. Contact residues for MAbs 5H2, 1F4, 14C10, and E103 are shown in green, magenta, purple, and cyan, respectively. aAmino acid sequences for wild-type rDENV1ic, rDENV4ic are shown with chimeric rDENV1ic-EDI residues highlighted in orange (DENV4 amino acids
transplanted into the DENV1 backbone sequence). rDENV1ic-EDI virus that was recovered contained an additional mutation (light orange) unrelated to the
transplanted 5H2 epitope. January/February 2017
Volume 2
Issue 1
e00380-16 RESULTS Contact residues for MAbs 5H2, 1F4, 14C10, and E103 are shown in green, magenta, purple, and cyan, respectively. Ablation of DENV1 monoclonal binding and neutralization. The epitope of
DENV4 MAb 5H2 overlaps with the known DENV1 type-specific epitopes recognized by
human neutralizing MAbs 1F4 and 14C10 (21). Importantly, 1F4 has more than one-
third of its predicted contact residues replaced in the rDENV1ic-EDI virus (Fig. 5A and
Table 1). Insertion of the DENV4 5H2 epitope partially disrupted the DENV1 1F4 epitope,
resulting in an 80-fold reduction in 50% effective concentration (EC50) but not complete
ablation in binding of 1F4 to rDENV1ic-EDI (Fig. 5B). Similarly, neutralization assays
indicate that 1F4 nearly lost all of its ability to neutralize the rDENV1ic-EDI mutant
(Fig. 5C). MAb 14C10 has a smaller percentage (15%) of its epitope disrupted in the
rDENV1ic-EDI virus (Fig. 5D and Table 1), as it has additional contact residues in EDIII
from the neighboring dimer that are maintained (Fig. S2) (26). Despite this smaller
percentage, binding of 14C10 is still reduced (Fig. 5E), and 14C10 neutralization of FIG 4 rDENV1ic-EDI gains binding and neutralization to DENV4 serotype-specific MAb 5H2. (A) Structure
of DENV envelope protein dimer showing transplanted residues from DENV4 (orange) and MAb 5H2
epitope contact residues (green). Residues that are part of both the 5H2 MAb epitope and rDENV1ic-EDI
virus are shown in orange. rDENV1ic-EDI virus that was recovered contained an additional mutation (light
orange) unrelated to the transplanted 5H2 epitope. (B) Viruses were analyzed in an ELISA virus capture
assay for their ability to bind DENV4-specific MAb 5H2. (C) Neutralization of viruses in C6/36 focus
reduction neutralization test (FRNT) with DENV4-specific MAb 5H2. January/February 2017
Volume 2
Issue 1
e00380-16 FIG 4 rDENV1ic-EDI gains binding and neutralization to DENV4 serotype-specific MAb 5H2. (A) Structure
of DENV envelope protein dimer showing transplanted residues from DENV4 (orange) and MAb 5H2
epitope contact residues (green). Residues that are part of both the 5H2 MAb epitope and rDENV1ic-EDI
virus are shown in orange. rDENV1ic-EDI virus that was recovered contained an additional mutation (light
orange) unrelated to the transplanted 5H2 epitope. (B) Viruses were analyzed in an ELISA virus capture
assay for their ability to bind DENV4-specific MAb 5H2. (C) Neutralization of viruses in C6/36 focus
reduction neutralization test (FRNT) with DENV4-specific MAb 5H2. msphere.asm.org
6 DENV1 Epitope Addition and Disruption FIG 5 rDENV1ic-EDI loses binding and neutralization to EDI DENV1 serotype-specific MAbs. RESULTS (A, D, and G) Structure of DENV envelope
protein dimer showing transplanted residues from DENV4 (orange) and MAb epitope contact residues for 1F4 (magenta) (A), 14C10
(purple) (D), and E103 (cyan) (G). Residues that are part of both the MAb epitope and rDENV1ic-EDI virus are shown in orange. rDENV1ic-EDI virus that was recovered contained an additional mutation (light orange) unrelated to the transplanted 5H2 epitope. (B,
E, and H) Viruses were analyzed in an ELISA virus capture assay for their ability to bind MAbs 1F4, 14C10, and E103. (C, F, and I)
Neutralization of viruses in C6/36 focus reduction neutralization test (FRNT) with MAbs 1F4, 14C10, and E103. FIG 5 rDENV1ic-EDI loses binding and neutralization to EDI DENV1 serotype-specific MAbs. (A, D, and G) Structure of DENV envelope
protein dimer showing transplanted residues from DENV4 (orange) and MAb epitope contact residues for 1F4 (magenta) (A), 14C10
(purple) (D), and E103 (cyan) (G). Residues that are part of both the MAb epitope and rDENV1ic-EDI virus are shown in orange. rDENV1ic-EDI virus that was recovered contained an additional mutation (light orange) unrelated to the transplanted 5H2 epitope. (B,
E, and H) Viruses were analyzed in an ELISA virus capture assay for their ability to bind MAbs 1F4, 14C10, and E103. (C, F, and I)
Neutralization of viruses in C6/36 focus reduction neutralization test (FRNT) with MAbs 1F4, 14C10, and E103. rDENV1ic-EDI is mostly lost (Fig. 5F). In contrast, DENV1 monoclonal antibody E103,
which targets an EDIII epitope (Fig. 5G) (27), had no significant reduction in ELISA
binding relative to wild-type virus or the infectious clone (Fig. 5H). Additionally, MAb
E103 maintained robust neutralization, indicating maintenance of other DENV1
epitopes within the mutant virus (Fig. 5I). In summary, the introduction of the 5H2
epitope residues to create the rDENV1ic-EDI virus leads to efficient display of a
heterologous DENV4 epitope and the disruption of two native DENV1 type-specific
epitopes. Our results illustrate the utility of the infectious clone for transferring DENV
epitopes between serotypes and identify functional consequences on other con-
served epitopes within the transferred amino acid regions. January/February 2017
Volume 2
Issue 1
e00380-16 DISCUSSION While a number of reverse genetic systems for dengue viruses have been devel-
oped, significant obstacles, including replication attenuation, sequence alteration, as
well as labor- and cost-intensive techniques, have limited their utility (6). In this study,
we further characterize a novel DENV1 molecular clone platform that is patterned after
coronavirus systems and describe additional details, including transcript infectivity and
recombinant virus phenotypes in vitro (19, 28–31). Generating a panel of contiguous
cDNAs that span the entire genome, the divided DENV1 reverse genetic system msphere.asm.org
7 January/February 2017
Volume 2
Issue 1
e00380-16 Gallichotte et al. overcomes toxic elements within itself and allows propagation in bacteria. Importantly,
directional assembly and in vitro transcription allow electroporation of full-length
infectious RNA that directly corresponds to the wild-type virus sequence. As a result,
the virus derived from the infectious clone maintains similar replication in multiple cell
types (Fig. 1E to G) as well as complete fidelity in regard to antibody binding and virus
neutralization (Fig. 2 and 3). Building on previous epitope swap mutants (19, 32), we
employed this reverse genetic system to generate a DENV1 viral mutant that displayed
a known monoclonal antibody epitope from DENV4, gaining 5H2 monoclonal antibody
binding and neutralization to the donor sequence strain. However, the mutant virus
also disrupted binding and neutralization of two DENV1-specific monoclonal antibodies
despite retaining the majority of their targeted antigenic residues (Table 1 and Fig. 5). While other DENV1-specific monoclonal antibodies maintain effective binding and
neutralization (Fig. 5C), the data highlight the opportunity cost of domain swaps even
in the context of partial epitope disruption. Overall, the results also illustrate the utility
of this newly developed infectious clone systems as a platform to study DENV1
infection, pathogenesis, and immunity. For the DENV vaccine field, this reverse genetic system amplifies opportunities in
virus design that are already being explored. Previous work by our lab has utilized the
DENV2 and DENV4 infectious clones to define and transfer a critical antibody binding
epitope in DENV2 identified by structural analysis (22, 32). In this case, we described a
recombinant DENV4 virus that displayed a heterologous DENV2 epitope, while preserv-
ing the major neutralizing epitopes on DENV4 (32). DISCUSSION In addition, previous work using this
DENV1 infectious clone was able to transfer part of the DENV3 MAb 5J7 epitope,
resulting in a partial gain of binding and neutralization by 5J7 but no loss of binding
to DENV1 MAb 1F4 (19). Importantly, both the DENV2 2D22 and DENV3 5J7 MAb
epitopes are distinct from the 1F4 and 14C10 epitopes transplanted here. Coupled with
data from the current study, the approach to disrupt epitopes within the context of live
virus highlights an independent and powerful approach to quickly validate structural
predictions of key residues. Importantly, full characterization of these viral epitopes and
their portability between DENV serotypes open new approaches to vaccine develop-
ment. This work defines a rationally designed chimeric virus that uses MAb-envelope
structural interactions to identify residues associated with the DENV4 MAb 5H2 epitope
that were sufficient for the gain of binding and neutralization. These changes lead to
the disruption of multiple overlapping DENV1 epitopes, highlighting a potential prob-
lem that must be addressed in DENV vaccine design. Interestingly, despite maintaining
nearly two-thirds of the DENV1 1F4 epitope in the chimeric virus, binding and neutral-
ization were almost completely lost, indicating that the critical residue determinants for
antibody interactions were among those that were changed. Another DENV1 MAb,
14C10, which maintained a much larger percentage of its epitope in the chimeric virus,
lost a smaller amount of binding yet still lost nearly complete neutralization by 14C10. This suggests that while the remaining epitope can still be partially bound by 14C10,
the interaction is insufficient to fully neutralize the virus. Structure-guided design could
identify additional residues to further expand the transplanted DENV4 epitope to fully
ablate DENV1 MAb and polyclonal binding and neutralization. Together, these data
illustrate the utility of mapping epitopes using a combination of structure and reveres
genetics. With a similar approach employed for human norovirus (33–37), these re-
sources can be applied to generate diagnostic reagents and to create a map of epitopes
ideal for designing chimeric bivalent vaccines that produce broad-spectrum neutral-
ization, a critical issue in DENV pathogenesis. Moving beyond vaccine immunity, the infectious clone system provides opportu-
nities to contribute to other areas of DENV research. Exploring virus-host interactions
has been complicated by attenuation of traditional clone-derived virus (6). January/February 2017
Volume 2
Issue 1
e00380-16 DISCUSSION Our system
maintains replication equivalent to that of the wild-type strain, allowing examination of
the impact of specific point mutations or viral protein deletion without the complica-
tion of interpreting baseline clone attenuation. In addition to these areas, the infectious
clone system may be a useful resource in identifying virulence determinants, host msphere.asm.org
8 DENV1 Epitope Addition and Disruption specificity, viral protein function, and RNA structural elements, as well as testing of
antiviral therapeutics. Overall, the reverse genetic system characterized in this study represents a major
resource for the study of DENV1 infection and pathogenesis. Building on previous
reports (19), this clone system provides several important advantages to study DENV1,
including robust propagation in bacteria, fidelity to wild-type sequence, and absence of
replication attenuation. Importantly, both antibody binding and virus neutralization
indicate uniform antigenicity with the wild-type strain permitting epitope mapping. Coupled with structural studies, the reverse genetic system can be manipulated to
produce chimeric vaccines harboring conserved epitopes from multiple serotypes. While it is unlikely that neutralizing epitopes from all four serotypes could be combined
into a single viable chimeric DENV virus, it is possible that two bivalent viruses that
contain neutralizing epitopes from all four serotypes (e.g., rDENV1/3 and rDENV4/2)
could be generated. This advance offers a promising strategy to produce broad
protection against the DENV family. January/February 2017
Volume 2
Issue 1
e00380-16 MATERIALS AND METHODS C6/36 cells were grown in
Gibco minimal essential medium (MEM) at 32°C. DC-SIGN-expressing U937 cells (U937DC-SIGN) were
maintained in RPMI 1640 at 37°C. Media were supplemented with fetal bovine serum (FBS) (5% for C6/36
and U937DC-SIGN cells) which was lowered to 2% after infection. C6/36 and U937DC-SIGN media
were supplemented with nonessential amino acids, and U937DC-SIGN medium were also supple-
mented with L-glutamine and 2-mercaptoethanol. All media were additionally supplemented with
100 U/ml penicillin, 100 g/ml streptomycin, and 0.25 g/ml amphotericin B. All cells were incubated in
5% CO2. Virus titration and immunostaining. Cell culture plates (24-well plates) were seeded with C6/36
cells to be confluent at the time of infection. The cell growth media were removed, and virus stocks were
serially diluted 10-fold and then added to cells for 1 h at 32°C (C6/36) with gentle rocking. After
incubation, cells were overlaid with 1% methylcellulose in Opti-MEM I (Gibco) supplemented with 2%
FBS, nonessential amino acids, 100 U/ml penicillin, 100 g/ml streptomycin, and 0.25 g/ml amphoter-
icin B and incubated at 32°C. After 4 to 6 days of incubation, the overlay was removed, and the cells were
washed with phosphate-buffered saline (PBS) and fixed in 80% methanol. The cells were blocked in 5%
nonfat dried milk in PBS (blocking buffer) and then incubated for 1 h at 37°C with anti-prM MAb 2H2 and
anti-E MAbs 4G2 and DV1-E103 diluted in blocking buffer. The cells were washed two times with PBS and
then incubated for 1 h at 37°C with horseradish peroxidase (HRP)-conjugated goat anti-mouse antibody
(Sigma) diluted in blocking buffer. The plates were washed two times with PBS, and foci were developed
using TrueBlue HRP substrate (KPL). Infectious center assay. C6/36 cells electroporated with rDENV1ic RNA were diluted in Opti-MEM I
(Gibco), added to a confluent monolayer of C6/36 cells, overlaid with 1% methylcellulose, and incubated
for 4 days. After incubation, cells were fixed and stained as described above. The percentage of
electroporated cells capable of making viable infectious virus was calculated as follows: (number of
foci/number of electroporated cells plated) 100. Growth curves. To determine the amount of virus cells can produce, C6/36 cells were inoculated at
a multiplicity of infection (MOI) of 0.01. Every 24 h, all cell culture supernatant was harvested (volume was
replaced with fresh medium) and frozen at 80°C. The titers of the virus samples were determined as
described above. MATERIALS AND METHODS Virus construction. Recombinant DENV1 West Pac ’74 infectious clone (rDENV1ic) was constructed
using a four-cDNA cloning strategy as previously described (19, 32, 38). Briefly, the DENV1 genome was
divided into four fragments and subcloned into separate cDNA plasmids with unique type IIS restriction
endonuclease cleavage sites at the 5= and 3= ends of each fragment. A PflMI site was removed using
standard molecular techniques. A T7 promoter was introduced into the 5= end of the plasmid A fragment,
and plasmid DNA was grown in Escherichia coli cells. Purified plasmid DNA was enzyme digested,
purified, and ligated together with T4 DNA ligase. Infectious genome-length capped viral RNA transcripts
were generated with T7 polymerase. RNA was electroporated into C6/36 cells and incubated 4 to 6 days. Cell culture supernatant containing virus was harvested, centrifuged at maximum speed to remove
cellular debris, and passaged onto C6/36 cells to generate a passage one virus stock. rDENV1ic-EDI mutant construction. For mutant virus generation, 12 predicted contact residues of
5H2 (24, 25) were identified that differ between DENV1 and DENV4 (Table 1). rDENV1ic plasmid A
fragment was redesigned to encode these 12-amino-acid changes in the envelope protein to create
rDENV1ic-EDI. The new plasmid A was digested and ligated with WT rDENV1ic plasmids B, C, and D as
described above to generate the rDENV1ic-EDI mutant virus. rDENV1ic-EDI mutant construction. For mutant virus generation, 12 predicted contact residues of
5H2 (24, 25) were identified that differ between DENV1 and DENV4 (Table 1). rDENV1ic plasmid A
fragment was redesigned to encode these 12-amino-acid changes in the envelope protein to create
rDENV1ic-EDI. The new plasmid A was digested and ligated with WT rDENV1ic plasmids B, C, and D as
described above to generate the rDENV1ic-EDI mutant virus. Cells. Cells were cultured as previously described by our group (19, 32). C6/36 cells were grown in
Gibco minimal essential medium (MEM) at 32°C. DC-SIGN-expressing U937 cells (U937DC-SIGN) were
maintained in RPMI 1640 at 37°C. Media were supplemented with fetal bovine serum (FBS) (5% for C6/36
and U937DC-SIGN cells) which was lowered to 2% after infection. C6/36 and U937DC-SIGN media
were supplemented with nonessential amino acids, and U937DC-SIGN medium were also supple-
mented with L-glutamine and 2-mercaptoethanol. All media were additionally supplemented with
100 U/ml penicillin, 100 g/ml streptomycin, and 0.25 g/ml amphotericin B. All cells were incubated in
5% CO2. Cells. Cells were cultured as previously described by our group (19, 32). Gallichotte et al. Gallichotte et al. Binding enzyme-linked immunosorbent assay. The plates were coated with either 100 ng/well
each mouse MAb 4G2 and 2H2 or 200 ng/well human MAb 1C19 overnight at 4°C. The plates were
washed with Tris-buffered saline with 0.05% Tween (TBST) and blocked in 3% nonfat dried milk in TBST
(blocking buffer), and equal quantities of virus (as previously titrated by enzyme-linked immunosorbent
assay [ELISA]) were added and incubated for 1 h at 37°C. The plates were washed, and primary human
MAbs were diluted fourfold in blocking buffer and added to the plates for 1 h. The plates were washed,
and alkaline phosphate (AP)-conjugated secondary antibodies were added for 1 h at 37°C. The plates
were washed and developed using p-nitrophenyl phosphate substrate, and color changes were quan-
tified by spectrophotometry as previously described (19, 32). y p
p
y
p
y
Neutralization assays. For the focus reduction neutralization test (FRNT), 24-well cell culture plates
were seeded with C6/36 cells to be confluent at time of infection. MAbs were diluted fourfold, mixed with
~45 focus-forming units (FFU) of virus, and incubated for 1 h at 32°C. After incubation, the virus-MAb
mixture was added to C6/36 cells for 1 h at 32°C with gentle rocking. The overlay was added, and the
cells were incubated for 4 to 6 days. The cells were fixed and stained as described above. For the
flow-based neutralization assay, MAbs were diluted fourfold, mixed with virus (previously titrated to
equal ~15% infection with no MAb present), and incubated for 1 h at 37°C. After incubation, the
virus-MAb mixture was added to 5 104 U937DC-SIGN cells for 2 h at 37°C. The cells were then
pelleted, washed two times with fresh medium, and then incubated for 24 h. After incubation, the cells
were fixed, permeabilized, and stained as described above for U937DC-SIGN growth curves. Accession number(s). Wild-type DENV1 and DENV4 sequences were derived from GenBank acces-
sion numbers U88535.1 and KJ160504.1. Monoclonal antibodies were synthesized from their deposited
Protein Data Bank sequences (PDB identifiers [ID] shown in brackets) (MAb 1F4 [4C2I], 14C10 [4CAU],
2D22 4UIF], 5J7 [3J6U], 5H2 [3UAJ]). REFERENCES hancement of dengue virus infection. Methods Mol Biol 1138:75–97. https://doi.org/10.1007/978-1-4939-0348-1_6. hancement of dengue virus infection. Methods Mol Biol 1138:75–97. https://doi.org/10.1007/978-1-4939-0348-1_6. 1. Bhatt S, Gething PW, Brady OJ, Messina JP, Farlow AW, Moyes CL, Drake
JM, Brownstein JS, Hoen AG, Sankoh O, Myers MF, George DB, Jaenisch
T, Wint GR, Simmons CP, Scott TW, Farrar JJ, Hay SI. 2013. The global
distribution and burden of dengue. Nature 496:504–507. https://doi.org/
10.1038/nature12060. 9. Shang W, Liu J, Yang J, Hu Z, Rao X. 2012. Dengue virus-like particles:
construction and application. Appl Microbiol Biotechnol 94:39–46. https://doi.org/10.1007/s00253-012-3958-7. 2. Guzman MG, Gubler DJ, Izquierdo A, Martinez E, Halstead SB. 2016. Dengue infection. Nat Rev 2:16055. https://doi.org/10.1038/nrdp
.2016.55. 10. Coffey LL, Vignuzzi M. 2011. Host alternation of Chikungunya virus
increases fitness while restricting population diversity and adaptability
to novel selective pressures. J Virol 85:1025–1035. https://doi.org/
10.1128/JVI.01918-10. 3. Diamond MS, Pierson TC. 2015. Molecular insight into dengue virus
pathogenesis and its implications for disease control. Cell 162:488–492. https://doi.org/10.1016/j.cell.2015.07.005. 3. Diamond MS, Pierson TC. 2015. Molecular insight into dengue virus
pathogenesis and its implications for disease control. Cell 162:488–492. https://doi.org/10.1016/j.cell.2015.07.005. 11. Pierro DJ, Salazar MI, Beaty BJ, Olson KE. 2006. Infectious clone construc-
tion of dengue virus type 2, strain Jamaican 1409, and characterization
of a conditional E6 mutation. J Gen Virol 87:2263–2268. https://doi.org/
10.1099/vir.0.81958-0. g
j
4. Halstead SB. 2007. Dengue. Lancet 370:1644–1652. https://doi.org/
10.1016/S0140-6736(07)61687-0. 4. Halstead SB. 2007. Dengue. Lancet 370:1644–1652. https://doi.org/
10.1016/S0140-6736(07)61687-0. 5. Khetarpal N, Khanna I. 2016. Dengue fever: causes, complications, and
vaccine strategies. J Immunol Res 2016:6803098. https://doi.org/
10.1155/2016/6803098. 12. Kinney RM, Butrapet S, Chang GJ, Tsuchiya KR, Roehrig JT, Bhamara-
pravati N, Gubler DJ. 1997. Construction of infectious cDNA clones for
dengue 2 virus: strain 16681 and its attenuated vaccine derivative,
strain PDK-53. Virology 230:300 –308. https://doi.org/10.1006/
viro.1997.8500. 6. Aubry F, Nougairède A, Gould EA, de Lamballerie X. 2015. Flavivirus
reverse genetic systems, construction techniques and applications: a
historical perspective. Antiviral Res 114:67–85. https://doi.org/10.1016/
j.antiviral.2014.12.007. 6. Aubry F, Nougairède A, Gould EA, de Lamballerie X. 2015. Flavivirus
reverse genetic systems, construction techniques and applications: a
historical perspective. Antiviral Res 114:67–85. https://doi.org/10.1016/
j.antiviral.2014.12.007. 13. Suzuki R, de Borba L, Duarte dos Santos CN, Mason PW. 2007. Construc-
tion of an infectious cDNA clone for a Brazilian prototype strain of
dengue virus type 1: characterization of a temperature-sensitive muta-
tion in NS1. Virology 362:374–383. https://doi.org/10.1016/j.virol.2006
.11.026. 7. SUPPLEMENTAL MATERIAL Supplemental material for this article may be found at https://doi.org/10.1128/
mSphere.00380-16. p
TABLE S1, PDF file, 0.04 MB. FIG S1, PDF file, 0.2 MB. TABLE S1, PDF file, 0.04 MB. TABLE S1, PDF file, 0.04 MB. FIG S1, PDF file, 0.2 MB. FIG S2 , PDF file, 0.4 MB. FIG S2 , PDF file, 0.4 MB. ACKNOWLEDGMENTS We thank James E. Crowe, Jr. (Vanderbilt University) for providing monoclonal
antibody 1C19.2 and Michael Diamond (Washington University) for providing mono-
clonal antibody E103. This research was supported by funding from GATES and the extramural (R01
AI107731 [principal investigator, Aravinda de Silva] and U19 AI109761 CETR [principal
investigator, Ralph Baric]) and P01AI106695 programs of the U.S. National Institute of
Allergy and Infectious Diseases. MATERIALS AND METHODS To determine the kinetics at which cells become infected, C6/36 cells were inoculated
at an MOI of 0.01. Every 12 h, cell culture medium was removed, and the cells were washed with PBS,
fixed, permeabilized, and probed with anti-prM MAb 2H2 conjugated to Alexa Fluor 488. Infected cells
were quantified using a Guava flow cytometer (Millipore). U937DC-SIGN cells were infected at an initial
infection of 2%, and every 12 h, a sample of cells were harvested, fixed, and stained as described for
C6/36 cells. Growth curves. To determine the amount of virus cells can produce, C6/36 cells were inoculated at
a multiplicity of infection (MOI) of 0.01. Every 24 h, all cell culture supernatant was harvested (volume was
replaced with fresh medium) and frozen at 80°C. The titers of the virus samples were determined as
described above. To determine the kinetics at which cells become infected, C6/36 cells were inoculated
at an MOI of 0.01. Every 12 h, cell culture medium was removed, and the cells were washed with PBS,
fixed, permeabilized, and probed with anti-prM MAb 2H2 conjugated to Alexa Fluor 488. Infected cells
were quantified using a Guava flow cytometer (Millipore). U937DC-SIGN cells were infected at an initial
infection of 2%, and every 12 h, a sample of cells were harvested, fixed, and stained as described for
C6/36 cells. msphere.asm.org
9 January/February 2017
Volume 2
Issue 1
e00380-16 msphere.asm.org
10 DENV1 Epitope Addition and Disruption infectious clone assembled in a bacterial artificial chromosome. Virus Res
180:12–22. https://doi.org/10.1016/j.virusres.2013.12.001. infectious clone assembled in a bacterial artificial chromosome. Virus Res
180:12–22. https://doi.org/10.1016/j.virusres.2013.12.001. BJ, Lok SM, MacAry PA. 2012. The structural basis for serotype-specific
neutralization of dengue virus by a human antibody. Sci Transl Med
4:139ra83. https://doi.org/10.1126/scitranslmed.3003888. 15. Polo S, Ketner G, Levis R, Falgout B. 1997. Infectious RNA transcripts from
full-length dengue virus type 2 cDNA clones made in yeast. J Virol
71:5366–5374. 27. Shrestha B, Brien JD, Sukupolvi-Petty S, Austin SK, Edeling MA, Kim T,
O’Brien KM, Nelson CA, Johnson S, Fremont DH, Diamond MS. 2010. The
development of therapeutic antibodies that neutralize homologous and
heterologous genotypes of dengue virus type 1. PLoS Pathog
6:e1000823. https://doi.org/10.1371/journal.ppat.1000823. 16. Pu SY, Wu RH, Yang CC, Jao TM, Tsai MH, Wang JC, Lin HM, Chao YS,
Yueh A. 2011. Successful propagation of flavivirus infectious cDNAs by a
novel method to reduce the cryptic bacterial promoter activity of virus
genomes. J Virol 85:2927–2941. https://doi.org/10.1128/JVI.01986-10. y
y
genomes. J Virol 85:2927–2941. https://doi.org/10.1128/JVI.01986-10. 28. Yount B, Curtis KM, Fritz EA, Hensley LE, Jahrling PB, Prentice E, Denison
MR, Geisbert TW, Baric RS. 2003. Reverse genetics with a full-length
infectious cDNA of severe acute respiratory syndrome coronavirus. Proc
Natl Acad Sci U S A 100:12995–13000. https://doi.org/10.1073/
pnas.1735582100. 17. Siridechadilok B, Gomutsukhavadee M, Sawaengpol T, Sangiambut S,
Puttikhunt C, Chin-inmanu K, Suriyaphol P, Malasit P, Screaton G, Mon-
gkolsapaya J. 2013. A simplified positive-sense-RNA virus construction
approach that enhances analysis throughput. J Virol 87:12667–12674. https://doi.org/10.1128/JVI.02261-13. 29. Yount B, Curtis KM, Baric RS. 2000. Strategy for systematic assembly of
large RNA and DNA genomes: transmissible gastroenteritis virus model. J Virol 74:10600 –10611. https://doi.org/10.1128/JVI.74.22.10600
-10611.2000. 18. Aubry F, Nougairède A, de Fabritus L, Querat G, Gould EA, de Lamballerie
X. 2014. Single-stranded positive-sense RNA viruses generated in days
using infectious subgenomic amplicons. J Gen Virol 95:2462–2467. https://doi.org/10.1099/vir.0.068023-0. 30. Donaldson EF, Yount B, Sims AC, Burkett S, Pickles RJ, Baric RS. 2008. Systematic assembly of a full-length infectious clone of human coronavirus
NL63. J Virol 82:11948–11957. https://doi.org/10.1128/JVI.01804-08. 19. Messer WB, Yount BL, Royal SR, de Alwis R, Widman DG, Smith SA, Crowe
JE, Jr, Pfaff JM, Kahle KM, Doranz BJ, Ibarra KD, Harris E, de Silva AM, Baric
RS. 2016. Functional transplant of a dengue virus serotype 3 (DENV3)-
specific human monoclonal antibody epitope into DENV1. J Virol 90:
5090–5097. https://doi.org/10.1128/JVI.00155-16. 31. Scobey T, Yount BL, Sims AC, Donaldson EF, Agnihothram SS, Menachery
VD, Graham RL, Swanstrom J, Bove PF, Kim JD, Grego S, Randell SH, Baric
RS. 2013. Reverse genetics with a full-length infectious cDNA of the
Middle East respiratory syndrome coronavirus. Proc Natl Acad Sci U S A
110:16157–16162. https://doi.org/10.1073/pnas.1311542110. 20. de Alwis R, Smith SA, Olivarez NP, Messer WB, Huynh JP, Wahala WM,
White LJ, Diamond MS, Baric RS, Crowe JE, Jr, de Silva AM. 2012. Identification of human neutralizing antibodies that bind to complex
epitopes on dengue virions. Proc Natl Acad Sci U S A 109:7439–7444. https://doi.org/10.1073/pnas.1200566109. 32. Gallichotte EN, Widman DG, Yount BL, Wahala WM, Durbin A, Whitehead
S, Sariol CA, Crowe JE, Jr, de Silva AM, Baric RS. 2015. A new quaternary
structure epitope on dengue virus serotype 2 is the target of durable
type-specific neutralizing antibodies. mBio 6(5):e01461-15. https://
doi.org/10.1128/mBio.01461-15. 21. Fibriansah G, Tan JL, Smith SA, de Alwis AR, Ng TS, Kostyuchenko VA,
Ibarra KD, Wang J, Harris E, de Silva A, Crowe JE, Jr, Lok SM. 2014. A
potent anti-dengue human antibody preferentially recognizes the con-
formation of E protein monomers assembled on the virus surface. EMBO
Mol Med 6:358–371. https://doi.org/10.1002/emmm.201303404. 33. Debbink K, Donaldson EF, Lindesmith LC, Baric RS. 2012. Genetic map-
ping of a highly variable norovirus GII.4 blockade epitope: potential role
in escape from human herd immunity. J Virol 86:1214–1226. https://
doi.org/10.1128/JVI.06189-11. 22. Fibriansah G, Ibarra KD, Ng TS, Smith SA, Tan JL, Lim XN, Ooi JS,
Kostyuchenko VA, Wang J, de Silva AM, Harris E, Crowe JE, Jr, Lok SM. 2015. Dengue virus. Cryo-EM structure of an antibody that neutralizes
dengue virus type 2 by locking E protein dimers. Science 349:88–91. https://doi.org/10.1126/science.aaa8651. 34. Debbink K, Lindesmith LC, Donaldson EF, Swanstrom J, Baric RS. 2014. Chimeric GII.4 norovirus virus-like-particle-based vaccines induce
broadly blocking immune responses. J Virol 88:7256–7266. https://
doi.org/10.1128/JVI.00785-14. 23. Fibriansah G, Tan JL, Smith SA, de Alwis R, Ng TS, Kostyuchenko VA, Jadi
RS, Kukkaro P, de Silva AM, Crowe JE, Lok SM. 2015. A highly potent
human antibody neutralizes dengue virus serotype 3 by binding across
three surface proteins. Nat Commun 6:6341. https://doi.org/10.1038/
ncomms7341. 35. Debbink K, Lindesmith LC, Ferris MT, Swanstrom J, Beltramello M, Corti
D, Lanzavecchia A, Baric RS. 2014. Within-host evolution results in
antigenically distinct GII.4 noroviruses. J Virol 88:7244–7255. https://
doi.org/10.1128/JVI.00203-14. 36. January/February 2017
Volume 2
Issue 1
e00380-16 REFERENCES Blaney JE, Jr, Durbin AP, Murphy BR, Whitehead SS. 2006. Development
of a live attenuated dengue virus vaccine using reverse genetics. Viral
Immunol 19:10–32. https://doi.org/10.1089/vim.2006.19.10. g
8. Mukherjee S, Pierson TC, Dowd KA. 2014. Pseudo-infectious reporter
virus particles for measuring antibody-mediated neutralization and en- 14. Usme-Ciro JA, Lopera JA, Enjuanes L, Almazán F, Gallego-Gomez JC. 2014. Development of a novel DNA-launched dengue virus type 2 January/February 2017
Volume 2
Issue 1
e00380-16 Lindesmith LC, Costantini V, Swanstrom J, Debbink K, Donaldson EF,
Vinjé J, Baric RS. 2013. Emergence of a norovirus GII.4 strain correlates
with changes in evolving blockade epitopes. J Virol 87:2803–2813. https://doi.org/10.1128/JVI.03106-12. 24. Lai CJ, Goncalvez AP, Men R, Wernly C, Donau O, Engle RE, Purcell RH. 2007. Epitope determinants of a chimpanzee dengue virus type 4
(DENV-4)-neutralizing antibody and protection against DENV-4 chal-
lenge in mice and rhesus monkeys by passively transferred humanized
antibody. J Virol 81:12766–12774. https://doi.org/10.1128/JVI.01420-07. 37. Lindesmith LC, Donaldson E, Leon J, Moe CL, Frelinger JA, Johnston RE,
Weber DJ, Baric RS. 2010. Heterotypic humoral and cellular immune
responses following Norwalk virus infection. J Virol 84:1800–1815. https://doi.org/10.1128/JVI.02179-09. 25. Cockburn JJ, Navarro Sanchez ME, Goncalvez AP, Zaitseva E, Stura EA,
Kikuti CM, Duquerroy S, Dussart P, Chernomordik LV, Lai CJ, Rey FA. 2012. Structural insights into the neutralization mechanism of a higher
primate antibody against dengue virus. EMBO J 31:767–779. https://
doi.org/10.1038/emboj.2011.439. 38. Messer WB, Yount B, Hacker KE, Donaldson EF, Huynh JP, de Silva AM,
Baric RS. 2012. Development and characterization of a reverse genetic
system for studying dengue virus serotype 3 strain variation and neu-
tralization. PLoS Neglect Trop Dis 6:e1486. https://doi.org/10.1371/
journal.pntd.0001486. 26. Teoh EP, Kukkaro P, Teo EW, Lim AP, Tan TT, Yip A, Schul W, Aung M,
Kostyuchenko VA, Leo YS, Chan SH, Smith KG, Chan AH, Zou G, Ooi EE,
Kemeny DM, Tan GK, Ng JK, Ng ML, Alonso S, Fisher D, Shi PY, Hanson January/February 2017
Volume 2
Issue 1
e00380-16 msphere.asm.org
11
|
https://openalex.org/W4240929404
|
https://archive.lstmed.ac.uk/15877/1/s12936-020-03443-x.pdf
|
English
| null |
A cohort study to identify risk factors for Plasmodium falciparum infection in Burkinabe children: implications for other high burden high impact countries
|
Research Square (Research Square)
| 2,020
|
cc-by
| 9,744
|
Yaro et al. Malar J (2020) 19:371
https://doi.org/10.1186/s12936-020-03443-x Yaro et al. Malar J (2020) 19:371
https://doi.org/10.1186/s12936-020-03443-x Malaria Journal RESEARCH
A cohort study to identify risk factors
for Plasmodium falciparum infection
in Burkinabe children: implications for other
high burden high impact countries
Jean Baptiste Yaro1,2, Alphonse Ouedraogo1, Z. Amidou Ouedraogo1, Amidou Diarra1, Malik Lankouande1,
Efundem Agboraw3, Eve Worrall3, Kobié Hyacinthe Toe1, Antoine Sanou1,4, W. Moussa Guelbeogo1,
N’Fale Sagnon1, Hilary Ranson3, Alfred B. Tiono1, Steven W. Lindsay2 and Anne L. Wilson3*
Open Access Open Access Abstract Background: Progress in controlling malaria has stalled in recent years. Today the malaria burden is increasingly con-
centrated in a few countries, including Burkina Faso, where malaria is not declining. A cohort study was conducted to
identify risk factors for malaria infection in children in southwest Burkina Faso, an area with high insecticide-treated
net (ITN) coverage and insecticide-resistant vectors. Methods: Incidence of Plasmodium falciparum infection was measured in 252 children aged 5 to 15 years, using
active and passive detection, during the 2017 transmission season, following clearance of infection. Demographic,
socio-economic, environmental, and entomological risk factors, including use of ITNs and insecticide resistance were
monitored. Results: During the six-month follow-up period, the overall incidence of P. falciparum infection was 2.78 episodes
per child (95% CI = 2.66–2.91) by microscopy, and 3.11 (95% CI = 2.95–3.28) by polymerase chain reaction (PCR). The
entomological inoculation rate (EIR) was 80.4 infective bites per child over the six-month malaria transmission season. At baseline, 80.6% of children were reported as sleeping under an ITN the previous night, although at the last survey,
23.3% of nets were in poor condition and considered no longer protective. No association was found between the
rate of P. falciparum infection and either EIR (incidence rate ratio (IRR): 1.00, 95% CI: 1.00–1.00, p = 0.08) or mortality in
WHO tube tests when vectors were exposed to 0.05% deltamethrin (IRR: 1.05, 95% CI: 0.73–1.50, p = 0.79). Travel his-
tory (IRR: 1.52, 95% CI: 1.45–1.59, p < 0.001) and higher socio-economic status were associated with an increased risk of
P. falciparum infection (IRR: 1.05, 95% CI: 1.00–1.11, p = 0.04). Conclusions: Incidence of P. falciparum infection remains overwhelmingly high in the study area. The study findings
suggest that because of the exceptionally high levels of malaria transmission in the study area, malaria elimination
cannot be achieved solely by mass deployment of ITNs and additional control measures are needed. Keywords: Malaria, Epidemiology, Cohort study, Burkina faso, Vector control, Insecticide resistance A cohort study to identify risk factors
for Plasmodium falciparum infection
in Burkinabe children: implications for other
high burden high impact countries Jean Baptiste Yaro1,2, Alphonse Ouedraogo1, Z. Amidou Ouedraogo1, Amidou Diarra1, Malik Lankouande1,
Efundem Agboraw3, Eve Worrall3, Kobié Hyacinthe Toe1, Antoine Sanou1,4, W. Moussa Guelbeogo1,
N’Fale Sagnon1, Hilary Ranson3, Alfred B. Tiono1, Steven W. Lindsay2 and Anne L. Wilson3* Background Malaria remains an acute public health problem
throughout sub-Saharan Africa (SSA) with an esti-
mated 213 million cases and 380,000 deaths in 2018 Malaria remains an acute public health problem
throughout sub-Saharan Africa (SSA) with an esti-
mated 213 million cases and 380,000 deaths in 2018 Department of Vector Biology, Liverpool School of Tropical Medicine
Liverpool, UK
Full list of author information is available at the end of the article iverpool, UK
ull list of author information is available at the end of the article Methods
Study siteh The study was conducted from June to December 2017
in Banfora Health District, Cascades region, southwest
Burkina Faso (Fig. 1), an area of Sudanian savannah cov-
ering 6,295 sq km and with an estimated population of
407,073 inhabitants [4]. Subsistence farming and animal
husbandry are the main activities. Banfora District has
intense seasonal malaria transmission over a six-month
period following seasonal rains from May to November
[20]. Plasmodium falciparum accounts for 90% of cases
[20]. The main malaria vector is Anopheles gambiae
sensu stricto (s.s.), but Anopheles coluzzii is also found
[21]. A universal coverage (defined as one ITN for every
two persons at risk of malaria) campaign in 2016 distrib-
uted ITNs with permethrin or deltamethrin (Sumitomo
Chemical, Vestergaard and BASF) and therefore no new
ITNs were distributed by the study. No indoor residual
spraying (IRS) was conducted. Since 2014, children under
5 years of age in the study area receive seasonal malaria
chemoprevention (SMC) during the transmission season
[22]. Despite the known protective efficacy of ITNs, the
2010 ITN universal coverage campaign in Burkina
Faso did not decrease malaria and all-cause mortality
in children younger than 5 years old, even with 92% of
children reportedly sleeping under ITNs [7]. The study
site in Burkina Faso has extremely high prevalence
and intensity of pyrethroid resistance in malaria vec-
tors [8, 9]. For example, mosquitoes reared from larvae
collected in Tengrela village between 2016 and 2018,
showed only 2% mortality when exposed to the stand-
ard diagnostic dose of deltamethrin of 0.05% designed
to kill all mosquitoes [10]. The public health impact
of insecticide resistance, however, remains contested
[11–14]. Insecticide resistance is only one important
factor affecting the efficacy of nets, since ITN cover-
age, durability and whether people actually sleep under
nets, as well as mosquito biting time and behaviour are
also important. There is increasing evidence that so-
called long-lasting insecticidal nets are not effective for
3 years [15–17], as claimed, and is the reason the term
ITN is used. Coverage and system inefficiencies mean
that ITNs are unevenly distributed among households
and an estimated 50% of ITNs are lost from households
after 23 months in Africa [18]. Social and environmen-
tal factors, including access to healthcare, socio-eco-
nomic status (SES) and house construction, found to
be protective against malaria in other studies [19], may
also impact malaria risk in Burkina Faso. © The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing,
adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and
the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material
in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material
is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the
permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativeco
mmons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/
zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Yaro et al. Malar J (2020) 19:371 Page 2 of 12 control in Burkina Faso and other countries in SSA expe-
riencing persistently high malaria transmission. control in Burkina Faso and other countries in SSA expe-
riencing persistently high malaria transmission. [1]. Despite unprecedented declines in malaria between
2000 and 2015, of which 68% can be attributed to the
scale-up of insecticide-treated nets (ITNs) [2], recent
years have seen stagnating progress in high burden
countries [1]. Reasons for this lack of progress are
unclear, but may include incomplete coverage of ITNs,
nets in poor condition and malaria vectors resist-
ant to the pyrethroid insecticides used for ITNs. Bur-
kina Faso, along with 10 other high-burden countries
in Africa, plus India, has been designated as a High
Burden to High Impact country by the World Health
Organization (WHO) and the Roll Back Malaria Part-
nership which calls for an aggressive new approach to
accelerate malaria control [3]. Burkina Faso has the
seventh highest number of malaria cases globally [1],
and has seen a rise in the number of malaria cases from
9 million in 2016 to over 11 million in 2017 and 2018
[4–6]. Recruitment of study cohort Ten villages were randomly selected from a list of villages
in the study area following a two-stage process. Firstly,
an area spanning the catchment areas of five health cen-
tres was chosen. Each health centre had a catchment
radius of approximately 10 km. Secondly, two villages at
least 3 km apart were chosen at convenience from each
catchment area, giving a total of 10 villages. Thirty chil-
dren were randomly selected from each village using the
Health and Demographic Surveillance System enumera-
tion list. Children were eligible to participate if they were
aged 5–15 years, likely to remain resident in the village
for the duration of the study and the caregiver provided
informed consent (assent of child if aged 12–15 years). Older children were selected as they have the highest
malaria incidence, relatively low immunity and contrib-
ute substantially to transmission [23], while children
under 5 years were excluded due to roll-out of SMC. Children were not eligible to participate if they were tak-
ing part in a malaria clinical trial, or had a contra-indi-
cation to the artemisinin-combination therapy (ACT),
artemether-lumefantrine (AL). At enrolment in June
2017, 300 children provided a blood film. Irrespective of
their malaria parasite status, all children received a cura-
tive dose of AL (Wellona Pharma Private Limited, Nana
Varachha, Surat, India) to clear any existing parasitaemia. Children were revisited 21 days later, at which time two A cohort study of children was conducted to determine
risk factors for Plasmodium falciparum infection in an
area of persistent and intense malaria transmission in
rural Burkina Faso, with high ITN coverage and high lev-
els of insecticide resistance. The study findings may help
to identify potential opportunities for improving malaria Yaro et al. Malar J (2020) 19:371 Page 3 of 12 Fig. 1 Study location. a Location of Burkina Faso; b Location of study site in Burkina Faso; c Location of the 10 study villages and Banfora (provincial
capital) in study site blood slides and a blood spot were taken and examined
to ensure parasite clearance. Those with a negative para-
site status confirmed by polymerase chain reaction (PCR)
were enrolled in the study. Children re-infected in the
21 day period were re-treated with AL and were eligible
for enrolment in the study after 28 days once parasite
clearance was confirmed using PCR. Recruitment of study cohort take their child to the nearest government health centre
should the child have a fever or feel unwell. Travel and
treatment costs for sick children were reimbursed by the
study. Study nurses were posted in the five health centres
close to the study villages and performed rapid diagnos-
tic tests for malaria (SD BIOLINE Malaria Ag P.f/Pan,
Abbott Laboratories, Illinois, USA) in study children pre-
senting with an axillary temperature ≥ 37.5 °C or history
of fever within the previous 48 h, and prepared two blood
films and a filter paper blood spot. Children diagnosed
with clinical malaria received AL [24]. Clinical data were
recorded on dedicated study logs and transcribed by
fieldworkers who visited each nurse weekly.hi Data management and statistical analysis Data were collected on android personal digital assistants
programmed using KoboCollect and included drop-
down boxes and consistency checks to reduce data entry
errors. Following cleaning, the dataset was locked and
saved in Microsoft Access. An analytical plan was devel-
oped prior to data analysis.h The primary outcome was the incidence rate of micro-
scopically confirmed P. falciparum infection during the
transmission season, detected using active and passive
case detection. PCR-confirmed P. falciparum incidence
rate was a secondary outcome. After ACT treatment,
further infections were censored for 28 days since infec-
tions during this time were most likely due to recrudes-
cent parasites. Time at risk was also censored for time
that study children spent away from their compound
should they be found to be absent at the two-weekly
home visits. The entomological inoculation rate (EIR)
or estimated number of infectious bites per study child
during the transmission season was calculated using the
formula EIR = MaSd where Ma is the human biting rate,
estimated from the arithmetic mean number of female
An. gambiae s.l. caught per light trap night across the six-
month transmission season, where S is the proportion
of female An. gambiae s.l. found to be sporozoite posi-
tive by village and d is the number of days in the trans-
mission season (n). Cone bioassay results for the netting
pieces from each sampled net were pooled by village
and by net type. QGIS Geographic Information System
(QGIS Development Team (2019), Open Source Geospa-
tial Foundation Project) was used to determine distances
between the child’s home and aquatic habitats. Distance
to the nearest health facility was determined based on
the shortest distance to travel by road. Principal com-
ponent analysis was used to calculate a SES factor score
based on asset ownership and household characteristics. SES factor scores (ranging from -1.8 to 3.2) were ranked
and households divided into five equal wealth quintiles (1
poorest, through to 5, least poor). Use of an ITN the previous night by each study child
and use of spatial or topical repellents were recorded at
enrolment and each active visit. Survivorship and integ-
rity of each study child’s ITN was measured in July, Octo-
ber and December. Each net was recorded as being in
use (i.e., hanging over the study child’s sleeping space), in
storage, being washed, or lost. Risk factors larval habitats were surveyed including irrigated fields,
puddles, muddy foot or hoof prints, streams and ponds. At enrolment, sociodemographic characteristics of the
child (age, gender, religion, ethnicity) and their caregiver
(education, occupation) were recorded. Questionnaires
recorded the presence or absence of large domestic ani-
mals (cattle, goats, sheep, donkeys, horses) within 5 m of
each study child’s house and the materials used to con-
struct the building in which the study child slept, includ-
ing presence of a metal roof, eaves and door and window
screening. The head of household completed a question-
naire on their asset ownership, house construction and
other variables, following standard procedures used in
the Burkina Faso Malaria Indicator Survey (MIS) [26]. Houses of study children were geolocated using a global
positioning system (GARMIN eTrex 20). Phenotypic insecticide resistance was measured using
WHO tube tests as per standard procedures [31]. Assays
were performed with An. gambiae s.l. mosquitoes reared
from immatures collected in seven study villages (larvae
were not found in the other three villages). Follow‑up of study cohort Symptomatic and asymptomatic Plasmodium infections
were recorded using both active and passive detection. Study children were visited at home every 2 weeks by
fieldworkers during the peak transmission season, from
July-December 2017. At each visit, fieldworkers meas-
ured a child’s axillary temperature and prepared two
blood films and a filter paper blood spot. Children with
an axillary temperature ≥ 37.5 °C or history of fever in
the previous 48 h were advised to visit the local health
centre and, if they were a malaria case, treated with
AL, following National Malaria Control Programme
(NMCP) guidelines [24]. If a child was absent at the time
of the visit, the fieldworker made one more attempt to
locate them the following day, after which the child was
recorded as being absent. Caregivers were encouraged by
the study team at enrolment and at fortnightly visits to i
Thick blood films were stained with Giemsa and exam-
ined under 1000-fold magnification by experienced
microscopists at the Centre National de Recherche et de
Formation sur le Paludisme (CNRFP) in Banfora. Para-
site counts were recorded per high power field and 100
fields counted before a slide was declared negative. Two
blood slides from each subject were read separately by
two microscopists. Discrepancies in positive and negative
reads and parasite counts differing by more than tenfold
between the two reads were resolved by the supervisor. Filter paper blood samples were analysed for the pres-
ence of 18 s rRNA gene using PCR [25]. Yaro et al. Malar J (2020) 19:371 Page 4 of 12 Data management and statistical analysis Loss was categorized as:
(i) net given away voluntarily; (ii) net stolen; or, (iii) net
destroyed, discarded or used for alternative purposes. Fabric integrity of the net was assessed by counting the
number of holes and their size according to WHO guid-
ance [27]. A weighted sum of hole counts, the propor-
tionate hole index (pHI), was calculated with a pHI of
0–64 categorized as good, 65–642 as acceptable and
643 + as too torn and non-protective [28]. To measure
ITN bio-efficacy, 26 bed nets were sampled (at least 2
randomly selected nets per village, except for Sitiena vil-
lage where 1 net was tested) in October 2017 and stored
at + 4 °C. ITNs taken for testing were replaced with new
ones. WHO cone bioassays were performed using the
pyrethroid-susceptible Kisumu strain of An. gambiae
sensu lato (s.l.) at the CNRFP insectaries in Banfora using
the WHO efficacy requirement of ≥ 80% mortality [29]. fi
Mosquitoes were sampled with CDC light traps, posi-
tioned with the light 1 m above the ground at the foot
end of the bed of each study child sleeping under an ITN
from 19.00 to 06.00, every 4 weeks from July to Decem-
ber 2017. In addition, each child’s net was systemati-
cally searched for mosquitoes between 06.00 and 07.00
every 4 weeks using a torch. Mosquitoes were identified
morphologically using established keys and female An. gambiae s.l. typed to species using PCR. The presence of
sporozoites in An. gambiae s.l. was determined using an
enzyme-linked immunosorbent assay [30]. Larval surveys
to determine the proximity of anopheline larval habitats
to study children’s houses were carried out in the vicin-
ity of all 10 villages during September 2017. All types of Mean values were compared using a t-test and propor-
tions compared using Chi-squared tests. Poisson regres-
sion models were used to identify risk factors associated
with P. falciparum infection incidence rate, adjusting for
clustering by village. Risk factors assessed were: child’s
age, gender, ethnic group, religion, caregiver’s education Yaro et al. Data management and statistical analysis Malar J (2020) 19:371 Page 5 of 12 and occupation, wealth quintile and SES factor score,
use of ITNs and other personal protection, ITN integ-
rity, number of people sleeping in the room with the
study child, housing materials (roof, eaves, wall and
floor material, door and window screening), presence
of cows, horses, sheep or goats within 5 m of the child’s
home, Euclidean distance to the nearest aquatic habitat
with larval anophelines, distance by road to the nearest
health centre, EIR at village level, and percentage mortal-
ity of An. gambiae s.l. mosquitoes from the village when
exposed to 0.05% deltamethrin in a WHO tube test. A
multivariate regression model was developed using a for-
ward stepwise approach. Statistical analysis was carried
out in Stata 15 (Statacorp, Texas, USA). Results Of 300 randomly selected children, 252 children aged
5–15 years old were enrolled in the cohort after confir-
mation of parasite clearance by PCR (Fig. 2). Of these 252
children, 228 were clear of infection at day 21 post-ACT,
while an additional 24 children were enrolled following
receipt of a second course of ACT due to re-infection. Three children withdrew from the study due to migra-
tion. No deaths were recorded among the cohort during
the study period.h The mean age of cohort participants was 9.9 years,
52.0% of whom were male (Table 1). 38.9% of children
were Gouin, 21.8% Karaboro, 11.5% Mossi, 9.1% Turka,
6.3% Fulani, and 4.4% Senoufo. Caregivers were predomi-
nantly illiterate (79.0%) and farmers (95.2%). Most sleep-
ing rooms of the children had metal roofs (75.8%), brick
walls (57.9%) and cement floors (70.2%). Over half the
children’s sleeping rooms had open eaves (54.8%) and the
vast majority did not have window screening (96.0%). Assuming two P. falciparum infections per child during
the transmission season, an intraclass correlation coeffi-
cient of 0.1 (design effect of 3.4), and a loss to follow-up
of 10%, the study had greater than 90% power to detect
effect sizes of > 50% at the 5% level of significance, assum-
ing 50% prevalence of the risk factor of interest in the
population using the formula for comparison of two rates
[32]. The study is reported following STROBE guidelines
[33]. During the follow-up period, 249 of the 252 chil-
dren experienced at least one P. falciparum infection, as
detected by microscopy. 31 children (12.3%) had one P. falciparum infection, 139 (55.2%) children experienced
two P. falciparum infections, 75 (29.8%) experienced
three P. falciparum infections, and 4 (1.6%) experienced Fig. 2 Study flowchart Page 6 of 12 Yaro et al. Malar J (2020) 19:371 four P. falciparum infections. A total of 550 P. Results falcipa-
Table 1 Baseline characteristics of the study cohort
Characteristic
Number (%) N = 252
Age at enrolment
5 years to < 8 years
76 (30.2%)
≥ 8 years
176 (69.8%)
Age (mean/standard deviation)
9.93 (2.8)
Gender
Male
131 (52.0%)
Female
121 (48.0%)
Ethnicity
Gouin
98 (38.9%)
Karaboro
55 (21.8%)
Mossi
29 (11.5%)
Turka
23 (9.1%)
Fulani
16 (6.3%)
Senoufo
11 (4.4%)
Others
20 (7.9%)
Reported bed net use
Used bed net usually
215 (85.3%)
Used a bed net the previous night
203 (80.6%)
Caregiver’s education level
Illiterate
199 (79.0%)
Primary school
45 (17.9%)
Secondary school or above
8 (3.2%)
Caregiver’s occupation
Not working/retired
6 (2.4%)
Farmer
240 (95.2%)
Commercial activities / government officer
6 (2.4%)
Eave status of child’s sleeping room
Closed
102 (40.5%)
Open
138 (54.8%)
Roof material of child’s sleeping room
Metal
191 (75.8%)
Thatch
34 (13.5%)
Other roof type
18 (7.1%)
Wall material of child’s sleeping room
Mud
65 (25.8%)
Brick
146 (57.9%)
Cement (plastered or painted)
32 (12.7%)
Floor material of child’s sleeping room
Cement
177 (70.2%)
Dirt floor
65 (25.8%)
Tiles
1 (0.4%)
Window screening of child’s sleeping room
Absent
242 (96.0%)
Present
1 (0.4%) Table 1 Baseline characteristics of the study cohort (96.0%) were detected using active case detection and
22 (4.0%) detected using passive case detection. Infec-
tions detected passively had a higher geometric mean P. falciparum density (19,875 mL, 95% CI = 7896–31,854)
compared to those detected through active surveillance
(3744 mL, 95% CI = 2,691–4,797, p < 0.001). The P. fal-
ciparum infection incidence rate was 2.78 episodes per
child during the six-month transmission season (95%
CI = 2.66–2.91) by microscopy, and 3.11 episodes (95%
CI = 2.95–3.28) by PCR. Among children suffering from
at least one infection, the median time to first infection
detected by microscopy was 27 days (range 14–123 days). detected by
c oscopy was 7 days ( a ge
3 days). At baseline, 80.6% of caregivers reported that the study
child slept under an ITN the previous night. Reported
ITN use the previous night at the baseline survey was
greater than 82% across the four lowest SES quintiles
compared to the least poor children (quintile 5 = 53.2%,
p < 0.001). Most study children’s bed nets were either
Permanet 2.0 (52.0%) or Olyset net (16.7%), with 85.5%
provided by the NMCP and 4.0% purchased on the open
market. Discussion and 2,590 (34.0%) An. coluzzii. 3.3% of the An. gambiae
s.l. were sporozoite positive. The overall EIR in the study
area was 80.4 infective bites/child over the six-month
transmission season. The village-level EIR ranged from
40.8 in Timperba to 191.9 in Tondoura. Monthly sys-
tematic searches of study children’s bed nets in the early
morning did not collect any mosquitoes. Anopheles gam-
biae s.l. were resistant to 0.05% deltamethrin in WHO
tube tests with a mean corrected mortality of 52.3% (95%
CI = 26.4–78.2%), with values ranging from 27.2% mor-
tality in Toumousseni to 93.0% in Yendere.h An extremely high incidence of P. falciparum infection
was observed, with only three of the 252 cohort children
remaining free from infection during the six-month fol-
low-up period and 86.5% of children experiencing two or
more infections. This high incidence of infection, despite
regular retreatment with an effective anti-malarial if a
child was infected, indicates the high force of infection in
the study area and is supported by an estimated EIR of
80.4 infective bites per child during the transmission sea-
son. Similarly high levels of P. falciparum infection and
malaria morbidity have been reported from other recent
studies in Burkina Faso in areas of high ITN coverage
[34–36].h The mean number of water bodies with anopheline lar-
vae within 500 m of study houses was 8.7 (95% CI = 7.0–
10.3). The average distance by road from the study house
to the nearest clinic was 3.6 km (95% CI = 3.2–4.0),
although for the villages of Toundoura and Gouera,
which did not have a clinic nearby, the distance was
7.5 km and 9.4 km, respectively.i The assessment of socio-demographic, entomologi-
cal and environmental risk factors for P. falciparum
infection did not elucidate any strong associations. This
may be because of the overwhelming force of infec-
tion in the study area which meant that all the children
were at extremely high risk of infection. Nevertheless,
there was an indication of increased malaria risk in the
few children that travelled overnight during the study
period. Whether staying with family or for farming rea-
sons, these children may be at higher risk of P. falcipa-
rum infection because they lack or have limited access
to malaria prevention including ITNs, and diagnosis
and treatment [37]. Results Sleeping place inspections in July, October and
December found 87.8% of children had a bed net hanging
over their sleeping place (638 out of 727 observations). The most common reason for not having a net hanging
was loss of the net (59/89 observations, 66.3%), while
15.7% (14/89 observations) of nets were stored and 2.2%
(2/89 observations) being washed. The proportions lost,
stored or being washed did not differ across the three
surveys. Of the nets that were reported as being lost,
76.3% (45/59 observations) were destroyed, 22.0% (13/59
observations) stolen and 1.7% (1/59 observations) given
to friends or family. It was common for children to share
a bed net with siblings and 61.4% of children slept with
three or more children. At the last survey in December,
62.2% (155/249) of ITNs were in good condition, 14.5%
(36/249) were damaged and 23.3% (58/249) badly torn
and non-protective. Net condition did not differ signifi-
cantly by survey round, although there was a tendency
towards net deterioration over the study period. Cone
testing of a random sample of 26 children’s bed nets
gave a mean knockdown at 1 h of 76.5% (95% CI = 61.9–
91.1%) and mortality after 24 h of 42.2% (95% CI = 18.8–
65.6%) for Olyset nets (9 nets, permethrin-treated) and
mean knockdown of 85.2% (95% CI = 77.9–92.4%) and
24 h mortality of 39.9% (95% CI = 27.7–52.0%) for Per-
manet (17 nets, deltamethrin-treated). A total of 20,929 mosquitoes were caught from 1,151
trap collections with 16,270 of these being An. gambiae
s.l.. Highest densities of An. gambiae s.l. occurred in
August (Fig. 3). Tengrela village had the highest density of
An. gambiae s.l. across the season, reaching a peak of 137
An. gambiae s.l. per trap /night in August. Of the 7,615
identified to species, 4,101 (53.9%) were An. gambiae s.s. four P. falciparum infections. A total of 550 P. falcipa-
rum infections were identified using microscopy while
608 infections were identified using PCR. Of the 550 P. falciparum infections confirmed using microscopy, 528 Yaro et al. Malar J (2020) 19:371 Page 7 of 12 Fig. 3 Mean number of Anopheles gambiae s.l. per trap night in sleeping rooms of study children during the transmission season Discussion Overnight travel history was a risk
factor for malaria in Uganda in a recent cohort study,
with those not using ITNs at particularly high risk [38]. The finding of an association between higher SES fac-
tor score and a higher incidence of P. falciparum infec-
tion was unexpected since it is widely reported that the
least poor children are typically at lower malaria risk than Univariate Poisson regression analysis identified two
variables associated with incidence of P. falciparum
infection in the study children and both remained signifi-
cant in a multivariate model (Table 2). Although a small
number of children travelled from the study area, this
was associated with a 52% increase in the incidence of P. falciparum infection compared to children that did not
travel (incidence rate ratio (IRR): 1.52, 95% CI: 1.45–1.59,
p < 0.001). The least poor children were found to have
a higher incidence of P. falciparum infection. A 1 unit
increase in the SES factor score was associated with a 5%
increase in infection rate (IRR: 1.05, 95% CI: 1.00–1.11,
p = 0.04). Yaro et al. Discussion Malar J (2020) 19:371 Page 8 of 12 Table 2 Risk factors for Plasmodium infection incidence among children aged 5–15 years in Banfora region of Burkina
Faso
Variables
Number
of children
Number
of infections
Time
at risk
(years)
Rate
Univariate analysis
Multivariate analysis
IRR (95% CI)
P value
IRR (95% CI)
P value
Age (years)
5–7
76
164
31.09
5.28
–
–
8–15
176
386
71.40
5.41
1.02 (0.94–1.12)
0.59
Gender
Male
131
288
52.93
5.44
–
–
Female
121
262
49.56
5.29
0.97 (0.90–1.05)
0.46
Ethnic group
Other ethnicity
236
519
95.82
5.42
–
–
Fulani
16
31
6.66
4.65
0.86 (0.65–1.13)
0.28
Caregiver’s education
Illiterate
199
443
80.45
5.51
–
–
Literate
53
107
22.04
4.86
0.88 (0.76–1.02)
0.09
Caregiver’s occupation
Farmer
240
523
97.39
5.37
–
–
Non farmer
12
27
5.09
5.30
0.99 (0.83–1.18)
0.89
Religion
Muslims
170
375
68.97
5.44
–
–
Christians
33
67
13.93
4.81
0.88 (0.77–1.02)
0.09
Animists
49
108
19.58
5.51
1.01 (0.87–1.18)
0.85
SES quintile
Poorest
46
102
20.16
5.06
1.04 (0.99–1.09)
0.14
Poor
44
95
18.47
5.14
Middle
44
98
18.21
5.38
Rich
46
103
19.34
5.33
Richest
47
106
17.79
5.96
SES factor score
1 unit increase
–
–
–
–
1.06 (1.01–1.11)
0.03
1.05 (1.00–1.11)*
0.04
Travel history during the study period
No
246
537
100.93
5.32
–
Yes
6
13
1.55
8.39
1.58 (1.31–1.90)
< 0.001
1.52 (1.45–1.59)$
< 0.001
Slept under bed net previous night
Yes
203
448
83.55
5.36
–
–
No
49
102
18.93
5.39
1.00 (0.78–1.29)
0.97
Number of people sleeping in the child room (including child)
≤ 6
55
124
23.10
5.37
–
6 < no. Discussion Malar J (2020) 19:371 IRR incidence rate ratio, *IRR adjusted for travel history, $IRR adjusted for SES factor score
Table 2 (continued)
Variables
Number
of children
Number
of infections
Time
at risk
(years)
Rate
Univariate analysis
Multivariate analysis
IRR (95% CI)
P value
IRR (95% CI)
P value
Housing: floor of the child’s sleeping room
Cement/tiles
178
388
72.91
5.32
–
–
Dirt
65
146
26.54
5.50
1.03 (0.94–1.13)
0.48
Housing: wall of the child’s sleeping room
Mud
65
151
26.54
5.69
–
–
Brick
146
309
59.15
5.22
0.92 (0.83–1.02)
0.12
Cement
32
74
13.77
5.37
0.94 (0.83–1.08)
0.39
Housing: eaves of the child’s sleeping room
Open
138
299
56.57
5.29
–
Closed
102
229
41.60
5.51
1.04 (0.91–1.20)
0.57
Cows, horses, sheep or goats within 5 m of child’s home
Present
169
371
67.80
5.47
–
Absent
80
174
33.51
5.19
0.95 (0.83–1.09)
0.46
Euclidean distance to the nearest positive aquatic habitat
< = 300 m
127
266
51.76
5.14
–
–
> 300 m
125
284
50.72
5.60
1.09 (1.00–1.19)
0.06
Distance by road to nearest health centre
< = 2 km
119
252
49.65
5.08
–
–
> 2 km
133
298
52.83
5.64
1.11 (1.00–1.24)
0.06
EIR (village-level)
-
–
–
–
1.00 (1.00–1.00)
0.08
% mortality in WHO tube test with 0.05%
deltamethrin diagnostic dose
-
–
–
–
–
1.05 (0.73–1.50)
0.79 IRR incidence rate ratio, *IRR adjusted for travel history, $IRR adjusted for SES factor score IRR incidence rate ratio, *IRR adjusted for travel history, $IRR adjusted for SES factor score has been demonstrated in several other studies [40, 41],
but could arise if vector densities in all villages were suf-
ficiently high to maintain high transmission, or due to
outdoor biting. Although levels of insecticide resistance
varied between villages, the rate of P. falciparum infec-
tion was not greater in villages with higher levels of
resistance. This finding may be partly due to the relatively
small number of villages surveyed for insecticide resist-
ance, and the resulting lack of statistical power, although
no evidence of an association between malaria and insec-
ticide resistance has been found in large area studies in
the Sudan and Kenya [14]. Despite the high levels of pyre-
throid resistance in the study area, no malaria vectors
were found under the children’s ITN after 1,156 searches. Discussion This would imply that the nets are still providing some
level of personal protection since a study in The Gam-
bia found malaria mosquitoes under 48.3% of untreated
bed nets following 1584 net searches [42]. Another study
conducted in Kenya in an area of pyrethroid resistance
found live An. gambiae s.l. in holed ITNs, with signifi-
cantly higher numbers in nets with holes greater than 50
sq cm in size [43]. Although not measured in this cohort, the most poor children [39]. The same pattern was also
observed when SES quintiles were included in the model. The SES factor score was used in the multivariable model
instead of the study quintiles since, unlike quintiles which
allocate children into categories, the factor score better
reflects the range of values in the dataset. The finding
that the least poor children have a higher P. falciparum
infection risk is not explained by a greater number of
passively detected infections in these children. Passive
cases contributed only 4% of all cases identified and there
were no differences in this proportion across wealth
quintiles. Plasmodium falciparum infection rates may be
higher in the least poor children due to lower ITN use
than the most poor children. Only 53.2% of the least poor
children were reported to use an ITN the previous night
compared to over 82.6% of children in the lowest quintile
(most poor). the most poor children [39]. The same pattern was also
observed when SES quintiles were included in the model. The SES factor score was used in the multivariable model
instead of the study quintiles since, unlike quintiles which
allocate children into categories, the factor score better
reflects the range of values in the dataset. The finding
that the least poor children have a higher P. falciparum
infection risk is not explained by a greater number of
passively detected infections in these children. Passive
cases contributed only 4% of all cases identified and there
were no differences in this proportion across wealth
quintiles. Plasmodium falciparum infection rates may be
higher in the least poor children due to lower ITN use
than the most poor children. Only 53.2% of the least poor
children were reported to use an ITN the previous night
compared to over 82.6% of children in the lowest quintile
(most poor). No association was found between P. Discussion ≤ 12
118
265
46.32
5.72
1.07 (0.94–1.21)
0.33
> 12
79
161
33.06
4.87
0.91 (0.79–1.04)
0.16
Bed net integrity (at final survey in December)
Good (pHI: 0–64)
155
331
62.63
5.28
–
Damaged (pHI: 65–642)
36
81
15.71
5.16
0.98 (0.83–1.15)
0.76
Too torn (pHI: 643 +)
58
134
23.52
5.70
1.08 (0.97–1.20)
0.18
Used other personal protective measures
No
184
407
74.64
5.45
–
–
Yes
58
125
24.53
5.10
0.93 (0.81–1.08)
0.36
Housing: roof of child’s sleeping room
Metal
191
420
77.60
5.41
–
Non metal
52
114
21.85
5.22
0.96 (0.85–1.09)
0.57 Table 2 Risk factors for Plasmodium infection incidence among children aged 5–15 years in Banfora region of Burkina
F modium infection incidence among children aged 5–15 years in Banfora region of Burkina en aged 5–15 years in Banfora region of Burkina Page 9 of 12 Yaro et al. Discussion This is in line with other sur-
veys including the 2017–8 MIS survey, which reported
that 76.0% children under 5 years slept under an ITN the
previous night [7]. The finding of lower reported ITN use
in the least poor children (quintile 5) was unexpected. Other studies indicate higher ITN use among the least
poor, including the 2018 Burkina Faso MIS survey in all
ages which shows the least poor (quintile 5) have 1.4–1.6
times the odds of using an ITN the previous night com-
pared to the most poor (quintile 1). It will be important
to explore the reasons for the apparent lower ITN use
among the least poor children in future studies. Data on
ITN ownership or access was not collected as part of this
study and so it is not known whether this was the cause
of lower ITN use among the least poor children. Stud-
ies across SSA indicate that the net-use gap is primarily
driven by intra-household access [48]. Despite the overall
high reported bed net use in the study population, and
considering that the NMCP campaign only took place
the year before the study started, there was cause for con-
cern about the durability of the ITNs since only 62.2% of
the children’s ITNs were in good condition at the final
survey. Although a longitudinal survey of the ITNs was
not conducted, the finding is supported by studies from
other countries. For example, in Tanzania a randomized
double-blind prospective evaluation of the lifespan of
three ITN products found that the functional survival
(ITNs in serviceable condition) was 2 years for Olyset™
and 2.5 years for Permanet® ITNs [16], the two types of
ITN delivered by the Burkina Faso NMCP. Bio-efficacy of
the sample of children’s ITNs evaluated showed low 24-h
mortality of 42.2% for Olyset™ nets and 39.9% for Per-
manet®, substantially below the ≥ 80% mortality thresh-
old set by WHO. Thus, there is a great deal of uncertainty
about net use and the protective efficacy of ITNs in y
Burkina Faso is one of ten SSA countries designated as
a High Burden High Impact country with a response plan
including increased political will, strategic use of data
to deploy tools for maximum impact and a multi-secto-
ral approach. Discussion falciparum infec-
tion risk and either of the two entomological variables
hypothesized to impact on the primary outcome, namely
EIR and insecticide resistance. The lack of association
with EIR and vector density is counter-intuitive given it Yaro et al. Malar J (2020) 19:371 Page 10 of 12 Page 10 of 12 Burkina Faso. The analysis shows that there was no dif-
ference in malaria risk between ITN users and non-users,
nor that children sleeping under badly torn nets were
more likely to have P. falciparum infections than those
that slept under good nets. early evening malaria vector biting is found in the study
area (Sanou, pers. commun.). This is a time when it is
common to find communities active in the peridomestic
environment, for example cooking, eating or socializing. In the study site an estimated 85% of exposure to malaria
vector bites can be prevented by use of ITNs from 22.00
to 05.00 but early evening biting outdoors and sporozoite
rates of 3.3%, mean that residents are still exposed to ~ 32
infectious bites per person per year even with high ITN
compliance (Sanou, pers. commun.). Early evening bit-
ing outdoors when people are active in the peridomestic
environment is common across Africa [44], and high-
lights the need for vector control tools that can pro-
tect outdoors, such as insecticide-treated ‘eave ribbons’,
attractive targeted sugar baits or larval source manage-
ment [45–47]. The study has several limitations. Firstly, and most
importantly, the study was probably underpowered to
detect small risk factors. The sample size calculation
assumed 50% prevalence of risk factors in the study
population, while the study children were, in reality, rela-
tively homogeneous with regard to risk factors shown
to be important in other studies, for example, house
construction. Secondly, while caregivers reported high
compliance with ITN use, assessing ITN use is notori-
ously difficult and this may have impacted on the ability
to identify this as an important risk factor. Indeed, social
desirability bias and other forms of error mean that sur-
veys are likely to substantially overestimate use [49], and
objective and unobtrusive tools to measure ITN compli-
ance are not currently available. ITN use was high with 80.6% of caregivers report-
ing that the study child slept under an ITN the previous
night at the baseline survey. Consent for publication
Not applicable. Consent for publication
Not applicable. Consent for publication
Not applicable. Funding This project was supported by the Wellcome Trust (Wellcome Trust Collabora-
tive Award “Improving the efficacy of malaria prevention in an insecticide
resistant Africa (MiRA)” to the Liverpool School of Tropical Medicine grant
agreement number 200222/Z/15/Z). The funder had no role in study design,
data collection and analysis, decision to publish, or preparation of the
manuscript. 12. Pryce J, Richardson M, Lengeler C. Insecticide-treated nets for preventing
malaria. Cochrane Database Syst Rev. 2018;11:CDd000363. 12. Pryce J, Richardson M, Lengeler C. Insecticide-treated nets for preventing
malaria. Cochrane Database Syst Rev. 2018;11:CDd000363. 13. Strode C, Donegan S, Garner P, Enayati AA, Hemingway J. The impact
of pyrethroid resistance on the efficacy of insecticide-treated bed nets
against African anopheline mosquitoes: systematic review and meta-
analysis. PLoS Med. 2014;11:e1001619. 14. Kleinschmidt I, Bradley J, Knox TB, Mnzava AP, Kafy HT, Mbogo C, et al. Implications of insecticide resistance for malaria vector control with long-
lasting insecticidal nets: a WHO-coordinated, prospective, international,
observational cohort study. Lancet Infect Dis. 2018;18:640–9. Conclusionsh The authors declare that they have no competing interests. All authors declare
that they had full access to all of the data in the study and take responsibility
for the integrity of the data and the accuracy of the data analysis. The study found overwhelmingly high levels of malaria
transmission in Banfora district, in southwest Burkina
Faso, and the risk factor survey did not identify any risk
factors for further investigation to reduce the malaria
burden. The findings have implications for achieve-
ment of the ambitious goals set out in the WHO Global
Technical Strategy [55]. Malaria elimination in this area
of intense seasonal transmission can only be achieved
through the use of additional interventions. References ACT: Artemisinin combination therapy; AL: Artemether-lumefantrine; CI:
Confidence interval; CNRFP: Centre National de Recherche et de Formation sur
le Paludisme; EIR: Entomological inoculation rate; IRR: Incidence rate ratio; IRS:
Indoor residual spraying; ITN: Insecticide-treated net; NMCP: National Malaria
Control Programme; PBO: Piperonyl butoxide; PCR: Polymerase chain reaction;
pHI: Proportionate hole index; SD: Standard deviation; SES: Socio-economic
status; SMC: Seasonal malaria chemoprevention; SSA: Sub-Saharan Africa;
WHO: World Health Organization. 1. WHO. World Malaria Report 2019. Geneva: World Health Organization;
2019. 2. Bhatt S, Weiss DJ, Cameron E, Bisanzio D, Mappin B, Dalrymple U, et al. The effect of malaria control on Plasmodium falciparum in Africa between
2000 and 2015. Nature. 2015;526:207–11. 2. Bhatt S, Weiss DJ, Cameron E, Bisanzio D, Mappin B, Dalrymple U, et al. The effect of malaria control on Plasmodium falciparum in Africa between
2000 and 2015. Nature. 2015;526:207–11. 3. WHO. RBM Partnership to End Malaria High burden to high impact: a
targeted malaria response. Geneva: World Health Organization; 2019. 3. WHO. RBM Partnership to End Malaria High burden to high impact: a
targeted malaria response. Geneva: World Health Organization; 2019. 4. Ministère de la Santé Burkina Faso. Annuaire statistique 2018. Ouag
gou: Ministère de la Santé Burkina Faso; 2019. q
g
gou: Ministère de la Santé Burkina Faso; 2019. 5. Ministère de la Santé Burkina Faso. Annuaire statistique 2016. Ouagadou-
gou: Ministère de la Santé Burkina Faso; 2017. 6. Ministère de la Santé Burkina Faso. Annuaire statistique 2017. Ouagadou-
gou: Ministère de la Santé Burkina Faso; 2018. Acknowledgements 5. Ministère de la Santé Burkina Faso. Annuaire statistique 2016. Ouagadou-
gou: Ministère de la Santé Burkina Faso; 2017. Authors wish to thank the CNRFP staff, community members, opinion leaders,
the community health workers, research assistants, field supervisors and work-
ers whose cooperation and help made this study possible. Special thanks to
Issiaka Soulama for supervising PCR analysis in CNRFP, Blami Kote for contribu-
tion to data analysis and Luca Nelli for providing the distances to the nearest
health centre. Thank you very much to Sodiomon B Sirima for all the support
during this work. 6. Ministère de la Santé Burkina Faso. Annuaire statistique 2017. Ouagadou-
gou: Ministère de la Santé Burkina Faso; 2018. 7. Louis VR, Schoeps A, Tiendrebéogo J, Beiersmann C, Yé M, Damiba MR,
et al. An insecticide-treated bed-net campaign and childhood malaria in
Burkina Faso. Bull World Health Organ. 2015;93:750–8. 7. Louis VR, Schoeps A, Tiendrebéogo J, Beiersmann C, Yé M, Damiba MR,
et al. An insecticide-treated bed-net campaign and childhood malaria in
Burkina Faso. Bull World Health Organ. 2015;93:750–8. 8. Namountougou M, Simard F, Baldet T, Diabaté A, Ouédraogo JB, Martin T,
et al. Multiple insecticide resistance in Anopheles gambiae s.l. populations
from Burkina Faso West Africa. PLoS ONE. 2012;7:e48412. 8. Namountougou M, Simard F, Baldet T, Diabaté A, Ouédraogo JB, Martin T,
et al. Multiple insecticide resistance in Anopheles gambiae s.l. populations
from Burkina Faso West Africa. PLoS ONE. 2012;7:e48412. The results of this study were presented at the American Society of Tropi-
cal Medicine and Hygiene Annual Meeting in 2019, National Harbor, USA. 9. Toé KH, Jones CM, N’Fale S, Ismail HM, Dabiré RK, Ranson H. Increased
pyrethroid resistance in malaria vectors and decreased bed net effective-
ness in Burkina Faso. Emerg Infect Dis. 2014;20:1691–6. 9. Toé KH, Jones CM, N’Fale S, Ismail HM, Dabiré RK, Ranson H. Increased
pyrethroid resistance in malaria vectors and decreased bed net effective-
ness in Burkina Faso. Emerg Infect Dis. 2014;20:1691–6. Author details 1 Centre National de Recherche et de Formation sur le Paludisme, Ouagadou-
gou, Burkina Faso. 2 Department of Biosciences, Durham University, Durham,
UK. 3 Department of Vector Biology, Liverpool School of Tropical Medicine, Liv-
erpool, UK. 4 Institute of Biodiversity Animal Health & Comparative Medicine,
Glasgow University, Glasgow, UK. Received: 17 July 2020 Accepted: 7 October 2020 Received: 17 July 2020 Accepted: 7 October 2020 Authors’ contributions Conceived and designed the study: SWL, ALW, ABT, NFS, HR, EW. Conducted
field and laboratory work: JBY, ABT, AO, AD, ML, KHT, AS, WMG. Conducted
data analysis: JBY, ALW, SWL, ABT, ZAO, AO, EA, EW. Contributed to and
approved the final manuscript: JBY, SWL, ALW, ABT, NFS, HR, AO, AD, ML, KHT,
AS, WMG, EA, EW. All authors read and approved the final manuscript. 10. Hughes A, Lissenden N, Viana M, Toé KH, Ranson H. Anopheles gambiae
populations from Burkina Faso show minimal delayed mortality after
exposure to insecticide-treated nets. Parasit Vectors. 2020;13:17. 10. Hughes A, Lissenden N, Viana M, Toé KH, Ranson H. Anopheles gambiae
populations from Burkina Faso show minimal delayed mortality after
exposure to insecticide-treated nets. Parasit Vectors. 2020;13:17. y
approved the final manuscript: JBY, SWL, ALW, ABT, NFS, HR, AO, AD, ML, KHT,
AS, WMG, EA, EW. All authors read and approved the final manuscript. 11. Churcher TS, Lissenden N, Griffin JT, Worrall E, Ranson H. The impact of
pyrethroid resistance on the efficacy and effectiveness of bednets for
malaria control in Africa. Elife. 2016;4:e16090. 11. Churcher TS, Lissenden N, Griffin JT, Worrall E, Ranson H. The impact of
pyrethroid resistance on the efficacy and effectiveness of bednets for
malaria control in Africa. Elife. 2016;4:e16090. Availability of data and materials The datasets used and/or analysed during the current study are available from
the corresponding author on reasonable request. 15. Obi E, Okoh F, Blaufuss S, Olapeju B, Akilah J, Okoko OO, et al. Monitoring
the physical and insecticidal durability of the long-lasting insecticidal net
DawaPlus® 20 in three States in Nigeria. Malar J. 2020;19:124. Discussion While this study generates useful data on
malaria burden in Banfora District, it is clear that addi-
tional tools will be needed to reduce this burden. Dual-
active ITNs (pyrethroid plus piperonyl butoxide (PBO) or
pyrethroid plus chlofenapyr) are now being deployed in
the study area. PBO-pyrethroid ITNs have been shown
to be more effective in reducing malaria than pyre-
throid-only ITNs in areas of pyrethroid-resistant vec-
tors [50, 51], and monitoring of the effectiveness of these
dual active ITNs is ongoing in Burkina Faso. IRS should
also be considered as it has been shown to be effective
in reducing malaria in other high-burden countries. In
an area of Uganda with an EIR of 176 infective bites/
year, three rounds of IRS with the carbamate insecti-
cide, bendiocarb, every six months reduced malaria inci-
dence from 3.3 episodes to 0.6 episodes per person year
[52]. Even this effective combination of interventions
is, however, insufficient to eliminate malaria, so further
interventions are required. SMC is currently being used
in 12 sub-Sahelian countries, including Burkina Faso, in
children up to 5 years of age, with a protective efficacy of
over 50% against parasitaemia in Burkina Faso [22, 53]. A recent trial in Senegal found similarly high reductions
in malaria when SMC was used in children aged under
5 years and in children aged 5 to 9 years [54]. Expanding
the age range eligible for SMC could, therefore, be effec-
tive in reducing malaria further in Burkina Faso. Burkina
Faso is also the site of pilot testing of gene drive mos-
quitoes, which if proven to be efficacious, feasible and Yaro et al. Malar J (2020) 19:371 Page 11 of 12 Page 11 of 12 acceptable, could be a potential option for malaria con-
trol in Burkina Faso. acceptable, could be a potential option for malaria con-
trol in Burkina Faso. Ethics approval and consent to participate The caregivers of study participants provided informed consent (or assent of
child if aged 12–15 years) to participate in the study. Study documents were
approved by the Burkina Faso Ministry of Health Research Ethics Commit-
tee (Deliberation No 2016-12-137), CNRFP Institutional Bioethics Committee
(No2016/000007/MS/SG/CNRFP/CIB), Durham University Department of
Biosciences Ethics Committee (SBBS/EC/MIRA) and Liverpool School of Tropi-
cal Medicine Ethical Committee (Protocol number: 16/047). The study was
conducted in compliance with principles set out by the International Confer-
ence on Harmonization Good Clinical Practice, the Declaration of Helsinki and
the regulatory requirements of Burkina Faso. 16. Lorenz LM, Bradley J, Yukich J, Massue DJ, Mboma ZM, Pigeon O, et al. Comparative functional survival and equivalent annual cost of three long
lasting insecticidal net (LLIN) products in Tanzania: a randomised trial
with 3-year follow up. PLoS Med. 2020;17:e1003248. y
17. Hakizimana E, Cyubahiro B, Rukundo A, Kabayiza A, Mutabazi A, Beach R,
et al. Monitoring long-lasting insecticidal net (LLIN) durability to validate
net serviceable life assumptions in Rwanda. Malar J. 2014;13:344. Yaro et al. Malar J (2020) 19:371 Page 12 of 12 Yaro et al. Malar J (2020) 19:371 18. Bhatt S, Weiss DJ, Mappin B, Dalrymple U, Cameron E, Bisanzio D, et al. Coverage and system efficiencies of insecticide-treated nets in Africa
from 2000 to 2017. Elife. 2015;4:e09672. malaria: a prospective cohort study at 3 sites in Uganda. Clin Infect Dis. 2019;68:313–20. 39. Tusting LS, Willey B, Lucas H, Thompson J, Kafy HT, Smith R, et al. Socio-
economic development as an intervention against malaria: a systematic
review and meta-analysis. Lancet. 2013;382:963–72. 19. Tusting LS, Ippolito MM, Willey BA, Kleinschmidt I, Dorsey G, Gosling RD,
et al. The evidence for improving housing to reduce malaria: a systematic
review and meta-analysis. Malar J. 2015;14:e209. 40. Kirby MJ, Ameh D, Bottomley C, Green C, Jawara M, Milligan PJ, et al. Effect of two different house screening interventions on exposure to
malaria vectors and on anaemia in children in The Gambia: a randomised
controlled trial. Lancet. 2009;374:998–1009. 20. Tiono AB, Kangoye DT, Rehman AM, Kargougou DG, Kabore Y, Diarra
A, et al. Malaria incidence in children in South-West Burkina Faso:
comparison of active and passive case detection methods. PLoS ONE. 2014;9:e86936. 41. Adiamah JH, Koram KA, Thomson MC, Lindsay SW, Todd J, Greenwood
BM. Entomological risk factors for severe malaria in a peri-urban area of
The Gambia. Ann Trop Med Parasit. 1993;87:491–500. 21. Ethics approval and consent to participate Tiono AB, Guelbeogo MW, Sagnon NF, Nebie I, Sirima SB, Mukhopadhyay
A, et al. Dynamics of malaria transmission and susceptibility to clinical
malaria episodes following treatment of Plasmodium falciparum asymp-
tomatic carriers: results of a cluster-randomized study of community-
wide screening and treatment, and a parallel entomology study. BMC
Infect Dis. 2013;13:535. 42. Lindsay SW, Alonso PL, Armstrong Schellenberg JR, Hemingway J, Adia-
mah JH, Shenton FC, et al. A malaria control trial using insecticide-treated
bed nets and targeted chemoprophylaxis in a rural area of The Gambia,
West Africa. 7. Impact of permethrin-impregnated bed nets on malaria
vectors. Trans R Soc Trop Med Hyg. 1993;87:45–51. 22. WHO. WHO policy recommendation: Seasonal Malaria Chemopreven-
tion (SMC) for Plasmodium falciparum malaria control in highly seasonal
transmission areas of the Sahel sub-region in Africa. Geneva: World
Health Organization; 2012. 43. Ochomo EO, Bayoh NM, Walker ED, Abongo BO, Ombok MO, Ouma C,
et al. The efficacy of long-lasting nets with declining physical integrity
may be compromised in areas with high levels of pyrethroid resistance. Malar J. 2013;12:368. 23. Gonçalves BP, Kapulu MC, Sawa P, Guelbéogo WM, Tiono AB, Grignard
L, et al. Examining the human infectious reservoir for Plasmodium falci-
parum malaria in areas of differing transmission intensity. Nat Commun. 2017;8:1133. 44. Sherrard-Smith E, Skarp J, Beale A, Fornadel C, Norris L, Moore SJ, et al. Mosquito feeding behaviour and how it influences residual malaria
transmission across Africa. Proc Natl Acad Sci USA. 2019;116:15086–95. 24. Ministère de la Santé Burkina Faso. Directives nationales pour la prise
en charge du paludisme dans les formations sanitaires du Burkina Faso. Ouagadougou: Ministère de la Santé Burkina Faso; 2014. 45. Choi L, Majambere S, Wilson AL. Larviciding to prevent malaria transmis-
sion. Cochrane Database Syst Rev. 2019;8:CD012736. 46. Mmbando AS, Ngowo H, Limwagu A, Kilalangongono M, Kifungo K,
Okumu FO. Eave ribbons treated with the spatial repellent, transfluthrin,
can effectively protect against indoor-biting and outdoor-biting malaria
mosquitoes. Malar J. 2018;17:368. 25. Snounou G, Viriyakosol S, Zhu XP, Jarra W, Pinheiro L. do RV, Thaithong
S, Brown KN: High sensitivity of detection of human malaria parasites
by the use of nested polymerase chain reaction. Mol Biochem Parasitol. 1993;61:315–20. 47. Traore MM, Junnila A, Traore SF, Doumbia S, Revay EE, Kravchenko
VD, et al. Large-scale field trial of attractive toxic sugar baits (ATSB) for
the control of malaria vector mosquitoes in Mali. West Africa Malar J. 2020;19:72. 26. Ethics approval and consent to participate Institut National de la Statistique et de la Démographie (INSD), Pro-
gramme National de Lutte contre le Paludisme (PNLP), ICF International. Enquête sur les indicateurs du paludisme (EIPBF). Ouagadougou: INSD,
PNLP and ICF International, 2015. 48. Koenker H, Kilian A. Recalculating the net use gap: a multi-country com-
parison of ITN use versus ITN access. PLoS ONE. 2014;9:e97496. 27. WHO. Guidelines for monitoring the durability of long-lasting insecticidal
mosquito nets under operational conditions. Geneva: World Health
Organization; 2011. 49. Krezanoski PJ, Bangsberg DR, Tsai AC. Quantifying bias in measuring
insecticide-treated bednet use: meta-analysis of self-reported vs objec-
tively measured adherence. J Glob Health. 2018;8:010411. 28. WHO. Guidance note for estimating the longevity of long-lasting insecti-
cidal nets in malaria control. Geneva: World Health Organization; 2013. 50. Protopopoff N, Mosha JF, Lukole E, Charlwood JD, Wright A, Mwalimu
CD, et al. Effectiveness of a long-lasting piperonyl butoxide-treated
insecticidal net and indoor residual spray interventions, separately and
together, against malaria transmitted by pyrethroid-resistant mosquitoes:
a cluster, randomised controlled, two-by-two factorial design trial. Lancet. 2018;391:1577–88. 29. WHO. Guidelines for laboratory and field testing of long-lasting insecti-
cidal nets. Geneva: World Health Organization; 2013. 30. Scott JABW, Collins FH. Identification of single specimens of the Anoph-
eles gambiae complex by the polymerase chain reaction. Am J Trop Med
Hyg. 1993;4:520–9. 31. WHO. Test procedures for insecticide resistance monitoring in malaria
vector mosquitoes -. 2nd ed. Geneva: World Health Organization; 2016. 51. Staedke SG, Gonahasa S, Dorsey G, Kamya MR, Maiteki-Sebuguzi C, Lynd
A, et al. Effect of long-lasting insecticidal nets with and without piperonyl
butoxide on malaria indicators in Uganda (LLINEUP): a pragmatic, cluster-
randomised trial embedded in a national LLIN distribution campaign. Lancet. 2020;395:1292–303. 31. WHO. Test procedures for insecticide resistance monitoring in malaria
vector mosquitoes -. 2nd ed. Geneva: World Health Organization; 2016. 32. Kirkwood BR, Sterne JAC. Essential Medical Statistics. 2nd ed. Hoboken:
Blackwell Science Ltd; 2003. 32. Kirkwood BR, Sterne JAC. Essential Medical Statistics. 2nd ed. Hoboken:
Blackwell Science Ltd; 2003. 33. von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke
JP, STROBE Initiative. The strengthening the reporting of observational
studies in epidemiology (STROBE) statement: guidelines for reporting
observational studies. Lancet. 2007;370:1453–7. 52. Katureebe A, Zinszer K, Arinaitwe E, Rek J, Kakande E, Charland K, et al. Ethics approval and consent to participate Measures of malaria burden after long-lasting insecticidal net distribu-
tion and indoor residual spraying at three sites in Uganda: a prospective
observational study. PLoS Med. 2016;13:e1002167. 34. Diallo A, Sié A, Sirima S, Sylla K, Ndiaye M, Bountogo M, et al. An epide-
miological study to assess Plasmodium falciparum parasite prevalence
and malaria control measures in Burkina Faso and Senegal. Malar J. 2017;16:63. y
53. Druetz T, Corneau-Tremblay N, Millogo T, Kouanda S, Ly A, Bicaba A, et al. Impact evaluation of seasonal malaria chemoprevention under routine
program implementation: a quasi-experimental study in Burkina Faso. Am J Trop Med Hyg. 2018;98:524–33. 35. Wehner S, Stieglbauer G, Traore C, Sie A, Becher H, Muller O. Malaria
incidence during early childhood in rural Burkina Faso: analysis of a birth
cohort protected with insecticide-treated mosquito nets. Acta Trop. 2017;175:78–83. 54. Ndiaye JLA, Ndiaye Y, Ba MS, Faye B, Ndiaye M, Seck A, et al. Seasonal
malaria chemoprevention combined with community case management
of malaria in children under 10 years of age, over 5 months, in south-east
Senegal: a cluster-randomised trial. PLoS Med. 2019;16:e1002762. 36. Ouédraogo A, Tiono AB, Diarra A, Sanon S, Yaro JB, Ouedraogo E, et al. Malaria morbidity in high and seasonal malaria transmission area of
Burkina Faso. PLoS ONE. 2013;8:e50036. 55. WHO. Global technical strategy for malaria 2016–2030. Geneva: World
Health Organization; 2016. 37. Smith C, Whittaker M. Beyond mobile populations: a critical review of the
literature on malaria and population mobility and suggestions for future
directions. Malar J. 2014;13:307. Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in pub-
lished maps and institutional affiliations. Springer Nature remains neutral with regard to jurisdictional claims in pub-
lished maps and institutional affiliations. 38. Arinaitwe E, Dorsey G, Nankabirwa JI, Kigozi SP, Katureebe A, Kakande
E, et al. Association between recent overnight travel and risk of
|
https://openalex.org/W3092129528
|
https://hal.science/hal-03183902/file/bg-18-1407-2021.pdf
|
English
| null |
Technical note: Interpreting pH changes
|
Biogeosciences
| 2,021
|
cc-by
| 8,382
|
1
Introduction In 1909, Danish biochemist Søren Peter Lauritz Sørensen
proposed using a logarithmic scale to display the wide range
of natural hydrogen ion concentrations (CH, expressed in
mol L−1) in a more compact numerical form (Sørensen,
1909). (1) Correspondence: Andrea J. Fassbender (andrea.j.fassbender@noaa.gov) Correspondence: Andrea J. Fassbender (andrea.j.fassbender@noaa.gov) Received: 23 September 2020 – Discussion started: 12 October 2020
Revised: 5 January 2021 – Accepted: 14 January 2021 – Published: 24 February 2021 Here, γH is the activity coefficient of H+ (aq) at molal-
ity mH, and m◦(1 mol (kg H2O)−1) is the standard molal-
ity. The negative logarithm was adopted by Sørensen and
Linderstrøm-Lang as a simpler way to express the original
reciprocal. Summaries of modern pH scale development and
refinement can be found elsewhere (Spitzer and Pratt, 2011). Still, since its inception, concerns have been raised about the
inverse and logarithmic relationship between hydrogen ion
concentration and pH being nonintuitive (see Clark, 1922,
especially p. 34) and the resulting increased likelihood of
misinterpreted results. This prompted scientists to argue for
alternatives to the pH scale, such as using specific acidity
(107 minus the [H+]) and its base 10 logarithm (i.e., 7−pH)
Clark et al., 1921; Wherry, 1919; Wherry and Adams, 1921). However, such efforts were unsuccessful, and the Sørensen
and Linderstrøm-Lang (1924) notional definition of pH, used
early on as the basis for a conventional definition of pH and to
assign values to pH standards (Bates and Guggenheim, 1960;
Cohen et al., 2007; Covington et al., 1985; Hamer and Acree,
1939; McGlashan, 1970), was ultimately adopted by the In-
ternational Union of Pure and Applied Chemistry in 2002,
thus defining pH explicitly through Eq. (2) (Baucke, 2002;
Buck et al., 2002; Cohen et al., 2007). Abstract. The number and quality of ocean pH measure-
ments have increased substantially over the past few decades
such that trends, variability, and spatial patterns of change
are now being evaluated. However, comparing pH changes
across domains with different initial pH values can be mis-
leading because a pH change reflects a relative change in the
hydrogen ion concentration ([H+], expressed in mol kg−1)
rather than an absolute change in [H+]. We recommend that
[H+] be used in addition to pH when describing such changes
and provide three examples illustrating why. A. J. Fassbender et al.: Interpreting pH changes 1
shows that the same pH change results in a 10-fold greater
change in [H+] when starting at pH 7.4 instead of pH 8.4
(which will be true of any magnitude of pH change starting
at these two values). The same point is made in a different
manner by Kwiatkowski and Orr (2018). For studies evalu-
ating trends and variability in pH, it is thus advantageous to
also report results in terms of [H+] to make clear how the
initial condition,
H+
1 in Eq. (5), influences the magnitude
of the perturbation. Equation (4) shows that changes in pH reflect a relative
change in [H+], while Eq. (5) shows that the same pH change
can equate to different [H+] changes when implemented at
different initial [H+] (or pH) values. For example, Fig. 1
shows that the same pH change results in a 10-fold greater
change in [H+] when starting at pH 7.4 instead of pH 8.4
(which will be true of any magnitude of pH change starting
at these two values). The same point is made in a different
manner by Kwiatkowski and Orr (2018). For studies evalu-
ating trends and variability in pH, it is thus advantageous to
also report results in terms of [H+] to make clear how the
initial condition,
H+
1 in Eq. (5), influences the magnitude
of the perturbation. In the discussion, we provide three real-world examples
that illustrate why reporting [H+] alongside pH can improve
the clarity of studies that aim to evaluate changes in ocean
chemistry. These examples include an evaluation of (1) mod-
ern sea surface trends, (2) the evolution of seasonal cycle
amplitudes over the 21st century, and (3) changing interior
ocean chemistry. Since the beginning of the industrial era, it is estimated
that ocean acidification has led to a global mean decline of
∼0.1 in surface ocean pH (8.2 to 8.1), which corresponds
to an [H+] increase of ∼1.6 nmol kg−1 (i.e., from 6.3 to
7.9 nmol kg−1). It has not always been realized, however, that
changes in pH reflect relative changes in [H+] rather than
absolute changes. Most pH fluctuations in the ocean appear A. J. Fassbender et al.: Interpreting pH changes The relationship between these parameters can be
derived as follows: 1pH = pH2 −pH1 = −log10
H+
2
+ log10
H+
1
, (3)
and thus 1pH = pH2 −pH1 = −log10
H+
2
+ log10
H+
1
, (3)
and thus (3) and thus −1pH = log10
H+
2
H+
1
! . (4) (4) (4) Here
H+
2 and
H+
1 represent the hydrogen ion concen-
trations corresponding to pH2 and pH1, respectively. The cor-
responding change in [H+] (i.e., 1
H+
=
H+
2 −
H+
1)
can then be shown to be p g
Ocean pH is considered an Essential Ocean Variable
(GOOS, 2019) and an Essential Climate Variable (GCOS,
2016) because it can be used to characterize ocean chem-
istry changes associated with anthropogenic carbon invasion
and climate change, and it also meets the other desired cri-
teria of measurement feasibility and cost-effectiveness. Dis-
tinct rates of persistent pH decline over decades have been
observed across the global surface ocean at well-maintained
time-series sites (e.g., Bates et al., 2014; Sutton et al., 2014). Repeat hydrographic sections have also made it possible
to characterize how ocean acidification is propagating into
the ocean interior over decadal timescales (e.g., Dore et al.,
2009; Lauvset et al., 2020). Autonomous pH sensors capa-
ble of sustained observations have begun to reveal the range
and frequency of pH variations in open ocean and coastal
waters (see Bushinsky et al., 2019). These observational ef-
forts, in addition to numerical modeling studies (Bopp et al.,
2013; Jiang et al., 2019; Kwiatkowski et al., 2020; Orr et
al., 2005; Steinacher et al., 2009), inform our understanding
of secular changes, patterns, and variability in ocean pH and
guide research probing the sensitivities of marine organisms
to changes in CO2 system variables. 1
H+
=
H+
1
10−1pH −1
. (5) (5) Equation (4) shows that changes in pH reflect a relative
change in [H+], while Eq. (5) shows that the same pH change
can equate to different [H+] changes when implemented at
different initial [H+] (or pH) values. For example, Fig. pH = log10 (1/CH) pH = log10 (1/CH) The logarithmic scaling of hydrogen ion concentration de-
rives from the Nernst equation, which relates the potential
of an electrochemical cell to ion concentrations in solution,
while the reciprocal form ensured predominantly positive
values for pH in an aqueous solution (aq; Sørensen, 1909). This definition was later amended to explicitly use the hy-
drogen ion activity (aH) in aqueous solution (rather than the
concentration) so as to take account of interionic forces when
treating electromotive force data (Sørensen and Linderstrøm-
Lang, 1924). This is the basis of the modern definition of pH
(Buck et al., 2002): Within the field of marine science, several scales, all go-
ing under the name pH, have been commonly applied. These
include one scale based on an operational approach that re-
lies on calibration standards from the National Bureau of
Standards (NBS; now the National Institute of Standards
and Technology) and a variety of other scales whose ap-
proaches all aim to realize pH as a “concentration” of hydro-
gen ions, usually expressed in moles per kilogram (mol kg−1)
(Bates, 1982; Dickson, 1984; Dickson et al., 2016; Marion
et al., 2011; Waters and Millero, 2013). Such approaches pH = −log10(aH) = −log10
mHγH/m◦
. (2) (2) Published by Copernicus Publications on behalf of the European Geosciences Union. Published by Copernicus Publications on behalf of the European Geosciences Union. Published by Copernicus Publications on behalf of the European Geosciences Union. A. J. Fassbender et al.: Interpreting pH changes A. J. Fassbender et al.: Interpreting pH changes 1408 A. J. Fassbender et al.: Interpreting pH changes Figure 1. (a) A 0.2 unit decrease in pH (blue portion of bars)
equates to (b) a 58 % increase in [H+] (red portion of bars) for
both initial pH values of 7.4 and 8.4. The absolute change in [H+]
depends on the initial conditions. were developed to simplify the use of acid–base equilibrium
calculations in seawater media. The pH values presented
here are on the total hydrogen ion scale, the scale that is
presently favored for measurement and reporting in observa-
tional oceanography (Dickson, 2010); however, the concern
we illustrate here applies similarly to all marine science pH
scales. The immediate interest in assessing ocean pH changes is to
help understand the consequences of rising atmospheric car-
bon dioxide (CO2) levels caused primarily by the combustion
of fossil fuels which result in a net transfer of CO2 from the
atmosphere to the ocean (Friedlingstein et al., 2020). Once
dissolved in the ocean, CO2 reacts with water to form a weak
acid that loses a hydrogen ion, which is largely neutralized
through reaction with a carbonate ion to form bicarbonate,
causing the seawater [H+] to increase and the pH to decrease
(Millero, 2007). This overall process is commonly referred to
as ocean acidification (Caldeira and Wickett, 2003; Doney et
al., 2009), and it may have far reaching effects on marine life
(Boyd et al., 2016; Doney et al., 2014; Hofmann et al., 2010;
Kleypas et al., 2006) and on the rates of a variety of carbon
cycle feedback processes within the ocean (e.g., Archer et
al., 1998; Boudreau et al., 2018; Passow and Carlson, 2012;
Revelle and Suess, 1957). As a result, it has become a prior-
ity in oceanography to monitor ocean pH and understand its
natural and anthropogenic variations (Brewer, 2013). Figure 1. (a) A 0.2 unit decrease in pH (blue portion of bars)
equates to (b) a 58 % increase in [H+] (red portion of bars) for
both initial pH values of 7.4 and 8.4. The absolute change in [H+]
depends on the initial conditions. small, but for a given pH change (1pH), the associated [H+]
change (1[H+]) varies depending on the initial [H+] con-
centration. A. J. Fassbender et al.: Interpreting pH changes The color map for this figure, and for all subsequent figures, was made using
cmocean (Thyng et al., 2016). Figure 2. Change in sea surface (a) pH and (b) [H+] over 20 years at two hypothetical locations. Changes are plotted relative to the initial
pH (8.1 and 7.9) and [H+] (7.9 and 12.6 nmol kg−1) values noted in the figures. A fixed pH trend (dpH / dt) of −0.0017 yr−1 was imposed
at both sites, resulting in [H+] trends (d[H+] / dt) of 0.03 and 0.05 nmol kg−1 yr−1. (c) Contour plot showing linearized trends in [H+]
(nmol kg−1 yr−1) associated with mean (or initial) pH values referenced to the year 2010 and the corresponding pH trends. The y axis is
reversed so that larger magnitude pH trends are near the top left corner. Symbols show observed surface ocean pH trends and uncertainties
(at in situ temperature) at select time-series sites, in which legend superscripts refer to (1) Sutton et al. (2014) and (2) Bates et al. (2014). A
total of 13 additional sites are included in Fig. S1. Details regarding the determination of mean pH values referenced to the year 2010 are
described in Text S1, and the values are presented in Table S1. The color map for this figure, and for all subsequent figures, was made using
cmocean (Thyng et al., 2016). The second opportunity to improve clarity concerns sea-
sonal and diurnal variability in ocean CO2 chemistry, both
of which may condition the fitness and survival of organisms
(Hales et al., 2017; Hofmann et al., 2011; Kapsenberg and
Cyronak, 2019; McNeil and Sasse, 2016). Identical peak-to-
peak amplitudes of pH variations at locations having differ-
ent annual mean pH implies different peak-to-peak ampli-
tudes in [H+]. While accounting for this concern affects the
interpretation of spatial patterns of pH variations, it appears
even more critical when assessing how conditions evolve
over time. For example, the seasonal amplitude of pH (A-pH)
is expected to decrease, while that of [H+] (A-[H+]) is ex-
pected to increase throughout much of the surface ocean over
the 21st century under the RCP8.5 scenario (Kwiatkowski
and Orr, 2018). This phenomenon arises because A-[H+]
increases relatively more slowly over time than the annual
mean [H+]. To illustrate how different these absolute and
relative changes can be, in Fig. A. J. Fassbender et al.: Interpreting pH changes 3 let us compare simulated
time series of pH and [H+] sampled at the locations of the
Kuroshio Extension Observatory (KEO; Table S2) and Drake
Passage region north of the Antarctic Polar Front (DPN; Ta-
ble S2) from the Geophysical Fluid Dynamics Laboratory’s
(GFDL) Earth System Model (ESM2M; Dunne et al., 2012,
2013) for the CMIP5 historical and RCP8.5 experiments (Ri-
ahi et al., 2011). Despite nearly identical decreases in A-pH
at KEO (−0.0139) and DPN: (−0.0141) from the 1950s to
2090s, the corresponding change in A-[H+] is not only pos-
itive at both sites but 10 times greater at the former than the
latter (1.70 versus 0.17 nmol kg−1). Thus, it is desirable to
assess A-[H+] as well as A-pH. open ocean surface pH typically fall between −0.001 and
−0.003 yr−1 (Lauvset et al., 2015; Takahashi et al., 2014). A
critical piece of information that is often missing when such
trends are compared (e.g., Table 3.2 of Rhein et al., 2013)
is the initial pH value for each region. That information is
key because regions with the same pH trend but different ini-
tial pH values will exhibit different [H+] trends over time
(e.g., Fassbender et al., 2017). For example, Fig. 2a–b il-
lustrate a scenario in which two locations each experience
a pH trend of −0.0017 yr−1 (similar to that of the subtrop-
ics; Bates et al., 2014) but have different initial pH values:
7.9 and 8.1. As a result, there is a 58 % greater change in
[H+] for the first relative to the second location. That is,
when the change in pH is identical, the ratio between the
two trends in [H+] is equal to the ratio of the two initial
[H+] values. As a real-world example, Fig. 2c shows similar
pH trends for two time series, the equatorial Pacific (0◦N,
125◦W; Sutton et al., 2014) and the Irminger Sea (64.3◦N,
28◦W; Bates et al., 2014), where the initial pH values dif-
fer (Table S1), causing the trends in [H+] to differ. Yet, at
another equatorial Pacific site (0◦N, 155◦W; Sutton et al.,
2014), there is a similar [H+] trend to that of the Irminger
Sea site because the initial pH differs. While we focus here
on pH changes in the open ocean, pH changes also occur in
coastal waters where they tend to be larger (Carstensen and
Duarte, 2019). 2
Discussion The first opportunity to improve clarity concerns the com-
parison of pH changes between regions. Observed trends in Biogeosciences, 18, 1407–1415, 2021 https://doi.org/10.5194/bg-18-1407-2021 A. J. Fassbender et al.: Interpreting pH changes 1409 Figure 2. Change in sea surface (a) pH and (b) [H+] over 20 years at two hypothetical locations. Changes are plotted relative to the initial
pH (8.1 and 7.9) and [H+] (7.9 and 12.6 nmol kg−1) values noted in the figures. A fixed pH trend (dpH / dt) of −0.0017 yr−1 was imposed
at both sites, resulting in [H+] trends (d[H+] / dt) of 0.03 and 0.05 nmol kg−1 yr−1. (c) Contour plot showing linearized trends in [H+]
(nmol kg−1 yr−1) associated with mean (or initial) pH values referenced to the year 2010 and the corresponding pH trends. The y axis is
reversed so that larger magnitude pH trends are near the top left corner. Symbols show observed surface ocean pH trends and uncertainties
(at in situ temperature) at select time-series sites, in which legend superscripts refer to (1) Sutton et al. (2014) and (2) Bates et al. (2014). A
total of 13 additional sites are included in Fig. S1. Details regarding the determination of mean pH values referenced to the year 2010 are
described in Text S1, and the values are presented in Table S1. The color map for this figure, and for all subsequent figures, was made using
cmocean (Thyng et al., 2016). Figure 2. Change in sea surface (a) pH and (b) [H+] over 20 years at two hypothetical locations. Changes are plotted relative to the initial
pH (8.1 and 7.9) and [H+] (7.9 and 12.6 nmol kg−1) values noted in the figures. A fixed pH trend (dpH / dt) of −0.0017 yr−1 was imposed
at both sites, resulting in [H+] trends (d[H+] / dt) of 0.03 and 0.05 nmol kg−1 yr−1. (c) Contour plot showing linearized trends in [H+]
(nmol kg−1 yr−1) associated with mean (or initial) pH values referenced to the year 2010 and the corresponding pH trends. The y axis is
reversed so that larger magnitude pH trends are near the top left corner. Symbols show observed surface ocean pH trends and uncertainties
(at in situ temperature) at select time-series sites, in which legend superscripts refer to (1) Sutton et al. (2014) and (2) Bates et al. (2014). A
total of 13 additional sites are included in Fig. S1. Details regarding the determination of mean pH values referenced to the year 2010 are
described in Text S1, and the values are presented in Table S1. A. J. Fassbender et al.: Interpreting pH changes Figure 3. Data used in this figure come from the GFDL ESM2M model for the combined historical and RCP8.5 experiments. Time series
of surface ocean (a) pH and (d) [H+] (nmol kg−1) at model grid points corresponding to the Kuroshio Extension Observatory (KEO) and
the Drake Passage region north of the Antarctic Polar Front (DPN), similar to Region 1 in Munro et al. (2015). Surface ocean seasonal
cycle amplitudes (A) were averaged for each decade and smoothed with a running mean filter using a four-element sliding window. Shown
are the decadal changes in (b) A-pH and (e) A-[H+] (nmol kg−1) relative to the 1950s, as well as the surface ocean (c) pH and (f) [H+]
(nmol kg−1) monthly anomalies relative to the annual mean at KEO and DPN during the 1950s (thin lines) and 2090s (thick lines). Global
maps show the total change in (g) A-pH and (h) A-[H+] (nmol kg−1) between the 1950s and 2090s. White boxes are centered at the KEO
and DPN time-series sites. Simulated 1950s and 2090s annual mean pH and [H+] values, as well as the 2090s minus 1950s change in A-pH
and A-[H+], at these locations are listed in Table S2. A total of 45 additional time-series locations are included in Table S2 and Fig. S2. Figure 3. Data used in this figure come from the GFDL ESM2M model for the combined historical and RCP8.5 experiments. Time series
of surface ocean (a) pH and (d) [H+] (nmol kg−1) at model grid points corresponding to the Kuroshio Extension Observatory (KEO) and
the Drake Passage region north of the Antarctic Polar Front (DPN), similar to Region 1 in Munro et al. (2015). Surface ocean seasonal
cycle amplitudes (A) were averaged for each decade and smoothed with a running mean filter using a four-element sliding window. Shown
are the decadal changes in (b) A-pH and (e) A-[H+] (nmol kg−1) relative to the 1950s, as well as the surface ocean (c) pH and (f) [H+]
(nmol kg−1) monthly anomalies relative to the annual mean at KEO and DPN during the 1950s (thin lines) and 2090s (thick lines). Global
maps show the total change in (g) A-pH and (h) A-[H+] (nmol kg−1) between the 1950s and 2090s. White boxes are centered at the KEO
and DPN time-series sites. A. J. Fassbender et al.: Interpreting pH changes Simulated 1950s and 2090s annual mean pH and [H+] values, as well as the 2090s minus 1950s change in A-pH
and A-[H+], at these locations are listed in Table S2. A total of 45 additional time-series locations are included in Table S2 and Fig. S2. studying 1[H+], which reveals aspects that studying 1pH
alone may conceal or overemphasize. The third opportunity to improve clarity concerns the in-
terpretation of changes with depth, such as those between re-
peat hydrography line occupations or model time steps. Re-
cently, the magnitude of chemical changes between repeat
hydrographic sections has been inferred using various linear
regression techniques (Carter et al., 2019; Chen et al., 2017;
Chu et al., 2016; Williams et al., 2015; Woosley et al., 2016)
and water mass characterization approaches (Resplandy et
al., 2013; Ríos et al., 2015), with results often plotted in terms
of 1pH. Most ocean regions exhibit a larger range of pH in
the upper 1000 m of the water column (∼7.4–8.5; Lauvset et
al., 2016, 2020) than across surface waters of the open ocean
(∼7.7–8.5; Lauvset et al., 2016; Fassbender et al., 2017). Because of these large vertical gradients in background pH,
one cannot interpret the magnitude and pattern of the corre-
sponding absolute chemical changes by studying only 1pH. An example is given in Fig. 4 for a meridional section in the
Pacific Ocean using the 2002-referenced Global Ocean Data
Analysis Project mapped climatologies (GLODAPv2.2016b;
Lauvset et al., 2016). Despite there being larger changes in
pH near the sea surface relative to the preindustrial period,
changes in [H+] with depth indicate a different structure due
to the heterogeneity of the background pH. An improved un-
derstanding of ongoing chemical changes comes from also A. J. Fassbender et al.: Interpreting pH changes Recognizing that a change in pH represents
a relative change in [H+] regardless of location and examin-
ing long-term trends in both parameters should improve the
interpretation of chemical changes across ocean domains. open ocean surface pH typically fall between −0.001 and
−0.003 yr−1 (Lauvset et al., 2015; Takahashi et al., 2014). A
critical piece of information that is often missing when such
trends are compared (e.g., Table 3.2 of Rhein et al., 2013)
is the initial pH value for each region. That information is
key because regions with the same pH trend but different ini-
tial pH values will exhibit different [H+] trends over time
(e.g., Fassbender et al., 2017). For example, Fig. 2a–b il-
lustrate a scenario in which two locations each experience
a pH trend of −0.0017 yr−1 (similar to that of the subtrop-
ics; Bates et al., 2014) but have different initial pH values:
7.9 and 8.1. As a result, there is a 58 % greater change in
[H+] for the first relative to the second location. That is,
when the change in pH is identical, the ratio between the
two trends in [H+] is equal to the ratio of the two initial
[H+] values. As a real-world example, Fig. 2c shows similar
pH trends for two time series, the equatorial Pacific (0◦N,
125◦W; Sutton et al., 2014) and the Irminger Sea (64.3◦N,
28◦W; Bates et al., 2014), where the initial pH values dif-
fer (Table S1), causing the trends in [H+] to differ. Yet, at
another equatorial Pacific site (0◦N, 155◦W; Sutton et al.,
2014), there is a similar [H+] trend to that of the Irminger
Sea site because the initial pH differs. While we focus here
on pH changes in the open ocean, pH changes also occur in
coastal waters where they tend to be larger (Carstensen and
Duarte, 2019). Recognizing that a change in pH represents
a relative change in [H+] regardless of location and examin-
ing long-term trends in both parameters should improve the
interpretation of chemical changes across ocean domains. https://doi.org/10.5194/bg-18-1407-2021 Biogeosciences, 18, 1407–1415, 2021 1410 A. J. Fassbender et al.: Interpreting pH changes A. J. Fassbender et al.: Interpreting pH changes 1411 A. J. Fassbender et al.: Interpreting pH changes A. J. Fassbender et al.: Interpreting pH changes Figure 4. Changes in (a) pH and (c) [H+] (nmol kg−1) associated with anthropogenic carbon (Canth) accumulation in the upper 1.5 km of the
ocean along a meridional transect (150◦W) in the Pacific Ocean from 60◦S to 55◦N. These values were estimated using GLODAPv2.2016b
climatology data, which are referenced to the year 2002 (Lauvset et al., 2016) by subtracting the estimated Canth from dissolved inorganic
carbon (DIC) and recalculating pH from the modified DIC values along with total alkalinity, silicate, phosphate, temperature, and salinity
climatology data. Plotted values are derived from the differences between the pH climatology and recalculated pH values that roughly reflect
preindustrial values. This simple approach neglects pH changes caused by processes other than Canth accumulation and is used merely to
display the concept of interest. Potential density contours are overlaid in white. Vertical profiles of (b) pH change and (d) [H+] change at
the gold and pink lines are shown in panels (a) and (c). Calculations were performed using the MATLAB program CO2SYS version 1.1 (van
Heuven et al., 2011; Lewis and Wallace, 1998) and applying the equilibrium constants of Lueker et al. (2000) and Dickson (1990) and the
boron-to-chlorinity ratio of Uppström (1974), following the recommendations of Orr et al. (2015) . Figure 4. Changes in (a) pH and (c) [H+] (nmol kg−1) associated with anthropogenic carbon (Canth) accumulation in the upper 1.5 km of the
ocean along a meridional transect (150◦W) in the Pacific Ocean from 60◦S to 55◦N. These values were estimated using GLODAPv2.2016b
climatology data, which are referenced to the year 2002 (Lauvset et al., 2016) by subtracting the estimated Canth from dissolved inorganic
carbon (DIC) and recalculating pH from the modified DIC values along with total alkalinity, silicate, phosphate, temperature, and salinity
climatology data. Plotted values are derived from the differences between the pH climatology and recalculated pH values that roughly reflect
preindustrial values. This simple approach neglects pH changes caused by processes other than Canth accumulation and is used merely to
display the concept of interest. Potential density contours are overlaid in white. Vertical profiles of (b) pH change and (d) [H+] change at
the gold and pink lines are shown in panels (a) and (c). A. J. Fassbender et al.: Interpreting pH changes Calculations were performed using the MATLAB program CO2SYS version 1.1 (van
Heuven et al., 2011; Lewis and Wallace, 1998) and applying the equilibrium constants of Lueker et al. (2000) and Dickson (1990) and the
boron-to-chlorinity ratio of Uppström (1974), following the recommendations of Orr et al. (2015) . ber 2020. GFDL ESM2M data used to make Fig. 3 can be accessed
at
ftp://nomads.gfdl.noaa.gov/CMIP5/output1/NOAA-GFDL/,
last access: 23 September 2020. The gridded GLODAPv2.2016b
dataset used to make Fig. 4 can be accessed at https://www.ncei. noaa.gov/access/ocean-carbon-data-system/oceans/GLODAPv2/,
last access: 23 September 2020. nition is in Weyer (2019, p. 693). This apparent emphasis
on pH should be considered in the light of the challenges we
have mentioned in interpreting pH changes in an ocean where
background pH varies both in space and time. Do ocean re-
gions with the same rate of pH decline really have the same
rate of acidification even if their initial conditions differ and
hence their [H+] change varies? Does a greater pH change
at the surface relative to the subsurface indicate greater acid-
ification even if the change in hydrogen ion concentration is
identical? Does a decline in the seasonal amplitude of pH im-
ply benefits given that the opposite trend is projected for the
seasonal amplitude of [H+]? Despite such concerns, the sim-
plicity of the IPCC definition of ocean acidification continues
to make it attractive. Whether or not it should be modified
merits further discussion. More important is that the commu-
nity move forward as a whole to go beyond reporting changes
in pH alone, thereby avoiding the unwitting focus on relative
rather than absolute changes in hydrogen ion concentration. Supplement. The supplement related to this article is available on-
line at: https://doi.org/10.5194/bg-18-1407-2021-supplement. Author contributions. AJF initiated the discussion among coau-
thors and wrote the first draft. All coauthors contributed to further
revisions throughout the paper. Competing interests. The authors declare that they have no conflict
of interest. Acknowledgements. We thank Stephen Gonski and two anonymous
reviewers for their helpful comments. Data availability. All data used in this analysis are publicly
accessible, and the appropriate references have been provided. Specifically, Fig. 2 was made using information from Sutton et
al. (2014) and Bates et al. (2014) and the data products described
in Fassbender et al. (2017), which can be accessed at https://www. socat.info/index.php/products-using-socat/, last access: 23 Septem- Financial support. Andrea J. 3
Conclusions When studying ocean acidification, the community often
refers to changes in pH along with changes in other CO2 sys-
tem variables, such as pCO2, total dissolved inorganic car-
bon (DIC), and the saturation state of seawater with respect
to aragonite. Yet the logarithmic scale of pH means that its
changes are equivalent to relative changes in [H+], unlike
for all other CO2 system variables whose changes are not
given on a log scale and are absolute. For absolute changes,
one must actually compute 1[H+]. We have illustrated this
with three simple examples. Thus, when discussing changes
in pH, it is recommended to show results as 1[H+] as well
as 1pH, and when reporting pH data, it is recommended to
provide the reference conditions as well as the changes. The Intergovernmental Panel on Climate Change (IPCC)
defines ocean acidification as “...a reduction in pH of the
ocean over an extended period, typically decades or longer,
caused primarily by the uptake of carbon dioxide (CO2) from
the atmosphere” (Rhein et al., 2013, p. 295); a similar defi- Biogeosciences, 18, 1407–1415, 2021 https://doi.org/10.5194/bg-18-1407-2021 References Chen, C.-T. A., Lui, H.-K., Hsieh, C.-H., Yanagi, T., Kosugi, N.,
Ishii, M., and Gong, G.-C.: Deep oceans may acidify faster than
anticipated due to global warming, Nat. Clim. Change, 7, 890–
894, https://doi.org/10.1038/s41558-017-0003-y, 2017. Archer,
D. E.,
Kheshgi,
H.,
and
Maier-Reimer,
E.:
Dy-
namics
of
fossil
fuel
CO2
neutralization
by
ma-
rine
CaCO3,
Global
Biogeochem. Cy.,
12,
259–276,
https://doi.org/10.1029/98GB00744, 1998. Chu, S. N., Wang, Z. A., Doney, S. C., Lawson, G. L., and Hoering,
K. A.: Changes in anthropogenic carbon storage in the Northeast
Pacific in the last decade, J. Geophys. Res.-Oceans, 121, 4618–
4632, https://doi.org/10.1002/2016JC011775, 2016. Bates, N., Astor, Y., Church, M. J., Currie, K., Dore, J., Gonaález-
Dávila, M., Lorenzoni, L., Muller-Karger, F., Olafsson, J.,
and Santana-Casiano, J. M.: A time-series view of chang-
ing ocean chemistry due to ocean uptake of anthropogenic
CO2 and ocean acidification, Oceanography, 27, 126–141,
https://doi.org/10.5670/oceanog.2014.16, 2014. Clark, W. M.: The determination of hydrogen ions, edn. 2, Williams
and Wilkins Company, Baltimore, Maryland, USA, 480 pp.,
1922. Bates,
R. G.:
pH
measurements
in
the
marine
en-
vironment,
Pure
Appl. Chem.,
54,
229–232,
https://doi.org/10.1351/pac198254010229, 1982. Clark, W. M., Wherry, E. T., and Adams, E. Q.: Reply to Wherry
and Adams’ article on methods of stating acidity, J. Wash-
ingt. Acad. Sci., 11, 199–202, available at: https://www.jstor.org/
stable/24532479 (last access: 1 February 2021), 1921. Bates, R. G. and Guggenheim, E. A.: Report on the standardization
of pH and related terminology, Pure Appl. Chem., 1, 163–168,
https://doi.org/10.1351/pac196001010163, 1960. Cohen, E. R., Cvitas, T., Frey, J. G., Holström, B., Kuchitsu, K.,
Marquardt, R., Mills, I., Pavese, F., Quack, M., Stohner, J.,
Strauss, H. L., Takami, M., and Thor, A. J.: Quantities, Units and
Symbols in Physical Chemistry, Third Edit., edited by: Cohen,
E. R., Cvitas, T., Frey, J. G., Holström, B., Kuchitsu, K., Mar-
quardt, R., Mills, I., Pavese, F., Quack, M., Stohner, J., Strauss,
H. L., Takami, M., and Thor, A. J., Royal Society of Chemistry,
Cambridge, 1–250, 2007. Baucke,
F. G. K.:
New
IUPAC
recommendations
on
the
measurement of pH – background and essentials, Anal. Bioanal. Chem., 374, 772–777, https://doi.org/10.1007/s00216-
002-1523-4, 2002. Bopp, L., Resplandy, L., Orr, J. C., Doney, S. C., Dunne, J. P.,
Gehlen, M., Halloran, P., Heinze, C., Ilyina, T., Séférian, R.,
Tjiputra, J., and Vichi, M.: Multiple stressors of ocean ecosys-
tems in the 21st century: projections with CMIP5 models,
Biogeosciences, 10, 6225–6245, https://doi.org/10.5194/bg-10-
6225-2013, 2013. Covington, A. A. J. Fassbender et al.: Interpreting pH changes Fassbender was supported by the
David and Lucile Packard Foundation/MBARI, Andrew G. Dickson https://doi.org/10.5194/bg-18-1407-2021 Biogeosciences, 18, 1407–1415, 2021 Biogeosciences, 18, 1407–1415, 2021 Biogeosciences, 18, 1407–1415, 2021 1412 by the US National Science Foundation (grant no. OCE 1657799),
and James C. Orr by the French ANR Project SOBUMS (grant no.
ANR-16-CE01-0014) and EU H2020 Project COMFORT (grant no.
820989). by the US National Science Foundation (grant no. OCE 1657799),
and James C. Orr by the French ANR Project SOBUMS (grant no. ANR-16-CE01-0014) and EU H2020 Project COMFORT (grant no. 820989). Caldeira, K. and Wickett, M. E.: Anthropogenic carbon and ocean
pH, Nature, 425, 365, https://doi.org/10.1038/425365a, 2003. Carstensen, J. and Duarte, C. M.: Drivers of pH Variability in
Coastal Ecosystems, Environ. Sci. Technol., 53, 4020–4029,
https://doi.org/10.1021/acs.est.8b03655, 2019. Carter, B. R., Feely, R. A., Wanninkhof, R., Kouketsu, S., Son-
nerup, R. E., Pardo, P. C., Sabine, C. L., Johnson, G. C., Sloyan,
B. M., Murata, A., Mecking, S., Tilbrook, B., Speer, K., Talley,
L. D., Millero, F. J., Wijffels, S. E., Macdonald, A. M., Gru-
ber, N., and Bullister, J. L.: Pacific anthropogenic carbon be-
tween 1991 and 2017, Global Biogeochem. Cy., 33, 597–617,
https://doi.org/10.1029/2018GB006154, 2019. Review statement. This paper was edited by Peter Landschützer
and reviewed by two anonymous referees. A. J. Fassbender et al.: Interpreting pH changes and Cyronak, T.: Ocean acidification refugia in
variable environments, Global Change Biol., 25, 3201–3214,
https://doi.org/10.1111/gcb.14730, 2019. Kleypas, J. A., Feely, R. A., Fabry, V. J., Langdon, C., Sabine, C. L.,
and Robbins, L. L.: Impacts of ocean acidification on coral reefs
and other marine calcifiers: a guide for future research, report of
a workshop held 18–20 April 2005, St. Petersburg, FL, sponsored
by NSF, NOAA, and the U.S. Geological Survey, 88 pp., 2006. Fassbender,
A. J.,
Sabine,
C. L.,
and
Palevsky,
H. I.:
Nonuniform
ocean
acidification
and
attenuation
of
the
ocean carbon sink, Geophys. Res. Lett., 44, 8404–8413,
https://doi.org/10.1002/2017GL074389, 2017. Kwiatkowski, L. and Orr, J. C.: Diverging seasonal extremes for
ocean acidification during the twenty-first century, Nat. Clim. Change, 8, 141–145, https://doi.org/10.1038/s41558-017-0054-
0, 2018. p
g
Friedlingstein, P., O’Sullivan, M., Jones, M. W., Andrew, R. M., Friedlingstein, P., O’Sullivan, M., Jones, M. W., Andrew, R. M.,
Hauck, J., Olsen, A., Peters, G. P., Peters, W., Pongratz, J., Sitch,
S., Le Quéré, C., Canadell, J. G., Ciais, P., Jackson, R. B., Alin,
S., Aragão, L. E. O. C., Arneth, A., Arora, V., Bates, N. R.,
Becker, M., Benoit-Cattin, A., Bittig, H. C., Bopp, L., Bultan,
S., Chandra, N., Chevallier, F., Chini, L. P., Evans, W., Florentie,
L., Forster, P. M., Gasser, T., Gehlen, M., Gilfillan, D., Gkritza-
lis, T., Gregor, L., Gruber, N., Harris, I., Hartung, K., Haverd, V.,
Houghton, R. A., Ilyina, T., Jain, A. K., Joetzjer, E., Kadono, K.,
Kato, E., Kitidis, V., Korsbakken, J. I., Landschützer, P., Lefèvre,
N., Lenton, A., Lienert, S., Liu, Z., Lombardozzi, D., Marland,
G., Metzl, N., Munro, D. R., Nabel, J. E. M. S., Nakaoka, S.-I.,
Niwa, Y., O’Brien, K., Ono, T., Palmer, P. I., Pierrot, D., Poul-
ter, B., Resplandy, L., Robertson, E., Rödenbeck, C., Schwinger,
J., Séférian, R., Skjelvan, I., Smith, A. J. P., Sutton, A. J., Tan-
hua, T., Tans, P. P., Tian, H., Tilbrook, B., van der Werf, G.,
Vuichard, N., Walker, A. P., Wanninkhof, R., Watson, A. J.,
Willis, D., Wiltshire, A. J., Yuan, W., Yue, X., and Zaehle, S.:
Global Carbon Budget 2020, Earth Syst. Sci. Data, 12, 3269–
3340, https://doi.org/10.5194/essd-12-3269-2020, 2020. Kwiatkowski, L., Torres, O., Bopp, L., Aumont, O., Chamberlain,
M., Christian, J. R., Dunne, J. P., Gehlen, M., Ilyina, T., John, J. G., Lenton, A., Li, H., Lovenduski, N. S., Orr, J. C., Palmieri,
J., Santana-Falcón, Y., Schwinger, J., Séférian, R., Stock, C. A. J. Fassbender et al.: Interpreting pH changes 1413 Line”, Willapa Bay, 2011–2014, Estuar. Coast., 40, 173–186,
https://doi.org/10.1007/s12237-016-0136-7, 2017. problem,
Annu. Rev. Mar. Sci.,
1,
169–192,
https://doi.org/10.1146/annurev.marine.010908.163834, 2009. Doney, S. C., Bopp, L., and Long, M.: Historical and future trends
in ocean climate and biogeochemistry, Oceanography, 27, 108–
119, https://doi.org/10.5670/oceanog.2014.14, 2014. Hamer, W. J. and Acree, S. F.: Primary pH measurements and stan-
dards, J. Res. Natl. Bur. Stand., 23, 647–657, 1939. Hofmann, G. E., Barry, J. P., Edmunds, P. J., Gates, R. D.,
Hutchins,
D. A.,
Klinger,
T.,
and
Sewell,
M. A.:
The
effect
of
ocean
acidification
on
calcifying
organ-
isms
in
marine
ecosystems:
an
organism-to-ecosystem
perspective,
Annu. Rev. Ecol. Evol. S.,
41,
127–147,
https://doi.org/10.1146/annurev.ecolsys.110308.120227, 2010. Dore, J., Lukas, R., Sadler, D. W., Church, M. J., and Karl, D. M.:
Physical and biogeochemical modulation of ocean acidification
in the central North Pacific, P. Natl. Acad. Sci. USA, 106, 12235–
12240, https://doi.org/10.1073/pnas.0906044106, 2009. Dunne, J. P., John, J. G., Adcroft, A. J., Griffies, S. M., Hallberg,
R. W., Shevliakova, E., Stouffer, R. J., Cooke, W., Dunne, K. A., Harrison, M. J., Krasting, J. P., Malyshev, S. L., Milly, P. C. D., Phillipps, P. J., Sentman, L. T., Samuels, B. L., Spelman,
M. J., Winton, M., Wittenberg, A. T., and Zadeh, N.: GFDL’s
ESM2 global coupled climate–carbon Earth System Models, Part
I: physical formulation and baseline simulation characteristics,
J. Climate, 25, 6646–6665, https://doi.org/10.1175/JCLI-D-11-
00560.1, 2012. Hofmann, G. E., Smith, J. E., Johnson, K. S., Send, U., Levin, L. A.,
Micheli, F., Paytan, A., Price, N. N., Peterson, B., Takeshita, Y.,
Matson, P. G., Crook, E. D., Kroeker, K. J., Gambi, M. C., Rivest,
E. B., Frieder, C. A., Yu, P. C., and Martz, T. R.: High-frequency
dynamics of ocean pH: a multi-ecosystem comparison, PLoS
One, 6, e28983, https://doi.org/10.1371/journal.pone.0028983,
2011. Jiang, L.-Q., Carter, B. R., Feely, R. A., Lauvset, S. K., and Olsen,
A.: Surface ocean pH and buffer capacity: past, present and fu-
ture, Sci. Rep., 9, 18624, https://doi.org/10.1038/s41598-019-
55039-4, 2019. Dunne, J. P., John, J. G., Shevliakova, E., Stouffer, R. J., Krasting,
J. P., Malyshev, S. L., Milly, P. C. D., Sentman, L. T., Adcroft,
A. J., Cooke, W., Dunne, K. A., Griffies, S. M., Hallberg, R. W., Harrison, M. J., Levy, H., Wittenberg, A. T., Phillips, P. J.,
and Zadeh, N.: GFDL’s ESM2 global coupled climate–carbon
Earth System Models, Part II: carbon system formulation and
baseline simulation characteristics, J. Climate, 26, 2247–2267,
https://doi.org/10.1175/JCLI-D-12-00150.1, 2013. Kapsenberg, L. References K., Bates, R. G., and Durst, R. A.: Definition of pH
scales, standard reference values, measurement of pH and re-
lated terminology (recommendations 1984), available at: http://
publications.iupac.org/pac/1985/pdf/5703x0531.pdf (last access:
15 January 2021), 1985. Boudreau, B. P., Middelburg, J. J., and Luo, Y.: The role of calci-
fication in carbonate compensation, Nat. Geosci., 11, 894–900,
https://doi.org/10.1038/s41561-018-0259-5, 2018. Dickson, A. G.: pH scales and proton-transfer reactions in saline
media such as sea water, Geochim. Cosmochim. Ac., 48, 2299–
2308, https://doi.org/10.1016/0016-7037(84)90225-4, 1984. Boyd, P. W., Cornwall, C. E., Davison, A., Doney, S. C.,
Fourquez, M., Hurd, C. L., Lima, I. D., and McMinn, A.:
Biological responses to environmental heterogeneity under fu-
ture ocean conditions, Global Change Biol., 22, 2633–2650,
https://doi.org/10.1111/gcb.13287, 2016. Dickson, A. G.: Standard potential of the reaction: AgCl(s)
+ 1/2H2(g) = Ag(s) + HCl(aq), and the standard acid-
ity constant of the ion HSO−
4
in synthetic sea water from
273.15 to 318.15 K, J. Chem. Thermodyn., 22, 113–127,
https://doi.org/10.1016/0021-9614(90)90074-Z, 1990. Brewer, P. G.: A short history of ocean acidification science in the
20th century: a chemist’s view, Biogeosciences, 10, 7411–7422,
https://doi.org/10.5194/bg-10-7411-2013, 2013. Dickson, A. G.: Seawater carbonate chemistry, Part I, in: Guide to
best practices for ocean acidification research and data reporting,
edited by: Riebesell, U., Fabry, V. J., Hansson, L., and Gattuso,
J. P., European Commission, Brussels, Belgium, 17–40, 2010. Buck, R. P., Rondinini, S., Covington, A. K., Baucke, F. G. K.,
Brett, C. M. A., Camoes, M. F., Milton, M. J. T., Mussini, T.,
Naumann, R., Pratt, K. W., Spitzer, P., and Wilson, G. S.: Mea-
surement of pH, Definition, standards, and procedures (IUPAC
Recommendations 2002), Pure Appl. Chem., 74, 2169–2200,
https://doi.org/10.1351/pac200274112169, 2002. Dickson, A. G., Camões, M. F., Spitzer, P., Fisicaro, P., Stoica,
D., Pawlowicz, R., and Feistel, R.: Metrological challenges for
measurements of key climatological observables, Part 3: seawa-
ter pH, Metrologia, 53, R26–R39, https://doi.org/10.1088/0026-
1394/53/1/R26, 2016. Bushinsky, S. M., Takeshita, Y., and Williams, N. L.: Ob-
serving
changes
in
ocean
carbonate
chemistry:
our
au-
tonomous future, Curr. Clim. Change Reports, 5, 207–220,
https://doi.org/10.1007/s40641-019-00129-8, 2019. Doney,
S. C.,
Fabry,
V. J.,
Feely,
R. A.,
and
Kley-
pas,
J. A.:
Ocean
acidification:
the
other
CO2 https://doi.org/10.5194/bg-18-1407-2021 Biogeosciences, 18, 1407–1415, 2021 A. J. Fassbender et al.: Interpreting pH changes Change, edited by: Stocker, T. F., Qin, D., Plattner, G.-K., Tig-
nor, M., Allen, S. K., Boschung, J., Nauels, A., Xia, Y., Bex,
V., and Midgley, P. M., Cambridge University Press, Cambridge,
United Kingdom and New York, NY, USA, 2013. Lewis, E. and Wallace, D. W. R.: Program developed for CO2
system calculations, Carbon Dioxide Information Analysis Cen-
ter, Oak Ridge National Laboratory, US Department of Energy,
Oak Ridge, Tennessee, USA, 4735, available at: https://www. nodc.noaa.gov/ocads/oceans/CO2SYS/co2rprt.html (last access:
2 July 2014), 1998. Riahi, K., Rao, S., Krey, V., Cho, C., Chirkov, V., Fischer, G., Kin-
dermann, G., Nakicenovic, N., and Rafaj, P.: RCP 8.5 – A sce-
nario of comparatively high greenhouse gas emissions, Climatic
Change, 109, 33–57, https://doi.org/10.1007/s10584-011-0149-
y, 2011. Lueker, T. J., Dickson, A. G., and Keeling, C. D.: Ocean pCO2
calculated from dissolved inorganic carbon, alkalinity, and equa-
tions for K1 and K2: validation based on laboratory measure-
ments of CO2 in gas and seawater at equilibrium, Mar. Chem.,
70, 105–119, https://doi.org/10.1016/S0304-4203(00)00022-0,
2000. Ríos, A. F., Resplandy, L., García-Ibáñez, M. I., Fajar, N. M., Velo,
A., Padín, X. A., Wanninkhof, R., Steinfeldt, R., Rosón, G.,
Pérez, F. F., and Morel, F. M. M.: Decadal acidification in the wa-
ter masses of the Atlantic Ocean, P. Natl. Acad. Sci. USA, 112,
9950–9955, https://doi.org/10.1073/pnas.1504613112, 2015. Marion, G. M., Millero, F. J., Camões, M. F., Spitzer, P., Feistel,
R., and Chen, C.-T. A.: pH of seawater, Mar. Chem., 126, 89–96,
https://doi.org/10.1016/j.marchem.2011.04.002, 2011. Sørensen,
S. P. L.:
Enzymstudien
II:
Über
die
Messung
und
Bedeutung
der
Wasserstoffionen-konzentration
bei
biologischen
Prozessen,
Biochem. Z.,
21,
131–200,
https://doi.org/10.1007/BF02325444, 1909. McGlashan, M. L.: Manual of symbols and terminology for physic-
ochemical quantities and units, Pure Appl. Chem., 21, 1–38,
1970. McNeil, B. I. and Sasse, T. P.: Future ocean hypercapnia driven by
anthropogenic amplification of the natural CO2 cycle, Nature,
529, 383–386, https://doi.org/10.1038/nature16156, 2016. Sørensen, S. P. L. and Linderstrøm-Lang, K.: On the determination
and value of po in electrometric measurements of hydrogen ion
concentrations, Compt. rend. trav. lab. Carlsberg, 15, 1–40, 1924. Millero, F. J.: The marine inorganic carbon cycle, Chem. Rev., 107,
308–341, https://doi.org/10.1021/cr0503557, 2007. Spitzer, P. and Pratt, K. W.: The history and development of a rig-
orous metrological basis for pH measurements, J. Solid State
Electr., 15, 69–76, https://doi.org/10.1007/s10008-010-1106-9,
2011. Munro, D. R., Lovenduski, N. S., Takahashi, T., Stephens, B. A. J. Fassbender et al.: Interpreting pH changes B.,
Newberger, T., and Sweeney, C.: Recent evidence for a strength-
ening CO2 sink in the Southern Ocean from carbonate system
measurements in the Drake Passage (2002–2015), Geophys. Res. Lett., 42, 7623–7630, https://doi.org/10.1002/2015GL065194,
2015. Steinacher, M., Joos, F., Frölicher, T. L., Plattner, G.-K., and Doney,
S. C.: Imminent ocean acidification in the Arctic projected
with the NCAR global coupled carbon cycle-climate model,
Biogeosciences, 6, 515–533, https://doi.org/10.5194/bg-6-515-
2009, 2009. Orr, J. C., Fabry, V. J., Aumont, O., Bopp, L., Doney, S. C.,
Feely, R. A., Gnanadesikan, A., Gruber, N., Ishida, A., Joos, F.,
Key, R. M., Lindsay, K., Maier-Reimer, E., Matear, R., Mon-
fray, P., Mouchet, A., Najjar, R. G., Plattner, G.-K., Rodgers,
K. B., Sabine, C. L., Sarmiento, J. L., Schlitzer, R., Slater, R. D., Totterdell, I. J., Weirig, M.-F., Yamanaka, Y., and Yool, A.:
Anthropogenic ocean acidification over the twenty-first century
and its impact on calcifying organisms, Nature, 437, 681–686,
https://doi.org/10.1038/nature04095, 2005. Feely, R. A., Gnanadesikan, A., Gruber, N., Ishida, A., Joos, F.,
Key, R. M., Lindsay, K., Maier-Reimer, E., Matear, R., Mon-
fray, P., Mouchet, A., Najjar, R. G., Plattner, G.-K., Rodgers,
K. B., Sabine, C. L., Sarmiento, J. L., Schlitzer, R., Slater, R. D
Totterdell I J
Weirig M F Yamanaka Y and Yool A : Sutton, A. J., Feely, R. A., Sabine, C. L., McPhaden, M. J., Taka-
hashi, T., Chavez, F. P., Friederich, G. E., and Mathis, J. T.: Nat-
ural variability and anthropogenic change in equatorial Pacific
surface ocean pCO2 and pH, Global Biogeochem. Cy., 28, 131–
145, https://doi.org/10.1002/2013GB004679, 2014. Sabine, C. L., Sarmiento, J. L., Schlitzer, R., Slater, D., Totterdell, I. J., Weirig, M.-F., Yamanaka, Y., and Yool, A.:
Anthropogenic ocean acidification over the twenty-first century
and its impact on calcifying organisms, Nature, 437, 681–686,
https://doi.org/10.1038/nature04095, 2005. Takahashi, T., Sutherland, S. C., Chipman, D. W., Goddard, J. G.,
and Ho, C.: Climatological distributions of pH, pCO2, total CO2,
alkalinity, and CaCO3 saturation in the global surface ocean, and
temporal changes at selected locations, Mar. Chem., 164, 95–
125, https://doi.org/10.1016/j.marchem.2014.06.004, 2014. Orr, J. C., Epitalon, J.-M., and Gattuso, J.-P.: Comparison of
ten packages that compute ocean carbonate chemistry, Biogeo-
sciences, 12, 1483–1510, https://doi.org/10.5194/bg-12-1483-
2015, 2015. Thyng, K., Greene, C., Hetland, R., Zimmerle, H., and DiMarco,
S.: True Colors of Oceanography: Guidelines for Effective
and Accurate Colormap Selection, Oceanography, 29, 9–13,
https://doi.org/10.5670/oceanog.2016.66, 2016. Passow, U. and Carlson, C. A. J. Fassbender et al.: Interpreting pH changes A., Tagliabue, A., Takano, Y., Tjiputra, J., Toyama, K., Tsu-
jino, H., Watanabe, M., Yamamoto, A., Yool, A., and Ziehn, T.:
Twenty-first century ocean warming, acidification, deoxygena-
tion, and upper-ocean nutrient and primary production decline
from CMIP6 model projections, Biogeosciences, 17, 3439–3470,
https://doi.org/10.5194/bg-17-3439-2020, 2020. Kwiatkowski, L., Torres, O., Bopp, L., Aumont, O., Chamberlain,
M., Christian, J. R., Dunne, J. P., Gehlen, M., Ilyina, T., John, J. ecker, M., Benoit-Cattin, A., Bittig, H. C., Bopp, L., Bultan,
, Chandra, N., Chevallier, F., Chini, L. P., Evans, W., Florentie, L., Forster, P. M., Gasser, T., Gehlen, M., Gilfillan, D., Gkritza- is, T., Gregor, L., Gruber, N., Harris, I., Hartung, K., Haverd, V., enton, A., Lienert, S., Liu, Z., Lombardozzi, D., Marland, Lauvset, S. K., Gruber, N., Landschützer, P., Olsen, A., and
Tjiputra, J.: Trends and drivers in global surface ocean pH
over the past 3 decades, Biogeosciences, 12, 1285–1298,
https://doi.org/10.5194/bg-12-1285-2015, 2015. Lauvset, S. K., Key, R. M., Olsen, A., van Heuven, S., Velo, A.,
Lin, X., Schirnick, C., Kozyr, A., Tanhua, T., Hoppema, M.,
Jutterström, S., Steinfeldt, R., Jeansson, E., Ishii, M., Perez, F. F., Suzuki, T., and Watelet, S.: A new global interior ocean
mapped climatology: the 1◦× 1◦GLODAP version 2, Earth
Syst. Sci. Data, 8, 325–340, https://doi.org/10.5194/essd-8-325-
2016, 2016. GCOS: The Global Observing System for climate: implementa-
tion needs, available at: https://library.wmo.int/doc_num.php? explnum_id=3417 (last access: 23 September 2020), 2016. GOOS:
Essential
Ocean
Variables,
available
at:
http:
//www.goosocean.org/index.php?option=com_content&view=
article&id=14&Itemid=114, last access: 1 August 2019. Lauvset, S. K., Carter, B. R., Pèrez, F. F., Jiang, L.-Q., Feely,
R. A., Velo, A., and Olsen, A.: Processes driving global inte-
rior ocean pH distribution, Global Biogeochem. Cy., 34, 1–17,
https://doi.org/10.1029/2019GB006229, 2020. Hales, B., Suhrbier, A., Waldbusser, G. G., Feely, R. A., and
Newton, J. A.: The Carbonate Chemistry of the “Fattening Biogeosciences, 18, 1407–1415, 2021 https://doi.org/10.5194/bg-18-1407-2021 1414 A. J. Fassbender et al.: Interpreting pH changes A.: The biological pump in a
high CO2
world, Mar. Ecol. Prog. Ser., 470, 249–271,
https://doi.org/10.3354/meps09985, 2012. Uppström, L. R.: The boron-chlorinity ratio of deep seawater from
the Pacific Ocean, Deep. Res. Part I, 21, 161–162, 1974. Resplandy, L., Bopp, L., Orr, J. C., and Dunne, J. P.: Role of mode
and intermediate waters in future ocean acidification: Analy-
sis of CMIP5 models, Geophys. Res. Lett., 40, 3091–3095,
https://doi.org/10.1002/grl.50414, 2013. van Heuven, S. M. A. C., Pierrot, D., Rae, J. W. B., Lewis, E.,
and Wallace, D. W. R.: MATLAB program developed for CO2
system calculations, ORNL/CDIAC-105b, Carbon Dioxide
Information Analysis Center, Oak Ridge National Laboratory,
US Department of Energy, Oak Ridge, Tennessee, USA,
https://www.ncei.noaa.gov/access/ocean-carbon-data-system/
oceans/CO2SYS/co2rprt.html, 2011. Revelle, R. and Suess, H. E.: Carbon dioxide exchange between
atmosphere and ocean and the question of an increase of at-
mospheric CO2 during the past decades, Tellus, 9, 18–27,
https://doi.org/10.1111/j.2153-3490.1957.tb01849.x, 1957. Waters, J. F. and Millero, F. J.: The free proton concen-
tration scale for seawater pH, Mar. Chem., 149, 8–22,
https://doi.org/10.1016/j.marchem.2012.11.003, 2013. Rhein, M., Rintoul, S. R., Aoki, S., Campos, E., Chambers, D.,
Feely, R. A., Gulev, S., Johnson, G. C., Josey, S. A., Kostianoy,
A., Mauritzen, C., Roemmich, D., Talley, L. D., and Wang, F.:
Observations: Ocean. In: Climate Change 2013: The Physical
Science Basis. Contribution of Working Group I to the Fifth
Assessment Report of the Intergovernmental Panel on Climate IPCC: Annex I: Glossary, edited by: Weyer, N. M., in: IPCC Spe-
cial Report on the Ocean and Cryosphere in a Changing Climate,
edited by: Pörtner, H.-O., Roberts, D. C., Masson-Delmotte, V., https://doi.org/10.5194/bg-18-1407-2021 Biogeosciences, 18, 1407–1415, 2021 1415 https://doi.org/10.5194/bg-18-1407-2021 Wherry, E. T.: The statement of acidity and alkalinity, with special
reference to soils, J. Washingt. Acad. Sci., 9, 305–309, avail-
able at: https://www.jstor.org/stable/24521412 (last access: 23
September 2020), 1919. Wherry, E. T. and Adams, E. Q.: Methods of stating acidity, J.
Washingt. Acad. Sci., 11, 197–199, available at: https://www.
jstor.org/stable/24532477 (last access: 23 September 2020),
1921. Biogeosciences, 18, 1407–1415, 2021 A. J. Fassbender et al.: Interpreting pH changes Williams, N. L., Feely, R. A., Sabine, C. L., Dickson, A. G.,
Swift, J. H., Talley, L. D., and Russell, J. L.: Quantify-
ing anthropogenic carbon inventory changes in the Pacific
sector of the Southern Ocean, Mar. Chem., 174, 147–160,
https://doi.org/10.1016/j.marchem.2015.06.015, 2015. Zhai, P., Tignor, M., Poloczanska, E., Mintenbeck, K., Alegría,
A., Nicolai, M., Okem, A., Petzold, J., Rama, B., and Weyer N. M., in press, 2019. Wherry, E. T.: The statement of acidity and alkalinity, with special
reference to soils, J. Washingt. Acad. Sci., 9, 305–309, avail-
able at: https://www.jstor.org/stable/24521412 (last access: 23
September 2020), 1919. Woosley, R. J., Millero, F. J., and Wanninkhof, R.: Rapid
anthropogenic changes in CO2
and pH in the Atlantic
Ocean: 2003–2014, Global Biogeochem. Cy., 30, 70–90,
https://doi.org/10.1002/2015GB005248, 2016. Wherry, E. T. and Adams, E. Q.: Methods of stating acidity, J. Washingt. Acad. Sci., 11, 197–199, available at: https://www. jstor.org/stable/24532477 (last access: 23 September 2020),
1921. Biogeosciences, 18, 1407–1415, 2021 https://doi.org/10.5194/bg-18-1407-2021
|
https://openalex.org/W2109353512
|
https://trialsjournal.biomedcentral.com/counter/pdf/10.1186/1745-6215-9-42
|
English
| null |
Design paper: The CapOpus trial: A randomized, parallel-group, observer-blinded clinical trial of specialized addiction treatment versus treatment as usual for young patients with cannabis abuse and psychosis
|
Trials
| 2,008
|
cc-by
| 6,978
|
Received: 30 April 2008
Accepted: 11 July 2008 Received: 30 April 2008
Accepted: 11 July 2008 This article is available from: http://www.trialsjournal.com/content/9/1/42 © 2008 Hjorthøj et al; licensee BioMed Central Ltd. j
j
;
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0),
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Open Ac
Study protocol
Design paper: The CapOpus trial: A randomized, parallel-group,
observer-blinded clinical trial of specialized addiction treatment
versus treatment as usual for young patients with cannabis abuse
and psychosis
Carsten Hjorthøj*1, Allan Fohlmann1, Anne-Mette Larsen1,
Mette TR Madsen1, Lone Vesterager1, Christian Gluud2, Mikkel C Arendt3 and
Merete Nordentoft1 Open Access Study protocol p y
ten Hjorthøj*1, Allan Fohlmann1, Anne-Mette Larsen1, Address: 1Psychiatric Center Bispebjerg, Faculty of Health Sciences, Copenhagen University, Copenhagen, Denmark, 2Center for Clinical
Intervention Research, Copenhagen Trial Unit, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark and 3Centre for
Psychiatric Research, Institute of Clinical Medicine, University of Aarhus, Aarhus, Denmark Email: Carsten Hjorthøj* - carsten@capopus.dk; Allan Fohlmann - allan@capopus.dk; Anne-Mette Larsen - anne-mette@capopus.dk;
Mette TR Madsen - mmad0048@bbh.regionh.dk; Lone Vesterager - lv12@bbh.regionh.dk; Christian Gluud - cgluud@ctu.rh.dk;
Mikkel C Arendt - mca@psykiatri.aaa.dk; Merete Nordentoft - mn@dadlnet.dk * Corresponding author Received: 30 April 2008
Accepted: 11 July 2008 Trials Trials BioMed Central BioMed Central BioMed Central CapOpus intervention – the experimental intervention CapOpus intervention the experimental intervention
The contents of the CapOpus intervention are briefly
schematized in figure 2. An important part of the CapO-
pus treatment is to help the patient understand the mech-
anisms that complicate cessation of cannabis use. The
overall target is harm reduction, i.e. that harm from can-
nabis consumption is thought to be alleviated even if con-
sumption is not terminated, only reduced. This is a
method that has proved effective in several studies
[23,24]. The CapOpus intervention consists of one month
of individual treatment, followed by a three-month group
treatment in combination with individual treatment, and
followed by two months of individual treatment. The con-
tents of each of these three stages will be described in
detail below. A randomized trial showed that the combination of cog-
nitive behavioral therapy, motivational interviewing [see
[21]], and family involvement had a significant positive
effect on level of functioning, psychotic symptoms, and
duration of periods of cannabis-abstinence, compared
with regular treatment [22]. This finding has been sup-
ported by two reviews, concluding that positive evidence
exists for integrated treatment with motivational inter-
views, cognitive behavioral therapy (individual or group-
based), and a harm-reduction approach [23,24]. Group-
based treatments are arguably less expensive, and in a lit-
erature review, Weiss et al. concluded that specialized
group therapy could reinforce the effect of an existing
treatment [25]. However, there is currently insufficient
evidence to show that group-based interventions for can-
nabis use are superior to individual treatment [26,27]. Similarly, authors of a recent Cochrane review concluded
that insufficient evidence exists to show that any psycho-
social treatment method for comorbid schizophrenia and
substance abuse is superior to others [28]. Upon inclusion, the patient's case manager at the referring
institution will be offered education and supervision by
one of the addiction consultants employed in the CapO-
pus trial. During the first month, one of the addiction consultants
will be in contact with each patient once or twice a week. A meeting will be held with the patient's family, and there
will be contact with the case manager every two weeks. During the three months of group intervention, one of the
addiction consultants will have weekly individual con-
tacts with the patient and two meetings with the family. In
addition, the patient will follow a weekly group interven-
tion and have consultative contacts with the case manager
every two weeks. Objectives of the CapOpus trial We plan to undertake a trial in which combined group-
based and individual treatment, incorporating motiva-
tional interviewing, psycho-education, cognitive behavio-
ral therapy, and social skills training in addition to
treatment as usual, is compared with treatment as usual. The primary outcome will be change in number of days
abstinent from cannabis within the preceding 30-day
period as measured with the Time-Line Follow Back
(TLFB) instrument [29,30]. Abstract Background: A number of studies indicate a link between cannabis-use and psychosis as well as
more severe psychosis in those with existing psychotic disorders. There is currently insufficient
evidence to decide the optimal way to treat cannabis abuse among patients with psychosis. Objectives: The major objective for the CapOpus trial is to evaluate the additional effect on
cannabis abuse of a specialized addiction treatment program adding group treatment and
motivational interviewing to treatment as usual. Design: The trial is designed as a randomized, parallel-group, observer-blinded clinical trial. Patients are primarily recruited through early-psychosis detection teams, community mental health
centers, and assertive community treatment teams. Patients are randomized to one of two
treatment arms, both lasting six months: 1) specialized addiction treatment plus treatment as usual
or 2) treatment as usual. The specialized addiction treatment is manualized and consists of both
individual and group-based motivational interviewing and cognitive behavioral therapy, and
incorporates both the family and the case manager of the patient. The primary outcome measure will be changes in amount of cannabis consumption over time. Other outcome measures will be psychosis symptoms, cognitive functioning, quality of life, social
functioning, and cost-benefit analyses. Trial registration: ClinicalTrials.gov NCT00484302. Page 1 of 9
(page number not for citation purposes) Page 1 of 9
(page number not for citation purposes) (page number not for citation purposes) Trials 2008, 9:42 http://www.trialsjournal.com/content/9/1/42 (Figure 1). Patients will receive either specialized CapO-
pus treatment or treatment as usual, as described below. Background g
A recent meta-analysis of eleven longitudinal studies con-
cluded that cannabis use is associated with increased risk
of lasting psychotic conditions later in life [1]. Assuming
causality, as much as 800 annual cases of schizophrenia
are preventable in the UK if exposure to cannabis was
eliminated [2]. Several studies have shown that use of can-
nabis increases the risk of developing schizophrenia-like
symptoms, especially in young men disposed to develop-
ing psychosis [3-10]. Furthermore, use of cannabis among
patients with psychosis can maintain and worsen the psy-
chotic symptoms [11-15], and comorbid schizophrenia
and substance abuse is associated with lack of compliance
to treatment and with more rehospitalizations [15-20]. This indicates both that effective interventions to limit
cannabis use in persons with psychosis are needed, and
that getting patients to follow such interventions may be
difficult. CapOpus intervention – the experimental intervention During the two months following the
group intervention, the addiction consultants will be in
weekly contact with the patient and the family will be
invited to a meeting. The addiction consultants will con-
tact the patient's case manager every three weeks. For the purpose of enhancing alliance and motivation, the
treatment will start with motivational interviewing with
the patient being aided in analyzing advantages and draw-
backs of continued use of cannabis [21,31]. There is good
evidence for the efficacy of motivational interviews in
short-term treatment [32,33]. The patient will formulate
individual goals for the treatment and be offered the
group intervention. The groups will consist of six to eight
patients, with the addiction consultants as trainers. Each
group will run for three months with weekly sessions last-
ing 1 1/2 hour. The intervention methods will gradually
shift from motivational interviewing to cognitive behav-
ioral therapy as the patients become more motivated to
change their cannabis use. There will be emphasis on ana-
lyzing advantages and disadvantages of continued use,
instructions in coping skills in relation to craving and sit- Page 2 of 9
(page number not for citation purposes) Methods
h
i l i The trial is designed as a two-armed, parallel-group,
observer-blinded randomized clinical superiority trial Page 2 of 9
(page number not for citation purposes) Page 2 of 9
(page number not for citation purposes) Trials 2008, 9:42 http://www.trialsjournal.com/content/9/1/42 Flowchart of the CapOpus trial
Figure 1
Flowchart of the CapOpus trial. See text for further information. Flowchart of the CapOpus trial
Figure 1
Flowchart of the CapOpus trial. See text for further information. Flowchart of the CapOpus trial
Figure 1
Flowchart of the CapOpus trial. See text for further information. Contingency management in the CapOpus trial will have
no connection to whether or not the use of cannabis is
decreased. uations that usually trigger cannabis use, and in develop-
ing personal strategies for avoiding or handling these
situations. The experimental CapOpus intervention is offered in
addition to treatment as usual. The interventions offered
to the patients will be registered so that it will be possible
to estimate if the two intervention groups receive different
forms of treatment as usual. The group intervention will be followed by two months
during which weekly meetings with the patient continue. The addiction consultants offer consultative assistance to
the patient's case manager, as well as meeting the patient's
family. The purpose is to mediate methods of the inter-
vention to the network surrounding the patient in order to
prolong beneficial effects. Page 3 of 9
(page number not for citation purposes) Control treatment – treatment as usual The control treatment consists of receiving the treatment
that would have been available without participation in
the trial, i.e. treatment as usual. The patient's case man-
ager will carry out the control treatment. In essence, treat-
ment as usual for cannabis abuse is part of the existing,
manualized psychosocial and/or pharmaceutical treat- To increase adherence to treatment, positive reinforce-
ment will be applied through contingency management
in the form of complimentary food and social experi-
ences, which may enhance outcomes of cognitive behav-
ioral therapy or motivational enhancement [34]. Page 3 of 9
(page number not for citation purposes) http://www.trialsjournal.com/content/9/1/42 Trials 2008, 9:42 Schematic timeline of the CapOpus intervention
Figure 2
Schematic timeline of the CapOpus intervention. Schematic timeline of the CapOpus intervention
Figure 2
Schematic timeline of the CapOpus intervention. Schematic timeline of the CapOpus intervention
Figure 2
Schematic timeline of the CapOpus intervention. Schematic
Figure 2
S h Schematic timeline of the CapOpus intervention
Figure 2
Schematic timeline of the CapOpus intervention. had such a comorbidity, which decreased to 16 – 17% for
OPUS patients and 21 – 22% for other patients [38]. ment for psychotic illness; however, no explicit manual
exists on ways in which cannabis abuse should be
approached. Treatment as usual is thus not expected to be
uniform. In particular, frequency of contacts may vary
between case managers, and this will be registered and
analyzed. However, the heterogeneous nature of the con-
trol treatment accurately reflects the current situation in
Denmark, and we therefore consider this to be the appro-
priate treatment for analytical control. Assessments Patients are subjected to three almost identical assess-
ments. The first assessment occurs at baseline before ran-
domization, because information from the baseline
assessment is used to perform stratified randomization
and to validate inclusion and exclusion criteria. The sec-
ond assessment occurs six months after the baseline
assessment, when the treatment programs have just fin-
ished. The final assessment occurs ten months after the
baseline assessment, in order to evaluate longer-term
effects of the treatments. The contents of the assessments
are outlined in figure 3 and explained in the following sec-
tions. The standard assessments are conducted at all three
assessment points. Recruitment and criteria for inclusion and exclusion ICD-10 diagnosis F10.2: Alcohol dependence syndrome
ICD-10 diagnosis F11.2: Opioid dependence syndrome
ICD-10 diagnosis F14.2: Cocaine dependence syndrome
Refusal to give informed consent Page 4 of 9
(page number not for citation purposes) Page 4 of 9
(page number not for citation purposes) Page 4 of 9
(page number not for citation purposes) Trials 2008, 9:42 http://www.trialsjournal.com/content/9/1/42 Assessment tools used in the CapOpus trial
Figure 3
Assessment tools used in the CapOpus trial. Assessment tools used in the CapOpus trial
Figure 3
Assessment tools used in the CapOpus trial. leads to insufficient numbers of included patients, expan-
sion of the geographic area of the trial will be considered. leads to insufficient numbers of included patients, expan-
sion of the geographic area of the trial will be considered. Patients must speak and understand Danish sufficiently to
participate in both treatment and assessment without an
interpreter. The diagnostic criteria for exclusion are chosen so as to
decrease the risk of treatment effects becoming con-
founded by the presence of other dependence syndromes. Only dependence syndromes of alcohol, opioids, and
cocaine are cause for exclusion – more sporadic uses of
these substances are not. Recruitment and criteria for inclusion and exclusion Physicians and therapists in the Danish municipalities of
Copenhagen and Frederiksberg (henceforth collectively
referred to as Copenhagen) are informed of the CapOpus
trial through meetings and leaflets. In particular, OPUS,
CMHC, and ACT-teams are targeted. Patients referring
themselves and patients referred by general practitioners
will be associated with one of these institutions prior to
inclusion. Treatment as usual is carried out in one of three estab-
lished facilities; the OPUS teams for early detection and
treatment of young people with psychosis [35], the com-
munity mental health centers (CMHC) [36], and the
assertive community treatment (ACT) teams [37]. The
effect of treatment as usual on cannabis abuse in Denmark
is unknown, but a randomized trial comparing OPUS
treatment with other treatment (primarily CMHC) inves-
tigated prevalence of any comorbid diagnosis of harm or
dependence syndrome at baseline and at one and two
years follow-up. At baseline, 27% in both treatment arms Inclusion criteria are presented in Table 1. The diagnostic
criteria are based on the ICD-10 system [39]. Inclusion criteria are presented in Table 1. The diagnostic
criteria are based on the ICD-10 system [39]. The age group is selected both to ensure a relatively
homogenous group of patients, and to reflect the age
group at highest risk of developing schizophrenia [40]. The criterion for residence in the Copenhagen area is an
attempt to maximize adherence to treatment by minimiz-
ing the distance to treatment facilities. If this criterion Table 1: Criteria for inclusion and exclusion in the CapOpus trial. Inclusion:
Exclusion:
ICD-10 diagnosis F2 (F20–F29): Schizophrenia, schizotypal and delusional disorders
ICD-10 diagnosis F10.2: Alcohol dependence syndrome
ICD-10 diagnosis F11.2: Opioid dependence syndrome
ICD-10 diagnosis F12: Mental and behavioral disorders due to use of cannabinoids
ICD-10 diagnosis F14.2: Cocaine dependence syndrome
Aged 18–35 years
Refusal to give informed consent
Residence in the Copenhagen area
Sufficient Danish-speaking capabilities
Able and willing to give informed consent Table 1: Criteria for inclusion and exclusion in the CapOpus trial. Table 1: Criteria for inclusion and exclusion in the CapOpus trial. Page 5 of 9
(page number not for citation purposes) *Severity of abuse
f Assessment of number of days with cannabis use in the
past 30 days will be measured at all three assessment
points using the TLFB [29]. The TLFB has been reported to
have high validity in measuring cannabis consumption
when compared with urinalysis [30]. Briefly, the TLFB is a
self-reported measurement tool in which the respondent
plots all memorable dates within a preceding period on a
calendar, and then uses these dates to aid in remembering
consumption of a given substance on each day in the
period. If the patients consent, self-reported cannabis con-
sumption will be validated with blood samples. *Psychosis symptoms and clinical improvement
Psychosis symptoms are assessed by the use of The Posi-
tive and Negative Syndrome Scale (PANSS) for schizo-
phrenia [42]. Changes in PANSS scores have been shown
to correlate well with clinical improvements as measured
by the Clinical Global Impressions Ratings (CGI) scale
[43-45]. Furthermore, the overall impression of symp-
toms and functioning is evaluated using the Global
Assessment of Functioning (GAF) scale [46,47]. Apart from using the TLFB, information will be obtained
about age of first use of cannabis, age of first regular use of
cannabis, and reasons for use of cannabis. *Cognitive function *Cognitive function
Various aspects of cognitive function will be measured
using a range of psychometric instruments. Prepsychotic
intelligence will be estimated using the Danish Adult
Reading Test (DART), a Danish adaptation of the
National Adult Reading Test [48]. Speed of information
processing will be assessed using the Brief Assessment of
Cognition in Schizophrenia (BACS) symbol coding and
Trail Making Part A [49-51]. Attention and vigilance are
assessed by Continuous Performance Test, Identical Pairs
version (CPT-IP) [52]. Working memory is assessed using
Trail Making Part B. Memory and verbal learning are
assessed with Hopkins Verbal Learning Test [53]. Execu- *Influence and severity of other substance use
The WHO's Schedules for Clinical Assessment in Neu-
ropsychiatry (SCAN) interview's chapters 11 and 12,
excluding the section on nicotine, will be used to estimate
influence and severity of other substance use, as well as
influence of cannabis abuse [41]. Chapter 11 measures
influence and severity of alcohol use, and chapter 12 of
other psychoactive substances, including prescription
medicine. Page 5 of 9
(page number not for citation purposes) http://www.trialsjournal.com/content/9/1/42 http://www.trialsjournal.com/content/9/1/42 Trials 2008, 9:42 Trials 2008, 9:42 tive functioning is assessed with Neuropsychological
Assessment Battery (NAB) Mazes [54]. tive functioning is assessed with Neuropsychological
Assessment Battery (NAB) Mazes [54]. The Copenhagen Trial Unit (CTU) will perform the cen-
tralized randomization, and only the CTU will know the
block size used to randomize. A research assistant pro-
vides information on the patients to the CTU after con-
ducting the baseline assessment. The CTU then performs
the randomization procedure based on computer-gener-
ated allocation sequences, and communicates the allo-
cated treatment to the CapOpus consultants responsible
for the CapOpus experimental intervention. If a patient is
allocated to CapOpus intervention, the consultants con-
tact the patient. Regardless of allocation, the consultants
also contact the patient's case manager, so that the treat-
ment as usual intervention can be commenced. This pro-
cedure ensures that the research assistant, who will be
doing the subsequent patient assessments, is blinded to
the allocated intervention. Blinding is maintained until
the end of the trial. Patients are instructed not to reveal
details that may cause the research assistant to deduce
which treatment they are receiving. At each of the follow-
up assessments, the research assistant will register a guess
as to which treatment the patient is receiving. Sample size and power calculation p
p
A 2008 Cochrane review of psychosocial interventions for
people with both severe mental illness and substance mis-
use [28] identified five papers with results from studies
using a combination of motivational interviewing and
cognitive behavioral therapy.[22,64-67] However, only
one of these contains information about reduction of days
with cannabis abuse, but presents only the median, not
the mean, and the range, not the standard deviation.[22]
However, 6 months after start of treatment, this particular
paper reported that those receiving integrated care had, as
median, 20.62 percent of days abstinent from all sub-
stances, compared to 1.10 in the routine care group, i.e. a
difference of 19.5. Extrapolating this to our study, with a
TLFB-period of 30 days, corresponds to 5.85 days. Trun-
cating this to a more conservative 5 days, and assuming a
standard deviation also of 5 days, it becomes possible to
calculate sample size for an independent samples t-test;
with an α-level of 0.05 and a power of 0.90, the required
number of patients in each intervention can be calculated
to be 22. Due to attrition, more patients will be required. Results from the OPUS trial, which may be comparable to
our study in terms of participant profiles, showed that
high attrition may be expected among substance-using
people with schizophrenia [38]. We obtained data about
one-year dropout from the OPUS trial among people with
substance misuse, and found that among those receiving
the control treatment, the dropout-rate was 37%. Gener-
alizing this to our study, regardless of intervention alloca- *Social functioning and quality of life *Social functioning and quality of life Social functioning within the major life areas of commu-
nity, social, and civil life will be estimated using the 12-
item interviewer administered version of the World
Health Organization's Disability Assessment Schedules
(WHODAS-II) [55]. Two measures of quality of life
(QOL) will be used in a combined attempt to compare
QOL improvements in the two treatment arms, namely
the five-item EQ-5D [56] and the seventeen-item Man-
chester Short Assessment of Quality of Life (MANSA) [57]. *Sociodemographic variables A number of sociodemographic variables will be assessed,
including age, sex, living conditions, marital status, educa-
tion, employment status, number of children, ethnicity,
and history of homelessness. *Other assessment tools All of the assessment tools mentioned above will form the
standard assessments that will be used at all three assess-
ment points and on all patients. In addition, a few other
assessment tools will be used. At six months follow up,
user satisfaction with the received treatment will be evalu-
ated using the eight-item Client Satisfaction Question-
naire (CSQ) [58]. Adherence to the CapOpus intervention
will be measured by number of contacts between CapO-
pus consultants on one side and the patient, the patient's
family, and the patient's case manager on the other side. Finally, cost of treatment and cost-benefit estimation will
be performed by comparing number of outpatient treat-
ments and number of bed days in the two treatment arms. This will be done register-based in The Danish Psychiatric
Central Register [59,60] and The Danish National Hospi-
tal Register [61], as all persons in Denmark are easily iden-
tifiable in registers using a unique personal identification
number given to all people either at birth or upon migra-
tion into Denmark [62]. *Cognitive function When the
trial is finished, inter-rater reliability between the actual
treatment and the research assistant's guess will be esti-
mated using Cohen's kappa coefficient [63] to assess the
degree to which blinding has been successful. Page 6 of 9
(page number not for citation purposes) Statistics
h The main null-hypothesis to be tested is that there is no
difference between the two treatment arms with regard to
decrease in cannabis use. All randomized patients will be
analyzed, including those who stop receiving treatment,
according to the intent-to-treat principle [68]. Continu-
ous outcome measures, including the primary outcome of
reduction of days with cannabis abuse, will be analyzed
using multivariate analysis of variance (ANOVA) mixed
models with repeated measurements. This will include
interaction analyses of time and type of treatment, in
order to evaluate the effect over time. Binary outcome
measures will be analyzed using multivariate logistic
regression models. The subgroup of patients who com-
plete the entire experimental treatment will be compared
with all those randomized into the trial in order to deter-
mine risk factors for attrition. Sensitivity analyses will be
carried out to evaluate the effect of treatment in patients
that are inaccessible for follow-up. This will be conducted
by multiple imputation methodology both using last
observation carried forward, and assuming an increase in
cannabis use among those lost to follow-up. Our trial may have several limitations. First, it is a rather
small trial aiming at demonstrating a substantial interven-
tion effect. In a sense, our trial may be viewed as a pilot for
potentially larger trials at a later stage. Second, the large
number of outcomes makes interpretation of significant
findings difficult. Accordingly, our interpretation of sig-
nificant findings at or close to the conventional level of p
= 0.05 will be conservative. One further limitation of the
trial is that there may be a crossover relating to the
patients' case-managers. Due to the randomization proce-
dure, the same case manager may have patients in both
the experimental intervention and the control treatment
arms. This spawns the risk that elements from the experi-
mental intervention are incorporated into the treatment
of patients in the control arm, potentially leading towards
type II errors. It will be attempted to bypass this limitation
by investigating outcome differences between control-
group patients whose case managers also have patients in
the CapOpus experimental intervention arm, and those
whose case managers do not. http://www.trialsjournal.com/content/9/1/42 http://www.trialsjournal.com/content/9/1/42 tion, at least 35 patients will be required in each of the two
intervention groups. However, we aim to include between
60 and 70 patients in each group, as this would enable us
to stratify the analyses. With 60 or 70 patients, it should
also be possible to measure even smaller differences in
secondary outcomes. Apart from gathering evidence about best practice in treat-
ment of cannabis abuse among young people with psy-
chosis, the study will allow us to validate the TLFB
measurement tool for cannabis against blood samples,
something that to our knowledge has not been done pre-
viously. Hopefully, the CapOpus intervention will carry positive
effects. If this is so, this could substantially improve treat-
ment of these patients. On the other hand negative conse-
quences cannot be ruled out. The extra interventions in
the experimental arm may potentially cause more patients
to drop out from usual treatment. Should this occur, the
addiction consultants in CapOpus will actively support
the patients in resuming contact with the case managers. Discussion The authors declare that they have no competing interests. The centralized randomization procedure offers strengths
to the CapOpus trial by reducing the risk of selection and
allocation bias [71,72]. The outcome assessments are
blinded with the intent of being unbiased [71,72]. The
planned intense follow up of patients coupled with inten-
tion-to-treat analyses should guard against attrition bias
[71,72]. Also, the broad array of outcome estimates allows
us to measure effects of treatment in many areas of life. Ethical considerations The regional ethics committee for the greater Copenhagen
area has approved the protocol under the file number H-
D-2007-0028, as has The Danish Data Protection Agency
under the file number 2007-41-0616. The trial is regis-
tered at ClinicalTrials.gov as NCT00484302. Both positive
and negative findings from the trial will be published, in
accordance with the CONSORT guidelines [69,70]. The fact that the current treatment in Denmark is not uni-
form is reflected in the control treatment, as no attempts
will be made to artificially introduce a level of homogene-
ity in this intervention arm. This may, however, lead to a
degree of selection bias if only a small proportion of eligi-
ble case managers actually refer patients to the trial. Results will be interpreted accordingly. Information about the trial is presented to potential par-
ticipants both verbally and in written form. It is stressed
that participation is voluntary, without expected negative
side effects, and that the patient can withdraw his or her
consent at any time without consequence for treatment
possibilities. Patients will receive a copy of their rights. Competing interests p
g
The authors declare that they have no competing interests. Randomization and blinding g
Randomization into one of the two treatment arms is per-
formed after the baseline assessment. Firstly, randomiza-
tion is stratified by severity of cannabis abuse as measured
by TLFB, by creating two sub-strata; one of patients having
used cannabis less than 15 days in the preceding 30 day
period, and one of patients having used cannabis 15 days
or more. This is done to avoid the risk of heavy-users of
cannabis being overrepresented in either of the treatment
groups. Similarly, randomization will be stratified based
on the referrer – OPUS, CMHC, or ACT, as it is unlikely
that patients from these three referrers are comparable
with regard to psychotic symptoms and level of function-
ing. Page 6 of 9
(page number not for citation purposes) Page 6 of 9
(page number not for citation purposes) Trials 2008, 9:42 Trials 2008, 9:42 Trials 2008, 9:42 http://www.trialsjournal.com/content/9/1/42 References Smit F, Bolier L, Cuijpers P: Cannabis use and the risk of later
schizophrenia: a review. Addiction 2004, 99:425-430. 31. Miller WR: Motivational Interviewing. Behav Psychother 1983,
11:91-111. 9. Stefanis NC, Delespaul P, Henquet C, Bakoula C, Stefanis CN, van OJ:
Early adolescent cannabis exposure and positive and nega-
tive dimensions of psychosis. Addiction 2004, 99:1333-1341. 32. Hettema J, Steele J, Miller WR: Motivational interviewing. Annual
Review of Clinical Psychology 2005, 1:91-111. 33. Burke BL, Arkowitz H, Menchola M: The efficacy of motivational
interviewing: a meta-analysis of controlled clinical trials. J
Consult Clin Psychol 2003, 71:843-861. p y
10. Hall W: Is cannabis use psychotogenic? Lancet 2006,
367:193-195. 11. Linszen DH, Dingemans PM, Lenior ME: Cannabis abuse and the
course of recent-onset schizophrenic disorders. Arch Gen Psy-
chiatry 1994, 51:273-279. y
34. Denis C, Lavie E, Fatseas M, Auriacombe M: Psychotherapeutic
interventions for cannabis abuse and/or dependence in out-
patient settings. Cochrane Database Syst Rev 2006, 3:CD005336. y
12. Grech A, van OJ, Jones PB, Lewis SW, Murray RM: Cannabis use
and outcome of recent onset psychosis. Eur Psychiatry 2005,
20:349-353. p
g
y
35. Jørgensen P, Nordentoft M, Abel MB, Gouliaev G, Jeppesen P, Kassow
P: Early detection and assertive community treatment of
young psychotics: the Opus Study Rationale and design of
the trial. Soc Psychiatry Psychiatr Epidemiol 2000, 35:283-287. 13. Hides L, Dawe S, Kavanagh DJ, Young RM: Psychotic symptom
and cannabis relapse in recent-onset psychosis. Prospective
study. Br J Psychiatry 2006, 189:137-143. 36. Nordentoft M, Knudsen HC, Jessen-Petersen B, Krasnik A, Sælan H,
Treufeldt P, Wetcher B: CCPP-Copenhagen Community Psy-
chiatric Project. Implementation of community mental
health centres in Copenhagen: effects of service utilization,
social integration, quality of life and positive and negative
symptoms. Soc Psychiatry Psychiatr Epidemiol 1996, 31:336-344. 3
f
A S
O y
J
y
y
14. van Os J, Bak M, Hanssen M, Bijl RV, de GR, Verdoux H: Cannabis
use and psychosis: a longitudinal population-based study. Am
J Epidemiol 2002, 156:319-327. J p
15. Caspari D: Cannabis and schizophrenia: results of a follow-up
study. Eur Arch Psychiatry Clin Neurosci 1999, 249:45-49. ' 37. Vendsborg P, Nordentoft M, Hvenegaard A, Søgaard J: Opsøgende
psykoseteam: Assertive Community Treatment Copenhagen, Institut for
sundhedsvæsen; 1999. y
y
y
16. Kamali M, Kelly L, Gervin M, Browne S, Larkin C, O'Callaghan E: Psy-
chopharmacology: insight and comorbid substance misuse
and medication compliance among patients with schizo-
phrenia. References 1. Moore THM, Zammit S, Lingford-Hughes A, Barnes TRE, Jones PB,
Burke M, Lewis G: Cannabis use and risk of psychotic or affec-
tive mental health outcomes: a systematic review. Lancet
2007, 370(9584):319-328. p
p
p
25. Weiss RD, Mirin SM, Griffin ML: Methodological considerations
in the diagnosis of coexisting psychiatric disorders in sub-
stance abusers. Br J Addict 1992, 87:179-187. 26. McRobert C, Burlingame GM, Hoag MJ: Comparative efficacy of
individual and group psychotherapy: A meta-analytic per-
spective. Group Dynamics: Theory, Research, and Practice 1998,
2:101-117. (
)
2. Nordentoft M, Hjorthøj C: Cannabis use and risk of psychosis in
later life. Lancet 2007, 370:293-294. 3. Zammit S, Allebeck P, Andreasson S, Lundberg I, Lewis G: Self
reported cannabis use as a risk factor for schizophrenia in
Swedish conscripts of 1969: historical cohort study. BMJ 2002,
325:1199. 27. Greene LR: Research in Group Psychotherapy for Substance
Abuse: Fiction, Fact, and Future. In The Group Therapy for Sub-
stance Abuse Edited by: Brook DW and Spitz HI. New York, The
Haworth Medical Press; 2002:391-410. 4. Arseneault L, Cannon M, Witton J, Murray RM: Causal association
between cannabis and psychosis: examination of the evi-
dence. Br J Psychiatry 2004, 184:110-117. 28. Cleary M, Hunt G, Matheson S, Siegfried N, Walter G: Psychosocial
interventions for people with both severe mental illness and
substance misuse. Cochrane Database Syst Rev 2008:CD001088. J
y
y
5. Arseneault L, Cannon M, Poulton R, Murray R, Caspi A, Moffitt TE:
Cannabis use in adolescence and risk for adult psychosis: lon-
gitudinal prospective study. BMJ 2002, 325:1212-1213. 29. Sobell LC, Sobell MB: Timeline Follow-Back: A Technique for
Assessing Self-Reported Alcohol Consumption. In Measuring
Alcohol Consumption: Psychosocial and Biological Methods Edited by: Lit-
ten RZ and Allen J. New Jersey, Humana Press; 1992:41-72. g
p
p
y
J
6. Henquet C, Murray R, Linszen D, van OJ: The environment and
schizophrenia: the role of cannabis use. Schizophr Bull 2005,
31:608-612. 30. Donohue B, Hill HH, Azrin NH, Cross C, Strada MJ: Psychometric
support for contemporaneous and retrospective youth and
parent reports of adolescent marijuana use frequency in an
adolescent outpatient treatment population. Addictive Behav-
iors 2007, 32:1787-1797. 7. Henquet C, Krabbendam L, Spauwen J, Kaplan C, Lieb R, Wittchen
HU, van OJ: Prospective cohort study of cannabis use, predis-
position for psychosis, and psychotic symptoms in young
people. BMJ 2005, 330:11. p
p
J
8. Authors' contributions All authors were involved in the conception and design of
the study protocol, drafting or revising the manuscript,
and have approved the final manuscript. AF, A-ML, and
MTRM are responsible for conducting the CapOpus inter-
vention. CH, AF, A-ML, MTRM, and MN are responsible
for inclusion of patients. CH is responsible for research Page 7 of 9
(page number not for citation purposes) Trials 2008, 9:42 http://www.trialsjournal.com/content/9/1/42 interviews and data analysis. MN, MCA, and CG are co-
responsible for data analysis. All authors will participate
in interpretation of results. 20. Coldham EL, Addington J, Addington D: Medication adherence of
individuals with a first episode of psychosis. Acta Psychiatrica
Scandinavica 2002, 106:286-290. 21. Miller WR, Rollnick S: Motivational Interviewing: Preparing People for
Change 2nd edition. New York, Guilford; 2002. 22. Barrowclough C, Haddock G, Tarrier N, Lewis SW, Moring J, O'Brien
R, Schofield N, McGovern J: Randomized controlled trial of
motivational interviewing, cognitive behavior therapy, and
family intervention for patients with comorbid schizophre-
nia and substance use disorders. Am J Psychiatry 2001,
158:1706-1713. Acknowledgements g
The trial has received funding from The Lundbeck Foundation, The Munic-
ipality of Copenhagen, The Egmont Foundation, Aase and Ejnar Danielsen's
Foundation, the Wørzner Foundation, and The Health Insurance Founda-
tion. Neither current nor future sponsors of the trial will have any role in
trial design, data collection, data analysis, data interpretation, or in publica-
tion of data from the trial. 23. RachBeisel J, Scott J, Dixon L: Co-occurring severe mental illness
and substance use disorders: a review of recent research. Psy-
chiatr Serv 1999, 50:1427-1434. 24. Ziedonis DM: Integrated treatment of co-occurring mental ill-
ness and addiction: clinical intervention, program, and sys-
tem perspectives. CNS Spectr 2004, 9:892-904, 925. References Psychiatr Serv 2001, 52:161-166. 38. Petersen L, Jeppesen P, Thorup A, Abel MB, Ohlenschlaeger J, Chris-
tensen TO, Krarup G, Jorgensen P, Nordentoft M: A randomised
multicentre trial of integrated versus standard treatment
for patients with a first episode of psychotic illness. BMJ 2005,
331:602. p
y
17. Olfson M, Mechanic D, Hansell S, Boyer CA, Walkup J, Weiden PJ:
Predicting Medication Noncompliance After Hospital Dis-
charge Among Patients With Schizophrenia. Psychiatr Serv
2000, 51:216-222. 39. WHO: International Classification of Diseases (ICD). 2007
[http://www.who.int/classifications/icd/en/]. 18. Fenton WS, Blyler CR, Heinssen RK: Determinants of medica-
tion compliance in schizophrenia: empirical and clinical find-
ings. Schizophr Bull 1997, 23:637-651. 40. Thorup A, Waltoft BL, Pedersen CB, Mortensen PB, Nordentoft M:
Young males have a higher risk of developing schizophrenia:
a Danish register study. Psychol Med 2007, 37:479-484. g
p
19. Wilk J, Marcus SC, West J, Countis L, Hall R, Regier DA, Olfson M:
Substance abuse and the management of medication nonad-
herence in schizophrenia. J Nerv Ment Dis 2006, 194:454-457. g
y
y
41. Wing JK, Babor T, Brugha T, Burke J, Cooper JE, Giel R, Jablenski A,
Regier D, Sartorius N: SCAN. Schedules for Clinical Assess-
ment in Neuropsychiatry. Arch Gen Psychiatry 1990, 47:589-593. Page 8 of 9
(page number not for citation purposes) Page 8 of 9
(page number not for citation purposes) http://www.trialsjournal.com/content/9/1/42 http://www.trialsjournal.com/content/9/1/42 42. Kay SR, Fiszbein A, Opler LA: The positive and negative syn-
drome scale (PANSS) for schizophrenia. Schizophr Bull 1987,
13:261-276. 67. Bellack AS, Bennett ME, Gearon JS, Brown CH, Yang Y: A rand-
omized clinical trial of a new behavioral treatment for drug
abuse in people with severe and persistent mental illness. Arch Gen Psychiatry 2006, 63:426-432. 43. Leucht S, Kane JM, Etschel E, Kissling W, Hamann J, Engel RR: Linking 43. Leucht S, Kane JM, Etschel E, Kissling W, Hamann J, Engel RR: Linking
the PANSS, BPRS, and CGI: Clinical Implications. Neuropsy-
chopharmacology 2006, 31:2318-2325. 43. Leucht S, Kane JM, Etschel E, Kissling W, Hamann J, Engel RR: Linking
the PANSS, BPRS, and CGI: Clinical Implications. Neuropsy- 68. y
y
68. Lachin JM: Statistical Considerations in the Intent-to-Treat
Principle. Controlled Clinical Trials 2000, 21:167-189. the PANSS, BPRS, and CGI: Clinical Implications. Neuropsy-
chopharmacology 2006, 31:2318-2325. p
gy
,
44. Leucht S, Kane JM, Kissling W, Hamann J, Etschel E, Engel RR: What
d
th PANSS
? S hi
ph
i R
h 2005 79 231 238 p
gy
44. Leucht S, Kane JM, Kissling W, Hamann J, Etschel E, Engel RR: What
does the PANSS mean? Schizophrenia Research 2005, 79:231-238. 69. Moher D, Schulz KF, Altman DG: The CONSORT statement:
revised recommendations for improving the quality of
reports of parallel-group randomised trials. Lancet 2001,
357:1191-1194. p
45. Levine SZ, Rabinowitz J, Engel R, Etschel E, Leucht S: Extrapolation
between measures of symptom severity and change: An
examination of the PANSS and CGI. Schizophrenia Research
2008, 98:318-322. 70. Boutron I, Moher D, Altman DG, Schulz KF, Ravaud P, for the CON-
SORT Group: Extending the CONSORT Statement to Rand-
omized
Trials
of
Nonpharmacologic
Treatment:
Explanation and Elaboration. Ann Intern Med 2008, 148:295-309. 46. Endicott J, Spitzer RL, Fleiss JL, Cohen J: The global assessment
scale. A procedure for measuring overall severity of psychi-
atric disturbance. Arch Gen Psychiatry 1976, 33:766-771. p
71. Gluud LL: Bias in clinical intervention research. Am J Epidemiol
2006, 163:493-501. y
y
47. Diagnostic and Statistical Manual of Mental Disorders, 4th ed. Washing-
ton, DC, American Psychiatric Association; 1994. 72. Gluud C: The culture of designing hepato-biliary randomised
trials. J Hepatol 2006, 44:607-615. 48. Nelson HE, O'Connell A: Dementia: the estimation of premor-
bid intelligence levels using the New Adult Reading Test. Cortex 1978, 14:234-244. 49. http://www.trialsjournal.com/content/9/1/42 Keefe RSE, Goldberg TE, Harvey PD, Gold JM, Poe MP, Coughenour
L: The Brief Assessment of Cognition in Schizophrenia: reli-
ability, sensitivity, and comparison with a standard neuro-
cognitive battery. Schizophrenia Research 2004, 68:283-297. g
y
p
50. Bowie CR, Harvey PD: Administration and interpretation of
the Trail Making Test. Nat Protocols 2006, 1:2277-2281. 51
S
O S
A A C
di
f N
h l
i
l T
Ad i g
,
51. Spreen O, Strauss A: A Compendium of Neuropsychological Test. Admin-
istration, Norms, and Commentary New York, Oxford University Press;
1998. 52. Cornblatt BA, Lenzenweger MF, Erlenmeyer-Kimling L: The contin-
uous performance test, identical pairs version: II. Contrast-
ing attentional profiles in schizophrenic and depressed
patients. Psychiatry Research 1989, 29:65-85. p
y
y
53. Brandt J: The Hopkins verbal learning test : development of a
new memory test with six equivalent forms. Clin Neuropsychol
1991, 5:125-142. 54. Stern RA, White T: Neuropsychological Assessment Battery Lutz, Florida,
Psychological Assessment Resources, Inc.; 2003. 55. WHO: World Health Organization Disability Assessment Schedule (WHO-
DAS II) Geneva, WHO; 2000. )
56. Brooks R: EuroQol: the current state of play. Health Policy 1996,
37:53-72. 57. Priebe S, Huxley P, Knight S, Evans S: Application and Results of
the Manchester Short Assessment of Quality of Life (Mansa). International Journal of Social Psychiatry 1999, 45:7-12. J
y
y
58. Larsen DL, Attkisson CC, Hargreaves WA, Nguyen TD: Assess-
ment of client/patient satisfaction: Development of a general
scale. Evaluation and Program Planning 1979, 2:197-207. g
g
59. Munk-Jørgensen P, Mortensen PB: The Danish Psychiatric Cen-
tral Register. Dan Med Bull 1997, 44:82-84. g
60. Munk-Jørgensen P, Kastrup M, Mortensen PB: The Danish psychi-
atric register as a tool in epidemiology. Acta Psychiatr Scand
Suppl 1993, 370:27-32. pp
61. Andersen TF, Madsen M, Jørgensen J, Mellemkjoer L, Olsen JH: The
Danish National Hospital Register. A valuable source of data
for modern health sciences. Dan Med Bull 1999, 46:263-268. 62. Pedersen CB, Gøtzsche H, Møller J, Mortensen PB: The Danish
Civil Registration System. A cohort of eight million persons. Dan Med Bull 2006, 53:441-449. ersen CB, Gøtzsche H, Møller J, Mortensen PB: The Dan
il R
i
i
S
A
h
f
i h
illi 63. Cohen J: A Coefficient of Agreement for Nominal Scales. Edu-
cational and Psychological Measurement 1960, 20:37-46. 72.
Gluud C: The culture of designing hepato-biliary randomised
trials. J Hepatol 2006, 44:607-615. Page 8 of 9 Trials 2008, 9:42 http://www.trialsjournal.com/content/9/1/42 Publish with BioMed Central and every
scientist can read your work free of charge
"BioMed Central will be the most significant development for
disseminating the results of biomedical research in our lifetime."
Sir Paul Nurse, Cancer Research UK
Your research papers will be:
available free of charge to the entire biomedical community
peer reviewed and published immediately upon acceptance
cited in PubMed and archived on PubMed Central
yours — you keep the copyright
Submit your manuscript here:
http://www.biomedcentral.com/info/publishing_adv.asp
BioMedcentral
Page 9 of 9
(page number not for citation purposes) Publish with BioMed Central and every
scientist can read your work free of charge
"BioMed Central will be the most significant development for
disseminating the results of biomedical research in our lifetime."
Sir Paul Nurse, Cancer Research UK
Your research papers will be:
available free of charge to the entire biomedical community
peer reviewed and published immediately upon acceptance
cited in PubMed and archived on PubMed Central
yours — you keep the copyright
Submit your manuscript here:
http://www.biomedcentral.com/info/publishing_adv.asp
BioMedcentral Publish with BioMed Central and every
scientist can read your work free of charge 64. Haddock G, Barrowclough C, Tarrier N, Moring J, O'Brien R,
Schofield N, Quinn J, Palmer S, Davies L, Lowens I, McGovern J, Lewis
S: Cognitive-behavioural therapy and motivational interven-
tion for schizophrenia and substance misuse. 18-month out-
comes of a randomised controlled trial. Br J Psychiatry 2003,
183:418-426. 65. Baker A, Bucci S, Lewin TJ, Kay-Lambkin F, Constable PM, Carr VJ:
Cognitive-behavioural therapy for substance use disorders in
people with psychotic disorders: Randomised controlled
trial. Br J Psychiatry 2006, 188:439-448. J
y
y
66. Baker A, Bucci S, Lewin TJ, Richmond R, Carr VJ: Comparisons
between psychosis samples with different patterns of sub-
stance use recruited for clinical and epidemiological studies. Psychiatry Res 2005, 134:241-250.
|
https://openalex.org/W3035684270
|
https://www.detstom.ru/jour/article/download/209/210
|
Russian
| null |
Assessment of pain and pain relief in children at a dental appointment
|
Stomatologiâ detskogo vozrasta i profilaktika
| 2,020
|
cc-by
| 3,280
|
Оригинальная статья Оригинальная статья DOI: 10.33925/1683-3031-2020-20-2-101-104 Резюме Резюме Актуальность. Субъективная оценка боли у детей традиционно определяется при помощи визуально-ана-
логовых шкал. Необходимость обеспечить комфортное стоматологическое лечение у детей очевидна, поэто-
му для получения максимально достоверных данных необходима разработка шкал для оценки боли и эффек-
тивности обезболивания в зависимости от возраста ребенка. р
р
Цель. Разработка аналого-визуальных шкал, предназначенных для оценки эффективности обезболивания
при выполнении амбулаторных стоматологических вмешательств у детей в зависимости от возраста ребенка. р
р
Цель. Разработка аналого-визуальных шкал, предназначенных для оценки эффективности обезболивания
при выполнении амбулаторных стоматологических вмешательств у детей в зависимости от возраста ребенка. Материалы и методы. Были разработаны аналого-визуальные шкалы оценки эффективности обезболива-
ния у детей на амбулаторном стоматологическом приеме в зависимости от возраста ребенка. Было обследо-
вано 100 пациентов в возрасте от 4 до 12 лет. Материалы и методы. Были разработаны аналого-визуальные шкалы оценки эффективности обезболива-
ния у детей на амбулаторном стоматологическом приеме в зависимости от возраста ребенка. Было обследо-
вано 100 пациентов в возрасте от 4 до 12 лет. р
Результаты. Основу разработанных шкал составили реакция и поведение ребенка во время стоматологи-
ческого лечения с использованием местного обезболивания. В возрастной группе от 4-7 лет аналого-визуаль-
ную шкалу заполняли врач, ребенок и родитель, а у второй группы пациентов, в возрасте от 7 до 12 лет, шкалу
заполняли ребенок и врач, так как в данной возрастной категории дети могли самостоятельно соотнести себя
с картинкой на шкале. р
Выводы. Разработанные шкалы субъективной оценки эффективности местного обезболивания у детей по-
зволяют определять качество исследуемых способов и средств местной анестезии в детской стоматологиче-
ской практике. 101 Ключевые слова: боль, шкала оценки боли, местное обезболивание, детская стоматологическая помощь. Для цитирования: Анисимова Е. Н., Анисимова Н. Ю., Ковылина О. С., Кравченко И. А. Оценка эффектив-
ности местного обезболивания у детей на амбулаторном стоматологическом приеме. Стоматология детского
возраста и профилактика.2020;20(2):101-104. DOI: 10.33925/1683-3031-2020-20-2-101-104. Assessment of pain and pain relief in children
at a dental appointment E.N. Anisimova, N.Yu. Anisimova, O.S. Kovylina, I.A. Kravchenko
Moscow State University of Medical and Dentistry named after A.I. Yevdokimov
Moscow, Russian Federation Оценка эффективности местного
обезболивания у детей на амбулаторном
стоматологическом приеме Анисимова Е.Н., Анисимова Н.Ю., Ковылина О.С., Кравченко И.А. Московский государственный медико-стоматологический университет имени А.И. Евдокимова
Москва, Российская Федерация Анисимова Е.Н., Анисимова Н.Ю., Ковылина О.С., Кравченко И.А. Московский государственный медико-стоматологический университет имени А.И. Евдокимова
Москва, Российская Федерация МАТЕРИАЛЫ И МЕТОДЫ
ИССЛЕДОВАНИЯ Сотрудниками кафедр обезбо-
ливания в стоматологии и детской
стоматологии ФГБОУ ВО МГМСУ
им. А.И. Евдокимова была разра-
ботана аналого-визуальная шкала
оценки эффективности обезболи-
вания у детей в амбулаторной сто-
матологии. В силу того, что нуждаемость в
стоматологической помощи у де-
тей доходит до 90% [2], врач – сто-
матолог детский сталкивается с
острой необходимостью проведе-
ния эффективного обезболивания
[3], использование которого может
быть затруднено, если изначально
у маленького пациента присутству-
ет эмоциональная напряженность. Выявление у детей страха перед
инъекцией, лечением и в последу-
ющем выработка индивидуально-
го подхода к ребенку во многом
обуславливают успех лечения [4]. По результатам социологического
опроса врачей-стоматологов, ра-
ботающих на детском амбулатор-
ном стоматологическом приеме,
94,5% респондентов отметили, что
эмоциональное состояние ребенка
мешало качественному оказанию
стоматологической помощи, а в
88,1% случаев врачам приходилось
отказывать в приеме [5]. Было обследовано 100 паци-
ентов в возрасте от 4 до 12 лет в
Клиническом центре челюстно-ли-
цевой, реконструктивно-восстано-
вительной и пластической хирургии
Клиники МГМСУ им. А.И. Евдоки-
мова и ГАУЗ МО «Королёвская сто-
матологическая поликлиника», ко-
торым было необходимо провести
местное обезболивание для лече-
ния кариеса и его осложнений. Для
проведения местного обезболива-
ния применялся 4% раствор артика-
ина с эпинефрином в концентрации
1:200 000, введенный пародонталь-
ным методом. Пациенты были раз-
делены на группы по возрастному
критерию: от 4 до 7 лет и от 7 до
12 лет. В первой группе в исследова-
нии приняли участие 40 пациентов
в возрасте от 4 до 7 лет, из которых
было 28 мальчиков и 12 девочек. Во второй группе проводили оценку
эффективности обезболивания при
лечении кариеса и его осложнений
у 60 пациентов в возрасте от 7 до
12 лет, из которых было 35 мальчи-
ков и 25 девочек. 102 По завершении лечения ребенок,
врач и родитель, опираясь на реак-
цию и поведение ребенка, заполня-
ют аналогово-визуальную шкалу. Отметка процентного балльного
показателя на уровне 100 – 90% со-
ответствует дескриптору пациента
«отсутствие боли», дескриптор вра-
ча «эффект местного обезболива-
ния выражен в полном объеме», то
есть глубина обезболивания была
достаточна для проведения стома-
тологического вмешательства. Ока-
зание стоматологической помощи
было безболезненным, эффектив-
ным и в полном объеме. Оценка
родителем в этом диапазоне указы-
вает на отсутствие боли у ребенка. Оценивать боль у детей во всех
областях медицины принято субъ-
ективно, проведенный анализ на-
учных работ по наличию анало-
го-визуальных шкал [6] показал
отсутствие в настоящее время
разработанного способа субъек-
тивной оценки болевых ощущений,
испытываемых детьми во время
стоматологического
вмешатель-
ства [7]. ЦЕЛЬ ИССЛЕДОВАНИЯ альная шкала разделена на три
части: «пациент – ребенок», «врач»
и «родитель». Для обозначения
интенсивности боли шкала име-
ет градиентный фон от зеленого,
обозначающего отсутствие боле-
вых ощущений во время лечения,
до красного, сигнализирующего о
сильной боли пациента; также шка-
ла градуирована от 0 до 100%. Сло-
ва дескрипторы для ребенка: «мне
не больно», «было больно, но тер-
пел (а)», «мне было больно», позво-
ляют уточнить у ребенка резуль-
тат. Врач использует следующие
слова дескрипторы для определе-
ния эффективности наступившего
обезболивания: «эффект местно-
го обезболивания выражен в пол-
ном объеме», «эффект местного
обезболивания выражен слабо»,
«местное обезболивание не на-
ступило». Родитель/опекун ребен-
ка применяет следующие слова
дескрипторы: «моему ребенку не
больно», «у моего ребенка была
слабовыраженная боль», «моему
ребенку было больно». Эмоциональное
проявление
боли у детей различно, оно отли-
чается по интенсивности, продол-
жительности и качеству. Специфи-
ка детских страхов заключается в
том, что дети пропускают их через
призму своей яркой фантазии, что
может привести в будущем к раз-
витию негативных последствий в
виде дентофорбии [1], которая в
дальнейшем затрудняет возмож-
ность стоматологического лечения. Разработка аналого-визуальных
шкал, предназначенных для оцен-
ки эффективности обезболивания
при
выполнении
амбулаторных
стоматологических вмешательств
у детей в зависимости от возраста. МАТЕРИАЛЫ И МЕТОДЫ
ИССЛЕДОВАНИЯ Также определено, что для
получения данных болезненных
ощущений у детей необходимо учи-
тывать мнение ребенка, родителей
и врача, так как мнение только ре-
бенка не всегда бывает объектив-
ным [8]. Именно поэтому важно вы-
являть чрезмерную тревожность у
пациентов на стоматологическом
приеме и корректировать ее [9]. Эмоциональное состояние паци-
ента напрямую влияет на болевую
чувствительность твердых тканей
зубов. При высоком уровне отри-
цательных эмоций (более 60%) у
некоторых
пациентов
отмечено
повышение порогов болевой чув-
ствительности [10]. Отметка процентного балльного
показателя на уровне 50% соответ-
ствует дескриптору «было больно,
но я терпел/а», дескриптор врача
«эффект обезболивания выражен
слабо» это обозначает, что эффек-
тивность обезболивания была не-
достаточной во время проведения
стоматологического
вмешатель-
ства. Родители, отталкиваясь от
позы и мимики ребенка, отмечают
присутствие болезненных ощуще-
ний у него во время лечения. Abstract Abstract Relevance. Subjective assessment of pain in children is traditionally implemented using visual analogue scales. The need for comfortable dental treatment in children is obvious, therefore, in order to obtain the most reliable
data, it is necessary to develop pain rating scales and the effectiveness of pain management in accordance with
the age of the child. g
Purpose. Development of visual analogue scales designed to assess the effectiveness of pain relief when performing
outpatient dental interventions in children, depending on the age of the child. Materials and methods. A visual analogue scale was designed to evaluate the effectiveness of pain relief in
children at an outpatient dental appointment, in accordance with the age of the child. 100 patients aged 4 to 12
years were examined. y
Results. The reaction and behaviour of the child during dental treatment using local anesthesia were the basis
of the designed pain rating scales. In the age group of 4-7 years, the visual analogue scale was filled in by the
doctor, the child and the parent, and in the second group of patients aged 7 to 12 years, the scale was filled in by
the child and the doctor, since in this age category children could independently correlate themselves with the
picture on the scale. p
Conclusions. The designed scales of subjective assessment of the effectiveness of local anesthesia in children
allow to determine the quality of the studied methods and means of local anesthesia in pediatric dental practice. d
i
i
i
l
l
l
h
i
di
i d
l Key words: pain, pain rating scale, local anesthesia, pediatric dental care. y
p
, p
g
,
, p
For citation: E. N. Anisimova, N. Yu. Anisimova, O. S. Kovylina, I. A. Kravchenko. Assessment of pain and pain
relief in children at a dental appointment. Pediatric dentistry and dental prophylaxis.2020;20(2):101-104. DOI:
10.33925/1683-3031-2020-20-2-101-104. y
p
p
g
p
For citation: E. N. Anisimova, N. Yu. Anisimova, O. S. Kovylina, I. A. Kravchenko. Assessment of pain and pain
relief in children at a dental appointment. Pediatric dentistry and dental prophylaxis.2020;20(2):101-104. DOI:
10.33925/1683-3031-2020-20-2-101-104. Оригинальная статья осуществление невозможно. Ро-
дители по реакции ребенка отме-
чают сохранение боли ребенка во
время лечения. разделена на две части: «ребенок»
и «врач». Для определения интен-
сивности боли используют про-
центную шкалу от 0% – красная
зона, сигнализирующая о боли во
время лечения, до 100% – зеленая
зона, характеризующая полную эф-
фективность обезболивания и от-
сутствие болезненных ощущений
во время всех стоматологических
манипуляций (рис. 2). дескриптору пациента «отсутствие
боли», дескриптор врача «эффект
местного обезболивания выражен
в полном объеме», отметка про-
центного балльного показателя на
уровне 100 – 90%, то есть глубина
обезболивания была достаточна
для проведения стоматологиче-
ского вмешательства. Дети в возрасте 7-12 лет (вторая
группа) были способны самостоя-
тельно, без привлечения помощи
родителей, дать оценку проведен-
ному лечению. Дети данной воз-
растной группы после оказанной
стоматологической помощи охот-
но соотносили себя и свои ощуще-
ния с ребенком на шкале. Шкала При недостаточной эффективно-
сти обезболивания во время про-
ведения стоматологического вме-
шательства отметка процентного Безболезненность
стоматоло-
гической помощи соответствует 2/2020 (74) Стоматология детского возраста и профилакти
ния с ребенком на шкале. Шкала
ес о
о ощ
соо
е с
уе
а е
с
а
о
е
а
роце
о о
Рис. 1. Аналого-визуальная шкала оценки эффективности обезболивания при выполнении
амбулаторных стоматологических вмешательств у детей 4-7 лет
Fig. 1. Analog-visual scale for assessing the effectiveness of pain relief in children at a dental appointment 4-7 age
Рис. 2. Аналого-визуальная шкала оценки эффективности обезболивания при выполнении
амбулаторных стоматологических вмешательств у детей 7-12 лет
Fig. 2. Analog-visual scale for assessing the effectiveness of pain relief in children at a dental appointment 7-12 age Рис. 1. Аналого-визуальная шкала оценки эффективности обезболивания при выполнении
амбулаторных стоматологических вмешательств у детей 4-7 лет
Fig. 1. Analog-visual scale for assessing the effectiveness of pain relief in children at a dental appointment 4-7 age 103 Рис. 1. Аналого-визуальная шкала оценки эффективности обезболивания при выполнении
амбулаторных стоматологических вмешательств у детей 4-7 лет
Analog-visual scale for assessing the effectiveness of pain relief in children at a dental appointment Fig. 1. Analog-visual scale for assessing the effectiveness of pain relief in children at a Рис. 2. Аналого-визуальная шкала оценки эффективности обезболивания при выполнении
амбулаторных стоматологических вмешательств у детей 7-12 лет
Fig. 2. Analog-visual scale for assessing the effectiveness of pain relief in children at a dental appointment 7-12 age Рис. 2. Аналого-визуальная шкала оценки эф у
амбулаторных стоматологических вмешательств у детей 7-12 лет
Fig. 2. РЕЗУЛЬТАТЫ ИССЛЕДОВАНИЯ
И ИХ ОБСУЖДЕНИЕ Для
получения
субъективной
оценки местного обезболивания,
проводимого в рамках амбулатор-
ного детского стоматологического
приема, у группы пациентов от 4 до
7 лет разработанную аналого-визу-
альную шкалу предлагали запол-
нить врачу, ребенку и родителю. Для удобства детей шкала допол-
нительно была разработана для
мальчиков и девочек отдельно, так
как детям было удобнее соотно-
сить себя с нарисованными деть-
ми их пола (рис. 1). Отметка процентного балльного
показателя на уровне менее 20%
до 0% соответствует дескриптору
пациента «было больно», врач от-
мечает, что эффект от анестезии
не наступил, стоматологическое
вмешательство болезненное и его Для
определения
эффектив-
ности обезболивания в данной
группе
пациентов
аналого-визу- 020 (74) Стоматология детского возраста и профилактика Оригинальная статья Список литературы / References Стоматология детского
возраста и профилактика. 2018;5(68):32-34. [S. A. Rabinovich, Yu. L. Vasil’ev. Features of local an-
esthesia in pediatric dental practice. Pediatric den-
tistry and prophylaxis. 2018;5(68):32-34. (In Russ.)]. https://doi.org/10.25636/PMP.3.2018.5.5. 7. Кравченко И. А., Анисимова Е. Н., Аниси-
мова Н. Ю., Ковылина О. С. Оценка боли и эф-
фективности обезболивания у детей. Обзор ли-
тературы. Стоматология детского возраста и
профилактика. 2019;19(3):56-58. [I. A. Kravchen-
ko, E. N. Anisimova, N. Yu. Anisimova, O. S. Kovy-
lina. Assessment of pain and pain relief in children. Literature review. Paediatric Dentistry and Prophy-
laxis. 2019;20(3):56-58. (In Russ.)]. https://doi. org/10.33925/1683-3031-2019-19-3-56-58. 104 4. J. M. Armfield, L. J. Heaton. Management
of fear and anxiety in the dental clinic: a review. Aust Dent J. 2013;58(4):390-407. https://doi. org/10.1111/adj.12118. 4. J. M. Armfield, L. J. Heaton. Management
of fear and anxiety in the dental clinic: a review. Aust Dent J. 2013;58(4):390-407. https://doi. org/10.1111/adj.12118. 4. J. M. Armfield, L. J. Heaton. Management
of fear and anxiety in the dental clinic: a review. Aust Dent J. 2013;58(4):390-407. https://doi. org/10.1111/adj.12118. Конфликт интересов:
Авторы декларируют отсутствие
конфликта интересов/
Сonflict of interests:
The authors declare no conflict of interests
Поступила/Article received 11.02.2020 Конфликт интересов:
Авторы декларируют отсутствие
конфликта интересов/
Сonflict of interests:
The authors declare no conflict of interests
Поступила/Article received 11.02.2020 5. Анисимова Е. Н., Анисимова Н. Ю., Ко-
вылина О. С., Кравченко И. А. Изучение ис-
пользования местного обезболивания у де-
тей. Институт стоматологии. 2019;2(83):28-29. 5. Анисимова Е. Н., Анисимова Н. Ю., Ко-
вылина О. С., Кравченко И. А. Изучение ис-
пользования местного обезболивания у де-
тей. Институт стоматологии. 2019;2(83):28-29. g
8. M. Johan, Berghmans, J. Poley Marten,
J. van der Ende, F. Weber, M. Van de Velde. A Vi- 8. M. Johan, Berghmans, J. Poley Marten,
J. van der Ende, F. Weber, M. Van de Velde. A Vi- sual Analog Scale to assess anxiety in children
during anesthesia induction (VAS‐I): Results
supporting its validity in a sample of day care
surgery patients. September 2017;27(9):955-96.
https://doi.org/10.1111/pan.13206. Выводы Разработанные
аналого-визу-
альные шкалы для субъективной
оценки
эффективности
местного
обезболивания в детской стомато-
логической практике в зависимости
от возраста ребенка определяет воз-
можность учета мнения врача, роди- Отметка процентного балльного
показателя на уровне менее 20% со-
ответствует дескриптору пациента
«было больно», врач отмечает, что
проведение лечения невозможно
из-за отсутствия эффекта от ане- Оригинальная статья Оригинальная статья стезии, дескриптор врача «местное
обезболивание не наступило». теля и ребенка, а также позволяет не
только определить эффективность
проведенного местного обезболива-
ния, но и выявить психоэмоциональ-
ную напряженность ребенка во вре-
мя лечения. Данный способ оценки
может
быть
рекомендован
для
определения качества исследуемых
новых способов и средств местной
анестезии в детской стоматологиче-
ской практике. балльного показателя на уровне
50% соответствует дескриптору па-
циента «было больно, но я терпел/а»,
дескриптор врача «эффект местного
обезболивания выражен слабо» Список литературы / References sual Analog Scale to assess anxiety in children
during anesthesia induction (VAS‐I): Results
supporting its validity in a sample of day care
surgery patients. September 2017;27(9):955-96. https://doi.org/10.1111/pan.13206. [E. N. Anisimova, N. Y. Anisimova, O. S. Kovy-
lina, I. A. Kravchenko. Study of the use of local
anesthesia in children. Institute of Dentistry. 2019;2(83):28-29 (In Russ.)]. https://elibrary.ru/
item.asp?id=39184691. 1. J. Porritt, Z. Marshman, H. D. Rodd. Understanding children's dental anxiety and
psychological approaches to its reduction. International Journal of Pediatric Dentistry. 2012;22(6):397-405. https://doi.org/10.1111/
j.1365-263X.2011.01208.x. 1. J. Porritt, Z. Marshman, H. D. Rodd. Understanding children's dental anxiety and
psychological approaches to its reduction. International Journal of Pediatric Dentistry. 2012;22(6):397-405. https://doi.org/10.1111/
j.1365-263X.2011.01208.x. 9. J. M. Armfield, L. J. Heaton. Management
of fear and anxiety in the dental clinic: a review. Aust Dent J. 2013;58(4):390-407. https://doi. org/10.1111/adj.12118. 6. Анисимова Е. Н., Зорян Е. В., Дзгоева О. В. Анализ современных методов оценки ноци-
цептивной боли и эффективности обезболи-
вания. Российская стоматология. 2012;4:65-69. [E. N. Anisimova, E. V. Zoryan, O. V. Dzgoeva. The
analysis of modern methods of nociceptiv pain
assessment and the effectiveness of anesthesia. Russian Stomatology. 2012;4:65-69 (In Russ.)]. https://elibrary.ru/item.asp?id=20810046. 2. A. М. Pishkovtsi, І. М. Rohach, A. O. Keretsman. State of dental health of children in uzhhorod and the
way of their nutrition. Wiad Lek. 2020;73(1):73-77.. https://www.ncbi.nlm.nih.gov/pubmed/32124810. 2. A. М. Pishkovtsi, І. М. Rohach, A. O. Keretsman. State of dental health of children in uzhhorod and the
way of their nutrition. Wiad Lek. 2020;73(1):73-77.. https://www.ncbi.nlm.nih.gov/pubmed/32124810. 2. A. М. Pishkovtsi, І. М. Rohach, A. O. Keretsman. State of dental health of children in uzhhorod and the
way of their nutrition. Wiad Lek. 2020;73(1):73-77.. https://www.ncbi.nlm.nih.gov/pubmed/32124810. 10. Московец О. Н., Демина Н. А., Рабино-
вич С. А. Влияние эмоционального состояния
на болевую чувствительность зубов у паци-
ентов на амбулаторном стоматологическом
приеме. Боль. 2003;1(1):44-46. [O. N. Mosk-
ovets, N. A. Demina, S. A. Rabinovich. The influ-
ence of the emotional state on the pain sensitivi-
ty of the teeth in patients on an outpatient dental
appointment. Pain. 2003;1(1):44-46. (In Russ.)]. https://elibrary.ru/item.asp?id=23774692. 3. Рaбинович С. А., Васильев Ю. Л. Особенно-
сти местного обезболивания в детской стома-
тологической практике. Стоматология детского
возраста и профилактика. 2018;5(68):32-34. [S. A. Rabinovich, Yu. L. Vasil’ev. Features of local an-
esthesia in pediatric dental practice. Pediatric den-
tistry and prophylaxis. 2018;5(68):32-34. (In Russ.)]. https://doi.org/10.25636/PMP.3.2018.5.5. 3. Рaбинович С. А., Васильев Ю. Л. Особенно-
сти местного обезболивания в детской стома-
тологической практике. Сведения об авторах / Information about the authors Анисимова Евгения Николаевна, к.м.н., доцент, заведу-
ющая кафедры обезболивания в стоматологии Федераль-
ного государственного бюджетного образовательного
учреждения высшего образования «Московский государ-
ственный медико-стоматологический университет им. А.И. Евдокимова» Министерства здравоохранения Рос-
сийской Федерации, Москва, Российская Федерация Ковылина Ольга Сергеевна, к.м.н., доцент кафедры
детской стоматологии Федерального государствен-
ного бюджетного образовательного учреждения выс-
шего образования «Московский государственный
медико-стоматологический университет им. А.И. Ев-
докимова» Министерства здравоохранения Россий-
ской Федерации, Москва, Российская Федерация Оригинальная статья Analog-visual scale for assessing the effectiveness of pain relief in children at a dental appointment 7-12 age saint.doctor@mail.ru saint.doctor@mail.ru evg-anis@mail.ru evg anis@mail.ru
ORCID: https://orcid.org/0000-0001-7109-6431 Kovylina Olga S., PhD, Associate Professor of the De-
partment of pediatric dentistry of the Federal State Bud-
getary Educational Institution of Higher Education «Mos-
cow State University of Medical and Dentistry named after
A.I. Yevdokimov» of the Ministry of health of the Russian
Federation, Moscow, Russian Federation Kovylina Olga S., PhD, Associate Professor of the De-
partment of pediatric dentistry of the Federal State Bud-
getary Educational Institution of Higher Education «Mos-
cow State University of Medical and Dentistry named after
A.I. Yevdokimov» of the Ministry of health of the Russian
Federation, Moscow, Russian Federation Anisimova Evgeniya N., PhD, Associate Professor of the
Department of anesthesia in dentistry of the Federal State
Budgetary Educational Institution of Higher Education
«Moscow State University of Medical and Dentistry named
after A.I. Yevdokimov» of the Ministry of health of the Rus-
sian Federation, Moscow, Russian Federation Кравченко Илона Александровна, аспирантка ка-
федры обезболивания в стоматологии Федерально-
го государственного бюджетного образовательного
учреждения высшего образования «Московский го-
сударственный медико-стоматологический универ-
ситет им. А.И. Евдокимова» Министерства здравоох-
ранения Российской Федерации, Москва, Российская
Федерация Кравченко Илона Александровна, аспирантка ка-
федры обезболивания в стоматологии Федерально-
го государственного бюджетного образовательного
учреждения высшего образования «Московский го-
сударственный медико-стоматологический универ-
ситет им. А.И. Евдокимова» Министерства здравоох-
ранения Российской Федерации, Москва, Российская
Федерация Анисимова Наталия Юрьевна, к.м.н., доцент кафе-
дры обезболивания в стоматологии Федерального
государственного бюджетного образовательного уч-
реждения высшего образования «Московский государ-
ственный медико-стоматологический университет им. А.И. Евдокимова» Министерства здравоохранения Рос-
сийской Федерации, Москва, Российская Федерация aanoli@mail.ru
ORCID: https://orcid.org/0000-0002-2673-5844 aanoli@mail.ru
ORCID: https://orcid.org/0000-0002-2673-5844 Anisimova Nataliya Y., PhD, Associate Professor of the
Department of anesthesia in dentistry of the Federal State
Budgetary Educational Institution of Higher Education
«Moscow State University of Medical and Dentistry named
after A.I. Yevdokimov» of the Ministry of health of the Rus-
sian Federation, Moscow, Russian Federation Kravchenko Ilona A., postgraduate student, Department
of anesthesia in dentistry, of the Federal State Budgetary
Educational Institution of Higher Education «Moscow State
University of Medical and Dentistry named after A.I. Yevdo-
kimov» of the Ministry of health of the Russian Federation,
Moscow, Russian Federation /2020 (74) Стоматология детского возраста и профилактика
|
https://openalex.org/W3031539088
|
https://www.imrpress.com/journal/CEOG/46/4/10.12891/ceog4781.2019/pdf
|
English
| null |
Pregnancy outcome of recurrent spontaneous abortion in Wilson’s disease after decoppering therapy
|
Clinical and experimental obstetrics & gynecology
| 2,019
|
cc-by
| 3,121
|
CEOG
Clinical and Experimental
Obstetrics & Gynecology CEOG
Clinical and Experimental
Obstetrics & Gynecology CEOG
Clinical and Experimental
Obstetrics & Gynecology G
Clinical and Experimental
Obstetrics & Gynecology ber is ChiCTR-ERC-17010522. ber is ChiCTR-ERC-17010522. Wilson’s disease (WD) is a disorder of copper metabo-
lism with a prevalence of 1:7,026 predicted by a recent ge-
netic study [1]. Copper accumulates and causes toxicity
primarily in the liver and brain [2, 3]. In essence, WD also
leads to toxicity in reproductive system [4-10], which are
usually neglected by neurologic doctors. Klee, J. G. and
Schagen van Leeuwen, J.H., respectively reported one case
of recurrent spontaneous abortion (RSA) in WD patients
[4, 8]. However, the pregnancy outcome in a series of pa-
tients with RSA and WD after treatment is not known until
now. The authors retrospectively analyzed the medical records of
the previous year, from which they found 109 cases of RSA pa-
tients, and then began their research. A large group (n=109) of
female patients of reproductive age (18–45 years) with con-
firmed WD is being followed from the Encephalopathy Center
of the 1st Affiliated Hospital of Anhui University of Chinese
Medicine range from January 2016 to January 2017. Fifty-eight
of them conceived at least once, one of them delivered one baby
after treatment and 13 of them suffered from two or more pre-
vious spontaneous abortions (RSA) [11] before standard treat-
ment. One of the 13 patients was ruled out because she used
contraception after diagnosed with WD. Twelve patients who
were involved in the study received the treatment with dimer-
captosuccinic acid and zinc gluconate for at least ten months. The average daily dose of dimercaptosuccinic acid and zinc glu-
conate was 1.00 and 1.68 grams, respectively. Dimercaptosuc-
cinic acid was discontinued, while zinc gluconate was
continued during pregnancy. Diagnosis of WD was established
by clinical features, laboratory evidence of low serum cerulo-
plasmin, increased 24-hour urinary copper excretion, and the
presence of Kayser–Fleischer (KF) rings by slit lamp examina-
tion [12]. A flow diagram of the selection process is shown in
Figure 1. The authors report 12 cases of RSA in patients with WD
after treatment with decoppering therapy, describing the re-
sponse to therapy and pregnancy outcome. Summary y
Purpose of Investigation: To report pregnancy outcome after decoppering therapy in patients with recurrent spontaneous abortion
(RSA) and Wilson’s disease (WD). Materials and Methods: In a retrospective study, 12 WD patients who suffered from RSA were
treated with dimercaptosuccinic acid and zinc gluconate. The average daily dose of dimercaptosuccinic acid and zinc gluconate was 1.00
and 1.68 grams, respectively. Dimercaptosuccinic acid was discontinued, while zinc gluconate was continued during pregnancy. The
primary clinical outcomes were the pregnancy outcome after decoppering therapy and the mean age at diagnosis. Results: Six patients
conceived at least once after treatment. Five of them had successful pregnancies with seven healthy live births. Mean age at diagnosis
was significantly lower in patients who delivered healthy babies than in those who failed to conceive. Conclusions: Decoppering ther-
apy is efficacious in reversing the pregnancy outcome of RSA in patients with WD, especially in the women who are diagnosed at
young age. Age at diagnosis is an important risk factor that affects the pregnancy outcome in these patients. Key words: Pregnancy outcome; Recurrent spontaneous abortion; Wilson’s disease; Decoppering therapy. Pregnancy outcome of recurrent spontaneous abortion in
Wilson’s disease after decoppering therapy L.Wu1*, M. Zheng2*, M. Bao1,2, X. Tong1, Y. Liu1, H. Han3
1Center for Reproductive Medicine, Prenatal Diagnosis Center, Anhui Provincial Hospital,
The First Affiliated Hospital of University of Science and Technology of China, Hefei
2Anhui University of Traditional Chinese Medicine, Hefei
3Department of Neurology, The First Affiliated Hospital of Anhui University of Traditional Chinese Medicine, Hefei (China) Published: 10 August 2019 *Contributed equally. L.Wu1*, M. Zheng2*, M. Bao1,2, X. Tong1, Y. Liu1, H. Han3
1Center for Reproductive Medicine, Prenatal Diagnosis Center, Anhui Provincial Hospital,
The First Affiliated Hospital of University of Science and Technology of China, Hefei
2Anhui University of Traditional Chinese Medicine, Hefei
3Department of Neurology, The First Affiliated Hospital of Anhui University of Traditional Chinese Medicine, Hefei (China) Revised manuscript accepted for publication May 24, 2018 Materials and Methods The study was conducted in compliance with the Declaration of
Helsinki and Ethics Committees on Human Research of Anhui
Provincial Hospital Affiliated to the Anhui Medical University
and The First Affiliated Hospital of Anhui University of Tradi-
tional Chinese Medicine, The research project received the ap-
proval of Ethics Committees on Human Research of Anhui
Provincial Hospital affiliated to the Anhui Medical University. The permit number is 2013030112 and the trial registration num- Statistical analyses were performed using SPSS version 23.0. Comparisons of quantitative data were performed with independ-
ent two-sample t-test and chi-square test, and were considered sig-
nificant when the p-value was less than 0.05. 7847050 Canada Inc. www.irog.net 7847050 Canada Inc. www.irog.net 627 L.Wu, M. Zheng, M. Bao, X. Tong, Y. Liu, H. Han Figure 1. — Flow diagram for study subject selection. Figure 1. — Flow diagram for study subject selection. ment. They had 11 pregnancies with spontaneous abortions
occurring on four occasions (4/11). Five of them (cases 1-
5) had successful pregnancies with seven live births (7/11). One of them successively delivered three babies after treat-
ment. All the newborn infants were healthy. The mean age
at diagnosis was 23.60 ± 4.45 years-old in the five patients
who delivered healthy babies, and the mean age at diag-
nosis was 34.33 ± 7.84 years in the other six patients who
failed to conceive after treatment. Mean age at diagnosis
was significantly lower in patients who delivered healthy
babies than in those who failed to conceive (p < 0.05). All
the patients who diagnosed before 25-years-old, 4/6 pa-
tients who diagnosed before 30-years-old, and 5/9 patients
were diagnosed before 35-years-old successfully gave
birth to healthy babies. While all of patients who diag-
nosed > 35-years-old failed to conceive. Discussion WD is the commonest monogenetic neurologic disorder
that is found all over the world [1]. It mainly leads to neu-
rological disturbances and hepatic damage. Reproductive
disorders, such as irregular menstruation, miscarriages, and
infertility are also common but usually are ignored in clinic. It was reported that decoppering therapies improved the
pregnancy outcome in patients with WD [15, 16], but the
pregnancy outcome in a series of patients with WD and
RSA is not known until now. Here, the authors firstly report
the pregnancy outcome in WD patients with RSA after
treatment with dimercaptosuccinic acid and zinc gluconate. After treatment, 83.8% (5/6) of the pregnant patients
successfully give birth to babies, which showed that de-
coppering therapy is highly efficacious in reversing the
pregnancy outcome of WD induced RSA. Meanwhile, it
seems that zinc gluconate has no obvious side effect on
embryos, since all the newborn infants were healthy. Un-
fortunately, there were six patients in this study group that
failed to conceive. Their age at diagnosis should be par-
tially responsible for their pregnancy outcome. Three of
them diagnosed with WD at the age of more than 38-years-
old. Age-related diminished ovarian function is probably a
primary cause for their failure to conceive. The other three
younger patients are still attempting to become pregnant. The authors found the rate of RSA in fertile women with
WD is 22.4 % (13/58), which is about 7-20 times as high as
noticed in fertile women (1–3%) [17-20], indicating that
WD is associated with RSA in these women. The exact
mechanism of miscarriage is unclear but it is believed that
excess copper deposition in uterus hampers implantation
of fetus. The mechanism has been assumed to be similar to
that of copper-containing intrauterine contraceptive devices
[21]. Scheinberg et al. [22] proposed that such a high mis-
carriage rate is likely due to excess free intrauterine copper
derived from the non-ceruloplasmin bound copper in fe-
male WD patients. In addition, other factors such as chronic
liver disease, anemia and endocrinal disorders, may also
contribute to the cause. The type of initial presentation of WD appears to be a
factor affecting the pregnancy outcome after treatment. The present authors observed that the patients initially pre-
senting with neurologic manifestations had a better preg-
nancy outcome than those who initially presented with
hepatic disorders. The exact cause is unknown. Results Among the 58 patients who conceived at least once, the
mean age of menarche (onset of menstruation) was 14.60
± 1.77 (normal range for Chinese girls: 12.43–14.70 [13,
14]) years. The mean age of menarche in this study group
of 12 patients was 14.42 ± 1.08 years. Irregular menstrua-
tion (41.7%) was the common clinical feature including
oligomenorrhea (33.3%), menostaxis (16.7%), and sec-
ondary amenorrhea (8.3%). Nine patients were presymp-
tomatic at the time of their first pregnancy and three
already had neurologic involvement. Eventually, all the pa-
tients had neurological features and, in addition, ten had
hepatic involvement, serological tests as well as by ultra-
sonography. Mean serum ceruloplasmin of the 12 patients who were
on treatment was 0.084 ± 0.008 g/L (normal range: < 0.1
g/L) and was reduced in all. The mean 24-hour urinary
copper excretion was 1065.40 ± 677.05 µg/24 hours (nor-
mal range: < 100 µg/24 hours) and was increased in all. KF rings were found in the cornea by slit lamp examina-
tion in all of the patients. Among the five patients who initially presented with
neurologic disorders, four delivered healthy babies. How-
ever, among the other seven patients initially presenting
with hepatic manifestations, only one had a health baby. The rate of patients who delivered healthy babies
in the former was significantly higher than the latter (p <
0.05). The mean age at diagnosis in patients initially pre-
sented with neurologic disorders was lower than in those
initially presented with hepatic manifestations (25.20 ± Table 1 provides basic clinical, obstetrical characteris-
tics, and the pregnancy outcome on the 12 women. There
were six patients (cases 1-6) conceived at least once be-
sides six patients (cases 7-12) failed to conceive after treat- Pregnancy outcome of recurrent spontaneous abortion in Wilson’s disease after decoppering therapy 628 Table 1. — Clinical characteristics and pregnancy outcome. Patient No. Results 1
2
3
4
5
6
7
8
9
10
11
12
Present age (years)
25
27
33
45
41
40 39 30 31 42 45 44
Type of initial presentation
N
N
N
N
H
H
H
H
H
N
H
H
Age at diagnosis (years)
19
22
23
23
31
34 26 27 29 39 43 42
Duration of decoppering therapy at first childbirth (years)
4.3
2.4
4.5
5.2
7.1
NA NA NA NA NA NA NA
Number of spontaneous abortions before decoppering therapy
2
4
3
2
2
4
2
2
2
2
5
5
Number of pregnancies after decoppering therapy
2
4
2
1
1
1
0
0
0
0
0
0
Number of spontaneous abortions after decoppering therapy
1
1
1
0
0
1
0
0
0
0
0
0
Number of live births
1
3
1
1
1
0
0
0
0
0
0
0
Condition of child at birth
Good Good Good Good Good NA NA NA NA NA NA NA
N = neurological presentation; H = hepatic presentation; NA = not applicable. 7.89 vs. 33.14 ± 6.91 years), but the difference was not sta-
tistically significant because of the small sample size (p >
0.05). patients will be effectively reversed. It is also recognized
that treatment of WD should be continued during preg-
nancy, with the exception of the presence of severe liver
disease [28]. Patients who have withheld or discontinued
treatment during pregnancy have experienced serious com-
plications, including death [25]. Thus, the present contin-
ued treatment with zinc gluconate during pregnancy in this
study group. Conclusion [13] Sun Y., Tao F.B., Su P.Y., Mai J.C., Shi H.J., Han Y.T., et al.: “Na-
tional estimates of the pubertal milestones among urban and rural
Chinese girls”. J. Adolesc. Health, 2012, 51, 279. In conclusion, this data showed that RSA was common in
WD patients, especially in untreated women. Decoppering
therapy is efficacious in reversing the pregnancy outcome
of RSA in patients with WD, especially in the women who
are diagnosed at young age. Age at diagnosis is an impor-
tant factor that affects the pregnancy outcome in these pa-
tients. Teratogenecity was not seen in the present series
with dimercaptosuccinic acid and zinc gluconate but fur-
ther studies need to be carried out. [14] Lyu Y., Mirea L., Yang J., Warre R., Zhang J., Lee S.K., et al.: “Sec-
ular trends in age at menarche among women born between 1955
and 1985 in Southeastern China”. BMC Womens Health, 2014, 14,
155. [15] Walshe J.M.: “Pregnancy in Wilson’s disease”. Q. J. Med., 1977, 46, 73. [16] Sternlieb I.: “Wilson’s disease and pregnancy”. Hepatology, 2000,
31, 531. [17] Donckers J., Scholten R.R., Oyen W.J., Hopman M.T., Lotgering
F.K., Spaanderman M.E.: “Unexplained first trimester recurrent
pregnancy loss and low venous reserves”. Hum. Reprod., 2012, 27,
2613. Discussion It may be
because the hepatic manifestations of WD are insidious
and multiple, which makes the diagnosis very complicated
and delayed, which was supported by the higher age at di-
agnosis in patients initially presenting with hepatic disor-
ders in this data. In addition, hepatic manifestations are
due to the accumulation of copper in the liver, which is
near the pelvis and uterus. WD not only leads to spontaneous abortion, but also can
lead to significant morbidity and can be potentially fatal if
not treated promptly [23]. So once the diagnosis has been
made, medical therapy must be life-long [24]. Patients
with WD may have a regular life expectancy when their
neurologic and hepatic manifestations improved with the
regular life-long decoppering treatment [25, 26]. Perma-
nent organ damage can be effectively prevented if early
decoppering treatment is initiated [27]. When hepatic and
neurologic signs improve, the pregnancy outcome of RSA A limitation was that the data had a small sample of in-
dividuals covered under the Encephalopathy Center of the
1st Affiliated Hospital of Anhui University of Chinese
Medicine. A comprehensive set of information should be
included in a database that contains an administrative data
which can be used to expand the sample and conduct fur-
ther research. However, this study employed clinical ob- L.Wu, M. Zheng, M. Bao, X. Tong, Y. Liu, H. Han 629 early puerperium in a patient with Wilson’s disease”. Ceska Gy-
nekol., 1999, 64, 198. early puerperium in a patient with Wilson’s disease”. Ceska Gy-
nekol., 1999, 64, 198. servation of WD patients with RSA after treatment with
dimercaptosuccinic acid and zinc gluconate. The research
findings may be reflective of treatment and outcomes for
WD patients with RSA which can provide evidence for
further clinical discussion. [11] Practice Committee of the American Society for Reproductive Med-
icine.: “Definitions of infertility and recurrent pregnancy loss”. Fer-
til. Steril., 2008, 89, 1603. [12] Roberts E.A., Schilsky M.L. and American Association for Study of
Liver D.: “Diagnosis and treatment of Wilson disease: an update”. Hepatology, 2008, 47, 2089. Acknowledgement [18] Rai R., Regan L.: “Recurrent miscarriage”. Lancet, 2006, 368, 601. [19] Almawi W.Y., Saldanha F.L., Mahmood N.A., Al-Zaman I., Sater
M.S., Mustafa F.E.: “Relationship between VEGFA polymorphisms
and serum VEGF protein levels and recurrent spontaneous miscar-
riage”. Hum. Reprod., 2013, 28, 2628. This research was supported by Key Projects of Science
and Technology of Anhui Province (No. 1604a0802070),
Key Projects of Young Support Program of Anhui Province
(gxyqZD2016137), and the National Natural Science Foun-
dation of China (No. 81373671, No. 81673811, and No. 81473534) [20] Wu L., Luo L.H., Zhang Y.X., Li Q., Xu B., Zhou G.X., et al.: “Al-
teration of Th17 and Treg cells in patients with unexplained recurrent
spontaneous abortion before and after lymphocyte immunization
therapy”. Reprod. Biol. Endocrinol., 2014, 12, 74. [21] Mustafa M.S., Shamina A.H.: “Five successful deliveries following
9 consecutive spontaneous abortions in a patient with Wilson dis-
ease”. Aust. N. Z. J. Obstet. Gynaecol., 1998, 38, 312. References [22] Scheinberg I.H., Sternlieb I.: “Pregnancy in penicillamine-treated
patients with Wilson’s disease”. N. Engl. J. Med., 1975, 293, 1300. [1] Coffey A.J., Durkie M., Hague S., McLay K., Emmerson J., Lo C.,
et al.: “A genetic study of Wilson’s disease in the United Kingdom”. Brain, 2013, 136, 1476. [23] Pfeiffer R.F.: “Wilson’s Disease”. Semin. Neurol., 2007, 27, 123. [24] Bandmann O., Weiss K.H. and Kaler S.G.: “Wilson’s disease and
other neurological copper disorders”. Lancet Neurol., 2015, 14, 103. [2] Neusser M., Rogenhofer N., Durl S., Ochsenkuhn R., Trottmann M.,
Jurinovic V., et al.: “Increased chromosome 16 disomy rates in
human spermatozoa and recurrent spontaneous abortions”. Fertil. Steril., 2015, 104, 1130. [25] Rich A.M., Lajoie T.M.: “Wilson’s disease—treatment of psychiatric
manifestations in pregnancy”. Psychosomatics, 2012, 53, 175. [26] Schaefer M., Gotthardt D.N., Ganion N., Wohnsland S., Seessle J.,
Stremmel W., et al.: “Wilson disease: Health-related quality of life
and risk for depression”. Clin. Res. Hepatol. Gastroenterol., 2016,
40, 349. [3] Brewer G.J.: “Wilson disease and canine copper toxicosis”. Am. J. Clin. Nutr., 1998, 67, 1087S. [4] Klee J.G.: “Undiagnosed Wilson’s disease as cause of unexplained
miscarriage”. Lancet, 1979, 2, 423. [27] Mak C.M., Lam C.W.: “Diagnosis of Wilson’s disease: a compre-
hensive review”. Crit. Rev. Clin. Lab. Sci., 2008, 45, 263. [5] Sinha S., Taly A.B., Prashanth L.K., Arunodaya G.R. and Swamy
H.S.: “Successful pregnancies and abortions in symptomatic and
asymptomatic Wilson’s disease”. J. Neurol. Sci., 2004, 217, 37. [28] Brewer G.J., Johnson V.D., Dick R.D., Hedera P., Fink J.K., Kluin
K.J.: “Treatment of Wilson’s disease with zinc. XVII: treatment dur-
ing pregnancy”. Hepatology, 2000, 31, 364. [6] Kaushansky A., Frydman M., Kaufman H. and Homburg R.: “En-
docrine studies of the ovulatory disturbances in Wilson’s disease (he-
patolenticular degeneration)”. Fertil. Steril,. 1987, 47, 270. [7] Frikha R., Abdelmoula N.B. and Rebai T.: “Wilson disease, geno-
type and infertility: is there a correlation?”. Endocrine, 2013, 44,
266. Corresponding Author:
HUI HAN, M.D., PH.D. Department of Neurology
The First Affiliated Hospital
of Anhui University of Traditional Chinese Medicine
117 Meishan Road
Hefei, Anhui 230031 (China)
e-mail: 46467654@qq.com Corresponding Author:
HUI HAN, M.D., PH.D. Department of Neurology
The First Affiliated Hospital
of Anhui University of Traditional Chinese Medicine
117 Meishan Road
Hefei, Anhui 230031 (China)
e-mail: 46467654@qq.com Corresponding Author:
HUI HAN, M.D., PH.D. References Department of Neurology
The First Affiliated Hospital
of Anhui University of Traditional Chinese Medicine
117 Meishan Road
Hefei, Anhui 230031 (China)
e-mail: 46467654@qq.com [8] Schagen van Leeuwen J.H., Christiaens G.C., Hoogenraad T.U.: “Re-
current abortion and the diagnosis of Wilson disease”. Obstet. Gy-
necol., 1991, 78, 547. [9] Tarnacka B., Rodo M., Cichy S., Czlonkowska A.: “Procreation abil-
ity in Wilson’s disease”. Acta Neurol. Scand., 2000, 101, 395. [10] Hlinst’ak K., Borovsky M., Hlinst’akova S.: “Pregnancy, labor and
|
https://openalex.org/W52621466
|
https://europepmc.org/articles/pmc4341153?pdf=render
|
English
| null |
Monitoring LFCN damage during scoliosis surgery
|
Scoliosis
| 2,015
|
cc-by
| 989
|
Behzadi Fard et al. Scoliosis 2015, 10(Suppl 1):P28
http://www.scoliosisjournal.com/content/10/S1/P28 Open Access Open Access Results The continuous monitoring was interrupted during elec-
trocautery. The changes in pressure on the chest pads
were able to detect cyclic breathing. Increases in pres-
sure were also noted at times such as screw placement
or correction. Maximum and average pressure for the
five cases is shown in Table 1. LFCN SSEP recordings
were variable and the preliminary results are inconclu-
sive. Two patients had numbness in one leg post-op. One of the injuries resolved on day four and the other
was still evident on discharge. Material and methods Three pressure mats (FSA, Vista Medical, Winnipeg)
were placed on the Jackson frame before positioning the
patient. Data was continuously recorded during surgery
and the average and maximum pressures on the chest,
left and right hip/thigh region was calculated (Figure 1). The LFCN SSEP was tested by stimulating the anterolat-
eral thigh and recording the evoked potentials over the
somatosensory cortex. An increase in latency and/or
decrease in SSEP amplitude may be indicative of LFCN
dysfunction. At present, data on five patients was
recorded. Post-operative evaluation of the front of the
iliac crests is performed and the appearance of redness
(Figure 2), blisters or pressure sores are documented. Monitoring LFCN damage during scoliosis surgery
Negar Behzadi Fard1*, Aleksandra Krajacic2, Francois D Roy3, Sarah Southon2, Kajsa Duke1,4
From The 10th Meeting of the International Research Society of Spinal Deformities (IRSSD 2014 Sapporo)
Sapporo, Japan. 29 June - 2 July 2014 Additionally, after surgery, the patients were asked if
they feel any numbness on the front of the thighs and
manual tests for sensation were performed every day
until discharge. Objective During scoliosis surgery damage to the lateral femoral
cutaneous nerve (LFCN) has been reported in 20% of
patients. The purpose of this study was to characterize
intraoperative pressures at the patient cushion interface
and examine the LFCN somatosensory evoked potential
(SSEP) to determine if there is any correlation to the
incidence of LFCN injury. Conclusions Scoliosis 2015, 10(Suppl 1):P28
http://www.scoliosisjournal.com/content/10/S1/P28 Figure 2 Redness over the iliac crest after surgery Figure 2 Redness over the iliac crest after surgery Table 1 Average and maximum pressures for the five
cases Table 1 Average and maximum pressures for the five
cases
chest
Left hip
Right hip
Case
Average
(mmHg)
Max
Average
(mmHg)
Max
Average
(mmHg)
Max
Duration
(hours)
1
51
310
23
175
22
357
6h3tf
2
42
220
29
303
34
371
6hl5’
3
68
310
29
199
27
313
4h27’
4
51
291
18
240
26
319
6hO2’
5
49
148
26
222
21
517
5h23’ Consent Written informed consent was obtained from the patient
for the image(s) used in this study. A copy of the writ-
ten consent is available for review by the Editor of this
journal. Conclusions Pressure on the LFCN during scoliosis surgery caused
numbness in 2/5 patients. Pressure mats were able to
record changes during surgery. More data is required to
determine if there is any correlation between elevated
pressure and LFCN injury. 1Department of Mechanical Engineering, University of Alberta, Canada
Full list of author information is available at the end of the article
Figure 1 Sample pressure mat data on the a) Chest b) left hip area and c) right hip area
© 2015 Behzadi Fard et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Figure 1 Sample pressure mat data on the a) Chest b) left hip area and c) right hip area 1Department of Mechanical Engineering, University of Alberta, Canada
Full list of author information is available at the end of the article
© 2015 Behzadi Fard et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. 1Department of Mechanical Engineering, University of Alberta, Canada
Full list of author information is available at the end of the article 1Department of Mechanical Engineering, University of Alberta, Canada
Full list of author information is available at the end of the article © 2015 Behzadi Fard et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Page 2 of 2 Page 2 of 2 Behzadi Fard et al. Scoliosis 2015, 10(Suppl 1):P28
http://www.scoliosisjournal.com/content/10/S1/P28 Behzadi Fard et al. Authors’ details
1
f 1Department of Mechanical Engineering, University of Alberta, Canada. 2Alberta Health Services, University of Alberta Hospital, Canada. 3Department
of Surgery and Centre for Neuroscience, University of Alberta, Canada. 4Division of Orthopaedic Surgery, University of Alberta, Canada. Published: 19 January 2015 Published: 19 January 2015 doi:10.1186/1748-7161-10-S1-P28
Cite this article as: Behzadi Fard et al.: Monitoring LFCN damage during
scoliosis surgery. Scoliosis 2015 10(Suppl 1):P28. Submit your next manuscript to BioMed Central
and take full advantage of:
• Convenient online submission
• Thorough peer review
• No space constraints or color figure charges
• Immediate publication on acceptance
• Inclusion in PubMed, CAS, Scopus and Google Scholar
• Research which is freely available for redistribution
Submit your manuscript at
www.biomedcentral.com/submit Submit your next manuscript to BioMed Central
and take full advantage of: Submit your next manuscript to BioMed Central
and take full advantage of:
|
https://openalex.org/W3203657367
|
https://www.scielo.br/j/cr/a/78XKdZ3fpffGNLyTfCmxrnR/?lang=en&format=pdf
|
English
| null |
Interaction between the body condition score, gait, hindlimb conformation, and claw conformation in dairy cows in Aydin, Turkey
|
Ciência rural
| 2,022
|
cc-by
| 7,642
|
Ibrahim Akin1* Husnu Erbay Bardakcioglu2 Elvan Hayat3
Yalcin Alper Ozturan1 Omer Kurt1 1Department of Surgery, Faculty of Veterinary Medicine, Aydin Adnan Menderes University, Isikli, ADU Veteriner Fakultesi, 09016, Efeler,
Aydin, Turkey. E-mail: ibraak@adu.edu.tr. *Corresponding author. 2Department of Animal Science, Faculty of Veterinary Medicine, Aydin Adnan Menderes University, Isikli, ADU Veteriner Fakultesi, Efeler, Aydin, Turkey. 3Aydin Faculty of Economics, Aydin Adnan Menderes University, Zafer, Efeler, Aydin, Turkey. ABSTRACT: Breeding strategies aim to reduce lameness in dairies by using predictor traits to increase the selection of dairy cows. This
study enhanced the present knowledge about association between the claw conformations (CC), hindlimb conformation (HiLC), gait, and body
condition score (BCS) in dairy cows. A total of 166 lactating Holstein cows were enrolled in the study and scored for BCS, CC, HiLC, and
gait. The abnormal HiLC group was statistically significant (P<0.001) to have more abnormal CC. Hock in (Hin) cows showed significance
(P<0.001) with CC abnormalities. Cows with abnormal gait have less abnormal claw and limb conformation than normal cows (P=0.032). Lactation number (P=0.036) and abnormal HiLC (P<0.001) were significantly increased risk for CC. The present results might be useful for
claw and hindlimb conformations, and breeding strategies of the herd. f
g
g
f
Key words: dairy cow, claw conformation, body condition score, limb conformation. Interação entre o escore corporal, marcha, conformação do membro posterior e conformação do
casco em vacas leiteiras em uma fazenda localizada em Aydin, Turquia RESUMO: Estratégias de melhoramento visam reduzir a claudicação em gado leiteiro usando características preditoras para aumentar
a seleção de vacas com alta produtividade. Os objetivos deste estudo foram aumentar o conhecimento atual sobre a associação entre as
conformações do casco (CC), conformação dos membros posteriores (HiLC), marcha e escore de condição corporal (BCS) em vacas leiteiras. Um total de 166 vacas Holandesas em lactação foram incluídas no estudo e pontuadas para BCS, CC, HiLC e marcha. O grupo HiLC anormal
foi considerado estatisticamente significativo (P <0,001) para ter mais CC anormal. Vacas Hock in (Hin) mostraram significância (P <0,001)
com anormalidades CC. Vacas com marcha anormal têm menos conformação anormal de cascos e membros do que vacas normais (P = 0,032). Número de lactação (P = 0,036) e HiLC anormal (P <0,001) aumentaram significativamente o risco de CC. Os presentes resultados podem ser
úteis para conformações de cascos e membros posteriores e estratégias de reprodução do rebanho. Palavras-chave: vaca leiteira, conformação da casco, escore de condição corporal, conformação do membro. f
ç
p
g
p
ç
as-chave: vaca leiteira, conformação da casco, escore de condição corporal, conformação do membro. ormation in dairy cows in Aydin, Turkey.
1
ISSNe 1678-4596
http://doi.org/10.1590/0103-8478cr20210158
CLINIC AND SURGERY ormation in dairy cows in Aydin, Turkey. 1
ISSNe 1678-4596
http://doi.org/10.1590/0103-8478cr20210158
CLINIC AND SURGERY Interaction between the body condition score, gait, hindlimb conformation, and claw
conformation in dairy cows in Aydin, Turkey Ciê
Received 02.26.21 Approved 06.22.21 Returned by the author 08.17.21
CR-2021-0158.R1
Editors: Rudi Weiblen Rüdiger Daniel Ollhoff Interaction between the body condition score, gait, hindlimb co
Ciência Rural, Santa Maria, v.52:4, e20210158, 2022 Interaction between the body condition score, gait, hindlimb co
Ciência Rural, Santa Maria, v.52:4, e20210158, 2022 INTRODUCTION (BICALHO et al., 2009) and lameness (RANDALL
et al., 2015). Providing a good locomotion score (LS)
via favorable limb and claw conformation, and BCS
may be achieved with genetic improvement. This may
be reached through the selections of good score bulls
or cows/heifers. Heritability estimation of the limb,
claw conformation, and claw disorders described
as low (VAN DER LINDE et al., 2010). Due to the
missing of producer/farm records of relatives, the
mentioned low heritability range may restrain genetic
transfer for good limb and claw conformation, which
are important to prevent lameness (ZWALD et al.,
2004). The minor effect of using bull’s information
on the genetic improvement of claw measurements
and the potential of the positive effect of additional
works on claw health was stated (HERINGSTAD et
al., 2018). Also, the association between BCS and Lameness is one of the well-known causes
of major economic losses and welfare issues and has
also a detrimental correlation with milk production
and fertility and leads to a higher risk of death or
culling in the dairy industry (WARNICK et al., 2001;
BICALHO et al., 2008). In this regard, one of the
priorities of the dairy industry may be improving the
dairy cows, requiring minimal foot trimming with
good conformed limbs and claws. Rehabilitation of
limb and claw conformation on cow level has been
not only a need for big and modern dairies but also
conventional farms, which constitute most of the
farms in many countries, such as our country. Also,
body condition score (BCS) has been considered
with claw lesions due to thinning of digital cushion Akin et al. 2 line separation, digital dermatitis, etc.) were not
enrolled in the study, due to the possible effect of
foot diseases on gait. lameness caused by claw lesions was emphasized
(GREEN et al., 2014; LIM et al., 2015; RANDALL
et al., 2015). Therefore, claw and limb conformation
characteristics, and their interaction with BCS still
need more observations, and records may serve as
data for the improvement of the dairy cows in any
size of the farm. Cows were milked two times daily in
a double herringbone milking parlor on the farm. Lactating cows were housed in free-stall barns with
concrete stalls covered with mattresses (Promat®,
Ontario, Canada) on lying areas. Study design and data collection All cows were scored for body condition
on a scale of 1 to 5 with 0.25 fractions based on visual
inspection defined by EDMONSON et al. (1989) a
score of 1 stated as poor condition, and a score of
5 indicated as an obese condition. Collection of data
on body condition score (BCS), claw conformation
(CC), and hindlimb conformation (HiLC) were
completed on feeding time. Data on lactation number
(LN) and days in milk (DIM) were extracted from the
farm’s records. BCS and HiLC were evaluated from
the backside of the cow during feeding in their pen. MATERIALS AND METHODS The data collection for this study was
carried out from a dairy farm located in Aydin,
Turkey between June 2016 and August 2016. The
selection of dairy farms was carried out with the
collaboration of the Cattle Breeders Association of
Aydin Province. Out of 4372 registered dairy farms
in the Cattle Breeders Association of Aydin Province,
a family dairy farm, which was established around
1955 and had not bought in any cattle entry since
then, was selected for the study. This means, the farm
selected for the study has been used only artificial
insemination, but not used outside sources (neighbor/
barn, sale/auction) heifer or cow. Consequently, the
mother line of the cows used in this study has not
been changed since 1955. Evaluation of claw conformation (CC) A total of 664 hind claws (166 left lateral,
166 left medial, 166 right lateral, and 166 right
medial) of 166 cows were observed in the milking
parlor for claw conformation. The conformation
of each claw (left lateral= LL, left medial= LM,
right lateral= RL, right medial= RM) was evaluated
and recorded in two main groups in regards to the
existence of abnormality; as “normal= claw has
normal shape and/or size” and “abnormal= claw has
abnormal shape and/or size)’’. The abnormal claw INTRODUCTION The walking alleys in
pens had grooved concrete flooring and were cleaned
by automatic scrapers; all walkways to and from the
milking barn and holding pen were covered (about
75-85 meters) with rubber mats (DeLaval® Tumba,
Sweden). In case of malfunctioned of automatic
scrapers the tractor was scraped the concrete flooring
once per day. All cows used in the study were
between first and fourth parity. Cows were fed a TMR
consisting of 45% concentrate (soybean and cornmeal
meal, cottonseed, and canola) and 55% forage (wheat
straw, alfalfa hay, haylage, and corn silage). There
was no regular claw trimming. This means that claw
trimming is performed when an employee or owner
of the farm was noticed overgrown hooves. It was
learned that routine claw trimming was performed
seven months before the study data was received,
by a claw trimmer and or veterinarian of the dairy. According to the farm records, all cows received
claw trimming during the dry-off period. Claws were
observed and recorded in the milking parlor. Naturally, the shape of the bovine claw
is formed by horn production and wear, and the
dimensions of the bovine claw shape have been well
described (VERMUNT & GREENOUGH, 1995). Although, modern dairy feeding techniques promote
high-quality horn production, due to less walking, the
wear of the claw is generally insufficient. Therefore,
one of the aim of the claw trimming routine in
dairies is to achieve normal-shaped claws, and it is
acceptable that long intervals between claw trimming
routines may result in abnormal shaped and wrong
balanced claws (SADIQ et al., 2020). In dairy cows,
limb conformation can have an impact on claw shapes
(van der WAAIJ et al., 2004), and further research is
proposed to reveal the relationship between limb and
claw conformation (ZWALD et al., 2004; VAN DER
LINDE et al., 2010; HERINGSTAD et al., 2018). The
objective of this study is to investigate the associations
between claw and hindlimb conformation with gait
and body condition score in dairy cows, and revealing
the relationship between the related traits. Thus, we
aimed to contribute to current knowledge of the
topics on claw and leg conformation of dairy cattle. Evaluation of hindlimb conformation (HiLC) Hindlimb conformation of each cow (n:
166) was evaluated and recorded into two main
groups in regards to the existence of abnormality
as “normal= cow has good/normal hindlimb
conformation” and “abnormal= cow has an abnormal
hindlimb conformation”. The abnormal HiLC group
was also divided into subgroups, hock in (Hin), one
side hock in (OHin), bow-legged (BL), and open
legged (OL) and evaluated (RAVEN et al., 1985;
PIJL, 2003). The relationship between main claw
conformation and main hindlimb conformation
groups; main claw conformation and abnormal
hindlimb conformation subgroups; hock in and
claw conformation of each claw; main hindlimb
conformation and main claw conformation and
gait abnormality was examined by using Pearson’s
chi-square test. Fisher’s exact test was used if the
expected count less than 5 for each cell. Animals A total of 166 lactating cows (n: 166) of a
farm consisted 550 Holstein cattle were used. Cows
with any signs of foot disease (sole ulcer, white Ciência Rural, v.52, n.4, 2022. Interaction between the body condition score, gait, hindlimb conformation, and claw conformation in dairy cows in Aydin, T 3 conformation group was also divided into subgroups
and recorded as, corkscrew claw (CoC), scissor/beak
claw (SC), and big/slipper claw (BC), and evaluated
(PIJL, 2003; NGUHIU-MWANGI et al., 2012;
EGGER-DANNER et al., 2015). A general linear model was performed
to determine the effect of claw conformation,
hindlimb conformation, categorized days in milk,
and categorized lactation number groups on body
condition score. Interactions were conducted between
claw conformation and categorized days in milk;
hindlimb conformation and categorized days in milk;
claw conformation, and categorized lactation number;
hindlimb conformation and categorized lactation
number, in the general linear model. The effect of
hindlimb conformation and claw conformation sub-
groups on body condition score was analyzed with
Analysis of Variance (ANOVA). Descriptive statistics A total of 166 cows were enrolled in the
study; BCS, DIM, the existence of abnormality of
claw conformation, hindlimb conformation, and
gait by lactation number (LN) are listed in table 1. Distributions of claw conformation according to
the right-left side and lateral-medial claw (%) were
shown in table 2. Categorization of days in milk and lactation number g
f
y
Cows were categorized into three groups
for the days in milk (CDIM) as early lactation (1-45
days in milk), peak lactation (46-75 days in milk),
and late lactation (>75 days in milk). Also, cows were
categorized into two groups for their lactation number
(CLN) as young cows (Lactation number= 1 and 2)
and old cows (Lactation number= 3 and 4). Then,
cows were categorized as the factors of age (Young:
Lactation number=1-2, Old: lactation number=3-4),
abnormality of HiLC (normal, abnormal), and gait
abnormality (normal, abnormal) to measure the effect
on claw conformation. Evaluation of gait After milking in the alley, all cows were
evaluated for gait assessment and recorded into two
groups as “normal= cow has a normal walk” and
“abnormal= cow has an abnormal walk” in regards
to the SPRECHER et al. (1997). If the cow’s gait was
normal (score=1), it was recorded into the normal
group, and if the cow was presenting any signs of
lameness (score=2, 3, 4 and 5) by SPRECHER et al. (1997) it was recorded into the abnormal group. The possible factors (lactation number,
hindlimb conformation, and gait) were further entered
into the logistic regression analysis to determine
independent predictors of cow outcome and odds
ratio (OR) with univariate analyses for lateral,
medial, and general claw conformation. Hosmer-
Lemeshow goodness of fit statistic was used to assess
model fit. An overall P-value of less than 0.05 was
considered to show a statistically significant result. Statistical analyses were performed using the IBM-
SPSS software version 22.0. Statistical analyses Descriptive statistics of 166 cows were
presented with means and standard deviations (SD)
for measured variables (BCS and day in milk) and
shown as numbers and percentages for categorized
as normal and abnormal hindlimb conformation,
claw conformation, and gait variables according
to the lactation numbers. The distribution of claw
conformation for each claw was given as a number
and percentages. Interaction between claw conformation, hindlimb
conformation, and body condition scorei There were no statistically significant
differences between the mean BCS of main claw
conformation
(abnormal
and
normal)
groups
(P>0.05) and main hindlimb conformation (abnormal
and normal) groups (P>0.05). The late lactation
group had the highest BCS mean (3.44±0.60) of the Ciência Rural, v.52, n.4, 2022. Ciência Rural, v.52, n.4, 2022. Akin et al. 4 Table 1 - Descriptive statistics of the cows according to the lactation numbers. Table 1 - Descriptive statistics of the cows according to the lactation numbers. Table 1 - Descriptive statistics of the cows according to the lactation numbers. ------------------------------Lactation number (n)--------------------------------
-------1 (68)-------
------2 (42)-----
-------3 (27)------
------4 (29)------
BCS (Mean ± SD)
3.27±0.64
3.50±0.52
3.26±0.75
3.19±0.60
Days in Milk (Mean ± SD)
219.97±101.62
230.45±97.93
185.00±77.66
201.48±102.92
Hindlimb conformation (n, %)
normal
41 (60.3)
21 (50.0)
10 (37.0)
12 (41.4)
abnormal
27 (39.7)
21 (50.0)
17 (63.0)
17 (58.6)
Claw conformation (n, %)
normal
41 (60.3)
20 (47.6)
8 (29.6)
9 (31.0)
abnormal
27 (39.7)
22 (52.4)
19 (70.4)
20 (69.0)
Gait (n, %)
normal
5 (7.4)
3 (7.1)
7 (25.9)
13 (44.8)
abnormal
63 (92.6)
39 (92.9)
20 (74.1)
16 (55.2)
BCS: Body condition score. SD: Standard deviation. ------------------------------Lactation number (n)-------------------------------- BCS: Body condition score. SD: Standard deviation. BCS: Body condition score. SD: Standard deviation. have more abnormal claw conformation (68.2%)
than normal hindlimb cows (33.3%). Abnormal Hin
conformation was statistically higher than expected
in cows with abnormal claw conformation (P<0.001). Only the Hin subgroup was have higher abnormalities
than expected (P<0.001) (Table 6). CDIM groups. This value was significantly higher
than the early and peak lactation groups (P<0.001). It was determined that different levels of lactation
(CDIM) did not affect claw conformation (P=0.886)
and hindlimb conformation groups (P=0.702), also
different lactation numbers (CLN) did not affect claw
conformation (P=0.587) and hindlimb conformation
(P=0.815) groups (Table 3). if It was determined that Hin was statistically
related (P<0.001) with the corkscrew claw, scissor
claw, and big claw. Statistical analyses Corkscrew claw incidence in
all claws (LL, LM, RL, and RM) of Hin cows was
a higher expected number than normal hindlimb
conformed cows (P<0.001). Right medial claws of
Hin cows had a higher expected number (P<0.001)
of scissor claw than normal cows. Besides, both
medial claws of Hin cows had a higher expected
number (P<0.001) of big claw than normal hindlimb
conformed cows (Table 7). A
statistically
significant
difference
(P=0.014) was found of BCS between Hin and OL
cows (Table 4). The Hin cows showed a lower BCS
(3.14) and OL cows had higher BCS (3.77) than other
HiLC groups (Table 4). Claw conformation had no
significant effect on BCS (Table 5). Interaction between claw conformation, hindlimb
conformation, and gait Interaction between claw conformation, hindlimb
conformation, and gait Ciência Rural, v.52, n.4, 2022. Interaction between claw conformation, hindlimb
conformation, and gait The cows, which had normal gait (n=28),
have a higher number of abnormal hindlimb The abnormal hindlimb conformation
group was statistically significant (P<0.001) to Table 2 - Distribution of claw conformations; each claw, number of the claws (n), and percentages (%). Table 2 - Distribution of claw conformations; each claw, number of the claws (n), and percentages (%). Claw conformation
----------------------------Claws, n (%)-----------------------------
LL
LM
RL
RM
Total
Normal claw
101 (60.8)
114 (68.7)
100 (60.2)
114 (68.7)
429 (64.6)
Scissor claw
22 (13.3)
23 (13.9)
17 (10.2)
22 (13.3)
84 (12.7)
Corkscrew claw
35 (21.1)
16 (9.6)
39 (23.5)
18 (10.8)
108 (16.3)
Big claw
8 (4.8)
13 (7.8)
10 (6.0)
12 (7.2)
43 (6.5)
LL: Hind left leg lateral claw; LM: Hind left leg medial claw; RL: Hind right leg lateral claw; RM: Hind right leg medial claw. LL: Hind left leg lateral claw; LM: Hind left leg medial claw; RL: Hind right leg lateral claw; RM: Hind right leg medial claw. Ciência Rural, v.52, n.4, 2022. Ciência Rural, v.52, n.4, 2022. Ciência Rural, v.52, n.4, 2022. nteraction between the body condition score, gait, hindlimb conformation, and claw conformation in dairy cows in Aydin, Turkey. Table 3 - Influence of abnormal claw conformation, abnormal hindlimb conformation, categorized days in milk (CDIM), and categorized
lactation number (CLN) on body condition score (BCS) (Mean±SD). -----------Groups-----------
-----n-----
---Mean±SD---
--------p-value--------
Claw Conformation
normal
78
3.31±0.57
0.461
abnormal
88
3.30±0.67
Hindlimb Conformation
normal
84
3.33±0.62
0.226
abnormal
82
3.28±0.63
CDIM
Early lactation
13
2.88±0.61b
<0.001
Peak lactation
31
2.95±0.48b
Late lactation
122
3.44±0.60a
CLN
Young
110
3.35±0.60
0.296
Old
56
3.22±0.67
Interactions
CC*CDIM
0.886
HiLC*CDIM
0.702
CC*CLN
0.587
HiLC*CLN
0.815
CC: Claw conformation; HiLC: Hindlimb conformation; CDIM: Categorized days in milk; CLN: Categorized lactation number. a, b:
Different superscripts are indicating the statistical difference. - Influence of abnormal claw conformation, abnormal hindlimb conformation, categorized days in milk (CDIM), and categorized
lactation number (CLN) on body condition score (BCS) (Mean±SD). CC: Claw conformation; HiLC: Hindlimb conformation; CDIM: Categorized days in milk; CLN: Categorized lactation number. a, b:
Different superscripts are indicating the statistical difference. CC: Claw conformation; HiLC: Hindlimb conformation; CDIM: Categorized days in milk; CLN: Categorized lactation number. a, b:
Different superscripts are indicating the statistical difference. conformation (n=19) than expected (P=0.032). Interaction between claw conformation, hindlimb
conformation, and gait These cows had also a higher number of abnormal
claw conformation (n=20) than expected; while
the abnormal gait group had a smaller number of
abnormal claw conformation than expected (P=0.032)
(Table 8). i univariate logistic regression analysis, an increase in
CLN (to be old) and having an abnormal hindlimb
conformation resulted in an increased risk of abnormal
claw conformation by 2.29 times (P=0.036) and 4.98
times (P<0.001), respectively (Table 9). DISCUSSION AND CONCLUSION -----------------------------------------------Claw conformation-------------------------------------------------
----------Normal---------
-----------------------------------Abnormal--------------------------------------
Claw
NC
n
CoC
n
SC
n
BC
n
p-value
BCS
LL
3.35± 0.06
101
3.21 ± 0.12
35
3.34 ± 0.16
22
3.35± 0.25
8
0.164
LM
3.36 ± 0.06
114
3.16 ± 0.18
16
3.28 ± 0.14
23
3.23± 0.16
13
0.113
RL
3.33 ± 0.06
100
3.32±0.11
39
3.35± 0.18
17
3.15± 0.21
10
0.363
RM
3.36 ± 0.06
114
3.22± 0.14
18
3.23± 0.15
22
3.21 ± 0.20
12
0.200
BCS: Body condition score; LL: Hind left leg lateral claw; LM: Hind left leg medial claw; RL: Hind right leg lateral claw; RM: Hind right
leg medial claw; NC: Normal claw; CoC: Corkscrew claw; SC: Scissor claw; BC: Big claw. Table 5 - Effect of different claw conformation on body condition score [mean ± SD]. Table 5 - Effect of different claw conformation on body condition score [mean ± SD]. BCS: Body condition score; LL: Hind left leg lateral claw; LM: Hind left leg medial claw; RL: Hind right leg lateral claw; RM: Hind right
leg medial claw; NC: Normal claw; CoC: Corkscrew claw; SC: Scissor claw; BC: Big claw. not change since 1955. The effect of the unchanged
mother line on limb and claw conformations has not
been investigated in the present study. Nevertheless,
this situation had a positive contribution to the study’s
aim and in the reliability of the results; and might be
investigated in future studies. level may contribute to reducing lameness prevalence
in the next generations (CHAPINAL et al., 2013;
ØDEGARD et al., 2014). Towards revealing this
contribution, investigating the relationship between
the leg and the claw of the cow enhances the current
knowledge. This article provided information about
this relationship through a commercial family dairy
farm. Since this study used only one farm, the number
of cows and claws in some of the subdivision groups
were rather small and some claw shape abnormalities
(such as asymmetric claws, concave wall, etc.) were
not observed. However, the farm used in this study
is one of the earliest established dairy farms in the
Aydin region. By the declaration of the owner, after
the establishment of the farm (since 1955), they did
not use outside sources heifer and/or cow. This means
that the mother line of the cows used in this study did Standardized and described 27 claw
disorders have been reported (RESZLER, 2006;
EGGER-DANNER, 2015). DISCUSSION AND CONCLUSION According to the fit statistics the model
used was compatible (P=0.747). As a result of Front limbs and claws were not evaluated
in this study since most claw disorders in dairy cows
appear on the hind claws (SOLANO et al., 2016). BCS was evaluated from the backside of the cow
(EDMONSON et al., 1989). Moreover, the evaluation
of BCS, hindlimb, and claws during the feeding time
might be made from the rear side and is thought that
the method used in the study may be more effective
for time management. Table 4 - Effect of hindlimb conformation on body condition
score (Mean±SD). Hindlimb conformation
n
Body Condition Score (Mean±SD)
Normal
84
3.34±0.62ab
Hock in (Hin)
51
3.14±0.62b
One side Hock in (OHin)
8
3.38±0.69ab
Bow Legged (BL)
8
3.19±0.53ab
Open Legged (OL)
15
3.77±0.49a
P-value
0.014
a,
b: Different superscripts are indicating the statistical
difference. Table 4 - Effect of hindlimb conformation on body condition
score (Mean±SD). Hindlimb conformation
n
Body Condition Score (Mean±SD)
Normal
84
3.34±0.62ab
Hock in (Hin)
51
3.14±0.62b
One side Hock in (OHin)
8
3.38±0.69ab
Bow Legged (BL)
8
3.19±0.53ab
Open Legged (OL)
15
3.77±0.49a
P-value
0.014
a,
b: Different superscripts are indicating the statistical
difference. Table 4 - Effect of hindlimb conformation on body condition
score (Mean±SD). Reduced lameness in dairy cows contributed
to animal welfare and farm economics (SOLANO et
al., 2015; AKIN & AKIN, 2018). It has been achieved
by regular claw trimming and treatment strategies on
claw diseases (LEACH et al., 2010; BICALHO &
OIKONOMOU, 2013; MAHENDRAN et al., 2017). However, improving on legs and claw conformation
of dairy cattle by breeding strategies on the farm Ciência Rural, v.52, n.4, 2022. Akin et al. 6 Table 5 - Effect of different claw conformation on body condition score [mean ± SD]. DISCUSSION AND CONCLUSION Also, the definition of
normal (RAVEN, 1985) and abnormal (PIJL, 2003;
RESZLER, 2006) conformation of the claw has been
well described. As an abnormal claw conformation
CoC, SC, and BC were recorded and evaluated in
the present study, the other described abnormal
conformations (PIJL, 2003; NGUHIU-MWANGI
et al., 2012; EGGER-DANNER et al., 2015) were
not encountered. Claw conformation was related Ciência Rural, v.52, n.4, 2022. Table 6 - Relationship between the claw conformation and hindlimb conformation groups, the number of cows (n) and percentages (%). ---------------------Claw Conformation--------------------
------abnormal, n (%)------
------normal, n (%)------
--------p-value-------
Main groups of HiLC
Normal
28 (33.3)
56 (66.7)
<0.001
Abnormal
60 (68.2)
22 (28.2)
Subgroups of abnormal HiLC
Hin*
44 (86.3)
7 (13.7)
<0.001
OHin
5 (62.5)
3 (37.5)
BL
4 (50.0)
4 (50.0)
OL
7 (46.7)
8 (53.3)
*: Abnormal claw conformation existence was higher than expected on Hin cows than other abnormal hindlimb conformation subgroups. HiLC: Hindlimb conformation; Hin: Hock in; OHin: One side hock in; BL: Bow-legged and OL: Open legs. Table 6 - Relationship between the claw conformation and hindlimb conformation groups, the number of cows (n) and percentages (%). ---------------------Claw Conformation--------------------
------abnormal, n (%)------
------normal, n (%)------
--------p-value-------
Main groups of HiLC
Normal
28 (33.3)
56 (66.7)
<0.001
Abnormal
60 (68.2)
22 (28.2)
Subgroups of abnormal HiLC
Hin*
44 (86.3)
7 (13.7)
<0.001
OHin
5 (62.5)
3 (37.5)
BL
4 (50.0)
4 (50.0)
OL
7 (46.7)
8 (53.3) - Relationship between the claw conformation and hindlimb conformation groups, the number of cows (n) and percentages (%). *: Abnormal claw conformation existence was higher than expected on Hin cows than other abnormal hindlimb conformation subgroups. HiLC: Hindlimb conformation; Hin: Hock in; OHin: One side hock in; BL: Bow-legged and OL: Open legs. *: Abnormal claw conformation existence was higher than expected on Hin cows than other abnormal hindlimb conformation subgroups. HiLC: Hindlimb conformation; Hin: Hock in; OHin: One side hock in; BL: Bow-legged and OL: Open legs. Ciência Rural, v.52, n.4, 2022. Ciência Rural, v.52, n.4, 2022. nteraction between the body condition score, gait, hindlimb conformation, and claw conformation in dairy cows in Aydin, Turkey. Table 7 - The comparison of Hin and normal cows by their claw conformation of their every claw, the number of claws (n), and
percentages (%). DISCUSSION AND CONCLUSION ----------------------------------Claw Conformation-------------------------------
-------Normal-------
-----------------------Abnormal-------------------------
Claw
---HiLC---
--Total, n (%)--
------NC, n (%)------
--CoC, n (%)--
-SC, n (%)-
--BC, n (%)---
----p-value----
LL
Normal
84 (62.2)
65 (78.3)
10 (33.3)
7 (46.7)
2 (28.6)
<0.001
Hin
51 (37.8)
18 (21.7)
20 (66.7)*
8 (53.3)
5 (71.4)
LM
Normal
84 (62.2)
73 (78.5)
3 (23.1)
6 (33.3)
2 (18.2)
<0.001
Hin
51 (37.8)
20 (21.5)
10 (76.9)*
12 (66.7)
9 (81.8)*
RL
Normal
84 (62.2)
65 (82.3)
10 (31.3)
7 (46.7)
2 (22.2)
<0.001
Hin
51 (37.8)
14 (17.7)
22 (68.8)*
8 (53.3)
7 (77.8)
RM
Normal
84 (62.2)
73 (79.3)
3 (21.4)
6 (31.6)
2 (20.0)
<0.001
Hin
51 (37.8)
19 (20.7)
11 (78.6)*
13 (68.4)*
8 (80.0)*
P values characterize the values obtained from the Chi-square test. * refers to the difference between statistically expected and observed
percentages of claw conformation (P<0.001). HiLC: Hindlimb conformation; LL: Hind left leg lateral claw; LM: Hind left leg medial
claw; RL: Hind right leg lateral claw; RM: Hind right leg medial claw; NC: Normal claw; CoC: Corkscrew claw; SC: Scissor claw; BC:
Big claw. Table 7 - The comparison of Hin and normal cows by their claw conformation of their every claw, the number of claws (n), and
percentages (%). P values characterize the values obtained from the Chi-square test. * refers to the difference between statistically expected and observed
percentages of claw conformation (P<0.001). HiLC: Hindlimb conformation; LL: Hind left leg lateral claw; LM: Hind left leg medial
claw; RL: Hind right leg lateral claw; RM: Hind right leg medial claw; NC: Normal claw; CoC: Corkscrew claw; SC: Scissor claw; BC:
Big claw. to lameness (GITAU et al., 1997) and lameness in
dairy cows linked positively with claw overgrowth
(CRAMER et al., 2009; SOLANO et al., 2015). Uneven paired digits in length may lead to differences
in hooves such as disbalance, chronic overload, and
deformation (KELLER et al., 2009; MUGGLI et al.,
2011; PARES-CASANOVA et al., 2020). Sickled rear
legs, old age, and abnormal hooves were previously
linked with locomotion problems (OSSENT et al.,
1987; BOELLING et al., 1998). In addition to these
findings, PARES-CASANOVA et al. (2020) have
proposed to investigate asymmetry for kinematic
analysis on old cow digits. In the present study, cows
with abnormal hind limb conformation and old cows
were more prone to have abnormal claws (P<0.001). DISCUSSION AND CONCLUSION Risk Factors
-----------------Lateral--------------
-----------------Medial----------------
-----------------General-----------------
OR (95% CI)
p-value
OR (95% CI)
p-value
OR (95% CI)
p-value
CLN (young/old)
2.98 (1.75-5.09)
<0.001
3.67 (2.07-6.48)
<0.001
2.29 (1.05-4.97)
0.036
HiLC (normal/abnormal)
4.18 (2.56-6.84)
<0.001
6.20 (3.52-10.92)
<0.001
4.98 (2.52-9.84)
<0.001
Gait (normal/abnormal)
1.14 (0.58-2.25)
0.695
0.94 (0.47-1.89)
0.857
0.71 (0.25-1.96)
0.509
OR: Odds ratio, CI: Confidence interval. CLN: Categorized lactation number; HiLC: Hindlimb conformation. 8
Akin et al. Table 9 - Odds ratios and 95% confidence intervals for claw conformation. Risk Factors
-----------------Lateral--------------
-----------------Medial----------------
-----------------General-----------------
OR (95% CI)
p-value
OR (95% CI)
p-value
OR (95% CI)
p-value
CLN (young/old)
2.98 (1.75-5.09)
<0.001
3.67 (2.07-6.48)
<0.001
2.29 (1.05-4.97)
0.036
HiLC (normal/abnormal)
4.18 (2.56-6.84)
<0.001
6.20 (3.52-10.92)
<0.001
4.98 (2.52-9.84)
<0.001
Gait (normal/abnormal)
1.14 (0.58-2.25)
0.695
0.94 (0.47-1.89)
0.857
0.71 (0.25-1.96)
0.509
OR: Odds ratio, CI: Confidence interval. CLN: Categorized lactation number; HiLC: Hindlimb conformation. Akin et al. 8 Table 9 - Odds ratios and 95% confidence intervals for claw conformation. Risk Factors
-----------------Lateral--------------
-----------------Medial----------------
-----------------General-----------------
OR (95% CI)
p-value
OR (95% CI)
p-value
OR (95% CI)
p-value
CLN (young/old)
2.98 (1.75-5.09)
<0.001
3.67 (2.07-6.48)
<0.001
2.29 (1.05-4.97)
0.036
HiLC (normal/abnormal)
4.18 (2.56-6.84)
<0.001
6.20 (3.52-10.92)
<0.001
4.98 (2.52-9.84)
<0.001
Gait (normal/abnormal)
1.14 (0.58-2.25)
0.695
0.94 (0.47-1.89)
0.857
0.71 (0.25-1.96)
0.509
OR: Odds ratio, CI: Confidence interval. CLN: Categorized lactation number; HiLC: Hindlimb conformation. Table 9 - Odds ratios and 95% confidence intervals for claw conformation. OR: Odds ratio, CI: Confidence interval. CLN: Categorized lactation number; HiLC: Hindlimb conformation. lateral claw conformation (especially for corkscrew
claw), and also the age of cows has a negative
effect on claw conformations. Because the claw is
produced, trimmed, and be a worn part of the limbs
(VERMUNT & GREENOUGH, 1995) and the most
cause of the lameness (SOLANO et al., 2016), the
effects of CLN (young/old), HiLC (normal/abnormal),
and gait (normal/abnormal) on claw conformation
were evaluated and presented (Table 9) in this study. It is quite difficult to reveal which’s conformation
(the hindlimb or the claw) is the result of the other’s
abnormal conformation. However, dairy calves
may be monitored until their first, second, or third
lactations to reveal this argument. In future research,
all claw shapes and hindlimb abnormalities can be
investigated by achieving a large number of cows and
considering the claw trimming effect. DISCUSSION AND CONCLUSION cushion (important structure for the inner claw tissue,
hence important to lameness) is profoundly linked to
body condition; also, for the optimum achievement
to reducing lameness incidence, BCS has been
described as 2.5 minimum/and above (BICALHO
et al., 2009; NEWSOME et al., 2017). Based on the
feeding practices for each farm, the BCS of dairy
cows may be changed. In our study, the late lactation
group has statistically higher (P<0.001) BCS than
early and peak lactation groups. However, according
to our results, there was no difference between the
mean BCS of abnormal claw conformation exist and
non-exist groups (P=0.461) and abnormal HiLC exist
and non-exist groups (P=0.226). Limb conformations
in dairy cows can be evaluated from the side and
rearview (RAVEN, 1985; PIJL, 2003). Hin was
the most encountered (n=51) abnormality for rear
evaluation of hindlimbs in this study, and Hin cows
have significantly more abnormal claw conformation
than other hindlimb conformation groups (P<0.001). According to the current knowledge and
the results of this study, during semen selection
for breeding, regarding the mother’s limb and
claw confirmation may be good for the future life
of calves, next generations, and farm economics. Further studies, considering the present results, might
be useful for breeding strategies of the herd. One of the major causes of lameness in cattle
is claw problems (MURRAY et al., 1996; PHILIPS,
2002). Limb conformation traits have been correlated
with claw disorders (VAN DER WAAIJ et al., 2004),
but further research into the association between claw
conformation and hindlimb conformation is needed. Accordingly, with the data used in this study, the
effect of CLN, hindlimb conformation, and gait on
claw conformation was tried to illustrate. Due to the
pregnancy and growing udder, altered postures of the
hindlimbs and weight distribution changes on claws
were described (BERGSTEN, 2001). Old cows in
this study have 2.29 times (P=0.036) more risk than
young cows to have abnormal claw conformation. Also having abnormal hindlimb conformation in
this study, 4.97 times (P<0.001) increases the risk
of abnormal claw conformation. Thus, the results
revealed that the hindlimb conformation of cows used
in the study has strong relation of both medial and ACKNOWLEDGMENTS The authors would like to thanks Assoc. Prof. Dr. Aykut
Gokturk Uner, Assist. Prof. Dr. Tugba Akin, the Cattle Breeders
Association of Aydin Province, and the Arif Gurdal Dairy Farm. This study was funded by the Aydin Adnan Menderes University,
Scientific Research Foundation (grant number: VTF-19022). DISCUSSION AND CONCLUSION Also, having abnormal claw and abnormal hindlimb
conformation were related to gait abnormality
(P=0.032; Table 8). Regarding the results of our
study and the suggestion of PARES-CASANOVA et
al. (2020), the investigation of the relation between
the claw conformation, hindlimb conformation, and
digit asymmetry for locomotion score would also be
very interesting. to lameness (GITAU et al., 1997) and lameness in
dairy cows linked positively with claw overgrowth
(CRAMER et al., 2009; SOLANO et al., 2015). Uneven paired digits in length may lead to differences
in hooves such as disbalance, chronic overload, and
deformation (KELLER et al., 2009; MUGGLI et al.,
2011; PARES-CASANOVA et al., 2020). Sickled rear
legs, old age, and abnormal hooves were previously
linked with locomotion problems (OSSENT et al.,
1987; BOELLING et al., 1998). In addition to these
findings, PARES-CASANOVA et al. (2020) have
proposed to investigate asymmetry for kinematic
analysis on old cow digits. In the present study, cows
with abnormal hind limb conformation and old cows
were more prone to have abnormal claws (P<0.001). The transition period and age are important
factors in asymmetric claw development (OSSENT
et al., 1987). However, high milk yields and poor
body conditions were associated with foot and leg
conformation, and low body condition seems to be
related to the non-infectious disorders of the claw
(GREEN et al., 2014). The thickness of the digital Ciência Rural, v.52, n.4, 2022. Table 8 - The relationship between gait and claw conformation and hindlimb conformation, the number of cows (n) and percentages (%). ----------Hindlimb conformation-----------
-------------Claw conformation--------------
Gait
--abnormal--
----normal----
--p-value--
--abnormal--
---normal---
--p-value--
--------Total-------
Abnormal
63 (45.7)
75 (54.3)
0.032
68 (49.3)
70 (50.7)
0.032
138 (83.1)
Normal
19 (67.9)
9 (32.1)
20 (71.4)
8 (28.6)
28 (16.9)
Total
82 (49.4)
84 (50.6)
88 (53.0)
78 (47.0)
166 (100) Table 8 - The relationship between gait and claw conformation and hindlimb conformation, the number of cows (n) and percentages (%). ----------Hindlimb conformation-----------
-------------Claw conformation--------------
Gait
--abnormal--
----normal----
--p-value--
--abnormal--
---normal---
--p-value--
--------Total-------
Abnormal
63 (45.7)
75 (54.3)
0.032
68 (49.3)
70 (50.7)
0.032
138 (83.1)
Normal
19 (67.9)
9 (32.1)
20 (71.4)
8 (28.6)
28 (16.9)
Total
82 (49.4)
84 (50.6)
88 (53.0)
78 (47.0)
166 (100) he relationship between gait and claw conformation and hindlimb conformation, the number of cows (n) and percentages (%). 8
Akin et al. Table 9 - Odds ratios and 95% confidence intervals for claw conformation. BIOETHICS
AND
COMMITTEE APPROVAL According to clause (b) of Article 2 of the Regulation
on the Working Procedures and Principles of the Animal
Experiments Ethics Committee published in the Official Gazette
of Turkey dated 15.02.2014 and numbered 28914, it has been
stated that there is no need for ethical committee approval in “Non-
experimental Clinical Veterinary Medicine practices”. Since the Ciência Rural, v.52, n.4, 2022. 9 CHAPINAL, N. et al. Genetic parameters for hoof lesions and
their relationship with feet and leg traits in Canadian Holstein
cows. Journal of Dairy Science, v. 96, n. 4, p. 2596-2694, 2013. Available from: <https://pubmed.ncbi.nlm.nih.gov/23415531/>. Accessed: Jan. 28, 2021. doi: 10.3168/jds.2012-6071. experiment in the present study was classified as “routine clinical
applications for diagnosis and treatment” and there was no contact
with the animal during the study period, there was no need to
report to the ethics committee. Aydin Adnan Menderes University,
Scientific Research Foundation has confirmed the study with the
number: VTF-19022. CRAMER, G. et al. Herd-level risk factors for seven different
foot lesions in Ontario Holstein cattle housed in tie stalls or free
stalls. Journal of Dairy Science, v. 92, n. 4, p. 1404-1411, 2009. Available from: <https://pubmed.ncbi.nlm.nih.gov/19307621/>. Accessed: Jan. 28, 2021. doi: 10.3168/jds.2008-1134. AUTHORS’ CONTRIBUTIONS All authors contributed equally to the conception
and writing of the manuscript. All authors critically revised the
manuscript and approved the final version. All authors contributed equally to the conception
and writing of the manuscript. All authors critically revised the
manuscript and approved the final version. EGGER-DANNER,
C. Züchterische
verbesserung
der
klauengesundheit – internationale entwicklungen und aktueller
stand in österreich. in: Seminar des ausschusses für genetik
der zentralen arbeitsgemeinschaft österreichischer rinderzüchter
(ZAR), Salzburg, Austria (2015), pp. 33-44. Available from:
<https://zar.at/Downloads/ZAR-Seminar.html>. Accessed: Jan. 28, 2021. We have no conflict of interest to declare. EDMONSON, A. J. et al. A body condition scoring chart for
Holstein dairy cows. Journal of Dairy Science, v.72, n. 1, p. 68-
78, 1989. Available from: <https://www.journalofdairyscience. org/article/S0022-0302(89)79081-0/abstract>. Accessed: Jan. 28,
2021. doi: 10.3168/jds.S0022-0302(89)79081-0. REFERENCES AKIN, I.; AKIN, T. Economic impact of digital dermatitis
treatment on a dairy farm: an application of the break-even
analysis. Ciencia Rural, v. 48, n. 8, p. e20170791, 2018. Available
from:
<https://www.scielo.br/scielo.php?script=sci_
arttext&pid=S0103 84782018000800604>. Accessed: Jan. 28,
2021. doi: 10.1590/0103-8478cr20170791. EGGER-DANNER, C. et al., 2015. ICAR claw health atlas. First edition. Available from: <https://www.icar.org/ICAR_Claw_
Health_Atlas.pdf.>. Accessed: May. 8, 2021. BERGSTEN, C. Effects of conformation and management system
on hoof and leg diseases and lameness in dairy cows. Veterinary GITAU, T. et al. Assessment of bovine hoof conformation and
its association with lameness, animal factors and management
practices on small-scale dairy farms in Kiambu district, Kenya. GITAU, T. et al. Assessment of bovine hoof conformation and
its association with lameness, animal factors and management
practices on small-scale dairy farms in Kiambu district, Kenya. Onderstepoort Journal of Veterinary Research, v. 64, n. 2,
p.135-140, 1997. Available from: <https://pubmed.ncbi.nlm.nih. gov/9352562/>. Accessed: Jan. 28, 2021. Clinics of North America: Food Animal Practice, v. 17, n. 1,
p.1-23, 2001. Available from: <https://pubmed.ncbi.nlm.nih. gov/11320689/>. Accessed: May. 2, 2021. doi: 10.1016/s0749-
0720(15)30051-7. PMID: 11320689. Onderstepoort Journal of Veterinary Research, v. 64, n. 2,
p.135-140, 1997. Available from: <https://pubmed.ncbi.nlm.nih. gov/9352562/>. Accessed: Jan. 28, 2021. BICALHO, R. C. et al. Strategies to analyze milk losses caused
by diseases with potential incidence throughout the lactation:
A lameness example. Journal of Dairy Science, v.91, n.7, p. 2653–2661, 2008. Available from: https://pubmed.ncbi.nlm.nih. gov/18565924/>. Accessed: Jan. 28, 2021.doi: 10.3168/jds.2007-
0744. GREEN, L. E. et al. Temporal associations between low body
condition, lameness and milk yield in a UK dairy herd. Preventive
Veterinary Medicine, v. 113, n. 1, p: 63-71, 2014. Available from:
<https://pubmed.ncbi.nlm.nih.gov/24183787/>. Accessed: Jan. 28,
2021. doi: 10.1016/j.prevetmed.2013.10.009. Veterinary Medicine, v. 113, n. 1, p: 63-71, 2014. Available from:
<https://pubmed.ncbi.nlm.nih.gov/24183787/>. Accessed: Jan. 28,
2021. doi: 10.1016/j.prevetmed.2013.10.009. HERINGSTAD, B. et al. Invited review: Genetics and claw
health: Opportunities to enhance claw health by genetic selection. Journal of Dairy Science, v. 101, n. 6, p. 4801-4821, 2018. Available from: <https://www.sciencedirect.com/science/article/
pii/S0022030218302078>. Accessed: Jan. 28, 2020. doi: 10.3168/
jds.2017-13531. BICALHO, R. C.; OIKONOMOU, G. Control and prevention of
lameness associated with hoof lesions in dairy cows. Livestock
Science, v. 156, n. p. 96-105, 2013. Available from: <https://www. sciencedirect.com/science/article/pii/S1871141313002679?casa_
token=I_p75
46mWwAAAAA:MNqWkGlLex5K7X8MqurQp
JDV5iaknNbEV51EG8ZYn3HZiXzfwpTa
hCl6xfqOOcwrJy-
oLSniA>. Accessed:
Jan. 28,
2021. doi:
10.1016/j. livsci.2013.06.007. BICALHO, R. C.; OIKONOMOU, G. Control and prevention of
lameness associated with hoof lesions in dairy cows. Livestock
Science, v. 156, n. p. 96-105, 2013. DECLARATION OF CONFLICT OF
INTEREST We have no conflict of interest to declare. REFERENCES PMID: 32867064; PMCID:
PMC7552284. MUGGLI, E. et al. Length asymmetry of the bovine digits. The
Veterinary Journal, v. 188, n, 3, p. 295-300, 2011. Available
from: <https://pubmed.ncbi.nlm.nih.gov/21570662/>. Accessed:
Jan. 28, 2021. doi: 10.1016/j.tvjl.2010.05.016. SOLANO, L. et al. Prevalence of lameness and associated risk
factors in Canadian Holstein Friesian cows housed in freestall
barns. Journal of Dairy Science, v. 98, n. 10, p. 6978–6991, 2015. Available from: <https://pubmed.ncbi.nlm.nih.gov/26254526/>. Accessed: Jan. 28, 2021. doi: 10.3168/jds.2015-9652. MURRAY, R. et al. Epidemiology of lameness in dairy cattle:
Description and analysis of foot lesions. Veterinary Record, v. 138, n. 24, p. 586-591, 1996. Available from: <https://pubmed. ncbi.nlm.nih.gov/8799985/>. Accessed: Jan. 28, 2021. doi:
10.1136/vr.138.24.586. SOLANO, L. et al., Prevalence and distribution of foot lesions in
dairy cattle in Alberta, Canada. Journal of Dairy Science, v. 99, n. 7, p. 6828-6841, 2016. Available from: <https://www.sciencedirect. com/science/article/pii/S0022030216302946>. Accessed: May. 1,
2021. doi: 10.3168/jds.2016-10941. NEWSOME, R. F. et al. A prospective cohort study of digital
cushion and corium thickness. Part 1: Associations with body
condition, lesion incidence, and proximity to calving. Journal of
Dairy Science, v. 100, n. 6, p. 4745–4758, 2017. Available from:
<https://pubmed.ncbi.nlm.nih.gov/28434744/>. Accessed: Jan. 28,
2021. doi: 10.3168/jds.2016-12012. SPRECHER, D. J. A lameness scoring system that uses posture
and gait to predict dairy cattle reproductive performance. Theriogenology, v. 47, n. 6, p. 11791116, 1997. Available from:
<https://pubmed.ncbi.nlm.nih.gov/16728067/>. Accessed: Jan. 28,
2021. doi: 10.1016/s0093-691x(97)00098-8. NGUHIU-MWANGI, J. et al. Risk (predisposing) factors for
non- infectious claw disorders in dairy cows under varying
zero-grazing systems. 2012. In: A Bird’s-Eye View of Veterinary
Medicine, Dr. Carlos C. Perez-Marin (Ed.), ISBN: 978-953-
51-0031-7, InTech, Available from: <https://www.intechopen. com/books/a-bird-s-eye-view-of-veterinary-medicine/risk-
predisposing-factors-for-non-infectious-claw-disorders-in-dairy-
cows-under-varying-zero-grazing>. Accessed: May. 8, 2021. VAN DER LINDE, et al. Claw health index for Dutch dairy cattle
based on claw trimming and conformation data. Journal of Dairy
Science, v. 93, n. 10, p. 4883-4891, 2010. Available from: <https://
www.sciencedirect.com/science/article/pii/S0022030210005205>. Accessed: Jan. 28, 2021.doi: 10.3168/jds.2010-3183. ØDEGARD, C. et al. Genetic correlations between claw health
and feet and leg conformation in Norwegian Red cows. Journal
of Dairy Science, 97, n. 7, p. 4522-4529, 2014. Available from:
<https://pubmed.ncbi.nlm.nih.gov/24767887/>. Accessed: Jan. 28,
2021. doi: 10.3168/jds.2013-7837. VAN DER WAAIJ, et al. Genetic parameters for claw disorders
in Dutch dairy cattle and correlations with conformation traits. Journal of Dairy Science, v. 88, n. 10, p. 3672–3678, 2005. Available from: <https://www.sciencedirect.com/science/article/
pii/S0022030205730538>. Accessed: May. 1, 2021. doi: 10.3168/
jds.S0022-0302(05)73053-8. OSSENT, P. et al. REFERENCES Available from: <https://www. sciencedirect.com/science/article/pii/S1871141313002679?casa_
token=I_p75
46mWwAAAAA:MNqWkGlLex5K7X8MqurQp
JDV5iaknNbEV51EG8ZYn3HZiXzfwpTa
hCl6xfqOOcwrJy-
oLSniA>. Accessed:
Jan. 28,
2021. doi:
10.1016/j. livsci.2013.06.007. KELLER, A. et al. Even-toed but uneven in length: the digits of
artiodactyls. Zoology, v. 112, n. 4, p. 270-278, 2009. Available
from: <https://pubmed.ncbi.nlm.nih.gov/19386479/>. Accessed:
Jan. 28, 2021. doi: 10.1016/j.zool.2008.11.001. BICALHO, R.C. et al. Lameness in dairy cattle: A debilitating
disease or a disease of debilitated cattle? A cross-sectional study of
lameness prevalence and thickness of the digital cushion. Journal
of Dairy Science, v. 92, n. 7, p. 3175-3184, 2009. Available from:
<https://pubmed.ncbi.nlm.nih.gov/19757545/>. Accessed: Jan. 28,
2021. doi: 10.3168/jds.2008-1827. LEACH, K. A. et al. Working towards a reduction in cattle
lameness: 1. Understanding barriers to lameness control on dairy
farms. Research in Veterinary Science, v. 89, n. 2, p. 311-317,
2010. Available from: <https://www.sciencedirect.com/science/
article/abs/pii/S0034528810000676>. Accessed: Jan. 28, 2021. doi: 10.1016/j.rvsc.2010.02.014. BOELLING, D.; POLLOTT, G. E. Locomotion, lameness, hoof
and leg traits in cattle II. Genetic relationships and breeding values. Livestock Production Science, v. 54, n. 3, p. 205 215, 1998. Available from: <https://www.sciencedirect.com/science/article/
abs/pii/S0301622697001735>. Accessed: Jan. 28, 2021. doi:
10.1016/S0301-6226(97)00173-5. LIM, P. Y. et al. Unravelling the temporal association between
lameness and body condition score in dairy cattle using a multistate
modelling approach. Preventive Veterinary Medicine, v. 118, n. 4, p. 370–377, 2015. Available from: <https://www.sciencedirect. Ciência Rural, v.52, n.4, 2022. Ciência Rural, v.52, n.4, 2022. Akin et al. 10 RAVEN, T. E. et al. Cattle footcare and hoof trimming. Farming
Press, Ipswich, Suffolk, UK. 1985. 126p. com/science/article/abs/pii/S0167587714004425>. Accessed: Jan. 28, 2021.doi: 10.1016/j.prevetmed.2014.12.015. MAHENDRAN, S. A. et al. Randomised controlled trial to
evaluate the effect of foot trimming before and after first calving
on subsequent lameness episodes and productivity in dairy heifers. The Veterinary Journal, v. 220, p. 105-110, 2017. Available
from: <https://pubmed.ncbi.nlm.nih.gov/28190486/>. Accessed:
Jan. 28, 2021. doi: 10.1016/j.tvjl.2017.01.011. RESZLER, G. Handbuch klauen: Grundlagen für die erhaltung
einer stabilen klauengesundheit. AVA-Broschüre, Nutztierpraxis
Rind, 1. ed. Agrar- und Veterinär-Akademie, Horstmar-Leer, 2006. MAHENDRAN, S. A. et al. Randomised controlled trial to
evaluate the effect of foot trimming before and after first calving
on subsequent lameness episodes and productivity in dairy heifers. The Veterinary Journal, v. 220, p. 105-110, 2017. Available
from: <https://pubmed.ncbi.nlm.nih.gov/28190486/>. Accessed:
Jan. 28, 2021. doi: 10.1016/j.tvjl.2017.01.011. SADIQ, M. B. et al. Claw trimming as a lameness management
practice and the association with welfare and production in
dairy cows. Animals (Basel), v. 10(9), 1515. Available from:
<https://pubmed.ncbi.nlm.nih.gov/32867064/>. Accessed: May. 3, 2021. doi: 10.3390/ani10091515. REFERENCES Distribution of load between the lateral and
medial hoof of the bovine hind limb. Journal of Veterinary
Medicine Series A, v. 34, n. 1-10, p. 296–300, 1987. Available
from:
<https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1439
0442.1987.tb00283.x>. Accessed: Jan. 28, 2021. doi: 10.1111/
j.1439-0442.1987.tb00283.x. VERMUNT, J. J.; GREENOUGH, P. R. Structural characteristics
of the bovine claw: Horn growth and wear, horn hardness and
claw conformation. British Veterinary Journal. v. 151, n. 2, p. 157–180, 1995. Available from: <https://www.sciencedirect.com/
science/article/abs/pii/S0007193595800077>. Accessed: May. 1,
2021. doi:10.1016/s0007-1935(95)80007-7. PARES-CASANOVA, P. M. et al. Asymmetries of forelimb digits
of young cattle. Veterinary Sciences, v. 7, n. 3, p. 83, 2020. Available from: <https://pubmed.ncbi.nlm.nih.gov/32630632/>. Accessed: Jan. 28, 2021. doi: 10.3390/vetsci7030083. WARNICK, L. D. et al. The effect of lameness on milk production
in dairy cows. Journal of Dairy Science, v. 84, n. 9, p. 1988–1897,
2001. Available from: <https://www.sciencedirect.com/science/
article/pii/S0022030201746425>. Accessed: Jan. 28, 2021. doi:
10.3168/jds.S0022-0302(01)74642-5. PIJL, R. Klauenprobleme schneller lösen. Landwirtsshaftsverlag
Gmbh, Münster-Hiltrup, Germany, 2003. 88p. PIJL, R. Klauenprobleme schneller lösen. Landwirtsshaftsverlag
Gmbh, Münster-Hiltrup, Germany, 2003. 88p. RANDALL, L. V. et al. Low body condition predisposes cattle
to lameness: An 8-year study of one dairy herd. Journal of
Dairy Science, v. 98, n. 6, p. 3766-3777, 2015. Available
from:
<https://www.sciencedirect.com/science/article/pii/
S002203021500209X>. Accessed: Jan. 28, 2021. doi: 10.3168/
jds.2014-8863. ZWALD, et al. Genetic selection for health traits using producer-
recorded data. I. Incidence rates, heritability estimates, and sire
breeding values. Journal of Dairy Science, v. 87, n. 12, p. 4287-
4294, 2004. Available from: <https://www.sciencedirect.com/
science/article/pii/S0022030204735730>. Accessed: Jan. 28,
2021. doi: 10.3168/jds.S0022-0302(04)73573-0. Ciência Rural, v.52, n.4, 2022.
|
https://openalex.org/W3039424313
|
https://hal.archives-ouvertes.fr/hal-02919709/file/fnins-14-00696.pdf
|
English
| null |
Short-Term Sensorimotor Deprivation Impacts Feedforward and Feedback Processes of Motor Control
|
Frontiers in neuroscience
| 2,020
|
cc-by
| 7,176
|
Edited by:
Giulia Cappagli,
Neurological Institute Foundation
Casimiro Mondino (IRCCS), Italy Reviewed by:
Jacopo Zenzeri,
Italian Institute of Technology (IIT), Italy
Dalia De Santis,
Italian Institute of Technology (IIT), Italy
*Correspondence:
Cécile R. Scotto
cecile.scotto@univ-poitiers.fr
†ORCID:
Cécile R. Scotto
orcid.org/0000-0002-7139-2502
Lucette Toussaint
orcid.org/0000-0001-8804-9121 Reviewed by:
Jacopo Zenzeri,
Italian Institute of Technology (IIT), Italy
Dalia De Santis,
Italian Institute of Technology (IIT), Italy *Correspondence:
Cécile R. Scotto
cecile.scotto@univ-poitiers.fr
†ORCID: Specialty section:
This article was submitted to
Perception Science,
a section of the journal
Frontiers in Neuroscience
Received: 12 March 2020
Accepted: 09 June 2020
Published: 01 July 2020
Citation:
Scotto CR, Meugnot A, Casiez G
and Toussaint L (2020) Short-Term
Sensorimotor Deprivation Impacts
Feedforward and Feedback
Processes of Motor Control. Front. Neurosci. 14:696. doi: 10 3389/fnins 2020 00696 Specialty section:
This article was submitted to
Perception Science,
a section of the journal
Frontiers in Neuroscience Received: 12 March 2020
Accepted: 09 June 2020
Published: 01 July 2020 Short-Term Sensorimotor
Deprivation Impacts Feedforward
and Feedback Processes of Motor
Control Cécile R. Scotto
†, Aurore Meugnot , , Géry Casiez , and Lucette Toussaint †
1 Université de Poitiers, Université de Tours, Centre National de la Recherche Scientifique, Centre de Recherches sur la
Cognition et l’Apprentissage, Poitiers, France, 2 Université Paris-Saclay CIAMS, Orsay, France, 3 CIAMS, Université
d’Orléans, Orléans, France, 4 Univ. Lille, CNRS, Centrale Lille, UMR 9189 – CRIStAL – Centre de Recherche en Informatique,
Signal et Automatique de Lille, Lille, France, 5 Institut Universitaire de France (IUF), Paris, France Sensory loss involves irreversible behavioral and neural changes. Paradigms of
short-term limb immobilization mimic deprivation of proprioceptive inputs and motor
commands, which occur after the loss of limb use. While several studies have
shown that short-term immobilization induced motor control impairments, the origin
of such modifications is an open question. A Fitts’ pointing task was conducted, and
kinematic analyses were performed to assess whether the feedforward and/or feedback
processes of motor control were impacted. The Fitts’ pointing task specifically required
dealing with spatial and temporal aspects (speed-accuracy trade-off) to be as fast
and as accurate as possible. Forty trials were performed on two consecutive days
by Control and Immobilized participants who wore a splint on the right arm during
this 24 h period. The immobilization modified the motor control in a way that the
full spatiotemporal structure of the pointing movements differed: A global slowdown
appeared. The acceleration and deceleration phases were both longer, suggesting
that immobilization impacted both the early impulse phase based on sensorimotor
expectations and the later online correction phase based on feedback use. First, the
feedforward control may have been less efficient, probably because the internal model
of the immobilized limb would have been incorrectly updated relative to internal and
environmental constraints. Second, immobilized participants may have taken more
time to correct their movements and precisely reach the target, as the processing of
proprioceptive feedback might have been altered. ORIGINAL RESEARCH
published: 01 July 2020
doi: 10.3389/fnins.2020.00696 Keywords: immobilization, sensorimotor deprivation, Fitts’ task, speed-accuracy trade-off, motor control Citation: Overall, studies investigating the anatomical cerebral changes
following limb immobilization agree on reductions in cortical
excitability of the sensorimotor representation linked to the
decrease in sensory input and motor output (Facchini et al., 2002;
Huber et al., 2006; Avanzino et al., 2011; Burianová et al., 2016). In the same vein, behavioral studies have highlighted the negative
immobilization-induced effects on the cognitive level of action. Alterations at the sensorimotor representation level evaluated
by means of an implicit motor imagery task were reported
following a few hours of arm non-use (Toussaint and Meugnot,
2013; Debarnot et al., 2018). The authors showed that motor
imagery processes used to identify the laterality of hand images
were slowed down for stimuli corresponding to the immobilized
hand. Other studies reported changes in the peripersonal space
representation (Bassolino et al., 2012; Toussaint et al., 2018). Using a reachability judgment task, Toussaint et al. reported that
the maximum distance at which objects are perceived as reachable
was reduced in subjects forced into arm and hand non-use for
24 h. Overall, these studies have shown that representations in
the brain are modified with immobilization. Apparatus The pointing task was performed on a MacBook Pro Retina
(OS X 10.11.6 El Capitan 2.5 GH Core i5) with a screen of
13.3 inches (900 × 1440 pixels) refreshed at 60 Hz. This laptop
included an 8.6 cm × 10.5 cm trackpad with a resolution of 400
CPI sampling at 125 Hz. Instructions, stimuli and data from the
pointing device were handled using a custom-built application
written in C++ using Qt and Libpointing (Casiez et al., 2011). The gain between the trackpad and the visual cursor was set to
1: what was seen on the screen corresponded to what was done
on the trackpad. Citation: Scotto CR, Meugnot A, Casiez G
and Toussaint L (2020) Short-Term
Sensorimotor Deprivation Impacts
Feedforward and Feedback
Processes of Motor Control. Front. Neurosci. 14:696. doi: 10.3389/fnins.2020.00696 The impact of sensory deprivation has been largely studied to identify behavioral and neural
changes following irreversible sensory loss. Over the past decade, such changes have been
studied for sensorimotor loss through paradigms involving short-term limb immobilization. Such
paradigms mimic the deprivation of motor inputs and outputs that induce maladaptive neural
plasticity without compromising brain function (disease-free model; Furlan et al., 2016). Short-
term immobilization consists of preventing a body part (often fingers, hand, and/or arm) from July 2020 | Volume 14 | Article 696 Frontiers in Neuroscience | www.frontiersin.org Immobilization Impacts Motor Planning/Control Scotto et al. moving by means of a splint or a bandage for a period
ranging from a few hours to a few days. While several
studies have shown that short-term immobilization induced
motor control impairments, the origin of such modifications
is an open question. Here, a short-term limb immobilization
paradigm was used to specify the impact of this sensorimotor
deprivation on performance in a Fitts’ task. This pointing task
specifically required dealing with spatial and temporal aspects
(speed-accuracy trade-off) to be as fast and as accurate as
possible. The associated kinematic analysis allowed us to assess
whether the feedforward and/or the feedback processes of motor
control were impacted. contrary to previously used paradigms with immobilization, the
Fitts’ task necessitates dealing with speed as well as accuracy
(i.e., speed-accuracy trade-off) to reach the target. A kinematic
analysis was provided to determine whether the feedforward
and/or feedback processes of motor control of the pointing
movement were affected. The feedforward model refers to the
initiation of early adjustments based on the comparison between
the motor commands and the expected outputs (efference copy;
Miall and Wolpert, 1996). This feedforward process would be
associated with early kinematic parameters (i.e., before peak
velocity; Meyer et al., 1982; Elliott et al., 2010). The feedback
process corresponds to the correction phase, with an online
sensory processing comparing the intended to the current state,
and would be associated with later kinematic parameters (i.e.,
after peak velocity; Meyer et al., 1982; Elliott et al., 2010). Participants Forty-nine right-handed participants (29 men and 20 women;
mean age ± SE: 20.0 ± 0.28 years) gave written informed consent
prior to the study, in accordance with the 1964 Declaration
of Helsinki. The experimental protocol was approved by the
ethics committee for research in sciences of physical and
sports activities (n◦2017250114). All participants reported having
normal or corrected-to-normal vision and no neurological or
sensorimotor disorders. As we expected, the immobilization
effects would disappear within a few trials (Bassolino et al.,
2012), and we used a between-subject design. The participants
were assigned into one of the two groups (e.g., Control or
Immobilized) and performed either the task with an Index of
Difficulty (ID) of 3 or 7 (see section “Procedure”). Fifteen
participants constituted the Control-ID3 group (seven men and
eight women; 20.4 ± 0.49 years), twelve were in the Control-
ID7 group (seven men and five women; 20.6 ± 0.49 years), ten
were in the Immobilized-ID3 group (six men and four women;
19.4 ± 0.33 years), and twelve were in the Immobilized-ID7 group
(nine men and three women; 19.6 ± 0.41 years). Although functional consequences of immobilization have
been demonstrated, these studies did not identify which
mechanisms of action were altered. The majority of studies
have tested how short-term immobilization impacted out-and-
back uncorrected movements toward visual targets (Huber et al.,
2006; Moisello et al., 2008; Debarnot et al., 2018). The hand
path trajectory of such movements deviated after immobilization,
showing that spatial parameters were impacted (Huber et al.,
2006; Moisello et al., 2008). Debarnot et al. (2018) added that
temporal parameters were also modified during this out-and-
back movement following immobilization. They showed that
movement time and reaction time were longer than those
of Control participants. While these studies demonstrated the
impact of immobilization on spatial parameters on the one
hand and temporal parameters on the other hand, the associated
kinematic analysis was not provided. This analysis was provided
in Bassolino et al. (2012) with a reach-to-grasp objects task. The authors showed that the transport phase was impaired
following 10 h of immobilization but not the grasping component
(Bassolino et al., 2012). To suppress the possible interaction of the
grasping component on the transportation phase, we investigated
how short-term immobilization impacts the kinematics of a
pointing movement (i.e., without a grasping component). A Fitts’
task was used to specifically assess how immobilization may
modify spatiotemporal aspects of motor control. Therefore, Frontiers in Neuroscience | www.frontiersin.org Data Processing For the Immobilized group, a quantitative check of the activity
amount was performed through the recording of both arms with
actimeters. During the 24 h immobilization period, 638 ± 59
counts/min were recorded for the right immobilized hand
and 2795 ± 115 counts/min were recorded for the left non-
immobilized hand (see Toussaint and Meugnot, 2013 for a
similar procedure). ANOVA performed on the actimeter values
confirmed that the level of manual activity was higher for the left
hand than for the right hand [F(1,21) = 525.5; p < 0.001]. screen height and a width (W), which was manipulated with
the task’s ID. The ID integrates both the W and the Distance
(D) from the starting point to the target’s center as follows:
ID = Log2(2D/W). Here, D was set to 8 cm, and W was either 2 or
0.125 cm, defining an ID of 3 or 7, respectively. The participants
in the two groups (Control and Immobilized) were assigned to
either ID3 or ID7 conditions (between-subject design; see section
“Participants”). p
)
In an illuminated room, the participants sat in a chair
adjustable in elevation. They were approximately at 50 cm faced
to a laptop. The experimenter placed their forearm on the table
perpendicular to the laptop, in a comfortable position. The joints
were not restrained, and the pointing mainly consisted of a
wrist movement (i.e., abduction when pointing from the left and
adduction when pointing from the right). Talcum was applied on
the participant’s finger before the experiment to reduce dampness
and allowed an easy finger slide on the trackpad. This talcum was
reapplied whenever the participants needed it. For each trial, the
participants were instructed to explore the trackpad with the right
finger to find the starting position on the trackpad (left or right
border). When the position was reached, the word “calibration”
was displayed on the screen. The trial was launched if the finger
was static at this specific location for 0.5 s. The trial started
with the simultaneous appearance of the cursor and the visual
target: The participants could then start the pointing whenever
they were ready. The required movement was to point the visual
target as precisely and as accurately as possible with a smooth and
continuous movement on the trackpad. The participants had to
avoid stopping before or after the target. Procedure The task consisted of horizontal 2D pointing (either left to right
or right to left; Figure 1) using Fitts’ paradigm (Fitts, 1954). The
cursor corresponded to a vertical line of 1 pixel width (0.2 mm),
and the target was a rectangle of a length corresponding to the July 2020 | Volume 14 | Article 696 2 Immobilization Impacts Motor Planning/Control Scotto et al. FIGURE 1 | Experimental setup. Subjects were asked to perform a pointing
task: They slided their right index on the laptop trackpad to move the visual
cursor (white line) into the target (green rectangle). The experiment was composed of two sessions of 40 trials on
2 consecutive days (Pre and Post tests). The first session (Pre)
also included a training of 20 trials to familiarize the participants
with the task prior to data recording. The Pre session lasted
40 min. Immediately after this first session, the participants
in the Immobilized group had their right arm immobilized
with a rigid splint (DONJOY “Comfort Digit”; DJO, Surrey,
United Kingdom) that firmly maintained the wrist and three
fingers (index, middle, and ring). An immobilization vest (model
DONJOY "Immo Axmed") restraining right shoulder, arm and
forearm movements was also used to ensure that the participants
kept their arm at rest as much as possible during the 24 h of
immobilization. The Immobilized group also wore actimeters
(ActiGraph wGT3X-BT) on the wrist of both hands to verify
if they had complied with these instructions. The actimeters
recorded the activity level (in counts/min) with ActiLife software
(ActiLife v6.11.8, Pensacola, FL, United States). Twenty-four hours after the first session, both groups
returned and performed the second session of 40 trials (Post). For the Immobilized group, the Post test was performed
immediately after splint removal by the experimenter. The Post
session lasted 15 min. FIGURE 1 | Experimental setup. Subjects were asked to perform a pointing
task: They slided their right index on the laptop trackpad to move the visual
cursor (white line) into the target (green rectangle). Frontiers in Neuroscience | www.frontiersin.org Data Processing After a period of 0.5 s
static in the target, the visual stimuli disappeared, and the trial
stopped. The trial direction alternated between rightward and
leftward. The vision of the arm was not restrained. Position data from the trackpad were low-pass filtered with
a dual-pass, no-lag Butterworth filter (cutofffrequency: 10 Hz;
order: 2). The data were then derivated to compute the finger
velocity used to determine the Movement Time (MT) of the
pointing. The MT corresponds to the period between the
movement onset and offset, which were defined when the velocity
reached above and below 5% of Peak Velocity (PV), respectively. We further assessed the impact of immobilization with the
analysis of pointing corrections. Although the participants were
instructed to point the target with a “smooth and continuous
movement,” some movements were stopped (velocity below 5%
of PV) before or after the target. We computed the percentage
of trials where corrections appeared (i.e., the correction rate). Movement kinematics were also analyzed to further determine
the impact of immobilization on the motor impulse phase and
online correction phase, associated to feedforward and feedback
processes, respectively. Modifications in the impulse phase were
assessed through the analysis of the time of acceleration (AT;
time from movement onset to PV). In addition, the time of
deceleration (DT; time between PV and movement offset) was
associated with the correction phase with online corrections
(Meyer et al., 1982; Elliott et al., 2010). DT includes the
deceleration period of the first submovement (from PV) as well
as the period lasting for all potential additional submovements. July 2020 | Volume 14 | Article 696 Frontiers in Neuroscience | www.frontiersin.org Frontiers in Neuroscience | www.frontiersin.org 3 Immobilization Impacts Motor Planning/Control Scotto et al. FIGURE 3 | Movement Time (MT) relative to the Session (Pre vs. Post) for the
Control and Immobilized (Immo) groups. **p < 0.01. Error bars denote
standard error. Bassolino
et
al. (2012)
found
that
the
influence
of
immobilization in a reach-to-grasp task did not last more
than a few trials. Therefore, we first assessed whether differences
appeared over trials by comparing the means of each eight
successive blocks of five trials. Repeated-measures ANOVAs
were then conducted using a mixed design with two between-
subjects factors: Group (Control vs. Immobilized) and ID (3 vs. 7) and two within-subjects factors: Session (Pre vs. Post) and
Block (1–8). RESULTS FIGURE 3 | Movement Time (MT) relative to the Session (Pre vs. Post) for the
Control and Immobilized (Immo) groups. **p < 0.01. Error bars denote
standard error. Data Processing A simple effect of Block appeared but no significant
interactions were revealed between the Block and the Group or
the Session on all the dependent variables. The analyses were
then conducted on the mean of the 40 trials. Post-hoc tests
(Newman-Keuls) were performed when necessary, and the level
of significance was set at 0.05 for all statistical analyses. Kinematic Profiles Figure 2 depicts velocity profiles for representative trials in the
Control and Immobilized groups. As classically shown, the ID FIGURE 2 | Velocity profiles from representative trials for the Control and
Immobilized (Immo) participants who performed in either the ID3 (A) or ID7 (B)
condition. Dashed lines represent session Pre, and full lines represent session
Post. Regardless of the ID, the Immobilized participants exhibited longer MT
and lower PV in the Post session than in the Pre session. seemed to modify pointing kinematics: ID7 was associated with a
lower PV, longer MT and more corrections than ID3. In addition,
Figure 1 suggests that the Immobilized participants exhibited a
longer MT and a lower PV in the Post session than in the Pre
session, regardless of the ID. These observations were statistically
tested with mean comparisons of selected kinematic parameters. Movement Time and Corrections The repeated-measures ANOVA Group × ID × Session for MT
revealed an effect of ID [F(1,45) = 349.0; p < 0.001] as well
as an interaction Group × Session [F(1,45) = 10.4; p < 0.001]. Overall, the MT was shorter in the ID3 than in the ID7 condition
(367 ± 12 ms vs. 970 ± 32 ms, respectively). No significant effect
of Group [F(1,45) = 1.6; p = 0.21], Session [F(1,45) = 2.4; p = 0.13],
Group × ID [F(1,45) = 0.0; p = 1.00], Session × ID [F(1,45) = 0.2;
p = 0.62] nor Group × ID × Session [F(1,45) = 2.0; p = 0.17]
appeared. Figure 3 depicts the Group × Session interaction. The
Control and Immobilized groups differed between the Pre and
Post sessions. For the Immobilized group, the MT increased
between the Pre and Post sessions (661 ± 70 ms vs. 710 ± 73 ms,
respectively; p < 0.01). In contrast, for the Control group, the
MT did not increase between the Pre and Post sessions and either
exhibited a trend toward a decrease (666 ± 64 ms vs. 639 ± 62 ms;
p = 0.06). The analysis of corrections (under- and overshoots) revealed
an effect of ID [F(1,45) = 26.9; p < 0.001] with a higher correction
rate for ID7 than ID3 (2.0 ± 0.6% vs. 14.1 ± 2.5%). No significant
effect of Group [F(1,45) = 0.9; p = 0.35], Session [F(1,45) = 0.1;
p = 0.70], Group × ID [F(1,45) = 0.5; p = 0.50], Session ×
ID [F(1,45) = 0.0; p = 0.95], Session × Group [F(1,45) = 0.0;
p = 0.87] nor Group × ID × Session [F(1,45) = 0.7; p = 0.42]
appeared. Therefore, the analysis failed to show an effect of
immobilization on corrections. FIGURE 2 | Velocity profiles from representative trials for the Control and
Immobilized (Immo) participants who performed in either the ID3 (A) or ID7 (B)
condition. Dashed lines represent session Pre, and full lines represent session
Post. Regardless of the ID, the Immobilized participants exhibited longer MT
and lower PV in the Post session than in the Pre session. FIGURE 2 | Velocity profiles from representative trials for the Control and
Immobilized (Immo) participants who performed in either the ID3 (A) or ID7 (B)
condition. Dashed lines represent session Pre, and full lines represent session
Post. Peak Velocity, Peak Acceleration, and
Peak Deceleration We analyzed how fast the pointing movements of the participants
were. The analysis of Peak Velocity (PV) revealed an effect of
ID [F(1,45) = 66.3; p < 0.001] and a Group × Session interaction
[F(1,45) = 13.3; p < 0.01; Figure 5A]. No significant effect of
Group [F(1,45) = 0.1; p = 0.77], Session [F(1,45) = 3.0; p = 0.09],
Group × ID [F(1,45) = 0.4; p = 0.53], Session × ID [F(1,45) = 0.5;
p = 0.50] nor Group × ID × Session [F(1,45) = 0.3; p = 0.57]
appeared. First, the PV was higher at ID3 (49.5 ± 2.0 cm.s−1)
than at ID7 (28.4 ± 1.9 cm.s−1). In addition, the post-hoc analysis
of the interaction showed that the PV in the Immobilized group
decreased between the Pre and Post sessions (41.5 ± 3.2 cm.s−1
vs. 35.6 ± 2.7 cm.s−1, respectively; p < 0.01). No difference was
found for the Control group between the Pre and Post sessions
(514 ± 2.7 cm.s−1 vs. 492 ± 3.0 cm.s−1; p = 0.06). A trend
appeared in the Post session between the two groups (p = 0.07). p
The Deceleration Time (DT) corresponds to the absolute
period between the PV and the end of the movement. This
parameter is associated with the homing phase of motor control
reflecting online movement corrections (e.g., Woodworth, 1899;
Meyer et al., 1982). The analysis showed an effect of ID
[F(1,45) = 553.1; p < 0.001] and a Group × Session interaction
[F(1,45) = 9.3; p < 0.01]. No significant effect of Group
[F(1,45) = 1.2; p = 0.27], Session [F(1,45) = 0.0; p = 0.83], Group ×
ID [F(1,45) = 0.6; p = 0.43], Session × ID [F(1,45) = 0.0; p = 0.88]
nor Group × ID × Session [F(1, 45) = 0.7; p = 0.42] appeared. Again, the DT was shorter at ID3 (242 ± 9 ms) than at ID7
(790 ± 23 ms), and post-hoc analysis of the interaction showed
that the Control and Immobilized groups differed between the Pre
and Post sessions (Figure 4B). For the Immobilized group, the
DT increased between the Pre and Post sessions (516 ± 65 ms
vs. 542 ± 65 ms, respectively; p < 0.05). Acceleration and Deceleration Time and exhibited a trend toward a reduction (514 ± 54 ms vs. 492 ± 53 ms; p = 0.06). The Acceleration Time (AT) corresponds to the absolute period
between the movement onset and the PV. This parameter is
associated with the impulse phase of motor control reflecting
the planning process of the movement. The analysis showed an
effect of ID [F(1,45) = 34.6; p < 0.001], Session [F(1,45) = 9.7;
p < 0.01] and a Group × Session interaction [F(1,45) = 11.5;
p < 0.01]. No significant effect of Group [F(1,45) = 2.5; p = 0.19],
Group × ID [F(1,45) = 0.1; p = 0.73], Session × ID [F(1,45) = 0.9;
p = 0.35] nor Group × ID × Session [F(1,45) = 1.4; p = 0.25]
appeared. Therefore, the AT was shorter at ID3 (113 ± 4 ms)
than at ID7 (172 ± 11 ms). Moreover, the post-hoc analysis of
the interaction showed that the Control and Immobilized groups
differed between the Pre and Post sessions (Figure 4A). For the
Immobilized group, the AT increased between the Pre and Post
sessions (138 ± 9 ms vs. 164 ± 11 ms, respectively; p < 0.001). For the Control group, the AT did not increase between the Pre
and Post sessions (136 ± 10 ms vs. 134 ± 9 ms; p = 0.86). Further analyses were conducted to determine what caused
the modifications in the temporal parameters (i.e., MT, AT, DT). More precisely, we computed the peak acceleration, velocity and
deceleration to determine whether those modifications occurred
at an early or late stage. Movement Time and Corrections Regardless of the ID, the Immobilized participants exhibited longer MT
and lower PV in the Post session than in the Pre session. July 2020 | Volume 14 | Article 696 Frontiers in Neuroscience | www.frontiersin.org 4 Immobilization Impacts Motor Planning/Control Scotto et al. FIGURE 4 | (A) Acceleration Time (AT) and (B) Deceleration Time (DT) relative to the Session (Pre vs. Post) for the Control and Immobilized (Immo) groups. *p < 0.05; **p < 0.01; ***p < 0.001. Error bars denote standard error. e to the Session (Pre vs. Post) for the Control and Immobilized (Immo) groups. FIGURE 4 | (A) Acceleration Time (AT) and (B) Deceleration Time (DT) relative to the Session (Pre vs. Post) for the Control and Immobilized (Immo) groups. *p < 0.05; **p < 0.01; ***p < 0.001. Error bars denote standard error. Peak Velocity, Peak Acceleration, and
Peak Deceleration For the Control group,
the DT did not increase between the Pre and Post sessions The analysis of Peak Acceleration (PA) revealed an effect
of ID [F(1,45) = 52.6; p < 0.001] and a Group × Session
interaction [F(1,45) = 10.3; p < 0.01; Figure 5B]. No significant
effect of Group [F(1,45) = 1.6; p = 0.21], Session [F(1,45) = 2.2;
p = 0.15], Group × ID [F(1,45) = 2.0; p = 0.16], Session × ID
[F(1,45) = 1.6; p = 0.21] nor Group × ID × Session [F(1,45) = 0.0;
p = 0.90] appeared. As with the PV, the PA was higher at ID3
(634 ± 40 cm.s−2) than at ID7 (306 ± 31 cm.s−2). In addition,
the post-hoc analysis of the interaction showed that the PA in the July 2020 | Volume 14 | Article 696 Frontiers in Neuroscience | www.frontiersin.org 5 Immobilization Impacts Motor Planning/Control Scotto et al. FIGURE 5 | (A) Peak Velocity (PV), (B) Peak Acceleration (PA), and (C) Peak Deceleration (PD) relative to the Session (Pre vs. Post) for the Control and Immobilized
(Immo) groups. *p < 0.05; **p < 0.01. Error bars denote standard error. FIGURE 5 | (A) Peak Velocity (PV), (B) Peak Acceleration (PA), and (C) Peak Deceleration (PD) relative to the Session (Pre vs. Post) for the Control and Immobilized
(Immo) groups. *p < 0.05; **p < 0.01. Error bars denote standard error. FIGURE 5 | (A) Peak Velocity (PV), (B) Peak Acceleration (PA), and (C) Peak Deceleration (PD) relative to the Session (Pre vs. Post) for the Control and Immobilized
(Immo) groups. *p < 0.05; **p < 0.01. Error bars denote standard error. DISCUSSION Immobilized group decreased between the Pre and Post sessions
(489 ± 44 cm.s−2 vs. 393 ± 36 cm.s−2, respectively; p < 0.01). No difference was found for the Control group between the
Pre and Post sessions (481 ± 48 cm.s−2 vs. 517 ± 58 cm.s−2;
p = 0.19). Finally, the Pre and Post sessions differed between the
two groups (p < 0.01). Here, we tested how short-term immobilization modified
behavioral responses. More precisely, we tested whether the
feedforward and/or feedback processes of pointing movements
were affected by 24 h of arm non-use. We first showed that
immobilization had an impact on sensorimotor control with
lengthened movement time without damaging accuracy. This
decrease in movement time seemed to result from a global
slowdown: The acceleration and deceleration phases were both
longer and were associated with lower peak acceleration, velocity,
and deceleration. Therefore, immobilization appeared to modify
sensorimotor control in such a way that the full spatiotemporal
structure of the pointing movements differed. The analysis of Peak Deceleration (PD) revealed an effect of
ID [F(1,45) = 57.6; p < 0.001] and a Group × Session interaction
[F(1,45) = 6.4; p < 0.01; Figure 5C]. No significant effect of Group
[F(1,45) = 0.3; p = 0.61], Session [F(1,45) = 3.6; p = 0.06], Group ×
ID [F(1,45) = 0.8; p = 0.37], Session × ID [F(1,45) = 1.0; p = 0.31]
nor Group × ID × Session [F(1,45) = 0.1; p = 0.72] appeared. As PA, the PD was also higher at ID3 (−438 ± 29 cm.s−2) than
at ID7 (−188 ± 21 cm.s−2). In addition, the post-hoc analysis
of the interaction showed that the PD in the Immobilized group
decreased between the Pre and Post sessions (−339 ± 37 cm.s−2
vs. −270 ± 35 cm.s−2, respectively; p < 0.05). No difference was
found for the Control group between the Pre and Post sessions
(−317 ± 35 cm.s−2 vs. −326 ± 37 cm.s−2; p = 0.60) or between
the Pre and Post sessions between the two groups (p = 0.14). First, our data confirmed that immobilization leads to a
decrease in motor performance (Huber et al., 2006; Moisello et al.,
2008; Bassolino et al., 2012; Bolzoni et al., 2012). Such declines
in pointing performance have been shown to arise from changes
in joint coordination around the deprived segment (Moisello
et al., 2008; Bassolino et al., 2012). DISCUSSION When the immobilized July 2020 | Volume 14 | Article 696 Frontiers in Neuroscience | www.frontiersin.org 6 Immobilization Impacts Motor Planning/Control Scotto et al. participants were instructed to make out-and-back straight
movements without correction, an increase in the hand-path
area amplitude and variability appeared (Huber et al., 2006;
Moisello et al., 2008; Bassolino et al., 2012). When the task
integrated spatial constraints for trial validation, immobilization
rather induced temporal impairments, such as an increase in
movement time. Therefore, Bassolino et al. (2012) showed an
increase in movement time for a reach-to-grasp task where spatial
constraints were defined (i.e., the object reaching movement
to perform the grasping) during the five first trials. Here
we found that this increase in movement duration could last
longer for a pointing task as we did not find an interaction
between the immobilization and the trial repetitions. Therefore,
no reactivation of the process of proprioceptive inputs would
appear contrary to the results of Bassolino et al. (2012). Albeit,
here the movement amplitude was reduced and required a less
complex motor control than a reach-to-grasp task involving
multiple joints from the arm, the hand and the digits. In
addition, spatial corrections (stops before or after the target) were
not amplified with immobilization, as Fitts’ paradigm requires
finishing the movement in the target position, and we instructed
the participants to perform a “smooth movement.” Therefore,
the participants would lengthen their movement rather than
doing several sub-movements to reach the target. In addition, we
hypothesized that the behavioral consequences of immobilization
would be modulated by task difficulty. Therefore, we expected a
higher impact with ID7 than ID3 because motor planning and
control is more complex. While we found the classic effect of ID
on the kinematic parameters, no statistical interaction appeared
with the immobilization factor. The lack of proprioceptive cues
would be sufficiently strong to affect any movement, as also
suggested by the work of Medina et al. (2009) on a deafferented
patient (JDY). In this study, the difference in movement time
between controls and JDY would not appear to be modulated by
the tested ID (i.e., 4, 4.5, and 5.5) of the pointing task. and its sensory consequences (e.g., future states of the arm
at the end of pointing; Wolpert et al., 1995). DISCUSSION Based on these
feedforward inputs of the limb, predictions of the future states are
compared to the current state which allow for early corrections
(Wolpert et al., 1995; Desmurget and Grafton, 2000; Wolpert and
Ghahramani, 2000). Our results suggested that the feedforward
control was impacted, probably because the internal model of
the immobilized limb would be incorrectly updated. In daily life,
the internal model of the limb is continuously updated through
motion (see Wolpert and Ghahramani, 2000). During the 24 h
of immobilization, motor commands of the limb were largely
reduced. Consequently, efference copy as well as dynamical
proprioceptive cues could not have been used to maintain or
calibrate the internal model with the limb dynamics relative
to the environment. Such a decrease in feedback would lead
to an altered prediction of the sensory consequences of the
action before its execution. Studies with deafferented patients
have previously shown that proprioception was critical to update
internal models of limb dynamics (Sainburg et al., 1995; Sarlegna
et al., 2006; Medina et al., 2009). On the other hand, our results suggested that immobilization
also modifies the feedback control of the pointing: A lengthened
deceleration duration as well as decreased peak deceleration
were observed. These results suggested disruptions in the process
of proprioceptive cues correcting the movement online. This
is in line with recent studies (Huber et al., 2006; Weibull
et al., 2011; Ngomo et al., 2012; Rosenkranz et al., 2014; Opie
et al., 2016), which found a decrease in excitability in the
somatosensory areas representing the previously immobilized
arm: The proprioceptive cues were less processed, as well as
the tactile cues (i.e., decrease of tactile discrimination; Weibull
et al., 2011). Therefore, immobilized participants would take
more time to correct their movement to precisely reach the target,
as the processing of proprioceptive cues might be altered. Visual
cues would be particularly used to compensate for this deficit,
notably with the online visual comparison between the cursor
and the target position. This feedback control of the pointing
movement throughout vision was shown to start later than the
proprioceptive one (Sarlegna et al., 2004; Saunders and Knill,
2004), which could explain the increase of the correction phase
duration. This hypothesis is supported by neurophysiological
data which showed that the decrease in cortical excitability of the
somatosensory areas of the immobilized limb is associated with
a sensitivity increase of the other sensory inputs (Rosenkranz
et al., 2014). Frontiers in Neuroscience | www.frontiersin.org DISCUSSION Further experiments would be necessary to
specifically isolate how visual cues impact sensorimotor control
after immobilization. Before debating what immobilization changed for feedforward
and/or feedback processing, we have to discard the possibility
that changes arising from peripheral structures declined. Indeed,
immobilization leads to modifications in muscle contractile
properties (from slow to fast fiber type) and motor units. However, such transformations appeared after several weeks of
immobilization (Desaphy, 2001; Seki et al., 2001a,b; Zanette
et al., 2004). In contrast, short-term immobilization (less than
3–4 days) do not impact muscle and nerve properties (Facchini
et al., 2002; Huber et al., 2006; Moisello et al., 2008). Therefore,
modifications of motor behavior in the present study cannot
be attributed to changes in muscle structure following short-
term immobilization. Although functional consequences of immobilization have
been demonstrated in the past, the impact of immobilization
on the motor control processes has not been fully elucidated. Contrary to previously used paradigms with immobilization, we
used a Fitts’ task which necessitates dealing with spatiotemporal
constraints
(i.e.,
speed-accuracy
trade-off). Thanks
to
a
spatiotemporal kinematic analysis, we specifically assessed
the impact of sensorimotor deprivation on the motor control
processes. For the first time, we showed early and late kinematic
changes following a short period of limb non-use, which Here, we showed that immobilization impacted both early and
late movement kinematics. Since Woodworth’s two-component
model, kinematic parameters before the peak velocity are
associated with feedforward control and those after are associated
with the feedback control (Meyer et al., 1982; Elliott et al., 2010). On the one hand, we showed that immobilization lengthened
acceleration duration as well as decreased peak acceleration. Early kinematics modifications have been shown to reflect the
use of internal models, i.e., a representation of the action July 2020 | Volume 14 | Article 696 7 Immobilization Impacts Motor Planning/Control Scotto et al. sciences of physical and sports activities (n◦2017250114). The
patients/participants provided their written informed consent to
participate in this study. may be caused by the modification of feedforward as well as
feedback processes. Even if these results would have to be
extended to a broader population, such as the elderly people,
they may have implications in rehabilitation and health care. Everybody has been or will be immobilized during his/her
own lifetime due to an accident (e.g., broken limb) or for
external reasons (e.g., long travel, prolonged bed rest). REFERENCES Huber, R., Ghilardi, M. F., Massimini, M., Ferrarelli, F., Riedner, B. A., Peterson,
M. J., et al. (2006). Arm immobilization causes cortical plastic changes and
locally decreases sleep slow wave activity. Nat. Neurosci. 9, 1169–1176. doi:
10.1038/nn1758 Avanzino, L., Bassolino, M., Pozzo, T., and Bove, M. (2011). Use-dependent
hemispheric balance. J. Neurosci. 31, 3423–3428. doi: 10.1523/JNEUROSCI. 4893-10.2011 Medina, J., Jax, S. A., and Coslett, H. B. (2009). Two-component models of
reaching: Evidence from deafferentation in a Fitts’ law task. Neurosci. Lett. 451,
222–226. doi: 10.1016/j.neulet.2009.01.002 Bassolino, M., Bove, M., Jacono, M., Fadiga, L., and Pozzo, T. (2012). Functional
effect of short-term immobilization: Kinematic changes and recovery on
reaching-to-grasp. Neuroscience 215, 127–134. doi: 10.1016/j.neuroscience. 2012.04.019 Meyer, D. E., Smith, J. E., and Wright, C. E. (1982). Models for the speed and
accuracy of aimed movements. Psychol. Rev. 89, 449–482. doi: 10.1037/0033-
295x.89.5.449 Bolzoni, F., Bruttini, C., Esposti, R., and Cavallari, P. (2012). Hand immobilization
affects arm and shoulder postural control. Exp. Brain Res. 220, 63–70. doi:
10.1007/s00221-012-3115-7 Miall, R. C., and Wolpert, D. M. (1996). Forward models for physiological motor
control. Neural Netw. 9, 1265–1279. doi: 10.1016/S0893-6080(96)00035-4 Moisello, C., Bove, M., Huber, R., Abbruzzese, G., Battaglia, F., Tononi, G., et al. (2008). Short-Term Limb Immobilization Affects Motor Performance. J. Mot. Behav. 40, 165–176. doi: 10.3200/JMBR.40.2.165-176 Burianová, H., Sowman, P. F., Marstaller, L., Rich, A. N., Williams, M. A.,
Savage, G., et al. (2016). Adaptive motor imagery: a multimodal study of
immobilization-induced brain plasticity. Cereb. Cortex 26, 1072–1080. doi: 10. 1093/cercor/bhu287 Ngomo, S., Leonard, G., and Mercier, C. (2012). Influence of the amount of
use on hand motor cortex representation: effects of immobilization and
motor training. Neuroscience 220, 208–214. doi: 10.1016/j.neuroscience.2012. 06.018 Casiez, G., Roussel, N., Vanbelleghem, R., and Giraud, F. (2011). “Surfpad: riding
towards targets on a squeeze film effect,” in Proceedings of the 2011 annual
conference on Human factors in computing systems - CHI ’11, (Vancouver, BC:
ACM Press), 2491. doi: 10.1145/1978942.1979307 Opie, G. M., Evans, A., Ridding, M. C., and Semmler, J. G. (2016). Short-term
immobilization influences use-dependent cortical plasticity and fine motor
performance. Neuroscience 330, 247–256. doi: 10.1016/j.neuroscience.2016.06. 002 Debarnot, U., Huber, C., Guillot, A., and Schwartz, S. (2018). Sensorimotor
representation and functional motor changes following short-term arm
immobilization. Behav. Neurosci. 132, 595–603. doi: 10.1037/bne0000274 Desaphy, J.-F. (2001). Skeletal muscle disuse induces fibre type-dependent
enhancement of Na+ channel expression. Brain 124, 1100–1113. DATA AVAILABILITY STATEMENT The datasets generated for this study are available on request to
the corresponding author. AUTHOR CONTRIBUTIONS CS, AM, and LT conceived and designed the research. CS and
GC set up the experiments. LT performed the experiments. CS
analyzed the data and prepared the figures. CS and LT interpreted
the results of the experiments and drafted the manuscript. CS,
AM, LT, and GC edited and revised the manuscript. All authors
contributed to the article and approved the submitted version. DISCUSSION The
understanding of the sensorimotor consequences of such short-
term immobilization thus appeared of particular interest. We thank Florian Petitcollin for his help in testing participants. We thank Florian Petitcollin for his help in testing participants. ACKNOWLEDGMENTS The studies involving human participants were reviewed
and
approved
by
the
ethics
committee
for
research
in The studies involving human participants were reviewed
and
approved
by
the
ethics
committee
for
research
in REFERENCES doi: 10.1093/
brain/124.6.1100 Rosenkranz, K., Seibel, J., Kacar, A., and Rothwell, J. (2014). Sensorimotor
deprivation induces interdependent changes in excitability and plasticity of
the human hand motor cortex. J. Neurosci. 34, 7375–7382. doi: 10.1523/
JNEUROSCI.5139-13.2014 Desmurget, M., and Grafton, S. (2000). Forward modeling allows feedback control
for fast reaching movements. Trends Cogn. Sci. 4, 423–431. doi: 10.1016/S1364-
6613(00)01537-0 Sainburg,
R. L.,
Ghilardi,
M. F.,
Poizner,
H.,
and
Ghez,
C. (1995). Control of limb dynamics in normal subjects and patients without
proprioception. J. Neurophysiol. 73,
820–835. doi:
10.1152/jn.1995.73. 2.820 Elliott, D., Hansen, S., Grierson, L. E. M., Lyons, J., Bennett, S. J., and Hayes, S. J. (2010). Goal-directed aiming: Two components but multiple processes. Psychol. Bull. 136, 1023–1044. doi: 10.1037/a0020958 Sarlegna, F., Blouin, J., Vercher, J.-L., Bresciani, J.-P., Bourdin, C., and
Gauthier, G. (2004). Online control of the direction of rapid reaching
movements. Exp. Brain Res. 157, 468–471. doi: 10.1007/s00221-004-1
860-y Facchini, S., Romani, M., Tinazzi, M., and Aglioti, S. M. (2002). Time-
related changes of excitability of the human motor system contingent upon
immobilisation of the ring and little fingers. Clin. Neurophysiol. 113, 367–375. doi: 10.1016/S1388-2457(02)00009-3 Sarlegna, F. R., Gauthier, G. M., Bourdin, C., Vercher, J.-L., and Blouin, J. (2006). Internally driven control of reaching movements: a study on a proprioceptively
deafferented subject. Brain Res. Bull. 69, 404–415. doi: 10.1016/j.brainresbull. 2006.02.005 Fitts, P. M. (1954). The information capacity of the human motor system in
controlling the amplitude of movement. J. Exp. Psychol. 47, 381–391. doi: 10. 1037/h0055392 Saunders, J. A., and Knill, D. C. (2004). Visual feedback control of hand
movements. J. Neurosci. 24, 3223–3234. doi: 10.1523/JNEUROSCI.4319-03. 2004 Furlan, L., Conforto, A. B., Cohen, L. G., and Sterr, A. (2016). Upper limb
immobilisation: a neural plasticity model with relevance to poststroke motor
rehabilitation. Neural Plast. 2016, 1–17. doi: 10.1155/2016/8176217 July 2020 | Volume 14 | Article 696 8 Frontiers in Neuroscience | www.frontiersin.org Immobilization Impacts Motor Planning/Control Scotto et al. Wolpert, D. M., and Ghahramani, Z. (2000). Computational principles of
movement neuroscience. Nat. Neurosci. 3, 1212–1217. doi: 10.1038/81497 Seki, K., Taniguchi, Y., and Narusawa, M. (2001a). Alterations in contractile
properties of human skeletal muscle induced by joint immobilization. J. Physiol. 530, 521–532. doi: 10.1111/j.1469-7793.2001.0521k.x Woodworth, R. S. (1899). The accuracy of voluntary movement. Psychol. Rev. (Monograph Suppl.), 3, 1–119. Seki, K., Taniguchi, Y., and Narusawa, M. (2001b). Effects of joint immobilization
on firing rate modulation of human motor units. J. Frontiers in Neuroscience | www.frontiersin.org July 2020 | Volume 14 | Article 696 REFERENCES Physiol. 530, 507–519. doi: 10.1111/j.1469-7793.2001.0507k.x Zanette,
G.,
Manganotti,
P.,
Fiaschi,
A.,
and
Tamburin,
S. (2004). Modulation of motor cortex excitability after upper limb immobilization. Clin. Neurophysiol. 115,
1264–1275. doi:
10.1016/j.clinph.2003. 12.033 Toussaint, L., and Meugnot, A. (2013). Short-term limb immobilization affects
cognitive motor processes. J. Exp. Psychol. Learn. Mem. Cogn. 39, 623–632. doi: 10.1037/a0028942 Conflict of Interest: The authors declare that the research was conducted in the
absence of any commercial or financial relationships that could be construed as a
potential conflict of interest. Conflict of Interest: The authors declare that the research was conducted in the
absence of any commercial or financial relationships that could be construed as a
potential conflict of interest. Toussaint, L., Wamain, Y., Bidet-Ildei, C., and Coello, Y. (2018). Short-term upper-
limb immobilization alters peripersonal space representation. Psychol. Res. 84,
907–914. doi: 10.1007/s00426-018-1118-0 Weibull, A., Flondell, M., Rosén, B., and Björkman, A. (2011). Cerebral and
clinical effects of short-term hand immobilisation: cerebral effects of hand
immobilisation. Eur. J. Neurosci. 33, 699–704. doi: 10.1111/j.1460-9568.2010. 07551.x Copyright © 2020 Scotto, Meugnot, Casiez and Toussaint. This is an open-access
article distributed under the terms of the Creative Commons Attribution License
(CC BY). The use, distribution or reproduction in other forums is permitted, provided
the original author(s) and the copyright owner(s) are credited and that the original
publication in this journal is cited, in accordance with accepted academic practice. No
use, distribution or reproduction is permitted which does not comply with these terms. Wolpert, D., Ghahramani, Z., and Jordan, M. (1995). An internal model
for sensorimotor integration. Science 269, 1880–1882. doi: 10.1126/science. 7569931 July 2020 | Volume 14 | Article 696 Frontiers in Neuroscience | www.frontiersin.org 9
|
https://openalex.org/W4300593359
|
https://zenodo.org/record/7135241/files/NeutrosophicSuperHyperBiTopological3.pdf
|
Latin
| null |
Neutrosophic SuperHyper Bi-Topological Spaces: Original Notions and New Insights
|
Zenodo (CERN European Organization for Nuclear Research)
| 2,022
|
cc-by
| 5,351
|
Abstract. This manuscript comes as first attempt in building a new type of neutrosophic topological
spaces, the aim is to shed the light on a new structure known as the 𝑛𝑡ℎ-power set 𝑃𝑛(𝑋) of a set,
this new kind of sets enables authors to create and built new topology spaces called Neutrosophic
SuperHyper Topological Spaces and Neutrosophic SuperHyper Bi-Topological Spaces , the 𝑛𝑡ℎ-
power sets are the optimal representation for the applications in our real world. In this article, new
concepts and theorems related to this new topologies have been discussed, which are pairwise
neutrosophic open 𝑛𝑡ℎ-power set, pairwise neutrosophic closed 𝑛𝑡ℎ-power set, as well as, the
closures and the interiors are defined with their properties. Many of relations for these concepts have
been introduced. Keywords: 𝑛𝑡ℎ-power set 𝑃𝑛(𝑋) ; Neutrosophic SuperHyper Topological Spaces (NSHTSs);
Neutrosophic SuperHyper Bi-Topological Spaces (NSHBi-TSs). Neutrosophic SuperHyper Bi-Topological Spaces: Original
Notions and New Insights Huda E. Khalid1* , Gonca D. GÜNGÖR2 , Muslim A. Noah Zainal3
1Telafer University, The Administration Assistant for the President of the Telafer University,
Telafer, Iraq. ; https://orcid.org/0000-0002-0968-5611 , dr.huda-ismael@uotelafer.edu.iq
2 Çankırı Karatekin University, Faculty of Sciences, Department of Mathematics, Çankırı, Turkey
gncmatematik@hotmail.com. *Correspondence: dr.huda-ismael@uotelafer.edu.iq University of New Mexico Neutrosophic SuperHyper Bi-Topological Spaces: Original
Notions and New Insights
Huda E. Khalid1* , Gonca D. GÜNGÖR2 , Muslim A. Noah Zainal3
1Telafer University, The Administration Assistant for the President of the Telafer University,
Telafer, Iraq. ; https://orcid.org/0000-0002-0968-5611 , dr.huda-ismael@uotelafer.edu.iq
2 Çankırı Karatekin University, Faculty of Sciences, Department of Mathematics, Çankırı, Turkey
gncmatematik@hotmail.com. 3 Çankırı Karatekin University, Faculty of Sciences, Department of Mathematics, MSc. Student, Çankırı,
Turky, moslmnooh1993@gmail.com
*Correspondence: dr.huda-ismael@uotelafer.edu.iq Neutrosophic SuperHyper Bi-Topological Spaces: Original
Notions and New Insights
Huda E. Khalid1* , Gonca D. GÜNGÖR2 , Muslim A. Noah Zainal3
1Telafer University, The Administration Assistant for the President of the Telafer University,
Telafer, Iraq. ; https://orcid.org/0000-0002-0968-5611 , dr.huda-ismael@uotelafer.edu.iq
2 Çankırı Karatekin University, Faculty of Sciences, Department of Mathematics, Çankırı, Turkey
gncmatematik@hotmail.com. 3 Çankırı Karatekin University, Faculty of Sciences, Department of Mathematics, MSc. Student, Çankırı,
Turky, moslmnooh1993@gmail.com
*Correspondence: dr.huda-ismael@uotelafer.edu.iq Huda E. Khalid, Gonca D. G., Muslim A. Noah Zainal ‘’ Neutrosophic SuperHyper Bi-Topological Spaces: Original Notions and Introduction. The concepts of the neutrosophic 𝑛𝑡ℎ-power set of a set, SuperHyperGraph and Pliothogenic
n-SuperHyperGraph, SuperHyperAlgebra, n-ary (classical-/Neutro-/Anti-) HyperAlgebra have been
firstly introduced by the father of neutrosophic theory F. Smarandache in 2016 [4]. As the
introduction for Neutrosophic SuperHyper Topological Spaces which is until yet is fathomless
branch of science, in this section we recalling the fundamental definitions of the neutrosophic logic
with preliminaries of related 𝑛𝑡ℎ-power set of a set. There is no doubt that the essential theory of
neutrosophic was introduced and built by F. Smarandache in 1995 [5,6]. Any mathematician who
tracking the trace of this knowledge will easily deduce that the neutrosophic theory was rapidly and
broadly radiated through Neutrosophic Sets and Systems journal, and International Journal of Huda E. Khalid, Gonca D. G., Muslim A. Noah Zainal ‘’ Neutrosophic SuperHyper Bi-Topological Spaces: Original Notions and New Insights’’ Neutrosophic Sets and Systems, Vol. 51, 2022 34 Neutrosophic Science, these two journals are very active and reputed journals indexed by dozens of
repositories, encyclopedias, and identifications' websites especially Scopus database. This manuscript has been organized as follow: Neutrosophic Science, these two journals are very active and reputed journals indexed by dozens of
repositories, encyclopedias, and identifications' websites especially Scopus database. This manuscript has been organized as follow: The authors present some basic preliminaries in section 1, while section 2 has been dedicated
to submit a new structure of neutrosophic topology called
Neutrosophic
SuperHyper
Topological Spaces, in this section and for the first time, this type of topology was discussed in details. The main core of this article is in section 3 which is contain definitions, theorems, and corollaries
covered the new subject that introduced firstly in this paper which is named Neutrosophic
SuperHyper Bi-Topological Spaces. The last section is the conclusion section. 1.1
System of Sub-System of Sub-Sub-System and so on [1] A system may be a set, space, organization, association, team, city, region, country, etc. One consider
both: the static and dynamic systems. With respect to various criteria, such as: political, religious, economic, military, educational, sportive,
touristic, industrial, agricultural, etc. A system 𝑆 is made up of several sub-systems 𝑆1, 𝑆2, … , 𝑆𝑝, for integer 𝑝≥1; then each su-system
𝑆𝑖, for 𝑖∈{1,2, … , 𝑝} is composed of many sub-sub-systems 𝑆𝑖1, 𝑆𝑖2, … , 𝑆𝑖𝑝𝑖, for integer 𝑝𝑖≥1; then
each sub-sub-systems 𝑆𝑖𝑗, for 𝑗∈{1,2, … , 𝑝𝑖} is composed sub-sub-sub-systems 𝑆𝑖𝑗1, 𝑆𝑖𝑗2, … , 𝑆𝑖𝑗𝑝𝑗, for
integers 𝑝𝑗; and so on. The following example of systems made of Sub-Sub-Sub-Systems (four levels) The following example of systems made of Sub-Sub-Sub-Systems (four levels) Huda E. Khalid, Gonca D. G., Muslim A. Noah Zainal ‘’ Neutrosophic SuperHyper Bi-Topological Spaces: Original Notions
The following example of systems made of Sub Sub Sub Systems (four levels)
i)
Using a Tree-Graph Representation, one has:
Level 1
Level 2
Level 3
Level 4
𝑆
𝑆1
𝑆2
𝑆3
𝑆11
𝑆12
𝑆13
𝑆121
𝑆122
𝑆21
𝑆22 i)
Using a Tree-Graph Representation, one has: Level 3 Level 4 Huda E. Khalid, Gonca D. G., Muslim A. Noah Zainal ‘’ Neutrosophic SuperHyper Bi-Topological Spaces: Original Notions and New Insights’’ Neutrosophic Sets and Systems, Vol. 51, 2022 35 Khalid, Gonca D. G., Muslim A. Noah Zainal ‘’ Neutrosophic SuperHyper Bi-Topological Spaces: Original Notions and
ii)
Using a Geometric Representation, one has:
iii)
Using an Algebraic Representation through pairs of braces {}, one has:
𝑃0(𝑆) = 𝑆= {𝑎, 𝑏, 𝑐, 𝑑, 𝑒, 𝑓, 𝑔, ℎ, 𝑙}
1 level of pairs of braces
Level 1
𝑃1(𝑆) = {{𝑎, 𝑏, 𝑐, 𝑑, 𝑒}, {𝑓, 𝑔, ℎ}, {𝑙}}
2 level of pairs of braces
i.e. 1.1
System of Sub-System of Sub-Sub-System and so on [1] a pair of braces {} inside, another
pair of braces {}, or {… {…} ...}
2 level of closed curves
Level 2
𝑃2(𝑆) = 𝑃(𝑃(𝑆))
= {{{𝑎}, {𝑏, 𝑐, 𝑑}, {𝑒}}, {{𝑓}, {𝑔, ℎ}}, {𝑙}}
3 levels of pairs of braces
3 level of closed curves
Level 3
𝑃3(𝑆) = 𝑃(𝑃2(𝑆))
= {{{𝑎}, {𝑏, 𝑐}, {𝑑}, {𝑒}}, {{𝑓}, {𝑔, ℎ}}, {𝑙}}
4 levels of pairs of braces
4 level of closed curves
Level 4
𝑆2
𝑆
𝑆1
a b c d e f g h i
a b c d
e
f g h
i
i
b c d
a
e
f
g h
i
a
e
f
g h
bc
d ii)
Using a Geometric Representation, one has:
𝑆2
𝑆
𝑆1 3 level of closed curves 4 level of closed curves
Level 4
i
a
e
f
g h
bc
d Huda E. Khalid, Gonca D. G., Muslim A. Noah Zainal ‘’ Neutrosophic SuperHyper Bi-Topological Spaces: Original Notions and New Insights’’ Neutrosophic Sets and Systems, Vol. 51, 2022 36 36 1.3
Example Suppose that the set of the grandparents represents the power set 𝑃2(𝑆) = 𝑃(𝑃(𝑆)), then the first
offspring is the parents themselves which can be regarded as the power set 𝑃(𝑆), and the second
offspring is the non-empty set 𝑃0(𝑆) = 𝑆, i.e. 𝑆= 𝑃0(𝑆) ⊂𝑃1(𝑆) ⊂𝑃2(𝑆). The following medical case study would be appropriate to demonstrate the importance of the power
set concept: Suppose that the set of the grandparents represents the power set 𝑃2(𝑆) = 𝑃(𝑃(𝑆)), then the first
offspring is the parents themselves which can be regarded as the power set 𝑃(𝑆), and the second
offspring is the non-empty set 𝑃0(𝑆) = 𝑆, i.e. 𝑆= 𝑃0(𝑆) ⊂𝑃1(𝑆) ⊂𝑃2(𝑆). offspring is the non empty set 𝑃(𝑆)
𝑆, i.e. 𝑆
𝑃(𝑆)
𝑃(𝑆)
𝑃(𝑆). The following medical case study would be appropriate to demonstrate the importance of the power
set concept: There are many diseases and conditions that can be passed on through genes. Some of these
diseases include Down syndrome, hemophilia, hypertension, sickle cell anemia, and cystic fibrosis. Most genetic diseases are a combination of mutations in multiple genes, often in combination with
environmental
factors. There
are three groups
of
genetic diseases, each
with their own
causes: monogenetic diseases, multifactorial inherited diseases, and chromosomal abnormalities. The couple of husband can be represented as PowerSet 𝑃(𝑆) , it is important to
know what 𝑃(𝑆) have inherited a genetic disease from their parents (i.e. represented the non-empty
set 𝑃0(𝑆) = 𝑆 as grandparents) and to remember that the above mentioned genetic diseases can
be passed on to their descendants (i.e. the offspring which is mathematically denoted by the power
set 𝑃2(𝑆) = 𝑃(𝑃(𝑆)) . If 𝑆 & 𝑃(𝑆) are aware of possible diseases that can be inherited to 𝑃(𝑆)&
𝑃2(𝑆) respectively , contact a specialist and see what 𝑆 & 𝑃(𝑆) can do to help 𝑃(𝑆)& 𝑃2(𝑆) and avoid
serious problems later. By working together with the help of family and doctor, the health risks can
be avoided instead of taking their toll later. 1.2
Definition of nth -Power of a set [1]: The 𝑛𝑡ℎ -Power of a set was firstly introduced by F. Smarandache at (2016) [4] by:
𝑃𝑛(𝑆) as the 𝑛𝑡ℎ -PowerSet of the set 𝑆, for integer 𝑛≥1, is recursively defined as:
𝑃2(𝑆) = 𝑃(𝑃(𝑆)) , 𝑃3(S) = 𝑃(𝑃(𝑃(𝑆))), …, 𝑃𝑛(𝑆) = 𝑃(𝑃𝑛−1(𝑆)) , where 𝑃0(𝑆) = 𝑆, 𝑎𝑛𝑑 𝑃1(𝑆) =
𝑃(𝑆), i.e. 𝑃0(𝑆) ⊂𝑃1(𝑆) ⊂𝑃2(𝑆) ⊂⋯⊂𝑃𝑛−1(𝑆) ⊂𝑃𝑛(𝑆). Power of a set was firstly introduced by F. Smarandache at (2016) [4] by: The 𝑛𝑡ℎ -PowerSet of a Set is better reflect for our complex reality, since a set 𝑆 ( that may represent
a group, a society, a country, a continent, etc.) of elements (such as: people, objects, and in general
any items) is organized onto subsets 𝑃(𝑆), which on their turns are also organized onto subsets of
subsets, and so on, that is our world. 1.4.2 #𝑚: 𝐻𝑚→𝑃(𝐻), for integer 𝑚≥1. Similarly, for 𝑚= 1 one gets a Neutrosophic
Unary HyperOperation. 2. Neutrosophic SuperHyper Topological Spaces This section gives an original creativity neutrosophic mathematical structure for new notion
named as Neutrosophic SuperHyper Topological Spaces (NSHTS) defined under a new kind of sets
called neutrosophic 𝑛𝑡ℎ-power set 𝑃𝑛(𝑋). 1.4
Neutrosophic HyperOperation and Neutrosophic HyperStructures
[2]: In the classical HyperOperation and classical HyperStructures, the empty-set ∅ does not belong
to the power set, (i.e. 𝑃∗(𝐻) = 𝑃(𝐻)/{∅}) . Nonetheless, in the real world we encounter many
situations when HyperOperation # is indeterminate, for example 𝑎 # 𝑏= ∅ ( unknown, or
undefined), or partially indeterminate, for example: 𝑎 # 𝑏= { [0.2, 0.3], ∅}. In our everyday life, there a E. Khalid, Gonca D. G., Muslim A. Noah Zainal ‘’ Neutrosophic SuperHyper Bi-Topological Spaces: Original Notions and New Insights’’ Neutrosophic Sets and Systems, Vol. 51, 2022 37 are many more operations and lows that have some degrees of indeterminacy (vagueness,
unclearness, unknowingness, contradiction, etc.), than those that are totally determined. That’s why
in 2016 the scientists F. Smarandache have extended the classical HyperOperation to the
Neutrosophic HyperOperation, by taking the whole power 𝑃(𝐻) ( that includes the empty-set ∅ as
well), instead of . 𝑃∗(𝐻)(that does not include the empty-set ∅), as follow. 1.4.1
Definition of Neutrosophic HyperOperation:
Let 𝑈 be a universe of discourse and 𝐻 be a non-empty set, 𝐻⊂𝑈. A Neutrosophic Binary HyperOperation #2 is defined as follows:
#2: 𝐻2 →𝑃(𝐻), where 𝐻 is a discrete or continuous set, and 𝑃(𝐻) is the powerset of
𝐻 that includes the empty-set ∅. 1.4.1 1.4.2
A Neutrosophic m-ary HyperOperation #𝒎 is defined as:
#𝑚: 𝐻𝑚→𝑃(𝐻), for integer 𝑚≥1. Similarly, for 𝑚= 1 one gets a Neutrosophic
Unary HyperOperation. 1.4.2
A Neutrosophic m-ary HyperOperation #𝒎 is defined as:
#𝑚: 𝐻𝑚→𝑃(𝐻), for integer 𝑚≥1. Similarly, for 𝑚= 1 one gets a Neutrosophic
Unary HyperOperation. 2.1 Definition Let 𝑋 be a non-empty set, 𝑃𝑛(𝑋) is the neutrosophic 𝑛𝑡ℎ-power set of a set 𝑋, for integer 𝑛≥1. A
Neutrosophic SuperHyper Topological space on 𝑃𝑛(𝑋) is a subfamily 𝜏𝑛𝑒𝑢𝑡𝑟𝑜𝑡𝑜𝑝𝑜 of 𝑁(𝑃𝑛(𝑋)), and
satisfying the following axioms: 1- The neutrosophic universal 𝑛𝑡ℎ-power set 1𝑃𝑛(𝑋) ,and the neutrosophic empty 𝑛𝑡ℎ-
power set 0𝑃𝑛(𝑋) both are belonging to 𝜏𝑛𝑒𝑢𝑡𝑟𝑜𝑡𝑜𝑝𝑜. 2- Any arbitrary (finite on infinite) union of members of 𝜏𝑛𝑒𝑢𝑡𝑟𝑜𝑡𝑜𝑝𝑜 belong to 𝜏𝑛𝑒𝑢𝑡𝑟𝑜𝑡𝑜𝑝𝑜. 3- 𝜏𝑛𝑒𝑢𝑡𝑟𝑜𝑡𝑜𝑝𝑜 is closed under finite intersection of members of 𝜏𝑛𝑒𝑢𝑡𝑟𝑜𝑡𝑜𝑝𝑜 (i.e. the
intersection of any finite number of members of 𝜏𝑛𝑒𝑢𝑡𝑟𝑜𝑡𝑜𝑝𝑜 belongs to 𝜏𝑛𝑒𝑢𝑡𝑟𝑜𝑡𝑜𝑝𝑜 ). Then (𝜏𝑛𝑒𝑢𝑡𝑟𝑜𝑡𝑜𝑝𝑜, 𝑃𝑛(𝑋)) is called Neutrosophic SuperHyper Topological Spaces (NSHTS). Because
of the definition of (NSHTS) via neutrosophic 𝑛𝑡ℎ-power open sets that commonly used in this
manuscript, the family of neutrosophic sets 𝜏𝑛𝑒𝑢𝑡𝑟𝑜𝑡𝑜𝑝𝑜 of the 𝑛𝑡ℎ-power sets are commonly called a
(NSHTS) on the neutrosophic 𝑛𝑡ℎ-power sets 𝑃𝑛(𝑋). Then (𝜏𝑛𝑒𝑢𝑡𝑟𝑜𝑡𝑜𝑝𝑜, 𝑃𝑛(𝑋)) is called Neutrosophic SuperHyper Topological Spaces (NSHTS). Because
of the definition of (NSHTS) via neutrosophic 𝑛𝑡ℎ-power open sets that commonly used in this
manuscript, the family of neutrosophic sets 𝜏𝑛𝑒𝑢𝑡𝑟𝑜𝑡𝑜𝑝𝑜 of the 𝑛𝑡ℎ-power sets are commonly called a
(NSHTS) on the neutrosophic 𝑛𝑡ℎ-power sets 𝑃𝑛(𝑋). a E. Khalid, Gonca D. G., Muslim A. Noah Zainal ‘’ Neutrosophic SuperHyper Bi-Topological Spaces: Original Notions and New Insights’’ Neutrosophic Sets and Systems, Vol. 51, 2022 38 A subpowerset 𝑃𝑚1(𝐶) ⊆𝑃𝑚2(𝑋) for integers 𝑚1 ≤𝑚2 is to be closed in (𝜏𝑛𝑒𝑢𝑡𝑟𝑜𝑡𝑜𝑝𝑜, 𝑃𝑛(𝑋)) if its
complement 𝑃𝑚2(𝑋)/𝑃𝑚1(𝐶) is an open set. A subpowerset 𝑃𝑚1(𝐶) ⊆𝑃𝑚2(𝑋) for integers 𝑚1 ≤𝑚2 is to be closed in (𝜏𝑛𝑒𝑢𝑡𝑟𝑜𝑡𝑜𝑝𝑜, 𝑃𝑛(𝑋)) if its
complement 𝑃𝑚2(𝑋)/𝑃𝑚1(𝐶) is an open set. 2.2 Numerical Example: What is the difference between 𝑃1(𝑥) & 𝑃2(𝑥) in the structured of the Neutrosophic SuperHyper
topological spaces (𝜏𝑛𝑒𝑢𝑡𝑟𝑜𝑡𝑜𝑝𝑜, 𝑃𝑛(𝑋)), and how it effects on the distribution of the internal elements? take a look on the following example: Suppose 𝑋= {𝑎, 𝑏, 𝑐} with the following Suppose 𝑋= {𝑎, 𝑏, 𝑐} with the following 𝑃1(𝑥) = {{𝑎, 𝑇= 0.3, 𝐼= 0.1, 𝐹= 0.6}, {𝑏, 𝑐}
𝑇= {0.7,0.4}
𝐼= {0,0.3}
𝐹= {0.4,0.3}
}, 𝑃2(𝑥) = {{𝑎, 𝑇= 0.3, 𝐼= 0.1, 𝐹= 0.6}, {{𝑏}, {𝑐}}
𝑇= {{0.7}, {0.4}}
𝐼= {{0}, {0.3}}
𝐹= {{0.4}, {0.3}}
}. For more details, we can see that In 𝑃1(𝑥) the element 𝑎 affected by its membership functions
{0.3, 0.1, 0.6} directly, while the element(s) {𝑏, 𝑐} has (have) two kinds of affected (directed affect)
and (indirect affect) as follow: -
The element b has a separate direct affect by its membership functions {0.7,0,0.4}, and -
The element b has a separate direct affect by its membership functions {0.7,0,0.4}, and
the element 𝑐 has a separate direct affect by its membership functions {0.4,0.3,0.3}. the element 𝑐 has a separate direct affect by its membership functions {0.4,0.3,0.3}. -
The structured element {𝑏, 𝑐} have common indirect affected by their membership
functions {0.7,0.4}, {0,0.3}, {0.4,0.3}. This is a very harmonic with the previous example (1.3) stated in section one, by expressing
the elements 𝑎, 𝑏 as the parents (husband and wife), each one of them can affected separately by the
inherited genes from their parents, also, they will crossing their parents’ gene to their offspring
mutually and their descendants will be affected directly by their parents and indirectly by their
grandparents. Then (𝜏𝑛𝑒𝑢𝑡𝑟𝑜𝑡𝑜𝑝𝑜, 𝑃𝑛(𝑋)) is the Neutrosophic SuperHyper Topological spaces, where: 𝜏𝑛𝑒𝑢𝑡𝑟𝑜𝑡𝑜𝑝𝑜= {0𝑃𝑛(𝑋), 1𝑃𝑛(𝑋), 𝑃1(𝑥), 𝑃2(𝑥)} 2.4 Definition The following mathematical phrases are true for any two neutrosophic 𝑛1𝑡ℎ-power set
𝑃𝑛1(𝑌1) and 𝑛2𝑡ℎ-power set 𝑃𝑛2(𝑌2) on the neutrosophic 𝑛𝑡ℎ-power set 𝑃𝑛(𝑋) , given that
𝑛1 𝑛2 ≤𝑛and that there is no restrictions on the relation between 𝑛𝑎𝑛𝑑𝑛
: 𝑛1, 𝑛2 ≤𝑛, and that there is no restrictions on the relation between 𝑛1 𝑎𝑛𝑑 𝑛2 : 1- 𝑇𝑃𝑛1(𝑌1)({𝑥}) ≤𝑇𝑃𝑛2(𝑌2)({𝑥}), 𝐼𝑃𝑛1(𝑌1)({𝑥}) ≤𝐼𝑃𝑛2(𝑌2)({𝑥}), 𝑎𝑛𝑑 𝐹𝑃𝑛1(𝑌1)({𝑥}) ≥
𝐹𝑃𝑛2(𝑌2)({𝑥}), for integers 𝑛1, 𝑛2 ≥1, and for all {𝑥} ⊆𝑃𝑛(𝑋) iff 𝑃𝑛1(𝑌1) ⊆𝑃𝑛2(𝑌2). 𝐹𝑃𝑛2(𝑌2)({𝑥}), for integers 𝑛1, 𝑛2 ≥1, and for all {𝑥} ⊆𝑃𝑛(𝑋) iff 𝑃𝑛1(𝑌1) ⊆𝑃𝑛2(𝑌2). 2- 𝑃𝑛1(𝑌1) ⊆𝑃𝑛2(𝑌2) and 𝑃𝑛2(𝑌2) ⊆𝑃𝑛1(𝑌1) iff 𝑃𝑛1(𝑌1) = 𝑃𝑛2(𝑌2), given that 𝑛1 = 𝑛2. {〈{𝑥}, min{𝑇𝑃𝑛1(𝑌1)({𝑥}), 𝑇𝑃𝑛2(𝑌2)({𝑥})} , min{ 𝐼𝑃𝑛1(𝑌1)({𝑥}), 𝐼𝑃𝑛2(𝑌2)({𝑥})}, max{𝐹𝑃𝑛1(𝑌1)({𝑥}), 𝐹𝑃𝑛2(𝑌2)({𝑥})}〉
∶{𝑥} ⊆𝑃𝑛(𝑋)} ( )}
4- 𝑃𝑛1(𝑌1) ∪𝑃𝑛2(𝑌2) = 4- 𝑃𝑛1(𝑌1) ∪𝑃𝑛2(𝑌2) =
{〈{𝑥}, max{𝑇𝑃𝑛1(𝑌1)({𝑥}), 𝑇𝑃𝑛2(𝑌2)({𝑥})} , max{ 𝐼𝑃𝑛1(𝑌1)({𝑥}), 𝐼𝑃𝑛2(𝑌2)({𝑥})}, min{𝐹𝑃𝑛1(𝑌1)({𝑥}), 𝐹𝑃𝑛2(𝑌2)({𝑥})}〉
∶{𝑥} ⊆𝑃𝑛(𝑋)} {〈{𝑥}, max{𝑇𝑃𝑛1(𝑌1)({𝑥}), 𝑇𝑃𝑛2(𝑌2)({𝑥})} , max{ 𝐼𝑃𝑛1(𝑌1)({𝑥}), 𝐼𝑃𝑛2(𝑌2)({𝑥})}, min{𝐹𝑃𝑛1(𝑌1)({𝑥}), 𝐹𝑃𝑛2(𝑌2)({𝑥})}〉
∶{𝑥} ⊆𝑃𝑛(𝑋)} In general, the union or the intersection of any arbitrary members of neutrosophic 𝑛𝑡ℎ-power set
𝑃𝑛𝑖(𝑋)𝑖∈𝐼 are defined by: In general, the union or the intersection of any arbitrary members of neutrosophic 𝑛𝑡ℎ-power set
𝑃𝑛𝑖(𝑋)𝑖∈𝐼 are defined by: In general, the union or the intersection of any arbitrary members of neutrosophic 𝑛𝑡ℎ-power set
𝑃𝑛𝑖(𝑋)𝑖∈𝐼 are defined by: ∩
𝑖∈𝐼𝑃𝑛𝑖(𝑋) = {〈{𝑥}, inf {𝑇𝑃𝑛𝑖({𝑥})} , inf {𝐼𝑃𝑛𝑖({𝑥})} , sup {𝐹𝑃𝑛𝑖({𝑥})}〉: {𝑥} ⊆𝑃𝑛(𝑋)},
∪
𝑖∈𝐼𝑃𝑛𝑖(𝑋) = {〈{𝑥}, sup {𝑇𝑃𝑛𝑖({𝑥})} , sup {𝐼𝑃𝑛𝑖({𝑥})} , inf {𝐹𝑃𝑛𝑖({𝑥})}〉: {𝑥} ⊆𝑃𝑛(𝑋)}. 5- The neutrosophic 𝑛𝑡ℎ-power universal set 𝑃𝑛(𝑋) is denoted by 1𝑃𝑛(𝑋) ,and it is exist if
and only if the following conditions are holding together:
𝑇𝑃𝑛({𝑥}) = 1𝑃𝑛(𝑋), 𝐼𝑃𝑛({𝑥}) = 1𝑃𝑛(𝑋), 𝑎𝑛𝑑 𝐹𝑃𝑛({𝑥}) = 0𝑃𝑛(𝑋). 5- The neutrosophic 𝑛𝑡ℎ-power universal set 𝑃𝑛(𝑋) is denoted by 1𝑃𝑛(𝑋) ,and it is exist if
and only if the following conditions are holding together: 6- The neutrosophic 𝑛𝑡ℎ-power empty set 𝑃𝑛(𝑋) is denoted by 0𝑃𝑛(𝑋) , and it is exist if
and only if the following conditions are holding together: 6- The neutrosophic 𝑛𝑡ℎ-power empty set 𝑃𝑛(𝑋) is denoted by 0𝑃𝑛(𝑋) , and it is exist if
and only if the following conditions are holding together:
𝑇𝑃𝑛({𝑥}) = 0𝑃𝑛(𝑋), 𝐼𝑃𝑛({𝑥}) = 0𝑃𝑛(𝑋), 𝑎𝑛𝑑 𝐹𝑃𝑛({𝑥}) = 1𝑃𝑛(𝑋). 7- Let 𝑃𝑛1(𝑌1) ⊆𝑃𝑛2(𝑌2) , given that 𝑛1 ≤𝑛2 , then the complementary of 𝑃𝑛1(𝑌1)
concerning to 𝑃𝑛2(𝑌2) is defined as follow:
𝑃𝑛1(𝑌1) ∖𝑃𝑛2(𝑌2) = {〈|𝑇𝑃𝑛1(𝑌1)({𝑥}) −𝑇𝑃𝑛2(𝑌2)({𝑥})|, |𝐼𝑃𝑛1(𝑌1)({𝑥}) −
𝐼𝑃𝑛2(𝑌2)({𝑥})|, 1𝑃𝑛(𝑋) −|𝐹𝑃𝑛1(𝑌1)({𝑥}) −𝐹𝑃𝑛2(𝑌2)({𝑥})|〉}. 2.3 Definition Let 𝑃𝑛(𝑋) be a neutrosophic 𝑛𝑡ℎ-power set over a non-empty set 𝑋, the neutrosophic interior and
the neutrosophic closure of 𝑃𝑛(𝑋) are respectively defined as:
𝑖𝑛𝑡𝑛( 𝑃𝑛(𝑋)) =∪{𝑃𝑚(𝑋): 𝑃𝑚(𝑋) ⊆𝑃𝑛(𝑋), 𝑃𝑚(𝑋) ∈𝜏𝑛𝑒𝑢𝑡𝑟𝑜𝑡𝑜𝑝𝑜} , this means that for the same Let 𝑃𝑛(𝑋) be a neutrosophic 𝑛𝑡ℎ-power set over a non-empty set 𝑋, the neutrosophic interior and
the neutrosophic closure of 𝑃𝑛(𝑋) are respectively defined as:
𝑖𝑛𝑡𝑛( 𝑃𝑛(𝑋)) =∪{𝑃𝑚(𝑋): 𝑃𝑚(𝑋) ⊆𝑃𝑛(𝑋), 𝑃𝑚(𝑋) ∈𝜏𝑛𝑒𝑢𝑡𝑟𝑜𝑡𝑜𝑝𝑜} , this means that for the same
collection of the neutrosophic 𝑛𝑡ℎ-power set 𝑃𝑛(𝑋) , all 𝑃𝑚(𝑋) given that 𝑚≤𝑛 regarded as
interior for 𝑃𝑛(𝑋). a E. Khalid, Gonca D. G., Muslim A. Noah Zainal ‘’ Neutrosophic SuperHyper Bi-Topological Spaces: Original Notions and New Insights’’ Neutrosophic Sets and Systems, Vol. 51, 2022 39 𝑐𝑙𝑛(𝑃𝑛(𝑋)) =∩{𝑃ℎ(𝑋): 𝑃𝑛(𝑋) ⊆𝑃ℎ(𝑋), (𝑃ℎ(𝑋))𝑐∈𝜏𝑛𝑒𝑢𝑡𝑟𝑜𝑡𝑜𝑝𝑜}. 2.8 Definition A sub-collection 𝜏𝑛
∗ of neutrosophic 𝑛𝑡ℎ- power set 𝑃𝑛(𝑋) on a non-empty set 𝑋 is said to be
Neutrosophic SuperHyper Supra Topological Space on 𝑋 if the 𝑛𝑡ℎ- power sets 0𝑃𝑛(𝑋), 1𝑃𝑛(𝑋) ∈𝜏𝑛
∗ ,
and
∞
∪𝑃𝑛𝑖(𝑋) ∈𝜏𝑛
∗
𝑖∈𝐼
for {𝑃𝑛𝑖(𝑋)}𝑖=1
∞
∈𝜏𝑛
∗ . Then (𝜏𝑛
∗, 𝑃𝑛(𝑋) ) is called Neutrosophic SuperHyper Supra Topological Space on 𝑋. 2.7 Definition Let 𝑃𝑛1(𝑋) ∈𝑁(𝑃𝑛(𝑋)), the belonging operation of the neutrosophic 𝑛𝑡ℎ- power point
𝑃𝑛(𝑥𝛼,𝛽,𝛾) to 𝑃𝑛1(𝑋) (i.e. 𝑃𝑛(𝑥𝛼,𝛽,𝛾) ∈𝑃𝑛1(𝑋) ) is satisfied if and only if 𝑇𝑃𝑛1({𝑥}) ≥𝛼, 𝐼𝑃𝑛1({𝑥}) ≥
𝛽, 𝐹𝑃𝑛1({𝑥}) ≤𝛾. 2.6 Definition Let 𝑋 be a non-empty set, 𝑃𝑛(𝑋) is the 𝑛𝑡ℎ-power neutrosophic set of a set 𝑋, for integer
𝑛≥1. If 𝛼, 𝛽, 𝛾 be real standard or non-standard subsets of ] 0
−, 1+ [ , then the neutrosophic 𝑛𝑡ℎ-
power set 𝑃𝑛(𝑥𝛼,𝛽,𝛾) is called a neutrosophic 𝑛𝑡ℎ- power point, and it is defined by:
𝑃𝑛(𝑥𝛼,𝛽,𝛾(𝑦)) = {
〈𝛼𝑃𝑛(𝑥), 𝛽𝑃𝑛(𝑥), 𝛾𝑃𝑛(𝑥)〉, 𝑖𝑓 𝑃𝑛(𝑥) = 𝑃𝑛(𝑦)
〈0𝑃𝑛(𝑥), 0𝑃𝑛(𝑥), 1𝑃𝑛(𝑥)〉, 𝑖𝑓 𝑃𝑛(𝑥) ≠𝑃𝑛(𝑦) For 𝑥, 𝑦 ∈𝑋, 𝑎𝑛𝑑 𝑃𝑛(𝑥𝛼,𝛽,𝛾), 𝑃𝑛(𝑦) ⊆𝑃𝑛(𝑋), here 𝑃𝑛(𝑦) is called the support of 𝑃𝑛(𝑥𝛼,𝛽,𝛾 For 𝑥, 𝑦 ∈𝑋, 𝑎𝑛𝑑 𝑃𝑛(𝑥𝛼,𝛽,𝛾), 𝑃𝑛(𝑦) ⊆𝑃𝑛(𝑋), here 𝑃𝑛(𝑦) is called the support of 𝑃𝑛(𝑥𝛼,𝛽,𝛾). 2.5 Proposition Let 𝑃𝑛1(𝑋), 𝑃𝑛2(𝑋), 𝑃𝑛3(𝑋), 𝑎𝑛𝑑 𝑃𝑛4(𝑋) ⊆𝑁(𝑃𝑛(𝑋)) without any restrictions on the
relations between 𝑛1, 𝑛2, 𝑛3, 𝑛4, 𝑎𝑛𝑑 𝑛 , then the following mathematical statements are true: i)
Let 𝑃𝑛1(𝑋) ⊆ 𝑃𝑛2(𝑋), 𝑎𝑛𝑑 𝑃𝑛3(𝑋) ⊆ 𝑃𝑛4(𝑋), given that 𝑛1 ≤𝑛2 , & 𝑛3 ≤𝑛4, this
implies that 𝑃𝑛1(𝑋) ∩ 𝑃𝑛3(𝑋) ⊆𝑃𝑛2(𝑋) ∩ 𝑃𝑛4(𝑋), iv)
(𝑃𝑛1(𝑋) ∪ 𝑃𝑛2(𝑋))𝑐= 𝑃𝑛1(𝑋)𝑐∩ 𝑃𝑛2(𝑋)𝑐. 2.4 Definition 8- Clearly, the neutrosophic complement of 1𝑃𝑛(𝑋) and 0𝑃𝑛(𝑋) are defined as: (1𝑃𝑛(𝑋))𝑐= 〈𝑇𝑃𝑛({𝑥}) = 0𝑃𝑛(𝑋), 𝐼𝑃𝑛({𝑥}) = 0𝑃𝑛(𝑋), 𝐹𝑃𝑛({𝑥}) = 1𝑃𝑛(𝑋)〉= 0𝑃𝑛(𝑋),
(0𝑃𝑛(𝑋))𝑐= 〈𝑇𝑃𝑛({𝑥}) = 1𝑃𝑛(𝑋), 𝐼𝑃𝑛({𝑥}) = 1𝑃𝑛(𝑋), 𝐹𝑃𝑛({𝑥}) = 0𝑃𝑛(𝑋)〉= 1𝑃𝑛(𝑋). a E. Khalid, Gonca D. G., Muslim A. Noah Zainal ‘’ Neutrosophic SuperHyper Bi-Topological Spaces: Original Notions and New Insights’’ Neutrosophic Sets and Systems, Vol. 51, 2022 40 40 3.3 Definition Let ( 𝜏1
1𝑠𝑡𝑝𝑎𝑖𝑟, 𝑃𝑛(𝑋)), 𝑎𝑛𝑑 (𝜏2
2𝑛𝑑𝑝𝑎𝑖𝑟, 𝑃𝑛(𝑋)) be two different Neutrosophic SuperHyper
topological spaces on 𝑋. Then (𝜏1
1𝑠𝑡𝑝𝑎𝑖𝑟, 𝜏2
2𝑛𝑑𝑝𝑎𝑖𝑟, 𝑃𝑛(𝑋)) is called Neutrosophic SuperHyper Bi-
Topological space (NSHBI-TS). 3 Neutrosophic SuperHyper Bi-Topological Spaces This section contains new concepts presents for the first time linking the concept of the
neutrosophic 𝑛𝑡ℎ- power sets with the traditional neutrosophic bi-topological spaces. Huda E. Khalid, Gonca D. G., Muslim A. Noah Zainal ‘’ Neutrosophic SuperHyper Bi-Topological Spaces: Original Notions and New Insights’’ Neutrosophic Sets and Systems, Vol. 51, 2022 41 41 3.4 Definition Let (𝜏1
1𝑠𝑡𝑝𝑎𝑖𝑟, 𝜏2
2𝑛𝑑𝑝𝑎𝑖𝑟, 𝑃𝑛(𝑋)) be a (NSHBI-TS). A collection of a neutrosophic 𝑛𝑡ℎ- power
set 𝑁= {〈{𝑥}: 𝑇𝑃𝑛({𝑥}), 𝐼𝑃𝑛({𝑥}), 𝐹𝑃𝑛({𝑥})〉: {𝑥} ⊆𝑃𝑛(𝑋)} over 𝑃𝑛(𝑋) is said to be a pairwise
neutrosophic 𝑛𝑡ℎ- power open set in (𝜏1
1𝑠𝑡𝑝𝑎𝑖𝑟, 𝜏2
2𝑛𝑑𝑝𝑎𝑖𝑟, 𝑃𝑛(𝑋)) if there exist a neutrosophic 𝑛𝑡ℎ-
power open set 𝑁1 = {〈{𝑥}: 𝑇𝑃𝑛1({𝑥}), 𝐼𝑃𝑛1({𝑥}), 𝐹𝑃𝑛1({𝑥})〉: {𝑥} ⊆𝑃𝑛(𝑋)} in 𝜏1
1𝑠𝑡𝑝𝑎𝑖𝑟and a neutrosophic
𝑛𝑡ℎ- power open set 𝑁2 = {〈{𝑥}: 𝑇𝑃𝑛2({𝑥}), 𝐼𝑃𝑛2({𝑥}), 𝐹𝑃𝑛2({𝑥})〉: {𝑥} ⊆𝑃𝑛(𝑋)} in 𝜏2
2𝑛𝑑𝑝𝑎𝑖𝑟 such that 𝑁=
𝑁1 ∪𝑁2 = {〈{𝑥}, 𝑇𝑃𝑛({𝑥}) = max{ 𝑇𝑃𝑛1({𝑥}), 𝑇𝑃𝑛2({𝑥})}, 𝐼𝑃𝑛({𝑥}) = max{𝐼𝑃𝑛1({𝑥}), 𝐼𝑃𝑛2({𝑥})}, 𝐹𝑃𝑛({𝑥}) =
min {𝐹𝑃𝑛1({𝑥}), 𝐹𝑃𝑛2({𝑥})}〉: {𝑥} ⊆𝑃𝑛(𝑋)}. 3.5 Definition Let (𝜏1
1𝑠𝑡𝑝𝑎𝑖𝑟, 𝜏2
2𝑛𝑑𝑝𝑎𝑖𝑟, 𝑃𝑛(𝑋)) be a (SHNBI-TS). A collection of a neutrosophic 𝑛𝑡ℎ- power
set 𝐶= {〈{𝑥}: 𝑇𝑃𝑐({𝑥}), 𝐼𝑃𝑐({𝑥}), 𝐹𝑃𝑐({𝑥})〉: {𝑥} ⊆𝑃𝑛(𝑋)} over 𝑃𝑛(𝑋) is said to be a pairwise neutrosophic
𝑛𝑡ℎ- power closed set in (𝜏1
1𝑠𝑡𝑝𝑎𝑖𝑟, 𝜏2
2𝑛𝑑𝑝𝑎𝑖𝑟, 𝑃𝑛(𝑋)) if its neutrosophic complement is a pairwise
neutrosophic 𝑛𝑡ℎ- power open set in (𝜏1
1𝑠𝑡𝑝𝑎𝑖𝑟, 𝜏2
2𝑛𝑑𝑝𝑎𝑖𝑟, 𝑃𝑛(𝑋)). Clearly, a neutrosophic 𝑛𝑡ℎ- power
set 𝐶 over 𝑃𝑛(𝑋) is a pairwise neutrosophic 𝑛𝑡ℎ- power closed set in (𝜏1
1𝑠𝑡𝑝𝑎𝑖𝑟, 𝜏2
2𝑛𝑑𝑝𝑎𝑖𝑟, 𝑃𝑛(𝑋))
if there exist a neutrosophic 𝑛𝑡ℎ- power closed set 𝐶1 = {〈{𝑥}: 𝑇𝑃𝑐1({𝑥}), 𝐼𝑃𝑐1({𝑥}), 𝐹𝑃𝑐1({𝑥})〉: {𝑥} ⊆𝑃𝑛(𝑋)}
in (𝜏1
1𝑠𝑡𝑝𝑎𝑖𝑟)𝑐 ,and a neutrosophic 𝑛𝑡ℎ- power closed set 𝐶2 = {〈{𝑥}: 𝑇𝑃𝑐2({𝑥}), 𝐼𝑃𝑐2({𝑥}), 𝐹𝑃𝑐2({𝑥})〉: {𝑥} ⊆
𝑃𝑛(𝑋)}
in
(𝜏2
2𝑛𝑑𝑝𝑎𝑖𝑟)𝑐
such
that
𝐶= 𝐶1 ∩𝐶2 = {〈{𝑥}, 𝑇𝑃𝑐({𝑥}) = min{ 𝑇𝑃𝑐1({𝑥}), 𝑇𝑃𝑐2({𝑥})},
𝐼𝑃𝑐({𝑥}) = min{𝐼𝑃𝑐1({𝑥}), 𝐼𝑃𝑐2({𝑥})}, 𝐹𝑃𝑐({𝑥}) = max {𝐹𝑃𝑐1({𝑥}), 𝐹𝑃𝑐2({𝑥})}〉: {𝑥} ⊆𝑃𝑛(𝑋)} . Where (𝜏𝑖
𝑖𝑝𝑎𝑖𝑟)𝑐=
{(𝑁)𝑐⊆𝑁(𝑃𝑛(𝑋)): 𝑁⊆𝜏𝑖
𝑖𝑝𝑎𝑖𝑟, 𝑖= 1𝑠𝑡, 2𝑛𝑑. The family of all pairwise neutrosophic 𝑛𝑡ℎ- power
open/closed
sets
in
(𝜏1
1𝑠𝑡𝑝𝑎𝑖𝑟, 𝜏2
2𝑛𝑑𝑝𝑎𝑖𝑟, 𝑃𝑛(𝑋))
is
denoted
by
PN
𝑛𝑡ℎ
POS
in
(𝜏1
1𝑠𝑡𝑝𝑎𝑖𝑟, 𝜏2
2𝑛𝑑𝑝𝑎𝑖𝑟, 𝑃𝑛(𝑋)) / PN𝑛𝑡ℎPCS in (𝜏1
1𝑠𝑡𝑝𝑎𝑖𝑟, 𝜏2
2𝑛𝑑𝑝𝑎𝑖𝑟, 𝑃𝑛(𝑋)), respectively. New Insights’’ 3. It is immediate from the definition (3.3). 3. It is immediate from the definition (3.3). 3.7 Corollary Let (𝜏1
1𝑠𝑡𝑝𝑎𝑖𝑟, 𝜏2
2𝑛𝑑𝑝𝑎𝑖𝑟, 𝑃𝑛(𝑋)) be Neutrosophic SuperHyper Bi-Topological space. Then, the family
of all pairwise neutrosophic 𝑛𝑡ℎ- power open sets is a Neutrosophic SuperHyper Supra Topological
Space (NSHSTS) on 𝑋. This (NSHSTS) is denoted by 𝜏12
𝑠𝑢𝑝𝑟𝑎. Proof: 1. Let 0𝑃𝑛1(𝑥), 0𝑃𝑛2(𝑥) ⊆ 𝜏1
1𝑠𝑡𝑝𝑎𝑖𝑟, 𝜏2
2𝑛𝑑𝑝𝑎𝑖𝑟 respectively, and 𝑛1 + 𝑛2 = 𝑛 ,
since 0𝑃𝑛1(𝑥)⋃0𝑃𝑛2(𝑥) = 0𝑃𝑛(𝑥) , hence 0𝑃𝑛(𝑥) is a PN 𝑛𝑡ℎPOS in
(𝜏1
1𝑠𝑡𝑝𝑎𝑖𝑟, 𝜏2
2𝑛𝑑𝑝𝑎𝑖𝑟, 𝑃𝑛(𝑋))
. Similarly,
1𝑃𝑛(𝑥)
is
a
PN
𝑛𝑡ℎ
PCS
in(𝜏1
1𝑠𝑡𝑝𝑎𝑖𝑟, 𝜏2
2𝑛𝑑𝑝𝑎𝑖𝑟, 𝑃𝑛(𝑋)). 2. Suppose
{𝑁𝑖= 〈{𝑥}: 𝑇𝑃𝑛𝑖({𝑥}), 𝐼𝑃𝑛𝑖({𝑥}), 𝐹𝑃𝑛𝑖({𝑥})〉: 𝑖∈𝐼} ⊆
PN𝑛𝑡ℎPOS in (𝜏1
1𝑠𝑡𝑝𝑎𝑖𝑟, 𝜏2
2𝑛𝑑𝑝𝑎𝑖𝑟, 𝑃𝑛(𝑋)). Then each 𝑁𝑖 is a pairwise
neutrosophic 𝑛𝑡ℎ power open set for all 𝑖∈𝐼 , this implies that there exist
𝑁𝑖
1 ∈𝜏1
1𝑠𝑡𝑝𝑎𝑖𝑟and 𝑁𝑖
2 ∈𝜏2
2𝑛𝑑𝑡𝑝𝑎𝑖𝑟 such that 𝑁𝑖= 𝑁𝑖
1 ∪𝑁𝑖
2 for all 𝑖∈𝐼
which implies that . ∪𝑁𝑖
𝑖∈𝐼=
∪
𝑖∈𝐼 [𝑁𝑖
1 ∪𝑁𝑖
2] = [∪𝑁𝑖
1
𝑖∈𝐼] ∪[∪𝑁𝑖
2
𝑖∈𝐼] Now, since 𝜏1
1𝑠𝑡𝑝𝑎𝑖𝑟 and 𝜏2
2𝑛𝑑𝑝𝑎𝑖𝑟 are both Neutrosophic SuperHyper
Topological Spaces on the neutrosophic 𝑛𝑡ℎ power set 𝑃𝑛(𝑋) , then
[∪𝑁𝑖
1
𝑖∈𝐼] ⊆𝜏1
1𝑠𝑡𝑝𝑎𝑖𝑟 , and [∪𝑁𝑖
2
𝑖∈𝐼] ⊆𝜏2
2𝑛𝑑𝑝𝑎𝑖𝑟 . Therefore, ∪𝑁𝑖
𝑖∈𝐼 is a pairwise
neutrosophic 𝑛𝑡ℎ- power open set. Now, since 𝜏1
1𝑠𝑡𝑝𝑎𝑖𝑟 and 𝜏2
2𝑛𝑑𝑝𝑎𝑖𝑟 are both Neutrosophic SuperHyper
Topological Spaces on the neutrosophic 𝑛𝑡ℎ power set 𝑃𝑛(𝑋) , then [∪𝑁𝑖
1
𝑖∈𝐼] ⊆𝜏1
1𝑠𝑡𝑝𝑎𝑖𝑟 , and [∪𝑁𝑖
2
𝑖∈𝐼] ⊆𝜏2
2𝑛𝑑𝑝𝑎𝑖𝑟 . Therefore, ∪𝑁𝑖
𝑖∈𝐼 is a pairwise neutrosophic 𝑛𝑡ℎ- power open set. neutrosophic 𝑛𝑡ℎ- power open set. 3.6 Theorem Let (𝜏1
1𝑠𝑡𝑝𝑎𝑖𝑟, 𝜏2
2𝑛𝑑𝑝𝑎𝑖𝑟, 𝑃𝑛(𝑋)) be Neutrosophic SuperHyper Bi-Topological space. Then, 𝜏2
2𝑛𝑑𝑝𝑎𝑖𝑟, 𝑃𝑛(𝑋)) be Neutrosophic SuperHyper Bi-Topological space. Then, 1. 0𝑃𝑛(𝑥), 𝑎𝑛𝑑 1𝑃𝑛(𝑥) are pairwise neutrosophic 𝑛𝑡ℎ- power open/closed sets. 2. An arbitrary neutrosophic union of pairwise neutrosophic 𝑛𝑡ℎ- power open sets
is a pairwise neutrosophic 𝑛𝑡ℎ- power open set. 3. An arbitrary neutrosophic intersection of pairwise neutrosophic 𝑛𝑡ℎ- power
closed sets is a pairwise neutrosophic 𝑛𝑡ℎ- power closed set. Huda E. Khalid, Gonca D. G., Muslim A. Noah Zainal ‘’ Neutrosophic SuperHyper Bi-Topological Spaces: Original No New Insights’’ Neutrosophic Sets and Systems, Vol. 51, 2022 42 3.8 Theorem Let (𝜏1
1𝑠𝑡𝑝𝑎𝑖𝑟, 𝜏2
2𝑛𝑑𝑝𝑎𝑖𝑟, 𝑃𝑛(𝑋)) be Neutrosophic SuperHyper Bi-Topological space. Then, Let (𝜏1
1𝑠𝑡𝑝𝑎𝑖𝑟, 𝜏2
2𝑛𝑑𝑝𝑎𝑖𝑟, 𝑃𝑛(𝑋)) be Neutrosophic SuperHyper Bi-Topological space. Then, 1. Every 𝜏1
1𝑠𝑡𝑝𝑎𝑖𝑟, 𝜏2
2𝑛𝑑𝑝𝑎𝑖𝑟- neutrosophic 𝑛𝑡ℎ- power open set is a pairwise
neutrosophic 𝑛𝑡ℎ- power open set, i.e. 𝜏1
1𝑠𝑡𝑝𝑎𝑖𝑟∪𝜏2
2𝑛𝑑𝑝𝑎𝑖𝑟⊆𝜏12
𝑠𝑢𝑝𝑟𝑎. 2. Every 𝜏1
1𝑠𝑡𝑝𝑎𝑖𝑟, 𝜏2
2𝑛𝑑𝑝𝑎𝑖𝑟- neutrosophic 𝑛𝑡ℎ- power closed set is a pairwise
neutrosophic 𝑛𝑡ℎ- power closed set, i.e. (𝜏1
1𝑠𝑡𝑝𝑎𝑖𝑟)𝑐∪(𝜏2
2𝑛𝑑𝑝𝑎𝑖𝑟)𝑐⊆(𝜏12
𝑠𝑢𝑝𝑟𝑎)𝑐. 3. If 𝜏1
1𝑠𝑡𝑝𝑎𝑖𝑟⊆𝜏2
2𝑛𝑑𝑝𝑎𝑖𝑟, then 𝜏12
𝑠𝑢𝑝𝑟𝑎= 𝜏2
2𝑛𝑑𝑝𝑎𝑖𝑟 and (𝜏12
𝑠𝑢𝑝𝑟𝑎)𝑐= (𝜏2
2𝑛𝑑𝑝𝑎𝑖𝑟)𝑐. 3.10 Theorem Let (𝜏1
1𝑠𝑡𝑝𝑎𝑖𝑟, 𝜏2
2𝑛𝑑𝑝𝑎𝑖𝑟, 𝑃𝑛(𝑋)) be Neutrosophic SuperHyper Bi-Topological space, and
𝑃𝑛1(𝑋), 𝑃𝑛2(𝑋) ∈𝑁(𝑃𝑛(𝑋)) , without restrictions on the relations between 𝑛1, 𝑛2, 𝑛. Then, the
following mathematical statements are true: 1. 𝑐𝑙𝑝
𝑛(0𝑃𝑛𝑖(𝑥)) = 0𝑃𝑛𝑖(𝑥), and 𝑐𝑙𝑝
𝑛(1𝑃𝑛𝑖(𝑥)) = 1𝑃𝑛𝑖(𝑥), 𝑖= 1,2. 1. 𝑐𝑙𝑝
𝑛(0𝑃𝑛𝑖(𝑥)) = 0𝑃𝑛𝑖(𝑥), and 𝑐𝑙𝑝
𝑛(1𝑃𝑛𝑖(𝑥)) = 1𝑃𝑛𝑖(𝑥), 𝑖= 1,2. 2. 𝑃𝑛(𝑋) ⊆𝑐𝑙𝑝
𝑛(𝑃𝑛(𝑋)). 3. 𝑃𝑛(𝑋) is a pairwise neutrosophic 𝑛𝑡ℎ- power closed set if and only if
𝑐𝑙𝑝
𝑛(𝑃𝑛(𝑋)) = 𝑃𝑛(𝑋) . 4. 𝑃𝑛1(𝑋) ⊆ 𝑃𝑛2(𝑋) ⟹ 𝑐𝑙𝑝
𝑛(𝑃𝑛1(𝑋)) ⊆ 𝑐𝑙𝑝
𝑛(𝑃𝑛2(𝑋)). 5. 𝑐𝑙𝑝
𝑛(𝑃𝑛1(𝑋)) ∪ 𝑐𝑙𝑝
𝑛(𝑃𝑛2(𝑋)) ⊆ 𝑐𝑙𝑝
𝑛(𝑃𝑛1(𝑋) ∪𝑃𝑛2(𝑋)). 6. 𝑐𝑙𝑝
𝑛 [ 𝑐𝑙𝑝
𝑛(𝑃𝑛𝑖(𝑋)] = 𝑐𝑙𝑝
𝑛(𝑃𝑛𝑖(𝑋), i.e., 𝑐𝑙𝑝
𝑛(𝑃𝑛𝑖(𝑋) is a pairwise neutrosophic 𝑛𝑡ℎ-
power closed set. 3.9 Definition Let (𝜏1
1𝑠𝑡𝑝𝑎𝑖𝑟, 𝜏2
2𝑛𝑑𝑝𝑎𝑖𝑟, 𝑃𝑛(𝑋)) be Neutrosophic SuperHyper Bi-Topological space, and
𝑃𝑛(𝑋) ∈𝑁(𝑃𝑛(𝑋)).The pairwise neutrosophic closure of 𝑃𝑛(𝑋), denoted by 𝑐𝑙𝑝
𝑛(𝑃𝑛(𝑋)) , is the
neutrosophic intersection of all pairwise neutrosophic closed supra 𝑛𝑡ℎ- power sets of 𝑃𝑛(𝑋), i.e.,
𝑐𝑙𝑝
𝑛(𝑃𝑛(𝑋)) =∩{𝑃𝑚(𝑋) ∈(𝜏12
𝑠𝑢𝑝𝑟𝑎)
𝑐: 𝑃𝑛(𝑋) ⊆𝑃𝑚(𝑋)} . It is clear that 𝑐𝑙𝑝
𝑛(𝑃𝑛(𝑋)) is the smallest
pairwise neutrosophic 𝑛𝑡ℎ- power closed set containing 𝑃𝑛(𝑋). Proof. Straightforward. Proof. Straightforward. Huda E. Khalid, Gonca D. G., Muslim A. Noah Zainal ‘’ Neutrosophic SuperHyper Bi-Topological Spaces: Original Notions and Huda E. Khalid, Gonca D. G., Muslim A. Noah Zainal ‘’ Neutrosophic SuperHyper Bi-Topological Spaces: Original New Insights’’ Neutrosophic Sets and Systems, Vol. 51, 2022 43 43 Proof. Straightforward.
3.11 Theorem Let (𝜏1
1𝑠𝑡𝑝𝑎𝑖𝑟, 𝜏2
2𝑛𝑑𝑝𝑎𝑖𝑟, 𝑃𝑛(𝑋)) be Neutrosophic SuperHyper Bi-Topological space, and 𝑃𝑛1(𝑋) ∈
𝑁(𝑃𝑛(𝑋)). Then, 𝑃𝑛1(𝑥𝛼,𝛽,𝛾) ∈𝑐𝑙𝑝
𝑛(𝑃𝑛1(𝑋)) ⟺𝑈(𝑃𝑛1(𝑥𝛼,𝛽,𝛾)) ∩𝑃𝑛1(𝑋) ≠0𝑃𝑛1(𝑥), ∀ 𝑈(𝑃𝑛1(𝑥𝛼,𝛽,𝛾)) ∈
𝜏12
𝑠𝑢𝑝𝑟𝑎(𝑃𝑛1(𝑥𝛼,𝛽,𝛾)), 𝑃𝑛1(𝑥𝛼,𝛽,𝛾) ∈𝑐𝑙𝑝
𝑛(𝑃𝑛1(𝑋)) ⟺𝑈(𝑃𝑛1(𝑥𝛼,𝛽,𝛾)) ∩𝑃𝑛1(𝑋) ≠0𝑃𝑛1(𝑥), ∀ 𝑈(𝑃𝑛1(𝑥𝛼,𝛽,𝛾)) ∈
𝜏12
𝑠𝑢𝑝𝑟𝑎(𝑃𝑛1(𝑥𝛼,𝛽,𝛾)), Where 𝑈(𝑃𝑛1(𝑥𝛼,𝛽,𝛾)) is any pairwise neutrosophic 𝑛𝑡ℎ- power open set contains 𝑃𝑛1(𝑥𝛼,𝛽,𝛾) , and
𝜏12
𝑠𝑢𝑝𝑟𝑎(𝑃𝑛1(𝑥𝛼,𝛽,𝛾)) is the family of all pairwise neutrosophic supra 𝑛𝑡ℎ- power open set contains
𝑃𝑛1(𝑥𝛼,𝛽,𝛾). Proof: Where 𝑈(𝑃𝑛1(𝑥𝛼,𝛽,𝛾)) is any pairwise neutrosophic 𝑛𝑡ℎ- power open set contains 𝑃𝑛1(𝑥𝛼,𝛽,𝛾) , and
𝜏12
𝑠𝑢𝑝𝑟𝑎(𝑃𝑛1(𝑥𝛼,𝛽,𝛾)) is the family of all pairwise neutrosophic supra 𝑛𝑡ℎ- power open set contains
𝑃𝑛1(𝑥𝛼,𝛽,𝛾). P
f Proof: Let 𝑃𝑛1(𝑥𝛼,𝛽,𝛾) ∈𝑐𝑙𝑝
𝑛(𝑃𝑛1(𝑋)), and suppose that there exist 𝑈(𝑃𝑛1(𝑥𝛼,𝛽,𝛾)) ∈𝜏12
𝑠𝑢𝑝𝑟𝑎(𝑃𝑛1(𝑥𝛼,𝛽,𝛾)),
such that 𝑈(𝑃𝑛1(𝑥𝛼,𝛽,𝛾)) ∩𝑃𝑛1(𝑋) = 0𝑃𝑛1(𝑥). Then 𝑃𝑛1(𝑋) ⊆( 𝑈(𝑃𝑛1(𝑥𝛼,𝛽,𝛾)))𝑐, thus 𝑐𝑙𝑝
𝑛(𝑃𝑛1(𝑋)) ⊆ Huda E. Khalid, Gonca D. G., Muslim A. Noah Zainal ‘’ Neutrosophic SuperHyper Bi-Topological Spaces: Original Notions and New Insights’’ New Insights’’ Neutrosophic Sets and Systems, Vol. 51, 2022 44 𝑐𝑙𝑝
𝑛(𝑈(𝑃𝑛1(𝑥𝛼,𝛽,𝛾)))
𝑐
= (𝑈(𝑃𝑛1(𝑥𝛼,𝛽,𝛾)))𝑐 which implies that 𝑐𝑙𝑝
𝑛(𝑃𝑛1(𝑋)) ∩ 𝑈(𝑃𝑛1(𝑥𝛼,𝛽,𝛾)) = 𝑐𝑙𝑝
𝑛(𝑈(𝑃𝑛1(𝑥𝛼,𝛽,𝛾)))
𝑐
= (𝑈(𝑃𝑛1(𝑥𝛼,𝛽,𝛾)))𝑐 which implies that 𝑐𝑙𝑝
𝑛(𝑃𝑛1(𝑋)) ∩ 𝑈(𝑃𝑛1(𝑥𝛼,𝛽,𝛾)) = 0𝑃𝑛1(𝑥) , this is a contradiction. hence 𝑈(𝑃𝑛1(𝑥𝛼,𝛽,𝛾)) ∩𝑃𝑛1(𝑋) ≠0𝑃𝑛1(𝑥). Conversely, assume that 𝑃𝑛1(𝑥𝛼,𝛽,𝛾) ∉𝑐𝑙𝑝
𝑛(𝑃𝑛1(𝑋)) , then 𝑃𝑛1(𝑥𝛼,𝛽,𝛾) ∈(𝑐𝑙𝑝
𝑛(𝑃𝑛1(𝑋)))𝑐. Thus,
(𝑐𝑙𝑝
𝑛(𝑃𝑛1(𝑋)))𝑐∈𝜏12
𝑠𝑢𝑝𝑟𝑎(𝑃𝑛1(𝑥𝛼,𝛽,𝛾)), therefore, by hypothesis, (𝑐𝑙𝑝
𝑛(𝑃𝑛1(𝑋)))𝑐∩𝑃𝑛1(𝑋) ≠0𝑃𝑛1(𝑥),
this is a contradiction. Hence we get 𝑃𝑛1(𝑥𝛼,𝛽,𝛾) ∈𝑐𝑙𝑝
𝑛(𝑃𝑛1(𝑋)). 3.12 Theorem Let (𝜏1
1𝑠𝑡𝑝𝑎𝑖𝑟, 𝜏2
2𝑛𝑑𝑝𝑎𝑖𝑟, 𝑃𝑛(𝑋)) be Neutrosophic SuperHyper Bi-Topological space. A
neutrosophic 𝑛𝑡ℎ- power set 𝑃𝑛1(𝑋) over 𝑃𝑛(𝑋) is a pairwise neutrosophic 𝑛𝑡ℎ- power closed set if
and only if 𝑃𝑛1(𝑋) = 𝑐𝑙𝜏11𝑠𝑡𝑝𝑎𝑖𝑟
𝑛
(𝑃𝑛1(𝑋)) ∩𝑐𝑙𝜏22𝑛𝑑𝑝𝑎𝑖𝑟
𝑛
(𝑃𝑛1(𝑋)). Proof: Suppose that 𝑃𝑛1(𝑋) is a pairwise neutrosophic 𝑛𝑡ℎ-power closed set and 𝑃𝑛1(𝑥𝛼,𝛽,𝛾) ∉
𝑃𝑛1(𝑋) . Then 𝑃𝑛1(𝑥𝛼,𝛽,𝛾) ∉𝑐𝑙𝑝
𝑛( 𝑃𝑛1(𝑋)) . Thus, by theorem (3.9), there exists 𝑈(𝑃𝑛1(𝑥𝛼,𝛽,𝛾)) ∈
𝜏12
𝑠𝑢𝑝𝑟𝑎(𝑃𝑛1(𝑥𝛼,𝛽,𝛾)) such that 𝑈(𝑃𝑛1(𝑥𝛼,𝛽,𝛾)) ∩𝑃𝑛1(𝑋) = 0𝑃𝑛1(𝑥) . Again, since 𝑈(𝑃𝑛1(𝑥𝛼,𝛽,𝛾)) ∈
𝜏12
𝑠𝑢𝑝𝑟𝑎(𝑃𝑛1(𝑥𝛼,𝛽,𝛾)) , then there exists 𝑃𝑚1(𝑋) ∈𝜏1
1𝑠𝑡𝑝𝑎𝑖𝑟 and 𝑃𝑚2(𝑋) ∈𝜏2
2𝑛𝑑𝑝𝑎𝑖𝑟 such that
𝑈(𝑃𝑛1(𝑥𝛼,𝛽,𝛾)) = 𝑃𝑚1(𝑋) ∪𝑃𝑚2(𝑋) . consequently, ( 𝑃𝑚1(𝑋) ∪𝑃𝑚2(𝑋)) ∩𝑃𝑛1(𝑋) = 0𝑃𝑛1(𝑥) , this
implies that 𝑃𝑚1(𝑋) ∩𝑃𝑛1(𝑋) = 0𝑃𝑛1(𝑥) , and 𝑃𝑚2(𝑋) ∩𝑃𝑛1(𝑋) = 0𝑃𝑛1(𝑥) . Since 𝑃𝑛1(𝑥𝛼,𝛽,𝛾) ∈
𝑈(𝑃𝑛1(𝑥𝛼,𝛽,𝛾)), then either 𝑃𝑛1(𝑥𝛼,𝛽,𝛾) ∈𝑃𝑚1(𝑋) or 𝑃𝑛1(𝑥𝛼,𝛽,𝛾) ∈𝑃𝑚2(𝑋), this implies that either
𝑃𝑛1(𝑥𝛼,𝛽,𝛾) ∉𝑐𝑙𝜏11𝑠𝑡𝑝𝑎𝑖𝑟
𝑛
(𝑃𝑛1(𝑋)) or
𝑃𝑛1(𝑥𝛼,𝛽,𝛾) ∉𝑐𝑙𝜏22𝑛𝑑𝑝𝑎𝑖𝑟
𝑛
(𝑃𝑛1(𝑋)) . Therefore,
𝑃𝑛1(𝑥𝛼,𝛽,𝛾) ∉
𝑐𝑙𝜏11𝑠𝑡𝑝𝑎𝑖𝑟
𝑛
(𝑃𝑛1(𝑋)) ∩𝑐𝑙𝜏22𝑛𝑑𝑝𝑎𝑖𝑟
𝑛
(𝑃𝑛1(𝑋)). Thus, 𝑐𝑙𝜏11𝑠𝑡𝑝𝑎𝑖𝑟
𝑛
(𝑃𝑛1(𝑋)) ∩𝑐𝑙𝜏22𝑛𝑑𝑝𝑎𝑖𝑟
𝑛
(𝑃𝑛1(𝑋)) ⊆𝑃𝑛1(𝑋). On
the other hand, we have 𝑃𝑛1(𝑋) ⊆𝑐𝑙𝜏11𝑠𝑡𝑝𝑎𝑖𝑟
𝑛
(𝑃𝑛1(𝑋)) ∩𝑐𝑙𝜏22𝑛𝑑𝑝𝑎𝑖𝑟
𝑛
(𝑃𝑛1(𝑋)) . Hence, 𝑃𝑛1(𝑋) =
𝑐𝑙𝜏11𝑠𝑡𝑝𝑎𝑖𝑟
𝑛
(𝑃𝑛1(𝑋)) ∩𝑐𝑙𝜏22𝑛𝑑𝑝𝑎𝑖𝑟
𝑛
(𝑃𝑛1(𝑋)). Conversely,
suppose
that
𝑃𝑛1(𝑋) = 𝑐𝑙𝜏11𝑠𝑡𝑝𝑎𝑖𝑟
𝑛
(𝑃𝑛1(𝑋)) ∩𝑐𝑙𝜏22𝑛𝑑𝑝𝑎𝑖𝑟
𝑛
(𝑃𝑛1(𝑋))
. Since,
𝑐𝑙𝜏11𝑠𝑡𝑝𝑎𝑖𝑟
𝑛
(𝑃𝑛1(𝑋)) is a neutrosophic
𝑛𝑡ℎ-power closed set in
(𝜏1
1𝑠𝑡𝑝𝑎𝑖𝑟, 𝑃𝑛(𝑋)) , and
𝑐𝑙𝜏22𝑛𝑑𝑝𝑎𝑖𝑟
𝑛
(𝑃𝑛1(𝑋)) is a neutrosophic 𝑛𝑡ℎ-power closed set in (𝜏2
2𝑛𝑑𝑝𝑎𝑖𝑟, 𝑃𝑛(𝑋)), so, by definition
(3.3), 𝑐𝑙𝜏11𝑠𝑡𝑝𝑎𝑖𝑟
𝑛
(𝑃𝑛1(𝑋)) ∩𝑐𝑙𝜏22𝑛𝑑𝑝𝑎𝑖𝑟
𝑛
(𝑃𝑛1(𝑋)) is a pairwise neutrosophic 𝑛𝑡ℎ- power closed set in
(𝜏1
1𝑠𝑡𝑝𝑎𝑖𝑟, 𝜏2
2𝑛𝑑𝑝𝑎𝑖𝑟, 𝑃𝑛(𝑋)), consequently, 𝑃𝑛1(𝑋) is a pairwise neutrosophic 𝑛𝑡ℎ- power closed set. 3.13 Corollary Let (𝜏1
1𝑠𝑡𝑝𝑎𝑖𝑟, 𝜏2
2𝑛𝑑𝑝𝑎𝑖𝑟, 𝑃𝑛(𝑋)) be Neutrosophic SuperHyper Bi-Topological space. Then, 𝑐𝑙𝑝
𝑛(𝑃𝑛(𝑋)) = 𝑐𝑙𝜏11𝑠𝑡𝑝𝑎𝑖𝑟
𝑛
(𝑃𝑛1(𝑋)) ∩𝑐𝑙𝜏22𝑛𝑑𝑝𝑎𝑖𝑟
𝑛
(𝑃𝑛1(𝑋)), ∀ 𝑃𝑛1(𝑋) ∈𝑁(𝑃𝑛(𝑋)). a E. Khalid, Gonca D. G., Muslim A. Noah Zainal ‘’ Neutrosophic SuperHyper Bi-Topological Spaces: Original Notions and New Insights’’ Neutrosophic Sets and Systems, Vol. 51, 2022 45 4 Conclusion The types of the topological spaces in neutrosophic theory are always changed
depending upon the structure of the sets, in this article, the Neutrosophic SuperHyper
Topological Spaces has been fathomed especially Neutrosophic SuperHyper Bi-Topological
Spaces. The definitions of the neutrosophic interior and the neutrosophic closure of 𝑃𝑛(𝑋)
have been presented. Also, the neutrosophic universal 𝑛𝑡ℎ-power set 𝑃𝑛(𝑋) and the
neutrosophic empty 𝑛𝑡ℎ-power set 𝑃𝑛(𝑋) were discussed. The union and the intersection
operations have been defined. As well as, the authors presented pairwise neutrosophic 𝑛𝑡ℎ-
power open set, pairwise neutrosophic closed 𝑛𝑡ℎ- power set, many of theorems,
propositions and examples to support the new notion. Huda E. Khalid, Gonca D. G., Muslim A. Noah Zainal ‘’ Neutrosophic SuperHyper Bi-Topological Spaces: Original Notions and References [1] F. Smarandache (2022). The SuperFunction and the Neutrosophic SuperHyperFunction. , Neutrosophic Set
and Systems, Vol 49.pp. 594-600. [1] F. Smarandache (2022). The SuperFunction and the Neutrosophic SuperHyperFunction. , Neutrosophic Set
and Systems, Vol 49.pp. 594-600. [2] F. Smarandache (2022). Introduction to SuperHyperAlgebra and Neutrosophic SuperHyperAlgebra , Journal
of Algebraic HyperStructures and Algebras, vol 3, No. 2 .pp. 17-24. [2] F. Smarandache (2022). Introduction to SuperHyperAlgebra and Neutrosophic SuperHyperAlgebra , Journal
of Algebraic HyperStructures and Algebras, vol 3, No. 2 .pp. 17-24. [3] F. Smarandache (2022). Introduction to n-SuperHyperGraph- the most general form of graph today,
Neutrosophic Set and Systems, vol 48.pp. 483-485. [3] F. Smarandache (2022). Introduction to n-SuperHyperGraph- the most general form of graph today,
Neutrosophic Set and Systems, vol 48.pp. 483-485. [4] F. Smarandache (2016), SuperHyperAlgebra and Neutrosophic SuperHyperAlgebra, Section into the authors
book Nidus Idearum. Scilogs, II: de rerum consectatione, second edition, Bruxelles: Pons, 107. [5] Ahmed B. AL-Nafee, Jamal K. Obeed, Huda E. Khalid (2021). Continuity and Compactness on Neutrosophic
Soft Bitopological Spaces, International Journal of Neutrosophic Science, Vol 16. No. 2, pp. 62-71. [6] C. Maheswari, M. Sathyabama & S. Chanderasekar (2018), Neutrosophic generalized b-closed sets in
Neutrosophic topological spaces. International conference on Applied and Computation Mathematics. IOP
Conf. Series: Journal of Physics 2018. Pp. 1-7. Received: June 15, 2022. Accepted: September 22, 2022 a E. Khalid, Gonca D. G., Muslim A. Noah Zainal ‘’ Neutrosophic SuperHyper Bi-Topological Spaces: Original Notions and New Insights’’ New Insights’’
|
https://openalex.org/W2114061213
|
https://europepmc.org/articles/pmc3116496?pdf=render
|
English
| null |
Respondent-driven sampling on the Thailand-Cambodia border. I. Can malaria cases be contained in mobile migrant workers?
|
Malaria journal
| 2,011
|
cc-by
| 8,178
|
Khamsiriwatchara et al. Malaria Journal 2011, 10:120
http://www.malariajournal.com/content/10/1/120 Open Access © 2011 Khamsiriwatchara et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited. Abstract Background: Reliable information on mobility patterns of migrants is a crucial part of the strategy to contain the
spread of artemisinin-resistant malaria parasites in South-East Asia, and may also be helpful to efforts to address
other public health problems for migrants and members of host communities. In order to limit the spread of
malarial drug resistance, the malaria prevention and control programme will need to devise strategies to reach
cross-border and mobile migrant populations. Methodology: The Respondent-driven sampling (RDS) method was used to survey migrant workers from
Cambodia and Myanmar, both registered and undocumented, in three Thai provinces on the Thailand-Cambodia
border in close proximity to areas with documented artemisinin-resistant malaria parasites. 1,719 participants (828
Cambodian and 891 Myanmar migrants) were recruited. Subpopulations of migrant workers were analysed using
the Thailand Ministry of Health classification based on length of residence in Thailand of greater than six months
(long-term, or M1) or less than six months (short-term, or M2). Key information collected on the structured
questionnaire included patterns of mobility and migration, demographic characteristics, treatment-seeking
behaviours, and knowledge, perceptions, and practices about malaria. Results: Workers from Cambodia came from provinces across Cambodia, and 22% of Cambodian M1 and 72% of
Cambodian M2 migrants had been in Cambodia in the last three months. Less than 6% returned with a frequency
of greater than once per month. Of migrants from Cambodia, 32% of M1 and 68% of M2 were planning to return,
and named provinces across Cambodia as their likely next destinations. Most workers from Myanmar came from
Mon state (86%), had never returned to Myanmar (85%), and only 4% stated plans to return. Conclusion: Information on migratory patterns of migrants from Myanmar and Cambodia along the malaria
endemic Thailand-Cambodian border within the artemisinin resistance containment zone will help target health
interventions, including treatment follow-up and surveillance. Myanmar and Cambodia still reveal provinces with a
high incidence of disease. Population movements along
the border areas often bring partially immune or non-
immune populations into close proximity to high trans-
mission forested areas, placing them at risk of acquiring
malaria. Population movements in these areas, together
with the high drug pressure, are considered responsible
for the development and spread of drug-resistant Plas-
modium falciparum [1,2]. In 2008, BVBD in collabora-
tion with the World Health Organization (WHO),
developed a programme for the containment of Respondent-driven sampling on the Thailand-
Cambodia border. I. Can malaria cases be
contained in mobile migrant workers? Amnat Khamsiriwatchara1, Piyaporn Wangroongsarb2, Julie Thwing3, James Eliades4, Wichai Satimai2,
Charles Delacollette4* and Jaranit Kaewkungwal1 * Correspondence: delacollettec@searo.who.int
4World Health Organization, Mekong Malaria Programme, c/o Faculty of
Tropical Medicine, Mahidol University; 420/6, Rajvithi Rd, Bangkok 10400,
Thailand
Full list of author information is available at the end of the article Background However, given the hidden
and mobile nature of these populations and the diffi-
culty in generating a sampling frame, traditional sam-
pling techniques such as cross sectional community-
based surveys or time-location sampling are unable to
produce an adequate and statistically valid sample. Respondent driven sampling (RDS) is a modified form
of chain-referral or snowball sampling that has been
used to sample hidden populations [9-12], and seeks to
overcome the biases in traditional snowball sampling. It
uses a structured system of incentives to encourage
recruitment by peers while limiting the number of indi-
viduals each participant can recruit, records the size of
each participant’s network to weight the sample, and
enables calculation of sampling error [9-11], thus allow-
ing for inferences about the characteristics of the popu-
lation from which the sample is drawn. Pre-survey focus
group discussions were held with migrants from Cam-
bodia and Myanmar to assess the feasibility of using
RDS. Discussions focused on migrants’ links to and rela-
tive size of social networks, willingness to participate,
and potential barriers to participation such as limitation
of local travel due to lack of transportation or poor
roads, a burdensome work schedule, or fear of authority
figures. There is substantial population movement across the
Thai-Cambodian border that is largely driven by eco-
nomics. Migrants from both Cambodia and Myanmar
settle for varying periods of time in Thailand, often in
search of work. The International Organization of
Migration (IOM) reported that Thailand has attracted
increasing numbers of migrant workers, mostly from
neighbouring countries with over one million registered
migrant workers entering the country since 2004 [7]. Channels for migration, in particular labour migration,
are defined by the policy of the destination country,
usually in response to the demand of domestic labour
markets for foreign workers. When the supply through
established channels does not match the demand, irre-
gular migration dynamics develop [8], and migrants
enter illegally and undocumented. While various govern-
ment ministries attempt to collect data on migrant
workers, they usually have information on the number
of registered migrants and those applying for work per-
mits, but little information on the unregistered migrants. The true size of the migrant worker population in Thai-
land, in particular of irregular migrants, is notoriously
difficult to quantify. Background In the past 50 years, the Bureau of Vector Borne Disease
(BVBD) of the Thailand Ministry of Public Health has
implemented an effective malaria prevention and control
programme in Thailand, resulting in large sections of
the country becoming malaria-free. However, surveil-
lance data along the endemic border areas with * Correspondence: delacollettec@searo.who.int
4World Health Organization, Mekong Malaria Programme, c/o Faculty of
Tropical Medicine, Mahidol University; 420/6, Rajvithi Rd, Bangkok 10400,
Thailand
Full list of author information is available at the end of the article Page 2 of 11 Khamsiriwatchara et al. Malaria Journal 2011, 10:120
http://www.malariajournal.com/content/10/1/120 counted among the M2. Migrants in Thailand account
for a higher proportion of cases than Thai citizens, espe-
cially among the M2 migrants [2]. Malaria surveillance
in undocumented migrants is challenging, and ensuring
treatment compliance and parasite clearance in an
environment in which increased parasite clearance times
need to be closely monitored is quite difficult in this
population. While undocumented and highly mobile
workers may receive diagnosis and treatment at malaria
clinics along the border areas free of charge, they are
often not followed up for compliance and parasite clear-
ance, as is the norm in the provinces targeted by the
containment project. Developing innovative strategies
for follow-up is critical to the containment effort. artemisinin-resistant P. falciparum malaria along the
Cambodia-Thailand border, funded by the Bill and
Melinda Gates Foundation (BMGF). It is anticipated
that the project will continue until mid-2011 [3], after
which extra funding from the Global Fund to Fight
AIDS, Tuberculosis, and Malaria Round 9 in Cambodia
and Round 10 in Thailand provides continued support
to containment activities [2]. A primary objective of the containment project is to
strengthen existing cross-sectoral and cross-border
efforts to ensure effective prevention and treatment of
malaria in migrant and mobile populations. Specific
strategies include examining in greater depth their pat-
terns of mobility, working with them to ensure better
access to health services, providing tailor-made preven-
tion tools and specific behaviour change and communi-
cation strategies, and attempting to incorporate them
into routine surveillance systems. Reliable information
regarding migrant movements, health status, and care-
seeking behaviour is crucial to the development of pre-
vention and control measures along the border areas
[4-6]. Little is known about migratory patterns along the
Thailand-Cambodia border. Recruitment The study staff members were health care workers in the
study areas and were trained on RDS methodology. After
preliminary interviews with the migrants in the commu-
nities, the staff selected six seeds per site for a total of 30
seeds, with a goal of reaching the sample size needed in
approximately two months. These seeds were given three Background RDS starts with purposeful selection of a few members
of the target population, or “seeds”, who are selected
based on: (1) diversity of demographic and geographic
factors; (2) diversity on key outcome variables; and (3)
commitment to the goals of the study [12]. Each partici-
pant receives an incentive for participating, and a preset
number of coupons with which to recruit peers. The
recruiter then receives a secondary incentive for each
recruited peer who participates. The method continues
as seeds recruit first-wave respondents, first-wave
respondents recruit second-wave respondents, and con-
tinues until the desired sample size is reached. Partici-
pants are encouraged to recruit randomly from their
personal social networks. Data are collected on the size Rather than classifying migrant workers as documen-
ted or undocumented, the Thailand Ministry of Public
Health defines migrants who have been in Thailand for
more than six months as M1, and migrants who have
been in Thailand for less than six months as M2. Both
M1 and M2 migrants are eligible to receive diagnosis
and treatment for malaria free of charge at malaria
clinics in border zones. Patients who cross the border
for a day to seek treatment at the border clinics are Khamsiriwatchara et al. Malaria Journal 2011, 10:120
http://www.malariajournal.com/content/10/1/120 Page 3 of 11 y
y
y
y
y
Figure 1 Location of the 5 study sites. Falciparum resistance to
artemisinin has been documented in the hotspot Zone 1 where
intensive containment operations are ongoing. of the social networks, and the analysis is weighted
based on the size of the social networks. RDS has typically been used to study urban popula-
tions, among highly networked communities, such as
injection drug users or commercial sex workers. While
the migrant population faces similar issues of stigma,
and those who are undocumented wish to remain unde-
tected by authorities, questions were raised as to
whether the networks in this population would be suffi-
cient to support this methodology. This analysis focuses
on the understanding of mobility dynamics of different
types of migrant workers in the border area as well as
the application of RDS methodology to the migrant
population; demographics, malaria prevention and treat-
ment-seeking behaviour of this population are described
in another publication [13]. Sampling
l Sample sizes were calculated separately for Myanmar
migrants and Cambodian migrants with the assumption
that the social networks of the two groups are indepen-
dent. As the main objective of the study was to estimate
the proportions of M1 or M2 among the Cambodian
and Myanmar migrant workers in the study areas and
there has been no clear sampling frame, the sample
sizes were calculated using a conservative target propor-
tion of 50% with a confidence level of 95% and a confi-
dence interval of 0.45, 0.55. A design effect of 2.0 and a
non-response rate of 10% were adopted. A sample size
of 900 participants for each of the two groups (total
1,800 participants) was required. Study area and population Five study sites within three of seven provinces along
the Thailand-Cambodia border were selected in areas
where there were known to be many migrant workers
and close by areas where P. falciparum resistance to
artemisinins has been documented [14]; three sites
recruited for Cambodian migrants (one each in Chanta-
buri, Trat, and Sa Kaeo provinces) and another two sites
for Myanmar migrants (both in Trat). The survey was
conducted from June to September 2009. Figure 1
shows the five locations in Thailand where surveys were
conducted as part of joint Cambodia-Thailand contain-
ment operations. Figure 1 Location of the 5 study sites. Falciparum resistance to
artemisinin has been documented in the hotspot Zone 1 where
intensive containment operations are ongoing. uniquely numbered and identifiable coupons to recruit
other migrant workers in their networks, who then
recruited other migrants in their networks, until the
desired sample size was reached. The seeds and their
recruits were offered minimal monetary incentives
(approximately US$ 10.00 for each recruiter). Each parti-
cipant was asked to respond to a questionnaire, with
questions regarding socio-demographics, migratory pat-
tern, work history, history of malaria infection, health-
seeking behaviour, knowledge about malaria and access
to health messages. Respondents were asked about the
size of their personal networks; both how many people
they perceived or knew as migrant workers in their areas,
and for weighting, the number of migrant workers from
their country of origin who were: (1) aged above 15 and
currently residing in the area, (2) personally known and
working in this area, (3) personally met in the past 30
days, (4) personally known male workers, (5) personally
known female workers, and (6) personally known and
recruited into the study. Figure 2 summarizes the recruit-
ment sampling procedures used in Thailand. Results and deemed to be exempt from full Institutional Review
Board review. Due to the sensitive nature of identity in
populations for which RDS methodology is used, con-
sent signed by the participant is not obtained. Following
careful explanation of the survey, eligible participants
were given the consent form to read or, if necessary, the
consent form was read to the survey participant by pro-
ject staff. All questions were addressed and consenting
participants verbally stated that they understood and
agreed to all of the items contained in the consent. Fol-
lowing this, a project staff member signed the consent
form in the appropriate space. Recruitment, social networks, and homophily ,
,
p
y
The initial 30 seeds in this study recruited 1719 study
participants during 8 weeks, ranging from 2-10 waves of
recruitment and 11-200 participants per seed. The
recruitment by seed and site is demonstrated in Figure
2. Among Cambodian migrants, 18 seeds (12 M1 and 6
M2) recruited a total of 828 Cambodian migrants; 350
M1 and 475 M2 (3 not determined). Most were
recruited by a neighbor (38.0%) or co-worker (31.1%)
among M1 and by a co-worker (77.3%) among M2. Respondents saw their recruiters a median of 20 times
in the past month for M1 and 12 times for M2, and had
known their recruiters for a median of 10 months for
M1 and 2 months for M2. Despite intensive search, only
one migrant from Myanmar who had resided in Thai-
land less than six months was identified to serve as a
seed. Among Myanmar migrants, 12 seeds (11 M1 and
1 M2) recruited a total of 891 migrants. In contrast to
Cambodian migrants, almost all (871) were M1, and
only 19 were M2. Most Myanmar migrants were
recruited by friends (M1 - 34.8%, M2 - 21.1%), relatives
(M1 - 35.7%, M2 - 42.1%) and neighbors (M1 - 17.0%,
M2 - 26.3%). Respondents saw their recruiters a median
of 24 times in the past month for M1 and 28 times for
M2. Respondents had known their recruiters for a med-
ian of 36 months for M1 and 13 months for M2 (Table
1). Ethical considerations The protocol was reviewed by Members of the Commu-
nicable Diseases Department of the Ministry of Health Page 4 of 11 Khamsiriwatchara et al. Malaria Journal 2011, 10:120
http://www.malariajournal.com/content/10/1/120 Page 4 of 11 Khamsiriwatchara et al. Malaria Journal 2011, 10:120
http://www.malariajournal.com/content/10/1/120 Figure 2 Recruitment methodology. case, M1 and M2. Homophily varies between -1 (com-
pletely heterophilous, or having network connections
exclusively outside own’s group) and +1 (completely
homophilous, or having connections exclusively within
one’s group). RDSAT software was used to estimate prevalence and
confidence intervals for categorical variables other than
location. For variables involving locations in Myanmar
and Cambodia, un-weighted percentages were reported
for each province or state. All analyses were separately
performed for Myanmar and Cambodian populations. Data management
h The recruitment was controlled by a coupon manage-
ment system, which was developed in Microsoft Excel,
and this system was used to track the relationships
between the recruiters and their recruits. The coupon
management system was developed by BIOPHICS and
implemented for use at each survey site. After the inter-
view, survey forms were faxed to BIOPHICS via iDatafax
data management system. Data quality on the survey
forms was checked and reconciled with the coupon
management system. Results Cambodian M1 migrants knew of more migrants
from their country (78) than either Myanmar M1 (26)
or Cambodian M2 (16), a relationship which carried
through to individuals known personally (41, 18, and 11,
respectively) and those seen in the last 30 days (31, 14,
and 11, respectively). Statistical analysis
h The estimates were performed using the Respondent
Driven Sampling Analysis Tool (RDSAT) version 5.6.0
[15]. To explore the information on mobility and work-
ing patterns, descriptive statistics and comparisons were
done by two types of migrant workers, M1 and M2,
among migrants from Cambodia and Myanmar. The
social network size was defined as all migrants living in
the same community that the participant knew by first
name or vice versa, and with whom they had met in the
past 30 days. RDSAT was used to calculate weighting of
the samples to control for differences in network size
and homophily of the population-based estimates for
M1 and M2 populations. An analysis of homophily was
done to determine the preference of members of a
group for connections within one’s own group, in this A homophily analysis was conducted to determine
whether M2 networks from Myanmar were adequately
reached. For migrants from Myanmar, homophily for
M1 migrants was 0.213 (some tendency for connections
with other M1) and for M2 migrants was -1.0 (connec-
tions exclusively with M1). For migrants from Cambo-
dia, homophily was 0.459 for M1 and 0.116 for M2
(both more likely to have in-group connections, M1
more so than M2). Khamsiriwatchara et al. Discussion Significant differences in the migration patterns of
migrant workers were found from Cambodia and Myan-
mar on the Thai-Cambodia border. Migrants from
Myanmar had a longer duration of residence in Thai-
land, rarely if ever returned to Myanmar, and were
more likely to consider Thailand home than Cambo-
dians. The vast majority had came from Mon state, had
used the services of a broker to enter Thailand, and
were more likely to have lived in other locations in
Thailand before arriving in their current location. The
majority of migrants from Cambodia are short-term
migrants, and more than half have been in Cambodia in
the last three months, usually for holidays or to visit
friends and family. While less than a third of Cambo-
dians who have lived in Thailand for more than six
months had plans to return to Cambodia, more than
two-thirds of short-term migrants had plans to return,
and almost three quarters had been in Cambodia in the
past three months. The provinces listed as province of
origin and of next destination covered most of Cambo-
dia, though the majority were western and central
provinces. y
Among Cambodian migrants, 5% of M1 and 6% of M2
returned to Cambodia more frequently than once
monthly. Among M2, 36% had not returned since their
arrival, 32% returned every 2-3 months, and 26% returned
every 6 months. Among M1, 21% returned every 2-3
months, 16% returned every six months, 23% returned
once annually, and 29% had not returned since their arri-
val. This pattern was very different for migrants from
Myanmar; 85% of M1 and 100% of M2 had never returned
to Myanmar. Only 2% reported returning as often as once
per year. Of those who returned, the primary reason
among long-term migrants from both Cambodia and
Myanmar was to visit friends and family. Cambodian M2
migrants were more likely to return for traditional or
national holidays. Public transportation was not a popular
option for Cambodians returning home; most travelled by
personal or hired vehicle (Table 2). While only 22% of M1
return at least every 2-3 months, 72% of M2 have been to
Cambodia in the last three months. Statistical analysis
h Malaria Journal 2011, 10:120
http://www.malariajournal.com/content/10/1/120 Page 5 of 11 Page 5 of 11 Table 1 Unweighted analysis of recruitment patterns and social network sizes
Cambodian
Myanmar
Variables
M1 * (n = 350)
(%)
M2 ** (n = 475)
(%)
M1 * (n = 871)
(%)
M2 ** (n = 19)
(%)
Received coupon from
Friend
17.1
9.3
34.8
21.1
Spouse
0.6
0.4
2.1
5.3
Relatives
9.7
2.5
35.7
42.1
Neighbour
38.0
4.6
17.0
26.3
Workplace
31.1
77.3
2.5
-
Employer
1.1
1.3
0.8
-
Newly met person
5.7
4.4
7.9
5.3
Number of times recruiter seen in past month
Mean
19.5
16.0
16.9
17.8
Median (IQR)
20 (10-29)
12(10-28)
24(4-28)
28(4-30)
Frequency of seeing recruiter
Daily
51.1
41.7
47.0
57.9
More than weekly
30.6
38.9
10.7
15.8
Weekly
10.3
13.1
25.5
15.8
Monthly
2.0
1.7
7.3
-
Less than monthly
2.6
1.9
9.1
10.5
Months known recruiter
Mean
30.3
4.3
62.4
77.9
Median(IQR)
10(4-28)
2(1-3)
36(12-72)
13(5-180)
Relationship with recruiter
Very close
30.3
11.2
28.4
26.3
Somewhat close
55.4
70.3
49.3
57.9
Not close
11.1
17.3
21.0
15.8
Reasons for enrollment
Compensation
35.4
59.6
20.9
31.6
Friend convincing
40.6
44.2
44.3
47.4
Interested in study
23.1
13.5
26.2
5.3
Have free time
6.6
0.8
10.1
5.3
Other
-
-
3.1
15.8
Number of labourers from your country aged > 15 in this village
(perceived)
Mean
78.0
16.2
26.3
11.4
Median(IQR)
40(15-100)
10(8-15)
15(7-30)
10(3-15)
Of those above, number known personally
Mean
41.4
11.0
17.7
10.5
Median(IQR)
21(11-42)
10(7-14)
10(6-20)
8(3-10)
Of those above, number seen in past 30 days
Total
Mean
30.9
11.4
13.7
8.7
Median(IQR)
20(10-32)
10(7-14)
10(6-20)
7(3-10)
Male
Mean
16.3
7.0
8.6
5.7
Median(IQR)
10(5-18)
6(4-9)
6(4-10)
5(3-6)
Female
Mean
16.0
4.7
6.6
4.4
Median(IQR)
10(4-19)
4(2-5)
5(3-9)
4(2-5)
Number attempted to recruit
Mean
4.6
4.6
4.0
3.1
Median(IQR)
3(3-3)
3(3-5)
3(3-3)
3(3-3) Table 1 Unweighted analysis of recruitment patterns and social network sizes Khamsiriwatchara et al. Malaria Journal 2011, 10:120
http://www.malariajournal.com/content/10/1/120 Page 6 of 11 Page 6 of 11 Migration patterns previous residence, and for Cambodians planning to
move on, the location of the next move, aggregating M1
and M2. With the exception of a few north-eastern pro-
vinces, Cambodian migrants came from most of the
provinces in Cambodia, though the majority came from
western Cambodia (Table 3). Most Cambodians came
from their province of birth to their current location in
Thailand (Table 2), and most still consider Cambodia
home. Among migrants from Myanmar, 86% came from
the Mon state, on the eastern border of Myanmar, and
24% now consider Thailand home. Migrants from
Myanmar had considerably more displacement from
their province of birth prior to arriving at their current
residence; almost one quarter reported living elsewhere
in Thailand before their current residence (Table 4). Migrants from Myanmar had a longer duration of resi-
dence in Thailand than migrants from Cambodia, with a
median duration of residence of 87 months in M1
migrants from Myanmar compared to 62 months in M1
migrants from Cambodia. Among M2 migrants, those
from Myanmar had been in Thailand 4.5 months, com-
pared to 2.6 months for those from Cambodia. Long term migrants were more likely to have crossed
the border by themselves (among Cambodians, 49% of
M1 vs. 35% of M2, and among those from Myanmar
45% of M1 vs. 34% of M2). Long term Cambodian
migrants had been helped by relatives (19%), friends
(16%), and employers (27%), while 57% of short term
Cambodian migrants were helped by employers. Among
migrants from Myanmar, 32% of M1 and 41% of M2
had used the services of a broker, compared to 1% of
Cambodians. Migrants from Myanmar were also helped
by relatives (19% of M1 and 26% of M2). Cambodian
M1 migrants were least likely to have paid money
upfront to come to Thailand (36%), compared to 53% of
Cambodian M2, 58% of Myanmar M1, and 76% of
Myanmar M2 (Table 2). Discussion RDS has historically been used to study other hidden
or difficult-to-reach populations, including men who
had sex with men, commercial sex workers, and injec-
tion drug users, often in the context of HIV prevention,
and has been shown to be a flexible and robust method
that can produce a sample representative of the hetero-
geneity of hidden populations [16-19]. This methodol-
ogy was successful in recruiting a sufficient sample of
both Cambodian and Myanmar migrants living and
working on the Thai-Cambodia border, despite initial
concerns that social networks might not be large
enough, and that restrictions in travel would hinder the
ability to recruit new participants. While the overall
design of this study was very similar to RDS studies
done with other populations, several additional factors In terms of future plans, of Cambodians, 32% of M1
and 68% of M2 planned to return to Cambodia. Only
4% of migrants from Myanmar planned to return. Among M1 migrants, 36% of Cambodians and 82% of
those from Myanmar had no plans to move, and an
additional 32% of Cambodians and 14% from Myanmar
did not know. By comparison, among Cambodian M2,
22% had no plans to move and 9% did not know. The
primary reason for an upcoming move was ‘work fin-
ished’ or ‘to live with family members (Table 2). Migration patterns were analysed in terms of province
or state of birth, location considered home, location of Khamsiriwatchara et al. Malaria Journal 2011, 10:120
http://www.malariajournal.com/content/10/1/120 Page 7 of 11 Page 7 of 11 Khamsiriwatchara et al. Discussion Malaria Journal 2011, 10:120
http://www.malariajournal.com/content/10/1/120
Page 8 of 11 Khamsiriwatchara et al. Malaria Journal 2011, 10:120
http://www.malariajournal.com/content/10/1/120 Khamsiriwatchara et al. Malaria Journal 2011, 10:120
http://www.malariajournal.com/content/10/1/120 Page 8 of 11 Table 2 Mobility patterns of migrant workers from Cambodia and Myanmar, RDS-weighted (Continued) Table 2 Mobility patterns of migrant workers from Cambodia and Myanmar, RDS-weighted (Continued)
Reason to move
Want a different job
3.2% (1.1-5.9)
9.7% (7.2-12.3)
0.2% (0.0-0.5)
—
My work is finished
11.4% (7.1-14.9)
32.7% (27.8-37.4)
0.4% (0.0-0.8)
My family member’s work
3.4% (1.1-6.0)
5.1% (2.9-7.1)
2.3% (1.3-3.2)
4.1% (0.0-10.9)
To live with my family
15.4% (8.5-22.2)
19.1% (14.4-24.8)
1.6% (0.8-2.5)
—
Immigration status expired
——
——
—
—
Other
3.6% (1.3-6.0)
1.8% (0.4-2.6)
1.6% (0.7-2.8)
—
IQR: Interquartile range
* Has lived in Thailand for 6 or more months; ** Has lived in Thailand for less than 6 months
‡ Denominator = total number in that column, thus may be < 100% for questions asked of a subset erns of migrant workers from Cambodia and Myanmar, RDS-weighted (Continued) Table 2 Mobility patterns of migrant workers from Cambodia and Myanmar, RDS-weighted (Continued) * Has lived in Thailand for 6 or more months; ** Has lived in Thailand for less than 6 months
‡ Denominator = total number in that column, thus may be < 100% for questions asked of a subset resulting in the recruitment of more short-term (M2)
migrants than long-term (M1) despite starting with
more M1 seeds. In the Myanmar community, very few
short-term migrants were recruited, which was con-
firmed by discussions with key informants stating that
there were in fact few short-term migrants from Myan-
mar, perhaps reflecting the amount of time required for
migrants to travel from the western to the eastern side
of Thailand. In addition, the homophily analysis showed
that M2 migrants from Myanmar were recruited exclu-
sively by and exclusively recruited M1 migrants, show-
ing that they are well-integrated into the long-term
migrant community and confirming that they are likely in recruiting this population had to be taken into
account. First, while most RDS studies have usually
been done in urban areas, this population is largely
rural, and issues around funding for transportation had
to be considered. Location of the study sites was extre-
mely important to assure access. Due to language bar-
riers in these migrant populations, translators were
necessary. Discussion Malaria Journal 2011, 10:120
http://www.malariajournal.com/content/10/1/120 Table 2 Mobility patterns of migrant workers from Cambodia and Myanmar, RDS-weighted
Variables
Cambodian
Myanmar
M1 * (n = 350) (%)
M2 ** (n = 475) (%)
M1 * (n = 871) (%)
M2 ** (n = 19) (%)
Duration of stay in Thailand (months)
Mean
61.5
2.6
86.8
4.5
Median(IQR)
23(12-60)
2(1-3)
72(33-113)
4 (3-5)
Border crossing assistance
None - by self
49.0% (42.1-56.8)
34.8% (30.9-39.7)
45.2% (41.0-48.7)
33.6% (9.6-58.6)
Broker
1.0% (0.1-2.2)
1.1% (0.2-2.0)
32.2% (28.3-36.3)
41.4% (10.7-67.6)
Relative
18.6% (13.1-22.3)
10% (7.3-12.8)
18.8% (16.1-21.4)
25.9% (8.5-50.7)
Friend
15.5% (10.9-20.2)
10.7% (8.3-13.3)
2.9% (1.7-4.3)
—
Employer
26.8% (18.9-35.9)
56.5% (50.2-61.8)
0.1% (0.0-0.3)
—
Other
2.4% (1.1-3.3)
0.1% (0.0-0.2)
9.6% (6.6-12.7)
—
Paid money upfront to enter
36.3% (30.6-46.5)
52.9% (46.0-58.3)
58.2% (54.1-62.2)
76.3% (50.7-100)
Province of residence before here same as birthplace
87.5% (82.9-92.0)
90.8% (87.5-94.1)
70.6% (66.6-74.6)
85.7% (67.9-100)
Return to home country
≥once per week
0.5% (0.0-0.3)
1.3% (0.3-1.9)
—
—
≥once per month
4.1% (1.2-6.2)
4.2% (2.5-6.0)
—
—
Every 2-3 months
20.6% (12.9-24.7)
32.0% (26.5-36.0)
—
—
Every 6 months
15.6% (10.9-20.4)
26.1% (20.2-29.6)
0.1%(0.0-0.6)
—
Once per year
23.1% (17.6-32.9)
—
2.1%(1.2-3.3)
—
< once per year
5.7% (3.3-9.3)
—
5.3% (3.8-7.2)
—
< once per 5 years
1.6% (0.3-2.6)
—
7.3% (5.5-9.1)
—
Have not been back
28.7% (23.9-37.1)
35.5% (32.0-44.2)
85.2% (82.1-87.8)
100%
Reasons for returning
Visit friends/family
35.5% (29.4-41.8)
23.9% (19.6-27.2)
22.5% (19.3-25.7)
—
Traditional / national holiday
26.6% (22.2-41.0)
51.5% (13.8-56.1)
1.3% (0.402.4)
—
Family event
3.4% (1.4-5.4)
2.2% (0.6-4.2)
0.2% (0.0-0.5)
—
Work
3.7% (1.3-6.7)
1.9% (0.3-3.9)
—
—
Buying/selling (market)
—
—
—
—
Other
5.7% (0.3-8.5)
1.2% (0.2-2.2)
5.3% (3.7-7.2)
—
Transportation mechanism
Bus
8.6% (6.0-11.6)
0.6% (0.1-1.5)
12.3% (10.5-15.2)
—
Taxi
4.8% (1.0-9.0)
0.3% (0.0-0.8)
—
—
Personal vehicle
30.1% (20.3-43.4)
58.7% (48.5-66.6)
0.1% (0.0-0.3)
—
Hired private vehicle
30.1% (23.6-35.4)
6.3% (4.0-8.7)
4.9% (3.3-6.4)
—
Other
0.9% (0.1-1.9)
3.% (1.6-5.6)
13.4% (10.7-16.0)
—
Frequency of migration
In Cambodia in past 3 months
21.9% (15.7-28.2)
72.4% (67.0-77.7)
—
—
Not returned in last 3 months
78.1% (71.8-84.3)
27.6% (22.3-33..0)
—
—
Plans to return
< 6 months
3.9% (0.6-7.1)
25.9% (20.9-30.9)
4.3% (3.1-6.4)
1.4% (0.0-5.4)
≥6 months
16.9% (10.5-23.4)
28.4% (23.5-33.3)
—
—
No plans to return
79.2% (72.4-86.1)
45.7% (40.3-51.2)
81.7% (78.5-84.9)
88.3% (75.4-100)
Median expense of returning
(32 B = 1 USD)
(212-501)
(58-140)
(3408-4440)
—
Plans for next move
Myanmar
—
—
4.3% (3.1-6.4)
1.4% (0.0-5.4)
Cambodia
31.6% (23.4-42.6)
68.1% (60.5-74.2)
—
—
No plan to move
36.0% (28.0-41.7)
22.1% (17.5-28.7)
81.7% (78.5-84.9)
88.3% (75.4-100)
Don’t know
32.4% (25.8-40.1)
9.3% (6.6-11.9)
13.8% (10.5-16.5)
10.3% (0.0-22.7) Table 2 Mobility patterns of migrant workers from Cambodia and Myanmar, RDS-weighted ers from Cambodia and Myanmar, RDS-weighted rom Cambodia and Myanmar, RDS weighted
Cambodian
Myanmar
M1 * (n = 350) (%)
M2 ** (n = 475) (%)
M1 * (n = 871) (%)
M2 ** (n = 19) (%)
61.5
2.6
86.8
4.5
23(12-60)
2(1-3)
72(33-113)
4 (3-5)
49.0% (42.1-56.8)
34.8% (30.9-39.7)
45.2% (41.0-48.7)
33.6% (9.6-58.6)
1.0% (0.1-2.2)
1.1% (0.2-2.0)
32.2% (28.3-36.3)
41.4% (10.7-67.6)
18.6% (13.1-22.3)
10% (7.3-12.8)
18.8% (16.1-21.4)
25.9% (8.5-50.7)
15.5% (10.9-20.2)
10.7% (8.3-13.3)
2.9% (1.7-4.3)
—
26.8% (18.9-35.9)
56.5% (50.2-61.8)
0.1% (0.0-0.3)
—
2.4% (1.1-3.3)
0.1% (0.0-0.2)
9.6% (6.6-12.7)
—
36.3% (30.6-46.5)
52.9% (46.0-58.3)
58.2% (54.1-62.2)
76.3% (50.7-100)
87.5% (82.9-92.0)
90.8% (87.5-94.1)
70.6% (66.6-74.6)
85.7% (67.9-100)
0.5% (0.0-0.3)
1.3% (0.3-1.9)
—
—
4.1% (1.2-6.2)
4.2% (2.5-6.0)
—
—
20.6% (12.9-24.7)
32.0% (26.5-36.0)
—
—
15.6% (10.9-20.4)
26.1% (20.2-29.6)
0.1%(0.0-0.6)
—
23.1% (17.6-32.9)
—
2.1%(1.2-3.3)
—
5.7% (3.3-9.3)
—
5.3% (3.8-7.2)
—
1.6% (0.3-2.6)
—
7.3% (5.5-9.1)
—
28.7% (23.9-37.1)
35.5% (32.0-44.2)
85.2% (82.1-87.8)
100%
35.5% (29.4-41.8)
23.9% (19.6-27.2)
22.5% (19.3-25.7)
—
26.6% (22.2-41.0)
51.5% (13.8-56.1)
1.3% (0.402.4)
—
3.4% (1.4-5.4)
2.2% (0.6-4.2)
0.2% (0.0-0.5)
—
3.7% (1.3-6.7)
1.9% (0.3-3.9)
—
—
—
—
—
—
5.7% (0.3-8.5)
1.2% (0.2-2.2)
5.3% (3.7-7.2)
—
8.6% (6.0-11.6)
0.6% (0.1-1.5)
12.3% (10.5-15.2)
—
4.8% (1.0-9.0)
0.3% (0.0-0.8)
—
—
30.1% (20.3-43.4)
58.7% (48.5-66.6)
0.1% (0.0-0.3)
—
30.1% (23.6-35.4)
6.3% (4.0-8.7)
4.9% (3.3-6.4)
—
0.9% (0.1-1.9)
3.% (1.6-5.6)
13.4% (10.7-16.0)
—
21.9% (15.7-28.2)
72.4% (67.0-77.7)
—
—
78.1% (71.8-84.3)
27.6% (22.3-33..0)
—
—
3.9% (0.6-7.1)
25.9% (20.9-30.9)
4.3% (3.1-6.4)
1.4% (0.0-5.4)
16.9% (10.5-23.4)
28.4% (23.5-33.3)
—
—
79.2% (72.4-86.1)
45.7% (40.3-51.2)
81.7% (78.5-84.9)
88.3% (75.4-100)
(212-501)
(58-140)
(3408-4440)
—
—
—
4.3% (3.1-6.4)
1.4% (0.0-5.4)
31.6% (23.4-42.6)
68.1% (60.5-74.2)
—
—
36.0% (28.0-41.7)
22.1% (17.5-28.7)
81.7% (78.5-84.9)
88.3% (75.4-100)
32.4% (25.8-40.1)
9.3% (6.6-11.9)
13.8% (10.5-16.5)
10.3% (0.0-22.7) Khamsiriwatchara et al. Discussion Because the agricultural work that many
migrants come to do is highly seasonal, it was critical to
time the study with the peak in the need for agricultural
work. In the Cambodian community, there were strong net-
works between recent and more long-term migrants, Table 3 Migration patterns by province of Cambodian migrants, including both short and long term migrants,
unweighted
Province
Province of birth
Province considered home
Prior province of residence
Plans for next move
N = 808
N = 729
N = 791
N = 310
In Cambodia
BANTEAY MEANCHEY
37 (4.5%)
35 (4.7%)
38 (4.7%)
23 (7.4%)
BATTAMBANG
225 (27.5%)
222 (30.0%)
239 (29.8%)
103 (33.1%)
KAMPONG CHAM
55 (6.7%)
31 (4.2%)
51 (6.4%)
8 (2.6%)
KAMPONG CHHNANG
10 (1.2%)
10 (1.4%)
11 (1.4%)
3 (1.0%)
KAMPONG SOM
1 (0.1%)
1 (0.1%)
2 (0.2%)
0.0%
KAMPONG SPEU
43 (5.3%)
35 (4.7%)
37 (4.6%)
30 (9.6%)
KAMPONG THOM
36 (4.4%)
33 (4.5%)
32 (4.0%)
27 (8.7%)
KAMPOT
102 (12.5%)
58 (7.8%)
86 (10.7%)
14 (4.5%)
KANDAL
9 (1.1%)
4 (0.5%)
7 (0.9%)
2 (0.6%)
KOH KONG
60 (7.3%)
10 (1.4%)
88 (11.0%)
2 (0.6%)
KRATIE
7 (0.9%)
7 (0.9%)
7 (0.9%)
1 (0.3%)
ODDAR MEANCHEY
6 (0.7%)
5 (0.7%)
6 (0.7%)
5 (1.6%)
PHNOM PENH
22 (2.7%)
13 (1.8%)
17 (2.1%)
8 (2.6%)
PREY VENG
22 (2.7%)
12 (1.6%)
14 (1.7%)
2 (0.6%)
PURSAT
25 (3.1%)
24 (3.2%)
23 (2.9%)
12 (3.9%)
SIEM REAP
77 (9.4%)
74 (10.0%)
70 (8.7%)
57 (18.3%)
SIHANOUKVILLE
0.0%
2 (0.3%)
1 (0.1%)
0.0%
SVAY RIENG
10 (1.2%)
8 (1.1%)
7 (0.9%)
4 (1.3%)
TAKEO
60 (7.3%)
46 (6.2%)
53 (6.6%)
6 (1.9%)
In Thailand
CHANTABURI
0.0%
14 (1.9%)
0.0%
1 (0.3%)
TRAT
0.0%
84 (11.4%)
0.0%
0.0% Table 3 Migration patterns by province of Cambodian migrants, including both short and long te
unweighted on patterns by province of Cambodian migrants, including both short and long term migrants, Table 3 Migration patterns by province of Cambodian migrants, including both short and long te
i h
d Table 3 Migration patterns by province of Cambodian migrants, including
unweighted Khamsiriwatchara et al. Discussion Malaria Journal 2011, 10:120
http://www.malariajournal.com/content/10/1/120 Page 9 of 11 Table 4 Migration patterns by province of migrants from Myanmar, including both short and long term migrants,
unweighted
Province or state
Province of birth
Province considered home
Prior province of residence
N = 870
N = 852
N = 879
In Myanmar
MON
747 (85.9%)
546 (64.1%)
543 (61.8%)
BAGO
12 (1.4%)
9 (1.1%)
8 (0.9%)
TANINTHARYI
32 (3.7%)
24 (2.8%)
26 (3.0%)
RANGOON
25 (2.9%)
22 (2.6%)
10 (1.1%)
OTHER
54 (6.2%)
46 (5.4%)
83 (9.4%)
In Thailand
BANGKOK
0.0%
0.0%
16 (1.8%)
KANCHANABURI
0.0%
0.0%
18 (2.0%)
RANONG
0.0%
0.0%
7 (0.8%)
SAMUT SAKHON
0.0%
0.0%
32 (3.6%)
TAK
0.0%
0.0%
10 (1.1%)
TRAT
0.0%
205 (24.1%)
77 (8.8%)
OTHER
0.0%
0.0%
39 (5.5%) Table 4 Migration patterns by province of migrants from Myanmar, including both sho
unweighted Table 4 Migration patterns by province of migrants from Myanmar, including both short and long term migrants,
unweighted by province of migrants from Myanmar, including both short and long term migrants, migrants come primarily from western and central Cam-
bodia, there has been migration from and back to
almost all provinces in Cambodia, some with very low
transmission levels and largely non-immune popula-
tions. Interestingly, no migrants claimed an origin in
Pailin Province, which has typically been thought to be
an epicenter of development of anti-malarial resistance. Finally, while most migrants had been in Cambodia in
the last three months, very few crossed the border more
frequently than monthly. Whether this reflects the true
reality of the situation or is due to sampling bias if the
networks of those who cross more frequently did not
intersect with those of the labourers in this sample, it
seems as if the population resides in Thailand long
enough to benefit from a treatment follow-up pro-
gramme. Frequent population movements, both across
the Thailand-Cambodia border and from the border
area across Cambodia, indicate the need for heightened
surveillance for artemisinin tolerance outside what has
been designated as the containment zone, as well as
close cooperation amongst Thai and Cambodian
authorities. few in number. Discussion While RDS methodology is not immune
from sampling bias [20,21], and discrepancies between
network compositions or the recruitment behaviours
(including social cohesion in recruiting from only one’s
own types) may impact the nature of the sample, this
does not appear to have been responsible for the pre-
ponderance of long-term migrants from Myanmar. While respondent driven sampling proved to be an
effective sampling methodology to study mobile migrant
populations, there were some challenges and limitations
in the implementation. While not inherent to RDS, staff
struggled with the length of the questionnaire, and this
as well as the need for interpreters may have limited
data quality. All answers were self-reported and not
based on observation, possibly resulting in some recall
or reporting biases. Blood samples were not collected. They would have given more information not only as to
the movement of the human population, but of parasites
as well. The migration patterns demonstrated here have impli-
cations for containment of artemisinin resistance. There
was a concern that migrants from Myanmar may carry
the resistant parasite back to their country of origin,
which is highly endemic, has not achieved the levels of
malaria control that other SE Asian countries have, and
has limited access by international agencies due to the
political situation. However, those residing along the
Thai-Cambodia border, primarily in Trat, have in fact
largely settled in Thailand, and do not return often, if at
all. The Cambodian population in the three border pro-
vinces of Trat, Chantaburi, and Sa Kaeo differ in three
important ways. First, there is considerably more fre-
quent cross-border mobility, with even long-term
migrants returning on a regular basis. Second, while Migration contributes to re-emergence of malaria in
previously malaria-free areas [22], and cases of malaria
in migrants are often reported among people who
recently returned to their countries of origin to visit
friends and family [23]. In Thailand, 46% of all malaria
cases reported were in short term migrants in 2003; this
increased to 55% in 2006 [2]. As national reports do not
take into account reports from non-state organizations
dealing with migrants, these figures are likely to be an
underestimate. As these individuals may then return to
homes across Cambodia, they may carry resistant para-
sites with them. Effective containment depends on Khamsiriwatchara et al. Competing interests The authors declare that they have no competing interests. The authors declare that they have no competing interests. Received: 18 January 2011 Accepted: 10 May 2011
Published: 10 May 2011 Received: 18 January 2011 Accepted: 10 May 2011
Published: 10 May 2011 Authors’ contributions All authors were involved in the conception and design of the study and
design of the application tools for data collection. PW were in charge of
managing the study and monitoring field research activities. CD arranged for
technical assistance and consultation of the study conceptual framework. WS was responsible for managing and supervising overall malaria control
programme activities. AK monitored field activities under RDS method and
extracted data for analysis. AK and JK performed statistical analyses and
drafting the manuscript. JT provided support for analysis and drafting of the
manuscript, and JE was instrumental in the study design and drafting of the
manuscript. All authors read and approved the final manuscript. Conclusion Respondent driven sampling methodology was an effec-
tive strategy to study the migrant populations from
Myanmar and Cambodia on the Thailand-Cambodia
border. Findings suggest that while populations from
Myanmar are relatively settled, populations from Cam-
bodia return home with relative frequency, not only to
the border areas, but to provinces across Cambodia,
indicating a need for heightened surveillance of artemi-
sinin resistance across Cambodia. However, migration
does not appear so frequent as to render case follow-up
impossible, and containment of resistance depends on
providing diagnostics, treatment, and follow-up to highly
mobile migrants as well as to more settled populations. Population mobility is a fact of global life; addressing
the health needs of migrants will not only improve
migrant health but also reduce long-term health and
social costs and protect public health. This information
on the mobility of cross-border migrants on the Thai-
land-Cambodia border will be valuable in planning
effective malaria prevention and control for the border
areas and help move forward the programme goals of
containment and elimination of the disease. References 1. Zhou G, Sirichaisinthop J, Sattabongkot J, Jones J, Bjonstad ON, Yan G,
Cui L: Spatio-temporal distribution of Plasmodium falciparum and P.vivax
malaria in Thailand. Am J Trop Med Hyg 2005, 72:256-262. 1. Zhou G, Sirichaisinthop J, Sattabongkot J, Jones J, Bjonstad ON, Yan G,
Cui L: Spatio-temporal distribution of Plasmodium falciparum and P.vivax
malaria in Thailand. Am J Trop Med Hyg 2005, 72:256-262. 2. Containment of artemisinin resistance and moving towards the
elimination of Plasmodium falciparum in Thailand. 2010, CCM-Thailand
Round 10 malaria proposal to the GFATM. 3. Confirmation, characterization and containment of artemisinin resistance
in South East Asia. A 2-year Bill and Melinda Gates-funded and WHO-led
project. The Bill and Melinda Gates Foundation and the World Health
Organization; [http://www.gatesfoundation.org/Grants-2008/Pages/World-
Health-Organization-OPP48821_01.aspx]. 4. Delacollette C, D’Souza C, Christophel E, Thimasarn K, Abdur R, Bell D,
Dai TC, Gopinath D, Lu S, Mendoza R, Ortega L, Rastogi R, Tantinimitkul C,
Ehrenberg J: Malaria trends and challenges in the Greater Mekong
subregion. Southeast Asian J Trop Med Public Health 2009, 40:674-691. 5. Containment of malaria multi-drug resistance on the Cambodia-Thailand
border. Report of an informal consultation. World Health Organization;
2007 [http://whothailand.healthrepository.org/handle/123456789/792]. 5. Containment of malaria multi-drug resistance on the Cambodia-Thailand
border. Report of an informal consultation. World Health Organization;
2007 [http://whothailand.healthrepository.org/handle/123456789/792]. 6. Global malaria report. World Health Organization; 2008 [http://www.who. int/malaria/publications/atoz/9789241563697/en/index.html]. 7. Huguet JW, Punpuing S: International Migration in Thailand. International
Organization for Migration, Regional Office Bangkok, Thailand; 2005. 8. Battistella G: Irregular Migration - World Migration 2008. International
Migration Institute (SIMI); 2008. p
p
y
g
6. Global malaria report. World Health Organization; 2008 [http://www.who. int/malaria/publications/atoz/9789241563697/en/index.html]. 7. Huguet JW, Punpuing S: International Migration in Thailand. International
Organization for Migration, Regional Office Bangkok, Thailand; 2005. 8. Battistella G: Irregular Migration - World Migration 2008. International
Migration Institute (SIMI); 2008. Author details
1 1Center of Excellence for Biomedical and Public Health Informatics
(BIOPHICS), Bangkok, Thailand. 2Bureau for Vector-borne Diseases, Ministry of
Public Health, Bangkok, Thailand. 3Centers for Disease Control and
Prevention, CDC, Atlanta, USA. 4World Health Organization, Mekong Malaria
Programme, c/o Faculty of Tropical Medicine, Mahidol University; 420/6,
Rajvithi Rd, Bangkok 10400, Thailand. Discussion Malaria Journal 2011, 10:120
http://www.malariajournal.com/content/10/1/120 Page 10 of 11 Page 10 of 11 Page 10 of 11 identifying and promptly treating all cases of malaria. However, unregistered migrants are in a vulnerable posi-
tion as they may be subject to arrest and deportation,
and do not have health insurance [7], discouraging health
care-seeking in Thailand. Furthermore, even if they seek
treatment from Thai malaria clinics that do not require
insurance, they often do not receive the same follow-up
to assure success of treatment, under the assumption
that they are too mobile to follow through the 28 days
follow-up period. While data were not collected on how
frequently migrants changed employers (and potentially
residences), these data suggest that only a small minority
return to Cambodia at least monthly, and that the major-
ity likely remain long enough to complete a 28-day fol-
low-up period. Case follow-up is crucial for artemisinin
resistance containment; further research should be done
to elucidate the future movement plans of short-term
migrants diagnosed in malaria clinics and determine the
best way to assure follow-up. development of questionnaire used to collect data in this study as well as
monitoring the early phase of the study implementation; all local malaria
personnel at malaria clinics in the study areas for their devotion in collecting
data under RDS mechanism; the IT and data management teams at
BIOPHICS for their contribution to the complex data management and
analysis; and all study participants who were both settled, mobile, and hard-
to-reach populations for their willingness to provide data that is useful for
malaria prevention and control programme. Authors wish to acknowledge the financial contribution from the Bill &
Melinda Gates Foundation (Grant-48821.01). Disclaimer The findings and conclusions in this report are those of
the authors and do not necessarily represent the official
position nor of the Centers for Disease Control and Pre-
vention neither of the WHO. 9. Heckathorn D: Respondent-driven sampling: A new approach to the
study of hidden populations. Social Problems 1997, 44:174-99. 9. Heckathorn D: Respondent-driven sampling: A new approach to the
study of hidden populations. Social Problems 1997, 44:174-99. 10. Heckathorn DD, Semaan S, Broadhead RS, Hughes JJ: Extensions of
respondent-driven sampling: a new approach to the study of injection
drug users aged 18-25. AIDS and Behavior 2002, 6:1. 11. Abdul-Quader AS, Heckathorn DD, Sabin K, Saidel T: Implementation and
analysis of respondent driven sampling: lessons learned from the field. Journal of Urban Health: Bulletin of the New York Academy of Medicine 2006,
83:7. Khamsiriwatchara et al. Malaria Journal 2011, 10:120
http://www.malariajournal.com/content/10/1/120 12. Coryn CLS, Gugiu PC, Davidson EJ, Schröter DC: Needs assessment in
hidden populations using respondent-driven sampling. Evaluation Journal
of Australia 2007, 7:3-11. 13. Wangroongsarb P, Satimai W, Khamsiriwatchara A, Thwing J, Eliades M,
Kaewkungwal J, Delacollette C: Respondent-driven sampling on the
Thailand-Cambodia border. II. Knowledge, perception, practice and
treatment-seeking behaviour of migrants in malaria endemic zones. Malar J 10:117. 14. Dondorp AM, Nosten F, Yi P, Das D, Phyo AP, Tarning J, Lwin KM, Ariey F,
Hanpithakpong W, Lee SJ, Ringwald P, Silamut K, Imwong M, Chotivanich K,
Lim P, Herdman T, An SS, Yeung S, Singhasivanon P, Day NP, Lindegardh N,
Socheat D, White NJ: Artemisinin resistance in Plasmodium falciparum
malaria. N Engl J Med 2009, 361:455-67, Erratum in: N Engl J Med. 2009
361: 1714. 15. Respondent Driven Sampling. [http://www.respondentdrivensampling.org]. 15. Respondent Driven Sampling. [http://www.respondentdrivensampling.org]. 16. Yeka W, Maibani-Michie G, Prybylski D, Colby D: Application of Respondent
Driven Sampling to Collect Baseline Data on FSWs and MSM for HIV Risk
Reduction Interventions in Two Urban Centres in Papua New Guinea. Journal of Urban Health: Bulletin of the New York Academy of Medicine 2006,
83:7. 17. Magnania R, Sabinb K, Saidela T, Heckathorn DD: Review of sampling
hard-to-reach and hidden populations for HIV surveillance. AIDS 2005,
19(suppl 2):S67-S72. 18. Johnston LG, Malekinejad M, Kendall C, Luppa IM, Rutherford GW:
Implementation challenges to using respondent-driven sampling
methodology for HIV biological and behavioral surveillance: field
experiences in international settings. AIDS Behav 2008, 12:S131-S141. 19. Stormer A, Tun W, Guli L, Harxhi A, Bodanovskaia Z, Yakovleva A,
Rusakova M, Levina O, Bani R, Rjepaj K, Bino S: An analysis of respondent
driven sampling with injection drug users (IDU) in Albania and the
Russian Federation. Journal of Urban Health: Bulletin of the New York
Academy of Medicine 2006, 83:7. 20. de Mello M, de Araujo Pinho A, Chinaglia M, Tun W, Júnior AB, Ilário M,
Reis P, Salles R, Westman S, Díaz J: Assessment of risk factors for HIV
infection among men who have sex with men in the metropolitan area
of Campinas city, Brazil, using respondent-driven sampling. Horizons Final
Report Washington, DC: Population Council; 2008. 21. Acknowledgements
Th
h
ld lik The authors would like to acknowledge WHO consultative experts and
Thailand MOPH-U.S.CDC staff for sharing their experiences of field research
management and providing assistance and consultation in RDS method and Page 11 of 11 Page 11 of 11 doi:10.1186/1475-2875-10-120
Cite this article as: Khamsiriwatchara et al.: Respondent-driven sampling
on the Thailand-Cambodia border. I. Can malaria cases be contained in
mobile migrant workers? Malaria Journal 2011 10:120. Khamsiriwatchara et al. Malaria Journal 2011, 10:120
http://www.malariajournal.com/content/10/1/120 Iguchi MY, Ober AJ, Berry SH, Fain T, Heckathorn DD, Gorbach PM,
Heimer R, Kozlov A, Ouellet LJ, Shoptaw S, Zule WA: Simultaneous
recruitment of drug users and men who have sex with men in the
United States and Russia using respondent-driven sampling: sampling
methods and implications. Journal of Urban Health: Bulletin of the New
York Academy of Medicine 2009, 86:1. 22. Martens P, Hall L: Malaria on the move: human population movement
and malaria transmission. Emerg Infect Dis 2000, 6:2. 22. Martens P, Hall L: Malaria on the move: human population movement
and malaria transmission. Emerg Infect Dis 2000, 6:2. 23. Health Protection Agency: Migrant Health UK. London; 2006. 23. Health Protection Agency: Migrant Health UK. London; 2006. doi:10.1186/1475-2875-10-120
Cite this article as: Khamsiriwatchara et al.: Respondent-driven sampling
on the Thailand-Cambodia border. I. Can malaria cases be contained in
mobile migrant workers? Malaria Journal 2011 10:120. Submit your next manuscript to BioMed Central
and take full advantage of:
• Convenient online submission
• Thorough peer review
• No space constraints or color figure charges
• Immediate publication on acceptance
• Inclusion in PubMed, CAS, Scopus and Google Scholar
• Research which is freely available for redistribution
Submit your manuscript at
www.biomedcentral.com/submit Submit your next manuscript to BioMed Central
and take full advantage of: Submit your next manuscript to BioMed Central
and take full advantage of: • Convenient online submission
|
https://openalex.org/W2089441359
|
http://pdf.blucher.com.br/designproceedings/11ped/01294.pdf
|
Portuguese
| null |
ADIÇÃO DE RESÍDUO INDUSTRIAL NO DESENVOLVIMENTO DE MASSAS CERÂMICAS PARA O ARTESANATO DO CABO DE SANTO AGOSTINHO - PERNAMBUCO
| null | 2,014
|
cc-by
| 4,133
|
Gramado
–
RS
De
30
de
setembro
a
2
de
outubro
de
2014
ADIÇÃO
DE
RESÍDUO
INDUSTRIAL
NO
DESENVOLVIMENTO
DE
MASSAS
CERÂMICAS
PARA
O
ARTESANATO
DO
CABO
DE
SANTO
AGOSTINHO
–
PERNAMBUCO
Germannya D’Garcia de Araújo Silva
Laboratório O Imaginário – Dep. Design - Universidade Federal de Pernambuco
germannyadgarcia@gmail.com
Juliana Carvalho da Silva
Laboratório de Cerâmicas Especiais – Dep. Eng. Mecânica - Universidade
Federal de Pernambuco
julianacarvalhodasilva0@gmail.com
Tiberio Cesar Macedo Tabosa
Laboratório O Imaginário – Dep. Design - Universidade Federal de Pernambuco
ttabosa@hotmail.com
Ana Maria Queiroz de Andrade
Laboratório O Imaginário – Dep. Design - Universidade Federal de Pernambuco
anamariadeandrade@gmail.com
Virginia Pereira Cavalcanti
Laboratório O Imaginário – Dep. Design - Universidade Federal de Pernambuco
cavalcanti.virginia@gmail.com
Resumo:
Neste
artigo
foram
avaliadas
as
propriedades
físicas
e
mecânicas
de
duas
massas
cerâmicas
a
base
de
resíduos
cerâmicos
industriais
d
l id
l
té
i
d
L b
tó i
d
D
i
O
I
i á i
d
Blucher Design Proceedings
Novembro de 2014, Número 4, Volume 1
www.proceedings.blucher.com.br/evento/11ped Blucher Design Proceedings
Novembro de 2014, Número 4, Volume 1
www.proceedings.blucher.com.br/evento/11ped Blucher Design Proceedings
Novembro de 2014, Número 4, Volume 1
www.proceedings.blucher.com.br/evento/11ped Gramado
–
RS Ana Maria Queiroz de Andrade
Laboratório O Imaginário – Dep. Design - Universidade Federal de Pernambuco
anamariadeandrade@gmail.com Virginia Pereira Cavalcanti
Laboratório O Imaginário – Dep. Design - Universidade Federal de Pernambuco
cavalcanti.virginia@gmail.com Virginia Pereira Cavalcanti
Laboratório O Imaginário – Dep. Design - Universidade Federal de Pernambuco
cavalcanti.virginia@gmail.com Resumo:
Neste
artigo
foram
avaliadas
as
propriedades
físicas
e
mecânicas
de
duas
massas
cerâmicas
a
base
de
resíduos
cerâmicos
industriais
desenvolvidas
pelos
técnicos
do
Laboratório
de
Design
O
Imaginário
da
UFPE
para
a
produção
de
produtos
artesanais
cerâmicos
do
Centro
de
Artesanato
Arq. Wilson
Campos
Júnior. As
massas
desenvolvidas
foram
caracterizadas
por
análise
química
e
por
ensaios
cerâmicos
normatizados:
Retração
linear
total
(%);
Absorção
de
água
(%);
Módulo
de
Ruptura
à
Flexão
(Kgf/cm²);
Perda
ao
fogo
(%);
e
Cor
após
queima. Como
principais
resultados
observou-‐se
que
a
inserção
de
diferentes
percentuais
do
resíduo
industrial
na
argila
in
natura
melhoraram
suas
propriedades
físicas
e
atendem
aos
requisitos
técnicos
e
estéticos
para
fabricação
da
cerâmica
artística
e
utilitária
do
grupo
ceramista
apoiado
pelo
Programa
Petrobras
Desenvolvimento
e
Cidadania. Palavras-‐chave:
Reaproveitamento
de
material,
Cerâmica
Vermelha,
Resíduo
Industrial,
Utilitários
de
mesa 2 1
Curau
-‐
pratos
que
os
plantadores
de
cana
levavam
para
uso
no
campo. 3
[...]
atividade
criativa,
que
tem
o
objetivo
de
estabelecer
múltiplas
qualidades
a
objetos,
processos,
serviços
e
sistemas
por
todo
o
seu
ciclo
de
vida.
Contudo,
design
é
o
fator
central
da
inovação
humanizadora
de
tecnologias
e
um
fator
crucial
para
a
troca
cultural
e
econômica.
ICSID
-‐
International
Council
of
Societies
of
Industrial
Design
(2007)
Se
o
design
tem
seu
surgimento
ligado
à
dissociação
entre
o
projetar
e
o
executar
[tarefa
delegada
à
indústria,
que
se
especializou
na
produção
repetitiva,
rápida
e
massiva],
hoje
se
percebe
uma
reaproximação
do
executor
original:
o
artesão.
BARROSO
[2005]
aponta
que
nos
últimos
anos
começam
a
surgir
intervenções
cada
vez
mais
frequentes
e
sistemáticas
na
produção
artesanal,
promovidas
por
diversos
organismos
da
esfera
pública
e
privada,
em
quase
todos
os
países
da
América
latina,
cuja
principal
motivação
tem
sido
a
necessidade
de
integrar
à
vida
econômica
destes
países
uma
atividade
que
durante
muito
tempo
foi
marginalizada
e
tratada
apenas
dentro
da
ótica
da
assistência
social. 2
O
Complexo
Industrial
Portuário
de
Suape
é
considerado
a
locomotiva
do
desenvolvimento
d
Pernambuco
e
um
dos
principais
polos
de
investimentos
do
país. 1. INTRODUÇÃO A
produção
de
cerâmica
vermelha
no
Cabo
de
Santo
Agostinho
é
uma
das
atividades
que
remonta
aos
tempos
da
colonização. Durante
séculos,
as
olarias
de
propriedade
dos
engenhos
de
açúcar
produziram
apenas
tijolos
e
telhas
para
atender,
exclusivamente,
às
necessidades
da
principal
atividade
econômica
da
zona
da
mata
sul
de
Pernambuco. Com
o
passar
do
tempo,
as
olarias
começaram
a
confeccionar
moringas,
jarras,
panelas,
potes,
alguidares
e
pratos
de
curau1. A
extração
da
matéria
prima
para
a
produção
das
peças,
a
argila,
sempre
foi
considerada
uma
atividade
não
econômica,
sendo
autorizada
por
SUAPE2
por
considerar
o
volume
mensal,
menos
de
oito
toneladas/mês,
apenas
para
a
produção
artesanal
dos
produtos. Atualmente,
com
o
desenvolvimento
econômico
da
região,
tais
jazidas
estão
sendo
aterradas
para
a
instalação
de
indústrias
de
grande
porte. Esta
situação
gerou
a
urgente
necessidade
de
se
estabelecer
alternativas
para
a
manutenção
do
fornecimento
de
matéria
prima
aos
ceramistas
do
Cabo. Diante
deste
cenário,
o
Laboratório
O
Imaginário
submeteu
e
aprovou,
no
ano
de
2013,
o
projeto
“Cerâmica
Artesanal
do
Cabo
de
Santo
Agostinho:
Centro
de
Artesanato
Arquiteto
Wilson
de
Queiroz
Campos
Júnior”
ao
edital
do
Programa
Petrobras
Desenvolvimento
e
Cidadania. O
Imaginário
é
um
Laboratório
de
pesquisa
e
extensão
multidisciplinar,
vinculado
ao
Departamento
de
Design
e
de
Cultura
da
Universidade
Federal
de
Pernambuco
composto
por
profissionais,
professores
e
estudantes
de
diversas
áreas
do
conhecimento,
que
atuam
com
foco
no
design3
como
instrumento
a
serviço
da
sustentabilidade,
ambiental,
econômica
e
social. É
o
resultado
da
evolução
de
projetos
de
pesquisa
e
extensão,
que
somavam
esforços
para
a
inserção
do
design
tanto
no
âmbito
industrial
quanto
artesanal. Sua
missão
é
oferecer
soluções
de
design
baseadas
em
pesquisa
e
que
estejam
comprometidas
com
o
usuário
e
o
desenvolvimento
sustentável
de
processos
e
sistemas. (ANDRADE;
CAVALCANTI,
2006) As
abordagens
metodológicas
utilizadas
pelo
Laboratório
O
Imaginário
tanto
no
ambiente
artesanal
quanto
no
industrial,
apontam
a
relação
entre
o
design
e
a
sustentabilidade
a
partir
de
suas
especificidades. Em
linhas
gerais,
estas
abordagens
utilizam
a
relação
entre
design
e
sustentabilidade,
tal
como
argumenta
Manzini
e 3 Vezzoli
(2005),
em
macro
dimensões:
a
econômica,
a
produtiva,
a
social,
a
ambiental
e
a
cultural. No
âmbito
industrial,
as
ações
do
laboratório
objetivam
fortalecer
a
articulação
da
Universidade
com
o
setor
produtivo,
visando
à
troca
de
informações
entre
academia
e
empresas,
ampliando
as
possibilidades
de
atuação
dos
designers
no
Estado. 4 O
resíduo
utilizado
é
resultado
da
drenagem
do
processo
produtivo,
ou
seja,
água
drenada
do
processo
contendo
componentes
da
massa:
argilas,
feldspatos,
quartzos,
entre
outros
elementos. 1. INTRODUÇÃO Na
abordagem
artesanal
a
diretriz
é
firmar
a
atividade
artesanal
em
Pernambuco
enquanto
meio
de
vida
sustentável,
através
de
intervenções
que
respeitem
os
valores
sociais,
econômicos,
ambientais
e
culturais
das
comunidades
produtoras
de
artesanato. Inicialmente,
os
técnicos
do
Laboratório
em
parceria
com
os
pesquisadores
do
Laboratório
de
Cerâmicas
especiais
da
UFPE
utilizaram
o
resíduo
de
uma
fábrica
de
piso
cerâmico
como
alternativa
para
a
sustentabilidade
produtiva
e
econômica
do
grupo
ceramista
(SILVA,
2008). Atualmente,
as
pesquisas
estão
sendo
direcionadas
a
utilização
do
resíduo
da
fabricação
de
Louças
Sanitárias
ROCA®4,
a
fim
de
atender
aos
parâmetros
de
produção
cerâmica
para
utilitários
de
mesa,
conforme
a
Tabela
1. Todavia,
existem
alguns
requisitos
para
a
incorporação
destes
resíduos
industriais,
bem
como
os
lodos
das
indústrias
cerâmicas
que
devem
ser
levados
em
consideração,
como
o
tratamento
adequado
deste
resíduo,
armazenamento
e
caracterização
do
mesmo. (ROCHA,
et. al.,
2008;
MORELLI
et. al.,
2003;
COSTA
et. al.,
2002) Tabela
1
Propriedades
físicas
exigidas
para
massas
de
cerâmica
artística,
louça
de
mesa
e
louça
sanitária. PROPRIEDADES
FÍSICAS
CERÂMICA
ARTÍSTICA
LOUÇA
DE
MESA
LOUÇA
SANITÁRIA
Temperatura
de
Queima
1050
0C
1180
0C
1250
0C
Absorção
(%)
15
-‐
19
4
-‐
6
0
Módulo
de
Ruptura
após
queima
(Kgf/cm2)
200
-‐
300
300
-‐
500
Maior
que
500
Densidade
da
Barbotina
(g/cm3)
1,71
–
1,73
1,72
–
1,75
1,77
–
1,80
Fonte:
Adaptado
de
MORELLI,
A.C,
BALDO
(2003). Tabela
1
Propriedades
físicas
exigidas
para
massas
de
cerâmica
artística,
louça
de
mesa
e
lou
sanitária. a
1
Propriedades
físicas
exigidas
para
massas
de
cerâmica
artística,
louça
de
mesa
e
louça
á i 2.1 Materiais Foram
elaboradas,
inicialmente,
três
composições
de
massa,
sendo
uma
para
modelagem
no
torno
(ET1),
sinterizada
à
850
0C
e
as
demais
para
colagem
de
barbotina
(EB1
e
EB2),
sinterizadas
a
1100
0C,
conforme
Tabela
2. Tabela
2
–
Composições
das
massas
cerâmicas
MATÉRIAS
PRIMA
ET1
EB1
EB2
Argila
Cabo
50%
15%
15%
Resíduo
Roca
30%
15%
30%
Feldspato
10%
50%
30%
Quartzo
10%
10%
9%
Caulim
-‐
10%
8%
Calcita
-‐
-‐
8%
TOTAL
100
%
100%
100%
Fonte:
Elaborado
pelo
autor,
com
base
na
pesquisa
realizada. Tabela
2
–
Composições
das
massas
cerâmicas 2.2 Análise
química q
Esse
ensaio
tem
como
finalidade
identificar
as
composições
químicas
teóricas
das
argilas
analisadas. As
amostras
foram
trituradas
na
forma
de
pó
e
uma
alíquota
de
cada
amostra
foi
colocada
em
estufa
para
secar
a
110
oC
e
então
levada
a
uma
mufla
a
1000
oC,
por
2
horas. Para
cada
amostra
foi
feita
uma
pérola
fundida,
usando
tetraborato
de
lítio
como
fundente
na
proporção
de
1:5. As
amostras
foram
analisadas
em
espectrômetro
de
fluorescência
de
raios
Rigaku
modelo
RIX
3000,
equipado
com
tubo
de
Rh,
pelo
método
de
curvas
de
calibração,
preparadas
com
materiais
de
referência
internacionais. Fonte:
Adaptado
de
MORELLI,
A.C,
BALDO
(2003). Fonte:
Adaptado
de
MORELLI,
A.C,
BALDO
(2003). Com
a
inserção
da
técnica
de
conformação
cerâmica
por
colagem
de
barbotina,
o
grupo
de
ceramistas
do
Cabo
está
atingindo
novos
mercados,
dentre
eles,
o
setor
gastronômico
e
a
utilização
de
uma
massa
cerâmica
adequada
a
tal
processo
é
de
fundamental
relevância
a
confiabilidade
do
grupo
no
mercado. Este
artigo
apresenta
os
primeiros
resultados
do
Laboratório
no
desenvolvimento
de
duas
massas
cerâmicas
adequadas
à
produção
dos
ceramistas
do
Cabo,
a
partir
da
inserção
de
percentuais
do
resíduo
cerâmico
das
louças
sanitárias
(R2),
na
argila
de
SUAPE
(S1)
e
matérias
primas
virgens
para
ajustes. Cumpre
salientar
que
estudos
sobre
esmaltes
cerâmicos,
sem
adição
de
chumbo,
também
veem
sendo
desenvolvidos
em
paralelo
para
o
atender
as
demandas
do
artesanato
do
Cabo. 4 2.3.1 Retração
Linear Este
ensaio
tem
a
finalidade
de
avaliar
a
redução
de
volume
do
corpo
de
prova
após
a
secagem
e
queima
além
de
explicar
indiretamente
o
ensaio
dimensional
mencionado
na
NBR
15099:2004. Existem
dois
tipos
de
retração:
uma
que
ocorre
antes
da
queima
a
110
oC
e
outra
que
ocorre
após
a
sinterização. ‐ Para
a
realização
do
ensaio
com
a
massa
de
barbotina,
mede-‐se
o
comprimento
inicial
no
molde
(C1),
em
seguida,
conforma-‐se
o
corpo
de
prova
inserindo
a
massa
na
cavidade
do
molde. Depois
do
tempo
adequado
de
fundição,
ocorre
o
destacamento
do
material
no
molde. Na
massa
de
torno,
corta-‐se
o
tarugo
compactado
nas
dimensões
desejadas,
neste
estudo,
10
cm. Os
corpos
de
prova
foram
colocados
na
estufa
para
secagem
na
temperatura
de
110
oC
durante
24
horas. 5 Figura. 1
–
Produção
dos
Corpos
de
prova
usado
nos
ensaios
de
retração,
perda
ao
fogo
e
absorção. Fonte:
Elaborado
pelo
autor,
com
base
na
pesquisa
realizada Figura. 1
–
Produção
dos
Corpos
de
prova
usado
nos
ensaios
de
retração,
perda
ao
fogo
e
absorção. Fonte:
Elaborado
pelo
autor,
com
base
na
pesquisa
realizada Após
este
tempo,
e
após
resfriamento
na
temperatura
ambiente,
com
o
auxilio
de
um
paquímetro,
mede-‐se
novamente
os
corpo-‐de-‐prova
para
obter
o
comprimento
a
seco
(CS),
Figura
1. ‐‐ Em
seguida,
os
corpos-‐de-‐prova
foram
levados
ao
forno
para
queima
em
temperatura
de
aproximadamente
850
oC,
para
a
massa
de
torno,
e
a
1100
oC,
para
a
massa
de
colagem
de
barbotina,
por
um
tempo
de
8
horas,
Figura
2. Figura
2
–
Sinterização
e
procedimentos
de
medição
dos
corpos
de
prova
Fonte:
Elaborado
pelo
autor,
com
base
na
pesquisa
realizada
Após
a
sinterização,
o
corpo-‐de-‐prova
é
medido
novamente
e
tem-‐se
então
o
comprimento
queimado
(CQ)
do
material. De
posse
destes
valores,
obtidos
na
experiência,
podemos
inserir
nas
equações
(1),
(2)
e
(3)
para
determinação
da
retração
de
secagem,
de
queima
e
total
respectivamente. Figura
2
–
Sinterização
e
procedimentos
de
medição
dos
corpos
de
prova
Fonte:
Elaborado
pelo
autor,
com
base
na
pesquisa
realizada Figura
2
–
Sinterização
e
procedimentos
de
medição
dos
corpos
de
prova
Fonte:
Elaborado
pelo
autor,
com
base
na
pesquisa
realizada Após
a
sinterização,
o
corpo-‐de-‐prova
é
medido
novamente
e
tem-‐se
então
o
comprimento
queimado
(CQ)
do
material. 2.3.1 Retração
Linear De
posse
destes
valores,
obtidos
na
experiência,
podemos
inserir
nas
equações
(1),
(2)
e
(3)
para
determinação
da
retração
de
secagem,
de
queima
e
total
respectivamente. Onde: Onde: CS
=
Comprimento
após
secagem
(110
oC); CS
=
Comprimento
após
secagem
(110
oC);
CQ
comprimento
após
a
queima
(850
e
1100
oC) CQ
=
comprimento
após
a
queima
(850
e
1100
oC). 6 2.3.2 Módulo
de
Ruptura
à
Flexão Os
moldes
dos
corpos
de
prova
para
ensaio
de
Módulo
de
Ruptura
à
Flexão
foram
cedidos
pela
fábrica
de
Louças
Sanitárias
ROCA®
e
os
corpos
de
prova
para
a
massa
de
torno
foram
realizados
numa
extrusora
a
vácuo
VERDES®
modelo
057. Todos
os
corpos
de
prova
foram
ensaiados
numa
maquina
EMIC
com
célula
de
carga
Trd
24
de
50N/cm3,
utilizando
o
programa
Tesc
versão
3.04,
conforme
a
norma
ABNT
NBR15310
–
telha
cerâmica,
seguindo
os
parâmetros
determinados
para
cada
condição
isto
é,
se
o
corpo
de
prova
apresenta
uma
seção
reta
retangular
ou
circular,
normatizado
para
ensaios
de
resistência
à
flexão
de
materiais
cerâmicos
avançados
em
temperatura
ambiente
Norma
ASTM
C1161,
Figura
3. Figura
3. Ensaio
de
Flexão
em
corpo
de
prova
de
secção
cilíndrica
Fonte:
Elaborado
pelo
autor,
com
base
na
pesquisa
realizada Figura
3. Ensaio
de
Flexão
em
corpo
de
prova
de
secção
cilíndrica
Fonte:
Elaborado
pelo
autor,
com
base
na
pesquisa
realizada Os
valores
encontrados
foram
lançados
na
equação
4
para
materiais
de
seção
retangular
no
caso
da
massa
de
torno
e
na
equação
5
para
as
massas
de
barbotina
cujos
corpos
de
prova
apresentavam
seção
reta
circular
e
assim
foram
calculados
os
módulos
de
ruptura
à
flexão
após
sinterização
1100
oC. Onde: Ff:
Carga
necessária
para
ruptura
em
N;
L:
Distância
entre
os
pontos
de
suporte
em
cm;
b:
largura
do
corpo
de
prova
em
cm;
d:
espessura
do
corpo
de
prova
em
cm; Ff:
Carga
necessária
para
ruptura
em
N;
L:
Distância
entre
os
pontos
de
suporte
em
cm;
b:
largura
do
corpo
de
prova
em
cm;
d:
espessura
do
corpo
de
prova
em
cm; Onde:
Ff:
Carga
necessária
para
ruptura
em
N;
L:
Distância
entre
os
pontos
de
suporte
em
cm;
R:
raio
do
corpo
de
prova Onde: Onde:
Ff:
Carga
necessária
para
ruptura
em
N;
L:
Distância
entre
os
pontos
de
suporte
em
cm;
R:
raio
do
corpo
de
prova 7 Fig. 5. Figura
4
–
Seções
transversais
dos
corpos
de
prova
no
local
da
ruptura
Fonte:
Elaborado
pelo
autor,
com
base
na
pesquisa
realizada Fig. 5. Figura
4
–
Seções
transversais
dos
corpos
de
prova
no
local
da
ruptura
Fonte:
Elaborado
pelo
autor,
com
base
na
pesquisa
realizada Após
a
ruptura
de
cada
corpo
de
prova,
foram
medidas
as
dimensões
das
seções
transversais
de
cada
amostra,
no
local
da
ruptura
e
foi
observado
as
cargas
necessárias
para
o
rompimento,
Figura
4 2.3.3 Absorção
de
água
(A.A.) Este
ensaio
avalia
a
queima
da
peça
cerâmica,
através
de
sua
porosidade,
a
partir
da
quantidade
de
água
absorvida
pela
peça
cerâmica
após
a
sinterização. O
corpo
de
prova
utilizado
no
ensaio
é
o
mesmo
usado
no
ensaio
de
retração. Este
ensaio
também
pode
ser
feito
com
regiões
distintas
do
produto
acabado
segundo
ABNT
NBR
15097:2004. O
corpo-‐de-‐prova
é
pesado
para
determinação
da
massa
seca
(MS),
logo
em
seguida
o
material
é
imerso
em
um
recipiente
com
água,
onde
se
eleva
a
temperatura
da
mesma
até
seu
ponto
de
ebulição,
permanecendo
por
2
horas. Após
2
horas
de
fervura,
deixa-‐se
esfriar
no
próprio
recipiente
com
água
por
24
horas,
Figura
5. Novamente
volta-‐se
a
pesar
os
corpos-‐de-‐prova
para
determinar
a
massa
úmida
(MU). De
posse
destes
números,
determinamos
então
o
percentual
de
absorção,
utilizando
a
equação
(6)
a
seguir: Onde: MS
=
Peso
do
material
seco; MU
=
Peso
do
material
úmido 8 Figura
5
–
Ensaio
de
absorção
de
água
em
ambos
os
corpos
de
prova
Fonte:
Elaborado
pelo
autor,
com
base
na
pesquisa
realizada Figura
5
–
Ensaio
de
absorção
de
água
em
ambos
os
corpos
de
prova
Fonte:
Elaborado
pelo
autor,
com
base
na
pesquisa
realizada O
valor
encontrado
para
utensílio
de
mesa
deve
estar
compreendido
entre
4-‐6
%. Fora
desse
parâmetro
a
peça
apresentará
um
alto
índice
de
porosidade
e
com
o
passar
do
tempo
o
acúmulo
de
umidade
nos
poros
causará
expansão
por
umidade,
podendo
haver
trincas. 2.3.4 Cor
após
queima Este
ensaio
consiste
em
avaliar
a
tonalidade
do
corpo
cerâmico
após
a
etapa
de
sinterização
à
850
oC,
para
massa
de
torno
e
1100
oC,
para
colagem
por
barbotina. Quando
o
corpo
de
prova
é
retirado
da
estufa,
onde
permaneceu
por
um
período
de
24
horas,
à
110
oC,
é
submetidos
a
queima
e
posteriormente
é
avaliado
com
relação
a
cor. 3.3.1 Análise
química Com
base
na
quantidade
de
óxidos
presentes
(álcalis,
sílica
entre
outros)
das
amostras
analisadas,
Tabela
3,
pode-‐se
afirmar
que
tanto
a
argila
de
SUAPE
quanto
o
resíduo
industrial
fornecido
pela
ROCA®
são
complementares
e
potencialmente
capazes
de
servir
como
matéria
prima
para
um
novo
composto
cerâmico. Em
sendo
as
matérias
primas
complementares,
a
inserção
do
R2
na
massa
S1
favorecerá
a
complementação
dos
álcalis
Na2O
e
K2O
responsáveis
pela
fusibilidade
do
material,
entre
outros
óxidos,
promovendo
melhores
propriedades
tecnológicas
ao
produto
final. Outra
consideração
importante
é
que
a
argila
de
SUAPE
apresenta
um
maior
percentual
de
Fe2O3,
que
contribui
para
a
coloração
avermelhada
da
peça
após
a
sinterização. Essa
cor
avermelhada
é
característica
da
cerâmica
do
Cabo
e
deve
ser
considerada
na
elaboração
das
formulações
de
massa. Todavia,
para
o
processo
de
colagem
de
barbotina
a
cor
do
produto
final
precisa
apresentar
um
tom
mais
claro,
em
função,
da
camada
de
esmalte
cerâmico
a
ser
aplicada. Essa
condição
favorece
o
uso
de
um
percentual
maior
do
R2
na
formulação,
tendo
em
vista
que
sua
cor
pós
queima
é
acinzentada. 9 Tabela
3
-‐
Composições
químicas
teóricas
da
argila
de
Suape
(S1)
e
Resíduo
Roca
(R2). DETERMINAÇÕES
AMOSTRAS
MASSAS
(%)
S1
R2
SiO2
56,80
52,65
Al2O3
20,31
21,75
TiO2
1,75
0,40
Fe2O3
7,01
1,92
MgO
0,78
0,63
CaO
1,18
3,76
Na2O
0,36
0,71
K2O
2,63
3,13
P2O5
0,25
0,30
MnO
0,05
Traços
ZrO2
0,34
1,63
BaO
-‐
-‐
P.F. 8,09
11,96
Fonte:
Elaborado
pelo
autor,
com
base
na
pesquisa
realizada. Tabela
3
-‐
Composições
químicas
teóricas
da
argila
de
Suape
(S1)
e
Resíduo
Roca
(R2). 3.3.2 Ensaios
Cerâmicos Todos
os
resultados
dos
ensaios
cerâmicos
foram
compilados
na
Tabela
4,
a
seguir. Todas
as
massas
cerâmicas
apresentaram
densidade
entre
1,65
–
1,75
g/cm3. Esses
valores
favorecem
o
processo
de
colagem
de
barbotina
pois,
diminui
o
encharcamento
do
molde
de
gesso
e
promove
o
aumento
da
velocidade
no
fluxo
produção
das
peças. Com
relação
ao
ensaio
de
retração
linear,
um
dos
dados
mais
importante
para
o
processo
de
design,
a
massa
de
torno
apresentou
um
maior
percentual
de
retração
na
secagem
(6%)
que
no
pós
queima
(2%). No
entanto,
a
retração
total
de
8%
confere
a
para
a
massa
de
torno
(ET1)
um
baixo
percentual
de
retração,
indicando
que
a
adição
do
Quartzo
e
do
Feldspato
foi
eficaz
na
formação
de
fases
vítreas
durante
a
sinterização. Já
com
relação
as
massas
para
colagem
de
barbotina,
a
experiência
EB1
apresentou
retração
total
(14,29%),
considerada
satisfatória. Porém,
a
retração
no
pós
queima
(8,5%)
foi
maior
que
na
secagem
(5,71%). A
massa
EB2
que
contém
as
mesmas
matérias
primas
da
massa
EB1,
exceto
pela
adição
de
calcita
apresentou
menor
variação
dimensional
total
(6,96
%). Quanto
a
resistência
mecânica,
a
partir
do
ensaio
de
Módulo
de
Ruptura
à
Flexão,
a
massa
ET1
apresentou
melhores
resultados
(89,24
Kgf/cm2)
quando
comparado
a
resistência
mecânica
da
argila
de
SUAPE
pura
(24,94
Kgf/cm²). Esse
resultado
comprova
que
a
mistura
um
percentual
de
15%
do
resíduo
da
Roca®
foi
satisfatória
para
melhoria
das
propriedades
tecnológicas
da
massa,
em
laboratório. 10 Tabela
4
–
Resultados
dos
ensaios
Cerâmicos
TIPO
DE
ENSAIO
ET1
850
(OC)
EB1
1100
(OC)
EB2
1100
(OC)
Densidade
(g/cm3)
1,65
1,75
1,75
Retração
secagem
(%)
6
5,71
4,29
Retração
Queima
(%)
2
8,50
2,68
Retração
Total
(%)
8
14,29
6,96
Absorção
(%)
19,34
15,08
18,73
Módulo
de
ruptura
flexão
(Kgf/cm2)
89,24
276,86
280,20
Cor
de
queima*
Alaranjado
moderado
Bege
Bege
Fonte:
Elaborado
pelo
autor,
com
base
na
pesquisa
realizada. (*)
Cor
definida
por
comparação
com
a
Rock
Color
Chart,
New
York,
1984. Tabela
4
–
Resultados
dos
ensaios
Cerâmicos (*)
Cor
definida
por
comparação
com
a
Rock
Color
Chart,
New
York,
1984. As
massas
EB1
e
EB2
apresentaram
valores
de
resistência
mecânica
próximos
a
especificação
para
utilitários
de
mesa,
respectivamente
276,86
e
280,20
Kgf/cm2. Esses
parâmetros
indicam
a
necessidade
de
ajustes
em
alguns
aspectos
do
processo:
Inicialmente,
no
ajuste
dos
materiais
fundentes
para
favorecer
a
formação
das
fases
vítreas,
ou
mesmo
diminuir
o
percentual
de
Calcita. 3.3.2 Ensaios
Cerâmicos Em
seguida,
no
ajuste
dos
parâmetros
de
queima
entre
1150
–
1180
oC. Como
os
corpos
de
prova
foram
sinterizados
a
uma
temperatura
de
1100
oC,
isso
também
pode
ter
contribuído
para
uma
resistência
mecânica
menor. Com
relação
ao
ensaio
de
absorção,
os
valores
ficaram
bastante
próximos
entre
as
três
massas
desenvolvidas:
ET1(19.34
%);
EB1(15,08
%)
e
EB2
(18,73
%). Estes
resultados
sugerem
que
as
massas
apresentam
alta
porosidade
necessitando
de
ajustes
em
sua
composição. A
calcita
contida
na
massa
EB2,
embora,
diminua
a
retração
pós
queima,
faz
com
que
o
corpo
de
prova
fique
com
uma
porosidade
maior. 4 CONCLUSÕES A
argila
SUAPE
é
adequada
para
fabricação
de
tijolos
manuais,
prensados,
furados,
telhas
e
artefatos
de
decoração. Entretanto,
em
função
da
sua
baixa
resistência
mecânica
(24,94
Kgf/cm²)
e,
tendo
como
foco
a
produção
de
utilitários
artesanais
de
mesa,
foram
necessários
ajustes
na
composição
da
massa
com
matérias
primas
complementares. Para
as
peças
de
revolução
confeccionadas
em
torno
cerâmico,
a
adição
de
15%
do
resíduo
da
fábrica
de
louça
sanitária
ROCA®
na
argila
de
SUAPE,
além
de
algumas
matérias
primas
virgens
para
ajustes,
apresentou
um
ganho
superior
a
200%
na
resistência
mecânica
do
material
(89,24
Kgf/cm2),
melhorando
também
os
índices
de
retração
e
de
absorção
de
água
do
novo
composto. Já
com
relação
as
massas
desenvolvidas
para
colagem
de
barbotina,
em
função
dos
resultados
ainda
não
satisfatórios,
EB1
(276,86
Kgf/cm2
/
Absorção
15,08%)
e
EB2
(280,20
Kgf/cm2/
Absorção
18,73%),
a
próxima
etapa
da
pesquisa
consistirá
em
ajustes
na
composição
para
melhorar
a
resistência
mecânica
e
absorção
do
material. Acredita-‐ 11 se
que
o
acréscimo
de
materiais
fundentes
como
a
sílica,
cuja
fonte
principal
é
o
quartzo
pode
contribuir
para
esse
objetivo,
além
de
aumentar
a
temperatura
de
sinterização
para
1150
oC. se
que
o
acréscimo
de
materiais
fundentes
como
a
sílica,
cuja
fonte
principal
é
o
quartzo
pode
contribuir
para
esse
objetivo,
além
de
aumentar
a
temperatura
de
sinterização
para
1150
oC. Contudo,
os
artesãos
do
Cabo
já
testaram
as
massas
ET1
e
EB2,
em
produtos
inclusive
com
geometria
complexa,
e
aprovaram
seu
comportamento
na
conformação
de
paredes
e
no
processo
de
queima. Avaliadas
como
satisfatórias,
as
massas
estão
sendo
utilizadas
na
produção
de
utilitários
de
mesa,
com
aplicação
de
esmalte
cerâmico
e
acredita-‐se
que
a
adequação
e
a
padronização
dos
processos
de
fabricação
serão
fundamentais
para
manutenção
desses
bons
resultados. AGRADECIMENTOS Este
trabalho
é
parte
do
projeto
‘‘
Cerâmica
Artesanal
do
Cabo
de
Santo
Agostinho:
Centro
de
Artesanato
Arquiteto
Wilson
de
Queiroz
Campos
Junior”
patrocinado
pelo
Programa
Petrobras
Desenvolvimento
e
Cidadania. Os
autores
ainda
agradecem
ao
Laboratório
Núcleo
de
estudos
geoquímicos
e
o
Laboratório
de
Frequência
de
Raio
X
ambos
do
Departamento
de
Geologia
da
UFPE
pelas
Análises
Químicas. E,
ao
Laboratório
de
Caracterização
de
Argilas
do
SENAI
Água
Fria-‐
Recife/PE
pela
produção
dos
corpos
de
prova. REFERÊNCIAS ANDRADE,
Ana
M;
CAVALCANTI,
Virginia
P
.(Coord.). Imaginário
Pernambucano:
design,
cultura,
inclusão
social
e
desenvolvimento
sustentável. Recife:
Ed. Zoludesign,
2006. ANDRADE,
Ana
M;
CAVALCANTI,
Virginia
P
.(Coord.). Imaginário
Pernambucano:
design,
cultura,
inclusão
social
e
desenvolvimento
sustentável. Recife:
Ed. Zoludesign,
2006. Eduardo:
O
design
como
ferramenta
para
o
incremento
da
joalheria BARROSO,
Eduardo:
O
design
como
ferramenta
para
o
incremento
da
joalheria
brasileira. Disponível
na
Internet
por
http
em
http://joiabr.com.br/artigos/ebneto.html. Acesso
em
xx
mes
2005 COSTA,
M. G.;
RIBEIRO,
M. J.;
LABRINCHA,
J. A. Reutilização
in
situ
das
lamas
residuais
de
uma
indústria
cerâmica,
Cerâmica
Industrial,
Vol. 7
(5),
pp. 44-‐50,
2002. ICSID
-‐
International
Council
of
Societies
of
Industrial
Design. http://www.icsid.org/about/about/articles31.htm MANZINI,
E.,
VEZZOLI,
C.:
O
desenvolvimento
de
produtos
sustentáveis. São
Paulo:
Ed. Universidade
de
São
Paulo,
2005,
pp. 50
-‐
55 MORELLI,
A.C,
BALDO,
J.B. Barbotinas
cerâmicas
contendo
rejeito
de
vidro
soda
cal
para
maturação
em
baixa
temperatura;
Cerâmica
Industrial,
São
Paulo,
v. 8,
n.3,
maio/junho,
2003. ROCHA,
R.R.,
ZANARDO,
A.,
MORENO,
M. Estudo
do
comportamento
reológico
de
barbotinas
preparadas
com
argilas
da
formação
Corumbataí
utilizadas
no
polo
cerâmico
de
Santa
Gertrudes
(SP). São
Paulo:
Cerâmica,
n.54,
p.332-‐337. 2008. SILVA,
Germannya
D
A
et. al. Refugo
industrial
como
insumo
para
a
cerâmica
artesanal:
uma
alternativa
sustentável
para
o
artesanato
do
Cabo
de
Santo
Agostinho
–
Pernambuco
/
Brasil. In:
Congresso
Internacional
de
Pesquisa
em
Design. Anais
do
Congresso
Internacional
de
Pesquisa
em
Design. São
Paulo,
2008.
|
https://openalex.org/W3200220624
|
https://publications.goettingen-research-online.de/bitstream/2/89901/1/document.pdf
|
English
| null |
Olivine-rich achondrites from Vesta and the missing mantle problem
|
Nature communications
| 2,021
|
cc-by
| 8,993
|
ARTICLE 1 Institute of Meteoritics, University of New Mexico, Albuquerque, NM, USA. 2 Department of Earth and Planetary Sciences, University of New Mexico,
Albuquerque, NM, USA. 3 Scripps Institution of Oceanography, University of California San Diego, La Jolla, CA, USA. 4 Department of Earth and Planetary
Sciences, University of California Davis, Davis, CA, USA. 5 Bartoschewitz Meteorite Laboratory, Gifhorn, Germany. 6 Georg-August-Universität,
Göttingen, Germany. ✉email: zmoney@unm.edu Olivine-rich achondrites from Vesta and the
missing mantle problem Zoltan Vaci
1,2✉, James M. D. Day
3, Marine Paquet
3, Karen Ziegler1,2, Qing-Zhu Yin
4,
Supratim Dey
4, Audrey Miller
4, Carl Agee1,2, Rainer Bartoschewitz5 & Andreas Pack6 Zoltan Vaci
1,2✉, James M. D. Day
3, Marine Paquet
3, Karen Ziegler1,2, Qing-Zhu Yin
4,
Supratim Dey
4, Audrey Miller
4, Carl Agee1,2, Rainer Bartoschewitz5 & Andreas Pack6 Zoltan Vaci
1,2✉, James M. D. Day
3, Marine Paquet
3, Karen Ziegler1,2, Qing-Zhu Yin
4,
Supratim Dey
4, Audrey Miller
4, Carl Agee1,2, Rainer Bartoschewitz5 & Andreas Pack6 Mantles of rocky planets are dominantly composed of olivine and its high-pressure poly-
morphs, according to seismic data of Earth’s interior, the mineralogy of natural samples, and
modelling results. The missing mantle problem represents the paucity of olivine-rich material
among meteorite samples and remote observation of asteroids, given how common differ-
entiated planetesimals were in the early Solar System. Here we report the discovery of new
olivine-rich meteorites that have asteroidal origins and are related to V-type asteroids or
vestoids. Northwest Africa 12217, 12319, and 12562 are dunites and lherzolite cumulates that
have siderophile element abundances consistent with origins on highly differentiated aster-
oidal bodies that experienced core formation, and with trace element and oxygen and
chromium isotopic compositions associated with the howardite-eucrite-diogenite meteorites. These meteorites represent a step towards the end of the shortage of olivine-rich material,
allowing for full examination of differentiation processes acting on planetesimals in the
earliest epoch of the Solar System. 1 Institute of Meteoritics, University of New Mexico, Albuquerque, NM, USA. 2 Department of Earth and Planetary Sciences, University of New Mexico,
Albuquerque, NM, USA. 3 Scripps Institution of Oceanography, University of California San Diego, La Jolla, CA, USA. 4 Department of Earth and Planetary
Sciences, University of California Davis, Davis, CA, USA. 5 Bartoschewitz Meteorite Laboratory, Gifhorn, Germany. 6 Georg-August-Universität,
Göttingen, Germany. ✉email: zmoney@unm.edu 1 NATURE COMMUNICATIONS | (2021) 12:5443 | https://doi.org/10.1038/s41467-021-25808-9 | www.nature.com/naturecommunications ARTICLE NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-021-25808-9 T the A-type asteroids instead supports differentiation of planete-
simals in the inner Solar System, where the abundance of
aluminum-26 allowed for early enhanced melting of these bodies,
followed by later migration and implantation into the asteroid
belt. The Nice32 and Grand Tack33 models provided dynamical
explanations for such early disruptions through large-scale orbital
excitations, migrations, and ejections in the early Solar System. Results
P
l Petrology. Northwest Africa (NWA) 12217, 12319, and 12562 are
recent meteorite finds containing abundant Mg-rich olivine, and
are consistent with a cumulate origin, probably representing
mantle materials similar to Vesta or the vestoids. The NWA
12217, 12319, and 12562 meteorites are monomict fragmental
breccias predominantly composed of olivine fragments up to
1 cm in size that appear cream-colored to light green in hand
sample (Figs. 1a, S1). All three breccia assemblages are crosscut
by dark veins. Dunite NWA 12217 is composed of 93 modal%
olivine, 4 modal% low and high-Ca pyroxene, minor chromite,
FeNi metal, andesine plagioclase, Fe-sulfide, merrillite, and trace
alkali feldspar and silica, whereas lherzolites NWA 12319 and
NWA 12562 have lesser olivine (85–87 modal%) and higher
abundances of low and high-Ca pyroxene (9–11 modal%), and
minor chromite, FeNi metal, and plagioclase. Northwest Africa
12319 is also notable for having 3 modal% sulfide. The dark veins
identified in all three meteorites are composed of variable
amounts of sulfide, chromite, and pyroxene, as well as ubiquitous
vermicular symplectites composed of chromite and both low and
high-Ca pyroxene. These symplectites appear both as inclusions
within veins and on their own. The veins and symplectites are
found both along grain boundaries and fully enclosed within
olivine grains. Despite being brecciated, all three rocks lack
“matrix” material. Olivine grains in NWA 12217 exhibit undulose
extinction indicative of shock (Fig. S2). The planar fractures and
mosaicism in olivine grains record a maximum shock pressure of
60–65 GPa36. However, given the lack of any partial melt veins or
pockets, the shock pressures that these meteorites experienced are
significantly lower. Several hypotheses have been put forward to explain the
apparently low abundance of olivine-rich mantle material in the
Solar System. The most obvious of these is that olivine-rich
material is not easily detected in the asteroid belt, and there have
not been enough impacts involving this undetected material to
bring samples of it to Earth. Such a biasing could be due to space
weathering, which could darken the spectra of A-type asteroids
and obscure them from optical observation25,26, or to cata-
strophic impacts that have systematically destroyed olivine-rich
planetary mantles in the early Solar System27. Dynamical mod-
eling demonstrates that large impacts primarily occurred in the
final stages of planetesimal accretion and were capable of strip-
ping away the silicate portions of early planets, leaving behind Fe-
rich cores28. Olivine-rich achondrites from Vesta and the
missing mantle problem Later models34,35 have suggested that the in situ formation of
Jupiter was enough to trigger widespread orbital instabilities in
the asteroid belt necessary for both the collisional erosion of early
planetesimals and their migration to different parts of the Solar
System. T
he mantle compositions of terrestrial planets are well
constrained compared with those of small bodies and
asteroids, although it is widely held that smaller differ-
entiated planetary bodies with metallic cores also have olivine-
dominated silicate mantles. For example, the asteroid 4 Vesta,
though only about 500 km in diameter, is suggested to have
undergone core formation and differentiation to form an olivine-
rich mantle during a magma ocean phase1–3, through partial
melting4–6,
or
through
serial
magmatism
and
fractional
crystallization7,8. If
differentiated
bodies
were
ubiquitous
throughout the early Solar System, as planetesimal accretion
theory suggests9,10, then olivine-rich asteroid interiors, and
meteorite samples of them, should be quite common. Here we reevaluate the missing mantle problem in light of the
discovery of three olivine-rich ultramafic achondrite meteorites. The mineralogy and petrology, stable isotope geochemistry, and
trace element geochemistry of these rocks suggest that they are
sourced from a fully differentiated parent body that is likely to be
Vesta or one of the vestoids. They are igneous cumulates that
represent the first olivine-rich mantle samples from a small body
that experienced core formation and silicate differentiation, likely
in the form of serial magmatism that produced large plutonic
bodies that were later disrupted by impact. Based on the currently available meteorites and remote sensing
of
asteroids,
olivine-rich
asteroid
materials
appear
to
be
remarkably sparse, implying a ‘missing mantle problem’11. Notably, the diversity of iron meteorite types suggests the pre-
sence of at least 50 different parent bodies with iron cores and
complementary olivine-dominated mantles not observed by
remote sensing12. In the asteroid belt, objects with spectral sig-
natures suggesting that their compositions are olivine-rich
(>80%) are classified as A-type asteroids13, and these account
for <0.16% of all objects larger than 2 km14. In the meteorite
record, diogenites, thought to represent deep crustal cumulate
material from Vesta, are mostly orthopyroxenites with under
40 vol% olivine15, and only small clasts of dunite have thus far
been identified in a mesosiderite breccia16. Other olivine-rich
asteroid-derived rocks include the brachinites, brachinite-like
achondrites (BLA), and ureilites. The brachinites and brachinite-
like achondrites contain 68–95 modal% olivine, which is some-
what ferroan (Fo64-74)17,18. Olivine-rich achondrites from Vesta and the
missing mantle problem Their nearly chondritic trace element
compositions indicate that they are dominantly residues formed
by partial melt extraction from a chondritic source17,19, with
some meteorites (ALH 84025, Brachina, EET 99402/99407, and
Eagles Nest) possibly representing cumulates20–22. Ureilites are
also primitive achondrites that are likely to represent samples
from a planetary mantle that was catastrophically disrupted
before it could fully differentiate23. They range in composition
from dunite to peridotite (olivine Fo74-97)24, but like brachinites
and brachinite-like achondrites, they are not from a fully differ-
entiated asteroid. MMUNICATIONS | (2021) 12:5443 | https://doi.org/10.1038/s41467-021-25808-9 | www.nature.com/naturecommunications Results
P
l This could be similar to Moama38 (a
cumulate eucrite), which has a higher Δ17O but normal ε54Cr, or
Sariçiçek, a recently observed howardite fall with lower Δ17O but
normal ε54Cr that shows signs of mixing with carbonaceous
chondrites40. Bulk major, minor, and trace element abundances for NWA
12217, 12319, and 12562 reflect the dominance of olivine, in
conjunction with a minor feldspar component. Dunite NWA
12217 has a Mg# [molar Mg/(Mg + Fe)] of 91, higher than
lherzolites NWA 12319 and NWA 12562 (Mg# = 85 and 83,
respectively). The incompatible trace element (ITE) compositions
of NWA 12217, 12319, and 12562 are nearly identical in relative
abundances (Fig. 3a). The patterns of NWA 12217 and 12562
contain slight enrichments in the light REE but otherwise are
almost flat relative to CI chondrites. The variability of the ITE in
brachinites makes meaningful comparison with the ultramafic
achondrites difficult. The diogenites, by contrast, show similar
trends in ITE depletions to NWA 12217, 12319, and 12562. p
Highly siderophile element (HSE) concentrations in NWA
12217, 12319, and 12562 are shown in Fig. 3b along with those of
the brachinites, diogenites, and bulk silicate Earth and Mars. Abundances of HSE are generally low (<0.002×CI chondrite) with
the exceptions of Pd and Re in NWA 12562. All three meteorites
have HSE abundances in the intermediate range of the diogenites,
with some heterogeneity among aliquots. The osmium isotopic
compositions of all three meteorites are almost identical. However, their 187Re/188Os ratios vary significantly with four
aliquots lying close to a 4.5 Ga Solar System isochron (Fig. S6)
whereas one fragment of NWA 12562 has experienced significant
Re gain. This combined evidence suggests that the high Re in
aliquots of NWA 12562 represent addition from terrestrial
weathering, and that the HSE in NWA 12217, 12319, and 12562
are in chondritic-relative abundances. While terrestrial distur-
bance of Re in meteorites is well documented, disturbance in Pd,
especially to the degree noted in NWA 12562, is not41. The
meteorite also has elevated abundances of Ni, Co, Cu, and Pb,
consistent with preferential sampling of sulfide-rich fractions. As
veins containing sulfide are found throughout each meteorite
(Fig. S7), the elevated Pd in NWA 12562 is consistent with sulfide
injection forming veins within the olivine cumulate. Results
P
l It is not
possible to accurately determine whether this process occurred
immediately after silicate crystallization or perhaps later, as the
Re/Os disturbance in the meteorite must be assumed to result
from weathering and rusting of sulfides and metals. Not including
the
additions
to
NWA
12562,
the
total
measured
HSE
abundances of all three meteorites are between 1 and 4 ppb,
and this is lower than in terrestrial peridotites41 and much lower
than in brachinites and brachinite-like achondrites17,18. Fig. 1 Hand sample and oxygen isotopic data. a Northwest Africa Fig. 1 Hand sample and oxygen isotopic data. a Northwest Africa
12217 showing large olivine clasts. The light to dark brown material is
terrestrial weathering, typically from oxidation of metal grains and sulfides. Remnant fusion crust is visible in the top right corner of the meteorite. Interstitial areas between grains have been darkened by shock, and they
reflect the primary lithology of the meteorites. b Δ17O diagram showing
NWA 12217, 12319, and 12562 in relation to other achondrite
groups39,62–64. The TFL is the mass-dependent terrestrial fractionation line. Errors are smaller than symbols. g
p
yg
p
12217 showing large olivine clasts. The light to dark brown material is
terrestrial weathering, typically from oxidation of metal grains and sulfides. Remnant fusion crust is visible in the top right corner of the meteorite. Interstitial areas between grains have been darkened by shock, and they
reflect the primary lithology of the meteorites. b Δ17O diagram showing
NWA 12217, 12319, and 12562 in relation to other achondrite
groups39,62–64. The TFL is the mass-dependent terrestrial fractionation line. Errors are smaller than symbols. fragments are often associated with high-SiO2 (>70 wt%) phases or
pure silica. In the dunite NWA 12217, feldspar also occurs as small
(~200–300 µm) inclusions within olivine, surrounded by radiating
fractures, with compositions ranging from andesine to oligoclase to
potassium feldspar (Figs. S4 and S5). No potassium feldspar was
identified in NWA 12562 or NWA 12319, but a small high-silica
(95 wt%) glassy inclusion was identified in NWA 12562 with 1 wt%
K2O. Chromite compositions in all three meteorites show a range in
Al2O3 content of 0 to 25 wt%. Iron-nickel metal in the meteorites
ranges in Ni content between 6 and 40 wt%, with Ni/Co between 2
and 192. Chemical zonation is not observed in any of the major or
minor phases such that variation in composition is attributed to
differences between individual grains. Results
P
l The disrupted mantle material from these ‘stripping’
events must then be removed from the accretion disc, presumably
by being incorporated into the terrestrial planets or falling into
the Sun. Such a scenario cannot account for the largest asteroids
Vesta or Ceres, which retain plentiful silicate materials29,30. All three meteorites have olivine grains and fragments that are
forsteritic and contain low CaO (average of 0.06 ± 0.04 wt%) and
Cr2O3 (average of 0.07 ± 0.05 wt%) relative to olivine in other
primitive achondrites37. Olivine compositions are generally more
variable in the lherzolites NWA 12319 (Fo77-91) and NWA 12562
(Fo73-92) than in the dunite NWA 12217 (Fo86-93). Pyroxene
compositions show similar variability in NWA 12217 (Fs3-48,
Wo1-43), NWA 12319 (Fs9-46, Wo2-44), and NWA 12562 (Fs14-56,
Wo2-37) (Fig. S3). These phases do not show zonation in major or
minor element composition. Feldspar is a minor (<1 vol%) but
ubiquitous phase in NWA 12217, 12319, and 12562, and is evenly
distributed as brecciated fragments in the lherzolites. Feldspar-bearing The paucity of olivine-rich material is potentially due to col-
lisional transport processes. Recent asteroid surveys have con-
cluded that there are no olivine-rich bodies in the asteroid belt
above ~2 km in size other than A-type asteroids14, and therefore,
there is no statistically significant remote sensing evidence for
widespread differentiation into Fe-rich cores, olivine-rich man-
tles, and basaltic crusts in the asteroid belt31. The distribution of NATURE COMMUNICATIONS | (2021) 12:5443 | https://doi.org/10.1038/s41467-021-25808-9 | www.nature.com/naturecommunications 2 ARTICLE NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-021-25808-9 Fig. 1 Hand sample and oxygen isotopic data. a Northwest Africa
12217 showing large olivine clasts. The light to dark brown material is
terrestrial weathering, typically from oxidation of metal grains and sulfides. Remnant fusion crust is visible in the top right corner of the meteorite. Interstitial areas between grains have been darkened by shock, and they
reflect the primary lithology of the meteorites. b Δ17O diagram showing
NWA 12217, 12319, and 12562 in relation to other achondrite
groups39,62–64. The TFL is the mass-dependent terrestrial fractionation line. Errors are smaller than symbols. meteorites, while NWA 12217 plots slightly above due to its
heavier oxygen isotopic composition (Fig. 2b). The isotopic
compositions of NWA 12319 and 12562 argue for a heritage from
a reservoir similar to normal eucrites and diogenites, while NWA
12217 may have been influenced by mixing with an ordinary
chondrite component38,39. Results
P
l fragments are often associated with high-SiO2 (>70 wt%) phases or
pure silica. In the dunite NWA 12217, feldspar also occurs as small
(~200–300 µm) inclusions within olivine, surrounded by radiating
fractures, with compositions ranging from andesine to oligoclase to
potassium feldspar (Figs. S4 and S5). No potassium feldspar was
identified in NWA 12562 or NWA 12319, but a small high-silica
(95 wt%) glassy inclusion was identified in NWA 12562 with 1 wt%
K2O. Chromite compositions in all three meteorites show a range in
Al2O3 content of 0 to 25 wt%. Iron-nickel metal in the meteorites
ranges in Ni content between 6 and 40 wt%, with Ni/Co between 2
and 192. Chemical zonation is not observed in any of the major or
minor phases such that variation in composition is attributed to
differences between individual grains. NATURE COMMUNICATIONS | (2021) 12:5443 | https://doi.org/10.1038/s41467-021-25808-9 | www.nature.com/naturecommunications NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-021-25808-9 b Δ17O-ε54Cr diagram showing NWA 12217, 12319, and 12562 (graphic circles) in comparison with the brachinites, Brachina, GRA 06128, GRA 06129, and
NWA 3151 (pink diamonds), angrites, along with the normal HEDs (open symbols) and anomalous eucrites (gray filled squares) (BR = Bunburra Rockhole). The y-axis error bars for NWA 12217 and 12562 represent the range of Δ17O measured, and for NWA 12319 it is the analytical error of a single
measurement. c Overview Δ17O-ε54Cr plot showing the three new ultramafic achondrites with relation to major fields of planetary materials in non-
carbonaceous (NC) and carbonaceous chondrites (CC) and mixing lines between normal HEDs with ordinary, enstatite, and carbonaceous chondrites. d Δ17O-ε54Cr plot of NWA 12217, 12319, and 12562 (graphic circles) along with the normal HEDs (open symbols) and anomalous eucrites (gray filled
squares). Open squares represent literature normal eucrite data (BR = Bunburra Rockhole; A = Asuka). Literature data are from refs. 39,62,63,65–70 and
references therein. Various dashed lines represent mixing curves between the average eucrite end member and specific chondritic end-members as
indicated in panel c or d. than twice that of the new ultramafic achondrites. Its composition
is typical of plutonic angrites and angrites in general, which have
superchondritic Ca/Al and higher amounts of Cr2O3 in their
olivines than these new meteorites. Also, these ultramafic
meteorites are clearly separated from the angrite field in
Δ17O-ε54Cr systematics (Fig. 2b). It is therefore unlikely that
NWA 12217, 12319, or 12562 bear affinities to the angrite
parent body. below those of the brachinites and BLA, effectively ruling out
association with those meteorites and any other primitive
achondrites that form as residues of low degrees of partial
melting. This distinction is also evident when comparing Fe/Mn
versus Fe/Mg (Fig. 4). In a reducing environment, a residue of
partial melting produces a linear trend with a near-constant,
chondritic Mn/Mg ratio, while a cumulate produced by fractional
crystallization results in a range of Fe/Mg with constant
Fe/Mn37,47. The ultramafic achondrites show a constant Fe/Mn
ratio and a range of Fe/Mg, as would be expected for cumulate
rocks, while many of the primitive achondrites, including bra-
chinites and BLA, show the constant Mn/Mg ratios expected for
residues of partial melting. The brachinites and BLA are the most obvious analogs to the
ultramafic achondrites because they are dunites and peridotites. NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-021-25808-9 Fig. 2 Chromium isotopic data. a Δ17O versus ɛ54Cr isotope systematics of NWA 12217, 12319, and 12562 (graphic circles) shown along with non-
carbonaceous chondrites and achondrites. Colored-filled circles represent literature data while the diamonds and squares are data measured at UC Davis. The fields for ordinary chondrites (OC), Mars (SNCs), Earth and earth-likes, Vesta (HEDs), brachinites, ureilites, winonaites (win), acapulcoites (acp)/
lodranites/ungrouped achondrites (ung) are marked with select representative samples with available data. Symbol colors indicate meteorite type or
grouping. Note that the carbonaceous chondrites and affiliated achondrites plot outside the field of this plot with highly positive ε54Cr (shown in panel c). b Δ17O-ε54Cr diagram showing NWA 12217, 12319, and 12562 (graphic circles) in comparison with the brachinites, Brachina, GRA 06128, GRA 06129, and
NWA 3151 (pink diamonds), angrites, along with the normal HEDs (open symbols) and anomalous eucrites (gray filled squares) (BR = Bunburra Rockhole). The y-axis error bars for NWA 12217 and 12562 represent the range of Δ17O measured, and for NWA 12319 it is the analytical error of a single
measurement. c Overview Δ17O-ε54Cr plot showing the three new ultramafic achondrites with relation to major fields of planetary materials in non-
carbonaceous (NC) and carbonaceous chondrites (CC) and mixing lines between normal HEDs with ordinary, enstatite, and carbonaceous chondrites. d Δ17O-ε54Cr plot of NWA 12217, 12319, and 12562 (graphic circles) along with the normal HEDs (open symbols) and anomalous eucrites (gray filled
squares). Open squares represent literature normal eucrite data (BR = Bunburra Rockhole; A = Asuka). Literature data are from refs. 39,62,63,65–70 and
references therein. Various dashed lines represent mixing curves between the average eucrite end member and specific chondritic end-members as
indicated in panel c or d. Fig. 2 Chromium isotopic data. a Δ17O versus ɛ54Cr isotope systematics of NWA 12217, 12319, and 12562 (graphic circles) shown along with non-
carbonaceous chondrites and achondrites. Colored-filled circles represent literature data while the diamonds and squares are data measured at UC Davis. The fields for ordinary chondrites (OC), Mars (SNCs), Earth and earth-likes, Vesta (HEDs), brachinites, ureilites, winonaites (win), acapulcoites (acp)/
lodranites/ungrouped achondrites (ung) are marked with select representative samples with available data. Symbol colors indicate meteorite type or
grouping. Note that the carbonaceous chondrites and affiliated achondrites plot outside the field of this plot with highly positive ε54Cr (shown in panel c). Discussion
F
h Further geochemical aspects of the ultramafic achondrites rule
out association with other meteorite groups such as angrites and
brachinites. The angrites in general appear to be more oxidized
than NWA 12217, 12319, and 12562, with analytical and
experimental studies suggesting that they crystallized well above
the iron-wüstite (IW) buffer42,43. The olivine compositions and
the presence of Fe-metal in these new meteorites suggest that they
were formed in a more reducing environment. A single dunitic
angrite, NWA 8535, has been identified44, and though it also
contains Mg-rich olivine (Fo70-88), its olivine Fe/Mn is ~90, more Isotopic and trace element geochemistry. The ultramafic
achondrites NWA 12319 and 12562 overlap in oxygen isotope
composition as to be virtually indistinguishable, while NWA
12217 is somewhat heavier in 17O (overall δ17Oʹ = 1.62 to 1.88;
δ18Oʹ = 3.48 to 3.87; Δ17Oʹ = −0.230 to −0.136) (Fig. 1b). The
chromium isotopic composition of the ultramafic achondrites
ranges from ε54Cr = −0.65 ± 0.06 to −0.70 ± 0.07 (Fig. 2). The
coupled Δ17O and ε54Cr systematics of NWA 12319 and 12562
plot in the middle of the region of the main group normal HED TURE COMMUNICATIONS | (2021) 12:5443 | https://doi.org/10.1038/s41467-021-25808-9 | www.nature.com/naturecommunications 3 NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-021-25808-9 ARTICLE NATURE COMMUNICATIONS | (2021) 12:5443 | https://doi.org/10.1038/s41467-021-25808-9 | www.nature.com/naturecommunicatio NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-021-25808-9 This implies that they originate from bodies
that experienced core formation events and whose mantles were
later enriched in the HSE from late accretion of chondritic
material. Their similarity to diogenites and Mg-rich harzburgites
suggests that these parent bodies are sampled by V-type asteroids. Fig. 3 Trace element and highly siderophile element geochemistry. CI-
chondrite normalized71 a ITE abundances for NWA 12217 (open circles),
NWA 12319 (half-filled circles), NWA 12562 (crossed circles),
brachinites17,72 (green), and diogenites15 (red). b Bulk CI-normalized HSE
abundances of ultramafic achondrites plotted with those of brachinites17
diogenites73 and estimates for bulk silicate Earth and Mars41. The Fe/Mn systematics of the olivines in NWA 12217, 12319,
and 12562 argue convincingly for a cumulate origin within a
fractionating magma chamber for these meteorites. The diogen-
ites and Mg-rich harzburgites included in howardites are similarly
cumulate rocks within this scheme, but whether they originated
on the same parent body is not fully resolved. The pyroxene
minor element diversity (Fig. S9) exhibited in particular by NWA
12319 and 12562 overlaps and broadens the fields plotted by the
diogenites, Mg-rich harzburgites, and NWA 12217. Coupled with
the oxygen and chromium isotopic evidence, this suggests that
the ultramafic achondrites could have originated on Vesta or a
V-type asteroid. Fig. 4 Plot of Fe/Mg versus Fe/Mn of olivine in the ultramafic
achondrites and other meteorite groups15,47,48,72,74,75. Mg-rich
harzburgites are ultramafic clasts found within howardites. HED olivine
analyses are overwhelmingly from diogenites. Primitive achondrites such as
the ureilites and brachinites plot with constant Mn/Mg, while NWA 12217,
12319, and 12562 plot with relatively constant Fe/Mn and variable Fe/Mg. y
The Dawn mission arguably created more questions regarding
Vesta and the HED meteorites than it solved by observing a large
metallic core over 100 km in diameter50 and not detecting large
volumes of olivine-rich mantle material exposed by deep impact
craters51. If the bulk composition of Vesta is chondritic, the
elevated REE contents of the crustal eucrites argue for the exis-
tence of a complementary REE-depleted and olivine-rich mantle
seven to ten times the size of the crust51,52. However, the large
Vestan core and the deep crust-mantle boundary suggested by
impact craters that excavated olivine-free material from 100 km
deep53, severely limit the potential size of this mantle. NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-021-25808-9 However, they are geochemically distinct in that their range in
forsterite content and trace element abundances is much more
variable. Olivine CaO and Cr2O3 content of brachinites is more
variable and in general higher than in the ultramafic achondrites
(Fig. S8). As shown from Δ17O-ε54Cr systematics, brachinites and
BLA are distinct from the three ultramafic achondrites (Fig. 2b),
suggesting the two lithologies are unlikely to be of common
origin. The ITE and HSE abundances of brachinites are also
highly variable, likely due to their origin as residues of partial
melting on a parent body that never fully differentiated17,37,45,46. The HSE abundances of the ultramafic achondrites plot well The ultramafic achondrites are most similar geochemically to
diogenites and the Mg-rich harzburgites found as clasts in
howardites48. Low olivine CaO and Cr2O3 contents and the low
variance in analyses from all three rocks are similar to those
reported for the HED clan15 (Fig. S7). Olivine from the HED
meteorites and Mg-rich harzburgites, like the ultramafic achon-
drites, show a constant Fe/Mn ratio and variable Fe/Mg. In
particular, the Mg-rich harzburgites overlap with NWA 12562 MMUNICATIONS | (2021) 12:5443 | https://doi.org/10.1038/s41467-021-25808-9 | www.nature.com/naturecommunications 4 ARTICLE NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-021-25808-9 Fig. 3 Trace element and highly siderophile element geochemistry. CI-
chondrite normalized71 a ITE abundances for NWA 12217 (open circles),
NWA 12319 (half-filled circles), NWA 12562 (crossed circles),
brachinites17,72 (green), and diogenites15 (red). b Bulk CI-normalized HSE
abundances of ultramafic achondrites plotted with those of brachinites17
diogenites73 and estimates for bulk silicate Earth and Mars41. metasomatism, such crustal incorporation is unlikely because
both meteorites appear to be monomict breccias with no evidence
of contamination by a different lithology. NWA 12319 contains
three times as much P2O5 as the other two rocks, so it is possible
that its flat REE pattern is a result of more contributions to its
REE budget from phosphate, or potentially a trapped melt
component, relative to pyroxene. Importantly, the HED meteorites show up to five orders of
magnitude of variations in HSE concentrations41, so this metric
alone is not sufficient to establish a relationship of the ultramafic
achondrites to the diogenites. However, in combination with
other lines of evidence discussed above, it rules out association
with other olivine-rich planetary material. NWA 12217, 12319,
and 12562 have broadly chondritic HSE patterns that are found
in
all
planetary
bodies
that
experienced
core-mantle
differentiation41. NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-021-25808-9 The dis-
covery of the ultramafic achondrites is in line with these obser-
vations, as they do not appear to represent a large uniform mantle
that crystallized from a magma ocean. Fig. 4 Plot of Fe/Mg versus Fe/Mn of olivine in the ultramafic
achondrites and other meteorite groups15,47,48,72,74,75. Mg-rich
harzburgites are ultramafic clasts found within howardites. HED olivine
analyses are overwhelmingly from diogenites. Primitive achondrites such as
the ureilites and brachinites plot with constant Mn/Mg, while NWA 12217,
12319, and 12562 plot with relatively constant Fe/Mn and variable Fe/Mg. y
g
The petrological and geochemical characteristics of the ultra-
mafic achondrites favor serial magmatism within fractionating
magma chambers on their parent bodies, just as the discovery of
olivine-rich material overlying eucritic material favors this model
on Vesta54. The variability in Mg# and pyroxene compositions
found within all three breccias suggests that they are sampling
heterogeneous igneous bodies, whereas under a magma ocean
scenario more homogeneity should be expected. The REE com-
positions of the ultramafic achondrites are likewise varied and
dependent on high-Ca pyroxene content, a phase that is not
expected to be in the mantle of a sodium-depleted parent body
such as Vesta51. While bulk analyses of the ultramafic achondrites
suggest they are as alkali-depleted as the HED meteorites, brec-
ciated ultramafic rocks are unlikely to precisely represent the
volatile budgets of their host bodies (Fig. S10). Thus, the com-
positions of these meteorites raise additional complexities in
piecing together the igneous histories of Vesta, the vestoids, and
any other differentiated planetesimals that produced fractionating
magmas. and 12319, with the latter showing significantly more spread in
Fe/Mg. Because the ultramafic achondrites are breccias, this
greater variability is likely due to impact sampling and mixing of
fragments from a large differentiated protolith. The similar shape of the REE patterns of NWA 12217 and
12562 suggests that they were formed by similar processes, while
the bulk abundance differences are likely an artifact of brecciation
processes that led to variance in modal pyroxene abundance. Residues
of partial
melting
are
expected
to
have LREE/
HREE < 149. Instead, NWA 12217 and 12562 show enrichments
in the LREE relative to the HREE, suggesting different formation
conditions such as accumulation in a fractionating magmatic
assemblage within a region of magma storage in their parent
body. References Offline corrections for Os
involved an oxide correction, an iterative fractionation correction using 192Os/
188Os = 3.08271, a 190Os spike subtraction, and finally, an Os blank subtraction. Precision for 187Os/188Os, determined by repeated measurement of the UMCP
Johnson-Matthey standard was better than ±0.2% (2 St. Dev.; 0.11390 ± 20; n = 5). Measured Re, Pd, Pt, Ru, and Ir isotopic ratios for sample solutions were corrected
for mass fractionation using the deviation of the standard average run of the day
over the natural ratio for the element. External reproducibility on HSE analyses was
better than 0.5% for 0.5 ppb solutions and all reported values are blank corrected. The total analytical blank run with samples had 187Os/188Os = 0.177 ± 0.02, with
quantities (in picograms) of 0.9 [Re], 1.9 [Pd], 1.4 [Pt], 2.1 [Ru], 1.2 [Ir], and 0.3
[Os]. Blank contributions represent <10% in NWA 12562, but >40% for Re, Pd, Pt,
and Ru for NWA 12217. We measured NWA 12217 and NWA 12562 in duplicate
and NWA 12319 once during the course of this study. Rhenium, Pd, Pt, Ru, and Ir were measured using a Cetac Aridus II desolvating
nebulizer coupled to a ThermoScientific iCAP q ICP-MS. Offline corrections for Os
involved an oxide correction, an iterative fractionation correction using 192Os/ 14. DeMeo, F. E. et al. Olivine-dominated A-type asteroids in the main belt:
distribution, abundance and relation to families. Icarus 322, 13–30 (2019). l f hld
d ( )
h h
d
d 15. Mittlefehldt, D. W. Asteroid (4) Vesta: I. The howardite-eucrite-diogenite
(HED) clan of meteorites. Chem. der Erde - Geochem. 75, 155–183 (2015). 16. Beck, A. W. et al. MIL 03443, a dunite from asteroid 4 Vesta: evidence for its
classification and cumulate origin. Meteorit. Planet. Sci. 46, 1133–1151 (2011). 17. Day, J. M. D. et al. Origin of felsic achondrites Graves Nunataks 06128 and
06129, and ultramafic brachinites and brachinite-like achondrites by partial
melting of volatile-rich primitive parent bodies. Geochim. Cosmochim. Acta
81, 94–128 (2012). 18. Day, J. M. D., Corder, C. A., Assayag, N. & Cartigny, P. Ferrous oxide-rich
asteroid achondrites. Geochim. Cosmochim. Acta 266, 544–567 (2019). 19. Gardner-Vandy, K. G., Lauretta, D. S. & McCoy, T. J. A petrologic,
thermodynamic and experimental study of brachinites: Partial melt residues of
an R chondrite-like precursor. Geochim. Cosmochim. Acta 122, 36–57 (2013). 20. Mittlefehldt, D. W., Bogard, D. D., Berkley, J. L. & Garrison, D. H. Methods W filaments (the total Cr load split among four filaments) and each set of sample
filaments bracketed with two filaments loaded with a similar amount of terrestrial
Cr standard (NIST SRM 979) before and after. The Cr isotopic composition was
measured at UC Davis using a Thermo Triton Plus thermal ionization mass
spectrometer60. Each filament analysis consisted of 1200 ratios with 8 s integrations
times. A gain calibration was made at the beginning of each filament, the baseline
was measured, and the amplifiers were rotated between each block of 25 ratios. The
mass fractionation was corrected using an exponential law and a 50Cr/52Cr ratio of
0.05185961. The 53Cr/52Cr and 54Cr/52Cr ratios are expressed in ɛ-notation (that is,
parts per 10,000 deviation from the NIST SRM 979 Cr standard). Sample preparation. Several fragments from deposit samples of NWA 12217 and
12562 were mounted in epoxy and polished to 0.05 µm smoothness. Two polished thin
sections were also produced from fragments of NWA 12217 and 12319 (BC2920.2). These samples were analyzed by optical microscopy, electron probe microanalysis
(EPMA), and scanning electron microscopy (SEM) at the Institute of Meteoritics,
UNM, Albuquerque, NM (NWA 12217, 12319, and 12562) and the Institut für Geo-
wissenschaften, Christian-Albrechts-Universität in Kiel, Germany (NWA 12319). Oxygen isotopic analysis. Six fresh fragments of interior materials of NWA 12217
and NWA 12562, weighing between 1 and 2 mg, were selected using a stereo-
microscope to avoid any possible contamination from fusion crust or terrestrial
staining. Oxygen isotopic analyses were performed using a CO2 laser + BrF5
fluorination system following modified procedures outlined in Sharp55. The ana-
lyses in Göttingen were performed following the protocol described in Pack et al.56
and Peters et al.57, and details regarding the UNM technique are given in Wost-
brock et al.58. Oxygen isotope compositions were calculated using the following
procedure: the δ17,18O values refer to the per mil deviation of a sample’s (17O/16O)
and (18O/16O) ratios from the V-SMOW standard values, respectively, expressed as
δ17,18O = [(17,18O/16O)sample/(17,18O/16O)V-SMOW −1] × 103. The delta values were
then converted to logarithmic δʹ in which δ17,18Oʹ = ln(δ17,18O/1000 + 1) × 1000. The Δ17Oʹ values were obtained from the δʹ values following Δ17O’ = δ17Oʹ −
0.528 * δ18Oʹ. Typical analytical precision of the laser-fluorination technique is
better than ±0.02‰ for Δ17Oʹ. Data availability
h
h
d
l
h y
The authors declare that all data supporting the findings of this study are available within
the paper and its Supplementary Information files. The authors declare that all data supporting the findings of this study are available within
the paper and its Supplementary Information files. Received: 4 December 2020; Accepted: 19 July 2021; ARTICLE NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-021-25808-9 References 191Ir, 194Pt), and 6 mL of a 1:2 mixture of multiply Teflon distilled HCl and HNO3
that was treated with H2O2 to expunge Os. Samples were digested to a maximum
temperature of 270 ˚C in an oven for 72 h. Osmium was triply extracted from the
acid using CCl4 and then back-extracted into HBr, prior to purification by micro-
distillation that was performed twice. Rhenium and the other HSE were recovered
and purified from the residual solutions using standard anion exchange separation
techniques. Isotopic compositions of Os were measured in negative-ion mode on a
ThermoScientific Triton thermal ionization mass spectrometer at the SIGL. 191Ir, 194Pt), and 6 mL of a 1:2 mixture of multiply Teflon distilled HCl and HNO3
that was treated with H2O2 to expunge Os. Samples were digested to a maximum
temperature of 270 ˚C in an oven for 72 h. Osmium was triply extracted from the
acid using CCl4 and then back-extracted into HBr, prior to purification by micro-
distillation that was performed twice. Rhenium and the other HSE were recovered
and purified from the residual solutions using standard anion exchange separation
techniques. Isotopic compositions of Os were measured in negative-ion mode on a
ThermoScientific Triton thermal ionization mass spectrometer at the SIGL. 10. Weiss, B. P. & Elkins-Tanton, L. T. Differentiated planetesimals and the
parent bodies of chondrites. Annu. Rev. Earth Planet. Sci. 41, 529–560 (2013). 10. Weiss, B. P. & Elkins-Tanton, L. T. Differentiated planetesimals and the
parent bodies of chondrites. Annu. Rev. Earth Planet. Sci. 41, 529–560 (2013). 11. Bell, J. F., Davis, D. R., Hartmann, W. K. & Gaffey, M. J. Asteroids: the big
i
i
A
id II
(
) parent bodies of chondrites. Annu. Rev. Earth Planet. Sci. 41, 529–560 (2013). 11. Bell, J. F., Davis, D. R., Hartmann, W. K. & Gaffey, M. J. Asteroids: the big
picture. in Asteroids II 921–945 (1989). 12. Goldstein, J. I., Scott, E. R. D. & Chabot, N. L. Iron meteorites: crystallization,
thermal history, parent bodies, and origin. Chemie der. Erde 69, 293–325
(2009). 13. Cruikshank, D. P. & Hartmann, W. K. The meteorite-asteroid connection: two
olivine-rich asteroids. Science 223, 281 LP–281283 (1984). fi
p
Rhenium, Pd, Pt, Ru, and Ir were measured using a Cetac Aridus II desolvating
nebulizer coupled to a ThermoScientific iCAP q ICP-MS. NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-021-25808-9 Although LREE enrichment is also possible through
incorporation
of
crustal
material
during
brecciation
or 5 TURE COMMUNICATIONS | (2021) 12:5443 | https://doi.org/10.1038/s41467-021-25808-9 | www.nature.com/naturecommunications 5 References 1. Ikeda, Y. & Takeda, H. A model for the origin of basaltic achondrites based on
the Yamato 7308 Howardite. J. Geophys. Res. 90, C649 (1985). 2. Righter, K. & Drake, M. J. A magma ocean on Vesta: core formation and
petrogenesis of eucrites and diogenites. Meteorit. Planet. Sci. 32, 929–944
(1997). Trace element and highly siderophile element analysis. Whole-rock fragments
of all three meteorites were partially disaggregated to obtain small chips that were
subsequently crushed with limited force in an agate mortar and pestle to make a
partially representative (~0.3 g) whole-rock powder for each sub-fragment. Bulk
rock major- and trace-element abundances were determined at the Scripps Isotope
Geochemistry Laboratory (SIGL) on sample powders by digestion in sealed Teflon
vessels at 140 °C in Optima grade concentrated HF and HNO3 (4:1 V/V) for >72 h
on a hot plate, along with total analytical blanks and terrestrial basalt standards. Samples were sequentially dried and taken up in concentrated HNO3 to remove
fluorides, followed by dilution and doping with indium to monitor instrumental
drift during analysis. Major- and trace-element abundance analyses were obtained
using a ThermoScientific iCAP Qc quadrupole inductively coupled plasma mass
spectrometer in normal mode. Reference materials were analyzed as “unknowns”
(BIR-1, BHVO-2, HARZ-01, and BCR-2) to assess external reproducibility and
accuracy (see also Day et al.46). For major and trace elements, reproducibility of
reference materials was better than 5% (RSD). 3. Mandler, B. E. & Elkins-Tanton, L. T. The origin of eucrites, diogenites, and
olivine diogenites: Magma ocean crystallization and shallow magma chamber
processes on Vesta. Meteorit. Planet. Sci. 48, 2333–2349 (2013). 4. Stolper, E. Petrogenesis of eucrite, howardite and diogenite meteorites. Nature
258, 220–222 (1975). 5. Stolper, E. Experimental petrology of eucritic meteorites. Geochim. Cosmochim. Acta 41, 587–611 (1977). 6. Jones, J. H. The composition of the mantle of the eucrite parent body and the
origin of eucrites. Geochim. Cosmochim. Acta 48, 641–648 (1984). 7. Shearer, C. K., Fowler, G. W. & Papike, J. J. Petrogenetic models for
magmatism on the eucrite parent body: evidence from orthopyroxene in
diogenites. Meteorit. Planet. Sci. 32, 877–889 (1997). 8. Beck, A. W. & McSween, H. Y. Diogenites as polymict breccias composed of
orthopyroxenite and harzburgite. Meteorit. Planet. Sci. 45, 850–872 (2010). reference materials was better than 5% (RSD). Osmium isotope and HSE abundance analyses were performed at the SIGL
using methods described in Day et al.41. References Homogenized powder aliquots of the
samples and total procedural blanks were digested in sealed borosilicate Carius
tubes, with isotopically enriched multi-element spikes (99Ru, 106Pd, 185Re, 190Os,
191Ir, 194Pt), and 6 mL of a 1:2 mixture of multiply Teflon distilled HCl and HNO3
that was treated with H2O2 to expunge Os. Samples were digested to a maximum
temperature of 270 ˚C in an oven for 72 h. Osmium was triply extracted from the
acid using CCl4 and then back-extracted into HBr, prior to purification by micro-
distillation that was performed twice. Rhenium and the other HSE were recovered
and purified from the residual solutions using standard anion exchange separation
techniques. Isotopic compositions of Os were measured in negative-ion mode on a
ThermoScientific Triton thermal ionization mass spectrometer at the SIGL. Rhenium, Pd, Pt, Ru, and Ir were measured using a Cetac Aridus II desolvating
nebulizer coupled to a ThermoScientific iCAP q ICP-MS. Offline corrections for Os
involved an oxide correction, an iterative fractionation correction using 192Os/
188Os = 3.08271, a 190Os spike subtraction, and finally, an Os blank subtraction. Precision for 187Os/188Os, determined by repeated measurement of the UMCP
Johnson-Matthey standard was better than ±0.2% (2 St. Dev.; 0.11390 ± 20; n = 5). Measured Re, Pd, Pt, Ru, and Ir isotopic ratios for sample solutions were corrected
for mass fractionation using the deviation of the standard average run of the day
over the natural ratio for the element. External reproducibility on HSE analyses was
better than 0.5% for 0.5 ppb solutions and all reported values are blank corrected. The total analytical blank run with samples had 187Os/188Os = 0.177 ± 0.02, with
quantities (in picograms) of 0.9 [Re], 1.9 [Pd], 1.4 [Pt], 2.1 [Ru], 1.2 [Ir], and 0.3
[Os]. Blank contributions represent <10% in NWA 12562, but >40% for Re, Pd, Pt,
and Ru for NWA 12217. We measured NWA 12217 and NWA 12562 in duplicate
and NWA 12319 once during the course of this study. Osmium isotope and HSE abundance analyses were performed at the SIGL
using methods described in Day et al.41. Homogenized powder aliquots of the
samples and total procedural blanks were digested in sealed borosilicate Carius
tubes, with isotopically enriched multi-element spikes (99Ru, 106Pd, 185Re, 190Os, 9. Hevey, P. J. & Sanders, I. S. A model for planetesimal meltdown by 26Al and
its implications for meteorite parent bodies. Meteorit. Planet. Sci. 41, 95–106
(2006). ARTICLE An internally consistent triple
oxygen isotope calibration of standards for silicates, carbonates and air relative
to VSMOW2 and SLAP2. Chem. Geol. 533, 119432 (2020). 30. Russell, C. T. et al. Dawn arrives at ceres: exploration of a small, volatile-rich
world. Science 353, 1008–1010 (2016). to VSMOW2 and SLAP2. Chem. Geol. 533, 119432 (2020). 31. Bottke, W. F., Nesvorný, D., Grimm, R. E., Morbidelli, A. & O’Brien, D. P. Iron meteorites as remnants of planetesimals formed in the terrestrial planet
region. Nature 439, 821–824 (2006). 59. Yamakawa, A., Yamashita, K., Makishima, A. & Nakamura, E. Chemical
separation and mass spectrometry of Cr, Fe, Ni, Zn, and Cu in terrestrial and
extraterrestrial materials using thermal ionization mass spectrometry. Anal. Chem. 81, 9787–9794 (2009). g
32. Tsiganis, K., Gomes, R., Morbidelli, A. & Levison, H. F. Origin of the orbital
architecture of the giant planets of the Solar System. Nature 435, 459–461
(2005). 60. Sanborn, M. E. et al. Carbonaceous achondrites Northwest Africa 6704/6693:
milestones for early Solar System chronology and genealogy. Geochim. Cosmochim. Acta 245, 577–596 (2019). 33. Walsh, K. J., Morbidelli, A., Raymond, S. N., O’Brien, D. P. & Mandell, A. M. A low mass for Mars from Jupiter’s early gas-driven migration. Nature 475,
206–209 (2011). 61. Shields, W. R., Murphy, T. J., Catanzaro, E. J. & Garner, E. L. Absolute
isotopic abundance ratios and the atomic weight of a reference sample of
chromium. J. Res. Natl Bur. Stand. Sect. A Phys. Chem. 70A, 193 (1966). 34. Turrini, D., Coradini, A. & Magni, G. Jovian early bombardment: planetesimal
erosion in the inner asteroid belt. Astrophys. J. 750, 8 (2012). y
62. Greenwood, R. C., Franchi, I. A., Jambon, A. & Buchanan, P. C. Widespread
magma oceans on asteroidal bodies in the early Solar System. Nature 435,
916–918 (2005). 35. Raymond, S. N. & Izidoro, A. Origin of water in the inner Solar System:
Planetesimals scattered inward during Jupiter and Saturn’s rapid gas accretion. Icarus 297, 134–148 (2017). 63. Greenwood, R. C., Franchi, I. A., Gibson, J. M. & Benedix, G. K. Oxygen
isotope variation in primitive achondrites: the influence of primordial,
asteroidal and terrestrial processes. Geochim. Cosmochim. Acta 94, 146–163
(2012). 36. Stöffler, D., Hamann, C. & Metzler, K. Shock metamorphism of planetary
silicate rocks and sediments: Proposal for an updated classification system. Meteorit. Planet. Sci. 53, 5–49 (2018). 37. Goodrich, C. A., Kita, N. T., Sutton, S. R., Wirick, S. ARTICLE ARTICLE NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-021-25808-9 Eagles Nest and Lewis Cliff 88763: comparison to brachinites. Meteorit. Planet. Sci. 33, 31–48 (1998). 52. Mittlefehldt, D. W. & Lindstrom, M. M. Geochemistry of eucrites: genesis of
basaltic eucrites, and Hf and Ta as petrogenetic indicators for altered antarctic
eucrites. Geochim. Cosmochim. Acta 67, 1911–1934 (2003). Eagles Nest and Lewis Cliff 88763: comparison to brachinites. Meteorit. Planet. Sci. 33, 31–48 (1998). g
Planet. Sci. 33, 31–48 (1998). 23. Goodrich, C. A. et al. Origin and history of ureilitic material in the solar
system: the view from asteroid 2008 TC3 and the Almahata Sitta meteorite. Meteorit. Planet. Sci. 50, 782–809 (2015). 53. Clenet, H. et al. A deep crust-mantle boundary in the asteroid 4 Vesta. Nature
511, 303–306 (2014). 24. Brugier, Y. A. et al. Zinc isotopic variations in ureilites. Geochim. Cosmochim. Acta 246, 450–460 (2019). 54. Cheek, L. C. & Sunshine, J. M. Merging spatial and spectral datasets to place
olivine in stratigraphic context at Arruntia crater, a rare window into Vesta’s
northern hemispheric crust. Icarus 345, 113718 (2020). 25. Pieters, C. M., Fischer, E. M., Rode, O. & Basu, A. Optical effects of space
weathering: the role of the finest fraction. J. Geophys. Res. 98, 20817–20824
(1993). northern hemispheric crust. Icarus 345, 113718 (2020). 55. Sharp, Z. D. A laser-based microanalytical method for the in situ
determination of oxygen isotope ratios of silicates and oxides. Geochim. Cosmochim. Acta 54, 1353–1357 (1990). 26. Clark, B. E., Hapke, B., Pieters, C. & Britt, D. Asteroid space weathering and
regolith evolution. in Asteroids III 583–599 (2003). 56. Pack, A. et al. The oxygen isotope composition of San Carlos olivine on the
VSMOW2-SLAP2 scale. Rapid Commun. Mass Spectrom. 1495–1504, https://
doi.org/10.1002/rcm.7582 (2016). g
27. Burbine, T. H., Meibom, A. & Binzel, R. P. Mantle material in the main belt:
battered to bits? Meteorit. Planet. Sci. 31, 607–620 (1996). 57. Peters, S. T. M. et al. Triple oxygen isotope variations in magnetite from iron-
oxide deposits, central Iran, record magmatic fluid interaction with evaporate
and carbonate host rocks. Geology 48, 211–215 (2020). 28. Asphaug, E. in Planetesimals: Early Differentiation and Consequences for
Planets 7–37, https://doi.org/10.1017/9781316339794.002 (2017). and carbonate host rocks. Geology 48, 211–215 (2020). 29. Russell, C. T. et al. Dawn at vesta: testing the protoplanetary paradigm. Science
336, 684–686 (2012). 58. Wostbrock, J. A. G., Cano, E. J. & Sharp, Z. D. ARTICLE Goodrich, C. A. et al. The Northwest Africa 1500 meteorite: not a
maybe a brachinite. Meteorit. Planet. Sci. 45, 1906–1928 (2010). 43. Jurewicz, A. J. G., Mittlefehldt, D. W. & Jones, J. H. Experimental partial
melting of the Allende (CV) and Murchison (CM) chondrites and the origin
of asteroidal basalts. Geochim. Cosmochim. Acta 57, 2123–2139 (1993). y
73. Day, J. M. D., Walker, R. J., Qin, L. & Rumble, D. Late accretion as a natural
consequence of planetary growth. Nat. Geosci. 5, 614–617 (2012). G
d
h C A
l
k
&
h
h 73. Day, J. M. D., Walker, R. J., Qin, L. & Rumble, D. Late accretion as a natural
consequence of planetary growth Nat Geosci 5 614 617 (2012) consequence of planetary growth. Nat. Geosci. 5, 614–617 (201 44. Santos, A. R., Agee, C. B., Shearer, C. K. & McCubbin, F. M. Northwest Africa
8535 and Northwest Africa 10463: new insights into the angrite parent body. in Lunar Planet. Sci. Conf. XLVII, 2590 (abstr.) (2016). 74. Goodrich, C. A., Wlotzka, F., Ross, D. K. & Bartoschewitz, R. Northwest
Africa 1500: plagioclase-bearing monomict ureilite or ungrouped achondrite? Meteorit. Planet. Sci. 41, 925–952 (2006). 45. Keil, K. Brachinite meteorites: partial melt residues from an FeO-rich asteroid. Chem. der Erde 74, 311–329 (2014). 75. Goodrich, C. A., Fioretti, A. M., Tribaudino, M. & Molin, G. Primary trapped
melt inclusions in olivine in the olivine-augite-orthopyroxene ureilite Hughes
009. Geochim. Cosmochim. Acta 65, 621–652 (2001). 46. Day, J. M. D. et al. Differentiation processes in FeO-rich asteroids revealed by
the achondrite Lewis Cliff 88763. Meteorit. Planet. Sci. 50, 1750–1766 (2015). 47. Goodrich, C. A. & Righter, K. Petrology of unique achondrite Queen
Alexandra Range 93148: a piece of the pallasite (howardite-eucrite-diogenite?)
parent body? Meteorit. Planet. Sci. 35, 521–535 (2000). ARTICLE & Gross, J. The Miller
Range 090340 and 090206 meteorites: Identification of new brachinite-like
achondrites with implications for the diversity and petrogenesis of the
brachinite clan. Meteorit. Planet. Sci. 52, 949–978 (2017). 64. Zhang, C., Miao, B. & He, H. Oxygen isotopes in HED meteorites and their
constraints on parent asteroids. Planet. Space Sci. 168, 83–94 (2019). 65. Sanborn, M. E. & Yin, Q.-Z. Chromium isotopic composition of the
anomalous eucrites: an additional geochemical parameter for evaluating their
origin. Lunar Planet. Sci. Conf. 45, #2018 (abstr.) (2014). brachinite clan. Meteorit. Planet. Sci. 52, 949–978 (2017). 38. Sanborn, M. E., Yin, Q.-Z. & Mittlefehldt, D. W. The diversity of anomalous
HEDs: isotopic constraints on the connection of EET 92023, GRA 98098, and
Dhofar 700 with Vesta. in Lunar Planet. Sci. Conf. XLVII, 2256 (abstr.) (2016). 66. Barrett, T. J. et al. The mineralogy and petrology of anomalous eucrite
Emmaville. in Lunar Planet. Sci. Conf. XLVI, #2108 (abstr.) (2015). 39. Scott, E. R. D., Greenwood, R. C., Franchi, I. A. & Sanders, I. S. Oxygen
isotopic constraints on the origin and parent bodies of eucrites, diogenites,
and howardites. Geochim. Cosmochim. Acta 73, 5835–5853 (2009). 67. Barrat, J. A. et al. Geochemistry of diogenites: still more diversity in their
parental melts. Meteorit. Planet. Sci. 43, 1759–1775 (2008). 68. Trinquier, A., Birck, J. & Allegre, C. J. Widespread 54Cr heterogeneity in the
inner solar system. Astrophys. J. 655, 1179–1185 (2007). 40. Unsalan, O. et al. The Sariçiçek howardite fall in Turkey: source crater of HED
meteorites on Vesta and impact risk of Vestoids. Meteorit. Planet. Sci. 54,
953–1008 (2019). 69. Wiechert, U. H., Halliday, A. N., Palme, H. & Rumble, D. Oxygen isotope
evidence for rapid mixing of the HED meteorite parent body. Earth Planet. Sci. Lett. 221, 373–382 (2004). 41. Day, J. M. D., Brandon, A. D. & Walker, R. J. Highly siderophile elements in
Earth, Mars, the Moon, and asteroids. Rev. Mineral. Geochemistry 81, 161–238
(2016). 70. Greenwood, R. C. et al. The oxygen isotope composition of diogenites:
evidence for early global melting on a single, compositionally diverse, HED
parent body. Earth Planet. Sci. Lett. 390, 165–174 (2014). 42. Keil, K. Angrites, a small but diverse suite of ancient, silica-undersaturated
volcanic-plutonic mafic meteorites, and the history of their parent asteroid. Chem. der Erde 72, 191–218 (2012). 71. Lodders, K., Palme, H. & Gail, H.-P. in Solar System Vol. III, 712–770 (2009). 72. References Brachinites:
igneous rocks from a differentiated asteroid. Meteorit. Planet. Sci. 38,
1601–1625 (2003). Chromium isotopic analysis. An interior fusion-crust-free chip of each sample
was ground to a powder using an agate mortar and pestle. For dissolution, an
aliquot (~15 mg) of the whole-rock powder was placed into a PTFE capsule with a
3:1 mixture of concentrated HF:HNO3 that was sealed in a stainless-steel Parr
bomb jacket. The Parr bomb was heated at 190 °C for 96 hours in an oven. After
complete dissolution, the sample was processed through a 3-column chemistry
extraction procedure to separate Cr from all other matrix elements59. Cr recovery
yields for the three ultramafic samples are all above 99% for the first column,
92–94% for the second column, and 91–97% for the third column, with a total
cumulative yield of 84–88%. The purified Cr fractions were loaded onto outgassed 21. Warren, P. H. & Kallemeyn, G. W. Allan Hills 84025: the second brachinite,
far more differentiated than brachina, and an ultramafic achondritic clast
from L Chondrite Yamato 75097. in Proc. 19th Lunar Planet. Sci. Conf. 475–486 (1989). 22. Swindle, T. D., Kring, D. A., Burkland, M. K., Hill, D. H. & Boynton, W. V. Noble gases, bulk chemistry, and petrography of olivine-rich achondrites NATURE COMMUNICATIONS | (2021) 12:5443 | https://doi.org/10.1038/s41467-021-25808-9 | www.nature.com/naturecommunications 6 The authors declare no competing interests. The authors declare no competing interests. ARTICLE ARTICLE Author contributions 48. Hahn, T. M., Lunning, N. G., McSween, H. Y., Bodnar, R. J. & Taylor, L. A. Mg-rich harzburgites from Vesta: mantle residua or cumulates from planetary
differentiation? Meteorit. Planet. Sci. 53, 514–546 (2018). Sample preparation, optical petrography, and scanning electron microscopy were per-
formed by Zoltan Vaci. Electron microprobe data were collected by Zoltan Vaci and
Rainer Bartoschewitz. Oxygen isotopic analysis was performed by Karen Ziegler and
Andreas Pack. Trace element and highly siderophile element geochemistry were analyzed
by James Day and Marine Paquet. Chromium isotopic analysis was performed by Qing-
zhu Yin, Audrey Miller, and Supratim Dey. Initial characterization of meteorites was
performed by Carl Agee. 49. Frey, F. A. in Developments in Geochemistry Vol. 2 (Elsevier B.V., 1984). 50. Ermakov, A. I. et al. Constraints on Vesta’s interior structure using gravity and
shape models from the Dawn mission. Icarus 240, 146–160 (2014). 51. Consolmagno, G. J. et al. Is Vesta an intact and pristine protoplanet? Icarus
254, 190–201 (2015). 7 NATURE COMMUNICATIONS | (2021) 12:5443 | https://doi.org/10.1038/s41467-021-25808-9 | www.nature.com/naturecommunications Competing interests Open Access This article is licensed under a Creative Commons
Attribution 4.0 International License, which permits use, sharing,
adaptation, distribution and reproduction in any medium or format, as long as you give
appropriate credit to the original author(s) and the source, provide a link to the Creative
Commons license, and indicate if changes were made. The images or other third party
material in this article are included in the article’s Creative Commons license, unless
indicated otherwise in a credit line to the material. If material is not included in the
article’s Creative Commons license and your intended use is not permitted by statutory
regulation or exceeds the permitted use, you will need to obtain permission directly from
the copyright holder. To view a copy of this license, visit http://creativecommons.org/
licenses/by/4.0/. Additional information Supplementary information The online version contains supplementary material
available at https://doi.org/10.1038/s41467-021-25808-9. Correspondence and requests for materials should be addressed to Zoltan Vaci. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations. © The Author(s) 2021, corrected publication 2021 NATURE COMMUNICATIONS | (2021) 12:5443 | https://doi.org/10.1038/s41467-021-25808-9 | www.nature.com/naturecommunications 8 8 NATURE COMMUNICATIONS | (2021) 12:5443 | https://doi.org/10.1038/s41467-021-25808-9 | www.nature.com/naturecommunicatio
|
https://openalex.org/W3172944631
|
https://eprints.ncl.ac.uk/fulltext.aspx?url=276985/D47FFF6A-861A-49C0-9C57-CFD2245DC152.pdf&pub_id=276985
|
English
| null |
Derivation and Validation of a 10-Year Risk Score for Symptomatic Abdominal Aortic Aneurysm: Cohort Study of Nearly 500 000 Individuals
|
Circulation
| 2,021
|
cc-by
| 9,796
|
Circulation is available at www.ahajournals.org/journal/circ
Correspondence to: Paul Welsh, PhD, Institute of Cardiovascular and Medical Sciences, University of Glasgow, British Heart Foundation Glasgow Cardiovascular
Research Centre, Glasgow, United Kingdom. Email paul.welsh@glasgow.ac.uk
This manuscript was sent to Mary McDermott, Guest Editor, for review by expert referees, editorial decision, and final disposition.
*P. Welsh and C. E. Welsh contributed equally.
The Data Supplement is available with this article at https://www.ahajournals.org/doi/suppl/10.1161/CIRCULATIONAHA.120.053022.
For Sources of Funding and Disclosures, see page 613–614.
© 2021 The Authors. Circulation is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the
terms of the Creative Commons Attribution License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited. ORIGINAL RESEARCH ARTICLE ORIGINAL RESEARCH ARTICLE ORIGINAL RESEARCH ARTICLE Circulation Circulation Derivation and Validation of a 10-Year Risk Score
for Symptomatic Abdominal Aortic Aneurysm
C h t St d
f N
l 500000 I di id
l Cohort Study of Nearly 500 000 Individuals Paul Welsh
, PhD*; Claire E. Welsh, PhD*; Pardeep S. Jhund, MD; Mark Woodward
, PhD; Rosemary Brown
, PhD;
Jim Lewsey
, PhD; Carlos A. Celis-Morales, PhD; Frederick K. Ho, PhD; Daniel F. MacKay, PhD; Jason M.R. Gill, PhD;
Stuart R. Gray, PhD; S. Vittal Katikireddi, MD; Jill P. Pell, MD; John Forbes, PhD; Naveed Sattar, MD BACKGROUND: Abdominal aortic aneurysm (AAA) can occur in patients who are ineligible for routine ultrasound screening. A
simple AAA risk score was derived and compared with current guidelines used for ultrasound screening of AAA. METHODS: United Kingdom Biobank participants without previous AAA were split into a derivation cohort (n=401 820, 54.6%
women, mean age 56.4 years, 95.5% White race) and validation cohort (n=83 816). Incident AAA was defined as first hospital
inpatient diagnosis of AAA, death from AAA, or an AAA-related surgical procedure. A multivariable Cox model was developed in
the derivation cohort into an AAA risk score that did not require blood biomarkers. To illustrate the sensitivity and specificity of
the risk score for AAA, a theoretical threshold to refer patients for ultrasound at 0.25% 10-year risk was modeled. Discrimination
of the risk score was compared with a model of US Preventive Services Task Force (USPSTF) AAA screening guidelines. What Are the Clinical Implications? • More work needs to be done to develop and test dif-
ferent approaches to refer patients for AAA ultrasound
screening. These data suggest that risk score–based
approaches are potentially feasible in clinical practice. Nonstandard Abbreviations and Acronyms AAA
Abdominal aortic aneurysm
AIC
Akaike information criterion
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
BMI
Body mass index (BMI)
CRP
C-reactive protein
CVD
Cardiovascular disease
DBP
Diastolic blood pressure
GGT
Gamma-glutamyl transferase
HDL
High density lipoprotein ()-cholesterol
ICD
International Classification of Diseases
and Related Health Problems
IQI
Interquartile interval
LDL
Low density lipoprotein cholesterol
Lp(a)
Lipoprotein (a)
NHS
National health service
NICE
National Institute for Health and Excellence
NRI
Net reclassification index
OPCS
Office of Population, Censuses and
Surveys: Classification of Interventions
and Procedures
PP
Pulse pressure
SBP
Systolic blood pressure
TRIPOD
Transparent reporting of a multivariable
prediction model for individual progno-
sis or diagnosis
USPSTF
US Preventive Services Task Force AAA
Abdominal aortic aneurysm
AIC
Akaike information criterion
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
BMI
Body mass index (BMI)
CRP
C-reactive protein
CVD
Cardiovascular disease
DBP
Diastolic blood pressure
GGT
Gamma-glutamyl transferase
HDL
High density lipoprotein ()-cholesterol
ICD
International Classification of Diseases
and Related Health Problems
IQI
Interquartile interval
LDL
Low density lipoprotein cholesterol
Lp(a)
Lipoprotein (a)
NHS
National health service
NICE
National Institute for Health and Excellence
NRI
Net reclassification index
OPCS
Office of Population, Censuses and
Surveys: Classification of Interventions
and Procedures
PP
Pulse pressure
SBP
Systolic blood pressure
TRIPOD
Transparent reporting of a multivariable
prediction model for individual progno-
sis or diagnosis
USPSTF
US Preventive Services Task Force This study aimed to use a large, well-phenotyped
United Kingdom database to develop, and internally vali-
date, an AAA risk score using simple clinical data. It was
hypothesized that such a risk score could more precisely
discriminate those at risk of adverse outcomes from AAA
than current approaches. RESULTS: RESULTS: In the derivation cohort, there were 1570 (0.40%) cases of AAA over a median 11.3 years of follow-up. Components
of the AAA risk score were age (stratified by smoking status), weight (stratified by smoking status), antihypertensive and
cholesterol-lowering medication use, height, diastolic blood pressure, baseline cardiovascular disease, and diabetes. In the
validation cohort, over 10 years of follow-up, the C-index for the model of the USPSTF guidelines was 0.705 (95% CI,
0.678–0.733). The C-index of the risk score as a continuous variable was 0.856 (95% CI, 0.837–0.878). In the validation
cohort, the USPSTF model yielded sensitivity 63.9% and specificity 71.3%. At the 0.25% 10-year risk threshold, the risk
score yielded sensitivity 82.1% and specificity 70.7% while also improving the net reclassification index compared with the
USPSTF model +0.176 (95% CI, 0.120–0.232). A combined model, whereby risk scoring was combined with the USPSTF
model, also improved prediction compared with USPSTF alone (net reclassification index +0.101 [95% CI, 0.055–0.147]). Downloaded from http://ahajournals.org by on September 13, 2021 CONCLUSIONS: In an asymptomatic general population, a risk score based on patient age, height, weight, and medical history
may improve identification of asymptomatic patients at risk for clinical events from AAA. Further development and validation
of risk scores to detect asymptomatic AAA are needed. ournals.org by on September 13, 2021 Key Words: aneurysm ◼ prediction ◼ risk score Key Words: aneurysm ◼ prediction ◼ risk score A
n aneurysm is a pathological distension of a
section of blood vessel, typically the aorta.1–4
Aortic aneurysms can occur anywhere in the
aorta’s length, but abdominal aortic aneurysms (AAAs) AA are associated with increased mortality if rupture occurs
(around 50% in those who reach the hospital) because
of catastrophic bleeding.1,5,6 In the Oxford Vascular
Study, among 65- to 74-year-olds, the incidence was 5.5 Circulation. 2021;144:604–614. DOI: 10.1161/CIRCULATIONAHA.120.053022 Circulation. 2021;144:604–614. DOI: 10.1161/CIRCULATIONAHA.120.053022 604 August 24, 2021 Welsh et al Prediction of AAA events per 10 000 person-years in men and 1.1 events
per 10 000 person-years in women.7 Death from AAA
accounts for around 2% of all deaths in men aged 65
and over, and few clinical symptoms are noted in AAA
that subsequently rupture. ORIGINAL RESEARCH
ARTICLE What Is New? • A model based on US Preventive Services Task
Force guidelines yielded sensitivity of 63.9% and
specificity 71.3% in identifying patients who would
potentially benefit from ultrasound on the basis of
incidence of abdominal aortic aneurysm (AAA). q
y
p
In the United Kingdom, a routine screening program
invites men in the year of their 65th birthday for abdomi-
nal ultrasonography, and more recent updates suggest
women of age 70 years and over be screened if they have
risk factors such as ever smoking, or if they have cardio-
vascular disease, chronic obstructive pulmonary disease,
peripheral arterial disease, hyperlipidemia, hypertension,
or a family history of AAA.8,9 If an AAA of >5.5 cm diam-
eter is detected, the patient is rapidly referred for surgical
intervention, with slower referral for smaller-sized AAA. In
2019, the US Preventive Services Task Force (USPSTF)
recommended screening for AAA in men aged 65 to 75
years who have ever smoked. The USPSTF recommends
against routine screening in women who have never
smoked and have no family history of AAA and states
that evidence is insufficient to recommend for or against
AAA screening in women with either history of smok-
ing or family history of AAA.10,11 Although not all interna-
tional recommendations agree on a precise screening
strategy, others are broadly similar.12 Screening for
AAA in women has not been demonstrated to be clini-
cally effective.13 In considering balancing the risks and
benefits of screening, ultrasonography itself has high
sensitivity (94%–100%) and specificity (98%–100%)
for the detection of AAA, although risk and benefits
of surgical intervention for smaller aneurysms must be
carefully considered.8,11 Although age-based screen-
ing thresholds in women may not be cost-effective,14
a more refined risk score based on systematic routine
clinical data may help improve clinical care. • In contrast, a model based on an AAA risk score,
with guidance to refer for abdominal ultrasound at a
threshold of 0.25% 10-year risk, yielded sensitivity
82.1% and specificity 70.7%. • In contrast, a model based on an AAA risk score,
with guidance to refer for abdominal ultrasound at a
threshold of 0.25% 10-year risk, yielded sensitivity
82.1% and specificity 70.7%. pi
y
• A simple 10-year AAA risk score, using routine clini-
cal information without the need for blood tests,
therefore gives excellent discrimination of those at
risk of adverse outcomes from incident AAA. What Is New? pi
y
• A simple 10-year AAA risk score, using routine clini-
cal information without the need for blood tests,
therefore gives excellent discrimination of those at
risk of adverse outcomes from incident AAA. Characteristics Associated With AAA Events disease (International Classification of Diseases, Tenth Revision
[ICD-10] codes I71–I73, I77–I79) before or within 30 days
after the UK Biobank assessment date (n=2969). After
further excluding 13 436 participants with missing data for
covariates, there were 485 636 participants with complete
data included in the study. ORIGINAL RESEARCH
ARTICLE Characteristics considered for a simple AAA risk score (ie, a
score that does not involve the use of blood biomarkers, and
involves variables routinely collected in clinical data) were
age, sex, systolic blood pressure, diastolic blood pressure,
pulse pressure, smoking status, alcohol use, height, weight,
body mass index, baseline cardiovascular disease (CVD; hos-
pitalization with diagnoses including ICD-10 codes I20–I25
and I60–I69 occurring before the date of assessment), fam-
ily history of CVD (self-report of heart disease or stroke in
a mother, father, or sibling), baseline diabetes (self-reported
type 1 or type 2 diabetes, and those who reported using
insulin), chronic kidney disease, atrial fibrillation, rheumatoid
arthritis (self-reported), use of blood pressure–lowering med-
ication (self-reported), and cholesterol-lowering medications
(self-reported). Rheumatoid arthritis was included in the list
of potential characteristics associated with AAA because it is
a systemic inflammatory condition that may confer increased
risk of AAA.21 A further AAA risk score, including the same
clinical variables as well as blood-based biomarkers, was
developed. Potential biomarkers tested for inclusion were
white blood cell count, platelet count, low-density lipoprotein
cholesterol, high-density lipoprotein cholesterol, triglycerides,
lipoprotein(a) (Lp[a]), liver function tests (aspartate amino-
transferase, alanine aminotransferase, alkaline phosphatase,
and γ-glutamyl transferase), glucose, cystatin-C, C-reactive
protein, and vitamin D. Blood collection sampling procedures
for the UK Biobank study have been previously described and
validated.22 Blood tests were performed at a dedicated cen-
tral laboratory, using rigorous quality control and external per-
formance monitoring. Further details of these measurements
and assay performances can be found in the UK Biobank
online showcase and protocol.22 Implementation of the United Kingdom National Health
Service (NHS) screening policy for AAA in men aged 65 or
over was complete in most parts of the United Kingdom by late
2009.17 In this analysis, the data were divided into 2 sets, the
derivation and validation sets (ie, a holdout set). The deriva-
tion group was those participants who attended their baseline
assessment on or before December 31, 2009 (n=401 820). Those whose baseline assessment was on or after January 1,
2010 (n=83 816) were used as a nonrandom holdout internal
validation cohort. Characteristics Associated With AAA Events The nonrandom design of the validation hold-
out cohort serves 2 purposes. First, it provides an estimate of
whether the risk score performs similarly once the new screen-
ing approach was implemented. Second, a nonrandom split may
be preferable as it reduces the similarity of the 2 sets of partici-
pants, thereby strengthening the intended validation.18 UK Biobank received ethical approval from the North West
Multi-Center Research Ethics Committee (REC reference: 11/
NW/03820). All participants gave written informed consent
before enrollment, in accordance with the principles of the
Declaration of Helsinki. This project was performed under UK
Biobank project approval No. 42475. Data Source and Cohort Selection The data used in this study are available via UK Biobank
(https://www.ukbiobank.ac.uk/), subject to necessary approv-
als. UK Biobank is a large population-based cohort study of
502 488 participants ranging in age from 37 to 73 years,
recruited between 2006 and 2010.15,16 All participants under-
went an assessment at 1 of 22 centers across England,
Scotland, and Wales, where touch-screen questionnaires
recorded health and lifestyle information, and a wide range of
biological measurements were taken. g
Participants were excluded if they self-reported history
of aortic aneurysm, aortic dissection, or cerebral aneurysm
(n=447), or if participants had a hospital diagnosis of vascular Circulation. 2021;144:604–614. DOI: 10.1161/CIRCULATIONAHA.120.053022 August 24, 2021
605 August 24, 2021
605 Welsh et al Prediction of AAA Characteristics Associated With AAA Events Outcome The NHS in the United Kingdom generates routine data on
admissions that includes details of all inpatient admissions
at all NHS hospitals, and these hospital records were linked
by anonymized numeric participant identification number to
UK Biobank participants.19,20 All clinical data in the hospi-
tal inpatient data were coded according to the World Health
Organization’s ICD-10 codes. All operations and procedures
were coded according to the Office of Population, Censuses
and Surveys: Classification of Interventions and Procedures
codes (OPCS-4). Dates and causes of death were obtained
from death certificates held by the NHS Information Center
for participants from England and Wales and the NHS Central
Register Scotland for participants from Scotland. Derivation Cohort In the derivation cohort of 401 820 participants (54.6%
women, mean age 56.4 years, 95.5% White, 1.3% Black,
2.0% South Asian, 1.3% other race) at baseline, 17.5%
of women and 20.0% of men were >65 years old, and
0.4% of women and 0.5% of men were >70 years old. Over a median of 11.3 (IQI 10.7, 11.9) years of follow-up,
62.1% of women and 62.8% of men attained an age of
at least 65 years, and 43.3% of women and 44.6% of
men attained an age of at least 70 years. There were 1570 (0.4%) incident cases of AAA over
the follow-up. Of 279 events in women, 107 (38.4%)
occurred before the age of 70 years, and of 1291 events
in men, 199 (15.4%) occurred before the age of 65
years (Figure 1). The mean age at which an AAA event
occurred was 70.8 years (SD 5.7 years) in women and
70.4 years (SD 5.5 years) in men. The incidence of AAA was 3.6 (95% CI, 3.4–3.7) per
10 000 person-years, 1.1 (95% CI, 1.0–1.3) per 10 000
person-years in women, and 6.5 (95% CI, 6.1–6.8) in
men per 10 000 person-years. In participants aged <65
years at baseline, the incidence was 0.7 (95% CI, 0.6–
0.8) per 10 000 person-years in women and 4.0 (95%
CI, 3.7–4.3) per 10 000 person-years in men. In partici-
pants aged 65 years or older at baseline, the incidence
was 3.4 (95% CI, 2.9–4.0) per 10 000 person-years
in women and 16.9 (95% CI, 15.7–18.3) in men per
10 000 person-years. A 10-year AAA risk score was then derived from the Cox
models, using the derivation cohort. Predicted 10-year risk was
derived for each participant, using appropriate centering for
each continuous variable (median age 58 years, weight 76 kg,
height 168 cm). The calibration of the risk score was evalu-
ated separately in the validation and derivation cohort, over 10
years, using the stcoxgrp command, as previously described.25
A range of binary thresholds (chosen pragmatically based on
observed data) were considered as potential “high-risk” thresh-
olds to refer for ultrasound screening (specifically, thresholds at
0.25% 10-year risk, 0.3% 10-year risk, and 0.5% 10-year risk). Using these thresholds, a range of sensitivities, specificities,
positive predictive values, and negative predictive values were
obtained. Downloaded from http://ahajournals.org by on September 13, 2021 A hypothetical model whereby all men are screened at
age 65 years, and all women are screened at age 70
years. This model is intended to act a comparative clinical
approach where sensitivity is prioritized over specificity for
an age-based approach to referral for ultrasound. and specificity. The performance of these risk score thresholds
was compared with “current clinical practice” models described
in Characteristics Associated With AAA Events. We also mod-
eled a “combined approach” whereby all participants in the
cohort would be given an AAA risk score at baseline (refer-
ring those at 0.30% 10-year risk for ultrasound), and also in
parallel referring all participants for ultrasound according to the
above model of USPSTF guidelines. Binary net reclassification
index (NRI) was also assessed in comparing the performance
of specific risk score thresholds to the performance of current
clinical practice. ORIGINAL RESEARCH
ARTICLE ORIGINAL RESEARCH
ARTICLE Details of the definitions underpinning these models are
given in the Expanded Methods in the Data Supplement. Statistical Analyses Continuous variables are presented as mean and SD if approxi-
mately symmetrically distributed, and median and interquartile
interval (IQI) if skewed. Categorical variables were presented
as counts and percentages. Each variable was tested for asso-
ciation with incident AAA, separately in derivation and valida-
tion cohorts, using an unpaired t test, the Wilcoxon rank-sum
test, or a χ2 test as appropriate. We followed recommendations for Transparent reporting
of a multivariable prediction model for individual prognosis or
diagnosis (TRIPOD) reporting guidelines for development and
validation.26 All analyses were performed in STATA (version
15.1) or in R (version 4.0.3) for C-index and NRI analyses. A forward model building process was implemented for the
“AAA risk score” in the derivation cohort, starting with a model
including age, sex, and baseline CVD and comparing models
for improvement in Akaike information criterion (>10 U dif-
ference) on addition of new variables.24 Where there was evi-
dence of potential collinearity (such as with pulse pressure and
systolic blood pressure), the variable that fit the model better
was preferentially used. Continuous variables were first tested
for linearity of the association with AAA using restricted cubic
splines, log transforming the marker if required. If the asso-
ciation was not linear, the variable was categorized based on
turning or inflection points (this was only the case for diastolic
blood pressure, where a binary model split at 90 mm Hg was
implemented). Once all variables had been tested and the vari-
ables for inclusion finalized, all potential pairwise multiplicative
interactions between retained variables were tested for addi-
tional inclusion, again on the basis of improving the Akaike
information criterion by >10 U. An additional AAA risk score
that included clinical variables and blood biomarkers (“AAA risk
score with blood biomarkers”) was an extension of the simple
AAA risk score, and tested model fit on addition of blood bio-
markers, in the same manner. The proportional hazard assump-
tion was tested by visual inspection of Schöenfeld residuals. The final Cox models were then run separately in the validation
cohort. The predictive ability of the Cox models, over 10 years
of follow-up, was tested by Harrell’s C-index separately in both
derivation and validation cohorts, using 2000 bootstraps. These
metrics were compared with the C-index from Cox models of
current clinical practice (which were time-varying models). Downloaded from http://ahajournals.org by on September 13, 2021 Systolic and diastolic blood pressure were measured in each
participant, following a standardized protocol. The average of
2 measurements was used, preferentially using an automated
reading where available. Pulse pressure was calculated as sys-
tolic blood pressure minus diastolic blood pressure. Weight was
measured using a Tanita BC418MA body composition analyzer,
and body mass index was calculated as weight (kg)/height
(m).2 Smoking status was categorized as never, former, or cur-
rent smoker. Postcode of residence was used to determine the
Townsend socioeconomic deprivation index at recruitment.23
Participants were asked, “What is your ethnic group?” and we
defined responses to this as race/ethnicity using categories of
White, Black, South Asian, or other. The outcome of interest was first hospital inpatient diag-
nosis of AAA or death from AAA (both based on ICD-10
codes I71.3 or I71.4), or an AAA-related surgical procedure
(Expanded Methods in the Data Supplement). The definition
of AAA-related inpatient diagnosis was therefore based on
diagnostic codes for AAA but did not relate to specific diag-
nostic criteria (such as aneurysm size). As a sensitivity analy-
sis to test performance of the model in discriminating the
most serious incident AAA cases, a composite outcome was
derived for death from AAA (ICD-10 codes I71.3 or I71.4) or
an AAA-related surgical procedure only. In deriving survival
models for each participant, the start of the period at risk
was the date of assessment, and the period at risk ended at
the first qualifying AAA event, or end of follow-up (June 30,
2020, in England; February 29, 2016, in Wales; October 31,
2017, in Scotland), whichever came first. For the 10-year risk
score, follow-up was curtailed to a maximum of 10 years for
each participant. For comparison with the AAA risk score, models of current
clinical practices for screening for AAA with ultrasonography
were as follows: 1. A model of current USPSTF guidelines (conduct abdomi-
nal ultrasound screening in men and women who have
ever smoked, and men who have cardiovascular disease,
at age 65–75 years)11 2. A model of current UK National Institute for Health and
Excellence guidelines (conduct abdominal ultrasound
screening in all men at age 66 years, and in women at
age 70 years if they have ever smoked, or if they have
cardiovascular disease, chronic obstructive pulmonary
disease, peripheral arterial disease, hyperlipidemia, or
hypertension).8 Circulation. 2021;144:604–614. DOI: 10.1161/CIRCULATIONAHA.120.053022 August 24, 2021
606 Welsh et al Prediction of AAA 3. August 24, 2021
607 Derivation, Calibration, and Discrimination of
the Clinical AAA Risk Score, and Comparison
With Current Clinical Practice The median 10-year predicted risk using the AAA
risk score was 0.10% (IQI 0.04%, 0.29%) in partici-
pants who did not experience AAA during follow-up. The median 10-year predicted risk was 1.13% (IQI
0.40%, 2.37%) in those who experienced AAA dur-
ing follow-up. The C-index of the AAA risk score was
0.879 (95% CI, 0.870–0.888), and model calibration
based on a “high-risk” threshold at 0.25% 10-year
risk was good (Figure 2). A binary 0.25% 10-year
risk threshold for the AAA risk score had sensitivity
84.1% and specificity 72.1% (Table 3). Choosing a
higher risk score threshold (at 0.30% 10-year risk)
reduced sensitivity (79.7%) while improving specific-
ity (75.8%), whereas a still higher risk score threshold
(at 0.50% 10-year risk) further reduced sensitivity
(70.2%) while improving specificity (84.4%; Table 3). A combination approach, encompassing a baseline
risk score (referring those at 0.3% 10-year risk) as
well as referring participants when they met USP-
STF guideline criteria, had sensitivity 85.1%, whereas
specificity was 63.2% (Table 3). Factors associated with AAA included male sex, taller
height, a diastolic blood pressure >90 mm Hg, and base-
line CVD, whereas baseline diabetes was associated
with lower risk of AAA (Table 2). There were also inter-
actions among other risk factors, which were allowed
for in the model (Table 2). Specifically, older age was a
risk factor, an association that was stronger in current
smokers. Heavier weight was a risk factor, an association
that was stronger in nonsmokers. Use of blood pressure
medication and use of cholesterol-lowering medication
were risk factors individually, as well as an interaction be-
tween them when taking both (Table 2). The clinical AAA
risk score was derived from these risk factors (Expanded
Methods in the Data Supplement). pp
Over 10 years of follow-up, current clinical practice
under the USPSTF guideline model yielded a C-index
of 0.738 (95% CI, 0.726–0.751) and had sensitivity of
69.2% and specificity 71.6% in referring participants
for abdominal ultrasound before AAA in the derivation
cohort (Table 3). The National Institute for Health and
Excellence guideline model yielded a C-index of 0.738
(95% CI, 0.725–0.750) and had sensitivity of 72.5% and
specificity 63.4% in the derivation cohort (Table 3). Derivation Cohort The 0.25% threshold was selected as the primary
threshold, based on maximizing the sum of observed sensitivity Participants diagnosed with AAA over the follow-up
were approximately 7 years older on average at baseline,
had a higher proportion of men, had a higher Townsend
socioeconomic deprivation index, were taller, and had a
more adverse general health profile including a higher
proportion of people who smoked, higher blood pressure
measurements (despite being more likely to take blood
pressure medication), a higher weight and body mass
index, a higher proportion of people with diabetes, and August 24, 2021
607 Circulation. 2021;144:604–614. DOI: 10.1161/CIRCULATIONAHA.120.053022 Prediction of AAA Welsh et al 0
10
20
30
Proportion (%) of incident AAA events
Women: age group (years)
Men: age group (years)
<50 50−54 55−59 60−64 65−69 70−74 ≥75
<50 50−54 55−59 60−64 65−69 70−74 ≥75
Figure 1. Proportion (%) of incident abdominal aortic aneurysm (AAA) events by sex and by age at which event occurred, in
1291 men and 279 women within the derivation cohort. Figure 1. Proportion (%) of incident abdominal aortic aneurysm (AAA) events by sex and by age at which event occurred, in
1291 men and 279 women within the derivation cohort. a higher proportion of people on cholesterol-lowering
medication (Table 1). C-index of 0.737 (95% CI, 0.726–0.749) and had sensi-
tivity of 78.3% and specificity of 54.8% in the derivation
cohort (Table 3). August 24, 2021
608 Derivation, Calibration, and Discrimination of
the Clinical AAA Risk Score, and Comparison
With Current Clinical Practice The
hypothetical strategy to refer all men at age 65 years
and all women at age 70 years for ultrasound yielded a The overall categorical NRI was improved under all
AAA risk score threshold models compared with the
USPSTF guideline model (Table 4). Compared with the
USPSTF model, the risk score at any of the 3 thresh-
olds improved the overall NRI. Specifically, the AAA risk
score threshold at 0.25% 10-year risk improved both
the case NRI +0.149, and the noncase NRI +0.005
(Table 4). Circulation. 2021;144:604–614. DOI: 10.1161/CIRCULATIONAHA.120.053022 August 24, 2021
608 Prediction of AAA Welsh et al Table 1. Derivation, Calibration, and Discrimination of
the Clinical AAA Risk Score, and Comparison
With Current Clinical Practice Baseline Characteristics of 401 820 UK Biobank Participants in the Derivation Cohort, and 83 816 Participants in the
Validation Cohort, by Incident AAA Status (Using Variables Included in the AAA Risk Score)
Variable
Derivation cohort
Validation cohort
Units
No AAA (n=400 250)
AAA (n=1570)
No AAA (n=83 533)
AAA (n=283)
Age at recruitment
Years
56.4 (8.1)
63.4 (5.1)
56.8 (8.1)
63.2 (4.9)
Sex
Male
181 041 (45.2%)
1291 (82.2%)
37 846 (45.3%)
237 (83.7%)
Race/ethnicity
White
382 121 (95.5%)
1549 (98.7%)
75 805 (90.7%)
273 (96.5%)
Black
5016 (1.3%)
8 (0.5%)
2675 (3.2%)
4 (1.4%)
South Asian
7866 (2.0%)
10 (0.6%)
3073 (3.7%)
2 (0.7%)
Other or mixed race
5247 (1.3%)
3 (0.2%)
1980 (2.4%)
4 (1.4%)
Townsend deprivation index
Score units
–1.39 (3.10)
–1.11 (3.15)
–1.03 (2.97)
–1.02 (2.90)
Smoking status
Never
220 582 (55.1%)
327 (20.8%)
46 804 (56.0%)
72 (25.4%)
Former
137 548 (34.4%)
766 (48.8%)
28 686 (34.3%)
144 (50.9%)
Current
42 120 (10.5%)
477 (30.4%)
8043 (9.6%)
67 (23.7%)
BMI
kg/m2
27.4 (4.8)
28.50 (4.5)
27.4 (4.8)
28.8 (4.4)
Standing height
cm
168.4 (9.3)
173.1 (8.3)
168.6 (9.3)
173.6 (8.4)
Weight
kg
77.9 (15.8)
85.6 (16.2)
78.2 (16.0)
87.1 (16.3)
SBP
mm Hg
137.9 (18.7)
144.2 (19.4)
137.5 (18.5)
142.6 (16.6)
DBP
mm Hg
82.3 (10.2)
84.5 (11.2)
82.0 (10.05)
83.2 (10.0)
PP
mm Hg
55.6 (13.7)
59.8 (14.3)
55.5 (13.6)
59.4 (13.6)
Baseline CVD
Yes
15 200 (3.8%)
273 (17.4%)
3500 (4.2%)
58 (20.5%)
Family history of CVD
Yes
226 478 (56.6%)
966 (61.5%)
46 113 (55.2%)
171 (60.4%)
Type 1 or type 2 diabetes
Yes
20 032 (5.0%)
144 (9.2%)
4665 (5.6%)
23 (8.1%)
Chronic kidney disease stage 3–5
Yes
645 (0.2%)
4 (0.3%)
115 (0.1%)
0 (0.0%)
Atrial fibrillation or flutter
Yes
2710 (0.7%)
27 (1.7%)
567 (0.7%)
4 (1.4%)
Rheumatoid arthritis
Yes
4466 (1.1%)
30 (1.9%)
816 (1.0%)
3 (1.1%)
Antihypertensive medication use
Yes
80 490 (20.1%)
726 (46.2%)
17 247 (20.6%)
126 (44.5%)
Cholesterol-lowering medication use
Yes
61 666 (15.4%)
693 (44.1%)
14 202 (17.0%)
116 (41.0%)
Townsend deprivation index is a postcode-based measure of socioeconomic deprivation, with higher scores indicating greater socioeconomic deprivation.23 Num-
bers are mean (SD) or n (%). In the derivation cohort, all variables significantly differ at P<0.001, apart from chronic kidney disease (P=0.36) and rheumatoid arthritis
(P=0.003). ORIGINAL RESEARCH
ARTICLE ORIGINAL RESEARCH
ARTICLE Townsend deprivation index is a postcode-based measure of socioeconomic deprivation, with higher scores indicating greater socioeconomic deprivation.23 Num-
bers are mean (SD) or n (%). In the derivation cohort, all variables significantly differ at P<0.001, apart from chronic kidney disease (P=0.36) and rheumatoid arthritis
(P=0.003). In the validation cohort, all variables significantly differ at P<0.001, apart from race (P=0.008), DBP (P=0.049), Townsend deprivation index (P=0.98), family
history of CVD (P=0.078), diabetes (P=0.063), chronic kidney disease (P=0.53), atrial fibrillation (P=0.13), and rheumatoid arthritis (P=0.89). AAA indicates abdominal
aortic aneurysm; BMI, body mass index; CVD, cardiovascular disease; DBP, diastolic blood pressure; PP, pulse pressure; and SBP, systolic blood pressure. Townsend deprivation index is a postcode-based measure of socioeconomic deprivation, with higher scores indicating greater socioeconomic deprivation.23 Num-
bers are mean (SD) or n (%). In the derivation cohort, all variables significantly differ at P<0.001, apart from chronic kidney disease (P=0.36) and rheumatoid arthritis
(P=0.003). In the validation cohort, all variables significantly differ at P<0.001, apart from race (P=0.008), DBP (P=0.049), Townsend deprivation index (P=0.98), family
history of CVD (P=0.078), diabetes (P=0.063), chronic kidney disease (P=0.53), atrial fibrillation (P=0.13), and rheumatoid arthritis (P=0.89). AAA indicates abdominal
aortic aneurysm; BMI, body mass index; CVD, cardiovascular disease; DBP, diastolic blood pressure; PP, pulse pressure; and SBP, systolic blood pressure. Derivation, Calibration, and Discrimination of
the Clinical AAA Risk Score, and Comparison
With Current Clinical Practice In the validation cohort, all variables significantly differ at P<0.001, apart from race (P=0.008), DBP (P=0.049), Townsend deprivation index (P=0.98), family
history of CVD (P=0.078), diabetes (P=0.063), chronic kidney disease (P=0.53), atrial fibrillation (P=0.13), and rheumatoid arthritis (P=0.89). AAA indicates abdominal
aortic aneurysm; BMI, body mass index; CVD, cardiovascular disease; DBP, diastolic blood pressure; PP, pulse pressure; and SBP, systolic blood pressure. Table 1. Baseline Characteristics of 401 820 UK Biobank Participants in the Derivation Cohort, and 83 816 Participants in the
Validation Cohort, by Incident AAA Status (Using Variables Included in the AAA Risk Score) DISCUSSION This study developed and validated a simple AAA risk
score, based on data available in routine primary care, for
estimating 10-year risk of AAA associated with adverse
outcomes in men and women. Using a model in which
“high-risk” was defined as a risk of at least 0.25% over
10 years, a risk score–based approach to refer patients
for abdominal ultrasound may detect asymptomatic AAA
with improved sensitivity and specificity, compared with
the existing clinical approaches based on age and sex. This supports the notion that, with availability of simple
clinical information plus measures of weight, height, and
blood pressure, a simple computer-based algorithm may
be able to efficiently recommend referral for abdominal
ultrasound using a range of risk factors. AAA indicates abdominal aortic aneurysm; BP, blood pressure; CVD, car-
diovascular disease; DBP, diastolic blood pressure; HR, hazard ratio; and Ref,
referent group for categorical variables. AAA indicates abdominal aortic aneurysm; BP, blood pressure; CVD, car-
diovascular disease; DBP, diastolic blood pressure; HR, hazard ratio; and Ref,
referent group for categorical variables. Downloaded from http://ahajournals.org by on September 13, 2021 0.856 (95% CI, 0.837–0.878) in the validation cohort;
therefore, discrimination from the risk score was slightly
lower than in the derivation cohort. Calibration of the risk
score was also good in the validation cohort (Figure 2). In the validation cohort, a threshold at 0.25% 10-year
risk had sensitivity 82.1% and specificity 70.7%. Higher-
risk score thresholds lowered sensitivity but increased
specificity (Table 3). 0.856 (95% CI, 0.837–0.878) in the validation cohort;
therefore, discrimination from the risk score was slightly
lower than in the derivation cohort. Calibration of the risk
score was also good in the validation cohort (Figure 2). In the validation cohort, a threshold at 0.25% 10-year
risk had sensitivity 82.1% and specificity 70.7%. Higher-
risk score thresholds lowered sensitivity but increased
specificity (Table 3). The categorical NRI was improved under the AAA
risk score model compared with the USPSTF guide-
line model in the validation cohort (Table 4). Specifi-
cally, the AAA risk score threshold at 0.25% 10-year
risk improved both the case NRI +0.182, but not the
noncase NRI –0.006 (Table 4). The rates of AAA reported here are in broad agree-
ment with other literature from similar cohorts. Validation of the AAA Risk Score and
Comparison With Current Clinical Practice Over 10 years of follow-up, current clinical practice
under the USPSTF guideline model yielded a C-index
of 0.705 (95% CI, 0.678–0.733) and had sensitivity of
63.9% and specificity 71.3% in the validation cohort
(Table 3). The National Institute for Health and Excellence
guideline model yielded a C-index of 0.719 (95% CI,
0.692–0.745) and had sensitivity of 71.4% and specificity
61.4% in the validation cohort (Table 3). The hypothetical
strategy to refer all men at age 65 years and all women
at age 70 years for ultrasound yielded a C-index of 0.724
(95% CI, 0.701–0.747) and had sensitivity of 78.6% and
specificity 52.5% in the validation cohort (Table 3). The validation cohort (83 816 participants, 54.6%
women, mean age 56.8 years, 90.8% White, 3.2%
Black, 3.7% South Asian, 2.4% other race) had dif-
ferent distributions of demographics and covariates
than the derivation cohort. Specifically, the validation
cohort was slightly older and more likely to be non-
White race; participants were slightly taller, weighed
slightly more, and were more likely to have baseline
CVD and diabetes than the derivation cohort (Table 1,
Table I in the Data Supplement). pi
y
The median 10-year predicted risk was 0.11% (IQI
0.04, 0.31) in participants who did not experience AAA
during follow-up in the validation cohort. The median
10-year predicted risk was 0.94% (IQI 0.36, 1.92) in par-
ticipants who experienced AAA during follow-up. Over
10 years, the C-index of the risk prediction model was In the validation cohort there were 283 (0.34%)
cases of AAA over a median of 10.2 years of follow-up
(IQI, 10.1–10.3). The incidence of AAA in the validation
cohort was 3.4 (95% CI, 3.0–3.8) per 10 000 person-
years (similar to the derivation cohort). Circulation. 2021;144:604–614. DOI: 10.1161/CIRCULATIONAHA.120.053022 August 24, 2021
609 Prediction of AAA Welsh et al ORIGINAL RESEARCH
ARTICLE Table 2. DISCUSSION For exam-
ple, in the Oxford Vascular Study, among men and women
aged 65 to 74 years, the AAA incidence was 3.2 events
per 10 000 person-years.7 In UK Biobank, it was 3.6
events per 10 000 person-years. These data are there-
fore likely identifying similar events to previous work. In
addition, the basic risk factors identified in UK Biobank
are entirely consistent with existing literature in that AAA
is associated with older age, male sex, high blood pres-
sure, smoking, baseline CVD disease, and height.1,27 In
particular, a separate meta-analysis also reported non-
linear association of diastolic blood pressure with AAA.28
Associations of incident AAA with an adverse lipid pro-
file,1 poor renal function,29 and inflammation30 have also
been reported. The finding of a continuous association
of Lp(a) with AAA is consistent with previous meta- Derivation and Validation of the AAA Risk
Score Including Clinical Variables and Blood
Biomarkers Table 2. Cox Proportional Hazard Model of Risk Predictors
for AAA, Using Variables Included in the AAA Risk Score, in
401 820 Participants in the Derivation Cohort In the AAA risk score including blood biomarkers
(N=309 077 participants, n=1237 AAA events in the
derivation cohort; N=65 591 participants, n=236 AAA
events in the validation cohort; Tables III and IV in the
Data Supplement), diabetes was no longer included in
the predictive model, but higher C-reactive protein, high-
er low-density lipoprotein cholesterol, lower high-density
lipoprotein cholesterol, higher Lp(a), higher cystatin-C,
lower alanine aminotransferase, and lower platelet count
were all associated with increased risk of AAA (Table V
in the Data Supplement). Model discrimination was good
(Figure I in the Data Supplement), with a C-index in the
derivation cohort of 0.889 (95% CI, 0.881–0.899) and
a C-index in the validation cohort of 0.849 (95% CI,
0.826–0.877). This suggests the AAA risk score includ-
ing blood biomarkers yielded similar discrimination to the
simple AAA risk score in the validation cohort (Tables VI
and VII in the Data Supplement). Validation of the AAA Risk Score and
Comparison With Current Clinical Practice Cox Proportional Hazard Model of Risk Predictors
for AAA, Using Variables Included in the AAA Risk Score, in
401 820 Participants in the Derivation Cohort
Variable
HR
95% CI
Age in nonsmokers (per year increase)
1.130
1.116–1.143
Age in former smokers (per year increase)
1.147
1.134–1.160
Age in current smokers (per year increase)
1.191
1.177–1.205
Weight in nonsmokers (per kg increase)
1.013
1.006–1.019
Weight in former smokers (per kg increase)
1.012
1.007–1.016
Weight in current smokers (per kg increase)
0.998
0.992–1.004
No BP or cholesterol-lowering medication use
Ref
Ref
BP-lowering medication use alone
1.712
1.473–1.988
Cholesterol-lowering medication use alone
1.993
1.696–2.341
Cholesterol-lowering and BP medication use
2.180
1.897–2.506
Height (per cm increase)
1.021
1.012–1.029
Sex (female)
Ref
Ref
Sex (male)
2.685
2.271–3.175
DBP (< 90 mm Hg)
Ref
Ref
DBP (≥ 90 mm Hg)
1.526
1.369–1.701
Baseline CVD (no)
Ref
Ref
Baseline CVD (yes)
1.802
1.560–2.082
Baseline diabetes (no)
Ref
Ref
Baseline diabetes (yes)
0.755
0.630–0.904
AAA indicates abdominal aortic aneurysm; BP, blood pressure; CVD, car-
diovascular disease; DBP, diastolic blood pressure; HR, hazard ratio; and Ref,
referent group for categorical variables. Sensitivity Analysis of the AAA Risk Score The AAA risk score was applied to composite outcome
of death from AAA or an AAA-related surgical procedure
only, to test discrimination of the most severe incident
AAA cases (Table II in the Data Supplement). The AAA
risk score thresholds maintained similar sensitivity and
specificity to those observed for the primary AAA out-
come. The PPV was lower under all strategies (ie, the
risk score models and current clinical practice models)
because of the lower incidence of cases. Circulation. 2021;144:604–614. DOI: 10.1161/CIRCULATIONAHA.120.053022 August 24, 2021
610 Welsh et al Prediction of AAA Table 3. Sensitivity Analysis of the AAA Risk Score Sensitivity, Specificity, Positive Predictive Value, and Negative Predictive Value of the Current Clinical Practice Mod-
els Compared With the AAA Risk Score at Selected Risk Thresholds
Model
Strategy
Sensitivity
(95% CI)
Specificity
(95% CI)
PPV
(95% CI)
NPV
(95% CI)
Derivation cohort (N at risk=401 820, n AAA cases over 10 yr=1241)
USPSTF
Ultrasound men and women who have ever
smoked at age 65–75 y*
Ultrasound men at age 65–75 y if they have
CVD*
69.2%
(66.6%–71.8%)
71.6%
(71.5%–71.8%)
0.75%
(0.70%–0.80%)
99.9%
(99.9%–99.9%)
NICE
Ultrasound all men at age 66 y*
Ultrasound women at age 70 y if they have spe-
cific risk factors*†
72.5%
(69.9%–75.0%)
63.4%
(63.3%–63.6%)
0.61%
(0.57%–0.65%)
99.9%
(99.9%–99.9%)
Hypothetical strategy
Ultrasound all men at age 65 y and all women at
age 70 y
78.3%
(75.9%–80.6%)
54.8%
(54.6%–54.9%)
0.53%
(0.50%–0.57%)
99.9%
(99.9%–99.9%)
Risk score
Ultrasound at ≥0.5% 10-y risk at baseline
70.2%
(67.6%–72.7%)
84.4%
(84.3%–84.5%)
1.38%
(1.29%–1.47%)
99.9%
(99.9%–99.9%)
Risk score
Ultrasound at ≥0.3% 10-y risk at baseline
79.7%
(77.3%–81.9%)
75.8%
(75.7%–75.9%)
1.01%
(0.95%–1.07%)
99.9%
(99.9%–99.9%)
Risk score
Ultrasound at ≥0.25% 10-y risk at baseline
84.1%
(82.0%–86.1%)
72.1%
(72.0%–72.3%)
0.93%
(0.87%–0.98%)
99.9%
(99.9%–99.9%)
Combination of guide-
lines and risk score
Ultrasound at ≥0.3% 10-y risk at baseline, or
when USPSTF conditions met
85.1%
(83.0%–87.0%)
63.2%
(63.1%–63.4%)
0.71%
(0.67%–0.76%)
99.9%
(99.9%–99.9%)
Validation cohort (N at risk =83 816, n AAA cases over 10 yr=280)
USPSTF
Ultrasound men and women who have ever
smoked at age 65–75 y*
Ultrasound men at age 65–75 y if they have CVD
63.9%
(58.0%–69.6%)
71.3%
(71.0%–71.6%)
0.74%
(0.64%–0.86%)
99.8%
(99.8%–99.9%)
NICE
Ultrasound all men at age 66 y*
Ultrasound women at age 70 y if they have spe-
cific risk factors*†
71.4%
(65.8%–76.6%)
61.4%
(61.0%–61.7%)
0.62%
(0.53%–0.71%)
99.8%
(99.8%–99.9%)
Hypothetical strategy
Ultrasound all men at age 65 y and all women at
age 70 y
78.6%
(73.3%–83.2%)
52.5%
(52.2%–52.8%)
0.55%
(0.48%–0.63%)
99.9%
(99.8%–99.9%)
Risk score
Ultrasound at ≥0.5% 10-y risk at baseline
68.6%
(62.8%–74.0%)
83.2%
(82.9%–83.4%)
1.35%
(1.16%–1.55%)
99.9%
(99.8%–99.9%)
Risk score
Ultrasound at ≥0.3% 10-y risk at baseline
78.2%
(72.9%–82.9%)
74.3%
(74.0%–74.6%)
1.01%
(0.88%–1.15%)
99.9%
(99.9%–99.9%)
Risk score
Ultrasound at ≥0.25% 10-y risk at baseline
82.1%
(77.1%–86.4%)
70.7%
(70.3%–71.0%)
0.93%
(0.81%–1.06%)
99.9%
(99.9%–99.9%)
Combination of guide-
lines and risk score
Ultrasound at ≥0.3% 10-y risk at baseline, or
when USPSTF conditions met
83.2%
(78.3%–87.4%)
62.1%
(61.8%–62.4%)
0.73%
(0.64%–0.83%)
99.9%
(99.9%–99.9%)
AAA indicates abdominal aortic aneurysm; NICE, National Institute for Health and Care Excellence; NPV, negative predictive value; PPV, positive predictive value;
and USPSTF, United States Preventive Services Task Force. Sensitivity Analysis of the AAA Risk Score *Under the model, participants screened at minimum qualifying age. In those over the minimum specified qualifying age at baseline, participants are screened at
baseline (assuming any other qualifying conditions are also met). †Risk factors specified in the Expanded Methods in the Data Supplement. Table 3. Sensitivity, Specificity, Positive Predictive Value, and Negative Predictive Value of the Current Clinical Practice Mod-
els Compared With the AAA Risk Score at Selected Risk Thresholds y, Positive Predictive Value, and Negative Predictive Value of the Current Clinical Practice Mod-
sk Score at Selected Risk Thresholds ORIGINAL RESEARCH
ARTICLE ORIGINAL RESEARCH
ARTICLE AAA indicates abdominal aortic aneurysm; NICE, National Institute for Health and Care Excellence; NPV, negative predictive value; PPV, positive predictive value;
and USPSTF, United States Preventive Services Task Force. *Under the model, participants screened at minimum qualifying age. In those over the minimum specified qualifying age at baseline, participants are screened at
baseline (assuming any other qualifying conditions are also met). †Risk factors specified in the Expanded Methods in the Data Supplement. analysis of small studies showing that that Lp(a) may be
associated with AAA.31 Recent phase 2 trial data show
that the drug AKCEA-APO(a)-LRx (also called TQJ230)
reduces Lp(a) substantially, with 80% to 90% reductions
in patients with established CVD and high Lp(a) levels,
and phase 3 trials are underway for CVD prevention.32 data. The option to include routine blood tests in the risk
score algorithm may also be of interest, but even a sim-
ple risk score based on routine clinical data without the
need for blood tests may help guide decision-making. The analysis investigating a dual approach, where risk
scoring is conducted as well as age-based referral, sug-
gests improved sensitivity of the referral approach, while
only having a moderate impact on specificity. As such,
the thresholds reported here present several options to
maximize either sensitivity or specificity depending on
the specific health care setting. This study further extends existing data by demon-
strating that simple and widely available measures can
help guide screening, by abdominal ultrasound, to those
that need it most. The information used in this risk score
can be easily and inexpensively ascertained by primary
care physicians, the patient’s medical history, blood
pressure measurement, and other outline primary care There are time pressures on primary care physicians,
and the burden of risk scoring for various conditions is Circulation. 2021;144:604–614. DOI: 10.1161/CIRCULATIONAHA.120.053022 August 24, 2021
611 August 24, 2021
611 August 24, 2021
611 Welsh et al Prediction of AAA Welsh et al onsiderable.33 Use of automated software to guide risk
oring and treatment decisions in primary care, with
nimal manual input, can be considered where possible. The strengths of this study include the use
well-phenotyped population, and the use of a
outcome based on multiple data sources, the
gure 2. ORIGINAL RESEARCH
ARTICLE Abdominal aortic aneurysm risk score calibration in the derivation and validation cohort across 10 years of
rves are predicted survival experience by the risk score, and data points are observed survival with 95% CI. Green curve represent
oup (those at <0.25% 10-year risk: N=289 081 participants, n=197 events in the derivation cohort; N=59 073 participants, n=50
idation cohort) and red curve the high-risk group (those at ≥0.25% 10-year risk: 112 739 participants, n=1044 events in the deriv
=24 743 participants, n=230 events in the validation cohort). Downloaded from http://ahajournals.org by on September 13, 2021 Figure 2. Abdominal aortic aneurysm risk score calibration in the derivation and validation cohort across 10 years of follow-up. Curves are predicted survival experience by the risk score, and data points are observed survival with 95% CI. Green curve represents the low-risk
group (those at <0.25% 10-year risk: N=289 081 participants, n=197 events in the derivation cohort; N=59 073 participants, n=50 events in the
validation cohort) and red curve the high-risk group (those at ≥0.25% 10-year risk: 112 739 participants, n=1044 events in the derivation cohort;
N=24 743 participants, n=230 events in the validation cohort). considerable.33 Use of automated software to guide risk
scoring and treatment decisions in primary care, with
minimal manual input, can be considered where possible. The extra effort required to improve referral practices
should be viewed in the context of health care resources
saved performing unnecessary ultrasounds. The strengths of this study include the use of a large,
well-phenotyped population, and the use of a composite
outcome based on multiple data sources, thereby maxi-
mizing the sensitivity of detection. Internal nonrandom
validation of the final model was carried out to ensure
that it performed well in the cohort assessed after 2009, Circulation. 2021;144:604–614. DOI: 10.1161/CIRCULATIONAHA.120.053022 August 24, 2021
612 Welsh et al Prediction of AAA Table 4. Affiliations Institute of Cardiovascular and Medical Sciences (P.W., P.S.J., R.B., C.A.C.-M.,
J.M.R.G., S.R.G., N.S.) and Institute of Health & Wellbeing (J.L., F.K.H., D.F.M., S.V.K.,
J.P.P.), University of Glasgow, United Kingdom. Population and Health Sciences
Institute, Newcastle University, United Kingdom (C.E.W.). The George Institute for
Global Health, School of Public Health, Imperial College London, United Kingdom
(M.W.). The George Institute for Global Health, University of New South Wales,
Sydney, Australia (M.W.). Department of Epidemiology, Johns Hopkins University,
Baltimore, Maryland (M.W.). University of Limerick, Ireland (J.F.). Acknowledgments The authors are grateful to the participants of UK Biobank for allowing use of
their data. The authors thank Liz Coyle (University of Glasgow) for her assistance
in the preparation of this article. ORIGINAL RESEARCH
ARTICLE ORIGINAL RESEARCH
ARTICLE 0.25% 10-year risk threshold (along with other potential
“high-risk” thresholds) was based on pragmatic thresh-
olds that illustrate a range of sensitivities and specifici-
ties. Other risk thresholds could also be derived from the
risk score. Last, the study did not investigate risk factors
that have an association with AAA but that are often not
routinely coded in primary care, such as physical activ-
ity.36 The causality of physical activity, and other risk fac-
tors, in the prevention of AAA require further study. ie, those where any diagnosis of AAA could have been
more likely after screening of eligible men. External vali-
dation and development of the risk score reported here
are now warranted in other cohorts. This study has limitations. First, the outcome used to
generate the risk score algorithm was a composite of
incident AAA diagnosis in hospital, death from AAA, or
an AAA-related operation. Given the generally asymp-
tomatic nature of minor AAA, the composite outcome
is therefore more likely to represent large or ruptured
AAA. Second, no information on aneurysm size was
available in the data used in this study; therefore, this
information could not be incorporated. Third, although
UK Biobank participants are not representative of the
general population (and hence cannot be used to pro-
vide representative disease prevalence and incidence
rates), valid assessment of exposure-disease relation-
ships are nonetheless widely generalizable and do not
require participants to be representative of the popula-
tion at large.34 Fourth, UK Biobank has a high proportion
of White race participants, and therefore race/ethnicity
was not included in the risk prediction model, but may
still be an important risk factor. Fifth, the current clinical
practice models used here are only approximations of
real-life clinical practice. As such, the model is likely to
misclassify relative to real-life current screening prac-
tices; this would also be true if the risk score is applied
in real clinical settings. Sixth, there was no information
on which hospital AAA diagnoses occurred because
of routine screening in the validation cohort. However,
discrimination was similar in the derivation cohort and
validation cohort. Seventh, family history of AAA was
not available, information on which will further improve
AAA prediction in both current clinical practice models
and the AAA risk score.35 Eighth, there are no current
“high-risk” treatment thresholds for AAA screening; the Conclusions In an asymptomatic general population, a risk score
based on patient age, height, weight, and medical histo-
ry may improve identification of asymptomatic patients
at risk for clinical events from AAA. Further develop-
ment and validation of risk scores to detect asymptom-
atic AAA are needed. ARTICLE INFORMATION Received December 1, 2020; accepted June 9, 2021. Received December 1, 2020; accepted June 9, 2021. ORIGINAL RESEARCH
ARTICLE Categorical NRI (Improvement in Decisions to Refer for Ultrasound: Correct Referral for AAA Cases, or Correct Non-
referral for AAA Noncases) Using the AAA Risk Score, at Selected Risk Thresholds, Compared With the USPSTF Model of Cur-
rent Clinical Practice Only
Model
Strategy
AAA case NRI (95% CI)
AAA noncase NRI
(95% CI)
Overall NRI (95% CI)
Derivation cohort (N at risk=401 820, n of AAA cases over 10 yr =1241)
Risk score
Ultrasound at ≥0.5% 10-year risk
0.010 (–0.016, 0.035)
0.128 (0.127, 0.129)
0.138 (0.112, 0.163)
Risk score
Ultrasound at ≥0.3% 10-year risk
0.105 (0.080, 0.130)
0.042 (0.040, 0.043)
0.146 (0.121, 0.171)
Risk score
Ultrasound at ≥0.25% 10-year risk
0.149 (0.124, 0.174)
0.005 (0.003, 0.006)
0.154 (0.129, 0.179)
Combination of guide-
lines and risk score
Ultrasound at ≥0.3% 10-year risk at base-
line, or when USPSTF conditions met
0.159 (0.138, 0.179)
–0.084 (–0.084, –0.083)
0.075 (0.055, 0.095)
Validation cohort (N at risk =83 816, n of AAA cases over 10 yr=280)
Risk score
Ultrasound at ≥0.5% 10-year risk
0.046 (–0.009, 0.102)
0.119 (0.116, 0.122)
0.165 (0.110, 0.220)
Risk score
Ultrasound at ≥0.3% 10-year risk
0.143 (0.088, 0.198)
0.030 (0.027, 0.033)
0.173 (0.118, 0.229)
Risk score
Ultrasound at ≥0.25% 10-year risk
0.182 (0.126, 0.238)
–0.006 (–0.010, 0.003)
0.176 (0.120, 0.232)
Combination of guide-
lines and risk score
Ultrasound at ≥0.3% 10-year risk at base-
line, or when USPSTF conditions met
0.193 (0.147, 0.239)
–0.092 (–0.094, –0.090)
0.101 (0.055, 0.147)
AAA indicates abdominal aortic aneurysm; NRI, net reclassification index; and USPSTF, United States Preventive Services Task Force. Table 4. Categorical NRI (Improvement in Decisions to Refer for Ultrasound: Correct Referral for AAA Cases, or Correct Non-
referral for AAA Noncases) Using the AAA Risk Score, at Selected Risk Thresholds, Compared With the USPSTF Model of Cur-
rent Clinical Practice Only Table 4. Categorical NRI (Improvement in Decisions to Refer for Ultrasound: Correct Referral for AAA Cases, or Correct Non-
referral for AAA Noncases) Using the AAA Risk Score, at Selected Risk Thresholds, Compared With the USPSTF Model of Cur-
rent Clinical Practice Only REFERENCES 21. Shovman O, Tiosano S, Comaneshter D, Cohen AD, Amital H, Sherf
M. Aortic aneurysm associated with rheumatoid arthritis: a population-
based cross-sectional study. Clin Rheumatol. 2016;35:2657–2661. doi:
10.1007/s10067-016-3372-0 1. Tang W, Yao L, Roetker NS, Alonso A, Lutsey PL, Steenson CC, Lederle
FA, Hunter DW, Bengtson LG, Guan W, et al. Lifetime risk and risk factors
for abdominal aortic aneurysm in a 24-year prospective study: the ARIC
Study (Atherosclerosis Risk in Communities). Arterioscler Thromb Vasc Biol. 2016;36:2468–2477. doi: 10.1161/ATVBAHA.116.308147 1. Tang W, Yao L, Roetker NS, Alonso A, Lutsey PL, Steenson CC, Lederle
FA, Hunter DW, Bengtson LG, Guan W, et al. Lifetime risk and risk factors
for abdominal aortic aneurysm in a 24-year prospective study: the ARIC
Study (Atherosclerosis Risk in Communities). Arterioscler Thromb Vasc Biol. 2016;36:2468–2477. doi: 10.1161/ATVBAHA.116.308147 22. UK Biobank. Biomarker Project Companion Document to Accompany
Serum Biomarker Data version 1.0. March 2019. Accessed June 10,
2021. https://biobank.ndph.ox.ac.uk/showcase/showcase/docs/serum_
biochemistry.pdf 2. Singh K, Bønaa KH, Jacobsen BK, Bjørk L, Solberg S. Prevalence of
and risk factors for abdominal aortic aneurysms in a population-based
study: the Tromsø Study. Am J Epidemiol. 2001;154:236–244. doi:
10.1093/aje/154.3.236 23. Townsend P, Phillimore M, Beattie A. Health and deprivation. Inequality and
the North. Croom Helm Ltd; 1988. 24. Stone M. An asymptotic equivalence of choice of model by cross-validation
and Akaike’s criterion. J R Stat Soc Series B Stat Methodol. 1977;39:44–47. doi: 10.1111/j.2517-6161.1977.tb01603.x 3. Bath MF, Saratzis A, Saedon M, Sidloff D, Sayers R, Bown MJ; UKAGS In-
vestigators. Patients with small abdominal aortic aneurysm are at significant
risk of cardiovascular events and this risk is not addressed sufficiently. Eur J
Vasc Endovasc Surg. 2017;53:255–260. doi: 10.1016/j.ejvs.2016.10.013 25. Royston P. Tools for checking calibration of a Cox model in external valida-
tion: Prediction of population-averaged survival curves based on risk groups. Stata J. 2015;15:275–291. doi: 10.1177/1536867X1501500116 g
j j
4. Nordkvist S, Sonestedt E, Acosta S. Adherence to diet recommendations
and risk of abdominal aortic aneurysm in the Malmö Diet and Cancer Study. Sci Rep. 2018;8:1–8. doi: 10.1038/s41598-018-20415-z. 26. Collins GS, Reitsma JB, Altman DG, Moons KG. Transparent report-
ing of a multivariable prediction model for individual prognosis or diag-
nosis (TRIPOD): the TRIPOD Statement. BMC Med. 2015;13:1. doi:
10.1186/s12916-014-0241-z 5. Bahia SS, Vidal-Diez A, Seshasai SR, Shpitser I, Brownrigg JR, Patterson
BO, Ray KK, Holt PJ, Thompson MM, Karthikesalingam A. REFERENCES Cardiovascu-
lar risk prevention and all-cause mortality in primary care patients with
an abdominal aortic aneurysm. Br J Surg. 2016;103:1626–1633. doi:
10.1002/bjs.10269 27. Forsdahl SH, Singh K, Solberg S, Jacobsen BK. Risk factors for abdominal aortic
aneurysms: a 7-year prospective study: the Tromsø Study, 1994-2001. Circula-
tion. 2009;119:2202–2208. doi: 10.1161/CIRCULATIONAHA.108.817619 6. Gokani VJ, Sidloff D, Bath MF, Bown MJ, Sayers RD, Choke E. A retrospective
study: factors associated with the risk of abdominal aortic aneurysm rupture. Vascul Pharmacol. 2015;65-66:13–16. doi: 10.1016/j.vph.2014.11.006 28. Kobeissi E, Hibino M, Pan H, Aune D. Blood pressure, hypertension and
the risk of abdominal aortic aneurysms: a systematic review and meta-
analysis of cohort studies. Eur J Epidemiol. 2019;34:547–555. doi:
10.1007/s10654-019-00510-9 7. Howard DP, Banerjee A, Fairhead JF, Handa A, Silver LE, Rothwell PM;
Oxford Vascular Study. Population-based study of incidence of acute ab-
dominal aortic aneurysms with projected impact of screening strategy. J Am
Heart Assoc. 2015;4:e001926. doi: 10.1161/JAHA.115.001926 29. Matsushita K, Kwak L, Ballew SH, Grams ME, Selvin E, Folsom AR, Coresh
J, Tang W. Chronic kidney disease measures and the risk of abdominal
aortic aneurysm. Atherosclerosis. 2018;279:107–113. doi: 10.1016/j. atherosclerosis.2018.08.043 8. National Institute for Health and Excellence. NICE Guideline NG156. Ab-
dominal aortic aneurysm: diagnosis and management. March 2020. Ac-
cessed June 10, 2021. https://www.nice.org.uk/guidance/ng156/chapter/
Recommendations. 30. Hellmann DB, Grand DJ, Freischlag JA. Inflammatory abdominal aortic an-
eurysm. JAMA. 2007;297:395–400. doi: 10.1001/jama.297.4.395 31. Kotani K, Sahebkar A, Serban MC, Ursoniu S, Mikhailidis DP, Mariscalco
G, Jones SR, Martin S, Blaha MJ, Toth PP, et al; Lipid and Blood Pressure
Meta-analysis Collaboration (LBPMC) Group. Lipoprotein(a) Levels in pa-
tients with abdominal aortic aneurysm. Angiology. 2017;68:99–108. doi:
10.1177/0003319716637792 9. Public Health Scotland Data and Intelligence. Abdominal Aortic Aneurysm
(AAA) Screening. Accessed June 10, 2021. https://beta.isdscotland.org/
topics/abdominal-aortic-aneurysm-aaa-screening/ 10. Guirguis-Blake JM, Beil TL, Senger CA, Coppola EL. Primary care screen-
ing for abdominal aortic aneurysm: updated evidence report and systematic
review for the US Preventive Services Task Force. JAMA. 2019;322:2219–
2238. doi: 10.1001/jama.2019.17021 32. Novartis Pharmaceuticals. Assessing the Impact of Lipoprotein (a) Lowering
With TQJ230 on Major Cardiovascular Events in Patients With CVD (LP(a)
HORIZON). July 2019. Accessed June 10, 2021. https://clinicaltrials. gov/ct2/show/NCT04023552 11. Owens DK, Davidson KW, Krist AH, Barry MJ, Cabana M, Caughey AB,
Doubeni CA, Epling JW, Kubik M, Landefeld CS, et al. Screening for
abdominal aortic aneurysm. US Preventive Services Task Force Recom-
mendation Statement JAMA. 2019;322:2211–2218. doi: 10.1001/
jama.2019.18928 33. Disclosures ge. PLoS Med. 2015;12:e1001779. doi: 10.1371/journal.pmed.1001 17. Davis M, Harris M, Earnshaw JJ. Implementation of the National Health
Service abdominal aortic aneurysm screening program in England. J Vasc
Surg. 2013;57:1440–1445. doi: 10.1016/j.jvs.2012.10.114 Dr Welsh reports grant income from Roche Diagnostics, Astrazeneca, Boehringer
Ingelheim, and Novartis outside the submitted work. Dr Sattar has received grant
and personal fees from Boehringer Ingelheim and personal fees from Amgen,
AstraZeneca, Eli Lilly, Merck Sharp & Dohme, Novartis, Novo Nordisk, Pfizer, and
Sanofi outside the submitted work. The other authors report no conflicts. 18. Altman DG, Vergouwe Y, Royston P, Moons KG. Prognosis and prognos-
tic research: validating a prognostic model. BMJ. 2009;338:b605. doi:
10.1136/bmj.b605 Sources of Funding This work was supported by Chest, Heart, and Stroke Association Scotland
(Res16/A165). S.V.K. acknowledges funding from a NHS Research Scotland Circulation. 2021;144:604–614. DOI: 10.1161/CIRCULATIONAHA.120.053022 August 24, 2021
613 Prediction of AAA Welsh et al ORIGINAL RESEARCH
ARTICLE Senior Clinical Fellowship (SCAF/15/02), the Medical Research Council (MC_
UU_00022/2), and the Scottish Government Chief Scientist Office (SPHSU17). 16. Sudlow C, Gallacher J, Allen N, Beral V, Burton P, Danesh J, Downey P, Elliott
P, Green J, Landray M, et al. UK Biobank: an open access resource for iden-
tifying the causes of a wide range of complex diseases of middle and old
age. PLoS Med. 2015;12:e1001779. doi: 10.1371/journal.pmed.1001779 Supplemental Materials 19. UK Biobank. Hospital inpatient data version 3.0. August 2020. Accessed
June 10, 2021. https://biobank.ndph.ox.ac.uk/ukb/ukb/docs/HospitalEpi-
sodeStatistics.pdf Expanded Methods Data Supplement Tables I–VII Data Supplement Tables I–VII
Data Supplement Figure I Data Supplement Tables I–VII 20. UK Biobank. Mapping inpatient hospital data across England, Scotland and
Wales version 1.5. March 2019. Accessed June 10, 2021. https://biobank. ctsu.ox.ac.uk/showcase/showcase/docs/inpatient_mapping.pdf Data Supplement Figure I REFERENCES Challener DW, Prokop LJ, Abu-Saleh O. The proliferation of reports on
clinical scoring systems: issues about uptake and clinical utility. JAMA. 2019;321:2405–2406. doi: 10.1001/jama.2019.5284 34. Batty GD, Gale CR, Kivimäki M, Deary IJ, Bell S. Comparison of risk fac-
tor associations in UK Biobank against representative, general popula-
tion based studies with conventional response rates: prospective cohort
study and individual participant meta-analysis. BMJ. 2020;368:m131. doi:
10.1136/bmj.m131 12. Stather PW, Dattani N, Bown MJ, Earnshaw JJ, Lees TA. International varia-
tions in AAA screening. Eur J Vasc Endovasc Surg. 2013;45:231–234. doi:
10.1016/j.ejvs.2012.12.013 13. Scott RA, Bridgewater SG, Ashton HA. Randomized clinical trial of screen-
ing for abdominal aortic aneurysm in women. Br J Surg. 2002;89:283–285. doi: 10.1046/j.0007-1323.2001.02014.x 35. Raunsø J, Song RJ, Vasan RS, Bourdillon MT, Nørager B, Torp-Pedersen C,
Gislason GH, Xanthakis V, Andersson C. Familial clustering of aortic size,
aneurysms, and dissections in the community. Circulation. 2020;142:920–
928. doi: 10.1161/CIRCULATIONAHA.120.045990 14. Sweeting MJ, Masconi KL, Jones E, Ulug P, Glover MJ, Michaels JA, Bown
MJ, Powell JT, Thompson SG. Analysis of clinical benefit, harms, and cost-
effectiveness of screening women for abdominal aortic aneurysm. Lancet. 2018;392:487–495. doi: 10.1016/S0140-6736(18)31222-4 36. Aune D, Sen A, Kobeissi E, Hamer M, Norat T, Riboli E. Physical activity
and the risk of abdominal aortic aneurysm: a systematic review and meta-
analysis of prospective studies. Sci Rep. 2020;10:22287. doi: 10.1038/
s41598-020-76306-9 15. Collins R. What makes UK Biobank special? Lancet. 2012;379:1173–1174. doi: 10.1016/S0140-6736(12)60404-8 Circulation. 2021;144:604–614. DOI: 10.1161/CIRCULATIONAHA.120.053022 August 24, 2021
614
|
https://openalex.org/W2460427056
|
https://www.epj-conferences.org/articles/epjconf/pdf/2016/16/epjconf-RICAP-14_05011.pdf
|
English
| null |
Potential of KM3NeT to observe galactic neutrino point-like sources
|
EPJ web of conferences
| 2,016
|
cc-by
| 3,253
|
Potential of KM3NeT to observe galactic
neutrino point-like sources Abstract. KM3NeT (http://www.km3net.org) will be the next-
generation cubic-kilometre-scale neutrino telescope to be installed in the
depths of the Mediterranean Sea. This location will allow for surveying the
Galactic Centre, most of the Galactic Plane as well as a large part of the
sky. We report KM3NeT discovery potential for the SNR RXJ1713.7-3946
and the PWN Vela X and its sensitivity to point-like sources with an E−2
spectrum. C
⃝The Authors, published by EDP Sciences. This is an Open Access article distributed under the terms of the
Creative Commons Attribution License 4.0 (http://creativecommons.org/licenses/by/4.0/). DOI: 10.1051/epjconf/201612105011 DOI: 10.1051/epjconf/201612105011 EPJ Web of Conferences 121, 05011 (2016)
RICAP-2014 ae-mail: atrovato@lns.infn.it ae-mail: atrovato@lns.infn.it
C
⃝The Authors, published by EDP Sciences. This is an Open Access article distributed under the terms of the
Creative Commons Attribution License 4.0 (http://creativecommons.org/licenses/by/4.0/). 1. Introduction In the last decades, also thanks to a multi-messenger approach, our knowledge of the high-
energy Universe has been widely extended. Nevertheless many open questions remain. Neutrinos, being uncharged and weakly interacting, can provide unique information on
astrophysical objects. Their measurement will allow for new insights into the acceleration
mechanisms, clarifying the role of the hadronic component. In this context, the first evidence for a high-energy neutrino flux of extraterrestrial origin
[1, 2] recently reported by the IceCube neutrino telescope, opens a new observational window
on our Universe. The origin of this signal is however not yet clear, due to the scarceness of
the detected neutrinos and mostly to the limited angular resolution of the IceCube detector. A
confirmation, possibly accompanied by the identification of the sources is therefore necessary. Candidate neutrino sources in the cosmos are numerous, but the estimate of their
extragalactic neutrino fluxes has large uncertainties due to model assumptions and to the
intergalactic absorption of VHE -rays that strongly modifies the spectra measured at Earth. On the other hand, in the hypothesis of hadronic gamma emission, models for galactic
neutrino sources are constrained by TeV -ray observations and allow to obtain realistic
expectations on the detection perspectives [3], as in the case of SuperNova Remnants (SNR)
and Pulsar Wind Nebulae (PWN) that are the among most intense sources. g
Neutrino telescopes detect the charged leptons produced in the neutrino weak interaction. In transparent media, relativistic particles can be detected through the light produced via
Cherenkov effect, with 3D arrays of optical sensors. The “golden channel” for neutrino
astronomy is the ν charged current (CC) interaction because the muon range in water is,
at E ∼TeV, of the order of kilometres and the muon track is almost co-linear to the ν
permitting to point back to the neutrino cosmic source. This is the channel considered in this
work. High energy neutrino astronomy requires detector volumes of the km3 scale hosted
in deep water or in deep Antarctic ice, where several thousands of metres of water (or ice)
reduce the flux of atmospheric muons by several orders of magnitude. Since neutrinos are the
only particles that can pass the whole Earth, neutrino telescopes look mainly at the up-going EPJ Web of Conferences 121, 05011 (2016)
RICAP-2014 DOI: 10.1051/epjconf/201612105011 neutrinos coming from the opposite hemisphere. 1. Introduction A detector in the northern hemisphere is
therefore necessary to complement the IceCube sky coverage. neutrinos coming from the opposite hemisphere. A detector in the northern hemisphere is
therefore necessary to complement the IceCube sky coverage. KM3NeT [4] is an international collaboration with the aim to build a research
infrastructure in the Mediterranean Sea hosting an underwater multi-km3 high-energy
neutrino telescope. Thanks to its geographical location in the Northern hemisphere, KM3NeT
can observe most of the Galactic Plane, including the galactic centre, so our Galaxy is its
prime field of investigation. The KM3NeT neutrino telescope will consist of a 3D-array of
Digital Optical Modules (DOMs) made of pressure resistant glass spheres each containing
31 photomultiplier tubes (PMTs) with a diameter of about 3 inch and their electronics. The first prototype of a DOM, called also “multi-PMT”, has been deployed at a depth of
2500 m in the Antares site. The analysis of first months of data taking highlights the
capabilities of the new module design in terms of background suppression and signal
recognition [5]. The DOMs are hosted in vertical string-like structures, approximately 1 km
in height, called Detection Units (DUs) and described in the Technical Design Report [6]
(TDR). The detector will be made of building blocks of 115 DUs each, arranged uniformly
in a circular area at an average distance of 90 m. Each block has a volume of about 0.5 km3. Two of these building blocks will be installed in Italian site of Capo Passero for the so called
KM3NeT/ARCA. An extension to 6 building blocks is also envisaged to fully exploit the
scientific potential of the detector especially in the search of Galactic point sources. 2. Simulation codes and analysis The simulation of detector response to astrophysical neutrino fluxes provides a guideline for
detector design and optimisation. The software used in this work has been developed by
the ANTARES Collaboration [7] and adapted to km3-scale detectors. The code provides a
complete simulation of the incident muon neutrinos with energy in the range 102–108 GeV,
including their interaction in the medium and the propagation of the resulting secondary
particles, the light generation and propagation in water and the detector response. The depth
and the optical water properties measured at the Sicilian Capo Passero site have been used
[8]. Background light due to the presence of 40K in salt water and bioluminescence has been
simulated adding an uncorrelated hit rate of 5 kHz per PMT and a time-correlated hit rate of
500 Hz per DOM (two coincident hits in different PMTs inside the same DOM) due to the
genuine coincidences from 40K decays. After the event generation, a track reconstruction algorithm is employed to estimate
muon (and consequently neutrino) direction from the arrival times of the photons on the
PMTs. After an initial hit selection requiring space-time coincidences between hits, the
reconstruction proceeds through four consecutive fitting procedures, each using the result
of the previous fit as starting point, except for the first one, called prefit, that is a linear fit
through the positions of the hits with the hit time as independent variable [9, 10]. The detector
resolution, i.e. the median angle between the reconstructed track and the generated neutrino
track, reaches about 0.2◦at 10 TeV. The simulated events are analysed through statistical technique to look for a statistical
excess originating in narrow regions of the sky around the sources. Indeed, the weak neutrino
signal from a cosmic source stems on the large background of atmospheric muons and
neutrinos, both produced by the interaction of primary cosmic rays with the atmosphere. The
atmospheric neutrino event rate is calculated assuming the Honda et al. [11] conventional
atmospheric model, the Enberg et al. [12] prompt component and adding the correction due
to the cosmic rays knee on the neutrino spectrum as described in [13]. Atmospheric muons
are simulated using the MUPAGE event generator [14]. The optimisation of the signal to 2 EPJ Web of Conferences 121, 05011 (2016)
RICAP-2014 DOI: 10.1051/epjconf/201612105011 background ratio is far from being trivial and it is strongly dependent on the source features
(e.g. energy spectrum, angular extension). 3. Results Amongst the galactic objects, SNRs are probably the most promising ones. In particular,
the SNR RXJ1713.7-3946 and the PWN VelaX are at present between the most intense
known galactic objects in the high-energy gamma-ray band and are used here to evaluate
the KM3NeT performances. In addition the discovery flux is evaluated also for a generic E−2
point-source. The young shell-type SNR RX J1713.7-3946 has been observed by HESS in several
campaigns [17] and its energy gamma spectrum is measured up to about 100 TeV. The source
has large intensity and a relatively large size with a complex morphology. Moreover, it is
visible for about the 80% of the time by KM3NeT therefore is a good reference case. This SNR has been simulated as an extended neutrino source of 0.6◦with an energy
spectrum calculated under the hypothesis of a transparent source and 100% hadronic emission
and parametrised as [18]: (E) = 16.8 × 10−15
E
TeV
−1.72
e−√E/2.1TeVGeV−1s−1cm−2. (1) (1) Vela X is one of the nearest pulsar wind nebulae (PWN) and it is associated with the energetic
Vela pulsar PSR B0833-45. Even if PWNs are generally treated as leptonic sources (-ray
emitters through inverse Compton), interpretation of TeV -ray emission from Vela X in
terms of hadronic interaction is discussed by some authors (see i.e. [19, 20]). The first VHE
-ray emission from Vela X was reported by the H.E.S.S. Collaboration [21] has been recently
updated [22] with data from the 2005–2007 and 2008–2009 observation campaigns and using
a more accurate method for the background subtraction. The new data are characterised by
a higher gamma flux and a harder energy spectrum. From the differential energy spectrum
extracted from an integration radius of 0.8◦around the centre at RA = 08h 35m 00s,
Dec = −45◦36′ 00′′, the corresponding neutrino emission spectrum has been derived using
the Vissani prescription [3] based on the hypothesis of a transparent source and 100%
hadronic emission. The neutrino spectrum is parametrised as: (E) = 7.2 × 10−15
E
TeV
−1.36
e−(E/7TeV) GeV−1s−1cm−2. (2) (2) Also in this case the source extension has been simulated as a flat spatial distribution within
a disk with 0.8◦radius. 2. Simulation codes and analysis As figure of merit of the telescope performance
we have taken the discovery potential, that is the signal flux required to obtain an observation
at a given significance level (e.g. 5 or 3) with 50% probability [15]. The method used in
this work to calculate the discovery potential is the “unbinned” method [16] that relies on the
maximisation of a likelihood ratio to evaluate the probability that a set of events is compatible
with the hypothesis of signal+background instead of the hypothesis of background only. 3. Results Under the assumed hypotheses, the significance of the sources observation as a function
of the observation years for KM3NeT/ARCA and the full KM3NeT with 6 building blocks
has been calculated at a confidence level (CL) of 50% and is shown in Fig. 1. An observation
with 5 significance is expected with the full KM3NeT after 2.5 and 4 years for the VelaX
and the RXJ1713.7-3946 respectively. Anyway, even with KM3NeT/ARCA a 3 observation
is possible after a reasonable amount of time (2.5 years for the VelaX and 4.5 years for
the RXJ1713.7-3946). Figure 1 shows also how the expected significance can change due 3 EPJ Web of Conferences 121, 05011 (2016) EPJ Web of Conferences 121, 05011 (2016)
RICAP-2014 DOI: 10.1051/epjconf/201612105011 RICAP-2014 KM
]
σ
Significance [ Observation time [years]
0
2
4
6
8
10
12
0
1
2
3
4
5
VelaX
conventional uncertainty
atm
ν
RXJ1713.7-3946
conventional uncertainty
atm
ν
KM3NeT preliminary - detector with 2 building blocks
]
σ
Significance [
Observation time [years]
0
1
2
3
4
5
0
1
2
3
4
5
KM3NeT preliminary - detector with 6 building blocks
]
σ
Significance [
VelaX
conventional uncertainty
atm
ν
RXJ1713.7-3946
conventional uncertainty
atm
ν
Figure 1. Significance of the RXJ1713.7-3946 and Vela X observation as a function of the years of data
taking for the KM3NeT with 2 (left) and 6 (right) building blocks. The shaded bands show the effect of
the uncertainties on the conventional component of the atmospheric neutrino flux. )
δ
sin(
-1
-0.8
-0.6
-0.4
-0.2
0
0.2
0.4
0.6
0.8
1
]
-1
s
-2
[TeV cm
2
E
ν
Φ
-12
10
-11
10
-10
10
-9
10
):
σ
Discovery potential (5
KM3NeT/ARCA (2 building blocks), 3 observation years
IceCube (IC86+IC79+IC59+IC40), 4 observation years
Astrophysical Journal 796 (2014) 109
Figure 2. KM3NeT 5 discovery potential for point sources emitting a neutrino flux with a E−2
spectrum, for 3 years of data taking with KM3NeT/ARCA. The flux values are shown as function
of the source declination. For comparison the corresponding discovery potential to sources with an E−2
spectrum is also shown for the IceCube detector [23]. 3. Results )
δ
sin(
-1
-0.8
-0.6
-0.4
-0.2
0
0.2
0.4
0.6
0.8
1
]
-1
s
-2
[TeV cm
2
E
ν
Φ
-12
10
-11
10
-10
10
-9
10
):
σ
Discovery potential (5
KM3NeT/ARCA (2 building blocks), 3 observation years
IceCube (IC86+IC79+IC59+IC40), 4 observation years
Astrophysical Journal 796 (2014) 109 Figure 2. KM3NeT 5 discovery potential for point sources emitting a neutrino flux with a E−2
spectrum, for 3 years of data taking with KM3NeT/ARCA. The flux values are shown as function
of the source declination. For comparison the corresponding discovery potential to sources with an E−2
spectrum is also shown for the IceCube detector [23]. to the major uncertainty in this calculation, that is the conventional component of the
conventional neutrino flux. This effect is taken into account assuming a variation of ±25% in
the normalization of the Honda et al. model [11]. In order to compare the KM3NeT performances with IceCube, the 5 discovery flux 5
has been calculated for generic point-sources with an E−2 spectrum as a function of their
declination (see Fig. 2). The 3 years observation time has been chosen in such a way that
KM3NeT/ARCA has a comparable exposure w.r.t. the IceCube results in [23]. The different
trend of the KM3NeT and IceCube curves is mainly due to the geographical location of the
detectors. 3. Results Observation time [years]
0
2
4
6
8
10
12
0
1
2
3
4
5
VelaX
conventional uncertainty
atm
ν
RXJ1713.7-3946
conventional uncertainty
atm
ν
KM3NeT preliminary - detector with 2 building blocks
]
σ
Significance [
Observation time [years]
0
1
2
3
4
5
0
1
2
3
4
5
KM3NeT preliminary - detector with 6 building blocks
]
σ
Significance [
VelaX
conventional uncertainty
atm
ν
RXJ1713.7-3946
conventional uncertainty
atm
ν
Figure 1. Significance of the RXJ1713.7-3946 and Vela X observation as a function of the years of data
taking for the KM3NeT with 2 (left) and 6 (right) building blocks. The shaded bands show the effect of
the uncertainties on the conventional component of the atmospheric neutrino flux. Observation time [years]
0
1
2
3
4
5
0
1
2
3
4
5
KM3NeT preliminary - detector with 6 building blocks
]
σ
Significance [
VelaX
conventional uncertainty
atm
ν
RXJ1713.7-3946
conventional uncertainty
atm
ν Observation time [years]
0
2
4
6
8
10
12
0
1
2
3
4
5
VelaX
conventional uncertainty
atm
ν
RXJ1713.7-3946
conventional uncertainty
atm
ν
KM3NeT preliminary - detector with 2 building blocks
]
σ
Significance [ KM3NeT preliminary - detector with 6 building bl KM3NeT preliminary - detector with 2 building bloc Figure 1. Significance of the RXJ1713.7-3946 and Vela X observation as a function of the years of data
taking for the KM3NeT with 2 (left) and 6 (right) building blocks. The shaded bands show the effect of
the uncertainties on the conventional component of the atmospheric neutrino flux. )
δ
sin(
-1
-0.8
-0.6
-0.4
-0.2
0
0.2
0.4
0.6
0.8
1
]
-1
s
-2
[TeV cm
2
E
ν
Φ
-12
10
-11
10
-10
10
-9
10
):
σ
Discovery potential (5
KM3NeT/ARCA (2 building blocks), 3 observation years
IceCube (IC86+IC79+IC59+IC40), 4 observation years
Astrophysical Journal 796 (2014) 109
Figure 2. KM3NeT 5 discovery potential for point sources emitting a neutrino flux with a E−2
spectrum, for 3 years of data taking with KM3NeT/ARCA. The flux values are shown as function
of the source declination. For comparison the corresponding discovery potential to sources with an E−2
spectrum is also shown for the IceCube detector [23]. 4. Conclusions and perspectives The results presented in this paper represent the status of the galactic point-like sources
analysis and show that at least the more intense ones are at reach for KM3NeT. In particular 4 EPJ Web of Conferences 121, 05011 (2016)
RICAP-2014 DOI: 10.1051/epjconf/201612105011 we report expectation for RXJ1713.7-3946 and Vela X. The inclusion in our simulation of
a realistic source morphology extrapolated from the high energy -ray maps measured by
HESS is in progress. This will provide a more realistic description of the spatial extension
of the sources. The estimate of discovery potential for other galactic sources, as well as a
staking analysis of several candidate galactic sources, will be investigated in the near future. we report expectation for RXJ1713.7-3946 and Vela X. The inclusion in our simulation of
a realistic source morphology extrapolated from the high energy -ray maps measured by
HESS is in progress. This will provide a more realistic description of the spatial extension
of the sources. The estimate of discovery potential for other galactic sources, as well as a
staking analysis of several candidate galactic sources, will be investigated in the near future. The discovery potential for point sources with E−2 spectrum show that KM3NeT has a
very large field of view thus not only complementing, but also overlapping to large extent to
the IceCube field of view. KM3NeT can thus provide important contributions to the new born
field of neutrino astronomy. References ]
M. G. Aartsen et al. (IceCube Collaboration), Science 342, 1242856 (2013) 2]
M. G. Aartsen et al. (IceCube Collaboration), Phys. Rev. Lett. 113, 101101 (2014) [2]
M. G. Aartsen et al. (IceCube Collaboration), Phys. Rev. Lett. 113, 101101 (2014)
[3]
F. L. Villante and F. Vissani, Phys. Rev. D 78, 103007 (2008); F. Vissani and F. L. Villante, NIM A 588, 123 (2008) and F. Vissani, Astr. Ph. 26, 310 (2006)
[4]
http://www.km3net.org/home.php. [3]
F. L. Villante and F. Vissani, Phys. Rev. D 78, 103007 (2008); F. Vissani and F. L. Villante, NIM A 588, 123 (2008) and F. Vissani, Astr. Ph. 26, 310 (2006) (
)
(
)
[4]
http://www.km3net.org/home.php. [4]
http://www.km3net.org/home.php. ]
S. Adrian-Martinez et al. (KM3NeT Collaboration), Eur. Phys. J. C74, 3056 (2014) [6]
KM3NeT Technical Design Report, available on http://www.km3net.org/TDR/
TDRKM3NeT.pdf [7]
D. Bailey, Ph.D. Thesis, available on http://antares.in2p3.fr/Publications/
index.html [8]
G. Riccobene et al., Astropart. Phys. 27, 1 (2006) [9]
A. Heijboer,
Ph.D. Thesis,
available
on
http://antares.in2p3.fr/
Publications/index.html [10]
A. Trovato, Development of reconstruction algorithms for large volume neutrino
telescopes and their application to the km3net detector, Ph.D. Thesis (2013) [11]
M. Honda, T. Kajita, K. Kasahara, S. Midorikawa, and T. Sanuki, Phys. Rev. D 75,
043006 (2007) [12]
R. Enberg, M. H. Reno, and I. Sarcevic, Phys. Rev. D 78, 043005 (2008) [13]
M. G. Aartsen et al. (IceCube Collaboration), Phys. Rev. D 89, 062007 (2014) [14]
Y. Becherini et al., Astropart. Phys. 25, 1 (2006) [15]
G.C. Hill et al., World Scientific eProceedings, Statistical problems in particle physics,
astrophysics and cosmology, 108 (2005) [15]
G.C. Hill et al., World Scientific eProceedings, Statistical problems in particle ph [15]
G.C. Hill et al., World Scientific eProceeding
astrophysics and cosmology, 108 (2005) astrophysics and cosmology, 108 (2005 [16]
J. Braun et al., Astropart. Phys. 29, 299 (2008) [17]
F. Aharonian et al., Astronomy & Astrophysics 464, 235–243 (2007) [18]
S.R. Kelner et al., Phys. Rev. D 74, 034018 (2006) [19]
D. Horns et al. Astronomy & Astrophysics 451, L1 (2006) [20]
L. Zhang and X. C. Yang, ApJ 699, L153 (2009) [21]
F. Aharonian et al., Astronomy & Astrophysics 448, L43 (2006) [22]
F. Aharonian et al., Astronomy & Astrophysics 548, A38 (2012) [23]
M. G. Aartsen et al. (IceCube Collaboration), Astroph. J. 796, 109 (2014) 5 5
|
https://openalex.org/W2060955024
|
https://europepmc.org/articles/pmc2794533?pdf=render
|
English
| null |
Neuropeptide Y Knockout Mice Reveal a Central Role of NPY in the Coordination of Bone Mass to Body Weight
|
PloS one
| 2,009
|
cc-by
| 7,675
|
Abstract The funders had no role in study design, data collection and analysis, decision
to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: h.herzog@garvan.org.au Neuropeptide Y Knockout Mice Reveal a Central Role of
NPY in the Coordination of Bone Mass to Body Weight Paul A. Baldock1,8, Nicola J. Lee2, Frank Driessler1, Shu Lin2, Susan Allison1, Bernhard Stehrer2, En-Ju D. Lin3, Lei Zhang2, Ronald F. Enriquez1, Iris P. L. Wong1, Michelle M. McDonald4, Matthew During5,
Dominique D. Pierroz6, Katy Slack2, Yan C. Shi2, Ernie Yulyaningsih2, Aygul Aljanova2, David G. Little4,
Serge L. Ferrari6, Amanda Sainsbury2,7, John A. Eisman1, Herbert Herzog2,8* 1 Osteoporosis and Bone Biology Program, Garvan Institute of Medical Research, St Vincent’s Hospital, Sydney, Australia, 2 Neuroscience Program, Garvan Institute of
Medical Research, St Vincent’s Hospital, Sydney, Australia, 3 Department of Physiology and Biophysics, Georgetown University Medical Center, Washington, D. C., United
States of America, 4 Department of Orthopaedic Research and Biotechnology, The Children’s Hospital at Westmead, Sydney, Australia, 5 Department of Molecular
Medicine and Pathology, University of Auckland, Auckland, New Zealand, 6 Service and Laboratory of Bone Diseases, Department of Rehabilitation and Geriatrics, Faculty
of Medicine, Geneva University Hospital, Geneva, Switzerland, 7 School of Medical Sciences, University of New South Wales, Sydney, New South Wales, Australia, 8 Faculty
of Medicine, University of New South Wales, Sydney, New South Wales, Australia Abstract Changes in whole body energy levels are closely linked to alterations in body weight and bone mass. Here, we show that
hypothalamic signals contribute to the regulation of bone mass in a manner consistent with the central perception of
energy status. Mice lacking neuropeptide Y (NPY), a well-known orexigenic factor whose hypothalamic expression is
increased in fasting, have significantly increased bone mass in association with enhanced osteoblast activity and elevated
expression of bone osteogenic transcription factors, Runx2 and Osterix. In contrast, wild type and NPY knockout (NPY 2/2)
mice in which NPY is specifically over expressed in the hypothalamus (AAV-NPY+) show a significant reduction in bone mass
despite developing an obese phenotype. The AAV-NPY+ induced loss of bone mass is consistent with models known to
mimic the central effects of fasting, which also show increased hypothalamic NPY levels. Thus these data indicate that, in
addition to well characterized responses to body mass, skeletal tissue also responds to the perception of nutritional status
by the hypothalamus independently of body weight. In addition, the reduction in bone mass by AAV NPY+ administration
does not completely correct the high bone mass phenotype of NPY 2/2 mice, indicating the possibility that peripheral NPY
may also be an important regulator of bone mass. Indeed, we demonstrate the expression of NPY specifically in osteoblasts. In conclusion, these data identifies NPY as a critical integrator of bone homeostatic signals; increasing bone mass during
times of obesity when hypothalamic NPY expression levels are low and reducing bone formation to conserve energy under
‘starving’ conditions, when hypothalamic NPY expression levels are high. Received September 10, 2009; Accepted October 15, 2009; Published December 22, 2009 Copyright: 2009 Baldock et al. This is an open-access article distributed under the terms of the Creative Commons
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Copyright: 2009 Baldock et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This study was supported by National Health and Medical Research Council Career Development Award - 481 355 to AS and 427638 to PB and a
National Health and Medical Research Council Principal Research Fellowship to HH. Neuropeptide Y Knockout Mice Reveal a Central Role of
NPY in the Coordination of Bone Mass to Body Weight Citation: Baldock PA, Lee NJ, Driessler F, Lin S, Allison S, et al. (2009) Neuropeptide Y Knockout Mice Reveal a Central Role of NPY in the Coordination of Bone
Mass to Body Weight. PLoS ONE 4(12): e8415. doi:10.1371/journal.pone.0008415 Introduction Importantly, these
changes in cortical bone mass and formation were evident in the
absence of any increases in motor activity in either male or female
NPY 2/2 mice, negating a potential role of activity and weight
bearing in the increases in bone mass seen in these mice
(Figure 2g). Indeed, a trend for reduced physical activity was
evident in NPY 2/2 mice in the dark phase, but this was not
significant, nor was it seen in the overall 24-hour period
(Figure 2g). have been identified on osteoblasts and a lack of Y1 receptors in
mice also leads to increased bone mass [10]. The Y1-mediated effect
on bone is not dependent on hypothalamic Y1 receptors suggesting
an additional direct action of the NPY system on bone homeostasis
[6,8,11]. [
]
Despite the demonstrated actions of NPY, Y receptors in the
control of bone homeostasis, the role of NPY in this process is yet to
be defined. Although NPY is the predominant ligand in the central
nervous system, Y receptors can also be activated by the two other
family members, peptide YY (PYY) and pancreatic polypeptide
(PP). Possible redundancy in the functions of NPY-like ligands may
explain why initial examination of NPY deficient mice suggested no
skeletal changes [12], a finding contradictory to experiments
showing significant increases in bone mass following loss of NPY-
producing neurons from the arcuate nucleus of the hypothalamus
using monosodium glutamate treatment by the same group [13]. Therefore we used a systematic approach to investigate the specific
role of NPY signalling on bone homeostasis employing several NPY
mutant mouse models including specific re-introduction of NPY
into the hypothalamus of otherwise NPY deficient adult mice. Generalized Increase in Bone Formation in NPY 2/2 Mice
In the distal femoral metaphysis, cancellous bone volume was
greater in NPY 2/2 mice, coincident with a 2-fold increase in bone
formation rate compared to that in wild type mice (Figure 3a, 3b). This change was associated with an increase in the extent
(mineralizing surface) and speed (mineral apposition rate) of bone
formation (Figure 3c, 3d). Bone resorption indices in NPY 2/2
mice – i.e. osteoclast surface and number – were not significantly
changed (Figure 3e, 3f), demonstrating that NPY preferentially
controls the anabolic aspects of bone homeostasis. Femoral data is
shown for male mice, but results were similar in females. Results High Bone Mass and Reduced Fat Mass in NPY 2/2 Mice
While there was no effect of NPY ablation on body weight
(Figure 1a), body fat mass was significantly reduced in NPY 2/2
compared to wild type mice, as evidenced by decreased whole
body fat mass measured by DXA (Figure 1b), with no effect of
genotype on lean body mass (Figure 1c). Importantly, lack of NPY
was associated with a greater whole body BMD as well as a greater
whole body BMC apparent in both genders, although the increase
in BMC only reached significance in female NPY 2/2 (Figure 1d,
1e). Consistent with the whole body measurement, lumbar BMD
and BMC were significantly increased in NPY 2/2 mice compared
to gender-matched wild type controls (Figure 1f, 1g). Introduction The
effects of NPY deletion on femoral cancellous bone were also
evident in micro computed tomographs of the distal femoral
metaphysis (Figure 1g) and cancellous bone volume of the 4th
lumbar vertebrae (Figure 1h), indicating a generalized anabolic
effect of NPY deletion throughout the skeleton. Introduction sion in the hypothalamus and in this way reduces appetite and
normalises energy expenditure [5]. Importantly however, the NPY
system has also been shown to regulate bone homeostasis [6]. Amongst the 5 known Y-receptors (Y1, Y2, Y4, Y5 and in certain
species also Y6) [7,8], NPY mediates its effects on energy
homeostasis via hypothalamic Y1 and Y2 receptors [6]. Interest-
ingly, these Y-receptors have also been reported to be critical in
the regulation of bone homeostasis with the specific deletion of the
Y2-receptor in the hypothalamus resulting in a bone anabolic
phenotype [6]. Bone
remodelling
has
traditionally
been
viewed
as
an
endocrine- and paracrine-regulated process. This view is rapidly
changing, however, with growing evidence demonstrating that
neuronal factors are critical for normal bone homeostasis. Moreover, efferent neural pathways from the hypothalamus
potently modify the activity of bone cells. Studies in leptin-
deficient (ob/ob) mice revealed that the adipokine leptin, in
addition to its actions as an important circulating indicator of the
level of adiposity, also modulates bone formation through
activation of central, hypothalamic relays via efferent sympathetic
nervous output which directly modulates osteoblast activity [1–3]. A major target of leptin in the hypothalamus is the neuropeptide Y
(NPY) system, one of the most prominent regulators of appetite
and energy homeostasis [4]. Leptin down-regulates NPY expres- However, the actions of the NPY system in bone are more
complex than a simple downstream mediator for leptin. Specifically,
Y2-mediated changes occur consistently throughout the skeleton in
these mice, while alterations in leptin levels induce opposing effects
on cortical and cancellous bone, as evident in studies involving
Y22/2;ob/ob double mutant mice [9]. Furthermore, Y1 receptors PLoS ONE | www.plosone.org 1 December 2009 | Volume 4 | Issue 12 | e8415 December 2009 | Volume 4 | Issue 12 | e8415 PLoS ONE | www.plosone.org NPY and Bone Mass significant increase in cortical bone size in NPY 2/2 mice. Total
bone volume and marrow volume of the mid-femur of NPY 2/2
mice were both increased, resulting in greater cortical bone
volume and cortical thickness in NPY 2/2 mice compared to wild
type (Figure 2a–2d). These changes were associated with enhanced
cortical bone formation, as shown by elevated endocortical
mineral apposition rate (MAR) (Figure 2e, 2f). Greater Cortical Bone Formation in NPY 2/2 Mice (g) 24 hour home cage activity. Scale bar represents 50 mm. # p,0.05 vs wild type. n = 8214, data
expressed as mean6SE. doi:10.1371/journal.pone.0008415.g002 adult wild type mice. Wild type mice were injected unilaterally
with a recombinant adenovirus-associated virus producing a
localized increase in NPY expression (rAAV-NPY+) in the
hypothalamus, targeting the arcuate nucleus (Arc) (Figure 4a),
the brain region critical in mediating the central effects of Y
receptor signaling on both energy balance and bone mass [6,8]. Four weeks post-injection, body weight was significantly increased
in wild type rAAV-NPY+-injected animals (WT NPY+) compared
to wild type controls, injected with an empty virus (WT empty)
(Figure 4b). This weight gain was associated with an increase in
white adipose tissue mass (Figure 4c). homeostasis were evident following rAAV-NPY+ injection into the
hippocampus [8]. Histological examination of bones revealed that
elevation of hypothalamic NPY expression decreased cortical
osteoblast activity, with a 7-fold reduction in endosteal MAR and a
significant reduction in periosteal MAR in WT NPY+ mice
compared to WT empty controls (Figure 4f, g). These changes can
be clearly seen on the endosteal surface after injection of dual
fluorescent labels (Figure 4h), demonstrating the powerful action of
hypothalamic-NPY activated pathways on inhibiting osteoblast
activity. adult wild type mice. Wild type mice were injected unilaterally
with a recombinant adenovirus-associated virus producing a
localized increase in NPY expression (rAAV-NPY+) in the
hypothalamus, targeting the arcuate nucleus (Arc) (Figure 4a),
the brain region critical in mediating the central effects of Y
receptor signaling on both energy balance and bone mass [6,8]. Four weeks post-injection, body weight was significantly increased
in wild type rAAV-NPY+-injected animals (WT NPY+) compared
to wild type controls, injected with an empty virus (WT empty)
(Figure 4b). This weight gain was associated with an increase in
white adipose tissue mass (Figure 4c). In order to determine whether the bone anabolic phenotype
observed in NPY
2/2 mice is wholly due to the lack of
hypothalamic NPY signaling, an additional transgenic mouse
model was generated where NPY expression was restricted solely
to the hypothalamus. This model was achieved by re-introducing
NPY specifically into the hypothalamus of NPY 2/2 mice via
stereotactic injection of rAAV-NPY+ (NPY 2/2 NPY+). Greater Cortical Bone Formation in NPY 2/2 Mice To investigate whether alterations in central NPY levels are
responsible for the anabolic bone phenotype seen in NPY 2/2
mice, NPY was over-expressed specifically in the hypothalamus of In order to evaluate the DXA results, cortical bone was
examined by peripheral quantitative tomography. There was a Figure 1. Generalized bone anabolic phenotype in 4 month old male and female NPY 2/2 mice. (a) Body weight. Dual X-ray
absorptiometry analysis of (b) fat mass, (c) lean mass indicate changed energy homeostasis in NPY 2/2 mice. Bone mass and density was also greater
as seen in (d) whole body BMD, (e) whole body BMC, (f) lumbar BMD and (g) lumbar BMC. n = 8214, data expressed as mean6SE. doi:10.1371/journal.pone.0008415.g001 Figure 1. Generalized bone anabolic phenotype in 4 month old male and female NPY 2/2 mice. (a) Body weight. Dual X-ray
absorptiometry analysis of (b) fat mass, (c) lean mass indicate changed energy homeostasis in NPY 2/2 mice. Bone mass and density was also greater
as seen in (d) whole body BMD, (e) whole body BMC, (f) lumbar BMD and (g) lumbar BMC. n = 8214, data expressed as mean6SE. doi:10.1371/journal.pone.0008415.g001 December 2009 | Volume 4 | Issue 12 | e8415 PLoS ONE | www.plosone.org 2 NPY and Bone Mass Figure 2. Greater cortical bone in NPY 2/2 mice. Peripheral quantitative computed tomography of mid-femur in male mice showing (a) total
bone volume, (b) marrow volume, (c) cortical bone volume and (d) cortical thickness. (e) Mid femoral endocortical mineral apposition rate, (f)
photomicrograph of endocortical bone formation. (g) 24 hour home cage activity. Scale bar represents 50 mm. # p,0.05 vs wild type. n = 8214, data
expressed as mean6SE. doi:10.1371/journal.pone.0008415.g002 Figure 2. Greater cortical bone in NPY 2/2 mice. Peripheral quantitative computed tomography of mid-femur in male mice showing (a) total
bone volume, (b) marrow volume, (c) cortical bone volume and (d) cortical thickness. (e) Mid femoral endocortical mineral apposition rate, (f)
photomicrograph of endocortical bone formation. (g) 24 hour home cage activity. Scale bar represents 50 mm. # p,0.05 vs wild type. n = 8214, data
expressed as mean6SE. doi:10.1371/journal.pone.0008415.g002 Figure 2. Greater cortical bone in NPY 2/2 mice. Peripheral quantitative computed tomography of mid-femur in male mice showing (a) total
bone volume, (b) marrow volume, (c) cortical bone volume and (d) cortical thickness. (e) Mid femoral endocortical mineral apposition rate, (f)
photomicrograph of endocortical bone formation. PLoS ONE | www.plosone.org Greater Cortical Bone Formation in NPY 2/2 Mice As shown
above, global deletion of NPY led to a 40% increase in MAR in
femoral cancellous bone compared to wild type controls (Figure 3d). However, restoration of NPY expression in the hypothalamus of
NPY 2/2 mice resulted only in a partial normalization of MAR to a
level approximately 20% lower then NPY 2/2 mice, with similar
reductions in the change in femoral bone mass and cancellous bone
volume (Figure 4k–4m). This inability of hypothalamic NPY to
completely restore a normal bone phenotype in NPY 2/2 mice
suggests that non-hypothalamic pathway(s) may also be important
in NPY mediated bone homeostasis. To further investigate what role NPY may play in osteoblast
function and development, mRNA was isolated from the bones of
wild type and NPY 2/2 mice and analysed for the expression of
key osteogenic markers. In keeping with their high bone mass and
anabolic phenotype, mRNA expression of alkaline phosphatase
(ALP) was significantly up-regulated in the long bones of NPY 2/2
mice (Figure 5c). Importantly, there was also an up-regulation of
both Runx2, and Osterix mRNA levels in the NPY 2/2 mice
(Figure 5c). Moreover, in vitro osteoblast activity was enhanced in
the absence of NPY, evident by a greater time-dependent increase
in mineralisation by NPY 2/2 bone marrow stromal cells under
osteogenic conditions than cells isolated from wild type mice
(Figure 5d). weight gain and more than doubled adiposity within 4 weeks
compared to NPY 2/2 empty mice, confirming the viability of the
NPY reintroduction procedure and demonstrating the critical role
hypothalamic NPY plays in regulating body weight and fat mass. Interestingly however, the elevated bone mass and bone formation
seen in NPY 2/2 mice was only partially corrected by hypothalamic
re-introduction of NPY in otherwise NPY deficient mice. As shown
above, global deletion of NPY led to a 40% increase in MAR in
femoral cancellous bone compared to wild type controls (Figure 3d). However, restoration of NPY expression in the hypothalamus of
NPY 2/2 mice resulted only in a partial normalization of MAR to a
level approximately 20% lower then NPY 2/2 mice, with similar
reductions in the change in femoral bone mass and cancellous bone
volume (Figure 4k–4m). This inability of hypothalamic NPY to
completely restore a normal bone phenotype in NPY 2/2 mice
suggests that non-hypothalamic pathway(s) may also be important
in NPY mediated bone homeostasis. NPY Signalling on Bone Cells Alters Osteogenesis In Vivo
and In Vitro In order to clarify whether NPY also regulates bone homeostasis
by direct action on bone cells and whether NPY is expressed in
bone tissue itself, bone sections were examined by in situ
hybridisation. Both cancellous and cortical osteoblasts from wild
type mice stained positively for NPY mRNA (Figure 5a) with no
staining in NPY 2/2 bone tissue (Figure 5b), providing the first
evidence of NPY expression in osteoblasts in vivo. Greater Cortical Bone Formation in NPY 2/2 Mice As shown
in Figures 4i and 4j, NPY 2/2 NPY+ -mice had a greater body Given the strong and positive association between increases in
body weight and bone mass, in part due to mechanical effects of
weight bearing [14], it is notable that tibial BMC was reduced by
19% (p,0.05) in WT NPY+ mice compared to WT empty
controls over the 4-week period, with no change in tibial BMD
(Figure 4d, 4e). This NPY-mediated bone loss was due to the
specific action of NPY in the hypothalamus, as no changes in bone PLoS ONE | www.plosone.org December 2009 | Volume 4 | Issue 12 | e8415 3 NPY and Bone Mass Figure 3. Greater cancellous bone volume and formation in NPY 2/2 mice. Histomorphometric analysis of distal femoral metaphysis in male
mice showing (a) cancellous bone volume, (b) bone formation rate, (c) mineralizing surface, (d) mineral apposition rate, (e) osteoclast surface and (f)
osteoclast number. (g) Representative micro-computed tomographs of the distal femoral metaphysis of 4 month old male wild type and NPY 2/2
mice. (h) 4th lumbar vertebral sections from male wild type and NPY 2/2 mice, displaying greater cancellous bone volume (BV/TV) in mutant mice. #
p,0.05 vs wild type. n = 8214, data expressed as mean6SE. doi:10.1371/journal.pone.0008415.g003 Figure 3. Greater cancellous bone volume and formation in NPY 2/2 mice. Histomorphometric analysis of distal femoral metaphysis in male
mice showing (a) cancellous bone volume, (b) bone formation rate, (c) mineralizing surface, (d) mineral apposition rate, (e) osteoclast surface and (f)
osteoclast number. (g) Representative micro-computed tomographs of the distal femoral metaphysis of 4 month old male wild type and NPY 2/2
mice. (h) 4th lumbar vertebral sections from male wild type and NPY 2/2 mice, displaying greater cancellous bone volume (BV/TV) in mutant mice. #
p,0.05 vs wild type. n = 8214, data expressed as mean6SE. doi:10.1371/journal.pone.0008415.g003 weight gain and more than doubled adiposity within 4 weeks
compared to NPY 2/2 empty mice, confirming the viability of the
NPY reintroduction procedure and demonstrating the critical role
hypothalamic NPY plays in regulating body weight and fat mass. Interestingly however, the elevated bone mass and bone formation
seen in NPY 2/2 mice was only partially corrected by hypothalamic
re-introduction of NPY in otherwise NPY deficient mice. Greater Cortical Bone Formation in NPY 2/2 Mice Taken together, these data indicate that global lack of NPY
induces effects inherent to osteoblasts in both cortical and
cancellous bone and in the apical and appendicular skeletons. Given that NPY is expressed in osteoblasts, these data further
support the concept that NPY could be a direct local regulator of
osteoblast function, in addition to effects mediated via the
hypothalamus, and highlights the fact that NPY may act via
neuronal as well as autocrine mechanisms to regulate bone
homeostasis. NPY Signalling on Bone Cells Alters Osteogenesis In Vivo
and In Vitro December 2009 | Volume 4 | Issue 12 | e8415 PLoS ONE | www.plosone.org Discussion This study has identified a powerful inverse relationship
between NPY signaling in the hypothalamus and bone formation. A generalized bone anabolic response resulting from loss of NPY PLoS ONE | www.plosone.org December 2009 | Volume 4 | Issue 12 | e8415 December 2009 | Volume 4 | Issue 12 | e8415 4 NPY and Bone Mass Figure 4. Hypothalamic NPY over-expression inhibits bone formation, despite increased body weight. Photomicrograph of coronal
brain section showing NPY over expression following unilateral rAAV-NPY+ injection in the arcuate nucleus (Arc). Changes in (b) body weight, (c)
white adipose tissue, (d) tibial BMD, (e) tibial BMC, (f) mid femoral endocortical and (g) mid femoral periosteal mineral apposition rate in response to
hypothalamic NPY over expression in wild type mice (WT NPY+) compared to control (WT empty). (h) Representative photomicrographs of femoral
endocortical mineral apposition rate WT empty or WT NPY+ mice. Changes in (i) body weight, (j) fat mass, (k) distal femoral metaphyseal mineral
apposition rate, (l) femoral BMD, and (m) distal femoral metaphyseal cancellous bone volume in germline NPY 2/2 mice after hypothalamic NPY over
expression (NPY 2/2 NPY+) compared to controls (NPY 2/2 empty). # p,0.05 vs empty. Scale bar represents 20 mm. n = 7212, data expressed as
mean6SE. doi:10.1371/journal.pone.0008415.g004 Figure 4. Hypothalamic NPY over-expression inhibits bone formation, despite increased body weight. Photomicrograph of coronal
brain section showing NPY over expression following unilateral rAAV-NPY+ injection in the arcuate nucleus (Arc). Changes in (b) body weight, (c)
white adipose tissue, (d) tibial BMD, (e) tibial BMC, (f) mid femoral endocortical and (g) mid femoral periosteal mineral apposition rate in response to
hypothalamic NPY over expression in wild type mice (WT NPY+) compared to control (WT empty). (h) Representative photomicrographs of femoral
endocortical mineral apposition rate WT empty or WT NPY+ mice. Changes in (i) body weight, (j) fat mass, (k) distal femoral metaphyseal mineral
apposition rate, (l) femoral BMD, and (m) distal femoral metaphyseal cancellous bone volume in germline NPY 2/2 mice after hypothalamic NPY over
expression (NPY 2/2 NPY+) compared to controls (NPY 2/2 empty). # p,0.05 vs empty. Scale bar represents 20 mm. n = 7212, data expressed as
mean6SE. doi:10 1371/journal pone 0008415 g004 occurred. Discussion While the decrease in bone formation in these mice may
in part also result from reduced physical activity [16] and thereby
altered weight bearing [17], this result is also consistent with a
skeletal response to the starvation signal induced by AAV NPY+
[18]. Thus the central perception of body weight may be important
to the regulation of bone mass, in addition to the actual mechanical
forces in the bone tissue itself. In this manner, during weight loss,
increasing NPY ensures calories are not wasted on the production/
maintenance of unneeded skeletal tissue, thereby also increasing the
supply of minerals and nutrients stored in skeletal tissue for other
vital processes. Conversely, during periods of high nutrient intake
and resultant weight gain, reduction in NPY expression ensures
sufficient bone formation to guarantee mechanical competence of
the skeleton during the period of increased weight bearing. Importantly, we showed here that reduced NPY levels in NPY
knockout mice are not associated with significant changes in activity
levels, indicating the skeletal response to NPY are not activity-
dependent. NPY is therefore ideally placed to match bone mass to
body weight, a major regulatory influence on bone homeostasis [19]
(Figure 6b). signaling was evident throughout the skeleton, including cortical
and cancellous bone as well as axial and appendicular sites. In
contrast, NPY over expression in the hypothalamus resulted in an
inhibition of bone formation. This central action is consistent with
signaling via Y2 receptors expressed on neurons of the arcuate
nucleus, as is evidenced by the opposing response reported
following specific deletion of Y2 receptors from this region of the
hypothalamus [6]. Thus NPY acts in the hypothalamus to
tonically inhibit bone formation, and likely does so through
signals transduced by Y2 receptors. Results from this study suggest that in addition to the well defined
actions of loading from body weight on bone mass, the central
‘perception’ of energy status may have an important influence on
bone mass. This is particularly evident in rAAV-NPY+ injected
mice. The viral promoter controlling NPY production prevents the
normal feedback by signals such as increased serum leptin from
inhibiting hypothalamic NPY expression [12,15]. As a result, the
‘‘starvation’’ signal is not attenuated and body weight continues to
increase. PLoS ONE | www.plosone.org Discussion Importantly, despite the marked increase in body weight
caused by this experimental condition, a decrease in bone mass PLoS ONE | www.plosone.org December 2009 | Volume 4 | Issue 12 | e8415 5 NPY and Bone Mass Figure 5. NPY expression and action in bone tissue. (a) Analysis of NPY expression by in situ hybridisation in wild type mice shows specific
staining of osteoblasts employing a NPY antisense probe in cancellous and cortical bone (arrows) and megakaryocytes (arrowheads). (b) This staining
is absent in NPY 2/2 mice. (c) Levels of ALP, Runx2 and Osterix are greater in NPY 2/2 mice compared to wild type as determined by quantitative real-
time PCR on mRNA from long bones. (mean6SE. n = 526 mice per genotype.). (d) Bone marrow stromal cells isolated from NPY 2/2 mice produce
more mineral in vitro than wild type mice. (mean6SE, n = 10215 wells per time, 3 independent experiments). # p,0.05, ## p,0.01 vs wild type,
scale bar represents 50 mm. doi:10.1371/journal.pone.0008415.g005 Figure 5. NPY expression and action in bone tissue. (a) Analysis of NPY expression by in situ hybridisation in wild type mice shows specific
staining of osteoblasts employing a NPY antisense probe in cancellous and cortical bone (arrows) and megakaryocytes (arrowheads). (b) This staining
is absent in NPY 2/2 mice. (c) Levels of ALP, Runx2 and Osterix are greater in NPY 2/2 mice compared to wild type as determined by quantitative real-
time PCR on mRNA from long bones. (mean6SE. n = 526 mice per genotype.). (d) Bone marrow stromal cells isolated from NPY 2/2 mice produce
more mineral in vitro than wild type mice. (mean6SE, n = 10215 wells per time, 3 independent experiments). # p,0.05, ## p,0.01 vs wild type,
scale bar represents 50 mm. doi:10.1371/journal.pone.0008415.g005 Central circuits alone, however, do not appear to explain the
entire NPY-mediated signaling pathway to bone, as restoration of
hypothalamic NPY expression in NPY
2/2 mice failed to
completely normalize osteoblast activity. This incomplete rescue
of the NPY 2/2 phenotype by central NPY replacement indicates a
potential role for non-hypothalamic NPY pathways. This finding is
consistent with a Y1 receptor-mediated action in the periphery,
since hypothalamus-specific deletion of Y1 receptors did not
replicate the greater bone formation evident in germline Y12/2
mice [10]. Generation of NPY 2/2 Mice The generation of the NPY 2/2 mice was described previously
[21]. All research and animal care procedures were approved by
the Garvan Institute/St Vincent’s Hospital Animal Experimenta-
tion Ethics Committee and were in agreement with the Australian
Code of Practice for the Care and Use of Animals for Scientific
Purpose. Discussion This opens the possibility that lack of NPY in
osteoblasts may have contributed to the phenoptype of NPY 2/2
mice, consistent with our demonstration of NPY expression in
osteoblasts, altered expression of osteogenic transcription factors in
bone as well as increased ex vivo mineralization of osteoblasts from
NPY 2/2 mice. Indeed, identification of NPY expression in the
osteoblast, along with local expression of Y1 receptor [10,20]
indicates the potential for local paracrine/autocrine control of
osteoblast activity by NPY. Interestingly, in terms of NPY’s
coordination of body weigh and bone mass, NPY expression has
been identified in both osteoblasts and osteocytes [10,20]. Moreover, this expression was reduced following exposure of
cultured osteoblasts to fluid sheer stress, indicating the potential for
a local, load-responsive regulation of NPY. In this manner,
increasing load would decrease NPY expression, thereby reducing
the tonic repression of osteoblast activity as body weight increased. Thus central efferent signals may provide a systemic regulatory
influence, via Y2 receptor action in the arcuate nucleus of the
hypothalamus, whilst osteoblastic Y1 receptor action may enable
local fine-tuning of the systemic response (Figure 6a). reduces central NPY signaling [12,15], bone formation is stimulated
as was the case in NPY 2/2 mice. Moreover, when central NPY
levels are elevated as in negative energy balance, bone formation is
inhibited as was the case in rAAV-NPY+ injected mice. While
hypothalamic NPY is ideally placed to modify bone mass to match
changes in body weight induced by altered energy homeostasis,
NPY produced in bone itself may play an important role in the
regulation of bone mass. This later circuit offers also an attractive
target to modulate and opens the possibility to increase bone mass
without affecting central NPY controlled pathways. Materials and Methods Generation of NPY 2/2 Mice
/ PLoS ONE | www.plosone.org Viral Vector Injection Elevation of NPY expression was achieved following procedures
reported previously [8]. Briefly, 10–12 week-old wild type or NPY 2/2
mice were anesthetized and injected in the PVN with recombinant
adeno-associated virus expressing either NPY (rAAV-NPY+) or an
empty cassette (rAAV-empty) using a stereotaxic table (David Kopf,
California, USA). Brain injection co-ordinates relative to Bregma
were
posterior,
2.1 mm; lateral, 60.4 mm;
ventral,
5.3 mm
corresponding to the PVN [22]. An additional control group was
injected with rAAV-NPY+ or rAAV-empty vector in the hippocam-
pus (Co-ordinates relative to Bregma were posterior, 1.7 mm; lateral,
60.8 mm; ventral, 2.2 mm). One microlitre of either rAAV-NPY+ Taken together, these data highlight the critical role of NPY in
the co-ordinated regulation of skeletal tissue. We propose that in
situations where hypothalamic NPY expression is decreased, as in
short-term overfeeding in which serum leptin levels rise and in turn December 2009 | Volume 4 | Issue 12 | e8415 PLoS ONE | www.plosone.org 6 NPY and Bone Mass Figure 6. Schematic representation of the co-ordinate regulation of body weight and bone by NPY. (a) Altered energy homeostatic
demand regulates hypothalamic NPY production, which signals via arcuate Y2 receptors through efferent sympathetic relays to the osteoblast. At the
osteoblast, tonic cell activity is modulated by exogenous neural inputs as well as local NPY production, acting through cell surface Y1 receptors. (b)
NPY exhibits an inverse relationship with both energy homeostasis and bone mass. As body weight increases as a result of positive energy
homeostasis, the decrease in NPY signaling stimulates the production of bone to match body weight to bone mass. Likewise, negative energy
homeostasis, and the coincident reduction of body weight is accompanied by increased NPY, which inhibits the production of bone, thereby
conserving energy and increasing the mobilization of nutrient stores form bone. doi:10.1371/journal.pone.0008415.g006 Figure 6. Schematic representation of the co-ordinate regulation of body weight and bone by NPY. (a) Altered energy homeostatic
demand regulates hypothalamic NPY production, which signals via arcuate Y2 receptors through efferent sympathetic relays to the osteoblast. At the
osteoblast, tonic cell activity is modulated by exogenous neural inputs as well as local NPY production, acting through cell surface Y1 receptors. (b)
NPY exhibits an inverse relationship with both energy homeostasis and bone mass. Viral Vector Injection As body weight increases as a result of positive energy
homeostasis, the decrease in NPY signaling stimulates the production of bone to match body weight to bone mass. Likewise, negative energy
homeostasis, and the coincident reduction of body weight is accompanied by increased NPY, which inhibits the production of bone, thereby
conserving energy and increasing the mobilization of nutrient stores form bone. doi:10.1371/journal.pone.0008415.g006 or rAAV-empty virus (16109 Pfu/ml) was injected bilaterally over 10
minutes using a 26 gauge guide cannula and a 33 gauge injector
(PlasticsOne, Roanoke, USA) connected to a Hamilton Syringe and a
syringe infusion pump (World Precision Instruments, Sarasota,
Florida). The recombinant AAV expressing NPY was under the
control of a neuron specific enolase promoter (rAAV-NPY+), which
confined the expression to nerve cells. Mice were housed individually
for the ensuing 28 days, with ad libitum access to standard chow and
water. The efficacy of viral NPY expression was confirmed by the
resultant weight gain, a characteristic response to elevated hypotha-
lamic NPY production [8]. 10 and 3 days prior to collection. At 14–16 weeks of age, WT and
NPY 2/2 mice were sacrificed by cervical dislocation between
10.00–14.00 h for collection of trunk blood in heparinized tubes. Both femora and the lumbar spine were excised and fixed in 4%
paraformadehyde for 16 h at 4uC. The right femur was bisected
transversely at the midpoint of the long axis and the distal half
embedded undecalcified in methacrylate resin (Medim-Medizi-
nische Diagnostik, Giessen, Germany). Similarly, the 4th lumbar
vertebrae was defleshed and embedded. Sagittal sections with
5 mm thickness were analysed as previously described [11]. Mineralized bone in the sections was visualized by von Kossa
stain. Cancellous bone volume, trabecular thickness and number
were calculated. The mineralizing surface (MS, %), mineral
apposition
rate
(MAR,
mm/d)
and
bone
formation
rate
(BFR = MS/BS
*
MAR,
mm2/ mm/d)
were
calculated
as
previously described [8], following fluorescence microscopy (Leica,
Heerbrugg,
Switzerland). Osteoclast
surface
and
osteoclast
number were estimated in tartrate-resistant acid phosphatase
stained sections where only multinucleated, TRAP-positive cells
were included in the analysis. Cortical mineral apposition rate was
measured on the anterior periosteal surface in a region extending
1000 mm distal from the mid point of the shaft and in an endosteal
region extending 1000 mm proximal from the posterior aspect of
the growth plate as previously described [8]. Activity Measurements Ambulatory activity of individually housed mice was evaluated
within the metabolic chambers using an OPTO-M3 sensor system
(Columbus Instruments, Columbus, OH, USA), whereby ambu-
latory counts were a record of consecutive adjacent photo-beam
breaks. Cumulative ambulatory counts of X, Y and Z directions
were recorded every minute and summed for 1-h intervals. Viral Vector Injection or rAAV-empty virus (16109 Pfu/ml) was injected bilaterally over 10
minutes using a 26 gauge guide cannula and a 33 gauge injector
(PlasticsOne, Roanoke, USA) connected to a Hamilton Syringe and a
syringe infusion pump (World Precision Instruments, Sarasota,
Florida). The recombinant AAV expressing NPY was under the
control of a neuron specific enolase promoter (rAAV-NPY+), which
confined the expression to nerve cells. Mice were housed individually
for the ensuing 28 days, with ad libitum access to standard chow and
water. The efficacy of viral NPY expression was confirmed by the
resultant weight gain, a characteristic response to elevated hypotha-
lamic NPY production [8]. Bone Densitometry Whole body bone mineral content (BMC), bone mineral density
(BMD), lean mass and fat mass were measured on mice ventral
side down with head exclusion and tail inclusion, using a dedicated
mouse dual X-ray absorpiometer (DXA) (Lunar Piximus II, GE
Medical Systems, Madison WI). Whole femoral BMC and BMD
were measured in excised left femora. Femora were scanned with
tibiae attached and the knee joint in flexion to ninety degrees to
ensure consistent placement and scan of the sagittal profile. Statistical Analyses Hybridisation was carried out overnight at 45uC in a humid
environment. Sections were incubated with hybridisation solution
containing 50% formamide, 5X SSC, 250 mg/ml salmon sperm
DNA, 250 mg/ml yeast tRNA, 1x Denhardt’s solution, 10%
dextran sulphate, 10 mM DTT and 200 ng/mL of digoxigenin-
labelled riboprobe. The sections were washed in 2X SSC for 5
minutes followed by 0.2X SSC at 62uC for 30 minutes and 0.1X
SSC at 65uC for 30 minutes. They were then incubated with
20 mg/mL RNase A (Roche) in 0.5 M NaCl, 10 mM Tris-HCl,
and 1 mM EDTA at 37uC for 15 minutes followed by washes with
2X SSC for 5 minutes, 0.1X SSC at 37uC for 30 minutes. Following the washes, antidigoxigenin Fab antibody fragments
conjugated with alkaline phosphatase (Roche) and NBT/BCIP Dual genotype comparisons were assessed using two-tailed
students T-test. Multiple genotype comparisons were assessed by
factorial ANOVA followed by Fisher’s or Contrasts post-hoc tests,
using StatView version 4.5 or Super-ANOVA (Abacus Concepts
Inc, CA, USA). For all statistical analyses, P,0.05 was accepted as
being statistically significant. In-Situ Hybridisation of Bone and Hypothalamic Tissue Sections were acetylated with 1X triethanolamine
containing 0.25% (v/v) acetic anhydride for 10 minutes and
washed in PBS before hybridisation. Isolation and Differentiation of Bone Marrow Stromal
C ll The isolation and differentiation of plastic adherent bone marrow
stromal cells (BMSCs) from 5 to 9 week old male mice was carried
out as previously described [10] with minor modifications. Following sacrifice by cervical dislocation, marrow was flushed
from femurs and tibias with control media and cells were plated at a
density of 1.96106 cells/cm2 in 50 cm2 plastic tissue culture plates. Control media consisted of a-minimum essential medium contain-
ing 10% fetal bovine serum, 2 mM L-glutamine, 2.2 g/L sodium
bicarbonate, 0.017 M HEPES, 100 mg/mL penicillin/streptomycin
and 34 mg/L gentamycin. The majority of non-adherent cells were
removed by medium changes at 3 and 5 days later and discarded. After 7 days in culture, cells were trypsinised, counted and re-plated
at 36104 cells/cm2 in 24-well plates in control media. From this
time onwards media was changed 3 times per week. Bone Histomorphometry Mice were injected with the fluorescent compound calcein
(Sigma Chemical Company, St Louis, USA) at 20 mg/kg (s.c.) at PLoS ONE | www.plosone.org December 2009 | Volume 4 | Issue 12 | e8415 7 NPY and Bone Mass stock solution (Roche) containing 1 mM levamisole were used for
colorimetric detection following the manufacturer’s instructions. stock solution (Roche) containing 1 mM levamisole were used for
colorimetric detection following the manufacturer’s instructions. In-Situ Hybridisation of Bone and Hypothalamic Tissue In-Situ Hybridisation of Bone and Hypothalamic Tissue
Antisense and sense riboprobes for mouse NPY were generated
from a cDNA region corresponding to bases 272 to +89 of the
coding sequence and subcloned into pGEM-T Easy plasmid
vector (Promega). Probes were labelled with digoxigenin-UTP by
in vitro transcription with either SP6 (antisense probe) or T7 (sense
probe) RNA polymerase using a DIG RNA labelling kit (Roche)
according to the manufacturer’s instructions and .purified using
Sephadex G25 spin columns and their yield was assessed by dot
blot. RNA Extraction and Quantitative Real-Time PCR
Following sacrifice by cervical dislocation, femurs and tibias
from 6–10 week old male mice were cleaned and snap frozen in
liquid nitrogen. Subsequently femurs and tibias from each leg were
homogenised separately in TRIzolH reagent using a polytron. RNA extractions were carried out using TRIzolH reagent
according to the manufacturer’s instructions. RNA samples were
checked for quality and quantified using the Agilent 2100
Bioanalyser (Agilent Technologies) according to the manufactur-
er’s instructions. One microgram of total RNA was taken for
cDNA synthesis with oligo(dT)20 and random hexamers using the
SuperScript III First-Strand Synthesis System for reverse tran-
scription-PCR (Invitrogen). Quantitative real-time PCR was then
carried out using the TaqMan Universal PCR master mix
(Applied Biosystems), ABI Prism 7900 HT Sequence Detection
System and Software and inventoried kits containing primers and
probes from Applied Biosystems. To control for variability in
amplification due to differences in starting mRNA concentrations,
GAPDH was used as an internal standard. The relative expression
of target mRNA was computed from the target Ct values and the
GAPDH Ct value using the standard curve method (Sequence
Detection Systems Chemistry Guide, Applied Biosystems). In situ hybridisation was carried out as previously described with
minor modifications [26] on 5 mm sections of decalcified sagittal
section of the distal femur. All procedures were carried out at
room temperature unless specified otherwise. Sections were
dewaxed in xylene, rehydrated through decreasing concentrations
of ethanol (100% to 70%), and then fixed in 2% paraformalde-
hyde in PBS on ice for 10 minutes. After washing in PBS, sections
were incubated at 37uC with proteinase K (Roche) at a
concentration of 5 mg/mL in 50 mM Tris-HCl (pH 7.5) and
5 mM EDTA for 20 minutes, followed by 0.1 M glycine in PBS
for 5 minutes. Micro Computed Tomography Cancellous bone architecture was evaluated at the distal femoral
metaphysis [23,24]using micro-computed tomography (Micro-
CT40, Scanco Medical AG, Basserdorf Switzerland), employing a
12-mm isotropic voxel size. Bone volume fraction (BV/TV, %) was
computed without assumptions regarding the underlying bone
architecture [25]. Quantitative Computed Tomography (QCT) Differentiation into mineral-producing osteoblasts was achieved
by culturing the cells in osteogenic media consisting of control
media supplemented with 50 mg/L ascorbic acid and 10 mM b-
glycerophosphate. Mineralisation of extracellular matrix was
visualised by von Kossa staining with 2% silver nitrate under
UV light for 30 minutes. The extent of mineralisation was
quantified using the Leica QWin imaging system (Leica Micro-
systems, Heerbrugg, Switzerland). QCT was used to isolate cortical bone for analysis in male mice,
using a Stratec XCT Research SA (Stratec Medizintechnik,
Pforzheim, Germany). Scans were conducted on excised left
femurs as previously described [9] with following settings: voxel
size of 70 mm, scan speed of 5 mm/sec and slice width of 0.2 mm. Bones were scanned in 2 consecutive slices, 7 and 7.5 mm from
the distal margin of the femur, representing a mid femoral aspect. References 1. Moore RE, Smith CK, Bailey CS, Voelkel EF, Tashjian AH (1993)
Characterization of beta-adrenergic receptors on rat and human osteoblast-
like cells and demonstration that beta-receptor agonists can stimulate bone
resorption in organ culture. Bone Miner 23: 301–315. 14. Reid IR (2008) Relationships between fat and bone. Osteoporos Int 19:
595–606. 15. Sipols AJ, Baskin DG, Schwartz MW (1995) Effect of intracerebroventricular
insulin infusion on diabetic hyperphagia and hypothalamic neuropeptide gene
expression. Diabetes 44: 147–151. p
g
2. Kellenberger S, Muller K, Richener H, Bilbe G (1998) Formoterol and
isoproterenol induce c-fos gene expression in osteoblast-like cells by activating
beta2-adrenergic receptors. Bone 22: 471–478. 16. Heilig M, Vecsei L, Widerlov E (1989) Opposite effects of centrally administered
neuropeptide Y (NPY) on locomotor activity of spontaneously hypertensive (SH)
and normal rats. Acta Physiol Scand 137: 243–248. 3. Takeda S, Elefteriou F, Levasseur R, Liu X, Zhao L, et al. (2002) Leptin
regulates bone formation via the sympathetic nervous system. Cell 111:
305–317. 17. Sample SJ, Behan M, Smith L, Oldenhoff WE, Markel MD, et al. (2008)
Functional adaptation to loading of a single bone is neuronally regulated and
involves multiple bones. J Bone Miner Res 23: 1372–1381. 4. Stanley BG, Kyrkouli SE, Lampert S, Leibowitz SF (1986) Neuropeptide Y
chronically injected into the hypothalamus: a powerful neurochemical inducer of
hyperphagia and obesity. Peptides 7: 1189–1192. 18. Hamrick MW, Ding KH, Ponnala S, Ferrari SL, Isales CM (2008) Caloric
restriction decreases cortical bone mass but spares trabecular bone in the mouse
skeleton: implications for the regulation of bone mass by body weight. J Bone
Miner Res 23: 870–878. yp
p
g
y
p
5. Erickson JC, Hollopeter G, Palmiter RD (1996) Attenuation of the obesity
syndrome of ob/ob mice by the loss of neuropeptide Y. Science 274: 1704–1707. 6. Baldock PA, Sainsbury A, Couzens M, Enriquez RF, Thomas GP, et al. (2002)
Hypothalamic Y2 receptors regulate bone formation. J Clin Invest 109:
915–921. 19. Reid IR, Cornish J, Baldock PA (2006) Nutrition-related peptides and bone
homeostasis. J Bone Miner Res 21: 495–500. 20. Igwe JC, Jiang X, Paic F, Ma L, Adams DJ, et al. (2009) Neuropeptide Y is
expressed by osteocytes and can inhibit osteoblastic activity. J Cell Biochem. 7. Blomqvist AG, Herzog H (1997) Y-receptor subtypes–how many more? Trends
Neurosci 20: 294–298. 21. Author Contributions Conceived and designed the experiments: PB NJL HH. Performed the
experiments: PB NJL FD SL SA BS EJDL LZ RFE IPW KS YCS EY AA
AS. Contributed reagents/materials/analysis tools: MMM MJD DDP
DGL SF. Wrote the paper: AS JE HH. PLoS ONE | www.plosone.org December 2009 | Volume 4 | Issue 12 | e8415 8 NPY and Bone Mass PLoS ONE | www.plosone.org References Karl T, Duffy L, Herzog H (2008) Behavioural profile of a new mouse model for
NPY deficiency. Eur J Neurosci 28: 173–180. 8. Baldock PA, Sainsbury A, Allison S, Lin EJ, Couzens M, et al. (2005)
Hypothalamic control of bone formation: distinct actions of leptin and y2
receptor pathways. J Bone Miner Res 20: 1851–1857. 22. Franklin KBJ, Paxinos G (1997) The Mouse Brain in Stereotaxic Coordinates. San Diego: Academic Press. p
p
y
J
9. Baldock PA, Allison S, McDonald MM, Sainsbury A, Enriquez RF, et al. (2006)
Hypothalamic regulation of cortical bone mass: opposing activity of Y2 receptor
and leptin pathways. J Bone Miner Res 21: 1600–1607. 23. Bouxsein ML, Pierroz DD, Glatt V, Goddard DS, Cavat F, et al. (2005) beta-
Arrestin2 regulates the differential response of cortical and trabecular bone to
intermittent PTH in female mice. J Bone Miner Res 20: 635–643. p
p
y
J
10. Baldock PA, Allison SJ, Lundberg P, Lee NJ, Slack K, et al. (2007) Novel role of
Y1 receptors in the coordinated regulation of bone and energy homeostasis. J Biol Chem 282: 19092–19102. 24. Ferrari SL, Pierroz DD, Glatt V, Goddard DS, Bianchi EN, et al. (2005) Bone
response to intermittent parathyroid hormone is altered in mice null for {beta}-
Arrestin2. Endocrinology 146: 1854–1862. 11. Allison SJ, Baldock P, Sainsbury A, Enriquez R, Lee NJ, et al. (2006)
Conditional deletion of hypothalamic Y2 receptors reverts gonadectomy-
induced bone loss in adult mice. J Biol Chem 281: 23436–23444. 25. Hildebrand T, Laib A, Muller R, Dequeker J, Ruegsegger P (1999) Direct three-
dimensional morphometric analysis of human cancellous bone: microstructural
data from spine, femur, iliac crest, and calcaneus. J Bone Miner Res 14:
1167–1174. 12. Ducy P, Amling M, Takeda S, Priemel M, Schilling AF, et al. (2000) Leptin
inhibits bone formation through a hypothalamic relay: a central control of bone
mass. Cell 100: 197–207. 26. Parker RM, Herzog H (1999) Regional distribution of Y-receptor subtype
mRNAs in rat brain. Eur J Neurosci 11: 1431–1448. 13. Elefteriou F, Takeda S, Liu X, Armstrong D, Karsenty G (2003) Monosodium
glutamate-sensitive hypothalamic neurons contribute to the control of bone
mass. Endocrinology 144: 3842–3847. PLoS ONE | www.plosone.org December 2009 | Volume 4 | Issue 12 | e8415 9
|
https://openalex.org/W4390747741
|
https://link.springer.com/content/pdf/10.1007/s42154-023-00272-x.pdf
|
English
| null |
Driver Steering Behaviour Modelling Based on Neuromuscular Dynamics and Multi-Task Time-Series Transformer
|
Automotive innovation
| 2,024
|
cc-by
| 10,951
|
Driver Steering Behaviour Modelling Based on Neuromuscular
Dynamics and Multi‑Task Time‑Series Transformer Yang Xing1 · Zhongxu Hu2 · Xiaoyu Mo2 · Peng Hang3 · Shujing Li4 · Yahui Liu5 · Yifan Zhao Received: 13 October 2022 / Accepted: 1 September 2023 / Published online: 11 January 2024
© The Author(s) 2024 Received: 13 October 2022 / Accepted: 1 September 2023 / Published online: 11 January 2024
© The Author(s) 2024 Abstract Although ADVs ca
* Yang Xing
yang.x@cranfield.ac.uk
1
School of Aerospace, Transport and Manufacturing,
Cranfield University, Cranfield MK43 0AL, United Kingdom
2
School of Mechanical and Aerospace Engineering, Nanyang
Technological University, Singapore 639798, Singapore
3
College of Transportation Engineering, Tongji University,
Shanghai 200092, China
4
College of Computer Science and Technology, Jilin
University, Changchun 130012, China
5
School of Vehicle and Mobility, Tsinghua University,
Beijing 100084, China Abbreviations
ADAS
Advanced driver assistance system
ADV
Automated driving vehicles
BRMSE
Balanced root mean square error. EEG
Electroencephalogram
EMG
Electromyography
FC
Fully connected
FFNN
Feedforward neural network
GRU
Gated recurrent unit
LOO
Leave one out
LSTM
Long-short term memory
MTS
Multi-task time-series
MTS-Trans
Multi-task time-series transformer
RMSE
Root mean square error
RP
Random prediction Automotive Innovation (2024) 7:45–58
https://doi.org/10.1007/s42154-023-00272-x Automotive Innovation (2024) 7:45–58
https://doi.org/10.1007/s42154-023-00272-x Abstract Driver steering intention prediction provides an augmented solution to the design of an onboard collaboration mechanism
between human driver and intelligent vehicle. In this study, a multi-task sequential learning framework is developed to pre-
dict future steering torques and steering postures based on upper limb neuromuscular electromyography signals. The joint
representation learning for driving postures and steering intention provides an in-depth understanding and accurate modelling
of driving steering behaviours. Regarding different testing scenarios, two driving modes, namely, both-hand and single-right-
hand modes, are studied. For each driving mode, three different driving postures are further evaluated. Next, a multi-task
time-series transformer network (MTS-Trans) is developed to predict the future steering torques and driving postures based
on the multi-variate sequential input and the self-attention mechanism. To evaluate the multi-task learning performance
and information-sharing characteristics within the network, four distinct two-branch network architectures are evaluated. Empirical validation is conducted through a driving simulator-based experiment, encompassing 21 participants. The pro-
posed model achieves accurate prediction results on future steering torque prediction as well as driving posture recognition
for both two-hand and single-hand driving modes. These findings hold significant promise for the advancement of driver
steering assistance systems, fostering mutual comprehension and synergy between human drivers and intelligent vehicles. Abbreviations
ADAS
Advanced driver assistance system
ADV
Automated driving vehicles
BRMSE
Balanced root mean square error. EEG
Electroencephalogram
EMG
Electromyography
FC
Fully connected
FFNN
Feedforward neural network
GRU
Gated recurrent unit
LOO
Leave one out
LSTM
Long-short term memory
MTS
Multi-task time-series
MTS-Trans
Multi-task time-series transformer
RMSE
Root mean square error
RP
Random prediction
1 Introduction
Intelligent vehicles are showing tremendous potential in th
improvement of traffic safety, efficiency, and energy-savin
[1]. Although many achievements have been obtained
the past decade, a challenging question still needs to b
answered for future intelligent vehicles: how we can ef
ciently devise collaboration and interaction mechanism
between human drivers and increasingly autonomous inte
ligent vehicles [2]? Before fully automated driving vehicl
(ADVs) can be realized, human drivers still need to sha
control authority with these vehicles. 1 Introduction Intelligent vehicles are showing tremendous potential in the
improvement of traffic safety, efficiency, and energy-saving
[1]. Although many achievements have been obtained in
the past decade, a challenging question still needs to be
answered for future intelligent vehicles: how we can effi-
ciently devise collaboration and interaction mechanisms
between human drivers and increasingly autonomous intel-
ligent vehicles [2]? Before fully automated driving vehicles
(ADVs) can be realized, human drivers still need to share
control authority with these vehicles. Although ADVs can (012 3456789) Y. Xing et al. 46 efficiently manage many driving tasks, the partial ADVs, for
example, the L3/L4 ADVs according to SAE J3016 [3], still
expect the human driver to assume control in emergencies. In this situation, mutual understanding in terms of anticipat-
ing the human physiological and psychological states such
as intention, attention, and behaviours will enable the two
agents (driver and intelligent vehicles) to interact efficiently
and safely with each other [4]. driving postures. This framework builds a connection
between the driver's neuromuscular dynamics and future
steering torque over a certain horizon. Notably, this study
represents the first attempt to jointly model steering postures
and steering torch predictions, with a further exploration of
multi-task learning framework design. Second, the impact
of different driving modes and driving postures are studied
based on the proposed model to exploit the impact of differ-
ent driving postures on steering intention prediction. Last,
quantitative analysis and comparison for the MTS-Trans
frameworks are proposed considering different driving
modes, postures, and features. The lateral steering collaboration between the driver and
intelligent vehicles or partial ADVs contributes to safer
steering control under normal and critical situations [5]. Jointly understanding human steering patterns and predict-
ing driver steering intention can benefit the advanced driver
assistance system (ADAS) and shared steering control sys-
tem [6]. Meanwhile, the risk assessment and hazard predic-
tion system can be developed based on the driver's steering
intention and steering quality analysis, thus preventing the
human driver from making dangerous steering manoeuvres
[7]. Besides, as the driver shares steering control authority
with ADVs, it is essential to estimate the steering intention
and quality and provide proper assistance and compensation
before the driver makes improper steering manoeuvres due
to the lack of sufficient situation awareness. Such a func-
tion could be especially important when the driver has to
take over control from secondary tasks or due to emergent
collision avoidance purposes [8]. 2 Related Works Many existing studies on driver steering intention focus on the
modelling of tactical behaviours and discrete intentions such as
lane change and turn manoeuvres using driver models, traffic
context perception, and vehicle dynamics information [10, 11]. Vision-based approaches have been widely studied in the past
for attention and intention predictions [12, 13]. For instance,
in Ref. [14], the vision and road context information were
adopted for the estimation of five common driving manoeuvres
by using a long-short term memory (LSTM)-based approach. An ensemble time-series network was proposed for real-time
driver intention prediction in a highway environment [15]. In
Ref. [16], a Bernoulli heatmap approach was developed for
a convolution neural network for driver's head pose estima-
tion. In Ref. [17], the relationship between eye gaze estimation
and steering performance was also studied. In general, driver
intention can be efficiently recognized with features from the
in-cabin vision system, vehicle states, and human physical and
cognitive states (e.g., heart rate and EEG) [18]. Vision-based
systems are normally used to capture driver behaviours such
as head pose, driving behaviours, and emotion, primarily due
to their easy implementation and low-cost advantages [19]. However, the prediction of continuous steering intention, like
steering torque prediction, remains relatively unexplored and
cannot be efficiently solved with vision-based methods due to
several reasons. For example, low-cost driver monitoring solu-
tions, like the vision-based approaches, have natural difficul-
ties in accurate and continuous steering behaviour prediction
due to many visual restrictions, such as occlusion, calibration,
diverse driving postures, and habits. Considering these superiorities, in this study, a multi-task
deep time-series modelling approach for sequential steering
torque and driving posture prediction is proposed to jointly
learn the representation and leverage the domain-specific
information for the two steering modes (single-hand and
both-hand). The predicted steering torque and steering pos-
tures can then optimize the design of advanced shared steering
control algorithms. Notably, it is found that a more accurate
steering torque prediction can be achieved if the model jointly
considers the steering postures during both the learning and
inference stages. To further quantify the impact of steering
postures, this study considers two driving modes (single-hand
and both-hand) and six driving postures (three for each driv-
ing mode). Specifically, for the both-hand driving mode, the
3-clock, 10–10-clock, and 12-clock driving postures are stud-
ied. While for the single-hand driving mode, the 3-clock, 130-
clock, and 12-clock driving postures are investigated. 1 Introduction Meanwhile, correlations
between the steering postures and steering efficiency and
quality have been analysed [9]. Accordingly, the recognition
of specific driving postures can also help to analyse driving/
steering behaviours, fatigue, and effectiveness and can also
help to understand the steering patterns and steering quali-
ties so that accurate assistance can be provided. This study is organized as follows. The related works are
discussed in Sect. 2. Then the detailed introduction to the
experimental design, simulation platforms, and simulation
scenarios are presented in Sect. 3. In Sect. 4, the proposed
MTS-Trans frameworks for continuous steering intention
prediction and driving posture recognition are discussed. In Sect. 5, the experimental results are evaluated. Finally,
conclusions are presented in Sect. 6. 3.1 Experiment Platform and Scenarios An experiment testbed was developed using a six-degrees-
of-freedom driving simulator. A detailed introduction of the
platform can be found in Ref. [6], which can be used for a
wide range of human-in-the-loop steering experiments. The
CarSim system was used to develop the simulation envi-
ronment. A DynPick WEF-6A1000 force sensor and TR-
60TC torque angle sensor, which were implemented under
the steering wheel of the driving simulator, were used to
collect the real-time steering dynamics. The Nihon Kohden
ZB-150H wireless sensors were used for the collection of
EMG signals with a sampling frequency of 1000 Hz. g p
Driver upper limb neuromuscular dynamics and their
impact on steering behaviours have been widely studied in
the past for advanced driver steering assistants. In Ref. [23],
it was found that the human-perceived steering force during
driving can be different from the physical force, and the
EMG signals can be used for the perceived force estimation. Co-contraction behaviours of upper limb muscles were iden-
tified through EMG signal analysis in Ref. [24]. Then, mus-
cle learning behaviours based on the co-contraction scheme
for the unusual steering tasks were further observed in Ref. [25]. To evaluate the impact of driving postures on the steer-
ing tasks, muscle activity and efficient steering evaluation
based on the EMG signals were developed [26]. It was found
that the driver usually performs push steering manoeuvres
when steering clockwise. Besides, muscle alternation and
co-contraction were found to be a clue for the estimation of
muscle workload. Then, an approach for estimating driver
steering efficiency was developed using the EMG signals
[27]. A multi-regression method was developed to build an
effective model for estimating steering force and steering
quality. In Ref. [28], Pick and Cole found that the steering
force is heavily determined by two major muscles in the
upper limb region. Then, a steering torque estimation model
based on the multiple regression analysis was developed. A similar continuous steering intent prediction model for
both-hand driving modes was developed in Ref. [29]. How-
ever, neither of these studies explores joint modelling for
continuous steering intention prediction and steering posture During the experiments, participants were required to drive
the simulator with two different driving modes. For each driv-
ing mode, ten EMG electrodes were used to extract the upper
limb neuromuscular dynamics, respectively. The detailed neu-
romuscular signals are summarized in Table 1. 2 Related Works Detailed
information will be discussed in Sect. 2. The main contributions of this study can be summarized
as follows. First, a multi-task time-series model is devised
for predicting driver steering intention and recognizing 47 Driver Steering Behaviour Modelling Based on Neuromuscular Dynamics and Multi‑Task Time‑Series… While some studies have explored vision-based
approaches for anticipating driving events, researchers
have also developed steering intention classification sys-
tems based on alternative sensor systems. For example, a
brain-machine interface for predicting human driver steer-
ing intentions using EEG was developed in Ref. [20]. How-
ever, EEG-based approaches can struggle to establish direct
connections between brain dynamics and neuromuscular
steering dynamics. Similarly, vehicle dynamic data from
the CAN bus, including steering force, vehicle heading, and
lateral acceleration, can be used for accurate steering inten-
tion recognition. For instance, an efficient curve speed model
was developed for a driving assistance system considering
various driving styles [21]. Driver lane change manoeuvre
can be recognized using an explicit mathematical model
of the steering behaviour based on vehicle dynamic states
[22]. However, using vehicle dynamics-based information
makes it challenging to make advance predictions for steer-
ing intention, as the steering intention can only be detected
after the driver has initiated the steering manoeuvre. There-
fore, a more efficient continuous steering torque prediction
method based on the electromyography (EMG) signals and
the upper limb neuromuscular dynamics is proposed in this
study to explore the potential for joint estimation of steering
intention and steering postures. recognition. Moreover, how different driving postures and
modes can influence steering intention prediction and
sequential neuromuscular dynamic modelling remains an
open question. Thus, to enhance long-term temporal steer-
ing feature representation, a multi-task Transformer-based
network is designed in this study due to the powerful time-
series modelling performance of the Transformer network
[30, 31]. By considering different driving modes and driv-
ing postures, the proposed model offers insight into distinct
steering patterns with different driving postures. 3 Experimental Design In this section, the experimental setup for the simulator-
based steering intention prediction system is presented,
along with details on signal collection and EMG data
processing. 3.1 Experiment Platform and Scenarios Twenty-one
voluntary male participants were involved in the experiment. All the participants were deeply informed about the purpose
and risks of this experiment and agreed to participate. The
21 participants were divided into three groups, namely, the
skilled group, the average group, and the unskilled group,
according to their reported driving experiences. The intro-
duction of different driving experience improves the pattern
diversity of the experiment data and help to avoid bias pat-
terns in the analysis of driver neuromuscular dynamics. All participants were instructed to control the steering
wheel by following a constant sinusoidal input. The driving
task assigned to them was a slalom manoeuvre conducted at
a velocity of approximately 60 km/h, as depicted in Fig. 1. This task adheres to international standards for evaluat-
ing vehicle dynamics and driver control performance. The
slalom task was chosen as it simulates scenarios in which Y. Xing et al. 48 Table 1 Summary of detected
neuromuscular signals for two
driving modes Summary of detected
uscular signals for two
modes
Driving modes
Detected neuromuscular signals
Both-hand (left & right hands)
Anterior deltoid of the clavicular portion
(PMA-C), deltoid anterior (DELT-A), deltoid
posterior (DELT-P), teres major (TM), and
long head of triceps brachii (TB-L)
Single-hand (right hand only)
PMA-C, DELT-A, DELT-P, TM, TB-L,
deltoid middle (lateral) (DELT-M), triceps
lateral head exterior (TB-LAT), biceps (BC),
infraspinatus (INFT), pectoralis major (PM) Anterior deltoid of the clavicular portion
(PMA-C), deltoid anterior (DELT-A), deltoid
posterior (DELT-P), teres major (TM), and
long head of triceps brachii (TB-L) Single-hand (right hand only) PMA-C, DELT-A, DELT-P, TM, TB-L,
deltoid middle (lateral) (DELT-M), triceps
lateral head exterior (TB-LAT), biceps (BC),
infraspinatus (INFT), pectoralis major (PM) R
L
R
L
L
R
Hand Position
(a)
(b)
(c)
(d)
(e)
(f)
Fig. 2 Six driving postures for the two different driving modes. The
red dot shows the hand grasp position. a–c single-hand driving mode
with 3-clock, 12-clock, and 130-clock driving positions. d–f both-hand
driving mode with 3-clock, 12-clock, and 10–10-clock driving posture,
respectively 30m
Fig.1 The Slalom driving task used in the simulation R
L
(a)
(d) R
L
Hand Position
(b)
(e) L
(a)
(d) L
R
(c)
(f) Fig.1 The Slalom driving task used in the simulation (c) drivers need to make lane changes or overtake other vehi-
cles, common responses when taking over control from a
partially automated driving vehicle. 3.1 Experiment Platform and Scenarios The critical aspect of
intention prediction arises when a driver initially assumes
control, making the slalom task an apt means of measuring
driver steering behaviours in this study. (f) Hand Position
(e) The participants were required to use both-hand driving
mode in the first with hands on the 3-clock positions, as
shown in Fig. 2(d). Then, they should perform a four to six-
second steering experiment by following a constant period
angle signal. The target sine-wave-like signal has about a
60-degree amplitude with a 0.25 Hz frequency to mimic
real-world steering behaviour. The driving cycle will be
repeated three to five times for each participant, respectively. In general, each participant will be measured with a 12 to 15
period of steering with around five seconds of steady hold-
ing phase after every three to five continuous steering. The
main objective of this task is to simulate the real-world steer-
ing manoeuvre and to obtain the naturalistic neuromuscular
dynamics from the participants. The data that support all the
findings of this study are available from the corresponding
authors upon reasonable research-purpose request. Fig. 2 Six driving postures for the two different driving modes. The
red dot shows the hand grasp position. a–c single-hand driving mode
with 3-clock, 12-clock, and 130-clock driving positions. d–f both-hand
driving mode with 3-clock, 12-clock, and 10–10-clock driving posture,
respectively filter with 100 Hz pass-band frequency is then applied to the
recorded EMG signals to filter the high-frequency outliers
and interference. The time-series EMG data is divided into
sequences with a fixed length of 200, which means a 200 ms
prediction horizon without overlap is used as the sliding win-
dow for sequential data generation. The historical EMG and
the steering torque signals will be used as the model input,
and the future sequential steering torque is the target output
of the model. All the signals are normalized within − 1 to 1
before feeding into the model to avoid the adverse impact of
a different unit. 3.2 EMG Signal Processing and Time‑Delay Analysis f
The input ( X ) and target outputs Y휖[Yt, Yc] of the model
can be denoted as: Before the commencement of the experiment, careful place-
ment of the EMG electrodes on each participant is ensured. Subsequently, participants can take at least three minutes
to prepare themselves on the testbed and sit in a preferred
position to make sure they are relaxed. When the experi-
ment starts, the EMG signals are collected and checked. The
baseline noise is recorded and filtered for each channel. The
steering torque for each participant is ranged within − 5 to
5 N·m, and the EMG signals are all ranged within − 5 to
5 mV. The sampling frequency is 1000 Hz and a low-pass (1)
X = [E1, E2, … , E9, E10, Yh
]
(2)
Ei = [et, … et−200]
(3)
Yt = [stt+1, ⋯, stt+200] (1) (2) (3) where X is the model input at each time step, Ei is the ith
EMG feature sequence that consists of the last 200 ms, Yt is Driver Steering Behaviour Modelling Based on Neuromuscular Dynamics and Multi‑Task Time‑Series… 49 findings from a previous study [9], it is found that the steer-
ing postures are highly correlated with steering performance. Therefore, to accurately predict future steering torques and
steering behaviours, the model will jointly learn how to rec-
ognize the steering postures to contribute to the accurate
prediction of continuous steering behaviours. However, it
is still unclear how these two tasks can be learned together
to avoid any negative transfer effects [32]. It is also unclear
whether the two tasks need to be learned at different rates
or whether one task will dominate the learning and result in
poorer performance on the other task [33]. predicted torque, which contains the future 200 ms torque
information, Yh is the historical steering torques in the past
200 ms, and stt+1 is the steering torque at time t + 1 . Hence,
the dimension of the model input sequence ( X ) is 11 × 200 ,
and the dimension of the output sequence ( Yt ) is 1 × 200 . Here Yc represents the predicted driving postures, which can
be one of the three categories for the both-hand and single-
hand driving modes, as shown in Fig. 2. The initial analysis undertaken in this study involved
measuring the time delay between the EMG signals and
steering torque. 3.2 EMG Signal Processing and Time‑Delay Analysis The aim is to estimate the relative phase shift
(time delay) between the two data streams by identifying the
point of maximum correlation. The largest phase shift reflects
where the two signals are best aligned. A statistical illustra-
tion of the time delay between the 21 participants and the
two driving modes is shown in Table 2. The mean and stand-
ard deviation of the time delay for each driving posture are
reported. As shown in Table 2, for both-hand driving modes,
the 3-clock hand position can generate the largest phase shift
compared to the other two postures. On the contrary, for the
single-hand driving mode, the 3-clock driving posture leads
to the lowest time delay among the three groups, while the
12-clock steering posture generates significantly larger time
delays (− 292 ± 160 ms). Based on Table 2, the average time
delay for the both-hand driving mode, considering the three
postures, is about − 197 ms, and the average time delay for
the single-hand driving mode is − 206 ms. It shows that the
mean time delay between the steering torque and the EMG
signals is about 200 ms for all three driving postures with
both the both-hand and single-hand driving modes. Hence,
the 200 ms prediction horizon is used for future steering
torque prediction and evaluation in this study. p
p
Hence, the design of an MTL-based steering behaviour
model necessitates an investigation into how much infor-
mation these two tasks should share and the extent to which
flexibility should be allotted to each task. As demonstrated in
previous studies [34], a hard-MLT network shares the com-
mon backbone networks for the different tasks with relatively
simple prediction heads for each task. As shown in Ref. [35],
soft-MLT networks can further improve network performance
by allowing information sharing and individual backbones for
each task. Therefore, in the soft-MLT networks, sub-networks
for different tasks may have more flexibility to tune their back-
bones [36]. It is also interesting to exploit that for the steering
behaviour modelling, what kind of MTL framework can be
used to benefit the joint optimization of the two different tasks,
and what kind of information sharing level is required for the
two tasks. Consequently, four different MTS-Trans models
are designed in this study by varying the flexibility level of
each sub-network. 3.2 EMG Signal Processing and Time‑Delay Analysis In summary, the basic MTS-Trans shares a
common backbone network and only uses several fully con-
nected layers as the prediction head. Then, a second MTS-
Trans slightly increases the flexibility of each task by adding
individual transformer networks on top of a shared transformer
encoder. The last two more flexible MTS-Trans models assign
individual transformer encoders, either with or without shared
input embedding layers. 4.2 MTS‑Trans Architecture Multi-task learning (MTL) can improve model generaliza-
tion ability and decrease the uncertainty and noise in the
data by jointly optimizing multiple tasks. In accordance with In this study, four different MTS-Trans architectures are devel-
oped, as shown in Fig. 3. Based on Eq. (1), a multi-variate
input sequence X ∈ℝl×d of length l and dimension d is fed
into the sequential transformer networks. In general, all four
architectures have similar blocks for the input embedding,
transformer encoders, and fully connected prediction heads. Table 2 Time delay (ms) analysis for different driving modes and
postures Table 2 Time delay (ms) analysis for different driving modes and
postures
Driving modes
Position
Time Delay
Both-Hand
3-clock
− 124 ± 109
10–10-clock
− 173 ± 192
12-clock
− 204 ± 174
Single-Hand
3-clock
− 135 ± 116
130-clock
− 193 ± 161
12-clock
− 292 ± 160 Embedding layer: the original embedding layer for dis-
crete tokens in Ref. [30] is replaced with a fully connected
layer. This fully connected layer is only applied to the feature
dimension d and transforms the original 11 dimensions into
64 dimensions to adapt to the transformer network. Following
the embedding layer, a standard sinusoid positional encod-
ing is applied to inject positional information into the input Y. Xing et al. 50 Fig. 3 Four developed multi-task time-series transformer networks,
respectively. a A shared embedding layer and three shared trans-
former encoder layers for the two tasks. b A shared embedding layer,
one shared transformer encoder layer, and two personalized trans- Fig. 3 Four developed multi-task time-series transformer networks,
former encoder layers for the two tasks. c Different embedding and former encoder layers for the two tasks. c Different embedding and
encoder layers for two tasks. d Has similar architecture with b but
without the shared transformer encoder layer. former encoder layers for the two tasks. c Different embedding and
encoder layers for two tasks. d Has similar architecture with b but
without the shared transformer encoder layer. Fig. 3 Four developed multi-task time-series transformer networks,
respectively. a A shared embedding layer and three shared trans-
former encoder layers for the two tasks. b A shared embedding layer,
one shared transformer encoder layer, and two personalized trans- sequences [30]. The sine and cosine of different frequencies
are calculated as follows: several self-attention heads. (5) (5) (7)
Odp = fc2_dp(Dropout(Relu(fc1_dp(Htrans))))
(8)
Ost = fc2_st(Dropout(Relu(fc1_st(Htrans)))) (7)
Odp = fc2_dp(Dropout(Relu(fc1_dp(Htrans)))) (7) where pos represents the position of the sequential inputs, i
is the ith dimension, and dmodel is the overall feature dimen-
sion (64 in this study) after the linear embedding layer. (8)
Ost = fc2_st(Dropout(Relu(fc1_st(Htrans)))) (8) Transformer encoder: the transformer network is used
here in order to capture both the long-term and short-term
dependencies in the time-series input based on the multi-
head self-attention mechanism. The transformer network
can avoid sequential modelling and prediction mechanisms
as used in LSTM but treat the past sentence as a whole
and assign self-attention along with the sequences. The
transformer is briefly introduced here, and the detailed
information refers to Ref. [30]. The multi-head self-atten-
tion mechanism in the encoder output H ∈ℝl×d of the
same size as X by attending over given l key-value pairs
K∈ℝl×d , V ∈ℝl×d: where Odp ∈ℝN×1 and Ost ∈ℝl×1 are predicted output for
driving postures and steering torque, N is the number of
driving postures. The output state Htrans from the trans-
former, the layer is flattened into a one-dimension vector
and passed into the two FC layers. The output size of fc1_dp
and fc1_st is 1024 uniformly. 4.2 MTS‑Trans Architecture In this study, four transformer
encoder layers are used in the four different architectures and
each layer has eight self-attention heads. (4)
PE(pos, 2i) = sin(pos∕100002i∕dmodel)
(5)
PE(pos, 2i + 1) = cos(pos∕100002i∕dmodel) (4)
PE(pos, 2i) = sin(pos∕100002i∕dmodel) (4) Fully connected prediction heads: on top of the trans-
former encoder layers are the FC prediction heads. The FC
prediction heads follow the following architectures: (5)
PE(pos, 2i + 1) = cos(pos∕100002i∕dmodel) PE(pos, 2i + 1) = cos(pos∕100002i∕dmodel) 4.3 Loss Function The optimization of the MTS-Trans model follows a multi-
task learning framework. The two tasks are jointly opti-
mized, and the model is trained in an end-to-end fashion. The overall training loss LT is a combination of the two
individual losses, where the Cross-Entropy loss Eq. (9) is
used for the posture recognition and the mean squared error
Eq. (10) is used for the steering torque prediction. To deal
with the homoscedastic uncertainty during model learning,
the weighted loss function is used [34]. The overall loss
function for MTS-Trans is denoted as Eq. (11). (6)
H = Attention(Q, K, V) = softmax
QK퐓
√
m
V (6) where Q, K, V are query, key, and value matrices for the self-
attention module, respectively. The scaled-dot product atten-
tion in Eq. (6) allows compressing the matrix V into smaller
representative bedding for simplified inference in down-
stream neural network operations. The scaled-dot product
attention scales the weights by
√
m to reduce the variance
of the weights, facilitating stable training. Then the standard
multi-head attention mechanism is applied to concatenate where Q, K, V are query, key, and value matrices for the self-
attention module, respectively. The scaled-dot product atten-
tion in Eq. (6) allows compressing the matrix V into smaller
representative bedding for simplified inference in down-
stream neural network operations. The scaled-dot product
attention scales the weights by
√
m to reduce the variance
of the weights, facilitating stable training. Then the standard
multi-head attention mechanism is applied to concatenate (9)
Lcla = −
N
n=1
C
c=1
log
exp(xn,yn)
∑C
c=1 exp(xn,c) (9) Driver Steering Behaviour Modelling Based on Neuromuscular Dynamics and Multi‑Task Time‑Series… 51 (10)
Lreg = 1
S
S
∑
i=0
(yi −̂yi)2
(11)
LT = W1Lcla + W2Lreg +
nT
∑
i=1
log휎i (12)
RMSE = 1
N
∑
j=1,2,⋯N
√
1
L
∑
i=1,2,⋯L
((̂xji −xji
)2) (12) (10) where N is the number of sequences used for model testing,
L is the length of each sequence, which is 200 according
to the time delay analysis. ̂xji is the ith prediction in the
sequence j , and xji is the ground truth value. 4.4 Model Implementation (1) Random Prediction (RP). This baseline always pre-
dicts a zero torque value, which serves as a simple
baseline. For posture recognition, it randomly selects
one posture. 4.3 Loss Function (11)
LT = W1Lcla + W2Lreg +
nT
∑
i=1
log휎i (11) where x is input, y is the target sequence, N is the minibatch
dimensions, C is the number of classes, S is the number of
samples, ̂yi is predicted torque, and Wi = exp(−log휎2
i ) is
the trainable weight for each sub-loss term considering the
homoscedastic uncertainty or the observation noise 휎i for
the specific task ( 휎i initialized to zero), Lcla , and Lreg are the
loss of posture recognition and steering torque prediction,
respectively. j
To avoid the adverse impact of the data unbalanced prop-
erty on the model evaluation results, the BRMSE metric split
the data into bins and calculated the mean RMSE for each bin,
and the final average BRMSE is then calculated [38]. As the
steering torque mostly ranged between − 5 and 5 N·m, ten
bins were selected with each bin size with a 1 N·m scale. The
BRMS is represented as follows: (13)
BRMSEd,k,j = 1
N
∑
i
RMSEi
(14)
BRMSE = 1
Nd
∑
BRMSEd.k,j (13)
BRMSEd,k,j = 1
N
∑
i
RMSEi (13) 4.4 Model Implementation In this study, 2 a total of 4011 sequences are collected for
the both-hand case from 20 participants. These sequences
are divided into three categories, with 8749 samples for the
3-clock posture, 7614 samples for the 10–10-clock pos-
ture, and 7648 samples for the 12-clock posture. For the
single-hand driving case, 25,886 data sequences were col-
lected from 20 participants. Among these, 9207 sequences
are generated from the 3-clock driving posture scenarios,
8766 sequences are from the 130-clock categories, and
7913 sequences are collected from the 12-clock scenarios. In the model training process, 80% of the sequence is used
for training, while the remaining 20% is reserved for model
validation. The leave-one-out (LOO) approach is used to
randomly select one participant and is only used for real-
time performance demonstration. The Adam optimizer is
used for model optimization [37]. An initial learning rate
(LR) of 0.001 is used, and a step LR schedule is imple-
mented to decay the LR by a factor of 0.1 every 100 epochs. The batch size is 64 and the maximum epoch is 300. The
model is developed using PyTorch and is trained on a single
NVIDIA RTX A5000 GPU. In general, the training process
takes around three hours to finish. (14)
BRMSE = 1
Nd
∑
BRMSEd.k,j (14) where BRMSEd,k,j is the BRMSE for the jth bin in which d =
1 N·m is the bin size, k = 10 N·m is the maximum range of
steering torque, RMSEi is the RMSE for ith sequence in the
bin j , N is the number of sequences in jth bin, Nd = 10 is the
overall number of bins, and BRMSE is the final calculated
balanced RMSE. The accuracy and F1 score for the driving
postures are defined as: (15)
Acc = Nc∕Nt
(16)
F1 = Tp∕(Tp + (FP + FN)∕2) (15)
Acc = Nc∕Nt Acc = Nc∕Nt (15) (16)
F1 = Tp∕(Tp + (FP + FN)∕2) (16) where Nc is the number of correct classifications, and Nt is
the total number of samples. Tp , Fp , and FN are the num-
ber of true positives, false positives, and false negatives,
respectively.f To evaluate the model performance on the different
tasks, several baseline methods are introduced below. (1) Random Prediction (RP). This baseline always pre-
dicts a zero torque value, which serves as a simple
baseline. For posture recognition, it randomly selects
one posture. 5.2 Single‑Hand Driving Results The analysis of the single-hand driving mode is presented
in Table 3. The results clearly demonstrate the effectiveness
of the proposed MTS-Trans model in predicting steering
torques and recognizing driving postures. Specifically, the
MTS-Trans models achieved around 90% accuracy in pos-
ture recognition tasks. Meanwhile, accurate prediction of
future steering torque is achieved within the range of 0.0678
N·m for RMSE with the MTS-Trans3 model. It is also shown
that the third MTS-Trans model, which uses separate embed-
ding layers and transformer encoder layers, generates the
most accurate results compared to other methods. The results of classification accuracy and prediction
error regarding different driving postures are depicted in
Fig. 5. Specifically, Fig. 5(a), (b) evaluate the classifica-
tion accuracy and prediction error for different models
with the three different driving postures, respectively. A
similar conclusion can be made that, among all the driv-
ing postures, the 130-clock is more likely to lead to worse
performance than the other two postures on the two tasks
(especially for the driving posture recognition). However,
there is no significant difference between the postures of
3-clock and 12-clock for the single-hand driving mode. The BRMSE results for the proposed MTS-Trans mod-
els are also evaluated. As shown in Fig. 6, the BRMSE
for the four MTS-Trans models shows consistent results. Specifically, the minimum prediction errors are usually
achieved between the 5th bin (prediction range from − 1
to 0N·m) and 7th bin (1–2N·m), which shows the models
are more easily to make much more accurate predictions
and better capture the neuromuscular dynamics when
expected steering torque or steering effort is low. Con-
versely, higher steering torque demands can lead to an
increased prediction error for continuous steering inten-
tion. This finding provides evidence to support the notion Comparing multi-task learning with the single-task learn-
ing method, it becomes evident that multi-task learning can
improve the overall model performance for both steering
torque prediction and posture recognition. Specifically,
when simultaneously learning the postures, the RMSE of
the steering torque prediction decreased to 0.0678 N·m
from 0.0794 N·m. Similarly, posture recognition accuracy
increased from 87.74 to 90.16% when considering the steer-
ing torque task. This suggests that simultaneous learning of
these two tasks and optimizing model parameters contributes
to higher accuracy in both steering torque prediction and
driving posture recognition. 5.1 Metrics and Baselines (2) Feedforward Neural Network (FFNN). An FFNN
model with a similar architecture to the prediction head
of the MTS-Trans models. (2) Feedforward Neural Network (FFNN). An FFNN
model with a similar architecture to the prediction head
of the MTS-Trans models. To assess the accuracy of continuous torque predictions,
two evaluation metrics, namely, the root-mean-square error
(RMSE) and balanced RMSE (BRMSE), are employed. Addi-
tionally, for evaluating the performance of driving posture
recognition, accuracy and F1 scores are utilized. Specifically,
RMSE is calculated as follows. (3) LSTM Models (LSTM/Bi-LSTM). A two-layer LSTM
model (with or without bi-directional connections) with
64 feature dimensions in a hidden state. (3) LSTM Models (LSTM/Bi-LSTM). A two-layer LSTM
model (with or without bi-directional connections) with
64 feature dimensions in a hidden state. (4) Gated Recurrent Unit (GRU) Models (GRU/Bi-
GRU). Similarly, a two-layer GRU model (with or (4) Gated Recurrent Unit (GRU) Models (GRU/Bi-
GRU). Similarly, a two-layer GRU model (with or 52 Y. Xing et al. without bi-directional connections) with 64 feature
dimensions in the hidden state. The confusion matrix generated with the MTS-Trans4
model is shown in Fig. 4. An interesting pattern emerges
where the 130-clock driving posture is more likely to be
misclassified into the other two postures, and conversely,
the other two postures are more likely to be misclassified as
the 130-clock posture. Specifically, 117 samples from the
130-clock are misclassified into the 3-clock case, and 106
samples are misclassified into the 12-clock. For the 3-clock
case, 156 samples are misclassified to the 130-clock sam-
ples, while only very few cases are misclassified into the
12-clock. Similar results can be found in the 12-clock case
as well.i (5) Single Task Transformer (STTrans). These models
have a structure similar to the MTS-Trans models as
shown in Fig. 3, but they have only one prediction head
at a time for single-task learning. (6) MTS-Trans. These are the multi-task sequential trans-
former models with different fusion methods, as shown
in Fig. 3. 5.2 Single‑Hand Driving Results Table 3 Experiment results for the single-hand driving modes
The bold values indicate the best results achieved by MTSTrans4 model
Methods
Torque prediction
Posture recognition
RMSE (N·m)
5% RMSE (N·m)
BRMSE (N·m)
Acc (%)
Precision (%)
Recall (%)
F1 (%)
RP
2.4267
3.5882
2.4266
33.33
33.33
33.33
33.33
FFNN
0.1734
0.5404
0.1842
73.86
73.99
73.93
73.96
GRU
0.1022
0.3640
0.1157
72.88
72.58
73.11
72.64
LSTM
0.0832
0.1954
0.0896
84.79
84.86
84.83
84.84
BiGRU
0.0768
0.2619
0.0944
84.92
84.97
84.89
84.92
BiLSTM
0.0778
0.1047
0.0865
84.04
84.02
84.13
84.07
STTrans
0.0794
0.2723
0.0877
87.74
87.93
87.86
87.82
MTSTrans1
0.0892
0.1549
0.1102
89.73
89.69
89.78
89.73
MTSTrans2
0.0617
0.2310
0.0672
90.10
90.10
90.10
90.11
MTSTrans3
0.0737
0.02395
0.0793
89.40
89.41
89.37
89.37
MTSTrans4
0.0564
0.2063
0.0622
90.10
90.20
90.14
90.16 Table 3 Experiment results for the single-hand driving modes Driver Steering Behaviour Modelling Based on Neuromuscular Dynamics and Multi‑Task Time‑Series… 53 3-clock
130-clock
12-clock
Target Class
3-clock
130-clock
12-clock
Output Class
Confusion Matrix
1748
32.2%
156
2.9%
21
0.4%
90.8%
9.2%
117
2.2%
1617
29.8%
106
2.0%
87.9%
12.1%
13
0.2%
125
2.3%
1529
28.1%
91.7%
8.3%
93.1%
6.9%
85.2%
14.8%
92.3%
7.7%
90.1%
9.9%
Fig. 6 Illustration of BRMSE prediction errors of four proposed MTS-
Trans models with single-hand driving modes 3-clock
130-clock
12-clock
Target Class
3-clock
130-clock
12-clock
Output Class
Confusion Matrix
1748
32.2%
156
2.9%
21
0.4%
90.8%
9.2%
117
2.2%
1617
29.8%
106
2.0%
87.9%
12.1%
13
0.2%
125
2.3%
1529
28.1%
91.7%
8.3%
93.1%
6.9%
85.2%
14.8%
92.3%
7.7%
90.1%
9.9%
Fig. 4 Confusion matrix for the single-hand driving mode posture
recognition with the MTS-Trans4 model Fig. 6 Illustration of BRMSE prediction errors of four proposed MTS-
Trans models with single-hand driving modes Fig. 6 Illustration of BRMSE prediction errors of four proposed MTS-
Trans models with single-hand driving modes Target Class Target Class
Fig. 4 Confusion matrix for the single-hand driving mode posture
recognition with the MTS-Trans4 model
FFNN
GRU
LSTM
BiGRU
BiLSTM
MTS-Trans1
MTS-Trans2
MTS-Trans3
MTS-Trans4
0
10
20
30
40
50
60
70
80
90
100
Acc (%)
FFNN
GRU
LSTM
BiGRU
BiLSTM
MTS-Trans1
MTS-Trans2
MTS-Trans3
MTS-Trans4
0
0.05
0.10
0.15
0.20
RMSE (N·m)
(a)
(b)
Fig. 5 Results comparison for driving postures recognition and steer-
ing torque prediction for different models and driving postures with
single-hand mode. a Diving posture recognition accuracy for the
three postures. 5.2 Single‑Hand Driving Results b Prediction error (RMSE) for three different postures
using different models postures while maintaining a prediction RMSE for steering
torque at 0.0564 N·m; among the three postures, the 130-
clock driving posture can lead to larger prediction errors
and lower classification accuracy; the testing results for an
unseen participant (employing the LOO approach) indicate
that the proposed MTS-Trans model demonstrates strong
generalization abilities for the single-hand driving modes,
with most prediction errors occurring when higher steer-
ing torque is required. Fig. 4 Confusion matrix for the single-hand driving mode posture
recognition with the MTS-Trans4 model FFNN
GRU
LSTM
BiGRU
BiLSTM
MTS-Trans1
MTS-Trans2
MTS-Trans3
MTS-Trans4
0
10
20
30
40
50
60
70
80
90
100
Acc (%)
(a) 5.3 Both‑Hand Driving Results In this section, the model developed for the both-hand driv-
ing mode is studied. Firstly, the steering torque prediction
and posture recognition results based on different methods
are presented in Table 4. It is shown that the MTS-Trans
models show great advantages over the other methods in this
case. Specifically, MTS-Trans3 and MTS-Trans 4 are the two
most successful networks, showcasing exceptional joint opti-
mization capabilities for both tasks. The RMSE values for
the MTS-Trans3 and MTS-Trans4 models are 0.0399 N·m
and 0.0401 N·m, respectively. The posture classification
accuracy of the MTS-Trans3 model (97.47%) slightly out-
performs that of the MTS-Trans4 model (97.22%). Com-
pared to the single-task learning case (SSTrans), the pro-
posed multi-task learning networks can increase overall
performance on the two individual tasks. Besides, with the
multi-task learning framework, the steering torque predic-
tion performances are increased significantly (from 0.0901
to 0.0399 N·m) than the posture recognition. FFNN
GRU
LSTM
BiGRU
BiLSTM
MTS-Trans1
MTS-Trans2
MTS-Trans3
MTS-Trans4
0
0.05
0.10
0.15
RMSE (N·m)
(b) Fig. 5 Results comparison for driving postures recognition and steer-
ing torque prediction for different models and driving postures with
single-hand mode. a Diving posture recognition accuracy for the
three postures. b Prediction error (RMSE) for three different postures
using different models that upper limb neuromuscular dynamics exhibit relatively
simple characteristics for a relatively light steering input. However, modelling these dynamics becomes more chal-
lenging when there is a need for heavy steering input. Hence, steering assistance from an intelligent vehicle can
be expected when heavy steering demand is needed. The confusion matrix generated with the MTS-Trans4
model is shown in Fig. 7. It is shown that for both-hand driv-
ing modes, 3-clock and 1010-clock postures are more likely
to be misclassified and confused. However, the 12-clock pos-
ture is less likely to be misclassified into the 1010-clock but
is more likely to be confused with the 3-clock posture (17
cases of 12-clock posture are misclassified into the 3-clock
group while only 9 cases are misclassified into the 1010-
clock group). For the single-hand driving mode, several key obser-
vations can be made: The proposed MTS-Trans model
achieves an approximate 90% recognition rate for the three Y. Xing et al. 54 The comparison of posture recognition accuracy and
steering torque prediction RMSE regarding different driv-
ing postures and models are shown in Fig. 8. 5.3 Both‑Hand Driving Results Contrary to
the single-hand modes, it is interesting to observe that
the 12-clock driving posture typically results in higher
Table 4 Experiment results for the both-hand driving mode
Methods
Torque prediction
Posture recognition
RMSE (N·m)
5% RMSE (N·m)
BRMSE (N·m)
Acc (%)
Precision (%)
Recall (%)
F1 (%)
RP
1.3576
3.5913
1.6851
33.33
33.33
33.33
33.33
FFNN
0.0643
0.1678
0.0744
79.60
79.50
79.97
79.69
GRU
0.0644
0.2251
0.0983
84.21
84.32
84.40
84.35
LSTM
0.0925
0.3216
0.1479
91.06
91.20
91.18
91.19
BiGRU
0.0616
0.2061
0.0884
84.81
84.84
85.03
84.92
BiLSTM
0.0810
0.2726
0.1238
94.28
94.30
94.43
94.36
STTrans
0.0901
0.2962
0.1416
95.52
95.65
95.53
95.58
MTSTrans1
0.0608
0.1981
0.0792
94.20
94.29
94.28
94.29
MTSTrans2
0.0764
0.2352
0.0919
95.68
95.93
95.62
95.72
MTSTrans3
0.0399
0.1336
0.0485
97.47
97.52
97.50
97.51
MTSTrans4
0.0401
0.1332
0.0471
97.22
97.29
97.21
97.25
3-clock
1010-clock
12-clock
Target Class
3-clock
1010-clock
12-clock
Output Class
Confusion Matrix
1784
35.2%
47
0.9%
8
0.2%
97.0%
3.0%
42
0.8%
1573
31.0%
5
0.1%
97.1%
2.9%
17
0.3%
9
0.2%
1583
31.2%
98.4%
1.6%
96.8%
3.2%
96.6%
3.4%
99.2%
0.8%
97.5%
2.5%
Fig. 7 Confusion matrix for both-hand driving mode posture recogni-
tion with the MTS-Trans3 model
FFNN
GRU
LSTM
BiGRU
BiLSTM
MTS-Trans1
MTS-Trans2
MTS-Trans3
MTS-Trans4
(a)
0
15
25
35
45
55
65
75
85
95
100
Acc (%)
FFNN
GRU
LSTM
BiGRU
BiLSTM
MTS-Trans1
MTS-Trans2
MTS-Trans3
MTS-Trans4
(b)
0
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
0.09
0.10
RMSE (N·m)
Fig. 8 Results comparison for diving postures recognition and steer-
ing torque prediction for different models and driving postures with
both-hand mode. a Diving posture recognition accuracy for three
postures. b Prediction error (RMSE) for three postures using different
models Table 4 Experiment results for the both-hand driving mode 3-clock
1010-clock
12-clock
Target Class
3-clock
1010-clock
12-clock
Output Class
Confusion Matrix
1784
35.2%
47
0.9%
8
0.2%
97.0%
3.0%
42
0.8%
1573
31.0%
5
0.1%
97.1%
2.9%
17
0.3%
9
0.2%
1583
31.2%
98.4%
1.6%
96.8%
3.2%
96.6%
3.4%
99.2%
0.8%
97.5%
2.5%
Fig. 7 Confusion matrix for both-hand driving mode posture recogni-
tion with the MTS-Trans3 model 3-clock
1010-clock
12-clock
Target Class
3-clock
1010-clock
12-clock
Output Class
Confusion Matrix
1784
35.2%
47
0.9%
8
0.2%
97.0%
3.0%
42
0.8%
1573
31.0%
5
0.1%
97.1%
2.9%
17
0.3%
9
0.2%
1583
31.2%
98.4%
1.6%
96.8%
3.2%
96.6%
3.4%
99.2%
0.8%
97.5%
2.5%
Fig. 5.3 Both‑Hand Driving Results 7 Confusion matrix for both-hand driving mode posture recogni-
tion with the MTS-Trans3 model FFNN
GRU
LSTM
BiGRU
BiLSTM
MTS-Trans1
MTS-Trans2
MTS-Trans3
MTS-Trans4
(b)
0
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
0.09
0.10
RMSE (N·m) Fig. 7 Confusion matrix for both-hand driving mode posture recogni-
tion with the MTS-Trans3 model Fig. 8 Results comparison for diving postures recognition and steer-
ing torque prediction for different models and driving postures with
both-hand mode. a Diving posture recognition accuracy for three
postures. b Prediction error (RMSE) for three postures using different
models The comparison of posture recognition accuracy and
steering torque prediction RMSE regarding different driv-
ing postures and models are shown in Fig. 8. Contrary to
the single-hand modes, it is interesting to observe that
the 12-clock driving posture typically results in higher
steering torque prediction errors than the other two pos-
tures, while also contributing to significantly higher pos-
ture recognition accuracy. This is notably different from
the outcomes observed in the single-hand driving modes. Conversely, the 3-clock driving posture typically results in
fewer steering torque prediction errors. Unlike the results
seen in the single-hand driving mode, in the both-hand
driving mode, the 3-clock driving postures appear to be
better suited for posture steering torque prediction and
understanding steering behaviour. The comparison of posture recognition accuracy and
steering torque prediction RMSE regarding different driv-
ing postures and models are shown in Fig. 8. Contrary to
the single-hand modes, it is interesting to observe that
the 12-clock driving posture typically results in higher
steering torque prediction errors than the other two pos-
tures, while also contributing to significantly higher pos-
ture recognition accuracy. This is notably different from
the outcomes observed in the single-hand driving modes. The BRMSE results for the proposed MTS-Trans mod-
els in both-hand driving modes are shown in Fig. 9. The
BRMSE for the four MTS-Trans models exhibit similar
results to those observed in the single-hand driving mode. Specifically, the minimum prediction errors are usually
achieved between the 5th bin (within a prediction range of
-1 to 0 N·m) and the 6th bin (0–1 N·m), while larger steer-
ing torque demand can lead to higher prediction error to
the continuous steering intention. Driver Steering Behaviour Modelling Based on Neuromuscular Dynamics and Multi‑Task Time‑Series… 55 Fig. 5.3 Both‑Hand Driving Results 9 Illustration of BRMSE prediction errors of four proposed MTS-
Trans models with both-hand driving modes and how these dynamics can be applied and developed for
driver steering intention prediction considering the different
driving postures and hand positions on the steering wheel. However, it's essential to acknowledge the potential con-
cerns associated with the proposed EMG-based system,
including intrusiveness, increased implementation time,
and real-world applicability challenges. Addressing these
concerns necessitates a forward-looking approach. This
study has shown that by using the selected EMG signals, the
number of EMG sensors can be reduced while similar steer-
ing torque prediction accuracy can be maintained. Future
works can concentrate on more efficient feature engineering
methods to select more efficient features for the EMG-based
machine learning approach. Here are several prospective
solutions: Fig. 9 Illustration of BRMSE prediction errors of four proposed MTS-
Trans models with both-hand driving modes The primary results for both-hand driving modes can be
summarized as follows: The proposed MTS-Trans model
can achieve a mean recognition accuracy of 97.47% for
the three postures, with a prediction RMSE of 0.0399 N·m
for steering torque. This results in more accurate steering
torque prediction than the single-hand driving mode. The
3-clock driving posture results in fewer prediction errors
than the other two methods, along with higher classifica-
tion accuracy among the three postures. Based on the test-
ing results for the unseen participant, it can be found that
the proposed MTS-Trans model exhibits good generaliza-
tion abilities in the single-hand driving mode, with most
prediction errors occurring in specific areas. (1) More challenging and critical steering manoeuvres can
be designed to evaluate the robustness as well as the
accuracy of the deep time-series model with upper limb
EMG signals. (2) The driving style has a critical impact on the steering
behaviour as well [39]. It is also interesting to under-
stand how to develop a personalized steering intention
prediction model according to more complex driving
style and experience aspects [40]. (3) With the development of wearable EMG sensors, such a
system will become more suitable for real-world imple-
mentation [41]. 5.4 Discussion (4) The EMG-based approach is more suitable for model-
ling individual neuromuscular dynamics and capturing
the personalized characteristics of operating the vehi-
cle or assistant mobility [42]. These characteristics will
significantly benefit those special groups with a specific
requirement or application domain, such as elder and
disabled persons, and professional racing drivers [43]. In this study, the sequential steering torque prediction and
driving posture recognition model are developed based on a
time-series transformer network. This model holds substan-
tial significance as it enables an enhanced understanding
between the driver and autonomous vehicle systems, pri-
marily by predicting future steering torque, which serves as
a proxy for the driver's steering intent. Moreover, based on
the proposed multi-task steering behaviour model, the driv-
ing postures can be further recognized and their impact on
steering intention prediction can be evaluated independently. This sequential steering torque prediction is instrumental
not only in forecasting steering performance but also in
facilitating the early detection of potential hazards or driver
misbehaviour. 6 Conclusions This study presents a novel multi-task learning framework for
modelling driving steering behaviour, employing a sequen-
tial transformer network. The proposed MTL-Trans model
accurately estimates future steering torques and recognizes
driving postures with upper limb neuromuscular dynamics. The investigation reveals that a prediction horizon of 200 ms
effectively captures future steering torque based on histori-
cal observations. Remarkably, the MTS-Trans model achieves
exceptional precision in steering torque prediction, yielding a
low RMSE of 0.0564 N·m for single-hand driving and an even
more impressive 0.0399 N·m for both-hand driving. This study presents a novel multi-task learning framework for
modelling driving steering behaviour, employing a sequen-
tial transformer network. The proposed MTL-Trans model
accurately estimates future steering torques and recognizes
driving postures with upper limb neuromuscular dynamics. The investigation reveals that a prediction horizon of 200 ms
effectively captures future steering torque based on histori-
cal observations. Remarkably, the MTS-Trans model achieves
exceptional precision in steering torque prediction, yielding a
low RMSE of 0.0564 N·m for single-hand driving and an even
more impressive 0.0399 N·m for both-hand driving. The advantages of the proposed system are summarized
as follows: An EMG-based system connects the neuromus-
cular dynamics of the upper limb with steering torque and
driving posture, which contributes to precise multi-task
modelling for steering behaviours; the EMG-sensor-based
approach is robust to the variation of situations and envi-
ronments, such as the illumination and occlusion issues in
vision-based systems; the proposed approach provides a
theoretical analysis of upper limb neuromuscular dynamics Furthermore, the proposed model exhibits a high degree
of accuracy in identifying driving postures, attaining recogni-
tion rates of 97.47% and 90.10% for both-hand and single-
hand driving modes, respectively. The research introduces a Y. Xing et al. 56 7. Hang, P., Lv, C., Xing, Y., Huang, C., Hu, Z.: Human-like decision
making for autonomous driving: a noncooperative game theoretic
approach. IEEE Trans. Intell. Transp. Syst. Intell. Transp. Syst. 22(4), 2076–2087 (2020). https://doi.org/10.1109/TITS.2020.
3036984 quantitative assessment of the influence of driving postures on
steering intent prediction, shedding light on how different pos-
tures impact steering behaviour modelling. Notably, this study
underscores the capacity of driving postures to affect steering
torque prediction accuracy, providing valuable insights into the
intricate relationship between posture and steering behaviour
modelling. 8. Lv, C., Li, Y., Xing, Y., et al.: Human–machine collaboration for
automated driving using an intelligent two-phase haptic interface. Adv. Intell. Syst. 3(4), 2000229 (2021). Declarations Conflict of interest On behalf of all the authors, the corresponding au-
thor states that there is no conflict of interest. p
g
12. Xing, Y., Lv, C., Cao, D., Velenis, E.: Multi-scale driver behavior
modeling based on deep spatial-temporal representation for intel-
ligent vehicles. Transp. Res. Part C Emerg. Technol. 130, 103288
(2021). https://doi.org/10.1016/j.trc.2021.103288 Open Access This article is licensed under a Creative Commons Attri-
bution 4.0 International License, which permits use, sharing, adapta-
tion, distribution and reproduction in any medium or format, as long
as you give appropriate credit to the original author(s) and the source,
provide a link to the Creative Commons licence, and indicate if changes
were made. The images or other third party material in this article are
included in the article’s Creative Commons licence, unless indicated
otherwise in a credit line to the material. If material is not included in
the article’s Creative Commons licence and your intended use is not
permitted by statutory regulation or exceeds the permitted use, you will
need to obtain permission directly from the copyright holder. To view a
copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. 13. Hu, Z., Lv, C., Hang, P., Huang, C., et al.: Data-driven estimation
of driver attention using calibration-free eye gaze and scene fea-
tures. IEEE Trans. Ind. Electron. Ind. Electron. 69(2), 1800–1808
(2021). https://doi.org/10.1109/TIE.2021.3057033 14. Jain, A., Koppula, H. S., Raghavan, B.,et al.: A car that knows
before you do: Anticipating maneuvers via learning temporal driv-
ing models. In: Proceedings of the IEEE International Conference
on Computer Vision, pp. 3182–3190 (2015) 15. Xing, Y., Lv, C., Wang, H., et al.: An ensemble deep learning
approach for driver lane change intention inference. Transp. Res. Part C Emerg. Technol. 115, 102615 (2020). https://doi.org/10.
1016/j.trc.2020.102615 16. Hu, Z., Xing, Y., Lv, C., et al.: Deep convolutional neural network-
based Bernoulli heatmap for head pose estimation. Neurocomput-
ing 436, 198–209 (2021). https://doi.org/10.1016/j.neucom.2021.
01.048 6 Conclusions https://doi.org/10.1002/
aisy.202000229 In conclusion, the MTL-Trans model's remarkable accuracy
in predicting future steering torques and recognizing driving
postures holds significant promise for the development of
shared steering systems in intelligent vehicles. This framework
enhances the potential for a more harmonious human-vehicle
collaboration system, paving the way for safer and more effi-
cient driving experiences. 9. Xing, Y., Lv, C., Zhao, Y., et al.: Pattern recognition and charac-
terization of upper limb neuromuscular dynamics during driver-
vehicle interactions. Iscience 23(9), 101541 (2020). https://doi.
org/10.1016/j.isci.2020.101541 g
j
10. Wang, W., Na, X., Cao, D., et al.: Decision-making in driver-
automation shared control: a review and perspectives. IEEE/CAA
J. Autom. Sin. 7(5), 1289–1307 (2020). https://doi.org/10.1109/
JAS.2020.1003294 11. Deng, Z., Hu, W., Yang, Y., et al.: Lane change decision-making
with active interactions in dense highway traffic: a Bayesian game
approach. In: 2022 IEEE 25th International Conference on Intel-
ligent Transportation Systems (ITSC), pp. 3290–3297. IEEE,
(2022). https://doi.org/10.1109/ITSC55140.2022.9922333. References 69(2), 1750–1761
(2021). https://doi.org/10.1109/TIE.2021.3059537 30. Vaswani, A., Shazeer, N., Parmar, N., et al.: Attention is all you
need. Advances in neural information processing systems, 30
(2017).fi Zhongxu Hu received a mechatronic Ph.D. degree from the Huazhong University of Sci-
ence and Technology of China, in 2018. He
was a senior engineer at Huawei. He is cur-
rently a research fellow at the School of
Mechanical and Aerospace Engineering of
Nanyang Technological University in Singa-
pore. His current research interests include
human–machine collaboration, human
cyber-physical systems, human digital twins,
and deep learning applied in intelligent vehi-
cle and industrial scenarios. 31. Zhou, H., Zhang, S., Peng, J., et al.: Informer: Beyond efficient
transformer for long sequence time-series forecasting. In: Pro-
ceedings of the AAAI Conference on Artificial Intelligence, vol. 35, no. 12, pp. 11106–11115 (2021). https://doi.org/10.1609/
aaai.v35i12.17325 32. Kumar, A., Daume III, H.: Learning task grouping and over-
lap in multi-task learning. In: Proceedings of the 29th Interna-
tional Coference on Machine Learning (2012). https://doi.org/
10.48550/arXiv.1206.6417. 33. Standley, T., Zamir, A., Chen, D., et al: Which tasks should be
learned together in multi-task learning? In: International Con-
ference on Machine Learning, pp. 9120–9132. PMLR (2020) Xiaoyu Mo received the Ph.D. degree from
Nanyang Technological University, Singapore,
in 2022, the M.E. degree from Huazhong Uni-
versity of Science and Technology, Wuhan,
China, in 2017, the B.E. degree from Yang-
zhou University, Yangzhou, China, in 2015. He is now a research fellow at Nanyang Tech-
nological University. His research interests
include trajectory prediction and planning for
connected autonomous vehicles. 34. Caruana, R.: Multitask learning: A knowledge-based source of
inductive bias1. In: Proceedings of the Tenth International Confer-
ence on Machine Learning, pp. 41–48 (1993) 35. Yang, Y., Hospedales, T. M.: Trace norm regularised deep multi-
task learning. In: 5th International Conference on Learning Rep-
resentations (2016). https://doi.org/10.48550/arXiv.1606.04038 36. Kendall, A., Gal, Y., Cipolla, R.: Multi-task learning using uncer-
tainty to weigh losses for scene geometry and semantics. In: Pro-
ceedings of the IEEE Conference on Computer Vision and Pat-
tern Recognition, pp. 7482–7491 (2018). https://doi.org/10.1109/
CVPR.2018.00781 Peng Hang is a Research Professor at the
Department of Traffic Engineering, Tongji
University, Shanghai, China. He received his
Ph.D. degree with the School of Automotive
Studies, Tongji University, Shanghai, China, in
2019. From 2020 to 2022, he served as a
Research Fellow with the School of Mechani-
cal and Aerospace Engineering, Nanyang
Technological University, Singapore. References 1. Rahman, M.H., Abdel-Aty, M., Wu, Y.: A multi-vehicle com-
munication system to assess the safety and mobility of connected
and automated vehicles. Transp. Res. Part C Emerg. Technol. 124,
102887 (2021). https://doi.org/10.1016/j.trc.2020.102887 17. Wang, Z., Zheng, R., Kaizuka, T., Nakano, K.: Relationship
between gaze behavior and steering performance for driver–
automation shared control: a driving simulator study. IEEE
Trans. Intell. Veh. 4(1), 154–166 (2018). https://doi.org/10.
1109/TIV.2018.2886654 p
g
j
2. Li, W., Tan, R., Xing, Y., et al.: A multimodal psychological,
physiological and behavioural dataset for human emotions in
driving tasks. Sci. Data 9, 481 (2022). https://doi.org/10.1038/
s41597-022-01557-2i 18. Li, W., Zeng, G., Zhang, J., et al.: Cogemonet: a cognitive-
feature-augmented driver emotion recognition model for smart
cockpit. IEEE Trans. Comput. Soc. Syst. 9(3), 667–678 (2021). https://doi.org/10.1109/TCSS.2021.3127935i 3. SAE, Taxonomy.: Definitions for terms related to driving automa-
tion systems for on-road motor vehicles. SAE Standard J 3016
(2016): 2016. p
g
19. Hu, Z., Xing, Y., Gu, W., et al.: Driver anomaly quantification
for intelligent vehicles: a contrastive learning approach with
representation clustering. IEEE Trans. Intell. Veh. (2022). https://doi.org/10.1109/TIV.2022.3163458 4. Hu, Z., Lou, S., Xing, Y., et al.: Review and perspectives on driver
digital twin and its enabling technologies for intelligent vehicles. IEEE Trans. Intell. Veh. (2022). https://doi.org/10.1109/TIV.2022.
3195635 20. Bi, L., Lu, Y., Fan, X., et al.: Queuing network modeling of
driver EEG signals-based steering control. IEEE Trans. Neu-
ral Syst. Rehabil. Eng.Rehabil. Eng. 25(8), 1117–1124 (2016). https://doi.org/10.1109/TNSRE.2016.2614003 5. Xing, Y., Lv, C., Cao, D., Hang, P.: Toward human-vehicle col-
laboration: Review and perspectives on human-centered collabo-
rative automated driving. Transp. Res. Part C Emerg. Technol. 128, 103199 (2021). https://doi.org/10.1016/j.trc.2021.103199 21. Chu, D., Deng, Z., He, Y., et al.: Curve speed model for driver
assistance based on driving style classification. IET Intel. Trans-
port Syst. 11(8), 501–510 (2017). https://doi.org/10.1049/iet-its.
2016.0294 p
g
j
6. Liu, Y., Liu, Q., Lv, C., Zheng, M., Ji, X.: A study on objective
evaluation of vehicle steering comfort based on driver’s electro-
myogram and movement trajectory. IEEE Trans. Human-Mach. Syst. 48(1), 41–49 (2017). https://doi.org/10.1109/THMS.2017.
2755469 22. Zhao, Z., Zhou, L., Luo, Y., Li, K.: Emergency steering eva-
sion assistance control based on driving behavior analysis. IEEE 57 Driver Steering Behaviour Modelling Based on Neuromuscular Dynamics and Multi‑Task Time‑Series… Trans. Intell. Transp. Syst.Intell. Transp. Syst. 20(2), 457–475
(2018). https://doi.org/10.1109/TITS.2018.2814687 Transport. Res. F Traffic Psychol. Behav. 65, 536–547 (2019). https://doi.org/10.1016/j.trf.2018.02.007 p
g
23. References Kishishita, Y., Takemura, K., Yamada, N., et al.: Prediction of
perceived steering wheel operation force by muscle activity. IEEE Trans. Haptics 11(4), 590–598 (2018). https://doi.org/10.
1109/TOH.2018.2828425 41. Hanbing, W., Yanhong, W., Xing, C., et al.: Human-vehicle
dynamic model with driver’s neuromuscular characteristic for
shared control of autonomous vehicle. In: Proceedings of the Insti-
tution of Mechanical Engineers, Part D: Journal of Automobile
Engineering (2020). https://doi.org/10.1177/0954407020977 24. Pick, A.J., Cole, D.J.: Neuromuscular dynamics in the driver–
vehicle system. Veh. Syst. Dyn. Syst. Dyn. 44(sup1), 624–631
(2006). https://doi.org/10.1080/00423110600882704 42. Sanchez-Comas, A., Synnes, K., Hallberg, J.: Hardware for rec-
ognition of human activities: a review of smart home and AAL
related technologies. Sensors 20(15), 4227 (2020). https://doi.org/
10.3390/s20154227 25. Pick, A.J., Cole, D.J.: Driver steering and muscle activity dur-
ing a lane-change manoeuvre. Veh. Syst. Dyn. Syst. Dyn. 45(9),
781–805 (2007). https://doi.org/10.1080/00423110601079276 43. Taborri, J., Keogh, J., Kos, A., Santuz, A., et al.: Sport biomechan-
ics applications using inertial, force, and EMG sensors: a literature
overview. Appl. Bionics Biomech. (2020). https://doi.org/10.1155/
2020/2041549 26. Hayama, R., Liu, Y., Ji, X., et al.: Preliminary research on mus-
cle activity in driver’s steering maneuver for driver’s assistance
system evaluation. In: Proceedings of the FISITA 2012 World
Automotive Congress: Volume 7: Vehicle Design and Testing
(I), pp. 723–735. Springer, Berlin (2013). https://doi.org/10.
1007/978-3-642-33835-9_66 . Yang Xing received his Ph.D. degree from
Cranfield University, UK. He is currently a
Lecturer in Applied Artificial Intelligence at
Cranfield University. He was a Research
Associate at the University of Oxford and a
Research Fellow at Nanyang Technological
University. His research interests include
human behaviour modelling, intelligent
multi-agent collaboration, and intelligent
vehicles. Yang Xing received his Ph.D. degree from
Cranfield University, UK. He is currently a
Lecturer in Applied Artificial Intelligence at
Cranfield University. He was a Research
Associate at the University of Oxford and a
Research Fellow at Nanyang Technological
University. His research interests include
human behaviour modelling, intelligent
multi-agent collaboration, and intelligent
vehicles. 27. Liu, Y., Ji, X., Hayama, R., Mizuno, T.: A novel estimating
method for steering efficiency of the driver with electromyogra-
phy signals. Chin. J. Mech. Eng. 27(3), 460–467 (2014). https://
doi.org/10.3901/CJME.2014.03.460 g
28. Pick, A.J., Cole, D.J.: Measurement of driver steering torque
using electromyography. J. Dyn. Syst. Meas. Control (2006). https://doi.org/10.1115/1.2363198 29. Xing, Y., Lv, C., Liu, Y., et al.: Hybrid-learning-based driver
steering intention prediction using neuromuscular dynamics. IEEE Trans. Ind. Electron. Ind. Electron. References His
research interests include vehicle dynamics and
control, decision-making, motion planning and
motion control for autonomous vehicles. 37. Kingma, D. P., Ba, J. Adam: A Method for Stochastic Optimiza-
tion. arXiv preprint arXiv:1412.6980 (2014) 38. Roth, M., Gavrila, D. M.: Dd-pose-a large-scale driver head pose
benchmark. In: 2019 IEEE Intelligent Vehicles Symposium, pp. 927–934. IEEE (2019). https://doi.org/10.1109/IVS.2019.8814103 p
g
39. Deng, Z., Chu, D., Wu, C., et al.: A probabilistic model for driv-
ing-style-recognition-enabled driver steering behaviors. IEEE
Trans. Syst. Man Cybernet. Syst. 52(3), 1838–1851 (2020). https://doi.org/10.1109/TSMC.2020.3037229 40. Deng, Z., Chu, D., Wu, C., et al.: Curve safe speed model con-
sidering driving style based on driver behaviour questionnaire. 58 Y. Xing et al. Shujing Li received the B.S., M.S., and Ph.D. degrees from the College of Computer Sci-
ence and Technology, Jilin University,
China, in 2008, 2011, and 2020, respectively. He is currently a post-doctoral researcher in
the College of Mathematics at Jilin Univer-
sity. He worked as an Assistant Engineer
with the Jiangsu Institute of Automation,
Lianyungang, China, from 2011 to 2012, and
then worked as an Engineer from 2013 to
2017. He is interested in topics related to
WBAN and VANET, especially for MAC
layer protocols, and cross-layer optimization. Shujing Li received the B.S., M.S., and Ph.D. degrees from the College of Computer Sci-
ence and Technology, Jilin University,
China, in 2008, 2011, and 2020, respectively. He is currently a post-doctoral researcher in
the College of Mathematics at Jilin Univer-
sity. He worked as an Assistant Engineer
with the Jiangsu Institute of Automation,
Lianyungang, China, from 2011 to 2012, and
then worked as an Engineer from 2013 to
2017. He is interested in topics related to
WBAN and VANET, especially for MAC
s-layer optimization. Yifan Zhao was born in Zhejiang, China. He
received the Ph.D. degree in automatic con-
trol and system engineering from the Univer-
sity of Sheffield, Sheffield, U.K., in 2007. He
is currently a Reader in data science at Cran-
field University, Cranfield, U.K. His research
interests include computer-vision-based pro-
cess monitoring, super resolution, active
thermography, and nonlinear system
identification. Chen Lv is currently an assistant professor
at Nanyang Technology University, Singa-
pore. He received a Ph.D. degree at the
Department of Automotive Engineering,
Tsinghua University, China in 2016. From
2014 to 2015, he was a joint Ph.D. researcher
at EECS Dept., University of California,
Berkeley. References His research focuses on cyber-
physical systems, hybrid systems, advanced
vehicle control, and intelligence, where he
has contributed over 40 papers and obtained
11 granted China patents. Yahui Liu received his B.S. degree from Jilin
University, China, in 2003 and Ph.D. degree
from Beihang University, China, in 2009
respectively. He is currently an Associate
Professor at State Key Laboratory of Auto-
motive Safety and Energy, Tsinghua Univer-
sity, China. His research interests include
driver-vehicle system dynamics, steering
system, and actuator design of ADAS.
|
https://openalex.org/W4310772015
|
https://ejournal.akprind.ac.id/index.php/snast/article/download/4157/2957
|
Indonesian
| null |
UJI AKTIVITAS ANTIOKSIDAN EKSTRAK DAUN PEPAYA JEPANG (CNIDOSCOLUS ACONITIFOLIUS)
|
Prosiding Seminar Nasional Aplikasi dan Teknologi (SNATS)
| 2,022
|
cc-by
| 2,850
|
P-ISSN: 1979-911X
E-ISSN: 2541-528X P-ISSN: 1979-911X
E-ISSN: 2541-528X Prosiding Seminar Nasional Aplikasi Sains & Teknologi (SNAST) 2022
Yogyakarta, 12 November 2022 INTISARI Radikal bebas adalah atom atau gugus yang memiliki satu atau lebih elektron yang tidak berpasangan. Radikal bebas dapat masuk ke dalam tubuh kemudian menyerang senyawa, seperti lipid, protein sehingga orang
tersebut berpotensi terkena berbagai penyakit. Radikal bebas tersebut dapat diredam dengan antioksidan. Antioksidan merupakan senyawa kimia yang dapat mendonorkan satu atau lebih elektron kepada radikal bebas. Manfaat antioksidan bagi tubuh yaitu melindungi sel-sel dari kerusakan akibat radikal bebas.Untuk mendapatkan
manfaat tersebut, mengonsumsi makanan yang kaya akan antioksidan perlu dilakukan. Salah satu tanaman yang
mengandung antioksidan dan dapat dikonsumsi yaitu daun papaya jepang. Daun pepaya jepang mengandung
antioksidan seperti vitamin C, alkaloid, saponin, tanin dan flavonoid. Antioksidan merupakan senyawa yang dapat
menghambat reaksi oksidasi dengan cara mengikat radikal bebas dan molekul yang sangat reaktif sehingga
radikal bebas tidak menyerang senyawa lain pada tubuh atau suatu lingkungan. Penelitian ini bertujuan untuk
mengetahui aktivitas antioksidan dari ekstrak daun papaya jepang melalui metode radikal bebas DPPH (1.1
Diphenyl-2-picrylhidrazyl). Hasil penelitian ini menunjukkan bahwa ekstrak daun pepaya jepang memiliki
aktivitas antioksidan IC50 yang besarnya 909,6 ppm. Nilai IC50 yang besarnya 909,6 ppm mendandakan bahwa
ekstrak daun papaya jepang merupakan antioksidan lemah. Selain itu, nilai IC50 tersebut menyatakan bahwa pada
konsentrasi ekstrak daun papaya jepang 909,6 ppm, 50% senyawa radikal dapat diredam. Kata kunci : antioksidan, cnidoscolus aconitifolius, DPPH Trirahayu5
1,2,3,4,5Politeknik Negeri Bandung
email : 1rizal.mutakin1@gmail.com, ,2ismaprasetiyaa@gmail.com,
Rizal Mutakin1, Isma Pra Setiya2, Surya Adi Ismail3, Rony Pasonang Sihombing4, Dhyna Analyes
3suryaadiismail@gmail.com,4rony.pasonang.sihombing@polban.ac.id, 5dhyna.analyes@polban.ac.id Trirahayu5
1,2,3,4,5Politeknik Negeri Bandung
1
2
Rizal Mutakin1, Isma Pra Setiya2, Surya Adi Ismail3, Rony Pasonang Sihombing4, Dhyna Analyes Trirahayu5
1,2,3,4,5Politeknik Negeri Bandung
email : 1rizal.mutakin1@gmail.com, ,2ismaprasetiyaa@gmail.com,
Rizal Mutakin1, Isma Pra Setiya2, Surya Adi Ismail3, Rony Pasonang Sihombing4, Dhyna Analyes
3suryaadiismail@gmail.com,4rony.pasonang.sihombing@polban.ac.id, 5dhyna.analyes@polban.ac.id ABSTRACT Free radicals are atoms or groups that have one or more unpaired electrons. Free radicals can enter the
body and then attack compounds, such as lipids, proteins so that the person has the potential to be exposed to
various diseases. These free radicals can be quenched with antioxidants. Antioxidants are chemical compounds
that can donate one or more electrons to free radicals. The benefits of antioxidants for the body is to protect cells
from damage caused by free radicals. To get these benefits, eating foods rich in antioxidants needs to be done. One of the plants that contain antioxidants and can be consumed is Japanese papaya leaves (Cnidoscolus
Aconitifolius). Japanese papaya leaves contain antioxidants such as vitamin C, alkaloids, saponins, tannins and
flavonoids. Antioxidants are compounds that can inhibit oxidation reactions by binding to free radicals and
molecules that are very reactive so that they are free from attacking other compounds in the body or the
environment. This study aims to determine the antioxidant activity of Japanese papaya leaf extract through the
free radical method DPPH (1.1 Diphenyl-2-picrylhydrazyl). The results of this study indicate that Japanese
papaya leaf extract has antioxidant activity IC50 which is 909.6 ppm. The IC50 value of 909.6 ppm indicates that
the Japanese papaya leaf extract is a weak antioxidant. In addition, the IC50 value states that at a concentration
of 909.6 ppm Japanese papaya leaf extract, 50% radical compounds can be reduced. 1. PENDAHULUAN Kandungan senyawa flavonoid, turunan coumarin dan lainnya yang ada pada tanaman dapat menangkal
stres oksidatif di tubuh manusia jika dikonsumsi. Senyawa tersebut membantu menangkal stress oksidatif karena
mampu mempertahankan keseimbangan oksidan dan antioksidan. Stres oksidatif terjadi ketika kandungan
antioksidan lebih sedikit daripada oksidan dan radikal bebas di dalam tubuh. (Prasonto et al., 2017). Radikal bebas adalah atom atau gugus yang memiliki satu atau lebih elektron yang tidak berpasangan. Radikal bebas di kehidupan sehari-hari dapat ditemukan pada asap rokok, obat-obatan, bahan aditif dan lain-lain
(Al Ridho, 2013). D-77 Prosiding Seminar Nasional Aplikasi Sains & Teknologi (SNAST) 2022
Yogyakarta, 12 November 2022 P-ISSN: 1979-911X
E-ISSN: 2541-528X Prosiding Seminar Nasional Aplikasi Sains & Teknologi (SNAST) 2022
Yogyakarta, 12 November 2022 P-ISSN: 1979-911X
E-ISSN: 2541-528X Radikal bebas dapat masuk ke dalam tubuh kemudian menyerang senyawa lipid, protein sehingga dapat
menyebabkan berbagai penyakit (Nanda Pratama & Busman, 2020) Radikal bebas tersebut dapat diredam dengan
antioksidan. Antioksidan merupakan senyawa kimia yang dapat mendonorkan satu atau lebih elektron kepada
radikal bebas, sehingga radikal bebas akan stabil dan reaksinya terhambat. Manfaat antioksidan bagi tubuh yaitu melindungi sel-sel tubuh dari kerusakan akibat radikal bebas. Untuk
mendapatkan manfaat tersebut, mengonsumsi makanan yang kaya akan antioksidan perlu dilakukan. Antioksidan
dapat diperoleh dari alam maupun buatan. Namun, penggunaan antioksidan sintetik atau buatan seperti butylated
hydroxytoluen (BHT), butylated hydroxyanisole (BHA) dan tertbutylhydroxy quinone (TBHQ) pada olahan
pangan dapat menimbulkan efek karsinogensik sehingga penggunaanya saat ini dibatasi. Hal tersebut mendorong
dilakukannya penelitian untuk mendapatkan sumber antioksidan dari alam yang dapat menggantikan penggunaan
antioksidan sintetik (Samin et al., 2013). Manfaat lain dari bahan alam yang mengandung antioksidan dapat dijadikan sebagai bahan baku inhibitor
korosi. Inhibitor korosi dari bahan alam lebih ramah lingkungan dan mampu menghentikan reaksi oksidasi dengan
cara menghambat radikal bebas seperti OH-. Dengan begitu, penggunaan inhibitor korosi sintetik yang bersifat
toxic dapat digantikan dengan inhibitor korosi berbahan dasar alami. Salah satu tanaman yang mengandung antioksidan dan dapat dikonsumsi yaitu pepaya jepang
(Cnidoscolus aconitifolius). Pepaya jepang (Cnidoscolus aconitifolius) adalah tanaman perdu yang tingginya
kurang lebih enam meter dan memiliki daun berjari seperti daun pepaya biasa dan memiliki bunga berwarna putih
(Jiménez-Arellanes et al., 2014). Berikut adalah gambar 1. yang menunjukkan tampilan fisik tanaman dan daun
papaya jepang. Gambar 1. Tampilan Fisik Tanaman dan Daun dari Pepaya Jepang Gambar 1. 1. PENDAHULUAN Tampilan Fisik Tanaman dan Daun dari Pepaya Jepang Menurut Grubben et al., (2004) daun pepaya jepang memiliki kandungan air, lemak, karbohidrat, protein,
kalsium, fosfor, β-karoten, besi, tiamin, riboflavin, niasin dan asam acrobit serta beberapa jenis flavonoid. Penelitian serupa yang dilakukan oleh Obichi et al., (2015) ditemukan bahwa daun pepaya jepang mengandung
tanin, fitat, saponin, alkaloid flavonoid serta vitamin C yang merupakan antioksidan. Namun, saat ini belum
banyak diteliti aktivitas antioksidan ekstrak daun pepaya jepang yang dapat menunjukan tingkat kekuatan daun
pepaya jepang dalam menghambat radikal bebas. Oleh karena itu, uji aktivitas antioksidan ekstrak daun pepaya
jepang dengan metode DPPH (1.1 Diphenyl-2-picrylhidrazyl) dilakukan. 2. METODE PENELITIAN Alat yang digunakan pada penelitian ini adalah blender, oven, neraca analitik, bejana maserasi, rotary
vaccum evaporator, spektrofotometer UV-Vis, ayakan 230 mesh, tabung reaksi dan labu ukur. Disamping itu,
bahan yang digunakan pada penelitian ini adalah daun papaya jepang, etanol 70%, aquadest, DPPH, metanol pro
analis (p.a). Prosedur penelitian dilakukan mulai dari persiapan bahan baku, proses maserasi untuk mendapatkan
ekstrak daun pepaya jepang dan analisis ekstrak daun pepaya jepang dengan uji DPPH. Prosedur penelitian dapat
dilihat pada gambar 2. D-78 P-ISSN: 1979-911X
E-ISSN: 2541-528X P-ISSN: 1979-911X
E-ISSN: 2541-528X Prosiding Seminar Nasional Aplikasi Sains & Teknologi (SNAST) 2022
Yogyakarta, 12 November 2022 Prosiding Seminar Nasional Aplikasi Sains & Teknologi (SNAST) 2022
Yogyakarta, 12 November 2022 Gambar 2. Diagram Alir Prosedur Penelitian
Mulai
Persiapan bahan
baku
Ekstraksi metode
maserasi
Analisis DPPH
Selesai Selesai Gambar 2. Diagram Alir Prosedur Penelitian Pada persiapan bahan baku, daun pepaya jepang dicuci dengan air mengalir untuk menghilangkan
pengotor seperti tanah atau lumpur yang menempel. Kemudian daun pepaya jepang dicacah untuk memudahkan
proses pengeringan yang dilakukan dengan cara diangin-angikan tanpa terkena sinar matahari. Lalu, daun pepaya
jepang yang sudah kering dan kadar airnya di bawah 5% dihancurkan dengan menggunakan blender sampai halus
sehingga dihasilkan serbuk daun papaya jepang. Kemudian, Serbuk daun pepaya jepang diayak untuk memperoleh
serbuk daun pepaya jepang 230 mesh (63 micron) (Luliana et al., 2016; Missuari & Naufal Attamimi, 2020) Pada tahapan maserasi, serbuk daun pepaya jepang direndam kedalam pelarut etanol selama 2x24 jam
dan dilakukan pengadukan secara berkala dengan perbandingan antara serbuk dan pelarut (1:8 b(g)/v(ml)). Kemudian, larutan ekstrak dipisahkan dari residunya dengan menggunakan metode filtrasi. Lalu, ekstrak daun
pepaya jepang dipekatkan menggunakan alat rotary vaccum evaporator dengan kecepatan putar 200 rpm dan suhu
pemanasan 70℃ (Missuari & Naufal Attamimi, 2020) Uji aktivitas antioksidan dari ekstrak daun papaya jepang dimulai dari membuat larutan induk pasta
ekstrak daun papaya jepang (DPJ) 1000 ppm dengan pelarut metanol p.a. Dari larutan induk ekstrak DPJ, larutan
encer DPJ dengan konsentrasi 0, 200, 400, 600, 800 dan 1000 ppm dibuat dengan pelarut metanol p.a. Kemudian,
larutan induk DPPH 50 ppm dibuat dengan pelarut metanol. Selanjutnya, masukan 1 ml ekstrak DPJ yang
konsentrasinya 0, 200, 400, 600, 800 dan 1000 ppm. Kemudian tambahkan 1 ml DPPH pada tabung pertama
sampai tabung enam sehingga diperoleh larutan dengan nama berturut-turut blanko, a, b, c, d dan e. Lalu, diamkan
selama 30 menit pada tempat gelap. 2. METODE PENELITIAN Kemudian Ukur absorbansi blanko (0 ppm DPJ), a, b, c, d dan e pada panjang
gelombang 517 nm dan hitung IC50. (Hidayati et al., 2017) Uji aktivitas antioksidan pada penelitian ini menggunakan metode DPPH (2,2-difenil-1-pikrilhidrazil). Metode uji ini dipilih karena mudah, cepat dan hanya memerlukan sedikit sampel. Oleh karena itu, uji DPPH
banyak digunakan untuk menguji kemampuan senyawa dalam menghambat radikal bebas. 3. HASIL DAN PEMBAHASAN Dari massa 900 gram daun pepaya jepang (DPJ) yang diangin-anginkan pada ruangan tanpa terkena sinar
matahari sampai kadar airnya 3% diperoleh daun pepaya kering sebanyak 175 gram. Dari hasil maserasi DPJ yang
kadar airnya dibawah 5% dan evaporasi ekstrak cair DPJ, ekstrak daun pepaya jepang dalam bentuk pasta diperoleh
20,9 gram. Dengan demikian, yield ekstraksi DPJ sebesar 20,9 gram/175 gram x 100% adalah 11,94 %. Dari hasil uji aktivitas antioksidan dengan metode DPPH, data absorbansi dan peredaman pada tiap
konsentrasi diperoleh yang dipaparkan pada tabel 1. dan gambar 3. sebagai berikut. Tabel 1. Aktivitas Antioksidan Ekstrak Daun Papaya Jepang
Ekstrak DPJ (ppm)
Absorbansi
%Inhibisi
0
0.261
0
200
0.226
13.410
400
0.195
25.287
600
0.165
36.782
800
0.141
45.977
1000
0.120
54.023 Tabel 1. Aktivitas Antioksidan Ekstrak Daun Papaya Jepang
Ekstrak DPJ (ppm)
Absorbansi
%Inhibisi Prosiding Seminar Nasional Aplikasi Sains & Teknologi (SNAST) 2022
P-ISSN: 1979-911X
Yogyakarta, 12 November 2022
E-ISSN: 2541-528X Prosiding Seminar Nasional Aplikasi Sains & Teknologi (SNAST) 2022
Yogyakarta, 12 November 2022 P-ISSN: 1979-911X
E-ISSN: 2541-528X Gambar 3. %Inhibisi Terhadap Konsentrasi DPJ
y = 0,05x + 4,52
R² = 0,99
0
10
20
30
40
50
60
0
200
400
600
800
1000
1200
% Inhibisi
C (ppm) Gambar 3. %Inhibisi Terhadap Konsentrasi DPJ Nilai IC50 ekstrak daun papaya jepang diperoleh dari persamaan regresi linier pada gambar 3.1. yang
persamaanya y = 0,05x +4,52 dan r = 0,9955. Kemudian, dengan mensubstitusikan angka 50 pada variabel y
diperoleh nilai x sebesar 909,6 ppm yang merupakan nilai IC50. Nilai IC50 yang besarnya 909,6 ppm menandakan
bahwa ekstrak daun papaya jepang mampu meredam 50% radikal bebas saat konsentrasinya 909,6 ppm. Nilai IC50
yang diperoleh dapat dibandingkan dengan Tabel 2 berikut. Tabel 2 Penggolongan Kekuatan Antioksidan dari Uji DPPH
No
Nilai IC50
Keterangan
1
IC50 < 50 ppm
Sangat Kuat
2
50 ppm < IC50 < 100 ppm
Kuat
3
100 ppm < IC50 < 150 ppm
Sedang
4
150 ppm < IC50 < 200 ppm
Lemah
5
IC50 > 200 ppm
Sangat Lemah
Sumber : Munandar Pratama et al., (2015) Tabel 2 Penggolongan Kekuatan Antioksidan dari Uji DPPH Berdasarkan tabel 3.2, ekstrak daun pepaya jepang temasuk dalam antioksidan sangat lemah karena nilai
IC50 nya lebih besar dari 200 ppm. Berdasarkan hasil penelitian Somade et al., (2021), nilai IC50 ekstrak daun
pepaya jepang sebesar 20,47 mg/dL yang sama dengan 204,7 ppm. 5. UCAPAN TERIMA KASIH Kami selaku penulis mengucapkan terima kasih atas bantuan dana yang telah diberikan oleh Politeknik
Negeri Bandung sehingga penelitian Uji Aktivitas Antioksidan Ekstrak Daun Pepaya Jepang (Cnidoscolus
aconitifolius) dapat terlaksana. Selain itu, kami ucapkan banyak terima kasih atas ilmu, arahan dan masukkan dari
para pembimbing kami sehingga penelitian ini menjadi sebuah artikel publikasi. 4. KESIMPULAN Ekstrak daun pepaya jepang termasuk dalam kategori antioksidan lemah karena nilai aktivitas
antioksidannya (IC50) lebih besar dari 200 ppm. Dengan demikian, daun pepaya jepang dapat dimanfaatkan sebagai
sumber antioksidan untuk pangan dan inhibitor korosi. 3. HASIL DAN PEMBAHASAN Nilai IC50 tersebut menunjukan bahwa ekstrak
daun pepaya jepang termasuk dalam kategori antioksidan lemah. Perbedaan nilai aktivitas antioksidan (IC50) yang
diperoleh mungkin karena cara ekstraksi, evaporasi , pemilihan daun dan faktor-faktor lain yang berbeda. Luliana, S., Purwanti, N. U., & Manihuruk, K. N. (2016). Pengaruh Cara Pengeringan Simplisia Daun Senggani
(Melastoma malabathricum L.) Terhadap Aktivitas Antioksidan Menggunakan Metode DPPH (2,2-difenil- f
y
( )
p
g
j
Jiménez-Arellanes, M. A., Garc\’\ia-Mart\’\inez, I., & Rojas-Tomé, S. (2014). Potencial biológico de especies
medicinales del género Cnidoscolus (Euphorbiacea). Revista Mexicana de Ciencias Farmacéuticas, 45(4),
1–6. Al Ridho, E. (2013). Uji aktivitas antioksidan ekstrak metanol buah lakum (Cayratia trifolia) dengan metode DPPH
(2, 2-Difenil-1-Pikrilhidrazil). Jurnal Mahasiswa Farmasi Fakultas Kedokteran UNTAN, 1(1).
Grubben, G. J. H., Denton, O. A., & others. (2004). Plant resources of tropical Africa 2. Vegetables. Plant
Resources of Tropical Africa 2. Vegetables.
Hidayati, M. D., Ersam, T., Shimizu, K., & Fatmawati, S. (2017). Antioxidant activity of Syzygium polynthum
extracts. Indonesian Journal of Chemistry, 17(1), 49–53. https://doi.org/10.22146/ijc.23545
Jiménez-Arellanes, M. A., Garc\’\ia-Mart\’\inez, I., & Rojas-Tomé, S. (2014). Potencial biológico de especies
medicinales del género Cnidoscolus (Euphorbiacea). Revista Mexicana de Ciencias Farmacéuticas, 45(4),
1–6.
Luliana, S., Purwanti, N. U., & Manihuruk, K. N. (2016). Pengaruh Cara Pengeringan Simplisia Daun Senggani
(Melastoma malabathricum L.) Terhadap Aktivitas Antioksidan Menggunakan Metode DPPH (2,2-difenil- DAFTAR PUSTAKA Al Ridho, E. (2013). Uji aktivitas antioksidan ekstrak metanol buah lakum (Cayratia trifolia) dengan metode DPPH
(2, 2-Difenil-1-Pikrilhidrazil). Jurnal Mahasiswa Farmasi Fakultas Kedokteran UNTAN, 1(1). Grubben, G. J. H., Denton, O. A., & others. (2004). Plant resources of tropical Africa 2. Vegetables. Plant
Resources of Tropical Africa 2. Vegetables. Grubben, G. J. H., Denton, O. A., & others. (2004). Plant resources of tropical Africa 2. Vegetables. Plant
Resources of Tropical Africa 2. Vegetables. Hidayati, M. D., Ersam, T., Shimizu, K., & Fatmawati, S. (2017). Antioxidant activity of Syzygium polynthum
extracts. Indonesian Journal of Chemistry, 17(1), 49–53. https://doi.org/10.22146/ijc.23545 Hidayati, M. D., Ersam, T., Shimizu, K., & Fatmawati, S. (2017). Antioxidant activity of Syzygium polynthum
extracts. Indonesian Journal of Chemistry, 17(1), 49–53. https://doi.org/10.22146/ijc.23545 Jiménez-Arellanes, M. A., Garc\’\ia-Mart\’\inez, I., & Rojas-Tomé, S. (2014). Potencial biológico de especies
medicinales del género Cnidoscolus (Euphorbiacea). Revista Mexicana de Ciencias Farmacéuticas, 45(4),
1–6. Jiménez-Arellanes, M. A., Garc\’\ia-Mart\’\inez, I., & Rojas-Tomé, S. (2014). Potencial biológico de especies
medicinales del género Cnidoscolus (Euphorbiacea). Revista Mexicana de Ciencias Farmacéuticas, 45(4),
1–6. Luliana, S., Purwanti, N. U., & Manihuruk, K. N. (2016). Pengaruh Cara Pengeringan Simplisia Daun Senggani
(Melastoma malabathricum L.) Terhadap Aktivitas Antioksidan Menggunakan Metode DPPH (2,2-difenil- Luliana, S., Purwanti, N. U., & Manihuruk, K. N. (2016). Pengaruh Cara Pengeringan Simplisia Daun Senggani
(Melastoma malabathricum L.) Terhadap Aktivitas Antioksidan Menggunakan Metode DPPH (2,2-difenil- D-80 P-ISSN: 1979-911X
E-ISSN: 2541-528X Prosiding Seminar Nasional Aplikasi Sains & Teknologi (SNAST) 2022
Yogyakarta, 12 November 2022 Prosiding Seminar Nasional Aplikasi Sains & Teknologi (SNAST) 2022
Yogyakarta, 12 November 2022 P-ISSN: 1979-911X
E-ISSN: 2541-528X P-ISSN: 1979-911X
E-ISSN: 2541-528X 1-pikrilhidrazil). Pharmaceutical
Sciences
and
Research,
3(3),
120–129. https://doi.org/10.7454/psr.v3i3.3291 Missuari, M. N., & Naufal Attamimi, Y. M. (2020). PEMANFAATAN EKSTRAK DAUN PEPAYA SEBAGAI
INHIBITOR ORGANIK PADA TUBE HEAT EXCHANGER DALAM MEDIA LARUTAN NACL
3,56%. In Politeknik Negeri Bandung. Politeknik Negeri Bandung. Missuari, M. N., & Naufal Attamimi, Y. M. (2020). PEMANFAATAN EKSTRAK DAUN PEPAYA SEBAGAI
INHIBITOR ORGANIK PADA TUBE HEAT EXCHANGER DALAM MEDIA LARUTAN NACL
3,56%. In Politeknik Negeri Bandung. Politeknik Negeri Bandung. Munandar Pratama, D., Mulkiya Yuliawati, K., Abdul Kodir, R., Farmasi, P., Ujung, P., Pratama, D. M., Yuliawati,
K. M., & Kodir, R. A. (2015). Identifikasi Senyawa Antioksidan dalam Rumput Laut Sargassum duplicatum
J. G. Agardh dari Pantai Ujung Genteng. Prosiding Penelitian SPeSIA Unisba, 429–434. Nanda Pratama, A., & Busman, H. (2020). Prosiding Seminar Nasional Aplikasi Sains & Teknologi (SNAST) 2022
Yogyakarta, 12 November 2022 DAFTAR PUSTAKA Potensi Antioksidan Kedelai Terhadap Penangkapan Radikal
BebasPotential of Soybean Antioxidant (Glycine Max L) on Capturing Free Radicals. Jurnal Ilmiah
Kesehatan Sandi Husada, 11(1), 497–504. https://doi.org/10.35816/jiskh.v10i2.333 Obichi, E. A., Monago, C. C., & Belonwu, D. C. (2015). Effect of Cnidoscolus aconitifolius (Family
Euphorbiaceae) aqueous leaf extract on some antioxidant enzymes and haematological parameters of high
fat diet and Streptozotocin induced diabetic wistar albino rats. Journal of Applied Sciences and
Environmental Management, 19(2), 201–209. g
( )
Prasonto, D., Riyanti, E., & Gartika, M. (2017). UJI AKTIVITAS ANTIOKSIDAN EKSTRAK BAWANG
PUTIH (Allium sativum). Dental Journal, 4, 122–128. g
( )
Prasonto, D., Riyanti, E., & Gartika, M. (2017). UJI AKTIVITAS ANTIOKSIDAN EKSTRAK BAWANG
PUTIH (Allium sativum). Dental Journal, 4, 122–128. (
)
Samin, A. A., Bialangi, N., & Salimi, Y. K. (2013). Penentuan kandungan fenolik total dan aktivitas antioksidan
dari rambut jagung (Zea mays L.) yang tumbuh di daerah Gorontalo. Jurnal Sainstek, 7(3), 1–3. Samin, A. A., Bialangi, N., & Salimi, Y. K. (2013). Penentuan kandungan fenolik total dan aktivitas antioksidan
dari rambut jagung (Zea mays L.) yang tumbuh di daerah Gorontalo. Jurnal Sainstek, 7(3), 1–3. Somade, O. T., Ugbaja, R. N., Idowu, M. A., & Akinloye, O. A. (2021). Cnidoscolus aconitifolius leaf extract and
ascorbate confer amelioration and protection against dimethyl nitrosamine-induced renal toxicity and
testicular
abnormalities
in
rats. Toxicology
Reports,
8(May),
1098–1108. https://doi.org/10.1016/j.toxrep.2021.05.011 Somade, O. T., Ugbaja, R. N., Idowu, M. A., & Akinloye, O. A. (2021). Cnidoscolus aconitifolius leaf extract and
ascorbate confer amelioration and protection against dimethyl nitrosamine-induced renal toxicity and
testicular
abnormalities
in
rats. Toxicology
Reports,
8(May),
1098–1108. https://doi.org/10.1016/j.toxrep.2021.05.011 D-81
|
https://openalex.org/W4313491779
|
https://www.researchsquare.com/article/rs-2349093/latest.pdf
|
English
| null |
Integrated Bioinformatic Analysis Reveals NOS2 as a Novel Ferroptosis-related Biomarker for Pre-eclampsia
|
Research Square (Research Square)
| 2,023
|
cc-by
| 5,745
|
Integrated Bioinformatic Analysis Reveals NOS2 as
a Novel Ferroptosis-related Biomarker for Pre-
eclampsia Shuangming Cai
Guangdong Women and Children Hospital
Shan Huang
Guangdong Women and Children Hospital
Wenni Zhang
Guangdong Women and Children Hospital
Huanshun Xiao
Guangdong Women and Children Hospital
Danfeng Yu
Guangdong Women and Children Hospital
Xuan Zhong
Guangdong Women and Children Hospital
Pei Tao
Guangdong Women and Children Hospital
Yiping Luo
(
427941842@qq.com
)
Guangdong Women and Children Hospital Shuangming Cai
Guangdong Women and Children Hospital
Shan Huang
Guangdong Women and Children Hospital
Wenni Zhang
Guangdong Women and Children Hospital
Huanshun Xiao
Guangdong Women and Children Hospital
Danfeng Yu
Guangdong Women and Children Hospital
Xuan Zhong
Guangdong Women and Children Hospital
Pei Tao
Guangdong Women and Children Hospital
Yiping Luo
(
427941842@qq.com
)
Guangdong Women and Children Hospital Shuangming Cai
Guangdong Women and Children Hospital
Shan Huang
Guangdong Women and Children Hospital
Wenni Zhang
Guangdong Women and Children Hospital
Huanshun Xiao
Guangdong Women and Children Hospital
Danfeng Yu
Guangdong Women and Children Hospital
Xuan Zhong
Guangdong Women and Children Hospital
Pei Tao
Guangdong Women and Children Hospital
Yiping Luo
(
427941842@qq.com
)
Guangdong Women and Children Hospital Results The most relevant module of PE in the GSE48424 dataset comprising the 565 identified DEGs contained
a total of 3661 genes. After overlapping, we obtained six ferroptosis-related genes involved in PE. Among
these genes, patients with PE displaying lower expression levels of NOS2 and higher expression levels of
PTGS2 had a higher ferroptosis potential index. The expression pattern of NOS2 was consistent in the
GSE48424 and GSE98224 datasets. RT-qPCR data confirmed that NOS2 expression was more
significantly elevated in patients with PE than in those with a normal pregnancy. Methods We downloaded the GSE48424 and GSE98224 datasets from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) between PE and healthy pregnancy samples were identified in the
GSE48424 dataset and subjected to weighted gene co-expression network analysis; the most relevant
modules were intersected with known ferroptosis-related genes to distinctly identify the role of ferroptosis
in PE. We further searched transcription factors and microRNAs that are predicted to regulate these
ferroptosis-related genes, and patients in the GSE48424 dataset were divided into two groups according
to high or low expression of the key ferroptosis-related genes associated with PE. To obtain robust key
ferroptosis-related genes in PE, we validated their expression levels in the external dataset GSE98224. Finally, we performed a reverse transcription-quantitative polymerase chain reaction (RT-qPCR) assay of
these genes to evaluate their expression in the placenta samples of patients with PE and normal
pregnancy. Conclusions Our study explored the diagnostic value of ferroptosis-related genes in PE, and identified NOS2 as the key
gene linking ferroptosis and PE, suggesting a new candidate biomarker for early PE diagnosis. Background Pre-eclampsia (PE) is a common condition in pregnancy; however, methods for early diagnosis and
effective treatment options are lacking. Ferroptosis is a newly identified iron-dependent cell death
pathway. The aim of this study was to investigate the role of ferroptosis-related genes in PE, the
underlying mechanism, and their potential diagnostic value using a bioinformatics approach. Research Article Keywords: pre-eclampsia, ferroptosis, WGCNA, differential gene expression, biomarker, NOS2, GEO
Posted Date: January 4th, 2023
DOI: https://doi.org/10.21203/rs.3.rs-2349093/v1 DOI: https://doi.org/10.21203/rs.3.rs-2349093/v1 License:
This work is licensed under a Creative Commons Attribution 4.0 International
License. Read Full License Additional Declarations: No competing interests reported. Version of Record: A version of this preprint was published at BMC Pregnancy and Childbirth on October
10th, 2023. See the published version at https://doi.org/10.1186/s12884-023-06051-0. Page 1/19 Page 1/19 Background Page 2/19 Page 2/19 Page 2/19 Pre-eclampsia (PE), characterized by organ damage and hypertension after 20 gestational weeks, has a
prevalence of 2–8%. PE is associated with short-term complications such as cardiac, hepatic, pulmonary,
renal, and neurological dysfunction, and high maternal and neonatal mortality. Long-term complications
include a higher risk of cardiovascular events [1, 2]. The abnormal migration and invasion of the
extravillous trophoblast toward the uterine spiral arteries, which is the main cause of PE, lead to
neovascularization and uteroplacental vascular resistance [3, 4]. However, the exact pathophysiology of
PE is unknown, and early diagnosis and treatment are lacking. Early diagnosis facilitates rapid clinical
intervention and minimizes maternal and fetal damage. Therefore, the pathogenesis of PE requires
further analysis, and it is important to find reliable diagnostic markers. Programmed cell death typically occurs in the biological development process. Although previous studies
in this regard have mainly focused on autophagy and apoptosis, the role of ferroptosis has become a
research hotspot in recent years. As another form of programmed cell death, ferroptosis is quite distinct
from the classical programmed cell death forms (e.g., apoptosis) [5, 6], with iron-dependent lipid-
peroxidative damage as the main mechanism. Ferroptosis has been shown to play a role in several
diseases such as asthma, brain damage, cancer, ischemic heart disease, and acute kidney injury [7–11]. The pathophysiological processes of PE, including placental development hypoxia-reperfusion, abnormal
placental perfusion, rich iron content in the trophoblast, and reduced glutathione peroxidation capacity
[12, 13], are linked to the conditions associated with ferroptosis; however, there are no studies
investigating the potential relationship of ferroptosis with PE. Investigation of the relationship between ferroptosis-related genes and PE can enrich our understanding
of PE etiology and guide the early detection of PE. Thus, the aim of this study was to identify diagnostic
ferroptosis-related biomarkers for the early diagnosis of PE using bioinformatics analysis and validation
assays with clinical samples . Data source We recruited six pairs of patients with PE matched with women undergoing a normal pregnancy from the
Department of Obstetrics of Guangdong Women and Children Hospital (China). The Ethics Committee of
Guangdong Women and Children’s Hospital approved the study (No. 202101012), and all participants
provided informed consent. Transcriptome data from patients with PE and normal pregnancies were downloaded from the GSE48424
dataset, including 18 control and 18 PE samples, and the GSE98224 dataset, including 18 control and 30
PE samples, of the Gene Expression Omnibus (GEO) (http://www.ncbi.nlm.nih.gov/geo) database to
screen for ferroptosis-related genes involved in PE. Ferroptosis scores of the control and PE groups in the
GSE48424 dataset were calculated by single-sample gene set enrichment analysis (ssGSEA) using a
ferroptosis-related gene set from the FerrDb database.fi Page 3/19 Page 3/19 Differentially expressed gene (DEG) identification and
functional analysis We used the “limma” package in R (version 4.0.0) to identify the DEGs between PE and control samples
with p-value < 0.05 and |fold change (FC)| >1.5. DEG function, interactions among enriched biological
processes, and pathways were analyzed using Metascape. We constructed a sample clustering tree map
from the GSE48424 dataset. Weighted gene co-expression network analysis (WGCNA) and identification of the most relevant module
associated with PE To eliminate outliers and ensure the best soft threshold depending on gene expression profiles and
patient grouping (control and PE groups), we performed WGCNA using R software package. We used
Pearson correlation coefficients to determine the most relevant module associated with PE. Identification of potential diagnostic ferroptosis-related
biomarkers in PE DEGs, ferroptosis-related genes downloaded from the FerrDb database, and genes in the most relevant
module identified by WGCNA were intersected to identify candidate ferroptosis-related genes involved in
PE. Subsequently, the diagnostic value of candidate ferroptosis-related genes involved in PE was
assessed by construction of receiver operating characteristic (ROC) curves. Candidate ferroptosis-related
genes with area under the ROC curve (AUC) values greater than 0.7 were identified as potential diagnostic
ferroptosis-related biomarkers in PE. The Harmonizome database was used to search for transcription factors (TFs) that regulate the
expression of the candidate diagnostic ferroptosis-related biomarkers in PE. The regulatory network of
microRNAs (miRNAs) and TF diagnostic biomarkers was visualized using Cytoscape. Potential
diagnostic ferroptosis-related biomarkers in PE were captured into the miRWalk database to screen for
miRNAs targeting the diagnostic biomarkers (score > 0.9). Patients with PE in the GSE48424 dataset were separated into high- and low-expression groups according
to the median expression value of each diagnostic biomarker. The ferroptosis potential index (FPI) was
calculated based on the expression levels of genes in the core ferroptosis machinery by ssGSEA,
including the positive regulators NFE2L2, LPCAT3, GPX4, NCOA4, ACSL4, SLC3A2, ALOX15, SLC7A11,
NOX3, NOX1, NOX5, and NOX4, and the negative regulators COQ10B, HMGCR, FDFT1, and COQ10A, as
described in a previous study [14]. Thereafter, candidate key ferroptosis-related genes were identified
according to a significant difference between the low- and high-expression groups. Gene expression was
validated in the external dataset GSE98224 to obtain robust key ferroptosis-related genes in PE. The
biological functions of key ferroptosis-related genes in PE were analyzed by GSEA. Page 4/19 Page 4/19 Validation with reverse transcription-quantitative
polymerase chain reaction (RT-qPCR) TRIzol reagent (Tiangen, Beijing, China) was used to extract the total RNA from patient samples. The
Revert Aid RT-PCR system was then used to perform reverse transcription to synthesize cDNA, and qPCR
was performed on the ABI 7500 Real-Time PCR System (Roche, Penzberg, Germany) by mixing cDNA,
primers, and the Rox Reference Dye. The conditions for qPCR were as follows: 40 cycles of denaturation
(95°C, 10 s), annealing (55°C, 20 s), and extension (72°C, 35 s). The primer sequences were as follows:
PTGS2 (forward, 5′- CAAGAGCACAAGAGGAAGAGAG − 3′; reverse, 5′- CTACATGGCAACTGTGAGGAG − 3′),
GCH1 (forward, 5′- CCTGGAAGCTGTTGCCTTAT − 3′; reverse, 5′- TGTGTTTCTGTGGAGGAGTTG − 3′),
HIF1A (forward, 5′- CCAGTTACGTTCCTTCGATCAG − 3′; reverse, 5′- GTAGTGGTGGCATTAGCAGTAG − 3′),
BACH1 (forward, 5′- CTCCGCAGGTATCAAGGAAAT − 3′; reverse, 5′- TAAAGAAGGCAAGGCCAGAG − 3′),
NOS2 (forward, 5′- CTCAGCCTCATTCCTGCTTTA − 3′; reverse, 5′- GACCTGTGCCTTGAGAACTT − 3′), and
GAPDH (forward, 5′- CAAGAGCACAAGAGGAAGAGAG − 3′; reverse, 5′- CTACATGGCAACTGTGAGGAG-3′). The mRNA expression levels were calculated using the ΔΔCT method with GAPDH as a reference. S
i
i
l
l
i Statistical analysis All data were analyzed using R software version 4.0.0. A p-value < 0.05 was considered to indicate
statistical significance. DEGs in PE are associated with immune and lipid
metabolism The workflow of the current study is displayed in Fig. 1. We identified 565 DEGs, including 378
downregulated and 187 upregulated genes in PE compared with control samples (Fig. 2a). Metascape
confirmed that these DEGs were largely enriched in immune- and lipid metabolism-related biological
processes, including the metabolism of lipids, regulation of the mitogen-activated protein kinase cascade,
T cell activation, inflammatory response, cytokine–cytokine receptor interaction, tumor necrosis factor
signaling pathway, and regulation of lipid metabolic process (Fig. 2b). Metascape further revealed that
these biological processes and pathways interact (Fig. 2c), indicating that the pathogenesis of PE is
complex and regulated by cross-talk among multiple biological processes and pathways. Most relevant module associated with PE identified by
WGCNA Regulatory network of diagnostic ferroptosis-related
biomarkers in PE The ChEA Transcription Factor Targets function in Harmonizome was used to screen TFs regulating the
expression of PTGS2, GCH1, HIF1A, BACH1, and NOS2. A regulatory network of PTGS2, GCH1, HIF1A,
BACH1, NOS2, and 85 TFs was constructed and visualized using Cytoscape (Fig. 5a). PTGS2, GCH1,
HIF1A, BACH1, and NOS2 expression was found to be regulated by both specific and common TFs. We
also detected the miRNAs targeting these five biomarkers using the miRWalk database and constructed
the miRNA–mRNA network using Cytoscape. We found 31 miRNA–GCH1 pairs, 37 miRNA–BACH1 pairs,
a has-miR-2467-5p–NOS2 pair, 17 miRNA–HIF1A pairs, and 16 miRNA–PTGS2 pairs (Fig. 5b). Identification of five diagnostic ferroptosis-related
biomarkers in PE We compared the ferroptosis scores between PE and control samples by ssGSEA. The PE group had
significantly (p < 0.05) lower ferroptosis scores than the control group (Fig. 4a), indicating that ferroptosis
is involved in the etiology of PE. Six candidate ferroptosis-related genes involved in PE were identified by
overlapping the 565 DEGs, 3661 genes identified in the most relevant WGCNA module, and 259 known
ferroptosis-related genes (Fig. 4b). ROC curve analysis was applied to evaluate the diagnostic value of
the six candidate ferroptosis-related genes. The AUC values for PTGS2, GCH1, HIF1A, BACH1, NOS2, and
ATF3 were 0.824, 0.794, 0.774, 0.758, 0.721, and 0.695, respectively (Fig. 4c). Therefore, PTGS2, GCH1,
HIF1A, BACH1, and NOS2 were identified as candidate diagnostic ferroptosis-related biomarkers in PE. Most relevant module associated with PE identified by
WGCNA No outlier sample was detected in the GSE48424 dataset (Fig. 3a). The trait heatmap and sample
dendrogram are shown in Fig. 3b. The optimal soft threshold power was identified as 6, for which the R2
was 0.85 (Fig. 3c). After merging similar modules, we identified 15 modules from the co-expression Page 5/19 network (Fig. 3d). The ME (blue) module, comprising 3661 genes, was the most relevant module
associated with PE (correlation coefficient = 0.41, p = 0.01) and was thus selected for further analysis. Discussion PE has dire consequences for both maternal and neonatal health. However, early diagnosis and radical
treatment for PE are lacking as its etiology is not well-understood. As a novel regulated form of cell death,
ferroptosis has recently been shown to play a role in the development of multiple diseases [15], making it
a promising biomarker to aid in early diagnosis. This study investigated the diagnostic value of
ferroptosis-related genes in PE. We identified 565 DEGs that mainly participate in the lipid metabolism and immune processes. Previous
studies reported that a large amount of energy required for placental and fetal development is provided
by free fatty acids (FFAs). Lorentzen et al. [16] reported that the serum levels of FFAs such as linoleic
acid, palmitic acid, and oleic acid are elevated in patients with PE, and lower levels of long-chain
polyunsaturated fatty acids in either the placenta or maternal circulation have also been related to PE
pregnancies [17–19]. Moreover, altered fatty acid oxidation may contribute to the pathophysiology of PE
[20]. Accumulating evidence indicates that improper activation of the immune system may lead to the
development of PE [21]. These findings suggested that lipid metabolism and immunity are closely related
to PE. Indeed, we found that the ferroptosis scores of patients with PE were significantly lower than those of
women undergoing a normal pregnancy, indicating that iron-mediated cell death is involved in PE
development. We subsequently found six ferroptosis-related genes associated with PE by intersecting the
genes obtained by WGCNA, DEGs analysis, and reported ferroptosis-related genes. Through the ROC
curve, we found that five genes—BACH1, GCH1, HIF1A, NOS2, and PTGS2—can effectively distinguish
between healthy and PE samples, which could be potential PE diagnostic biomarkers. Hui et al. [22] reported that miR-133a-3p could relieve oxidative stress-induced apoptosis by targeting
BACH1 via regulating the BACH1/NRF2/HO-1 signaling pathway in trophoblast cells. In mammals, GCH1
is the rate-limiting enzyme in biosynthetic processes, which is involved in the synthesis of
tetrahydrobiopterin and the pteridine portion of tetrahydrofolate, playing a crucial role in maintaining
inflammatory, neurovascular, and cardiovascular homeostasis [23, 24]. However, no studies have
identified a role of GCH1 in PE to date. The expression of HIF1A, which is a negative regulator of RSL3- and erastin-induced ferroptosis in Calu-1
and HT1080 cells [25], was found to be upregulated in the placenta tissues of patients with PE. Takayuki
et al. Identification of NOS2 as the key ferroptosis-related gene in PE To investigate the importance of these six candidate biomarkers in mediating the ferroptosis-related
etiology of PE, we divided pregnant women with PE into low- and high-expression groups according to the
median expression level of each biomarker. The low-NOS2 group had a significantly (p < 0.05) higher FPI
than that of the high-NOS2 group (Fig. 6a),and the high-PTGS2 group had a significantly (p < 0.05) higher
FPI than the low-PTSG2 group(Fig. 6b). No significant difference was detected between low- and high-
expression groups with respect to the levels of GCH1, HIF1A, and BACH1 (Fig. 6c–e), indicating that NOS2
and PTGS2 have greater contributions to the ferroptosis-related etiology of PE. Furthermore, the
abundance of NOS2 was higher in the PE group, whereas the abundance of PTGS2 was higher in the
control group in the GSE48424 dataset (Fig. 7a). The expression pattern of NOS2 was validated in the
GSE98224 dataset (Fig. 7b). Thus, NOS2 was considered to be a key ferroptosis-related gene in PE. ssGSEA showed that sympathetic nervous system development was significantly enriched in the high-
NOS2 expression group (p < 0.01, Fig. 7c), suggesting the potential mechanism by which NOS2 is involved
in PE. Validation with RT-qPCR confirmed that the NOS2 mRNA expression level was significantly elevated
in patients with PE compared with that of pregnant women undergoing a normal pregnancy (Fig. 8). Page 6/19 Page 6/19 Discussion [26] verified that knockdown of HIF1A mRNA could alleviate the syndromes of PE, such as
hypertension, organ damage, elevated circulating sFlt-1, and proteinuria, in PE mouse models. Upregulated NOS2 expression could produce elevated levels of nitric oxide (NO) over extended periods of
time. Li et al. [27] found that an increase of the NOS2 level in lysosomes may cause the continuous
accumulation of NO, which will induce autophagy and result in raising the lysosomal membrane
permeabilization to its threshold along with lysosomal lipid peroxidation, finally leading to ferroptosis. NO
is required for uterine spiral artery remodeling and trophoblast migration in early pregnancy. Patients with Page 7/19 Page 7/19 PE exhibit lower plasma levels of NO, indicating that the reduced bioavailability of NO is involved in PE
development [28, 29]. PE exhibit lower plasma levels of NO, indicating that the reduced bioavailability of NO is involved in PE
development [28, 29]. PTGS2 is an inducible enzyme brought about by hypoxia and oxidative stress [30, 31]. Although PTGS2
does not regulate ferroptosis, it has been reported that increased PTGS2 levels could be a suitable marker
for ferroptosis [32]. The increased expression of PTGS2 indicates an inflammatory response in PE [33,
34]. We used the FPI to identify that NOS2 and PTGS2 contribute more substantially to the ferroptosis-related
etiology of PE among the six candidate biomarkers. The expression pattern of NOS2 was consistent in
the GSE48424 dataset, and the expression level of NOS2 in patients with PE was significantly higher than
that in women undergoing a normal pregnancy. Collectively, these results suggest that NOS2 is a key
ferroptosis-related gene involved in PE. To explain the relevant mechanisms by which NOS2 participates
in PE, we conducted ssGSEA, which showed that sympathetic nervous system development was
significantly enriched in the high-NOS2 expression group. Furthermore, Lina et al. [35] showed that levels
of neuron-specific enolase and S100B, which are two cerebral biomarkers indicating neurological injury,
remain elevated 1 year postpartum in PE pregnancies versus normal pregnancies. Other studies have
reported that ferroptosis plays a significant role in nervous system development and nerve-related
diseases [36–39]. Therefore, we speculate that NOS2 may participate in PE through ferroptosis-mediated
neuronal injury. However, this hypothesis needs to be confirmed through further experimental studies. There are some limitations of this study. Discussion The data we used to construct the diagnostic model were
downloaded from the GEO database; thus, larger sample sizes should be analyzed. We found a
relationship between ferroptosis-related gene signatures and immune-related biological processes. Although we used RT-qPCR analysis to confirm the expression level of hub genes, further in vitro and in
vivo experiments are required for validation and functional analyses. List Of Abbreviations AUC Area under the curve Conclusions To the best of our knowledge, this is the first study to use the WGCNA method to explore ferroptosis-
related genes as biomarkers for the diagnosis of PE. We identified that NOS2 may serve as a diagnostic
biomarker for PE. Our findings revealed that ferroptosis plays a role in PE etiology, thereby enhancing our
knowledge of the molecular mechanisms underlying PE. AUC Area under the curve DEG Differentially expressed gene Page 8/19 FFA Free fatty acid ROC Receiver operating characteristic
RT-qPCR Reverse transcription quantitative polymerase chain reaction
ssGSEA Single-sample gene set enrichment analysis
TF Transcription factor
WGCNA Weighted gene co-expression network analysis Consent for publication Not applicable. Availability of data and materials The GSE48424 and GSE98224 mRNA profiles were downloaded from the GEO database
(https://www.ncbi.nlm.nih.gov/geo/). Ethics approval and consent to participate The Ethics Committee of Guangdong Women and Children’s Hospital approved the study (No. 202101012), and all patients who agreed to participate in the study signed written informed consent. All
the methods and procedures described in the present study were performed according to the relevant
guidelines and regulations following the declaration of Helsinki. Competing interests The authors declare that they have no competing interests. We would like to thank Editage (http://www.editage.cn) for English language editing. We would like to thank Editage (http://www.editage.cn) for English language editing. Page 9/19 This work was supported by a Scientific Research Project of Traditional Chinese Medicine of Guangdong
Province grant (No. 20221047). Authors’ contributions Conception and design: Yiping Luo. Material preparation, data collection: Wenni Zhang, Huanshun Xiao
and Danfeng Yu. Data analysis: Shuangming Cai and Shan Huang. Manuscript writing: Xuan Zhong and
Pei Tao. All authors read and approved the final manuscript. References 1. Phipps EA, Thadhani R, Benzing T, Karumanchi SA. Pre-eclampsia: Pathogenesis, novel diagnostics
and therapies. Nat Rev Nephrol. 2019;15:275–89. 2. Jiang S, Chen Q, Liu H, Gao Y, Yang X, Ren Z, et al. Preeclampsia-associated lncRNA INHBA-AS1
regulates the proliferation, invasion, and migration of placental trophoblast cells. Mol Ther Nucleic
Acids. 2020;22:684–95. 3. Aplin JD, Myers JE, Timms K, Westwood M. Tracking placental development in health and disease. Nat Rev Endocrinol. 2020;16:479–94. Fisher SJ. Why is placentation abnormal in preeclampsia? Am J Obstet Gy 5. Liang C, Zhang X, Yang M, Dong X. Recent progress in ferroptosis inducers for cancer therapy. Adv
Mater. 2019;31:e1904197. 6. Stockwell BR, Jiang X, Gu W. Emerging mechanisms and disease relevance of ferroptosis. Trends
Cell Biol. 2020;30:478–90. 7. Wu X, Li Y, Zhang S, Zhou X. Ferroptosis as a novel therapeutic target for cardiovascular disease. Theranostics 2021;11:3052–9. 8. Weiland A, Wang Y, Wu W, Lan X, Han X, Li Q, et al. Ferroptosis and its role in diverse brain diseases. Mol Neurobiol. 2019;56:4880–93. 9. Hu Z, Zhang H, Yang SK, Wu X, He D, Cao K, et al. Emerging role of ferroptosis in acute kidney injury. Oxid Med Cell Longev. 2019;2019:8010614. 10. Li B, Yang L, Peng X, Fan Q, Wei S, Yang S, et al. Emerging mechanisms and applications of
ferroptosis in the treatment of resistant cancers. Biomed Pharmacother. 2020;130:110710. 11. Xu W, Deng H, Hu S, Zhang Y, Zheng L, Liu M, et al. Role of ferroptosis in lung diseases. J Inflamm
Res. 2021;14:2079–90. 12. Ng SW, Norwitz SG, Norwitz ER. The impact of iron overload and ferroptosis on reproductive
disorders in humans: Implications for preeclampsia. Int J Mol Sci. 2019;20:3283. 12. Ng SW, Norwitz SG, Norwitz ER. The impact of iron overload and ferroptosis on reproductive
disorders in humans: Implications for preeclampsia. Int J Mol Sci. 2019;20:3283. Page 10/19 Page 10/19 13. Zhang H, He Y, Wang JX, Chen MH, Xu JJ, Jiang MH, et al. miR-30-5p-mediated ferroptosis of
trophoblasts is implicated in the pathogenesis of preeclampsia. Redox Biol. 2020;29:101402. 14. Liu Z, Zhao Q, Zuo ZX, Yuan SQ, Yu K, Zhang Q, et al. Systematic analysis of the aberrances and
functional implications of ferroptosis in cancer. iScience. 2020;23:101302. 15. Sun Y, Chen P, Zhai B, Zhang M, Xiang Y, Fang J, et al. The emerging role of ferroptosis in
inflammation. Biomed Pharmacother. 2020;127:110108. 16. References Lorentzen B, Drevon CA, Endresen MJ, Henriksen T. Fatty acid pattern of esterified and free fatty
acids in sera of women with normal and pre-eclamptic pregnancy. Br J Obstet Gynaecol. 1995;102:530–7. 17. Wadhwani N, Patil V, Pisal H, Joshi A, Mehendale S, Gupte S, et al. Altered maternal proportions of
long chain polyunsaturated fatty acids and their transport leads to disturbed fetal stores in
preeclampsia. Prostaglandins Leukot Essent Fatty Acids. 2014;91:21–30. 18. Wang Y, Walsh SW, Kay HH. Placental tissue levels of nonesterified polyunsaturated fatty acids in
normal and preeclamptic pregnancies. Hypertens Pregnancy. 2005;24:235–45. 18. Wang Y, Walsh SW, Kay HH. Placental tissue levels of nonesterified polyunsaturated fatty acids in
normal and preeclamptic pregnancies. Hypertens Pregnancy. 2005;24:235–45. 19. Kulkarni AV, Mehendale SS, Yadav HR, Joshi SR. Reduced placental docosahexaenoic acid levels
associated with increased levels of sFlt-1 in preeclampsia. Prostaglandins Leukot Essent Fatty Acids. 2011;84:51–5. 20. Bartha JL, Visiedo F, Fernández-Deudero A, Bugatto F, Perdomo G. Decreased mitochondrial fatty
acid oxidation in placentas from women with preeclampsia. Placenta. 2012;33:132–4. 20. Bartha JL, Visiedo F, Fernández-Deudero A, Bugatto F, Perdomo G. Decreased mitochondrial fatty
acid oxidation in placentas from women with preeclampsia. Placenta. 2012;33:132–4. 21. Zolfaghari MA, Arefnezhad R, Parhizkar F, Hejazi MS, Motavalli Khiavi F, Mahmoodpoor A, Yousefi M. T lymphocytes and preeclampsia: The potential role of T-cell subsets and related MicroRNAs in the
pathogenesis of preeclampsia. Am J Reprod Immunol. 2021;86(5):e13475. 22. Guo H, Wang Y, Jia W, Liu L. MiR-133a-3p relieves the oxidative stress induced trophoblast cell
apoptosis through the BACH1/Nrf2/HO-1 signaling pathway. Physiol Res. 2021;70:67–78. 22. Guo H, Wang Y, Jia W, Liu L. MiR-133a-3p relieves the oxidative stress induced trophoblast cell
apoptosis through the BACH1/Nrf2/HO-1 signaling pathway. Physiol Res. 2021;70:67–78. 23. Ichinose H, Homma D, Sumi-Ichinose C, Nomura T, Kondo K. GTP cyclohydrolase regulation:
Implications for brain development and function. Adv Pharmacol. 2013;68:23–35. 23. Ichinose H, Homma D, Sumi-Ichinose C, Nomura T, Kondo K. GTP cyclohydrolase regulation:
Implications for brain development and function. Adv Pharmacol. 2013;68:23–35. 24. McNeill E, Channon KM. The role of tetrahydrobiopterin in inflammation and cardiovascular disease. Thromb Haemostas. 2012;108:832–9. 24. McNeill E, Channon KM. The role of tetrahydrobiopterin in inflammation and cardiovascular disease. Thromb Haemostas. 2012;108:832–9. 25. Liu J, Yang M, Kang R, Klionsky DJ, Tang D. Autophagic degradation of the circadian clock regulator
promotes ferroptosis. Autophagy. 2019;15:2033–5. 25. Liu J, Yang M, Kang R, Klionsky DJ, Tang D. References Autophagic degradation of the circadian clock regulator
promotes ferroptosis. Autophagy. 2019;15:2033–5. 26. Iriyama, Wang W, Parchim NF, Song A, Blackwell SC, Sibai BM, et al. Hypoxia-independent
upregulation of placental hypoxia inducible factor-1α gene expression contributes to the
pathogenesis of preeclampsia. Hypertension. 2015;65:1307–15. 26. Iriyama, Wang W, Parchim NF, Song A, Blackwell SC, Sibai BM, et al. Hypoxia-independent
upregulation of placental hypoxia inducible factor-1α gene expression contributes to the
pathogenesis of preeclampsia. Hypertension. 2015;65:1307–15. 27. Jiang L, Zheng H, Lyu Q, Hayashi S, Sato K, Sekido Y, et al. Lysosomal nitric oxide determines
transition from autophagy to ferroptosis after exposure to plasma-activated ringer’s lactate. Redox
Biol. 2021;43:101989. 27. Jiang L, Zheng H, Lyu Q, Hayashi S, Sato K, Sekido Y, et al. Lysosomal nitric oxide determines
transition from autophagy to ferroptosis after exposure to plasma-activated ringer’s lactate. Redox
Biol. 2021;43:101989. Page 11/19 28. Sandrim VC, Palei AC, Metzger IF, Gomes VA, Cavalli RC, Tanus-Santos JE. Nitric oxide formation is
inversely related to serum levels of antiangiogenic factors soluble fms-like tyrosine kinase-1 and
soluble endogline in preeclampsia. Hypertension. 2008;52:402–7. 29. Eleuterio NM, Palei AC, Rangel Machado JS, Tanus-Santos JE, Cavalli RC, Sandrim VC. Relationship
between adiponectin and nitrite in healthy and preeclampsia pregnancies. Clinica Chimica Acta. 2013;423:112–5. 30. Rumzhum NN, Ammit AJ. Cyclooxygenase 2: Its regulation, role and impact in airway inflammation. Clin Exp Allergy. 2016;46:397–410. 31. Hashemi Goradel N, Najafi M, Salehi E, Farhood B, Mortezaee K. Cyclooxygenase-2 in cancer: A
review. J Cell Physiol. 2019;234:5683–99. 32. Yang WS, SriRamaratnam S, Welsch ME, Shimada K, Skouta R, Viswanathan VS, et al. Regulation of
ferroptotic cancer cell death by GPX4. Cell. 2014;156:317–31. 33. Afroze SH, Kalagiri RR, Reyes M, Zimmerman JD, Beeram MR, Drever N, et al. Apoptotic and stress
signaling markers are augmented in preeclamptic placenta and umbilical cord. BBA Clin. 2016;6:25–
30. 34. Shah TJ, Walsh SW. Activation of NF-kappaB and expression of COX-2 in association with neutrophil
infiltration in systemic vascular tissue of women with preeclampsia. Am J Obstet Gynecol. 2007;196:48. 35. Bergman L, Åkerud H, Wikström AK, Larsson M, Naessen T, Akhter T. Cerebral biomarkers in women
with preeclampsia are still elevated 1 year postpartum. Am J Hypertens. 2016;29:1374–9. 36. Ratan RR. The chemical biology of ferroptosis in the central nervous system. Cell Chem Biol. 2020;27:479–98. 36. Ratan RR. The chemical biology of ferroptosis in the central nervous system. Cell Chem Biol. 2020 27 479 98 37. References Shen L, Lin D, Li X, Wu H, Lenahan C, Pan Y, et al. Ferroptosis in acute central nervous system
injuries: The future direction? Front Cell Dev Biol. 2020;8:594. 38. Abdalkader M, Lampinen R, Kanninen KM, Malm TM, Liddell JR. Targeting Nrf2 to suppress
ferroptosis and mitochondrial dysfunction in neurodegeneration. Front Neurosci. 2018;12:466. 39. Reichert CO, de Freitas FA, Sampaio-Silva J, Rokita-Rosa L, de Lima Barros P, Levy D, et al. Ferroptosis
mechanisms involved in neurodegenerative diseases. Int J Mol Sci. 2020;21:8765. Figures Page 12/19 Page 12/19 Figure 1
Study workflow. PE, pre-eclampsia; WGCNA, weighted gene co-expression network analysis; DEG,
differentially expressed gene; ROC, receiver operating characteristic; TF, transcription factor; miRNA,
microRNA. Figure 1 Study workflow. PE, pre-eclampsia; WGCNA, weighted gene co-expression network analysis; DEG,
differentially expressed gene; ROC, receiver operating characteristic; TF, transcription factor; miRNA,
microRNA. Page 13/19 Page 13/19 Page 13/19 Figure 2
Identification and functional analysis of differentially expressed genes (DEGs) between pre-eclampsia
(PE) and control samples. (a) Volcano plot of DEGs between PE and control samples; DEGs were
screened according to a threshold of p-value < 0.05 and |fold change|> 1.5. (b) Bar chart showing the top
20 enriched terms determined by Metascape. (c) Interactive network of the top 20 enrichment terms. Figure 2 Identification and functional analysis of differentially expressed genes (DEGs) between pre-eclampsia
(PE) and control samples. (a) Volcano plot of DEGs between PE and control samples; DEGs were
screened according to a threshold of p-value < 0.05 and |fold change|> 1.5. (b) Bar chart showing the top
20 enriched terms determined by Metascape. (c) Interactive network of the top 20 enrichment terms. Page 14/19 Figure 3 Page 15/19
Figure 3
Screening the key gene modules correlated with pre-eclampsia (PE) by weighted gene co-expression
network analysis (WGCNA). (a and b) Sample clustering to detect outliers. There were no samples outside
of clusters. (c) Scale-free index calculated under different soft thresholds. The average connectivity is
calculated at different soft thresholds. (d) Gene clustering tree (tree view) obtained from the hierarchical
clustering of adjacency correlation. The colored rows below the tree represent the gene modules identified Figure 3 Screening the key gene modules correlated with pre-eclampsia (PE) by weighted gene co-expression
network analysis (WGCNA). (a and b) Sample clustering to detect outliers. There were no samples outside
of clusters. (c) Scale-free index calculated under different soft thresholds. The average connectivity is
calculated at different soft thresholds. (d) Gene clustering tree (tree view) obtained from the hierarchical
clustering of adjacency correlation. The colored rows below the tree represent the gene modules identified Page 15/19 Page 15/19 by the dynamic cutting tree method. (e) Heatmap of the correlation between module eigengenes and
traits (healthy pregnancy and PE). Each row corresponds to a module. Each column corresponds to a
trait. Each cell contains the corresponding correlation coefficient and p value. Figure 4
Identification of diagnostic ferroptosis-related biomarkers in pre-eclampsia (PE). (a) Ferroptosis score
calculated by single-sample gene set enrichment analysis between PE and control samples. (b) Venn
diagram showing six overlapping candidate ferroptosis-related genes and differentially expressed genes
(DEGs) involved in PE. (c) Receiver operating characteristic curve analysis to evaluate the diagnostic
value of the six candidate ferroptosis-related genes in PE. Figure 5 Regulatory network of potential diagnostic ferroptosis-related biomarkers in pre-eclampsia. (a) Regulatory
network of transcription factor–diagnostic biomarkers constructed and visualized by Cytoscape. (b)
Regulatory network of microRNA–diagnostic biomarkers visualized by Cytoscape. network of transcription factor–diagnostic biomarkers constructed and visualized by Cytoscape. (b)
Regulatory network of microRNA–diagnostic biomarkers visualized by Cytoscape. Figure 6
Ferroptosis potential index (FPI) of high- and low-expression groups calculated by single-sample gene set
enrichment analysis (ssGSEA). (a) Box plot showing the FPI score between high- and low-NOS2
expression groups. (b) Box plot showing the FPI score between high- and low-PTGS2 expression groups. (c) Box plot showing the FPI score between high- and low-GCH1 expression groups. (d) Box plot showing
the FPI score between high- and low-HIF1A expression groups. (e) Box plot showing the FPI score
between high- and low-BACH1 expression groups. ns, not significant; *p < 0.05; **p < 0.01. Figure 4 Identification of diagnostic ferroptosis-related biomarkers in pre-eclampsia (PE). (a) Ferroptosis score
calculated by single-sample gene set enrichment analysis between PE and control samples. (b) Venn
diagram showing six overlapping candidate ferroptosis-related genes and differentially expressed genes
(DEGs) involved in PE. (c) Receiver operating characteristic curve analysis to evaluate the diagnostic
value of the six candidate ferroptosis-related genes in PE. Page 16/19 Page 16/19 Page 16/19 Figure 6 Ferroptosis potential index (FPI) of high- and low-expression groups calculated by single-sample gene set
enrichment analysis (ssGSEA). (a) Box plot showing the FPI score between high- and low-NOS2
expression groups. (b) Box plot showing the FPI score between high- and low-PTGS2 expression groups. (c) Box plot showing the FPI score between high- and low-GCH1 expression groups. (d) Box plot showing
the FPI score between high- and low-HIF1A expression groups. (e) Box plot showing the FPI score
between high- and low-BACH1 expression groups. ns, not significant; *p < 0.05; **p < 0.01. Page 17/19 Figure 7
Gene expression and gene set enrichment analysis of ferroptosis-related genes. (a) Box plot showing
gene expression of NOS2and PTGS2 between pre-eclampsia (PE) and healthy groups in the GSE48424
dataset. (b) Box plot showing gene expression of NOS2 and PTGS2 between PE and control groups in the
GSE98224 dataset. (c) Potential mechanism of the involvement of NOS2 in PE assessed by gene set
enrichment analysis. Figure 7 Gene expression and gene set enrichment analysis of ferroptosis-related genes. (a) Box plot showing
gene expression of NOS2and PTGS2 between pre-eclampsia (PE) and healthy groups in the GSE48424
dataset. (b) Box plot showing gene expression of NOS2 and PTGS2 between PE and control groups in the
GSE98224 dataset. (c) Potential mechanism of the involvement of NOS2 in PE assessed by gene set
enrichment analysis. Gene expression and gene set enrichment analysis of ferroptosis-related genes. (a) Box plot showing
gene expression of NOS2and PTGS2 between pre-eclampsia (PE) and healthy groups in the GSE48424
dataset. (b) Box plot showing gene expression of NOS2 and PTGS2 between PE and control groups in the
GSE98224 dataset. (c) Potential mechanism of the involvement of NOS2 in PE assessed by gene set
enrichment analysis. Page 18/19
Figure 8 Figure 8 Page 18/19 Relative mRNA expression levels of the identified potential diagnostic ferroptosis-related genes in blood
from women undergoing a normal pregnancy (control) and pre-eclampsia (PE) patients. *p < 0.05
compared with the normal pregnant women group. Relative mRNA expression levels of the identified potential diagnostic ferroptosis-related genes in blood
from women undergoing a normal pregnancy (control) and pre-eclampsia (PE) patients. *p < 0.05
compared with the normal pregnant women group. Page 19/19
|
https://openalex.org/W1057725506
|
http://telesnakultura.upol.cz/doi/10.5507/tk.2015.001.pdf
|
Czech
| null |
Seasonal variation in isokinetic strength of knee flexors and extensors in soccer players
|
Tělesná kultura
| 2,015
|
cc-by
| 7,535
|
Lidská motorika/Tělesná výkonnost Lidská motorika/Tělesná výkonnost Michal Lehnert, Petr Chvojka, Rudolf Psotta Michal Lehnert, Petr Chvojka, Rudolf Psotta Fakulta tělesné kultury, Univerzita Palackého, Olomouc, Česká republika Fakulta tělesné kultury, Univerzita Palackého, Olomouc, Česká republika Předloženo v srpnu 2013 Předloženo v srpnu 2013 VÝCHODISKA: Síla má ve fotbale zásadní význam z hlediska sportovní
vý konnosti i z hlediska prevence zranění. Informace o tom, jak se v průběhu
ročního tréninkového cyklu mění svalová síla a poměr síly fl exorů a extenzorů
u mladých fotbalistů schází. CÍLE: Cílem studie bylo posoudit z výkonnostního a zdravotního hlediska
sezónní proměnlivost vybraných charakteristik izokinetické síly fl exorů a exten-
zorů kolenního kloubu u elitních fotbalistů kategorie U19. METODIKA: Síla fl exorů a extenzorů kolenního kloubu dominantní a nedo-
minantní dolní končetiny byla měřena u hráčů kategorie U19 (n = 9; průměrný
věk 18,5 ±0,4 let) na izokinetickém dynamometru IsoMed 2000 (D. & R. Ferstl
GmbH, Hemau, Germany) při úhlové rychlosti 60° × s–1. Měření bylo provedeno
v režimech svalové činnosti koncentrický/koncentrický a excentrický/excentrický
před začátkem zimního přípravného období, po skončení zimního přípravného
období a po skončení jarního soutěžního období. Pro vyhodnocení byly použity
parametry maximální moment síly (MMAX), konvenční poměr (H/QKON), tj. poměr
MMAX fl exorů a extenzorů v koncentrickém režimu, funkční poměr (H/QFUN),
tj. poměr MMAX fl exorů v excentrickém režimu a extenzorů v koncentrickém re-
žimu a funkční poměr v rozsahu 10–30° kolenní fl exe (H/QFUN 10–30). _
VÝSLEDKY: V průběhu sledovaného období došlo k signifi kantním změnám
maximálního momentu síly (p < ,05) pouze u extenzorů na nedominantní dolní
končetině v koncentrickém režimu. Hodnocení dysbalance sil kolenních fl exorů
a extenzorů pomocí H/QKON a H/QFUN poměru neprokázalo signifi kantní změny,
avšak byl potvrzen statisticky významný pokles (p = ,03) hodnot H/QFUN_10–30
na dominantní dolní končetině mezi měřeními na začátku a na konci zimního
přípravného období. ZÁVĚRY: Výsledky studie ukázaly, že ve sledovaných obdobích ročního tré-
ninkového cyklu nedošlo u souboru fotbalistů k žádoucím změnám síly kolenních 9 fl exorů a extenzorů. Hodnoty, resp. pokles hodnot funkčních poměrů ukazují
na možnost narušení dynamické stabilizace kolenního kloubu. Rozdílná dynami-
ka změn poměrů H/QKON, H/QFUN a H/QFUN_10–30 potvrdila, že tyto charakteristiky
poskytují odlišné informace o tělesné kondici hráčů. Z uvedeného důvodu dopo-
ručujeme při diagnostice síly fotbalistů využívat všech tří poměrů. fl exorů a extenzorů. Hodnoty, resp. pokles hodnot funkčních poměrů ukazují
na možnost narušení dynamické stabilizace kolenního kloubu. Rozdílná dynami-
ka změn poměrů H/QKON, H/QFUN a H/QFUN_10–30 potvrdila, že tyto charakteristiky
poskytují odlišné informace o tělesné kondici hráčů. Z uvedeného důvodu dopo-
ručujeme při diagnostice síly fotbalistů využívat všech tří poměrů. Klíčová slova: fotbal, funkční H/Q poměr, konvenční H/Q poměr, maximální mo-
ment síly, periodizace, síla, zranění. ÚVOD Síla je důležitou komponentou specifi cké kondice sportovců a má zásadní
význam nejen z hlediska sportovní výkonnosti, ale rovněž z hlediska prevence
zranění (Cheung, Smith, & Wong, 2012; Lehance, Binet, Bury, & Croisier, 2009). Ve fotbale se při specifi ckých pohybech jako jsou sprinty, výskoky, osobní soubo-
je, změny směru a kopy do míče významně uplatňuje svalová síla fl exorů a exten-
zorů kolenního kloubu (Bradley, Sheldon, Wooster, Olsen, Boanas, & Krustrup.,
2009; Bravo, Impellizzery, Rampinini, Castagna, Bishop, & Wisloff , 2008; Psotta,
Bunc, Mahrová, Netscher, & Nováková, 2006; Verheijen, 1998). Unilaterální a bilaterální asymetrie síly fl exorů a extenzorů kolenního kloubu
jsou jednou z příčin zranění hamstringů a měkkých struktur kolenního klou-
bu (Bangsbo, 1994; Croisier, 2004; Dauty, Potiron, & Rochcongar, 2003; Iga,
George, Lees, & Reilly, 2006; Li, Maff ulli, Hsu, & Chan, 1996; Söderman, Alf-
redson, Pietilä, & Werner, 2001). Fotbalové herní činnosti jsou ve značné míře
jednostranné, což může způsobovat bilaterální svalové dysbalance dolních konče-
tin, které mohou být jednou z příčin svalových zranění. Při unilaterálních srovná-
ních se pro posuzování a identifi kaci sportovců s rizikem zranění a k posouzení
připravenosti k soutěžení hodnotí poměr síly hamstringů a kvadricepsu (Ayala,
De Ste Croix, Sainz de Baranda, & Santonja, 2012; Colak, 2012; Coombs &
Gar butt, 2002; Dauty et al., 2003; Houweling & Hamzeh, 2010; Lehance et al.,
2009). Ve sportu a v rehabilitaci jsou poměry H/Q využívány k popisu dynamické
stability kolene, identifi kaci možných rizikových faktorů pro vznik a obnovení
zranění hamstringů a kolene, monitorování rehabilitačních programů a k určení,
kdy se sportovec může bezpečně vrátit k tréninku (Croisier, 2004). Většina autorů se shoduje, že je-li tzv. konvenční poměr síly hamstringů a kva-
dricepsu, tj. poměr při koncentrické kontrakci (H/QKON), v případě rychlosti
60° × s–1 menší než 0,6 (60 %), pravděpodobnost výskytu zranění hamstringů se
zvyšuje (Dauty et al., 2003; Yeung, Suen, & Yeung, 2009). Ukazuje se, že při 10 nízkém poměru H/QKON dochází k většímu zatížení intraartikulárních struktur
a je snížena také schopnost znovu nastavení optimální pozice kloubu, což vede
ke změně biomechaniky kolenního kloubu (Dauty et al., 2003; Dvir, 2004). Po-
měrem H/QKON při nízkých rychlostech (60° × s–1) je možné určit výskyt předcho-
zího zranění (zejména hamstringů) (Houweling, Head, & Hamzeh, 2009). ÚVOD Podle
některých autorů je nedostatkem poměru H/QKON fakt, že popisuje svalovou akci,
která se fyziologicky nevyskytuje (Ayala et al., 2012; Dauty et al., 2003; Wright,
Ball, & Wood, 2009). Jiní autoři naopak upozorňují na význam současné aktivace excentricky pra-
cujících hamstringů v extenzích kolenního kloubu a jejich dynamickou roli při
udržování stability kolenního kloubu (Coombs & Garbutt, 2002). Ačkoliv se
může současná aktivace hamstringů během koncentrické kolenní extenze zdát
jako kontraproduktivní, byl prokázán její stabilizační vliv na funkci kolenní-
ho kloubu a funguje jako přirozený ochranný mechanismus (Chan & Maff uli,
1996). Zvýšení antagonistické aktivace hamstringů redukuje nadbytečné napětí
předního zkříženého vazu (Tourny-Chollet & Leroy, 2002). Uvedené poznatky
vedly k vývoji tzv. funkčního poměru síly hamstringů a kvadricepsu (H/QFUN),
tj. poměru maximální excentrické síly hamstringů a maximální koncentrické síly
kvadricepsu (Dvir, Eger, Halperin, & Shklar, 1989). Zatímco poměr H/QKON
poukazuje na svalovou dysbalanci, poměr H/QFUN vyjadřuje schopnost fl exorů
kolene brzdit pohyb prováděný zapojením kvadricepsu (De Ste Croix, 2007;
Dvir, 2004). Hodnota poměru H/QFUN 1,0 (100 %) při úhlové rychlosti 60° × s–1
vyjadřuje rovnováhu mezi sílou kolenních fl exorů a extenzorů, a tedy jejich opti-
mální schopnost dynamické stabilizace kolenního kloubu (Aagaard, Simonsen,
Anderson, Magnusson, Bojsen-Moller, & Dyhre-Poulsen, 2000; Coombs & Gar-
butt, 2002). Hodnoty poměrů nad 0,7 (70 %) se považují za dostačující (Dauty
et al., 2003). Epidemiologická zjištění ukazují důležitost úhlu v kloubu a úhlové rychlosti
při výpočtu především funkčního poměru hamstringů a kvadricepsu. Bylo zjiš-
těno, že k ruptuře předního zkříženého vazu dochází obvykle v blízkosti plné
extenze (0–30° kolenní fl exe) při pohybech vysoké rychlosti. Avšak koncent-
rický a excentrický maximální moment síly (MMAX) hamstringů a kvadricepsu
je nejčastěji dosahován mezi 30–80° kolenní fl exe (Forbes, Sutcliff e, Lovell,
McNaughton, & Siegler, 2009). Na základě těchto znalostí se ukazuje jako vhod-
né stanovit funkční poměr H/QFUN pomocí hodnot momentu síly ve specifi ckých
úhlech blíz kých plné extenzi. Další užitečnou formou může být stanovení funkč-
ního poměru H/QFUN pomocí průměrných hodnot momentu síly dosažených
ve specifi ckém rozsahu pohybu 0–30° kolenní fl exe – H/QFUN_0–30 (Ayala et al.,
2012). 11 11 V průběhu ročního tréninkového cyklu se v rámci jeho periodizace pro zvý-
šení maximální síly a explosivity zařazují fáze tréninku síly zaměřené na vyvolání
relativně odlišných adaptací (Bompa & Carrera, 2004; Fleck & Kraemer, 2004;
Wirth & Schmidtbleicher, 2007). ÚVOD V přechodném období a na začátku příprav-
ného období převládá nespecifi cký trénink s cílem připravit svaly, vazy, šlachy
a klouby pro nadcházející zatížení a kompenzovat individuální nedostatky. Po-
stupně se trénink síly stává více specifi ckým s tendencí zvyšování intenzity. Tré-
nink je zaměřen na zvyšování síly na základě zlepšení nervosvalové koordinace,
ale i hypertrofi e, je-li to žádoucí, a následně na uplatnění síly při specifi ckých
fotbalových pohybech (Gamble, 2010; Stōlen, Chamari, Castagna, & Wisloff ,
2005; Schmid & Alejo, 2002; Ratamess, 2008). V průběhu soutěžního období
je důležité úroveň síly udržet a zejména u mladých hráčů ji dále zvyšovat. Nic-
méně v průběhu soutěžního období může docházet ke ztrátě některých adaptací
a k jejímu poklesu (Mujika & Padilla, 2000). Přestože existuje velký počet studií zaměřených na hodnocení izokinetické
síly dolních končetin u fotbalistů, tyto studie se zaměřují na zhodnocení síly
po absolvování tréninkového programu v přípravném období (Askling, Karls-
son, & Thorstensson, 2003; Gioftsidou, Ispirlidis, Pafis, Malliou, Bikos, &
Go dolias, 2008) nebo v soutěžním období (Brito et al., 2010; Steff en, Bakka,
Myklebust, & Bahr, 2008). Studie, ve kterých je sledována izokinetická síla svalů
dolních končetin ve více obdobích ročního tréninkového cyklu, jsou ojedinělé
(Eniseler, Sahan, Vurgun, & Mavi, 2012; Malliou, Ispirlidis, Beneka, Taxilda-
ris, & Godolias, 2003). Tyto studie byly navíc provedeny pouze u profesionálních
fotbalistů seniorské kategorie. Otázka, jak se v průběhu ročního tréninkového
cyklu může měnit síla fl exorů a extenzorů a její poměr u mladých fotbalistů, proto
zůstává nezodpovězena. Cílem studie je posoudit z výkonnostního a zdravotního
hlediska sezónní proměnlivost vybraných charakteristik izokinetické síly fl exorů
a extenzorů kolenního kloubu u elitních fotbalistů kategorie U19. Výzkumný soubor Soubor probandů tvořilo devět hráčů (průměrný věk 18,5 ±0,4 roků) kate-
gorie U19 hrajících nejvyšší soutěž v ČR v dané kategorii. Z původního dvace-
tičlenného souboru bylo vyřazeno jedenáct hráčů z důvodu neúčasti na všech
měřeních v důsledku zranění nebo účasti na reprezentačních srazech. Celkem
osm probandů mělo dominantní pravou dolní končetinu, jeden levou dolní kon-
četinu. Funkční lateralita dolních končetin byla stanovena podle preference dolní 12 končetiny při kopu do míče. Všichni probandi byli seznámení s cílem a metodi-
kou měření, souhlasili s participací na výzkumu a s použitím získaných dat pro
výzkumné účely. Studie byla schválena etickou komisí Fakulty tělesné kultury
Univerzity Palackého v Olomouci. Termíny měření První měření proběhlo před začátkem zimního přípravného období v lednu
2012. Druhé měření následovalo po 10 týdnech zimního přípravného období
v únoru 2012. Třetí měření bylo uskutečněno v červnu 2012 po skončení jarního
soutěžního období. Tabulka 1 Schéma testovacího protokolu pro jednu dolní končetinu 1. série
2. série
3. série
4. série
RČ
con/con
con/con
ecc/ecc
ecc/ecc
PO
6
6
6
6
ZS
rozcvičovac í
testovací
rozcvičovací
testovací
Vysvětlivky: RČ – režim svalové činnosti; PO – počet opakování; ZS – zaměření série;
con/con – koncentrická fl exe následovaná koncentrickou extenzí; ecc/ecc – excentrická
fl exe následovaná excen trickou extenzí Vysvětlivky: RČ – režim svalové činnosti; PO – počet opakování; ZS – zaměření série;
con/con – koncentrická fl exe následovaná koncentrickou extenzí; ecc/ecc – excentrická
fl exe následovaná excen trickou extenzí Vysvětlivky: RČ – režim svalové činnosti; PO – počet opakování; ZS – zaměření série;
con/con – koncentrická fl exe následovaná koncentrickou extenzí; ecc/ecc – excentrická
fl exe následovaná excen trickou extenzí Z naměřených hodnot byl pro vyhodnocení použit MMAX a průměrný moment
síly z redukovaného rozsahu pohybu 10–30° (MMAX_10–30). Dále byl vydělením
hodnot MMAX fl exorů a extenzorů v koncentrickém režimu vypočten konvenční
poměr síly H/QKON. Pomocí hodnot MMAX fl exorů v excentrickém a MMAX exten-
zorů v koncentrickém režimu byl vypočten funkční poměr H/QFUN a dělením
hodnot MMAX_10–30 fl exorů v excentrickém a extenzorů v koncentrickém režimu
byl vypočten funkční poměr H/QFUN_10–30. Postup měření Testování předcházelo rozcvičení probandů s cílem přípravy na maximální si-
lový výkon. Rozcvičení se skládalo z rozehřátí na bicyklovém ergometru po dobu
6 minut, poté následoval 5minutový strečink s využitím postizometrické relaxace
testovaných svalových partií. ý
ý
p
Unilaterální koncentrická síla fl exorů a extenzorů kolenního kloubu byla mě-
řena použitím izokinetického dynamometru IsoMed 2000 (D. & R. FerstlGmbH,
Hemau, Germany). Probandi byli testováni v pozici vsedě s rukama na madlech
podél sedadla. Opěrka sedadla byla sklopena o 15°, úhel v kyčelním kloubu byl
přibližně 110°. Probandi byli zafi xování v oblasti ramen, pánve a stehna pracující
končetiny. Osa otáčení dynamometru byla shodná s osou otáčení kolenního klou-
bu (laterální femorální kondyl). Rameno páky dynamometru bylo zafi xováno
v distální části bérce, umístěno 2,5 cm nad mediálním malleolem. Nastavení
sedadla bylo uloženo do paměti dynamometru a při měření druhostranné konče-
tiny bylo automaticky nastaveno pomocí funkce „memotronic“. Rozsah pohybu
byl 80°, přičemž výchozí poloha byla 10° fl exe a konečná 90° fl exe v kolenním
kloubu. Pro měření byla použita úhlová rychlost 60° × s–1 (Brown, 2000; Dvir,
2004; Perrin, 1993). Měření bylo provedeno ve dvou režimech svalové kontrak-
ce fl exorů a extenzorů – koncentrický/koncentrický a excentrický/excentrický. V průběhu měření byla aktivována gravitační korekce. Testovací protokol jedné dolní končetiny se skládal ze čtyř sérií po 6 opako-
váních. Účelem rozcvičovací série byla familiarizace a proband byl v této sérii
veden k postupnému zvyšování intenzity. Po 30sekundovém intervalu zotavení
následovala vlastní testovací série šesti kontrakcí provedených s maximálním
úsilím. Tyto dvě série (rozcvičovací a testovací) byly provedeny pro oba režimy
svalové kontrakce (Tabulka 1). Interval zotavení mezi měřením v jednotlivých
rychlostech byl 1 min., mezi měřením pravé a levé dolní končetiny 3 min. V prů-
běhu měření byla probandům poskytována zpětná vazba v podobě křivky mo-
mentu svalové síly na monitoru dynamometru. 13 13 Tréninkové zatížení hráčů Sledované tréninkové období trvalo celkem 22 týdnů (10 týdnů zimní pří-
pravné období, 12 týdnů jarní soutěžní období). Tréninkový program vycházel
z modelu, který je v klubu dlouhodobě používán. Hodnoty ukazatelů tréninkové-
ho zatížení hráčů ve sledovaných obdobích jsou uvedeny v Tabulce 2 a 3. Tabulka 2 Tabulka 2
Ukazatele tréninkového zatížení hráčů v přípravném období
Tréninkové zatížení
Čas (min.)
1. Kondiční trénink
a) Trénink síly
– plyometrický trénink
180
– trénink jádra těla
540
– trénink maximální síly
360 Ukazatele tréninkového zatížení hráčů v přípravném období 14 b) Trénink rychlosti bez míče
480
c) Trénink vytrvalosti bez míče
480
2. Dovednostně orientovaný trénink
a) Technicko-taktický trénink
240
b) Herní trénink
450
3. Utkání
720
4. Regenerace
270
Tabulka 3
Ukazatele tréninkového a soutěžního zatížení hráčů v soutěžním období
Tréninkové zatížení
Čas (min.)
1. Kondiční trénink
a) Trénink síly
– plyometrický trénink
90
– trénink jádra těla
360
– trénink maximální síly
180
b) Trénink rychlosti bez míče
180
c) Trénink vytrvalosti bez míče
420
2. Dovednostně orientovaný trénink
a) Technicko-taktický trénink
1 080
b) Herní trénink
840
3. Utkání
1 080
4. Regenerace
540 b) Trénink rychlosti bez míče
480
c) Trénink vytrvalosti bez míče
480
2. Dovednostně orientovaný trénink
a) Technicko-taktický trénink
240
b) Herní trénink
450
3. Utkání
720
4. Regenerace
270 Trénink síly v přípravném období obsahoval 1× týdně trénink maximální síly
a 1× týdně plyometrický trénink a trénink jádra těla. V soutěžním období došlo
k redukci objemu tréninku síly. Statistické zpracování dat Pro popis sledovaných parametrů byl vypočten průměr a směrodatná odchyl-
ka. Ke stanovení významnosti rozdílů sledovaných parametrů byla použita Fried-
manova jednofaktorová ANOVA(p < ,05). Významnost rozdílů mezi jednotlivými
měřeními byla stanovena pomocí Wilcoxonova párového testu. Pro statistické
zpracování dat byl použit software Statistica, v. 10 (StatSoft, Inc., Tulsa, USA). VÝSLEDKY V koncentrickém režimu se výsledky u extenzorů dominantní dolní končetiny
(DDK) a nedominantní dolní končetiny (NDK) lišily (Obrázek 1 a 2). Signifi - 15 kantní efekt času byl pozorován pouze v případě MMAX extenzorů v koncentric-
kém režimu na NDK (Tabulka 4). Hlubší analýza ukázala na statisticky významný
roz díl (p = ,03) mezi druhým a třetím měřením (po absolvování přípravného
období a na konci soutěžního období). V případě průměrných hodnot MMAX
fl exorů nebyly změny na DDK ani na NDK statisticky významné (Obrázek 1 a 2). kantní efekt času byl pozorován pouze v případě MMAX extenzorů v koncentric-
kém režimu na NDK (Tabulka 4). Hlubší analýza ukázala na statisticky významný
roz díl (p = ,03) mezi druhým a třetím měřením (po absolvování přípravného
období a na konci soutěžního období). V případě průměrných hodnot MMAX
fl exorů nebyly změny na DDK ani na NDK statisticky významné (Obrázek 1 a 2). Obrázek 1 Průměrné hodnoty maximálního momentu síly [N × m] fl exorů a extenzorů ko-
lenního kloubu v koncentrickém režimu na dominantní dolní končetině při rych-
losti 60° × s–1 v jednotlivých měřeních Průměrné hodnoty maximálního momentu síly [N × m] fl exorů a extenzorů ko-
lenního kloubu v koncentrickém režimu na dominantní dolní končetině při rych-
losti 60° × s–1 v jednotlivých měřeních
140,00±22,58
132,00±22,42
138,56±16,98
214,78±34,05
217,22±33,71
218,00±36,14
100
120
140
160
180
200
220
240
0
1
2
3
MĢƎení
Extenzory
Flexory
Obrázek 2
Průměrné hodnoty maximálního momentu síly [N × m] fl exorů a extenzorů ko-
lenního kloubu v koncentrickém režimu na nedominantní dolní končetině při
rychlosti 60° × s–1 v jednotlivých měřeních
215,56±31,78
206 33±33 91
219,33±29,68
240 140,00±22,58
132,00±22,42
138,56±16,98
214,78±34,05
217,22±33,71
218,00±36,14
100
120
140
160
180
200
220
240
0
1
2
3
MĢƎení
Extenzory
Flexory Tabulka 4 Změny v hodnotách maximálního momentu síly [N × m] fl exorů a extenzorů
kolenního kloubu mezi jednotlivými měřeními na dominantní a nedominantní
dolní končetině v koncentrickém režimu (n = 9) DDK
NDK
χ2
p
χ2
p
MMAX_Fcon_1, 2, 3
0,06
,97
0,94
,63
MMAX_Econ_1, 2, 3
1,77
,41
6,00
< ,05* Vysvětlivky: χ2 – chí-kvadrát; p – hladina statistické významnosti; * – statisticky význam-
né hodnoty (p < ,05); DDK – dominantní dolní končetina; NDK – nedominantní dolní
končetina; MMAX_Fcon – maximální moment síly fl exorů kolenního kloubu v koncentrickém
režimu; MMAX_Econ – maximální moment síly extenzorů kolenního kloubu v koncentrickém
režimu; 1, 2, 3 – jednotlivá měření v průběhu ročního tréninkového cyklu V excentrickém režimu nebyly změny MMAX v žádném případě statisticky
významné (Tabulka 5). Zatímco u extenzorů NDK došlo v průběhu sledované-
ho období k zvýšení MMAX o 26 N × m, u fl exorů jsme pozorovali opačný trend
(Obrázek 3 a 4). Obrázek 2 Obrázek 2
Průměrné hodnoty maximálního momentu síly [N × m] fl exorů a extenzorů ko-
lenního kloubu v koncentrickém režimu na nedominantní dolní končetině při
rychlosti 60° × s–1 v jednotlivých měřeních 129,56±17,67
128,00±17,73
133,00±24,23
215,56±31,78
206,33±33,91
219,33±29,68
100
120
140
160
180
200
220
240
0
1
2
3
MĢƎení
Extenzory
Flexory 129,56±17,67
128,00±17,73
133,00±24,23
215,56±31,78
206,33±33,91
219,33±29,68
100
120
140
160
180
200
220
240
0
1
2
3
MĢƎení
Extenzory
Flexory 16 Tabulka 5 Změny v hodnotách maximálního momentu síly [N × m] fl exorů a extenzorů
kolenního kloubu mezi jednotlivými měřeními na dominantní a nedominantní
dolní končetině v excentrickém režimu (n = 9) dolní končetině v excentrickém režimu (n = 9)
DDK
NDK
χ2
p
χ2
p
MMAX_Fecc_1, 2, 3
0,667
,717
0,743
,700
MMAX_Eecc_1, 2, 3
0,889
,641
2,667
,264
Vysvětlivky: χ2 – chí-kvadrát; p – hladina statistické významnosti; * – statisticky význam-
né hodnoty (p < ,05); DDK – dominantní dolní končetina; NDK – nedominantní dolní
končetina; MMAX_Fecc – maximální moment síly fl exorů kolenního kloubu v excentrickém
režimu; MMAX_Eecc – maximální moment síly extenzorů kolenního kloubu v excentrickém
režimu; 1, 2, 3 – jednotlivá měření v průběhu ročního tréninkového cyklu DDK
NDK
χ2
p
χ2
p
MMAX_Fecc_1, 2, 3
0,667
,717
0,743
,700
MMAX_Eecc_1, 2, 3
0,889
,641
2,667
,264 Vysvětlivky: χ2 – chí-kvadrát; p – hladina statistické významnosti; * – statisticky význam-
né hodnoty (p < ,05); DDK – dominantní dolní končetina; NDK – nedominantní dolní
končetina; MMAX_Fecc – maximální moment síly fl exorů kolenního kloubu v excentrickém
režimu; MMAX_Eecc – maximální moment síly extenzorů kolenního kloubu v excentrickém
režimu; 1, 2, 3 – jednotlivá měření v průběhu ročního tréninkového cyklu Vysvětlivky: χ2 – chí-kvadrát; p – hladina statistické významnosti; * – statisticky význam-
né hodnoty (p < ,05); DDK – dominantní dolní končetina; NDK – nedominantní dolní
končetina; MMAX_Fecc – maximální moment síly fl exorů kolenního kloubu v excentrickém
režimu; MMAX_Eecc – maximální moment síly extenzorů kolenního kloubu v excentrickém
režimu; 1, 2, 3 – jednotlivá měření v průběhu ročního tréninkového cyklu 17 Obrázek 3 Obrázek 3
Průměrné hodnoty maximálního momentu síly [N × m] fl exorů a extenzorů ko-
lenního kloubu v excentrickém režimu na dominantní dolní končetině při rych-
losti 60° × s–1 v jednotlivých měřeních
153,44±31,46
149,78±32,48
144,89±28,69
266,56±54,28
260,67±58,27
262,44±66,56
120
150
180
210
240
270
0
1
2
3
MĢƎení
Extenzory
Flexory
Obrázek 4
Průměrné hodnoty maximálního momentu síly [N × m] fl exorů a extenzorů ko-
lenního kloubu v excentrickém režimu na nedominantní dolní končetině při
rychlosti 60° × s–1 v jednotlivých měřeních
134,44±24,34
123,00±37,03
128,11±31,00
234,00±84,21
249,89±61,60
260,11±57,39
120
150
180
210
240
270
0
1
2
3
MĢƎení
Extenzory
Flexory Průměrné hodnoty maximálního momentu síly [N × m] fl exorů a extenzorů ko-
lenního kloubu v excentrickém režimu na dominantní dolní končetině při rych-
losti 60° × s–1 v jednotlivých měřeních 153,44±31,46
149,78±32,48
144,89±28,69
266,56±54,28
260,67±58,27
262,44±66,56
120
150
180
210
240
270
0
1
2
3
MĢƎení
Extenzory
Flexory Obrázek 5 Průměrné hodnoty H/QKON na dominantní dolní končetině (DDK) a nedomi-
nantní dolní končetině (NDK) při rychlosti 60° × s–1 v jednotlivých měřeních 0,66±0,09
0,61±0,09
0,65±0,09
0,61±0,11
0,63±0,10
0,61±0,11
0,5
0,6
0,7
0
1
2
3
MĢƎení
DDK
NDK
Kritérium 0,66±0,09
0,61±0,09
0,65±0,09
0,61±0,11
0,63±0,10
0,61±0,11
0,5
0,6
0,7
0
1
2
3
MĢƎení
DDK
NDK
Kritérium Průměrné hodnoty H/QFUN na DDK se pouze v prvním měření pohybovaly
nad hraniční hodnotou (0,7) a ve druhém a třetím měření klesly těsně pod hra-
niční hodnotu. Na NDK se hodnoty H/QFUN nacházely pod hraniční hodnotou
ve všech třech měřeních (Obrázek 6). Obrázek 4 Obrázek 4
Průměrné hodnoty maximálního momentu síly [N × m] fl exorů a extenzorů ko-
lenního kloubu v excentrickém režimu na nedominantní dolní končetině při
rychlosti 60° × s–1 v jednotlivých měřeních 134,44±24,34
123,00±37,03
128,11±31,00
234,00±84,21
249,89±61,60
260,11±57,39
120
150
180
210
240
270
0
1
2
3
MĢƎení
Extenzory
Flexory 18 Obrázek 6 Průměrné hodnoty H/QFUN na dominantní dolní končetině (DDK) a nedomi-
nantní dolní končetině (NDK) při rychlosti 60° × s–1 v jednotlivých měřeních 0,63±0,09
0,59±0,13
0,69±0,19
0,72±0,12
0,69±0,13
0,58±0,12
0,5
0,6
0,7
0,8
0
1
2
3
MĢƎení
DDK
NDK
Kritérium 19 V případě H/QFUN_10–30 došlo na DDK i NDK k poklesu průměrné hodnoty
ve druhém měření a následnému nárůstu ve třetím měření. Ve všech měřeních
byly hodnoty H/QFUN_10–30 na DDK vyšší než na NDK (Obrázek 7). Obrázek 7
Průměrné hodnoty H/QFUN_10–30 na dominantní dolní končetině (DDK) a ne do-
minantní dolní končetině (NDK) při rychlosti 60° × s–1 v jednotlivých měřeních Obrázek 7 Obrázek 7
Průměrné hodnoty H/QFUN_10–30 na dominantní dolní končetině (DDK) a ne do-
minantní dolní končetině (NDK) při rychlosti 60° × s–1 v jednotlivých měřeních
1,49±0,27
1,31±0,31
1,34±0,33
1,64±0,30
1,45±0,28
1,60±0,39
1,2
1,3
1,4
1,5
1,6
1,7
0
1
2
3
MĢƎení
DDK
NDK
DISKUSE
V souladu s ostatními studiemi dosahovali hráči našeho souboru v koncent-
rickém režimu vyšších hodnot MMAX při extenzi (koncentrická práce extenzorů)
než při fl exi (koncentrická práce fl exorů), a to na DDK i NDK (Lehance et al.,
2009; Tourny-Chollet, Leroy, Léger, & Beuret-Blanquart, 2000). V excentrickém
režimu dosahovali vyšších hodnot MMAX ve fl exi (excentrická práce extenzorů)
než v extenzi (excentrická práce fl exorů), a to na DDK i NDK (Cometti, Maffi -
uletti, Pousson, Chatard, & Maff ulli, 2001; Fousekis, Tsepis, & Vagenas, 2010;
Tourny-Chollet et al., 2000). Síla v excentrickém režimu byla vždy vyšší než
v kon centrickém režimu (Kellis, Gerodimos, Kellis, & Manou, 2001; Tourny-
-Chollet et al., 2000). Podle Brown (2000) se izokinetická síla zdá být citlivým ukazatelem změn
v síle způsobené jinými druhy silového tréninku. Výsledky provedené studie uka-
zují že hodnoty M
flexorů a extenzorů kolenního kloubu se u sledovaného 1,49±0,27
1,31±0,31
1,34±0,33
1,64±0,30
1,45±0,28
1,60±0,39
1,2
1,3
1,4
1,5
1,6
1,7
0
1
2
3
MĢƎení
DDK
NDK
DISKUSE DISKUSE V souladu s ostatními studiemi dosahovali hráči našeho souboru v koncent-
rickém režimu vyšších hodnot MMAX při extenzi (koncentrická práce extenzorů)
než při fl exi (koncentrická práce fl exorů), a to na DDK i NDK (Lehance et al.,
2009; Tourny-Chollet, Leroy, Léger, & Beuret-Blanquart, 2000). V excentrickém
režimu dosahovali vyšších hodnot MMAX ve fl exi (excentrická práce extenzorů)
než v extenzi (excentrická práce fl exorů), a to na DDK i NDK (Cometti, Maffi -
uletti, Pousson, Chatard, & Maff ulli, 2001; Fousekis, Tsepis, & Vagenas, 2010;
Tourny-Chollet et al., 2000). Síla v excentrickém režimu byla vždy vyšší než
v kon centrickém režimu (Kellis, Gerodimos, Kellis, & Manou, 2001; Tourny-
-Chollet et al., 2000). V souladu s ostatními studiemi dosahovali hráči našeho souboru v koncent-
rickém režimu vyšších hodnot MMAX při extenzi (koncentrická práce extenzorů)
než při fl exi (koncentrická práce fl exorů), a to na DDK i NDK (Lehance et al.,
2009; Tourny-Chollet, Leroy, Léger, & Beuret-Blanquart, 2000). Obrázek 7 V excentrickém
režimu dosahovali vyšších hodnot MMAX ve fl exi (excentrická práce extenzorů)
než v extenzi (excentrická práce fl exorů), a to na DDK i NDK (Cometti, Maffi -
uletti, Pousson, Chatard, & Maff ulli, 2001; Fousekis, Tsepis, & Vagenas, 2010;
Tourny-Chollet et al., 2000). Síla v excentrickém režimu byla vždy vyšší než
v kon centrickém režimu (Kellis, Gerodimos, Kellis, & Manou, 2001; Tourny-
-Chollet et al., 2000). Podle Brown (2000) se izokinetická síla zdá být citlivým ukazatelem změn
v síle způsobené jinými druhy silového tréninku. Výsledky provedené studie uka-
zují, že hodnoty MMAX fl exorů a extenzorů kolenního kloubu se u sledovaného
souboru fotbalistů mezi měřeními na začátku přípravného období, na konci zim-
ního přípravného období a na konci jarního soutěžního období měnily odlišně. Nicméně ke statisticky významným změnám došlo pouze v případě MMAX exten - 20 zorů na NDK v koncentrickém režimu svalové kontrakce. Z hlediska kondice
hráčů a herního výkonu je rovněž podstatný rozdíl hodnot MMAX extenzorů NDK
v excentrickém režimu mezi prvním a třetím měřením (zvýšení o 11 %). Statis-
tická významnost rozdílu však nebyla potvrzena. Mezi měřeními na začátku a na konci zimního přípravného období jsme za-
znamenali pokles síly fl exorů DDK i NDK v koncentrickém (DDK 6 %, NDK 1 %)
i excentrickém režimu (DDK 2 %, NDK 9 %). U extenzorů došlo v kon centrickém
režimu k minimálnímu zvýšení (0,5 %) průměrných hodnot MMAX na DDK
a poklesu (4 %) na NDK, v excentrickém režimu došlo k poklesu hodnot MMAX
na DDK (2 %) a k nárůstu na NDK (7 %). Absence významných pozitivních změn
může mít více příčin. V přípravném období byl trénink maximální síly dolních
končetin zařazen pouze 1× týdně, což lze z hlediska zvyšování síly považovat
za nedostatečné. Dalším důvodem mohou být nedostatky ve skladbě tréninku. Ten
byl kombinací intenzivního tréninku vytrvalosti, rychlosti a síly, což mohlo mít
za důsledek stagnaci sledovaných silových parametrů (Fleck & Kraemer, 1987;
Fry, 2004). Jako další vysvětlení se nabízí nedostatečná kompenzace vysokého
tréninkového zatížení v přípravném období, na což ukazuje zpětná analýza tré-
ninkového zatížení. Tato skutečnost mohla vést ke kumulaci únavy a tím ke sní-
žení síly testovaných svalových skupin. Uvedenou domněnku podporují rovněž
výsledky dřívější studie provedené u kategorie U19 stejného klubu (Botek et al.,
2010). Obrázek 7 Síla svalů dolních končetin sledovaných hráčů po absolvování přípravné-
ho období stagnovala, a to i přes to, že v jeho průběhu prováděli dvakrát týdně
podřepy (90° v kolenním kloubu) s 85–90 % 1 OM. Porovnání výsledků na konci zimního přípravného období a na konci jarního
soutěžního období ukazuje, že došlo ke zvýšení hodnot MMAX fl exorů v koncent-
rickém režimu na DDK (5 %) i NDK (4 %), zatím co síla extenzorů v koncentric-
kém režimu na DDK stagnovala, resp. se zvýšila na NDK (6 %). Výsledky měření
síly v excentrickém režimu ukazují na snížení hodnot MMAX fl exorů na DDK
(3 %) a zvýšení na NDK (4 %). Síla extenzorů v excentrickém režimu stagnovala
na DDK a zvýšila se na NDK (4 %). Z výše uvedených změn se lze domnívat, že
v průběhu jarního soutěžního období se maximální síla měřených svalů dolních
končetin u měřených hráčů významně nezměnila. V tomto období byl trénink
maximální síly zařazen jedenkrát týdně, což společně s herním a soutěžním
zatížením bylo pravděpodobně pro signifi kantní zvýšení síly nedostačující. Při
interpretaci výsledků hodnot MMAX fl exorů a extenzorů kolenního kloubu u sledo-
vané skupiny hráčů musíme vzít v úvahu tři aspekty. Za prvé je třeba vzít v úva-
hu malý počet sledovaných probandů. Za druhé, ačkoliv byla reliabilita měření
izokinetického dynamometru IsoMed 2000 shledána jako vysoká (Dirnberger,
Kösters, & Müller, 2012), je při interpretaci výsledků izokinetického testování 21 nutné počítat s chybou měření. Za třetí, srovnání s výsledky elitních fotbalistů
stejné nebo po dobné kategorie ukazuje na rezervy v síle svalových skupin a pro-
stor pro zlep šování. V porovnání s hráči U19 studie Botek et al. (2010) naši hráči
celkově dosahovali v prvním měření nižších hodnot MMAX fl exorů (DDK 15 %,
NDK 24 %) i extenzorů (DDK 9 %, NDK 12 %), přičemž ve druhém měření došlo
jen k minimálním změnám v silovém defi citu hráčů. Výsledky studie Lehnerta,
Urbana, Procházkay, a Psotty (2011), uskutečněné na konci soutěžního období
u o rok mladší kategorie U18 (n = 15), v rámci které byla měřena izokinetická síla
v koncentrickém režimu (DDK: F = 132,0 ±20,0, N × m, E = 225,8 ±36,4 N × m,
NDK: F = 129,6 ±19,5, N × m, E = 216,2 ±34,7, N × m) ukazují na srovnatelnou
úroveň MMAX fl exorů a extenzorů kolenního kloubu obou souborů. Obrázek 7 Rovněž po-
rovnání s výsledky dospělých fotbalistů naznačuje potřebu dalšího zvyšování síly
svalů dolních končetin (Cometti et al., 2001; Cotte & Chatard, 2011; Eniseler
et al., 2012; Fousekis, Tsepis, & Vagenas, 2010; Gioftsidou et al., 2008; Lehance
et al., 2009; Malý, Zahálka, & Malá, 2011). Dynamiku změn MMAX v průběhu sledovaných období ročního trénin kového
cyklu je možno v případě koncentrické síly extenzorů porovnat s hráči první belgické
divize (n = 57, průměrný věk 27,2 ±3,2), které testovali Mal liou et al. (2003) na konci
soutěžního období (DDK = 233,8 ±26,9 N × m, NDK = 230,9 ±25,0 N × m), po pře-
chodném období (DDK = 234,0 ±30,0 N × m, NDK = 277,7 ±28,5 N × m) a po ukon-
čení přípravného období (DDK = 228,8 ±22,5 N × m, NDK = 222,5 ±33,5 N × m). Autoři zaznamenali po přípravném období mírný pokles hodnot MMAX extenzorů
(2 %) na obou dolních končetinách, zatímco u našich hráčů byl pozorován po-
kles hodnot MMAX extenzorů na NDK (4 %) a stagnace hodnot MMAX extenzorů
na DDK. Izokinetickou sílu fl exorů a extenzorů kolenního kloubu u profesionálních
tureckých fotbalistů (n = 14, průměrný věk 25,8 ±3,9, resp. 26,3 ±3,9) a její
změny po 24 týdnech přípravného a soutěžního období sledovali Eniseler et al. (2012). Autoři zjistili, že hodnoty při rychlosti 60° × s–1 se mezi měřeními sig-
nifi kantně nezměnily (DDK: F1 = 150,49 ±19,92, N × m; F2 = 177,97 ±64,84,
N × m; DDK: E1 = 272,72 ±38,98, N × m; E2 = 253,03 ±42,16, N × m; NDK:
F1 = 148,24 ± 15,30, N × m; F2 = 158,86 ±40,39, N × m; NDK: E1 = 271,61±38,66,
N × m; E2 = 250,93 ±54,24, N × m). Hráči neabsolvovali speciální silový trénink
nad rámec běžných fotbalových tréninků, stejně jako hráči našeho souboru. Vý sledky naznačují, že specifi cký fotbalový trénink v kombinaci s přípravnými
a soutěžními utkáními nevede k signifi kantním změnám v izokinetické síle fl exorů
a extenzorů kolenního kloubu v nízkých úhlových rychlostech pohybu. 22 22 Svalové dysbalance mezi kolenními fl exory a extenzory u fotbalistů byly hod-
noceny pomocí konvenčního (H/QKON) a funkčních (H/QFUN a H/QFUN_10–30)
po měrů (Ayala et al., 2012; Houweling, Head, & Hamzeh, 2009; Kannus, 1994). Obrázek 7 Hodnoty H/QKON poměru se u našich fotbalistů nacházely ve všech měřeních
nad stanovenou hranici 0,6 (60 %), což nepoukazuje na zvýšené riziko zranění
hamstringů a měkkých struktur kolenního kloubu v důsledku dysbalancí mezi ko-
lenními fl exory a extenzory. Změny H/QKON u našeho souboru můžeme porovnat
s výsledky seniorských hráčů výše uvedené studie Eniseler et al. (2012). Při rych-
losti 60° × s–1 došlo u hráčů během přípravného a soutěžního období k nárůstu
hodnot H/QKON z 55 % na 63 % na DDK a z 56 % na 61 % na NDK. Stejně jako
u námi sledovaného souboru ve vybraném období nedošlo při rychlosti 60° × s–1
k významným změnám dysbalance sil kolenních fl exorů a extenzorů. Výsledky H/QKON poměru naší skupiny jsou srovnatelné s výsledky jednorá-
zového měření skupin belgických profesionálních hráčů, hráčů U21 a U17, které
sledovali Lehance et al. (2009) a lepší ve srovnání s výsledky jednorázového
měření skupiny českých elitních juniorských hráčů (průměrný věk 18,5 ±0,4 let)
(Malý, Zahálka, & Malá, 2010). Hodnoty H/QFUN poměru, které dosáhl námi
sledovaný soubor fotbalistů na DDK, se pohybují na hranici 0,7 (70 %), která je
považována za dostatečnou z hlediska stabilizace kolenního kloubu (Dauty et al.,
2003). Za závažné zjištění považujeme zjištěné nižší hodnoty H/QFUN po měru
v jednotlivých měřeních na NDK (první měření: 0,63; druhé měření: 0,59; třetí
měření: 0,58). Tento stav poukazuje na vyšší míru dysbalance mezi silou kolen-
ních fl exorů a extenzorů a tedy narušení dynamické stabilizace kolenního kloubu
v extenzích kolene. Pokles hodnot H/QFUN ve druhém a třetím měření může
ukazovat na rezervy v kondiční přípravě zaměřené na prevenci zra nění. Hodnoty
H/QFUN_10–30 poměru hráčů našeho souboru nelze srovnávat s hodnotami získaný-
mi při výpočtu poměru H/QFUN v plném rozsahu pohybu. Můžeme je orientačně
srovnat pouze s výsledky souboru dospělých rekreačních sportovců a sportovců
(Ayala et al., 2012). Námi sledovaní hráči dosáhli ve všech měřeních v průběhu
RTC vyšších hodnot H/QFUN_10–30 poměru, což ukazuje na lepší předpoklady
hamstringů pro stabilizaci kolenního kloubu v počátečních fázích extenze a tím
ke snižování napětí předního zkříženého vazu. Z hlediska dynamiky změn jsme
zaznamenali nevýznamné snížení hodnot poměru ve druhém a třetím měření
(na konci zimního přípravného, resp. v průběhu soutěžního období), oproti první-
mu měření, což podporuje výše uvedenou domněnku o nedostatcích v tréninku
síly dolních končetin se zaměřením na prevenci zranění. 23 23 DEDIKACE Studie vznikla za podpory Ministerstva školství, mládeže a tělovýchovy České
republiky při řešení výzkumného záměru „Pohybová aktivita a inaktivita obyva-
tel České republiky v kontextu behaviorálních změn“ s identifi kačním kódem
MSM 6198959221 a za podpory výzkumného grantu Univerzity Palackého v Olo-
mouci FTK_2012_006. ZÁVĚRY V průběhu zimního přípravného období a jarního soutěžního období nedošlo
u sledovaného souboru fotbalistů k žádoucím změnám síly kolenních fl exorů
a extenzorů. Hodnoty H/QFUN u NDK, pokles hodnot H/QFUN ve druhém a tře-
tím měření a statisticky významný pokles hodnot H/QFUN_10–30 na DDK mezi
prvním a druhým měřením ukazují na možnost narušení dynamické stabilizace
kolenního kloubu. Rozdílná dynamika změn hodnot poměrů H/QKON, H/QFUN
a H/QFUN_10–30 potvrdila, že tyto charakteristiky poskytují odlišné informace o tě-
lesné kondici hráčů. Z uvedeného důvodu doporučujeme při diagnostice síly
fotbalistů využívat všech tří parametrů. REFERENČNÍ SEZNAM Aagaard, P., Simonsen, E. B., Anderson, J. L., Magnusson, S. P., Bojsen-Moller, F., &
Dyhre-Poulsen, P. (2000). Antagonist muscle contraction during isokinetic knee ex-
tension. Scandinavian Journal of Medicine and Science in Sport, 10, 58–67. Ayala, F., De Ste Croix, M. B., Sainz de Baranda, P., & Santonja, F. (2012). Absolute
reliability of hamstring to quadriceps strength imbalance ratios calculated using peak
torque, joint angle-specifi c torque and joint ROM specifi c torque values. International
Journal of Sports Medicine, 33, 1–8. Bangsbo, J. (1994). Physiological demands. In B. Ekblom (Ed.), Football (Soccer) (pp. 43–59). London: Blackwell Scientifi c. Bompa, T., & Carrera, M. (2005). Periodization training for sports (2nd ed.).Champaign,
IL: Human Kinetics. Botek, Z., Gába, A., Lehnert, M., Přidalová, M., Vařeková, R., Botek, M., & Langer, F. (2010). Condition and body constitution of soccer players in category U19 before
and after completing a preparatory period. Acta Universitatis Palackianae Olomucensis. Gymnica, 40(2), 47–54. 24 Bradley, P. S., Sheldon, W., Wooster, B., Olsen, P., Boanas, P., & Krustrup, P. (2009). High intensity running in English FA Premier League soccer matches. Journal of
Sports Sciences, 27(2), 159–168. Bravo, D. F., Impellizzery, F. M., Rampinini, E., Castagna, C., Bishop, D., & Wisloff , U. (2008). Sprint vs. interval training in football. Internationa Journal of Sports Medicine,
29(8), 668–674. Brito, J., Figueiredo, P., Fernandes, L., Seabra, A., Soares, J., Krustrup, P., & Rebelo, A. (2010). Isokinetic strength eff ects of FIFA’s “The 11+” injury prevention training
programme. Isokinetics and Exercise Science, 18(4), 211–215. Brown, L. E. (2000). Isokinetics in human performance. Champaign, IL: Human Kinetics. Colak, S. (2012). Eff ects of dynamic stretches on isokinetic hamstring and quadriceps
femoris muscle strength in elite female soccer players. South African Journal for Re-
search in Sport, Physical Education and Recreation, 34(2), 15–25. Cometti, G., Maffi uletti, N. A., Pousson, M., Chatard, J. C., & Maff ulli, N. (2001). Iso-
kinetic strength and anaerobic power of elite, subelite and amateur French soccer
players. International Journal of Sports Medicine, 22, 45–51. Coombs, R., & Garbutt, G. (2002). Developments in the use of the hamstrings/quadriceps
ratio for the assessment of muscle balance. Journal of Sports Science and Medicine, 1,
56–62. Cotte, T., & Chatard, J. C. (2011). Isokinetic strength and sprint times in english premier
league football players. Biology of Sport, 28, 89–94. Croisier, J. L. (2004). Factors associated with recurrent hamstring injuries. Sports Me-
dicine, 34, 681–695. REFERENČNÍ SEZNAM Dauty, M., Potiron, M., & Rochcongar, P. (2003). Identifi cation of previous hamstring
injuries by isokinetic concentric and eccentric torque measurement in elite soccer
players. Isokinetics and Exercise Science, 11, 139–144. Dirnberger, J., Kösters, A., & Müller, E. (2012). Concentric and eccentric isokinetic knee
extension: A reproducibility study using the IsoMed 2000-dynamometer. Isokinetics
and Exercise Science, 20, 31–35. Dvir, Z. (2004). Isokinetics. Muscle testing, interpretation and clinical aplications. London:
Elsevier Health Science Dvir, Z., Eger, G., Halperin, N., & Shklar, A. (1989). Thigh muscle activity and anterior
cruciate ligament insuffi ciency. Clinical Biomechanics, 4, 87–91. Eniseler, N., Şahan, Ç., Vurgun, H., & Mavi, H. F. (2012). Isokinetic strength responses
to season-long training and competition in Turkish elite soccer players. Journal of
Human Kinetics, 31, 159–168. Fleck, S. J., & Kraemer, W. (2004). Designing resistance training programs. Champaign,
IL: Human Kinetics. 25 Fleck, S. J., & Kraemer, W. J. (1987). Designing resistance training programs. Champaign,
IL: Human Kinetics. Forbes, H. A., Sutcliff e, S., Lovell, A., McNaughton, L. R., & Siegler, J. C. (2009). Isoki-
netic thigh muscle ratio in youth football: Eff ect of age and dominance. International
Journal of Sports Medicine, 30, 602–606. Fousekis, K., Tsepis, E., & Vagenas, V. (2010). Lower limb strength in professional soccer
players: Profi le, asymmetry, and training age. Journal of Sports Science and Medicine, 9,
364–373. Fry, A. C. (2004). The role of resistance exercise intensity on muscle fi bre adaptations. Sports Medicine, 34, 663–679. Gamble, P. (2010). Strength and conditioning for team sports: Sport-specifi c physical prepa-
ration for high performance. London; New York, N. Y.: Routledge. Gioftsidou, A., Ispirlidis, I., Pafi s, G., Malliou, P., Bikos, C., & Godolias, G. (2008). Iso kinetic strength training program for muscular imbalances in professional soccer
players. Sport Sciences for Health, 2, 101–105. Gioftsidou, A., Beneka, A., Malliou, P., Pafi s, G., & Godolias, G. (2006). Soccer players’
muscular imbalances: Restoration with an isokinetic strength training program. Per-
ceptual and Motor Skills, 103, 151–159. Houweling, T. A. W., & Hamzeh, M. A. (2010). Does knee joint alignment with the axis
of the isokinetic dynamometer aff ect peak torque. Isokinetics and Exercise Science, 18,
217–221. Houweling, T. A. W., Head, A., & Hamzeh, M. A. (2009). Validity of isokinetic testing
for previous injury detection in soccer players. Isokinetics and Exercise Science, 17(4),
213–220. Chan, K. M., & Maff uli, N. (1996). REFERENČNÍ SEZNAM Principles and practice of isokinetics in sports medicine
and rehabilitation. Hong Kong: William & Wilkins Asia-Pacifi c Ltd. Cheung, R. T. H., Smith, A. W., & Wong, D. P. (2012). H:Q ratios and bilateral leg strength
in college fi eld and court sports players. Journal of Human Kinetics, 33, 63–71. Iga, J., George, K., Lees, A., & Reilly, T. (2006). Reliability of assessing indices of isoki-
netic leg strength in pubertal soccer players. Pediatric Exercise Science, 18, 436–445. Kannus, P. (1994). Isokinetic evaluation of muscular performance: Implications for muscle
testing and rehabilitation. International Journal of Sports Medicine, 15, 11–18. Kellis, S., Gerodimos, V., Kellis, E., & Manou, V. (2001). Bilateral isokinetic concentric
and eccentric strength profi les of the knee extensors and fl exors in young soccer
players. Isokinetics and Exercise Science, 9, 31–39. Lehance, C., Binet, J., Bury, T., & Croisier, J. L. (2009). Muscular strength, functional
performances and injury risk in professional and junior elite soccer players. Scandi-
navian Journal of Medicine &Science in Sports, 19, 243–251. 26 Lehnert, M., Urban, J., Procházka, J., & Psotta, R. (2011). Isokinetic strength of knee
fl exors and extensors of adolescent soccer players and its changes based on movement
speed and age. Acta Universitatis Palackianae Olomucensis. Gymnica, 41, 45–53. Li, R. C., Maff ulli, N., Hsu, Y. C., & Chan, K. M. (1996). Isokinetic strength of the quad-
riceps and hamstrings and functional ability of anterior cruciate defi cient knees in
recreational athletes. British Journal of Sports Medicine, 30, 161–164. Malliou, P., Ispirlidis, I., Beneka, A., Taxildaris, K., & Godolias, G. (2003). Vertical jump
and knee extensors isokinetic performance in professional soccer players related to
the phase of the training period. Isokinetics and Exercise Science, 11, 165–169. Malý, T., Zahálka, F., & Malá, L. (2011). Diff erences between isokinetic strength cha-
racteristic of more and less successful professional soccer teams. Journal of Physical
Education and Sport, 11, 306–312. Malý, T., Zahálka, F., & Malá, L. (2010). Isokinetic strength, ipsilateral and bilateral ratio
of peak muscle torque in knee fl exors and extensors in elite young soccer players. Acta
Kinesiologica, 4(2), 14–23. Mujika, I., & Padilla, S. (2000a). Detraining: Loss of training-induced physiological and
performance adaptations. Part I. Sports Medicine, 30(2), 79–87. Perrin, D. H. (1993). Isokinetic exercise and assessment. Champaign, IL: Human Kinetics. Psotta, R., Bunc, V., Mahrová, A., Netscher, J., & Nováková H. (2006). Fotbal – kondiční
trénink. Praha: Grada. Wright, J., Ball, N., & Wood, L. (2009). Fatigue, H/Q ratios and muscle coactivation in
recreational football players. Isokinetics and Exercise Science, 17, 161–167.
Yeung, S. S., Suen, A. M. Y., & Yeung, E. W. (2009). A prospective cohort study of ham-
string injuries in competitive sprinters: Preseason muscle imbalance as a possible risk
factor. British Journal of Sports Medicine, 43, 589–594. REFERENČNÍ SEZNAM Ratamess, N. A. (2008). Adaptations to anaerobic training programs. In T. R. Beachle, &
W. R. Earle (Eds.), Essentials of strength training and conditioning (3rd ed.) (pp. 93–120). Champaign, IL: Human Kinetics. Schmid, S., & Alejo, B. (2002). Complete conditioning for soccer. Champaign, IL: Human
Kinetics. Söderman, K., Alfredson, H., Pietilä, T., & Werner, S. (2001). Risk factors for leg injuries
in female soccer players: A prospective investigation during one outdoor season. Knee
Surgery, Sports Traumatology, Arthroscopy, 9, 313–321. Stølen, T., Chamari, K., Castagna, C., & Wisløff , U. (2005). Physiology of soccer: An
update. Sports Medicine, 35, 501–536. Tourny-Chollet, C., & Leroy, D. (2002). Conventional vs. dynamic hamstring-quadriceps
strength ratios: A comparison between players and sedentary subjects. Isokinetics and
Exercise Science, 10, 183–192. Tourny-Chollet, C., Leroy, D., Léger, H., & Beuret-Blanquart, F. (2000). Isokinetic knee
muscle strength of soccer players according to their position. Isokinetics and Exercise
Science, 8, 187–193. Verheijen, R. (1998). Conditioning for soccer. Spring City: Reedswain. Wirth, K., & Schmidtbleicher, D. (2007). Periodisierung im schnellkrafttraining. Leis-
tugssport, 37(2), 16–20. 27 Wright, J., Ball, N., & Wood, L. (2009). Fatigue, H/Q ratios and muscle coactivation in
recreational football players. Isokinetics and Exercise Science, 17, 161–167. Doc. PaedDr. Michal Lehnert, Dr. Univerzita Palackého v Olomouci
Fakulta tělesné kultury
třída Míru 117
771 11 Olomouc
e-mail: michal.lehnert@upol.cz 28 28 Key words: conventional H/Q ratio, functional H/Q ratio, peak torque, periodi za-
tion, soccer, strength, injury. SEASONAL VARIATION IN ISOKINETIC STRENGTH OF KNEE
FLEXORS AND EXTENSORS IN SOCCER PLAYERS BACKGROUND: Muscle strength is an important factor in soccer from the
performance and health perspective. There is a lack of knowledge about changes
in muscle strength of the knee fl exors and extensors and their ratios during an-
nual training cycle. OBJECTIVES: The aim of this study was to evaluate the seasonal variability
of the observed parameters of isokinetic strength of the knee fl exors and exten-
sors in soccer players, U19, from the performance and health perspective. METHODS: The strength of the knee fl exors and extensors was measured in
players U19 category (n = 9; the average age 18.5 ±0.4 years) on the isokinetic
dynamometer IsoMed 2000 in angular velocity 60° × s–1. Measurement was per-
formed in concentric/concentric and excentric/excentric mode of muscle action
at the beginning of the winter preparatory period, at the end of the preparatory
period and at the end of the spring competitive period. Monitored parameters
were absolute peak torque (PT), conventional H/Q ratio (H/QCON), functional
H/Q ratio (H/QFUN) and functional H/Q ratio in range 10–30° of knee fl exion
(H/QFUN 10–30). RESULTS: Signifi cant change in PT (p < .05) was noted only in cases of the
knee extensors of the nondominant leg in the concentric mode. The evaluation
of imbalance of the knee fl exors and extensors by H/QCON and H/QFUN ratios did
not show any signifi cant changes, but there was found a signifi cant decrease of
the H/QFUN_10–30 ratio in the dominant leg between measurements at the beginning
and at the end of the winter preparatory period. CONCLUSIONS: The results of the current study indicate that throughout
the monitored periods of the annual training cycle desirable changes in knee
fl exors and extensors strength did not occur. The values suggest the disruption of
the dynamic stabilization of the knee joint and increase in injury risk. Diff erent
dynamics of the three observed ratios confi rmed that they provide diff erent in-
formation about the physical fi tness of players. For this reason we recommend
the use of all of them in strength diagnostics in soccer. 29
|
https://openalex.org/W2400439336
|
https://europepmc.org/articles/pmc4882840?pdf=render
|
English
| null |
Research protocol for an epidemiological study on estimating disease burden of pediatric HIV in Belgaum district, India
|
BMC public health
| 2,016
|
cc-by
| 5,082
|
© 2016 The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Research protocol for an epidemiological
study on estimating disease burden of
pediatric HIV in Belgaum district, India Anju Sinha1*, Anita Nath2, Rajeev Sethumadhavan3, Shajy Isac3 and Reynold Washington4 * Correspondence: apradhandr@gmail.com
1Indian Council of Medical Research, New Delhi, India
Full list of author information is available at the end of the article * Correspondence: apradhandr@gmail.com
1Indian Council of Medical Research, New Delhi, India
Full list of author information is available at the end of the article
© 2016 The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Sinha et al. BMC Public Health (2016) 16:446
DOI 10.1186/s12889-016-3132-8 Sinha et al. BMC Public Health (2016) 16:446
DOI 10.1186/s12889-016-3132-8 Background from high to low prevalence states) as major drivers of
the epidemic, the transmission is expected to be affect-
ing the unsuspecting monogamous women, resulting in
a much higher rate of vertical transmission than pro-
jected by the sentinel surveillance data. The existing
PMTCT services based in the public health system may
not detect all the pediatric cases since it does not cover
the private health care providers & NGOs etc. HIV/AIDS is a leading cause of preventable death in
children in 42 countries lacking progress towards MDG4
[1]. Advent of HIV threatens advances in child health made
over few decades. Globally, there were 2.6 million children
living with HIV in 2014, 220,000 new infections among
children, and 150,000 AIDS deaths were reported [2]. Global success of prevention of Mother- to- Child
transmission has brought down the number of newly in-
fected infants by 58 %, however, only a proportion of the
total target women are reached with universal coverage
in developing countries. Even under most optimistic sce-
nario for preventive interventions, expected to reach 95 %
infected mothers, it is estimated that 1.94 million children
will be living with HIV in 2020 [3]. This protocol proposes to use an innovative epidemio-
logic design with a multipronged approach in the form
of three distinct strategies describe under methods that
includes active surveillance with involvement of public
and private health care facilities, blood banks, involvement
of Non Governmental Organizations (NGOs), screen-
ing of PLHIVs & children seeking care in specialized
clinics) to get an accurate disease burden in Belgaum,
Karnataka –a district with HIV prevalence >1 % among
pregnant women. Developing countries account for 95 % of vertical
transmission of HIV which has resulted in an increasing
number of children with HIV [4]. India has an estimated
220,000 children infected by HIV/AIDS wherein about
55,000 to 60,000 children are born every year to mothers
who are HIV infected [5]. The prevalence in India is
lower than many countries in the south East Asian re-
gion. However, a 1 % increase in the HIV prevalence in
adults would result in an additional 5 million infected
people [6], because of the large size of the population. There is a rising trend of HIV infection among monogam-
ous pregnant women in the medium and low prevalence
states in India; therefore, pediatric HIV is poised to be-
come a major public health problem [7]. Background This is likely to
happen in our society where child bearing is considered
essential for a woman and is accorded high priority. This
emphasizes the need for better integration of prevention
of maternal to child transmission (PMTCT) with maternal
and child health services in the country. It is hoped that the methodology used in this study
could serve as a baseline for planning and implementing
HIV prevention and care services in districts with high
HIV prevalence in India. It would be applicable for esti-
mating the burden of other diseases and may be used as
a benchmark. Abstract BMC Public Health (2016) 16:446 Page 2 of 7 Page 2 of 7 Page 2 of 7 Methods The study is implemented in Belgaum district (Fig. 1),
which is a Category“A” district as defined by NACO. The district, Belgaum is chosen after conducting a baseline
assessment of three ‘A’ category districts in India. The
multipronged approach proposed in the study is based
on three strategies aimed at different source populations
contributing to pediatric disease burden. A conceptual
framework of the study is given in Fig. 2. Strategy I: Would use a longitudinal approach aiming
early case detection in infants (0–18 months) born to
HIV positive women who are registered at PPTCT cen-
ter in the district. Pregnant women would be followed
through their pregnancy & delivery, early testing in in-
fants using DNA PCR dry blood spot (DBS) method
would be conducted at 6–8 weeks, & 6 months of age
for detection of HIV infection. Infants would be followed
up for HIV testing till the age of 20 months. From the very beginning of the global response to the
HIV/AIDS pandemic, prevention has been marginalized. There is a need to strengthen prevention efforts by using
data to determine the most appropriate interventions,
address the factors that put women and girls at greater
risk and emphasize evidence-based approaches [8]. It is
important to estimate the disease burden of Pediatric HIV
infection in infants born to known HIV positive mothers,
and to start the anti-retroviral treatment (ART) for the in-
fected children at the earliest, so as to save and improve
the lives of affected children. p
g
g
Eligibility for strategy I: 1) HIV infected pregnant
women residing in any of the 10 ‘taluka’ of Belgaum district,
2) All live born infants born to these pregnant women 3)
Mother/parent who are willing to give consent to under-
take the age-specific HIV blood test for their infant. There is lack of information on the epidemiology of
pediatric HIV infection in India. Most of the studies that
have been done are hospital based being clinical in nature
[9]. It is important to diagnose the burden of Pediatric HIV
infection in order to develop evidence driven management. There is lack of information on the epidemiology of
pediatric HIV infection in India. Most of the studies that
have been done are hospital based being clinical in nature
[9]. It is important to diagnose the burden of Pediatric HIV
infection in order to develop evidence driven management. Abstract Background: Pediatric HIV is poised to become a major public health problem in India with the rising trend of HIV
infection in pregnant women (Department of AIDS Control, Ministry of Health and Family Welfare, http://www.naco. gov.in). There is lack of information on the epidemiology of pediatric HIV infection in India. Existing surveillance
systems tend to underestimate the Pediatric burden. The overall aim of the present study is to estimate the disease
burden of pediatric HIV among children in Belgaum district in the state of Karnataka in Southern India. An
innovative multipronged epidemiological approach to comb the district is proposed. Methods: The primary objectives of the study would be attained under three strategies. A prospective cohort
design for objective (i) to determine the incidence rate of HIV by early case detection in infants and toddlers
(0–18 months) born to HIV infected pregnant women; and cross sectional design for objectives (ii) to determine the
prevalence of HIV infection in children (0–14 years) of HIV infected parents and (iii) to determine the prevalence of HIV
in sick children (0–14 years) presenting with suspected signs and symptoms using age specific criteria for screening. Burden of pediatric HIV will be calculated as a product of cases detected in each strategy multiplied by a net inflation
factor for each strategy. Study participants (i) (ii) (iii): HIV infected pregnant women and their live born children (ii) Any HIV-infected
man/woman, of age 18–49 years, having a biological child of age 0–14 years (iii) Sick children of age 0–14
years presenting with suspected signs and symptoms and satisfying age-specific criteria for screening. Setting and conduct: Belgaum district which is a Category ‘A’ district (with more than 1 % antenatal prevalence
in the district over the last 3 years before the study). Age-appropriate testing is used to detect HIV infection. Discussion: There is a need to strengthen existing pediatric HIV estimation methods in India and other
developing countries. We hope that the novel methodology emanating from this study would be applicable
for estimating the burden of HIV in other settings and it would be adaptable for estimating the burden of other
infectious/chronic diseases. Findings from this study will give future direction to the national program for prevention
and control of HIV in India and other developing countries. Keywords: HIV infection, Pediatric, Burden, Estimation, Case detection Sinha et al. Strategy I The HIV positive pregnant women receive antiretroviral
prophylaxis in the district. Assuming a risk of mother to
child transmission as 20 %, a 20 % relative precision at
95 % confidence level, the number of children required
is 461 with a design effect of 1.2. Setting and design The study is being conducted in Belgaum, a Category ‘A’
district (with more than 1 % antenatal prevalence in the
district over the last 3 years before the start of the study)
as defined by the National AIDS Control Organization
(NACO). The district is divided into ten sub-districts or
‘talukas’ [Fig. 1]. We are using a multipronged approach
by adopting three strategies to enhance the detection of
pediatric HIV infection [Fig. 2]. Strategy III Strategy III
Assuming that 10 % of the sick children meeting the cri-
teria for testing at health facilities in the district could
be infected, at 90 % confidence level with 20 % precision,
sample size required is 1037 with a design effect of 1.2. Strategy II Assuming that 20 % of the children of parents tested
positive are infected, the sample size required at 95 %
confidence level with 20 % relative precision is 461 with
a design effect of 1.2. During the preparatory phase a mapping of all existing
health care facilities (HCFs) in Belgaum district [11] has
been conducted by consolidating various secondary sources
of information, key informant survey and snow-ball
technique [13, ref published report], Government and
private HCFs belonging to all ten talukas of Belgaum
District providing HIV testing will be covered under
strategy I and strategy II. Activities for strategy III will
be conducted in four ‘talukas’; HCFs with “in-patient
care facility, “an in-house physician or pediatrician”,
and “at least 30 pediatric cases in a month” and all govern-
ment and subsidiary HCFs, are planned to be included. These four ‘talukas’ have been identified based on the HIV
prevalence representing each of the low, medium and high
prevalence ‘talukas’. Methods Even though the overall prevalence of HIV in India is
0.27 [10] per cent, the country is divided into three
zones based on the prevalence as high, medium and low
prevalence states. With migrant populations (travelling Strategy II: Would use a cross sectional approach for
case detection in children by family screening of HIV
positive parents (PLHAs) referred from ICTC centers,
blood banks and community based NGOs in all ten talukas
of Belgaum. If a positive male is detected his wife and chil-
dren would be tested, if a positive female is detected her Even though the overall prevalence of HIV in India is
0.27 [10] per cent, the country is divided into three
zones based on the prevalence as high, medium and low
prevalence states. With migrant populations (travelling Page 3 of 7 Sinha et al. BMC Public Health (2016) 16:446 Fig. 1 Map of Belgaum District. (Source: www.southindiaonline.com/karnataka/belgaum/locationmap.htm) Fig. 1 Map of Belgaum District. (Source: www.southindiaonline.com/karnataka/belgaum/locationmap.htm) Strategy III: Would use screening of sick children visit-
ing health care facilities, in four talukas of Belgaum. IMCI HIV criteria has been adapted by Indian experts to
include children >5 upto 14 years into the algorithm. Sick
children presenting with common signs symptoms, at
shortlisted Govt./Pvt. Health facilities would be assessed
and screened. Those screened positive would be subjected
to age appropriate HIV testing. husband and children would be tested. Age appropriate
testing would be conducted in children (DNA PCR DBS
for <18 months, and antibody based HIV testing- ELISA
for children aged >18 up to 14 years). This would provide a
cross sectional prevalence among 0–14 years age group. p
g
y
g g
p
Eligibility for strategy II:1) Any HIV infected man/
woman, of age 18–49 years, having a biological child of
0–14 years, residing in any ‘taluka’ of Belgaum district,
2) Those willing to give consent to test their spouse and
children for HIV during the study period. Eligibility for strategy III: 1) Children 5–14 years fulfilling
adapted IMCI HIV criteria, or having one of the ‘special Sinha et al. BMC Public Health (2016) 16:446 Page 4 of 7 Fig. 2 Conceptual framework of the study Fig. 2 Conceptual framework of the study clues’ in the algorithm, 2) Parents who are willing to
provide consent undertake the age-specific test for their
child.3) Resident of Belgaum district. Primary outcomes Strategy II Aims for case detection in children born to
HIV positive parents referred from ICTC centers, blood
banks and NGOs in the districts by age appropriate testing
(DNA PCR DBS for <18 months, antibody based HIV test-
ing- ELISA/Rapid Tests for children aged >18 months up
to 18 years). Strategy I: Cumulative incidence will be calculated as the
number of new infections per total number of children
at risk. Age-specific cumulative incidence rate of HIV in-
fection will also be calculated. The denominator for all
the indicators is total person-months. A child will be at
risk till first positive result by any test at any age, by age
appropriate testing. For censored observations, time will
be duration of follow up. Public and private Health care facilities identified
through the mapping exercise, that provide HIV testing
will be visited twice a week, by the study team, to collect
information about HIV infected individuals aged 18–49
years. The list would be refined after removing dupli-
cates etc as described under strategy I. These individuals
would be contacted to find out those having a biological
child aged 0–14 years (wherever known). The spouse
and all children in the nuclear family of the positive per-
son (Male or Female) would undergo the age-appropriate
HIV test. Data will be collected on a household form; dur-
ing the first contact, or as and when the family members
complete testing. A unique identification number for the
positive person as well as other family members testing
positive would be created. Strategy II: Prevalence of HIV infection among chil-
dren 0–14 years of age would be calculated. Two levels
of analysis are proposed using the following denomina-
tors: (i) Total children (0–14 year) tested, and (ii) Total
children (0–14 year) enrolled (as refusals for testing are
expected). Strategy III: Prevalence of HIV among sick children 0–
14 years of age would be calculated. Analysis would be
conducted at two levels; using the denominators of total
number of children 0–14 years who have been enrolled
or tested. From all the strategies: Burden of pediatric HIV in the
population can be calculated as a product of cases de-
tected in each strategy multiplied by the Net inflation
factor, and then consolidated for the total study. Study enrolment and data collection Strategy I: Aims early case detection in infants (0–18
months) born to HIV positive women registered at PPTCT
center in the district by the DNA PCR dry blood spot
(DBS) method at 4–6 weeks and 6–9 months of age. The
study team will visit the identified health care facilities twice
a week. A crude line list will be made from secondary data
collected from various HCFs providing HIV testing facilities
to all the positive pregnant women in Belgaum district. The Sinha et al. BMC Public Health (2016) 16:446 Page 5 of 7 Page 5 of 7 list would be refined by removing duplicates and applying
eligibility criteria. All HIV infected pregnant women found
to be eligible would be contacted over phone (wherever
possible) and subsequently visited at their home (if permit-
ted) or elsewhere at her convenience (if home visits are not
permitted). Possible deletions could be due to migration,
death or wrong addresses. In case of any change in address,
this would be updated in the records. The list of eligible
contacted women would be updated for any corrections in
addresses, landmarks etc. Possible deletions could be due
to those testing positive after delivery, MTP/abortion, or
wrong reporting of pregnancy. IRB approval is obtained
from St. John’s Research Institute, Bangalore. Informed
written consent would be obtained from HIV infected preg-
nant women or their spouses, for enrolling them as a study
participant as per ethics guidelines. case history) have been added to make the screening for
HIV age appropriate. Operational definitions have been
developed for each criteria included in the screening al-
gorithm. All participating physicians from the selected
health care facilities have been trained in the use of the
screening algorithm. These facilities and doctors would
be visited once a week by the research team. Information
about children satisfying the screening criteria for HIV
testing and their referrals, would be collected, children
would be tested and tracked for test results. Primary outcomes Strategy III Aims for case detection in sick children
(0 months to 18 years) presenting with suspected signs
symptoms at selected heath care facilities, & screened
positive by the modified IMNCI HIV algorithm. Age ap-
propriate HIV testing would be done. Data management & statistical analysis Data Management: Data entry will be done using Micro-
soft Access Data will then be exported to SPSS software
version 22.0. for further analysis. Data Analysis: Will be done as per the Statistical Ana-
lytical Plan developed by the research team. Each ‘taluka’
is regarded as a cluster for analysis purposes. Crude and
adjusted odds ratios will be computed to assess presence
of association of child positivity with different variables
and the magnitude of statistical significance. A P-value
of less than 0.05 at 95 % CI data will be considered as
statistically significant. Each recruited pregnant women will be visited once in
a month until delivery and thereafter till (i) the infant at-
tains 18 months of age, or (ii) till end study, or (iii) the
family migrates permanently out of the district, or (iv)
the death of the infant. Each mother-infant pair will be
given a unique identification number. Demographic in-
formation at the household level and Information on
mother and infant would be collected. Availability of data and materials This is a protocol for an epidemiological study; hence there are presently no
data to be shared. Funding
d
f Funding for the study is provided by the Indian Council of Medical Research
(ICMR). Funding agency played no role in the study design, data collection,
analysis and interpretation, writing of the report or decision to submit it for
publication. Abbreviations ART, antiretroviral therapy; DAPKU, District AIDS prevention and control unit;
DBS, dot blood spot; DHO, District Health Officer; DNA PCR, deoxyribonucleic
acid polymerase chain reaction; ELISA, enzyme linked immune sorbant assay;
HCF, health care facility; ICMR, Indian Council of Medical Research; ICTC,
integrated counseling and testing centre; IMCI, integrated management of
childhood illnesses; IRB, Institutional Review Board; KSAPS, Karnataka State
AIDS Prevention Society; MDG, millennium development goals; MTP, medical
termination of pregnancy; NACO, National AIDS Control Organization; NGO,
Non-Governmental Organization; PLHIV, people living with HIV; PMTCT,
prevention of mother to child transmission; PPTCT, prevention of parent to
child transmission; UNICEF, United Nations Children Fund; WHO, World
Health Organization Strategy III : based on actual/projected 0–14 year
population during the study period, estimated number of
0–14 year children experiencing any morbidity, estimated
morbid children reaching a HCF for care, estimated chil-
dren satisfying screening algorithm, and suitable inflation
factors for geographical and institutional factors, morbid
children not reaching selected HCF but reaching other
facilities in the district, un-screened, non-enrolled and
untested children. (Further details on calculation of Net
inflation factor and burden of pediatric HIV are given
as Additional file 1). Secondary outcomes The following indicators will be analyzed and inferred
upon: Child mortality rates- Infant mortality rate, Neonatal
mortality rate, Early neonatal mortality rate & Perinatal
mortality rate. Pregnancy wastage: Abortion and stillbirth
rate; maternal mortality rate and its causes. The results are also expected to inform the reasons for
gap or delay between detection of HIV, pre-anti-retroviral
treatment registration and anti-retroviral treatment initi-
ation. It is also envisaged to retain and follow up this cohort
of positive women and their children for program relevant
studies in the next phase. Authors’ contributions This work was carried out in collaboration between all authors. Author AS
conceptualized the study, developed the draft proposal, contributed towards
selection of study district selected the district for study implementation and
contributed towards the study design. Author AN did drafting of the
manuscript. Author RNS contributed to implementation of the project and
provided comments and guidance on the draft. Author SI conceptualized and
wrote the methods section. Author RW conceptualized the paper, revised and
refined methods adapting to the local context, reviewed sections and overall
supervision of the project. All authors read and approved the final manuscript. Discussion The present study seeks to measure the burden of pediatric
HIV in a district of high HIV prevalence. Prevalence re-
ported by ongoing surveillance underestimates the burden. Effort is being made in the current study to include health
care facilities belonging to the private health system, and
also the NGOs & CBOs. Three strategies have been de-
signed to cover all the age groups which fall in the pediatric
range; as well as to include all new and pre-existing HIV in-
fections. It is hoped that the novel methodology emanating
from this study would be applicable for estimating the
burden of HIV in other settings and it would be adaptable
for estimating the burden of other infectious/chronic dis-
eases. Knowledge that is generated in this study could be
used to strengthen existing pediatric HIV intervention
strategies and design novel measures towards prevention
and control of HIV infection in India and other developing
countries. Additional file Additional file Strategy II: based on the actual/projected 18–49 year
population during the study period, estimated number
of 18–49 year population having a child of age 0–14 years,
proportion of eligible index persons not enrolled in the
study and proportion of eligible children not tested. Additional file 1: Calculation of Net Inflation factor. (DOC 175 kb) Acknowledgements The authors wish to thank officials of National AIDS Control Organization
(NACO), New Delhi, Karnataka State AIDS Prevention Society (KSAPS),
Bangalore, National Rural Health Mission (NRHM), Bangalore, District Health
Office (DHO), Belgaum, District AIDS Prevention and Control Unit (DAPCU),
Belgaum, for providing permission, support and data for the study. Indian
Council of Medical Research (ICMR), New Delhi has supported the research
project financially, and has also guided the project by providing support
through an expert Project Advisory Group (Dr. N.K. Arora, Dr. R.M.Pandey, Dr. Ajay Khera, Dr. Rakesh Lodha, Dr. Vasantha Thavraj). ICMR also facilitated
adaptation of the generic IMCI-HIV algorithm to include ages up to 14 years
(A Sub-Committee was appointed by ICMR, members included Dr. Jagdish
Chandra, Dr. Vinod Anand and Dr. Rakesh Lodha), and training the health
care providers in this algorithm. The contribution and support of administra-
tors and staff of St. John’s Research Institute, Bangalore, Karnataka Health Pro-
motion Trust, Bangalore, various government and private health care facilities
and non-government organizations (NGOs) in Belgaum district is humbly ac-
knowledged. The authors also wish to acknowledge the field and support
staff of the research study for their continued & sincere efforts. Competing interests Competing interests
The authors declare that they have no competing interests. p
g
The authors declare that they have no competing interests. Determination of ‘Net inflation factor’ Generic WHO/UNICEF IMCI-HIV algorithm has been
modified for the ICMR study by an expert committee to
include children up to the age of 14 years. Sign symp-
toms from the IAMI and ‘special clues’ (elements from Strategy I: The net inflation factor would be derived based
on the estimated number of pregnancies in the district, and
proportion of un-tested pregnancies, pregnant mothers not
enrolled in the study and un-tested children. Sinha et al. BMC Public Health (2016) 16:446 Page 6 of 7 Sinha et al. BMC Public Health (2016) 16:446 Sinha et al. BMC Public Health (2016) 16:446 Sinha et al. BMC Public Health (2016) 16:446 Received: 29 March 2016 Accepted: 18 May 2016 Received: 29 March 2016 Accepted: 18 May 2016 References
1. Coovadia H, Schaller JG. HIV/AIDS in children: a disaster in the making. Lancet. 2008;372(9635):271–3. 2. The Global HIV/AIDS Epidemic http://kff.org/global-health-policy/fact-sheet/
the-global-hivaids-epidemic/accessed 2015-12-18 10:46:31. 3. Luzuriaga K, Mofenson LM. Challenges in the elimination of pediatric HIV-1
infection. N Engl J Med. 2016;374:761–70. doi:10.1056/NEJMra1505256. 4. Lala MM, Merchant RH. Vertical transmission of HIV-an update. Indian J
Pediatr. 2010;77:1270–6. 5. UNICEF India. Available on www.unicef.org/india/children_2358.htm. Accessed on 4 Feb 2015. 6. Prasada Rao JVR, Ganguly NK, Mehendale SM et al: India's response to the
HIV epidemic.www.thelancet.com Vol 364 October 9, 2004. 7. Department of AIDS Control. Ministry of Health and Family Welfare. Annual
Report 2013-14. Accessed on 8 March 2015. Available on http://www.naco. gov.in% 20msln s/NACO_English%202013-14.pdf
8. Horton, Richard and Das, Pam. Putting Prevention at the Forefront of
HIV/AIDS [online]. Aboriginal and Islander Health Worker Journal, Vol. 32, No. 6, Nov/Dec 2008: 26-27. Availability: <http://www.Search. informit.com.au/documentSummary;dn=614620910946016 =IELIND >
ISSN: 1037-3403. [cited 09 Mar 16]. 9. Lodha R, Singhal T, Jain Y, et al. Pediatric HIV in a tertiary care centre in
North India: Early impressions. Indian Pediatr. 2000;37:982–6. 10. National AIDS Control Organization Annual Report 2013-2014. Department
of AIDS control, Ministry of Health and Family welfare http://www.naco.gov. in %20mslns/NACO_English%202013-14.pdf. 11. Mapping of Health Care Facilities in Belgaum District; Estimating Disease
Burden of Pediatric HIV in a “A” Category district: An ICMR Task Force Study. www.icmr.nic.in. St. John’s Research institute, Karnataka Health Promotion
Trust, Karnataka State AIDS Prevention Society. Current status Ethics approval has been obtained from St. John’s Research Institute,
Bangalore the agency implementing the study. Informed written consent
would be obtained from HIV infected pregnant women or their spouses, for
enrolling them as a study participant as per ethics guidelines. Ethics approval has been obtained from St. John’s Research Institute,
Bangalore the agency implementing the study. Informed written consent
would be obtained from HIV infected pregnant women or their spouses, for
enrolling them as a study participant as per ethics guidelines. The study is nearing completion. The development of
study database and data cleaning is currently going on. Page 7 of 7 Author details
1I di
C
il 1Indian Council of Medical Research, New Delhi, India. 2Public Health
Foundation of India, Bangalore, Karnataka, India. 3Karnataka Health Promotion
Trust, Bangalore, Karnataka, India. 4Karnataka Health Promotion Trust, St
John’s Research Institute, Bangalore, Karnataka, India. References • We accept pre-submission inquiries
• Our selector tool helps you to find the most relevant journal
• We provide round the clock customer support
• Convenient online submission
• Thorough peer review
• Inclusion in PubMed and all major indexing services
• Maximum visibility for your research
Submit your manuscript at
www.biomedcentral.com/submit
Submit your next manuscript to BioMed Central
and we will help you at every step: References 1. Coovadia H, Schaller JG. HIV/AIDS in children: a disaster in the making. Lancet. 2008;372(9635):271–3. 1. Coovadia H, Schaller JG. HIV/AIDS in children: a disaster in the making. Lancet. 2008;372(9635):271–3. 2. The Global HIV/AIDS Epidemic http://kff.org/global-health-policy/fact-sheet/
the-global-hivaids-epidemic/accessed 2015-12-18 10:46:31. 2. The Global HIV/AIDS Epidemic http://kff.org/global-health-policy/fact-sheet/
the-global-hivaids-epidemic/accessed 2015-12-18 10:46:31. 3. Luzuriaga K, Mofenson LM. Challenges in the elimination of pediatric HIV-1
infection. N Engl J Med. 2016;374:761–70. doi:10.1056/NEJMra1505256. 3. Luzuriaga K, Mofenson LM. Challenges in the elimination of pediatric HIV-1
infection. N Engl J Med. 2016;374:761–70. doi:10.1056/NEJMra1505256. 4. Lala MM, Merchant RH. Vertical transmission of HIV-an update. Indian J
Pediatr. 2010;77:1270–6. 5. UNICEF India. Available on www.unicef.org/india/children_2358.htm. Accessed on 4 Feb 2015. 6. Prasada Rao JVR, Ganguly NK, Mehendale SM et al: India's response to the
HIV epidemic.www.thelancet.com Vol 364 October 9, 2004. 7. Department of AIDS Control. Ministry of Health and Family Welfare. Annual
Report 2013-14. Accessed on 8 March 2015. Available on http://www.naco. gov.in% 20msln s/NACO_English%202013-14.pdf 8. Horton, Richard and Das, Pam. Putting Prevention at the Forefront of
HIV/AIDS [online]. Aboriginal and Islander Health Worker Journal, Vol. 32, No. 6, Nov/Dec 2008: 26-27. Availability: <http://www.Search. informit.com.au/documentSummary;dn=614620910946016 =IELIND >
ISSN: 1037-3403. [cited 09 Mar 16]. 8. Horton, Richard and Das, Pam. Putting Prevention at the Forefront of
HIV/AIDS [online]. Aboriginal and Islander Health Worker Journal, Vol. 32, No. 6, Nov/Dec 2008: 26-27. Availability: <http://www.Search. informit.com.au/documentSummary;dn=614620910946016 =IELIND >
ISSN: 1037-3403. [cited 09 Mar 16]. 9. Lodha R, Singhal T, Jain Y, et al. Pediatric HIV in a tertiary care centre in
North India: Early impressions. Indian Pediatr. 2000;37:982–6. 10. National AIDS Control Organization Annual Report 2013-2014. Department
of AIDS control, Ministry of Health and Family welfare http://www.naco.gov. in %20mslns/NACO_English%202013-14.pdf. 11. Mapping of Health Care Facilities in Belgaum District; Estimating Disease
Burden of Pediatric HIV in a “A” Category district: An ICMR Task Force Study. www.icmr.nic.in. St. John’s Research institute, Karnataka Health Promotion
Trust, Karnataka State AIDS Prevention Society. 11. Mapping of Health Care Facilities in Belgaum District; Estimating Disease
Burden of Pediatric HIV in a “A” Category district: An ICMR Task Force Study. www.icmr.nic.in. St. John’s Research institute, Karnataka Health Promotion
Trust, Karnataka State AIDS Prevention Society. Submit your next manuscript to BioMed Central
and we will help you at every step: • We accept pre-submission inquiries
• Our selector tool helps you to find the most relevant journal
• We provide round the clock customer support
• Convenient online submission
• Thorough peer review
• Inclusion in PubMed and all major indexing services
• Maximum visibility for your research
Submit your manuscript at
www.biomedcentral.com/submit
Submit your next manuscript to BioMed Central
and we will help you at every step:
|
https://openalex.org/W4292640246
|
https://periodicos.ufba.br/index.php/crh/article/download/18956/12314
|
Portuguese
| null |
REPRESENTAÇÃO, PARTIDOS E SOCIEDADE CIVIL NA ARGENTINA E NO BRASIL
|
Caderno CRH
| 2,008
|
cc-by
| 13,405
|
* Professora de Ciências Políticas na Universidade do Novo
México. Research Fellow in Politics, Centre for Brazilian Studies.
MSC05 3070, University of New Mexico, Albuquerque, NM
87131. hochstet@unm.edu. REPRESENTAÇÃO, PARTIDOS E SOCIEDADE CIVIL NA
ARGENTINA E NO BRASIL1 Kathryn Hochstetler*
Elisabeth Jay Friedman** ** Professora do Departamento de Política na Chair of the
Latin American Studies Programna Universidade de São
Francisco. ejfriedman@usfca.edu. 1 Tradução de Elisa Larroude e revisão técnica de Diogo
Antonio Rodriguez e Roberta Soromenho. REPRESENTAÇÃO POR ORGANIZAÇÕES DA
SOCIEDADE CIVIL NO BRASIL E NA ARGENTINA pos informais de cidadãos e organizações não go-
vernamentais (ONGs)” (Chandoke, 2005, p.308;
Bartolini; Mair 2001; Lawson; Merkl, 1988;
Lawson; Poguntke, 2004; Pearce, 2004). Para tan-
to, examinamos práticas recentes de representa-
ção no Brasil e na Argentina, dois países em que
os partidos políticos têm passado por fortes cri-
ses, após décadas de reações mistas aos seus siste-
mas partidários. Em momentos como esses, a subs-
tituição de partidos por OSCs deveria ser muito
evidente. Como demonstramos a seguir, a crise
partidária argentina era consideravelmente mais
profunda que a brasileira; pela hipótese de crise
de representação, portanto, deveria haver mais
provas de uma troca por formas não-partidárias
de representação na Argentina. Quão bem as organizações da sociedade ci-
vil (OSCs) representam os cidadãos? No contexto
da crise dos partidos políticos na América Latina
e em boa parte do mundo democrático, essa per-
gunta tem se tornado particularmente relevante. Este artigo indaga se organizações da sociedade civil
(OSCs) podem desempenhar, e se de fato desem-
penham, a função essencial de representação nes-
ses tempos de crise partidária. Em especial, inves-
tigamos a seguinte hipótese de crise de representa-
ção: de que “cidadãos, em todo o mundo, troca-
ram formas mais antigas e tradicionais de repre-
sentação, como partidos políticos e sindicatos, por
‘novos’ modelos, como movimentos sociais, gru- CADERNO CRH, Salvador, v. 21, n. 52, p. 47-66, Jan./Abr. 2008 Começamos por um exame teórico a respei-
to de como as OSCs podem desempenhar a fun-
ção de representação, usando o modelo de repre-
sentação partidária como guia. Sobre a relação en-
tre representação partidária e de OSCs, pergunta-
mos: é complementar ou concorrente? Nas próxi-
mas seções empíricas, caracterizamos a natureza
das recentes crises partidárias nesses dois países, 47 REPRESENTAÇÃO, PARTIDOS E SOCIEDADE CIVIL ... ideais. As OSCs costumam pretender dar voz po-
lítica àqueles marginalizados do sistema político
formal. Como nos partidos, há grande variação
entre seus graus de institucionalização e estrutura
geral. Organizações não governamentais (ONGs)
tendem a ser mais estruturadas, com equipe per-
manente e financiamento de seus associados ou
fontes externas. Movimentos sociais não são
institucionalizados e freqüentemente dependem de
uma rede preexistente de associações, mas tornam-
se visíveis apenas esporadicamente. Suas estraté-
gias de mobilização também variam, desde lobby
com tomadores de decisão a apoio ao desenvolvi-
mento comunitário à mobilização de milhares de
pessoas para manifestações públicas. O grande le-
que de ações e aparências de OSCs sugere que é
preciso revisitar e revisar conceitos de representa-
ção democrática na região (Friedman; Hochstetler,
2002; Gurza Lavalle; Houtzager; Castello, 2006). bem como o papel dos chamados novos modos de
representação durante e após as crises. Concluí-
mos que não houve substituição de partidos por
OSCs como mecanismos de representação dos
valores e interesses dos cidadãos – e nem sequer
houve tentativa de substituição (exceto por um bre-
ve período no auge da crise argentina). Em ambos
os países, porém, as OSCs melhoraram a qualida-
de da representação para cidadãos. ORGANIZAÇÕES DA SOCIEDADE CIVIL E
PARTIDOS POLÍTICOS COMO MECANISMOS
DE REPRESENTAÇÃO ado , . ,
. 5 , p. 66, Ja ./ b . 008
Em sua essência, a representação democrá-
tica exige que os valores e interesses dos cidadãos,
de alguma forma, guiem aqueles que falam por eles
em processos políticos coletivos. Assim sendo, a
representação é fundamental para outros proces-
sos democráticos vitais como responsabilização e
legitimidade. Processos de representação são par-
ticularmente relevantes – e difíceis – em democra-
cias de transição, e diversos estudos recentes se
desafiaram a entender a representação em seus
aspectos teóricos e empíricos. Há um estranho
descompasso entre os estudos teóricos e a maioria
dos estudos empíricos da representação. Teorica-
mente, a representação é um conceito disputado,
com múltiplos significados de base histórica e fi-
losófica (Manin, 1997; Pitkin, 1967; Saward, 2001). Empiricamente, os estudiosos tendem a restringir
seus domínios, limitando-se ao mundo dos parti-
dos, eleições e sistemas eleitorais, freqüentemente
sem comentários ou justificativas especiais
(Kitschelt, 2000; Powell, 2004; Przeworski; Stokes;
Manin, 1999). Este artigo questiona essa restrição
empírica e defende que OSCs também têm o po-
tencial de desempenhar importantes funções de
representação política. Como agentes de representação, as OSCs
diferem de partidos de duas maneiras fundamen-
tais: não são eleitas por um eleitorado e não gover-
nam. Dessa forma, muitos analistas hesitam em
utilizar o termo representação para descrever as
atividades de OSCs (Mainwaring, 2006; Norden,
2006; Peruzzotti, 2006). De forma distinta, segui-
mos a visão de Rehfeld (2006), que defende que
tanto bom senso quanto compreensões teóricas da
representação exigem uma definição mais ampla
do que aquela baseada no processo eleitoral demo-
crático. Ele vê representação sempre que existe “o
juízo de algum público de que determinado indi-
víduo, e não outro, representa um grupo no de-
sempenho de determinada função” (Rehfeld, 2006,
p.2). Por exemplo, quando um oficial do governo
da Líbia se dirige à Organização Mundial do Co-
mércio em nome da Líbia, essa pessoa é conside-
rada um representante, ainda que não tenha sido
observada nenhuma das regras eleitorais ou de-
mocráticas de reconhecimento e representação
(2006, p.1). Rehfeld observa algo ainda mais rele-
vante para este estudo: que ONGs buscam repre-
sentar os interesses daqueles que “não têm voz na
seleção de seus representantes” (tais como os pri-
sioneiros de guerra defendidos pela Cruz Verme- REPRESENTAÇÃO COMO RELACIONAMENTO
COM O ELEITORADO OU CIDADÃOS lha) e que talvez nem sejam humanos (como a rela-
ção com o meio-ambiente para grupos ambientalistas)
(2006, p.1). O público pertinente dependerá da fi-
nalidade da representação; suas regras decisórias
para reconhecimento podem ser ou não formaliza-
das e bem formuladas, anteriormente à instancia de
representação. O reconhecimento do público é um
fator-chave na identificação de instâncias de repre-
sentação, em vez de instituições. O primeiro conjunto de funções envolve as
relações do partido com o eleitorado. Nesse papel,
os partidos atuam como intérpretes do público
votante, apresentando diferentes modos de com-
preender as questões políticas e ajudar os eleito-
res a determinarem suas identidades e interesses
políticos gerais. Para tanto, alguns partidos se or-
ganizam intensamente, articulando-se profunda-
mente com a sociedade civil. Outros, geralmente
em sistemas unipartidários, têm interpenetração
com o Estado. Mas muitos atuam somente como
veículos eleitorais que ficam um tanto dormentes
no ínterim dos ciclos eleitorais.2 Os vínculos entre
partidos e sociedade já são fracos há muito tempo
na América Latina, mas continuam a se enfraque-
cer no ciclo democrático pós-transição. Mesmo em
lugares onde os sistemas partidários antes se base-
aram em conexões mais programáticas e
participativas de massa, tais vínculos já se afrou-
xaram. Prevalecem as conexões carismáticas,
clientelistas e personalistas. Conseqüentemente, as
relações entre partido e sociedade se fundamen-
tam quase exclusivamente nas ambições eleitorais
dos partidos – uma relação tênue, com pouco inte-
resse e legitimidade para os cidadãos (Pearce, 2004;
Roberts, 2002; Taylor-Robinson, 2001).3 Há pro-
cessos similares que ocorrem na Europa Ociden-
tal, ainda que historicamente partam de níveis mais
altos de integração (Dalton; Wattenberg, 2000;
Lawson; Poguntke, 2004). Em novas e antigas de-
mocracias, os cidadãos são cada vez mais consu-
midores e não sujeitos da política (Bartolini; Mair,
2001, p.333). Com foco especial em representação e OSCs,
defendemos que tanto públicos de cidadãos quan-
to de governo freqüentemente aceitam OSCs como
representantes de valores e interesses coletivos
específicos – como também fazem muitas das pró-
prias OSCs (Gurza Lavalle; Houtzager; Castello,
2006). Para discutir como isso ocorre, utilizamos
abaixo a influente formulação de V.O. Key sobre
representação partidária. Para ele, partidos políti-
cos desempenham três grandes grupos de funções
representativas: partidos no eleitorado, partidos
como organizações, e partidos no governo (Dalton;
Wattenberg, 2000, p.5-10). CADERNO CRH, Salvador, v. 21, n. 52, p. 47-66, Jan./Abr. 2008 CADERNO CRH, Salv
Aqui definimos OSCs como organizações
voluntárias que podem se formar para promover o
auto-interesse de seus membros, o bem da socie-
dade, a provisão de serviços e (ou) advocacy, em
nome de uma determinada causa ou conjunto de 48 48 Kathryn Hochstetler, Elisabeth Jay Friedman 3 Partidos excessivamente enraizados na sociedade, che-
gando a sufocar outras instituições, constituem um pro-
blema mais raro na América Latina. Dois exemplos his-
tóricos de tais sistemas partidários, agora já bastante
alterados, vêm da Venezuela e do México. 2 A clássica distinção de Panebianco entre partidos “buro-
cráticos de massa” e “profissionais-eleitorais” separa os
partidos pelo grau de organização e penetração social
(Panebianco, 1988). REPRESENTAÇÃO POR MEIO DE FUNÇÕES
ORGANIZACIONAIS concebem como cidadãos. A representação de ci-
dadãos por OSCs também assume um formato um
tanto diferente. A representação de base partidária
aspira a se conectar a um público amplo, geral-
mente a maior parte da população adulta. Essa
amplitude de escopo dos partidos é citada como
um dos motivos pelos quais eles não podem ser
substituídos por OSCs, muitas das quais focali-
zam um público mais específico (Mainwaring, 1999,
p.13). As OSCs têm uma vantagem de escopo dis-
tinta. Suas atividades tendem a ser mais contínu-
as ao longo do tempo, enquanto os partidos são
mais ativos em ciclos eleitorais. Atividades e cam-
panhas de OSCs podem oferecer aos cidadãos, ain-
da que em menor número, símbolos de lealdade e
identificação, educação, oportunidades para ma-
nifestações políticas e a simplificação de escolhas
a todo tempo. Durante as campanhas eleitorais, as
atividades de OSCs podem coincidir com as de
partidos, ajudando eleitores a identificar os “can-
didatos ambientalistas” e assim por diante. Os partidos, como organizações, desempe-
nham as funções centrais de recrutar elites para
cargos e gerir suas campanhas, além da tarefa crucial
de levantar recursos. São funções relacionadas à
articulação de interesses políticos e sua agregação
em amplos programas de governo. Partidos da
América Latina têm, em geral, desempenhado tais
funções partidárias razoavelmente bem, com exce-
ção da função de agregação. A natureza individua-
lista dos partidos latino-americanos significa que
muitos carecem de programas coerentes de
governança (Roberts, 2002), uma lacuna que pre-
judica diversas outras funções partidárias. Quanto ao argumento de que OSCs, como
partidos, articulam interesses políticos, há pouca
controvérsia; por exemplo, é o único argumento re-
conhecido por Dalton e Wattenberg (2000, p.8). Mui-
tas OSCs entendem que essa é sua função central e
afirmam representar idéias ou identidades essenci-
ais que são negligenciadas por outros mecanismos. Essas podem ser idéias que já têm grande aceitação,
mas é muito comum que as OSCs tragam idéias no-
vas para a arena dos sistemas partidários, tais como
insistir na proteção de direitos humanos em regimes
autoritários (Peruzzotti, 2006; De Piero, 2005). 4 Van Cott (2005) traz um contraponto interessante, exa-
minando quando e porque alguns movimentos indíge-
nas sul-americanos migraram para ativismo partidário
pela primeira vez nos anos noventa. Antes e depois,
porém, também participaram do papel das OSCs, aqui
identificado como de agregação de interesses. REPRESENTAÇÃO COMO RELACIONAMENTO
COM O ELEITORADO OU CIDADÃOS Os comportamentos de
OSCs reconhecidos como representativos
freqüentemente se assemelham a tais funções par-
tidárias, ainda que não sejam tão vinculadas ao
processo eleitoral. Ao desempenharem tais fun-
ções, as OSCs geralmente estão menos restritas (ou
habilitadas) por procedimentos e regras formais do
que partidos. A maioria dos sistemas políticos tem
regras formais para formação de partidos; as OSCs
normalmente têm mais liberdade de se constituí-
rem em torno de interesses específicos. Mas elas
também podem estar sujeitas a regras relativas à
sua formação ou atuação, especialmente quando
isso envolve financiamento externo, lobby políti-
co, formulação ou implementação de políticas. Comparativamente, a flexibilidade dos processos
de agregação das OSCs cria uma relação mais amorfa
com seus públicos (Roberts, 2002). Em cada uma
das próximas seções, discutiremos como partidos
políticos desempenham as funções representati-
vas de Key, e, então, especificaremos como OSCs
também podem desempenhar a mesma função. Enquanto esse papel partidário concebe o
público de massa como um eleitorado, as OSCs o 49 REPRESENTAÇÃO, PARTIDOS E SOCIEDADE CIVIL ... REPRESENTAÇÃO POR MEIO DE FUNÇÕES
ORGANIZACIONAIS Na
América Latina, as OSCs também são ativas na agre-
gação de interesses, na elaboração de programas de
larga escala para gestão e compreensão de direitos
humanos, em estratégias de desenvolvimento (espe-
cialmente alternativas ao neoliberalismo), e em refor-
mas institucionais (Bonner, 2005; Lucero, 2001; Van
Cott, 2005).4 As OSCs até desempenharam funções
de recrutamento e treinamento de elites políticas, iso-
ladamente ou em conjunto com partidos políticos. Dentre os atuais presidentes que alcançaram estatura
nacional pelas OSCs, há Lula, no Brasil, um sindi-
calista, e Evo Morales, na Bolívia, do movimento in-
dígena e de associações de plantadores de coca. RH, Salvador, v. 21, n. 52, p. 47-66, Jan./Abr. 2008
Na relação com cidadãos, cada mecanismo
tem uma base específica em que faz suas afirma-
ções de representação. Os partidos justificam suas
reivindicações de representação com base no nú-
mero de filiados ou em resultados eleitorais, uma
medida relativamente direta. As OSCs, ao contrá-
rio, raramente “medem” seu apoio por eleições ou,
em muitos casos, número de sócios. O apoio a
OSCs pode ser rastreado pela quantidade de pes-
soas que apóiam suas campanhas, por exemplo,
respondendo às chamadas para manifestações
públicas. Pesquisas de opinião pública, às vezes,
apuram a aprovação pública de segmentos de mo-
vimentos específicos de OSCs como um todo, ou
valores de movimentos. O aspecto voluntário de
OSCs significa que um aumento numérico é
indicativo de que as pessoas confiam mais nas
OSCs para conexões políticas, ainda que o
surgimento de novas OSCs possa indicar também
que os cidadãos pensem que as atuais OSCs se-
jam inadequadas. CADERNO CRH, Salvador, v. 21, n. 52, p. 47-66, Jan./Abr. 2008 CADERNO CRH, Salvador, v. 21, n. 52, 50 Kathryn Hochstetler, Elisabeth Jay Friedman REPRESENTAÇÃO POR MEIO DE GOVERNO E
ESPAÇO PÚBLICO a esfera pública é um lugar em que associações
podem trazer questões para a agenda pública, in-
troduzir práticas políticas alternativas e até desen-
volver novos formatos institucionais para abordar
suas questões (Avritzer, 2002, p.7). Avritzer argu-
menta que essas são funções claramente importan-
tes e essenciais à democratização. Se candidatos partidários são eleitos, os par-
tidos continuam a mediar interesses de cidadãos,
agora em um papel singular, como tomadores de
decisão. No governo, os partidos políticos organi-
zam tanto coalizões de governo quanto de oposição
e dissidência (com sorte) leais. Organizam o proces-
so legislativo e supervisionam a implementação e a
gestão de políticas. Os partidos têm mantido um
monopólio de quase todas as funções de governo,
normalmente preservadas em constituições nacio-
nais ou outras legislações não-ordinárias, que exi-
gem a filiação partidária para concorrer a cargos
políticos. Os procedimentos para a agregação de
votos individuais e a alocação dos cargos com auto-
ridade decisória são estabelecidos por complexas
regras eleitorais. Em democracias, elas também es-
tabelecem procedimentos para reavaliação periódi-
ca pelos eleitores e a possibilidade de substituição. O resultado concreto pretende promover estabili-
dade de governo por meio da continuidade que vai
além de indivíduos e determinar seqüências de
responsabilização por atos governamentais. Boa
parte da avaliação dos partidos como mecanismos
de representação analisa as conseqüências de varia-
ção dessas normas (Carey, 2003; Crisp et al, 2004;
Mainwaring; Scully, 1995). Ao longo do tempo e
do espaço, tem variado bastante a capacidade de os
partidos latino-americanos assegurarem tais funções
governamentais (Mainwaring, 1999a, 2006). Ainda que não sejam formas de tomada de
decisão com autoridade que vincula a sociedade,
as ações de OSCs, na esfera pública, podem de-
sempenhar algumas das mesmas funções dos par-
tidos no governo. De maneira particularmente dra-
mática, os protestos de massa organizados parcial-
mente por OSCs são o novo poder moderador para
os presidentes sul-americanos, sancionando sua
capacidade de continuar a governar ou atando-os
antes que terminem seus mandatos “fixos”
(Hochstetler, 2006a, p.403). As OSCs também exer-
cem funções de responsabilização social,
monitorando os atores governamentais e a quali-
dade administrativa do governo (Smulovitz;
Peruzzotti, 2000). 5 Argumento resumido em Thomas, 2001; ver também
Lawson; Poguntke, 2004; Mainwaring, 2006, p.15;
Nordon, 2006. REPRESENTAÇÃO POR PARTIDOS POLÍTI-
COS E (OU) OSCS? Até agora, a discussão especificou os pa-
péis de representação que partidos e OSCs podem
desempenhar. Esta seção focaliza a relação entre
eles. Partidos políticos e OSCS prosperarão jun-
tos, como mecanismos de representação, ou o su-
cesso de um implica um desfortúnio do outro? A
emergente literatura sobre crise de partidos políti-
cos freqüentemente presumiu que o crescimento
de modalidades não-partidárias de representação
é, no mínimo, sintomático do declínio de legitimi-
dade e quantidade de sócios de partidos, se não
diretamente causal.5 Esse argumento tem sua
contraparte na literatura sobre movimentos soci-
ais, que freqüentemente defende que políticas de Somente os partidos políticos têm um es-
paço representacional que lhes permite diretamente
ter a autoridade de tomar decisões para a socieda-
de como um todo, para além de seus eleitores es-
pecíficos: no governo, governam. As OSCs, por
sua vez, promovem os interesses de seus públicos
respectivos no espaço público – isto é, na esfera
de debate e de discussão coletivas, externas às de-
cisões políticas formais (ainda que também pos-
sam, é claro, fazer lobby internamente às institui-
ções estatais). Essa esfera pública tem sido histori-
camente subdesenvolvida na América Latina, mas
tem crescente potencial. Na concepção de Avritzer, 51 REPRESENTAÇÃO, PARTIDOS E SOCIEDADE CIVIL ... base partidária podem distorcer e sobrepujar for-
mas alternativas de participação.6 vas formas de organização podem “atuar como
guardiões republicanos”, fornecendo informações
que aprimoram a responsabilização (O’Donnell,
1998, p.122; Fuchs; Klingemann, 1995, p.435-36;
Smulovitz; Peruzzotti, 2000). Nessa visão, os dife-
rentes mecanismos de representação se
complementam e se aprimoram. Também é possí-
vel que ambas as formas de representação sejam
fracas, com nenhuma melhorando as falhas da outra
(Chandoke, 2005). Em ambos os lados dessa discussão, auto-
res tendem a concordar que a verdadeira democra-
cia será prejudicada sem o mecanismo cuja auto-
nomia e existência são alvo de ataques. REPRESENTAÇÃO POR PARTIDOS POLÍTI-
COS E (OU) OSCS? Dessa for-
ma, por exemplo, livros sobre partidos políticos
na América Latina regularmente enfatizam que
“organizações não-partidárias como sindicatos,
movimentos sociais e ONGs não podem ser subs-
titutos de partidos em seu papel de gerar (Bruhn),
preservar (McGuire), ou aprofundar (Roberts) de-
mocracia (Levitsky, 2001b, p.105).” Do mesmo
modo, a democracia eleitoral por meio de compe-
tição partidária é vista como a preservação de uma
série de instituições de elite na recente política la-
tino-americana, sem melhoria das “experiências vi-
vidas por cidadãos” (Foweraker, Krznaric, 2002,
p.33), e até, com o neoliberalismo, levando à
“subarticulação de interesses sociais, excessiva
atomização social, e aquiescência política” (Kurtz,
2004, p.263). Para escolher dentre esses argumentos, exa-
minamos evidencias recentes a respeito de quão
bem partidos e OSCs têm desempenhado suas
funções organizacionais e de público de massa no
Brasil e na Argentina. Concentramos nelas por
serem as funções em que partidos e OSCs mais
coincidem e podem competir, especialmente em
tempos de crise partidária. A literatura sobre par-
tidos, mais desenvolvida e com dados quantitati-
vos disponíveis, fornece claras relações de indica-
dores que usaremos (Mainwaring, 2006, p.15;
Poguntke, 1996; Webb, 2005). Eles incluem dados
de survey a respeito do desafeto com partidos em
geral, erosão de identificação partidária, quantida-
de de eleitores que comparecem às urnas, maior
incerteza eleitoral e crescente quantidade de votos
em partidos e candidatos “outsiders”. Para as OSCs,
examinaremos tanto o surgimento de novas orga-
nizações – e especialmente novos tipos de organi-
zações – e as fortunas de organizações existentes. Apresentaremos evidências a respeito das variações
de apoio, dentre diferentes públicos potenciais, para
determinadas campanhas e organizações, bem como
quaisquer dados de survey disponíveis. Por fim,
rastrearemos os esforços das OSCs na articulação e
agregação de interesses de grandes públicos. p
J
Na contramão desses argumentos de soma-
zero, há um crescente número de acadêmicos que
sugerem que os diferentes mecanismos de repre-
sentação podem se relacionar de maneiras com-
plementares. O argumento geralmente começa com
a compreensão de que os partidos são atores cen-
trais na representação de valores e interesses de
cidadãos, mas que outros atores podem ajudar a
solucionar alguns dos problemas da democracia
eleitoral. 6 Argumento discutido e criticado em Hellman, 1992; ver
também Alvarez, 1990; Panizza, 2005; Zibechi, 2005. REPRESENTAÇÃO POR PARTIDOS POLÍTI-
COS E (OU) OSCS? A participação não-partidária pode sim-
plesmente ser uma opção melhor do que as elei-
ções para a expressão de determinados tipos de
preferências, dado que o voto é apenas uma opção
para cidadãos cada vez mais capacitados em de-
mocracias, dentro de um repertório mais amplo
de estratégias de ação (Fuchs; Klingemann, 1995,
p.432; Dalton; Scarrow; Cain, 2004). Como discu-
timos acima, partidos e OSCs têm diferentes van-
tagens de escopo na relação com o público de mas-
sa (Goldstone, 2004; Kitschelt, 2003). Por fim, no- Colocar a crise em contexto Ainda que esses números sugiram que os
partidos tenham entrado em crise aguda, uma aná-
lise detalhada do comportamento eleitoral traz uma
história diferente. Como uma pista geral a respeito
das atitudes da população, a participação eleitoral
mostrou alguma recuperação do ponto baixo de
2001. Nas eleições presidenciais de 2003, o índice
de abstenção foi 22% mais baixo do que em 2001,
e os votos brancos e nulos, com 2,6%, tiveram o
índice mais baixo desde 1983. Ao todo, 77% dos
eleitores registrados votaram (Sanchez, 2005,
p.468). Ainda que o voto tenha sido dividido en-
tre um leque de candidatos presidenciais, metade
era peronista e a outra metade tinha origens na
UCR (2005, p.461-465,471). A incapacidade de os
partidos se unirem por trás de um candidato de-
monstra a erosão de identidade partidária até en-
tre as elites partidárias, mas os grandes partidos
ainda são atores relevantes. Historicamente, o sistema partidário argen-
tino era classificado entre bi-partidário e modera-
damente multipartidário; além dos dois partidos
dominantes, o peronista Partido Justicialista (PJ) e
a União Cívica Radical (UCR), havia considerável
representação de terceiros na Esquerda e na Direi-
ta. Os partidos dominantes refletiam a principal
divisão de classe, com apoio das classes baixas e
trabalhadoras para os Peronistas e apoio das clas-
ses médias e altas para os Radicais, ainda que
ambos os partidos se dirigissem a pessoas em todo
o espectro econômico. As regras constitucionais
reforçavam o controle bi-partidário: eleições simul-
tâneas, nesse sistema presidencialista, produzem
o efeito legislativo de “carona” de eleições presi-
denciais, em que o vencedor leva tudo. Mas ou-
tras regras permitiam representação mais ampla:
eleições legislativas com listas partidárias e repre-
sentação proporcional; estrutura federal; e a elei-
ção indireta do Senado por assembléias das pro-
víncias. Tais fatores levaram a mais partidos que
ocupavam cargos, especialmente nas províncias
(Calvo; Escolar, 2005; McGuire, 1995, p.231). Apesar de controlar cerca de um quarto dos
estados e municípios, a UCR “efetivamente desa-
pareceu como formação política de nível nacional
representante da classe média, uma identidade e
um papel que datam da década de 1890” (p.472,
467). Aliás, na primeira década de democracia, o
declínio de poder eleitoral nacional dos dois gran-
des partidos conjuntamente considerados (de 92%
a 67% do voto presidencial e 86% a 65% do voto
legislativo) se deveu principalmente ao desempe-
nho da UCR (Torre, 2003, p.649). CRISE PARTIDÁRIA E REPRESENTAÇÃO
ALTERNATIVA NA ARGENTINA A sociedade argentina rebelou-se fortemen-
te contra sua classe política em meados de dezem-
bro de 2001. Sob a bandeira de que se vayan todos,
desde defensores de direitos humanos e Mães da 52 Kathryn Hochstetler, Elisabeth Jay Friedman uma queda de 86,2%, a maior da América Latina,
que terminou com apenas quatro por cento do elei-
torado expressando confiança nos partidos
(Latinobarometer, apud Sanchez 2005, p.457). Essa
desconfiança se refletiu no péssimo desempenho
das eleições de 2001: pela primeira vez, somente
30% do eleitorado optaram por votar em um dos
dois grandes partidos, e 15% votaram nulo ou em
branco. Mesmo a maioria do PJ no Senado se ba-
seava em 30% dos votos distritais (Calvo; Escolar,
p.211-212). Como foi dito à época, o vencedor
dessa eleição foi “ninguém”: mais eleitores prefe-
riram não votar ou inutilizar suas cédulas a votar
em um candidato. Praça de Maio a movimentos de desempregados
foram às ruas protestar contra o fracasso dos me-
canismos formais de participação. Em 2002, pare-
cia que um conjunto diverso de OSCs não-parti-
dárias estava construindo uma arena alternativa
para participação política horizontal e localizada. Mas quão profunda foi essa mudança? O sistema
partidário argentino está em uma fase de incerteza,
mas nem todos os partidos entraram em crise. E
ainda que a sociedade civil tenha oferecido formas
alternativas de representação, elas não estão subs-
tituindo a política de partidos. 8 Também houve protestos significativos contra a impu-
nidade por violações de direitos humanos, tais como as
marchas para exigir justiça nos casos de María Soledad
Morales, uma jovem cujo assassinato foi acobertado pela
polícia na tentativa de proteger seus assassinos politica-
mente bem-relacionados, e José Luis Cabezas, um fotó-
grafo que foi assassinado por causa de seus esforços
para expor brutalidade policial e a corrupção política. REPRESENTAÇÃO, PARTIDOS E SOCIEDADE CIVIL ... REPRESENTAÇÃO, PARTIDOS E SOCIEDADE CIVIL ... O PJ – que obteve o primeiro e o segundo
lugar nas eleições presidenciais de 2003 – parece,
como a fênix, estar ressurgindo das cinzas. Torre
(2003, p.659) afirma que existe um “núcleo duro”
de apoiadores do PJ, cerca de 37% do eleitorado,
que votarão no partido independentemente das
políticas que ele promover no cargo. A lealdade
histórica ao partido de Juan e Evita Perón (Sanchez,
2005, p.468) é reforçada por recompensas materi-
ais. A bem-sucedida transição do partido da base
sindicalista para vínculos clientelistas, durante a
neoliberal década de 1990, na gestão do Presidente
Carlos Menem, significou que mesmo os eleitores
mais pobres continuam a ter acesso limitado a re-
cursos (Delamata, 2004; Auyero, 2001; Levitsky,
2001c). O desenho institucional também contribui
para sua duração no poder: o PJ ganha uma quanti-
dade desproporcional de cargos, especialmente no
Senado, por causa de sua super-representação em
pequenas províncias (Mustapic, 2005; Torre, 2003). tidos novos que têm mais sofrido o impacto de
seu desejo de punir governantes inadequados, en-
quanto o PJ mantém seu apoio. Torre (2003, p.15)
descreve o impacto desses eleitores como um para-
doxo: “aquilo que é positivo sobre a crise, em ter-
mos de expansão da democracia partidária, também
é a causa de um impacto institucional negativo”. Apesar de não estarem desempenhando seu
papel representacional histórico, os partidos polí-
ticos e o sistema partidário não estão inteiramente
em crise. Tendo ou não um “núcleo duro” de se-
guidores, o PJ parece ter sobrevivido à reviravolta
de 2001-2002. Como será demonstrado a seguir,
sua capacidade de oferecer benefícios materiais aos
seus apoiadores também tem impacto no grau re-
lativo de autonomia de outros mecanismos de re-
presentação. Contudo, os partidos não têm con-
quistado a confiança (recente) de muitos cidadãos. O que oferece a sociedade civil? Entretanto, uma leitura concorrente do voto
peronista defende que ele não é estável, mas sim
composto de “configurações distintas de eleitores
fiéis, eleitores ocasionais, e eleitores estratégicos”
(Calvo; Escolar, 2005, p.197). Analistas argumen-
tam que, em vez de existir um único partido domi-
nante em âmbito nacional, o sistema partidário foi
desnacionalizado, com perfis bastante diferentes
pelo país: reformas constitucionais e eleitorais no
âmbito da província reforçaram partidos de domí-
nio local (2005, p.197). 7 Alguns observadores constataram que redes políticas
preexistentes fomentaram essas mobilizações (Auyero,
2005, 2004). Colocar a crise em contexto A incapacidade de os partidos responde-
rem ao desastre econômico que, em meados de
2002, correspondia a 50% de pobreza e 25% de
desemprego deixou o sistema político em caos. Entre 1997 e 2002, a confiança geral dos argenti-
nos nos partidos políticos caiu vertiginosamente: 53 53 Formas emergentes de representação: auto-
nomia, cooptação e cooperação A sociedade civil estava pronta para se re-
voltar em 2001. Na década de 1990, os desloca-
mentos econômicos provocados pelas reformas
neoliberais de Menem geraram devastação nas pro-
víncias. A resposta estabeleceu um padrão que
marcaria a década. Praticamente cidades inteiras
se levantaram nas províncias de Salta, Jujuy e
Neuquén, atacando repartições governamentais e
cortando grandes vias de transporte, em demons-
trações caracterizadas como espontâneas7 contra
condições vertiginosamente decrescentes de traba-
lho e vida.8 Nessas áreas e na Grande Buenos Aires,
uniram-se movimentos de desempregados, exigindo CADERNO CRH, Salvador, v. 21, n. 52, p. 47-66, Jan./Abr. 2008 CADERNO CRH, Salvador, v. 21, n. 52, p. 47-66, Jan./Ab
Qualquer que seja a visão dos analistas a
respeito do atual sistema partidário, é provável que
concordem com a leitura de Sanchez (2005, p.473)
de que ele está agora “em um estado altamente flui-
do”. Torre afirma que eleitores de Centro-Direita e
Centro-Esquerda têm sido especialmente voláteis,
com práticas que simultaneamente aprimoram e
prejudicam a democracia de base partidária. Cida-
dãos mais exigentes, educados pelos movimentos
de direitos humanos e civis das décadas de 1980 e
1990, recusam-se a manter fidelidade a partidos
corruptos, ineficientes e ideologicamente incoeren-
tes diante de crises. Entretanto, sua volatilidade
tem significado que são as coalizões fracas ou par- 54 54 Kathryn Hochstetler, Elisabeth Jay Friedman torná-las mais inclusivas, ao menos internamente. Recusava identificações partidárias e realizava elei-
ções diretas de sua liderança. Acolhia membros
não-sindicalizados, buscando ser uma “ferramen-
ta de organização que unificasse todo o mundo do
trabalho, inclusive trabalhadores informais e de-
sempregados” (Rodríguez, 2006). Por fim, buscou
conectar formas de organização baseadas no local
de trabalho com formas novas, declarando que seu
público-alvo de mobilização era “a fábrica nova que
está no bairro” (Camarero; Pozzi; Schneider, 1998;
www.cta.org.ar). que os governos das províncias e nacional forne-
cessem seguridade e emprego (González Bombal,
2003; Svampa, 2005; Svampa; Pereira, 2005). Em seu aspecto mais radical, esses movi-
mentos buscaram romper com formas de repre-
sentação que constatassem ser fundamentadas em
relações clientelistas, dependentes. Promoviam
relações horizontais e tomada de decisão por de-
mocracia direta. Como explicou um participante: Não é que houve uma decisão de ser horizontal... [as pessoas] simplesmente se encontraram, sen-
tindo grande rejeição por... todos que ocupavam
espaços no Estado, ou se organizavam para ocu-
par espaços no Estado... com uma espécie de de-
cisão de “vamos fazer nós mesmos” (Sitrin, 2005,
p.iv-v, 27). No auge da crise política, muitos desses ato-
res se uniram na sua crítica à legitimidade dos
partidos e da classe política. Isso estava mais for-
temente articulado na exigência da sociedade de
que “devem ir todos”. Esse formato, originalmen-
te levantado nas grandes demonstrações contra o
governo de la Rúa9 em dezembro de 2001, foi eco-
ado por aqueles que fortemente recriminavam per-
sonagens políticas em espaços públicos, desde cafés
a aeroportos, responsabilizando-os pelo fracasso
do sistema político. 9 Os protestos foram catalisados pelo congelamento das
contas bancárias domésticas pelo governo central, numa
tentativa de estancar a hemorragia de capital que saía do
país antes da forte desvalorização. Cidadãos de classe
média se juntaram a desempregados em enormes de-
monstrações na Plaza de Mayo, no centro, em 19 e 20 de
dezembro. Quando de la Rua declarou estado de emer-
gência e a Polícia Federal usou força letal contra os pro-
testos, estes só aumentaram. Para um detalhamento di-
ário a respeito de como se desdobraram essas demons-
trações, ver Iñego Carrera e Cotarelo 2004. CADERNO CRH, Salvador, v. 21, n. 52, p. 47-66, Jan./Abr. 2008 À medida que a crise se ampliava e se
aprofundava, espalhava-se a rejeição da represen-
tação de base partidária e eleitoral em favor de pro-
cessos políticos autônomos. Esses novos movimentos foram inspirados
por seus antecessores. A geração de grupos de di-
reitos humanos que se opuseram à autoritária
“Guerra Suja” (1976/1983) continuava seu traba-
lho após a transição para a democracia. Apesar de
dividido a respeito de quanto cooperar com gover-
nos que não enfrentavam adequadamente a impu-
nidade do passado, o movimento também inspi-
rou uma segunda geração (ainda que coincidente)
de proponentes de direitos (Peruzzotti, 2002). Es-
sas organizações, como o exemplar Centro de Es-
tudos Legais e Sociais (CELS), lutaram contra a
impunidade enquanto fortaleciam instituições de-
mocráticas para proteger direitos humanos e civis. Conforme crescia essa onda de protesto, sua
capacidade de mobilização e interpretação apro-
veitou símbolos e lutas passadas. Um membro de
uma assembléia de bairro recordou sua experiên-
cia do maior dia de protesto em dezembro: “Eu
liguei o rádio e escutei que havia pessoas indo à
Plaza de Mayo, que as Mães da Plaza de Mayo
estavam sendo presas... Eu fui imediatamente”
(Sitrin, 2005, p.3). A essa altura as Mães já havi-
am expandido seu discurso para refletir o contex-
to contemporâneo, com slogans como “os desapa-
recidos de ontem são os desempregados de hoje”
(ver Borland, 2006, esp. p.9). As repressões às vezes
fatais aos desempregados persuadiram muitos gru- Ainda mais próximo dos novos movimen-
tos sociais e de sua rejeição da “política de sem-
pre”, havia um novo movimento sindicalista (Bielsa
et al, 2002, p.71). Na década de 1990, sindicatos
de professores e servidores públicos lideraram os
esforços de formação do anti-neoliberal Congresso
de Trabalhadores Argentinos (CTA) (Rodríguez,
2006). Com mudanças na organização social e po-
lítica, o CTA oferecia uma nova forma de repre-
sentação para um público muito mais diverso. Em
vez de rejeitar eleições, esse movimento buscou 55 REPRESENTAÇÃO, PARTIDOS E SOCIEDADE CIVIL ... pos de direitos a respeito do paralelo entre exigên-
cias novas e antigas. nham o dobro do nível de aceitação (80%) pela
população geral do que os movimentos de desem-
pregados (40%) (2003, p.26). Pouco após os protestos e a renúncia de De
La Rúa e do presidente interino que o sucedeu,
houve um boom de organização econômica e soci-
al de maneira autônoma. CADERNO CRH, Salvador, v. 21, n. 52, p. 47-66, Jan./Abr. 2008 Assembléias populares
ou de bairro, um fenômeno predominantemente
da classe média, seguiram os passos dos movi-
mentos emergentes de desempregados (Bielsa et
al, 2002, p.24), envolvendo-se em ações de pro-
testo – inclusive os famosos batedores de panelas
(cacerolazos), o bloqueio de vias (piquetes) e
escrachos (escratches) de personagens públicas –
bem como em tomada horizontal de decisões em
questões de importância local. A afirmação de de-
mocracia direta em lugar da democracia represen-
tativa (p.15, 31) concretizou-se nas horas
despendidas em discussão aberta. Um participan-
te observador relatou um ritual “quase compulsi-
vo” de votar todas as pequenas decisões, com essa
auto-representação sendo “o ato pelo qual vizinhos
se tornaram membros da assembléia, a personifi-
cação (la puesta en escena) da condição de serem
iguais, vinculados horizontalmente entre si”
(Bergel, 2003, p.87). Alguns trabalhadores ocupa-
ram e reabriram fábricas fechadas, expandindo-se
em um movimento de fábricas “recuperadas”
(Lavaca 2004; Korol, 2004). Movimentos sociais
ofereciam oportunidades não só em classe, mas
também em gênero; por meio deles, mulheres po-
bres e da classe média encontraram a “possibilida-
de de alcançar espaços públicos” (Sanchís, 2006;
Di Marco, 2006). As crises dos partidos e das instituições po-
líticas criaram uma abertura para outros grupos
marginalizados. Sua exclusão da política
mainstream se tornou um ativo, dado que suas
reputações “imaculadas” e exigências “puras” eram
vistas como engajamento político ético. Fernando
Ojeda e Cristina Lescano, da organização
socioambiental de base El Ceibo, notaram que seu
projeto de empoderamento popular e reciclagem
urbana já tinha quase dez anos em 2001, quando
as pessoas começaram a procurar programas lo-
cais eficazes para ajudar os que não tinham em-
prego regular (Lescano, 2006; Ojeda, 2006). De
repente, todos queriam trabalhar com eles, e eles
puderam expandir e institucionalizar seus progra-
mas. Líderes da Comunidade Homossexual da
Argentina (CHA) descobriram que a crise os aju-
dava a avançar sua proposta de uniões civis em
Buenos Aires, promulgada em dezembro de 2002. Como afirmou Marcelo Sundheim, “a sociedade
estava muito insatisfeita com os políticos, e o sen-
timento de que era preciso haver justiça... estava
crescendo muito rapidamente. Aquela situação
contextual era muito forte e foi decisiva para o pro-
jeto de união civil” (Sundheim, 2006). “Atores
sociais” como a CHA preenchiam uma necessida-
de básica: “À medida que o projeto avançava e
nós íamos às ruas, muitas pessoas nos aplaudi-
am... CADERNO CRH, Salvador, v. 21, n. 52, p. 47-66, Jan./Abr. 2008 Não éramos importantes como líderes políti-
cos, mas éramos referências éticas [ou seja]... pes-
soas que não mentiam... referências... de uma
mudança, de algo mais justo” (2006). 10 Organizações que alegam representar um setor também
vêem um papel na reforma institucional. José
Blumenfeld, um membro de Memória Ativa, que repre-
senta “o grupo de familiares e amigos de familiares” dos
mortos na explosão por bomba da Associação Mutual
Israelita da Argentina em 1994, explicou que, junta-
mente com sua luta particular por verdade e justiça, seu
objetivo “ajuda a melhorar a saúde institucional da Re-
pública.” Ele ofereceu provas, como sua ação judicial no
país e o recurso, deferido, à Comissão Inter-Americana
de Direitos Humanos, pedindo o julgamento desta, o
que levou o governo a aceitar a responsabilidade por
deixar de prevenir a explosão por bomba e negando jus-
tiça a suas vítimas (Blumenfeld, 2006). CADERNO CRH, Salvador, v. 21, n. 52, p. 47-66, Jan./Abr. 2008 CADERNO CRH, Salvador, v. 21, n. 52, p. 47-66,
Os movimentos uniam forças, com algumas
assembléias assumindo projetos tais como insta-
lações médicas para auxiliar os trabalhadores de
fábricas recuperadas e desempregados. Suas es-
tratégias compartilhadas (auto-organização, delibe-
ração horizontal) articularam os valores e deman-
das de um grande público. Ou, nas palavras de
um canto de protesto, “bloqueio de ruas ou baten-
do panelas, a luta é uma só” (Piquete y cacerola, la
lucha es una sola) (Bielsa et al, 2002, p.101). Ha-
via, porém, diferenças em termos de sua recepção
pelos públicos-alvo: em 2002, as assembléias ti- OSCs institucionalizadas também encontra-
ram na crise uma oportunidade de avançar suas
agendas de reforma. Entre 2000 e 2004, 16 ONGs
foram formadas com foco em reforma do Estado
(CIPPEC, 2006). Como a crise econômica piorou
as condições de vida em um momento em que o
estado estava “sumido”, isso “abriu o caminho para
uma boa pressão por parte das ONGs para... exigir
o fortalecimento de instituições” (Martín Vezzulla,
2006). Como exemplo primário, um grupo de 56 56 Kathryn Hochstetler, Elisabeth Jay Friedman ONGs, liderado pela Associação de Direitos Civis
(ADC) e incluindo CELS e o grupo ambientalista
nacional FARN, decidiu abordar os problemas com
a desabonada Suprema Corte. Com uma interpre-
tação da exigência de que “devem ir todos” se apli-
cava a mais do que os próprios juízes, elas ofere-
ceram críticas ao desenho da Corte, inclusive ao
processo de nomeação. O grupo propôs reformas
no documento “Uma Corte pela Democracia.” Em
2003, o Presidente Nestor Kirchner assinou um
decreto aceitando a maior parte das suas idéias
(Asociación por los Derechos Civiles, 2005, p.I.1). Assim, uma coalizão de ONGs foi reconhecida
como tendo agregado, e agora como representante
interesses sociais perante o público a que se diri-
gia, tomadores de decisão estatais. os direitos individuais, pois seu trabalho será sem-
pre “contra-majoritário” (Saba, 2006).11 Ainda que
não majoritários, seu trabalho claramente promo-
ve interesses dos cidadãos que são fundamentais
para as democracias. Observadores acadêmicos escreveram com
entusiasmo a respeito da forma como esses novos
atores desafiaram e pareciam substituir formas
institucionais e partidárias de representação
(Svampa, 2003). Acharam particularmente
inspirador o desafio dos novos movimentos: “Os
movimentos sociais autônomos da Argentina... começaram a articular uma política nova e revolu-
cionária... uma política da vida diária” (Sitrin,
2005, p.iii); as assembléias de bairro ofereceram
uma nova radicalidade ‘irreversível’... 11 Essa defesa de seu papel – cumprir a constituição e
proteger direitos individuais – pode ser usada para res-
ponder a qualquer analista que veja o financiamento
estrangeiro da ADC e de outras como determinante de
sua agenda, assim tornando-as não-representativas de
interesses domésticos (majoritários). Ver Norden, 2006. CADERNO CRH, Salvador, v. 21, n. 52, p. 47-66, Jan./Abr. 2008 que tomou
corpo na nova geração” (Bielsa et al, 2002, p.55). Mas desenvolvimentos contemporâneos revelam
um panorama mais sóbrio da atual política de re-
presentação. Aqueles que focavam em reforma
institucional não se declaravam substitutos da re-
presentação eleitoral democrática de partidos polí-
ticos.10 Como explicou Roberto Saba, diretor exe-
cutivo da ADC, “ONGs de direitos humanos não
têm necessidade de provar que representam al-
guém. Estão lutando pelos direitos das pessoas”. Ele ofereceu um exemplo de seu papel singular,
contando uma história de ter deposto perante o
Congresso durante um debate sobre uma lei de
liberdade de informação. Quando uma poderosa
senadora tentou negar sua legitimidade como
interlocutor, dado que ela representava diretamen-
te os milhares de eleitores que a elegeram, ele res-
pondeu: “Eu não represento nenhum eleitor. Es-
tou aqui para assegurar que as leis sejam observa-
das, para cumprir a constituição”. Ele disse que
“ter de demonstrar que uma posição é apoiada por
um determinado grupo de pessoas” era um truque
ou uma armadilha para aqueles que promoviam As políticas do presidente Kirchner provo-
caram uma divisão entre atores da sociedade civil,
com alguns abraçando seus esforços e outros rejei-
tando suas técnicas políticas familiares. Como seus
maiores rivais à presidência eram do seu próprio
partido, ele buscou aliados não-tradicionais, in-
clusive grupos de direitos humanos, o CTA, inte-
lectuais progressistas e movimentos de desempre-
gados. Suas ações para reverter a impunidade de
décadas daqueles responsáveis pela “Guerra Suja”,
inclusive uma “limpeza” militar, agraciou-o peran-
te diversas organizações de direitos humanos. De
início, parecia que questões mais recentes também
estavam em pauta: ele aceitou as reformas da Su-
prema Corte e recusou-se a reprimir assembléias e
desempregados (Gaudin, 2005). Alguns grupos se aliaram a um governo que
parecia disposto a lidar com suas necessidades. Em um símbolo marcante, a líder das Mães, Hebe
de Bonifini, declarou desnecessária a “Marcha de 57 REPRESENTAÇÃO, PARTIDOS E SOCIEDADE CIVIL ... Resistência” anual, de 24 horas, porque “o inimi-
go não está mais na Casa do Governo” (Clarin,
2006). Dois líderes proeminentes dos movimen-
tos de desempregados e de bairro entraram para o
governo Kirchner como Subsecretário de Habita-
ção Social e Terra e Diretor Nacional de Assistên-
cia Comunitária no Ministério do Desenvolvimen-
to Social. 12 O vínculo entre impunidade passada e injustiça atual é
marcadamente exemplificado por acontecimentos recen-
tes: logo após o proferimento de uma sentença de prisão
perpétua em um dos primeiros casos reabertos contra um
chefe de polícia que ordenou o assassinato e a tortura de
prisioneiros durante a Guerra Suja, desapareceu uma das
principais testemunhas da acusação – e outra recebeu
ameaças de bomba em seu trabalho (Valente, 2006). CADERNO CRH, Salvador, v. 21, n. 52, p. 47-66, Jan./Abr. 2008 Estas OSCs, que deram forte apoio ao
bem-sucedido pleito presidencial da esposa de
Kirchner, aceitam um partido como tendo ofereci-
do representação legítima, e trabalham para forta-
lecer sua posição. Como antes, há incentivo mate-
rial para esse apoio; Kirchner continuou e aumen-
tou os benefícios de assistência social de seu
antecessor. Em dezembro de 2001, 1% da força de
trabalho recebia subsídios do governo; em abril de
2003, eram 18% (Sanchez, 2005, p.468-469). Se-
gundo uma estimativa de 2005, o plano nacional
de seguridade tinha 1.700,000 beneficiários
(Svampa; Pereyra, 2005). sembléias de bairro já declinantes. O Coordena-
dor Contra Repressão Policial e Institucional
(CORREPI), que é politicamente independente, usa
o sistema judiciário e as organizações educacio-
nais de base para lutar contra a contínua repressão
física utilizada pelas forças de segurança do esta-
do (Verdú, 2006). A exigência de 2001 por uma renovação da
vida política falhou: não houve uma substituição
da classe política. Juan Martin Vezzulla (2006), da
FARN, reflete que o intenso surgimento de parti-
cipação cidadã inovadora foi fugaz: Esse movimento por parte dos cidadãos não du-
rou muito... havia o axioma de que ‘devem ir
todos’ e na verdade não se foi nenhum. E os cida-
dãos rapidamente voltaram para o problema mais
diário da crise, de seus próprios problemas eco-
nômicos, sociais etc... O CTA relatou, em 2004, que quase 90%
dos protestos sociais contemporâneos atraíram
menos de 5.000 participantes (Lozano et al, 2004). Alguns entendem que o clientelismo é responsá-
vel por esse refluxo de energia. Como afirma Néstor
Jeifetz, presidente de um movimento habitacional,
a “superseguridade” levou muitos grupos a “prá-
ticas que geram dependência e perda de dignida-
de” (Jeifetz, 2006). Kirchner agora aposta em uma
“receita” de estratégias para “integrar, cooptar, dis-
ciplinar e/ou isolar” movimentos sociais (Sardá
2007; Svampa; Pereyra, 2005, p.107). A persisten-
te desilusão com os partidos foi afirmada em en-
trevistas de 2006, em que perguntas a respeito dos
papéis representacionais das OSCs eram
freqüentemente respondidas por uma forte
dissociação com fundamentos partidários, i.e., ale-
gações de representar quantidades de indivíduos.13 Outros oferecem uma gama de críticas ao
atual governo, desde rejeição direta a uma avalia-
ção mais cautelosa das ações contemporâneas. 13 Como dito por Pablo Secchi, de Poder Cidadão, “Não
queremos nem dizemos que representamos alguém.”
(2006). CADERNO CRH, Salvador, v. 21, n. 52, p. 47-66, Jan./Abr. 2008 María
Adela Antokoletz, das Mães da Plaza de Mayo –
Linha Fundadora, distingue entre o apoio de
Kirchner à celebração das vítimas da Guerra Suja,
proclamando o mais notório centro de tortura em
um museu à memória, e as necessidades que ain-
da restam tanto de verdade quanto de justiça
(Antokoletz, 2006). Questões mais contemporâne-
as foram ofuscadas pelo foco no passado, pois
persiste a impunidade dos atuais responsáveis por
violações de direitos humanos (Walger, 2006).12 CADERNO CRH, Salvador, v. 21, n. 52, p. 47-66, Jan./Abr. 2008 CRISE PARTIDÁRIA E PARTICIPAÇÃO EMER-
GENTE NO BRASIL Há muito, os partidos políticos brasileiros
são criticados como alguns dos mais fracos da
América Latina, apesar de o Partido dos Trabalha-
dores (PT) ter se destacado como um partido ex-
traordinariamente programático e disciplinado
(Hunter; Power, 2005; Samuels, 2006). Quando
surgiram grandes acusações de corrupção contra o
PT em 2005, isso gerou uma sensação de crise
para o primeiro governo nacional do PT e para o
próprio partido. Por causa da natureza ostensiva-
mente extraordinária do PT, sua crise provocou
um questionamento generalizado a respeito de pro-
blemas com a representação de base partidária, ain-
da que não tenha tido o mesmo alcance que na
Argentina. C
CRH S l
d
21
52
47 66 J
/Ab
2008
Em 1998, ao término do primeiro mandato
completo de um presidente civil no Brasil, os bra-
sileiros julgavam suas instituições políticas com
alguns nuances. No tocante aos níveis de confian-
ça nas instituições como um todo, os brasileiros
estavam exatamente no ponto central dos países
da América Latina: classificavam bem suas tropas
e mal sua polícia e sua televisão, e sua confiança
nas instituições de governo era próxima da medi-
ana. Vinte por cento expressaram muita ou consi-
derável confiança em seus partidos, situando-se
entre o Uruguai, no alto, com 34%, e o Equador e
a Venezuela, com 15%, no patamar mais baixo de
confiança manifestada (Latinobarometer, apud
Turner; Carballo, 2005, p.181). Em 2005, somente
13% dos brasileiros expressavam tais níveis de
confiança, mas ainda estavam próximos da média
latino-americana de 13,8 (Latinobarometer, apud
Sanchez, 2005, p.457). Medidas de partidarismo
– expressas pela auto-identificação de indivíduos
com determinado partido – contam uma história
similar. A maior parte dos brasileiros não se con-
sidera adepta de algum partido, mas a grande mai-
oria dos que assim se consideram já esteve com-
prometida com o PT. A preferência pelo PT “cres-
ceu mais ou menos consistentemente de 6% em
1989 para 24% no final de 2004 (Samuels, 2006, Esta seção inicia com uma descrição da re-
presentação de base partidária no Brasil até e após
a crise de corrupção de 2005. Passa, então, para as
respostas de OSCs à crise e para as formas com
que tentaram remediar o que muitas viam como
um fracasso da democracia representativa em seu
país. Como muitas tinham ligações históricas com
o PT, suas respostas começaram por reafirmar sua
própria autonomia. Representação partidária, corrupção e crise dade civil evoluiu” desde a década de 1990 e há
consciência da necessidade de profissionalizar os
esforços de articulação, com bastante envolvimento
em lobby para reformas. Do lado dos movimentos,
ativistas de direitos sexuais e reprodutivos atribu-
em a ampliação de suas coalizões e o aprimora-
mento de sua capacidade de mobilização à experi-
ência de larga colaboração durante a crise (Rachid,
2007; Schvartzman, 2007). Como é notado, os partidos políticos brasi-
leiros têm uma reputação antiga como fracos e in-
coerentes, mal conectados com a sociedade (Ames,
2001; Mainwaring, 1999b). Diversos estudos re-
centes defendem que o sistema partidário brasilei-
ro é consideravelmente mais capaz de governar do
que sugere sua reputação, com base em comporta-
mento partidário disciplinado no Congresso
(Amorim Neto, 2002; Figueredo; Limongi, 1999). Em questões mais centrais a este artigo – a impor-
tância de fisiologismo, a falta de governança
programática, e os vínculos fracos com cidadãos,
há mais consenso sobre as fraquezas dos partidos
brasileiros. De diversas maneiras, o sistema repre-
sentativo proporcional de lista aberta no Brasil cria
e recria esses atributos. CADERNO CRH, Salvador, v. 21, n. 52, p. 47-66, Jan./Abr. 2008 or, v. 21, n. 52, p. 47-66,
Aqueles que rejeitam o partido governante
e seu presidente carismático fazem suas críticas
por veículos partidários e não-partidários. Setores
do movimento dos desempregados cooperam com
ou são liderados por partidos de extrema esquer-
da (Delamata, 2004), assim como diversas das as- Ainda que a liderança partidária – especial-
mente do sempre presente PJ – permaneça no mes-
mo lugar, a sociedade civil continua fornecendo
alguns aspectos de representação, mesmo que ago-
ra em formato menos dramático. Do lado
institucionalizado, Saba (2006) nota que “a socie- 58 Kathryn Hochstetler, Elisabeth Jay Friedman CRISE PARTIDÁRIA E PARTICIPAÇÃO EMER-
GENTE NO BRASIL A crise não resultou em mui-
tas novas organizações, mas promoveu um grande
esforço de mobilização de redes (networking) en-
tre as organizações existentes, que tentavam agre-
gar e articular alternativas políticas – agora sem o
PT. Seus esforços obtiveram um misto de respos-
tas, tanto do governo quanto do público cidadão. 59 REPRESENTAÇÃO, PARTIDOS E SOCIEDADE CIVIL ... p.5).” Contudo, em agosto de 2005, com o escân-
dalo da corrupção chegando ao auge, a preferência
autodeclarada pelo PT caiu para 18,5% e ainda
estava em 18,8% em setembro de 2006, mesmo
com Lula, o candidato do PT à presidência, pres-
tes a vencer a reeleição (DataFolha, 2005, 2006). Os antigos partidários do PT não migraram para
outros partidos; o declínio gradual do PMDB o
levou a manter apenas 7% dos partidários com-
prometidos e outros partidos flutuam em 5% ou
menos (Samuels, 2006, p.5). A única categoria em
ascensão em 2005 e 2006 foi “sem preferência par-
tidária”, apesar da recuperação nos índices de apro-
vação do Congresso e de Lula (DataFolha). alcançara a presidência e níveis extraordinários de
apoio partidário, e virou o segundo componente
se esvair rapidamente. Mas a extensão da crise
partidária era limitada em comparação com a da
Argentina poucos anos antes. Cerca de 10.000 pes-
soas protestaram pelo impeachment de Lula em
agosto; entretanto, não apenas deixaram de alcan-
çar os milhões que haviam ajudado a derrubar o
Presidente Collor em 1992 (Weyland, 1993), mas
também enfrentaram igual número de contra-pro-
testantes em apoio a Lula (Estado de São Paulo 17
e 20 ago. 2005). Esse momento agudo da crise foi
formado pela lógica partidária corrente: os
apoiadores históricos de Lula nas OSCs, decepci-
onados, não se mobilizaram a seu desfavor em parte
porque isso implicaria aliarem-se ao PSDB contra
o PT (Barbosa, 2006). Além disso, as pessoas que
se mobilizaram para exigir o impeachment de Lula
foram organizadas pelos dissidentes do PSOL e
seus apoiadores partidários. Assim, mesmo no auge
da crise, as OSCs brasileiras não tentaram organi-
zar questionamentos diretos ao controle dos parti-
dos sobre as funções governamentais, com exce-
ção da escolha de alguns por migrar de partido. Assim, de diversas maneiras, os dados dos
surveys apóiam o argumento de que o ano de 2005
trouxe uma crise nas relações dos partidos com o
eleitorado, especialmente para o PT. CRISE PARTIDÁRIA E PARTICIPAÇÃO EMER-
GENTE NO BRASIL Eleitores não
se identificam com partidos nem os consideram
em alta estima; 57% dos brasileiros entrevistados
em agosto de 2006 nem sequer lembravam em quem
haviam votado para deputado federal e deputado
estadual nas eleições de 2002 (DataFolha, 2006). Em 2005, apenas 42% dos brasileiros pensavam
que não se podia ter uma democracia sem parti-
dos políticos.14 Nas eleições de outubro de 2006,
as primeiras a exigirem que partidos alcançassem
um mínimo de 5% dos votos válidos para deputa-
do federal, como condição para manter o status
pleno de partido, houve 46% de rotatividade na
Câmara dos Deputados. Não obstante, os mesmos
quatro partidos que dominaram a política brasilei-
ra desde a década de 1990 continuaram a domi-
nar, demonstrando pouco da incerteza ou
volatilidade eleitoral que era considerada um indi-
cador do sentimento antipartidarista. O PSOL, um
novo partido dissidente do PT em 2003, era o mais
provável a receber os votos de protesto ou
“outsiders”, mas não alcançou o patamar de 5%. O auge da crise partidária na política brasi-
leira recente ocorreu claramente em agosto de 2005. Isso foi particularmente evidente para o PT, que CADE
14 www.consulta.com.mx/interiores/14_entorno_int/
ei_latinbarometro05.html Formas emergentes de representação: recu-
perar autonomia, fazer propostas Os vínculos históricos do PT com muitas
das OSCs mais visíveis e ativas do Brasil significa-
va que sua crise as atingia mais do que uma crise
em outro partido as atingiria (Flynn, 2005). OSCs
ajudaram a formar o PT como um instrumento de
questionamento, primeiramente do governo mili-
tar e depois da desigualdade socioeconômica (Keck,
1992). Em níveis subnacionais, forneceu-lhes opor-
tunidades singulares de participação política
(Baiocchi, 2003; Nylen, 2000). As OSCs e o PT se
uniram em diversas campanhas, desde as diretas
já, na década de 1980, aos esforços de
antiprivatização na década de 1990. As OSCs tra-
balharam de bom grado pela eleição de Lula em
2002 (Hochstetler, 2006b). Quatro anos depois, a
Coordenação de Movimentos Sociais, um agrupa- CADERNO CRH, Salvador, v. 21, n. 52, p. 47-66, Jan./Abr. 2008 60 Kathryn Hochstetler, Elisabeth Jay Friedman afirmando que seus esforços estavam sendo des-
perdiçados internamente (Hochstetler, 2006b; Pro-
jeto Mapas, 2005, p.21). mento de OSCs que estivera historicamente próxi-
mo do PT, propositadamente deixou de dar apoio
direto no primeiro turno da campanha de reelei-
ção de Lula, mas foi às ruas contra o retorno ao
poder da coalizão PSDB-PFL. Em uma manha de
discursos, organizações como a Central Única dos
Trabalhadores (CUT), o Movimento dos Trabalha-
dores Sem Terra (MST) e a Marcha Mundial das
Mulheres insistiam que somente a sua mobilização
poderia mudar a política econômica, qualquer que
fosse o resultado eleitoral.15 O problema, do ponto de vista das OSCs,
não era que não tinham um público. O governo
Lula ansiava por ouvi-los e aplaudia seus esfor-
ços. O próprio Lula se encontrou regularmente com
OSCs ao longo de suas gestões e enfatizou sua
importância como vozes de valores e interesses
sociais (Informes Abong n.246, 2004). O proble-
ma é que a articulação e a agregação de interesses
das OSCs não produziam impacto nas escolhas
de governo. Dezenas de milhares de organizações,
em 33 redes que compõem a Inter-Redes, uma rede
de redes, chegaram a essa conclusão quando for-
malmente renunciaram ao Plano Plurianual em que
haviam trabalhado (Inter-Redes, 2004). Esse resul-
tado demonstra a importância da persistente
dominância dos partidos políticos sobre o espaço
de governo. Esse argumento, de que as OSCs isolada-
mente poderiam e de fato articulariam um modelo
alternativo de desenvolvimento já estava em ela-
boração há algum tempo. Antes de o PT alcançar a
presidência, era o maior agregador de tais afirma-
ções, com vínculos próximos às OSCs (Nylen,
2003; Cabral, 2005). À medida que a campanha de
2002 de Lula progredia com diversos apazigua-
mentos de que ele continuaria as políticas econô-
micas neoliberais de FHC, um grande grupo de
OSCs formou o Fórum Brasileiro do Orçamento
em agosto (antes das eleições em outubro), para
dar voz a um clamor por aumento nos gastos soci-
ais. Também salientaram a necessidade de – e for-
neceram – maior debate público a respeito de ques-
tões orçamentárias, distribuindo 30.000 cópias de
um livreto que descrevia conceitos, como o de
superávit primário, em linguagem acessível (Fórum
Brasileiro do Orçamento, 2004). 15 Observação de marchas de protesto em 28 de junho de
2006, em São Paulo, e entrevistas com organizadores
(Barbosa, 2006; Marcelino; Coelho, 2006). 16 www.gritodosexcluidos.com.br/gritoAmericas/grAm01.
Acesso em: 30 set. 2006. CADERNO CRH, Salvador, v. 21, n. 52, p. 47-66, Jan./Abr. 2008 Diversas ONGs,
às vezes com trabalhos coincidentes, prepararam
propostas econômicas alternativas: o Grito dos Ex-
cluídos, a Coordenação dos Movimentos Sociais,
o Fórum Brasileiro do Orçamento, a Assembléia
Popular, entre outros. No início do governo Lula,
debatiam essas propostas em fóruns organizados
pelo governo, como o Conselho de Desenvolvi-
mento Econômico e Social e as consultas formais
do governo acerca de seu Plano Plurianual 2004/
2007: Um Brasil para Todos. Ao longo dos dife-
rentes estágios, retiraram-se destas arenas para se
concentrarem em iniciativas extra-governamentais, Durante esse período, as OSCs reiteradamente
tentaram mobilizar para a ação seu outro público,
o público de massa, na esperança de utilizar am-
plas demandas públicas para forçar sua visão eco-
nômica. Um lugar para medir seu sucesso em al-
cançar esse público é no Grito dos Excluídos, uma
marcha realizada anualmente em 7 de setembro,
dia da Independência. Organizações próximas à
Igreja Católica iniciaram o primeiro Grito em 1995,
e ele se espalhou pelas Américas em 2000. Um
ponto alto para essas mobilizações foi em 2002,
quanto os organizações contaram 214.000
marchadores e mais de 10 milhões de participan-
tes em um plebiscito sobre o Acordo de Livre Co-
mércio das Américas. Mais de 98% dos eleitores
rejeitaram o tratado.16 Em 2006, os organizadores
esperavam uma mobilização massiva de um mi-
lhão ou mais, para chamar a atenção para suas
demandas de transformação econômica e política,
e definiram regras rígidas proibindo os políticos
de falaram – o que também era proibido pela lei
eleitoral (Folha de São Paulo, 7 set., 2006). As es- 61 REPRESENTAÇÃO, PARTIDOS E SOCIEDADE CIVIL ... timativas dos participantes, de fato, variavam en-
tre a contagem inicial e otimista dos organizadores,
em 300.000,17 e a do Estado de São Paulo (7 set.,
2006), que não chegava a 10.000. Os organizadores
também superestimaram sua capacidade de atrair
apoio popular na mobilização eleitoral acima refe-
rida – somente algumas centenas apareceram, ao
invés dos cerca de 30.000 esperados. Os pobres
brasileiros, um grande público em nome do qual
essas organizações afirmam falar, são o maior blo-
co eleitoral de Lula nas pesquisas pré-eleitorais
(DataFolha, 2006), em vez de “votarem com os pés”
e inflarem tais protestos. tivo constitucional de iniciativas populares (art.14),
enfatizando que a Constituição de 1988 insistia
nas origens populares do poder, a ser exercido tan-
to direta quanto indiretamente. CADERNO CRH, Salvador, v. 21, n. 52, p. 47-66, Jan./Abr. 2008 Quando veio a cri-
se, a lei ainda estava percorrendo calmamente as
Comissões do Congresso. Um grupo maior de OSCs
passou então a ecoar por ela. Em junho de 2005,
centenas delas assinaram uma Carta ao Povo Brasi-
leiro, em que criticam fortemente a democracia re-
presentativa e clamavam por mecanismos políticos
diretos.18 Diversos encontros de organizações ecoa-
ram esses aspectos nos meses seguintes, ainda que
em termos relativamente vagos (Hochstetler, 2006b). As OSCs brasileiras têm lutado para mobi-
lizar seus públicos a respeito de questões econô-
micas desde muito antes da recente crise partidá-
ria. A principal mudança de pauta em virtude da
crise é a renovação de uma iniciativa significativa
de reforma política. Com muitas organizações e
biografias pessoais de ativismo tendo origem na
luta pela democracia, há um antigo interesse em
instituições políticas e reforma política. Na década
de 1990, boa parte dessa pauta era focada em es-
forços para obter e consolidar a representação po-
pular e de OSCs nos processos decisórios do go-
verno, como os ubíquos conselhos ou os proces-
sos de orçamento participativo (Baiocchi, 2003;
Friedman; Hochstetler, 2002). Esses esforços
freqüentemente contavam com o PT como colabo-
rador ou mesmo proponente. A experiência das
OSCs com o PT no poder, especialmente após a
crise de corrupção, levou-as a repensar esse foco. Nos primeiros três anos de Lula no poder, quase 2
milhões de pessoas participaram nas conferências
nacionais de sua gestão a respeito de diferentes
questões (Reforma Política, 2006, Apêndice 3), mas,
como notado acima, as OSCs quase sempre fica-
vam desapontadas com os resultados substantivos. Em 2004, bem antes da crise de corrupção, Afora essa insatisfação generalizada, um gru-
po de OSCs tomou a iniciativa de trabalhar em
propostas mais específicas. De agosto a novembro
de 2005, 60 participantes que representavam 21
estados discutiram estratégias para lidar com a cri-
se política. Como eles mesmos apontam, suas pro-
postas iniciais de reforma política eram substanci-
almente mais amplas do que o processo paralelo
de reforma dos partidos, que focava apenas a re-
forma eleitoral e partidária (Reforma Política, 2006,
p.25). As OSCs propuseram diversas reformas que
mudariam o funcionamento da democracia repre-
sentativa – desde limites de mandato ao fim dos
votos secretos – mas traziam propostas adicionais
para a democracia direta, medidas participativas,
democratização da informação e da comunicação e
transparência judiciária. 18 www.lainsignia.org/2005/junio/ibe_087.htm. Acesso
em: 23 jun. 2005. 17 www.gritodosexcluidos.com.br/gritoBrasil/grBr30/. Aces-
so em: 30 set. 2006. CADERNO CRH, Salvador, v. 21, n. 52, p. 47-66, Jan./Abr. 2008 Incorporaram a proposta
da OAB e do CNBB como parte de seu projeto
maior. Ao longo do ano seguinte, diversos partici-
pantes se reuniram para discutir e refinar as pro-
postas, graças a intensivas consultas e discussões
no fórum social brasileiro e diversos fóruns de base
geográfica. Ignoraram o calendário eleitoral nessas
discussões, preferindo ter seu último encontro no
final de novembro de 2006, quando já teriam se
encerrado as eleições. As OSCs apresentaram suas
propostas ao recém-eleito Congresso em março de
2007, recebendo considerável apoio parlamentar. Isso marcou seu retorno ao segundo mandato de CADER
17 www.gritodosexcluidos.com.br/gritoBrasil/grBr30/. Aces-
so em: 30 set. 2006.
18 www.lainsignia.org/2005/junio/ibe_087.h
em: 23 jun. 2005. CADERNO CRH, Salvador, v. 21, n. 52, p. 47-66, Jan./Abr. 2008 RH, Salvador, v. Em 2004, bem antes da crise de corrupção,
a Ordem dos Advogados do Brasil (OAB) e a Con-
gregação Nacional dos Bispos do Brasil (CNBB)
propuseram uma lei que regulamentava o disposi- 62 Kathryn Hochstetler, Elisabeth Jay Friedman se apresentaram como alternativas organizacionais
aos partidos, mas lutaram para representar valores
e idéias que não estavam sendo representados. Es-
ses incluíam tanto propostas econômicas substan-
tivas e propostas para melhorar o processo político,
inclusive o processo de representação partidária. Lula como tendente a uma estratégia mais clássica
de lobby, uma que reconhece o papel central das
tomadas de decisão partidária. Em julho de 2007,
a maior parte dos representantes do PT votou em
sua primeira proposta, sobre uma reforma do sis-
tema eleitoral de lista aberta. A reforma foi rejeita-
da pelo Congresso, juntamente com muitos mem-
bros de partidos da coalizão de governo de Lula
(Vigna, 2007). Lula como tendente a uma estratégia mais clássica
de lobby, uma que reconhece o papel central das
tomadas de decisão partidária. Em julho de 2007,
a maior parte dos representantes do PT votou em
sua primeira proposta, sobre uma reforma do sis-
tema eleitoral de lista aberta. A reforma foi rejeita-
da pelo Congresso, juntamente com muitos mem-
bros de partidos da coalizão de governo de Lula
(Vigna, 2007). Essas experiências corroboram nosso argu-
mento teórico mais amplo, de que as OSCs podem
operar como mecanismos de representação, ainda
que não da mesma forma que partidos. Tanto cida-
dãos quanto governos têm reconhecido que as
OSCs dão voz a importantes idéias e têm respon-
dido às suas propostas. OSCs deram voz aos cida-
dãos no sistema político. No final das contas, as
funções representativas das OSCs não substituí-
ram a representação partidária de maneira perene. Em vez disso, sua representação parece comple-
mentar a dos partidos, com cidadãos utilizando
ambos os mecanismos para influenciar os resulta-
dos políticos. Como sugerem essas propostas de reforma,
as OSCs brasileiras não têm a intenção de substi-
tuir instituições democráticas representativas, como
os partidos políticos e o poder legislativo. Elas
querem que tais instituições funcionem melhor e
têm diversas idéias a respeito de como melhorar
seu funcionamento. Ao mesmo tempo, as OSCs
insistem que partidos políticos não podem mono-
polizar o exercício da soberania popular. Querem
consideravelmente mais participação direta para
cidadãos brasileiros individuais. CADERNO CRH, Salvador, v. 21, n. 52, p. 47-66, Jan./Abr. 2008 Também prevê-
em uma necessidade contínua de pressão da soci-
edade civil organizada, independentemente do
partido que vencer as eleições. (Recebido para publicação em janeiro de 2008)
(Aceito em março de 2008) REPRESENTAÇÃO, PARTIDOS E SOCIEDADE CIVIL ... BARBOSA, Benedito (Coord.) Central of Popular
Movements and National Movement for Urban Reform. Interview, São Paulo, june 29, 2006. workers in greater Buenos Aires. In: ______. CLAS working
papers. Berkeley, California: Center for Latin American
Studies, 2004. BARTOLINI, Stefano, and Peter Mair. Challenges to
contemporary political parties. In: DIAMOND L.;
GUNTHER, R. (Ed.) Political parties and democracy. Baltimore: Johns Hopkins University Press, 2001. DI MARCO, Graciela. Igualdad de género y movimientos
sociales en Argentina. Paper Read at Latin American
Studies Association Meeting, San Juan, Puerto Rico, 2006. FIGUEIREDO, Argelina C.; LIMONGI, Fernando. Presidential power, legislative organization, and party
behavior in Brazil. Comparative Politics, Boston, v.32, n.2,
p.151-170, 2000. BERGEL, Pablo. Nuevas Formas Asociativas: asambleas
vecinales y Movimientos de Trabajadores Desocupados
(MTD). In: GONZÁLEZ BOMBAL, I. (Ed.). Nuevos
Movimientos Sociales e ONGs en la Argentina de la crisis. Buenos Aires: CEDES, 2003. FÓRUM Brasileiro do Orçamento. Superávit primário. Cadernos para Discussão. Brasilía, 2004. BIELSA, Rafael A. et al. Que son las asambleas popula-
res. Buenos Aires: Ediciones Continente, 2002. FOWERAKER, Joe; KRZNARIC, Roman. The uneven
performance of third wave democracies: electoral politics
and the imperfect rule of law in Latin America. Latin
American Politics and Society, Coral Gables, University of
Miami, v. 44, n.3, p.29-59, 2002. BLUMENFELD, José. Member, active memory. Interview,
Buenos Aires, july 4, 2006. BONNER, Michelle D. Defining rights in democratization:
the argentine government and human rights
organizations. Latin American Politics and Society, [S.l.],
v.47, n.4, p.55-76, 2005. FRIEDMAN, Elisabeth Jay; HOCHSTETLER, Kathryn. Assessing the third transition in Latin American
Democratization: civil society in Brazil and Argentina. Comparative Politics, New York, v.35, n.1, p.21-42, 2002. BORLAND, Elizabeth. Mature Resistance: The Madres de
Plaza de Mayo in Argentina. Latin American Studies
Association Meeting, San Juan, Puerto Rico, 2006. FUCHS, Dieter; KLINGEMANN, Hans-Dieter. Citizens and
the state: a relationship Transformed. In: ______; ______. (Ed.) Citizens and the state. Oxford, UK: Oxford University
Press, 1995. CABRAL, Gilda. Technical advisor, CFEMEA; executive
secretary, Brazilian Budget Forum (FBO). Interview, Brasília,
aug. 9, 2005. GAUDIN, Andres. The kirchner factor. NACLA, [S.l.],
v.38, n.4, p.16-19, 2005. CALVO, Ernesto; ESCOLAR, Marcelo La nueva política
de partidos en la Argentina: crisis política, realineamentos
partidarios y reforma electoral. Buenos Aires: Prometeo
Libros, 2005. GOLDSTONE, Jack A.; THOMAS, Cliva S. More social
movements or fewer? Beyond political opportunity
structure to relational fields. Theory and Societ, Norwell,
n.33, p.333-365, 2004. CAMARERO, Hernàn; POZZI, Pablo; SCHNEIDER,
Alejandro. REPRESENTAÇÃO, PARTIDOS E SOCIEDADE CIVIL ... Unrest and repression in Argentina. New
Politics, Usuhuaia, Argentina, v.7, n.1, 1998. Disponível
em: www.wpunj.edu/newpol/issue25/camare25.htm GONZÁLES BOMBAL, Inés (Ed.). Nuevos movimientos
sociales y ONGs en la Argentina de la crisis. Buenos Aires:
CEDES, 2003. CAREY, John.. Discipline, accountability, and legislative
voting in Latin America. Comparative Politics,[S.l.], v.35,
n.2, p.191-211, 2003. GURZA LAVALLE, Adrián; HOUTZAGER, Peter P.;
CASTELLO, Graziela. Representação política e organiza-
ções civis: novas instâncias de mediação e os desafios da
legitimidade. Revista Brasileira de Ciências Sociais, São
Paulo, v.21, n.60, 2006. CHALMERS, Douglas A. et al (Ed.) The new politics of
inequality in Latin America: rethinking participation and
representation. Oxford: Oxford University Press, 1997. HELLMAN, Judith Adler. The study of new social
movements in Latin America and the question of
autonomy. In: ESCOBAR, A.; ALVAREZ, S. E. (Ed.) The
making of social movements in Latin America: identity,
strategy, and democracy. Boulder: Westview Press, 1992. CHANDOKE, Neera. Revisiting the crisis of representation
thesis: the Indian context. Democratization v.12, n.3,
p.308-330, 2005. CIPPEC. Centro de Implementación de Políticas Públicas
para la Equidad y el Crecimiento. Directorio de ONGs vin-
culadas con políticas públicas, 2006. Disponível em:
www.directoriodeongs.org/ HOCHSTETLER, Kathryn. Rethinking presidentialism:
challenges and presidential falls in South America. Comparative Politics, New York, v.38, n.4, p.401-418, 2006a. ______. Organized civil society in Lula’s Brazil. PAPER
PREPARED FOR PRESENTATION AT THE LATIN
AMERICAN STUDIES ASSOCIATION CONFERENCE,
[S.l.], 2006b. 7-66, Jan
COELHO, Sonia. Sempreviva Feminist Organization (SOF)
and World March of Women. Interview, São Paulo, june
29, 2006. . 52, p. 4
CRISP, Brian F. et al. Vote-seeking incentives and legislative
representation in six presidentialdemocracies. Journal of
Politics, [S.l.], v.66, n.3, p.823-846. 2004. IÑIGO CARRERA, Nicolás; COTARELO, María Celia. La
insurrección espontánea, Argentina Diciembre 2001. Descripción, periodización, conceptualización. PIMSA,
Documento de Tranbajo, n.43, 2003. ador, v. 21, n
DALTON, Russell J.; WATTENBERG, Martin P. Unthinkable Democracy: Political Change in Advanced
Industrial Democracies. In: ______; ______ (Ed.) Parties
without partisans: political change in advanced industrial
societies. Oxford: Oxford University Press, 2000. INTER-REDES. 2005. Comunicado Inter-redes e ABONG
2004. Disponível em: www.forumfbo.org.br/publique/cgi/
cgilua.exe/sys/start.htm?infoid=35&sid=10 JEIFETZ, Néstor R. President, Movement of Residents
and Tenants (MOI). Interview, Buenos Aires, july 9, 2006. RH, Salv
______; SCARROW, Susan E.; CAIN, Bruce E. Advanced
democracies and the new politics. Journal of Democracy,
Washington, v.15, n.1, p. 124-138, 2004. KECK, Margaret. The worker’s party and democratization
in Brazil. New Haven: Yale University Press, 1992. DERNO CR
DE PIERO, Sergio. CONCLUSÕES ALVAREZ, Sonia E. Engendering democracy in Brazil:
women’s movements in transition politics. Princeton:
Princeton University Press, 1990. Os partidos políticos podem deixar muitas
lacunas de representação. No Brasil e na Argenti-
na, tais lacunas estão sempre presentes, mas as
recentes crises partidárias acentuaram a sensação
dos cidadãos de que seus partidos políticos não
as preenchem adequadamente. Em ambos os paí-
ses, as OSCs se prontificaram a preencher algu-
mas das lacunas, ainda que o tenham feito de for-
mas diferentes. Na Argentina, cidadãos formaram
novas OSCs para contornar a representação parti-
dária, rejeitando a classe política em favor de se
representarem diretamente. OSCs novas e já exis-
tentes detinham uma posição especial como ato-
res éticos, de princípios. Ao longo do tempo, po-
rém, os partidos se reorganizaram e até consegui-
ram cooptar algumas das novas OSCs. Outras con-
tinuam, agora trabalhando em paralelo aos repre-
sentantes partidários. No Brasil, as OSCs nunca AMES, Barry. The deadlock of democracy in Brazil. Ann
Arbor: University of Michigan Press, 2001. AMORIM NETO, Octavio. Critical debates: The puzzle of
party discipline in Brazil. Latin American Politics and
Society, v.44, n.1, p.127-144, 2002. 47-66, Jan
ANTOKOLETZ, María Adela. Communications director,
mothers of the Plaza de Mayo – founding line. Interview,
Buenos Aires, july 3, 2006. 52, p. 4
ASOCIACION POR LOS DERECHOS CIVILES. La corte y
los derechos. Buenos Aires: Siglo Veintiuno Editores, 2005. ador, v. 21, n. 5
AUYERO, Javier. Protest in contemporary Argentina. A
contentious repertoire in the making. In: ______. FERNÁNDEZ-KELLY, P; SHEFNER, J. (Ed.) Out of the
shadows: political action and the informal economy in
Latin America. [S.l.]; University park Penn State Press,
2005. H, Salv
______. Poor people’s politics. Durham and London: Duke
University Press, 2001. O CRH
AVRITZER, Leonardo. Democracy and the public space in
Latin America. Princeton: Princeton University Press, 2002. CADERN
BAIOCCHI, Gianpaolo. (Ed.) Radicals in power: the
worker’s party and experiments in urban democracy in
Brazil. New York: Palgrave, 2003b. 63 REPRESENTAÇÃO, PARTIDOS E SOCIEDADE CIVIL ... Inside the black box: recent studies of Latin
American party organizations. Studies in Comparative
International Development [S.l.], v.36, n.2, p.92-110,
2001b. PERUZZOTTI, Enrique. Civil society, Representation and
accountability: restating current debates on the
representativeness and accountability of civic associations. forthcoming. In: VAN TUJIL, P.; JORDAN L. (Ed.) The
politics of NGO accountability. London: Earthscan, 2006. LEVITSKY, Steven. An “organized disorganisation”: in-
formal organisation and the persistence of local party
structures in Argentine peronism. Journal of Latin
American Studies, [S.l.], v.33, n.1, p.29-65, 2001c. ______. Towards a new politics: citizenship and rights in
contemporary Argentina. Citizenship Studies, [S.l.], v.6,
n.1, p.77-93, 2002. LOZANO, Claudio et al. Protestas sociales en la Argentina
contemporanea: principales caracteristicas. abril/junio,
2004. Buenos Aires: CTA Instituto de Estudios y
Formacion, 2004. PITKIN, Hanna Fenichel. The concept of representation. Berkeley: University of California Press, 1967. LUCERO, José Antonio. High anxiety in the Andes: crisis
and contention in Ecuador. Journal of Democracy, Wa-
shington, n.12, apr., p.59-73, 2001. POGUNTKE, Thomas. European Journal of Political
Research, [S.l.], v.29, n.3, p.319-344. 1996. POWELL, G. Bingham. Political representation in
comparative politics. Annual Review of Political Science,
Paolo Alto, n.7, p.273-96, 2004. MANIN, Bernard. Principles of representative government. Cambridge, UK: Cambridge University Press, 1997. MAINWARING, Scott. The surprising resilience of elected
governments. Journal of Democracy, Washington, v.10,
n.3, p.101-114, 1999a. PRZEWORSKI, Adam; STOKES, Susan C.; MANIN,
Bernard (Ed.) Democracy, accountability, and
representation. Cambridge, UK: Cambridge University
Press, 1999. ______. Rethinking party systems in the third wave of
democratization: the case of Brazil. Stanford: Stanford
University Press, 1999b. 7-66, Jan
RACHID, Maria. President, Argentine federation of
lesbians, gays, bisexuals and trans. Interview, Buenos
Aires, aug., 6, 2007 ______. The crisis of representation in the Andes. Journal
of Democracy, Washington, v.17, n.3, p.13-27, 2006. n. 52, p. 4
REFORMA política: construindo a plataforma dos movi-
mentos sociais para a reforma do sistema político no Bra-
sil - reflexões para o debate. 2006. Disponível em:
www.abong.org ______; SCULLY, Timothy R. (Ed.). Building democratic
institutions: party systems in Latin America. Stanford,
CA: Stanford University Press, 1995. or, v. 21,
REHFELD, Andrew. Towards a general theory of political
representation. Journal of Politics [S.l.], v.68, n.1, p.1-21,
2006. MARECLINO, Maria Fernanda. Sempreviva Feminist
Organization (SOF) and World March of Women. Interview,
São Paulo, june 29, 2006. RH, Salvad
ROBERTS, Kenneth M. Party-society linkages and the
transformation of political representation in Latin
America. REPRESENTAÇÃO, PARTIDOS E SOCIEDADE CIVIL ... Organizaciones de la sociedad civil:
tensiones de una agenda en construcción. Buenos Aires:
Paidós, 2005. KITSCHELT, Herbert. Landscapes of political interest
intermediation: social movements, interest groups, and
parties in the early twenty-first century. In: IBARRA, P. (Ed.) Social movements and demcracy. New York; CA
DELAMATA, Gabriela. The Organizations of unemployed 64 Kathryn Hochstetler, Elisabeth Jay Friedman Basingstoke: Palgrave Macmillan, 2003. MUSTAPIC, Ana Maria. Inestabilidad sin colapso. La re-
nuncias de los presidentes: Argentina en el año 2001. Desarrollo Económico, Buenos Aires, v.45, n.178, p.263-
279, 2005. Basingstoke: Palgrave Macmillan, 2003. ______. Linkages between citizens and politicians in
democratic politics. Comparative Political Studies, [S.l.],
Sage, v.33, n.6/7, p.845-879, 2000. NORDEN, Deborah L. Democracy beyond elections? The
shifting nature of representation in Argentina. PAPER
PREPARED FOR PRESENTATION AT THE LATIN
AMERICAN STUDIES ASSOCIATION CONFERENCE. [S.l.], 2006. KOROL, Claudia (Ed.). Obreros sin patron: sistematizacion
de la experiencia de los obreros y obreras de Zanon. Buenos
Aires: Ediciones Madres de Plaza de Mayo, 2004. KURTZ, Marcus. The dilemmas of democracy in the open
economy: lessons from Latin America. World Politics,
Baltimore, v.56, n.1, p.262-302, 2004. NYLEN, William R. The making of al loyal opposition:
The workers’ party (PT) and the consolidation of
democracy in Brazil. In: KINGSTONE, P. R.; POWER, T. J. (Ed.) Democratic Brazil: actors, institutions, and proces-
ses. Pittsburgh: University of Pittsburgh Press, 2000. LAVACA. Sin patron: fabricas y empresas recuperadas por
sus trabajadores. Una historia, una guia. Buenos Aires:
Lavaca Editora, 2004. O’DONNEL, Guillermo. Horizontal accountability in new
democracies. Journal of Democracy, Washington, v.9, n.3,
p.112-126, 1998. LAWSON, Kay; POGUNTKE,Thomas (Ed.). How political
parties respond: interest aggregation revisited. London;
New York: Routledge, 2004. OJEDA, Fernando. El ceibo neighborhood work. Interview,
Buenos Aires, july 6, 2006. ______; MERKL, Peter H. (Ed.) When parties fail: emerging
alternative organizations. Princeton: Princeton University
Press, 1988. PANEBIANCO, Angelo. Political parties: organization and
power. Cambridge: Cambridge University Press, 1988. LESCANO, Escano, Cristina. El ceibo neighborhood work. Interview, Buenos Aires, july 6, 2006. PANIZZA, Fransisco. Unarmed utopia revisited: the
resurgence of left-of-centre politics in Latin America. Political Studies, [S.l.], v.53, n.4, p.716-734, 2005. LEVITSKY, Steven. Organization and labor-based party
adaptation: the transformation of Argentine peronism in
comparative perspective. World Politics, Baltimore, v.54,
n.1, p.27-56, 2001a. PEARCE, Jenny. Debate: collective action or public
participation? Complementary or contradictory
democratisation strategies in Latin America? Bulletin of
Latin American Research, [S.l.], v.23, n.4, p.483-504, 2004. ______. REPRESENTAÇÃO, PARTIDOS E SOCIEDADE CIVIL ... Canadian Journal of Latin American and
Caribbean Studies, [V.l.], v.27, n.53, p.9-34, 2002. MARTÍN VEZZULLA, Juan. Legal Advisor, Environment
and Natural Resources Foundation (FARN). Interview,
Buenos Aires, july 12, 2006. MCGUIRE, James W. Political parties and democracy in
Argentina. In: MAINWARING, Scott; SCULLY, T. R. (Ed.)
Building democratic institutions: party systems in Latin
America. Stanford, CA: Stanford University Press, 1995. CADERNO CR
RODRIGUEZ, María Carla. Co-founder, Movement of
Residents and Tenants (MOI); Researcher, Gino Germani
Institute, University of Buenos Aires. Interview, Buenos
Aires, july 9, 2006. 65 REPRESENTAÇÃO, PARTIDOS E SOCIEDADE CIVIL ... SABA, Roberto. Executive Director, Association of Civil
Rights (ADC). Interview, Buenos Aires, july 12, 2006. dimensiones y desafíos de las organizaciones de desocu-
pados en Argentina. Medio Ambiente y Urbanización,
Buenos Aires, v.61, n.1, p.97-112, 2005. SAMUELS, David. Sources of mass partisanship in Brazil. Latin American Politics and Society, Coral Gables,
University Miami, v.48, n.2, p.1-27, 2006. TAYLOR-ROBINSON, Michelle M. Old parties and new
democracies: do they bring out the best in each other? Party Politics, [S.l.], v.7, n.5, p.581-604. 2001. SANCHEZ, Omar. Argentina’s landmark 2003, presidential
election: renewal and continuity. Bulletin of Latin
American Research, [S.l.], v.24, n.4, p. 454-475, 2005. THOMASs, Clive S. Studying the political party-interest
group relationship. In: ______. (Ed.). Political parties and
interest groups. Boulder: Lynne Rienner. 2001. SANCHÍS, Norma. Regional Coordinator, International
Network of Gender and Commerce. Interview, Buenos
Aires, july 12, 2006. TORRE, Juan Carlos. Los heurfanos de la política de par-
tidos. sobre los alcances y la naturaleza de la crisis de
representación partidaria. Desarrollo Económico, Buenos
Aires, v.42, n.168, p.647-665, 2003. SARDÁ, Alejandra. Resisting kirchner’s Recipe
(sometimes): ‘LGBTTTI’ Organizing in Argentina. NACLA
Report on the Americas, [S.l.], v.40, n.2, p.30-32, 42, 2007. TURNER, Frederick; CARBALLO, Marita. Argentina:
economic disaster and the rejection of the political class. Comparative Sociology, [S.l.], v.4, n.1/2, p.175-206, 2005. SAWARD, Michael, ed. Democratic innovation:
deliberation, representation and association. New York:
Routledge, 2001. VALENTE, Marcela. Argentina: human rights trials trigger
wave of threats. Inter Press Service New Agency, [S.l.], 10/
4/2006. SCHVARTZMAN, Elsa. Member, Forum for Reproductive
Rights and National Campaign for for the Right to Legal,
Safe, and Free Abortion. Interview, Buenos Aires, aug., 6,
2007. VAN COTT, Donna Lee. From movements to parties in
Latin America: the evolution of ethnic politics. Cambridge, UK: Cambridge University Press, 2005. SECCHI, Pablo. Co-coordinator, Political Action Area,
Citizen Power. Interview, Buenos Aires, july 3, 2006. ZIBECHI, Raúl. Subterranean echoes: resistance and
politics “Desde el Sótano.” Socialism and Democracy,
[S.l.], v.19, n.3, p.13-39, 2005. REPRESENTAÇÃO, PARTIDOS E SOCIEDADE CIVIL ... VERDÚ, Maria del Carmen. Spokesperson and lawyer. Coordinator Against Police and Institution Repression
(CORREPI). Interview, Buenos Aires, july 10, 2006. SITRIN, Marina [Ed.]. Horizontalidad: voces de poder
popular. Buenos Aires: Cooperativa Chilavert Artes
Graficas, 2005. VIGNA, Edélcio. O futuro da reforma política. Disponível
em: www.ciranda.net/ spip/article1422.html. Acesso em:
20 sept., 2007. SMULOVITZ, Catalina; PERUZZOTTI, Enrique. Societal
accountability in Latin America. Journal of Democracy,
Washington, p.147-158, 2000. WALGER, Sylvina, PERUZZOTTI, Enrique. El govierno
actua sin el debido control. La Nacion, [S.l.], 09/9/2006. SUNDHEIM,
Marcelo. Secretary,
Homosexual
Community of Argentina (CHA). Interview, Buenos Aires,
july 5, 2006. WEBB, Paul. Political parties and democracy: the
ambiguous crisis. Democratization, [S.l.], v.12, n.5, p.633-
650, 2005. SVAMPA, Maristella. La sociedad excluyente: la Argenti-
na bajo el signo del neoliberalismo. Buenos Aires: Taurus,
2005. WEYLAND, Kurt. The rise and fall of President Collor
and its impact on Brazilian democracy. Journal of
Interamerican Studies and World Affairs, [S.l.], n.35, p.1-
37, 1993. ___; PEREYRA, Sebastián. La experiencia piquetera: ZIBECHI, Raúl. Subterranean echoes: resistance and
politics “Desde el Sótano.” Socialism and Democracy,
[S.l.], v.19, n.3, p.13-39, 2005. CADERNO CRH, Salvador, v. 21, n. 52, p. 47-66, Jan./Abr. 2008 66
|
https://openalex.org/W2125160951
|
https://www.scielo.br/j/rbccv/a/VTb5StjdZQMS3DvsyrpcDYj/?lang=pt&format=pdf
|
Portuguese
| null |
Fatores de risco no desenvolvimento de insuficiência renal aguda após cirurgia de revascularização miocárdica com CEC
|
Brazilian Journal of Cardiovascular Surgery
| 2,007
|
cc-by
| 5,066
|
1.
Doutorado. Chefe do Departamento de Clínica Cirúrgica e Chefe
do Serviço de Cirurgia Cardiovascular do Hospital Universitário –
Universidade Federal do Mato Grosso do Sul (UFMS). Trabalho realizado na Universidade Federal de Mato Grosso do Sul,
Departamento de Clínica Cirúrgica Disciplina de Cirurgia
Cardiotorácica, Campo Grande, MS. Rev Bras Cir Cardiovasc 2007; 22(4): 484-490 Rev Bras Cir Cardiovasc 2007; 22(4): 484-490 EXPERIÊNCIA DE SERVIÇO Risk factors for the development of acute renal failure following on-pump coronary artery bypass grafting José Carlos Dorsa Vieira PONTES1, Guilherme Viotto Rodrigues da SILVA2, Ricardo Adala BENFATTI3, Natália
Pereira MACHADO4, Renato PONTELLI4, Elenir Rose Jardim Cury PONTES5 Endereço para correspondência:
José Carlos Dorsa Vieira Pontes. Departamento de Clínica Cirúrgica,
Universidade Federal do Mato Grosso do Sul. Av. Senador Filinto
Muller, 1. Campo Grande - MS, Brasil.
Telefone: (67)3345-3109.
E-mail: carlosdorsa@uol.com.br RBCCV 44205-932 5,56% necessitaram de diálise, correspondendo a 1,35% do
total de pacientes avaliados. A mortalidade por IRA foi de
5,56%. O uso de drogas inotrópicas ou vasoconstritoras no
pós-operatório (p=0,048) e o IMC maior que 25 kg/m2 (p=0,004)
foram fatores determinantes para o desenvolvimento de IRA. O tempo de circulação extracorpórea foi baixo, não
influenciando um aumento significativo de IRA pós-operatória
neste estudo. 2.
Graduando do curso de Medicina, UFMS. 3.
Cirurgião Cardiovascular Assistente do Serviço de Cirurgia
Cardiovascular do Hospital Universitário – UFMS. Artigo recebido em 10 de abril de 2007
Artigo aprovado em 6 de setembro de 2007 5.
Doutorado; Professora responsável pela disciplina de Bioestatística
- Departamento de Tecnologia de Alimentos – UFMS. 4.
Médico Residente– UFMS. Endereço para correspondência:
José Carlos Dorsa Vieira Pontes. Departamento de Clínica Cirúrgica,
Universidade Federal do Mato Grosso do Sul. Av. Senador Filinto
Muller, 1. Campo Grande - MS, Brasil. Telefone: (67)3345-3109. 2.
Graduando do curso de Medicina, UFMS. Endereço para correspondência: E-mail: carlosdorsa@uol.com.br Resumo Resumo Objetivos: Avaliar a incidência, a mortalidade e os fatores
de risco no desenvolvimento de insuficiência renal aguda
(IRA) após cirurgia de revascularização miocárdica com o
emprego de circulação extracorpórea (CEC), no serviço de
Cirurgia Cardiovascular do Hospital Universitário da
Universidade Federal de Mato Grosso do Sul, de janeiro de
2002 a novembro de 2004. Conclusão: O tempo de CEC não esteve associado a um
aumento estatisticamente significativo da incidência de
IRA pós-operatória na cirurgia de revascularização do
miocárdio. Métodos: Estudo retrospectivo de 74 pacientes submetidos
à revascularização miocárdica com circulação extracorpórea,
distribuídos em dois grupos segundo o desenvolvimento ou
não de insuficiência renal aguda, diagnosticada por critérios
laboratoriais. Foram realizadas análises estatísticas
bivariada e multivariada, com significância de 5%. Descritores: Revascularização miocárdica. Insuficiência
renal aguda. Circulação extracorpórea. Resultados: A incidência de IRA foi de 24,32%, sendo que 5. Doutorado; Professora responsável pela disciplina de Bioestatística
- Departamento de Tecnologia de Alimentos – UFMS. Artigo recebido em 10 de abril de 2007
Artigo aprovado em 6 de setembro de 2007 E-mail: carlosdorsa@uol.com.br 484 Rev Bras Cir Cardiovasc 2007; 22(4): 484-490 PONTES, JCDV ET AL - Fatores de risco no desenvolvimento de
insuficiência renal aguda após cirurgia de revascularização miocárdica
com CEC Abstract developed acute renal failure (ARF); 1 patient (1.35%), who
required dialysis, died. Associated risk factors identified in-
between the development of ARF was: the postoperative use
of inotropic or vasoconstrictor drugs (p=0.048) and body mass
index greater than 25 (p=0.004). The CPB time did not
determine the ARF increase (p=0.0668). Objectives: To evaluate incidence, mortality, and risk
factors related to the development of acute renal failure
(ARF) after on-pump coronary artery bypass grafting
(CABG), between January 2002 and November 2004. Methods: Seventy four patients who underwent on-pump
CABG were analyzed retrospectively and distributed into two
groups according to the development of ARF. Bivariate and
multivariate analyses were performed to analyze. P ≤ 0.05
was considered statistically significant. Conclusion: The CPB time was not associated with an
increased of ARF following on-pump CABG. Descriptors: Myocardial revascularization. Renal
insufficiency, acute. Extracorporeal Circulation. Results: During the period analyzed, 18 patients (24.32%) INTRODUÇÃO de suma importância identificar os fatores de risco
relacionados com uma das mais importantes complicações
pós-operatórias decorrentes de tal procedimento
terapêutico, a insuficiência renal aguda. As revascularizações do miocárdio são realizadas,
muitas vezes, com o auxílio de circulação extracorpórea
(CEC) e hipotermia sistêmica leve a moderada. Entretanto,
existem complicações pós-operatórias decorrentes dessa
terapia, entre elas a insuficiência renal aguda (IRA), que
tem sido causa de alta morbidade e mortalidade [1-22]. O
aumento da incidência de lesão renal tem sido relacionado
a vários fatores, sendo os mais importantes a utilização e o
tempo de CEC, idade, função renal pré-operatória, uso de
drogas inotrópicas, uso de furosemide intra-operátorio e
comorbidades associadas, como diabetes, insuficiência
cardíaca e doença vascular periférica, entre outras [2-14]. Após revisão da literatura disponível, observou-se uma
incidência de 0,7% a 31% [2-14] de IRA pós-revascularização
miocárdica com circulação extracorpórea e necessidade de
terapia dialítica de 0,9% a 4,9% [5,11,12]. Estes pacientes
tiveram taxas de mortalidade de 1,3 a 90% [2-14]. Não há atualmente consenso sobre os fatores mais
preponderantes associados à IRA pós-cirúrgica, tornando
difícil uma estratificação de risco para o seu
desenvolvimento. Vale ressaltar que a comparação entre
os trabalhos é, de certa forma, difícil em decorrência dos
vários critérios de classificação entre função renal normal e
IRA utilizados nos mesmos. A natureza do impacto da cirurgia cardíaca na função
renal não é completamente esclarecida, tendo como um dos
fatores de risco o uso da CEC. Entre as conseqüências
desse método provavelmente envolvidas na fisiopatologia
da IRA podemos citar: fluxo sanguíneo renal não pulsátil,
aumento das catecolaminas e mediadores inflamatórios
circulantes (IL-1, IL-6, IL-8), insultos micro e
macroembólicos aos rins, distúrbios eletrolíticos
(hipomagnesemia) e o aumento da hemoglobina livre
decorrente de hemólise [5,18-20]. Entretanto, alguns autores
desconsideram os efeitos adversos da CEC, atribuindo os
danos renais à redução do fluxo sanguíneo e ao aumento
da resistência vascular renais, alterações hemodinâmicas
decorrentes da própria cirurgia [2]. Considerando-se os dados atualmente existentes na
literatura pertinente e a carência de trabalhos nacionais a
respeito do tema abordado, foi proposto este estudo, na
tentativa de reconhecer os fatores de risco dos pacientes
predispostos a tal complicação, para melhor assistência
aos mesmos nos períodos pré, intra e pós-operatórios. RESULTADOS Após esternotomia mediana longitudinal padrão, em
todos os pacientes, a CEC foi instalada com canulação da
aorta ascendente e drenagem venosa através de canulação
única (duplo estágio), após heparinização sistêmica com
4mg/kg, repetida de acordo com o TCA (tempo de
coagulação ativado), com o objetivo de mantê-lo acima de
450 segundos. As perfusões foram realizadas em hipotermia
leve (32°C), com pinçamento aórtico intermitente. Todo o
material artificial descartável empregado na CEC não possuía
revestimento de heparina (circuito não heparinizado). A
neutralização da heparina foi realizada, em todos os casos,
com infusão de sulfato de protamina na dose de 1:1, diluída
em soro glicosado 5%. Foram utilizados bomba de rolete na
linha arterial e oxigenadores de membranas de fibras ocas
com filtro de linha arterial (Braile Biomédica - São José do
Rio Preto - SP) e com perfusato de 1500 ml aproximadamente. Entre os pacientes analisados, encontram-se 51 (68,9%)
homens e 23 (31,1%) mulheres, cuja idade média foi 61,82
anos (DP ± 9,86). A idade média dos pacientes que
apresentaram IRA foi de 63±11 anos e a dos que não
apresentaram foi de 61±9 anos, não havendo diferença
estatisticamente significativa (p=0,4591). O IMC médio dos
pacientes do grupo I foi de 275 25 kg/m2 e o do grupo II foi
de 25±4 kg/m2, havendo diferença estatisticamente
significativa (p=0,0191). A incidência de IRA foi de 24,32%
(18 pacientes), dentre os quais 5,56% (um paciente)
necessitaram de diálise, correspondendo a 1,35% do total
de pacientes avaliados. A mortalidade por IRA foi de 5,56%
(um paciente), sendo este o mesmo que necessitou de
terapia dialítica. As características gerais dos pacientes
encontram-se na Tabela 1. O tempo médio de permanência
na UTI dos pacientes que apresentaram IRA foi de 5 dias
(DP ± 4), enquanto que dos que não a apresentaram foi de
4 dias (DP ± 2), não havendo diferença estatisticamente
significativa entre estes pacientes (p=0,6411). Referentes ao período pós-operatório constam os níveis
de creatinina sérica, pressão venosa central, pressão arterial
média, débito urinário, necessidade de diálise, tempo de
permanência na unidade de terapia intensiva e tempo de
internação hospitalar. Entre as variáveis categóricas comparadas entre os grupos
que apresentaram ou não IRA, houve diferença significativa
nas seguintes: IMC > 25 kg/m2 (p=0,004) e uso de drogas
inotrópicas ou vasoconstritoras no pós-operatório (p=0,048)
- Tabela 2. As variáveis quantitativas foram comparadas
estatisticamente e expressadas no Quadro 1. OBJETIVO Avaliar a incidência, mortalidade e fatores de risco
associados à IRA no pós-operatório da cirurgia de
revascularização do miocárdio com CEC, nos pacientes
atendidos no serviço de Cirurgia Cardiovascular do Hospital
Universitário da Universidade Federal de Mato Grosso do
Sul, no período de janeiro de 2002 a novembro de 2004. Em virtude do envelhecimento da população brasileira
e necessidade dos pacientes cada vez mais serem
submetidos a cirurgias de revascularização miocárdica, é 485 Rev Bras Cir Cardiovasc 2007; 22(4): 484-490 PONTES, JCDV ET AL - Fatores de risco no desenvolvimento de
insuficiência renal aguda após cirurgia de revascularização miocárdica
com CEC Podem-se considerar limitações deste estudo o fato de
ser retrospectivo; de conter uma amostra significativa,
porém menor em relação aos trabalhos abordados e de
utilizar a creatinina plasmática como preditor de disfunção
renal, sendo o clearance da creatinina mais sensível para
tal diagnóstico [21]. MÉTODOS Foram analisados, retrospectivamente, os prontuários
médicos de 103 pacientes, sendo que 74 deles atenderam
aos critérios de inclusão: pacientes submetidos à cirurgia
de revascularização do miocárdio com o uso de circulação
extracorpórea. Estes pacientes foram operados pela mesma
equipe de cirurgiões, perfusionistas e anestesiologistas,
de forma consecutiva, durante o período citado. Os pacientes foram divididos em dois grupos: grupo I -
que evoluiu com IRA, e grupo II - que evoluiu sem IRA. Para comparação das variáveis categóricas entre os
grupos que desenvolveram e os que não desenvolveram
IRA no pós-operatório, utilizou-se o teste do qui-quadrado,
teste qui-quadrado corrigido por Yates (tabelas 2x2) ou teste
exato de Fisher. A análise das variáveis quantitativas foi
realizada pela comparação entre médias (com checagem
prévia da normalidade das distribuições), utilizando o teste
t, Mann Whitney ou Kruskal Wallis. Foram selecionadas
para realização de regressão logística múltipla, as variáveis
que apresentaram p < 0,15 (IMC, tempo de internação, uso
de drogas inotrópicas ou vasoconstritoras no pós-
operatório e tempo de CEC). Para análise da relação entre o
tempo de circulação extracorpórea e a creatinina sérica pós-
cirúrgica, foi realizada regressão linear simples. Para tanto,
utilizou-se o Epi Info versão 3.3.2 e o Bio Estat versão 4.0. Os critérios de exclusão foram: óbito nas primeiras 24h
após cirurgia, reoperação de possíveis complicações
cirúrgicas, ter creatinina sérica pré-operatória > 3,0 mg/dl e
ter resultados de exames incompletos, impossibilitando a
definição de insuficiência renal aguda. Os pacientes foram
acompanhados no pós-operatório por cinco dias ou durante
o período de internação na unidade de tratamento intensivo. Os dados pesquisados correspondentes ao período pré-
operatório incluíram: idade, sexo, índice de massa corpórea
(IMC), número de artérias coronárias acometidas, valores
de creatinina sérica e comorbidades como diabetes mellitus,
hipertensão arterial crônica, insuficiência cardíaca
congestiva, insuficiência arterial periférica e episódio prévio
de acidente vascular encefálico, angina ou infarto agudo
do miocárdio. No intra-operatório, avaliou-se o tempo de
duração da CEC. RESULTADOS O tempo de
CEC não apresentou diferença estatisticamente significativa
(p=0,0668), entre os dois grupos. Como critério diagnóstico de IRA, considerou-se: para
pacientes com níveis de creatinina sérica pré-operatória ≤
1,2 mg/dl, aumento até valores ≥ 1,8 mg/dl; elevação de
creatinina sérica > 0,5 mg/dl para aqueles com creatinina
sérica pré-operatória > 1,2 mg/dl e ≤ 2,0 mg/dl; ou elevação
de 1,0 mg/dl nos pacientes com creatinina pré-operatória >
2,0 mg/dl [11]. - Tabela 2. As variáveis quantitativas foram comparadas
estatisticamente e expressadas no Quadro 1. O tempo de
CEC não apresentou diferença estatisticamente significativa
(p=0,0668), entre os dois grupos. 486 PONTES, JCDV ET AL - Fatores de risco no desenvolvimento de
insuficiência renal aguda após cirurgia de revascularização miocárdica
com CEC
Rev Bras Cir Cardiovasc 2007; 22(4): 484-490 Rev Bras Cir Cardiovasc 2007; 22(4): 484-490 PONTES, JCDV ET AL - Fatores de risco no desenvolvimento de
insuficiência renal aguda após cirurgia de revascularização miocárdica
com CEC Tabela 1. Número e porcentagem de pacientes, segundo sexo, idade, ocorrência de óbito e insuficiência renal (IRA) presente ou ausente,
Hospital Universitário / UFMS, 2002-2004 (n=74)
Variáveis
Sexo
Feminino
Masculino
Idade (em anos)
42 a 60
61 a 74
75 a 83
Óbito
Sim
Não
No
8
10
7
7
4
1
17
%
34,8
19,6
20,6
22,6
44,4
50,0
23,6
No
15
41
27
24
5
1
55
%
65,2
80,4
79,4
77,4
55,6
50,0
76,4
p
(1) 0,2647
(2) 0,3185
(3) 0,4298
OR
2,19
-
3,24
OR (IC95%)
0,64-7,56
-
0,04-258,46
NOTA: se p ≤ 0,05 - diferença estatisticamente significativa; (1) Qui-quadrado corrigido por Yates; (2) Qui-quadrado ; (3) Teste Exato de Fisher
Pacientes com IRA
Pacientes sem IRA
T b l 2 Nú
t
d
i
t
d
iá
i d
t d
i
fi iê
i
l (IRA)
t
t
H
it l agem de pacientes, segundo sexo, idade, ocorrência de óbito e insuficiência renal (IRA) presente ou ausente,
ário / UFMS, 2002-2004 (n=74) Tabela 1. Número e porcentagem de pacientes, segundo sexo, idade, ocorrência de óbito e insuficiência r
Hospital Universitário / UFMS, 2002-2004 (n=74) Tabela 2. RESULTADOS Número e porcentagem de pacientes, segundo variáveis de estudo e insuficiência renal (IRA) presente ou ausente, Hospital
Universitário / UFMS, 2002-2004 (n=74)
Variáveis
Índice de massa corporal > 25
Tabagismo
Infarto agudo do miocárdio
Angina
Hipertensão arterial sistêmica
Diabetes mellitus
Dislipidemia
Drogas inotrópicas ou vasconstritoras no
pós-operatório
Insuficiência cardíaca congestiva
Diálise
Acidente vascular encefálico
Insuficiência vascular periférica
No
14
5
3
6
12
5
6
17
2
1
0
0
%
36,8
15,6
13,6
30,0
27,9
27,8
28,6
29,3
25,0
33,3
0,0
0,0
No
24
27
19
14
31
13
15
41
6
2
1
2
%
63,2
84,4
86,4
70,0
72,1
72,2
71,4
70,7
75,0
66,7
100,0
100,0
p
(1) 0,021(3)
0,004
(1) 0,212
(1) 0,272
(2) 0,547
(1) 0,568
(2) 0,756
(1) 0,814
(2) 0,097(3)
0,048
(2) 1,000
(2) 1,000
(2) 1,000
(2) 1,000
OR
4,67(3)
6,76
0,41
0,39
1,50
1,61
1,27
1,37
6,22(3)
10,31
1,04
1,59
0,00
0,00
OR (IC95%)
1,23-21,52(3)
1,83-25,04
0,10-1,46
0,07-1,65
0,41-5,44
0,47-5,98
0,30-4,77
0,37-4,91
0,81-276,97(3)
1,03-103,76
0,09-6,62
0,03-32,08
0,00-121,33
0,00-16,79
Pacientes com IRA
Pacientes sem IRA
NOTA: se p ≤ 0,05 - diferença estatisticamente significativa; (1) Qui-quadrado corrigido por Yates; (2) Teste Exato de Fisher; (3) Valores
ajustados pela Regressão Logística Múltipla
Quadro 1.Variáveis de estudo (valores descritivos e comparação entre médias), segundo a presença ou não de insuficiência renal (IRA),
Hospital Universitário/UFMS, 2002-2004 (n=74)
Variáveis
Creatinina sérica no pós-operatório (2)
Circulação Extracorpórea (em min.)
Tempo de internação (em dias)
Pressão Venosa Central pós-operatório(1)
Pressão Arterial Média pós-operatório(1)
Coronárias acometidas
Creatinina sérica pré-operatória
Tempo de permanência na UTI (em dias)
Volume da diurese (1)
Volume diurese CEC
Clearance da Creatinina pós-operatório
Média
1,8
65,8
11
11,3
76,8
2,6
1,3
5
3388
295
60,3
DP
0,3
29,4
9
4,4
9,3
0,6
0,3
4
954
92
24,8
Min. 1,4
20,0
5
2,0
63,0
1,0
1,0
1
1980
80
35,5
Máx. 2,3
120,0
38
17,0
93,0
3,0
1,9
15
5260
400
132,4
IRA
Média
1,3
52,9
9
9,8
78,8
2,4
1,3
4
3288
320
60,7
DP
0,3
32,4
6
3,8
8,7
0,8
0,2
2
1175
180
18,0
Min. 0,8
15,0
2
2,5
55,9
1,0
0,8
1
1150
150
29,7
Máx. RESULTADOS 1,8
160,0
37
19,5
96,0
4,0
1,7
10
6763
450
99,4
Não IRA
P
(3) <0,0001
(4) 0,0668
(4) 0,1491
(3) 0,1669
(3) 0,4064
(4) 0,4274
(4) 0,4611
(4) 0,6411
(3) 0,7421
(3) >0,05
(3) 0,9467
NOTA: se p ≤ 0,05 - diferença estatisticamente significativa; (1) Primeiro dia; (2) Média dos cinco primeiros dias; (3) Teste t; (4) Teste Mann
Whitney Tabela 2. Número e porcentagem de pacientes, segundo variáveis de estudo e insuficiência renal (IRA) presente ou ausente, Hospital
Universitário / UFMS, 2002-2004 (n=74) entes, segundo variáveis de estudo e insuficiência renal (IRA) presente ou ausente, Hospital
4 (
74) Tabela 2. RESULTADOS Número e porcentagem de pacientes, segundo variáveis de estudo e insuficiência renal (IRA) presente ou ausente, Hospital
Universitário / UFMS, 2002-2004 (n=74)
Variáveis
Índice de massa corporal > 25
Tabagismo
Infarto agudo do miocárdio
Angina
Hipertensão arterial sistêmica
Diabetes mellitus
Dislipidemia
Drogas inotrópicas ou vasconstritoras no
pós-operatório
Insuficiência cardíaca congestiva
Diálise
Acidente vascular encefálico
Insuficiência vascular periférica
No
14
5
3
6
12
5
6
17
2
1
0
0
%
36,8
15,6
13,6
30,0
27,9
27,8
28,6
29,3
25,0
33,3
0,0
0,0
No
24
27
19
14
31
13
15
41
6
2
1
2
%
63,2
84,4
86,4
70,0
72,1
72,2
71,4
70,7
75,0
66,7
100,0
100,0
p
(1) 0,021(3)
0,004
(1) 0,212
(1) 0,272
(2) 0,547
(1) 0,568
(2) 0,756
(1) 0,814
(2) 0,097(3)
0,048
(2) 1,000
(2) 1,000
(2) 1,000
(2) 1,000
OR
4,67(3)
6,76
0,41
0,39
1,50
1,61
1,27
1,37
6,22(3)
10,31
1,04
1,59
0,00
0,00
OR (IC95%)
1,23-21,52(3)
1,83-25,04
0,10-1,46
0,07-1,65
0,41-5,44
0,47-5,98
0,30-4,77
0,37-4,91
0,81-276,97(3)
1,03-103,76
0,09-6,62
0,03-32,08
0,00-121,33
0,00-16,79
Pacientes com IRA
Pacientes sem IRA
NOTA: se p ≤ 0,05 - diferença estatisticamente significativa; (1) Qui-quadrado corrigido por Yates; (2) Teste Exato de Fisher; (3) Valores
ajustados pela Regressão Logística Múltipla
Quadro 1.Variáveis de estudo (valores descritivos e comparação entre médias), segundo a presença ou não de insuficiência renal (IRA),
Hospital Universitário/UFMS, 2002-2004 (n=74)
Variáveis
IRA
Não IRA Quadro 1.Variáveis de estudo (valores descritivos e comparação entre médias), segundo a presença ou não de insuficiência renal (IRA),
Hospital Universitário/UFMS, 2002-2004 (n=74) p
,
(
)
Variáveis
Creatinina sérica no pós-operatório (2)
Circulação Extracorpórea (em min.)
Tempo de internação (em dias)
Pressão Venosa Central pós-operatório(1)
Pressão Arterial Média pós-operatório(1)
Coronárias acometidas
Creatinina sérica pré-operatória
Tempo de permanência na UTI (em dias)
Volume da diurese (1)
Volume diurese CEC
Clearance da Creatinina pós-operatório
Média
1,8
65,8
11
11,3
76,8
2,6
1,3
5
3388
295
60,3
DP
0,3
29,4
9
4,4
9,3
0,6
0,3
4
954
92
24,8
Min. 1,4
20,0
5
2,0
63,0
1,0
1,0
1
1980
80
35,5
Máx. 2,3
120,0
38
17,0
93,0
3,0
1,9
15
5260
400
132,4
IRA
Média
1,3
52,9
9
9,8
78,8
2,4
1,3
4
3288
320
60,7
DP
0,3
32,4
6
3,8
8,7
0,8
0,2
2
1175
180
18,0
Min. 0,8
15,0
2
2,5
55,9
1,0
0,8
1
1150
150
29,7
Máx. DISCUSSÃO A IRA tem sido amplamente documentada como
importante complicação no período pós-operatório da
cirurgia de revascularização do miocárdio, haja vista o
considerável aumento da morbi-mortalidade associada a
este evento. No presente estudo, foi constatada uma incidência de
IRA de 24,32%, e mortalidade de 5,56% para os que a
desenvolveram, sendo que na literatura estes valores
variaram de 0,7% a 31% e 1,3% a 90%, respectivamente [2-
14]. Vale ressaltar que os discrepantes valores das
incidências devem-se, muitas vezes, aos diferentes critérios
de definição de IRA utilizados. Na tentativa de não
subestimar os vários graus de disfunção renal, utilizamos
critérios mais rígidos do que alguns dos trabalhos
analisados. A escolha da creatinina sérica como parâmetro
de avaliação da função renal deveu-se ao fato de ser um
exame de fácil execução e utilizado como rotina no serviço
de cirurgia cardiovascular da UFMS. Comparando-se a creatinina sérica pós-operatória e o
tempo de circulação extracorpórea, através de regressão
linear simples (b = 0,0037; t = 3,1797; p = 0,0022; R2
(ajustado) = 11,10%), apenas 11% da variável dependente
(creatinina) é explicada pela variável independente (CEC). Isto significa que outras variáveis estão envolvidas no
aumento da creatinina sérica após a cirurgia (Figura 2). Fig. 1 - Média da creatinina sérica no pré-operatório (Pré-op) e
pós-operatório (Pós-op) do 1o ao 5o dia, segundo a presença ou
não de insuficiência renal (IRA), Hospital Universitário / UFMS,
2002-2004 (n=74) Alguns estudos [3,5,11,14] demonstraram maior tempo
de permanência hospitalar nos pacientes que evoluíram
para IRA, aumentando a exposição destes a morbidades
decorrentes do ambiente hospitalar, além dos custos de
internação. Porém, neste trabalho, o tempo médio de
permanência na unidade de terapia intensiva (UTI) dos
pacientes que desenvolveram IRA foi 5 dias e dos que não
a desenvolveram, 4 dias, não tendo esta diferença
significância estatística (p= 0,6411). Fig. 1 - Média da creatinina sérica no pré-operatório (Pré-op) e
pós-operatório (Pós-op) do 1o ao 5o dia, segundo a presença ou
não de insuficiência renal (IRA), Hospital Universitário / UFMS,
2002-2004 (n=74) Vários fatores têm sido relacionados na literatura
científica com o aumento da incidência de lesão renal, sendo
os mais importantes a utilização e o tempo de CEC [3-
5,7,11,13]; idade [3,5,7,11]; função renal pré-operatória [3-
5,7-11,22]; uso de drogas inotrópicas [11]; uso de
furosemide intra-operatório [10] e comorbidades associadas,
como diabetes [5,7], insuficiência cardíaca [5,7,8] e doença
vascular periférica [8]. Fig. RESULTADOS 1,8
160,0
37
19,5
96,0
4,0
1,7
10
6763
450
99,4
Não IRA
P
(3) <0,0001
(4) 0,0668
(4) 0,1491
(3) 0,1669
(3) 0,4064
(4) 0,4274
(4) 0,4611
(4) 0,6411
(3) 0,7421
(3) >0,05
(3) 0,9467
NOTA: se p ≤ 0,05 - diferença estatisticamente significativa; (1) Primeiro dia; (2) Média dos cinco primeiros dias; (3) Teste t; (4) Teste Mann
Whitney 487 Rev Bras Cir Cardiovasc 2007; 22(4): 484-490 PONTES, JCDV ET AL - Fatores de risco no desenvolvimento de
insuficiência renal aguda após cirurgia de revascularização miocárdica
com CEC Não houve diferença estatisticamente significativa na
creatinina pré-operatória quando se compara pacientes com
IRA e sem IRA (p = 0,4611), no entanto, houve diferença
estatisticamente significativa no pós-operatório, do 1o ao
5o dia (p variando entre < 0,0001 a 0,0002). Considerando
apenas a creatinina sérica pós-operatória em cada grupo,
separadamente, não houve diferença estatisticamente
significativa do 1o ao 5o dia, nos pacientes com IRA (p =
0,6709), e sem IRA (p = 0,7230) - Figura 1. DISCUSSÃO 2 - Creatinina sérica pós-cirúrgica em relação ao tempo de
circulação extracorpórea, de pacientes com a presença ou não de
insuficiência renal, Hospital Universitário / UFMS, 2002-2004
(n=74) No presente estudo, a análise estatística de todos os
prováveis fatores de risco demonstrou uma correlação do
sobrepeso ou obesidade dos pacientes e o uso de drogas
inotrópicas ou vasoconstritoras no pós-operatório -
evidenciando a gravidade de alguns pacientes, devido a
complicações, como disfunção ventricular - com a incidência
de IRA após a cirurgia. Além disso, não foi observada
relação entre comorbidades prévias e o desenvolvimento
de IRA. A relação entre a redução das médias diárias da PAM e
PVC, no primeiro dia pós-operatório, e o aumento da
creatinina sérica nestes pacientes refletiu a importância do
mecanismo pré-renal, contribuindo para a deterioração da
função renal pós-operatória. Segundo Mangano et al. [5],
no período pós-operatório, o principal fator de risco para o
desenvolvimento de disfunção renal foi a síndrome do baixo Fig. 2 - Creatinina sérica pós-cirúrgica em relação ao tempo de
circulação extracorpórea, de pacientes com a presença ou não de
insuficiência renal, Hospital Universitário / UFMS, 2002-2004
(n=74) 488 Rev Bras Cir Cardiovasc 2007; 22(4): 484-490 PONTES, JCDV ET AL - Fatores de risco no desenvolvimento de
insuficiência renal aguda após cirurgia de revascularização miocárdica
com CEC orientação específica quanto à profilaxia do
desenvolvimento da IRA no pós-operatório de cirurgias
cardíacas com uso de CEC, na presente investigação,
pudemos observar um melhor prognóstico de função renal
quando o tempo de CEC não for prolongado e quando uma
adequada otimização do débito cardíaco no pós-operatório
for alcançada. débito cardíaco e a instabilidade hemodinâmica, cujos
indicadores foram hemorragia, uso de drogas inotrópicas e
balão intra-aórtico. Tal estudo demonstrou que entre os
pacientes com índice cardíaco menor que 1,5 l/min/m²., no
dia da cirurgia, 20% desenvolveram IRA e entre os que
apresentaram este índice no 1º dia pós-operatório 61%
evoluíram para disfunção renal. Neste estudo, o tempo de CEC não foi fator de maior
importância na evolução para IRA, fato evidenciado por
outros trabalhos [3-5,7,11,13]. Tentativas de explicar tal
fenômeno têm sido controversas na literatura, atribuindo a
IRA à redução do fluxo sangüíneo renal durante a CEC. Boldt et al. REFERÊNCIAS 1. Almeida FF, Barreto SM, Couto BR, Starling CE. Fatores
preditores da mortalidade e de complicações per-operatórias
graves em cirurgia de revascularização do miocárdio. Arq Bras
Cardiol. 2003;80(1):51-60. Já Ascione et al. [6] observaram que, durante a CEC,
houve aumento significante do clearance da creatinina no
grupo de pacientes submetidos à CEC, devido ao
mecanismo renal de auto-regulação, aumentando a
capacidade de filtração glomerular. Entretanto, neste mesmo
grupo, houve uma queda do clearance nos dias
subseqüentes, acompanhada por um aumento da n-acetil-
β glicosaminidase (NAG), importante marcador de lesão
tubular renal, comprovando a influência do uso da CEC na
fisiopatologia da IRA pós-operatória. 2. Lema G, Meneses G, Urzua J, Jalil R, Canessa R, Moran S, et
al. Effects of extracorporeal circulation on renal function in
coronary surgical patients. Anesth Analg. 1995;81(3):446-51. 3. Mangos GJ, Brown MA, Chan WY, Horton D, Trew P,
Whitworth JA. Acute renal failure following cardiac surgery:
incidence, outcomes and risk factors. Aust N Z J Med. 1995;25(4):284-9. Deve-se ressaltar que a média do tempo de CEC no
presente trabalho foi baixa (56,08 minutos) em relação aos
demais estudos, embora alguns trabalhos tenham incluído
outras modalidades de cirurgia cardíaca, além da
revascularização miocárdica. Apenas um dos trabalhos
analisados [6], que avaliou somente cirurgias de
revascularização do miocárdio, forneceu dados sobre o
tempo de duração da CEC, cuja média foi de 70,3 minutos. 4. Chertow GM, Lazarus JM, Christiansen CL, Cook EF,
Hammermeister KE, Grover F, et al. Preoperative renal risk
stratification. Circulation. 1997;95(4):878-84. 5. Mangano CM, Diamondstone LS, Ramsay JG, Aggarwal A,
Herskowitz A, Mangano DT. Renal dysfunction after
myocardial revascularization: risk factors, adverse outcomes,
and hospital resource utilization. The Multicenter Study of
Perioperative Ischemia Research Group. Ann Intern Med. 1998;128(3):194-203. No presente estudo, guardadas suas limitações, em
função de se tratar de um estudo clínico, com análise de
múltiplos fatores, pode-se concluir que a CEC não
determinou impacto na ocorrência de IRA no pós-operatório
de cirurgia de revascularização do miocárdio, provavelmente
pelo baixo tempo médio de CEC no grupo estudado, o que
também proporcionou baixa morbi-mortalidade e melhor
evolução da função renal pós-operatória destes pacientes. O IMC aumentado se mostrou como fator de risco para o
desenvolvimento de IRA, além do uso de drogas
inotrópicas ou vasoconstritoras, em pacientes mais graves,
que apresentaram disfunção ventricular. Todas as outras
variáveis estudadas não se apresentaram como fator de
risco na ocorrência de IRA para este grupo. 6. DISCUSSÃO [13] concluíram que o tempo de CEC > 90 minutos
foi o mais importante fator de risco para IRA, atribuindo o
fato aos efeitos hipóxicos da perfusão sangüínea diminuída,
que leva ao sofrimento e à morte das células tubulares
proximais renais. Outros autores destacam ainda as
alterações da homeostase das citocinas inflamatórias
plasmáticas, sendo a maior filtração destas, possivelmente
responsável por dano tubular [5,14-17]. PONTES, JCDV ET AL - Fatores de risco no desenvolvimento de
insuficiência renal aguda após cirurgia de revascularização miocárdica
com CEC REFERÊNCIAS Ascione R, Lloyd CT, Underwood MJ, Gomes WJ, Angelini
GD. On-pump versus off-pump coronary revascularization:
evaluation of renal function. Ann Thorac Surg. 1999;68(2):493-8. 7. Conlon PJ, Stafford-Smith M, White WD, Newman MF, King
S, Winn MP, et al. Acute renal failure following cardiac surgery. Nephrol Dial Transplant. 1999;14(5):1158-62. 8. Fortescue EB, Bates DW, Chertow GM. Predicting acute
renal failure after coronary bypass surgery: cross-validation
of two risk-stratification algorithms. Kidney Int. 2000;57(6):2594-602. Embora ainda não se tenha, na literatura acessível, uma 489 Rev Bras Cir Cardiovasc 2007; 22(4): 484-490 9. Ostermann ME, Taube D, Morgan CJ, Evans TW. Acute renal
failure following cardiopulmonary bypass: a changing picture. Intensive Care Med. 2000;26(5):565-71. 18. Rastan AJ, Bittner HB, Gummert JF, Walther T, Schewick
CV, Girdauskas E, et al. On-pump beating heart versus off-
pump coronary artery bypass surgery-evidence of pump-
induced myocardial injury. Eur J Cardiothorac Surg. 2005;27(6):1057-64. 10. Lombardi R, Ferreiro A, Servetto C. Renal function after cardiac
surgery: adverse effect of furosemide. Ren Fail. 2003;25(5):775-86. 19. Volpe MA, Carneiro JJ, Magna LA, Viaro F, Origuela EAL,
Évora PRB. Disfunção endotelial após isquemia global e
reperfusão em cirurgia cardíaca com circulação extracorpórea:
estudo do papel do magnésio em artérias coronarianas caninas. Rev Bras Cir Cardiovasc. 2002;17(3):187-200. 11. Santos FO, Silveira MA, Maia RB, Monteiro MDC, Martinelli
R. Insuficiência renal aguda após cirurgia de revascularização
miocárdica com circulação extra-corpórea: incidência, fatores
de risco e mortalidade. Arq Bras Cardiol. 2004;83:145-9. 20. Moura HV, Pomerantzeff PMA, Gomes WJ. Síndrome da
resposta inflamatória sistêmica na circulação extracorpórea:
papel das interleucinas. Rev Bras Cir Cardiovasc. 2001;16(4):376-87. 12. Stallwood MI, Grayson AD, Mills K, Scawn N. Acute renal
failure in coronary artery bypass surgery: independent effect
of cardiopulmonary bypass. Ann Thorac Surg. 2004;77(3):
968-72. 21. Noyez L, Plesiewicz I, Verheugt FW. Estimated creatinine
clearance instead of plasma creatinine level as prognostic test
for postoperative renal function in patients undergoing coronary
artery bypass surgery. Eur J Cardiothorac Surg. 2006;29(4):461-5. 13. Boldt J, Brenner T, Lehmann A, Suttner SW, Kumle B, Isgro F. Is kidney function altered by duration of cardiopulmonary
bypass? Ann Thorac Surg. 2003;75(3):906-12. 14. Yallop KG, Smith DC. The incidence and pathogenesis of acute
renal failure following cardiac surgery, and strategies for its
prevention. Ann Card Anaesth. 2004;7(1):17-31. 22. Devbhandari MP, Duncan AJ, Grayson AD, Fabri BM, Keenan
DJ, Bridgewater B, et al. PONTES, JCDV ET AL - Fatores de risco no desenvolvimento de
insuficiência renal aguda após cirurgia de revascularização miocárdica
com CEC PONTES, JCDV ET AL - Fatores de risco no desenvolvimento de
insuficiência renal aguda após cirurgia de revascularização miocárdica
com CEC REFERÊNCIAS Effect of risk-adjusted, non-dialysis-
dependent renal dysfunction on mortality and morbidity
following coronary artery bypass surgery: a multi-centre
study. Eur J Cardiothorac Surg. 2006;29(6):964-70. 15. Gormley SM, McBride WT, Armstrong MA, Young IS,
McClean E, MacGowan SW, et al. Plasma and urinary cytokine
homeostasis and renal dysfunction during cardiac surgery. Anesthesiology. 2000;93(5):1210-6. 23. Dean AG, Arner TG, Sunki GG, Friedman R, Lantinga M,
Sangam S, et al. Epi InfoTM, a database and statistics program
for public health professionals. Atlanta:Centers for Disease
Control and Prevention;2002. 16. Sheinbaum R, Ignacio C, Safi HJ, Estrera A. Contemporary
strategies to preserve renal function during cardiac and vascular
surgery. Rev Cardiovasc Med. 2003;4(Suppl 1):S21-S8. 24. Ayres M, Ayres Jr. M, Ayres DL, Santos AAS. Bio Estat,
aplicações estatísticas nas áreas das Ciências Biomédicas. Belém:Instituto de Desenvolvimento Sustentável
Mamirauá;2005. 17. Verrier ED, Morgan EN. Endothelial response to
cardiopulmonary bypass surgery. Ann Thorac Surg. 1998;66(5
Suppl):S17-9. 490
|
https://openalex.org/W2901327188
|
https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0207724&type=printable
|
English
| null |
High-density multi-population consensus genetic linkage map for peach
|
PloS one
| 2,018
|
cc-by
| 8,919
|
RESEARCH ARTICLE Cassia da Silva Linge1, Laima Antanaviciute1, Asma AbdelghafarID1, Pere Aru´s2,
Daniele Bassi3, Laura RossiniID3, Stephen Ficklin4, Ksenija GasicID1* 1 Clemson University, Department of Plant and Environmental Sciences, Clemson, SC, United States of
America, 2 Institut de Recerca i Tecnologia Agroalimentàries (IRTA), Centre de Recerca en Agrigenòmica
Consejo Superior de Investigaciones Cientı´ficas (CSIC)-IRTA–Universitat Autònoma de Barcelona (UAB)–
University of Barcelona (UB), Campus UAB, Bellaterra (Cerdanyola del Vallès), Barcelona, Spain,
3 Università degli Studi di Milano, Department of Agricultural and Environmental Sciences–Production,
Landscape, Agroenergy, Milan, Italy, 4 Washington State University, Department of Horticulture, Pullman,
WA, United States of America a1111111111
a1111111111
a1111111111
a1111111111
a1111111111 a1111111111
a1111111111
a1111111111
a1111111111
a1111111111 * kgasic@clemson.edu * kgasic@clemson.edu * kgasic@clemson.edu Abstract Highly saturated genetic linkage maps are extremely helpful to breeders and are an essen-
tial prerequisite for many biological applications such as the identification of marker-trait
associations, mapping quantitative trait loci (QTL), candidate gene identification, develop-
ment of molecular markers for marker-assisted selection (MAS) and comparative genetic
studies. Several high-density genetic maps, constructed using the 9K SNP peach array, are
available for peach. However, each of these maps is based on a single mapping population
and has limited use for QTL discovery and comparative studies. A consensus genetic link-
age map developed from multiple populations provides not only a higher marker density and
a greater genome coverage when compared to the individual maps, but also serves as a
valuable tool for estimating genetic positions of unmapped markers. In this study, a previ-
ously developed linkage map from the cross between two peach cultivars ‘Zin Dai’ and
‘Crimson Lady’ (ZC2) was improved by genotyping additional progenies. In addition, a
peach consensus map was developed based on the combination of the improved ZC2
genetic linkage map with three existing high-density genetic maps of peach and a reference
map of Prunus. A total of 1,476 SNPs representing 351 unique marker positions were
mapped across eight linkage groups on the ZC2 genetic map. The ZC2 linkage map spans
483.3 cM with an average distance between markers of 1.38 cM/marker. The MergeMap
and LPmerge tools were used for the construction of a consensus map based on markers
shared across five genetic linkage maps. The consensus linkage map contains a total of
3,092 molecular markers, consisting of 2,975 SNPs, 116 SSRs and 1 morphological marker
associated with slow ripening in peach (SR). The consensus map provides valuable infor-
mation on marker order and genetic position for QTL identification in peach and other
genetic studies within Prunus and Rosaceae. * kgasic@clemson.edu High-density multi-population consensus
genetic linkage map for peach Cassia da Silva Linge1, Laima Antanaviciute1, Asma AbdelghafarID1, Pere Aru´s2,
Daniele Bassi3, Laura RossiniID3, Stephen Ficklin4, Ksenija GasicID1* Introduction (2014-51181-22378) to KG. The Spanish Ministry
of Economy and Competitiveness (project
RTA2015-00050-00-00, Severo Ochoa Program
for Centres of Excellence in R&D 201-2019 (SEV-
2015-0533) and CERCA Programme-Generalitat de
Catalunya). This work was in part supported by the
Ministero delle Politiche Agricole Alimentari e
Forestali (MiPAAF, Italy) through the projects
DRUPOMICS (grant DM14999/7303/08), and
’MAS.PES: apricot and peach breeding by
molecular-assisted selection’ a project funded by
private and public agencies. (2014-51181-22378) to KG. The Spanish Ministry
of Economy and Competitiveness (project
RTA2015-00050-00-00, Severo Ochoa Program
for Centres of Excellence in R&D 201-2019 (SEV-
2015-0533) and CERCA Programme-Generalitat de
Catalunya). This work was in part supported by the
Ministero delle Politiche Agricole Alimentari e
Forestali (MiPAAF, Italy) through the projects
DRUPOMICS (grant DM14999/7303/08), and
’MAS.PES: apricot and peach breeding by
molecular-assisted selection’ a project funded by
private and public agencies. A genetic linkage map represents positions and genetic distances of molecular markers on
chromosomes allocated based on segregation data and recombination events of individuals in
a mapping population [1,2]. Genetic maps are important tools for a vast number of genetic
applications and are widely used in plant breeding programs, genetics and genomics studies. In particular, these maps are crucial for a better understanding of marker-trait associations
through quantitative trait loci (QTL) mapping, discovery of genes associated with economi-
cally important fruit quality and disease resistance traits, and successful deployment of molec-
ular markers in plant breeding programs via marker-assisted selection (MAS) [3–5]. In
addition, linkage maps provide an important foundation for other biological applications
including candidate gene identification, map-based gene cloning, genome evolution, compara-
tive genomics studies and genome assembly [6–11]. High-resolution maps which cover the
entire genome with co-segregating, reproducible and high-throughput markers at short inter-
vals are most valuable because of the increased resolution that leads to more effective QTL
mapping, candidate gene detection, and more precise estimates of QTL effect [5, 12,13]. Competing interests: The authors have declared
that no competing interests exist. Peach is a recognized model for Rosaceae genetics and genomics with a wealth of publicly
available resources [14,15]. Recent advances in next-generation high-throughput sequencing
and genotyping techniques, such as development of the IPSC 9K peach array [16], have per-
mitted rapid development of high-quality genetic linkage maps [17–20]. In peach (Prunus persica L. Consensus peach linkage map OPEN ACCESS Citation: da Silva Linge C, Antanaviciute L,
Abdelghafar A, Aru´s P, Bassi D, Rossini L, et al. (2018) High-density multi-population consensus
genetic linkage map for peach. PLoS ONE 13(11):
e0207724. https://doi.org/10.1371/journal. pone.0207724 Citation: da Silva Linge C, Antanaviciute L,
Abdelghafar A, Aru´s P, Bassi D, Rossini L, et al. (2018) High-density multi-population consensus
genetic linkage map for peach. PLoS ONE 13(11):
e0207724. https://doi.org/10.1371/journal. pone.0207724 Editor: Rosalyn B. Angeles-Shim, Texas Tech
University, UNITED STATES
Received: August 24, 2018
Accepted: November 4, 2018
Published: November 21, 2018 Copyright: © 2018 da Silva Linge et al. This is an
open access article distributed under the terms of
the Creative Commons Attribution License, which
permits unrestricted use, distribution, and
reproduction in any medium, provided the original
author and source are credited. Data Availability Statement: The ZC2 improved
map and peach consensus map reported in this
study are available at the Genome Database for
Rosaceae (www.rosaceae.org) under the
accession number tfGDR1036. Funding: This project was supported in part by the
USDA-NIFA-Specialty Crop Research Initiative
project, RosBREED: Enabling marker-assisted
breeding in Rosaceae (2009-51181-05808) to KG,
and RosBREED 2: Combining disease resistance
with horticultural quality in new rosaceous cultivars 1 / 16 PLOS ONE | https://doi.org/10.1371/journal.pone.0207724
November 21, 2018 PLOS ONE | https://doi.org/10.1371/journal.pone.0207724
November 21, 2018 Genotypic data DNA samples for a total of 65 ‘Zin Dai’ × ‘Crimson Lady’ seedlings and parental genotypes
were submitted to the Research Technology Support Facility at Michigan State University
(East Lansing, MI, USA) for genotyping by the peach Illumina 9K SNP array v1. The iScan
data output files were analyzed as previously described by Frett et al. [17]. Briefly, the Geno-
meStudio software was used to verify the quality for all samples and SNPs observed. Markers
with GenTrain score above 0.4 were inspected. The failed and monomorphic markers were
excluded, whereas the polymorphic SNPs were further inspected for clustering analysis. Mark-
ers with more than three expected clusters (AA, AB and BB) and missing in at least one of the
parental genotypes were excluded from further analysis. SNP markers for which the number
of missing genotypes was greater than 10% were not considered for map construction. Consensus peach linkage map Consensus maps built using freely available MergeMap [40] and LPMerge algorithms [41]
were reported in different plants, including barley [42,43], cowpea [44], rapeseed [45], spring
wheat [46], loblolly pine [47], cassava [48], oak [49], oilseed rape [50] and faba bean [51], pear
[38], and two integrated linkage maps in apple [5, 39]. In this study, we report the improvement of the previously developed peach linkage map
‘Zin Dai’ x ‘Crimson Lady’ (ZC2) by genotyping additional progenies. In addition, a consensus
peach linkage map was created based on the improved ZC2 map and four other unrelated
high-density maps using two algorithms (MergeMap and LPMerge). The consensus map pro-
vides valuable information on marker order and genetic position and will be useful in future
studies of pedigree-based QTL analyses in peach. Plant material and DNA extraction An F2 mapping population obtained from selfing an individual from the cross between ‘Zin
Dai’ and ‘Crimson Lady’ (ZC2) was previously reported [17]. A map was elaborated based on
25 selected seedlings, genotyped with the 9k peach SNP array [16]. In this paper, we have geno-
typed an additional set of 65 individuals (for a total of 90 individuals) for the development of
an improved genetic linkage map. DNA was isolated from young and healthy leaf tissue as
described previously by Dellaporta et al. [52]. The concentration and purity of DNA was mea-
sured by a NanoDrop ND-1000 spectrophotometer. The final concentrations of all DNA sam-
ples were adjusted to 50 ng/μl for high-throughput genotyping. PLOS ONE | https://doi.org/10.1371/journal.pone.0207724
November 21, 2018 Introduction Batsch), linkage maps have been used in QTL discovery of phys-
iological traits, key fruit quality traits such as fruit size, diameter, firmness, acidity, individual
sugars (fructose, glucose, sucrose and sorbitol), aroma, flesh, peel related phenolic compounds,
and disease resistance traits [17,18,21–31]. These maps were typically developed for mapping
particular traits in specific parental backgrounds and differ in population size and molecular
markers used [4,5] resulting in limited value for comparative studies. Multiple maps developed for the same species usually contain many common markers,
which can be used as anchor points for consensus map integration [4,5,32,33]. Highly satu-
rated genetic maps with evenly distributed markers across linkage groups, with no regions of
low marker density are most suitable for the construction of a consensus map. Consensus
maps developed from multiple populations provide a higher marker density and a greater
genome coverage when compared to the individual maps. They also serve as valuable tools for
estimating genetic positions, detecting inconsistencies among maps, comparing marker distri-
butions and QTL locations [5]. Consensus maps could also aid estimation of genetic positions
of unmapped markers (markers without genetic position) included in genotyping arrays. This
is especially important in pedigree-based QTL analyses [34] that require precise genetic posi-
tions of the markers to accurately detect QTLs in pedigree-related individuals, when develop-
ment of mapping populations is improbable. To assign genetic positions to unmapped
markers, the common approach was to use a genome-wide mean as a conversion factor [35]. In order to overcome the problem of using the static conversion factor, Fresnedo et al. [30]
developed a consensus RosBREED [36] linkage map (RC1) for peach predicting genetic dis-
tances by incorporating the physical and genetic positions of 68 markers from the Prunus bin
map [37]. However, this map was developed by calculating genetic positions using polynomial
equations, not by merging individual peach linkage maps. In the Rosaceae family, a consensus map was developed for pear [38] and two integrated
linkage maps have been reported in apple based on merging five and three populations [5,39]. Although a peach consensus map was previously reported [25], it was constructed using only
two peach linkage maps and the GoldenGate genotyping platform which is less commonly
used in the peach community compared to the IPSC 9k SNP array. 2 / 16 PLOS ONE | https://doi.org/10.1371/journal.pone.0207724
November 21, 2018 SNP-based linkage map construction The improvement of the existing SNP-based genetic linkage map was based on combining
polymorphic SNP marker data, observed in this study, with previously mapped marker data
from the ZC2 mapping population [17]. A genetic linkage map was constructed using SNPs
homozygous for alternate allele in two grandparents (AA in one parent and BB in other) as
well as SNPs homozygous in one and heterozygous in the other grandparent. F2 population
type codes were applied [53]. SNP markers mapped to the same location, identical markers, were grouped into single
bins with the purpose of reducing map complexity for linkage analysis. A single SNP contain-
ing no missing data for a progeny was used for linkage analysis from each bin. Linkage map construction was performed by the JoinMap 4.1 (Kyazma, NL) software
applying Maximum Likelihood (ML) function [53]. The parameters used for map construction
were as follows: a minimum of a logarithm of the odds (LOD) score of 3.0 was used to assign 3 / 16 PLOS ONE | https://doi.org/10.1371/journal.pone.0207724
November 21, 2018 Consensus peach linkage map markers to linkage groups with a maximum recombination fraction of 0.4, goodness-of-fit
jump threshold of 5.0 and a triplet threshold of 1.0. Markers exhibiting segregation distortion
were identified applying the Chi-square (X2)-goodness-of-fit test (p < 0.05) and also inte-
grated into the map. Graphical presentation of an improved SNP-based genetic linkage map of
the ZC2 progeny consisting of eight linkage groups was generated by MapChart version 2.3
software [54]. Marker genetic distances on the linkage groups were presented in centimorgans
(cM). Comparison of an improved ZC2 linkage map with the peach genome
sequence v2.0 The genetic positions of each SNP marker mapped to the ZC2 linkage map was aligned with
their physical position on the peach genome v2.0 sequence [55] by MapChart 2.3 [54], simi-
larly to what had been previously described by Frett et al. [17]. Consensus map construction Genetic distances of SSR and SNP markers, as well as slow ripening locus (Sr), mapped across
four integrated F2 linkage maps: PI91459(‘NJ Weeping’) × ‘Bounty’ (WB) [18], ‘O’Henry’ ×
‘Clayton’ (OC) [19], ‘Venus’ × ‘Venus’ (VxV) [20] and ‘Texas’ × ‘Earlygold’ (T×E) [56] were
obtained from the Genome Database for Rosaceae (GDR) [14–15]. The MergeMap software
[40] and LPmerge R package [41] were used to merge four previously reported genetic linkage
maps with the improved (ZC2) map developed in this study. To prepare input data for Merge-
map and LPmerge, the SNP markers that were non-collinear in comparison with the peach
genome were removed from individual maps. For LPmerge, the maximum interval parameter
K varied from 1 to 4, and the composite map with the lowest root mean square error (RMSE)
was selected. The consistency of all marker names across five linkage maps was verified to
avoid marker duplications on the consensus map. The consensus map was constructed by
merging a single linkage group (LG) of all five maps at the time, following the protocol
reported by Khan et al. [5]. A weight of 1.0 was applied to all linkage groups across all maps. The RMSE in marker order between the consensus maps and the input maps, were calculated
by the R package hydroGOF [57], as described in Westbrook et al. [47], and the consensus
map with the lowest average RMSE was used for further analysis. The physical positions of all
markers mapped to the consensus peach linkage map were compared to the peach genome
sequence v2.0 [55] and visualized in Mapchart 2.0 [54]. PLOS ONE | https://doi.org/10.1371/journal.pone.0207724
November 21, 2018 cM estimate ¼ snp1 cM þ delta cM ðsnp bp snp1 bpÞ=delta bpÞ The improved linkage map for ZC2 population The construction of the improved SNP-based linkage map was based on heterozygous SNPs
observed in this study combined with SNP marker data previously reported by Frett et al. [17]. A total of 1,478 SNPs were informative in the ZC2 progeny. Out of those, 2 SNPs were
unlinked (0.1%) and 1,476 were used for map construction. Maximum Likelihood mapping
successfully mapped 1,476 SNP markers with 351 unique positions (S1 Table; Fig 1). The revised linkage map of the ZC2 progeny spanned a total genetic distance of 483.3 cM,
with linkage group 1 (LG1) being the longest (95.3 cM) and LG5 the shortest (31.2 cM). The
highest number of SNPs mapped to a single linkage group was 263 on LG7 and the lowest was
40 on LG5. The number of unique map positions mapped on a single linkage group ranged
from 63 on LG6 to 17 on LG5. The largest gap was observed in LG1 (24.2 cM) between
SNP_IGA_103771 and SNP_IGA_120926 (Table 1). SNP marker density per linkage group
ranged from 0.96 to 2.58 cM with the average of 1.38 cM. Comparison of the two versions of the ZC2 map The reconstruction of the ZC2 linkage map resulted in a higher number of mapped markers,
from 1,335 mapped on existing map [17] up to 1,476 SNPs mapped on the improved ZC2 map. The number of unique SNP positions mapped increased from 190 in the previous map to 351
in the improved map. In addition, the SNP marker density in the improved map (1.38 cM/
marker) was higher than that reported in the previous one (2.3 cM/marker). The improved
genetic linkage map consisted of eight linkage groups, corresponding to the number of scaf-
folds in the peach genome, while the previous map consisted of 14 linkage groups. Consensus peach linkage map where: delta_bp is distance in bp between mapped SNPs in the consensus map; delta_cM is
distance in cM between mapped SNPs in the consensus map; snp_bp is the physical position
of the peach SNP being estimated (in bp); snp1_bp and snp2_bp are the immediate left and
right physical positions (bp) of SNPs that map to the genetic map and snp1_cM and snp2_cM
are their corresponding genetic positions (in cM). In cases where a SNP was beyond the last mapped SNP, the same delta_cM from the last
two SNPs on the linkage group and snp2_bp became the position at the scaffold end. Comparison of the ZC2 linkage map with the peach physical map v 2.0 The ZC2 map covers approximately 82.7% of the peach genome v2.0 (Table 2). LG3 had the
largest coverage (96%), while the lowest coverage (26%) was observed on LG5. The improved
ZC2 genetic map had 97.8% of all SNP markers in agreement with their positions on the scaf-
folds of the peach genome v 2.0 with differences in the marker order identified in LGs 1, 2, 3
and 6 (Table 2, Fig 2). LG3 had the highest number of non-collinear SNP markers (28). The
recombination rate of different chromosomes was estimated as the quotient between the
genetic distance (cM) covered by the corresponding LG and the size in Mb of the chromosome
fragment covered with markers. This value ranged from 2.20 cM/Mb on LG6 to 6.53 cM/Mb
on LG5, almost a three-fold difference in the recombination rate of the corresponding geno-
mic regions (Table 2). Estimating the genetic position (cM) for unmapped SNP markers in the 9K
SNP array A Perl Script was developed to estimate the genetic positions for the unmapped SNP markers
in the 9K SNP array using the peach consensus map as a reference. The term “unmapped” des-
ignates the markers from the genotyping array that were not mapped in one of the individual
maps used for building the consensus map. The genetic position for each unmapped marker
was estimated using the two closest mapped SNPs in the peach consensus map reported in this
study. The equations are as follows: delta bp ¼ snp2 bp snp1 bp
delta cM ¼ snp2 cM snp1 cM delta bp ¼ snp2 bp snp1 bp delta cM ¼ snp2 cM snp1 cM cM estimate ¼ snp1 cM þ delta cM ðsnp bp snp1 bpÞ=delta bpÞ cM estimate ¼ snp1 cM þ delta cM ðsnp bp snp1 bpÞ=delta bpÞ 4 / 16 Consensus genetic map of peach Four previously published bi-parental linkage maps, WB [18], OC [19], VxV [20], TxE [56]
and an improved ZC2 map developed in this study, were used to construct the consensus 5 / 16 PLOS ONE | https://doi.org/10.1371/journal.pone.0207724
November 21, 2018 Consensus peach linkage map Fig 1. The improved SNP-based genetic linkage map of ‘Zin Dai’ × ‘Crimson Lady’ (ZC2) progeny. Marker names are listed at the right side of each LG and the genetic
(
)
l
d
h l f
f
h
k Fig 1. The improved SNP-based genetic linkage map of ‘Zin Dai’ × ‘Crimson Lady’ (ZC2) progeny. Marker names are listed at the right side of each LG and the genetic
position (in cM) is listed at the left of each marker. Fig 1. The improved SNP-based genetic linkage map of ‘Zin Dai’ × ‘Crimson Lady’ (ZC2) progeny. Marker names are listed at the right side of each LG and the genetic
position (in cM) is listed at the left of each marker kage map of ‘Zin Dai’ × ‘Crimson Lady’ (ZC2) progeny. Marker names are listed at the right side of each LG and the genetic
arker Fig 1. The improved SNP-based genetic linkage map of ‘Zin Dai’ × ‘Crimson Lady’ (ZC2) progeny. Marker names are listed at the right side of each LG and the genetic
position (in cM) is listed at the left of each marker. Fig 1. The improved SNP-based genetic linkage map of ‘Zin Dai’ × ‘Crimson Lady’ (ZC2) progeny. Marker names are
position (in cM) is listed at the left of each marker. https://doi.org/10.1371/journal.pone.0207724.g001 https://doi.org/10.1371/journal.pone.0207724.t001 peach map. The number of markers mapped on these maps ranged from 1,948 in TxE to 877
in WB. peach map. The number of markers mapped on these maps ranged from 1,948 in TxE to 877
in WB. SNPs that mapped to positions that are non-collinear with their physical position on the
peach genome were removed from individual maps and 3,092 markers, including 2,975 SNPs,
116 SSRs and one morphological marker (SR) associated with slow ripening in peach [31] Table 1. The improved SNP-based genetic linkage map of ‘Zin Dai’ × ‘Crimson Lady’ (ZC2) progeny. LG
Length (cM)
Mapped markers
Uniquely mapped
SNPs mapped to the same position
Largest gap (cM)
LG1
95.3
131
37
94
24.2
LG2
62.2
259
50
209
15.3
LG3
69.1
161
46
115
10.9
LG4
63.9
211
35
176
23.4
LG5
31.2
40
17
23
2.6
LG6
62.4
234
63
171
2.4
LG7
51.7
263
54
209
4.3
LG8
47.5
177
49
128
6.4
ZC2 map
483.3
1,476
351
1,125 Table 1. The improved SNP-based genetic linkage map of ‘Zin Dai’ × ‘Crimson Lady’ (ZC2) progeny. PLOS ONE | https://doi.org/10.1371/journal.pone.0207724
November 21, 2018 6 / 16 Consensus genetic maps built by MergeMap and LPmerge algorithms Consensus maps were successfully developed by MergeMap and LPMerge algorithms. How-
ever, mismatch in marker order between the two versions of the consensus map was observed
(S2 and S3 Tables). The MergeMap consensus map had a genetic distance of 830.62 cM with
the length of individual LGs ranging from 86.96 to 143.95 cM, observed in LG5 and LG1,
respectively (S2 Table). Average distance between the markers was 0.92 cM and the largest gap
size was 8.8 cM on LG2. There were 906 uniquely mapped positions ranging from 156 on LG1
to 76 on LG5 (Table 4; S1 Fig). The consensus map built with the LPMerge algorithm spanned 537.92cM, with the length
of individual LGs ranging from 46.6 to 96.05cM for LG3 and LG1, respectively (S3 Table). Average distance between the markers was 0.78 cM and the largest gap of 7.31 cM was
observed on LG5 (Table 4; Fig 3). The number of uniquely mapped positions were 693, with
the lowest in LG3 (59), and the largest in LG1 (121). The LPMerge peach consensus map had
the lowest average RMSE and was further referred to as the peach consensus map (S4 Table). Consensus peach linkage map Table 2. Comparison of the ZC2 linkage map with the peach physical map v 2.0. Table 2. Comparison of the ZC2 linkage map with the peach physical map v 2.0. LGs
ZC2 linkage map
Marker density
Ratio
(cM/Mb)2
# of SNPs (non-collinear)
# of bins1
Genetic distance (cM)
Physical length (Mb)
Physical coverage (%)
cM
Mb
1
131 (1)
37
95.3
43.04
90.2
2.57
1.16
2.21
2
259 (3)
50
62.2
28.07
92.8
1.24
0.56
2.21
3
161 (28)
46
69.1
26.39
96.8
1.50
0.57
2.63
4
211 (-)
35
63.9
23.13
91.2
1.82
0.66
2.75
5
40 (-)
17
31.2
4.83
26.5
1.83
0.28
6.53
6
234 (1)
63
62.4
28.21
92.9
0.99
0.45
2.20
7
263 (-)
54
51.7
20.77
93.2
0.95
0.38
2.50
8
177 (-)
49
47.5
17.41
77.8
0.96
0.36
2.66
1 Groups of markers with the same genetic position
2 Ratio between genetic distance and physical length that estimates the recombination rate per chromosome 1 Groups of markers with the same genetic position Groups of markers with the same genetic position
2 Ratio between genetic distance and physical length that estimates the recombination rate per chromosome distributed in eight linkage groups, were used to build the consensus map by two different
algorithms, i.e. MergeMap and LPmerge. g
g
g
A total of 1,416 SNPs were common to at least two linkage maps with 2,547 anchor points
(Table 3). There were 457 anchor points between VxV and TxE maps, while only 98 anchor
points were observed between WB and ZC2 maps. LG4 had the highest number of anchors
points (648), while the lowest number was detected in LG5 (100). The highest number of com-
mon markers among the LGs was observed in LG4 (325) and the lowest was observed on the
LG5 with only 70 common markers. https://doi.org/10.1371/journal.pone.0207724.t002 1 Groups of markers with the same genetic position 2 Ratio between genetic distance and physical length that estimates the recombination rate per chromosome Discussion Discussion
The improved linkage map for ZC2 population
Genotyping of additional 65 F2 individuals from the cross ‘Zin Dai’ and ‘Crimson Lady’
improved the existing ZC2 map [17] and resulted in a map with a better resolution and more
Fig 2. Alignment of the ZC2 linkage map and the peach genome sequence v2.0. Peach genome scaffolds and ZC2 linkage groups are shown on the left and right of
each pair, respectively. https://doi.org/10.1371/journal.pone.0207724.g002 Comparison of the peach consensus map with the peach physical map v2.0 The physical length of the peach consensus map was estimated to cover approximately 98% of
the pseudomolecules of peach genome v2.0 with most of the scaffolds having a coverage above
95%, except for scaffold 5 (91.0%). The recombination rate of different chromosomes ranged
from 1.63 cM/Mb on LG4 to 3.77 cM/Mb on LG5. The consensus map was collinear with the
peach genome revealing complete agreement in the SNP marker order (S2 Fig; Table 5). PLOS ONE | https://doi.org/10.1371/journal.pone.0207724
November 21, 2018 7 / 16 Consensus peach linkage map The peach consensus map was used as a reference with a Perl script (developed in-house) to
calculate genetic positions of markers from the peach 9K array, and the genetic positions of
6,019 unmapped SNP markers were provided in S5 Table. Consensus peach linkage map netic maps for common markers and anchor points across different linkage groups used to construct a consensus genetic Table 3. Comparison between five peach genetic maps for common markers and anchor points across different linkage groups used to construct a consensus genetic
map. Table 3. Comparison between five peach genetic maps for common markers and anchor points across different linkage groups used to construct a consensus genetic
map. Linkage Maps
LG1
LG2
LG3
LG4
LG5
LG6
LG7
LG8
Anchors/Map
WB vs. OC
51
11
35
33
6
12
33
29
210
WB vs. VxV
82
10
45
54
1
19
22
26
259
WB vs. TxE
62
24
44
38
36
37
29
33
303
WB vs. ZC2
14
2
9
19
13
12
14
15
98
OC vs. VxV
89
19
76
138
1
10
38
26
397
OC vs. TxE
38
66
45
110
14
20
53
38
384
OC vs. ZC2
10
11
17
22
10
1
42
20
133
VxV vs. TxE
75
39
65
144
1
45
32
56
457
VxV vs. ZC2
6
8
16
62
1
9
13
14
129
TxE vs. ZC2
13
15
17
28
17
25
30
32
177
Anchors/LG
440
205
369
648
100
190
306
289
2547
Number of markers
217
149
178
325
70
133
177
167
The anchor points between pair of genetic maps and corresponding linkage groups, as well as the total number of markers in common on each linkage group are shown. WB, ‘NJ Weeping’ x ‘Bounty’ [18]; OC, ‘O’Henry’ x ‘Clayton’ [19]; VxV, ‘Venus’ × ‘Venus’ [20]; TxE, ‘Texas’ x ‘Earlygold’ [56]; ZC2, ‘Zin Dai’ x ‘Crimson Lady’
improved map. The anchor points between pair of genetic maps and corresponding linkage groups, as well as the total number of markers in common on each linkage group are shown. WB, ‘NJ Weeping’ x ‘Bounty’ [18]; OC, ‘O’Henry’ x ‘Clayton’ [19]; VxV, ‘Venus’ × ‘Venus’ [20]; TxE, ‘Texas’ x ‘Earlygold’ [56]; ZC2, ‘Zin Dai’ x ‘Crimson Lady’
improved map. https://doi.org/10.1371/journal.pone.0207724.t003 uniquely mapped positions. In comparison to the previous ZC2 map, the number of linkage
groups decreased from 14 to eight and the number of mapped markers increased from 1,335
to 1.476. The number of unique positions increased by approximately 84% (Table 1) as well as
marker density (from 2.4 to 1.38cM/marker). Number of bins, linkage group length and marker density per linkage group generated by MergeMap and LPmerge
are shown on left and right, respectively. The improved linkage map for ZC2 population Genotyping of additional 65 F2 individuals from the cross ‘Zin Dai’ and ‘Crimson Lady’
improved the existing ZC2 map [17] and resulted in a map with a better resolution and more Fig 2. Alignment of the ZC2 linkage map and the peach genome sequence v2.0. Peach genome scaffolds and ZC2 linkage groups are shown on the left and right of
each pair, respectively. each pair, respectively. https://doi.org/10.1371/journal.pone.0207724.g002 https://doi.org/10.1371/journal.pone.0207724.g002 https://doi.org/10.1371/journal.pone.0207724.g002 PLOS ONE | https://doi.org/10.1371/journal.pone.0207724
November 21, 2018 8 / 16 1 Groups of markers with the same genetic position. https://doi.org/10.1371/journal.pone.0207724.t004 https://doi.org/10.1371/journal.pone.0207724.t004 1 Groups of markers with the same genetic position. https://doi.org/10.1371/journal.pone.0207724.t003 0207724
November 21, 2018
9 / 16 PLOS ONE | https://doi.org/10.1371/journal.pone.0207724
November 21, 2018 The first version of the map covered 61.6% of
the pseudomolecules of the peach genome, while the improved map covered 82.7%. Genetic
length (483.3 cM) and SNP density (1.38 cM/SNP) of the improved ZC2 map were similar to
previously reported SNP maps in peach [25,28,19]. The new ZC2 map had a higher marker
density than the other maps based on the 9K SNP array [28,19]. The observed gaps on LGs 1
and 6 (24.2 and 23.4 cM, respectively) agreed with those reported by Yang et al. [19] and Frett
et al. [17] who used the same genotyping strategy. Marker order comparison between the ZC2 genetic map and the physical map, based on
peach genome v2.0, revealed discrepancies in marker positions across LGs 1, 2, 3 and 6. Non- Table 4. Comparison between peach consensus maps built using MergeMap and LPmerge. LG
No. of Markers
# of bins1
LG length (cM)
SNP density
1
460
156 |121
143.95 | 96.05
0.92 | 0.79
2
406
84 | 64
97.37 | 63.48
1.16 | 0.99
3
335
118 | 59
96.64 |46.6
0.82 |0.79
4
670
132 | 86
104.22 | 64.13
0.79 | 0.75
5
182
76 | 61
86.96 | 62.44
1.14 | 1.02
6
363
119 | 113
96.57 |78.6
0.81 | 0.70
7
317
109 | 98
102.61 | 68.92
0.94 | 0.70
8
359
112 | 91
102.30 | 57.7
0.91 | 0.63
Total
3,092
906 | 693
830.62 | 537.92
0.92 | 0.78 Table 4. Comparison between peach consensus maps built using MergeMap and LPmerge. PLOS ONE | https://doi.org/10.1371/journal.pone.0207724
November 21, 2018 9 / 16 PLOS ONE | https://doi.org/10.1371/journal.pone.0207724
November 21, 2018 Consensus peach linkage map urnal.pone.0207724
November 21, 2018
10 / 16 10 / 16 PLOS ONE | https://doi.org/10.1371/journal.pone.0207724
November 21, 2018 Consensus peach linkage map Fig 3. Peach consensus linkage map built using four previously published bi-parental linkage maps, PI91459(‘NJ
Weeping’) × ‘Bounty’ (WB) [18], ‘O’Henry’ × ‘Clayton’ (OC) [19], ‘Venus’ × ‘Venus’ (VxV) [20] and ‘Texas’ ×
‘Earlygold’ (T×E) [56], and an improved ‘Zin Dai’ × ‘Crimson Lady’2 map developed in this study with LPMerge
algorithm. Marker names are listed at the right side of each LG and the genetic position (in cM) is listed at the left of
each marker. https://doi.org/10.1371/journal.pone.0207724.g003 collinearity in other peach maps has been reported when both the peach genome v1 [24–
25,17,18] and v2.0 [28] were used for comparison. Non-collinearity in marker order could be
due to specific characteristics of the population, such as size, presence of chromosome rear-
rangements, and/or linkage mapping and genotyping errors. It could also indicate misassem-
blies in the peach genome sequence v2.0 [55]. The improved ZC2 map provides an excellent
resource for mapping QTLs associated with fruit quality and phytochemical compounds, since
the ZC2 progeny segregate for many traits including flowering and ripening time, blush, fruit
size, flesh adhesion and texture, and phytochemical content [58]. Thus, the improved ZC2
map provides a valuable tool for future work to better understand genetic mechanisms that
control these traits in peach. 1Ratio genetic distance/physical length that estimates the recombination rate per chromosome. https://doi.org/10.1371/journal.pone.0207724.t005 https://doi.org/10.1371/journal.pone.0207724.t005 1Ratio genetic distance/physical length that estimates the recombination rate per chromosome. 1Ratio genetic distance/physical length that estimates the recombination rate per chromosome. PLOS ONE | https://doi.org/10.1371/journal.pone.0207724
November 21, 2018 hat estimates the recombination rate per chromosome. PLOS ONE | https://doi.org/10.1371/journal.pone.0207724
November 21, 2018
11 / 16 nce/physical length that estimates the recombination rate per chromosome. https://doi.org/10.1371/journal.pone.0207724.t005 Conclusions In this study, we genotyped 65 additional F2 individuals using the 9K SNP array and signifi-
cantly increased the resolution of the previously published ZC2 map. Using the improved ZC2
map with four other high-density linkage maps (all genotyped with the 9K SNP array), we
developed a high-resolution consensus map for peach using LPMerge algorithm. The peach
consensus linkage map contains a total of 3,092 molecular markers (2,975 SNPs, 116 SSRs and
1 morphological marker associated with slow ripening in peach), 2,547 anchor points and cov-
ers approximately 98% of the physical length of the peach genome v2.0. This consensus genetic
linkage map represents the most comprehensive peach map available to date and could serve
as a new reference map for peach. The consensus map provides valuable information on
marker order and genetic position for QTL identification and molecular marker development
in peach and other genetic studies within the Prunus and Rosaceae. Consensus peach linkage map The MergeMap algorithm resulted in consensus map with a higher genetic length
(830.62cM) and a lower marker density (0.92cM/marker) compared to the LPMerge algorithm
(537.92 cM and 0.78cM/marker, respectively). A possible explanation for the observed differ-
ences between the two algorithms is that the MergeMap assigned unique positions to most of
the markers, while the LPMerge binned markers into the same map positions. Thus, the non-
binning attribute of the MergeMap provided higher genetic length of the consensus map [47]. The overestimated genetic length in the consensus map constructed by the MergeMap was
previously reported in pear [38], barley [43] Pinus taeda, and Pinus elliottii [47]. On the other
hand, the genetic length of the LPMerge peach consensus map was within the range of the five
individual maps used in this study (336.0–536.6 cM). In addition, each algorithm ordered
markers differently in the consensus map resulting in non-collinearity in the MergeMap peach
consensus map with peach genome v2.0. A possible explanation is that MergeMap simplified
consensus graphs were not ordinally equivalent to the original linkage maps used for building
the consensus map [61]. The LPMerge map had the lowest RMSE compared to the input maps
and was chosen as the consensus map. The peach consensus map described here exhibited approximately 98% coverage and full
SNP collinearity with the pseudomolecules/scaffolds of the peach genome v2.0 [55], which is
similar to coverage obtained with consensus maps developed for apple [5] and pear [38]. The
high level of genome coverage confirms the correct positioning of the markers in the consen-
sus map that emerges as reliable tool for future genetic studies such as QTL mapping and can-
didate gene analyses [5]. This is, to our knowledge, the most comprehensive peach consensus map constructed thus
far. Although two consensus peach maps have been previously reported, their application is
limited due to either small number of genotypes providing recombination events and less
common genotyping platform in the peach community [25], or being developed not by merg-
ing individual peach linkage maps but by calculating genetic positions [30]. The consensus
map reported in this study is an alternative source of information for calculating genetic posi-
tions of unmapped markers in the 9K peach SNP array and QTL mapping via pedigree [34]. Consensus genetic map of peach The peach research community has been using a Prunus genetic map based on an interspecific
cross between almond ‘Texas’ and peach ‘Earlygold’ (TxE) [3,56,59] as a reference for estab-
lishing linkage group orientation and comparative QTL studies. Prior to the availability of the
peach genome sequence, the TxE map was a valuable tool as a source of mapped and transfer-
able markers (mainly SSRs and RFLPs) for the construction of low density maps and the com-
parison between intraspecific peach and other Prunus species maps [59]. The release of the
peach genome sequence [55,60] triggered the development of the 9K peach SNP array [16] and
promoted genetic studies in peach using a common genotyping strategy [17,18,19,20,56]. This
established the foundation for the development of the peach consensus map reported in this
study. The five highly saturated maps used for building the consensus peach map were based on
SSR and SNP markers [20,56] or exclusively SNP markers [17,18]. The high number of com-
mon markers (1,416) and anchor points (2,547) facilitated the integration of the individual
linkage maps into the consensus map and provided reliable information about SNP marker
order and genetic distance in the consensus map. The number of anchor points observed in
the peach consensus map was higher than that observed in the consensus maps developed for
apple [5,39] and pear [38]. Table 5. Comparison of the peach consensus map with the peach genome sequence v2.0. LG
No. of Markers
Genetic distance
Physical length
Physical coverage
Marker density
Ratio
(cM)
(Mb)
(%)
cM
Mb
(cM/Mb)1
1
460
96.05
47.44
99
0.79
0.39
2.03
2
406
63.48
30.13
99
0.99
0.47
2.10
3
335
46.60
27.25
99
0.79
0.46
1.71
4
670
64.13
25.15
99
0.75
0.29
2.59
5
182
62.44
16.52
91
1.02
0.27
3.77
6
363
78.60
30.10
99
0.70
0.27
2.59
7
317
68.92
22.19
98
0.70
0.22
3.18
8
359
57.70
21.91
97
0.63
0.24
2.63 e 5. Comparison of the peach consensus map with the peach genome sequence v2.0. 11 / 16 Supporting information S1 Fig. MergeMap peach consensus map with 3,092 markers. Marker names are listed at the
right side of each LG and the genetic position (in cM) are listed at the left of each marker. (TIF) 12 / 16 PLOS ONE | https://doi.org/10.1371/journal.pone.0207724
November 21, 2018 Consensus peach linkage map S2 Fig. Alignment of the peach consensus map and the peach genome sequence v2.0. Peach
genome scaffolds and linkage groups are shown on the left and right of each pair, respectively. (TIF)
S1 Table. The improved SNP-based genetic linkage map of ‘Zin Dai’ × ‘Crimson Lady’
(ZC2) progeny. (XLSX)
S2 Table. Peach consensus map with 3,092 molecular markers and constructed using Mer-
geMap algorithm. (XLSX)
S3 Table. Peach consensus map with 3,092 molecular markers and constructed using
LPMerge algorithm. (XLSX)
S4 Table. Root mean squared error (RMSE) in marker order between the MergeMap and
LPmerge peach consensus maps and the five input maps. (XLSX)
S5 Table. Estimated genetic position of the SNPs markers from 9K SNP array using peach
consensus map as a reference. (XLSX) S4 Table. Root mean squared error (RMSE) in marker order between the MergeMap and
LPmerge peach consensus maps and the five input maps. (XLSX) S5 Table. Estimated genetic position of the SNPs markers from 9K SNP array using peach
consensus map as a reference. (XLSX) Author Contributions Author Contributions
Conceptualization: Ksenija Gasic. Formal analysis: Cassia da Silva Linge, Laima Antanaviciute. Funding acquisition: Ksenija Gasic. Investigation: Asma Abdelghafar. Resources: Asma Abdelghafar, Pere Aru´s, Daniele Bassi, Laura Rossini, Stephen Ficklin, Kse-
nija Gasic. Supervision: Ksenija Gasic. Writing – original draft: Cassia da Silva Linge, Laima Antanaviciute. Writing – review & editing: Pere Aru´s, Daniele Bassi, Laura Rossini, Stephen Ficklin, Ksenija
Gasic. Conceptualization: Ksenija Gasic. Formal analysis: Cassia da Silva Linge, Laima Antanaviciute. Formal analysis: Cassia da Silva Linge, Laima Antanaviciute. Resources: Asma Abdelghafar, Pere Aru´s, Daniele Bassi, Laura Rossini, Stephen Ficklin, Kse-
nija Gasic. Resources: Asma Abdelghafar, Pere Aru´s, Daniele Bassi, Laura Rossini, Stephen Ficklin, Kse-
nija Gasic. Supervision: Ksenija Gasic. Writing – original draft: Cassia da Silva Linge, Laima Antanaviciute. Writing – review & editing: Pere Aru´s, Daniele Bassi, Laura Rossini, Stephen Ficklin, Ksenija
Gasic. Writing – review & editing: Pere Aru´s, Daniele Bassi, Laura Rossini, Stephen Ficklin, Ksenija
Gasic. References 1. Collard BC, Jahufer MZ, Brouwer J, Pang EC. An introduction to markers, quantitative trait loci (QTL)
mapping and marker-assisted selection for crop improvement: The basic concepts. Euphytica 2005;
142:169–196. 2. Wu J, Li LT, Li M, Khan MA, Li XG, Chen H, et al. High-density genetic linkage map construction and
identification of fruit-related QTLs in pear using SNP and SSR markers. J Exp Bot. 2014; 65(20): 5771–
5781. https://doi.org/10.1093/jxb/eru311 PMID: 25129128 3. Joobeur T, Viruel MA, de Vicente MC, Ja´uregui B, Ballester J, Dettori MT, et al. Construction of a satu-
rated linkage map for Prunus using an almond × peach F2 progeny. Theor. Appl. Genet. 1998; 97:
1034–1041. 4. Wu Y, Close TJ, Lonardi S. On the accurate construction of consensus genetic maps. Comput. Syst. Bioinformatics Conf. 2008; 7: 285–296. PMID: 19642288 13 / 16 PLOS ONE | https://doi.org/10.1371/journal.pone.0207724
November 21, 2018 Consensus peach linkage map 5. Khan MA, Han Y, Zhao YF, Troggio M, Korban SS. A multi-population consensus genetic map reveals
inconsistent marker order among maps likely attributed to structural variations in the apple genome. PLoS ONE 2012; 7: e47864. https://doi.org/10.1371/journal.pone.0047864 PMID: 23144832 6. Diaz A, Fergany M, Formisano G, Ziarsolo P, Blanca J, Fei Z, et al. A consensus linkage map for molec-
ular markers and quantitative trait loci associated with economically important traits in melon (Cucumis
melo L.). BMC plant biology 2011; 11: 111. https://doi.org/10.1186/1471-2229-11-111 PMID:
21797998 7. Illa E, Sargent DJ, Lopez Girona E, Bushakra J, Cestaro A, Crowhurst R, et al. Comparative analysis of
rosaceous genomes and the reconstruction of a putative ancestral genome for the family. BMC Evolu-
tionary Biology 2011; 11:9. https://doi.org/10.1186/1471-2148-11-9 PMID: 21226921 8. Pirona R, Eduardo I, Pacheco I, Da Silva Linge C, Miculan M, Verde I, et al. Fine mapping and identifica-
tion of a candidate gene for a major locus controlling maturity date in peach. BMC Plant Biol 2013; 13
(1):166. https://doi.org/10.1186/1471-2229-13-166 PMID: 24148786 9. Yagi M, Yamamoto T, Isobe S, Hirakawa H, Tabata S, Tanase K. Construction of a reference genetic
linkage map for carnation (Dianthus caryophyllus L.). BMC Genomics 2013; 14(1): 734. https://doi.org/
10.1186/1471-2164-14-734 PMID: 24160306 10. Longhi S, Giongo L, Buti M, Surbanovski N, Viola R, Velasco R, et al. Molecular genetics and genomics
of the Rosoideae: state of the art and future perspectives. Horticulture Research 2014; 1. https://doi. org/10.1038/hortres.2014.1 PMID: 26504527 11. References Vendramin E, Pea G, Dondini L, Pacheco I, Dettori MT, Gazza L, et al. A unique mutation in a MYB
gene cosegregates with the nectarine phenotype in peach. PLoS ONE 2014; 9:e90574. https://doi.org/
10.1371/journal.pone.0090574 PMID: 24595269 12. Davey JW, Hohenlohe PA, Etter PD, Boone JQ, Catchen JM, Blaxter ML. Genome-wide genetic marker
discovery and genotyping using next-generation sequencing. Nature Reviews Genetics 2011; 12: 499–
510. https://doi.org/10.1038/nrg3012 PMID: 21681211 13. Xu Y, Huang L, Ji D, Chen C, Zheng H, Xie C. Construction of a dense genetic linkage map and map-
ping quantitative trait loci for economic traits of a doubled haploid population of Pyropia haitanensis
(Bangiales, Rhodophyta). BMC Plant Biol 2015; 15:228. https://doi.org/10.1186/s12870-015-0604-4
PMID: 26391981 14. Jung S, Staton M, Lee T, Blenda A, Svancara R, Abbott A, et al. GDR (Genome Database for Rosa-
ceae): integrated web-database for Rosaceae genomics and genetics data. Nucleic Acids Research,
2008; 36(Database issue): D1034–D1040. https://doi.org/10.1093/nar/gkm803 PMID: 17932055 15. Jung, S., Lee, T., Cheng, C-H., Buble, K., Zheng, P., Yu, J., et al (2018) 15 years of GDR: New data and
functionality in the Genome Database for Rosaceae. Nucleic Acid Research https://doi.org/10.1093/
nar/gky1000 16. Verde I, Bassil NV, Scalabrin S, Gilmore B, Lawley CT, Gasic K, et al. Development and Evaluation of a
9K SNP Array for Peach by Internationally Coordinated SNP Detection and Validation in Breeding
Germplasm. PLoS One 2012; 7(6): e35668. https://doi.org/10.1371/journal.pone.0035668 PMID:
22536421 17. Frett T, Reighard G, Okie W, Gasic K. Mapping quantitative trait loci associated with blush in peach
[Prunus persica (L.) Batsch]. Tree Genet Genomes 2014; 10: 367–381. 18. Da Silva Linge C, Bassi D, Bianco L, Pacheco I, Pirona R, Rossini L. Genetic dissection of fruit weight
and size in an F2 peach (Prunus persica (L.) Batsch) progeny. Mol Breed 2015; 35:71. https://doi.org/
10.1007/s11032-015-0271-z 19. Yang N, Reighard GL, Ritchie D, Okie WR, Gasic K. Mapping quantitative trait loci associated with
resistance to bacterial spot (Xanthomonas arboricola pv. pruni) in peach. Tree Genet Genomes 2013;
https://doi.org/10.1007/s11295-012-0580-x 20. Nuñez-Lillo G, Cifuentes-Esquivel A, Troggio M, Micheletti D, Infante R, Campos-Vargas R, et al. Identi-
fication of candidate genes associated with mealiness and maturity date in peach [Prunus persica (L.)
Batsch] using QTL analysis and deep sequencing. Tree Genet. Gen. 2015; 11:86 https://doi.org/10. 1007/s11295-015-0911-9 21. Foulongne M, Pascal T, Pfeiffer F, Kervella J. QTLs for powdery mildew resistance in peach × Prunus
davidiana crosses: consistency across generations and environments. References Yan Z, Denneboom C, Hattendorf A, Dolstra O, Debener T, Stam P, et al. Construction of an integrated
map of rose with AFLP, SSR, PK, RGA, RFLP, SCAR and morphological markers. Theor. Appl. Genet. 2005; 110: 766–777. https://doi.org/10.1007/s00122-004-1903-6 PMID: 15672277 33. N’Diaye A, Van de Weg WE, Kodde LP, Koller B, Dunemann F, Thiermann M, et al. Construction of an
integrated consensus map of the apple genome based on four mapping populations. Tree Genet. Genomes 2008; 4: 727–743. https://doi.org/10.1007/s11295-008-0146-0 34. Bink M, Jansen J, Madduri M, Voorrips R, Durel C, Kouassi A, et al. Bayesian QTL analyses using pedi-
greed families of an outcrossing species, with application to fruit firmness in apple. TheorAppl Genet
2014; 127: 1073–1090. 35. Herna´ndez Mora JR, Micheletti D, Bink M, Van de Weg E, Cantı´n C, Nazzicari N, et al. Integrated QTL
detection for key breeding traits in multiple peach progenies. BMC Genomics 2017; 18: 404. https://doi. org/10.1186/s12864-017-3783-6 PMID: 28583082 36. Iezzoni A, Weebadde C, Luby J, Yue C, Van de Weg E, Fazio G, et al. RosBREED: enabling marker-
assisted breeding in Rosaceae. Acta Hortic 2010; 859: 389–394. 37. Howad W, Yamamoto T, Dirlewanger E, Testolin R, Cosson P, Cipriani G, et al. Mapping with a few
plants: using selective mapping for microsatellite saturation of the Prunus reference map. Genetics
2005; 171: 1305–1309. https://doi.org/10.1534/genetics.105.043661 PMID: 16118196 38. Li L, Deng C, Knaebel M, Chagne D, Kumar S, Sun J, et al. Integrated high-density consensus genetic
map of Pyrus and anchoring of the ‘Bartlett’ v1.0 (P. communis) genome. DNA Res 2017; 24: 289–301. https://doi.org/10.1093/dnares/dsw063 PMID: 28130382 39. Clark M, Schmitz C, Rosyara U, Luby J, Bradeen J. A consensus ‘Honeycrisp’ apple (Malus × domes-
tica) genetic linkage map from three full-sib progeny populations. Tree Gen Genomes 2014; 10(3):
627–639. 40. Wu Y, Close TJ, Lonardi S. Accurate construction of consensus genetic maps via integer linear pro-
gramming. IEEE/ACM Trans. Comput. Biol. Bioinform. 2011; 8: 381–394. 41. Endelman JB, Plomion C. LPmerge: an R package for merging genetic maps by linear programming. Bioinformatics 2014; 30: 1623–1624. https://doi.org/10.1093/bioinformatics/btu091 PMID: 24532720 42. Close TJ, Bhat PR, Lonardi S, Wu Y, Rostoks N, Ramsay L, et al. Development and implementation of
high throughput SNP genotyping in barley. BMC Genomics 2009; 10: 582. https://doi.org/10.1186/
1471-2164-10-582 PMID: 19961604 43. Muñoz-Amatriaı´n M, Moscou MJ, Bhat PR, Svensson JT, Bartos J, Sucha´nkova´ P, et al. References Mol Breed 2003; 12: 33–50. 22. Fan S, Bielenberg DG, Zhebentyayeva TN, Reighard GL, Okie WR, Holland D, et al. Mapping quantita-
tive trait loci associated with chilling requirement, heat requirement and bloom date in peach (Prunus
persica). The New Phytologist 2010; 185: 917–930. https://doi.org/10.1111/j.1469-8137.2009.03119.x
PMID: 20028471 23. Eduardo I, Pacheco I, Chietera G, Bassi D, Pozzi C, Vecchietti A, et al. QTL analysis of fruit quality traits
in two peach intraspecific populations and importance of maturity date pleiotropic effect. Tree Genet
Genomes 2011; 7: 323–335. PLOS ONE | https://doi.org/10.1371/journal.pone.0207724
November 21, 2018 14 / 16 Consensus peach linkage map 24. Eduardo I, Chietera G, Pirona R, Pacheco I, Troggio M, Banchi E, et al. Genetic dissection of aroma vol-
atile compounds from the essential oil of peach fruit: QTL analysis and identification of candidate genes
using dense SNP maps. Tree Genet Genomes 2013; 9: 189–204. 25. Martınez-Garcıa P, Parfitt D, Ogundiwin E, Fass J, Chan H, Ahmad R, Lurie S, et al. High-density SNP
mapping and QTL analysis for fruit quality characteristics in peach (Prunus persica L.). Tree Genet
Genomes 2013; 9: 19. https://doi.org/10.1007/s11295-012-0522-7 26. Pacheco I, Bassi D, Eduardo I, Ciacciulli A, Pirona R, Rossini L, et al. QTL mapping for brown rot (Moni-
linia fructigena) resistance in an intraspecific peach (Prunus persica L. Batsch) F1 progeny. Tree Genet
Genomes 2014; 10: 1223–1242. https://doi.org/10.1007/s11295-014-0756-7 27. Zeballos J, Abidi W, Gime´nez R, Monforte AJ, Moreno MA, Gogorcena Y. QTL analysis of fruit quality
traits in peach [Prunus persica (L.) Batsch] using dense SNP maps. Acta Hortic 2015; 1084: 703–710. 28. Zeballos JL, Abidi W, Gime´nez S, Monforte AJ, Moreno MA., Gogorcena Y. Mapping QTLs associated
with fruit quality traits in peach [Prunus persica (L.) Batsch] using SNP maps. Tree Genet. Genomes
2016; 12:37. https://doi.org/10.1007/s11295-016-0996-9 29. Fresnedo-Ramı´rez J, Bink M, de Weg E, Famula TR, Crisosto CH, Frett TJ, et al. QTL mapping of
pomological traits in peach and related species breeding germplasm. Mol Breeding 2015; 35: 166. https://doi.org/10.1007/s11032-015-0357-7 30. Fresnedo-Ramı´rez J, Frett TJ, Sandefur PJ, Salgado-Rojas A, Clark JR, Gasic K, et al. QTL mapping
and breeding value estimation through pedigree-based analysis of fruit size and weight in four diverse
peach breeding programs. Tree Genet Genomes 2016; 12: 25. https://doi.org/10.1007/s11295-016-
0985-z 31. Cirilli M, Bassi D, Ciacciulli A. Sugars in peach fruit: a breeding perspective. Horticulture Research
2016; 3: 15067. https://doi.org/10.1038/hortres.2015.67 PMID: 26816618 32. References An improved
consensus linkage map of barley based on flow-sorted chromosomes and single nucleotide polymor-
phism markers. The Plant Genome 2011; 4: 238–249. 44. Muchero W, Diop NN, Bhat PR, Fenton RD, Wanamaker S, Pottorff M, et al. A consensus genetic map
of cowpea [Vigna unguiculata (L) Walp.] and synteny based on EST-derived SNPs. Proc. Natl Acad. Sci. 2009; 106: 18159–18164. https://doi.org/10.1073/pnas.0905886106 PMID: 19826088 PLOS ONE | https://doi.org/10.1371/journal.pone.0207724
November 21, 2018 15 / 16 Consensus peach linkage map 45. Wang J, Lydiate IA, Parkin IAP, Falentin C, Delourme R, Carion PWC, et al. Integration of linkage maps
for the amphidiploid Brassica napus and comparative mapping with Arabidopsis and Brassica rapa. BMC Genomics 2011; 12:101. https://doi.org/10.1186/1471-2164-12-101 PMID: 21306613 46. Patel JS, Mamidi S, Bonman JM, Adhikari T. Identification of QTL in spring wheat associated with resis-
tance to a novel isolate of Pyrenophoratritici-repentis. Crop Sci 2013; 53: 842–852. 47. Westbrook JW, Chhatre VE, Wu L-S, Chamala S, Neves LG, Muñoz P, et al. A consensus genetic map
for Pinus taeda and Pinus elliottii and extent of linkage disequilibrium in two genotype-phenotype dis-
covery populations of Pinus taeda. G3: Genes Genomes. Genetics 2015; 5: 1685–1694. https://doi. org/10.1534/g3.115.019588 PMID: 26068575 48. International Cassava Genetic Map Consortium. High-resolution linkage map and chromosome-scale
genome assembly for cassava (Manihot esculenta Crantz) from 10 populations. G3: Genes/Genomes/
Genetics 2015; 5: 133–144. 49. Bode´nès C, Chancerel E, Ehrenmann F, Kremer A, Plomion C. High-density linkage mapping and distri-
bution of segregation distortion regions in the oak genome. DNA Research 2016; 23: 115–124. https://
doi.org/10.1093/dnares/dsw001 PMID: 27013549 50. Yu B, Boyle K, Zhang W, Robinson SJ, Higgins E, Ehman L, et al. Multi-trait and multi-environment QTL
analysis reveals the impact of seed colour on seed composition traits in Brassica napus. Mol Breeding
2016; 36: 111. https://doi.org/10.1007/s11032-016-0521-8 51. Webb A, Cottage A, Wood T, Khamassi K, Hobbs D, Gostkiewicz K, et al. A SNP-based consensus
genetic map for synteny-based trait targeting in faba bean (Vicia faba L.). Plant Biotechnology 2015;
14: 177–185. 52. Dellaporta SL, Wood J, Hicks JB. A plant DNA minipreparation: version II. Plant Mol Biol Rep 1983; 1:
19–21. 53. Van Ooijen JW. JoinMap 4. Software for the Calculation of Genetic Linkage Maps in Experimental Pop-
ulations. Kyazma BV, Wageningen, The Netherlands. 2006. 54. Voorrips RE. MapChart: software for the graphical presentation of linkage maps and QTLs. J. Hered. 2002; 93: 77–78. PMID: 12011185 55. PLOS ONE | https://doi.org/10.1371/journal.pone.0207724
November 21, 2018 References Verde I, Jenkins J, Dondini L, Micali S, Pagliarani G, Vendramin E, et al. The Peach v2.0 release: high-
resolution linkage mapping and deep resequencing improve chromosome-scale assembly and contigu-
ity. BMC Genomics 2017; 18: 225. https://doi.org/10.1186/s12864-017-3606-9 PMID: 28284188 56. Donoso JM, Eduardo I, Picañol R, Batlle I, Howad W, Aranzana MJ, et al. High-density mapping sug-
gests cytoplasmic male sterility with two restorer genes in almond × peach progenies. Hortic Res 2015;
2: 15016. https://doi.org/10.1038/hortres.2015.16 PMID: 26504569 57. Zambrano-Bigiarini, M. hzambran/hydroGOF: v0.3–10: CITATION change (Version v0.3–10). Zenodo
2017; https://doi.org/10.5281/zenodo.840087 58. Abdelghafar A, Reighard G, Gasic K. Antioxidant capacity and bioactive compounds accumulation in
modern peach breeding germplasm. J Am Pomo Soc 2018; 72(1):40–69. 59. Dirlewanger E, Graziano E, Joobeur T, Garriga-Caldere´ F, Cosson P, Howad W. Comparative mapping
and marker-assisted selection in Rosaceae fruit crops. Proc Natl Acad. Sci. 2004; 101: 9891–9896. https://doi.org/10.1073/pnas.0307937101 PMID: 15159547 60. International Peach Genome Initiative. The high-quality draft genome of peach (Prunus persica) identi-
fies unique patterns of genetic diversity, domestication and genome evolution. Nat Genet 2013; 45:
487–494. https://doi.org/10.1038/ng.2586 PMID: 23525075 61. Endelman JB. New algorithm improves fine structure of the barley consensus SNP map. BMC Geno-
mics 2011; 12: 407. https://doi.org/10.1186/1471-2164-12-407 PMID: 21831315 16 / 16
|
https://openalex.org/W3014778059
|
https://hal.science/hal-02904004/document
|
English
| null |
Coronavirus – Scientific insights and societal aspects
|
Mathematical modelling of natural phenomena
| 2,020
|
cc-by
| 5,844
|
Coronavirus – Scientific insights and societal aspects
Vitaly Volpert, Malay Banerjee, Alberto D’onofrio, Tomasz Lipniacki, Sergei
Petrovskii, Viet Chi Tran Coronavirus – Scientific insights and societal aspects
Vitaly Volpert, Malay Banerjee, Alberto D’onofrio, Tomasz Lipniacki, Sergei
Petrovskii, Viet Chi Tran To cite this version: Vitaly Volpert, Malay Banerjee, Alberto D’onofrio, Tomasz Lipniacki, Sergei Petrovskii, et al.. Coro-
navirus – Scientific insights and societal aspects. Mathematical Modelling of Natural Phenomena,
2020, 15, pp.E2. 10.1051/mmnp/2020010. hal-02904004 Distributed under a Creative Commons Attribution 4.0 International License HAL Id: hal-02904004
https://hal.science/hal-02904004v1
Submitted on 21 Jul 2020 L’archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d’enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés. HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers. Distributed under a Creative Commons Attribution 4.0 International License Mathematical Modelling of Natural Phenomena
www.mmnp-journal.org Mathematical Modelling of Natural Phenomena
www.mmnp-journal.org Math. Model. Nat. Phenom. 15 (2020) E2
https://doi.org/10.1051/mmnp/2020010 Mathematics Subject Classification. 92D30. Mathematics Subject Classification. 92D30. Received April 2, 2020. Accepted April 2, 2020. 1. Current situation On April 1, 2020, there are more than 900 thousand confirmed cases in the world and more than 46 thousand
deaths. The real situation on the number of infected can be much worse, and the total number of cases continues
its exponential growth. World Health Organization publishes daily reports on the situation with COVID-19 since
January 20, 2020. It was written in the first report [1]: WHO is working with our networks of researchers and Keywords and phrases: COVID-19, epidemic progression, mathematical models, crisis management, open questions. 6 Department of Biosystems and Soft Matter, Institute of Fundamental Technological Research, Polish Academy of Sciences,
02-106 Warsaw, Poland. 1 Institut Camille Jordan, UMR 5208 CNRS, University Lyon 1, 69622 Villeurbanne, France.
2 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0),
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Vitaly Volpert1,2,3,*, Malay Banerjee4, Alberto d’Onofrio5,
Tomasz Lipniacki6, Sergei Petrovskii7 and Viet Chi Tran8 Abstract. In December 2019, the first case of infection with a new virus COVID-19 (SARS-CoV-2),
named coronavirus, was reported in the city of Wuhan, China. At that time, almost nobody paid any
attention to it. The new pathogen, however, fast proved to be extremely infectious and dangerous,
resulting in about 3–5% mortality. Over the few months that followed, coronavirus has spread over
entire world. At the end of March, the total number of infections is fast approaching the psychological
threshold of one million, resulting so far in tens of thousands of deaths. Due to the high number of
lives already lost and the virus high potential for further spread, and due to its huge overall impact
on the economies and societies, it is widely admitted that coronavirus poses the biggest challenge to
the humanity after the second World war. The COVID-19 epidemic is provoking numerous questions
at all levels. It also shows that modern society is extremely vulnerable and unprepared to such events. A wide scientific and public discussion becomes urgent. Some possible directions of this discussion are
suggested in this article. Keywords and phrases: COVID-19, epidemic progression, mathematical models, crisis management, open questions. 6 Department of Biosystems and Soft Matter, Institute of Fundamental Technological Research, Polish Academy of Sciences,
02-106 Warsaw, Poland.
7 S h
l
f M th
ti
& A t
i l S i
U i
it
f L i
t
L i
t
LE1 7RH UK * Corresponding author: volpert@math.univ-lyon1.fr p
p
y
(
y),
y
4 Department of Mathematics & Statistics, IIT Kanpur, Kanpur 208016, India.
5 2 INRIA Team Dracula, INRIA Lyon La Doua, 69603 Villeurbanne, France.
3 7 School of Mathematics & Actuarial Science, University of Leicester, Leicester LE1 7RH, UK.
8 LAMA, University Gustave Eiffel, UPEM, University Paris Est Creteil, CNRS, 77447 Marne-la- International Prevention Research Institute, 18 Chemins de Cuers, 69570 Dardilly (Lyon), France. International Prevention Research Institute, 18 Chemins de Cuers, 69570 Dardilly (Lyon), France.
6 Department of Biosystems and Soft Matter, Institute of Fundamental Technological Research, Polish Academy of Sciences,
02-106 Warsaw, Poland.
7 School of Mathematics & Actuarial Science, University of Leicester, Leicester LE1 7RH, UK.
8 CORONAVIRUS – SCIENTIFIC INSIGHTS AND SOCIETAL
ASPECTS Vitaly Volpert1,2,3,*, Malay Banerjee4, Alberto d’Onofrio5,
Tomasz Lipniacki6, Sergei Petrovskii7 and Viet Chi Tran8 Mathematics & Actuarial Science, University of Leicester, Leicester LE1 7RH, UK.
niversity Gustave Eiffel, UPEM, University Paris Est Creteil, CNRS, 77447 Marne-la-Vall´ee, France. c⃝The authors. Published by EDP Sciences, 2020 c⃝The authors. Published by EDP Sciences, 2020 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0),
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 2 V. VOLPERT ET AL. 2 other experts to coordinate global work on surveillance, epidemiology, modelling, diagnostics, clinical care and
treatment, and other ways to identify, manage the disease and limit onward transmission. WHO has issued
interim guidance for countries, updated to take into account the current situation. The sufficiency of those
recommendations to avoid the dramatic developments that followed have been disputed by experts and the
public; also it remains questionable whether they were followed strictly enough by the national governments. Even more important questions now are how to stop pandemic, how to overcome its consequences, and what
lessons should be learnt for the future. other experts to coordinate global work on surveillance, epidemiology, modelling, diagnostics, clinical care and
treatment, and other ways to identify, manage the disease and limit onward transmission. WHO has issued
interim guidance for countries, updated to take into account the current situation. The sufficiency of those
recommendations to avoid the dramatic developments that followed have been disputed by experts and the
public; also it remains questionable whether they were followed strictly enough by the national governments. Even more important questions now are how to stop pandemic, how to overcome its consequences, and what
lessons should be learnt for the future. Coronavirus pandemic has apparently taken the world completely unprepared, but is it really so? After the
first SARS epidemic in 2003 and the H1N1 flu pandemic in 2009, a large body of research and technical work
has been done to design accurate and effective plans to prevent and to curb a possible future pandemic,1,2,3
including even communication-related issues.4,5 Regretfully, these measures were not fully taken into account
at any level. Presently, there are several important issues arising: – A key consequence of the epidemic is its impact on the national health systems, probably more than its
direct mortality. Indeed, if one takes into account the asymptomatic and the mildly symptomatic cases,
the percentage of serious cases is small, yet it requires a huge number of hospital beds equipped with
ventilators. Thus, the whole bed capacity of Intensive Care Units is rapidly saturated. 1https://cordis.europa.eu/project/id/201823
2https://cordis.europa.eu/project/id/652868
3https://cordis.europa.eu/project/id/201601
4https://www.tellmeproject.eu/
5http://www.asset-scienceinsociety.eu/ 2. Epidemiological data and models Epidemiological data have a crucial importance for the evaluation of the current situation and for making
a prediction of its possible progression. There are available data on the situation in different countries.6,7
However, it is not clear whether these data describe the real situation. Obviously, the number of reported
daily cases depends on the number of tests performed but the approach to testing is considerably different
in different countries ranging from testing only the patients with severe symptoms (e.g. in France), hence in
many cases confirming the obvious, to the blanket testing (e.g. in the USA) to include patients with mild
symptoms and even people with no symptoms if they were in contact with infected. Numerous media reports
from many countries as well as personal evidences indicate shortage of tests and lack of availability of test
kits, and hence difficulties to perform the sufficient number of examinations. Thus, one has to evaluate the
situation under considerable uncertainty, with only partial, unreliable information available. In particular, there
are some estimates suggesting that the actual number of infected individuals can be several times larger than
those officially reported [9, 10]. Epidemiological data have a crucial importance for the evaluation of the current situation and for making
a prediction of its possible progression. There are available data on the situation in different countries.6,7 One of possible ways to proceed is to compare the data from different countries. All of them show that, after
some initial period, the growth rate of the number of infected individuals becomes exponential. Typically, the
number of infected increases from 100 to 1000 in 7–8 days. After that, exponential growth continues with the
same or with a slightly lower rate. The exponential growth of the number of infected individual that can be seen in the data is a common feature
predicted by the various possible models for the spread of a disease in a population, which suggests a certain
universality of this dynamics. It therefore provides a framework to show and compare the data from different
countries regardless the national policies of testing and data collection, even though the total number of infected
can be underestimated (preserving the same growth rate). The main question is how we can predict the further development of the epidemic, in particular by using
mathematical modelling. There are several possible ways to do it. Modelling epidemic without public health intervention (Scenario E). 6Worldometer, https://www.worldometers.info/coronavirus/
7https://coronavirus.jhu.edu/map.html c⃝The authors. Published by EDP Sciences, 2020 As an immediate
consequence, this near-collapse of national health systems causes a large amount of indirect deaths and
critical health conditions. Medical doctors in ICUs are today facing terrible choices due to the lack of
necessary equipment and the enormous work pressure on them. – Many countries around the world decided to introduce strict quarantine, eventually leading to complete
lockdown. However, these measures could have been adopted earlier [3, 4], so that the quarantine was
often “too late, too little” compared to actual need. – Many countries around the world decided to introduce strict quarantine, eventually leading to complete
lockdown. However, these measures could have been adopted earlier [3, 4], so that the quarantine was
often “too late, too little” compared to actual need. – Once introduced, lockdown will certainly be effective in reducing the transmission rate of COVID-19
and eventually its prevalence. However, its effectiveness in disease eradication is much less obvious as
it critically depends on the actual value of the COVID-19 Basic Reproduction Number (BRN), which
is currently poorly known. Indeed, one third of contagions are in households [2]. Many people continue
to work to provide essential services and they can be infected and transmit the disease to their family
members. This mean that if the BRN is 2.4, in the best of cases, lockdown can bring it down to 0.9. This
implies a slow reduction of the prevalence, thus requiring longer period of lockdown. If the BRN is larger
than 3, reducing it under the value of 1 is most challenging. – There has been blatant lack of coordination between national governments in the implementation of the
home quarantine and the nationwide lockdown decisions. In any particular country, the effectiveness of
quarantine can be seriously hampered if the quarantine has not been adopted, or adopted in a much milder
form, in the neighboring countries. In other words, there has been a dramatic lack of understanding that
coronavirus pandemic is a global phenomenon and, as such, requires decision-making coordinated on the
global scale. Timely and efficient solution to the above issue requires a joint effort of medical professionals, health care
practitioners and scientists across a broad spectrum of life sciences, biology, medical sciences and public health
care. An important contribution to this effort can be made by data analysis and mathematical modelling. 3 CORONAVIRUS – INSIGHTS AND SOCIETAL ASPECTS 2. Epidemiological data and models The estimates of the total number of infected vary; one
estimate available for France shows that, in the worst case scenario, 10 million people can become infected with
influenza (out of 67 million total population in 2020) resulting in about 10,000 deaths. Thus, about 1/6 of the
population falls ill. On top of that, a certain number of others can get the pathogen without symptoms or with
mild symptoms and develop the immunity. Another fraction of the population may have (partial) immunity
resulting from previous infections if the new pathogen is not completely different. These three sub-populations
are subtracted from the total number of susceptible people, eventually changing the fast growth mode to the
fast decay mode. If a vaccine is available, then it can also essentially decrease the number of susceptible people
by making them immune. The scenario of influenza epidemic is close to the previous Scenario E with one difference that the transition
to the fast exponential growth is not described by baseline epidemiological models. It can be related to the
heterogeneity of the population. For instance, disease spread can begin among people with a weaker immune
response and then continue in the whole population [5]. [ ]
We do not yet know whether COVID-19 can manifest the acceleration in its growth when the fraction of
infected individuals becomes sufficiently large. However, the possibility of such development should be taken
into account, because its apparent disastrous consequences. Another unknown factor is whether COVID-19 is a
seasonal epidemic, similar to influenza, e.g. how it will evolve during the summer season. Applying quarantine measures (Scenario Q). Strong quarantine measures were introduced in China on
January 23, 2020 (Q-day) when the total number of infected individuals was just about 830. However, due to
the long incubation time of the disease, the effect was not seen until after two weeks: the maximum number of
daily new cases was reached on February 4 (M-day). A singular large outbreak occurred on February 12 but
its origin is not clear; it may be related to the way the data were collected. Restrictions in South Korea were
introduced on February 22 when the number of infected was 436. The M-day was on March 3. Thus, the M-day
was reached 12 days after the Q-day in China and after 10 days in South Korea. 2. Epidemiological data and models Keeping the main focus on
the number of infected individuals, classical epidemiological models suggest that new cases appear with the
rate λI(t)S(t), hence proportional to the average number I(t)S(t) of possible contacts between the infected
individuals (I(t)) and the susceptible individuals (S(t)) in the given population at time t, where λ quantifies
the rate at which the disease is transmitted along each single connection due to social contacts. Note that this
model has several simplifying assumptions, for instance that the population is well mixed. Refinements and more
elaborated models can also include the age structure, a finer modelling of contact pattern between individuals
(e.g. to account for the structure of social networks), etc. (
)
At the initial stage of epidemic development, when the number of infected is relatively small, S can be
approximated by a constant. Essentially, it is the approximation that gives the exponential growth in the
number of infected. The period of exponential growth eventually turns into a slower growth, because the number
of susceptible individuals S(t) decreases. One typical pattern of the epidemic development over time predicts
that the total number of infected individuals reaches its maximum and then starts exponentially decaying, to
0 in the case where the disease becomes eradicated or to some small background density if the disease becomes
endemic. This situation implies that the majority of the population that became infected and survived the disease
develops immunity to the pathogen. Some of the infected individuals can overcome the disease in a weak form
without manifestation of the symptoms due to the strong immune response which keeps the level of infection
within the human body at a low level. Comparing with the influenza epidemic (Scenario I). There are abundant statistical data about sea-
sonal influenza epidemic. It is known to have three clearly identified stages: (i) slow exponential growth during V. VOLPERT ET AL. 4 first 3-4 months followed by (ii) fast exponential growth for about one month, and then (iii) fast decay for about
two months (e.g. see [6]). The proportion of infected when slow exponential growth changes to the fast exponen-
tial growth is called the epidemic threshold. It varies from year to year but usually is of the order of magnitude
of one new case per one thousand individuals per week. 2. Epidemiological data and models These two examples are hardly
sufficient to draw general conclusions but they allow to work out a working hypothesis, for instance about the
importance of the time lag [11]. We want to mention here that, if the number of infected people remains relatively small in comparison with
the total population (e.g. during early stages of the epidemic development), number S of susceptible individuals
can be regarded as constant. Epidemiological models then become linear and the exponential growth is their
generic solution. This means that all numbers are proportional. It also suggests that, to model the growth
during the early stages, there is no qualitative difference between simple (conceptual) and complex (‘realistic’)
epidemic models. In Italy, the Q-day was March 10 (with some softer measures being adopted prior to that) with about 10,000
total cases at the time. The M-day was reached on March 21, that is, 11 days after the Q-day. During several
days after the M-day, there was stabilization at the level of about 5000 new daily cases, with a tendency to
decrease. In France, the Q-day was March 16 with about 6500 total reported cases. The M-day can therefore be
expected on March 26–27, however there has been no reliable data so far to check this prediction. The number
of daily cases undergoes strong variations, probably due to a variable daily number of administered tests. y
g
g
, p
y
y
We also note here that the daily multiplication coefficient on the Q-day was 1.19 in Italy and 1.23 in France
(1.23), which is less than in China (1.4). What can happen next under Scenario Q? In China and South Korea, a rather rapid transition to the
exponential decay mode was observed. It continued for about 2–3 weeks, then followed by the stabilization
at a low level of newly infected individuals, several dozens of daily cases in China and about 100 in South
Korea. Most of the new cases were imported to have been brought from abroad by the citizens returning after
international travel. Quarantine models [8, 11] present all three regimes: exponential growth, exponential decay,
and constant number of daily cases (linear growth of the total number of infected) [11]. One can expect the CORONAVIRUS – INSIGHTS AND SOCIETAL ASPECTS 5 transition to the decay and stabilization modes after the M-day. 2. Epidemiological data and models If this stabilization occurs, then it is important
to know what the new growth rate is going to be, in order for the public health system to get prepared and be
able to manage it. Importantly, stabilization is likely to require prolongation of the quarantine over considerable
time. Otherwise, the disease dynamics can return again to the exponential growth mode. This seems to have
happen in Iran where the number of daily cases stabilized at about 1000 per day during 20 days period, followed
by a new period of rapid growth. 3. Question to be answered to improve the understanding
of pandemic The above overview of the coronavirus pandemic brings forward several questions that are crucial to improve
our understanding of this phenomenon: – What is the actual total number of infected individuals with respect to the identified infected individ-
uals and the number of death cases? Are there individuals that are resistant (immune) or may become
infected without becoming infectious? These questions concern the estimation of the unobserved part of
the epidemic (asymptomatic infectious individuals and non-reported/nonidentified cases). – What is the actual total number of infected individuals with respect to the identified infected individ-
uals and the number of death cases? Are there individuals that are resistant (immune) or may become
infected without becoming infectious? These questions concern the estimation of the unobserved part of
the epidemic (asymptomatic infectious individuals and non-reported/nonidentified cases). p
(
y
p
p
/
– How the huge differences between the fatality rates in different countries should be
Wh
h
ff
d
h
? (
y
p
p
/
)
he huge differences between the fatality rates in different countries should be explained? – What is the effective death rate? A heuristic estimate that has been widely used so far is obtained by dividing the current cumulative number
of deaths by identified infected individuals. However, this definition fails in the exponential growth phase. The
delay between the detection of infection and the instance of death leads to substantial underestimation of the
true fatality rate. When the average time between the onset of symptoms or positive test and death is m days, the current
cumulative number of deaths should be divided by the cumulative number of cases recorded m days before. In
Germany, where the lowest fatality rate has been observed (among countries with a high number of reported
cases), the program of identification of infected people by testing them at early stages of the disease and the
high standard of public health care may have resulted in large m. Together with high daily growth (of about
30% during March 14–20, 2020), that may have resulted in significant underestimation of the true fatality rate. Assuming m between 10 and 14 days, one can find that the reported fatality rate may be smaller than the true
one by the factor between 1.310 and 1.314, that is 14–40 times. 3. Question to be answered to improve the understanding
of pandemic – Can we estimate the level of immunity in the population at the end of the quarantine, in particular with
then purpose to predict a possibility of the ‘second wave’, its specific features and an efficient and least
costly way to suppress it? – Can we estimate the level of immunity in the population at the end of the quarantine, in particular with
then purpose to predict a possibility of the ‘second wave’, its specific features and an efficient and least
costly way to suppress it? – What is the potential for evolution of the virus and could it have an impact on the fu Practical questions regarding containment. While it is conceivable that the above questions can be
successfully addressed by using epidemiological modelling (in combination with data analysis and necessary
insights from biology and especially virology), there are also a number of broader, societal, economic and political
issues and questions that may require a more interdisciplinary approaches and different types of mathematical
modelling. – There are urgent needs to better understand the effect of different ways of the quarantine introduction,
e.g. through partial or complete lockdown, in the abrupt (as in China) or progressive manner (as in Italy),
at the local, national and international levels. Similarly, scientifically checked advise must be provided
as to how the quarantine is lifted and the borders are reopen, for instance what could be the global
consequences of this, in particular for countries that are at the early stage of the epidemics? – What social/professional groups should be tested extensively? Doctors? Salesmen? Essential service
providers? Other people that have high number of contacts per day? People that had primary (or
secondary) contact with infected person? How frequently these people should be tested? – What social/professional groups should be tested extensively? Doctors? Salesmen? Essential service
providers? Other people that have high number of contacts per day? People that had primary (or
secondary) contact with infected person? How frequently these people should be tested? )
– How we should restrict contacts? – only for people above given age (e.g. children and/or senior citizens),
for people with potentially high number of contacts, everybody? – How we should restrict contacts? – only for people above given age (e.g. children and/or senior citizens),
for people with potentially high number of contacts, everybody? 3. Question to be answered to improve the understanding
of pandemic We mention here that, given the high negative impact that quarantine has on the economy, this is a
highly nontrivial question that has no intuitive answer. The approach taken by the national governments
was sometimes contradictory and inconsistent. For example, the UK government first advocated the idea
of developing the ‘herd immunity’ where only people from vulnerable, high risk groups (such as senior
citizens and people with underline health conditions) would be isolated while the rest of the population
was expected to get infected and to develop immunity. However, that idea was later dropped, as it was
estimated that the number of infected that could need intensive care would lead to the collapse of the
NHS. In the USA, soon after the quarantine was introduced in most parts of the country, it was announced
that ‘cure cannot be worse than the disease’ and hence the economy should restart (and hence quarantine
lifted/relaxed) in a short time. That idea however was later suspended. – Whether people will voluntarily reduce contacts? What can be an acceptable level of risk and how it will
change in time? – Whether people will voluntarily reduce contacts? What can be an acceptable level of risk and how it will
change in time? 3. Question to be answered to improve the understanding
of pandemic On the other hand, the unknown fraction of hidden (or undetected) infected individuals may substantially
lower the effective death rate. A possible way to answer the question could be obtained by tracing disease
development in a group of selected individuals in which infection was detected by testing only. – What is the basic reproduction number (BRN) in the case of free epidemic growth? BRN is the mean number of infectious contacts that an infected individual has, on average, during
the early stage of the outbreak. Its value determines the exponential growth phase. Supercritical values
BRN > 1 are associated with an epidemic outbreak, BRN < 1 corresponds to a subcritical regime where
the epidemic will decay exponentially. In order to restrain the epidemic, estimation of this parameter is
thus crucial. However, its mathematical expression depends heavily on the choice of the model: although
the exponential growth at the early stage is generic, the dependence of the exponent on the parameters is
not. – Based on the existing experience, what should be the most efficient measure to quickly suppress the disease
spread in newly affected countries? – Based on the existing experience, what should be the most efficient measure to quickly suppress the disease
spread in newly affected countries? Arguably, this question should best be addressed by taking into account the costs and/or potential
economic impact of the suggested measures. At the very early stage of disease development when there
are just a few infectious individuals, tracing all their contacts (like it was successfully implemented in
Singapore) and to place them into mandatory isolation may be expensive, but it can prevent the huge Arguably, this question should best be addressed by taking into account the costs and/or potential
economic impact of the suggested measures. At the very early stage of disease development when there
are just a few infectious individuals, tracing all their contacts (like it was successfully implemented in
Singapore) and to place them into mandatory isolation may be expensive, but it can prevent the huge LPERT ET AL. onwide lockdown become nece
nefit analysis. population at the end of the q
econd wave’, its specific featu V. VOLPERT ET AL. 6 negative impact on the economy if the nationwide lockdown become necessary. Thus, epidemiological
modelling should be combined with a cost-benefit analysis. 4. Crisis management Coronavirus pandemic induces a large scale crisis across the globe with many immediate and long-lasting
consequences for public health and economy. The choice of efficient strategies and their timely implementations
are crucial for the crisis management. Clearly, it is hardly possible to be prepared for all situations; however, there
are only a relatively small number of major risks and some common rules to manage them. Crisis management
should primarily focus on public health, the availability of basic daily food, products and needs including regular
and essential medicines and transportation. Public health. In many countries with significant number of reported cases, the situation is almost disastrous. Not only the essential equipment (such as ventilators) for severe cases are lacking and there is shortage of beds
in hospitals, but even simple protective masks are often lacking even for the medical personnel who are at the
frontline of this battle. For the general public, masks are even less available, also there are no clear guidelines
from the medical authorities about the necessity to wear them. The situation is further exacerbated by the CORONAVIRUS – INSIGHTS AND SOCIETAL ASPECTS 7 confusing statement made by WHO during the early stages of the epidemics when it was officially announced
that masks are not needed. That statement was later revoked. confusing statement made by WHO during the early stages of the epidemics when it was officially announced
that masks are not needed. That statement was later revoked. Production and shipping of food and daily needs. Another question of major importance is the produc-
tion and distribution of food and basic goods during the quarantine. In particular, they should be considered
taking into account of the geographical location in order to minimise the shipping effort. There should be a
sufficient number of production lines that could be quickly changed/redesigned for the production of alternative
products required during the pandemic and under quarantine conditions, for instance, medical masks, sanitizers,
etc. Internet, and communication. One of the very few positive elements in this otherwise sombre picture is the
quite remarkable progress in distant work and education. While it still faces many technical difficulties (some
of them being stressful and time consuming, e.g. because of insufficient capacity of networks or inadequate
teleconferencing software), the quarantine seems to have a significant positive impact on their development and
broad use. 4. Crisis management This arguably provide a valuable asset that authorities and business companies should further build
after the quarantine is lifted and life returns to normal, in particular to reduce unnecessary travel. Further
development of online platforms to share pedagogical content with simpler and more efficient access would also
be useful. The surge in the use of online facilities has revealed some difficulties and inconsistencies too. The capacity
for online shopping and especially shipping to residences of ordinary people (mainly senior citizens) should be
massively increased. Mental health. For many people, spending a prolonged time in self-isolation poses a significant challenge. In effect, it amounts to a jail service (albeit spent in a comfortable surrounding) and it can have a considerable
negative effect on the mental health of the general public. Increasing stress can result in antisocial behaviour
and violation of the quarantine riles, which is of course unacceptable. This problem could to some extent be
moderated through social contacts using internet and various social media. However, its solution should not be
left to a chance. While it does not seem possible that the governments take care of this issue directly, at least
they should delegate it to local authorities and social care departments. [1] https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200121-sitrep-1-2019-ncov.pdf?sfvrsn=
20a99c10 4. References
[1] https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200121-sitrep-1-2019-ncov.pdf?sfvrsn=
20a99c10 4. 5. Conclusions Coronavirus epidemic has exposed the vulnerability of the modern world and put the humanity to a global
crisis. The epidemics brought forward a number of great challenges, some of them apparently incompatible, for
instance, how to minimize the number of infections by a strict quarantine and yet not to cause an irretrievable
damage to the economy. While we believe that all these challenges can be solved, it will require careful, efficient
and well-informed decision making. In its turn, this will require a good understanding of the epidemic dynamics
and of the subtle interplay between numerous factors and processes involved. Designing and thorough analysis
of efficient mathematical models, with adequate inputs from the experts of various discipline, is essential to
achieve this goal. Acknowledgements. V.V. acknowledges the IHES visiting program during which this work was done. The work was
supported by the Ministry of Science and Education of Russian Federation, project number FSSF-2020-0018, and by
the French-Russian program PRC2307. V.C.T. acknowledges support from the Chaire Mod´elisation Math´ematique et
Biodiversit´e of Veolia Environnement-Ecole Polytechnique-Museum National dHistoire Naturelle-Fondation X and ANR
CADENCE (ANR-16-CE32-0007). References V. VOLPERT ET AL. 8 [2] N.M. Ferguson, D. Laydon, G. Nedjati-Gilani, N. Imai, K. Ainslie, M Baguelin, S. Bhatia, A. Boonyasiri, Z. Cucunub,
G. Cuomo-Dannenburg, A. Dighe, I. Dorigatti, H. Fu, K. Gaythorpe, W. Green, A. Hamlet, W. Hinsley, L.C. Okell,
S. van Elsland, H. Thompson, R. Verity, E. Volz, H. Wang, Y. Wang, P.G.T. Walker, C. Walters, P. Winskill, C. Whittaker, C.A. Donnelly, S. Riley and A.C. Ghani, Impact of non-pharmaceutical interventions (NPIs) to reduce COVID19
mortality and healthcare demand. Available at: https://www.imperial.ac.uk/media/imperial-college/medicine/sph/ide/gida-
fellowships/Imperial-College-COVID19-NPI-modelling-16-03-2020.pdf (2020). [3] A. Remuzzi and G. Remuzzi, COVID-19 and Italy: what next? The Lancet (2020) S0140-6736(20)30627-9. [4] M. Supino, A. d’Onofrio, F. Luongo, G. Occhipinti, A. Dal Co, World governments should protect their population from
COVID-19 pandemic using Italy and Lombardy as precursor. Preprint medRxiv https://doi.org/10.1101/2020.03.25.20042713
(2020). [5] M. Banerjee,
A. Tokarev
and
V. Volpert,
Immuno-epidemiological
model
of
two-stage
epidemic
growth. MMNP
https://doi.org/10.1051/mmnp/2020012 (2020). //
/
/
/
(
)
[6] S. Bernard-Stoecklin, C. Campese, Y. Savitch et al., Influenza activity in France, season 2018–20 d-Stoecklin, C. Campese, Y. Savitch et al., Influenza activity in France, season 2018–2019. BEH 28 (201 [6] S. Bernard-Stoecklin, C. Campese, Y. Savitch et al., Influenza activity in France, season 2018–2019. BEH 28 (2019) 552–563. [7] Influenza season 2019–2020: early situation assessment. World Health Organization (2019). [6] S. pert, M. Banerjee and S. Petrovskii, On a quarantine model of coronavirus infection and data analys
24. 5. Conclusions Bernard Stoecklin, C. Campese, Y. Savitch et al., Influenza activity in France, season 2018 2019. BEH 28 (2019) 552 563. [7] Influenza season 2019–2020: early situation assessment. World Health Organization (2019). [7] Influenza season 2019–2020: early situation assessment. World Health Organization (2019). [7] Influenza season 2019–2020: early situation assessment. World Health Organization (2019). [8] M. Kochanczyk, F. Grabowski and T. Lipniacki, Impact of the contact and exclusion rates on the spread of COVID-19
pandemic. Preprint medRxiv https://doi.org/10.1101/2020.03.13.20035485 (2020). [ ]
//
/
/ ecting under-reported COVID-19 case numbers. Preprint medRxiv https://doi.org/10.1101/2020.03 A. Lachmann, Correcting under-reported COVID-19 case numbers. Preprint medRxiv https://doi
14.20036178 (2020). [10] Z. Liu, P. Magal, O. Seydi and G. Webb, Understanding unreported cases in the COVID-19 epidemic outbreak in Wuhan,
China, and the importance of major public health interventions. Biology (MDPI) 9 (2020) 50. [11] V. Volpert, M. Banerjee and S. Petrovskii, On a quarantine model of coronavirus infection and data analysis. MMNP 15
(2020) 24.
|
https://openalex.org/W2783550374
|
https://europepmc.org/articles/pmc5989895?pdf=render
|
English
| null |
Safety and immunogenicity of a meningococcal B recombinant vaccine when administered with routine vaccines to healthy infants in Taiwan: A phase 3, open-label, randomized study
|
Human vaccines & immunotherapeutics
| 2,018
|
cc-by
| 7,183
|
ABSTRACT ARTICLE HISTORY
Received 23 October 2017
Revised 13 December 2017
Accepted 5 January 2018 ARTICLE HISTORY
Received 23 October 2017
Revised 13 December 2017
Accepted 5 January 2018 Neisseria meningitidis is associated with high mortality and morbidity in infants and children worldwide. This
phase 3 study (NCT02173704) evaluated safety and immunogenicity of a 4-component serogroup B
recombinant meningococcal vaccine (4CMenB) co-administered with routine vaccines in Taiwanese infants. In
total, 225 healthy infants were randomized (2 : 1 ) to receive 4CMenB and routine vaccines (4CMenBCRoutine) or
routine vaccines only (Routine group) at 2, 4, 6 and 12 months of age. Routine vaccines were diphtheria-tetanus-
acellular pertussis-inactivated poliovirus-Haemophilus influenzae type b, 13-valent pneumococcal, hepatitis B,
measles-mumps-rubella and varicella vaccines. Immune responses to 4CMenB components (factor H binding
protein [fHbp], Neisserial adhesin A [NadA], porin A [PorA] and Neisseria heparin-binding antigen [NHBA]) were
evaluated at 1 month post-primary and post-booster vaccination, using human serum bactericidal assay (hSBA). Reactogenicity and safety were also assessed. A sufficient immune response was demonstrated for fHbp, NadA
and PorA, at 1 month post-primary and booster vaccination. In the 4CMenBCRoutine group, hSBA titers 5 were
observed in all infants for fHbp and NadA, in 79% and 59% of infants for PorA and NHBA, respectively, at
1 month post-primary vaccination and in 92–99% of infants for all antigens, at 1 month post-booster vaccination. In the 4CMenBCRoutine group, hSBA geometric mean titers for all antigens increased post-primary (8.41–963)
and post-booster vaccination (17–2315) compared to baseline (1.01–1.36). Immunogenicity of 4CMenB was not
impacted by co-administration with routine pediatric vaccines in infants. Reactogenicity was slightly higher in
the 4CMenBCRoutine group compared with Routine group, but no safety concerns were identified. KEYWORDS
Neisseria meningitidis;
serogroup B meningococcal
vaccine; immunogenicity;
co-administration; safety;
infant HUMAN VACCINES & IMMUNOTHERAPEUTICS
2018, VOL. 14, NO. 5, 1075–1083
https://doi.org/10.1080/21645515.2018.1425659 HUMAN VACCINES & IMMUNOTHERAPEUTICS
2018, VOL. 14, NO. 5, 1075–1083
https://doi.org/10.1080/21645515.2018.1425659 Department of Pediatrics, National Taiwan University Children’s Hospital, National Taiwan University College of CONTACT Li-Min Huang
lmhuang@ntu.edu.tw
Department of Pediatrics, National Taiwan University Children’s Hospital, National Taiwan University College of
Medicine, Taipei, Taiwan.
Supplemental data for this article can be accessed on the publisher’s website.
© 2018 GlaxoSmithKline Biologicals SA. Published with license by Taylor & Francis
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribu-
tion, and reproduction in any medium, provided the original work is properly cited. Safety and immunogenicity of a meningococcal B recombinant vaccine when
administered with routine vaccines to healthy infants in Taiwan: A phase 3,
open-label, randomized study Nan-Chang Chiua,b,c, Li-Min Huangd, Arnold Willemsene, Chiranjiwi Bhusalf, Ashwani Kumar Aroraf, Zenaida Reynoso
M j
f
d D
i l T
f Nan-Chang Chiua,b,c, Li-Min Huangd, Arnold Willemsene, Chiranjiwi Bhusalf, Ashwani Kumar Aroraf, Zenaida Reynoso
Mojaresf, and Daniela Toneattof in Huangd, Arnold Willemsene, Chiranjiwi Bhusalf, Ashwani Kumar Aroraf, Zenaida Reynoso
f aDepartment of Pediatrics, MacKay Children’s Hospital, Taipei, Taiwan; bMackay Junior College of Medicine, Nursing, and Management, Taipei, Taiwan;
cMackay Medical College, Taipei, Taiwan; dDepartment of Pediatrics, National Taiwan University Children’s Hospital, National Taiwan University College
of Medicine, Taipei, Taiwan; ePlus100 B.V. c/o Biostatistics, GSK, Amsterdam, the Netherlands; fResearch and Development Center, GSK, Siena, Italy One
month
post-primary
vaccination,
in
the
4CMenBCRoutine group, hSBA titers 5 were achieved in
100%, 100%, 79% and 59% of infants against the indicator
strains for fHbp, NadA, PorA and NHBA, respectively (Fig. 3). In the Routine group, 8% of infants had hSBA titers 5
against any of the indicator strains. Pre-booster vaccination, 81%, 99%, 17% and 22% of infants
in the 4CMenBCRoutine group had hSBA titers 5 for fHbp,
NadA, PorA and NHBA, respectively. One month post-booster
vaccination, hSBA titers 5 were observed in 99% of infants
for fHbp and NadA, 94% of infants for PorA and in 92% of
infants for NHBA (Fig. 3). In the Routine group, 13% of
infants had hSBA titers 5 against all indicator strains post-
booster vaccination. Figure 1. Focus on patient section 4CMenB is currently licensed in the US, Europe, Canada,
Australia and some countries in South America.12 Vaccine effec-
tiveness data has recently been reported for the first time in the
United Kingdom, 10 months after the introduction of 4CMenB in
the infant national immunization schedule. In vaccine-eligible
infants below 12 months of age who received the first 2 doses of a
reduced 2 C 1 schedule, the reported 4CMenB effectiveness was
82.9% against all meningococcal serogroup B cases.14 The percentages of infants with hSBA antibody titers 4
for all vaccine components are presented in Supplementary
Figure S1. Currently, no meningococcal conjugate vaccine against
group B is available in Taiwan. This study evaluated the safety
and immunogenicity of 4CMenB when co-administered with
routine vaccines to healthy Taiwanese infants at 2, 4 and
6 months of age, followed by a booster dose at 12 months of age
and was designed to support licensure of 4CMenB in Taiwan. In both groups, pre-vaccination hSBA geometric mean titers
(GMTs) against all serogroup B indicator strains were 1.75 in
both groups. One month post-primary vaccination, in the
4CMenBCRoutine group, antibody GMTs against indicator
strains increased 71-, 875-, 9.18- and 5.69-fold for fHbp, NadA,
PorA and NHBA, respectively. hSBA GMTs for all vaccine
components decreased at the pre-booster timepoint, but
remained above baseline levels, and increased 155-, 2110-, 25-,
and 12-fold compared to baseline, for fHbp, NadA, PorA and
NHBA, respectively, following booster vaccination (Table 1). In
the Routine group, no increase from baseline levels was
observed in hSBA GMTs against serogroup B indicator strains,
throughout the study (Table 1). Demographics A total of 225 infants were enrolled: 150 in the 4CMenBCRoutine
group, who received 4CMenB at 2, 4, 6 months of age and a booster
dose at 12 months together with routine vaccines and 75 in the
Routine group, who received routine vaccines alone. Of these, 221
were included in the full analysis set (Fig. 2). Both groups received
diphtheria-tetanus-acellular pertussis, inactivated poliovirus, Hae-
mophilus influenzae type b (DTaP-IPV-Hib; Infanrix/IPVCHib,
GSK) and 13-valent pneumococcal (PCV13; Prevenar 13, Pfizer)
vaccines at 2, 4, 6 months of age, hepatitis B vaccine (HepB;
Engerix-B, GSK) at 6 months, and measles, mumps, rubella
(MMR; Priorix, GSK) and varicella (Varilrix, GSK) vaccines at
12 months of age. g
pp
Figure 1 represents a Focus on Patient Section, which elabo-
rates on the research clinical relevance and impact to be shared
to patients by Health Care Professionals. Introduction Invasive meningococcal disease (IMD) is caused by Neisseria
meningitidis and is associated with high morbidity and mortal-
ity in children 5 years of age.1,2 Among the 12 known
serogroups of N. meningitidis, 6 ( A, B, C, W, X and Y) account
for nearly all meningococcal disease worldwide.3 and 2016, corresponding to 3–8 confirmed meningococcal
cases each year. The majority of cases are attributed to
serogroup B (67%), with serogroups C (11%) and Y (3%) hav-
ing a lower prevalence.11 At present, meningococcal vaccina-
tion is not included in the immunization program in Taiwan,
but the Taiwanese Advisory Committee on Immunization
Practices recommends vaccination with a quadrivalent vaccine
against serogroups A, C, W and Y for people at high-risk for
disease and travelers to areas affected by IMD.11 Following the introduction of meningococcal vaccination
(monovalent or quadrivalent conjugate vaccines against serogroups
A, C, W and Y) in national immunization programs worldwide, the
incidence and epidemiology of IMD changed over the last decade,
with declines in the prevalence of serogroups A (particularly in the
African meningitis belt where mass vaccination campaigns were
successfully implemented), and C and Y (in Europe and the United
States).4 However, serogroup B persists5 and is now the prominent
cause of IMD in Australia, New Zealand,6 Northern Africa,7
Europe8 and the United States9 and a leading cause along
serogroup C in Latin America.10 The 4-component meningococcal serogroup B vaccine
(4CMenB, Bexsero, GSK) is a recombinant protein-based vac-
cine targeting N. meningitidis serogroup B. The vaccine con-
tains factor H-binding protein (fHbp), Neisserial adhesin A
(NadA), Neisseria heparin-binding antigen (NHBA), and outer
membrane vesicles (OMV) expressing porin A (PorA) pro-
tein.12 The 4 components are expressed by most serogroup B
strains and the vaccine is predicted to provide 66–91% coverage
against serogroup B strains worldwide.13 In Taiwan, levels of IMD are low; however, an incidence of
0.013 to 0.034 per 100,000 persons was reported between 2011 1076
N.-C. CHIU ET AL. Figure 1. Focus on patient section Immunogenicity Immunogenicity Post-primary vaccination, in the 4CMenBCRoutine group, the
lower limits (LLs) of the 95% confidence intervals (CIs) were
97.2%, 97.2% and 71.4% for the percentage of infants with
human serum bactericidal assay (hSBA) titers 5 against 3
indicator strains specific for fHbp, NadA and PorA, respec-
tively, above the pre-specified margin of 70%. Post-booster vac-
cination, the LLs of the 95% CIs were 95.7%, 94.7% and 88.7%,
respectively, above the margin of 75%. Thus, a sufficient
immune response to 4CMenB vaccination when administered
with routine pediatric vaccines was demonstrated both post-
primary and post-booster vaccination (Fig. 3). Reactogenicity and safety In general, all infants in the 4CMenBCRoutine group and 93%
of infants in the Routine group experienced at least 1 solicited
AE, regardless of the vaccination. The percentage of infants
experiencing at least 1 solicited AE tended to decrease from the
first to subsequent vaccinations, both in the 4CMenBCRoutine
group (95%, 91%, 90% and 88% for first, second, third and
booster vaccination, respectively) and the Routine group (79%,
76%, 74% and 56% for first, second, third and booster vaccina-
tion, respectively). In the 4CMenBCRoutine group, the most frequently reported
solicited local AEs were injection site tenderness (for 48%–51% of
infants) after each 4CMenB vaccination and injection site tender-
ness (for 27%–34% of infants) after each of the routine vaccina-
tions. Injection site tenderness was the only severe solicited local Demographic characteristics were well-balanced across the 2
study groups. The mean age of the infants at enrollment was
68.3 days; 99% of infants were Asian, and 48% were girls
(Supplementary Table S1). HUMAN VACCINES & IMMUNOTHERAPEUTICS 1077 4CMenB, 4-component serogroup B recombinant meningococcal recombinant vaccine; M, month; DTaP-
ated poliovirus types 1, 2, 3 and Haemophilus influenzae type b vaccine, PCV13, 13-valent pneumococcal
umps and rubella vaccine; Varicella, varicella vaccine; WC, withdrawal of consent; AE, adverse event; O,
o the Taiwanese Immunization Program for Infants, the first 2 doses of HepB are given at 0 (M0) and 1 Figure 2. Participant flowchart. Footnotes: N, number of infants; 4CMenB, 4-component serogroup B recombinant meningococcal recombinant vaccine; M, month; DTaP-
IPV-Hib, combined diphtheria, tetanus, acellular pertussis, inactivated poliovirus types 1, 2, 3 and Haemophilus influenzae type b vaccine, PCV13, 13-valent pneumococcal
conjugate vaccine; HepB, hepatitis B vaccine; MMR, measles, mumps and rubella vaccine; Varicella, varicella vaccine; WC, withdrawal of consent; AE, adverse event; O,
other; LFU, lost to follow-up; PV, protocol violation. According to the Taiwanese Immunization Program for Infants, the first 2 doses of HepB are given at 0 (M0) and 1
month (M1) of age. chart. Footnotes: N, number of infants; 4CMenB, 4-component serogroup B recombinant meningococcal recombinant vacc
eria, tetanus, acellular pertussis, inactivated poliovirus types 1, 2, 3 and Haemophilus influenzae type b vaccine, PCV13, 13-
hepatitis B vaccine; MMR, measles, mumps and rubella vaccine; Varicella, varicella vaccine; WC, withdrawal of consent;
up; PV, protocol violation. According to the Taiwanese Immunization Program for Infants, the first 2 doses of HepB are g Figure 2. Participant flowchart. Discussion The study demonstrated a robust immune response to 4CMenB
vaccine, when given concomitantly with routine vaccines to
healthy infants at 2, 4, 6 and 12 months of age, in terms of per-
centage of infants achieving hSBA titers 5 against indicator
strains for fHbp, NadA and PorA at 1 month post-primary and
post-booster vaccination. Our results are in line with previous studies, which demon-
strated a sufficient immune response following primary and
booster vaccination of infants with 4CMenB, when co-adminis-
tered with routine pediatric vaccines and according to various
schedules.15-18 The same criteria to assess sufficient immune
response to 4CMenB were used in our study and endorsed by
the European Medicines Agency during the 4CMenB clinical
development phase.15 However, no suitable indicator strain
had been identified for NHBA at the time, and therefore the and 7% of infants in the Routine group, respectively. Overall, 74%
and 62% of infants in the 4CMenBCRoutine and Routine groups,
respectively, received paracetamol therapeutically. Overall, following any vaccination, any unsolicited AE was
reported for 72% and 42% of infants in groups 4CMenBCRoutine
and Routine, respectively. Any probably or possibly related AEs
were
reported
for
59%
and
24%
of
infants
in
groups
4CMenBCRoutine and Routine and the majority were due to soli-
cited AEs ongoing after the 7-day reporting period. The incidence Table 1. Reactogenicity and safety Footnotes: N, number of infants; 4CMenB, 4-component serogroup B recombinant meningococcal recombinant vaccine; M, month; DTaP-
IPV-Hib, combined diphtheria, tetanus, acellular pertussis, inactivated poliovirus types 1, 2, 3 and Haemophilus influenzae type b vaccine, PCV13, 13-valent pneumococcal
conjugate vaccine; HepB, hepatitis B vaccine; MMR, measles, mumps and rubella vaccine; Varicella, varicella vaccine; WC, withdrawal of consent; AE, adverse event; O,
other; LFU, lost to follow-up; PV, protocol violation. According to the Taiwanese Immunization Program for Infants, the first 2 doses of HepB are given at 0 (M0) and 1
month (M1) of age. AE reported in the 4CMenBCRoutine group, after each vaccina-
tion with 4CMenB (5%) or routine vaccines (2%) (Table 2). In
the Routine group, the most frequently reported solicited local AEs
were injection site induration (8%–24% of infants) and erythema
(4%–21% of infants) (Table 2). booster vaccination. Medically-attended fever was reported for 1
(1%), 3 (2%) and 4 (3%) infants after the first, third and the booster
dose in the 4CMenBCRoutine group and for 2 (3%) infants after
the booster dose in the Routine group. Most solicited systemic AEs
were mild to moderate in intensity. The most frequently reported solicited systemic AE after each
vaccination was irritability in both the 4CMenBCRoutine and
Routine groups, reported for 52%–75% and 22–44%) of infants,
respectively
(Table
3). After
each
vaccination
in
the
4CMenBCRoutine
group,
fever
(temperature
38C)
was
reported by a higher percentage of infants (44%–51%) than in the
Routine group (8%–17%) (Table 3). Severe fever (temperature
40C) was reported for one infant in the 4CMenBCRoutine
group after second vaccination and for one in each group after The most frequently reported symptoms during a 28-day period
post-MMR/varicella vaccination were rash for 36% and 33% of
infants in the 4CMenBCRoutine and Routine groups, respectively. Lymphadenopathy (parotid/salivary gland swelling) was reported
for 25% of infants in group 4CMeBC Routine and 29% of infants
in the Routine group). Rash was the most reported severe symptom
in 4% of infants in the 4CMenBCRoutine group and 7% of infants
in Routine group. Fever and severe fever was reported in 66% and
1% of infants in the 4CMenBCRoutine respectively, and in 46% 1078
N.-C. CHIU ET AL. of medically-attended AEs was similar between groups (Supple-
mentary Table S2). Figure 3. Participants in the 4CMenBCRoutine group with hSBA titers 5 against
each of the indicator strains for the four vaccine antigens (full analysis set). Reactogenicity and safety Foot-
notes: 4CMenB, 4-component serogroup B recombinant meningococcal vaccine;
hSBA, human serum bactericidal assay; M, month; fHbp, factor H-binding protein;
NadA, Neisserial adhesin A; PorA, porin A; NHBA, Neisseria heparin-binding antigen. Note: Error bars represent 95% confidence intervals. Dotted horizontal lines repre-
sent the criteria for assessment of sufficient immune response at 1 month post-pri-
mary (M7) and post-booster (M13) vaccination. The immune response was
considered sufficient if the lower limit of the 95% confidence intervals for the per-
centage of infants with hSBA titers 5 post-primary or booster vaccination was
above 70% at M7 or 75% at M13, respectively. One infant from 4CMenBCRoutine group was withdrawn
from the study on day 57 due to an AE (congenital cystic kid-
ney disease and renal dysplasia) which was not considered
related to the study vaccines. At least one serious AE (SAE) was reported for 21 infants: 13
in the 4CMenBCRoutine group (9%) and 8 in the Routine
group (11%) and all were resolved before study end. No SAEs
were considered as possibly or probably related to the study
vaccine. Figure 3. Participants in the 4CMenBCRoutine group with hSBA titers 5 against
each of the indicator strains for the four vaccine antigens (full analysis set). Foot-
notes: 4CMenB, 4-component serogroup B recombinant meningococcal vaccine;
hSBA, human serum bactericidal assay; M, month; fHbp, factor H-binding protein;
NadA, Neisserial adhesin A; PorA, porin A; NHBA, Neisseria heparin-binding antigen. Note: Error bars represent 95% confidence intervals. Dotted horizontal lines repre-
sent the criteria for assessment of sufficient immune response at 1 month post-pri-
mary (M7) and post-booster (M13) vaccination. The immune response was
considered sufficient if the lower limit of the 95% confidence intervals for the per-
centage of infants with hSBA titers 5 post-primary or booster vaccination was
above 70% at M7 or 75% at M13, respectively. hSBA, human serum bactericidal assay; GMT, geometric mean titer; 4CMenB, 4-component serogroup B recombinant meningococcal vaccine; n, number of infants with
available results; GMR, geometric mean ratio; CI, confidence interval; fHbp, factor H-binding protein; NadA, Neisserial adhesin A; PorA, porin A; NHBA, Neisseria heparin-
binding antigen. Discussion hSBA GMTs for 4CMenB components (full analysis set)
4CMenBCRoutine Group
Routine Group
n
GMT/GMR (95% CI)
n
GMT/GMR (95% CI)
fHbp
Baseline (pre-vaccination)
132
1.01 (0.99–1.02)
65
1.02 (0.98–1.05)
1 month post-primary vaccination
130
72 (64–81)
66
1.01 (0.99–1.03)
GMR (1 month post-primary/baseline)
116
71 (63–80)
59
0.99 (0.95–1.04)
Pre-booster vaccination
123
11 (9.27–13)
64
1.26 (1.06–1.50)
1 month post-booster vaccination
127
157 (131–188)
64
1.1 (1.01–1.19)
GMR (1 month post-booster/baseline)
113
155 (127–188)
56
1.07 (0.97–1.19)
NadA
Baseline (pre-vaccination)
141
1.08 (0.98–1.18)
72
1.03 (0.98–1.08)
1 month post-primary vaccination
129
963 (864–1073)
70
1.00 (1.00–1.00)
GMR (1 month post-primary/baseline)
124
875 (752–1019)
69
0.97 (0.93–1.03)
Pre-booster vaccination
135
205 (174–242)
70
1.10 (0.91–1.33)
1 month post-booster vaccination
134
2315 (1893–2832)
71
1.00 (1.00–1.00)
GMR (1 month post-booster/baseline)
129
2110 (1674–2659)
70
0.97 (0.93–1.03)
PorA
Baseline (pre-vaccination)
145
1.01(0.99–1.02)
73
1.00 (1.00–1.00)
1 month post-primary vaccination
135
9.20 (7.82–11.00)
71
1.02 (0.98–1.05)
GMR (1 month post-primary/baseline)
134
9.18(7.79–11.00)
71
1.02 (0.98–1.05)
Pre-booster vaccination
136
1.91 (1.63–2.25)
70
1.04 (0.98–1.10)
1 month post-booster vaccination
136
26 (21–31)
71
1.00 (1.00–1.00)
GMR (1 month post-booster/baseline)
135
25 (21–31)
71
1.00 (1.00–1.00)
NHBA
Baseline (pre-vaccination)
121
1.36 (1.20–1.54)
64
1.75 (1.37–2.24)
1 month post-primary vaccination
123
8.41 (6.63–11.00)
65
1.25 (1.08–1.46)
GMR (1 month post-primary/baseline)
100
5.69 (4.25–7.61)
57
0.68 (0.54–0.85)
Pre-booster vaccination
130
2.18 (1.81–2.63)
65
1.60 (1.34–1.91)
1 month post-booster vaccination
130
17 (14–20)
69
1.58 (1.33–1.89)
GMR (1 month post-booster/baseline)
105
12 (8.99–15.00)
60
0.91 (0.68–1.21) HUMAN VACCINES & IMMUNOTHERAPEUTICS 1079 Table 2. Number and percentage of infants with local adverse events after each dose and each vaccine, reported in the 7-day period post-vaccination (solicited
safety set). fants with local adverse events after each dose and each vaccine, reported in the 7-day period post-vaccination (solicited Table 2. Number and percentage of infants with local adverse events after each dose and each vaccine, reported in the 7-day period post-vaccination (solicited
safety set). Discussion Note: ND136 assessment of a sufficient immune response was only planned
for fHbp, NadA and PorA. NadA and PorA, post-primary vaccination16,18 and for fHbp
and NadA, post-booster dose.18 The majority of infants in the 4CMenBCRoutine group
achieved hSBA titers 5 against all 4 serogroup B indicator
strains after both primary and booster vaccination. At 1
month after primary vaccination, hSBA GMTs for all vac-
cine components increased significantly from pre-vaccination
levels, with fold-increases similar to those observed in Euro-
pean infants following the administration of a 3-dose pri-
mary
series
of
4CMenB
with
routine
vaccines.18
As
expected, GMTs waned by 12 months of age, but remained
above baseline levels and were significantly increased follow-
ing the booster dose. Our results are consistent with those
from previous studies where 4CMenB was administered with
routine vaccines and similar schedules where most of infants
achieved hSBA titers 5 against indicator strains for fHbp The observed GMT increase from baseline levels was higher
following the booster dose than following primary vaccination,
suggesting a boosting of the immune response. This confirms
previous results reported in European infants, for whom booster
responses were observed after the administration of 4CMenB
according to similar schedules.18,19 A recent persistence study,
following 4CMenB booster vaccinations at 12, 18 or 24 months
reported that antibody concentration waned after 12–36 months
regardless of the timing of boosters, but an additional 4CMenB
dose given at 4 years of age induced a robust memory response.20 g
y
g
y
The tolerability profile of 4CMenB vaccine was acceptable,
with no major safety concerns that were identified when admin-
istered concomitantly with routine vaccinations. The majority
of the reactions was mild in nature and resolved within a few Table 3. Number and percentage of infants with systemic reactions and fever after each dose reported in the 7-day period post-vaccination (solicited safety set). Discussion Tenderness
Severe tenderness
Erythema
Swelling
Induration
4CMenB
CRoutine
Routine
4CMenB
CRoutine
4CMenB
CRoutine
Routine
4CMenB
CRoutine
Routine
4CMenB
CRoutine
Routine
1st dose
ND148
ND73
ND148
ND148
ND73
ND148
ND73
ND148
ND73
4CMenB
75 (51%)
—
8 (5%)
54 (36%)
—
34 (23%)
—
63 (43%)
PCV13
50 (34%)
12 (16%)
3 (2%)
26 (18%)
9 (12%)
11 (7%)
4 (5%)
29 (20%)
15 (21%)
DTaP-IPV-Hib
45 (31%)
12 (16%)
2 (1%)
26 (18%)
3 (4%)
15 (10%)
3 (4%)
23 (16%)
11 (15%)
2nd dose
ND140
ND72
ND140
ND140
ND72
ND140
ND72
ND140
ND72
4CMenB
67 (48%)
—
5 (4%)
59 (42%)
—
35 (25%)
—
51 (36%)
PCV13
44 (31%)
9 (13%)
3 (2%)
35 (25%)
12 (17%)
12 (9%)
6 (8%)
18 (13%)
8 (11%)
DTaP-IPV-Hib
45 (32%)
10 (14%)
3 (2%)
39 (28%)
12 (17%)
18 (13%)
6 (8%)
23 (16%)
16 (22%)
3rd dose
ND138
ND72
ND138
ND138
ND72
ND138
ND72
ND138
ND72
4CMenB
68 (49%)
—
6 (4%)
55 (40%)
—
49 (36%)
—
57 (41%)
—
PCV13
45 (33%)
9 (13%)
3 (2%)
27 (20%)
12 (17%)
17 (12%)
4 (6%)
21 (15%)
11 (15%)
DTaP-IPV-Hib
42 (30%)
8 (11%)
2 (1%)
28 (20%)
15 (21%)
20 (14%)
10 (14%)
25 (18%)
16 (22%)
HepB
45 (33%)
7 (10%)
3 (2%)
33 (24%)
12 (17%)
25 (18%)
6 (8%)
33 (24%)
17 (24%)
Booster dose
ND137
ND72
ND137
ND137
ND72
ND137
ND72
ND137
ND72
4CMenB
66 (49%)*
6 (4%)
53 (39%)
44 (33%)
56 (41%)
MMR
37 (27%)
6 (8%)
3 (2%)
24 (18%)
13 (18%)
19 (14%)
4 (6%)
15 (11%)
6 (8%)
Varicella
41 (30%)
5 (7%)
3 (2%)
32 (23%)
14 (19%)
21 (15%)
6 (8%)
14 (10%)
7 (10%)
4CMenB, 4-component serogroup B recombinant meningococcal vaccine; N, number of exposed infants; DTaP-IPV-Hib, combined diphtheria, tetanus, acellular pertussis,
inactivated poliovirus types 1, 2, 3 and Haemophilus influenzae type b vaccine; PCV13, 13-valent pneumococcal conjugate vaccine; HepB, hepatitis B vaccine; MMR, mea-
sles, mumps and rubella vaccine; Varicella, varicella vaccine. Note: ND136 4CMenB, 4-component serogroup B recombinant meningococcal vaccine; N, number of exposed infants; DTaP-IPV-Hib, combined diphtheria, tetanus, acellular pertussis,
inactivated poliovirus types 1, 2, 3 and Haemophilus influenzae type b vaccine; PCV13, 13-valent pneumococcal conjugate vaccine; HepB, hepatitis B vaccine; MMR, mea-
sles, mumps and rubella vaccine; Varicella, varicella vaccine. p
g
p
g
ote: Body temperature (C) was solicited but it was not reported as a systemic adverse event in this study.
D
d f
N
hild
(N
b
f
d i f
) CMenB, 4-component serogroup B recombinant meningococcal vaccine. y
p
(
)
p
y
y
Data reported for N-1 children (N, number of exposed infants). 4CMenB, 4-component serogroup B recombinant meningococcal vaccine. Note: Body temperature (C) was solicited but it was not reported as a systemic adverse event in this study.
Data reported for N-1 children (N, number of exposed infants). Study design and participants The incidence of AEs following co-administration of
4CMenB and routine vaccines was comparable with previous
reports for infants.16,18 The percentage of infants in the
4CMenBCRoutine group with fever 38C after any dose
(44%–51%) seemed lower than in another study where infants
were vaccinated with 4CMenB, DTaP-HBV-IPV/Hib and 7-
valent PCV (57%–77%), and similar to the percentage of
infants
reporting
fever
when
prophylactic
paracetamol
was administered with 4CMenB, DTaP-HepB-IPV/Hib and 7-
valent PCV (37%–60%).21 This phase 3, randomized, controlled, open-label study with 2
parallel groups was conducted in healthy infants between
September 2014 and June 2016, at 2 centers in Taiwan. This phase 3, randomized, controlled, open-label study with 2
parallel groups was conducted in healthy infants between
September 2014 and June 2016, at 2 centers in Taiwan. Infants were healthy 2 month-olds (55–89 days) at the time
of enrollment, born after a gestation period of 37 weeks and
with a birth weight of 2.5 kg, and were available for all the
scheduled study visits. Criteria of exclusion from study enroll-
ment are presented in Supplementary Text S1. p
pp
y
The infants were randomized in a 2:1 ratio to receive either
4CMenB with routine vaccines (4CMenBCRoutine group) or
routine vaccines alone (Routine group). 4CMenB was adminis-
tered as a 3-dose primary vaccination at 2, 4 and 6 months of
age followed by a booster dose at 12 months of age. Routine
vaccines were (co-) administered according to the National
Immunization Program in Taiwan as follows: DTaP-IPV-Hib
and PCV13 at 2, 4 and 6 months of age, HepB vaccine at
6 months of age and MMR and varicella vaccine at 12 months
of age. After the study, at 15 months of age, all participants
were offered a booster dose of PCV13 to complete the recom-
mended vaccination schedule. This is the first study to report on 4CMenB administration
to Asian infants, with the only other 4CMenB vaccination trial
being carried out among Korean adolescents.22 Therefore, our
results provide the basis for comparisons with other age groups
and geographical regions and contribute to the generalization
of 4CMenB vaccination data to the Asian population. Study vaccines Each dose of 4CMenB contains 50 mg of the following N. men-
ingitidis purified antigens: 961c (NadA), 936–741 (fHbp) and
287–953 (NHBA); 25 mg of OMV from N. meningitidis strain
NZ98/254 (PorA), and aluminium hydroxide; sodium chloride,
sucrose; histidine and water up to 5 ml. The routine vaccines used in this study were commercial prepa-
rations, and were prepared/used according to instructions. All vaccines were administered in the anterolateral area of the
right or left thigh, intramuscularly (4CMenB, DTaP-IPV-Hib,
PCV13 and HepB) or subcutaneously (MMR and varicella). Study design and participants The inci-
dence of IMD peaks in infancy,4 with case fatality ratios of up
to 8.1% being attributed to serogroup B-caused IMD in chil-
dren <1 year of age.7 In view of the effectiveness data emerging
following the introduction of 4CMenB in the national immuni-
zation program in the United Kingdom,14 the implementation
of a similar measure in Taiwan could have an important
impact. Our study shows that 4CMenB can be safely adminis-
tered to Taiwanese infants together with routine immuniza-
tions, which would allow the administration of the vaccine
without increasing the number of visits and associated costs. Randomization was done accounting for center, using a
web-based block randomization system. Written informed consent was obtained from each parent/
legally acceptable representative before vaccination. The study
was conducted in accordance with Good Clinical Practice and
the Declaration of Helsinki, and is registered at www.Clinical
trials.gov (NCT02173704). A summary of the protocol is avail-
able at http://www.gsk-clinicalstudyregister.com (study ID
205249). The trial was designed with sufficient power to assess the
confirmatory objectives and to comply with the current pediat-
ric vaccination scheme in Taiwan. However, there are potential
limitations. A relatively low number of infants were evaluated,
compared with other similar meningococcal studies where up
to 3,630 infants were enrolled.18 As is the case for all meningo-
coccal vaccine trials, efficacy cannot be measured due to the
low incidence of IMD and the low sample size further limits
the evaluation of 4CMenB vaccination against IMD caused by
serogroup B in Taiwan. Although hSBA titers 4 against
serogroup B tested strains are usually considered protective, a
serological correlate of protection was only clearly established
for serogroup C.23 Another potential limitation is the fact that
immune responses to the routine vaccines were not measured
in our study. However, a similar study showed that immunoge-
nicity of DTaP-HepB-IPV/Hib was not impacted by co-admin-
istration with 4CMenB.18 Additionally, the open-label design
may have impacted the safety data towards higher AE reporting
rates. Study objectives The primary objective was to demonstrate sufficient immune
response to 4CMenB co-administered with routine vaccines at
1 month post-primary vaccination, as measured by the percent-
age of infants with hSBA titer 1:5 against indicator strains for
fHbp, NadA and PorA. Discussion 4CMenBCRoutine
Routine
1st dose
2nd dose
3rd dose
Booster dose
1st dose
2nd dose
3rd dose
Booster dose
Changing in eating habits
92 (62%)
72 (51%)
72 (52%)
58 (42%)
26 (36%)
21 (29%)
17 (24%)
19 (26%)
Sleepiness
79 (53%)
66 (47%)
49 (36%)
36 (26%)
33 (45%)
21 (29%)
13 (18%)
9 (13%)
Irritability
111 (75%)
90 (64%)
94 (68%)
71 (52%)
32 (44%)
31 (43%)
28 (39%)
16 (22%)
Persistent crying
96 (65%)
82 (59%)
72 (52%)
58 (42%)
30 (41%)
23 (32%)
28 (39%)
15 (21%)
Vomiting
21 (14%)
16 (11%)
15 (11%)
10 (7%)
6 (8%)
9 (13%)
7 (10%)
6 (8%)
Diarrhea
28 (19%)
30 (21%)
19 (14%)
27 (20%)
8 (11%)
9 (13%)
4 (6%)
10 (14%)
Rash
18 (12%)
18 (13%)
16 (12%)
25 (18%)
4 (5%)
8 (11%)
4 (6%)
9 (13%)
Fever* 38.0 C
71 (48%)
72 (51%)
68 (49%)
60 (44%)
11 (15%)
11 (15%)
12 (17%)
6 (8%)
Fever 40.0 C
0
1 (1%)
0
1 (1%)
0
0
0
1 (1%)
Medically-attended fever
1 (1%)
0
3 (2%)
4 (3%)
1 (1%)
0
0
2 (3%)
Analgesic/antipyretic treatment used
35 (24%)**
38 (27%)
30 (22%)
20 (15%)
1 (1%)
2 (3%)**
5 (7%)
3 (4%)
4CMenB, 4-component serogroup B recombinant meningococcal vaccine. N.-C. CHIU ET AL. 1080 days after vaccination. These results were consistent with what
was observed in studies with infants of similar age.17,18 Immunogenicity assessments Blood samples (5 ml) were collected pre-vaccination (M2), 1
month post-primary vaccination (M7), pre-booster dose (M12)
and 1 month post-booster vaccination (M13) (Fig. 2). p
g
Immune responses to 4CMenB were assessed using hSBA
against 4 meningococcal B indicator strains: H44/76 (fHbp), 5/
99 (NadA), NZ98/254 (PorA) and M10713 (NHBA), con-
ducted at the GSK Biologicals Clinical Laboratory Science,
Marburg, Germany. The percentages of infants with hSBA
titers 4 and 5, and hSBA GMTs were assessed at each time-
point. An hSBA titers 4 is the accepted surrogate of protec-
tion against serogroup C-caused meningococcal disease and
this threshold is routinely extended to the other serogroups.9
However, a more conservative threshold of 5 ensures with
95% confidence that the titer achieved is 4 and therefore,
both endpoints were evaluated here. Geometric mean ratios
(GMRs) relative to pre-vaccination levels were also calculated
at M7 and M13. Titers below the limit of quantification (1:2) were set to half
that limit, for the quantitative analysis purpose. Unadjusted
GMTs and GMRs were constructed by exponentiating the
means of the log10-transformed hSBA titers with corresponding
2-sided
95%
CIs (computed
using the Clopper-Pearson
method24). Safety assessment All infants were observed for 30 minutes after each vaccination
for any immediate reactions. Solicited local AEs (injection site
erythema, induration, tenderness and swelling), solicited sys-
temic or general AEs (body temperature 38C, change in eat-
ing habits, sleepiness, irritability, persistent crying, vomiting,
diarrhea and rash) and unsolicited AEs were recorded using
diary cards by the childrens’ parents or legally accepted repre-
sentatives for 7 days after each vaccination. Fever, rash,
parotid/salivary gland swelling were collected for an extended
period of 28 days after the administration of MMR and vari-
cella vaccines. All solicited local and systemic AEs were summarized
according to defined severity grading scales. SAEs, medically attended AEs and AEs leading to with-
drawal from the study were recorded throughout the entire
study. Abbreviations 4CMenB
4-component
serogroup
B
recombinant
meningococcal vaccine
AE
adverse event
CI
confidence interval
DTaP-IPV-Hib
diphtheria-tetanus-acellular pertussis, inacti-
vated
poliovirus,
Haemophilus
influenzae
type b vaccine
fHbp
factor H-binding protein
GMR
geometric mean ratio
GMT
geometric mean titer
HepB
hepatitis B vaccine
hSBA
human serum bactericidal assay
IMD
invasive meningococcal disease
LL
lower limit
MMR
measles, mumps and rubella
NadA
Neisserial adhesin A
NHBA
Neisseria heparin-binding antigen
OMV
outer membrane vesicles
PCV13
13-valent pneumococcal vaccine
PorA
porin A
SAE
serious adverse event
SD
standard deviation
UL
upper limit
US
United States HUMAN VACCINES & IMMUNOTHERAPEUTICS 1081 HUMAN VACCINES & IMMUNOTHERAPEUTICS and NHBA at baseline (pre-vaccination, 2 months of age), 1
month post-primary vaccination (7 months of age), prior to
the booster dose (12 months of age) and 1 month post-booster
dose (13 months of age). The reactogenicity and safety of
4CMenB co-administered with routine vaccines and of routine
vaccines were also evaluated. The primary objective was considered met if the LL of the 2-
sided 95% CI for the percentage of infants with hSBA titer 5
against the indicator strains for fHbp, NadA and PorA post-pri-
mary vaccination was >70%. The secondary confirmatory objec-
tive was considered met if the LL of the 2-sided 95% CI for the
percentage of infants with hSBA titer 5 against the indicator
strains for fHbp, NadA and PorA post-booster was >75%. Safety and immunogenicity analyses were carried out on the
full analysis set at each timepoint, which included exposed par-
ticipants with evaluable safety and immunogenicity data,
respectively. Additional analyses to evaluate immune response
to 4CMenB vaccination were performed on the per-protocol
set (Supplementary Table S3). Statistical analysis For the 4CMenBCRoutine group, a sample size of 120 evaluable
infants was calculated, assuming that the proportion of infants
achieving hSBA titers 5 would be 84%, 99% and 99% for the
PorA, fHbp, and NadA strains, respectively, at 1 month after
primary vaccination, based on results from a previous trial.18
The power to reject the null hypothesis associated with the pri-
mary objective and demonstrate sufficient response was 94%,
99% and 99%, respectively (calculated using an exact test for a
single binomial proportion and a 2-sided alpha error of 0.05). Assuming the results for the 3 strains to be independent, the
overall power to demonstrate sufficiency of response was 92%. Conclusions The 4CMenB vaccine showed a robust immune response
against strains specific for each of the vaccine components
(fHbp, NadA, PorA and NHBA) and an acceptable safety and
tolerability profile similar to that seen in other clinical trials. The vaccination schedule used in the study, which was in line
with the current schedule of the Taiwan National Immuniza-
tion Program, has the potential to be adopted as an add-on to
the currently recommended pediatric vaccination schedule
once the 4CMenB vaccine is licensed in Taiwan. Secondary objectives were to demonstrate sufficient immune
response to 4CMenB co-administered with routine vaccines
evaluated at 1 month post-booster, measured by percentage of
infants with hSBA titer 1:5 against indicator strains for fHbp,
NadA and PorA (confirmatory objective) and to assess bacteri-
cidal antibodies against indicator strains for fHbp, NadA, PorA Trademark statement Bexsero, Infanrix, Engerix-B, Priorix and Varilrix are trade-
marks owned by the GSK group of companies. Prevenar 13 is a
trademark of Pfizer. Funding 12. Toneatto D, Pizza M, Masignani V, Rino R. Emerging experience with
meningococcal serogroup B protein vaccines. Expert Rev of Vacc. 2017;16(5):433–51. doi:10.1080/14760584.2017.1308828. This study was funded by Novartis Vaccines and Diagnostics Inc., now
part of the GSK group of companies. GlaxoSmithKline Biologicals SA took
responsibility for all costs associated with the development and publishing
of the present manuscript. 13. O’Ryan M, Stoddard J, Toneatto D, Wassil J, Dull PM. A multi-com-
ponent meningococcal serogroup B vaccine (4CMenB): the clinical
development program. Drugs. 2014;74(1):15–30. doi:10.1007/s40265-
013-0155-7. PMID:24338083. 14. Parikh SR, Andrews NJ, Beebeejaun K, Campbell H, Ribeiro S, Ward
C, White JM, Borrow R, Ramsay ME, Ladhani SN. Effectiveness and
impact of a reduced infant schedule of 4CMenB vaccine against group
B meningococcal disease in England: a national observational cohort
study. Lancet. 2016;388(10061):2775–82. doi:10.1016/S0140-6736(16)
31921-3. PMID:28100432. Disclosure of potential conflicts of interest CB, AKA and DT were employees of Novartis Vaccines (on 2 March 2015
Novartis non-influenza Vaccines Business was acquired by the GSK group
of companies) and are currently employed by the GSK group of compa-
nies; DT holds shares in the GSK group of companies as part of her
employee remuneration. ZRM was an employee of Novartis Vaccine at the 1082
N.-C. CHIU ET AL. N.-C. CHIU ET AL. 1082 8. Whittaker R, Dias JG, Ramliden M, Kodmon C, Economopoulou
A, Beer N, Pastore Celentano L. The epidemiology of invasive
meningococcal disease in EU/EEA countries, 2004-2014. Vaccine. 2017;35(16):2034–41. doi:10.1016/j.vaccine.2017.03.007. PMID:
28314560. time the study started and of the GSK group of companies at the time the
manuscript was developed. NCC through the Mackay Memorial Hospital,
received grants for clinical trials from the GSK groups of companies. AW
is employee of the Plus100 B.V. c/o the GSK groups of companies for bio-
statistics support. LMH received grants for clinical trials from the GSK
group of companies through the National Taiwan University Hospital and
served as consultant in GSK advisory boards. 9. Centers for Disease Control and Prevention. Active bacterial Core
surveillance (ABCs) report, Emerging Infections Program Net-
work, Neisseria meningitidis (2015). Available from www.cdc. gov/abcs/reports-findings/survreports/mening15.html; [accessed 2
October 2017]. Authors’ contributions All authors had full access to all the data in the study and take responsibil-
ity for the integrity of the data and the accuracy of the data analysis. All
authors reviewed and commented critically drafts of the manuscript for
important intellectual content and gave final approval to submit for publi-
cation. LMH, CB, AKA, ZRM and DT were involved in the conception or
the design of the study. NCC, LMH, CB, AKA and ZRM participated in
the collection or generation of the study data and performed the study. LMH, CB and ZRM contributed to the study with materials/analysis tools. LMH, AW, CB, AKA, ZRM and DT were involved in the analyses or inter-
pretation of the data. 15. European Medicines Agency. Bexsero. Meningococcal group B Vac-
cine (rDNA, component, adsorbed). Procedure No. EMEA/H/C/
002333. 2012. Available from http://www.ema.europa.eu/docs/en_GB/
document_library/EPAR_-_Public_assessment_report/human/
002333/WC500137883.pdf; [accessed 10 April 2017]. 16. Gossger N, Snape MD, Yu LM, Finn A, Bona G, Esposito S, Prin-
cipi N, Diez-Domingo J, Sokal E, Becker B, et al. Immunogenicity
and tolerability of recombinant serogroup B meningococcal vac-
cine administered with or without routine infant vaccinations
according to different immunization schedules: a randomized con-
trolled trial. JAMA. 2012;307(6):573–82. doi:10.1001/jama.2012.85. PMID:22318278. Acknowledgments 10. Safadi MA, O’Ryan M, Valenzuela Bravo MT, Brandileone MC, Gorla
MC, de Lemos AP, Moreno G, Vazquez JA, Lopez EL, Taha MK, et al. The current situation of meningococcal disease in Latin America and
updated Global Meningococcal Initiative (GMI) recommendations. Vaccine. 2015;33(48):6529–36. doi:10.1016/j.vaccine.2015.10.055. PMID:26597036. The authors would like to thank the parents and their children who
participated in this trial and acknowledge the assistance of all the
investigators, study nurses, clinicians, laboratory personnel and other
staff members in conducting the study. The authors would also like to
thank Petronela M. Petrar and Maria Cornelia Maior (XPE Pharma &
Science c/o GSK) for medical writing support and Maria Ana de la
Grandiere (XPE Pharma & Science c/o GSK) for manuscript coordina-
tion and editorial support. 11. Centers for Disease Control, R.O.C (Taiwan). Communicable Disease
&Prevention. Meningococcal meningitis. 2017. Available from http://
www.cdc.gov.tw/english/info.aspx?treeidDE79C7A9E1E9B1C
DF&nowtreeidDE02C24F0DACDD729&tidDE3F090F82DB3B457;
[accessed 22 September 2017]. 22. Lee HJ, Choe YJ, Hong YJ, Kim KH, Park SE, Kim YK, Oh CE, Lee H,
Song
H,
Bock
H,
et
al.
Immunogenicity
and
safety
of
a 4years of age-a phase 3 extension to a randomised controlled trial.
Vaccine. 2017;35(2):395–402. doi:10.1016/j.vaccine.2016.11.009.
PMID:27914744. References 1. Rosenstein NE, Perkins BA, Stephens DS, Popovic T, Hughes JM. Meningococcal
disease. N
Engl
J
Med. 2001;344(18):1378–88. doi:10.1056/NEJM200105033441807. PMID:11333996. 17. Safadi MAP, Martinon-Torres F, Weckx LY, Moreira Junior ED,
da Fonseca Lima EJ, Mensi I, Calabresi M, Toneatto D. Immuno-
genicity and safety of concomitant administration of meningococ-
cal
serogroup
B
(4CMenB)
and
serogroup
C
(MenC-CRM)
vaccines in infants: A phase 3b, randomized controlled trial. Vac-
cine. 2017;35(16):2052–9. doi:10.1016/j.vaccine.2017.03.002. PMID:28318767. 2. World Health Organization. WHO position paper. Meningococcal
vaccines: polysaccharide and polysaccharide conjugate vaccines. Wkly
Epidemiol Rec. 2002;77(40):329–40. p
3. World Health Organization. 2015. Meningococcal meningitis. Fact
sheet no 141. http://www.who.int/mediacentre/factsheets/fs141/en/;
[accessed 6 June 2017]. 18. Vesikari T, Esposito S, Prymula R, Ypma E, Kohl I, Toneatto D,
Dull P, Kimura A. Immunogenicity and safety of an investiga-
tional multicomponent, recombinant, meningococcal serogroup B
vaccine (4CMenB) administered concomitantly with routine infant
and child vaccinations: results of two randomised trials. Lancet. 2013;381(9869):825–35. doi:10.1016/S0140-6736(12)61961-8. PMID:23324563. 4. Pelton SI. The global evolution of meningococcal epidemiology following
the introduction of meningococcal vaccines. J Adolesc Health. 2016;59
(Suppl 2):S3¡S11. doi:10.1016/j.jadohealth.2016.04.012. PMID:27449148. 5. Sridhar S, Greenwood B, Head C, Plotkin SA, Safadi MA, Saha S,
Taha MK, Tomori O, Gessner BD. Global incidence of serogroup
B invasive meningococcal disease: a systematic review. Lancet
Infect Dis. 2015;15(11):1334–46. doi:10.1016/S1473-3099(15)
00217-0. PMID:26453240. 19. Snape MD, Voysey M, Finn A, Bona G, Esposito S, Principi N,
Diez-Domingo J, Sokal E, Kieninger D, Prymula R, et al. Persistence
of Bactericidal Antibodies After Infant Serogroup B Meningococcal
Immunization and Booster Dose Response at 12, 18 or 24 Months of
Age. Pediatr Infect Dis J. 2016;35(4):e113¡23. doi:10.1097/
INF.0000000000001056. PMID:26756390. 6. Borrow R, Lee J-S, Vazquez JA, Enwere G, Taha M-K, Kamiya H, Kim
HM, Jo DS. Meningococcal disease in the Asia-Pacific region: Find-
ings and recommendations from the Global Meningococcal Initiative. Vaccine. 2016;34(48):5855–62. doi:10.1016/j.vaccine.2016.10.022. PMID:27780631. 20. Iro MA, Snape MD, Voysey M, Jawad S, Finn A, Heath PT, Bona G,
Esposito S, Diez-Domingo J, Prymula R, et al. Persistence of bacteri-
cidal antibodies following booster vaccination with 4CMenB at 12, 18
or 24 months and immunogenicity of a fifth dose administered at 7. Martinon-Torres F. Deciphering the Burden of Meningococcal Dis-
ease: Conventional and Under-recognized Elements. J Adolesc Health. 2016;59(2 Suppl):S12¡20. doi:10.1016/j.jadohealth.2016.03.041. PMID:27449145. HUMAN VACCINES & IMMUNOTHERAPEUTICS HUMAN VACCINES & IMMUNOTHERAPEUTICS 1083 4years of age-a phase 3 extension to a randomised controlled trial. Vaccine. 2017;35(2):395–402. doi:10.1016/j.vaccine.2016.11.009. PMID:27914744. multicomponent meningococcal serogroup B vaccine in healthy ado-
lescents in Korea–A randomised trial. Vaccine. 2016;34(9):1180–6. doi:10.1016/j.vaccine.2016.01.033. PMID:26826544. multicomponent meningococcal serogroup B vaccine in healthy ado-
lescents in Korea–A randomised trial. Vaccine. 2016;34(9):1180–6. doi:10.1016/j.vaccine.2016.01.033. PMID:26826544. 23. 21. Prymula R, Esposito S, Zuccotti GV, Xie F, Toneatto D, Kohl I,
Dull PM. A phase 2 randomized controlled trial of a multi-
component meningococcal serogroup B vaccine (I). Hum Vaccin
Immunother. 2014;10(7):1993–2004. doi:10.4161/hv.28666. PMID:
25424809. 23. Goldschneider I, Gotschlich EC, Artenstein MS. Human immunity
to the meningococcus. I. The role of humoral antibodies. J Exp
Med. 1969;129(6):1307–26. doi:10.1084/jem.129.6.1307. PMID:4977280. 24. Clopper C. J., Pearson E. S. The use of confidence limits illustrated in
the case of the binomial. Biometrika. 1934;26(4):404–13. doi:10.1093/
biomet/26.4.404. 22. Lee HJ, Choe YJ, Hong YJ, Kim KH, Park SE, Kim YK, Oh CE, Lee H,
Song
H,
Bock
H,
et
al. Immunogenicity
and
safety
of
a
|
https://openalex.org/W4321015339
|
https://journal.uinjkt.ac.id/index.php/jko/article/download/31027/pdf_1
|
Indonesian
| null |
INDUSTRI BUDAYA DAN KOMODITAS (STUDI KASUS TENUN TRADISIONAL NUSA TENGGARA BARAT SEBAGAI KOMODITAS DAN SENI DALAM KERANGKA BUDAYA DAN RELIGI)
|
Jurnal Kummunity Online
| 2,023
|
cc-by-sa
| 7,689
|
Abstract Woven or woven fabrics are the result of human technology that has a long history. Producing woven
fabrics has been done by almost all human beings on earth. Textiles produced from weaving activities
go through various processes which are not only physical processes but also the experiences of the
weavers before, while, or after weaving and the social purposes of the weaving so that woven fabrics
not only have a purely biological function but must also be able to fulfill these functions. namely
aesthetic, social, economic, and religious. Woven cloth which is a material object is produced
through the stages of the process that the weavers go through from their experiences in everyday life
which are felt then interpreted by the symbols made in the process of their creativity and aesthetic
sense of these symbols. This study aims to see how changes have occurred in giving meaning to
woven fabrics which are not only of artistic value but also have economic value because woven
fabrics are a commodity in industrial culture and tourism on Lombok Island and the religious values
contained in the woven motifs and their changes changes that occur in the social environment of the
craftsmen. Significantly shows that there has been a change in meaning and symbol in the Lombok
weaving motif which is a concrete manifestation of the changing pattern of life of the local community
from traditional economic patterns to modern economic patterns by making traditional weaving a
commodity of local residents. Keywords: Cultural Industry; Commodities; Traditional Weaving. Keywords: Cultural Industry; Commodities; Traditional Weaving. Keywords: Cultural Industry; Commodities; Traditional Weaving. INDUSTRI BUDAYA DAN KOMODITAS (STUDI KASUS TENUN
TRADISIONAL NUSA TENGGARA BARAT SEBAGAI KOMODITAS
DAN SENI DALAM KERANGKA BUDAYA DAN RELIGI) WG. Pramita Ratnasari
Universitas Islam Negeri (UIN) Syarif Hidayatullah Jakarta
Email: wg pramita@uinjkt ac id WG. Pramita Ratnasari
Universitas Islam Negeri (UIN) Syarif Hidayatullah Jakarta
Email: wg.pramita@uinjkt.ac.id
Submit: 20 Maret 2022, Revisi: 20 April 2022, Approve: 10 Oktober 2022 Availabe online at Website:
http://journal.uinjkt.ac.id/index.php/jko
Jurnal Kommunity Online, 3 (2), 2022, 201-218 Availabe online at Website:
http://journal.uinjkt.ac.id/index.php/jko
Jurnal Kommunity Online, 3 (2), 2022, 201-218 Copyright © 2022, Jurnal Kommunity Online, 3 (2) 2022
© 2022 The Author(s). This is an open access article under CC-BY-SA license (https://creativecommons.org/licenses/by-sa/4.0/)
Kata kunci : Industri Budaya; Komoditas; Tenun tradisional. Copyright © 2022, Jurnal Kommunity Online, 3 (2) 2022
© 2022 The Author(s). This is an open access article under CC-BY-SA license (https://creativecommons.org/licenses/by-sa/4.0/ Abstrak Tenunan atau kain tenun merupakan hasil teknologi manusia yang memiliki sejarah yang panjang. Memproduksi kain tenun telah dilakukan oleh hampir seluruh umat manusia di muka bumi. Tekstil
yang dihasilkan dari kegiatan menenun melewati berbagai proses yang bukan hanya proses fisik
semata namun juga pengalaman para penenun sebelum, sedang, atau setelah menenun dan tujuan
sosial dari tenunan sehingga menjadikan kain tenun bukan hanya memiliki fungsi biologi semata
namun juga harus dapat memenuhi fungsi-fungsi lain yaitu estetika, sosial, ekonomi, dan juga religi. Kain tenun yang menjadi objek materi diproduksi melalui tahapan-tahapan proses yang dilewati oleh
para penenun dari pengalaman-pengalamannya dalam kehidupan sehari-sehari yang dirasakan
kemudian dimaknai dengan simbol-simbol yang dibuat dalam proses kreatifitas dan rasa estetika
mereka terhadap simbol tersebut. Kajian ini bertujuan untuk melihat bagaimana perubahan yang
terjadi dalam pemberian makna kain tenun yang tidak hanya bernilai seni tetapi juga memiliki nilai
ekonomi karena kain tenun merupakan komoditas dalam industri budaya serta pariwisata di Pulau
Lombok dan nilai religi yang tertuang dalam motif-motif tenun beserta perubahan-perubahan yang
terjadi dalam lingkungan kehidupan sosial para pengrajinnya. Secara signifikan menunjukkan bahwa
terjadi perubahan makna dan simbol pada motif tenun Lombok yang merupakan implikasi dari
perubahan pola kehidupan masyarakat setempat dari pola ekonomi tradisional menjadi pola ekonomi
modern dengan menjadikan tenun tradisional sebagai komoditas warga setempat. Kata kunci : Industri Budaya; Komoditas; Tenun tradisional. WG. Pramita Ratnasari
Pengitupan : Pramita Ratnasari, Wg. Industri Budaya Dan Komoditas (Studi Kasus Tenun
Tradisional Nusa Tenggara Barat Sebagai Komoditas Dan Seni Dalam Kerangka Budaya Dan Religi. Jurnal Kommunity Online, 3 (2), 2022, 201-218. doi :10.15408/jko.v3i2.31027 WG. Pramita Ratnasari Pengitupan : Pramita Ratnasari, Wg. Industri Budaya Dan Komoditas (Studi Kasus Tenun
Tradisional Nusa Tenggara Barat Sebagai Komoditas Dan Seni Dalam Kerangka Budaya Dan Religi. Jurnal Kommunity Online, 3 (2), 2022, 201-218. doi :10.15408/jko.v3i2.31027 202
Jurnal Kommunity Online, 3 (2) 2022, e ISSN: 2797 5754
© 2022 The Author(s). This is an open access article under CC-BY-SA license (https://creativecommons.org/licenses/by-sa/4.0/) 202
Jurnal Kommunity Online, 3 (2) 2022, e-ISSN: 2797-5754
© 2022 The Author(s). This is an open access article under CC-BY-SA license (https://creativecommons.org/licenses/by-sa/4.0/) Jurnal Kommunity Online, 3 (2) 2022, e-ISSN: 2797-5754 Pendahuluan Indonesia memiliki kain tenun tradisional yang beraneka ragam yang disesuaikan
dengan adat istiadat setempat. Kain-kain tenun tersebut tercipta juga karena kondisi
geografis di Indonesia dan factor-faktor lain. Meskipun tidak dipungkiri bahwa
perkembangan pakaian dengan modelnya sudah menjadi konsumsi masyarakat secara
global. Tenunan atau kain tenun merupakan hasil teknologi manusia yang memiliki sejarah
yang panjang. Memproduksi kain tenun telah dilakukan oleh hampir seluruh umat manusia
di muka bumi. Tekstil yang dihasilkan dari kegiatan menenun melewati berbagai proses
yang bukan hanya proses fisik semata namun juga pengalaman para penenun sebelum,
sedang, atau setelah menenun dan tujuan sosial dari tenunan sehingga menjadikan kain
tenun bukan hanya memiliki fungsi biologi semata namun juga harus dapat memenuhi
fungsi-fungsi lain yaitu estetika, sosial, dan ekonomi. Kain tenun yang menjadi objek
materi diproduksi melalui tahapan-tahapan proses yang dilewati oleh para penenun dari
pengalaman-pengalamannya dalam kehidupan sehari-sehari yang dirasakan kemudian
dimaknai dengan simbol-simbol yang dibuat dalam proses kreatifitas dan rasa estetika
mereka terhadap simbol tersebut. Selain proses terciptanya rasa estetika, ada hal lain yang
juga menjadi bagian dari proses menenun yaitu system pembagian kerja (Wengrow,2001;
Berlo, 1992). Dalam sistem pembagian kerja ada berbagai permasalahan yang akhirnya
juga muncul, seperti masalah ekonomi dan juga gender (Berlo, 1992, Messick, 1987;
Bowie, 1992). Menjalankan fungsi sosialnya, tenun tradisional di Lamalera, Lembata selatan, Nusa
Tenggara Timur (Banes, 1982, dalam Coote, 1992) memiliki tanda-tanda atau simbol-
simbol yang menggambarkan aktivitas sosial masyarakat dan digunakan dalam pernikahan. Selain itu, keahlian menenun merupakan suatu proses yang harus dijalani oleh para
perempuan di Lamalera. Para gadis mengawali proses pembelajaran pembuatan tenun
dengan berlajar memintal, menenun ikat, dan mewarnai pada pakaian yang digunakan
sehari-hari. Para perempuan tersebut mempelajari motif-motif tenun yang “wajib” karena
merupakan tradisi turun temurun, tetapi mereka juga memiliki kesempatan atau
“kebebasan” untuk mencoba menenun dengan motif-motif baru yang dimodifikasi dengan
tradisi mereka sendiri. Industri Budaya Dan Komoditas (Studi Kasus Tenun Tradisional… Tenun tradisional lain yang ada di Indonesia, misalnya tenun dari daerah Sidemen,
Karangasem, Bali, yang merupakan sentra produksi kain tenun di Bali (Kompas, Minggu,
17 April 2011). Di daerah tersebut semua orang bisa menenun karena belajar dari para orang
tua. Adapun fungsi tenunan pada masa lalu bagi sejumlah warga adalah untuk keperluan
keluarga sendiri sebagai bagian dari alat upacara (agama) dan sebagian lain menenun untuk
memenuhi permintaan warga Bali di bagian lain pulau. 203
J
y
,
( )
,
© 2022 The Author(s). This is an open access article under CC-BY-SA license (https://creativecommons.org/licenses/by-sa/4.0/) Pendahuluan Berdasarkan penggolongan paling
sederhana, terdapat dua jenis kain tenun di Bali, yaitu tenun ikat yang disebut endek, dipakai
sehari-hari dan kain tenun songket yang digunakan untuk upacara penting dalam siklus
kehidupan masyarakat Bali, antara lain upacara potong gigi, perkawinan, hari raya atau
ngaben (Kompas, 17 april 2011). Mayoritas masyarakat yang berdomisili di pulau Lombok adalah dari suku Sasak. Salah
satunya yang bermukim di desa Sukarara. Sukarara adalah sebuah desa yang terletak di
wilayah kecamatan Jonggat, Kabupaten Lombok Tengah. Mata pencaharian utama dari
penduduk desa Sukarara adalah bertani. Adapun kegiatan menenun merupakan kegiatan
yang biasa dilakukan oleh kaum perempuan di desa tersebut. Dalam hal ini, laki-laki bekerja
di sawah terutama mencangkul dan mengolah lahan dan apabila lahan telah siap, maka yang
melakukan pekerjaan menanam adalah para wanita, selain itu para laki-laki juga
mengumpulkan kayu dan menggembalakan ternak dan pekerjaan lain yang membutuhkan
kekuatan fisik, sedangkan para wanita mengurus berbagai masalah domestik seperti
mengurus anak, memasak, menenun, menganyam tikar dan membuat alat-alat rumah tangga
lainnya (museum NTB, 2000). 203
Jurnal Kommunity Online, 3 (2) 2022, e-ISSN: 2797-5754
Dalam sejarah sistem produksi tenun, kegiatan menenun dilakukan oleh para wanita,
karena ketrampilan ini merupakan ketrampilan turun temurun dari nenek kepada sang ibu
lalu berlanjut kepada anak gadisnya dengan harapan bahwa ketrampilan menenun yang
dimiliki itu kelak sebagai bekal hidup jika telah berumah tangga (Museum NTB, 2000). Sejak usia kanak-kanak, si gadis telah diarahkan untuk meraih ketrampilan menenun. Alat
yang dipakai sangat sederhana dan dalam ukuran kecil. Dalam tahap belajar mereka
memakai daun pisang yang ditoreh-toreh secara vertical. Kegiatan ini dilakukan untuk
menghasilkan tenunan dari bahan daun pisang dan serat pisang sebagai proses
pembelajaran sang anak, kemudian ketika si gadis kecil memasuki usia remaja dan sudah
dianggap menguasai ketrampilan menenun, barulah si gadis remaja diperkenalkan dengan
kegiatan menenun yang sesungguhnya. Mula-mula memintal kapas menjadi benang, anak
gadis yang sudah memasuki usia remaja wajib menenun, disamping agar menguasai
ketrampilan tersebut dengan mahir juga dengan adanya niat dari orang tua agar anak 203
J
y
,
( )
,
© 2022 The Author(s). This is an open access article under CC-BY-SA license (https://creativecommons.org/licenses/by-sa/4.0/) WG. Pramita Ratnasari gadisnya tidak keluar rumah (seperti dipingit) karena merupakan hal yang kurang pantas
apabila gadis remaja keluar rumah untuk bermain ke rumah tetangga. Suara alat tenun dari
rumah penduduk merupakan penanda bahwa dalam rumah tersebut ada anak gadis remaja,
maka para perjaka pun datang untuk bertandang (midang) (Museum NTB, 2000). Pendahuluan Berdasarkan tradisinya, sudah menjadi kewajiban bagi gadis remaja agar
mempersiapkan kain tenun untuk dirinya dan calon suaminya. Jenis kain yang harus
dimiliki dari tenunan sendiri disebut kain pucuk melung dan paling sedikit harus
menyiapkan dua kain tersebut. Setelah menikah, tidak hanya ketrampilan menenun yang
menjadi bekalnya tetapi juga alat tenun akan dihadiahkan oleh orang tuanya sebagai bekal
dan dengan harapan anak gadisnya yang telah menikah atau berstatus ibu rumah tangga
akan mampu mengolah bahan-bahan untuk memenuhi kebutuhan pangan dan pakaian
anak-anak dan suaminya (sasak: tao nyeseq misah) (Museum NTB, 2000). Konsep ini
merupakan dasar awal dari sistem produksi tenun dan seiring dengan perkembangan sistem
ekonomi dan perubahan social lainnya, memproduksi kain tenun bukan hanya sebagai ritual
dalam siklus kehidupan semata tetapi mulai menjadi komoditi yang dapat diperjual belikan
secara bebas terutama ketika di masa sekarang sektor pariwisata dikemukakan sebagai
komoditas untuk dapat memasarkan produk-produk budaya tertentu. Bagi orang Sukarara dewasa ini, kegiatan menenun bukan hanya sebagai sebuah tradisi
yang berlangsung secara turun temurun tetapi juga menjadi mata pencaharian yang dapat
mendukung kehidupan ekonomi dan kegiatan pariwisata yang sedang menjadi program
pemerintah di propinsi Nusa Tenggara Barat. Hal ini dapat dilihat dari didirikannya art
shop di sepanjang jalan desa tersebut. Kegiatan menenun telah mengalami transformasi manjadi kegiatan ekonomi namun
tradisi adat untuk menciptakan motif-motif tenun di desa tersebut masih berlangsung. untuk
membuat suatu motif tenun songket maka penenun akan melalui suatu proses tidak
sebentar. Hal ini lah yang membuat suatu tenun songket memiliki nilai ekonomi atau harga
jual yang tinggi. Proses seseorang dapat membuat motif songket di desa Sukarara memiliki
ritual tersendiri. Yaitu ketika seorang anak perempuan yang telah berusia remaja di desa
telah cukup umur dan dianggap memiliki kemampuan untuk menyusun motif maka ia akan
tinggal di sebuah rumah adat selama beberapa hari untuk ritual tersebut. Setelah selesai
ritual di rumah adat tersebut maka perempuan tersebut telah memiliki pengetahuan atau
ilmu untuk membuat motif tenun. 204
Jurnal Kommunity Online, 3 (2) 2022, e-ISSN: 2797-5754
© 2022 The Author(s). This is an open access article under CC-BY-SA license (https://creativecommons.org/licenses/by-sa/4.0/) 204
Jurnal Kommunity Online, 3 (2) 2022, e ISSN: 2797 5754
© 2022 The Author(s). This is an open access article under CC-BY-SA license (https://creativecommons.org/licenses/by-sa/4.0/) 4
Jurnal Kommunity Online, 3 (2) 2022, e-ISSN: 2797-5754 Permasalahan Industri Budaya Dan Komoditas (Studi Kasus Tenun Tradisional… Kondisi semakin dinamisnya masyarakat di pedesaan pada umumnya mengakibatkan
timbulnya persoalan-persoalan baru dimana telah terjadi perubahan-perubahan secara sosial,
budaya dan ekonomi. Pengaruh pasar bebas dan globalisasi memyebabkan produksi tenun
bukan semata-semata sebagai alat upacara tertentu tetapi mengalami pergeseran-pergeseran
makna yang juga berpengaruh terhadap pemilihan motif-motif tenun yang diproduksi oleh
komunitas tenun tersebut. Proses kreatifitas pemilihan motif dalam produksi tenun di daerah
NTB memunculkan berbagai pertanyaan yaitu, Bagaimana proses estetikasi dan kreatifitas
para penenun dalam pemilihan motif;dan dari mana pengetahuan tentang motif tenun tersebut
diperoleh serta alasan para penenun dalam menentukan motif tenun yang akan dikerjakan
sehingga tercipta motif tenun yang memiliki nilai-nilai tertentu dalam masyarakat, dan
bagaimana strategi para penenun dalam menghadapi perubahan sistem tradisi menenun
sebagai kegiatan ritual adat menjadi kegiatan penghasil komoditas yang bernilai ekonomi
sebagai bagian dari industri budaya. Kajian ini bertujuan dapat memberikan pemahaman terhadap ragam hias tenun lombok
beserta perubahan-perubahan yang terjadi dalam lingkungan kehidupan sosial para
pengrajinnya. Khususnya yang terdapat di desa sukarara dan di propinsi nusa Tenggara Barat
pada umumnya. Signifikansi Penelitian Penelitian sebelumnya mengenai penggunaaan maupun ragam hias kain tenun maupun
kain lainnya telah dilakukan oleh para peneliti lain. Kain merupakan salah satu kebutuhan
manusia yang kemudian diproduksi dan dikonsumsi serta digunakan dalam hubungan-
hubungan sosial dan bagaiamana identitas-identitas sosial (Schneider, 1987). Kegiatan
menenun berkaitan dengan masalah gender (Berlo, 1992; Messick, 1987). Berkaitan
dengan sistem ekonomi, (Barnes, 2004; Miller, 1995; Bowie, 1992). Dan kain tenun juga
berkaitan dengan perilaku berkesenian dari individu tersebut (Wood, 2000; Firth,1992). 20
J
y
( )
© 2022 The Author(s). This is an open access article under CC-BY-SA license (https://creativecommons.org/licenses/by-sa/4.0/) 205
Jurnal Kommunity Online, 3 (2) 2022, e-ISSN: 2797-5754 Industri budaya Industri budaya adalah salah satu konsep yang diusung oleh mazhab Frankfurt yang
mencerminkan konsolidasi fetisisme komoditas, dominasi asas pertukaran dan
meningkatnya kapitalisme monopoli negara. Dalam industri budaya, terbentuk selera dan
kecenderungan massa sehingga mencetak kesadaran mereka dengan cara menanamkan
keinginan mereka atas kebutuhan-kebutuhan palsu (Strinati, 1995). Konsep ini juga
merupakan perkembangan dari konsep yang pernah dikemukakan sebelumnya oleh Adorno 205
J
y
,
( )
,
© 2022 The Author(s). This is an open access article under CC-BY-SA license (https://creativecommons.org/licenses/by-sa/4.0/) WG. Pramita Ratnasari (1991 [1972]) tentang industri budaya yaitu sebagai sesuatu yang sama halnya budaya yang
muncul secara spontan dalam massa itu sendiri sperti bentuk-bentuk budaya popular. Adorno sendiri merupakan ilmuwan dari mazhab Frankfurt, dimana mazhab ini berfungsi
untuk pengembangan teori dan penelitian kritis yang dianggap dapat memberikan kritik
pencerahan dengan pengembangan teori-teorinya (Strinati, 1995). Melanjutkan konsep industri budaya, Adorno mendukung gagasan-gagasan mengenai
pembedaan industri budaya dari budaya massa, karena budaya massa mengasumsikan
bahwa massa memiliki tanggung jawab yang sama atas budaya yang mereka konsumsi
sehingga hal itu ditentukan oleh kecenderungan-kecenderungan massa itu sendiri. Ia juga
menambahkan bahwa pada semua cabangnya, produk-produk yang dihasilkan untuk
konsumsi massa dan pada suatu takaran besar menentukan sifat konsumsi itu yang dibuat
kurang lebih sesuai rencana. Masing-masing cabang itu strukturnya mirip satu sama lain
dengan menata dirinya sendiri ke dalam sebuah system yang nyaris tanpa ada suatu
kesenjangan; industri budaya secara sengaja memadukan para konsumennya dari atas. Kerugian dari keduanya mendorong sekaligus bidang seni tinggi dan seni rendah yang
terpisah selama ribuan tahun. Keseriusan seni tinggi dihancurkan dalam spekulasi tentang
keunggulannya; keseriusan seni rendah sirna bersama kekangan-kekangan peradaban yang
dipaksakan pada perlawanan yang berontak yang inheren di dalamnya sepanjang control
social belum terjadi sepenuhnya. Jadi sekalipun industri budaya tak pelak lagi berspekulasi
pada kondisi sadar maupun tidak sadar (terhadap) jutaan orang yang dituju, massa itu tidak
bersifat primer tetapi sekunder. Mereka adalah obyek kalkulasi, bagian dari alat. Konsumen
bukanlah raja, sebagaimana diyakinkan oleh industri budaya kepada kita, bukan sebagai
subyek tetapi sebagai obyek. 206
Jurnal Kommunity Online, 3 (2) 2022, e ISSN: 2797 5754
© 2022 The Author(s). This is an open access article under CC-BY-SA license (https://creativecommons.org/licenses/by-sa/4.0/) 206
Jurnal Kommunity Online, 3 (2) 2022, e-ISSN: 2797-5754
© 2022 The Author(s). This is an open access article under CC-BY-SA license (https://creativecommons.org/licenses/by-sa/4.0/) Estetikasi J
l K
it
O li
3 (2) 2022
ISSN 2797 5754
Benda-benda yang memiliki unsur seni tidak hanya dilihat sebagai benda-benda
pajangan semata tetapi juga mengalami proses-proses sosial yaitu dari para produsen dan
para konsumen benda-benda tersebut. Ketika benda seni mulai menjadi komoditas, maka
terjadi berbagai proses yang juga berkaitan dengan aspek ekonomi yaitu produksi dan
konsumsi. Benda-benda yang dibuat manusia bukan hanya dilihat berdasarkan fungsi
semata, tetapi juga ada nilai tersendiri yang terkandung didalamnya, misalnya nilai estetika
suatu benda dapat dilihat dalam berbagai artifak yang yang dihasilkannya. Ketika suatu
benda memiliki nilai estetika, maka benda tersebut adalah hasil dari proses penglihatan
manusia terhadapnya ‘dunianya’, bahkan dapat terjadi perbedaan atau variasi dalam 206
Jurnal Kommunity Online, 3 (2) 2022, e-ISSN: 2797-5754
© 2022 The Author(s). This is an open access article under CC-BY-SA license (https://creativecommons.org/licenses/by-sa/4.0/) Industri Budaya Dan Komoditas (Studi Kasus Tenun Tradisional… menilai makna estetika dari suatu tradisi dan budaya satu dengan yang lain (Coote,1992). Ditambahkan oleh Firth (dalam Coote, 1992) bahwa seni dari sudut pandang antropologi,
meskipun hanya sebagai sebuah nama dari suatu objek (seni), mengindikasikan suatu
kesadaran dari lingkup sosial, ritual, dan ekonomi dimana produk tersebut diproduksi. Lebih lanjut, dikatakan oleh Firth bahwa seni merupakan hasil atribut yang memiliki pola
bermakna dari suatu pengalaman atau pengalaman imajinasi. Pernyataan ini menunjukkan
bahwa seni muncul dari persepsi seseorang dalam sebuah tatanan relasi yang digabungkan
dengan perasaan terhadap kebenaran dari tatanan tersebut, bagi kepentingan kesenangan
atau keindahan tetapi memuaskan beberapa pengakuan dari nilai-nilai. Bagi Eaton (2004:63) estetika bukan hanya hal-hal yang berkaitan dengan objek seni
seperti puisi, tari, lukisan, nyanyian, dan lain sebagainya, tetapi estetika juga terdapat pada
alam (matahari terbit dan terbenam, kicauan burung, tawa anak-anak) meskipun hal tersebut
bukan hasil karya (kerja) seni. Jadi segala sesuatu dapat bersifat artistic tetapi hanya
sebagian (benda/objek) yang dapat dikategorikan artistik (dalam estetika). 20
y
© 2022 The Author(s). This is an open access article under CC-BY-SA license (https://creativecommons.org/licenses/by-sa/4.0/) Estetikasi Eaton (2004)
mengemukakan empat premis yang berhubungan dengan teori estetik, yaitu pertama, kelas
objek-objek artistik dan kelas/kelompok objek estetik adalah serupa atau identik, yaitu
ketika bukan hanya lukisan dan puisi sebagai hasil seni, tetapi hal-hal yang terdapat dalam
alam juga mengandung unsure seni; kedua, ketika orang-orang beranggapan bahwa
kebalikan dari poin pertama, yaitu benda-benda yang merupakan hasil kerja seni, belum
tentu memiliki nilai estetika, demikian pula ada orang-orang yang memandang bahwa
kicauan burung bukan sebagai hasil seni; ketiga, kelas/kelompok objek artistic dengan tegas
termasuk ke dalam kelas/kelompok estetik tetapi tidak serupa dengan objek estetika yang
bukan hasil dari kerja seni; keempat, tidak ada keterkaitan antara objek-objek artistic dan
objek-objek estetik, tetapi premis ini dibantah oleh Eaton sendiri sebagai suatu hal yang
tidak mungkin terjadi dalam kontek ini. Estetika selalu berkaitan dengan suatu objek, baik yang dibuat oleh manusia seperti
lukisan, puisi, tarian, dan lain sebagainya, maupun yang berasal dari alam seperti kicauan
burung, pemandangan alam, suara anak kecil dan lain sebagainya. Oleh karena berbentuk
sebagai objek maka benda yang mengandung nilai estetika dapat dirasakan oleh panca
indera manusia, sehingga manusia dapat “mengkonsumsi”nya sebagai bagian dari
keseharian hidupnya. 207
Jurnal Kommunity Online, 3 (2) 2022, e-ISSN: 2797-5754
Ada tiga pengertian tentang estetikasi yang terjadi dalam kehidupan sehari-hari
menurut Featherstone (1991) pertama, merujuk pada sub-sub budaya artistik yang
menghasilkan gerakan kaum surealis dalam PD I dan tahun 1920-an yang pada masa 207
J
y
,
( )
,
© 2022 The Author(s). This is an open access article under CC-BY-SA license (https://creativecommons.org/licenses/by-sa/4.0/) WG. Pramita Ratnasari tersebut mereka mencoba untuk menghapus batas antara seni dengan kehidupan sehari-
hari; kedua, estetikasi merujuk pada proyek yang merubah kehidupan menjadi suatu
lembaga seni, yang didalamnya menjadi gaya hidup dalam masyarakat; ketiga, estetikasi
dalam kehidupan sehari-hari merujuk pada gerak cepat dan image yang memenuhi jaring-
jaring kehidupan sehari-hari dalam masyarakat kontemporer. Pada pengertian yang ketiga
inilah berkaitan dengan teori yang dikemukakan oleh Marx mengenai fetisime komoditas. Menurut Adorno (dalam Featherstone, 1991:161) semakin meningkatnya dominasi nilai
tukar (exchange value) tidak hanya menghapuskan nilai-manfaat (use-value) asli benda-
benda dan menggantikannya dengan nilai tukar abstrak, tetapi juga membebaskan
komoditas untuk mengambil nilai manfaat pengganti atau nilai manfaat sekunder. Pakaian dapat dikategorikan sebagai penanda atau identitas bagi seseorang. Ketika
seseorang mengenakan pakaian tertentu, maka ada identitas yang dilekatkan padanya,
seperti pakaian seragam yang berkaitan dengan profesi, baju putih sering digunakan oleh
para dokter, seragam polisi atau tentara, dan profesi-profesi lainnya. Estetikasi Sahlin (dalam Lury)
menyatakan bahwa sistem pakaian bukan hanya sekedar seperangkat objek materi untuk
membuat pemakainya merasa hangat, tetapi juga sebagai kode simbolik yang digunakan
pemakainya untuk mengkomunikasikan keanggotaan mereka dalam kelompok sosial. Jika merujuk fashion sebagai pakaian, dan pakaian tersebut menjadi ciri tertentu bagi
seseorang yang berujung pada identitasnya, maka identitas tersebut dapat berupa asal
wilayah atau bahkan pola konsumsi dari individu itu sendiri, sebagaimana Sahlins (1976)
menegaskan bahwa dalam ideologi para produsen dan para konsumen, ada saling
menguatkan antara subjek dan objek yang mendasari esensi dari identitas, seperti
penggunaan bahan sutera yang identik dengan perempuan, kelembutan, (bahan) terbaik,
sedangkan sebaliknya, maskulinitas digambarkan pada bahan tekstil yang terbuat dari wol. 208
Jurnal Kommunity Online, 3 (2) 2022, e ISSN: 2797 5754
© 2022 The Author(s). This is an open access article under CC-BY-SA license (https://creativecommons.org/licenses/by-sa/4.0/) 208
Jurnal Kommunity Online, 3 (2) 2022, e-ISSN: 2797-5754
© 2022 The Author(s). This is an open access article under CC-BY-SA license (https://creativecommons.org/licenses/by-sa/4.0/) Komoditas Ketika memasuki dunia pasar, maka mulai terjadi perilaku konsumsi, bahkan juga
dapat memunculkan kelompok kelas atau golongan tertentu dalam masyarakat. Proses
konsumsi oleh Baudrillard (2004) dianalisis dalam dua aspek yang mendasar, yaitu (1)
sebagai proses signifikansi dan komunikasi yang didasarkan pada peraturan (kode-kode) di
mana praktik-praktik konsumsi masuk dan mengambil maknanya; di sini konsumsi
merupakan sistem pertukaran dan sepadan dengan bahasa. (2) sebagai proses klasifikasi
dan diferensiasi sosial, di mana objek-objek/tanda-tanda ditahbiskan bukan hanya sebagai
perbedaan yang signifikan dalam satu kode tetapi sebagai nilai yang sesuai (aturan) dalam 208
Jurnal Kommunity Online, 3 (2) 2022, e-ISSN: 2797-5754
© 2022 The Author(s). This is an open access article under CC-BY-SA license (https://creativecommons.org/licenses/by-sa/4.0/) 208 Industri Budaya Dan Komoditas (Studi Kasus Tenun Tradisional… hirarki. Di sini konsumsi dapat menjadi objek pembahasan strategis yang menentukan
kekuatan, khususnya dalam distribusi nilai yang sesuai aturan (melebihi hubungannya
dengan pertanda sosial lainnya seperti pengetahuan, kekuasaan, budaya, dan lain-lain). Komoditas menurut Appadurai (1986) dapat didefinisikan sebagai objek yang
memiliki nilai ekonomi. Komoditi dapat diteliti dari bidang antropologi sebagai bagian dari
budaya materi. Konsep konsumsi terkait pula dengan konsep komoditas (Miller, 1995), menurut Miller,
konsumsi dan komoditas yang berkaitan dengan kebudayaan bukan sekedar sistem
kapitalisme Marx semata namun juga mengandung unsur-unsur budaya yaitu budaya
materi bahkan kekerabatan. Seperti halnya kain tenun tradisional yang akhir-akhir ini
memiliki nilai komoditas yang cukup tinggi karena motif yang dinilai memiliki unsur seni
yang menarik, harga yang tinggi karena proses pengerjaannya yang rumit, dan menjadi
daya tarik pariwisata yang baru dengan mengusung tema wisata budaya, menjadikan kain
tenun mengalami pergeseran nilai-nilai adat dan tradisional menjadi nilai-nilai komoditas
dan modern. Dalam komoditas dapat terjadi proses industrialisasi yang berimplikasi keseragaman
(konformitas) (Strinati, 1995; Adorno, 1991) yang menyebabkan standardisasi dan
individualisasi semu (sebuah contoh pada perkembangan musik pop). Sebagaimana halnya
tenun tradisional yang termasuk sebagai barang komoditas, dan dapat menjadi bagian
industri budaya karena komoditi tersebut diarahkan oleh kebutuhan untuk menyadari
nilainya di pasaran. Motif keuntungan menentukan sifat berbagai bentuk budaya dan secara
industrial, produksi budaya merupakan sebuah proses standardisasi tempat produk-produk
tersebut mendapatkan bentuk yang sama pada semua komoditas 209
J
y
( )
© 2022 The Author(s). This is an open access article under CC-BY-SA license (https://creativecommons.org/licenses/by-sa/4.0/) Metodologi Penelitian tentang kain tenun dari Desa Sukarara ini dilakukan dengan
mewawancara dan mengamati kegiatan warga desa tersebut. Penelitian ini akan
menggunakan metode kualitatif dalam proses pengambilan data sekaligus analisisnya. 209
Jurnal Kommunity Online 3 (2) 2022 e ISSN: 2797 5754
Metode ini dilakukan dengan asumsi bahwa (1) penelitian kualitatif lebih menkankan
pehatian pada proses, bukannya hasil atau produk; (2) peneliti kualitatif tertarik pada
makna, yaitu bagaimana orang membuat hidup, pengalaman, dan struktur dunianya masuk
akal; (3) peneliti kualitatif merupakan instrumen pokok untuk pengumpulan dan analisis
data. Data didekati melalui instrumen manusia, bukannya melalui inventaris, daftar
pertanyaan, atau mesin; (4) peneliti kualitatif melibatkan kerja lapangan. Peneliti secara 209
J
y
,
( )
,
© 2022 The Author(s). This is an open access article under CC-BY-SA license (https://creativecommons.org/licenses/by-sa/4.0/) WG. Pramita Ratnasari fisik berhubungan dengan orang, latar, lokasi, atau institusi untuk mengamati atau
mencatat perilaku dalam latar alamiahnya; (5) peneliti kualitatif bersifat deskriptif dalam
arti peneliti tertarik pada proses, makna, dan pemahaman yang didapat melalui kata atau
gambar; (6) proses penelitian kualitatif bersifat induktif di mana peneliti membangun
abstraksi, konsep, hipotesa, dan teori. (Creswell, 1994). Masyarakat yang akan diteliti adalah masyarakat penenun di desa Sukarara, Lombok
Barat. Kegiatan menenun menjadi salah satu aktifitas yang menjadi aset perekonomian
warga di desa tersebut. Selain bercocok tanam dan mata pencaharian lain, tradisi menenun
masih menjadi kegiatan yang dilakukan oleh warga setempat. Tradisi menenun yang
berawal sebagai tradisi adat semata sekarang mengalami perubahan menjadi kegiatan
ekonomi bagi masyarakat desa Sukarara. Oleh karena itu, sebagaimaan pertanyaan di atas,
maka penelitian ini dirancang untuk melihat lebih jauh perubahan sosial, budaya, dan
ekonomi yang terjadi di desa tersebut, Para penenun melakukan kegiatan menenun adalah informan dalam penelitian ini, yaitu
para perempuan warga Desa Sukarara, dari berbagai Usia, khusunya mereka yang telah
memasuki usia remaja hingga dewasa. para penenun tersebut juga membuat kelompok-
kelompok tenun yang memiliki cirri khas padasetiap kelompok. 210
J
y
( )
© 2022 The Author(s). This is an open access article under CC-BY-SA license (https://creativecommons.org/licenses/by-sa/4.0/) Jurnal Kommunity Online, 3 (2) 2022, e-ISSN: 2797-5754
© 2022 The Author(s). This is an open access article under CC-BY-SA license (https://creativecommons.org/licenses/by-sa/4.0/) Pembahasan Pulau Lombok adalah bagian dari Propinsi Nusa tenggara Barat. Wilayah
pemerintahannya terbagi atas empat kabupaten dan satu kota administratif. Kabupaten
Lombok Barat, Kabupaten Lombok Tengah, Kabupaten Lombok Utara, Kabupaten
Lombok Timur dan Kota Madya Mataram. Berdasarkan sejarah politik dan pemerintahan,
pulau Lombok pada awalnya merupakan sebuah sistem pemerintahan kerajaan yaitu
Selaparang. Penduduk asli pulau Lombok adalah suku Sasak. Tiga hal yang berpengaruh
dalam kehidupan masyarakat Sasak pada abad ke 19 adalah; (1) pengaruh kebudayaan
Jawa yang kuat yang mungkin bermula dari awal abad 15-abad 16, (2) gabungan pengaruh
politik Bali dan Makasar dalam abad 17, (3) konsolidasi penguasaan politik Bali dari
permulaan abad 18 (van der Kraan, 2009). Tidak dapat dipungkiri bahwa pengaruh
kebudayaan Jawa dan Bali terdapat dalam kehidupan masyarakat Sasak. Kepercayaan
masyarakat setempat bahwa mereka masih keturunan Raja Majapahit (van der Kraan)
dengan disebutkan bahwa adanya makam kerabat Raja Majapahit dikubur di
daerahSembalun, Lombok. Pengaruh Jawa lainnya adalah pengislaman penduduk di Pulau
Lombok yang terdapat dalam Babad Lombok. Sehingga ke masa berikutnya dikenal istilah
Islam waktu-telu dan islam waktu-lima. 210
Jurnal Kommunity Online, 3 (2) 2022, e-ISSN: 2797-5754
© 2022 The Author(s). This is an open access article under CC-BY-SA license (https://creativecommons.org/licenses/by-sa/4.0/) 210
Jurnal Kommunity Online, 3 (2) 2022, e-ISSN: 2797-5754
© 2022 The Author(s). This is an open access article under CC-BY-SA license (https://creativecommons.org/licenses/by-sa/4.0/) Industri Budaya Dan Komoditas (Studi Kasus Tenun Tradisional… Selain pengaruh Jawa dalam kehidupan masyarakat Sasak, faktor lain adalah
pengaruh pendudukan Bali dari kerajaan Karangasem ke tanah Lombok pada abad 17. Kerajaan Karangasem dari Bali menyerang kerajaan Pejanggik di Lombok sehingga
akhirnya kerajaan tersebut dikuasai oleh raja Bali dan para raja Lombok yang malah
meminta bantuan dari Hindia Belanda untuk mempertahankan wilayah merekasehingga
timbul perang memeperebutkan wilayah pada akhir abad 19. Pada masa-masa tersebut
berkembang kisah-kisah (patriotik) yang menggambarkan perjuangan masyarakat
masyarakat Sasak dengan perlawannannya. Kisah-kisah tersebut masih tersimpan di
lembaran lontar yang dibaca pada waktu-waktu tertentu sebagai bagian dari prosesi adat. Suku asli di Pulau Lombok adalah etnis Sasak yang jumlah populasinya sekitar 90%
dari keselurahan etnis yang bermukim di pulau Lombok yaitu etnis Bali, Mbojo,
Sumbawa, Jawa, Arab, Cina dan etnis lain yang merupakan pendatang di pulau tersebut. Pemakaian bahasa Sasak dalam keseharian masyarakat juga menunjukkan adanya
pengaruh Jawa dan Bali karena aksara Jawa lah yang tertulis pada lembaran lontar yang
menjadi bagian kisah sejarah etnis Sasak. 211
J
y
( )
© 2022 The Author(s). This is an open access article under CC-BY-SA license (https://creativecommons.org/licenses/by-sa/4.0/) Pembahasan Meskipun demikian, bahasa Sasak dalam
perkembangannya memiliki klasifikasi tertentu seperti kuto-kute di bagian Lombok
Utara, ngeto-ngete di bagian Lombok Tenggara, Meno-mene di wilayah Lombok
Tengah, ngeno-ngene di wilayah Lombok Tengah dan mriak-mriku di wilayah Lombok
Selatan (Jaelani, 2007). Struktur sosial dalam masyarakat Sasak mengenal penggolongan masyarakat dalam
tingkatan tertentu, yaitu golongan bangsawan yang disebut perwangsa dan masyarakat
kebanyakan yang disebut jajar karang. Pada golongan bangsawan atau perwangsa
dibagi menjadi dua, yaitu para bangsawan penguasa yang menggunakan gelar datu
dengan penyebutan untuk kaum laki-laki golongan ini adalah raden dan perempuan
bangsawan disebut denda dan jika kelompok raden telah mencapai usia cukup dewasa
dan menggantikan kedudukan ayahnya maka mereka berhak memakai gelar datu dengan
melalui upacara tertentu. Kelompok bangsawan dibawah kelompok perwangsa adalah
triwangsa yang menggunakan gelar lalu untuk laki-laki dan baiq untuk perempuan. Golongan masyarakat kebanyakan disebut jajar karang dengan sebutan loq untuk laki-
laki dan le untuk perempuan (jaelani 2007). Adapula penggolongan masyarakat yang
disebut arupadatu yang menggunakan sebutan amaq untuk laki-laki dan inaq untuk
perempuan yang sudah menikah. Sedangkan hubungan kekerabatan menganut pola
patrilineal yaitu dari keturunan garis laki-laki yang meliputi kakek, ayah, saudara laki-
laki ayah (paman), anak laki-laki saudara lelaki ayah (sepupu) dan anak-anak mereka. 211
Jurnal Kommunity Online, 3 (2) 2022, e-ISSN: 2797-5754 211
J
y
,
( )
,
© 2022 The Author(s). This is an open access article under CC-BY-SA license (https://creativecommons.org/licenses/by-sa/4.0/) WG. Pramita Ratnasari 212
Jurnal Kommunity Online, 3 (2) 2022, e-ISSN: 2797-5754
© 2022 The Author(s). This is an open access article under CC-BY-SA license (https://creativecommons.org/licenses/by-sa/4.0/) 212
Jurnal Kommunity Online, 3 (2) 2022, e-ISSN: 2797-5754
© 2022 The Author(s). This is an open access article under CC-BY-SA license (https://creativecommons.org/licenses/by-sa/4.0/) Jurnal Kommunity Online, 3 (2) 2022, e-ISSN: 2797-5754 Sukarara Sebagai Bagian Suku Sasak Desa Sukarara sendiri merupakan salah satu desa yang berada di wilayah
Kecamatan Jonggat, Kabupaten Lombok Tengah, dengan luas wilayah Desa tersebut
dipimpin oleh seorang kepala desa. Pada awal berdirinya desa Sukara dipimpin oleh
kepala adat di mulai pada tahun 1755. Pemerintahan dengan sistem kepala adat ini
berakhir pada tahun 1840. Setelah tahun tersebut sistem pemerintahan desa dipimpin
oleh kepala desa. Sistem tersebut terjadi karena sejarah masuknya penjajahan Belanda
ke Pulau Lombok. Masyarakat desa Sukarara memiliki kedekatan sejarah dengan
masyarakat Pujut yang berdiam di daerah selatan Lombok. Desa ini terbentuk karena adanya jalur yang dibuat ketika terjadi penyerangan
pasukan dari kerajaan Bali terhadap penguasa atau Raja di Lombok yaitu ketika
pasukan dari kerajaan Bali menggempur pasukan dari Lombok sehingga mereka harus
mundur menghindari serangan tersebut. Dalam proses menghindar serangan tersebut
maka terbentuklah wilayah-wilayah baru sebagai tempat persembunyian pasukan raja
yang akhirnya berkembang menjadi desa-desa di sekitar Lombok tengah. Desa Sukarara dengan luas sekitar 7.585 m² merupakan wilayah dengan sebagian
besar lahan digunakan untuk pertanian dan sebagian lagi untuk pemukiman penduduk. Batas-batas wilayah desa Sukarara, di Utara berbatas dengan desa Nyerot dan desa
Puyung, di barat berbatasan dengan desa Labulie dan desa Ungga, di selatan berbatasan
dengan wilayah Praya. Secara administratif, wilayah desa Sukara sendiri terdiri atas
beberapa dusun, tepatnya 10 dusun: Blong Lauq, Blong Daye, Ketangge, Dasan Duah,
Bun Sambang, Dasan Baru, Burhana, Bun Putri, Bun Calang, dan Batu Entek. Penduduk desa Sukarara berdasarkan data desa pada tahun 2013 berjumlah ± 10848
jiwa dengan persentase usia produktif dewasa sebesar 51% , anak-anak dan remaja
27% dan kelompok lansia 22%. Selain berdasarkan usia, data penduduk berdasarkan
tingkat pendidikan pada tahun 2013 menunjukkan bahwa tingkat buta aksara di desa
tersebut cukup tinggi yaitu 1274 orang, sedangkan secara berturut-turut jumlah
penduduk yang menyelesaikan pendidikan dasar dan menengah atas ±2950 orang
sedangkan penduduk yang mengenyam dan menamatkan pendidikan perguruan tinggi
sebanyak 286 orang. Dari data ini manunjukkan bahwa masih kurangnya penduduk
yang memahami baca tulis dan hal ini diakui oleh informan akan tetapi meskipun tidak
memiliki kemampuan baca tulis namun mereka lah yang memiliki kemampuan untuk
menghapal motif-motif tenun yang diwariskan secara turun temurun, Industri Budaya Dan Komoditas (Studi Kasus Tenun Tradisional… “…biasanya yang pintar membuat motif itu orang-orang yang buta huruf, jarang
yang bersekolah biasa…saya sampai terheran-heran, pintar juga mereka membuat
motif, siapa yang ngajar?”. 21
J
y
,
( )
,
© 2022 The Author(s). This is an open access article under CC-BY-SA license (https://creativecommons.org/licenses/by-sa/4.0/) 213
Jurnal Kommunity Online, 3 (2) 2022, e-ISSN: 2797-5754 Sukarara Sebagai Bagian Suku Sasak “…biasanya yang pintar membuat motif itu orang-orang yang buta huruf, jarang
yang bersekolah biasa…saya sampai terheran-heran, pintar juga mereka membuat
motif, siapa yang ngajar?”. “…biasanya yang pintar membuat motif itu orang-orang yang buta huruf, jarang
yang bersekolah biasa…saya sampai terheran-heran, pintar juga mereka membuat
motif, siapa yang ngajar?”. Tetapi untuk masa sekarang tidak semua pembuat motif benar-benar buta huruf,
akan tetapi mereka tidak melanjutkan pendidikan dan biasanya hanya sampai tingkat
sekolah dasar. Mata pencaharian penduduk desa Sukarara memang tidak sepenuhnya dari
bertenun melainkan sebagian besar warga mengandalkan bertani di sawah dan lading
sebagai mata pencaharian utama mereka. Sebagian lagi bermata pencahiran sebagai
peternak khususnya beternak sapi yang memang mendapat bantuan dari pemerintah. Tetapi jika dilihat dari hasil pendapatan desa pada tahun 2013, maka sektor hasil
kerajinan rumah tangga memiliki jumlah yang lebih besar dibanding sektor lain (tabel
terlampir). Di desa Sukara juga terdapat pasar desa yang berlangsung hanya pada hari
tertentu tepatnya setiap hari Kamis dimana para pedagang dari sekitar desa Sukarara
berdatangan untuk berjualan di sana. Selain hari tersebut pasar desa tidak digunakan
oleh warga dan mereka berbbelanja keperluan ke pasar terdekat dari desa. Kegiatan
perekonomian lainnya yang dapat dilihat di desa sukarara adalah terdapat took-toko
kerajinan yang menjual kain tenun yang ditenun para perempuan warga desa Sukarara. Pekerjaan lain yang dijalani warga desa Sukarara selain bertani/beternak dan menenun
adalah di sektor jasa kesehatan, guru dan TKI. Selain organisasi pemerintah desa, organisasi sosial lain yang ada dalam
lingkungan warga Sukarara adalah organisasi pemuda dan karangtaruna, LKMD atau
sebutan lain, organisasi bagi perempuan yang terutama dalam bentuk kelompok
perempuan penenun, dan lembaga adat yang bertugas untuk menyelesaikan konflik
(tabel terlampir). Masyarakat di desa Sukarara masih terdapat stratifikasi yaitu masih adanya
pembedaan antara kelompok bangsawan yang terlihat dalam penamaan (Lalu untuk
laki-laki dan Lale untuk perempuan) dan kelompok non bangsawan yang tidak
menggunakan gelar tertentu. Yang terjadi adalah dalam proses komunikasi, warga yang
tidak bergelar bangsawan harus menggunakan bahasa sasak yang halus kepada warga
yang bergelar bangsawan meskipun proses ini tidak terlihat secara eksplisit namun ada
warga yang enggan untuk sering berkomunikasi dengan warga yang bergelar
bangsawan tersebut. 213
Jurnal Kommunity Online, 3 (2) 2022, e-ISSN: 2797-5754 WG. Pramita Ratnasari Kegiatan-kegiatan adat masih sering diselenggarakan di desa Sukarara
sebagaimana kegiatan adat yang berlaku di masyarakat Sasak pada umumnya, mulai
dari kelahiran (kurisan) hingga kematian (nelu, mitu, nyiwak, nyatus) dan pembacaan
lontar. Sukarara Sebagai Bagian Suku Sasak Bahkan beberapa alat pusaka berupa gong dan gamelan masih terdapat di desa
tersebut yang disimpan di sebuah rumah adat yang dibangun khusus untuk menyimpan
benda-benda adat milik desa. 214
Jurnal Kommunity Online, 3 (2) 2022, e ISSN: 2797 5754
© 2022 The Author(s). This is an open access article under CC-BY-SA license (https://creativecommons.org/licenses/by-sa/4.0/) 214
Jurnal Kommunity Online, 3 (2) 2022, e-ISSN: 2797-5754
© 2022 The Author(s). This is an open access article under CC-BY-SA license (https://creativecommons.org/licenses/by-sa/4.0/) Sukarara Dan Tradisi Tenun Menenun benang menjadi selembar kain merupakan kegiatan keseharian para
perempuan Sukarara. Kegiatan ini dilakuakan terutama ketika musim tanam telah usai
dan menunggu masa panen. Tradisi menenun merupakan tradisi turun temurun di
kalangan perempuan suku Sasak pada umumnya dan di Sukarara pada khususnya. Keahlian menenun diajarkan pada anak perempuan dari masa kanak-kanak hingga
mereka dewasa. Ketika dewasa dan hendak menikah, mereka akan menenun sendiri kain
songket yang akan digunakan ketika menikah kelak sebagai bukti kepada calon suami
dan keluarganya bahwa mereka telah memiliki keahlian menenun sehingga dapat
membantu kehidupan reumah tangganya kelak. Jurnal Kommunity Online 3 (2) 2022 e-ISSN: 2797-5754
Secara keseluruhan, kegiatan menenun di rumah disebut nyesek sedangkan perangkat
alat tenun (songket) itu sendiri disebut ranggon yang terdiri dari (a) ane yaitu berupa
balok kayu memanjang dengan tiga buah kaki, untuk merancang (benang) lungsi menjadi
lungsi atas dan lungsi bawah serta untuk merancang balengun; (b) batang jajak berupa
dua batang balok kayu tempat mendirikan jajak; (c) jajak, batang kayu yang didirikan
pada batang jajak tempa tmenambatkan tutuk; (d) tutuk, berupa sebilah papan tempat
menggulung lungsi yang akan atau sedang ditenun; (e) suri, berupa alat seperti sisir
sebagai alat untuk mengatur jarak lungsi dan sebagai alat untuk menekan (benang) pakan;
(f) golong, yaitu sebilah bambu yang berguna untuk meratakan dan mebatasi lungsi atas
dan lungsi bawah; (g) gun, bambu bergaris tengah 1 cm yang dimasukan padabalen gun
untuk menaikturunkan lungsi atas dan lungsi bawah; (h) belida, terbuat dari kayu asam
menyerupai pedang untuk merapatkan pakan dengan cara dihentakan, (i) apit, bilah kayu
yang digunakan untuk menggulung bagian kain yang sudah ditenun; (j) lekot, sebilah
kayu seperti busur panah untuk sandaran pinggang penenun, kedua ujung lekot diikat
dengan tali pada kedua ujung apit; (k) tekah, batang bambu bergaris tengah ± 0,8 cm
untuk meratakan atau merentangkan bidang tenunan agar suri tidak mudah patah; (l)
peniring, bambu tempat menggulung pakan; (m) terudak atau teropong berupa potongan
seruas bambu bergaris tengah ± 3 cm sebagai tempat peniring untuk membantu Industri Budaya Dan Komoditas (Studi Kasus Tenun Tradisional… memperlancar masuknya pakan; (n) erek-erek yaitu sejenis kerekan dengan tali dan batu
pemberat untuk menggantung gun kedua agar bidang tenun tidak berat di bagian tengah;
(o) wede pembatas lungsi atas dan lungsi bawah; (p) gun gantung untuk menggantung
gun agar bidang kain tidak berat (q) penggun yaitu gun tambahan. Setelah alat tenun siap, maka penenun akan melakukan persiapn berikutnya yaitu
benang yang akan digunakan untuk menjadi kain. Sukarara Dan Tradisi Tenun Jika pada jaman dahulu benang yang
dibuat berasal dari tanaman kapas yang ditanam sendiri oleh penenun dan keluarganya
tetapi sekarang lebih banyak penggunaan benang sintetis yang dapat dibeli di toko. Sehingga proses pewarnaan benang pun sudah tidak terjadi lagi di Sukarara. Ketika
benang songket sudah siap untuk ditenun maka penenun akan mulai menenun. Tetapi
ternyata untuk menenun harus disusun dahulu motif yang akan dibuat dan tidak semua
perempuan dapat menyusun motif kain tenun. Mereka akan memesan ke pembuat motif
tenun dan memberikan imbalan atas hasil penusunan motif tersebut. Menyusun motif
tenun juga membutuhkan waktu yang tidak sebentar, karena benang disusun helai demi
helai dan tidak boleh terjadi kesalahan dalam hitungan penyusunan benang. Tradisi menenun ini masih berlangsung hingga saat ini tetapi telah terjadi pergeseran-
pergeseran dimana anak perempuan tidak lagi diwajibkan untuk bisa menenun atau
nyesek bahkan ada orang tua yang tidak mengijinkan anak perempuannya untuk
menenun, seperti disampaikan oleh salah satu anak perempuan informan bahwa ia tidak
dijinkan menenun dengan ungkapan “…gak dikasih nyesek ma inak”, sehingga kegiatan
hariannya hanya bersekolah di salah satu madrasah tsanawiyah di kota kecamatan. Selain
itu semakin banyaknya pernikahan dengan laki-laki yang tidak bekerja desa Sukarara
juga menyebabkan ada perempuan-perempuan sukarara yang tidak menlanjutkan
kegiatan menenunnya. 21
y
© 2022 The Author(s). This is an open access article under CC-BY-SA license (https://creativecommons.org/licenses/by-sa/4.0/) Perubahan Makna Motif Tenun Salah satu pulau terdekat dari Bali dan juga memiliki tenun tradisional adalah
Lombok. Di pulau tersebut, masyarakatnya juga memiliki tradisi menenun kain tradisional. Sebagaimana diketahui, meskipun berdekatan serta memiliki persamaan dan percampuran
sejarah dan budaya, tetapi antara Bali dan Lombok memiliki tradisi yang juga berbeda. Di
Lombok memiliki tradisi yang kental dengan nuansa Islam, sedangkan di Bali dikenal
dengan tradisi Hindu. 215
Jurnal Kommunity Online, 3 (2) 2022, e-ISSN: 2797-5754
Kain tenun Lombok sendiri merupakan hasil kreasi masyarakat setempat sebagai suatu
proses yang dilakukan oleh masyarakat untuk memnuhi kebutuhan hidupnya yang bersifat
mendasar yaitu sebagai alat untuk melindungi tubuh. Tetapi fungsi dasar ini tidak bersifat 215
J
y
,
( )
,
© 2022 The Author(s). This is an open access article under CC-BY-SA license (https://creativecommons.org/licenses/by-sa/4.0/) WG. Pramita Ratnasari statis, karena ada faktor-faktor lain yang mempengaruhi proses terbentuknya sehelai kain
tenun. Adanya modifikasi tenunan tradisional baik dari segi motif maupun fungsinya juga
berimplikasi terhadap kehidupan masyarakat di Lombok. Kain tenun tradisional telah mengalamai transformasi dari fungsi awalnya menjadi
bagian dari komoditas dengan proses komodifikasinya. Kain tenun bukan hanya dikenal
dikalangan pemakai dan pembuatnya saja tetapi juga menjadi bagian dari gaya hidup
masyarakat lain yang beranggapan bahwa kain tenun tradisional memiliki nilai seni
tersendiri yang bisa dikonsumsi bukan lagi sebagai kebutuhan dasar melainkan hanya
sebagai kebutuhan “palsu” (Adorno, 1991). Ketika terjadi proses produksi suatu benda,
maka dapat disertai oleh proses pemaknaan dari benda tersebut yang dilekatkan oleh aktor-
aktor yang terlibat di dalamnya, sebagai suatu jaringan yang terus berputar. Bagi orang Sukarara dewasa ini, kegiatan menenun bukan hanya sebagai sebuah tradisi
yang berlangsung secara turun temurun tetapi juga menjadi mata pencaharian yang dapat
mendukung kehidupan ekonomi dan kegiatan pariwisata yang sedang menjadi program
pemerintah di propinsi Nusa Tenggara Barat. Hal ini dapat dilihat dari didirikannya art
shop di sepanjang jalan desa tersebut. Kegiatan menenun telah mengalami transformasi manjadi kegiatan ekonomi namun
tradisi adat untuk menciptakan motif-motif tenun di desa tersebut masih berlangsung. untuk
membuat suatu motif tenun songket maka penenun akan melalui suatu proses tidak
sebentar. Hal ini lah yang membuat suatu tenun songket memiliki nilai ekonomi atau harga
jual yang tinggi. Proses seseorang dapat membuat motif songket di desa Sukarara memiliki
ritual tersendiri. Yaitu ketika seorang anak perempuan yang telah berusia remaja di desa
telah cukup umur dan dianggap memiliki kemampuan untuk menyusun motif maka ia akan
tinggal di sebuah rumah adat selama beberapa hari untuk ritual tersebut. J
y
,
( )
,
© 2022 The Author(s). This is an open access article under CC-BY-SA license (https://creativecommons.org/licenses/by-sa/4.0/) 216
Jurnal Kommunity Online, 3 (2) 2022, e-ISSN: 2797-5754
© 2022 The Author(s). This is an open access article under CC-BY-SA license (https://creativecommons.org/licenses/by-sa/4.0/) Jurnal Kommunity Online, 3 (2) 2022, e-ISSN: 2797-5754 Perubahan Makna Motif Tenun Setelah selesai
ritual di rumah adat tersebut maka perempuan tersebut telah memiliki pengetahuan atau
ilmu untuk membuat motif tenun. Tidak semua perempuan di desa sukarara memiliki kemampuan untuk menyusun motif
tenun songket, karena kemapuan tersebut salah satunya membutuhkan daya ingat yang kuat
untuk dapat menyusun benang-benang menjadi motif tenun yang dibuat. Selain itu semakin
terbukanya kesempatan bagi perempuan untuk melanjutkan pendidikan ke jenjang yang
lebih tinggi juga mengakibatkan waktu yang biasa digunakan untuk menenun berkurang
karena waktu tersebut dimanfaatkan untuk belajar di bidang formal. Tetapi kegiatan
menenun tetap berjalan sebagai bagian dari kegiatan penggerak perekonomian masyarakat
desa. 216 Industri Budaya Dan Komoditas (Studi Kasus Tenun Tradisional… Kesimpulan Perubahan makna dan penggunaan kain tenun sebagai bagian dari proses kehidupan
manusia, misalnya untuk penggunaan sebagai kegiatan upacara adat seperti pernikahan, status
sosial mengalami perubahan fungsi. Fungsi awal sebagai bagian dari pranata sosial berubah
menjadi komoditas yang bernilai ekonomi dan sebagian kecil terdampak pada sistem religi
yaitu ketika agama islam masuk dan dianut oleh masyarakat Sasak di Lombok yang
sebelumnya terpengaruh oleh sistem kepercayaan Hindu Bali. Perkembangan dunia pariwisata di Indonesia berdampak pada berbagai perubahan
sistem dalam masyarakat, salah satunya dalam aspek seni, dan industri budaya dalam
penggunaan kain tenun pada masyarakat adat sasak di Pulau Lombok, Nusa Tenggara Barat,
pada proses menenun dan di sisi lain dapat terjadi pergeseran atau perubahan fungsi dari hasil
tenun tersebut yang bukan hanya sebagai pelengkap tradisi dan ritual tetapi juga sebagai
komoditas baru yang memberikan nuansa baru dalam kancah perkembangan wastra dan tenun
nusantara. 218
Jurnal Kommunity Online, 3 (2) 2022, e-ISSN: 2797-5754
© 2022 The Author(s). This is an open access article under CC-BY-SA license (https://creativecommons.org/licenses/by-sa/4.0/) Referensi Adorno, T., (1991) , The Culture Industry, London and New York, Routledge. Appadurai, A, 1986, The Social Life of Things, New York, Cambridge University
Press. Adorno, T., (1991) , The Culture Industry, London and New York, Routledge. Appadurai, A, 1986, The Social Life of Things, New York, Cambridge University
Press. Baudrillard, J., 2004, Masyarakat Konsumsi (terjemahan), Yogyakarta, Penerbit
Kreasi Wacana. Baudrillard, J., 2004, Masyarakat Konsumsi (terjemahan), Yogyakarta, Penerbit
Kreasi Wacana. Berlo, J.C., 1992, Beyond Bricolage: Women and Aesthetic Strategies in Latin
American Textile, Antrhopology and Aesthetic,no.22 pp.115-134. Berlo, J.C., 1992, Beyond Bricolage: Women and Aesthetic Strategies in Latin
American Textile, Antrhopology and Aesthetic,no.22 pp.115-134. Bowie, Katherine A. ,1992 “Unraveling the Myth of the Subsistence Economy:
Textile Production in Nineteenth-Century Northern Thailand The Journal of Asian
Studies, Vol. 51 no.4 Bowie, Katherine A. ,1992 “Unraveling the Myth of the Subsistence Economy: Coote, J., & Shelton, A.,1992, Anthropology, Art and Aesthetics, Oxford, Clarendon
Press. Creswell, J.W., 1994, Research Design:Quantitative & Qualitative Approaches
(terjemahan), Sage Publication. Eaton , M. M., 2004 Art and the Aesthetic, dalam The Blackwell Guide to Aesthetics
(Kivy,P., 2004), UK, Blackwell Publishing Ltd. Elayne Zorn (2004), “Weaving a Future: Tourism, cloth, and culture on an Andean
Island”, Iowa University Press. WG. Pramita Ratnasari Featherstone, M., 1991, Consumer Culture and Postmodernism, London, Sage
Publication. Finkelstein, J., 1993, Fashion and Eating Out, dalam The Polity Reader in
Cultural Theory, Cambridge, Polity Press. Hammersley, M., & Atkinson, P.,1983, Ethnography: principle in practice,
Routledge, London. Hansen, K.T., 2004, The World In Dress: Anthropological Perspective on Clothing, Hansen, K.T., 2004, The World In Dress: Anthropological Perspective on Clothing,
Fashion, and Culture, Annual Review Anthropology, 2004, 33:369-92. Fashion, and Culture, Annual Review Anthropology, 2004, 33:369-92. Geliat Kreasi Baru Tenun Bali, (Kompas, 17 April 2011) hal.17. Fashion, and Culture, Annual Review Anthropology, 2004, 33:369-92. Geliat Kreasi Baru Tenun Bali, (Kompas, 17 April 2011) hal.17. Inda, J.X., & Rosaldo, R., 2002, The Anthropology of Globalization, A Reader,
Blackwell Publisher Ltd. Lowe, C., 2006,Kajian Antropologi tentang Globalisasi: Catatan tentang Studi-
studi Keterkaitan Dunia, Antropologi Indonesia, Vol. 30 no.3,2006. 263-279. Lury, C., 1996, Budaya Konsumen, Jakarta, Yayasan Obor. Miller, D., 1995, Consumption and Commodities, Annual Review Anthropology
1995,24: 141-161. Messick, B., 1987, Subordinate Discourse: Women, Weaving, and Gender
Relations in North Africa, American Ethnologist, Vol.14, no.2 pp.210-225. Sahlins, M., 1976, Culture and Practical Reason, The University of Chicago Press. Referensi Seni Ragam Hias Pada Kain Tenun Nusa Tenggara Barat, 1990, Departemen
Pendidikan dan Kebudayaan, Museum Negeri Nusa Tenggara Barat. Messick, B., 1987, Subordinate Discourse: Women, Weaving, and Gender
Relations in North Africa, American Ethnologist, Vol.14, no.2 pp.210-225. Sahlins M 1976 Culture and Practical Reason The University of Chicago Press Sahlins, M., 1976, Culture and Practical Reason, The University of Chicago Press. Seni Ragam Hias Pada Kain Tenun Nusa Tenggara Barat, 1990, Departemen
Pendidikan dan Kebudayaan, Museum Negeri Nusa Tenggara Barat. Strinati, D., 1995, Popular Culture (Terjemahan), Yogyakarta, Ar-Ruzz Media. Schneider, J., 1987, The Anthropology of Cloth, Annual Review Antrhopology,
(1984) 409-448 Tedlock, B., and Tedlock, D., 1985, Text and Textile: Language and Technology in
The Arts of The Quiche Maya, Journal of Anthropological Research, Vol.41 pp. 121-
146. Kraan, A., 2009, Lombok, Penaklukan, Penjajahsan dan Keterbelakangan, Lengge
Printika, Mataram. Wengrow, D., 2001, The Evolution of Simplicity: aesthetic labour and social
change in neolitic Near East 218
Jurnal Kommunity Online, 3 (2) 2022, e-ISSN: 2797-5754
© 2022 The Author(s). This is an open access article under CC-BY-SA license (https://creativecommons.org/licenses/by-sa/4.0/)
|
https://openalex.org/W4239207946
|
https://www.qeios.com/read/V7CTM8/pdf
|
English
| null |
Tasisulam Sodium
|
Definitions
| 2,020
|
cc-by
| 93
|
Qeios · Definition, February 7, 2020 Open Peer Review on Qeios Open Peer Review on Qeios Tasisulam Sodium National Cancer Institute National Cancer Institute Qeios ID: V7CTM8 · https://doi.org/10.32388/V7CTM8 Source National Cancer Institute. Tasisulam Sodium. NCI Thesaurus. Code C88304. The sodium salt of an acyl-sulfonamide with potential antineoplastic activity. Selectively
toxic towards tumor cells, tasisulam appears to induce tumor cell apoptosis by a
mitochondrial-targeted mechanism involving the loss of mitochondrial membrane
potential and induction of reactive oxygen species (ROS). In combination with an
angiogenesis inhibitor, this agent may exhibit synergistic antiangiogenic activity. 1/1
|
https://openalex.org/W2005311136
|
https://europepmc.org/articles/pmc3741144?pdf=render
|
English
| null |
cAMP Level Modulates Scleral Collagen Remodeling, a Critical Step in the Development of Myopia
|
PloS one
| 2,013
|
cc-by
| 9,194
|
Introduction sclera [9–12]. Thus, scleral fibroblasts that synthesize collagen and
matrix metalloproteinases play an important role in the mainte-
nance of the extracellular matrix and refractive development. Myopia is the most common visual disorder in the world, with a
prevalence estimated to be 25% in the US and Europe and as high
as 80% in Asian countries such as China and Japan [1,2]. It is the
fifth most common cause of impaired vision and the seventh most
common cause of legal blindness worldwide [3]. The main
characteristic morphological change in myopia is elongation of the
axial length of the eye, especially evident in the vitreous chamber. This elongation is associated with other pathological changes,
including retinal detachment, macular degeneration, cataract, and
glaucoma, all of which can cause irreversible vision damage. The
current treatment options for myopia are limited. Cyclic
adenosine
monophosphate
(cAMP)
is
involved
in
conduction
of
visual
signals
and
other
neurotransmissions
[13,14] and in control of collagen synthesis [15–17]. Previous
studies showed that intracellular cAMP increased in response to
the adenylyl cyclase (AC) activator forskolin, and inhibited both
cell proliferation and collagen synthesis in human pulmonary
fibroblasts
[15]. Also,
increasing
cAMP
levels
by
cAMP-
elevating
agents
inhibits
the
transforming
growth
factor-b
(TGF-b)-stimulated collagen synthesis in cardiac and dermal
fibroblasts [16,17]. Although the neurochemical mechanisms underlying myopia
are largely unknown, it has been postulated that a visually-evoked
signaling cascade in the retina traverses the choroid and triggers
scleral remodeling and eye growth [4]. In both human and animal
myopia, biomechanical properties of the sclera determine the
shape of the eyeball and therefore influence the refractive state of
the eye [5–7]. Scleral thinning and abnormal scleral fibrils such as
fissured and star-shaped fibrils have been observed in human
myopic eyes [8]. Myopic development in marmosets, monkeys,
and tree shrews is associated with a reduction in scleral thickness
and collagen density, in the diameter of scleral collagen fibrils, and
in scleral glycosaminoglycan content, particularly at the posterior Based on the critical involvement of cAMP in the control of
collagen synthesis and scleral remodeling during myopia develop-
ment, we hypothesized that the cAMP levels could underlie
myopia development by controlling fibroblast activation and
extracellular matrix remodeling. In this study, we first investigated
the change of cAMP levels during form-deprivation-induced
myopia and recovery in guinea pigs. Abstract Competing Interests: The authors have declared that no competing interests exist. Competing Interests: The authors have declared that no competing interests exist. * E-mail: jqu@wz.zj.cn (JQ); zxt-dr@wz.zj.cn (XZ) * E-mail: jqu@wz.zj.cn (JQ); zxt-dr@wz.zj.cn (XZ) . These authors contributed equally to this work. cAMP Level Modulates Scleral Collagen Remodeling, a
Critical Step in the Development of Myopia Yijin Tao1,2., Miaozhen Pan1,2., Shufeng Liu1,2, Fang Fang1,2, Runxia Lu1,2, Chanyi Lu1,2, Min Zheng1,2,
Jianhong An1,2, Hongjia Xu1,2, Fuxin Zhao1,2, Jiang-fan Chen1,3, Jia Qu1,2*, Xiangtian Zhou1,2*
1 School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical College, Wenzhou, Zhejiang, China, 2 State Key Laboratory Cultivation Base and Key
Laboratory of Vision Science, Ministry of Health and Zhejiang Provincial Key Laboratory of Ophthalmology and Optometry, Wenzhou, Zhejiang, China, 3 Department of
Neurology, Boston University, School of Medicine, Boston, Massachusetts, United States of America Abstract The development of myopia is associated with decreased ocular scleral collagen synthesis in humans and animal models. Collagen synthesis is, in part, under the influence of cyclic adenosine monophosphate (cAMP). We investigated the
associations between cAMP, myopia development in guinea pigs, and collagen synthesis by human scleral fibroblasts
(HSFs). Form-deprived myopia (FDM) was induced by unilateral masking of guinea pig eyes. Scleral cAMP levels increased
selectively in the FDM eyes and returned to normal levels after unmasking and recovery. Unilateral subconjunctival
treatment with the adenylyl cyclase (AC) activator forskolin resulted in a myopic shift accompanied by reduced collagen
mRNA levels, but it did not affect retinal electroretinograms. The AC inhibitor SQ22536 attenuated the progression of FDM. Moreover, forskolin inhibited collagen mRNA levels and collagen secretion by HSFs. The inhibition was reversed by
SQ22536. These results demonstrate a critical role of cAMP in control of myopia development. Selective regulation of cAMP
to control scleral collagen synthesis may be a novel therapeutic strategy for preventing and treating myopia. Citation: Tao Y, Pan M, Liu S, Fang F, Lu R, et al. (2013) cAMP Level Modulates Scleral Collagen Remodeling, a Critical Step in the Development of Myopia. PLoS
ONE 8(8): e71441. doi:10.1371/journal.pone.0071441 Editor: Philip C. Trackman, Boston University Goldman School of Dental Medicine, United States of America Editor: Philip C. Trackman, Boston University Goldman School of Dental Medicine, United States of America Received January 15, 2013; Accepted June 28, 2013; Published August 12, 2013 et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted
roduction in any medium, provided the original author and source are credited. Copyright: 2013 Tao et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License,
use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This study was supported by funding from National Basic Research Program of China (973 project, 2011CB504602 to JQ), National Natural Science
Foundation of China (81271039 and 81070751 to JQ), Zhejiang Provincial Natural Science Foundation (Z2100065 to XZ), and Zhejiang Provincial Program for the
Cultivation of High-level Innovative Health talents, and an Education Grant from the National Ministry (NCET-10–0977 to XZ). The funders had no role in study
design, data collection and analysis, decision to publish, or preparation of the manuscript. August 2013 | Volume 8 | Issue 8 | e71441 Form Deprivation and Recovery Guinea pigs were randomly assigned to either the normal group
or the FDM group. Each was composed of subgroups including
non-injection group, vehicle group, and drug-treated group. The
right eyes of unanesthetized, restrained normal and FDM animals
were injected in the inferior palpebral subconjunctiva with 100 ml
of drug or vehicle solution once daily for the period indicated. Form-deprived myopia (FDM) was induced by monocular
deprivation using a facemask made of latex. The procedure for
preparing and wearing the facemask for two weeks over the right
eye has been detailed previously [18]. The recovery group wore
the facemask for 2 weeks to induce myopia. The facemask was
then removed, and the myopic eye was allowed re-exposure to the
normal environment for 2 days. Animals and Ethics Statement Animals and Ethics Statement Three-week-old pigmented guinea pigs were reared in 12-hour
light-dark cycles, with food and water freely available. The
treatment and care of animals was conducted according to the
Association for Research in Vision and Ophthalmology’s ‘‘State-
ment for the Use of Animals in Ophthalmic and Vision Research’’. The protocol for handling animals was in strict accordance with
the recommendations and approved by the Wenzhou Medical
College Animal Care and Use Committee (Permit Number:
WZMCOPT-090316). Introduction Next, we used pharmaco-
logical manipulation to determine if there is a causal relationship
between cAMP levels and the control of refraction and ocular axial
dimensions in guinea pigs under normal and form-deprivation
environments. Lastly, we studied the effect of cAMP on collagen August 2013 | Volume 8 | Issue 8 | e71441 1 August 2013 | Volume 8 | Issue 8 | e71441 PLOS ONE | www.plosone.org cAMP Modulates Scleral Remodeling in Myopia Table 1. Sequences for primers and RT-PCR product length. Gene
Forward primer (59-39)
Reverse primer (59-39)
Length
Collagen I
CGAGCGTGGTGTGCAAGGTC
CTGCACCACGTTCACCAGGC
158 bp
Collagen III
ACTCAAGTCTGTTAATGGAC
TATTCTCCACTCTTGAGTTC
120 bp
Collagen V
CAATGGACCCCAAGGACCCA
TTTCTCCCGTGGGACCCTGA
173 bp
GAPDH
GCTCTCTGCTCCTCCTGTTC
GACTCCGACCTTCACCTTCC
100 bp
doi:10.1371/journal.pone.0071441.t001 Gene
Forward primer (59-39)
Reverse primer (59-39)
Length
Collagen I
CGAGCGTGGTGTGCAAGGTC
CTGCACCACGTTCACCAGGC
158 bp
Collagen III
ACTCAAGTCTGTTAATGGAC
TATTCTCCACTCTTGAGTTC
120 bp
Collagen V
CAATGGACCCCAAGGACCCA
TTTCTCCCGTGGGACCCTGA
173 bp
GAPDH
GCTCTCTGCTCCTCCTGTTC
GACTCCGACCTTCACCTTCC
100 bp
doi:10.1371/journal.pone.0071441.t001 doi:10.1371/journal.pone.0071441.t001 spin, and dried at 60uC overnight. The residue was dissolved in
1 ml acetate buffer, and 0.1 ml was assayed according to the
manufacturer’s protocol. Counts in the re-suspended residue were
determined by a gamma scintillation counter (xh6080, Xi’an
Nuclear Instrument Factory, Xi’an, Shaanxi, China) for at least 60
seconds and were converted to fmol cAMP/ml. synthesis by human scleral fibroblasts (HSFs) to explore the
molecular basis for cAMP control of myopia. Drug Preparation and Injection Forskolin (Tocris Bioscience, Bristol, UK), an AC activator, was
used to elevate the tissue cAMP level. It was dissolved in 3%
dimethyl sulfoxide (DMSO) and diluted with 0.9% saline. The
vehicle solution was 0.1% DMSO in saline. SQ22536 (Tocris
Bioscience, Bristol, UK), an inhibitor of AC, was used to reduce
the tissue cAMP level. It was dissolved in double distilled H2O and
diluted with 0.9% saline. The vehicle solution was 0.1% saline in
double distilled H2O. Sircol Collagen Assay The concentration of soluble collagen in the cell culture
medium was measured using the Sircol Collagen Assay Kit
(Biocolor Ltd., Carrickfergus, UK). In brief, a 200 ml aliquot of
culture medium was added to 1 ml of Sircol dye and mixed in a
mechanical shaker at room temperature for 30 min, then
centrifuged to pellet the collagen-dye complex. The pellet was
dissolved in 0.5 M NaOH to release the collagen-dye complex,
and the concentration of collagen was determined by the
spectrophotometric absorbance at 540 nm. doi:10.1371/journal.pone.0071441.g001 cAMP Modulates Scleral Remodeling in Myopia Figure 1. Effect of form-deprived myopia (FDM) on refraction
and cAMP levels in the sclera and retina. (A) After 2 weeks of
monocular form deprivation, significant myopia was induced in the
form-deprived eyes (FDM 2w). Refraction in FDM eyes was significantly
increased after 2 days of recovery (FDM 2w+Rec 2d) from FDM (***:
p,0.001, independent sample t-test). (B) Scleral cAMP levels in FDM
eyes were significantly increased compared to normal eyes (*: p,0.05,
independent sample t-test) and fellow eyes (p,0.01, paired-sample t-
test). The cAMP level in the deprived eyes was decreased after 2 days of
recovery from FDM (**: p,0.01, independent sample t-test). (C) There
were no significant changes in retinal cAMP levels between FDM and
normal or fellow eyes (Normal, n = 22; FDM 2w, n = 21; FDM 2w+Rec 2d, Figure 1. Effect of form-deprived myopia (FDM) on refraction
and cAMP levels in the sclera and retina. (A) After 2 weeks of
monocular form deprivation, significant myopia was induced in the
form-deprived eyes (FDM 2w). Refraction in FDM eyes was significantly
increased after 2 days of recovery (FDM 2w+Rec 2d) from FDM (***: Cell Culture and cAMP Assay Normal HSFs were established previously as described [21,22]. All fibroblasts were grown in Dulbecco’s modified Eagle’s medium
(DMEM) supplemented with 10% heat-inactivated fetal bovine
serum and 2 mM glutamine, and kept in a 37uC incubator with
5% CO2. At 80–90% confluence, the cells were plated into 12-well
plates to incubate for 24 h. For forskolin and forskolin+SQ22536
treatments, the culture medium was replaced by serum-free
DMEM for 24 h before the addition of reagents. Intracellular cAMP levels were detected by CatchPointTM
Cyclic-AMP Fluorescent Assay Kit (Molecular Devices Corpora-
tion, Sunnyvale, CA, USA). HSF cells grown to confluence in
serum for 24 h were treated for 30 min with 10 mM forskolin
[16,23]. The cells were lysed using Cell Lysis Buffer (Molecular
Devices Corporation) and transferred to 96-well plates coated with
a rabbit anti-cAMP antibody. Changes in cAMP levels, measured
as pmol of cAMP per mg of protein, were determined in duplicates
based on the fluorescence intensity at 590 nm. Figure 1. Effect of form-deprived myopia (FDM) on refraction
and cAMP levels in the sclera and retina. (A) After 2 weeks of
monocular form deprivation, significant myopia was induced in the
form-deprived eyes (FDM 2w). Refraction in FDM eyes was significantly
increased after 2 days of recovery (FDM 2w+Rec 2d) from FDM (***:
p,0.001, independent sample t-test). (B) Scleral cAMP levels in FDM
eyes were significantly increased compared to normal eyes (*: p,0.05,
independent sample t-test) and fellow eyes (p,0.01, paired-sample t-
test). The cAMP level in the deprived eyes was decreased after 2 days of
recovery from FDM (**: p,0.01, independent sample t-test). (C) There
were no significant changes in retinal cAMP levels between FDM and
normal or fellow eyes (Normal, n = 22; FDM 2w, n = 21; FDM 2w+Rec 2d,
n = 18). d i 10 1371/j
l
0071441 001 Electroretinograms (ERGs) After 4 weeks of subconjunctival injections with either vehicle or
forskolin, scotopic and photopic ERGs were recorded. ERGs of
age-matched, untreated guinea pigs were used as the normal
control. Full-field ERGs were recorded with a custom-built
Ganzfeld dome connected to a computer-based system (Q450SC
UV, Roland Consult, Wiesbaden, Germany). After dark-adapta-
tion for 6 h, scotopic ERGs were recorded between 1 PM and
6 PM, and were followed by the photopic ERGs. White, green
(50566 nm), and blue (47066 nm) light emitting diodes were
used as stimulation light sources for recording the photopic ERGs. All testing was performed in a climate-controlled, electrically
isolated dark room under dim red light illumination. The guinea
pigs were anesthetized by intraperitoneal administration of
ketamine (85 mg/kg) and xylazine (5 mg/kg), and the pupils were
dilated with 0.5% tropicamide and 0.5% phenylephrine hydro-
chloride. A small amount of 2.5% methylcellulose gel was applied
to the eye, and a special Ag/AgCl wire loop electrode was placed
over the cornea as the active electrode. Needle reference and
ground electrodes were placed in the mouth and subcutaneously in
the right hind leg, respectively. Recordings were started from the
lowest light intensity to the highest. Body temperature was
maintained by placing the animals on a 37uC warming pad
during the experiment. Scleral and Retinal cAMP Assay Refraction was measured in triplicate by an eccentric infrared
photoretinoscope as previously described [19], and a trial lens was
used for system calibration. Corneal curvature was measured with
a keratometer (OM-4, Topcon, Tokyo, Japan) on which a +8
diopter (D) aspherical lens was attached [18]. Ocular dimensions
including the anterior chamber depth, lens thickness, vitreous
chamber depth (VCD), and the axial length (AL) were measured
with an A-scan ultrasonograph (AVISO Echograph Class I-Type
Bat; Quantel Medical, Clermont-Ferrand, France). The A-scan
ultrasonography was performed in alert guinea pigs, and the
cornea was topically anesthetized with one drop of 0.5%
proparacaine hydrochloride (Alcon, Puurs, Belgium). Velocities
of sound were assumed as described previously: 1557.5 m/s for
aqueous humor, 1723.3 m/s for the lens, and 1540 m/s for the A 125I-cAMP radioimmunoassay (RIA) kit (Institute of Isotopes
Ltd, Budapest, Hungary) was used to measure cAMP levels in the
sclera and retina. After enucleation, each eye was placed on ice,
and the anterior segment (cornea, iris, and crystalline lens) along
with the vitreous body were removed from the posterior segment
containing the sclera and retina. The sclera and retina were
separated from one another, and each was homogenized in 1 ml of
acetate buffer (50 mM Na+ acetate, 50 mM H+ acetate, 4 mM
ethylenediaminetetraacetic acid, pH 4.75). Then 2 ml of dehy-
drated ethanol was added prior to centrifugation at 3,000 rpm for
15 min at 4uC. The supernatants were collected, and the pellets
were re-suspended in another 2 ml of 75% ethanol. The re-
suspended pellets were again centrifuged as before. The superna-
tants were collected, pooled with the supernatants from the first Table 2. Sequences for primers and RT-PCR product length. Gene
Forward primer (59-39)
Reverse primer (59-39)
Length
Collagen I
CGAGCGTGGTGTGCAAGGTC
CTGCACCACGTTCACCAGGC
158 bp
Collagen III
GTGAAATGGGTCCCGCTGGTAT
GGATCACCTTTGGCACCGTTCT
142 bp
Collagen V
TGAGTTTCTACCCGAAGATGCT
GCAGGAGGGCACATTTCAC
165 bp
18S rRNA
GCAATTATTCCCCATGAACG
GGGACTTAATCAACGCAAGC
68 bp
doi:10.1371/journal.pone.0071441.t002
PLOS ONE | www.plosone.org
2
August 2013 | Volume 8 | Issue 8 | e71441 Table 2. Sequences for primers and RT-PCR product length. Table 2. Sequences for primers and RT-PCR product length. doi:10.1371/journal.pone.0071441.t002 August 2013 | Volume 8 | Issue 8 | e71441 PLOS ONE | www.plosone.org 2 cAMP Modulates Scleral Remodeling in Myopia Real-time Reverse Transcription Polymerase Chain
Reaction (RT-PCR) vitreous [20]. Each eye was measured six times. Guinea pig
intraocular pressure (IOP) was measured using a TonoVet TV01
Tonometer (TioLat, Helsinki, Finland) at the central cornea of
conscious animals according to the manufacturer’s recommenda-
tions. The TonoVet takes six measurements deemed reliable by
internal software, and then generates and displays the average
IOP. In this study, six mean values were obtained from each eye,
and the mean of the means treated as a single datum. Total RNA was extracted from HSF cultures with Trizol
reagent (Invitrogen, Grand Island, NY, USA), and 0.2 mg from
each sample was reverse transcribed with M-MLV reverse
transcriptase according to the Promega (Promega Corporation,
Madison, WI, USA) manufacturer’s instructions. The primers
(Table 1) were designed using Primer Express 3.0 software August 2013 | Volume 8 | Issue 8 | e71441 PLOS ONE | www.plosone.org 3 cAMP Modulates Scleral Remodeling in Myopia (Applied Biosystems, Foster City, CA, USA). RT-PCR was
performed in an Applied Biosystems 7500 Real-Time PCR
System using 26SYBRH Green PCR Master Mix (Applied
Bi
t
) Th
lt
li
d t
th
h
k
i
transcriptase according to the manufacturer’s instruction
mega Corporation, Madison, WI, USA). The primers (T
were designed using Primer Express 3.0 software (
Biosystems
Foster City
CA
USA)
RT PCR was per
Figure 2. Effect of the adenylyl cyclase activator forskolin on refraction, vitreous chamber depth (VCD), and axial length (
Subconjunctival injection of 10 mM forskolin induced the development of myopia in normal guinea pigs compared to non-injected and
injected controls at 2 and 4 weeks (**: p,0.01, ***: p,0.001, independent sample t-test). (B) Forskolin also induced an increase in vitreous c
depth (VCD, *: p,0.05, **: p,0.01), and (C) axial length (AL, **: p,0.01, ***: p,0.001) in normal eyes. (D–F) The 1- and 2-week treatm
subconjunctival forskolin had no effects on FDM eyes. (Normal groups: non-injection n = 16, vehicle n = 12, 10 mM forskolin n = 16; FDM
FDM+non-injection n = 12, FDM+vehicle n = 9, FDM+10 mM forskolin n = 11). doi:10.1371/journal.pone.0071441.g002
cAMP Modulates Scleral Remodeling in Figure 2. Effect of the adenylyl cyclase activator forskolin on refraction, vitreous chamber depth (VCD), and axial length (A
Subconjunctival injection of 10 mM forskolin induced the development of myopia in normal guinea pigs compared to non-injected and v
injected controls at 2 and 4 weeks (**: p,0.01, ***: p,0.001, independent sample t-test). Real-time Reverse Transcription Polymerase Chain
Reaction (RT-PCR) (B) Forskolin also induced an increase in vitreous ch
depth (VCD, *: p,0.05, **: p,0.01), and (C) axial length (AL, **: p,0.01, ***: p,0.001) in normal eyes. (D–F) The 1- and 2-week treatm
subconjunctival forskolin had no effects on FDM eyes. (Normal groups: non-injection n = 16, vehicle n = 12, 10 mM forskolin n = 16; FDM
FDM+non-injection n = 12, FDM+vehicle n = 9, FDM+10 mM forskolin n = 11). doi:10.1371/journal.pone.0071441.g002
cAMP Modulates Scleral Remodeling in Figure 2. Effect of the adenylyl cyclase activator forskolin on refraction, vitreous chamber depth (VCD), and axial length (AL). (A)
Subconjunctival injection of 10 mM forskolin induced the development of myopia in normal guinea pigs compared to non-injected and vehicle-
injected controls at 2 and 4 weeks (**: p,0.01, ***: p,0.001, independent sample t-test). (B) Forskolin also induced an increase in vitreous chamber
depth (VCD, *: p,0.05, **: p,0.01), and (C) axial length (AL, **: p,0.01, ***: p,0.001) in normal eyes. (D–F) The 1- and 2-week treatments of
subconjunctival forskolin had no effects on FDM eyes. (Normal groups: non-injection n = 16, vehicle n = 12, 10 mM forskolin n = 16; FDM groups:
FDM+non-injection n = 12, FDM+vehicle n = 9, FDM+10 mM forskolin n = 11). doi:10.1371/journal.pone.0071441.g002 (Applied Biosystems, Foster City, CA, USA). RT-PCR was
performed in an Applied Biosystems 7500 Real-Time PCR
System using 26SYBRH Green PCR Master Mix (Applied
Biosystems). The results were normalized to the house-keeping
gene glyceraldehyde-3-phosphate dehydrogenase. (Applied Biosystems, Foster City, CA, USA). RT-PCR was
performed in an Applied Biosystems 7500 Real-Time PCR
System using 26SYBRH Green PCR Master Mix (Applied
Biosystems). The results were normalized to the house-keeping
gene glyceraldehyde-3-phosphate dehydrogenase. transcriptase according to the manufacturer’s instructions (Pro-
mega Corporation, Madison, WI, USA). The primers (Table 2)
were designed using Primer Express 3.0 software (Applied
Biosystems, Foster City, CA, USA). RT-PCR was performed
inan Applied Biosystems ViiATM 7 Real-Time PCR System using
26SYBRH Green PCR Master Mix (Applied Biosystems). The
results were normalized to the house-keeping gene 18S rRNA. Following the forskolin injection, the guinea pig eyes were
enucleated and prepared as described above. Age-matched,
untreated guinea pigs were used as the normal control. The
sclera was homogenized in 250 ml of RNAlaterH solution (Ambion,
Carlsbad, CA, USA). Total RNA was extracted with RNeasy
Fibrous Tissue Mini Kit (Qiagen), and 0.5 mg total RNA from
each sample was reverse transcribed with M-MLV reverse Statistical Analysis Descriptive statistics, including means 6 standard error of the
means, and statistical tests were determined using the Statistical
Package for the Social Sciences (SPSS version 15.0, Chicago, IL, PLOS ONE | www.plosone.org August 2013 | Volume 8 | Issue 8 | e71441 August 2013 | Volume 8 | Issue 8 | e71441 4 cAMP Modulates Scleral Remodeling in Myopia Figure 3. Effect of the adenylyl cyclase inhibitor SQ22536 on refraction, vitreous chamber depth (VCD), and axial length (AL
In normal eyes, subconjunctival injection of 100 mM SQ22536 had no significant effect on refraction, vitreous chamber depth (VCD) or axia
(AL). In FDM eyes, SQ22536 reduced (D) refraction (*: p,0.05, ***: p,0.001, independent sample t-test), (E) VCD (***: p,0.001, independent sa
test), and (F) AL (**: p,0.01, ***: p,0.001, independent sample t-test) in a time-dependent manner. (Normal groups: non-injection n = 11,
n = 14, 100 mM SQ22536 n = 17; FDM groups: FDM+non-injection n = 16, FDM+vehicle n = 17, FDM+100 mM SQ22536 n = 21). doi:10.1371/journal.pone.0071441.g003
cAMP Modulates Scleral Remodeling in Figure 3. Effect of the adenylyl cyclase inhibitor SQ22536 on refraction, vitreous chamber depth (VCD), and axial length (AL). (A–C)
In normal eyes, subconjunctival injection of 100 mM SQ22536 had no significant effect on refraction, vitreous chamber depth (VCD) or axial length
(AL). In FDM eyes, SQ22536 reduced (D) refraction (*: p,0.05, ***: p,0.001, independent sample t-test), (E) VCD (***: p,0.001, independent sample t-
test), and (F) AL (**: p,0.01, ***: p,0.001, independent sample t-test) in a time-dependent manner. (Normal groups: non-injection n = 11, vehicle
n = 14, 100 mM SQ22536 n = 17; FDM groups: FDM+non-injection n = 16, FDM+vehicle n = 17, FDM+100 mM SQ22536 n = 21). doi:10.1371/journal.pone.0071441.g003 USA). Paired sample t-tests were used to compare biometric data
between the experimental and fellow eyes within the same group. Independent sample t-tests were used to compare control and
vehicle groups and vehicle and drug groups. Cyclic-AMP Levels Increased Selectively in Scleras of FDM
Eyes Two weeks of form deprivation induced significant myopia in
guinea pigs (26.1960.41D, difference between experimental and
fellow eyes, p,0.001, paired-sample t-test, Fig. 1A). Refraction in
the FDM eyes significantly increased after removal of the facemask
for 2 days (p,0.01, independent sample t-test, Fig. 1A). RIA
analysis showed that the cAMP levels after 2 weeks of form
deprivation were selectively increased in the scleras of FDM eyes
in comparison with the fellow eyes (p,0.01, paired-sample t test)
and normal eyes (p,0.05, independent sample t test). After 2 days
of recovery from FDM, the amount of cAMP in the deprived eyes The relative quantity (RQ) of mRNAs and collagen production
of HSFs were compared between control and drug-treated groups
using independent sample t-tests. Comparisons of effects among
groups treated with different concentrations of drugs were
performed by one-way analysis of variance (ANOVA) with
Bonferroni correction. The RQ of mRNAs for guinea pig scleral
collagen was compared between drug-treated and fellow eyes
using paired sample t-tests. Independent sample t-tests were used
to compare normal and drug-treated eyes. PLOS ONE | www.plosone.org August 2013 | Volume 8 | Issue 8 | e71441 5 cAMP Modulates Scleral Remodeling in Myopia Figure 4. Effect of forskolin on scotopic and photopic ERGs. The scotopic and photopic ERG luminance response curves (peak time,
amplitude) for the a-and b-waves were obtained from age-matched normal guinea pigs and forskolin or DMSO injected guinea pigs (normal n = 12,
vehicle n = 12, forskolin n = 15). At all stimulus intensities, there were no significant differences between forskolin- and vehicle-treated guinea pigs for
either scotopic or photopic ERG parameters. Ordinate, (A–D) peak times in milliseconds (ms) or (E–H) amplitude (mV); Abscissa, flash intensity. doi:10.1371/journal.pone.0071441.g004
cAMP Modulates Scleral Remodeling in Myopia Figure 4. Effect of forskolin on scotopic and photopic ERGs. The scotopic and photopic ERG luminance response curves (peak time,
amplitude) for the a-and b-waves were obtained from age-matched normal guinea pigs and forskolin or DMSO injected guinea pigs (normal n = 12,
vehicle n = 12, forskolin n = 15). At all stimulus intensities, there were no significant differences between forskolin- and vehicle-treated guinea pigs for
either scotopic or photopic ERG parameters. Ordinate, (A–D) peak times in milliseconds (ms) or (E–H) amplitude (mV); Abscissa, flash intensity. doi:10.1371/journal.pone.0071441.g004 accompanied by increased VCD (0.0560.01 mm, p = 0.001,
independent
sample
t-test,
Fig. Cyclic-AMP Levels Increased Selectively in Scleras of FDM
Eyes 2B)
and
increased
AL
(0.0760.01 mm, p = 0.001, independent sample t-test, Fig. 2C). After 4 weeks of daily injection, forskolin induced greater myopia
(22.4260.27 D, p,0.001, independent sample t-test, Fig. 2A),
accompanied by increased VCD (0.0560.01 mm, p = 0.029,
independent
sample
t-test,
Fig. 2B)
and
increased
AL
(0.0960.01 mm, p,0.001, independent sample t-test, Fig. 2C). The myopic shift and associated axial elongation changes were not
associated with any significant change in corneal curvature,
anterior chamber depth, or lens thickness between forskolin-
injected and fellow eyes or between the drug and vehicle-treated
groups (data not shown). decreased significantly, reaching the level of fellow eyes (p,0.01,
independent sample t test, Fig. 1B). In contrast, the cAMP levels in
the retinas of the FDM eyes were not significantly different from
the fellow eyes or from normal eyes, and also displayed no
significant change after the 2-day recovery from FDM (Fig. 1C). August 2013 | Volume 8 | Issue 8 | e71441 SQ22536 Reduced Myopia in Form-deprived Eyes but
had No Effect on Normal Eyes In normal animals, after 2 and 4 weeks of daily subconjunctival
injection, 100 mM SQ22536 treatment did not produce any
significant change in refraction, VCD, or AL compared to the
vehicle-treated groups or to the fellow eyes (Fig. 3A–C). Similarly,
SQ22536 treatment also did not affect corneal curvature, anterior
chamber depth, or lens thickness compared to the vehicle
treatment (data not shown). Figure 6. Effect of forskolin and SQ22536 on collagen secretion
and mRNA expression in HSFs. (A) Treatment of cultured human
scleral fibroblasts (HSFs) for 24 h with forskolin significantly decreased
the total soluble collagen recovered in the culture medium in a
concentration-dependent manner (*: p,0.05, **: p,0.01, ANOVA, n = 6;
m: p,0.01, ANOVA, n = 6). (B) Treatment with forskolin for 24 h
significantly decreased the expression of mRNAs for collagens I, III, and
V. Forskolin reduced the mRNA level in a concentration-dependent
manner. (*: p,0.05, **: p,0.01, ANOVA, n = 6). (C) The reductions in
collagen I, III, and V mRNA expression levels by forskolin were
significantly decreased by SQ22536 treatment. (**: p,0.01, indepen-
dent sample t-test, n = 6; m: p,0.05, independent sample t-test, n = 6). doi:10.1371/journal.pone.0071441.g006 (
)
We also investigated the effect of SQ22536 on the progression
of FDM. After 2 weeks of daily subconjunctival injection, 100 mM
SQ22536 treatment significantly reduced the myopic refraction in
the FDM eyes compared to the vehicle group (24.2460.30 D vs. 25.3860.39 D, Fig. 3D). SQ22536 treatment also significantly
reduced the VCD in the FDM eyes when compared to the vehicle
group (0.0760.01 mm vs. 0.1360.01 mm, p = 0.013, independent
sample t-test, Fig. 3E). Similarly, SQ22536 treatment significantly
reduced the AL in FDM eyes compared to the vehicle group
(0.0960.01 mm vs. 0.1360.01 mm, p = 0.004, independent sam-
ple t-test, Fig. 2F). After 4 weeks of daily subconjunctival injection,
SQ22536 treatment significantly reduced myopic refraction in
FDM
eyes
compared
with
the
vehicle-treated
animals
(26.2160.33D vs. 28.6760.40 D, p,0.001, independent sample
t-test, Fig. 3D). The diminished myopia was accompanied with
reduced VCD (0.1160.01 mm vs. 0.1960.02 mm, p,0.001,
independent sample t-test, Fig. 3E) and AL (0.1260.01 mm vs. 0.2160.02 mm, p,0.001, independent sample t-test, Fig. 3F) in
FDM eyes compared with the vehicle group. Forskolin Induced Myopia in Normal Eyes but had No
Effect on Form-deprived Eyes In normal animals after 2 weeks of daily subconjunctival
injection, 10 mM forskolin treatment induced significant myopic
refraction (21.5360.24D, difference between experimental and
fellow eyes) in comparison with the vehicle-treated animals
(p = 0.001, independent sample t-test, Fig. 2A). This change was August 2013 | Volume 8 | Issue 8 | e71441 PLOS ONE | www.plosone.org 6 cAMP Modulates Scleral Remodeling in Myopia cAMP Modulates Scleral Remodeling in Myopia Figure 6. Effect of forskolin and SQ22536 on collagen secretion
and mRNA expression in HSFs. (A) Treatment of cultured human
scleral fibroblasts (HSFs) for 24 h with forskolin significantly decreased
the total soluble collagen recovered in the culture medium in a
concentration-dependent manner (*: p,0.05, **: p,0.01, ANOVA, n = 6;
m: p,0.01, ANOVA, n = 6). (B) Treatment with forskolin for 24 h
significantly decreased the expression of mRNAs for collagens I, III, and
V. Forskolin reduced the mRNA level in a concentration-dependent
manner. (*: p,0.05, **: p,0.01, ANOVA, n = 6). (C) The reductions in
collagen I, III, and V mRNA expression levels by forskolin were
significantly decreased by SQ22536 treatment. (**: p,0.01, indepen-
dent sample t-test, n = 6; m: p,0.05, independent sample t-test, n = 6). doi:10.1371/journal.pone.0071441.g006 Figure 5. Intracellular cAMP concentration. Cultured human
scleral fibroblasts (HSFs) were treated with 10 mM forskolin for
30 min. Forskolin increased the intracellular cAMP levels. (n = 3, **:
p,0.01, independent sample t-test). doi:10.1371/journal.pone.0071441.g005 Figure 5. Intracellular cAMP concentration. Cultured human
scleral fibroblasts (HSFs) were treated with 10 mM forskolin for
30 min. Forskolin increased the intracellular cAMP levels. (n = 3, **:
p,0.01, independent sample t-test). doi:10.1371/journal.pone.0071441.g005 We also investigated the effect of forskolin on the progression of
FDM. After form deprivation for 2 weeks, forskolin treatment
failed to produce any further significant changes in refraction,
VCD, or AL in the FDM eyes (Fig. 2D–F). Similarly, forskolin
treatment also did not affect corneal curvature, anterior chamber
depth, or lens thickness in FDM eyes (data not shown). Taken
together, forskolin treatment induced myopic refraction and
increased VCD and AL in normal eyes, but had no effect on
the myopic shift and associated axial elongation in FDM eyes. SQ22536 Reduced Myopia in Form-deprived Eyes but
had No Effect on Normal Eyes As expected, there
were no significant changes in corneal curvature, anterior
chamber depth, or lens thickness between SQ22536 injected and
fellow eyes or between the SQ22536 and vehicle-treated groups
(data not shown). Taken together, SQ22536 had no effect on
normal eyes but reduced myopic refraction, VCD, and AL in
FDM eyes. Forskolin had No Significant Effect on Intraocular
Pressure The IOP was measured in each eye before and after the
injection of forskolin at weeks 2 and 4. There were no significant
differences in the mean IOPs between the forskolin-injected eyes
and the untreated eyes or between the forskolin and vehicle-
treated groups at any time point after the injection (data not
shown). Forskolin Inhibited Collagen Expression in vitro and
in vivo Following treatment with 10 mM forskolin for 30 min, the
intracellular cAMP level of the HSFs increased significantly (Fig. 5). Treatment with 0.1 mM to 10 mM forskolin reduced the total
soluble collagen secreted by cultured HSFs in a concentration-
dependent manner (Fig. 6A). Forskolin (0.1 mM to 10 mM) also
significantly inhibited in a concentration-dependent manner HSF
expression of collagen I, III, and V mRNAs (Fig. 6B). Conversely,
100 mM SQ22536 reversed or blunted the forskolin-induced
reduction of the collagen I, III, and V mRNA levels that were
decreased by forskolin (Fig. 6C). The critical role of the cAMP levels in myopia is consistent with
the involvement of scleral remodeling in development of myopia
and cAMP as a negative regulator of fibroblast activation and
differentiation [4,17]. In fact, the cAMP pathway may be a
common
mechanism
underlying
myopia
development,
and
provides a plausible explanation for the previous finding that
several G-protein coupled receptors modify FDM. For example,
the activation of D2 dopamine receptor attenuated FDM [30]. Since the D2 receptor is a Gi-coupled receptor, most likely the
effect of D2 activation is achieved through inhibition of AC and
reduction of cAMP accumulation [31], rather than due to
disturbance of neurotransmitter release [31]. Furthermore, we also examined the effect of subconjunctival
injection of forskolin for one week on collagen I, III, and V mRNA
expression in intact animals. We determined by qPCR analysis the
expressions of collagen I, III, and V mRNAs in guinea pig sclera
after forskolin treatment. We found that collagen III and V
mRNA levels were significantly decreased in the forskolin-treated
eyes compared with the fellow eyes. Collagen I mRNA levels
tended to decrease but the change was not statistically significant
after forskolin treatment (Fig. 7). The non-selective and M1-selective muscarinic antagonists, e.g. atropine and pirenzepine respectively, effectively prevent the axial
elongation and myopic shift induced by form-deprivation in
animal models [32–34]. They also halt childhood myopia
development [35–37]. The expression of the muscarinic M1
subtype is increased in the posterior sclera of FDM eyes in guinea
pigs [38]. Levels of cAMP are also regulated by muscarinic
receptors, and muscarinic M1 receptors can couple with Gs
mediating the stimulation of AC activity and cAMP accumulation
[39]. Thus, it is possible that atropine and other muscarinic
antagonists affect the development of myopia by controlling cAMP
levels in the sclera. Forskolin Inhibited Collagen Expression in vitro and
in vivo However, G-protein coupled receptors may
modulate myopia by signaling pathways other than cAMP [40]. For example, in contradiction to the predicted results, genetic
deletion of the Gs-coupled adenosine A2A receptor (A2AR) and the
consequent reduction in cAMP level in fact induces, rather than
attenuates, myopia in mice [41].This is accompanied by the
finding that A2AR activation by the agonist CGS21680 induces
expression of mRNAs for collagens I, III, and V and increases
production of soluble collagen in cultured HSFs [41]. A2AR
activation signals through multiple pathways, such as src, ERK1/
2, and p38 MAPK, to modulate collagen synthesis [42]. Therefore
we speculate that A2ARs may signal through complex pathways to
affect collagen synthesis and scleral remodeling and thereby affect
myopia development. cAMP Modulates Scleral Remodeling in Myopia cAMP Modulates Scleral Remodeling in Myopia Figure 7. Effect of forskolin on collagen mRNA expression in
guinea pig sclera. Injection of forskolin for 1 week significantly
decreased the expression of mRNAs for collagens III and V in the
experimental eyes. Collagen I mRNA levels also showed a tendency to
decrease. (*: p,0.05, paired sample t-test, normal n = 10, forskolin-
treated and fellow eyes n = 10). doi:10.1371/journal.pone.0071441.g007 Importantly, ACs and cAMP are widespread in ocular tissues. Non-selective AC drugs could lead to side-effects, such as ocular
hypertension or retinal function disorder. We showed that
pharmacological reduction of cAMP level with the AC inhibitor
SQ22536 selectively inhibited FDM, but had no effect on normal
guinea pig eyes. This suggests that FDM eyes with high levels of
scleral cAMP are sensitive to AC inhibition but not activation. An
important therapeutic implication of our findings is that targeted
approaches to reduce cAMP levels in the eye may selectively
counteract myopic pathogenesis without affecting normal visual
development. Because the onset of myopia occurs mostly in
children when normal eye growth and myopic pathogenesis are
taking place at the same time, a drug that can distinguish between
these two processes will be particularly beneficial. Our data
provide strong support for the development of therapeutic
strategies for treating myopia that target ‘‘super-normal levels’’
of cAMP. Several AC isoforms are therapeutic targets in brain and
heart diseases. For example, AC1 and AC2 are stimulatory targets
for treating Alzheimer’s and other neurodegenerative diseases
[25,26], and activation of AC5 and AC6 plays important roles in
improving the function of the failing heart [27–29]. Thus,
investigations into the specific AC isoform(s) and selective
inhibitor(s) that specifically decrease cAMP levels in the sclera
might lead to development of a novel pharmacological therapy for
myopia. Figure 7. Effect of forskolin on collagen mRNA expression in
guinea pig sclera. Injection of forskolin for 1 week significantly
decreased the expression of mRNAs for collagens III and V in the
experimental eyes. Collagen I mRNA levels also showed a tendency to
decrease. (*: p,0.05, paired sample t-test, normal n = 10, forskolin-
treated and fellow eyes n = 10). doi:10.1371/journal.pone.0071441.g007 Forskolin had No Significant Influence on Retinal
Function After 4 weeks of injections, retinal function was examined by
dark- and light-adapted ERGs. There were no significant
differences in either scotopic or photopic ERG parameters at
any stimulus intensity between the forskolin and vehicle injection
groups or age-matched normal controls (Fig. 4). PLOS ONE | www.plosone.org August 2013 | Volume 8 | Issue 8 | e71441 7 Scleral Remodeling Represents the Main Locus whereby
the cAMP Levels Affect Myopia Development by
Modulation of Collagen Synthesis g
y
The exact mechanism by which the cAMP levelcontrols myopia
development is not entirely clear. Cyclic AMP is present in various
ocular tissues, such as the cornea, iris-ciliary body, and sclera [43]. Increased anterior chamber cAMP is associated with increased
outflow facility for aqueous humor that, in turn, decreases the IOP
[44,45]. Higher IOP is postulated as a potential mechanical factor
for the development of myopia. However, mixed results have been
reported, with some studies showing that higher IOP is associated
with myopia [46,47], while others found no significant associations
between them [48–50]. For example, studies in tree shrew and
chick eyes reported that the weakened biomechanical properties of
the sclera in myopia reduce the resistance of eye to elongation
under the normal IOP [6,51]. The present study detected no
difference in IOP among the normal, vehicle- and forskolin-
treated guinea pigs. Consistent with this, there was no significant
change in anterior chamber depth and corneal curvature after
forskolin or SQ22536 treatment in either normal or FDM guinea
pigs. Thus, manipulation of cAMP level by subconjunctival
injection did not affect the IOP or the structure of anterior
segment. Our study provides the mechanistic evidence that localizes the
sclera as the locus of myopic changes. In guinea pig eyes, the
cAMP pathway modified development of myopia by controlling
scleral remodeling and collagen synthesis. This notion is supported
by three lines of evidences: First, cAMP levels were selectively
increased in the scleras, but not retinas, after form deprivation,
and they returned to the normal level after 2 days of FDM
recovery. This suggests that the sclera represents the main locus
where the cAMP level controls myopia development. Taken together, the selective increase of scleral cAMP, lack of
forskolin-induced change in ERG (i.e., retinal function), and
robust modulation of collagen synthesis in HSFs by forskolin lead
us to propose that scleral remodeling represents the main locus
whereby cAMP regulates myopia development via control of the
sclera collagen synthesis. In summary, using ophthalmological and pharmacological
manipulation coupled with optometric measurements, these
studies uncovered a critical role of the cAMP level in control of
myopia development. Specifically, an abnormally high level of
cAMP induced by forskolin is sufficient to induce myopia similar
to FDM. Increased cAMP levels result in the myopic shift in
guinea pigs, probably by inhibiting scleral collagen synthesis. 4. McBrien NA, Gentle A (2003) Role of the sclera in the development and
pathological complications of myopia. Prog Retin Eye Res 22: 307–338.
5. Curtin BJ, Teng CC (1958) Scleral changes in pathological myopia. Trans Am
Acad Ophthalmol Otolaryngol 62: 777–788; discussion 788–790.
6. Phillips JR, Khalaj M, McBrien NA (2000) Induced myopia associated with
increased scleral creep in chick and tree shrew eyes. Invest Ophthalmol Vis Sci
41: 2028–2034. Acknowledgments We thank Dr. Britt Bromberg of Xenofile Editing (www.xenofileediting. com) for providing critical review and editing for this manuscript. Scleral Remodeling Represents the Main Locus whereby
the cAMP Levels Affect Myopia Development by
Modulation of Collagen Synthesis Moreover, the AC inhibitor SQ22536 can selectively attenuate the
progression of FDM without affecting normal visual growth. Thus
we hypothesize that inhibition of scleral collagen synthesis is the
cause of myopia development. These findings suggest that
targeting the cAMP control of collagen synthesis and scleral
remodeling may be a novel therapeutic strategy for preventing and
treating myopia. The second line of evidence that the sclera is the locus of myopic
changes is that subconjunctival injection of forskolin did not affect
the ERG parameters of guinea pig eyes. Electroretinography is an
effective test of retinal function. Forskolin-elevated cAMP and
cAMP analogues delivered by intravitreal perfusion increase a-, b-
and c-wave amplitudes in chick and rabbit eyes [52–54]. However,
the absence of retinal response to subconjunctival forskolin
indicated that the development of myopia in guinea pig eyes was
independent of any changes in retinal cAMP levels or functions. It
is likely that compared to the intravitreal perfusion of forskolin by
Jarkman [52] significantly less forskolin permeated through sclera
to the retina in this study. Our previous study found that only
approximately 1/10,000 of the amount of agent (apomorphine)
subconjunctivally injected actually reaches the vitreous [55]. We
speculate that forskolin after subconjunctival injection probably
acted mainly on the sclera, and thus had no significant influence
on retinal function. This finding, together with the selective
increase in cAMP in sclera of FDM eyes, suggests that the sclera,
with fibroblasts as the main cellular components, is probably the
principal locus whereby the cAMP plays a critical role in control of
development of myopia. 1. Goh WS, Lam CS (1994) Changes in refractive trends and optical components
of Hong Kong Chinese aged 19–39 years. Ophthalmic Physiol Opt 14: 378–382.
2. Lin LL, Shih YF, Hsiao CK, Chen CJ (2004) Prevalence of myopia in
Taiwanese schoolchildren: 1983 to 2000. Ann Acad Med Singapore 33: 27–33.
3. Zejmo M, Forminska-Kapuscik M, Pieczara E, Filipek E, Mrukwa-Kominek E,
et al. (2009) Etiopathogenesis and management of high-degree myopia. Part I.
Med Sci Monit 15: RA199–202. Author Contributions Conceived and designed the experiments: YT MP SL FF LR JA XZ JQ. Performed the experiments: YT MP SL FF RL CL MZ JA HX FZ. Analyzed the data: YT MP SL FF RL CL MZ JA HX FZ. Contributed
reagents/materials/analysis tools: JA FZ. Wrote the paper: YT JC XZ JQ. The third line of evidence that the sclera is the locus of myopic
changes is that forskolin treatment reduced the expression of
mRNA for collagens III and V in guinea pig sclera, and it tended cAMP Modulates Scleral Remodeling in Myopia cAMP Modulates Scleral Remodeling in Myopia to reduce the expression for collagen I mRNA. Consistently,
forskolin-elevated cAMP levels reduced the amount of the total
soluble collagen produced and the expression of mRNA for
collagens I, III and V in cultured HSFs. The AC inhibitor
SQ22536 blunts the elevation of cAMP content caused by
forskolin [56]. Consequently in the current study, the decreased
collagen expression by forskolin treatment was partly reversed by
SQ22536 treatment. The reduction of collagen I and V by
forskolin was consistent with the findings in other human
fibroblasts, including dermal, cardiac, and pulmonary fibroblasts
[15–17]. Of note, the regulation of collagen III expression by
forskolin appears to be cell-type specific with a reported increase in
pulmonary fibroblasts [15], but a reduction in cultured fibroblasts
(present study) as well as in cardiac fibroblasts [16] and Schwann
cells [57]. Myopia is characterized by scleral thinning and
decreased scleral collagen synthesis [4,7,12]. In previous studies,
the scleral thinning in myopic eyes of human donors was detected
many years after the myopia developed, and in animal studies, the
myopia was present for several months. Thus in those studies, it is
not clear if the changes in the scleral collagen were consequences
or causes of the myopia. In the present study, we showed that the
alteration of cAMP levels regulated the development of refraction
and the progression of myopia via control over sclera collagen
synthesis. Scleral Remodeling Represents the Main Locus whereby
the cAMP Levels Affect Myopia Development by
Modulation of Collagen Synthesis The cAMP Level in Sclera Plays a Critical Role in Control of
Development of Myopia The cAMP Level in Sclera Plays a Critical Role in Control of
Development of Myopia The most interesting result of this study is the demonstration of
the critical role that cAMP plays in the development of myopia by
controlling scleral remodeling and collagen synthesis. Specifically,
we showed that pharmacological elevation of the cAMP level by
the AC activator forskolin induced axial elongation and refractive
myopic shift in normal guinea pig eyes, but had no effect on the
FDM eyes. Induction of myopia by the forskolin-induced increase
in cAMP level argues that the cAMP level is critical to normal
development of visual growth during postnatal development. Similar to form-deprivation (Fig. 2) or hyperopic-defocus [24], an
above-normal level of cAMP alone is sufficient to induce myopic
changes. This pharmacological finding establishes a causal role of
cAMP level in development of myopia. To the best of our
knowledge, our results provide the first direct evidence that
increases in cAMP level in the eye can cause myopia. August 2013 | Volume 8 | Issue 8 | e71441 PLOS ONE | www.plosone.org 8 cAMP Modulates Scleral Remodeling in Myopia Liu Q, Wu J, Wang X, Zeng J (2007) Changes in muscarinic acetylcholine
receptor expression in form deprivation myopia in guinea pigs. Mol Vis 13:
1234–1244. 14. Wrobel LJ, Dupre A, Raggenbass M Excitatory action of vasopressin in the
brain of the rat: role of cAMP signaling. Neuroscience 172: 177–186. 39. Burford NT, Nahorski SR (1996) Muscarinic m1 receptor-stimulated adenylate
cyclase activity in Chinese hamster ovary cells is mediated by Gs alpha and is not
a consequence of phosphoinositidase C activation. Biochem J 315 (Pt 3): 883–
888. 15. Liu X, Ostrom RS, Insel PA (2004) cAMP-elevating agents and adenylyl cyclase
overexpression promote an antifibrotic phenotype in pulmonary fibroblasts. Am J Physiol Cell Physiol 286: C1089–1099. 40. Galandrin S, Oligny-Longpre G, Bouvier M (2007) The evasive nature of drug
efficacy: implications for drug discovery. Trends Pharmacol Sci 28: 423–430. 16. Liu X, Sun SQ, Hassid A, Ostrom RS (2006) cAMP inhibits transforming
growth factor-beta-stimulated collagen synthesis via inhibition of extracellular
signal-regulated kinase 1/2 and Smad signaling in cardiac fibroblasts. Mol
Pharmacol 70: 1992–2003. 41. Zhou X, Huang Q, An J, Lu R, Qin X, et al. (2010) Genetic deletion of the
adenosine A2A receptor confers postnatal development of relative myopia in
mice. Invest Ophthalmol Vis Sci 51: 4362–4370. 42. Che J, Chan ES, Cronstein BN (2007) Adenosine A2A receptor occupancy
stimulates collagen expression by hepatic stellate cells via pathways involving
protein kinase A, Src, and extracellular signal-regulated kinases 1/2 signaling
cascade or p38 mitogen-activated protein kinase signaling pathway. Mol
Pharmacol 72: 1626–1636. 17. Schiller M, Dennler S, Anderegg U, Kokot A, Simon JC, et al. (2010) Increased
cAMP levels modulate transforming growth factor-beta/Smad-induced expres-
sion of extracellular matrix components and other key fibroblast effector
functions. J Biol Chem 285: 409–421. 18. Lu F, Zhou X, Zhao H, Wang R, Jia D, et al. (2006) Axial myopia induced by a
monocularly-deprived facemask in guinea pigs: A non-invasive and effective
model. Exp Eye Res 82: 628–636. 43. Neufeld AH, Sears ML (1974) Cyclic-AMP in ocular tissues of the rabbit,
monkey, and human. Invest Ophthalmol 13: 475–477. p
y
19. Jiang L, Schaeffel F, Zhou X, Zhang S, Jin X, et al. (2009) Spontaneous axial
myopia and emmetropization in a strain of wild-type guinea pig (Cavia
porcellus). Invest Ophthalmol Vis Sci 50: 1013–1019. 44. cAMP Modulates Scleral Remodeling in Myopia 7. McBrien NA, Cornell LM, Gentle A (2001) Structural and ultrastructural
changes to the sclera in a mammalian model of high myopia. Invest Ophthalmol
Vis Sci 42: 2179–2187. 32. McBrien NA, Moghaddam HO, Reeder AP (1993) Atropine reduces
experimental myopia and eye enlargement via a nonaccommodative mecha-
nism. Invest Ophthalmol Vis Sci 34: 205–215. 8. Curtin BJ, Iwamoto T, Renaldo DP (1979) Normal and staphylomatous sclera of
high myopia. An electron microscopic study. Arch Ophthalmol 97: 912–915. p
33. Leech EM, Cottriall CL, McBrien NA (1995) Pirenzepine prevents form
deprivation myopia in a dose dependent manner. Ophthalmic Physiol Opt 15:
351–356. gh myopia. An electron microscopic study. Arch Ophthalmol 97: 912 g
y p
p
y
p
9. Funata M, Tokoro T (1990) Scleral change in experimentally myopic monkeys. Graefes Arch Clin Exp Ophthalmol 228: 174–179. g
y p
p
y
p
9. Funata M, Tokoro T (1990) Scleral change in experim
Graefes Arch Clin Exp Ophthalmol 228: 174–179. 34. Rickers M, Schaeffel F (1995) Dose-dependent effects of intravitreal pirenzepine
on deprivation myopia and lens-induced refractive errors in chickens. Exp Eye
Res 61: 509–516. Graefes Arch Clin Exp Ophthalmol 228: 174–179. 10. McBrien NA, Lawlor P, Gentle A (2000) Scleral remodeling during the
development of and recovery from axial myopia in the tree shrew. Invest
Ophthalmol Vis Sci 41: 3713–3719. 35. Chua WH, Balakrishnan V, Chan YH, Tong L, Ling Y, et al. (2006) Atropine
for the treatment of childhood myopia. Ophthalmology 113: 2285–2291. p
11. Rada JA, Nickla DL, Troilo D (2000) Decreased proteoglycan synthesis
associated with form deprivation myopia in mature primate eyes. Invest
Ophthalmol Vis Sci 41: 2050–2058. 36. Wu PC, Yang YH, Fang PC (2011) The long-term results of using low-
concentration atropine eye drops for controlling myopia progression in
schoolchildren. J Ocul Pharmacol Ther 27: 461–466. 12. Troilo D, Nickla DL, Mertz JR, Summers Rada JA (2006) Change in the
synthesis rates of ocular retinoic acid and scleral glycosaminoglycan during
experimentally altered eye growth in marmosets. Invest Ophthalmol Vis Sci 47:
1768–1777. 37. Hakonarson H, Grant SF, Bradfield JP, Marchand L, Kim CE, et al. (2007) A
genome-wide association study identifies KIAA0350 as a type 1 diabetes gene. Nature 448: 591–594. 13. Koyanagi M, Takano K, Tsukamoto H, Ohtsu K, Tokunaga F, et al. (2008)
Jellyfish vision starts with cAMP signaling mediated by opsin-G(s) cascade. Proc
Natl Acad Sci U S A 105: 15576–15580. 38. cAMP Modulates Scleral Remodeling in Myopia Neufeld AH, Dueker DK, Vegge T, Sears ML (1975) Adenosine 39,59-
monophosphate increases the outflow of aqueous humor from the rabbit eye. Invest Ophthalmol 14: 40–42. p
45. Neufeld AH, Sears ML (1975) Adenosine 39,59-monophosphate analogue
increases the outflow facility of the primate eye. Invest Ophthalmol 14: 688–689. p
)
p
20. Zhou X, Qu J, Xie R, Wang R, Jiang L, et al. (2006) Normal development of
refractive state and ocular dimensions in guinea pigs. Vision Res 46: 2815–2823. 46. Edwards MH, Brown B (1996) IOP in myopic children: the relationship between
increases in IOP and the development of myopia. Ophthalmic Physiol Opt 16:
243–246. 21. Qu J, Zhou X, Xie R, Zhang L, Hu D, et al. (2006) The presence of m1 to m5
receptors in human sclera: evidence of the sclera as a potential site of action for
muscarinic receptor antagonists. Curr Eye Res 31: 587–597. 47. Quinn GE, Berlin JA, Young TL, Ziylan S, Stone RA (1995) Association of
intraocular pressure and myopia in children. Ophthalmology 102: 180–185. 22. Lu F, Zhou X, Xie R, Wu Y, Hu Y, et al. (2007) Feasibility of two-dimensional
gel electrophoresis used for proteomic analysis of human scleral fibroblasts. Curr
Eye Res 32: 319–329. 48. Lee AJ, Saw SM, Gazzard G, Cheng A, Tan DT (2004) Intraocular pressure
associations with refractive error and axial length in children. Br J Ophthalmol
88: 5–7. y
23. Swaney JS, Roth DM, Olson ER, Naugle JE, Meszaros JG, et al. (2005)
Inhibition of cardiac myofibroblast formation and collagen synthesis by
activation and overexpression of adenylyl cyclase. Proc Natl Acad Sci U S A
102: 437–442. 49. Puell-Marin MC, Romero-Martin M, Dominguez-Carmona M (1997) Intraoc-
ular pressure in 528 university students: effect of refractive error. J Am Optom
Assoc 68: 657–662. 24. Lu F, Zhou X, Jiang L, Fu Y, Lai X, et al. (2009) Axial myopia induced by
hyperopic defocus in guinea pigs: A detailed assessment on susceptibility and
recovery. Exp Eye Res 89: 101–108. 50. Manny RE, Mitchell GL, Cotter SA, Jones-Jordan LA, Kleinstein RN, et al. Intraocular pressure, ethnicity, and refractive error. Optom Vis Sci 88: 1445–
1453. y
p
y
25. Yamamoto M, Gotz ME, Ozawa H, Luckhaus C, Saito T, et al. (2000)
Hippocampal level of neural specific adenylyl cyclase type I is decreased in
Alzheimer’s disease. Biochim Biophys Acta 1535: 60–68. 51. cAMP Modulates Scleral Remodeling in Myopia Siegwart JT, Jr., Norton TT (1999) Regulation of the mechanical properties of
tree shrew sclera by the visual environment. Vision Res 39: 387–407. p y
26. Mons N, Guillou JL, Decorte L, Jaffard R (2003) Spatial learning induces
differential changes in calcium/calmodulin-stimulated (ACI) and calcium-
insensitive (ACII) adenylyl cyclases in the mouse hippocampus. Neurobiol
Learn Mem 79: 226–235. y
52. Jarkman S (1987) Effects of low doses of forskolin on the c-wave of the direct
current electroretinogram and on the standing potential of the eye. Doc
Ophthalmol 67: 305–314. 53. Bragadottir R, Jarkman S (1995) A cyclic adenosine monophosphate agonist
elevates the b- and c-waves of the rabbit direct-current electroretinogram. Doc
Ophthalmol 90: 291–303. 27. Iwatsubo K, Minamisawa S, Tsunematsu T, Nakagome M, Toya Y, et al. (2004)
Direct inhibition of type 5 adenylyl cyclase prevents myocardial apoptosis
without functional deterioration. J Biol Chem 279: 40938–40945. p
54. Nao-i N, Gallemore RP, Steinberg RH (1990) Effects of cAMP and IBMX on
the chick retinal pigment epithelium. Membrane potentials and light-evoked
responses. Invest Ophthalmol Vis Sci 31: 54–66. 28. Gao MH, Tang T, Guo T, Miyanohara A, Yajima T, et al. (2008) Adenylyl
cyclase type VI increases Akt activity and phospholamban phosphorylation in
cardiac myocytes. J Biol Chem 283: 33527–33535. responses. Invest Ophthalmol Vis Sci 31: 54–66. 55. Dong F, Zhi Z, Pan M, Xie R, Qin X, et al. (2011) Inhibition of experimental
myopia by a dopamine agonist: different effectiveness between form deprivation
and hyperopic defocus in guinea pigs. Mol Vis 17: 2824–2834. y
y
J
29. Lai NC, Tang T, Gao MH, Saito M, Takahashi T, et al. (2008) Activation of
cardiac adenylyl cyclase expression increases function of the failing ischemic
heart in mice. J Am Coll Cardiol 51: 1490–1497. y p
y
p
g
and hyperopic defocus in guinea pigs. Mol Vis 17: 2824–2834. 56. Gao Y, Raj JU (2001) SQ22536 and W-7 inhibit forskolin-induced cAMP
elevation but not relaxation in newborn ovine pulmonary veins. Eur J Pharmacol
418: 111–116. 30. Nickla DL, Totonelly K, Dhillon B (2010) Dopaminergic agonists that result in
ocular growth inhibition also elicit transient increases in choroidal thickness in
chicks. Experimental eye research 91: 715–720. 57. Yamamoto M, Sobue G, Li M, Mitsuma T, Kimata K, et al. (1994) cAMP-
dependent differential regulation of extracellular matrix (ECM) gene expression
in cultured rat Schwann cells. Brain Res 653: 335–339. p
y
31. References August 2013 | Volume 8 | Issue 8 | e71441 August 2013 | Volume 8 | Issue 8 | e71441 PLOS ONE | www.plosone.org 9 cAMP Modulates Scleral Remodeling in Myopia Missale C, Nash SR, Robinson SW, Jaber M, Caron MG (1998) Dopamine
receptors: from structure to function. Physiol Rev 78: 189–225. August 2013 | Volume 8 | Issue 8 | e71441 10 PLOS ONE | www.plosone.org
|
https://openalex.org/W4360615346
|
https://digital.csic.es/bitstream/10261/308022/1/agronomy-13-00950-v2.pdf
|
English
| null |
Sustainable Management of Anaerobic Digestate: From Biogas Plant to Full-Scale Cultivation of Pleurotus ostreatus
|
Agronomy
| 2,023
|
cc-by
| 14,162
|
Citation: Zuffi, V.; Puliga, F.;
Zambonelli, A.; Trincone, L.;
Sanchez-Cortes, S.; Francioso, O. Sustainable Management of
Anaerobic Digestate: From Biogas
Plant to Full-Scale Cultivation of
Pleurotus ostreatus. Agronomy 2023, 13,
950. https://doi.org/10.3390/
agronomy13040950 Keywords: by-products; agro-waste; biomass valorization; circular economy; mushroom cultivation;
SERS spectroscopy; ATR-FTIR Academic Editor: Gerardo Fernández
Barbero Sustainable Management of Anaerobic Digestate: From Biogas
Plant to Full-Scale Cultivation of Pleurotus ostreatus Veronica Zuffi1,*
, Federico Puliga 1
, Alessandra Zambonelli 1
, Lorenzo Trincone 1,
S
ti
S
h
C
t
2
d O
ll F
i
1 Veronica Zuffi1,*
, Federico Puliga 1
, Alessandra Zambonelli 1
, Lorenzo Trincone 1
Santiago Sanchez-Cortes 2
and Ornella Francioso 1 1
Department of Agricultural and Food Sciences, University of Bologna, Viale G. Fanin 40-50,
40127 Bologna, Italy; federico.puliga2@unibo.it (F.P.); alessandr.zambonelli@unibo.it (A.Z.);
lorenzo.trincone@studio.unibo.it (L.T.); ornella.francioso@unibo.it (O.F.) (
);
(
)
2
Instituto de Estructura de la Materia, Consejo Superior de Investigaciones Cientificas (IEM-CSIC
Serrano, 121, E-28006 Madrid, Spain; s.sanchez.cortes@csic.es p
*
Correspondence: veronica.zuffi3@unibo.it Abstract: In the last decades, the number of studies about the valorization of agricultural by-products
has strongly increased due to the growing focus on the circular economy. In this context, mushroom
cultivation is raising attention for its nutritional properties and adaptability to different growing
conditions. The goal of this project is, therefore, to create a link between two production chains,
valorizing the solid anaerobic digestate fraction from the biogas plant as a potential substrate for
Pleurotus ostreatus full-scale cultivation. A preliminary in vitro trial shows that the mycelia can
colonize at the same rate in both the conventional substrate, which was wheat straw added with
sunflower cake and the experimental ones supplemented with corn digestate. The most important
and innovative part of the work was full-scale cultivation. Quantitative analyses demonstrate that
P. ostreatus is capable of growing on the conventional substrate as well as on the substrate containing
15% of digestate without reducing the mushroom harvest. Even better, digestate seems to stimulate a
precocious and more homogeneous production. Chemical and spectroscopic analyses on the fruiting
bodies confirm the results; in fact, mushrooms show a comparable structural composition, highlighted
with FTIR and SERS spectroscopic evaluations. Moreover, the nutrient content did not change due to
the addition of digestate. These promising results demonstrate that anaerobic digestate can become a
resource for P. ostreatus cultivation without production losses and maintaining the same qualitative
characteristics. agronomy agronomy agronomy agronomy agronomy Citation: Zuffi, V.; Puliga, F.;
Zambonelli, A.; Trincone, L.;
Sanchez-Cortes, S.; Francioso, O.
Sustainable Management of
Anaerobic Digestate: From Biogas
Plant to Full-Scale Cultivation of
Pleurotus ostreatus. Agronomy 2023, 13,
950. https://doi.org/10.3390/
agronomy13040950 1. Introduction In recent years the nutritional value and the sustainability of the food chain are
becoming increasingly relevant; consumers search for more healthy food whose production
has a low environmental footprint in terms of greenhouse gasses emissions (GHG) and
biodiversity preservation [1]. In this context, mushrooms have received great attention for
their medicinal and nutritional properties; they are, indeed, rich in protein, essential amino
acids, vitamins, and fiber and, at the same time, low in calories and fat [2–4]. Moreover,
their cultivation is not so impactful, considering the energy input, the land usage, and the
growth time required [5]. For these reasons, mushroom production has strongly increased
in the last decades, reaching a global production of approximately 9 million tons in 2018 [6],
and it is expected to continue growing in the next years [7]. Received: 22 February 2023
Revised: 20 March 2023
Accepted: 21 March 2023
Published: 23 March 2023 Copyright:
© 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article
distributed
under
the
terms
and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/). Nowadays, to effectively face climate change, more and more industries have to re-
evaluate their production processes. In accordance with the above, mushroom cultivation
can be easily placed in the context of a circular economy. Placing the focus on the growing
substrates, waste matrices different from those commonly used have been tested with https://www.mdpi.com/journal/agronomy Agronomy 2023, 13, 950. https://doi.org/10.3390/agronomy13040950 Agronomy 2023, 13, 950 2 of 19 the purpose of reducing costs in the meantime valorizing by-products from other supply
chains [8,9]. Agriculture is one of the main activities that produce large volumes of by-products
every year. Most of these residues remain underutilized and usually are disposed of in
landfills or burned, becoming a risk to the environment [10,11]. In recent years, great
attention has been given to innovative agricultural or correlated activities [12] commonly
considered sustainable, such as the biogas industry [13]. The European Commission,
in the REPowerEU plan, calls for a rapid speed-up of renewable energy that includes
35 billion biomethane by 2030 and a new biomethane industry partnership to “support
the achievement of the target and set the stage for further increase towards 2050” [14]. Although its potential as a renewable resource, the sustainability of its production also
depends on waste management, mainly represented by anaerobic digestate. It is estimated
that its production reaches almost 180 million tons per year only in Europe [15]. This
by-product is principally used as an amendment or fertilizer since it is rich in macro- and
micro-elements and it is an important source of organic matter. However, its land spreading
is strictly regulated (Nitrate Directive 91/676/ECC) to protect vulnerable areas from nitrate
pollution. Other critical issues are the variability of the starting matrices as well as the
degradation rate, which makes digestate not always suitable for direct usage [13,16,17]. As
reported by Dahlin et al. (2015) [18], the high productivity and potential of this product
without any alternative application may cripple the industry. Hence, it seems essential to
research other methods to manage and valorize digestate in view of the environmental and
economic sustainability of the biogas production chain. The fungi of the genus Pleurotus, commonly known as oyster mushrooms, are among
the most cultivated mushrooms worldwide [19]. Their adaptability to various growing
conditions makes their cultivation easier compared to others. For example, they generally
require a short growth time, tolerate a wide range of temperatures and chemical input,
and are not often attacked by pathogens [20]. In addition, as saprotrophs, they naturally
grow on waste or dead substrates for which they are primary decomposers thanks to
their complex enzyme machinery (e.g., laccase, endoglucanase enzymes) [10,21]. In fact,
it has been observed that many Pleurotus spp. can degrade macromolecules such as
cellulose, hemicellulose, and lignin which are the main compounds of vegetable residues [8]. Concerning the industrial production of Pleurotus mushrooms, the principal matrix used is
wheat straw [22]; however, diversifying the growing media may represent an economic
advantage so as to create a new chain of products and support local economies, perhaps
minimizing transport requirements. Several previous works have shown that different species of Pleurotus are able to grow
on various agro-residues, including grape pomace [2], hazelnut shells [23], banana leaves,
sunflower stalk, cotton stalk, and sugar cane straw, proving their potentiality [10]. The
mycelial growth of different fungi on digestate, including Pleurotus spp., has already been
demonstrated in previous works [24,25]. Nevertheless, there is a general lack of research
on the industrial application of this promising cultivation substrate. pp
p
g
The purpose of this study is, therefore, to explore the potential of solid anaerobic
digestate as an alternative substrate for industrial-scale cultivation of mushrooms. The key
point is the recycling of agricultural waste to create new products with high added value. In this perspective, a strain of Pleurotus ostreatus (Jacq.) P. Kumm., the most popular oyster
mushroom, was grown on corn silage digestate in vitro and in vivo trials. The adaptability
of full-scale cultivation was tested in an industrial mushroom company, which is also near
the biogas plant, in order to minimize transport costs and sustain the local economy. To
this end, the productivity, biological efficiency, and quality parameters of the mushrooms
were evaluated and compared with those cultivated on a conventional substrate. Fourier
transform infrared spectroscopy (FTIR) was employed to explore the substrates before and
after cultivation as well as the molecular structure of the fruiting bodies. Additionally,
Surface-enhanced Raman spectroscopy (SERS) was used to analyze the polysaccharides of
the fruiting bodies. Actually, these methods have been successfully proven for the study Agronomy 2023, 13, 950 3 of 19 3 of 19 of organic material as well as for biological tissues [26–28]. Specifically, SERS is a highly
sensitive vibrational technique that, thanks to the use of nanostructured metals (Au and Ag),
permits a better and more rapid detection of trace amounts of molecules, including some
typical fungal compounds, as previously reported by Fornasaro et al. (2021) and Puliga
et al. (2022) [29–32]. The efficiency of SERS is based on the interaction between the incident
light and the metal nanostructures resulting in the so-called localized surface plasmon
resonance effect. This resonance leads to a strong enhancement of the Raman scattering up
to 1014 orders of magnitude in comparison to the normal Raman spectroscopy. [33,34]. This
enhancement strongly depends on the optical properties of the nanostructures provided
by the metal nature, the nanoparticle size and shape, as well as on the laser excitation
wavelength and the Raman cross sections of analytes [35,36]. 2. Materials and Methods
2.1. Substrates Durum wheat straw (Triticum durum Desf., WS) and sunflower cake (SC) were supplied
by Funghitex company (Latina, Italy). The SC is added to 2–4% of the total weight of the
dry straw. Durum wheat straw (Triticum durum Desf., WS) and sunflower cake (SC) were supplied
by Funghitex company (Latina, Italy). The SC is added to 2–4% of the total weight of the
dry straw. y
Corn digestate was kindly provided by the Mascetti-Sbardella farm, which is located
in Latina, Italy. The biogas plant can be defined as of compact dimension since it works
with high concentrations of substrate, and it can produce around one million kWh/year
of gross renewable electric energy. The plant is fed primarily with energy crops such as
maize or alfa-alfa and, to a small extent, with olive pomace and horticultural wastes. The
digestate for this study was obtained in January and collected as soon as it fell out of the
mechanical separation and mixed for 24 h. 2.2. Mycelial Cultures and Growth Rate Evaluation The commercial strain of P. ostreatus (W.H.90 from White2000) was provided by Funghi-
tex company. One grain spawn was inoculated in each Petri dish with 20 g/L of Potato
Dextrose Agar (PDA) added with 0.3 mg/mL of streptomycin sulfate. After one week,
the mycelia were transferred to a new Petri dish with another antibiotic (0.3 mg/mL of
chloramphenicol). The pure mycelial cultures were kept at 22 ± 1 ◦C in darkness and
subcultured every 60 d. To evaluate the mycelial growth on the plate, a 9 cm sterilized Petri dish was filled with
the different substrates: digestate (D), wheat straw added with sunflower cake (WS + SC)
as control, WS + SC 80% −D 20% (D20), WS + SC 90% −D 10% (D10). After that, plugs
of 10 mm diameter were taken by 15-day-old colonies and inoculated in the center of the
plates. To evaluate the growth on the plate, the substrates were previously soaked for
30 min with distilled water and brought to 70–80% humidity. An amount of almost 30 g
of each substrate was transferred to a Petri dish and autoclaved at 121 ◦C for 1 h. Five
replicates were made for each experimental sample and incubated at 22 ± 1 ◦C in darkness. To assess the fungal growth, we measured the diameter of the colony along two preset
diametrical lines every day. The mycelium colony area (A, cm2) was calculated assuming
an elliptical shape using the following formula: A = π × R1 × R2
(1) (1) where R1 and R2 are the two perpendicular radii, respectively [37]. The area growth rate (AGR) was calculated through the formula: where R1 and R2 are the two perpendicular radii, respectively [37]. where R1 and R2 are the two perpendicular radii, respectively [37]. The area growth rate (AGR) was calculated through the formula: The area growth rate (AGR) was calculated through the formula: AGR = (Af −Ai)
(Tf −Ti)
(2) (2) as described by Sinclair and Cantero [38], where Af and Ai are the colony area at the final
growth time (Tf) and initial growth time (Ti), respectively. Agronomy 2023, 13, 950 4 of 19 2.3. Preparation of Substrates for Full-Scale Mushroom Cultivation Full-scale cultivation was performed directly at the Funghitex farm. For the fruiting
body production, two substrates were tested, WS + SC as the control and WS added with
15% of digestate (D15) as the experimental one. 2.2. Mycelial Cultures and Growth Rate Evaluation For both trials (WS + SC and D15), wheat straw was previously crushed into small
portions and mixed with sunflower cake pellets (4% of WS dry weight). The mix was then
hydrated and stored for 12 h to drain excess water and to reach a humidity content of about
75% [39]. Subsequently, it was subjected to a first controlled aerobic fermentation; after
36 h, the substrate was amalgamated and transferred in a second fermentation tunnel, thus
avoiding anaerobic conditions. The second phase was pasteurization, which is essential to
prevent pathogen contamination. This process includes a first step around 72–74 ◦C with
water vapor insufflation. Then the substrate was conditioned to 48 ◦C for 24 h through
the addition of cool air filtered with a High Efficiency Particulate Air (HEPA) filter. The
aim is to stimulate the growth of positive spontaneous Actinomycetes, which compete
with other microorganisms and maintain low temperatures. After the pasteurization, the
optimal sowing parameters must be reached, around 20–26 ◦C, 75% of humidity, and pH
greater than 8. g
The starting matrix was composed of sterilized millet grain inoculated with the P. os-
treatus strain W.H.90. The cultivation bags consisted of 20 L of millet grains (11.2 kg) per
ton of substrate. For the experimental substrate (D15), the addition of a 15% digestate mixture was
chosen for a dry weight of wheat straw. The choice of this percentage was made in
accordance with the company based on the outcome obtained from the mycelial cultivation
and with the purpose of starting testing this new compound on a full scale. The mix was
then fermented and pasteurized to avoid pathogen contamination, as described in the
previous section. p
Bags were moved to a climate chamber for the incubation phase. The environmental
conditions were maintained to optimum levels for P. ostreatus development (~20 ◦C for the
colonization, ~13–15 ◦C for fruiting, and relative humidity 80–85%) as described by Oei
(2003) [39]. 2.3.2. Mushroom Parameters 2.3.2. Mushroom Parameters The mature fruiting bodies were collected after one month, and their fresh weight was
recorded. For the dry weight, a sample of mushrooms was collected from each row and
dried in a stove at 40 ◦C for 48 h. The fresh weight of the substrate was measured before
the cultivation. The dry weight is obtained by the fresh weight divided by the coefficient
2.5 corresponding to the company’s standard moisture content. This coefficient is based
on a number of statistically validated measurements made previously by the company
to standardize the dry weight of the bags. Biological efficiency (BE, %) was estimated
as follows: BE =
Mushroom Fresh Weight
Substrate Dry Weight
× 100
(3) (3) The precociousness (P) was calculated as the yield in the first half of harvest time
divided by the yield in total harvest time and represented a measure of the yield at the mid-
cycle of the production (higher values mean better P) as previously reported by Janinska
et al. (2022) [40]. 2.4. Chemical Analyses of Substrates and Mushrooms 2.3.1. Experimental Design The experimental design was organized into 8 rows randomly divided into 4 control
rows with WS + SC and 4 with D15. Each row consisted of 15 bags stacked in threes, for a
total amount of 60 bags (Figure 1). VIEW
5 of 20 Figure 1. Mushroom growing room at the Funghitex company (Photo courtesy of Funghitex). Figure 1. Mushroom growing room at the Funghitex company (Photo courtesy of Funghitex). Figure 1. Mushroom growing room at the Funghitex company (Photo courtesy of Funghitex). Figure 1. Mushroom growing room at the Funghitex company (Photo courtesy of Funghitex). Agronomy 2023, 13, 950 5 of 19 2.4. Chemical Analyses of Substrates and Mushrooms Total carbon and nitrogen contents of substrates, previously finely ground by a ball
mill, were carried out by an elemental analyzer (CHNS-O EA 1110 Thermo Fisher Scientific,
Waltham, MA, USA). The concentration of ammonium nitrogen was performed according
to APHA (1992). Metal contents were determined in finely ground substrates and mushrooms (500–700 mg). The samples were kept in a Teflon tube with HNO3 suprapur (Carlo Erba Reagents Srl,
Milan, IT) and H2O2 (30%) in a microwave oven for acid digestion (Milestone, Shelton, CT,
USA), according to the procedure described by Cocchi et al. (2006) [41]. After mineraliza-
tion, the samples were diluted with Milli-Q® ultrapure distilled water. Each element was
assayed via Inductive Coupled Plasma-Optic Emission Spectroscopy (Spectro Amatek Ar-
cos II ICP-OES, Kleve, Germany). All analyses were performed in triplicate. The pH values
were determined by a digital pH meter using a 1:2 sample-to-water ratio. Additionally, the
fruiting bodies were examined for the presence of coliform bacteria according to ISO 4832
(2006) and agrochemical residues according to UNI EN 15662 (2018). 2.4.1. ATR-FTIR Spectroscopy Different substrates before P. ostreatus inoculation and after 30 d of mycelial growth
and fruiting bodies after full-scale cultivation were characterized by using a Bruker Tensor
FTIR instrument (Bruker Optics, Ettlingen, Germany) equipped with an Attenuated Total
Reflectance (ATR) accessory (Specac Quest ATR, Specac Ltd., Orpington, Kent, UK). The
sampling device contained a microDiamond crystal, a single reflection with an angle of
incidence of 45◦, and a penetration of around 2 µm. The spectra were acquired against
a pre-established background by averaging 64 scans from 4000 to 400 cm−1 at a 4 cm−1
resolution. Grams/386 spectroscopic software (version 6.00, Galactic Industries Corporation,
Salem, NH, USA) was used for spectra processing. 2.4.2. Polysaccharides Extraction The extraction of polysaccharides from the fruiting bodies was carried out as described
by Puliga et al. (2022) [30]. Briefly, the powder was immersed in an 85% ethanol solution
and treated overnight. The samples follow a first centrifugation at 4500× g for 15 min
and then an extraction in distilled water (25 mL for each g of precipitate) at 70 ◦C for
140 min. The second centrifugation was carried out for 10 min at 4500× g. The supernatant
was deproteinized using a Sevag reagent (butanol:chloroform, 1:4 v/v) and centrifuged at
4500× g for 10 min. The precipitation of crude polysaccharides was obtained by removing
the upper layer of the centrifugate and mixing that with a four-fold volume of absolute Agronomy 2023, 13, 950 6 of 19 ethanol for 12 h at 4 ◦C. Finally, another centrifugation was conducted, and the precipitate
was washed with ethanol and acetone, and lyophilized. ethanol for 12 h at 4 ◦C. Finally, another centrifugation was conducted, and the precipitate
was washed with ethanol and acetone, and lyophilized. 2.5. Statistical Analyses Statistical analyses were carried out using the RStudio graphical interface for the
R software environment v.4.2.1 (R Foundation, Vienna, Austria). Preliminary tests were
performed in order to evaluate the data, such as Shapiro and Levene tests. The analysis of
variance (ANOVA) was used to determine the significant difference in fresh weight, AGR,
and BE among different growing media. Tukey post hoc test (p < 0.05) was used to compare
AGR means. 2.4.3. SERS Analyses To carry out SERS analyses, silver nanoparticles were prepared as previously described
by Leopold and Lendl (2003) [42]. For sample preparation, small portions of dry fruiting
bodies, supplemented with 1 mL of Milli-Q® ultrapure distilled water, were soaked for
24 h into a 1.5 mL microtube, centrifuged at 11,000 × g for 10 min and, in the end, all the
water was removed. The wet portions were next deposited on a microscope slide glass and
coated with 5 µL of a concentrated Ag-NPs suspension. This last was previously obtained
by centrifugation of 500 µL and successive redispersion to 10% of the initial volume, as
described by Puliga et al. (2022) [30]. Prior to SERS analyses, the resulting samples were
dried at room temperature. SERS measurements were performed by using the portable spectrometer Raman
Virsa™(Renishaw, Wotton-under-Edge, UK) with a 785 nm laser. Prior to the analysis, a
calibration of the instrument was needed by using a Si reference sample. A 50× objective
long focal lens with the laser power set at 2 mW and an integration time of 10 s was
employed to analyze the mushroom fragments. 1 Abbreviations: OC—organic carbon, N tot—total nitrogen, d.m.—dry matter, n.d.—not detected. If not specified,
the error value is less than 0.05%. 3. Results 3.1. Chemical and Spectroscopical Analyses of the Substrates 3.1. Chemical and Spectroscopical Analyses of the Substrates Figure 2. ATR-FTIR spectra of WS + SC (blue line) and D (orange line) before the cultivation. Figure 2. ATR-FTIR spectra of WS + SC (blue line) and D (orange line) before the cultivation. In addition, connected to the structure of the polysaccharides, there are two bands at
1421 cm−1 and 1319 cm−1 assigned to CH2 bending at C-6 of the crystalline cellulose, and a
In addition, connected to the structure of the polysaccharides, there are two bands at
1421 cm−1 and 1319 cm−1 assigned to CH2 bending at C-6 of the crystalline cellulose, and
a peak at 1375 cm−1 associated with CH2 bending vibrations in cellulose and hemicellu-
lose [24]. A small band at 1733 cm−1 is observed, probably ascribed to the C=O stretching
vibration in the ester linkage connected to the hemicellulose structure [43,44]. Lastly, the
peak around 898 cm−1, in either WS + SC and D and that at 875 cm−1 in WS + SC, are
related to C-H deformation in cellulose. Another fundamental compound detectable in
both matrices is lignin. Although it is more evident in D, both spectra show two bands
around 1590 and 1510 cm−1 attributed to the aromatic skeletal vibration and aromatic
breathing in lignin, respectively [43]. The broad peak around 1640 cm−1 is possibly due
to C=O stretching in conjugated ketones, water, and Amide I (proteins), while that at
1550 cm−1 is attributed to Amide II (proteins) [24,45]. 3.1. Chemical and Spectroscopical Analyses of the Substrates Table 1 provides the results obtained from the chemical analyses of the two matrices. Organic carbon content was approximately 40% in WS + SC as in D. The total amount
of nitrogen was much higher in D (1.20%) as compared to WS + SC (0.48%). Further on,
D appears to be rich in some macroelements such as N, P, S, and K as well, as it shows
a high content in some microelements like Na, Mg, Zn, and Mn. On the other hand, the
conventional substrate seems to have a similar composition in K, Cu, Zn, and Mn, whereas
the amount of Ca and Fe is higher. The pH value tends to neutrality in WS + SC, while D is
more alkaline, possibly due to the NH4+ and carbonate components. Table 1. Chemical analyses of the conventional substrate (WS + SC) and digestate (D). Parameters 1
Unit
WS + SC
D
OC
% d.m. 40.15 ± 0.002
37.66 ± 0.96
N tot
% d.m. 0.48 ± 0.001
1.20 ± 0.005
NH4+
% d.m. n.d. 0.27
pH
6.5
9.06
P
mg/kg
334
2417
S
mg/kg
617
1148
K
mg/kg
6328
6514
Na
mg/kg
150
1598
Ca
mg/kg
10,147
4863
Mg
mg/kg
992
1598
Fe
mg/kg
1401
595
Cu
mg/kg
7
9
Zn
mg/kg
29
47
Mn
mg/kg
53
67
1 Abbreviations: OC—organic carbon, N tot—total nitrogen, d.m.—dry matter, n.d.—not detected. If not specified,
the error value is less than 0.05%. 1. Chemical analyses of the conventional substrate (WS + SC) and digestate (D). 7 of 19
ected. 7 of 19
ected. Agronomy 2023, 13, 950 The ATR-FTIR spectra (1800–850 cm−1) of the starting substrates are shown in Figure 2. The spectroscopic analysis of both WS + SC and D reveals a predominant peak at 1029 and
1038 cm−1, respectively, which is characteristic of the polysaccharide region (cellulose and
hemicellulose) for C-O and C-H group deformations [24,43]. The ATR-FTIR spectra (1800–850 cm−1) of the starting substrates are shown in Figure
2. The spectroscopic analysis of both WS + SC and D reveals a predominant peak at 1029
and 1038 cm−1, respectively, which is characteristic of the polysaccharide region (cellulose
and hemicellulose) for C-O and C-H group deformations [24,43]. Figure 2. ATR-FTIR spectra of WS + SC (blue line) and D (orange line) before the cultivation. Figure 2. ATR-FTIR spectra of WS + SC (blue line) and D (orange line) before the cultivation. 3.2. In Vitro Mycelial Growth of P. ostreatus and ATR-FTIR of Exhausted Substrates The in vitro mycelial growth of P. ostreatus on four different substrates (WS + SC, D10,
D20, and D) is illustrated in Figure 3. It is apparent from the trend that the complete
colonization of the plate took almost two weeks. The exponential phase in which the
growth is more rapid ends around day 10 for all the tested substrates, although D seems to
stimulate a faster initial development. Agronomy 2023, 13, 950 8 of 19
wth
tim- Figure 3. Mycelial growth and AGR of P. ostreatus in Petri dishes on WS + SC (blue), D10 (orange),
D20 (green), and D (yellow). Statistical differences (p < 0.05) between D-D10. Figure 3. Mycelial growth and AGR of P. ostreatus in Petri dishes on WS + SC (blue), D10 (orange),
D20 (green), and D (yellow). Statistical differences (p < 0.05) between D-D10. igure 3. Mycelial growth and AGR of P. ostreatus in Petri dishes on WS + SC (blue), D10 (orange),
20 (green), and D (yellow). Statistical differences (p < 0.05) between D-D10. Figure 3. Mycelial growth and AGR of P. ostreatus in Petri dishes on WS + SC (blue), D10 (orange),
D20 (green), and D (yellow). Statistical differences (p < 0.05) between D-D10. To corroborate this hypothesis, an ANOVA test was performed among different
AGRs calculated. From the box plot, statistical differences were observed only between D
nd D10. Despite this, D shows high values of AGR in some cases, up to 6 cm2/d. To corroborate this hypothesis, an ANOVA test was performed among different AGRs
calculated. From the box plot, statistical differences were observed only between D and
D10. Despite this, D shows high values of AGR in some cases, up to 6 cm2/d. nd D10. Despite this, D shows high values of AGR in some cases, up to 6 cm /d. In order to evaluate changes in the molecular structure of the matrices used, the ATR-
TIR spectra after 30 d of cultivation were compared to that of the starting substrates (Fig-
re 2). Figure 4 shows a specific spectral range, between 1800–1300 cm−1, where the main
ifferences were observed. As can be seen from Figure 4a, WS + SC exhibits consistent
tructural variation in this region. 3.2. In Vitro Mycelial Growth of P. ostreatus and ATR-FTIR of Exhausted Substrates Specifically, the spectrum highlights a decrease of the
bsorption band at 1507 cm−1 corresponding to the aromatic skeletal vibration as well as
hose at 1454 and 1421 cm−1, which derive from C-H bending in lignin. In addition, an
mportant reduction in the peak at 1733 cm−1 may be ascribed to p-coumaric acids in the
gnin structure and likewise to the ester group in hemicellulose. The enhancement of the
and at 1322 cm−1 due to C-H bending vibration, as well as that at around 1643 cm−1, as-
igned to C=O stretching in conjugated ketones and carboxylate in lignin, were noted. hese spectral changes were previously observed by Fornito et al. (2020) [24] on the effec-
ve degradation of the substrate by Pleurotus spp. Specifically, the mushroom selectively
d
li
i
d ‘h
i
ll l
i
t
ll l
tt
k
p
g
p
In order to evaluate changes in the molecular structure of the matrices used, the
ATR-FTIR spectra after 30 d of cultivation were compared to that of the starting substrates
(Figure 2). Figure 4 shows a specific spectral range, between 1800–1300 cm−1, where the
main differences were observed. As can be seen from Figure 4a, WS + SC exhibits consistent
structural variation in this region. Specifically, the spectrum highlights a decrease of the
absorption band at 1507 cm−1 corresponding to the aromatic skeletal vibration as well as
those at 1454 and 1421 cm−1, which derive from C-H bending in lignin. In addition, an
important reduction in the peak at 1733 cm−1 may be ascribed to p-coumaric acids in the
lignin structure and likewise to the ester group in hemicellulose. The enhancement of the
band at 1322 cm−1 due to C-H bending vibration, as well as that at around 1643 cm−1,
assigned to C=O stretching in conjugated ketones and carboxylate in lignin, were noted. These spectral changes were previously observed by Fornito et al. (2020) [24] on the effective
degradation of the substrate by Pleurotus spp. Specifically, the mushroom selectively
degrades lignin and ‘hemicellulose prior to cellulose attack. egrades lignin and ‘hemicellulose prior to cellulose attack. g
g
p
Less structural changes emerged in D spectra, as illustrated in Figure 4b. The intensity
of the band taken as a reference of lignin (1510 cm−1) and amide II in proteins (1550 cm−1)
shortly decreased. 3.3. Full-Scale Cultivation The bar chart in Figure 5a compares the summary statistics for the fresh weight
average of the fruiting bodies harvested from the two substrates. The total yield for the
conventional sample (WS + SC) was about 237.50 kg, while for the experimental one (D15)
was about 249.60 kg of fruiting bodies. The ANOVA did not show any statistical differences
between the fresh weight of the two groups. Furthermore, in Figure 5b, BE for each matrix
is reported. Statistical analysis did not show any differences in this case as well, between
the conventional matrix and the experimental one. Nevertheless, a slight increase in the
fresh weight and more homogeneous results in terms of standard error can be noticed
using D15. Agronomy 2023, 13, 950
Agronomy 2023, 13, x FO 9 of 19 Figure 4. ATR-FTIR spectra (1800–1300 cm−1) of WS + SC (a) and D (b) before the mycelial growth
(dotted line) and after P. ostreatus mycelial growth (solid line). Figure 4. ATR-FTIR spectra (1800–1300 cm−1) of WS + SC (a) and D (b) before the mycelial growth
(dotted line) and after P. ostreatus mycelial growth (solid line). R REVIEW
10 of 20
in the fresh weight and more homogeneous results in terms of standard error can be no-
ticed using D15. Figure 4. ATR-FTIR spectra (1800–1300 cm−1) of WS + SC (a) and D (b) before the mycelial growth
Figure 4. ATR-FTIR spectra (1800–1300 cm−1) of WS + SC (a) and D (b) before the mycelial growth
REVIEW
10 of 20
in the fresh weight and more homogeneous results in terms of standard error can be no- EVIEW
10 of 20 Figure 4. ATR-FTIR spectra (1800–1300 cm−1) of WS + SC (a) and D (b) before the mycelial growth
(dotted line) and after P. ostreatus mycelial growth (solid line). Figure 4. ATR-FTIR spectra (1800–1300 cm−1) of WS + SC (a) and D (b) before the mycelial growth
(dotted line) and after P. ostreatus mycelial growth (solid line). in the fresh weight and more homogeneous results in terms of standard error can be no-
ticed using D15. Less structural changes emerged in D spectra, as illustrated in Figure 4b. The inten-
sity of the band taken ass a reference of lignin (1510 cm−1) and amide II in proteins (1550
cm−1) shortly decreased. 3.3. 3.3. Full-Scale Cultivation Full-Scale Cultivation
The bar chart in Figure 5a compares the summary statistics for the fresh weight av-
erage of the fruiting bodies harvested from the two substrates. The total yield for the con-
ventional sample (WS + SC) was about 237.50 kg, while for the experimental one (D15)
was about 249.60 kg of fruiting bodies. The ANOVA did not show any statistical differ-
ences between the fresh weight of the two groups. Furthermore, in Figure 5b, BE for each
matrix is reported. Statistical analysis did not show any differences in this case as well,
between the conventional matrix and the experimental one. Nevertheless, a slight increase
Figure 5. Fresh weight (a) and BE (b) of P. ostreatus grown on D15 (orange) and WS + SC (blue). Figure 5. Fresh weight (a) and BE (b) of P. ostreatus grown on D15 (orange) and WS + SC (blue). Less structural changes emerged in D sp
sity of the band taken ass a reference of ligni
cm−1) shortly decreased. 3.3. Full-Scale Cultivation
The bar chart in Figure 5a compares the
erage of the fruiting bodies harvested from th
ventional sample (WS + SC) was about 237.5
was about 249.60 kg of fruiting bodies. The
ences between the fresh weight of the two gr
matrix is reported. Statistical analysis did no
between the conventional matrix and the expe pectra, as illustrated in Figure 4b. The inten-
n (1510 cm−1) and amide II in proteins (1550
summary statistics for the fresh weight av-
he two substrates. The total yield for the con-
50 kg, while for the experimental one (D15)
ANOVA did not show any statistical differ-
oups. Furthermore, in Figure 5b, BE for each
ot show any differences in this case as well,
erimental one. Nevertheless, a slight increase Figure 5. Fresh weight (a) and BE (b) of P. ostreatus grown on D15 (orange) and WS + SC (blue). Figure 5. Fresh weight (a) and BE (b) of P. ostreatus grown on D15 (orange) and WS + SC (blue). Agronomy 2023, 13, 950 10 of 19 Another parameter evaluated was P during the first and second flushes. Again, as
can be seen from Table 2, we found no statistical differences between D15 and the control. Nevertheless, using the experimental substrate, higher percentages were achieved in the
first half of both harvesting periods as well as more homogeneous values among replicates. 3.3. Full-Scale Cultivation Figure 6 presents the trend of the daily global production of each trial through the two
flushes. Especially in the first one, it is immediately evident that D stimulates the production
around days 2 and 3 instead of WS + SC, whose production reaches a peak around day
5. In the second flush, the two substrates tend to have almost the same trend, with the
maximum production around day 4. Table 2. P expressed in percentage of P. ostreatus grown on WS + SC and D15. Table 2. P expressed in percentage of P. ostreatus grown on WS + SC and D15. Sample
First Flush
Second Flush
Yield
1 Half
Total
Yield
P (%)
Yield
1 Half
Total
Yield
P (%)
WS + SC
32.75
49.70
66%
6.00
19.85
30%
WS + SC
13.95
38.50
36%
16.10
19.30
83%
WS + SC
13.90
40.00
35%
8.20
14.35
57%
WS + SC
11.05
42.60
26%
5.60
13.20
42%
Mean
17.91 ± 9.98
42.70 ± 4.96
41%
8.98 ± 4.88
16.68 ± 3.89
53%
D15
21.20
38.00
56%
19.05
22.90
83%
D15
27.15
43.50
62%
13.40
21.00
64%
D15
24.50
40.40
61%
15.35
20.60
75%
D15
33.70
45.50
74%
12.85
17.70
73%
Mean
26.64 ± 5.30
41.85 ± 3.32
63%
15.16 ± 2.80
20.55 ± 2.15
74%
PEER REVIEW
11 of 20 Table 2. P expressed in percentage of P. ostreatus grown on WS + SC and D15. Sample
First Flush
Second Flush
Yield
1 Half
Total
Yield
P (%)
Yield
1 Half
Total
Yield
P (%)
WS + SC
32.75
49.70
66%
6.00
19.85
30%
WS + SC
13.95
38.50
36%
16.10
19.30
83%
WS + SC
13.90
40.00
35%
8.20
14.35
57%
WS + SC
11.05
42.60
26%
5.60
13.20
42%
Mean
17.91 ± 9.98
42.70 ± 4.96
41%
8.98 ± 4.88
16.68 ± 3.89
53%
D15
21.20
38.00
56%
19.05
22.90
83%
D15
27.15
43.50
62%
13.40
21.00
64%
D15
24.50
40.40
61%
15.35
20.60
75%
D15
33.70
45.50
74%
12.85
17.70
73%
Mean
26.64 ± 5.30
41.85 ± 3.32
63%
15.16 ± 2.80
20.55 ± 2.15
74%
23, 13, x FOR PEER REVIEW
11 of 20
Figure 6. Yield trend of P. ostreatus grown on WS + SC (blue line) and D15 (orange line), expressed
as total fresh weight per day in the first and second flushes. 3.4. Qualitative Evaluation of the Fruiting Bodies
Figure 6. 3.3. Full-Scale Cultivation Yield trend of P. ostreatus grown on WS + SC (blue line) and D15 (orange line), expressed as
total fresh weight per day in the first and second flushes. 3.4. Qualitative Evaluation of the Fruiting Bodies Table 2. P expressed in percentage of P. ostreatus grown on WS + SC and D15. Sample
First Flush
Second Flush
Yield
1 Half
Total
Yield
P (%)
Yield
1 Half
Total
Yield
P (%)
WS + SC
32.75
49.70
66%
6.00
19.85
30%
WS + SC
13.95
38.50
36%
16.10
19.30
83%
WS + SC
13.90
40.00
35%
8.20
14.35
57%
WS + SC
11.05
42.60
26%
5.60
13.20
42%
Mean
17.91 ± 9.98
42.70 ± 4.96
41%
8.98 ± 4.88
16.68 ± 3.89
53%
D15
21.20
38.00
56%
19.05
22.90
83%
D15
27.15
43.50
62%
13.40
21.00
64%
D15
24.50
40.40
61%
15.35
20.60
75%
D15
33.70
45.50
74%
12.85
17.70
73%
Mean
26.64 ± 5.30
41.85 ± 3.32
63%
15.16 ± 2.80
20.55 ± 2.15
74%
Agronomy 2023, 13, x FOR PEER REVIEW
11 of 20
Figure 6. Yield trend of P. ostreatus grown on WS + SC (blue line) and D15 (orange line), expressed
as total fresh weight per day in the first and second flushes. 3 4 Q
lit ti
E
l
ti
f th F
iti
B di
Figure 6. Yield trend of P. ostreatus grown on WS + SC (blue line) and D15 (orange line), expressed as
total fresh weight per day in the first and second flushes. Figure 6. Yield trend of P. ostreatus grown on WS + SC (blue line) and D15 (orange line), expressed
as total fresh weight per day in the first and second flushes. Figure 6. Yield trend of P. ostreatus grown on WS + SC (blue line) and D15 (orange line), expressed as
total fresh weight per day in the first and second flushes. 3.4. Qualitative Evaluation of the Fruiting Bodies
h
l
3.4. Qualitative Evaluation of the Fruiting Bodies 3.4.1. Chemical Parameters
Table 3 shows the outpu
3.4.1. Chemical Parameters 3.4.2. ATR-FTIR Analysis
3 4 2 ATR FT Figure 7 illustrates the ATR-FTIR spectra of the fruiting bodies of P. ostreatus harvested
from the two growing substrates (WS + SC and D15). Overall, no significant differences
were found between mushrooms produced on WS + SC and those on the experimental
matrix. In both spectra are well evident the protein bands, including Amide I at 1641 cm−1,
Amide II at 1544 cm−1, and Amide III around 1240 cm−1 [23,46]; however, a slight increase
can be seen in those mushrooms cultivated with the addition of digestate. Furthermore,
the region around 1000 cm−1, which corresponds to the polysaccharide vibration, is clearly
apparent. For instance, the peak at 1146 cm−1, as well as that at 1035 cm−1, can be attributed
to the C-O-C asymmetric stretching of glycosidic linkage and the stretching vibration of the
C-O-C group, respectively [23]. The lipid component that can be found in cell membrane
phospholipids, just like in the surface of the cap and stipe, can be observed at 1741 cm−1
and 1239 cm−1 due to the stretching of ester groups [47]. Along with this, the bands 1451
and 1239 cm−1 correspond to the aliphatic compounds. 3.4.2. ATR-FTIR Analysis
Figure 7 illustrates the ATR-FTIR spectra of the fruiting bodies of P. ostr
vested from the two growing substrates (WS + SC and D15). Overall, no significa
ences were found between mushrooms produced on WS + SC and those on th
mental matrix. In both spectra are well evident the protein bands, including A
1641 cm−1, Amide II at 1544 cm−1, and Amide III around 1240 cm−1 [23,46]; howeve
increase can be seen in those mushrooms cultivated with the addition of diges
thermore, the region around 1000 cm−1, which corresponds to the polysacchari
tion, is clearly apparent. For instance, the peak at 1146 cm−1, as well as that at 1
can be attributed to the C-O-C asymmetric stretching of glycosidic linkage and th
ing vibration of the C-O-C group, respectively [23]. The lipid component that can
in cell membrane phospholipids, just like in the surface of the cap and stipe, c
served at 1741 cm−1 and 1239 cm−1 due to the stretching of ester groups [47]. A
this, the bands 1451 and 1239 cm−1 correspond to the aliphatic compounds. Figure 7. ATR-FTIR spectra (1800–800 cm−1) of the fruiting bodies of P. ostreatus harvested
two growing substrates WS + SC (blue line) and D15 (orange line). Figure 7. 3.4.1. Chemical Parameters
Table 3 shows the outpu
3.4.1. Chemical Parameters ATR-FTIR Analysis
3 4 2 ATR FTIR Analysis 3.4.1. Chemical Parameters
Table 3 shows the outpu
3.4.1. Chemical Parameters Table 3 shows the output of the chemical analyses of the fruiting bodies. The resulting
values reveal that the nutrient composition is statistically comparable between mush-
rooms grown on WS + SC and those grown on the experimental substrate. The pH value
was neutral and did not exhibit any changes; Fe seems to be the most abundant microele-
ment, and its content results a little higher in those mushrooms grown in the presence of
D. At that condition. Conversely, the amount of Zn undergoes a reduction. Moreover, it is
important to note that nitrates and heavy metal content remain under the permitted limits
in both cases. Similarly, the microbiological parameters, as well as the agrochemical resi-
dues, were under detectable levels. Table 3. Chemical parameters of the fruiting bodies of P. ostreatus harvested from the conventional
substrate (WS+SC) and the experimental one (D15)
Table 3 shows the output of the chemical analyses of the fruiting bodies. The resulting
values reveal that the nutrient composition is statistically comparable between mushrooms
grown on WS + SC and those grown on the experimental substrate. The pH value was
neutral and did not exhibit any changes; Fe seems to be the most abundant microelement,
and its content results a little higher in those mushrooms grown in the presence of D. At that
condition. Conversely, the amount of Zn undergoes a reduction. Moreover, it is important
to note that nitrates and heavy metal content remain under the permitted limits in both
cases. Similarly, the microbiological parameters, as well as the agrochemical residues, were
under detectable levels. Agronomy 2023, 13, 950 11 of 19 Table 3. Chemical parameters of the fruiting bodies of P. ostreatus harvested from the conventional
substrate (WS+SC) and the experimental one (D15). Table 3. Chemical parameters of the fruiting bodies of P. ostreatus harvested from the conventional
substrate (WS+SC) and the experimental one (D15). Parameter
Unit
WS + SC
D15
pH
6.2 ± 0.8
6.2 ± 0.8
NO3−
mg/kg
<50
<50
NO2−
mg/kg
<50
<50
Fe
mg/kg
6.2 ± 1.5
7.4 ± 1.8
Cu
mg/kg
0.9 ± 0.3
2.0 ± 0.6
Zn
mg/kg
6.1 ± 0.5
1.0 ± 2.1
Mn
mg/kg
0.8 ± 0.3
1.2 ± 0.4
Cd
mg/kg
n.d. 1
n.d. Pb
mg/kg
n.d. n.d. Co
mg/kg
n.d. n.d. Ni
mg/kg
n.d. n.d. Total coliforms
UFC/g
<10
<10
Agrochemicals
mg/kg
n.d. n.d. 1 n.d.—not detected. 13, x FOR PEER REVIEW 3.4.2. 3.4.3. SERS Analysis 3.4.3. SERS Analysis SERS spectra are characterized by strong bands at 1583, 1445, 1324, and 1223 cm−1,
which can be attributed to the imidazole-2-thione structure that forms the ergothioneine
amino acid (Figure 8). The strong band seen at 486 cm−1 is a characteristic feature of
this compound, and it was attributed to NCS bending coupled to C-S stretching from
the imidazole thione ring [29]. Overall, the SERS spectral profiles of the fruiting bodies
of P. ostreatus harvested from the two growing substrates, WS + SC and D15, are quite
comparable. However, some differences can be noticed in the relative intensities of bands at
1324 and 1223 cm−1, which correspond to the in-plane stretching motions of the imidazole
thione ring. 13, x FOR PEER REVIEW Figure 8. SERS spectra of the fruiting bodies of P. ostreatus harvested from the two gro
strates WS + SC (blue line) and D15 (orange line). Figure 8. SERS spectra of the fruiting bodies of P. ostreatus harvested from the two growing substrates
WS + SC (blue line) and D15 (orange line). Figure 8. SERS spectra of the fruiting bodies of P. ostreatus harvested from the two gro
strates WS + SC (blue line) and D15 (orange line). Figure 8. SERS spectra of the fruiting bodies of P. ostreatus harvested from the two growing substrates
WS + SC (blue line) and D15 (orange line). Apart from the bands due to ergothioneine, other bands can also be observ
SERS spectra. The 1100–500 cm−1 region is practically empty of ergothioneine ba
there appear two prominent bands at 659 and 734 cm−1 that can be assigned to rin
ing bands of the guanine and adenine. The bands at 865, 911, 965, and 1023 cm
assigned to the ribose-phosphate chain in nucleic acids, but with possible cont
from other specific fungi compounds such as chitin. Furthermore, the weak band
ing at 1639, 1682, and 1693 cm−1 can be attributed to the amide I in proteins an
ketonic C=O stretching. Finally, the presence of ester groups is evidenced by the
of the weak band at 1769 cm−1. Apart from the bands due to ergothioneine, other bands can also be observed in the
SERS spectra. The 1100–500 cm−1 region is practically empty of ergothioneine bands,
and there appear two prominent bands at 659 and 734 cm−1 that can be assigned to ring
breathing bands of the guanine and adenine. 3.4.2. ATR-FTIR Analysis
3 4 2 ATR FT ATR-FTIR spectra (1800–800 cm−1) of the fruiting bodies of P. ostreatus harvested from the
two growing substrates WS + SC (blue line) and D15 (orange line). Figure 7. ATR-FTIR spectra (1800–800 cm−1) of the fruiting bodies of P. ostreatus harvested
two growing substrates WS + SC (blue line) and D15 (orange line). Figure 7. ATR-FTIR spectra (1800–800 cm−1) of the fruiting bodies of P. ostreatus harvested from the
two growing substrates WS + SC (blue line) and D15 (orange line). 12 of 19 12 of 19 Agronomy 2023, 13, 950 3.4.3. SERS Analysis The bands at 865, 911, 965, and 1023 cm−1
can be assigned to the ribose-phosphate chain in nucleic acids, but with possible contribu-
tions from other specific fungi compounds such as chitin. Furthermore, the weak bands
appearing at 1639, 1682, and 1693 cm−1 can be attributed to the amide I in proteins and
also to ketonic C=O stretching. Finally, the presence of ester groups is evidenced by the
presence of the weak band at 1769 cm−1. 4. Discussion At 1640 a d 1550
1
e a
fid the a
ide
ou
the e t
o ba d a e
Preliminary structural evaluation of the matrices reveals that both WS + SC and D
are rich in polysaccharides, such as cellulose and hemicellulose, and that is confirmed by
the chemical analyses of the two substrates, which are quite similar regarding the organic
carbon content, around 40% of the dry matter. C content is a fundamental factor for the
optimal metabolism of fungi, and the ideal range is approximately 40% which is quite
coincident with that of our matrices [20]. Moreover, the ATR-FTIR spectra show some
characteristic bands linked to aromatic compounds, more evident in D, which can confirm
the presence of lignin, as described by previous research [24,43]. At 1640 and 1550 cm−1, we can find the amide groups; these two bands are
tense in D spectra, probably indicating a higher content in N-compounds, as a
lighted in the chemical evaluation. It has already been established that an optima
ability can promote fungi growth [57,58]. As reported by Sozbir et al. (2015) [59]
age between 1.94 and 2.08% seems to be an ideal range for Pleurotus spp. grow
than higher values which can be poisonous to its development [8]. Wan Mahari et
[20] report that matrices with high nutritional values will promote the coloniza
cess. Indeed, in this work, the higher nutrient composition of D, such as S, P, K,
compared to WS + SC, can better support mycelial growth. pH is one of the most i
environmental factors that affect the enzyme activity in Pleurotus spp. [60]. The
At 1640 and 1550 cm−1, we can find the amide groups; these two bands are more
intense in D spectra, probably indicating a higher content in N-compounds, as also high-
lighted in the chemical evaluation. It has already been established that an optimal N
availability can promote fungi growth [57,58]. As reported by Sozbir et al. (2015) [59]
percentage between 1.94 and 2.08% seems to be an ideal range for Pleurotus spp. growth,
rather than higher values which can be poisonous to its development [8]. Wan Mahari et al. (2020) [20] report that matrices with high nutritional values will promote the colonization
process. Indeed, in this work, the higher nutrient composition of D, such as S, P, K, and Mg,
compared to WS + SC, can better support mycelial growth. 4. Discussion Anaerobic digestate, a by-product of biogas production, which was born as
able industry, may become unsustainable if inadequate management occurs. Al
driven research toward different solutions to exploit it [13,18,50,51]. Similarly, m
farming is another developing industry thanks to the several promising prop
these organisms. Recent studies have focused on alternative and more sustainab
ing substrates in terms of production and costs, and among these, digestate seem
vide good perspectives [24,40,52–56]. Anaerobic digestate, a by-product of biogas production, which was born as a sustain-
able industry, may become unsustainable if inadequate management occurs. All this has
driven research toward different solutions to exploit it [13,18,50,51]. Similarly, mushroom
farming is another developing industry thanks to the several promising properties of these
organisms. Recent studies have focused on alternative and more sustainable growing
substrates in terms of production and costs, and among these, digestate seems to provide
good perspectives [24,40,52–56]. With this in mind, we tried to examine the relationship between the solid fr
anaerobic digestate and P. ostreatus full-scale cultivation, using this agro-waste
ternative or supplementary growing media. Chemical evaluations of matrices an
rooms were carried out by using ATR-FTIR and SERS spectroscopies. g
With this in mind, we tried to examine the relationship between the solid fraction of
anaerobic digestate and P. ostreatus full-scale cultivation, using this agro-waste as an alterna-
tive or supplementary growing media. Chemical evaluations of matrices and mushrooms
were carried out by using ATR-FTIR and SERS spectroscopies. Preliminary structural evaluation of the matrices reveals that both WS + SC a
rich in polysaccharides, such as cellulose and hemicellulose, and that is confirm
chemical analyses of the two substrates, which are quite similar regarding th
carbon content, around 40% of the dry matter. C content is a fundamental facto
optimal metabolism of fungi, and the ideal range is approximately 40% which
coincident with that of our matrices [20]. Moreover, the ATR-FTIR spectra sh
characteristic bands linked to aromatic compounds, more evident in D, which can
the presence of lignin, as described by previous research [24,43]. 3.4.4. Pol
3.4.4. Polysaccharides The ATR-FTIR spectra of polysaccharides extracted from the fruiting bodie
played in Figure 9. In both spectra, two small peaks are evident between 750–
described as the signature bands for glucan [48]. The figure reveals a strong ba
region within 1200–1000 cm−1, representing CO and CC stretching vibration. shoulders visible at 1037 and 1071 cm−1 can be attributed to glucans, as reported b
et al. (2015) [49]. The strong peak that appears at 1642 cm−1 is assigned to Amide
but also to O-H-O bending of bound water in glucan, while that at 1535 cm−1
corresponds to Amide II vibration in chitin [49]. From the ATR-FTIR spectra is ev
band at 1398 cm−1, which corresponds to the C-H stretching of the pyranose ring
Globally, the spectra of polysaccharides from mushrooms obtained on WS + SC
are quite overlapping. The ATR-FTIR spectra of polysaccharides extracted from the fruiting bodies are dis-
played in Figure 9. In both spectra, two small peaks are evident between 750–950 cm−1,
described as the signature bands for glucan [48]. The figure reveals a strong band in the
region within 1200–1000 cm−1, representing CO and CC stretching vibration. The two
shoulders visible at 1037 and 1071 cm−1 can be attributed to glucans, as reported by Gomba
et al. (2015) [49]. The strong peak that appears at 1642 cm−1 is assigned to Amide I in chitin
but also to O-H-O bending of bound water in glucan, while that at 1535 cm−1 probably
corresponds to Amide II vibration in chitin [49]. From the ATR-FTIR spectra is evident the
band at 1398 cm−1, which corresponds to the C-H stretching of the pyranose ring of chitin. Globally, the spectra of polysaccharides from mushrooms obtained on WS + SC and D15
are quite overlapping. Agronomy 2023, 13, 950
Agron 13 of 19 13 of 19 Figure 9. ATR-FTIR spectra (1800–700 cm−1) of the polysaccharides extracted from fruiting
P. ostreatus harvested from the two growing substrates WS + SC (blue line) and D15 (oran
Figure 9. ATR-FTIR spectra (1800–700 cm−1) of the polysaccharides extracted from fruiting bodies of
P. ostreatus harvested from the two growing substrates WS + SC (blue line) and D15 (orange line). i
i Figure 9. ATR-FTIR spectra (1800–700 cm−1) of the polysaccharides extracted from fruiting
P. ostreatus harvested from the two growing substrates WS + SC (blue line) and D15 (oran
Figure 9. 3.4.4. Pol
3.4.4. Polysaccharides ATR-FTIR spectra (1800–700 cm−1) of the polysaccharides extracted from fruiting bodies of
P. ostreatus harvested from the two growing substrates WS + SC (blue line) and D15 (orange line). 4. Discussion pH is one of the most important
environmental factors that affect the enzyme activity in Pleurotus spp. [60]. The optimum
pH established for mycelia growth was 5–6.5, which is that of the conventional substrate Agronomy 2023, 13, 950 14 of 19 14 of 19 used in this work; although D shows a pH of 9.05, it was previously described that higher
values could encourage the development of mycelia rather than smaller values [8,20]. used in this work; although D shows a pH of 9.05, it was previously described that higher
values could encourage the development of mycelia rather than smaller values [8,20]. g
p
y
As a consequence of all the factors mentioned above and as previously analyzed by
Fornito et al. (2020) [24], initial tests in Petri dishes confirm the capability of the selected
strain of P. ostreatus (WH90) of colonizing in the same way the conventional substrate (WS
+ SC) and the experimental ones (D10, D20, D). From the growing curves, it is indeed
apparent that the trend of mycelia development is comparable in conventional plates as
well as in those added with D and with pure D; nonetheless, in the first phase, D stimulates
faster mycelial colonization. Despite the absence of statistical differences, AGR values corroborate these results. In fact, the average growth per day on the digestate matrix was more than 5 cm2/d. The
above findings are consistent with the work of Santi et al. (2015) [53], which demonstrated
that P. ostreatus could proliferate on a digestate medium with positive results compared to
wheat straw. The consumption of N and C components is highlighted in the ATR-FTIR spectra reg-
istered after the cultivation. Indeed, variations in the lignin bands (1507, 1454, 1421 cm−1)
in WS + SC and in the amine bands (1550 cm−1) in D, are emerged. The degradation
of lignin may be verified through the reduction of the characteristic peaks at 1507 cm−1
and 1733 cm−1. The colonization can be registered by looking at the increase at 1322
and 1643 cm−1, which may correspond to the depolymerization of the lignocellulosic
compounds as well as to residual mycelial protein groups. The resulting efficiency of
mycelial colonization of both substrates is in line with the above and with previous findings
presented by Fornito et al. (2020) [24] and Puliga et al. (2022) [23]. 4. Discussion Although further Agronomy 2023, 13, 950 15 of 19 15 of 19 studies are required to have a complete quality evaluation, this work provides a preliminary
overview of the fruiting bodies derived from digestate and how their composition is
perfectly comparable to that of mushrooms grown on conventional media. p
y
p
g
An interesting method that can be used to better understand the molecular structure
of the fruiting bodies is SERS spectroscopy. This technique allows better intercept of
some vibrational signals, thus enhancing the identification of chemical compounds [30]. The resulting SERS spectra are dominated by the bands attributed to the amino acid
ergothioneine [29]. This compound was ubiquitously found in plants and animals, and it is
specifically very abundant in P. ostreatus [66]. This amino acid molecule was also detected
in a previous work made by us on different mushrooms and displayed a high SERS activity,
as also revealed by the Raman study in an analysis done on biological materials [30,67,68]. The characteristic band at 486 cm−1 can serve to identify it from other biomolecules that
may occur in the same biological matrix. The high affinity of the S-containing five-member
ring to the silver surface accounts for the high intensity of ergothioneine in SERS spectra. In addition, the high intensity of the ergothioneine SERS bands suggests that it could
be exposed to the external part of the fungi because it is included in the fungi cell wall,
although a possible breakdown of the fungal wall is not discharged. Despite the similarity
of the SERS spectral profiles of fruiting bodies resulting from the two growing media, some
variations can still be observed at 1324 and 1223 cm−1. Since these bands are attributed to
in-plane stretching motions of the imidazole thione ring, this difference could indicate a
slight change in the orientation of this ring regarding the metal surface of Ag nanoparticles,
according to the specific selection rules of SERS [31]. The appearance of intense bands of
nucleic acids (DNA and RNA) between 600 and 900 cm−1 might be due to the disruption
of the fungal membrane through the formation of holes in the fungal cell wall, as described
elsewhere [69,70]. On the other hand, the strong intensity of the nucleic bases can be
attributed to the high affinity of silver for purine and pyrimidine bases [71,72]. The analysis of polysaccharides reveals more details about mushroom composition. 4. Discussion The most frequent compounds found are glucans, specifically two main types: branched
(1→3)(1→6)-β-D-glucan and linear (1→3)-α-D-glucan. In ATR-FTIR spectra, these are
visible at 790 and 872 cm−1. The peak around 790 cm−1 is probably due to mannan [α(1-6)
linked backbone with α(1-3) and α (1-2) linked branches], a type of glucan that is one com-
ponent of fungal cell walls [46]. This finding agrees with the study of Baeva et al. (2020) [73],
who defines the structure of several polysaccharide fractions of P. ostreatus. Numerous
works have identified those compounds for their antioxidant and anti-inflammatory activ-
ity, thus enriching the mushroom’s beneficial properties [62,63]. Usually combined with
glucan, chitin is another important polysaccharide characteristic of the fungal cell wall
structure. Its several biotechnological applications, among them pharmaceutical, nutraceu-
tical, agricultural, and material science, make it a biopolymer of high interest [74,75]. From
the spectra is evident the strong peak around 1398 cm−1 corresponds to C-H stretching of
the pyranose ring of chitin; the two protein bands around 1630 and 1530 cm−1 can be useful
as well to confirm the presence of chitin molecules [46,73,76]. The vibrational methods
described above can be proposed as faster, non-destructive, and cheaper techniques to
analyze some quality parameters of mushrooms. 4. Discussion With these promising outcomes, we decided to proceed with full-scale cultivation
in collaboration with the mushroom company. Considering it was the first trial and the
availability of both WS and D, we decided to test a mixture of both as the experimental
sample to evaluate the development of fruiting bodies. Interestingly, the production was
almost the same with both substrates and even better with D, nearly 250 kg of fresh
mushrooms. To strengthen our results, BE, resulting from the analyses, shows that at least
half of the dry weight of both WS + SC and D15 was transformed into fruiting bodies. Again,
with D15, results are distributed more homogeneously through the replicates. Overall,
the production was perfectly comparable. However, D seems to stimulate a precocious
development of mushrooms, as can be seen from P data. Previous research on Agaricus spp. has shown that P may depend on the type of growing matrix, as well as its formulation,
texture, and environmental conditions [40,61]. In order to test the quality parameters, we compared chemical and spectroscopic
analyses of mushrooms grown on the two matrices. The preliminary chemical evaluation
reveals that the composition of macro and microelements is statistically equivalent, so the
addition of D did not modify the nutrient content. Even more, nitrate and coliform bacteria
values and agrochemical residues were not detectable, as well as heavy metals were below
consented thresholds. The structural analysis shows a predominance of carbohydrates which are generally
known to represent more than 50% of the dry matter of mushrooms [3]. Besides, some
medicinal and beneficial properties of fungi can be ascribed to the presence of some
polysaccharides [62,63]. The spectra band at 1640 and 1544 cm−1 highlight the presence of
N-compound, which means to a great extent, amino acids, proteins, and enzymes. These
compounds can constitute up to 35% of the mushroom’s dry matter and contribute to
some of their fundamental characteristics [3]. Regarding the human diet, for instance,
mushrooms provide a high amount of essential amino acids, among others, arginine,
glutamic acid, aspartic acid, tryptophan, and lysine, which makes them a great alternative
to animal products [3]. In addition, Pleurotus spp. has been studied for its remarkable
production of lignocellulolytic enzymes that have a key role in the degradation of complex
organic materials [64,65]. Some previous works have revealed that the growing substrate
can emphasize the metabolites composition of the fruiting bodies [63]. 5. Conclusions In the last years, several studies have already confirmed the potential of mushroom
cultivation as a valid tool to valorize different agro-wastes. Among these, anaerobic
digestate, which is currently produced in large quantities, has proved to be an optimal
substitute or supplement for conventional growing substrates. The quantity and quality of
the fruiting body obtained in this work, using the substrate containing 15% of digestate,
support the applicability of digestate in the industrial cultivation of P. ostreatus, which is
the second most cultivated mushroom worldwide. The optimal composition of macro- and
micronutrients, as well as the structural characteristics, have led to productivity comparable
to that of the conventional substrate. In addition, qualitative parameters of the fruiting Agronomy 2023, 13, 950 16 of 19 bodies exhibit no differences. It is, therefore, possible to create a new chain of products
with high added value and, at the same time, reduce the costs of raw materials. bodies exhibit no differences. It is, therefore, possible to create a new chain of products
with high added value and, at the same time, reduce the costs of raw materials. g
Partnering with mushroom growers is a potential new business opportunity and an
attractive new market for the biogas production sector. In our case study, we have shown
that farms need to be located nearby to minimize transportation needs and GHG emissions
and that providing zero-kilometer products can support local economies. On the other
hand, from a wider perspective, the substitution of raw materials for agricultural waste
benefits the sustainability of the production chain in agreement with circular economy
criteria, providing a great impact for both the mushroom and biogas industries. The future outlook is to recycle spent substrates for biogas plants on the basis of the
European Commission’s recent “REPowerEU” plan of 2022, which is aimed to gradually
eliminate European dependence on Russian fossil resources and increase the resilience of
the European Union’s energy system. Author Contributions: Conceptualization, V.Z. and F.P.; methodology, V.Z., F.P. and L.T.; formal
analysis, V.Z.; investigation, V.Z., F.P. and L.T.; resources, O.F., A.Z. and S.S.-C.; data curation, V.Z. and F.P.; writing—original draft preparation, V.Z.; writing—review and editing, V.Z., F.P., A.Z., O.F. and S.S.-C.; visualization, V.Z. and L.T.; supervision, O.F., A.Z. and S.S.-C.; funding acquisition, O.F.,
A.Z. and S.S.-C. All authors have read and agreed to the published version of the manuscript. Author Contributions: Conceptualization, V.Z. and F.P.; methodology, V.Z., F.P. 5. Conclusions and L.T.; formal
analysis, V.Z.; investigation, V.Z., F.P. and L.T.; resources, O.F., A.Z. and S.S.-C.; data curation, V.Z. and F.P.; writing—original draft preparation, V.Z.; writing—review and editing, V.Z., F.P., A.Z., O.F. and S.S.-C.; visualization, V.Z. and L.T.; supervision, O.F., A.Z. and S.S.-C.; funding acquisition, O.F.,
A.Z. and S.S.-C. All authors have read and agreed to the published version of the manuscript. Funding: This research was funded by Grant PON “Ricerca e Innovazione” 2014–2020, Ministero
dell’Università e della Ricerca. This work was also financially supported by Ministerio de Ciencia e
Innovación/FEDER funds (Project PID2020-113900RB-I00/AEI/10.13039/501100011033). Data Availability Statement: The data presented in this study are available on request from the
corresponding author. Acknowledgments: We would like to thank Funghitex company (Latina, Italy) for giving us the
opportunity to carry on the industrial cultivation process and the Mascetti-Sbardella farm (Latina,
Italy) for providing us with corn digestate. Acknowledgments: We would like to thank Funghitex company (Latina, Italy) for giving us the
opportunity to carry on the industrial cultivation process and the Mascetti-Sbardella farm (Latina,
Italy) for providing us with corn digestate. Conflicts of Interest: The authors declare no conflict of interest. References New Opportunities for Agricultural Digestate
Valorization: Current Situation and Perspectives. Energy Environ. Sci. 2015, 8, 2600–2621. [CrossRef] 14. European Commission and Industry Leaders Launch Biomethane Industrial Partnership to Support the 35 Bcm Target on
Biomethane by 2030 European Biogas Association. Available online: https://www.europeanbiogas.eu/european-commission-and-
industry-leaders-launch-biomethane-industrial-partnership-to-support-the-35-bcm-target-on-biomethane-by-2030/ (accessed on
20 February 2023). 15. Corden, C.; Bougas, K.; Cunningham, E.; Tyrer, D.; Kreißig, J.; Zetti, E.; Gamero, E.; Wildey, R.; Crookes, M. Digestate and
Compost as Fertilisers: Risk Assessment and Risk Management Options. Wood Environment & Infrastructure Solutions UK
Limited (Doc Ref 40039CL003i3) 2019 Available online: https://ec europa eu/environment/chemicals/reach/pdf/40039%20 15. Corden, C.; Bougas, K.; Cunningham, E.; Tyrer, D.; Kreißig, J.; Zetti, E.; Gamero, E.; Wildey, R.; Crookes, M. Digestate and
Compost as Fertilisers: Risk Assessment and Risk Management Options. Wood Environment & Infrastructure Solutions UK
Limited. (Doc Ref. 40039CL003i3). 2019. Available online: https://ec.europa.eu/environment/chemicals/reach/pdf/40039%20
Digestate%20and%20Compost%20RMOA%20-%20Final%20report%20i2 20190208 pdf (accessed on 20 March 2023) g
p
p
p
16. Gioelli, F.; Dinuccio, E.; Balsari, P. Residual Biogas Potential from the Storage Tanks of Non-Separated Digestate and Digested
Liquid Fraction. Bioresour. Technol. 2011, 102, 10248–10251. [CrossRef] [PubMed] q
17. Menardo, S.; Gioelli, F.; Balsari, P. The Methane Yield of Digestate: Effect of Organic Loading Rate, Hydraulic Retention Time,
and Plant Feeding. Bioresour. Technol. 2011, 102, 2348–2351. [CrossRef] [PubMed] 18. Dahlin, J.; Herbes, C.; Nelles, M. Biogas Digestate Marketing: Qualitative Insights into the Supply Side. Resour. Conserv. Recycl. 2015, 104, 152–161. [CrossRef] 19. Phan, C.-W.; Sabaratnam, V. Potential Uses of Spent Mushroom Substrate and Its Associated Lignocellulosic Enzymes. Appl. Microbiol. Biotechnol. 2012, 96, 863–873. [CrossRef] [PubMed] 20. Wan Mahari, W.A.; Peng, W.; Nam, W.L.; Yang, H.; Lee, X.Y.; Lee, Y.K.; Liew, R.K.; Ma, N.L.; Mohammad, A.; Sonne, C.; et al. A
Review on Valorization of Oyster Mushroom and Waste Generated in the Mushroom Cultivation Industry. J. Hazard. Mater. 2020,
400, 123156. [CrossRef] 21. Sánchez, C. Lignocellulosic Residues: Biodegradation and Bioconversion by Fungi. Biotechnol. Adv. 21. Sánchez, C. Lignocellulosic Residues: Biodegradation and Bioconversion by Fungi. Biotechnol. Adv. 2009, 27, 185–194. [CrossRef]
22. Philippoussis, A.; Zervakis, G.; Diamantopoulou, P. Bioconversion of Agricultural Lignocellulosic Wastes through the Cultivation
of the Edible Mushrooms Agrocybe aegerita, Volvariella volvacea and Pleurotus spp. World J. Microbiol. Biotechnol. 2001, 17, 191–200. [CrossRef] 23. Puliga, F.; Leonardi, P.; Minutella, F.; Zambonelli, A.; Francioso, O. Valorization of Hazelnut Shells as Growing Substrate for
Edible and Medicinal Mushrooms. Horticulturae 2022, 8, 214. [CrossRef] 24. References 1. Lesa, K.N.; Khandaker, M.U.; Mohammad Rashed Iqbal, F.; Sharma, R.; Islam, F.; Mitra, S.; Emran, T.B. Nutritional Value,
Medicinal Importance, and Health-Promoting Effects of Dietary Mushroom (Pleurotus ostreatus). J. Food Qual. 2022, 2022, 2454180. [CrossRef] 2. Papadaki, A.; Kachrimanidou, V.; Papanikolaou, S.; Philippoussis, A.; Diamantopoulou, P. Upgrading Grape Pomace through
Pleurotus spp. Cultivation for the Production of Enzymes and Fruiting Bodies. Microorganisms 2019, 7, 207. [CrossRef] 3. Sharifi-Rad, J.; Butnariu, M.; Ezzat, S.M.; Adetunji, C.O.; Imran, M.; Sobhani, S.R.; Tufail, T.; Hosseinabadi, T.; Ramírez-Alarcón,
K.; Martorell, M.; et al. Mushrooms-Rich Preparations on Wound Healing: From Nutritional to Medicinal Attributes. Front. Pharmacol. 2020, 11, 567518. [CrossRef] 4. Corrêa, R.C.G.; Brugnari, T.; Bracht, A.; Peralta, R.M.; Ferreira, I.C. Biotechnological, nutritional and therapeutic uses of Pleurotus
spp. (Oyster mushroom) related with its chemical composition: A review on the past decade findings. Trends Food Sci. Technol. 2016, 50, 103–117. [CrossRef] 5. Feeney, M.J.; Miller, A.M.; Roupas, P. Mushrooms—Biologically Distinct and Nutritionally Unique: Exploring a “Third Food
Kingdom”. Nutr. Today 2014, 49, 301–307. [CrossRef] 6. FAOSTAT. Available online: https://www.fao.org/faostat/en/#home (accessed on 19 January 2023). p
g
y
7. Giving Intelligence Teams an AI-Powered Advantage. Available online: https://www.reportlinker.com/ (accessed on 19 January
2023). 8. Bellettini, M.B.; Fiorda, F.A.; Maieves, H.A.; Teixeira, G.L.; Ávila, S.; Hornung, P.S.; Júnior, A.M.; Ribani, R.H. Factors Affecting
Mushroom Pleurotus spp. Saudi J. Biol. Sci. 2019, 26, 633–646. [CrossRef] pp
9. Philippoussis, A.; Diamantopoulou, P. Agro-food industry wastes and agricultural residues convertion into high value products
by mushroom cultivation. In Proceedings of the 7th International Conference on Mushroom Biology and Mushroom Products
(ICMBMP7), Arcachon, France, 4–7 October 2011; pp. 4–7. (
),
,
,
; pp
10. Kumla, J.; Suwannarach, N.; Sujarit, K.; Penkhrue, W.; Kakumyan, P.; Jatuwong, K.; Vadthanarat, S.; Lumyong, S. Cultivation of
Mushrooms and Their Lignocellulolytic Enzyme Production through the Utilization of Agro-Industrial Waste. Molecules 2020, 25,
2811. [CrossRef] [PubMed] [
] [
]
11. Anwar, Z.; Gulfraz, M.; Irshad, M. Agro-Industrial Lignocellulosic Biomass a Key to Unlock the Future Bio-Energy: A Brief
Review. J. Radiat. Res. Appl. Sci. 2014, 7, 163–173. [CrossRef] 17 of 19 17 of 19 Agronomy 2023, 13, 950 12. Singh, N.B.; Chaudhary, R.G.; Desimone, M.F.; Agrawal, A.; Shukla, S.K. Green Synthesized Nanomaterials for Safe Technology
in Sustainable Agriculture. Curr. Pharm. Biotechnol. 2023, 24, 61–85. [CrossRef] g
13. Monlau, F.; Sambusiti, C.; Ficara, E.; Aboulkas, A.; Barakat, A.; Carrère, H. References Fornito, S.; Puliga, F.; Leonardi, P.; Di Foggia, M.; Zambonelli, A.; Francioso, O. Degradative Ability of Mushrooms Cultivated on
Corn Silage Digestate. Molecules 2020, 25, 3020. [CrossRef] 25. Hultberg, M.; Asp, H.; Bergstrand, K.J.; Golovko, O. Production of Oyster Mushroom (Pleurotus ostreatus) on Sawdust Supple-
mented with Anaerobic Digestate. Waste Manag. 2023, 155, 1–7. [CrossRef] 26. Movasaghi, Z.; Rehman, S.; ur Rehman, D.I. Fourier Transform Infrared (FTIR) Spectroscopy of Biological Tissues. Appl. Spectrosc. Rev. 2008, 43, 134–179. [CrossRef] 27. Meenu, M.; Xu, B. Application of Vibrational Spectroscopy for Classification, Authentication and Quality Analysis of Mushroom:
A Concise Review. Food Chem. 2019, 289, 545–557. [CrossRef] [PubMed] 28. Dina, N.E.; Gherman, A.M.R.; Chi¸s, V.; Sârbu, C.; Wieser, A.; Bauer, D.; Haisch, C. Characterization of C
via SERS Fingerprinting Assisted by Novel Chemometric Models. Anal. Chem. 2018, 90, 2484–2492. [C 29. Fornasaro, S.; Gurian, E.; Pagarin, S.; Genova, E.; Stocco, G.; Decorti, G.; Sergo, V.; Bonifacio, A. Ergothioneine, a Dietary Amino
Acid with a High Relevance for the Interpretation of Label-Free Surface Enhanced Raman Scattering (SERS) Spectra of Many
B
l
l S
l
S
hi
A
P
A M l Bi
l S
246 119024 [C
R f] 29. Fornasaro, S.; Gurian, E.; Pagarin, S.; Genova, E.; Stocco, G.; Decorti, G.; Sergo, V.; Bonifacio, A. Ergothioneine, a Dietary Amino
Acid with a High Relevance for the Interpretation of Label-Free Surface Enhanced Raman Scattering (SERS) Spectra of Many
Biological Samples. Spectrochim. Acta Part A Mol. Biomol. Spectrosc. 2021, 246, 119024. [CrossRef] Acid with a High Relevance for the Interpretation of Label-Free Surface Enhanced Raman Scattering (SERS) Spectra of Many
Biological Samples. Spectrochim. Acta Part A Mol. Biomol. Spectrosc. 2021, 246, 119024. [CrossRef] g
p
Biological Samples. Spectrochim. Acta Part A Mol. Biomol. Spectrosc. 2021, 246, 119024. [CrossRef] g
p
g (
) p
y
Biological Samples. Spectrochim. Acta Part A Mol. Biomol. Spectrosc. 2021, 246, 119024. [CrossRef] 30. Puliga, F.; Zuffi, V.; Zambonelli, A.; Francioso, O.; Sanchez-Cortes, S. Spectrosco
Raman Scattering (SERS). Chem. Biol. Technol. Agric. 2022, 9, 100. [CrossRef] g
p
p
Raman Scattering (SERS). Chem. Biol. Technol. Agric. 2022, 9, 100. [CrossRef] g
g
31. Aroca, R. Surface Enhanced Vibrational Spectroscopy; Wiley: Hoboken, NJ, USA, 2006; ISBN 978-0-471-60731-1. 31. Aroca, R. Surface Enhanced Vibrational Spectroscopy; Wiley: Hoboken, NJ, USA, 2006; ISBN 978-0-471 32. Aroca, R.F. Plasmon enhanced spectroscopy. Phys. Chem. Chem. Phys. 2013, 15, 5355–5363. [CrossR 32. Aroca, R.F. References Food Chem. 2006, 98, 277–284. [CrossRef] 41. Cocchi, L.; Vescovi, L.; Petrini, L.E.; Petrini, O. Heavy metals in edible mushrooms in Italy. Food Chem. 2006, 98, 277–284. [CrossRef] 42. Leopold, N.; Lendl, B. A New Method for Fast Preparation of Highly Surface-Enhanced Raman Scattering (SERS) Active Silver
Colloids at Room Temperature by Reduction of Silver Nitrate with Hydroxylamine Hydrochloride. J. Phys. Chem. B 2003, 107,
5723–5727. [CrossRef] [
]
43. Liu, R.; Yu, H.; Huang, Y. Structure and Morphology of Cellulose in Wheat Straw. Cellulose 2005, 12, 25–34. [CrossRef] 3. Liu, R.; Yu, H.; Huang, Y. Structure and Morpholo 44. Gao, A.H.; Bule, M.V.; Laskar, D.D.; Chen, S. Structural and Thermal Characterization of Wheat Straw Pretreated with Aqueous
Ammonia Soaking. J. Agric. Food Chem. 2012, 60, 8632–8639. [CrossRef] [PubMed] 45. Provenzano, M.R.; Iannuzzi, G.; Fabbri, C.; Senesi, N. Qualitative Characterization and Differentiation of
Biowastes Using FTIR and Fluorescence Spectroscopies. JEP 2011, 02, 83–89. [CrossRef] g
p
p
46. Das, B.; Rajkonwar, J.; Jagannath, A.; Raul, P.K.; Deb, U. Infra Red Spectra of Different Species of Cultivated Oyster Mushrooms
Possible Tool for Identifying Bioactive Compounds and Establishing Taxonomic Linkage. Def. Life Sci. J. 2020, 5, 118–124. [CrossRef] 47. Zervakis, G.I.; Bekiaris, G.; Tarantilis, P.A.; Pappas, C.S. Rapid Strain Classification and Taxa Delimitation within the Edible
Mushroom Genus Pleurotus through the Use of Diffuse Reflectance Infrared Fourier Transform (DRIFT) Spectroscopy. Fungal
Biol. 2012, 116, 715–728. [CrossRef] y y y
y
g
49. Gomba, G.K.; Synytsya, A.; Švecová, P.; Coimbra, M.A.; ˇCopíková, J. Distinction of Fungal Polysaccharides by N/C Ratio and y y y
y
g
49. Gomba, G.K.; Synytsya, A.; Švecová, P.; Coimbra, M.A.; ˇCopíková, J. Distinction of Fungal Polysaccharides by N/C Ratio and
Mid Infrared Spectroscopy. Int. J. Biol. Macromol. 2015, 80, 271–281. [CrossRef] 49. Gomba, G.K.; Synytsya, A.; Švecová, P.; Coimbra, M.A.; ˇCopíková, J. Distinction of Fu
Mid Infrared Spectroscopy. Int. J. Biol. Macromol. 2015, 80, 271–281. [CrossRef] p
py
Sheets, J.P.; Yang, L.; Ge, X.; Wang, Z.; Li, Y. Beyond Land Application: Emerging Technologies for the Tre Yang, L.; Ge, X.; Wang, Z.; Li, Y. Beyond Land Application: Emerging Technologies for the Treatment and R 50. Sheets, J.P.; Yang, L.; Ge, X.; Wang, Z.; Li, Y. Beyond Land Application: Emerging Technologies for the Treatment and Reuse of
Anaerobically Digested Agricultural and Food Waste. Waste Manag. 2015, 44, 94–115. [CrossRef] [PubMed] 50. References Plasmon enhanced spectroscopy. Phys. Chem. Chem. Phys. 2013, 15, 5355–5363. [CrossRef] [PubMed]
33. Butler, H.J.; Ashton, L.; Bird, B.; Cinque, G.; Curtis, K.; Dorney, J.; Esmonde-White, K.; Fullwood, N.J.; Gardner, B.; Martin-Hirsch,
P.L.; et al. Using Raman spectroscopy to characterize biological materials. Nat. Protoc. 2016, 11, 664–687. [CrossRef]
34. Le Ru, E.; Etchegoin, P. Principles of Surface Enhanced Raman Spectroscopy (and Related Plasmonic Effects); Elsevier: Amsterdam, The
Netherlands, 2009. ,
J ;
,
;
,
;
q
,
;
,
;
y, J ;
,
;
,
J ;
,
;
,
P.L.; et al. Using Raman spectroscopy to characterize biological materials. Nat. Protoc. 2016, 11, 664–687. [CrossRef]
34. Le Ru, E.; Etchegoin, P. Principles of Surface Enhanced Raman Spectroscopy (and Related Plasmonic Effects); Elsevier: Amsterdam, The
Netherlands, 2009. 35. Moskovits, M. Surface-enhanced spectroscopy. Rev. Mod. Phys. 1985, 57, 783–826. [CrossRef] 36. Moskovits, M.; Suh, J.S. Surface selection rules for surface-enhanced Raman spectroscopy: Calculations and application to the
surface-enhanced Raman spectrum of phthalazine on silver. J. Phys. Chem. 1984, 88, 5526–5530. [CrossRef] 37. Tryfinopoulou, P.; Chourdaki, A.; Nychas, G.-J.E.; Panagou, E.Z. Competitive Yeast Action against Aspergillus carbonarius Growth
and Ochratoxin A Production. Int. J. Food Microbiol. 2020, 317, 108460. [CrossRef] 38. Sinclair, C.G.; Cantero, D. Fermentation modelling. In Fermentation a Practical Approach; McNeil, B.L., Harvey, M., Eds.; IRL Press:
New York, NY, USA, 1989; pp. 65–112. ISBN 978-0-19-963044-8. pp
39. Oei, P. Mushroom Cultivation: Appropriate Technology for Mushroom Growers, 3rd ed.; Backhuys: Leiden, The Netherlands, 2003;
ISBN 978-90-5782-137-0. 18 of 19 Agronomy 2023, 13, 950 40. Jasi´nska, A.; Dawidowicz, L.; Siwulski, M.; Kilinowski, P. Growth of Mycelium of Different Edible and Medicinal Mushrooms on
Medium Supplemented with Digestate from AD Biogas Plant. Not. Bot. Horti. Agrobo. 2017, 45, 498–506. [CrossRef]
41. Cocchi, L.; Vescovi, L.; Petrini, L.E.; Petrini, O. Heavy metals in edible mushrooms in Italy. Food Chem. 2006, 98, 277–284. 40. Jasi´nska, A.; Dawidowicz, L.; Siwulski, M.; Kilinowski, P. Growth of Mycelium of Different Edible and Medicinal Mushrooms on
Medium Supplemented with Digestate from AD Biogas Plant. Not. Bot. Horti. Agrobo. 2017, 45, 498–506. [CrossRef]
41. Cocchi, L.; Vescovi, L.; Petrini, L.E.; Petrini, O. Heavy metals in edible mushrooms in Italy. Food Chem. 2006, 98, 277–284. [CrossRef] Medium Supplemented with Digestate from AD Biogas Plant. Not. Bot. Horti. Agrobo. 2017, 45, 498–506. [CrossRef]
41. Cocchi, L.; Vescovi, L.; Petrini, L.E.; Petrini, O. Heavy metals in edible mushrooms in Italy. 66.
Pang, L.; Wang, T.; Liao, Q.; Cheng, Y.; Wang, D.; Li, J.; Fu, C.; Zhang, C.; Zhang, J. Protective Role of Ergothioneine Isolated
from Pleurotus ostreatus against Dextran Sulfate Sodium-Induced Ulcerative Colitis in Rat Model. J. Food Sci. 2022, 87, 415–426.
[CrossRef] References Sheets, J.P.; Yang, L.; Ge, X.; Wang, Z.; Li, Y. Beyond Land Application: Emerging Technologies for the Treatment and Reuse of
Anaerobically Digested Agricultural and Food Waste. Waste Manag. 2015, 44, 94–115. [CrossRef] [PubMed] robically Digested Agricultural and Food Waste. Waste Manag. 2015, 44, 94–115. [CrossRef] [PubMed] 51. Udayasimha, D.L.; Vijayalakshmi, Y.C. Sustainable Waste Managementby Growing Mushroom (Pleurotus florida) on Anaerobically
Digested Waste and Agro Residues. Int. J. Eng. Res. 2012, 1, 1–8. g
g
52. O’Brien, B.J.; Milligan, E.; Carver, J.; Roy, E.D. Integrating Anaerobic Co-Digestion of Dairy Manu
Cultivation of Edible Mushrooms for Nutrient Recovery. Bioresour. Technol. 2019, 285, 121312. [CrossRe 52. O’Brien, B.J.; Milligan, E.; Carver, J.; Roy, E.D. Integrating Anaerobic Co-Digestion of Dairy Manure and Food Waste with
Cultivation of Edible Mushrooms for Nutrient Recovery. Bioresour. Technol. 2019, 285, 121312. [CrossRef] [PubMed]
53
Santi G ; Muzzini VG ; Galli E ; Proietti S ; Moscatello S ; Battistelli A Mycelial growth and enzymatic activities of white rot 53. Santi, G.; Muzzini, V.G.; Galli, E.; Proietti, S.; Moscatello, S.; Battistelli, A. Mycelial growth and enzyma
fungi on anaerobic digestates from industrial biogas plants. Environ. Eng. Manag. J. 2015, 14, 1713–171 54. Singh, S.; Harms, H.; Schlosser, D. Screening of Ecologically Diverse Fungi for Their Potential to Pretreat Lignocellulosic Bioenergy
Feedstock. Appl. Microbiol. Biotechnol. 2014, 98, 3355–3370. [CrossRef] 55. Schimpf, U.; Schrader, A.; Hübner, A.; Schulz, R.; Neubauer, P. Utilisation of Solid Digestate from Acidification Reactors of
Continues Two-Stage Anaerobic Digestion Processes in Lentinula edodes Cultivation. Bioresour. Technol. Rep. 2019, 8, 100322. [CrossRef] [
]
56. Zhou, J.-L.; Song, S.; Huang, Z.-X.; Yang, L.; Jiao, A.-G.; Liu, Y.; Wang, S.-X. Cultivation of Pleurotus ostreatus, a Potential Candidate
for Biogas Residues Degradation. BioRes 2018, 13, 5432–5449. [CrossRef] 57. Hoa, H.T.; Wang, C.-L.; Wang, C.-H. The Effects of Different Substrates on the Growth, Yield, and Nutritional Composition of
Two Oyster Mushrooms (Pleurotus ostreatus and Pleurotus cystidiosus). Mycobiology 2015, 43, 423–434. [CrossRef] 58. Osunde, M.O.; Olayinka, A.; Fashina, C.D.; Torimiro, N. Effect of Carbon-N
Yield of Mushroom (Pleurotus pulmonarius). OALib 2019, 6, 1–8. [CrossRef] 58. Osunde, M.O.; Olayinka, A.; Fashina, C.D.; Torimiro, N. Effect of Carbon-Nitrogen Ratios of Lignocellulosic Substrates on the
Yield of Mushroom (Pleurotus pulmonarius). OALib 2019, 6, 1–8. [CrossRef] 59. Sözbir, G.D.; Bektas, I.; Zulkadir, A. Lignocellulosic Wastes Used for the Cultivation of Pleurotus ostreatus Mushrooms: Effects on
Productivity. BioResources 2015, 10, 4686–4693. References [CrossRef] .; Ayyub, C.M.; Ahmad, R. Effects of different culture media, temperature and pH levels on the growth of
rotus species. Pak. J. Phytopathol. 2015, 27, 139–145. 60. Sardar, H.; Ali, M.A.; Ayyub, C.M.; Ahmad, R. Effects of different culture media, temperature and pH
wild and exotic Pleurotus species. Pak. J. Phytopathol. 2015, 27, 139–145. p
y p
61. Zied, D.C.; Minhoni, M.T.A.; Kopytowski-Filho, J.; Andrade, M.C.N. Production of Agaricus blazei Ss. Heinemann (A. brasiliensis)
on Different Casing Layers and Environments. World J. Microbiol. Biotechnol. 2010, 26, 1857–1863. [CrossRef] on Different Casing Layers and Environments. World J. Microbiol. Biotechnol. 2010, 26, 1857–1863. [CrossRef]
62. Berger, R.G.; Bordewick, S.; Krahe, N.-K.; Ersoy, F. Mycelium vs. Fruiting Bodies of Edible Fungi—A Comparison of Metabolites. Microorganisms 2022, 10, 1379. [CrossRef] [PubMed] 62. Berger, R.G.; Bordewick, S.; Krahe, N.-K.; Ersoy, F. Mycelium v
Microorganisms 2022, 10, 1379. [CrossRef] [PubMed] g
63. Zhang, Y.; Dai, L.; Kong, X.; Chen, L. Characterization and in Vitro Antioxidant Activities of Polysaccharides from Pleurotus
ostreatus. Int. J. Biol. Macromol. 2012, 51, 259–265. [CrossRef] [PubMed] 64. Kurt, S.; Buyukalaca, S. Yield Performances and Changes in Enzyme Activities of Pleurotus spp. (P. ostreatus and P. sajor-caju)
Cultivated on Different Agricultural Wastes. Bioresour. Technol. 2010, 101, 3164–3169. [CrossRef] [PubMed] 65. Pérez-Chávez, A.M.; Alberti, M.M.; Albertó, E. Evaluation of Ligninolytic Activity in Spent Mushroom Substrate from Four
Cultivated Mushrooms. J. Bioresour. Bioprod. 2022, 7, 288–294. [CrossRef] 66. Pang, L.; Wang, T.; Liao, Q.; Cheng, Y.; Wang, D.; Li, J.; Fu, C.; Zhang, C.; Zhang, J. Protective Role of Ergothioneine Isolated
from Pleurotus ostreatus against Dextran Sulfate Sodium-Induced Ulcerative Colitis in Rat Model. J. Food Sci. 2022, 87, 415–426. [CrossRef] 19 of 19 19 of 19 Agronomy 2023, 13, 950 67. Witkowska, E.; Jagielski, T.; Kami´nska, A.; Kowalska, A.; Hryncewicz-Gwó´zd´z, A.; Waluk, J. Detection and Identification of
Human Fungal Pathogens Using Surface-Enhanced Raman Spectroscopy and Principal Component Analysis. Anal. Methods 2016,
8, 8427–8434. [CrossRef] [
]
68. Feng, S.; Lin, J.; Cheng, M.; Li, Y.-Z.; Chen, G.; Huang, Z.; Yu, Y.; Chen, R.; Zeng, H. Gold Nanoparticle Based Surface-Enhanced
Raman Scattering Spectroscopy of Cancerous and Normal Nasopharyngeal Tissues under Near-Infrared Laser Excitation. Appl. Spectrosc. 2009, 63, 1089–1094. [CrossRef] p
69. Kim, J.S.; Kuk, E.; Yu, K.N.; Kim, J.-H.; Park, S.J.; Lee, H.J.; Kim, S.H.; Park, Y.K.; Park, Y.H.; Hwang, C.-Y.; et al. Antimicrobial
Effects of Silver Nanoparticles. Nanomed. Nanotechnol. Biol. Med. 2007, 3, 95–101. Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual
author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to
people or property resulting from any ideas, methods, instructions or products referred to in the content. References [CrossRef] 70. Kim, J.; Lee, J.; Kwon, S.; Jeong, S. Preparation of Biodegradable Polymer/Silver Nanoparticles Composite and Its Antibacterial
Efficacy. J. Nanosci. Nanotechnol. 2009, 9, 1098–1102. [CrossRef] [PubMed] den Tweel, T.J.J.; de Mul, F.F.M.; Greve, J. Surface-Enhanced Raman Spectroscopy of DNA Bases. J. Raman Sp
–298. [CrossRef] 71. Otto, C.; van den Tweel, T.J.J.; de Mul, F.F.M.; Greve, J. Surface-Enhanced Raman Spectroscopy of D
1986, 17, 289–298. [CrossRef] 72. Rivas, L.; Murza, A.; Sánchez-Cortés, S.; García-Ramos, J.V. Interaction of Antimalarial Drug Quinacrine with Nucleic Acids of
Variable Sequence Studied by Spectroscopic Methods. J. Biomol. Struct. Dyn. 2000, 18, 371–383. [CrossRef]
Š
ˇ 73. Baeva, E.; Bleha, R.; Sedliaková, M.; Sushytskyi, L.; Švec, I.; ˇCopíková, J.; Jablonsky, I.; Klouˇcek, P.; Synytsya, A. Evaluation of the
Cultivated Mushroom Pleurotus ostreatus Basidiocarps Using Vibration Spectroscopy and Chemometrics. Appl. Sci. 2020, 10, 8156. [CrossRef] [
]
74. Joseph, S.M.; Krishnamoorthy, S.; Paranthaman, R.; Moses, J.A.; Anandharamakrishnan, C. A Review on Source-Specific
Chemistry, Functionality, and Applications of Chitin and Chitosan. Carbohydr. Polym. Technol. Appl. 2021, 2, 100036. [CrossRef]
75. Harish Prashanth, K.V.; Tharanathan, R.N. Chitin/Chitosan: Modifications and Their Unlimited Application Potential—An
Overview. Trends Food Sci. Technol. 2007, 18, 117–131. [CrossRef] 76. Boureghda, Y.; Satha, H.; Bendebane, F. Chitin–Glucan Complex from Pleurotus ostreatus Mushroom: Physicochemical Characteri-
zation and Comparison of Extraction Methods. Waste Biomass Valor. 2021, 12, 6139–6153. [CrossRef] Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual
author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to
people or property resulting from any ideas, methods, instructions or products referred to in the content.
|
https://openalex.org/W2737501727
|
https://www.openbookpublishers.com/10.11647/OBP.0117.pdf
|
English
| null |
4. The Troubadours and Fin’amor: Love, Choice, and the Individual
|
Open Book Publishers
| 2,017
|
cc-by
| 251,383
|
Love and its Critics Love and its Critics From the Song of Songs to From the Song of Songs to
Shakespeare and Milton’s Eden Shakespeare and Milton’s Eden MICHAEL BRYSON AND ARPI MOVSESIAN
Shakespeare and Milton s Eden https://www.openbookpublishers.com © 2017 Michael Bryson and Arpi Movsesian This work is licensed under a Creative Commons Attribution 4.0 International license (CC
BY 4.0). This license allows you to share, copy, distribute and transmit the work; to adapt
the work and to make commercial use of the work providing attribution is made to the
authors (but not in any way that suggests that they endorse you or your use of the work). Attribution should include the following information: Michael Bryson and Arpi Movsesian, Love and its Critics: From the Song of Songs to
Shakespeare and Milton’s Eden. Cambridge, UK: Open Book Publishers, 2017, https://doi. org/10.11647/OBP.0117 Michael Bryson and Arpi Movsesian, Love and its Critics: From the Song of Songs to
Shakespeare and Milton’s Eden. Cambridge, UK: Open Book Publishers, 2017, https://doi. org/10.11647/OBP.0117 Michael Bryson and Arpi Movsesian, Love and its Critics: From the Song of Songs to
Shakespeare and Milton’s Eden. Cambridge, UK: Open Book Publishers, 2017, https://doi. org/10.11647/OBP.0117 In order to access detailed and updated information on the license, please visit https://
www.openbookpublishers.com/product/611#copyright In order to access detailed and updated information on the license, please visit https://
www.openbookpublishers.com/product/611#copyright Further details about CC BY licenses are available at http://creativecommons.org/licenses/
by/4.0/ Further details about CC BY licenses are available at http://creativecommons.org/licenses/
by/4.0/ All external links were active at the time of publication unless otherwise stated and have
been archived via the Internet Archive Wayback Machine at https://archive.org/web Digital material and resources associated with this volume are available at https://www. openbookpublishers.com/product/611#resources Every effort has been made to identify and contact copyright holders and any omission or
error will be corrected if notification is made to the publisher. Every effort has been made to identify and contact copyright holders and any omission or
error will be corrected if notification is made to the publisher. California State University Northridge has provided support for the publication of
this volume. https://www.openbookpublishers.com ISBN Paperback: 978–1-78374–348–3
ISBN Hardback: 978–1-78374–349–0
ISBN Digital (PDF): 978–1-78374–350–6
ISBN Digital ebook (epub): 978–1-78374–351–3
ISBN Digital ebook (mobi): 978–1-78374–352–0
DOI: 10.11647/OBP.0117 ISBN Paperback: 978–1-78374–348–3 ISBN Hardback: 978–1-78374–349–0 ISBN Digital (PDF): 978–1-78374–350–6 ISBN Digital ebook (epub): 978–1-78374–351–3 ISBN Digital ebook (mobi): 978–1-78374–352–0 Cover image: Ary Scheffer, Dante and Virgil Encountering the Shades of Francesca da Rimini and
Paolo in the Underworld (1855), Wikimedia, https://commons.m.wikimedia.org/wiki/File:1855_
Ary_Scheffer_-_The_Ghosts_of_Paolo_and_Francesca_Appear_to_Dante_and_Virgil.jpg All paper used by Open Book Publishers is SFI (Sustainable Forestry Initiative), PEFC
(Programme for the Endorsement of Forest Certification Schemes) and Forest Stewardship
Council(r)(FSC(r) certified. Printed in the United Kingdom, United States, and Australia
by Lightning Source for Open Book Publishers (Cambridge, UK) I went to the Garden of Love,
And saw what I never had seen:
A Chapel was built in the midst,
Where I used to play on the green. And the gates of this Chapel were shut,
And Thou shalt not, writ over the door;
So I turn’d to the Garden of Love,
That so many sweet flowers bore. And I saw it was filled with graves,
And tomb-stones where flowers should be:
And Priests in black gowns, were walking their rounds,
And binding with briars, my joys & desires. —William Blake, “The Garden of Love”, Songs of Experience Et si notre âme a valu quelque chose, c’est qu’elle a brûlé plus ardemment
que quelques autres. —André Gide, Les Nourritures terrestres —André Gide, Les Nourritures terrestres —André Gide, Les Nourritures terrestres Die Wissenschaft unter der Optik des Künstlers zu sehn, die Kunst aber
unter der des Lebens. —Friedrich Nietzsche, Die Geburt der Tragödie aus dem Geiste der Musik Contents Acknowledgements
ix
A Note on Sources and Languages
x
1. Love and Authority: Love Poetry and its Critics
1
I. The Poetry of Love
1
II. Love’s Nemesis: Demands for Obedience
3
III. Love’s Critics: The Hermeneutics of Suspicion and the
Authoritarian Approach to Criticism
10
IV. The Critics: Poetry Is About Poetry
23
V. The Critics: The Author Is Dead (or Merely Irrelevant)
29
2. Channeled, Reformulated, and Controlled: Love Poetry from the
Song of Songs to Aeneas and Dido
37
I. Love Poetry and the Critics who Allegorize: The Song of Songs
37
II. Love Poetry and the Critics who Reduce: Ovid’s Amores and
Ars Amatoria
57
III. Love or Obedience in Virgil: Aeneas and Dido
77
IV. Love or Obedience in Ovid: Aeneas, Dido, and the Critics
who Dismiss
89 Acknowledgements Acknowledgements 3. Love and its Absences in Late Latin and Greek Poetry
97
I. Love in the Poetry of Late Antiquity: Latin
97
II. Love in the Poetry of Late Antiquity: Greek
113
4. The Troubadours and Fin’amor: Love, Choice, and the Individual
121
I. Why “Courtly Love” Is Not Love
121
II. The Troubadours and Their Critics
136
III. The Troubadours and Love
165
5. Fin’amor Castrated: Abelard, Heloise, and the Critics who Deny
195
6. The Albigensian Crusade and the Death of Fin’amor in Medieval
French and English Poetry
215
I. The Death of Fin’amor: The Albigensian Crusade and its
Aftermath
215
II. Post-Fin’amor French Poetry: The Roman de la Rose
238
III. Post-Fin’amor English Romance: Love of God and Country
in Havelok the Dane and King Horn
275
IV. Post-Fin’amor English Poetry: Mocking “Courtly Love”
in Chaucer—the Knight and the Miller
280
V. Post-Fin’amor English Poetry: Mocking “Auctoritee”
in Chaucer—the Wife of Bath
286
7. The Ladder of Love in Italian Poetry and Prose, and the Reactions
of the Sixteenth-Century Sonneteers
295
I. The Platonic Ladder of Love
295
II. Post-Fin’amor Italian Poetry: The Sicilian School to Dante
and Petrarch
300
III. Post-Fin’amor Italian Prose: Il Libro del Cortegiano (The Book of
the Courtier)
330
IV. The Sixteenth-Century: Post-Fin’amor Transitions in
Petrarchan-Influenced Poetry
336 7. The Ladder of Love in Italian Poetry and Prose, and the Reactions
of the Sixteenth-Century Sonneteers
295
I. The Platonic Ladder of Love
295
II. Post-Fin’amor Italian Poetry: The Sicilian School to Dante
and Petrarch
300
III. Contents Post-Fin’amor Italian Prose: Il Libro del Cortegiano (The Book of
the Courtier)
330
IV. The Sixteenth-Century: Post-Fin’amor Transitions in
Petrarchan-Influenced Poetry
336 8. Shakespeare: The Return of Fin’amor
353
I. The Value of the Individual in the Sonnets
353
II. Shakespeare’s Plays: Children as Property
367
III. Love as Resistance: Silvia and Hermia
378
IV. Love as Resistance: Juliet and the Critics who Disdain
393
9. Love and its Costs in Seventeenth-Century Literature
421
I. Carpe Diem in Life and Marriage: John Donne and the
Critics who Distance
422
II. The Lyricist of Carpe Diem: Robert Herrick and the
Critics who Distort
445
10. Paradise Lost: Love in Eden, and the Critics who Obey
467
Epilogue. Belonging to Poetry: A Reparative Reading
501
Bibliography
513
Index
553 Acknowledgements This book emerges from multiple experiences and perspectives:
teaching students at California State University and the University
of California; leaving a religious tradition, and leaving a country and
an entire way of life; extensive written and verbal conversations with
people from all over the world—from the Middle East, Africa, Sri
Lanka, Western Europe, the former Soviet Union, and the Asian Pacific
Rim; and finally, an attempt to understand what has happened to the
study of poetry, especially love poetry, in modern literary education. Our thanks go out to Alessandra Tosi, Lucy Barnes and Francesca
Giovannetti at Open Book Publishers, who worked tirelessly with
us on the manuscript to make this book possible. Thanks are due
especially to Nazanin Keynejad, who read and commented upon the
first draft of this book, and to Modje Taavon, who provided valuable
insight into the similarities between the early modern European and
contemporary Middle Eastern cultures. Special thanks are also due to
Robert Bryson, Naomi Bryson, Heather Bryson, Alan Wolstrup, Steven
Wolstrup, Yeprem Movsesian, Ruzan Petrosian, Haik Movsesian,
and Edgar Movsesian, not only for their differing experiences and
perspectives, but for personal encouragement and support. 1
Aharon Ben-Zeʼev and Ruhama Goussinsky. In the Name of Love: Romantic Ideology
and Its Victims (Oxford: Oxford University Press, 2008), 63. © 2017 Michael Bryson and Arpi Movsesian, CC BY 4.0 A Note on Sources and Languages This book works with material that spans two thousand years and
multiple languages. Many, though by no means all, of the sources it
works with are from older editions that are publicly available online. This is done deliberately in order to allow readers who may not be
attached to insitutions with well-endowed libraries to access as much of
the information that informs this work as possible, without encountering
paywalls or other access restrictions. It was not possible to follow this
procedure in all cases, but every effort has been made. Where the book
works with texts in languages other than English, the original is provided
along with an English translation. This is done in order to emphasize
that the poetic and critical tradition spans both time and place, reflecting
arguments that are conducted in multiple language traditions. This is also
done, frankly, to make a point about language education in the English-
speaking world, especially in the United States, where foreign-language
requirements are increasingly being questioned and enrollment figures
have declined over the last half-century—according to the 2015 MLA
report, language enrollments per 100 American college students stands
at 8.1 as of 2013, which is half of the ratio from 1960 (https://www.mla. org/content/download/31180/1452509/EMB_enrllmnts_nonEngl_2013. pdf, 37). Languages matter. Words matter. One of the arguments of
this book is that the specific words and intentions of the poets and the
critics matter; though English translation is necessary, it is not sufficient. Quoting the original words of the poets and the critics is a way of giving
the authors their voice. I
The Poetry of Love Love has always had its critics. They range far and wide throughout
history, from Plato and the Neoplatonists, to the Rabbinic and Christian
interpreters of the Song of Songs, from the clerics behind the savage
Albigensian Crusade, to the seventeenth-century English Puritan
author William Prynne, who never met a joy he failed to condemn. Love has never lacked for those who try to tame it for “higher”
purposes, or those who would argue that “the worst evils have been
committed in the name of love”.1 At the same time, love has always
had its passionate defenders, though these have more often tended
to be poets—the Ovids, Shakespeares, and Donnes—than critics of
poetry. The relationship between the two—poets and critics—is one of
the central concerns of this book. The story this book tells follows two paths: it is a history of love,
a story told through poetry and its often adversarial relationship to
the laws and customs of its times and places. But it is also a history
of the way love and poetry have been treated, not by our poets, but
by those our culture has entrusted with the authority to perpetuate the
understanding, and the memory, of poetry. This authority has been © 2017 Michael Bryson and Arpi Movsesian, CC BY 4.0 https://doi.org/10.11647/OBP.0117.01 Love and its Critics 2 2 abused by a tradition of critics and criticism over two thousand years
old, a tradition dedicated to reducing poetry to allegory or ideology,
insisting that the words of poems do not mean what they appear to mean
to the average reader. And yet, love and its poetry fight back, not just
against critics but against all the real and imagined tyrants of the world. As we will see in the work of Shakespeare, love stands against a system
of arranged marriages in which individual desires are subordinated to
the rule of the Father, property, and inherited wealth. Sometimes, as in
Milton’s Paradise Lost, love will even stand against God himself. As Dante
demonstrates with his account of Paolo and Francesca, love lives the truth
that Milton’s Satan speaks: it is better to reign in hell than serve in heaven. p
g
What is this love? And how is it treated in our poetry? 2
This working definition is at odds with much, though by no means all, of the
specialized scholarship on troubadour poetry. One of the major contentions of this
book is that too much of the work by specialists in many literary fields minimizes,
reinterprets, or outright ignores the human elements of love and desire in poetry,
a situation which scholars like Simon Gaunt and Sarah Kay admit has gone too
far. See “Introduction”. In Simon Gaunt and Sarah Kay, eds. The Troubadours: An
Introduction (Cambridge: Cambridge University Press, 1999), 6. I
The Poetry of Love Ranging from
the ancients to the early moderns, from the Bible to medieval literature,
from Shakespeare to the poetry of the seventeenth century and our own
modern day, the love presented here is neither exclusively of the body,
nor exclusively of the spirit. It is not merely sex—though some critics
have been eager to dismiss it in just this way. Neither, however, is it
only spiritual, intellectual, emotional, or what is popularly referred to
as Platonic. The love this book considers, and that so much of our poetry
celebrates, is a combination of the physical and the emotional, the sexual
and the intellectual, the embodied and the ethereal. Above all, it is a
matter of mutual choice between lovers who are each at once Lover and
Beloved. Often marginalized by, and in opposition to church, state, and
the institutions of marriage and law, this love is what the troubadour
poets of the eleventh and twelfth centuries referred to as fin’amor.2 It is
anarchic and threatening to the established order, and a great deal of
cultural energy has gone into taming it. Fin’amor—passionate and mutually chosen love, desire, and regard—
has been invented and reinvented over the centuries. It appears in
Hellenistic Jerusalem as a glimpse back into the age of Solomon, then
fades into the dim background of Rabbinical and Christian allegory. It 1. Love and Authority: Love Poetry and its Critics 3 3 is revived in France, in the eleventh and twelfth centuries, by poets and
an unusual group of Rabbis, only to fade once again, betrayed by later
poets writing under the twin spells of Neoplatonism and Christianizing
allegory. These later poets radically reshape the ideas of love expressed
in the poems of medieval Provençe and the ancient Levant, writing in
what Dante calls the “sweet new style” (dolce stil novo) that changed love
into worship, men into idolators, and women into idols. The influence of
their verse is still observable in the English poetry of Philip Sidney two
hundred years after the death of Petrarch, the dolce stil novo’s high priest. Subsequently, writers such as Shakespeare, Donne, Herrick, and Milton
re-invent the love that had almost been lost, putting a new version of
fin’amor on the stage and on the page, pulling it back into the light and
out of the shadows of theology, philosophy, and law. 3
“ὅτι μὲν τοίνυν εἰσὶ φύσει τινὲς οἱ μὲν ἐλεύθεροι οἱ δὲ δοῦλοι, φανερόν, οἷς
καὶ συμφέρει τὸ δουλεύειν καὶ δίκαιόν ἐστιν”(Aristotle. Politics, ed. by Harris
Rackham [Cambridge, MA: Loeb Classical Library, Harvard University Press],
1932, 1255a, 22, 24). Unless otherwise noted, all translations are ours. I
The Poetry of Love For better, or for
worse, fin’amor has been with us ever since. II
Love’s Nemesis: Demands for Obedience II 5
“Ordo autem iustitiae requirit ut inferiores suis superioribus obediant, aliter
enim non posset humanarum rerum status conservari” (Thomas Aquinas. Summa
Theologiae: Vol. 41, Virtues of Justice in the Human Community, ed. by T. C. O’Brien
[Cambridge: Cambridge University Press, 2006], 2a2ae. Q104, A6, 72). 4
“Nullus autem natura, in qua prius Deus hominem condidit, seruus est hominis
aut peccati. Verum et poenalis seruitus ea lege ordinatur, quae naturalem ordinem
conseruari iubet, perturbari uetat; quia si contra eam legem non esset factum, nihil
esset poenali seruitute coërcendum” (Augustine of Hippo. De Civitate Dei [Paris:
1586], Book 19, Chapter 15, 250, https://books.google.com/books?id=pshhAAAAcA
AJ&pg=PA250). 6
“Nun aber kein Mensch von Natur Christ oder fromm ist, sondern sie allzumal
Sünder und böse sind, wehret ihnen Gott allen durchs Gesetz, daß sie ihre Bosheit
nicht äußerlich mit Werken nach ihrem Mutwillen zu üben wagen” (Martin Luther.
Von Weltlicher Obrigkeit [Berlin: Tredition Classics, 2012], 10). 7
Verùm si in Dei verbum respicimus, longius nos deducet, ut non eorum modò principú imperio
subditi simus, qui probè, & qua debét fide munere suo erga nos defungútur: sed omnium qui
quoquo modo rerum potiuntur, etiamsi nihil minus praestét quàm quod ex officio principum.
[…] simul tamen declarat, qualescunque sint, nonnisi à se habere imperium. Love’s Nemesis: Demands for Obedience Running parallel with the tradition of love poetry is a style of thought
which argues that obedience, rather than passion, is the prime virtue of
humankind. Examples of obedience demanded and given are abundant
in our scriptures, such as the injunction in Genesis against eating from
the Tree of Knowledge; in our poetry, such as the Aeneid’s portrayal
of Aeneas rejecting Dido in obedience to the gods; and even in our
philosophy, as in Aristotle’s distinction between free men and slaves:
“It is true, therefore, that there are by natural origin those who are truly
free men, but also those who are visibly slavish, and for these slavery is
both beneficial and just”.3 Such expectations of obedience often appear
in the writing of those who argue that human law derives from divine
law. Augustine argues that though God did not intend that Man should
have dominion over Man, it now exists because of sin: 4 Love and its Critics Love and its Critics But by nature, as God first created us, no one was a slave either of man or
of sin. In truth, our present servitude is penal, a penalty which is meant
to preserve the natural order of law and forbids its disturbance; because,
if nothing had been done contrary to that law, there would have been
nothing to restrain by penal servitude.4 Nearly a millennium later, Thomas Aquinas argues from a similar
perspective: “The order of justice requires that inferiors obey their
superiors, for otherwise the stability of human affairs could not be
maintained”.5 Even a famous rebel like Martin Luther directs ordinary
citizens to obey the law God puts in place: “No man is by nature Christian
or religious, but all are sinful and evil, wherefore God restrains them all
through the law, so that they do not dare to practice their wickedness
externally with works”.6 According to John Calvin, absolute obedience
is due not only to benevolent rulers, but also to tyrants. Wicked rulers
are a punishment from God: Truthfully, if we look at the Word of God, this will lead us further. We
are not only to be subject to their authority, who are honest, and rule by
what ought to be the gift of God’s love to us, but also to the authority
of all those who in any way have come into power, even if their rule is
nothing less than that of the office of the princes of the blind. […] at the
same time he declares that, whatever they may be, they have their rule
and authority from him.7 1. Love and Authority: Love Poetry and its Critics 5 5 For these thinkers, obedience is the prime duty of humankind, because
it is ultimately in service to the God who established all authority in the
first place. To be obedient is therefore to be pleasing to God. Such demands for obedience are ancient, and widespread, but
resistance has its own long tradition. Jean Calvin. Institutio Christianae Religionis (Geneva: Oliua Roberti Stephani, 1559),
559, https://books.google.com/books?id=6ysy-UX89f4C&dq=Oliua+Roberti+Stepha
ni,+1559&pg=PA559
8
“Il n’est pas croyable comme le peuple, dès lors qu’il est assujetti, tombe si soudain
en un tel et si profond oubli de la franchise, qu’il n’est pas possible qu’il se réveille
pour la ravoir, servant si franchement et tant volontiers qu’on dirait, à le voir, qu’il a
non pas perdu sa liberté, mais gagné sa servitude” (Étienne de La Boétie. Discours de
la Servitude Volontaire [1576] [Paris: Éditions Bossard, 1922], 67, https://fr.wikisource.
org/wiki/Page:La_Boétie_-_Discours_de_la_servitude_volontaire.djvu/73).
9
“Ils disent qu’ils ont été toujours sujets, que leurs pères ont ainsi vécu; ils pensent
qu’ils sont tenus d’endurer le mal et se font accroire par exemple, et fondent eux-
mêmes sous la longueur du temps la possession de ceux qui les tyrannisent; mais
pour vrai, les ans ne donnent jamais droit de mal faire, ains agrandissent l’injure”
(ibid.,
74–75,
https://fr.wikisource.org/wiki/Page:La_Boétie_-_Discours_de_la_
servitude_volontaire.djvu/80). Jean Calvin. Institutio Christianae Religionis (Geneva: Oliua Roberti Stephani, 1559),
559, https://books.google.com/books?id=6ysy-UX89f4C&dq=Oliua+Roberti+Stepha
ni,+1559&pg=PA559 9
“Ils disent qu’ils ont été toujours sujets, que leurs pères ont ainsi vécu; ils pensent
qu’ils sont tenus d’endurer le mal et se font accroire par exemple, et fondent eux-
mêmes sous la longueur du temps la possession de ceux qui les tyrannisent; mais
pour vrai, les ans ne donnent jamais droit de mal faire, ains agrandissent l’injure”
(ibid.,
74–75,
https://fr.wikisource.org/wiki/Page:La_Boétie_-_Discours_de_la_
servitude_volontaire.djvu/80). 8
“Il n’est pas croyable comme le peuple, dès lors qu’il est assujetti, tombe si soudain
en un tel et si profond oubli de la franchise, qu’il n’est pas possible qu’il se réveille
pour la ravoir, servant si franchement et tant volontiers qu’on dirait, à le voir, qu’il a
non pas perdu sa liberté, mais gagné sa servitude” (Étienne de La Boétie. Discours de
la Servitude Volontaire [1576] [Paris: Éditions Bossard, 1922], 67, https://fr.wikisource.
org/wiki/Page:La Boétie - Discours de la servitude volontaire djvu/73) 8
“Il n’est pas croyable comme le peuple, dès lors qu’il est assujetti, tombe si soudain
en un tel et si profond oubli de la franchise, qu’il n’est pas possible qu’il se réveille
pour la ravoir, servant si franchement et tant volontiers qu’on dirait, à le voir, qu’il a
non pas perdu sa liberté, mais gagné sa servitude” (Étienne de La Boétie. Discours de
la Servitude Volontaire [1576] [Paris: Éditions Bossard, 1922], 67, https://fr.wikisource.
org/wiki/Page:La_Boétie_-_Discours_de_la_servitude_volontaire.djvu/73).
9
“Ils disent qu’ils ont été toujours sujets, que leurs pères ont ainsi vécu; ils pensent
qu’ils sont tenus d’endurer le mal et se font accroire par exemple, et fondent eux-
mêmes sous la longueur du temps la possession de ceux qui les tyrannisent; mais
pour vrai, les ans ne donnent jamais droit de mal faire, ains agrandissent l’injure” 10
“[L]a première raison pourquoi les hommes servent volontiers, est pour ce qu’ils
naissent serfs et sont nourris tels. De celle-ci en vient une autre, qu’aisément les gens
deviennent, sous les tyrans, lâches et efféminés” (ibid., 77–78, https://fr.wikisource.
org/wiki/Page:La_Boétie_-_Discours_de_la_servitude_volontaire.djvu/83). g
g
j
)
11
“il n’a jamais été que les tyrans, pour s’assurer, ne se soient efforcés d’accoutumer
le peuple envers eux, non seulement à obéissance et servitude, mais encore à
dévotion” (ibid., 89, https://fr.wikisource.org/wiki/Page:La_Boétie_-_Discours_de_
la_servitude_volontaire.djvu/95). 12
Renoncer à sa liberté, c’est renoncer à sa qualité d’homme, aux droits de l’humanité, même
à ses devoirs. […] Une telle renonciation est incompatible avec la nature de l’homme, et c’est
ôter toute moralité à ses actions que d’ôter toute liberté à sa volonté. Enfin c’est une convention
vaine et contradictoire de stipuler d’une part une autorité absolue et de l’autre une obéissance
sans bornes.
Jean-Jacques Rousseau. Contrat Social. In The Political Writings of Jean-Jacques Rosseau,
Vol. 2, ed. by C. E. Vaughan (Cambridge: Cambridge University Press, 1915), 28,
https://books.google.com/books?id=IqhBAAAAYAAJ&pg=PA28 j
12
Renoncer à sa liberté, c’est renoncer à sa qualité d’homme, aux droits de l’humanité, même
à ses devoirs. […] Une telle renonciation est incompatible avec la nature de l’homme, et c’est
ôter toute moralité à ses actions que d’ôter toute liberté à sa volonté. Enfin c’est une convention
vaine et contradictoire de stipuler d’une part une autorité absolue et de l’autre une obéissance
sans bornes. Jean-Jacques Rousseau. Contrat Social. In The Political Writings of Jean-Jacques Rosseau,
Vol. 2, ed. by C. E. Vaughan (Cambridge: Cambridge University Press, 1915), 28,
https://books.google.com/books?id=IqhBAAAAYAAJ&pg=PA28 Love and its Critics Étienne de La Boétie, the sixteenth-
century author, judge, and friend to Michel Montaigne, argues that
human beings have long become so used to servitude that they no
longer know how to be free: It is incredible how a people, when it becomes subject, falls so suddenly
and profoundly into forgetfulness of its freedom, so that it is not possible
for them to win it back, serving so frankly and so happily that it seems, at
a glance, that they have not lost their freedom but won their servitude.8 It is incredible how a people, when it becomes subject, falls so suddenly
and profoundly into forgetfulness of its freedom, so that it is not possible
for them to win it back, serving so frankly and so happily that it seems, at
a glance, that they have not lost their freedom but won their servitude.8 La Boétie maintains that obedience has become so engrained in most
people, that they regard their subjection as normal and necessary: They will say they have always been subjects, and their fathers lived the
same way; they will think they are obliged to endure the evil, and they
demonstrate this to themselves by examples, and find themselves in the
length of time to be the possessions of those who lord it over them; but
in reality, the years never gave any the right to do them wrong, and this
magnifies the injury.9 This “injury” leads La Boétie to reject the idea of natural obedience,
proposing instead a model through which he accuses “the tyrants”
(“les tyrans”) of carefully inculcating the idea of submission into the
populations they dominate: 9
“Ils disent qu’ils ont été toujours sujets, que leurs pères ont ainsi vécu; ils pensent
qu’ils sont tenus d’endurer le mal et se font accroire par exemple, et fondent eux-
mêmes sous la longueur du temps la possession de ceux qui les tyrannisent; mais
pour vrai, les ans ne donnent jamais droit de mal faire, ains agrandissent l’injure”
(ibid.,
74–75,
https://fr.wikisource.org/wiki/Page:La_Boétie_-_Discours_de_la_
servitude_volontaire.djvu/80). 6 6 Love and its Critics Love and its Critics The first reason why men willingly serve, is that they are born serfs and
are nurtured as such. From this comes another easy conclusion: people
become cowardly and effeminate under tyrants.10 […] It has never been
but that tyrants, for their own assurance, have made great efforts to
accustom their people to them, [training them] not only in obedience
and servitude, but also in devotion.11 Two centuries later, Jean-Jacques Rousseau raises his voice against the
authority of “les tyrans”, arguing that liberty is the very basis of humanity: To renounce liberty is to renounce being a man, the rights of humanity,
even its duties. […] Such a renunciation is incompatible with the nature
of man, and to remove all liberty from his will is to remove all morality
from his actions. Finally, it is a vain and contradictory convention to
stipulate on the one hand an absolute authority, and on the other an
unlimited obedience.12 But what Rousseau calls a renunciation of liberty, framing it as a
conscious act, La Boétie presents as something that is done to rather than
done by average men and women: “they are born as serfs and nurtured as
such”. In the latter’s view, it is those in authority who “nurture” (raise,
nourish, even instruct) their populations into the necessary attitudes of
what Rousseau will later call une obéissance sans bornes. Such “nurture” performs a pedagogical function, teaching men and
women to think their bondage is natural: for La Boétie, “it is certain
that custom, which in all things has great power over us, has no greater 1. 13
“Mais certes la coutume, qui a en toutes choses grand pouvoir sur nous, n’a en
aucun endroit si grande vertu qu’en ceci, de nous enseigner à servir” (La Boétie,
68,
https://fr.wikisource.org/wiki/Page:La_Boétie_-_Discours_de_la_servitude_
volontaire.djvu/74). 17
David Hume. “Of the First Principles of Government”. In Essays, Literary, Moral,
and Political (London: Ward, Lock & Co., 1870), 23, https://babel.hathitrust.org/cgi/
pt?id=uc2.ark:/13960/t1fj2db8p;view=1up;seq=27 14
John Milton. The Tenure of Kings and Magistrates (London, 1649), 1, Sig. A2r, http://
quod.lib.umich.edu/e/eebo/A50955.0001.001/1:2?rgn=div1;view=fulltext;q1=Te
nure+of+Kings+and+Magistrates
and
https://books.google.com/books?id=EIg-
AQAAMAAJ&pg=PA1 (1650 edition). 15
John Milton. Eikonoklastes (London, 1650), 3, Sig. A3r, http://quod.lib.umich.edu/e/
eebo/A50898.0001.001/1:2?rgn= div1;view=fulltext;rgn1=author;q1=Milton%2C+John
16
John Milton. The Doctrine and Discipline of Divorce. London, 1644, Sig. A2r, https://
books.google.com/books?id=6oI-AQAAMAAJ&pg=PP9 14
John Milton. The Tenure of Kings and Magistrates (London, 1649), 1, Sig. A2r, http://
quod.lib.umich.edu/e/eebo/A50955.0001.001/1:2?rgn=div1;view=fulltext;q1=Te
nure+of+Kings+and+Magistrates
and
https://books.google.com/books?id=EIg-
AQAAMAAJ&pg=PA1 (1650 edition).
15
John Milton. Eikonoklastes (London, 1650), 3, Sig. A3r, http://quod.lib.umich.edu/e/
eebo/A50898.0001.001/1:2?rgn= div1;view=fulltext;rgn1=author;q1=Milton%2C+John
16
John Milton. The Doctrine and Discipline of Divorce. London, 1644, Sig. A2r, https://
books.google.com/books?id=6oI-AQAAMAAJ&pg=PP9 p
g
g
volontaire.djvu/74).
14
John Milton. The Tenure of Kings and Magistrates (London, 1649), 1, Sig. A2r, http://
quod.lib.umich.edu/e/eebo/A50955.0001.001/1:2?rgn=div1;view=fulltext;q1=Te
nure+of+Kings+and+Magistrates
and
https://books.google.com/books?id=EIg-
AQAAMAAJ&pg=PA1 (1650 edition).
15
John Milton. Eikonoklastes (London, 1650), 3, Sig. A3r, http://quod.lib.umich.edu/e/
eebo/A50898.0001.001/1:2?rgn= div1;view=fulltext;rgn1=author;q1=Milton%2C+John
16
John Milton. The Doctrine and Discipline of Divorce. London, 1644, Sig. A2r, https://
books.google.com/books?id=6oI-AQAAMAAJ&pg=PP9
17
David Hume. “Of the First Principles of Government”. In Essays, Literary, Moral,
and Political (London: Ward, Lock & Co., 1870), 23, https://babel.hathitrust.org/cgi/
pt?id=uc2.ark:/13960/t1fj2db8p;view=1up;seq=27 18
“Die hierbei zur Herrschaft kommende Tradition macht zunächst und zumeist
das, was sie ‘übergibt’, so wenig zugänglich, daß sie es vielmehr verdeckt. Sie
überantwortet das Überkommene der Selbstverständlichkeit und verlegt den
Zugang zu den ursprünglichen ‘Quellen’, daraus die überlieferten Kategorien und
Begriffe z. T. in echter Weise geschöpft wurden. Die Tradition macht sogar eine
solche Herkunft überhaupt vergessen” (Sein und Zeit [Tübingen: Max Niemeyer,
1967], 21). Love and its Critics Love and Authority: Love Poetry and its Critics 7 strength than this, to teach us how to serve”.13 Some seventy years later, the
English revolutionary John Milton makes a similar argument, describing
“custom” as part of the double tyranny that keeps mankind in subjection: If men within themselves would be govern’d by reason and not generally
give up their understanding to a double tyrannie, of custome from
without and blind affections within, they would discerne better what it
is to favour and uphold the Tyrant of a Nation.14 Milton, in pamphlets that ridicule the pro-monarchical propaganda
of his day, berates what he calls “the easy literature of custom and
opinion”,15 the authoritative-sounding, but empty writing and speaking
that teaches “the most Disciples” and is “silently receiv’d for the best
instructer”, despite the fact that it offers nothing but a “swoln visage of
counterfeit knowledge and literature”.16 David Hume later notes “the
easiness with which the many are governed by the few; and the implicit
submission with which men resign their own sentiments and passions
to those of their rulers”. Hume explains this submission as a function
of “opinion”, or the “sense” that is inculcated into the many “of the
general advantage” to be had by obeying “the particular government
which is established”.17 By the twentieth century, Martin Heidegger condemns “tradition”
as a manipulative force that obscures both its agenda and its origins: The tradition that becomes dominant hereby makes what it “transmits”
so inaccessible that at first, and for the most part, it obscures it instead. It hands over to the self-evident and obvious what has come down to us,
and blocks access to the original “sources”, from which the traditional 8 8 Love and its Critics categories and concepts in part were actually drawn. The tradition even
makes us forget there ever was such an origin.18 In contrast, Edward Bernays—a member of the Creel Committee which
influenced American public opinion in favor of entering WWI—regards
such manipulation as necessary to ensure the obedience of the masses: The conscious and intelligent manipulation of the organized habits and
opinions of the masses is an important element in democratic society. Those who manipulate this unseen mechanism of society constitute an
invisible government which is the true ruling power of our country. 19
Edward Bernays. Propaganda (New York: Horace Liveright, 1928), 9, https://archive.
org/details/EdwardL.BernaysPropaganda#page/n3 20
It was, of course, the astounding success of propaganda during the war that
opened the eyes of the intelligent few in all departments of life to the possibilities
of regimenting the public mind. […] If we understand the mechanism and motives
of the group mind, is it not possible to control and regiment the masses according
to our will without them knowing it? (Bernays, 27, 47). Bernays’ ideas are not far
removed from those being promulgated on the other side of the Atlantic ocean by
an aspiring literary critic and author whose Ph.D. in literature was obtained at the
University of Heidelberg in 1921, and whose critical acumen was given a real-world
application approximately a decade later: 21
“Обычай деспот меж людей”. Evgeny Onegin, 1.25.4. In Aleksandr Sergeevich
Pushkin. Sobraniye Sochinenii. 10 Vols., ed. by D. D. Blagoi, S. M. Bondi, V. V.
Vinogradov and Yu. G. Oksman (Moscow: Khudozhestvennaia literatura, 1959),
Vol. 4, 20, http://rvb.ru/pushkin/01text/04onegin/01onegin/0836.htm
22
John Milton. The Doctrine and Discipline of Divorce. London, 1644, Sig. A2r, https://
books.google.com/books?id=6oI-AQAAMAAJ&pg=PP9
23
Simon May. Love: A History (New Haven: Yale University Press, 2011), xii. Love and its Critics We are governed, our minds are molded, our tastes formed, our ideas
suggested, largely by men we have never heard of.19 Though Bernays thinks of such techniques as a good thing
(foreshadowing developments elsewhere in the twentieth century),20 for
earlier thinkers like La Boétie, Milton, and Hume, it is crucial to keep a
watchful eye on those who draw “the most Disciples” after them, for Though Bernays thinks of such techniques as a good thing
(foreshadowing developments elsewhere in the twentieth century),20 for
earlier thinkers like La Boétie, Milton, and Hume, it is crucial to keep a
watchful eye on those who draw “the most Disciples” after them, for 20
It was, of course, the astounding success of propaganda during the war that
opened the eyes of the intelligent few in all departments of life to the possibilities
of regimenting the public mind. […] If we understand the mechanism and motives
of the group mind, is it not possible to control and regiment the masses according
to our will without them knowing it? (Bernays, 27, 47). Bernays’ ideas are not far
removed from those being promulgated on the other side of the Atlantic ocean by
an aspiring literary critic and author whose Ph.D. in literature was obtained at the
University of Heidelberg in 1921, and whose critical acumen was given a real-world
application approximately a decade later: Propaganda is not an end in itself, but a means to an end. […] Whether or not it conforms
adequately to aesthetic demands is meaningless. […] The end of our movement was to mobilize
the people, to organize the people, and win them for the idea of national revolution. Propaganda is not an end in itself, but a means to an end. […] Whether or not it conforms
adequately to aesthetic demands is meaningless. […] The end of our movement was to mobilize
the people, to organize the people, and win them for the idea of national revolution. Denn Propaganda ist nicht Selbstzweck, sondern Mittel zum Zweck. […] ob es in jedem Falle
nun scharfen ästhetischen Forderungen entspricht oder nicht, ist dabei gleichgültig. […] Der
Zweck unserer Bewegung war, Menschen zu mobilisieren, Menschen zu organisieren und für
die nationalrevolutionäre Idee zu gewinnen. [March 15, 1933]. n Joseph Goebbels, Revolution der Deutschen: 14 Jahre Nationalsozialismus
Oldenburg: Gerhard Stalling, 1933), 139. In Joseph Goebbels, Revolution der Deutschen: 14 Jahre Nationalsozialismus
(Oldenburg: Gerhard Stalling, 1933), 139. 23
Simon May. Love: A History (New Haven: Yale University Press, 2011), xii. p
p
22
John Milton. The Doctrine and Discipline of Divorce. London, 1644, Sig. A2r, https://
books.google.com/books?id=6oI-AQAAMAAJ&pg=PP9 21
“Обычай деспот меж людей”. Evgeny Onegin, 1.25.4. In Aleksandr Sergeevich
Pushkin. Sobraniye Sochinenii. 10 Vols., ed. by D. D. Blagoi, S. M. Bondi, V. V.
Vinogradov and Yu. G. Oksman (Moscow: Khudozhestvennaia literatura, 1959),
Vol. 4, 20, http://rvb.ru/pushkin/01text/04onegin/01onegin/0836.htm Love and its Critics 1. Love and Authority: Love Poetry and its Critics 9 what they are teaching may well be the lessons of obedience to what
Aleksandr Pushkin calls “Custom, despot between the people”.21 Alongside the long narrative of demands for obedience, stands a
counter-narrative and counter-instruction in our poetry, framed in
terms of forbidden love and desire. Love challenges obedience; it is one
of the precious few forces with sufficient power to enable its adherents
to transcend themselves, their fears, and their isolation to such a degree
that it is possible to refuse the demands of power. Love does not always
succeed. But for its more radical devotees—the Dido of Ovid’s Heroides,
the troubadour poets of the eleventh and twelfth centuries in Occitania,
the famous lovers of Shakespeare, and Milton’s Adam and Eve—love is
revolutionary, an attempt to tear down the world and build it anew, not
in the image of authority, but that of a love that is freely chosen, freely
given, and freely received. Love rejects the claims of law, property,
and custom. It opposes the claims of determinism—whether theological
(Augustine, Luther, and Calvin, and the notions of original sin and
predestination), philosophical (Foucault, and the idea that impersonal
systems of power create “free subjects” in their image), or biological (as in
Baron d’Holbach’s 1770 work Système de la Nature, which maintains that
all human thought and action results from material causes and effects). These points of view can be found all too frequently, often dressed
in the robes of what John Milton calls “pretended learning, mistaken
among credulous men […] filling each estate of life and profession, with
abject and servil[e] principles”.22 But in the more radical examples of our
poetry, love defies servile principles, and is unimpressed by pretended
learning. Neither is love merely a Romantic construct, a product of “the
long nineteenth century [that extends] well into the twenty-first”,23 nor
a secular replacement for religious traditions. ,
25
Obedience is the soil in which universities first took root. In their beginnings,
universities were training grounds for service in the church or at court (for those
students who took degrees), and institutions that inculcated obedience in the wider
population. The subversiveness of an Abelard or a Wycliffe—which in each case
came at a far greater cost than any paid, or even contemplated by the academic
critic today—is most clearly understood in that context. This is best illustrated
by the Authentica Habita, the 1158 decree of the German Emperor Frederick I
(Barbarossa) granting special privileges to teachers and students of the still-forming
University of Bologna in order that “students, and divine teachers of the sacred
law, […] may come and live in security” (“scholaribus, et maxime divinarum atque
sacrarum legum professoribus, […] veniant, et in eis secure habitient”). This decree
also outlined what Frederick believed to be the essential purpose of education:
“knowledge of the world is to illuminate and inform the lives of our subjects, to
obey God, and ourself, his minister” (“scientia mundus illuminatur ad obediendum
deo et nobis, eius ministris, vita subjectorum informatur”) (Paul Krueger, Theodor
Mommsen, Rudolf Schoell, and Whilhelm Kroll, eds. Corpus Iuris Civilis, Vol. 2
[Berlin: Apud Weidmannos, 1892], 511, https://books.google.com/books?id=2hvTA
AAAMAAJ&pg=PA511). Love and its Critics As Simon May points out,
“[b]y imputing to human love features properly reserved for divine
love, such as the unconditional and the eternal, we falsify the nature
of this most conditional and time-bound and earthly emotion, and 10 Love and its Critics 10 force it to labor under intolerable expectations”.24 It is precisely “time-
bound and earthly” love—a passion that always brings an awareness
of time running out, and the concomitant urge to fight to extend that
time even by the merest moments—that is the powerful counterweight
to the “servil[e] principles” imposed on us by the individuals and
institutions that demand our obedience. Too often, the poetry written
about this love has been ill-served by its ancient and modern critics. Reading the theological and academic critics of poetry inspires the
troubling realization that many such critics are part of the very system
of authority and obedience which, La Boétie argues, accustoms people
to tyrants, and against which the poetry itself protests.25 26
In the “human sciences”, critics often “act as agents of the micro-physics of power”
(Elisabeth Strowick. “Comparative Epistemology of Suspicion: Psychoanalysis,
Literature, and the Human Sciences”. Science in Context, 18.4 [2005], 654, https://doi. 24
Ibid., 4–5. g
(
)
29
Frederic Jameson. The Political Unconscious: Narrative as a Socially Symbolic Act
(Ithaca: Cornell University Press, 1981), 13. 28
Along with the “right-wing” authoritarianism cited above, Altermeyer also defines
a “left-wing” authoritarianism which displays “a high degree of submission to
authorities who are dedicated to overthrowing the established authorities” (219). 27
Bob Altermeyer. The Authoritarian Specter (Cambridge: Havard University Press,
1996), 6. org/10.1017/S0269889705000700). Noam Chomsky, when asked how “intellectuals
[…] get away with their complicity [with] powerful interests”, gives a telling
response: “They are not getting away with anything. They are, in fact, performing
a service that is expected of them by the institutions for which they work, and they
willingly, perhaps unconsciously, fulfill the requirements of the doctrinal system”
(“Beyond a Domesticating Education: A Dialogue”. In Noam Chomsky, Chomsky on
Miseducation [Lanham: Rowman & Littlefield, 2004], 17). III
Love’s Critics: The Hermeneutics of Suspicion and the
Authoritarian Approach to Criticism How does this alignment between literary criticism and repressive
authority function? By denying poetry—particularly love poetry—
the ability to serve as a challenge to the structures of authority in
the societies in which it is written.26 As we will see especially clearly 26 1. Love and Authority: Love Poetry and its Critics 11 when we consider the commentary that surrounds the poetry of John
Milton, the thinking behind such work often displays “a high degree
of submission to the authorities who are perceived to be established”,27
whether that authority is political, cultural, or intellectual. There is an
endless body of criticism that serves not only to undermine poetry’s
potential for political, theological, and even aesthetic resistance, but
to restrict the manner in which readers encounter and understand
poetry. From the beginning, together with the tradition of love poetry,
a tradition of criticism (expressed now from both “conservative” and
“radical” points of view)28 has grown that subordinates and dismisses
human passion and desire, often arguing that what merely seems to
be passionate love poetry is actually properly understood as something
else (worship of God, subordination to Empire, entanglement within
the structures of language itself). The pattern of such criticism—from
the earliest readings of the Song of Songs to contemporary articles
written about a carpe diem poem like Robert Herrick’s “To the Virgins
to Make Much of Time”—is to argue that the surface of a poem hides
a “real” or “deeper” meaning that undermines the apparent one, and
that the critic’s job is to tear away the misleading surface in order to
expose the “truth” that lies beneath it. Frederic Jameson exemplifies
this technique in his argument that the true function of the critic is to
analyze texts and culture through “a vast interpretive allegory in which
a sequence of historical events or texts and artifacts is rewritten in terms
of some deeper, underlying, and more ‘fundamental’ narrative”.29
Louis Althusser describes interpretation similarly, as “detecting the
undetected in the very same text it reads, and relating it to another 12 Love and its Critics 12 text, present as a necessary absence in the first”.30 We can trace similar
thinking all the way back to the controversies over Homer and Hesiod
in the sixth century BCE:31 The Homeric representations of the gods roused a protest on the part of
the founder of the Eleatics, Xenophanes of Colophon (fl. Do you believe, in faith, that Homer, when he was writing the Iliad and Odyssey, thought of the
allegories that Plutarch, Heraclides Ponticq, Eustalius, and Cornutus dressed him in, and which
Politian took from them? If you believe that, you don’t approach by foot or by hand anywhere
near my opinion. 31
BCE (Before Common Era) and CE (Common Era) are used here throughout
(except in quotations, where usage may differ) in lieu of the theologically-inflected
BC (Before Christ) and AD (Anno Domini). 32
Sir John Edwin Sandys. A History of Classical Scholarship, Vol. I: From the Sixth
Century B.C. to the End of the Middle Ages (Cambridge: Cambridge University Press,
1903), 29–31, https://archive.org/stream/historyofclassic00sanduoft#page/29 30
“décèle l’indécelé dans le texte même qu’elle lit, et le rapporte à un autre texte,
présent d’une absence nécessaire dans le premier” (Louis Althusser. Lire le Capital
[Paris: Presses Universitaires de France, 1996], 23). p
g
y
p g
33
Francois Rabelais, who finds a good reason to laugh at nearly everything, laughs
also at this particular absurdity of literary history: 30
“décèle l’indécelé dans le texte même qu’elle lit, et le rapporte à un autre texte,
présent d’une absence nécessaire dans le premier” (Louis Althusser. Lire le Capital
[Paris: Presses Universitaires de France, 1996], 23).
31
BCE (Before Common Era) and CE (Common Era) are used here throughout
(except in quotations, where usage may differ) in lieu of the theologically-inflected
BC (Before Christ) and AD (Anno Domini).
32
Sir John Edwin Sandys. A History of Classical Scholarship, Vol. I: From the Sixth
Century B.C. to the End of the Middle Ages (Cambridge: Cambridge University Press,
1903), 29–31, https://archive.org/stream/historyofclassic00sanduoft#page/29
33
Francois Rabelais, who finds a good reason to laugh at nearly everything, laughs
also at this particular absurdity of literary history:
Do you believe, in faith, that Homer, when he was writing the Iliad and Odyssey, thought of the
allegories that Plutarch, Heraclides Ponticq, Eustalius, and Cornutus dressed him in, and which
Politian took from them? If you believe that, you don’t approach by foot or by hand anywhere
near my opinion.
Croyez vous en vostre foy qu’oncques Homere, escripvant Iliade et Odyssée, pensast es
allegories lesquelles de lui ont calefreté Plutarque, Heraclides Ponticq, Eustatie, Phornute, et
ce d’yceulx Politian ha desrobé? Si li croyez, vous n’aprochez ne de piedz, ne de mains a mon
opinion.) (Francois Rabelais. “Prolog”. Gargantua et Pantagruel. In Œuvres de Rabelais, Vol. 1 [Paris:
Dalibon, 1823], 24–25, https://books.google.com/books?id=a6MGAAAAQAAJ&pg=PA24) g
y
y
35
Philip Sidney. The Defence of Poesie. In The Complete Works of Sir Philip Sidney, Vol. III,
ed. by Albert Feuillerat (Cambridge: Cambridge University Press, 1923), 29, https://
archive.org/stream/completeworks03sidnuoft#page/29 36
Troi maîtres en apperance exclusifs l’un de l’autre la dominent, Marx, Nietzsche et Freud. […]
La catégorie fondamentale de la conscience, pour eux trois, c’est le rapport caché-montré ou, si
l’on préfére, simulé-manifesté. […] Ce qu’ils ont tenté tous trois, sur des voies différentes, ce’st
de faire coïncider leurs methods “conscientes” de déchiffrage avec le travail “inconscient” du
chiffrage qu’ils attribuaient à la volonté de puissance, à l’être social, au psychisme inconscient.
[…] Ce qui distingue alors Marx, Freud et Nietzsche, c’est l’hypothèse gènèrale concernant à la
fois le processus de la conscience “fausse” et la méthode de déchiffrage. Les deux vont de pair,
puisque l’homme du soupçon fait en sens inverse le travail de falsification de l’homme de la ruse.
Paul Ricoeur. De l’interprétation. Essai sur Freud (Paris: Seuil, 1965), 32, 33–34. III
Love’s Critics: The Hermeneutics of Suspicion and the
Authoritarian Approach to Criticism 540–500 B.C),
who says that “Homer and Hesiod have imputed to the gods all that is
blame and shame for men”. […] In reply to protests such as these, some
of the defenders of Homer maintained that the superficial meaning of
his myths was not the true one, and that there was a deeper sense lying
below the surface. This deeper sense was, in the Athenian age, called the
ὑπόνοια [hyponoia–suspicion], and the ὑπόνοια of this age assumed the
name of “allegories” in the times of Plutarch. […] Anaxagoras […] found
in the web of Penelope an emblem of the rules of dialectic, the warp being
the premises, the woof the conclusion, and the flame of the torches, by
which she executed her task, being none other than the light of reason. […] But no apologetic interpretation of the Homeric mythology was of
any avail to save Homer from being expelled with all the other poets
from Plato’s ideal Republic.32 Such readings originally tried to defend poetry against its critics,33
though in a rather different sense than did Eratosthenes, the third-
century BCE librarian of Alexandria, who held that “poets… in all Such readings originally tried to defend poetry against its critics,33
though in a rather different sense than did Eratosthenes, the third-
century BCE librarian of Alexandria, who held that “poets… in all Croyez vous en vostre foy qu’oncques Homere, escripvant Iliade et Odyssée, pensast es
allegories lesquelles de lui ont calefreté Plutarque, Heraclides Ponticq, Eustatie, Phornute, et
ce d’yceulx Politian ha desrobé? Si li croyez, vous n’aprochez ne de piedz, ne de mains a mon
opinion.) (Francois Rabelais. “Prolog”. Gargantua et Pantagruel. In Œuvres de Rabelais, Vol. 1 [Paris:
Dalibon, 1823], 24–25, https://books.google.com/books?id=a6MGAAAAQAAJ&pg=PA24) 1. Love and Authority: Love Poetry and its Critics 13 things aim to persuade and delight, not instruct”,34 or Philip Sidney,
for whom “the Poet, he nothing affirmeth, and therefore never lieth”.35
But suspicion has long since been adopted by the critics as a method of
attack, rather more in the spirit of Plato than in the spirit of Sidney or
those early defenders of Homer and Hesiod. 34
“Ποιητὴν […] πάντα στοχάζεσθαι ψυχαγωγίας, οὐ διδασκαλίας”. Strabo,
Geography, 1.2.3. In Strabo, Geography, Vol. I: Books 1–2, ed. by Horace Leonard Jones.
Cambridge, MA: Loeb Classical Library, Harvard University Press, 1917, 54. Paul Ricoeur. De l’interprétation. Essai sur Freud (Paris: Seuil, 1965), 32, 33–34. III
Love’s Critics: The Hermeneutics of Suspicion and the
Authoritarian Approach to Criticism Employing a method Paul Ricoeur calls the hermeneutics of
suspicion (les herméneutiques du soupçon), the modern version of this
reading strategy is a matter of cunning (falsification) encountering
a greater cunning (suspicion), as the “false” appearances of a text are
systematically exposed by the critic: Three masters, who appear exclusive from each other, are dominant:
Marx, Nietzsche, and Freud. […] The fundamental category of
consciousness, for the three of them, is the relation between hidden-
shown or, if one prefers, simulated-manifest. […] What they have all
three tried, by different routes, is to align their “conscious” methods of
decryption with the “unconscious” work of encryption they attributed to
the will to power, to social being, to the unconscious psyche. […] What
then distinguishes Marx, Freud and Nietzsche is the general hypothesis
concerning both the process of “false” consciousness and the decryption
method. The two go together, since the suspicious man reverses the
falsifying work of the deceitful man.36 For Ricoeur, the hermeneutics of suspicion is not something that is
simply borrowed from the “three masters”; rather, it is modern literature
itself that teaches a reader to read suspiciously: 14 14 Love and its Critics It may be the function of more corrosive literature to contribute to making
a new type of reader appear, a suspicious reader, because the reading
ceases to be a confident journey made in the company of a trustworthy
narrator, but reading becomes a fight with the author involved, a struggle
that brings the reader back to himself.37 It may be the function of more corrosive literature to contribute to making
a new type of reader appear, a suspicious reader, because the reading
ceases to be a confident journey made in the company of a trustworthy
narrator, but reading becomes a fight with the author involved, a struggle
that brings the reader back to himself.37 Yet suspicion is more fundamental, more deeply rooted than can be
explained by the lessons of reading. Not long after outlining his analysis
of the “three masters”, Ricoeur makes an even starker and more
dramatic statement: “A new problem has emerged: that of the lie of
consciousness, and of consciousness as a lie”.38 Here, if one desires it, is
a warrant to regard all apparent meaning (indeed, all appearance of any
kind) as a lie in need of being dismantled and exposed. 37
Ce peut être la fonction de la littérature la plus corrosive de contribuer à faire apparaître un
lecteur d’un nouveau genre, un lecteur lui-même soupçonneux, parce que la lecture cesse
d’être un voyage confiant fait en compagnie d’un narrateur digne de confiance, mais devient
un combat avec l’auteur impliqué, un combat qui le reconduit à lui-même.
Paul Ricoeur Temps et Récit, Vol 3: Le Temps Raconté (Paris: Seuil, 1985), 238 39
These readings demonstrate
the thought pattern that’s at the basis of literary studies, and of any self-enclosed hermetically
sealed sub-world that seeks to assert theoretical hegemony over the rest of the world. […]
The individual is not the measure of all things: I, the commentator, am the measure of all
things. You always have to wait for me, the academic or theoretician, to explain it to you. For
example, you’re really doing A or B because you’re a member of a certain class and accept its
presuppositions. Or you’re really doing C and D because of now-inaccessible events in your
childhood. What you personally think about this doesn’t matter.
Bruce Fleming. What Literary Studies Could Be, And What It Is (Lanham: University
Press of America, 2008), 100. 38
“Une problème nouveau est né: celui du mensonge de la conscience, de la
conscience comme mensonge” (Paul Ricoeur. Le Conflit des Interprétations: Essais
D’Herméneutique [Paris: Seuil, 1969], 101). Paul Ricoeur. Temps et Récit, Vol. 3: Le Temps Raconté (Paris: Seuil, 1985), 238. un combat avec l auteur impliqué, un combat qui le reconduit à lui même.
Paul Ricoeur. Temps et Récit, Vol. 3: Le Temps Raconté (Paris: Seuil, 1985), 238. III
Love’s Critics: The Hermeneutics of Suspicion and the
Authoritarian Approach to Criticism Such ideas, and
the reading strategies they have inspired, have done yeoman’s work in
literary and historical scholarship over the last several decades. But as
with so many useful tools, this one can be, and has been overused.39 Rita
Felski pointedly questions why this approach has become “the default
option” for many critics today: Why is it that critics are so quick off the mark to interrogate, unmask,
expose, subvert, unravel, demystify, destabilize, take issue, and take
umbrage? What sustains their assurance that a text is withholding
something of vital importance, that their task is to ferret out what lies
concealed in its recesses and margins?40 37
Ce peut être la fonction de la littérature la plus corrosive de contribuer à faire apparaître un
lecteur d’un nouveau genre, un lecteur lui-même soupçonneux, parce que la lecture cesse
d’être un voyage confiant fait en compagnie d’un narrateur digne de confiance, mais devient
un combat avec l’auteur impliqué, un combat qui le reconduit à lui-même. Bruce Fleming. What Literary Studies Could Be, And What It Is (Lanham: University
Press of America, 2008), 100. 40 40
Rita Felski. The Limits of Critique (Chicago: University of Chicago Press, 2015), 5. 1. Love and Authority: Love Poetry and its Critics 15 Maintaining that “suspicious reading has settled into a mandatory method
rather than one approach among others”, Felski describes this method
as “[i]ncreasingly prescriptive as well as excruciatingly predictable”,
portraying its influence as one that “can be stultifying, pushing thought
down predetermined paths and closing our minds to the play of detail,
nuance, quirkiness, contradiction, happenstance”. Literary criticism
that leans heavily on this method can lend itself to an authoritarian
approach to reading, as “the critic conjures up ever more paralyzing
scenarios of coercion and control”,41 while readers “have to appeal to
the priestly class that alone can explain”42 the text. Such criticism treats
texts as “imaginary opponents to be bested”43 in service of an accusatory,
prosecutorial agenda, as “[s]omething, somewhere—a text, an author, a
reader, a genre, a discourse, a discipline—is always already guilty of
some crime”.44 The trials have become so zealous and overwhelmingly
numerous that they have long since become formulaic,45 products of
a template-driven approach whose verdicts can be anticipated at the
beginning of the essays and books that use this method. But why? What is the appeal of this approach? 41
Ibid., 34.
42
Fleming, 100.
43
Felski, The Limits of Critique, 111.
44
Ibid., 39.
45
As Felski notes:
Anyone who attends academic talks has learned to expect the inevitable question: “But what
about power?” Perhaps it is time to start asking different questions: “But what about love?”
Or: “Where is your theory of attachment?” To ask such questions is not to abandon politics
for aesthetics. It is, rather, to contend that both art and politics are also a matter of connecting,
composing, creating, coproducing, inventing, imagining, making possible: that neither is
reducible to the piercing but one-eyed gaze of critique.
The Limits of Critique, 17–18.
46
Felski traces this attitude back to “the medieval heresy trial”, noting that “[h]eresy
presented a hermeneutic problem of the first order and the transcripts of religious
inquisitions reveal an acute awareness on the part of inquisitors that truth is not
self-evident, that language conceals, distorts, and contains traps for the unwary, 46
Felski traces this attitude back to “the medieval heresy trial”, noting that “[h]eresy
presented a hermeneutic problem of the first order and the transcripts of religious
inquisitions reveal an acute awareness on the part of inquisitors that truth is not
self-evident, that language conceals, distorts, and contains traps for the unwary, 41
Ibid., 34.
42
Fleming, 100.
43
Felski, The Limits of Critique, 111.
44
Ibid., 39.
45
As Felski notes:
Anyone who attends academic talks has learned to expect the inevitable question: “But what
about power?” Perhaps it is time to start asking different questions: “But what about love?”
Or: “Where is your theory of attachment?” To ask such questions is not to abandon politics
for aesthetics. It is, rather, to contend that both art and politics are also a matter of connecting,
composing, creating, coproducing, inventing, imagining, making possible: that neither is
reducible to the piercing but one-eyed gaze of critique.
The Limits of Critique, 17–18. g
43
Felski, The Limits of Critique, 111. 51
In the extant fragments, Parmenides describes τὸ ἐὸν as the kind of eternal,
unchanging whole that later Christian theologians will use as a basis for their
understandings of the divine: 50
“Die Unverborgenheit des Seienden als solchen ist der Grund der Möglichkeit der
Richtigkeit” (ibid., 102). 49
“hat ihren Grund in der Wahrheit als Unverborgenheit” (Martin Heidegger.
Grundfragen der Philosophie. Ausgewählte “Probleme” der “Logik”. Gesamtausgabe.
II. Abteilung: Vorlesungen 1923–1944. Band 45 [Frankfurt am Main: Vittorio
Klostermann Verlag, 1984], 97–98). that words should be treated cautiously and with suspicion” (“Suspicious Minds”.
Poetics Today, 32: 2 [Summer 2011], 219, https://doi.org/10.1215/03335372-1261208).
47
Karl Popper. Conjectures and Refutations: The Growth of Scientific Knowledge (New
York: Basic Books, 1963), 34.
48
Mark A. Wrathall. Heidegger and Unconcealment: Truth, Language, and History
(Cambridge: Cambridge University Press, 2010), 12.
49
“hat ihren Grund in der Wahrheit als Unverborgenheit” (Martin Heidegger.
Grundfragen der Philosophie. Ausgewählte “Probleme” der “Logik”. Gesamtausgabe.
II. Abteilung: Vorlesungen 1923–1944. Band 45 [Frankfurt am Main: Vittorio
Klostermann Verlag, 1984], 97–98).
50
“Die Unverborgenheit des Seienden als solchen ist der Grund der Möglichkeit der
Richtigkeit” (ibid., 102).
51
In the extant fragments, Parmenides describes τὸ ἐὸν as the kind of eternal,
unchanging whole that later Christian theologians will use as a basis for their
understandings of the divine: that words should be treated cautiously and with suspicion” (“Suspicious Minds”.
Poetics Today, 32: 2 [Summer 2011], 219, https://doi.org/10.1215/03335372-1261208). 48
Mark A. Wrathall. Heidegger and Unconcealment: Truth, Language, and History
(Cambridge: Cambridge University Press, 2010), 12. y,
[
],
,
p
g
)
47
Karl Popper. Conjectures and Refutations: The Growth of Scientific Knowledge (New
York: Basic Books, 1963), 34. III
Love’s Critics: The Hermeneutics of Suspicion and the
Authoritarian Approach to Criticism Love and Authority: Love Poetry and its Critics 17 17 of Zeno (designed, as in the example of Achilles and the Tortoise, to
demonstrate the unreality of the world of motion and appearances52),
and the dialogues of Plato (for whom the eidos or Idea is the ultimate
reality that the world of appearances merely exemplifies or participates
in—μέθεξις / methexis—in an incomplete and shadowy way53). Heidegger argues that to get at truth not merely in its surface, concrete,
or ontic sense, but in its deeper, structural, ontological sense, the seeker
must go through a process of unveiling, reaching a state he called
disclosedness (Erschslossenheit), accompanied by a process of clearing
(Lichtung), removing what is inessential and shining a light (Licht) on
the core that remains. The basic working method of much literary criticism in its modern
European and American forms is indebted to Heidegger’s recovery and ἔστιν ἄναρχον ἄπαυστον
[…]
Ταὐτόν τ’ ἐν ταὐτῷ τε μένον καθ’ ἑαυτό τε κεῖται
χοὔτως ἔμπεδον αὖθι μένει· κρατερὴ γὰρ Ἀνάγκη
πείρατος ἐν δεσμοῖσιν ἔχει, τό μιν ἀμφὶς ἐέργει,
οὕνεκεν οὐκ ἀτελεύτητον τὸ ἐὸν θέμις εἶναι·. It exists without beginning or ending
[…]
Identical in its sameness, it remains itself and standing
Thus firmly-set there, for strong and mighty necessity
Limits it, holds it in chains, and shuts it in on both sides. Because of this, it is right what is should not be incomplete. Fragment 8, ll. 26, 29–32, Die Fragmente der Vorsokratiker, ed. by Hermann Diels
(Berlin: Weidmannsche Buchhandlung, 1903), 124, https://archive.org/stream/
diefragmenteder00krangoog#page/n140 ἔστιν ἄναρχον ἄπαυστον
[…]
Ταὐτόν τ’ ἐν ταὐτῷ τε μένον καθ’ ἑαυτό τε κεῖται
χοὔτως ἔμπεδον αὖθι μένει· κρατερὴ γὰρ Ἀνάγκη
πείρατος ἐν δεσμοῖσιν ἔχει, τό μιν ἀμφὶς ἐέργει,
οὕνεκεν οὐκ ἀτελεύτητον τὸ ἐὸν θέμις εἶναι·. It exists without beginning or ending
[…]
Identical in its sameness, it remains itself and standing
Thus firmly-set there, for strong and mighty necessity
Limits it, holds it in chains, and shuts it in on both sides. Because of this, it is right what is should not be incomplete. Fragment 8, ll. 26, 29–32, Die Fragmente der Vorsokratiker, ed. by Hermann Diels
(Berlin: Weidmannsche Buchhandlung, 1903), 124, https://archive.org/stream/
diefragmenteder00krangoog#page/n140 Fragment 8, ll. 26, 29–32, Die Fragmente der Vorsokratiker, ed. by Hermann Diels
(Berlin: Weidmannsche Buchhandlung, 1903), 124, https://archive.org/stream/
diefragmenteder00krangoog#page/n140 g
g
g p g
52
According to Aristotle’s summary,
The second of these is called “Achilles”. III
Love’s Critics: The Hermeneutics of Suspicion and the
Authoritarian Approach to Criticism Karl Popper suggests
that it is because “[t]hese theories appear to be able to explain practically
everything”, while a devotion to this method has the effect “of an
intellectual conversion or revelation, opening your eyes to a new truth
hidden from those not yet initiated”. Those who undergo this conversion
behave in much the same way as new cult members, on the lookout for
heresy,46 dividing the world into believers and unbelievers: “Once your 46
Felski traces this attitude back to “the medieval heresy trial”, noting that “[h]eresy
presented a hermeneutic problem of the first order and the transcripts of religious
inquisitions reveal an acute awareness on the part of inquisitors that truth is not
self-evident, that language conceals, distorts, and contains traps for the unwary, Love and its Critics 16 eyes [are] thus opened you [see] confirmed instances everywhere: the
world [is] full of verifications of the theory […] and unbelievers [are]
clearly people who [do] not want to see the manifest truth; who refuse
to see it”.47 In addition to the influence of Ricoeur’s “three masters”, this
approach also hinges on on a widely-diffused (mis)use of the work
of Martin Heidegger, especially his engagement with the meaning
of “truth” or Wahrheit. For Heidegger, “the essence of truth is always
understood in terms of unconcealment”,48 a notion he derives from
the Greek term ἀλήθεια (aletheia—discovered or uncovered truth) in
the pre-Socratic philosophers Parmenides and Heraclitus. Heidegger
divides the concept of truth into correctness (Richtigkeit) or accurate
correspondence of ideas with things as they presently are in the world, and
the unconcealedness or discoveredness (Unverborgenheit or Entdecktheit)
of entities. The first is necessarily grounded in, and dependent upon the
second, for there can be no truth about things in the world without things
in the world. For Heidegger, truth as correctness “has its basis in the truth
as unconcealedness”,49 while “the unconcealment of Being as such is the
basis for the possibility of correctness”.50 Thus Wahrheit is both the surface
truth of what exists and the deeper truth that existence itself exists. But what has any of this to do with the reading of literature? Heidegger’s thought proposes a two-level structure, much like that
found in Parmenides, who argued that τὸ ἐὸν—to eon, or What Is—
should be understood in terms of an unchanging reality behind the
changing appearances of the world.51 It is also seen in the paradoxes 1. 54
Walter A. Brogan refers to Derrida’s concept of différance as “a radical and liberated
affirmation of Heidegger’s thought” (“The Original Difference”. Derrida and
Différance, ed. by David Wood and Robert Bernasconi [Evanston: Northwestern
University Press, 1985], 32). As Andre Gingrich notes, “Heidegger’s own
phenomenological appreciation of literature influenced Ricouer’s hermeneutic
approach”, and “[b]oth Ricouer and Derrida acknowledged Heidegger’s strong
influence upon major areas of their respective works” (“Conceptualising Identities:
Anthropological Alternatives to Essentialising Difference and Moralizing
about Othering”. In Gerd Baumann and Andre Gingrich, eds. Grammars of
Identity / Alterity: A Structural Approach [New York: Berghahn Books, 2004], 6–7).
For a comprehensive account of Heidegger’s influence on French intellectuals of
the mid-twentieth century, see Dominique Janicaud’s Heidegger in France, Indiana
University Press, 2015. III
Love’s Critics: The Hermeneutics of Suspicion and the
Authoritarian Approach to Criticism Much of the criticism we
encounter in this book operates on the assumption that a poem has a
surface (the actual words and relationships between them) that must be
cleared away in order to reveal the truth. The complexity of Heidegger’s
thought is often left behind by such a process,57 but what remains is the 54
Walter A. Brogan refers to Derrida’s concept of différance as “a radical and liberated
affirmation of Heidegger’s thought” (“The Original Difference”. Derrida and
Différance, ed. by David Wood and Robert Bernasconi [Evanston: Northwestern
University Press, 1985], 32). As Andre Gingrich notes, “Heidegger’s own
phenomenological appreciation of literature influenced Ricouer’s hermeneutic
approach”, and “[b]oth Ricouer and Derrida acknowledged Heidegger’s strong
influence upon major areas of their respective works” (“Conceptualising Identities:
Anthropological Alternatives to Essentialising Difference and Moralizing
about Othering”. In Gerd Baumann and Andre Gingrich, eds. Grammars of
Identity / Alterity: A Structural Approach [New York: Berghahn Books, 2004], 6–7). For a comprehensive account of Heidegger’s influence on French intellectuals of
the mid-twentieth century, see Dominique Janicaud’s Heidegger in France, Indiana
University Press, 2015. 55 55
“De Man’s relation to Heidegger is especially contorted. De Man from the start
contests Heidegger’s signature notion of Being, but does so in an authentically
deconstructive fashion, such that de Man’s own counter-notion of ‘language’
cannot be grasped apart from an appreciation of Heidegger’s project” (Joshua
Kates. “Literary Criticism”. In The Routledge Companion to Phenomenology, ed. by
Sebastian Luft [New York: Routledge, 2012], 650–51). 56
In Foucault’s account, “Heidegger has always, for me, been the essential
philosopher” (“Heidegger a toujours été pour moi le philosophe essential”). In his
“Le retour de la morale”. In his Dits et écrits, 1954–1988. Vol. IV: 1980–1988 (Paris:
Gallimard, 1994), 696–707 (703). 57
For Heidegger, art itself (and not its interpretation or interpreters) is that which
reveals (or unconceals) the truth of Being: “The artwork opens the Being of
beings in its own way. In the work this opening, this unconcealing, of the truth
of beings happens. In art, the truth of beings has set itself in motion. Art is the
truth setting itself-into-works” (“Das Kunstwerk eröffnet auf seine Weise das Sein
des Seienden. Im Werk geschieht diese Eröffnung, d.h. das Entbergen, d.h. die
Wahrheit des Seiended. Im Kunstwerk hat sich die Wahrheit des Seienden ins Werk
gesetzt. Die Kunst ist das Sich-ins-Werk-Setzen der Wahrheit”) (“Der Ursprung
des Kunstwerkes”. Holzwege: Gesamtusgabe, Vol. III
Love’s Critics: The Hermeneutics of Suspicion and the
Authoritarian Approach to Criticism It is this in which the slowest runner is never overtaken
by the fastest; because since the swifter runner in the chase is always, at any given moment,
first forced to reach the point where the fleeing runner set into motion, of necessity the slowest
runner, who had the headstart, will always be in the lead. Δεύτερος δ΄ ὁ καλούμενος Ἀχιλλεύς. ἔστι δ΄ οὗτος ὅτι τὸ βραδύτατον οὐδέποτε
καταληφθήσεται θέον ὑπὸ τοῦ ταχίστου· ἔμπροσθεν γὰρ ἀναγκαῖον ἐλθεῖν τὸ διῶκον,
ὅθεν ὥρμησε τὸ φεῦγον, ὥστ΄ ἀεί τι προέχειν ἀναγκαῖον τὸ βραδύτερον. Aristotle, Physics, Vol. II, Books 5–8, ed. by P. H. Wicksteed and F. M. Cornford (Loeb
Classical Library, Cambridge, MA: Harvard University Press, 1934), 180, 182. This
paradox is helpfully visualized in the following Open University video: https://
www.youtube.com/watch?v=skM37PcZmWE Δεύτερος δ΄ ὁ καλούμενος Ἀχιλλεύς. ἔστι δ΄ οὗτος ὅτι τὸ βραδύτατον οὐδέποτε
καταληφθήσεται θέον ὑπὸ τοῦ ταχίστου· ἔμπροσθεν γὰρ ἀναγκαῖον ἐλθεῖν τὸ διῶκον,
ὅθεν ὥρμησε τὸ φεῦγον, ὥστ΄ ἀεί τι προέχειν ἀναγκαῖον τὸ βραδύτερον. Δεύτερος δ΄ ὁ καλούμενος Ἀχιλλεύς. ἔστι δ΄ οὗτος ὅτι τὸ βραδύτατον οὐδέποτε
καταληφθήσεται θέον ὑπὸ τοῦ ταχίστου· ἔμπροσθεν γὰρ ἀναγκαῖον ἐλθεῖν τὸ διῶκον,
ὅθεν ὥρμησε τὸ φεῦγον, ὥστ΄ ἀεί τι προέχειν ἀναγκαῖον τὸ βραδύτερον. Aristotle, Physics, Vol. II, Books 5–8, ed. by P. H. Wicksteed and F. M. Cornford (Loeb
Classical Library, Cambridge, MA: Harvard University Press, 1934), 180, 182. This
paradox is helpfully visualized in the following Open University video: https://
www.youtube.com/watch?v=skM37PcZmWE 53 53
The Instance (or the Particular) shares in the nature of the Eidos (or form / idea),
though imperfectly: “The term Methexis, Participation […] connote[s] a closer
relation of the Instance to the Eidos […]: the Instance really has something of the
Eidos in it, if not the Eidos in its full purity” (John Niemeyer Findlay. Plato: The
Written and Unwritten Doctrines [New York: Routledge, 1974], 37). Love and its Critics 18 reformulation of this pre-Socratic notion of truth as disguised, hidden
away, and obscured by a layer of what one might call “lesser truth”
or illusion. Heidegger’s influence on French thinkers like Ricoeur and
Jacques Derrida is profound,54 and its traces work their way through
American criticism like that of “Deconstructionists” such as Paul de
Man,55 and even the “New Historicist” work of Stephen Greenblatt
(through Foucault56) and the innumerable scholars and critics who
have followed in his wake in recent decades. 55
“De Man’s relation to Heidegger is especially contorted. De Man from the start
contests Heidegger’s signature notion of Being, but does so in an authentically
deconstructive fashion, such that de Man’s own counter-notion of ‘language’
cannot be grasped apart from an appreciation of Heidegger’s project” (Joshua
Kates. “Literary Criticism”. In The Routledge Companion to Phenomenology, ed. by
Sebastian Luft [New York: Routledge, 2012], 650–51). 60
“The first pivots on a division between manifest and latent, overt and covert, what
is revealed and what is concealed. Reading is imagined as an act of digging down
to arrive at a repressed or otherwise obscured reality”, while the second works
by “distancing rather than by digging, by the corrosive force of ironic detachment
rather than intensive interpretation. The goal is now to ‘denaturalize’ the text,
to expose its social construction by expounding on the conditions in which it is
embedded” (ibid., 53, 54). Felski, The Limits of Critique, 69. 61
Richard Rorty. The Consequences of Pragmatism (Minneapolis: University of
Minnesota Press, 1982), 151. III
Love’s Critics: The Hermeneutics of Suspicion and the
Authoritarian Approach to Criticism V [Frankfurt am Main: Vittorio
Klostermann, 1977], 25). 1. Love and Authority: Love Poetry and its Critics 19 basic notion that the truth of a poem is concealed by its words, and by
its writer, and that the job of the critic is to pull back the curtains. Some critics argue, however, that “truth” is a naïve concept,
especially where the interpretation of poetry is concerned.58 These
critics argue that “to impute a hidden core of meaning [is] to subscribe
to a metaphysics of presence, a retrograde desire for origins, a belief in
an ultimate or foundational reality”.59 Richard Rorty addresses the split
between the two camps that Felski calls “Digging Down” and “Standing
Back”60 by first emphasizing their similarity, arguing that “they both
start from the pragmatist refusal to think of truth as correspondance to
reality”,61 before outlining the crucial difference: The first kind of critic […] thinks that there really is a secret code and
that once it’s discovered we shall have gotten the text right. He believes
that criticism is discovery rather than creation. [The other kind of critic]
doesn’t care about the distinction between discovery and creation […] 58
For Roland Barthes, the critical search for “truth” is quite useless, as there is no
“truth”, nor even any operant factor in a text, except language itself:
Once the author is removed, the claim to “decipher” a text becomes quite useless. To give an
Author to a text is to impose a knife’s limit on the text, to provide it a final signification, to close
the writing. This design is well suited to criticism, which then wants to give itself the important
task of discovering the Author (or his hypostases: society, history, the psyche, liberty) beneath
the work: the Author found, the text is “explained”, the critic has conquered; so there is nothing
surprising that, historically, the reign of the Author has also been that of the Critic, but also that
criticism (even if it be new) should on this day be shaken off at the same time as the Author. L’Auteur une fois éloigné, la prétention de “déchiffrer” un texte devient tout à fait inutile. Donner un Auteur à un texte, c’est imposer à ce texte un cran d’arrêt, c’est le pourvoir d’un
signifié dernier, c’est fermer l’écriture. III
Love’s Critics: The Hermeneutics of Suspicion and the
Authoritarian Approach to Criticism Cette conception convient très bien à la critique, qui veut
alors se donner pour tâche importante de découvrir l’Auteur (ou ses hypostases: la société,
l’histoire, la psyché, la liberté) sous l’œuvre: l’Auteur trouvé, le texte est “expliqué”, le critique
a vaincu; il n’y a donc rien d’étonnant à ce que, historiquement, le règne de l’Auteur ait été aussi
celui du Critique, mais aussi à ce que la critique (fût-elle nouvelle) soit aujourd’hui ébranlée en
même temps que l’Auteur. “La mort de l’auteur”. In Le Bruissement de la Langue. Essais Critiques IV. Paris: Seuil,
1984, 65–66. 59
Felski, The Limits of Critique, 69. 60
“The first pivots on a division between manifest and latent, overt and covert, what
is revealed and what is concealed. Reading is imagined as an act of digging down
to arrive at a repressed or otherwise obscured reality”, while the second works
by “distancing rather than by digging, by the corrosive force of ironic detachment
rather than intensive interpretation. The goal is now to ‘denaturalize’ the text,
to expose its social construction by expounding on the conditions in which it is
embedded” (ibid., 53, 54). 61
Richard Rorty. The Consequences of Pragmatism (Minneapolis: University of
Mi
P
1982) 151 58
For Roland Barthes, the critical search for “truth” is quite useless, as there is no
“truth”, nor even any operant factor in a text, except language itself:
Once the author is removed, the claim to “decipher” a text becomes quite useless. To give an
Author to a text is to impose a knife’s limit on the text, to provide it a final signification, to close
the writing. This design is well suited to criticism, which then wants to give itself the important
task of discovering the Author (or his hypostases: society, history, the psyche, liberty) beneath
the work: the Author found, the text is “explained”, the critic has conquered; so there is nothing
surprising that, historically, the reign of the Author has also been that of the Critic, but also that
criticism (even if it be new) should on this day be shaken off at the same time as the Author. L’Auteur une fois éloigné, la prétention de “déchiffrer” un texte devient tout à fait inutile. Donner un Auteur à un texte, c’est imposer à ce texte un cran d’arrêt, c’est le pourvoir d’un
signifié dernier, c’est fermer l’écriture. III
Love’s Critics: The Hermeneutics of Suspicion and the
Authoritarian Approach to Criticism Cette conception convient très bien à la critique, qui veut
alors se donner pour tâche importante de découvrir l’Auteur (ou ses hypostases: la société,
l’histoire, la psyché, la liberté) sous l’œuvre: l’Auteur trouvé, le texte est “expliqué”, le critique
a vaincu; il n’y a donc rien d’étonnant à ce que, historiquement, le règne de l’Auteur ait été aussi
celui du Critique, mais aussi à ce que la critique (fût-elle nouvelle) soit aujourd’hui ébranlée en
même temps que l’Auteur. “La mort de l’auteur”. In Le Bruissement de la Langue. Essais Critiques IV. Paris: Seuil, 58
For Roland Barthes, the critical search for “truth” is quite useless, as there is no
“truth”, nor even any operant factor in a text, except language itself: Once the author is removed, the claim to “decipher” a text becomes quite useless. To give an
Author to a text is to impose a knife’s limit on the text, to provide it a final signification, to close
the writing. This design is well suited to criticism, which then wants to give itself the important
task of discovering the Author (or his hypostases: society, history, the psyche, liberty) beneath
the work: the Author found, the text is “explained”, the critic has conquered; so there is nothing
surprising that, historically, the reign of the Author has also been that of the Critic, but also that
criticism (even if it be new) should on this day be shaken off at the same time as the Author. L’Auteur une fois éloigné, la prétention de “déchiffrer” un texte devient tout à fait inutile. Donner un Auteur à un texte, c’est imposer à ce texte un cran d’arrêt, c’est le pourvoir d’un
signifié dernier, c’est fermer l’écriture. Cette conception convient très bien à la critique, qui veut
alors se donner pour tâche importante de découvrir l’Auteur (ou ses hypostases: la société,
l’histoire, la psyché, la liberté) sous l’œuvre: l’Auteur trouvé, le texte est “expliqué”, le critique
a vaincu; il n’y a donc rien d’étonnant à ce que, historiquement, le règne de l’Auteur ait été aussi
celui du Critique, mais aussi à ce que la critique (fût-elle nouvelle) soit aujourd’hui ébranlée en
même temps que l’Auteur. “La mort de l’auteur”. In Le Bruissement de la Langue. Essais Critiques IV. Paris: Seuil,
1984, 65–66. III
Love’s Critics: The Hermeneutics of Suspicion and the
Authoritarian Approach to Criticism 59
60 59
60 60
“The first pivots on a division between manifest and latent, overt and covert, what
is revealed and what is concealed. Reading is imagined as an act of digging down
to arrive at a repressed or otherwise obscured reality”, while the second works
by “distancing rather than by digging, by the corrosive force of ironic detachment
rather than intensive interpretation. The goal is now to ‘denaturalize’ the text,
to expose its social construction by expounding on the conditions in which it is
embedded” (ibid., 53, 54). 60
“The first pivots on a division between manifest and latent, overt and covert, what
is revealed and what is concealed. Reading is imagined as an act of digging down
to arrive at a repressed or otherwise obscured reality”, while the second works
by “distancing rather than by digging, by the corrosive force of ironic detachment
rather than intensive interpretation. The goal is now to ‘denaturalize’ the text,
to expose its social construction by expounding on the conditions in which it is
embedded” (ibid., 53, 54). 61
Richard Rorty. The Consequences of Pragmatism (Minneapolis: University of
Minnesota Press, 1982), 151. 65
New Historicism falls into the first camp. It is perpetually in a state of high alert
for the operations of power, and constantly on the lookout for “complicity with
structures of power in whose language [knowledge] would have no choice but
to speak” (Vincent P. Pecora. “The Limits of Local Knowledge”. In Harold Aram
Veeser, ed. The New Historicism [New York: Routledge, 1989], 267). As Foucault—
in many ways, the “godfather” of New Historicism—puts it: “there is no power
relationship without a correlative constitution of a field of knowledge, nor any field
of knowledge that does not presuppose and constitute power relations at the same
time” (“qu’il n’y a pas de relation de pouvoir sans constitution corrélative d’un
champ de savoir, ni de savoir qui ne suppose et ne constitue en même temps des
relations de pouvoir”) (Surveiller et Punir: Naissance de la Prison [Paris: Gallimard,
1975], 32). The New Historicist critic looks to unveil or reveal the operations (and
cooperations) of power and knowledge, all the while risking being complicit
with the very structures of power he or she seeks to unmask, since “every act of
unmasking, critique, and opposition uses the tools it condemns and risks falling 62
Ibid., 152.
63
Such a “Nietzschean” reading can be seen in J. Hillis Miller’s deconstructive reading
of Percy Shelley’s “The Triumph of Life”, in which Miller claims that Shelley’s
poem, “like all texts, is ‘unreadable’, if by ‘readable’ one means open to a single,
definitive, univocal interpretation” (J. Hillis Miller. “The Critic as Host”. Critical
Inquiry, 3: 3 [Spring, 1977], 447). III
Love’s Critics: The Hermeneutics of Suspicion and the
Authoritarian Approach to Criticism 20 20 Love and its Critics He is in it for what he can get out of it, not for the satisfaction of getting
something right.62 He is in it for what he can get out of it, not for the satisfaction of getting
something right.62 Though Rorty might be accused of cynicism here, there is an identifiable
split between the kinds of critics who apply a hermeneutics of suspicion
in what might be called a “Freudian” sense—digging down through
the layers and strata of a culture or text as a psychoanalyst would dig
through the manifest content of a patient’s dreams in search of a deeper,
but hidden, content (or truth)—and those who apply a hermeneutics
of suspicion in what might be called a “Nietzschean” sense, stripping
away the pretenses and postures of a culture or text in order to
demonstrate that it is pretenses and postures all the way down (that
there is no truth but the provisional one we create, dismantle, modify,
destroy, etc.).63 But as Felski points out, “[in] spite of the theoretical and
political disagreements between styles of criticism, there is a striking
resemblance at the level of ethos—one that is nicely captured by François
Cusset in his phrase ‘suspicion without limits’”.64 Each kind of criticism
is in the business of near-perpetual unveiling. Where they differ is that
one school seeks to reveal what they believe lies behind the veils, while
the other school seeks to reveal the “fact” that there are only veils with
nothing behind them.65 65
New Historicism falls into the first camp. It is perpetually in a state of high alert
for the operations of power, and constantly on the lookout for “complicity with
structures of power in whose language [knowledge] would have no choice but
to speak” (Vincent P. Pecora. “The Limits of Local Knowledge”. In Harold Aram
Veeser, ed. The New Historicism [New York: Routledge, 1989], 267). 62
Ibid., 152. q
y
p
g
64
Felski, The Limits of Critique, 20. 66
Felski, The Limits of Critique, 148. Bruce Fleming expresses a similar idea: “[t]he
people in charge of contemporary classrooms see themselves as overthrowing
prejudices, fiercely challenging the status quo. In fact, for the purposes of literary
studies, they are the status quo” (27). prey to the practice it exposes” (Harold Aram Veeser. “Introduction”. In his, ed. The
New Historicism, xi). Deconstruction belongs to the second camp. For Paul de Man,
literature obsessively points to “a nothingness”, while “[p]oetic language names
this void […] and never tires of naming it again”. For de Man, “[t]his persistant
naming is what we call literature” (Blindness and Insight, Essays in the Rhetoric of
Contemporary Criticism [New York: Oxford University Press, 1971], 18). For J.
Hillis Miller, an author’s works “are at once open to interpretation and ultimately
indecipherable, unreadable. His texts lead the critic deeper and deeper into a
labyrinth until he confronts a final aporia”. The critic burrows further and further
beneath the veil of surface appearances only to find unresolvability, an impasse,
which leads us to understand that “personification” in literature “will always
be divided against itself, folded, manifold, dialogical rather than monological”.
The final assertion (or unveiling) of the essay is that literature is best understood
through “multiple contradictory readings in a perpetual fleeing away from any
fixed sense” (J. Hillis Miller. “Walter Pater: A Partial Portrait”. Daedalus, 105: 1, In
Praise of Books [Winter, 1976], 112). 67
Kate McGowan. Key Issues in Critical and Cultural Theory (Buckingham: Open
University Press, 2007), 26. Emphasis added. prey to the practice it exposes” (Harold Aram Veeser. “Introduction”. In his, ed. The
New Historicism, xi). Deconstruction belongs to the second camp. For Paul de Man,
literature obsessively points to “a nothingness”, while “[p]oetic language names
this void […] and never tires of naming it again”. For de Man, “[t]his persistant
naming is what we call literature” (Blindness and Insight, Essays in the Rhetoric of
Contemporary Criticism [New York: Oxford University Press, 1971], 18). For J.
Hillis Miller, an author’s works “are at once open to interpretation and ultimately
indecipherable, unreadable. His texts lead the critic deeper and deeper into a
labyrinth until he confronts a final aporia”. The critic burrows further and further
beneath the veil of surface appearances only to find unresolvability, an impasse,
which leads us to understand that “personification” in literature “will always
be divided against itself, folded, manifold, dialogical rather than monological”.
The final assertion (or unveiling) of the essay is that literature is best understood
through “multiple contradictory readings in a perpetual fleeing away from any
fixed sense” (J. Hillis Miller. “Walter Pater: A Partial Portrait”. Daedalus, 105: 1, In
Praise of Books [Winter, 1976], 112). III
Love’s Critics: The Hermeneutics of Suspicion and the
Authoritarian Approach to Criticism As Foucault—
in many ways, the “godfather” of New Historicism—puts it: “there is no power
relationship without a correlative constitution of a field of knowledge, nor any field
of knowledge that does not presuppose and constitute power relations at the same
time” (“qu’il n’y a pas de relation de pouvoir sans constitution corrélative d’un
champ de savoir, ni de savoir qui ne suppose et ne constitue en même temps des
relations de pouvoir”) (Surveiller et Punir: Naissance de la Prison [Paris: Gallimard,
1975], 32). The New Historicist critic looks to unveil or reveal the operations (and
cooperations) of power and knowledge, all the while risking being complicit
with the very structures of power he or she seeks to unmask, since “every act of
unmasking, critique, and opposition uses the tools it condemns and risks falling 1. Love and Authority: Love Poetry and its Critics 1. Love and Authority: Love Poetry and its Critics 21 21 Such skeptical criticism, whose two branches are more alike than
different, “thinks of itself as battling orthodoxy yet it is now the reigning
orthodoxy, no longer oppositional but obligatory”.66 This “obligatory”
stance is frequently taken up in service of what its practitioners
claim is an adversarial agenda, a way of reading texts that resists the
ideologies and practices of power by revealing or unveiling them. It
is in such criticism that we encounter terms like interrogation, with all
of its none-too-subliminal suggestions of violence; a fire-against-fire
use of violent analysis to uncover or reveal (or fabricate) a “violence”
inherent in the text. As Kate McGowan puts it, “[t]he value of unrelenting
interrogation is the value of resistance”.67 But it is often “far from evident”
how interrogations of poems, plays, and novels “published in […]
undersubscribed academic journal[s]”68 serve as effective resistance to
anything except poetry itself. Such criticism and its “close ties to modes
of professionalization and scholarly gatekeeping make it hard to sustain
the claim that there is something intrinsically radical or resistant”69 prey to the practice it exposes” (Harold Aram Veeser. “Introduction”. In his, ed. The
New Historicism, xi). Deconstruction belongs to the second camp. For Paul de Man,
literature obsessively points to “a nothingness”, while “[p]oetic language names
this void […] and never tires of naming it again”. For de Man, “[t]his persistant
naming is what we call literature” (Blindness and Insight, Essays in the Rhetoric of
Contemporary Criticism [New York: Oxford University Press, 1971], 18). For J. Hillis Miller, an author’s works “are at once open to interpretation and ultimately
indecipherable, unreadable. His texts lead the critic deeper and deeper into a
labyrinth until he confronts a final aporia”. The critic burrows further and further
beneath the veil of surface appearances only to find unresolvability, an impasse,
which leads us to understand that “personification” in literature “will always
be divided against itself, folded, manifold, dialogical rather than monological”. The final assertion (or unveiling) of the essay is that literature is best understood
through “multiple contradictory readings in a perpetual fleeing away from any
fixed sense” (J. Hillis Miller. “Walter Pater: A Partial Portrait”. Daedalus, 105: 1, In
Praise of Books [Winter, 1976], 112). prey to the practice it exposes” (Harold Aram Veeser. “Introduction”. In his, ed. The
New Historicism, xi). Deconstruction belongs to the second camp. 68
Felski, The Limits of Critique, 143.
69
Ibid., 138. 68
Felski, The Limits of Critique, 143. 70
In Noam Chomsky’s view, such interrogations are impediments to meaningful resistance:
In the United States, for example, it’s mostly confined to Comparative Literature departments.
If they talk to each other in incomprehensible rhetoric, nobody cares. The place where it’s been
really harmful is in the Third World, because Third World intellectuals are badly needed in the
popular movements. They can make contributions, and a lot of them are just drawn away from
this—anthropologists, sociologists, and others—they’re drawn away into these arcane, and in
my view mostly meaningless discourses, and are dissociated from popular struggles.
“Noam Chomsky on French Intellectual Culture & Post-Modernism [3/8]”. Interview
conducted at Leiden University (March 2011. Posted March 15, 2012), https://www.
youtube.com/v/2cqTE_bPh7M&feature=youtu.be&start=409&end=451 [6:49–7:31]. 72
Eve Kosofsky Sedgwick. Touching Feeling: Affect, Pedagogy, Performativity (Durham
and London: Duke University Press, 2003), 131. 1. Love and Authority: Love Poetry and its Critics They can make contributions, and a lot of them are just drawn away from
this—anthropologists, sociologists, and others—they’re drawn away into these arcane, and in
my view mostly meaningless discourses, and are dissociated from popular struggles. “Noam Chomsky on French Intellectual Culture & Post-Modernism [3/8]”. Interview
conducted at Leiden University (March 2011. Posted March 15, 2012), https://www. youtube.com/v/2cqTE_bPh7M&feature=youtu.be&start=409&end=451 [6:49–7:31]. 71
This term, from Judges 12:5–6, comes out of a context of war and violence, in which
one tribe needed a quick and easy way of identifying infiltrators from the enemy side:
וַיִּלְכֹּ ֥ ד גִּלְעָ֛ד אֶֽ ת־מַעְ בְ ּרֹ ֥ ות הַיַּרְ דֵּ ֖ ן לְאֶ פְ רָ֑ יִם וְֽ֠ הָיָה כִ ּ ֣ י יֹאמְ ר֞ ּו פְ ּלִיטֵ֤י אֶ פְ רַ֙יִם֙ אֶ עֱבֹ֔ רָ ה וַיֹּ֨אמְ רּו ֹל֧ ו אַ נְשֵֽ ׁי־גִלְעָ֛ד הַֽ אֶ פְ רָ תִ֥ י אַ֖תָ ּה וַיֹּ֥אמֶֽ ר ׀ לֹ ֽ א׃
וַיֹּ֣אמְ רּו ֹלו֩ אֱמָר־נָ֨א שִ ׁבֹּ ֜ לֶת וַיֹּ֣אמֶר סִ בֹּ ֗ לֶת וְלֹ ֤ א יָכִ ין֙ לְדַבֵּ ֣ ר כֵּ ֔ ן וַיֹּאחֲזּ֣ו אֹותֹ֔ ו וַיִּשְ ׁחָט֖ ּוהּו אֶ ל־מַעְ בְ ּרֹ ֣ ות הַיַּרְ דֵּ ֑ ן וַיִּפֹּ ֞ ל בָּעֵ֤ת הַהִ יא֙ מֵֽ אֶ פְ רַ֔ יִם
אַ רְ בָּעִ֥ים ּושְ ׁנַ�֖יִם אָֽ לֶף׃
And the Gileadites captured the passages of the Jordan to Ephraim, and it happened that when
the fugitive Ephraimites said “let me cross over”, the men of Gilead said to them “are you an
Ephraimite?” And if he said, “no”, then they said, “say Shibboleth”, and if he said “Sibboleth”,
because he could not pronounce it right, then they took him and slew him at the passages of the
Jordan, and there fell at that time forty two thousand Ephraimites. Unless otherwise noted, all Hebrew Biblical text is quoted from Biblia Hebraica
Stuttgartensia, ed. by Karl Elliger and Willhelm Rudolph (Stuttgart: Deutsche
Bibelgesellschaft, 1983). All Greek Biblical text is quoted from The Greek New
Testament, ed. by Barbara Aland (Stuttgart: Deutsche Bibelgesellschaft, 2014). 72
Eve Kosofsky Sedgwick. Touching Feeling: Affect, Pedagogy, Performativity (Durham
and London: Duke University Press, 2003), 131. 1. Love and Authority: Love Poetry and its Critics For Paul de Man,
literature obsessively points to “a nothingness”, while “[p]oetic language names
this void […] and never tires of naming it again”. For de Man, “[t]his persistant
naming is what we call literature” (Blindness and Insight, Essays in the Rhetoric of
Contemporary Criticism [New York: Oxford University Press, 1971], 18). For J. Hillis Miller, an author’s works “are at once open to interpretation and ultimately
indecipherable, unreadable. His texts lead the critic deeper and deeper into a
labyrinth until he confronts a final aporia”. The critic burrows further and further
beneath the veil of surface appearances only to find unresolvability, an impasse,
which leads us to understand that “personification” in literature “will always
be divided against itself, folded, manifold, dialogical rather than monological”. The final assertion (or unveiling) of the essay is that literature is best understood
through “multiple contradictory readings in a perpetual fleeing away from any
fixed sense” (J. Hillis Miller. “Walter Pater: A Partial Portrait”. Daedalus, 105: 1, In
Praise of Books [Winter, 1976], 112). 68
Felski, The Limits of Critique, 143. 22 Love and its Critics 22 about either its style or its substance.70 Suspicion becomes its own point,
perpetuating itself for itself, operating as a tribal shibboleth71 that allows
members of an in-group to recognize one another. In Eve Sedgwick’s
view, readings that stem from this method battle with and obscure
poetry, “blotting out any sense of the possibility of alternative ways of
understanding or things to understand”.72 As these alternative ways of
understanding are blotted out, poetry, and its readers, can be reshaped
into a desired ideological form. This reshaping presents itself in a
number of ways, but two lines of argument have long been dominant:
first, the idea that poetry, and language more generally, refers only to
itself; and second, the idea that the author is “dead” and irrelevant—
perhaps even an impediment—to the understanding of poetry. 70
In Noam Chomsky’s view, such interrogations are impediments to meaningful resistance:
In the United States, for example, it’s mostly confined to Comparative Literature departments. If they talk to each other in incomprehensible rhetoric, nobody cares. The place where it’s been
really harmful is in the Third World, because Third World intellectuals are badly needed in the
popular movements. 1. Love and Authority: Love Poetry and its Critics y
/ /
q
_
y
[
]
71
This term, from Judges 12:5–6, comes out of a context of war and violence, in which
one tribe needed a quick and easy way of identifying infiltrators from the enemy side:
וַיִּלְכֹּ ֥ ד גִּלְעָ֛ד אֶֽ ת־מַעְ בְ ּרֹ ֥ ות הַיַּרְ דֵּ ֖ ן לְאֶ פְ רָ֑ יִם וְֽ֠ הָיָה כִ ּ ֣ י יֹאמְ ר֞ ּו פְ ּלִיטֵ֤י אֶ פְ רַ֙יִם֙ אֶ עֱבֹ֔ רָ ה וַיֹּ֨אמְ רּו ֹל֧ ו אַ נְשֵֽ ׁי־גִלְעָ֛ד הַֽ אֶ פְ רָ תִ֥ י אַ֖תָ ּה וַיֹּ֥אמֶֽ ר ׀ לֹ ֽ א׃
וַיֹּ֣אמְ רּו ֹלו֩ אֱמָר־נָ֨א שִ ׁבֹּ ֜ לֶת וַיֹּ֣אמֶר סִ בֹּ ֗ לֶת וְלֹ ֤ א יָכִ ין֙ לְדַבֵּ ֣ ר כֵּ ֔ ן וַיֹּאחֲזּ֣ו אֹותֹ֔ ו וַיִּשְ ׁחָט֖ ּוהּו אֶ ל־מַעְ בְ ּרֹ ֣ ות הַיַּרְ דֵּ ֑ ן וַיִּפֹּ ֞ ל בָּעֵ֤ת הַהִ יא֙ מֵֽ אֶ פְ רַ֔ יִם
אַ רְ בָּעִ֥ים ּושְ ׁנַ�֖יִם אָֽ לֶף׃ y
q
y
71
This term, from Judges 12:5–6, comes out of a context of war and violence, in which
one tribe needed a quick and easy way of identifying infiltrators from the enemy side: And the Gileadites captured the passages of the Jordan to Ephraim, and it happened that when
the fugitive Ephraimites said “let me cross over”, the men of Gilead said to them “are you an
Ephraimite?” And if he said, “no”, then they said, “say Shibboleth”, and if he said “Sibboleth”,
because he could not pronounce it right, then they took him and slew him at the passages of the
Jordan, and there fell at that time forty two thousand Ephraimites. And the Gileadites captured the passages of the Jordan to Ephraim, and it happened that when
the fugitive Ephraimites said “let me cross over”, the men of Gilead said to them “are you an
Ephraimite?” And if he said, “no”, then they said, “say Shibboleth”, and if he said “Sibboleth”,
because he could not pronounce it right, then they took him and slew him at the passages of the
Jordan, and there fell at that time forty two thousand Ephraimites. Unless otherwise noted, all Hebrew Biblical text is quoted from Biblia Hebraica
Stuttgartensia, ed. by Karl Elliger and Willhelm Rudolph (Stuttgart: Deutsche
Bibelgesellschaft, 1983). All Greek Biblical text is quoted from The Greek New
Testament, ed. by Barbara Aland (Stuttgart: Deutsche Bibelgesellschaft, 2014). 72
Eve Kosofsky Sedgwick. 1. Love and Authority: Love Poetry and its Critics Touching Feeling: Affect, Pedagogy, Performativity (Durham
and London: Duke University Press, 2003), 131. 1. Love and Authority: Love Poetry and its Critics 23 76
[l]’art de la prose est solidaire du seul régime où la prose garde un sens: la
démocratie” (ibid., 82). 78
“l’œuvre d’art, l’œuvre littéraire—n’est nini achevé ni inachevée: elle est. Ce qu’elle
dit, c’est exclusivement cela: qu’elle est—et rien de plus. En dehors de cela, elle
n’est rien. Qui veut lui faire exprimer davantage, ne trouve rien, trouve qu’elle q
75
“l’écrivain, homme libre s’adressant à des hommes libres, n’a qu’un seul sujet: la
liberté” (ibid., 70). 74
“pour celui-ci, l’art est une fuite; pour celui-la, un moyen de conquérir” (Jean-Paul
Sartre. Qu’est-ce que la littérature? [Paris: Gallimard, 1948], 45). 73
“On a constaté avec surprise que la question: ‘Qu’est‑ce que la littérature?’ n’avait
jamais reçu que des réponses insignifiantes” (Maurice Blanchot. “La Littérature et
le droit à la mort”. La Part de Feu [Paris: Gallimard, 1949], 294). 77
“adressée au langage, derrière l’homme qui écrit et lit, par le langage devenu
littérature” (Blanchot. “La Littérature et le droit à la mort”, 293). IV This notion can be traced to Maurice Blanchot, a right-wing journalist
who became a left-wing philosopher and literary critic after the Second
World War. Blanchot argues—in a sideswipe at Jean-Paul Sartre’s 1948
work What is Literature?—that “it has been found, surprisingly, that the
question ‘What is literature?’ has never received anything other than
insignificant answers”.73 Sartre argues that the poet writes to escape the
world, while the prose writer engages with it, “for one, art is a flight;
for the other, a means of conquest”.74 The politically-committed prose
writer works for the cause of liberty: “the writer, a free man addressing
other free men, has only one subject: liberty”,75 and such work only has
meaning in a free society: “the art of prose is tied to the only regime in
which prose holds any meaning: democracy”.76 While Sartre’s ideas are certainly contestable, Blanchot goes to the
opposite extreme: what writers seek to accomplish is irrelevant, since
the meaning of literature, its essence, its “one subject” is nothing more
than language itself. For Blanchot, the question of literature only finds
meaningful answers when it is “addressed to language, behind the
man who writes and reads, to the language that becomes literature”.77
Literature says nothing except to affirm its own existence: “the work
of art, the literary work—is neither completed nor unfinished: it is. What it says is only this: it is—and nothing more. Apart from that, it is
nothing. Whoever wants it to express more, will find nothing, find that it
expresses nothing”.78 This articulates a view of writing in which words 24 Love and its Critics 24 do not and cannot represent any world in which writers and readers
live: for Blanchot, the “writer must commit to […] words rather than
the things that words represent. This is nothing less than the writer’s
abandonment of representation’s claim to be able truly to conjure things
before the reader”.79 This basic idea informs a great deal of modern criticism, much of it
based in French thought of the latter half of the twentieth century. n’exprime rien” (Maurice Blanchot. “La Solitude Essentielle”. L’Espace Littéraire
[Paris: Gallimard, 1955], 12). “Précisons donc ce que le langage signifie en ce qu’il communique: il n’est ni signal,
ni signe, ni même signe de la chose, en tant que réalité extérieure. La relation entre Jacques Derrida. De la Grammatologie [Paris: Éditions de Minuit, 1967], 227. 79
Eric Richtmeyer. “Maurice Blanchot: Saboteur of the Writers’ War”. Proceedings of
the Western Society for French History, 35 (2007), 255. 80
Et pourtant, si la lecture ne doit pas se contenter de redouble le texte, elle ne peut légitimement
transgresser le texte vers autre chose que lui, vers un référent (réalité métaphysique, historique,
psycho-biographique, etc.) ou vers un signifié hors texte dont le contenu pourrait avoir lieu,
aurait pu avoir lieu hors de la langue, c’est-à-dire, au sens que nous donnons ici à ce mot, hors de
l’écriture en général. C’est pourquoi les considérations méthodologiques que nous risquons ici sur
un exemple sont étroitement dépendantes des propositions générales que nous avons élaborées
plus haut, quant à l’absence du référent ou du signifié transcendantal. ll n’y a pas de hors-texte.
Jacques Derrida. De la Grammatologie [Paris: Éditions de Minuit, 1967], 227.
81
“P é i
d
l l
i
ifi
’il
i
il
’
i i
l n’exprime rien” (Maurice Blanchot. “La Solitude Essentielle”. L’Espace Littéraire
[Paris: Gallimard, 1955], 12).
79
Eric Richtmeyer. “Maurice Blanchot: Saboteur of the Writers’ War”. Proceedings of
the Western Society for French History, 35 (2007), 255.
80
Et pourtant, si la lecture ne doit pas se contenter de redouble le texte, elle ne peut légitimement
transgresser le texte vers autre chose que lui, vers un référent (réalité métaphysique, historique,
psycho-biographique, etc.) ou vers un signifié hors texte dont le contenu pourrait avoir lieu,
aurait pu avoir lieu hors de la langue, c’est-à-dire, au sens que nous donnons ici à ce mot, hors de
l’écriture en général. C’est pourquoi les considérations méthodologiques que nous risquons ici sur
un exemple sont étroitement dépendantes des propositions générales que nous avons élaborées
plus haut, quant à l’absence du référent ou du signifié transcendantal. ll n’y a pas de hors-texte.
Jacques Derrida. De la Grammatologie [Paris: Éditions de Minuit, 1967], 227.
81
“Précisons donc ce que le langage signifie en ce qu’il communique: il n’est ni signal,
ni signe, ni même signe de la chose, en tant que réalité extérieure. La relation entre IV For
example, Jacques Derrida argues that one cannot understand a text by
referring to something outside it: Yet if reading must not simply redouble the text, it cannot legitimately
transgress the text toward something other than itself, to a referent
(metaphysical reality, historical, psycho-biographical, etc.) or to a
signified outside text whose content could take place, could have taken
place outside language, that is to say, in the sense that we give here to
that word, outside of writing in general. This is why the methodological
considerations that we risk here on an example are closely dependent on
general propositions that we have elaborated above, as to the absence of
the referent or the transcendental signified. There is no outside-text.80 Similarly, Jacques Lacan argues that language is a closed system, in
which our signifiers cannot ever point to a “thing” that is somehow
outside the system: Similarly, Jacques Lacan argues that language is a closed system, in
which our signifiers cannot ever point to a “thing” that is somehow
outside the system: Therefore, let me specify what language means in that which it
communicates; it is neither signal, nor sign, nor even a sign of the thing
as an external reality. The relationship between signifier and signified
is entirely enclosed in the order of language itself, which completely
determines the two terms.81 81 1. Love and Authority: Love Poetry and its Critics 25 These ideas can be traced back further to the ideas of the Swiss linguist
Ferdinand de Saussure, whose work (first published in 1916) analyzes
language as a system of signs, which “unite not a thing and a name,
but a concept and a sound-image”82 or what he will later refer to as a
signified and a signifier, using ideas that date back to Sextus Empiricus
(c. 160–210 CE) who claimed of the Stoics “three things, they say, are
yoked with one another, the signified, the signifier, and the thing that
happens to exist”.83 Saussure, unlike the Stoics, attempts to define
linguistic signs purely internally, with as little reference as possible to
any “thing that happens to exist”. 82
“unit non une chose et un nom, mais un concept et une image acoustique”
(Ferdinand de Saussure. Cours de Linguistique Générale, ed. by Tullio de Mauro
[Paris: Payot & Rivages, 1967], 98). 83
“τρία φάμενοι συζυγεῖν ἀλλήλοις, τό τε σημαινόμενον καὶ τὸ σημαῖνον καὶ τὸ
τυγχάνον” (Sextus Empiricus. Against Logicians, 2.11, ed. by R. G. Bury [Cambridge,
MA: Loeb Classical Library, Harvard University Press, 1935], 244). 84
“Quand on dit qu’elles correspondent à des concepts, on sous-entend que ceux-ci
sont purement différentiels, définis non pas positivement par leur contenu, mais
négativement par leurs rapports avec les autres termes du système” (Saussure, 162). g
p
pp
y
(
)
85
dans la langue il n’y a que des différences. Bien plus: une différence suppose en général des
termes positifs entre lesquels elle s’établit; mais dans la langue il n’y a que des différences
sans termes positifs. Qu’on prenne le signifié ou le signifiant, la langue ne comporte ni des
idées ni des sons qui préexisteraient au système linguistique, mais seulement des différences
conceptuelles et des différences phoniques issues de ce système. IV Such signs are not to be read in terms
of any positive content or reference, but in terms of their difference from
other signs in the overall system: When we say they correspond to concepts, we imply that these are
purely differential, defined not by their positive content but negatively
by their relations with other terms of the system.84 In fact, for Saussure, language is entirely composed of differential
relationships, a series of differences without any positive terms: In fact, for Saussure, language is entirely composed of differential
relationships, a series of differences without any positive terms: signifiant et signifié est tout entière incluse dans l’ordre du langage lui-même qui
en conditionne intégralement les deux termes” (“Discours de Jacques Lacan”. La
Psychanalyse, 1 [1956], 243). signifiant et signifié est tout entière incluse dans l’ordre du langage lui-même qui
en conditionne intégralement les deux termes” (“Discours de Jacques Lacan”. La
Psychanalyse, 1 [1956], 243). signifiant et signifié est tout entière incluse dans l’ordre du langage lui-même qui
en conditionne intégralement les deux termes” (“Discours de Jacques Lacan”. La
Psychanalyse, 1 [1956], 243).
82
“unit non une chose et un nom, mais un concept et une image acoustique”
(Ferdinand de Saussure. Cours de Linguistique Générale, ed. by Tullio de Mauro
[Paris: Payot & Rivages, 1967], 98).
83
“τρία φάμενοι συζυγεῖν ἀλλήλοις, τό τε σημαινόμενον καὶ τὸ σημαῖνον καὶ τὸ
τυγχάνον” (Sextus Empiricus. Against Logicians, 2.11, ed. by R. G. Bury [Cambridge,
MA: Loeb Classical Library, Harvard University Press, 1935], 244).
84
“Quand on dit qu’elles correspondent à des concepts, on sous-entend que ceux-ci
sont purement différentiels, définis non pas positivement par leur contenu, mais
négativement par leurs rapports avec les autres termes du système” (Saussure, 162).
85
dans la langue il n’y a que des différences. Bien plus: une différence suppose en général des
termes positifs entre lesquels elle s’établit; mais dans la langue il n’y a que des différences
sans termes positifs. Qu’on prenne le signifié ou le signifiant, la langue ne comporte ni des
idées ni des sons qui préexisteraient au système linguistique, mais seulement des différences
conceptuelles et des différences phoniques issues de ce système. 89
“Die Dichtkunst ist die allgemeine Kunst des in sich freigewordenen, nicht an
das äußerlich-sinnliche Material zur Realisation gebundenen Geistes, der nur im
inneren Raume und der inneren Zeit der Vorstellungen und Empfindungen sich
ergeht” (Georg Wilhelm Friedrich Hegel. Vorlesungen über die Aesthetik, Vol. 1
[Berlin: Dunder und Humblot, 1835], 115, https://books.google.com/books?id=Fss
9AQAAMAAJ&pg=PA115). 88
“Blanchot […] rendu possible tout discours sur la littérature” […] “un creux
qui parcourt comme un grand mouvement tous les langages littéraires” (Michel
Foucault. “Sur les façons d’écrire l’Histoire” [interview with Raymond Bellour]. Les
Lettres françaises, 1187 (15–21 June 1967), 6–9. Reprinted in his Dits et écrits, Vol. 1:
1954–1975, 593). 86
It should be noted here that these observations apply to Sassure’s discussion of
what he calls langue, the system of language (or the abstract rules of a signifying
system), as opposed to parole, the actions of speech and understanding though
which that language is used by human beings. A great deal of so-called Saussurian
and post-Saussurian theory seems to operate as if the latter did not exist. 87
“Le lien unisssant le signifiant au signifié est arbitraire, ou encore, puisque nous
entendons par signe le total résultant de l’association d’un signifiant à un signifié,
nous pouvons dire plus simplement: le signe linguistique est arbitraire” (ibid., 100).
é Ibid., 166. In fact, for Saussure, language is entirely composed of differential
relationships, a series of differences without any positive terms: [I]n language there are only differences. Even more: a difference generally
supposes positive terms between which it is established; but in language
there are only differences without positive terms. Whether we take the
signified or the signifier, language has neither ideas nor sounds that pre-
exist the language system, but only conceptual differences and phonic
differences issuing from the system.85 signifiant et signifié est tout entière incluse dans l’ordre du langage lui-même qui
en conditionne intégralement les deux termes” (“Discours de Jacques Lacan”. La
Psychanalyse, 1 [1956], 243). 26 26 Love and its Critics Saussure’s analysis treats language as a sealed system, internally-
focused and without reference.86 In Saussure’s view, the basic unit of
language, le signe linguistique, is arbitrary. It has no necessary link with
the world of objects and actions outside of language, and is simply an
association of sounds and concepts: The unifying link between the signifier and the signified is arbitrary, or
again, as we intend by signs the whole that results from the association
of a signifier with a signified, we can say it more simply: the linguistic
sign is arbitrary.87 Blanchot views literature in much the same way Derrida, Lacan, and
Saussure view language, and this view of the self-referentiality of
both language and literature has been enormously important for later
critics. “Blanchot […] made possible all discourse on literature” in
Foucault’s view, reducing it to “an empty space that runs as a grand
movement through all literary languages”.88 In so doing, Blanchot owes
a significant debt to Hegel, who in his Vorlesungen über die Aesthetik
argues that poetry, properly speaking, is disconnected from materiality
or any concrete reference to the material world: “Poetry is the universal
art of self-liberated spirit, not bound to external sensuous material
for its realization, but moving only in the inner space and inner time
of ideas and feelings”.89 However, Blanchot adds a twist to Hegel’s 1. Love and Authority: Love Poetry and its Critics 27 disconnection of poetry and materiality by working with an idea of
language as an arbitrary yoking of words and ideas, pursuing an
argument that ultimately derives from Plato in the dialogue Cratylus. y
91
In a discussion of Hans-Georg Gadamer’s ideas about “propositional” versus
“eminent” or “absolute” texts, Rod Coltman puts the case in the starkest possible
terms: “Because it does not refer to anything outside of itself, there is nothing
beyond the poem that is more important than the poem itself. The text of the poem
remains, in other words, because the poem is not about anything, or rather, it is only
about itself” (Rod Coltman. “Hermeneutics: Literature and Being”. The Blackwell
Companion to Hermeneutics, ed. by Niall Keane and Chris Lawn [Chichester: John
Wiley & Sons, 2016], 550–51). Richard Klein makes a similar point, asserting that
the “fragility of literature, its susceptibility to being lost, is linked to its having no
real referent” (“The Future of Literary Criticism”. PMLA, 125: 4 [October 2010], 920,
https://doi.org/10.1632/pmla.2010.125.4.920). 92
Damián E. Blasia, Søren Wichmannd, Harald Hammarströmb, Peter F. Stadlerc,
and Morten H. Christiansen. “Sound–meaning Association Biases Evidenced across
Thousands of Languages”. Proceedings of the National Academy of Sciences, 113: 39 (27
September 2016, https://doi.org/10.1073/pnas.1605782113). 90
“οὐ γὰρ φύσει ἑκάστῳ πεφυκέναι ὄνομα οὐδὲν οὐδενί, ἀλλὰ νόμῳκαὶ ἔθει τῶν
ἐθισάντων τε καὶ καλούντων” (Plato. Cratylus. Parmenides. Greater Hippias. Lesser
Hippias, ed. by Harold North Fowler [Cambridge, MA: Loeb Classical Library,
Harvard University Press, 1926], 10). In fact, for Saussure, language is entirely composed of differential
relationships, a series of differences without any positive terms: For
Lacan, the signifier, in its most pristine state, is not what Saussure described as
the instrument of thought; in fact, it signifies nothing at all: “all real signifiers, in
themselves, are signifiers that signify nothing. […] The more a signifier signifies
nothing, the more indestructible it is” (“tout vrai signifiant en tant que tel est un
signifiant qui ne signifie rien. […] car c’est précisément dans la mesure où, plus il
ne signifie rien, plus il est indestructible”) (Le Séminaire de Jacques Lacan, Livre III:
Les Psychoses: 1955–1956, ed. by Jacques Alain Miller [Paris: Seuil, 1981], 210). This
conception of language had been rejected a decade before by the Danish linguist
Louis Hjelmslev, for whom there can be no signifier without a signified because
“expressional meaning” (“udtryksmening”) is always connected to “expressional
form as expressional substance” (“udtryksform som udtrykssubstans”), due to “the
unity of content-form and expression-form established by the solidarity of what we
have called the sign-function” (“den enhed af indholdsform og udtryksform der
etableres af den solidaritet som vi har kaldt tegnfunktionen”) (Omkring Sprogteoriens
Grundlæggelse [Copenhagen: Bianco Lunos Bogtrykkeri, 1943], 51, 53). gg
p
g
g y
Even before Lacan’s sleight-of-hand rearrangment, Claude Lévi-Strauss had
inverted Saussure’s relation between the signifier and the signified: “symbols are
more real than that which they symbolize; the signifier precedes and determines
the signified” (“les symboles sont plus réels que ce qu’ils symbolisent, le signifiant
précède et détermine le signifié”) (“Introduction à l’œuvre de Marcel Mauss”. In
Marcel Mauss, Sociologie et Anthropologie [Paris: Presses Universitaires de France,
1950], xxxii). This latter view makes it possible to “read” language as wholly
determinative of thought, which when combined with Barthes’ and Foucault’s
differing formulations of the “death of the Author”, renders literature—already
denied any externally-referential ability—a mere function of language itself. Barthes traces this idea back to the French poet Stephan Mallarmé, claiming that
“for Mallarmé, as for us, it is language that speaks, not the author; to write, is
through a prior impersonality […] to reach that point where only language acts,
‘performs’, and not ‘me’” (“pour [Mallarmé], comme pour nous, c’est le langage qui
parle, ce n’est pas l’auteur; écrire, c’est, à travers une impersonnalité préalable […]
atteindre ce point où seul le langage agit, ‘performe’ et non ‘moi’”) (Barthes, “La
mort de l’auteur”, 62). In fact, for Saussure, language is entirely composed of differential
relationships, a series of differences without any positive terms: In that work, Hermogenes disputes Cratylus’s notion that words are
derived directly from nature, by insisting that “on the contrary, for
their origins, each name is produced, not by nature, but by the customs,
habits, and character of those who are both accustomed to use it and
called it forth”.90 From Hegel’s declaration that poetry is “not bound to external
sensuous material”, to Blanchot’s idea that the question of poetry is
properly “addressed to language” and “expresses nothing” is but a
short step, and thus we find ourselves facing contemporary critics who
advance the argument to insist that poetry is always and only about
itself.91 However, the linguistic ideas that underlie much of this (post-
Hegel) have been seriously questioned by recent research: a careful statistical examination of words from nearly two-thirds of the
world’s languages reveals that unrelated languages very often use (or
avoid) the same sounds for specific referents. For instance, words for
tongue tend to have l or u, “round” often appears with r, and “small” with
i. These striking similarities call for a reexamination of the fundamental
assumption of the arbitrariness of the sign.92 28 28 Love and its Critics These new findings threaten to unsettle the entire line of thought
based on a long-held assumption, including the oft-repeated claims
that language refers only to itself and that poetry refers only to poetry. Perhaps, at long last, such claims can be reconsidered.93 These new findings threaten to unsettle the entire line of thought
based on a long-held assumption, including the oft-repeated claims
that language refers only to itself and that poetry refers only to poetry. Perhaps, at long last, such claims can be reconsidered.93 93
The irony of such claims is that a number of later thinkers who engage with
Saussure rewrite him, covertly reversing his relation between the signifier and the
signified. Saussure gives precedence to the concept over the sound-image: “One
cannot reduce language to sound, […] it is merely the instrument of thought,
and does not exist for itself” (“On ne peut donc réduire la langue au son, […] il
n’est que l’instrument de la pensée et n’existe pas pour lui-même”) (24). Jacques
Lacan reverses Saussure’s relation, representing it as S/s, with “S” referring to the
signifier (Saussure’s “sound-image”) and “s” referring to the signified (Saussure’s
“concept”). In fact, for Saussure, language is entirely composed of differential
relationships, a series of differences without any positive terms: But rather than acknowledge his wholesale reversal of the relation
of the terms, Lacan ascribes his own formula to Saussure: “the sign thus written,
deserves to be attributed to Ferdinand de Saussure” (“Le signe écrit ainsi, mérite
d’être attribué a Ferdinand de Saussure”) (Écrits [Paris: Seuil, 1966], 497). For
Lacan, the signifier, in its most pristine state, is not what Saussure described as
the instrument of thought; in fact, it signifies nothing at all: “all real signifiers, in
themselves, are signifiers that signify nothing. […] The more a signifier signifies
nothing, the more indestructible it is” (“tout vrai signifiant en tant que tel est un
signifiant qui ne signifie rien. […] car c’est précisément dans la mesure où, plus il
ne signifie rien, plus il est indestructible”) (Le Séminaire de Jacques Lacan, Livre III:
Les Psychoses: 1955–1956, ed. by Jacques Alain Miller [Paris: Seuil, 1981], 210). This
conception of language had been rejected a decade before by the Danish linguist
Louis Hjelmslev, for whom there can be no signifier without a signified because
“expressional meaning” (“udtryksmening”) is always connected to “expressional
form as expressional substance” (“udtryksform som udtrykssubstans”), due to “the
unity of content-form and expression-form established by the solidarity of what we
have called the sign-function” (“den enhed af indholdsform og udtryksform der
etableres af den solidaritet som vi har kaldt tegnfunktionen”) (Omkring Sprogteoriens
Grundlæggelse [Copenhagen: Bianco Lunos Bogtrykkeri, 1943], 51, 53). The irony of such claims is that a number of later thinkers who engage with
Saussure rewrite him, covertly reversing his relation between the signifier and the
signified. Saussure gives precedence to the concept over the sound-image: “One
cannot reduce language to sound, […] it is merely the instrument of thought,
and does not exist for itself” (“On ne peut donc réduire la langue au son, […] il
n’est que l’instrument de la pensée et n’existe pas pour lui-même”) (24). Jacques
Lacan reverses Saussure’s relation, representing it as S/s, with “S” referring to the
signifier (Saussure’s “sound-image”) and “s” referring to the signified (Saussure’s
“concept”). But rather than acknowledge his wholesale reversal of the relation
of the terms, Lacan ascribes his own formula to Saussure: “the sign thus written,
deserves to be attributed to Ferdinand de Saussure” (“Le signe écrit ainsi, mérite
d’être attribué a Ferdinand de Saussure”) (Écrits [Paris: Seuil, 1966], 497). In fact, for Saussure, language is entirely composed of differential
relationships, a series of differences without any positive terms: In summary, much literary theory and criticism over the last
century is based on a questionable linguistic paradigm, the terms of which were 1. Love and Authority: Love Poetry and its Critics 29 inverted by its most prominent adherents to allow them to make claims for which
there was otherwise no support.
94
W. K. Wimsatt Jr. and M. C. Beardsley. “The Intentional Fallacy”. The Sewanee
Review, 54: 3 (July–September 1946), 470.
95
Ibid., 487. inverted by its most prominent adherents to allow them to make claims for which
there was otherwise no support. 94
W. K. Wimsatt Jr. and M. C. Beardsley. “The Intentional Fallacy”. The Sewanee
Review, 54: 3 (July–September 1946), 470.
95
Ibid 487 97
On peut dire d’abord que l’écriture d’aujourd’hui s’est affranchie du thème de l’expression:
elle n’est référée qu’à elle-même, et pourtant, elle n’est pas prise dans la forme de l’intériorité;
elle s’identifie à sa propre extériorité déployée. […] l’écriture se déploie comme un jeu […] où
le sujet écrivant ne cesse de disparaître. […] le sujet écrivant déroute tous les signes de son
individualité particulière; la marque de l’écrivain n’est plus que la singularité de son absence;
il lui faut tenir le rôle du mort dans le jeu de l’écriture. Tout cela est connu; et il y a beau temps
que la critique et la philosophie ont pris acte de cette disparition ou de cette mort de l’auteur.
Michel Foucault “Qu’est-ce qu’un auteur?” In his Dits et écrits Vol 1 792–93 96
“nous savons que, pour rendre à l’écriture son avenir, il faut en renverser le mythe:
la naissance du lecteur doit se payer de la mort de l’Auteur” (Roland Barthes. “La
mort de l’auteur”. In Le Bruissement de la Langue. Essais Critiques IV [Paris: Seuil,
1984], 67). V This idea is one we will encounter, among other places, in critical work
on John Donne, a poet whose life and poetry might otherwise seem
inseparable, so closely do the emotional themes of the poetry match
the known struggles of the poet. The idea that emotions, thoughts,
and experiences of the poet are immaterial to an understanding of the
poem is one that has been with us since the advent of the so-called
New Criticism. Wimsatt and Beardsley have argued that the author’s
intentions are both undiscoverable and irrelevant: [a] poem is not the critic’s own and not the author’s (it is detached from
the author at birth and goes about the world beyond his power to intend
about it or control it). The poem belongs to the public. It is embodied
in language, the peculiar possession of the public, and it is about the
human being, an object of public knowledge.94 From the idea that a poem is “embodied in language” and “detached
from the author”, it is but a short step to criticism that insists a poem
is solely about language, and communicates no other meaning of any
kind. At the time Wimsatt and Beardsley were writing this article, this
argument was already being made across the Atlantic. From the idea that a poem is “embodied in language” and “detached
from the author”, it is but a short step to criticism that insists a poem
is solely about language, and communicates no other meaning of any
kind. At the time Wimsatt and Beardsley were writing this article, this
argument was already being made across the Atlantic. The irony of the authors’ closing statement—“Critical inquiries are
not settled by consulting the oracle”95—is that too much criticism of
the last several decades has been written by those who have bypassed
consulting the oracle by becoming the oracle. This idea can be seen in
more highly developed form in the notion promulgated by Roland
Barthes and Michel Foucault in the 1960s that the author does not exist
for readers in any traditional sense—what exists or is perceived to exist
is an author function. L’œuvre pure implique la disparition élocutoire du poëte, qui cède l’initiative aux mots, par
le heurt de leur inégalité mobilisés; ils s’allument de reflets réciproques comme une virtuelle
traînée de feux sur des pierreries, remplaçant la respiration perceptible en l’ancien souffle
lyrique ou la direction personnelle enthousiaste de la phrase. Une ordonnance du livre de vers
poind innée ou partout, élimine le hasard; encore la faut-il, pour omettre l’auteur. V For Barthes, “we know that in order to give writing
its future, the myth must be reversed: the birth of the reader must be 30 Love and its Critics 30 paid for by the death of the author”.96 In Foucault’s view, writing refers
primarily to two things—language, and the death of the author: We can say first that today’s writing has freed itself of the theme of
expression: it refers only to itself, and yet it is not caught in the form
of interiority; it identifies with its own unfolded externality. […]
Writing unfolds like a game […] where the writing subject constantly
disappears. […] The writing subject destroys all the signs of his particular
individuality; the writer’s hallmark is nothing more than the singularity
of his absence; he must take the role of death in the game of writing. All
of this is well known; and in its own good time, criticism and philosophy
has taken note of this disappearance or this death of the author.97 In turn, the entire concept owes a debt to the nineteenth-century French
poet Stéphane Mallarmé, who in “Crise de Vers” argued for a pure form
of poetry from which the author would be eliminated: In turn, the entire concept owes a debt to the nineteenth-century French
poet Stéphane Mallarmé, who in “Crise de Vers” argued for a pure form
of poetry from which the author would be eliminated: The pure work implies the disappearance of the speaker of poetry,
who yields the initiative to words, mobilized by the clash of their own
inequality; they illuminate each other’s reflections, passing like a virtual
trail of fire on precious stones, replacing the breathing perceptible in the
old lyrical verse or the enthusiastic personality that directed the phrase. The structure of a book of verse must be everywhere its own, innate,
eliminating chance; still, the author must be omitted.98 98
L’œuvre pure implique la disparition élocutoire du poëte, qui cède l’initiative aux mots, par
le heurt de leur inégalité mobilisés; ils s’allument de reflets réciproques comme une virtuelle
traînée de feux sur des pierreries, remplaçant la respiration perceptible en l’ancien souffle
lyrique ou la direction personnelle enthousiaste de la phrase. Une ordonnance du livre de vers
poind innée ou partout, élimine le hasard; encore la faut-il, pour omettre l’auteur. Stéphane Mallarmé. “Crise de Vers”. Michel Foucault. “Qu’est-ce qu’un auteur?” In his Dits et écrits. Vol. 1, 792–93. 98
L’œuvre pure implique la disparition élocutoire du poëte, qui cède l’initiative aux mots, par
le heurt de leur inégalité mobilisés; ils s’allument de reflets réciproques comme une virtuelle
traînée de feux sur des pierreries, remplaçant la respiration perceptible en l’ancien souffle
lyrique ou la direction personnelle enthousiaste de la phrase. Une ordonnance du livre de vers
poind innée ou partout, élimine le hasard; encore la faut-il, pour omettre l’auteur.
Stéphane Mallarmé. “Crise de Vers”. In Divagations (Paris: Bibliothèque-Charpentier,
1897), 246–47, https://fr.wikisource.org/wiki/Divagations/Texte_entier 99
Paul de Man. Blindness and Insight, 12.
100 Geoffrey Hartman. Criticism in the Wilderness: The Study of Literature Today (New
Haven: Yale University Press, 1980), 191.
101 Ibid., 202.
102 Deborah Larson, John Donne and Twentieth-Century Criticism (London: Associated
University Presses, 1989), 15. V In Divagations (Paris: Bibliothèque-Charpentier,
1897), 246–47, https://fr.wikisource.org/wiki/Divagations/Texte_entier L’œuvre pure implique la disparition élocutoire du poëte, qui cède l’initiative aux mots, par
le heurt de leur inégalité mobilisés; ils s’allument de reflets réciproques comme une virtuelle
traînée de feux sur des pierreries, remplaçant la respiration perceptible en l’ancien souffle
lyrique ou la direction personnelle enthousiaste de la phrase. Une ordonnance du livre de vers
poind innée ou partout, élimine le hasard; encore la faut-il, pour omettre l’auteur. Stéphane Mallarmé. “Crise de Vers”. In Divagations (Paris: Bibliothèque-Charpentier,
1897), 246–47, https://fr.wikisource.org/wiki/Divagations/Texte_entier 102 Deborah Larson, John Donne and Twentieth-Century Criticism (London: Associated
University Presses, 1989), 15. 1. Love and Authority: Love Poetry and its Critics 1. Love and Authority: Love Poetry and its Critics 31 This decades-long trend has marked a struggle in which critics have
kidnapped poetry, subordinated it to their own imperatives, and reduced
literature to the status of just one more cultural “text”, or object of analysis,
upon which to demonstrate their acumen. For Paul de Man, such criticism
has a quasi-theological function akin to unmasking idolatry: Criticism […] functions more and more as a demystification of the belief
that literature is a privileged language. The dominant strategy consists
of showing that certain claims to authenticity attributed to literature
are in fact expressions of a desire that, like all desires, falls prey to the
duplicities of expression. The so-called “idealism” of literature is then
shown to be an idolatry, a fascination with a false image that mimics
the presumed attributes of authenticity when it is in fact just the hollow
mask with which a frustrated, defined consciousness tries to cover up its
own negativity.99 Geoffrey Hartman speaks of this as a criticism that “liberates […] critical
activity from its positive or reviewing function, from its subordination
to the thing commented on”.100 Hartman argues for infinite freedom
for the critic, since “there is no absolute knowledge but rather a textual
infinite, an interminable web of texts or interpretations”, which needn’t
be subordinate to something called “literature” because, as Hartman
puts it, “literary commentary is literature”.101 With each new “reading” of a poem, or play, or novel, etc., the critics
displace the original authors, making themselves supreme as both
author and interpreter. But not quite all readers have given their assent to
this state of affairs. With the poet John Donne, for example, what upsets
a critic like Deborah Larson is that too many readers refuse to align
themselves with this view, resulting in “the continuing interpretations
of Donne’s poetry through his life and of his life through his poetry”.102
Larson argues that such meetings of literature and life are wholly
inappropriate, insisting that “Donne’s poems should be recognized as a
group of mainly unrelated monologues, spoken by several varying and 32 Love and its Critics 32 contradictory personae playing a number of roles”.103 Note the language
of compulsion, even duty—the poems should be read as unrelated, not
only to the life of the poet, but to each other. 107 Many critics would sign on to half of Barthes’ death-of-the-author formula, while
ignoring the part that threatens their own profession: “criticism […] should on
this day be shaken off at the same time as the Author” (66) (“la critique […] soit
aujourd’hui ébranlée en même temps que l’Auteur”). 104 Ibid.
105 T. S. Eliot. “Donne in Our Time”. A Garland for John Donne, 1631–1931, ed. by
Theodore Spencer (Cambridge: Harvard University Press, 1931), 10.
106 L
71 103 Ibid., 14.
104 Ibid.
105 T. S. Eliot. “Donne in Our Time”. A Garland for John Donne, 1631–1931, ed. by
Theodore Spencer (Cambridge: Harvard University Press, 1931), 10.
106 Larson, 71.
107 Many critics would sign on to half of Barthes’ death-of-the-author formula, while
ignoring the part that threatens their own profession: “criticism […] should on
this day be shaken off at the same time as the Author” (66) (“la critique […] soit
aujourd’hui ébranlée en même temps que l’Auteur”). 106 Larson, 71. 103 Ibid., 14.
104 Ibid. 103 Ibid., 14.
104 Ibid.
105 T. S. Eliot. “Donne in Our Time”. A Garland for John Donne, 1631–1931, ed. by
Theodore Spencer (Cambridge: Harvard University Press, 1931), 10. 111 “Willst du etwas über ihn vermögen, so mußt du mehr tun, als ihn blos anreden,
du mußt ihn machen, ihn also machen, das er gar nicht anders wollen könne, als du
willst, das er wolle” (Johann Gottlieb Fichte. Johann Gottlieb Fichte: Fichtes Reden an y
p
109 The most famous example of this is Paul de Man, who in his work Allegories of
Reading (1979), rewrote (by the simple insertion of ne) a passage from Rousseau’s
Confessions. As first pointed out by Ortwin de Graef, de Man “adds a negation to
Rousseau’s sentence, as if this did not make a difference, as if one was entitled to
do so on the basis of the main clause” (“Silence to be Observed: A Trial for Paul de
Man’s Inexcusable Confessions”. In (Dis)continuities: Essays on Paul de Man, ed. by
Luc Herman, Kris Humbeeck, and Geert Lernout [Amsterdam: Rodopi, 1989], 61). 108 G. R. F. Ferrari. “Plato and Poetry”. In The Cambridge History of Literary Criticism, Vol.
1: Classical Criticism, ed. by George Alexander Kennedy (Cambridge: Cambridge
University Press, 1989), 92. Emphasis added. p
110 Noam Chomsky. Online discussion that took place on LBBS, Z-Magazine’s Left
On-Line Bulletin Board. Posted at rec.arts.books, 13 November 1995, 03:21:23,
http://bactra.org/chomsky-on-postmodernism.html 1. Love and Authority: Love Poetry and its Critics The problem, however, is
that too many readers are breaking the rules: otherwise we “would not
have been arguing for the last hundred years over Donne’s rakish youth
and his conversion to ‘sincere’ love, nor would any one of his poses
become the dominant one, as has often happened”.104 This, in a nutshell, is what a great deal of literary criticism has become
over the last several decades—an explicit argument that art should be
held at a wide remove from life, that art has little or nothing to do with
the artist except as a locus of linguistic, socio-historical, economic, and
political forces, and that art reflects nothing more than a set of sterile
techniques and conventions. This attitude of superiority of the critic to
the poet, with its distancing of life from poetry, is aptly expressed by the
poet-critic T. S. Eliot: “If Donne in youth was a rake, then I suspect he
was a conventional rake; if Donne in age was devout, then I suspect he
was conventionally devout”.105 The obvious gesture here is reduction—
Donne’s lived experience is described as “conventional”, and therefore
of small importance, scant account, and slight claim on the attention of
the critic who tells readers move along, nothing to see here. But, as Larson
complains, “[b]iographical interpretation […] is difficult to escape from,
even with a conscious effort”.106 Why should it be escaped from? Why
may it not be one tool among many? Because to the extent that the poet is
allowed to exist, the free reign of the critic is threatened.107 The authoritarian relationship between critic and poet goes back to
the very beginnings of what we define as the Western tradition: Philosophy has long had a need to keep poetry in its place—as Plato,
alluding to the “ancient quarrel” between the two, was among the first
to tell us (Rep. 10.607b). But what is striking in Plato’s attitude is that 1. Love and Authority: Love Poetry and its Critics 108 G. R. F. Ferrari. “Plato and Poetry”. In The Cambridge History of Literary Criticism, Vol.
1: Classical Criticism, ed. by George Alexander Kennedy (Cambridge: Cambridge
University Press, 1989), 92. Emphasis added.
109 The most famous example of this is Paul de Man, who in his work Allegories of
Reading (1979), rewrote (by the simple insertion of ne) a passage from Rousseau’s
Confessions. As first pointed out by Ortwin de Graef, de Man “adds a negation to
Rousseau’s sentence, as if this did not make a difference, as if one was entitled to
do so on the basis of the main clause” (“Silence to be Observed: A Trial for Paul de
Man’s Inexcusable Confessions”. In (Dis)continuities: Essays on Paul de Man, ed. by
Luc Herman, Kris Humbeeck, and Geert Lernout [Amsterdam: Rodopi, 1989], 61).
110 Noam Chomsky. Online discussion that took place on LBBS, Z-Magazine’s Left
On-Line Bulletin Board. Posted at rec.arts.books, 13 November 1995, 03:21:23,
http://bactra.org/chomsky-on-postmodernism.html
111 “Willst du etwas über ihn vermögen, so mußt du mehr tun, als ihn blos anreden,
du mußt ihn machen, ihn also machen, das er gar nicht anders wollen könne, als du
willst, das er wolle” (Johann Gottlieb Fichte. Johann Gottlieb Fichte: Fichtes Reden an 1. Love and Authority: Love Poetry and its Critics 33 […] he regards poetry at all times and in all its uses with suspicion, as a
substance inherently volatile.108 Such hostile criticism reduces poetry to mere “convention”, or it views
poetry as a secret code which plays “hide and seek” with its readers,
as critics argue that the “real” meaning of the poetry is either wildly
different from the apparent meaning, or is so lost in textual, contextual,
and linguistic tangles as to be wholly undiscoverable. This book argues for readings of love poetry that oppose such
hostility, that challenge the free reign of the critics, and resist criticism’s
unrelenting interrogation of poetry. Along the way we will frequently
encounter critics for whom love in poetry must be defined reductively
as a “convention” or a “literary commonplace”, or in one especially
egregious case, as “a citation” of the perceived experiences of others. We will encounter eminent scholars who describe individual poets
as “sick”, and others who would—if only they could—literally rather
than interpretively rewrite the poems and other texts upon which they
expound.109 This authoritarian approach to literary criticism is perhaps
an understandable side-effect of what Noam Chomsky calls “the self-
selection for obedience that is […] part of elite education”.110 It reflects
the goals that Fichte, the German Idealist philosopher, outlines for the
new education (der neuen Erziehung): If you would have power over a man, you have to do more than merely
address him; you must shape him, and shape him so that he cannot want
otherwise than you would have him want.111 34 34 Love and its Critics Such critics often seem unable or unwilling to see poetry as anything
other than a self-referential system of conventions, tropes, and signs,
disconnected from life, irrelevant except for the urgent need felt by the
critics to make sure that readers are trained to see as they see, and read
as they read. Obedience, once selected, becomes the lens through which
these critics read, and the method by which they would shape readers
in their own image, so that they cannot want otherwise, a process we
can see at work in the long history of the relation between literature and
criticism, beginning with the allegorical readings of the Song of Songs. 112 Though Stephen Best and Sharon Marcus claim that “[i]n the last decade or so, we
have been drawn to modes of reading that attend to the surfaces of texts rather than
plumb their depths” (“Surface Reading: An Introduction”. Representations, 108: 1
[Fall 2009], 1–2), the trends of the last decade and a half seem ephemeral when
compared to a style of reading and interpretation that has held sway for over two
millennia. die Deutsche Nation, ed. by Samantha Nietz [Hamburg: Severus, 2013], 32). Fichte’s
idea is reflected in Spivak’s fairly recent description of Humanities education as
an “uncoercive rearrangement of desires” (Gayatri Chakravorty Spivak. “Righting
Wrongs”. The South Atlantic Quarterly, 103: 2/3 [Spring/Summer 2004], 526).
The “uncoercive” nature of such “rearrangement” is perhaps best attested by
the experience of one of the current authors who had the occasion to observe a
discussion of this idea among a group of Ph.D. students. One student noted the
possibility that such “uncoercive rearrangement” might be a subtle means of
stifling minority opinion. Every other student in the group condemned that idea, and
the discussion was quickly dropped. die Deutsche Nation, ed. by Samantha Nietz [Hamburg: Severus, 2013], 32). Fichte’s
idea is reflected in Spivak’s fairly recent description of Humanities education as
an “uncoercive rearrangement of desires” (Gayatri Chakravorty Spivak. “Righting
Wrongs”. The South Atlantic Quarterly, 103: 2/3 [Spring/Summer 2004], 526).
The “uncoercive” nature of such “rearrangement” is perhaps best attested by
the experience of one of the current authors who had the occasion to observe a
discussion of this idea among a group of Ph.D. students. One student noted the
possibility that such “uncoercive rearrangement” might be a subtle means of
stifling minority opinion. Every other student in the group condemned that idea, and
the discussion was quickly dropped. 113 “Grau, teurer Freund, ist alle Theorie, / Und grün des Lebens goldner Baum”
(Johann Wolfgang Von Goethe. Faust, Part I, ed. by Walter Kaufmann [New York:
Anchor Books, 1990], 206, ll. 2038–39). 1. Love and Authority: Love Poetry and its Critics 1
Susan Sontag. Against Interpretation: And Other Essays (New York: Farrar, Straus
and Giroux, 2013), 5–6. This kind of interpretation-through-alteration has reached
the point of altering (or suggesting alterations to) texts. Such critical rewriting by 1. Love and Authority: Love Poetry and its Critics A consideration of the Song of Songs and its interpretive history
reveals that criticism claiming to expose the hidden has a very long
history, shaping the way we have been taught to read and understand
poetry and other literary forms for over two thousand years. The earliest
examples are not rooted merely in suspicion, but in the openly-expressed
desire to exercise authority over the hearts and minds of others, and
many modern examples of suspicion-based criticism retain more than a
trace of that original impulse. But if we can learn to hear their voices once
again, the poems considered here have more than enough power to fight
back against such entrenched ways of reading—not merely through the
brilliance of their surfaces,112 but through the passionate depths of their
engagements with the love that was once called fin’amor. Such love—
often forbidden by those who would be obeyed—is presented by the
poets as a temptation, a seduction, a siren’s call to the too-easily missed 1. Love and Authority: Love Poetry and its Critics 35 experience of being truly and fully alive. As Goethe’s Mephistopheles
slyly observes: “Gray, dear Friend, is all theory, / And green is life’s
golden tree”,113 and in such beautifully mortal seductions lies the heart
of love’s response to its critics. those determined to save the reputations of poetry’s gods has been going on since
the days of Aristotle, who mentions a figure named Hippias of Thasos (unknown
to us) who sought to solve the “problem” of Zeus’ apparent dishonesty in Book
Two of the Iliad, by “following prosody, as in Hippias of Thasos” “we grant to
him that he achieve his prayer” (“κατὰ δὲ προσῳδίαν, ὥσπερ Ἱππίας ἔλυεν
ὁ Θάσιος, τὸ “δίδομεν δέ οἱ εὖχος ἀρέσθαι”) (Poetics, 1461a, 22–23. In Aristotle:
Poetics. Longinus: On the Sublime. Demetrius: On Style, ed. by Stephen Halliwell [Loeb
Classical Library, Cambridge, MA: Harvard University Press, 1995], 30). As Richard
Janko explains it, “[i]t was thought offensive that Zeus deceives Agamemmnon,
e.g. by Plato (Republic, II 383A). By altering the accent on “grant” (from “δίδομεν” to
“διδόμεν”), Hippias tried to shift the blame for the deceit away from Zeus” (Aristotle.
Poetics. Trans. by Richard Janko [Indiannapolis: Hackett, 1987], 149, n. 61a21). p
g
g
g
jpg
3
Gerson Cohen. “The Song of Songs and the Jewish Religious Mentality”. In Studies in
the Variety of Rabbinic Cultures (Philadelphia: The Jewish Publication Society, 1991), 13. y
[
p
]
)
2
https://commons.wikimedia.org/wiki/File:Song_of_songs_Rothschild_mahzor.jpg y
p
)
2
https://commons.wikimedia.org/wiki/File:Song_of_songs_Rothschild_mahzor.jpg
3
Gerson Cohen. “The Song of Songs and the Jewish Religious Mentality”. In Studies in
the Variety of Rabbinic Cultures (Philadelphia: The Jewish Publication Society, 1991), 13. I
Love Poetry and the Critics who Allegorize:
The Song of Songs Susan Sontag, in her now-classic essay “Against Interpretation”, protests
against a form of criticism which reshapes texts like the Song of Songs
into new and ideologically compliant forms: Interpretation […] presupposes a discrepancy between the clear meaning
of the text and the demands of (later) readers. It seeks to resolve that
discrepancy. The situation is that for some reason a text has become
unacceptable; yet it cannot be discarded. Interpretation is a radical
strategy for conserving an old text, which is thought too precious to
repudiate, by revamping it. The interpreter, without actually erasing
or rewriting the text, is altering it. But he can’t admit to doing this. He
claims to be only making it intelligible, by disclosing its true meaning. However far the interpreters alter the text ([as in] the Rabbinic and
Christian “spiritual” interpretations of the clearly erotic Song of Songs),
they must claim to be reading off a sense that is already there.1 1
Susan Sontag. Against Interpretation: And Other Essays (New York: Farrar, Straus
and Giroux, 2013), 5–6. This kind of interpretation-through-alteration has reached
the point of altering (or suggesting alterations to) texts. Such critical rewriting by © 2017 Michael Bryson and Arpi Movsesian, CC BY 4.0 https://doi.org/10.11647/OBP.0117.02 https://doi.org/10.11647/OBP.0117.02 38 Love and its Critics 38 One of the most powerfully erotic, celebratory, and secular love poems
in all the world’s literature, the Song of Songs (שיר השירים, or Shir
ha-Shirim) has endured nearly two thousand years of interpretation that
attempts to tame it and explain it away. Traditionally dated to sometime
around 950 BCE, the Song has a complicated textual history. Illumination for the opening verse of Song of Songs, the Rothschild Mahzor,
Manuscript on parchment. Florence, Italy, 1492.2 Illumination for the opening verse of Song of Songs, the Rothschild Mahzor,
Manuscript on parchment. Florence, Italy, 1492.2 Gerson Cohen suggests that “while the Song of Songs may contain very
ancient strata, the work as we have it now cannot have been completed
before the Macedonian conquest of the Near East and rise of the
Hellenistic culture”.3 Likely written down between 400 and 100 BCE, it 2. Love Poetry from the Song of Songs to Aeneas and Dido 39 may be, as M. H. 6
Ibid., 481–82. The method and date of composition of the Song is a matter of ongoing
controversy, and estimates vary from the 10th century BCE to the end of the 2nd
century BCE. For a summation of the various positions, see Abraham Mariaselvam,
The Song of Songs and Ancient Tamil Love Poems: Poetry and Symbolism (Rome: Editrice
Pontificio Intituto Biblico, 1988), 43–44. 7
The only mention of the deity is embedded in the term שַ ׁלְהֶ֥בֶתְ יָֽה (shalhevetyah) in
8:6, which literally translated is “Yahweh-flame”, but serves poetically as a way of
intensifying the idea of flame—shalhevet—into the idea of a “colossal” or “roaring”
flame, like a lightning strike. 9
Origen composed a ten-book commentary on the Canticle of Canticles [the Song of Songs],
conscious of the work of the great Rabbi Akibah and with the explicit intent of showing how the
Song was of relevance to the Christian canon of the Bible. […] Origen continues the exegetical
tradition of Akibah, who approached the love song allegorically. 8
Zhang Longxi. “The Letter or the Spirit: The Song of Songs, Allegoresis, and the
Book of Poetry”. Comparative Literature, 39: 3 (Summer 1987), 194. 4
M. H. Segal. “The Song of Songs”. Vetus Testamentum, 12: 4 (October 1962), 477.
5
Ibid., 478. I
Love Poetry and the Critics who Allegorize:
The Song of Songs He gave the saying that “there are eunuchs
who make themselves eunuchs for the kingdom of heaven” too absolute
and violent an understanding, and thinking at once to fulfill the
Saviour’s utterance, as well as to shut down any suspicion and slander
by unbelievers due to the fact that he, a young man, did not discourse
about divine things only with men, but also with women, he rushed to
complete the Saviour’s words by his deeds.10 Origen’s introduction to his commentary on the Song makes his attitude
toward the text clear. It is absolutely not to be read in its literal sense.11
A reader who cannot or will not transcend the literal meaning of the
Song’s words should not read it at all: One who does not know how to listen to the language of love with pure
and chaste ears will distort what he hears and turn from the inner man
to the outer man, and shall be converted from the spirit to the flesh;
nourishing concupiscence and carnality within himself, brought to carnal
lust by reason of the Scriptures. On this account, then, I warn and counsel
everyone who is not yet rid of the molestations of flesh and blood, nor has John Anthony McGuckin. “The Scholarly Works of Origen”. The Westminster
Handbook to Origen, ed. by John Anthony McGuckin (Louisville: Westminster John
Knox Press, 2004), 31. 10
Ἐν τούτῳ δὲ τῆς κατηχήσεως ἐπὶ τῆς Ἀλεξανδρείας τοὔργον ἐπιτελοῦντι τῷ Ὠριγένει
πρᾶγμά τι πέπρακται φρενὸς μὲν ἀτελοῦς καὶ νεανικῆς, πίστεώς γε μὴν ὁμοῦ καὶ
σωφροσύνης μέγιστον δεῖγμα περιέχον. τὸ γὰρ “εἰσὶν εὐνοῦχοι οἵτινες εὐνούχισαν
ἑαυτοὺς διὰ τὴν βασιλείαν τῶν οὐρανῶν” ἁπλούστερον καὶ νεανικώτερον ἐκλαβών, ὁμοῦ
μὲν σωτήριον φωνὴν ἀποπληροῦν οἰόμενος, ὁμοῦ δὲ καὶ διὰ τὸ νέον τὴν ἡλικίαν ὄντα μὴ
ἀνδράσι μόνον, καὶ γυναιξὶ δὲ τὰ θεῖα προσομιλεῖν, ὡς ἂν πᾶσαν τὴν παρὰ τοῖς ἀπίστοις
αἰσχρᾶς διαβολῆς ὑπόνοιαν ἀποκλείσειεν, τὴν σωτήριον φωνὴν ἔργοις ἐπιτελέσαι ὡρμήθη. Eusebius. Ecclesiastical History, ed. by J. E. L. Oulton (Loeb Classical Library,
Cambridge, MA: Harvard University Press, 1932), 28. 11 11
Richard A. Layton differs, arguing that the literal sense is important, but only in
support of the allegorical: Origen “pairs [his] allegorical reading with a pioneering
literal interpretation of the Canticle. He interprets the lovers’ exchanges in the Song
as a drama that unfolds in dialogue among four characters: the bride, the groom
and their respective entourages. I
Love Poetry and the Critics who Allegorize:
The Song of Songs Segal argues, “a collection of love poetry of a varied
character” preserved by “oral transmission through the generations”,4 a
collection written in a popular, rather than classical Hebrew, a Mishnaic
Hebrew more like Aramaic than the Hebrew of the prophets.5 The Song
looks back to details of city life and attitudes about relations between
the sexes that reflect the Jerusalem of Solomon’s time, as well as the
Jerusalem of the Hellenistic period,6 testifying to the power of love and
desire, even staging a sex scene between its male and female lovers. It
is wholly without disapproval and judgment, frank in its depiction of
passion, and absolutely uninterested in a world beyond love—not only
is God not discussed,7 neither is the relationship of Israel to its religious
traditions or the surrounding nations. As Zhang Longxi describes it:
“[t]he language of the Song of Songs is the secular language of love. It
speaks of the desire and the joy of love, [but not] of law and covenant,
the fear and worship of God, or sin and forgiveness”.8 For that very reason, on both the Judaic and Christian sides of the
controversy, this Hellenistic text that treats of Bronze-age lovers has
been made to wear the mantle of an allegory, cast as a poem describing
the relationship between God and Israel by Rabbinic interpreters, or
between God and the Christian Church by early Church Fathers. In
one of the great ironies of literary history, the Christian tradition of
de-eroticizing the Song is powerfully advanced by Origen9 (c. 184–254
CE), a man who castrated himself to avoid the temptations of sexual
desire. As the early Church historian Eusebius tells it: 40 40 Love and its Critics In the time that he was applying himself to the work of teaching in
Alexandria, Origen did a thing which gave surpassing proof of an
incomplete and immature mind, though it also served as a supreme
example of self-restraint. John Anthony McGuckin. “The Scholarly Works of Origen”. The Westminster
Handbook to Origen, ed. by John Anthony McGuckin (Louisville: Westminster John
Knox Press, 2004), 31. 10
Ἐν τούτῳ δὲ τῆς κατηχήσεως ἐπὶ τῆς Ἀλεξανδρείας τοὔργον ἐπιτελοῦντι τῷ Ὠριγένει
πρᾶγμά τι πέπρακται φρενὸς μὲν ἀτελοῦς καὶ νεανικῆς, πίστεώς γε μὴν ὁμοῦ καὶ
σωφροσύνης μέγιστον δεῖγμα περιέχον. τὸ γὰρ “εἰσὶν εὐνοῦχοι οἵτινες εὐνούχισαν
ἑαυτοὺς διὰ τὴν βασιλείαν τῶν οὐρανῶν” ἁπλούστερον καὶ νεανικώτερον ἐκλαβών, ὁμοῦ
μὲν σωτήριον φωνὴν ἀποπληροῦν οἰόμενος, ὁμοῦ δὲ καὶ διὰ τὸ νέον τὴν ἡλικίαν ὄντα μὴ
ἀνδράσι μόνον, καὶ γυναιξὶ δὲ τὰ θεῖα προσομιλεῖν, ὡς ἂν πᾶσαν τὴν παρὰ τοῖς ἀπίστοις
αἰσχρᾶς διαβολῆς ὑπόνοιαν ἀποκλείσειεν, τὴν σωτήριον φωνὴν ἔργοις ἐπιτελέσαι ὡρμήθη.
Eusebius. Ecclesiastical History, ed. by J. E. L. Oulton (Loeb Classical Library,
Cambridge, MA: Harvard University Press, 1932), 28. 11
Richard A. Layton differs, arguing that the literal sense is important, but only in
support of the allegorical: Origen “pairs [his] allegorical reading with a pioneering
literal interpretation of the Canticle. He interprets the lovers’ exchanges in the Song
as a drama that unfolds in dialogue among four characters: the bride, the groom
and their respective entourages. […] [T]he letter constitutes an indispensable and
persistent experience in Origen’s reading of the Song” (Richard A. Layton. “Hearing
Love’s Language: The Letter of the Text in Origen’s Commentary on the Song of
Songs”. In The Reception and Interpretation of the Bible in Late Antiquity: Proceedings of
the Montréal Colloquium in Honour of Charles Kannengiesser, 11–13 October 2006, ed. by
Lorenzo DiTommaso and Lucian Turcescu [Leiden: Brill, 2008], 288). Eusebius. Ecclesiastical History, ed. by J. E. L. Oulton (Loeb Classical Library,
Cambridge, MA: Harvard University Press, 1932), 28. 12
Audire enim pure et castis auribus amoris nomina nesciens, ab interiore homine ad exteriorem
et carnalem virum omnem deflectet auditum, et a spiritu convertetur ad carnem nutrietque
in semet ipso concupiscentias carnales, et occasione divinae scripturae commoveri et incitari
videbitur ad libendem carnis. Ob hoc ergo moneo, et consilium do omni qui nondum carnis
et sanguinis molestiis caret, neque ab affectu materialis abscedit, ut a lectione libelli huius
eorumque quae in eum dicentur penitus temperet.
Origen. Origene: Commentaire sur le Cantique des Cantiques. Vol. 1. Texte de la Version
Latine de Rufin, ed. by Luc Bresard, Henri Crouzel, and Marcel Borret (Paris:
Éditions du Cerf, 1991), 84. 14
Ariel and Chana Bloch point out that the Hebrew ֹּדֶ֖יָך (dodeyka) though often
translated as “your love”, should be more accurately rendered as “your lovemaking”
in order to capture the sense of physical, sexual love that is being referred to in this
verse, and in similar uses of the term in Prov. 7:18, Ezek. 16:8 and 23:17, as well
as elsewhere in the Song of Songs 1:4, 4:10, 5:1, and 7:13 (The Song of Songs: A New
Translation and Commentary [New York: Random House, 1995], 137). 13
Song of Songs (Song of Solomon) 1:2. Origen. Origene: Commentaire sur le Cantique des Cantiques. Vol. 1. Texte de la Version
Latine de Rufin, ed. by Luc Bresard, Henri Crouzel, and Marcel Borret (Paris:
Éditions du Cerf, 1991), 84. 15
Propter hoc ad te Patrem sponsi mei precem fundo et obsecro, ut tandem miseratus amorem
meum mittas eum, ut iam non mihi per ministros suos angelos dumtaxat et prophetas loquatur, sed ipse per semet ipsum veniat et osculetur me ab osculis oris sui, verba scilicet in os meum
sui oris infundat, ipsum audiam loquentem, ipsum videam docentem. Haec enim sunt Christi
oscula quae porrexit ecclesiae, cum in adventu suo ipse praesens in carne positus locutus est ei
verba fidei et caritas et pacis. I
Love Poetry and the Critics who Allegorize:
The Song of Songs […] [T]he letter constitutes an indispensable and
persistent experience in Origen’s reading of the Song” (Richard A. Layton. “Hearing
Love’s Language: The Letter of the Text in Origen’s Commentary on the Song of
Songs”. In The Reception and Interpretation of the Bible in Late Antiquity: Proceedings of
the Montréal Colloquium in Honour of Charles Kannengiesser, 11–13 October 2006, ed. by
Lorenzo DiTommaso and Lucian Turcescu [Leiden: Brill, 2008], 288). 2. Love Poetry from the Song of Songs to Aeneas and Dido 41 withdrawn from the inclinations of the physical, to regulate themselves
by entirely abstaining from the reading of this book.12 Origen probably did not use a knife to be “rid of the molestations of flesh
and blood” merely in order that he might read the Song in peace. But he
is at great pains to explain every sensual detail of the poem in terms of
the relationship between Christ (the Bridegroom) and the Church (the
Bride). Origen’s comments on the famous opening of the Song illustrate
his method. First, the poetry: 13יִשָ ּׁקֵ֙נִי֙ מִ נְּשִ ׁיק֣ ֹות פִ ּ ֔ יהּו כִ ּ ֽ י־ טֹובִ֥ ים דֹּדֶ֖יָך מִ יָּֽיִן׃ Let him kiss me with the kisses of his mouth: for your lovemaking is
better than wine.14 And now, Origen’s ingenious attempt to explain what those “kisses”
really mean: For this reason I beg you, Father of my spouse, pouring out this prayer
that you will have pity for the sake of my love for him, so that not only
will the angels and the prophets speak to me through his ministers,
but that he will come, and “let him kiss me with the kisses of his
mouth” by his own self, that is, to pour his words into my mouth with
his breath, that I might hear him speak, and see him teach. For these
are the kisses of Christ, who offered them to the Church when at his
coming, he made himself present in the flesh, and spoke the words of
faith and love and peace.15 42 42 Love and its Critics The lengths to which Origen goes here to explain away the “kisses”
of a lover are revealing. There was no need to wait for Ricoeur’s
hermeneutics of suspicion—the fundamentals of that tradition are here
in Origen’s work. The lengths to which Origen goes here to explain away the “kisses”
of a lover are revealing. g
,
16
Ann W. Astell. The Song of Songs in the Middle Ages (Ithaca: Cornell University Press,
1990), 3. 17
Cohen, 6. 18
Hosea 1:2. 19
Ibid., 2:19–20. I
Love Poetry and the Critics who Allegorize:
The Song of Songs There was no need to wait for Ricoeur’s
hermeneutics of suspicion—the fundamentals of that tradition are here
in Origen’s work. For Ann Astell, Origen’s entire method is a flight from the literal
toward the mystical, an attempt to leave behind the carnal in favor of a
union with the Spirit: Origen’s method of exegesis […] moves away from the Canticum’s literal,
carnal meaning to its sensus interioris, [while] the bridal soul, renouncing
what is earthly, reaches out for the invisible and eternal […] An almost
violent departure from the body itself and from literal meaning energizes
the soul’s ascent.16 Gerson
Cohen
suggests
something
similar
about
Rabbinical
interpretations of the Song, grounding his case in the marriage imagery
used to describe the human-divine relationship in the Hebrew scriptures. Putting Israelite religion in the context of the religions of surrounding
cultures, Cohen argues “the Hebrew God alone was spoken of as the
lover and husband of his people, and only the house of Israel spoke of
itself as the bride of the Almighty”.17 Perhaps the most famous example
of this marital motif, however, is the negative example found in Hosea,
where Israel is likened to a “wife of whoredom”: Gerson
Cohen
suggests
something
similar
about
Rabbinical
interpretations of the Song, grounding his case in the marriage imagery
used to describe the human-divine relationship in the Hebrew scriptures. Putting Israelite religion in the context of the religions of surrounding
cultures, Cohen argues “the Hebrew God alone was spoken of as the
lover and husband of his people, and only the house of Israel spoke of
itself as the bride of the Almighty”.17 Perhaps the most famous example
of this marital motif, however, is the negative example found in Hosea,
where Israel is likened to a “wife of whoredom”: 18לְֵ֣ך קַח־ לְָך֞ אֵ֤שֶ ׁת זְנּונִים֙ וְיַלְדֵ֣י זְנּונִ֔ים כִ ּ ֽ י־ זָנֹ֤ה תִ זְנֶה֙ הָאָ֔ רֶ ץ מֵֽ אַ חֲרֵ֖ י יְהוָֽה׃ Go take to yourself a wife of whoredom and children of whoredom, for
the land has committed great whoredom by departing from Yahweh. Though a jealous God promises to take Israel back, וְאֵ רַ שְ ׂתִ ּ ֥ יְך לִ֖י לְעֹולָ֑ם וְאֵ רַ שְ ׂתִ ּ ֥ יְך לִי֙ בְ ּצֶ֣דֶק ּובְ מִ שְ ׁפָּ ֔ ט ּובְ חֶ֖סֶד ּוֽ בְ רַ חֲמִֽ ים׃
19וְאֵ רַ שְ ׂתִ ּ ֥ יְך לִ֖י בֶּאֱמּונָ֑ה וְיָדַ֖עַתְ ּ אֶ ת־ יְהוָֽה׃ 17
Cohen, 6. I
Love Poetry and the Critics who Allegorize:
The Song of Songs 18
Hosea 1:2. 2. Love Poetry from the Song of Songs to Aeneas and Dido 2. Love Poetry from the Song of Songs to Aeneas and Dido 43 And I will wed you to me forever, in righteousness and justice, in loving
kindness and compassion. I will wed you to me faithfully, and you shall
know Yahweh. such reconciliation will come only after the “husband” humiliates
the “wife”: לָכֵ֣ן אָ ׁש֔ ּוב וְלָקַחְ תִ ּ ֤ י דְ גָנִי֙ בְ ּעִ ּת֔ ֹו וְתִ ירֹושִ ׁ ֖ י בְ ּמֽ ֹועֲד֑ ֹו וְהִ צַּלְתִ ּי֙ צַמְ רִ֣ י ּופִ שְ ׁתִ ּ ֔ י לְכַּס֖ ֹות אֶ ת־ עֶרְ וָתָֽ ּה׃
20וְעַתָ ּ ֛ ה אֲגַלֶּ ֥ ה אֶ ת־ נַבְ לֻתָּ֖ה לְעֵינֵ֣י מְ אַ הֲבֶ֑יהָ וְאִ֖ יׁש לֹ ֽ א־ יַצִ ּילֶ֥נָּה מִ יָּדִֽ י׃ So I will return and take back my grain in its season, and my wine in
its season, and I will strip away my wool and flax, which clothed her
nakedness. And then I will uncover her shamelessness in her lovers’
eyes, and none shall deliver her from my hand. More disturbing than the angry-God-as-husband motif in Hosea,
however, is the violently-abusive-God-as-husband of Ezekiel 16. Here,
readers encounter “a fairy tale marriage that has gone horribly awry”.21
Ezekiel portrays God as a man who finds an infant girl (Israel) who
has been exposed, thrown out upon the hills or fields to be killed and
eaten by predators, one of the ancient world’s forms of birth control
(Athenians of the fifth century BCE exposed “10 percent or more
of their newborn girls”22). Scholars often claim the Jews refused to
engage in such practices. y
(
)
22
Mark Golden. “Demography and the Exposure of Girls at Athens”. Phoenix, 35: 4
(Winter 1981), 321. 23
Margaret L. King. “Children in Judaism and Christianity”. In The Routledge History
of Childhood in the Western World, ed. by Paula S. Fass, 39–60 (New York: Routledge,
2013), 47. 20
Ibid., 2:9 10.
21
Nancy R. Bowen. “A Fairy Tale Wedding?” In A God So Near: Essays on Old Testament
Theology in Honor of Patrick D. Miller, ed. by Patrick D. Miller, Brent A. Strawn, and
Nancy R. Bowen (Winona Lake, IN: Eisenbrauns, 2003), 65. 20
Ibid., 2:9–10. )
24
Ezekiel 16:3–5. 20
Ibid., 2:9–10.
21
Nancy R. Bowen. “A Fairy Tale Wedding?” In A God So Near: Essays on Old Testament
Theology in Honor of Patrick D. Miller, ed. by Patrick D. Miller, Brent A. Strawn, and
Nancy R. Bowen (Winona Lake, IN: Eisenbrauns, 2003), 65.
22
Mark Golden. “Demography and the Exposure of Girls at Athens”. Phoenix, 35: 4
(Winter 1981), 321.
23
Margaret L. King. “Children in Judaism and Christianity”. In The Routledge History
of Childhood in the Western World, ed. by Paula S. Fass, 39–60 (New York: Routledge,
2013), 47.
24
Ezekiel 16:3–5. I
Love Poetry and the Critics who Allegorize:
The Song of Songs For example, Margaret King contends that
“Jews and Christians […] steadily opposed the linked practices
of infanticide, exposure, and abortion by which the Greeks and
Romans controlled population”.23 But despite such contentions, the
picture in Ezekiel is plain: וְאָ מַרְ תָ ּ ֞ כֹּה־ אָ מַ֨ ר אֲדֹנָ֤י יְהוִה֙ לִיר֣ ּושָ ׁלִ ַ ֔ ם מְ כֹרֹתַ֙ יְִך֙ ּומֹ֣ לְדֹתַ֔ יְִך מֵאֶ֖רֶ ץ הַֽ כְ ּנַעֲנִ֑י אָ בִ֥ יְך הָאֱמֹרִ֖ י וְאִ מֵּ ֥ ְך חִ תִ ּ ֽ ית׃
ּומֹולְדֹותַ֗ יְִך בְ ּיֹ֨ום הּולֶּ ֤ דֶת אֹתָ ְך֙ לֹ ֽ א־ כָרַ ּ ֣ ת שָ ׁרֵ ּ ֔ ְך ּובְ מַ֥יִם לֹ ֽ א־ רֻחַ֖צְ תְ ּ לְמִ שְ ׁעִ֑י וְהָמְ לֵ ֙ חַ֙ לֹ ֣ א הֻמְ לַ ֔ חַתְ ּ וְהָחְ תֵ ּ ֖ ל
לֹ ֥ א חֻתָ ּ ֽ לְתְ ּ׃ לֹא־ חָ֨ סָה עָלַ ֜ יְִך עַ֗ יִן לַעֲׂש֥ ֹות לְָ֛ך אַ חַ֥ת מֵאֵ֖לֶּה לְחֻמְ לָ֣ה עָלָ֑יְִך וַֽתֻּשְ ׁלְכִ֞ י אֶ ל־ פְ ּנֵ֤י הַשָ ּׂדֶה֙ בְ ּגֹ֣ עַל
24נַפְ שֵ ׁ ֔ ְך בְ ּיֹ֖ום הֻלֶּ ֥ דֶת אֹתָֽ ְך׃ 44 44 Love and its Critics Thus says the Lord Yahweh to Jerusalem: your origin and your birth is
of the land of Canaan; your father was an Amorite, and your mother a
Hittite. At your birth, on the very day you were born, your navel was
not cut, nor were you washed in cleansing water, massaged with salt, or
wrapped in swaddling bands. No eye had pity on you to do any of these
things for you, but you were cast into an open field, for you were hated
on the day you were born. Though it is blamed on the Amorites and Hittites, exposure clearly
was not unknown in Israel, as Israel is described here as a baby girl left
outside to die: “Ezekiel’s allegory draws particular attention to the […]
cruel but often regrettably practised offense of leaving an infant girl to
die at birth, because families preferred boys”.25 The man who rescues
her describes seeing this baby girl “ְךִיָ֑מָדְּב תֶסֶ֖סֹוּבְתִמ”—“polluted in [her]
blood” before he says to her26 “יִ֔יֲח”—“Live!” and takes her home to raise
her to womanhood. After raising her as his own daughter, he takes a
fancy to her: For jewels her breasts were well-fashioned, and her hair grown, and
[she] was naked and bare. 25
Ronald E. Clements. Ezekiel (Louisville: Westminster John Knox Press, 1996), 74.
26
Ezekiel 16:6.
27
Ibid., 16:7.
28
Ibid., 16:8–12. 26
Ezekiel 16:6. 27
Ibid., 16:7. I
Love Poetry and the Critics who Allegorize:
The Song of Songs Having taken the child he raised as a daughter and married her
(converting incestuous thoughts into deeds), this much older man (God)
explodes in rage over the infidelities of his young daughter-wife: וַתִ ּבְ טְ חִ֣ י בְ יָפְ יְֵ֔ך וַתִ ּזְנִ֖י עַל־ שְ ׁמְֵ֑ך וַתִ ּשְ ׁפְ ּכִ֧י אֶ ת־ תַ ּזְנּותַ֛יְִך עַל־ כָּל־ עֹובֵ֖ר
[…]
יַ֣עַן הִ שָ ּׁפְֵ֤ך נְחֻשְ ׁתֵ ְּך֙ וַתִ ּגָּלֶ֣ה עֶרְ וָתֵ֔ ְך בְ ּתַ זְנּותַ֖יְִך עַל־ מְ אַ הֲבָ֑יְִך וְעַל֙ כָּל־ גִּּלּולֵ֣י תֹועֲבֹותַ֔ יְִך וְכִ דְ מֵ֣י
בָנַ֔יְִך אֲשֶ ׁ ֥ ר נָתַ֖תְ ּ לָהֶֽ ם׃ לָ ֠ כֵן הִ נְנִ֨י מְ קַבֵּ ֤ ץ אֶ ת־ כָּל־
[…]
וְנָתַ תִ ּ ֨ י אֹותָ֜ ְך בְ ּיָדָ֗ ם וְהָרְ ס֤ ּו גַבְֵּך֙ וְנִתְ ּצ֣ ּו רָ מֹתַ֔ יְִך וְהִ פְ שִ ׁ ֤ יטּו אֹותָ ְך֙ בְ ּגָדַ֔ יְִך וְלָקְח֖ ּו כְ ּלֵ֣י תִ פְ אַ רְ תֵ ּ ֑ ְך
29וְהִ נִּיח֖ ּוְך עֵירֹ ֥ ם וְעֶרְ יָֽה׃ וְהֶעֱל֤ ּו עָלַ ֙ יְִך֙ קָהָ֔ ל וְרָ גְמ֥ ּו אֹותְָ֖ך בָּאָ֑בֶן ּובִ תְ ּק֖ ּוְך בְ ּחַרְ בֹותָֽ ם׃ But you trusted in your beauty, and played the whore because of your
fame, and lavished your whorings on any passer-by. […] Because your
filth was poured out and your nakedness uncovered as you whored with
your lovers, and the abominations of your idols, and the blood of your
children that you poured out to them, behold, I will bring together all
your lovers, [and] I will give you into their hands, and they will throw
down your defenses and break down your high places; they will strip
you of your clothes and take your jewels and leave you naked and bare. They will bring a great multitude against you, and they will stone you
with stones and thrust you through with their swords. The young girl he had once saved from death, he now has beaten, stoned,
and cut to pieces. 29
Ibid., 16:15, 36–37, 39–40.
30
Ibid., 16:42. 29
Ibid., 16:15, 36–37, 39–40. I
Love Poetry and the Critics who Allegorize:
The Song of Songs The note of father-daughter incest is disturbing enough, but what
follows makes that pale into insignificance: וָאֶ עֱבֹ֨ ר עָלַ ֜ יְִך וָאֶ רְ אֵ֗ ְך וְהִ נֵּ֤ה עִ תֵ ְּך֙ עֵ֣ת דֹּדִ֔ ים וָאֶ פְ רֹ ֤ ׂש כְ ּנָפִ י֙ עָלַ ֔ יְִך וָאֲכַסֶּ ֖ ה עֶרְ וָתְֵ֑ך וָאֶ שָ ּׁ ֣ בַֽ ע לָ ֠ ְך וָאָ ב֨ ֹוא
בִ בְ רִ֜ ית אֹתָ֗ ְך נְאֻ֛ם אֲדֹנָ֥י יְהוִ֖ה וַתִ ּ ֥ הְ יִי לִֽ י׃ וָאֶ רְ חָצְֵ֣ך בַּמַּ ֔ יִם וָאֶ שְ ׁטֹ֥ ף דָּמַ֖יְִך מֵֽ עָלָ֑יְִך וָאֲסֻכְֵ֖ך בַּשָ ּ ֽ ׁמֶן׃ וָאַ לְבִ ּישֵ ׁ ֣ ְך
רִ קְמָ֔ ה וָאֶ נְעֲלְֵ֖ך תָ ּ ֑ חַׁש וָאֶ חְ בְ ּשֵ ׁ ֣ ְך בַּשֵ ּׁ ֔ ׁש וַאֲכַסֵּ ֖ ְך מֶֽ שִ ׁי׃ וָאֶ עְ דֵּ ֖ ְך עֶ֑דִ י וָאֶ תְ ּנָ֤ה צְ מִ ידִ ים֙ עַל־ יָדַ֔ יְִך וְרָ בִ֖ יד עַל־
28גְּרֹונֵ�ְֽך׃ וָאֶ תֵ ּ ֥ ן נֶ֙זֶם֙ עַל־ אַ פֵּ ֔ ְך וַעֲגִילִ֖ים עַל־ אָ זְנָ�֑יְִך וַעֲטֶ֥רֶ ת תִ ּפְ אֶ֖רֶ ת בְ ּרֹאשֵֽ ְׁך׃ When I passed by you and looked at you, behold, your season was
the time for love. I spread my garment over you, covering your
nakedness. I made an oath to you, and entered a covenant with you,
declared the Lord Yahweh, and you belonged to me. Then I washed
you with water, thoroughly washing your blood away, and anointed
you with oil. I covered you in embroidered garments, and gave you
leather sandals. I bound you in fine linens and covered you in silks. 2. Love Poetry from the Song of Songs to Aeneas and Dido 45 I decked you in jewelry, putting bracelets on your wrists, a necklace
around your neck, a ring in your nose, earrings in your ears, and a
glorious crown on your head. I decked you in jewelry, putting bracelets on your wrists, a necklace
around your neck, a ring in your nose, earrings in your ears, and a
glorious crown on your head. 30
Ibid., 16:42. I
Love Poetry and the Critics who Allegorize:
The Song of Songs Having saved her, claimed her, but been unable to
keep her, God spends his truly impotent rage in the fashion of a violent
cuckold: he turns her over to those men who will brutalize her for him,
and only then will his rage be abated: 30וַהֲנִחֹתִ֤ י חֲמָתִ י֙ בָּ ֔ ְך וְסָ֥רָ ה קִנְאָ תִ֖ י מִ מֵּ ֑ ְך וְשָ ׁ ֣ קַטְ תִ ּ ֔ י וְלֹ ֥ א אֶ כְ עַ֖ס עֽ ֹוד׃ So toward you I will rest my fury, and abolish my jealousy, and I will be
quiet and calm, and I will not be angry any more. 46 Love and its Critics 46 After her near-fatal beating, God’s daughter-wife will return to him
in shame—he will accept her back merely so that he may further
humiliate her: 31לְמַ֤עַן תִ ּזְכְ ּרִ י֙ וָבֹ֔ שְ ׁתְ ּ וְלֹ ֨ א יִֽהְ יֶה־ לָּ ֥ ְך עֹוד֙ פִ ּתְ ח֣ ֹון פֶּ ֔ ה מִ פְ ּנֵ֖י כְ ּלִמָּתְֵ֑ך בְ ּכַפְ ּרִ י־ לְָך֙ לְכָל־ אֲשֶ ׁ ֣ ר עָשִ ׂ ֔ ית So that you will remember and be ashamed, and never let it come to
pass that you open your mouth because of your humiliation, when I am
appeased concerning all that you have done. It is tempting to think that the infant girl of so many years before might
have been better off if only God had passed her by in that open field,
leaving her to the mercy of beasts less systematically savage than
himself. Hardly a story of love, this “fairy tale marriage gone horribly
awry” is more akin to a tale of domestic abuse, as “the profile of YHWH
in Ezekiel 16 matches that of real-life batterers in significant ways”.32 There is no love in these allegorical accounts of what Cohen ominously
calls “the inseverable marital union between God and Israel”,33 unless by
“love” we mean ownership and domination, or vengeance and impotent
wrath that uses others to inflict its bloody will, or the desire to silence
and shame a daughter-bride into compliant and docile submission. This
is the powerful impression given by the multiple instances to be found
in the Biblical prophets of the marriage allegory. 31
Ibid., 16:63.
32
Linda Day. “Rhetoric and Domestic Violence in Ezekiel 16”. Biblical Interpretation, 8:
3 (July 2000), 218, https://doi.org/10.1163/156851500750096327
33
Cohen, 12.
34
Isaiah 54:6–8. 31
Ibid., 16:63. 34
Isaiah 54:6–8. I
Love Poetry and the Critics who Allegorize:
The Song of Songs Whether in Hosea, or
Ezekiel 16 and 23, or in Jeremiah 3 and 13, the portrait of the human-
divine marriage is an overwhelmingly negative one, which the relative
lightness of Isaiah 54 cannot atone for: כִ ּ ֽ י־ כְ אִ שָ ּׁ ֧ ה עֲזּובָ֛ה וַעֲצ֥ ּובַת ר֖ ּוחַ קְרָ אְָ֣ך יְהוָ֑ה וְאֵ֧שֶ ׁת נְעּורִ֛ ים כִ ּ ֥ י תִ מָּאֵ֖ס אָ מַ֥ר אֱֹלהָֽ יְִך׃
בְ ּרֶ֥ גַע קָטֹ֖ ן עֲזַבְ תִ ּ ֑ יְך ּובְ רַ חֲמִ֥ ים גְּדֹלִ֖ים אֲקַבְ ּצֵֽ ְך׃
34בְ ּשֶ ׁ ֣ צֶף קֶ֗ צֶף הִ סְ תַ ּ ֨ רְ תִ ּי פָנַ֥י רֶ֙גַע֙ מִ מֵּ ֔ ְך ּובְ חֶ֥סֶד עֹולָ֖ם רִֽ חַמְ תִ ּ ֑ יְך אָ מַ֥ר גֹּאֲלְֵ֖ך יְהוָֽה׃ ס For as a forsaken wife Yahweh has called you, pained in spirit like the
wife of a man’s youth when she is refused, said your God. For the briefest
instant I left you, but with great mercy I will gather you. In an outburst of
wrath, for a moment I hid my face from you, but with everlasting loving
kindness I will have mercy on you, says Yahweh, your redeemer. 2. Love Poetry from the Song of Songs to Aeneas and Dido 47 Far from being comforting, the latter passage sounds like the insincere
apology uttered by a husband who has just beaten his wife—again. The relationship described in the Song is radically different—there is
no sense of punishment, and no dominant theme of domestic violence,
rage and bloody revenge. What a reader encounters in this ancient
love poem is something missing elsewhere in the Bible: “whereas the
other books of the Bible do indeed proclaim the bond of love between
Israel and the Lord, only the Song of Songs is a dialogue of love”,35
though Cohen insists that the dialogue is between “man and God”.36
However this very insistence, grounded as it is in the tradition of the
Christian exegesis of Origen and the Rabbinic exegesis of Akiba (c. 50–137 CE), is just one more instance of the ongoing attempts to tame
the Song, and force it to say what its guardians demand it should say. 38
Cohen, 14. Emphasis added. 35
Whereas in Hosea and Ezekiel there is no dialogue—the railed-upon woman gets
no voice. 39
Song of Songs 5:2–6. 37
Longxi, 207. 36
Cohen, 12. I
Love Poetry and the Critics who Allegorize:
The Song of Songs Such commentary on love poetry tries to “eliminate any implication of
erotic love and to attach to poetry a significance that demonstrates […]
ethical and political propriety”.37 As Cohen explains, “if love could not
be ignored, it could be channeled, reformulated, and controlled, and this
is precisely what the rabbinic [and Christian] allegory of the Song of
Songs attempted to achieve”.38 This attempt to channel, reformulate,
and control is exactly what we will see love being subjected to in both
poetry and criticism as we move through time. One of the most evocative portions of the Song is a wonderfully
explicit scene played out between the young man and woman of the
poem. The young man comes to her door, calling for her in desire, but
when she answers, he has slipped away: פִ ּתְ חִ י־ לִ֞ י אֲחֹתִ֤ י רַ עְ יָתִ י֙ יֹונָתִ֣ י תַ מָּתִ֔ י שֶ ׁרֹּאשִ ׁי֙ נִמְ לָא־ טָ֔ ל קְוֻּּצֹותַ֖י רְ סִ֥ יסֵי לָֽיְלָה׃
פָּשַ ׁ֙טְ תִ ּי֙ אֶ ת־ כֻּתָ ּנְתִ ּ ֔ י אֵ יכָ֖כָה אֶ לְבָּשֶ ׁ ֑ נָּה רָ חַ֥צְ תִ ּי אֶ ת־ רַ גְלַ֖י אֵ יכָ֥כָה אֲטַנְּפֵֽם׃
ּדֹודִ֗ י שָ ׁלַ֤ח יָדֹו֙ מִ ן־ הַחֹ֔ ר ּומֵעַ֖י הָמ֥ ּו עָלָֽיו׃
קַ֥ מְ תִ ּ ֽ י אֲנִ֖י לִפְ תֹּ ֣ חַ לְדֹודִ֑ י וְיָדַ֣י נָֽטְ פּו־ מ֗ ֹור וְאֶ צְ בְ ּעֹתַ י֙ מ֣ ֹור עֹבֵ֔ ר עַ֖ל כַּּפ֥ ֹות הַמַּנְעֽ ּול׃
39פָּתַ֤חְ תִ ּ ֽ י אֲנִי֙ לְדֹודִ֔ י וְדֹודִ֖ י חָמַ֣ק עָבָ֑ר 35
Whereas in Hosea and Ezekiel there is no dialogue—the railed-upon woman gets
no voice. 36
C h
12 48 Love and its Critics Open to me, my sister, my darling, my dove, my perfect one: for my head
is drenched with dew, my hair with midnight’s drops. I have stripped
off my garments; how shall I put them back on? I have washed my feet;
how shall I soil them? My lover put in his hand by the hole, and my
womb moved for him. I rose up to open to my lover; and my hands
dripped with myrrh, and my fingers with sweet smelling myrrh, with
my hands upon the bolt of the lock. I opened to my lover; but my lover
had withdrawn, and he was gone. 40
Chris Ray. Song of Solomon for Teenagers: And Anyone Else Who Wonders Why They Are
Here (Bloomington: AuthorHouse, 2010), 29.
41
Longxi, 195. 41
Longxi, 195. 2. Love Poetry from the Song of Songs to Aeneas and Dido 2. Love Poetry from the Song of Songs to Aeneas and Dido 49 But when the allegory is stripped away and the commentary is
removed, what happens in this exquisite passage? A young man calls
late at night at a girl’s door: “open to me”, he says, “for my head is
drenched with dew, my hair with midnight’s drops”. The young man
is expressing sexual desire for his “darling”, his “perfect one”. She
hesitates: “I have washed my feet; how shall I soil them?” (“Feet” are
often used in the Bible as a euphemism for more intimate parts of the
body—the story of Ruth and Boaz is an excellent example). But he
persists, putting “his hand by the hole”, as her “womb moved for him”. The Hebrew word here is מְ עֵי (meeh or me-yeh), which when used about a
woman, can generally be translated as “womb” just as it is at Ruth 1:11,
where Naomi bemoans her age and infertility: וַתֹּ ֤ אמֶר נָעֳמִ י֙ שֹׁ ֣ בְ נָה בְ נֹתַ֔ י לָ֥מָּה תֵ לַ֖כְ נָה עִ מִ ּ ֑ י הַֽ עֽ ֹוד־ לִ֤י בָנִים֙ בְ ּ ֽ מֵעַ֔ י וְהָיּ֥ו לָכֶ֖ם לַאֲנָשִֽ ׁים׃ וַתֹּ ֤ אמֶר נָעֳמִ י֙ שֹׁ ֣ בְ נָה בְ נֹתַ֔ י לָ֥מָּה תֵ לַ֖כְ נָה עִ מִ ּ ֑ י הַֽ עֽ ֹוד־ לִ֤י בָנִים֙ בְ ּ ֽ מֵעַ֔ י וְהָיּ֥ו לָכֶ֖ם לַאֲנָשִֽ ׁים׃ וַתֹּ ֤ אמֶר נָעֳמִ י֙ שֹׁ ֣ בְ נָה בְ נֹתַ֔ י לָ֥מָּה תֵ לַ֖כְ נָה עִ מִ ּ ֑ י הַֽ עֽ ֹוד־ לִ֤י בָנִים֙ בְ ּ ֽ מֵעַ֔ י וְהָיּ֥ו לָכֶ֖ם לַאֲנָשִֽ ׁים׃
Return, my daughters, why will you go with me? Are there yet sons in
my womb that may become your husbands? Return, my daughters, why will you go with me? Are there yet sons in
my womb that may become your husbands? With her womb stirring, the young woman is suddenly wet with myrrh,
her hands and her fingers dripping with the scented, sensual oil. As
she slips her oiled fingers around “the bolt of the lock”, she opens to
him, and the consummation is near. Here, the Hebrew word is מַּנְעֽ ּול
(manul), which, translated as “bolt”, is like the deadbolt that is inserted
between the door and the doorjamb, making the phallic reference of
the verse obvious. 42
Macbeth 2.3.32. All quotations from the plays are from William Shakespeare: The
Complete Works, ed. by Stephen Orgel and A. R. Braunmuller (New York: Pelican,
2002). מִ֤ י יִתֶ ּנְָך֙ כְ ּאָ֣ח לִ֔ י יֹונֵ֖ק שְ ׁדֵ֣י אִ מִ ּ ֑ י אֶֽ מְ צָאֲָך֤ בַחּוץ֙ אֶ שָ ּׁ ֣ קְָך֔ גַּ ֖ ם לֹא־ יָב֥ ּוזּו לִֽ י׃ I
Love Poetry and the Critics who Allegorize:
The Song of Songs We do not have commentary by Origen for this passage (of his ten
original volumes, only four remain), so let’s look at something from
seemingly the opposite end of the exegetical spectrum, a book called
Song of Solomon for Teenagers: Imagine the King of Kings. He is not just a great man. He is God! Imagine
He loved you when you were unlovable. He cleaned you up and made
you somebody. He wants to love you and protect you. He wants to enjoy
you. He wants you to love and enjoy Him. How dare you say no. Don’t
you realize that without Him you can do nothing. […] How dare you
reject One who is altogether lovely. The problem we have is that He is
the one that picks the time of visitation.40 Though the lack of question marks can be disconcerting, and the
remarks about enjoying and being enjoyed are borderline disturbing,
the allegorical method of interpreting the Song is essentially the same in
this simple twenty-first-century text as it is in Origen’s complex third-
century writings. The young man in the poem is erased as a human
being and turned into a symbol for God, while the young woman is
denied her sexuality and made to serve as a metaphor for those who
do not turn quickly enough to Him. The story of passion, sex, longing,
and love is completely dismissed in favor of a meaning which is forced
onto the text like the attentions of an unwanted suitor, and this forcing
has a long history: “[t]he fundamental way to justify the canonicity of
the Song of Songs, among both Jews and Christians, has always been
to read the text as an allegory, a piece of writing which does not mean
what it literally says”.41 2. Love Poetry from the Song of Songs to Aeneas and Dido Just as the young woman fondles the manul with her
wet fingers, at that precise moment, the young man had “withdrawn,
and he was gone”, leaving the young woman open, wet with oil, and
absolutely frustrated. In the terms of the Porter from Macbeth, the young
man (and his manul) can stand to, or not stand to,42 and in this case, he
and it have done the latter. Near the end of the Song, it appears that the relationship between the
young man and young woman is illicit, for she wishes he could be as her
brother, so that when they met in public there would be no suspicion: מִ֤ י יִתֶ ּנְָך֙ כְ ּאָ֣ח לִ֔ י יֹונֵ֖ק שְ ׁדֵ֣י אִ מִ ּ ֑ י אֶֽ מְ צָאֲָך֤ בַחּוץ֙ אֶ שָ ּׁ ֣ קְָך֔ גַּ ֖ ם לֹא־ יָב֥ ּוזּו לִֽ י׃ 50 50 Love and its Critics אֶ נְהָֽ גֲָך֗ אֲבִֽ יאֲָך֛ אֶ ל־ בֵּ ֥ ית אִ מִ ּ ֖ י תְ ּלַמְ ּדֵ֑נִי אַ שְ ׁקְָך֙ מִ יַּ֣יִן הָרֶ֔ קַח מֵעֲסִ֖ יס רִ מֹּנִֽי׃
43שְ ׂמֹאלֹו֙ תַ ּ ֣ חַת רֹאשִ ׁ ֔ י וִֽ ימִ ינֹ֖ו תְ ּחַבְ ּקֵֽ נִי׃ אֶ נְהָֽ גֲָך֗ אֲבִֽ יאֲָך֛ אֶ ל־ בֵּ ֥ ית אִ מִ ּ ֖ י תְ ּלַמְ ּדֵ֑נִי אַ שְ ׁקְָך֙ מִ יַּ֣יִן הָרֶ֔ קַח מֵעֲסִ֖ יס רִ מֹּנִֽי׃
43שְ ׂמֹאלֹו֙ תַ ּ ֣ חַת רֹאשִ ׁ ֔ י וִֽ ימִ ינֹ֖ו תְ ּחַבְ ּקֵֽ נִי׃ O that you were as my brother, who sucked the breasts of my mother! When I should meet you outside, I would kiss you, yes, and no one would
despise me. I would lead you, and bring you to my mother’s house, and
she would teach me; I would give you a drink of the spiced wine of the
juice of my pomegranate. Your left hand would be under my head, and
your right hand would embrace me. None of this makes any sense if seen through the allegorical lens of
Origen. The young woman is wishing she could invite the young man
home to have sex with her—with his left hand under her head, and
his right hand embracing her, she is imagining them either making
love or dancing the tango (arguably the same thing), and the image of
drinking the spiced wine of the juice of her pomegranate could not be
more obvious. 43
Song of Songs 8:1–3.
44
Ibid., 7:11–13. 43
Song of Songs 8:1–3. 44
Ibid., 7:11–13. g
48
Benjamin Edidin Scolnic. “Why Do We Sing the Song of Songs on Passover?”
Conservative Judaism, 48: 4 (1996), 55, https://www.rabbinicalassembly.org/sites/
default/files/public/jewish-law/holidays/pesah/why-do-we-sing-the-song-of-
songs-on-passover.pdf p
46
The urge to allegorize the Song may well have developed in reaction to a changing
imperial atmosphere, in light of a series of laws, penalties, and taxation measures
designed to control the whos, whats, whys, and hows of marriage and sexuality
(laws the poet Ovid seems to have been punished for violating). 45
Weston Fields. “Early and Medieval Interpretation of the Song of Songs”, Grace
Theological Journal, 1: 2 (Fall, 1980), 222, https://biblicalstudies.org.uk/pdf/gtj/01-
2_221.pdf 2. Love Poetry from the Song of Songs to Aeneas and Dido It echoes an earlier scene which is clearly a reference to a
sexual assignation: ְ ָ ֽ
ָ ֖ ָ
ָ ֶ
ֹ֣
ְ ָ֤
44נַשְ ׁכִ ּ֙ימָה֙ לַכְ ּרָ מִ֔ ים נִרְ אֶ֞ ה אִ ם פָּ ֽ רְ חָ֤ה הַגֶּ֙פֶן֙ פִ ּתַ ּ ֣ ח הַסְ ּמָדַ֔ ר הֵנֵ֖צּו הָרִ ּמֹונִ֑ים שָ ׁ ֛ ם אֶ תֵ ּ ֥ ן אֶ ת־ דֹּדַ֖י לְָֽך׃ I am my lover’s, and his desire is for me. Come, my love, let us go into the
field; let us spend the night in the village. Come, let us rise early and go
to the vineyards; let us see whether the vines flourish, the tender grapes
appear, and the pomegranates bud and blossom. There I will give my
love to you. If the “vines flourish” and the “pomegranates bud and blossom”, then
perhaps this love scene will work out better than the last one. So how did we get to the point where a poem so obviously sexual
as the Song of Songs is commonly tamed into submission as a religious
allegory, where even teenagers are taught to read a poem that openly
features youthful eroticism and unceasing sexual innuendo as if it were
written by virgins, for virgins, and about virgins? For centuries after its
composition—perhaps as long as a millennium, if the most generous
estimates are correct—the Song appears to have been read and sung in
the spirit of love and desire, for “there is no record of allegorization in 2. Love Poetry from the Song of Songs to Aeneas and Dido 51 51 the earliest period”.45 The allegorical reading of the Song began under
a Roman imperial rule that since the days of Caesar Augustus had
been slowly tightening its grip on the sexual behaviors of its subjects,46
developing at approximately the same time among the Jews and the
Christians: At the council of Jamnia at the end of the first century, […] Rabbi Judah
argued that the Song of Songs defiled the hands, i.e., was taboo or sacred,
hence canonical, while Ecclesiastes did not. 47
Longxi, 194. 51
Sara Japhet. “Rashi’s Commentary on the Song of Songs: The Revolution of the
Peshat and its Aftermath”. In J. Männchen and T. Reiprich, eds. Mein Haus wird ein
Bethaus für alle Völker genannt werden. Festschrift für Thomas Wille sum 75. Gerburgstag
(Neukirchen: Neukirchener Verlag, 2007), 202. 49
Tractate Sanhedrin. In Hebrew English Edition of the Babylonian Talmud, ed. by Rabbi
Isidore Epstein (London: Socino Press, 1969), 37a.
50
Ibid 101 2. Love Poetry from the Song of Songs to Aeneas and Dido Rabbi Jose then expressed
his doubt about the propriety of including the Song in the canon, but
Rabbi Aquiba made a powerful plea [and he] angrily denounced those
who treated this holy Song as an ordinary song (zemîr) and chanted it in
“Banquet Houses”.47 Rabbi Akiba argued for the inclusion of the Song in the Hebrew canon
by claiming “all the world is not as worthy as the day on which the
Song of Songs was given to Israel, for all the writings are holy, but the
Song of Songs is the holy of holies”.48 Arguing against other Rabbis who
thought, based on a literal interpretation, that the text was obscene,
Akiba seems to have been the earliest known advocate for an allegorical
approach to the Song. Rabbi Akiba argued for the inclusion of the Song in the Hebrew canon
by claiming “all the world is not as worthy as the day on which the
Song of Songs was given to Israel, for all the writings are holy, but the
Song of Songs is the holy of holies”.48 Arguing against other Rabbis who
thought, based on a literal interpretation, that the text was obscene,
Akiba seems to have been the earliest known advocate for an allegorical
approach to the Song. In the centuries that follow, allegory becomes orthodoxy. The
Babylonian Talmud makes repeated allegorical references to the Song. In
the Gemara (a section completed c. 500 CE) of the Tractate Sanhedrin,
verses from the Song are interpreted as signifying the Sanhedrin, the
judicial body appointed in each Israelite city: 52 52 Love and its Critics זו סנהדרי […] בטנך ערימת חטים מה ערימת חטים-שררך אגן הסהר אל יחסר המזג וגו’ שררך
49הכל נהנין ממנה אף סנהדרין הכל נהנין מטעמיהן Your navel is like a round goblet which lacks no wine: that navel—that is
the Sanhedrin. […] Your belly is like a heap of wheat [Song of Songs 7:2]:
even as we profit from wheat, so also we profit from the Sanhedrin’s
reasonings. 2. Love Poetry from the Song of Songs to Aeneas and Dido Those reading the Song as a poem about love and desire are condemned
as bringing evil to the world, and unless the Rabbis are condemning
something wholly imaginary, this is evidence that there were still
people who approached the Song in exactly this way: הקורא פסוק של שיר השירים ועושה אותו כמין זמר והקורא פסוק בבית משתאות בלא זמנו
מביא רעה לעולם מפני שהתורה חוגרת שק ועומדת לפני הקב”ה ואומרת לפניו רבונו של עולם
50עשאוני בניך ככנור שמנגנין בו לצים A reader of a verse from the Song of Songs who sings it at the wrong
time, turning it into a festival song, brings evil into the world. The Torah,
dressed in sackcloth, stands before the Holy One and cries out, “Lord of
the Universe! Your children treat me as a lyre played by scornful fools”. For centuries, the perspectives of Akiba, Origen, and the Talmud
remain the dominant mode of reading and understanding the Song. But a change comes at the end of the eleventh century, in France, at the
same time the first of the troubadour poems are appearing in the world. Rabbi Solomon the Izakhite, known to history as Rashi, champions
the Peshat method of Scriptural interpretation, “the interpretation of
the text according to its ‘plain meaning’”.51 Rashi has little use for
the Talmudic idea that the Song should not be sung on festival days;
rather than bringing evil into the world, he regards such singing as
bringing good: 2. Love Poetry from the Song of Songs to Aeneas and Dido 53 52
Rashi’s commentary is quoted here from the Tractate Sanhedrin (101a), Part VII,
Vol. 21. In The Talmud: The Steinsaltz Edition, ed. by Rabbi Adin Steinsaltz (New
York: Random House, 1999), 52–53. As is traditional, Steinsaltz uses the semi-
cursive Rashi script, rather than the more familiar square or block Hebrew script, to
reproduce Rashi’s commentary. 4
Mikraot Gedolot: Torah with Forty-Two Commentaries (מקראות גדולות: חמישה חמישי תורה עם
שניים וארבעים פרושים), Vol. 3 (The Widow and Brothers Ram: Truskavets/Glukhov,
Ukraine, 1907), 418, https://books.google.com/books?id=fEUpAAAAYAAJ. Also in
Mikraot Gedolot (מקראות גדולות), Vol. 4, ed. by Yaakov ben Hayyim. Printed by Daniel
Bomberg (Venice, 1524), 130r, https://archive.org/stream/The_Second_Rabbinic_
Bible_Vol_4/4#page/n261. Further discussed in Yehoshafat Nevo. French Biblical
Interpretation: Studies in the Interpretive Methods of the Bible Commentators in Northern
France in the Middle Ages (פרשנות המקרא הצפרתית עיונים בדרכי פרשנותם של מפרשי המקרא בצפון
צרפת בימי הביניים) (Reḥovot: Moreshet Yaʻaḳov, 2004), 274. Edward L. Greenstein. “Medieval Bible Commentaries”. In Back to the Sources:
Reading the Classic Jewish Texts, ed. by Barry W. Holtz (New York: Simon & Schuster,
2006), 219, 220. אבל אם אומרו בזמנו על המשתה, כגון שהוא יום טוב, ונוטל כוס בידו ואומר עליו
52מביא טובה לעולם-דברי הגדה ופסוקים מענינו של יום But I say the time for the feast is a good day, and for a man to take a glass
in his hand and tell others the words of ancient legends and the verses
relevant to the day—this always brings good to the world. Rashi also gets right to the “plain meaning”53 of the famous “kisses” of
the Song, arguing that they are literal kisses being desired by an actual
woman whose husband has become neglectful. The resulting view of
the text is at once less strained (having no need to compare a woman’s
body to an all-male judiciary), more responsive to textual detail, and
entirely more human than the interpretations of Akiba, Origen, and the
innumerable commentators who follow them: זה השיר אומרת בפיה בגלותה ובאלמנותה מי יתן וישקני המלך שלמה מנשיקות פיהו
כמו מאז לפי שיש מקומות שנושקין על גב היד ועל הכתף אך אני מתאוה ושוקקת
54להיותו נוהג עמי כמנהג הראשון כחתן אל כלה פה אל פה זה השיר אומרת בפיה בגלותה ובאלמנותה מי יתן וישקני המלך שלמה מנשיקות פיהו
כמו מאז לפי שיש מקומות שנושקין על גב היד ועל הכתף אך אני מתאוה ושוקקת
54להיותו נוהג עמי כמנהג הראשון כחתן אל כלה פה אל פה 53
Edward L. Greenstein suggests that the “plain” meaning is often actually much
more complex than the allegorical meaning. In arguing for historical context as a
crucial element of Rashi’s peshat method of reading, Greenstein makes Rashi sound
like an early ancestor of today’s historicists:
Most secondary literature on Jewish exegesis defines peshat as the “simple”, “plain”, or “literal”
approach, but these terms are misleading. The historical meaning of the biblical text may
actually be complex and figurative, neither simple nor straightforward. […] The peshat method,
therefore, should perhaps be glossed in English as the direct, contextual mode of exegesis, not
“plain” or “literal”, which it often is not. The derash method is the acontextual approach because
it disregards the constrictions of the historical, literary and linguistic condition in which the text
first came to us. 55
Japhet, 202.
56
Ibid., 211.
57
Ibid., 212.
58
Ibid., 214.
59
Ibid., 215. זה השיר אומרת בפיה בגלותה ובאלמנותה מי יתן וישקני המלך שלמה מנשיקות פיהו
כמו מאז לפי שיש מקומות שנושקין על גב היד ועל הכתף אך אני מתאוה ושוקקת
54להיותו נוהג עמי כמנהג הראשון כחתן אל כלה פה אל פה 52
Rashi’s commentary is quoted here from the Tractate Sanhedrin (101a), Part VII,
Vol. 21. In The Talmud: The Steinsaltz Edition, ed. by Rabbi Adin Steinsaltz (New
York: Random House, 1999), 52–53. As is traditional, Steinsaltz uses the semi-
cursive Rashi script, rather than the more familiar square or block Hebrew script, to
reproduce Rashi’s commentary. p
y
53
Edward L. Greenstein suggests that the “plain” meaning is often actually much
more complex than the allegorical meaning. In arguing for historical context as a
crucial element of Rashi’s peshat method of reading, Greenstein makes Rashi sound
like an early ancestor of today’s historicists: Edward L. Greenstein. “Medieval Bible Commentaries”. In Back to the Sources:
Reading the Classic Jewish Texts, ed. by Barry W. Holtz (New York: Simon & Schuster,
2006), 219, 220. 54 4
Mikraot Gedolot: Torah with Forty-Two Commentaries (מקראות גדולות: חמישה חמישי תורה עם
שניים וארבעים פרושים), Vol. 3 (The Widow and Brothers Ram: Truskavets/Glukhov,
Ukraine, 1907), 418, https://books.google.com/books?id=fEUpAAAAYAAJ. Also in
Mikraot Gedolot (מקראות גדולות), Vol. 4, ed. by Yaakov ben Hayyim. Printed by Daniel
Bomberg (Venice, 1524), 130r, https://archive.org/stream/The_Second_Rabbinic_
Bible_Vol_4/4#page/n261. Further discussed in Yehoshafat Nevo. French Biblical
Interpretation: Studies in the Interpretive Methods of the Bible Commentators in Northern
France in the Middle Ages (פרשנות המקרא הצפרתית עיונים בדרכי פרשנותם של מפרשי המקרא בצפון
צרפת בימי הביניים) (Reḥovot: Moreshet Yaʻaḳov, 2004), 274. 54 54 Love and its Critics She sings this song with her mouth, in exile and widowhood: “Would
that King Solomon would kiss me, like he used to, with the kisses of
his mouth, since in some places they kiss the back of the hand or the
shoulder, but I long for the familiarity with which he first treated me,
like a bridegroom with his bride, kissing mouth to mouth”. She sings this song with her mouth, in exile and widowhood: “Would
that King Solomon would kiss me, like he used to, with the kisses of
his mouth, since in some places they kiss the back of the hand or the
shoulder, but I long for the familiarity with which he first treated me,
like a bridegroom with his bride, kissing mouth to mouth”. Rashi may be the first Rabbinical interpreter to apply this “plain
meaning” method to the Song,55 but he would not be the last. 60
“Dilectus mens misit manum suam per foramen, et venter meus intumuit ad tactum
ejus, Quam visitationem gratiae, missionem manus per foramen vocat. Quasi
enim per rimam gratiam infundit, cum non total animam perfundit” (Richard of
St. Victor. Exposition in Cantica Canticorum. In Patrologiae Cursus Completus: Series
Latina, Vol. 196, ed. by Jacques-Paul Migne [Paris, 1855], col. 503c, https://archive.
org/stream/patrologiaecurs104unkngoog#page/n271). 61
“Intentio principalis huius opis est exprimere mutua desideria inter sponsum &
sponsam, sive inter christum & ecclesiam” (Giles of Rome. Librum Solomonis qui
Cantica Canticorum Inscribitur Commentaria D. Aegidii Romani [Rome: Antonium
Bladum, 1555], 2v, https://books.google.com/books?id=ZcjIK13ZCXAC&pg=PP4). 62
“Ita sponsus attraxit me: unde non volens vel valens resistere ei, (surrexi) a
contemplatione, (ut aperirem dilecto meo) per praedicationem; et non solum aperui
ei praedicando verbo, sed etiam praedicando exemplo. Ideo subditur, (manus meae,)
idest, operationes meae, (stillaverunt myrrham,) idest carnis mortificationem”
(ibid., 11v, https://books.google.com/books?id=ZcjIK13ZCXAC&pg=PP22). זה השיר אומרת בפיה בגלותה ובאלמנותה מי יתן וישקני המלך שלמה מנשיקות פיהו
כמו מאז לפי שיש מקומות שנושקין על גב היד ועל הכתף אך אני מתאוה ושוקקת
54להיותו נוהג עמי כמנהג הראשון כחתן אל כלה פה אל פה Two
anonymous commentators of the twelfth century in France take the
Peshat methodology to its logical conclusion, arguing that the Song was
merely a song, was not sacred, and was included in the canon because it
was popular. The first commentator, finally published for the first time
in 1866,56 makes the point directly: Rashi may be the first Rabbinical interpreter to apply this “plain
meaning” method to the Song,55 but he would not be the last. Two
anonymous commentators of the twelfth century in France take the
Peshat methodology to its logical conclusion, arguing that the Song was
merely a song, was not sacred, and was included in the canon because it
was popular. The first commentator, finally published for the first time
in 1866,56 makes the point directly: the interpretation of “the Song of Songs” is: This is one of the songs
composed by Solomon, who wrote many songs, as it is said: “And his
songs numbered one thousand and five” (1 Kgs 5:12). Why was this one
written [written down and included in the canon] of all the others? It was
written because it was loved by the people.57 The second twelfth-century commentator, first published in 1896,
“explained the Song of Songs as a secular love song, did not present
it as a parable, did not regard it as a prophecy, and did not include an
allegorical interpretation”.58 At the time the troubadours are working, it appears that the love
poetry of the Song is being read and explained, by at least a few, as
love poetry about human beings desiring each other, regardless of the
laws of God or man. As Japhet explains, “this kind of commentary on
the Song of Songs—an exclusive adherence to the plain meaning and
total avoidance of any kind of allegory—is a unique phenomenon, with
no parallel in the long history of Jewish exegesis of the Song of Songs
until the modern period”.59 Sadly, this unique phenomenon does not
last. In the thirteenth century, at about the same time the troubadour
movement is being crushed by the Church, and the notably allegorical g/
/p
g
g
g p g /
)
61
“Intentio principalis huius opis est exprimere mutua desideria inter sponsum &
sponsam, sive inter christum & ecclesiam” (Giles of Rome. Librum Solomonis qui
Cantica Canticorum Inscribitur Commentaria D. Aegidii Romani [Rome: Antonium
Bladum, 1555], 2v, https://books.google.com/books?id=ZcjIK13ZCXAC&pg=PP4).
62
“Ita sponsus attraxit me: unde non volens vel valens resistere ei, (surrexi) a
contemplatione, (ut aperirem dilecto meo) per praedicationem; et non solum aperui
ei praedicando verbo, sed etiam praedicando exemplo. Ideo subditur, (manus meae,)
idest, operationes meae, (stillaverunt myrrham,) idest carnis mortificationem”
(ibid., 11v, https://books.google.com/books?id=ZcjIK13ZCXAC&pg=PP22). 2. Love Poetry from the Song of Songs to Aeneas and Dido 2. Love Poetry from the Song of Songs to Aeneas and Dido 55 “sweet new style” (dolce stil novo) adopted by Dante is taking over, the
Peshat school dies out, and the allegorical reading of the Song returns. In some quarters, it never disappeared in the first place. For Richard
of St. Victor, the twelfth-century mystical theologian, even the most
erotic portions of the Song are to be interpreted in terms of the visitation
of Grace, or “visitationem gratiae”: My beloved put in his hand through the hole of the mind, and my belly is
swollen to the touch thereof; and this visitation of grace, is sent through
the hole by the hands that, as through a chink, infuse grace into the souls
of the faithful.60 This is also evident in the work of Giles of Rome (Egidio Colonna), the
thirteenth-and fourteenth-century cleric and Archbishop of Bourges,
who argues that “the principal intention of [the Song] is to express the
mutual desire between the bridegroom and bride, or between Christ
and the Church”.61 Giles—who served in the same Provençal region
whose theological, sexual, and poetical heresies the Church spent
decades subduing during the Crusades and the Inquisition—insists that
the language of opening to the lover is to be understood in terms of
preaching: This is also evident in the work of Giles of Rome (Egidio Colonna), the
thirteenth-and fourteenth-century cleric and Archbishop of Bourges,
who argues that “the principal intention of [the Song] is to express the
mutual desire between the bridegroom and bride, or between Christ
and the Church”.61 Giles—who served in the same Provençal region
whose theological, sexual, and poetical heresies the Church spent
decades subduing during the Crusades and the Inquisition—insists that
the language of opening to the lover is to be understood in terms of
preaching: My bridegroom attracted me so much, that being unwilling or unable to
resist him, I got up from contemplation to open to my beloved through
preaching, and not only through preaching in word, but also through
preaching in example. 63
Bart Vanden Auweele argues a different case, emphasizing the relatively recent
academic voices that have challenged the secular reading of the Song of Songs:
As long as the Song was read and understood allegorically, it was regarded as one of the
most important, most inspiring and most used books of Scripture. Strangely enough, from the
emergence of modern exegesis onwards, the poem fell gradually into a kind of oblivion as
its obvious meaning became recognised. In the nineteenth and the first half of the twentieth
century, the Song was scarcely read in Church and at university. […] Moreover, modern
exegetes approached the Song as a collection of diverse short erotic poems instead of being a
coherent story with a well-constructed plot. […] In recent years, however, the possibility and
legitimacy of a reading of the Song according to its so-called “obvious and literal meaning”
has been challenged. Modern interpreters such as Ricoeur, Patmore and Berder have criticised
secular erotic readings of the Canticle for representing modern reader expectations rather than
expressing a genuine biblical view on sexuality. 2. Love Poetry from the Song of Songs to Aeneas and Dido by
Anders-Christian Jacobson, Bart Vanden Auweele, and Carmen Cvetkovic [Aarhus:
Aarhus University Press, 2009], 158). The irony is that Auweele’s case is based on
critics whose techniques stem from the interpretive strategies of those who reduced
the Song to allegory in the first place. What exactly is “a genuine biblical view on
sexuality” if the Song is not allowed to speak for itself on that matter? Here, we have a
circular argument which insists that the Song is properly read as expressing a “genuine
biblical view”, while that “view” is imposed on the text by critics. The Bible says what
we say it says (a statement to which the Inquisition would have been amenable). 64
For an excellent overview of this process, see J. Paul Tanner, “The History of
Interpretation of the Song of Songs”, Bibliotheca Sacra, 154: 613 (1997), 23–46, https://
biblicalstudies.org.uk/article_song1_tanner.html, or http://www.paultanner.org/
English HTML/Publ Articles/Hist Song of Songs - P Tanner.pdf 63
Bart Vanden Auweele argues a different case, emphasizing the relatively recent
academic voices that have challenged the secular reading of the Song of Songs:
As long as the Song was read and understood allegorically, it was regarded as one of the
most important, most inspiring and most used books of Scripture. Strangely enough, from the
emergence of modern exegesis onwards, the poem fell gradually into a kind of oblivion as
its obvious meaning became recognised. In the nineteenth and the first half of the twentieth
century, the Song was scarcely read in Church and at university. […] Moreover, modern
exegetes approached the Song as a collection of diverse short erotic poems instead of being a
coherent story with a well-constructed plot. […] In recent years, however, the possibility and
legitimacy of a reading of the Song according to its so-called “obvious and literal meaning”
has been challenged. Modern interpreters such as Ricoeur, Patmore and Berder have criticised
secular erotic readings of the Canticle for representing modern reader expectations rather than
expressing a genuine biblical view on sexuality. Bart Vanden Auweele. “The Song of Songs as Normative Text”. In Religion and
Normativity Vol. 1: The Discursive Struggle over Religious Texts in Antiquity, ed. by
Anders-Christian Jacobson, Bart Vanden Auweele, and Carmen Cvetkovic [Aarhus:
Aarhus University Press, 2009], 158). 63
Bart Vanden Auweele argues a different case, emphasizing the relatively recent
academic voices that have challenged the secular reading of the Song of Songs: 2. Love Poetry from the Song of Songs to Aeneas and Dido Therefore it continues: my hands, that is, my
works, dripped with myrrh, that is, with the mortification of the flesh.62 56 Love and its Critics This reading of the Song, insisting that what it really says is opposed
to what it merely seems to say, served the immediate ideological needs
of the Inquisition-era Church, and has remained dominant ever since.63
Even now, the movement to restore the erotic sense of the verse is
largely confined to academia, and has little impact on the way most
readers encounter the poem.64 The story of the Song is a miniature reflection of the story of this
book. Love, passionate and mutually chosen regard between two
people, without concern for gods, laws, or institutions, has always
struggled to survive in a hostile world. Its literary monuments have
been appropriated for the purposes of those opposed to it, as verses
speaking of desire and frustration, passion and joy, the sensual
details of liquids, oils, and sweets, and open admiration of the body’s
form, are “channeled, reformulated, and controlled” into metaphors,
allegories, and symbols of an eros redirected toward the sky. “It is
amusing”, as Longxi notes, “to see how the priggish commentators 63
Bart Vanden Auweele argues a different case, emphasizing the relatively recent
academic voices that have challenged the secular reading of the Song of Songs:
As long as the Song was read and understood allegorically, it was regarded as one of the
most important, most inspiring and most used books of Scripture. Strangely enough, from the
emergence of modern exegesis onwards, the poem fell gradually into a kind of oblivion as
its obvious meaning became recognised. In the nineteenth and the first half of the twentieth
century, the Song was scarcely read in Church and at university. […] Moreover, modern
exegetes approached the Song as a collection of diverse short erotic poems instead of being a
coherent story with a well-constructed plot. […] In recent years, however, the possibility and
legitimacy of a reading of the Song according to its so-called “obvious and literal meaning”
has been challenged. Modern interpreters such as Ricoeur, Patmore and Berder have criticised
secular erotic readings of the Canticle for representing modern reader expectations rather than
expressing a genuine biblical view on sexuality. Bart Vanden Auweele. “The Song of Songs as Normative Text”. In Religion and
Normativity Vol. 1: The Discursive Struggle over Religious Texts in Antiquity, ed. 2. Love Poetry from the Song of Songs to Aeneas and Dido The irony is that Auweele’s case is based on
critics whose techniques stem from the interpretive strategies of those who reduced
the Song to allegory in the first place. What exactly is “a genuine biblical view on
sexuality” if the Song is not allowed to speak for itself on that matter? Here, we have a
circular argument which insists that the Song is properly read as expressing a “genuine
biblical view”, while that “view” is imposed on the text by critics. The Bible says what
we say it says (a statement to which the Inquisition would have been amenable). 64 64
For an excellent overview of this process, see J. Paul Tanner, “The History of
Interpretation of the Song of Songs”, Bibliotheca Sacra, 154: 613 (1997), 23–46, https://
biblicalstudies.org.uk/article_song1_tanner.html, or http://www.paultanner.org/
English HTML/Publ Articles/Hist Song of Songs - P Tanner.pdf 2. Love Poetry from the Song of Songs to Aeneas and Dido 57 stretch the words out of all proportion […]. Such farfetched exegeses
[…] consistently read love songs as about anything but love”.65 We will
see versions of this pattern repeatedly, as passion becomes worship,
and desire becomes the decorous admiration of objects whose best use
is to transport the admirer beyond the hated and distrusted flesh, and
toward a union with what one cannot speak to, cannot draw near to,
and most definitely cannot touch. 65
Longxi, 207.
66
G. P. Goold. “The Cause of Ovid’s Exile”. Illinois Classical Studies, 8: 1 (Spring 1983),
96, http://hdl.handle.net/2142/11861
67
Ibid. g
,
66
G. P. Goold. “The Cause of Ovid’s Exile”. Illinois Classical Studies, 8: 1 (Spring 1983),
96, http://hdl.handle.net/2142/11861
67
Ibid. 65
Longxi, 207. 68
Ovid. Amores 1.4. In Ovid: Heroides and Amores, ed. by Grant Showerman (Loeb
Classical Library, Cambridge, MA: Harvard University Press, 1958), 328, ll. 1–4.
69
Ibid., 328, 330, ll. 13–26. II
Love Poetry and the Critics who Reduce:
Ovid’s Amores and Ars Amatoria Two collections of poetry that have no pretensions to being allegories
of the sacred, the Amores and the Ars Amatoria, despite their often
scurrilous reputations, are actually no more explicit in their passions
and descriptions than the Song of Songs. But while the Song, after
much debate, was included in the canons of Judaism and Christianity,
the Ars Amatoria, and Ovid along with it, were banished from Rome to
the shores of the Black Sea. Born in 43 BCE, Ovid was an established
poet by his early twenties, and he “poured forth with uninterrupted
regularity a series of elegiac works that far surpassed anything ever
previously attempted in their open mockery of accepted sexual
morality”.66 The Amores (an early work loosely centered around the
poet’s wry and self-aware fascination with a woman he refers to as
Corrina) are completed by the time Ovid was twenty-eight, and by this
time “he had established himself as Rome’s foremost poet, and was
the idol of the capital”.67 The Amores have the feel of a young man’s poetry, mixing bravado
with uncertainty in their treatment of love and desire. The poems
often talk of love as something that is sweeter when stolen, especially
in poems like Elegy 1.4, “Amicam qua arte”, and the famous Elegy 1.5 Love and its Critics 58 “Corrina Concubitus”. The former mockingly bemoans the fact that the
lady’s husband would be at dinner: Vir tuus est epulas nobis aditurus easdem—
ultima coena tuo sit, precor, illa viro! ergo ego dilectam tantum conviva puellam
adspiciam?68 Your husband will be at the same supper with us—
let that supper, I pray, be your husband’s last! Shall I be so close to a girl I love
and merely be a guest? But the lover soon finds the husband’s presence exciting, since it
challenges him to remain undetected in public: But the lover soon finds the husband’s presence exciting, since it
challenges him to remain undetected in public: ante veni, quam vir—nec quid, si veneris ante,
possit agi video; sed tamen ante veni. cum premet ille torum, vultu comes ipsa modesto
ibis, ut accumbas—clam mihi tange pedem! me specta nutusque meos vultumque loquacem;
excipe furtivas et refer ipsa notas. verba superciliis sine voce loquentia dicam;
verba leges digitis, verba notata mero. cum tibi succurret Veneris lascivia nostrae,
purpureas tenero pollice tange genas. 70
Ibid., 330, ll. 43–46.
71
Ibid., 332, ll. 69–70. II
Love Poetry and the Critics who Reduce:
Ovid’s Amores and Ars Amatoria siquid erit, de me tacita quod mente queraris,
pendeat extrema mollis ab aure manus. cum tibi, quae faciam, mea lux, dicamve, placebunt,
versetur digitis anulus usque tuis.69 Come before your husband, why not, come before,
I don’t see what’s possible, but arrive before. When he lies on the couch, look, with modest
demeanor recline beside him—secretly touch my foot! 59 2. Love Poetry from the Song of Songs to Aeneas and Dido 72
Amores 1.5, 334, ll. 9–12. 73
Ibid., ll. 13–24. 2. Love Poetry from the Song of Songs to Aeneas and Dido Look at me and my nods and my expressive face;
catch my secrets and return them. Without saying a word, my eyebrows will speak to you;
words from my fingers, words traced in wine. When you think of the pleasures of our love,
with a tender thumb touch your cheeks. If you remember some silent complaint against me,
gently grasp the bottom of your ear with your hand. When you are pleased, my light, with what I do or say,
fiddle with the ring on your finger. Ironically, the lover giving this advice descends into jealousy. What if
the woman with whom he is cuckolding her husband, cuckolds him
with her husband? An intolerable thought: nec femori committe femur nec crure cohaere
nec tenerum duro cum pede iunge pedem. multa miser timeo, quia feci multa proterve,
exemplique metu torqueor, ecce, mei.70 Do not engage or touch him with the thigh
not the tip of the foot with his hard foot. Alas, I fear much, because I have often been wanton,
tormented, look you, by my own example. The young man (Ovid himself?) wants to believe that his love (Corinna
perhaps, though unnamed in this poem) is faithful to him, despite her
marriage to another. And if necessary, he would prefer that she lie in
order to maintain this belief: sed quaecumque tamen noctem fortuna sequetur,
cras mihi constanti voce dedisse nega!71 sed quaecumque tamen noctem fortuna sequetur,
cras mihi constanti voce dedisse nega!71 sed quaecumque tamen noctem fortuna sequetur,
cras mihi constanti voce dedisse nega!71 Nevertheless, whatever the night’s fortune proves,
tomorrow, in a firm voice, deny that you gave yourself! Nevertheless, whatever the night’s fortune proves,
tomorrow, in a firm voice, deny that you gave yourself! Love and its Critics 60 The more famous elegy, “Corrina Concubitus”, reflects none of the
teasing and self-tormenting doubts of the fourth elegy, and is filled with
the delights of physical eros, desire and fulfillment. First, the poem gives
voice to the delights of seeing: ecce, Corinna venit, tunica velata recincta,
candida dividua colla tegente coma—
qualiter in thalamos famosa Semiramis isse
dicitur, et multis Lais amata viris.72 Behold, Corinna comes, draped in a loose gown,
hair parted over her white neck—
just as Semiramis came to her bed,
so they say, and Lais loved by many men. 72
Amores 1.5, 334, ll. 9–12.
73
Ibid., ll. 13–24. 2. Love Poetry from the Song of Songs to Aeneas and Dido Next, the poem moves to touch mixed with sight: Deripui tunicam—nec multum rara nocebat;
pugnabat tunica sed tamen illa tegi. quae cum ita pugnaret, tamquam quae vincere nolle
victa est non aegre proditione sua. ut stetit ante oculos posito velamine nostros,
in toto nusquam corpore menda fuit. quos umeros, quales vidi tetigique lacertos! forma papillarum quam fuit apta premi! quam castigato planus sub pectore venter! quantum et quale latus! quam iuvenale femur! Singula quid referam? nil non laudabile vidi
et nudam pressi corpus ad usque meum.73 Deripui tunicam—nec multum rara nocebat;
pugnabat tunica sed tamen illa tegi. quae cum ita pugnaret, tamquam quae vincere nollet,
victa est non aegre proditione sua. ut stetit ante oculos posito velamine nostros,
in toto nusquam corpore menda fuit. quos umeros, quales vidi tetigique lacertos! forma papillarum quam fuit apta premi! quam castigato planus sub pectore venter! quantum et quale latus! quam iuvenale femur! Singula quid referam? nil non laudabile vidi
et nudam pressi corpus ad usque meum.73 I tore off her coat—it was thin, and covered little;
but, she held the tunic, fighting to be covered,
fighting as if she would win,
or be conquered easily, but not by her own betrayal. As she stood before my eyes with drapery set by,
she hadn’t a flaw in her entire body. 2. Love Poetry from the Song of Songs to Aeneas and Dido 61 What shoulders, what arms I saw and touched! The form of her breasts, how fit to be caressed! How flat is her belly, beneath her breasts! Her side’s quantity and quality! What a thrilling thigh! Why refer to more? I saw nothing unpraiseworthy
and pressed her naked body against mine. Finally, as desire has played its scene, and quiet satisfaction remains,
the poem turns to a wish for many more such afternoons as this one: Finally, as desire has played its scene, and quiet satisfaction remains,
the poem turns to a wish for many more such afternoons as this one: Cetera quis nescit? lassi requievimus ambo. proveniant medii sic mihi saepe dies!74 Who knows not what followed? Weary, we rested. May such afternoons come for me often! Who knows not what followed? Weary, we rested. May such afternoons come for me often! Corinna is neither a goddess, nor an allegory for the sacred. 74
Ibid., ll. 25–26.
75
See John C. Thibault. The Mystery of Ovid’s Exile (Berkeley: University of California
Press, 1964), 38–54.
76
Goold, 107. 75
See John C. Thibault. The Mystery of Ovid’s Exile (Berkeley: University of California
Press, 1964), 38–54.
76
Goold, 107. 74
Ibid., ll. 25–26. 2. Love Poetry from the Song of Songs to Aeneas and Dido There
has never been a critical impulse to explain “Corrina Concubitus” as
if it were really portraying the relationship between humanity and
the gods. Corinna is portrayed as a flesh-and-blood woman, desired
and worried over by a flesh-and-blood man. If Corinna is a stand-in
for anything or anyone, perhaps it is Julia, the daughter of Augustus,
the Roman Emperor who would, some twenty-plus years after the
publication of the Amores, banish Ovid from Rome for life. While this
possibility has long been a matter of debate,75 it does tie in with the
overall feeling in many of the elegies of forbidden love—an eros that is
more exciting because of the possibility of getting caught and severely
punished. If Corinna is Julia, and the famous twofold reason for Ovid’s
banishment (carmen et error, the poem and the mistake Ovid refers to
in his poem Tristia, 2.207) was “for writing the Ars Amatoria and for
committing a transgression”76 with her, then what a reader encounters
in both the Amores and the Ars Amatoria is life and experience,
transgression and joy, transformed into poetry that celebrated love
and desire which was enjoyed in the shadow of condemnation and Love and its Critics 62 banishment. Rather than passion sublimated into a search for the
divine, these poems are perhaps our first clear example, unsullied by
the allegorizing and temporizing mood, of what the troubadours will
call fin’amor, love as an end in itself. Title page of a 1644 edition of Ovid’s Ars Amatoria.77 Title page of a 1644 edition of Ovid’s Ars Amatoria.77 However, in what will soon become a familiar move in the criticism of
many different authors and periods, some commentary on Ovid’s work
returns it to the realm of allegory, not of the human-divine relationship,
but, in this case, of poetry itself. Reducing Ovid’s work to a series of
conventions and tropes, Peter Allen argues that it amounts to little more
than poetry gazing at its own reflection: The lesson is in fact a lesson in literary theory. The Ars and Remedia reveal
(though often in indirect ways) that the love described in elegiac poetry
is essentially the same as the poetry itself: both are artistic fantasies,
constructed by the reader and the poetic lover together. 77
https://commons.wikimedia.org/wiki/File:Ovid_Ars_Amatoria_1644.jpg 78
Peter Allen. The Art of Love: Amatory Fiction from Ovid to the Romance of the Rose
(Philadelphia: University of Pennsylvania Press, 1992), 20.
79
Ibid. 2. Love Poetry from the Song of Songs to Aeneas and Dido Elegiac love
depends for its existence on the presence of recognizable conventions,
which help the reader situate it within a literary context, to recognize
it as fiction. Through such conventions the poet involves the reader in
the act of literary creation, which is itself an amatory relationship and, 77
https://commons.wikimedia.org/wiki/File:Ovid_Ars_Amatoria_1644.jpg 2. Love Poetry from the Song of Songs to Aeneas and Dido 63 in fact, the most intimate relationship in these texts; the preceptor’s true
task is to teach the reader how to be a creator, like himself.78 in fact, the most intimate relationship in these texts; the preceptor’s true
task is to teach the reader how to be a creator, like himself.78 Once, in the mid-twentieth century work of a critic like Blanchot, this
kind of argument—reducing literature to a meta-discourse in which
all that literature talks about is itself—might have seemed fresh, even
profound. It draws loosely on the now-familiar idea that language refers
only to language, and that only by a series of shared conventions do we
credit it with an illusory signifying power. Such criticism categorically
denies any possibility of poetry’s intervention in the world, turning
literature into a passive prop for political, military, economic, and
epistemological regimes of power to which it cannot even refer, much
less oppose. It presents an appearance of radicalism, while deliberately
entangling itself in its own refusals and withdrawals. Such an argument about Ovid insists that, “[d]espite the Amores’
pose of sincerity, well-informed readers will recognize that each of
their characters and situations are conventional”.79 Note the rhetorical
pressure applied to the reader—to resist the critic’s insistence that
Ovid’s work is merely conventional, relating only to the experience of
writing about love and not love itself, puts the reader outside the camp of
the “well-informed”. Thus we are told how we should read Ovid, and
how we should not read Ovid; “well-informed” readers will naturally
obey such prescriptions and proscriptions. But this is all a symptom
of an authoritarian strain in criticism that can be seen running all the
way back through Origen, Rabbi Akiba, and Giles of Rome, for whom
the Song of Songs had to be read with the ideological demands of
empire and church in mind. To demand, even implicitly as Allen does,
obedience in the reading of a poet whose delight in disobedience is
reflected throughout his poetry, is more than faintly absurd. And here
we see a new assertion—one we will encounter later in criticism of
medieval poetry: that the “poetic ‘I’” does not represent an individual
point of view (neither that of a poet nor a narrative voice), but is instead a
conventional and collective illusion. 80
Allen, 21.
81
Ibid.
82
Alison Sharrock. Seduction and Repetition in Ovid’s Ars Amatoria, 2 (Oxford:
Clarendon Press, 1994), 296. 81
Ibid.
82
Alison Sharrock. Seduction and Repetition in Ovid’s Ars Amatoria, 2 (Oxford:
Clarendon Press, 1994), 296. 83
Barbara Weiden Boyd. “The Amores: The Invention of Ovid”. In Brill’s Companion to
Ovid, ed. by Barbara Weiden Boyd (Leiden: Brill, 2002), 116.
84
The Lex Iulia de Maritandis Ordinibus of 18 BCE restricted marriage between the
social classes, and the Lex Iulia de Adulteriis Coercendis of the same year made
adultery punishable by banishment—the latter was applied to Julia in 2 BCE.
85
For a comprehensive survey of this theme across world literature, see Eos: An
Enquiry into the Theme of Lover’s Meetings and Partings at Dawn in Poetry, ed. by
Arthur T. Hatto (The Hague: Mouton & Co.), 1965.
86
Ovid Amores 1 13 368 ll 3 9 (
g
86
Ovid. Amores, 1.13, 368, ll. 3–9. in fact, the most intimate relationship in these texts; the preceptor’s true
task is to teach the reader how to be a creator, like himself.78 It would be ill-informed, according
to such criticism, to believe otherwise: 64 64 Love and its Critics The amator is little more than a convention himself, a reuse of the traditional
Roman poetic “I”, which derives from Propertius, Tibullus, Gallus, and
Catullus, as well as Catullus’s Alexandrian model, Callimachus. This
poetic “I” is a ventriloquist’s voice, a literary echo of an echo of an echo. Even the sincerity that post-Romantic readers, at least, traditionally
attribute to the poet-lover is undermined by the amator’s confessions of
infidelity and multifarious desire. His affirmations of love are “sincere”
not in the sense that they unify the amator, the poet, and the historical
Ovid, but in the sense that they create an effective illusion of a poet in
love.80 From Allen’s perspective, the “well-informed” reader will also reject
the possibility that “Corrina” had any referent in the world of flesh-
and-blood, regarding it as obvious that “she” is merely another literary
convention: Corinna is no more real than her lover. Historical identities have been
found for the women in earlier elegy, but literary history is silent on
Corinna, and efforts to re-create her are not only fruitless but even
irrelevant to an understanding of the Amores. Rather than existing as
a person in her own right […] she is the object of the amator’s desire,
the grain of sand that provokes the poetic oyster to produce a string of
literary pearls […]. Poetry, not Corinna, is the true star of the Amores.81 And thus the “well-informed” and properly compliant reader will
approach the Amores in order to read about poetry, not about love. We will see this same move made by other critics, though in different
contexts, ad infinitum. Even a less apparently prescriptive critic like
Alison Sharrock ultimately cannot resist turning Ovid’s poetry into an
allegory for the act of reading: “the Ars itself is a spell (a carmen) with
great seductive power. […] Just as texts are magically seductive, so is
interpretation, so is theory. It is the act of reading that draws us into the
poem. Reading about desire provokes the desire to read”.82 Such critics
have become temperamentally averse to the idea of poetry speaking of
anything but itself, as if it were the self-obsessed bore most of us try to
avoid at parties. 2. Love Poetry from the Song of Songs to Aeneas and Dido 85
For a comprehensive survey of this theme across world literature, see Eos: An
Enquiry into the Theme of Lover’s Meetings and Partings at Dawn in Poetry, ed. by
Arthur T. Hatto (The Hague: Mouton & Co.), 1965. 2. Love Poetry from the Song of Songs to Aeneas and Dido 65 But Ovid was anything but a bore. He was the kind of poet dedicated
to “pushing the limits (of convention, genre, discretion) and refusing to
be bound to or by anything other than his own genius”.83 Ovid gives
every appearance of refusing to take seriously the pieties that surround
love, and especially refuses to take seriously the laws that surround
marriage and procreation in Augustus’ Rome.84 However, he does take
quite seriously the joys of transgressive love itself. For example, “Ad
Auroram”, Elegy 1.13 from the Amores, shows a lover railing against the
rising sun—in a way that foreshadows the passions of the alba form of
twelfth-century Occitania85—for cutting short his time with his beloved: Quo properas, Aurora? mane!-sic Memnonis umbris
annua sollemni caede parentet avis! nunc iuvat in teneris dominae iacuisse lacertis;
si quando, lateri nunc bene iuncta meo est. nunc etiam somni pingues et frigidus aer,
et liquidum tenui gutture cantat avis. quo properas, ingrata viris, ingrata puellis?86 Quo properas, Aurora? mane!-sic Memnonis umbris
annua sollemni caede parentet avis! nunc iuvat in teneris dominae iacuisse lacertis;
si quando, lateri nunc bene iuncta meo est. nunc etiam somni pingues et frigidus aer,
et liquidum tenui gutture cantat avis. quo properas, ingrata viris, ingrata puellis?86 Where do you hurry, Aurora? Stay, so to Memmnon’s shades
his birds may make annual festival in combat! Now I delight to lie in the tender arms of my mistress;
if at any time, now it is best that she lies close to me. now, too, sleep is deep and the air is cold,
and slender-throated birds sing liquid songs. Why do you hurry, unwelcome to men, unwelcome to girls? The lover berates the oncoming light, knowing his course is futile, but
driven by passion and the desire to remain in his “girl’s soft arms”,
crying out over how many times dawn has torn him away from them: The lover berates the oncoming light, knowing his course is futile, but
driven by passion and the desire to remain in his “girl’s soft arms”,
crying out over how many times dawn has torn him away from them: 66 Love and its Critics 66 optavi quotiens, ne nox tibi cedere vellet,
ne fugerent vultus sidera mota tuos! 87
Ibid., 370, ll. 27–30. 88
Ibid., ll. 35–41. 87
Ibid., 370, ll. 27–30.
88
Ibid., ll. 35–41. 87
Ibid., 370, ll. 27–30.
88
Ibid., ll. 35–41. 2. Love Poetry from the Song of Songs to Aeneas and Dido optavi quotiens, aut ventus frangeret axem,
aut caderet spissa nube retentus equus!87 often have I wished night would not give place to thee,
so that the stars would not flee before your face! often have I wished the wind would break your axle,
or that a thick cloud would trip and fell your horse! Then, rehearsing the myth of Aurora, the goddess of dawn who is herself
married to the eternally old Tithonus, the lover accuses the goddess of
hypocrisy for wanting to stay with her young lover Cephalus, while
repeatedly denying the lover of the poem the chance to stay in the arms
of his beloved: Tithono vellem de te narrare liceret;
fabula non caelo turpior ulla foret. illum dum refugis, longo quia grandior aevo,
surgis ad invisas a sene mane rotas. at si, quem mavis, Cephalum conplexa teneres,
clamares: “lente currite, noctis equi!”
Cur ego plectar amans, si vir tibi marcet ab annis?88 I wish Tithonus were licensed to tell about you;
there is no more shameful story in heaven. Fleeing from him, for he is so many ages older than you,
you rise early from the old man, to morning’s chariot wheels. Whereas, if you had your beloved Cephalus in your embrace,
then you would cry: “Run slowly, horses of the night!”
Why must I suffer in love since your man is wasted with years? It is especially notable that human desire and frustration are at the center
of Ovid’s poem, and the goddess Aurora, with her serial attractions to,
and affairs with, mortal men, is a reflection of and comment upon the 88
Ibid., ll. 35–41. 2. Love Poetry from the Song of Songs to Aeneas and Dido 67 love between men and women, not a transcendent and otherwise body-
denying goal for which lovers must strive. Ovid mocks the pretensions of controlling husbands, and by
extension those of Augustus in passing a law against adultery, in “Ad
virum servantem coniugem”, Amores 3.4. This poem laughs at the man
who would too strictly defend the sexual fidelity of a woman; such a
man makes himself a tyrant, a fool, and a cuckold: Dure vir, inposito tenerae custode puellae
nil agis; ingenio est quaeque tuenda suo. siqua metu dempto casta est, ea denique casta est;
quae, quia non liceat, non facit, illa facit! ut iam servaris bene corpus, adultera mens est;
nec custodiri, ne velit, ulla potest. 89
Ovid. Amores, 3.4, 458, 460, ll. 1–8. 90
Ibid., 460, ll. 17–26. 2. Love Poetry from the Song of Songs to Aeneas and Dido nec corpus servare potes, licet omnia claudas;
omnibus exclusis intus adulter erit.89 Harsh man, setting a guard over your tender girl
gets you nothing; her own character is what will defend her. If she is chaste when free from fear, then she is pure;
but if she doesn’t sin because she’s not allowed to, she’ll do it! Even if you have well guarded the body, the mind is adulterous;
no watchman has any power over her will. Neither can you guard her body, though you close every door,
excluding all; for the adulterer will be within. Harsh man, setting a guard over your tender girl
gets you nothing; her own character is what will defend her. If she is chaste when free from fear, then she is pure;
but if she doesn’t sin because she’s not allowed to, she’ll do it! Even if you have well guarded the body, the mind is adulterous;
no watchman has any power over her will. Neither can you guard her body, though you close every door,
excluding all; for the adulterer will be within. In Ovid’s elegy, adultery is a natural response to the tyranny of unwanted
husbands and absurdly impractical laws that create (or enhance) the
very effects they seek to prevent. In fact, the strict laws of the husband
or the emperor inculcate the desire to break those laws and achieve the
forbidden (a motif familiar from Genesis 2–3): In Ovid’s elegy, adultery is a natural response to the tyranny of unwanted
husbands and absurdly impractical laws that create (or enhance) the
very effects they seek to prevent. In fact, the strict laws of the husband
or the emperor inculcate the desire to break those laws and achieve the
forbidden (a motif familiar from Genesis 2–3): nitimur in vetitum semper cupimusque negata;
sic interdictis imminet aeger aquis. centum fronte oculos, centum cervice gerebat
Argus—et hos unus saepe fefellit Amor; 89
Ovid. Amores, 3.4, 458, 460, ll. 1–8. 68 Love and its Critics 68 in thalamum Danae ferro saxoque perennem
quae fuerat virgo tradita, mater erat;
Penelope mansit, quamvis custode carebat,
inter tot iuvenes intemerata procos. Quidquid servatur cupimus magis, ipsaque furem
cura vocat; pauci, quod sinit alter, amant.90 We strive for what is forbidden and desire what is denied;
just as a sick man gazes over prohibited waters. 91
Ibid., 462, ll. 41–48. 90
Ibid., 460, ll. 17–26.
91
Ibid., 462, ll. 41–48. 2. Love Poetry from the Song of Songs to Aeneas and Dido A hundred eyes before, a hundred behind, had
Argus—and these were often deceived only by Love;
in a chamber of eternal iron and rock Danae was shut,
though she had been shut in as a maid, she became a mother;
Penelope remained steadfast, although without a guard,
among many youthful suitors. Whatever is guarded we desire the more, the thief
is invited by worry; few love what is permitted by another. We strive for what is forbidden and desire what is denied;
just as a sick man gazes over prohibited waters. A hundred eyes before, a hundred behind, had
Argus—and these were often deceived only by Love;
in a chamber of eternal iron and rock Danae was shut,
though she had been shut in as a maid, she became a mother;
Penelope remained steadfast, although without a guard,
among many youthful suitors. Whatever is guarded we desire the more, the thief
is invited by worry; few love what is permitted by another. Finally, the elegy ends with a bit of advice for old husbands—pretend,
as Shakespeare will write, to believe her when she says “she is made
of truth”, even though you know she lies. Pretend not to notice the
dalliances, even the affairs, because unless you are willing to be rid of
her, there is really nothing you can do about them: Finally, the elegy ends with a bit of advice for old husbands—pretend,
as Shakespeare will write, to believe her when she says “she is made
of truth”, even though you know she lies. Pretend not to notice the
dalliances, even the affairs, because unless you are willing to be rid of
her, there is really nothing you can do about them: quo tibi formosam, si non nisi casta placebat? non possunt ullis ista coire modis. Si sapis, indulge dominae vultusque severos
exue, nec rigidi iura tuere viri,
et cole quos dederit—multos dabit—uxor amicos. gratia sic minimo magna labore venit;
sic poteris iuvenum convivia semper inire
et, quae non dederis, multa videre domi.91 Why did you marry beauty if only chastity would please you? Those two things can never be combined. If you are wise, indulge your lady—and the stern looks? Why did you marry beauty if only chastity would please you? Those two things can never be combined. If you are wise, indulge your lady—and the stern looks? 2. Love Poetry from the Song of Songs to Aeneas and Dido Why did you marry beauty if only chastity would please you? Those two things can never be combined. If you are wise, indulge your lady—and the stern looks? 2. Love Poetry from the Song of Songs to Aeneas and Dido 69 Ditch them. Do not rigidly insist on the rights of a husband,
and cherish her very generous and loving…friends. You will receive great thanks, with little effort on your part;
so in this way, you can always celebrate and feast with youths,
and see many gifts at home which you did not give. Ditch them. Do not rigidly insist on the rights of a husband,
and cherish her very generous and loving…friends. You will receive great thanks, with little effort on your part;
so in this way, you can always celebrate and feast with youths,
and see many gifts at home which you did not give. The last lines are a wry joke—those gifts the husband did not give to
his much-younger wife may very well be gifts he can no longer give
her: children resulting from sexual encounters with young men who
can still “stand to” in a way that the husband has long since stopped
being able to do. Beyond pure social and sexual satire, the Amores are a work of pointed
political critique. The passing of such laws as the Lex Iulia de Maritandis
Ordinibus and the Lex Iulia de Adulteriis Coercendis (of 18 and 17 BCE) and
the Lex Papia Poppaea (of 9 CE) represented an ongoing attempt to use
the power of government to “reform Roman private morality”.92 Thus,
more than merely claiming that the husband creates or encourages
adultery in a wife over whom he keeps too strict a watch, the Amores
make a political point we might characterize as libertarian today: the
government encourages rebellion by being tyrannical. In such a reading
of the Amores, Augustus is the cuckolded husband who foolishly creates
the conditions and the impetus for his own cuckolding by trying to
control what cannot be controlled—the social and sexual mores of
his “wife”, the Roman people. Read in this way, Ovid’s poems can be
seen as an allegory which describes the relationship between Augustus
and Rome in the terms of relationships between men and women. 92
These laws proscribed class intermarriage, fornication/adultery, and celibacy,
respectively. P. J. Davis. “Ovid’s Amores: A Political Reading”. Classical Philology,
94: 4 (October 1999), 435, https://doi.org/10.1086/449457
93
Ibid., 431. 2. Love Poetry from the Song of Songs to Aeneas and Dido But
though they can be seen so, there are no powerful cultural forces that
demand they must be seen so, and “[i]t is only in recent years, that
Ovid’s Amores has come to be viewed as a political work”.93 The poetry
itself, unlike that of the Song, has not been “channeled, reformulated,
and controlled” to the point that its frankly erotic content has been
subjected to wholesale interpretive erasure, and that is an unqualifiedly
good thing. But the suggestion (not mandate) for reading the Amores in
a political light makes it easier for us to see the way in which love itself 70 Love and its Critics 70 is often “channeled, reformulated, and controlled” in order to serve the
agendas of the powerful. In passing laws designed to regulate sexuality, Augustus is trying
to establish a Julian dynasty that will survive the vicissitudes of time
and unforeseen circumstance. Just as the early critics like Xenophanes,
Akiba, and Origen seek to control the reading of eros-driven poetry,
Augustus seeks to control eros itself. But like the husband of “Ad virum
servantem coniugem”, he is trying to control the uncontrollable. Ovid
even treats the myth of the founding of Rome, the story of Romulus
and Remus, in a way designed to puncture the pretensions of an
Augustus determined to control private behavior: “Ovid’s treatment of
the Romulus and Remus legend is similarly disrespectful. Where Virgil
chooses his language carefully and speaks of Ilia as merely ‘pregnant
by Mars’ […], Ovid points to Romulus and Remus as the product of
adultery”.94 As Ovid puts it: Rusticus est nimium, quem laedit adultera coniunx,
et notos mores non satis urbis habet
in qua Martigenae non sunt sine crimine nati
Romulus Iliades Iliadesque Remus.95 Rusticus est nimium, quem laedit adultera coniunx,
et notos mores non satis urbis habet
in qua Martigenae non sunt sine crimine nati
Romulus Iliades Iliadesque Remus.95 He is a rustic fool, who hurts over an adulterous wife,
and he surely doesn’t know the ways of this city,
in which the sons of Mars were not born without crime,
Romulus, and Remus, Ilia’s twins. He is a rustic fool, who hurts over an adulterous wife,
and he surely doesn’t know the ways of this city,
in which the sons of Mars were not born without crime,
Romulus, and Remus, Ilia’s twins. 96
The Lex Papia Poppaea targeted both celibate people and childless couples. 95
Ovid. Amores. 462, ll. 37–40.
96
The Lex Papia Poppaea targeted both celibate people and childless couples. 94
Ibid., 443.
95
Ovid. Amores. 462, ll. 37–40.
96
The Lex Papia Poppaea targeted both celibate people and childless couples. 95
Ovid. Amores. 462, ll. 37–40. 94
Ibid., 443.
95
Ovid. Amores. 462, ll. 37–40. 94
Ibid., 443. 2. Love Poetry from the Song of Songs to Aeneas and Dido To all the self-important men and women of the world who would
legislate private morality, who would pass laws about who can do
what to whom, with whom, under what circumstances, in what
positions, and with what ends in mind,96 Ovid’s Amores say: Oh please,
get over yourselves. In Ovid, we see love being both celebrated for its
own sake and for its subversive potential as a private weapon against
public tyranny. 2. Love Poetry from the Song of Songs to Aeneas and Dido 71 This subversive potential is developed to extremes of sharpness and
power in the Ars Amatoria, a work that “exudes urban hipness”,97 by
identifying itself and its ethos with the cosmopolitan and imperial city
of Rome. These are the poems of a sophisticated and experienced older
man, a Pandar-like figure who tells a world full of young men how to
find, approach, speak to, and seduce a world full of women, and in so
doing, undermine the values of the Augustine state: The poem really is subversive—not in the challenge it offers to the new
morality, or because it has the effrontery to claim for the lover the same
“professional” status as the farmer, the soldier, the holder of high public
office, but because it […] establishes the lover/poet as the emperor of an
alternative and privately constituted state.98 One can see why the Augustus, who was busily trying to clean up
Roman morality, restore the wholly imaginary mos maiorum99 (the good
old ways of the good old days), and channel Roman sexuality into
childbirth and the maintenance of social class distinctions, would find
offense in a poem that valued the private over the public, the lover over
the warrior, the poet over the emperor. Subversive notes begin playing almost as soon as the poetry starts. The Ars Amatoria is “a book that, proposing to teach Romans how to love
and be loved, in fact achieved the result of winning for its author the
implacable hatred of the most important Roman of all”, and is a major
part of “Ovid’s project of constructing his poetic career as a constant
pain in Augustus’ neck”.100 It isn’t hard to see why, when Ovid’s critique
of Rome’s self-mythologizing is so often front and center in his work. y
100 Sergio Casali. “The Art of Making Oneself Hated: Rethinking (Anti-)Augustanism
in Ovid’s Ars Amatoria”. In The Art of Love: Bimillennial Essays on Ovid’s Ars Amatoria
and Remedia Amoris, ed. by Roy Gibson, Steven Green, and Alison Sharrock (Oxford:
Oxford University Press, 2006), 216, 219. 97
Peter White. “Ovid and the Augustan Mileau”. In Brill’s Companion to Ovid, ed. by
Barbara Weiden Boyd (Leiden: Brill, 2002), 12.
98
Ovid. The Art of Love. Trans. by James Michie. Introduction by David Malouf (New
York: Modern Library, 2002), xii.
99
Karl-J. Hölkeskamp. Reconstructing the Roman Republic: An Ancient Political Culture
and Modern Research (Princeton: Princeton University Press, 2010), 17.
100 Sergio Casali. “The Art of Making Oneself Hated: Rethinking (Anti-)Augustanism
in Ovid’s Ars Amatoria”. In The Art of Love: Bimillennial Essays on Ovid’s Ars Amatoria
and Remedia Amoris, ed. by Roy Gibson, Steven Green, and Alison Sharrock (Oxford:
Oxford University Press, 2006), 216, 219. 101 Ovid. Ars Amatoria, 1.101–10, 114–16, 127–32. In Ovid: The Art of Love and other Poems,
ed. by J. H. Mozley (Loeb Classical Library, Cambridge, MA: Harvard University
Press, 1962), 18, 20. 102 Iam res Romana adeo erat valida ut cuilibet finitimarum civitatum bello par esset; sed penuria
mulierum hominis aetatem duratura magnitudo erat, quippe quibus nec domi spes prolis nec
cum finitimis conubia essent. […] ex consilio patrum Romulus legatos circa vicinas gentes
misit, qui societatem conubiumque novo populo peterent. […] nusquam benigne legatio audita
est. […] Romulus, aegritudinem animi dissimulans ludos ex industria parat Neptuno equestri
sollemnis; Consualia vocat. indici deinde finitimis spectaculum iubet, quantoque apparatu tum
sciebant aut poterant, concelebrant, ut rem claram exspectatamque facerent. […] ubi spectaculi
tempus venit deditaeque eo mentes cum oculis erant, tum ex composito orta vis, signoque dato
iuventus Romana ad rapiendas virgines discurrit. magna pars forte, in quem quaeque inciderat,
raptae: quasdam forma excellentes primoribus patrum destinatas ex plebe homines, quibus
datum negotium erat, domos deferebant. Livy. Titi Livi Ab vrbe condita libri praefatio, liber primvs, Vol. 1, ed. by H. J. Edwards
(Cambridge: Cambridge University Press, 1912), 12–14, https://books.google.com/
books?id=gsNEAAAAIAAJ&pg=PA12 2. Love Poetry from the Song of Songs to Aeneas and Dido For example, while recommending that young men look for women in
the theatre, Ovid compares the founding of Rome with rape and the
(im)morality of a military empire: 72 Love and its Critics Primus sollicitos fecisti, Romule, ludos,
Cum iuvit viduos rapta Sabina viros. Tunc neque marmoreo pendebant vela theatro,
Nec fuerant liquido pulpita rubra croco;
Illic quas tulerant nemorosa Palatia, frondes
Simpliciter positae, scena sine arte fuit;
In gradibus sedit populus de caespite factis,
Qualibet hirsutas fronde tegente comas. Respiciunt, oculisque notant sibi quisque puellam
Quam velit, et tacito pectore multa movent. […]
Rex populo praedae signa petita dedit. Protinus exiliunt, animum clamore fatentes,
Virginibus cupidas iniciuntque manus. […]
Siqua repugnarat nimium comitemque negabat,
Sublatam cupido vir tulit ipse sinu,
Atque ita “quid teneros lacrimis corrumpis ocellos? Quod matri pater est, hoc tibi” dixit “ero”. Romule, militibus scisti dare commoda solus:
Haec mihi si dederis commoda, miles ero.101 Primus sollicitos fecisti, Romule, ludos,
Cum iuvit viduos rapta Sabina viros. Tunc neque marmoreo pendebant vela theatro,
Nec fuerant liquido pulpita rubra croco;
Illic quas tulerant nemorosa Palatia, frondes
Simpliciter positae, scena sine arte fuit;
In gradibus sedit populus de caespite factis,
Qualibet hirsutas fronde tegente comas. Respiciunt, oculisque notant sibi quisque puellam
Quam velit, et tacito pectore multa movent. […]
Rex populo praedae signa petita dedit. Protinus exiliunt, animum clamore fatentes,
Virginibus cupidas iniciuntque manus. […]
Siqua repugnarat nimium comitemque negabat,
Sublatam cupido vir tulit ipse sinu,
Atque ita “quid teneros lacrimis corrumpis ocellos? Quod matri pater est, hoc tibi” dixit “ero”. Romule, militibus scisti dare commoda solus:
Haec mihi si dederis commoda, miles ero.101 You first instituted these games, Romulus,
when the single men profited by raping the Sabine women
Back then no awnings hung over a marble theatre,
nor was the platform stained with red saffron;
there artless and thick Palatine branches
were simply placed, while the stage was unadorned;
the audience sat on steps made from turf,
the branches covering their shaggy hair. Each cast his eyes around, noting the girls
he wanted, and was deeply stirred in his silent heart. […] The king gave the signal for the rape. Immediately they burst forth, shouting, betraying their
virgins with greedy, lustful hands. 2. 2. Love Poetry from the Song of Songs to Aeneas and Dido Love Poetry from the Song of Songs to Aeneas and Dido 73 […]
If a girl resisted too much, or refused her companion,
lifted up on his lustful bosom, the man carried her,
saying, “And what’s that ruining your eyes with tears? What your father was to your mother, that will I be to you”. Romulus, only you knew what was fitting:
if you give me such advantages, I will be a soldier too. […]
If a girl resisted too much, or refused her companion,
lifted up on his lustful bosom, the man carried her,
saying, “And what’s that ruining your eyes with tears? What your father was to your mother, that will I be to you”. Romulus, only you knew what was fitting:
if you give me such advantages, I will be a soldier too. The rape, or abduction (from the Latin raptio) of the Sabine women, is
a well-known element of early Roman legend. As Livy tells the story: The rape, or abduction (from the Latin raptio) of the Sabine women, is
a well-known element of early Roman legend. As Livy tells the story: The Roman State was now strong enough in war, a match for any of
its neighbors; but the absence of women, and the lack of the right of
intermarriage with their neighbors, meant their greatness would last for
a generation only, for they had no hope of offspring. […] On the advice
of the senate, Romulus sent envoys amongst the surrounding nations
to ask for alliance and intermarriage on behalf of his new community. […] Nowhere did the embassy get a friendly hearing. […] Romulus,
disguising his resentment, made elaborate preparations for the games
in honor of equestrian Neptune, which he called Consualia. He ordered
the spectacle proclaimed to the surrounding peoples, and the Romans
began preparations, with every resource of their knowledge and ability,
to celebrate, in order to create amongst the peoples a clear and eager
expectation. […] When the time came for the show, when the peoples’
eyes and minds were together occupied, then the forceful attack arose. The signal was given for the young Romans to carry off the virgins. 103 Ovid. Ars Amatoria, 1.171–76, 24. 2. Love Poetry from the Song of Songs to Aeneas and Dido A
great part of them were carried off indiscriminately, but some particularly
beautiful girls were marked out for the prime leaders, to whose servants
had been given the task to carry them to their houses.102 74 74 Love and its Critics Livy’s tale is one of a necessary action taken out of the need for self-
preservation, because Rome’s “absence of women” meant its “greatness
would last for a generation only”. Brutal and dishonest and wicked as
it was, it had a recognizable motive. The way Ovid transforms the tale,
however, it becomes an extension of the Consualia games, a game in its
own right. The women are “pay” for soldiers and Romulus is praised
for knowing how to treat military men properly. With such rewards,
the poem’s narrator—a lover, not a fighter—would be willing to enlist
right away. The journey from Livy’s earnestness to Ovid’s satire is a
comment on how far Rome has fallen—what was once a republic is now
an empire, a realm in which the emperor, far from being an establisher
of new worlds, is the enforcer of people’s bedrooms. Later, Ovid continues the none-too-subtle undermining of Augustus,
describing his vainglorious public re-staging of the naval battles between
the Persians and Greeks as a fine place to seduce women: Quid, modo cum belli navalis imagine Caesar
Persidas induxit Cecropiasque rates? Nempe ab utroque mari iuvenes, ab utroque puellae
Venere, atque ingens orbis in Urbe fuit. Quis non invenit turba, quod amaret, in illa? Eheu, quam multos advena torsit amor!103 When Ceasar, in the manner of a naval battle,
brought on Persian and Cecropian vessels? Of course, young men and girls came from both seas,
Venus, the mighty world was in our city. Who did not find one they might love in that crowd? Alas, how many were tortured by love! In ridiculing a mock battle by describing it as a seduction zone where
foreign flames may burn the men who get too close to them, Ovid equates
sex with conquest, and eros with war. From such a vantage point, an
empire is a vast screwing over of the world, and its emperor the screwer
in chief. The result of such accusatory descriptions was predictable:
according to Lanham, “Ovid wanted to be honest and Augustus did 2. Love Poetry from the Song of Songs to Aeneas and Dido 75 75 not. 104 Richard A. Lanham. The Motives of Eloquence: Literary Rhetoric in the Renaissance
(New Haven: Yale University Press, 1976), 63.
105 Ibid.
106 Ibid., 2.739–40, 743–44, 116.
107 Sharrock, 87. 104 Richard A. Lanham. The Motives of Eloquence: Literary Rhetoric in the Renaissance
(New Haven: Yale University Press, 1976), 63. 2. Love Poetry from the Song of Songs to Aeneas and Dido No wonder Augustus banished him”.104 In a dictatorship, telling
the truth can be, and often is, considered a subversive act, and “Ovid
paid a political penalty for a political crime”.105 In the final section of Book II, the sharp satire takes a new form,
as “Ovid” becomes a character in the verse, and sets himself up as an
alternative emperor whose name will be shouted throughout the world: Cantetur toto nomen in orbe meum. Celebrate me as a poet, men, speak my praises,
let my name be known through all the world. […]
But whoever shall overcome an Amazon with my steel,
let him inscribe upon his spoils, “Ovid was my master”. Celebrate me as a poet, men, speak my praises,
let my name be known through all the world. But whoever shall overcome an Amazon with my steel,
let him inscribe upon his spoils, “Ovid was my master”. And why not? According to the incisive logic of the poem, why
shouldn’t a poet be emperor of a world based on love, or at the very
least desire? But critics have been in a rush to disapprove, as “‘excess’,
‘irrelevance’, ‘narcissism’, ‘self-indulgence’, [and] ‘vacuity’”, are “the
standard accusations levelled against Ovid” and “Ovidian poetry”107
more generally. It is nearly impossible to support such a reading of the
poet or his poetry when both are returned to the context of an imperial
dictatorship, but that doesn’t stop critics from trying: The judgements of two influential critics may be taken as representative
of the long and dominant tradition in Ovidian scholarship, which,
although it has been challenged in recent years, remains the orthodoxy. Wilkinson says of Ovid’s didactic poetry: “Quite apart from the sameness
of tone, there is too much crambe repetita. Surely we have heard before,
and more than once, of lovers communicating by writing on the table in 76 76 Love and its Critics wine, exchanging glances and signs, drinking from the side of the cup
where the other has drunk, and touching hands” (Wilkinson 1955: 143). This view is echoed by Otis (1966: 18): “so many of the same themes [as
in the Amores] are repeated and so often repeated in a much less striking
way”. 108 Ibid., 3.
109 Percy Shelley. “A Defence of Poetry”. In Essays, Letters From Abroad, Vol.1 (London:
Edward Moxon, 1852), 49, https://babel.hathitrust.org/cgi/pt?id=wu.89000649913;vi
ew=1up;seq=77
110 Casali, “The Art of Making Oneself Hated”, 221. 108 Ibid., 3. 112 There is, in Virgil’s portrayal of Aeneas, very little of the spirit with which he had
once infused his character Gallus (based on his contemporary and friend Gaius
Cornelius Gallus), for whom “Love conquers all; and we must yield to love”
(“Omnia vincit amor; et nos cedamus Amori”) (Eclogue 10.69. In Virgil, 2 vols,
ed. by H. Rushton Fairclough [Loeb Classical Library, Cambridge, MA: Harvard
University Press, 1960], 74). 2. Love Poetry from the Song of Songs to Aeneas and Dido According to this view, the Ars is rather a heavy reworking of the
well known topoi of Latin love elegy.108 To paraphrase the preacher of Nazareth, “the poor [in poetic spirit] we
will always have with us”. Despite those critics determined to diminish
Ovid, his poems, even at their lightest-seeming, have a serious question
to ask: why? Why must life be dominated by the Augustus Caesars of
the world—who command with soldiers and laws, who banish their
own daughters and granddaughters for adultery, and exile one of the
finest poets in the history of the world for carmen et error, a poem and
a mistake—rather than be gifted to us in all its imaginative possibility
by the Ovids and Shakespeares and Shelleys? Why should not poets, the
“unacknowledged legislators of the world”,109 be celebrated instead of
emperors, soldiers, and all those who use the power of the sword and the
state to forbid the actions and pursuits that bring men and women joy? Though Ovid died in exile far from Rome, his influence, his ideas, his
words, even his jokes have survived the millennia in ways that Augustus,
despite his power and the legions at his disposal, has not. The great man
who would both rule the world and banish its adulterers from his sight,
has himself been banished by death, while the poet of love and seduction,
sly satire and disrespect for the rules, lives on in his verses, and in the
works of countless other poets and writers who have been influenced by
him. Ovid “attacks unnamed detractors, censors, thunderbolt-hurlers,
who look suspiciously like Augustus”,110 the political moralists who
condemn, and the academic critics who dismiss a body of poetic work
that celebrates love and desire against the pinched and pursed-lipped
claims of law and authority. Power and Law may have banished Ovid,
but the poet of Love and Laughter has long since had the last word. 2. Love Poetry from the Song of Songs to Aeneas and Dido 77 77 111 David Shotter. Rome and Her Empire (New York: Routledge, 2014), 218. III
Love or Obedience in Virgil: Aeneas and Dido From laughter we come to tragedy, from joy to tears. For in the Aeneid’s
story of Aeneas and Dido, readers encounter one of the best and worst
love stories the ancient world has to offer. Faced with the choice of
human love, or divine will, Dido chooses love, while Aeneas—the epic’s
hero in the most unfortunate sense of the term—chooses as the tamers of
the Song of Songs would have readers choose, and as Augustus would
have Rome choose. Pius Aeneas chooses obedience to the will and law
of the gods, and Dido is destroyed. Having escaped from burning Troy, Aeneas and his brave but
bedraggled followers have landed at Carthage, on the North African
coast. In part, the story of Aeneas’ devastation of Dido is a poeticizing
of the military relations between Rome and Carthage in a later era,
when after many battles, Carthage is razed to the ground by Rome,
never to rise again. But in the time of the Aeneid, such conflict is a
thousand years in the future: Carthage is rising, founded by exiles
from Tyre who fled violence and bloodshed at home. Aeneas, an exile
from the Trojan war, is in need of mercy. Dido gives it. Perhaps she
shouldn’t have. Aeneas is the perfect hero for an empire busy tightening its grip
at home while seeking to expand its reach abroad. The Aeneid is
written during the early, expansionist portion of Augustus’ time
as emperor, approximately 29–19 BCE, when “campaigning was
virtually continuous in western and southern Europe”.111 Unlike the
later Ovid, who ridicules the puritanism of Augustus, Virgil flatters
the emperor by creating a proto-Roman hero whose prime virtue is
obedience.112 Aeneas is not passionless, at least where love and sex
are concerned, but he prefers to direct his strength, his emotions, his
eros toward mourning for the loss of Troy and founding a new city 78 Love and its Critics 78 for his descendants and those of the men who follow him. His cry,
“Oh fatherland! Troy, home of the gods!”113 has far more passion and
pathos than does his recounting of the loss of his wife in the final battle
at Troy. 113 “O patria, o divum domus Ilium” 2.241. All references are from The Aeneid. In Virgil,
2 vols, ed. by H. Rushton Fairclough (Loeb Classical Library, Cambridge, MA:
Harvard University Press, 1960).
114 Ibid., 2.707–11. 115 Ibid., 2.738–44. 114 Ibid., 2.707–11. 119 Jean H. Hagstrum. Esteem Enlivened by Desire: The Couple from Homer to Shakespeare
(Chicago: University of Chicago Press, 1992), 58. y
118 “ὣς φάτο, τῷ δ᾿ ἔτι μᾶλλον ὑφ᾿ ἵμερον ὦρσε γόοιο· / κλαῖε δ᾿ ἔχων ἄλοχον
θυμαρέα, κεδνὰ ἰδυῖαν” (Homer. Odyssey, 23.231–32. Vol. II: Books 13–24, ed. by
A. T. Murray). 117 “σὴν ἄλοχον, τῆς τ᾽ αἰὲν ἐέλδεαι ἤματα πάντα” (Homer. Odyssey, 5.210. Vol. I:
Books 1–12, ed. by A. T. Murray [Loeb Classical Library, Cambridge, MA: Harvard
University Press, 1919]). 116 “quaerenti et tectis urbis sine fine furenti” (ibid., 2.771). III
Love or Obedience in Virgil: Aeneas and Dido Escaping with his family, Aeneas sees to the safety of his father
and son, but leaves his wife, Creusa, vulnerable: ergo age, care pater, cervici imponere nostrae;
ipse subibo umeris nec me labor iste gravabit;
quo res cumque cadent, unum et commune periclum,
una salus ambobus erit. mihi parvus Iulus
sit comes, et longe servet vestigia coniunx.114 ergo age, care pater, cervici imponere nostrae;
ipse subibo umeris nec me labor iste gravabit;
quo res cumque cadent, unum et commune periclum,
una salus ambobus erit. mihi parvus Iulus
sit comes, et longe servet vestigia coniunx.114 Come then, dear father, upon my neck;
this task will not be too heavy for my shoulders;
However things may fall, we two have one common peril,
and we will have one salvation. My little Iulus
come with me, and at a distance let my wife follow our steps. Having his wife follow at a distance leads to the predictable result;
Creusa is lost in the battle, killed by the Greeks: Having his wife follow at a distance leads to the predictable result;
Creusa is lost in the battle, killed by the Greeks: heu misero coniunx fatone erepta Creusa
substitit, erravitne via seu lapsa resedit,
incertum; nec post oculis est reddita nostris. nec prius amissam respexi animumue reflexi
quam tumulum antiquae Cereris sedemque sacratam
venimus: hic demum collectis omnibus una
defuit, et comites natumque virumque fefellit.115 Ah, wretched fate snatched Creusa. Did she stop for a while, lose the way, or slip and fall back? I am not certain; nor afterwards was she returned to our eyes. Ah, wretched fate snatched Creusa. Ah, wretched fate snatched Creusa. Did she stop for a while, lose the way, or slip and fall back? I am not certain; nor afterwards was she returned to our eyes. Did she stop for a while, lose the way, or slip and fall back? I am not certain; nor afterwards was she returned to our eyes. 115 Ibid., 2.738–44. 2. Love Poetry from the Song of Songs to Aeneas and Dido 79 Neither did I turn my mind or thought toward my lost one
until to the ancient Ceres’ hallowed home
we came; when all were gathered, she alone
was absent, lost to her son and her husband. 120 https://commons.wikimedia.org/wiki/File:Affreschi_romani_-_Enea_e_didone_-_
pompei.JPG
121 Hamlet, 5.2.60–61. III
Love or Obedience in Virgil: Aeneas and Dido Neither did I turn my mind or thought toward my lost one
until to the ancient Ceres’ hallowed home
we came; when all were gathered, she alone
was absent, lost to her son and her husband. He does not lack emotion when describing her loss, even claiming that
he went back into the battle zone trying to find her, crying out her name
as he “rushed furiously and endlessly from house to house through the
city”.116 However, the telling detail is that during the initial escape, he
never gave her any thought, and only realized that his wife was missing
after he had brought father and son to safety. Aeneas is no Odysseus. Odysseus, even amid his serial philandering
and flirting with witches, goddesses, and the daughters of kings,
still longs to be reunited with Penelope, whom the goddess Calypso
describes as “your wife, she that you ever long for daily, in every
way”,117 and for whom “he cried out, still calling forth tears, / Crying as
he held his beloved, trustworthy, and strong-minded wife”.118 It appears
the feelings were mutual. From Penelope’s point of view, theirs was a
reunion of joy and passion: “Hers and her husband’s tears mingle, her
knees melt (that sure sign of Aphrodite’s presence), [and] she proceeds
formally to their bed with him, led by a maid with torches, as though to
renew the days of their beginnings”.119 But far from pining for his wife,
Aeneas can barely be bothered to remember her even as they are trying
to escape from burning Troy. Later, he gives her no more thought while
falling in “love” (or lust) with Dido than he gives Dido after issuing the
orders to sail away from Carthage. 80 Love and its Critics Dido and Aeneas. Ancient Roman fresco (10 BC–45 AC). Pompeii, Italy.120 Dido and Aeneas. Ancient Roman fresco (10 BC–45 AC). Pompeii, Italy.120 The love story between the two is mostly one-sided, primarily on Dido’s
part. The deck is strangely stacked against her, as well. She falls in love
unwillingly, forced by the gods to play the role that will destroy her,
despite the fact that Juno regards Dido as dying an undeserved death. The gods—as is their usual course in Homer, Virgil, and most Greek and
Roman mythology—play with human beings like chess pieces on a grand
game board. III
Love or Obedience in Virgil: Aeneas and Dido Dido’s passion comes over her against her will as part of an
ongoing struggle between Juno and Venus that dates all the way back to
the famous judgment of Paris, that Venus was more beautiful than Juno. Dido is not a tragic figure in the later Senecan model, whose wounds are
often self-inflicted. No, Dido, like so many tragic figures from the earlier
Greek tradition of Aeschylus, Sophocles, and Euripides, is made a victim
by the gods as they play out their petty rivalries on the human stage,
with mortals as their unwitting proxies. Dido is caught, as Hamlet would
say, between “the pass and fell incensed points / Of mighty opposites”:121
Juno, who opposed Troy and opposes the founding of Rome, and Venus,
who aids her son Aeneas wherever and whenever possible. Venus sends
Cupid, in the guise of Aeneas’ son, to pierce Dido’s heart with the first
fatal pangs of love for Aeneas: 81 2. Love Poetry from the Song of Songs to Aeneas and Dido Tu faciem illius noctem non amplius unam
falle dolo, et notos pueri puer indue voltus,
ut, cum te gremio accipiet laetissima Dido
regalis inter mensas laticemque Lyaeum,
cum dabit amplexus atque oscula dulcia figet,
occultum inspires ignem fallasque veneno.122 Do you, just for this one night,
imitate his form, and boy as you are, take his familiar face,
so that, when Dido takes you into her lap
amidst the royal tables and flowing wine,
and she embraces you and kisses you sweetly,
breathe into her a hidden fire and secretly poison her. The famous night that Aeneas and Dido spend in a cave while taking
shelter from a rainstorm, the night of their first lovemaking, is arranged
as a trap by the dueling goddesses, Juno and Venus. As Juno designs it: venatum Aeneas unaque miserrima Dido
in nemus ire parant, ubi primos crastinus ortus
extulerit Titan radiisque retexerit orbem. his ego nigrantem commixta grandine nimbum,
dum trepidant alae saltusque indagine cingunt,
desuper infundam et tonitru caelum omne ciebo. diffugient comites et nocte tegentur opaca:
speluncam Dido dux et Troianus eandem
devenient. adero et, tua si mihi certa voluntas,
conubio iungam stabili propriamque dicabo. hic hymenaeus erit.123 Aeneas and unhappy Dido, as one
prepare to go hunting in the woods, where the first risings
Of brilliant Titan will have raised his rays, lighting the world. 122 The Aeneid, 1.683–88.
123 Ibid., 4.117–27. 122 The Aeneid, 1.683–88. 123 Ibid., 4.117–27. 124 “Libyae magnas it Fama per urbes” (ibid., 4.173).
125 Ibid., 4.191–95.
126 “regnum Italae Romanaque” (ibid., 4.275).
127 “ardet abire fuga dulcisque relinquere terras” (ibid., 4.348).
128 “heu quid agat? quo nunc reginam ambire furentem / audeat adfatu? quae prima
exordia sumat?” (ibid., 4.283–84). g
q
q
128 “heu quid agat? quo nunc reginam ambire furentem / audeat adfatu? quae prima
exordia sumat?” (ibid., 4.283–84). g
q
(
)
127 “ardet abire fuga dulcisque relinquere terras” (ibid., 4.348). 129 Ibid., 4.314–19. 2. Love Poetry from the Song of Songs to Aeneas and Dido 83 As with Creusa, he never looks back, and she does not cross his mind,
except as an immovable anchor he must cut loose and pull away from. The confrontation between them is heartbreaking and baffling to Dido,
but merely embarrassing for Aeneas, whose eyes are now solely fixed
on his dearly-beloved gods as he seeks to navigate the awkward final
moments of his time with yet another woman he will leave behind on
his journey. Dido begs him, uselessly, not to go: mene fugis? per ego has lacrimas dextramque tuam te
(quando aliud mihi iam miserae nihil ipsa reliqui),
per conubia nostra, per inceptos hymenaeos,
si bene quid de te merui, fuit aut tibi quicquam
dulce meum, miserere domus labentis et istam,
oro, si quis adhuc precibus locus, exue mentem.129 You’re running from me? By these tears and by your hand,
(since there is nothing else for my miserable self),
through our marriage, by the way our wedding took place,
if I have deserved well of you, or if there was anything
sweet about me, have mercy on a falling house, and yet,
I pray you, if there is room for prayers, change your mind. You’re running from me? By these tears and by your hand,
(since there is nothing else for my miserable self),
through our marriage, by the way our wedding took place,
if I have deserved well of you, or if there was anything
sweet about me, have mercy on a falling house, and yet,
I pray you, if there is room for prayers, change your mind. But Aeneas, possessed by an immovable determination to obey the very
gods who have so long betrayed him and his beloved Troy, gives an
answer that sounds like little more than the It’s not you, it’s me cliché of
innumerable modern breakup scenes: ego te, quae plurima fando
enumerare vales, numquam, regina, negabo
promeritam, nec me meminisse pigebit Elissae
dum memor ipse mei, dum spiritus hos regit artus. […]
sed nunc Italiam magnam Gryneus Apollo,
Italiam Lyciae iussere capessere sortes;
hic amor, haec patria est. […] ego te, quae plurima fando
enumerare vales, numquam, regina, negabo
promeritam, nec me meminisse pigebit Elissae
dum memor ipse mei, dum spiritus hos regit artus. […]
sed nunc Italiam magnam Gryneus Apollo,
Italiam Lyciae iussere capessere sortes;
hic amor, haec patria est. III
Love or Obedience in Virgil: Aeneas and Dido I shall pour on them a black storm mixed with hail,
whilst the hunters run back and forth with their nets,
from above I will shake the whole sky with thunder. 82 82 Love and its Critics The comrades will scatter and be covered with opaque night:
into a cave will Dido and the Trojan chief
vanish. I will be present, and, if your will is firm,
in a stable and proper marriage and wedlock,
this will be a wedding. Once word spreads of the love affair, as “Rumor runs through Libya’s
great cities”,124 the common people, King Iarbus (long a suitor for Dido’s
love), and the poem itself turn against the idea of the “marriage” into
which Juno has bound the pair. The people’s talk turns sour and critical,
turning the night in the cave into something sordid and “shameful”: venisse Aenean Troiano sanguine cretum,
cui se pulchra viro dignetur iungere Dido;
nunc hiemem inter se luxu, quam longa, fovere
regnorum immemores turpique cupidine captos. haec passim dea foeda virum diffundit in ora.125 Aeneas is come, born of Trojan blood,
with whom in marriage fair Dido deigns to join;
now, between them, in luxury they waste the length of winter,
reigning heedlessly, enthralled by shameful desire. These tales the foul goddess spreads through men’s mouths. Soon enough (too soon, from Dido’s perspective), Jove orders Aeneas
to leave Carthage and sail across the Mediterranean in search of the
shores where he will lay the foundations for the “kingdom of Italy and
Rome”.126 Immediately, Aeneas “burns to depart in flight, and relinquish
that pleasant land”,127 strategizing not how to leave, but how to make his
excuses to Dido: “Ah, what could he do? What can he dare say now to
the furious queen / to pacify her? What opening speech could he use?”128
Aeneas is more concerned with how to manipulate Dido into approving
of his sudden plan than he is with the effect his leaving will have on her. 2. Love Poetry from the Song of Songs to Aeneas and Dido 131 “nec coniugis umquam / praetendi taedas aut haec in foedera veni” (ibid., 4.422–23).
132 Ibid., 4.166–72. 130 Ibid., 4.333–37, 345–47, 359–60. 130 Ibid., 4.333–37, 345–47, 359–60.
131 “nec coniugis umquam / praetendi taedas aut haec in foedera veni” (ibid., 4.422–23).
132 Ibid., 4.166–72. 134 [Virgil] quidquid ubicumque invenit imitandum; adeo ut de Argonauticorum quarto, quorum
scriptor est Apollonius, librum Aeneidos suae quartum totum paene formaverit, ad Didonem
vel Aenean amatoriam incontinentiam Medeae circa Iasonem trasferendo. quod ita elegantius 133 Ibid., 4.23–24, 27. 2. Love Poetry from the Song of Songs to Aeneas and Dido […] sed nunc Italiam magnam Gryneus Apollo, Italiam Lyciae iussere capessere sortes; hic amor, haec patria est. 129 Ibid., 4.314–19. 84 Love and its Critics desine meque tuis incendere teque querelis;
Italiam non sponte sequor.130 I will, because of many things which
you are able to recount, never, queen, deny that you
are deserving, nor shall I regret my memory of Dido
while I am mindful of myself, while breath reigns in this
[…]
But now of great Italy has Grynean Apollo spoken,
Italy, his Lycian lots order me to take hold of;
this must be my love, this my fatherland. […]
Stop inflaming both of us with your complaints;
I do not go to Italy of my own free will. Virgil works especially hard here to make Aeneas sympathetic, despite
the fact that such a move comes at the cost of making him seem weak
and dishonest, denying the fact that he chooses to obey power—as he
once did with Priam, and as he now does with Jove. He is at pains to
deny that his relationship with Dido is a marriage—“I never held out
the conjugal torch, / nor ever pretended to such a contract”131—despite
the fact that Juno calls it a marriage from the very beginning. Virgil
is so eager to excuse Aeneas, in fact, that his poem blames Dido for
impropriety in getting involved in a relationship arranged by the gods
who call the action “marriage” (this, in a Rome in which Augustus
Caesar is legislating private relationships): pronuba Iuno
dant signum; fulsere ignes et conscius aether
conubiis summoque ulularunt vertice Nymphae. ille dies primus leti primusque malorum
causa fuit; neque enim specie famave movetur
nec iam furtivum Dido meditatur amorem:
coniugium vocat, hoc praetexit nomine culpam.132 2. Love Poetry from the Song of Songs to Aeneas and Dido 2. Love Poetry from the Song of Songs to Aeneas and Dido 85 Nuptial Juno
gave the signal; fires flashed in the heavens
witnessing the marriage, as Nymphs howl from the peaks. That day was the first of death and evil,
the cause of woe; no longer does reputation concern her,
nor does Dido dream of a secret love:
she calls it marriage, and in this name covers her guilt. Nuptial Juno
gave the signal; fires flashed in the heavens
witnessing the marriage, as Nymphs howl from the peaks. That day was the first of death and evil,
the cause of woe; no longer does reputation concern her,
nor does Dido dream of a secret love:
she calls it marriage, and in this name covers her guilt. Any guilt that Dido feels may come from her feeling that she has
somehow betrayed the memory of Sychaeus, her long-dead husband,
by falling in love with Aeneas: agnosco veteris vestigia flammae. ante, pudor, quam te violo aut tua iura resolvo.133 But guilt aside, it is not only Dido that calls the relationship between
herself and Aeneas a marriage. In this case, Aeneas, always so ready
to align himself with the will of the gods, denies what the gods affirm. According to Macrobius (c. 400 CE), Virgil puts Dido into a completely
untenable position, violently transforming a figure of legendary
faithfulness into the passionate victim of love he portrays in the Aeneid: [Virgil] imitated whatever, and wherever he found; so that the fourth
book of the Argonautica by Apollonius served as the model for his fourth
book of the Aeneid, upon which he almost entirely formed the tale of
Dido and Aeneas’ love on the wildly incontinent passion Medea bore
for Jason. [Virgil] so elegantly arranged this that his account of a lustful
Dido, which he and all the world knows is false, has for many centuries
maintained the appearance of truth.134 86 Love and its Critics There is a split tradition about Dido, a pre-Virgilian tradition “that
represents her only as a leader”135 and a post-Virgilian account in which
she has been turned into a victim of passion. In the earlier tradition,
“preserved among the fragments attributed to the Greek historian
Timaeus of Tauromenium (ca. 137 Cum successu rerum florentes Karthaginis opes essent, rex Maxitanorum Hiarbas decem
Poenorum principibus ad se arcessitis Elissae nuptias sub belli denuntiatione petit. Quod
legati reginae referre metuentes Punico cum ea ingenio egerunt, nuntiantes regem aliquem
poscere, qui cultiores victus eum Afrosque perdoceat; sed quem inveniri posse, qui ad barbaros
et ferarum more viventes transire a consanguineis velit? Tunc a regina castigati, si pro salute
patriae asperiorem vitam recusarent, cui etiam ipsa vita, si res exigat, debeatur, regis mandata
aperuere, dicentes quae praecipiat aliis, ipsi facienda esse, si velit urbi consultum. Hoc dolo auctore digessit, ut fabula lascivientis Didonis, quam falsam novit universitas, per tot tamen
saecula speciem veritatis. auctore digessit, ut fabula lascivientis Didonis, quam falsam novit universitas, per tot tamen
saecula speciem veritatis.
Macrobius. Saturnalia, Books 3–5, ed. by Robert A. Kaster (Loeb Classical Library,
Cambridge, MA: Harvard University Press, 2011), 408.
135 Marilynn Desmond. Reading Dido: Gender, Textuality, and Medieval Aeneid
(Minneapolis: University of Minnesota Press, 1994), 24.
136 Ibid auctore digessit, ut fabula lascivientis Didonis, quam falsam novit universitas, per tot tamen
saecula speciem veritatis. 135 Marilynn Desmond. Reading Dido: Gender, Textuality, and Medieval Aeneid
(Minneapolis: University of Minnesota Press, 1994), 24. Macrobius. Saturnalia, Books 3–5, ed. by Robert A. Kaster (Loeb Classical Library,
Cambridge, MA: Harvard University Press, 2011), 408. capta diu Acherbae viri nomine cum multis lacrimis et lamentatione flebili invocato ad
postremum ituram se quo sua et urbis fata vocarent, respondit. In hoc trium mensium sumpto
spatio, pyra in ultima parte urbis exstructa, velut placatura viri manes inferiasque ante nuptias
missura multas hostias caedit et sumpto gladio pyram conscendit atque ita ad populum
respiciens ituram se ad virum, sicut praeceperint, dixit vitamque gladio finivit Marcus Junianus Justinus. Epitoma Historiarum Philippicarum Pompei Trogi (Leipzig:
B. G. Teubner, 1886), VI. 1–7, 134–35), https://babel.hathitrust.org/cgi/pt?id=uiug.30
112023680843;view=1up;seq=202 138 Catherine Edwards. Death in Ancient Rome (New Haven: Yale University Press,
2007), 2. 2. Love Poetry from the Song of Songs to Aeneas and Dido 356–260 BCE)” Dido is no one’s victim,
but “is a heroic figure [whose] suicide is an act of defiance that testifies
to the nobility of her nature”.136 In this story, Dido dies in order to avoid
dishonor to herself and Carthage: With the success of the opulent wealth of Carthage, Hiarbas of the
Maxitani summoned ten African leaders in order to claim [Dido] in
marriage under threat of war. The deputies, fearing to report this to the
queen of the Carthaginians, acted falsely towards her with the news
that the king asked for and awaited one who could teach he and his
and Africans together a more cultured life; but who could be found,
who would wish to leave his relations and cross over to live among the
barbarians and wild beasts? Then, castigated by the queen, in case they
refused a hard life for the salvation of the rest of the country, to which, if
necessary, their life itself was owed, they disclosed the king’s message,
saying that she will have to act according to the precepts she gives to
others, if she wishes to her city to have security. Taken by this deceit, in
the name of Acerbas she called, for a long time and with many tears and
piteous wailings. At last she replies that she will go where the fate of her
city has summoned her. Taking three months, pyres were built in the
outer quarter of the city, and many victims mounted and were consumed
by the fires, as if she would placate the ghost of her husband, and make her
offerings to him before the wedding; then with a sword she mounted the
pyre, and looking at the people, said that she would go to her husband
just as she was instructed, and ended her life with the sword.137 2. Love Poetry from the Song of Songs to Aeneas and Dido 2. Love Poetry from the Song of Songs to Aeneas and Dido 87 Virgil also stacks the deck against Dido by portraying her, though her
Tyrian roots and Carthaginian power, as a passionate and irrational
Eastern woman, the very model of the Parthian threat that Rome
faced on its Eastern frontiers, and a clear and contemporary reference
to the all-too-recent troubles brought upon Rome by the dalliance
between Augustus’ defeated rival Marc Antony and the Egyptian
Queen, Cleopatra. She is cast as precisely the kind of “unstable”
element (uncontrolled female desire) that Aeneas is supposedly well
rid of, and that Augustus (in the persons of his daughter Julia, and his
granddaughter Julia) will eventually banish from Rome. Her frenzied
suicide is a far cry from the resigned calm of such Romans as Cato, who
killed himself in a gesture designed to value liberty above life in the
dying days of the Roman Republic: The night before his death Cato is calm and discusses Stoic philosophy
over dinner with his companions. […] Later that night he tries to kill
himself with his own sword—but because his hand is injured, the blow
is not quite powerful enough. His companions come to his rescue and his
wound is sewn up by a surgeon. But such is Cato’s determination that he
tears open the wound again with his bare hands […]. Cato’s bravery and
determination in taking his own life brought him immediate glory.138 Dido, on the other hand, is portrayed as wild, out of control, made
insane with passion due to the poison of Cupid. First, she curses Aeneas,
and calls for never-ending war between the people of Carthage and the
future people of Rome: haec precor, hanc vocem extremam cum sanguine fundo. tum vos, o Tyrii, stirpem et genus omne futurum
exercete odiis, cinerique haec mittite nostro 88 88 Love and its Critics munera. nullus amor populis nec foedera sunto. exoriare aliquis nostris ex ossibus ultor
qui face Dardanios ferroque sequare colonos,
nunc, olim, quocumque dabunt se tempore vires. litora litoribus contraria, fluctibus undas
imprecor, arma armis: pugnent ipsique nepotesque.139 This is my prayer, with these words I pour out my blood. Then do you, O Tyrians, pursue his race, and his children
with hatred, and to my dust offer this
gift—let no love nor federation be between our peoples. Rise from my ashes, unknown avenger
to fight with fire and sword the Dardan colonies,
now, hereafter, whenever we have the strength. 139 The Aeneid, 4.621–29. 140 Ibid., 4.657–62. 139 The Aeneid, 4.621–29.
140 Ibid., 4.657–62. 141 R. G. Austin. P. Vergili Maronis Aneidos Liber Quartos (Oxford: Clarendon Press
1955), 106. 2. Love Poetry from the Song of Songs to Aeneas and Dido Let shore clash with shore, waves with waves clash. This is my curse: endless war between us and their children. Then, climbing atop the burning pyre on which she will die, she cries
out over the life she has lived, and bemoans the fate that brought Aeneas
to the shores of Carthage: ‘felix, heu nimium felix, si litora tantum
numquam Dardaniae tetigissent nostra carinae’. dixit, et os impressa toro ‘moriemur inultae,
sed moriamur’ ait. ‘sic, sic iuvat ire sub umbras. hauriat hunc oculis ignem crudelis ab alto
Dardanus, et nostrae secum ferat omina mortis’.140 “I had been happy, indeed too happy, if only the
Trojan ships had never touched our shores”. She spoke, face pressed on the bed: “We die unavenged,
but let us die. Thus, it pleases to go down to the shades. May he drink this fire with his eyes, from far at sea, that cruel
Trojan, and carry with him omens of our death”. 2. Love Poetry from the Song of Songs to Aeneas and Dido 89 Dido’s fate, written by Virgil to glorify the authoritarian and imperial
Rome of Augustus Caesar, is to die for love. Aeneas’ fate is to live in the
annals of poetry as the ultimate symbol of those who choose obedience,
and the gods, over passion. An entire tradition of later poetry takes
Aeneas to task, including John Milton, who writes his Adam as the
founder of a world (not merely a city) who chooses love over God. This
tradition has its deepest roots in the poet who most admired Virgil’s
skill, and most despised his politics: Ovid—whose more serious side is
evident in his treatment of Dido, giving her a voice and a dignity that
Virgil denied her. Dido’s fate, written by Virgil to glorify the authoritarian and imperial
Rome of Augustus Caesar, is to die for love. Aeneas’ fate is to live in the
annals of poetry as the ultimate symbol of those who choose obedience,
and the gods, over passion. An entire tradition of later poetry takes
Aeneas to task, including John Milton, who writes his Adam as the
founder of a world (not merely a city) who chooses love over God. 2. Love Poetry from the Song of Songs to Aeneas and Dido This
tradition has its deepest roots in the poet who most admired Virgil’s
skill, and most despised his politics: Ovid—whose more serious side is
evident in his treatment of Dido, giving her a voice and a dignity that
Virgil denied her. Aeneas, Dido, and the Critics who Dismiss Dido is a character Ovid would (and does) sympathize with. Aeneas,
the curiously dispassionate son of the goddess of love, and the
unquestioningly obedient servant of power, is the character that
Virgil would have readers admire. We are assured by some classical
scholars that those of us who sympathize with Dido (finding Aeneas a
combination of inexplicable and abhorrent) are simply wrong, because
all Romans read the poem in favor of Aeneas: “His speech, though we
may not like it, was the Roman answer to the conflict between two
compelling forms of love, an answer such as a Roman Brutus once gave,
when he executed his two sons for treason against Rome”.141 But what of
Ovid? What of the many Roman readers who read, enjoyed, and admired
Ovid’s verse? Were they not Romans as well? Despite Augustus, Rome
was no more monolithic in its literary and political sympathies than had
been Athens before it, or would be London after it. Ovid’s most famous treatment of the episode is quite short, but more
in line with what might be expected from the author of the Amores than
with the author of the Aeneid. His focus is on Dido, the pain she feels at the
loss of Aeneas, and her death. Aeneas is given no more than a sidelong
glance in the few lines Ovid spends on the story in his Metamorphoses: 90 90 Love and its Critics excipit Aenean illic animoque domoque
non bene discidium Phrygii latura mariti
Sidonis; inque pyra sacri sub imagine facta
incubuit ferro deceptaque decipit omnes.142 Aeneas received there her heart and home,
but she could not abide parting from her Phrygian husband;
on a fire intended for sacred rites, she fell upon her sword,
deceiving all, as she had been deceived. Aeneas received there her heart and home,
but she could not abide parting from her Phrygian husband;
on a fire intended for sacred rites, she fell upon her sword,
deceiving all, as she had been deceived. Ovid’s treatment of the relationship, described as a marriage, takes on a
more expansive and unqualifiedly pro-Dido tone in The Heroides, which
appear to be “an early work, contemporary with the earliest Amores”.143
If so, the sensitivity displayed by a poet still in his twenties makes it
hard to understand what those critics who regard Ovid as having
“excessive desire for himself”144 are seeing when they read his work. 145 Richard Tarrant. “Ovid and Ancient Literary History”. In The Cambridge Companion to
Ovid, ed. by Philip R. Hardie (Cambridge: Cambridge University Press, 2002), 25. 143 Peter E. Knox. “The Heroides: Elegaic Voices”. In Brill’s Companion to Ovid, ed. by
Barbara Weiden Boyd (Leiden: Brill, 2002), 120. 142 Ovid. Metamorphoses. 14.78–82 (Berlin: De Gruyter, 1998), 332. 144 Sharrock, 293. 146 Rebecca Armstrong. Ovid and His Love Poetry (London: Bloomsbury Academic,
2005), 111.
147 Ovid. “Heroides VII: Dido to Aeneas”. In Ovid: Heroides and Amores, ed. by Grant
Showerman, 34, ll. 19–30. Aeneas, Dido, and the Critics who Dismiss Far from reflecting anything like narcissism, Ovid’s treatment of Dido
“constitutes one of the earliest surviving reactions to the Aeneid, and one
of the boldest [and most] scathing about Aeneas”.145 A letter written from Dido’s point of view, Ovid’s Heroides 7, “Dido
to Aeneas”, is one of the single most heart-wrenching things that ever
came from his pen, and gives the lie to scholarly insistence that the
Roman answer to Dido would have been the one Virgil gave to Aeneas. Ovid writes Dido as someone who sees Aeneas, sees through the pro-
imperial Roman propaganda of the Augustan regime, and no more
reads things the single right Roman way than Ovid does himself: In the Aeneid, Dido seems never quite able to accept that wandering has
now become a fundamental part of Aeneas’ character. […] Ovid’s Dido,
by contrast, can see that Aeneas is the kind of man who needs to keep
moving, and who avoids facing up to the things he has done by simply 2. Love Poetry from the Song of Songs to Aeneas and Dido 2. Love Poetry from the Song of Songs to Aeneas and Dido 91 leaving town. This Dido sees Aeneas as addicted to wandering, and
doomed to the repetition of his mistakes.146 Ovid’s Dido does not go wild with anger as does Virgil’s, does not call
down curses, and make predictions of catastrophic future wars; she
merely tells Aeneas, sadly, that he will never find another love like hers: quando erit, ut condas instar Karthaginis urbem
et videas populos altus ab arce tuos? omnia ut eveniant, nec di tua vota morentur,
unde tibi, quae te sic amet, uxor erit? Uror ut inducto ceratae sulpure taedae,
ut pia fumosis addita tura rogis. Aeneas oculis vigilantis semper inhaeret;
Aenean animo noxque diesque refert. ille quidem male gratus et ad mea munera surdus
et quo, si non sim stulta, carere velim. non tamen Aenean, quamvis male cogitat, odi,
sed queror infidum questaque peius amo.147 When will you establish a city like Carthage,
and see the people from your own high citadel? Should all take place exactly in the event as in your prayers,
where will you find the lover who loves as I do? I burn, like waxen torches covered with sulfur,
as the pious incense placed upon a smoking altar. Aeneas, to you my waking eyes were always drawn;
Aeneas lives in my heart both night and day. But he is ungrateful, and spurns my gifts,
and were I not a fool, I would be rid of him. Yet, however ill he thinks of me, I cannot hate him. I complain of his faithlessness, but my love grows worse. Ovid also catches Aeneas’s odd remark about having not given his wife
a single thought while helping his father and son escape the fires of 92 92 Love and its Critics Troy. He gives Dido a sharp, yet gentle response, far from the raving to
which Virgil subjects her. In her Ovidian letter, she reproves Aeneas for
his hypocrisy to his gods and to his previous wife: Troy. He gives Dido a sharp, yet gentle response, far from the raving to
which Virgil subjects her. In her Ovidian letter, she reproves Aeneas for
his hypocrisy to his gods and to his previous wife: quid puer Ascanius, quid di meruere Penates? ignibus ereptos obruet unda deos? sed neque fers tecum, nec, quae mihi, perfide, iactas,
presserunt umeros sacra paterque tuos. 148 Ibid., 88, ll. 77–86.
149 Ibid., 96, ll. 184–90. 148 Ibid., 88, ll. 77–86. 149 Ibid., 96, ll. 184–90. 2. Love Poetry from the Song of Songs to Aeneas and Dido omnia mentiris; neque enim tua fallere lingua
incipit a nobis, primaque plector ego:
si quaeras ubi sit formosi mater Iuli—
occidit a duro sola relicta viro!148 What has little Ascanius done to deserve this fate? Snatched from the fire only to be drowned in the waves? No, neither are you bearing them with you, false boaster;
your shoulders neither bore the sacred relics, nor your father. You lie about everything; and I am not the first victim of your lies,
nor I am the first to suffer a blow from you:
do you ever ask, where Iulus’ mother is? She died because her unfeeling husband left her behind! What has little Ascanius done to deserve this fate? Snatched from the fire only to be drowned in the waves? No, neither are you bearing them with you, false boaster;
your shoulders neither bore the sacred relics, nor your father. You lie about everything; and I am not the first victim of your lies,
nor I am the first to suffer a blow from you:
do you ever ask, where Iulus’ mother is? She died because her unfeeling husband left her behind! In remarking that she is not the first that Aeneas has abandoned, Dido
makes it clear that she regards herself as his second left-behind wife, a
critique that Ovid employs both here and in the Metamorphoses to reject
Aeneas’ Virgilian excuse that he had never married her. Finally, describing
the form her death will take, Dido places the blame squarely on Aeneas: scribimus, et gremio Troicus ensis adest;
perque genas lacrimae strictum labuntur in ensem,
qui iam pro lacrimis sanguine tinctus erit. quam bene conveniunt fato tua munera nostro! instruis impensa nostra sepulcra brevi. nec mea nunc primum feriuntur pectora telo:
ille locus saevi vulnus amoris habet.149 2. Love Poetry from the Song of Songs to Aeneas and Dido 93 I write, and in my bosom the Trojan sword is here;
over my cheeks the tears run, onto the drawn sword,
which soon will be stained with blood rather than tears. How fitting is your gift in my fateful hour! You bring my death so cheaply. Nor is now the first time my heart feels a weapon’s blow:
it already bears the cruel wounds of love. Ovid, unlike Virgil, doesn’t lift a finger to make readers sympathize
with Aeneas. 150 John Watkins. The Specter of Dido: Spenser and Virgilian Epic (New Haven: Yale
University Press, 1995), 31. 2. Love Poetry from the Song of Songs to Aeneas and Dido Quite the opposite—he portrays his abandonment of Dido
as the betrayal of life as it is lived by ordinary human beings who are
neither emperors, nor the epic heroes meant to justify them: Ovid transfers Dido’s story from an account of Rome’s imperial origins
to a collection of letters written by classical heroines lamenting erotic
betrayals. A more intimate, cyclical view of history as repeated instances
of male treachery replaces Virgil’s portrait of it as a linear progress from
Troy to Actium. From this feminine perspective, the crucial events are not
the rise and fall of empires but the births, deaths, and love affairs of private
individuals. By disregarding Aeneas’s public accomplishments, Ovid
undermines the official justification for Dido’s abandonment. If Aeneas
is a hero according to one account, he is a traitor according to the other.150 It should come as no surprise, however, that among Ovid’s critics are
those who would rather sympathize with Augustus, and his proxy figure
Aeneas, than with Dido. Lancelot Patrick Wilkinson dismisses Dido in
Heroides 7, and, in so doing, very neatly embodies a too-common condition
among literary critics—the cultivated inability to respond emotionally to
poetry (except, perhaps, with the impatience of a reader no longer able
to respond other than as a literary-reference-detection machine): [T]he more Ovid tries to excel, the less he succeeds. The forced epigrams
creak […]. We are not really convinced when Virgil’s Dido, exaggerating
a curse that had come naturally in Homer, less naturally in Catullus, raves
that Aeneas was the son of a Caucasian crag, nurtured by Hyrcanian
tigresses; still less, when Ovid’s Dido attributes his origin to stone and
mountain-oaks, wild beasts or, better still, the sea in storm as now it is. 94 94 Love and its Critics […] So it goes on, argument after weary argument, conceit after strained
conceit (to our way of thinking), for close on to two hundred lines.151 Here we have a glimpse inside the mind of a critic who, recounting
“argument after weary argument”, is no longer able, or willing—so
impressed is he by the Virgilian virtues of warfare and obedience—to
respond to anything in poetry which is not immediately redolent of
masculine blood and iron. Ovid was never the kind of poet an admirer of power and empire
would find amenable, and such admiration is amply represented in the
critical literature. 151 L. P. Wilkinson. Ovid Recalled (Cambridge: Cambridge University Press, 1955), 93.
152 Howard Jacobson. Ovid’s Heroidos (Princeton: Princeton University Press, 1974), 90.
153 Ibid., 90.
154 Ibid. 155 David Scott Wilson-Okamura. Virgil in the Renaissance (Cambridge: Cambridge
University Press, 2010), 234.
156 Linda S. Kauffman. Discourses of Desire: Gender, Genre, and Epistolary Fictions (Ithaca:
Cornell University Press, 1986), 48.
157 W. S. Anderson. “The Heroides”. In Ovid, ed. by J. W. Binns (London: Routledge,
1973), 60.
158 Ibid., 61.
159 Lanham, 63. 2. Love Poetry from the Song of Songs to Aeneas and Dido For example, Howard Jacobson argues that “Ovid’s
[…] inability to separate out his personal feelings from the mythical
situation is one reason why this poem fails”.152 Here a literary critic
points to a poet and says that the poet’s “inability” to get beyond
“personal feelings” is a reason for poetic failure. It is difficult to think
of a more perfect illustration of the unbridgeable chasm that often
seems to separate poetry and its critics. But more than his “feelings”,
for Jacobson it is Ovid’s politics that represent his real failing: “Ovid
was congenitally averse to the Vergilian world-view and quite unable to
sympathize with a Weltenschauung that could exalt grand, abstract—not
to mention divine—undertakings over simple individual, human and
personal considerations”.153 This is an extraordinary argument, brutal
in its frank dismissal of the value of individual human life: Ovid was
wrong to the extent that he did not value empire over the individual heart; and
so, too, are you. For Jacobson, Heroides 7 is merely an agon, a struggle of
one poet with another, “Ovid waging war against Vergil”. Ovid, just as
those who admire him, “is doomed to defeat from the start because of
his incapacity and unwillingness to appreciate the Vergilian position”.154
Note the weasel word, appreciate. Not understand and reject: Ovid failed,
as do readers for whom Ovid’s treatment of Dido is more appealing than
Virgil’s, because of a failure to agree with and align with the obvious
rightness of the imperial, the “grand, abstract [and] divine”, rather than
the “individual, human and personal”. 2. Love Poetry from the Song of Songs to Aeneas and Dido 2. Love Poetry from the Song of Songs to Aeneas and Dido 95 But even critics not quite so imperially inclined find reason to
dismiss Ovid’s Dido: for David Scott Wilson-Okamura, “[c]ompared
with Virgil’s Dido, Ovid’s Dido (in Heroides 7) is a simplification. A
mere victim, she is sad, but somehow not tragic—not tragic because not
strong. We pity her more and care about her less”.155 For such critics,
compared with the martial glories of Virgil’s Aeneas, and even the
rage of Virgil’s Dido, the quiet, sad, but ultimately not-to-be-deceived
understanding of Ovid’s Dido offers too little in the way of excitement
or what is mistaken for strength. But Ovid’s Dido is much stronger
than Virgil’s, for she sees what Aeneas really is (and by extension, what
Rome and its servants really are, what any empire and its servants, even
its academic servants, really are). Such critics ignore a crucial point,
since the “difference between Virgil’s Dido and Ovid’s illuminates the
differences in style and politics between epic and epistle. […] In Ovid,
national glory is irrelevant […]”.156 All too many (primarily male) literary
critics condescendingly dismiss Dido in the fashion of W. S. Anderson,
who writes of what he calls “a contrast between a heroic and a charming
Dido”,157 then goes on rather back-handedly to credit Ovid for freeing
Dido “from the grandeur and majesty Virgil sought” while giving her
“arguments [that] tend to produce an impression of a charming, even
coquettish woman of passion”.158 If you listen carefully there, you can
hear the tsk tsk being delivered along with a pat on the head. But as so
often, the critic says more about himself here than about the poet or the
poem. Perhaps it is ever thus. For Ovid, and for many of his readers, “[y]ou cannot leave Dido
behind. She will not oblige by sacrificing the private life, the life of
feelings, to the greater glory of Rome”.159 And yet, from a practical
and political point of view, perhaps Ovid should have left her behind. Perhaps the poet erred in writing his Dido as he did. In all likelihood, it
was at least partly Ovid’s own poetry, perhaps even his letter from Dido
to Aeneas, that got him into trouble with the imperial dictator. It could Love and its Critics 96 well be that “Ovid’s version of an impius Aeneas predisposed Augustus
against him and the Ars, was, as it were, the straw that broke the camel’s
back”.160 I. I. K. Horvath. “Impius Aeneas”. Acta Antiqua: Academiae Scientarum Hungaricae, ed.
by A. Dobrovits, J. Harmatta, and G. Y. Moravcsik. Book 6, Vols 3–4 (1958), 390,
http://real-j.mtak.hu/441/1/ACTAANTIQUA_06.pdf 160 Jacobson, 90, n. 26. 161 den VII. Gesang der Heroides näher ins Auge zu fassen, den sogenannten Dido-Brief, der
unserer Überzeugung nach in hohem Masse dazu angetan war, bei Augustus Anstoss und
Ärgernis zu erregen, und der zumeist mit der einfachen Feststellung dessen abgetan wird, dass
aus dem “pius” Aeneas bei Ovid ein “nichtswürdiger Eidbrüchiger” wird. 161 den VII. Gesang der Heroides näher ins Auge zu fassen, den sogenannten Dido-Brief, der
unserer Überzeugung nach in hohem Masse dazu angetan war, bei Augustus Anstoss und
Ärgernis zu erregen, und der zumeist mit der einfachen Feststellung dessen abgetan wird, dass
aus dem “pius” Aeneas bei Ovid ein “nichtswürdiger Eidbrüchiger” wird.
I. K. Horvath. “Impius Aeneas”. Acta Antiqua: Academiae Scientarum Hungaricae, ed.
by A. Dobrovits, J. Harmatta, and G. Y. Moravcsik. Book 6, Vols 3–4 (1958), 390,
http://real-j.mtak.hu/441/1/ACTAANTIQUA_06.pdf 160 Jacobson, 90, n. 26. y
2
Patrick McCloskey and Edward Phinney, Jr. “Ptolemaeus Tyrannus: The
Typification of Nero in the Pharsalia”. Hermes, 96 (1968), 80. 1
Sergio Casali. “The Bellum Civile as an Anti-Aeneid”. In Brill’s Companion to Lucan,
ed. by Paolo Asso (Leiden: Brill, 2011), 84. 2. Love Poetry from the Song of Songs to Aeneas and Dido K. Horváth tells readers “to take a closer look at Heroides 7,
the so-called Dido-letter, which was, in our opinion, written largely to
offend and annoy Augustus, and is usually dismissed with the simple
statement that in Ovid, ‘Pius’ Aeneas is a ‘worthless liar’”.161 If it is true that Ovid was making a deliberate jibe at Augustus and the
Roman myth of Aeneas by writing from the point of view of a betrayed
and abandoned Carthaginian queen, then we have in “Dido to Aeneas”
a powerful example of love and its poetry standing up to power and
saying “No”. In giving Aeneas no reply to Dido’s words, the poet of
love, as opposed to imperial piety, throws his weight behind Dido. And
so have countless readers and poets since. 3
Nigel Holmes. “Nero and Caesar: Lucan 1.33–66”. Classical Philology, 94: 1 (January
1999), 80, https://doi.org/10.1086/449419
4
M Cl
k
d Phi
82 6
Lucan. The Civil War, 9.253–61, 264–65, 274–75, ed. by J. D. Duff (Cambridge, MA:
Harvard University Press, 1962), 522, 524. Love in the Poetry of Late Antiquity: Latin After Virgil and Ovid, the poetry of love begins to fade into the
background of the literary scene. Many of the later Latin poets, like
Claudian and Sidonius of the late fourth and the fifth centuries, follow
Lucan rather than Ovid, in a poetic tradition that puts love aside
entirely: “Lucan’s poem, programmatically, declares the absence of
‘love’ at the outset. The Bellum Civile has no ‘love’. It does not have an
Iliadic part […] or an Odyssean part. It has only war”.1 Lucan’s epic The
Civil War (or Pharsalia) is a lengthy account of the defeat of Pompey the
Great by Julius Caesar, whose victory at the battle of Pharsalus in 48
BCE put Rome on the path to the empire it would hold for centuries:
“in the Pharsalia [Lucan] universalized his personal grievance into all
Rome’s, and therefore the world’s, loss of libertas […] to the whimsy
of a Caesar”.2 Though Lucan was not politically sympathetic either to
Pompey or to Caesar, being instead a great admirer of Cato (a staunch
defender of the old Roman Republic), he looks back with an odd
nostalgia to the saner despot of the previous century. Lucan’s poem is © 2017 Michael Bryson and Arpi Movsesian, CC BY 4.0 https://doi.org/10.11647/OBP.0117.03 Love and its Critics 98 one in which “two incompatible attitudes are presented […] at least as
long as Lucan remained in Nero’s circle: not only does he praise him, he
does so against his own political beliefs”.3 On the other hand, Lucan “did not object to monarchy, but to severe
and despotic tyranny, as practiced in the Hellenized East and in Rome
during Nero’s later years. In the Pharsalia, tyranny was exemplified
by Caesar and Alexander. Its emblem was the sword”.4 Julius Caesar
serves Lucan as “the prototype of the tyrant Nero [… though] Caesar
had more virtues than Lucan cared or was able to attribute to Nero”.5
And yet, despite his oddly ambivalent attitude toward Nero, Lucan’s
love for Rome, and his longing for the old days of the Republic, shine
through the poem’s portrayal of a charismatic Cato, the last line of
defence, protecting a freedom Lucan had never known: Actum Romanis fuerat de rebus, et omnis
Indiga servitii fervebat litore plebes:
Erupere ducis sacro de pectore voces:
“Ergo pari voto gessisti bella, iuventus,
Tu quoque pro dominis, et Pompeiana fuisti,
Non Romana manus? 4
McCloskey and Phinney, 82. 5
Ibid., 83. 7
McCloskey and Phinney, 87. 8
Lucan, 1.33, 44–52, 25, 27. Love in the Poetry of Late Antiquity: Latin quod non in regna laboras,
Quod tibi, non ducibus, vivis morerisque, quod orbem
Adquiris nulli, quod iam tibi vincere tutum est,
Bella fugis
[…]
nunc patriae iugulos ensesque negatis,
Cum prope libertas? […]
O famuli turpes, domini post fata prioris
Itis ad heredem.6 nunc patriae iugulos ensesque negatis, 3. Love and its Absences in Late Latin and Greek Poetry 9
Claudian. “Panegyric on the Sixth Consulship of the Emperor Honorius”. 28.53–
55, 65–76. Claudian: Vol. II, ed. by Maurice Platnauer (Loeb Classical Library,
Cambridge, MA: Harvard University Press, 1998), 78. 3. Love and its Absences in Late Latin and Greek Poetry 99 The campaign for Rome was nearly ended, and the mob,
on fire for servitude, swarmed across the beach. Then from the leader’s sacred breast, these words burst forth:
“So did you young men go to war, fighting for the same vows,
defending the masters—and were you the troops of Pompey,
and not of Rome? Now that you no longer labor for a tyrant;
now that your lives and deaths, belong to you, not your leaders;
now that you fight for no one else but yourselves, now you
fly from the war, now you deny your country your swords and throats
when freedom is near? […]
Cowardly slaves! Your former master has met his fate,
and you go to serve his heir”. […]
Cowardly slaves! Your former master has met his fate,
and you go to serve his heir”. Lucan, who was eventually drawn into a plot to assassinate Nero,
established a pattern, with Pharsalia, of celebrating the greater glories of
an unrecoverable Roman past, longing for a world he portrayed as more
civilized than the present age. At the same time, he perversely praises
the dictator Nero—whom modern historians call “a Caesar worse
than Caesar, a tyrant whose vices were compounded by the petulant
inhumanity of a childlike man who acted thirteen even when he was as
old as thirty-two”7—by describing him as the glorious final goal toward
which all Roman history had been striving: Quod si non aliam uenturo fata Neroni
[…]
Multum Roma tamen debet ciuilibus armis
Quod tibi res acta est. te, cum statione peracta
Astra petes serus, praelati regia caeli
Excipiet gaudente polo: seu sceptra tenere
Seu te flammigeros Phoebi conscendere currus
Telluremque nihil mutato sole timentem
Igne uago lustrare iuuet, tibi numine ab omni
Cedetur, iurisque tui natura relinquet
Quis deus esse uelis, ubi regnum ponere mundi.8 Quod si non aliam uenturo fata Neroni
[…]
Multum Roma tamen debet ciuilibus armis
Quod tibi res acta est. te, cum statione peracta
Astra petes serus, praelati regia caeli
Excipiet gaudente polo: seu sceptra tenere
Seu te flammigeros Phoebi conscendere currus
Telluremque nihil mutato sole timentem
Igne uago lustrare iuuet, tibi numine ab omni
Cedetur, iurisque tui natura relinquet
Quis deus esse uelis, ubi regnum ponere mundi.8 100 Love and its Critics Yet, if fate could in no other way bring Nero,
[…]
much will Rome owe to these civil wars
because they were conducted for you. 3. Love and its Absences in Late Latin and Greek Poetry When your task is done,
and you go to seek the stars, the palaces of heaven will be yours,
heaven will be joyful: and whether you hold a sceptre
or choose to ride Phoebus’ fiery chariot
circling with moving fire the undisturbed earth,
by the light of fire you will be given power, from all
granted to you, and nature will leave you to decide
what god to be, and where to put your universal throne. Yet, if fate could in no other way bring Nero,
[…]
much will Rome owe to these civil wars
because they were conducted for you. When your task is done,
and you go to seek the stars, the palaces of heaven will be yours,
heaven will be joyful: and whether you hold a sceptre
or choose to ride Phoebus’ fiery chariot
circling with moving fire the undisturbed earth,
by the light of fire you will be given power, from all
granted to you, and nature will leave you to decide
what god to be, and where to put your universal throne. We still see this combination of nostalgia and perversity nearly four
centuries later in the work of Claudian, whose panegyrics to a failing
Rome, and its forgettable (and essentially forgotten) ruler Honorius,
show how far poets had declined into grateful subservience since the
days of the banished Ovid: Do you recognize your house, adored Prince? It is the same that first you marveled at in the years of old
When your pious Father, showed it to you as a child. [
] Though your life was yet rude, and the crown had not yet 3. Love and its Absences in Late Latin and Greek Poetry 101 enclosed your head, your father shared his honors,
his royal purple, fondling you in his lap, sharing his triumphs,
teaching you, in your youth, the overture to your mighty destiny. Peoples of different nations and languages sent requests,
Persian nobles sought treaties while sitting with your father,
but having once seen the crown on your head,
they also bent their knees to you. One can imagine Ovid’s disdain for such flattery (even Virgil might
find this level of obsequiousness embarrassing). 10
F. J. E. Raby. A History of Secular Latin Poetry in the Middle Ages (Oxford: Clarendon
Press, 1934), 90.
11
William E. Dunstan. Ancient Rome (Lanham: Rowman & Littlefield Publishers,
2011), 515.
12
F. J. E. Raby. A History of Christian-Latin Poetry: From the Beginnings to the Close of the
Middle Ages (Oxford: Clarendon Press, 1927), 80, 81. 3. Love and its Absences in Late Latin and Greek Poetry Raby describes
Sidonius as “the most distinguished literary figure of his day”, famous
for “his panegyrics on successive emperors”, before noting that “the
poems themselves are poor in content”, though they have an “ineffectual
ingenuity”.12 It is not hard to tell why: Sidonius’s work, like Claudian’s,
is pure propaganda designed to prop up a weak ruler: 102 Love and its Critics Claudian’s panegyrics have been defined as propaganda, and Sidonius’
panegyrics certainly have a definite political purpose, but […] an
important fact should always be borne in mind: Claudian wrote his
imperial panegyrics for an apparently established dynasty, [while] Sidonius
was writing half a century later and lived in a period of political chaos.13 Claudian’s panegyrics have been defined as propaganda, and Sidonius’
panegyrics certainly have a definite political purpose, but […] an
important fact should always be borne in mind: Claudian wrote his
imperial panegyrics for an apparently established dynasty, [while] Sidonius
was writing half a century later and lived in a period of political chaos.13 By Sidonius’s time, Rome had long since begun its decline. But Sidonius
was loyal to the bitter end, presenting “what remained of the empire as
a model society that was worthy of unquestioning loyalty. To be loyal to
Rome was to be loyal to civilization itself”.14 Yet Rome, and its civilization,
had passed its peak long before Sidonius was born. Diocletian had
split the Empire into western and eastern portions in 285 CE, while
Constantine had transferred the center of real power from Rome to
Constantinople sometime between 324 and 330 CE. Since the move
east, the west had become increasingly vulnerable to northern invaders,
such as Alaric in 410, and by the time of Sidonius, it was under foreign
domination: “The years from 456 to 472 saw the Roman west under
the virtual rule of a German named Flavius Ricimer, a Suevian general
whose maternal grandfather had ruled as a Visigothic king. Ricimer
made and unmade a series of puppet emperors occupying the Ravenna
throne”,15 one of whom was Anthemius. 13
Lynette Watson. “Representing the Past, Redefining the Future: Sidonius
Appolinaris’ Panegyrics of Avitus and Anthemius”. In The Propaganda of Power: The
Role of Panegyric in Late Antiquity, ed. by Mary Whitby (Boston: Brill, 1998), 181.
14
Peter Brown. Through the Eye of a Needle: Wealth, the Fall of Rome, and the Making of
Christianity in the West, 350–550 AD (Princeton: Princeton University Press, 2012), 404.
15
Dunstan, 518. 14
Peter Brown. Through the Eye of a Needle: Wealth, the Fall of Rome, and the Making of
Christianity in the West, 350–550 AD (Princeton: Princeton University Press, 2012), 404.
15
D
t
518 3. Love and its Absences in Late Latin and Greek Poetry For Claudian “no
exaggeration, however gross, suggested to him that here he must, for
the sake of decency, draw the line”.10 If it seems that the purpose of
poetry in the Roman world of the early fifth century (404 CE) was the
unseemly celebration of mediocrity in power, that is because of work
like Claudian’s fawning poem to Honorius, the first Roman Emperor to
see Rome sacked during his reign: The ambitious Alaric comprehended Honorius’ feebleness and again
invaded Italy, intending to march on Rome. At the time, Honorius
presided over the imperial court from a town on the Adriatic coast,
Ravenna, surrounded by great protective marshes […]. Alaric besieged
Rome three times between 408 and 410, [and] in 410 venerable Rome
finally fell.11 But later fifth-century poets would not fail to rise (or sink) to the
challenge represented by Claudian’s flattery. Sidonius Appolinaris,
the fifth-century Bishop of Auvergne, writes his Carmen II, or Panegyric
on Anthemius to address the late-fifth century ruler (the Augustus)
of a nearly-collapsed Western Roman Empire. F. J. E. Raby describes
Sidonius as “the most distinguished literary figure of his day”, famous
for “his panegyrics on successive emperors”, before noting that “the
poems themselves are poor in content”, though they have an “ineffectual
ingenuity”.12 It is not hard to tell why: Sidonius’s work, like Claudian’s,
is pure propaganda designed to prop up a weak ruler: But later fifth-century poets would not fail to rise (or sink) to the
challenge represented by Claudian’s flattery. Sidonius Appolinaris,
the fifth-century Bishop of Auvergne, writes his Carmen II, or Panegyric
on Anthemius to address the late-fifth century ruler (the Augustus)
of a nearly-collapsed Western Roman Empire. F. J. E. 13
Lynette Watson. “Representing the Past, Redefining the Future: Sidonius
Appolinaris’ Panegyrics of Avitus and Anthemius”. In The Propaganda of Power: The
Role of Panegyric in Late Antiquity, ed. by Mary Whitby (Boston: Brill, 1998), 181. 15
Dunstan, 518. Christianity in the West, 350–550 AD (Princeton: Princeton University Press, 2012), 404.
15
Dunstan, 518. 3. Love and its Absences in Late Latin and Greek Poetry But despite Anthemius’s status
as Ricimer’s pawn, Sidonius addresses this inconsequential ruler as if he
were the great Augustus Caesar himself: Auspicio et numero fasces, Auguste, secundos
erige et effulgens trabealis mole metalli
annum pande novum consul vetus ac sine fastu
scribere bis fastis; quamquam diademate crinem
fastigatus eas umerosque ex more priorum
includat Sarrana chlamys, te picta togarum
purpura plus capiat, quia res est semper ab aevo
rara frequens consul, tuque o cui laurea, lane,
annua debetur, religa torpore soluto 3. Love and its Absences in Late Latin and Greek Poetry 103 quavis fronde comas, subita nee luce pavescas
principis aut rerum credas elementa moveri. nil natura novat: sol hie quoque venit ab ortu.16 quavis fronde comas, subita nee luce pavescas
principis aut rerum credas elementa moveri. nil natura novat: sol hie quoque venit ab ortu.16 Your fortunes, Augustus, and your second fasces,
take up, and in your ceremonial robe gleaming with gold,
open, as a veteran consul, the new year; without scorn
write your name again in the rolls; though the diadem in your hair,
and your sloping shoulders, are like those of your predecessors
who wore Tyrian robes, your consul’s togas painted
purple might please you more, for since Rome’s earliest years
repeated consulships are rare; and you, Janus, whose laurel
is due to you annually, bind up your weariness,
bind up your hair with leaves, do not give in to sudden fear,
or imagine the elements are all in motion. Nature is unchanged: the sun rises in the East, but also here. Your fortunes, Augustus, and your second fasces,
take up, and in your ceremonial robe gleaming with gold,
open, as a veteran consul, the new year; without scorn
write your name again in the rolls; though the diadem in your hair,
and your sloping shoulders, are like those of your predecessors
who wore Tyrian robes, your consul’s togas painted
purple might please you more, for since Rome’s earliest years
repeated consulships are rare; and you, Janus, whose laurel
is due to you annually, bind up your weariness,
bind up your hair with leaves, do not give in to sudden fear,
or imagine the elements are all in motion. Nature is unchanged: the sun rises in the East, but also here. 16
Sidonius. “Panegyric on Anthemius”, 2.1–12. In Poems and Letters. 2 Vols, ed. by W.
B. Anderson (Loeb Classical Library, Cambridge, MA: Harvard University Press,
1963), 1: 5, 7. 18
Alan Cameron. Claudian: Poetry and Propaganda at the Court of Honorius (Oxford:
Clarendon Press, 1970), 246. 17
Sidonius seems to have known this, as “he dated his death by the reign of the
eastern emperor, Zeno. Sidonius considered Zeno, as emperor at Constantinople,
to be the sole surviving head of the legitimate Roman empire” (Brown, 406). B. Anderson (Loeb Classical Library, Cambridge, MA: Harvard University Press,
1963), 1: 5, 7.
17
Sidonius seems to have known this, as “he dated his death by the reign of the
eastern emperor, Zeno. Sidonius considered Zeno, as emperor at Constantinople,
to be the sole surviving head of the legitimate Roman empire” (Brown, 406).
18
Alan Cameron Claudian: Poetry and Propaganda at the Court of Honorius (Oxford: 16
Sidonius. “Panegyric on Anthemius”, 2.1–12. In Poems and Letters. 2 Vols, ed. by W.
B. Anderson (Loeb Classical Library, Cambridge, MA: Harvard University Press,
1963), 1: 5, 7.
17
Sidonius seems to have known this, as “he dated his death by the reign of the
eastern emperor, Zeno. Sidonius considered Zeno, as emperor at Constantinople,
to be the sole surviving head of the legitimate Roman empire” (Brown, 406).
18
Alan Cameron. Claudian: Poetry and Propaganda at the Court of Honorius (Oxford:
Clarendon Press 1970) 246 19
Prudentius. “Hymnus Ante Somnum”. In Patrologiae Cursus Completus, Vol. 59, ed.
by Jacques Paul Migne (Paris: Apud Garnier Fratres, 1855), cols. 831–41, ll. 9–12,
149–52, https://books.google.com/books?id=jnzYAAAAMAAJ&pg=RA1-PT325 y,
21
Venantius Fortunatus. Venanti Honori Clementiani Fortunati Presbyteri Italici Opera
Poetica, ed. by Frederick Leo (Berlin: Apud Weidmannos, 1881), 34–35, ll. 1–4, 29–32,
https://archive.org/stream/venantihonoricl00unkngoog#page/n68
22
“μόνον ὕμνους θεοῖς καὶ ἐγκώμια τοῖς ἀγαθοῖς ποιήσεως” (Republic 607a. In
Plato: Republic. Books 6–10, ed. by Christopher Emlyn-Jones and William Preddy
[Loeb Classical Library, Cambridge, MA: Harvard University Press, 2013], 436). 20
Raby, 89. 22
“μόνον ὕμνους θεοῖς καὶ ἐγκώμια τοῖς ἀγαθοῖς ποιήσεως” (Republic 607a. In
Plato: Republic. Books 6–10, ed. by Christopher Emlyn-Jones and William Preddy
[Loeb Classical Library, Cambridge, MA: Harvard University Press, 2013], 436). 3. Love and its Absences in Late Latin and Greek Poetry There is something absurd in lauding a weak western Augustus in an
era in which power has long since flowed east to Constantinople (where
the sun of wealth and power really rises in Sidonius’ era).17 No one
there likely knew or cared much about the rump emperors of the feeble
and abandoned west. In all likelihood, no one outside an increasingly
irrelevant Rome would ever have heard or read the propaganda
produced by either Claudian or Sidonius: “whether or not Claudian
found many readers in the East, his propaganda is not likely to have
had much more effect there than communist propaganda in western
capitals today”.18 After such unseemly adulation of past power in a perilously fragile
present, the rest is silence. By 476, with the deposition of the western
Emperor Romulus by Flavius Odoacer, who proceeded to call himself
(and reign as) the first king of Italy, the west fell into irrelevance. The Love and its Critics 104 poems of praise written by a fifth-century bishop seem, in retrospect,
like insincere love letters written to a dying world, as the age of secular
civilization was about to begin its long struggle with the western
Church Sidonius served. Theology would soon begin to dominate Latin
writing, a development reflected in much of the new Christian poetry
of the period. Christianity comes to have a transformative effect (and
not often for the better) on both Latin and later vernacular poetry; its
influence can be seen initially in the poetry of Prudentius, a Roman
Christian of the fourth century. His Hymnus Ante Somnum (Hymn Before
Sleep) is representative: Rather than the idea of human love being introduced after “the day’s
labor has flowed past” (as one might expect in Ovid), the turn here is
away from the human and toward the divine. This turn is even more
prominent in the sixth-century poet Venantius Fortunatus, who may 3. Love and its Absences in Late Latin and Greek Poetry 105 well represent the high point of artistic achievement in the Christian
Latin poetry of the period. His hymn, Vexilla Regis, is “one of the first
creations of purely medieval religious feeling”,20 a sentiment expressed
in words of joy over a human sacrifice. 21
Venantius Fortunatus. Venanti Honori Clementiani Fortunati Presbyteri Italici Opera
Poetica, ed. by Frederick Leo (Berlin: Apud Weidmannos, 1881), 34–35, ll. 1–4, 29–32,
https://archive.org/stream/venantihonoricl00unkngoog#page/n68 24
Bembo’s poetry did not have the lasting appeal of the vernacular work of the time,
and in the estimate of a later scholar, it was at least partly because Bembo’s Latin
poetry has “more elegance than vigour”, resulting in a verse that seems “polished
and cold” (John Edwin Sandys. A History of Classical Scholarship Vol. II: From the
Revival of Learning to the End of the Eighteenth Century in Italy, France, England and
the Netherlands [Cambridge: Cambridge University Press, 1903], 114, 115, https://
archive.org/stream/historyofclassic02sandiala#page/114). 25
The theoretical justification for this move appears first in Dante: “[t]his concern
first appears in La Vita Nuova, where Dante informs the reader that what drew
him and Guido Cavalcanti together was their agreement that this work would
be written entirely in the vernacular” (Richard J. Quinones. “Dante Alighieri”.
In Medieval Italy: An Encyclopedia, ed. by Christopher Kleinhenz [New York:
Routledge, 2004], 281). 23
Vexilla Regis was “composed for the the solemn reception of [a] special relic of the
Holy Cross sent by the Eastern Roman Emperor Justin II to Saint Radegund for
a convent of nuns she had founded near Poitiers, and [it is] now [2010] used in
the liturgy for Passiontide” (Gabriel Díaz Patri. “Poetry in the Latin Liturgy”. In
The Genius of the Roman Rite: Historical, Theological, and Pastoral Perspectives on Catholic
Liturgy, ed. by Uwe Michael Lang [Chicago: Hillenbrand Books, 2010], 45–82, 57) 27
Ausonius. “Attusia Lucana Sabina Uxor”, Parentalia IX. In Ausonius. Vol. I: Books
1–17, ed. by Hugh G. Evelyn-White [Loeb Classical Library, Cambridge, MA:
Harvard University Press, 1919], 70, ll. 7–10, 18. 26
“Ad Uxorem”, Epigram 20. In Ausonius: Epigrams. Text with Introduction and
Commentary, ed. by Nigel M. Kay (London: Duckworth, 2001), 45. 26
“Ad Uxorem”, Epigram 20. In Ausonius: Epigrams. Text with Introduction and
Commentary, ed. by Nigel M. Kay (London: Duckworth, 2001), 45.
27
Ausonius. “Attusia Lucana Sabina Uxor”, Parentalia IX. In Ausonius. Vol. I: Books
1–17, ed. by Hugh G. Evelyn-White [Loeb Classical Library, Cambridge, MA:
Harvard University Press, 1919], 70, ll. 7–10, 18. 3. Love and its Absences in Late Latin and Greek Poetry There is no trace here of the
spirit of Ovid, or the Song of Songs, as all emotion is directed toward
the heavens: Vexilla regis prodeunt,
fulget crucis mysterium,
quo carne carnis conditor
suspensus est patíbulo. […]
Salve ara, salve victima
de passionis gloria,
qua vita mortem pertulit
et morte vitam reddidit.21
The Royal banner advances,
the mystical Cross glows,
where the maker of flesh, flesh was made,
suspended on the gallows pole. […]
Hail the altar, hail the victim
of the glorious passion,
by which life suffered death,
and life was delivered from death. Here, poetry serves as a vehicle for worship, a means through which
imagination and emotion can be “channeled, reformulated, and
controlled” away from the here and toward the hereafter. At this point,
poetry is approaching the condition Plato once envisioned, in which
“only hymns to the gods and poems to great men”22 can be written. Here Love and its Critics 106 also we can see the way in which love poetry has often been redirected
and repurposed, not only by such commentators and critics as Akiba
and Origen, but by poets working in the spirit of their ideas (Dante will
be one of the pre-eminent examples of this phenomenon). Christian-
themed Latin poetry such as that of Prudentius and Fortunatus
remained popular23 despite the failed attempts of Italian humanists like
Pietro Bembo in the fifteenth and sixteenth centuries to revive Latin
as the dominant language of secular poetry.24 Throughout the Europe
of Bembo’s time, and long before, many of the most talented writers
of love poetry had shifted to the vernacular,25 in a creative and poetic
mood that started with the eleventh-century poets of the area we now
know as the South of France. There are, however, some notable exceptions to the overall trend. Among them is the fourth-century poet Ausonius (from Bordeaux),
who wrote a wide variety of verse: descriptions of everyday life (the
Ephemeris), epitaphs, idylls (the most famous of which is a loving
description of the Mosel region in Germany, the Mosella), but perhaps
the single most memorable piece he ever wrote was included among his
epigrams, a poem called Ad Uxorem (To My Wife). Here, he celebrates
love and the wife he would lose all too soon upon her death at the age
of twenty-seven: 3. Love and its Absences in Late Latin and Greek Poetry 107 26
“Ad Uxorem”, Epigram 20. In Ausonius: Epigrams. Text with Introduction and
Commentary, ed. by Nigel M. Kay (London: Duckworth, 2001), 45.
27
Ausonius. “Attusia Lucana Sabina Uxor”, Parentalia IX. In Ausonius. Vol. I: Books
1 17 ed by Hugh G Evelyn White [Loeb Classical Library Cambridge MA: 3. Love and its Absences in Late Latin and Greek Poetry uxor, vivamus quod viximus et teneamus
nomina quae primo sumpsimus in thalamo,
nec ferat ulla dies, ut commutemur in aevo,
quin tibi sim iuvenis tuque puella mihi. Nestore sim quamvis provectior aemulaque annis
vincas Cumanam tu quoque Deiphoben,
nos ignoremus quid sit matura senectus:
scire aevi meritum, non numerare decet.26 Wife, let us live as we have lived and hold fast
to those names we first took privately,
and not be changed by transporting time. Why should I not be youthful, you a maiden in years? Though I should live longer than Nestor,
though you should outstrip Cumaean Sibyl,
let us be ignorant of maturity and age,
and know Time’s worth, not count its years. Remember this poem, when we later encounter theological and academic
critics who deride husbands for “uxoriousness”, or being too much in
love with their wives (and too little in love with God). Remember too,
the pain Ausonius describes feeling—a full thirty-six years later—as he
remembers his wife Sabina: te iuvenis primis luxi deceptus in annis
perque novem caelebs te fleo Olympiadas,
nec licet obductum senio sopire dolorem;
semper crudescit nam mihi paene recens. […]
…tu mihi semper ades.27 …tu mihi semper ades.27 In my youth, I mourned for you, cheated of the years,
and I have wept, unmarried, for nine Olympiads. Growing old has not obscured or dulled my sorrow; 108 Love and its Critics for me, the pain ever grows, always recent. …you are always with me. These lines were written “thirty-six years after [Sabina’s] death, when
Ausonius was seventy years old; yet the wound caused by her loss is
still fresh, and time, which to others brings relief, has but intensified his
sorrow”.28 This is not a poem that speaks only of poetry itself. Far from being merely conventional figures, “some of Latin amatory
poetry’s addressees probably were based on real people”, and here
we have a perfect example: “Ausonius’s uxor […] is no figment of his
imagination: she is in fact his wife, nor is Epigram 20 the only occasion
on which he refers to her. 31
John Boswell. Christianity, Social Tolerance, and Homosexuality: Gay People in Western
Europe from the Beginning of the Christian Era to the Fourteenth Century (Chicago:
University of Chicago Press, 1980), 188–89. 28
Sister Marie José Byrne. Prolegomena to an Edition of the Works of Decimus Magnus
Ausonius. New York: Columbia University Press, 1916, 12.
29
Robert J. Sklenár. “Ausonius’ Elegiac Wife: Epigram 20 and the Traditions of Latin
Love Poetry”. The Classical Journal, 101: 1 (October-November 2005), 52.
30
Ibid., 51. 28
Sister Marie José Byrne. Prolegomena to an Edition of the Works of Decimus Magnus
Ausonius. New York: Columbia University Press, 1916, 12.
29
Robert J. Sklenár. “Ausonius’ Elegiac Wife: Epigram 20 and the Traditions of Latin
Love Poetry”. The Classical Journal, 101: 1 (October-November 2005), 52.
30
Ibid., 51.
31
John Boswell. Christianity, Social Tolerance, and Homosexuality: Gay People in Western
Europe from the Beginning of the Christian Era to the Fourteenth Century (Chicago:
University of Chicago Press, 1980), 188–89. 29
Robert J. Sklenár. “Ausonius’ Elegiac Wife: Epigram 20 and the Traditions of Latin
Love Poetry”. The Classical Journal, 101: 1 (October-November 2005), 52.
30
Ibid., 51. 28
Sister Marie José Byrne. Prolegomena to an Edition of the Works of Decimus Magnus
Ausonius. New York: Columbia University Press, 1916, 12. Pectus amor nostrum penetravit flamma
Atque calore novo semper inardet amor. 32
Alcuin. “Pectus amor nostrum penetravit flamma”. Monumenta Germaniae historica
inde ab anno Christi quingentesimo usque ad annum millesimum et quingentesimum
(Berlin: Apud Weidmannos, 1881), Vol. I: 236, ll. 1–6, https://books.google.com/
books?id=U6woAAAAMAAJ&pg=PA236 33
“Christian friendship”—we will see this argument resorted to again, when scholars
need to explain away what appears to be an “inconvenient” passion in the Occitan
poem “Na Maria”. 35
David Clark. Between Medieval Men: Male Friendship and Desire in Early Medieval
English Literature (Oxford: Oxford University Press, 2009), 79. Clark makes
this argument based on a single passage in Alcuin’s voluminous output. In
Interrogationes et Responsiones in Genesin, Alcuin takes on the following question:
“In the days of Noah, why were the sins of the world punished by water, but those 34
Allen J. Frantzen. Before the Closet: Same-Sex Love from “Beowulf” to “Angels in
America” (Chicago: University of Chicago Press, 1998), 198, 199. 3. Love and its Absences in Late Latin and Greek Poetry The ninth poem of his Parentalia, a collection
of epitaphs for dead family members, tells of her death at the age of
twenty-seven”.29 In referencing Catullus’ Fifth Ode (Vivamus mea
Lesbia), “Ausonius’s matrimonial love poem is […] noteworthy for its
engagement with an inherently non-matrimonial tradition”,30 a note
that we will hear again, in different ways, in both Shakespeare and John
Donne, over a thousand years later. The most famous examples of later Latin love poetry, however, do
not appear for centuries after the periods of Claudian, Sidonius, and
Ausonius. Alcuin, the late eighth-to early ninth-century poet and scholar
in the court of Charlemagne, writes some curiously passionate verses to
male friends. John Boswell argues that a “distinctly erotic element […]
is notable in the circle of clerical friends presided over by Alcuin at the
court of Charlemagne. […] The prominence of love in Alcuin’s writings,
all of which are addressed to males, is striking”.31 One notable example
is found in the opening lines of Pectus amor nostrum penetravit flamma: Pectus amor nostrum penetravit flamma Atque calore novo semper inardet amor. 109 3. Love and its Absences in Late Latin and Greek Poetry 36
Frantzen, 199. This letter never explicitly references the sin being spoken of: “What
is it, my son, that I hear of, not from one muttering in a corner, but from many
publicly laughing about the story that you are still devoted to childish uncleanness,
and have never been able to dismiss what you never should have wished to do?”
(“Quid est, fili, quod de te audio, non uno quolibet in angulo susurrante, sed plurimis
publice cum risu narrantibus: quod puerilibus adhuc deservias immunditiis, et
quae nunquam facere debuisses, nunquam dimittere voluisses [velis]”.) (Alcuin.
“Epistola CCVI, Ad Disciplum”. In Patrologiae Cursus Completus, Vol. 100, col.
481–82, https://books.google.com/books?id=-JqsZH3ajIgC&pg=PT171).
37
Cl
k 80 3. Love and its Absences in Late Latin and Greek Poetry Nec mare, nec tellus, montes nec silva vel alpes
Huic obstare queunt aut inhibere viam,
Quo minus, alme pater, semper tua viscera lingat,
Vel lacrimis lavet pectus, amate, tuum.32 The flames of our love have penetrated my breast
And new heat always relights this love. Neither sea, nor land, mountain nor forest, nor the Alps
Can obstruct or inhibit it
In the slightest, bountiful father, from always licking your flesh,
Or bathing your breast, my love, in my tears. Though scholars after Boswell have been at great pains to explain away
the apparent eroticism of such lines as “semper tua viscera lingat”
(“always licking your flesh”, or perhaps even more intimately, “always
licking your inmost flesh”), it should come as no surprise to anyone
familiar with the history of interpreting the Song of Songs that there are
always ready arguments to explain what appears to be erotic passion as
actually something else. Allen Frantzen, for example, argues that “such
effusions […] belong to a venerable tradition of ‘Christian amicitia’33
and need not have any direct relation to sexual passion”, then does his
best to argue that Alcuin “deplored same-sex intercourse”,34 although
this claim is undermined because Frantzen mistakes references to
masturbation in Alcuin’s letters for references to sex. David Clark argues
along similar lines, maintaining that while “Boswell is wrong to suggest
that Alcuin did not condemn same-sex activity”, what Alcuin is really
doing is “euphemistically referring to the sin of masturbation”,35 in a 110 Love and its Critics letter where he threatens one of his young students that such sinners
will “burn in the flames of Sodom”.36 Clark insists that “[i]t is simply
not possible to say whether Alcuin’s […] desires were the outward
expression of personally recognised erotic feelings and whether those
feelings were sexually expressed”, then goes on to make this contrary
claim: nor is the question important or productive. It is perfectly possible
for an individual to feel and express homoerotic desires and yet be
utterly opposed to, even repulsed by, their physical expression, just
as it is possible for an individual to condemn same-sex acts and yet be
homosexually active.37 When trying to understand the apparent passions expressed in a poem
like Pectus amor nostrum penetravit flamma, how can knowledge of the
passions of the author be deemed unimportant and unproductive? of the Sodomites were punished by fire?” (“Quare diebus Noe peccatum mundi
aqua ulciscitur, hoc vero Sodomitarum igne punitur?”) Alcuin answers by drawing
the reliably orthodox conclusion that the sins of Noah’s world were natural, while
those of Sodom were unnatural: “Because the sin of lust with women is natural,
it is condemned as though by a lighter element; but the sin of lust against nature
with men is avenged by the harsher burning element; there the ground is washed
with water and returns to fertility; but this one is made eternally barren, burned by
fire” (“Quia illud naturale libidinus cum feminis peccatum quasi leviori elemento
damnatur: hoc vero contra naturam libidinis peccatum cum viris, aeriois elementi
vindicatur incendio: et illic terra aquis abluta revirescit; hic flammis cremata
aeterna steriliate arescit”.) (Patrologiae Cursus Completus, ed. by Jacques Paul Migne
[Paris: Apud Garnier Fratres, 1863], Vol. 100, col. 543, https://books.google.com/
books?id=-JqsZH3ajIgC&pg=PT202). 38
See Peter Dronke, The Medieval Poet and His World (Rome: Edizioni di Storia e
Letteratura, 1984), specifically Chapter 8, “The Song of Songs and Medieval Love
Lyric”, 209–36.
39
Ibid 221 22 40
Ibid., 234–35. The original text from Paris BnF Latin 1118 fol 247v. is available online
at http://gallica.bnf.fr/ark:/ 12148/btv1b8432314k/f504.item 39
Ibid., 221–22. 3. Love and its Absences in Late Latin and Greek Poetry No
proof is given for such a claim; readers are apparently simply supposed
to accept this pronouncement without question. This is a prescriptive
style of argument that we will see again and discuss in greater depth,
especially in critical discussion of Donne’s work. Here we will merely
observe that such arguments, which separate the poet from the poem, of the Sodomites were punished by fire?” (“Quare diebus Noe peccatum mundi
aqua ulciscitur, hoc vero Sodomitarum igne punitur?”) Alcuin answers by drawing
the reliably orthodox conclusion that the sins of Noah’s world were natural, while
those of Sodom were unnatural: “Because the sin of lust with women is natural,
it is condemned as though by a lighter element; but the sin of lust against nature
with men is avenged by the harsher burning element; there the ground is washed
with water and returns to fertility; but this one is made eternally barren, burned by
fire” (“Quia illud naturale libidinus cum feminis peccatum quasi leviori elemento
damnatur: hoc vero contra naturam libidinis peccatum cum viris, aeriois elementi
vindicatur incendio: et illic terra aquis abluta revirescit; hic flammis cremata
aeterna steriliate arescit”.) (Patrologiae Cursus Completus, ed. by Jacques Paul Migne
[Paris: Apud Garnier Fratres, 1863], Vol. 100, col. 543, https://books.google.com/
books?id=-JqsZH3ajIgC&pg=PT202). 36 36
Frantzen, 199. This letter never explicitly references the sin being spoken of: “What
is it, my son, that I hear of, not from one muttering in a corner, but from many
publicly laughing about the story that you are still devoted to childish uncleanness,
and have never been able to dismiss what you never should have wished to do?”
(“Quid est, fili, quod de te audio, non uno quolibet in angulo susurrante, sed plurimis
publice cum risu narrantibus: quod puerilibus adhuc deservias immunditiis, et
quae nunquam facere debuisses, nunquam dimittere voluisses [velis]”.) (Alcuin. “Epistola CCVI, Ad Disciplum”. In Patrologiae Cursus Completus, Vol. 100, col. 481–82, https://books.google.com/books?id=-JqsZH3ajIgC&pg=PT171). 3. Love and its Absences in Late Latin and Greek Poetry 42
Carmina Burana: Lateinische und deutsche Lieder und Gedichte einer Handschrift des
XIII Jahihunderts aus Benedictbeuern auf der K. Bibliothek gu München, ed. by Johann
Andreas Schmeller (Stuttgart: Literarischen Vereins, 1847), 211–12, https://books.
google.com/books?id=0XN3YW-EqacC&pg=PA211 41
Ibid., 233. 3. Love and its Absences in Late Latin and Greek Poetry 111 often serve to explain away the unruly and uncontrolled desires
expressed in the poetry of love. The anonymous lyric Iam dulcis amica, a late tenth-or early eleventh-
century poem existing in three versions,38 celebrates a love that will
begin to sound very familiar when we consider the vernacular poems
of the troubadours. Peter Dronke explicitly compares this poem to the
Song of Songs, arguing that the “Song of Songs language emerges in the
terms of endearment—soror, amica, electa, dilecta […] but most of all it
belongs to the final strophe of the Paris version, with its linking of the
melting snows and nascent greenness with the quickening warmth of
love”.39 This can be seen in the final two stanzas of the Paris manuscript: Ego fui sola in silva
et dilexi loca secreta:
Frequenter effugi tumultum
et vitavi populum multum. Iam nix glaciesque liquescit,
Folium et herba virescit,
Philomena iam cantat in alto,
Ardet amor cordis in antro.40 Ego fui sola in silva
et dilexi loca secreta:
Frequenter effugi tumultum
et vitavi populum multum. Iam nix glaciesque liquescit,
Folium et herba virescit,
Philomena iam cantat in alto,
Ardet amor cordis in antro.40 I was alone in the forest
and I delighted in secret places:
Frequently I fled from the tumult
and avoided the popular crowds. Now, as snow and ice melt,
Leaves and grass grow green,
The nightingale sings from high above,
While love burns in the cave of my heart. As Dronke argues, this song reflects a woman’s perspective, and this
evocation of “the fear and longing, the emotional heights and depths
of the woman in love” owes a great deal “to the Song of Songs”, and 112 Love and its Critics “recur[s] spontaneously in similar forms in the ancient Near East, in
medieval Spain [and] Anglo-Saxon England”.41 Perhaps more famous still are the Latin poems from the Carmina
Burana, a manuscript from the early thirteenth century collecting Latin
and German songs of mockery, morality, drinking, and love. Among the
best known now, due to the music of Carl Orff, is Tempus est iocundum,
a lyric in the carpe diem tradition: Tempus est iocundum, o virgines,
modo congaudete vos iuvenes. Oh-oh, totus floreo, iam amore virginali
totus ardeo,
novus, novus amor est, quo pereo. […]
Veni, domicella, cum gaudio;
veni, veni, pulchra, iam pereo. 43
Richard F. Hardin. Love in a Green Shade: Idyllic Romances Ancient to Modern (Lincoln,
NE: University of Nebraska Press, 2000), 11.
44
“φίλημα καὶ περιβολὴ καὶ συγκατακλινῆναι γυμνοῖς σώμασι” (Longus. Daphnis
and Chloe, ed. by Jeffrey Henderson [Loeb Classical Library, Cambridge, MA:
Harvard University Press, 2009], 2.7.7, 68). 3. Love and its Absences in Late Latin and Greek Poetry Oh-oh, totus floreo, iam amore virginali
totus ardeo,
novus, novus amor est, quo pereo.42
The time is now for happiness, O virgins,
rejoice together now you young men. Oh, oh, I am blooming, now with my first love. totally on fire,
new, new love is what I am dying of. […]
Come, my mistress, with joy;
come, come, my beauty, for now I am dying. Oh, oh, I am blooming, now with my first love,
totally on fire,
new, new love is what I am dying of. B t h
h
h d b th th ti
d th
i it
f th O
it new, new love is what I am dying of. But here, we have reached both the time, and the spirit of the Occitan
troubadours, and have left, properly speaking, the realm of late classical But here, we have reached both the time, and the spirit of the Occitan
troubadours, and have left, properly speaking, the realm of late classical 3. Love and its Absences in Late Latin and Greek Poetry 113 and early medieval Latin poetry. In lyrics such as these, we can hear the
voice of Ovid and the Song of Songs once again, and see something of
the essence of fin’amor. II
Love in the Poetry of Late Antiquity: Greek Greek literature, by the early centuries of the Common Era, had long
since been considered lesser than Latin poetry and prose. But for a time,
Greek writers kept love alive in their work, especially through the work
of a group of writers known as the Erotici Graeci, Greek writers of love
stories. Of these, the most famous is Longus, “probably a rhetorician of
the period known as the Second Sophistic, [who] reveals a crafted style,
wide literary learning, and an unusually sophisticated, self-conscious
narrative technique”.43 Daphnis and Chloe, Longus’ verse novel of
approximately 200 CE, tells the story of two infants, a boy and a girl,
exposed to die on hillsides about two years apart. In the way of such
stories, the children are rescued before they are eaten by wild animals,
and they are raised by rural families who live in close proximity to each
other. Over the years, the two—the boy Daphnis and the girl Chloe—fall
in love (Chloe when she sees Daphnis bathing, and Daphnis some time
later after Chloe kisses him). However, they haven’t the slightest idea
about the physical aspect of love—sex is a mystery to both of them, and
neither of them knows anyone willing to explain it to them. An aging
cowherd named Philetas, having accidentally encountered the naked god
of love in his orchard, and remembered his long-ago love for a girl named
Amaryllis as a result, tells the pair that the only cure for their condition
is “kissing and embracing and lying down with naked bodies”.44 The
young lovers take to this activity with regularity and enthusiasm, but find
themselves confused about the “lying down with naked bodies” part, 114 Love and its Critics thinking that “in any case, there must be something in it stronger than
kissing”,45 without knowing what that something might be. In the meantime, a series of misadventures threaten to separate
the pair, often menacing the two lovers through “the forms of sexual
violence to which Chloe—and to a certain extent Daphnis—is subject”.46
Daphnis is kidnapped by Tyrian pirates, and is only rescued by Chloe’s
quick thinking in playing a cowherd’s pipe that induces dozens of cows
to jump from a low cliff into the water near the ship (and some even
onto the ship itself), causing the ship to capsize and drown the heavily-
armored pirates, enabling Daphnis to swim back ashore. 45
“πάντως ἐν αὐτῷ τι κρεῖττόν ἐστι φιλήματος” (ibid., 2.9.2, 70).
46
John J. Winkler. The Constraints of Desire: The Anthropology of Sex and Gender in
Ancient Greece (New York: Routledge, 1990), 103.
47
If the reader is beginning to catch a whiff of a later story like The Princess Bride, he
or she is probably not alone—and yes, it is still probably good advice not to get
involved in a land war in Asia, though your mileage may vary whether or not to go
in against a Sicilian when death is on the line.
48
Stephen Epstein raises the serious, yet profoundly comic question: “What purpose
does the text achieve by bringing its male protagonist into such close connection
with goats?” (“The Education of Daphnis: Goats, Gods, the Birds and the Bees”.
Phoenix, 56: 1–2 [Spring-Summer 2002], 26, https://doi.org/10.2307/1192468). 48
Stephen Epstein raises the serious, yet profoundly comic question: “What purpose
does the text achieve by bringing its male protagonist into such close connection
with goats?” (“The Education of Daphnis: Goats, Gods, the Birds and the Bees”.
Phoenix, 56: 1–2 [Spring-Summer 2002], 26, https://doi.org/10.2307/1192468). 52
“Δάφνις ὧν αὐτὸν ἐπαίδευσε Λυκαίνιον, καὶ τότε Χλόη πρῶτον ἔμαθεν ὅτι τὰ
ἐπὶ τῆς ὕλης γενόμενα ἦν ποιμένων παίγνια” (Longus 4.40.3, 196). 49
Εὑροῦσα δὴ ἡ Λυκαίνιον αἰπολικὴν ἀφθονίαν, οἵαν οὐ προσεδόκησεν, ἤρχετο παιδεύειν
τὸν Δάφνιν τοῦτον τὸν τρόπον. Ἐκέλευσεν αὐτὸν καθίσαι πλησίον αὐτῆς, ὡς εἶχε, καὶ
φιλήματα φιλεῖν οἷα εἰώθει καὶ ὅσα, καὶ φιλοῦντα ἅμα περιβάλλειν καὶ κατακλίνεσθαι
χαμαί. Ὡς δὲ ἐκαθέσθη καὶ ἐφίλησε καὶ κατεκλίνη, μαθοῦσα ἐνεργεῖν δυνάμενον καὶ
σφριγῶντα, ἀπὸ μὲν τῆς ἐπὶ πλευρὰν κατακλίσεως ἀνίστησιν, αὑτὴν δὲ ὑποστορέσασα
ἐντέχνως ἐς τὴν τέως ζητουμένην ὁδὸν ἦγε. Τὸ δὲ ἐντεῦθεν οὐδὲν περιειργάζετο ξένον:
αὐτὴ γὰρ ἡ φύσις λοιπὸν ἐπαίδευσε τὸ πρακτέον.
Longus 3.18.3–4, 126. This episode was expurgated from translations of this text as
recently as the 1950s by academics and publishers determined to protect the moral
decency of their readers II
Love in the Poetry of Late Antiquity: Greek A fellow
shepherd tries to rape Chloe, and she is abducted by Methymnean
raiders seeking revenge on Daphnis. (They blame him for the loss of
their ship, since one of his goats chewed through the line with which
they had moored their vessel, causing it to float away with the tide
while they were on shore). Longus resorts to a deus ex machina here,
having Pan rescue Chloe.47 After a number of misadventures—including an episode in which
Daphnis tries to imitate goats in his absurdly ineffectual claspings with
Chloe48—Daphnis is finally taught how to make use of the “lying down
with naked bodies” advice that has puzzled him for so long: Finding a freedom from envy and a liberality in the goatherd that she had
not expected, Lycaenium began then to teach Daphnis in this manner. She ordered him to sit down next to her, and to give her the customary
kind and number of kisses, and to throw his arms around her as he kissed
her, and lie down upon the ground. Then he sat down, and kissed her,
and lay down with her, learning in action to be able and vigorous while
lying upon his side, and as he raised himself up, she slipped beneath him
skillfully, bringing him into that path he had sought for so long. From 3. Love and its Absences in Late Latin and Greek Poetry 50
“Χλόη δὲ συμπαλαίουσά σοι ταύτην τὴν πάλην καὶ οἰμώξει καὶ κλαύσεται κἀν
αἵματι κείσεται πολλῷ” (ibid. 3.19.2, 126).
51
Hardin, 15, 16. 51
Hardin, 15, 16. Longus 3.18.3–4, 126. This episode was expurgated from translations of this text as
recently as the 1950s by academics and publishers determined to protect the moral
decency of their readers.
ξ 3. Love and its Absences in Late Latin and Greek Poetry 115 that point on, there was no need to take more pains with him; Nature
taught him the rest of what was necessary.49 However, Lycaenion also tells Daphnis that the experience will be
different with the virgin Chloe: “Chloe, if you wrestle with her in this
way, will be injured, and cry aloud while bleeding”,50 advice which
frightens Daphnis and nearly dissuades him from even kissing Chloe. Daphnis here shows a concern similar to that found in the poetry of
the later troubadours, as well as the works of Shakespeare and Milton,
a “mutuality in love, so crucial to the meaning of this story, [which]
sets the Greek romances apart”. Daphnis, “exercising restraint out of
consideration for Chloe, shows a different kind of love”,51 caring for
her as an individual whose feelings and desires are just as important to
Daphnis as his own. In the background of the two young lovers’s misadventures, Chloe’s
parents are trying to arrange a financially advantageous marriage for
her, which leaves Daphnis, a poor goatherd, in desperation. In another
deus ex machina, the nymphs of the fields give Daphnis three thousand
drachmas for him to take to Chloe’s father in order that he might be
the chosen suitor. In a further development—as again, is the way with
such stories—events are set in motion which reveal each of the two
lovers to be of high and noble birth, and they are brought together in a
marriage that brings joy to everyone. Finally, “Daphnis himself taught
Lycaenium’s lessons, and then Chloe learned that what had happened
before in the the woods had been but shepherds’ games”.52 Their love, 116 Love and its Critics now passionately and physically expressed, brings mutuality and desire
together in the fashion of fin’amor. In addition to pastoral comedies like Daphnis and Chloe, which Jean
Hagstrum refers to as “one of the subtlest explorations of dawning
love in literature”,53 Greek poetry of the first millenium also gives us
Musaeus’ version of the legend of Hero and Leander. Musaeus, a late
fifth-or early sixth century poet, transforms the tale of “the nightly
marriage of Hero” and “the swimming of Leander”54 into the tragedy
that will later inspire Renaissance English poets like Christopher
Marlowe and George Chapman (who finishes the version Marlowe left
at his death, and translates Musaeus’ version in 1616). 53
Hagstrum, 134.
54
“γάμον ἔννυχον Ἡροῦς” […] “νηχόμενόν τε Λέανδρον” Musaeus. Hero and
Leander, ed. by Thomas Gelzer (Loeb Classical Library, Cambridge, MA: Harvard
University Press, 1973), ll. 4–5.
55
“Κύπριδος ἦν ἱέρεια” (ibid., l. 31).
56
“πύργον ἀπὸ προγόνων παρὰ γείτονι ναῖε θαλάσσῃ” (ibid., l. 32).
57
“αὐτίκα τεθναίην λεχέων ἐπιβήμενος Ἡροῦς” (ibid., l. 79).
58
“σὺν βλεφάρων δ᾿ ἀκτῖσιν ἀέξετο πυρσὸς Ἐρώτων” (ibid., l. 90).
59
Ibid., ll. 96–98. 56
πύργον ἀπὸ προγόνων παρὰ γείτονι ναῖε θαλάσσῃ (ibid.,
57
“αὐτίκα τεθναίην λεχέων ἐπιβήμενος Ἡροῦς” (ibid., l. 79). 53
Hagstrum, 134.
54
“γάμον ἔννυχον Ἡροῦς” […] “νηχόμενόν τε Λέανδρον” Musaeus. Hero and
Leander, ed. by Thomas Gelzer (Loeb Classical Library, Cambridge, MA: Harvard
University Press, 1973), ll. 4–5. 55
“Κύπριδος ἦν ἱέρεια” (ibid., l. 31). 58
“σὺν βλεφάρων δ᾿ ἀκτῖσιν ἀέξετο πυρσὸς Ἐρώτων” (ibid., l. 90). 60
“ταῦτα δὲ πάντα μάτην ἐφθέγξαο” (ibid., l. 177).
61
Ibid., ll. 177–84.
62
Nicola Nina Dümmler. “Musaeus, Hero and Leander: Between Epic and Novel”.
In Brill’s Companion to Greek and Latin Epyllion and Its Reception, ed. by Manuel
Baumbach and Silvio Bär (Leiden: Brill, 2012), 427. 3. Love and its Absences in Late Latin and Greek Poetry Hero laments Leander’s eloquence, because her father’s control
over her marriage prospects means “these words are entirely spoken
in vain”.60 She then outlines the basic dilemma that we will see
frequently—children (especially daughters) are treated as the property
of their fathers, and cannot love freely where they would: …πῶς γὰρ ἀλήτης
ξεῖνος ἐὼν καὶ ἄπιστος ἐμοὶ φιλότητι μιγείης;
ἀμφαδὸν οὐ δυνάμεσθα γάμοις ὁσίοισι πελάσσαι·
οὐ γὰρ ἐμοῖς τοκέεσσιν ἐπεύαδεν· ἢν δ᾿ ἐθελήσῃς
ὡς ξεῖνος πολύφοιτος ἐμὴν εἰς πατρίδα μίμνειν,
οὐ δύνασαι σκοτόεσσαν ὑποκλέπτειν Ἀφροδίτην·
γλῶσσα γὰρ ἀνθρώπων φιλοκέρτομος, ἐν δὲ σιωπῇ
ἔργον ὅ περ τελέει τις, ἐνὶ τριόδοισιν ἀκούει.61 …πῶς γὰρ ἀλήτης
ξεῖνος ἐὼν καὶ ἄπιστος ἐμοὶ φιλότητι μιγείης;
ἀμφαδὸν οὐ δυνάμεσθα γάμοις ὁσίοισι πελάσσαι·
οὐ γὰρ ἐμοῖς τοκέεσσιν ἐπεύαδεν· ἢν δ᾿ ἐθελήσῃς
ὡς ξεῖνος πολύφοιτος ἐμὴν εἰς πατρίδα μίμνειν,
οὐ δύνασαι σκοτόεσσαν ὑποκλέπτειν Ἀφροδίτην·
γλῶσσα γὰρ ἀνθρώπων φιλοκέρτομος, ἐν δὲ σιωπῇ
ἔργον ὅ περ τελέει τις, ἐνὶ τριόδοισιν ἀκούει.61 …πῶς γὰρ ἀλήτης
ξεῖνος ἐὼν καὶ ἄπιστος ἐμοὶ φιλότητι μιγείης;
ἀμφαδὸν οὐ δυνάμεσθα γάμοις ὁσίοισι πελάσσαι·
οὐ γὰρ ἐμοῖς τοκέεσσιν ἐπεύαδεν· ἢν δ᾿ ἐθελήσῃς
ὡς ξεῖνος πολύφοιτος ἐμὴν εἰς πατρίδα μίμνειν,
οὐ δύνασαι σκοτόεσσαν ὑποκλέπτειν Ἀφροδίτην·
γλῶσσα γὰρ ἀνθρώπων φιλοκέρτομος, ἐν δὲ σιωπῇ
ἔργον ὅ περ τελέει τις, ἐνὶ τριόδοισιν ἀκούει.61 …how, may a wanderer,
a stranger, not to be trusted, unite with me in love? We are not able to draw near in holy marriage,
for it is not my father’s will and pleasure; if you wish
as a far-roaming stranger to stay in my father’s land,
you will not be able to shroud Aphrodite in night,
for the tongues of men are fond of jeering, and the silent
deeds of a man are soon heard of in the marketplace. …how, may a wanderer,
a stranger, not to be trusted, unite with me in love? We are not able to draw near in holy marriage,
for it is not my father’s will and pleasure; if you wish
as a far-roaming stranger to stay in my father’s land,
you will not be able to shroud Aphrodite in night,
for the tongues of men are fond of jeering, and the silent
deeds of a man are soon heard of in the marketplace. Despite the fact that Hero is a “priestess of Aphrodite” she is not “the
willingly chaste priestess who seeks the isolation of her tower and
wants to appease the gods of love. 3. Love and its Absences in Late Latin and Greek Poetry Musaeus’ Hero is
a “priestess of Aphrodite”55 and is locked away each night by her father
“in the Tower of her ancestors, dwelling as a neighbor to the sea”,56
ostensibly to serve the goddess, but really to keep her out of the reach
of young men. Even so, Leander knows he must have her, “at once let
me die, but let me spend my strength in Hero’s bed”,57 because he is on
fire after looking into her eyes: “by means of her eyes’ light, his love rose
high like flames”.58 Leander struggles with this new-found passion and
tries to master it, even briefly thinking it shameful that he has been so
overpowered by love, before he determines to venture whatever it takes
to have Hero: εἷλε δέ μιν τότε θάμβος, ἀναιδείη, τρόμος, αἰδώς,
ἔτρεμε μὲν κραδίην, αἰδὼς δέ μιν εἶχεν ἁλῶναι,
θάμβεε δ᾿ εἶδος ἄριστον, ἔρως δ᾿ ἀπενόσφισεν αἰδῶ.59 seized by astonishment, impudence, trepidation, shame,
he trembled at heart, shame possessed him to be so conquered,
but in amazement at her excellent form, love put shame asunder. seized by astonishment, impudence, trepidation, shame,
he trembled at heart, shame possessed him to be so conquered,
but in amazement at her excellent form, love put shame asunder. 3. Love and its Absences in Late Latin and Greek Poetry 117 After Leander ventures, and wins Hero’s love, there is still a problem:
her father. 61
Ibid., ll. 177–84. 63
Musaeus, ll. 203–05, 210–12.
Ib d ll 64
Ibid., ll. 260–63. 65
Ibid., ll. 285–87.
66
Ibid., ll. 327–30.
67
Ibid., ll. 341–43. 3. Love and its Absences in Late Latin and Greek Poetry According to Hero, it is because of
her parents’ hated decision […] that she lives in the tower outside the
city, with only wind and sea as her neighbours”.62 The arrangement the lovers make, as anyone familiar with the legend
has already anticipated, is a dangerous one, as Leander plans to come to 118 Love and its Critics her at night by swimming across the Hellespont. All he asks is that Hero
leave the light on: her at night by swimming across the Hellespont. All he asks is that Hero
leave the light on: Παρθένε, σὸν δι᾿ ἔρωτα καὶ ἄγριον οἶδμα περίήσω,
εἰ πυρὶ παφλάζοιτο καὶ ἄπλοον ἔσσεται ὕδωρ. οὐ τρομέω βαρὺ χεῖμα τεὴν μετανεύμενος εὐνήν
[…]
μοῦνον ἐμοὶ ἕνα λύχνον ἀπ᾿ ἠλιβάτου σεὸ πύργου
ἐκ περάτης ἀνάφαινε κατὰ κνέφας, ὄφρα νοήσας
ἔσσομαι ὁλκὰς Ἔρωτος ἔχων σέθεν ἀστέρα λύχνον.63 Maiden, for your love, I will cross the wild waves,
though fire boil them, and rain push back the ships,
I fear no heavy storm, in pursuit of your bed. […]
Only light me a lamp from your high tower
to shine above the darkness that I may see it;
I will be love’s sailing ship, guided by your light. At first, it works. Their interval of passion and mutual desire begins as
Hero leads Leander to her tower: καί μιν ἑὸν ποτὶ πύργον ἀνήγαγεν· ἐκ δὲ θυράων
νυμφίον ἀσθμαίνοντα περιπτύξασα σιωπῇ
ἀφροκόμους ῥαθάμιγγας ἔτι στάζοντα θαλάσσης
ἤγαγε νυμφοκόμοιο μυχοὺς ἔπι παρθενεῶνος.64 and she led him to her high tower, where at the door
her panting bridegroom she silently embraced,
still foam-drenched and dripping from the sea
she led him deep within her bridal chamber. And for some time to come, Hero and Leander manage both to keep
their love and their secret: 119 3. Love and its Absences in Late Latin and Greek Poetry Ἡρὼ δ᾿ ἑλκεσίπεπλος ἑοὺς λήθουσα τοκῆας
παρθένος ἠματίη, νυχίη γυνή. ἀμφότεροι δὲ
πολλάκις ἠρήσαντο κατελθέμεν εἰς δύσιν Ἠῶ.65 Hero of the long-trained robes, keeping secret from her father,
maiden was day, but wife by night, and both
often prayed for the setting of the sun. Many nights that summer they enjoy each other’s love, but as winter
comes, the swim across the Hellespont grows more difficult, until one
night, the waters are too rough to be crossed: πολλὴ δ᾿ αὐτόματος χύσις ὕδατος ἔρρεε λαιμῷ,
καὶ ποτὸν ἀχρήιστον ἀμαιμακέτου πίεν ἅλμης. 68
Pamela Royston Macfie. “Lucan, Marlowe, and the Poetics of Violence”. In
Renaissance Papers 2008, ed. by Christopher Cobb and M. Thomas Hester (Rochester:
Camden House, 2009), 49.
69
Audrey L. Meaney. “The Ides of the Cotton Gnomic Poem”. Medium Ævum, 48: 1
(1979), 36, https://doi.org/10.2307/43628412 69
Audrey L. Meaney. “The Ides of the Cotton Gnomic Poem”. Medium Ævum, 48: 1
(1979), 36, https://doi.org/10.2307/43628412 68
Pamela Royston Macfie. “Lucan, Marlowe, and the Poetics of Violence”. In
Renaissance Papers 2008, ed. by Christopher Cobb and M. Thomas Hester (Rochester:
Camden House, 2009), 49. 1
“[f]ür die Provenzalen und die Dichter des Neuen Stils war die hohe Minne das
einzige große Thema” (Erich Auerbach. Mimesis: Dargestellte Wirklichkeit in der
abendländischen Literatur. 2nd ed. [Bern: Francke, 1959], 180). 4. The Troubadours and Fin’amor:
Love, Choice, and the Individual In Erich Auerbach’s view, “for the Provençal poets and the [Italian]
poets of the new style [dolce stil novo], ‘high love’ was the only major
theme”.1 Speaking of die hohe Minne (what French scholars call amour
courtois, and English scholars “courtly love”), Auerbach gives voice to
a critical consensus that over the last century-and-a half has dominated
our understanding of the origins and development of western love
poetry. Both the consensus, and Auerbach, are wrong. 3. Love and its Absences in Late Latin and Greek Poetry καὶ δὴ λύχνον ἄπιστον ἀπέσβεσε πικρὸς ἀήτης
καὶ ψυχὴν καὶ ἔρωτα πολυτλήτοιο Λεάνδρου.66 Great waves of water poured themselves into his throat,
and he drank deep of the worthless, irresistible brine,
and then the traitorous lamp was blown out by a sharp wind,
and with it died the breath and love of long-suffering Leander. When Leander does not come that night, Hero fears the worst, and upon
seeing his body washed up on the shore, Hero strips off her robe and
joins him: ῥοιζηδὸν προκάρηνος ἀπ᾿ ἠλιβάτου πέσε πύργου. κὰδ δ᾿ Ἡρὼ1 τέθνηκε σὺν ὀλλυμένῳ παρακοίτῃ,
ἀλλήλων δ᾿ ἀπόναντο καὶ ἐν πυμάτῳ περ ὀλέθρῳ.67 with a rushing sound, she fell head-first from her high tower. Hero died next to her dead husband, and at last in death, each had joy in the other. 120 Love and its Critics As we will also see in poetry from the troubadours to Shakespeare and
Milton, Musaeus emphasizes the “theme of love’s mutuality”, in which
lovers are willing “to take deadly risks in a universe that is careless of
their suffering”.68 They will risk all for love, whether the physical danger
of the Hellespont, the death-threats of a god, or the social, legal, and
financial dangers of defying a system of arranged marriages that leaves
no room for any passion (except perhaps for greed), so dedicated is that
system to the profitable gains to be had through marriage and children. Slowly but surely, however, it is that very pragmatism, combined with
the increasing influence of the church in Europe, that brings the classical
and early-medieval eras of love poetry to their conclusion. Love and longing are vitally present in the poetry we have so
far encountered, despite the best efforts of societal law-givers and
the frequent attempts of the Akibas and Origens to erase, rewrite
and reinterpret this poetry. There is much more such longing in the
eleventh-and twelfth-century poetry of the troubadours. As we see
love thrive, proving that “powerful passion will not be constrained
by the normal bonds of society”,69 so we will also see the attempts to
channel, reformulate, and control it grow stronger, more systematic,
and infinitely more lethal. 3
Even so recent an analysis as that of William M. Reddy relies on this term. Reddy
defines the troubadour conception of fin’amor in terms of “an opposition between
love and desire” (The Making of Romantic Love: Longing and Sexuality in Europe, South
Asia, and Japan, 900–1200 CE [Chicago: University of Chicago Press, 2012], 2), even
aligning the troubadour concept with what he calls the “‘courtly love’ phenomenon
[that] is well known to medievalists” (2). Reddy, does, however, note that the
literature of so-called “courtly love”, can “represent a kind of resistance”, and an
“escaping [from the mid twelfth-century Church’s] blanket condemnation of all
sexual partnerships as sinful and polluting” (26). 2
Appearing as amour courtois in his article “Études sur les romans de la Table Ronde”
in Romania, 10: 40 (October 1881), 465–96, and in “Études sur les romans de la Table
Ronde. Lancelot du Lac, I. Le Lanzelet d’Ulrich de Zatzikhoven; Lancelot du Lac, II.
Le Conte de la charrette”, Romania, 12: 48 (October 1883), 459–534. l’amour est un art, une science, une vertu, qui a ses règles tout comme la chevalerie ou la
courtoisie […] Dans aucun ouvrage français, autant qu’il me semble, cet amour courtois
n’apparaît avant le Chevalier de la Charrette. L’amour de Tristran et d’Iseut est autre chose: c’est
une passion simple, ardente, naturelle, qui ne connaît pas les subtilités et les raffinements de
celui de Lancelot et de Guenièvre. Dans les poèmes de Benoit de Sainte-More, nous trouvons la
galanterie, mais non cet amour exalté et presque mystique, sans cesser pourtant d’être sensual. ,
,
(
),
3
Even so recent an analysis as that of William M. Reddy relies on this term. Reddy
defines the troubadour conception of fin’amor in terms of “an opposition between
love and desire” (The Making of Romantic Love: Longing and Sexuality in Europe, South
Asia, and Japan, 900–1200 CE [Chicago: University of Chicago Press, 2012], 2), even
aligning the troubadour concept with what he calls the “‘courtly love’ phenomenon
[that] is well known to medievalists” (2). Reddy, does, however, note that the
literature of so-called “courtly love”, can “represent a kind of resistance”, and an
“escaping [from the mid twelfth-century Church’s] blanket condemnation of all
sexual partnerships as sinful and polluting” (26).
4
l’amour est un art, une science, une vertu, qui a ses règles tout comme la chevalerie ou la
courtoisie […] Dans aucun ouvrage français, autant qu’il me semble, cet amour courtois
n’apparaît avant le Chevalier de la Charrette. L’amour de Tristran et d’Iseut est autre chose: c’est
une passion simple, ardente, naturelle, qui ne connaît pas les subtilités et les raffinements de
celui de Lancelot et de Guenièvre. Dans les poèmes de Benoit de Sainte-More, nous trouvons la
galanterie, mais non cet amour exalté et presque mystique, sans cesser pourtant d’être sensual. I
Why “Courtly Love” Is Not Love Start with adultery. Start, at least, with the idea of adultery. Breaking
the rules, doing something you are not supposed to do. Doing someone
you are not supposed to do. This is the key idea that allows us to
understand a literary tradition that stretches from the troubadours
through Petrarch to Shakespeare, Milton, and beyond. Illicit desire—
whether celebrated in the passionate poems of medieval Occitania, or
sublimated in the poetic tradition of idealized females worshiped by
abject males in Dante, Petrarch and Sidney—is central to the energy
of Shakespeare and the poetic tradition that follows in his wake. Love, © 2017 Michael Bryson and Arpi Movsesian, CC BY 4.0 https://doi.org/10.11647/OBP.0117.04 122 Love and its Critics will, desire, and the willingness (even determination) to risk everything,
up to and including death—these are the passions that draw readers
and audiences back again and again. Centuries of transformation have left many of us ill-equipped to
recognize the frankness and passion of troubadour verse. Some of this
change was wrought merely by time and changing customs, but some
of it was brought about by the best efforts of historians and literary
critics to understand and interpret the past through the expectations,
reverences, and distastes of later eras. Perversely, we often approach
these poems through the lens of late nineteenth-century notions of
propriety and decency that are alien to our own time, and to the time
of the troubadours. The dangerous, even life-risking, desires expressed
in these poems have been carefully tamed, hidden behind the ill-fitting
phrase “courtly love”. This term, invented by Gaston Paris in 1881,2 has
become commonplace in critical analyses of troubadour poetry.3 Paris
argues that love is an art, a science, a virtue, which has its rules as chivalry and
courtesy […]. In no French work, as it seems to me, does this courtly
love appear before the Knight of the Cart. The love of Tristran and Isolde
is a different thing: it is a simple passion, ardent, natural, which does
not know the subtleties and refinements of that between Lancelot and
Guinevere. In the poems of Benoit de Sainte-Maure, we find gallantry,
but not this exalted, almost mystical, yet still sensual, love.4
4. Gaston Paris, “Études sur les romans de la Table Ronde” (1883), 519, http://www.
persee.fr/ doc/roma_0035–8029_1883_num_12_48_6277
5
Moshe Lazar. “Cupid, the Lady, and the Poet: Modes of Love at Eleanor of
Aquitaine’s Court”. In Eleanor of Aquitaine: Patron and Politician, ed. by William W.
Kibler (Austin: University of Texas Press, 1976), 42.
6
A common shorthand term for The Knight of the Cart.
7
Lazar, 43.
8
Ibid.
9
“Amor est passio quedam innata procedens ex vision et immoderate cogitatione
formae alterius sexus, ob quam aliquis super Omnia cupit alterius potiri amplexibus
et Omnia de ultriusque voluntate in ipsius amplexu amoris praecepta compleri”
(Andreas Capellanus. De amore libri tres: Von der Liebe. Drei Bücher [Berlin and
Boston: De Gruyter, 2006], 6). “Amor est passio quedam innata procedens ex vision et immoderate cogitatione
formae alterius sexus, ob quam aliquis super Omnia cupit alterius potiri amplexibus
et Omnia de ultriusque voluntate in ipsius amplexu amoris praecepta compleri”
(Andreas Capellanus. De amore libri tres: Von der Liebe. Drei Bücher [Berlin and
Boston: De Gruyter, 2006], 6). Gaston Paris, “Études sur les romans de la Table Ronde” (1883), 519, http://www.
persee.fr/ doc/roma_0035–8029_1883_num_12_48_6277
5
Moshe Lazar. “Cupid, the Lady, and the Poet: Modes of Love at Eleanor of
Aquitaine’s Court”. In Eleanor of Aquitaine: Patron and Politician, ed. by William W.
Kibler (Austin: University of Texas Press, 1976), 42.
6
A common shorthand term for The Knight of the Cart.
7
Lazar, 43. 10
Andreas Capellanus. The Art of Courtly Love. Trans. by John Jay Perry (New York: W.
W. Norton & Co., 1941), 28.
11
Ibid. The original is as follows: “Quod amor sit passio facile est videre. Nam
antequam amor sit ex utraque parte libratus, nulla est angustia maior” (Capellanus,
De amore libri tres: Von der Liebe, 6).
12
“Et purus quidem amor est, qui omnimoda directonis affection duorum amantium
corda coniungit. Hic autem in mentis contemplation cordisque consistit affect;
procedit autem usque ad oris osculum lacertique amplexum et verecundum
amantis nudae contactum” (Andreas Capellanus. De amore libri tres: Von der Liebe, 282).
13
“extremo praetermisso solatio” (ibid.). I
Why “Courtly Love” Is Not Love The Troubadours and Fin’amor: Love, Choice, and the Individual 123 Tellingly, Paris bases his notion of amour courtois on the only tale by
the northern trouvére Chrétien de Troyes that differs from his normal
pattern: the Knight of the Cart, a story about the adulterous relationship
between Lancelot and Guinevere. Ordinarily, Chrétien opposes the
“new mode of love and the central theme of the Provençal Troubadours
poetry”, by “refusing the adulterous relationship […] and the idolatrous
passion which binds the lovers”.5 This refusal is “exemplified in all of
Chrétien’s romances except Lancelot”,6 and in all of his other work,
Chrétien “proclaims a mode of love which, dominated by the rules of
reason and the code of courtliness, should lead to marriage and exist
only inside of marriage”.7 This bears repeating, for there is something
odd and contradictory at work in the way Paris comes to define his most
famous term: the critical definition of “courtly love” as a chaste and
rule-bound mode of relationship is based on the only one of Chrétien’s
romances that breaks those rules, illustrating a love that “fell outside
Christian teaching and was the exact opposite of the traditional view on
marriage”,8 while at the same time, the critic comes to his definition by
underplaying these transgressive features of the poem. The effect of Paris’ misbegotten definition can be seen by looking at
Andreas Capellanus’ twelfth-century treatise, De amore (Of Love), which
is now (mis)leadingly translated as The Art of Courtly Love. Capellanus’
text begins by addressing itself to a young man named Walter, and by
defining what love is: Love is some kind of an inborn passion that proceeds from looking
and thinking immoderately on the form of the opposite sex, a passion
that makes one wish more than anything to embrace the other, and by
mutual desire accomplish all of love’s precepts in the other’s embrace.9 124 Love and its Critics Paris’ idea of amour courtois has affected the way Capellanus’ text
is understood by rewriting it after the fact. The widely-used English
translation by John Jay Parry reads as a courtly love treatise that
often incorporates the main characteristic of this ethos—suffering. By translating the text in a way that supports this pre-existing
interpretation, Parry has created a kind of circular argument. The word
passio is translated as “suffering”, although it can also be translated as
“passion”. I
Why “Courtly Love” Is Not Love If passio stood by itself, then either translation might suffice;
however, an “inborn passion” makes more sense with what follows,
even as Parry renders it: “[love] causes each one to wish above all things
the embraces of the other”.10 In the following lines, Parry continues his
translation in the same circular manner: “That love is suffering is easy
to see, for before the love becomes equally balanced on both sides there
is no torment greater”.11 The word “torment” is meant to stand in for
the Latin angustia, which means narrowness, want, or perplexity. By far
the better choice for translation is want (in the sense of desire and lack). The lover wants, more than anything else in the world, to gain the object
of his desire. Capellanus makes this clear in a later protion of his work
when he refers to the passion he is discussing as pure love: Pure love is that which joins and unites the hearts of the two lovers with
the affection of love. This, however, consists in the contemplation of the
mind and the affection of the heart; it proceeds as far as a kiss, the arms’
embrace, and modestly touching the nude lover.12 The “pure love” spoken of is both of the body and of the mind, only
“the final consolation is omitted”,13 though that, too, is allowed in
what Capellanus calls amor mixtus, mixed, or compounded love. The
flesh in De amore is not marginalized as it is in the later spiritualized
poetry of the Dantean and Petrarchan traditions. The man in De amore
4. The Troubadours and Fin’amor: Love, Choice, and the Individual 125 prays to God, not for wisdom, not for piety, but for the opportunity to
see his lover again. The manner in which he makes this supplication
resembles the open passions of troubadour poetry: “For not an hour
of the day or night could pass that I did not beg God to allow me the
bounty of seeing you close to me in the flesh”.14 Amor purus is both
emotional and physical. It is not the stylized “courtly love” of the later
scholarly tradition. Perhaps C. S. Lewis did the most to popularize this term, as he traced
“courtly love” in twelfth-century poetry from the southern troubadours
to the northern trouvére Chrétien de Troyes. 17
The idea that a lover’s admiration for a beloved serves the lover as the first step on
a ladder, in which each successive rung represents an increasingly refined notion of
love, until by the top, the lover has left earthly love behind in favor of divine love.
18
Ibid., 4. 14
“Non enim poterat diei vel noctis hora pertransire continua, qua Deum non
exorarem attentius, ut corporaliter vos ex propinquo videndi mihi concederet
largitatem” (ibid., 192). 15
C. S. Lewis. The Allegory of Love: A Study in Medieval Tradition (London: Oxford
University Press, 1936), 2.
16
Ibid 14 14
“Non enim poterat diei vel noctis hora pertransire continua, qua Deum non
exorarem attentius, ut corporaliter vos ex propinquo videndi mihi concederet
largitatem” (ibid., 192).
15
C. S. Lewis. The Allegory of Love: A Study in Medieval Tradition (London: Oxford
University Press, 1936), 2.
16
Ibid., 14.
17
The idea that a lover’s admiration for a beloved serves the lover as the first step on
a ladder, in which each successive rung represents an increasingly refined notion of
love, until by the top, the lover has left earthly love behind in favor of divine love.
18
Ibid., 4. 14
Non enim poterat diei vel noctis hora pertransire continua, qua Deum non
exorarem attentius, ut corporaliter vos ex propinquo videndi mihi concederet
largitatem” (ibid., 192).
15
C. S. Lewis. The Allegory of Love: A Study in Medieval Tradition (London: Oxford
University Press, 1936), 2.
16
Ibid., 14.
17
The idea that a lover’s admiration for a beloved serves the lover as the first step on
l dd
i
hi h
h
i
i
i
l
fi
d
i
f largitatem” (ibid., 192).
15
C. S. Lewis. The Allegory of Love: A Study in Medieval Tradition (London: Oxford
University Press, 1936), 2.
16
Ibid., 14.
17
Th id
th t
l
’
d
i
ti
f
b l
d
th l
th fi
t t a ladder, in which each successive rung represents an increasingly refined notion of
love, until by the top, the lover has left earthly love behind in favor of divine love.
18
Ibid., 4. 19
Ibid.
20
Ibid., 19. The name translates as Ovid the Peerless [or Excellent] Doctor.
21
Ibid., 37.
22
Ibid., 28. I
Why “Courtly Love” Is Not Love In so doing, Lewis
identifies four marks—Humility, Courtesy, Adultery, and the Religion
of Love15—that he claims characterize the “new feeling” that arose in
the poets and the time and place in which they lived. However, though
Lewis acknowledges that “courtly love necessitates adultery”, he also
insists that “adultery hardly necessitates courtly love”.16 This revealing
turn of phrase captures the ambiguity, the division in feelings between
excitement and disapproval that characterizes the long poetic tradition
that springs from troubadour roots. Poems of desire that would be
fulfilled, no matter the cost—if only the opportunity manifested itself—
gave rise to later poems of decorous and often tormented sublimations
of desire, using such Neoplatonic metaphors as the ladder of love.17
Desire became worship, as flesh became once again an object of shame. Lewis’s ambivalent refusal to credit fully the significance of the
troubadours and their poetry is exceedingly odd, given that he describes
their work as “momentous” and “revolutionary” and “the background
of European literature for eight hundred years”.18 For Lewis, “French
poets, in the eleventh century, discovered or invented, or were the first
to express, that romantic species of passion which English poets were 126 Love and its Critics still writing about in the nineteenth”.19 But his use of French rather than
Provençal or Occitan is telling—Lewis spends as little time with the
troubadours as possible, referencing none of their poetry specifically,
preferring to spend his time with Ovid, the anonymous author of the
twelfth-century Concilium Romarici Montis (a mock-council on love
which references the classical poet as Ovidii Doctoris egregii20), Chrétien
de Troyes, and Andreas Capellanus. As Lewis reads them, each of these
sources are fixated on rules, codes, official judgments, and elaborate
enactments of dominance and submission that parody the rituals of
Catholicism. 23
Chrétien de Troyes. Le Chevalier de la Charrette, ed. by Alfred Foulet and Karl D. Uitti
(Paris: Classiques Garnier, 1989), ll. 352–68.
24
Ibid., ll. 4501–07. I
Why “Courtly Love” Is Not Love In his reading of Chrétien’s Lancelot, for example, the
issue is not “love [as] a noble form of experience [and] a theory of
adultery”,21 but obedience given too slowly: “The Queen has heard of
his [Lancelot’s] momentary hesitation in stepping on to the tumbril, and
this lukewarmness in the service of love has been held by her sufficient
to annihilate all the merit of his subsequent labours and humiliations”.22 Lancelot is momentarily ashamed to ride a cart whose driver
promises to take him to the kidnapped Queen Guenivere, because the
cart is used to carry prisoners, and any knight seen on such a transport
will be shamed, and his reputation for honor destroyed. But though he
hesitates, he climbs aboard, and willingly suffers the resulting shame
(described in several following scenes), in order to be led to the Queen: Et li chevaliers dit au nain:
«Nains, fet il, por Deu, car me di
Se tu as veü par ici
Passer ma dame la reïne». Li nains cuiverz de pute orine
Ne l’an vost noveles conter,
Einz li dist: «Se tu viax monter
Sor la charrete que je main,
Savoir porras jusqu’a demain
Que la reïne est devenue». Tantost a sa voie tenue, Et li chevaliers dit au nain:
«Nains, fet il, por Deu, car me di
Se tu as veü par ici
Passer ma dame la reïne». Li nains cuiverz de pute orine
Ne l’an vost noveles conter,
Einz li dist: «Se tu viax monter
Sor la charrete que je main,
Savoir porras jusqu’a demain
Que la reïne est devenue». Tantost a sa voie tenue, 127
4. The Troubadours and Fin’amor: Love, Choice, and the Individual Qu’il ne l’atant ne pas ne ore. Tant solemant deus pas demore
Li chevaliers que il n’i monte. Mar le fist et mar en ot honte
Que maintenant sus ne sailli,
Qu’il s’an tendra por mal bailli!23 And the Knight told the dwarf:
Dwarf, for God’s sake, tell me right away
If you have seen here
Pass by my lady the queen. The perfidious low-born dwarf
Would not tell him the news,
But merely said: If you want to ride
On the cart that I drive,
By tomorrow you’ll be able to know
What happened to the queen. With that, he maintained his way forward
Without waiting for the other for a moment. 25
Ibid., ll. 4687–99. I
Why “Courtly Love” Is Not Love For only the time of two steps
The Knight hesitated to get in. What a pity he hesitated, ashamed to go,
And he failed to jump without delay,
For this will cause him great suffering! And the Knight told the dwarf:
Dwarf, for God’s sake, tell me right away
If you have seen here
Pass by my lady the queen. The perfidious low-born dwarf
Would not tell him the news,
But merely said: If you want to ride
On the cart that I drive,
By tomorrow you’ll be able to know
What happened to the queen. With that, he maintained his way forward
Without waiting for the other for a moment. For only the time of two steps
The Knight hesitated to get in. What a pity he hesitated, ashamed to go,
And he failed to jump without delay,
For this will cause him great suffering! The momentary delay earns him the displeasure of the Queen, who
berates him for failing to immediately obey Love’s promptings: Et la reïne li reconte:
«Comant? Don n’eüstes vos honte
De la charrete et si dotastes? Molt a grant enviz i montastes
Quant vos demorastes deus pas. Por ce, voir, ne vos vos je pas
Ne aresnier ne esgarder.24 Et la reïne li reconte:
«Comant? Don n’eüstes vos honte
De la charrete et si dotastes? Molt a grant enviz i montastes
Quant vos demorastes deus pas. Por ce, voir, ne vos vos je pas
Ne aresnier ne esgarder.24 128 Love and its Critics And the Queen replied:
What? Were you not ashamed
Of the cart and its lowly endowments? With much hesitation you mounted,
Since you delayed two steps. For this, I did not want to see you,
Nor speak to you, nor look at you. And though Chrétien eventually brings the knight and the queen
together physically, he remains somewhat coy (though not as purely
“courtly” as Gaston Paris might suggest): Or a Lanceloz quanqu’il vialt
Qant la reïne an gré requialt
Sa conpaignie et son solaz,
Qant il la tient antre ses braz
Et ele lui antre les suens. 28
“Bernart de Ventadorn provides one context in which to read the Lancelot—and
with it, modern discussions of courtly love—since he and Chrétien appear to
have known one another: they exchanged lyric poems in which they debate the
passionate versus the rational aspects of love” (Sarah Kay. “Courts, Clerks, and
Courtly Love”. In The Cambridge Companion to Medieval Romance, ed. by Roberta L.
Krueger [Cambridge: Cambridge University Press, 2000], 86. I
Why “Courtly Love” Is Not Love Tant li est ses jeus dolz et buens
Et del beisier et del santir
Que il lor avint sanz mantir
Une joie et une mervoille
Tel c’onques encore sa paroille
Ne fu oïe ne seüe;
Mes toz jorz iert par moi teüe,
Qu’an conte ne doit estre dite.25 Lancelot now has everything he wants,
Because the Queen accepts with joy
His company and solace,
Since he holds her in his arms
And she holds him between hers. Their pleasure is so sweet and good,
And the kisses and the caresses,
What happened to them, without lying,
Was a joy and a marvel
As has never before been spoken
Nor heard of, nor known;
4. The Troubadours and Fin’amor: Love, Choice, and the Individual 129 26
Matilda Tomaryn Bruckner. “‘Redefining the Center’ Verse and Prose Charrette”.
In A Companion to the Lancelot-Grail Cycle, ed. by Carol Dover (Cambridge, UK:
Brewer, 2003), 95.
27
C S L
i
1 27
C. S. Lewis, 1. But still, I maintain the most perfect silence
About what not to say in a story. Despite this scene, however, there remains throughout the poem an
ever-present sense that the issue is one of knightly obedience rather
than human passion, that the knight and the queen of the tale are less
individual than archetypal, less fully human than artfully allegorical. As Matilda Tomaryn Bruckner notes, the figure of Lancelot in Chrétien
and the later prose romancers serves primarily as an object lesson in the
relative inferiority and impurity of human desire, when compared to the
purity of a love directed toward the heavens: “Across the large canvas
of the Lancelot-Grail Cycle, the Cart episode remains at the center of
Lancelot’s story, even as it marks an important shift in Lancelot as hero,
still the best of Arthurian chivalry, but not ‘the good knight’ who will
achieve the Grail”.26 Despite the note of desire in their story, Chrétien’s knight and the
queen he “serves” are ultimately, as Lewis highlights, more allegorical
than human—high examples of what Lewis calls the “allegorical
love poetry of the Middle Ages”27 He is correct to call it so, but he is
in a hurry to move past the troubadours for such authors as Chrétien
precisely because the latter is writing allegory and the former are not. There is nothing allegorical about the passionate poems of Bernart
de Ventadorn,28 Guilhem IX, or the Comtessa de Dia, nor is there an
emphasis on rules, ceremonies, mock judgments in high-church style,
or demands for obedience—whether instantly or otherwise delivered. What Lewis finds discomfiting in the troubadour poetry is precisely
that element of adultery that he repeatedly mentions, but consistently
refuses to illustrate with quotation. He is much happier to tell us the 130 Love and its Critics opinions of Peter Lombard, Albertus Magnus, and Thomas Aquinas on
love and passion29 than he is to give the Occitan poets their voice. Of course, Lewis is not the only figure at whose feet can be laid the
blame for the oddly misbegotten notion of “courtly love”, a notion all
too often applied to the troubadours without actually being derived
from their poetry or from an analysis of their poetry. This latter trend
can also be seen in twentieth-century French psychoanalysis, in Jacques
Lacan’s use of the troubadours to develop his own ideas about desire. The effect of Gaston Paris’s nineteenth-century recasting of fin’amor
as amour courtois is evident in Lacan’s work. 31
Le premier des troubadours est un nommé Guillaume de Poitiers, septième comte de Poitiers,
neuvième duc d’Aquitaine, qui paraît avoir été, avant qu’il se consacrât à ses activités poétiques
inaugurales dans la poésie courtoise, un fort redoutable bandit, du type de ce que, mon Dieu,
tout grand seigneur qui se respectait pouvait être à cette époque. En maintes circonstances
historiques que je vous passe, nous le voyons se comporter selon les normes du rançonnage le
plus inique. Voilà les services qu’on pouvait attendre de lui. Puis, à partir d’un certain moment,
il devient poète de cet amour singulier.
Ibid., 177. 30
“un exercice poétique, une façon de jouer avec un certain nombre de thèmes de
convention idealisants, qui ne pouvaient avoir aucun repondant concret reel” (Le
Seminiare de Jacques Lacan. Livre VII. L’Éthique de la Psychanalyse [1959–60] [Paris:
Seuil, 1986], 177–78). 29
C. S. Lewis, 15–16. 32
Lacan is engaged in a project that is less exegetic (reading out of) than it is eisegetic
(reading on to) where his engagement with troubadour poetry is concerned. For
Lacan “[t]he arbitrary Lady, who is coterminous with privation and inaccessibility
[…] represents both negation and signification and […] is not just a symbolic
function, but a representaton of the rules and limits of the Symbolic” (Nancy
Frelick. “Lacan, Courtly Love and Anamorphosis”. In The Court Reconvenes: Courtly
Literature Across the Disciplines: Selected Papers from the Ninth Triennial Congress of the
International Courtly Literature Society, University of British Columbia, 25–31 July
1998 [Cambridge, UK: Brewer, 2003], 110). Rather than using his psychoanalytical
categories to shed light on the poetry, Lacan is using the poetry to shed light on
his categories. He is certainly not alone in approaching troubadour poetry (or any
other poetry) in this way. 33
David F. Hult suggests that Paris’ invention of the term amour courtois had much less
to do with analysis of poetry than it did with “a personal and professional dilemma
in Paris’ career”, arguing that the term’s curious appeal to later generations can
be explained by the “suggestions of a continuity between […] academic life, its
founding disjunction between pleasure and science, and the ideal scheme of an
eroticism grounded in rules and progressive mastery” (David F. Hult. “Gaston Paris
and the Invention of Courtly Love”. In Medievalism and the Modernist Temper, ed. by
R. Howard Bloch and Stephen G. Nichols [Baltimore: Johns Hopkins University
Press, 1996], 216). In other words, Hult implies that “courtly love” is a notion only
an academic could love. But still, I maintain the most perfect silence
About what not to say in a story. Consistently using the
term amour courtois in his own analysis, Lacan dismisses the work of
the troubadours as anything other than “a poetic exercise, a fashion of
playing with a certain number of idealizing and conventional themes,
which could have no actual concrete reality”.30 What intrigues him
is what he regards as a contradiction between the “idealizing and
conventional themes” and the obviously non-idealizing behavior of a
poet like Guilhem IX: The first of the troubadours is named Guilhem IX, seventh Earl of Poitiers,
ninth Duke of Aquitaine, who appears to have been, before he devoted
his inaugural poetic activities to courtly poetry, a most redoubtable
bandit, the type that, my God, all nobleman could be expected to be at
this time. In many historical circumstances that I will not pass on to you,
we see him behave according to the standards of the most iniquitous
shakedowns. These are the services that could be expected of him. Then
at a certain point, he became a poet of this singular love.31
4. The Troubadours and Fin’amor: Love, Choice, and the Individual 131 But there is no contradiction at all between the poet of passion and
the faintly criminal nobleman who practiced rançonnage (shakedowns
for ransom) in order to fill his coffers, because the “idealizing and
conventional themes” Lacan speaks of are largely a post-troubadour
invention.32 Lacan imposes an entirely extrinsic logic on the poetry of
the troubadours, derived from his own concepts and those borrowed
from Gaston Paris. The irony inherent in the positions of these two
French intellectuals is that each imposes an interpretive violence on the
southern poets from the perspectives of northern Parisian culture—and
as we will see, such impositions, and such violence, reflect the pattern
of a long and shockingly bloody history. That “courtly love” has very little to do with the troubadours33 can be
seen not only in the way that Paris derives the concept from the northern
poet Chrétien, but also because he slights the influence of the southern
poets at every turn. In La Poésie du Moyen Âge, Paris tips his hand. First,
only the literature of the north counts as properly “French” poetry: “the
proper domain of Carolingian [eighth-to-twelfth-century] poetry was the
north of France, the Ile-de-France, Orleans, Anjou, Maine, Champagne,
the Vermandois, Picardy”.34 The literature produced south of the Loire p
y
y
33
David F. But still, I maintain the most perfect silence
About what not to say in a story. Hult suggests that Paris’ invention of the term amour courtois had much less
to do with analysis of poetry than it did with “a personal and professional dilemma
in Paris’ career”, arguing that the term’s curious appeal to later generations can
be explained by the “suggestions of a continuity between […] academic life, its
founding disjunction between pleasure and science, and the ideal scheme of an
eroticism grounded in rules and progressive mastery” (David F. Hult. “Gaston Paris
and the Invention of Courtly Love”. In Medievalism and the Modernist Temper, ed. by
R. Howard Bloch and Stephen G. Nichols [Baltimore: Johns Hopkins University
Press, 1996], 216). In other words, Hult implies that “courtly love” is a notion only
an academic could love. 34
“le domaine propre de la poésie carolingienne avait été le nord de la France,
l’Ile-de-France, l’Orléanais, l’Anjou, le Maine, la Champagne, le Vermandois, 34
“le domaine propre de la poésie carolingienne avait été le nord de la France,
l’Ile-de-France, l’Orléanais, l’Anjou, le Maine, la Champagne, le Vermandois, 132 Love and its Critics river valley, was that of an entirely different civilization: “all that was
south of the Loire actually belonged to another civilization, where the
Germanic element had penetrated less deeply, and where the language
remained nearer the Latin”,35 and that which can be referred to as truly
“French” was produced only in lands of the langue d’oil36 in the north:
“literature, like the French language, belongs to northern France”.37 For Paris, Chrétien de Troyes was “the first master of French style”,38
and French literature was the premier vernacular expression in Europe,
reaching even into southern Italy and the court of Sicily: “Southern
Italy and Sicily also had Norman kings, and there again French
literature found a homeland”.39 Paris credits French poetry with the
flourishing of the poetic culture in the thirteenth-century Sicilian court
of Frederick II, though he is forced to acknowledge the influence of that
“autre civilisation” of the south, as he quickly, if reluctantly, mentions
the poetry of Provençe. 35
“Tout ce qui se trouvait au sud de la Loire appartenait en réalité à une autre
civilisation, où l’élément germanique avait moins profondément pénétré, et où
la langue était restée plus voisine du latin” (ibid., 9, https://books.google.com/
books?id=LdHs-jMItRQC&pg=PA9). la Picardie” (Gaston Paris. La Poesie du Moyen Age [Paris: Librarie Hachette,
1895], 8). Paris does not mention, however, that the vast majority of this period’s
poetry was written in Latin, not the vernacular, https://books.google.com/
books?id=LdHs-jMItRQC&pg=PA8 36
The terms langue d’oil and langue d’oc refer to the way northerners and southerners,
respectively, pronounced the word “yes”. la Picardie” (Gaston Paris. La Poesie du Moyen Age [Paris: Librarie Hachette,
1895], 8). Paris does not mention, however, that the vast majority of this period’s
poetry was written in Latin, not the vernacular, https://books.google.com/
books?id=LdHs-jMItRQC&pg=PA8 37
“la littérature, comme la langue française, appartient à la France du nord” (Paris, La
Poesie du Moyen Age, 9). la Picardie” (Gaston Paris. La Poesie du Moyen Age [Paris: Librarie Hachette,
1895], 8). Paris does not mention, however, that the vast majority of this period’s
poetry was written in Latin, not the vernacular, https://books.google.com/
books?id=LdHs-jMItRQC&pg=PA8
35
“Tout ce qui se trouvait au sud de la Loire appartenait en réalité à une autre
civilisation, où l’élément germanique avait moins profondément pénétré, et où
la langue était restée plus voisine du latin” (ibid., 9, https://books.google.com/
books?id=LdHs-jMItRQC&pg=PA9).
36
The terms langue d’oil and langue d’oc refer to the way northerners and southerners,
respectively, pronounced the word “yes”.
37
“la littérature, comme la langue française, appartient à la France du nord” (Paris, La
Poesie du Moyen Age, 9).
38
“le premier maître du style français” (ibid., 18, https://books.google.com/
books?id=LdHs-jMItRQC&pg=PA18).
39
“Le sud de l’Italie et la Sicile avaient aussi pour rois des Normands, et là aussi
la littérature française retrouva une patrie” (ibid., 36, https://books.google.com/
books?id=LdHs-jMItRQC&pg=PA36).
40
“en Sicile, et elle y détermina peut-être, au XIIIe siècle, autant que la poésie
provençale, l’éclosion de la poésie italienne” (ibid.). 38
“le premier maître du style français” (ibid., 18, https://books.google.com/
books?id=LdHs-jMItRQC&pg=PA18). But still, I maintain the most perfect silence
About what not to say in a story. French poetry flourished “in Sicily, and it
influenced in the thirteenth-century, as much as Provençal poetry, the
birth of Italian poetry”.40 Paris further argues that the poetry of the north
influenced the poetry of the south, setting up a hierarchy by which
French poetry could be seen as the original high literary form in any
of the European vernaculars, influencing even the troubadour poets:
“the southern provinces had a language and a literature of their own,
which had grown under conditions and with a quite different character. 38
“le premier maître du style français” (ibid., 18, https://books.google.com/
books?id=LdHs-jMItRQC&pg=PA18). 39
“Le sud de l’Italie et la Sicile avaient aussi pour rois des Normands, et là aussi
la littérature française retrouva une patrie” (ibid., 36, https://books.google.com/
books?id=LdHs-jMItRQC&pg=PA36). 40
“en Sicile, et elle y détermina peut-être, au XIIIe siècle, autant que la poésie
provençale, l’éclosion de la poésie italienne” (ibid.). 40
“en Sicile, et elle y détermina peut-être, au XIIIe siècle, autant que la poésie
provençale, l’éclosion de la poésie italienne” (ibid.).
4. The Troubadours and Fin’amor: Love, Choice, and the Individual 133 It is true, however, that the first effect our literature had on a foreign
literature was that it had on the poetry of the troubadours”.41 Paris’ preference is always for the trouvère poets of the north. He
claimed that the troubadours were nourished by French poetry—“it
is our poetry which the troubadours fed themselves on, and to which
they made frequent allusions”42—and all the Romance lands fell under
the influence of French literature, to which Paris subtly subordinates
the poetry of the south: “the Romance nations […] became as it were
branches of the great French school”.43 The term amour courtois, or
“courtly love”, refers to the literature its inventor preferred, his
much-favored poetry of the north, rather than the lyrics of that “autre
civilisation” in the troubadour south. Paris’ dismissive attitude reflects
a long history of northern contempt for, and violence against the south
(le Midi), its culture, languages, and poetry. This history stretches back
to the tensions leading up to the Albigensian Crusade of the thirteenth
century, in which the domination of the northern Franks was established
with sword, fire, and blood. The imposition of the term amour courtois on
a poetry that has nothing whatsoever to do with the concept is another
in a long line of acts of domination and erasure. 41
“Les provinces du Midi avaient une langue et une littérature à elles, qui s’étaient
développées dans des conditions et avec des caractères assez différents. C’est donc,
à vrai dire, la première action de notre littérature sur une littérature étrangère que
celle qu’elle exerça sur la poésie des troubadours” (ibid., 38, https://books.google.
com/books?id=LdHs-jMItRQC&pg=PA38). 43
“les nations romanes […] devinrent pour ainsi dire des succursales de la grande école
française” (ibid., 41, https://books.google.com/books?id=LdHs-jMItRQC&pg=PA41). 42
“ce sont nos poèmes dont les troubadours se nourrissaient et auxquels
ils
font
de
fréquentes
allusions”
(ibid.,
39,
https://books.google.com/
books?id=LdHs-jMItRQC&pg=PA39). 44
Bernardi Silvestris. De Mundi Universitate, ed. by Carl Sigmund Barach and Johann
Wrobel (Innsbruck: Verlag der Wagnerschen Universitaets-Buchandlung, 1876),
14.153–56, 161–62, https://archive.org/stream/bernardisilvest00silvgoog#page/n66
45
D. W. Robertson. “The Subject of the ‘De Amore’ of Andreas Capellanus”. Modern
Philology, 50: 3 (February 1953), 146–48, https://doi.org/10.1086/388953
46
Ibid., 155.
47
D. W. Robertson. “The Concept of Courtly Love”. In The Meaning of Courtly Love,
ed. by F. X. Newman (Albany: State University of New York Press, 1968), 17.
Emphasis added. 47
D. W. Robertson. “The Concept of Courtly Love”. In The Meaning of Courtly Love,
ed. by F. X. Newman (Albany: State University of New York Press, 1968), 17.
Emphasis added. But still, I maintain the most perfect silence
About what not to say in a story. In such ways, often
unnoticed, literary critics reiterate and support the violence of power
and authority by denying poetry its voice. Many modern scholars have questioned the idea of “courtly love”. D. W. Robertson, for example, spent years waging war against the whole
notion. Robertson’s view is that the discussion of De amore through this
concept is not only inaccurate, but confusing. Robertson argues that
Capellanus does not reject “worldly delights”, but looks on them as an
unfortunate, if necessary, “malady”. This idea is loosely based on the
twelfth-century philosopher Bernardi Silvestris’ notion that worldly 134 Love and its Critics love is acceptable as long as it contributes to procreation. Silvestris,
however, expresses this view in a fairly genial fashion: love is acceptable as long as it contributes to procreation. Silvestris,
however, expresses this view in a fairly genial fashion: love is acceptable as long as it contributes to procreation. Silvestris,
however, expresses this view in a fairly genial fashion: Corporis extremum lascivum terminat inguen,
Pressa sub occidua parte pudenda latent. Iocundus que tamen et eorum commodus usus,
Si quando, qualis quantus oportet, erit. […]
Cum morte invicti pugnamt genialibus armis,
Naturam reparant perpetuant que genus.44 The body ends in the lascivious groin,
Where the use of these private parts, hidden away,
Is pleasant and comfortable, so long as their use
Is in quality, quantity, and opportunity, as it should be. […]
Against death they fight invincibly with nuptial arms,
Repair our nature, and perpetuate our kind. Robertson maintains that Capellanus does not fully embrace the
sublimation and spiritualization of earthly love; in fact, Capellanus
shows inclination for the “natural” Venus.45 Cupidity, lust, and sensuality
are only seen as maladies because these are “inborn”, and they often go
against reason. As Robertson puts it, “If ‘Walter’ becomes a lover by
virtue of prolonged lascivious thought, his resulting uneasiness will be
entirely self-engendered”.46 In his famous essay “The Concept of Courtly Love”, Robertson goes on
to deny that the whole concept has any validity whatsoever, except as “an
aspect of nineteenth and twentieth century cultural history”. He insists
that “[t]he subject has nothing to do with the Middle Ages, and its use as
a governing concept can only be an impediment to our understanding
of medieval texts”.47 Robertson’s is a powerful argument—so far as it
4. The Troubadours and Fin’amor: Love, Choice, and the Individual 135 goes. 48
Ibid.
49
Roger Boase. The Origin and Meaning of Courtly Love (Manchester: Manchester
University Press, 1977), 122.
50
Moshe Lazar. “Fin’amor”. In A Handbook of the Troubadours, ed. by F. R. P. Akehurst
and Judith M. Davis (Berkeley: University of California Press, 1995), 64.
51
For Jennifer Wollock, “courtly love” reflects the experience of Gaston Paris more
than it does medieval social mores: But still, I maintain the most perfect silence
About what not to say in a story. But it performs an even more powerful surgical excision of the
Occitan poets than had the arguments of Lewis and Paris. Robertson
builds the “courtly love” concept that he then mockingly tears down,
using the building blocks of French poetry (the Roman de la rose), Latin
prose (Andreas Capellanus’ De amore), and English poetry (Chaucer’s
Troilus and Crysede). The troubadours appear not at all, except in the faint
echoes of their world glancingly referenced by Robertson’s mocking
of “pseudo-Albigensian heresies”, and “pseudo-Arabic doctrines”.48
Robertson is partially right, but for the wrong reasons. “Courtly love” is
an invention of “nineteenth and twentieth century cultural history”, but
the term describes a complicated phenomenon with roots that go back
as far as the thirteenth-century writings of Matfré Ermengaud, whose
work serves a very specific ideological purpose: to tame love and desire
(by persuasion if possible, or violence if necessary) into service and
obedience, to reduce the most powerfully anarchic part of the human
spirit into quiescence and tractability. Robertson pursues this agenda by
tacitly and through omission denying that any such love (or any such
poetry) exists at all, except as irony; for Robertson, “if a poet appears to
extol sexual passion his intentions will prove, on a closer inspection, to
be ironical and moralistic”.49 This then allows Robertson to bludgeon
“courtly love” into submission in service of a worldview in which the
troubadours are defined out of the very possibility of existence. Moshe Lazar, examining the stark differences between the terms
most often used to describe and analyze love in this period—courtoise,
amour courtois, and fin’amor—scoffs at the idea that these terms are
interchangeable: “[These words] are used as though it were possible to
lump together all the periods of the Middle Ages and to interchange the
order of authors and works”.50 The invented phenomenon of “courtly
love”, in which a young man feels passionate love for an unavailable
woman to whose service he dedicates himself in the absence of any
possibility of sexual union,51 is at best a parody of a love that does exist, Love and its Critics 136 a love called fin’amor, written about by the eleventh-and twelfth-century
troubadours. But still, I maintain the most perfect silence
About what not to say in a story. Calling it “the direct ancestor of romantic love as we know
it today”, Jennifer Wollock describes fin’amor as a radically subversive
cultural force: [Fin’amor] gave medieval men and women a vent for their dissatisfaction
with the institution of marriage as it then existed, holding up a
different, much more exciting, and dangerous model of the male-female
relationship. Its socially subversive force can still be felt today not just in
the West but in cultures all across the world where traditional models of
marriage as arranged by parents are still maintained.52 The frankly passionate, erotic, and embodied poetry of the troubadours
is transformed into something decorous, pious, and bloodless by a later
tradition of critics and poets. The work of the troubadours has been
subjected to a systematic distortion, one that reflects the values of the
distorters, but does violence to the poetry. For Gaston Paris, courtly love was defined by the lover’s worship of an idealized lady. His
love was an ennobling discipline, not necessarily consummated, but based on sexual attraction.
Hult and Bloch have analyzed the psychology of Gaston Paris and his circle as it affected their
understanding of medieval love literature, suggesting that the scholars’ own experiences with
unattainable ladies of the nineteenth century may have led them to stress the unattainability of
the troubadours’ objects of affection.
Jennifer G. Wollock. Rethinking Chivalry and Courtly Love (Santa Barbara: Praeger,
2011), 31.
2
Ibid., 6. 53
Eglal Doss-Quinby. Songs of the Women Trouvères (New Haven: Yale University
Press, 2001), 184–86.
54
Bertran de Born. The Poems of the Troubadour Bertran de Born, ed. by William D.
Paden, Tilde Sankovitch, and Patricia H. Stablein (Berkeley: University of California
Press, 1986), 339, ll. 1–9. II
The Troubadours and their Critics To begin seeing this in the poetry, let’s linger for a moment with Paris’
beloved trouvères, and consider a short snippet of an anonymous late
twelfth-century song: Soufrés maris, et si ne vous anuit,
Demain m’arés et mes amis anuit. Je vous deffenc k’un seul mot n’en parlés
—Soufrés, maris, et si ne vous mouvés.—
La nuis est courte, aparmains me rarés,
Quant mes amis ara fait sen deduit. Soufrés maris, et si ne vous anuit,
Demain m’arés et mes amis anuit. Je vous deffenc k’un seul mot n’en parlés
—Soufrés, maris, et si ne vous mouvés.—
La nuis est courte, aparmains me rarés,
Quant mes amis ara fait sen deduit. Soufrés maris, et si ne vous anuit, 137
4. The Troubadours and Fin’amor: Love, Choice, and the Individual
4. The Troubadours and Fin’amor: Love, Choice, and the Individual Soufrés maris, et si ne vous anuit,
Demain m’arés et mes amis anuit.53 Suffer in silence husband, be not vexed tonight,
Tomorrow I will be yours, but I am my lover’s tonight. I forbid you to speak a single word. —Suffer in silence husband, and do not move.—
The night is short, soon I will be yours again,
When my lover has had his senses’ share. Suffer in silence husband, be not vexed tonight,
Tomorrow I will be yours, but I am my lover’s tonight. These lines are not about rules and codes of “courtly” behavior, a
disembodied love, or a sacramentalized eros given to ethereally disembodied
devotion, as one might see in the works of Petrarch, for example. They do
not reflect an ethos which is anti-body, anti-sex, anti-female. Even in the
north, the spirit of a love that is neither courtly nor sacred is thriving. Among the southern poets during this period there are a number of
female writers, or trobairitz, though the majority are male. Many of the
poets are famous for writing love poems (called cansos), though there are
others who write often caustic verses of war and political conflict (called
sirventes). 55
Ronald Martinez. “Italy”. In A Handbook of the Troubadours, ed. by F. R. P. Akehurst
and Judith M. Davis (Berkeley: University of California Press, 1995), 285.
56
Inferno. Canto 28.118–23, 133–42. In La Divina Commedia. Inferno, ed. by Ettore Zolesi
(Rome: Armando, 2009), 470–71. 55
Ronald Martinez. “Italy”. In A Handbook of the Troubadours, ed. by F. R. P. Akehurst
and Judith M. Davis (Berkeley: University of California Press, 1995), 285. 56
Inferno. Canto 28.118–23, 133–42. In La Divina Commedia. Inferno, ed. by Ettore Zolesi
(Rome: Armando, 2009), 470–71. II
The Troubadours and their Critics Bertran de Born is the most exultant example of the latter: Be·m platz lo gais temps de pascor,
que fai fuoillas e flors venir;
e plai me qand auch la baudor
dels auzels que fant retintir
lo chant per lo boscatge;
e plai me qand vei per los pratz
tendas e pavaillons fermatz;
qan vei per campaignas rengatz
cavalliers e cavals armatz.54 Be·m platz lo gais temps de pascor,
que fai fuoillas e flors venir;
e plai me qand auch la baudor
dels auzels que fant retintir
lo chant per lo boscatge;
e plai me qand vei per los pratz
tendas e pavaillons fermatz;
qan vei per campaignas rengatz
cavalliers e cavals armatz.54 138 Love and its Critics I am pleased by the gay season of Spring,
that makes the leaves and the flowers come;
and it pleases me when I overhear
the birds’ faint echoes
of song through the woods;
and it pleases me when I see on the meadow
tents and pavillions well-built;
when I see the fields filled with ranks
of armed knights and horses. Bertran’s love for war was such that Dante puts him into the Inferno as a
sower of discord for his “persistence in dividing [King] Henry [II] from
the jove rei Engles”, Prince Henry.55 Dante has Bertan accuse himself, as
the warrior-troubadour stands amidst the flames: Io vidi certo, e ancor par ch’io ‘l veggia,
un busto sanza capo andar sì come
andavan li altri de la trista greggia;
e ‘l capo tronco tenea per le chiome,
pesol con mano a guisa di lanterna:
e quel mirava noi e dicea: “Oh me!”. Io vidi certo, e ancor par ch’io ‘l veggia,
un busto sanza capo andar sì come
andavan li altri de la trista greggia;
e ‘l capo tronco tenea per le chiome,
pesol con mano a guisa di lanterna:
e quel mirava noi e dicea: “Oh me!”. […]
“E perché tu di me novella porti,
sappi ch’i’ son Bertram dal Bornio, quelli
che diedi al re giovane i ma’ conforti. Io feci il padre e ‘l figlio in sé ribelli;
Achitofèl non fé più d’Absalone
e di Davìd coi malvagi punzelli. Perch’ io parti’ così giunte persone,
partito porto il mio cerebro, lasso!,
dal suo principio ch’è in questo troncone. II
The Troubadours and their Critics Così s’osserva in me lo contrapasso”.56 “E perché tu di me novella porti,
sappi ch’i’ son Bertram dal Bornio, quelli
che diedi al re giovane i ma’ conforti. Io feci il padre e ‘l figlio in sé ribelli;
Achitofèl non fé più d’Absalone
e di Davìd coi malvagi punzelli. Perch’ io parti’ così giunte persone,
partito porto il mio cerebro, lasso!,
dal suo principio ch’è in questo troncone. Così s’osserva in me lo contrapasso”.56
4. The Troubadours and Fin’amor: Love, Choice, and the Individual 139 I truly saw, and still seem to see it,
a body without a head, walking just like
the others in its dismal herd;
the body carried its severed head by the hair,
swaying in its hand, in the fashion of a lantern;
and it looked at us and said: “Oh me!”
[…]
“And because you will carry news of me,
know that I am Bertran de Born, he
who gave comfort to the young King. I made father and son turn against each other;
Achitophel did not do more with Absalom
and David, through his malevolent provocations. Because I severed people so joined,
severed now I bear my brain, alas!,
from its origin, which is in this body. In this can be seen my retribution”. But many of the troubadour and trobairitz poems come from, and
represent, the female perspective, and some break boundaries one
might not initially expect. For example, consider a piece called Na Maria,
attributed to a poet named Bietris (or Bieris) de Romans. Na Maria, pretz e fina valors,
e·l joi e·l sen e la fina beutatz,
e l’aculhir e·l pretz e las onors,
e·l gen parlar e l’avinen solatz,
e la dous car’ e la gaja cuendansa,
e·l dous esgart e l’amoros semblan
que son en vos, don non avetz engansa,
me fan traire vas vos ses cor truan. Per que vos prec, si·us platz que fin’ amors
e gausiment e dous umilitatz
me posca far ab vos tan de socors,
que mi donetz, bella domna, si·us platz,
so don plus ai d’aver joi e’speransa;
car en vos ai mon cor e mon talan,
e per vos ai tot so qu’ai d’alegransa
e per vos vauc mantas vetz sospiran. 57
Bietris de Romans. “Na Maria, prètz e fina valors”. In The Women Troubadours, ed.
by Meg Bogin (New York: Norton & Co., 1980), 132. 58
“ταὶς κάλαισ᾿ ὔμμιν <τὸ> νόημμα τὦμον / οὐ διάμειπτον” (Sappho, Greek Lyric,
Vol. I: Sappho and Alcaeus, ed. by David A. Campbell [Loeb Classical Library,
Cambridge, MA: Harvard University Press, 1982], Fragment 41, 86).
59
“Na Maria: Courtliness and Marian Devotion in Old Occitan Lyric”. In Shaping
Courtliness in Medieval France: Essays in Honor of Matilda Tomaryn Bruckner, ed. by
Daniel E. O’Sullivan and Laurie Shepard (Cambridge, UK: Brewer, 2013), 184.
60
Ibid., 195.
61
Ibid.
62
Ibid. II
The Troubadours and their Critics E car beutatz e valors vos enansa 140 Love and its Critics sobre totas, qu’una no·us es denan,
vos prec, si·us platz, per so que·us es onransa,
que non ametz entendidor truan. Bella domna, cui pretz e joi enansa,
e gen parlar, a vos mas coblas man,
car en vos es gajess’e alegranssa
e tot lo ben qu’om en domna deman.57 Lady Maria, for your esteem and pure worthiness,
joy, wisdom, and pure beauty,
graciousness and praise and distinction,
noble speech and delightful company,
sweet face and lively charm,
the sweet glance and the amorous appearance
that are in you without deception,
I am drawn to you with nothing false in my heart. For this, I pray, please, let true love
delight and sweet humility
give me, with you, the relief I need,
so you will grant me, beautiful lady, please,
what I most hope to enjoy. Because in you, alas, are my heart and desire
and for you, alas, are all my joys
and for you, I go, freely sighing many sighs. And since beauty and merit advances you,
superior to all others, for there is no one before you,
I pray you, please, by all that brings you honor,
do not love those false suitors. Beautiful Lady, whom praise and joy advances,
and noble speech, my verses are for you,
for in you is merriment and all delight,
and every good thing one could want in a woman. On an initial reading, this poem seems to be an erotic poem written by
a woman to a woman. Though there are no explicitly sexual details, it
appears to portray a jealous lover trying to fend off rivals, a poem in
the tradition of Sappho, the ancient Greek poet who wrote much of her
4. The Troubadours and Fin’amor: Love, Choice, and the Individual 141 verse describing her erotic longings for beautiful women: “Toward you
bare-shouldered beauties my mind / surely never changes”.58 Thus, Na
Maria is not poetically unprecedented, nor in any way to be considered
outside the realm of human erotic experience. And yet, there is no shortage of claims that this poem is not what it
seems. The apparent lesbian eroticism is explained away through the
use of two arguments, which we will see again and again with only
minor variations. Firstly, the religious or spiritualizing argument that
sublimates love into worship: 58
“ταὶς κάλαισ᾿ ὔμμιν <τὸ> νόημμα τὦμον / οὐ διάμειπτον” (Sappho, Greek Lyric,
Vol. I: Sappho and Alcaeus, ed. by David A. Campbell [Loeb Classical Library,
Cambridge, MA: Harvard University Press, 1982], Fragment 41, 86). 65
Angelica Rieger. “Was Bieiris de Romans Lesbian? Women’s Relations with Each
Other in the World of the Troubadours”. In The Voice of the Trobairitz: Perspectives
on the Women Troubadours, ed. by William D. Paden (Philadelphia: University of
Pennsylvania Press, 1989), 73. 63
As Rita Felski has complained, historicism of this stripe has bound us into “a
remarkably static view of meaning, where texts are corralled amidst long-gone
contexts and obsolete intertexts, incarcerated in the past, with no hope of parole”
(The Limits of Critique, 157). This is a metaphor for the Virgin Mary. This is Daniel E. O’Sullivan’s argument.59 He suggests that the line
“so you will grant me, beautiful lady, please / what I most hope to
enjoy” (“qe mi donetz, bella dompna, si·us platz, / so don plus ai d’aver
esperansa”) should be interpreted in the context of “Marian songs, [in
which] the singer makes similar requests of the Virgin where the hoped-
for reward is eternal salvation”.60 Though the critic acknowledges
that “the question of asking Mary to shun deceitful lovers or suitors
(entendidor) may seem odd given the Virgin’s role in helping to save
all of mankind”,61 he does not let that difficulty discourage him, and
argues that the poet’s entreaty has to do with prayer: “such requests
for divine intercession must be made sincerely, thus the qualification
that such people must not be deceitful (truan)”.62 Thus the critic erases
the eroticism that seems evident on the text’s surface, and allegorizes
that eroticism in the traditional way (as seen in the case of the Song of
Songs), by transforming its energy into an expression of divine love. If that line of argument fails to convince, another line of attack comes
in the form of an historicism that assumes every human expression of a
particular time and place can necessarily be explained by and reduced Love and its Critics 142 to the majority standards of that time and place. Such a position leaves
no room for dissent or “non-normative” desires and points of view, thus
dismissing the possibility of any such dissent or desires:63 This poem is merely expressing the contemporary reality of an affectionate, but
non-sexual regard between women.64 This is the argument of Angelica Rieger, who attempts to bury the passion
of the poem through a series of remarks on its rhetorical reversals: [c]omposed by a woman and addressed to another, it acquires a special
position not only within the works of the trobairitz but within the entire
Occitan literature of the thirteenth century. f
q
64
This is a varation of the amicitia argument we have already seen used to explain
away the apparent eroticism in Alcuin’s poetry. 63
As Rita Felski has complained, historicism of this stripe has bound us into “a
remarkably static view of meaning, where texts are corralled amidst long-gone
contexts and obsolete intertexts, incarcerated in the past, with no hope of parole”
(The Limits of Critique, 157).
64
This is a varation of the amicitia argument we have already seen used to explain
away the apparent eroticism in Alcuin’s poetry.
65
Angelica Rieger. “Was Bieiris de Romans Lesbian? Women’s Relations with Each
Other in the World of the Troubadours”. In The Voice of the Trobairitz: Perspectives
on the Women Troubadours, ed. by William D. Paden (Philadelphia: University of
Pennsylvania Press, 1989), 73. 69
Alain de Lille only scratches the surface of the possibilities. For other examples,
see the discussions of the anonymous twelfth-century poem “Altercatio Ganimedes
et Helene” in Newman (2003), as well as in John Boswell’s Christianity, Social
Tolerance, and Homosexuality (Chicago: University of Chicago Press, 1980), and Rolf
Lenzen, “Altercatio Ganimedis et Helene”. Kritische Edition mit Kommentar. In
Mittellateinisches Jahrbuch, 7 (1972), 161–86. As Thomas Stehling argues, pg
)
68
Barbara Newman. Gods and the Goddesses: Vision, Poetry, and Belief in the Middle Ages
(Philadelphia: University of Pennsylvania Press, 2003), 87. 67
“Jupiter enim adolescentem Ganymedem transferens ad superna, […] et quem
in mensa per diem propinandi sibi statuit praepositum, in toro per noctem
sibi fecit suppositum” (Alain de Lille. Alani de Insulis doctoris universalis opera
omnia. In Patrologiae Cursus Completus, ed. by Jacques Paul Migne [Paris:
Apud Garnier Fratres, 1855], Vol. 210, col. 451B, https://books.google.com/
books?id=c10k8WCYMBoC&pg=RA1-PA470). 69
Alain de Lille only scratches the surface of the possibilities. For other examples,
see the discussions of the anonymous twelfth-century poem “Altercatio Ganimedes
et Helene” in Newman (2003), as well as in John Boswell’s Christianity, Social
Tolerance, and Homosexuality (Chicago: University of Chicago Press, 1980), and Rolf
Lenzen, “Altercatio Ganimedis et Helene”. Kritische Edition mit Kommentar. In
Mittellateinisches Jahrbuch, 7 (1972), 161–86. As Thomas Stehling argues,
[t]he recurrent reference to classical literature in medieval homosexual poetry represents
more than just an appeal to a shared education; it may also be interpreted as an attempt to
place homosexual love in a respectable context [
] Engaged like other poets in this great 66
Ibid., 82. This is a variation of the amicitia argument we have already seen applied
to Alcuin. This is a metaphor for the Virgin Mary. Since the troubadour typically
speaks to the domna, it is clear that the inversion of this configuration in
the poems of the trobairitz may be regarded as a marginal phenomenon;
that the masculine element should be eliminated, however, so that the
lyrical dialogue takes place exclusively between one woman and another,
is an extraordinary rarity.65 Rare though its female address to another female may be, and as
apparently erotic as its language is, Rieger argues that we misread the
poem if we see it as expressing sexual desire: The poem is indeed by a woman, addressed to another, but nevertheless
does not concern a lesbian relationship. In addition to the […] rejection
of homosexuality within troubadour poetry, which makes a public,
positive depiction of such a relationship very improbable, the poem does
not contain any indecent passages either. Bieiris addresses Maria only
in a manner customary for her time and her world; she expresses her
sympathy for her in a conventionally codified form—which the choice of
genre would also support—just as one, or better, a woman, speaks with
a female acquaintance, friend, confidante, or close relative. In short, the
4. The Troubadours and Fin’amor: Love, Choice, and the Individual 143 colloquial tone used between women differed from that used today, and
what modern readers deem erotic was simply tender.66 g
71
Hilarius, “Ad Puerum Anglicum II”. ll. 1–4. Hilarii Aurelianensis Versus et Ludi
Epistolae. Mittellateinische Studien und Texte, ed. by Walther Bulst and M. L. Bulst-
Thiele (Leiden and New York: Brill, 1989), Vol. 16, 46. Thomas Stehling. “To Love a Medieval Boy”. In Literary Versions of Homosexuality,
ed. by Stuart Kellogg (New York: Haworth Press, 1983), 167. Reddy insists,
however, that “recent scholarship on courtly love has accurately characterized the
strict heterosexuality” (25) of the Occitan poetry. 70
Stehling, 161. colloquial tone used between women differed from that used today, and
what modern readers deem erotic was simply tender.66 As Rieger would have it, the poem “does not concern a lesbian
relationship” because that would be “improbable”, and therefore
evidently impossible. But to speak of a “rejection of homosexuality
within troubadour poetry” is a very careful circumscribing of the
argument, since troubadour poetry exists within the context of a wider
cultural and poetic practice in which same-sex desire is very much
part of the picture. One need only look at Alain de Lille (Alanus ab
Insulis), and his twelfth-century De Planctu Naturae for confirmation. Herein, Alain questions Nature about love and sexuality, and explains
the prevalence of same-sex relations through a reference to the gods of
Antiquity: “Jupiter, for the adolescent Ganymede, transferred him to
the heavens, […] and while he made him the governor of his drinks on
the table by day, he made him the subject of his bed by night”.67 Though
Alain portrays this state of affairs as the result of a fallen Nature who
has “betrayed her God-given responsibility by placing sexuality in the
hands of Venus [and her] moral licentiousness”,68 the very existence of
the discussion makes Rieger’s immediate dismissal of the possibility
of homosexuality in Na Maria problematic.69 Further evidence appears As Rieger would have it, the poem “does not concern a lesbian
relationship” because that would be “improbable”, and therefore
evidently impossible. But to speak of a “rejection of homosexuality
within troubadour poetry” is a very careful circumscribing of the
argument, since troubadour poetry exists within the context of a wider
cultural and poetic practice in which same-sex desire is very much
part of the picture. One need only look at Alain de Lille (Alanus ab
Insulis), and his twelfth-century De Planctu Naturae for confirmation. [t]he recurrent reference to classical literature in medieval homosexual poetry represents
more than just an appeal to a shared education; it may also be interpreted as an attempt to
place homosexual love in a respectable context. […] Engaged like other poets in this great
revival of classical learning, poets writing homosexual verse learned to employ this respect
in a particular way. colloquial tone used between women differed from that used today, and
what modern readers deem erotic was simply tender.66 Love and its Critics 144 in the poetry of Hilarius, or Hilary the Englishman, four of whose five
surviving love poems are written to boys.70 Ad Puerum Anglicum makes
the idea fairly clear: Puer decens, decor floris,
Genma micans, velim noris
Quia tui decus oris
Fuit mihi fax amoris.71 Puer decens, decor floris,
Genma micans, velim noris
Quia tui decus oris
Fuit mihi fax amoris.71 Demure boy, beautiful as a flower,
Sparkling jewel, if only you knew
That the glory of your eyes
Has set my love on fire. Such poetry makes plain that Na Maria exists in a context in which same-
sex desires exist, and are expressed in powerful verse. But Rieger will have
none of it. By trying to erase the very possibility of non-majority desires,
she struggles mightily to force this female-voiced poem to revolve around
a man, not as rival for the poet’s sexual desires and affections (which
would apparently require “indecent passages”), but as the wrong choice
of man among what are presumably better choices of men. Thus the
critic redefines the expressions of desire in the poem in terms of a wish
that Lady Maria make the right choice among male suitors: Does Maria have a choice between several admirers, and is she to decide
on the “right one”, and are Bieiris’s words spoken out of a sort of maternal
concern that this young, beautiful, and intelligent woman might choose
the wrong one? Or does the man in question stand between the two
women, and is Bieiris’s poem an appeal to Maria not to take him, thereby
making herself and Bieiris unhappy? The list of possible situations could
certainly go on, but the two cited may suffice to demonstrate that Bieiris’s
4. 73
Bietris de Romans, ll. 9–16. 72
Rieger, 92. colloquial tone used between women differed from that used today, and
what modern readers deem erotic was simply tender.66 The Troubadours and Fin’amor: Love, Choice, and the Individual 145 canso—following the feminine lyrical tradition—revolves around the
absent third party, the man.72 But both O’Sullivan’s and Rieger’s decorous explanations get strained
by the second stanza: Per que vos prec, si·us platz que fin’ amors
e gausiment e dous umilitatz
me posca far ab vos tan de socors,
que mi donetz, bella domna, si·us platz,
so don plus ai d’aver joi e’speransa;
car en vos ai mon cor e mon talan,
e per vos ai tot so qu’ai d’alegransa
e per vos vauc mantas vetz sospiran.73 For this, I pray, please, let true love
delight and sweet humility
give me, with you, the relief I need,
so you will grant me, beautiful lady, please,
what I most hope to enjoy. Because in you, alas, are my heart and desire
and for you, alas, are all my joys
and for you, I go, freely sighing many sighs. These lines are practically drenched in anxious longing—the voice we
hear begs for relief, and the fulfilment of desire. In the meantime, she
sighs as she walks abroad, praying that “fin’ amors” will give her the
heart of the woman she so desperately admires. It is tenuous, at best,
to argue that what she prays her bella domna will grant her is to choose
the right man. As the poem concludes, the feminine voice praises Maria
as the embodiment of all that is desirable: “for in you is merriment and
all delight, / and every good thing one could want in a woman”. This,
along with the warning “do not love those false suitors”, especially
when paired with the claim “I am drawn to you with nothing false in
my heart”—sets the female voice of the poem directly in opposition to,
and rivalry with those “entendidor”, the (grammatically, at least) male Love and its Critics 146 wooers who will betray and lie to Maria. As Meg Bogin has observed,
“Scholars have resorted to the most ingenious arguments to avoid
concluding that [Bietris] is a woman writing a love poem to another
woman”,74 and this, perhaps, is the best indication that Bietris is in
fact writing a love poem to another woman: the scholar doth protest too
much, methinks. Rieger hedges her bets, admitting that “[t]he possibility of an
element of female jealousy (which might even bear lightly homoerotic
characteristics) need not be ruled out entirely”. 74
Meg Bogin. The Women Troubadours (New York: Norton & Co., 1980), 176.
75
Rieger, 92.
76
Alison Ganze. “‘Na Maria, pretz e fina valors’: A New Argument for Female
Authorship”. Romance Notes, 49: [1] (2009), 25–26, https://doi.org/10.1353/
rmc.2009.0010
77
William E. Burgwinkle. Love for Sale: Materialist Readings of the Troubadour Razo
Corpus (New York: Garland, 1997), 100. Emphasis added. colloquial tone used between women differed from that used today, and
what modern readers deem erotic was simply tender.66 Burgwinkle decries the fact that troubadour love
poems “continue to be read as personal love missives […] rather than as
musings on language”, repeating the familiar critical move that reduces
poetry only to language, or to a meta-discourse in which it always and
only speaks of itself. He then declares that his argument will “show
just how deeply representation, even of what seems to be the most
personal nature, is imbued with issues of profit, marketing, and self-
promotion”.79 Everything that comes after “seems” is the not-X of the
formula. Troubadour love poems seem to be personal, but are actually
[fill in the blank]. This same basic argument is made so often, about so
many different poems, plays, novels, etc., that one begins to wonder
if it is hard-wired into the academic psyche. What Harold Rosenberg
once called “The Herd of Independent Minds”80 is alive and well and
publishing books and journal articles. With the inclusion of the “empty category”, the critic claims that what
appears to be X is not only not X, but is potentially anything in the
world other than X. Burgwinkle decries the fact that troubadour love
poems “continue to be read as personal love missives […] rather than as
musings on language”, repeating the familiar critical move that reduces
poetry only to language, or to a meta-discourse in which it always and
only speaks of itself. He then declares that his argument will “show
just how deeply representation, even of what seems to be the most
personal nature, is imbued with issues of profit, marketing, and self-
promotion”.79 Everything that comes after “seems” is the not-X of the
formula. Troubadour love poems seem to be personal, but are actually
[fill in the blank]. This same basic argument is made so often, about so
many different poems, plays, novels, etc., that one begins to wonder
if it is hard-wired into the academic psyche. What Harold Rosenberg
once called “The Herd of Independent Minds”80 is alive and well and
publishing books and journal articles. What we encounter in troubadour poetry, if we allow ourselves
to see it, is a crossing of boundaries, love as resistance to, or rejection
of, the ordinarily assigned categories or roles. It challenges the idea of
faithfulness in marriage and questions the heteronormativity of our
typical approaches to sex and desire. 78
Ibid., 100–01.
79
Ibid., 11. Emphasis added.
80
Commentary, 6 (1 Jan 1948), 244–52, https://www.commentarymagazine.com/
articles/the-herd-of-independent-mindshas-the-avant-garde-its-own-mass-culture/ colloquial tone used between women differed from that used today, and
what modern readers deem erotic was simply tender.66 Nevertheless, she is
determined to “substantiate that [Bietris’s] poetic motivation does
not spring from a lesbian relationship”.75 Alison Ganze, however,
argues undauntedly in the familiar and predictable what appears to be
X is actually Y style of the hermeneutics of suspicion, that it is a “faulty
assumption […] that the erotic language in the poem must be taken as a
literal expression of sexual desire”, before she goes on to assert that “‘Na
Maria’ fits within the conventional mode expressing friendship between
women”.76 Note how Ganze’s gesture makes the poem safe, orthodox,
predictable, and not at all disturbing to conservative sensibilities. It’s
just about women being friends. What appears to be erotic longing is
actually just friendship. What appears to be [fill in the blank] is actually
[fill in the blank differently]. William Burgwinkle argues along similar
lines when he suggests that the poem Tanz salutz e tantas amors, perhaps
by the mid-thirteenth century troubadour Uc de Saint Circ, “mocks all
future discussions of whether ladies writing to ladies might be lesbians
by simply pulling the linguistic rug from beneath the supposed signs of
sentiment, the words in question”77 Once a critic is in the habit of suspicion,
regarding words as always or even usually meaning something other
than they merely seem to mean, it appears that the habit is never
broken. Thus Burgwinkle argues that love poems are not actually love
poems, because they are really something else, in this case, a currency
for exchange:
4. The Troubadours and Fin’amor: Love, Choice, and the Individual 147 love songs should probably be seen more as a sort of currency in these
Southern courts than as personal love missives. […]. The “Lady” in such
songs is often more an empty signifier than a flesh-and-blood woman. As in much of classical literature, the woman is an allegorical stand-in
for something else. [This could be] an actual woman at court, the court
itself, a fiefdom or castle, a male patron, or an empty category.78 With the inclusion of the “empty category”, the critic claims that what
appears to be X is not only not X, but is potentially anything in the
world other than X. colloquial tone used between women differed from that used today, and
what modern readers deem erotic was simply tender.66 In the spirit of crossing boundaries, let’s look at the troubadours
for a moment from outside the perspective of specialist scholars in the
field. The popular myth and religion scholar Joseph Campbell wrote
perceptively about the troubadours, and his analysis is acute: all too
often writers, thinkers, theologians, poets, and academics treat love
and desire as if they are definable only in terms of absolute antithesis, 148 Love and its Critics “writing of agape and eros and their radical opposition, as though these
two were the final terms of the principle of ‘love’”.81 It is as if love must
be regarded in terms of extremes: “whatever is at hand, one loves—
either in the angelic way of charity or in the orgiastic, demonic way
of a Dionysian orgy; but in either case, religiously: in renunciation of
ego, ego judgment, and ego choice”.82 Such thinking supports either the
idea that impersonal principle is more important than personal choice,
or that the drives of the body are more important than individual
judgment. Campbell suggests that the primary poetic, philosophical,
and cultural importance of this period, of the troubadour movement
itself, is the elevation of the perspectives and choices of the individual
over the impersonal claims of law and dogma and the body’s claims of
lust and desire. This stance often set the troubadours at odds with the
theological ideas of their time: According to the Gnostic-Manichean view nature is corrupt […] in the
poetry of the troubadours […] nature […] is an end and glory in itself. […] Hence, if the courtly cult of amor is to be catalogued according
to heresy, it should be indexed rather as Pelagian than as Gnostic or
Manichean, for […] Pelagius and his followers absolutely rejected the
doctrine of our inheritance of the sin of Adam and Eve, and taught that
we have finally no need of supernatural grace, since our nature itself is
full of grace; no need of a miraculous redemption, but only of awakening
and maturation.83 This tension between worldviews, between the insistence that the world
is corrupt, and the celebration of the world as full of its own grace, is
reflected in the simultaneous existence of two groups that the twelfth-
and thirteenth-century church regarded as heretical and dangerous:
the troubadours—who celebrated the body—and the Cathars—who
rejected that body as corrupt and fallen. 81
Joseph Campbell. Creative Mythology (New York: Viking, 1968), 177.
82
Ibid.
83
Ibid., 176. colloquial tone used between women differed from that used today, and
what modern readers deem erotic was simply tender.66 The name Cathar comes from a
Greek root meaning “purged” or “pure”, and for them, the flesh needed
to be “purged” and the entire physical world was a prison from which
to escape. But the troubadours’ “heresy” was not the more Gnostic,
flesh-and world-denying belief characteristic of the Cathars who were
the primary target of the Albigensian Crusade of the early thirteenth
4. The Troubadours and Fin’amor: Love, Choice, and the Individual 149 century: “there is little sign of Cathar influence on [troubadour]
poetry. The delight in the senses found in much of the love-lyric is
hardly compatible with the Cathar notion of the evil of matter”.84 If the
troubadours were heretics, theirs was the more life-and world-affirming
heresy (at its root, the word merely means “opinion”) of Pelagius, a
British monk who was a contemporary of the now-famous Augustine
of Hippo. This obscure monk thought the doctrine of original sin was
the single most pernicious thing he had ever heard of, and he devoted a
great deal of his time and energy to arguing against the idea. Imagine this: from the moment you are conceived, you are flawed,
broken, and sick, while at the same time you are commanded to be well
and denied the medicine that would cure you: O wearisome condition of humanity,
Borne under one law, to an other bound,
Vainely begot, and yet forbidden vanity,
Created sicke, commanded to be sound.85 O wearisome condition of humanity,
Borne under one law, to an other bound,
Vainely begot, and yet forbidden vanity,
Created sicke, commanded to be sound.85 You are denied this medicine (unless you are one of a lucky few) by the
will of a perfect, just, and unbending deity—and this denial comes as a
result of no action or inaction, no deserving or failing of your own—in
fact, you have not done, and cannot do anything either to elicit or forestall
the pleasure or displeasure of this deity. Judgment was rendered upon
you before the founding of the world into which you would one day be
born as a helpless, broken, and already-condemned infant. 84
Linda M. Paterson. The World of the Troubadours: Medieval Occitan Society c.1100-c.1300
(Cambridge: Cambridge University Press, 1993), 342–43. g
g
y
85
Fulke Greville. The Tragedy of Mustapha (London: Printed for Nathaniel
Butler, 1609), “Chorus Sacerdotum”, Sig. B2r, https://archive.org/stream/
tragedyofmustaph00grev#page/n16 84
Linda M. Paterson. The World of the Troubadours: Medieval Occitan Society c.1100-c.1300
(Cambridge: Cambridge University Press, 1993), 342–43.
85
Fulke Greville. The Tragedy of Mustapha (London: Printed for Nathaniel
Butler, 1609), “Chorus Sacerdotum”, Sig. B2r, https://archive.org/stream/
tragedyofmustaph00grev#page/n16
86
Jean de Meun’s thirteenth-century reaction to this problem takes 625 lines of the
Roman de la Rose to work through what might be called a semi-Pelagian solution,
ending a discussion of free will with the idea that “It is above all destiny / no matter
what will or will not be destined” (“Il est seur toutes destinees, / ja si ne seront 86
Jean de Meun’s thirteenth-century reaction to this problem takes 625 lines of the
Roman de la Rose to work through what might be called a semi-Pelagian solution,
ending a discussion of free will with the idea that “It is above all destiny / no matter
what will or will not be destined” (“Il est seur toutes destinees, / ja si ne seront colloquial tone used between women differed from that used today, and
what modern readers deem erotic was simply tender.66 Since you
are fatally flawed from the very beginning, the only possibility that
you have of salvation, joy, and fulfillment is the forcible manipulation
of your sin-infected will by God (through a power known as grace),
because you are entirely unable to take any positive responsibility for
your life.86 Pelagius opposed all of this in the name of human freedom: 150 Love and its Critics “the relationship of human freedom to divine grace was the crucial issue
on which Augustine and Pelagius differed. […] Augustine [refused] to
admit that the debate was between freedom and determinism. Pelagius,
on the other hand, was just as adamant in insisting that it was”.87 For Pelagius, Augustine’s doctrine of original sin contributes to the
decay of society, and to the breakdown of the ordinary restraints that
our sense of responsibility for our actions puts on our baser impulses. Pelagius regards “man’s sin as the result not of an inheritance from
Adam but of imitation of his example”.88 Pelagius believes that “each
soul was created by God at the time of conception […] and thus could
not come into the world tainted by original sin transmitted from Adam. […] Adam’s sin did have disastrous consequences for humanity;
it introduced death and the habit of disobedience. But the latter was
propagated by example, not by physical descent”.89 Pelagius argues that Augustine’s doctrine acts as a carte blanche, a
cosmic get-out-of-jail-free card that gives people perverse permission
to abandon themselves to their baser, more aggressive and violent
impulses, resulting in the chaos that Thomas Hobbes describes as the
war of all against all, in which life is “solitary, poore, nasty, brutish,
and short”.90 In a letter to a follower named Demetrias, Pelagius argues If God predetermined and foreknew everything, how can a man sin? Yes, this is an early
question, but you can see that it is still a very modern question as well. This has created an
extremely intriguing representation of God. We offend him by his own consent; he even forces
us to transgressions for which he will blame us. He not only knows about it beforehand […],
but he caused it! Wenn Gott alles vorher bestimmt und weiß, wie kann der Mensch sündigen? So wurde ja früher
gefragt, und sehen Sie, es ist noch immer eine ganz moderne Fragestellung. Eine ungemein
intrigante Vorstellung von Gott hatte man sich da gemacht. 90
Thomas Hobbes. Leviathan: Or, The Matter, Forme & Power of a Commonwealth,
Ecclesiasticall and Civill (London: Andrew Crooke, 1651), 62, https://books.google.
com/books?id=L3FgBpvIWRkC&pg=PA62 89
John Toews. The Story of Original Sin (Eugene, OR: Wipf and Stock Publishers, 2013), 76. 87
Brinley Roderick Rees. Pelagius: Life and Letters (Woodbridge: Boydell Press, 1998), 54.
88
Ibid., 76. destinees”) (Lorris and de Meun [1965], v.3. ll. 17695–96). Robert Musil’s modern
reaction to this dilemma is fully Pelagian: colloquial tone used between women differed from that used today, and
what modern readers deem erotic was simply tender.66 Man beleidigt ihn mit seinem
Einverständnis, er zwingt den Menschen zu einer Verfehlung, die er ihm übelnehmen wird; er
weiß es ja nicht nur vorher […], sondern er veranlaßt es! Der Mann Ohne Eigenschaften [The Man Without Qualities] (Berlin: Rowohlt Verlag,
1957), 485–86. Der Mann Ohne Eigenschaften [The Man Without Qualities] (Berlin: Rowohlt Verlag,
1957), 485–86. Der Mann Ohne Eigenschaften [The Man Without Qualities] (Berlin: Rowohlt Verlag,
1957), 485–86. 87
Brinley Roderick Rees. Pelagius: Life and Letters (Woodbridge: Boydell Press, 1998), 54. 88
Ibid., 76.
4. The Troubadours and Fin’amor: Love, Choice, and the Individual 151 that “the ignorant vulgar are at fault”91 for allowing themselves to be
persuaded “that mankind has not, in truth, been created good, because
it is able to do evil”,92 insisting that we are “capable of both good and
evil”,93 but that either involves an exercise of will: “neither good nor
evil is done without the will”.94 And the will can be trained; it is not
hopelessly corrupt as the result of an inherent fault, a fundamental
brokenness or wickedness in human nature, but weakened as a result
of “being instructed in evil”,95 in no small part by those, like Augustine,
who preach that human nature is fundamentally evil due to inherited
sin. Pelagius, like Rousseau, thinks people are basically good and need
only a little development, maturation, and guidance. In the words of
the seventeenth-century English Pelagian, John Milton, they require
education. Milton’s belief that human beings are not irretrievably
wicked is made clear in his 1644 treatise Of Education, where he outlines
the ultimate purpose of human education: “The end of learning is to
repair the ruins of our first parents by regaining to know God aright,
and out of that knowledge to love him, to imitate him, to be like him, as
we may the nearest by possessing our souls of true virtue”.96 The troubadours are more closely aligned to this Pelagian (and
Miltonic) point of view that the world and its people are basically
good. 91
“imperitum vulgus offendit” (Pelagius. Pelagii Sancti et eruditi monachi
Epistola ad Demetriadem, ed. by Johann Salomo Semler [Halae Magdeburgicae:
Carol
Herman
Hemmerde,
1775],
14,
https://books.google.com/books?id=
uw5qbOfGtgoC&pg=PA14). 97
The more recognizably orthodox point of view is memorably expressed in the
sixteenth-century English poet George Gascoigne’s poem “Gascoigne’s Good
Morrow”, where readers are informed that we must “deeme our days on earth, / But
hell to heavenly joye” (The Complete Works of George Gascoigne: Vol. 1, The Posies, ed. 93
“boni et mali capacem etiam” (ibid., 32, https://books.google.com/books?id=
uw5qbOfGtgoC&pg=PA32). 95
“mali etiam esse studuimus” (ibid., 34, https://books.google.com/books?id=
uw5qbOfGtgoC&pg=PA34). 94
“nec bonum sine voluntate faciamus, nec malum” (ibid.). 92
“non vere bonum factum hominem putes, quia is facere malum potest” (ibid.). 96
John Milton. Of Education (London: 1644), Sig. A1v, https://books.google.com/
books?id=7rJDAAAAcAAJ&pg=PP4 91
“imperitum vulgus offendit” (Pelagius. Pelagii Sancti et eruditi monachi
Epistola ad Demetriadem, ed. by Johann Salomo Semler [Halae Magdeburgicae:
Carol
Herman
Hemmerde,
1775],
14,
https://books.google.com/books?id=
uw5qbOfGtgoC&pg=PA14).
92
“non vere bonum factum hominem putes, quia is facere malum potest” (ibid.).
93
“boni et mali capacem etiam” (ibid., 32, https://books.google.com/books?id=
uw5qbOfGtgoC&pg=PA32).
94
“nec bonum sine voluntate faciamus, nec malum” (ibid.).
95
“mali etiam esse studuimus” (ibid., 34, https://books.google.com/books?id=
uw5qbOfGtgoC&pg=PA34).
96
John Milton. Of Education (London: 1644), Sig. A1v, https://books.google.com/
books?id=7rJDAAAAcAAJ&pg=PP4
97
The more recognizably orthodox point of view is memorably expressed in the
sixteenth-century English poet George Gascoigne’s poem “Gascoigne’s Good
Morrow”, where readers are informed that we must “deeme our days on earth, / But
hell to heavenly joye” (The Complete Works of George Gascoigne: Vol. 1, The Posies, ed. colloquial tone used between women differed from that used today, and
what modern readers deem erotic was simply tender.66 This is the heritage that the troubadours passed down to the
Renaissance and eventually to our own time: the idea that nature is
good and love is an end in itself, not something to be denied or escaped
from, not a trap, not an object of shame, but a source of joy.97 It contains
a hint of later ideas to come, like the carpe diem motif of so much English 152 Love and its Critics Renaissance poetry. From this point of view, the claims of this life, and
this world, rather than the airy promises of a future existence, take on an
urgency that is otherwise denied them. In the view of the troubadours,
“not heaven but this blossoming earth was to be recognized as the true
domain of love, as it is of life”.98 Hand-in-hand with this immediacy of
earthly life and love, goes a concept of individualism that is vital for
understanding the troubadours and their poetry: The troubadour’s new time expresses a new individualism. […] It is the
Occitan troubadour, with his self-promoting songs of desperate love
for the wife of his patron, who ignores war and nation to disguise a
revolutionary individualist intent (whether as illicit desire or as social
gain) behind the spiritual quality of true love. He is a figure who is from
our perspective recognizably Keatsian, certainly Romantic, and therefore
perceptively modern and out of his time.99 There is, of course, no shortage of critics who will deny such a proposition,
arguing instead for the near-inaccessibility of medieval poetry. One
such critic is Paul Zumthor, who insists that “A first obvious piece of
evidence becomes clear to our eyes: the remoteness of the Middle Ages,
and the irrecoverable distance that separates us […]. Medieval poetry
belongs to a universe that has become foreign to us”.100 For Zumthor: When a man of our century confronts a work of the twelfth century,
the time that separates one from the other distorts, or even erases the
relationship that ordinarily develops between the author and the reader
through the mediation of the text: such a relationship can hardly be
spoken of any more. What indeed is a true reading, if not an effort that
involves both the reader and the culture in which the reader participates,
an effort corresponding to that textual production involving the author
and his own universe? by John W. Cunliffe [Cambridge: Cambridge University Press, 1907], 57, https://
archive.org/stream/cu31924013121292#page/n68).
98
Campbell, Creative Mythology, 183.
99
Elizabeth Fay. Romantic Medievalism: History and the Romantic Literary Ideal (New
York: Palgrave, 2002), 15.
100 “Une première évidence éclate aux yeux: l’éloignement du moyen âge, la distance
irrécupérable qui nous en sépare […] la poésie médiévale relève d’un univers qui
nous est devenu étranger” (Paul Zumthor. Essai de Poétique Médiévale [Paris: Seuil,
1972], 19). 101 Lorsqu’un homme de notre siècle affronte une œuvre du XIIe siècle, la durée qui les sépare l’un
de l’autre dénature jusqu’à l’effacer la relation qui, ordinairement, s’établit entre l’auteur et le
lecteur par la médiation du texte: c’est à peine si l’on peut parler encore de relation. Qu’est-ce
en effet qu’un lecture vraie, sinon un travail où se trouvent à la fois impliqués le lecteur et la
culture à laquelle il participe? Travail correspondant à celui qui produsuit le texte et où furent
impliqués le auteur et son propre univers. A l’égard d’un texte médiéval, la correspndance
ne se produit plus spontanément. La perception même de la forme devient équivoque. Les
métaphores s’obscurcissent, le comparant s’écarte du comparé. Le lecteur reste engagé dans son
temps; le texte, par un effet tenant à l’accumulation des durées intermédiaires, apparaît comme
hors du temps, ce qui est une situation contradictoire.
Ibid 20 103 Lucien Febvre. The Problem of Unbelief in the Sixteenth Century: The Religion of
Rabelais. Trans. by Beatrice Gottlieb (Cambridge, MA: Harvard University Press,
1985), Translator’s Introduction, xxviii. 102 See Michael Bryson, The Atheist Milton (London: Routledge, 2012), 36–50. 104 [S]pricht man vom Geist einer Zeit, vom Geist des Mittelalters, der Aufklärung. Damit ist
zugleich gegeben, daß jede solcher Epochen eine Begrenzung findet in einem Lebenshorizont.
Ich verstehe darunter die Begrenzung, in welcher die Menschen einer Zeit in bezug auf ihr
Denken, Fühlen und Wollen leben. Es besteht in ihr ein Verhältnis von Leben, Lebensbezügen,
Lebenserfahrung und Gedankenbildung, welche die Einzelnen in einem bestimmten Kreis colloquial tone used between women differed from that used today, and
what modern readers deem erotic was simply tender.66 In respect to a medieval text, the correspondence
no longer occurs spontaneously. The perception of form becomes
ambiguous. Metaphors are darkened, comparisons no longer make
4. The Troubadours and Fin’amor: Love, Choice, and the Individual 153 sense. The reader remains embedded within his own time; while the
text, through an effect produced by the passage of time, seems timeless,
which is a contradictory situation.101 But to give in to an idea like this, is to give in to an absolute and
unprovable claim which is structurally identical to the mentalités idea
of Lucien Febvre, who argued in 1947 that there was no such thing as
an atheist in the Renaissance (despite the fact that many were accused
of atheism, and even executed on the charge102) because “the mental
equipment available in the sixteenth century made it as good as
impossible for anyone to be an atheist, and, perhaps more important,
[…] an atheist could only have been a solitary figure to whom nobody
would have paid any significant attention”.103 Febvre’s claim, in turn,
has its roots in the work of Wilhelm Dilthey (1910), for whom one speaks of the spirit of a time, of the spirit of the Middle Ages, or
the Enlightenment. At the same time, it is a fact that in such epochs
limitations are met with in the form of a life-horizon. By that, I mean the
limit on the people of a time in terms of their life’s thinking, feeling, and
will. There is a proportion of life, lifestyle, experience, and ability to form
concepts, which tightly binds the individual within a certain range of
modifications of opinions, value formation, and purposes. Inevitabilities
rule herein over particular individuals.104 104 [S]pricht man vom Geist einer Zeit, vom Geist des Mittelalters, der Aufklärung. Damit ist
zugleich gegeben, daß jede solcher Epochen eine Begrenzung findet in einem Lebenshorizont. Ich verstehe darunter die Begrenzung, in welcher die Menschen einer Zeit in bezug auf ihr
Denken, Fühlen und Wollen leben. Es besteht in ihr ein Verhältnis von Leben, Lebensbezügen,
Lebenserfahrung und Gedankenbildung, welche die Einzelnen in einem bestimmten Kreis 104 [S]pricht man vom Geist einer Zeit, vom Geist des Mittelalters, der Aufklärung. Damit ist
zugleich gegeben, daß jede solcher Epochen eine Begrenzung findet in einem Lebenshorizont. Ich verstehe darunter die Begrenzung, in welcher die Menschen einer Zeit in bezug auf ihr
Denken, Fühlen und Wollen leben. 108 Simon Gaunt. “The Châtelain de Couci”. In The Cambridge Companion to Medieval
French Literature, ed. by Simon Gaunt and Sarah Kay (Cambridge: Cambridge
University Press, 2008), 96. von Modifikationen der Auffassung, Wertbildung und Zwecksetzung festhält und bindet. von Modifikationen der Auffassung, Wertbildung und Zwecksetzung festhält und bindet.
Unvermeidlichkeiten regieren hierin über den einzelnen Individuen.
Wilhelm Dilthey. Der Aufbau der geschichtlichen Welt in den Geisteswissenschaften
(Frankfurt am Main: Suhrkamp, 1970), 217. colloquial tone used between women differed from that used today, and
what modern readers deem erotic was simply tender.66 Es besteht in ihr ein Verhältnis von Leben, Lebensbezügen,
Lebenserfahrung und Gedankenbildung, welche die Einzelnen in einem bestimmten Kreis 154 Love and its Critics Foucault makes a similar argument, insisting that “in a given culture and
time, there is never more than one episteme that defines the conditions
of possibility of all knowledge”.105 Such claims, if taken seriously,
render it almost futile to read the poetry of any era or any culture that
is separated from one’s own by enough time, and geographic and/or
linguistic difference, because of the differences between the mentalités
and life-horizons (Lebenshorizont) and epistemes of the past and the
present. Claims like this (commonly made, though rarely substantiated)
allow the scholar to put up “No Trespassing” signs, warning away
interested—though non-specialist—readers, and creating what amount
to obscure literary fiefdoms ruled over by critics who have blanketed
their subject areas in a forbidding darkness.106 Zumthor insists that “the song is its own proper subject, without a
predicate. […] The poem is its own mirror”.107 From this point of view,
Zumthor sees all poetry as “self-referential”, a structure “in which the
‘I’ who speaks has a purely grammatical function, devoid of reference
to anything other than the act of singing which it performs, records,
re-enacts, and anticipates”.108 Though Zumthor says that “this is not a von Modifikationen der Auffassung, Wertbildung und Zwecksetzung festhält und bindet. Unvermeidlichkeiten regieren hierin über den einzelnen Individuen. Wilhelm Dilthey. Der Aufbau der geschichtlichen Welt in den Geisteswissenschaften
(Frankfurt am Main: Suhrkamp, 1970), 217. 105 “Dans une culture et à un moment donné, il n’y a jamais qu’une épistémè, qui définit
les conditions de possibilité de tout savoir” (Les mots et les choses: Une archéologie des
sciences humaines [Paris: Gallimard, 1966], 179). 105 “Dans une culture et à un moment donné, il n’y a jamais qu’une épistémè, qui définit
les conditions de possibilité de tout savoir” (Les mots et les choses: Une archéologie des
sciences humaines [Paris: Gallimard, 1966], 179). 106 Rita Felski describes this impulse as one in which “the critic feels impelled to beat
off the barbarians by raising the drawbridge—a too-drastic response that cuts off
the text from the moral, affective, and cognitive bonds that infuse it with energy and
life. Thus the literary work is treated as a fragile and exotic artifact of language, to
be handled only by curators kitted out in kid gloves” (The Limits of Critique, 28). 107 “Le chanson et ainsi son propre sujet, sans prédicat […] Le poèmee est miroir de
soi” (Zumthor, 218). von Modifikationen der Auffassung, Wertbildung und Zwecksetzung festhält und bindet.
Unvermeidlichkeiten regieren hierin über den einzelnen Individuen. 105 “Dans une culture et à un moment donné, il n’y a jamais qu’une épistémè, qui définit
les conditions de possibilité de tout savoir” (Les mots et les choses: Une archéologie des
sciences humaines [Paris: Gallimard, 1966], 179). 114 “Das beharrende Element der esoterischen Haltung, der Feudaladel, wird sich
mehr und mehr der Interessenverschiebung bewußt, die ihn vom Kleinadel
immer entscheidender trennt” (Erich Köhler. “Zum ‘Trobar Clus’ Der Trobadors”.
Romanische Forschungen, 64: 1–2 [1952], 101). Köhler goes on to argue that the “trobar
clus” serves as as “deepening of the conscious sense of one’s own existence”, and
“as a mystical recovery and concealment of the sense of being” (“Vertiefenwollen
des bewußt werdenden Sinns der eigenen Existenz, als ein mystisches Bergen und
gleichzeitiges Verbergen der vom standischen Sein”) (98). colloquial tone used between women differed from that used today, and
what modern readers deem erotic was simply tender.66 She
then notes that “[s]uch a vision of reading remains notably silent on the question
of how literature enters life” (28–29). R. Howard Bloch and Stephen G. Nichols
describe a similar attitude, decrying what they see as the use of “philological
expertise […] not as a tool to make medieval literature accessible, but as a cordon
sanitaire to prevent the reading of such works” (“Introduction”. In Medievalism and
the Modern Temper, ed. by R. Howard Bloch and Stephen G. Nichols [Baltimore:
Johns Hopkins University Press, 1996], 3). 106 Rita Felski describes this impulse as one in which “the critic feels impelled to beat
off the barbarians by raising the drawbridge—a too-drastic response that cuts off
the text from the moral, affective, and cognitive bonds that infuse it with energy and
life. Thus the literary work is treated as a fragile and exotic artifact of language, to
be handled only by curators kitted out in kid gloves” (The Limits of Critique, 28). She
then notes that “[s]uch a vision of reading remains notably silent on the question
of how literature enters life” (28–29). R. Howard Bloch and Stephen G. Nichols
describe a similar attitude, decrying what they see as the use of “philological
expertise […] not as a tool to make medieval literature accessible, but as a cordon
sanitaire to prevent the reading of such works” (“Introduction”. In Medievalism and
the Modern Temper, ed. by R. Howard Bloch and Stephen G. Nichols [Baltimore:
Johns Hopkins University Press, 1996], 3). 107 “Le chanson et ainsi son propre sujet, sans prédicat […] Le poèmee est miroir de
soi” (Zumthor, 218). 107 “Le chanson et ainsi son propre sujet, sans prédicat […] Le poèmee est miroir de
soi” (Zumthor, 218). 107 “Le chanson et ainsi son propre sujet, sans prédicat […] Le poèmee est miroir de
soi” (Zumthor, 218). 108 Simon Gaunt. “The Châtelain de Couci”. In The Cambridge Companion to Medieval
French Literature, ed. by Simon Gaunt and Sarah Kay (Cambridge: Cambridge
University Press, 2008), 96.
4. The Troubadours and Fin’amor: Love, Choice, and the Individual 155 claim for the freezing of the text”,109 that is, in effect, what has happened to
a great deal of troubadour criticism. 110 This is a curious reworking of what Holmes calls a “Burckhardtian opposition
of medieval conformism, or community values, and Renaissance individualism”
(Olivia Holmes. Assembling the Lyric Self: Authorship from Troubadour Song to Italian
Poetry [Minneapolis: University of Minnesota Press, 2000], 3). 113 See Simon Gaunt, “Poetry of Exclusion: A Feminist Reading of Some Troubadour
Lyrics”. The Modern Language Review, 85: 2 (April 1990), 310–29. 112 See Tilde Sankovitch, “The Trobairitz”. In The Troubadours: An Introduction, ed.
by Simon Gaunt and Sarah Kay (Cambridge: Cambridge University Press, 1999),
113–26. 109 “On ne prétend pas en cela geler le texte” (Zumthor, 20). 111 “des analogies simplifiantes et des justifications mythiques” (Zumthor, 20). 115 Simon Gaunt and Sarah Kay. “Introduction”. In The Troubadours: An Introduction,
ed. by Simon Gaunt and Sarah Kay (Cambridge: Cambridge University Press,
1999), 4. Emphasis added.
116 E. Jane Burns. “Courtly Love: Who Needs It? Recent Feminist Work in the Medieval
French Tradition”. Signs: Journal of Women in Culture and Society, 27: 1 (Autumn
2001), 40. It is important to note, however, that for Köhler, this is not necessarily
true of the troubadours who write in the “trobar leu” or open style. Speaking of the
poet Guirat de Bornelh, Köhler argues for the importance of recognizing desire and
joy in this style of troubadour poetry: “Whoever knows the meaning of “joy” in the
troubadors, […] in the interrelationship with the woman as the source, […] who
knows this notion as the dominant motif of Provençal poetry, is able to measure
what the light style [or trobar leu] must mean for Guiraut” (“Wer um den Sinn
des ‘joy’ bei den Trobadors weiẞ, […] in der Wechselbeziehung zur Frau als ihrer
Quelle […] wer diese Vorstellung als das beherrschende Motiv der provenzalischen
Dichtung erkennt, vermag zu ermessen, was der leichte Stil für Guiraut bedeuten
muẞ”) (Köhler, 91–92). In a later article, Köhler makes a clear distinction between
the two styles, arguing that for the high nobility, obscurity served as an insiders’
code from which the lower nobility (to say nothing of the common people) were
excluded: “the obscure and difficult style, the trobar clus, is suitable for the high
nobility, who speak an esoteric language to set up a barrier between the profane and
the treasure of true love, to which they [the high nobility] alone must have access”
(“le style obscur et difficile, le trobar clus, convient à la haute noblesse, qui parle
une langue ésotérique pour mettre à l’abri des profanes le trésor du vrai amour,
auquel elle seule doit avoir accès”) (“Observations historiques et sociologiques sur
la poésie des troubadours”. Cahiers de civilisation médiévale, 7: 25 [1964], 31, http://
www.persee.fr/doc/ccmed_0007–9731_1964_num_7_25_1296).
117 L
i 207 colloquial tone used between women differed from that used today, and
what modern readers deem erotic was simply tender.66 Zumthor’s assertion that there is an
unbridgeable gap between the medieval era and our own was followed
by the insistence that the poems must not be understood as being about
love and desire in any real and still-understandable sense, but about
language and performance.110 This tendency has been exacerbated by
Zumthor’s concomitant claim that any attempt by a modern reader to
read twelfth-century work is doomed because “the period that separates
one from the other distorts, or even erases the relationship” necessary
for understanding. Despite the caveat Zumthor adds about not applying
“simplified analogies and mythical justifications”111 this is precisely what
a number of critics of the last few decades have done, applying French
feminist thought,112 or making accusations of troubadour misogyny and
narcissism,113 or arguing that what appear to be love poems are actually
disguised representations of political struggles. The latter is argued by
Erich Köhler, for whom the more esoteric style of troubadour poetry
(the closed song or trobar clus) indicates a class struggle between higher
and lower levels of nobility: “the persistent element of esotericism in
the attitude of the feudal nobility, becomes more and more a deliberate
stance that crucially separates it from the lower nobility”.114 Köhler not
only “argued vigorously that the troubadour lyric mediated the tension
between the different sections of the nobility” but he also maintained Love and its Critics 156 that “the erotic love to which the songs were ostensibly devoted was
invariably a metaphor for other desires, other drives”.115 As E. Jane
Burns explains it, the passions expressed in the troubadour poems are
merely masks, disguising the desire for wealth, status, and power: [T]roubadour poets’ professed love of the domna actually masked a
concerted social aspiration to be elevated to the status of her husband. Thus could poor, landless knights of the lower nobility attempt to attain
higher standing (Köhler 1964). colloquial tone used between women differed from that used today, and
what modern readers deem erotic was simply tender.66 […] Provencal love songs [have] less to
do with eroticism, passion, or desire than with class conflict between the
disenfranchised squirine and the established nobility (Köhler 1970).116 One has to marvel at the lengths to which scholars will go to rewrite
poetry in order to “consistently read love songs as about anything
but love”.117 And as one follows Burns’ explanation a little further,
the idea at work becomes clear—what is aimed at is nothing less than
the dissolving of the text in the solvent of criticism: “The courtly lady
dissolves further in Lacanian analyses of lyric and romance where she One has to marvel at the lengths to which scholars will go to rewrite
poetry in order to “consistently read love songs as about anything
but love”.117 And as one follows Burns’ explanation a little further,
the idea at work becomes clear—what is aimed at is nothing less than
the dissolving of the text in the solvent of criticism: “The courtly lady
dissolves further in Lacanian analyses of lyric and romance where she 115 Simon Gaunt and Sarah Kay. “Introduction”. In The Troubadours: An Introduction,
ed. by Simon Gaunt and Sarah Kay (Cambridge: Cambridge University Press,
1999), 4. Emphasis added. 116 E. Jane Burns. “Courtly Love: Who Needs It? Recent Feminist Work in the Medieval
French Tradition”. Signs: Journal of Women in Culture and Society, 27: 1 (Autumn
2001), 40. It is important to note, however, that for Köhler, this is not necessarily
true of the troubadours who write in the “trobar leu” or open style. Speaking of the
poet Guirat de Bornelh, Köhler argues for the importance of recognizing desire and
joy in this style of troubadour poetry: “Whoever knows the meaning of “joy” in the
troubadors, […] in the interrelationship with the woman as the source, […] who
knows this notion as the dominant motif of Provençal poetry, is able to measure
what the light style [or trobar leu] must mean for Guiraut” (“Wer um den Sinn
des ‘joy’ bei den Trobadors weiẞ, […] in der Wechselbeziehung zur Frau als ihrer
Quelle […] wer diese Vorstellung als das beherrschende Motiv der provenzalischen
Dichtung erkennt, vermag zu ermessen, was der leichte Stil für Guiraut bedeuten
muẞ”) (Köhler, 91–92). 115 Simon Gaunt and Sarah Kay. “Introduction”. In The Troubadours: An Introduction,
ed. by Simon Gaunt and Sarah Kay (Cambridge: Cambridge University Press,
1999), 4. Emphasis added.
116 E J
B
“C
l L
Wh N
d I ? R
F
i i
W
k i
h M di
l 117 Longxi, 207. colloquial tone used between women differed from that used today, and
what modern readers deem erotic was simply tender.66 In a later article, Köhler makes a clear distinction between
the two styles, arguing that for the high nobility, obscurity served as an insiders’
code from which the lower nobility (to say nothing of the common people) were
excluded: “the obscure and difficult style, the trobar clus, is suitable for the high
nobility, who speak an esoteric language to set up a barrier between the profane and
the treasure of true love, to which they [the high nobility] alone must have access”
(“le style obscur et difficile, le trobar clus, convient à la haute noblesse, qui parle
une langue ésotérique pour mettre à l’abri des profanes le trésor du vrai amour,
auquel elle seule doit avoir accès”) (“Observations historiques et sociologiques sur
la poésie des troubadours”. Cahiers de civilisation médiévale, 7: 25 [1964], 31, http://
www.persee.fr/doc/ccmed_0007–9731_1964_num_7_25_1296). 117 L
i 207
4. The Troubadours and Fin’amor: Love, Choice, and the Individual 157 becomes a textualized object of masculine desire, a metaphor for the
enigma of femininity and a cipher for male poetic practice”.118 This
argument has long been a paradigm in studies of troubadour poetry. Frederick Goldin argues that the women being addressed in troubadour
poems are essentially mirrors that reflect the troubadour back to
himself, showing him what he “wants to become” but also “what he can
never be”.119 Burns argues that the apparent passions of the troubadour
poems are actually “a misreading of the feminine in terms of the
masculine”,120 while O’Sullivan states the case baldly, openly using the
what appears to be X is really Y formula: “[t]he male-authored canso is
narcissistic in nature: while it may be ostensibly about the praiseworthy
Other, it’s really about praising the Self”.121 Tilde Sankovitch turns
the troubadours into auto-eroticists, claiming that Narcissus serves as
a model for “the troubadours’ self-referential erotic quest for beauty
and perfection” while the poetry refers not to “the domna’s intimate
Otherness but to the poet’s wish to penetrate into his own perfection’s
space”.122 All of these arguments follow Paris in furthering the trend
of violent ideological impositions tracing back to the early thirteenth
century, by subordinating the troubadours and their poetry to the
concepts and dictates of outside authority. The pen and the sword are
merely different means to the same end. 118 Burns, 40.
119 Frederick Goldin. The Mirror of Narcissus and the Courtly Love Lyric (Ithaca: Cornell
University Press, 1967), 75.
120 Jane E. Burns. Courtly Love Undressed: Reading through Clothes in Medieval French
Culture (Philadelphia: University of Pennsylvania Press, 2002), 252, n. 14.
121 Daniel O’Sullivan. “The Man Backing Down from the Lady in Trobairitz Tensos”.
In Founding Feminisms in Medieval Studies: Essays in Honor of E. Jane Burns, ed. by
Laine E. Doggett and Daniel E. O’Sullivan (Cambridge: Boydell & Brewer, 2016), 45.
122 Tilde Sankovitch. “Lombarda’s Reluctant Mirror: Speculum of Another Poet”. In
The Voice of the Trobairitz: Perspectives on the Women Troubadours, ed. by William
Paden (Philadelphia: University of Philadelphia Press, 1989), 184, 185. colloquial tone used between women differed from that used today, and
what modern readers deem erotic was simply tender.66 What is especially noteworthy is how closely the critics adhere to a
basic paradigm, essentially repeating each other’s arguments with some
minor changes in terminology and theory. The effect is like listening to
a chorus singing a song with only one verse, each singer replicating the
others, with minor variations available only in the register and timbre
of the voices, whose individuality is otherwise lost in the repetitiveness
of the musical theme. And it has to be asked, if this is truly all that 158 Love and its Critics troubadour poetry is, why read any of it, much less any of the criticism
which shows so much disdain for it? This kind of argument, despite
its theoretical and secular sheen, is fundamentally religious in nature,
reflecting the assumptions of the Akibas and Origens of the world
for whom a text must be forced to obey, forced to yield a morally (or
theoretically) edifying sense or be righteously and roundly accused,
before being abandoned altogether. As Longxi points out, for such
readers, this has long meant systematically turning away from the literal
meanings of words and texts: As allegory etymologically means “speaking of the other”, in reading this
we should then understand it as that. Of the four levels (or the fourfold
scheme) of meaning, which constitute the theoretical foundation of
biblical allegory, the least important or relevant to true understanding,
according to the allegorists, is the literal sense. The revelation of the
Spirit must be at the cost of the suppression of the Letter. For Origen and
his followers, the written word should be cast off and forgotten in order
to free the spirit of the Logos from the shell of human language.123 Along similar lines, and with similar goals in mind, Gregory Stone uses
what he calls a “grammatical” argument—similar to that of Zumthor,
but based on categories from Dante’s De Vulgari Eloquentia—to erase the
individuality of the troubadour poets by claiming that it never existed
in the first place. 123 Longxi, 200.
124 Gregory B. Stone. The Death of the Troubadour: The Late Medieval Resistance to the
Renaissance (Philadelphia: University of Pennsylvania Press, 1994), 4.
125 Ibid. Renaissance (Philadelphia: University of Pennsylvania Press, 1994), 4.
125 Ibid. 124 Gregory B. Stone. The Death of the Troubadour: The Late Medieval Resistance to the
Renaissance (Philadelphia: University of Pennsylvania Press, 1994), 4.
125 Ibid. 123 Longxi, 200. colloquial tone used between women differed from that used today, and
what modern readers deem erotic was simply tender.66 His argument is based on the notion of a “mature
rejection of the new Renaissance model of the self-determining singular
ego, a model with which the late Middle Ages is already quite familiar
yet regards as a lie”.124 While one wonders how such notably retiring,
self-effacing personalities as Guilhem IX and his famous granddaughter
Eleanor of Aquitaine would react to such an idea, Stone goes on to
maintain that “[t]he Middle Ages consciously insists that I am they:
that the individual subject is never singular, is always in some essential
sense general, collective, objective”.125 Miraculously, an entire era and
all of its people can be described as insisting that “I am they”, as if the
scene in Monty Python’s Life of Brian where Graham Chapman’s Brian
insists to the crowd “You are all individuals”, while they respond in
4. The Troubadours and Fin’amor: Love, Choice, and the Individual 159 unison, “Yes. We are all individuals” has been inverted and turned into
an interpretive principle.126 As Daniel Heller-Roazen demonstrates, critics frequently claim that
the “I” in medieval texts testifies to the absence of poetic individuality: [t]he critical works on the problem of the medieval poetic “I” concur
precisely in their uncertainty about the referential status of the first-
person pronoun; and in many instances they deny, implicitly or
explicitly, the possibility of attributing the “I” of a medieval author
to a historical individual. […] the “I” is not the name of an actual
individual but essentially the product of a rhetorical operation, [and]
the significatum of the first-person pronoun in medieval poetry cannot
be presupposed by criticism. […] The “I”, which for many recent critics
of “literary subjectivity” is what names an actual being, is precisely
what, for many medieval authors, appears to express a fundamental
anonymity: something without any determined nature or properties, a
work of artifice and fiction in every sense. The definition of the “I” as the
sign of an existing subject, which appears almost self-evident today, is
therefore foreign to the texts of medieval literature.127 The syllogistic argument here is as familiar as it is threadbare: 1) Critics
concur about their “uncertainty” over the meaning of “I” in medieval
poetry. 2) The “I” appears to such critics to “express a fundamental
anonymity”. 3) Therefore the “I” (as “the sign of an existing subject”
or actual person) is “foreign to medieval texts”. p
y
127 Daniel Heller-Roazen. Fortune’s Faces: The Roman de la Rose and the Poetics of
Contingency (Baltimore: Johns Hopkins University Press, 2003), 30, 33. And so
Heller-Roazen essentially repeats Stone’s repetition of Zumthor. With such
repetition careers are made. And so it continues… 126 https://www.youtube.com/watch?v=QereR0CViMY colloquial tone used between women differed from that used today, and
what modern readers deem erotic was simply tender.66 Die Cultur der Renaissance in Italien: Ein Versuch (Basel:
Schweighauser, 1860), 131, https://babel.hathitrust.org/cgi/pt?id=gri.ark:/13960/
t7fr4fg3z;view=1up;seq=137
130 G
bl
b
hi
h
i
h
h
R
i
i
ibl
f 129 In Burckhardt’s formulation, the condescension is nearly overwhelming:
In the Middle Ages the two sides of consciousness—that turned toward the world and that
turned toward the inner self of man—were dreaming or half awake under a common veil. The
veil was woven of faith, childish partiality, and delusion, through which the world and its
history appeared in miraculous hues, but Man recognized himself only as a race, a people, a
party, a corporation, a family, or otherwise in any general or common form. Im Mittelalter lagen die beiden Seiten des Bewußtseins—nach der Welt hin und nach dem
Innern des Menschen selbst—wie unter einem gemeinsamen Schleier träumend oder
halbwach. Der Schleier war gewoben aus Glauben, Kindesbefangenheit und Wahn; durch
ihn hindurch gesehen erschienen Welt und Geschichte wundersam gefärbt, der Mensch aber Im Mittelalter lagen die beiden Seiten des Bewußtseins—nach der Welt hin und nach dem
Innern des Menschen selbst—wie unter einem gemeinsamen Schleier träumend oder
halbwach. Der Schleier war gewoben aus Glauben, Kindesbefangenheit und Wahn; durch
ihn hindurch gesehen erschienen Welt und Geschichte wundersam gefärbt, der Mensch aber
erkannte sich nur als Race, Volk, Partei, Corporation. Familie oder sonst in irgend einer Form
des Allgemeinen. Jacob Burckhardt. Die Cultur der Renaissance in Italien: Ein Versuch (Basel:
Schweighauser, 1860), 131, https://babel.hathitrust.org/cgi/pt?id=gri.ark:/13960/
t7fr4fg3z;view=1up;seq=137 130 Greenblatt bases his case on the notion that the Renaissance is responsible for
establishing a sense of individuality of which earlier periods were incapable:
“Something happened in the Renaissance, something that surged up against the
constraints that centuries had constructed around curiosity, desire, individuality,
sustained attention to the material world, the claims of the body” (The Swerve: How
the World Became Modern [New York: W. W. Norton & Co., 2011], pp. 9–10). But such
expressions of “desire, individuality, sustained attention to the material world,
[and] the claims of the body” are readily evident in the poetry of the troubadours,
trobairitz, and Minnesingers, as well as the earlier work of the Greek erotici, Ovid,
and the writer(s) of the Song of Songs. colloquial tone used between women differed from that used today, and
what modern readers deem erotic was simply tender.66 The conclusion simply
does not follow from the premises, but in arguments of this type that
is almost irrelevant; the authoritative tone is intended to carry the day. The “I” is simply asserted to be “the product of a rhetorical operation”,
without any argument or evidence being put forward to support
this, and successive critics perform essentially this same maneuver
in analyses of medieval poetry. Their thinking is is “governed to a
remarkable degree by [Jacob] Burckhardt’s apparently ineradicable
[nineteenth-century] assumption that in the Middle Ages ‘man was
conscious of himself only as a member of a race, people, party, family, Love and its Critics 160 or corporation’”,128 a case that critics like Zumthor, Heller-Roazen, and
Stone repeat practically word-for-word,129 and which forms one of the
governing assumptions for Stephen Greenblatt’s much-contested book
The Swerve.130 This repetition from one critic to the next functions as a
kind of groupthink by which modern critics who mimic one another’s
voices deny the individuality of medieval men and women: 128 Lee Patterson. “On the Margin: Postmodernism, Ironic History, and Medieval
Studies”. Speculum, 65: 1 (January 1990), 95. p
(J
y
)
129 In Burckhardt’s formulation, the condescension is nearly overwhelming:
In the Middle Ages the two sides of consciousness—that turned toward the world and that
turned toward the inner self of man—were dreaming or half awake under a common veil. The
veil was woven of faith, childish partiality, and delusion, through which the world and its
history appeared in miraculous hues, but Man recognized himself only as a race, a people, a
party, a corporation, a family, or otherwise in any general or common form. Im Mittelalter lagen die beiden Seiten des Bewußtseins—nach der Welt hin und nach dem
Innern des Menschen selbst—wie unter einem gemeinsamen Schleier träumend oder
halbwach. Der Schleier war gewoben aus Glauben, Kindesbefangenheit und Wahn; durch
ihn hindurch gesehen erschienen Welt und Geschichte wundersam gefärbt, der Mensch aber
erkannte sich nur als Race, Volk, Partei, Corporation. Familie oder sonst in irgend einer Form
des Allgemeinen. Jacob Burckhardt. 131 Patterson, 97.
132 G. B. Stone, 4.
133 Ibid., 5.
134 William Blake. The Works of William Blake, Vol. 2, ed. by Edwin John Ellis and
William Butler Yeats (London: Benard Quartich, 1893), 323, https://archive.org/
stream/worksofwilliambl02blakrich#page/323 colloquial tone used between women differed from that used today, and
what modern readers deem erotic was simply tender.66 The historian John Monfasani describes
Greenblatt’s book as a “Burckhardtian, or, perhaps more accurately, Voltairean
view of the Renaissance as an outburst of light after a long medieval darkness”,
and calls it an echo of Burckhardt’s “caricature of the poor benighted medievals as
incapable of conceiving of themselves other than as part of some corporate structure
(as opposed to us liberated modern individualists)” (“The Swerve: How the
Renaissance Began”. Reviews in History, 1283, http://www.history.ac.uk/reviews/
review/1283). Marjorie Curry Woods argues that Greenblatt “reinforces a tired old
master-narrative, in which one or another renaissance man changes the world”
(“Where’s the Manuscript”. Exemplaria, 25: 4 [Winter 2013], 322), while John Parker
calls Greenblatt’s account “a venerable and familiar story” (“The Epicurean Middle
Ages”. Exemplaria, 25: 4 [Winter 2013], 325), and Lee Morrissey and Will Stockton
refer to it as a kind of monstrosity or caricature: “New Historicism on steroids
(all anecdotes, all the time)” (“What Swirls around The Swerve”. Exemplaria, 25: 4
[Winter 2013], 334, https://doi.org/10.1179/1041257313Z.00000000036).
4. The Troubadours and Fin’amor: Love, Choice, and the Individual 161 What this fashionable prose produces is of course that most reactionary
of accounts, a hierarchical Middle Ages in which not merely alternative
modes of thought but thought per se is proscribed—an account that at
one stroke wipes out not merely the complexity of medieval society but
the centuries of struggle by which medieval men and women sought to
remake their society.131 What this fashionable prose produces is of course that most reactionary
of accounts, a hierarchical Middle Ages in which not merely alternative
modes of thought but thought per se is proscribed—an account that at
one stroke wipes out not merely the complexity of medieval society but
the centuries of struggle by which medieval men and women sought to
remake their society.131 Following obediently along with his scholarly tribe, Stone then takes
from Dante the idea that “Grammar, which is nothing else but a kind
of unchangeable identity of speech in different times and places […]
[has] been settled by the common consent of many peoples, [and] seems
exposed to the arbitrary will of none in particular”132 before going on to
make the crucial gesture of erasure: The language of troubadour song is “grammatical” in the sense that it is
universal: troubadour song, says Dante, “suffuses its perfume in every
city, yet it has its lair in none”. 135 G. B. Stone, 6.
136 Ibid.
137 An infinitely expandable and flexible principle whereby anything can be defined
into or out of existence at the whim of authority.
138 G. B. Stone, 6.
139 Lewis Carroll. Through the Looking Glass: And what Alice Found There (Philadelphia:
Henry Altemus Company, 1897), 123. colloquial tone used between women differed from that used today, and
what modern readers deem erotic was simply tender.66 The locus of song is everywhere in general
and nowhere in particular, its place is no place. […] The language of
troubadour love poetry does not permit the identification of its speaker
as a certain historical and singular individual: the time and place of the I
is no particular time and no particular place. Grammar or the language of
song transcends the concrete historical situation; in Heideggerian terms,
it is an ontological rather than an ontic language; it expresses Being in
general rather than a certain particular being.133 And thus, rather neatly, individual poets can be erased, and the
passions their poems expressed can be transformed from those of living
men and women to generalized expressions of “Being”, and love—a
passion between individuals who have been lifted clean out of time and
existence—no longer exists except as a function of “grammar”. Such arguments, reducing individuality to generality, bring to mind
William Blake’s statement that “[t]o generalize is to be an Idiot”.134
But to be fair, what is on display here is not so much idiocy as it is
a carefully-constructed limiting of poetry’s ability to reach potential
readers. Readings like those of Zumthor or Stone cannot erase the 162 Love and its Critics existence of the poems, and cannot prevent readers from reading the
poems, but they do attempt to dictate the terms on which readers can
understand those poems. This is one of the primary problems readers
encounter in much of the literary scholarship and criticism of the last
several decades—an insistence, exercised through analytical terms that
seek to make disagreement either impossible or easily-dismissible as
“naive” or “uninformed”, that poetry must be read against its apparent
grain, that its human life and light must be drained out of it as it is
transformed into an allegory for whatever the critic seeks to impose on
readers. 140 This idea can be seen, among other places, in Paul de Man’s assertion that language
ultimately refers only to itself, because of a “discrepancy between the power of
words as acts and their power to produce other words” (The Rhetoric of Romanticism
[New York: Columbia University Press, 1984], 101), though he complicates his
argument with the assertion that literature and criticism are one and the same,
equally unreliable: “[l]iterature as well as criticism—the difference between them
being delusive—is condemned (or privileged) to be forever the most rigorous and,
consequently, the most unreliable language in terms of which man names and
transforms himself” (Allegories of Reading, 19). colloquial tone used between women differed from that used today, and
what modern readers deem erotic was simply tender.66 In Stone’s case, readers, if they are to avoid being naive, must
understand these poems as mere artifacts of “an anonymous or universal
language, as essentially identical to the language of others”,135 lifeless
items that are “always repeating the same rather than saying something
different, repeating the topoi, the conventions of courtly love poetry”.136
It comes as no surprise, then, that from this critical point of view, the
expression of genuine human emotion is impossible, because for such a
critic it seems that there is no genuine human emotion to be expressed
in the first place. Making an argument that sounds like a distillation of
Kafka’s nightmare scenarios of bureaucratic imprisonment and Joseph
Heller’s Catch-22,137 Stone argues that the attempt to express individual
emotions makes one precisely not individual. Citing Jonathan Culler’s
work On Deconstruction as his authority, Stone delivers what he fancies
is the death blow: “Saying ‘I love you’, […] is always a convention, a
citation; it does not so much distinguish an individual as it makes him
resemble everyone else”.138 Such a critical position takes a for thee but not for me stance, exempting
itself as the special case to which its own reductive principles do not
apply. My language, says the critic, signifies what I mean it to signify; as
Humpty-Dumpty would have it: “When I use a word […] it means just
what I choose it to mean—neither more nor less”.139 The poet’s language,
however, is merely “conventional”, a series of “tropes” that refer, not to
4. The Troubadours and Fin’amor: Love, Choice, and the Individual 163 any extra-linguistic reality, but to language itself.140 Thus, poetry always
and only refers to poetry, revealing the inherent impossibility of its
doing otherwise. But the work of the critic is never conceived as being
subject to the same limitations—criticism does not refer only to itself, but
claims authority over any and all other forms of discourse, including—
and especially—the discourse of poetry. And like Plato, it seems that
critics would deny poetry a place in their carefully-wrought Republic. 142 Simon Gaunt and Sarah Kay. “Introduction”. In The Troubadours: An Introduction,
ed. by Simon Gaunt and Sarah Kay (Cambridge: Cambridge University Press,
1999), 6. 141 Sarah Kay. Subjectivity in Troubadour Poetry (Cambridge: Cambridge University
Press, 1990), 212–13. colloquial tone used between women differed from that used today, and
what modern readers deem erotic was simply tender.66 There has been some resistance to this trend, notably from Sarah
Kay, whose argument in Subjectivity in Troubadour Poetry tries to
recover the notion that the “I” of troubadour lyric may, in fact, refer
to actual persons: There is evidence of a relationship between the lyric first person and
the characters of other medieval genres, which suggests that medieval
readers were prepared to take the first person as referring to an
ontological entity (a person). […] The subject then, can be read not just
as a grammatical position, but as articulating a self.141 Truly, a dizzyingly radical notion. Simon Gaunt and Sarah Kay have
suggested that “perhaps the time has come now to reassess the nature of
love in troubadour poetry and to take what the troubadours said about
themselves seriously again”.142 The fact that such a statement needs
to be made at all is remarkable. The critics here admit that they have
dismissed the troubadours’ testimony about themselves, and confess
that the trend has gone too far and gone on for too long: “[s]ince 1945
[…] concerted efforts have been made to downplay (or at the very
least to reinterpret) the significance of what made troubadour poetry 164 Love and its Critics famous in the first place: love”.143 Such efforts have a lengthy history,
long preceding the period the critics here refer to, and a clear agenda in
service of “the power which demands submission”.144 But if the critics are set aside, it is easy to see that the troubadours
celebrate love, often with a frank eroticism that is reminiscent of the
Song of Songs. The troubadours celebrate love and desire in a way that
is true to immediate experience, true to the life that men and women
of flesh actually inhabit, an attitude that may have been an unexpected
side-effect of the first Crusades: [T]he crusaders had discovered the marvels across the seas with their
own eyes. 143 Ibid.
144 L. T. Topsfield. Troubadours and Love (Cambridge: Cambridge University Press,
1975), 39.
145 Lazar, 62.
146 Ibid., 71.
147 Ibid., 71–72.
148 Ibid., 74. colloquial tone used between women differed from that used today, and
what modern readers deem erotic was simply tender.66 A new world had revealed itself to them: a civilization that
was not Christian, that accorded a positive attitude to life on earth, that
gave free expression to love and sensual pleasures rather than dwelling
on sin, contrition, and penitence.145 The troubadours are dedicated to an ethos that is “a secular unchristian
idea of love […] a love dominated by a strong expression of sensuality
and eroticism, free from any principle of sin and guilt, achristian and
amoral in the context of prevalent church standards”.146 And though, as
Lazar bemusedly notes, “[a] good number of scholars have attempted
to allegorize it and represent it as essentially religious and mystical in
nature” these arguments are little more than “a wishful denial of the
adulterous tenor of fin’amor and an exercise in literary exorcism”.147
The troubadours do not—as Dante and Petrarch will do—climb a
Neoplatonic ladder of love in search of God. In fact, “[i]n the fin’amor
tradition of the twelfth century, one might say that God is always on
the side of the adulterous lovers and never on that of the deceived
husband”.148 The troubadours and trobairitz write a poetry that insists love and life
is to be experienced now, here, without unnecessary delay and needless
obstacles. The beauty they celebrate is here, in living and breathing
4. The Troubadours and Fin’amor: Love, Choice, and the Individual 165 never-to-be-replicated individuals. In a sense, these poems illustrate the
dynamic of the central scene in Raphael’s painting The School of Athens,
where Plato and Aristotle walk together, while Plato points up to the
heavens and Aristotle points down to the Earth to indicate where each
man saw truth, beauty, and reality as having its origin. Unlike so many
of the Italian and English poets who will follow them, the troubadours
point—with Aristotle—to the Earth beneath their feet. In these poems,
you are invited to see, not through an allegory or the doctrines of a
philosophical position, but through a pair of eyes; and what these eyes
are gazing into is not a gateway to a soul, or a vision of the love that
moves the sun and the other stars—they are gazing with rapture and
delight into the eyes of another person just like you. 149 Robert S. Briffault. The Troubadours (Bloomington: University of Indiana Press,
1965), 25.
150 Elizabeth Salter. “Courts and Courtly Love”. In The Medieval World, ed. by David
Daiches and Anthony Thorlby (London: Aldus Books, 1973), 424. III
The Troubadours and Love The roots of the troubadour poetic tradition are obscure. One prominent
argument suggests that it is indebted to Spanish-Arabic poetry of the
eleventh century in terms of its themes and motifs: Spanish-Arabian poetry […] celebrates love as the highest form of
happiness and the noblest source of inspiration; it sings of the beloved’s
beauty, the sorrow of the rejected lover and the cruelty of the lady. It introduces new fashions in composition, as in its hymns to Spring. Anticipating Provençal lyrics by close on two centuries, Hispano-
Moorish poetry was the only one, in Europe, to cultivate those themes
and to exhibit those characteristics.149 According to this interpretation, it was through “contacts with the courts
of Aragon and Castile, […] intermarriage such as that of Guilhem of
Poitou with Philippa of Aragon in 1094, and [ongoing] political dealings
that knowledge of Hispano-Arabic love philosophies and love poetry
of the tenth and eleventh centuries came to the courts and poets”150
of Occitania. We can see, if not direct influence, at least shared poetic Love and its Critics 166 genes, by looking at a Spanish Arabic poem contemporary to those of
the troubadours. This twelfth-century work, “Gentle Now, Doves of
the Thornberry and Moringa Thicket”, by a poet named Ibn Arabi,151
demonstrates many of the same themes of yearning and devotion to
human, embodied love. The poet fears the “sad cooing”152 of the doves will betray him, and
asks them not to “reveal the love I hide / the sorrow I hide away”.153
This love, and its sorrow, leads to thoughts of “a grove of tamarisks”
where “spirits wrestled, / bending the limbs down over me, / passing
me away”, bringing him “yearning”, and “breaking of the heart”.154 The
tamarisks may reference the story of Abraham, or as the Qur’án refers to
him, Ibrahim, who plants a tamarisk grove in Genesis 21 as a recognition
of the struggle, negotiation, and coming to peace in a property dispute
between Abraham and Abimelech. The wrestling of the spirits could
be those of the two ancient patriarchs, or it could be something more
like the struggle captured in the story of Abraham’s grandson, Jacob,
who wrestles, not with an angel, but with El (God) himself, reflected in
the name he is given in Genesis 32:28 after the dusk-to-dawn wrestling
match, “Israel”, or, “he struggled with God”. 151 The translation used here is that of Michael Sells, in Maria Rosa Menocal, Shards of
Love: Exile and the Origins of the Lyric (Durham, NC: Duke University Press, 1994),
70–71.
152 Ibid., l. 6.
153 Ibid., ll. 7–8
154 Ibid., ll. 13–18.
155 Ibid., ll. 39–40. 151 The translation used here is that of Michael Sells, in Maria Rosa Menocal, Shards of
Love: Exile and the Origins of the Lyric (Durham, NC: Duke University Press, 1994),
70–71.
152 Ibid l 6 III
The Troubadours and Love Perhaps this captures part
of Arabi’s suggestion, but references to “yearning” and “breaking of the
heart”, raise the possibility that something more intimate and personal
is happening. Is it more of an internal struggle, the spirit who took me
and forced me to struggle with and confront my own yearning? Perhaps
the spirit Arabi is wrestling with is the difficulty he experiences in
discovering the meaning of his own yearnings, the desires that dogmatic
religion would tell him to reject. This wrestling leads Arabi through images of a “faithless” woman
“who dyes herself red with henna”,155 a person (perhaps a tradition)
practiced in taking the devotion of another, soaking it up, and then
throwing that other away. The image evokes a woman who soaks up a
dying man’s blood with her own hair, draining the life of a fool who gave
4. The Troubadours and Fin’amor: Love, Choice, and the Individual 167 it in return for nothing. Finally, Arabi comes to the extremity of saying
that “the house of stone” (a house of worship blessed by the Prophet of
Islam) pales in comparison to “a man or a woman”.156 The Ka’bah, the
cubic building in Mecca that is circled seven times counterclockwise—
what does that mean, what significance does that hold, when compared
to the living reality of the man or woman standing in front of you? Even
the sacred books, the Torah, the Qur’án, are held lightly next to what
Arabi calls “the religion of love”, pledging that “wherever its caravan
turns along the way, / that is the belief, / the faith I keep”.157 What the
poem suggests is the necessity of struggling with and accepting one’s
own yearnings before coming to a place of peace. We are not sinful
because we desire; we are not broken because we want. This is an
emphatically humane vision. 156 Ibid., ll. 35–36.
157 Ibid., ll. 57–60.
158 Menocal, 75.
159 William Blake. “The Marriage of Heaven and Hell”. In The Complete Poetry and Prose
of William Blake, ed. by David V. Erdman (Berkeley and Los Angeles: University of
California Press, 2008), 35. III
The Troubadours and Love While this poem is not exactly the same in its emphasis as the
troubadour poems, it makes precisely the same kinds of people
uncomfortable: “the poem is the ‘yes and no’ that makes the Averroist—
and all other priests—blanch […] [due to its] intractable and purposeful
blurring of sacred and profane love”.158 The power in this work is that
of the individual perspective, of singular passion, of the realization that
there is something more important in this world than can be found
in the traditional symbols and institutions of law, religion, state, and
family. Each of these speak a language that essentially boils down to the
same demand: “obey”. But the “religion of love” is not about obeying. It
is about being led where passion, insight, and desire lead you—the path
Blake called “the road of excess” which “leads to the palace of wisdom”.159 The road of excess was the favored highway of the first troubadour
poet, Guilhem IX, the duke of Aquitaine and Count of Poitou (modern
Poitiers). He was a man who did not care for any authority other than
his own—twice excommunicated from the Church, on the first occasion
he threatened to behead the bishop who pronounced the sentence, only
to think better of it and tell the cleric whose neck was already extended
for the sword’s blow: “you shall never enter Heaven with the help of 168 Love and its Critics my hand”. The second time, Guilhem was excommunicated for refusing
to give up his mistress, the Viscountess of Châtellraut, telling the bald
bishop of Angoulême that “the comb shall curl your wayward hair
before I give up the Viscountess”.160 Guilhem was a man of action and of words, who had a “sardonic wit:
he ordered that his mistress’s portrait should be painted on his shield
[…] declaring that ‘it was his will to bear her in battle as she had borne
him in bed’”.161 His poems combine frank enjoyment of sex with longing
for love, but the clearest indication of his preference for love in deeds
rather than merely in words can be seen in the final lines of his poem Ab
la dolchor del temps novel (In the sweetness of the new times): Que tal se van d’amor gaban
Nos n’avem la pessa e·l coutel.162
Those others vainly talk of love
But we have a piece [of bread], and a knife. g
p g
163 Ibid., 21, ll. 25–28, https://archive.org/stream/leschansonsdegui00willuoft#page/21 160 Topsfield, 12–13.
161 Helen Castor. She-Wolves: The Women Who Ruled England Before Elizabeth (London:
Faber and Faber, 2010), 133–34.
162 Guillaume IX. Les Chansons de Guillaume IX, Duc d’Aquitaine, ed. by Alfred Jeanroy
(Paris: Honoré Champion, 1913), 26, ll. 29–30, https://archive.org/stream/leschanso
nsdegui00willuoft#page/26
163 Ibid., 21, ll. 25–28, https://archive.org/stream/leschansonsdegui00willuoft#page/21 160 Topsfield, 12–13. 162 Guillaume IX. Les Chansons de Guillaume IX, Duc d’Aquitaine, ed. by Alfred Jeanroy
(Paris: Honoré Champion, 1913), 26, ll. 29–30, https://archive.org/stream/leschanso
nsdegui00willuoft#page/26 III
The Troubadours and Love Love was not sublimated in worship for Guilhem—its passions were
raw, and its excitements were those of the heart, the eyes, and the senses. In Farai chansoneta nueva (I will write a new song), Guilhem asks what
the use could possibly be in withdrawing from the world of life, love,
and pleasure: Qal pro y auretz, s’ieu m’enclostre
E no·m retenetz per vostre? Totz lo joys del mon es nostre,
Dompna, s’amduy nos amam.163 What can it bring you if I cloister myself
And you do not keep me for your own? All the joys of the world are ours
Lady, if we love each other in turn.
4. The Troubadours and Fin’amor: Love, Choice, and the Individual 169 This idea of lovers loving each other in turn is one of the first and most
basic elements of the concept that will come to be called fin’amor. As the
later poet Bernart de Ventadorn argues, love must be mutual in order
for it to be true. Though Guilhem wishes for a mutual love, he also wishes for a
physical love, and the physicality of his desire is made clear in a number
of places. In Ben vuelh que sapchon li pluzor (I want everyone to know),
he writes of “a bawdy game” (“un joc grossier”)—in which, after being
told “your dice are too small” (“vostre dat som menudier”), he “raised
the table” (“levat lo taulier”) and then “tossed the dice” (“empeis los
datz”), upon which toss “two of them rolled and the third plumbed
the depths” (“duy foron cairavallier / e·l terz plombatz”).164 A poem in
which a man attempts to prove that two of his “dice” are not too small
for that third one to plombatz is not a poem with any great allegorical
potential. Neither is Companho faray un vers…convinen (I will make a
poem as it should be), in which Guilhem compares two mistresses to
horses he greatly enjoys riding:165 Dos cavalhs ai a ma selha ben e gen;
Bon son e adreg per armas e valen;
Mas no·ls puesc amdos tener que l’us l’autre non cossen. Si·ls pogues adomesjar e mon talen,
Ja no volgra alhors mudar mon guarnimen,
Que miels for’ encavalguatz de nuill [autr’] ome viven.166 Dos cavalhs ai a ma selha ben e gen;
Bon son e adreg per armas e valen;
Mas no·ls puesc amdos tener que l’us l’autre non cossen. 166 Guillaume IX, 1, ll. 7–12, https://archive.org/stream/leschansonsdegui00willuoft#
page/n24 164 Ibid., 15–16, ll. 45, 51, 57–60, https://archive.org/stream/leschansonsdegui00willuoft
#page/15 165 As Peter Dronke asks, “would it ever have occurred to any reader or listener to
interpret” such poems as this, or many other troubadour verses, “in any other
than a sexual way if scholars had not invented the troubadours’ ‘platonic’ love?”
(Dronke, 242, n. 3). III
The Troubadours and Love Si·ls pogues adomesjar e mon talen,
Ja no volgra alhors mudar mon guarnimen,
Que miels for’ encavalguatz de nuill [autr’] ome viven.166 I have two horses, noble and good for my saddle:
Good and strong in combat and valor;
But I can’t keep both, because they hate each other. If I could tame them to my desire,
I would not move my equipment anywhere else,
For I would be mounted better than any man alive. 164 Ibid., 15–16, ll. 45, 51, 57–60, https://archive.org/stream/leschansonsdegui00willuoft
#page/15 165 As Peter Dronke asks, “would it ever have occurred to any reader or listener to
interpret” such poems as this, or many other troubadour verses, “in any other
than a sexual way if scholars had not invented the troubadours’ ‘platonic’ love?”
(Dronke, 242, n. 3). 170 Love and its Critics In Ab la dolchor del temps novel, Guilhem prays for nothing so much as the
gift of more life, and more erotic love—not in words, but in the deeds
forbidden by the churchmen who speak in “foreign Latin”: Enquer me lais Dieus viure tan
C’aja mas manz soz so mantel. Qu’eu non ai soing d’estraing lati
Que·m parta de mon Bon Vezi.167 God give me a life long enough
To get my hands beneath her dress. For I have no fear that foreign Latin
Will part me from my Good Neighbor. This is not “courtly love”. This is the expression of frankly physical
desire. The first troubadour was not a man who regarded love as a path
to the divine, or the woman right in front of him as a window through
which he should learn to see God. For the passionate and sometimes
violent Guilhem, love was a crucial part of a life here and now that is to
be celebrated without apology and without genuflection to gods above
or devils below. Love—in all its emotional and physical glories—needed
no justification. Guilhem was a man many modern academics would
not like, and the feeling would probably be mutual. Ab la dolchor del temps novel is a poem that openly praises “the
physical love which can be desired, hoped for, shared and enjoyed”.168
The poem’s “switch from delicacy” to “rough desire” is “characteristic
of Guilhem and intentional”—especially in the “jest at those who talk
and never do”,169 where Guilhem anticipated at least a few of his later
critics. 167 Ibid., 26, ll. 23–26, https://archive.org/stream/leschansonsdegui00willuoft#page/26
168 Topsfield, 27.
169 Ibid.
170 Sarah Spence, for example, insists that “the lady here is presented as a Christ figure”
(Texts and the Self in the Twelfth Century [Cambridge: Cambridge University Press,
1996], 91), basing this on the lines “And since I wish to return to joy / It is right, that
I seek for the best” (“E pus en joy vuelh revertir / Ben dey, si puesc, al mielhs anar”) 170 Sarah Spence, for example, insists that “the lady here is presented as a Christ figure”
(Texts and the Self in the Twelfth Century [Cambridge: Cambridge University Press,
1996], 91), basing this on the lines “And since I wish to return to joy / It is right, that
I seek for the best” (“E pus en joy vuelh revertir / Ben dey, si puesc, al mielhs anar”) 167 Ibid., 26, ll. 23–26, https://archive.org/stream/leschansonsdegui00willuoft#page/26
168 Topsfield, 27.
169 Ibid (Guillaume IX, 21–22, ll. 3–4). The lenses of “courtly love”, once donned, appear to
make it impossible to see otherwise.
171 “Per lo cor dedins refrescar / E per la carn renovellar” (Guillaume IX, 23, ll. 34–35,
https://archive.org/stream/leschansonsdegui00willuoft#page/23).
172 Topsfield, 36.
173 Guillaume IX, 17, ll. 19–20, https://archive.org/stream/leschansonsdegui00willuoft#
page/17
174 Topsfield, 30.
175 Ibid. Reddy repeats this distinction throughout his discussion of Guilhem’s poetry
(92–104). III
The Troubadours and Love In Mout jauzens me prenc en amar (I take a great joy in love), a
favorite of those commentators who try to squeeze Guilhem into the
category of “courtly love”,170 he writes of keeping love for himself, “to
4. The Troubadours and Fin’amor: Love, Choice, and the Individual 171 refresh the heart / and renew the flesh”,171 in verses that present “all
excellence in physical reality”.172 And yet, Guilhem had something of
the sceptic of Ecclesiastes about him, as if desire’s fulfillment would
never really bring him what he hoped for. In Pus vezem de novel florir
(Since we see new blossoms), Guilhem complains: Per tal n’ai meyns de bon saber
Quar vuelh so que no puesc aver173
So I know less than any what is good
Because I want what I cannot get. Per tal n’ai meyns de bon saber
Quar vuelh so que no puesc aver173
So I know less than any what is good
Because I want what I cannot get. Per tal n’ai meyns de bon saber
Quar vuelh so que no puesc aver173 So I know less than any what is good
Because I want what I cannot get. This scepticism leads him to the position (adopted perhaps, only in his
more reflective of moments) that Tot is niens—all is nothing, rather in
the fashion of Koheleth, from Ecclesiastes 1:14: רָ אִ֙ יתִ י֙ אֶ ת־ כָּל־ הַֽ מַּעֲשִ ׂ ֔ ים שֶֽ ׁנַּעֲׂש֖ ּו תַ ּ ֣ חַת הַשָ ּׁ ֑ מֶׁש וְהִ נֵּ֥ה הַכֹּ ֛ ל הֶ֖בֶל ּורְ ע֥ ּות רֽ ּוחַ׃ רָ אִ֙ יתִ י֙ אֶ ת־ כָּל־ הַֽ מַּעֲשִ ׂ ֔ ים שֶֽ ׁנַּעֲׂש֖ ּו תַ ּ ֣ חַת הַשָ ּׁ ֑ מֶׁש וְהִ נֵּ֥ה הַכֹּ ֛ ל הֶ֖בֶל ּורְ ע֥ ּות רֽ ּוחַ׃ I have seen all the works done beneath the sun; behold, all are vanity, a
striving after the wind. In Topsfield’s view, “Guilhem appears to reject Amors as an embryonic
regulated system of courtly wooing. He is dissatisfied with it and the
small amount of Jois it affords. He stands to one side and looks for
the Jois which is the reward of each individual man”,174 an individual
man who loves, wholly and physically, an individual woman, but not
in accordance with anyone’s expected code of behavior, courtly or
otherwise. 174 Topsfield, 30. 172 Topsfield, 36. 176 Ibid., 39.
177 Ibid.
178 Marcabru., ed. by Jean Dejeanne (Toulouse: Édouard Privat, 1909), XXXVII, 178–83,
l. 28, http://gallica.bnf.fr/ark:/12148/bpt6k4240c/f191.image
179 Topsfield, 83–84.
180 Marcabru, ll. 14, 20, 51, http://gallica.bnf.fr/ark:/12148/bpt6k4240c/f191.image and
http://gallica.bnf.fr/ark:/12148/bpt6k4240c/f193.image p
180 Marcabru, ll. 14, 20, 51, http://gallica.bnf.fr/ark:/12148/bpt6k4240c/f191.image and
http://gallica.bnf.fr/ark:/12148/bpt6k4240c/f193.image 179 Topsfield, 83–84. p
g
p
g
182 Charles Camproux argues that mutuality and equality are the primary characteristics
of fin’amor: “Cette notion d’égalité entre les partenaires est une des plus importantes
qui entrent dans la conception de l’amour chez les troubadours” [This notion of
equality between partners is one of the most important that go into the concept of
love in the troubadours] (Charles Camproux. Le “joy d’amor” des troubadours. Jeu et
joie d’amour [Montpellier: Causse et Castelnau], 1965, 179). 183 Topsfield, 103. 181 Ibid., ll. 61–62, http://gallica.bnf.fr/ark:/12148/bpt6k4240c/f194.image III
The Troubadours and Love Discussion of this poem has long been divided over whether
it is “a burlesque” or “a serious love lyric”.175 The dichotomy is a false
one, reflecting a Neoplatonic, anti-body, anti-sex bias. For Guilhem,
the so-called burlesques (a term imposed by scholars) and the so-called 172 Love and its Critics serious love lyrics (another imposition) are expressions of different
aspects of the same desire: “He desires the joys of shared love, and that
the lady shall belong to him, and he to her”.176 Guilhem was a man who bristled at restrictions, found the claims of
those who would tell him what to do intolerable and absurd, and wanted
to find a way to achieve and maintain Jois, an “individual happiness” in
a world in which Amor was constantly threatened with extinction.177 In
that way, Guilhem embodies both the troubadours’ distinctiveness and
that which made them a threat to be eliminated by thirteenth-century
Crusaders and Inquisitors, or an embarrassing excess to be allegorized
away by the Akibas and Origens of the modern academy. These poets
sought for a way to find Jois in a world of rules, laws, and demands
for obedience; they sought—even in what many scholars insist on
describing as “conventional” language—to find a way to express a new
(or long-suppressed) desire, not for stability or order, not for matrimony
and fidelity, but for love: mutual, embodied, and not to be abandoned at
the commands of any bishop, bald or otherwise. The mutuality of fin’amor, the love sought and celebrated by the
troubadours, is wonderfully expressed by Marcabru, a poet often
described as a moralist who condemned the excesses of court life. But
in Per savi·l tenc ses doptanssa (Doubtless, I think him wise), he defines
what he calls bon’Amors (good love, or the best love) as “two desires in
a single longing” (“dos desirs d’un enveia”),178 and further identifies
Jois as one of the benefits of fin’amor or bon’Amors, which itself is “the
assured happiness of a love which does not deceive”, a love that is
wholly “without deceit and cannot be degraded”.179 What Marcabru
rails against is what he calls “false love against true” (“Falss’ Amor
encontra fina”), condemning “the group of liars” (“la gen frairina”)
who slander love, and the man “whose love lives by rape and pillage”
(“car s’Amors viu de rapina”).180 Marcabru finally curses all such liars
and defamers of fin’amor:
4. 183 Topsfield, 103. III
The Troubadours and Love The Troubadours and Fin’amor: Love, Choice, and the Individual 173 La cuida per qu’el bobanssa
li sia malaventura.181 Let the ideas they are so proud of
bring them to bad ends. From the troubadours themselves, we see emerging at this point a
definition of fin’amor that is comprised of mutual desire between lovers,
honesty, and a refusal to let love be defined by social convention, or
become a vehicle of self-interest and rapina.182 As Topsfield explains: [B]ehind Marcabru’s Fin'amors there is also the idea of man as part of
the nature which was created by God, and able to respond entirely to
this nature that has been given to him […]. His merit is that he […] can
assimilate his carnal desire, which is his God-given natura, to a higher
concept of love, Fin'amors, which is constant and free from deceit.183 Here we have a poet for whom human natura is not inherently wicked,
for whom carnal sexuality is not fallen, and the body is not shameful. If
there is a “heresy” here, it is not the “Gnostic” view of the Cathars, but
the rather gentler “Pelagian” view—a belief that human nature is not
fallen and that the world is a good and beautiful place. The fact that this
is a “heresy” speaks volumes about the perversity of “orthodoxy”. From Marcabru, then, we can add another element to our definition
of fin’amor: the mutuality of bodily and sexual desire between equal
partners. The mutual desire between lovers is both physical and
emotional. It is not merely a repressed or sublimated eros; it is the fully
and powerfully physical expression of love and desire, combined with
mutual choice and honesty. It is a love which does not live by rapina,
by taking, forcing, pillaging, raping. It is a love in which we can see
dos desirs d’un’ enveia, one longing formed from two desires, one heart
formed from two. 174 Love and its Critics One reason that Marcabru is often referred to as a moralist may
be because of his oft-made distinction between fin’amor and fals’amor
(or Amar). He is angry with those who would turn love into a tool of
rapina, those for whom the pairings between lovers are either merely
about lust (Amar), or for whom money and power are the primary
motivations for their pairings (a dynamic that will become all too
familiar in Shakespeare’s plays). 185 Bernart de Ventadorn. Bernart von Ventadorn, seine Lieder, mit Einleitung und Glossar,
ed. by Carl Appel (Halle: Max Niemeyer, 1915), 188, ll. 9–10, https://archive.org/
stream/bernartvonventad00bern#page/188 184 Colin Morris. The Discovery of the Individual, 1050–1200 (New York: Harper & Row,
1972), 113. III
The Troubadours and Love For Marcabru, such people see the
world as fragmented, frait, rather than whole, entier. To adopt the path
of wholeness requires both body and mind, sexual desire and honesty,
a synthesis of the physical and spiritual that subordinates neither, an
intermingling we will see best exemplified by the centuries-later poetry
of John Donne, in a dynamic he calls a “dialogue of one”. This search for
wholeness and Jois was not a disguised religious quest. The troubadours
wrote “a poetry of desire, telling of the poet’s joy or sorrow as he waits
for his [earthly and embodied] reward”, a point perpetually—and
it seems deliberately—misconstrued by critics who argue for “the
conclusion that the poets, amid their perpetual longing, did not desire
physical intercourse with the beloved. Most of them […] frankly said
that they did. The love of which they spoke was a physical one”.184 Bernart de Ventadorn, perhaps the most passionate of all the
troubadour poets, even regards love as a necessity for survival: in Non
es meravelha s’eu chan (It is no marvel if I sing), Bernart writes that one
who does not know love is already dead: Ben es mortz qui d’amor no sen
al cor cal que dousa sabor.185 He is truly dead who has no sense of love
or its sweet savor in his heart. Bernart further develops the theme of mutual love and desire that we
have seen in Guilhem and Marcabru. In Chantars no pot gaire valer (A
4. The Troubadours and Fin’amor: Love, Choice, and the Individual 175 song can have no value), Bernart defines fin’amor as agreement and
wanting between two lovers: En agradar et en voler
es l’amors de dos fis amans. nula res no i pot pro tener,
si·lh voluntatz non es egaus.186 In pleasing and in wanting
is the love of two noble lovers. Nothing in it can be good
If the will is not mutual. 190 Morris, 113.
191 Bernart de Ventadorn, 220, ll. 1–8, https://archive.org/stream/bernartvonventad00
bern#page/220 190 Morris, 113. 186 Ibid., 86, ll. 29–32, https://archive.org/stream/bernartvonventad00bern#page/86
187 Morris, 115.
188 Charles Homer Haskins. The Renaissance of the Twelfth Century (Cambridge, MA:
Harvard University Press, 1927), 108.
189 Ibid.
190 Morris, 113.
191 Bernart de Ventadorn, 220, ll. 1–8, https://archive.org/stream/bernartvonventad00
bern#page/220 186 Ibid., 86, ll. 29–32, https://archive.org/stream/bernartvonventad00bern#page/86
187 Morris, 115.
188 Charles Homer Haskins. The Renaissance of the Twelfth Century (Cambridge, MA:
Harvard University Press, 1927), 108.
189 Ibid.
190 Morris 113 III
The Troubadours and Love For Bernart, “[i]t was love which gave purpose to life.,187 and for him,
as for other vernacular poets of the twelfth century, the love poetry of
Ovid had a tremendous influence, serving as “the highest authority in
matters pertaining to love”.188 This poetic ethos differs from that of the
later Italian poets, in whom one finds “the usual attempt to allegorize
and point a moral”.189 Bernart, who “goes far outside the conventional
into the language of passion”,190 is perhaps the best example among the
troubadours of this passionate and non-allegorical ethos. To see how Bernart both uses and transcends the “conventional”,
look at the first stanza of his poem Can l’erba fresch’e·lh folha par: Can l’erba fresch’ e·lh folha par
e la flors boton’ el verjan,
e·l rossinhols autet e clar
leva sa votz e mou so chan,
joi ai de lui, e joi ai de la flor
e joi de me e de midons major;
daus totas partz sui de joi claus e sens,
mas sel es jois que totz autres jois vens.191 e joi de me e de midons major; daus totas partz sui de joi claus e sens, 188 Charles Homer Haskins. The Renaissance of the Twelfth Century (Cambridge, MA:
Harvard University Press, 1927), 108. 189 Ibid. 176 Love and its Critics When fresh grass and leaves appear
And flowers bloom among the orchards,
And the nightingales, high and clear,
Lift their voices, pouring out their songs;
Joy to them and joy to the flowers,
And joy to me, and to my Lady even more,
Joy is all around me; Joy enfolds my mind,
But here my joy quite overwhelms the rest. By the time Bernart is writing this, in the mid to late twelfth-century,
this is already a familiar opening. We see it reflected later in Chaucer:
the opening reference to springtime, the budding of growth, and the
reawakening of nature. Chaucer writes his famous opening lines to the
Canterbury Tales, “Whan that April, with his shoures soote, / The drought
of March hath perced to the roote”, some two hundred and forty years
after Bernart, but Bernart has already perfected the metaphor. The
difference is that Bernart, unlike Chaucer, powerfully places himself
(pace Zumthor and the “no-medieval-I” chorus) into the love narrative
of his poems. 192 William D. Paden and Frances Freeman Paden, trans. Troubadour Poems from the
South of France (Cambridge, UK: Brewer, 2007), 184.
193 Ibid. 194 Bernart de Ventadorn, 222, ll. 41–45, https://archive.org/stream/bernartvonventad00
bern#page/222
195 Ibid., 221, ll. 25–28, https://archive.org/stream/bernartvonventad00bern#page/221 III
The Troubadours and Love The main theme is the repeated expression of the painful
effect of the passion he feels, the desire that he has for a woman, the lady
Aliu Anor, better known as Eleanor of Aquitaine. According to the vida
(the later biography of Bernart, ostensibly written by Uc de Saint Circ),
the love was mutual: Bernart de Ventadorn […] went to the duchess of Normandy, who was
young and of great merit, and devoted herself to reputation and honor
and praise. And the songs and verses of Sir Bernart pleased her very
much, and she received him and welcomed him warmly. He stayed in
her court a long time, and fell in love with her and she with him, and
he made many good songs about her. And while he was with her, King
Henry of England took her as his wife and took her from Normandy and
led her to England. Sir Bernart remained on this side [of the Channel],
sad and grieving, and went to the good Count Raymond of Toulouse,
and stayed with him until the count died. And because of that grief, Sir
Bernart entered the order of Dalon, and there he died.192 The vidas are later and often fanciful accounts of the poets’ lives, but
“some elements of the vida may be true”.193 If true, Bernart finds himself
4. The Troubadours and Fin’amor: Love, Choice, and the Individual 177 in an impossible situation. He has developed an urgent passion for
a woman of wealth, nobility, and power, a woman whose station far
exceeds either his reach or his grasp. And though the poems suggest that
perhaps this passion was requited at some point, Bernart often appears
to berate himself over the ridiculous inequality in terms of rank, wealth,
influence, and power between himself and his beloved. The passion that is gently suggested in Arabi’s poem is frank and
open in Bernart’s work. In Can l’erba fresch’e·lh folha par, Bernart fervently
wishes for the opportunity to find his lover alone: Be la volgra sola trobar,
que dormis, o·n fezes semblan,
per qu’e·lh embles un doutz baizar,
pus no valh tan qu’eu lo·lh deman. per Deu, domna, pauc esplecham d’amor!194 I yearn to find her all alone,
Asleep, or merely seeming so,
Because I’d steal the sweet kiss
That I am not worthy to ask for. By God, my Lady, we have little success in love! 196 Ibid., 221–22, ll. 33–40, https://archive.org/stream/bernartvonventad00bern#page/221 197 Paden, 186.
198 Barbara Smythe. Trobador Poets: Selections from the Poems of Eight Trobadors (New
York: Cooper Square Publishers, 1966), 149.
199 [In] the dawn song (Middle High German tagelied, Old Provençal alba, Old French aube) […]
two lovers embrace in the secrecy of the night before their necessary parting at the arrival
of dawn. A watchman or a little bird may take the role of an ally warning the two of the
encroaching daybreak, with dawn signalling the need for the reluctant lovers to separate in
order to avoid discovery by the spies of courtly society. It is in this moment of anguish that
joy and sorrow intermingle, and the lovers lament their impending separation by desperately
embracing one last time. Then the man leaves his beloved while she expresses her longing to see
him again soon. […] In the forbidden nature of the tryst, the relationship is adulterous since the
lady is married. Because the lovers possess no power to change their predicament, their desire
for each other may be fulfilled only in secret.
Rasma Lazda-Cazers. “Oral Sex in the Songs of Oswald von Wolkenstein: Did
it Really Happen?” In Sexuality in the Middle Ages and Early Modern Times: New
Approaches to a Fundamental Cultural-Historical and Literary-Anthropological Theme,
ed. by Albrecht Classen (Berlin: De Gruyter, 2008), 581–82. Rasma Lazda-Cazers. “Oral Sex in the Songs of Oswald von Wolkenstein: Did
it Really Happen?” In Sexuality in the Middle Ages and Early Modern Times: New
Approaches to a Fundamental Cultural-Historical and Literary-Anthropological Theme,
ed. by Albrecht Classen (Berlin: De Gruyter, 2008), 581–82. III
The Troubadours and Love Bernart cannot act on his desires because of the difference in station
between himself and his love: Tan am midons e la tenh char,
e tan la dopt’ e la reblan
c’anc de me no·lh auzei parlar,
ni re no·lh quer ni re no·lh man.195 I so love and cherish my lady,
That I am afraid and draw back;
I do not speak of myself in her hearing,
Nor do I ask for anything from her. 194 Bernart de Ventadorn, 222, ll. 41–45, https://archive.org/stream/bernartvonventad00
bern#page/222
195 Ibid., 221, ll. 25–28, https://archive.org/stream/bernartvonventad00bern#page/221 178 Love and its Critics This poem is both sexually and socially transgressive. While many
of the troubadours are knights and minor nobles, a number of them
are referred to as Joglars (from which we get our word juggler), mere
performers, like Bernart, who have nothing else to fall back on. Such
performers, because of their art, are invited into circles to which they
would normally have no access. In Bernart’s case, the singer/poet has
fallen in love with the epitome of the unattainable woman. And yet,
desire cannot and will not be reasoned with: S’eu saubes la gen enchantar,
mei enemic foran efan,
que ja us no saubra triar
ni dir re que·ns tornes a dan. adoncs sai eu que vira la gensor
e sos bels olhs e sa frescha color,
e baizera·lh la bocha en totz sens,
si que d’un mes i paregra lo sens.196 If I knew how to cast a spell;
I’d turn my enemies into infants,
So none of them could understand
Gossip, or play its hurtful games. Then I could see how nobly she turned
Her beautiful eyes, with their vibrant color,
I’d kiss her mouth so sensually,
The mark would show for a month. Though one is tempted to paraphrase Rosalind from As You Like It—try
the day, without the month—that final image is fascinating. How hard
would you have to kiss someone for the effects to show after an hour,
much less a month? Such foolishness as Bernart’s could have serious—even life and
death—consequences. The most famous story that illustrates the high
stakes of the loves the troubadour poets celebrate comes from the vida
of Guilhem de Cabestanh: Guilhem de Cabestanh [loved] a lady who was called My Lady
Sermonda, the wife of Sir Raimon del Castel de Roussillon, who was 196 Ibid., 221–22, ll. 33–40, https://archive.org/stream/bernartvonventad00bern#page/221
4. 197 Paden, 186.
b 200 Matilda Tomaryn Bruckner, Laurie Shepard, and Sarah White, eds. Songs of the
Women Troubadours (New York: Garland Publishing, 2000), 134. III
The Troubadours and Love The Troubadours and Fin’amor: Love, Choice, and the Individual 179 very rich and noble and wicked and cruel and proud. […] And the lady,
who was young and noble and beautiful and pleasing, loved him more
than anything else in the world. And this was told to Raimon del Castel
de Roussillon, and he, like a wrathful and jealous man, investigated the
story and learned that it was true and had his wife guarded closely. And
one day, Raimon del Castel de Roussillon found Guillem eating without
much company and killed him and drew his heart from his body and
had a squire carry it to his lodging and had it roasted and prepared with
a pepper sauce and had it given to his wife to eat. And when the lady
had eaten it, the heart of Sir Guilhem de Cabestanh, Sir Raimon told her
what it was. When she heard this, the lady lost sight and hearing. And
when she came around, she said, “Lord, you have given me such a good
meal that I will never eat another”. And when he heard what she said, he
ran to his sword and tried to strike her on the head, and she went to the
balcony and let herself fall, and she died.197 This story is difficult to credit as anything like literal truth, but it does
go hand in hand with other stories of the risks taken by troubadour
poets in their declarations of adulterous love. Another poet, Peire Vidal,
is said to have had his tongue cut out by the husband of his love: “a
knight of Saint Gili cut out his tongue because he gave out that he was
his wife’s lover”.198 The poetic evidence for the danger of the adulterous passions the
troubadours celebrated comes through most strongly from the alba,
the dawn song, in which two adulterous lovers are guarded by a
watchman whose job it is to warn them of the coming of the first rays
of morning.199 The night, which has been the lovers’ shelter and given Love and its Critics 180 them opportunity to act on their mutual desire, is too short, and the
dawn, which comes all too soon, threatens to expose the lovers to the
jealousy and violent reprisals of the angry husband. III
The Troubadours and Love The most famous
example is the anonymous poem, En un vergier sotz fuella d’albespi: En un vergier sotz fuella d’albespi
tenc la dompna son amic costa si
tro la gayta crida que l’alba vi,
Oy Dieus! Oy Dieus! de l’alba tan tost ve. “Plagues a Dieu ia la nueitz non falhis
ni·l mieus amicx lonc de mi no·s partis
ni la gayta iorn ni alba no vis,
Bels dous amicx, baizem nos yeu e vos
aval e·ls pratz on chanto·ls auzellos
tot o fassam en despieg de gilos,
Oy Dieus! Oy Dieus! de l’alba tan tost ve. Bels dous amicx, fassam un ioc novel
yns el iardi on chanton li auzel
tro la gaita toque son caramelh,
Oy Dieus! Oy Dieus! de l’alba tan tost ve. Per la doss’aura qu’es venguda de lay
del mieu amic belh e cortes e gay
del sieu alen ai begut un dous ray,
Oy Dieus! Oy Dieus! de l’alba tan tost ve”. La dompna es agradans e plazens
per sa beutat la gardon mantas gens
et a son cor en amar leyalmens,
Oy Dieus! Oy Dieus! de l’alba tan tost ve.200 In an orchard under leaves of hawthorn
the lady holds her lover beside her
until the watchman cries out the coming of dawn,
O God! O God! the dawn, it comes too soon. Please God, do not let the night end already
nor let my lover part from my side
nor let the watchman see the dawn,
4. The Troubadours and Fin’amor: Love, Choice, and the Individual 181 Fair sweet friend, let us kiss, you and I,
down in the meadow where the songbirds sing,
let us do all this in spite of that jealous man. O God! O God! the dawn, it comes too soon. Fair sweet friend, let us play a new game
in the garden where the songbirds sing
until the watchman plays his pipe. O God! O God! the dawn, it comes too soon. For the gentle breeze which comes from there
from my lover, beautiful, and courteous, and merry,
of his breath I have drunk a sweet ray of sun. O God! O God! the dawn, it comes too soon. The lady is delightful and pleasing
And many admire her for her beauty,
and for her heart which is true in love. O God! O God! the dawn, it comes too soon. 201 Wolfram von Eschenbach. Werke, ed. by Karl Lachmann (Berlin: G. Reimer, 1879),
3–4, https://books.google.com/books?id=-rwFAAAAQAAJ&pg=PA3 III
The Troubadours and Love The pathos of this poem is haunting, nearly nine centuries later. Two
lovers, who choose each other in the face of law, arranged marriages,
social convention, church doctrine, and the very real possibility
of getting caught and punished, wish the night could last just a few
moments longer. Only in the darkness is their freedom possible, only
at night can they feel the one they love next to them, hear the rise and
fall of breath, and know themselves as one and at peace. But with light
comes the law, with light come the claims of ownership and property,
church and state. The watchman cries out the coming of dawn so that the
lovers can escape undetected, and hopefully, live to love again another
night. The evident frustration in these poems is fueled by the absurdity
of being unable to love the one of your choice except under the cover of
darkness and lies. This poem expresses an idea we can see as early as
the Song of Songs: the right to decide for oneself, and the insistence that
love is a personal choice, a potentially risky enterprise engaged with,
and embarked upon, by two partners. The same constellation of ideas is powerfully expressed in the
tagelieder (dawn songs) of the Minnesingers (love singers) from
Germany, perhaps most memorably by the late-twelfth and early-
thirteenth-century poet Wolfram von Eschenbach in his Den morgenblic
bî wahtaeres sange erkôs: 182 Love and its Critics Den morgenblic bî wahtaeres sange erkôs
ein froue, dâ si tougen
an ir werden friundes arme lac;
dâ von si… freuden vil verlôs. des muosen liehtiu ougen
aver nazzen. sî sprach ‘ôwê tac! wilde und zam daz frewet sich dîn
und siht dich gerne,
wan ich ein. wie sol iz mir ergên! nu enmac niht langer hie bî mir bestên
mîn vriunt: den jaget von mir dîn schîn’. Der tac mit kraft al durh diu venster dranc. vil slôze si besluzzen:
daz half niht: des wart in sorge kunt. diu friundîn den vriunt vast an sich dwanc:
ir ougen diu beguzzen
ir beider wangel. sus sprach zim ir munt. ‘Zwei herze und ein lip hân wir
gar ungescheiden:
unser triuwe mit ein ander vert. der grôzen liebe der bin ich gar vil verhert,
wan sô du kumest und ich zuo dir’. Der trûric man nam urloup balde alsus. ir liehten vel diu slehten
kômen nâher. 203 Dietmar von Aist and Wolfram von Eschenbach were two of the most crucial
figures in the development of the tagelied in German poetry: “[a]round 1170 202 “The type first appears in a poem by Dietmar von Aist […], the earliest Minnesinger
who seems to have an acquaintance with troubadour lyrics” (“Tagelied”. In
Princeton Encyclopedia of Poetry and Poetics, ed. by Alex Preminger, Frank J. Warnke,
and O. B. Hardison Jr. [Princeton: Princeton University Press, 1972], 841). III
The Troubadours and Love sus der tac erschein. weindiu ougen, süezer frouen kus. sus kunden sî dô vlehten
ir munde, ir brüste, ir arme, ir blankiu bein:
swelch schiltaer entwurfe daz
geselleclîche
als si lâgn, des waere ouch dem genuoc. ir beider liebe doch vil sorgen truoc. si pflâgen minne ân allen haz.201
The morning light shone, and the Watchman The morning light shone, and the Watchman sang,
while a lady secretly
lay in the arms of her lover. The morning light shone, and the Watchman sang,
while a lady secretly
lay in the arms of her lover. The morning light shone, and the Watchman sang,
while a lady secretly
lay in the arms of her lover.
4. The Troubadours and Fin’amor: Love, Choice, and the Individual Dietmar von Aist cultivated the Tagelied as a genre already well known; about 1200
Wolfram von Eschenbach turned its conventions upside down” (William D. Paden.
“Introduction”. In Medieval Lyric: Genres in Historical Context, ed. by William D.
Paden [Urbana and Chicago: University of Illinois Press, 2000], 11). 204 Dietmar von Aist. “Slâfest du, friedel ziere”. In Des minnesangs frühling, ed. by
Friedrich Vogt (Leipzig: Verlag von S. Hirzel, 1920), 37, https://books.google.com/
books?id=DcQPAAAAMAAJ&pg=PA37
4. The Troubadours and Fin’amor: Love, Choice, and the Individual 183 Because of this, she lost all her joy,
and her moist though beaming eyes
filled with tears. She said, ‘Alas, day! everything that lives, wild and tame, rejoices over you
and longs to see you,
except for me. What will become of me? Now my beloved can no longer stay here with me,
for your light chases my lover away. The day shone powerfully through the windows,
and though they bolted many locks,
they were of no use against sorrow. The lady pressed her lover tight,
and her eye’s flowing tears
made both cheeks wet. She spoke to him with her lips:
“Two hearts and only one body we have. Inseparable,
we remain truly connected to each other. My whole happiness in love is destroyed,
unless you come back to me and I to you”. The sorrowful man would soon have departed,
but their bright, smooth bodies
came close again, although the day already shone. With weeping eyes, and the sweet lady’s kiss,
they intertwined themselves,
mouths, breasts, arms and their bright white legs. Any painter who wanted to represent
their companionship
as they lay beside each other, would be overwhelmed. Although their love caused them great care,
they gave themselves entirely to each other. ll b
h
li
l
f
li d Because of this, she lost all her joy, and her moist though beaming eyes filled with tears. She said, ‘Alas, day! everything that lives, wild and tame, rejoices over you
and longs to see you, as they lay beside each other, would be overwhelmed. In what may well be the earliest example of a tagelied poem,202 Slâfest
du, friedel ziere, Dietmar von Aist203 powerfully expresses the pain of
separation at dawn: In what may well be the earliest example of a tagelied poem,202 Slâfest
du, friedel ziere, Dietmar von Aist203 powerfully expresses the pain of
separation at dawn: 184 Love and its Critics “Slâfest du, friedel ziere
man wecket uns leider schiere:
ein vogellîn sô wol getân
daz ist der linden an daz zwî gegân”. “Ich was vil sanfte entslâfen:
nu rüefestu kint Wâfen. liep âne leit mac niht gesîn. swaz du gebiutest, daz leiste ich, friundîn mîn”. Diu frouwe begunde weinen. “Du rîtest und lâst mich einen. wenne wilt du wider her zuo mir? ôwê, du füerest mîn fröude sament dir!”204 “Do you sleep still, my dearest love? Unfortunately, we will both soon awake. 208 Though they are a minority, within the Church there are voices at this time beginning
to speak up for individual choice in marriage. In the Decretum Gratiani (c. 1140 CE),
a Benedictine monk named Gratian argues that “mutual consent makes a marriage”
(“consensus utiusque matrimonium facit”) (Corpus Iuris Canonici, Vol. 1: Decretum
Magistri Gratiani [Leipzig: Bernhard Tauchnitz, 1879. Reprint Graz: Akademische
Druck-u. Verlagsanstalt, 1959], 1091, http://www.columbia.edu/cu/lweb/digital/
collections/cul/texts/ldpd_6029936_001/pages/ldpd_6029936_001_00000604.html). 205 https://commons.wikimedia.org/wiki/File:Codex_Manesse_314v_Günther_von_
dem_Vorste.jpg
206 Catholic theologians are referring to marriage as a sacrament as early as the twelfth
century, though it will not be until the Council of Trent in 1563 that this arrangement
is formalized.
207 “ὃ οὖν ὁ Θεὸς συνέζευξεν, ἄνθρωπος μὴ χωριζέτω”.
208 Though they are a minority, within the Church there are voices at this time beginning
to speak up for individual choice in marriage. In the Decretum Gratiani (c. 1140 CE),
a Benedictine monk named Gratian argues that “mutual consent makes a marriage”
(“consensus utiusque matrimonium facit”) (Corpus Iuris Canonici, Vol. 1: Decretum
Magistri Gratiani [Leipzig: Bernhard Tauchnitz, 1879. Reprint Graz: Akademische
Druck-u. Verlagsanstalt, 1959], 1091, http://www.columbia.edu/cu/lweb/digital/
collections/cul/texts/ldpd_6029936_001/pages/ldpd_6029936_001_00000604.html). 206 Catholic theologians are referring to marriage as a sacrament as early as the twelfth
century, though it will not be until the Council of Trent in 1563 that this arrangement
is formalized. 207 “ὃ οὖν ὁ Θεὸς συνέζευξεν, ἄνθρωπος μὴ χωριζέτω”. 205 https://commons.wikimedia.org/wiki/File:Codex_Manesse_314v_Günther_von_
dem_Vorste.jpg
206 C th li th
l
i
f
i
t
i
t
l
th t
lfth
4. The Troubadours and Fin’amor: Love, Choice, and the Individual A most beautiful songbird
Has flown into the branches of the tree”. “I slept gently in your arms,
until you called: child, awake! Love without suffering cannot be:
what you command, I will do, my love”. The Lady began to cry:
“You ride away and leave me alone. When will you return to me again? Alas, you take my joy away with you!” In the alba and the tagelied, the lady and her lover are opposed by the
entire structure of the European world in which marriage is a contractual
arrangement of property, while at the lower social and economic levels it
finds its raison d’etre in the pretense of avoiding the “sin” of fornication.
4. The Troubadours and Fin’amor: Love, Choice, and the Individual 185 Codex Manesse, UB Heidelberg, Cod. Pal. germ. 848, fol. 314v Herr Günther von
dem Vorste (between 1305 and 1315).205 Codex Manesse, UB Heidelberg, Cod. Pal. germ. 848, fol. 314v Herr Günther von
dem Vorste (between 1305 and 1315).205 It becomes a sacrament of the church, controlled by religion, government,
and God.206 As Matthew 19:6, written during the height of the Roman
Imperial era, puts it, “What, therefore, God has joined together, let no
man tear apart”.207 Where is the choice for those who are married? In the
dawn songs like En un vergier sotz fuella d’albespi, and Den morgenblic bî
wahtaeres sange erkôs, we see the awareness that there can be a choice.208
But the awareness is painful because it comes with the knowledge of It becomes a sacrament of the church, controlled by religion, government,
and God.206 As Matthew 19:6, written during the height of the Roman
Imperial era, puts it, “What, therefore, God has joined together, let no
man tear apart”.207 Where is the choice for those who are married? In the
dawn songs like En un vergier sotz fuella d’albespi, and Den morgenblic bî
wahtaeres sange erkôs, we see the awareness that there can be a choice.208
But the awareness is painful because it comes with the knowledge of But the awareness is painful because it comes with the knowledge of 186 Love and its Critics being profoundly trapped. Two hearts and only one body we have, but O
God, the dawn! It comes too soon! 209 Victoria Cirlot, ed. Antología de textos románicos medievales: siglos XII–XIII (Barcelona:
Edicions Universitat Barcelona, 1984), 151–52, ll. 17–24.
4. The Troubadours and Fin’amor: Love, Choice, and the Individual The dawn comes, demands a return to
obedience and conformity and custom, and the “one body” of the lovers
torn back in two by the harsh light of day. None of this is the “courtly love” of Victorian scholarly invention. Neither are the poems written by the two poets below, who each found
love famously vexing. The twelfth-century troubadour, Raimbaut
d’Aurenga writes with frank and playful passion. In Non chant per auzel
ni per flor (I do not sing for bird or flower), Raimbaut references the
conventional vernal opening to Troubadour poetry by renouncing it. He
then writes directly and openly of his physical desire for his lover, and
the joy he takes in her: Ben aurai, dompna, grand honor
Si ja de vos m’es jutgada
Honranssa que sotz cobertor
Vos tenga nud’embrassada;
Car vos valetz las meillors cen! Q’ieu non sui sobregabaire –
Sol del pes ai mon cor gauzen
Plus que s’era emperaire!209 It shall be, Lady, a great honor
if you will grant me
the benefit under the covers
Of having you in naked embrace;
for you are worth more than a hundred;
And though I do not boast:
At this thought alone my heart joys
more than were I the emperor. The trobairitz Comtessa de Dia writes in much the same frankly erotic
fashion in the poem Estat ai en greu cossirier, in which she is explicit
about her desire to replace her husband with her lover:
4. The Troubadours and Fin’amor: Love, Choice, and the Individual
4. The Troubadours and Fin’amor: Love, Choice, and the Individual 187 Estat ai en greu cossirier
per un cavallier qu’ai agut,
e vuoil sia totz temps saubut
cum ieu l’ai amat a sobrier. Ara vei qu’ieu sui trahida
car ieu non li donei m’amor,
don ai estat en gran error
en lieig e quan sui vestida. Ben volria mon cavallier
tener un ser en mos bratz nut,
qu’el s’en tengra per ereubut
sol qu’a lui fezes cosseillier;
car plus m’en sui abellida
no fetz Floris de Blancheflor;
ieu l’autrei mon cor e m’amor,
mon sen, mos huoills e ma vida. Bels amics avinens e bos,
cora·us tenrai en mos poder,
e que iagues ab vos un ser,
e que·us des un bais amoros? 210 Bruckner, et al., 10. 211 Cirlot, 151–52, ll. 46–48.
4. The Troubadours and Fin’amor: Love, Choice, and the Individual Sapchatz, gran talan n’auria
qu·us tengues en luoc del marit
ab so que m’aguessetz plevit
de far tot so qu’eu volria.210 I have been in great distress
about a knight I once had,
I want it known for all time
how much I loved him
but now, I feel betrayed
because I did not tell him of my love
and I am in great torment
naked in my bed or fully dressed. If only I could hold my knight
naked in my arms until the dawn,
drunk with my beauty
he’d feel like he was in paradise;
for I am more in love with him 188 Love and its Critics than Floris was with Blancheflor;
I give him my heart and my love,
my mind, my eyes, and my life. Sweet lover, so charming and so good,
when will I have you in my power
to lie with you at night
and give you all my passionate kisses? Know this for certain, I greatly desire
to have you in my husband's place
as soon as you will promise me
to do everything I desire. This isn’t spiritualized adoration. These two poets do not sing for birds
or flowers, and in this breaking away from the conventional opening
of lyric poetry, these poets also break away from sexual, social, and
even psychological convention. These poets write of lovers who choose. What else can those last lines mean, “as soon as you will promise
me / to do everything I desire”, except come take me, especially after the
euphemistic line “to have you in my husband's place” (qu·us tengues en
luoc del marit)? The poets express the anxiety that they may not get the
opportunity to act on their desires. For Raimbaut: Qu’il fetz a son marit crezen
C’anc hom que nasques de maire
Non toques en lieis.—Mantenen
Atrestal podetz vos faire!211 She made her husband believe
That no man born of woman
Could say he had touched her. Soon
You will be able to prove the same thing of me! In Raimbaut’s poem, thinking of his lover, and comparing her
situation to that of the legendary Isolde, he bases his hopes on a
deception that may or may not succeed. In the Comtessa de Dia’s
poem, she has been “in great distress”, feels “betrayed”, and suffers
“in bed or fully dressed”.
4. 212 Betran de Born, 343, ll. 51–60.
4. The Troubadours and Fin’amor: Love, Choice, and the Individual The Troubadours and Fin’amor: Love, Choice, and the Individual 189 The poems by the troubadours, even the myths that surround them,
belie any notion that the love of which they write is a decorous matter
of rules and codes, of obedience demanded and given. Their poems are
filled with desire, frustration, joy, despair, and the tantalizing possibility
of freedom, of choice, of life lived, not spent in mechanical compliance
with the expectations of others. These are poems of rebellion, not
obedience, of chaos, not conformity. Perhaps this can best be illustrated
by returning briefly to Bertran de Born, the warrior troubadour more
famous for poems of war than for poems of love and desire. Even
Bertran reflects something of the larger troubadour ethos in Be·m platz
lo gais temps de pascor (I Am Pleased by the Gay Season of Spring), a
celebration of war and love in which he mocks the entire notion of sin: Amors vol drut cavalgador
bon d’armas e larc de servir,
gen parlan e gran donador
e tal qi sapcha far e dir
fors e dinz son estatge
segon lo poder qi l’es datz. E sia d’avinen solatz,
cortes e d’agradatge. E domna c’ab aital drut jaz
es monda de totz sos pechatz.212 Love wants a knightly rider for a lover,
good with arms and generous in service,
noble in speech and a lavish giver
one who knows what to say and what to do
outside and inside his realm
according to the ability he has been given. Let him be attractive, a good fit,
elegant and pleasing,
and the lady who lies with such a lover
is cleansed of all her sins. Love wants a knightly rider for a lover,
good with arms and generous in service,
noble in speech and a lavish giver
one who knows what to say and what to do
outside and inside his realm
according to the ability he has been given. Let him be attractive, a good fit,
elegant and pleasing,
and the lady who lies with such a lover
is cleansed of all her sins. Love wants a knightly rider for a lover,
good with arms and generous in service,
noble in speech and a lavish giver
one who knows what to say and what to do
outside and inside his realm
according to the ability he has been given. 213 Zumthor, 170.
214 G. B. Stone, 4.
215 Ibid., 5.
216 Bruckner et al., 130, ll. 1–15. 214 G. B. Stone, 4.
4. The Troubadours and Fin’amor: Love, Choice, and the Individual Let him be attractive, a good fit,
elegant and pleasing,
and the lady who lies with such a lover
is cleansed of all her sins. For Bertran, love is not a sin; he laughs at the idea. Love is physical
and vigorous—like war. Clearly, he doesn’t think war is a sin; it’s his 190 Love and its Critics favorite thing on earth, the very reason for living. For Bertran, the lover
should be a great warrior. The lady who is herself a great warrior in love,
who “wins” her love the way a warrior defeats an honorable enemy,
is cleansed of any foolishly-imagined “sin” of love to begin within. If
there is “sin” here, it is in the attempt to reduce this poem (and the
troubadour/trobairitz corpus in its entirety) to “a mirror of itself”,213 a
“mature rejection of the new Renaissance model of the self-determining
singular ego”,214 or “an ontological rather than an ontic language [which]
expresses Being in general rather than a certain particular being”.215
With such formulations, scholars attempt to erase a soldier, poet, and
lover who lived more fully than most of us ever will. The young singer of the anonymous ballad Coindeta Sui would no
doubt concur with Bertran. Though the song is playful, it expresses
serious determination about a serious dilemma. The singer is caught in
an arranged, loveless, and passionless marriage to a much older man. She is stewing in her own actively hostile emotions, as she is repulsed
by her husband: Coindeta sui! si cum n’ai greu cossire
per mon marit, quar ne·l voil ne·l desire. Q’eu be·us dirai per que son aisi drusa,
Coindeta sui! qar pauca son, ioveneta e tosa,
Coindeta sui! e degr’aver marit dunt fos ioiosa,
ab cui toz temps pogues iogar e rire:
Coindeta sui! Ia Deus mi·n sal se ia sui amorosa,
Coindeta sui! de lui amar mia sui cubitosa,
Coindeta sui! anz quant lo vei ne son tant vergoignosa
qu’e prec la mort qe·l venga tost aucire.216 Coindeta sui! si cum n’ai greu cossire
per mon marit, quar ne·l voil ne·l desire. Q’eu be·us dirai per que son aisi drusa,
Coindeta sui! qar pauca son, ioveneta e tosa,
Coindeta sui! e degr’aver marit dunt fos ioiosa,
ab cui toz temps pogues iogar e rire:
Coindeta sui! Ia Deus mi·n sal se ia sui amorosa,
Coindeta sui! de lui amar mia sui cubitosa,
Coindeta sui! 215 Ibid., 5. 216 Bruckner et al., 130, ll. 1–15. 217 “chant tota domna ensegnada, / del meu amic q’eu tant am e desire” (ibid., ll. 28–29).
218 Even those “who divorced because of adultery by the other party” were forced to “remain
unmarried so long as the first spouse lived” (James A. Brundage. Law, Sex, and Christian
Society in Medieval Europe [Chicago: University of Chicago Press, 2009], 244). Love and its Critics Passion must and will have an out, especially in this period when
a new way of thinking about life and the individual was emerging. But the movement these poems participated in was destroyed, as the
troubadour culture and the courts that supported it were crushed in
the Albigensian crusade (1209–29 CE). Due in large part to pressures
applied after the establishment of the Inquisition in 1232, the emphasis
changed in much of the poetry that followed: [A]fter the crusade against the Albigensians (the heretic Cathars), […]
there begins a process of psychological inhibition and repression in the
domain of love songs, a trend toward spiritualization and allegorization
that would eventually lead to the Roman de la Rose, to the dolce stil novo of
Guido Guinizelli or Cavalcanti, and to the Vita Nuova of Dante.219 However, despite the fact that the spirit of poetry was changed and
softened by a later tradition, the troubadour poems and their spirit
survived, though in dormancy. The basic assumptions of the modern
Western world have long rested on the foundational idea of individual
choice that the troubadours fought for bravely, but unsuccessfully. We,
through Shakespeare and the poets who followed him, now live, for
better or worse, in the world of the troubadour ethos—a spirit which
Shakespeare makes his own in his most powerful plays, and around
which Milton centers his crucial scene of human choice in Paradise Lost. By the seventeenth century in England, the troubadours have won a
victory more complete than the Crusaders of thirteenth-century France
could ever have imagined. However, despite the fact that the spirit of poetry was changed and
softened by a later tradition, the troubadour poems and their spirit
survived, though in dormancy. The basic assumptions of the modern
Western world have long rested on the foundational idea of individual
choice that the troubadours fought for bravely, but unsuccessfully. We,
through Shakespeare and the poets who followed him, now live, for
better or worse, in the world of the troubadour ethos—a spirit which
Shakespeare makes his own in his most powerful plays, and around
which Milton centers his crucial scene of human choice in Paradise Lost. By the seventeenth century in England, the troubadours have won a
victory more complete than the Crusaders of thirteenth-century France
could ever have imagined. 219 Lazar, 92.
220 Topsfield, 39.
221 James J. Wilhelm. Seven Troubadours: The Creators of Modern Verse (University Park:
Pennsylvania State University Press, 1970), 113.
4. The Troubadours and Fin’amor: Love, Choice, and the Individual anz quant lo vei ne son tant vergoignosa
qu’e prec la mort qe·l venga tost aucire.216 191
4. The Troubadours and Fin’amor: Love, Choice, and the Individual I’m pretty, and yet my heart’s in distress
for I have no desire for my husband. I’ll tell you all of my longing for love:
I’m pretty! I’m small, young and well-groomed,
I’m pretty! and should have a husband who gives me joy
with whom I climb, play and laugh all the time. I’m pretty! Now God save me if I ever loved him:
I’m pretty! I have not the least passion for him,
I’m pretty! yet seeing his age, I feel so ashamed,
I pray Death will come kill him, and soon. The song is about what she desires, how she will get it, and what
others should learn from her getting it. After all, she sings so that
“every lady will learn to sing / about my friend whom I so love and
desire”.217 It is very much in the spirit of Bertran de Born. Imagine a
girl of fifteen married to a man who is fifty. Imagine that they have
nothing in common (unsurprisingly), that he is a tyrant, and that his
body has decayed into undesirability, while his libido still tells him that
he is a young man, so that he is a thoroughgoing combination of all
things that would likely be considered disgusting and oppressive by a
young girl. All too often, marriages in the medieval and early modern
eras were arrangements of contentment, at best. At worst, they were
hellish traps of jealousy, disgust, lack of desire, and differences in
age or temperament. In the world of the troubadours, divorce was no
longer the practical possibility it had once been in the Roman world. For most, the only way out of a failed marriage was through the death
of the marriage partner.218 Thus the young girl of Coindeta Sui sings the
line “I pray Death will come kill him and soon”. In such circumstances
of lifelong passionless entrapment, one wonders how often death was
willing and able to oblige. 192 Love and its Critics 220 Topsfield, 39.
221 James J. Wilhelm. Seven Troubadours: The Creators of Modern Verse (University Park:
Pennsylvania State University Press, 1970), 113. Love and its Critics Perhaps it should come as no surprise that a movement so radical
as that of the troubadours was crushed. Perhaps it should be even less
surprising that so many contemporary scholars have worked so hard to
insist that there was nothing particularly remarkable about this poetry. Authority often has its way both by force and by deception, and those
who stand against “the power which demands submission”220 are often
defeated. Though “Ovid defended love against the vulgar material
Roman capitalists, [and] Bernart and his fellows seem to have faced down
the Church”,221 each suffered the consequences. Ovid was banished for
4. The Troubadours and Fin’amor: Love, Choice, and the Individual 193 life, never to see his beloved Rome again. And the troubadours, their
way of life, and even their language, were all quite nearly removed
from the Earth: “In 1539, the Ordonnance de Villers-Cotterêts established
French as the only authorized language for official documents [while]
Occitan was progressively banned from public and high-prestige
contexts and relegated to private use”.222 This denigration of all non-
langue d’oil forms reached new levels of intensity with the release of
Abbé Grégoire’s Rapport sur la nécessité et les moyens d’anéantir le patois,
et d’universaliser l’usage de la langue française (Report on the Need and
Means to Annihilate the Patois and to Universalize the Use of the French
Language) to the French National Convention in 1794. 222 Rafëu Sichel-Bazin, Carolin Buthke and Trudel Meisenburg. “Prosody in Language
Contact: Occitan and French”. Prosody and Language in Contact: L2 Acquisition,
Attrition and Languages in Multilingual Situations, ed. by Elisabeth Delais-Roussarie,
Mathieu Avanzi, and Sophie Herment (Berlin: Springer, 2015), 73–74. 223 “probablement, au lieu de la langue des Trouvères, nous parlerions celle des
Troubadours, si Paris, le centre du gouvernement, avoit été situé sur la rive gauche
de la Loire” (Henri Grégoire. Rapport sur la nécessité et les moyens d’anéantir le patois,
et d’universaliser l’usage de la langue française [Paris: Imprimerie Nationale, 1794], 8,
https://books.google.co.uk/books?id=8PB2RBNrLZYC&pg=PA8). 224 William Burgwinkle. “The Troubadours: The Occitan Model”. In The Cambridge
History of French Literature, ed. by William E. Burgwinkle, Nicholas Hammond, and
Emma Wilson (Cambridge: Cambridge University Press, 2011), 21. 226 See R. Anthony Lodge. French: From Dialect to Standard (London: Routledge, 1993), 219. 225 12–13. 1
Jean Hagstrum observes that the story of Abelard and Heloise is “an invaluable
guide to what lies behind the imaginative literatures of love” (Hagstrum 203). Love and its Critics There, Gregoire
argues that the question of language use is properly to be determined
by the winners of the centuries-long struggle between north and south
in France, while acknowledging that the contest could have turned out
differently: “probably, instead of the language of Trouvères, we would
now be speaking the language of the Troubadours, if Paris, the center of
government, had been located on the left bank of the Loire”.223 Even today, while “Italian and Catalan scholars” are commonly
taught Occitan because the language “remains a necessary step in the
acquisition of philological expertise”, in France the attitude is different:
“The northern French academy […] has gradually backed away from
medieval Occitan studies […] as something that either does not really
concern it, or as a phenomenon that can simply be alluded to—a stepping
stone to something better that replaced it’.224 This dismissive attitude
is hardly new, as demonstrated by Antoine de Rivarol’s Discours de
l’Universalité de la langue Française (1784), where he writes approvingly
of “la Langue Latine”, and “la Langue Toscane”, while referring Love and its Critics 194 dismissively to “le patois des Troubadours”.225 With the educational
reforms of Jules Ferry in 1881–82 came measures designed to prevent
schoolchildren from speaking anything other than “standard” Parisian
French.226 Visitors to le Midi can still encounter evidence of this in a sign
in an abandoned schoolhouse in Ayguatébia which says Parlez Français,
Soyez Propres—“Speak French, Be Clean”—marking what locals call la
vergonha, a policy of shaming people who speak one of the Occitanian
languages. Such words illustrate how far the enemies of troubadour
culture have been willing to go in order to “channel, reformulate, and
control” its ideas, the language(s) in which they were expressed, and
the human joys and freedoms they tried to convey. And yet, despite a
history of theological, governmental, and critical disdain and erasure,
the poetry survives. © 2017 Michael Bryson and Arpi Movsesian, CC BY 4.0 5. Fin’amor Castrated: Abelard, Heloise,
and the Critics who Deny The brief flowering of the troubadours helps us to understand the
love story, in twelfth-century Paris, of Peter Abelard and Heloise
d’Argenteuil, who lived the passions and the dangers often spoken of
in the poetry of the age. The letters between Abelard and Heloise are
among the world’s most vibrant embodiments of fin’amor,1 as well as
its most tragic testaments to the violence and determination of those
who would prevent men and women from living and loving as they
choose. Written around 1128, this Latin correspondence tells a story of
love that is both of the body and the mind. It is a painful account of what
Shakespeare would one day call the “marriage of true minds”, as the
lovers are separated by difficult circumstances including a jealous uncle,
castration, character assassination, shame, inner conflict, and religion. Abelard was an esteemed teacher and philosopher in Paris whose
lectures drew students from all over Europe: [Abelard’s] fame as a teacher and great reputation as a scholar helped
establish the University of Paris as students arrived from all over Europe
to study with him […]. In Paris, Abelard was regarded as a young [star]
among the schoolmen of the monastic orders, whose theological lectures
were considered dusty and boring as they commented endlessly on the
traditions of the church fathers and earlier medieval thinkers. Abelard’s © 2017 Michael Bryson and Arpi Movsesian, CC BY 4.0 https://doi.org/10.11647/OBP.0117.05 196 Love and its Critics lectures challenged revered traditions, and his students were often
rowdy and disrespectful to the accepted traditions of the church.2 During his time in the schools of Paris, Abelard was hired to tutor
Heloise, the niece of one of the city’s most influential citizens, a secular
canon named Fulbert. According to Abelard, this new pupil Heloise,
“in her outward appearance, was not the lowest; but for her wealth in
letters, she was supreme”.3 Abelard tells the story of how they met in
Historia calamitatum or A Story of His Misfortunes, which he addresses
to a “Friend”. Who exactly this piece was meant for is unknown, but it
has long served to give readers an intimate and painful portrait of the
significant details of Abelard’s love for Heloise and the price both he
and she paid for that love. 2
Roger E. Olson. The Story of Christian Theology: Twenty Centuries of Tradition & Reform
(Downers Grove, IL: InterVarsity Press, 2009), 326. 3
“Quae cum per faciem non esset infirma, per abundantium litterarum erat
suprema” (Peter Abelard and Heloise d’Argenteuil. Magistri Petri Abaelardi
epistola quae est Historia calamitatum: Heloissae et Abaelardi epistolae, ed. by Johann
Caspar von Orelli [Turici: Officina Ulrichiana, 1841], 6, https://archive.org/stream/
magistripetriaba00abel#page/6). This one is not better because he is richer or more powerful; the latter depends on fortune, the
former on virtue. Nor should she be estimated as less than venal, who freely marries the rich
man rather than the poor one, and desires what her husband has more than what he is. To such
a one, certainly, pay is due rather than gratitude. Certainly it is true that she thinks more of his
property than of him, and she, if she could, would prostitute herself to a richer man. 4
Betty Radice. “Introduction”. The Letters of Abelard and Heloise. Trans. by Betty
Radice (London: Penguin, 1974), 16. 5
Heloise seems to have had an even lower opinion of marriage than did Abelard
(practiced, as it was, primarily for economic reasons): 2
Roger E. Olson. The Story of Christian Theology: Twenty Centuries of Tradition & Reform
(Downers Grove, IL: InterVarsity Press, 2009), 326. 6
In 1031, the Council of Bourges declared that “[p]riests, deacons and subdeacons
were to refrain from taking wives and concubines, and those already married were
to separate from their wives, or face the threat of degradation” (Helen Parish.
Clerical Celibacy in the West: C.1100–1700 [Farnham: Ashgate, 2010], 96). By 1059,
instructions were given that “the laity should refuse the sacraments of married
priests” (97). In 1095, the Council of Clermont demanded that “any priest, deacon,
or subdeacon who was married must refrain from the celebration of the Mass” (103),
and by 1119, “Pope Calixtus II made further attempts to enforce the prohibitions
on clerical marriage at the Council of Rheims […], at which it was determined that
all married clergy were to be expelled from their benefices, and threatened with
the penalty of excommunication if they did not separate from their wives” (103).
Abelard and Heloise’s relationship takes place in a context in which the primary
employer of intellectuals (the Church) is in the process of forbidding them to have
anything like a “normal” sexual and emotional life. It is this same institution that
will soon establish the Inquisition and come to dominate the university: 5. Fin’amor Castrated: Abelard, Heloise,
and the Critics who Deny In the Letters, Heloise remembers the secret
and passionate love-making in the convents and in her uncle’s house,
clandestine meetings which resulted in Heloise getting pregnant. After
“being found in bed together”,4 Abelard and Heloise secretly married,
in a failed attempt to satisfy Fulbert, even though neither had a high
opinion of the institution.5 The Church disapproved of Abelard’s
marriage (during this period, clerical celibacy was slowly being imposed 5
Heloise seems to have had an even lower opinion of marriage than did Abelard
(practiced, as it was, primarily for economic reasons): [N]on enim quo quisque ditior sive potentior, ideo et melior; fortunae illud est, hoc virtutis. Nec
se minime venalem aestimet esse, quae libentius ditiori quam pauperi nubit, et plus in marito
sua quam ipsum concupiscit. Certe quamcunque ad nuptias haec concupiscentia ducit, merces
ei potius quam gratia debetur. Certum quippe est eam res ipsas, non hominem sequi, et se, si
posset, velle prostituere ditiori. Peter
Abelard
and
Heloise
d’Argenteuil,
33,
https://archive.org/stream/
magistripetriaba00abel#page/n40
5. Fin’amor Castrated: Abelard, Heloise, and the Critics who Deny 197 on the Western Church6), and his once-promising career ground to a
halt (something we will see again centuries later in the story of John and
Anne Donne). In his later years, Abelard was accused of heresy by the French abbot
Bernard of Clairvaux.7 Bernard (the heresy-hunter8 whose preaching 6
In 1031, the Council of Bourges declared that “[p]riests, deacons and subdeacons
were to refrain from taking wives and concubines, and those already married were
to separate from their wives, or face the threat of degradation” (Helen Parish. Clerical Celibacy in the West: C.1100–1700 [Farnham: Ashgate, 2010], 96). By 1059,
instructions were given that “the laity should refuse the sacraments of married
priests” (97). In 1095, the Council of Clermont demanded that “any priest, deacon,
or subdeacon who was married must refrain from the celebration of the Mass” (103),
and by 1119, “Pope Calixtus II made further attempts to enforce the prohibitions
on clerical marriage at the Council of Rheims […], at which it was determined that
all married clergy were to be expelled from their benefices, and threatened with
the penalty of excommunication if they did not separate from their wives” (103). Ernst Robert Curtius. Europäische Literatur und Lateinisches Mittelalter. Berlin: A.
Francke, 1948, 63. Perhaps it should not come as a surprise that the methods of
academic and theological critics of poetry can so often seem identical.
Joseph R. Strayer. Western Europe in the Middle Ages: A Short History (New York:
Appleton-Century-Crofts, Inc., 1955), 130.
“Otto of Freising described Bernard of Clairvaux as rather too ready to pounce upon
hints of heresy, and Bernard was instrumental in branding innovative philosophy
as dangerous heresy” (Christine Caldwell Ames. Medieval Heresies: Christianity,
Judaism, and Islam [Cambridge: Cambridge University Press, 2015], 199). 14
Jacques Le Goff, ed. The Medieval World. Trans. by Lydia G. Cochrane (London:
Collins & Brown, 1990), 21. 9
“Henry led a popular anti-clerical uprising, proclaiming a reform of marriage and
elimination of degrees of consanguinity” (Ryan P. Freeburn. Hugh of Amiens and the
Twelfth-Century Renaissance [Farnham: Ashgate, 2011], 150–51). f
y
g
10
Constant J. Mews. “Accusations of Heresy and Error in the Twelfth Century
Schools: The Witness of Gerhoh of Reichersberg and Otto of Freising”. In Heresy in
Transition: Transforming Ideas of Heresy in Medieval and Early Modern Europe (London:
Routledge, 2005), 44. 5. Fin’amor Castrated: Abelard, Heloise,
and the Critics who Deny Abelard and Heloise’s relationship takes place in a context in which the primary
employer of intellectuals (the Church) is in the process of forbidding them to have
anything like a “normal” sexual and emotional life. It is this same institution that
will soon establish the Inquisition and come to dominate the university: Gregory IX, in 1231, endowed the University [of Paris] with the great Papal privilege that
completed its organization. It was the self-same Pope, who in 1233 entrusted the Dominicans
with the office of the Inquisition. The Church, that under the great Innocent III (1198–1216)
had reached the peak of its power, regarded this as a necessary defense against the heretical
movements of the twelfth century. But the Church also saw a danger in the laity’s culture at
the end of the twelfth century, so it felt it had to subject education to its control. Thus, there is
a close internal link between the introduction of the Inquisition and the enforcement of papal
supervision of the universities. [S]tattete Gregor IX. im Jahre 1231 die Universität mit dem großen päpstlichen Privileg aus,
das ihre Organisation abschloß. Es was derselbe Papst, der 1233 den Dominikanern das Amt
der Inquisition übertrug. Gegen die ketzerischen Bewegungen des 12. Jahrhunderts schien der
Kirche, die unter dem großen Innozenz III (1198–1216) den Höhenpunkt ihrer Machstellung
erreicht hatte, diese Gegenwehr geboten. Sie durfte aber auch in der stark von Alterum
befruchteten Laienkultur des ausgehenden 12. Jahrhunderts eine Gefahr sehen, mußte also das
Bildungswesen ihrer Kontrolle unterwerfen. So hängt die Einfürung der Inquisition und die
Durchsetzung der päpistlichen Oberaufsicht über die Universitäten innerlich zusammen. Ernst Robert Curtius. Europäische Literatur und Lateinisches Mittelalter. Berlin: A. Francke, 1948, 63. Perhaps it should not come as a surprise that the methods of
academic and theological critics of poetry can so often seem identical. Ernst Robert Curtius. Europäische Literatur und Lateinisches Mittelalter. Berlin: A. Francke, 1948, 63. Perhaps it should not come as a surprise that the methods of
academic and theological critics of poetry can so often seem identical. Joseph R. Strayer. Western Europe in the Middle Ages: A Short History (New York:
Appleton-Century-Crofts, Inc., 1955), 130. “Otto of Freising described Bernard of Clairvaux as rather too ready to pounce upon
hints of heresy, and Bernard was instrumental in branding innovative philosophy
as dangerous heresy” (Christine Caldwell Ames. Medieval Heresies: Christianity,
Judaism, and Islam [Cambridge: Cambridge University Press, 2015], 199). 13
Ames, 199. 11
John Marenbon. Medieval Philosophy: An Historical and Philosophical Introduction
(London: Routledge, 2007), 136.
12
Strayer, 130. 9
“Henry led a popular anti-clerical uprising, proclaiming a reform of marriage and
elimination of degrees of consanguinity” (Ryan P. Freeburn. Hugh of Amiens and the
Twelfth-Century Renaissance [Farnham: Ashgate, 2011], 150–51).
10
Constant J. Mews. “Accusations of Heresy and Error in the Twelfth Century
Schools: The Witness of Gerhoh of Reichersberg and Otto of Freising”. In Heresy in
Transition: Transforming Ideas of Heresy in Medieval and Early Modern Europe (London:
Routledge, 2005), 44.
11
John Marenbon. Medieval Philosophy: An Historical and Philosophical Introduction
(London: Routledge, 2007), 136.
12
Strayer, 130.
13
Ames, 199. 12
Strayer, 130. 5. Fin’amor Castrated: Abelard, Heloise,
and the Critics who Deny 198 Love and its Critics against Henry the Monk9 was part of the long ideological buildup to
the Albigensian Crusade) “considered that Abelard did not so much
invent a new heresy, as reassert old heresies, whether that of Arius,
Pelagius, or Nestorius, all of which had been condemned by the Fathers
of the Church”.10 Abelard’s acute and competitive interest in combining
philosophical and theological questions got him into trouble: “his first
theological work, on the Trinity”, was “condemned as heretical”.11
During the course of his academic career, Abelard made enemies by
being too willing to mock current teaching methods, while others were
more reliably orthodox: Other men used methods which were essentially like his, and even
borrowed directly from his work, without losing their reputation for
orthodoxy. […] They were less shocking than Abelard because they were
not innovators and because they were careful not to claim too much for
their methods. They admitted that some articles of the faith were beyond
rational analysis and they were careful to find orthodox solution to
problems in which they had cited conflicting authorities.12 In all likelihood, however, it was not primarily his innovative thinking and
lecturing that got him into so much trouble, but rather his complicated,
and impolitic personality: “[a]rrogant and abrasive—he could not find a
teacher smarter than he, and made this blazingly clear”.13 Abelard was a proudly independent thinker, who reveled in
controversy, and “was not blindly submissive to his authorities […]; he
knew how to compare them, criticize them, and combine them”, while
letting reason have “the last word”.14 Abelard emphasized intellectual
independence in his teaching, and his students were “enthralled by
5. Fin’amor Castrated: Abelard, Heloise, and the Critics who Deny 199 the novelty of his pedagogy, which challenged them not just to absorb
the definitive statements (auctoritates) in revered authors (auctores), but
also to interrogate the texts and passages with the strength of their own
logic”.15 Abelard’s students, seemingly willing to follow him anywhere
in order to learn from him, were often notably loyal, though none were
finally more loyal than Heloise. Abelard writes frankly of Heloise in his Historia calamitatum, revealing
his fascination with her intelligence and determination. 17
The ages of Abelard and Heloise in 1115 are dated from a birthdate for Abelard
of 1079, and for Heloise of 1100, making Abelard thirty six and Heloise fifteen.
However, Constant Mews has recently argued that “[t]he tradition that she was
born in 1100, and thus only a teenager when she met Abelard, is a pious fabrication
from the seventeenth century, without any firm foundation. In 1115, she is more
likely to have been around twenty-one years old” (Constant J. Mews, Abelard and
Heloise [Oxford: Oxford University Press, 2005], 59). 18
“Nam quo bonum hoc, litteratorie scilicet scientiae, in mulieres es rarius: eo amplius
puellam commendabat, et in toto regno nominatissimam fecerat” (Peter Abelard and
Heloise d’Argenteuil, 6, https://archive.org/stream/magistripetriaba00abel#page/6).
19
“cum iam me solum in mundo superesse philosophum aestimarem, nec ullam
ulterius inquietationem formidarem, frena libidini coepi laxare” (ibid., 5–6, https://
archive.org/stream/magistripetriaba00abel#page/5). 15
Jan M. Ziolowski, editor and translator. Letters of Peter Abelard, Beyond the Personal
(Washington: The Catholic University Press of America, 2008), xxii. 16
Denis de Rougemont differs, positing a first meeting in 1118. L’Amour et l’Occident
(Paris: Plon, 1939), n. 12, 289. 20
“dormientem in secreta hospicii mei camera” (ibid., 11, https://archive.org/stream/
magistripetriaba00abel#page/11).
21
eis videlicet corporis mei partibus amputatis, quibus id quod plangebant commiseram, […]
Mane autem facto, tota ad me civitas congregata, quanta stuperet admiratione, quanta se
affligeret lamentatione, quanto me clamore vexarent, quanto planctu perturbarent: difficile,
immo impossibile est exprimi. Maxime vero clerici ac precipue scolares nostri intolerabilibus
me lamentis et eiulatibus cruciabant, ut multo amplius ex eorum compassione quam ex vulneris
lederer passione, et plus erubescentiam quam plagam sentirem. […] quod professioni meae
convenientius erat, sacre plurimum lectioni studium intendens.
Ibid., 11–12, 13, https://archive.org/stream/magistripetriaba00abel#page/12 5. Fin’amor Castrated: Abelard, Heloise,
and the Critics who Deny They are now
thought to have met sometime in 1115,16 at a time when Heloise was
still fairly young.17 Very few women of the time, much less women so
young, knew how to read and write, especially in formal Latin, or were
educated in the classics: “this gift of the science of letters, which is rare
in women, highly recommended the young girl, and made her highly
praised throughout the entire realm”,18 writes Abelard, describing
Heloise’s intelligence, the shared quality that aroused their passion and
led to their perilous choice. “I began to hold an estimate of myself as
the only philosopher in the world, with no reason to fear anyone, and
so I relaxed and gave in to my lustful desires”.19 The negative emphasis
he puts on his recollections, reducing his love for Heloise to “lustful
desires”, is understandable, given the mutilated state of his body while
writing these lines. It is impossible fully to imagine the horror he must 200 Love and its Critics have experienced the night when, “sleeping in my private lodging”,20
hired thugs took Fulbert’s revenge on him: They cut off those parts of my body with which I had committed the act
about which they mourned. […] First thing the next morning, the entire
city gathered before my house, and the crying out stunned with wonder,
the prostrated lamentations, the upsetting and exasperating moaning and
weeping is difficult, even impossible to describe. Honestly, it was primarily
the clerks and my students who crucified me with their intolerable grieving
and lamenting, and I suffered more from their sympathy than from the
pain of the wound, and I felt the shame more than the dismemberment. […] From then on, I applied myself principally to the study of the sacred
lessons, which to my present state was more convenient.21 What we see here is not the extinguishing or renouncing of Abelard’s
once-passionate love, but the words of a man who has built a protective
wall behind which he can hide so that he will not be further harmed. Historia calamitatum reflects the guarded inner world that its author
creates as a direct response to his mutilation and humiliation. In a way,
it also reflects a painful internalization of the judgment rendered on him,
and his love, by the world. 22
Vidi siquidem Parisius, quod quidam clericus nomine Fulbertus te ut hospitem in domo sua
recepit, te in mensa sua ut amicum familiarem et domesticum honorifice pavit, neptim etiam
suam, puellam prudentissimam et indolis egregiae, ad docendum commisit. Tu vero viri
illius nobilis et clerici, Parisiensis etiam ecclesiae canonici, hospitis insuper tui ac domini, et
gratis et honorifice te procurantis non immemor, sed contemptor, commissae tibi virgini non
parcens, quam conservare ut commissam, docere ut discipulam debueras, effreno luxuriae
spiritu agitatus non argumentari, sed eam fornicari docuisti, in uno facto multorum criminum,
proditionis scilicet et fornicationis, reus et virginei pudoris violator spurcissimus. Sed Deus
ultionum, Dominus Deus ultionum, libere egit, qui ea qua tantum parte peccaveras te privavit. Roscelin of Compiègne. “Epistola XV: Quae est Roscelini ad P. Abaelardum”.
Patrologiae Cursus Completus, Vol. 178, ed. by Jacques Paul Migne (Paris:
Apud Garnier Fratres, 1885), col. 369, https://archive.org/stream/patrologia
ecurs53unkngoog#page/n189 23
“ubi cum quodam clerico nostro latitans, illud vere Domino poteram decantare:
‘Ecce elongavi fugiens et mansi in solitudine’” (Peter Abelard and Heloise
d’Argenteuil, 19, https://archive.org/stream/magistripetriaba00abel#page/19). 5. Fin’amor Castrated: Abelard, Heloise,
and the Critics who Deny A letter from his former teacher, Roscelin of
Compiègne, provides powerful testimony to that judgment: I saw in Paris, in the house of a stranger, a certain clerk by the name
of Fulbert received you and fed you with honor at his table, treating
you as a member of his household and as an intimate friend. He also
introduced you to his niece, a young girl of great abilities, and great
prudence, engaging you to be her teacher. You were not unmindful, but
contemptuous, in the way you treated that man of noble birth, your host
and Lord, a clergyman, the canon of the church of Paris, who hosted you
free of charge and with honor. Not sparing the virgin, whom you should
have preserved and taught as a disciple, instead, with your spirit tossed
about by unbridled lust, you taught her not to argue, but to commit
5. Fin’amor Castrated: Abelard, Heloise, and the Critics who Deny 201 fornication. In this one fact you are guilty of many crimes: of treason,
and fornication, and the filthiest violation of virginal modesty. But the
Lord God, to whom vengeance belongs, has freely acted, depriving you
of that part by which you sinned.22 Of his later escape to Troyes, Abelard describes himself as one hiding
away from condemnation: “Here, hidden alone, except for one of our
clerks, I could truly sing out to the Lord: ‘Lo! I’ve become a fugitive from
the world, and have found refuge in solitude’”.23 But even the solitude
does not lessen his sense of shame or relieve his anguish. At some
point he considers joining the “gentes” or “heathens” and “passing the
boundaries of Christendom”.24 Having been forcibly separated from Abelard for years, Heloise,
now abbess of the Paraclete in Ferreux-Quincey, reads his Historia
calamitatum only after it is brought to her by chance.25 The letters Heloise
writes in response reveal a passionate woman who agonizes over
Abelard’s misfortunes and “his life’s continual persecutions”.26 Heloise,
unlike Abelard, rejects the derision of society,27 voicing that rejection 24
“ut Christianorum finibus excessis” (ibid., 23, https://archive.org/stream/magistr
petriaba00abel#page/n31). 24
“ut Christianorum finibus excessis” (ibid., 23, https://archive.org/stream/magistri
petriaba00abel#page/n31). 25
“Missam ad amicum pro consolatione epistolam, dilectissime, vestram ad me
forte quidam nuper attulit” [Recently it chanced, most beloved, that the letter of
consolation you sent to a friend was brought to me] (ibid., 30, https://archive.org/
stream/magistripetriaba00abel#page/n37). 24
“ut Christianorum finibus excessis” (ibid., 23, https://archive.org/stream/magistri
petriaba00abel#page/n31). 22
Vidi siquidem Parisius, quod quidam clericus nomine Fulbertus te ut hospitem in domo sua
recepit, te in mensa sua ut amicum familiarem et domesticum honorifice pavit, neptim etiam
suam, puellam prudentissimam et indolis egregiae, ad docendum commisit. Tu vero viri
illius nobilis et clerici, Parisiensis etiam ecclesiae canonici, hospitis insuper tui ac domini, et
gratis et honorifice te procurantis non immemor, sed contemptor, commissae tibi virgini non
parcens, quam conservare ut commissam, docere ut discipulam debueras, effreno luxuriae
spiritu agitatus non argumentari, sed eam fornicari docuisti, in uno facto multorum criminum,
proditionis scilicet et fornicationis, reus et virginei pudoris violator spurcissimus. Sed Deus
ultionum, Dominus Deus ultionum, libere egit, qui ea qua tantum parte peccaveras te privavit.
Roscelin of Compiègne. “Epistola XV: Quae est Roscelini ad P. Abaelardum”.
Patrologiae Cursus Completus, Vol. 178, ed. by Jacques Paul Migne (Paris:
Apud Garnier Fratres, 1885), col. 369, https://archive.org/stream/patrologia
ecurs53unkngoog#page/n189
23
“ubi cum quodam clerico nostro latitans, illud vere Domino poteram decantare:
‘Ecce elongavi fugiens et mansi in solitudine’” (Peter Abelard and Heloise
d’Argenteuil, 19, https://archive.org/stream/magistripetriaba00abel#page/19).
24
“ut Christianorum finibus excessis” (ibid., 23, https://archive.org/stream/magistri
petriaba00abel#page/n31).
25
“Missam ad amicum pro consolatione epistolam, dilectissime, vestram ad me
forte quidam nuper attulit” [Recently it chanced, most beloved, that the letter of
consolation you sent to a friend was brought to me] (ibid., 30, https://archive.org/ 28
Barbara Newman. From Virile Woman to WomanChrist: Studies in Medieval Religion
and Literature (University Park: University of Pennsylvania Press, 1995), 19. 5. Fin’amor Castrated: Abelard, Heloise,
and the Critics who Deny 25
“Missam ad amicum pro consolatione epistolam, dilectissime, vestram ad me
forte quidam nuper attulit” [Recently it chanced, most beloved, that the letter of
consolation you sent to a friend was brought to me] (ibid., 30, https://archive.org/
stream/magistripetriaba00abel#page/n37). 26
“continuas vitae persecutiones” (ibid., 30, https://archive.org/stream/magistripetri
aba00abel#page/n37). 26
“continuas vitae persecutiones” (ibid., 30, https://archive.org/stream/magistripetri
aba00abel#page/n37). 27
What made Peter Abelard so unusual in the eyes of Heloise was his gift for combining his skill
in philosophy with a gift for composing and singing songs of love. When she read the Historia 27
What made Peter Abelard so unusual in the eyes of Heloise was his gift for combining his skill
in philosophy with a gift for composing and singing songs of love. When she read the Historia Love and its Critics 202 in the words of two intensely passionate letters, and then a third, more
philosophical and intellectual in its approach. In each case, what she
appears to be seeking is not absolution, but a restored connection to
Abelard, a return of words for words. As Barbara Newman describes
the correspondence, it moves from passion to intellectual exchange: In the early 1130s Peter Abelard received three letters from Heloise, once
his mistress and wife, now his sister and daughter in religion. The first
two made such painful reading that he must have thought twice before
scanning the third, in which Heloise resolutely turned from the subject of
tragic love to the minutiae of monastic observance. For romantic readers,
the correspondence lapses from titillation into tedium with this epistle. But Abelard was no doubt immensely relieved. Laying aside her griefs,
Heloise now wrote to him as abbess to abbot, asking for only two things:
a treatise explaining “how the order of nuns began”, and a rule for her
daughters at the Paraclete.28 And yet, one can imagine why Heloise asks for these things in her
third letter—she had been, and was still, in love with Abelard’s mind,
and such a request would elicit more words, more thoughts, more of
Abelard’s voice to which Heloise could return in the most intimate of
unions, hearing her long-absent husband in the quiet hours of night and
morning as she scanned the words he would send her. They needn’t be
words of love—his words alone would sustain her. Constant J. Mews. The Lost Love Letters of Heloise and Abelard (New York: Palgrave
MacMillan, 1999), 82. calamitum, she reminded him of these public declarations of love and of the incessant letters
he had showered on her in the past. From her perspective, a true relationship was not an illicit
sexual encounter but a mutual profession of true love.
Constant J. Mews. The Lost Love Letters of Heloise and Abelard (New York: Palgrave
MacMillan, 1999), 82.
28
B
b
N
F
Vi il W
t W
Ch i t St di
i
M di
l R li i calamitum, she reminded him of these public declarations of love and of the incessant letters
he had showered on her in the past. From her perspective, a true relationship was not an illicit
sexual encounter but a mutual profession of true love. calamitum, she reminded him of these public declarations of love and of the incessant letters
he had showered on her in the past. From her perspective, a true relationship was not an illicit
sexual encounter but a mutual profession of true love.
Constant J. Mews. The Lost Love Letters of Heloise and Abelard (New York: Palgrave
MacMillan, 1999), 82.
28
Barbara Newman. From Virile Woman to WomanChrist: Studies in Medieval Religion
and Literature (University Park: University of Pennsylvania Press, 1995), 19. 29
“Hos autem in me stimulos carnis, haec incentiva libidinis ipse iuvenilis fervor
aetatis, et iocundissimarum experientia volputatum, plurimum accendunt. […]
Castam me raedicant, qui non deprehenderunt hypocritum. Munditiam carnis
conferunt in virtutem, cum non sit corporis, sed animi virtus” (Peter Abelard and
Heloise d’Argenteuil, 43–44, https://archive.org/stream/magistripetriaba00abel#p
age/43). q
pp
q
q
32
Bernart de Ventadorn, 260–63, ll. 13–16, https://archive.org/stream/bernartvon
ventad00bern#page/260 g
)
30
Ibid., 32, https://archive.org/stream/magistripetriaba00abel#page/n39 I i ,
,
p //a
i e o g/
ea
/
agi
ipe ia a
a e page/
31
“Solus quippe es, qui me contristare, qui me laetificare seu consolari valeas” (ibid.) 5. Fin’amor Castrated: Abelard, Heloise,
and the Critics who Deny And yet, one can imagine why Heloise asks for these things in her
third letter—she had been, and was still, in love with Abelard’s mind,
and such a request would elicit more words, more thoughts, more of
Abelard’s voice to which Heloise could return in the most intimate of
unions, hearing her long-absent husband in the quiet hours of night and
morning as she scanned the words he would send her. They needn’t be
words of love—his words alone would sustain her. But in her first two letters, Heloise’s words overflow with passion and
the bittersweet memories of the sensual and emotional delights she had
shared with Abelard. She often reveals her sexual frustrations and longing,
writing of her desire to be with the man she loves, despite the disapproval
of the world. But only her memories will allow her that luxury: But those stimuli of the flesh, these instigators of sensuality, the very
passions of youth, with the experience of longing and delight and
pleasure, all greatly inflame [me]. […] They praise me as chaste, when
5. Fin’amor Castrated: Abelard, Heloise, and the Critics who Deny 203 they do not see that I am a hypocrite. They think of the cleanness of the
flesh as virtue, but virtue is not of the body, but of the soul.29 they do not see that I am a hypocrite. They think of the cleanness of the
flesh as virtue, but virtue is not of the body, but of the soul.29 Nothing could sublimate or redirect Heloise’s love, not even being a nun,
for she says she feels “immoderate love”—“immoderato amore”,30 not
for God, but for Abelard. She makes her preference for Abelard above
all others on Earth or in Heaven clear when she tells him that “only you
have the power to make me sad, or to bring me delight or comfort”.31 If
her words were put to music, one could hear the troubadours and their
songs of fin’amor. Bernart de Ventadorn’s poem, Tant ai mo cor ple de joya
(My heart is full of joy), in its treatment of love and comfort, echoes
Heloise’s paradoxical sense of naked exposure and warm reassurance
in her confessions of love to Abelard: Anar posc ses vestidura,
nutz en ma chamiza,
car fin’ amors m’asegura
de la freja biza.32 I walk undressed,
naked in my shirt,
for love secures me
from the coldest winds. 31
“Solus quippe es, qui me contristare, qui me laetificare seu consolari v 34
Constant J. Mews. “Abelard, Heloise, and Discussion of Love in the Twelfth-
Century Schools”. In Babette S. Hellemans, eds. Rethinking Abelard: A Collection of
Critical Essays (Leiden: Brill, 2014), 26. 33
Nihil unquam, deus scit, in te nisi requisiui; te pure, non tua concupiscens. […] Et si uxoris
nomen sanctius ac validius videtur, dulcius mihi semper exstitit amicae ocabulum, aut, si non
indigneris, concubinae vel scorti. […] sed plerisque tacitis, quibus amorem coniugio, libertatem
vinculo praeferebam. Deum leslcm invoco, si me Augustus universo praesidens mundo
matrimonii honore dignaretur totumque mihi orbem confirmaret in perpetuo praesidendum,
carius mihi et dignius videretur tua dici meretrix, quam illius imperatrix.
Peter Abelard and Heloise d’Argenteuil, 32–33, https://archive.org/stream/magistri
petriaba00abel#page/n40 35
Peter Abelard and Heloise d’Argenteuil, 34, https://archive.org/stream/magistri
petriaba00abel#page/n41 Peter Abelard and Heloise d’Argenteuil, 32–33, https://archive.org/stream/magistri
petriaba00abel#page/n40 33
Nihil unquam, deus scit, in te nisi requisiui; te pure, non tua concupiscens. […] Et si uxoris
nomen sanctius ac validius videtur, dulcius mihi semper exstitit amicae ocabulum, aut, si non
indigneris, concubinae vel scorti. […] sed plerisque tacitis, quibus amorem coniugio, libertatem
vinculo praeferebam. Deum leslcm invoco, si me Augustus universo praesidens mundo
matrimonii honore dignaretur totumque mihi orbem confirmaret in perpetuo praesidendum,
carius mihi et dignius videretur tua dici meretrix, quam illius imperatrix.
Peter Abelard and Heloise d’Argenteuil, 32–33, https://archive.org/stream/magistri
petriaba00abel#page/n40
34
Constant J. Mews. “Abelard, Heloise, and Discussion of Love in the Twelfth-
Century Schools”. In Babette S. Hellemans, eds. Rethinking Abelard: A Collection of
Critical Essays (Leiden: Brill, 2014), 26.
35
Peter Abelard and Heloise d’Argenteuil, 34, https://archive.org/stream/magistri
petriaba00abel#page/n41 5. Fin’amor Castrated: Abelard, Heloise,
and the Critics who Deny Fin’amor Castrated: Abelard, Heloise, and the Critics who Deny 205 administrative duties in a convent, and certainly not her vows, which
were far from freely or religiously taken.36 She makes it painfully clear that she never chose the religious life, and
that had she been free to make her own choices, both their lives would
have been very different: Truthfully, the young girl had no calling for the monastic profession,
nor any religious devotion, but I did this to obey you. And if, in that,
I deserve nothing from you, be the judge yourself of how vain all my
hardships are. I expect no reward from God, for certainly I have never
done anything for the love of him. You hurried to God, and I followed
in the habit; indeed, I went first. […] I have never had the slightest
hesitation, were it to run into the Vulcanian flames of Hell, to follow you
or precede you at your bidding. My heart was not with me, but with you. Even now, if it is not wholly with you, it is nowhere. In fact, without you,
it does not exist at all.37 Heloise’s love for Abelard, after many years of separation, shows no
signs of having diminished. This is painfully clear in the way she begins
and ends her letters. She addresses her first letter, “To her lord, or rather
her father, to her husband, or rather her brother; his servant, or rather his
daughter, his wife, or rather his sister; to Abelard, Heloise”.38 Abelard,
in contrast, distances himself from Heloise by opening the letters with
“To Heloise, his dearly beloved sister in Christ, Abelard her brother
in the same”.39 The ending of the letters play almost the same notes:
“Farewell, my only”,40 versus “Live, but in Christ I pray, remember Heloise’s love for Abelard, after many years of separation, shows no
signs of having diminished. This is painfully clear in the way she begins
and ends her letters. 5. Fin’amor Castrated: Abelard, Heloise,
and the Critics who Deny I walk undressed,
naked in my shirt,
for love secures me
from the coldest winds. Sometimes, Heloise’s tone becomes more urgent, even demanding,
as she desires to love and be loved despite Fulbert, the Church, or the
jealous God himself. However, Abelard cannot respond in the way that
Heloise yearns for. After his intial diffidence, Heloise’s words become
even more intensely heartfelt, revealing the passionate and courageous 204 Love and its Critics person she has always been, determined to love fully, and on her own
terms, despite a world that disdains her love for Abelard: God knows I have never required anything from you except for yourself;
I only wanted you, not anything that belonged to you. […] And if the
name of wife appears more sacred and honorable, for me the word
friend will always be sweeter, or—though you might be indignant—
concubine or whore. […] I preferred love to marriage, freedom to fetters. I call God as witness, if Augustus, the whole world’s ruler, had deemed
me worthy of marriage, and raised me to preside with him over the earth
forever, it would have been dearer to me to be called your whore than
his Empress.33 Heloise refuses the idea that she may only love Abelard for the sake
of God, and in that way, she is more akin to the troubadours than to
the later Italian poets who see love as a ladder by which to reach the
divine: “[w]hen Heloise protested that she desired him for himself,
[she] echoed the Ciceronium dictum that one should love a friend, for
that person’s sake—without reference to loving someone for the sake
of God”.34 Heloise is unwilling to believe that such love is a sin: “I am
innocent”—“sum innocens”,35 for she views love as something greater
than anything the world can oppose it with: She wants freedom from compulsion in loving her paragon, who had
every grace of mind and body, making her the envy of queens and
great ladies. She wants him for herself alone, without the restraints
or sanctions of marriage—her love is single, obsessive, possessive,
eternal, extramarital. And nothing can overcome her passion, not his
castration, not his unavailability, not his theological arguments, not her
5. 36
Hagstrum, 204. g
37
quam quidem iuvenculam ad monastice conversationis asperitatem non religionis devotio
sed tua tantum pertraxit iussio. Ubi si nihil a te promerear, quam frustra laborem, diiudica.
Nulla mihi super hoc merces exspectanda est a deo, cuius adhuc amore nihil me constat egisse.
Properantem te ad deum secuta sum habitu, immo praecessi. […] Ege autem (deus scit) ad
Vulcania loca te properantem praecedere vel sequi pro iussu tuo minime dubitarem. Non enim
mecum animus meus sed tecum erat. Sed et nunc maxime si tecum non est, nusquam est: esse
vero sine te nequaquam potest.
Peter Abelard and Heloise d’Argenteuil, 34, https://archive.org/stream/magistri
petriaba00abel#page/n41
38
“Domino suo, immo patri; coniugi suo, immo fratri; ancilla sua, immo filia, ipsius uxor,
immo soror” (ibid., 30, https://archive.org/stream/magistripetriaba00abel#page/n37).
39
“Heloissae, dilectissimae sorori suae in Christo, Abaelardus, frater eius in ipso”
(ibid., 35, https://archive.org/stream/magistripetriaba00abel#page/n42).
40
“Vale unice” (ibid.). 37
quam quidem iuvenculam ad monastice conversationis asperitatem non religionis devotio
sed tua tantum pertraxit iussio. Ubi si nihil a te promerear, quam frustra laborem, diiudica.
Nulla mihi super hoc merces exspectanda est a deo, cuius adhuc amore nihil me constat egisse.
Properantem te ad deum secuta sum habitu, immo praecessi. […] Ege autem (deus scit) ad
Vulcania loca te properantem praecedere vel sequi pro iussu tuo minime dubitarem. Non enim
mecum animus meus sed tecum erat. Sed et nunc maxime si tecum non est, nusquam est: esse
vero sine te nequaquam potest.
P
Ab l
d
d H l i
d’A
il 34 h
//
hi
/
/
i
i Peter Abelard and Heloise d’Argenteuil, 34, https://archive.org/stream/magistri
petriaba00abel#page/n41 38
“Domino suo, immo patri; coniugi suo, immo fratri; ancilla sua, immo filia, ipsius uxor,
immo soror” (ibid., 30, https://archive.org/stream/magistripetriaba00abel#page/n37).
39
“Heloissae, dilectissimae sorori suae in Christo, Abaelardus, frater eius in ipso”
(ibid., 35, https://archive.org/stream/magistripetriaba00abel#page/n42).
40
“Vale unice” (ibid.). 5. Fin’amor Castrated: Abelard, Heloise,
and the Critics who Deny She addresses her first letter, “To her lord, or rather
her father, to her husband, or rather her brother; his servant, or rather his
daughter, his wife, or rather his sister; to Abelard, Heloise”.38 Abelard,
in contrast, distances himself from Heloise by opening the letters with
“To Heloise, his dearly beloved sister in Christ, Abelard her brother
in the same”.39 The ending of the letters play almost the same notes:
“Farewell, my only”,40 versus “Live, but in Christ I pray, remember 206 Love and its Critics me”.41 As Newman notes, “Abelard’s Historia is a quasipublic document
[…]. But Heloise’s letters are relentlessly private […]. While Heloise,
like an Ovidian heroine, gestures toward the whole world as witness to
her woes, she addresses her appeal to Abelard alone”.42 me”.41 As Newman notes, “Abelard’s Historia is a quasipublic document
[…]. But Heloise’s letters are relentlessly private […]. While Heloise,
like an Ovidian heroine, gestures toward the whole world as witness to
her woes, she addresses her appeal to Abelard alone”.42 There is, perhaps, a physical as well as emotional explanation for
Abelard’s detached style: “Disgust with his mutilated person may have
made him want to shut the past out of his mind; he was changed, and
[…] he may have been all too ready to believe that she was changed
too”.43 Abelard’s stiffness can easily be seen as selfishness on his part,
and yet, his attempts at formality may well lie in his desire to shut
out what he feels cannot be restored, passions he can remember but
no longer feel physically, insisting, despite the pain of loss, on what
he thinks is best for both of them. Perhaps he believed that if he kept
holding on to the past, his suffering, and hers, would never diminish. However, in Historia calamitatum, when he is not yet corresponding with
Heloise, and allows himself room for honesty, Abelard shows the true
colors of his love; it is fleshly, sensual, and romantic: First we were joined together in one house, soon we joined by mind and
spirit. Using her instruction as an occasion for privacy, we gave all our
time to love, and the secret recesses that love chose, and that her studies
afforded us. With our books open, we spent more words on love than on
our readings; we shared more kisses than sentences. 43
Radice, 27. 44
Primum domo una coniungimur, postmodum animo. Sub occasione itaque disciplinae amori
penitus vacabamus, et secretos regressus, quos amor optabat, studium lectionis offerebat.
Apertis itaque libris, plura de amore, quam de lectione verba se ingerebant, plura erant
oscula, quam sententiae. Saepius ad sinus quam ad libros educebantur manus. […] nullus
a cupidis intermissus est gradus amoris. […] Taediosum mihi vehementer erat ad scholas
procedere, vel in eis morari; pariter et laboriosum, cum nocturnas amori vigilias et diurnas
studio conservarem. 42
Newman, 56. 41
“Vivite, sed Christo quaeso mei memores” (ibid., 39, https://archive.org/stream/
magistripetriaba00abel#page/39)
42
N
56 41
“Vivite, sed Christo quaeso mei memores” (ibid., 39, https://archive.org/stream/
magistripetriaba00abel#page/39)
42
Newman, 56.
43
Radice, 27.
44
Primum domo una coniungimur, postmodum animo. Sub occasione itaque disciplinae amori
penitus vacabamus, et secretos regressus, quos amor optabat, studium lectionis offerebat.
Apertis itaque libris, plura de amore, quam de lectione verba se ingerebant, plura erant
oscula, quam sententiae. Saepius ad sinus quam ad libros educebantur manus. […] nullus
a cupidis intermissus est gradus amoris. […] Taediosum mihi vehementer erat ad scholas
procedere, vel in eis morari; pariter et laboriosum, cum nocturnas amori vigilias et diurnas
studio conservarem.
Peter
Abelard
and
Heloise
d’Argenteuil,
7,
https://archive.org/stream/
magistripetriaba00abel#page/7 Peter
Abelard
and
Heloise
d’Argenteuil,
7,
https://archive.org/stream/
magistripetriaba00abel#page/7 45
Alice V. Clark. “From Abbey to Cathedral and Court: Music Under the Merovingian,
Carolingian and Capetian Kings in France until Louis IX”. The Cambridge Companion
to French Music (Cambridge: Cambridge University Press, 2015), 12.
46
Ibid., 13. 47
Latin text from Lorenz Weinrich. “‘Dolorum solatium’: Text und Musik von
Abaelards Planctus”. Mittellateinisches Jahrbuch, 5 (1968), 72, ll. 69–80. 5. Fin’amor Castrated: Abelard, Heloise,
and the Critics who Deny My hands found
their way to her bosom more often than to our books. […] No stage of
love is skipped by cupid-struck people such as we. […] It was incredibly
irritating for me to have to go to the School, and equally irritating when
I had to maintain nightly vigils to love, and then turn around and study
all the next day.44 44
Primum domo una coniungimur, postmodum animo. Sub occasione itaque disciplinae amori
penitus vacabamus, et secretos regressus, quos amor optabat, studium lectionis offerebat. Apertis itaque libris, plura de amore, quam de lectione verba se ingerebant, plura erant
oscula, quam sententiae. Saepius ad sinus quam ad libros educebantur manus. […] nullus
a cupidis intermissus est gradus amoris. […] Taediosum mihi vehementer erat ad scholas
procedere, vel in eis morari; pariter et laboriosum, cum nocturnas amori vigilias et diurnas
studio conservarem. Peter
Abelard
and
Heloise
d’Argenteuil,
7,
https://archive.org/stream/
magistripetriaba00abel#page/7
5. Fin’amor Castrated: Abelard, Heloise, and the Critics who Deny 207 Here, his passions are uninhibited, and his words belong to the pages that
tell the story of fin’amor. Similar words and passions can be found in his
songs. One notable development in Latin song, from about 1100 (thus
co-existent with the songs of the troubadours and Minnesingers), is what
are called “planctus or laments”.45 Abelard “wrote six planctus”,46 including
one based on the laments of David over the deaths of Saul and Jonathan. But in the scriptural story, a reader can still hear Abelard’s passion: Heu! cur consilio
acquievi pessimo,
ut tibi praesidio
non essem in praelio? Vel confossus pariter
morerer feliciter
cum, quid amor faciat
majus hoc non habeat,
Et me post te vivere
mori sit assidue
nec ad vitam anima
satis sit dimidia.47 Alas! Why did I plan,
acquiescing to debasement,
that you would protect yourself
and I would not be in the battle? Even pierced alike
we would die happily
when love would fashion it so. Greater than this we cannot have. And to live after you
would be to die continually
For with only half a soul
Life is not enough. Alas! Why did I plan,
acquiescing to debasement,
that you would protect yourself
and I would not be in the battle? Even pierced alike
we would die happily
when love would fashion it so. Greater than this we cannot have. 48
W. G. East. “This Body of Death: Abelard, Heloise and the Religious Life”. In
Peter Biller and Alastair J. Minnis, eds. Medieval Theology and the Natural Body
(Woodbridge, Suffolk: Boydell & Brewer, 1997), 51. 49
“quocunque casu viam universae carnis absens a vobis ingrediar, cadaver obsecro
nostrum, ubicunque vel sepultum vel expositum iacuerit, ad cimiterium vestrum
deferri faciatis” (Peter Abelard and Heloise d’Argenteuil, 39). g
50
Charles J. Reid. Power Over the Body, Equality in the Family: Rights and Domestic
Relations in Medieval Canon Law (Grand Rapids: William B. Eerdmans, 2004), 130. 51
Bernart de Ventadorn, 250–54, ll. 9–16, https://archive.org/stream/bernartvon
ventad00bern#page/250 48
W. G. East. “This Body of Death: Abelard, Heloise and the Religious Life”. In
Peter Biller and Alastair J. Minnis, eds. Medieval Theology and the Natural Body
(Woodbridge, Suffolk: Boydell & Brewer, 1997), 51.
49
“quocunque casu viam universae carnis absens a vobis ingrediar, cadaver obsecro
nostrum, ubicunque vel sepultum vel expositum iacuerit, ad cimiterium vestrum
deferri faciatis” (Peter Abelard and Heloise d’Argenteuil, 39).
50
Charles J. Reid. Power Over the Body, Equality in the Family: Rights and Domestic
Relations in Medieval Canon Law (Grand Rapids: William B. Eerdmans, 2004), 130.
51
Bernart de Ventadorn, 250–54, ll. 9–16, https://archive.org/stream/bernartvon
ventad00bern#page/250 5. Fin’amor Castrated: Abelard, Heloise,
and the Critics who Deny And to live after you
would be to die continually
For with only half a soul
Life is not enough. 208 Love and its Critics His “letters of direction”, as the latter highly didactic letters are called,
might bear the mask of indifference, but as a result of Heloise’s letters,
Abelard throws himself into a frenzy of literary activity on her behalf:
in addition to the famous, if painfully diffident letters, Abelard wrote
“a hundred hymns, thirty-five sermons, […] a substantial series of
solutions of Heloise’s theological problems [and a] half-dozen Planctus
[…] which touch very closely on the state of mind of Heloise and
himself”. Through these works, “Abelard had found an acceptable
medium in which to express his love for Heloise”.48 On top of all of this,
it is evident that Abelard’s heart remained with Heloise when he asked
if she would bury him: “by whatever cause I go the way of all flesh,
proceeding absent from you, I pray you to bring my body, whether it lie
buried or exposed, to your cemetary”.49 Years later, “Peter the Venerable
[…] made sure to return the body to Heloise” and when Heloise herself
died, she “was laid to rest next to Abelard”.50 Her jealous uncle, his
hired thugs, and the society in which they lived, may have separated the
lovers physically, but they could not extinguish their love. Their words
and cries of desire and suffering echo yet another poem by Bernart de
Ventadorn, Can vei la lauzeta mover (When I see the lark move): Ai, las! Tan cuidava saber
d’amor, e tan petit en sai,
car eu d’amor no·m posc tener
celeis don ja pro non aurai. Tout m’a mo cor, e tout m’a me
e se mezeis e tot lo mon;
e can se.m tolc, no·m laisset re
mas desirer e cor volon.51 209
5. Fin’amor Castrated: Abelard, Heloise, and the Critics who Deny Alas! So much, I believed I knew
about love, and how little I really know
because I cannot hold back from loving
her, the lady I will not ever have. All my heart, and all of me,
myself and the whole world,
she has taken, and left behind nothing
except desire and a yearning heart. 52
Newman, 47.
53
Ibid., 49.
54
Ibid., 50. 5. Fin’amor Castrated: Abelard, Heloise,
and the Critics who Deny And yet, in a now-familiar pattern, literary critics devoted to a “thou
shalt” and “thou shalt not” authoritarian style of interpretation have
long insisted that these letters are not about love, with some going to the
extent of arguing that the letters are not even genuine. Barbara Newman
argues strenuously against those critics who deny the authenticity of
Heloise’s letters, identifying their aim as “not only the repression of
Heloise’s desire, but the complete obliteration of her voice”, locating
the urge to obliterate that voice “in a priori notions of what a medieval
abbess could write, frank disapproval of what Heloise did write, and
at times outright misogyny”.52 Newman takes D. W. Robertson as her
prime example: Robertson’s condescension toward Heloise is blatant. He refers to her
twice as “poor Heloise” and once even as “little Heloise”; at least a half
dozen times, he calls her discourse on marriage in the Historia calamitatum
a “little sermon”. In a display of stunning inconsistency, he manages
to deny that “little Heloise actually said anything like” what Abelard
records, and at the same time to ridicule her for saying it. 5. Fin’amor Castrated: Abelard, Heloise,
and the Critics who Deny Embodying
all the negative stereotypes of the feminine, Robertson’s Heloise is both
minx and shrew.53 As Newman observes, “Robertson himself would read these letters,
like all medieval texts that purport to celebrate erotic love, as witty
and ironic; they form part of an exemplary conversion narrative
authored by Abelard”.54 Robertson is a wonderful example of the
kind of authoritarian reader Longxi refers to when he observes that
critics attempt to transform literature into “a model of propriety
and good conduct, something that carries a peculiar ethico-political 210 Love and its Critics import”.55 In pointing out that the works of Marie de France, “one of
the most celebrated erotic writers of the twelfth century”, enjoyed
widespread popularity in their day, Newman remarks that “some
twelfth-century audiences were less fastidious in these matters than
their modern interpreters”.56 The tradition of scholars and critics arguing that the love story of
Abelard and Heloise is not what it seems to be has been active since
Ignaz Fessler in 1806, who first suggested that the letters between
Abelard and Heloise were a fraud.57 In 1972, John Benton argued that
the letters were the result of a collaborative forgery between two men,
a “‘twelfth-century epistolary ‘novelist’ and a ‘thirteenth-century
institutional scoundrel’”.58 Though Benton later abandoned this theory,
Hubert Silvestre persisted, arguing in 1985 that: The Historia and the correspondence are […] the work of a late thirteenth-
century forger, working on the basis of some authentic material, who
wished to uphold the right of clerics to have a concubine, and who
found a powerful way of doing so by putting the arguments for clerical
concubinage not into the mouth of a man, as might be expected, but of
an outstanding woman. This forger was none other than the famous poet
Jean de Meun, whose vast completion of Guillaume de Lorris’ Roman de la
Rose, one of the most widely read French works of the later Middle Ages,
contains a passage recounting the romance of Abelard and Heloise, and
who translated the Historia and the correspondence into French.59 But as John Marenbon notes, this theory is simply illogical: There are […] a number of instances in the Old French translation, not
explicable by variants in the Latin text or defects in the manuscript
of the French, where Jean de Meun, failing to grasp the meaning of a
phrase in the correspondence, mistranslates it. 55
Longxi, 205.
56
Newman, 52.
57
Ignas Fessler. Abälard und Heloise, Vol. II (Berlin, 1806), 352.
58
John Marenbon. The Philosophy of Peter Abelard (Cambridge: Cambridge University
Press. 1997), 83.
59
Ibid.
60
Ibid., 83–84. 58
John Marenbon. The Philosophy of Peter Abelard (Cambridge: Cambridge University
Press. 1997), 83. 56
Newman, 52.
57
Ignas Fessler. Abälard und Heloise, Vol. II (Berlin, 1806), 352. 61
Ibid., 93.
62
Ibid., 90.
63
Wellcome Images, https://commons.wikimedia.org/wiki/File:Abelard_and_Eloise_
confessing_their_love_to_his_brother_monk_Wellcome_V0033159.jpg 5. Fin’amor Castrated: Abelard, Heloise,
and the Critics who Deny How could Jean de Meun
misunderstand a text which he himself had forged?60 The compulsion that many critics have to “channel, reformulate, and
control” texts that describe human love is enabled by “the wish, among
5. Fin’amor Castrated: Abelard, Heloise, and the Critics who Deny 211 some literary theorists, to treat texts as if they were not the products
of their authors, but independent signifiers, awaiting the reader
to interpret them in one of the unlimited ways in which they can be
understood”.61 That this wish drives the Bentons and Silvestres of the
world to spin elaborate (and ultimately unsupportable) theories of
fraud and conspiracy is at once sad and instructive. But such an impulse
needn’t drive us. Those who contend that the letters are a fraud because
they were composed by Abelard himself, make claims that are entirely
free of any actual evidence: “[t]here is nothing intrinsically impossible
about the suggestion, but it requires strong evidence. This its supporters
signally fail to provide”.62 Abelard and Eloise confessing their love to his brother monks and her
sister nuns. Coloured stipple engraving by Miss Martin after Perolia.63 Abelard and Eloise confessing their love to his brother monks and her
sister nuns. Coloured stipple engraving by Miss Martin after Perolia.63 The passionate love of Abelard and Heloise, with all its struggles and
complications, is not a fraud perpetrated by “novelists”, “scoundrels” or
by Abelard himself. The sheer energy that has gone into constructing and
defending such arguments (primarily by male critics) speaks eloquently
of the determination to achieve “not only the repression of Heloise’s 212 Love and its Critics desire, but the complete obliteration of her voice”.64 What is it about the
idea of a powerfully intellectual and passionately eros-driven Heloise
that so disturbs such critics? It is “neither improbable nor anachronistic
to attribute to Heloise the sentiments expressed in her letters”,65 despite
the urge of moralizing critics to explain them away. Nor does the love
of Abelard and Heloise fit the bloodless and library-bound scholarly
idea of “courtly love”, a passionless construct that reveals its adherents’
disdain: “Abelard and Heloise speak a different language of sensuous
frankness […]. 64
Newman, 47.
65
Marenbon, The Philosophy of Peter Abelard, 89.
66
Radice, 49.
67
Newman, 50.
68
Longxi, 215. The response to this position is predictable. As David Dawson argues,
although the “literal sense” has often been thought of as an inherent quality of a literary text that
gives it a specific and invariant character (often, a “realistic” character), the phrase is simply
an honorific title given to a kind of meaning that is culturally expected and automatically
recognized by readers. It is the “normal”, “commonsensical” meaning, the product of a
conventional, customary reading. The “literal sense” thus stems from a community’s generally
unself-conscious decision to adopt and promote a certain kind of meaning, rather than from its
recognition of a text’s inherent and self-evident sense.
Allegorical Readers and Cultural Revision in Ancient Alexandria (Los Angeles:
U i
it
f C lif
i
P
1992) 7 8 N t
h
ft
th
iti
t
t Allegorical Readers and Cultural Revision in Ancient Alexandria (Los Angeles:
University of California Press, 1992), 7–8. Note how often the critic resorts to 5. Fin’amor Castrated: Abelard, Heloise,
and the Critics who Deny Their relationship found physical expression, and
Heloise is neither cold nor remote but loving and generous, eager to
give service and not to demand it”.66 Far from being something so bloodless as Robertson’s “exemplary
conversion narrative authored by Abelard”,67 the story of Abelard
and Heloise is defined by passion, desire, and loss. Their love cannot
be confined to an academic’s tale, a somnolent morality play that fits
comfortably within the paradigm of “courtly love”, with its emphasis
on love as a flawed if necessary path to Heaven. Theirs is a tale of the
delights and dangers of fin’amor in a world determined to control love
and sexuality—a world in which too many seem determined to write
such a story out of existence by insisting that it does not really mean
what it says. But as Zang Longxi reminds us, in response to those critics
who would torture texts into “saying” what they do not say, while
vigorously denying what they do say: “the plain literal sense of the text
must always act as a restraint to keep interpretation from going wild,
[…] bringing the letter into harmony with the spirit, rather than into
opposition to it”.68 Allegorical Readers and Cultural Revision in Ancient Alexandria (Los Angeles:
University of California Press, 1992), 7–8. Note how often the critic resorts to
5. Fin’amor Castrated: Abelard, Heloise, and the Critics who Deny 213 The history of Abelard and Heloise is one of delight and suffering—
real suffering, not the stylized variety of the courtly stories—and just
perhaps, it is also a story of a new joy at being reunited, through words
on a page (one can only imagine how many times Abelard read and read
again those words Heloise had given him, and as for Heloise, she leaves
us in no doubt). For beside the sensual delight each took in the other,
what else more than their words, their intellects, their thoughts, brought
Abelard and Heloise together as two sighted lovers amidst the eyeless
crowds? Those who would condemn Heloise’s passions, argue that her
words were really not her own, or adopt any other tactic that might serve
to explain her away, will always be with us. But they need no longer
have any claim on our attention, much less our readerly obedience to
their insistent demands that we read as they do. condescending language that insists on the naïveté and “conventional” quality of
readings that attempt to recover a literal sense of a text. Such readings are “unself-
conscious”, “conventional”, “customary”, and otherwise to be revealed, unmasked,
and debunked by the clear-eyed, self-conscious, and most definitely unconventional
critic. Who benefits from such relentless and widely-shared (in some sense also
“conventional” and “customary”) interpretive stances by critics? Other, that is, than
the critics themselves?
69
Newman 70 condescending language that insists on the naïveté and “conventional” quality of
readings that attempt to recover a literal sense of a text. Such readings are “unself-
conscious”, “conventional”, “customary”, and otherwise to be revealed, unmasked,
and debunked by the clear-eyed, self-conscious, and most definitely unconventional
critic. Who benefits from such relentless and widely-shared (in some sense also
“conventional” and “customary”) interpretive stances by critics? Other, that is, than
the critics themselves?
69
Newman, 70. 69
Newman, 70. 1
Briffault, 132. 5. Fin’amor Castrated: Abelard, Heloise,
and the Critics who Deny Abelard and Heloise
loved as few ever will, and Heloise in particular stands above the mean
and base denunciations of the passionless, and sanctimonious critics
who would silence or shame her across the centuries. Heloise was a
woman of strength, substance, and character who would merely laugh
at her modern detractors, for her focus was always on love: “[m]ore than
any ancient Roman, perhaps, Heloise fulfilled to perfection the classical
ideal of the univim, the woman who belonged solely and wholly to
a single man. Whatever the role she played, Abelard was always her
solus, her unicus, he alone could grieve her, comfort her, instruct her,
command her, destroy her, or save her”.69 In the end, love found a way to thrive, through the lovers’ passionate
and painful lines, and through our own open and honest reading of
those lines nearly a thousand years later. The love of Abelard and
Heloise was neither ironic, nor faked—such claims say more about the
critics than about the words of two twelfth-century lovers who, even
now, face the condemnation of the moral scolds among us who never
miss a chance to drain the joy out of life, love, and poetry. 2
En paradis qu’ai je a faire? Je n’i quier entrer, mais que j’aie Nicolete, ma tres douce amie que
j’aim tant. C’en paradis ne vont fors tex gens con je vous dirai. Il i vont ci viel prestre et cil viel
clop et cil manke, qui tote jor et tote nuit cropent devant ces autex et en ces viés creutes, et cil
a ces viés capes eraéses et a ces viés tateceles vestues, qui sont nu et decauç et estrumelé, qui
moeurent de faim et de soi et de froit et de mesaises. Icil vont en paradis; avec ciax n’ai jou que
faire; mais en infer voil jou aler. Car en infer vont li bel clerc, et li bel cevalier, qui sont mort as
tornois et as rices gueres, et li boin sergant, et li franc home. Aveuc ciax voil jou aler. Et s’i vont
les beles dames cortoises, que eles ont .ii. amis ou .iii. avoc leur barons. Et s’i va li ors et li argens,
et li vairs et li gris; et si i vont harpeor et jogleor et li roi del siecle. Avoc ciax voil jou aler, mais
quĕ j’aie Nicolete, ma tres douce amie, aveuc mi.
Aucassin et Nicolette, ed. by Francis William Bourdillon (London: Kegan Paul, Trench
& Co., 1887), 14–17, https://archive.org/stream/AucassinEtNicoletteALoveStory/
Aucassin_et_Nicolette_Bourdillon_1887#page/n102
3
https://commons.wikimedia.org/wiki/File:Marianne_Stokes05.jpg 3
https://commons.wikimedia.org/wiki/File:Marianne_Stokes05.jpg The Death of Fin’amor: The Albigensian Crusade
and its Aftermath At the beginning of the thirteenth century, everything changed. In
its earliest days, the mood in Provençe was ebullient and defiant. It
radiates from the tale of Aucassin et Nicolette, which, though written in
the northern dialect of Picardy, “gives a faithful picture”1 of the attitudes
held in Occitania—sensual, anticlerical, and fiercely independent: In Paradise what would I do? I do not seek to enter there, but only wish
for Nicolette, my sweet friend that I love so much. For no one goes to
Paradise except the kinds of people I will tell you about now: there is
where the old priests go, crippled and maimed old men, who cower all
day and night in front of the altars, and in the crypts; and people wearing
old tattered cloaks, naked and with no shoes, covered in sores, diseased
and dying of hunger and thirst and cold. These are the people who go
to Paradise; I want nothing to do with them. I would rather go to Hell,
where there are fine clerks and knights, who have died in tournaments
and noble wars, brave soldiers and noble men. These are who I would https://doi.org/10.11647/OBP.0117.06 © 2017 Michael Bryson and Arpi Movsesian, CC BY 4.0 https://doi.org/10.11647/OBP.0117.06 216 Love and its Critics go with. And there, also, are the beautiful and courteous women who
have two or three lovers in addition to their husbands. There is to be
found all gold, silver, fine furs, musicians and poets, and the prince of
this world. Let me go with these, as long as I have Nicolette, my sweet
love, with me.2 Marianne Stokes, Aucassin and Nicolette (1898).3 Marianne Stokes, Aucassin and Nicolette (1898).3 Better to love in hell, than serve in heaven. Such rhetorical bravery was still
relatively easy in 1200, nine years before the opening of the Albigensian
Crusade with the wholesale slaughter of the men, women, and children
of the southern town of Béziers. Occitania was still cosmopolitan and
6. The Death of Fin’amor in Medieval French and English Poetry 217 tolerant, a place in which “the influence of the Church never went as
deep […] as it did in the Kingdom of the Franks”.4 The people were
characterized by a “political particularism” which “was intensified by
their traditional opposition to the religion of the French”.5 All seemed well, especially because Occitan culture was successful
and growing. 6
Nigel F. Palmer. “The High and later Middle Ages (1100–1450)”. In Hellen
Watanabe-O’Kelly, ed. The Cambridge History of German Literature (Cambridge:
Cambridge University Press, 1997), 47–48. 4
Briffault, 130.
5
Ibid., 131.
6
Nigel F. Palmer. “The High and later Middle Ages (1100–1450)”. In Hellen
Watanabe-O’Kelly, ed. The Cambridge History of German Literature (Cambridge:
Cambridge University Press, 1997), 47–48. 5
Ibid., 131. 7
Walther von der Vogelweide. “Under der linden”. In Karl Lachmann, ed. Die
Gedichte Walthers von der Vogelweide (Berlin: George Reimer, 1891), 39–40, https://
archive.org/stream/diegedichtewalt00lachgoog#page/n62 The Death of Fin’amor: The Albigensian Crusade
and its Aftermath The poetic culture of the troubadours had spread beyond
the borders of Occitania into Italy and Spain. One of the most powerful
areas of troubadour influence was in Germany, where a group of poets
known as the Minnesingers followed in the footsteps of the troubadours
“with a time lag of some fifteen years”.6 The most famous of these,
Walther von der Vogelweide (c. 1170–1230) illustrates the spread of the
idea of fin’amor as passionate, embodied, and often forbidden love from
the lands of the langue d’oc to the valley of the Rhine: Under der linden
an der heide,
dâ unser zweier bette was,
dâ mugent ir vinden
schône beide
gebrochen bluomen unde grass. vor dem walde in einem tal,
tandaradei,
schône sane diu nahtegal. Ich kam gegangen
zuo der ouwe:
dô was min friedel komen ê. dâ wart ich enpfangen,
hêre frouwe,
daz ich bin sælic iemer mê. kuster mich? wol tûsentstunt:
tandaradei,
seht wie rôt mir ist der munt. Dô hât er gemachet
alsô riche seht wie rôt mir ist der munt. alsô riche 218 Love and its Critics von bluomen eine bettestat. des wirt noch gelachet
inneclîche,
kumt iemen an daz selbe pfat. bî den rôsen er wol mac,
tandaradei,
merken wâ mirz houbet lac. Daz er bî mir læge,
wessez iemen,
(nu enwelle got!), sô schamt ich mich. wes er mit mir pflæge,
niemer niemen
bevinde daz, wan er unt ich,
und ein kleinez vogellîn,
tanderadei,
daz mac wol getriuwe sin.7
Under the Linden
Out on the heath,
Where our bed for two was,
You may still find
Beauty both
In broken blooms and grass,
Where, in a field at the forests’ edge,
Tandaradei! So sweetly sang the nightingale. I came walking
Through the meadow:
My lover had come before. And he greeted me,
Highest Lady! So that my joy is always with me. Did he kiss me? A thousand times:
Tandaradei! See how red my mouth is. He prepared for us a place
Walther von der Vogelweide. “Under der linden von bluomen eine bettestat. des wirt noch gelachet
inneclîche,
kumt iemen an daz selbe pfat. bî den rôsen er wol mac,
tandaradei,
merken wâ mirz houbet lac. Daz er bî mir læge,
wessez iemen,
(nu enwelle got!), sô schamt ich mich. 10
Andreas Krass. “Saying It with Flowers: Post-Foucauldian Literary History and the
Poetics of Taboo in a Premodern German Love Song”. In Scott Spector, Helmut
Puff, and Dagmar Herzog, eds. After the History of Sexuality: German Genealogies with
and Beyond Foucault (New York: Berghahn Books, 2012), 64. 8
W. T. H. Jackson. “Faith Unfaithful—The German Reaction to Courtly Love”. In F.
X. Newman, ed. The Meaning of Courtly Love (Albany: State University of New York
Press, 1968), 74.
9
Jackson, 74. The Death of Fin’amor: The Albigensian Crusade
and its Aftermath wes er mit mir pflæge,
niemer niemen
bevinde daz, wan er unt ich,
und ein kleinez vogellîn,
tanderadei,
daz mac wol getriuwe sin.7 Under the Linden
Out on the heath,
Where our bed for two was,
You may still find
Beauty both
In broken blooms and grass,
Where, in a field at the forests’ edge,
Tandaradei! So sweetly sang the nightingale. I came walking
Through the meadow:
My lover had come before. And he greeted me,
Highest Lady! So that my joy is always with me. Did he kiss me? A thousand times:
Tandaradei! See how red my mouth is. He prepared for us a place Highest Lady! So that my joy is always with me. See how red my mouth is. He prepared for us a place 219
6. The Death of Fin’amor in Medieval French and English Poetry Of riches
A bed from flowers. It made me laugh
With delight. One who comes along the same path,
At the roses he may well
Tandaradei! Mark where I lay my head. That he lay with me,
If anyone knew,
God forbid—I would be shamed. What there he did with me,
None must ever know,
Except for he and I,
And a little bird,
Tandaradei! Who will probably be true. What the lovers of Under der linden enjoy, and what the notably female
voice describes, is the freedom to love each other passionately, and
physically, removed from the constraints of the world of law, authority,
and religion. This poem has none of the “sterile”, and “exhausted”
quality of poetry in which love “rested not on an emotion or even a noble
heart but on a feudal concept of service”.8 It is, rather, a demonstration
of Walther’s idea that “true love [is] mutual and natural”.9 We have not
yet reached the stage at which love and desire are wholly sublimated
into service and worship, the stage that most comfortably fits the
term “courtly love”. Under der linden has nothing in common with the
romances of Chrétien de Troyes, in which a figure like Lancelot can and
will be punished by his lady for a failure of swift and cheerful obedience. “The song does not sing of spiritual frailty or squandered joy. 11
Ibid.
12
Frederic L. Cheyettee. Ermengard of Narbonne and the World of the Troubadours (Ithaca:
Cornell University Press, 2001), 4.
13
David Boyle. Troubadour’s Song: The Capture, Imprisonment and Ransom of Richard the
Lionheart (New York: Walker & Co., 2005), 5. The Death of Fin’amor: The Albigensian Crusade
and its Aftermath Instead,
it sings of the joys of consummated love”.10 Hovering over this poem’s 220 Love and its Critics delight is a powerful awareness “of the moral taboo that looms over
extramarital love affairs”,11 a sense of the ever-present shadow of the
oppressive and disapproving world, precisely the kind of place, in fact,
in which love and desire will be turned into service and obedience. The
lady would be shamed if anyone knew of the love she and her lover
shared, if anyone but the (probably) discreet birds could ever tell of her
love. Even here, it seems, joy must be stolen in small moments hidden
from a society determined to grind its inhabitants into a dry and near-
lifeless compliance. In Occitania, however, love, music, and passion were not yet lost. Located primarily between the Rhone and the Pyrenees, the world of
the troubadours was a desirable one. The most powerful people of the
time, including the lords of Montpellier, the viscounts of Narbonne,
and the Trencavels, maintained tight political alliances, which along
with strategic marriages between the powerful families of Poitiers and
Toulouse, consolidated regional powers and rivalries that lasted until
the Albigensian Crusade of the early thirteenth century: The counts of Poitiers arranged a marriage between Count William
VII of Poitou (also known as William IX of Aquitaine, the first known
troubadour) and Philippa, the daughter of Count William IV of Toulouse. Duke William X, Philippa’s son inherited all the titles, and passed on to
his only child, Eleanor of Aquitaine.12 Eleanor of Aquitaine’s royal husbands, Louis VII of France and Henry
II of England also had influence in the region. These men, along with
Henry II’s sons, Geoffrey, Henry, Richard, and John, knew many of the
troubadours of the time, and one is known to have composed his own
lyrics. Richard, who would later become Richard I, loved music, and
“would stand alongside the choir at the royal chapel, urging them with
his hands to sing louder”.13 The era that gleamed with poetic inspiration was also a period of
cosmopolitan spirit. It was a culture characterized by a sophisticated
ethic of tolerance regarding opinion and belief, whose ethos could be
6. 17
Paratge, with its basic “respect for human beings was also applied to Jews”, a state
of affairs which did not sit well with the Catholic authorities under Innocent III, so
“at the Council of Saint Gilles, Raymond VI, Count of Toulouse, and twelve of his
major vassals had to swear they would stop giving official positions to Jews” (Henri
Jeanjean. “Flamenca: A Wake for a Dying Civilization?”, Parergon, 16: 1 [July 1998],
21, http://ro.uow.edu.au/cgi/viewcontent.cgi?article=2958&context=artspapers). 14
“honneur, droiture, égalité, négation du droit du plus fort, respect de la personne
humaine pour soi et pour les autres. Le paratge s’applique dans tous les domaines,
politique, religieux, sentimental” (Ferdinand Niel, Albigeois et Cathares [Paris:
Presses Universitaires de France, 1974], 67). 19
Approximately 45% of Cathar ministers were female (Richard Abels and Ellen
Harrison. “The Participation of Women in Languedocian Catharism”. Mediaeval
Studies, 41 [1979], 225, https://doi.org/10.1484/J.MS.2.306245). 16
On the massacres of Jews in Cologne, Metz, Trier and anti-Jewish hostilities
brought about by the First Crusade toward the end of the eleventh century see
Norman Golb, The Jews in Medieval Normandy: A Social and Intellectual History (NY:
Cambridge, University Press, 1998). 15
“Les seigneurs du Midi […] contre les Croises pour la defendre et non pour la
spolier” (Charles Camproux. Le “joy d’amor” des troubadours. Jeu et joie d’amour
[Montpellier: Causse et Castelnau, 1965], 95). 18
Cheyettee, 295. p
g
g
p p
18
Cheyettee, 295. The Death of Fin’amor: The Albigensian Crusade
and its Aftermath The Death of Fin’amor in Medieval French and English Poetry 221 summed up in the word paratge, a word meaning: “honor, righteousness,
equality, denial of the right of the strongest, respect for the human
person for itself and for others. Paratge applies in all fields, political,
religious, and emotional”.14 Such a concept led “the lords of the South
[…] against the Crusaders to defend and not to plunder”.15 But in the background, under the bright surfaces of life in a relatively
liberal and highly cultured Occitania, trouble was slowly coming to a
boil. The First Crusade in 1099 brought turmoil to the region, including
pogroms against the Jews16 (a group that had long been treated relatively
well in Occitan culture17). This period also saw the rise of heretical sects,
especially a religious group known to present-day historians as the
Cathars, who established themselves in the south, with an openly-run
diocese in the town of Albi (thus the name “Albigensians”). Cathars,
literally, “the cleansed” or “the purged”, spread through Languedoc
and into major cities of northern Italy. The religion of the Cathars—or
“boni homines, ‘good men’, […] the popular Occitan name for the Cathar
‘Perfects’”18—allowed for something like gender equality,19 and became
so influential by the mid-twelfth century that they could hold public
debates with the bishops of Albi and Toulouse. 20
Boyle, 282.
21
Sean McGlynn. Kill Them All: Cathars and Carnage in the Albigensian Crusade (Stroud:
The History Press, 2015), 16.
22
Ibid., 17.
23
Briffault, 137. y ,
21
Sean McGlynn. Kill Them All: Cathars and Carnage in the Albigensian Crusade (Stroud:
The History Press, 2015), 16.
22
Ibid., 17. 20
Boyle, 282. 23
Briffault, 137. The Death of Fin’amor: The Albigensian Crusade
and its Aftermath For powerful churchmen,
such independence was intolerable, as “this was also a period when the
centralized Church was turning its back on women again and found 222 Love and its Critics the influence of the powerful women behind Cathar society particularly
threatening”.20 The widespread practice of a religion that so openly challenged
social and political norms, while it rejected the orthodox claims of
Rome, made the weak and indecisive Count Raymond V of Toulouse
nervous enough that he wrote a letter in 1177 explaining the situation to
Church authorities: The disease of heresy has grown so strong in my lands that almost all
those who follow it believe that they are serving God… The priesthood
is corrupted with heresy; ancient churches, once held in reverence, are
no longer used for divine worship but have fallen into ruins; baptism
is denied; the Mass is hated; confession is derided… Worst of all, the
doctrine of two principles is taught.21 The “doctrine of two principles” refers to the dualist Cathar belief,
familiar from various strands of Gnosticism, and Plato’s Timaeus, that the
creator of this world was a demiurge, an inferior—and for the Cathars,
evil—god who “kept the divine souls of humans imprisoned in their
physical bodies (or other warm-blooded animals), condemning them to
perpetual reincarnation. This cycle could only be broken by adherence
to Cathar beliefs”.22 The Cathar belief system, in its skepticism and
refusal of Catholic authority, represented just the latest in a long line of
rebellious sentiments in the Languedoc: Skeptical Provençe was the natural refuge of all heretics. From the ninth
century, when the Adoptionist heresy spread from Toledo, where it
originated, over Languedoc, down to the foretokenings of Protestantism,
medieval heresies were primarily inspired by revolt against the spiritual
and material tyranny of the Roman Church. […] The teachings of the
Cathars [were] affiliated with similar kernels of resistance scattered
throughout Christendom, and deriving in direct continuity from the
earliest years of the Church.23 This resistance was shared nearly across the board in Occitania, even by
those who were not Cathar believers. The differences between the north 23
Briffault, 137.
6. 24
McGlynn, 24.
25
Ibid.
26
Ibid., 24–25.
27
Ibid., 25.
28
Simon Pegg. A Most Holy War: The Albigensian Crusade and the Battle for Christian
Freedom (Oxford: Oxford University Press, 2008), 60–61. The Death of Fin’amor: The Albigensian Crusade
and its Aftermath The Death of Fin’amor in Medieval French and English Poetry 223 and south were as much cultural and linguistic as they were religious:
“for southerners, the langue d’oil of northern France was more of a foreign
language”.24 The southerners, whose langue d’oc was closer to Catalan
than to the language of Paris, regarded the northerners as uncultured
barbarians: “crude, unrefined, brutish and bellicose, altogether lacking
in manners and culture”,25 and the northerners regarded the residents
of Languedoc as the twelfth-and thirteenth-century equivalents of
Chardonnay-sipping elitists, “sybaritic, indulgent, indolent and
effete”.26 Occitania was a rich land as well, and made a tempting prize
for less wealthy northern nobles when the Church-sponsored invasion
of the south began in 1209. The Cathar refusal of Catholic authority
was certainly what rankled Pope Innocent III, who had attempted to
rouse the northern nobles to a crusade against the south in 1205 and
1207 before his successful effort of 1209. But it was money, land, and
power that motivated the warriors who besieged the towns of Béziers,
Carcassone, and Albi (and others over the following decades). Occitania,
as McGlynn notes, had a booming economy “boosted by trade across
the Mediterranean, including with Egypt and Syria; they exported
wine, dyed woollens, olive oil and grain while importing spices, silks
and luxury items”.27 In the leadup to the Crusade, Pope Innocent III demanded both the
submission of Raymond VI, and the turning over of Cathar heretics
to Catholic authorities. Northern nobles like Simon de Montfort, as
orthodox as they may have been, were primarily interested in wealth,
seeing the chance to enrich themselves by dispossessing the southern
nobility. The pope had bigger concerns, since he saw himself as
inhabiting a unique position of power and responsibility: “no pope had
ever envisioned himself with so magnificent a mandate over the world”,
and as he saw it, the heresy of the south had to be eliminated—“if it were
not obliterated […] then all Christian existence would come to an end. […] The crusade against heresy in the lands of the count of Toulouse
was a holy war for the very survival of Christendom”.28 But the pope 224 Love and its Critics was a practical man who knew how to win the princes and nobles of the
north to his cause—money talks, then as now. 29
Catherine Léglu, Rebecca Rist, and Claire Taylor, eds. The Cathars and The Albigensian
Crusade: A Sourcebook (New York: Routledge, 2014), 64.
30
Ibid 65 (Caesarii Heisterbacences. Dialogus Miraculorum, ed. by Josephus Strange, 2
Vols. [Cologne: H. Lempertz & Co., 1851], 1, 302), https://archive.org/stream/
caesariiheister00stragoog#page/n318 31
Cognoscentes ex confessionibus illorum catholicos cum haereticis esse permixtos, dixerunt
Abbati: Quid faciemus, domine? Non possumus discenere inter bonos et malos. Timens
tam Abbas quam reliqui, ne tantum timore mortis se catholicos simularent, et post ipsorum
abcessum iterum ad perfidiam redirent, fertur dixisse: Caedite eos. Novit enim Dominus qui
sunt eius. 31
Cognoscentes ex confessionibus illorum catholicos cum haereticis esse permixtos, dixerunt
Abbati: Quid faciemus, domine? Non possumus discenere inter bonos et malos. Timens
tam Abbas quam reliqui, ne tantum timore mortis se catholicos simularent, et post ipsorum
abcessum iterum ad perfidiam redirent, fertur dixisse: Caedite eos. Novit enim Dominus qui
sunt eius.
(Caesarii Heisterbacences. Dialogus Miraculorum, ed. by Josephus Strange, 2
Vols. [Cologne: H. Lempertz & Co., 1851], 1, 302), https://archive.org/stream/
caesariiheister00stragoog#page/n318 30
Ibid., 65. 32
Guilhem de Tudela and Anonymous. Historie de la Croisade contre les Hérétiques
Alibgeois, ed. by M. C. Fauriel (Paris: Imprimerie Royale, 1837), ll. 481–88, 492–99,
https://archive.org/stream/histoiredelacroi00guil#page/36 The Death of Fin’amor: The Albigensian Crusade
and its Aftermath The Death of Fin’amor in Medieval French and English Poetry Quaneson a la espaza e quom les aucezis
E pois no trobarian qui vas lor se tenguis
Per paor que aurian e per so cauran vist
[…]
Perso son a Bezers destruit e a mal mis
Que trastotz los aucisdron no lor podo far pis
E totz sels aucizian quel mostier se son mis
Que nols pot gandir crotz autar ni cruzifis
E los clercs aucizian li fols ribautz mendics
E femnas e efans canc no cug us nichis
Dieus recepia las armas sil platz en paradis
Canc mais tan fera mort del temps Sarrazinis.32 The lords of France and those of Paris
And the clerics and princes and marquises
And all others employed between them
Were of the same mind: a castle whose owner
Would not surrender to the gathered forces
Should be put to the sword, even the animals. And then they would find no others to resist them,
For fear of what had already been seen. […]
This is why those of Béziers were destroyed,
For it was the most evil that could be done. And they killed all who fled into the church,
No cross, nor altar, nor crucifix saved them,
And the madmen killed the clerks like beasts,
And women and children, I think none survived. May God please to take them in his arms to heaven:
Such death has not been known since Saracen times. The lords of France and those of Paris
And the clerics and princes and marquises
And all others employed between them
Were of the same mind: a castle whose owner
Would not surrender to the gathered forces
Should be put to the sword, even the animals. And then they would find no others to resist them,
For fear of what had already been seen. Such slaughter often goes by the name of genocide today. The
contemporary chronicler Peter of Vaux-de-Cernay defends and even
celebrates the near-extermination by claiming that the population was
consumed by “heretical depravity which infected the citizens of Béziers,
who are not only heretics, but also robbers, lawbreakers, adulterers, Such slaughter often goes by the name of genocide today. The Death of Fin’amor: The Albigensian Crusade
and its Aftermath In a letter of November
17, 1207, Innocent III appealed to King Philip II of France, complaining
of what he called “[t]he age-old seduction of wicked heresy, which is
constantly sprouting in the regions of Toulouse”,29 and promising both
“remission of sins” for the crusaders and the confiscation “of all the
goods of the heretics themselves”.30 The offer was clear: go to war in the
south, clear out the heretics, and your reward will be their lands and
possessions, with no need to worry about sin in the process. At Béziers,
when the papal legate Arnaud Amaury was asked by the Crusaders
how they would be able to tell heretics from the orthodox, he told them
not to worry about it: Those who realized that Catholics and heretics were mixed together, said
to the Abbot: “What shall we do, my lord? We can not discern between
the good and the evil”. Both the Abbot and the rest feared the heretics
would pretend to be Catholics, from fear of death, and afterwards return
again to their perfidy; so he is reported to have said: “Kill them. For the
Lord knows who are his”.31 According to Guilhem de Tudela, one of two early thirteenth-century
authors of the Cansó de la croisada, or Song of the Crusade, the slaughter
was meant to terrorize the entire region into submission to both the
Church and the French King in Paris: Le barnatges de Fransa e sels devas Paris
E li clerc e li laic li princeps els marchis
E li un e li autre an entre lor empris
Que a calque castel en que la o’st venguis
Que nos volguessan redre entro que lost les prezis 225
6. 33
“hereticae, pravitatis infecta nec solú haeretici cives Biterrenses, sed erant raptores
iniusti, adulteri, latrones pessimi, pleni omni genere peccatorum” (Pierre de Vaux-
Cernay. Historia Albigensium et sacri belli in eos anno MCCIX [Trecis: Venundantur
Parisiis, Apud N. Rousset, 1617], 42). One detects the faintest hint of the fin’amor
ethos of the troubadours in the reference to “adulterers”, https://archive.org/
stream/historiaalbigens00pier#page/n73 34
“Fuit autem capta civitas saepe dicta in festo S. Mariae Magdalenai” (ibid., 44,
https://archive.org/stream/historiaalbigens00pier#page/n75). 38
Michael C. Thomsett. Heresy in the Roman Catholic Church: A History (Jefferson:
McFarland Publishers, 2011), 3. 37
Stephen Pinker. The Better Angels of Our Nature: Why Violence has Declined (New
York: Viking, 2011), 141. 35
“justissima divinae dispensationis mensura” (ibid.). 39
Laurence W. Marvin. The Occitan War: A Military and Political History of the Albigensian
Crusade, 1209–1218 (Cambridge: Cambridge University Press, 2008), 45. 36
McGlynn, 61. The Death of Fin’amor: The Albigensian Crusade
and its Aftermath The
contemporary chronicler Peter of Vaux-de-Cernay defends and even
celebrates the near-extermination by claiming that the population was
consumed by “heretical depravity which infected the citizens of Béziers,
who are not only heretics, but also robbers, lawbreakers, adulterers, 226 Love and its Critics and thieves, all of the worst sort, filled with every kind of sin”.33 After
noting that nearly all of these “heretics” had been killed, Peter revels
in the fact that “the city was captured on what is often called the feast
day of Saint Mary Magdalene”,34 calling the timing of the mass murder
of the men, women, and children of Béziers “a just measure of divine
dispensation”.35 Reports of the numbers of dead differ widely. “The Song does not
give a number; William of Puylaurens simply and starkly says ‘many
thousands’; Peter of Vaux de Cernay claims ‘7,000’ were killed in the
church of St Mary Magdalene; in a letter to Rome the legates wrote
that ‘none was spared’ and that ‘almost 20,000’ were put to the sword. William the Breton heard that 60,000 perished; others take it up to
100,000”.36 Estimates of the total number of dead in the years from
1209–1229 range from 200,00037 to 1,000,000 or more.38 Such a massacre changes a world, and the southern region of
Occitania, the land of langue d’oc, would never again be the same:
“Béziers introduced the people of Occitania to the high stakes they
faced. These included inevitable punishment, if not execution, for
recalcitrant Cathars, changes in religious practices for those afraid to
die for their beliefs, and political domination from the outside even
for those who had always remained faithful to the church”.39 Those
who had participated—and continued to participate—in the ongoing
slaughter were rewarded: “On 24 June 1213, in a field outside the walls
of Castelnaudary, between Toulouse and Carcassonne, Amaury of
6. The Death of Fin’amor in Medieval French and English Poetry 227 Montfort was knighted by Bishop Manasses of Orléans”.40 The close
relationship between the crusaders and the Church, the military and
theological powers of the day, is made evident in this gesture. Under
a cloak of sanctity, the Church had its way by force of bloody arms. Four years before the ceremony, Simon de Montfort, Amaury’s father,
had been made the commander of the forces that would carry out the
Albigensian Crusade. 40
Christopher Tyerman. God’s War: A New History of the Crusades (Cambridge, MA:
Belknap Press of Harvard University Press, 2006), 563.
41
Ibid. 42
Ibid., 566. 43
Boyle, 284. 40
Christopher Tyerman. God’s War: A New History of the Crusades (Cambridge, MA:
Belknap Press of Harvard University Press, 2006), 563.
41
Ibid.
42
Ibid., 566.
43
Boyle, 284. The Death of Fin’amor: The Albigensian Crusade
and its Aftermath In order to be safe from any and all criticism
for the slaughters, Simon urged the bishop to dub his son, Amaury, a
knight of Christ. The father-son duo fully dedicated itself to Innocent
III’s vision of “sacred” violence, using bloodshed to restore the power of
the Church in Occitania: “The Castelnaudary ceremony […] represented
[…] the rededication of the Montfort clan to Pope Innocent III’s vision of
holy violence by creating almost a fresh category of knight, dedicated to
Christ’s war yet without the religious vows of the military orders”.41 It
was as much a political as an economic move, and the sanctifying of the
knights meant one thing in particular: [It] emphasized the sanction of orthodox religion in the exercise of
political authority, a crude identification of church and secular power
that disconcerted the bishop of Orléans. Castelnaudary showed how
Simon specifically identified his and his family’s mission as holy. The
primacy of the anti-heretical message that had inspired Innocent III
to call for a crusade in 1208–9 was increasingly drowned out by the
secular implications of Simon’s conquests: the political reorganization
of Languedoc.42 The brutal massacres of the Albigensian Crusade destroyed the once-
optimistic and humanistic culture of Occitania, and “[r]epression now
was the spirit of the age”.43 The Crusade granted new lands and wealth
to the northern French nobility, who along with the Church, made sure
that much of what remained of a vibrant culture in the south was rooted
out over the next century. The Inquisition was established in 1229
precisely in order to ensure that heresy would be found wherever it
was hiding, with confessions extracted and “heretics” burned, an effort 228 Love and its Critics to enforce theological and political conformity that began with the
slaughter at Béziers which Innocent III blandly referred to as negotium
pacis et fidei,44 a “business of peace and the faith” that looks like genocide: The pope argued that all peaceful efforts of the Church had failed because
of the obstinacy of the heretics, and that only armed action could help to
resolve the situation. This official “reconstruction” […] aimed to impose
the idea of the crusade as a final solution.45 It is difficult to pinpoint one cause of the atrocities that began in 1209,
as there is no single factor that can be isolated. y
p
g
g
p
p g
45
“Le pape soutint que tous les efforts pacifiques de l’Église avaient échoué à cause
de la pertinacia des hérétiques, et que seule une action armée pouvait permettre de
résoudre la situation. Cette reconstruction officielle […] visait à imposer l’idée de la
croisade comme extrema ratio” (Marco Meschini. “‘Smoking sword’: le meurtre du
legat Pierre de Castelnau et la premiere croisade albigeoise”. In Michel Balard, ed.
La Papauté et les Croisades [Farnham: Ashgate, 2011], 72). 46
Guilhem de Tudela and Anonymous. Historie de la Croisade contre les Hérétiques
Alibgeois, ll. 1499–1500, https://archive.org/stream/histoiredelacroi00guil#page/108 44
Pierre de Vaux-Cernay, 296, https://archive.org/stream/historiaalbigens00pier#page/n327
É
é
é à 49
This former troubadour understood the non-spiritual nature of fin’amor: he
“displayed his awareness of the distinction between the kind of love he portrayed
as fin’amor, and the spiritual love appropriate to religious sentiments, by doing
penance whenever he heard the love songs he had written” (Nicole M. Schulman.
Where Troubadours Were Bishops [London: Routledge, 2001], 18). The Death of Fin’amor: The Albigensian Crusade
and its Aftermath The troubadours and
the Cathars, each in their different ways, contributed to what might
be called a twelfth-century Renaissance, the ideals of which did not
necessarily serve the interests of numerous powerful players in the
region. Territorial greed, the ambitions of the northern French nobility,
the blossoming of the Cathars and their independence, all played a role
in triggering the Albigensian Crusade. Even the Cansó de la croisada
takes two different points of view. The poem has two authors, one
anonymous and one Guilhem de Tudela, and consists of two parts. Guilhem is eager to condemn heresy, and his verse energetically
denounces the heretical sects in the south of France. In his accounts of
Simon de Montfort’s pillaging of the town of Lavaur, Guilhem often
tries to depict de Montfort as a courteous and gentle knight, perfoming
the most praiseworthy of deeds: Oi Dieus dizon trastuil dama santa Maria
Co a fait gran proeza e granda cortezia!46 “Oh God, and our holy lady Mary,
What a deed of great prowess and grand courtesy!”
6. The Death of Fin’amor in Medieval French and English Poetry 229 But what underlines Guilhem’s support for de Montfort and the
crusaders is a powerfully authoritarian ideal: But what underlines Guilhem’s support for de Montfort and the
crusaders is a powerfully authoritarian ideal: But what underlines Guilhem’s support for de Montfort and the
crusaders is a powerfully authoritarian ideal: Lai doncas fo laor faita aitant grans mortaldat
Quentro la fm del mon cug quen sia parlat
Senhor be sen devrian ilh estre castiat
Que so vi e auzi e son trop malaurat
Car no fan so quels mando li clerc e li Crozad.47 Then there was so great a mortal slaughter
I believe it will be talked of to the world’s end. My lords, it is right they should be chastised,
For, unfortunately, as I have seen and heard,
They refuse obedience to the clerks and crusaders. The anonymous author, however, deplores the bloodthirsty attitudes of
the crusaders and sides with the southerners. 48
“totz crestianesmes aonitz abassatz” (ibid., l. 2933, https://archive.org/stream/histoi
redelacroi00guil#page/210). 47
Ibid., ll. 1566–70, https://archive.org/stream/histoiredelacroi00guil#page/112 50
Guilhem de Tudela and Anonymous, ll. 3309–16, https://archive.org/stream/
histoiredelacroi00guil#page/234
51
Ibid., ll. 3809–10, https://archive.org/stream/histoiredelacroi00guil#page/268
52
Ibid., ll. 8685–96, https://archive.org/stream/histoiredelacroi00guil#page/586 52
Ibid., ll. 8685–96, https://archive.org/stream/histoiredelacroi00guil#page/5 The Death of Fin’amor: The Albigensian Crusade
and its Aftermath This author provides more
dialogue and information from the other side, but most importantly, a
certain sympathy for those who have chosen to live how their hearts
desired, combined with a caustic cynicism toward the crusaders and
the Church, whom he describes as having “shamed and disgraced
Christianity”.48 One cleric, Folquet de Marselha—himself a former
troubadour49—comes in for especially sharp criticism: E dic vos de lavesque que tant nes afortitz
Quen la sua semblansa es Dieus e nos trazitz
Quab cansos messongeiras e ab motz coladitz
Dont totz hom es perdutz quels canta ni os ditz
Ez ab sos reproverbis afdatz e forbitz
Ez ab los nostres dos don fo enjotglaritz E dic vos de lavesque que tant nes afortitz
Quen la sua semblansa es Dieus e nos trazitz
Quab cansos messongeiras e ab motz coladitz
Dont totz hom es perdutz quels canta ni os ditz
Ez ab sos reproverbis afdatz e forbitz
Ez ab los nostres dos don fo enjotglaritz 230 Love and its Critics Ez ab mala doctrina es tant fort enriquitz
Com non auza ren diire a so quel contraditz.50
And of this bishop, so full of his own righteousness,
He with his false-seeming betrayed God and us,
With his chants and his smoothly-polished lies,
And his songs, the damnation of any who sing them. And by his powerfully sharp and slick reproofs,
And by our gifts whereby he lived like a celebrity,
And by his evil doctrines, he has risen so high,
That no one dares say anything to contradict him. The author depicts the crusaders’ opponent, Raymond VI, the count of
Toulouse, in a notably positive light:
Que sieu ai enemics ni mals ni orgulhos
Si degus mes laupart eu li serei leos.51
I defy the strongest and most wicked enemies,
and I will be like a lion or a leopard unto them. The Death of Fin’amor: The Albigensian Crusade
and its Aftermath But the same author has withering contempt for the crusaders’ leader,
Simon de Monfort:
Si per homes aucirre ni per sanc espandir,
Ni per esperitz perdre ni per mortz cosentir,
E per mals cosselhs creire, e per focs abrandir,
E per baros destruire, e per Paratge aunir,
E per Las terras toldre, e per Orgilh suffrir,
E per los mals escendre, e pel[s] bes escantir,
E per donas aucirre e per efans delire,
Pot hom en aquest segle Jhesu Crist comquerir,
El deu porta corona e el cel resplandir!52
50
Guilhem de Tudela and Anonymous, ll. 3309–16, https://archive.org/stream/
histoiredelacroi00guil#page/234 Ez ab mala doctrina es tant fort enriquitz
Com non auza ren diire a so quel contraditz.50 And of this bishop, so full of his own righteousness,
He with his false-seeming betrayed God and us,
With his chants and his smoothly-polished lies,
And his songs, the damnation of any who sing them. And by his powerfully sharp and slick reproofs,
And by our gifts whereby he lived like a celebrity,
And by his evil doctrines, he has risen so high,
That no one dares say anything to contradict him. And of this bishop, so full of his own righteousness,
He with his false-seeming betrayed God and us,
With his chants and his smoothly-polished lies,
And his songs, the damnation of any who sing them. And by his powerfully sharp and slick reproofs,
And by our gifts whereby he lived like a celebrity,
And by his evil doctrines, he has risen so high,
That no one dares say anything to contradict him. The author depicts the crusaders’ opponent, Raymond VI, the count of
Toulouse, in a notably positive light: Si per homes aucirre ni per sanc espandir,
Ni per esperitz perdre ni per mortz cosentir,
E per mals cosselhs creire, e per focs abrandir,
E per baros destruire, e per Paratge aunir,
E per Las terras toldre, e per Orgilh suffrir,
E per los mals escendre, e pel[s] bes escantir,
E per donas aucirre e per efans delire,
Pot hom en aquest segle Jhesu Crist comquerir,
El deu porta corona e el cel resplandir!52 50
Guilhem de Tudela and Anonymous, ll. 3309–16, https://archive.org/stream/
histoiredelacroi00guil#page/234
51
Ibid., ll. 3809–10, https://archive.org/stream/histoiredelacroi00guil#page/268
52
Ibid., ll. 8685–96, https://archive.org/stream/histoiredelacroi00guil#page/586 231
6. 53
Boyle, 288.
54
Briffault, 148.
55
Ibid.
56
Ibid., 149. The Death of Fin’amor: The Albigensian Crusade
and its Aftermath The Death of Fin’amor in Medieval French and English Poetry If by killing men and spilling their blood,
Or by wasting their souls and preaching murder,
And by following evil counsel, and setting fires,
And by destroying barons, and dishonoring Paratge,
And by stealing lands and exalting pride,
And by praising evil and scanting good,
And by massacring women and their children,
A man can win Jesus Christ in this world,
Then he surely wears a splendid crown in heaven. The decades-long crusade altered the course of the European world. But
for our purposes, the most dramatic change brought about by Béziers
and all the massacres that followed affected the poetry of the thirteenth
century. No longer were poets free to flout the morality of the Church
without trepidation. Fear now dominated the land, and in turn, the
minds and hearts of those who would write of love. Decades after the
Albigensian Crusade, poetry had lost its sensual edge, and repression
had triumphed: “A manuscript of trouvère music in the British Library,
dating from the middle of the thirteenth century, includes the songs
of Blondel and his contemporaries, but some of the words have been
scrubbed out and replaced with religious ones”.53 As the Church moved
against heresy, poetry was immediately put under tighter controls:
“The Papal Legate made noble knights swear never again to compose
verses”.54 From now on, verse was to conform to the demands of Church
orthodoxy, as evidenced by the example of the prior of Villemeir, “a
zealous Dominican” who “published a theological poem addressed
to recalcitrant poets, in which the truths of each article of faith [were]
reinforced”55 by the use of an ominous and repeated formula: “If
you refuse to believe this, turn your eyes to the flames in which your
companions are roasting. Answer forthwith, in one word or two; either
you will burn in that fire or you will join us”.56 Given the sudden and
violent changes brought by the crusaders, “[t]hese forcible arguments
did not fail in their appeal. In the minds of the poets, inspired by holy 232 Love and its Critics terror, they speeded with marvelous effect the transformation in their
‘conception of love’”.57 The slaughter at Béziers changed everything: “Corpses fouled rivers. […] Skulls were crushed. Murder was a path to redemption. Vines and
fields were devastated. […] Good men became heretics. […] Heretics
dangled from walnut trees. 57
Ibid.
58
Pegg, 191.
59
Briffault, 104.
60
Ibid., 128.
61
Ce n’est donc pas seulement l’amour, mais la vie courtoise tout entière que les poésies de
Montanhagol nous montrent transformée. La nouvelle doctrine de l’amour n’est à vrai dire
qu’une forme du changement survenu dans l’esprit du temps. On ne peut l’expliquer l’une sans The Death of Fin’amor: The Albigensian Crusade
and its Aftermath Very few who began the war lasted to the
end. The world was changed forever”.58 As the world changed, so did
poetry: “the activity of a few poets of Languedoc continued for a while
on a much reduced scale, and in a form almost unrecognizable […]. Prior to that date, nothing is to be found in the poetry of the troubadours
that suggests a platonic idealization of passion”.59 After the violent
destruction of Occitanian culture, troubadour poetry—what little was
left of it—became a tool of Church-mandated morality. In so doing,
the poetry all but died: “[t]he change took place in the corruption and
dissolution of the grave”.60 The effects of this change can be seen in the work of Guilhem
Montanhagol, who worked sometime between 1233 and 1268, during
the time in which the Inquisition was established to finish the job the
Albigensian Crusade had started. Montanhagol’s poetry is a kind of
adaptation-as-appeasement, reacting to the Inquisition’s condemnation
of fin’amor by recasting love in more “acceptable” terms: It is not only love, but the entirety of courtly life that Montanhagol’s
poems show us being transformed. The new doctrine of love is indeed a
form of change in the spirit of the times. We cannot explain one without
the other. They are the consequence of the domination of religious
power. The theory of chaste love, as the new ideal of life, was born of
a moral and religious idea. […] This Provençal poetry, which is soon to
succumb to the enmity of the clergy, first seems to have tried to disarm
its opponent. Accused of immorality and prosecuted as an accomplice
of heresy, it tries to comply with the moral orthodoxy of Christianity
in order to survive. This is an interesting attempt and one of the most
curious periods in the history of Provençal poetry.61 57
Ibid. 58
Pegg, 191. 59
Briffault, 104. 60
Ibid., 128. 61
Ce n’est donc pas seulement l’amour, mais la vie courtoise tout entière que les poésies de
Montanhagol nous montrent transformée. La nouvelle doctrine de l’amour n’est à vrai dire
qu’une forme du changement survenu dans l’esprit du temps. On ne peut l’expliquer l’une sans
6. l’autre. Elles sont la conséquence de la domination du pouvoir religieux. La théorie de l’amour
chaste, comme le nouvel idéal de la vie, est née d’une idée morale et religieuse. […] Cette poésie
provençale, qui doit bientôt succomber sous l’inimitié du clergé, semble d’abord s’être efforcée
de désarmer son adversaire. Accusée d’immoralité & poursuivie comme complice de l’hérésie,
elle veut se conformer à l’orthodoxie & à la morale chrétiennes afin de conserver le droit de
vivre. C’est une tentative intéressante & une des périodes les plus curieuses de l’histoire de la
poésie provençale. Jules Coulet, in Guilhem Montanhagol, Le troubadour Guilhem Montanhagol, ed. by
Jules Coulet [Toulouse: Imprimerie et Librairie Édouard Privat, 1898], 54–55, 57,
https://archive.org/stream/letroubadourguil00guil#page/54 63
En réalité, cette transformation […] était avant tout une nécessité j pour que la chanson d’amour
pût vivre, il fallait qu’elle s’accommodât aux exigences du pouvoir religieux. Les troubadours
ne pouvaient désormais chanter qu’un amour conforme à la morale chrétienne, ignorant des
désirs mauvais & par essence vertueux chaste. 62
Ibid., 69–75, https://archive.org/stream/letroubadourguil00guil#page/70 64
Briffault, 151. The Death of Fin’amor: The Albigensian Crusade
and its Aftermath The Death of Fin’amor in Medieval French and English Poetry 233 Perhaps Montanhagol’s most famous line is from his canso entitled Ar
ab lo coinde pascor.62 In this work, his claim is that “chastity comes from
love”, “d’amor mou castitatz” (l.18). This is a far cry from the earlier
Guilhem IX, for whom amor led to anything but castitatz. But times have
changed for Montanhagol, and the idea of love portrayed in the poetry
of the thirteenth century has changed with them. This was a necessary
transformation, if poetry was to survive: In reality, this transformation […] was primarily from necessity; in order
that love songs could survive, they had to accommodate themselves to
the requirements of religious power. The troubadours now had to sing
of a love consistent with Christian morality, rejecting evil desires for the
essence of virtue and chastity.63 With poetry no longer free to celebrate fin’amor, Platonic love became
the refuge to which new and conformist poets quickly learned to fly:
“[t]he principles governing this remarkable reform are set forth in […]
the Brevaries of Love, by Master Matfré Ermengaud. The excellence of
platonic love is therein demonstrated [and] supported with quotations
drawn from the troubadours”.64 So old is the tradition of making
the troubadours say what they do not say, and so old are the clearly
identifiable and repressive purposes for doing so. Matfré’s late-
thirteenth-century work is an “encyclopedia describing the universe 62
Ibid., 69–75, https://archive.org/stream/letroubadourguil00guil#page/ 63
En réalité, cette transformation […] était avant tout une nécessité j pour que la chanson d’amour
pût vivre, il fallait qu’elle s’accommodât aux exigences du pouvoir religieux. Les troubadours
ne pouvaient désormais chanter qu’un amour conforme à la morale chrétienne, ignorant des
désirs mauvais & par essence vertueux chaste. Ibid 52 https://archive org/stream/letroubadourguil00guil#page/52 Ibid., 52, https://archive.org/stream/letroubadourguil00guil#page/52
64
Briffault, 151. 234 Love and its Critics as emanating from God’s love”,65 a nearly thirty-five-thousand-verse
poem which “surveys the natural and moral orders and concludes with
an exhortation to human marital love”,66 precisely the opposite of that
fin’amor celebrated by the troubadours. Even more interesting, however,
is the critical impulse behind Matfré’s writing: He claims to be writing at the request of his fellow troubadours in order
to expound what is worthwhile (and what reprehensible) in the poetry of
fin’amors. 65
Sarah Kay. Parrots and Nightingales: Troubadour Quotations and the Development of
European Poetry (Philadelphia: University of Pennsylvania Press, 2013), 5. 68
Matfré Ermengaud. Le Breviari d’Amor, ed. by Gabriel Azaïs (Béziers: Secrétariat
de la Société archéologique, scientifigue et littéraire de Béziers, 1862), ll. 1657–63,
https://archive.org/stream/lebreviaridamor01ermeuoft#page/63 69
Sarah Kay, The Place of Thought, 33. 66
Sarah Kay. The Place of Thought: The Complexity of One in Late Medieval French Didactic
Poetry (Philadelphia: University of Pennsylvania Press, 2007), 23.
67
Ibid., 24. 69
Sarah Kay, The Place of Thought, 33. The Death of Fin’amor: The Albigensian Crusade
and its Aftermath […] Sexuality, we are taught, has its place in human behavior
so long as it is morally vitruous and oriented toward reproduction.67 Matfré makes this emphasis clear, arguing that the highest forms of
amor must be redirected from earth to the heavens: Si tôt nol connoisson lh’enfan,
Mas ges en quascun home gran,
Quez a de Dieu conoissensa,
Non habita, ses falhensa,
Si non l’ama d’aquel amor
Qu’om deu amar son creator,
Quar non habita mas els bos.68 An infant does not understand everything,
But not so the noble man
Who knows God:
It is not life, but disloyalty,
Nor is it true love, this love of women,
For a man owes love to his creator,
If he would live, not in evil, but in goodness. An infant does not understand everything,
But not so the noble man
Who knows God:
It is not life, but disloyalty,
Nor is it true love, this love of women,
For a man owes love to his creator,
If he would live, not in evil, but in goodness. It is not life, but disloyalty, Nor is it true love, this love of women, For a man owes love to his creator, For Matfré, fin’amor must be “chaste”, and “prefer wisdom to the folly of
the world”, and “defend and praise ladies”.69 But, as must be painfully
6. The Death of Fin’amor in Medieval French and English Poetry 235 evident at this point, Matfré’s notion of fin’amor is radically different
from, even directly opposed to those of Guilhem IX, or Bernart de
Ventadorn, or the Comtessa de Dia. For Matfré, the Holy Spirit “is the
source and root of love”.70 Here we see the origins of the sublimated
(and un-troubadour-like) version of love that Gaston Paris will come
to define as “courtly” in the nineteenth century. When William Reddy
describes the troubadours’ “dissent against the Gregorian Reform
doctrine that all sexual behavior […] longing, [and] pleasure was bound
up with the realm of sin”71 he is right about the erotic dissent, but wrong
to describe it as “courtly love”. y
72
The effects of this can be seen in Reddy’s insistence on reading fin’amor as something
that somehow transcends “mere” desire: “Fin’amors, in its most developed form,
combined […] sublimity, patience, and loyalty […] and the satisfactions it offered
were a “hundredfold” greater than the satisfaction of mere desire” (162). With
“sublimity”, and its superiority to “mere desire”, we enter the territory of Matfré
Ermengaud and Gaston Paris, an over seven-century-long tradition of rewriting the
troubadours. 73
“Sol Dieus es e non es res als” (Matfré Ermengaud, l. 1373, https://archive.org/
stream/lebreviaridamor01ermeuoft#page/53). 71
Reddy, 106. 70
“es d’amor fons e razitz” (Matfré Ermengaud, ll. 659–60, https://archive.org/stream/
lebreviaridamor01ermeuoft#page/28). The Death of Fin’amor: The Albigensian Crusade
and its Aftermath Especially as defined and used since
Paris, that deliberately misleading term has been part of a rearguard
action meant to declaw and domesticate the love the troubadours called
fin’amor by deemphasizing its physical and illicit aspects, in order to
“channel, reformulate, and control” desire.72 This imperative can already
be seen in the work of a thirteenth-century cleric who was determined,
at the behest of a demonstrably violent and authoritarian Church, to
rewrite troubadour poetry into a demure and acceptably Christian
form, reflecting the belief that “only God is, and nothing else is”,73 that
all things have their existence through God, and that all love is love of
God. Matfré even claims authority for this rewriting of the troubadours
by describing himself as a truer lover than any who have written, or
been written about, before: [Doncx] pueis la natura d’amor
Sabon li veray amador,
Ne dey hien saber tot quan n’es,
Quar plus fis aymans non veg ges,
Ni fo anc plus fis en amor 70
“es d’amor fons e razitz” (Matfré Ermengaud, ll. 659–60, https://archive.org/stream/
lebreviaridamor01ermeuoft#page/28). y
72
The effects of this can be seen in Reddy’s insistence on reading fin’amor as something
that somehow transcends “mere” desire: “Fin’amors, in its most developed form,
combined […] sublimity, patience, and loyalty […] and the satisfactions it offered
were a “hundredfold” greater than the satisfaction of mere desire” (162). With
“sublimity”, and its superiority to “mere desire”, we enter the territory of Matfré
Ermengaud and Gaston Paris, an over seven-century-long tradition of rewriting the
troubadours. 236 Love and its Critics De me Floris am Blanca flor
Ni Tisbes anc ni Piramus
Ni Serena ni Elidus,
Alion ni Filomena
Ni Paris ni Elena
Ni l bel’ [Ise]uts ni Tristans.74 Therefore, since the nature of love
is known by true lovers,
None should know everything better than me
For there is no lover alive,
Who was ever truer in love
Than me, neither Floris nor Blancheflor,
Neither Thisbe nor Piramus,
Neither Serena nor Elidus,
Not even Filomena
Or Paris, or Helen,
Or beautiful Isolde, or Tristan. 74
Ibid., ll. 27833–43, https://archive.org/stream/lebreviaridamor02ermeuoft#page/431
75
Ibid., ll. 9330–34, https://archive.org/stream/lebreviaridamor01ermeuoft#page/318 The Death of Fin’amor: The Albigensian Crusade
and its Aftermath Just in case there is any doubt about the extent and intensity of the
priestly attitudes toward love and the status of women in the new
world, in which the troubadours have been turned into the mouthpieces
of Catholic orthodoxy, Matfré explains: Cert es qu’a luy la port naelhor;
E qui Dieu per bes temporals
Ama, l’amor non es corals
Ni veraia ni certana,
Ans es amors de putana.75 Certain it is that he whose end is women;
Who for God has but a temporal
Love, whose love is not of the heart,
Neither true nor certain,
Follows after the love of whores. 74
Ibid., ll. 27833–43, https://archive.org/stream/lebreviaridamor02ermeuoft#page/431
75
Ibid., ll. 9330–34, https://archive.org/stream/lebreviaridamor01ermeuoft#page/318 74
Ibid., ll. 27833–43, https://archive.org/stream/lebreviaridamor02ermeuoft#page/431
75
Ibid ll 9330–34 https://archive org/stream/lebreviaridamor01ermeuoft#page/318 74
Ibid., ll. 27833 43, https://archive.org/stream/lebreviaridamor02ermeuoft#page/431
75
Ibid., ll. 9330–34, https://archive.org/stream/lebreviaridamor01ermeuoft#page/318
6. The Death of Fin’amor in Medieval French and English Poetry 237 From Bernart de Ventadorn, even from Guilhem IX, this is a fall from
the heights of joy and sensuality into the depths of pious wickedness. Though he is writing decades after the violence of the Albigensian
Crusade, the shadow of orthodoxy’s war on heresy further darkens
Matfré’s verse beyond his frequent expressions of misogyny, increasing
the disdain with which he regards those who would cling too tightly to
the “sins” of life, love, and independently-chosen faith that the Crusade
had attempted to destroy in the south: Writing in the third quarter of the thirteenth century in Languedoc,
Matfre is surrounded by the continuing battles with heterodoxy and
in particular with Cathar heresy. Matfre himself is a native of Béziers,
which was the first city taken during the Albigensian crusade. […] As
a result, the Breviari reflects the contemporary anxiety of the thirteenth-
century Church concerning widespread heterodoxy, particularly in
southern France.76 Matfré regarded the troubadours as having been all too often the
unwitting servants of the devil himself: “Satan […] in his desire to make
men suffer, inspires them with an idolatrous love for women. 78
The tendency in northern French poetry to portray women as idealized saints is
traceable all the way back to the ninth century, though it comes to full flower in the
thirteenth century. The ninth-century poem Séquence de sainte Eulalie tells the story
of “a young Spanish maiden who was tortured and burned to death in Merida
around the year 304”, while it “exalts death by martyrdom as the ultimate Christian
achievement” (Brigitte Cazelles. The Lady as Saint [University Park: University of
Pennsylvannia Press, 1991], 27). There is something more than faintly pornographic
about the narrative, as Eulalia’s death puts her in the role of “a powerless victim
whose death engenders life” for others (29), even as the poem makes note of her
budding sexuality: 76
Michelle Bolduc. “The Breviari d’Amor: Rhetoric and Preaching in Thirteenth-
Century Languedoc”. Rhetorica: A Journal of the History of Rhetoric, 24: 4 (Autumn
2006), 419.
77
B iff
l
1 1 77
Briffault, 151. II This process, as well as hints of resistance to the process, can be seen in
the thirteenth-century French poem Roman de la Rose. The Roman is the
work of two authors, Guillaume de Lorris and Jean de Meun, whose
writing styles are radically different, but whose attitudes towards love
and its sublimation into worship have more in common than might
initially appear. Their collaboration, although they were separated by
decades and by death, produced the dream vision of a young man,
Lover (Amant), who falls in love with a rosebud, Rose. In the dream,
Lover wanders into a garden where he meets the God of Love (Li dex
d’Amors), who shoots Lover with an arrow, subjecting him to great
pain and suffering. At the same time, Lover sees and falls hopelessly
in love with Rose, though he is kept at a distance from her by various
characters, Resistance (Dangier), Shame (Honte), Jealousy (Jalousie), Fair
Welcoming (Bel Acueil), and Chastity (Chasteé), among others. Lover
does not want to give up on Rose, and as he pursues his desire, many
other characters, including Venus and Reason (Reson) try to help, giving
him different, and often contradictory advice. After much suffering, Buona pulcella fut eulalia. Bel auret corps bellezour anima
Voldrent la ueintre li deo Inimi. Voldrent la faire diaule seruir
[…]
Melz sostendreiet les empedementz
Qu’elle perdesse sa virginitét. Eulalia was a good girl. She had a beautiful body, a more beautiful soul. They would force her will, the enemies of God. They would force her will to serve the devil. […]
But she would rather endure prison and torture
Than lose her virginity. Léopold Eugène Constans. “Séquence de Sainte Eulalie”. In Chrestomathie de l’ancien
f
i (IX XV
ié l ) (P
i
d L i
i
H W lt
1906) 28 29 ll 1 4 16 17) She had a beautiful body, a more beautiful soul. They would force her will, the enemies of God. They would force her will to serve the devil. Léopold Eugène Constans. “Séquence de Sainte Eulalie”. In Chrestomathie de l’ancien
français (IXe-XVe siécles) (Paris and Leipzig: H. Welter, 1906), 28–29, ll. 1–4, 16–17),
https://archive.org/stream/chrestomathiede00cons#page/28 Léopold Eugène Constans. “Séquence de Sainte Eulalie”. In Chrestomathie de l’ancien
français (IXe-XVe siécles) (Paris and Leipzig: H. Welter, 1906), 28–29, ll. The Death of Fin’amor: The Albigensian Crusade
and its Aftermath Instead
of adoring their Creator […] they entertain guilty passions for women,
whom they transform into divinities”.77 Ironically, however, the latter
part of Matfré’s pious accusation can serve as a nearly-perfect description
of exactly the path that love poetry will follow as it moves into its later
French, Italian, and English incarnations, as women are removed from
their bodies, denied their sexuality, idolized, dehumanized, and turned
into goddesses of light and air.78 238 Love and its Critics Léopold Eugène Constans. “Séquence de Sainte Eulalie”. In Chrestomathie de l’ancien
français (IXe-XVe siécles) (Paris and Leipzig: H. Welter, 1906), 28–29, ll. 1–4, 16–17),
https://archive.org/stream/chrestomathiede00cons#page/28 II 1–4, 16–17),
https://archive.org/stream/chrestomathiede00cons#page/28 The poem treats Eulalia’s subsequent burning and beheading as a substitute
for sexuality, as an even more intense version of le petit mort, subjecting the girl’s
“beautiful body” to the sensations of burning flames rather than burning passion,
with le gran mort as the climax, emphasizing what Cazelles refers to as “an ultimate
exposure of the female body” (81), in service of “the traditionally sacrificial
interpretation of female holiness” (83).
6. The Death of Fin’amor in Medieval French and English Poetry 239 persuasion, and confusion, Lover finally possesses Rose. Much more
than telling a simple story of desire, however, the poem creates a space
within which both authors argue for love and condemn the Church and
its violence to tell the story of fin’amor, its forceful sublimation, and the
nostalgic urge to return to the days of “pure love”. Ultimately, the goal
of the poem is for “Lover to be successful in [his] defeat of Christian and
courtly morality”.79 A more conservative view of the Roman and its depictions of love
suggests that “Lover’s desire for the rose is the classic form of cupidity,
a love of an earthly object for its own sake rather than for the sake of
God”.80 Here, Charles Dahlberg expresses the doctrine of the thirteenth-
century Church, which insisted that all love, properly channeled, was
love of God. However, this is precisely the position we have already
seen rejected by Héloïse d’Argenteuil, who references Cicero, not the
Bible or any Christian thinker, in support of her view that love is both
of and for the beloved, without reference to God: “How can friendship
be possible, or who can be a friend to anyone, who does not love him
for himself?”81 The Roman hinges principally on these opposing views
of love: love for the sake of God, or love for the sake of the beloved. This opposition controls the poem’s development, and the way the
poem shows love manifesting in different forms is its way of dealing
with the transition from the fin’amor ethos present in the work of the
troubadours to the Christianized form of love that comes to dominate
post-Albigensian-Crusade poetry. Guillaume de Lorris begins the poem with a cautionary statement
about dreams seeming deceitful at first, solely because of the fact that
they are dreams. 79
Christine McWebb. “Hermeneutics of Irony: Lady Reason and the Romance of the
Rose”. Dalhousie French Studies, 69 (Winter 2004), 3–13, 411.
80
Guillaume de Lorris and Jean de Meun. The Romance of the Rose. Trans. and ed. by
Charles Dahlberg. 3rd ed. (Princeton: Princeton University Press, 1971), 15.
81
“Amicitiae vero locus ubi esse potest aut quis amicus esse cuiquam, quem non
ipsum amet propter ipsum?” Cicero. De Finibus Bonorum et Malorum. In Cicero,
On Ends, ed. by H. Rackham (Loeb Classical Library, Cambridge, MA: Harvard
University Press, 1914), 2.78, 168.
82
“ne tine pas songes a lobes” (Guillaume de Lorris and Jean de Meun. Le Roman de la
Rose. 3 vols, ed. by Felix Lecoy [Paris: Honoré Champion, 1965], Vol. 1, l. 8). 82
“ne tine pas songes a lobes” (Guillaume de Lorris and Jean de Meun. Le Roman de la
Rose. 3 vols, ed. by Felix Lecoy [Paris: Honoré Champion, 1965], Vol. 1, l. 8). 81
“Amicitiae vero locus ubi esse potest aut quis amicus esse cuiquam, quem non
ipsum amet propter ipsum?” Cicero. De Finibus Bonorum et Malorum. In Cicero,
On Ends, ed. by H. Rackham (Loeb Classical Library, Cambridge, MA: Harvard
University Press, 1914), 2.78, 168. 83
“li plusors songent de nuitz / Maintes choses couvertement / Que l’en voit puis
apertement” (ibid., ll. 18–20).
84
“qu’en may estoie, ce sonjoie, / el tens enmoreus, plain de joie” (ibid., ll. 47–48).
85
“Li bois recueverent lor vedure” (ibid., l.53).
86
Heather M. Arden. The Romance of the Rose (Boston: Twayne Publishers, 1987), 22.
87
This censored quality can be seen even in the love-making scene in Chrétien’s La
Chevalier de la Charrette (the romance upon which Gaston Paris constructed his idea 86
Heather M. Arden. The Romance of the Rose (Boston: Twayne Publishers, 1987), 22. 87
This censored quality can be seen even in the love-making scene in Chrétien’s La
Chevalier de la Charrette (the romance upon which Gaston Paris constructed his idea 83
“li plusors songent de nuitz / Maintes choses couvertement / Que l’en voit puis
apertement” (ibid., ll. 18–20).
4
“
’
/ l
l
d
” (ibid ll 4
4 ) of amor courtois), where Chrétien slyly suggests, but will not speak of, the joys of
Lancelot and Guinevere.
88
https://commons.wikimedia.org/wiki/File:Meister_des_Rosenromans_001.jpg II However, Lover, who tells the story, asserts that dreams
should be taken seriously, because Macrobius, a Roman philosopher
from the fifth century, “did not think dreams at all deceitful”.82 Despite 240 Love and its Critics the disbelief of others, Lover maintains that “most men dream at
night / many hidden things / which later may be seen openly”.83 Similar to the famous opening of the Canterbury Tales, the dream
vision of the Roman begins with the description of spring when Lover,
“in joyful May, so I dreamed, / the amorous time, full of joy”,84 wanders
alone and enjoys the delights of nature. In poetry, such images of
springtime have long been associated with rebirth, sex, and a time
when “the trees recover their green”.85 Similarly, there are certain
words that have become “code” for recognizing certain authors and
their themes. We associate the word “pandemonium” with Milton,
“prick” with Shakespeare, and so on. The word that appears frequently
in both sections of the Roman is the word “joy”. The relation to the
work of the troubadours is immediately evident—if one opens a book
of troubadour poetry to nearly any page, the word joy will appear. Sensual like the lyrics of the troubadours, the Roman has the perfume
of fin’amor, disguised within a dream vision. Heather M. Arden, in her
explication of the Roman, notes the connection between the poem and
the troubadours, though with some diffidence: This new view of love had gone through three stages by the time it
reached Guillaume de Lorris. It began at the end of the eleventh century
in southern France and was expressed in the songs of the troubadours. […] Several important themes in courtly songs recur in the first part
of the Rose. The main theme of the songs is the lover’s simultaneous
feelings of great joy and great suffering.86 Arden’s move is one often made in criticism of the troubadours. To
assume that the troubadour poems were “courtly” is to assume that
their songs had the characteristics of the later invention called “courtly
love”. But this is a typical, and, one begins to suspect, deliberate
confusion, for fin’amor is highly sexual and earthly, while “courtly love”
is spiritualized, sublimated, and censored.87
6. The Death of Fin’amor in Medieval French and English Poetry 241 Meister des Rosenromans, Dancing before the genius of love,
in Roman de la Rose (ca. 88
https://commons.wikimedia.org/wiki/File:Meister_des_Rosenromans_001.jpg II 1420–1430).88 Meister des Rosenromans, Dancing before the genius of love,
in Roman de la Rose (ca. 1420–1430).88 Writers often use their villains to assert certain inconvenient truths. Milton does this with his Satan; Shakespeare does this with his Edmund,
and Guillaume de Lorris and Jean de Meun do this with a number of
their characters. What can be confusing about the the Roman, however,
is the fact that criticisms about a wide variety of things come from every
character and even from the narration; the reader is left to decide what is
“trifling” and what is truth. One common thread is hypocrisy, which is
underscored in both sections of the poem, and often revisited directly or
indirectly. Lover walks through the garden and sees a wall covered with
images. He describes each one carefully, and when he gets to the image
of Hypocrisy (Papelardie), he gives a particularly cutting description: C’est cele qui en reclee,
quant nus ne s’en puet peure garde,
de nul man fere n’est coarde;
et fet dehors le marmiteus, 242 Love and its Critics s’a ele vis simple et pietus
et semble seinte creature.89 It is she who, in private,
when no one can see her,
of no evil-doing is afraid;
In public faith she is an apostle,
her face is simple and pious
and she resembles a saintly creature. This is an obvious criticism of the Church and its hypocritical repression
of love and sexuality, clothed with terms like “pietus” and “semble”,90
and in this section of the Roman, it is not difficult to see a number of
pointedly pro-fin’amor allusions being made. The songbirds that Lover
admires during his walk sings of “les dances d’amors”.91 The description
of “a girl / who was both gentle and beautiful”92 whom Lover meets is not
a “courtly” account; her “flesh more tender than a chick’s”93 is depicted
in great detail. Lover tells his readers, “into a small gap / I entered
where Delight [or Diversion] was”,94 where he meets another lady,
named Joy, who has a “voice clear and pure”.95 Not only is the entire
troubadour frame of reference in place here, but Lover even seems to
see the troubadours, as he views the part of the garden where there are
“flutists / and minstrels and jongleurs”.96 The perfect or “pure” garden
of these loving singers, as the story shows, goes through a major change. 89
Lorris and de Meun (1965), Vol. 1, ll. 408 13.
90
One also catches a whiff here of pius Aeneas, who can go toe-to-toe with anyone
where hypocrisy is concerned.
91
Ibid., l. 493.
92
“une pucele, / qui estoit assez gente et bele” (ibid., ll. 523–24).
93
“char plus tender que poucins” (ibid., l. 526).
94
“en un reduit / m’en entrai ou Deduiz estoit” (ibid., ll. 716–17).
95
“voiz clere et saine” (ibid., l. 733).
96
“fleüteors / et menestreus et jugleors” (ibid., ll. 745–46).
97
“[m]out i avoit tableteresses / ilec entor et timberesses” (ibid., ll. 751–52). 89
Lorris and de Meun (1965), Vol. 1, ll. 408–13. 98
Ibid., l. 760.
99
“ert en totes corz bien dine / d’estre empereriz ou roïne” (ibid., ll. 1241–42).
100 Arden, 22–23.
101 Ibid., 25.
102 Lorris and de Meun (1965), Vol. 1, ll. 1882–89. II Not only does the poem allude to the troubadours (in the references to
“minstrels and jongleurs”), but also to the trobairitz, as “many ladies in
the middle danced / and played on tambourines”.97 However, in the middle of the festivities is a character named
Diversion (Deduiz) who appears “with great nobility” (“par grant
6. The Death of Fin’amor in Medieval French and English Poetry 243 noblece”),98 and the “courtly” sublimation and spiritualized redirection
of fin’amor is clearly referenced as the “Diversion” that it really is. The
moment another character, Courtesy (Cortoisie), who “was worthy in
any court / to be an empress or queen”,99 enters the garden, the language
shifts, and the scene changes from pleasant songbirds and joy to the
“highly ornamented” description of Diversion. The earlier instances of
the “flesh” and desire are sublimated to a “dance” and a mere “kiss”
where Diversion courts Joy. After the appearance of the God of Love, love in the Roman becomes
about suffering. The grief comes from different obstacles, but Arden
emphasizes two in particular: “social barriers due to the status of
the beloved which is higher than the lover’s, or barriers set up by the
aloofness or coldness of the lady”.100 As a result, the experience of the
lover is one of suffering until he receives the pity of his lady. In the
Roman, pity becomes the key that will open the prison in which Lover
finds himself, just as the character Pity softens up Resistance who guides
and protects the Rose. Arden notes that the “rules guide the lover in his
relations with others and with the beloved in particular, they condemn
certain vices […] and urge certain virtues”.101 The “courtly lover” is
imprisoned by a set of clearly-defined and rigidly-enforced codes, while
“love” is a matter of regulated and controlled behaviors prescribed for
anyone in the scripted role of “the lover” to follow. In the Roman, the
God of Love commands Lover as just such a prisoner: Vasaus, pris estes, rien n’i a
de destorner ne de desfendre,
ne fai pas dangier de toi render. Quant plus volentiers te rendras,
et plus tost a meri vendras. Il est fox qui moine dangier
vers celui que doit losengier
et qu’il covient a souplier.102 Vasaus, pris estes, rien n’i a
de destorner ne de desfendre,
ne fai pas dangier de toi render. 103 Lorris and de Meun (1965), Vol. 1, ll. 935–69. II Quant plus volentiers te rendras,
et plus tost a meri vendras. Il est fox qui moine dangier
vers celui que doit losengier
et qu’il covient a souplier.102 Vasaus, pris estes, rien n’i a
de destorner ne de desfendre,
ne fai pas dangier de toi render. Quant plus volentiers te rendras,
et plus tost a meri vendras. Il est fox qui moine dangier
vers celui que doit losengier
et qu’il covient a souplier.102 244 Love and its Critics Vassal, you are taken, do not hope
for escape or defense,
now faithfully surrender to my power. The more willingly you surrender
the sooner you will have mercy. He is a fool who resists my power
when he should flatter
and desire to make supplication. In the Roman, the description of the arrows used by the God of Love
illustrate authority, but they also invoke images from the Albigensian
Crusade and its horrific slaughter, as well as the Church’s frequent use
of “Bel Samblant” or “Fair Seeming” to achieve its goals: La meillor et la plus isnele
de ces floiches, et la plus bele,
et cele ou li melor penon
furent ante, Biautez ot non. Une de cles qui plus bleice
rot non, ce m’est avis, Simpleice. Una autre en i ot, apelee
Franchise: cele iert empanee
de valor et de cortoisie. La quarte avoit non Compaignie:
en cele ot mout pesant saiete,
el n’iere pas d’aler loig preste;
mes qui de pres en vosist traire,
il em peust assez mal feire. La cinquieme ot non Bel Samblant:
ce fu toute la mains grevant;
ne por quant el fet mout grant plaie;
[…]. .v. floiches i ot d’autre guise,
qui furent laides a devise;
li fust estoient et li fer
plus noir que deables d’enfer. La premiere avoit non Orguelz;
l’autre, qui ne valoit pas melz,
fu apelee Vilennie:
cele si fu de felonnie cele si fu de felonnie 245
6. The Death of Fin’amor in Medieval French and English Poetry tote tainte et envenimee;
la tierce fu Honte clamee,
et la quarte Desesperance;
Noviaus Pensers fu sanz doutance
Pelee la derreniere.103 The best and most swift
of these arrows, the most beautiful,
and the one with the best feathers
affixed to its tail, was called Beauty. The one that gave the deepest wounds
was, in my view, Simplicity. 104 “nu tenez ore pas a lobe” (ibid., l. 1052).
105 Ibid., ll. 1169–72. II Another one there was, called
Freedom: this one was feathered
with valor and courtesy. The fourth was called Company:
this arrow had a very heavy point,
it was not ready to fly far;
but if fired from close range,
could cause a terrible wound. The fifth was named Fair Seeming:
and though of all, his was the least grievous,
nonetheless, it could leave a serious hurt;
[…]
Five arrows of another sort there were,
as ugly as you can imagine;
whose shafts and points were by far
blacker than all the devils of hell. The first was known as Pride;
the other, which had no more value,
was named Villany:
that one was filled with crimes,
wholly tainted and venomous;
the third called Disgrace,
and the fourth Despair;
New Thought was without doubt
the name of the last. 103 Lorris and de Meun (1965), Vol. 1, ll. 935–69. 246 Love and its Critics What the Albigensian Crusade accomplished was to divorce passion
from the obedient minds of the faithful, and what was brought forth by
the Crusade’s horrific violence, was, as Lover says, a “New Thought”. Despite Innocent III’s hand-wringing about Cathar heresy, the lands
and wealth of Occitania were major motivators of the Crusade, and
Guillaume de Lorris does not disregard that kind of venality in his
verse. In the passages on wealth and its rich purple robe, Lover uses
a revealing phrase that alerts a reader to look carefully for a trick: “do
not take this as a trick of flattery or deceit”.104 The trick, of course, is a
reference to Diversion—the favored technique of a Church that would
have its flock believe that human love is sinful, and that slaughter is
negotium pacis et fidei, “the business of peace and faith”. Even though already well into the time of love’s sublimation into
piety, Guillaume de Lorris, through the character of Lover, includes
vestiges of troubadour sensuality. Referring to Saracens and paganism,
Lover describes a lady named Generosity, and finds it delightful that la cheveçaille ert overte,
s’avoit sa gorge descoverte
si que par outre la chemise
li blancheoit la char alise”105 her hood and collar were open,
and her neck revealed
so that beyond her blouse
her soft flesh showed its whiteness. Before being struck by an arrow and “poisoned” with sublimation, for
a moment Lover describes couples who sang and danced together. Dex! Com menoient bone vie!
Fox est qui n’a de tel envie!
Qui autel vie avoir porroit,
de meillor bien se soufreoit, 106 Ibid., ll. 1293–98.
107 Ibid., ll. 1397–1401.
108 “qui me mostroient / mil choses qui entor estoinet” (ibid., ll. 1603–04). ,
108 “qui me mostroient / mil choses qui entor estoinet” (ibid., ll. 1603–04). 107 Ibid., ll. 1397–1401. II Of
them he speaks: Dex! Com menoient bone vie! Fox est qui n’a de tel envie! Qui autel vie avoir porroit,
de meillor bien se soufreoit, 247
6. The Death of Fin’amor in Medieval French and English Poetry qu’il n’est nus graindres paradis
d’avoir amie a son devis.106 God knows what a wonderful life they led
Only fools do not envy them! He who might live this way,
can do without any greater good,
since there is no grander paradise
than to be with the love of one’s choice. It almost sounds nostalgic, as if the author is speaking here of
something that has been lost, something precious that may already be
unrecoverable. In the same yearning tone, the author alludes to the the
topography of the south of France: Mes mout rembelissoit l’afaire
li leus, qui ere de tel aire
qu’il i avoit de flore planté
tot jorz et iver et esté:
violete i avoit trop bele.107 But the best thing about the state of things
was that the land would always
have flowers and plants
all through the winter and the summer:
the violets were especially beautiful. Even now, summer visitors to Provençe will see lavender fields full of
the violet flowers the author speaks of—similar to those that perhaps
inspired troubadour lyrics. By this point of the Roman, Lover has lost touch with the fin’amor ethos
of the troubadours, and is fully infected by “courtly love”. By the fountain
“which revealed to [Lover] the thousand things that appeared there”,108 a
multitude of things Lover is no longer able to experience, he sits and sighs. Pierced by an arrow shot by the God of Love, Lover gives in to suffering, 248 Love and its Critics later claiming that “Death would not grieve me, / if I might die in the
arms of my lover. / I am much grieved and tormented by Love”.109 Far
from the joi spoken of by the troubadours, suffering consumes the courtly
lover, since for him there is no greater pain (and perversely, no greater
pleasure) than the desire for the unattainable beloved. 109 “la mort ne me greveroit mie, / se ge moroie es braz m’amie. / Mout me grieve
Amors et tormente” (ibid., ll. 2449–51).
110 “sanz grant contenz” (ibid., l. 1745).
111 “la saiete remaint enz” (ibid., l. 1746).
112 “foibles et vains” (ibid., l. 1792).
113 Bernard V. Brady. Christian Love (Washington: Georgetown University Press, 2003), 152. 112 “foibles et vains” (ibid., l. 1792). 113 Bernard V. Brady. Christian Love (Washington: Georgetown University Press, 2003), 152. 111 “la saiete remaint enz” (ibid., l. 1746). II Lover realizes that
he can remove Love’s arrow shaft “without great effort”,110 but no matter
how hard he tries, he cannot remove the point or head of the arrow, for
“the point remains within”.111 Lover is now “weak and defeated”,112 and
in passage after passage, the descriptions of his condition mine the poet’s
vocabulary for words synonymous with “sad”. After the demise of fin’amor, love becomes sacrificial; this is one crucial
aspect of diverted pure love (a diversion we can already see at work
in Ermengaud). In later poetry, lovers are often portrayed as martyrs. In fact, the similarity between the treatments of love and sacrifice
becomes so strong that some later English romances resemble another
genre, saints’ lives (vita). While every genre has its own vocabulary,
“courtly love” romances are replete with such terms as suffering, pain,
pity, mercy, angelic, courtesy, noble, and gentle. The language leaves
no doubt that “courtly love”, unlike fin’amor, is a Christianized and
sublimated form of love. But scholars continue to blur the lines between
the two ideas: In place of the theologian, courtly love has the troubadour. Instead of
God (or in some instances Mary), courtly love posits the lady. In place
of the monastery, monks, and contemplation, courtly love speaks of the
courts, knights, and battle.113 The idea that “[i]n place of the theologian, courtly love has the
troubadour” is risible when one thinks of actual troubadours like
Guilhem IX. Such an interpretation does violence to the poetry, as can
be seen when looking at Arnaut Daniel’s Lo ferm voler qu’el cor m’intra
(The firm will that enters my heart), which has precisely nothing to do
with either Christianity or Platonic thought: 249
6. The Death of Fin’amor in Medieval French and English Poetry Del cors li fos, non de l’arma,
e cossentis m’a celat dinz sa cambra! Que plus mi nafra·l cor que colps de verga
car lo sieus sers lai on il es non intra;
totz temps serai ab lieis cum carns et ongla,
e non creirai chastic d’amic ni d’oncle.114 I would be of her body, not of her soul,
if she would consent to hide me in her chamber! Since it wounds my heart more than blows of the rod
that her servant is not entering there:
with her I will be as flesh and nail
and believe no chastisement of friend or of uncle. 115 Lorris and de Meun (1965), Vol. 1, ll. 2055–58. 114 Daniel, 112, ll. 13–18. 114 Daniel, 112, ll. 13–18. II The change from fin’amor to spiritualized and sublimated “courtly
love” is not particularly subtle, and it involves an inordinate amount
of violence—physical violence in the Crusade, physical, “moral”, and
psychological violence in the subsequent Inquisition, and intellectual
violence in the long tradition of allegorically-inspired literary criticism
dedicated to rewriting the poetry of love in its own passionless image. Such a change is not obscured in the Roman. The God of Love’s
commandments are just one aspect of this alteration, which Lover
points out: Li diex d’Amors lors m’encharja,
tot issi com vos oroiz ja,
mot a mot ses copmmandemenz. Bien les devise cist romanz.115 The God of Love then charged me,
as you shall hear them now,
word for word, with his commandments;
this romance is an excellent device. The God of Love then charged me,
as you shall hear them now,
word for word, with his commandments;
this romance is an excellent device. Before Lover was wounded with the arrow of (courtly) love, he referred
to this poem as a “songes” or dream that was not to be considered a Love and its Critics 250 mere fable. Now, however, this has changed, as his story has become
more serious, taking on a spiritual vocabulary and theme. When Love
speaks to Lover, he says: mere fable. Now, however, this has changed, as his story has become
more serious, taking on a spiritual vocabulary and theme. When Love
speaks to Lover, he says: Si maudi et escommenie
touz ceus qui aiment Vilenie. […]
vilains est fel et sanz pitié
sanz servise et sanz amitié.116 I curse and excommunicate
all those who love wickedness. […]
A wicked man is cruel and without pity;
without service and without friendship. Many things are forbidden to Lover, including obscene language:
“Next, be on your guard that you never use / any filthy words or
ribaldry. / Do not name base things, / and never open your mouth to
disclose them”.117 Baseness does not only refer to language here, but
also to passions, which are animalistic, and thus not highly regarded in
the new, post-crusade and post-fin’amor world (the poems of Guilhem
IX, would doubtless be regarded as “base” in this context—that, as
much as anything else, illustrates the extent and nature of the change
we are dealing with). 118 “Adés aime, mes que tu soies / loing de mes roses totes voies” (ibid., ll. 3183–84). 117 “Aprés gardes que tu ne dies / ces orz moz ne ces ribaudies: / ja por nomer vilainne
chose / ne doit ta bouche ester desclouse” (ibid., ll. 2097–2100). 116 Ibid., ll. 2073e-f, i-j. ,
,
j
117 “Aprés gardes que tu ne dies / ces orz moz ne ces ribaudies: / ja por nomer vilainne
chose / ne doit ta bouche ester desclouse” (ibid., ll. 2097–2100).
118 “Adés aime, mes que tu soies / loing de mes roses totes voies” (ibid., ll. 3183–84). II The God of Love urges Lover, on many occasions,
to serve well and be courteous, for decorum is expected (and in this
case demanded). Resistance, who guards the Rose, gives similar advice:
“You are free to love, as long as you keep / always far away from my
roses”.118 119 Ibid., ll. 3339–60. Look, he says, but do not touch. Look, he says, but do not touch. Look, he says, but do not touch. Look, he says, but do not touch. Passionate love is viewed negatively by many of the characters in
this section of the Roman. Religious language becomes steadily more
prominent toward the end of Guillaume de Lorris’ portion, but in the
6. The Death of Fin’amor in Medieval French and English Poetry 251 midst of the poem’s increasingly powerful air of sublimation, a burst of
erotic passion shines through in this speech by Lover: Si con j’oi la rose apressie,
un poi la trovai engroisie
et vi qu’ele estoit puis creüe
que quant je l’oi premiers veüe. La rose auques s’eslargissoit
par amont, si m’abellissoit
ce qu’el n’iere pas si overte
que la graine fust descovierte;
ençois estoit encor enclose
entre les fueilles de la rose
qui amont droites se levoient
et la place dedenz emploient,
si ne pooit paroir la graine
por la rose qui estoit pleine. Ele fu, Diex la beneïe! asez plus bele espanie
qu’el n’iere avant, et plus vermeille,
dont m’esbahis de la mervoille;
et Amors plus et plus me lie
de tant come ele est embelie,
et tot adés estraint ses laz
tant con je voi plus de solaz.119 When I approached the rose,
I found it had grown
and was larger than it had been
the first time I had seen it. The rosebud was a little bigger
at the top, but I was happy
to see that it was not so open
as to reveal its seed within,
but was still enclosed
by the leaves of the rose
which made it stand upright 119 Ibid., ll. 3339–60. 252 Love and its Critics and fill the place within
so that the seed could not appear
though the rose was full. And thanks be to God’s blessing! it was even more beautiful,
more open, and redder than before. I was amazed at the marvel;
and Love more and more bound me,
to the extent its beauty grew,
the cords tightened to restrain me
and my pleasure grew all the more. Torn between his passions and courtesy, Lover still desires to possess
the Rose. He meets Venus, the mother of the God of Love. 120 “un besier douz et savoré / pris de la rose erraument” (ibid., ll. 3460–61).
121 “Tote l’estoire veil parsuivre, / ja ne m’est parece d’escrivre” (ibid., ll. 3487–88).
122 “qui me donront, ce croi, la mort” (ibid., l. 4014).
123 McWebb, 10. Look, he says, but do not touch. Interestingly,
mother and son differ in their principles, and with the mother’s help,
Lover “a kiss sweet and delicious / took from the rose immediately”.120
If Lover had strictly followed the “courtly” rules, then he would have
been satisfied with the kiss; however, this is not the case, as he desires
the Rose in more ways than permitted. Guillaume de Lorris, speaking
through Lover, informs the reader that “[he] will pursue the whole
history, / and never be lazy in writing it down”.121 This is exactly what
he does: he writes about the love he and his forefathers knew, and what
has become of it. It is a cautious portrait, replete with complexity and
subtlety, and it ends with Lover’s sorrow over his apparent frustration
at not being able to love fully. He is in despair, but more than anything,
he fears: “for my fear and pain, I think, means death”.122 More satirical than Guillaume de Lorris, Jean de Meun continues
the Roman from this point by pursuing the love theme that unifies the
poem. De Meun’s portion of the Roman is “a promotional treatise of
procreative love versus […] chaste, regulated courtly love”,123 and his
satire of courtly love is apparent from the opening lines which show
Lover in great sorrow: “And if I have lost hope, / then I am at the point
6. The Death of Fin’amor in Medieval French and English Poetry 253 of despair. / Despair! Alas!”124 Such exclamation recalls Shakespeare’s
treatment of the disingenuous hysteria in the Capulet household as
they mourn over Juliet’s (seeming) death on the day of her arranged
marriage to the County Paris: CAPULET’S WIFE
Alack the day, she’s dead, she’s dead, she’s dead! CAPULET
Ha! let me see her. Out alas! […]
NURSE
O lamentable day!125 CAPULET’S WIFE
Alack the day, she’s dead, she’s dead, she’s dead! CAPULET
Ha! let me see her. Out alas! […]
NURSE
O lamentable day!125 This nearly comical grief goes on for another page, replete with
exclamations that underscore the hysterics of the characters in the scene. 126 Ibid. 4.5.96. 125 Romeo and Juliet, 4.5.24–25, 30. 127 Lorris and de Meun (1965), Vol. 1, ll. 7433–40. 124 “Et si l’ai je perdue, espoir, / a poi que ne m’en desespoir. / Desespoir! Las!” (Lorris
and de Meun [1965], Vol. 1, ll. 4029–31).
125 R
d J li t 4 5 24 25 30 124 “Et si l’ai je perdue, espoir, / a poi que ne m’en desespoir. / Desespoir! Las!” (Lorris
and de Meun [1965], Vol. 1, ll. 4029–31).
125 Romeo and Juliet, 4.5.24–25, 30.
126 Ibid. 4.5.96.
127 Lo i a d de Meu
(1965) Vol 1 ll 7433 40 Look, he says, but do not touch. Even the musicians who are there to play wedding music recognize the
histrionics of the Capulet family: “Faith, we may put up our pipes and
be gone”.126 Jean de Meun makes fun of such behavior throughout his
portion of the Roman: Et se vos ne poez plorer,
covertement sanz demorer
de vostre salive pregniez,
ou jus d’oignons, et l’esprengniez,
ou d’auz ou d’autres liqueurs meintes,
don voz palperes soient teintes;
s’ainsinc le fetez, si plorrez
toutes les foiz que vos vorrez.127 And if you cannot cry,
fake it without delay,
mix your saliva
with the juice of onions, and squeeze it out 124 “Et si l’ai je perdue, espoir, / a poi que ne m’en desespoir. / Desespoir! Las!” (Lorris
and de Meun [1965], Vol. 1, ll. 4029–31). 124 “Et si l’ai je perdue, espoir, / a poi que ne m’en desespoir. / Desespoir! Las!” (Lorris
and de Meun [1965], Vol. 1, ll. 4029–31). 125 Romeo and Juliet, 4.5.24–25, 30. 127 Lorris and de Meun (1965), Vol. 1, ll. 7433–40. 254 Love and its Critics into your eyes (many other liquors will do),
anoint your eyelids with these stains;
if you make this preparation, you may cry
as often as you like. The difference that is apparent between the authors of the Roman is not
only the treatment of the theme of love, but the writing style as well. When Guillaume de Lorris’ Lover spoke of despair and sorrow, he did
not use overwrought exclamations; Jean de Meun uses them to mock
courtliness and decorum and the artificiality of the love they underscore. Jean de Meun’s satirical verse opposes “the inhibitions of courtly and
ecclesiastical moralism, and [seeks] to exempt vernacular poetry from
euphemistic censorship and rigid rules of literary decorum”.128 Intially, Jean de Meun maintains Guillaume de Lorris’ take on
sublimated, sacrificial love by portraying love as salvation, and Lover
as a saint: Donc n’i a mes fors du soffrir
et mon cors a martire offrir
et d’atendre en bone esperance
tant qu’Amors m’envoit alejance. Atendre merci me couvient.129 Donc n’i a mes fors du soffrir
et mon cors a martire offrir
et d’atendre en bone esperance
tant qu’Amors m’envoit alejance. Atendre merci me couvient.129 Donc n’i a mes fors du soffrir
et mon cors a martire offrir
et d’atendre en bone esperance
tant qu’Amors m’envoit alejance. 128 Noah Guynn. Allegory and Sexual Ethics in the High Middle Ages (New York: Palgrave
Macmillan, 2007), 138.
129 Lorris and de Meun (1965), Vol. 1, ll. 4145–49. 128 Noah Guynn. Allegory and Sexual Ethics in the High Middle Ages (New York: Palgrave
Macmillan, 2007), 138. 129 Lorris and de Meun (1965), Vol. 1, ll. 4145–49. 130 Ibid., ll. 4247–54.
131 Ibid., ll. 4263–64, 4269–70, 4279–80. 130 Ibid., ll. 4247–54. 132 “car ausint bien sunt amoretes / souz bureaus conme souz brunets” (ibid., ll.
4303–04).
133 Ibid., ll. 4615–20.
134 “ne peut autre ester” (ibid., l. 6871). 134 “ne peut autre ester” (ibid., l. 6871). Look, he says, but do not touch. Atendre merci me couvient.129 So there is nothing for me to do but suffer
and offer my heart and body to martyrdom
and wait in good hope
until Love sends me relief. I will wait for mercy to come to me. Here, love is not for another person on Earth, but it is aimed toward
martydom and Heaven. However, Jean de Meun, through his character
Reason, defines for Lover a rather different kind of love. Reason’s
explication of love describes it as an emotion that cannot be easily
explained: 255
6. The Death of Fin’amor in Medieval French and English Poetry Par mon chief, je la t’en veill prendre,
puis que tes queurs i veust entendre. Or te demonstreré sanz fable
chose qui n’est pas demonstrable,
si savras tantost sanz sciance
et connoistras sanz connoissance
ce qui ne peut estre seü
ne demonstré ne conneü.130 By my head, I want to teach you,
if your heart is ready to understand,
I will give to you without falsehood
things that are in no other way demonstrable,
and you will know without science
and understand without understanding
What can in no other way be shown
Demonstrated or understood. By my head, I want to teach you,
if your heart is ready to understand,
I will give to you without falsehood
things that are in no other way demonstrable,
and you will know without science
and understand without understanding
What can in no other way be shown
Demonstrated or understood. Reason then goes on to describe love in the most negative terms she can
muster as an irrational meeting of opposites: 256 Love and its Critics 132 “car ausint bien sunt amoretes / souz bureaus conme souz brunets” (ibid., ll.
4303–04).
133 Ibid ll 4615 20 133 Ibid., ll. 4615–20. 135 “Ceste amor, […] / n’a los ne blame ne merite, / n’en font n’a blamer n’a loer” (ibid.,
ll. 5747–48).
136 Ibid., ll. 5375–80.
137 Ibid., ll. 5425–28. It is the thirst that is always drunk,
A drunkenness that always thirsts. It is the thirst that is always drunk,
A drunkenness that always thirsts. Replete with oxymorons, Reason’s description conveys the essentially
irrational truth—love is undefinable and unrestrainable. This assertion
by Reason is in clear opposition to the commandments of the God
of Love that dictate how Lover should feel, as if it were a rationally
codifiable and controllable activity, a game that can and should be
played by following prescribed rules. Such “courtly love” is a sanctified
and sanctimonious fraud, but as Reason indicates, love does not wish to
follow rules or play games, and realizes that “good lovers are found / in
both coarse clothes and rich fabrics”.132 Lover patiently listens to Reason
until she begins trying to dissuade him from the path he has chosen. Then Lover objects strongly: Dame, bien me voulez traïr. Doi je donques les genz haïr? Donc harré je toutes persones? Puis qu’amors ne sunt mie bones,
ja mes n’ameré d’amors fines,
ainz vivrai toujorz en haïnes?133 Lady, your good to me is treason. Should I hate everyone? Must I despise all people? If Love is not favorable to me,
Then must I not love purely,
But live in hatred of all? As Lover later says, “I cannot be other than I am”.134 What Lover desires
is not the highly-codified and stylized artifice of “courtly love”, but the
reality—messy and irrational as it can be—of fin’amor, a love purged of
religion, whose gaze is brought from the heavens back down to Earth. It is the human, and humane, version of the “natural love” of which
6. The Death of Fin’amor in Medieval French and English Poetry 257 Reason speaks, when she says “This love, […] / deserves neither praise nor
blame nor merit”.135 Reason then takes Lover on a journey through history,
demonstrating how love underwent the process of sublimation, losing its
passion along the way. Speaking of “pure love”, Reason notes that Neïs Tulles, qui mist grant cure
en cerchier secrez d’escripture,
n’i pot tant son engin debatre
qu’onc plus de .iii. pere ou de .iiii.,
de touz les siecles trespassez
puis que cist mond fu conpassez.136 Even Cicero, who took great care
in searching the secrets of ancient texts,
could not find, no matter his ingenuity,
more than three or four pairs of such loves
in all the centuries that have passed
since the world was composed. 138 Ibid., ll. 5532–33, 5537–43, 5549–52, 5554–55. 139 “Or me dites donques ainceis, / non en latin, mes en françois, / de quoi volez vos
que je serve?” (ibid., ll. 5809–11).
140 Lorris and de Meun (1965), Vol. 2, ll. 12052–66. 139 “Or me dites donques ainceis, / non en latin, mes en françois, / de quoi volez vos
que je serve?” (ibid., ll. 5809–11). q
j
(
)
140 Lorris and de Meun (1965), Vol. 2, ll. 12052–66. […]
Such judges condemn thieves,
when they ought to be hanged themselves. […]
Such judges condemn thieves,
when they ought to be hanged themselves. Justice and judges are a none-too-subtle reference to the power and
corruption of the Church, and in this obvious criticism of its workings,
Jean de Meun does not hold back. According to Innocent III, “justice”
was served by the Albigensian Crusade, which “tallied”, “counted”, and
evidently, “erased”, what it willed of the material and cultural wealth
of the south, while the poor paid in blood. The criticism of the Church
continues throughout the poem, though often in less direct form: “Now
tell me, not in Latin, but in French, how you wish me to serve you?”139
Latin, the language of the Church (and of scholarship), is here figured as
the language of dishonesty and manipulation, in contrast to the truthful
and straightforward vernacular. Justice and judges are a none-too-subtle reference to the power and
corruption of the Church, and in this obvious criticism of its workings,
Jean de Meun does not hold back. According to Innocent III, “justice”
was served by the Albigensian Crusade, which “tallied”, “counted”, and
evidently, “erased”, what it willed of the material and cultural wealth
of the south, while the poor paid in blood. The criticism of the Church
continues throughout the poem, though often in less direct form: “Now
tell me, not in Latin, but in French, how you wish me to serve you?”139
Latin, the language of the Church (and of scholarship), is here figured as
the language of dishonesty and manipulation, in contrast to the truthful
and straightforward vernacular. Jean de Meun is most severely critical in his portrayal of the character
False Seeming, equating the character and the Church: Faus Semblant, qui bien se ratorne,
ot, ausinc con por essaier,
vestuz les dras frere Saier. La chiere ot mout simple et piteuse,
ne regardeüre orgueilleuse
n’ot il pas, mes douce et pesible. A son col portoit une bible. Emprés s’en va sanz esquier,
et por ses menbres apuier
ot ausinc con par impotance
de traïson une potance,
et fist en sa manche glacier
un bien trainchant rasoer d’acier
qu’il fist forgier en une forge
que l’en apele Coupe Gorge.140 Faus Semblant, qui bien se ratorne,
ot, ausinc con por essaier,
vestuz les dras frere Saier. La chiere ot mout simple et piteuse,
ne regardeüre orgueilleuse
n’ot il pas, mes douce et pesible. A son col portoit une bible. It is the thirst that is always drunk,
A drunkenness that always thirsts. Then Reason encourages Lover to pursue his desires: et s’ainsinc voloies amer,
l’en t’en devroit quite clamer;
et ceste iés tu tenuz a sivre,
sanz ceste ne doit nus hom vivre.137 And if you want to love in this way,
men should not exclaim against you;
for this is the love you must follow,
and no man should suffer without it. The reference to “men” instead of the “God of Love” or any other
character standing in Lover’s way, brings this dream vision back to
reality. It is men using religion and violence who have created barriers 258 Love and its Critics for love. Reason then condemns Justice, for Justice has all too often been
unjust, especially where love is concerned: for love. Reason then condemns Justice, for Justice has all too often been
unjust, especially where love is concerned: […] Amor
simplement que ne fet Joutice,
[…]
car se ne fust maus et pechiez,
dom li mondes est entechiez,
l’en n’eüst onques roi veü
ne juige en terre conneü. Si s’i preuvent il malement,
qu’il deüssent premierement
els meïsme justifier,
[…]
Mes or vendent les juigemanz
et bestornent les erremanz
et taillent et content et raient,
et les povres genz trestout paient:
[…]
Tels juiges fet le larron pendre,
qui mieuz deüst estre penduz.138 […] Love
alone is better than Justice,
[…]
because without evil or sin,
with which everyone is tainted,
we would have never seen kings
or judges on this Earth. Such men judge with malice
where their first obligation
is to judge and justify themselves,
[…]
But they sell the judgments,
and reverse the mistakes,
and tally, and count, and erase,
and the poor people pay for everything 138 Ibid., ll. 5532–33, 5537–43, 5549–52, 5554–55.
6. The Death of Fin’amor in Medieval French and English Poetry 259 141 Ibid., ll. 12334–37. 142 “un mauves acointement” (Lorris and de Meun [1965], Vol. 1, l. 3507).
143 Ibid., ll. 6898–6906. […]
Such judges condemn thieves,
when they ought to be hanged themselves. Emprés s’en va sanz esquier,
et por ses menbres apuier
ot ausinc con par impotance
de traïson une potance,
et fist en sa manche glacier
un bien trainchant rasoer d’acier
qu’il fist forgier en une forge
que l’en apele Coupe Gorge.140 Faus Semblant, qui bien se ratorne,
ot, ausinc con por essaier,
vestuz les dras frere Saier. La chiere ot mout simple et piteuse,
ne regardeüre orgueilleuse
n’ot il pas, mes douce et pesible. A son col portoit une bible. Emprés s’en va sanz esquier,
et por ses menbres apuier
ot ausinc con par impotance
de traïson une potance,
et fist en sa manche glacier
un bien trainchant rasoer d’acier
qu’il fist forgier en une forge
que l’en apele Coupe Gorge.140 260 Love and its Critics False Seeming, who arrayed himself well,
had, as if to give it a try,
dressed himself as a faithful friar. His features were simple, even piteous;
nor was his gaze proud,
but rather sweet and peaceful. And he had a Bible hanging from his neck. He went without a squire,
but to support his members as he walked,
he carried, against his weakness,
a crutch of treason,
and he slipped his into his sleeve
a razor-sharp blade
which he had made in a forge
and named Cut-Throat. The heavy censorship exercised by the Church and its ongoing
Inquisition is here personified in the figure of the single most
untrustworthy character of the Roman. Innocent III’s “sharp steel razor”
was the military force of northern French nobleman led by Simon de
Montfort. This razor cut through Occitania, slicing through the land of
fin’amor and its poetic expression. The violence inflicted on the citizens of
Béziers is reenacted when the innocent-looking False Seeming commits
a sudden atrocity against Foul Mouth as he par la gorge l’ahert,
a .ii. poinz l’estraint, si l’estrangle,
si li a tolue la jangle:
la langue a son rasoer li oste.141 grabbed [him] by the throat,
and with two hands held and strangled him,
then silenced his foolish talk
by cutting his tongue out with a razor.
6. […]
Such judges condemn thieves,
when they ought to be hanged themselves. The Death of Fin’amor in Medieval French and English Poetry 261 In this scene, Foul Mouth—who accuses Lover of “a corrupt liason”142—
is more than the malicious gossip of Guillaume’s portion of the Roman as
here he personifies those voices and ideas the Church would suppress,
such as the troubadours and their free expression of love, whether of
the mind or the body. Foul Mouth also recalls the religious liberty of
the Cathars, and their free expression of a faith that fell afoul of the
requirements of the Church for obedience in all matters of heart, mind,
body, and conscience. The strangling and the cutting of the tongue are
intentional and meaningful choices of attack. Like the troubadours,
Foul Mouth is silenced in horrific circumstances by a corrupt authority. The troubadours before the Albigensian Crusade did not censor their
lyrics, and through this incident, Lover is taught that such a free way of
speaking will not be tolerated. A “courteous” society does not express
itself in bawdy terms and phrases like those of Guilhem IX, Bernart de
Ventadorn, or Bertran de Born, and it most certainly does not insist on
liberty of conscience, as did the Cathars. The effect of all this can be seen
in Lover in the Roman, who, manipulated by various authority figures
in his dream, has been so addled by the process of attitude-shaping that
he censures Reason for using the terms for genitalia: In this scene, Foul Mouth—who accuses Lover of “a corrupt liason”142—
is more than the malicious gossip of Guillaume’s portion of the Roman as
here he personifies those voices and ideas the Church would suppress,
such as the troubadours and their free expression of love, whether of
the mind or the body. Foul Mouth also recalls the religious liberty of
the Cathars, and their free expression of a faith that fell afoul of the
requirements of the Church for obedience in all matters of heart, mind,
body, and conscience. The strangling and the cutting of the tongue are
intentional and meaningful choices of attack. Like the troubadours,
Foul Mouth is silenced in horrific circumstances by a corrupt authority. The troubadours before the Albigensian Crusade did not censor their
lyrics, and through this incident, Lover is taught that such a free way of
speaking will not be tolerated. […]
Such judges condemn thieves,
when they ought to be hanged themselves. A “courteous” society does not express
itself in bawdy terms and phrases like those of Guilhem IX, Bernart de
Ventadorn, or Bertran de Born, and it most certainly does not insist on
liberty of conscience, as did the Cathars. The effect of all this can be seen
in Lover in the Roman, who, manipulated by various authority figures
in his dream, has been so addled by the process of attitude-shaping that
he censures Reason for using the terms for genitalia: Si ne vos tiegn pas a cortaise
quant ci m’avez coilles nomees,
qui ne sunt pas bien renomees
en bouche a cortaise pucele. Vos, qui tant estes sage et bele,
ne sai con nomer les osastes,
au mains quant le mot ne glosastes
par quelque cortaise parole,
si con preude fame en parole.143 But I do not think of you as courteous
when you have named the testicles to me,
they are not well thought of
in the mouth of a courteous girl. How can you, who are so wise and beautiful, 142 “un mauves acointement” (Lorris and de Meun [1965], Vol. 1, l. 3507). 143 Ibid., ll. 6898–6906. 262 Love and its Critics name such things aloud
without giving the word a euphemistic gloss,
some courteous word instead,
to fit the honest speech of a woman. name such things aloud
without giving the word a euphemistic gloss,
some courteous word instead,
to fit the honest speech of a woman. The apparent criticism here of the phenomenon of glossing and
definition is important, and one we will later see in Chaucer. The
sublimation of passionate love after the Albigensian Crusade was made
possible not only through erasure, but also through the substitution
of original words with a more “proper” language. This has been done
to the songs of the troubadours, both through the imposition of the
“courtly love” concept and, in some cases, through translations and
interpretations that hide more than they reveal. Translations of the
Roman have suffered likewise. The first modern English translation of
the “entire” poem, done by Frederick Startridge Ellis, leaves its ending
untranslated for reasons of “decency”: With a view to justify the plan adopted of giving a summary conclusion
to the story in place of following the author’s text to the end, the original
is here printed of the lines which the translator of the rest has forborne to
put into English. 144 F. S. Ellis, trans. The Romance of the Rose. 3 Vols (London: J. M. Dent, 1900), 3, xii.
145 Ibid. 146 Lorris and de Meun (1965), Vol. 1, ll. 7132–34.
147 Joanna Luft. “The Play of Repetition and Resemblance in The Romance of the Rose”.
The Romanic Review, 102: 1–2 (2011), 50. 146 Lorris and de Meun (1965), Vol. 1, ll. 7132–34. […]
Such judges condemn thieves,
when they ought to be hanged themselves. He believes that those who read them will allow that he
is justified in leaving them in the obscurity of the original.144 But Ellis does not merely refuse to translate the ending. He actually
rewrites it: The remainder of the poem, in which the story of Pygmalion and
the image is introduced, is mixed with a symbolism which certainly
could not be put into English without giving reasonable offence, and
the translator has therefore had the hardihood to bring the story to a
conclusion by an invention of his own. Whether he is to be pardoned
for so doing, apart from any defect in his work, those will be the most
competent judges who take the trouble to read the original, which is
given by way of appendix.145 Apparently, those “who take the trouble to read the original” in the Old
French, are mature enough to be entrusted with the erotic secrets of Jean
de Meun’s conclusion, while those readers who have only English will
have Ellis to protect their delicate moral state for them. The paternalistic 144 F. S. Ellis, trans. The Romance of the Rose. 3 Vols (London: J. M. Dent, 1900), 3, xii. 145 Ibid.
6. The Death of Fin’amor in Medieval French and English Poetry 263 arrogance is overwhelming (and it should be noted that the era that gave
us Ellis’ morally improved version of the Roman, is the same Victorian
era that gave us the concept of “courtly love”). The irony, of course is that the Roman anticipates such priggish
bowdlerizing, by having Reason suggest that euphemistic and
allegorical readings of texts, far from illuminating meaning, serve as a
deliberate disguise behind which meaning is hidden: et qui bien entendroit la letre,
le sen verroit en l’escriture,
qui esclarcist la fable occure.146 he that understands the letter well,
can see the truth in the writing
which clarifies the obscurity of the fable. Jean de Meun censures this kind of hypocrisy frequently, often
approaching it through criticisms of ecclesiastical dishonesty. 147 Joanna Luft. “The Play of Repetition and
The Romanic Review, 102: 1–2 (2011), 50. […]
Such judges condemn thieves,
when they ought to be hanged themselves. The
characters Hypocrisy and False Seeming frequently represent such
views, since the Roman “suggests the continuity of love in order to
highlight the corrupting effect that False Seeming has on it”.147 Nature’s
speech on mirrors brings the theme of hypocrisy into the visual realm of
deception and illusion: Si font bien diverses distances,
sanz mirouers, granz decevances:
[…]
Neïs d’un si tres petit home
que chascuns a nain le renome
font eus parair aus euz veanz
qu’il soit plus granz que .x. geanz,
[…]
et li geant nain i resamblent
par les euz qui si les desvoient
quant si diversement les voient. Si font bien diverses distances,
sanz mirouers, granz decevances:
[…]
Neïs d’un si tres petit home
que chascuns a nain le renome
font eus parair aus euz veanz
qu’il soit plus granz que .x. geanz,
[…]
et li geant nain i resamblent
par les euz qui si les desvoient
quant si diversement les voient. 264 Love and its Critics […]
qui leur ont fet tex demontrances,
si vont puis au peuple et se vantent,
et ne dient pas voir, ainz mantent,
qu’il ont les deables veüz.148
The great differences between distances,
with mirrors, can greatly deceive us:
[…]
One born a very small man
who is called a dwarf by everyone
can be made to watching eyes
seem higher than ten giants,
[…]
and yet, Giants might resemble the dwarves
because the eyes are deceived
by the differences in appearances. […]
Those who have seen such things
will go to the people and boast,
and do not speak truths, but many lies,
saying they have seen the devils. Such mirrors and deceptions abound, not only in the poem, but in critical
readings. A common critical move is to posit an endless multiplicity of
possible readings and meanings; while this may be true in some cases,
it is an argument that can be made to insist there is no particular value
to any one reading: thus, troubadour poetry may just as well be about
rivalry between different classes of Occitanian nobility as about love,
and the Song of Songs may just as well be about the love of a god who
plays no role in the text at all as about the love of human beings. 148 Lorris and de Meun (1965), Vol. 3, ll. 18179–80, 18191–94, 18198–18200, 18204–07. […]
Such judges condemn thieves,
when they ought to be hanged themselves. Thus,
for a critic like Joanna Luft, it is impossible to know just what the Roman
shows us when Lover plucks his Rose: the account of the plucking cannot be fixed as either one type of sexual
activity or another—as either heterosexual, homosexual, or autoerotic. All are possible readings of what the Narrator describes. While the
allegorical meaning of the Lover’s picking the rosebud cannot be reduced 148 Lorris and de Meun (1965), Vol. 3, ll. 18179–80, 18191–94, 18198–18200, 18204–07.
6. The Death of Fin’amor in Medieval French and English Poetry 265 to one reading, this does not mean that no reading is valid. Rather, a
number are. The indeterminacies that permeate the Rose create tensions
that are irresolvable and force the reader to acknowledge that any one
reading of the rosebud, and the allegory itself, is partial. […] In its
evasion of fixed meaning, the rosebud is a synecdoche of the poem itself. Like the rosebud, the poem cannot be pinned down to one reading.149 Those who argue for indeterminacy in readings of poetry which might
otherwise be interpreted as challenges to power, serve the interests of
that power by insisting that no such (defiant) reading can be established:
if a critic is determined enough, “a text may be demonstrated to mean
ever more fully, comprising even that which it is not, and affording no
resistance”.150 To return for a moment to Longxi’s observations about
why there is such a thing as a better or worse reading of a text, it serves
no reader well to be inculcated with the idea of the endless multiplicity
of equally “valid” readings, any more than it serves a reader well to
be hammered with the notion that there is always only one. When
used well, interpretation contributes to a reader’s experience and
understanding of a text a basis for making choices between readings:
“To put it simply, one reading is better than another if it accounts for
more details of the text, bringing the letter into harmony with the spirit,
rather than into opposition to it”.151 It is only through the ability to choose
that we have any hope of resisting the blandishments of False Seeming
and the threatenings of those who would demand our obedience as
readers, and as citizens, in things both small and great. 149 Luft, 60–61.
150 Alan Sinfield. Shakespeare, Authority, Sexuality: Unfinished Business in Cultural
Materialism (London: Routledge, 2006), 92. Emphasis added.
151 Longxi, 215. 150 Alan Sinfield. Shakespeare, Authority, Sexuality: Unfinished Business in Cultural
Materialism (London: Routledge, 2006), 92. Emphasis added.
151 Longxi, 215. 149 Luft, 60–61. 153 Mais en accordant a l’oppinion a laquelle contrediséz, sans faille a mon avis, trop traicte
deshonnestment en aucunes pars—et mesmement ou personnage que il claime Raison, laquelle
nommes les secréz membres plainement par nom. […] Mais vrayement puis que en general
ainsi toutes blasma, de croire par ceste raison suis contrainte que oneques n’ot accoinctance ne
hantise de femme honnourable ne vertueuse, mais par pluseurs femmes dissolues et de male vie
hanter—comme font communement les luxurieux—, cuida ou faingny savoir que toutes telles
feussent, car d’autres n’avoit congnoissance. Et se seullement eust blasmé les deshonnestes et
conseillié elles fuir, bon enseignement et juste seroit. Mais non! ains sans exception toutes les
accuse. Mais se tant oultre les mettes de raison se charga l’aucteur de elles accuser ou jugier
nonveritablement, blasme aucun n’en doit estre imputé a elles, mais a cellui qui si loing de
verité dit la mençonge qui n’est mie сrеablе, comme le contraire appere manifestement. 152 David F. Hult. “The Roman de la Rose, Christine de Pizan, and the querelle des femmes”.
In Carolyn Dinshaw and David Wallace, eds. The Cambridge Companion to Medieval
Women’s Writing (Cambridge: Cambridge University Press, 2003), 186. Christine de Pizan. Le Débat sur le Roman de la Rose, ed. by Eric Hicks (Paris: Honoré
Champion, 1977), 13, 18. y
156 Ibid., 140. This X-is-actually-Y move has been made even by defenders of the poem.
In a strategy that goes all the way back to the original guardians of Homer, Jean
Molinet, the late-fifteenth century author, “accuses Gerson of having misread”
the work, whose “actual meaning […] is sweet, savory, and moral” (Renate
Blumenfeld-Kosinski. “Jean Gerson and the Debate on the Romance of the Rose”.
In Brian Patrick McGuire, eds. A Companion to Jean Gerson [Leiden: Brill, 2006], 355).
“For Molinet” the “text means whatever Molinet wants it to mean” (366). 154 “scripta, verba et picturas provacatrices libidinose lascivie penitus excecrandas esse
et a re publica christiane religionis exulandas” (Christine McWebb, ed. Debating the
Roman de la Rose: A Critical Anthology [London: Routledge, 2007], 352).
155 G
138 […]
Such judges condemn thieves,
when they ought to be hanged themselves. Curiously, however, one thing critics have not been shy about fixing
beyond notions of indeterminacy or multiplicity have been accusations
of misogyny and immorality in Jean de Meun’s portion of the Roman. The poet has been on the receiving end of such criticism ever since the
fourteenth-and fifteenth-century author Christine de Pizan objected to
his treatment of women and equality in the Roman: Christine took issue with essentially three interrelated aspects of the
work: its verbal obscenity and the indecency of the concluding allegorical
description of sexual intercourse; the negative portrayals of women, 266 Love and its Critics which tended to treat them as a group and not as individuals, thereby
making their “vices” natural and universal; the work’s ambiguity, the
absence of a clear authorial voice and intention which would serve as a
moral guide to susceptible or ignorant readers.152 For Pizan, the issue is one of decency and of the attitudes of some of
the characters toward women (while she conflates the author and his
characters): For Pizan, the issue is one of decency and of the attitudes of some of
the characters toward women (while she conflates the author and his
characters): In my opinion, which seems to be accordant with facts not to be
contradicted, he speaks most dishonestly in certain parts, and especially
through the person he calls Reason, who names the secret members
plainly by name. […] Since he blames all women generally, for that
reason, I am constrained to believe that he never had the acquaintance
of any honorable or virtuous women, but having haunted the paths of
dissolute and evil women (as is common with lustful men) he believes
that all women are like this, for he has had no knowledge of others. And if
only he had blamed dishonest women alone, advising others to flee from
them, this would have been a good and just lesson. But no, he accuses all
without exception. But having gone so far past the limits of reason, the
author’s charges and accusations and false judgments of women should
not be imputed to them, but to the one who tells such lies (so incredible
and wildly off the mark), since the opposite is plainly manifest.153 For Pizan’s contemporary, the theologian Jean Gerson, de Meun’s
work was of a kind with the “writings, words, and pictures that are Champion, 1977), 13, 18.
6. 157 Felski, The Limits of Critique, 128. 155 Guynn, 138. 158 David F. Hult argues that […]
Such judges condemn thieves,
when they ought to be hanged themselves. The Death of Fin’amor in Medieval French and English Poetry 267 provocative, libidinous, and lacivious that should be utterly abhorred
and excluded from a Christian republic”.154 A modern critic like Noah Guynn aligns himself with this morally
condemnatory tradition of reading Jean de Meun’s poetry by rejecting
the idea that the “attacks on women in the Rose are neutralized by the
poem’s dialectical structure, its relativist, ironic critique of opinion, or its
avoidance of an overarching, sovereign authorial voice”.155 Despite the
“dialectical structure” of the poem, its “relativist, ironic critique”, and its
deliberate “avoidance” of a “sovereign authorial voice”, for Guynn, the
entire poem is to be accused and convicted of misogyny because of the
attitudes of individual characters (like the jealous husband). This should
probably come as no surprise from a critic who also argues that the poem
appears to do one thing, while it really does another: “the poem appears
to celebrate unfettered, procreative desire and offers a formidable critique
of celibacy”, but it actually “seeks a shelter for male power in the
apparent disruption and demystification, but also the subtle affirmation
and perpetuation, of a variety of patriarchal cultural codes”.156 The poem, according to the critic, apparently disrupts and demystifies,
but actually affirms and perpetuates. David F. Hult. “Jean de Meun’s Continuation of Le Roman de la Rose”. In Denis
Hollier, ed. A New History of French Literaure [Cambridge: Harvard University Press,
1989], 101). The answer to Hult’s question is that there is no justification, other than
the desire of the critics to put the text on trial and find it guilty. As previously
noted, Rita Felski traces this desire back to “the medieval heresy trial”, a practice
that emerged from the Inquisition, which was itself established shortly after the
Albigensian Crusade to deal with heresy in southern France (“Suspicious Minds”.
Poetics Today, 32: 2 [Summer 2011], 219). Where earlier inquisitors tortured bodies,
our modern variety torture texts, https://doi.org/10.1215/03335372-1261208 g
the most outrageous (and most frequently criticized) instance of antifeminist haranguing occurs
in the speech of the “jealous husband” that is used as an illustrative example by the allegorical
character Friend (Ami), who is, in turn, interacting with the Lover inside the allegorical dream
construct. No fewer than three distinct fictional frames separate him from the voice of the
narrator. What justification, then, do we have for deeming Jean de Meun a misogynist?
David F. Hult. “Jean de Meun’s Continuation of Le Roman de la Rose”. In Denis
Hollier, ed. A New History of French Literaure [Cambridge: Harvard University Press,
1989], 101). The answer to Hult’s question is that there is no justification, other than
the desire of the critics to put the text on trial and find it guilty. As previously
noted, Rita Felski traces this desire back to “the medieval heresy trial”, a practice
that emerged from the Inquisition, which was itself established shortly after the
Albigensian Crusade to deal with heresy in southern France (“Suspicious Minds”.
Poetics Today, 32: 2 [Summer 2011], 219). Where earlier inquisitors tortured bodies,
our modern variety torture texts, https://doi.org/10.1215/03335372-1261208 the most outrageous (and most frequently criticized) instance of antifeminist haranguing occurs
in the speech of the “jealous husband” that is used as an illustrative example by the allegorical
character Friend (Ami), who is, in turn, interacting with the Lover inside the allegorical dream
construct. No fewer than three distinct fictional frames separate him from the voice of the
narrator. What justification, then, do we have for deeming Jean de Meun a misogynist? y
p
159 Lorris and de Meun (1965), Vol. 2, ll. 9703–10. […]
Such judges condemn thieves,
when they ought to be hanged themselves. As Rita Felski remarks, “we are
regularly apprised”, by critics inclined to this maneuver, “that what looks
like difference is yet another form of sameness, that what appears to be
subversion is a more discreet form of containment, that any attempt[s]
at inclusion spawn yet more exclusions”.157 By such logic, the speech
Shakespeare will give Shylock (“Hath not a Jew eyes?”) subtly supports, Love and its Critics 268 rather than vigorously contests, anti-Semitism—and for anyone, poet or
otherwise, to write or say “X” is really to mean “not-X”.158
In the case of the Roman, however, the jealous husband’s
“misogynistic” point of view is rejected, even mocked, by the character
Friend in his “equality” speech about husbands and wives: rather than vigorously contests, anti-Semitism—and for anyone, poet or
otherwise, to write or say “X” is really to mean “not-X”.158 rather than vigorously contests, anti-Semitism—and for anyone, poet or
otherwise, to write or say “X” is really to mean “not-X”.158
In the case of the Roman, however, the jealous husband’s
“misogynistic” point of view is rejected, even mocked, by the character
Friend in his “equality” speech about husbands and wives: In the case of the Roman, however, the jealous husband’s
“misogynistic” point of view is rejected, even mocked, by the character
Friend in his “equality” speech about husbands and wives: Ja ses vices ne li reproche
ne ne la bate ne ne toche,
car cil qui veust sa fame batre
por soi mieuz en s’amour enbatre,
quant la veust aprés rapesier,
c’est cil qui por aprivesier
bat son chat et puis le rapele
por le lier en sa cordele.159 He must not reproach her with her vices
Nor must he ever beat or touch her. For he who beats a women
To make her love him better,
When he wants to soothe her later,
Is like one who tries to tame
His cat by beating it, and calls it back
To try to get it to wear a collar.
6. The Death of Fin’amor in Medieval French and English Poetry 269 Love, additionally, should be about equality of regard, not one-sided
worship. In fact, Friend warns quite specifically against the danger of
“courtly love” based on service and obedience, warning that it is little
more than an illusion that will quickly spoil: Love, additionally, should be about equality of regard, not one-sided
worship. 160 Ibid., ll. 9427–43. […]
Such judges condemn thieves,
when they ought to be hanged themselves. In fact, Friend warns quite specifically against the danger of
“courtly love” based on service and obedience, warning that it is little
more than an illusion that will quickly spoil: li conmandast: “Amis, sailliez!”
ou: “Ceste chose me bailliez”,
tantost li baillast sanz faillir,
et saillist s’el mandast saillir. Voire neïs, que qu’el deïst,
saillet il por qu’el le veïst,
car tout avoit mis son desir
en fere li tout son plesir. Mes quant sunt puis entrespousé,
si con ci raconté vous é,
lors est tornee la roële,
si que cil qui seut servir cele
conmande que cele le serve
ausinc con s’ele fust sa serve,
et la tient courte et li conmande
que de ses fez conte li rande,
et sa dame ainceis l’apela!160 If she commanded: “Lover, Jump!”
Or: “Give that thing to me’”,
He would give it to her immediately,
and jump whenever she ordered him. In fact, whatever she might demand,
he would jump for her sight,
because he had invested all his desires
in doing her pleasure in everything. But after they get married,
as I have told you before,
the wheel turns,
so that he who was used to serving her
commands her to serve him,
treating her exactly like his slave, If she commanded: “Lover, Jump!”
Or: “Give that thing to me’”,
He would give it to her immediately,
and jump whenever she ordered him. In fact, whatever she might demand,
he would jump for her sight,
because he had invested all his desires
in doing her pleasure in everything. But after they get married,
as I have told you before,
the wheel turns,
so that he who was used to serving her
commands her to serve him,
t eati
he e a tly like hi
la e treating her exactly like his slave, 160 Ibid., ll. 9427–43. 270 Love and its Critics holding her with a short leash,
demanding that she account for her doings. She whom he used to call his lady! holding her with a short leash,
demanding that she account for her doings. She whom he used to call his lady! Friend preaches against the dangers of “courtly love”, and explains how
it can turn into (and may very well start out as) misogyny. 162 “Mes je ne croi mie, par m’ame, / c’onques puis fust nule tel fame” (ibid., ll. 8795–96).
163 Ibid., ll. 9961–69. 161 “Amor […] en queur franc et delivre” (ibid., ll. 9411–12).
162 “M
j
i
i
’
/ ’
i f
l 163 Ibid., ll. 9961–69. […]
Such judges condemn thieves,
when they ought to be hanged themselves. However,
Friend expresses great admiration for true lovers, for whom “love […]
is honest and free in the heart”.161 Referring to the passionate lovers,
Abelard and Heloise, and speaking particularly of Heloise’s boldness
and passion, Friend says, “I can hardly credit, by my soul, / that there
ever lived another such woman”.162 After that note of homage to Heloise, Friend finishes his speech on a
liberating and optimistic note: uant vos en serez en sesine,
si conme esperance devine,
et vostre joie avrez pleniere,
si la gardez en tel maniere
con l’en doit garder tel florete. Lors si jorrez de l’amorete
a cui nul autre ne comper;
vos ne troveriez son per
espoir en .xiiii. citez.163 uant vos en serez en sesine,
si conme esperance devine,
et vostre joie avrez pleniere,
si la gardez en tel maniere
con l’en doit garder tel florete. Lors si jorrez de l’amorete
a cui nul autre ne comper;
vos ne troveriez son per
espoir en .xiiii. citez.163 When at last you are in possession,
As your hope divines,
And your joys are plentiful,
Guard it in the manner
In which one should guard such a flower. Then will you enjoy a little love
With which no other can compare;
You will not find its like,
Perhaps, in fourteen cities. The passage echoes Shakespeare in one of his most outstanding
manifestations of earthly love, the closing couplet of his sonnet 130:
6. The Death of Fin’amor in Medieval French and English Poetry 271 “And yet, by heaven, I think my love as rare / As any she belied with
false compare”. What Friend refers to as “a little love / With which
no other can compare” is akin to Shakespeare’s declaration that the
quite ordinary “she” of his sonnet is, in fact, anything but ordinary
at all. She is beyond compare, not a symbol of higher love, not a
gateway to God, and not to be loved for the sake of God. She is her
own argument for love, and her equal will not be found “in fourteen
cities” or fourteen thousand. In that speech by Friend, Jean de Meun gives away the game. No
longer is he writing about the love that must be directed toward the
heavens, offered to a jealous God who cannot stand the idea that any
affection in the universe might be directed anywhere other than him. 164 “des geus d’amors” (ibid., l. 12733).
165 Ibid., ll. 12771–74 166 “Mes Nature ne peut mentir, / qui franchise li fet sentir, / […] / Trop est fort chose
que Nature, / el passe neïs nourreture” (ibid., ll. 13987–88, 14007–08).
167 Ibid., ll. 21647–50.
168 Ibid., ll. 21607–16. 166 “Mes Nature ne peut mentir, / qui franchise li fet sentir, / […] / Trop est fort chose
que Nature, / el passe neïs nourreture” (ibid., ll. 13987–88, 14007–08).
167 Ibid ll 21647–50 […]
Such judges condemn thieves,
when they ought to be hanged themselves. This “little love” is the kind that topples such gods, and changes worlds. But in the thirteenth century, it is still something that must be carefully
hidden, kept safe from the prying eyes and savage hands, arms, and
armories of the post-Albigensian-Crusade world. To keep love safe will
require wisdom, and the advice and strategies of those old enough to
remember how different the past had been—here, the somewhat cynical
Old Woman fits the bill nicely. La Vielle, whose later equivalent will
be found in Chaucer’s Wife of Bath, speaks of”the games of Love”,164
passing on what she has learned: Bele iere, et jenne et nice et fole,
N’onc ne fui d’Amors a escole
ou l’en leüst la theorique,
mes je sai tout par la practique.165 I was beautiful, and young, wild and foolish,
And never went to any school of Love
Or read in its theory,
But I know it all through practical experience. She emphasizes the same point throughout her speech in which she
underscores the importance of nature. Loving is a natural act, and
as Old Woman says, “Nature cannot lie, / who makes a man feel 164 “des geus d’amors” (ibid., l. 12733). 165 Ibid., ll. 12771–74 272 Love and its Critics freedom, / […] / A most powerful thing is Nature; / she surpasses even
nurture”.166 Finally, despite all obstacles of obedience, violence, and outright
dishonesty, Lover reaches the Rose, and he is in ecstasy. Once again,
the description of spring returns, and Lover advises young people who
seek its pleasures: quant la douce seson vandra,
seigneur vallet, qu’il convandra
que vos ailliez cueillir les roses,
ou les ouvertes ou les closes.167 quant la douce seson vandra,
seigneur vallet, qu’il convandra
que vos ailliez cueillir les roses,
ou les ouvertes ou les closes.167 When the sweet season comes again,
You will find it necessary
To go plucking roses yourselves,
Whether they be opened or closed. There is no more insistence here on “courtly” codes and mannerisms. In
an openly erotic speech reminiscent of Guilhem IX, Lover describes his
initial misadventures: Par la santele que j’ai dite,
qui tant iert estroite et petite,
par ou le passaige quis ai,
le paliz au bourdon brisai,
sui moi dedanz l’archiere mis,
mes je n’i antrai pas demis. Pesoit moi que plus n’i antraie,
mes outre poair ne poaie. 168 Ibid., ll. 21607–16. 169 Ibid., ll. 21765–88. 170 Lorris and de Meun (1965), Vol. 2, ll. 15975–82. […]
Such judges condemn thieves,
when they ought to be hanged themselves. 274 Love and its Critics I did not destroy any of them,
for I did not wish to wound anything;
and yet, I had to force my way a little,
but did little damage to the bark,
for I did not know how else to enjoy
the beauty which I so much desired. I did not destroy any of them,
for I did not wish to wound anything;
and yet, I had to force my way a little,
but did little damage to the bark,
for I did not know how else to enjoy
the beauty which I so much desired. I did not destroy any of them,
for I did not wish to wound anything;
and yet, I had to force my way a little,
but did little damage to the bark,
for I did not know how else to enjoy
the beauty which I so much desired. Within a dream filled with images of “courtly love” and all the
cultural, clerical, and even military authority behind it, glimpses of
fin’amor shine through, telling readers that the love celebrated by the
troubadours has not completely disappeared, though it is now well-
hidden and to be found only by the few. The Roman carefully, but
compellingly, condemns love’s sublimation and those responsible
for it. In a dream vision created for a courtly and controlled world,
the authors hold out hope for love’s return in and through future
generations (and ongoing generation): Within a dream filled with images of “courtly love” and all the
cultural, clerical, and even military authority behind it, glimpses of
fin’amor shine through, telling readers that the love celebrated by the
troubadours has not completely disappeared, though it is now well-
hidden and to be found only by the few. The Roman carefully, but
compellingly, condemns love’s sublimation and those responsible
for it. […]
Such judges condemn thieves,
when they ought to be hanged themselves. Mes por riens nule ne lessasse
que le bourdon tout n’i passasse.168 Par la santele que j’ai dite,
qui tant iert estroite et petite,
par ou le passaige quis ai,
le paliz au bourdon brisai,
sui moi dedanz l’archiere mis,
mes je n’i antrai pas demis. Pesoit moi que plus n’i antraie,
mes outre poair ne poaie. Mes por riens nule ne lessasse
que le bourdon tout n’i passasse.168 273
6. The Death of Fin’amor in Medieval French and English Poetry But this passage I have told you of,
which was both narrow and small,
through which I sought to pass,
I broke down the barrier with my staff,
placed myself inside the opening,
but I could not enter more than halfway. I was peeved at being unable to enter further,
but I did not have the power to go on. I would slacken for nothing
though, till I had pushed my staff in all the way. And after that brief comic interlude, Lover relates his final success: Par les rains saisi le rosier,
qui plus sunt franc que nul osier;
et quant a .ii. mains m’i poi joindre,
tretout soavet, san moi poindre,
le bouton pris a elloichier,
qu’anviz l’eüsse san hoichier. Toutes an fis par estovoir
les branches croller et mouvoir,
san ja nul des rains depecier,
car n’i vouloie riens blecier;
et si m’an convint il a force
entamer un po de l’escorce,
qu’autrement avoir ne savoie
ce don si grant desir avoie.169 By its branches I seized the rosebush,
fresher and more noble than any willow;
and when I could grasp it with both hands,
I began, gently, and without pricking myself,
to slowly shake the bud,
for I wanted to disturb it as little as possible. Though I could not help but cause
the branches to shake and move, By its branches I seized the rosebush,
fresher and more noble than any willow;
and when I could grasp it with both hands,
I began, gently, and without pricking myself,
to slowly shake the bud,
for I wanted to disturb it as little as possible. Though I could not help but cause
the branches to shake and move, 169 Ibid., ll. 21765–88. […]
Such judges condemn thieves,
when they ought to be hanged themselves. In a dream vision created for a courtly and controlled world,
the authors hold out hope for love’s return in and through future
generations (and ongoing generation): Mes nature, douce et piteuse,
quant el voit que Mort l’envieuse,
antre lui et Corrupcion,
vienent metre a destrucion
quan qu’el treuvent, dedanz sa forge
torjorz martele, torjorz forge,
tourjorz ses pieces renovele
par generacion novele.170 When Nature, sweet and piteous,
through her vision sees envious Death
join together with Corruption,
to measure out destruction
to whatever the find within her forge,
she continues to hammer and forge,
always renewing the pieces of life
through new generation. When Nature, sweet and piteous,
through her vision sees envious Death
join together with Corruption,
to measure out destruction
to whatever the find within her forge,
she continues to hammer and forge,
always renewing the pieces of life
through new generation. 275
6. The Death of Fin’amor in Medieval French and English Poetry 171 All quotations are from “Havelok the Dane”. In Ronald B. Herzman, Graham
Drake, and Eve Salisbury, eds. Four Romances of England (Kalamazoo: Medieval
Institute Publications, 1999), 73–160. 173 See Kimberly K. Bell and Julie Nelson Couch. The Texts and Context of Oxford, Bodleian
Library, MS Laud Misc. 108 (Boston: Brill, 2011), especially the Introduction and Part
One, for an insightful analysis on the manuscript, its compilation and provenance. 171 All quotations are from “Havelok the Dane”. In Ronald B. Herzman, Graham
Drake, and Eve Salisbury, eds. Four Romances of England (Kalamazoo: Medieval
Institute Publications, 1999), 73–160.
172 All quotations are from “King Horn”. In Four Romances of England, 11–57.
173 See Kimberly K. Bell and Julie Nelson Couch. The Texts and Context of Oxford, Bodleian
Library, MS Laud Misc. 108 (Boston: Brill, 2011), especially the Introduction and Part
One, for an insightful analysis on the manuscript, its compilation and provenance. 172 All quotations are from “King Horn”. In Four Romances of England, 11–57. III
Post-Fin’amor English Romance: Love of God and
Country in Havelok the Dane and King Horn In the Roman de la Rose, something of the old spirit of the troubadours
can still be felt. Across the water to the west, however, in early English
romances, we find the sublimated and spiritualized forms of love so
enthusiastically approved by the Akibas, Origens, and Ermengauds of
the world, the authoritative glossators and critics for whom poetry and
passion must be turned to higher purposes. Laud Misc. 108 (a late thirteenth-century manuscript referred to
hereafter as L) contains a collection of saints’ lives—the South English
Legendary (SEL), the two Middle English romances Havelok the Dane171
and King Horn,172 the poems Somer Soneday and Sayings of St. Bernard, the
dream narrative Vision of St. Paul, and the Dispute Between the Body and
the Soul.173 The sanctification of love is a common element found among
the various tales and protagonists of the manuscript, and the possible
differences between saints and lovers do not seem to have preoccupied
the authors of the texts. Although seemingly very distinct genres, the
presence in L of both the saints’ lives and the romances suggests that
there was more in common between the two than might be supposed,
and together they further explain how human love had been transformed
into worship and earthly gazes redirected toward the heavens. A common misconception about England after the Norman Conquest
is that English was the silenced language, at least when it came to legal,
political, religious, and literary use. This is only partially true, even in
the eleventh and twelfth centuries, and the evidence of a thirteenth-
century manuscript such as L, written entirely in English, demonstrates
that the use of English was significant, not only in oral practice, but also
as a written medium. The preparation of such a manuscript in terms of
its copying and ornamentation, and the assembling of texts of different Love and its Critics 276 genres therein, reflect a clear sense of purpose, and suggest that it
was intended for a wide audience and not merely for private use.174
These works seem to have served a pedagogical function, and though
originally such collections were for clerical reading in the context of
the church, by the thirteenth century, manuscripts of saints’ lives were
made available to the laity. This period in England saw great efforts by the Church to dominate,
order, and unify the English people. 174 For a detailed explanation on medieval manuscript culture, text, and audience,
see Chapter 6 of Peter Brown, ed. A Companion to Medieval English Literature and
Culture: c.1350–1500 (Malden: Blackwell, 2007). Such purposes can be seen in a
text’s physical form: “a text acquires new meanings within the physical context of
the codex. The manuscript’s illustrations, rubrics, and other paratextual features, as
well as any other texts that are transmitted along with it, influence the reception of
a text by its readers” (Lori J. Walters. “‘The Foot on Which He Limps’: Jean Gerson
and the Rehabilitation of Jean de Meun in Arsenal 3339”. Digital Philology, 1: 1
[Spring 2012], 112, https://doi.org/10.1353/dph.2012.0006). 177 As Innocent III tried to do in 1213, taking control of England from King John only to
restore it, on John’s submission, as a papal fiefdom—a humilating agreement John
promptly broke in 1214. 175 Carl Horstmann, ed. “St. Austyn”. The Early South English Legendary or Lives
of Saints (London: N. Trubner, 1887), 24, l. 1, https://archive.org/stream/
earlysouthenglis00hors#page/24 176 Ibid., ll. 3–4. III
Post-Fin’amor English Romance: Love of God and
Country in Havelok the Dane and King Horn This was necessary for the Church
to implement its agenda in a more peaceful fashion than it had used in
the chaotic environment of early-thirteenth century Occitania. If, during
the Albigensian Crusade, the motto was “for the love of God, get rid of
heresy”, in England it was “for the love of the nation, get rid of heresy”. Thus, in the lives of these saints, their connection with England is
strongly emphasized; in this way, the agenda of the Church is wrapped
in the flag of nationalism, and human passions are directed away from
love and toward Nation and Deity. St. Augustine, for example, begins
with “SEint Augustin, þat cristendom: brouhte in-to Engelonde”,175
stating this connection outright. A few lines down, the vita introduces
St. Gregory, who “pope was of Rome, / Engelond he louede muche”.176
References to England are many, and the focus on everything English
is quite consistent. It is not surprising that the Roman pope’s love for
England abounds, as does his eagerness to “love” it even more by
Christianizing it and subordinating it to his will.177 Upon his arrival in
England, Augustine is rather saddened, “for he ne couþe: þe speche of
6. The Death of Fin’amor in Medieval French and English Poetry 277 Engelonde”.178 This line points out the fact that Augustine was initially
an outsider, sent by Pope Gregory the Great to undertake the mission
of Christianizing England. Augustine’s non-Englishness is indicated by
the author’s choice of not giving Augustine any direct lines. In order to
create an atmosphere in which the English king and his people appear
to be fully self-determining, the king has more lines than the saint. This
is a subtle technique to make readers feel that the king is one of them,
and as he receives the Christian faith, they receive it through him. Engelonde”.178 This line points out the fact that Augustine was initially
an outsider, sent by Pope Gregory the Great to undertake the mission
of Christianizing England. Augustine’s non-Englishness is indicated by
the author’s choice of not giving Augustine any direct lines. In order to
create an atmosphere in which the English king and his people appear
to be fully self-determining, the king has more lines than the saint. 178 Carl Horstman, ed. “St. Austyn”, l. 15.
179 Bell and Couch, 250.
180 Ibid., 9. 179 Bell and Couch, 250. 178 Carl Horstman, ed. “St. Austyn”, l. 15. 181 See Peter Hunter Blair, Ango-Saxon England (Cambridge: Cambridge University
Press, 1959), Chapter 2, “England and the Vikings”, for more on the Danish rule
and Danish presence in English life.
182 On the reworkings of Havelok and its speculative history, see Scott Kleinman,
“Animal Imagery and Oral Discourse in Havelok’s First Fight”, Viator: Medieval and
Renaissance Studies, 35 (2004), 311–27, https://doi.org/10.1484/J.VIATOR.2.300201
183 Herzman, “Havelok”, ll. 2984–85.
184 Ibid., ll. 1–2. III
Post-Fin’amor English Romance: Love of God and
Country in Havelok the Dane and King Horn This
is a subtle technique to make readers feel that the king is one of them,
and as he receives the Christian faith, they receive it through him. y
g
In L, one might think that the romances would be different from the
saints’ lives, that their distinguishing feature would be love; however,
that is the subject with which the romances are least concerned. As
a whole, L suggests a sacralizing and nationalist agenda. The most
important subjects are England, the sanctifying of a newly-formed
nation, and God: “The writers and audience of L acknowledge their own
innate, inherited, God-given power of identity and defining that identity
in terms of Englishness”.179 Some scholars have even suggested that the
two romances of L can be seen as continuations of the saints’ lives: “the
rubricator who titled many of the lives in red ink titled Havelok as a vita:
[Incipit] Vita Hauelok quondam Rex Anglie. Et Denmarchie”.180 This is not
accidental, for Havelok acts as a saint and a martyr, building monasteries
and going through suffering in order to restore the two nations England
and Denmark. Havelok is also often portrayed as a Christ figure who
has a special destiny, indicated by the “kynmerk” on his right shoulder
and the fiery light that shines from his mouth while he is sleeping; these
traits are common romance devices, emphasizing the special destiny of
the person to whom they are attributed, despite any outward changes
of state the character may have to endure due to villainy, usury, or other
aspects of fortune or malice. This distinctiveness is also seen through the
poet’s constant use of the adjectives “fair” and “bold” when describing
Havelok. These features are also used to describe the saints, who are
martyrs, endowed with celestial identity, who sacrifice themselves for
a specific cause. There is, in fact, some ambiguity about the genre of Havelok. Many
editors have treated it as an English equivalent of the Anglo-Norman 278 Love and its Critics Lai d’Haveloc. That poem is in fact called a “lai” in its opening lines,
and there might be reasons for composing a Breton lay about a Danish
prince, considering the fact that after the death of Edmund Ironside
in 1016, England was ruled by Danish kings for about thirty years,181
though Havelok could also be derived from Geoffrey Gaimar’s Estoire
des Engleis (c. III
Post-Fin’amor English Romance: Love of God and
Country in Havelok the Dane and King Horn 1136–1140).182 Toward the end of the poem, Havelok calls
itself a gest: “Nu have ye heard the gest al thoru / Of Havelok and of
Goldeboru”;183 it is the gesta, the doings, the history of these two that
bring about religious order. But while there is ambiguity here about
genre, there is none about purpose. Although the poem opens in a
leisurely fashion, a firmly didactic tone is consistently maintained
throughout, making it clear that the poem and its lessons will concern
virtues and villains, law and disorder. Havelok is not intended only for a
noble audience, but for all types of people; in the beginning, the narrator
addresses “gode men—/ wives, maydnes, and alle men”,184 solidly
planting the poem in an everyman’s England where religious order
and peace are the predominant factors upon which a nation is founded. Ordinary life is described in great detail, and the poem extols Havelok’s
humble nature. Havelok possesses Christ-like features, and lives in a
similarly simple way, despite his royal origins. Havelok grows up with
the people, and it is the people who nourish and care for him, which
enables Havelok’s eventual defeat of his enemies, and the restoration of
England as a Christian nation. The narrative of King Horn is quite similar, as the heroes in both
romances appear first as vulnerable children who are in danger of
being killed, but grow to be bold and strong men who defeat their
enemies. Horn and Havelok take their thrones as rightful heirs, and
each restores order. At first, King Horn appears to be about the love of
Horn and Rymenhild, but soon it becomes clear that Horn is more saint
than lover: he is “well kene”, “gret and strong, / Fair and evene long”,
6. The Death of Fin’amor in Medieval French and English Poetry 279 and his fairness reflects the goodness of God.185 Horn’s Christian piety
is reflected in his defeat of the Saracens, and in the fact that England
and Christianity always come first for him, whereas his love for the
lady Rymenhild is never more than a secondary concern. The lovers do
finally get married and rule the realm of Suddene together in happiness,
but their marriage takes place only after all other pressing matters are
resolved. Before departing to regain his father’s lands from the pagans,
Horn tells Rymenhild, “beo stille! 185 Herzman, “King Horn”, ll. 95, 97–98.
186 Ibid., ll. 545–46, 548–49.
187 Theresa D. Kemp. Women in the Age of Shakespeare (Santa Barbara: Greenwood Press,
2010), 12.
188 Ibid. 187 Theresa D. Kemp. Women in the Age of Shakespeare (Santa Barbara: Greenwood Press,
2010), 12.
188 Ibid 185 Herzman, “King Horn”, ll. 95, 97–98. 186 Ibid., ll. 545–46, 548–49. 186 Ibid., ll. 545 46, 548 49.
187 Theresa D. Kemp. Women in the Age of Shakespeare (Santa Barbara: Greenwood Press,
2010), 12.
188 Ibid. 189 Geoffrey Chaucer. The Canterbury Tales: Complete, ed. by Larry D. Benson (Boston:
Wadsworth, 2000), I. 3111.
190 https://commons.wikimedia.org/wiki/File:Canterbury-west-Winter-Highsmith.
jpeg?uselang=en-gb
191 William George Dodd. Courtly Love in Chaucer and Gower (Gloucester: Peter Smith,
1959), 9. III
Post-Fin’amor English Romance: Love of God and
Country in Havelok the Dane and King Horn / Ich wulle don al thi wille”, but “I
schal furst ride, / And mi knighthod prove”.186 Rymenhild must wait for
seven years, until Horn restores the stability that Suddene had enjoyed
during his father Athulf’s reign. Any love Horn has for Rymenhild is
completely sublimated here into the “higher” concerns of Christianity
and the English nation, while Rymenhild must wait patiently with
religion as her solace, an increasingly common situation in the period:
“[f]rom the Anglo-Saxon period through the Middle Ages, […] Christian
religion was increasingly central to the routines of women’s daily lives
and to the ways in which their culture viewed women as a group”.187 Christianity has contributed to a very long tradition of seeing women
as inferior beings, and though a prominent thinker like Augustine
argues “that women are created human and in the image of God, […]
ultimately sexual difference stands at the foundation of his theology”.188
It is that sexual difference which is thrown into sharp focus in post
fin’amor poetry and prose, as no longer do women have the voice given
them by the trobairitz poets, nor even the sympathetic portrayals of them
as desiring and desirable human beings created by the troubadours. The
status of women may well mirror the status of love (and poetry) itself,
and in the time of Havelok and King Horn women are supporting players
at best, existing at a time in which the love written of in poetry is not
directed from person to person, but to the Nation, the Church, and God. 280 Love and its Critics IV By the late fourteenth century in England, things are beginning to
change. Geoffrey Chaucer was by that time certainly aware of the
approach to love that would later be described by scholars as “courtly”. His works often parody this attitude, and in the Canterbury Tales,
Chaucer provides rich soil for just such a parody in the “Knight’s Tale” a
long and highly stylized romance that is reworked by the bawdy Miller. The tension between mind and matter, soul and body, is at the root of
much of the poetry written after the decline of fin’amor, until the ideas
of the troubadour ethos slowly begin to reappear in Chaucer’s works. Chaucer satirizes the sublimated, desexualized, and “courtly” love of
the “Knight’s Tale” through the raucous and unapologetic celebration
of sexuality and the senses in the “Miller’s Tale”. The Knight recounts a
medieval romance with “courtly” lovers, daring battles, and a beautiful
and worship-inspiring lady named Emily. After hearing the tale,
Chaucer’s pilgrims all agree that they regard it as a “noble storie”.189 Canterbury Tales mural by Ezra Winter (1939). North Reading Room, west wall,
Library of Congress John Adams Building, Washington.190 Canterbury Tales mural by Ezra Winter (1939). North Reading Room, west wall,
Library of Congress John Adams Building, Washington.190 The beloved in such “noble storie[s]” is a perfect, or near-perfect being,
and “in character, she is distinguished for her courtesy, kindness,
refinement, and good sense”.191 Arcite cannot go anywhere in the world
that would require him to leave behind the sight of Emily: “Oonly the
sighte of hire whom that I serve, / Though that I nevere hir grace may The beloved in such “noble storie[s]” is a perfect, or near-perfect being,
and “in character, she is distinguished for her courtesy, kindness,
refinement, and good sense”.191 Arcite cannot go anywhere in the world
that would require him to leave behind the sight of Emily: “Oonly the
sighte of hire whom that I serve, / Though that I nevere hir grace may
6. The Death of Fin’amor in Medieval French and English Poetry 281 deserve, / Wolde han suffised right ynough for me”.192 Similarly, Palamon
is a hapless and helpless worshiper of Emily. Both are madly in love with
her, or with the idea of her. 192 Chaucer, I. 1231–33.
193 Ibid., I. 3077–79.
194 Susan Crane. Gender and Romance in Chaucer’s Canterbury Tales (Princeton: Princeton
University Press, 1994), 51.
195 Chaucer, I. 2396–97.
196 Chaucer, I. 1055.
197 Ibid., I. 1157.
198 Margaret Hallissy. A Companion to Chaucer’s Canterbury Tales (Westport: Greenwood
Press, 1995), 59. IV As Theseus describes Palamon to Emily, he
is her servant: “That gentil Palamon, youre owene knyght, / That serveth
yow with wille, herte, and myght / And ever hath doon syn ye first
hym knewe”.193 This dynamic is common in “courtly” tales: “[a]mong
the most familiar devices taken into romance is the address to an absent
and uncaring object of love”.194 In the “Knight’s Tale”, Chaucer parodies
the extreme sublimation of love in romances of his time, and sets up
both Palamon and Arcite for further suffering and heartache, ensuring
that readers will not miss the ridiculousness of the many situations in
which the two “courtly” lovers find themselves. Arcite, when praying
to Mars, complains that Emily does not seem to care whether he lives
or dies: “For she that dooth me al this wo endure, / Ne reccheth nevere
wher I synke or fleete”.195 Emily’s portrayal, as the female object of courtly adoration, is
replete with religious symbolism; she appears in the garden on a May
morning, singing “as an aungel hevenysshly”,196 embodying purity,
beauty, and inaccessibility. Here, springtime is not about eroticism
and the awakening of sensual desires, but about the transcendence of
such things with heaven as the ultimate goal. It is unclear to Palamon
and Arcite “wheither she be a woman or goddesse!”197 For the courtly
lover, “[the beloved] can never be reduced to a mere object of physical
gratification”,198 nor, it seems, even be thought of in terms of anything
like human love and desire. Courtly love, as depicted in the “Knight’s Tale”, is a Neoplatonized
and Christianized caricature of fin’amor. Unlike the lovers in troubadour
poetry, the lovers in the “Knight’s Tale” relegate the object (not subject)
of their love to a position of near-irrelevance. Palamon and Arcite are so
eager to find out whether Emily is “my lady” or “thy lady” that they are Love and its Critics 282 willing to die without any response from her. 199 Hallissy, 75.
200 Reddy suggests that Guilhem IX was “the author of the first fabliau” (101–02).
201 Joseph R. Strayer. Western Europe in the Middle Ages: A Short History (New York:
Appleton-Century-Crofts, 1955), 183.
202 Chaucer, I. 3167–69.
203 Ibid., I. 3179–80.
204 Derek Pearsall. The Canterbury Tales (New York: Routledge, 2002), 178. 201 Joseph R. Strayer. Western Europe in the Middle Ages: A Short History (New York:
Appleton-Century-Crofts, 1955), 183.
202 Chaucer, I. 3167–69. 204 Derek Pearsall. The Canterbury Tales (New York: Routledge, 2002), 178. 203 Ibid., I. 3179–80. IV In contrast, the “Miller’s
Tale” tells a story in which a response is definitely expected from the
lady, and physical fulfillment is not denied, though the common critical
reaction is tellingly reductive: “Love [in the “Miller’s Tale”] is a matter
not of the heart, mind, and spirit as it is in the romance, but of the body
only”.199 By pairing the Knight’s and Miller’s tales, Chaucer strongly
suggests that love must be a matter of heart, mind, spirit, and body all
at once—a combination of elements that is much closer to the spirit of
fin’amor than to that of “courtly love”. Generally categorized as an example of the fabliaux, a genre whose
inventor may have been Guilhem IX, the first troubadour,200 the “Miller’s
Tale” satirizes the courtly attitudes of the “Knight’s Tale”. In contrast
with romances, such tales: exaggerate the real as much as allegory exaggerates the ideal. Their
heroes are clever tricksters; their victims are the naïve and the stupid. All
women in the fabliaux are lustful; all priests are gluttons or lechers; most
representatives of public authority are corrupt. The peasant who makes
a fool of his priest, the woman who makes a fool of her husband, and the
priest who makes a fool of his bishop are glorified.201 The reader is comically warned about the Miller and his less-than-courtly
sensibilities in advance of the tale: “What sholde I moore seyn, but this
Millere / He nolde his wordes for no man forbere, / But tolde his cherles
tale in his manere”.202 The reader is also encouraged to “turne over the
leef and chese another tale” if he prefers “storial thyng that toucheth
gentillesse, / And eek moralitee and hoolynesse”,203 a rhetorical move
designed to increase the transgressive appeal of the tale that follows. What a reader who does not “chese another tale” will find, however,
is that the “courtly idealism of love, initially a theme picked up from
the Knight’s Tale, is present throughout the Miller’s Tale as an implied
and ludicrously inappropriate standard of conduct”,204 which enables
the laugh-out-loud humor of the story. What had been initially elevated 204 Derek Pearsall. The Canterbury Tales (New York: Routledge, 2002), 178.
6. 205 Strayer, 183.
206 Chaucer, I. 3441.
207 Bernard F. Huppé. A Reading of the Canterbury Tales (Albany: SUNY Press, 1964), 76.
208 Chaucer, I. 3287.
209 Pearsall, 176.
210 Chaucer, I. 3233–70. 210 Chaucer, I. 3233–70. IV The Death of Fin’amor in Medieval French and English Poetry 283 almost to the heavens in the language and content of the “Knight’s Tale”
topples to the ground in the “Miller’s Tale”, and is brought back to more
recognizably earthly matters. Elements of courtly love are taken out of
the context of romance and put into a frame where the celebration of
“divine” ideals and figures seem like the ridiculous obsessions of the
“naïve and the stupid”.205 A look at the main characters of the “Miller’s
Tale” offers ample evidence for this conclusion. After the Knight’s long story, the Miller will tell a “legend and a
lyf”,206 not of a saint-like figure or a Platonic lover, but “of a down-to-
earth, here-and-now lover, who wins a real flesh-and-blood woman”.207
The female character of the “Miller’s Tale”, Alison, is not an Emily,
and the younger men showing interest in her do not act like Arcite or
Palamon. The Miller tells of two lovers, just like the Knight does, but
with a difference: the Miller portrays one of his tale’s lovers, Nicholas,
as a realist who knows what he wants and goes after it without illusions. The other lover, Absolon, is afflicted with self-delusion and pretensions
to grand manners and high style, and is both tricked, and foiled in his
planned revenge for the trick. In all this, we can see a small victory for
fin’amor over “courtly love”. In dramatic contrast to the goddess-like, yet absent Emily, Alison
has a mind of her own: she is an unmistakably human creature. In
her genteel protestations and appeals to Nicholas’s “curteisye”,208 she
embodies a deliberate parody of a courtly lady. While the introduction of
Alison is “modeled after the descriptio feminae which would traditionally
introduce the heroine of a romance”,209 one should not miss the
description of Alison in terms of animal imagery at the beginning of the
tale,210 comparisons which illustrate the physical passions highlighted
by the fabliau. Alison knows the rules of that world, and lives her life
in accordance with nature, without pretense and affectation. She does
what she wants, chooses and refuses whom she pleases. 211 Ibid., I. 3308, I.3307.
212 II Sam. 14: 25.
213 Ibid., 16: 22. 212 II Sam. 14: 25. 211 Ibid., I. 3308, I.3307. IV Alison is most definitely not the courtly lady who is described in
religious terms, and although this “goode wyf” attends church to “Cristes Love and its Critics 284 owene werkes for to wirche”, church is not the setting of an episode of
courtly love here as it might have been in a traditional romance.211 She
is not the heroine of such a romance, nor is the absurd and preening
Absolon, whom she meets at the church, its hero. Religious allusions
in this story are placed in an entirely different context from that of the
“Knight’s Tale”; they are not celebrations of courtly love, but devices
indicating the distance of the fabliau characters from the world of the
“sacred” and “spiritual”, where physical desires are objectionable, since
these characters live in an unabashedly fleshly world in which such
body-denying ideals are viewed as comical. The humour of the treatment of courtly ideals in the “Miller’s Tale”
increases when one remembers the extreme length and artificiality of
the wooing of Emily by Palamon and Arcite; thousands of lines pass
during which no thoughts of sexual desire ever cross either of the two
knights’ minds. In the “Miller’s Tale”, sexual thoughts are present
right from the beginning, starting with the way Chaucer plays with the
knowledge and established expectations of his audience in the case of
Absolon. His biblical namesake, Absolom the rebellious son of King
David, is described as incomparably fair: 212ּוכְ אַ בְ שָ ׁל֗ ֹום לֹא־ הָיָ֧ה אִ יׁש־ יָפֶ֛ה בְ ּכָל־ יִשְ ׂרָ אֵ֖ל לְהַלֵּ ֣ ל מְ אֹ֑ ד מִ כַּ ֤ ף רַ גְלֹו֙ וְעַ֣ד קָדְ קֳד֔ ֹו לֹא־ הָ֥יָה ב֖ ֹו מֽ ּום׃ 212ּוכְ אַ בְ שָ ׁל֗ ֹום לֹא־ הָיָ֧ה אִ יׁש־ יָפֶ֛ה בְ ּכָל־ יִשְ ׂרָ אֵ֖ל לְהַלֵּ ֣ ל מְ אֹ֑ ד מִ כַּ ֤ ף רַ גְלֹו֙ וְעַ֣ד קָדְ קֳד֔ ֹו לֹא־ הָ֥יָה ב֖ ֹו מֽ ּום׃ And as for Absolom, there was no man for beauty in all Israel so much to
be praised; from the sole of his foot to the crown of his head, there was
no defect in him. IV Absolom is also described as someone more than willing to use his
nearly-uncontrollable lust as a weapon: Absolom is also described as someone more than willing to use his
nearly-uncontrollable lust as a weapon: 213וַיַּּט֧ ּו לְאַ בְ שָ ׁל֛ ֹום הָאֹ֖ הֶל עַל־ הַגָּ ֑ ג וַיָּבֹ ֤ א אַ בְ שָ ׁלֹום֙ אֶ ל־ פִ ּ ֽ לַגְשֵ ׁ ֣ י אָ בִ֔ יו לְעֵינֵ֖י כָּל־ יִשְ ׂרָ אֵֽ ל׃ 213וַיַּּט֧ ּו לְאַ בְ שָ ׁל֛ ֹום הָאֹ֖ הֶל עַל־ הַגָּ ֑ ג וַיָּבֹ ֤ א אַ בְ שָ ׁלֹום֙ אֶ ל־ פִ ּ ֽ לַגְשֵ ׁ ֣ י אָ בִ֔ יו לְעֵינֵ֖י כָּל־ יִשְ ׂרָ אֵֽ ל׃ They spread for Absolom a tent on the roof, and Absolom went in to his
father’s concubines before the eyes of all Israel. Chaucer’s Absolon is not nearly so ambitious as the son of Israel’s king,
though he is quite nearly as lustful and deceptive. Although Absolon
“assume[s] all the poses of the courtly lover (more music, sleepless
6. The Death of Fin’amor in Medieval French and English Poetry 285 nights, gifts)”,214 and uses “high style language […] right out of the
courtly love tradition”,215 he is not quite what anyone would expect
a courtly lover to be. It is through Absolon that Chaucer satirizes the
pain and suffering involved in the concept of courtly love by displaying
the young man’s wooing of Alison in all its comic absurdity. Absolon’s
“unfortunate kiss [of Alison’s unwashed rear] is preceded by a love-
song”, which is “charged with the echoes of the Song of Songs”.216
Absolon’s singing and ass-kissing bring the parody of courtly love to an
absurdly comic climax. The “song” element can also be seen with Nicholas, whose initial
wooing of Alison includes an angel’s song that salutes the Virgin: “And
Angelus ad virginem he song”.217 Nonetheless, what might seem like
courtliness is deflated when “prively he caughte hire by the queynte”.218
Once more, a religious and sacred image is taken out of its context,
and put in the realm of its non-spiritual, fleshly opposite. Although
described “lyk a mayden meke for to see”,219 Nicholas is anything but
maiden-like or meek, as far as his behavior toward Alison is concerned. He is attracted to her, and with no signs of hesitation, he makes his
attraction known. 214 Hallissy, 78.
215 Ibid., 81.
216 Winthrop Wetherbee. Chaucer: The Canterbury Tales. 2nd ed. (Cambridge: Cambridge
University Press, 1989), 58.
217 Chaucer, I. 3215.
218 Ibid., I. 3276. For those unfamiliar with the meaning of “queynte” (kānt), simply
change the first vowel sound. The meaning will become clear.
219 Ibid., I. 3202. 218 Ibid., I. 3276. For those unfamiliar with the meaning of “queynte” (kānt), simply
change the first vowel sound. The meaning will become clear.
219 Ibid., I. 3202. 220 Helen M. Jewell. Women in Medieval England (Manchester: Manchester University
Press, 1996), 16. IV The “Miller’s Tale” certainly stands as a work on its own; however,
its context in the Canterbury Tales gives it greater satirical power than it
might otherwise have, by serving as a direct contrast with the “Knight’s
Tale”. The description of Alison establishes her as the sensuous contrast
to the remote and saint-like Emily. The Neoplatonized and Christianized
love of the “Knight’s Tale” is parodied in the “Miller’s Tale”, where the
“courtly” ideals are treated as a joke and the pointless, and seemingly-
endless suffering of Palamon and Arcite is implicitly mocked. Romance
entertains the illusion that humans are more angel than animal, all mind
and heart and soul, while the fabliau declares that humans are animals,
bodies whose passions and sensual desires are not to be restrained. 286 Love and its Critics Chaucer’s attitude toward the “courtly” idealizing of love, on the
whole, is a critical one, and the pairing of the Knight’s and Miller’s tales
strongly suggests an ideal that is to be found in the real, a combination
of mind, heart, soul, and body. In this respect, Chaucer’s treatment of
love is closer to the spirit of fin’amor than to that of “courtly love”. V
Post-Fin’amor English Poetry: Mocking “Auctoritee”
in Chaucer—the Wife of Bath 221 https://commons.wikimedia.org/wiki/File:Wife-of-Bath-ms.jpg
222 James Edward Geoffrey De Montmorency. The Progress of Education in England: A
Sketch of the Development of English Educational Organization from Early Times to the
Year 1904 (London: Knight & Co., 1904), 27.
223 Ibid., 28. V The sublimation and spiritualization of love that took place between
the times of the troubadours and Chaucer was not only accomplished
through the Inquisition and the Albigensian Crusade’s wholesale
slaughter. It was also effected in a subtler fashion, through the glossing
and alteration of what had once been an openly sensual literature (a
practice that continues in too much modern criticism). Many authors
no longer wrote in the fashion of Guilhem IX or Bernart de Ventadorn,
but told tales of miracles, citing Christian authority figures in order to
add weight to their lines. Chaucer’s pilgrims, for example, often quote
Christian figures. The Middle English word “auctoritee” is often used
in the Canterbury Tales, and is a key term in the “Wife of Bath’s Prologue
and Tale”. The word comes from the Latin auctōritās, meaning authority,
reputation, credibility. To medieval readers, this word signified the
important thoughts of the past as recorded and glossed in texts. However,
the education required to become familiar with the ideas of previous
auctōrēs was the privilege of a small minority. The majority of texts were
in Latin, and illiteracy rates in medieval England were extremely high,
running to about 90 per cent of males and 99 per cent of females.220 Even
among that ten per cent of literate men, however, only the clergy were
educated in the languages of scholarship; thus, the books of the great
authority figures were mainly read by clerics. However, these clerics
did more than just read and study; they aimed to interpret and gloss,
which in many cases amounts to a revision and rewriting of the texts in
question (as we have seen with the Song of Songs).
6. 221 https://commons.wikimedia.org/wiki/File:Wife-of-Bath-ms.jpg 224 The word “gloss” today has a few different meanings: “luster”, “sheen”, or “to give
false a false appearance of acceptableness”. The Greek word for gloss, γλώσσα,
and the Latin word, glossa both mean “tongue, speech” (Francis E. Gigot. “Glosses,
Scriptural—I. Etymology and Principal Meanings”. In The Catholic Encyclopedia:
An International Work of Reference on the Constitution, Doctrine, Discipline, and
History of the Catholic Church: Father to Gregory, ed. by Charles G. Herbermann,
et. al. [New York: Robert Appleton Company, 1907], Vol. 6, 588, https://archive.
org/stream/07470918.6.emory.edu/07470918_6#page/n665).
More
broadly,
the
term means an “interpretation or explanation of isolated words. […] A glossary
is therefore a collection of words about which observations and notes have been
gathered, and a glossarist is one who thus explains and illustrates given texts”
(Gigot, 588). In its early usage, the term was assigned to “words of Greek texts that
required some exposition” (Gigot, 588). It was only later that “gloss” came to refer
to the interpretation itself. V The Death of Fin’amor in Medieval French and English Poetry 287 287 Opening page of the “Prologue of the Wife of Bath’s Tale”, from the Ellesmere
manuscript of Geoffrey Chaucer’s Canterbury Tales (early fifteenth century).221 Opening page of the “Prologue of the Wife of Bath’s Tale”, from the Ellesmere
manuscript of Geoffrey Chaucer’s Canterbury Tales (early fifteenth century).221 To medieval readers, this pool of writing, which the Wife of Bath calls
“auctoritee”, was not to be questioned lightly, though the challenging
spirit of Wycliffe and the so-called Lollards can already be seen in
Richard II’s rejection of the petition of the Commons in 1391 which
sought to restrict education to the nobility, “that no neif or villein shall
henceforth put his children to school in order to advance them”.222 This
was part of a movement that by 1406 resulted in the Statute of Education
in which “Parliament declared that ‘every man or woman, of what state
or condition that he be, shall be free to set their son or daughter to
take learning at any school that pleaseth them within the realm’ […]
a triumph for Wycklifism”.223 Though formal education had formerly
been considered strictly a matter of men teaching authoritative men’s
thoughts and glosses to other men, things were slowly changing. To medieval readers, this pool of writing, which the Wife of Bath calls
“auctoritee”, was not to be questioned lightly, though the challenging
spirit of Wycliffe and the so-called Lollards can already be seen in
Richard II’s rejection of the petition of the Commons in 1391 which
sought to restrict education to the nobility, “that no neif or villein shall
henceforth put his children to school in order to advance them”.222 This
was part of a movement that by 1406 resulted in the Statute of Education
in which “Parliament declared that ‘every man or woman, of what state
or condition that he be, shall be free to set their son or daughter to
take learning at any school that pleaseth them within the realm’ […]
a triumph for Wycklifism”.223 Though formal education had formerly
been considered strictly a matter of men teaching authoritative men’s
thoughts and glosses to other men, things were slowly changing. V 288 Love and its Critics Chaucer illustrates some of this change by having the Wife seize
“auctoritee”, and as a result, appropriate the interpretive authority of
the masculine, clerical glossators (the academics and critics of Chaucer’s
day).224 The post-Albigensian period gave rise to an energetic proliferation
of such glosses, in which the marginal commentary often undermined
the primary text.225 What is notable about glossing in this period is that
Scripture is not the only work that is being glossed; secular writing is
also undergoing heavy glossing. “To give a false appearance”, one of
today’s definitions of the term gloss, conveys the self-interestedness that
is potentially expressed in the act of glossing, which can be understood
as a form of appropriation. The glosser speaks the text, asserts authority
over it, provides an explanation, and consequently, limits (and even
seeks to prevent) the possibility of other meanings.226 As the friar
from the “Summoner’s Tale” testifies, “Glosynge is a glorious thyng,
certeyn, / For lettre sleeth, so as we clerkes seyn”,227 describing a process
in which he “twists the text of Scripture to serve his own material needs 225 Early Greek grammarians and Christian writers, who commented on Scripture,
adopted the word “gloss” to indicate ambiguous verbal usage, whether foreign
or obsolete, as opposed to an interpretation of difficult doctrinal or theological
passages. Such glosses were mainly written on the margins of manuscripts. However, as glossing became more popular, the word “gloss” referred to more
elaborate explication of Scripture, ranging from interpretative sentences to large
commentaries on entire books that would either be marginal or interlinear. The
exemplum of glossing, Glossa Ordinaria, or The Gloss, was a compilation of all
glosses on the Bible, which itself consisted of layers of glosses (Gigot, 587). 226 On this point, see C. S. Lewis, who in A Preface to Paradise Lost (Oxford: Oxford
University Press, 1942), openly states that his aim is to “prevent the reader from
ever raising certain questions” (69). 227 Chaucer, III. 1793–94.
6. The Death of Fin’amor in Medieval French and English Poetry 289 and those of his brother friars”.228 “Glosynge” subordinates the text to
the desires of the critic: “it is all too easy for this act of interpretation to
become a matter of reading something into the text […]. 228 Alastair Minnis. Fallible Authors: Chaucer’s Pardoner and Wife of Bath (Philadelphia:
University of Pennsylvania Press, 2008), 261.
229 Jill Mann. Life in Words: Essays on Chaucer, the Gawain-Poet, and Malory (Toronto:
University of Toronto Press, 2014), 82.
230 Catherine S. Cox. Gender and Language in Chaucer (Tampa: University Press of
Florida, 1997), 19. V The text then
becomes no more than a tool to serve the interests of the interpreter,
meaning whatever he or she wishes it to”.229 The Wife rebels against all of this, but especially against the idea
that other people (notably men) are entitled to tell her how she should
read and understand the texts of her day, which in turn influence how
she lives (and understands) her life. The Wife is an earth-bound woman
who wants to control her own existence and her own loves, rather than
submit to another’s pre-scripted role, courtly or otherwise. In pursuit of
this control, the Wife of Bath defies the walls built by “auctoritee” and
its attempts to rewrite poetry. However, though the Wife’s prologue and tale can be understood
as her attempts to address the misogynistic assumptions, and the
misrepresentations of women found in “courtly love”, some critics
view her narrative as ambiguous, regarding it as both feminist and anti-
feminist. Other arguments insist that in her prologue, the Wife is merely
enacting an anti-feminist stereotype of the rapacious and imperious wife,
and rather than being the embodiment of what misogynistic discourse
can’t say, she is embodying precisely what it does say. According to
Catherine Cox, for example, the Wife of Bath does not, in any sense,
produce what can be described as feminine discourse: “This sense of
the narrative becomes clearer when we consider the Wife to be a textual
‘feminine’ representation, one constructed within the parameters of
‘masculine’ discourse and articulated in masculine terms”.230 From this
point of view, the Wife’s arguments are not essentially different from
those of her cleric husband, Jankyn, who often quotes “auctoritee” in his
anti-feminist literature in order to justify his actions toward the Wife,
reading to her from his book of “wicked wives” that contains passages
from Adversus Jovinianum, Dissuasio Ad Rufinum, the Golden Book on
Marriage, Tertulan, and other misogynistic works. 290 Love and its Critics But far from being confined to the thralldom of an anti-feminist
discourse, the Wife speaks as the dismissed “other”, explicitly mimicking
the operations of patriarchal (and explicitly anti-fin’amor) discourse in
order to mock it, defuse it, and deny it any power over her. 231 Susan Crane. Gender and Romance in Chaucer’s Canterbury Tales (Princeton: Princeton,
University Press, 1994), 116.
232 Ibid.
233 Hallissy, 103.
234 Ibid.
235 Chaucer, General Prologue, 453, 456–57. V When she
delivers her tirade against her three previous husbands, she repeats the
very words anti-feminist writers have used about domineering wives:
“When [Alison] accuses her old husbands […] she cites the stereotype
within her performance of it, establishing a link but also a distinction
between the proverbial ‘chidying wyves’ and her own chiding objection
to the proverb”.231 The Wife’s performance is an instance of imitation
designed to defuse the rhetorical attacks made against her, “a strategic
repetition of sanctioned positions on gender from the crucially different
position of a feminine voice”.232 The Wife refuses to play the roles
assigned to her by the “courtly” and other misogynistic discourses of
her era, and so she becomes, through imitation and appropriation, her
own “auctour”, her own “auctoritee”. The Wife’s defiance goes beyond language, expressing itself also
through her clothing and outward presentation. At the time of the
pilgrimage that frames the Canterbury Tales, she is a widow. As such,
she is expected “to wear widow’s garb [and] modest attire in a somber
hue”,233 and even more importantly, “her demeanor should match her
clothing”.234 And yet, the Wife’s exterior defies those expectations: “Hir
coverchiefs ful fyne weren of ground; / […] Hir hosen weren of fyn
scarlet reed, / Ful streite yteyd, and shoes ful moyste and newe”.235 The
Wife is not about to accept anyone else’s terms, and by being flamboyant
in demeanor and assertive in speech, the Wife defies auctoritee, while
at the same time claiming her own, and reveling in her seductive and
vibrant appearance. She is not afraid of sensuality, nor is she willing to
have it “glossed” for her by any dry-as-dust and cloistered clerics (like
Ermengaud, for example) who presume to counsel men and women
of the world about human sexuality. She is the “other” that the gloss,
written by clerical, anti-body and anti-pleasure men, opposes—the gloss
6. The Death of Fin’amor in Medieval French and English Poetry 291 that runs on the notion that all women are functionally interchangeable. The Wife, though her opposition to and appropriation of this patriarchal
hermeneutic, turns the tables and puts men in the same position:
“Yblessed be God that I have wedded five! 236 Ibid., III. 44–46.
237 Carolyn Dinshaw. Chaucer’s Sexual Poetics (Madison: University of Wisconsin Press,
1989), 124.
238 “amor et seigneurie / ne s’entrefirent compaignie” (Lorris, Guillaume and Jean de
Meun, ll. 8421–22). 236 Ibid., III. 44–46. V / Welcome the sixte, whan
that evere he shal”.236 The Wife of Bath, through her imitation and
appropriation, makes it abundantly clear what “auctoritee” refuses to
acknowledge, or reluctantly acknowledges only by seeing it as “other”. The beginning of the Wife’s prologue repeats the points of the
unorthodox theologian Jovinian (a fourth-century-CE opponent of
Christian asceticism), but it also mimics the rather drearily orthodox,
anti-feminist (and ascetic) Jerome. If the Wife’s reasoning is inconsistent,
a point that provokes a number of critics to reprove her, it is because
there is inconsistency and disagreement in the texts from which she
quotes, especially, perhaps, in the anti-feminist texts: “Commenting on
Saint Paul’s statement that it is good for a man to be unmarried […]
Jerome contends, ‘If it is good for a man to be so, then it is bad for a
man not to be so’”.237 Impeccable logic, to be sure. It is thus unsurprising
that the Wife revamps biblical passages to fit her arguments; she is but
imitating the techniques of the male glossators who adjust and alter
texts to fit their ideology. Toward the end of her prologue, in her descriptions of her last
marriage, the Wife not only speaks of joys and woes in a marriage, but
also depicts a relationship between women and (male) glossators. The
conclusion of her prologue suggests that despite her appropriation of
“auctoritee” and talk of “maistrie”, and “soveraynetee”, what the Wife
most wants is mutuality and satisfaction of desires, much like the ideal
expressed by Marcabru as “dos desirs d’un enveia”—“two desires in a
single longing” and by Bernart de Ventadorn when he writes that love
requires mutuality between the lovers: “Nothing in it can be good / If the
will is not mutual” (“Nula res no i pot pro tener, / Si·lh voluntatz non
es egaus”). She is yearning for the equality written of by Jean de Meun,
for whom “love and lordship / do not keep each other company”.238 But 292 Love and its Critics the Wife of Bath lives in a different time, a post Albigensian-Crusade era
dominated by religious dogma, and so such equality is hard, perhaps
even impossible, to find. 239 Chaucer, III.787.
240 Ibid., III.516. The potential double meaning here of “queynte’ also presents difficulties.
241 Jean Hagstrum argues that “[t]he raped solitary country girl of the Arthurian
landscape in the tale surely symbolizes what society had done to Alisoun in her
loveless marriages” (271).
242 Chaucer, III.905.
243 Ibid., III.1038–40. 239 Chaucer, III.787.
240 Ibid., III.516. The potential double meaning here of “queynte’ also presents difficulties. p
g
q
y
p
241 Jean Hagstrum argues that “[t]he raped solitary country girl of the Arthurian
landscape in the tale surely symbolizes what society had done to Alisoun in her
loveless marriages” (271). V However, once Jankyn apologizes and burns
the misogynistic book with which he has has caused her so much “wo”
and “pyne”,239 she becomes loving and kind to him, and she gains
“soveraynetee” (the key term of her tale). But the question of whether or
not she actually has attained her desire, despite her positive declaration
of the fact, is made difficult to answer because of the very language in
which she makes her declaration: it is the language of a fairy tale; as
the Wife says, it is “in this matere a queynte fantasye”.240 There is no
equality; there is no fin’amor. These are (yet) things of the past. And yet,
in her words, there is a return of at least the imagined possibility for full
understanding between husband and wife. When the Wife of Bath manipulates authoritative texts, she suggests
something about glossing and its misogynistic strategy: it deprives
the female of her significance and therefore completely undermines
both female and male sexuality. In this light, her tale of the knight and
the Loathly Lady is a tale of resistance, an instance of the interpreted
siezing control of the act of interpretation. The domestic sphere of the
tale has as its main participants a married couple—King Arthur and
his queen—and a knight who, overcome with lust and his own sense
of entitlement, has raped a young maiden, and is to be executed for
his crime.241 But after intercession on his behalf by the queen and other
ladies of the court, the knight is given one chance to save his life. If he is
to do so, he must find the answer to the question, “what thyng is it that
women moost desiren”.242 As the tale goes on, the answer is revealed:
“Wommen desiren to have sovereynetee / As wel over hir housbound
as hir love, / And for to been in maistrie hym above”.243 By the tale’s end,
the rapist knight, who both embodies and enacts the patriarchal power
structure of female oppression (and the glossator’s/critic’s structure
6. The Death of Fin’amor in Medieval French and English Poetry 293 of poetic oppression), must learn his lesson and act in deference to
feminine desire. 244 Crane, 131.
245 Chaucer, III.1–3.
246 Ibid., III.1257–58.
247 Ibid., III.1255–56. V For the Wife, “Auctoritee involves not only being an author, but
also a master or a teacher”.244 This state, seldom achieved by females
in the medieval period, is the one to which both the Wife of Bath and
the Loathly Lady aspire. The Wife has been a student of marriage
through five unions, and though she claims, “Experience, though noon
auctoritee / Were in this world, is right ynogh for me / To speke of wo
that is in marriage”,245 she still quotes authority, realizing that experience
alone is not enough to adopt “auctoritee”. The Loathly Lady lectures her
husband by quoting great “auctours”, such as Dante, Seneca, Boethius,
and others. Her monologue, also known as the “pillow lecture”, argues
that women should be valued not only for their beauty and youth, but
also for their intelligence. The knight does not learn his lesson from
authoritative texts, or from “courtly” tales that strip the flesh-and-blood
humanity from women, but by listening to his wife’s lecture. He learns
from the real woman who is right there in front of him. However, the tale ends with a contradiction. Despite the tale’s
declaration, “And thus they lyve unto hir lyves ende / In parfit joye”,246
the lines before it contend that “she obeyed hym in every thyng / That
myghte doon hym plesance or liking”.247 This ending seems to bring
the reader back to the realm of romance and “courtly love” literature,
where the beloved is only exalted in the wooing period. But the Wife
ends her tale with a hint of the mutuality of which Marcabru and
Bernart wrote, a relationship in which each renders to each “every
thyng / That myghte doon hym [and her] plesance or likyng”, and in
which love is, as Jean de Meun described it, “en queur franc et delivre”,
honest and free in the heart. By Chaucer’s time, the troubadours had been gone for well over a
century. Since that time, passionate, embodied, and erotic love had often
been treated as a dangerous element, one which Christian “auctors”
had laboriously identified as a sin. In Chaucer’s world, book learning Love and its Critics 294 conveyed “auctoritee”, and in his portrayal of the Wife, the Loathly
Lady of her tale, and the anti-feminist discourse the Wife rails against,
Chaucer imagines patriarchy from the “other’s” perspective, carefully
reckoning the costs of misogynistic clerical and “courtly” discourse. V Chaucer, through the Wife of Bath, maintains that women’s desire, and
desire in general, cannot be denied. © 2017 Michael Bryson and Arpi Movsesian, CC BY 4.0 I
The Platonic Ladder of Love Despite the changes that are beginning to appear in fourteenth-century
England, by the same time in Italy the sublimation and spiritualization
of love has long established itself as the dominant theme of European
poetry, a theme that is exported to England in the sixteenth century,
briefly sweeping aside much of the spirit we have seen developing in
Chaucer. To understand how and why this happened, we will have to
circle back and spend a little time with Plato. Perhaps the single most basic element of Platonic metaphysical
thought is the separation between the world we see and the world we
do not see, a temporal world of motion and change, and an eternal
realm of stasis. This idea stems from earlier Greek philosophers, such
pre-Socratics as Heraclitus, for example, who is most famous for
trying to illustrate the difference between the two realms, as well as
their interdependence, with the image of a river (stasis) in which new
waters continually flow (motion). But in Plato, this theme of the relation
between the eternal and the temporal reaches its most powerfully
articulated form, and his ideas are traceable through the history of
thought in literature and art in the Western world. © 2017 Michael Bryson and Arpi Movsesian, CC BY 4.0 https://doi.org/10.11647/OBP.0117.07 296 Love and its Critics In the Symposium this theme takes shape in an argument that
posits an idea of Forms and Copies—not merely the idea of a realm
of eternal Forms or Ideas which are the templates for the individual
and ephemeral Copies we see here in the world of flux and change,
but the idea that there are higher and lower, nobler and baser ways of
using those Copies as ways to understand those eternal Forms. The
Symposium regards the baser ways of understanding with suspicion,
because they are stuck within the changing conditions of a world in
which, as Shakespeare says, “everything that grows holds in perfection
but a little moment”, but they are also necessary, a means to an end. In
what becomes the well-worn image of a “ladder of love”, the dialogue
pictures such baser understandings as the lower rung on a ladder that
leads to higher understandings, a progression in which lower forms of
love lead to higher loves, and eventually the highest love of all—the
love of the Forms. 1
“ἔφη, οὐ τοῦ καλοῦ ὁ ἔρως, ὡς σὺ οἴει” (Plato. Symposium, ed. by W. R. M. Lamb
[Loeb Classical Library, Cambridge, MA: Harvard University Press, 1925], 206e).
2
“γεννήσεως καὶ τοῦ τόκου ἐν τῷ καλῷ” (ibid.).
3
ὅτι ἀειγενές ἐστι καὶ ἀθάνατον ὡς θνητῷ ἡ γέννησις. ἀθανασίας δὲ ἀναγκαῖον ἐπιθυμεῖν
μετὰ ἀγαθοῦ ἐκ τῶν ὡμολογημένων, εἴπερ τοῦ ἀγαθὸν1 ἑαυτῷ εἶναι ἀεὶ ἔρως ἐστίν.
ἀναγκαῖον δὴ ἐκ τούτου τοῦ λόγου καὶ τῆς ἀθανασίας τὸν ἔρωτα εἶναι.
Ibid., 206e-207a. 1
“ἔφη, οὐ τοῦ καλοῦ ὁ ἔρως, ὡς σὺ οἴει” (Plato. Symposium, ed. by W. R. M. Lamb
[Loeb Classical Library, Cambridge, MA: Harvard University Press, 1925], 206e).
2
“γεννήσεως καὶτοῦτόκου ἐν τῷκαλῷ” (ibid ) 3
ὅτι ἀειγενές ἐστι καὶ ἀθάνατον ὡς θνητῷ ἡ γέννησις. ἀθανασίας δὲ ἀναγκαῖον ἐπιθυμεῖν
μετὰ ἀγαθοῦ ἐκ τῶν ὡμολογημένων, εἴπερ τοῦ ἀγαθὸν1 ἑαυτῷ εἶναι ἀεὶ ἔρως ἐστίν.
ἀναγκαῖον δὴ ἐκ τούτου τοῦ λόγου καὶ τῆς ἀθανασίας τὸν ἔρωτα εἶναι.
Ibid., 206e-207a. I
The Platonic Ladder of Love Organized around a series of speeches offering competing definitions
of love, the Symposium reaches its philosophical climax when Socrates
tells the story of his conversation with the prophetess Diotima. Diotima
first defines what love is, then moves on to an elaborate description of
how love may be realized or achieved: “think not that love is of the
beautiful”,1 rather, love “is for the engendering and producing offspring
upon beauty”.2 Why? That is because it is an undying thing in our mortal life. Immortality
constrains us to set our hearts upon it even as we pursue the good, and so
it comes about that love always exists as one’s highest good. Necessarily
then, from this reckoning, love is of immortality.3 But how can we fulfill such longing for immortality? In Diotima’s
conception, we do so through generation. As Diotima puts it, “the mortal
condition always desires to enter an immortal existence. This is possible
only through engendering, so that in the future, a young generation But how can we fulfill such longing for immortality? In Diotima’s
conception, we do so through generation. As Diotima puts it, “the mortal
condition always desires to enter an immortal existence. This is possible
only through engendering, so that in the future, a young generation 7. The Ladder of Love in Italian Poetry and Prose 297 can take the place of the old one”.4 But the generation—or “increase”—
being referred to is of two different kinds, a lower and higher. There is
the physical generation engaged in by those who are “pregnant in the
body”.5 These “turn toward women”6 and “through begetting children
they achieve immortality”.7 The higher example, however, is a spiritual
generation, engaged in by those with “the pregnancy of the spirit”.8 It
is to these that wisdom truly belongs, and their realm is that of Beauty
itself: they have “prudence and goodness, which exist in all poets and
creators and skilled craftsmen who are called inventors”.9 This splitting of “pregnancy” into attempts to achieve immortality
through the flesh and through the spirit leads Diotima to describe—
using the metaphor of a ladder—a pedagogical process by which
a student of Love and Beauty may move from first lessons to a final
revelation. 4
“θνητὴ φύσις ζητεῖ κατὰ τὸ δυνατὸν ἀεὶ τὸ εἶναι ἀθάνατος. δύναται δὲ ταύτῃ
μόνον, τῇ γενέσει, ὅτι ἀεὶ καταλείπει ἕτερον νέον ἀντὶ τοῦ παλαιοῦ” (ibid., 207d).
5
“ἐγκύμονες […] κατὰ σώματα” (ibid., 209a).
6
“πρὸς τὰς γυναῖκας” (ibid.).
7
“διὰ παιδογονίας ἀθανασίαν” (ibid.).
8
“δὲ κατὰ τὴν ψυχήν” (ibid.).
9
“φρόνησίν τε καὶ τὴν ἄλλην ἀρετήν· ὧν δή εἰσι καὶ οἱ ποιηταὶ πάντες γεννήτορες
καὶ τῶν δημιουργῶν ὅσοι λέγονται εὑρετικοὶ” (ibid.).
10
“ἑνὸς αὐτὸν σώματος ἐρᾶν καὶ ἐνταῦθα γεννᾶν Bλόγους καλούς” (ibid., 210b).
11
ἔπειτα δὲ αὐτὸν κατανοῆσαι, ὅτι τὸ κάλλος τὸ ἐπὶ ὁτῳοῦν σώματι τῷ ἐπὶ ἑτέρῳ σώματι
ἀδελφόν ἐστι, καὶ εἰ δεῖ διώκειν τὸ ἐπ᾿ εἴδει καλόν, πολλὴ ἄνοια μὴ οὐχ ἕν τε καὶ ταὐτὸν
ἡγεῖσθαι τὸ ἐπὶ πᾶσι τοῖς σώμασι κάλλος· τοῦτο δ᾿ ἐννοήσαντα καταστῆναι πάντων τῶν
καλῶν σωμάτων ἐραστήν.
Ibid. 4
“θνητὴ φύσις ζητεῖ κατὰ τὸ δυνατὸν ἀεὶ τὸ εἶναι ἀθάνατος. δύναται δὲ ταύτῃ
μόνον, τῇ γενέσει, ὅτι ἀεὶ καταλείπει ἕτερον νέον ἀντὶ τοῦ παλαιοῦ” (ibid., 207d).
5
“ἐγκύμονες […] κατὰσώματα” (ibid., 209a). μ
ῇγ
ρ
5
“ἐγκύμονες […] κατὰ σώματα” (ibid., 209a). 12
“μετὰ δὲ ταῦτα τὸ ἐν ταῖς ψυχαῖς κάλλος τιμιώτερον ἡγήσασθαι τοῦ ἐν τῷ
σώματι” (ibid., 210c).
13
“τοῖς νόμοις καλὸν” (ibid.).
14
“παιδαρίου κάλλος ἢ ἀνθρώπου” (ibid., 210d).
15
“ἐπὶ τὸ πολὺ πέλαγος τετραμμένος τοῦ καλοῦ” (ibid.).
16
“μὲν ἀεὶ ὂν καὶ οὔτε γιγνόμενον οὔτε ἀπολλύμενον” (ibid., 211a).
17
τῶνδε τῶν καλῶν ἐκείνου ἕνεκα τοῦ καλοῦ ἀεὶ ἐπανιέναι, ὥσπερ ἐπαναβαθμοῖς χρώμενον,
ἀπὸ ἑνὸς ἐπὶ δύο καὶ ἀπὸ δυοῖν ἐπὶ πάντα τὰ καλὰ σώματα, καὶ ἀπὸ τῶν καλῶν σωμάτων
ἐπὶ τὰ καλὰ ἐπιτηδεύματα, καὶ ἀπὸ τῶν ἐπιτηδευμάτων ἐπὶ τὰ καλὰ μαθήματα, καὶ ἀπὸ
τῶν μαθημάτων ἐπ᾿ ἐκεῖνο τὸ μάθημα τελευτῆσαι, ὅ ἐστιν οὐκ ἄλλου ἢ αὐτοῦ ἐκείνου τοῦ
καλοῦ μάθημα.
Ibid., 211c. I
The Platonic Ladder of Love This process starts at the lowest rung of the ladder, where
the student needs “to devote himself to the beautiful and good in the
body”.10 The student then must thereupon in his true self understand that the beauty of that body is that
of many associated bodies that exist, and he if means to pursue the idea
and form of beauty, it would be great foolishness not to consider and
establish for himself the whole, how the beauty of one body is like the
the beauty of all bodies.11 Stepping from the first rung to the second rung of the ladder involves
moving from individual example to collective examples—but it does not
yet involve moving from example to concept, from concrete to abstract. That is the work of the third and fourth steps. Step three demands that Stepping from the first rung to the second rung of the ladder involves
moving from individual example to collective examples—but it does not
yet involve moving from example to concept, from concrete to abstract. That is the work of the third and fourth steps. 18
“Ὅτι δὲ οὕτω χρὴ νομίζειν ἔχειν, ὡς ἔστι μὲν τὸ ἐπέκεινα ὄντος τὸ ἕν, […] ἔστι
δὲ ἐφεξῆς τὸ ὂν καὶ νοῦς, τρίτη δὲ ἡ τῆς ψυχῆς φύσις, ἤδη δέδεικται” (Plotinus.
Ennead, Vol. V, ed. by A. H. Armstrong [Loeb Classical Library, Cambridge, MA:
Harvard University Press, 1984], 5.1.10, 44, 46). y
19
“Ποθεῖ δὲ πᾶν τὸ γεννῆσαν καὶ τοῦτο ἀγαπᾷ, καὶ μάλιστα ὅταν ὦσι μόνοι
τὸ γεννῆσαν καὶ τὸ γεγεννημένον· ὅταν δὲ καὶ τὸ ἄριστον ᾖ τὸ γεννῆσαν, ἐξ
ἀνάγκης σύνεστιν αὐτῷ, ὡς τῇ ἑτερότητι μόνον κεχωρίσθαι” (ibid., 5.1.6, 32). I
The Platonic Ladder of Love Step three demands that 298 Love and its Critics “besides this, in the meantime he must understand what is the soul’s
beauty, worthiness, and value over that of the body”,12 and learn to
see “beauty in the laws”.13 This definitively moves the student’s focus
beyond the individual and toward the collective and conceptual: no
longer will he direct his love toward “beauty in a boy or a man”,14 but
he will instead turn “toward the mighty sea of beauty”.15 Here, at last,
the student is ready to climb to the top of the ladder, ready for the final
revelation of the true nature of beauty as eternity: “indeed it always
existed, and neither comes into being nor is destroyed”.16 Finally,
Diotima gives a summary description of how the student learns to move
from lower to higher forms of devotion: Beginning with the beauty of the individual, the quest for beauty always
rises, even as it were using the steps of a ladder, from one to two, and
from two to all beautiful bodies, and from the beauty in all bodies to
the beauty of of customs and observances, and from the customs and
observances to the beauty of knowledge and mathematics, and from
such knowledge to the individual learning that has its end solely in the
knowledge of the existence of beauty itself.17 From Plato we come to the later Neoplatonist philosopher, Plotinus. The modification Plotinus makes to Platonic thought pushes it to the
point of religiosity, transforming Platonic philosophy into a theology
in all but name that is first cousin to Christianity. Plotinus describes
the reality of everything that exists in a layered or structured form, like
that presented in the Symposium, but with an extra twist. There is an
ultimate level of reality, beyond all description, conception, idea, and
imagination. Plotinus calls this level τὸ ἕν, or the One: 7. The Ladder of Love in Italian Poetry and Prose 7. The Ladder of Love in Italian Poetry and Prose 299 In this manner we can proclaim a Principle, which exists beyond
Being—the One. […] Existing next in order to the One is Mind. Third is
Spirit, and then physical Nature, which by this procession is shown and
brought to light.18 All things proceed from the One. From this indescribable source the
next level emanates, in what Plotinus describes as an unwilled process
of creation in which lower levels come from higher levels, but not due
to any purpose held by those higher levels. This next level is called
Nous, or Mind. Here is where all thought, reason, ideas exist. Nous, for
Plotinus, is the level Plato described as the realm of the Forms. Nous then
produces Psyche or Spirit, the level of soul, engagement, and (willed)
creative activity. Finally, from Psyche, comes the physical world of
matter. Everything emanates from the one ultimate, indescribable, non-
understandable source. Emanation proceeds downward, but is part of a
cyclical process, conducted within a self-contained environment. How? Because, according to Plotinus, the proper motion of
emotional, intellectual, and spiritual life is never a focus here, on the
world in which we live as physical and mortal beings, but above, to
the realms from which matter emanated. Plotinus paints a picture of
yearning and desire, though not of bodies for other bodies. The yearning
Plotinus describes is of the mortal for the immortal, the temporary for
the permanent, the changing for the changeless. As Plotinus describes it,
this yearning is for one’s origin: Everything longs for, and in this way loves its engenderer, and especially
whenever they are solitary the engendered seeks the engenderer; but
when the engenderer is the highest good, the engendered does so out of
necessity, divided, existing alone in its otherness and distinction.19 We desire, if properly oriented and instructed, that level of existence
that exceeds our own, and this upward-focus is reflected in the process
of emanation (non-willed creation that descends from higher to lower 300 Love and its Critics levels) and return (a willed focus that ascends from lower to higher
levels). For the Neoplatonists who follow Plotinus, love is properly
understood as an ascent through higher levels of experience, thought,
and awareness, with a corresponding move away from a focus on or
attachment to the here and now. According to this way of thinking,
love is not love for an individual. 20
“The highest and final thing that a man may leave is this: that he leaves God
for God” (“Daz hœhste unde daz nêhste, daz der mensche gelàzen mac, daz
ist, daz er got dur got làze” [“Qui audit me, non confundetur”]). Franz Pfeiffer,
ed. Deutsche Mystiker des Vierzehnten Jahrhunderts: Bd. Meister Eckhart. Erste
Abtheilung (Leipzig: G. J. Göschen, 1857), 310, ll. 34–35, https://books.google.com/
books?id=-78FAAAAQAAJ&pg=PA310 7. The Ladder of Love in Italian Poetry and Prose It seeks to leave behind the embodied
physical experiences of life. This movement away from the individual
and physical, and toward the eternal and ethereal leads to something
divine. In the Symposium it leads to the finest sense of knowledge. In
Plotinus—and in the Christian thinkers and writers who incorporate his
thought into their own—it becomes something like a God beyond God,
what the thirteenth-century German mystic Meister Eckhart called the
God that you must leave for God’s sake.20 Where Plato stops a step short
of that, Plotinus’s structure puts an unknowable “divine” principle at
the top. This idea of love as a yearning for the divine and immortal, a
yearning which must be shaped and trained away from individuals, is
taken up by Dante, Petrarch, and other Italian poets, and passed down
through them to English sixteenth-century authors. This idea works
against the destabilizing effect of individual choice in love (which
itself undermines the force of Church, State, and marital and social
conventions) that is so powerfully emphasized in troubadour poetry. 21
Michael R. G. Spiller. The Development of the Sonnet: An Introduction (London:
Routledge, 1992), 14.
22
Ffiona Swabey. Eleanor of Aquitaine, Courtly Love, and the Troubadours (Westport:
Greenwood Press, 2004), 67.
23
Ibid.
24
Olive Sayce. Exemplary Comparison from Homer to Petrarch (Cambridge, UK: Brewer,
2008), 289. 24
Olive Sayce. Exemplary Comparison from Homer to Petrarch (Cambridge, UK: Brewer,
2008), 289. II
Post-Fin’amor Italian Poetry: The Sicilian School to
Dante and Petrarch Among the earliest poetry in the Italian tradition was the work of
the Sicilian poets in the court of Frederick II (1194–1250). Frederick’s
was a court that anticipated many of the great aesthetic and academic
achievements of the Renaissance: 7. The Ladder of Love in Italian Poetry and Prose 301 22
Ffiona Swabey. Eleanor of Aquitaine, Courtly Love, and the Troubadours (Westport:
Greenwood Press, 2004), 67.
23
Ibid 7. The Ladder of Love in Italian Poetry and Prose The Holy Roman Emperor Frederick II, who ruled from 1208 to 1250 […],
was an absolute ruler, but an enlightened and (for those days) tolerant
one […]; the philosophy and literature of the Arabs, of the Sicilian and
Byzantine Greeks, of classical and neo-Latin Italy, and of southern
France and Spain, all flowed into Frederick’s realm […]. [A] patron of
scholars, translators, poets and musicians, as he moved about among his
various cities and castles, […] he required the centralised control of the
imperium to be administered by a highly loyal staff of professional legal
administrators […]. It was to this secular corps that the inventor of the
sonnet belonged.21 This new poetry was written in a style heavily influenced by the
troubadours, as the poets “modeled their songs on the Occitan […]
themes, but composed in the Sicilian dialect”.22 However, these poets
added three crucial elements: first, their radically enhanced “descriptions
of the pain and sorrow of love, which had enormous emotional power”,
and second, their “invention of the sonnet, which became the dominant
form for love poetry, not only in renaissance Italy but all over Europe”.23
The third element, however, is the most important: the Sicilian poets
wrote in service and deference to imperial authority: “It was probably
Frederick II […] who encouraged the composition of poetry on the
model of that of the troubadours at his Sicilian court. […] Thus the
foundations of the Italian lyric were laid”.24 In this more deferential
poetry, something new appears—the tendency, which grows more
pronounced in the poetry that follows, to turn love into worship and
women into divine objects of adoration: The Sicilians followed closely in the track of the Provençal poets […]. The subject matter of this imitative poetry was love—but love that bore
a peculiar relation to ordinary human feeling. Woman was regarded as
an ideal being, to be approached with worship bordering on adoration. The lover derived personal force, virtue, elevation, energy, from his 302 Love and its Critics enthusiastic passion. […] Love was the consummation of spiritual
felicity, which surpassed all other modes of happiness in its beatitude.25 enthusiastic passion. 26
Sayce 290. See also Martin J. Duffell’s brief outlining of the history of the sonnet
form in A New History of English Metre (London: Modern Humanities Research
Association and Maney Publishing, 2008), 117–18, and Ernest Hatch Wilkins’
account in The Invention of the Sonnet and Other Studies in Italian Literature (Rome:
Edizioni de Storia e Letteratura, 1959), 14–17, as well as Pierre Blanc’s account of
the cultural and political forces that shaped the sonnet in the court of Frederick II,
in “Sonnet des origines, origine du sonnet: Giacomo da Lentini”. Yvonne Bellenger,
ed. Le Sonnet a la Renaissance: Des Origenes au XVIIe Siecle (Paris: Aux Amateurs de
Livres, 1998), 9–18. Finally, and most importantly, see Paul Oppenheimer’s account
of the origin of the sonnet in The Birth of the Modern Mind: Self, Consciousness, and the
Invention of the Sonnet (Oxford: Oxford University Press, 1989), and his earlier article
“The Origin of the Sonnet”, Comparative Literature, 34: 4 (Autumn 1982), 289–304. 27
Swabey, 67–68. 25
John Addington Symonds. Renaissance in Italy, Vol. 4, part 1 (London: Mith, Elder &
Co., 1881), 59–60, https://books.google.com/books?id=K4sTAQAAIAAJ&dq=Symo
nds+Renaissance+in+Italy+1881&pg=PA59 25
John Addington Symonds. Renaissance in Italy, Vol. 4, part 1 (London: Mith, Elder &
Co., 1881), 59–60, https://books.google.com/books?id=K4sTAQAAIAAJ&dq=Symo
nds+Renaissance+in+Italy+1881&pg=PA59 28
Giacomo da Lentini. A Critical Edition of the Poetry of Giacomo da Lentini, ed. by
Stephen Popolizio (Ph.D. dissertation, Indiana University, 1975; Ann Arbor
Michigan: University Microfilms, 1980), 156. 7. The Ladder of Love in Italian Poetry and Prose […] Love was the consummation of spiritual
felicity, which surpassed all other modes of happiness in its beatitude.25 One of the best examples of the Sicilian style survives in the work of the
man usually credited with the invention of the sonnet form, Giacomo
da Lentini.26 Working at the court of Frederick in the early thirteenth
century, Giacomo’s lyrics straddle the line between troubadour
sensuality, and the later spiritualization of the poets of the dolce stil
novo, a style that “owed much to the Sicilian school, [but most of whose
practitioners] were from Florence and wrote in the Tuscan dialect”.27
In perhaps his most famous poem, Io m’aggio posto in core a Dio servire,
Giacomo writes of being torn between love of God and love of his Lady,
and is not at all sure that the former outweighs the latter: Io m’aggio posto in core a Dio servire
com’io potesse gire in paradiso,
al santo loco c’aggio audito dire
si mantien sollazo, gioco, e riso. Sanza mia donna non vi voria gire
(quella c’a blonda testa e claro viso)
che sanza lei non poteria gaudire,
estando da la mia donna diriso. Ma non lo dico a tale intendimento
perch’io pecato ci volesse fare,
se non veder lo suo bel portamento,
lo bel viso, e l[o] morbido aguardare: 303 7. The Ladder of Love in Italian Poetry and Prose 7. The Ladder of Love in Italian Poetry and Prose che lo mi teria in gran consolamento,
vegiendo la mia donna in ghiora stare.28 I have it deeply in my heart to serve God,
so that I will come into paradise,
The holy place I hear everywhere spoken of,
where always is solace, joy and laughter. Without my lady I would not want to go,
she with the blond hair and bright face,
for without her, I could take no pleasure,
being separated from my lady. Although I do not intend to say
that I would sin with her there;
if I did not see her beautiful bearing,
and her beautiful face and soft look,
I could not have great consolation
unless I saw my lady standing there in glory. The poet bargains with God over the love he has for his lady—assuring
heaven’s monarch, or trying to, that he means not to “sin”, but insisting
that if she were not in heaven, he “would not want to go”, and would
“take no pleasure”. The sentiments of Giacomo’s poem and those of
Aucassin in Aucassin et Nicolette seem to have rather more in common
than might appear at a first glance. While Aucassin speaks harshly of the
corruption of heaven and of those who are ticketed for that particularly
joyless destination, a place of “naked folks and shoeless, and covered
with sores, perishing of hunger and thirst, and of cold, and of little
ease”, Giacomo’s lover speaks more quietly, perhaps a bit timorously,
but no less determinedly of his distaste for a heaven in which his lady
might not be found. Elsewhere, however, the developing tendency to idealize the lady,
to both raise and reduce her by comparing her to jewels, the stars, the
sun, can be seen in Giacomo’s sonnet Diamante, né smeraldo, né zaffino. The lady is worth more than any jewel, and is like the stars themselves: 304 Love and its Critics [D]iamante, nè smiraldo, nè zaffino,
nè vernul’altra gemma prezïosa,
topazo, nè giaquinto, nè rubino,
nè l’aritropia, ch’è sì vertudiosa,
nè l’amatisto, nè’l carbonchio fino,
lo qual è molto risprendente cosa,
non àno tanta beleze in domino,
quant’a in se la mia donna amorosa. E di vertute tutte l’altre avanza,
somigliante [a stella è] di splendore
co la sua conta e gaia innamoranza;
e più bellè[sti] che rose e che frore. 29
Ibid., 193. 31
“L’amore divenne un’arte, col suo codice di leggi e costumi. Non ci fu più questa o
quella donna, ma la donna con forme e lineamenti fissati, così come era concepita
ne’ libri di cavalleria. Tutte le donne sono simili” (Francesco De Sanctis. Storia della
letteratura italiana, Vol. 1 [Neaples: Morano, 1870], 11, https://books.google.com/
books?id=VtuDUIv5cvUC&pg=PA11). 30
Ibid., 107. 7. The Ladder of Love in Italian Poetry and Prose Cristo le doni vita ed alegranza,
e sì l’acresca in gran pregio ed onore.29 Diamonds, nor emeralds, nor sapphires,
nor any other precious gems,
topaz, nor pearl, nor rubies,
neither heliotrope, so great in power,
nor amethyst, nor the finest stones,
the things which are most resplendent,
none have beauty and power,
so much as is in my beloved lady. And her virtue advances beyond all others,
it shines like the stars in its splendor
through her cheerful and charming face. She is more beautiful than a rose, or a flower. Christ give her the gifts of life and joy,
and may she grow great in praise and honor. At the same time, she exceeds the stars in brilliance; indeed, she is the
sun itself in Giacomo’s Dolce cominciamento: Dolce cominciamento
canto per la più fina
che sia, al mio parimento
d’Agri infino in Messina,
ciòe la più avenente, 305 7. The Ladder of Love in Italian Poetry and Prose ‘O stella rilucente,
che levi la maitina. quando m’apar davanti,
li tuo’ dolzi sembianti
mi’ncendon la corina’.30 Sweet beginning,
I sing for the finest
there is, in my opinion,
from Agri, all the way to Messina,
that is the most charming and fair. “Oh shining star,
that rises at dawn! When you appear before me,
your sweet face
sets fire to my heart”. As beautiful as this is, what has gone missing, even at this early stage,
is precisely what goes missing from the poetry of a post-Crusade
troubadour like Guilhem Montanhagol: the open description and
celebration of physical passion and sexual desire as an element of love. Even in Giacomo’s verse, whose lover seems on the precipice of refusing
heaven if his lady is not to be there, the ideas of God and heaven and
future punishment and reward are working their way prominently into
the poetry. Here, we are entering a period in which poetry withdraws
from individual passions, taking refuge in idealized descriptions: “Love
became an art, with its code of laws and customs. There was no longer
this or that particular woman, but a woman with fixed shapes and
features, as conceived in books of chivalry. 32
Paul Oppenheimer. “The Origin of the Sonnet”. Comparative Literature, 34: 4
(Autumn 1982), 297, https://doi.org/10.2307/1771151
33
Ibid., 304.
34
Symonds, 81, https://books.google.com/books?id=K4sTAQAAIAAJ&pg=PA81
35
Guido Guinizelli. The Poetry of Guido Guinizelli, ed. by Robert Edwards (New York:
Garland Publishing, 1987), 54, ll. 9–14. 34
Symonds, 81, https://books.google.com/books?id=K4sTAQAAIAAJ&pg=PA81
35
Guido Guinizelli. The Poetry of Guido Guinizelli, ed. by Robert Edwards (New York:
Garland Publishing, 1987), 54, ll. 9–14. 32
Paul Oppenheimer. “The Origin of the Sonnet”. Comparative Literature, 34: 4
(Autumn 1982), 297, https://doi.org/10.2307/1771151
33
Ibid., 304. 36
“Au chant XXVI, parmi une bande de luxurieux, sodomites et autres, Dante
rencontre Guido Guinicelli. Il le salue du nom de ‘père’, lui qui fut son initiateur et
son maître dans sa 3 e manière, sensuelle et savante” (René Lavaud, in Daniel, 133,
https://archive.org/stream/lesposiesdarna00arna#page/133). 7. The Ladder of Love in Italian Poetry and Prose All women were alike”.31
This is a distinct departure from the work of the Occitan poets: Giacomo
is “deliberately turning away from the kinds of songs made and sung by Love and its Critics 306 the troubadours”.32 His poems are not expressions of person-to-person
love, but “lyric[s] sung by the soul to the soul, in the silent music of
the soul”, songs that “echo those celestial and silent proportions and
ratios described by Plato”, constructed “according to the architecture
of the soul and of heaven”.33 One can imagine Guilhem IX snorting at
such ideas, but such was the change from the late eleventh to the early
thirteenth centuries, as the Church grew more powerful, and learned to
exert more control over the lives of those under its sway, even dictating
what would, and would not, be appropriate in the realm of art and poetry: The Church proscribed the poets of antiquity; and it had become an
axiom that poetry was the art of lies. Poetry was hardly suffered to exist
except as a veil to cloak some hidden doctrine; and allegory presented a
middle way of escape, whereby the pleasure of art could be enjoyed with
a safe conscience.34 The effects of this increasing control can be seen as we move from
the Sicilians to the practitioners of what Dante calls the dolce stil novo. Guido Guinizelli (c. 1230–1276) is writing at about the same time as
Montanhagol, while the last of the old troubadour spirit in Occitania is
dying. In Guinizelli’s poems, a transition between the embodied love of
the troubadours and the spiritualized love of the emerging allegorical
and Neoplatonist tradition is evident. There is still a powerful sense of
bodily desire, but in Chi vedesse a Lucia un var cappuzzo (Who sees Lucia in
her fur hat) something has gone wrong, and become twisted into the foul
deformity of a rape fantasy: Ah, prender lei a forza, ultra a su’ grato
e bagiarli la bocca e ‘l bel visaggio
e li occhi suoi, ch’èn due fiamme de foco! Ma, pentomi, però che m’ho pensato,
ch’esto fatto poria portar dannaggio
ch’altrui despiaceria forse non poco.35 Ah, prender lei a forza, ultra a su’ grato
e bagiarli la bocca e ‘l bel visaggio
e li occhi suoi, ch’èn due fiamme de foco! 7. The Ladder of Love in Italian Poetry and Prose Ma, pentomi, però che m’ho pensato,
ch’esto fatto poria portar dannaggio
ch’altrui despiaceria forse non poco.35 307 7. The Ladder of Love in Italian Poetry and Prose Splende ‘n la ‘ntelligenzïa del cielo
Deo Crïator più che ‘n nostr’ occhi ‘l sole:
ella intende suo fattor oltra ‘l cielo,
e ‘l ciel volgiando, a lui obedir tole,
e con’ segue al primero 37
Guinizelli, 22, ll. 41–50.
38
“Servit aurai longamen”, ll. 46–49. In Alfred Jeanroy, ed. Poesies de Uc de Saint-
Circ (Toulouse: Édouard Privat, 1913), 30–34, https://archive.org/stream/ 37
Guinizelli, 22, ll. 41–50. 7. The Ladder of Love in Italian Poetry and Prose Oh, to take her by force, even against her will,
And kiss her mouth and beautiful face
And her eyes, like two flames of fire! But I repent that thought,
For this would cause harm and sorrow,
And displease her not a little. The violent lust of this poem may partly explain why Dante puts
Guinizelli in hell: “In canto XXVI, amidst a band of the lustful, sodomites
and others, Dante meets Guido Guinizelli. He salutes him by the name
of the ‘father’, because he was both the initiator and [Dante’s] master
in the [dolce stil novo’s] third way, sensual and scholarly”.36 Alongside
the hellish note, there is a ring of the future in Guinizelli’s poem, a hint
of the poetry that will follow a Neoplatonic path, with the increasingly
intense sublimation of the physical into the spiritual, the rhetorical
excesses of the comparisons of the beloved’s eyes to the stars of heaven,
the beloved’s voice to the music of angels, or the beloved’s eyelids
to flame. The women of these poems will be described in ways that
separate them from the realm of physically identifiable human beings. The woman is light, a star, radiant; she is not embodied, but a spiritual
figure who draws the male poet toward heaven. In the above example,
we can clearly see that the “Lucia” of the poem is not regarded by the
narrator as a fully human woman; rather, she is an object—either of
rape fantasies, or of worship—not a desired and desiring subject. The
change in the lady’s status in Guinizelli (as opposed to Marcabru or
Bernart de Ventadorn) is already obvious. The sublimation and spiritualization that is merely hinted at elsewhere
is openly expressed in Guinizelli’s Al cor gentil (Of the gentle heart): 308 Love and its Critics del giusto Deo beato compimento,
così dar dovria, al vero,
la bella donna, poi che ‘n gli occhi splende
del suo gentil, talento
che mai di lei obedir non si disprende.37 So shines in the Intelligence of heaven
God the creator, more than sun in our eyes;
She understands her maker beyond heaven,
And turning to heaven, prepares to obey;
And in first consequence thereof,
As God blesses the just
So in her true duty
The beautiful lady, whose eyes shine
On the gentle, and talented,
Blesses those who do not cease to obey her. 41
Lowry Nelson. Poetic Configurations: Essays in Literary History and Criticism
(University Park: Penn State University Press, 1992), 100. posiesdeucdesa00ucde#page/32
39
William J. Kennedy. “European Beginnings and Transmissions: Dante Petrarch,
and the Sonnet Sequence”. In A. D. Cousins and Peter Horwarth, eds. The
Cambridge Companion to the Sonnet (Cambridge: Cambridge University Press,
2011), 87. )
40
“non me fu fallo, s’in lei posi amanza” (Guinizelli, 22, l.60). 7. The Ladder of Love in Italian Poetry and Prose So shines in the Intelligence of heaven
God the creator, more than sun in our eyes;
She understands her maker beyond heaven,
And turning to heaven, prepares to obey;
And in first consequence thereof,
As God blesses the just
So in her true duty
The beautiful lady, whose eyes shine
On the gentle, and talented,
Blesses those who do not cease to obey her. Here, the lady is a conduit between the poet and God, a spiritual
figure in whose eyes truth is glorified, and to whose service the poet is
dedicated. In this poem, the beloved is barely a woman at all; instead, she
is something more like a saint, an object of devotion and praise whose
main purpose is to bring the poet to God. The shift—even as early as
Guinizelli—is evident and profound: rather than being regarded as an
individual (as a subject) who is desired by the male for her own beauties
and merits, as in the troubadour poems, this woman is portrayed as the
personification of an abstract principle—truth—and is desired primarily
for her function or utility (as an object) in bringing the poet to God. This is an idea we can trace to an Inquisition-era troubadour, Uc
de Saint Circ, who was writing in northern Italy in the mid-thirteenth
century, perhaps a generation before Guinizelli. Uc writes of aspiring to
heaven through a lady: De ma vida·m faitz esmenda,
Bella de dura merce,
Ab sol que soffratz de me
Qu’eu per vos al cel entenda.38 De ma vida·m faitz esmenda,
Bella de dura merce,
Ab sol que soffratz de me
Qu’eu per vos al cel entenda.38 Qu’eu per vos al cel entenda.38 309 7. The Ladder of Love in Italian Poetry and Prose 7. The Ladder of Love in Italian Poetry and Prose posiesdeucdesa00ucde#page/32
39
William J. Kennedy. “European Beginnings and Transmissions: Dante Petrarch,
and the Sonnet Sequence”. In A. D. Cousins and Peter Horwarth, eds. The
Cambridge Companion to the Sonnet (Cambridge: Cambridge University Press,
2011), 87.
40
“non me fu fallo, s’in lei posi amanza” (Guinizelli, 22, l.60).
41
Lowry Nelson. Poetic Configurations: Essays in Literary History and Criticism
(University Park: Penn State University Press, 1992), 100. posiesdeucdesa00ucde#page/32 42
Guinizelli, 40, ll. 1–4. 43
Ibid., ll. 11–14. 7. The Ladder of Love in Italian Poetry and Prose Take my life in homage,
Beautiful unmerciful one,
As long as you suffer me
To aspire through you to heaven. This is the point at which the emphasis of love poetry clearly changes,
shifting its focus from here to the hereafter. Though it may well be
true that “Guinizelli […] refuses to define sacred and profane love as
mutually exclusive”, this merely leads us back to Diotima’s notion that
human love is nothing more than a transitional stage in the seeking of
divine love, especially since Guinizelli appeals to “a subtle Augustinian
philosophical sense of love as a continuum from human to divine”, and
“treats the amatory situation as an inward and high-mindedly ethical
event, connected with the larger process of order and purpose in God’s
universe”.39 In Guinizelli’s poetry, the woman praised by the poet is
not an end in herself, but a glorified means to an end. In fact, Guinizelli
expresses anxiety lest he had at any point slipped up and paid too much
regard to the woman, and therefore not enough to God: “It was not my
fault, to fall in love with her”.40 God is portrayed here as jealous because not all praise and love is
going to him. Part of it may have, in quiet moments, gone too directly
to the unnamed “her” of Guinizelli’s song, making that “her” a rival to
God, another deity. Such a gesture makes clear that this woman is not a
woman, or at the very least is not treated so by the poem. This woman
is a paragon, no mere fleshly mortal, and the poem goes to great lengths
to give love a Christian doctrinal basis: The dramatized self-justification leaves the lady still enhanced and
angel-like and at the same time allows a distant analogy to the Virgin. Thus [Guinizelli] by his mode of argument puts the love situation on an
inward ethical basis, connects it with the macro-cosmic process of God’s
universe, and gives it a Christian justification.41 310 Love and its Critics Guinizelli’s sonnet Io vogl’ del ver la mia donna laudare is less blatant in
its treatment of the “lady” as a means rather than an end than is Al cor
gentil. 42
Guinizelli, 40, ll. 1–4.
43
Ibid., ll. 11–14. 44
Marianne Shapiro. Woman Earthly and Divine in the Comedy of Dante (Lexington:
University Press of Kentucky, 2015), 28.
45
“Ed infra l’altre par lucente sole” (Guinizelli, 2, l.23).
46
Ibid., ll. 18–22. 44
Marianne Shapiro. Woman Earthly and Divine in the Comedy of Dante (Lexington:
University Press of Kentucky, 2015), 28. 45
“Ed infra l’altre par lucente sole” (Guinizelli, 2, l.23). 46
Ibid., ll. 18–22. 7. The Ladder of Love in Italian Poetry and Prose But even here, the reader encounters a meditation on a subject
that serves to ennoble the meditator, and represents the woman as a
glorious means to a higher and even more glorious end: Guinizelli’s sonnet Io vogl’ del ver la mia donna laudare is less blatant in
its treatment of the “lady” as a means rather than an end than is Al cor
gentil. But even here, the reader encounters a meditation on a subject
that serves to ennoble the meditator, and represents the woman as a
glorious means to a higher and even more glorious end: Io vogl’ del ver la mia donna laudare
ed asembrarli la rosa e lo giglio:
più che stella dïana splende e pare,
e ciò, ch’è lassù è bello a lei somiglio.42 I will in truth praise my lady,
Comparing her to the rose and the lily. She shines brighter than Diana’s star;
And so, all that is beautiful, resembles her. Again, we see the comparison of the woman to heaven, to “Diana’s star”
(Venus, or the “morning star”) which the unnamed lady exceeds. It’s
lovely. The poetry of this period and place is aesthetically at least equal
to, and arguably an advance beyond, much of the earlier troubadour
poetry. But it also represents a significant shift in point of view and
philosophical orientation. Far from being desirable for beauty, from
passion, and through disregard for the consequences attending a nearly-
always adulterous inclination and arousal, the woman is treated as an
exemplar, a spiritual guide for the righteous man, and a transcendent
agent of shame and reproach for the unrighteous man: e fa ‘l di nostra fè se non la crede. e non la pò appressare om che sia vile;
ancor ve dirò c’ha maggior virtute;
null’uom pò mal pensar fin che la vede.43 She makes you of our faith, if you do not believe. For no man can be near her, if he is vile:
I tell you, she has an even greater strength;
No man can think evil who has seen her. 46
Ibid., ll. 18–22. 7. The Ladder of Love in Italian Poetry and Prose 7. The Ladder of Love in Italian Poetry and Prose 311 All of this eloquence is put into the service of an argument which is
essentially this: love is only that which leads to, and is finally revealed
as having always been, love of God: “To Guido Guinizelli love, always
guided by reason, is a pure form of man’s aspiration toward God. Originating largely in the aesthetic admiration of physical beauty, love
thereafter turns to the moral beauty which is its true goal. In the cor
gentil the beautiful lady may induce a blessedness that is the image
of the beatitude of heaven”.44 The love of another, the love of a freely
chosen individual, a flesh and blood man or woman, is next door to
idolatry. Such love of another is only excusable if it leads you to the
love of God. And while the veils between idolatry and love of God
here might seem thin, that is only because they are thin. The early
Italian poets, much like the late troubadour Montanhagol, are trying
to shoehorn notions of eros (from a tradition that spans from Ovid
through the high-period troubadours) into the new dispensation, the
rules set down by the post-Albigensian-Crusade Church (in which
the theological and military powers-that-be demonstrated that they
were ready and willing to turn against Europeans, not just a distant
Muslim “other”). How far, at this point, we have come from the letters
of Héloïse, and the poems of the troubadours. One final poem from Guinizelli brings a number of ideas together
in one place. In Tegno di folle ‘mpres’, a lo ver dire, the poet distinguishes
his love from other women by resorting to the now familiar comparison
to the sun: “Among others she is a shining sun”.45 The woman of this
canzone, however, is also proud, perhaps a touch too proud, in the
poet’s view: ella non mette cura di neente
ma vassen disdegnosa,
ché si vede alta, bella, e avvenente. Ben si pò tener alta quanto vòle;
ché la plu bella donna è che si trove46 ella non mette cura di neente
ma vassen disdegnosa,
ché si vede alta, bella, e avvenente. Ben si pò tener alta quanto vòle;
ché la plu bella donna è che si trove46 312 Love and its Critics She does not care about a single thing,
But walks away disdainfully,
Seeing herself as beautiful and fair. 47
Ibid.,11.1–7 7. The Ladder of Love in Italian Poetry and Prose Well, she can have all the pride she wants,
For she is the most beautiful woman anywhere. The implication is that because the lover loves, the beloved is supposed
to have mercy on, extend favor to, and in some cases reciprocate the
love of the lover. When she does not, she is described as haughty, even
imperious, while the man who loves her is a helpless fool: Tegno di folle ‘mpres’, a lo ver dire,
chi s’abandona inver’ troppo possente,
si como gli occhi miei che fér esmire
nincontr’ a quelli de la più avenente. che sol per lor è vinti
senza ch’altre bellezze li dian forza,
ché a ciò far son pinti.47 I think him foolish, truthfully,
who abandons himself to a power too strong,
like I, with my eyes, have done in this sort
to the power of those eyes most fair,
and by them are overcome. No need for other beauties to lend their force,
To what had gone before. This idea of the proud and unmerciful lady who refuses her love to the
young male who pines for it is one that appears often in the later poetry
of Petrarch, and in the verses of English poets like Philip Sidney. In
Guinizelli, we can see an early example of what will become a well-worn
pairing: the ladder of love, and the pride or intractability of the beloved. This
pairing strongly suggests that the female is responsible for the spiritual
life and death of the male. If the woman is the conduit through which the
man is to learn to ascend to heaven on the ladder of his own increasingly
refined, and upward-directed thoughts and emotions, and the woman is
too proud to be as affable and obedient as the male would have her be, 47
Ibid.,11.1–7 7. The Ladder of Love in Italian Poetry and Prose 313 then the man will fail to ascend, suffer spiritual death, and end up in a
hell of eternal judgment and torment. From this develops the idea that
love is something you die for, or die of, rather than live for. In his work,
Petrarch makes frequent use of this idea, and Shakespeare will often
mock characters who give voice to such weeping and gnashing of teeth. 48
Piero Cudini, ed. Poesia Italiana. Il Duecento (Milan: Lampi di Stampa, 1999), 27, ll.
27–39. 7. The Ladder of Love in Italian Poetry and Prose In the troubadour poems, what is different is the idea of
individual value and mutual desire. In those poems, the will is mutual,
as is the choice. Where is the volition of the women being spoken of in
the poems of Guinizelli and Colonne? Where is the voice of the female? She has become a beautifully spoken-of but slightly-regarded object, a
consistent feature of Colonne’s larger body of work, where “[h]is tone
is overtly moralizing and didactic [and] he muses on the instability of
human affairs, the unpredictable workings of Fortune, and […] the
fickleness of women and their dangerous and corrupting influence”.49
This crucial shift in perspective lays down the foundations of ideas and
imagery that work their way through a developing poetic tradition that
has enormous influence on the poetry of later centuries. Colonne’s final
lines bring this point home: In the terms of these lines, if the poet does not gain the love of the figure
he refers to possessively as “my lady”, then he will rail at length about
her “haughty pride” and “harshness”, berating her for her lack of “pity”,
while never considering her desires even for a moment. Nowhere is
it clearer than in these lines that the beloved is a means, not an end
in herself. In the troubadour poems, what is different is the idea of
individual value and mutual desire. In those poems, the will is mutual,
as is the choice. Where is the volition of the women being spoken of in
the poems of Guinizelli and Colonne? Where is the voice of the female? She has become a beautifully spoken-of but slightly-regarded object, a
consistent feature of Colonne’s larger body of work, where “[h]is tone
is overtly moralizing and didactic [and] he muses on the instability of
human affairs, the unpredictable workings of Fortune, and […] the
fickleness of women and their dangerous and corrupting influence”.49
This crucial shift in perspective lays down the foundations of ideas and
imagery that work their way through a developing poetic tradition that
has enormous influence on the poetry of later centuries. Colonne’s final
lines bring this point home: Gli occi a lo core sono gli messaggi
de’ suoi incominciamenti per natura. Dunqua. 49
Jane E. Everson. The Italian Romance Epic in the Age of Humanism: The Matter of Italy
and the World of Rome (Oxford: Oxford University Press, 2001), 44.
50
Cudini, 28, ll. 54–60. 7. The Ladder of Love in Italian Poetry and Prose Guinizelli’s contemporary, Guido delle Colonne, develops the idea
of the lady’s pride and failure to be “affable” in Amor, che lungiamente
m’hai menato (Love, which so long has driven me): Non dico c’ a la vostra gran bellezza
orgoglio non convegna e stiale bene,
c’a bella donna orgoglio ben convene,
che si mantene—in pregio ed in grandezza. Troppa alterezza—è quella che sconvene;
di grande orgoglio mai ben non avene. Però, madonna, la vostra durezza
convertasi in pietanza e si rinfreni:
non si distenda tanto ch’io ne pèra. Lo sole è alto, e sì face lumera,
e tanto più quanto ‘n altura pare:
vostr’ argogliare—donqua e vostra altezze
facciami prode e tornimi in dolcezze.48 I do not say, that with your great beauty
Pride does not agree, it serves you well;
That pride in a beautiful woman is fitting
Which maintains esteem and grandeur. But too much pride, that is not fitting;
A great and haughty pride is never attractive. But my lady, your harshness
Convert to pity, and restraint;
Do not stretch so much, to seem so posh. The sun is high, and brilliantly lighted,
And even more so, the higher it seems:
So let your pride and your haughtiness
Turn its face to me in sweetness and delight. I do not say, that with your great beauty
Pride does not agree, it serves you well;
That pride in a beautiful woman is fitting
Which maintains esteem and grandeur. But too much pride, that is not fitting;
A great and haughty pride is never attractive. But my lady, your harshness
Convert to pity, and restraint;
Do not stretch so much, to seem so posh. The sun is high, and brilliantly lighted,
And even more so, the higher it seems:
So let your pride and your haughtiness
Turn its face to me in sweetness and delight. Turn its face to me in sweetness and delight. 314 Love and its Critics In the terms of these lines, if the poet does not gain the love of the figure
he refers to possessively as “my lady”, then he will rail at length about
her “haughty pride” and “harshness”, berating her for her lack of “pity”,
while never considering her desires even for a moment. Nowhere is
it clearer than in these lines that the beloved is a means, not an end
in herself. 51
Dante. The Canzoniere of Dante Alighieri, ed. by Charles Lyell (London: James Bohn,
1840), 36, https://books.google.com/books?id=E6JWAAAAcAAJ&pg=PA36 7. The Ladder of Love in Italian Poetry and Prose madonna, gli occhi e lo meo core
avete in vostra mano, entro e di fore,
c’Amor me sbatte e smena, che no abento,
sì come vento—smena nava in onda:
voi siete meo pennel che non affonda.50 The eyes bring messages to the heart
Of all that begins by nature. Therefore, my lady, my eyes and my heart
You have in your hand, inside and out;
That love leads my life into battle,
And beats, as the winds against a ship,
But you are my banner, which will not sink. 7. The Ladder of Love in Italian Poetry and Prose 315 7. The Ladder of Love in Italian Poetry and Prose And yet where is this lady in those gorgeous lines? She is a thing that
exists in his emotions, in his head, in his thoughts, in his language, in
his verse. She is given no detailed description, no voice or validity or
ability to speak back except as an adjunct to his desires or an aid to what
he would have. If we look at the poem as a powerful expression of what
the poet most desires, aesthetically it is beautiful. But when we consider
how that desire is spoken, what use the poems make of the idea of the
beloved, that desire, and that poem, become dark and troubling things. p
g
g
By the time we come to the poetry of Dante, written in the late
thirteenth and early fourteenth centuries, we are on ground that is
more familiar to many readers. His collection La Vita Nuova (The new
life) contains even clearer alterations of troubadour themes than do the
works of his predecessors. These verses describe the effect on the poet
that is wrought by seeing a young girl named Beatrice, who will become
the muse of La Divina Commedia, or The Divine Comedy. The sonnet Negli
occhi porta la mia donna Amore makes the effect especially clear: Negli occhi porta la mia donna Amore;
Per che si fa gentil ciò ch’ ella mira:
Ov’ ella passa ogni uom ver lei si gira:
E cui saluta fa tremar lo core;
Sì che bassando il viso tutto smore,
E d’ogni suo difetto allor sospira:
Fugge davanti a lei superbia, ed ira. Aitatemi voi, donne, a farle onore. Ogni dolcezza, ogni pensiero umile
Nasce nel core a chi parlar la sente;
Ond’ è beato chi prima la vide. Quel ch’ella par quando un poco sorride
Non si può dicer, nè tenere a mente,
Si è nuovo miracolo e gentile.51 The door to love is in my lady’s eyes,
So where she looks all things grow gentle;
And where she passes all men turn to her, 316 Love and its Critics And those she blesses tremble to their core,
Cast their faces down in shame, wholly pale,
And instantly confess their every sin in sighs. Pride and anger flee before her,
Help me honor her, noble ladies. 52
Ibid., 50, https://books.google.com/books?id=E6JWAAAAcAAJ&pg=PA36 53
Hagstrum, 236. 7. The Ladder of Love in Italian Poetry and Prose And I saw Love himself approach from afar,
So cheerfully, I scarcely recognized him,
He said, think now to give me honor;
And with every word he laughed. And, when my Lord had stayed a little while,
I gazed in the direction from which he came
And saw lady Vanna and lady Beatrice
Coming to the place where I stood,
The one surpassing the other as a marvel,
And now, as memory brings back their words
Love said to me, this lady is the Springtime,
But this one is called Love, she so resembles me. Beatrice, as were the various “ladies” of the Guinizelli and Colonne
poems, is made an abstraction, stripped of humanity in order better to
serve to stir the poet’s heart, and work him into an attitude of worship. Beatrice, as were the various “ladies” of the Guinizelli and Colonne
poems, is made an abstraction, stripped of humanity in order better to
serve to stir the poet’s heart, and work him into an attitude of worship. In the sonnet Di donne io vidi una gentile schiera, Dante takes the
deifying and sacralizing of Beatrice even further. Here, Beatrice is not
merely Love itself, no mere miracle—rather, she is “an angel through
whom man reaches God”,53 accompanied by Love as by an attendant, a
lady birthed in Heaven itself: Di donne io vidi una gentile schiera
Quest’ Ognissanti prossimo passato;
Ed una ne venia quasi primiera,
Seco menando Amor dal destro lato. Dagli occhi suoi gittava una lumiera,
La qual pareva un spirito infiammato;
Ed i’ ebbi tanto ardir, che la sua cera
Guardando, vidi un angiol figurato. A chi era degno poi dava salute
Con gli occhi suoi quella benigna e piana,
Empiendo il core a ciascun di virtute. Credo che in ciel nascesse esta soprana,
E venne in terra per nostra salute:
Dunque beata chi l’è prossimana.54 Di donne io vidi una gentile schiera
Quest’ Ognissanti prossimo passato;
Ed una ne venia quasi primiera,
Seco menando Amor dal destro lato. Dagli occhi suoi gittava una lumiera,
La qual pareva un spirito infiammato;
Ed i’ ebbi tanto ardir, che la sua cera
Guardando, vidi un angiol figurato. A chi era degno poi dava salute
Con gli occhi suoi quella benigna e piana,
Empiendo il core a ciascun di virtute. g
,
54
Dante, Canzoniere, 378, https://books.google.com/books?id=E6JWAAAAcAAJ&pg=PA378 7. The Ladder of Love in Italian Poetry and Prose All sweetness, all humble thoughts
Be born in the hearts that hear her speak;
And blessed be they who have once known
How she appeared with a little smile;
Nor words nor thoughts can describe her,
She is so new and noble a miracle. Dante describes this young girl as a “miracle” more than she is a flesh-
and-blood human being; her value is not in her humanity, but in her
function. Beatrice transforms (“where she looks all things grow gentle”)
the wicked hearts of evil men, who, as they “[c]ast their faces down in
shame, wholly pale, / And instantly confess their every fault in sighs”,
become suddenly aware of their insufficiency in the face, not of a girl, but
of a goddess. This sacramental function that Dante assigns to Beatrice is
even clearer in the following lines from Io mi sentii svegliar dentro a lo core: Io mi sentii svegliar dentro a lo core
Un spirito amoroso che dormia,
E poi vidi venir di lungi Amore,
Allegro sì che appena il conoscìa,
Dicendo: or pensa pur di farmi onore;
E ciascuna parola sua ridia:
E, poco stando, meco il mio signore,
Guardando in quella parte ond’ ei venia,
Io vidi monna Vanna e monna Bice
Venire in verso il loco dov’ io era,
L’una appresso dell’ altra meraviglia. E sì, come la mente mi ridice,
Amor mi disse: questa è Primavera,
E quella ha nome Amor, sì mi somiglia.52 52
Ibid., 50, https://books.google.com/books?id=E6JWAAAAcAAJ&pg=PA36 52
Ibid., 50, https://books.google.com/books?id=E6JWAAAAcAAJ&pg=PA36 317 7. The Ladder of Love in Italian Poetry and Prose 56
https://commons.wikimedia.org/wiki/File:Ary_Scheffer_-_Dante_and_Beatrice.
jpg?uselang=en-gb 55
Nelson, 100. 7. The Ladder of Love in Italian Poetry and Prose Credo che in ciel nascesse esta soprana,
E venne in terra per nostra salute:
Dunque beata chi l’è prossimana.54 318 Love and its Critics I saw a group of gentle ladies
On All Saint’s Day just past;
And one, without apology, as if the prime,
Led Love along at her right hand. From her eyes shone forth a light,
That seemed a spirit burning in flame;
With great daring, at her form
I gazed, and saw an angel’s figure. Then with dignity and calm she blessed
With her eyes, kindly and simply, all those
Wicked at heart, filling them all with virtue. I believe she was born in highest heaven,
And came to earth to be our blessing,
So blissful are those who are close to her. Here again, love for the “woman” is not love of a human being, but
worship of an angel, and a conduit for salvation: “Beatrice gradually
becomes a bearer not only of health and of salutation […] but of
salvation. Dante’s overwhelming experience of love […] for Beatrice
becomes transformed into a sacred spiritual force”.55 Ary Scheffer, Dante and Beatrice (1851). Museum of Fine Arts, Boston.56 Ary Scheffer, Dante and Beatrice (1851). Museum of Fine Arts, Boston.56 7. The Ladder of Love in Italian Poetry and Prose 319 At this point, we have long since left behind the idea of love as a radically
destabilizing force, between two people who have no business choosing
each other, yet do, despite all the boundaries that separate them. We
have moved from that, to a poetry that describes love in sacred terms,
a love that is amenable to being channeled within the Church, a love
that is not an anarchic threat. The love described by Guinizelli and
Colonne, and even more powerfully by Dante, is not a two-way choice,
but something that begins to reflect increasingly a single point of view:
the desires of the male heart, the male voice, and the male passions,
while the female heart, voice, and passions are set aside, and the female
herself is increasingly dehumanized, dematerialized, and deified: Dante may be said to have rediscovered the Platonic mystery, whereby
love is an initiation into the secrets of the spiritual world. 57
Symonds, 90, https://books.google.com/books?id=K4sTAQAAIAAJ&dq=Symonds
Renaissance in Italy 1881&pg=PA90 58
Dante. Inferno, Canto 5.127–42. In La Divina Commedia. Inferno, ed. by Ettore Zolesi
(Rome: Armando, 2009), 124–25. 7. The Ladder of Love in Italian Poetry and Prose […] In
proportion as Beatrice personified abstractions, she ceased to be a
woman even for her lover; nor was it possible except by diminishing
her individuality, to regard her as a symbol, of the universal. She passed
from the sphere of the human into the divine.57 One of the most outstanding examples of Dante’s sublimation of love into
a spiritual value is found, not in his sonnets, but in his epic. In Inferno,
Dante rehearses the then-already-famous story of the lovers Paolo and
Francesca. Brought together by the circumstances of an arranged
marriage between Francesca da Rimini and Paolo’s brother Gianciotto
de Malatesta, the lovers carried on an affair for years before getting
caught in the bedroom by Gianciotto, who stabs them to death, affixing
them both on his sword at the same time. As Dante’s pilgrim is guided
through Hell by Virgil, he encounters Francesca, who tells her story: “Noi leggiavamo un giorno per diletto
di Lancialotto come amor lo strinse;
soli eravamo e sanza alcun sospetto. Per più fiate li occhi ci sospinse
quella lettura, e scolorocci il viso;
ma solo un punto fu quel che ci vinse. Quando leggemmo il disiato riso
esser basciato da cotanto amante, 320 Love and its Critics questi, che mai da me non fia diviso,
la bocca mi basciò tutto tremante. Galeotto fu ‘l libro e chi lo scrisse:
quel giorno più non vi leggemmo avante”. Mentre che l’uno spirto questo disse,
l’altro piangea; sì che di pietade
io venni men così com’io morisse. E caddi come corpo morto cade.58 “We were reading, one day, to our delight,
Of Lancelot, held tightly by love;
We were alone, without doubt or suspicion. Many times, our eyes were drawn together
By that reading, and the color left our faces:
But one point only had defeated us. When we read of the longed-for lips
Being kissed by the happy lover,
He, from whom may I never be parted,
Kissed me, trembling, on the mouth. A Galahad was the book and its author,
But that day we read no further”. While the one spirit said this,
The other wept, and from pity
I grew sick, as if to die,
And I fell as a dead body falls. “We were reading, one day, to our delight,
Of Lancelot, held tightly by love;
We were alone, without doubt or suspicion. 7. The Ladder of Love in Italian Poetry and Prose Many times, our eyes were drawn together
By that reading, and the color left our faces:
But one point only had defeated us. When we read of the longed-for lips
Being kissed by the happy lover,
He, from whom may I never be parted,
Kissed me, trembling, on the mouth. A Galahad was the book and its author,
But that day we read no further”. While the one spirit said this,
The other wept, and from pity
I grew sick, as if to die,
And I fell as a dead body falls. Dante is playing a sly game of poetic sleight-of-hand here. As so often
in the vidas, the imaginative biographies of the troubadours, the costs
of passion between two people who choose each other in the face of
law, marriage, church, and other institutional impediments, can be
enormous. Viewed from that perspective, Dante has written, in this
scene with Francesca, the most devastatingly romantic vida of them all. But from the perspective of those Dantean poems which regard love as
a vehicle for disembodied sublimation and worship, Dante has given
Paolo and Francesca the most lasting of punishments for having dared
to love each other rather than God, for having dared to be devoted 7. The Ladder of Love in Italian Poetry and Prose 321 to each other rather than to the laws, codes, and expectations of their
time and place. They will spend an eternity in Hell, suffering infinite
punishment for a finite period of human sin, at the hands of a God who
also arranges for them to regret and weep eternally over the love they
had shared. 62
“questa donna libresca, questa creatura cartecea, che proietta sul pellegrino le
ombre della propria ambivalenza morale, sembra disegnata su antichi cartoni
[…] nella preistoria poetica della Commedia” (Antonio Enzo Quaglio. Al di là di
Francesca e Laura [Padova: Liviana Editrice, 1973], 29). 59
Barbara Reynolds. Dante: The Poet, the Political Thinker, the Man (London: I. B.Tauris,
2007), 135. 61
Elspeth Kennedy. “The Rewriting and Re-reading of a Text: The Evolution of the
Prose Lancelot”. In Alison Adams, Armel H. Diverres, and Karen Stern, eds. The
Changing Face of Arthurian Romance: Essays on Arthurian Prose Romance in Memory of
Cedric E. Pickford (Cambridge, UK: Brewer, 1986), 9. 60
“una Bovary del Duecento, che sogna i baci di Lancillotto, e fruisce, in tragica
riduzione, degli abbracciamenti del cognate” (Edoardo Sanguineti. Il Realismo di
Dante [Florence: Sansoni, 1966], 28). 7. The Ladder of Love in Italian Poetry and Prose Greater
than all the Inferno’s scenes of torture and pain, greater even than the
agony of Count Ugolino, who will spend eternity chewing on the bloody
skull of his most hated rival, the passion and punishment of Paolo and
Francesca walks a tightrope between fascination and condemnation,
between the old attitudes of the troubadours, and the new dispensation
in which love will be disembodied, tamed, and turned toward the very
God who sentences human beings to an eternity of agony for a finite
lifetime of human “error”, a God whom Dante describes in the final line
of Paradiso, as l’amor che move il sole e l’altre stelle, the love that moves the
sun and the other stars. From fin’amor, we have now come to the kind of
amor that consigns lovers to Hell and torment forever. But far from being the conventionally moral tale that satisfies the
instincts of the moral scolds within academia (or the moral scold within
Dante himself), the speech of Francesca da Rimini powerfully illustrates
the immorality at the heart of the Christian myth, and the shocking
cruelty of the “moral” codes that take their inspiration from it. Greater
than all the Inferno’s scenes of torture and pain, greater even than the
agony of Count Ugolino, who will spend eternity chewing on the bloody
skull of his most hated rival, the passion and punishment of Paolo and
Francesca walks a tightrope between fascination and condemnation,
between the old attitudes of the troubadours, and the new dispensation
in which love will be disembodied, tamed, and turned toward the very
God who sentences human beings to an eternity of agony for a finite
lifetime of human “error”, a God whom Dante describes in the final line
of Paradiso, as l’amor che move il sole e l’altre stelle, the love that moves the
sun and the other stars. From fin’amor, we have now come to the kind of
amor that consigns lovers to Hell and torment forever. Less famously, but perhaps even more astoundingly, the forced
Christianizing of the poetic tradition, and the shoehorning of the
troubadours into the new, spiritualized poetry of love, is nowhere
made more evident than in Dante’s treatment of Arnaut Daniel, the poet
among the troubadours whom he most admired. 63
Mary-Kay Gamel. “This Day We Read Further: Feminist Interpretation and the
Study of Literature”. Pacific Coast Philology, 22: 1–2 (November 1987), 8.
64
“Arnaut se vante de réaliser l’impossible” (René Lavaud, in Daniel, 134). 7. The Ladder of Love in Italian Poetry and Prose As far as some literary critics are concerned, this is all to the good, for
such lovers, in the eyes of our rigid moralists, deserve to be punished,
and tormented for eternity: Barbara Reynolds argues that Dante puts
Francesca in hell “for a reason; [her words] are a key to her character, as
is her use of poetry to justify her adultery and of Arthurian romance to
blame for its influence”.59 Edoardo Sanguineti condemns Francesca as
“a [Madame] Bovary of the thirteenth century, who dreams of kissing
Lancelot, and who enjoys, in tragic reduction, the embraces of her
brother-in-law”.60 Elspeth Kennedy blames not only poor moral choices
but also faulty reading habits for Paolo and Francesca’s consignment
to an eternity of torment: “If Paolo and Francesca had read the whole
of the cyclic romance, they too might have seen the kiss of Lancelot
and Guinevere in a different way and resisted their own desire to
imitate it”.61 Antonio Enzo Quaglio dismisses Francesca as an immoral
dilettante, who should have left reading to her moral betters, sneering at
“this bookish woman, this creature of print, [who,] projecting shadows
on the pilgrim’s own moral ambivalence, seems drawn as an ancient
cartoon […] from the poetic prehistory of the Commedia”.62 And in a
move so dismissive it reads as high comedy, Mary Kay-Gamel reduces
Francesca and her eternal torment to the (apparently deserved) agonies
of a failed graduate student: 322 Love and its Critics Francesca is not a well-trained student of literature. She doesn’t finish
the work, she misremembers an important detail (Guinevere kisses
Lancelot, not vice versa), she is guilty of the intentional fallacy, and her
interpretation is entirely too mimetic. If she had read further, she would
have discovered how grave, in emotional and spiritual terms, were the
consequences of Lancelot and Guinevere’s illicit love, and she might have
acted differently. Francesca is a female reader who does not adequately
question the object of her reading, the method she uses to read, and the use
to which she puts her reading.63 But far from being the conventionally moral tale that satisfies the
instincts of the moral scolds within academia (or the moral scold within
Dante himself), the speech of Francesca da Rimini powerfully illustrates
the immorality at the heart of the Christian myth, and the shocking
cruelty of the “moral” codes that take their inspiration from it. y
f
gy,
(
),
64
“Arnaut se vante de réaliser l’impossible” (René Lavaud, in Daniel, 134). 65
Dante. Purgatorio, Canto 26.139–48. In La Divina Commedia. Purgatorio, ed. by Ettore
Zolesi (Rome: Armando, 2003), 428–29. 7. The Ladder of Love in Italian Poetry and Prose In Purgatorio, “Arnaut
boasts of achieving the impossible”,64 while Dante has the troubadour
speak as though he regrets his life and work, and looks forward only to
being fully purged of his sin as he ascends toward God: 323 7. The Ladder of Love in Italian Poetry and Prose 7. The Ladder of Love in Italian Poetry and Prose Tan mabellis vostre cortes deman,
qu’ieu no me puesc ni voill a vos cobrire. Ieu sui Arnaut, que plor e vau cantan;
consiros vei la passada folor,
e vei jausen lo joi qu’esper, denan. Ara vos prec, per aquella valor
que vos guida al som de l’escalina,
sovenha vos a temps de ma dolor!65 I am so pleased by your courteous question,
That I am not able or willing to hide from you. I am Arnaut, who goes weeping in song;
Grieving, I look back on my past folly,
And I foresee with joy the hope before me. So now I beg you, by that brave merit
That guides you to the summit of the stairway,
Remember, when the time comes, my sorrow. In the eloquence and economy of this gesture, and in the pathos of the
scene, a reader may miss the enormity of what Dante has just done. He
has reduced an entire world, an entire language, an entire way of life, an
entire experience of love and delight to the status of benighted sin. And
though he could not bring himself to condemn to Hell the poet he so
admired (whom he has another of his heroes, Guinizelli, describe as “the
greater maker” (“il miglior fabbro”), he reduces him to a mouthpiece for
the newly-ascendant orthodoxy of an Inquisition-era Roman Church. In this moment, and through this gesture, Dante—among the greatest
poets our world has ever seen, or will ever see—climbs his mountain
of Purgatory, and the new literary mountain of the dolce stil novo, as a
traitor to poetry. At the peak of this new literary mountain, we find the later figure
of Petrarch. Though he is one of the towering figures in the Western
literary tradition, Petrarch is not a solitary genius who establishes a
new poetic point of view, creating ex nihilo a poetic form that had not
existed before. His original contribution is more evident in terms of
emphasis than form: it is not the choice to write about love, sublimated Love and its Critics 324 into a passion for heaven, but rather to make the subject of sublimated,
spiritualized love the dominant focus of his verse, and to change the
vocabulary of love poetry. 66
Neal L. Goldstien. “Love’s Labour’s Lost and the Renaissance Vision of Love”. In
Stephen Orgel and Sean Kellen, eds. Shakespeare and the Literary Tradition (London:
Routledge, 1999), 205.
67
“vostr’ occhi, Donna, mi legaro” (Francesco Petrarca. Il Canzoniere, ed. by Paola
Vecchi Galli [Milan: Rizzoli, 1954], 3.4). All further references to Petrarch’s
Canzionere will be to this volume.
68
“Trovommi Amor del tutto disarmato, / et aperta la via per gli occhi al core, / che di
lagrime son fatti uscio et varco” (ibid., 3.9–11).
69
Ibid., 11.5–11. 66
Neal L. Goldstien. “Love’s Labour’s Lost and the Renaissance Vision of Love”. In
Stephen Orgel and Sean Kellen, eds. Shakespeare and the Literary Tradition (London:
Routledge, 1999), 205. 68
“Trovommi Amor del tutto disarmato, / et aperta la via per gli occhi al core, / che di
lagrime son fatti uscio et varco” (ibid., 3.9–11). 67
“vostr’ occhi, Donna, mi legaro” (Francesco Petrarca. Il Canzoniere, ed. by Paola
Vecchi Galli [Milan: Rizzoli, 1954], 3.4). All further references to Petrarch’s
Canzionere will be to this volume. 69
Ibid., 11.5–11. 70
Ibid., 12.1.
71
Ibid., 12.5–8.
72
“I’ benedico il loco e ‘l tempo et l’ora / che sí alto miraron gli occhi mei” (ibid.,
13.5–6).
73
Ibid., 36.1–4. 7. The Ladder of Love in Italian Poetry and Prose “Petrarch effected the first major stage in
the spiritualization of love and beauty through his insistence upon the
spiritual nature of womanly beauty—he contributed, as well, a unique
vocabulary which permeates most of the love poetry which follows his:
the beloved as tormenter, [and] the lover as sufferer”.66 Much of the imagery and point of view in Petrarch’s poetry is similar
to what we have already seen. The idea of personified love appears
first in Sonnet 3: captured and unable to defend himself because “your
eyes, lady, had bound me”,67 Petrarch’s narrator complains that “Love
found me altogether disarmed / and opened the way to the heart
through my eyes / which have become the doors and gates of tears”.68
Captured by Love, and bound by the eyes of the “lady” the reader
will soon know as Laura, Petrarch’s poetic voice grows increasingly
pained and desperate. In Sonnet 11 it begins to appear evident this
love is not returned. In fact his expression of love gets in the way and
makes the beloved weary of him: Mentr’io portava i be’ pensier’ celati,
ch’ànno la mente desïando morta,
vidivi di pietate ornare il volto;
ma poi ch’Amor di me vi fece accorta,
fuor i biondi capelli allor velati
et l’amoroso sguardo in sé raccolto. Quel ch’i’ piú desiava in voi m’è tolto.69 While I kept my loving thoughts hidden,
that brought my mind to wish for death,
I beheld Pity’s face adorned;
but when Love made you notice me, While I kept my loving thoughts hidden,
that brought my mind to wish for death,
I beheld Pity’s face adorned;
but when Love made you notice me, 325 7. The Ladder of Love in Italian Poetry and Prose ,
72
“I’ benedico il loco e ‘l tempo et l’ora / che sí alto miraron gli occhi mei” (ibid.,
13.5–6).
73
Ibid., 36.1–4. 7. The Ladder of Love in Italian Poetry and Prose you hid your blond hair behind a veil,
and drew back your loving gaze. What I wanted most in you, he took from me. Sonnet 12 describes his life as one of “bitter torment” (“l’aspro
tormento”)70 that might yet afford him the opportunity to gaze once
more upon: cape’ d’oro fin farsi d’argento,
et lassar le ghirlande e i verdi panni,
e ‘l viso scolorir che ne’ miei danni
a llamentar mi fa pauroso et lento71 a head of golden hair spun like silver,
and the garlands laid by and green cloth,
and your pale face that wounds me
making my lamentations slow and fearful. At other, more optimistic moments, Petrarch’s narrator is less pained
by than grateful for the opportunity to worship his beloved from afar:
“I bless the place, the time and the hour / that brought so high the
gazing of my eyes”.72 But more often, it is pain that characterizes love
in Petrarch’s verse. Sonnet 36 meditates on the possibility of escaping
this agony by dying: S’io credesse per morte essere scarco
del pensiero amoroso che m’atterra,
colle mie mani avrei già posto in terra
queste mie membra noiose, et quello incarco.73 If I believed that by death I could be released
from amorous thoughts that bind me to earth,
with my hands I would already have buried
these my tiresome limbs, and that burden If I believed that by death I could be released
from amorous thoughts that bind me to earth,
with my hands I would already have buried
these my tiresome limbs, and that burden 326 Love and its Critics But by Sonnet 90, Petrarch is reliably trading on the imagery of earlier
poets like Guinizelli, Colonne, and Dante, including the kinds of
objectification and idealisation that will be a staple of the English poets
who model themselves after Petrarch in the sixteenth century: Non era l’andar suo cosa mortale,
ma d’angelica forma; et le parole
sonavan altro che pur voce humana:
uno spirito celeste, un vivo sole
fu quel ch’i’ vidi; et se non fosse or tale,
piagha per allentar d’arco non sana.74 The way she moved was not a mortal thing,
but in the form of the angels, and her speech
soared higher than any human voice. 75
https://commons.wikimedia.org/wiki/File:Affresco_di_Petrarca_e_Laura,_Casa_
del_Petrarca_(Arquà_Petrarca).JPG?uselang=en-gb 74
Ibid., 90.9–14. 77
“un laccio che di seta ordiva” (ibid., 106.5). 78
“sí dolce lume uscia degli occhi suoi” (ibid., 106.8). 76
“Nova angeletta sovra l’ale accorta” (ibid. 106.1).
l
h d
d
b d 7. The Ladder of Love in Italian Poetry and Prose A celestial spirit, a living sun
was what I saw there; if she is no longer so,
my wound, though the bow be slack, will not heal. Like his predecessors, Petrarch does not write of love for a woman. He
writes of passion incited by an object in female form, whose embodied
reality he is all too ready to transform into a living goddess. Petrarch and Laura. Fresco in Petrarch’s house in Arquà Petrarca.75 Petrarch and Laura. Fresco in Petrarch’s house in Arquà Petrarca.75 7. The Ladder of Love in Italian Poetry and Prose 79
Ibid., 121.1–9. 79
Ibid., 121.1–9. 76
“Nova angeletta sovra l’ale accorta” (ibid. 106.1).
77
“un laccio che di seta ordiva” (ibid., 106.5).
78
“sí dolce lume uscia degli occhi suoi” (ibid., 106.8).
79
Ibid., 121.1–9. ,
81
This idea of the woman’s ability to kill her lover by failing to return his affections is
already present in Le Roman de la Rose, where they are warned that God will punish
them for cruelty: “Ladies, learn from this example, / those of you who mistreat
your lovers, / for if you let them die, / God will know well how to repay you”
(“Dames, cest essample aprenez, / qui vers vos amis mesprenez; / car se vos les
lessiez morir, / Dex le vos savra bien merir”) (Vol. 1, l. 1505–08). 82
“‘l dolce sguardo di costei m’ancide / et le soavi parolette accorte” (Francesco
Petrarca. Il Canzoniere. 183.1–2). 7. The Ladder of Love in Italian Poetry and Prose 327 The same transformation is evident in Sonnet 106, where the poet’s
beloved is “a new little angel on graceful wings”,76 who captures the
poet in “a silk-woven net”,77 while “a sweet light issued forth from her
eyes”.78 In Sonnet 121 we see the now-familiar idea that the beloved
is haughty for not returning love. In this case, the beloved should be
punished by Love for this failure: Or vedi, Amor, che giovenetta donna
tuo regno sprezza e del mio mal non cura,
e tra duo ta’ nemici è sì secura. Tu se’ armato, et ella in treccie e ‘n gonna
si siede, e scalza, in mezzo i fiori e l’erba,
vèr’ me spietata, e ‘n contra te superba. I’ son pregion; ma se pietà ancor serba
l’arco tuo saldo, e qualcuna saetta,
fa di te, e di me, signor, vendetta.79 Now see, Love, how this young lady
despises your rule, cares not for my pain,
and between two enemies is so secure. You are in arms, and she in tresses and gown
sits barefoot amidst flowers and the grass,
without pity for me, set against you in pride. I am in prison, but if some mercy still keeps
your bow strong, with a few arrows,
for yourself and me, my Lord, take revenge. The popular image of Petrarch is that of the long-suffering lover who
pines with desire, but a recurring feature of his poetry is resentment. The lover in his poems expresses resentment over the refusal of the
beloved to love in return, and expresses the desire that the beloved be
made to pay for this. 328 Love and its Critics Sonnets 133 and 183 are similar expressions of another common idea:
the lover is wounded by the experience of love and by the mere glance of
the beloved. In Sonnet 133, the beloved is blamed for failing to have mercy: […] son già roco,
donna, mercé chiamando, e voi non cale. 80
Ibid., 133.3–8. 83
Ibid., 183.12–14. 84
Ibid., 364.1–4.
85
“Trionfo della Divinita, Capitolo Unico”. ll. 140–45. In Triunfi, ed. by Cristoforo
Pasqualigo (Venezia: Giuseppe Bresciani, 1874), 116, https://books.google.com/
books?id=5_0FAAAAQAAJ&pg=PA115 84
Ibid., 364.1–4. 7. The Ladder of Love in Italian Poetry and Prose Da gli occhi vostri uscìo ‘l colpo mortale,
contra cui non mi val tempo né loco;
da voi sola procede, e parvi un gioco,
il sole e ‘l foco e ‘l vento ond’io son tale.80 […] I am already hoarse,
lady, from begging mercy, and you disregard me
From your eyes issued the mortal blow
from which I’ve no help, not time or place;
from you all proceeds, and you think it a joke,
the sun, fire, and wind that make me so. In Sonnet 183, the beloved can kill the poet with the merest look,81 for “that
sweet glance of hers can kill me, / and her gentle shrewd little words”,82
and women in general are berated for being unreliable and fickle in love: Femina è cosa mobil per natura;
ond’io so ben ch’un amoroso stato
in cor di donna picciol tempo dura.83 A woman is changeable by nature;
And I know well that love’s state
in the heart of a lady lasts but a short time. A woman is changeable by nature;
And I know well that love’s state
in the heart of a lady lasts but a short time. A woman is changeable by nature; And I know well that love’s state 7. The Ladder of Love in Italian Poetry and Prose She was merely a rung
on the ladder of love for the poet to climb. 7. The Ladder of Love in Italian Poetry and Prose 7. The Ladder of Love in Italian Poetry and Prose 329 As Petrarch’s sequence of poems nears its end, it becomes evident that
the beloved Laura is now dead. Sonnet 364 makes reference to having
been held, “burning”, for “twenty-one years” before her death: Tennemi Amor anni vent’uno ardendo,
lieto nel foco, e nel duol pien di speme;
poi che madonna e ‘l mio cor seco inseme
saliro al ciel, dieci altri anni piangendo.84 Love held me burning twenty-one years,
happy in the fire, in my grief, full of hope;
then, when my lady took my heart with her
rising to Heaven, another ten years crying. As the lover asks to be released by God, it is distressingly clear that
the thirty-one years of focus testified to by the poems were not spent
meditating upon an individual in a relationship of mutual choice,
passion, and regard. Those years were spent instead in something like
worship, not of an individual, but of a paragon, an idol, or a goddess. By
the end of Petrarch’s less-famous collection, the Triunfi, the poet looks to
Laura as a promise of heaven itself: Amor mi diè per lei sì lunga guerra
che la memoria ancora il cor accenna. Felice sasso che ‘l bel viso serra! ché, poi ch’avrà ripreso il suo bel velo,
se fu beato chi la vide in terra,
or che fia dunque a rivederla in cielo?85 Love gave to me for her so long a war
that the memory still marks my heart. Happy the stone that covers her face! For now that she has resumed her beautiful veil,
if he was blessed who saw her on Earth,
What will it be to see her again in heaven? Love gave to me for her so long a war
that the memory still marks my heart. Happy the stone that covers her face! For now that she has resumed her beautiful veil,
if he was blessed who saw her on Earth,
What will it be to see her again in heaven? Love and its Critics 330 Beautiful but unattainable, the beloved Laura of Petrarch’s poems
serves as a passion-drenched metaphor, a stairway to heaven, salvation,
and God. She was never loved as a woman, at least not by Petrarch. She
was an object, not a subject, a means, not an end. 86
Hagstrum, 300. III
Post-Fin’amor Italian Prose: Il Libro del Cortegiano
(The Book of the Courtier) As we can see in Il Libro del Cortegiano, by the Italian courtier and
author Baldassarre Castiglione, Diotima’s ladder of love becomes a
powerful inspiration to the thinking of the Italian literati. Written some
time after 1507 (the year during which its conversations take place),
and first published in 1528, it is a relatively late, though still useful,
encapsulation of Neoplatonic thought in the Italian Renaissance. For the
English Renaissance, however, it arrived right on time. First translated
into English by Thomas Hoby in 1561, The Book of the Courtier became
enormously influential on English literature. In the work’s famous final
section, the main speaker is an actual Italian courtier named Pietro
Bembo, who was thirty-seven years old at the time of the writing. When
Bembo describes the difference between the young and old courtiers, it
is important to remember that the old Courtier is still relatively young,
and that he is speaking from the perspective of high Neoplatonism. Bembo is at pains to define love as a spiritual and idealized force
corrupted by its association with human bodies and physical beauty. Already, we can see how forceful is the retreat from the frank eroticism
and individualism of troubadour poetry: [A]fter a steady dialectical movement that respects man and woman, soul
and body, the humanist and Neoplatonist Pietro Bembo’s climactically
placed hymn to love turns out to be another grand evasion of the human
and an exaltation of angelic beauty and virtue in the tradition of Dante
[and] Petrarch.86 7. The Ladder of Love in Italian Poetry and Prose 331 For Bembo’s ideal courtier, sexual passion and the love of an individual
woman is dangerous, something that needs to be tightly reined in by
the firm hand of philosophy, and this is why he says of courtiers that
“the old can not only love without blame, but more happily than the
young”.87 By “the young”, he means boys of an age with Shakespearean
teenagers such as Romeo, Lysander, and Valentine. For Bembo, a
man in his mid-thirties can love more happily than a boy in his mid-
teens because young men lack the capacity Bembo assumes he has—a
capacity to resist physical and emotional desires and redirect them onto
something like a sacred path. 87
“i vecchi possano non solamente amar senza biasimo, ma talor più felicemente che i
giovani” (Baldassarre Castiglione. Il Libro del Cortegiano [Milano: Giovanni Silvestri,
1822], 448, https://archive.org/stream/illibrodelcorteg00cast#page/448
88
“amar fuor della consuetudine del profano vulgo” (ibid., 462, https://archive.org/
stream/illibrodelcorteg00cast#page/462).
89
il Cortegiano, sentendosi preso, deliberarsi totalmente di fuggir ogni bruttezza dell’amor
vulgare, e così entrar nella divina strada amorosa con la guida della ragione; e prima considerar
che’l corpo, ove quella bellezza risplende, non è il fonte ond’ella nasce; anzi che la bellezza, per
esser cosa incorporea, e (come avemo detto) un raggio divino, perde molto della sua dignità
trovandosi congiunta con quel subietto vile e corruttibile perchè tanto più è perfetta, quanto
men di lui participa e da quello in tutto separata è perfettissima.
Ibid., 463, https://archive.org/stream/illibrodelcorteg00cast#page/463 87
“i vecchi possano non solamente amar senza biasimo, ma talor più felicemente che i
giovani” (Baldassarre Castiglione. Il Libro del Cortegiano [Milano: Giovanni Silvestri,
1822], 448, https://archive.org/stream/illibrodelcorteg00cast#page/448 88
“amar fuor della consuetudine del profano vulgo
stream/illibrodelcorteg00cast#page/462). 89
il Cortegiano, sentendosi preso, deliberarsi totalmente di fuggir ogni bruttezza dell’amor
vulgare, e così entrar nella divina strada amorosa con la guida della ragione; e prima considerar
che’l corpo, ove quella bellezza risplende, non è il fonte ond’ella nasce; anzi che la bellezza, per
esser cosa incorporea, e (come avemo detto) un raggio divino, perde molto della sua dignità
trovandosi congiunta con quel subietto vile e corruttibile perchè tanto più è perfetta, quanto
men di lui participa e da quello in tutto separata è perfettissima.
Ibid., 463, https://archive.org/stream/illibrodelcorteg00cast#page/463 III
Post-Fin’amor Italian Prose: Il Libro del Cortegiano
(The Book of the Courtier) This will enable foolish young men
to become wise courtiers, who know how “to love outside the custom
of the profane [and] vulgar”,88 by turning their attention away from
beautiful individuals to Beauty itself: The Courtier, feeling caught, must get rid of every ugliness and totally
escape vulgar love, and so enter into the divine way of love with the
guidance of reason; and first consider that the body in which that beauty
shines, is not the source from which it is born; indeed that beauty is an
incorporeal thing, and (as we have said) a divine ray, and it loses much
of its dignity being combined with that vile and corruptible subject,
because it is the more perfect, the less it participates in matter, and it is
most perfect, when entirely separate.89 With this sense of the vileness of the flesh established, the rest of the
Courtier’s mental and emotional journey is a sequential and upward
bound chain: “remove from yourself the blind judgment of sense […] With this sense of the vileness of the flesh established, the rest of the
Courtier’s mental and emotional journey is a sequential and upward
bound chain: “remove from yourself the blind judgment of sense […] Love and its Critics 332 and love her no less for the beauty of her soul than of her body”.90 The
point is to “devour sweet food for his soul […] without going to the
body with appetites anything less than honest”.91 And while loving the
beauty of the soul is a wonderful thing, that love takes on an oddly
pedagogical tone, for the Courtier must become the moral instructor of
the woman who has inspired him with the passion he is trying to deny
in himself by turning it to “higher” purposes: But let him be careful not to let her run into some error, but with
admonitions and good reminders always try to induce in her modesty,
temperance, true honesty; and be sure that in her mind there come to
be no thoughts but those that are candid and alien to all ugliness and
vice; and thus spreading virtue in the garden of her soul, he will reap
beautiful fruits, and taste them with wonder and delight; and this will be
the true generation and expression of beauty in beauty, which is said by
some to be the purpose and purity of love.92 This directly echoes Pausanius’ speech on the Heavenly and Earthly
Aphrodites in the Symposium. III
Post-Fin’amor Italian Prose: Il Libro del Cortegiano
(The Book of the Courtier) What the Romeos of the world have to do (according to Bembo) is
learn how to transcend the love engaged in by ordinary people who
adore what is right in front of them. 90
“Rimovasi adunque dal cieco giudizio del senso […] e in lei ami non meno la
bellezza dell’animo, che quella del corpo” (ibid., 463–64, https://archive.org/stream/
illibrodelcorteg00cast#page/463).
91
“pascerà di dolcissimo cibo l’anima […] senza passar col desiderio verso il corpo ad
appetito alcuno men che onesto” (ibid., 464, https://archive.org/stream/illibrodelcor
teg00cast#page/464).
92
però tenga cura di non lasciarla incorrere in errore alcuno, ma con le ammonizioni e buoni
ricordi cerchi sempre d’ indurla alla modestia, alla temperanza, alla vera onestà; e faccia che
in lei non abbian mai luogo se non pensieri candidi e alieni da ogni bruttezza di vizi; e cosi
seminando virtù nel giardìn di quel bell’animo, raccorrà ancora frutti di bellissimi costumi,
e gusteragli con mirabil diletto; e questo sarà il vero generare, ed esprimere la bellezza nella
bellezza, il che da alcuni si dice esser il fin d’amore.
Ibid., 464, https://archive.org/stream/illibrodelcorteg00cast#page/464 90
“Rimovasi adunque dal cieco giudizio del senso […] e in lei ami non meno la
bellezza dell’animo, che quella del corpo” (ibid., 463–64, https://archive.org/stream/
illibrodelcorteg00cast#page/463). 91
“pascerà di dolcissimo cibo l’anima […] senza passar col desiderio verso il corpo ad
appetito alcuno men che onesto” (ibid., 464, https://archive.org/stream/illibrodelcor
teg00cast#page/464). g
p g
92
però tenga cura di non lasciarla incorrere in errore alcuno, ma con le ammonizioni e buoni
ricordi cerchi sempre d’ indurla alla modestia, alla temperanza, alla vera onestà; e faccia che
in lei non abbian mai luogo se non pensieri candidi e alieni da ogni bruttezza di vizi; e cosi
seminando virtù nel giardìn di quel bell’animo, raccorrà ancora frutti di bellissimi costumi,
e gusteragli con mirabil diletto; e questo sarà il vero generare, ed esprimere la bellezza nella
bellezza, il che da alcuni si dice esser il fin d’amore.
Ibid., 464, https://archive.org/stream/illibrodelcorteg00cast#page/464 93
“essa sempre se gli mostrerà ossequente, dolce e affabile, e così desiderosa di
compiacergli, come d’esser da lui amata; e le voglie dell un e dell’altro saranno
onestissime e concordi; ed essi conseguentemente saranno felicissimi” (ibid., 464,
https://archive.org/stream/illibrodelcorteg00cast#page/464). 94
perchè per essere il bacio congiungimento e dei corpo e dell’anima, pericolo è che l’amante
sensuale non inclini più alla parte dei corpo, che a quella dell’anima, ma l’a mante razionale
conosce che ancora che la bocca sia parte del corpo, nientedimeno per quella si dà esito alle
parole, che sono interpreti dell’anima, […] e perciò si diletta d’unir la sua bocca con quella della
donna amata col bacio, non per moversi a desiderio alcuno disonesto, ma perchè sente che
quello legame è un aprir l’adito alle anime, che tratte dal desiderio l’una dell’altra si trasfondono
alternamente ancor l’una nel corpo dell’altra […] il bacio si può più presto dir congiungimento
d’anima, che di corpo; perchè in quella ha tanta forza, che la tira a sé, e quasi ìa separa dal corpo;
per questo tutti gì’ innamorati casti desiderano il bacio, come congiungimento d’anima.
Ibid., 466–67, https://archive.org/stream/illibrodelcorteg00cast#page/466 93
“essa sempre se gli mostrerà ossequente, dolce e affabile, e così desiderosa di
compiacergli, come d’esser da lui amata; e le voglie dell un e dell’altro saranno
onestissime e concordi; ed essi conseguentemente saranno felicissimi” (ibid., 464,
https://archive.org/stream/illibrodelcorteg00cast#page/464).
94
perchè per essere il bacio congiungimento e dei corpo e dell’anima, pericolo è che l’amante
sensuale non inclini più alla parte dei corpo, che a quella dell’anima, ma l’a mante razionale
conosce che ancora che la bocca sia parte del corpo, nientedimeno per quella si dà esito alle
parole, che sono interpreti dell’anima, […] e perciò si diletta d’unir la sua bocca con quella della
donna amata col bacio, non per moversi a desiderio alcuno disonesto, ma perchè sente che
quello legame è un aprir l’adito alle anime, che tratte dal desiderio l’una dell’altra si trasfondono
alternamente ancor l’una nel corpo dell’altra […] il bacio si può più presto dir congiungimento
d’anima, che di corpo; perchè in quella ha tanta forza, che la tira a sé, e quasi ìa separa dal corpo;
per questo tutti gì’ innamorati casti desiderano il bacio, come congiungimento d’anima.
Ibid., 466–67, https://archive.org/stream/illibrodelcorteg00cast#page/466 III
Post-Fin’amor Italian Prose: Il Libro del Cortegiano
(The Book of the Courtier) For Pausanius, as for Bembo, the higher
love revolves around education and development of the capacities—
moral, intellectual, ethical—of the beloved (though for Pausanius, the
beloved is a young male rather than Bembo’s young female). While the
male is to be the patient, reason-driven teacher, the female is to be the
pliant and willing pupil: she always will show herself obedient and respectful, sweet and affable,
and as eager to please him, as to be loved by him; and the desires of each bid., 464, https://archive.org/stream/illibrodelcorteg00cast#page/464 7. The Ladder of Love in Italian Poetry and Prose 333 Love and its Critics Through Peter Bembo’s speech, Castiglione repeatedly makes the
point that love of an individual, appreciation for human beauty and
erotic attraction are impure and degraded forms of love,95 which the
Courtier is wise to reject in favor of Beauty itself: To escape torment, then, and enjoy beauty without passion, it is necessary
that the Courtier, with the help of reason, revokes entirely his desire to
enjoy beauty in the body, and, as much as he can, meditates on beauty
as something simple and pure, and in the imagination abstract its form
from matter, making it friendly and dear to his soul, and there enjoy
it, keeping it day and night, in any time and place without ever losing
it; always remembering that the body is something very different from
beauty, and not only does not increase it, but decreases its perfection.96 For the Courtier who is well-instructed and who governs his passions
appropriately, love leads beyond the mortal and fleshly beloved,
directly to God: Therefore, we must direct all the thoughts and powers of our souls to
this most holy light that shows us the way that leads to heaven, and
following it, strip off the affects in which we were dressed as we fell,
and by the lowest rung on the ladder that bears the image of sensual 95
There are voices that oppose this notion at the time. One especially notable example
can be found in the work of Tullia d’Aragona, in her Dialogo dell’infinità d’amore of
1547, where the eponymous character claims that erotic love is not to be blamed,
since it arises wholly from nature: At first I say, that I know well that of those things that we are by nature, we can be neither
blamed nor praised; and therefore, neither plants nor animals can be blamed or praised for such
love; neither should it be called lascivious, or dishonest in them, nor even in men. Al primo dico, che io so bene che di quelle cose, che ci vengono dalla natura, non possiamo
essere biasmati, né lodati; e perciò né nelle piante, né negli animali non si può biasmar cotale
amore; né in loro si chiama lascivo, o disonesto, né negli uomini ancora. Tullia d’Aragona. Dialogo della infinità d’amore (1547). In Della infinita d’amore dialogo
di Tullia D’Aragona (Milan: G. will be in harmony with those of the other; and consequently they will
both be happy.93 will be in harmony with those of the other; and consequently they will
both be happy.93 A great deal of Italian and English poetry plays with this notion of the
male who expects the female to be both “obedient” and “affable” where
the pedagogical efforts of his love are concerned, although he is often
disappointed in this regard. Bembo suggests that even kissing should be
regarded as part of this drive toward the spiritual and moral education
of both the male and the “obedient” female. The reasonable lover knows
that mouths are where speech comes from, which reflects rational
thoughts and interprets the soul. Kissing as an erotic act is, for Bembo,
something to be feared, but kissing as a spiritual act is something very
much to be desired: Because a kiss is the conjoining of body and soul, the danger is that the
sensual lover may be more inclined to the body, than to the soul, but
the rational lover knows that though the mouth is part of the body, it is
the source of words, which are interpreters of souls, […] and because of
this a man delights in bringing his mouth to the mouth of his beloved
lady, not for dishonest desires, but because he feels that the bond is a
transfusion of souls from one body to another […] the kiss, you could
say, is the union of souls instead of bodies; because it has so much force,
that it pulls the soul, and almost separates it from the body; which is why
all chaste lovers want a kiss, as a union of souls.94 Any physically-based passion is described as dishonest, filthy, a
distraction, so a kiss isn’t engaged for desire, nor does it raise any. The
kiss, when properly understood by the Courtier, does not take place at
the level of flesh, but points lovers upward on the ladder of love. 334 Love and its Critics 95
There are voices that oppose this notion at the time. One especially notable example
can be found in the work of Tullia d’Aragona, in her Dialogo dell’infinità d’amore of
1547, where the eponymous character claims that erotic love is not to be blamed,
since it arises wholly from nature:
At first I say, that I know well that of those things that we are by nature, we can be neither
blamed nor praised; and therefore, neither plants nor animals can be blamed or praised for such
love; neither should it be called lascivious, or dishonest in them, nor even in men.
Al primo dico, che io so bene che di quelle cose, che ci vengono dalla natura, non possiamo
essere biasmati, né lodati; e perciò né nelle piante, né negli animali non si può biasmar cotale
amore; né in loro si chiama lascivo, o disonesto, né negli uomini ancora.
Tullia d’Aragona. Dialogo della infinità d’amore (1547). In Della infinita d’amore dialogo
di Tullia D’Aragona (Milan: G. Daelli & Co., 1864), 67, https://archive.org/stream/
bub_gb_1FOekK6PUbsC#page/n103
96
Per fuggir adunque il tormento di questa assenza, e goder la bellezza senza passione, bisogna
che l Cortegiano con l’aiuto della ragione, revochi in tutto il desiderio dal corpo alla bellezza
sola, e, quanto più può, la contempli in sé stessa semplice e pura, e dentro nella im imaginazione
la formi astratta da ogni materia e così la faccia amica e cara all’anima sua, ed ivi la goda, e seco
l’abbia giorno e notte, in ogni tempo e luogo senza dubbio di perderla mai; tornandosi sempre
a memoria che l corpo è cosa diversissima dalia bellezza, e non solamente non le accresce, ma
le diminuisce la sua perfezione.
Castiglione, 469, https://archive.org/stream/illibrodelcorteg00cast#page/469 95
There are voices that oppose this notion at the time. One especially notable example
can be found in the work of Tullia d’Aragona, in her Dialogo dell’infinità d’amore of
1547, where the eponymous character claims that erotic love is not to be blamed,
since it arises wholly from nature: p
g
g
p g
98
“la donna bella, è il piu bello obietto che si rimiri: et la belleza è il maggior dono
che faceβe Iddio all humana creatura. Concio sia che per la di lei uirtù, noi ne
indiriziamo l’animo alla contemplatione, et per la contemplatione al desiderio delle
cose del Cielo” (Agnolo Firenzuola. “Belleza delle Donne”. In Prose di M. Agnolo
Firenzuola Fiorentino [Florence: Bernardo Guinta, 1548], 62, https://archive.org/
stream/bub_gb_hdGH5df6NxIC#page/n127). 97
Indrizziamo adunque tutti i pensieri e le forze dell’anima nostra a questo santissimo lume che
ci mostra la via che al ciel conduce, e drieto a quello, spogliandoci gli affetti che nei descendere
ci eravamo vestiti, per la scala che neìl’ infimo grado tiene l’ombra di bellezza sensuale,
ascendiamo alla sublime stanza ove abita la celeste, amabile e vera bellezza che nei secreti
penetrali di Dio sta nascosta, acciocché gli occhi profani veder non la possano.
Ibid 474 https://archive org/stream/illibrodelcorteg00cast#page/474 Ibid., 474, https://archive.org/stream/illibrodelcorteg00cast#page/474 Love and its Critics Daelli & Co., 1864), 67, https://archive.org/stream/
bub_gb_1FOekK6PUbsC#page/n103 96 Per fuggir adunque il tormento di questa assenza, e goder la bellezza senza passione, bisogna
che l Cortegiano con l’aiuto della ragione, revochi in tutto il desiderio dal corpo alla bellezza
sola, e, quanto più può, la contempli in sé stessa semplice e pura, e dentro nella im imaginazione
la formi astratta da ogni materia e così la faccia amica e cara all’anima sua, ed ivi la goda, e seco
l’abbia giorno e notte, in ogni tempo e luogo senza dubbio di perderla mai; tornandosi sempre
a memoria che l corpo è cosa diversissima dalia bellezza, e non solamente non le accresce, ma
le diminuisce la sua perfezione. Castiglione, 469, https://archive.org/stream/illibrodelcorteg00cast#page/469 7. The Ladder of Love in Italian Poetry and Prose 335 beauty, ascend to the sublime rooms where the heavenly, lovable, and
real beauty lives, secreted in the hidden chambers of God, so that the
profane eye cannot see it.97 In such thought the individual is valuable only in terms of its connection
to the universal. The beauty of an individual person is only of any
significance in that it points beyond that individual, serving as a symbol
for the universal concept of beauty. From this point of view, the body is a prison to be escaped from. For Bembo, a focus on the body distracts lovers from the holy way of
love dependent on reason, which leads them from the world of matter,
through the higher contemplative stages, on a spiritual approach to the
divine. As Agnolo Firenzuola expressed it in 1548: a beautiful woman is the most beautiful object you will ever see, and
beauty is the greatest gift God has given all human creatures; and
through its virtue, the soul is guided to contemplation, and through
contemplation to the desire of all the things of heaven.98 From this point of view, love is reason coupled with informed desire
for the highest beauty, the highest reality, for God himself. In short, for
the wise older Courtier, love is a spiritual exercise that is approached
through bodies that are left behind as soon as possible. 336 Love and its Critics 99
Maurice Scève. “Délie 439”. In I. D. McFarlane, ed. The Délie of Maurice Scève
(Cambridge: Cambridge University Press, 1966), 360. 100 Louise Labé. “Sonnet 16”. Oeuvres de Louise Labé, ed. by Prosper Blancheman
(Paris: Librarie des Bibliophiles, 1875), 124, https://books.google.com/books?id=
w_fl8BM3_SUC&pg=PA124 IV It was eventually in England that the troubadour spirit—quite nearly
destroyed by the ascendancy of the Inquisition in Europe—once again
found rich soil in which to take root and thrive. In a nation of “heretics”
the idea of human love was resurrected from the pious grave into which
Innocent III had tried to have it eternally immured. Ironically, the
Occitan poets disappeared quite nearly without a trace in France, where
Neopetrarchism took hold in the sixteenth-century work of, among
others, Maurice Scève and Louise Labé. Scève’s work, in ten-line units
called dizains, is thematically modeled after Petrarch’s Canzoniere, and
faithful to the traditions of Plato and Diotima: Bien que raison soit nourrice de l’ame,
Alimenté est le sens du doulx songe
De vain plaisir, qui en tous lieux m’entame,
Me penetrant, comme l’eau en l’esponge. Dedans lequel il m’abysme, & me plonge
Me suffocquant toute vigueur intime. Dont pour excuse, & cause legitime
Je ne me doibs grandement esbahir,
Si ma tressaincte, & sage Dyotime
Tousjours m’enseigne a aymer, & hair.99 Though reason is nursemaid to the soul,
The sweet power of my sensuous dreams
Of vain pleasure, follows me everywhere,
Penetrating me, like water in a sponge,
Thrusting and plunging me into the abyss,
Suffocating me in my inmost heart. This for excuse, although legitimate
Cannot amaze me or leave me in shock,
If my holy and wise Diotima
Still teaches me to love, and how to hate. 7. The Ladder of Love in Italian Poetry and Prose 7. The Ladder of Love in Italian Poetry and Prose 337 Labé, on the other hand, writes a Petrarchan style of verse that reverses
the typical gender roles of the genre: the voice of the lover who burns
unrequitedly is female, while the cruel and unforthcoming beloved is
male. In her sixteenth sonnet, Apres qu’un tems la gresle et le tonnere, she
laments what appears to be her lover’s sexual impotence: Après qu’un tems la gresle et le tonnerre
Ont le haut mont de Caucase batu,
Le beau jour vient, de lueur revêtu. Quand Phebus ha son cerne fait en terre,
Et l’Ocean il regaigne à grand erre,
Sa seur se montre avec son chef pointu. Quand quelque tems le Parthe ha combatu,
Il prent la fuite et son arc il desserre. Un tems fay vù et consolé pleintif,
Et defiant de mon feu peu hatif;
Mais, maintenant que tu m’as embrasée
Et suis au point auquel tu me voulois,
Tu as ta flame en quelque eau arrosée,
Et es plus froit qu’estre je ne soulois.100 After a time in which hail and thunder
Have beaten the top of Mount Caucasus,
A beautiful day comes, clothed again in light. When Phoebus encircles his land again,
And dives into the sea, his pale sister
Moves back into our view with pointed crown. When for too long the Parthian warrior fights,
He turns from his arc and loosens his bow. I consoled you once when I saw you sad,
And that aroused my long slow-burning fire;
But now that you have brought me to a burn
And brought me to the point you wished,
You’ve doused your flame with flowing drink,
And yours is colder than mine can ever be. After a time in which hail and thunder
Have beaten the top of Mount Caucasus,
A beautiful day comes, clothed again in light. When Phoebus encircles his land again,
And dives into the sea, his pale sister
Moves back into our view with pointed crown. When for too long the Parthian warrior fights,
He turns from his arc and loosens his bow. I consoled you once when I saw you sad,
And that aroused my long slow-burning fire;
But now that you have brought me to a burn
And brought me to the point you wished,
You’ve doused your flame with flowing drink,
And yours is colder than mine can ever be. 101 Labé. “Sonnet 18”, 126, https://books.google.com/books?id=w_fl8BM3_SUC&pg=PA126 7. The Ladder of Love in Italian Poetry and Prose 338 Love and its Critics Here, the woman pines in vain desire for the man, and must, like poor
Petrarch, rest in unrest, and abide in perpetual frustration. Still, despite
the change of gender roles, the song remains the same—the beloved
remains just as inaccessible in the sixteenth-century Lyonaisse poetry of
Labé as in the fourteenth-century Tuscan poetry of Petrarch. Even in her
famous eighteenth sonnet, Baise m’encor, rebaise moy et baise, a reworking
of Catullus’ fifth ode Let Us Live, My Lesbia, and Let Us Love (Vivamus,
mea Lesbia, atque amemus), Labé writes of a love that is passionate, but
frustrated and impossible to encompass fully: Here, the woman pines in vain desire for the man, and must, like poor
Petrarch, rest in unrest, and abide in perpetual frustration. Still, despite
the change of gender roles, the song remains the same—the beloved
remains just as inaccessible in the sixteenth-century Lyonaisse poetry of
Labé as in the fourteenth-century Tuscan poetry of Petrarch. Even in her
famous eighteenth sonnet, Baise m’encor, rebaise moy et baise, a reworking
of Catullus’ fifth ode Let Us Live, My Lesbia, and Let Us Love (Vivamus,
mea Lesbia, atque amemus), Labé writes of a love that is passionate, but
frustrated and impossible to encompass fully: Baise m’encor, rebaise moy et baise;
Donne m’en un de tes plus savoureus,
Donne m’en un de tes plus amoureus:
Je t’en rendray quatre plus chaus que braise. Las! te pleins tu? Ça, que ce mal j’apaise,
En t’en donnant dix autres doucereus. Ainsi meslans nos baisers tant heureus,
Jouissons nous l’un de l’autre à notre aise. Lors double vie à chacun en suivra;
Chacun en soy et son ami vivra. Permets m’Amour penser quelque folie:
Tousjours suis mal, vivant discrettement,
Et ne me puis donner contentement
Si hors de moy ne fay quelque saillie.101 Kiss me again, kiss and kiss me once more;
Give me one of your most savory,
Give me one of your most amorous,
I’ll return them four times hotter than coals. Does sadness fill you? I’ll appease that pain,
By giving you ten other sweets;
Thus mixing our happy kisses
We may enjoy each other at our ease. Then we will live twice:
Each ourselves, and each in the other’s love. 102 Gaius Valerius Catullus. Catullus. Tibullus. Pervigilium Veneris, ed. by F. W. Cornish
(Loeb Classical Library, Cambridge, MA: Harvard University Press, 1913), 6,8. 7. The Ladder of Love in Italian Poetry and Prose Love, let me dream about such foolish things:
It hurts me, living so discreetly, Kiss me again, kiss and kiss me once more;
Give me one of your most savory,
Give me one of your most amorous,
I’ll return them four times hotter than coals. Does sadness fill you? I’ll appease that pain,
By giving you ten other sweets;
Thus mixing our happy kisses
We may enjoy each other at our ease. Then we will live twice:
Each ourselves, and each in the other’s love. Love, let me dream about such foolish things:
It hurts me, living so discreetly, 7. The Ladder of Love in Italian Poetry and Prose 7. The Ladder of Love in Italian Poetry and Prose 103 “About 1370 Gregory XI appointed the Dominican Friar John Gallus as inquisitor
in the East, who in conjunction with Friar Elias Petit planted the institution […]
in Armenia” (Henry Charles Lea. A History of the Inquisition of the Middle Ages,
Vol. 1 [New York: Macmillan, 1906], 355). Gregory “regarded the members of the
Armenian Church in Cilicia as schismatics” (Krzysztof Stopka. Armenia Christiana:
Armenian Religious Identity and the Churches of Constantinople and Rome [Krakow:
Jagiellonian University Press, 2016], 270), but the fall of the Cilician Kingdom in
1375 placed the area under Muslim rule, and beyond the reach of any Pope. 7. The Ladder of Love in Italian Poetry and Prose 339 And nothing will give me contentment
Unless I break outside myself. Despite the open eroticism of this sonnet, with the double meaning of
“baise” (kiss and/or fuck—make the latter choice and the poem feels
somewhat different), the troubadour notes are overwhelmed by the
Petrarchan score: “Permets m’Amour penser quelque folie”—human love
will only be a dream, and a foolish one at that. There will be no kisses,
and no contentment. Compare this to Catullus’ poem, in which there is
no dominant note of frustration, though condemnation is reserved for
the old moralists who would prevent lovers from enjoying each other: Vivamus mea Lesbia, atque amemus,
rumoresque senum severiorum
omnes unius aestimemus assis! soles occidere et redire possunt:
nobis cum semel occidit brevis lux,
nox est perpetua una dormienda. da mi basia mille, deinde centum,
dein mille altera, dein secunda centum,
deinde usque altera mille, deinde centum. dein, cum milia multa fecerimus,
conturbabimus illa, ne sciamus,
aut ne quis malus invidere possit,
cum tantum sciat esse basiorum.102 Let us live, my Lesbia, and let us love,
and the rumors of the old and strict
all value as a single penny! The sun sets and dies but will return again:
But for us, when our brief light has died,
The night is eternal sleep. Give me a thousand kisses, then a hundred,
then another thousand, then a second hundred,
then yet another thousand, then a hundred. Then, when we have made many thousands, 340 Love and its Critics jumble the count, refuse to know the total,
lest anyone judge with an evil eye,
when he knows how many have been our kisses. By way of contrast, in a distant area of the continent where the Inquisition
had been relatively weak,103 and the urge to transform the passion of
love poetry into the piety of worship had not found expression in a
dolce stil novo, love poetry has much of the passionate essence found
in troubadour verse, without the note of frustration and failure often
found in Labé. 104 Hayren 20. Nahaphet Quchak, Haryur u mek hayren, ed. by Arshak Madoyan and
Irina Karumyan (Yerevan: Sovetakan Grokh, 1976). 105 Ibid., Hayren 65. 106 Ibid., Hayren 81.
107 Briffault, 193–94.
108 E. M. W. Tillyard. In E. M. W. Tillyard, ed. The Poetry of Sir Thomas Wyatt (London:
The Scholartis Press, 1929), 23. 7. The Ladder of Love in Italian Poetry and Prose The sixteenth-century Armenian poet Nahaphet Quchak,
known for his short lyric poems of love, or hayren, writes in a frankly
passionate and physical manner that is reminiscent of Guilhem IX: Իմ սիրծ ի qո վար սիրւդ’
զետ աշնան խազել կւ դոխայ։
Արծւնq ի յերեսս Ի վեր’
զետ գարնան անձրեվ կւ ծոխայ։
Հոգիս ի յիսնե ելավ՝
մեկ մի qո ծոծոյդ ճար արա։
Ծոծիկս ե ծոծիդ սովոր՝
այլ ւհնդ վոր յերտայ՝ մեկ ասա’.104 From your burning love,
my heart trembles like an autumnal leaf:
My tears streaming down my face:
as if a spring rain drizzles. My soul is being tortured,
Give me the cure of your bosom. My breast is used to your breasts,
Tell me, how will I live if they leave? 7. The Ladder of Love in Italian Poetry and Prose 341 For Quchak, love is physical and joyful, not something to be sublimated
into spiritual devotion, or made to serve as a means to an end, the
merest first rung on a ladder of love leading from Earth to Heaven. For
Quchak, as for the troubadours, heaven is here, and its temple is the
body of his beloved: Qանի մարն զիս բերեր՝
qահանի ճեմ խոստովաներ։
Ւրտեխ qահանայ տեսեր՝
նայ ծրեր ճամպւս ւ յելեր։
Վորտեխ մեկ ախվոր տեսել’
գիրկ ւ ծոծ վի դեմ գնածեր։
Ծոծիկն եմ ձամպտւն արել՝
ծւհծերւն եմ խոստովաներ.105 How many faults are born,
I haven’t confessed to the priest:
Wherever a priest I’ve seen,
I’ve changed my route and left:
Wherever a beauty I’ve seen,
I’ve straight gone to her bosom and embrace,
Made her bosom my altar,
To her tits I’ve made my confessions. In the final line, the refusal of euphemism drives home the point: love
is its own justification, and needn’t apologize to anyone or pretend its
desires are in any way shameful. 110 Rachel Falconer. “A Reading of Wyatt’s ‘Who so list to hunt’”. In Michael Hattaway,
ed. A Companion to English Renaissance Literature and Culture (London: Blackwell,
2003), 181. 7. The Ladder of Love in Italian Poetry and Prose Quite the opposite, in fact; love is to be
celebrated in wine and song: Իմ բարծրագնած լւսին՝
շատ բարեվ տար իմ կիվսելին:
—Զ բարեվդ յես Ի ւր տանեմ՝
ճեմ գիտեր ւհզտւնն կիվզելին:
—Գնա Ի վերայ տախին՝
բարձր պատ ւ ծարն Ի միձին։
Նստեր Ի ծարի շqին՝
կ խմե իր լւրձ ապիկին՝ շատ բարեվ տար իմ կիվսելին: —Զ բարեվդ յես Ի ւր տանեմ՝
ճեմ գիտեր ւհզտւնն կիվզելին: —Գնա Ի վերայ տախին՝
բարձր պատ ւ ծարն Ի միձին։
Նստեր Ի ծարի շqին՝
կ խմե իր լւրձ ապիկին՝ 342 Love and its Critics Խմե ւ հայրեն կ’ասե։
տ’ «Ինճ անւշ ե սերն ւ գինին».106 My high and noble moon,
Take many greetings to my beauty
—Where should I take your greeting? I don’t know the house of your beauty. —Go to the upper neighborhood
Where she sits between high wall and tree:
Sitting in the shadow of the tree,
Drinking with seriousness,
Drinking and singing hayrens:
As “How sweet are love and wine!” As “How sweet are love and wine!” It is this spirit—this unapologetic celebration of passion and desire, so like
that of the troubadours—that French and Italian poetry lost, and English
poetry would successfully struggle to recover: “the Provençal tradition
was much more continuous and lasting in England than in France. […]
The manner, style, metrical models, and the very themes and conceits
of the troubadour tradition, [were] transported bodily one might say,
into England”.107 For decades, however, the influence of Petrarch, and
not the troubadours, was the dominant force in the English poetry of
the sixteenth century before Shakespeare. Such early Tudor sonneteers
as Thomas Wyatt and Henry Howard, the Earl of Surrey, and later
Elizabethan figures like Philip Sidney both borrow from and struggle
against Petrarch, creating a new vocabulary of poetry in English. These
poems often reveal their Petrarchan roots, as they treat such subjects
as the impossibility of being loved in return by the chosen object of the
poet’s love. Wyatt made extensive use of Petrarch in his own poetry: Of the Italian poets it was Petrarch whom Wyatt copied most freely. From Petrarch he derived the sonnet and certain conventional
sentiments, which, once introduced into English love poetry, formed its
staple subject-matter, with certain interruptions and revolts, for about a
century and a half.108 7. The Ladder of Love in Italian Poetry and Prose 109 Thomas Wyatt. Sir Thomas Wyatt: The Complete Poems, ed. by R. A. Rebholz (New
Haven: Yale University Press, 1978), 77.
110 R
h l F l
“A R
di
f W
tt’ ‘Wh
li t t h
t’” I Mi h
l H tt 109 Thomas Wyatt. Sir Thomas Wyatt: The Complete Poems, ed. by R. A. Rebholz (New
Haven: Yale University Press, 1978), 77.
110 Rachel Falconer. “A Reading of Wyatt’s ‘Who so list to hunt’”. In Michael Hattaway,
ed. A Companion to English Renaissance Literature and Culture (London: Blackwell,
2003), 181. 7. The Ladder of Love in Italian Poetry and Prose 343 For example, Wyatt’s famous 1557 sonnet, “Whoso List to Hunt”, makes clear
the poet’s painful longing, his extensive borrowings from Petrarch, and his
acute awareness of how love and desire are affected by rank and station: Whoso list to hunt, I know where is an hind,
But as for me, helas, I may no more. The vain travail hath wearied me so sore,
I am of them that farthest cometh behind. Yet may I by no means my wearied mind
Draw from the deer, but as she fleeth afore
Fainting I follow. I leave off therefore,
Sithens in a net I seek to hold the wind. Who list her hunt, I put him out of doubt,
As well as I may spend his time in vain. And graven with diamonds in letters plain
There is written, her fair neck round about:
‘Noli me tangere for Caesar’s I am,
And wild for to hold, though I seem tame’.109 Wyatt’s sonnet, a loose adaptation of Petrarch’s Sonnet 190, borrows the
Petrarchan model while changing its terms: Wyatt’s [Caesar] is secular, possessive and tyrannous, but his Diere is also
secular and arguably powerful herself. Wyatt’s added description of her
as “wylde for to hold: though I seme tame” hints at a powerful duplicity
not present in Petrarch. There is a suggestion that this duplicity might
equally be exercised against the speaker, his rivals, or [Caesar] himself.110 The “hind” in all likelihood was Anne Boleyn, the paramour, later the
wife, of Henry VIII, and Wyatt’s poem captures the angst of a man who
desires a high-placed woman whom he can never have, in much the
same way that Bernart de Ventadorn’s twelfth-century poem, When
Fresh Leaves and Shoots Appear (Can l’erba fresch’e·lh folha par), describes
the passionate devotion of Bernart for Eleanor of Aquitaine. Just as
Bernart’s poem describes the impossibility of loving the Queen of 344 Love and its Critics Henry II, Wyatt’s poem recognizes the futility and danger of crossing
the power of Henry VIII, the “Caesar” of the poem.111 Wyatt’s sonnets often feature the kinds of woman-as-cruel-angel
imagery seen in Petrarch, including the comparisons of the beloved’s
eyes with fire, or sparks, or the stars and sun. 111 Though the question of whether or not Wyatt had an affair with Anne Boylen has
been long debated, it does not seem likely ever to be proven on the positive side.
“There is no evidence that Wyatt’s verses or his attention ever deeply moved Anne,
for she played for higher stakes, with the crown as her goal” (Retha M. Warnicke.
“The Eternal Triangle and Court Politics: Henry VIII, Anne Boleyn, and Sir Thomas
Wyatt”. Albion: A Quarterly Journal Concerned with British Studies, 18: 4 [Winter,
1986], 578, https://doi.org/10.2307/4050130). There is also “no record linking Anne’s
name to Wyatt’s […] prior to the date of his imprisonment in 1536 when five
other men were executed for committing adultery and incest with her” (Retha M.
Warnicke. The Rise and Fall of Anne Boleyn: Family Politics at the Court of Henry VIII
[Cambridge: Cambridge University Press, 1991], 65). Modern scholarship denies
the latter charges, seeing them as part of the vicious push and pull of Tudor politics,
as illustrated in Adam Blackwood’s pamphlet broadside: “The marriage of the King
with Anne Boleyn could not stand by any law in the world, Anne being his natural
daughter. [It is] an illegitimate marriage, and that which it begot a bastard […],
Elizabeth” (“Le mariage du Roy avec Anne Boullen ne pouvoit subsister par aucune
loy du monde, estant icelle Anne sa filie naturelle, [c’est un] mariage illegitime, &
celle qui en estoit procree bastarde […], Elizabet”) (Martyre de la Royne d’Escosse.
Edimbourg, 1587, Sig. C3v, 37 [misprinted as 73], https://books.google.com/
books?id=_mZUAAAAcAAJ&pg=PA37). 112 Wyatt (1978), 84, l. 4. 113 Ibid., ll. 5–8. 114 Ibid., 84, ll. 5–10. 115 Ibid., 71, ll. 9–13.
116 Raimie Targoff. Posthumous Love: Eros and the Afterlife in Renaissance England
(Chicago: University of Chicago Press, 2014), 50.
117 Ibid.
118 Ibid., 66. 7. The Ladder of Love in Italian Poetry and Prose In “Such Vain Thought as
Wonted to Mislead Me”, the beloved is described as “her whom reason
bids me flee”112 before the poet cries out in resignation, “She fleeth as
fast by gentle cruelty / And after her my heart would fain be gone, / But
armed sighs my way do stop anon, / ‘Twixt hope and dread locking my
liberty”.113 In another sonnet, “The Lively Sparks that Issue from those
Eyes”, Wyatt’s lines bemoan the power of the beloved’s gaze: Was never man could any thing devise
Sunbeams to turn with so great vehemence
To daze man’s sight, as by their bright presence
Dazed am I; much like unto the guise
Of one stricken with dint of lightning,
Blind with the stroke, and crying here and there.114 114 Ibid., 84, ll. 5–10. 7. The Ladder of Love in Italian Poetry and Prose 7. The Ladder of Love in Italian Poetry and Prose 345 Wyatt’s poems also work the theme of the lady who cruelly fails to
be “tractable” and “willing” where a man’s professions of love are
concerned. In “Behold, Love, Thy Power How She Despiseth” (a loose
translation of Petrarch’s Sonnet 121), the beloved who refuses love in
return is to be punished: Behold, Love. I am in hold. If thee pity moveth,
Go bend thy bow that stony hearts breaketh
And with some stroke revenge the displeasure
Of thee and him that sorrow doth endure
And, as his lord, thee lowly entreateth.115 At times, however, Wyatt will depart from his Petrarchan model in
serious and purposeful ways: “Wyatt was writing from within a culture
in which erotic love was not a celebrated subject of contemplation”, and
that fact “needs to be fully accounted for when we consider the changes
he made to Petrarch’s poems”.116 One of the most striking differences is
the attitude taken toward the woman in the works: Whereas Petrarch famously idealizes Laura’s virtues in a manner
comparable to Dante’s depiction of the heavenly Beatrice in La Vita
Nuova, Wyatt is reluctant to praise his mistress, either physically or
spiritually. There are almost no descriptions of Wyatt’s mistress in any
of his poems—no blazons or paeans to her beauty—and she is certainly
not treated as a flawless angelic creature.117 Another major difference is that “Wyatt conspicuously avoids […]
Petrarch’s notion that dying of love is the desired end. […] Thus in the
sonnet that begins, ‘Eche man me telleth I chaunge moost my devise’,
Wyatt informs his mistress that he shall remain steadfast in his affection
so long as his body and soul remain together”, but no longer.118 Nor does
Wyatt write of human love as a ladder or pathway to divine love: “When
Wyatt wants to write about love of God, he does not move through the
vehicle of loving an earthly woman. 121 Henry Howard, Earl of Surrey. The Poetical Works of Henry Howard, Earl of Surrey, ed.
by Robert Bell (Boston: Little, Brown & Co., 1854), 79, ll. 3–11, https://archive.org/ 119 Ibid., 78.
120 Wyatt (1978), 79, ll. 3–4, 11–14. 120 Wyatt (1978), 79, ll. 3–4, 11–14. 119 Ibid., 78.
120 Wyatt (1978), 79, ll. 3–4, 11–14.
121 Henry Howard, Earl of Surrey. The Poetical Works of Henry Howard, Earl of Surrey, ed.
by Robert Bell (Boston: Little, Brown & Co., 1854), 79, ll. 3–11, https://archive.org/ 119 Ibid., 78. stream/poeticalworkshe00vauxgoog#page/n89 stream/poeticalworkshe00vauxgoog#page/n89
122 Ibid., 80, ll. 18–21, https://archive.org/stream/poeticalworkshe00vauxgoog#page/n90
123 Ibid., 81–82, ll. 26–27, 68–71, https://archive.org/stream/poeticalworkshe00vaux
goog#page/n91
124 Ibid., 52–53, ll. 8–11, https://archive.org/stream/poeticalworkshe00vauxgoog#page/n62 122 Ibid., 80, ll. 18–21, https://archive.org/stream/poet g
g p g
124 Ibid., 52–53, ll. 8–11, https://archive.org/stream/poeticalworkshe00vauxgoog#page/n62 7. The Ladder of Love in Italian Poetry and Prose Instead, in a pattern that becomes Love and its Critics 346 typical of sixteenth-and seventeenth-century English poets, he shifts
decisively from erotic to devotional poetry”.119 Wyatt’s verse will also
turn to bitter humor, as it casts a cynical eye on the subject of truth and
lies in a poem written to his tongue, “Because I have thee still kept from
lies and blame”, in which Wyatt berates that often-speechless organ for
failing to keep faith with him, like an intractable and unwilling beloved: Unkind tongue, right ill hast thou me rendered,
For such desert to do me wreak and shame. […]
Then are ye gone when I should make my moan. And you so ready sighs to make me shright,
Then are ye slack when that ye should outstart,
And only my look declareth my heart.120 Where Wyatt both uses and resists Petrarch, altering his themes in
critical ways, the Earl of Surrey, Henry Howard, is at once more faithful
and more whimsical an imitator of his Italian model, often letting flights
of fancy loose while expressing the familiar themes of the cruel lady, the
blazing power of her eyes, and the pain of the rejected lover. In “Each
Beast can Choose his Fere According to his Mind”, first published in
Tottel’s Miscellany in 1557, Howard creates a beast fable to dramatize the
cruelty of a lady who refused to dance with a man who asked her. The
man is described as a noble lion, while the woman is a coy wolf: A lion saw I late, as white as any snow,
Which seemed well to lead the race, his port the same did show. Upon the gentle beast to gaze it pleased me,
For still methought he seemed well of noble blood to be. And as he pranced before, still seeking for a make,
As who would say, ‘There is none here, I trow, will me forsake’,
I might perceive a Wolf as white as whalèsbone,
A fairer beast of fresher hue, beheld I never none;
Save that her looks were coy, and froward eke her grace.121 Save that her looks were coy, and froward eke her grace.121 7. The Ladder of Love in Italian Poetry and Prose p
g
g p g
122 Ibid., 80, ll. 18–21, https://archive.org/stream/poeticalworkshe00vauxgoog#page/n90 7. The Ladder of Love in Italian Poetry and Prose 347 On asking her to dance, the lion is repulsed by the wolf in no
uncertain terms: ‘Lion’, she said, ‘if thou hadst known my mind before,
Thou hadst not spent thy travail thus, nor all thy pain for-lore. Do way! I let thee weet, thou shalt not play with me:
Go range about, where thou mayst find some meeter fere for thee’.122 ‘Lion’, she said, ‘if thou hadst known my mind before,
Thou hadst not spent thy travail thus, nor all thy pain for-lore. Do way! I let thee weet, thou shalt not play with me:
Go range about, where thou mayst find some meeter fere for thee’.122 The lion’s response is at once indignant and impotent, filled with the
rage of the lover who expects the beloved to be compliant and responsive
to his advances: ‘Cruel! you do me wrong, to set me thus so light;
Without desert for my good will to shew me such despite. […]
And thus farewell, Unkind, to whom I bent and bow;
I would you wist, the ship is safe that bare his sails so low. Sith that a Lion’s heart is for a Wolf no prey,
With bloody mouth go slake your thirst on simple sheep, I say’.123 Elsewhere, Howard is more typically Petrarchan, as in a poem that
bemoans a young woman’s refusal to show her face or hair to a man
who has declared his love for her. In “I Never Saw my Lady Lay
Apart” (a translation of Petrarch’s Sonnet 11, Lassare il velo per sole o
per ombra), the poet writes of the pain of being refused the sight for
which he longs: Yet since she knew I did her love and serve,
Her golden tresses clad alway with black,
Her smiling looks that hid thus evermore,
And that restrains which I desire so sore.124 And that restrains which I desire so sore.124 Here, the reader is at home in the familiar language and imagery of
the Italian sonnets of the thirteenth and fourteenth centuries. The lover ,
,
,
p //
g/
/p
g
g p g /
123 Ibid., 81–82, ll. 26–27, 68–71, https://archive.org/stream/poeticalworkshe00vaux
goog#page/n91 124 Ibid., 52–53, ll. 8–11, https://archive.org/stream/poeticalworkshe00vauxgoog#page/n62 348 Love and its Critics is denied access to even the sight of his beloved; the lady is described
as cruel—denying the lover specifically because he loves, the ultimate
in intractable and unwilling behavior. 125 Ibid., 47, ll. 47–48, https://archive.org/stream/poeticalworkshe00vauxgoog#page/n57
126 Michael Drayton. “To the Reader of these Sonnets”, l. 13. Idea. In Arundell Esdaile, ed.
Daniel’s Delia and Drayton’s Idea (London: Chatto & Windus, 1908), 67, https://books.
google.com/books?id=mOiobc0PmsgC&pg=PA67
127 Philip Sidney. The Poems of Sir Philip Sidney, ed. by William A. Ringler, Jr. (Oxford:
Clarendon Press, 1962), 168, ll. 1–2.
128 Ibid., ll. 7–8. 129 Ibid., 171, ll. 12–14.
130 Ibid., 189, ll. 12–14.
131 Ibid., 201, ll. 1–14. 7. The Ladder of Love in Italian Poetry and Prose The Ladder of Love in Italian Poetry and Prose 349 Sonnet 12 describes Stella in terms that fit squarely within the tradition
seen in Bembo’s speech and Petrarch’s poetry of regarding the beloved
as cruel and intractable for refusing to return the love of the young man
who worships her: “O no, her heart is such a Cittadell, / So fortified with
wit, stor’d with disdaine, / That to win it, is all the skill and paine”.129 Sonnet 12 describes Stella in terms that fit squarely within the tradition
seen in Bembo’s speech and Petrarch’s poetry of regarding the beloved
as cruel and intractable for refusing to return the love of the young man
who worships her: “O no, her heart is such a Cittadell, / So fortified with
wit, stor’d with disdaine, / That to win it, is all the skill and paine”.129 The “cruelty” of the beloved who rejects the lover leads, in Sonnet 48,
to a declaration that the lover will die from his wounds, and a plea for the
beloved to kill him quickly if she cannot love him: “Yet since my death-
wound is already got, / Deare Killer, spare not thy sweet cruell shot: / A
kind of grace it is to kill with speed”.130 We can hear echos of Petrarch’s
Sonnets 133 and 183 in these lines, in which the lady can kill with a look. Perhaps the most famous of Sidney’s sonnets, Sonnet 71, appears
initially to be a sublime mix of Petrarchan ingredients: Stella’s eyes
are like the sun (“inward sun in thine eyes shineth”); love for Stella is
soon turned toward away from physical desire and toward love for the
spiritual good (“So while thy beauty draws the heart to love, / As fast
thy virtue bends that love to good”:); and Astrophil is in pain for the
lack of Stella, the physical absence of Stella metaphorized as food (“‘But
ah’, Desire still cries, ‘give me some food’”.): Who will in fairest booke of Nature know
How Vertue may best lodg’d in beauty be;
Let him but learne of Love to reade in thee,
Stella, those faire lines which true goodnesse show. There shall he find all vices’ overthrow,
Not by rude force, but sweetest soveraigntie
Of reason, from whose light those night-birds flie;
That inward sunne in thine eyes shineth so. 7. The Ladder of Love in Italian Poetry and Prose Love is described as painful,
dangerous, and next door to fatal in these poems, and as Howard
ends his poem “When summer took in hand the winter to assail”, the
poet warns readers away from love: “A mirror let me be unto ye lovers
all; / Strive not with love; for if ye do, it will ye thus befall”.125 But though Wyatt and Howard are important, by far the more
famous, and still more widely-read poet is Philip Sidney. Soldier,
courtier, diplomat, and poet, Sidney packed more into his not-quite
thirty-two years than many of us do into a span of seventy or eighty. He defended poetry, in The Defence of Poesie, against anti-theatricalists
and moralists like Stephen Gosson (himself a failed playwright). He
wrote one of the most popular and influential prose romances in the
English language—The Countess of Pembroke’s Arcadia—which exists in
multiple forms due to his death mid-revision. But most famously, he
is the author of the first of the so-called sonnet sequences in English. Sidney’s Astrophil and Stella (first printed in 1591, five years after his
death), took the passion and pain, the devotion and loneliness, the hope
and despair of Petrarch’s poetry and made them English. However,
what Michael Drayton would, in 1619, call a “Muse […] rightly of the
English strain”,126 is not quite what we see in Sidney. Though he was—
along with Spenser—the most brilliant lyric poet of his time, he was
heavily in debt to his Petrarchan model, no matter how powerfully he
reworked it into English verse. The physical imagery with which Sidney has Astrophil (star-lover)
describe Stella (star) demonstrates the debt. Right away, we see the
focus on the eyes of the beloved, in sonnet 7: “When Nature made her
chiefe worke, Stella’s eyes, / In colour blacke why wrapt she beames so
bright?”127 Stella’s eyes are so bright, in fact, that if “if no vaile those brave
gleames did disguise, / They sun-like should more dazle than delight”.128 7. 7. The Ladder of Love in Italian Poetry and Prose And not content to be Perfection’s heire
Thy selfe, doest strive all minds that way to move,
Who marke in thee what is in thee most faire. So while thy beautie drawes the heart to love,
As fast thy Vertue bends that love to good:
“But ah”, Desire still cries, “give me some food”.131 Who will in fairest booke of Nature know
How Vertue may best lodg’d in beauty be;
Let him but learne of Love to reade in thee,
Stella, those faire lines which true goodnesse show. There shall he find all vices’ overthrow,
Not by rude force, but sweetest soveraigntie
Of reason, from whose light those night-birds flie;
That inward sunne in thine eyes shineth so. And not content to be Perfection’s heire
Thy selfe, doest strive all minds that way to move,
Who marke in thee what is in thee most faire. So while thy beautie drawes the heart to love,
As fast thy Vertue bends that love to good:
“But ah”, Desire still cries, “give me some food”.131 350 Love and its Critics But in this poem, one can hear a touch of the troubadour melody mixed
into the Petrarchan score. While Astrophil extravagantly praises his
beloved, he does not necessarily idealize her, describing Stella’s virtues
as impediments to his desire. This conflict is clearly evident in Sonnet 72: Desire, though thou my old companion art,
And oft so clings to my pure Love, that I
One from the other scarcely can descrie,
While each doth blow the fier of my hart;
Now from thy fellowship I needs must part,
Venus is taught with Dian’s wings to flie:
I must no more in thy sweet passions lie;
Vertue’s gold now must head my Cupid’s dart. Service and Honor, wonder with delight,
Feare to offend, will worthie to appeare,
Care shining in mine eyes, faith in my sprite,
These things are left me by my only Deare;
But thou Desire, because thou wouldst have all,
Now banisht art, but yet alas how shall?132 Sidney makes his Astrophil suffer from unsatisfied desire, no matter
how purifying his love for Stella should be from the Neoplatonist or
Petrarchan point of view. In the tension between Astrophil’s often-
Petrarchan attitudes and his powerful desire, we can also see the
influence of Dante, for whom Beatrice’s beauty was figured as a solemn
promise of heavenly reward. 132 Ibid., 202, ll. 1–14.
133 Katona Gábor. “The Lover’s Education: Psychic Development in Sidney’s ‘Astrophil
and Stella’”. Hungarian Journal of English and American Studies, 1: 2 (1995), 4. 132 Ibid., 202, ll. 1–14. 133 Katona Gábor. “The Lover’s Education: Psychic Development in Sidney’s ‘Astrophil
and Stella’”. Hungarian Journal of English and American Studies, 1: 2 (1995), 4. From fairest creatures we desire increase,
That thereby beauty’s rose might never die, 1
Briffault, 197. 8. Shakespeare: The Return of Fin’amor 8. Shakespeare: The Return of Fin’amor I 7. The Ladder of Love in Italian Poetry and Prose Astrophil’s contemplation of Stella’s
beauty educates him as a lover, but it also spurs his will and desire:
“No matter how fallen Astrophil’s will becomes, he remains valiant and
ready for self-sacrifice, although he cannot resolve the psychic tension
resulting from the opposing demands of love and virtue in his mind”.133 It is in Sidney’s later sonnets where the carefully-constructed
Neoplatonic balance between “love and virtue” topples to the ground. Sidney does this by changing the poems’ focus from the divine powers
of the beloved’s beauty to the human anguish of the lover’s emotional
conflict. The poems of Sidney’s sequence read like a painful exercise in 7. The Ladder of Love in Italian Poetry and Prose 351 a young man’s trying (and failing) to tamp down physical desire—a
desire that will never be sated, consummated, or satisfied—while
attempting to convince himself that it is acceptable to sublimate or
spiritualize that desire for a woman he will never have, against whom
he now and then breaks out into resentful accusation, and for whom
his physical and emotional desires never slacken even in the slightest. The orthodox Neoplatonist position outlined by Peter Bembo in The
Book of the Courtier insists that such a resolution is not only acceptable,
but decidedly preferable. But as Astrophil bids farewell to the world,
at the end of the sequence, the stated preference for “Eternal Love”,
the love of heaven, seems forced: “Then farewell world; thy uttermost
I see: / Eternal Love, maintain thy life in me”. One cannot help but hear,
if faintly, the earlier plea of Desire: “give me some food”. 2
William Shakespeare. “Sonnet 1”, ll. 1–4. William Shakespeare: The Complete Works,
ed. by Stephen Orgel and A. R. Braunmuller (New York: Pelican, 2002), 67. All
further references to the sonnets will be from this edition, and will be referenced in
the notes by sonnet number and line number(s). The Value of the Individual in the Sonnets The true recovery of the troubadour tradition comes with Shakespeare,
the poet and playwright who “towers like a mountain peak above
the surrounding foothills, but is one substance and structure with
them”.1 Most truly “of the English strain”, Shakespeare’s sonnets are a
reversing, even a mocking of the Petrarchan mode and the Neoplatonic
sublimation of passion into worship that sometimes marks the poetry
of Sidney. Rather than treating the individual as a means to an end, the
lowest rung on the ladder of love, Shakespeare’s sonnets reverse this
emphasis, valuing the individual as an end in itself, not a means to some
higher goal. In effecting this reversal, Sonnet 1 begins with a recognizably Platonic
image, “beauty’s rose”, which is something like the form of rose, rather
than the tangible flower which, for a good Platonist or Neoplatonist,
is merely a copy of the higher reality. In the terms of the sonnet, “we”
want to see a proliferation of such copies in order that the form or idea
will not disappear from the world: https://doi.org/10.11647/OBP.0117.08 https://doi.org/10.11647/OBP.0117.08 © 2017 Michael Bryson and Arpi Movsesian, CC BY 4.0 354 Love and its Critics But as the riper should by time decease,
His tender heir might bear his memory;2 In the following lines the young man addressed in the sonnet is chided
for not reproducing himself and his beauty, thus removing that beauty
from the world, and limiting the ability of others to perceive the higher
form due to the slow degradation of the copy. But thou contracted to thine own bright eyes,
Feed’st thy light’s flame with self-substantial fuel,
Making a famine where abundance lies,
Thy self thy foe, to thy sweet self too cruel:3 The young man is accused of being what we might call a narcissist
today. He is “contracted” (married, bound) to his own eyes, rather than
the brilliantly blazing eyes of a Petrarchan beloved; he seems in love
with himself, like someone who wakes up, looks in the mirror, and falls
in love all over again every morning. So far, the sonnet seems to fit the
religious and allegorical frame with which Helen Vendler surrounds it: When God saw his creatures, he commanded them to increase and
multiply. 4
Helen Vendler. The Art of Shakespeare’s Sonnets (Cambridge, MA: Belknap Press of
Harvard University Press, 1997), 46. 3
1. 5–8. 5
Shakespeare, 1. 9–14. 6
Ibid., 3.9–10. The Value of the Individual in the Sonnets Shakespeare, in this first sonnet of the sequence, suggests
we have internalized the paradisal command in an aestheticized form
[…] We are also educated in the speaker’s culture—here, in such stock
figures as the medieval Rose of beauty, […] the command from Genesis
to increase and multiply, the dynastic obligation to produce heirs, and
so on.4 However, as the sonnet continues, it becomes clear that the religious and
allegorical frame does not fit; the poet regards this young man’s beauty
as something both important and tragically ephemeral, a moment’s
brightness that will soon be overwhelmed by the darkness of the grave. However, as the sonnet continues, it becomes clear that the religious and
allegorical frame does not fit; the poet regards this young man’s beauty
as something both important and tragically ephemeral, a moment’s
brightness that will soon be overwhelmed by the darkness of the grave. 355 8. Shakespeare: The Return of Fin’amor 5
Shakespeare, 1. 9–14.
6
Ibid., 3.9–10. 7
Ibid., 3.11–14.
8
Paul Edmondson and Stanley Wells. Shakespeare’s Sonnets (Oxford: Oxford
University Press, 2004), 65.
9
“Die Kunst ist lang! Und kurz ist unser Leben” (Goethe. Faust, Part I, 106, ll. 558–59).
Goethe reverses the emphasis of Hippocrates of Cos (460–370 BCE): “Life is short,
and art is long” (“Ὁ βίος βραχύς, ἡ δὲ τέχνη μακρή”). 8. Shakespeare: The Return of Fin’amor In
taking action—through reproduction—to preserve the memory of his
own beauty, the young man will ensure that he does not disappear, like
tears in rain, in the never-ceasing flow of Time: So thou through windows of thine age shalt see,
Despite of wrinkles this thy golden time. But if thou live remembered not to be,
Die single and thine image dies with thee.7 By Sonnet 15, however, Time has become a more pressing factor. How
long can the memory of individual beauty can be preserved merely
through reproduction? Edmondson and Wells insist that nothing has
changed: Sonnets 1–17 are concerned with procreation, with breeding and
re-creating the image of oneself in another living and autonomous
being in order to combat the ravages of Time and so vicariously to
achieve everlasting life. In this respect they are grounded firmly in the
Platonic ideal of procreative love expressed in the Symposium, “because
procreation is the nearest thing to perpetuity and immortality that a
mortal being can attain”. It is through procreation that Shakespeare wills
the re-creation and transcendence of his lover through time.8 But something has changed. Reproduction through children, though
still encouraged in this poem, and a number of those that follow, is
no longer put forward as the most effective preservation technique. In
Goethe’s formulation, “Art is long! And our life is short”.9 Everything
and everyone, in the terms of Sonnet 15, is a thing of a moment, soon to
disappear. In Neoplatonic terms, even in Petrarchan terms, this is only
a problem of incorrect perception and valuation. What Diotima teaches,
what Bembo describes, and what Sidney’s Astrophil struggles to
believe and act upon, is the idea that individual beauty—no matter how
compelling—is only a doorway to wider spaces and greater wonders, a But something has changed. Reproduction through children, though
still encouraged in this poem, and a number of those that follow, is
no longer put forward as the most effective preservation technique. In
Goethe’s formulation, “Art is long! And our life is short”.9 Everything
and everyone, in the terms of Sonnet 15, is a thing of a moment, soon to
disappear. In Neoplatonic terms, even in Petrarchan terms, this is only
a problem of incorrect perception and valuation. 8. Shakespeare: The Return of Fin’amor 8. Shakespeare: The Return of Fin’amor Thou that art now the world’s fresh ornament,
And only herald to the gaudy spring,
Within thine own bud buriest thy content,
And tender churl mak’st waste in niggarding:
Pity the world, or else this glutton be,
To eat the world’s due, by the grave and thee.5 The shift in emphasis is already clear—rather than being primarily
concerned with “beauty’s rose”, the form of beauty, or with any
God-given command to reproduce, this poem is concerned with the
preservation of the individual rose (the young man himself), or at least
with the preservation of the memory of that rose. The next several sonnets make that concern obvious. Their power
depends on the tragic sense of watching as a beautiful individual slowly
but surely fades away. These sonnets focus on the value inherent in the
person, not on preserving the form of Beauty for the next generation. That can take care of itself; the poems speak of preserving the all-too-
ephemeral beauty of an individual subject to time, decay, and death. As with the troubadour poems, the individual takes center stage here, a
flesh-and-blood mortal who is of worth in himself. In Sonnet 3 the young man is placed in a sequence of acts of
memory—each generation’s beauty serving, not to remind onlookers
of Beauty itself, but to remind them of the beauty of those individuals
Time and Death have taken or will soon take. The young man is asked
to consider his mother: Thou art thy mother’s glass and she in thee
Calls back the lovely April of her prime.6 Your mother’s beauty, the poem suggests, is preserved in you. In turn,
it is important that the young man have a child, in order to pass on
the memory of his own beauty. The concern here is for the memory
of individuals, the attempt to preserve what a Diotima or Bembo
would regard as copies of the real, not the real itself. But the sonnets
disagree—what is important is precisely the individual, the so-called Love and its Critics 356 copy, the unique manifestation of beauty, not a philosophical ideal. 7
Ibid., 3.11–14. 10
Shakespeare, 15.1–2.
11
Ibid., 15.5–8.
12
Ibid., 15.9–14. 11
Ibid., 15.5–8. 10
Shakespeare, 15.1–2. 14
The most profound of modern work often shares the same spirit. It can be found,
for example, in Ingmar Bergman’s 1957 film Det sjunde inseglet, or The Seventh Seal,
especially in the scene where the Crusades-era knight Antonius Bloch realizes
how precious the ordinary moments can be in a life much too intimately engaged
with death: “I will remember this moment. The stillness, the twilight, the bowl of
strawberries, the bowl of milk, your faces in the evening light. […] And it will serve
as a sign for me, and it will be enough" (“Jag ska minnas den här stunden. Stillheten,
skymningen, skålen med smultron, skålen med mjölk, era ansikten i kvällsljuset.
[…] Och detta ska vara mig ett tecken och en stor tillräcklighet”.) (55:39–56:25)
h k 8. Shakespeare: The Return of Fin’amor What Diotima teaches,
what Bembo describes, and what Sidney’s Astrophil struggles to
believe and act upon, is the idea that individual beauty—no matter how
compelling—is only a doorway to wider spaces and greater wonders, a 8. Shakespeare: The Return of Fin’amor 357 window through which one can see the light, though it is not the light
itself. Sonnet 15 rejects these ideas in no uncertain terms. It starts with
a seemingly orthodox statement of the ephemerality of all things in this
world of flux and change: When I consider every thing that grows
Holds in perfection but a little moment.10 Everything that grows, eventually dies. Our peak moments, our
moments of “perfection”, are but “little”, consigned to the past as soon
as they arrive in the ever-changing present: When I perceive that men as plants increase,
Cheered and checked even by the self-same sky:
Vaunt in their youthful sap, at height decrease,
And wear their brave state out of memory.11 None of us are exempt. No philosophical or theological conceits of being
somehow one with a larger universe, an emanation of a larger One, or
the creation of an immortal God who promises mortals an eternity of
blessing or punishment, can stop even the simplest movement of one
moment to the next, or the loss of a single hair in the perceptible process
of aging and eventual death. This idea of inevitable loss brings the poem
to Art, to poetry itself: Then the conceit of this inconstant stay,
Sets you most rich in youth before my sight,
Where wasteful time debateth with decay
To change your day of youth to sullied night,
And all in war with Time for love of you,
As he takes from you, I engraft you new.12 In a war against Time itself, who can do anything but lose? Each of us
will die, and many of us will go through the process of saying goodbye
to the things and people we love. If we have enough time, we will bid 358 Love and its Critics farewell to ourselves, to our sense of who and what we have been in
a world into which we were thrown without preparation, and from
which we are taken without remorse. It is a war we all lose, eventually. But the war this poem, and this poet, fights is slightly different. 13
J. B. Leishman. Themes and Variations in Shakespeare’s Sonnets (London: Routledge,
1961), 41. 15
Shakespeare, 18.1–4. 16
Ibid., 18.5–8.
17
Ibid., 18.9–14. 8. Shakespeare: The Return of Fin’amor Art
cannot keep the young man from aging and eventually dying. But it
can lift a moment out of Time, describe it, keep it, and pass it on to
those who will live their own all-too-short lives in the future. This is the
power the sonnet describes—poetry as immortalization: “[t]he theme of
Horace’s Censorinus ode, Donarem pateras, often reappears: […] the gifts
bestowed by the poets will endure forever”.13 It may be a Pyrrhic victory, achieved at great cost and impossible to
hold for long, but it is the only victory the artist, the poet, the mortal can
win. To say to Time and Death, No. Not this one. Not this moment. You
can’t have him. You can’t have her. You can’t have this. This we will save. This
we will preserve, as best we can, against you—this is the “war with Time”
the sonnet fights.14 Far from valuing the young man as a Beatrice, or as
a Laura, or as a Stella, as a means to higher ends, this sonnet, and others
that follow, value the temporary over the permanent, the ephemeral
over the eternal. The fight to recognize, revalue, and preserve the
individual is powerfully expressed in one of the most famous of all the
sonnets, number 18: Shall I compare thee to a summer’s day? Thou art more lovely and more temperate:
Rough winds do shake the darling buds of May,
And summer’s lease hath all too short a date:15 Shall I compare thee to a summer’s day? Thou art more lovely and more temperate:
Rough winds do shake the darling buds of May,
And summer’s lease hath all too short a date:15 13
J. B. Leishman. Themes and Variations in Shakespeare’s Sonnets (London: Routledge,
1961), 41. 8. Shakespeare: The Return of Fin’amor 8. Shakespeare: The Return of Fin’amor 359 A summer’s day is the perfect comparison to the beauty of the young
man. The day will not last, and neither will he or his beauty. It is here
for a moment, then gone forever, and though other days may follow,
none of them are that day, none are quite the same. From the perspective
of this sonnet, it is that day, that beauty, that individual that must be
preserved in the face of inevitable loss. Since summer days are not equal
in their beauty, they are not interchangeable: Sometime too hot the eye of heaven shines,
And often is his gold complexion dimmed,
And every fair from fair sometime declines,
By chance, or nature’s changing course untrimmed:16 Therefore, this one must be kept, no matter the cost, using every power
and technique at the poet’s disposal: But thy eternal summer shall not fade,
Nor lose possession of that fair thou ow’st,
Nor shall death brag thou wand’rest in his shade,
When in eternal lines to time thou grow’st,
So long as men can breathe or eyes can see,
So long lives this, and this gives life to thee.17 Perhaps the cliché is true—perhaps the pen really is mightier than the
sword, for who has gone to war with Time, wielding, as Hamlet puts
it, “a bare bodkin”? Though the troubadours do not speak of fighting
against time and death in their poetry, their spirit is here, much more
than is the spirit of the Dante who would put Paolo and Francesca in
Hell, or the spirit of the Petrarch who transforms a young girl into a
symbol for heavenly transcendence. These sonnets value one man’s life
far more than they value philosophical or theological abstractions. This is not to say, however, that the philosophical heights of a Bembo
have no place in Shakespeare’s sonnets—such heights are scaled, most
notably in a sonnet often used in perhaps the most inappropriate
context of all: wedding ceremonies. 18
Dympna Callaghan. Shakespeare’s Sonnets (Malden: Blackwell, 2007), 62. 19
Charity, however, has taken on a rather different sense in the twenty-first century
than the seventeenth century, and there may not be a one-word translation
in contemporary English that can capture the complexity in the orginal term
ἀγάπη [agape]. The closest analog available may be the Hindu concept of bhakti,
a word that, though usually translated as devotion, is probably better rendered as
participation. Thus, agape or caritas might be most accurately translated as “the love
that participates in highest things”. 8. Shakespeare: The Return of Fin’amor It seems a rare experience to attend
a wedding in an English-speaking country in which Sonnet 116 does Love and its Critics 360 not make an appearance, and it has been popular with “[g]enerations of
readers [who] have understood this poem to constitute a lyrical definition
of true love, that is, love that transcends time and is unperturbed by age
and change”.18 This famous sonnet is often included beside the words
of Paul from 1 Corinthians 13:4–8, which is usually read aloud from a
modern translation that renders the central term as “love”. For example,
the popular New International Version (NIV) translation expresses the
passage this way: Love is patient, love is kind. It does not envy, it does not boast, it is not
proud. It does not dishonor others, it is not self-seeking, it is not easily
angered, it keeps no record of wrongs. Love does not delight in evil but
rejoices with the truth. It always protects, always trusts, always hopes,
always perseveres. Love never fails. A lovely sentiment, this passage as it is usually read seems to establish
“love” as the basis for a marriage between two people who have chosen
each other freely, and are solemnizing that choice in a modern marriage
ceremony. The only problem is that the translation is misleading—while
the word “love” is not, strictly speaking, inaccurate, the word “charity”
would be closer to the mark. The King James Bible (or Authorized
Version of 1611) renders the passage with “charity” in place of “love”: Charity suffereth long, and is kind; charity envieth not; charity vaunteth
not itself, is not puffed up, Doth not behave itself unseemly, seeketh
not her own, is not easily provoked, thinketh no evil; Rejoiceth not in
iniquity, but rejoiceth in the truth; Beareth all things, believeth all things,
hopeth all things, endureth all things. Charity never faileth. The English sense of the two passages is quite different. Love may, or
may not, be “patient” or “suffereth long”. But charity, from the Latin
caritas, definitely is, and does. The difference is found in the shadings
of meaning offered by the three classical Greek words used for love:
eros (desire, lack, a need to have an emptiness filled), philia (friendship,
familial affection, close familiarity and warmth), and agape (a love based
on principle, respect and acknowledgment of the value of another—in
that sense, a very unPetrarchan love). 8. 21
Shakespeare, 116.1–4. p
p
g
g
20
John Kerrigan. The Sonnets; and A Lover’s Complaint (New York: Penguin, 1986), 53.
21
Sh k
116 1 4 22
Ibid., 116.5–8. 20
John Kerrigan. The Sonnets; and A Lover’s Complaint (New York: Penguin, 1986), 53.
21
Shakespeare, 116.1–4. 23
Ibid., 116.9–14.
24
Callaghan (2007), 61.
25
Stephen Booth. Shakespeare’s Sonnets (New Haven: Yale University Press, 1977), 387. ,
24
Callaghan (2007), 61.
25
Stephen Booth. Shakespeare’s Sonnets (New Haven: Yale University Press, 1977), 387. 8. Shakespeare: The Return of Fin’amor Shakespeare: The Return of Fin’amor 361 The “charity”19 of the King James rendition, based on the Latin caritas,
which is itself a translation of the Greek agape, comes much closer to the
sense of “love” as it appears in Sonnet 116. As John Kerrigan cynically
notes, “[t]his sonnet has been misread so often and so mawkishly that it
is necessary to say at once, if brutally, that Shakespeare is writing about
what cannot be attained”.20 While it may be too much to insist that the
“love” of Sonnet 116 “cannot be attained”, it is important to understand
that, rather than being a celebration of desire, or even of friendship,
Sonnet 116 celebrates the relative permanency of a “love” defined in
terms of principle and an unchanging recognition of the inherent value
of another person: Let me not to the marriage of true minds
Admit impediments, love is not love
Which alters when it alteration finds,
Or bends with the remover to remove.21 The union is not between true hearts or bodies (though these are by no
means incompatible), but “true minds”. Even here, it is the individual
that is valued for his or her own sake, for the value and truth of the mind
each brings to the other. Each is regarded as an end in itself, and love, in
the sense of agape, caritas, and charity is fixed and constant: O no, it is an ever-fixed mark
That looks on tempests and is never shaken;
It is the star to every wand’ring bark,
Whose worth’s unknown, although his height be taken[.]22 O no, it is an ever-fixed mark
That looks on tempests and is never shaken;
It is the star to every wand’ring bark,
Whose worth’s unknown, although his height be taken[.]22 The passage of time will not, cannot, alter this love, for it is both freely
given, and freely received, a love of choice, of mutual recognition of The passage of time will not, cannot, alter this love, for it is both freely
given, and freely received, a love of choice, of mutual recognition of 362 Love and its Critics each other as inherently valuable, an appreciation of truth, substance,
and goodness as found in each other, not as a guidepost to something
or someone greater. 25
Stephen Booth. Shakespeare’s Sonnets (New Haven: Yale University Press, 1977), 387. 24
Callaghan (2007), 61. 27
Callaghan (2007), 64. 28
Philip Martin. Shakespeare’s Sonnets: Self, Love and Art (Cambridge, Cambridge
University Press, 1972), 123.
29
Ed
d
d W ll
15 26
Vendler, 491, 493. 8. Shakespeare: The Return of Fin’amor Those who give and receive this love will not be
dissuaded from it: Love’s not Time’s fool, though rosy lips and cheeks
Within his bending sickle’s compass come,
Love alters not with his brief hours and weeks,
But bears it out even to the edge of doom:
If this be error and upon me proved,
I never writ, nor no man ever loved.23 As Héloïse d’Argenteuil proves in her letters, and as Milton demonstrates
in Paradise Lost, those who love with even a spark of this unalterable
regard, will defy God himself in its name. As Héloïse d’Argenteuil proves in her letters, and as Milton demonstrates
in Paradise Lost, those who love with even a spark of this unalterable
regard, will defy God himself in its name. As we have seen, and will often see again, there are any number of
literary critics dedicated to diminishing poetry’s power, telling readers
that poems do not mean what they merely seem to say (or that they do not
mean at all, in some extreme cases). Dypmna Callaghan has remarked
on this phenomenon with Sonnet 116, and “the many ways in which
critics and editors have argued that this poem does not mean what it
says”,24 a point borne out by both Vendler and Stephen Booth. Booth
argues that the virtues of Sonnet 116 “are more than usually susceptible
to dehydration in critical comment. The more one thinks about this
grand, noble, absolute, convincing and moving gesture, the less there
seems to be to it”,25 while Vendler regards Sonnet 116 as a statement
against love by a faithless lover: The young man has, after all, said, “I did love you once, but now
impediments have arisen through alterations and removes”. The
speaker argues by means of the couplet that the performative speech-
act of Platonic fidelity in quasi-marital mental love cannot be qualified;
if it is qualified, it does not represent love. […] The poem entertains,
in the couplet, the deconstructive notion of its own self-dissolution; the
impossibility of error is proved by the contrary-to-fact hypothesis, I never
writ. […] The young man, by his mentioning of “impediments”, has 8. Shakespeare: The Return of Fin’amor 363 29
Edmondson and Wells, 15. 26
Vendler, 491, 493.
27
Callaghan (2007), 64.
28
Philip Martin. Shakespeare’s Sonnets: Self, Love and Art (Cambridge, Cambrid
University Press, 1972), 123.
29
Edmondson and Wells, 15.
30
Shakespeare, 130.1–4. 30
Shakespeare, 130.1–4. 26
Vendler, 491, 493.
27
Callaghan (2007), 64.
28
Philip Martin. Shakespear
University Press, 1972), 12
29
Edmondson and Wells, 15
30
Shakespeare, 130.1–4. g
(
),
28
Philip Martin. Shakespeare’s Sonnets: Self, Love and Art (Cambridge, Cambridge
University Press, 1972), 123.
29
Edmondson and Wells, 15. 32
The modern bristle toothbrush, though invented by the Chinese Tang dynasty of
609–917 CE, did not make its first appearance in England, even among the wealthy,
until 1690. See Michael Olmert. Milton’s Teeth & Ovid’s Umbrella: Curiouser and
Curiouser Adventures in History (New York: Touchstone, 1996), 62.
33
V
dl
557 8. Shakespeare: The Return of Fin’amor announced the waning of his own attachment to the speaker, dissolving
the “marriage of true minds”.26 Where the sonnet speaks of a love that does not admit impediments,
the critic has rewritten it into a scenario in which impediments are the
very thing that has altered—even ended—a love that was not of “true
minds”. With that familiar what-seems-to-be-X-is-actually-Y move, the
sonnet is inverted, and made to represent the opposite of what its words
seem to convey. This is not the first time, nor will it be the last, that a
critic has become so deeply engaged with his or her terms of analysis
that a text has simply become invisible under the bright light of the
critic’s scrutiny. But it is not necessary to submit to the idea “that the
consensus of generations of readers is so completely wide of the mark
as some recent editors suggest”.27 Shakespeare’s sonnets are not always concerned with so high and
noble a conception of love as is Sonnet 116. Their feet are more likely to
tread on the ground, to paraphrase another of the most famous sonnets,
number 130. This poem is “a clever piece of literary satire” in which “we
see [Shakespeare’s] amused and discerning awareness of Petrarchan
excess”.28 In this poem, Shakespeare openly mocks the Petrarchan
mode, holding up most of its major themes for ridicule: “Shakespeare
proclaims his independence from convention in Sonnet 130 in which,
while declaring love for his mistress, he mocks the standard vocabulary
of praise”.29 For example, the beloved, here rendered as “mistress”, thus
discarding the sense of a woman who is angelic and unapproachable,
does not have, as do so many Petrarchan and Neopetrarchan beloveds,
eyes like the sun or hair like flaxen strands of gold: My mistress’ eyes are nothing like the sun,
Coral is far more red, than her lips red,
If snow be white, why then her breasts are dun:
If hairs be wires, black wires grow on her head:30 364 Love and its Critics His mistress’ eyes are nothing like the sun, and a good thing too. A
woman with eyes like the sun would be well and truly unapproachable,
for who could make eye contact with a woman whose eyes had the power
to strike one blind? 31
Ibid., 130.5–12. 33
Vendler, 557. 31
Ibid., 130.5–12.
32
The modern bristle toothbrush, though invented by the Chinese Tang dynasty of
609–917 CE, did not make its first appearance in England, even among the wealthy,
until 1690. See Michael Olmert. Milton’s Teeth & Ovid’s Umbrella: Curiouser and
Curiouser Adventures in History (New York: Touchstone, 1996), 62.
33
Vendler, 557. 8. Shakespeare: The Return of Fin’amor In the very first line of the sonnet, Shakespeare has
dismantled the most common of the Petrarchan conceits—the lady as
somehow heavenly or divine—and the next lines proceed to dismantle
poetic notions of the lady’s physical perfection. As the sonnet continues,
the embodied reality of the mistress is celebrated, while the poetic cliché
is mocked: I have seen roses damasked, red and white,
But no such roses see I in her cheeks,
And in some perfumes is there more delight,
Than in the breath that from my mistress reeks. I love to hear her speak, yet well I know,
That music hath a far more pleasing sound:
I grant I never saw a goddess go,
My mistress when she walks treads on the ground.31 Here we have a woman whose breath stinks,32 whose voice is delicately
described as being less pleasing than music, and whose feet, unlike
those of a goddess, walk on English dirt. This description has sometimes
caused readers to react negatively, so accustomed are they to the inflated
praise of the “divine lady” in the tradition of poetry beginning with
Giacomo da Lentini and working its way through Petrarch to Sidney:
“Shakespeare’s mock-blazon has sometimes been thought misogynistic,
in part because readers have formed their idea of it from its octave,
where nothing positive is predicated of the mistress”.33 But this is a
mistake, for all of the criticisms that come before the closing couplet are
rejections of Petrarchan clichés, not of the woman herself. The woman
being described in these lines is no poetic ideal, no angel or goddess. This is a real woman with faults of the flesh. But the last two lines of the 8. Shakespeare: The Return of Fin’amor 365 sonnet, even more than the previous twelve, blow the Petrarchan mode
of idealized description right out of the water: And yet by heaven I think my love as rare,
As any she belied with false compare.34 Perhaps the most romantic lines in all of English literature, this final
couplet declares for the individual over the ideal, for the flesh over
the spirit, for immediate desire over sublimated worship. The woman
described in this poem exists in the world where everything that grows
holds in perfection but a little moment, and she is very probably past that
little moment. 34
Shakespeare, 130.13–14.
35
Callaghan (2007), 57.
36
Shakespeare, 138.1–4. 35
Callaghan (2007), 57. 34
Shakespeare, 130.13–14. 36
Shakespeare, 138.1–4. 34
Shakespeare, 130.13 14.
35
Callaghan (2007), 57. 34
Shakespeare, 130.13–14.
35
Callaghan (2007), 57. 8. Shakespeare: The Return of Fin’amor But she is “rare”, more singular and valuable than any of the
laughably false “shes” of the post-troubadour poetic tradition who have
been misrepresented through the “false compare” of poets less attuned to
the beauty of this world than to the imperious demands of worlds beyond. The final couplet “effects a shift from the lyrical to the colloquial register in
order to demonstrate that even goddesses are overrated”.35 Even more cutting in its rejection of the Petrarchan mode is the
description of a relationship between a man and a (much younger) woman
in Sonnet 138. This poem gives us a picture of compromise and lies as
the basis for an apparently successful relationship. No ladder of love or
pathway to the divine here: this poem describes a union in which each
deceives the other in order to keep the other reasonably, if not ecstatically,
happy. The lies, such as they are, seem thin, relatively harmless, and
perhaps even necessary if the two are going to stay together: When my love swears that she is made of truth,
I do believe her, though I know she lies,
That she might think me some untutored youth,
Unlearned in the world’s false subtleties.36 When my love swears that she is made of truth,
I do believe her, though I know she lies,
That she might think me some untutored youth,
Unlearned in the world’s false subtleties.36 We begin with the depiction of two lies: the speaker’s lover “swears
that she is made of truth” (a more obvious lie is almost inconceivable),
and the speaker knows that she lies; but the speaker also pretends to
“believe her”, to give an impression of simplicity and youthfulness Love and its Critics 366 in order to manipulate her thinking: “That she might think me some
untutored youth”. He pretends to believe her lies because it is useful to
him to have her believe that he is falling for those lies. 37
Ibid., 138.5–8
38
Ibid., 138.9–12. 8. Shakespeare: The Return of Fin’amor The subject of her
lies is probably his greater age (and possibly her desire for a younger
man), as evidenced by the following lines: Thus vainly thinking that she thinks me young,
Although she knows my days are past the best,
Simply I credit her false-speaking tongue,
On both sides thus is simple truth suppressed:37 The speaker is both vain (trying to pretend to himself that he is still
young, and that she is buying into his pretense), and thinking in vain,
thinking thoughts which are obviously not true, as neither he nor she
really regard him as young, because “she knows” his days are “past
the best”. But he pretends to believe her when she says he is young,
both simply (without criticism or confrontation about what each knows
is a lie) and as if a simpleton (thus furthering his own lie of being too
naïve to catch on to her lies). When the speaker thinks about this, he gets
angry for a moment, but then recovers his balance, and remembers his
reasons for compromise: But wherefore says she not she is unjust? And wherefore say not I that I am old? O love’s best habit is in seeming trust,
And age in love, loves not to have years told.38 Why don’t they just drop the masks, stop lying, and tell each other the
truth? Because that would upset the delicate balance of a relationship
that neither one of them is apparently willing to see come to an end. She
is unjust, and he is old (and unjust in his own way), but honesty in love
is not always the best policy. This couple, who have found something
in each other (perhaps once it was eros, and perhaps philia has settled in,
and there might even be a touch of agape or caritas in there somewhere),
clearly do not intend to upset the delicate balance they have achieved 8. Shakespeare: The Return of Fin’amor 367 by insisting on absolute truth between them. In fact, “seeming trust”
is their love’s “best habit” (best repeated action, and best guise or
disguise), and since neither one of them broaches the topic of “age in
love”, those “years” will not be “told”. 8. Shakespeare: The Return of Fin’amor The final couplet makes the
compromise clear: Therefore I lie with her, and she with me,
And in our faults by lies we flattered be.39 Here is no Astrophil agonizing over a Stella, Dante worshiping a
Beatrice, or Petrarch gazing to the point of idolatry on his own carefully-
wrought “she belied with false compare”. The love described in this
poem does not point the way to heaven or to higher philosophical truth. It merely enables two people to keep and maintain companionship in
an often lonely world where at least one of the poem’s figures held “in
perfection but a little moment” a very long time ago. Sonnet 138 portrays
a relationship in which two people compromise the ideal in favor of the
real. Without the rhetorical heights of more famous poems like Sonnet
18 or Sonnet 116, and without the visual humor and obvious mocking
of Petrarchism in Sonnet 130, Sonnet 138, in its quiet way, is the most
thorough rejection of the Beatrices, Lauras, and Stellas of Italian and
English poetry. It returns, as does Shakespeare’s larger body of work,
to the spirit of the troubadours, and to the spirit of Ovid, for whom
love may have involved compromise and lies, but was always love of
an individual. It returns to love as it was in the Song of Songs—love of a
man or woman of flesh and blood, rather than a God. 39
Ibid., 138.13–14. II
Shakespeare’s Plays: Children as Property In Shakespeare’s plays love thrives, not as allegory, but as the passionate
desire and regard between two who choose each other, often in the face
of fierce resistance. To trace the power and presentation of love, we will
consider two elements: the treatment of children as property by fathers,
and the claims of love, individual choice, and agency that defy paternal Love and its Critics 368 demands in order to assert the rights of one’s own heart. In so doing, we
will look at three daughters—Silvia, Hermia, and Juliet—whose desires
are regarded as impediments to the plans, purposes, and passions of the
fathers who begot them, before turning to the occasionally successful,
sometimes disastrous, but always disruptive challenges that love
and lovers will make to the forces that demand the exclusive right to
obedience, fidelity, and life itself. Shakespeare is not staging his plays of love in the face of resistance
in order to demonstrate, as the historian Lawrence Stone would have
it, that “the tragedy of Romeo and Juliet, [lay] in the way they brought
destruction upon themselves by violating the norms of the society in
which they lived”.40 Many members of Shakespeare’s audience may
have thought as Stone thinks—initially. But others did not. And during
the 1590s and 1600s, Shakespeare’s plays consistently present characters
that reject the forces of tradition: In the comedies and romantic tragedies, love emerges as a force of
inspiration and renewal for individuals and the enduring bond that
comprises human society. Time and again, he presents young men and
women who marry for love, rejecting the traditional arrangements of
their parents. The moral vision in Shakespeare’s plays is not ironclad
obedience to the ancién regime but a new moral order based on free will,
choice, and commitment, a personal bond of love and trust between two
individuals that becomes an inspiration to their world.41 Shakespeare’s Romeo and Juliet does not condemn its title characters,
but sympathizes with the lovers whose disobedience brings them
momentarily to the brink of a truly chosen life, only to be crushed by the
forces of obedience, law, and profit. Such a work does not criticize those
who violate the norms of society; rather, it criticizes the norms themselves. 40
Lawrence Stone. The Family, Sex, and Marriage in England 1500–1800 (New York:
Harper and Row, 1977), 87.
41
Diane Dreher. Domination and Defiance: Fathers and Daughters in Shakespeare
(Lexington: University Press of Kentucky, 1986), 38. 40
Lawrence Stone. The Family, Sex, and Marriage in England 1500–1800 (New York:
Harper and Row, 1977), 87.
41
Di
D
h
D
i
i
d D fi
F h
d D
h
i
Sh k 41
Diane Dreher. Domination and Defiance: Fathers and Daughters in Shakespeare
(Lexington: University Press of Kentucky, 1986), 38. II
Shakespeare’s Plays: Children as Property Shakespeare’s Romeo and Juliet does not condemn its title characters,
but sympathizes with the lovers whose disobedience brings them
momentarily to the brink of a truly chosen life, only to be crushed by the
forces of obedience, law, and profit. Such a work does not criticize those
who violate the norms of society; rather, it criticizes the norms themselves. Shakespeare writes during a time of transition. His life and career
cross over the end of the sixteenth-century Elizabethan world into
the beginnings of the seventeenth-century Stuart dynasty, which
will eventually see a people rise against its king, a gentleman farmer
become the Lord Protector of England, and a poet of revolution become 8. Shakespeare: The Return of Fin’amor 369 the country’s international voice. Even as he is writing his earliest
plays, such as Two Gentlemen of Verona, England is already beginning
to stir with discontent and the unmistakable signs of future rebellion. The resentment of Catholic citizens at being forced to conform to the
doctrines and disciplines of a new faith, denying the dictates of their
consciences, will soon enough burst out into the attempt to assassinate
a king and a parliament together in the infamous Gunpowder Plot. The
discontents of many Protestants with the quasi-Catholic ceremonies,
hierarchies, and vestments of the English Church break out into
vituperative pamphlet broadsides such as the Marprelate controversy
of 1588–89. Elizabeth’s last Archbishop of Canterbury, John Whitgift,
uses his position to enforce conformity in religion, attempting to
crush the Presbyterian and Independent church movements, even
as he moves to codify and mandate English belief in the Calvinist
doctrine of predestination with the Lambeth Articles of 1595. Francis
Walsingham, Elizabeth’s spymaster, makes the 1570s and 1580s a period
of repression and abject terror for the country’s Catholics, who can be
jailed for celebrating Mass or hiding a priest (who was himself liable to
execution for carrying out his then-illegal function). England undergoes
tremendous upheaval during Shakespeare’s lifetime, moving from
majority Catholic at his birth to majority Protestant at his death, while
matters of faith, family, marriage, and emotion are all too often matters
of conformity and obedience to the imperious demands of authority:
whether that of God, the monarch, or the father. In a sense, Stone may be right—“an Elizabethan courtier [who
saw] where duty lay”42 may have condemned the disobedience of a
character like Juliet. 42
L. Stone, 87. 43
For detailed discussions of the composition of such audiences (in terms of
economics, gender, and numerous other factors), see Andrew Gurr, Playgoing in
London (Cambridge: Cambridge University Press, 2004).
44
The as yet unsolved question of the authorship of this play revolves primarily
around two candidates: William Shakespeare and Thomas Kyd. Arguments
for Kyd go back to Charles Crawford and Walter Miksch in the early twentieth
century (in, respectively, “The Authorship of Arden of Faversham”. In Jahrbuch der
Deutschen Shakespeare-Gesellschaft, 39 [1903], 74–86, and Die verfasserschaft des Arden
of Feversham [Breslau: H. Fleischmann, 1907]), and have recently been championed 43
For detailed discussions of the composition of such audiences (in terms of
economics, gender, and numerous other factors), see Andrew Gurr, Playgoing in
London (Cambridge: Cambridge University Press, 2004). 44
The as yet unsolved question of the authorship of this play revolves primarily
around two candidates: William Shakespeare and Thomas Kyd. Arguments
for Kyd go back to Charles Crawford and Walter Miksch in the early twentieth
century (in, respectively, “The Authorship of Arden of Faversham”. In Jahrbuch der
Deutschen Shakespeare-Gesellschaft, 39 [1903], 74–86, and Die verfasserschaft des Arden
of Feversham [Breslau: H. Fleischmann, 1907]), and have recently been championed 46
See Greenblatt’s argument—published in several different forms—in Shakespearean
Negotiations: The Circulation of Social Energy in Renaissance England (Berkeley and
Los Angeles: University of California Press, 1998); ‘Invisible Bullets: Renaissance
Authority and its Subversion’, in Glyph 8: Johns Hopkins Textual Studies (Baltimore:
Johns Hopkins University Press, 1981), 40–61; ‘Invisible Bullets: Renaissance
Authority and its Subversion, Henry IV and Henry V’, in Political Shakespeare:
New Essays in Cultural Materialism, eds, Jonathan Dollimore and Alan Sinfield
(Manchester: Manchester University Press, 1985), 18–47; and in “Invisible Bullets:
Renaissance Authority and its Subversion”, in eds. Peter Erickson and Coppélia
Kahn, Shakespeare’s ‘Rough Magic’: Renaissance Essays in Honor of C. L. Barber
(Newark: University of Delaware Press, 1985), 276–302. This argument, as Gabriel 45
Arden of Faversham. In Martin Wiggins, ed. A Woman Killed with Kindness and Other
Domestic Plays (Oxford: Oxford University Press, 2008), 1.98–102. by Brian Vickers (“Thomas Kyd, Secret Sharer”. Times Literary Supplement [18 April
2008], 13–15). The most recent argument for Shakespeare’s authorship (especially
of the middle section of the play) has been made by MacDonald P. Jackson in
Determining the Shakespeare Canon: “Arden of Faversham” and “A Lover’s Complaint”
(Cambridge: Cambridge University Press, 2015), while the editors of The New
Oxford Shakespeare (Gary Taylor, et al., 2016) include the play, listing its authorship
as by Anonymous and Shakespeare. by Brian Vickers (“Thomas Kyd, Secret Sharer”. Times Literary Supplement [18 April
2008], 13–15). The most recent argument for Shakespeare’s authorship (especially
of the middle section of the play) has been made by MacDonald P. Jackson in
Determining the Shakespeare Canon: “Arden of Faversham” and “A Lover’s Complaint”
(Cambridge: Cambridge University Press, 2015), while the editors of The New
Oxford Shakespeare (Gary Taylor, et al., 2016) include the play, listing its authorship
as by Anonymous and Shakespeare. 48
Roger Stilling. Love and Death in Renaissance Tragedy (Baton Rouge: Louisiana State
University Press, 1976), 148.
49
L St
103 Egan explains, insists that any resistance to authority portrayed in Shakespeare,
Marlowe, and others was merely illusory, because “the theatre industry of
Shakespeare’s time was a special device for the containment of progressive forces
precisely because it appeared to produce subversion” (Gabriel Egan. Shakespeare
and Marx [Oxford: Oxford University Press, 2004], 95).
47
L S
490 91 II
Shakespeare’s Plays: Children as Property But courtiers were a minority among the public
theatre audiences of the 1590s and early 1600s,43 for whom the distinctly
uncourtly scenario presented in Arden of Faversham (1592)44 was already Love and its Critics 370 familiar. In that play, a wife named Alice is willing—even eager—to
murder her husband in order to be with her lover, Mosby. And despite
the fact that this is presented as a crime which will be punished, the
idea is still present that marriage without love is a despotism in which
the husband is an illegitimate usurper, whose fate is to be cast out and
overthrown. As Alice expresses it: Sweet Mosby is the man that hath my heart,
And he [Arden] usurps it, having nought but this,
That I am tied to him by marriage. Love is a god, and marriage is but words;
And therefore Mosby’s title is the best.45 Shakespeare’s audiences filled the Globe Theatre for spectacles
of disobedience and passionate assertions of the right to choose,
performances which enabled them to imagine themselves, not as
criminals, but as living and loving in the same free and chosen manner
as those men and women they saw enacted on the stage. Far from being a
bastion of convention-confirming conservatism—as Stephen Greenblatt
contends through his idea of subversion and containment, a process
which continually produces rebellion and tames it at the same time
(thus subverting and containing the rebellious force)46—Shakespeare’s 8. Shakespeare: The Return of Fin’amor 371 plays not only encourage, but as we will see in Two Gentlemen of Verona,
A Midsummer Night’s Dream, and Romeo and Juliet, they celebrate
disobedience in the name of love, the power of men and women to
choose their own hearts’ path, and the right to live as they see fit. The
driving force behind this celebration of disobedience, this rejection of the
notion that children are the property of their parents and citizens are the
helpless subjects of their monarch, is the power of an old idea—fin’amor: Beginning as a purely extra-marital emotion in troubadour literature of
the twelfth century, it was transformed by the invention of the printing
press and the spread of literacy in the sixteenth and seventeenth centuries. 47
L. Stone, 490–91. Egan explains, insists that any resistance to authority portrayed in Shakespeare,
Marlowe, and others was merely illusory, because “the theatre industry of
Shakespeare’s time was a special device for the containment of progressive forces
precisely because it appeared to produce subversion” (Gabriel Egan. Shakespeare
and Marx [Oxford: Oxford University Press, 2004], 95).
47
L. Stone, 490–91.
48
Roger Stilling. Love and Death in Renaissance Tragedy (Baton Rouge: Louisiana State
University Press, 1976), 148.
49
L.Stone, 103. II
Shakespeare’s Plays: Children as Property It was a theme which dominated the poetry, theatre and romances of the
late sixteenth and seventeenth centuries and found its way into real life
in the mid-eighteenth century.47 However, the mid-eighteenth century is far too late a period to identify
as the time in which the love described in poetry, theatre, and romances
works its way into real life. One only need look at the story of John Donne
and Anne More, discussed in Chapter 9, to be disabused of that notion. This is very much a development of the literature of Shakespeare’s time,
and “the movement of lovers toward each other may well be the most
important single motive force in Elizabethan literature”.48 Love is not “a
reality which existed in one very restricted social group”, nor is it merely
“the subject of much poetry of the sixteenth and early seventeenth
centuries, and of many of Shakespeare’s plays”.49 For many, both in
Shakespeare’s audience and his larger world, love is an urgent concern. It is here and now that love enters “real life”, as art and life engage in a
mutually affirming, mutually embracing dance of cultural, intellectual,
and philosophical upheaval which moves the world from one in which
all human devotion is directed upward—to God, monarch, and father—
to one in which love is shared between relative equals; a move away However, the mid-eighteenth century is far too late a period to identify
as the time in which the love described in poetry, theatre, and romances
works its way into real life. One only need look at the story of John Donne
and Anne More, discussed in Chapter 9, to be disabused of that notion. 372 Love and its Critics from a world in which love, beauty, and other people are means to an
end, steps on a ladder leading to the divine, and to a world in which
love, beauty, and all our beloveds are ends in themselves. In his way,
Shakespeare helps to push the intellectual world from Plato to Kant,
from the forms to the things in themselves, from a focus on the abstract
idea of a rose, to the beauty of the rose that is right in front of us. 50
As Bloom lays out the case,
[t]he idea of Western character, of the self as a moral agent, has many sources: Homer and Plato,
Aristotle and Sophocles, the Bible and St. Augustine, Dante and Kant, and all you might care
to add. Personality, in our sense, is a Shakespearean invention, and is not only Shakespeare’s
greatest originality but also the authentic cause of his perpetual pervasiveness. Insofar as we
ourselves value, and deplore, our own personalities, we are the heirs of Falstaff and of Hamlet,
and of all the other persons who throng Shakespeare’s theater of what might be called the
colors of the spirit. 51
For a review and critique, see Linda A. Pollock. Forgotten Children: Parent-Child
Relations from 1500 to 1900. Cambridge: Cambridge University Press, 1983, 1–67. See
also Lois G. Schwoerer, “Seventeenth-Century English Women Engraved in Stone?”
Albion, 16.4 (1984), 389–403, who analyzes Stone’s work from a feminist perspective;
Alan MacFarlane, “The Family, Sex, and Marriage in England”, History and Theory,
18 (1979), 103–26, who critiques Stone’s readings of secondary material; Philippe
Ariès, “Lawrence Stone. The Family, Sex and Marriage in England, 1500–1800”,
American Historical Review, 83 (1978), 1221–24, who, in an otherwise complimentary
review, argues that Stone distorts early modern child-rearing practices; and John
Gillis, “Affective Individualism and the English Poor”, Journal of Interdisciplinary
History, 10 (1979), 121–28, who argues that Stone ignores the lower economic levels
of society in his work. Harold Bloom. Shakespeare: The Invention of the Human (New York: Penguin, 1998), 4. 50
As Bloom lays out the case,
[t]he idea of Western character, of the self as a moral agent, has many sources: Homer and Plato,
Aristotle and Sophocles, the Bible and St. Augustine, Dante and Kant, and all you might care
to add. Personality, in our sense, is a Shakespearean invention, and is not only Shakespeare’s
greatest originality but also the authentic cause of his perpetual pervasiveness. Insofar as we
ourselves value, and deplore, our own personalities, we are the heirs of Falstaff and of Hamlet,
and of all the other persons who throng Shakespeare’s theater of what might be called the
colors of the spirit.
Harold Bloom. Shakespeare: The Invention of the Human (New York: Penguin, 1998), 4.
51
For a review and critique, see Linda A. Pollock. Forgotten Children: Parent-Child
Relations from 1500 to 1900. Cambridge: Cambridge University Press, 1983, 1–67. See
also Lois G. Schwoerer, “Seventeenth-Century English Women Engraved in Stone?”
Albion, 16.4 (1984), 389–403, who analyzes Stone’s work from a feminist perspective;
Alan MacFarlane, “The Family, Sex, and Marriage in England”, History and Theory,
18 (1979), 103–26, who critiques Stone’s readings of secondary material; Philippe
Ariès, “Lawrence Stone. The Family, Sex and Marriage in England, 1500–1800”,
American Historical Review, 83 (1978), 1221–24, who, in an otherwise complimentary
review, argues that Stone distorts early modern child-rearing practices; and John
Gillis, “Affective Individualism and the English Poor”, Journal of Interdisciplinary
History, 10 (1979), 121–28, who argues that Stone ignores the lower economic levels
of society in his work. 55
“un dispositif d’alliance: système de mariage, de fixation et de développement
des parentés, de transmission des noms et des biens” (Michael Foucault. Histoire
de La Sexualité Vol. 1: la Volonté de Savoir [Paris: Gallimard, 1976], 140). Foucault
opposes this “deployment of alliance” not with the concept of fin’amor that we are
identifying here as a combination of love, mutual recognition, and mutual choice
between lovers, but with what he calls “the deployment of sexuality” (“le dispositif de
sexualité”) (140), a concept he defines as operating “based on techniques of power
that are mobile, polymorphous, and cyclical” (“d’après des techniques mobiles,
polymorphes et conjoncturelles de pouvoir”), and as concerned with “the body’s
sensations, the quality of its pleasures, and the nature of its impressions, as tenuous 52
Richard Allestree. The Practice of Christian Graces, or The Whole Duty of Man (London:
Printed by D. Maxwell for T. Garthwait, 1658), 291, https://quod.lib.umich.edu/
cgi/t/text/pageviewer-idx?cc=eebo;c=eebo;idno=a23760.0001.001;node=A23760.000
1.001%3A19;seq=318;vid=96830;page=root;view=text
53
L Sto e 181 54
Hagstrum, 220. II
Shakespeare’s Plays: Children as Property Harold
Bloom, that old Falstaff of American literary criticism, was at least partly
right: Shakespeare helped to invent the modern sense of what it means
to be a human being in the Western world.50 Unfortunately, it is not hyperbolic to describe the parent-child
relationships of Early Modern England as proprietary. Though Stone’s
thesis of the cold emotional detachment of parents from their children
in the period may have been overstated,51 the hierarchical relationships
within families are well-documented. As late as 1658, in an era of
revolution and upheaval, the pater familias-style conservatism of parent-
child relations, though beginning its decline, is still alive and well and
speaking with a clear voice about the rights of parents to determine the
marital and family futures of their children. From this perspective, for
sons or daughters to choose their own mates is among the worst kinds
of disobedience possible: 373 8. Shakespeare: The Return of Fin’amor 53
L. Stone, 181. 8. Shakespeare: The Return of Fin’amor But of all acts of disobedience, that of marrying against the consent of
the Parent, is one of the highest. Children are so much the goods, the
possessions of the Parent, that they cannot without a kind of theft, give away
themselves without the allowance of those, that have the right in them.52 But of all acts of disobedience, that of marrying against the consent of
the Parent, is one of the highest. Children are so much the goods, the
possessions of the Parent, that they cannot without a kind of theft, give away
themselves without the allowance of those, that have the right in them.52 From this point of view, children are portable wealth; not as fixed as
land, though not so permanent either, children represent an opportunity
to improve the family’s fortunes through advantageously-arranged
marriages. And the fathers of the respective families that were matched
in such a union were not about to allow the romantic notions of their
children to interfere with business. The era struggled with a clear conflict of values between the idealization of love by some
poets, playwrights and the authors of romances on the one hand, and
its rejection as a form of imprudent folly and even madness by all
theologians, moralists, authors of manuals of conduct, and parents and
adults in general.53 It was the fathers who stood most to gain from the marriages they arranged
for their children: “[t]he marital pactum was too important to be created
by the individuals concerned; instead it was forged by the two men who
headed the two families involved. or imperceptible as these may be” (“les sensations du corps, la qualité des plaisirs,
la nature des impressions aussi ténues ou imperceptibles qu’elles soient”) (140).
But far from being anything like an avenue for resistance to the authorities of a
given time and place, for Foucault, this alliance of sexuality is merely one more
means of control: “The deployment of sexuality does not have its reason for being
in reproduction, but in […] controlling populations in an ever more global manner”
(“Le dispositif de sexualité a pour raison d’être non de se reproduire, mais de […]
contrôler les populations de manière de plus en plus globale”) (141). 56
Dreher, 28. 57
Diana O’Hara. Courtship and Constraint: Rethinking the Making of Marriage in Tudor
England (Manchester: Manchester University Press, 2000), 215.
58
Ibid., 32. 59
L. Stone, 180. 58
Ibid., 32. 60
Dreher, 21.
61
L. Stone, 171.
62
Ibid.
63
John Aubrey. Wiltshire. The Topographical Collections of John Aubrey, 1659–70, ed. by
John Edward Jackson (London: Longman, 1862), 16, https://archive.org/stream/
wiltshiretopogra00aubr#page/16 8. Shakespeare: The Return of Fin’amor Negotiations resembled statecraft on
a smaller scale”.54 For many generations, marriage had been treated
as a business deal, an economic exchange between families—or more
precisely, between fathers, in what Foucault describes as “a deployment
of alliance: a system of marriage, of the securing and developing of
kinship ties, of the transmission of names and possessions”.55 As a result 374 Love and its Critics of this system of alliance-forming, “[m]ost marriages in the sixteenth
and early seventeenth centuries were arranged by parents or guardians
[and] economic interests and parental pressures prevailed, [though]
the poor, with no considerations of lineage and property, could often
choose for themselves”.56 The idea that money was often, if not always,
at the root of such arranged marriages is supported by English court
documents, in which “[o]f all the depositions studied for the period
1542–1600, at least a third sufficiently illustrates the weighting of
financial considerations in the making of marriages”.57 It was not, of course, the situation that no child ever had any
input into the choice of his or her eventual spouse. But neither were
theirs the voices that spoke most persuasively on the matter: “‘I must
be ruled by my friends’, said Elizabeth Fletcher of Canterbury, ‘as
well as by myself’”.58 Even in cases where individual expression was
accommodated, children were expected, in keeping with their role as
goods and possessions, to maintain obedience. This expectation was
especially pronounced where the subject of marriage was concerned: The choice of marriage partner concerned both boys and girls and was
especially important in a society where there were large financial and
political stakes in marriage and where divorce was virtually impossible. The choice of marriage partner concerned both boys and girls and was
especially important in a society where there were large financial and
political stakes in marriage and where divorce was virtually impossible. Almost all children until the end of the sixteenth century were so
conditioned by their upbringing and so financially helpless that they
acquiesced without much objection in the matches contrived for them
by their parents.59 Almost all children until the end of the sixteenth century were so
conditioned by their upbringing and so financially helpless that they
acquiesced without much objection in the matches contrived for them
by their parents.59 While “[t]he notion of children as property”, seems inhumane to us,
it “was deeply imbedded in Renaissance thought. Children were their 8. 8. Shakespeare: The Return of Fin’amor Shakespeare: The Return of Fin’amor 375 parents’ goods, to be used as they saw fit, and owed them lifelong
obedience for begetting them”.60 Even titled children, who outranked
their parents in the hierarchy of the nation, were expected to perform
acts of fealty and submission that seem incredible today. For example,
the playwright, translator, and author Elizabeth Cary (née Tanfield),
became Lady Falkland the Viscountess Falkland, when her husband
was made Viscount in 1634. And yet she was still required to show,
not merely respect, but outright submission to her mother: “Elizabeth,
Countess of Falkland, always knelt in her mother’s presence, sometimes
for an hour at a time, despite the fact that she had married above her
parents into the peerage, and that she was ‘but an ill kneeler and worse
riser’”.61 And though Cary’s case seems especially counter-intuitive
today, it was far from uncommon in her time: [the] stress on domestic discipline and the utter subordination of the
child found expression in extraordinary outward marks of deference
which English children were expected to pay to their parents in the
sixteenth and early seventeenth centuries. It was customary for them
when at home to kneel before their parents to ask their blessing every
morning, and even as adults on arrival at and departure from the home. This was a symbolic gesture of submission which John Donne believed
to be unique in Europe.62 As John Aubrey describes conditions of the period: 63
John Aubrey. Wiltshire. The Topographical Collections of John Aubrey, 1659–70, ed. by
John Edward Jackson (London: Longman, 1862), 16, https://archive.org/stream/
wiltshiretopogra00aubr#page/16 As John Aubrey describes conditions of the period: The child perfectly loathed the sight of his parents as the slave his torture. Gentlemen of 30 and 40 years old were to stand like mutes and fools
bareheaded before their parents; and the daughters […] were to stand
at the cupboard-side, during the whole time of the proud Mother’s visit
[until] they had done sufficient penance in standing.63 Failure to obey, especially in the matter of marital choice, could have serious
negative consequences even with one’s siblings, much less one’s parents: No amount of pleading would move some kinsmen. The widow
Christine Marsh fell down on her knees before her brother George 376 Love and its Critics Coppyn, desiring him to be a good brother unto her and a friend also,
for he had rebuked and threatened her for the promise she had made to
George Gaunt.64 Coppyn, desiring him to be a good brother unto her and a friend also,
for he had rebuked and threatened her for the promise she had made to
George Gaunt.64 To marry without permission often brought financial repercussions, as
displeased parents would use the threat of disinheritance to prevent
and/or punish the “disobedience” involved in making one’s own choice. Elizabeth Evelyn was punished in precisely this way by her father, who
describes with a certain methodical and self-righteous tone the reasons
for his decision to disinherit his eldest child: [July] 27 This night when we were all asleep went my daughter Elizabeth
away to meet a young fellow, nephew to Sir John Tippet (Surveyor of the
Navy, and one of the Commissioners), whom she married the next day,
being Tuesday, without in the least acquainting either of her parents,
or any soul in the house. […] This accident caused me to alter my will,
as was reasonable; for though there may be a reconciliation upon her
repentance, and that she suffered her folly; yet I must let her see what
her undutifulness in this action deprives her of, as to the provision she
else might have expected, solicitous as she knew I now was of bestowing
her very worthily.65 The fathers of Shakespeare’s plays, who may well seem to modern
readers and spectators like so many tinpot dictators, were not at all
unusual for their time. To Shakespeare’s contemporaries, they would
have been entirely familiar, on-and off-stage. 64
O’Hara, 33.
65
Ralph A. Houlbrooke, ed. “‘Stealing a Marriage’: The Marriage of Elizabeth Evelyn
in 1685 Described by Her Father”. English Family Life, 1576–1716: An Anthology from
Diaries (Oxford: Blackwell, 1988), 39.
66
Hamlet 3.1.21–24. 64
O Hara, 33.
65
Ralph A. Houlbrooke, ed. “‘Stealing a Marriage’: The Marriage of Elizabeth Evelyn
in 1685 Described by Her Father”. English Family Life, 1576–1716: An Anthology from
Diaries (Oxford: Blackwell, 1988), 39.
66
Hamlet 3 1 21–24 As John Aubrey describes conditions of the period: Hamlet explains why: art
serves “to hold, as ‘twere, the mirror up to nature; to show virtue her
own feature, scorn her own image, and the very age and body of the
time his form and pressure”.66 In giving this speech to the players, he
is not telling them that art uncritically mirrors the values and practices
of a civilization to its members while encouraging them to remain
compliant. His entire purpose for the play-within-the-play is angry and
accusatory. That is what art—Shakespeare’s art—is when at its best. Art holds up the mirror to show the time and place within which it
appears, to which it reacts, and against which it often struggles, that the 8. Shakespeare: The Return of Fin’amor 377 “customs of [its] island and tribe are [not] the laws of nature”.67 Thus,
when portraying the Duke of Milan in The Two Gentlemen of Verona, or
Egeus in A Midsummer Night’s Dream, or Capulet in Romeo and Juliet,
Shakespeare is not soothing, he is savaging, He is holding them up for
scorn as images of what not to do rather than as examples of the idea
that Father knows best. The play’s the thing, in which he will catch the
consciences of countless fathers who think themselves king. The plots initially revolve around marriage as a bond, not between a
young man and a young woman, but between two men over and through
the body of a woman. In what Eve Sedgwick describes as a dynamic of
homosociality,68 the fathers in these plays bond themselves to men of
their choosing (often quite a bit older than their daughters), who offer
advantages in terms of wealth, land, and power. 67
George Bernard Shaw. “Caesar and Cleopatra”. Three Plays for Puritans (New York:
Brentano’s, 1906), 119, https://babel.hathitrust.org/cgi/pt?id=hvd.32044014213078;v
iew=1up;seq=167 67
George Bernard Shaw. “Caesar and Cleopatra”. Three Plays for Puritans (New York:
Brentano’s, 1906), 119, https://babel.hathitrust.org/cgi/pt?id=hvd.32044014213078;v
iew=1up;seq=167
68
A term originally coined in 1976 by Jean Lipmen-Blumen to describe a social, rather
than sexual, preference for members of one’s own sex.
69
Eve Kosofsky Sedgwick. Between Men: English Literature and Male Homosocial Desire
(New York: Columbia University Press, 1985), 26.
70
[l]a relation globale d’échange qui constitue le mariage ne s’établit pas entre un homme et
une femme qui chacun doit, et chacun reçoit quelque chose: elle s’établit entre deux groupes
d’hommes, et la femme y figure comme un des objets des objets d l’échange, et non comme un
des partenaires entre lesquels il a lieu.
Claude Lévi-Strauss. Les Structures Élémentaires de la Parenté (Berlin: De Gruyter), 2002). Claude Lévi-Strauss. Les Structures Élémentaires de la Parenté (Berlin: De Gruyter), 2002). 70
[l]a relation globale d’échange qui constitue le mariage ne s’établit pas entre un homme et
une femme qui chacun doit, et chacun reçoit quelque chose: elle s’établit entre deux groupes
d’hommes, et la femme y figure comme un des objets des objets d l’échange, et non comme un
des partenaires entre lesquels il a lieu. 69
Eve Kosofsky Sedgwick. Between Men: English Literature and Male Homosocial Desire
(New York: Columbia University Press, 1985), 26. 68
A term originally coined in 1976 by Jean Lipmen-Blumen to describe a social, rather
than sexual, preference for members of one’s own sex. 71
John Rutherford, ed. The Troubadours: Their Loves and their Lyrics (London:
Smith, Elder & Co., 1873), 34, ll. 1–4, https://archive.org/stream/troubadoursthei
01ruthgoog#page/n48 As John Aubrey describes conditions of the period: Sedgwick, following
Gayle Rubin, describes this as “traffic in women”, or “the use of women
as exchangeable, perhaps symbolic, property for the primary purpose of
cementing the bonds of men with men”.69 In this claim, she rearticulates
the argument of the French anthropologist Claude Lévi-Strauss: [t]he overall relationship of exchange which constitutes marriage is not
established between a man and a woman, in which everyone has rights
and everyone gets something: it is between two groups of men, and the
woman figures as one of the objects of exchange, and not as one of the
partners between whom exchange occurs.70 In just this fashion, the fathers in Shakespeare attempt to partner with
other men, while using their daughters as “objects of exchange”. Love—
passionate and mutually chosen attachment between those who would
otherwise be caught up in the pattern—serves as the primary means of
resistance. Silvia and Hermia choose their loves despite their fathers, In just this fashion, the fathers in Shakespeare attempt to partner with
other men, while using their daughters as “objects of exchange”. Love—
passionate and mutually chosen attachment between those who would
otherwise be caught up in the pattern—serves as the primary means of
resistance. Silvia and Hermia choose their loves despite their fathers, Love and its Critics 378 and would likely do so again, despite the hardships that ensue. Romeo
and Juliet choose each other in the face of family hatred and violence,
even enacting their own version of a dawn song in which they lament
the coming of day and the short moments they have left to be together. In many of his most powerful plays, Shakespeare casts love and its
pursuit in the light of rebellions that are both justified and long overdue. As wielded in Shakespeare’s plays, love serves as the primary challenge
to the authority of fathers and rulers who claim obedience from children
and subjects alike. III
Love as Resistance: Silvia and Hermia III As the Troubadour poet Giraut de Borneilh (1138–1215) describes it,
love enters through the eyes: Tam cum los oills el cor ama parvenza
Car li oill son del cor drogoman
E ill oill van vezer,
Lo cal cor plaz retener.71 So through the eyes love enters the heart,
Because the eyes are the agents of the heart
And the eyes go forth to gaze,
On what the heart would like to own. So through the eyes love enters the heart,
Because the eyes are the agents of the heart
And the eyes go forth to gaze,
On what the heart would like to own. For Giraut, love cannot be tamed and controlled, nor does it develop as
an emotional balm to heal the frictions of an arranged marriage between
strangers; rather it is something that hits from the outside and works its
way inwards in a near-immediate process of transformation. Gottfried
Von Strassburg’s image for this is the effect of the love-drink: meant to
provide the bond between King Mark and his young bride-to-be Isot
(Iseult or Isolde in other versions of the story), it instead transforms 8. Shakespeare: The Return of Fin’amor 379 Tristan and Isot from two into one, “who had both one heart”.72 It is this
transformative power that causes Gottfried’s lovers to defy King Mark,
and this power is shown again and again in Shakespeare as the driving
force behind the resistance to the homosocial structure of exchange. Tristan and Isot from two into one, “who had both one heart”.72 It is this
transformative power that causes Gottfried’s lovers to defy King Mark,
and this power is shown again and again in Shakespeare as the driving
force behind the resistance to the homosocial structure of exchange. Such resistance can be seen initially in the early comedy The Two
Gentleman of Verona. In this relatively light, yet humorously bizarre and
revealing play, the triangular pattern of fathers matching themselves to
men through their daughters is evident. But Shakespeare uses an old
comic device, the cuckolding plot, to add a fourth element: a young
man who will try to break up the sexual match between the often-older
man and the daughter by stealing her away (with her enthusiastic
assistance), thus scotching the proposed partnership between the men. 72
“si heten beide ein herze” (Gottfried Von Strassburg. Tristan, l. 11,731, ed. by
Karl Marold [Leipzig: E. Avenarius, 1906], https://archive.org/stream/gottfried
vonstr00unkngoog#page/n240). g
g p g
73
Two Gentlemen of Verona 2.4.172–73. 74
Ibid., 3.1.68–79.
75
See Linda Woodbridge. Vagrancy, Homelessness, and English Renaissance Literature
(Urbana: University of Illinois Press, 2001).
76
Two Gentlemen of Verona 4.3.14–17, 27–31.
77
L. Stone, 180. III
Love as Resistance: Silvia and Hermia The Duke of Milan wishes to match his daughter Silvia (whom he
keeps locked in a tower at night) to a wealthy, if otherwise unappealing
man named Thurio. He is swayed in this choice because Thurio is rich,
despite an evident lack of any other desirable qualities. As Valentine
describes Thurio, he is a “foolish rival, that her father likes / Only for his
possessions are so huge”.73 But in arranging this match, the Duke has a
problem: Silvia despises Thurio, and has fallen in love with Valentine. As
Valentine is busily arranging to run away with Silvia by using a rope
ladder (which he is hiding underneath his cloak), he encounters the
Duke, who complains of his daughter’s disobedience: she is peevish, sullen, froward,
Proud, disobedient, stubborn, lacking duty,
Neither regarding that she is my child
Nor fearing me as if I were her father;
And, may I say to thee, this pride of hers,
Upon advice, hath drawn my love from her;
And, where I thought the remnant of mine age
Should have been cherished by her child-like duty,
I now am full resolved to take a wife
And turn her out to who will take her in: 380 Love and its Critics Then let her beauty be her wedding-dower;
For me and my possessions she esteems not.74 In this speech, we encounter elements we will see again. The father
demands his daughter’s obedience, in this case specifically to his will in
terms of his choice for her marriage partner. When she does not comply
with his will, he threatens to disown her, despite the fact that he had
planned to rely on her as a caretaker as he aged, and resolves to throw
her out of his house and let her fend for herself by living the life of an
early modern vagrant.75 However, the perspective the Duke either does not understand or
does not care to understand—his daughter’s side of the question—is
exactly what the play highlights for its audience, showing “the very age
and body of the time his form and pressure”. Silvia regards the match
with Thurio, not merely as undesirable, but as unholy. III
Love as Resistance: Silvia and Hermia In pleading with
a gentleman to help her escape, she describes the match as one worthy
of punishment by heaven itself: Thou art not ignorant what dear good will
I bear unto the banished Valentine,
Nor how my father would enforce me marry
Vain Thurio, whom my very soul abhors. […]
Urge not my father’s anger, Eglamour,
But think upon my grief, a lady’s grief,
And on the justice of my flying hence,
To keep me from a most unholy match,
Which heaven and fortune still rewards with plagues.76 This is no mere foolery, or adolescent madness, nor is Shakespeare here
running “directly across the norms and practices of [his audience]”.77
This is Shakespeare showing his audience that “the norms and practices”
of their society run “directly across” their hearts. Silvia wants and needs
to be stolen from her father, in a “theft’ that involves giving herself away 77
L. Stone, 180. 8. Shakespeare: The Return of Fin’amor 381 “without the allowance of those, that have the right in [her]”.78 But in
their mutual defiance of her father’s will, Valentine and Silvia seek no
harm each to the other, nor any dominance one over the other. The same
cannot be said of the “lover” Proteus. Proteus’ love is destructive, and actively seeks to subordinate the
will of others. Proteus does not so much rebel against the authority of
the Duke of Milan as try to sneak around it, pretending to serve the
Duke while imposing himself on Silvia, who absolutely does not want
him. Proteus, who feared his father at the beginning of the play,79 fears
any honest confrontation with the Duke as much or more, and takes
the coward’s way out consistently. Determining to betray his friendship
with Valentine because “I to myself am dearer than a friend”,80 and
because the merest sight of Silvia has “dazzled [his] reason’s light”,81
Proteus behaves as if Silvia owes him her love because of the frequent,
though unwelcome, declarations he makes of his love. g
It is in Proteus’ threat to rape Silvia, and the odd way that threat
plays out—not between himself and Silvia, but between himself and
Valentine—where this play’s most unusual twist on love can be found. 78
Allestree, 291.
79
Two Gentlemen of Verona 1.3.78–87.
80
Ibid., 2.6.23.
81
Ibid., 2.4.208.
82
Ibid., 2.4.33.
83
Ibid., 5.4.59. 78
Allestree, 291. 79
Two Gentlemen of Verona 1.3.78–87. III
Love as Resistance: Silvia and Hermia Despite the fact that Silvia has declared that she would rather be eaten,
digested, and then presumably excreted by a “hungry lion”82 than have
anything to do with Proteus, the perversely determined young man
simply will not take “no” for an answer. Insisting that he will finally
bend Silvia’s will to his own, and not about to be satisfied with any
courtly tricks or delays, Proteus declares that he will love Silvia “‘gainst
the nature of love” by forcing her to submit to his desire.83 Whatever
else may be said of fin’amor, it is not rape. The ultimate in fals’amor, rape
seeks, not mutual choice in a one-to-one relationship, but a perverse
form of obedience. Rape seeks exactly the opposite of that sought by
love. Where love wishes to be free from the authority of the father, rape
reimposes that authority by the most intimately violent means, changing
the agent or enactor of that authority from the father to the rapist. In 382 Love and its Critics essence, Proteus does not seek to rebel against the Duke so much as become
the Duke: declaring his authority over the flesh, the sexuality, of Silvia. Even odder, and to many contemporary readers less explicable, is
Valentine’s reaction. Rather than show any concern for Silvia, he directs
his emotional investment—not merely anger, but what looks like the
genuine disappointment of a jilted lover—toward Proteus: […] Proteus,
I am sorry I must never trust thee more,
But count the world a stranger for thy sake. The private wound is deepest: O time most accurst,
‘Mongst all foes that a friend should be the worst!84 […] Proteus,
I am sorry I must never trust thee more,
But count the world a stranger for thy sake. The private wound is deepest: O time most accurst,
‘Mongst all foes that a friend should be the worst!84 Valentine is less worried about the trauma inflicted on Silvia than he is
about his own feelings of betrayal. If it is true that the ones we love the
most also have the power to hurt us most deeply, then it is apparent
that Valentine’s “true” love is Proteus, not Silvia. 84
Ibid., 5.468–72.
85
Ibid., 5.4.82–83.
86
Jeffrey Masten. “The Two Gentlemen of Verona”. A Companion to Shakespeare’s
Works, Vol. III (Malden: Blackwell, 2003), 273. III
Love as Resistance: Silvia and Hermia He demonstrates that
by quickly accepting the thinnest of apologies from Proteus—whom
the play has been at pains to portray as genuinely untrustworthy—and
then simply giving Silvia to him: “that my love may appear plain and
free, / All that was mine in Silvia I give thee”.85 In this gesture, Valentine
behaves as if Silvia’s love, and his “right” to it, is a transferable property. Far from being the mutual partner she was with Valentine in their earlier
plan of escape, Silvia is now given no voice at all, leaving many readers
and audiences wondering if something has gone wrong: To a modern audience accustomed to a sex/gender system that clearly
designates cross-sex marriage as more important than same-sex
friendship and furthermore sees same-sex and cross-sex affection as
linked to mutually exclusive categories of identity, Valentine’s valuation
of his love of Proteus over his love of Silvia is unexpected, and has struck
many critics and directors of the play as simply erroneous.86 We are on firmer ground, however, if we see this ending, not as a
mistake, but as part of the play’s design. Far from being erroneous, 8. Shakespeare: The Return of Fin’amor 383 the odd ending of this play suggests that we have been following the
misadventures of young people who play at love, whether cross-sex or
same-sex, without ever really understanding it, or lending themselves
to its power. The “Gentlemen” neither choose their female loves, nor
ever have the courage to do anything more than faintly and indirectly
choose each other, through Valentine’s declaration that their wedding
days shall be “One feast, one house, one mutual happiness”.87 Their
rebellions are in form only, resisting the “property” claims of older men
to women that they themselves go on to treat as exchangable property,
and the two “Gentlemen” seem especially happy to be received back
into the arms of authority at the end, as the Duke declares: […] Sir Valentine,
Thou art a gentleman and well derived;
Take thou thy Silvia, for thou hast deserved her.88 […] Sir Valentine,
Thou art a gentleman and well derived;
Take thou thy Silvia, for thou hast deserved her.88 Rather than challenge authority as Silvia does, Proteus and Valentine
adopt its roles, acting as the fathers and older males act, by
exchanging (or intending to exchange) Silvia between them, just as
the Duke had meant to do with Thurio. 87
Two Gentlemen of Verona 5.4.175.
88
Ibid., 5.4.145–47.
89
A Midsummer Night’s Dream 1.1.16–17.
90
Ibid., 2.1.170–71. III
Love as Resistance: Silvia and Hermia Not yet the love of mutual
choice in defiance of authority, the loves toyed with by Valentine and
Proteus are but that—toys. A more powerful resistance to the “between men” structure can be
seen in A Midsummer Night’s Dream. Love and marriage—not always
in tandem—are central to the play. But of the human pairs presented
therein, only one is not brought together by violence or an authoritarian
insistence on obedience to the force of another’s will, sword, or magic. Theseus and Hippolyta, the ruling pair of the play, are the couple of
the will crossed with the sword, as Theseus “wooed [her] with [his]
sword, / And won [her] love doing [her] injuries”,89 while the eventual
pairing of Demetrius with Helena is the result of an herb which “[t]he
juice of it on eyelids laid, / Will make man or woman madly dote”.90
What the play illustrates and condemns through these pairings is an Love and its Critics 384 “obedience […] enforced with brutality”.91 Only Hermia and Lysander
freely choose each other—in the midst of the delightful chaos of this
play, is that supposed to be the example of what Stone calls love’s
“imprudent folly and even madness”?92 Or, as Alan Sinfield suggests, is
it merely the illusion of choice? If I were directing the play […] the more effective move would be to
disclose the tragedy in the conventional ending. This would involve
presenting the boys and girls as manifestly brainwashed and infantilized
by Puck’s manipulations of their minds and bodies into cross-gender
pairings. […] Puck could be shown putting electrodes on to their heads;
they would lose their vigour and engagement with life, and sink into
marriage as into a stupor.93 These critics’ urge to discount and dismiss Hermia’s choice is cut from
the same cloth as the tyranny of her father. Critic and father are closer
together than it might initially seem. One may not expect a literary critic
to adopt the emphatic physical presence of an actor. Neither might one
expect a dramatic character to express himself in the terms of academic
prose. But the dismissal of Hermia’s will features prominently in the
thinking of both figures. 91
L. Stone, 112.
92
Ibid., 181.
93
Sinfield, 109.
94
A Midsummer Night’s Dream 1.1.22.
95
Ibid., 1.1.110.
96
Allestree, 291. 97
A Midsummer Night’s Dream 1.1.27–38.
98
Ibid., 1.1.39–45.
99
A Midsummer Night’s Dream 1.1.56. III
Love as Resistance: Silvia and Hermia Egeus storms into the presence of the Duke,
demanding that the public State enforce his private authority: he is “full
of vexation” and “complaint” with Hermia,94 who has refused his choice
of marriage partner for her—the “spotted and inconstant” Demetrius95—
and has further defied his will by, in “a kind of theft”,96 giving her
love to Lysander. Egeus rages at Lysander for having used witchcraft
(Sinfield’s “manipulations”) to steal his daughter away from him: This [man] hath bewitched the bosom of my child;
Thou, thou, Lysander, thou hast given her rhymes,
And interchanged love-tokens with my child:
Thou hast by moonlight at her window sung,
With feigning voice verses of feigning love,
And stolen the impression of her fantasy This [man] hath bewitched the bosom of my child;
Thou, thou, Lysander, thou hast given her rhymes,
And interchanged love-tokens with my child:
Thou hast by moonlight at her window sung,
With feigning voice verses of feigning love,
And stolen the impression of her fantasy 8. Shakespeare: The Return of Fin’amor 98
Ibid., 1.1.39–45. 8. Shakespeare: The Return of Fin’amor 385 With bracelets of thy hair, rings, gawds, conceits,
Knacks, trifles, nosegays, sweetmeats, messengers
Of strong prevailment in unharden’d youth:
With cunning hast thou filch’d my daughter’s heart,
Turn’d her obedience, which is due to me,
To stubborn harshness.97 Egeus demands either that his daughter be forced to obey him, or be
forced to face the death penalty: Be it so she will not here before your grace
Consent to marry with Demetrius,
I beg the ancient privilege of Athens,
As she is mine, I may dispose of her:
Which shall be either to this gentleman
Or to her death, according to our law
Immediately provided in that case.98 Be it so she will not here before your grace
Consent to marry with Demetrius,
I beg the ancient privilege of Athens,
As she is mine, I may dispose of her:
Which shall be either to this gentleman
Or to her death, according to our law
Immediately provided in that case.98 Even harsher than the Duke of Milan, Egeus would rather that
his daughter die than be allowed to exercise a will and judgment
independent of, or even slightly different from his own. Egeus’ demands
appear to put Theseus—with the conspicuously silent Hippolyta beside
him—in something of an awkward position. He can give Egeus his will,
and sit back while the raving old man makes a mockery of the authority
of his state by demanding that public justice be meted out for private
faults. He can simply dismiss Egeus, possibly creating trouble for
himself with the patrician class of Athens. Or, he can do what so many
of Shakespeare’s characters do: seem to do, say, or think one thing while
acting in an entirely different manner. In this case, Theseus seems to take
Egeus’ side, telling Hermia that she must subordinate her judgment
(and her eyes—thus, her attraction to Lysander) to her father. When
Hermia says “I would that my father looked but with my eyes”,99 a line
practically calculated to appeal to the anti-authoritarian sentiments
that the poetry and drama of this period are increasingly trading on, 386 Love and its Critics Theseus responds with the conservative instruction: “Rather your eyes
must with his judgment look”.100 So far, so predictable. But the Thesean “fix” is in, though Egeus is too dull-witted to see
it. 100 Ibid., 1.1.57.
101 Ibid., 1.1.65–66. Emphasis added.
102 Ibid., 1.1.90.
103 A Midsummer Night’s Dream 1.1.91–92.
104 Ibid., 1.1.95–98. 8. Shakespeare: The Return of Fin’amor As the conversation between the warrior duke and the spirited
daughter of a tyrant-father proceeds, it becomes evident that Theseus
is looking for a loophole, a way to bend the rules. When Hermia asks
what the worst-case scenario is if she refuses to obey Egeus, Theseus
subtly alters the terms of the old man’s demands: Hermia will be forced
“Either to die the death or to abjure / For ever the society of men”.101
There is the loophole. Hermia has a choice—limited though it is—of
three options: obedience, “austerity and single life”,102 or death. It is not
nearly as draconian a choice as the obedience or death ultimatum that
Egeus would impose. As the scene progresses, Egeus’ absurdity, and Demetrius’ unsavory
character, each becomes more evident. In a clever mocking of the entire
“between men” structure, Lysander turns to Demetrius and demands
that he leave off his pursuit of Hermia: “You have her father’s love,
Demetrius; / Let me have Hermia’s: do you marry him”.103 And why
not? Why not just cut out the middle woman? If this bond is to be one
between Egeus and Demetrius, what need for so obvious an object of
exchange as Hermia? And though this is a laugh-line, and a big one,
Egeus steps right into the role of the butt of the joke, insisting on his
right to dispose of both his love and his property as he sees fit: Scornful Lysander! true, he hath my love,
And what is mine my love shall render him
And she is mine, and all my right of her
I do estate unto Demetrius.104 Scornful Lysander! true, he hath my love,
And what is mine my love shall render him. And she is mine, and all my right of her
I do estate unto Demetrius.104 Demetrius has Egeus’ “love”, and as a sign of that soon-to-be-bonded
love between men, Egeus will “estate” (like the value of moveable
goods that can be passed from one owner to another) his daughter upon
the man of his love’s choice. The joke here, if the audience has ears to 8. 105 Ibid., 1.1.106–10.
106 Ibid., 1.1.111–12.
107 Ibid., 1.1.123–126.
108 Ibid., 1.1.134. 109 Ibid., 4.1.76.
110 https://commons.wikimedia.org/wiki/File:Edwin_Landseer_-_Scene_from_A_
Midsummer_Night's_Dream._Titania_and_Bottom_-_Google_Art_Project.jpg
111 Ibid., 2.1.165–66, 70.
112 Ibid., 3.1.139. 8. Shakespeare: The Return of Fin’amor Shakespeare: The Return of Fin’amor 387 hear, and the reader has eyes to see, is that it is not “love” that is being
portrayed here as folly or madness—it is the absurdity of allowing the
eros of the father to be the sole legitimate and determining factor in the
making of a marriage. “Do you marry him”, indeed. Another notable point about the ridiculous nature of Egeus’
insistence on estating his daughter unto Demetrius, is that Demetrius
has a reputation as what we might now call a player. As Lysander
charges, with no self-defense whatsoever coming from the accused: Demetrius, I’ll avouch it to his head,
Made love to Nedar’s daughter, Helena,
And won her soul; and she, sweet lady, dotes,
Devoutly dotes, dotes in idolatry,
Upon this spotted and inconstant man.105 Demetrius has cruelly dallied with Helena, and is now, apparently
to be “estated” with another young girl for his troubles. As Theseus,
somewhat perturbed at this, notes: “I must confess that I have heard
so much, / And with Demetrius thought to have spoke thereof”.106 At
this point, Theseus goes from finding the loophole to finding the escape
clause. He tells both Demetrius and Egeus to come with him: I must employ you in some business
Against our nuptial and confer with you
Of something nearly that concerns yourselves.107 In so doing, he creates the situation in which, being left utterly alone,
Hermia and Lysander can do as they will—obey, escape, or pursue
whatever other options occur to them. Theseus has worked his way out
of an awkward, ridiculous, and unwanted situation, and given himself
a layer of plausible deniability as a shield against any further trouble. From this point, “the course of true love” may not “run smooth”,108 but
at least it has a fighting chance. In so doing, he creates the situation in which, being left utterly alone,
Hermia and Lysander can do as they will—obey, escape, or pursue
whatever other options occur to them. Theseus has worked his way out
of an awkward, ridiculous, and unwanted situation, and given himself
a layer of plausible deniability as a shield against any further trouble. From this point, “the course of true love” may not “run smooth”,108 but
at least it has a fighting chance. 388 Love and its Critics Love and its Critics The relation of judgment to the eyes, seeing, sight, and insight, and
their association with love are the dominant themes of the mix of magic
and comedy that plays out in the forest scenes in the middle of the
play. It is through the eyes, manipulated with herbal magic, that love
is changed, conjured out of nothing, and (for some) restored. The comic
action suggests both the fragility and the power of love, the ease with
which surfaces can be mistaken for depths, especially for the young
men of the play—though even the fairy queen Titania finds herself
“enamored of an ass”.109 Edwin Henry Landseer, Scene from A Midsummer Night's Dream. Titania and
Bottom (1848–1851).110 Edwin Henry Landseer, Scene from A Midsummer Night's Dream. Titania and
Bottom (1848–1851).110 The fairy king Oberon, who orders his servant Puck to fetch “a little
western flower” on which “the bolt of Cupid fell”, determines to use
“the juice of it, on sleeping eyelids laid”111 to control who will pair with
whom. In so doing, he acts as a satire on Egeus and the entire structure of a
society in which marriage and love not only “keep little company together
nowadays”,112 but are regarded as incompatible, while “love” is regarded
as madness, and marriage—arranged, of course, by the father—is thought 8. Shakespeare: The Return of Fin’amor 389 to be the “reasonable” and “sane” alternative. In the Comedy-of-Errors-style
identity confusion that the plot relies on, Puck ends up squeezing the juice
into the eyes of both young men, rather than merely putting Demetrius
under its magic spell, and then the game is on. Lysander, in love with
Hermia at the beginning, now wakes up and finds Helena irresistible,
and is filled with the urge to fight Demetrius for her love:113 Transparent Helena! Nature shows art,
That through thy bosom makes me see thy heart. Where is Demetrius? O, how fit a word
Is that vile name to perish on my sword!114 When Helena, naturally enough, is shocked by Lysander’s sudden outburst,
and reminds him of his love for Hermia, the formerly stable young man
illustrates the extremes of thought and behavior to which the drug can lead
(in a comic illustration of the effects of authority and obedience): Content with Hermia! No; I do repent
The tedious minutes I with her have spent. 113 The drug apparently makes Lysander forgetful of more than his love for Hermia,
as he seems to have forgotten the fact that Demetrius—until he is also drugged—
wants nothing to do with Helena.
114 A Midsummer Night’s Dream 2.2.103–07.
115 Ibid 2 2 111 22 114 A Midsummer Night’s Dream 2.2.103–07. 115 Ibid., 2.2.111–22. 115 Ibid., 2.2.111–22. Love and its Critics Not Hermia but Helena I love:
Who will not change a raven for a dove? The will of man is by his reason swayed;
And reason says you are the worthier maid. Things growing are not ripe until their season
So I, being young, till now ripe not to reason;
And touching now the point of human skill,
Reason becomes the marshal to my will
And leads me to your eyes, where I o’erlook
Love’s stories written in love’s richest book.115 Reason, as much or more than love, is mocked by this speech. Reason,
which as John Milton will write, “also is choice”, cannot operate when
the will is overridden, when it is “[u]seless and vain, of freedom both 115 Ibid., 2.2.111–22. Love and its Critics 390 despoiled, / Made passive”, and made to serve “necessitie”.116 Under the
influence of the drug that has been applied to his eyes, Lysander is less
free to use, as Bertram would, “[t]he help of [his] own eyes”117 than he
was when confronting the authority of Egeus and Theseus. Lysander,
who while pursuing the goals of fin’amor was willing to stand with
Hermia before the authority of the father and the state, is now, while
under the influence of fals’amor, a toady, a lackey, a slave who speaks
and acts as authority—the drug—would have him speak and act. This
is especially obvious to Hermia, when Lysander explains his sudden
transformation: HERMIA What love could press Lysander from my side? LYSANDER Lysander’s love, that would not let him bide,
Fair Helena, who more engilds the night
Than all you fiery oes and eyes of light. Why seek’st thou me? could not this make thee know,
The hate I bear thee made me leave thee so? HERMIA You speak not as you think: it cannot be.118 Hermia is right for two reasons: Lysander speaks not as he thinks because
he is not actually thinking, merely reacting obediently to the power of
the drug—the former rebel now a comically absurd conformist—and
Lysander speaks not as himself, but as someone under the influence, not
of a chosen love, a fin’amor, but of a drug that renders his will “useless
and vain”. Hermia knows Lysander; her sight is insight, as Lysander’s
had been before the drug. 116 John Milton. Paradise Lost 3.108, 109–10. All citations of Milton’s poetry are from
John Milton: Complete Poems and Major Prose, ed. by Merritt Hughes (New York:
Odyssey Press, 1957).
117 All’s Well that Ends Well 2.3.106–07.
118 A Midsummer Night’s Dream 3.2.185–91. 116 John Milton. Paradise Lost 3.108, 109–10. All citations of Milton’s poetry are from
John Milton: Complete Poems and Major Prose, ed. by Merritt Hughes (New York:
Odyssey Press, 1957).
117 All’ W ll h
E d W ll 2 3 106 07 118 A Midsummer Night’s Dream 3.2.185–91. y
y
117 All’s Well that Ends Well 2.3.106–07. 119 Ibid., 2.2.93–99.
120 Ibid., 3.2.137–44. Love and its Critics Thus, far from being a lover like Proteus,
who can find in one object the same superficial attractions he finds in
any other object, Hermia is the kind of lover of whom the troubadours
wrote—one who knows the beloved, and chooses, despite the trouble it
may cause, love over obedience. Demetrius and Helena are at the opposite end of the spectrum. Neither of them appears to have any insight whatsoever, as Helena
continues to chase a man who has little but contempt for her, and 8. Shakespeare: The Return of Fin’amor 8. Shakespeare: The Return of Fin’amor 391 Demetrius—before being drugged—continues to chase a woman who
wants nothing to do with him. Demetrius’ reasons for his behavior—
venal and mercenary as they are—are at least rational. Helena, on the
other hand, is the one of the four who is portrayed as helpless in the face
of an unchosen passion, almost as if she were a female version of Sidney’s
Astrophil, or of Petrarch himself, chasing an always-uncatchable Stella
or Laura. The effect of this unfortunate sickness is to make her think
herself uniquely undesirable in comparison with Hermia: […] I am as ugly as a bear;
For beasts that meet me run away for fear:
Therefore no marvel though Demetrius
Do, as a monster fly my presence thus. What wicked and dissembling glass of mine
Made me compare with Hermia’s sphery eyne?119 Demetrius, in contrast, suffers no such negative self-opinion. His
beloved is not, like a heavenly principality, beyond his grasp, nor would
it be sullied by his touch, because his beloved is Egeus and his money. As the play makes clear, that love is most certainly requited. But under
the influence of the drug, Demetrius becomes just as untrue to money as
Lysander becomes to Hermia: O Helena, goddess, nymph, perfect, divine! To what, my love, shall I compare thine eyne? Crystal is muddy. O, how ripe in show
Thy lips, those kissing cherries, tempting grow! That pure congealed white, high Taurus snow,
Fann’d with the eastern wind, turns to a crow
When thou hold’st up thy hand: O, let me kiss
This princess of pure white, this seal of bliss!120 The effect of the drug is to override the will, rendering it compliant to
the demands of the one who administers it, and in a sense, of the readers
and audiences who look on in mirth. Underneath the laughter is a dark
thread of reflection on just how fragile love can be as a challenger to the Love and its Critics 392 claims of authority and power, when the human will can so easily be
manipulated, even in those cases in which it could not be intimidated. Lysander, who like Hermia, is a good judge of character, a young
man with insight (it was he, after all, who “outed” Demetrius as the
unsavoury man he is), does not have that ability beaten out of him, but
drugged out of him. 121 A Midsummer Night’s Dream 2.1.120–21.
122 Ibid., 2.1.136–37.
123 Ibid., 2.1.176–79, 182.
124 Ibid., 3.1.136. 8. Shakespeare: The Return of Fin’amor Egeus would likely give a pretty penny to have the
juice of that magic flower with which to cancel his daughter’s will, and
bring her back to heel. Beyond the mere enforcement of the administrator’s will, the drug
serves a punitive function when it is administered to Titania, who has
dared defy Oberon over his request for “a little changeling boy / To be
[his] henchman”.121 As they argue and then part, Oberon darkly mutters
“[t]hou shalt not from this grove / Till I torment thee for this injury”.122
Titania’s refusal to obey is punished by having her sight manipulated
and her will stripped away by being made a foolish slave to the effects
of the flower whose “liquor” is squeezed upon her eyes: Having once this juice,
I’ll watch Titania when she is asleep,
And drop the liquor of it in her eyes. The next thing then she waking looks upon,
[…]
She shall pursue it with the soul of love.123 The first thing Titania sees on awakening, of course, is the comic
character Bottom, who has been transformed by Puck so that he has the
head of an ass. Titania’s drugged reaction is to do exactly as Oberon had
demanded: “on the first view”, she says while gazing into the eyes of the
ass, “I love thee”.124 This is, of course, not love, and that is exactly the joke. So much of what passes for love in a culture of arranged marriages is a
command performance, intended to gloss the ugly reality of having been
bought and sold into a relationship and a life not of one’s own choosing,
from which there are few avenues of escape, except for perhaps “the
ecclesiastical separation a mensa et thoro”—a separation from bed and 8. Shakespeare: The Return of Fin’amor 393 board under which an “ecclesiastical judge permitted a man and wife
to live apart, but without granting them the right to remarry”.125 Unlike
comedy, in the real world no one was magically released from arranged
marriages from which only death (theirs or their spouse’s) would
release them. But in A Midsummer Night’s Dream, Lysander is released
to be himself again, and once more be able to choose Hermia. Titania is
released from her punishment of foolish illusion, and is shown the very
ass of whom she thought she had been enamored. 125 Monique Vleeschouwers-Van Melkebeek. “Separation and Marital Property”.
In Mia Korpiola, ed. Regional Variations in Matrimonial Law and Custom in Europe,
1150–1600 (Leiden: Brill, 2011), 81–82.
126 A Midsummer Night’s Dream, 4.2.154.
127 Ibid., 4.2.178. 8. Shakespeare: The Return of Fin’amor Even Egeus’ claims
of “the law, the law”126 are swept away in a grand gesture by Theseus,
who tells the old tyrant that “I will overbear your will”.127 Everything is
made right, and all is restored. Except that it isn’t. One man, Demetrius, is left under the influence of
the drug, forced to love Helena, while at the same time, Helena is trapped
in a situation in which the man she loves—for whatever inexplicably
pathetic Petrarchan reasons—does not really love her. Oh certainly,
he plays the part well, unbeknownst even to himself, but Demetrius
does not choose Helena. In effect, he is left under the spell of authority
and obedience for the rest of his life. Readers and audience members
who approve this as part of a “happy ending” should ask themselves
if they would like to have their own wills rendered useless, or whether
that is a treatment they would reserve strictly for people of whom they
disapprove. For thee, but not for me. 125 Monique Vleeschouwers-Van Melkebeek. “Separation and Marital Property”.
In Mia Korpiola, ed. Regional Variations in Matrimonial Law and Custom in Europe,
1150–1600 (Leiden: Brill, 2011), 81–82. IV
Love as Resistance: Juliet and the Critics who Disdain IV 128 Romeo and Juliet 1.1.76–77. 131 See Michael K. Jones and Malcolm G. Underwood. The King’s Mother: Lady Margaret
Beaufort, Countess of Richmond and Derby (Cambridge: Cambridge University Press,
1993), 95. 129 Ibid., 1.1.95–96. 132 Romeo and Juliet 1.1.12. 130 Ibid., 1.2.8–11. 134 Ibid., 1.3.70–71. 133 Ibid., 1.3.72–73. 136 Romeo and Juliet 1.2.13. Love as Resistance: Juliet and the Critics who Disdain Moving from comedy to tragedy, we see the same pattern at work. A
father seeks to match himself to another man, using the daughter as
a medium of exchange, while a fourth element—the younger man—
interferes with the planned match, aided by the enthusiastic participation
of the daughter. In Romeo and Juliet, the father is Capulet, the leader of
one of the two rival families in Verona. His family’s ongoing contention 127 Ibid., 4.2.178. Love and its Critics 394 with the Montague family—expressed in Capulet’s early determination
to strike because “Old Montague is come / And flourishes his blade in
spite of me”128—has caused enough trouble that the Prince has warned
both houses: “If ever you disturb our streets again, / Your lives shall pay
the forfeit of the peace”.129 Capulet needs a way to best “Old Montague”,
and what better way than by matching himself to a foreign nobleman
who is kinsman to the Prince—the County Paris—in order to raise the
status of his family, trump Montague, and do a little flourishing in spite
of him? Capulet’s daughter, Juliet, will be the glue that seals the two
men together, if only Paris will be patient enough to let her grow up a
little more. Capulet says that she is too young: My child is yet a stranger in the world;
She hath not seen the change of fourteen years,
Let two more summers wither in their pride,
Ere we may think her ripe to be a bride.130 Paris thinks she is old enough at thirteen, an idea with more than
adequate precedent in English history, even among the Tudors—Henry
VII’s mother, Margaret Beaufort, was thirteen while pregnant with the
child that would eventually win the kingship at Bosworth Field.131 As
Paris notes: “Younger than she are happy mothers made”,132 a position
indirectly supported by Juliet’s mother, who tells the girl that she had
already been her mother “much upon these years / That you are now
a maid”,133 and that younger girls than Juliet “in Verona, ladies of
esteem, / Are already made mothers”.134 This kind of early marriage,
while shocking today, is not unusual in Shakespeare’s time: Child betrothals and adolescent marriages are a source for scandal in the
West today […] but were quite normal for much of our history. Catherine 134 Ibid., 1.3.70–71. 135 Hanne Blank. Virgin: The Untouched History (New York: Bloomsbury, 2007), 14.
136 R
d J li t 1 2 13 137 Ibid., 1.2.16–19. 135 Hanne Blank. Virgin: The Untouched History (New York: Bloomsbury, 2007), 14.
136 Romeo and Juliet 1.2.13.
137 Ibid., 1.2.16–19.
138 Ibid., 1.3.65.
139 Ibid., 1.3.74.
140 Ibid., 1.3.96.
141 Ibid., 1.3.97–99. 135 Hanne Blank. Virgin: The Untouched History (New York: Bloomsbury, 2007), 14.
136 Romeo and Juliet 1.2.13.
137 Ibid 1 2 16–19 135 Hanne Blank. Virgin: The Untouched History (New York: Bloomsbury, 2007), 14.
136 Romeo and Juliet 1.2.13.
137 Ibid., 1.2.16–19.
138 Ibid., 1.3.65. 142 https://commons.wikimedia.org/wiki/File:DickseeRomeoandJuliet.jpg
143 Romeo and Juliet 3.5.161–65. 8. Shakespeare: The Return of Fin’amor 8. Shakespeare: The Return of Fin’amor 395 of Aragon was betrothed at age three to Arthur, son of Henry VII of
England, and married to him when she was fifteen.135 But Capulet is reluctant: “And too soon marred are those so early
made”.136 At this point in the play, the father seems at least as concerned
with his daughter’s welfare, even with her heart and will, as he is with
making the match between himself and Paris. He tells the suitor to take
his time, get to know Juliet, and see if something develops organically. He, Capulet, cannot or will not force his daughter’s heart, so Paris will
have to appeal to Juliet on his own: But woo her, gentle Paris, get her heart,
My will to her consent is but a part;
An she agree, within her scope of choice
Lies my consent and fair according voice.137 Capulet will play a quite different tune, of course, when matters grow
more urgent later in the play. Capulet will play a quite different tune, of course, when matters grow
more urgent later in the play. Juliet’s mother is working, not the other side of the match, but the
proposed object of exchange for the match, as she questions Juliet. “How stands your disposition to be married?”138 she asks, telling Juliet
“[t]he valiant Paris seeks you for his love”.139 Unlike Silvia and Hermia,
who find their fathers’ choices repellent, Juliet appears amenable. When
her mother presses the point—“Speak briefly, can you like of Paris’
love?”140—Juliet responds as a model of obedience and cooperation: “I’ll
look to like, if looking liking move: / But no more deep will I endart
mine eye / Than your consent gives strength to make it fly”.141 All of this,
of course, flies out of the proverbial balcony window after she meets,
falls in love with, and secretly marries Romeo—a state of affairs about
which her parents are entirely unaware. 396 Love and its Critics Frank Dicksee, Romeo and Juliet (1884). Southampton City Art Gallery.142 Frank Dicksee, Romeo and Juliet (1884). Southampton City Art Gallery.142 When her initial willingness to cooperate changes into what seems to
him an inexplicable and moody resistance, Capulet makes it clear what
Juliet’s position is: Hang thee, young baggage! disobedient wretch! 143 Romeo and Juliet 3.5.161–65. 144 Ibid., 3.5.191–97.
145 Ibid., 3.5.176, 170.
146 Ibid., 3.5.159–60. 8. Shakespeare: The Return of Fin’amor I tell thee what: get thee to church o’ Thursday,
Or never after look me in the face:
Speak not, reply not, do not answer me;
My fingers itch.143 Because of the tumult that has arisen in Verona over the street brawl that
resulted in the deaths of Tybalt and Mercutio, as well as the banishment
of Romeo, Capulet acts quickly to seal the match between himself and
Paris. There is now no time for wooing, and Capulet’s will is now the
whole, not just a part, of Juliet’s consent. Or so he thinks, as he threatens
to beat his daughter for her disobedience. All the while, Juliet finds
herself unable—out of fear—to tell him why she is suddenly refusing
the marriage to Paris. Her stammerings further enrage Capulet, who—
having reached a nearly Jehovean state of wrath—tells his daughter that
she will obey, or else be thrown out with the trash: 397 8. Shakespeare: The Return of Fin’amor 8. Shakespeare: The Return of Fin’amor Look to’t, think on’t, I do not use to jest. Thursday is near; lay hand on heart, advise:
An you be mine, I’ll give you to my friend;
And you be not, hang, beg, starve, die in the streets,
For, by my soul, I’ll ne’er acknowledge thee,
Nor what is mine shall never do thee good:
Trust to’t, bethink you; I’ll not be forsworn.144 In this outburst, Capulet makes it perfectly clear what Juliet is—property. At this point, even his wife thinks that he is “too hot”, while the Nurse
tells him that he “is to blame […] to rate her so”.145 But these proxies
for audience reaction are nowhere near powerful enough to change
Capulet’s mind. His daughter—who in his mind owes him obedience
for her begetting, and should be to him as creation is to its god—will
either obey the commandments wrapped in his titanic thundering, or
she will be thrown out into the streets. An you be mine, I’ll give you to my
friend. A starker statement of proprietary relationship can scarcely be
found. Juliet is capital, a movable good that can be used as a medium
of exchange in the purchase of something lasting and valuable. To
Capulet, her lack of obedience lowers her value to nothing, and he
finds her assertion of will enraging and confusing all at once—as if a
man’s cash suddenly lost all of its value, even announcing that it was
not going to be used to make purchases. Capulet, in his moment of rage,
would rather see Juliet in prison, in alehouses, a criminal, than allow
her to make up her own mind and exercise her own heart’s will. Juliet’s
“scope of choice” is the same the Father will later give Adam and Eve in
Milton’s Paradise Lost. Obey or be cast out. Capulet may seem less extreme than Egeus, since he is not openly
demanding his daughter’s death. However, Juliet’s fear hints that
Capulet may be more dangerous than he appears. Even as she begs
her “[g]ood father” to hear her “but to speak a word”,146 she is terrified
of telling him that she is already married—contracted in the presence
of witnesses, solemnified by the Friar, and consummated through a 398 Love and its Critics clandestine night’s passion—and for her to marry Paris would be a
crime and a sin. Chicago Press, 2004, 27).
148 Elizabeth S. Cohen and Thomas V. Cohen. Daily Life in Renaissance Italy (Westport:
Greenwood Press, 2001), 93. Astonishingly, “the notion of honor killing disappeared
from the Italian Penal code only as recently as 1981 with the law no. 442 of 5 August
called ‘Abrogazione della rilevanza penale della causa d’onore e del matrimonio
riparatore’ [Abolishment of the ‘honour motive’ and of ‘shotgun’ marriages in
criminal proceedings]” (Donatella Barazzetti, Franca Garreffa, and Rosaria Marsico.
National Report: Italia. Daphne Project: Proposing New Indicators: Measuring Violence’s
Effects. University of Calabria, Rende: Italy, 2007, 3, http://www.surt.org/gvei/docs/
national_report_italy.pdf). Credit for this insight is due to Modje Taavon, who in
conversation pointed out the similarities between the Renaissance and modern
practices of “honor killing”. 149 Romeo and Juliet 3.5.190. 150 L. Stone, 218. 147 Thomas V. Cohen. Love and Death in Renaissance Italy (Chicago: University of
Chicago Press, 2004, 27).
148 Eli
b
h S C h
d Th
V C h
D il Lif i
R
i
I l (W 152 Romeo and Juliet 4.1.91–94, 102–06. 151 Measure for Measure 4.4.156–57. 8. Shakespeare: The Return of Fin’amor But she is so afraid of her storming, raging father, that
she would rather fake her own death than tell him the truth. She has good reason to be afraid. His “fingers itch” in a time and
place in which the killing of “disobedient” daughters was far from
unheard of. The phenomenon known as “honor killing” was well-
known in sixteenth-century Italy, with a particularly famous instance
of it occurring in the killing by Giovanni Battista of his wife, Vittoria
Savelli on 26 July 1563: “He first hit her forehead and then slit her throat,
cutting her head half off, […] the method used to dispatch livestock”.147
Another such incident, in 1555, involved a father killing his daughter in
the same fashion: “the father took his [pregnant] daughter by the elbow
and, under the eyes of the whole village, led her across the field to her
lover’s corpse. There, as all watched, as if she were his heifer, he slit her
throat”.148 Having been told by her father to “Graze where [she] will”,149
as if she were an animal, Juliet is right to be afraid, and she is never fully
able to break out of the role of “baggage” that her father assigns her. The
audiences that watched this play for the first time were being “offered
an alternative model to that of blind obedience to paternal dictate”,150
but they were also being shown with what violent fury paternal dictate
will defend its prerogatives. In terror and confusion, Juliet seeks the intervention of Friar
Lawrence, a significantly less powerful advocate than the one Hermia
finds in Theseus. Even more manipulative than the “fantastical duke
of dark corners” who spends his time posing as a friar in Measure for 150 L. Stone, 218. 153 Ibid., 4.5.38–40. 8. Shakespeare: The Return of Fin’amor 8. Shakespeare: The Return of Fin’amor 399 Measure,151 Friar Lawrence is at once more than faintly disreputable,
and nearly as afraid of direct confrontation as Juliet is. His plan
is practically the archetype of a cowardly and foolish brand of
Machiavellian scheming: Tomorrow night look that thou lie alone;
Let not thy nurse lie with thee in thy chamber:
Take thou this vial, being then in bed,
And this distilled liquor drink thou off;
[…]
Each part, deprived of supple government,
Shall, stiff and stark and cold, appear like death:
And in this borrow’d likeness of shrunk death
Thou shalt continue two and forty hours,
And then awake as from a pleasant sleep.152 The plot has its intended effect, getting her out of the marriage to Paris,
but at the cost of sowing the seeds of Juliet’s real, rather than merely
pretended, death. The plot has its intended effect, getting her out of the marriage to Paris,
but at the cost of sowing the seeds of Juliet’s real, rather than merely
pretended, death. Even upon discovering her “dead”, however, the grief Capulet
expresses centers more on the loss of his match with Paris, than it does on
the loss of his daughter. Paris will now not be his son-in-law, since that
position is already taken (though by someone other than he assumes): Death is my son-in-law, Death is my heir;
My daughter he hath wedded: I will die,
And leave him all; life, living, all is Death’s.153 His concern here is over the question of the “heir” to whom he will
leave his wealth and estate. He grieves that he has been unable to
match himself with Paris, and has instead matched himself with Death
(to whom all are matched in the end): “I will die, / And leave him all;
[…] all is Death’s”. He has lost the one thing that mattered most to
him in life—the mechanism though which he would be able to pass on
his property, wealth, and inheritable legacy. Juliet, while valuable, is 153 Ibid., 4.5.38–40. 400 Love and its Critics enumerated as merely a possession, now lost, among all those that will
be bequeathed to Death. Through the tragic outcome of Romeo and Juliet, we can easily see
how love functions as a challenge to and a rejection of the authority
of the father. 154 Ibid., 1.1.131–39.
155 Ibid., 1.1.207–08.
156 Valerie Traub. The Renaissance of Lesbianism in Early Modern England (Cambridge:
Cambridge University Press, 2002), 237. See especially her discussion of Thomas
Heywood’s 1609 play The Golden Age. 8. Shakespeare: The Return of Fin’amor Romeo starts out unpromisingly, as the young man in
love with Love, more Neopetrarchan than neo-troubadourian, moping,
sighing and crying in a way that makes some want to reassure him and
others to smack him. According to his father, Romeo spends most of his
pre-dawn mornings in a competition with himself over how intensely
he can grieve: With tears augmenting the fresh morning dew. Adding to clouds more clouds with his deep sighs;
But all so soon as the all-cheering sun
Should in the furthest east begin to draw
The shady curtains from Aurora’s bed,
Away from the light steals home my heavy son,
And private in his chamber pens himself,
Shuts up his windows, locks far daylight out
And makes himself an artificial night.154 All this excessive emotion is related to Romeo’s unsuccessful courting
of a girl named Rosaline, whose identity we learn from Romeo’s
friend, Benvolio, rather than from Romeo himself. She will simply
not cooperate with, or be impressed by, any of Romeo’s shopworn
techniques. First, Romeo claims that the as-yet-unnamed Rosaline will
“not be hit / With Cupid’s arrow; she hath Dian’s wit”.155 Diana, the
Roman goddess of the hunt who is strongly associated with images of
lesbian love in the Renaissance, if “subtly authorized under the idiom
of chastity”,156 serves as Romeo’s shorthand explanation to Benvolio
for his failure. Romeo seems unable (or unwilling) to imagine that his
failure to attract Rosaline has anything to do with him. It must be her. In
Romeo’s mind, she apparently also has a deaf ear for poetry: “She will 8. Shakespeare: The Return of Fin’amor 401 not stay the siege of loving terms”.157 How is it that his verses—staged
as they are in military terms as weapons with which to force his way
past the defenses of the walled town of Rosaline’s assent—are unable
to conquer her resistance? It must be that she hath Dian’s wit. That same
“wit” must be why she will not “bide the encounter of assailing eyes”
or “ope her lap to saint-seducing gold”158 either. Romeo cannot talk his
way, stalk his way, or buy his way into Rosaline’s affections. Wisely, Benvolio does not comment on any of this nonsense, except
by telling his ridiculous young friend to turn his attention elsewhere,
“[b]y giving liberty to thine eyes”, and examining “other beauties”.159
Romeo’s response is straight out of the Petrarchan lover’s handbook. 157 Romeo and Juliet 1.1.211.
158 Ibid., 1.1.212–13.
159 Ibid., 1.1.226–27.
160 Ibid., 1.1.234–35.
161 Ibid., 1.l2.90. 157 Romeo and Juliet 1.1.211. 158 Ibid., 1.1.212–13. 8. Shakespeare: The Return of Fin’amor Rosaline—whom he has just absurdly implied is a tin-eared lesbian—is
also the unreachable measure of all other beauties, any one of whom
would serve merely as “a note / Where [he] may read” of his beloved’s
beauty, as if Rosaline (whose name Romeo never actually pronounces)
were the Platonic form of which all other women were merely copies.160
Romeo is made idiotic as he follows the path of superficial, sight-
without-insight fals’amor. But he will soon learn what Giraut de Borneilh
meant when he wrote “through the eyes love enters the heart”, as
what Romeo terms “the devout religion of mine eye”161—an image of
obedience, doctrine, and authority—gives way to fin’amor, whose only
doctrines are wonder and desire. At the feast Capulet gives to mark what is meant to be the matching
of Juliet to the County Paris, Romeo sees something he claims, at least,
never to have seen before: true beauty. Watching Juliet dance, possibly
with Paris himself, Romeo is flabbergasted: O, she doth teach the torches to burn bright! It seems she hangs upon the cheek of night
Like a rich jewel in an Ethiope’s ear;
Beauty too rich for use, for earth too dear! So shows a snowy dove trooping with crows,
As yonder lady o’er her fellows shows. O, she doth teach the torches to burn bright! It seems she hangs upon the cheek of night
Like a rich jewel in an Ethiope’s ear;
Beauty too rich for use, for earth too dear! So shows a snowy dove trooping with crows,
As yonder lady o’er her fellows shows. 402 Love and its Critics The measure done, I’ll watch her place of stand,
And, touching hers, make blessed my rude hand. Did my heart love till now? forswear it, sight! For I ne’er saw true beauty till this night.162 The measure done, I’ll watch her place of stand,
And, touching hers, make blessed my rude hand. Did my heart love till now? forswear it, sight! For I ne’er saw true beauty till this night.162 At this point, it is hard to know how much of this is genuine passion,
the entering of love through the eyes, and how much of it is Romeo’s
established mode of framing everything in terms of poetic opposites,
filtering lived experience through the “devout religion” of his eye. Does he truly see here, and if so, what can he possibly be seeing? 162 Ibid., 1.5.45–54. 163 Walther von der Vogelweide. “Saget mir ieman, waz ist minne?” In Karl Lachmann,
ed., Die Gedichte Walthers von der Vogelweide (Berlin: George Reimer, 1891), 69,
https://archive.org/stream/diegedichtewalt00lachgoog#page/n92
164 Romeo and Juliet 1 5 94 97 164 Romeo and Juliet 1.5.94–97. 164 Romeo and Juliet 1.5.94–97. 162 Ibid., 1.5.45–54.
163 Walther von der Vogelweide. “Saget mir ieman, waz ist minne?” In Karl Lachmann,
ed., Die Gedichte Walthers von der Vogelweide (Berlin: George Reimer, 1891), 69,
https://archive.org/stream/diegedichtewalt00lachgoog#page/n92
164 Romeo and Juliet 1.5.94–97. 8. Shakespeare: The Return of Fin’amor A beautiful girl, with every grace imaginable, dancing with another
man—thus adding a hint of the adulterous, or quasi-adulterous angle
of so much troubadour and trobairitz poetry—Juliet is, to this point,
someone with whom he has never exchanged so much as a single
word. What does he know of her? What can he know of her? As the
scene reveals, he does not even know her name when he approaches
her, and speaks to her for the first time. And then, something remarkable happens. In true troubadour and
trobaritz fashion, this young man and young woman, who do not
know each other at all, discover that they have “one joy in two hearts”
(“zweier herzen wünne”),163 as they compose a sonnet, together, as their
first meeting and first words. Romeo approaches, and begins: If I profane with my unworthiest hand
This holy shrine, the gentle fine is this:
My lips, two blushing pilgrims, ready stand
To smooth that rough touch with a tender kiss.164 Admittedly, it is difficult not to wonder whether or not this is an
example of the “siege of loving terms” that had worked so poorly with
Rosaline. Is this a stanza that Romeo has memorized, and keeps for
occasions such as these? Perhaps. But even if so, perhaps especially if Admittedly, it is difficult not to wonder whether or not this is an
example of the “siege of loving terms” that had worked so poorly with
Rosaline. Is this a stanza that Romeo has memorized, and keeps for
occasions such as these? Perhaps. But even if so, perhaps especially if 8. Shakespeare: The Return of Fin’amor 403 so, what he then encounters—in Juliet’s like-for-like response—has to
be all the more amazing. so, what he then encounters—in Juliet’s like-for-like response—has to
be all the more amazing. Good pilgrim, you do wrong your hand too much,
Which mannerly devotion shows in this;
For saints have hands that pilgrims’ hands do touch,
And palm to palm is holy palmers’ kiss.165 Some might argue that this exchange is merely conventional. Even so
respected a critic as Ralph Berry argues in this way. 165 Ibid., 1.5.98–101.
166 Ralph Berry. The Shakespearean Metaphor (New York: Macmillan, 1978), 38. 166 Ralph Berry. The Shakespearean Metaphor (New York: Macmillan, 1978), 38. 165 Ibid., 1.5.98–101. 167 “Whatever we have words for, we are already beyond” (“Wofür wir Worte haben,
darüber sind wir auch schon hinaus”) (Friedrich Nietzsche. Zur Genealogie der
Moral [1887] Götzendämmerung [1889] [Hamburg: Felix Meiner Verlag, 2013], 244).
Robert Musil expresses a similar idea: “The truth between two people cannot be
spoken. As soon as we speak, we close doors; words are best used for insubstantial
messages; we speak in the hours in which we are not alive” (“Die wahre Wahrheit
zwischen zwei Menschen kann nicht ausgesprochen werden. Sobald wir sprechen,
schließen sich Türen; das Wort dient mehr den unwirklichen Mitteilungen, man
spricht in den Stunden, wo man nicht lebt”) (Musil, 516). The Russian poet Fyodor
Tyutchev makes much the same observation in his poem Silentium: “The thought,
spoken, is a lie” (“Мысль изреченная есть ложь”) (Stephen Prickett, ed. European
Romanticism: A Reader [London: Bloomsbury, 2010], 638, l. 10). 8. Shakespeare: The Return of Fin’amor For him the sonnet
that Romeo and Juliet compose together is part of “a tranced process of
courtly reciprocity”, an “inward-turning, acquiescent” phenomena that
reflects “the fluency, the intensity, and the superficiality of the means
through which this society orders its experience, and its relationships”.166
One of the current authors had a graduate professor some years ago
who professed to be thrilled during the first few minutes of the 1993
Kenneth Branagh film of Much Ado About Nothing because, “someone
has finally figured out that love is merely a construct in Shakespeare, a
conventional game”. She then related her disappointment at the way the
film departed from her reading of the play. The remark made in response
to her observations, “Shakespeare doesn’t belong to academics”, did not
go over well. But it is just as true now as it was then. Literary critics are too often, despite pretensions to be defenders of
the unfettered intellect, among the most conformist members of society. We follow the fashionable codes of our “discourse communities” in
looking for ways to tame our material, to allegorize it—if not through
the categories of religion, then through those of history or theory—into
saying something very different from what a “naive” or “surface”
reading of the text might suggest to an ordinary reader, one less artfully
trained in the ways of interrogating a literary object in order to bend it
to one’s will, or make it disappear entirely. Regardless of whether or not
Romeo’s first stanza is a memorized performance piece, a Petrarchan
pick-up line that he has at the ready, Juliet’s response is not preplanned,
rehearsed, or otherwise the kind of utterance that Nietzsche argues
is only possible because the sentiment it expresses is already dead in Love and its Critics 404 our hearts.167 Juliet’s response is only conventional in the sense that it
uses a known form in order to express thoughts and emotions of her
own—in that same sense, the guitar solo in Carlos Santana’s Europa is
“conventional”, as is the fourth movement of Tchaikovsky’s Symphony
No. 6, the Pathetique. Juliet’s response does not indicate that she is a slave to convention;
she is a mere girl who has yet to become sophisticated enough to be
knowing and jaded about the poetical and musical forms of her time. 168 Regina Schwartz. Loving Justice, Living Shakespeare (Oxford: Oxford University
Press, 2016), 50, 51. 8. Shakespeare: The Return of Fin’amor Juliet gives us an example of what a more generous critic like Regina
Schwartz calls a “communication [that] is instantaneous and complete”,
which teaches both lovers to “[leave] behind the Petrarchan lover’s
conventions”, in favor of “a devotion without guile and without
measure”.168 In fact, what makes Juliet’s response at once more bracing
and delightful is that she gets the form of the sonnet ever so slightly
wrong—a deliberate cue, it seems, on the author’s part to the freshness
and originality of her response to Romeo. Where Romeo is predictably
correct in following his author’s ABAB rhyme scheme (hand, this,
stand, kiss), Juliet’s improvised response, while beautiful, is written as a
mistaking of the typical scheme for the second stanza of a Shakespearean
sonnet. Rather than CDCD, introducing two new rhymes to the mix,
Juliet introduces only one new rhyme, while re-using one of Romeo’s in
a CBCB scheme (much, this, touch, kiss). However, one might read this,
not as a mistake, but as an adaptation of the form that makes Juliet’s
second stanza even more responsive to Romeo’s first than a purely
“conventional” second stanza might have been. In this case, far from
a girl who is merely giving the expected, “acquiescent” response her 8. Shakespeare: The Return of Fin’amor 405 culture demands, we have an artist, a poet in her own right, who then
matches Romeo line by line in composing the sonnet: culture demands, we have an artist, a poet in her own right, who then
matches Romeo line by line in composing the sonnet: ROMEO Have not saints lips, and holy palmers too? JULIET Ay, pilgrim, lips that they must use in prayer. ROMEO O, then, dear saint, let lips do what hands do; They pray,
grant thou, lest faith turn to despair. JULIET Saints do not move, though grant for prayers’ sake. ROMEO Then move not, while my prayer’s effect I take.169 The couple then starts another sonnet, this time getting through only
the first four lines, before they are interrupted. 169 Romeo and Juliet 1.5.102–07.
170 Ibid., 1.5.111.
171 Ibid., 1.5.135–36.
172 Berry, 40. 173 Kiernan Ryan. “King Lear”. In A Companion to Shakespeare’s Works, Vol. 1, The
Tragedies, ed. by Richard Dutton and Jean E. Howard (Maldan, MA: Blackwell,
2003), 376–77. 8. Shakespeare: The Return of Fin’amor But even though Romeo
may, as Juliet observes, “kiss by th’ book”,170 and though Juliet may
be expressing herself with unnecessary emphasis by declaring that
if Romeo is “marriéd, / My grave is like to be my wedding bed”,171 it
hardly seems necessary to dismiss them as mere puppets of structural
expectations and conventions: The young lovers feel intensely that which the [sonnet] mode incites
them to feel. Confronted with the image of the ideal lover, each reverts to
stereotype. What we have here is an existential drama of sonnet-life. The
world of Romeo and Juliet […] is a world of fixed relations and closed
assumptions. They appear as quotations, and they speak in quotations:
the cliché, of which the sonnet is exemplar, is the dominant thought-
form of Verona.172 Here we have a touch of the Zumthor/Stone/Heller-Roazen argument
that seeks to erase individuality. One begins to wonder what it is in
this argument that appeals to the academic mind. Understood in this
way, one also wonders why anyone would bother paying the price
of admission to see this play. Kiernan Ryan, in a brilliant chapter on
King Lear, addresses the reductive nature of too much critical writing
about these plays, and about literature and art in general, and boils the
problem down into three ingredients that are applicable to any number
of other plays: 406 Love and its Critics The first is [the critics’] supposition that the tragedy is the symptom of
some ulterior phenomenon, whether it be language, the unconscious,
patriarchy, or power. The play’s autonomy and integrity as a work of
art are ditched by critics bent on recruiting it to confirm their theoretical
assumptions or preconceptions of the past. The second reason is
endemic to critics raring to immure [the play] in its early modern matrix:
a blindness to the possibility that the tragedy may not be fully intelligible
in terms of its time, because its gaze is fixed on horizons that still lie
ahead of our time. Even when radical historicists like Patterson hold [the
play] must have been subversive in Shakespeare’s day, it remains the
imprint of an obsolete era, the pawn of a purely retrospective viewpoint. 174 Romeo and Juliet 2.2.33, 40. 176 Between joy and its external cause there is always some separation and some obstacle: society,
sin, virtue, our bodies, our separate selves. And from this arises the heat of passion. And from
this comes the fact that our wish for total union is bound indissolubly with a desire for the death
that frees us.
Entre la joie et sa cause extérieure il y a toujours quelque séparation et quelque obstacle: la
societé, le peché, la vertu, notre corps, notre moi distinct. Et de là vient l’ardeur de la passion.
Et de là vient que le desir d’union totale se lie indissolublement au désir de la mort qui libere.
Denis de Rougemont. L’Amour et l’Occident (Paris: Plon, 1939), 176.
177 Romeo and Juliet 2 2 38 175 Ibid., 2.2.1–3, 10–11, 15–17, 23–25. 178 Ibid., 2.2.40–41. Henrik Lagerlund. “The Assimilation of Aristotelian and Arabic Logic up to the
Later Thirteenth Century”. Medieval and Renaissance Logic, ed. by Dov M. Gabbay
and John Woods (Amsterdam: Elsevier, 2008), 288. In the sentence: “This human being is white and an animal”, the predication of “white” and
“animal” of “human being” is quite different. Al-Ghāzalī calls the first accidental and the
second essential. […] He seems to mean, as Aristotle indeed thought, that what is essentially
tied to each other is also ordered in a special way, namely in the sense that animal is prior to
human being [and thus prior still to white]. 175 Ibid., 2.2.1–3, 10–11, 15–17, 23–25. 8. Shakespeare: The Return of Fin’amor And the third reason is the failure to engage in detail with the poetic
language and dramatic form […], which in some cases, as Greenblatt’s
essays demonstrate, simply furnishes a pretext for expounding another
text altogether.173 But there is no shortage of interesting material in the plays, despite the
desire of many critics to rewrite the texts, or, as Ryan suggests, abandon
them for others. In Romeo and Juliet, Juliet addresses fundamental
questions of identity, politics, and love’s tenuous existence in a world in
which so many will fight for so long over what finally amounts to so little. In asking “wherefore art thou Romeo?” and “What’s Montague?”174 Juliet
shows that her thinking is already more advanced than is Romeo’s, who
is still half caught in his own facility with Petrarchan poetic imagery, as
he compares her to the sun and the stars, and wishes—rather than to be
with her at the moment—to be a glove upon her hand so that he might
touch her cheek: But, soft! what light through yonder window breaks? It is the east, and Juliet is the sun. […]
It is my lady, O, it is my love! O, that she knew she were! […]
Two of the fairest stars in all the heaven,
Having some business, do entreat her eyes But, soft! what light through yonder window breaks? It is the east, and Juliet is the sun. […]
It is my lady, O, it is my love! O, that she knew she were! […]
Two of the fairest stars in all the heaven,
Having some business, do entreat her eyes 407 8. Shakespeare: The Return of Fin’amor 177 Romeo and Juliet 2.2.38. 179 Al-Ghāzalī, an eleventh-and twelfth-century interpreter of Aristotle explained the
distinction as a matter of prior and latter categories:
In the sentence: “This human being is white and an animal”, the predication of “white” and
“animal” of “human being” is quite different. Al-Ghāzalī calls the first accidental and the
second essential. […] He seems to mean, as Aristotle indeed thought, that what is essentially
tied to each other is also ordered in a special way, namely in the sense that animal is prior to
human being [and thus prior still to white].
Henrik Lagerlund. “The Assimilation of Aristotelian and Arabic Logic up to the
Later Thirteenth Century”. Medieval and Renaissance Logic, ed. by Dov M. Gabbay
and John Woods (Amsterdam: Elsevier, 2008), 288. 180 Dympna Callaghan. “The Ideology of Romantic Love: the Case of Romeo and
Juliet”. The Weyward Sisters: Shakespeare and Feminist Politics (Cambridge, MA:
Blackwell, 1994), 59.
Ibid 182 “la gamme du sado-masochisme que les deux partenaires avaient annoncé déjà
dans la version pourtant relativement paisible du texte shakespearien” (Julia
Kristeva. Histoires d’amour. Paris: Denoël, 1983, 210). 181 Ibid., 60. 8. Shakespeare: The Return of Fin’amor To twinkle in their spheres till they return. […]
See, how she leans her cheek upon her hand! O, that I were a glove upon that hand,
That I might touch that cheek!175 In contrast, Juliet is already thinking about the practical obstacles to their
ability to be together, and how those obstacles might be overcome, pace
Denis De Rougemont’s argument that it is the obstacles themselves that are
the incitements to love.176 In Juliet’s speech, “‘Tis but thy name that is my
enemy”,177 and the obstacles of name and position can be overcome if the
lovers will see beyond the historically contingent categories of politics
and Veronese identity to the nature or essence of what each person is, or
can be In referring to body parts like hand and foot, arm and face,178 Juliet
argues that in moving beyond what a Renaissance thinker, following
Aristotle, would call “the accidental”,179 she and Romeo can find love in
spite of the obstacles that stand between them. Whether or not this is possible, or even desirable, is contested. For
some, like Callaghan, Romeo and Juliet serves to create and impose “a
certain formation of desiring subjectivity attendant upon Protestant and
especially Puritan ideologies of marriage and the family required by Denis de Rougemont. L’Amour et l’Occident (Paris: Plon, 1939), 176. 177 R
d J li t 2 2 38 179 Al-Ghāzalī, an eleventh-and twelfth-century interpreter of Aristotle explained the
distinction as a matter of prior and latter categories: 408 Love and its Critics […] the emergent economic formation of capitalism”.180 Callaghan also
argues that the play has served as a powerful artifact that supports the
“dominant ideology of romantic love”, which oppressively “relegates
homosexuality to the sphere of deviance, secures women’s submission
to the asymmetrical distribution of power between men and women,
and bolsters individualism by positing sexual love as the expression
of authentic identity”.181 For Julia Kristeva, the play’s portrayal of
love disguises a dark undercurrent in which, if Romeo and Juliet
had survived, their passion would have revealed “the whole range
of sadomasochism that both partners had already announced in the
relatively quiet version of the Shakespearean text”.182 But if that is what
Romeo and Juliet depicts, if Callaghan’s argument about the play being
oppressive is correct, or Kristeva’s contention about its love’s perversity
is correct, then what should the play portray instead? 8. Shakespeare: The Return of Fin’amor Rather than
presenting what these critics regard as an oppressively heterosexual
and/or sadomasochistic “romantic love”, should it, after all, proceed
with the orderly demonstration of Juliet’s obedience to her father? Would unfettered patriarchy be preferable? Or should it show Romeo
and Mercutio running off together, while Juliet finds happiness with
Rosaline or expresses her “authentic identity” through celibacy, or
perhaps a hobby of some sort? Perhaps, as Sinfield suggests, it would
be more interesting if the play were rewritten in order that “every man
or woman may have his or her Jack and his or her Jill”, so that we might
have combinations that go beyond “even same-gender couples”?183
Maybe it would be preferable to “amputate” the play, after the fashion of
the avant-garde writer/director Carmelo Bene, who, in Gilles Deleuze’s
view, opens up amazing possibilities by eliminating Romeo altogether? […] the emergent economic formation of capitalism”.180 Callaghan also
argues that the play has served as a powerful artifact that supports the
“dominant ideology of romantic love”, which oppressively “relegates
homosexuality to the sphere of deviance, secures women’s submission
to the asymmetrical distribution of power between men and women,
and bolsters individualism by positing sexual love as the expression
of authentic identity”.181 For Julia Kristeva, the play’s portrayal of
love disguises a dark undercurrent in which, if Romeo and Juliet
had survived, their passion would have revealed “the whole range
of sadomasochism that both partners had already announced in the
relatively quiet version of the Shakespearean text”.182 But if that is what
Romeo and Juliet depicts, if Callaghan’s argument about the play being
oppressive is correct, or Kristeva’s contention about its love’s perversity
is correct, then what should the play portray instead? Rather than
presenting what these critics regard as an oppressively heterosexual
and/or sadomasochistic “romantic love”, should it, after all, proceed
with the orderly demonstration of Juliet’s obedience to her father? Would unfettered patriarchy be preferable? Or should it show Romeo
and Mercutio running off together, while Juliet finds happiness with
Rosaline or expresses her “authentic identity” through celibacy, or
perhaps a hobby of some sort? 183 Sinfield, 112, 111. 184 CB [Carmelo Bene] […] soustrait quelque chose de la pièce originaire. […] Mais, par exemple, il
ampute Roméo, il neutralise Roméo dans la pièce originaire. […] Si vous amputez Roméo, vous
allez assister à un étonnant développement, le développement de. Mercuzio, qui n’était qu’une
virtualité dans la pièce de Shakespeare. Mercuzio meurt vite chez Shakespeare, mais, chez CB,
il ne veut pas mourir, il ne peut pas mourir, n’arrive pas à mourir, puisqu’il va constituer la
nouvelle pièce.
Gilles Deleuze. “Un manifeste de moins”. Superpositions (Paris: Éditions de Minuit,
1979), 87–88.
185 Ryan, “King Lear”, 377–78. 185 Ryan, “King Lear”, 377–78. 8. Shakespeare: The Return of Fin’amor Perhaps, as Sinfield suggests, it would
be more interesting if the play were rewritten in order that “every man
or woman may have his or her Jack and his or her Jill”, so that we might
have combinations that go beyond “even same-gender couples”?183
Maybe it would be preferable to “amputate” the play, after the fashion of
the avant-garde writer/director Carmelo Bene, who, in Gilles Deleuze’s
view, opens up amazing possibilities by eliminating Romeo altogether? CB [Carmelo Bene] […] subtracts something from the original piece. […] For example, he amputates Romeo, neutralizes Romeo in the
original piece. […] If you ampute Romeo, you will witness an amazing 8. Shakespeare: The Return of Fin’amor 8. Shakespeare: The Return of Fin’amor 409 development. Mercutio was only a virtuality in Shakespeare’s play. Mercutio dies quickly in Shakespeare, but in [Carmelo Bene’s version]
he does not want to die, cannot die, cannot reach the point of dying, since
he is going to constitute the new play.184 Or should it, perhaps, remain exactly as it is, serving as an object
of scorn tied to the critical whipping-post while modern, morally
superior critics vent their spleens? At long last, it becomes impossible
to tell whether there is any sense of decency left in criticism, as so
many of us pound a work until it threatens to die beneath our urgent
bludgeoning. This entire dynamic of morally outraged criticism is
wonderfully described by Ryan: One of the least appealing features of literary studies today is the smug
diagnostic attitude that has swept through them like foot-and-mouth
disease through a fine herd of Friesians. It is this attitude that reduces
Shakespeare’s drama to an allegory or appendix of something else and
then passes sentence on it from the supposedly superior vantage point of
hindsight. It thereby denies the plays the power not only to arraign the
world in which they were first forged and the world in which we now
encounter them, but also to foreshadow futures that would otherwise
remain intangible. It is an approach that goes hand in hand with a scorn
for close reading, a contempt for the belief that there is something special
about the creative use of language and form in imaginative writing at its
best that sets it apart from other kinds of discourse and gives us ways of
seeing the world which no other kind of writing can deliver.185 Perhaps it is in the dawn-song scene of Act 3 where Romeo and Juliet
might mount a defense against its more disdainful critics. In a scene
in which two young people, who about to be separated forever, have
fallen in love—not to injure anyone, and certainly not to “relegate”
anything or anyone “to the sphere of deviance”—and now face the
full power of the father and the state arrayed against them, perhaps 410 Love and its Critics here some redeeming value might be found in the play. The scene is
nearly a point-by-point recreation of the alba form of the troubadour
poets. 186 “Then anguish satisfied by response, longing satisfied by presence, we cease to
call for a sensitive and delicate happiness, cease to suffer, accept our day. And
then marriage is possible, for we two are contented” (“Alors l’angoisse comblée
par la réponse, la nostalgie comblée par la présence cessent d’appeler un bonheur
sensible, cessent de souffrir, acceptent notre jour. Et alors le mariage est possible.
Nous sommes deux dans le contentement”) (Denis de Rougemont, 273). 187 See Simon Gaunt. “Poetry of Exclusion: A Feminist Reading of Some Troubadour
Lyrics”. The Modern Language Review, 85: 2 (April 1990), 310–329, https://doi.
org/10.2307/3731812 188 Jonathan Saville. The Medieval Erotic Alba: Structure as Meaning (New York: Columbia
University Press, 1972), 122. Emphasis added. 189 William Butler Yeats. The Scholars [1929 version], in Yeats’s Poetry, Drama, and Prose:
Authoritative Texts, Contexts, Criticism, ed. by James Pethica (New York: W. W.
Norton & Co., 2000), 60. 189 William Butler Yeats. The Scholars [1929 version], in Yeats’s Poetry, Drama, and Prose:
Authoritative Texts, Contexts, Criticism, ed. by James Pethica (New York: W. W.
Norton & Co., 2000), 60.
190 Ewan Fernie. The Demonic: Literature and Experience (New York: Routledge, 2013), 88.
191 “человек умнейший и даровитейший, человек, так сказать, даже науки,
хотя, впрочем, в науке… ну, одним словом, в науке он сделал не так много и,
кажется, совсем ничего. Но ведь с людьми науки у нас на Руси это сплошь да
рядом случается" (Fyodor Dostoevesky. Бесы [Demons, aka The Possessed, or The
Devils] [St. Petersburg: Azbuka, 2008], 20). 190 Ewan Fernie. The Demonic: Literature and Experience (New York: Routledge, 2013), 88.
191 “человек умнейший и даровитейший, человек, так сказать, даже науки,
хотя, впрочем, в науке… ну, одним словом, в науке он сделал не так много и,
кажется, совсем ничего. Но ведь с людьми науки у нас на Руси это сплошь да
рядом случается" (Fyodor Dostoevesky. Бесы [Demons, aka The Possessed, or The
Devils] [St. Petersburg: Azbuka, 2008], 20). 8. Shakespeare: The Return of Fin’amor The genre assumes an oppressive and tightly-controlled world
of social, financial, and political power. It includes marriage, not, as
De Rougemont would have it, as the happy cure to love,186 but as the
oppressive institution through which love’s flourishing is strangled in
its cradle. And yet, authority fails. Love flourishes in spite of the power
of the jealous husband (lo gilos), as the eyes go forth to gaze and desire
(ill oill van vezer) despite the demands of authority and obedience. The
lovers, invariably adulterous, can only meet in secrecy, under cover of
darkness, and they need a watchman or guard to warn them as soon as
the first rays of the too-quickly rising sun appear. These poems are not biographical, of course, though the situations
they describe are well within the range of human experience. They are
literary constructions—as is Romeo and Juliet—whose effect depends
on their contact with lived events and emotion. However, if regarded
as merely literary constructions, or the occasions for formal dramatic
performances, or as self-ironizing and self-aggrandizing pieces
reflecting the narcissism and misogyny of the poets,187 then they are just
as dead as their authors. If were are to believe that “[a] poet wrote albas,
not because he had experienced the situation depicted by the alba, and
not even because he fancied himself experiencing it with a particular woman he
was in love with, but simply because it was one of the current literary
genres”,188 then we are being asked to believe that the most passionate
poems written at the very dawn of the modern Western literary tradition
can, and should, be coolly regarded as mere exercises in form, a day’s
work at the poet’s office in eleventh-and twelfth-century Occitania. 8. Shakespeare: The Return of Fin’amor 411 With friends like these, what need has poetry of enemies? Finally, what
comes to mind are these lines by William Butler Yeats: With friends like these, what need has poetry of enemies? Finally, what
comes to mind are these lines by William Butler Yeats: Bald heads forgetful of their sins,
Old, learned, respectable bald heads
Edit and annotate the lines
That young men, tossing on their beds,
Rhymed out in love’s despair
To flatter beauty’s ignorant ear. All shuffle there; all cough in ink;
All wear the carpet with their shoes;
All think what other people think;
All know the man their neighbour knows. Lord, what would they say
Did their Catullus walk that way?189 Yeat’s riposte is one of the classic examples of a poet speaking back to
critics, and is of a piece with the picture the novelist Fyodor Dostoevsky
gives of a particular critic, a character named Stepan Verkhovensky,
who represents a “creed [that] unavoidably involves a degree of
alienation—from the concrete immediacy of life, from our feeling for
what is”.190 As Dostoevsky describes him, this critic is all surfaces and
no depths, a proto-nihilistic poseur who has little real use for either
poetry or scholarship. Verkhovensky is “the cleverest man and a gifted
man, so to speak, even a scholar, though, indeed, in scholarship… well,
in a word, in scholarship, he did not so much, and it seems, nothing. But with the scholarship we have in Russia this very often happens”.191
Despite the “Old, learned, respectable bald heads”, whose work both
the poet and the novelist appear to regard as “not so much, and it
seems, nothing”, passionate poetry is not mere form, no matter how
many books and journal articles pile up claiming that it is so, nor is it 412 Love and its Critics reducible to ideology, nor, finally, is it merely biography (which could
be seen, in a mean-spirited way, as narcissism). It is an attempt to reflect,
capture, transmit, and communicate at least some part of the experience
(or range of experiences) that people have when they love, for good
or ill, another than themselves in a passionate, vulnerable, sometimes
possessive and insecure, and erotic way. It is not mere lust these poems
describe. It is not mere poetic form that they rehearse. If the latter were
all that such poetry had to offer, few besides Yeats’ imagined scholars
would read any of it. 193 In Aristotle’s definition:
Tragedy, then, is imitation of an elevated action that is both great and complete, in language
embellished by distinctive forms in each section, rendered by action and not by recitation,
accomplishing through pity and fear the catharsis of such sufferings.
ἔστιν οὖν τραγῳδία μίμησις πράξεως σπουδαίας καὶ τελείας μέγεθος ἐχούσης, ἡδυσμένῳ
λόγῳ χωρὶς ἑκάστῳ τῶν εἰδῶν ἐν τοῖς μορίοις, δρώντων καὶ οὐ δι᾿ ἀπαγγελίας, δι᾿ ἐλέου καὶ
φόβου περαίνουσα τὴν τῶν τοιούτων παθημάτων κάθαρσιν.
Aristotle, Poetics, ed. by Stephen Halliwell. In Aristotle: Poetics. Longinus: On the
Sublime. Demetrius: On Style (Loeb Classical Library, Cambridge, MA: Harvard
University Press, 1995, 46, 1449b 24–28). 192 Aileen Ann Macdonald. “A Refusal to be Silenced or to Rejoice in any Joy that Love
may Bring: The anonymous Old Occitan canso, ‘Per ioi que d’amor m’avegna’”.
Dalhousie French Studies, 36 (Fall 1996), 10. 194 Hagstrum, 221.
195 R. B. Outhwaite. Clandestine Marriage in England, 1500–1850 (London: Hambledon
Press, 1995), 7.
196 Richard Bagot. “Letter from Richard Bagot to Richard Broughton, 1587 June 3”.
Papers of the Bagot Family of Blithfield, Staffordshire, 1428–1671 (bulk 1557–1671).
Folger MS L.a.68 (Folger Shakespeare Library, Washington, http://luna.
folger.edu/luna/servlet/workspace/handleMediaPlayer?lunaMediaId=FOLGE
RCM1~6~6~361296~130605). With friends like these, what need has poetry of enemies? Finally, what
comes to mind are these lines by William Butler Yeats: y
But such has not been the fate of the troubadour albas, nor has it been
the fate of Romeo and Juliet, whose alba, or dawn-song, is among the most
affecting moments in the play despite the attempts of authority—that of
Capulet in the play, and that of too many academic critics in the modern
world—to eliminate its power. As Aileen Ann Macdonald observes: The alba […] recounts the continuing events of a love affair after it has
been initiated, for it describes the lovers’ clandestine meetings at night,
culminating in their passionate and poignant parting as dawn breaks. […] It has been suggested […] that the alba was in the beginning another
woman’s song, where the lady laments that dawn is coming to part her
from her lover—just as does Juliet in the most famous alba of all after her
night of love with Romeo.192 Juliet’s alba is the emotional core of a play designed to take audiences
and readers on a wrenching journey of what Aristotle once called
catharsis (κάθαρσις)—the raising of intense emotion that is held, and
then released during the play.193 Far from being rendered merely
“conventional”, Juliet’s emotions and predicament are even more 8. Shakespeare: The Return of Fin’amor 413 powerfully expressed through the use of the alba, especially since she
and her husband do not belong in the situation the genre describes. Romeo and Juliet are married, not an adulterous couple, and the jealous
male here (lo gilos) is a father, not a husband. Though the couple’s marriage is clandestine and not yet formalized
with a church ceremony, it is legally-binding, and would be known to
be so by the English audience watching this play for the first time: Consensus facit nuptias had been a principle of Roman and early canonical
law […]. With friends like these, what need has poetry of enemies? Finally, what
comes to mind are these lines by William Butler Yeats: The church wanted a union of hearts as well as hearths, and
so private vows and promises with or without consummation were
understood to constitute a valid marriage, and the desponsatio (betrothal)
became more important than the final ceremony.194 There were forces that opposed such marriages, but “clandestine
contracts” remained part of the tapestry of marriage practices, in spite
of the opposition: There were forces that opposed such marriages, but “clandestine
contracts” remained part of the tapestry of marriage practices, in spite
of the opposition: A note of “matters to be moved by the clergy” in the Parliament and
Synod of 1563 included pleas […] for the raising of the age of consent
for girls to fifteen; for sterner punishments of adulterers, fornicators, and
abductors; and pleas that both the marriage of minors without parental
permission and “all clandestine contracts” be made void.195 The anger such clandestine marriages caused fathers who were thereby
deprived of their ability to control—and profit from—the marriages of
their children is attested to by a letter, dated June 3 1587 and written
by Richard Bagot to Richard Broughton. In the letter, Bagot complains
bitterly about his daughter Margaret’s secret marriage, describing his
“daughters lewde dealings in this her match, [which] hath not a litle
trobled me and her mother”. Bagot then wonders how he will ever be
able to “digest such a villainy”, before wishing that “god give them joye
and some sorrowe, as they have given us cause of grief”.196 The secret— 414 Love and its Critics and not-so-secret—rebellions that Shakespeare presents on stage are
already beginning to take root in the England from which he derives his
audiences and readers. Romeo and Juliet should not be in this position, and yet, due to the
authority of Prince Escalus, who has banished Romeo over the killing
of Tybalt, the overbearing authority of Capulet, and Juliet’s fear of
confronting him, here they are—in a strangely misplaced alba, hoping
that it is not the dawn’s first light they are seeing, light that will separate
them forever. The female voice—Juliet—begins, noting and denying the
coming of day: Wilt thou be gone? 197 Romeo and Juliet 3.5.1–5.
198 Ibid., 3.5.6–11. 197 Romeo and Juliet 3.5.1–5. 198 Ibid., 3.5.6–11. With friends like these, what need has poetry of enemies? Finally, what
comes to mind are these lines by William Butler Yeats: it is not yet near day:
It was the nightingale, and not the lark,
That pierced the fearful hollow of thine ear;
Nightly she sings on yon pomegranate-tree:
Believe me, love, it was the nightingale.197 And as they had begun, composing their poetry in the scene of their first
meeting, so they end, writing the final poem of their vanishingly brief
marriage. Romeo responds by acknowledging the light, and framing his
choice between life and banishment, or love and death: It was the lark, the herald of the morn,
No nightingale: look, love, what envious streaks
Do lace the severing clouds in yonder east:
Night’s candles are burnt out, and jocund day
Stands tiptoe on the misty mountain tops. I must be gone and live, or stay and die.198 After several more lines of back and forth, during which they switch
rhetorical and emotional positions, with Juliet now urging Romeo to
escape, Romeo pledging to stay and die, and each bemoaning how little
time they have left together, the watchman of the alba enters. Juliet’s
nurse, who has aided and abetted the relationship between Romeo and
Juliet to the best of her ability, comes in to warn them of the coming
of day: “Your lady mother is coming to your chamber: / The day is 8. Shakespeare: The Return of Fin’amor 415 broke; be wary, look about”.199 With each wondering if they “shall ever
meet again”,200 Romeo says Adieu, adieu! as he escapes out the balcony
window, and they are never truly together again. What renders this scene so powerful is the feeling of helplessness in
the face of hostile and jealous authority that the alba genre brings with
it, amplified by Shakespeare’s modification of the marital situations
usually found therein. These are lovers who should be together, who
have every right to be together, and whom every single person in an
audience wants to see together. The sense of love and unjust interference
is palpable, powerful, and profound. To remark, as if there were some
particularly insightful observation contained therein, that Shakespeare
is merely making use of “one of the current [or past] literary genres” is
to miss, even actively to obscure, the point. It does not matter whether,
while writing these words, Shakespeare was, or had recently been,
experiencing the emotions his work evokes. 199 Ibid., 3.5.39–40.
200 Ibid., 3.5.51.
201 Colin Falck. Myth, Truth and Literature: Towards a True Postmodernism (Cambridge:
Cambridge University Press, 1989), 122.
202 So, without going into a more serious explanation, we will say only that, in reality, the typicality
of persons is, as it were, diluted with water, and all those Georges Dandins and Podkoleosins
are actually there scurrying and running in front of us every day, but as if in a somewhat
liquefied state.
Итак, не вдаваясь в более серьезные объяснения, мы скажем только, что в действительности
типичность лиц как бы разбавляется водой, и все эти Жорж-Дандены и Подколесины
существуют действительно, снуют и бегают пред нами ежедневно, но как бы несколько в
разжиженном состоянии.
Fyodor Dostoevsky. Идиот [The Idiot] (St. Petersburg: A. Suvorin, 1884), 452. Итак, не вдаваясь в более серьезные объяснения, мы скажем только, что в действительности
типичность лиц как бы разбавляется водой, и все эти Жорж-Дандены и Подколесины
существуют действительно, снуют и бегают пред нами ежедневно, но как бы несколько в
разжиженном состоянии. 202 So, without going into a more serious explanation, we will say only that, in reality, the typicality
of persons is, as it were, diluted with water, and all those Georges Dandins and Podkoleosins
are actually there scurrying and running in front of us every day, but as if in a somewhat
liquefied state. ,
201 Colin Falck. Myth, Truth and Literature: Towards a True Postmodernism (Cambridge:
Cambridge University Press, 1989), 122. Fyodor Dostoevsky. Идиот [The Idiot] (St. Petersburg: A. Suvorin, 1884), 452. With friends like these, what need has poetry of enemies? Finally, what
comes to mind are these lines by William Butler Yeats: What matters is that the
emotions are evoked, that art and an audience have similar enough
frames of reference (“conventional” thoughts and objects of thought,
if one must use such ground-to-dust terminology) that sympathy,
empathy, even pity and fear can be evoked—that lived experience can be
recalled, reframed, and made new again, even if only for a moment. Art
“reveals in a more concentrated or intense way what ordinary life reveals
in its expressive aspects”.201 This is what Dostoevsky refers to when he
describes everyday people as “разбавляется водой”202—“diluted with
water”, or “watered-down” versions of literary characters—not that
human beings in their ordinary lives are less than real, but that our artistic
representations of ourselves and our experiences are concentrated and 416 Love and its Critics sharpened to a point. Just as we depend on our art for an intensified
experience of life, our art depends on us for contact with everyday
reality. Art, perhaps especially narrative and dramatic art, depends on
its ability to refer to and represent the lived experience of human beings
in order for it to have any power at all. It cannot be locked away inside
the structures of language, or inside a self-referentiality of techniques
and formal elements from which it cannot escape. Denied that contact
with “ordinary life”, literature, music, painting, sculpture, dance, dies,
just as do Romeo and Juliet, alone, and with no one to mourn until it is
too late. The love between the young pair has served as their impetus to defy
authority and social convention, while risking the sharp disapproval
(and possible violence) of their families. But it has not given them the
strength to stand up, and openly acknowledge what they have done. Romeo’s banishment, and Juliet’s faked death, show each of them
turning in fear from the face of authority, as their celebrated love is
not enough to enable them to face the wrath of those to whom they
have long been in the habit of submissiveness. And that is their tragedy,
not in “violating the norms of the society in which they lived”,203 but
in failing to sufficiently honor love, and each other, by bringing their
disobedience and rejection of those norms out into the open. 203 L. Stone, 87.
204 Evelyn Gajowski. The Art of Loving: Female Subjectivity and Male Discursive Traditions
in Shakespeare’s Tragedies (Cranbury, NJ: Associated University Presses, 1992), 52. 203 L. Stone, 87. 205 Romeo and Juliet 4.1.105.
206 Ibid., 5.3.91–96.
207 Ibid., 5.3.97.
208 Ibid., 5.3.101–05. With friends like these, what need has poetry of enemies? Finally, what
comes to mind are these lines by William Butler Yeats: Juliet, who
is in some ways the stronger of the two, is still too young, and is not yet
sure-footed and strong-willed enough to defy Capulet; she “possesses
the strength to choose a Montague for her husband, but not to stand up
to her father”.204 Given Capulet’s wrath and potential for violence, it is
all too easy to understand why. One of the starkest differences between this pair, who are otherwise
presented as having “zweier herzen wünne”, is revealed in their death
scenes. Romeo still has a bit too much of the Petrarchan sonneteer about
him, and despite his love for Juliet, has not yet learned to see her apart
from his own poetic fantasies of the ideal love she represents to him. Had
he only been given time, he might have grown beyond his idealizing
tendencies; but time is what the play—and all its sources, from the works
of Arthur Brooke, to Pierre Boaistuau, to Matteo Bandello—will not give 8. Shakespeare: The Return of Fin’amor 417 him. In the heart of the Capulet mausoleum, with Juliet’s awakening
face and form in front of him, Romeo does not see. Her “two and forty
hours”205 of unconsciousness are all but up, and Romeo’s own remarks
indicate that she is warming and nearly surfacing past the waters of
unconsciousness even as he looks at her. Far from being a cold corpse
that will suddenly reanimate, Juliet is ruddy of cheek and lip; she looks
alive, and Romeo finds that puzzling: O my love! my wife! Death, that hath sucked the honey of thy breath,
Hath had no power yet upon thy beauty:
Thou art not conquered; beauty’s ensign yet
Is crimson in thy lips and in thy cheeks,
And death’s pale flag is not advanced there.206 But rather than stop for a moment with Juliet, he turns and speaks to the
body of Tybalt, lying in a “bloody sheet”,207 though perhaps something
now registers with him about the contrast between the two bodies. He
turns back to Juliet, and asks—as if speaking to her one last time—why
she looks so much like she is still alive: Ah, dear Juliet,
Why art thou yet so fair? shall I believe
That unsubstantial death is amorous,
And that the lean abhorred monster keeps
Thee here in dark to be his paramour?208 Ah, dear Juliet,
Why art thou yet so fair? 205 Romeo and Juliet 4.1.105. 206 Ibid., 5.3.91–96. 207 Ibid., 5.3.97. 208 Ibid., 5.3.101–05. 209 ἀνεῖσαν ἀγασθέντες τῷ ἔργῳ οὕτω καὶ θεοὶ τὴν περὶ τὸν ἔρωτα σπουδήν τε καὶ ἀρετὴν
μάλιστα τιμῶσιν. Ὀρφέα δὲ τὸν Οἰάγρου ἀτελῆ ἀπέπεμψαν ἐξ Ἅιδου, φάσμα δείξαντες τῆς
γυναικὸς ἐφ᾿ ἣν ἧκεν, αὐτὴν δὲ οὐ δόντες, ὅτι μαλθακίζεσθαι ἐδόκει, ἅτε ὢν κιθαρῳδός,
καὶ οὐ τολμᾶν ἕνεκα τοῦ ἔρωτος ἀποθνῄσκειν ὥσπερ Ἄλκηστις, ἀλλὰ διαμηχανᾶσθαι ζῶν
εἰσιέναι εἰς Ἅιδου.
Plato. Symposium, ed. by W. R. M. Lamb (Loeb Classical Library, Cambridge, MA:
Harvard University Press, 1925), 179D. With friends like these, what need has poetry of enemies? Finally, what
comes to mind are these lines by William Butler Yeats: shall I believe
That unsubstantial death is amorous,
And that the lean abhorred monster keeps
Thee here in dark to be his paramour?208 The simple solution to the problem, of course, is that Juliet is alive. But Romeo, overwhelmed by a grief the like of which he has never
experienced, that he can only understand through the Petrarchan and
Platonic images and concepts he has not yet had time enough to master
and move beyond, does not adopt the simple solution. In fact, it does
not even occur to him. Instead, he mythologizes and poeticizes Juliet’s
death-which-is-not-death, by casting Juliet in the part of Eurydice in 418 Love and its Critics the myth of Orpheus, especially perhaps, the version from Phaedrus’
speech in Plato’s Symposium: The gods let loose their wonder for the works of love, and haste to
hold valour in high honor. Orpheus, son of Oeagrus, they sent away
unsuccessful from Hades, showing him only the ghost of the wife he
had come for, and did not deliver her true self to him. For they regarded
him as soft of purpose, like a mere player and singer of songs, because
he lacked the courage to die for love as Alcestis had, but sought to enter
Hades alive.209 Perhaps with the idea of “the ghost of [his] wife” in mind, and not
wanting to be thought “soft” like Phaedrus’ version of Orpheus, Romeo
proceeds to die for love, while indulging in one last poetic speech: Perhaps with the idea of “the ghost of [his] wife” in mind, and not
wanting to be thought “soft” like Phaedrus’ version of Orpheus, Romeo
proceeds to die for love, while indulging in one last poetic speech: Eyes, look your last! Arms, take your last embrace! and, lips, O you
The doors of breath, seal with a righteous kiss
A dateless bargain to engrossing death! Come, bitter conduct, come, unsavoury guide! Thou desperate pilot, now at once run on
The dashing rocks thy sea-sick weary bark! Here’s to my love! [Drinks] O true apothecary! Thy drugs are quick. Thus with a kiss I die.210 As he kisses her, is he so wrapped up in the poetry of the Orphean
myth211 that he does not feel the warmth of Juliet’s lips? J
211 Romeo is a kind of inverted Orpheus—one who loses his Eurydice, not because he
looks back at her, but because he cannot get his head out of his songs. y
210 Romeo and Juliet, 5.3.112–20. y
)
210 Romeo and Juliet, 5.3.112–20. Plato. Symposium, ed. by W. R. M. Lamb (Loeb Classical Library, Cambridge, MA:
Harvard University Press, 1925), 179D. Where be these enemies? Capulet! Montague! g
214 In Gramsci’s thought, literary critics—at least as much as, if not more than,
poets and playwrights and and novelists—are complicit in the dissemination of
the ruling ideas of a given time and place. Gramsci proposed what he called “a
study of how, in fact, the ideological structure of the dominant class is organized”
(“Uno studio di come è organizzata di fatto la struttura ideologica di una classe
dominante”), before noting that “the most remarkable and dynamic part of it is the
press in general: publishers (that have implicit and explicit programs, and support
a determined, or pre-given, current), political journals, and magazines of all kinds,
scientific, literary, philological, popular, etc., various periodicals even down to
church parish bulletins” (“La parte più ragguardevole e più dinamica di esso è la
stampa in generale: case editrici (che hanno implicito ed esplicito un programma e
si appoggiano a una determinata corrente), giornali politici, riviste di ogni genere,
scientifiche, letterarie, filologiche, di divulgazione ecc., periodici vari fino ai
bollettini parrocchiali”) (Antonio Gramsci. Quarderi del carcere, Vol. I, Quaderni 1–5,
ed. by Valentino Gerratana [Turin: Giulio Einaudi, 1977], Q3§ 49, 332–33). 213 Callaghan (1994), 59. With friends like these, what need has poetry of enemies? Finally, what
comes to mind are these lines by William Butler Yeats: It is impossible
to know, but given the focus on himself and his own emotions Romeo
has shown throughout the play, it seems the likely answer is “yes”. 419 212 Ibid., 5.3.167. 8. Shakespeare: The Return of Fin’amor 8. Shakespeare: The Return of Fin’amor Juliet, on the other hand, sees Romeo. As she awakes and takes stock
of where she is and what is going on, she sees Romeo’s lifeless body,
mere moments after it had crossed over into death. As she kisses him,
she feels traces of life: “Thy lips are warm!”212 In that moment, more
than any other in the play, the full tragedy of love, fear, and authority
hits home, and catharsis kicks into high gear. These two never had a
chance, to love, to live, even to grow up past the initial blooming of
their passions and potential. The story of their lives and deaths does
not bolster “individualism by positing sexual love as the expression of
authentic identity”;213 rather, it shows how an attempt to use such love
as an expression of identity can be ruthlessly crushed by the “dominant
ideology”, not of love, but of (usually male) authority and its demands
for “submission to the asymmetrical distribution of power” between
fathers and daughters, fathers and sons. The Gramscian hegemon in this
play, which embodies the cultural norms promoted by an elite class to
maintain dominance over everyone else,214 is hardly “romantic love”,
nor does that love relegate anything to “the realm of deviance”. It is that
love itself which is regarded as deviant by the authority figures of the
play, only to have the play turn the tables on them by showing them
to be blind and tyrannical murderers of their own children. As Prince
Escalus bitterly sums up: 420 Love and its Critics See, what a scourge is laid upon your hate,
That heaven finds means to kill your joys with love. And I for winking at your discords too
Have lost a brace of kinsmen: all are punished.215 It is as if Shakespeare is making the argument of a prosecutor in a
courtroom in which, rather than the lovers, their parents, their city, their
world are on trial: “Shakespeare […] is making a closing demonstration:
‘Look at the corpses in front of you—your own son and daughter! Why
are they dead? For God’s sake think!’ And he is requiring his audience
to do the same”.216 Far from being any kind of dominant ideology, in
Romeo and Juliet, love is portrayed as a breathtaking, bittersweet, but
doomed challenger to paternal authority and its demands for obedience. 215 Romeo and Juliet, 5.3.291–95.
216 John Vyvyan. Shakespeare and the Rose of Love (London: Shepheard-Walwyn, 1960), 134. 216 John Vyvyan. Shakespeare and the Rose of Love (London: Shepheard-Walwyn, 1960), 134. 215 Romeo and Juliet, 5.3.291–95. 1
Ruth F. Glancy. Thematic Guide to British Poetry (Westport: Greenwood Press, 2002),
43.
2
Horace. Horace: Epodes and Odes, ed. by Daniel H. Garrison (Norman: University of
Oklahoma Press, 1998), 39. 8. Shakespeare: The Return of Fin’amor Love, unsublimated passion for another human being, the fin’amor of the
troubadour and trobairitz poets of the eleventh and twelfth centuries,
is no idle game in Shakespeare. It is a tool of resistance in a contest
between generations that is all too often, a matter of life and death. 9. Love and its Costs in
Seventeenth-Century Literature There could be
no mention of the soul’s eventual journey to heaven in poems that urge
an immediate seizing of the present; there could be no deferral of joy in
poems that imagine this day as the lovers’ only chance for bliss.5 In a worldview that rejects the notion of an afterlife, that breaks with
“Christian metaphysics”, and sees love in terms of “an immediate seizing
of the present”, we see an intensification of the troubadour ethos. The
carpe diem poems are revolutionary, “a stripping from the afterlife of all
forms of pleasure that could compensate for erotic loss, […] overturning
both Petrarchan ideas of heavenly continuity and English reactions to
this Petrarchan paradigm”.6 In the carpe diem poets, the reactionary
and flesh-denying poetics of the tradition running through Akiba and
Origen to Dante and Petrarch meets its strongest challenge yet. Love,
though it cannot prevent death, becomes the primary power behind the
urge to live one’s own life and to make one’s own choices before that
“necessary end”7 finally comes. In a worldview that rejects the notion of an afterlife, that breaks with
“Christian metaphysics”, and sees love in terms of “an immediate seizing
of the present”, we see an intensification of the troubadour ethos. The
carpe diem poems are revolutionary, “a stripping from the afterlife of all
forms of pleasure that could compensate for erotic loss, […] overturning
both Petrarchan ideas of heavenly continuity and English reactions to
this Petrarchan paradigm”.6 In the carpe diem poets, the reactionary
and flesh-denying poetics of the tradition running through Akiba and
Origen to Dante and Petrarch meets its strongest challenge yet. Love,
though it cannot prevent death, becomes the primary power behind the
urge to live one’s own life and to make one’s own choices before that
“necessary end”7 finally comes. 3
Targoff, 165.
4
Ibid., 166.
5
Ibid., 171.
6
Ibid., 176.
7
Julius Caesar 2.2.36. 9. Love and its Costs in
Seventeenth-Century Literature The theme of love as resistance to authority is transformed and amplified
in the lyric poetry of John Donne and Robert Herrick. In work filled with
a sense of the fragility and shortness of life, these poets contribute to an
ethos that has come to be known by the name carpe diem, a phrase made
famous by Horace, “who in Ode, I. xi, tells his mistress that […] life is
short, so they must ‘enjoy the day’, for they do not know if there will
be a tomorrow”.1 Horace’s line, “carpe diem quam minimum credula
postero”2 (“Seize the day, put little trust in tomorrow”), tells Leuconoe,
and all who have followed since, to live now, and love now, because
each second of scruple, doubt, and delay brings men and women closer
to a death that is non-negotiable and eternal. In poetry, and in life,
the idea of death becomes love’s greatest ally in its battle against the
demands of authority, convention, and law. Death hovers over the poetry of this period, and “English love
poetry evolved through an understanding of human love as mortal”, a
perspective that shines clearly through carpe diem poetry. These poems
“magnify the pleasures of this world at the expense of the next”, drawing
much of their power from “the nothingness that awaits lovers in the
afterlife” as a means to persuade readers to live now and “embrace © 2017 Michael Bryson and Arpi Movsesian, CC BY 4.0 https://doi.org/10.11647/OBP.0117.09 Love and its Critics 422 what this life has to offer”.3 We can explicitly connect this poetry to the
earlier work of Shakespeare, as “English carpe diem poetry [follows] in
the path of Romeo and Juliet, [imagining] the intensification of erotic
experience by virtue of its temporal limits”.4 This intensification played
upon an emerging sense of what we would now call atheism, rejecting
the authority of father and state, religion and church: For English Renaissance poets, the act of writing carpe diem lyrics
required a decisive break with Christian metaphysics. 8
Stanley Fish. “Masculine Persuasive Force: Donne and Verbal Power”. In Elizabeth
D. Harvey and Katharine Eisaman Maus, eds. Soliciting Interpretation: Literary
Theory and Seventeenth-Century English Poetry (Chicago: University of Chicago Press,
1990), 223. 9
John Roberts. “John Donne’s Poetry: An Assessment of Modern Criticism”. John
Donne Journal, 1 (1982), 60.
Ib d ,
11
https://commons.wikimedia.org/wiki/File:John_Donne_by_Isaac_Oliver.jpg 10
Ibid., 67. I
Carpe Diem in Life and Marriage: John Donne and the
Critics who Distance John Donne is perhaps the most famous writer of love poetry in the
English language, a man who lived the carpe diem motif even more
powerfully than he used it in his poetry; however, to dig to any depth 9. Love and its Costs in Seventeenth-Century Literature 423 in the commentary that surrounds him is to wander into territory
filled with dramatic conflicts. Some critics—like Ilona Bell—portray
a flawed but fascinating writer whose work is filled with passionate
desire for beautiful women, and devoted love for a particular woman,
while others—like Stanley Fish—regard Donne’s work as “sick”, and
the poet himself equally so, someone who can be read only through
“the pleasures of diagnosis”.8 Such extremes of analysis probably tell
us more about the analysts than about Donne, as John Roberts observes:
“I often feel that many books and essays on Donne tell me more about
the critics writing them than they do about Donne’s poetry”.9 For
Roberts, the goal of criticism should be to make “Donne’s poetry more,
not less accessible to an even wider reading audience than he enjoys at
the present time”.10 One wonders how declaring the poet and his work
“sick” helps accomplish that goal. John Donne, portrait after Isaac Oliver (possibly late 17th century,
based on a work of 1616).11 John Donne, portrait after Isaac Oliver (possibly late 17th century,
based on a work of 1616).11 424 Love and its Critics To understand Donne and his poetry, we will need to engage with
his critics, but not, as William Empson remarks, on their terms: “The
habitual mean-mindedness of modern academic criticism, its moral
emptiness combined with incessant moral nagging, its scrubbed prison-
like isolation, are particularly misleading in the case of Donne; in fact,
we are the ones who need rescuing, not the poet”.12 Where the critics
enlighten, and even where they usefully enrage, we will look to them. 16
Catherine Belsey. Desire: Love Stories in Western Culture (Oxford: Oxford University
Press, 1994), 133. 12
William Empson. “Rescuing Donne”. In John Haffenden, ed. Essays on Renaissance
Literature, Vol. One: Donne and the New Philosophy (Cambridge: Cambridge University
Press, 1993), 159. 15
Anthony Easthope. Poetry and Phantasy (Cambridge: Cambridge University Press,
1989), 193. 13
Achsah Guibbory. Returning to John Donne (Farnham: Ashgate, 2015), 3. 14
Die Geburt der Tragödie aus dem Geiste der Musik (Leipzig: C. G. Naumann, 1894) 4,
https://books.google.com/books?id=lSk2AQAAMAAJ&pg=PA4 12
William Empson. “Rescuing Donne”. In John Haffenden, ed. Essays on Renaissance
Literature, Vol. One: Donne and the New Philosophy (Cambridge: Cambridge University
Press, 1993), 159.
13
Achsah Guibbory. Returning to John Donne (Farnham: Ashgate, 2015), 3.
14
Die Geburt der Tragödie aus dem Geiste der Musik (Leipzig: C. G. Naumann, 1894) 4,
https://books.google.com/books?id=lSk2AQAAMAAJ&pg=PA4
15
Anthony Easthope. Poetry and Phantasy (Cambridge: Cambridge University Press,
1989), 193.
16
Catherine Belsey. Desire: Love Stories in Western Culture (Oxford: Oxford University
Press, 1994), 133. 17
Guibbory, 3.
18
Richard Baker. A Chronicle of the Kings of England (London: Printed by George
Sawbridge at the Bible on Ludgate-hill, 1670), 447, https://books.google.com/
books?id=BnIVsU0RtzUC&pg=PA447 I
Carpe Diem in Life and Marriage: John Donne and the
Critics who Distance But the weakness of such critical and scholarly communities is that they
tend to talk primarily to each other, despite the best intentions of scholars
such as Achsah Guibbory, who tries to make her work “accessible to
the educated, interested general reader and the intelligent student”.13
Donne did not seek to be read by scholars, any more than Yeats or his
imagined Catullus did, nor do “interested general reader[s]” often seek
to approach his work through the various lenses of academic literary
criticism rather than what Nietzsche calls “the lens of life” (“der Optik
[…] des Lebens”).14 Critical work insisting that a poem like “Elegy 19:
To His Mistress Going to Bed” is merely an instance of “scopophilic
male narcissism”,15 or that “the love poems of John Donne” express
the “imperatives of empire” in which “[d]esire is boundless [and]
formulated in a series of imperatives that do not invite debate”,16 has
little or no interest in making “Donne’s poetry more, not less accessible”. Such work is primarily concerned with establishing the credentials of
its various authors as properly “serious” and “professional” members
of an academic literary establishment that long ago signaled its lack of
concern with “the educated, interested general reader” who reads love
poetry as something other than a coded expression of all the darkest
impulses of the human species. 9. Love and its Costs in Seventeenth-Century Literature 17
Guibbory, 3. 9. Love and its Costs in Seventeenth-Century Literature 425 Donne’s passionate poetry reflects his turbulent life. Though the
poetry is not a straightforward biography (a simple account of his
life in verse), it is an emotional representation (impressionist, if not
photorealist) of the complex man who wrote it. And while Donne’s
poems engage with and challenge pre-existing literary forms like the
Ovidian elegy and the Petrarchan sonnet, they are no more reducible
to those forms than they are to “imperatives of empire” or “scopophilic
male narcissism”. To read poetry in this way, reduced to “the pleasures
of diagnosis”, is more lawyerly than literary, more prosecutorial than
poetic. Poetry treated in this way is essentially a corpse undergoing an
autopsy, dead to the very readers that academics as teachers ostensibly
hope to reach, if as Guibbory argues, “the survival of the humanities”17
is of any concern. It is in the life of the poet that we will find the life of the poetry. Born in 1572 to a Catholic family in a militantly Protestant England,
John Donne spent a lifetime never quite fitting in, never quite belonging
to any group or institution to which he attached himself. By his late
twenties, Donne had been a sailor on military expeditions, a student
of law at the Inns of Court in London, and had already shown the
tendency to restlessness and contradiction that would characterize him
throughout his life. Donne was “not dissolute, but very neat; a great
visiter of Ladies, a great frequenter of Playes, a great writer of conceited
Verses” who later in life “became so rare a Preacher, that he was not
only commended, but even admired by all that heard him”.18 The “great
visiter of Ladies” can perhaps be seen in the famous—and critically
oft-abused—Elegy 19, “On His Mistress Going to Bed”. In urging “His
Mistress” to remove her clothes just a little more quickly (“in a series
of imperatives” that according to Catherine Belsey apparently should
have invited “debate”—one can only imagine the Parliamentary-style
bedroom encounter the critic imagines as more appropriate), Donne
praises the glories of nakedness: 426 Love and its Critics Full nakedness, all joys are due to thee. 19
John Donne. John Donne: The Complete English Poems, ed. by A. J. Smith (New York:
Penguin, 1971), 125, ll. 33–35. Further references to this volume will be by line
number, Donne, and page number.
20
ll. 17–24, Donne, 125. 9. Love and its Costs in Seventeenth-Century Literature As souls unbodied, bodies unclothed must be
To taste whole joys […].19 Here, Donne matches two ideas he will often pair in his writing—the
Neoplatonic concern (seen in Peter Bembo’s speech from The Courtier)
with ascending beyond the body to experience the fullness of joy, and
the more radical idea of experiencing “whole joys” in and through the
body itself. This pairing is incredibly important for understanding the
dynamics of love, especially erotic love in Donne’s poetry. His insistence
that bodies are not shameful fleshly prisons inside which noble souls
are entrapped, but beautiful and worthy of celebration, exploration, and
desire, is the next step in the journey we have already seen Shakespeare
taking, away from the nearly disembodied idolatry expressed by the
poetry of Dante and Petrarch. Donne returns to the open eroticism, the
fleshly sexuality and passion of the troubadour and trobairitz poetry. We see further evidence of this ethos in the Elegy, when Donne’s speaker
both uses and mocks the religious imagery of love: Now off with those shoes, and then safely tread
In this love’s hallowed temple, this soft bed. In such white robes, heaven’s angels used to be
Received by men; thou, angel, bring’st with thee
A heaven like Mahomet’s paradise; and though
Ill spirits walk in white, we easily know
By this these angels from an evil sprite,
Those set our hairs, but these our flesh upright.20 While the male speaker very likely has his “flesh upright” here, the phrase
has a less humorously salacious meaning as well: flesh is “upright”,
good, worthy to be praised and not condemned. It is not the flesh and
its desires that come in for mocking here so much as the urge to cloak
that flesh in the robes of religion—the joke is made rather obvious by
the reference to “Mahomet’s Paradise”, an image of “infidelity” (from a While the male speaker very likely has his “flesh upright” here, the phrase
has a less humorously salacious meaning as well: flesh is “upright”,
good, worthy to be praised and not condemned. It is not the flesh and
its desires that come in for mocking here so much as the urge to cloak
that flesh in the robes of religion—the joke is made rather obvious by
the reference to “Mahomet’s Paradise”, an image of “infidelity” (from a 9. 21
ll. 25–32, Donne, 125.
22
Achsah Guibbory. “‘Oh Let Mee Not Serve So’: The Politics of Love in
Donne’s Elegies”. English Literary History, 57: 4 (Winter 1990), 812, https://doi.
org/10.2307/2873086
23
Ibid. 22
Achsah Guibbory. “‘Oh Let Mee Not Serve So’: The Politics of Love in
Donne’s Elegies”. English Literary History, 57: 4 (Winter 1990), 812, https://doi.
org/10.2307/2873086
23
Ibid. 21
ll. 25–32, Donne, 125. 9. Love and its Costs in Seventeenth-Century Literature Love and its Costs in Seventeenth-Century Literature 427 Christian perspective) that both satirizes and amplifies the philosophical
and theological unease of bien pensant readers, whose “right thinking”
takes human sexuality and warps it into sin, while promising—in
“Paradise”—to reward abstinence with delight (referencing the myth
of the seventy-two virgins—houris—promised in the Islamic concept
of heaven, loosely derived from the Qur’an, 56:35–37). Here the idea of
carpe diem is presented as opposing the claims of religion—though with
the safety of hiding behind the notion of “false” religion, as an English
reader would see it. Erotic love, practiced with “Full nakedness”, not
only redeems flesh (or demonstrates that it never needed redemption in
the first place) by showing it “upright”, but it renders “angels” (whether
from good or evil “sprite[s]”) unnecessary. However, it is the motif of exploration that catches the eye of many
critics today. Donne’s speaker requests permission to “explore’ the naked
body of “His Mistress” like a Walter Raleigh licensed by Elizabeth I: Licence my roving hands, and let them go
Before, behind, between, above, below. O my America, my new found land,
My kingdom, safeliest when with one man manned,
My mine of precious stones, my empery,
How blest am I in this discovering thee! To enter in these bonds is to be free;
Then where my hand is set, my seal shall be.21 Guibbory argues that this is a masculine power play, and a metaphor
for politics: “Donne repeatedly in these poems envisions relations
between the sexes as a site of conflict, thereby mirroring a larger society
in which there is considerable anxiety about the lines and boundaries
of power”.22 Where the present authors see love in Donne (and others)
as anti-authoritarian, Guibbory sees its use as authoritarian and as part
of a pattern of “persistent misogyny”,23 as the male speaker subjugates
both the mistress and the “new-found-land”: 428 Love and its Critics At the beginning of this passage the woman is the monarch, providing a
license, but the moment she gives this license she loses her sovereignty. […] The man becomes not only explorer but conquerer, and she becomes
his land and kingdom. 24
Ibid., 822.
25
Ibid., 821.
26
Here, the observation of Foucault is useful: “The relationship of power and the
rebelliousness of freedom cannot be separated” (“La relation de pouvoir et
l’insoumission de la liberté ne peuvent donc être séparées”) (“Le Sujet e le Pouvoir”.
In his Dits et Écrits. Vol. IV: 1980–1988, 237).
27
ll 41–43 Donne 125 27
ll. 41–43, Donne, 125. ,
26
Here, the observation of Foucault is useful: “The relationship of power and the
rebelliousness of freedom cannot be separated” (“La relation de pouvoir et
l’insoumission de la liberté ne peuvent donc être séparées”) (“Le Sujet e le Pouvoir”.
In his Dits et Écrits. Vol. IV: 1980–1988, 237). 9. Love and its Costs in Seventeenth-Century Literature The repeated possessives reinforce the sense of his
mastery, and by the end of this passage he has now become the monarch,
setting his “seal”.24 Guibbory goes on to argue that Donne’s poetry “betrays a discomfort
with (indeed, a rejection of) the political structure headed by a female
monarch. Intimate private relations between man and woman and the
power structure of the body politic mirror and reinforce each other”.25
But in her drive to read the Elegy as mysognistic and patriarchal,
Guibbory underplays any sense of the mutuality of the power
dynamic—dominance and submission26—in her own description of
the poem. The speaker asks for “License”, performing his exploration
of the woman who is figured as both Queen and land, dominant and
submissive. The speaker remains licensed throughout—that formal
permission is neither usurped nor withdrawn—and is thus submissive,
while he remains the explorer, and is thus dominant. The logic is one
of contraries as complements, a yin-yang of eroticism whose key can
be found in the line “To enter in these bonds is to be free”. Bound and
free—on both sides. The “licensing” power of the woman is further enhanced by being
transformed from monarchical to divine power; all women, including
the “Mistress” being spoken to here, “are mystic books, which only
we / Whom their imputed grace will dignify / Must see revealed”.27
The idea of “grace” here places the male speaker in a position distinctly
inferior to that of the woman being addressed, who is figured as God
reaching out in mercy toward a sinner. Grace, the divinely-given power
that compensates for the inability of “fallen man” to “save himself in
his own corrupt nature” repairs the ability of the sinner to reach toward 9. 28
R. V. Young. Doctrine and Devotion in Seventeenth-century Poetry: Studies in Donne,
Herbert, Crashaw, and Vaughan (Cambridge: Boydell & Brewer, 2000), 75.
29
For further discussion, see Michael Bryson, The Tyranny of Heaven: Milton’s Rejection
of God as King (London: Associated University Presses, 2004), 119–22.
30
Here we can see in Donne a reworking of the idea of the woman as angel, found
in so much Italian poetry of the period between Lentini and Petrarch, through the
recovery of the idea of eroticism and desire in a dynamic in which power is mutual.
31
Robert Sternberg. Cognitive Psychology (Belmont: Wadsworth Cengage, 2009), 512.
This kind of thinking is rampant in what Karl Popper calls “pseudo-science”. Popper
maintains that “It is easy to obtain confirmations, or verifications, for nearly every
theory—if we look for confirmations”, but that “[e]very genuine test of a theory is
an attempt to falsify it, or to refute it” (Karl Popper, 36, 37). 28
R. V. Young. Doctrine and Devotion in Seventeenth-century Poetry: Studies in Donne,
Herbert, Crashaw, and Vaughan (Cambridge: Boydell & Brewer, 2000), 75. 32
Ilona Bell. “Gender Matters: The Women in Donne’s Poems”. In Achsah Guibbory,
ed. The Cambridge Companion to John Donne (Cambridge: Cambridge University
Press, 2006), 201.
33
Ibid., 208.
34
ll. 28–29, Donne, 125.
35
ll. 62–64, Donne, 162. 9. Love and its Costs in Seventeenth-Century Literature Love and its Costs in Seventeenth-Century Literature 429 the good, as “freedom of will is precisely what grace restores”.28 Having
grace “imputed” to them, the “we” who are so gifted are treated as if
worthy of the gift, much in the same manner that a sinner who has grace
imputed to him is treated as if he is worthy of God.29 Not only do we not
have an image of masculine subjugation of the feminine here, but we
have something entirely different: an image of nearly-godlike female
power over a male supplicant.30 Readers and interpreters who are determined—for professional
or political reasons—to see this poem as “evidence” that John Donne
rejects “the political structure headed by a female monarch” transform
his poetry into a tool of oppression (while arguing that they are merely
“revealing” the oppression already inherent therein). Such critics reflect
the voices of the gilos (the jealous and controlling spouses), rather than
those of the lovers in troubadour and trobaritz poetry. But “On His
Mistress Going to Bed” is only evidence of imperialistic misogyny if one
can no longer see the poetic forest for the critical trees. Psychologists
describe such thinking as confirmation bias, a filtering of ideas whereby
we “seek confirmation rather than disconfirmation of what we already
believe”. For example, “a doctor [who] assumes that a patient has
condition X, […] may interpret the set of symptoms as supporting the
diagnosis” without regard to any counter-evidence of any kind.31 In
other words, we see what we are determined to see. So, at least, does
Bell describe recent trends among Donne’s critics: For theoretical or ideological reasons, twentieth-[and twenty-first-]
century critics generally assume that the woman in Donne’s poems is
a shadowy figure, the object or reflection of male desire, a pretext for
self-fashioning, a metaphor […]. a sex object […]. In the last two decades 430 34
ll. 28–29, Donne, 125. 35
ll. 62–64, Donne, 162. Love and its Critics Love and its Critics […] it has become clear that it was not Donne, but the critics who
disembodied and disregarded the women in Donne’s poems.32 What critics see—and authoritatively present to students and general
readers as that which there is to see—in poetry and other forms of
literature changes with the passing of the years, decades, and centuries. But the poetry remains, its words unchanged by the changing fashions
of academic and cultural authority. Even Bell, whose readings of Donne are less pinched than those of
other critics, cannot resist describing the dynamics of “On His Mistress
Going to Bed” as a matter of “masculine desire to conquer and control”,
and “masculine dominion” over the woman,33 while ignoring the line in
which the speaker sues for “Licence” from the woman. It is the woman—
in the role of monarch and grace-giving deity—who grants that “Licence”
to the male explorer, whose exclamations of joy at his “kingdom” and
“empery”34 are made over “dominion” (to borrow Bell’s term) which
is merely on loan, not owned by the male of the poem. One begins to
wonder at the unanimity of critics who insist on morally condemning
the poem and its male speaker, as if there is a misandrist imperative at
work which demands that male sexuality (at least in relation to women)
be regarded and described negatively. When even an obvious admirer
of Donne and his poetry seems compelled to describe male sexuality in
the poem as “a military campaign”, as “control”, and as “dominion”, it
is tempting to think that there are barely-suppressed whispers of rape in
the background. Would a poem by Sappho, or a diary entry by Anaïs
Nin be treated in the same way? Perhaps Donne himself can be looked to for some guidance. In his
third Satire, he emphasizes the need to judge in terms of particulars. He gives two examples: “Careless Phrygius”, who “doth abhor / All,
because all cannot be good, as one / Knowing some women whores,
dares marry none”,35 and “Gracchus”, who “loves all as one, and thinks
that so / As women do in divers countries goe / In divers habits, yet 9. Love and its Costs in Seventeenth-Century Literature 431 are all still one kind”.36 Phrygius mistakenly thinks all women bad,
while Gracchus mistakenly believes all women good. 36
ll. 65–67, Donne, 162.
37
l. 68, Donne, 162.
38
l. 70, Donne, 162.
39
Bell, 204.
40
ll. 1–2, Donne, 149.
41
ll. 1–2, Donne, 149.
42
ll. 1–2, Donne, 151. 41
ll. 1–2, Donne, 149. 40
ll. 1–2, Donne, 149. 42
ll. 1–2, Donne, 151. Love and its Critics But reason
demands that we throw off such indiscriminate “blindness”37 and value
the particular, the individual, while leaving behind the generalizing
patterns of ideology and ignorance: “and forced but one allow”.38 Far
from there being any “persistent misogyny” in his poetry, Donne’s
verse often shows us women and men who choose each other under
circumstances of extreme duress, neither one using the other in any
kind of power play, but facing the consequences of their mutual choice
together. Donne’s shortest poems, his epigrams, show us “clandestine
lovers whose daring and devotion triumph over the death they incur”.39
This can easily be seen in “Hero and Leander”: Both robbed of air, we both lie in one ground,
Both whom one fire had burnt, one water drowned.40 And in “Pyramus and Thisbe”: Two, by themselves, each other, love and fear
Slain, cruel friends, by parting have joined here.41 Two, by themselves, each other, love and fear
Slain, cruel friends, by parting have joined here.41 “Disinherited” paints a rather stark portrait of the economic consequences
that could ensue for such “clandestine lovers” in Donne’s own day: Thy father all from thee, by his last will,
Gave to the poor; thou hast good title still.42 This latter situation is exactly what Donne experienced when he became
just such a clandestine lover as Leander or Pyramus. No longer content
to be a “great visiter of Ladies”, Donne fell in love with Anne More, the
daughter of Sir George More (the Chancellor of the Garter), and the
niece by marriage to Sir Thomas Egerton (the Lord Keeper of the Great 432 Love and its Critics Seal, and Donne’s own employer). Socially, Anne More was of a much
higher rank than Donne, and any officially sanctioned match between
the pair was impossible. 43
David Edwards. John Donne: Man of Flesh and Spirit (New York: Continuum, 2001), 282.
44
John Stubbs. John Donne: The Reformed Soul (New York: W. W. Norton & Co., 2006), 154.
45
Ibid., 154. Love and its Critics The growing love between the mismatched
couple (also mismatched in age, as Donne was in his late twenties, while
More was in her mid-to-late teens when their relationship began), and
the difficult position that their affection put the lovers in, is reflected in
Donne’s poetry, where he writes of “two situations which he had never
experienced before and which changed the course of his life: courting
a young woman whom he desperately wanted to marry despite the
obvious difficulties, and being married in defiance of society’s code
of conduct and at the cost of his career”.43 Getting marrried cost them
everything: money, career, and future prospects. But like the lovers of
his epigrams, John and Anne chose each other in spite of the worst the
rule-bound world of fathers and monarchs could throw at them. In late 1601, “about three weeks before Christmas”,44 John Donne
and Anne More married in a secret ceremony. The anxiety that ensued
“about the trouble that he and [Anne] had now brought on themselves”
resulted in the circulation of “a joke about the furtive couple’s situation”: Doctor Donne after he was married to a Maid, whose name was Anne, in
a frolick (on his Wedding day) chalkt this on the back-side of his Kitchin-
door, John Donne, Anne Donne, Undone.45 The consequences were as severe as they were immediate when George
More found out about the clandestine marriage, from Donne’s own
letter to him on 2 February 1602. After informing More of the marriage,
Donne tries to explain why he and Anne had deceived him by marrying
secretly, and asks More not to be too angry with either Anne or himself: I knew my present estate lesse then fitt for her; I knew, (yet I knew not
why) that I stood not right in your Opinion; I knew that to have giuen
any intimacion of yt had been to impossibilitate the whole Matter. […]
But for her whom I tender much more, then my fortunes, or lyfe (els I
would I might neyther ioy in this lyfe, nor enioy the next) I humbly beg
of yow, that she may not, to her danger, feele the terror of your sodaine
anger. […] if yow incense my lordship [Thomas Egerton], yow Destroy
her and me; that yt is easye to give vs happines, And that my Endevors 9. Love and its Costs in Seventeenth-Century Literature 46
L.b.526: Letter from John Donne, The Savoy, London, to Sir George More, 1601/1602
February 2. Early Modern Manuscripts Online, http://emmo.folger.edu/view/Lb526/
semiDiplomatic
47
ll 1 9 D
47 48
Nancy Jo Coover Andreasen. John Donne: Conservative Revolutionary (Princeton:
Princeton University Press, 1967). Quoted in Larson, 164. 46
L.b.526: Letter from John Donne, The Savoy, London, to Sir George More, 1601/1602
February 2. Early Modern Manuscripts Online, http://emmo.folger.edu/view/Lb526/
semiDiplomatic
47
ll. 1–9, Donne, 47.
48
Nancy Jo Coover Andreasen. John Donne: Conservative Revolutionary (Princeton:
Princeton University Press, 1967). Quoted in Larson, 164. 47
ll. 1–9, Donne, 47. 9. Love and its Costs in Seventeenth-Century Literature 433 and industrie, if it please yow to prosper them, may soone make me
somewhat worthyer of her.46 The letter simply enraged More, setting him on to do exactly what Donne
had hoped he would not do: turn Egerton against Donne, who was
immediately fired from his position as Egerton’s secretary, imprisoned,
and on his release, left without any practical prospects for employment. A poem like “The Canonization” reflects this experience of forbidden
love, punished by all the forces a society determined to control the
marriages of its (adult) children can bring to bear. Its first stanza
captures the sense of frustration and helplessness at being punished for
following one’s own heart: For God’s sake hold your tongue, and let me love,
Or chide my palsy, or my gout,
My five grey hairs, or ruined fortune flout,
With wealth your state, your mind with arts improve,
Take you a course, get you a place,
Observe his Honour, or his Grace,
Or the King’s real, or his stampèd face
Contemplate; what you will, approve,
So you will let me love.47 A critic like Nancy Andreasen reduces this poem to a mere rehearsal of
conventional elements, claiming that “Donne is dramatizing the stock
comic situation of an extramarital love affair between an aging man
of the world and a youthful mistress, an affair which further injures
the debilitated rake’s already-ruined fortune”.48 But this shrinking
of the poem from a howl of protest against an unjust world (in
which daughters are the property of fathers, marriages are economic
arrangements made by and for those fathers, and lives can be ruined
by the simple, yet radical, act of choosing for oneself) to a rather tired
exercise in comic convention is of a piece with many of the readings we Love and its Critics 434 have already encountered. It is a perfect example of how critics often
rewrite poems. But the “five grey hairs” of the third line are not those
of an aging man of the world—whose worldliness and age would have
gifted him with many more than five—nor is the “ruined fortune” that
of a rake who has simply spent too much keeping up with the young
girls he likes to entertain and be entertained by. 49
The most infamous of the “rakes” was John Wilmott, the 2nd Earl of Rochester,
whose life and poetry was a scandal in the court of Charles II. As Samuel Johnson
describes his life and death: Samuel Johnson. The Lives of the Most Eminent English poets, with Critical Observations
on Their Works, Vol. 1. (London: J. Fergusson, 1819), 150–51, https://books.google.
com/books?id=e_sTAAAAQAAJ&pg=PA150). [I]n a course of drunken gaiety, and gross sensuality, with intervals of study, perhaps, yet more
criminal, with an avowed contempt of all decency and order, a total disregard of every moral,
and a resolute denial of every religious obligation, he lived worthless and useless, and blazed
out his youth and his health in lavish voluptuousness, till, at the age of one-and-thirty, he had
exhausted the fund of life, and reduced himself to a state of weakness and decay [and] died July
26, 1680, before he had completed his thirty-fourth year. 49
The most infamous of the “rakes” was John Wilmott, the 2nd Earl of Rochester,
whose life and poetry was a scandal in the court of Charles II. As Samuel Johnson
describes his life and death:
[I]n a course of drunken gaiety, and gross sensuality, with intervals of study, perhaps, yet more
criminal, with an avowed contempt of all decency and order, a total disregard of every moral,
and a resolute denial of every religious obligation, he lived worthless and useless, and blazed
out his youth and his health in lavish voluptuousness, till, at the age of one-and-thirty, he had
exhausted the fund of life, and reduced himself to a state of weakness and decay [and] died July
26, 1680, before he had completed his thirty-fourth year.
Samuel Johnson. The Lives of the Most Eminent English poets, with Critical Observations
on Their Works, Vol. 1. (London: J. Fergusson, 1819), 150–51, https://books.google.
com/books?id=e_sTAAAAQAAJ&pg=PA150).
50
ll 10 18 D
47 50
ll. 10–18, Donne, 47. 51
Stubbs, 170.
52
Ibid., 174.
53
ll. 28–36, Donne, 47–48. 9. Love and its Costs in Seventeenth-Century Literature All of this can be seen
in the references to official positions, the kind Donne depended on, and
has now lost: “get you a place”, but “let me love”; “Observe his Honour,
or his Grace”, but “let me love”. It can also be seen in the mention of
approval, a social currency the “rake”49 actively disdains, but on whose
continuance Donne had absolutely relied: “what you will, approve”,
but “let me love”. The poem’s second stanza raises another howl of protest. Whom
have we injured with our love? The answer, of course, in an economy in
which daughters are valuable property, is George More: Alas, alas, who’s injured by my love? What merchant’s ships have my sighs drowned? Who says my tears have overflowed his ground? When did my colds a forward spring remove? When did the heats which my veins fill
Add one more to the plaguy bill? Soldiers find wars, and lawyers find out still
Litigious men, which quarrels move,
Though she and I do love.50 50 9. Love and its Costs in Seventeenth-Century Literature 53
ll. 28–36, Donne, 47–48. 52
Ibid., 174. 9. Love and its Costs in Seventeenth-Century Literature 435 Lawyers and litigious men trying to move quarrels began to interfere in
Donne’s situation immediately: “Sir George determined to extricate his
daughter from Donne if it was humanly and legally possible. He had
instigated proceedings, and a hearing was due at the High Commission
to assess the legality of the marriage”.51 But both Anne and John Donne
insisted that they had not only plighted troth (a standard of commitment
often held to be as binding as a public marriage ceremony), but were
legally married. Some weeks later, “the Archbishop of Canterbury himself
finally ruled that the marriage was valid in the eyes of the established
Church”.52 For the Donnes, however, the economic struggles had only
just begun, as John Donne would be turned down for every position to
which he applied, with the exception of a temporary job as the traveling
secretary to Sir Robert Drury in 1611–12, until he took orders in the
church in 1615. For fourteen years, the Donnes struggled, as the society
of their time and place punished them for choosing each other, rather
than allowing a father (or fathers) to choose instead. In this context, the
fourth stanza of “The Canonization” takes on a meaning wholly alien to
Andreasen’s scenario of a ruined rake with a young mistress: We can die by it, if not live by love,
And if unfit for tombs and hearse
Our legend be, it will be fit for verse;
And if no piece of chronicle we prove,
We’ll build in sonnets pretty rooms;
As well a well-wrought urn becomes
The greatest ashes, as half-acre tombs,
And by these hymns, all shall approve
Us canonized for love.53 The “pretty rooms” are refuges against the bruising demands of a world
that sneers at the foolishness of lovers, and if the world will afford no
place for love, at least “a well-wrought urn” will give the lovers a final
unified resting place, much after the fashion and feeling of those resting
places afforded to the lovers in the epigrams. As the poem ends, the idea
of it being reducible to a stock comic situation becomes contemptible and 436 Love and its Critics absurd. After their deaths, the lovers become a pilgrimage destination
for future lovers who are still struggling with the Egeuses, Capulets, and
Mores of the world. 55
Achsah Guibbory. “Erotic Poetry”. In her, ed. The Cambridge Companion to John
Donne (Cambridge: Cambridge University Press, 2006), 138. 54
ll. 44–45, Donne, 48. 54
ll. 44–45, Donne, 48. 9. Love and its Costs in Seventeenth-Century Literature At the grave, these new lovers pray that their own
fathers will learn from the example of the dead couple, now canonized
as saints, and grow mild: “Countries, towns, courts: beg from above / A
pattern of your love!”54 But as powerfully evocative as “The Canonization” is, we do not have
a precise date for its composition, which opens the door to those critics
who wish to separate the poet from the poem. As Guibbory argues: Readers have long identified the “mutual love” poems with Donne’s secret
courtship and marriage to Anne More. […] Certain lyrics that privilege
the sacred space of clandestine love and describe the world’s opposition
fit with what we know of Donne’s situation at the time. Yet so long as
we lack evidence for the dates and occasions of Donne’s lyrics, poems
like “The Relique” or “The good-morrow” [or “The Canonization”] must
frustrate the autobiographical readings they invite.55 Must? Note the language of compulsion and authoritative limitation. The poems may “fit with what we know of Donne’s situation at the
time”, yet we are told, ex cathedra, that “we lack evidence” (or what the
critic considers admissable as evidence, a dated manuscript), and we
must continue to hold off identifying the life of a poet who lived fin’amor,
from the poetry which describes fin’amor, love between individuals who
face all the consequences the world can throw at them for making their
choice. Just as much current scholarship on the troubadours would
deny readers the ability to see love poems as anything other than
documentary evidence of misogyny and performative narcissism, so it
would seem that many specialists in John Donne are determined to tell
us to reject the evidence of the words in the poems themselves, and
reject what we know about the correlation between those words and the
known facts of the love and life of John and Anne Donne. The argument
is an oddly familiar one, that correlation is not causation. But while
such reasoning is valid in the realm of statistics, it is a great deal shakier
in other realms (there is a reason that the argument is often resorted 9. Love and its Costs in Seventeenth-Century Literature 437 to by tobacco companies and climate-change deniers), and it sounds
especially jarring coming from literary critics. 56
l.2, Donne, 53.
57
l.4, Donne, 53.
58
ll. 5–13, Donne, 53–54.
59
ll. 14–20, Donne, 54. 58
ll. 5–13, Donne, 53–54. 59
ll. 14–20, Donne, 54. 57
l.4, Donne, 53. 56
l.2, Donne, 53. 9. Love and its Costs in Seventeenth-Century Literature But despite his critics, Donne’s passions will not be contained—even
the long Platonic tradition of regarding human love as the lowest rung
on a ladder leading to the divine are made to serve the purposes of
a poet who will not be reduced to quiet submission and conformity. In “The Extasie”, Donne writes of a love between two who are one, a
passion at once reflective and active, spiritual and embodied. Beginning
with a description of “A pregnant bank swell’d up to rest”56 where the
lovers “Sat we two, one another’s best”,57 the poem portrays these two
who are one as being both in and out of their bodies as they silently gaze
at one another. Their hands and eyes are joined: Our hands were firmly cemented
With a fast balm, which thence did spring,
Our eye-beams twisted, and did thread
Our eyes upon one double string;
So to’ intergraft our hands, as yet
Was all our means to make us one,
And pictures in our eyes to get
Was all our propagation.58 Our hands were firmly cemented
With a fast balm, which thence did spring,
Our eye-beams twisted, and did thread
Our eyes upon one double string;
So to’ intergraft our hands, as yet
Was all our means to make us one,
And pictures in our eyes to get
Was all our propagation.58 At the same time, their “souls” are suspended outside of their bodies, in
the same silent contemplation of each other: As ‘twixt two equal armies Fate
Suspends uncertain victory,
Our souls (which to advance their state
Were gone out) hung ‘twixt her and me. And whilst our souls negotiate there,
We like sepulchral statues lay;
All day, the same our postures were,
And we said nothing, all the day.59 438 Love and its Critics There is no “masculine desire to conquer and control” or “masculine
dominion” here, despite the metaphor of souls as armies. Instead, we
have silent mutuality, a communication that does not require words, as
painfully sincere yet artfully deceitful as words can so often be. We have
a sense of souls and bodies that are—like the lovers—themselves two-
who-are-one. The souls can come forth from, but are always grounded in
the bodies that are crucial parts of the “We” who “like sepulchral statues
lay”. 61
A similar spirit is found in Shakespeare’s poem “The Phoenix and the Turtle”
(published in Robert Chester’s Loves Martyr of 1601), where two lovers “lov’d, as 60
ll. 21–28, Donne, 54. 60
ll. 21–28, Donne, 54. 9. Love and its Costs in Seventeenth-Century Literature The bodies are not mere objects, not fallen flesh to be derided and
condemned, but a crucial part of the entire two-in-one reality that is
being described. Each dynamic is fueled by love—between the two
lovers, and between the bodies and souls themselves. The pairing is
mutually desired and mutually sustaining, and that is the secret referred
to by the following lines: If any, so by love refined
That he soul’s language understood,
And by good love were grown all mind,
Within convenient distance stood,
He (though he knew not which soul spake
Because both meant, both spake the same)
Might thence a new concoction take
And part far purer than he came.60 The “soul’s language” is silence—mutually understood—a touch that
is offered and accepted, felt both with and without the bodies of the
lovers. The imagined audience here is someone who understands that
these bodies and souls are not opposites, but necessary complements,
ingredients or elements of a far more complex synthesis, a “new
concoction” (using the language of alchemy as psychological and/
or spiritual transformation and purification as well as physical
transmutation). Observing this, even hearing this, the imagined other
is himself or herself transformed through the realization that the binary
division between body and soul is an illusion, just as is the binary
between lover and lover. The two are one, for those with ears to hear
and eyes to see.61 9. Love and its Costs in Seventeenth-Century Literature 439 The poem then goes on to make explicit that bodies and souls are a
synthesis of elements that forms the individual self of each lover, who are
themselves one, a union that forms the highest and most profound whole: But O alas, so long, so far
Our bodies why do we forbear? They are ours, though they are not we, we are
The intelligences, they the sphere. We owe them thanks, because they thus,
Did us, to us, at first convey,
Yielded their forces, sense, to us,
Nor are dross to us, but allay.62 But O alas, so long, so far
Our bodies why do we forbear? They are ours, though they are not we, we are
The intelligences, they the sphere. 62
ll. 49–56, Donne, 55. love in twain / Had the essence but in one; / Two distincts, division none: / Number
there in love was slain” (ll. 25–28).
62
ll 49 56 D
55 63
ll. 68–76, Donne, 55–56. love in twain / Had the essence but in one; / Two distincts, division none: / Number
there in love was slain” (ll. 25–28).
62
ll. 49–56, Donne, 55.
63
ll. 68–76, Donne, 55–56. 9. Love and its Costs in Seventeenth-Century Literature We owe them thanks, because they thus,
Did us, to us, at first convey,
Yielded their forces, sense, to us,
Nor are dross to us, but allay.62 Their bodies are a necessary part of the synthesis, the whole. The
“intelligences” without “the sphere” are like an energy without a
vehicle through which to express itself, thus the bodies are not “dross”
(unnecessary trash) but “allay” (part of an alloy, two substances
combined into a stronger and more complex whole). Returning once
again to the imagined other who sees, hears, and understands all of this,
the poem concludes by erasing the difference between the disembodied
and embodied lovers: To our bodies turn we then, that so
Weak men on love revealed may look;
Love’s mysteries in souls do grow,
But yet the body is his book. And if some lover, such as we,
Have heard this dialogue of one,
Let him still mark us, he shall see
Small change, when we’are to bodies gone.63 This “dialogue of one” is a dialogue of oneness: the oneness of opposites
that are not opposites. The “lover” who understands this, who sees
“Small change” between the language spoken in silence between the
lovers without and within their bodies, understands the both sacred 440 Love and its Critics and radically secular point this poem makes about love: the highest
form of love is that which is had here, now, with that he or she who is
right in front of you. Much of the essence of “The Extasie” is expressed in that idea, and
much of the challenge this poem makes to Platonic and Neoplatonic
orthodoxies about love can be understood through this idea as well. There is no need to climb a “ladder of love”, no need to turn one’s focus
away from those beloveds in the here and now, in the world of flesh
and blood, in order to experience the “true” or “transcendent” love that
will allow the lover, as Diotima argues, to come to know “the soul’s
beauty”.64 There is no need to believe, in Peter Bembo’s terms, that
“the body is something very different from beauty, and not only does
not increase beauty but lessens its perfection”.65 “The Extasie” sweeps
all of this aside as so much body-shaming, flesh-hating, life-denying
nonsense. 64
“ταῖς ψυχαῖς κάλλος” (Plato. Symposium 210c).
65
“l corpo è cosa diversissima dalia bellezza, e non solamente non le accresce, ma le
diminuisce la sua perfezione” (Castiglione, 254–55).
66
Merritt Hughes. “The Lineage of ‘The Extasie’”. Modern Language Review, 27: 1
(January 1932), 2, https://doi.org/10.2307/3716215
67
Ibid.
68
Ibid. 9. Love and its Costs in Seventeenth-Century Literature The love portrayed in “The Extasie” is already fully embodied
and fully spiritual, passionately physical and supremely sacred all at
once. Let those understand who are able, the poem suggests, and they
will part more pure and whole than when they came. And yet, this poem has caused more arguments between the critics
than perhaps any other of Donne’s works. With “The Extasie”, the
critical drive to allegory, to diagnosis, to a hermeneutics of suspicion,
to seeing the poem in terms of anything other than open, embodied
passion becomes crystal clear. As far back as 1932, Merritt Hughes
is arguing that the poem is not passionate at all, but is “merely the
dramatisation of a conflict and reconciliation of ideas which had long
been familiar in Italy and France, if not in England”.66 Hughes works
hard to put “The Extasie” back in the cramped box of convention by
insisting that it is a “minor heresy [to believe] that The Extasie was felt by
its author as a revolt against Platonism”,67 and by arguing that “we owe
The Extasie to the stream of tradition rather than to an original dramatic
impulse on Donne’s part”.68 In this last gesture, we can see the early 9. Love and its Costs in Seventeenth-Century Literature 441 stages of the “death of the author” impulse at work. “Tradition” wrote
the poem, not Donne. By 1934, Frank Doggett is reclaiming the poem
for passion by describing “The Extasie as “Donne’s most complete
declaration of the nature of love, and of the part taken by soul and by
body in that passion”,69 arguing that “[t]he inner meaning of Donne’s
thought, here, is the necessity of the functions of both soul and body
for complete love”.70 At the same time, however, Doggett contends that
Donne’s poem is essentially in agreement with the anti-body mysticism
of Bembo in The Courtier.71 By the 1960s, Charles Mitchell argues that “The Extasie” portrays a
love in which body and soul are indispensable parts of a larger whole. 74
T. Katharine Thomason. “Plotinian Metaphysics and Donne’s ‘Extasie’”. Studies in
English Literature, 1500–1900, 22: 1, The English Renaissance (Winter 1982), 93–94,
https://doi.org/10.2307/450219 69
Frank A. Doggett. “Donne’s Platonism”. The Sewanee Review, 42: 3 (July–September
1934), 285.
70
Ibid 288 72
Charles Mitchell. “Donne’s ‘The Extasie’: Love’s Sublime Knot”. Studies in English
Literature, 1500–1900, 8: 1, The English Renaissance (Winter 1968), 92, https://doi.
org/10.2307/449412
73
Ibid 100 71
Ibid., 289–90. 70
Ibid., 288. 73
Ibid., 100. 75
Catherine Gimelli Martin. “The Erotology of Donne’s ‘Extasie’ and the Secret
History of Voluptuous Rationalism”. Studies in English Literature 1500–1900, 44: 1
(2004), 123, https://doi.org/10.1353/sel.2004.0008
76
Ibid., 123. 9. Love and its Costs in Seventeenth-Century Literature But Mitchell’s emphasis is Neoplatonic, for “The Extasie” does its work
by showing “how the outward union of man and woman effects the
union of body and soul within man”.72 Lovers (and observers) are
shown in the poem as having “grown inwardly from a mere body to a
synthesis of body and soul by the outgoing power of love”.73 Katherine
Thompson reverses that emphasis in 1982, making an argument that
serves as a counterpoint to those who try to shoehorn “The Extasie” into
a tidy Neoplatonic container: Even the initial stroke of wit in “The Extasie” depends on Donne’s
turning the tables on the conventional Neoplatonists, or one should say,
it depends on Donne’s inversion of their ladder of love. […] Donne, by
fiat, begins with ecstasy achieved […then proves] the compatibility of
the lovers at the level of soul; and then has his speaker argue for descent
on the ladder rather than ascent.74 As Catherine Gimelli Martin observes, modern critical reaction to “The
Extasie” has tended toward a reductive and cynical view: As Catherine Gimelli Martin observes, modern critical reaction to “The
Extasie” has tended toward a reductive and cynical view: 442 Love and its Critics most modern critics seem to agree that [Donne’s poetry] is typically or
even universally put to cynically seductive purposes. But this consensus
is both newer and more tenuous than it seems; only a generation ago,
literary critics regularly followed Herbert J. C. Grierson and Helen
Gardner in regarding the major love lyrics as sincere […]. This view
first faded under the influence of Pierre Legouis, whose rereading of
“The Extasie” as a seduction poem proved broadly influential among
second-generation New Critics, for whom the ironic mode was fast
becoming the insincere mode later canonized in Stephen Greenblatt’s
Renaissance Self-Fashioning.75 What Martin calls “the new orthodoxy”76 insists that readers discount
the presence of love and desire in Donne’s poetry as nothing more than
a cynically seductive lie. But “The Extasie” shows us a Donne who
cannot be contained by criticism that reduces sincere passion to tattered
convention, turning “all forms of inwardness […] into mere social
constructions”.77 Again, one wonders what it is about such reductively
life-denying arguments that appeals to so many critics. 79
Martin, 123, quoting from Robert Watson, The Rest Is Silence: Death as Annihilation
in the English Renaissance (Berkeley and Los Angeles: University of California Press,
1994), 164. 78
William Blake. “There is No Natural Religion”. In The Complete Poetry and Prose of
William Blake, ed. by David V. Erdman (Berkeley and Los Angeles: University of
California Press, 2008), 3. 75
Catherine Gimelli Martin. “The Erotology of Donne’s ‘Extasie’ and the Secret
History of Voluptuous Rationalism”. Studies in English Literature 1500–1900, 44: 1
(2004), 123, https://doi.org/10.1353/sel.2004.0008
76
Ibid., 123.
77
Ibid.
78
William Blake. “There is No Natural Religion”. In The Complete Poetry and Prose of
William Blake, ed. by David V. Erdman (Berkeley and Los Angeles: University of
California Press, 2008), 3.
79
Martin, 123, quoting from Robert Watson, The Rest Is Silence: Death as Annihilation
in the English Renaissance (Berkeley and Los Angeles: University of California Press,
1994), 164. 78
William Blake. “There is No Natural Religion”. In The Complete Poetry and Prose of
William Blake, ed. by David V. Erdman (Berkeley and Los Angeles: University of
California Press, 2008), 3.
79
Martin, 123, quoting from Robert Watson, The Rest Is Silence: Death as Annihilation
in the English Renaissance (Berkeley and Los Angeles: University of California Press, 9. Love and its Costs in Seventeenth-Century Literature 443 Donne, like Shakespeare, like Milton, is an entire world—a writer
of astonishing virtuosity and versatility, a poet who can inhabit
experience, emotion, and passion, yet maintain an ironic distance—he
is at once an artist of the inside and the outside, the “is” and the “seems”
of Hamlet’s retort to Getrude.80 One thing remains consistent, however. Donne’s poetry, far from being the merely conventional fare described
by those critics who “wear the carpet with their shoes”, gives love its
due. A more immediately playful poem like “The Sun Rising”, shows
us a Donne who regards love and its pleasures and demands as far
more important, and far worthier of respect, than the demands of the
world and its temporary rulers. Starting with a variation on the alba
form of the troubadours, the poem decries the presence of the sun, and
its interference with the pleasures of love: Donne, like Shakespeare, like Milton, is an entire world—a writer
of astonishing virtuosity and versatility, a poet who can inhabit
experience, emotion, and passion, yet maintain an ironic distance—he
is at once an artist of the inside and the outside, the “is” and the “seems”
of Hamlet’s retort to Getrude.80 One thing remains consistent, however. Donne’s poetry, far from being the merely conventional fare described
by those critics who “wear the carpet with their shoes”, gives love its
due. A more immediately playful poem like “The Sun Rising”, shows
us a Donne who regards love and its pleasures and demands as far
more important, and far worthier of respect, than the demands of the
world and its temporary rulers. Starting with a variation on the alba
form of the troubadours, the poem decries the presence of the sun, and
its interference with the pleasures of love: Busy old fool, unruly sun,
Why dost thou thus,
Through windows, and through curtains, call on us? Must to thy motions lovers’ seasons run?81 In the alba, the rising of the sun threatens to betray the lovers, and calls
an end to the all too brief night they have spent together, out of the
reach and beyond the prying eyes of jealous spouses and a controlling
world. 80
Hamlet 1.2.76.
81
ll. 1–4, Donne, 80. 9. Love and its Costs in Seventeenth-Century Literature It is as if we
have trained several generations of academics to be like the man who,
as Blake puts it, “sees the Ratio only” and thus “sees himself only”,78 so
incapable or unwilling are they to see past what the troubadour poet
Marcabru calls the fragmented, frait, in order to glimpse the whole,
entier. Donne’s work demands that we see past the Ratio, past the
fragmented, past the commitments of any contemporary critical school,
in order to understand his desire. Perhaps a little less dissection and
a little more synthesis is in order. As Martin argues, “[m]ore than any
other poet of the period, Donne represents his inner search for religious
and erotic authenticity”79 through the passionate intensity of his work. What Martin calls “the new orthodoxy”76 insists that readers discount
the presence of love and desire in Donne’s poetry as nothing more than
a cynically seductive lie. But “The Extasie” shows us a Donne who
cannot be contained by criticism that reduces sincere passion to tattered
convention, turning “all forms of inwardness […] into mere social
constructions”.77 Again, one wonders what it is about such reductively
life-denying arguments that appeals to so many critics. It is as if we
have trained several generations of academics to be like the man who,
as Blake puts it, “sees the Ratio only” and thus “sees himself only”,78 so
incapable or unwilling are they to see past what the troubadour poet
Marcabru calls the fragmented, frait, in order to glimpse the whole,
entier. Donne’s work demands that we see past the Ratio, past the
fragmented, past the commitments of any contemporary critical school,
in order to understand his desire. Perhaps a little less dissection and
a little more synthesis is in order. As Martin argues, “[m]ore than any
other poet of the period, Donne represents his inner search for religious
and erotic authenticity”79 through the passionate intensity of his work. 9. Love and its Costs in Seventeenth-Century Literature Saucy pedantic wretch, go chide
Late school-boys and sour prentices, 9. Love and its Costs in Seventeenth-Century Literature Donne captures that sense of resentment against the sun, against
the demands of the daylight world of law, loveless marriages, and
obedience which ends only in death, by calling the sun a “fool” that
serves the interests of the hateful and powerful, enforcing the schedule
of a world that demands conformity. The question “Must to thy motions
lovers’ seasons run?” has only one practical answer: yes. But Donne
rejects and mocks the practical answer, insisting that such drudgery is
for those even more foolish than the sun their messenger: Saucy pedantic wretch, go chide
Late school-boys and sour prentices, 444 Love and its Critics Go tell court-huntsmen that the King will ride,
Call country ants to harvest offices;
Love, all alike, no season knows, nor clime,
Nor hours, days, months, which are the rags of time.82 The “pedantic” sun (fussy, punctilious, and over-eager to obey times
and seasons) is a fit alarum for children and workers chained to the
drudgery of low pay and long hours, a proper herald for foolish kings
and the greater fools who serve them, a necessary prompter for the
activities of insects, but it is no authority for those men and women
who love. Love transcends the petty rules and forms, the bowings and
scrapings of lives spent jostling for position in a hierarchical society,
the strict schedulings of time into “hours, days, months”, man-made
concepts which are merely “rags”. Love rejects the calls of the world
for obedience, for Love is its own law, its own world, as Donne tells
the unwelcome and too-bright morning star that has intruded upon
love’s peace and quiet: “Princes do but play us; compared to this, / All
honour’s mimic, all wealth alchemy”.83 Finally, love makes lovers a world entire unto themselves, their own
rulers, their own subjects, beholden to no one but each other. And it is in
this state that true human happiness can be sought and found: Thou sun art half as happy as we,
In that the world’s contracted thus;
Thine age asks ease, and since thy duties be
To warm the world, that’s done in warming us. 82
Ibid., ll. 5–10.
83
ll. 23–24 Donne, 81.
84
Ibid., ll. 25–30. 83
ll. 23–24 Donne, 81. 82
Ibid., ll. 5–10. 9. Love and its Costs in Seventeenth-Century Literature Shine here to us, and thou art everywhere;
This bed thy center is, these walls, thy sphere.84 Where the lovers of “The Extasie” are two who are one, united each
with the other in body and soul, the lovers of “The Sun Rising” become
an entire world in their private room, within whose walls no laws but
those of love hold sway. 445 9. Love and its Costs in Seventeenth-Century Literature 85
https://commons.wikimedia.org/wiki/File:Robert_Herrick_(poet).jpg II
The Lyricist of Carpe Diem: Robert Herrick and
the Critics who Distort Though his name may not be as well-recognized as Donne’s, there are
probably more readers who recognize fragments of the poetry of Robert
Herrick than almost any other English poet save Shakespeare. Robert Herrick, portrait by Edward Everett Hale,
in The Hawthorne Readers, Book 4 (1904).85 Robert Herrick, portrait by Edward Everett Hale,
in The Hawthorne Readers, Book 4 (1904).85 His most famous poem, “To the Virgins to Make Much of Time”, is for
many readers the very definition of the carpe diem poem: His most famous poem, “To the Virgins to Make Much of Time”, is for
many readers the very definition of the carpe diem poem: Gather ye Rose-buds while ye may,
Old Time is still a-flying:
And this same flower that smiles to day,
To morrow will be dying. The glorious Lamp of Heaven, the Sun,
The higher he’s a-getting;
The sooner will his Race be run,
And neerer he’s to Setting. That Age is best, which is the first, To morrow will be dying. The glorious Lamp of Heaven, the Sun, The sooner will his Race be run, That Age is best, which is the first, 85
https://commons.wikimedia.org/wiki/File:Robert_Herrick_(poet).jpg 446 Love and its Critics When Youth and Blood are warmer;
But being spent, the worse, and worst
Times, still succeed the former. Then be not coy, but use your time;
And while ye may, goe marry:
For having lost but once your prime,
You may for ever tarry.86 The famous carpe diem lyric is also a carpe florem poem: pluck the flower
(of virginity) before it begins to fade. As Shakespeare observes in the
opening lines of Sonnet 15, “everything that grows / Holds in perfection
but a little moment”, and Herrick here asks, why wait? What are you
waiting for? This deceptively simple poem challenges everything. In the
absence of an afterlife (and the irony must be noted that Herrick was
an Anglican minister, having been ordained at the age of 32 in 1623),
life must be lived now, and time lost will never be regained, thus it
is absolutely vital to “use your time”. Those who choose to be “coy”,
holding back out of fear of consequences for “sin” or disobedience, will
be punished by the only authority that matters: death. 86
Robert Herrick. The Complete Poems of Robert Herrick, ed. by Alexander B. Grosart.
3 vols. (London: Chatto & Windus, 1876), Vol. 1, 144–45, ll. 1–16, https://books.
google.com/books?id=n14JAAAAQAAJ&pg=PA144. Further references to these
volumes will be by line number, Herrick, volume number, and page number.
87
Macbeth 4 3 230–31 88
Sarah Gilead. “Ungathering ‘Gather ye Rosebuds’: Herrick’s Misreading of Carpe
Diem”. Criticism, 27: 2 (Spring 1985), 135. 86
Robert Herrick. The Complete Poems of Robert Herrick, ed. by Alexander B. Grosart.
3 vols. (London: Chatto & Windus, 1876), Vol. 1, 144–45, ll. 1–16, https://books.
google.com/books?id=n14JAAAAQAAJ&pg=PA144. Further references to these
volumes will be by line number, Herrick, volume number, and page number.
87
Macbeth 4.3.230–31.
88
Sarah Gilead. “Ungathering ‘Gather ye Rosebuds’: Herrick’s Misreading of Carpe
Diem”. Criticism, 27: 2 (Spring 1985), 135. II
The Lyricist of Carpe Diem: Robert Herrick and
the Critics who Distort In a world for
which there may be no heaven that looks on and takes anyone’s part,87
Herrick’s famous exhortation is no mere literary cliché, no mere exercise
in convention. It is a powerful and beautiful statement of the outrageous,
sad, and ultimately fatal predicament we all find ourselves in. Yet, for some critics, Herrick’s most famous poem is curiously
removed from life, and, as Sarah Gilead argues, incapable of anything
other than pointing to “the deceptive capacity of language to contain
experience”.88 The intellectual genealogy of this idea is clear enough,
partaking as it does of the flavor of Paul de Man’s assertion that
“Language always occurs within a range of deceptive appearances
which it created itself; for that reason, it always endangers its own 9. Love and its Costs in Seventeenth-Century Literature 447 innermost being, that is, the authentic act of saying”.89 Consistent with
the “hermeneutics of suspicion”, the idea Gilead shares with de Man
is that language conceals what it pretends to reveal, and thus poetic
language does not actually say what it seems to say. This idea that
language conceals, that language is an unstable and untrustworthy
medium, is widely shared in mid-to-late twentieth-century continental
(and continentally-influenced) thought. For philosophers like Maurice
Merleau-Ponty and Martin Heidegger, “it is in language that the
unconcealment of things happens. Yet every disclosure, every revelation,
is, at the same time, a concealment; language covers things over in the
very process of thematization or unconcealment”.90 Jacques Derrida falls
right in line by declaring that we have reached a point in which “the
simple signifying nature of language appears very uncertain, partial, or
inessential”.91 Literary criticism that takes such ideas as a starting point
regards poetry as a pretense of meaning that needs to be exposed as
meaningless in order that the machinations of languguage and ideology
might be revealed. Making use of these ideas with enough ingenuity and determination,
a remorselessly skilled critical practitioner can quite nearly destroy any
sense of life-affirmation in Herrick’s poem, rewriting it to the point of
turning it into a verse tract on suicide. The first step is to assert and then
emphasize the contradictory nature of Herrick’s theme: A carpe diem poem exists within an established literary subcategory,
inhabits an enclosed ontological and significatory space. 89
Paul de Man. The Paul de Man Notebooks, ed. by Martin McQuillan (Edinburgh:
Edinburgh University Press, 2014), 174.
90
Martin C. Dillon. Merleau-Ponty’s Ontology (Evanston: Northwestern University
Press, 1997), 179.
91
“la nature simplement signitive du langage paraît bien incertaine, partielle ou
inessentielle” (Jacques Derrida. L’Ecriture et la Différence [Paris: Seuil, 1967], 9–10). II
The Lyricist of Carpe Diem: Robert Herrick and
the Critics who Distort […] the
meanings of the poem are secured by both external traditions
(conventional motifs, arguments, moods and tropes) and by the poem’s
internal patterning. And yet the carpe diem theme itself celebrates not
the rule-bound realms of art, conventionality, contextualization, but
rather pure sensory experience. That is, it recommends that which by
its form it denies. Pure experience is precisely what language does not
offer; experience is always processed, mediated by the cultural forms
(including language and art) through which we apprehend it. The carpe 448 Love and its Critics diem poem seems to point to, even provide access to, a mysteriously life-
enhancing realm of experience but simultaneously substitutes a highly
artificial construct—itself—for such experience.92 Let’s break that last sentence down. In order to do that, we will move
from direct statements to indirect statements, and as Polonius would
say, “by indirections find directions out”.93 First, let’s look at the
simplest and most direct level of meaning available: “The carpe diem
poem […] point[s] to […] a […] life-enhancing realm of experience”. That would be a direct, straightforward, and relatively uncontroversial
statement. But note how the critic builds (or tears down) from that
basis. The simple suggestion of seeming is added: “The carpe diem poem
seems to point to […] a life-enhancing realm of experience”. Though still
quite straightforward, this version introduces the smallest of doubts. Next, the critic adds a disingenuous claim about the poem’s power, an
absurd strawman: “The carpe diem poem seems to point to, even provide
access to, a […] life-enhancing realm of experience”. It is easy to see how
a poem might point to such a thing, but how could a poem provide
access thereto? The obvious answer is that it cannot. Through the sly
suggestion that a poem might seem to have powers that it cannot have,
our critic establishes a “sensible” or “common sense” doubt about the
poem’s seeming in general. From here, the critic adds more doubt: “The
carpe diem poem seems to point to, even provide access to, a mysteriously
life-enhancing realm of experience”. This introduces the idea that the
seeming is not limited to the poem, but to the world of experience that
the poem only seems to point to (and with each move, Herrick’s verse
recedes further and further to invisibility). 92
Gilead, 135.
93
Hamlet, 2.1.65. II
The Lyricist of Carpe Diem: Robert Herrick and
the Critics who Distort Finally, the finishing touch
is added: “The carpe diem poem seems to point to, even provide access to,
a mysteriously life-enhancing realm of experience but simultaneously
substitutes a highly artificial construct—itself—for such experience”. This
last move relies on meaningless inflation of its terms. What is “a highly
artificial construct”? As all constructs are “artificial” (made by and
through art and artifice), how is it possible for such a construct to be
highly artificial, as opposed to simply and plainly artificial? The effect
looked for, however, is not precision of definition, so much as it is the 9. Love and its Costs in Seventeenth-Century Literature 449 enhancement—through rhetorical inflation—of an already threadbare
line of reasoning. The last assertion—as no evidence whatsoever is
given for the notion that the poem substitutes for experience—completes
the trick whereby Herrick’s poem is replaced by an absurd version
written by the critic, for the critic, with the express purpose of being
deconstructed by the critic. Rewritten in this way, Herrick’s “To the Virgins” is merely a
tiresome rehearsal of “established” literary forms and ideas, trapped
within an old-fashioned and no-longer-negotiable set of conventions
regarding life and the communication of emotions and ideas. For the
critic, the “meaning” that “naive” readers take from this poem is a
philosophical version of fast food: prepackaged in familiar wrapping
(the “conventional motifs, arguments, moods and tropes”) with
standardized cooking and presentation techniques (“the poem’s internal
patterning”). As refashioned by the critic, the product does not, indeed
cannot, deliver on its promises. With the first, and most crucial step now taken (the construction
of a strawman version of the poem), the second step is to distance it
from any aspect of life that does not somehow refer to poetry itself,
and is not somehow about the acts of writing and meaning. For Gilead,
Herrick’s poem can be reduced to “a metaphor for the act of reading
and interpreting (‘gathering’ a message)”. For the critic, “the persuasion
to pleasure of Herrick’s carpe diem may be read as a persuasion to seek
signification: textuality replaces sexuality”.94 This move makes it possible
to claim that Herrick’s lyric is an artifact of ruthless competitiveness,
a testament to the demands of the male poet’s ego (an idea borrowed
from T. S. 94
Ibid.
95
Ibid., 140. II
The Lyricist of Carpe Diem: Robert Herrick and
the Critics who Distort Eliot’s essay “Tradition and the Individual Talent” and Harold
Bloom’s book The Anxiety of Influence): “Herrick’s ‘To the Virgins’
is compensatorily self-effacing, quiet, small, innocent, easy, almost
anonymous-seeming. But its modesty, its virginal unaggressiveness
conceals, perhaps, a kind of textual ruthlessness”.95 This critical formula
relies heavily on the use of “shocking” reversals and combinations
of ideas, images, and even sound patterns all strung together on the
extremely thin thread of “perhaps”. “Textual” is intended to remind
the reader of “sexual”, and “virginal […] ruthlessness” is designed to 450 Love and its Critics raise the spectre of violence, even rape. Naturally, what else would we
expect to find concealed behind “virginal unaggressiveness”, other than
“textual ruthlessness”? For the critic, that “ruthlessness” reveals itself in
an Oedipal competition in which Herrick establishes his poetic persona
as an “aggressive rival to and replacement of the poetic father” through
the “acts of textual castration that create ‘To the Virgins’ from the bits
and pieces of precursor texts” from “the classical age which produces
the literary genera Herrick follows”.96 As the critical assertions mount ever higher, the third step is to employ
the “hermeneutics of suspicion” to argue that the poem does not mean
what it merely seems to mean, and may, in fact, mean quite the opposite: By illustrating the unstoppable rush of time, the need to seize the day is
made manifest. But the poem’s “aging” also undermines the carpe diem
assertion, for if the linear succession from “best” to “worst” is absolutely
impervious to human will, action, or decision, then the choice between
seizing the day or letting it pass is no choice at all. Not to tarry, not to
defer the gathering of rosebuds, is not to defer death, the final gathering,
the end of the race. Thus the poem simultaneously illustrates both the
wisdom and the folly of heeding its message.97 Again, the argument relies on unsubstantiated claims that present
themselves as authoritative critical judgments. The critic supplies
no evidence at all for the “shocking” conclusion that “the poem
simultaneously illustrates both the wisdom and the folly of heeding its
message”. It is true, of course, that “not to defer”98 gathering rosebuds “is
not to defer” death itself. But that is not what the poem claims. 96
Gilead, 141.
97
Ibid., 146.
98
Note how the critic uses the negation, the inversion there to add the appearance
of complexity: “not to defer gathering”, rather than merely “gathering”. Gathering
rosebuds does not defer death—this is a simple, straightforward statement. Not to
defer gathering rosebuds is not to defer death—this statement cloaks itself, through its
negations and convolutions, in an appearance of profundity, which lends a kind of
thinly-woven authority to the statement that follows. II
The Lyricist of Carpe Diem: Robert Herrick and
the Critics who Distort Instead
it asserts that to defer gathering rosebuds is to defer (possibly until it is
too late) the all-too-short experience of the most pleasurable aspects of
life. Death is not the question of the poem—the question is what each of
us will do with the time left before death. To argue seriously that there is
“no choice at all” between grabbing experience and allowing it to pass 9. Love and its Costs in Seventeenth-Century Literature 451 by, between living actively in the face of inevitable death and waiting
passively and obediently for that death to arrive, is to reveal oneself as
incapable of (or uninterested in) coherent argument. Only a critic who
cannot or will not see past his or her ideological commitments could
expect to be taken seriously when advancing this argument. But this is
the kind of reasoning required by the step-by-step, paint-by-numbers
process of the hermeneutics of suspicion method of reading. Finally, the fourth and most crucial step is to reveal the “hidden”
meaning of the poem, which in this case means rewriting the entire carpe
diem motif. For the critic, far from urging that life be lived to the fullest
while there is yet time, Herrick’s famous poem rushes headlong toward
death, driven by its own desire into a form of suicide: The carpe diem strategy posits sexual pleasure as life-intensifying, and thus
a defense against mortality; intense pleasure, whether in anticipation,
experience, or memory, in a sense displaces the consciousness or fear of
death. But sexuality viewed not as pleasure but as reproduction makes
the individual, his experiences, his consciousness, and his very existence,
superfluous, expendable. The only perfect defense against fear of death,
against the paralyzing anxiety of the coy virgin, is death itself. […] Carpe
diem urges “satisfaction” of desire, the feeding of it, but to satisfy desire
is to get rid of desire, to destroy desire in the total discharge of need that
is accomplished by death. 100 Note the sly way in which the critic shifts the ground beneath sexuality from
“pleasure” to “reproduction”, before making the unsupported assertion that
“reproduction makes the individual […] expendable”. 99
Ibid., 147–48. II
The Lyricist of Carpe Diem: Robert Herrick and
the Critics who Distort The final rosebud to be gathered is death itself
[…] Aggression against the self thus occurs both in rejecting desire and in
seeking it; the first denies to the self a range of possible experiences […];
the second is that impulse through which is created the replacement for
the self in the next generation […]—to seek desire is thus, paradoxically,
a form of indirect suicide.99 Here we have a veritable tour de force of sleights-of-hand,100 reversals,
and unsupported assertions dressing themselves up as arguments. Sexuality as reproduction makes the individual expendable. Proof? None is
offered. The only perfect defense against the fear of death is death itself. Proof? None. Seeking desire is a form of “indirect suicide”. Proof? Of course not. The point of that final statement lies, not in any actual truth claim, but
in its rhetorical effect. Dress up a series of counter-intuitive reversals Love and its Critics 452 in negations and inverted syntax, repeat those reversals in forceful
language, backed up by the “authority” lent by the reputable journal
or publishing house which has printed the piece in which the reversals
appear, and wait for compliant, graduate-school-trained readers to fall
in line, and start repeating your claims in their presentations, papers,
and other “intellectual” productions. After being put through this
process, the poem that generations of readers thought they had read
has nearly disappeared,101 and the most famous of carpe diem poems
has been transformed into a carpe mortem poem. From the critical point
of view offered by Gilead, there is no call to life and love in “To the
Virgins”, only literary convention, the remorseless progress of time, and
the inevitability of death. Inherent in much of the criticism this book discusses are the twin
ideas that literature inevitably serves the interests of the powerful, and
that resistance is impossible. Jacques Lacan, for example, insists that
resistance always traps one inside the discourse of the power one is
resisting, “the revolutionary aspiration has only one possible outcome,
always, the discourse of the master. This is what experience proves. What you aspire to as revolutionaries is a Master. You will have one”.102
From this point of view, criticism like Gilead’s ends up arguing that the
appearance of a radically life-affirming spirit in Herrick’s poem actually
undermines itself, and ends up affirming death. 101 This is consistent with the “nothingness” de Man claims is at the heart of literature:
“Here the human self has experienced the void within itself, and the invented
fiction, far from filling the void, asserts itself as a pure nothingness, our nothingness
stated and restated by a subject that is the agent of its own instability” (Blindness and
Insight, 19). 102 “l’aspiration révolutionnaire, ça n’a qu’une chance d’aboutir, toujours, au discours
du maître. C’est ce que l’expérience en a fait la preuve. Ce à quoi vous aspirez
comme révolutionnaire, c’est à un Maître. Vous l’aurez” (Jacques Lacan. Le Séminaire
de Jacques Lacan, Livre XVII: L’envers de la Psychanalyse, ed. by Jacques Alain Miller
[Paris: Seuil, 1991], 239). 101 This is consistent with the “nothingness” de Man claims is at the heart of literature:
“Here the human self has experienced the void within itself, and the invented
fiction, far from filling the void, asserts itself as a pure nothingness, our nothingness
stated and restated by a subject that is the agent of its own instability” (Blindness and
Insight, 19).
102 “l’aspiration révolutionnaire, ça n’a qu’une chance d’aboutir, toujours, au discours
du maître. C’est ce que l’expérience en a fait la preuve. Ce à quoi vous aspirez
comme révolutionnaire, c’est à un Maître. Vous l’aurez” (Jacques Lacan. Le Séminaire
de Jacques Lacan, Livre XVII: L’envers de la Psychanalyse, ed. by Jacques Alain Miller
[Paris: Seuil, 1991], 239). 105 “La difficulté est une monoye que les sçavans employent, comme les joueurs de
passe-passe, pour ne descouvrir la vanité de leur art, et de la quelle l’humaine bestise
se paye ayséement” (Michel de Montaigne. “Apologie de Raimond de Sebonde”. In
Les Essais de Michel de Montaigne, Vol. 2, ed. by Fortunat Strowski [Bordeaux: Pech,
1906], 234, https://archive.org/stream/lesessaisdemi02mont#page/234). Montaigne
goes on to quote from Lucretius’ De Rerum Natura 1.639, 641–42, speaking of the
famously obscure Heraclitus, who was: 103 One notable exception to this trend has been Alexander Leggatt, who regrets what he
calls “a current tendency to see society as a structure of oppression and exploitation,
and to read Shakespeare accordingly” (Alexander Leggatt. Shakespeare’s Political
Drama: The History Plays and the Roman Plays [New York: Routledge, 2003], viii).
104 Gilead 150 II
The Lyricist of Carpe Diem: Robert Herrick and
the Critics who Distort What is perhaps even
more astonishing than these oddly authoritarian ideas is how little
thought is necessary to put them to use in an interpretive process whose
template-driven results are determined in advance of the reading: follow
the steps, complete the formula, and voilà, the critic has “revealed” that
a poem long-thought to say “X” actually says “not-X”. Gilead’s article is an artifact of its time, the mid 1980’s, and its place, a
Ph.D. written at Northwestern University in 1980, during the peak of the 9. Love and its Costs in Seventeenth-Century Literature 453 fascination with deconstruction that swept through English departments
in American academia. But it is part of a much longer story in literary
criticism and interpretation, one that stretches back all the way to Akiba
and Origen and their insistence that the Song of Songs be read against its
own text. Theological interpreters of the Song of Songs take great care in
telling us that the poem’s frankly erotic treatment of love between a man
and a woman is really a metaphor for loving God. Modern academic
criticism of the troubadours is at pains to assure us that the poetry does
not actually mean what it merely appears to mean. Much new historicist
and cultural materialist criticism of Shakespeare aims to convince us
that despite their anti-authoritarian appearances, Shakespeare’s plays
are part of the apparatus of Elizabethan and Jacobean state control.103 fascination with deconstruction that swept through English departments
in American academia. But it is part of a much longer story in literary
criticism and interpretation, one that stretches back all the way to Akiba
and Origen and their insistence that the Song of Songs be read against its
own text. Theological interpreters of the Song of Songs take great care in
telling us that the poem’s frankly erotic treatment of love between a man
and a woman is really a metaphor for loving God. Modern academic
criticism of the troubadours is at pains to assure us that the poetry does
not actually mean what it merely appears to mean. 104 Gilead, 150. II
The Lyricist of Carpe Diem: Robert Herrick and
the Critics who Distort Much new historicist
and cultural materialist criticism of Shakespeare aims to convince us
that despite their anti-authoritarian appearances, Shakespeare’s plays
are part of the apparatus of Elizabethan and Jacobean state control.103
Many Donne scholars are particularly concerned with separating the
poet’s life from the poet’s written work, as part of a strategy of larger
claims that insist that the poems are misogynist and imperialist. And
a critic like Gilead tells us that the message of the carpe diem motif in
Herrick’s “To the Virgins” is impossible to find: “The longer the reader
searches for the carpe diem message in Herrick’s obviously carpe diem
poem, the greater difficulty she has in finding it. […] Herrick’s poem
disintegrates into a tangle of conflicting concepts, images, and tropes”.104 Many Donne scholars are particularly concerned with separating the
poet’s life from the poet’s written work, as part of a strategy of larger
claims that insist that the poems are misogynist and imperialist. And
a critic like Gilead tells us that the message of the carpe diem motif in
Herrick’s “To the Virgins” is impossible to find: “The longer the reader
searches for the carpe diem message in Herrick’s obviously carpe diem
poem, the greater difficulty she has in finding it. […] Herrick’s poem
disintegrates into a tangle of conflicting concepts, images, and tropes”.104 Not to put too fine a point on it, this is a form of critical violence that
works to undermine poetry’s potential for resistance, and dismiss the
sense that poetry is something that might be enjoyed. II
The Lyricist of Carpe Diem: Robert Herrick and
the Critics who Distort Such criticism is
often written in the kind of deliberately obtuse language that illustrates
Montaigne’s maxim: “Difficulty is the currency that the learned employ,
like tricksters, in order not to reveal the vanity of their art, and which
human stupidity is easily led to take as payment”.105 Things do not seem 454 Love and its Critics to have changed since Montaigne’s time: as Felski notes, the “sheer
difficulty [of a work] accentuate[s] its allure to a certain kind of critic,
convinced, akin to Burke commenting on the sublime, that the obscure
is inherently more affecting and awe-inspiring than the clear”.106
There is “a fannish dimension” to this work, “evidenced in a cult of
exclusiveness and intense attachment to charismatic figures”.107 What
this kind of literary criticism reveals is an antagonism toward poetry,
or as Derrida describes it, with an eye on the tradition stretching back
to Plato, an intolerance for poetry as a threat to the dominance of the
prose-bound philosopher: the history of philosophy is the history of prose; or, if you will, the
prosifying of the world. Philosophy is the invention of prose. Philosophy
speaks in prose. […] Before writing, verse served as a kind of spontaneous
engraving, a writing before the letter. Intolerant of poetry, philosophy
took writing to be the letter.108 Clarus, ob obscurum linguam, magis inter inanes,
Omnia enim stolidi magis admirantur amantque
Inversis quae sub verbis latitantia cernunt. Celebrated for his obscurity, especially among the inane,
For all the stupid greatly admire and love
That which is concealed beneath inverted words. Clarus, ob obscurum linguam, magis inter inanes, Aristotle makes a similar comment when he notes that “knowing themselves
ignorant, men worship those whose speech lies above their reckoning” (συνειδότες
δ᾽ ἑαυτοῖς ἄγνοιαν τοὺς μέγα τι καὶ ὑπὲρ αὐτοὺς λέγοντας θαυμάζουσιν)
(Aristotle. Nichomachean Ethics I, ed. by H. Rackham [Loeb Classical Library,
Cambridge, MA: Harvard University Press, 1926], 10, ll. 26–27). In writing of the
Paul de Man affair, Robert Alter sounds like a modern (if somewhat angrier)
Montaigne, as he describes the situation as one in which “to his American admirers,
with their cultural inferiority complex, it seemed that if things were difficult to
grasp, something profound was being said”, and that de Man “got away with
it because of the gullibility of American scholars” (“Paul de Man Was a Total
Fraud”. New Republic. April 5, 2014, https://newrepublic.com/article/117020/
paul-de-man-was-total-fraud-evelyn-barish-reviewed). 110 “le sujet agit en tant qu’il est agi par le système” (Louis Althusser. “Idéologie et
Appareils Idéologiques d’État” [1970]. Les Classiques des Sciences Sociales [Quebec:
Université du Québec à Chicoutimi], 44, http://classiques.uqac.ca/contemporains/
althusser_louis/ideologie_et_AIE/ideologie_et_AIE.pdf).
111 Gilead, 150. 109 Paul de Man, Blindness and Insight, 9. II
The Lyricist of Carpe Diem: Robert Herrick and
the Critics who Distort 106 Felski, The Limits of Critique, 27. This kind of devotion to the difficult can be seen
in the almost de rigueur political contempt for the idea of clarity expressed (with
ironic clarity) by Trink T. Minh-ha: “Clarity is a means of subjection, a quality both
of official taught language and of correct writing, two old mates of power: together
they flow, together they flower, vertically, to impose an order” (Trink T. Minh-ha. Woman, Native, Other [Bloomington, Indiana: Indiana University Press, 1989, 16–17). l k
h
i i
f C i i 106 Felski, The Limits of Critique, 27. This kind of devotion to the difficult can be seen
in the almost de rigueur political contempt for the idea of clarity expressed (with
ironic clarity) by Trink T. Minh-ha: “Clarity is a means of subjection, a quality both
of official taught language and of correct writing, two old mates of power: together
they flow, together they flower, vertically, to impose an order” (Trink T. Minh-ha. Woman, Native, Other [Bloomington, Indiana: Indiana University Press, 1989, 16–17). 107 Felski, The Limits of Critique, 27. 107 Felski, The Limits of Critique, 27. 108 l’histoire de la philosophie est l’histoire de la prose; ou plutôt du devenir-prose du monde. La
philosophie est l’invention de la prose. Le philosophe parle en prose. […] Avant l’écriture, le
vers serait en quelque sorte une gravure spontanée, une écriture avant la lettre. Intolérant à la
poésie, le philosophe aurait pris l’écriture à la lettre. Jacques Derrida. De la Grammatologie, 406. Emphasis added. 9. Love and its Costs in Seventeenth-Century Literature Let’s live in hast; use pleasures while we may:
Co’d life return, ‘twod never lose a day.112 Let’s live in hast; use pleasures while we may:
Co’d life return, ‘twod never lose a day.112 “Let’s” (let us) is directed toward all, male and female, young and old
alike. “Pleasures” may, of course, be sexual pleasures, but they needn’t
be limited thereto (unless a critic has a particular ideological point to
hammer home). A considerable effort will have to be invested in this
short lyric to ensure that it “disintegrates into a tangle of conflicting
concepts, images, and tropes” or becomes intelligible primarily as “a
form of indirect suicide”. Here, perhaps, the reading method of Rashi is
what best serves: the plain meaning of this text is an exhortation to enjoy
each day, each moment, because we are all running out of time. And
could “life return”, were we given, after the diagnosis of a fatal illness, a
short reprieve, an extra week or month, or even year of life, how many
of us would waste even a day on drudgery, obedience, and ascetic self-
denial?113 Perhaps those who read the poetry of life and love as being
actually about a desire for death, but not many others. “Let’s” (let us) is directed toward all, male and female, young and old
alike. “Pleasures” may, of course, be sexual pleasures, but they needn’t
be limited thereto (unless a critic has a particular ideological point to
hammer home). A considerable effort will have to be invested in this
short lyric to ensure that it “disintegrates into a tangle of conflicting
concepts, images, and tropes” or becomes intelligible primarily as “a
form of indirect suicide”. Here, perhaps, the reading method of Rashi is
what best serves: the plain meaning of this text is an exhortation to enjoy
each day, each moment, because we are all running out of time. And
could “life return”, were we given, after the diagnosis of a fatal illness, a
short reprieve, an extra week or month, or even year of life, how many
of us would waste even a day on drudgery, obedience, and ascetic self-
denial?113 Perhaps those who read the poetry of life and love as being
actually about a desire for death, but not many others. Faire Daffadills, we weep to see
You haste away so soone: pg
113 These are the same kinds of questions that Dostoevsky’s novel The Idiot (Идиот)
poses as Prince Myshkin tells the story (based on Dostoevsky’s own experience of
a narrowly-averted execution) of a man who faced what he believed would be the
last moments of his life, and suddenly thought of how precious time would be to
him, if only he were spared: 112 ll. 1–2, Herrick, Vol. 2, 115, https://books.google.com/books?id=C21DAQAAMAAJ
&pg=PA115 9. Love and its Costs in Seventeenth-Century Literature 455 As de Man approvingly defines it, such criticism is “a methodologically
motivated attack on the notion that a literary or poetic consciousness
[…] can pretend to escape, to some degree, from the duplicity, the
confusion, the untruth that we take for granted in the everyday use of
language”.109 In the critic’s terms, the old claim of the English Puritan
William Prynne is revived: poetry is a lie, and a dangerous one at that. Criticism dedicated to a “hermeneutics of suspicion” gives us no
exit, no recourse as it continually rewrites poetry as compliant with
authority (a move the critic couches in the guise of “unmasking” or
“revealing” poetry’s hidden ideological nature). In transforming or
rewriting such poetry as appears to offer even the slightest glimmer of
resistant possibility, the critic makes him or herself into an agent of the
oppressive structures of authority, part of a vicious circle of ideology in
which “the subject acts as it is acted by the system”.110 He or she does
this through a criticism that is tinged with both compulsion and violence
in a project which seems to disdain the very poetry it works with:
witness the critic’s celebration of violence in her reading of Herrick: “an
interrogative reading [of Herrick’s poem] parries with its anti-textual
analytical violence the poem’s assertion of its own innocence, and of the
reader’s innocent desire to preserve inviolate the simplicity, integrity,
and obvious good sense of carpe diem”.111 But a poem like “To the Virgins” is innocent, in the etymological
sense of harmless. No virgins are oppressed or subjugated by being
encouraged to live a little before they die; not even if the poem is
interpreted as a seduction lyric is its advice harmful to anyone except
to the extent to which they are locked within systems of control in a
society in which female sexuality is regarded as a valuable commodity
to be bought and sold by fathers and (father-chosen) husbands. A short,
epigrammatic poem like “To Live Freely”, condenses “To the Virgins”
into two lines which only a critic devoted to suspicion could read with
interrogative violence: 456 Love and its Critics 112 ll. 1–2, Herrick, Vol. 2, 115, https://books.google.com/books?id=C21DAQAAMAAJ
&pg=PA115
113 These are the same kinds of questions that Dostoevsky’s novel The Idiot (Идиот)
poses as Prince Myshkin tells the story (based on Dostoevsky’s own experience of
a narrowly-averted execution) of a man who faced what he believed would be the
last moments of his life, and suddenly thought of how precious time would be to
him, if only he were spared:
What if I did not die! What if I came back to life-what infinity! And all this would be mine! I
would then treat every minute as a century, not losing anything, calculate every minute, so as
to spend none of them in vain!
Что, если бы не умирать! Что, если бы воротить жизнь,-какая бесконечность! И всё это
было бы мое! Я бы тогда каждую минуту в целый век обратил, ничего бы не потерял,
каждую бы минуту счетом отсчитывал, уж ничего бы даром не истратил!’
Fyodor Dostoevsky. Идиот [The Idiot] (St. Petersburg: A. Suvorin, 1884), 62. pg
113 These are the same kinds of questions that Dostoevsky’s novel The Idiot (Идиот)
poses as Prince Myshkin tells the story (based on Dostoevsky’s own experience of
a narrowly-averted execution) of a man who faced what he believed would be the
last moments of his life, and suddenly thought of how precious time would be to
him, if only he were spared:
What if I did not die! What if I came back to life-what infinity! And all this would be mine! I
would then treat every minute as a century, not losing anything, calculate every minute, so as
to spend none of them in vain!
Что, если бы не умирать! Что, если бы воротить жизнь,-какая бесконечность! И всё это
было бы мое! Я бы тогда каждую минуту в целый век обратил, ничего бы не потерял, What if I did not die! What if I came back to life-what infinity! And all this would be mine! I
would then treat every minute as a century, not losing anything, calculate every minute, so as
to spend none of them in vain! 114 ll. 1–19, Herrick, Vol. 2, 35, https://books.google.com/books?id=C21DAQAAMAAJ
&pg=PA35
115 Targoff, 176. Let’s live in hast; use pleasures while we may:
Co’d life return, ‘twod never lose a day.112 In similar fashion, a poem like “To Daffadills” expresses grief at the
shortness of life, and the fading of beauty, not to hide anything from the
reader by disintegrating into “a tangle”, not to seduce anyone, nor even
to persuade, but merely to commiserate across time and distance, one
mortal writer with countless equally mortal readers: What if I did not die! What if I came back to life-what infinity! And all this would be mine! I
would then treat every minute as a century, not losing anything, calculate every minute, so as
to spend none of them in vain! Что, если бы не умирать! Что, если бы воротить жизнь,-какая бесконечность! И всё это
было бы мое! Я бы тогда каждую минуту в целый век обратил, ничего бы не потерял,
каждую бы минуту счетом отсчитывал, уж ничего бы даром не истратил!’ Fyodor Dostoevsky. Идиот [The Idiot] (St. Petersburg: A. Suvorin, 1884), 62. Fyodor Dostoevsky. Идиот [The Idiot] (St. Petersburg: A. Suvorin, 1884), 62. 457 9. Love and its Costs in Seventeenth-Century Literature 9. Love and its Costs in Seventeenth-Century Literature As yet the early-rising Sun
Has not attain’d his Noone. Stay, stay,
Untill the hasting day
Has run
But to the Even-song;
And, having pray’d together, we
Will go with you along. We have short time to stay, as you,
We have as short a Spring;
As quick a growth to meet Decay,
As you, or any thing. We die,
As your hours doe, and drie
Away, Like to the Summers raine;
Or as the pearles of Mornings dew
Ne’r to be found againe.114 As yet the early-rising Sun
Has not attain’d his Noone. Stay, stay,
Untill the hasting day
Has run
But to the Even-song;
And, having pray’d together, we
Will go with you along. We have short time to stay, as you,
We have as short a Spring;
As quick a growth to meet Decay,
As you, or any thing. We die,
As your hours doe, and drie
Away, Like to the Summers raine;
Or as the pearles of Mornings dew
Ne’r to be found againe.114 In the face of such awful and meaningless ephemerality, in a world
where beauty is born seemingly for the purpose of decaying and dying
and disappearing forever, how can anyone take seriously the idea that
the carpe diem motif needs to be subjected to an “interrogative reading
[that] parries with […] analytical violence the poem’s assertion of its
own innocence”? The carpe diem poem is itself what interrogates the real
(not merely interpretive) violence of a world in which life exists only to
be snuffed out. The carpe diem motif in English poetry is a response to a
world which seemed to many to be falling apart: [T]he instability of the political climate leading up to and during the
English Civil War created more incentives for seizing immediate and
temporary pleasures; the idea that the world was coming to its end had
a sufficiently wide reach […]. 116 This is the period in which the first stirrings of what we consider the modern form
of Atheism are developing. For further discussion, see Michael Bryson, The Atheist
Milton (London: Routledge, 2012).
117 H
l t 3 1 81 82 Drink Wine, and live here blithefull, while ye may:
The morrowes life to late is, Live to-day.119 119 ll. 1–2, Herrick, Vol. 2, 209, https://books.google.com/books?id=C21DAQAAMAAJ
&pg=PA209 118 Ibid., 2.2.273, 278. 117 Hamlet 3.1.81–82. 120 David Landrum. “Robert Herrick and the Ambiguities of Gender”. Texas Studies in
Literature and Language, 49: 2 (2007), 195, https://doi.org/10.1353/tsl.2007.0012
121 Shaw, 119. 9. Love and its Costs in Seventeenth-Century Literature Many responded to this threat by devoting
themselves to repentance and prayer, but others translated this anxiety
into a kind of seductive energy, urging the pleasures of the day before
the day was no more.115 458 Love and its Critics With death lurking seemingly around every corner, and with the
Christian promises of heaven seeming ever more remote to many,116
who, like Hamlet, regarded death as the “undiscovered country from
whose bourn / No traveller returns”,117 carpe diem made sense to many
contemporary readers in an urgent, visceral way that transcends
the cool detachments of our own frames of reference in reading and
criticism. The daffodils of Herrick’s poem are not merely a metaphor,
they are a frailly beautiful but relentless reminder of death. From the
speaker’s point of view, the demise of daffodils is senseless, too hasty,
and without any redemptive point or purpose, just like human death,
for which there is no remedy, and to which there is no point. Humanity,
in Shakespeare’s terms, is “noble in reason, […] infinite in faculty!” But
we are also merely a “quintessence of dust”.118 Herrick captures this
tragic and perplexing quality by showing the aspiration and uselessness
of prayer to a god for whom the deaths of human beings and daffodils
appear to be matters of equally depraved indifference: “And, having
pray’d together, we / Will go with you along”. From the daffodil to the man, death is the end of all lives and all
joys, and while the Neoplatonized and Christianized poetic tradition
of Dante and Petrarch assumed an afterlife in which greater joys (or
greater torments) would be had by all, the carpe diem tradition is rather
closer to the metaphysics on offer in King Lear, where “nothing”, and
“never” sum up the hopes for life and love after death. Thus, a poem
like “To Youth” offers what is, from this perspective, the best possible
advice. What point is there in sacrifice and prayer, when heaven seems
indifferent to all living things below? Far better to 9. Love and its Costs in Seventeenth-Century Literature 122 Landrum, 205–06. 120 David Landrum. “Robert Herrick and the Ambiguities of Gender”. Texas Studies in
Literature and Language, 49: 2 (2007), 195, https://doi.org/10.1353/tsl.2007.0012
121 Shaw, 119.
122 Landrum, 205–06.
123 Ibid., 187. 123 Ibid., 187. 9. Love and its Costs in Seventeenth-Century Literature 459 Herrick’s poetry often displays a disregard for social and literary
convention, exercising an imaginative freedom that allows him to
portray the “imaginary mistresses” of his poems in ways that flout the
expectations of his time and place: The subversive quality of Herrick’s imaginary mistresses derives from
their existence in a space imaginatively removed from the conventional
restraints that limited women’s freedom […]. This device of creating
imaginary women who exist outside social reality enables Herrick [to] be
innovative, disruptive, even subversive in his depictions of gender roles.120 This freedom is created by the carpe diem theme itself. In a world in
which “nothing” and “never” are our defining expectations of the
afterlife, what does it matter if people disobey the conventions set by
their societies and peers? Donne serves as an excellent example of the
consequences that can ensue from flouting the customs of one’s time and
place, but in terms of the eternal death waiting for all of us, how much
did it really matter that John Donne and Anne More married without
something so temporal as the permission of a father who would soon
be, and is now, dead forever? In Herrick’s hands, the carpe diem motif
begins to seem like the only rational response to a temporary existence
for men and women who would not live as slaves to geographically and
temporally fixed authority, and recognised that the “customs of [their]
island and tribe are [not] the laws of nature”.121 Neither Herrick nor the
carpe diem tradition can be fully understood without recognizing this
subversive element: Trying to understand Herrick’s poetry dealing with women without
recognizing this subversive, parodic element only leads one into a
pathless quagmire as far as interpretation goes. 124 Ceri Sullivan. “The carpe diem topos and the ‘geriatric gaze’ in early modern verse”.
Early Modern Literary Studies, 14: 3 (January 2009), 8.1–21 http://extra.shu.ac.uk/
emls/14–3/Sullcarp.html 9. Love and its Costs in Seventeenth-Century Literature Herrick defies the limits
of standard interpretation […] using text and language, using poetic
liturgy, as a means by which accepted injustices might be mollified and
eventually perhaps even corrected.122 Rather than regarding Herrick through a more jaundiced lens as “the
voyeuristic, effeminate pervert that many critics have suggested”,123 460 Love and its Critics or as the old man who inflicts his “geriatric gaze” on the “bouncing
mistress” whom he expects to increase “the effort she must make to
rouse his manhood”124 when he can no longer “stand to” so quickly as he
once did in his youth, seeing Herrick as both parodic and disrespectful
of convention helps us understand the urgency of what is perhaps his
second most famous poem, “Corinna’s going a Maying”. In “Corinna” (whose titular mistress is a reference to the Corrina
of Ovid’s Amores), we have the entire carpe diem theme and all of its
implications put together in a powerful and beautiful whole. In
encouraging Corrina to “goe a Maying”, Herrick’s poem stands up for
the joys of the May Day festival, a celebration of spring, fertility, and life,
against the increasingly powerful efforts of Puritan authority figures to
shut it down. On a day such as this, the poem suggests it would be a sin
to refrain: When all the Birds have Mattens seyd,
And sung their thankfull Hymnes: ‘tis sin,
Nay, profanation to keep in,
Whenas a thousand Virgins on this day,
Spring, sooner than the Lark, to fetch in May.125 For the Puritans, however, the “sin” was in the keeping of the celebration
itself, given the dancing, sexual play, and occasional gender-bending
that would go on: May Day was condemned by Puritan writers for the sexual license it
encouraged; the phallic symbolism of the maypole was noted by many. […] These processions contained a strong element of role reversal, for
in some the [chimney] sweeps dressed as females [,] but music and
collecting contributions from bystanders were common to all.126 May Day was condemned by Puritan writers for the sexual license it
encouraged; the phallic symbolism of the maypole was noted by many. 126 Joan Lane. Apprenticeship in England, 1600–1914 (London: University College
London Press, 1996), 95. 125 Lines 10–14, Herrick, Vol. 1, 116, https://books.google.com/books?id=n14JAAAA
QAAJ&pg=PA116 124 Ceri Sullivan. “The carpe diem topos and the ‘geriatric gaze’ in early modern verse”.
Early Modern Literary Studies, 14: 3 (January 2009), 8.1–21 http://extra.shu.ac.uk/
emls/14–3/Sullcarp.html
125 Lines 10–14, Herrick, Vol. 1, 116, https://books.google.com/books?id=n14JAAAA
QAAJ&pg=PA116
126 Joan Lane. Apprenticeship in England, 1600–1914 (London: University College
London Press, 1996), 95. p
125 Lines 10–14, Herrick, Vol. 1, 116, https://books.google.com/books?id=n14JAAAA
QAAJ&pg=PA116
126 Joan Lane. Apprenticeship in England, 1600–1914 (London: University College
London Press, 1996), 95. 127 Richard L. Greaves. Society and Religion in Elizabethan England (Minneapolis:
University of Minnesota Press, 1981), 426.
128 William Prynne. Histriomastix (London: Printed by E. A. and W. I. for Michael
Sparke, 1633), Sig. B1v, https://archive.org/stream/maspla00pryn#page/2
129 Ibid., Sig. G2r, https://archive.org/stream/maspla00pryn#page/43
130 Ibid., Sig. K3v, https://archive.org/stream/maspla00pryn#page/70
131 Ibid., Sig. S1v, https://archive.org/stream/maspla00pryn#page/130
132 Ibid., Sig. Ii1r, https://archive.org/stream/maspla00pryn#page/241
133 Ibid., Sig. Ll3r, https://archive.org/stream/maspla00pryn#page/261
134 Ibid., Sig. Nn4r, https://archive.org/stream/maspla00pryn#page/279
135 Ibid., Sig. Kkkkk4r, https://archive.org/stream/maspla00pryn#page/n922 9. Love and its Costs in Seventeenth-Century Literature g
p
y
yp
y
y
[…] These processions contained a strong element of role reversal, for
in some the [chimney] sweeps dressed as females [,] but music and
collecting contributions from bystanders were common to all.126 By Herrick’s day, the authorities had been trying, with limited success,
to shut down the May Day celebrations for decades. Elizabethan 9. Love and its Costs in Seventeenth-Century Literature 461 constables gave orders on several occasions for the maypoles to be
pulled down, the festivals themselves to be prohibited, and any resisters
to be arrested: In Shrewsbury in 1588, the maypole was banned and members of the
shearmen’s guild were jailed for opposing the order. At Banbury, Oxon,
a Puritan center whose M. P. was Anthony Cope, the high constable
ordered the parish constables to take down all maypoles and prohibit
festivities in May 1589.127 By the 1630s, the political mood in England had grown dark and
contentious, with many of the Puritan faction condemning nearly
all entertainments as the works of the Devil. The year 1633 saw the
publication of William Prynne’s Histriomastix, a broadside against
everything the author thought sinful in an England rapidly moving
toward revolution and civil war. Prynne censures “prophane, and
poysonous” plays as “the common Idole, and prevailing evill of our
dissolute and degenerous Age”,128 describing them as “the Workes,
and Pompes of the very Devill”129 which deal with “nothing else but
the Adulteries, Fornications, Rapes, Love-passions, Meritricious,
Unchast, and Amorous practices of Lacivious Wicked men”,130 and have
“the Divell himselfe for their author”.131 Prynne condemns dancing as
“unavoydably sinfull and abominable”,132 and further denounces all
“obscene, lacivious, lust-provoking Songs and Poems”,133 “effeminate,
amorous, wanton Musicke”,134 and “May-games, Revels, dancing, and
other unlawfull pastimes on the Lords day”.135 By the 1630s, the political mood in England had grown dark and
contentious, with many of the Puritan faction condemning nearly
all entertainments as the works of the Devil. The year 1633 saw the
publication of William Prynne’s Histriomastix, a broadside against
everything the author thought sinful in an England rapidly moving
toward revolution and civil war. 9. Love and its Costs in Seventeenth-Century Literature Prynne censures “prophane, and
poysonous” plays as “the common Idole, and prevailing evill of our
dissolute and degenerous Age”,128 describing them as “the Workes,
and Pompes of the very Devill”129 which deal with “nothing else but
the Adulteries, Fornications, Rapes, Love-passions, Meritricious,
Unchast, and Amorous practices of Lacivious Wicked men”,130 and have
“the Divell himselfe for their author”.131 Prynne condemns dancing as
“unavoydably sinfull and abominable”,132 and further denounces all
“obscene, lacivious, lust-provoking Songs and Poems”,133 “effeminate,
amorous, wanton Musicke”,134 and “May-games, Revels, dancing, and
other unlawfull pastimes on the Lords day”.135 In this environment, “Corinna’s going a Maying” is hardly a light,
conventional piece which can be dismissed as being about merely “the
deceptive capacity of language to contain experience”, or as a piece in
which “textuality replaces sexuality” but all too soon “disintegrates into 462 Love and its Critics a tangle of conflicting concepts, images, and tropes”. In the dark and
dangerous mood of an increasingly agitated and Puritan-influenced
England, “Corinna’s going a Maying” is a radical affirmation of the
simple, flesh-bound, sensual delights of being alive. Celebrating life
against death—especially in an environment in which life is denigrated
as sinful, while death is lauded as a final release from human
wickedness—is in itself a revolutionary act. Herrick’s point of view,
far from being the conventional tangle of predictable, if contradictory
tropes to which Gilead would reduce it, is far-reaching enough that
it anticipates the radical freedom asserted by the twentieth-century
existentialist Albert Camus, for whom the only sin was the sin against
life itself, committed by refusing to live now because of promises or
hopes of another life to come: “For if there is a sin against life, it is
perhaps not so much in despair, as in hoping to have another life, and
evading the implacable grandeur of this one”.136 For Camus, just as for
Herrick, we are physical creatures whose loves, lives, and pleasures
are neither beastly nor angelic, but fundamentally human; and the only
truth worthy of the name lies in the acknowledgement of the ephemeral,
and therefore precious, quality of human life: I realize that there is no superhuman happiness, no eternity outside of
the arc of time. These trivial and basic necessities, these relative truths
are the only things that move me. The others, the “ideals”, I don’t have
soul enough to understand them. 136 Car s’il y a un péché contre la vie, ce n’est peut-être pas tant d’en désespérer que d’espérer une
autre vie, et se dérober à l’implacable grandeur de celle-ci.
Albert Camus. “L’été à Alger”. In his Noces suivi de L’été (Paris: Gallimard, 1959), 49.
137 J’apprends qu’il n’est pas de bonheur surhumain, pas d’éternité hors de la courbe des journées.
Ces biens dérisoires et essentiels, ces vérités relatives sont les seules qui m’émeuvent. Les
autres, les “idéales”, je n’ai pas assez d’âme pour les comprendre. Non qu’il faille faire la bête,
mais je ne trouve pas de sens au bonheur des anges.
Ibid., 47–48. Albert Camus. “L’été à Alger”. In his Noces suivi de L’été (Paris: Gallimard, 1959), 49.
137 J’apprends qu’il n’est pas de bonheur surhumain, pas d’éternité hors de la courbe des journées.
Ces biens dérisoires et essentiels, ces vérités relatives sont les seules qui m’émeuvent. Les
autres, les “idéales”, je n’ai pas assez d’âme pour les comprendre. Non qu’il faille faire la bête,
mais je ne trouve pas de sens au bonheur des anges.
Ibid., 47–48. 136 Car s’il y a un péché contre la vie, ce n’est peut-être pas tant d’en désespérer que d’espérer une
autre vie, et se dérober à l’implacable grandeur de celle-ci.
Albert Camus. “L’été à Alger”. In his Noces suivi de L’été (Paris: Gallimard, 1959), 49.
137 J’apprends qu’il n’est pas de bonheur surhumain pas d’éternité hors de la courbe des journées 138 Lines 37–42, Herrick, Vol. 1, 118, https://books.google.com/books?id=n14JAAAA
QAAJ&pg=PA118
139 The Tempest 4.1.158.
140 Lines 57–70, Herrick, Vol. 1, 119, https://books.google.com/books?id=n14JAAAAQ
AAJ&pg=PA119 the interpretive method approved by William Prynne, a man for whom
no expressions of moral condemnation could go too far: [T]he
obscenity,
ribaldry,
amorousnesse,
heathenishnesse,
and
prophanesse of most Play-bookes, Arcadiaes, and fained Histories that
are now so much in admiration, is such, that it is not lawfull for any
(especially for Children, Youthes, or those of the female sex, who take
most pleasure in them) so much as once to read them, for feare they
should inflame their lusts, and draw them on to actuall lewdnesse,
and prophanesse. Hence Origen, Hierom and others informe us that in
ancient times Children and Youthes among the Jews were not permitted
to read the Booke of Canticles [the Song of Songs] before they came to the
age of 30 years, for feare they should draw those spirituall love passages
to a carnall sence, and make them instruments to inflame their lusts.141 If the old saying is true that you can know someone by the company he
or she keeps, then what are we to make of literary critics (and schools of
criticism) whose working methods and assumptions are so compatible
with those of William Prynne, a man who would shut down theaters,
eliminate dancing, and deny even the reading of poetry to anyone who
is not a male of thirty or older? William Kerrigan once observed that
such ideologically-driven criticism had “disdain for the personal sphere
of existence”, and told an interesting story of a conversation between
academics to illustrate his point: If the old saying is true that you can know someone by the company he
or she keeps, then what are we to make of literary critics (and schools of
criticism) whose working methods and assumptions are so compatible
with those of William Prynne, a man who would shut down theaters,
eliminate dancing, and deny even the reading of poetry to anyone who
is not a male of thirty or older? William Kerrigan once observed that
such ideologically-driven criticism had “disdain for the personal sphere
of existence”, and told an interesting story of a conversation between
academics to illustrate his point: In the days when New Historicism was first in the air a prominent scholar
explained to me over a beer that Herrick’s lyrics on silks and petticoats
were really about the vestment controversies. I must have chuckled. “What do you think they’re about?” the scholar demanded. I shrugged. 141 Prynne, Sig. Aaaaaa2r-Aaaaaa2v, https://archive.org/stream/maspla00pryn#page/912
142 William Kerrigan. “Kiss Fancies in Robert Herrick”. George Herbert Journal, 14: 1–2
(Fall 1990), 157, https://doi.org/10.1353/ghj.1990.0014
143 Ibid. 9. Love and its Costs in Seventeenth-Century Literature Not that we should be like beasts, but
the happiness of angels is meaningless to me.137 For Herrick, the life here and now is perhaps the only truly sacred thing,
and the only “sin” is found in refusing the joys of the sacredness of each
never-to-be-repeated moment: Can such delights be in the street,
And open fields, and we not see’t? And open fields, and we not see’t? 9. Love and its Costs in Seventeenth-Century Literature 463 Come, we’ll abroad; and let’s obey
The Proclamation made for May:
And sin no more, as we have done, by staying;
But my Corinna, come, let’s goe a Maying.138 Should they delay, or miss their chance, they will be showing
themselves unworthy of the precious and rare gifts that this all too
brief existence “rounded with a sleep”,139 offers to those reverent
enough to appreciate them: Should they delay, or miss their chance, they will be showing
themselves unworthy of the precious and rare gifts that this all too
brief existence “rounded with a sleep”,139 offers to those reverent
enough to appreciate them: Come, let us goe, while we are in our prime;
And take the harmlesse follie of the time. We shall grow old apace, and die
Before we know our liberty. Our life is short; and our dayes run
As fast away as do’s the Sunne:
And as a vapour, or a drop of raine
Once lost, can ne’r be found againe:
So when or you or I are made
A fable, song, or fleeting shade;
All love, all liking, all delight
Lies drown’d with us in endlesse night. Then while time serves, and we are but decaying;
Come, my Corinna, come, let’s goe a Maying.140 The passion for life, for love, for the sheer joy of sensation and experience
overflows from this poem like a floodtide overwhelming the shore. Or
so it does, at least, from the point of view of a Peshat style of reading,
based on the “plain sense” hermeneutic of Rashi. However, from the
point of view of Rabbi Akiba, or the early Church father Origen, or the
theological readers devoted to the allegorical reading of texts, or the
countless academic critics who practise a hermeneutics of suspicion,
the poem is a blank canvas, to be written over in ways that suit the
ideological demands of the particular and present moment. 9. Love and its Costs in Seventeenth-Century Literature Such was Love and its Critics 464 the interpretive method approved by William Prynne, a man for whom
no expressions of moral condemnation could go too far: 1
“Tout choix est effrayant, quand on y songe: effrayante une liberté que ne guide
plus un devoir” (André Gide. Les Nourritures terrestres [Paris: Gallimard, 1921], 14). the interpretive method approved by William Prynne, a man for whom
no expressions of moral condemnation could go too far: “Women’s clothes?” Her icy expression let me know in no uncertain
terms that great lyrics could not be attached to such unworthy objects.142 The “icy expression” of the humorless critic is the telling detail. We
need, as Kerrigan notes, to find a way of writing about poems that
“allows them to be what they seem to be”,143 because too many critics
no longer read poetry so much as pillage it, occupy it, and force it to
submit. When we end up looking and sounding like William Prynne, 9. Love and its Costs in Seventeenth-Century Literature 465 a humorless Puritan fanatic and ideologue, perhaps it really is time to
pull back from gazing into the abyss. Carpe diem poetry poses a simple choice. Will you live now, as
you would if there were no laws—either human or divine, secular or
theological—against the joys of life, the joys of love, the joys of living
uninhibitedly in the fullest and most human and embodied sense? Or
will you obey, do as you are told, refrain from the physical and passionate
side of a life that you have been taught is sinful and shameful, spending
your only years on Earth apologizing for being alive, apologizing for
wanting the things you want but are convinced that you should not
want? Will you take off the mind forg’d manacles? Or will you wear
them, for the rest of your life, as you patiently and obediently wait for
death? Choose. © 2017 Michael Bryson and Arpi Movsesian, CC BY 4.0 10. Paradise Lost: Love in Eden, and
the Critics who Obey To choose is not so easy as it sounds. “All choice is frightening, when
one thinks about it: a terrifying liberty, unguided by a greater duty”.1
Choices open some doors, while closing others. New lives, new
possibilities, often come at the expense of other lives now foreclosed or
lost. The wages of choice are death, as every life leads, eventually, to that
ending that may be the only true universal of the human experience—
not the understanding or the experience of the end, but the physical
cessation itself, the transition from animate to inert, from you to it. Authority figures—the imperious gods and kings, the angry Egeuses
and Capulets of the world—insist that choice must be circumscribed,
that only certain choices are allowable or legitimate, even when, as
in the case of the Father in Paradise Lost, they insist that choice itself
must remain free: Not free, what proof could they have giv’n sincere
Of true allegiance, constant Faith, or Love,
Where only what they needs must do appear’d,
Not what they would? What praise could they receive? What pleasure I, from such obedience paid,
When Will and Reason (Reason also is choice)
Useless and vain, of freedom both despoil’d, 1
“Tout choix est effrayant, quand on y songe: effrayante une liberté que ne guide
plus un devoir” (André Gide. Les Nourritures terrestres [Paris: Gallimard, 1921], 14). © 2017 Michael Bryson and Arpi Movsesian, CC BY 4.0 https://doi.org/10.11647/OBP.0117.10 468 Love and its Critics Love and its Critics Made passive both, had serv’d necessity,
Not mee.2 From this perspective, however, the key function of choice is to elicit
praise—praise for one’s obedience, delivered by the authority figure
who takes pleasure in being obeyed. Choice in the ruled, which includes
by design the possibility of choosing not to obey, enhances the pleasures
of power for the ruler. Subjects without choice, without free will, or with
wills so broken as to be no longer functional, offer this kind of sublimely
sadistic ruler no satisfaction: what pleasure I, from such obedience paid? The
pleasure is precisely in the sensation of an active and functioning will
submitting to your own. 2
John Milton. Paradise Lost 3.103–11.
3
Ibid., 3.209–10.
4
Christopher Hill. Milton and the English Revolution (London: Faber and Faber, 1977), 3.
5
William Empson. Milton’s God (Norfolk, CT: New Directions, 1961), 231. 2
John Milton. Paradise Lost 3.103–11. 4
Christopher Hill. Milton and the English Revolution (London: Faber and Faber, 1977), 3.
5
William Empson. Milton’s God (Norfolk, CT: New Directions, 1961), 231. 10. Paradise Lost: Love in Eden, and
the Critics who Obey In the case of those who choose incorrectly,
those who disobey, the necessary and enjoyable response for the ruler is
to inflict punishment, up to and including death: He, with his whole posterity must die,
Die hee or justice must;3 At first glance, Paradise Lost might seem an odd choice with which to
illustrate the primacy of human love and choice, over the imperious
demands of authority that even the most arbitrary of dictates be
unquestioningly obeyed. After all, does not Milton’s epic poem relate
the “tragic” consequences of disobedience to God, representing
Adam’s choice to eat the forbidden fruit along with Eve as foolish, and
uxorious—the result of an excessive and misguided love for Eve over
God? Such is the impression given by much of the criticism of Milton’s
poem, which the English historian Christopher Hill describes as a self-
confirming enterprise “whose vast output appears to be concerned less
with what Milton wrote […] than with the views of Professor Blank on
the views of Professor Schrank on the views of Professor Rank on what
Milton may or may not have written”.4 William Empson compares such
criticism to the kinds of groupthink that insist “a man ought to concur
with any herd in which he happens to find himself”.5 10. Paradise Lost: Love in Eden, and the Critics who Obey 469 In this case, the “herd” has spent decades of scholarly and interpretive
energy convincing itself that Adam’s choice in Paradise Lost, Book 9, is
the “fallen” choice of a disobedient sinner and an effeminate fool. As so
often in the criticism we have encountered, the voice of authority can
be heard loudly and clearly as it pronounces for obedience and against
love. Milton criticism, which Will Stockton calls “a hell of ideological
conservatives”6 is a near perfect example: with a few important
exceptions, the “Milton industry”7 has lined up on the side of God,
obedience, and submission where the question of Adam’s choice is
concerned, many even suggesting that Adam should have been written
differently, so as to make the choice the critic confidently declares the
only possible “correct” decision.8 As Milton writes the scene, Adam is suddenly confronted with an Eve
who has disobeyed the primary injunction given to the first human pair,
not to eat of the fruit from the tree of the knowledge of good and evil. 6
Will Stockton. “An Introduction Justifying Queer Ways”. Early Modern Culture: An
Electronic Seminar. Issue 10. Queer Milton, ed. by Will Stockton and David L. Orvis,
http://emc.eserver.org/1-10/stockton.html
7
Hill 3 8
Peter Herman notes that the trend of critics rewriting Milton goes all the way back to
the seventeenth-and eighteenth-century Cambridge professor and classical scholar
Richard Bentley. “Bentley decided that Milton could not possibly have meant
what got published as Paradise Lost, and so he offered (in the notes) suggestions
for what Milton really meant to write” (Destabilizing Milton: “Paradise Lost” and the
Poetics of Incertitude [New York: Palgrave MacMillan, 2005], 12). Herman further
remarks that though “a distance of 300 years separates […] Bentley from twentieth-
and early-twenty-first-century Milton criticism, the fundamental assumptions
governing the reading of Paradise Lost have remained largely the same” (14). For
Empson, Bentley’s now-infamous 1732 edition of Paradise Lost “makes one feel that
Bentley is trying to write his own poetry” (Some Versions of Pastoral [London: Chatto
& Windus, 1935], 150). And as Gilbert Highet notes, “This was not the last time that
an arrogant professor was to spoil great poetry in the belief that, while the poet had
been blind, he himself could see perfectly” (The Classical Tradition: Greek and Roman
Influences on Western Literature [New York and Oxford: Oxford University Press,
1949], 285). 10. Paradise Lost: Love in Eden, and
the Critics who Obey His reaction, at first, is to silently bemoan her decision to disobey God: Speechless he stood and pale, till thus at length
First to himself he inward silence broke. O fairest of Creation, last and best
Of all God’s Works, Creature in whom excell’d
Whatever can to sight or thought be form’d, 6
Will Stockton. “An Introduction Justifying Queer Ways”. Early Modern Culture: An
Electronic Seminar. Issue 10. Queer Milton, ed. by Will Stockton and David L. Orvis,
http://emc.eserver.org/1-10/stockton.html
7
Hill 3 8
Peter Herman notes that the trend of critics rewriting Milton goes all the way back to
the seventeenth-and eighteenth-century Cambridge professor and classical scholar
Richard Bentley. “Bentley decided that Milton could not possibly have meant
what got published as Paradise Lost, and so he offered (in the notes) suggestions
for what Milton really meant to write” (Destabilizing Milton: “Paradise Lost” and the
Poetics of Incertitude [New York: Palgrave MacMillan, 2005], 12). Herman further
remarks that though “a distance of 300 years separates […] Bentley from twentieth-
and early-twenty-first-century Milton criticism, the fundamental assumptions
governing the reading of Paradise Lost have remained largely the same” (14). For
Empson, Bentley’s now-infamous 1732 edition of Paradise Lost “makes one feel that
Bentley is trying to write his own poetry” (Some Versions of Pastoral [London: Chatto
& Windus, 1935], 150). And as Gilbert Highet notes, “This was not the last time that
an arrogant professor was to spoil great poetry in the belief that, while the poet had
been blind, he himself could see perfectly” (The Classical Tradition: Greek and Roman
Influences on Western Literature [New York and Oxford: Oxford University Press,
1949], 285). 470 Love and its Critics Holy, divine, good, amiable, or sweet! How art thou lost, how on a sudden lost,
Defac’t, deflow’r’d, and now to Death devote? Rather how hast thou yielded to transgress
The strict forbiddance, how to violate
The sacred Fruit forbidd’n!9 It should be noted that Adam thinks this inwardly, relating none of this to
Eve herself. Until this point, he is with the critics whose orthodox frames
of reference lead them to perceive disobedience as the great original sin
that led, once upon a time, to the mixed human condition of joy and
pain, life and loss, hope and despair that is the definition of “fallen”. William Blake, The Temptation and Fall of Eve. 10
https://commons.wikimedia.org/wiki/File:William_Blake_-_The_Temptation_and_
Fall_of_Eve_(Illustration_to_Milton’s_”Paradise_Lost”)_-_Google_Art_Project.jpg 9
Paradise Lost 9.894–904. ,
13
A. J. A Waldock. Paradise Lost and its Critics (Cambridge: Cambridge University
Press, 1947), 56. 11
Paradise Lost 4.427. on with Eve: “God hath pronounc’t it death to taste that Tree”,11 and then
later with the angel Raphael, where he tells the story of what God told him: on with Eve: “God hath pronounc’t it death to taste that Tree”,11 and then
later with the angel Raphael, where he tells the story of what God told him: on with Eve: “God hath pronounc’t it death to taste that Tree”,11 and then
later with the angel Raphael, where he tells the story of what God told him: […] of the Tree whose operation brings
Knowledge of good and ill, which I have set
The Pledge of thy Obedience and thy Faith,
Amid the Garden by the Tree of Life,
Remember what I warn thee, shun to taste,
And shun the bitter consequence: for know,
The day thou eat’st thereof, my sole command
Transgrest, inevitably thou shalt dye.12 Adam, in this crisis moment, has nothing more than these words to fall
back on, and is thus certain that Eve will die. And as A. J. A. Waldock
notes, “it seems hardly fair to blame [Adam] for taking God at his word”.13 Adam, in this crisis moment, has nothing more than these words to fall
back on, and is thus certain that Eve will die. And as A. J. A. Waldock
notes, “it seems hardly fair to blame [Adam] for taking God at his word”.13 As Adam stands before Eve, still processing the gravity of her choice,
and the consequences that have been threatened for doing precisely
what Eve has now done, he decides, in the space of perhaps only the
shortest of awkward pauses, to face with her whatever will ensue, up to
and including death: […] some cursed fraud
Of Enemy hath beguil’d thee, yet unknown,
And mee with thee hath ruin’d, for with thee
Certain my resolution is to Die;
How can I live without thee, how forgo
Thy sweet Converse and Love so dearly join’d,
To live again in these wild Woods forlorn? 12
Ibid., 8.323–30. 14
Paradise Lost 9.904–16. 10. Paradise Lost: Love in Eden, and
the Critics who Obey Illustration to Milton’s Paradise Lost (1808).10 William Blake, The Temptation and Fall of Eve. Illustration to Milton’s Paradise Lost (1808).10 Adam’s love and admiration for Eve come through clearly in these lines,
even as he decries her decision: she is the “fairest of Creation”, the “last
and best / Of all God’s works”, even though she is—so far as Adam
can tell—“lost” and now “to Death devote”. He believes this latter, of
course, because as he twice relates, the poem’s God has told him that the
penalty for eating the forbidden fruit is death. He speaks of this early 10. Paradise Lost: Love in Eden, and the Critics who Obey 471 on with Eve: “God hath pronounc’t it death to taste that Tree”,11 and then
later with the angel Raphael, where he tells the story of what God told him: Should God create another Eve, and I
Another Rib afford, yet loss of thee
Would never from my heart; no no, I feel
The Link of Nature draw me: Flesh of Flesh,
Bone of my Bone thou art, and from thy State
Mine never shall be parted, bliss or woe.14 […] some cursed fraud
Of Enemy hath beguil’d thee, yet unknown,
And mee with thee hath ruin’d, for with thee
Certain my resolution is to Die;
How can I live without thee, how forgo
Thy sweet Converse and Love so dearly join’d,
To live again in these wild Woods forlorn? Should God create another Eve, and I
Another Rib afford, yet loss of thee
Would never from my heart; no no, I feel
The Link of Nature draw me: Flesh of Flesh,
Bone of my Bone thou art, and from thy State
Mine never shall be parted, bliss or woe.14 472 Love and its Critics Adam thinks all this in silence before he speaks to Eve. And though
the narrative voice of the poem insists that Adam is “fondly overcome
with Female charm”,15 this is the same narrative voice that throughout
the poem demands that readers deny the evidence of what they have
just read, or spin the words in favor of heaven (and thus obedience). This narrative voice is so eager to redirect readers (rather like some
modern critics) that it sometimes simply gets its facts wrong in its rush
to impose the desired spin. For example, at the beginning of Book 4, the
archangel Uriel is able to see through Satan’s disguise because of the
latter’s cloudy and tempestuous emotions: Satan’s “borrow’d visage”
was “marr’d” by “pale, ire, envy, and despair”. The narrative voice
then insists that readers understand that “heav’nly minds from such
distempers foul / Are ever clear”,16 but this turns out to be not quite true:
“ire” lurks in a variety of “heav’nly minds” throughout the poem. The
“ire” of the Son is referred to by Raphael at 6.843. The “just avenging
ire” of God is celebrated by the angels at 7.184. Michael speaks of how
“willingly God doth remit his Ire” at 9.885. The “ire” of the Father is also
spoken of repeatedly by Satan and his followers, and this, perhaps, is
one time when they just might be trusted after all. 15
Ibid., 9.999.
16
Ibid., 4.115–19.
17
John Peter. A Critique of Paradise Lost (New York: Columbia University Press, 1960), 133.
18
Waldock, 46.
19
C. S. Lewis. A Preface to Paradise Lost (London: Oxford University Press, 1942), 69.
20
Ibid., 122. 21
Ibid., 123.
22
Greenblatt, Renaissance Self-Fashioning, 247–48.
23
Adulter est inquit in sua uxore amator ardentior. In aliena quippe uxore ois amor turpis est,
in sua nimius. Sapies uir iudicio debet amare coiugem, no affectu. Reget impetus uoluptatis,
nec praeceps feretur in coitu, nihil est foedius q uxore amare quasi adulteram… nec amatores
uxoribus se exhibeat, sed maritos.
Jerome. Contra Jovinianum (Vienna: Joannes Singrenius, 1516), 43, https://books.
google.com/books?id=SUZRAAAAcAAJ&dq=Contra Jovinianum&pg=PA43
24
Reddy, 3–4.
25
“Vnde a sapientib dictum est, q, omnis amator feruentior est adulter, videlicet
i
li
d
d l
i
ff
i
di
& id
i
i
i on with Eve: “God hath pronounc’t it death to taste that Tree”,11 and then
later with the angel Raphael, where he tells the story of what God told him: Against the insistence of the narrator, John Peter notes that there
is an ambiguity in “fondly” that can be read positively: “Adam falls
‘fondly’—foolishly, lovingly. And we fall with him, sharing his generous
improvidence, trusting his love”.17 Waldock concurs, arguing that “[if]
Adam’s words are permitted to have the meanings that words usually
have in English, these lines mean love”.18 But C. S. Lewis begs to differ. For the great orthodox critic, whose stated ambition about Paradise Lost is
to “prevent the reader from ever raising certain questions”,19 love is not
the correct term. In Lewis’ description, “Adam fell by uxoriousness”,20
and failed the test of absolute value: If conjugal love were the highest value in Adam’s world, then of course
his resolve would have been the correct one. But if there are things that 10. Paradise Lost: Love in Eden, and the Critics who Obey 473 have an even higher claim on a man, if the universe is imagined to be
such that, when the pinch comes, a man ought to reject wife and mother
and his own life also, then the case is altered, and then Adam can do no
good to Eve (as, in fact, he does no good) by becoming her accomplice.21 What is interesting and ironic about Lewis’ stance is how high a bar he sets
for Adam. In dismissing Adam’s love for Eve as “uxoriousness”, Lewis is
working the same mines in which Stephen Greenblatt will later dig when
he characterizes Othello as being too much in love with his wife: Omnis amator feruentior est adulter, goes the Stoic epigram, and Saint
Jerome does not hesitate to draw the inevitable inference: “An adulterer
is he who is too ardent a lover of his wife”. Jerome quotes Seneca: “All
love of another’s wife is shameful; so too, too much love of your own. A wise man ought to love his wife with judgment, not affection. Let
him control his impulses and not be borne headlong into copulation. Nothing is fouler than to love a wife like an adulteress… Let them show
themselves to their wives not as lovers, but as husbands”.22 Jerome’s Latin23 becomes a commonplace of anti-erotic Christian
polemic in the early modern era. y
25
“Vnde a sapientib dictum est, q, omnis amator feruentior est adulter, videlicet
cp no maritali, sed adulterino affectu cōiugē suā accedit, & idē est si coniunx sit 24
Reddy, 3–4. on with Eve: “God hath pronounc’t it death to taste that Tree”,11 and then
later with the angel Raphael, where he tells the story of what God told him: This reflects a long-term attempt by
the Church, which gained momentum among the Gregorian reformers
of the eleventh and twelfth centuries, “to outlaw sexual pleasure for
all Christians”, insisting that sexual pleasure was sinful, and that
even pleasureless sexual encounters in a marriage were enough to
“permanently taint both soul and body”.24 It reappears, in slightly altered
form, in the fifteenth-century Flemish monk Dionysius the Carthusian:
“Therefore, a wise dictum is, that every too-fervent lover is an adulterer,
such that, all things being equal, his [love of his wife] is no marriage,
but like an adulterous passion in its continual approaches, and the same
is the case if the wife is a too-fervent lover of her husband”.25 Calvin Jerome’s Latin23 becomes a commonplace of anti-erotic Christian
polemic in the early modern era. This reflects a long-term attempt by
the Church, which gained momentum among the Gregorian reformers
of the eleventh and twelfth centuries, “to outlaw sexual pleasure for
all Christians”, insisting that sexual pleasure was sinful, and that
even pleasureless sexual encounters in a marriage were enough to
“permanently taint both soul and body”.24 It reappears, in slightly altered
form, in the fifteenth-century Flemish monk Dionysius the Carthusian:
“Therefore, a wise dictum is, that every too-fervent lover is an adulterer,
such that, all things being equal, his [love of his wife] is no marriage,
but like an adulterous passion in its continual approaches, and the same
is the case if the wife is a too-fervent lover of her husband”.25 Calvin Love and its Critics 474 expresses the same idea in the sixteenth century: “a marriage contracted
in the Lord, should not overflow into extremes of wantonness. Ambrose
gravely, but not unworthily noted his opinion, that when a man has no
modesty or dignity in conjugal relations, he is an adulterer with his wife”.26 One might wonder at the continual repetition of this idea by clerics
whose sexuality is ostensibly sublimated into “spiritual” pursuits, and
wonder again at the attractiveness of this idea for presumably “secular”
academic critics, but that would be a book in itself. In the present case,
this seems an unfair standard to apply to Adam’s love for Eve, especially
since in his conversations with Raphael, his mentions of passion are few,
while his mentions of his admiration for Eve’s wisdom and intelligence
are many, indicating a relative standard of values that hardly qualifies
as uxorious. 28
Adorno, Theodore. “Studies in the Authoritarian Personality”. In T. W.
Adorno, Else Frenkel-Brunswik, Daniel J. Levinson, and R. Nevitt Sanford, The
Authoritarian Personality, Vol. I of Studies in Prejudice, ed. by Max Horkheimer
and Samuel H. Flowerman (Social Studies Series: Publication No. III) (New
York: Harper & Brothers, 1950), 199, https://www.scribd.com/doc/35738019/
Adorno-Theodor-W-Studies-in-the-Authoritarian-Personality). p
g
g
y y
pg
27
Alister McGrath. C. S. Lewis A Life: Eccentric Genius, Reluctant Prophet (Carol Stream,
IL: Tyndale House Publishers, 2013), 61–62. 29
John Leonard. Faithful Labourers: A Reception History of Paradise Lost, 1667–1970, Vol.
2. Interpretive Issues (Oxford: Oxford University Press, 2013), 633. viri sui amatrix feruetior” (Dionysius the Carthusian. Epistolarum ac Euangeliorum
[Cologne: Petrus Quentell, 1537], fol. LVII, https://books.google.com/books?id=CqP
4kICSulwC&dq=Epistolarum ac Euangeliorum&pg=PT114). 26
“coniugium in Domino contractum, non in extremam quanque lasciuiam exundare.
Ambrosius graui quidem, sed non indigna sententia notauit, quum vxoris
adulterum vocauit qui in coniugali nullam verecundiae vel honestatis curam habet”
(Jean Calvin. Institutio Christianae Religionis [Geneva: Oliua Roberti Stephani, 1559],
2.8.44, 139, https://books.google.com/books?id=6ysy-UX89f4C&pg=PA139). on with Eve: “God hath pronounc’t it death to taste that Tree”,11 and then
later with the angel Raphael, where he tells the story of what God told him: What relation Lewis’ own attraction to what he calls “the
sensuality of cruelty” (expressed in the form of whipping)27 plays in
his enthusiasm for condemning Adam’s relatively milder passions is
unclear, though perhaps Adorno’s observation is illuminating: “[t]he
individual who has been forced to give up basic pleasures and to live
under a system of rigid restraints, […] is likely not only to seek an object
upon which he can ‘take it out’ but also to be particularly annoyed at the
idea that another person is ‘getting away with something’”.28 Empson disagrees with Lewis’ entire line of thought, arguing, as
John Leonard notes, that “Adam makes the right moral choice when he
chooses to die for love”.29 John Peter agrees, claiming that “the highest 10. Paradise Lost: Love in Eden, and the Critics who Obey 475 degree of human love as we know it, is now the focus of attention, and
Adam and Eve’s speeches emphasize its power. […] Adam’s devotion
to his wife can fairly be called magnificent, and we should be less than
human if we did not admire and honor him for it”.30 And yet, many critics
not only do not “admire and honor him for it”, they actively condemn
Adam for the choice he makes (the choice his poetic creator, following
scripture and existing literary tradition, has him make). As Leonard has
demonstrated, the attitude among modern critics has often been one of
condemnation of Adam’s action along with speculation about what he
should have done, which implicitly is a criticism of Milton for writing
the scene as he did. For these critics, “[t]he question inevitably arises:
‘What else could Adam have done?’ Lewis is the first critic to raise
this question, but he declines to engage with it”.31 In Lewis’ treatment,
the matter is uncertain, but he takes Adam to task for what Waldock
describes as “taking God at his word”: For all Adam knew, God might have had other cards in His hand; but
Adam never raised the question, and now nobody will ever know. […]
Perhaps God would have killed Eve and left Adam “in those wilde
Woods forlorn” […]. But then again, perhaps not. You can find out only
by trying it. 30
Peter, 132.
31
Leonard, 617.
32
Lewis, A Preface to Paradise Lost, 123.
33
Leonard, 624.
34
Irene Samuel. “The Dialogue in Heaven: A Reconsideration of Paradise Lost, III.
1–417”. PMLA, 72: 4 (Sep., 1957), 611.
35
Ibid.
36
Empson, Milton’s God, 189. 32
Lewis, A Preface to Paradise Lost, 123. 34
Irene Samuel. “The Dialogue in Heaven: A Reconsideration of Paradise Lost, III.
1–417”. PMLA, 72: 4 (Sep., 1957), 611.
35
Ibid. on with Eve: “God hath pronounc’t it death to taste that Tree”,11 and then
later with the angel Raphael, where he tells the story of what God told him: The only thing Adam knows is that he must hold the fort,
and he does not hold it.32 Later critics like Irene Samuel, Dennis Burden, and Stanley Fish will, as
Leonard observes, “speculate about missed opportunities and possible
remedies”.33 Samuel argues that Adam should “have risked himself to
redeem Eve”,34 going on to argue that he should have maintained “faith
that the benevolence he had always known would remain benevolent”,35
a pious observation that Empson wryly counters with his own remark
that Paradise Lost’s “God is […] peculiarly unfitted to inspire trust”.36
Burden asserts that Adam should have divorced Eve, an astounding
rewriting of a poem in which such a concept does not even exist: “the Love and its Critics 476 important thing is that Adam has a remedy and Milton of all people
must know it,37 and “[w]hat he should do is leave her. He would have
good grounds for divorce”.38 Yes, by all means, divorce her and leave her to
die. A better summation of the “less than human” responses of all too
many critics to this scene is quite nearly impossible to find. At this point, it is necessary to ask on what basis critics ground
their contentions about what Adam should have done, rather than
what he does. For example, consider Samuel’s insistence—as Leonard
describes it—that “Adam could have (and should have) saved Eve by
dying in her place”.39 What indication do readers have that God would
have accepted such an arrangement, and what is more, kept his word
about it? His rhetoric is absolute—“Die hee or Justice must”40—and the
Son even has difficulty in corralling God into an agreement to show
mankind “Mercy”41 in exchange for his own torture and execution. This
does not sound like the kind of character likely to show anything like
understanding or lenience for Eve, despite the arguments of what must
finally be called the Obedience Chorus in Milton studies. Rather than a
ruler that would offer mercy, Paradise Lost’s God seems rather more like
Angelo from Shakespeare’s Measure for Measure, a character who would
accept Adam’s sacrifice, then kill Eve anyway. But not to be outdone in his enthusiasm for obedience, Stanley Fish takes
the argument for what Adam should have done even further than Samuel
or Burden. 37
This is a reference to Milton’s own writings (Doctrine and Discipline of Divorce, among
other works) in an England where Burden’s “remedy” was all but impossible for
most people to obtain. 38
Dennis Burden. The Logical Epic: A Study of the Argument of “Paradise Lost’
(Cambridge, MA: Harvard University Press, 1967), 169–170; also quoted in
Leonard, 643. 40
Paradise Lost 3.210. 42
Leonard, 637. 41
Ibid., 3.134. 39
Leonard, 637. on with Eve: “God hath pronounc’t it death to taste that Tree”,11 and then
later with the angel Raphael, where he tells the story of what God told him: Fish “takes it as axiomatic that a freely chosen Fall cannot be
understood”,42 and then spends hundreds of pages explaining it: If the Fall is explained or “understood” it is no longer free, but the result
of some analysable “process” which attracts to itself a part of the guilt. Thus freedom of will is denied, the obloquy of the action returns to God 10. Paradise Lost: Love in Eden, and the Critics who Obey 477 (who set the process in motion), and again reason—the reader’s reason—
has given law to God.43 According to Fish, we can’t have readers giving law to God, even
though that “God” is merely a literary character.44 For Fish, Adam’s
choice of Eve is selfish—he makes her, in fact, a victim: “for by choosing
her he implicates her in his idolatry, absorbing her into a love that is
self-love”.45 Here, once again, is the what-seems-to-be-X-is-actually-Y
move, as Fish claims that Adam’s romantic outburst is really love of self. Asking “What, then, ought Adam to have done?” Fish acknowledges
that anything other than what Paradise Lost actually gives us “would
seem forced and ‘unnatural’ in comparison to what he does do”.46 Not
to be daunted by a little thing like that, however, Fish goes on to develop
further Samuel’s suggestion that Adam should have interceded with
God on Eve’s behalf: He might have said to Eve, “what you say is persuasive (impregn’d with
reason to my seeming), but I would rather not make such a momentous
decision without further reflection’. Or, as Lewis suggested, he might
have ‘chastised Eve and then interceded with God on her behalf. [Or as
Irene Samuel suggests,] he ‘might, like the Son, have risked himself to
redeem Eve”.47 Fish’s first suggestion demonstrates the wide gap that too often exists
between poet and critic. There is no music in Fish’s would-be emendation,
and one almost gets the sense that Fish is ridiculing his own suggestion
by the time the word “impregn’d” lumbers along. His second and third
suggestions follow other critics with whom Fish shares a desire to
rewrite the scene, and thus the suggestions are simply pointless, unless
the object is to raise the critic above the poetry and to tell readers more
about the critic’s desires, commitments, and complexes than about the
ideas and structures of the poem. 43
Stanley Fish. Surprised by Sin: The Reader in “Paradise Lost”. 2nd ed. (Cambridge,
MA: Harvard University Press, 1998, 256–57.
44
As John Peter rather dryly notes: “this is a character in a poem” (9).
45
Fish, Surprised by Sin, 263.
46
Ibid., 269.
47
Ibid., 269–70. y
44
As John Peter rather dryly notes: “this is a character in a poem” (9).
45
Fi h S
i d b Si
263 43
Stanley Fish. Surprised by Sin: The Reader in “Paradise Lost”. 2nd ed. (Cambridge,
MA: Harvard University Press, 1998, 256–57. 45
Fish, Surprised by Sin, 263. 48
Leonard, 624.
49
Waldock, 30.
50
Dennis Danielson. “Through the Telescope of Typology: What Adam Should Have
Done”. Milton Quarterly, 23: 3 (1989), 121.
51
Ibid., 124.
52
Ibid. 53
Das blutiger Menschenopfer sind in der Tat nur roh-sinnliche Ausdrücke von dem Geheimnissen
der Religion. Wo blutige Menschenopfer Gott dargebracht werden, da gelten diese Opfer für
die höchsten, das sinnliche Leben für das höchste Gut. Deswegen opfert man das Leben Gott
auf, und zwar in außerordentlichen Fällen; man glaubt, damit ihm die größte Ehre zu erweisen.
Ludwig Feuerbach. Das Wesen des Christentums, ed. by Werner Schuffenhauer
(Berlin: De Gruyter, 2006), 446. 58
Gordon Teskey. The Poetry of John Milton (Cambridge: Harvard University Press,
2015), 462. The Milton Society of America recently gave Teskey its highest award for
the book containing this argument. on with Eve: “God hath pronounc’t it death to taste that Tree”,11 and then
later with the angel Raphael, where he tells the story of what God told him: More recent criticism has continued along the lines of Lewis, Samuel,
Burden, and Fish. As Leonard points out, “The question of what Adam 478 Love and its Critics should have done is still an issue in Milton criticism”,48 which, if
anything, indicates the tenuous connection much literary criticism has
to reality. Waldock’s observation that Lewis “declines to acknowledge
the facts of the poem”,49 could be applied much more broadly now than
in 1947. Dennis Danielson pursues the question in this way: Given Eve’s fall, does Adam face a dilemma: either to disobey God or
else to break the bond of human love, whose goodness we perceive as
fundamental? And if Adam has no choice but to reject the sinner with the
sin, or else to accept the sin with the sinner, then will most of us applaud
Adam’s choosing the latter?50 Danielson answers his own questions by saying that Adam “could
have [offered] to take the punishment of fallen humanity on himself, to
fulfill exactly “The law of God”, as Michael puts it in Book 12”.51 And
here, at last, we have a key to understanding the mentality of those
who would rewrite Milton’s scene: obedience and “love” go hand-in-
hand in a way that for Danielson is illustrated by “the analogy between
Adam-and-Eve and Christ-and-the-church”, which according to a
Christianizing critic like Danielson “breaks down precisely at the point
where Adam chooses to sin with Eve rather than sinlessly face death for
her”.52 Danielson manages to turn a scene of intense human emotion,
of love and Adam’s all-too-human realization of how utterly bereft he
would be in a world without Eve, into a scene advertising the obedient
virtues of human sacrifice, dying in supplication rather than defiance. Danielson claims, with all seriousness, that Adam’s love for Eve should
be given its highest form of expression through the same mechanism by
which human beings in the pre-scientific ages of our species have tried
to propitiate the implacable gods for millennia. As Ludwig Feuerbach, the great nineteenth-century critic of Christianity,
puts it, human sacrifice is at the heart of the religious worldview: Bloody human sacrifices are, in fact, the most rawly sensual expressions
of the mysteries of religion. Where bloody human sacrifices are offered 10. Paradise Lost: Love in Eden, and the Critics who Obey 479 to God, they are offered as the highest form of life for the highest good. 57
Gerald Richman. “A Third Choice: Adam, Eve, and Abdiel”. Early Modern Literary
Studies, 9: 2 (September 2003), 6.1–5, https://extra.shu.ac.uk/emls/09-2/richthir.html 56
Ibid., 277. 54
“nur sein menschliches Blut macht Gott barmherzig, stillt seinen Zorn” (ibid., 101)
55
Empson, Milton’s God, 247, 251. 55
Empson, Milton’s God, 247, 251. on with Eve: “God hath pronounc’t it death to taste that Tree”,11 and then
later with the angel Raphael, where he tells the story of what God told him: That’s why one sacrifices life to God, in exceptional circumstances. It is
believed therefore to give him the greatest honor.53 In Feuerbach’s analysis, “only human blood makes God merciful, and
stills his wrath”.54 Such a god, as Empson argues, is not worthy of worship: Men always try to imitate their gods, so that to worship a wicked one
is sure to make them behave badly. But no god before had ever known
before how to be so eerily and profoundly wicked. […] The Christian
God, the Father, the God of Tertullian, Augustine and Aquinas, is the
wickedest thing yet invented by the black heart of man.55 Nor is a literary representation of such a God—the Father of Paradise
Lost—worthy of the sacrifice of one of the poem’s human characters,
or the strangely submissive admiration of literary critics. In Empson’s
closing phrase, “If you praise it as the neo-Christians do, what you are
getting from it is evil”.56 More recent critics have persisted in arguing that the poem should
be other than it is, and that Adam should choose differently than he
does. Gerald Richman argues that Adam should have remonstrated
with Eve in the way that Abdiel does with Satan in Book 5 of Paradise
Lost. Richman claims that “if Eve had repented and Adam had refused
to join her in sin, Eve would have found pardon”.57 Gordon Teskey
argues that “Adam should trust God to find a better solution than his
own. He forgot to trust, and might have remembered to if he had taken
more time”,58 as if Milton’s Adam is standing there with Eve muttering,
“wait, I’m forgetting something…Eve, can you give me a minute?…I’ve Love and its Critics 480 got it! 63
David Quint. Inside Paradise Lost: Reading the Designs of Milton’s Epic (Princeton:
Princeton University Press, 2014), 153.
64
Ibid., 178. 62
The (probably misnamed) critic described by Aristotle (Poetics, 1461a, 22–23) as
trying to save Zeus’ honesty by suggesting that “δίδομεν” should be changed to
“διδόμεν” in the speech in which Zeus sends a dream to Agammenon in Book 2
of the Illiad. y
61
Teskey seems to try having it both ways, however. Not long after arguing that
Adam “forgot to trust”, he goes on to claim that “Adam’s decision to remain with
Eve is moving, and surely right”. He then maintains that “[t]he place of criticism
is not to take sides at such moments” (464), a high-minded and disingenuous
statement coming from someone who just took sides two pages earlier by arguing
(very much in the tradition of Lewis, Samuels, Fish, and Danielson) that Adam
should have chosen otherwise than he did. That’s exactly what “tak[ing] sides at
such moments” looks like. 59
Richard III, 4.2.114.
60
Teskey, xiii.
61
Teskey seems to try having it both ways, however. Not long after arguing that
Adam “forgot to trust”, he goes on to claim that “Adam’s decision to remain with
Eve is moving, and surely right”. He then maintains that “[t]he place of criticism
is not to take sides at such moments” (464), a high-minded and disingenuous
statement coming from someone who just took sides two pages earlier by arguing
(very much in the tradition of Lewis, Samuels, Fish, and Danielson) that Adam
should have chosen otherwise than he did. That’s exactly what “tak[ing] sides at
such moments” looks like.
62
The (probably misnamed) critic described by Aristotle (Poetics, 1461a, 22–23) as
trying to save Zeus’ honesty by suggesting that “δίδομεν” should be changed to
“διδόμεν” in the speech in which Zeus sends a dream to Agammenon in Book 2
of the Illiad.
63
David Quint. Inside Paradise Lost: Reading the Designs of Milton’s Epic (Princeton:
Princeton University Press, 2014), 153.
64
Ibid., 178. 60
Teskey, xiii. 65
Stanley Fish. How Milton Works (Cambridge, MA: Belknap Press of Harvard
University Press, 2001), 53.
66
“If Adam was Perfect, How Was It Possible for Him to Sin?” The Watchtower, 129: 19
(1 October 2008), 27, https://wol.jw.org/en/wol/d/r1/lp-e/2008733 on with Eve: “God hath pronounc’t it death to taste that Tree”,11 and then
later with the angel Raphael, where he tells the story of what God told him: I should trust God!” The continuing insistence that the literary
character called God in Paradise Lost is in what Richard of Gloucester
might call the “[for]giving vein”59 is astounding, and while Teskey
claims that he finds himself “a little bored by […] discussions of the
frigidity, or the wickedness, or the goodness of Milton’s God”,60 here
he lays his cards on the table: Adam should have remembered to trust
what Teskey (following along with Lewis, Samuel, Burden, Fish, and
Danielson) simply assumes is a good and merciful “God”.61 And so the
Hippias of Thasos-styled rewriting of the poem in the image of its more
pious critics62 goes on and on (Teskey even refers back to C. S. Lewis as
he delivers his judgment). David Quint argues a more humane case, writing that Adam’s is
“an act that combines marital love, human solidarity, and Adam’s fear
of repeating his earlier loneliness before Eve’s creation”,63 thus taking
at least a brief break from the decades-long trend of moralizing over,
and rewriting, Milton’s scene. Quint emphasizes that it is “the force
of his love [that] causes Adam to stay by [Eve’s] side”, and describes
the narrative voice that accuses Adam of being “fondly overcome”
as “censorious”.64 But despite Quint’s more sympathetic reading, the
Obedience Chorus has not left the stage, and perhaps never will; for
as long as there are those among us who are more comfortable when
subordinate to another—or who benefit from such subordination —
there will be those who argue for necessary and natural subordination. Such ideas go back as far as Aristotle, thus it is no surprise to see Stanley 10. Paradise Lost: Love in Eden, and the Critics who Obey 481 Fish, as recently as in 2001’s How Milton Works, arguing that obedience
is Milton’s single overarching idea: In Milton’s world, however, there are no moral ambiguities, because
there are no equally compelling values. There is only one value—the
value of obedience—and not only is it a mistake to grant independence
to values other than the value of obedience, it is a temptation. on with Eve: “God hath pronounc’t it death to taste that Tree”,11 and then
later with the angel Raphael, where he tells the story of what God told him: Indeed,
it is the temptation—the temptation to seek a separate, self-sustaining
existence—that Milton obsessively explores.65 A poet who sees the world as a simple matter of obedience and
disobedience has done something rather odd in writing an epic poem
in which he does nearly everything possible to convince readers that
such things are not so simple as moralists like Fish claim (Fish will say,
of course, that the idea that things are not simple is “a temptation”). A
poet for whom “there are no equally compelling values” (at least when
compared to the delights of obedience and submission) has done an
even odder thing by writing a long work in which compelling values are
put into nearly constant conflict and competition. But those who see the poetry of Donne as “sick” will go on doing so,
just as those who see the poetry of a revolutionary as a nearly endless
hymn singing the praises and glories of obedience will go on doing so. In fact, the entire trend of critics insisting that Milton’s Adam should
have chosen otherwise than he does, resembles nothing so much as
fundamentalist Christian thinking. Consider this passage on the same
subject from The Watchtower, the publication arm of the Jehovah’s
Witnesses: Adam decided to accede to the wishes of his wife, who had already
chosen to eat from the forbidden tree. His desire to please her was greater
than his desire to obey his Creator. Surely, upon being presented with
the forbidden fruit, Adam should have paused to reflect on the effect that
disobedience would have on his relationship with God. Without a deep,
unbreakable love of God, Adam was vulnerable to pressure, including
that from his wife.66 482 Love and its Critics Given the difficulty of telling the difference between evangelists and
academics on this topic, it is tempting to conclude that there has
been little or no progress in the treatment of poetry over the last two
millennia. Critics who make an interpretive principle out of faith in an
authoritarian deity are not to be reasoned with, any more than they
aim to reason about the faith they seek to impose on poetry. 67
David Hawkes. John Milton, A Hero of Our Time (Berkeley: Counterpoint Press,
2009), 10.
68
Hawkes, 12.
69
Ibid., 12, 13.
70
Terry Eagleton. Literary Theory: An Introduction (Oxford: Blackwell, 1983), 34. 67
David Hawkes. John Milton, A Hero of Our Time (Berkeley: Counterpoint Press,
2009), 10.
68
H
k
12 70
Terry Eagleton. Literary Theory: An Introduction (Oxford: Blackwell, 1983), 34. 69
Ibid., 12, 13. 69
Ibid., 12, 13.
70
Terry Eagleton. Literary Theory: An Introduction (Oxford: Blackwell, 1983), 34. on with Eve: “God hath pronounc’t it death to taste that Tree”,11 and then
later with the angel Raphael, where he tells the story of what God told him: As David
Hawkes argues, “the habits of thought developed by slavery are easily
formed and hard to break”.67 That we seem to have forgotten, or deliberately elided, Milton’s
status as a revolutionary—not a stiff-collared Puritan or a humorless
William Prynne-style ideologue who never met a human joy he did
not condemn—is an ironic testament to the increasingly authoritarian
political character of our own time. It was not always so, as Hawkes
reminds us: The Romantic poets worshipped him; Byron, Keats and Shelley were
restrained from making him a god only by his own stern injunctions against
idolotry. Wordsworth called for a Miltonic response to the industrial age
[…]. The founding fathers of America saw themselves as completing the
Miltonic reforms that had been thwarted in England. Karl Marx cited
him as the ultimate exemplar of unalienated human activity.68 And yet somehow, today, Milton has been transformed into a prophet
of obedience, a preacher of original sin, and a poet whose work inspires
the crushing authoritarianism reflected in numerous critics’ assertions
that Adam should choose obedience over love. In Hawkes’s view, this
transformation began with “a critical campaign waged in the early
twentieth century by T. S. Eliot and F. R. Leavis”, who were “nostalgic
for the world [Milton] helped to destroy”.69 Eliot, a poet and critic whose
“solution”, is “an extreme right-wing authoritarianism” in which “men
and women must sacrifice their petty ‘personalities’ and opinions to
an impersonal order”,70 provides a template for the history of Milton
criticism in the twentieth century and until very recently in the twenty-
first. This history has been dominated (with notable exceptions like 10. Paradise Lost: Love in Eden, and the Critics who Obey 483 Empson, Waldock, and a small number of other outliers) by a sustained
effort to put the revolutionary back into the box of conformity. Is it any
wonder that “Milton is now read mostly by reluctant undergraduates”,
and “retains a precarious position on university curriculums”, while “the
popular audience he enjoyed for centuries has largely evaporated”?71 Such critics argue in a style Bob Altermeyer describes as High Right-
Wing Authoritarianism, which demonstrates a “tendency to disengage
critical thinking when considering religion”, and rewards “placing faith
over reason”.72 Fish’s argument that “affirming God is not something
you do on the basis of evidence”, but is instead “something you do
against the evidence”,73 is a perfect example. 71
Hawkes, 12.
72
Altermeyer, 104.
73
Fish, How Milton Works, 10.
74
Authoritarians do not spend a great deal of effort “examining evidence, thinking
critically, reaching independent conclusions […]. Instead, they have largely
accepted what they were told by the authorities in their lives” (Altermeyer 93).
75
John Milton. Areopagitica. London, 1644, Sig.D2v, 26, https://books.google.com/
books?id=tvhAAQAAMAAJ&pg=PA26 73
Fish, How Milton Works, 10. 72
Altermeyer, 104. 74
Authoritarians do not spend a great deal of effort “examining evidence, thinking
critically, reaching independent conclusions […]. Instead, they have largely
accepted what they were told by the authorities in their lives” (Altermeyer 93). 75
John Milton. Areopagitica. London, 1644, Sig.D2v, 26, https://books.google.com/
books?id=tvhAAQAAMAAJ&pg=PA26 71
Hawkes, 12. 76
Altermeyer, 99.
77
Ibid., 96.
78
Ibid., 104. on with Eve: “God hath pronounc’t it death to taste that Tree”,11 and then
later with the angel Raphael, where he tells the story of what God told him: It is an argument for
the suspension of reason in favor of unreason. According to this line
of unreason, God—for whom there is no evidence that is not always
already trapped within a circular argument—must be taken as the
foundational principle of a world for which there is evidence. At best,
this is merely begging the question, taking the desired conclusion as
part of the evidence for the desired conclusion, a maneuver that would
not pass muster in an undergraduate essay, much less the magnum
opus of a half-century-long career of critical writing about literature and
culture. But at worst, it is classic authoritarian thinking, an insistence that
evidence does not matter because the truth has already been provided
by authority.74 A style of thinking more different from Milton’s own is
inconceivable: “A man may be a heretick in the truth; and if he beleeve
things only because his Pastor sayes so, or the Assembly so determins,
without knowing other reason, though his belief be true, yet the very
truth he holds, becomes his heresie”.75 Insisting that the man who stood
up for reason must be understood as advocating for unreason, and
that the revolutionary argues for submission at any price (even to God)
simply makes no sense. 484 Love and its Critics 77
Ibid., 96. 76
Altermeyer, 99. Love and its Critics But, as we have now seen again and again, the argument does not
need to make sense; it merely needs to be asserted with enough eloquent
force that the poetry can be bent to the critic’s will. Obedience is the
principle through which Fish and numerous other critics will work
to tame Milton’s poetry, taking the scene in which Adam chooses Eve
over God, and turning it into something that celebrates the virtues of
obedience through the absence of obedience in the scene. Such manifest illogic
dovetails nicely with Altermeyer’s findings that authoritarian thinkers
“contradict themselves more often than [others], and apparently do not
notice it”.76 As an example, he relates an experience with his psychology
students at the University of Manitoba: I asked students what they thought of Jesus’ admonition […], “Do
not judge, that you may not be judged. For with what judgment you
judge, you shall be judged” (Matthew 7:1). I also asked about Jesus’
resolution […]: “Let he who is without sin among you be the first to
cast a stone at her”. Twenty […] said we should take the teachings
literally. Twenty-seven [others] said we should judge and punish others,
but none of them explained how they reconciled this view with Jesus’
teachings. Apparently, they “believed” both (contradictory) things. But
the kicker came when I looked at various measures of authoritarian
aggression I had gathered from these students. No matter what they said
they believed, both these groups […] were quick with the stones on the
Attitudes towards Homosexuals Scale, [and] the Ethnocentrism Scale.77 What Altermeyer’s anecdote illustrates is the attractiveness, for
authoritarian thinkers, of judgment and punishment of perceived
offenders, a tendency that “extends beyond religion and has deeper
roots, namely, authoritarian submission”.78 The deeply authoritarian
strain in Milton criticism comes nowhere more sharply into focus than
in the long-sustained argument that Adam should have submitted,
and chosen Authority (God) over Love (Eve). Why has the rhetorical
window of Milton criticism shifted so far, and for so long, to the right,
into authoritarian reverence for submission and power? Why has the
work of a regicide and revolutionary been so thoroughly co-opted by
a reactionary insistence that Milton is not “a man who embraces the
Hierarchical principle with reluctance, but rather [is] a man enchanted 10. y
81
Oscar Wilde. The Soul of Man under Socialism (Portland: Thomas B. Mosher, 1905),
11. 80
See Bryson, The Atheist Milton, 75–76. 79
Lewis, A Preface to Paradise Lost, 78.
80
See Bryson, The Atheist Milton, 75–76.
81
Oscar Wilde. The Soul of Man under Socialism (Portland: Thomas B. Mosher, 1905),
11.
82
Paradise Lost 8.530–33. 80
See Bryson, The Atheist Milton, 75–76.
81
Oscar Wilde. The Soul of Man under Socialism (Portland: Thomas B. Mosher, 1905),
11.
82
Paradise Lost 8.530–33. 79
Lewis, A Preface to Paradise Lost, 78. y
Oscar Wilde. The Soul of Man under Socialism (Portland: Thomas B. Mosher, 1905),
11 82
Paradise Lost 8.530–33. Love and its Critics Paradise Lost: Love in Eden, and the Critics who Obey 485 by it”?79 The lovers of authority, it seems, see that love in others wherever
and whenever possible. It is by such principles, and in such hands, that poems about love
between human beings become poems of love for God. It is by such
principles, and in such hands that Romeo and Juliet comes to be described
as part of a system of hegemony and oppression. And it is by such
principles, and in such hands, that an epic poem defining disobedience
as its hero’s most noteworthy trait80 comes to be twisted into an ornate
tract that genuflects to the glories of obedience. But as Oscar Wilde
remarks, it is “[d]isobedience” that “in the eyes of anyone who has read
history, is man’s original virtue”. Not only that, but “[i]t is through
disobedience that progress has been made, through disobedience and
through rebellion”.81 And so it is with Milton’s Adam. The attentive
reader of the poem who has not yet been overmuch addled by criticism
is by no means surprised by Adam’s choice. In writing this scene,
Milton is more Ovid than Virgil, despite the critics for whom obedience,
sovereignty, and the glory of a heavenly Augustus are the prime virtues
of life and poetry. In fact, the poem has prepared the reader for this
choice, not just by following the bare outlines of the story as presented
in Genesis 3, but through the characterization of Adam and his
tempestuous emotions—feelings he seeks advice about from precisely
the wrong person, but also the only available person: the angel Raphael. g p
y
p
g
p
In Book 8, Adam tries to explain to the alien creature (who hasn’t
the slightest clue what it is like to be human) what and how he feels
about Eve, and admits that he does not always know how to handle
those feelings, while at the same time telling the angel that the lessons
God has taught him do not always seem to match the facts of his
experience. 83
Lewis, A Preface to Paradise Lost, 112.
84
Paradise Lost 8.540–46. 83
Lewis, A Preface to Paradise Lost, 112. 84
Paradise Lost 8.540–46. Love and its Critics With Eve: […] passion first I felt,
Commotion strange, in all enjoyments else
Superior and unmov’d, here only weak
Against the charm of Beauty’s powerful glance.82 486 Love and its Critics This sensation of weakness—which any human being who has lived
through adolescence will recognize as among the signs of passionate
love and desire—is one Adam has insufficient experience to handle. He
is a boy who often pretends to a knowledge and confidence he does
not possess, in the mold of Shakespeare’s Valentine or Romeo, despite
Lewis’ claim that both he and Eve “were never young, never immature
or undeveloped”, but were “created full-grown and perfect”.83 This
bright but unseasoned boy admits that he is not at all sure that what he
has been taught by God—another wholly alien life form—makes sense
when compared to the experience of being a human male. And as, in the
logic of the poem, Adam is the only one of these creatures who has ever
existed, he is the only one who can speak with anything other than the
hollow insistences of the ideologue about what is as opposed to what
should be. As Adam explains it, he has been told one thing by God: For well I understand in the prime end
Of Nature her th’ inferior, in the mind
And inward Faculties, which most excel,
In outward also her resembling less
His Image who made both, and less expressing
The character of that Dominion giv’n
O’er other Creatures;84 But his own experience tells him quite another thing, throwing the
accuracy of his school-lesson in doubt: yet when I approach
Her loveliness, so absolute she seems
And in herself complete, so well to know
Her own, that what she wills to do or say,
Seems wisest, virtuousest, discreetest, best;
All higher knowledge in her presence falls
Degraded, Wisdom in discourse with her
Looses discount’nanc’t, and like folly shewes;
Authority and Reason on her waite,
As one intended first, not after made 487 10. 86
At this point, Milton is giving his Adam a set of observations about Eve’s possible
superiority to him that has long been part of Renaissance thought by the time of
Paradise Lost. Juan Rodríguez de la Cámara expresses similar ideas in 1438, in Triumph
of Women (Triunfo de las Donas). Speaking of the creation story of Genesis 2, in which
woman is created after man, Rodríguez writes that “The less noble creatures were
created first and foremost in the world, and the most noble later, so that the more
noble could be served by the hordes of the less noble” (“las criaturas menos nobles
ayan seydo primeramente en el mundo criadas, e las mas nobles vltimamente, por
que las menos nobles pudiesen por horden alas mas nobles seruir”) (Juan Rodríguez
de la Cámara. Triunfo de las Donas. In Obras de Juan Rodríguez de la Cámara: (ó del
Padrón), ed. by Antonio Paz y Meliá [Madrid: La Sociodad de Bibliofilos Españoles,
1884], 88, https://archive.org/stream/ObrasJuanRodriguezCamara/Obras_de_Juan_
Rodriguez_de_la_Camara#page/n133). Cornelius Agrippa argued that “Woman is
the ultimate end of creation, the most perfect accomplishment of all God’s works”
(“mulier sit ultima creaturarŭ, ac finis, & cŏplementŭoĭm operŭ Dei perfectisimŭ”)
(De Nobilitate et Praecellentia Foeminei Sexus. Antwerp: Michael Hillenius, 1529, Sig.
A6r, https://books.google.com/books?id=ZoQNUzFZ5UEC&pg=PT12). 85
Ibid., 8.546–59. Love and its Critics Paradise Lost: Love in Eden, and the Critics who Obey Occasionally; and to consummate all,
Greatness of mind and nobleness thir seat
Build in her loveliest, and create an awe
About her, as a guard Angelic plac’t.85 What Adam is asking for, begging for, is some practical help with how
to deal with his feelings and what to make of the fact that his experience
of Eve does not match the lessons he has been given.86 The theory is not
matching the practice, and there is nothing in the textbook, so to speak,
to help him deal with his confusion. What Adam desperately needs at
this point is a human father—not a self-aggrandizing alien a being calling
itself “the Father” who insists on being obeyed and worshipped without
demonstrating either the slightest understanding of, or concern with,
the actual experiences of its creations. In the absence of that, at least
Adam could use a big brother—again, a human figure who has been
through what Adam is going through. But Adam gets nothing besides
lectures delivered by bloodless aliens who have experienced none of
his confusions, and regard his questions as disturbing deviations from
the approved curriculum. Certainly, Raphael demonstrates neither
understanding nor sympathy: Accuse not Nature, she hath done her part;
Do thou but thine, and be not diffident
Of Wisdom, she deserts thee not, if thou Accuse not Nature, she hath done her part;
Do thou but thine, and be not diffident
Of Wisdom, she deserts thee not, if thou 488 Love and its Critics Dismiss not her, when most thou needst her nigh,
By attributing overmuch to things
Less excellent, as thou thy self perceiv’st. For what admir’st thou, what transports thee so,
An outside?…
[…]
But if the sense of touch whereby mankind
Is propagated seem such dear delight
Beyond all other, think the same voutsaf’t
To Cattle and each Beast; which would not be
To them made common and divulg’d, if aught
Therein enjoy’d were worthy to subdue
The Soule of Man, or passion in him move.87 Raphael simply ignores “everything in what Adam has said that is at
all inconvenient”;88 in fact, Raphael appears neither to understand, nor
care to understand, Adam’s point. 87
Paradise Lost, 8.561–68, 579–85.
88
Waldock, 44.
89
Ibid. 87
Paradise Lost, 8.561–68, 579–85. 88
Waldock, 44. 87
Paradise Lost, 8.561–68, 579–85.
88
Waldock 44 Love and its Critics Adam is saying that Eve seems better
and wiser than he has constantly been told she is, and that “what she
wills” generally seems to be the right, best, and smartest thing to do. He
says nothing about sex in his conversation with Raphael, and yet that is
immediately what the alien leaps to: not just sex, but cow sex. Raphael’s
response to Adam’s urgent emotional confusion is to compare him to a
cow (or a bull, though it is by no means certain the alien really knows the
difference). Raphael’s rhetoric is outlandish, and he “willfully misses
the point”.89 The shame is that all too many critics are akin to Raphael;
perhaps if they were not, Milton’s failure to have written the scene of
Adam’s choice in the way that meets with their approval would not be
so continually disappointing to them. But a reader who is not a determined rewriter of the poem knows
what to expect from Adam at the critical juncture. Adam will make
the choice he was designed to make—the decision he was intended
to make by his poet. Adam will choose Eve over God, love over
obedience. After his shock at Eve’s action, his pause for thought, and
his silent decision for humanity over alien demands for obedience, 10. Paradise Lost: Love in Eden, and the Critics who Obey 489 Adam delivers a speech that none of Milton’s impassively virtuous
critics could have written, or even conceived. He confirms that he will
not be parted from her, despite God, despite Death, because he values
his love for her above all other considerations: I with thee have fixt my Lot,
Certain to undergo like doom, if Death
Consort with thee, Death is to mee as Life;
So forcible within my heart I feel
The Bond of Nature draw me to my owne,
My own in thee, for what thou art is mine;
Our State cannot be sever’d, we are one,
One Flesh; to lose thee were to lose myself.90 And so the choice is made, and human life as we know it is begun. What
humankind has joined together, no God will put asunder. Adam will
have his weak and petulant moments after making this choice; most of
Book 10 is dedicated to Adam’s doubts and recriminations. 90
Paradise Lost 9.952–59. Love and its Critics But the fact
remains that Adam made the truly human choice; not just the only one
the source story allows for, but the only one that shows humanity—
in all its weaknesses and shortcomings—as a noble enterprise worth
rooting for. No reader should be surprised by this choice. It is the choice that
much of the literature we have dealt with here illustrates, and it is the
choice made in other treatments of the Edenic scene written before
Milton’s poem. The path of Christian in John Bunyan’s Pilgrim’s Progress,
running away from his wife and children, sticking his fingers in his ears
so as not to able to hear their cries, while crying out Life! Life! Eternal
Life! is not Milton’s way, though it seems to be the way of many of his
critics. Milton’s choices are more akin to those of Hugo Grotius, who
in his Latin drama Adamus Exul (Adam in Exile) of 1601, portrays the
scene of Adam’s choice in terms similar to those that will later feature
prominently in Paradise Lost. After a long debate with Eve, and with his
own doubts, Grotius’ Adam chooses Eve over God: 490 Love and its Critics Quid est agendum? lubricas agitant duo
Curas amores: hinc Dei, atque hinc conjugis:
[…]
Quid huîc negandum? vilis unius tibi
Iactura pomi est. Ut ne contemnam boni
Legem parentis? Fallor? an voluit Deus
Conjugis amores anteserri caeteris
Etiam parentum? Voluit: huc Pommum mihi.91 What should I do? A dangerous provocation in two
Cares and loves: for God and for my wife:
[…]
Which shall I deny? Worthless to you is the loss
Of one apple. Should I condemn the good
Parental law? Am I mistaken? Is it not God’s will
That marital love shall be preferred over all others,
Even of parents? It is his will: give me the apple. Later, Adam, amidst his doubts about whether or not he has done the
right thing, decides that he will continue to choose Eve no matter the
consequences: “What can I deny to you, my wife? 91
Hugo Grotius. Hugonis Groth Sacra in quibus Adamus exul tragoedia (Hague:
Alberti Henrici, 1601), Act IV, 54–55, https://books.google.com/books?id=pR
Y_AAAAcAAJ&pg=PP72 92
“…quid tibi, cunjux, negen? / Iubente te vel jussa contemnam Dei, / Iubente
te vel sustinebo vivere” (ibid. Act V, 68, https://books.google.com/books?id=
pRY_AAAAcAAJ&pg=PP86). 93
Authoritarians “want a God to exist as the absolute authority to which they can
bow, [and the] concept of God underlying this way of thinking is that of the
absolute essence of punitiveness” (T. Adorno. “Studies in the Authoritarian
Personality”,
444,
https://www.scribd.com/doc/35738019/Adorno-Theodor-W-
Studies-in-the-Authoritarian-Personality). 91
Hugo Grotius. Hugonis Groth Sacra in quibus Adamus exul tragoedia (Hague:
Alberti Henrici, 1601), Act IV, 54–55, https://books.google.com/books?id=pR
Y_AAAAcAAJ&pg=PP72
92
“…quid tibi, cunjux, negen? / Iubente te vel jussa contemnam Dei, / Iubente
te vel sustinebo vivere” (ibid. Act V, 68, https://books.google.com/books?id=
pRY_AAAAcAAJ&pg=PP86).
93
Authoritarians “want a God to exist as the absolute authority to which they can
bow, [and the] concept of God underlying this way of thinking is that of the
absolute essence of punitiveness” (T. Adorno. “Studies in the Authoritarian
Personality”,
444,
https://www.scribd.com/doc/35738019/Adorno-Theodor-W-
Studies-in-the-Authoritarian-Personality). 94
Giambattisti Andreini. L’Adamo, ed. by Ettore Allodoli (Lanciano: Carabba, 1913),
3.1.1839–57, 1907–11, https://archive.org/stream/ladamoand00andruoft#page/78,
https://archive.org/stream/ladamoand00andruoft#page/80 Love and its Critics / At your bidding, I
will condemn the justice of God; / At your bidding, I will go on living”.92 The consequences follow immediately, of course, so those who not only
insist on, but seem to revel in the punishments inflicted on humanity for
daring to chart its own course needn’t worry overmuch.93 But the point has
been the choice—far more elaborate than the one found in Genesis 3.6: וַתֵ ּ ֣ רֶ א הָֽ אִ שָ ּׁ ֡ ה כִ ּ ֣ י טֹוב֩ הָעֵ֨ ץ לְמַאֲכָ֜ ל וְכִ֧י תַֽ אֲוָה־ ה֣ ּוא לָעֵינַ֗יִם וְנֶחְ מָ֤ד הָעֵץ֙ לְהַשְ ׂכִ ּ ֔ יל וַתִ ּקַּ ֥ ח מִ פִ ּרְ יֹ֖ו וַתֹּאכַ֑ל
וַתִ ּתֵ ּ ֧ ן גַּם־ לְאִ ישָ ׁ ֛ ּה עִ מָּ ֖ ּה וַיֹּאכַֽל׃ וַתֵ ּ ֣ רֶ א הָֽ אִ שָ ּׁ ֡ ה כִ ּ ֣ י טֹוב֩ הָעֵ֨ ץ לְמַאֲכָ֜ ל וְכִ֧י תַֽ אֲוָה־ ה֣ ּוא לָעֵינַ֗יִם וְנֶחְ מָ֤ד הָעֵץ֙ לְהַשְ ׂכִ ּ ֔ יל וַתִ ּקַּ ֥ ח מִ פִ ּרְ יֹ֖ו וַתֹּאכַ֑ל
וַתִ ּתֵ ּ ֧ ן גַּם־ לְאִ ישָ ׁ ֛ ּה עִ מָּ ֖ ּה וַיֹּאכַֽל׃ And when the woman saw that the tree was good for food, and that it
was pleasant to the eyes, a tree desirable to look at and gain insight from, And when the woman saw that the tree was good for food, and that it
was pleasant to the eyes, a tree desirable to look at and gain insight from, 10. Paradise Lost: Love in Eden, and the Critics who Obey 491 she took from its fruit and ate, and gave it also to the man who was with
her, and he ate. Genesis makes little of Adam’s choice, and makes comparatively little
of Eve’s. There is no tortured questioning, deep soul-searching, or
weighing of comparative values. There is desire for the fruit, for the
wisdom the fruit was thought to offer, and a quick decision to eat. Eve
eats, then gives the fruit to Adam, “who was with her”, and he eats as
well. But for Grotius, the scene is one of agonizing choices. Similarly,
in L’Adamo, an Italian play of 1613, Adam’s decision to eat the fruit is
passionate, agonizing, and lengthy: Genesis makes little of Adam’s choice, and makes comparatively little
of Eve’s. There is no tortured questioning, deep soul-searching, or
weighing of comparative values. Love and its Critics There is desire for the fruit, for the
wisdom the fruit was thought to offer, and a quick decision to eat. Eve
eats, then gives the fruit to Adam, “who was with her”, and he eats as
well. But for Grotius, the scene is one of agonizing choices. Similarly,
in L’Adamo, an Italian play of 1613, Adam’s decision to eat the fruit is
passionate, agonizing, and lengthy: Ahi, mi si spezza il core;
Che far deggia non so; s’io miro il Cielo
Sento vagarmi un gelo
Per l’ossa che mi strugge,
Vago sol d’ osservar precetti eterni;
Se la compagna miro. Piango al suo pianto, a’ suoi sospir sospiro,
E mi struggo, e m’ accoro,
S’ ubbidirla rifiuto; il cor amante
Fa eh’ al Pomo veloce apra la mano,
L’ alma nel sen dubbiante
La respinge, e la chiude;
Misero Adamo, o quanti
Accampano il tuo i or vari desire! Qui per r un tu sospiri,
Per r altro godi, né saper t’ è dato
Se tu sarà’ piegato
Da sospiri o da gioia,
Da la Donna o da Dio. […]
Dammi il frutto rapito,
Rapitrice cortese,
Dammi ill frutto gradito;
S’ubidisca a chi tanto,
Per farmi un Dio.94 Ahi, mi si spezza il core;
Che far deggia non so; s’io miro il C
Sento vagarmi un gelo
Per l’ossa che mi strugge,
Vago sol d’ osservar precetti eterni;
Se la compagna miro. Piango al suo pianto, a’ suoi sospir
E mi struggo, e m’ accoro,
S’ ubbidirla rifiuto; il cor amante
Fa eh’ al Pomo veloce apra la mano
L’ alma nel sen dubbiante
La respinge, e la chiude;
Misero Adamo, o quanti
Accampano il tuo i or vari desire! Qui per r un tu sospiri,
Per r altro godi, né saper t’ è dato
Se tu sarà’ piegato
Da sospiri o da gioia,
Da la Donna o da Dio. 95
Serafino della Salandra. Adamo Caduto (Cosenza: Giovanni Battista Moio and Francesco
Rodella, 1647), 2.10., 92, https://archive.org/stream/bub_gb_fbI8kobTkMQC#page/n110
96
“M’hàmasso in parte, il cor m’hà in tenerito; / Ma pìu di quel l’amor del Ciel
prevale” (ibid., 93, https://archive.org/stream/bub_gb_fbI8kobTkMQC#page/n111).
97
Ibid., 95, https://archive.org/stream/bub_gb_fbI8kobTkMQC#page/n113 Love and its Critics […]
Dammi il frutto rapito,
Rapitrice cortese,
Dammi ill frutto gradito;
S’ubidisca a chi tanto,
Per farmi un Dio.94 Dammi il frutto rapito, Rapitrice cortese, S’ubidisca a chi tanto, Per farmi un Dio.94 492 Love and its Critics Alas, it breaks my heart;
I do not know what to do; if I think of Heaven
Then I feel a cold tremor
Oppressing me even in my bones,
And I want only to obey the eternal precepts;
If I think of my companion,
I share her tears and sigh with her sighs;
I am tortured and distracted,
To refuse her would wound her, and my loving
Would teach me to sieze the apple with open ha
But my breast is doubtful
Rejects, and closes;
Miserable Adam, how many
And various are the desires that assail your hea
One makes you sigh,
Another gives you joy, nor can you know
Which will most win you,
The sighs or the joy. The woman or God. […]
Give me the stolen fruit,
Courteous thief,
Give me the pleasing fruit;
It is right to obey
The one who works to make me a God. The woman or God. Give me the stolen fruit, Courteous thief, Again, we have an Adam who agonizes over the choice of Eve or
God, and whose passion and love for his wife leads him to choose
love for another human being over love for a figure who is wholly
other, a figure whose benevolence always seems to be insisted on by
the very same people who take delight in recounting his punishments
of disobedience. Here, as in Grotius, the pious reader need not wait
long for the penalties to ensue—but again, the passionate, human
choice has already been made, and will not be unmade, no matter
the lethal intent of God. Even in the 1647 Italian play Adamo Caduto,
Adam’s choice is agonizing, but human. At first Adam resists, even
remonstrating with Eve the way Gerald Richman would have Adam
do in Paradise Lost: 493 10. Paradise Lost: Love in Eden, and the Critics who Obey Noon si deue piu tosto, ch’una volta
Offender Dio, morir ben volte mille? Saprò vestir di rigidezza il volto,
Saprò armar il cor’anco di idegno,
Donna, nel tuo mal fare. Stop your tears, no more tearing your hair, Love and its Critics […]
Iniquio è quel che pecca;
Ma di gran lunga è biasimevol quello;
Ch’à le viste ruine altrui conduce.95 Should you not, rather, but once avoid
Offending God, than die a thousand times? I’ll know how to clothe myself severely,
I’ll know how to arm my heart with shame,
Lady, against your evil machinations. […]
Wicked is the sinner;
But far more blameworthy are those
That with clear sight lead others to their ruin. But eventually, Adam begins to realize that he cannot resist his wife:
“She weighs on me, in part, making my heart tender; / But the love of
Heaven still prevails”.96 Finally, here, as in the other versions of the
Edenic story, Adam chooses Eve over God: Dolce ben mio,
Cessa dal pianto, non stracciar più l’crine,
Che ti prometto di mangiar’ il Pomo. […]
Ecco delitía mia, che’l mangio anch’io.97 Dolce ben mio,
Cessa dal pianto, non stracciar più l’crine,
Che ti prometto di mangiar’ il Pomo. […]
Ecco delitía mia, che’l mangio anch’io.97 Che ti prometto di mangiar’ il Pomo. My sweetest, Stop your tears, no more tearing your hair, Stop your tears, no more tearing your hair, 494 Love and its Critics I promise to eat the apple. […]
Behold, my delight, as I eat it too. I promise to eat the apple. Behold, my delight, as I eat it too. An astute reader will have noticed a difference, however, between the
three versions just dealt with and Milton’s rendering in Paradise Lost. Where the other seventeenth-century Adams agonize over their choices,
Milton’s Adam knows quietly, inwardly, immediately what he is going
to do. For him the choice is obvious: he will love Eve, and he will choose
Eve, despite the God who threatens him with pain and death, despite
the willful mishearers and misconstruers like Raphael, and despite the
long line of literary critics who would rewrite him into the image of
their dry and pious imaginations. Many of Milton’s modern critics appear to read his treatment of
Adam’s choice, not in light of the seventeenth-century context outlined
above, but as if Milton were following the much harsher example of
Alcimus Ecdicius Avitus, the sixth-century Bishop of Vienne. Avitus’
treatment of the scene, far from being sympathetic to the human
emotions involved, is an exercise in condemnation: Accipit infelix malesuadi verba susurri,
Inflexosque retro deiecit ad ultima sensus. 98
De Mosaice Historiae Gestis. 2.254–60. In S. Aviti, Archiepiscopi Viennensis Opera
(Paris, 1643), 233, https://babel.hathitrust.org/cgi/pt?id=dul1.ark:/13960/t1hh95n3b;
view=1up;seq=253 Love and its Critics Non illum trepidi concussit cura pavoris,
Nec quantum gustu cunctata est femina primo;
Sed sequitur velox, miseraeque ex coniugis ore
Constanter rapit inconstans dotale venenum. Faucibus et patulis inimicas porrigit escas.98 Unhappily, he accepts the seductive, whispered words,
Bent back, hurled down finally from his proper senses. Nor does fear strike him with pain and trembling,
Not so much as when the woman first hesitated to taste;
But he follows quickly, from his wretched wife’s mouth
Firmly the unsteady man seizes the poisonous dowry,
Stretches wide his mouth, and fills it with the hostile dish. 10. Paradise Lost: Love in Eden, and the Critics who Obey 495 However, that is not the way Milton treats the scene. His Adam
chooses Eve, not because he has been seduced by “whispered words”,
and not because he is inconstans (weak, unsteady, infirm of purpose),
but because he is faced with the choice between human love and
nonhuman (or inhuman) power, and he—like any truly decent man
would—chooses the former. To choose the ruler over one’s own wife—that is the kind of choice
that authoritarian regimes try to convince their subjects is good, right,
and honorable. A primary feature of such regimes is that they have
“forced individuals to renounce their private life, and especially to
sacrifice their family life”.99 This phenomenon can be seen through an
analysis of the literature of one such regime—North Korea: Love in North Korean literature is always achieved via the lovers’
devotion for the suryeong [the Leader]. They recognize each other’s human
worth by measuring and examining the depth, breadth, and, above all,
authenticity of the loyalty shown to the sovereign Leader. Without this
quality, no one in North Korea is worthy of love or even deserves to live. […] They love each other because the other loves the suryeong.100 A love filtered through adoration of the ruler, what Sonia Ryang calls
“sovereign love”,101 is the opposite of human love between two lovers
who choose each other for each other—the love treated by the Song of
Songs, Ovid, the troubadours, and Shakespeare. Such “sovereign love”
is designed, in fact, to prevent the possibility of the human love so many
of our literary critics seem curiously determined to dismiss or explain
away: “romance should only develop if it is between two individuals,
both of whom are equally loyal toward the Leader. 99
Gabriel A. Barhaim. Public-Private Relations in Totalitarian States (London:
Transaction Publishers, 2012), 15.
100 Sonia Ryang. “Biopolitics or the Logic of Sovereign Love—Love’s Wherabouts
in North Korea”. In Sonia Ryang, ed. North Korea: Toward a Better Understanding
(Lanham: Lexington Books, 2009), 61, 62.
101 Ibid., 74.
102 Ibid., 65. Love and its Critics No private feelings
must be prioritized over […] endless reverence, adoration, and longing
for, and loyalty toward, the Leader”,102 who is portrayed as “all-sagacious
and all-loving” while great emphasis is laid on his “kindness, holiness Love and its Critics 496 [and] wisdom”.103 Even one’s worth as an individual is related solely
to the extent of one’s loyalty to the sovereign: “[t]he worth of another
individual is recognized only when the other person is shown to be as
loyal toward the Leader as oneself”.104 By this latter criterion, a North
Korean literary critic (in an environment in which Kim Jong-il is reputed
to have said, “I rule through music and literature”105) would argue that
a man whose wife has been disloyal to the Leader must abandon her
to demonstrate his loyalty: “judgment is made as to whether the self is
good or evil based on this criterion: how deeply and how truthfully one
loves the Leader”.106 Such is the way so many Milton critics would have Adam choose. The obvious objection (often resorted to in Milton scholarship) is that
it is one thing for a human sovereign to demand one’s total love and
loyalty, and quite another for a “divine” sovereign to do the same. In
this line of thought, what is left implicit is the assumption that the same
techniques that are evil and oppressive when used by a human being
are good and just (even loving) when used by a god. Such arguments
regard not principle but degree, and those who accept them provide
fertile soil in which, with only a minimum of careful tending, tyranny
will rarely fail to thrive. Milton writes his Adam otherwise. Milton’s Adam—despite his
later doubts and accusations—makes the choice (in what Lewis
calls “the pinch [in which] a man ought to reject his wife”107) not to y
g
107 Lewis, A Preface to Paradise Lost, 123. Hannah Arendt notes that such “pinches” were
a feature of Nazi purges that even affected privileged party organizations like the
SS: “a Fuehrer decree dated May 19, 1943, ordered that all men who were bound
to foreigners by family ties, marriage or friendship were to be eliminated from
state, party, Wehrmacht and economy; this affected 1,200 SS leaders” (The Origins of
Totalitarianism [San Diego: Harcourt, 1968], 391, n. 7). 103 Ibid., 70.
104 Ibid., 65.
105 Jang Jin-sung. Dear Leader: My Escape from North Korea. Trans. by Shirley Lee (New
York: Simon & Schuster, 2014), 3.
106 Ryang, 74. 106 Ryang, 74. 104 Ibid., 65.
105 Jang Jin-sung. Dear Leader: My Escape from North Korea. Trans. by Shirley Lee (New
York: Simon & Schuster, 2014), 3. abandon? What kind of ruler, what kind of god, would demand such a thing, and
what kind of coward would submit to it? What Lewis, et al., have been advocating
for the last several decades is precisely the kind of submission and loyalty to the
powerful leader that characterizes the worst tyrannies of human history. p
108 Paradise Lost 3.203–10. 109 Ibid., 3.210–16. p
y
y
108 Paradise Lost 3.203–10. Love and its Critics Here, the decree of Ezra 10:3
also comes to mind: y
g
107 Lewis, A Preface to Paradise Lost, 123. Hannah Arendt notes that such “pinches” were
a feature of Nazi purges that even affected privileged party organizations like the
SS: “a Fuehrer decree dated May 19, 1943, ordered that all men who were bound
to foreigners by family ties, marriage or friendship were to be eliminated from
state, party, Wehrmacht and economy; this affected 1,200 SS leaders” (The Origins of
Totalitarianism [San Diego: Harcourt, 1968], 391, n. 7). Here, the decree of Ezra 10:3
also comes to mind: Now, let us carve out an agreement with our God, to send away our foreign wives, and such
hildren as they have borne. Now, let us carve out an agreement with our God, to send away our foreign wives, and such
children as they have borne. When the “pinch” Lewis refers to comes, are we after all to believe that the moral
thing, the humane thing is to abandon anyone our gods and dictators demand we 10. Paradise Lost: Love in Eden, and the Critics who Obey 497 reject his wife; he makes the choice to face death with Eve, rather
than abandon her, rather than lose her, and rather than indulge any
hopes about the mercy of a God who is not going to forgive an Eve
whom he has already condemned in advance of her choice to eat
the fruit. In the eyes of the God so many critics would have Adam
approach, it is always already too late: Man disobeying,
Disloyal breaks his fealty, and sins
Against the high Supremacy of Heav’n,
Affecting God-head, and so losing all,
To expiate his Treason hath naught left,
But to destruction sacred and devote,
He with his whole posteritie must dye,
Dye hee or Justice must;108 This is a serious and deadly speech. There is no mercy to be found
therein, nor is there any indication that the speaker is inclined to listen
to Adam’s (wholly imaginary) intercession. In fact, the speaker has
already decided that the only remedy for a crime that has not yet been
committed is a human sacrifice: unless for him
Som other able, and as willing, pay
The rigid satisfaction, death for death. p
y
y
108 Paradise Lost 3.203–10.
109 Ibid 3 210–16 Love and its Critics Say Heav’nly Powers, where shall we find such love,
Which of ye will be mortal to redeem
Man’s mortal crime, and just th’ unjust to save,
Dwells in all Heaven charity so deare?109 unless for him
Som other able, and as willing, pay
The rigid satisfaction, death for death. Say Heav’nly Powers, where shall we find such love,
Which of ye will be mortal to redeem
Man’s mortal crime, and just th’ unjust to save,
Dwells in all Heaven charity so deare?109 unless for him
Som other able, and as willing, pay
The rigid satisfaction, death for death. Say Heav’nly Powers, where shall we find such love,
Which of ye will be mortal to redeem
Man’s mortal crime, and just th’ unjust to save,
Dwells in all Heaven charity so deare?109 All of this sets the stage for the drama of the incarnation and crucifixion
of the Son, a death by torture and slow exposure to the elements, a 498 Love and its Critics practice that Martin Hengel describes as an expression of obscene
cruelty and sadism toward its victim: for the men of antiquity, Greeks, Romans, and Jews, the cross was not
an indifferent or arbitrary matter, but an absolutely offensive thing,
even “obscene” in the original sense of the word. […] Even in the
Roman empire, where the process of executions might be seen as having
a standard or “normal” form—it included an initial flogging, and the
criminal often carried the crossbar to the place of execution, where his
arms were outstretched as he was nailed to the bar—the form of execution
was quite variable: crucifixion was a punishment in which the capriciousness
and sadism of the executioner could run wild.110 And here, we come to the darkest truth, and the greatest heroism of the
choice Milton creates his Adam to make: it is in the face of a God who
demands grotesque torture and death for the crime of disobedience
(and the disobedience of relative children, at that), that Milton’s Adam
makes his decision for Eve, and for love. Critics like Lewis, Samuel, Fish,
Danielson, Teskey, and those who follow them, will never, as Waldock
observes, “acknowledge the facts of the poem”, because for them, the
power and passion of Adam’s choice pales next to the “should” and
“should not” of a prescriptive and obedience-driven rewriting of the
poem. 110 für die antiken Menschen, Griechen, Römer und Juden, keine gleichgültige, beliebige, sondern
eine durchaus anstößige, ja im ursprünglichen Sinne des Worte “obzöne” Sache bedeute. […]
Selbst in römischen Machtbereich, wo der Ablauf der Exekution in gewisser Weise als “genormt”
erscheinen konnte—er schloß die vorausgehende Geißelung und häufig auch das Tragen des
Balkens zur Richtstätte ein, wo der Delinquent emporgehoben und mit ausgestreckten Händen
angenagelt wurde—, blieb die Form der Hinrichtung recht variabel: Die Kreuzigung are eine
Strafe, bei der sich die Willkür und der Sadismus der Henker austoben konnten.
Martin Hengel. “Mors Turpissima Crucis: Die Kreuzigung in der Antiken Welt und
die ‘Toheit’ des Wortes vom Kreuz”. In Johannes Friederich, Wolfgang Pöhlmann,
and Peter Stuhlmacher, eds. Rechtfertigung: Festschrift für Ernst Käsemann zum 70
Geburtstag (Tübingen: J. C. B. Mohr, 1976), 137, 139). 111 The term translates literally as Love-Death, but what it refers to in the realm of art
is a duet between lovers—whether in song, poetry, dramatic performance, or some
combination—in which they affirm their love in the face of death. Martin Hengel. “Mors Turpissima Crucis: Die Kreuzigung in der Antiken Welt und
die ‘Toheit’ des Wortes vom Kreuz”. In Johannes Friederich, Wolfgang Pöhlmann,
and Peter Stuhlmacher, eds. Rechtfertigung: Festschrift für Ernst Käsemann zum 70
Geburtstag (Tübingen: J. C. B. Mohr, 1976), 137, 139). 112 Waldock, 44. 112 Waldock, 44. Love and its Critics The facts are there, however, easily perceived as long as one
does not make, as Raphael does, a willful attempt to misunderstand by
letting one of the greatest Liebestod111 scenes in all of world literature fall
“on ears which have been deliberately deafened”.112 10. Paradise Lost: Love in Eden, and the Critics who Obey 499 For Samuel Taylor Coleridge, the poet and critic whose ears were
definitely not deliberately deafened, the mutual love between Adam
and Eve was perhaps the noblest part of Paradise Lost: The love of Adam and Eve in Paradise is of the highest merit—not
phantomatic, and yet removed from everything degrading. It is the
sentiment of a rational being towards another made tender by a specific
difference in that which is essentially the same in both; it is a union of
opposites, a giving and receiving mutually of the permanent in either, a
completion of each in the other.113 In choosing death with Eve, Adam chooses a human life, a life of love
rather than an existence of obedience, a mortal life faced with a courage
Heidegger describes as “authentic being-toward-death”;114 thus
Adam makes the only possible human choice, which the poet knows,
even if his critics do not. In a sense, Adam makes the same choice
that Odysseus makes, who when offered immortality by Calypso,
can think only of return to Penelope, whom the goddess describes as
“your wife, she that you ever long for daily, in every way”.115 Perhaps,
in the spirit of Lewis, Samuel, Fish, Danielson, Teskey, and countless
others, Odysseus should have chosen otherwise. But think how much
poetry we would have lost if he had. In choosing death with Eve, Adam chooses a human life, a life of love
rather than an existence of obedience, a mortal life faced with a courage
Heidegger describes as “authentic being-toward-death”;114 thus
Adam makes the only possible human choice, which the poet knows,
even if his critics do not. In a sense, Adam makes the same choice
that Odysseus makes, who when offered immortality by Calypso,
can think only of return to Penelope, whom the goddess describes as
“your wife, she that you ever long for daily, in every way”.115 Perhaps,
in the spirit of Lewis, Samuel, Fish, Danielson, Teskey, and countless
others, Odysseus should have chosen otherwise. But think how much
poetry we would have lost if he had. 113 Samuel Taylor Coleridge. The Literary Remains of Samuel Taylor Coleridge, Vol. 1, ed.
by Henry Nelson Coleridge (London: William Pickering, 1836), 177, https://archive.
org/stream/literaryremainso01coleuoft#page/177
114 “eigentlichen Seins zum Tode” (Sein und Zeit. 266).
115 “σὴν ἄλοχον, τῆς τ᾽ αἰὲν ἐέλδεαι ἤματα πάντα” (Homer. Odyssey, 5.210. Vol. I,
Books 1–12, ed. by A. T. Murray [Loeb Classical Library, Cambridge, MA: Harvard
University Press, 1919]).
116 Maurice Kelley. “The Provenance of John Milton’s Christian Doctrine: A Reply to
William B. Hunter”. SEL, 34 (1994), 159, https://doi.org/10.2307/450791
117 Ibid.
118 Paradise Lost, 2.561. 113 Samuel Taylor Coleridge. The Literary Remains of Samuel Taylor Coleridge, Vol. 1, ed.
by Henry Nelson Coleridge (London: William Pickering, 1836), 177, https://archive.
org/stream/literaryremainso01coleuoft#page/177 1
Sontag, 7.
2
Martin Paul Eve. Literature Against Criticism (Cambridge: Open Book Publishers,
2016), 26, https://doi.org/10.11647/OBP.0102. Emphasis added.
3
Felski, The Limits of Critique, 47.
4
Ibid., 47. Love and its Critics Somehow, all too many modern critics of Milton can no longer see
or hear, so deliberately blind and deaf have they become to the love
the poet tried to portray. Such critics, in Maurice Kelley’s terms, are
“proof-proof”,116 and will forever insist on their “homemade brand of
orthodoxy”117 in rewriting Milton’s epic. But we needn’t follow them
into “wand’ring mazes lost”,118 wondering what might have been if only
Milton had written his poem to conform to the expectations of his more
obedience-focused readers. Despite the critics, in Paradise Lost, love Love and its Critics 500 Love and its Critics becomes most fully human. Mortal, and therefore even more precious
in the face of death, love is the defining feature of a truly human life,
chosen, as it seems it must ever be, in disobedience. becomes most fully human. Mortal, and therefore even more precious
in the face of death, love is the defining feature of a truly human life,
chosen, as it seems it must ever be, in disobedience. Epilogue Over fifty years ago, Susan Sontag described “the project of
interpretation” as “largely reactionary, stifling”, and placed it in
the context of “a culture whose […] dilemma is the hypertrophy of
the intellect at the expense of energy and sensual capacity”, before
concluding that “interpretation is the revenge of the intellect upon art”.1
The situation does not seem to have improved in the intervening half-
century. As Martin Paul Eve has very recently observed, “traditional
literary criticism always coerces texts into new narrative forms”, as “its
practitioners [read] to seek case studies suited for exegetic purpose”.2
To come back to the observation with which this book began, one of
the great shocks caused by reading love poetry alongside the work
of its critics, is just how often the critics seem hostile to poetry, while
aligning themselves with the very systems of power and authority
poetry has tried to resist. Literary critics immersed in what Rita Felski
calls the “institutionally mandated attitude” of an “institutionalized
suspicion” are part of a system of authoritative and authoritarian
cultural practices that are “diffused throughout society via the legal
and executive branches of the modern state”.3 Inspiring “surveillance,
investigation, interrogation, and prosecution”,4 such criticism is the https://doi.org/10.11647/OBP.0117.11 © 2017 Michael Bryson and Arpi Movsesian, CC BY 4.0 502 Love and its Critics ethos of a prestige-driven elite claiming it “terrorizes received ideas”,5
while too often identifying with (or at least cooperating with) the
systems of privilege and power it pretends to expose. 6
Henry Giroux. Neoliberalism’s War on Higher Education (Chicago: Haymarket Books,
2014), 16–17. 9
Sedgewick, Touching Feeling: Affect, Pedagogy, Performativity, 150–51. Sedgwick’s
discussion has elicited a great deal of commentary, an interesting amount of which
seems dedicated to using a suspicion-based style of reading to claim that her
argument means something other than it might otherwise appear. Heather Love’s
article, “Truth and Consequences: On Paranoid Reading and Reparative Reading”
(Criticism, 52: 2 [Spring 2010], 235–41) is an excellent recent example of that trend.
Love describes Sedgwick’s article as “an act of aggression […] that endlessly
produces its own bad objects”, readers who feel “personally” accused of being the
type of critic “who picks up paranoid habits of mind as critical tools or weapons but
is detached from the living contexts in which these frameworks were articulated”
(236). Love deftly manages both to praise and bury Caesar all at once, arguing for
the utility of a non-reparative reading of Sedgwick’s call for a reparative reading
practice. The long tradition of suspicion-based criticism will not, it seems, go down
without a fight. 5
Robert Con Davis and Ronald Schleifer. Criticism and Culture: The Role of Critique in
Modern Literary Theory (New York: Longman, 1991), 2. 7
Empson. “Rescuing Donne”, 159. 5
Robert Con Davis and Ronald Schleifer. Criticism and Culture: The Role of Critique in
Modern Literary Theory (New York: Longman, 1991), 2.
6
Henry Giroux. Neoliberalism’s War on Higher Education (Chicago: Haymarket Books,
2014), 16–17.
7
Empson. “Rescuing Donne”, 159.
8
Ibid., 152.
9
Sedgewick, Touching Feeling: Affect, Pedagogy, Performativity, 150–51. Sedgwick’s
discussion has elicited a great deal of commentary, an interesting amount of which
seems dedicated to using a suspicion-based style of reading to claim that her
argument means something other than it might otherwise appear. Heather Love’s
article, “Truth and Consequences: On Paranoid Reading and Reparative Reading”
(Criticism, 52: 2 [Spring 2010], 235–41) is an excellent recent example of that trend.
Love describes Sedgwick’s article as “an act of aggression […] that endlessly
produces its own bad objects”, readers who feel “personally” accused of being the
type of critic “who picks up paranoid habits of mind as critical tools or weapons but
is detached from the living contexts in which these frameworks were articulated”
(236). Love deftly manages both to praise and bury Caesar all at once, arguing for
the utility of a non-reparative reading of Sedgwick’s call for a reparative reading
practice. The long tradition of suspicion-based criticism will not, it seems, go down
without a fight. 11
The findings of the infamous Milgram and Zimbardo experiments of the 1960s
and 1970s have been updated by Halsam and Reicher in 2012. Where Milgram
and Zimbardo portray their subjects as cooperating passively with authority, even
when given instructions that seem malevolent in nature, Halsam and Reicher
conclude that subjects will obey eagerly and actively, no matter the instruction, as
long as they “actively identify with those who promote vicious acts as virtuous” (S.
A. Haslam and S. D. Reicher (2012) “Contesting the ‘Nature’ Of Conformity: What
Milgram and Zimbardo’s Studies Really Show”, PLoS Biol 10[11]: e1001426, https://
doi.org/10.1371/journal.pbio.1001426). 10
Edward S. Herman and Noam Chomsky. Manufacturing Consent: The Political
Economy of the Mass Media (New York: Knopf Doubleday, 2011), 305. 12
Eric Anthony Grollman recently addressed this problem from the perspective
of gender norms in the American academy, arguing that “academic training is
about beating graduate students into submission and conformity”, especially over
the issue of self-presentation: “professional (re)socialization of graduate school
is centrally a task of eliminating passion, love, creativity and originality from
would-be scholars’ lives—or at least presenting ourselves as detached, subdued,
conforming” (Eric Anthony Grollman. “Gender Policing in Academe”. Inside
Higher Education, https://www.insidehighered.com/advice/2016/07/29/academy-
polices-gender-presentation-scholars-essay). Joseph Katz noted some forty years
ago that the academy “give[s] lip service to the value of originality, while in fact
expecting products that conform rather strictly to specific canons of inquiry,
schools of thought, and the personalities of the people on examining committees”
(“Development of Mind”. In Scholars in the Making: The Development of Graduate and
Professional Students [Cambridge, MA, Ballinger, 1976], 124). And as A. W. Strouse
poignantly notes, “[t]he profession is a closet that shuts up doctoral students and
makes [them] write in prose rather than in poetry” (“Getting Medieval on Graduate
Education: Queering Academic Professionalism”. Pedagogy: Critical Approaches to
Teaching Literature, Language, Composition, and Culture, 15: 1 [2014], 124, https://doi.
org/10.1215/15314200-2799260). 14
Noam Chomsky. The Common Good (Berkeley: Odonian Press, 1998), 43. Epilogue At a time when we are facing “the near-death of the university
as a democratic public sphere”, while caught in a situation in which
“cynicism, accommodation, and a retreat into a sterile form of
professionalism”6 have become the coins of the realm, our poetry cannot
be left to what Empson once called the “habitual mean-mindedness
of modern academic criticism”.7 As Felski maintains, “[l]iterary
studies sorely needs alternatives” to a style of criticism that traces
“textual meaning back to an opaque and all-determining power, while
presuming the critic’s immunity from the weight of this ubiquitous
domination”.8 We need a criticism that practices what Eve Sedgwick
refers to as reparative reading, which teaches “the many ways in which
selves and communities succeed in extracting sustenance from the
objects of a culture—even a culture whose avowed desire has often been
not to sustain them”.9 This is especially true now, in a Western world
where so much of modern life is structured around obedience, a world
in which, as Edward Herman and Noam Chomsky argue, the governing
model is to “manufacture consent” in the various populations whose
compliance is being demanded. In describing the “propaganda model”
of the mass media, Herman and Chomsky outline “the rewards that Epilogue. Belonging to Poetry: A Reparative Reading 503 accrue to conformity and the costs of honest dissidence” as well as the
“considerations that tend to induce obedience”10 at all levels of our
society.11 This includes academia,12 where what Chomsky refers to as
“the self-selection for obedience that is […] part of elite education”13
influences the discourse and defines its possibilities and limits, “strictly
limit[ing] the spectrum of acceptable opinion, but allow[ing] very lively
debate within that spectrum”.14 The reparative reading Sedgwick called for might, if put into
practice, be able to give us a new relation to poetry, provide us a chance
to hear the voices of the poets again, bring their music to the fore, and
unearth it from beneath a century-long avalanche of modern criticism,
much of which has insisted on its primacy over poetry. 13
Chomsky, 13 Nov 1995. Epilogue Those of us who
teach, study, and write about poetry are enmeshed within a more than 12
Eric Anthony Grollman recently addressed this problem from the perspective
of gender norms in the American academy, arguing that “academic training is
about beating graduate students into submission and conformity”, especially over
the issue of self-presentation: “professional (re)socialization of graduate school
is centrally a task of eliminating passion, love, creativity and originality from
would-be scholars’ lives—or at least presenting ourselves as detached, subdued,
conforming” (Eric Anthony Grollman. “Gender Policing in Academe”. Inside
Higher Education, https://www.insidehighered.com/advice/2016/07/29/academy-
polices-gender-presentation-scholars-essay). Joseph Katz noted some forty years
ago that the academy “give[s] lip service to the value of originality, while in fact
expecting products that conform rather strictly to specific canons of inquiry,
schools of thought, and the personalities of the people on examining committees”
(“Development of Mind”. In Scholars in the Making: The Development of Graduate and
Professional Students [Cambridge, MA, Ballinger, 1976], 124). And as A. W. Strouse
poignantly notes, “[t]he profession is a closet that shuts up doctoral students and
makes [them] write in prose rather than in poetry” (“Getting Medieval on Graduate
Education: Queering Academic Professionalism”. Pedagogy: Critical Approaches to
Teaching Literature, Language, Composition, and Culture, 15: 1 [2014], 124, https://doi. org/10.1215/15314200-2799260). 12
Eric Anthony Grollman recently addressed this problem from the perspective
of gender norms in the American academy, arguing that “academic training is
about beating graduate students into submission and conformity”, especially over
the issue of self-presentation: “professional (re)socialization of graduate school
is centrally a task of eliminating passion, love, creativity and originality from
would-be scholars’ lives—or at least presenting ourselves as detached, subdued,
conforming” (Eric Anthony Grollman. “Gender Policing in Academe”. Inside
Higher Education, https://www.insidehighered.com/advice/2016/07/29/academy-
polices-gender-presentation-scholars-essay). Joseph Katz noted some forty years
ago that the academy “give[s] lip service to the value of originality, while in fact
expecting products that conform rather strictly to specific canons of inquiry,
schools of thought, and the personalities of the people on examining committees”
(“Development of Mind”. In Scholars in the Making: The Development of Graduate and
Professional Students [Cambridge, MA, Ballinger, 1976], 124). And as A. W. Strouse
poignantly notes, “[t]he profession is a closet that shuts up doctoral students and
makes [them] write in prose rather than in poetry” (“Getting Medieval on Graduate
Education: Queering Academic Professionalism”. Pedagogy: Critical Approaches to
Teaching Literature, Language, Composition, and Culture, 15: 1 [2014], 124, https://doi. org/10.1215/15314200-2799260). 15
Fish, “Masculine Persuasive Force: Donne and Verbal Power”, 223.
16
Kiernan Ryan, “King Lear”, 377.
17
The Scots Observer, 4: 91, 332, https://books.google.com/books?id=94oeAQ
AAMAAJ&pg=PA332
18
Oscar Wilde. “The Critic as Artist”. The Complete Works of Oscar Wilde (New York:
Barnes & Noble, 1994), 1021. Epilogue 14
Noam Chomsky. The Common Good (Berkeley: Odonian Press, 1998), 43. 4
Noam Chomsky. The Common Good (Berkeley: Odonian Press, 1998), 43. 504 Love and its Critics two-thousand-year-old tradition of suspicion-based stances toward
literature, and since the rise of theories that posit the non-referentiality
of language, the irrelevance of the artist, and the primacy of the critic,
that tradition has been contributing to poetry’s demise in a world that
may need poetry now more than it ever has. But in an age in which
criticism has long been enamoured of the idea that texts are deceptive,
what potential for resistance does poetry have? What power can it have
when so many of its critics seem dedicated to the idea that poetry must
be approached through what Fish calls “the pleasures of diagnosis”15
and what Kiernan Ryan decries as “the diagnostic attitude”16 that has
swept through literary studies? In such an environment, what is left of
passion and desire, not only in poetry, but in its interpretation? p
y
p
y
p
We might begin to address that question by taking our cue from a
writer of both poetry and criticism. In an August 16, 1890 letter to the
editor of The Scots Observer, Oscar Wilde noted that while “the critic
has to educate the public”, the responsibility of the artist is different,
for “the artist has to educate the critic”.17 In that observation there is
something crucial that contemporary academic criticism sometimes
seems to have forgotten: artists respond to art differently than do critics
(especially of the university-trained and theoretically-inclined variety). Wilde, who made a point in his work of exploring both sides of that
dynamic (especially in such essays as The Decay of Lying and The Critic as
Artist), is not favoring one over the other, but recommending a synthesis
of approaches to experiencing, understanding, and commenting upon
art. The ideas this approach leads to in his writing are not often of
the sort likely to be welcome in modern criticism, as for example, his
connection between life and art and his emphasis on the individual
artist behind the work: “[t]he longer one studies life and literature, the
more strongly one feels that behind everything that is wonderful stands
the individual”.18 Reparative reading might well give us an opportunity
to reincorporate both aspects of Wilde’s statement into our critical
practices—the reconnection of literature to life (not regarding literature Epilogue. 19
Aleksandr Sergeevich Pushkin. “Когда в объятия мои”. In Sobranie sochinenii, Vol.
2, 294, http://rvb.ru/pushkin/01text/01versus/0423_36/1830/0532.htm Epilogue Belonging to Poetry: A Reparative Reading 505 as purely self-referential after the fashion of Blanchot and others), and the
reconnection of that literature to the individual writer and reader. This
reparative reading, as imagined here, does not advocate a prescriptive
method of reading, or lay down rules for what one must or must not
see, hear, and feel in poetry and other forms of literature. But in the twin
spirit of Sontag and Wilde, it suggests a defense of poetry, and in Sontag’s
terms, a less revenge-driven relation between the intellect and art, less
driven by the hermeneutics of suspicion which often seems to triumph
over texts rather than explore them or explain them. Such a reading
practice suggests that now and then critics might do well to be educated
by the artist, rather than the theorist—and that works of criticism, this one
included, might do well to recover a sense of the passions of poetry, and
what Sontag refers to as the “energy and sensual capacity” of art and life. That sensual energy is still with us, and is amply represented in a
wide variety of modern literature, across multiple genres and languages. It appears in places like the poetry of Aleksandr Pushkin, who, though
most famous for his long-form works such as Evgeny Onegin (Евгений
Онегин) and Boris Godunov (Борис Годунов), also wrote a number of
powerful shorter poems. “When in My Embrace” (“Когда в объятия
мои”), from 1830, is filled with the frustrated eros often found in the
troubadour albas, where the lovers are threatened with separation by a
jealous husband and the coming of the dawn. But in Pushkin’s poem,
something even more forbidding separates the lovers: their own doubts. The poem shows us the painful regrets experienced by a lover who is
abashed before his beloved, filled with a sense of his own guiltiness and
unworthiness before a woman whom he imagines as recalling previous
betrayals by men such as himself: Когда в объятия мои
Твой стройный стан я заключаю
И речи нежные любви
Тебе с восторгом расточаю,
Безмолвна, от стесненных рук
Освобождая стан свой гибкой,
Ты отвечаешь, милый друг,
Мне недоверчивой улыбкой;
Прилежно в памяти храня
Измен печальные преданья, 506 Love and its Critics Ты без участья и вниманья
Уныло слушаешь меня…
Кляну коварные старанья
Преступной юности моей
И встреч условных ожиданья
В садах, в безмолвии ночей. 20
Pablo Neruda. “Puedo escribir los versos más tristes esta noche”. In Veinte Poemas
de Amor y una Canción Desesperada (Bogotá and Barcelona: Editorial Norma, 2002),
45–6, ll. 20–22, 28–32. Epilogue Кляну речей любовный шепот,
Стихов таинственный напев,
И ласки легковерных дев,
И слезы их, и поздний ропот.19 When in my embrace,
I enclose your shapely form,
And in a gentle voice of love
I delightfully praise you,
Silently, from my shy arms
By skillfully disentangling your figure,
You answer, sweet friend,
Smiling at me distrustfully;
Keenly kept in your memory,
The betrayal of sad devotion,
You, without sympathy and attention,
Are sadly listening to me…
I curse my subtle schemes,
My youthful crimes,
And my arranged meetings, waiting
In gardens, in the silence of night. I curse the speech of love’s whispers,
Poems with mysterious melodies,
And the caresses of credulous maidens,
And their tears, and their murmurs. Though there is a note here of the unachievable beloved found in Dante
and Petrarch, the lady is all-too-human, unachievable not because of
her demi-divine status, but because of her distrust, and the self-doubts
of a lover keenly aware of his own past and potential dishonesty. No
authority, divine or otherwise keeps the lovers apart, except for the Epilogue. Belonging to Poetry: A Reparative Reading 507 promptings and warnings of their own hearts. Pushkin’s poem speaks
to an older tradition of poetry, and is informed by it, while transforming
and internalizing its themes of separation and loss. Here, we have an
initial clue as to what at least one kind of reparative reading practice
might look like: reading those older poets can help us understand
Pushkin, and reading Pushkin can help us understand them in turn. We can see a further indication of what such a reading practice might
look like by turning to Pablo Neruda’s “I Can Write the Saddest Verses
Tonight” (“Puedo escribir los versos más tristes esta noche”), poem 20
from his 1924 collection Twenty Poems of Love and a Song of Despair (Veinte
Poemas de Amor y una Canción Desesperada). Neruda’s verse laments a
loss of love so affecting and so powerful that it feels like the tearing
away of one’s own soul: Mi corazón la busca, y ella no está conmigo. La misma noche que hace blanquear los mismos árboles. Nosotros, los de entonces, ya no somos los mismos. […]
Es tan corto el amor, y es tan largo el olvido. Porque en noches como esta la tuve entre mis brazos,
mi alma no se contenta con haberla perdido. Epilogue Aunque éste sea el último dolor que ella me causa,
y éstos sean los últimos versos que yo le escribo.20 My heart looks for her, and she is not with me. The same night whitens the same trees,
But we, who were then, are no longer the same. […]
Love is so short, and forgetting is so long. Because on nights like this I held her in my arms,
My soul has no peace, having lost her. Although this be the last pain that she causes me,
and these the last verses that I write. 508 Love and its Critics The voice in Neruda’s poem—a lover who cannot seem to let go of the
memories and regrets that revolve around the loss of love, the loss of a
woman, and the peace of soul that came with her presence—can help
us understand the Adam that Milton’s critics would have choose God
over Eve. Despite the vast differences between the poems in terms of
their language, their time of authorship, and their place of origin, these
poems speak to each other, and each speaks to us about the other. But
they are not poems that speak only of other poetry. The key is, that they
are poems that speak to us. They speak to and about poetry, yes; but
more importantly, they speak about life, about human beings and our
loves, losses, passions, and desires. That such a point has to be made at
all, is a testament to how long it has been since we have truly been able
to hear poetry over the urgent clamor of a suspicion-based criticism. In learning to hear the poets again, one of the most important things
we might begin to recover now is a practice of reading poetry, not
through academic criticism, but through other poetry. Reading Milton
through Neruda gives us an entirely different perspective on Adam’s
choice. As Adam expresses it to Eve, “to lose thee were to lose myself”,21
and as Neruda writes “love is so short, and forgetting is so long”—such
poetry teaches us to imagine the weight and sadness of what happens
after choosing God over Eve, after losing the love one once held in
one’s arms, finding her impossible to forget, and living with the regrets
and loneliness across the seemingly-endless years. 21
Paradise Lost 9.959.
22
In Stalinist Russia, only one form of literature was allowed to be written and published: socialist
realism. The Soviet government required complete acceptance of sanctioned forms of Marxist
ideology […]. Early Soviet policies regarding literature were shaped by the ideas of Andrei
Zhdanov, who believed that literature had a powerful influence over readers, claiming at the
first Soviet Writers’ Congress that socialists were writing “a literature which has organized the 21
Paradise Lost 9.959. 23
Вы всегда были горячим проповедником той теории, что по отрезании головы жизнь в
человеке прекращается, он превращается в золу и уходит в небытие. […] каждому будет
дано по его вере. Да сбудется же это! Вы уходите в небытие, а мне радостно будет из чаши,
в которую вы превращаетесь, выпить за бытие.
Mikhail Bulgakov. Мастер и Маргарита [Master and Margarita] (Moscow: Olma
Media Group, 2005), 352. Ilona Urquhart. “Diabolical Evasion of the Censor in Mikhail Bulgakov’s The Master
and Margarita”. In Nicole Moore, ed. Censorship and the Limits of the Literary: A Global
View (New York: Bloomsbury Academic, 2015), 133. toilers and oppressed for the struggle to abolish once and for all every kind of exploitation”. As
a consequence, Zhdanov was wary of literature that might encourage dissenting views.
Ilona Urquhart. “Diabolical Evasion of the Censor in Mikhail Bulgakov’s The Master
and Margarita”. In Nicole Moore, ed. Censorship and the Limits of the Literary: A Global
View (New York: Bloomsbury Academic, 2015), 133. 24
“Эх я, дурак! Зачем, зачем я не улетел с нею? Чего я испугался, старый осел!
[…] Эх, терпи теперь, старый кретин!” (ibid., 507). 23
Вы всегда были горячим проповедником той теории, что по отрезании головы жизнь в
человеке прекращается, он превращается в золу и уходит в небытие. […] каждому будет
дано по его вере. Да сбудется же это! Вы уходите в небытие, а мне радостно будет из чаши,
в которую вы превращаетесь, выпить за бытие. toilers and oppressed for the struggle to abolish once and for all every kind of exploitation”. As
a consequence, Zhdanov was wary of literature that might encourage dissenting views. в которую вы превращаетесь, выпить за бытие.
Mikhail Bulgakov. Мастер и Маргарита [Master and Margarita] (Moscow: Olma
Media Group, 2005), 352. toilers and oppressed for the struggle to abolish once and for all every kind of exploitation”. As
a consequence, Zhdanov was wary of literature that might encourage dissenting views.
Ilona Urquhart. “Diabolical Evasion of the Censor in Mikhail Bulgakov’s The Master
d M
it ” I
Ni
l M
d C
hi
d th Li it
f th Lit
A Gl b l Epilogue That empathy, that
creative sympathy, is where the “energy and sensual capacity” of poetry,
and the courage to commit to a reparative reading practice, might yet
be found. It can also be found in serious tales of fantasy, as in Mikhail
Bulgakov’s novel Master and Margarita (Мастер и Маргарита). A story
of black magic, love, and the triumph of art, written between 1928
and 1940 as a gesture of defiance against the Stalinist norms of Soviet
Socialist Realism (a form of literary criticism raised to the level of state
power),22 Bulgakov’s novel stands up powerfully against the forces Epilogue. Belonging to Poetry: A Reparative Reading 509 hostile to poetry. In a scene at once comic and profound, the value of life
and all its passions is voiced by the Devil, as he speaks to the severed
head of a disdainful literary critic named Berlioz who is about to find
out that his options were not quite so narrow as he had believed: You have always been an ardent preacher of the theory that cutting off
a man’s head ends his life, and then he turns into ashes and goes into
non-being. […] Each will be given according to his faith. Yes, it comes
true! You will go into non-being, and happily, from the cup of your
transformation, I will drink to being.23 And in a scene more wistful than comic, Bulgakov gives us the reflections
of a man who once had the chance to choose love and passion, but chose
as Milton’s critics would have his Adam choose, and passed them by
from fear of disobedience: “Oh, I am a fool! Why, why didn’t I fly away
with her? What was I afraid of, old ass! […] Suffer it now, old cretin!”24
This twentieth-century Russian novel, and that seventeenth-century
English epic poem also speak to one another, and to us, and the fire that
burns in them both is the energy and sensuality of an art that is very
much connected to life. Epilogue But the spirit of poetry as resistance, of literature as the medium
through which love is expressed and received in defiance of the critical,
theological, and political authorities who would (and still do) censor
it, is even more memorably captured by Nizār Qābbanī, the twentieth-
century Syrian poet whose entire body of work served as an act of
defiance against those who would channel, reformulate, and control Love and its Critics 510 poetry, passion, and human desire,25 from the governments that banned
his work, to the academic and theological critics who still regard his
poetry with disdain and disapproval.26 For Qābbanī, poetry and love
were the only laws of life: يوم تعثرينَ على رَجُل
ِيقدر أن يحوّل كلَّ ذرَة من ذرّاتك
ْإلى شِعْر.. ويجعل كلَ شَعْرة من شَعَراتكِ .. قصيدة
يوم تعثرين على رَجُل.. يقدر _ كما فعلتُ أنا _
ْأن يجعلك تغتسلينَ بالشِعر.. ْوتتكحّلين بالشِعر.. ْوتتمشّطين بالشِعر.. ِفسوفَ أتوسّلُ إليك.. أن تتبعيه بال تردّد.. فليس المهمّ أن تكوني لي.. وليس المهمّ .. أن تكوني له
27ْالمُهِمُّ .. أن تكُوني للشِعر 25
As Amila Buturovic notes, Qābbanī’s poetry was immediately regarded as
blasphemous by the clerical powers-that-be in Syria, while revered by younger
readers:
His pointed criticism of the social milieu was directed at the relationship between the
sexes in particular. His […] rejection of the blunt misogynist attitudes which left the Arab
woman under the constant scrutiny of patriarchal canons [informed his call] to liberate the
body from sexual repression and more specifically, to allow the Arab woman to cherish
her erotic ecstasy openly and freely. Controversy erupted instantly: Sheikh al-Tantāwī
characterized the poems as “blasphemous and stupid”, while young Syrian readers
treated the collection as a kind of manifesto of their culturally suppressed sexuality. “‘Only Women and Writing Can Save Us From Death’: Erotic Empowering in
the Poetry of Nizār Qābbanī”. In Tradition, Modernity, and Postmodernity in Arabic
Literature: Essays in Honor of Professor Issa J. Boullata, ed. by Kamal Abdel-Malek and
Wael Hallaq (Leiden: Brill, 2000), 141. And in a a trenchant observation that might
remind us that the theoretical stances of the West are not necessarily those of the
rest of the world, Buturovic argues that “while much of the postmodern world
speaks of the ‘death of the author’, we are reminded, quite lucidly, of Qābbanī’s
engaged presence every time we revisit his poetic corpus”. (142). Epilogue 26
F
f
i
i
l
f hi
d Q bb
’
k
B
A 25
As Amila Buturovic notes, Qābbanī’s poetry was immediately regarded as
blasphemous by the clerical powers-that-be in Syria, while revered by younger
readers:
His pointed criticism of the social milieu was directed at the relationship between the
sexes in particular. His […] rejection of the blunt misogynist attitudes which left the Arab
woman under the constant scrutiny of patriarchal canons [informed his call] to liberate the
body from sexual repression and more specifically, to allow the Arab woman to cherish
her erotic ecstasy openly and freely. Controversy erupted instantly: Sheikh al-Tantāwī
characterized the poems as “blasphemous and stupid”, while young Syrian readers
treated the collection as a kind of manifesto of their culturally suppressed sexuality. 25
As Amila Buturovic notes, Qābbanī’s poetry was immediately regarded as
blasphemous by the clerical powers-that-be in Syria, while revered by younger
readers:
His pointed criticism of the social milieu was directed at the relationship between the
sexes in particular. His […] rejection of the blunt misogynist attitudes which left the Arab
woman under the constant scrutiny of patriarchal canons [informed his call] to liberate the
body from sexual repression and more specifically, to allow the Arab woman to cherish
her erotic ecstasy openly and freely. Controversy erupted instantly: Sheikh al-Tantāwī
characterized the poems as “blasphemous and stupid”, while young Syrian readers
treated the collection as a kind of manifesto of their culturally suppressed sexuality. “‘Only Women and Writing Can Save Us From Death’: Erotic Empowering in
the Poetry of Nizār Qābbanī”. In Tradition, Modernity, and Postmodernity in Arabic
Literature: Essays in Honor of Professor Issa J. Boullata, ed. by Kamal Abdel-Malek and
Wael Hallaq (Leiden: Brill, 2000), 141. And in a a trenchant observation that might
remind us that the theoretical stances of the West are not necessarily those of the
rest of the world, Buturovic argues that “while much of the postmodern world
speaks of the ‘death of the author’, we are reminded, quite lucidly, of Qābbanī’s
engaged presence every time we revisit his poetic corpus”. (142). “‘Only Women and Writing Can Save Us From Death’: Erotic Empowering in
the Poetry of Nizār Qābbanī”. In Tradition, Modernity, and Postmodernity in Arabic
Literature: Essays in Honor of Professor Issa J. Boullata, ed. by Kamal Abdel-Malek and
Wael Hallaq (Leiden: Brill, 2000), 141. Epilogue And in a a trenchant observation that might
remind us that the theoretical stances of the West are not necessarily those of the
rest of the world, Buturovic argues that “while much of the postmodern world
speaks of the ‘death of the author’, we are reminded, quite lucidly, of Qābbanī’s
engaged presence every time we revisit his poetic corpus”. (142). 26
For a fascinating example of this stance toward Qābbanī’s work, see Bacem A. Essam. “Nizarre Qabbani’s Original Versus Translated Pornographic Ideology:
A Corpus-Based Study”. Sexuality and Culture, 20 (2016), 965–86, https://doi. org/10.1007/s12119-016-9369-7 27
Nizār Qābbanī. “Love Letter 71”. Arabic text published in Bassam K. Frangieh and
Clementia R. Brown, eds. Arabian Love Poems (London: Lynne Rienner Publishers,
1999), 134. 511 Epilogue. Belonging to Poetry: A Reparative Reading The day you find a man
Who can transform your every atom
Into Poetry,
And who turns each strand of your hair into a poem,
The day you find a man
Who can — as I did —
Make you bathe in Poetry,
Line your eyes with Poetry,
Comb your hair with Poetry,
Then I will beg you
To follow him without hesitation. It doesn’t matter that you belong to me,
And it doesn’t matter that you belong to him. What matters… is that you belong to Poetry.28 The day you find a man
Who can transform your every atom
Into Poetry,
And who turns each strand of your hair into a poem,
The day you find a man
Who can — as I did —
Make you bathe in Poetry,
Line your eyes with Poetry,
Comb your hair with Poetry,
Then I will beg you
To follow him without hesitation. It doesn’t matter that you belong to me,
And it doesn’t matter that you belong to him. What matters… is that you belong to Poetry.28 The poet’s final words are the key: belonging to poetry is feeling it
inside oneself, feeling its music flowing through and over and around
oneself. It is knowing eros as desire and joy. It is seeing life through
art, and art through life. It is the passion in the Song of Songs, the
troubadours, and Donne, the humor in Chaucer, the carpe diem ethos in
Herrick, the empathy in Shakespeare, Milton, and Pushkin, the sadness
in Neruda, and the irreverent joy in Ovid and Bulgakov. 28
Translated by Modje Taavon. y
j
29
Walter Isaacson. Benjamin Franklin: An American Life (New York: Simon & Schuster,
2003), 459. 28
Translated by Modje Taavon.
29
Walter Isaacson. Benjamin Franklin: An American Life (New York: Simon & Schuster,
2003), 459. Epilogue Those feelings
are the very core of the human spirit that we might still hope poetry,
and all forms of literature, can help us recover and defend. But whether
that spirit of belonging to poetry will survive, in this era of renewed
and intensified demands for obedience to the dictates of political and
cultural authority, is up to all of us, not our theologians, philosophers,
politicians, or literary critics. It is up to ordinary readers, everyday men
and women who will act in the spirit hoped for by Benjamin Franklin. After the Constitutional Convention of 1787, “an anxious lady named
Mrs. Powel” asked, “What type of government […] have you delegates
given us?” Franklin replied, “A republic, madam, if you can keep it”.29
What the poets have given us is Love. If only we can keep it. Bibliography Abelard, Peter, and Heloise d’Argenteuil. Magistri Petri Abaelardi epistola quae
est Historia calamitatum: Heloissae et Abaelardi epistolae, ed. by Johann Caspar
von Orelli. Turici: Officina Ulrichiana, 1841, https://archive.org/details/
magistripetriaba00abel Abels, Richards and Ellen Harrison. “The Participation of Women in
Languedocian Catharism”. Mediaeval Studies, 41 (1979), 215–51, https://doi. org/10.1484/J.MS.2.306245 Adorno, Theodore. “Studies in the Authoritarian Personality”. In T. W. Adorno,
Else Frenkel-Brunswik, Daniel J. Levinson, and R. Nevitt Sanford, The
Authoritarian Personality, Vol. I of Studies in Prejudice, ed. by Max Horkheimer
and Samuel H. Flowerman (Social Studies Series: Publication No. III). New York: Harper & Brothers, 1950, 145–509, https://www.scribd.com/
doc/35738019/Adorno-Theodor-W-Studies-in-the-Authoritarian-Personality Agrippa, Cornelius. De Nobilitate et Praecellentia Foeminei Sexus. Antwerp:
Michael Hillenius, 1529, https://books.google.it/books?id=ZoQNUzFZ5UE
C&pg=PT2&redir_esc=y Aist, Dietmar von. “Slâfest du, friedel ziere?” In Des minnesangs frühling, ed. by
Friedrich Vogt. Leipzig: Verlag von S. Hirzel, 1920, https://books.google. com/books?id=DcQPAAAAMAAJ&pg=PR1 Alcuin. “Epistola CCVI, Ad Disciplum”. In Patrologiae Cursus Completus, Vol. 100,
ed. by Jacques Paul Migne. Paris: Apud Garnier Fratres, 1863, cols. 481–82,
https://books.google.com/books?id=-JqsZH3ajIgC&pg=PA12 —. “Interrogationes et Responsiones in Genesin”. In Patrologiae Cursus Completus,
Vol. 100, ed. by Jacques Paul Migne. Paris: Apud Garnier Fratres, 1863, cols. 551–70, https://books.google.com/books?id=-JqsZH3ajIgC&pg=PA12 —. “Pectus
amor
nostrum
penetravit
flamma”. Monumenta
Germaniae
historica inde ab anno Christi quingentesimo usque ad annum millesimum et
quingentesimum, Vol. 1. Berlin: Apud Weidmannos, 1881, https://books. google.com/books?id=U6woAAAAMAAJ&pg=PP10 514 Love and its Critics Allen, Peter L. The Art of Love: Amatory Fiction from Ovid to the Romance of the Rose. Philadelphia: University of Pennsylvania Press, 1992. Allestree, Richard. The Practice of Christian Graces, Or, The Whole Duty of Man Laid
down in a Plaine and Familiar Way for the Use of All, but Especially the Meanest
Reader: Divided into XVII Chapters. London: Printed by D. Maxwell for T. Garthwait, 1658, https://quod.lib.umich.edu/e/eebo/A23760.0001.001/1:4?rg
n=div1;vid=96830;view=fulltext Alter, Robert. “Paul de Man Was a Total Fraud”. New Republic. April 5, 2014,
https://newrepublic.com/article/117020/paul-de-man-was-total-fraud-
evelyn-barish-reviewed Altermeyer, Bob. The Authoritarian Specter. Cambridge, MA: Havard University
Press, 1996. Althusser, Louis. “Idéologie et Appareils Idéologiques d’État” (1970). Les
Classiques des Sciences Sociales. Quebec: Université du Québec à Chicoutimi,
1–60, http://classiques.uqac.ca/contemporains/althusser_louis/ideologie_et_
AIE/ideologie_et_AIE.pdf —. Lire le Capital. Paris: Presses Universitaires de France, 1996. Ames, Christine Caldwell. Medieval Heresies: Christianity, Judaism, and Islam. Cambridge: Cambridge University Press, 2015. Anderson, W. S. “The Heroides”. In Ovid, ed. by James Wallace Binns. London:
Routledge, 1973, 49–83. Andreasen, Nancy Jo Coover. John Donne: Conservative Revolutionary. Princeton:
Princeton University Press, 1967. Andreini, Giambattisti. L’Adamo, ed. by Ettore Allodoli. Bibliography Lanciano: Carabba,
1913, https://archive.org/details/ladamoand00andruoft Arden of Faversham. In A Woman Killed with Kindness and Other Domestic Plays, ed. by Martin Wiggins. Oxford: Oxford University Press, 2008. Aucassin et Nicolette, ed. by Francis William Bourdillon. London: Kegan Paul,
Trench & Co., 1887, https://archive.org/details/AucassinEtNicoletteALove
Story Aquinas, Thomas. Summa Theologiae: Vol. 41, Virtues of Justice in the Human
Community, ed. by T. C. O’Brien. Cambridge: Cambridge University Press,
2006. Arden, Heather. The Romance of the Rose. Boston: Twayne Publishers, 1987. Arendt, Hannah. The Origins of Totalitarianism. San Diego: Harcourt, 1968. Aries, Philippe. “The Family, Sex and Marriage in England, 1500–1800”. The American Historical Review, 83: 5 (1978), 1221–24, https://doi.org/
10.2307/1854694 Aristotle. Nichomachean Ethics I, ed. by H. Rackham. Loeb Classical Library,
Cambridge, MA: Harvard University Press, 1926. 515 Bibliography —. Physics, Vol. II, Books 5–8. Ed. and trans. by P. H. Wicksteed and F. M. Cornford. Loeb Classical Library, Cambridge, MA: Harvard University Press, 1934. —. Poetics. Ed. and trans. by Stephen Halliwell. In Aristotle: Poetics. Longinus:
On the Sublime. Demetrius: On Style. Loeb Classical Library, Cambridge,
MA: Harvard University Press, 1995, https://doi.org/10.4159/dlcl.aristotle-
poetics.1995 —. Poetics. Trans. by Richard Janko. Indiannapolis: Hackett, 1987. —. Politics. Ed. and trans. by Harris Rackham. Loeb Classical Library, Cambridge,
MA: Harvard University Press, 1932. Armstrong, Rebecca. Ovid and His Love Poetry. London: Bloomsbury Academic,
2005, https://doi.org/10.5040/9781472539977 Astell, Ann W. The Song of Songs in the Middle Ages. Ithaca: Cornell University
Press, 1990. Aubrey, John. Wiltshire. The Topographical Collections of John Aubrey, 1659–70,
ed. by John Edward Jackson. London: Longman, 1862, https://archive.org/
details/wiltshiretopogra00aubr Auerbach, Erich. Mimesis: Dargestellte Wirklichkeit in Der Abendländischen Literatur. 2nd ed. Bern: A. Francke, 1959. Augustine of Hippo. De Civitate Dei. Paris: 1586, https://books.google.com/
books?id=pshhAAAAcAAJ&printsec=frontcover&source=gbs_ge_
summary_r&cad=0 Ausonius. “Ad Uxorem”, Epigram 20. In Ausonius: Epigrams. Text with Introduction
and Commentary. Ed. and trans. by Nigel M. Kay. London: Duckworth, 2001,
45. —. “Attusia Lucana Sabina Uxor”, Parentalia IX. In Ausonius. Vol. I: Books 1–17. Ed. and trans. by Hugh G. Evelyn-White. Loeb Classical Library, Cambridge,
MA: Harvard University Press, 1919, 70, 72. Austin, R. G. P. Vergili Maronis Aneidos Liber Quartos. Oxford: Clarendon Press, 1955. Auweele, Bart Vanden. “The Song of Songs as Normative Text”. In Religion and
Normativity, Vol. 1: The Discursive Struggle over Religious Texts in Antiquity,
ed. by Anders-Christian Jacobson, Bart Vanden Auweele, and Carmen
Cvetkovic. Aarhus: Aarhus University Press, 2009, 157–67. Avitus of Vienne (Alcimus Ecdicius Avitus). De Mosaice Historiae Gestis. Bibliography In S. Aviti, Archiepiscopi Viennensis Opera. Paris, 1643, https://babel.hathitrust.org/
cgi/pt?id=dul1.ark:/13960/t1hh95n3b;view=1up;seq=5 Bagot, Richard. “Letter from Richard Bagot to Richard Broughton, 1587 June 3”. In Papers of the Bagot Family of Blithfield, Staffordshire, 1428–1671 (bulk 1557–
1671). Folger MS L.a.68, Folger Shakespeare Library, Washington, http://
luna.folger.edu/luna/servlet/workspace/handleMediaPlayer?lunaMediaId=
FOLGERCM1~6~6~361296~130605 516 Love and its Critics Baker, Richard. A Chronicle of the Kings of England (London: Printed by George
Sawbridge at the Bible on Ludgate-hill, 1670, https://books.google.com/
books?id=BnIVsU0RtzUC&pg=PP12 Barazzetti, Donatella, Franca Garreffa, and Rosaria Marsico. National Report:
Italia. Daphne Project: Proposing New Indicators: Measuring Violence’s Effects. University of Calabria, Rende: Italy, 2007, http://www.surt.org/gvei/docs/
national_report_italy.pdf Barhaim, Gabriel A. Public-Private Relations in Totalitarian States. London:
Transaction Publishers, 2012. Barthes, Roland. “La mort de l’auteur”. In Le Bruissement de la Langue. Essais
Critiques IV. Paris: Seuil, 1984, 61–69. Bell, Ilona. “Gender Matters: The Women in Donne’s Poems”. In The Cambridge
Companion to John Donne, ed. by Achsah Guibbory Cambridge: Cambridge
University Press, 2006, 201–16, https://doi.org/10.1017/ccol0521832373.013 Bell, Kimberly K., and Julie Nelson Couch. The Texts and Contexts of Oxford,
Bodleian Library, Ms Laud Misc. 108: The Shaping of English Vernacular Narrative. Boston: Brill, 2011, https://doi.org/10.1163/ej.9789004192065.i-342 Belsey, Catherine. Desire: Love Stories in Western Culture. Oxford: Oxford
University Press, 1994. Ben-Zeʼev, Aharon and Ruhama Goussinsky. In the Name of Love: Romantic
Ideology and Its Victims. Oxford: Oxford University Press, 2008, https://doi. org/10.1093/acprof:oso/9780198566496.001.0001 Bernays, Edward. Propaganda. New York: Horace Liveright, 1928, https://archive. org/details/EdwardL.BernaysPropaganda Berry, Ralph. The Shakespearean Metaphor: Studies in Language and Form. New
York: Macmillan, 1978, https://doi.org/10.1007/978-1-349-03563-2 Best, Stephen and Sharon Marcus. “Surface Reading: An Introduction”. Representations,
108:
1
(Fall
2009),
1–21,
https://doi.org/10.1525/
rep.2009.108.1.1 Biblia Hebraica Stuttgartensia, ed. by Karl Elliger and Willhelm Rudolph. Stuttgart:
Deutsche Bibelgesellschaft, 1983. Blackwood, Adam. Martyre de la Royne d’Escosse. Edinburgh, 1587, https://books. google.com/books?id=_mZUAAAAcAAJ&printsec=frontcover&source=g
bs_ge_summary_r&cad=0 Blair, Peter Hunter. Ango-Saxon England. New York: Cambridge University
Press, 1959. Blake, William. The Complete Poetry and Prose of William Blake, ed. by David V. Erdman. Berkeley and Los Angeles: University of California Press, 2008. —. The Works of William Blake, ed. by Edwin John Ellis and William Butler Yeats,
Vols. 1–3. London: Benard Quartich, 1893, https://archive.org/details/
worksofwilliambl02blakrich 517 Bibliography Blanc, Pierre. “Sonnet des origines, origine du sonnet: Giacomo da Lentini”. In
Le sonnet a la Renaissance: des origenes au XVIIe siècle, ed. by Yvonne Bellenger. Paris: Aux Amateurs de Livres, 1998, 9–18. Blanchot, Maurice. “La Littérature et le droit à la mort”. In La Part de Feu. Paris:
Gallimard, 1949, 291–331. Bibliography —. “La Solitude Essentielle”. In L’Espace Littéraire. Paris: Gallimard, 1955, 9–25. Blank, Hanne. Virgin: The Untouched History. New York: Bloomsbury, 2007. Blasia, Damián E., Søren Wichmannd, Harald Hammarströmb, Peter F. Stadlerc,
and Morten H. Christiansen. “Sound-meaning association biases evidenced
across thousands of languages”. Proceedings of the National Academy of Sciences
(27 September 2016), 113: 39, http://www.pnas.org/content/113/39/10818.full,
https://doi.org/10.1073/pnas.1605782113 Blevins, Jacob. Catullan Consciousness and the Early Modern Lyric in England: From
Wyatt to Donne. Aldershot: Ashgate, 2004. Bloch, Ariel and Chana. The Song of Songs: A New Translation and Commentary. New York: Random House, 1995. Bloch, R. Howard, and Stephen G. Nichols. “Introduction”. In Medievalism
and the Modern Temper, ed. by R. Howard Bloch and Stephen G. Nichols. Baltimore: Johns Hopkins University Press, 1996, 1–22. Bloom, Harold. Shakespeare: The Invention of the Human. New York: Penguin, 1998. —. The Western Canon: The Books and School of the Ages. New York: Harcourt Brace,
1994. Blumenfeld-Kosinski, Renate. “Jean Gerson and the Debate on the Romance of
the Rose”. A Companion to Jean Gerson, ed. by Brian Patrick McGuire. Leiden:
Brill, 2006, 317–56. Boase, Roger. The Origin and Meaning of Courtly Love: A Critical Study of European
Scholarship. Manchester: Manchester University Press, 1977. Boccalini, Traiano. I ragguagli di Parnasso: Or, Advertisements from Parnassus. Trans. by Henry, Earl of Monmouth. London, 1674. Bogin, Magda, ed. The Women Troubadours. New York: Paddington Press, 1976. Bolduc, Michelle. “The Breviari D’Amor: Rhetoric and Preaching in Thirteenth-
Century Languedoc”. Rhetorica, 24: 4 (2006), 403–25, https://doi.org/10.1525/
rh.2006.24.4.403 Born, Bertan de. The Poems of the Troubadour Bertran De Born, ed. by William D. Paden, Tilde Sankovitch, and Patricia H. Stablein. Berkeley: University of
California Press, 1986. Boswell, John. Christianity, Social Tolerance, and Homosexuality: Gay People in
Western Europe from the Beginning of the Christian Era to the Fourteenth Century. Chicago, University of Chicago Press, 1980. 518 Love and its Critics Boyd, Barbara Weiden. “The Amores: The Invention of Ovid”. In Brill’s Companion
to Ovid, ed. by Barbara Weiden Boyd. Leiden: Brill, 2002, 91–116, https://doi. org/10.1163/9789047400950_004 Boyle, David. Troubadour’s Song: The Capture, Imprisonment and Ransom of Richard
the Lionheart. New York: Walker & Co., 2005. Brady, Bernard V. Christian Love. Washington: Georgetown University Press,
2003. Briffault, Robert. The Troubadours, ed. by Lawrence F. Koons. Bloomington:
Indiana University Press, 1965. Brogan, Walter A. “The Original Difference”. In Derrida and Différance, ed. by
David Wood and Robert Bernasconi. Evanston: Northwestern University
Press, 1985, 31–39. Carmina Burana: Lateinische und Deutsche Lieder und Gedichte einer Handschrift des
XIII Jahihunderts aus Benedictbeuern auf der K. Bibliothek gu München, ed. by
Johann Andreas Schmeller. Stuttgart: Literarischen Vereins, 1847, https://
books.google.com/books?id=0XN3YW-EqacC&pg=PP1 Bibliography Brown, Peter, ed. A Companion to Medieval English Literature and Culture,
c.1350-c.1500. Malden: Blackwell, 2007, https://doi.org/10.1002/9780470996355 —. Through the Eye of a Needle: Wealth, the Fall of Rome, and the Making of Christianity
in the West, 350–550 AD. Princeton: Princeton University Press, 2012, https://
doi.org/10.1515/9781400844531 Bruckner, Matilda Tomaryn, Laurie Shepard, and Sarah White, eds. Songs of the
Women Troubadours. New York: Garland Publishing, 2000. Bruckner, Matilda Tomaryn. “‘Redefining the Center’ Verse and Prose
Charrette”. In A Companion to the Lancelot-Grail Cycle, ed. by Carol Dover. Cambridge, UK: Brewer, 2003, 95–106. Bryson, Michael. The Atheist Milton. Farnham: Ashgate, 2012, https://doi. org/10.4324/9781315613796 —. The Tyranny of Heaven: Milton’s Rejection of God as King. London: Associated
University Presses, 2004. Bulgakov, Mikhail. Мастер и Маргарита [Master and Margarita]. Moscow: Olma
Media Group, 2005. Burckhardt, Jacob. Die Cultur der Renaissance in Italien: Ein Versuch. Basel:
Schweighauser, 1860, https://babel.hathitrust.org/cgi/pt?id=gri.ark:/13960/
t7fr4fg3z;view=1up;seq=5 Burden, Dennis H. The Logical Epic: A Study of the Argument of “Paradise Lost’. Cambridge, MA: Harvard University Press, 1967. Burgwinkle, William E. Love for Sale: Materialist Readings of the Troubadour Razo
Corpus. New York: Garland, 1997. —. “The Troubadours: The Occitan Model”. In The Cambridge History of French
Literature, ed. by William E. Burgwinkle, Nicholas Hammond, and Emma
Wilson. Cambridge: Cambridge University Press, 2011, 20–27, https://doi. org/10.1017/chol9780521897860.004 519 Bibliography Burns, E. Jane. Courtly Love Undressed: Reading Through Clothes in Medieval French
Culture. Philadelphia: University of Pennsylvania Press, 2002, https://doi. org/10.9783/9780812291247 —. “Courtly Love: Who Needs It? Recent Feminist Work in The Medieval French
Tradition”. Signs: Journal of Women in Culture and Society, 27: 1 (2001), 23–57,
https://doi.org/10.1086/495669 Buturovic, Amila. “‘Only Women and Writing Can Save Us From Death’: Erotic
Empowering in the Poetry of Nizār Qābbanī”. In Tradition, Modernity, and
Postmodernity in Arabic Literature: Essays in Honor of Professor Issa J. Boullata,
ed. by Kamal Abdel-Malek and Wael Hallaq. Leiden: Brill, 2000, 141–57. Byrne, Sister Marie José. Prolegomena to an Edition of the Works of Decimus Magnus
Ausonius. New York: Columbia University Press, 1916. Callaghan, Dympna. “The Ideology of Romantic Love: The Case of Romeo
and Juliet”. In The Weyward Sisters: Shakespeare and Feminist Politics, ed. by
Dympna Callaghan, Lorraine Rae Helms, and Jyotsna Singh, Cambridge,
MA: Blackwell, 1994, 59–101. —. Shakespeare’s Sonnets. Malden: Blackwell, 2007, https://doi.org/10.1002
/9780470774878 Calvin, Jean. Institutio Christianae Religionis. Geneva: Oliua Roberti Stephani,
1559, https://books.google.com/books?id=6ysy-UX89f4C&printsec=frontcov
er&source=gbs_ge_summary_r&cad=0 Cameron, Alan. Claudian: Poetry and Propaganda at the Court of Honorius. Oxford:
Clarendon Press, 1970. Bibliography Campbell, Joseph. The Masks of God: Creative Mythology. New York: Viking Press,
1968. —. The Power of Myth, ed. by Betty Sue Flowers. New York: Doubleday, 1988. Camproux. Charles. Le “joy d’amor” des troubadours. Jeu et joie d’amour. Montpellier:
Causse et Castelnau, 1965. Camus, Albert. “L’été à Alger”. In his Noces suivi de L’été. Paris: Gallimard, 1959,
33–52. Capellanus, Andreas. De Amore Libri Tres: Von Der Liebe. Drei Bücher. Berlin and
Boston: De Gruyter, 2006. —. The Art of Courtly Love. Trans. by John Jay Perry. New York: W. W. Norton &
Co., 1941. Carmina Burana: Lateinische und Deutsche Lieder und Gedichte einer Handschrift des
XIII Jahihunderts aus Benedictbeuern auf der K. Bibliothek gu München, ed. by
Johann Andreas Schmeller. Stuttgart: Literarischen Vereins, 1847, https://
books.google.com/books?id=0XN3YW-EqacC&pg=PP1 520 Love and its Critics Carroll, Lewis. Through the Looking Glass: and What Alice Found There. Philadelphia:
Henry Altemus Company, 1897. Casali, Sergio. “The Art of Making Oneself Hated: Rethinking (Anti-)
Augustanism in Ovid’s Ars Amatoria”. In The Art of Love: Bimillennial Essays
on Ovid’s Ars Amatoria and Remedia Amoris, ed. by Roy Gibson, Steven Green,
and Alison Sharrock. Oxford: Oxford University Press, 2006, 216–34, https://
doi.org/10.1093/acprof:oso/9780199277773.003.0011 —. “The Bellum Civile as an Anti-Aeneid”. Brill’s Companion to Lucan, ed. by Paolo
Asso. Leiden: Brill, 2011, 81–109, https://doi.org/10.1163/9789004217096_006 Castiglione, Baldassarre. Il Libro del Cortegiano. Milano: Giovanni Silvestri, 1822,
https://archive.org/details/illibrodelcorteg00cast Castor, Helen. She-Wolves: The Women Who Ruled England before Elizabeth. London: Faber and Faber, 2010. Catullus, Gaius Valerius. Catullus. Tibullus. Pervigilium Veneris. Ed. and trans. by. F. W. Cornish. Loeb Classical Library, Cambridge, MA: Harvard University
Press, 1913. Cazelles, Brigitte. The Lady as Saint: A Collection of French Hagiographic Romances
of the Thirteenth Century. University Park: University of Pensylvannia Press,
1991. Chaucer, Geoffrey. The Canterbury Tales: Complete, ed. by Larry Dean Benson. Boston: Houghton Mifflin, 2000. Cheyette, Fredric L. Ermengard of Narbonne and the World of the Troubadours. Ithaca: Cornell University Press, 2001. Chomsky, Noam. “Beyond a Domesticating Education: A Dialogue”. In Noam
Chomsky, Chomsky on Miseducation. Lanham: Rowman & Littlefield, 2004,
15–37. —. LBBS, Z-Magazine’s Left On-Line Bulletin Board. Online discussion posted at
rec.arts.books, 13 November 1995, 03:21:23, http://bactra.org/chomsky-on-
postmodernism.html —. “Noam Chomsky on French Intellectual Culture & Post-Modernism [3/8]”. Interview conducted at Leiden University, in March 2011 (posted March
15,
2012),
https://www.youtube.com/v/2cqTE_bPh7M&feature=youtu. be&start=409&end=451 [6:49–7:31]. —. The Common Good (Berkeley: Odonian Press, 1998). Chrétien de Troyes. Le Chevalier de la Charrette, ed. Bibliography by Alfred Foulet and Karl D. Uitti. Paris: Classiques Garnier, 1989. Cicero. De Finibus Bonorum et Malorum. In Cicero, On Ends, ed. by H. Rackham. Loeb Classical Library, Cambridge, MA: Harvard University Press, 1914. Cirlot, Victoria, ed. Antología de textos románicos medievales: siglos XII–XIII. Barcelona: Edicions Universitat Barcelona, 1984. 521 Bibliography Clark, Alice V. “From Abbey to Cathedral and Court: Music Under the
Merovingian, Carolingian and Capetian Kings in France until Louis IX”. The
Cambridge Companion to French Music. Cambridge: Cambridge University
Press, 2015, 3–20, https://doi.org/10.1017/cco9780511843242.003 Clark, David. Between Medieval Men: Male Friendship and Desire in Early Medieval
English Literature. Oxford: Oxford University Press, 2009, https://doi. org/10.1093/acprof:oso/9780199558155.001.0001 Claudian (Claudius Claudianus). Claudian: Vol. II. Ed. and trans. by Maurice
Platnauer. Loeb Classical Library, Cambridge, MA: Harvard University
Press, 1998. Clements, Ronald. E. Ezekiel. Louisville: Westminster John Knox Press, 1996. Cohen, Elizabeth S. and Thomas V. Cohen. Daily Life in Renaissance Italy. Westport: Greenwood Press, 2001. Cohen, Gerson D. “The Song of Songs and the Jewish Religious Mentality”. In
Studies in the Variety of Rabbinic Cultures. Philadelphia: Jewish Publication
Society, 1991, 3–17. Cohen, Thomas V. Love and Death in Renaissance Italy. Chicago: University of
Chicago Press, 2004, https://doi.org/10.7208/chicago/9780226112602.001.0001 Coleridge, Samuel Taylor. The Literary Remains of Samuel Taylor Coleridge, Vol. 1,
ed. by Henry Nelson Coleridge. London: William Pickering, 1836, https://
archive.org/details/literaryremainso01coleuoft Coltman, Rod. “Hermeneutics: Literature and Being”. The Blackwell Companion
to Hermeneutics, ed. by Niall Keane and Chris Lawn. Chichester: John Wiley
& Sons, 2016, 548–56, https://doi.org/10.1002/9781118529812.ch67 Constans, Léopold Eugène. “Séquence de Sainte Eulalie”. In Chrestomathie de
l’ancien français (IXe-XVe siécles). Paris and Lepzig: H. Welter, 1906, https://
archive.org/details/chrestomathiede00cons Cox, Catherine S. Gender and Language in Chaucer. Gainesville: University Press
of Florida, 1997. Crane, Susan. Gender and Romance in Chaucer’s Canterbury Tales. Princeton:
Princeton University Press, 1994, https://doi.org/10.1515/9781400863754 Cudini, Piero, ed. Poesia Italiana del Duecento. Milan: Lampi Di Stampa, 1999. Curtius, Ernst Robert. Europäische Literatur und Lateinisches Mittelalter. Berlin: A. Francke AG Verlag, 1948. Daniel, Arnaut. Les Poesies D’Arnaut Daniel, ed. by René Lavaud. Toulouse:
Edouard Privat, 1910, https://archive.org/details/lesposiesdarna00arna Danielson, Dennis. “Through the Telescope of Typology: What Adam Should
Have Done”. Milton Quarterly, 23: 3 (1989), 121–27, https://doi.org/10.1111/
j.1094-348x.1989.tb00770.x 522 Love and its Critics Dante (Dante Alighieri). The Canzoniere of Dante Alighieri, ed. by Charles Lyell. London: James Bohn, 1840. —. La Divina Commedia. Inferno, ed. by Ettore Zolesi. Rome: Armando, 2009. —. La Divina Commedia. Purgatorio, ed. by Ettore Zolesi. Bibliography Rome: Armando, 2003. Davis, P. J. “Ovid’s Amores: A Political Reading”. Classical Philology, 94: 4 (1999),
431–49, https://doi.org/10.1086/449457 Davis, Robert Con and Ronald Schleifer. Criticism and Culture: The Role of Critique
in Modern Literary Theory. New York: Longman, 1991. Dawson, David. Allegorical Readers and Cultural Revision in Ancient Alexandria
[Los Angeles: University of California Press, 1992. Day, Linda. “Rhetoric and Domestic Violence In Ezekiel 16”. Biblical
Interpretation: A Journal of Contemporary Approaches, 8: 3 (2000), 205–30,
https://doi.org/10.1163/156851500750096327 Debating the Roman de la Rose: A Critical Anthology, ed. by Christine McWebb. London: Routledge, 2007. De Graef, Ortwin. “Silence to be Observed: A Trial for Paul de Man’s Inexcusable
Confessions”. In (Dis)continuities: Essays on Paul de Man, ed. by Luc Herman,
Kris Humbeeck, and Geert Lernout. Amsterdam: Rodopi, 1989, 51–73. Deleuze, Gilles. “Un manifeste de moins”. Superpositions. Paris: Éditions de
Minuit, 1979, 87–131. De Man, Paul. Allegories of Reading: Figural Language in Rousseau, Nietzsche, Rilke,
and Proust. New Haven: Yale University Press, 1979. —. Blindness and Insight: Essays in the Rhetoric of Contemporary Criticism. New
York: Oxford University Press, 1971. —. The Paul de Man Notebooks, ed. by Martin McQuillan. Edinburgh:
Edinburgh University Press, 2014, https://doi.org/10.3366/edinburgh/
9780748641048.001.0001 —. The Rhetoric of Romanticism. New York: Columbia University Press, 1984. Derrida, Jacques. De la Grammatologie. Paris: Éditions de Minuit, 1967. —. L’Ecriture et la Différence. Paris: Seuil, 1967. —. L’Ecriture et la Différence. Paris: Seuil, 1967. De Sanctis, Francesco. Storia della letteratura italiana, Vol. 1. Neaples: Morano,
1870. Desmond, Marilynn. Reading Dido: Gender, Textuality, and Medieval Aeneid. Minneapolis: University of Minnesota Press, 1994. Dillon, Martin C. Merleau-Ponty’s Ontology. Evanston: Northwestern University
Press, 1997. Dilthey, Wilhelm. Der Aufbau der geschichtlichen Welt in den Geisteswissenschaften. Frankfurt am Main: Suhrkamp, 1970. 523 Bibliography Dinshaw, Carolyn. Chaucer’s Sexual Poetics. Madison, WI: University of
Wisconsin Press, 1989. Dionysius the Carthusian. Epistolarum ac Euangeliorum. Cologne: Petrus Quentell,
1537, https://books.google.com/books?id=CqP4kICSulwC&pg=PP5 Dodd, William George. Courtly Love in Chaucer and Gower. Gloucester: Peter
Smith, 1959. Doggett, Frank. “Donne’s Platonism”. The Sewanee Review, 42: 3 (1934), 274–92. Donne, John. John Donne: The Complete English Poems, ed. by A. J. Smith. London:
Penguin, 1986. —. L.b.526: Letter from John Donne, The Savoy, London, to Sir George More,
1601/1602 February 2. Early Modern Manuscripts Online, http://emmo. folger.edu/view/Lb526/semiDiplomatic Doss-Quinby, Eglal, ed. Songs of the Women Trouvères. New Haven: Yale
University Press, 2001. Dostoevsky, Fyodor. Братья Карамазовы [Brothers Karamazov]. St. Petersburg:
A. F. Marx, 1895. —. Бесы [Demons]. Bibliography St. Petersburg: Azbuka, 2008. —. Идиот [The Idiot]. St. Petersburg: A. Suvorin, 1884. Dratyon, Michael. Idea. In Daniel’s Delia and Drayton’s Idea, ed. by Arundell
Esdaile. London: Chatto & Windus, 1908, 67–141, https://books.google. com/books?id=mOiobc0PmsgC&printsec=frontcover&source=gbs_ge_
summary_r&cad=0 Dreher, Diane. Domination and Defiance: Fathers and Daughters in Shakespeare. Lexington: University Press of Kentucky, 1986. Dronke, Peter. The Medieval Poet and His World. Rome: Edizioni di Storia e
Letteratura, 1984. Duffell, Martin J. A New History of English Metre. London: Modern Humanities
Research Association and Maney Publishing, 2008. Dümmler, Nicola Nina. “Musaeus, Hero and Leander: Between Epic and
Novel”. In Brill’s Companion to Greek and Latin ‘epyllion’ and Its Reception, ed. by Manuel Baumbach and Silvio Bär. Leiden: Brill, 2012, 411–446, https://doi. org/10.1163/9789004233058_019 Dunstan, William E. Ancient Rome. Lanham: Rowman & Littlefield, 2011. Eagleton, Terry. Literary Theory: An Introduction. Oxford: Blackwell, 1983. East, W. G. “This Body of Death: Abelard, Heloise and the Religious Life”. In
Medieval Theology and the Natural Body, ed. by Peter Biller and Alastair J. Minnis. Woodbridge, Suffolk: Boydell & Brewer, 1997, 43–59. Easthope, Antony. Poetry and Phantasy. Cambridge: Cambridge University
Press, 1989. 524 Love and its Critics Eckhart, Meister. “Qui audit me, non confundetur”. Deutsche Mystiker des
Vierzehnten Jahrhunderts: Meister Eckhart. Erste Abtheilung, ed. by Franz Pfeiffer. Leipzig: G. J. Göschen, 1857, 309–12, https://books.google.com/books?id=-
78FAAAAQAAJ&printsec=frontcover&source=gbs_ge_summary_r&cad=0 Edmondson, Paul, and Stanley Wells. Shakespeare’s Sonnets. Oxford: Oxford
University Press, 2004. Edwards, Catharine. Death in Ancient Rome. New Haven: Yale University Press,
2007. Edwards, David L. John Donne: Man of Flesh and Spirit. New York: Continuum,
2001. Egan, Gabriel. Shakespeare and Marx. Oxford: Oxford University Press, 2004. Eliot, T. S. “Donne in Our Time”. In A Garland for John Donne, 1631–1931, ed. by
Theodore Spencer. Cambridge, MA: Harvard University Press, 1931, 3–19. Ellis, F. S., trans. The Romance of the Rose. 3 Vols. London: J. M. Dent, 1900. Empson, William. Milton’s God. Norfolk, CT: New Directions, 1961. —. “Rescuing Donne”. In Essays on Renaissance Literature, ed. by John Charles
Robert Haffenden. Cambridge: Cambridge University Press, 1993, 159–99,
https://doi.org/10.1017/cbo9780511627477.006 —. Some Versions of Pastoral. London: Chatto & Windus, 1935. Epstein, Isidore, ed. Tractate Sanhedrin. In Hebrew English Edition of the Babylonian
Talmud, Vol. 19. London: Socino Press, 1969. Epstein, Stephen. “The Education of Daphnis: Goats, Gods, the Birds and the
Bees”. Phoenix, 56: 1–2 (2002), 25–39, https://doi.org/10.2307/1192468 Ermengaud, Matfré. Le Breviari D’Amor, ed. by Gabriel Azaïs. Bibliography Béziers: Secrétariat
de la Société Archéologique, Scientifique et Littéraire de Béziers, 1862,
https://archive.org/details/lebreviaridamor01ermeuoft, https://archive.org/
details/lebreviaridamor02ermeuoft Eschenbach, Wolfram von. Werke, ed. by Karl Lachmann. Berlin: G. Reimer,
1879, https://books.google.com/books?id=-rwFAAAAQAAJ&pg=PR1 Essam, Bacem A. “Nizarre Qabbani’s Original Versus Translated Pornographic
Ideology: A Corpus-Based Study”. Sexuality and Culture, 20 (2016), 965–986,
https://doi.org/10.1007/s12119-016-9369-7 Eusebius, Bishop of Caesarea. Ecclesiastical History. Ed. and trans. by J. E. L. Oulton. Loeb Classical Library, Cambridge, MA: Harvard University Press,
1932. Eve, Martin Paul. Literature Against Criticism. Cambridge: Open Book Publishers,
2016, https://doi.org/10.11647/OBP.0102 Everson, Jane E. The Italian Romance Epic in the Age of Humanism: The Matter of
Italy and the World of Rome. Oxford: Oxford University Press, 2001, https://
doi.org/10.1093/acprof:oso/9780198160151.001.0001 525 Bibliography Falck, Colin. Myth, Truth, and Literature: Towards a True Post-modernism. Cambridge: Cambridge University Press, 1989. Falconer, Rachel. “A Reading of Wyatt’s ‘Who so List to Hunt’”. In A Companion
to English Renaissance Literature and Culture, ed. by Michael Hattaway. Oxford: Blackwell, 2003, 176–86, https://doi.org/10.1002/9780470998731.ch14 Fay, Elizabeth A. Romantic Medievalism History and the Romantic Literary Ideal. New York: Palgrave, 2002, https://doi.org/10.1057/9781403913616 Febvre, Lucien. The Problem of Unbelief in the Sixteenth Century, the Religion of
Rabelais. Trans. by Beatrice Gottlieb. Cambridge, MA: Harvard University
Press, 1985. Felski, Rita. The Limits of Critique. Chicago: University of Chicago Press, 2015,
https://doi.org/10.7208/chicago/9780226294179.001.0001 —. “Suspicious Minds”. Poetics Today, 32: 2 (Summer 2011), 215–34, https://doi. org/10.1215/03335372-1261208 Fernie, Ewan. The Demonic: Literature and Experience. New York: Routledge, 2013. Ferrari, G. R. F. “Plato and Poetry”. In The Cambridge History of Literary Criticism,
Vol. 1: Classical Criticism, ed. by George Alexander Kennedy. Cambridge:
Cambridge University Press, 1989, 92–148. Fessler, Ignatius Aurelius. Abälard und Heloisa, Vol. 2. Berlin, 1806. Feuerbach, Ludwig. Das Wesen des Christentums, ed. by Werner Schuffenhauer. Berlin: De Gruyter, 2006, https://doi.org/10.1524/9783050085456 Fichte, Johann Gottlieb. Johann Gottlieb Fichte: Fichtes Reden an die Deutsche Nation,
ed. by Samantha Nietz. Hamburg: Severus, 2013. Fields, Weston. “Early and Medieval Interpretation of the Song of Songs”. Grace
Theological Journal, 1: 2 (1980), 222–33, https://biblicalstudies.org.uk/pdf/
gtj/01-2_221.pdf Findlay, John Niemeyer. Plato: The Written and Unwritten Doctrines. New York:
Routledge, 1974. Firenzuola, Agnolo. “Belleza delle Donne”. In Prose di M. Agnolo Firenzuola
Fiorentino. Florence: Bernardo Guinta, 1548, 55–109. Fish, Stanley Eugene. How Milton Works. Cambridge, MA: Belknap Press of
Harvard University Press, 2001. —. “Masculine Persuasive Force: Donne and Verbal Power”. In Soliciting
Interpretation: Literary Theory and Seventeenth-Century English Poetry, ed. by
Elizabeth D. Harvey and Katharine Eisaman Maus. Bibliography Chicago: University of
Chicago Press, 1990, 223–52. —. Surprised by Sin: The Reader in “Paradise Lost”. 2nd ed. Cambridge, MA:
Harvard University Press, 1998. Fleming, Bruce. What Literary Studies Could Be, And What It Is. Lanham: University
Press of America, 2008. 526 Love and its Critics Fortunatus (Venantius Fortunatus). Venanti Honori Clementiani Fortunati Presbyteri
Italici Opera Poetica, ed. by Frederick Leo. Berlin: Apud Weidmannos, 1881,
https://archive.org/details/venantihonoricl00unkngoog Foucault, Michel. Histoire de la sexualité, Vol. 1: la volonté de savoir. Paris: Gallimard,
1976. —. Les mots et les choses: Une archéologie sciences humaines. Paris: Gallimard, 1966. —. “Le retour de la morale”. In his Dits et écrits, 1954–1988. Vol. IV: 1980–1988. Paris: Gallimard, 1994, 696–707, https://doi.org/10.14375/np.9782070739899 —. “Le sujet e le pouvoir”. In his Dits et écrits. Vol. IV: 222–43, https://doi. org/10.14375/np.9782070739899 —. “Qu’est-ce qu’un auteur?” In his Dits et écrits. Vol. I: 1954–1975, 789–821,
https://doi.org/10.14375/np.9782070738441 —. “Sur les façons d’écrire l’Histoire” [interview with Raymond Bellour]. Les
Lettres françaises, 1187 (15–21 juin 1967), 6–9. Reprinted in his Dits et Écrits. Vol. I, 585–600, https://doi.org/10.14375/np.9782070738441 —. Surveiller et Punir: Naissance de la Prison. Paris: Gallimard, 1975. Frantzen, Allen J. Before the Closet: Same-Sex Love from “Beowulf” to “Angels
in America”. Chicago: University of Chicago Press, 1998, https://doi. org/10.4324/9781315587271 Freeburn, Ryan P. Hugh of Amiens and the Twelfth-Century Renaissance. Farnham:
Ashgate, 2011. Frelick, Nancy. “Lacan, Courtly Love and Anamorphosis”. In The Court
Reconvenes: Courtly Literature Across the Disciplines: Selected Papers from
the Ninth Triennial Congress of the International Courtly Literature Society,
University of British Columbia, 25–31 July, 1998. Cambridge, UK: Brewer,
2003, 107–14. Fuchs, Stephen. Against Essentialism: A Theory of Culture and Society. Cambridge,
MA: Harvard University Press, 2009. Gábor, Katona. “The Lover’s Education: Psychic Development in Sidney’s
‘Astrophil and Stella’”. Hungarian Journal of English and American Studies, 1:
2 (1995), 3–17. Gajowski, Evelyn. The Art of Loving: Female Subjectivity and Male Discursive
Traditions in Shakespeare’s Tragedies. Cranbury, NJ: Associated University
Presses, 1992. Gamel, Mary-Kay. “This Day We Read Further: Feminist Interpretation and the
Study of Literature”. Pacific Coast Philology, 22: 1–2 (1987), 7–14. Ganze, Alison. “Na Maria, pretz e fina valors”: A New Argument for Female
Authorship”. Romance Notes, 49: 1 (2009), 23–33, https://doi.org/10.1353/
rmc.2009.0010 527 Bibliography Gascoigne, George. The Complete Works of George Gascoigne: Vol. 1, The Posies, ed. by John W. Cunliffe. Cambridge: Cambridge University Press, 1907, https://
archive.org/details/cu31924013121292 Gaunt, Simon. “Poetry of Exclusion: A Feminist Reading of Some Troubadour
Lyrics”. Bibliography The Modern Language Review, 85: 2 (1990), 310–29, https://doi. org/10.2307/3731812 —. “The Châtelain De Couci”. In The Cambridge Companion to Medieval French
Literature, ed. by Simon Gaunt and Sarah Kay. Cambridge: Cambridge
University Press, 2008, 95–108, https://doi.org/10.1017/ccol9780521861755.007 Gaunt, Simon, and Sarah Kay. “Introduction”. In The Troubadours: An
Introduction, ed. by Simon Gaunt and Sarah Kay. Cambridge: Cambridge
University Press, 1999, 1–7. Gide, André. Les Nourritures terrestres. Paris: Gallimard, 1921. Gide, André. Les Nourritures terrestres. Paris: Gallimard, 1921. Gigot, Francis E., and Charles G. Herbermann. “Glosses, Scriptural-I. Etymology
and Principal Meanings”. In The Catholic Encyclopedia: An International
Work of Reference on the Constitution, Doctrine, Discipline, and History of the
Catholic Church: Father to Gregory, ed. by Charles G. Herbermann et al. New
York: Robert Appleton Company, 1909, Vol. 6, 588, https://archive.org/
details/07470918.6.emory.edu Gilead, Sarah. “Ungathering ‘Gather Ye Rosebuds’: Herrick’s Misreading of
Carpe Diem”. Criticism, 27: 2 (1985), 133–53. Giles of Rome. Librum Solomonis qui Cantica Canticorum Inscribitur Commentaria
D. Aegidii Romani. Rome: Antonium Bladum, 1555, https://books.google. com/books?id=ZcjIK13ZCXAC&pg=PP4 Gillis, John R. “Affective Individualism and the English Poor”. Journal of
Interdisciplinary History, 10: 1 (1979), 121–28. Gingrich, Andre. “Conceptualising Identities: Anthropological Alternatives
to Essentialising Difference and Moralizing about Othering”. Grammars of
Identity/Alterity: A Structural Approach, ed. by Gerd Baumann and Andre
Gingrich. New York: Berghahn Books, 2004, 3–17. Giroux, Henry. Neoliberalism’s War on Higher Education. Chicago: Haymarket
Books, 2014. Glancy, Ruth F. Thematic Guide to British Poetry. Westport: Greenwood Press,
2002. Goebbels, Joseph. “Rede vor der Presse über die Errichtung des
Reichspropagandaministeriums”. In Joseph Goebbels, Revolution der
Deutschen: 14 Jahre Nationalsozialismus. Oldenburg: Gerhard Stalling, 1933,
135–50. Goethe, Johann Wolfgang von. Faust, Part I, ed. by Walter Kaufmann. New
York: Anchor Books, 1990. 528 Love and its Critics Golb, Norman. The Jews in Medieval Normandy: A Social and Intellectual History. New York: Cambridge University Press, 1998. Golden, Mark. “Demography and the Exposure of Girls at Athens”. Phoenix, 35:
4 (1981), 316–31, https://doi.org/10.2307/1087926 Goldin, Frederick. The Mirror of Narcissus and the Courtly Love Lyric. Ithaca:
Cornell University Press, 1967. Goldstien, Neal L. “Love’s Labour’s Lost and the Renaissance Vision of Love”. In Shakespeare and the Literary Tradition, ed. by Stephen Orgel and Sean Kellen,
London: Routledge, 1999, 201–16. Goold, C. P. “The Cause of Ovid’s Exile”. Illinois Classical Studies, 8: 1 (1983),
94–107, http://hdl.handle.net/2142/11861 Gramsci, Antonio. Quarderi del carcere, Vol. I: Quaderni 1–5, ed. by Valentino
Gerratana. Turin: Einaudi, 1977. Gratian. Corpus Iuris Canonici, Vol. 1: Decretum Magistri Gratiani. Leipzig:
Bernhard
Tauchnitz,
1879,
http://www.columbia.edu/cu/lweb/digital/
collections/cul/texts/ldpd_6029936_001/index.html Greaves, Richard L. Society and Religion in Elizabethan England. Minneapolis:
University of Minnesota Press, 1981. Greek New Testament, ed. by Barbara Aland. Stuttgart: Deutsche Bibelgesellschaft,
2014. Greenblatt, Stephen. Renaissance Self-Fashioning: From More to Shakespeare. Chicago: University of Chicago Press, 1980. —. Shakespearean Negotiations: The Circulation of Social Energy in Renaissance
England. Berkeley and Los Angeles: University of California Press, 1998. —. Gide, André. Les Nourritures terrestres. Paris: Gallimard, 1921. The Swerve: How the World Became Modern. New York: W. W. Norton & Co.,
2011. Greenstein, Edward L. “Medieval Bible Commentaries”. In Back to the Sources:
Reading the Classic Jewish Texts, ed. by Barry W. Holtz. New York: Simon &
Schuster, 2006, 213–59. Grégoire, Henri. Rapport sur la nécessité et les moyens d’anéantir le patois, et
d’universaliser l’usage de la langue française. Paris: Imprimerie Nationale, 1794,
https://books.google.co.uk/books?id=8PB2RBNrLZYC&pg=PA1 Greville, Fulke. The Tragedy of Mustapha. London: Printed for Nathaniel Butler,
1609, https://archive.org/details/tragedyofmustaph00grev Grollman, Eric Anthony. “Gender Policing in Academe”. Inside Higher Education,
https://www.insidehighered.com/advice/2016/07/29/academy-polices-
gender-presentation-scholars-essay 529 Bibliography Grotius, Hugo. Hugonis Groth Sacra in quibus Adamus exul tragoedia. Hague:
Alberti Henrici, 1601, https://books.google.com/books?id=pRY_AAAAcAAJ
&pg=PP11 Guibbory, Achsah. “Erotic Poetry”. In The Cambridge Companion to John Donne,
ed. by Achsah Guibbory. Cambridge: Cambridge University Press, 2006,
133–48, https://doi.org/10.1017/ccol0521832373.009 —. “‘Oh, Let Mee Not Serve So’: The Politics of Love in Donne’s Elegies”. English
Literary History, 57: 4 (1990), 811–33, https://doi.org/10.2307/2873086 —. Returning
to
John
Donne. Farnham:
Ashgate,
2015,
https://doi. org/10.4324/9781315606170 Guilhem de Tudela and Anonymous. Historie de la Croisade contre les Hérétiques
Alibgeois, ed. by M. C. Fauriel. Paris: Imprimerie Royale, 1837, https://
archive.org/details/histoiredelacroi00guil Guilhem IX (Guillaume IX, Duc D’Aquitaine). Les Chansons De Guillaume
IX, Duc d’Aquitaine (1071–1127), ed. by Alfred Jeanroy. Paris: Honoré
Champion, 1913, https://archive.org/details/leschansonsdegui00willuoft Guinizelli, Guido. The Poetry of Guido Guinizelli, ed. by Robert Edwards. New
York: Garland Publishing, 1987. Guynn, Noah D. Allegory and Sexual Ethics in the High Middle Ages. New York:
Palgrave Macmillan, 2007, https://doi.org/10.1057/9780230603660 Hagstrum, Jean H. Esteem Enlivened by Desire: The Couple from Homer to
Shakespeare. Chicago: University of Chicago Press, 1992. Hallissy, Margaret. A Companion to Chaucer’s Canterbury Tales. Westport:
Greenwood Press, 1995. Hara, Diana. Courtship and Constraint: Rethinking the Making of Marriage in Tudor
England. Manchester: Manchester University Press, 2000. Hardin, Richard F. Love in a Green Shade: Idyllic Romances Ancient to Modern. Lincoln: University of Nebraska Press, 2000. Hartman, Geoffrey H. Criticism in the Wilderness: The Study of Literature Today. New Haven: Yale University Press, 1980. Haskins, Charles Homer. The Renaissance of the Twelfth Century. Cambridge, MA:
Harvard University Press, 1927. Haslam, Alexander S., and Stephen. D. Reicher. “Contesting the ‘Nature’ of
Conformity: What Milgram and Zimbardo’s Studies Really Show”. PLoS
Biology, 10: 11 (2012), https://doi.org/10.1371/journal.pbio.1001426 Hawkes, David. John Milton, A Hero of Our Time. Berkeley: Counterpoint Press, 2009. Hayyim, Yaakov Ben, ed. Mikraot Gedolot (תולודג תוארקמ), Vol. 4. Gide, André. Les Nourritures terrestres. Paris: Gallimard, 1921. Printed by Daniel
Bomberg: Venice, 1524, https://archive.org/stream/The_Second_Rabbinic_
Bible_Vol_4/4#page/n262 530 Love and its Critics Hegel, Georg Wilhelm Friedrich. Vorlesungen über die Aesthetik, Vol. 1. Berlin:
Dunder und Humblot, 1835. Heidegger, Martin. “Der Ursprung des Kunstwerkes”. Holzwege: Gesamtusgabe,
Vol. V. Frankfurt am Main: Vittorio Klostermann, 1977, 1–74. —. Grundfragen der Philosophie. Ausgewählte “Probleme” der “Logik”. Gesamtausgabe. II. Abteilung: Vorlesungen 1923–1944. Band 45. Frankfurt am Main: Vittorio
Klostermann, 1984. —. Sein und Zeit. Tübingen: Max Niemeyer, 1967. —. Sein und Zeit. Tübingen: Max Niemeyer, 1967. Heisterbacences, Caesarii. Dialogus Miraculorum, ed. by Josephus Strange,
Vol. 1. Cologne:
H. Lempertz,
1851,
https://archive.org/details/
caesariiheister00stragoog Heller-Roazen, Daniel. Fortune’s Faces: The Roman de la Rose and the Poetics of
Contingency. Baltimore: Johns Hopkins University Press, 2003. Hengel, Martin. “Mors Turpissima Crucis: Die Kreuzigung in der Antiken Welt
und die ‘Toheit’ des Wortes vom Kreuz”. In Rechtfertigung: Festschrift für
Ernst Käsemann zum 70 Geburtstag, ed. by Johannes Friederich, Wolfgang
Pöhlmann, and Peter Stuhlmacher. Tübingen: J. C. B. Mohr, 1976, 125–184. Herman, Edward S., and Noam Chomsky. Manufacturing Consent: The Political
Economy of the Mass Media. New York: Knopf Doubleday, 2011. Herman, Peter C. Destabilizing Milton: “Paradise Lost” and the Poetics of Incertitude. New York: Palgrave MacMillan, 2005. Herrick, Robert. The Complete Poems of Robert Herrick, 3 Volumes, ed. by Alexander
Balloch Grosart. London: Chatto & Windus, 1876. Herrick, Robert. The Complete Poems of Robert Herrick, 3 Volumes, ed. by Alexander
Balloch Grosart. London: Chatto & Windus, 1876. Vol. 1: https://books.google.com/books?id=n14JAAAAQAAJ
Vol. 2: https://books.google.com/books?id=l_c7AQAAMAAJ
Vol. 3: https://books.google.com/books?id=wM0qAQAAIAAJ Vol. 1: https://books.google.com/books?id=n14JAAAAQAAJ Vol. 2: https://books.google.com/books?id=l_c7AQAAMAAJ Vol. 3: https://books.google.com/books?id=wM0qAQAAIAAJ Herzman, Ronald B., Graham Drake, and Eve Salisbury, eds. Four Romances of
England: King Horn, Havelok the Dane, Bevis of Hampton, Athelston. Kalamazoo,
MI: Medieval Institute Publications, Western Michigan University, 1999. Highet, Gilbert. The Classical Tradition: Greek and Roman Influences on Western
Literature. New York and Oxford: Oxford University Press, 1949. Hilarius (Hilary the Englishman). Versus et Ludi Epistolae. Mittellateinische
Studien und Texte, Vol. 16, ed. by Walther Bulst und M. L. Bulst-Thiele. Leiden and New York: Brill, 1989. Hill, Christopher. Milton and the English Revolution. London: Faber and Faber, 1977. Hjelmslev, Louis. Omkring Sprogteoriens Grundlæggelse. Copenhagen: Bianco
Lunos Bogtrykkeri, 1943. 531 Bibliography Hobbes, Thomas. Leviathan: Or, The Matter, Forme & Power of a Commonwealth,
Ecclesiasticall and Civill (London: Andrew Crooke, 1651), https://books. google.com/books?id=L3FgBpvIWRkC&pg=PP19 Holmes, Nigel. “Nero and Caesar: Lucan 1.33–66”. Classical Philology, 1999, 75–
81, https://doi.org/10.1086/449419 Holmes, Olivia. Assembling the Lyric Self Authorship from Troubadour Song to
Italian Poetry Book. Minneapolis: University of Minnesota Press, 2000. Hölkeskam, Karl-J. Reconstructing the Roman Republic: An Ancient Political Culture
and Modern Research. Princeton: Princeton University Press, 2010, https://doi. org/10.1515/9781400834907 Homer. Odyssey, Vol. I: Books 1–12. Ed. and trans. by A. T. Murray. Loeb
Classical Library, Cambridge, MA: Harvard University Press, 1919. —. Odyssey, Vol. I: Books 13–24. Ed. and trans. by A. T. Murray. Horace. Horace: Epodes and Odes, ed. by Daniel H. Garrison. —. Sein und Zeit. Tübingen: Max Niemeyer, 1967. Norman: University
of Oklahoma Press, 1998. Horstmann, Carl, ed. The Early South English Legendary or Lives of Saints. London:
N. Trubner, 1887, https://archive.org/details/earlysouthenglis00hors Horváth, I. K. “Impius Aeneas”. Acta Antiqua Academiae Scientiarum Hungaricae,
3–4 (1958), 385–93, http://real-j.mtak.hu/441/1/ACTAANTIQUA_06.pdf Houlbrooke, Ralph A., ed. English Family Life: 1576–1716: An Anthology from
Diaries. Oxford: Blackwell, 1988. Hughes, Merritt Y. “The Lineage of ‘The Extasie’”. The Modern Language Review,
27: 1 (1932), 1–5. Hult, David F. “Gaston Paris and the Invention of Courtly Love”. In Medievalism
and the Modernist Temper, ed. by R. Howard Bloch and Stephen G. Nichols. Baltimore: Johns Hopkins University Press, 1996, 192–224. —. “Jean de Meun’s Continuation of Le Roman de la Rose”. In A New History of
French Literaure, ed. by Denis Hollier. Cambridge, MA: Harvard University
Press, 1989, 97–103. —. “The Roman de la Rose, Christine de Pizan, and the querelle des femmes”. In The Cambridge Companion to Medieval Women’s Writing, ed. by Carolyn
Dinshaw and David Wallace, 184–194. Cambridge: Cambridge University
Press, 2003, https://doi.org/10.1017/ccol052179188x.013 Hume, David. “Of the First Principles of Government”. In Essays, Literary,
Moral, and Political. London: Ward, Lock & Co., 1870, 23–25, https://catalog. hathitrust.org/Record/007662825 Huppé, Bernard F. A Reading of the Canterbury Tales. Albany: State University of
New York Press, 1964. 532 Love and its Critics “If Adam was Perfect, How Was It Possible for Him to Sin?” The Watchtower, 129:
19 (October 1, 2008), 27, https://wol.jw.org/en/wol/d/r1/lp-e/2008733 Isaacson, Walter. Benjamin Franklin: An American Life. New York: Simon &
Schuster, 2003. Jackson, W. T. H. “Faith Unfaithful—The German Reaction to Courtly Love”. In
The Meaning of Courtly Love, ed. by Francis X. Newman, 55–76. Albany: State
University of New York Press, 1969. Jacobson, Howard. Ovid’s Heroidos. Princeton: Princeton University Press, 1974. Jameson, Frederic. The Political Unconscious: Narrative as a Socially Symbolic Act. Ithaca: Cornell University Press, 1981. Jang, Jin-sung. Dear Leader: My Escape from North Korea. Trans. by Shirley Lee. New York: Simon & Schuster, 2014. Japhet, Sara. “Rashi’s Commentary on the Song of Songs: The Revolution of
the Peshat and Its Aftermath”. In Mein Haus Wird Ein Bethaus Für Alle Völker
Genannt Werden. Festschrift Für Thomas Wille Sum 75. Gerburgstag, ed. by J. Männchen and T. Reiprich. Neukirchen: Neukirchener Verlag, 2007, 199–219. Jeanjean, Henri. “Flamenca: A Wake for a Dying Civilization?”, Parergon, 16: 1
(July 1998), http://ro.uow.edu.au/cgi/viewcontent.cgi?article=2958&context
=artspapers Jerome. Contra Jovinianum. Vienna: Joannes Singrenius, 1516, https://books. google.com/books?id=SUZRAAAAcAAJ&pg=PP7 Jewell, Helen M. Women in Medieval England. —. Sein und Zeit. Tübingen: Max Niemeyer, 1967. Manchester: Manchester University
Press, 1996. Johnson, Samuel. The Lives of the Most Eminent English Poets, with Critical
Observations on Their Works, Vol. 1. London: J. Fergusson, 1819, https://books. google.com/books?id=e_sTAAAAQAAJ&pg=PP9 Jones, Michael K., and Malcolm G. Underwood. The King’s Mother: Lady Margaret
Beaufort, Countess of Richmond and Derby. Cambridge: Cambridge University
Press, 1993. Justinus, Marcus Junianus. Epitoma Historiarum Philippicarum Pompei Trogi. Leipzig: B. G. Teubner, 1886, https://babel.hathitrust.org/cgi/pt?id=uiug.30
112023680843;view=1up;seq=7 Kauffman, Linda S. Discourses of Desire: Gender, Genre, and Epistolary Fictions. Ithaca: Cornell University Press, 1986. Kaplan, David M. Ricoeur’s Critical Theory. Albany: State University of New
York Press, 2003. Kates, Joshua. “Literary Criticism”. In The Routledge Companion to Phenomenology. Ed. by Sebastian Luft. New York: Routledge, 2012, 644–54. 533 Bibliography Katz, Joseph. “Development of Mind”. In Scholars in the Making: The Development
of Graduate and Professional Students, ed. by Joseph Katz and Rodney T. Hartnett. Cambridge, MA, Ballinger, 1976, 107–26. Kay, Sarah. “Courts, Clerks, and Courtly Love”. In The Cambridge Companion
to Medieval Romance, ed. by Roberta L. Krueger. Cambridge: Cambridge
University Press, 2000, 81–97, https://doi.org/10.1017/ccol0521553423.006 —. Parrots and Nightingales: Troubadour Quotations and the Development of European
Poetry. Philadelphia: University of Pennsylvania Press, 2013, https://doi. org/10.9783/9780812208382 —. Subjectivity in Troubadour Poetry. Cambridge: Cambridge University Press,
1990, https://doi.org/10.1017/cbo9780511519550 —. The Place of Thought: The Complexity of One in Late Medieval French Didactic
Poetry. Philadelphia: University of Pennsylvania Press, 2007. Kelley, Maurice. “The Provenance of John Milton’s Christian Doctrine: A Reply
to William B. Hunter”. Studies in English Literature, 1500-1900, 34 (1994), 153–
63, https://doi.org/10.2307/450791 Kemp, Theresa D. Women in the Age of Shakespeare. Santa Barbara: Greenwood
Press, 2010. Kennedy, Elspeth. “The Rewriting and Re-reading of a Text: The Evolution
of the Prose Lancelot”. In The Changing Face of Arthurian Romance: Essays
on Arthurian Prose Romances in Memory of Cedric E. Pickford: A Tribute by
the Members of the British Branch of the International Arthurian Society, ed. by
Alison Adams, Armel H. Diverres, and Karen Stern. Cambridge, UK: Brewer,
1986, 1–9. Kennedy, William J. “European Beginnings and Transmissions: Dante Petrarch,
and the Sonnet Sequence”. In The Cambridge Companion to the Sonnet, ed. by A. D. Cousins and Peter Horwarth, 84–104. Cambridge: Cambridge University
Press, 2011, https://doi.org/10.1017/ccol9780521514675.006 Kerrigan, William. “Kiss Fancies in Robert Herrick”. George Herbert Journal, 14:
1–2 (1990), 155–71, https://doi.org/10.1353/ghj.1990.0014 King, Margaret L. “Children in Judaism and Christianity”. In The Routledge
History of Childhood in the Western World, ed. by Paula S. Fass. —. Sein und Zeit. Tübingen: Max Niemeyer, 1967. London:
Routledge, 2013, 39–60. Klein. Richard. “The Future of Literary Criticism”. PMLA, 125: 4 (October 2010),
920–23, https://doi.org/10.1632/pmla.2010.125.4.920 Kleinman, Scott. “Animal Imagery and Oral Discourse in Havelok’s First
Fight”, Viator: Medieval and Renaissance Studies, 35 (2004), 311–27, https://doi. org/10.1484/j.viator.2.300201 534 Love and its Critics Knox, Peter E. “The Heroides: Elegaic Voices”. In Brill’s Companion to Ovid,
ed. by Barbara Weiden Boyd. Leiden: Brill, 2002, 117–40, https://doi. org/10.1163/9789047400950_005 Köhler, Erich. “Zum ‘Trobar Clus’ Der Trobadors”. Romanische Forschungen, 64:
1–2 (1952), 71–101. —. “Observations historiques et sociologiques sur la poésie des troubadours”. Cahiers de civilisation médiévale, 7: 25 [1964], pp. 27–51, http://www.persee.fr/
doc/ccmed_0007-9731_1964_num_7_25_1296 Krass, Andreas. “Saying It with Flowers: Post-Foucauldian Literary History and
the Poetics of Taboo in a Premodern German Love Song”. In After the History
of Sexuality: German Genealogies with and Beyond Foucault, ed. by Scott Spector,
Helmut Puff, and Dagmar Herzog. New York: Berghahn Books, 2012, 63–75. Kristeva, Julia. Histoires d’amour. Paris: Denoël, 1983. Krueger, Paul, Theodor Mommsen, Rudolf Schoell, and Whilhelm Kroll, eds. Corpus Iuris Civilis, Vol. 2. Berlin: Apud Weidmannos, 1892, https://books. google.com/books?id=2hvTAAAAMAAJ&printsec=frontcover&source=g
bs_ge_summary_r&cad=0 Labé, Louise. Oeuvres De Louise Labé, ed. by Prosper Blancheman. Paris: Librarie
des Bibliophiles, 1875, https://books.google.com/books?id=w_fl8BM3_SUC
&printsec=frontcover&source=gbs_ge_summary_r&cad=0 La Boétie, Étienne de. Discours de la Servitude Volontaire [1576]. Paris: Editions
Bossard, 1922, https://fr.wikisource.org/wiki/Livre:La_Boétie_-_Discours_
de_la_servitude_volontaire.djvu Lacan, Jacques. “Discours de Jacques Lacan”. La Psychanalyse, 1 (1956), 202–11,
242–55. —. Écrits. Paris: Seuil, 1966. —. Le Séminaire de Jacques Lacan, Livre III: Les Psychoses: 1955–1956, ed. by Jacques
Alain Miller. Paris: Seuil, 1981. —. Le Seminiare de Jacques Lacan. Livre VII. L’Éthique de la Psychanalyse: 1959–1960,
ed. by Jacques Alain Miller. Paris: Seuil, 1986. —. Le Séminaire de Jacques Lacan, Livre XVII: L’envers de la Psychanalyse: 1969–1970,
ed. by Jacques Alain Miller. Paris: Seuil, 1991. Lagerlund, Henrik. “The Assimilation of Aristotelian and Arabic Logic up to the
Later Thirteenth Century”. In Mediaeval and Renaissance Logic, ed. by Dov M. Gabbay and John Woods. Amsterdam: Elsevier, 2008, 281–346, https://doi. org/10.1016/s1874-5857(08)80026-x Landrum, David. “Robert Herrick and the Ambiguities of Gender”. Texas Studies
in Literature and Language, 49: 2 (2007), 181–207, https://doi.org/10.1353/
tsl.2007.0012 535 Bibliography Lane, Joan. Apprenticeship in England: 1600–1914. London: UCL Press, 1996. Lanham, Richard A. The Motives of Eloquence: Literary Rhetoric in the Renaissance. New Haven: Yale University Press, 1976. Larson, Deborah Aldrich. John Donne and Twentieth-century Criticism. London:
Associated University Presses, 1989. Layton, Richard A. —. Sein und Zeit. Tübingen: Max Niemeyer, 1967. “Hearing Love’s Language: The Letter of the Text in Origen’s
Commentary on the Song of Songs”. In The Reception and Interpretation of
the Bible in Late Antiquity: Proceedings of the Montréal Colloquium in Honour
of Charles Kannengiesser, 11–13 October 2006, ed. by Lorenzo DiTommaso
and Lucian Turcescu. Leiden: Brill, 2008, 287–315, https://doi.org/10.1163/
ej.9789004167155.i-608.75 Lazar, Moshe. “Cupid, the Lady, and the Poet: Modes of Love at Eleanor of
Aquitaine’s Court”. In Eleanor of Aquitaine: Patron and Politician, ed. by
William W. Kibler. Austin: University of Texas Press, 1976, 35–60. —. “Fin’amor”. In A Handbook of the Troubadours, ed. by F. R. P. Akehurst and
Judith M. Davis. Berkeley: University of California Press, 1995, 61–100. Lazda-Cazers, Rasma. “Oral Sex in the Songs of Oswald von Wolkenstein: Did it
Really Happen?” In Sexuality in the Middle Ages and Early Modern Times: New
Approaches to a Fundamental Cultural-Historical and Literary-Anthropological
Theme, ed. by Albrecht Classen. Berlin: De Gruyter, 2008, 579–98, https://doi. org/10.1515/9783110209402.579 Lea, Henry Charles. A History of the Inquisition of the Middle Ages, Vol. 1. New
York: Macmillan, 1906. Leggatt, Alexander. Shakespeare’s Political Drama: The History Plays and the Roman
Plays. New York: Routledge, 2003. Léglu, Catherine, Rebecca Rist, and Claire Taylor. The Cathars and Albigensian
Crusade: A Sourcebook. New York: Routledge, 2014. Le Goff, Jacques, ed. The Medieval World. Trans. by Lydia G. Cochrane. London:
Collins & Brown, 1990. Leishman, J. B. Themes and Variations in Shakespeare’s Sonnets. London: Routledge,
1961. Lentini, Giacomo da. A Critical Edition of the Poetry of Giacomo da Lentini, ed. by
Stephen Popolizio. Ph.D. dissertation, Indiana University, 1975; Ann Arbor:
University Microfilms, 1980. Leonard, John. Faithful Labourers: A Reception History of Paradise Lost, 1667–1970,
Vol. 2. Interpretive Issues. Oxford: Oxford University Press, 2013. Levi-Strauss, Claude. “Introduction à l’œuvre de Marcel Mauss”. In Marcel
Mauss, Sociologie et Anthropologie. Paris: Presses Universitaires de France,
1950, xxiv–xl. 536 Love and its Critics —. Les Structures Élémentaires de la Parenté. Berlin: De Gruyter, 2002. Lewis, C. S. A Preface to Paradise Lost. London: Oxford University Press, 1942. —. The Allegory of Love: A Study in Medieval Tradition. London: Oxford University
Press, 1936. Lille, Alain de. Alani de Insulis doctoris universalis opera omnia. In Patrologiae Cursus
Completus, Vol. 210, ed. by Jacques Paul Migne. Paris: Apud Garnier Fratres,
1855, https://books.google.com/books?id=c10k8WCYMBoC&pg=PA7 Livy (Titus Livius Patavinus). Titi Livi Ab vrbe condita libri praefatio, liber primvs,
Vol. 1, ed. by H. J. Edwards. —. Sein und Zeit. Tübingen: Max Niemeyer, 1967. Cambridge: Cambridge University Press, 1912,
https://books.google.com/books?id=gsNEAAAAIAAJ&printsec=frontcover
&source=gbs_ge_summary_r&cad=0 Locke, John. Concerning Civil Government, Second Essay, ed. by Robert Maynard
Hutchins. Great Books of the Western World, Vol. 35. Chicago: Encyclopedia
Britannica, 1952. Longus. Daphnis and Chloe. Ed. and trans. by Jeffrey Henderson. Loeb Classical
Library, Cambridge, MA: Harvard University Press, 2009, https://doi. org/10.4159/dlcl.longus-story_daphnis_chloe.2009 Longxi, Zhang. “The Letter or the Spirit: The Song of Songs, Allegoresis,
and the Book of Poetry”. Comparative Literature: 193–217, https://doi. org/10.2307/1770241 Lorris, Guillaume de, and Jean de Meun. Le Roman de la Rose. 3 vols, ed. by Felix
Lecoy. Paris: Honoré Champion, 1965. —. The Romance of the Rose. Ed. and trans. by Charles Dahlberg. Princeton:
Princeton University Press, 1971. Love, Heather. “Truth and Consequences: On Paranoid Reading and Reparative
Reading”. Criticism, 52: 2 (Spring 2010), 235–241, https://doi.org/10.1353/
crt.2010.0022 Lucan (Marcus Annaeus Lucanus). The Civil War (Pharsalia). Ed. and trans. by J. D. Duff. Loeb Classical Library, Cambridge, MA: Harvard University Press,
1962. Luft, Joanna. “The Play of Repetition and Resemblance in The Romance of the
Rose”. The Romanic Review, 102: 1–2 (2011), 49–63. Luther, Martin. Martin Luther. Von Weltlicher Obrigkeit. Berlin: Tredition Classics,
2012, 10. —. B. Patris Martini Lutheri Liber de Servo Arbitrio, ed. by Sebastian Schmid. Strasburg: J. R. Dulsseckeri, 1707. Macdonald, Aileen Ann. “A Refusal to Be Silenced or to Rejoice in Any Joy That
Love May Bring: The Anonymous Old Occitan Canso, ‘Per Ioi Que D’amor
M’avegna’”. Dalhousie French Studies, 36 (1996), 3–13. 537 Bibliography MacFarlane, Alan. “Review of the Family, Sex and Marriage in England: 1500–
1800, by Lawrence Stone”. History and Theory, 18 (1979), 103–26, https://doi. org/10.2307/2504675 Macfie, Pamela Royston. “Lucan, Marlowe, and the Poetics of Violence”. In
Renaissance Papers 2008, ed. by Christopher Cobb and M. Thomas Hester. Rochester, NY: Camden House, 2009, 47–64, https://doi.org/10.1017/
upo9781571137494.005 Macrobius. Saturnalia. Ed. and trans. by Robert A. Kaster. Loeb Classical Library,
Cambridge, MA: Harvard University Press, 2011. Mallarmé, Stéphane. “Crise de Vers”. In Divagations. Paris: Bibliothèque-
Charpentier, 1897, 235–49, https://fr.wikisource.org/wiki/Divagations/Texte_
entier Mann, Jill. Life in Words: Essays on Chaucer, the Gawain-Poet, and Malory. Toronto:
University of Toronto Press, 2014. Marcabru. Poésies Complètes du Troubadour Marcabru, ed. by Jean Dejeanne. Toulouse: Édouard Privat, 1909, http://gallica.bnf.fr/ark:/12148/bpt6k4240c/
f3.item Marenbon, John. Medieval Philosophy: An Historical and Philosophical Introduction. London: Routledge, 2007. —. The Philosophy of Peter Abelard. Cambridge: Cambridge University Press, 1997. Mariaselvam, Abraham. The Song of Songs and Ancient Tamil Love Poems: Poetry
and Symbolism. —. Sein und Zeit. Tübingen: Max Niemeyer, 1967. Roma: Editrice Pontificio Istituto Biblico, 1988. Marlowe, Christopher. “Hero and Leander”. In Christopher Marlowe: The Complete
Poems and Translations, ed. by Stephen Orgel. London: Penguin, 2007. Martin, Catherine Gimelli. “The Erotology of Donne’s ‘Extasie’; And The Secret
History Of Voluptuous Rationalism”. Studies in English Literature, 1500-1900,
44: 1 (2004), 121–47, https://doi.org/10.1353/sel.2004.0008 Martinez, Ronald. “Italy”. In A Handbook of the Troubadours, ed. by F. R. P. Akehurst and Judith M. Davis. Berkeley: University of California Press, 1995,
279–94. Marvin, Laurence W. The Occitan War: A Military and Political History of the Albigensian
Crusade, 1209–1218. Cambridge: Cambridge University Press, 2008, https://doi. org/10.1017/cbo9780511496561 Masten, Jeffrey. “The Two Gentlemen of Verona”. In A Companion to Shakespeare’s
Works, Vol. III, ed. by Richard Dutton. Malden: Blackwell, 2003, 266–85, https://
doi.org/10.1002/9780470996553.ch14 May, Simon. Love: A History. New Haven: Yale University Press, 2011. McCloskey, Patrick, and Edward Phinney, Jr. “Ptolemaeus Tyrannus: The
Typification of Nero in the Pharsalia”. Hermes, 96 (1968), 80–87. 538 Love and its Critics McGlynn, Sean. Kill Them All: Cathars and Carnage in the Albigensian Crusade. Stroud, UK: History Press, 2015. McGowan, Kate. Key Issues in Critical and Cultural Theory. Buckingham: Open
University Press, 2007. McGrath, Alister. C. S. Lewis A Life: Eccentric Genius, Reluctant Prophet. Carol
Stream, IL: Tyndale House Publishers, 2013. McGuckin, John Anthony. “The Scholarly Works of Origen”. The Westminster
Handbook to Origen, ed. by John Anthony McGuckin. Louisville: Westminster
John Knox Press, 2004, 25–41. McWebb, Christine. “Hermeneutics of Irony: Lady Reason and the Romance of
the Rose”. Dalhousie French Studies, 69 (2004), 3–13. Meaney, Audrey L. “The Ides of the Cotton Gnomic Poem”. Medium Ævum, 48:
1 (1979), 23–39, https://doi.org/10.2307/43628412 Meschini, Marco. “‘Smoking Sword’: Le Meurtre Du Legat Pierre De Castelnau
Et La Premiere Croisade Albigeoise”. In La Papauté et les Croisades, ed. by
Michel Balard. Farnham: Ashgate, 2011, 67–75. Mews, Constant J. Abelard and Heloise. Oxford: Oxford University Press, 2005,
https://doi.org/10.1093/0195156889.001.0001 —. “Abelard, Heloise, and Discussion of Love in the Twelfth-Century Schools”. In
Rethinking Abelard: A Collection of Critical Essays, ed. by Babette S. Hellemans. Leiden: Brill, 2014, 11–36. —. “Accusations of Heresy and Error in the Twelfth Century Schools: The Witness
of Gerhoh of Reichersberg and Otto of Freising”. In Heresy in Transition:
Transforming Ideas of Heresy in Medieval and Early Modern Europe. London:
Routledge, 2016, 43–58. —. The Lost Love Letters of Heloise and Abelard. New York: Palgrave MacMillan,
1999. Miller, J. Hillis. “The Critic as Host”. —. Sein und Zeit. Tübingen: Max Niemeyer, 1967. Critical Inquiry, 3: 3 (Spring 1977), 439–447,
https://doi.org/10.1086/447899 —. “Walter Pater: A Partial Portrait”. Daedalus, In Praise of Books, 105: 1 (Winter
1976), 97–113. Miller, Patrick D. “A Fairy Tale Wedding?” In A God so Near: Essays on Old
Testament Theology in Honor of Patrick D. Miller, ed. by Brent A. Strawn and
Nancy R. Bowen, 53–71. Winona Lake, IN: Eisenbrauns, 2003. Milton,
John. Areopagitica. London,
1644,
https://books.google.com/
books?id=tvhAAQAAMAAJ&pg=PA26 —. A Treatise of Civil Power. London, 1659, http://quod.lib.umich.edu/e/eebo/A50
959.0001.001/1:3?rgn=div1;view=fulltext 539 Bibliography —. Complete Poems and Major Prose, ed. by Merritt Hughes. New York: Odyssey
Press, 1957. —. Eikonoklestes. London, 1650, http://quod.lib.umich.edu/e/eebo/A50898.0001.0
01/1:2?rgn=div1;view=fulltext —. Of Education. London, 1644, https://books.google.com/books?id=7rJDAA
AAcAAJ&pg=PP3 —. The Doctrine & Discipline of Divorce. London, 1644, https://books.google. com/books?id=6oI-AQAAMAAJ&printsec=frontcover&source=gbs_ge_
summary_r&cad=0 —. The Tenure of Kings and Magistrates. London, 1649, http://quod.lib. umich.edu/e/eebo/A50955.0001.001/1:2?rgn=div1;view=fulltext,
https://books.google.com/books?id=EIg-AQAAMAAJ&pg=PA1
(1650
edition). Minh-ha, Trink T. Woman, Native, Other. Bloomington, IN: Indiana University
Press, 1989. Minnis, Alastair. Fallible Authors: Chaucer’s Pardoner and Wife of Bath. Philadelphia:
University
of
Pennsylvania
Press,
2008,
https://doi. org/10.9783/9780812205718 —. Medieval Theory of Authorship: Scholastic Literary Attitudes in the Later Middle
Ages. 2nd ed. Philadelphia: University of Pennsylvania Press, 1988. Mitchell, Charles. “Donne’s “The Extasie”: Love’s Sublime Knot”. Studies
in English Literature, 1500–1900, 8: 1 (1968), 91–101, https://doi. org/10.2307/449412 Monfasani, John. “The Swerve: How the Renaissance Began”. Reviews in History,
1283, http://www.history.ac.uk/reviews/review/1283 Montahagol, Guilhem. Le Troubadour Guilhem Montanhagol. Par Jules
Coulet (Poésies De Guilhem Montanhagol), ed. by Jules Coulet. Toulouse:
Imprimerie et Librairie Édouard Privat, 1898, https://archive.org/details/
letroubadourguil00guil Montaigne, Michel de. “Apologie de Raimond de Sebonde”. In Les Essais de
Michel de Montaigne, Vol. 2, ed. by Fortunat Strowski. Bordeaux: Pech, 1906,
140–370, https://archive.org/details/essaispublisda02montuoft Montmorency, James Edward Geoffrey. The Progress of Education in England. A
Sketch of the Development of English Educational Organization from Early times
to the Year 1904. London: Knight & Co., 1904. Morris, Colin. The Discovery of the Individual, 1050–1200. New York: Harper &
Row, 1972. Morrissey, Lee and Will Stockton. “What Swirls around The Swerve”. Exemplaria
25.4 [Winter 2013], 332–36, https://doi.org/10.1179/1041257313Z.00000000036 540 Love and its Critics Musaeus (Musaeus Grammaticus). Hero and Leander, ed. by Thomas Gelzer. Loeb Classical Library, Cambridge, MA: Harvard University Press, 1973,
https://doi.org/10.4159/dlcl.musaeus-hero_leander.1973 Musgrove, S. “Is The Devil An Ass?” Review of English Studies, 21 (1945), 302–15. Musil, Robert. Der Mann Ohne Eigenschaften. Berlin: Rowohlt Verlag, 1957. Nelson, Lowry. Poetic Configurations: Essays in Literary History and Criticism. University Park: Pennsylvania State University Press, 1992. Neruda, Pablo. —. Sein und Zeit. Tübingen: Max Niemeyer, 1967. “Puedo escribir los versos más tristes esta noche”. In Veinte
Poemas de Amor y una Canción Desesperada. Bogotá and Barcelona: Editorial
Norma, 2002, 45–46. Nevo, Yehoshafaṭ. פרשנות המקרא הצרפתית: עיונים בדרכי פרשנותם של מפרשי המקרא בצפון
צרפת בימי הביניים [French Biblical Interpretation: Studies in the Interpretive
Methods of the Bible Commentators in Northern France in the Middle Ages]. Reḥovot: Moreshet Yaʻaḳov, 2004. Newman, Barbara. From Virile Woman to WomanChrist: Studies in Medieval
Religion and Literature. Philadelphia: University of Pennsylvania Press, 1995,
https://doi.org/10.9783/9780812200263 —. Gods and the Goddesses: Vision, Poetry, and Belief in the Middle Ages. Philadelphia:
University
of
Pennsylvania
Press,
2003,
https://doi. org/10.9783/9780812202915 Niel, Ferdinand. Albigeois et Cathares. Paris: Presses Universitaires de France, 1974. Nietzsche, Friedrich Wilhelm. Jenseits Von Gut und Böse: Vorspiel einer Philosophie
der Zukunft. Leipzig: C. G. Naumann, 1886. —. Die Geburt der Tragödie aus dem Geiste der Musik. Leipzig: C. G. Naumann, 1894,
https://books.google.com/books?id=lSk2AQAAMAAJ&pg=PP17 —. Zur Genealogie der Moral: Eine Streitschrift. Leipzig: C. G. Naumann, 1887. —. Zur Genealogie der Moral (1887); Götzen-Dämmerung (1889), ed. by Claus
Scheier. Hamburg: F. Meiner Verlag, 2013. O’Sullivan, Daniel E. “Na Maria: Courtliness and Marian Devotion in Old
Occitan Lyric”. In Shaping Courtliness in Medieval France: Essays in Honor of
Matilda Tomaryn Bruckner, ed. by Daniel E. O’Sullivan and Laurie Shepard,
Cambridge, UK: Brewer, 2013, 183–200. —. “The Man Backing Down from the Lady in Trobairitz Tensos”. In Founding
Feminisms in Medieval Studies: Essays in Honor of E. Jane Burns, ed. by Laine
E. Doggett and Daniel E. O’Sullivan. Cambridge: Boydell & Brewer, 2016,
45–60. Okamura, David Scott. Virgil in the Renaissance. Cambridge, UK: Cambridge
University Press, 2010, https://doi.org/10.1017/CBO9780511762581 Olmert, Michael. Milton’s Teeth & Ovid’s Umbrella: Curiouser and Curiouser
Adventures in History. New York: Touchstone, 1996. 541 Bibliography Olson, Roger E. The Story of Christian Theology: Twenty Centuries of Tradition &
Reform. Downers Grove: InterVarsity Press, 1999. Oppenheimer, Paul. The Birth of the Modern Mind: Self, Consciousness, and the
Invention of the Sonnet. Oxford: Oxford University Press, 1989. —. “The Origin of the Sonnet”. Comparative Literature, 34: 4 (1982), 289–304,
https://doi.org/10.2307/1771151 Origen. Origene: Commentaire sur le Cantique des Cantiques, Vol. 1. Texte de la
Version Latine de Rufin, ed. by Luc Bresard, Henri Crouzel, and Marcel Borret. Paris: Éditions du Cerf, 1991. Outhwaite, R. B. Clandestine Marriage in England, 1500–1850. London: Hambledon
Press, 1995. Ovid. Amores. In Ovid: Heroides and Amores. Ed. and trans. by Grant Showerman. —. Sein und Zeit. Tübingen: Max Niemeyer, 1967. Loeb Classical Library, Cambridge, MA: Harvard University Press, 1958. —. Ars Amatoria. In Ovid: The Art of Love and other Poems. Ed. and trans. by J. H. Mozley. Loeb Classical Library, Cambridge, MA: Harvard University Press,
1962. —. Metamorphoses. Berlin: De Gruyter, 1998. —. The Art of Love. Trans. by James Michie. Introduction by David Malouf. New
York: Modern Library, 2002. Paden William D. “Introduction”. In Medieval Lyric: Genres in Historical Context,
ed. by William D. Paden. Urbana and Chicago: University of Illinois Press,
2000, 1–17. Paden, William D., and Frances Freeman Paden, eds. and trans. Troubadour
Poems from the South of France. Cambridge, UK: Brewer, 2007. Palmer, Nigel F. “The High and Later Middle Ages (1100–1450)”. In The
Cambridge History of German Literature, ed. by Hellen Watanabe-O’Kelly. Cambridge: Cambridge University Press, 1997, 40–90, https://doi. org/10.1017/chol9780521434171.003 Paris, Gaston. “Études sur les romans de la table ronde. Lancelot du lac, I. Le Lanzelet d’Ulrich de Zatzikhoven; Lancelot du Lac, II. Le Conte de
la Charrette”. Romania, 12 (1883), 459–534, http://www.persee.fr/doc/
roma_0035-8029_1883_num_12_48_6277 —. La Poesie du Moyen Age. Paris: Librarie Hachette, 1895, https://books.google. com/books?id=LdHs-jMItRQC&pg=PR3 Parker, John. “The Epicurean Middle Ages”. Exemplaria 25.4 [Winter 2013], 324–
29, https://doi.org/10.1179/1041257313Z.00000000036 Parmenides. Die Fragmente der Vorsokratiker, ed. by Hermann Diels. Berlin:
Weidmannsche Buchhandlung, 1903, 108–29. Paterson, Linda M. The World of the Troubadours: Medieval Occitan Society, C. 1100-c. 1300. Cambridge: Cambridge University Press, 1993. 542 Love and its Critics Patri, Gabriel Díaz. “Poetry in the Latin Liturgy”. In The Genius of the Roman Rite:
Historical, Theological, and Pastoral Perspectives on Catholic Liturgy, ed. by Uwe
Michael Lang: Hillenbrand Books, 2010. Patterson, Lee. “On the Margin: Postmodernism, Ironic History, and Medieval
Studies”. Speculum, 65: 1 (1990), 87–108, https://doi.org/10.2307/2864473 Pearsall, Derek. The Canterbury Tales. New York: Routledge, 2002. Pecora, Vincent P. “The Limits of Local Knowledge”. In The New Historicism, ed. by Harold Aram Veeser. New York: Routledge, 1989, 243–76. Pegg, Simon. A Most Holy War: The Albigensian Crusade and the Battle for Christian
Freedom. Oxford: Oxford University Press, 2008. Pelagius. Pelagius: Life and Letters, ed. by B. R. Rees. Woodbridge: Boydell Press,
1998. —. Pelagii Sancti et eruditi monachi Epistola ad Demetriadem, ed. by Johann Salomo
Semler. Halae Magdeburgicae: Carol Herman Hemmerde, 1775, https://
books.google.com/books?id=uw5qbOfGtgoC&pg=PP7 Peter, John Desmond. A Critique of Paradise Lost. New York: Columbia University
Press, 1960. Petrarca, Francesco. Il Canzoniere, ed. by Paola Vecchi Galli. Milan: Rizzoli, 1954. —. Triunfi, ed. by Cristoforo Pasqualigo. —. Sein und Zeit. Tübingen: Max Niemeyer, 1967. Venezia: Giuseppe Bresciani, 1874,
https://books.google.com/books?id=5_0FAAAAQAAJ&printsec=frontcover
&source=gbs_ge_summary_r&cad=0 Pinker, Steven. The Better Angels of Our Nature: Why Violence Has Declined. New
York: Viking, 2011. Pizan, Christine de. Le Débat sur le Roman de la Rose, ed. by Eric Hicks. Paris:
Honoré Champion, 1977. Plato. Cratylus. Parmenides. Greater Hippias. Lesser Hippias. Ed. and trans. by
Harold North Fowler. Loeb Classical Library, Cambridge, MA: Harvard
University Press, 1926. —. Republic. Books 6–10. Ed. and trans. by Christopher Emlyn-Jones and William
Preddy. Loeb Classical Library, Cambridge, MA: Harvard University Press,
2013. —. Symposium. Ed. and trans. by W. R. M. Lamb. Loeb Classical Library,
Cambridge, MA: Harvard University Press, 1925. Plotinus. Ennead, Vol. V. Ed. and trans. by A. H. Armstrong. Loeb Classical
Library, Cambridge, MA: Harvard University Press, 1984. Pollock, Linda A. Forgotten Children: Parent-child Relations from 1500 to 1900. Cambridge: Cambridge University Press, 1983. Popper, Karl. Conjectures and Refutations: The Growth of Scientific Knowledge. New
York: Basic Books, 1963. 543 Bibliography Prudentius. “Hymnus Ante Somnum”. In Patrologiae Cursus Completus, Vol. 59, ed. by Jacques Paul Migne. Paris: Apud Garnier Fratres, 1855, 831–41,
https://books.google.com/books?id=jnzYAAAAMAAJ&pg=PA18 Prynne, William. Histriomastix. London: Printed by E. A. and W. I. for Michael
Sparke, 1633, https://archive.org/details/maspla00pryn Pushkin, Aleksandr Sergeevich. Cобрание сочинений (Sobranie sochinenii). Collected Works, 10 Vols, ed. by D. D. Blagoi, S. M. Bondi, V. V. Vinogradov
and Yu. G. Oksman. Moscow: Khudozhestvennaia literatura, 1959, Vols. 2, 4,
http://rvb.ru/pushkin/toc.htm Qābbanī, Nizār. “Love Letter 71”. Trans. by Modje Taavon from the Arabic text
published in Arabian Love Poems, ed. by Bassam K. Frangieh and Clementia
R. Brown. London: Lynne Rienner Publishers, 1999, 134. Quaglio, Antonio Enzo. Al di là di Francesca e Laura. Padova: Liviana Editrice,
1973. Quchak, Nahapet. Haryur u mek hayren, ed. by Arshak Madoyan and Irina
Karumyan. Yerevan: Sovetakan Grokh, 1976. Quinones, Richard J. “Dante Aligheiri”. In Medieval Italy: An Encyclopedia, ed. by
Christopher Kleinhenz. New York: Routledge, 2004, 278–286. Quint, David. Inside Paradise Lost: Reading the Designs of Milton’s Epic. Princeton:
Princeton University Press, 2014, https://doi.org/10.1515/9781400850488 Rabelais, Francois. Gargantua et Pantagruel. In Œuvres de Rabelais, Vol. 1. Paris:
Dalibon, 1823, https://books.google.com/books?id=4EKEULv3EMkC&print
sec=frontcover&source=gbs_ge_summary_r&cad=0 Raby, F. J. E. A History of Secular Latin Poetry in the Middle Ages. Oxford:
Clarendon Press, 1934. —. A History of Christian-Latin Poetry: From the Beginnings to the Close of the Middle
Ages. Oxford: Clarendon Press, 1927. Radice, Betty, ed. The Letters of Abelard and Heloise. London: Penguin, 1974. Radice, Betty, ed. The Letters of Abelard and Heloise. London: Penguin, 1974. Ram, Widow and Brothers, eds. Mikraot Gedolot: Torah with Forty-Two
Commentaries (םישורפ םיעבראו םיינש םע הרות ישימח השימח :תולודג תוארקמ), Vol. 3. The Widow and Brothers Ram: Truskavets/Glukhov, Ukraine, 1907, https://
books.google.com/books?id=fEUpAAAAYAAJ&pg=PA418 Ray, Chris. Song of Solomon for Teenagers: And Anyone Else Who Wonders Why They
Are Here. Bloomington, IN: AuthorHouse, 2010. Reddy, William M. The Making of Romantic Love: Longing and Sexuality in Europe,
South Asia, and Japan, 900–1200 CE. Chicago: University of Chicago Press, 2012,
https://doi.org/10.7208/chicago/9780226706283.001.0001 544 Love and its Critics Reid, Charles J. Power Over the Body, Equality in the Family: Rights and Domestic
Relations in Medieval Canon Law. Grand Rapids: William B. Eerdmans, 2004. Reynolds, Barbara. Dante: The Poet, the Political Thinker, the Man. London: I. B. Tauris, 2006. Richard of St. Victor. Exposition in Cantica Canticorum. In Patrologiae Cursus
Completus: Series Latina, Vol. 196, ed. by Jacques-Paul Migne. Paris, 1855,
https://archive.org/stream/patrologiaecurs104unkngoog#page/n271 Richman, Gerald. “A Third Choice: Adam, Eve, and Abdiel”. Early Modern
Literary Studies, 9: 2 (2003), https://extra.shu.ac.uk/emls/09-2/richthir.html Richtmeyer, Eric. “Maurice Blanchot: Saboteur of the Writers’ War”. Proceedings
of the Western Society for French History, 35 (2007), 247–62. Ricoeur, Paul. De l’interprétation. Essai sur Freud. Paris: Seuil, 1965. —. Le Conflit des Interprétations: Essais D’Herméneutique. Paris: Seuil, 1969. —. Temps et Récit, Vol. 3: Le Temps Raconté. Paris: Seuil, 1985. Rieger, Angelica. “Was Bieiris De Romans Lesbian? Women’s Relations
with Each Other in the World of the Troubadours”. In The Voice of the
Trobairitz: Perspectives on the Women Troubadours, ed. by William D. Paden. Philadelphia: University of Pennsylvania Press, 1989, 73–94, https://doi. org/10.9783/9781512805444-005 Rivarol, Antoine de. Discours de l’Universalité de la langue Française. Berlin, 1784. Roberts, John. “John Donne’s Poetry: An Assessment of Modern Criticism”. John Donne Journal, 1 (1982), 55–67. Robertson, D. W. “The Concept of Courtly Love”. In The Meaning of Courtly
Love, ed. by Francis X. Newman. Albany: State University of New York Press,
1968, 1–18, https://doi.org/10.1086/388953 —. “The Subject of the ‘De Amore’ of Andreas Capellanus”. Modern Philology,
1953, 145–61, https://doi.org/10.1086/388953 Rodríguez de la Cámara, Juan. Triunfo de las Donas. In Obras de Juan Rodríguez
de la Cámara: (ó del Padrón), ed. by Antonio Paz y Meliá. Madrid: La
Sociodad de Bibliofilos Españoles, 1884, https://archive.org/details/
ObrasJuanRodriguezCamara Romans, Bietris de. “Na Maria, prètz e fina valors”. In The Women Troubadours,
ed. by Meg Bogin. New York: Norton & Co., 1980, 132. Rorty, Richard. The Consequences of Pragmatism. —. “The Trobairitz”. In The Troubadours: An Introduction, ed. by Simon Gaunt and
Sarah Kay, 113–26, https://doi.org/10.1017/cbo9780511620508.010 Radice, Betty, ed. The Letters of Abelard and Heloise. London: Penguin, 1974. Minneapolis: University of
Minnesota Press, 1982. Roscelin of Compiègne. “Epistola XV: Quae est Roscelini ad P. Abaelardum”. Patrologiae Cursus Completus, Vol. 178, ed. by Jacques Paul Migne. Paris: Apud Garnier Fratres, 1885, 358–72, https://archive.org/details/
patrologiaecurs53unkngoog 545 Bibliography Rougemont, Denis de. L’Amour et l’Occident. Paris: Plon, 1939. Rousseau, Jean Jacques. Contrat Social. In The Political Writings of Jean-Jacques
Rosseau, Vol. 2, ed. by C. E. Vaughan. Cambridge: Cambridge University
Press, 1915, 21–134, https://books.google.com/books?id=IqhBAAAAYAAJ&
printsec=frontcover&source=gbs_ge_summary_r&cad=0 —. Discours sur l’Origine et les Fondements de l’Inégalité Parmi les Hommes (1754),
1–99. Les Classiques des Sciences Sociales. Quebec: Université du Québec
à
Chicoutimi,
http://classiques.uqac.ca/classiques/Rousseau_jj/discours_
origine_inegalite/discours_inegalite.pdf Rutherford, John, ed. The Troubadours: Their Loves and Their Lyrics. London: Smith,
Elder, & Co., 1873, https://archive.org/details/troubadoursthei01ruthgoog Ryan, Kiernan. “King Lear”. In A Companion to Shakespeare’s Works, ed. by
Richard Dutton and Jean E. Howard. Malden: Blackwell Publishing, 2003,
375–92, https://doi.org/10.1002/9780470996539.ch20 Ryang, Sonia. “Biopolitics or the Logic of Sovereign Love—Love’s Wherabouts
in North Korea”. In North Korea: Toward a Better Understanding, ed. by Sonia
Ryang. Lanham: Lexington Books, 2009. Saint Circ, Uc de. Poesies de Uc de Saint-Circ, ed. by Alfred Jeanroy. Toulouse:
Édouard Privat, 1913. Salandra, Serafino della. Adamo Caduto. Cosenza: Gio. Battista Moio and
Francesco Rodella, 1647, https://archive.org/details/bub_gb_fbI8kobTkMQC Salter, Elizabeth. “Courts and Courtly Love”. In The Medieval World, ed. by
David Daiches and Anthony Thorlby. London: Aldus Books, 407–444. Samuel, Irene. “The Dialogue in Heaven: A Reconsideration of Paradise Lost, III. 1–417”. PMLA, 72: 4 (1957), 601–11. Sandys, John Edwyn. A History of Classical Scholarship, Vol. I: From the Sixth
Century B.C. to the End of the Middle Ages. Cambridge: Cambridge University
Press, 1903, https://archive.org/details/historyofclassic00sanduoft —. A History of Classical Scholarship, Vol. II: From the Revival of Learning to the
End of the Eighteenth Century in Italy, France, England and the Netherlands. Cambridge: Cambridge University Press, 1908, https://archive.org/details/
historyofclassic02sandiala Sanguineti, Edoardo. Il Realismo di Dante. Florence: Sansoni, 1966. Sankovitch, Tilde. “Lombarda’s Reluctant Mirror: Speculum of Another Poet”. In The Voice of the Trobairitz: Perspectives on the Women Troubadours, ed. by
William Paden. Philadelphia: University of Philadelphia Press, 1989, 183–93. —. “The Trobairitz”. In The Troubadours: An Introduction, ed. by Simon Gaunt and
Sarah Kay, 113–26, https://doi.org/10.1017/cbo9780511620508.010 546 Love and its Critics Sappho. Greek Lyric, Vol. I: Sappho and Alcaeus. Ed. and trans. by David A. Campbell. Loeb Classical Library, Cambridge, MA: Harvard University Press, 1982,
https://doi.org/10.4159/dlcl.sappho_alcaeus_lyric_poet-fragments.1982 Sartre, Jean-Paul. Qu’est-ce que la littérature? Paris: Gallimard, 1948. Saussure, Ferdinand de. Radice, Betty, ed. The Letters of Abelard and Heloise. London: Penguin, 1974. Cours de Linguistique Générale, ed. by Tullio de Mauro. Paris: Payot & Rivages, 1967. Saville, Jonathan. The Medieval Erotic Alba: Structure as Meaning. New York:
Columbia University Press, 1972. Sayce, Olive. Exemplary Comparison from Homer to Petrarch. Cambridge, UK:
Brewer, 2008, https://doi.org/10.1515/9783110940237.3 Schulman, Nicole M. Where Troubadours Were Bishops. London: Routledge, 2001,
https://doi.org/10.4324/9780203412213 Schultz-Gora, Oscar. Die Provenzalischen Dichterinnen. Leipzig: Gustav Fock,
1888. Schwartz, Regina. Loving Justice, Living Shakespeare. Oxford: Oxford University
Press, 2016, https://doi.org/10.1093/acprof:oso/9780198795216.001.0001 Schwoerer, Lois G. “Seventeenth-Century English Women Engraved in Stone?”
Albion: A Quarterly Journal Concerned with British Studies, 16: 4 (1984), 389–403,
https://doi.org/10.2307/4049387 Scolnic, Benjamin Edidin. “Why Do We Sing the Song of Songs on Passover?”
Conservative Judaism, 1996, 53–72, https://www.rabbinicalassembly.org/sites/
default/files/public/jewish-law/holidays/pesah/why-do-we-sing-the-song-
of-songs-on-passover.pdf Scève, Maurice. The Délie of Maurice Scève, ed. by I. D. McFarlane. Cambridge:
Cambridge University Press, 1966. Sedgwick, Eve Kosofsky. Between Men: English Literature and Male Homosocial
Desire. New York: Columbia University Press, 1985. —. Touching Feeling: Affect, Pedagogy, Performativity. Durham and London: Duke
University Press, 2003. Segal, M. H. “The Song of Songs”. Vetus Testamentum, 12: 4 (October 1962), 470–
90, https://doi.org/10.2307/1516936 Sextus Empiricus. Against Logicians. Ed. and trans. by R. G. Bury. Loeb Classical
Library, Cambridge, MA: Harvard University Press, 1935. Shakespeare, William. Shakespeare’s Sonnets, ed. by Stephen Booth. New Haven:
Yale University Press, 1977. —. The Complete Works, ed. by Stephen Orgel and A. R. Braunmuller. New York:
Pelican, 2002. 547 Bibliography —. The Sonnets; And, A Lover’s Complaint, ed. by John Kerrigan. New York:
Penguin, 1986. Shapiro, Marianne. Woman Earthly and Divine in the Comedy of Dante. Lexington:
University Press of Kentucky, 2015. Sharrock, Alison. Seduction and Repetition in Ovid’s Ars Amatoria, 2. Oxford:
Clarendon Press, 1994. Shaw, George Bernard. “Caesar and Cleopatra”. In Three Plays for Puritans. New
York: Brentano’s, 1906, , 87–208, https://babel.hathitrust.org/cgi/pt?id=hvd.3
2044014213078;view=1up;seq=9 Shelley, Percy Bysshe. “A Defence of Poetry”. In Essays, Letters from Abroad, ed. by Mary Wollstonecraft Shelley, Vol. 1. London: Moxon, 1852, 1–49, https://
babel.hathitrust.org/cgi/pt?id=wu.89000649913;view=1up;seq=7 Shotter, David. Rome and Her Empire. New York: Routledge, 2014, https://doi. org/10.4324/9781315798394 Sichel-Bazin, Rafëu, Carolin Buthke, and Trudel Meisenburg. “Prosody in
Language Contact: Occitan and French”. In Prosody and Language in Contact:
L2 Acquisition, Attrition and Languages in Multilingual Situations; [Session Speech
Prosody, Shanghai, 2012], ed. by Elisabeth Roussarie, Mathieu Avanzi, and
Sophie Herment. Berlin: Springer, 2015, 71–100, https://doi.org/10.1007/978-
3-662-45168-7_5 Sidney, Philip. The Defence of Poesie. In The Complete Works of Sir Philip Sidney,
Vol. III, ed. Radice, Betty, ed. The Letters of Abelard and Heloise. London: Penguin, 1974. by Albert Feuillerat. Cambridge: Cambridge University Press,
1923, 3–46, https://archive.org/details/completeworks03sidnuoft —. The Poems of Sir Philip Sidney, ed. by William A. Ringler. Oxford: Clarendon
Press, 1962. Sidonius (Gaius Sollius Apollinaris). Sidonius Poems and Letters: In Two Volumes. Ed. and trans. by William B. Anderson, Vol. 1. Loeb Classical Library,
Cambridge, MA: Harvard University Press, 1963. Silvestris, Bernardi. De Mundi Universitate, ed. by Carl Sigmund Barach
and Johann Wrobel. Innsbruck: Verlag der Wagnerschen Universitaets-
Buchandlung, 1876, https://archive.org/details/bernardisilvest00silvgoog Sinfield, Alan. Shakespeare, Authority, Sexuality: Unfinished Business in Cultural
Materialism. London: Routledge, 2006, https://doi.org/10.4324/9780203965023 Sklenár, Robert J. “Ausonius” Elegiac Wife: Epigram 20 and the Traditions of
Latin Love Poetry”. The Classical Journal, 101: 1 (October-November 2005),
51–62. Smythe, Barbara. Trobador Poets: Selections from the Poems of Eight Trobadors. New
York: Cooper Square Publishers, 1966. Sontag, Susan. Against Interpretation: And Other Essays. New York: Farrar, Straus
and Giroux, 2013. 548 Love and its Critics Spence, Sarah. Texts and the Self in the Twelfth Century. Cambridge: Cambridge
University Press, 1996. Spiller, Michael R. G. The Development of the Sonnet an Introduction. London:
Routledge, 1992, https://doi.org/10.4324/9780203401507 Spivak, Gayatri Chakravorty. “Righting Wrongs”. The South Atlantic Quarterly,
103: 2–3 (Spring/Summer 2004), 523–81, https://muse.jhu.edu/article/169150,
https://doi.org/10.1215/00382876-103-2-3-523 Stehling, Thomas. “To Love a Medieval Boy”. In Literary Versions of Homosexuality,
ed. by Stuart Kellogg. New York: Haworth Press, 1983, 151–70. Steinsaltz, Adin, ed. Tractate Sanhedrin. In The Talmud: The Steinsaltz Edition, vols. New York: Random House, 1996–1999, 15–21. Sternberg, Robert. Cognitive Psychology. Belmont: Wadsworth Cengage, 2009. Stilling, Roger. Love and Death in Renaissance Tragedy. Baton Rouge: Louisiana
State University Press, 1976. Stockton, Will. “An Introduction Justifying Queer Ways”. Ed. by Will Stockton
and David L. Orvis. Early Modern Culture: An Electronic Seminar, 10: Queer
Milton, http://emc.eserver.org/1-10/stockton.html Stone, Gregory B. The Death of the Troubadour: The Late Medieval Resistance to
the Renaissance. Philadelphia: University of Pennsylvania Press, 1994, https://
doi.org/10.9783/9781512807332 Stone, Lawrence. The Family, Sex and Marriage in England, 1500–1800. New York:
Harper & Row, 1977. Stopka, Krzysztof. Armenia Christiana: Armenian Religious Identity and the Churches
of Constantinople and Rome. Krakow: Jagiellonian University Press, 2016. Strabo. Geography. Vol. I: Books 1–2, ed. by Horace Leonard Jones. Loeb Classical
Library, Cambridge, MA: Harvard University Press, 1917. Strayer, Joseph R. Western Europe in the Middle Ages: A Short History. New York:
Appleton-Century-Crofts, 1955. Strouse, A. W. “Getting Medieval on Graduate Education: Queering Academic
Professionalism”. Radice, Betty, ed. The Letters of Abelard and Heloise. London: Penguin, 1974. Pedagogy: Critical Approaches to Teaching Literature,
Language, Composition, and Culture, 15: 1 (2015), 119–38, https://doi. org/10.1215/15314200-2799260 Strowick, Elisabeth. “Comparative Epistemology of Suspicion: Psychoanalysis,
Literature, and the Human Sciences” Science in Context, 18.4 (2005), 649–69,
https://doi.org/10.1017/S0269889705000700 Stubbs, John. John Donne: The Reformed Soul. New York: W. W. Norton & Co., 2007. Sullivan, Ceri. “The Carpe Diem Topos and the ‘geriatric Gaze’ in Early Modern
Verse”. Early Modern Literary Studies, 14: 3, https://extra.shu.ac.uk/emls/14-3/
Sullcarp.html 549 Bibliography Surrey, Henry Howard, Earl of. The Poetical Works of Henry Howard, Earl of
Surrey, ed. by Robert Bell. Boston: Little, Brown & Co., 1854, https://archive. org/details/poeticalworkshe00vauxgoog Swabey, Ffiona. Eleanor of Aquitaine, Courtly Love, and the Troubadours. Westport:
Greenwood Press, 2004. Symonds, John Addington. Renaissance in Italy, Vol. 4, Part 1. New York: Mith, Elder
& Co., 1881, https://books.google.com/books?id=K4sTAQAAIAAJ&pg=PP1 “Tagelied”. In Princeton Encyclopedia of Poetry and Poetics, ed. by Alex Preminger,
Frank J. Warnke, and O. B. Hardison Jr. Princeton: Princeton University
Press, 1972, 841–42. Tanner, J. Paul. “The History of Interpretation of the Song of Songs”. Bibliotheca
Sacra, 154: 513 (1997), 23–46, https://biblicalstudies.org.uk/article_song1_
tanner.html or http://paultanner.org/English HTML/Publ Articles/Hist Song
of Songs-P Tanner.pdf Targoff, Ramie. Posthumous Love: Eros and the Afterlife in Renaissance England. Chicago: University of Chicago Press, 2014, https://doi.org/10.7208/
chicago/9780226110462.001.0001 Tarrant, Richard. “Ovid and Ancient Literary History”. In The Cambridge
Companion to Ovid, ed. by Philip R. Hardie. Cambridge, UK: Cambridge
University Press, 2002, 13–33, https://doi.org/10.1017/ccol0521772818.002 Teskey, Gordon. The Poetry of John Milton. Cambridge, MA: Harvard University
Press, 2015, https://doi.org/10.4159/9780674286740 Thibault, John C. The Mystery of Ovid’s Exile. Berkeley: University of California
Press, 1964. Thomason, T. Katharine. “Plotinian Metaphysics and Donne’s ‘Extasie’”. Studies in English Literature, 1500–1900, 22: 1 (1982), 91–105, https://doi. org/10.2307/450219 Thomsett, Michael C. Heresy in the Roman Catholic Church: A History. Jefferson,
NC: McFarland, 2011. Toews, John E. The Story of Original Sin. Eugene: Wipf and Stock Publishers,
2013. Topsfield, L. T. Troubadours and Love. Cambridge: Cambridge University Press,
1975. Traub, Valerie. The Renaissance of Lesbianism in Early Modern England. Cambridge:
Cambridge University Press, 2002. Tullia d’Aragona. Dialogo della infinità d’amore [1547]. In Della infinita d’amore
dialogo di Tullia D’Aragona. Milan: G. Daelli & Co., 1864, https://archive.org/
details/bub_gb_1FOekK6PUbsC Tyerman, Christopher. God’s War: A New History of the Crusades. Cambridge,
MA: Belknap Press of Harvard University Press, 2006. 550 Love and its Critics Tyutchev, Fyodor. “Silentium”. European Romanticism: A Reader, ed. by Stephen
Prickett. London: Bloomsbury, 2010, 638–39. Urquhart, Ilona. Radice, Betty, ed. The Letters of Abelard and Heloise. London: Penguin, 1974. “Diabolical Evasion of the Censor in Mikhail Bulgakov’s The
Master and Margarita”. In Censorship and the Limits of the Literary: A Global View,
ed. by Nicole Moore. New York: Bloomsbury Academic, 2015, 133–46. Vaux-de-Cernay, Pierre. Historia Albigensium et sacri belli in eos anno MCCIX. Trecis: Venundantur Parisiis, Apud N. Rousset, 1617. Veeser, Harold Aram. “Introduction”. In The New Historicism, ed. by Harold
Aram Veeser. New York: Routledge, 1989, ix–xvi. Vendler, Helen. The Art of Shakespeare’s Sonnets. Cambridge, MA: Belknap Press
of Harvard University Press, 1997. Ventadorn, Bernart de. Bernart Von Ventadorn: Seine Lieder, Mit Einleitung und
Glossar, ed. by Carl Appel. Halle: Max Niemeyer, 1915, https://archive.org/
details/bernartvonventad00bern Villaverde. Marcelino Agís. Knowledge and Practical Reason: Paul Ricoeur’s Way of
Thinking. Berlin: LIT Verlag Münster, 2012. Virgil. The Aeneid. In Virgil, 2 vols. Ed. and trans. by H. Rushton Fairclough. Loeb Classical Library, Cambridge, MA: Harvard University Press, 1960. —. “Eclogue X”. In Virgil, 2 vols. Ed. and trans. by H. Rushton Fairclough. Loeb
Classical Library, Cambridge, MA: Harvard University Press, 1960. Vleeschouwers-Van
Melkebeek,
Monique. “Separation
and
Marital
Property”. In Regional Variations in Matrimonial Law and Custom in Europe,
1150–1600, ed. by Mia Korpiola. Leiden: Brill, 2011, 78–97, https://doi. org/10.1163/9789004211438_005 Vogelweide, Walther von der. Die Gedichte Walthers von der Vogelweide, ed. by
Karl Lachmann. Berlin: George Reimer, 1891, https://archive.org/details/
diegedichtewalt00lachgoog Von Strassburg, Gottfried. Tristan, ed. by Karl Marold. Leipzig, E. Avenarius,
1906, https://archive.org/details/gottfriedvonstr00unkngoog Vyvyan, John. Shakespeare and the Rose of Love. London: Shepheard-Walwyn, 1960. Waldock, A. J. A. Paradise Lost and its Critics. Cambridge: Cambridge University
Press, 1947. Walters, Lori J. “‘The Foot on Which He Limps’: Jean Gerson and the
Rehabilitation of Jean de Meun in Arsenal 3339”. Digital Philology, 1: 1
(Spring 2012), 110–38, https://doi.org/10.1353/dph.2012.0006 Watkins, John. The Specter of Dido: Spenser and Virgilian Epic. New Haven: Yale
University Press, 1995. Watson, Lynette. “Representing the Past, Redefining the Future: Sidonius
Appolinaris’ Panegyrics of Avitus and Anthemius”. In The Propaganda of
Power: The Role of Panegyric in Late Antiquity, ed. by Mary Whitby. Boston:
Brill, 1998. 551 Bibliography Warnicke, Retha M. “The Eternal Triangle and Court Politics: Henry VIII, Anne
Boleyn, and Sir Thomas Wyatt”. Albion: A Quarterly Journal Concerned with
British Studies, 18: 4 (Winter 1986), 565–579, https://doi.org/10.2307/4050130 —. The Rise and Fall of Anne Boleyn: Family Politics at the Court of Henry VIII. Cambridge: Cambridge University Press, 1991. Weinrich, Lorenz. “‘Dolorum solatium’: Text und Musik von Abaelards
Planctus”. Radice, Betty, ed. The Letters of Abelard and Heloise. London: Penguin, 1974. Mittellateinisches Jahrbuch, 5 (1968), 59–78. Wetherbee, Winthrop. Geoffrey Chaucer: The Canterbury Tales. Cambridge:
Cambridge University Press, 1989. White, Peter. “Ovid and the Augustan Mileau”. In Brill’s Companion to Ovid, ed. by Barbara Weiden Boyd. Leiden: Brill, 2002, 1–27. Wilde, Oscar. “The Critic as Artist”. In The Complete Works of Oscar Wilde. New
York: Barnes & Noble, 1994, 1009–59. —. The Soul of Man under Socialism. Portland: Thomas B. Mosher, 1905. —. “To the Editor of the Scots Observer”. The Scots Observer, 4: 91, 332–33, https://
books.google.com/books?id=94oeAQAAMAAJ&pg=PA332 Wilhelm, James J. Seven Troubadours: The Creators of Modern Verse. University
Park: Pennsylvania State University Press, 1970. Wilkins, Ernest Hatch. The Invention of the Sonnet, and Other Studies in Italian
Literature. Rome: Edizioni De Storia e Letteratura, 1959. Wilkinson, L. P. Ovid Recalled. Cambridge, UK: Cambridge University Press,
1955. Wimsatt Jr., W. K. and M. C. Beardsley. “The Intentional Fallacy”. The Sewanee
Review, 54: 3 (July-September 1946), 468–488, http://www.jstor.org/
stable/27537676 Winkler, John J. The Constraints of Desire: The Anthropology of Sex and Gender in
Ancient Greece. New York: Routledge, 1990. Woodbridge, Linda. Vagrancy, Homelessness, and English Renaissance Literature. Urbana: University of Illinois Press, 2001. Wollock, Jennifer G. Rethinking Chivalry and Courtly Love. Santa Barbara: Praeger,
2011. Woods, Marjorie Curry. “Where’s the Manuscript”. Exemplaria, 25.4 [Winter
2013], 321–24, https://doi.org/10.1179/1041257313Z.00000000036 Wrathall Mark A. Heidegger and Unconcealment: Truth, Language, and History. Cambridge: Cambridge University Press, 2010, https://doi.org/10.1017/
cbo9780511777974 Wyatt, Thomas. Sir Thomas Wyatt: The Complete Poems, ed. by R. A. Rebholz. New Haven: Yale University Press, 1978. —. The Poetry of Sir Thomas Wyatt, ed. by E. M. W. Tillyard. London: Scholartis
Press, 1929. 552 Love and its Critics Yeats, William Butler. Yeats’s Poetry, Drama, and Prose: Authoritative Texts, Contexts,
Criticism, ed. by James Pethica. New York: W. W. Norton & Co., 2000. Young, R. V. Doctrine and Devotion in Seventeenth-century Poetry: Studies in Donne,
Herbert, Crashaw, and Vaughan. Cambridge: Boydell & Brewer, 2000. Ziolowski, Jan M. Letters of Peter Abelard, Beyond the Personal. Washington: The
Catholic University Press of America, 2008. Zumthor, Paul. Essai de Poétique Médiévale. Paris: Seuil, 1972. Andreini, Giambattisti 491 Ariès, Philippe 372 Ames, Christine Caldwell 197 Anderson, W.S. 95 Anderson, W.S. 95 Arden, Heather M. 240, 243 Andreasen, Nancy Jo Coover 433, 435 Arendt, Hannah 496 Index Anonymous
Concilium Romarici Montis 126
Anonymous
“En un vergier sotz fuella
d’albespi” 185, 190
Anonymous
Flamenca 221
Anonymous
“Havelok the Dane” 275, 277, 278,
279
Anonymous
King Horn 275, 278, 279
Anonymous
“Soufrés maris, et si ne vous anuit”
191
Anonymous
St. Austyn 276
Anthemius 101, 102, 103
Aquinas, Thomas 4, 130, 479
Arabi, Ibn
“Gentle Now, Doves of the
Thornberry and Moringa Thicket”
166, 167, 177
Arden, Heather M. 240, 243
Arendt, Hannah 496
Ariès, Philippe 372
Aristotle 3, 17, 38, 165, 372, 407, 412,
454, 480
Astell, Ann W. 42
Aubrey, John 375
Auerbach, Erich 121
Augustine of Hippo 3, 4, 9, 149, 150,
151, 279, 372, 479 Abelard, Peter 10, 195, 196, 197, 198,
199, 200, 201, 202, 203, 204, 205,
206, 207, 208, 209, 210, 211, 212,
213, 270 Abels, Richard and Ellen Harrison
221 Adorno, Theodore 474, 490 Agrippa, Cornelius
De Nobilitate et Praecellentia Foeminei
Sexus 487 Aist, Dietmar von
“Slâfest du, friedel ziere” 183, 184 Akiba (Rabbi Akiba ben Joseph) 47,
51, 53, 63, 106, 120, 158, 172, 453,
463 Alcuin 108, 109, 110 Alcuin 108, 109, 110 Al-Ghāzalī 407 Allen, Peter 62, 63, 64 Allestree, Richard 373, 381, 384 Altermeyer, Bob 483, 484 Althusser, Louis 11, 12, 455 Amaury, Arnaud 224, 226, 227 Ames, Christine Caldwell 197 Bulgakov, Mikhail 508, 509 Bell, Ilona 423, 429, 430, 431
Belsey, Catherine 424, 425 Мастер и Маргарита (Master and
Margarita) 508, 509, 511
Bunyan, John
Pilgrim’s Progress 489
Burckhardt, Jacob 159, 160
Burden, Dennis 475, 476, 477, 480
Burgwinkle, William 146, 147, 193
Burns, E. Jane 156, 157
Buturovic, Amila 510
Byrne, Marie José 108 Bembo, Pietro 106, 330, 331, 332, 333,
334, 349, 351, 355, 356, 359, 426,
440, 441 Bene, Carmelo 408 Bene, Carmelo 408 Benton, John 210, 211 Benton, John 210, 211 Burden, Dennis 475, 476, 477, 480 Ben-Ze’ev, Aharon, and Ruhama
Goussinsky 1 Bernays, Edward 8 Bernays, Edward 8 Berry, Ralph 403, 405 Berry, Ralph 403, 405 Best, Stephen, and Sharon Marcus 34 Blair, Peter Hunter 278 Cabestanh, Guilhem de 178, 179 Blake, William 161, 167, 442 Callaghan, Dympna 360, 362, 363,
365, 407, 408, 419 Blanchot, Maurice 23, 24, 26, 27 Calvin, John 4, 5, 9, 473, 474 Blanc, Pierre 302 Blank, Hanne 395 Blank, Hanne 395 Cameron, Alan 103 Bloch, Ariel and Chana 41 Campbell, Joseph 141, 147, 148, 152 Bloch, R. Howard, and Stephen G. Nichols 154 Camproux, Charles 173, 221 Camus, Albert 462 Camus, Albert 462 Bloom, Harold 372, 449 Bloom, Harold 372, 449 L’Adamo 491 Anonymous
Arden of Faversham 369, 370 Anonymous
Arden of Faversham 369, 370 Astell, Ann W. 42 Anonymous
Aucassin et Nicolette 215, 303 Anonymous
Aucassin et Nicolette 215, 303 Aubrey, John 375 Anonymous
“Coindeta sui” 136, 180 Anonymous
“Coindeta sui” 136, 180 Augustine of Hippo 3, 4, 9, 149, 150,
151, 279, 372, 479 Love and its Critics 554 Borneilh, Giraut de 378, 401
Boswell, John 108, 109, 143 Augustus Caesar 65, 84, 89, 102
Lex Papia Poppaea (law penalizing
married couples with no children)
70 Boswell, John 108, 109, 143 Boyd, Barbara Weiden 65, 71, 90 Boyle, David 220, 222, 227, 231 Ausonius 106, 107, 108 Ausonius 106, 107, 108 Brady, Bernard V. 248 Austin, R.G. 89 Branagh, Kenneth 403 Branagh, Kenneth 403 Auweele, Bart Vanden 56 Auweele, Bart Vanden 56 Briffault, Robert S. 165, 215, 217, 222,
231, 232, 237, 342, 353 Avitus, Alcimus Ecdicius
De Mosaice Historiae Gestis 494 Avitus, Alcimus Ecdicius Brogan, Walter A. 18 Brown, Peter 102, 276 Babylonian Talmud, Tractate Sanhedrin
51, 52 Bruckner, Matilda Tomaryn 129, 141,
180, 187, 190 Bagot, Richard 413 Brundage, James A. 191 Brundage, James A. 191 Baker, Richard 425 Bryson, Michael 153, 429, 458, 485,
518 Barthes, Roland 19, 28, 29, 30, 32 Barthes, Roland 19, 28, 29, 30, 32
Bell, Ilona 423, 429, 430, 431
Belsey, Catherine 424, 425 Bulgakov, Mikhail 508, 509 dolce stil novo 249, 252, 256, 262, 263, 269, 274, Italian poetry, love as worship 3,
55, 121, 192, 302, 306, 307, 323, 342 Italian poetry, love as worship 3,
55, 121, 192, 302, 306, 307, 323, 342 282, 283, 284, 285, 286, 289, 293 Cox, Catherine S. 289 Donne, John 3, 31, 32, 108, 110, 174,
197, 335, 338, 371, 375, 421, 422,
423, 425, 426, 427, 428, 429, 430,
431, 432, 433, 434, 435, 436, 437,
438, 439, 440, 441, 442, 443, 444,
445, 453, 459, 481, 502, 504 Crane, Susan 281, 290 Crawford, Charles 369 Culler, Jonathan 162 Cusset, François 20 Bloom, Harold 372, 449 Capellanus, Andreas 123, 124, 126,
133, 134, 135 Blumenfeld-Kosinski, Renate 267 Boase, Roger 135 Cary, Elizabeth 375 Boétie, Étienne de La 5, 6, 7, 8, 10 Casali, Sergio 71, 76, 97 Castiglione, Baldassarre 330, 331,
334, 351, 440
Il Libro del Cortegiano (The Book of the
Courtier) 330
Castor, Helen 168
Catherine of Aragon 395
Cato the Younger 87, 97, 98 Bogin, Meg 140, 146 Castiglione, Baldassarre 330, 331,
334, 351, 440 Castiglione, Baldassarre 330, 331,
334, 351, 440
Il Libro del Cortegiano (The Book of the
Courtier) 330 Boleyn, Anne 343, 344 Il Libro del Cortegiano (The Book of the
Courtier) 330 Booth, Stephen 362 Born, Bertran de 137, 138, 139, 189,
190, 191, 261
“Be·m platz lo gais temps de
pascor” 137, 189 Castor, Helen 168 Catherine of Aragon 395 Cato the Younger 87, 97, 98 Index 555 Catullus 64, 93, 108, 338, 339, 411, 424 Catullus 64, 93, 108, 338, 339, 411, 424
Cavalcanti, Guido 106, 192 Catullus 64, 93, 108, 338, 339, 411, 424
Cavalcanti, Guido 106, 192 Dante Alighieri 2, 3, 55, 106, 138, 158,
161, 164, 192, 293, 300, 306, 307,
309, 311, 315, 316, 317, 318, 319,
320, 321, 322, 323, 326, 330, 345,
350, 359, 367, 372, 422, 426, 458,
506 Cavalcanti, Guido 106, 192 Charles II 434 Charles II 434 289
Crane, Susan 281, 290
Crawford, Charles 369
Culler, Jonathan 162
Cusset, François 20
Daniel, Arnaut 248, 322, 323
“Lo ferm voler qu’el cor m’intra”
248
Danielson, Dennis 478, 480, 498, 499 Dia, Comtessa de 129, 186, 188, 235 Dia, Comtessa de 129, 186, 188, 235
“Estat ai en greu cossirier” 186
Dillon, Martin C. 447
Dilthey, Wilhelm 153, 154
Dinshaw, Carolyn 266, 291
Dionysius the Carthusian 473, 474
Dodd, William George 280
Doggett, Frank A. 157, 441
dolce stil novo Dia, Comtessa de 129, 186, 188, 235
“Estat ai en greu cossirier” 186
Dillon, Martin C. 447
Dilthey, Wilhelm 153, 154
Dinshaw, Carolyn 266, 291 “Amor, che lungiamente m’hai
menato” 313, 314 “Amor, che lungiamente m’hai
menato” 313, 314 Coltman, Rod 27 Coulet, Jules 233 as an artificial construct 121, 122, 123, 124, 125, 129, 130, 131, 133, 136, 162, 212, 235, 240, 247, 248, Charles II 434 Chaucer, Geoffrey 135, 176, 271, 280,
281, 282, 283, 284, 285, 286, 288,
289, 290, 291, 292, 293, 294, 295,
523 Chaucer, Geoffrey 135, 176, 271, 280,
281, 282, 283, 284, 285, 286, 288,
289, 290, 291, 292, 293, 294, 295,
523
The Canterbury Tales 176, 240, 280,
281, 282, 283, 285, 286, 290
“The Knight’s Tale” 280, 281, 282,
283, 284, 285
“The Miller’s Tale” 280, 282, 283,
284, 285 “Di donne io vidi una gentile
schiera” 317 “Di donne io vidi una gentile
schiera” 317 The Canterbury Tales 176, 240, 280,
281, 282, 283, 285, 286, 290 Inferno 138, 320, 322 Inferno 138, 320, 322 “Io mi sentii svegliar dentro a lo
core” 316 “The Knight’s Tale” 280, 281, 282,
283, 284, 285 “Negli occhi porta la mia donna
Amore” 315 “The Miller’s Tale” 280, 282, 283,
284, 285 Purgatorio 323 Cheyettee, Frederic L. 220, 221 d’Aurenga, Raimbaut 186, 188 Chomsky, Noam 11, 22, 33, 502, 503 “Non chant per auzel ni per flor”
186 Chrétien de Troyes 123, 125, 126, 127,
128, 129, 131, 132, 219, 240, 241 Davis, P.J. 69 Le Chevalier de la Charrette 127
Cicero 239, 257 Day, Linda 46
de Graef, Ortwin 33 Day, Linda 46 de Graef, Ortwin 33 Clark, David 109
Claudian 97, 100, 101, 102, 103, 108 Clark, David 109
Claudian 97, 100, 101, 102, 103, 108
Clements, Ronald E. 44
Cohen, Gerson 38, 42, 46, 47
Coleridge, Samuel Taylor 499 Deleuze, Gilles 408 de Man, Paul 18, 21, 31, 33, 163, 446,
447, 452, 454 Clements, Ronald E. 44 de Meun, Jean 254, 291, 293, 531 de Meun, Jean 254, 291, 293, 531 Derrida, Jacques 18, 24, 26, 447, 454 Derrida, Jacques 18, 24, 26, 447, 454 Colonne, Guido delle 313, 314, 317,
319, 326 Colonne, Guido delle 313, 314, 317,
319, 326 Colonne, Guido delle 313, 314, 317,
319, 326
“Amor, che lungiamente m’hai
menato” 313, 314
Coltman, Rod 27
Coulet, Jules 233
courtly love
as an artificial construct 121, 122,
123, 124, 125, 129, 130, 131, 133,
136, 162, 212, 235, 240, 247, 248,
249, 252, 256, 262, 263, 269, 274,
282, 283, 284, 285, 286, 289, 293
Cox, Catherine S. Daniel, Arnaut 248, 322, 323
“Lo ferm voler qu’el cor m’intra”
248 “On His Mistress Going to Bed”
425, 426, 427, 428, 429 “The Canonization” 433, 435, 436 “The Extasie” 437, 440, 441, 442, 444 556 Love and its Critics “The Sun Rising” 443, 444
Doss-Quinby, Elgal 137
Dostoevsky, Fyodor 411, 415, 456
Бесы (Demons, aka The Possessed, or
The Devils) 411
Идиот (The Idiot) 415, 456
Drayton, Michael 348
Dreher, Diane 368, 374, 375
Dronke, Peter 111, 169
Duffell, Martin J. 302
Dümmler, Nicola Nina 117
Dunstan, William E. 101
Dutton, Richard 406
Eagleton, Terry 482
Easthope, Anthony 424
Eckhart, Meister 300
Edwards, Catherine 87
Edwards, David 432
Egan, Gabriel 371
Eleanor of Aquitaine 123 158 176
Fernie, Ew
Ferrari, G.R
Fessler, Ign
Feuerbach,
Fichte, Joh
Fields, Wes
fin’amor 3,
135, 136
195, 203
233, 234
243, 247
274, 279
290, 292
381, 390
definitio
Findlay, Jo
Firenzuola
Fish, Stanle
477, 480
504
Fleming, B “The Sun Rising” 443, 444
Doss-Quinby, Elgal 137
Dostoevsky, Fyodor 411, 415, 456
Бесы (Demons, aka The Possessed, or
The Devils) 411
Идиот (The Idiot) 415, 456
Drayton, Michael 348
Dreher, Diane 368, 374, 375
Dronke, Peter 111, 169
Duffell, Martin J. 302
Dümmler, Nicola Nina 117
Dunstan, William E. 101
Dutton, Richard 406
Eagleton, Terry 482
Easthope, Anthony 424
Eckhart, Meister 300
Edwards, Catherine 87
Edwards, David 432
Egan, Gabriel 371
Eleanor of Aquitaine 123 158 176
Fernie, Ewan 411
Ferrari, G.R.F. 33
Fessler, Ignas 210
Feuerbach, Ludwig 478, 479
Fichte, Johann Gottlieb 33, 34
Fields, Weston 51
fin’amor 3, 34, 62, 113, 116, 122, 130,
135, 136, 164, 169, 172, 174, 175,
195, 203, 207, 212, 217, 226, 232,
233, 234, 235, 238, 239, 240, 242,
243, 247, 248, 249, 250, 256, 260,
274, 279, 280, 281, 282, 283, 286,
290, 292, 300, 322, 330, 336, 371,
381, 390, 401, 420, 436
definition of 2, 173
Findlay, John Niemeyer 17
Firenzuola, Agnolo 335
Fish, Stanley Eugene 423, 475, 476,
477, 480, 481, 483, 484, 498, 499,
504
Fleming, Bruce 14, 21 “The Sun Rising” 443, 444
Doss-Quinby, Elgal 137
Dostoevsky, Fyodor 411, 415, 456
Бесы (Demons, aka The Possessed, or
The Devils) 411
Идиот (The Idiot) 415, 456
Drayton, Michael 348
Dreher, Diane 368, 374, 375
Dronke, Peter 111, 169
Duffell, Martin J. 302
Dümmler, Nicola Nina 117
Dunstan, William E. Daniel, Arnaut 248, 322, 323
“Lo ferm voler qu’el cor m’intra”
248 101
Dutton, Richard 406
Eagleton, Terry 482
Easthope, Anthony 424
Eckhart, Meister 300
Edwards, Catherine 87
Edwards, David 432 Fernie, Ewan 411
Ferrari, G.R.F. 33
Fessler, Ignas 210
Feuerbach, Ludwig 478, 479
Fichte, Johann Gottlieb 33, 34
Fields, Weston 51
fin’amor 3, 34, 62, 113, 116, 122, 130,
135, 136, 164, 169, 172, 174, 175,
195, 203, 207, 212, 217, 226, 232,
233, 234, 235, 238, 239, 240, 242,
243, 247, 248, 249, 250, 256, 260,
274, 279, 280, 281, 282, 283, 286,
290, 292, 300, 322, 330, 336, 371,
381, 390, 401, 420, 436
definition of 2, 173
Findlay, John Niemeyer 17
Firenzuola, Agnolo 335
Fish, Stanley Eugene 423, 475, 476,
477, 480, 481, 483, 484, 498, 499,
504 Dümmler, Nicola Nina 117 Dunstan, William E. 101 Dunstan, William E. 101
Dutton, Richard 406 Dutton, Richard 406 Eagleton, Terry 482 Easthope, Anthony 424 Eckhart, Meister 300 Fish, Stanley Eugene 423, 475, 476,
477, 480, 481, 483, 484, 498, 499,
504 Edwards, Catherine 87 Edwards, David 432 Egan, Gabriel 371 Fleming, Bruce 14, 21 Eleanor of Aquitaine 123, 158, 176,
220, 301, 343 Fortunatus, Venantius 104, 105, 106 Foucault, Michel 9, 18, 20, 26, 28, 29,
30, 154, 219, 373, 374, 428 Eliot, T.S. 32, 449, 482 Elizabeth I 427 Grotius, Hugo Grotius, Hugo
Adamus Exul 489, 490, 491, 492 Hengel, Martin 498 Hengel, Martin 498 Henry VII 394, 395 Henry VII 394, 395 Guibbory, Achsah 424, 425, 427, 428,
436 Henry VIII 343, 344 Heraclitus 16, 295, 453 Guilhem IX 129, 130, 158, 167, 168,
169, 170, 171, 172, 174, 233, 235,
237, 250, 261, 286, 306, 340 Herman, Edward S. 502, 503 Guilhem IX 129, 130, 158, 167, 168,
169, 170, 171, 172, 174, 233, 235,
237, 250, 261, 286, 306, 340
“Ab la dolchor del temps novel”
168, 170
author of the first fabliau 282
“Companho faray un vers... convinen” 169
“F
i h
” 168 Herman, Peter C. 469 Elizabeth I 427 Francesca da Rimini (Paulo and
Francesca) 319, 321, 322 Ellis, Frederick Startridge 262 Empson, William 424, 468, 469, 474,
475, 479, 483, 502 Franklin, Benjamin 511 Franklin, Benjamin 511
Frantzen, Allen 109, 110 Frantzen, Allen 109, 110 Eratosthenes 12 Frederick I (Barbarossa) 10 Ermengard of Narbonne 220 Ermengard of Narbonne 220
Ermengaud, Matfré 248
Le Breviari d’Amor 233, 234, 235,
236, 237
Eschenbach, Wolfram von 181, 182,
183, 184
“Den morgenblic bî wahtaeres
sange erkôs” 181, 185
Essam, Bacem A. 510
Eusebius of Caesarea 39, 40
Eve, Martin Paul 501
Everson, Jane E. 314
Falck, Colin 415
Fay, Elizabeth 152
Febvre, Lucien 153
Felski, Rita 14, 15, 19, 20, 21, 142, 154,
267, 268, 454, 501, 502 Frederick II 132, 300, 301, 302 Ermengaud, Matfré 248
Le Breviari d’Amor 233, 234, 235,
236, 237
Eschenbach, Wolfram von 181, 182,
183, 184
“Den morgenblic bî wahtaeres
sange erkôs” 181, 185
Essam, Bacem A. 510
Eusebius of Caesarea 39, 40
Eve, Martin Paul 501
Everson, Jane E. 314
Falck, Colin 415
Fay, Elizabeth 152
Febvre, Lucien 153
Felski, Rita 14, 15, 19, 20, 21, 142, 154
267 268 454 501 502 Freeburn, Ryan P. 198 Freeburn, Ryan P. 198 Frelick, Nancy 131 Frelick, Nancy 131 Gajowski, Evelyn 416 Eusebius of Caesarea 39, 40
Eve, Martin Paul 501
Everson, Jane E. 314 George Chapman 116 Felski, Rita 14, 15, 19, 20, 21, 142, 154,
267, 268, 454, 501, 502 557 Index “Chi vedesse a Lucia un var
cappuzzo” 306 “Chi vedesse a Lucia un var
cappuzzo” 306 Gilead, Sarah 22, 446, 447, 448, 449,
450, 452, 453, 455, 462 Giles of Rome 55 Giles of Rome 55 “Io vogl’ del ver la mia donna
laudare” 310 Gillis, John 372 “Tegno di folle ‘mpres’, a lo ver
dire” 311 Giroux, Henry 37, 502 Glancy, Ruth F. 421 Guynn, Noah 254, 267 Guynn, Noah 254, 267 Goebbels, Joseph 8 Goethe, Johann Wolfgang von 35, Goethe, Johann Wolfgang von 35,
356 Hagstrum, Jean H. 79, 116, 195, 205,
292, 317, 330, 373, 413 Golb, Norman 221 Golb, Norman 221 Hallissy, Margaret 281, 282, 285, 290 Golden, Mark 43 Hardin, Richard F. 113, 115 Goldin, Frederick 157 Hartman, Geoffrey 31 Goldstien, Neal L. 324 Haskins, Charles Homer 175 Goold, G.P. 57 Hawkes, David 482, 483 Hawkes, David 482, 483 Gramsci Antonio 419 Hegel, Georg Wilhelm Friedrich 26,
27 hermeneutics of suspicion “Ab la dolchor del temps novel”
168, 170 style of interpretation 10, 12, 13,
14, 20, 22, 33, 34, 40, 42, 49, 146,
296, 320, 440, 447, 450, 451, 455,
463, 501 style of interpretation 10, 12, 13,
14, 20, 22, 33, 34, 40, 42, 49, 146,
296, 320, 440, 447, 450, 451, 455,
463, 501 author of the first fabliau 282 “Companho faray un vers... convinen” 169 Herrick, Robert 3, 11, 421, 445, 446,
447, 448, 449, 450, 452, 453, 455,
456, 457, 458, 459, 460, 462, 463,
464 “Farai chansoneta nueva” 168 “Farai chansoneta nueva” 168 Gratian
Decretum Magistri Gratiani 185 Gratian
Decretum Magistri Gratiani 185 Decretum Magistri Gratiani 185 Heidegger, Martin 7, 16, 17, 18, 447,
499 Greaves, Richard L. 461 Greenblatt, Stephen 18, 160, 370, 406,
442, 473 Heisterbacences, Caesarii 224 Heller, Joseph 162 Greenstein, Edward L. 53 Heller-Roazen, Daniel 159, 160, 405 Grégoire, Henri 193 Heloise d’Argenteuil 195, 196, 197,
199, 201, 202, 203, 204, 205, 206,
208, 209, 210, 211, 212, 213, 270 Greville, Fulke 149 Grollman, Eric Anthony 503 Grollman, Eric Anthony 503 208, 209, 210, 211, 212, 213, 270 “Mout jauzens me prenc en amar”
170 “Mout jauzens me prenc en amar”
170 “Pus vezem de novel florir” 171
Guinizelli, Guido 192, 306, 307, 308,
309, 310, 311, 312, 313, 314, 317,
319, 323, 326
“Al cor gentil” 307 “Corinna’s going a Maying” 460,
461, 462 “To Daffadills” 456 “To Daffadills” 456 “To the Virgins to Make Much of
Time” 11, 445, 449, 450, 452, 453,
455 “Al cor gentil” 307 558 Love and its Critics Kafka, Franz 162
Kahn, Coppélia 370
Kates, Joshua 18
Katz, Joseph 503
Kauffman, Linda 95
Kay, Sarah 2, 107, 129, 154, 155, 156,
163, 234, 321
Kelley, Maurice 499
Kemp, Theresa D. 279
Kennedy, Elspeth 321
Kennedy, William J. 309
Kerrigan, John 361
Kerrigan, William 464
Kim Jong-il 496
King, Margaret L. 43
Kleinman, Scott 278
Klein, Richard 27
Knox, Peter E. 90
Köhler, Erich 155, 156
Krass, Andreas 219
Kristeva, Julia 408
Labé, Louise 336, 337, 338, 340
Sonnet 16 337
Sonnet 19 338
Lacan, Jacques 24, 25, 26, 28, 130, 131,
452
Lagerlund, Henrik 407
Landrum, David 459
Lane, Joan 460
Lanham, Richard A. 75
Larson, Deborah 31, 32, 433
Layton, Richard A. 40
Lazar, Moshe 123, 135, 164, 192
Lazda-Cazers, Rasma 179
Leggatt, Alexander 453
Léglu, Catherine, Rebecca Rist, and
Claire Taylor 224
Le Goff, Jacques 198
Leishman, J.B. 358
d Kafka, Franz 162
Kahn, Coppélia 370
Kates, Joshua 18
Katz, Joseph 503
Kauffman, Linda 95
Kay, Sarah 2, 107, 129, 154, 155, 156,
163, 234, 321
Kelley, Maurice 499
Kemp, Theresa D. 279
Kennedy, Elspeth 321
Kennedy, William J. 309
Kerrigan, John 361
Kerrigan, William 464
Kim Jong-il 496
King, Margaret L. 43
Kleinman, Scott 278
Klein, Richard 27
Knox, Peter E. 90
Köhler, Erich 155, 156
Krass, Andreas 219
Kristeva, Julia 408
Labé, Louise 336, 337, 338, 340
Sonnet 16 337
Sonnet 19 338
Lacan, Jacques 24, 25, 26, 28, 130, 131,
452
Lagerlund, Henrik 407
Landrum, David 459
Lane, Joan 460
Lanham, Richard A. 75
Larson, Deborah 31, 32, 433
Layton, Richard A. “Mout jauzens me prenc en amar”
170 40
Lazar, Moshe 123, 135, 164, 192
Lazda-Cazers, Rasma 179
Leggatt, Alexander 453
Léglu, Catherine, Rebecca Rist, and
Claire Taylor 224 Hesiod 12, 13
Highet, Gilbert 469
Hilarius (Hilary the Englishman) 144
Hill, Christopher 468
Hippias of Thasos 38, 480
Hjelmslev, Louis 28
Hobbes, Thomas 150
Holbach, Paul Henri Thiry 9 Kafka, Franz 162
Kahn, Coppélia 370
Kates, Joshua 18
Katz, Joseph 503
Kauffman, Linda 95
Kay, Sarah 2, 107, 129, 154, 155, 156,
163, 234, 321 Hilarius (Hilary the Englishman) 144 Hill, Christopher 468 Hippias of Thasos 38, 480 Hjelmslev, Louis 28 Hobbes, Thomas 150 Kelley, Maurice 499 Holbach, Paul Henri Thiry 9 Kemp, Theresa D. 279 Holmes, Nigel 98 Holmes, Olivia 155 Homer 12, 13, 79, 80, 93, 175, 301,
372, 499 Kerrigan, John 361 Honorius 100, 101, 103 Honorius 100, 101, 103 Kim Jong-il 496 Honor killing 398
relation to Romeo and Juliet 398 Horace 8, 13, 358, 421 Horace 8, 13, 358, 421 Horváth, I.K. 96 Houlbrooke, Ralph A. 376 Howard, Henry, Earl of Surrey 346,
347, 348
“Each beast can choose his fere
according to his mind” 346
“I never saw my lady lay apart”
347 Howard, Henry, Earl of Surrey 346,
347, 348 Krass, Andreas 219 “Each beast can choose his fere
according to his mind” 346 Labé, Louise 336, 337, 338, 340 “I never saw my lady lay apart”
347 Sonnet 16 337 Sonnet 19 338 Hughes, Merritt Y. 390, 440 Hughes, Merritt Y. 390, 440
Hult, David F. 131, 136, 266, 268
Hume, David 7, 8 Lacan, Jacques 24, 25, 26, 28, 130, 131,
452 Lacan, Jacques 24, 25, 26, 28, 130, 131,
452 Hult, David F. 131, 136, 266, 268
Hume, David 7, 8 Lagerlund, Henrik 407 Huppé, Bernard F. 283 Landrum, David 459 Innocent III 197, 221, 223, 227, 228,
246, 259, 260, 336 Lane, Joan 460 Lanham, Richard A. 75 Isaacson, Walter 511 Larson, Deborah 31, 32, 433 Layton, Richard A. 40 Jackson, MacDonald P. 370 Jackson, MacDonald P. 370 Lazar, Moshe 123, 135, 164, 192 Jacobson, Howard 56, 94, 96 Lazda-Cazers, Rasma 179 Jameson, Frederic 11
Jang Jin-sung 496
Janko, Richard 38
Japhet, Sara 52, 54
Jeanjean, Henri 221
Jerome (Eusebius Sophronius
Hieronymus) 291, 473
Jewell, Helen M. 286
Jones, Michael K., and Malcolm G. Underwood 394
Julius Caesar 97, 98, 422 Jameson, Frederic 11
Jang Jin-sung 496
Janko, Richard 38
Japhet, Sara 52, 54
Jeanjean, Henri 221
Jerome (Eusebius Sophronius
Hieronymus) 291, 473
Jewell, Helen M. 286
Jones, Michael K., and Malcolm G. Underwood 394
Julius Caesar 97, 98, 422 Leggatt, Alexander 453 Léglu, Catherine, Rebecca Rist, and
Claire Taylor 224
Le Goff, Jacques 198
Leishman, J.B. 358 Léglu, Catherine, Rebecca Rist, and
Claire Taylor 224 May, Simon 9 May, Simon 9 McCloskey, Patrick, and Edward
Phinney, Jr. 97 McCloskey, Patrick, and Edward
Phinney, Jr. 97
McGlynn, Sean 222, 223, 226 Livy 73, 74 McGlynn, Sean 222, 223, 226 Longus 113, 114, 115
Daphnis and Chloe 113, 116
Longxi, Zhang 39, 47, 48, 51, 56, 57,
156, 158, 209, 210, 212, 265 Longus 113, 114, 115
Daphnis and Chloe 113, 116 McGowan, Kate 21 McGrath, Alister 474 Longxi, Zhang 39, 47, 48, 51, 56, 57,
156, 158, 209, 210, 212, 265 McWebb, Christine 239, 252 Menocal, Maria Rosa 166, 167 Lorris, Guillaume and Jean de Meun
291 Meschini, Marco 228 Meun, Jean de 149, 210, 238, 239, 241,
252, 253, 254, 259, 262, 263, 265,
267, 268, 271 Lorris, Guillaume de 210, 238, 239,
240, 241, 246, 250, 252, 254 267, 268, 271 Lorris, Guillaume de, and Jean de
Meun 192, 210, 238, 239, 266, 268,
275, 328
Roman de la Rose 106, 135, 192, 226,
239, 240, 241, 242, 243, 244, 245,
247, 249, 250, 252, 253, 254, 259,
260, 261, 262, 263, 264, 265, 268,
274, 275, 453
Lucan 97, 98, 99, 120
Pharsalia 97, 98, 99
Lucretius 453
Luft, Joanna 263, 265
Luther, Martin 4, 9 Lorris, Guillaume de, and Jean de
Meun 192, 210, 238, 239, 266, 268,
275, 328 Lorris, Guillaume de, and Jean de
Meun 192, 210, 238, 239, 266, 268,
275, 328
Roman de la Rose 106, 135, 192, 226,
239, 240, 241, 242, 243, 244, 245,
247, 249, 250, 252, 253, 254, 259,
260, 261, 262, 263, 264, 265, 268,
274, 275, 453
Lucan 97, 98, 99, 120
Pharsalia 97, 98, 99
Lucretius 453
Luft, Joanna 263, 265
Luther, Martin 4, 9 Mews, Constant J. 198, 199, 202, 204 Miksch, Walter 369 Miller, J. Hillis 20, 21 Milton, John 2, 3, 7, 8, 9, 89, 115, 151,
153, 240, 241, 362, 364, 389, 390,
397, 429, 443, 468, 469, 475, 476,
478, 479, 480, 481, 482, 483, 484,
485, 488, 489, 494, 495, 496, 498,
499, 508, 509 239, 240, 241, 242, 243, 244, 245, 247, 249, 250, 252, 253, 254, 259, 260, 261, 262, 263, 264, 265, 268, 274, 275, 453 Doctrine and Discipline of Divorce 7, 9 Eikonoklastes 7 Eikonoklastes 7 Léglu, Catherine, Rebecca Rist, and
Claire Taylor 224 Claire Taylor 224 Le Goff, Jacques 198 Lentini, Giacomo da 302, 303, 304,
305, 306, 364
“Diamante, né smeraldo, né
zaffino” 303
“D l
i
i
” 304 “Diamante, né smeraldo, né
zaffino” 303 “Diamante, né smeraldo, né
zaffino” 303 “Dolce cominciamento” 304 “Dolce cominciamento” 304 559 Index Marselha, Folquet de 229
Martin, Catherine Gimelli 441, 442
Martinez, Ronald 138
Martin, Philip 363
Marvell, Andrew 421
Marvin, Laurence W. 226
Marx, Karl 13, 371, 482
Masten, Jeffrey 382
May Simon 9 Marselha, Folquet de 229
Martin, Catherine Gimelli 441, 442
Martinez, Ronald 138
Martin, Philip 363
Marvell, Andrew 421
Marvin, Laurence W. 226
Marx, Karl 13, 371, 482
Masten, Jeffrey 382
May Simon 9 “Io m’aggio posto in core a Dio
servire” 302
Leonard John 475 476 477 “Io m’aggio posto in core a Dio
servire” 302 “Io m’aggio posto in core a Dio
servire” 302 Leonard, John 475, 476, 477 Lévi-Strauss, Claude 28, 377 Lewis, C.S. 125, 126, 129, 130, 135,
162, 288, 472, 473, 474, 475, 477,
478, 480, 485, 486, 496, 497, 498,
499 Marvin, Laurence W. 226 Marx, Karl 13, 371, 482 Masten, Jeffrey 382 Lille, Alain de 143
De Planctu Naturae 143
Lipmen-Blumen, Jean 377
Livy 73, 74 Lille, Alain de 143
De Planctu Naturae 143
Lipmen-Blumen, Jean 377 Nietzsche, Friederich 13, 403, 404 Nietzsche, Friederich 13, 403, 404 Patterson, Lee 160, 161, 406 Musil, Robert Der Mann Ohne Eigenschaften (The
Man Without Qualities) 150, 404 Der Mann Ohne Eigenschaften (The Metamorphoses 89, 90, 92
Tristia 61
Paden, William D. 137, 142, 157, 176,
179, 184
Paris, Gaston 122, 124, 128, 130, 131,
132, 133, 135, 136, 235, 240
Parker, John 160
Parmenides 16, 27
Parry, John Jay 124
Paterson, Linda 149
Pater, Walter 21
Patri, Gabriel Díaz 106
Patterson, Lee 160, 161, 406
Pearsall, Derek 282, 283
Pecora, Vincent P. 20
Pegg, Simon 223, 232
Pelagius 148, 149, 150, 151, 198
Peter, John 472, 474, 477
Petrarch, Francesco 3, 121, 137, 164,
300, 301, 309, 312, 313, 323, 324,
325, 326, 327, 328, 329, 330, 336,
338, 342, 343, 344, 345, 346, 347,
348, 349, 350, 359, 364, 367, 391,
422, 426, 458, 506
Sonnet 11 324
Sonnet 12 325
Sonnet 36 325
Sonnet 90 326
Sonnet 106 327
Sonnet 121 327
Sonnet 133 328
Sonnet 183 328
Sonnet 364 329
Pinker, Stephen 226
Pizan, Christine de 265, 266 Negotium pacis et fidei (The business of
peace and faith) 228, 246 Paden, William D. 137, 142, 157, 176,
179, 184
Paris, Gaston 122, 124, 128, 130, 131,
132, 133, 135, 136, 235, 240
Parker, John 160
Parmenides 16, 27
Parry, John Jay 124
Paterson, Linda 149
Pater, Walter 21
Patri, Gabriel Díaz 106
Patterson, Lee 160, 161, 406
Pearsall, Derek 282, 283
Pecora, Vincent P. 20
Pegg, Simon 223, 232
Pelagius 148, 149, 150, 151, 198
Peter, John 472, 474, 477
Petrarch, Francesco 3, 121, 137, 164,
300, 301, 309, 312, 313, 323, 324,
325, 326, 327, 328, 329, 330, 336,
338, 342, 343, 344, 345, 346, 347,
348, 349, 350, 359, 364, 367, 391,
422, 426, 458, 506
Sonnet 11 324
Sonnet 12 325
Sonnet 36 325
Sonnet 90 326
Sonnet 106 327
Sonnet 121 327
Sonnet 133 328
Sonnet 183 328
Sonnet 364 329
Pinker, Stephen 226
Pizan, Christine de 265, 266 Paden, William D. 137, 142, 157, 176,
179, 184 Nelson, Lowry 309 Nelson, Lowry 309 Paris, Gaston 122, 124, 128, 130, 131,
132, 133, 135, 136, 235, 240 Nero 97, 98, 99, 100 Nero 97, 98, 99, 100 Neruda, Pablo
“Puedo escribir los versos más
tristes esta noche” 507 Parker, John 160 Parmenides 16, 27 Parry, John Jay 124 Nevo, Yehoshafat 53 Paterson, Linda 149 Newman, Barbara 134, 143, 202, 206,
209, 210, 212, 213 Pater, Walter 21 Pater, Walter 21 Patri, Gabriel Díaz 106 obedience demands for, opposition to love 3,
4, 5, 6, 8, 9, 10, 33, 63, 77, 89, 94,
126, 129, 135, 186, 189, 197, 213,
219, 220, 229, 261, 265, 272, 368,
369, 374, 375, 376, 378, 380, 381,
383, 384, 385, 386, 390, 393, 395,
397, 398, 401, 408, 410, 420, 443,
444, 456, 467, 468, 469, 472, 476,
478, 481, 482, 484, 485, 488, 498,
499, 502, 503, 511 demands for, opposition to love 3,
4, 5, 6, 8, 9, 10, 33, 63, 77, 89, 94,
126, 129, 135, 186, 189, 197, 213,
219, 220, 229, 261, 265, 272, 368,
369, 374, 375, 376, 378, 380, 381,
383, 384, 385, 386, 390, 393, 395,
397, 398, 401, 408, 410, 420, 443,
444, 456, 467, 468, 469, 472, 476,
478, 481, 482, 484, 485, 488, 498,
499, 502, 503, 511 369, 374, 375, 376, 378, 380, 381, 383, 384, 385, 386, 390, 393, 395, Obedience Chorus, The 476, 480 O’Hara, Diana 374, 376 Olmert, Michael 364 Olson, Roger E. 196 Olson, Roger E. 196 Oppenheimer, Paul 302, 306 Oppenheimer, Paul 302, 306 Orff, Carl 112 Orff, Carl 112 Of Education 151 Paradise Lost (or its characters) 2, 9,
22, 89, 148, 150, 288, 344, 362, 390,
397, 467, 468, 469, 470, 471, 472,
473, 474, 475, 476, 477, 478, 479,
480, 481, 482, 484, 485, 486, 487,
488, 489, 490, 491, 492, 493, 494,
495, 496, 497, 498, 499, 502, 508, 509
Tenure of Kings and Magistrates 7
Minnis, Alastair 208, 289
Mitchell, Charles 441
Monfasani, John 160
Montaigne, Michel 5, 453, 454
Montanhagol, Guilhem 232, 233, 305,
306 Paradise Lost (or its characters) 2, 9, Paradise Lost (or its characters) 2, 9,
22, 89, 148, 150, 288, 344, 362, 390,
397, 467, 468, 469, 470, 471, 472,
473, 474, 475, 476, 477, 478, 479,
480, 481, 482, 484, 485, 486, 487,
488, 489, 490, 491, 492, 493, 494,
495, 496, 497, 498, 499, 502, 508, 509 397, 467, 468, 469, 470, 471, 472, MacFarlane, Alan 372 473, 474, 475, 476, 477, 478, 479, Macfie, Pamela Royston 120 480, 481, 482, 484, 485, 486, 487, Macrobius 85, 86, 239 488, 489, 490, 491, 492, 493, 494, Mallarmé, Stephan 28, 30 495, 496, 497, 498, 499, 502, 508, 509 Mann, Jill 289 Tenure of Kings and Magistrates 7
Minnis, Alastair 208, 289
Mitchell, Charles 441
Monfasani, John 160
Montaigne, Michel 5, 453, 454
Montanhagol, Guilhem 232, 233, 305,
306 Marcabru 172, 173, 174, 291, 293, 307,
442 Marcus Junianus Justinus 87 Marenbon, John 198, 210 Mariaselvam, Abraham 39 Marlowe, Christopher 116, 120, 371 306 Love and its Critics 560 Ovid 9, 57, 58, 59, 61, 62, 63, 64, 65,
66, 67, 69, 70, 71, 72, 74, 75, 76, 77,
87, 89, 90, 91, 92, 93, 94, 95, 96, 97,
100, 101, 104, 106, 113, 126, 160,
192, 364, 367, 460, 485, 495
Amores 57, 58, 60, 61, 63, 64, 65, 67,
69, 70, 76, 89, 90, 91, 460
Ars Amatoria 57, 61, 62, 64, 71, 72, 74
Heroides 9, 58, 90, 91, 93, 94, 95, 96
Metamorphoses 89, 90, 92
Tristia 61 Montfort, Simon de 223, 227, 228, 260 Montfort, Simon de 223, 227, 228, 260
Montmorency, James Edward
Geoffrey De 287 Ovid 9, 57, 58, 59, 61, 62, 63, 64, 65,
66, 67, 69, 70, 71, 72, 74, 75, 76, 77,
87, 89, 90, 91, 92, 93, 94, 95, 96, 97,
100, 101, 104, 106, 113, 126, 160,
192, 364, 367, 460, 485, 495 Montmorency, James Edward
Geoffrey De 287 y
Morris, Colin 174, 175 y
Morris, Colin 174, 175 Morrissey, Lee and Will Stockton 160 Amores 57, 58, 60, 61, 63, 64, 65, 67,
69, 70, 76, 89, 90, 91, 460 Musaeus 116, 117, 118, 120 Musaeus 116, 117, 118, 120 Musaeus 116, 117, 118, 120
Hero and Leander 116, 117, 118, 431
Musil, Robert Hero and Leander 116, 117, 118, 431 Ars Amatoria 57, 61, 62, 64, 71, 72, 74
H
id
9 58 90 91 93 94 95 96 Orff, Carl 112 Orgel, Stephen 49, 324, 354 Origen of Alexandria 39, 40, 41, 42,
47, 48, 50, 52, 53, 63, 106, 120, 158,
172, 453, 463, 464 561 Index Richard I 220
Richard II
rejection of 1391 petition to restrict
education to the nobility 287
Richard of St. Victor 55
Richman, Gerald 479, 492
Richtmeyer, Eric 24
Ricoeur, Paul 13, 14, 18, 42, 56
Rieger, Angelica 142, 143, 144, 145,
146
Roberts, John 423
Robertson, D.W. 133, 134, 135, 209,
212
Rodríguez de la Cámara, Juan
Triunfo de las Donas 487
Romans, Bietris de
“Na Maria” 139, 141, 142, 144, 145, Richard I 220 Plato 1, 12, 13, 17, 27, 32, 33, 38, 105,
163, 165, 222, 295, 296, 298, 299,
300, 306, 336, 372, 418, 440, 454
Cratylus 27
Symposium 296, 298, 300, 332, 356,
418, 440 Richard II rejection of 1391 petition to restrict
education to the nobility 287 Richard of St. Victor 55 Richman, Gerald 479, 492 Plotinus 298, 299, 300 Plotinus 298, 299, 300 Richtmeyer, Eric 24 Pollock, Linda A. 372 Ricoeur, Paul 13, 14, 18, 42, 56 Pompey the Great 97, 99 Rieger, Angelica 142, 143, 144, 145,
146 Popper, Karl 16, 429 Princess Bride, The 114 Prudentius 104, 106 Robertson, D.W. 133, 134, 135, 209, Robertson, D.W. 133, 134, 135, 209,
212 Prynne, William 1, 455, 461, 464, 482 Rodríguez de la Cámara, Juan
Triunfo de las Donas 487 Rodríguez de la Cámara, Juan
Triunfo de las Donas 487
Romans, Bietris de
“Na Maria” 139, 141, 142, 144, 145,
146 Pushkin, Alexander Sergeyevich 9,
505, 506 “Когда в объятия мои” (“Kogda v
ob”yatiya moi”) 505 Romans, Bietris de
“Na Maria” 139, 141, 142, 144, 145,
146 Евгений Онегин (Evgeny Onegin) 9,
505 Rorty, Richard 19, 20 Rorty, Richard 19, 20 Борис Годунов (Boris Godunov) 505 Roscelin of Compiègne 200, 201 Rosenberg, Harold
“The Herd of Independent Minds”
147 Qābbanī, Nizār 509–510 Qābbanī, Nizār 509–510 Quaglio, Antonio Enzo 321 Quaglio, Antonio Enzo 321 Quchak, Nahaphet 340, 341
“Hayren 20” 340
“Hayren 65” 341
“Hayren 81” 342 Rougemont, Denis de 199, 407, 410 Q
,
p
,
“Hayren 20” 340
“Hayren 65” 341
“Hayren 81” 342
Quinones, Richard J. 106
Quint, David 480 g
Rousseau, Jean-Jacques 6, 33, 151
Rubin, Gayle 377
Ryang, Sonia 495, 496
Ryan, Kiernan 405, 406, 409, 504 Rousseau, Jean-Jacques 6, 33, 151 Rousseau, Jean-Jacques 6, 33, 151 Rubin, Gayle 377 Rubin, Gayle 377 “Hayren 81” 342 Ryang, Sonia 495, 496 Ryang, Sonia 495, 496 Quinones, Richard J. 106 Quinones, Richard J. 106
Quint, David 480 Ryan, Kiernan 405, 406, 409, 504 Ryan, Kiernan 405, 406, 409, 504 Quint, David 480 Saint Circ, Uc de 146, 176, 308 Smythe, Barbara 179 Smythe, Barbara 179 King Lear 405, 406, 409, 458, 504 Song of Songs 1, 11, 34, 37, 38, 39, 40,
41, 42, 47, 48, 50, 51, 52, 54, 56, 57,
63, 77, 109, 111, 113, 141, 160, 164,
264, 285, 286, 367, 453, 464, 495 Macbeth 49, 446 Measure for Measure 399, 476 Much Ado About Nothing 403 Much Ado About Nothing 403
Othello 369, 377, 416, 473 Sontag, Susan 37, 501 De Mundi Universitate 134 Hamlet 80, 359, 372, 376, 443, 458 Sklenár, Robert 108 Henry V 370 Henry V 370 Saint Circ, Uc de 146, 176, 308 Rabelais, Francois 12 Rabelais, Francois 12 Salandra, Serafino della 493
Adamo Caduto 492 Raby, F.J.E. 101, 105 Raby, F.J.E. 101, 105 Radice, Betty 196, 206, 212 Radice, Betty 196, 206, 212 Salter, Elizabeth 165 Raphael (Raffaello Sanzio da Urbino)
165 Samuel, Irene 475, 477, 480, 498, 499 Sandys, John Edwin 12, 106 Rashi (Rabbi Solomon the Izakhite)
52, 53, 54, 456, 463 Sandys, John Edwin 12, 106
Sankovitch, Tilde 137, 155, 157 Sankovitch, Tilde 137, 155, 157 Santana, Carlos 404 Ray, Chris 48 Ray, Chris 48 Sappho 140, 141 Raymond VI of Toulouse 221, 223,
230 Saussure, Ferdinand de 25, 26, 28
arbitrary nature of the sign
challenged 27
Sayce, Olive 301, 302
Scève, Maurice 336
“Délie 439” 336 Raymond V of Toulouse 222 Reddy, William M. 122, 144, 171, 235,
282 Rees, Brinley Roderick 150 Reid, Charles J. 208 Reynolds, Barbara 321 562 Love and its Critics Schulman, Nicole M. 229
Schwartz, Regina 404
Schwoerer, Lois G. 372
Two Gentlemen of Verona 369, 377,
379, 380, 381, 382, 383, 390, 416,
486 Schulman, Nicole M. 229
Schwartz, Regina 404
Schwoerer, Lois G. 372
Two Gentlemen of Verona 369, 377,
379, 380, 381, 382, 383, 390, 416,
486 Schulman, Nicole M. 229
Schwartz, Regina 404
Schwoerer, Lois G. 372
Sedgwick, Eve 22, 377, 386, 502
Segal, M.H. 39
Seneca 293, 473
Sextus Empiricus 25
Shakespeare, William 2, 9, 49, 68, 79
108, 115, 121, 137, 174, 192, 195,
240, 241, 253, 270, 271, 279, 313,
324, 342, 353, 354, 356, 357, 358,
359, 360, 361, 362, 363, 364, 365,
367, 368, 369, 370, 371, 372, 376,
377, 378, 379, 380, 382, 385, 394,
403, 406, 408, 409, 413, 414, 415,
416, 420, 422, 426, 443, 445, 446,
453, 458, 476, 486, 495 Schulman, Nicole M. 229
Schwartz, Regina 404
Schwoerer, Lois G. 372
Sedgwick, Eve 22, 377, 386, 502
Segal, M.H. 39
Seneca 293, 473
Sextus Empiricus 25
Shake
ea e Willia
2 9 49 68 79 Schulman, Nicole M. 229
Schwartz, Regina 404
Schwoerer, Lois G. 372
Two Gentlemen of Verona 369, 377,
379, 380, 381, 382, 383, 390, 416,
486 Schulman, Nicole M. 229
Schwartz, Regina 404
Schwoerer, Lois G. 372
Sedgwick, Eve 22, 377, 386, 502
Segal, M.H. Saint Circ, Uc de 146, 176, 308 39
Seneca 293, 473
Sextus Empiricus 25
Shakespeare William 2 9 49 68 79
Two Gentlemen of Verona 369, 3
379, 380, 381, 382, 383, 390, 4
486
Shapiro, Marianne 311
Sharrock, Alison 64, 71, 75, 90
Shaw, George Bernard 377, 459
Shelley, Percy 20, 76, 482
Shotter, David 77 Two Gentlemen of Verona 369, 377,
379, 380, 381, 382, 383, 390, 416,
486 Shapiro, Marianne 311 Sharrock, Alison 64, 71, 75, 90 Segal, M.H. 39 Shaw, George Bernard 377, 459 Seneca 293, 473 Shelley, Percy 20, 76, 482 Sextus Empiricus 25 Shotter, David 77 Shakespeare, William 2, 9, 49, 68, 79, p
108, 115, 121, 137, 174, 192, 195, Sichel-Bazin, Rafëu, Carolin Buthke,
and Trudel Meisenburg 193 240, 241, 253, 270, 271, 279, 313, Sidney, Philip 3, 13, 312, 342, 348,
349, 350, 353, 356, 364, 391
Astrophil and Stella 348, 349, 350,
351, 356, 367, 391
The Countess of Pembroke’s Arcadia
348 324, 342, 353, 354, 356, 357, 358, Sidney, Philip 3, 13, 312, 342, 348,
349, 350, 353, 356, 364, 391 359, 360, 361, 362, 363, 364, 365, 367, 368, 369, 370, 371, 372, 376, Astrophil and Stella 348, 349, 350,
351, 356, 367, 391 377, 378, 379, 380, 382, 385, 394, 403, 406, 408, 409, 413, 414, 415, The Countess of Pembroke’s Arcadia
348 416, 420, 422, 426, 443, 445, 446, 453, 458, 476, 486, 495 The Defence of Poesie 13, 348 A Midsummer Night’s Dream 377,
384, 385, 386, 387, 388, 389, 390, Sidonius 97, 101, 102, 103, 104, 108 Silvestre, Hubert 210 Silvestre, Hubert 210 391, 392, 393, 395, 397, 398 Silvestris, Bernardi 133, 134 As You Like It 178 Tudela, Guilhem de 224, 225, 228, 230 Wilson-Okamura, David Scott 95 Toews, John 150 Topsfield, L.T. 164, 170, 171, 172, 173,
192 Walsingham, Francis 369 Walsingham, Francis 369 Walters, Lori J. 276 Vleeschouwers-Van Melkebeek,
Monique 393 Teskey, Gordon 479, 480, 498, 499 Thibault, John C. 61 Thibault, John C. 61 Vogelweide, Walther von der 217,
218, 402 Thomason, T. Katharine 441 Thomsett, Michael C. 226 “Under der linden” 217, 218, 219
Vyvyan, John 420 “Under der linden” 217, 218, 219
Vyvyan, John 420 Tillyard, E.M.W. 342 Timaeus of Tauromenium 86 Symonds, John Addington 302, 306,
319 Taavon, Modje 398, 511 Virgil 70, 77, 78, 80, 84, 85, 87, 89, 90,
91, 92, 93, 94, 95, 97, 101, 319, 485
The Aeneid 3, 77, 78, 81, 85, 86, 88,
89, 90, 97 Tanner, J. Paul 56 Targoff, Ramie 345, 422, 457 Tarrant, Richard 90 Timaeus of Tauromenium 86 Waldock, A.J.A. 471, 472, 475, 478,
483, 488, 498 Richard III 480 Spence, Sarah 170 Richard III 480
Romeo and Juliet 253, 368, 369, 377,
378, 393, 394, 395, 396, 397, 398,
399, 400, 401, 402, 403, 404, 405,
406, 407, 408, 409, 410, 412, 413,
414, 415, 416, 417, 418, 419, 420,
422, 485, 486
Sonnet 1 353, 354, 355
Sonnet 3 355, 356
Sonnet 15 356, 357, 358
Sonnet 18 358, 359
Sonnet 116 359, 360, 361, 362
Sonnet 130 363, 364, 365
Sonnet 138 365, 366, 367
The Tempest 463 Romeo and Juliet 253, 368, 369, 377,
378, 393, 394, 395, 396, 397, 398,
399, 400, 401, 402, 403, 404, 405,
406, 407, 408, 409, 410, 412, 413,
414, 415, 416, 417, 418, 419, 420,
422, 485, 486
Sonnet 1 353, 354, 355
Sonnet 3 355, 356
Sonnet 15 356, 357, 358
Sonnet 18 358, 359
Sonnet 116 359, 360, 361, 362
Sonnet 130 363, 364, 365
Sonnet 138 365, 366, 367
The Tempest 463 Romeo and Juliet 253, 368, 369, 377,
378, 393, 394, 395, 396, 397, 398,
399, 400, 401, 402, 403, 404, 405,
406, 407, 408, 409, 410, 412, 413,
414, 415, 416, 417, 418, 419, 420,
422, 485, 486
Sonnet 1 353, 354, 355
Sonnet 3 355, 356
Sonnet 15 356, 357, 358
Sonnet 18 358, 359
Sonnet 116 359, 360, 361, 362
Sonnet 130 363, 364, 365
Sonnet 138 365, 366, 367
The Tempest 463 Romeo and Juliet 253, 368, 369, 377, Spiller, Michael R.G. 301 378, 393, 394, 395, 396, 397, 398, Spivak, Gayatri 34 399, 400, 401, 402, 403, 404, 405, Stehling, Thomas 143, 144 406, 407, 408, 409, 410, 412, 413, Sternberg, Robert 429, 548 414, 415, 416, 417, 418, 419, 420, Stilling, Roger 371 Stockton, Will 469 Sonnet 1 353, 354, 355 Stone, Gregory B. 158, 161, 190, 405 Sonnet 3 355, 356 Stone, Lawrence 368, 369, 371, 372,
373, 374, 375, 380, 384, 398, 416 Strabo 13 Strayer, Joseph R. 197, 198, 282, 283 Strayer, Joseph R. 197, 198, 282, 283 Sonnet 130 363, 364, 365 Sonnet 130 363, 364, 365 Strouse, A.W. Richard III 480 503 Sonnet 138 365, 366, 367 Sonnet 138 365, 366, 367 Stubbs, John 432, 435 Sullivan, Ceri 460 Index 563 Swabey, Ffiona 301
Symonds, John Addington 302, 306,
319 “Chantars no pot gaire valer” 174
“Non es meravelha s’eu chan” 174
Vickers, Brian 370
Vidal, Peire 179
Virgil 70, 77, 78, 80, 84, 85, 87, 89, 90,
91, 92, 93, 94, 95, 97, 101, 319, 485
The Aeneid 3, 77, 78, 81, 85, 86, 88,
89, 90, 97 “Chantars no pot gaire valer” 174 Symonds, John Addington 302, 306, Tarrant, Richard 90 89, 90, 97
Vleeschouwers-Van Melkebeek,
Monique 393
Vogelweide, Walther von der 217,
218, 402
“Under der linden” 217, 218, 219
Vyvyan, John 420 Tchaikovsky, Pyotr Ilyich 404 Vleeschouwers-Van Melkebeek,
Monique 393 Vleeschouwers-Van Melkebeek,
Monique 393
Vogelweide, Walther von der 217,
218, 402
“Under der linden” 217, 218, 219
Vyvyan, John 420 Traub, Valerie 400 Watchtower, The 481
“If Adam was Perfect, How Was It
Possible for Him to Sin?” 481 trobairitz 137, 139, 142, 160, 164, 186, trobairitz 137, 139, 142, 160, 164,
190, 242, 279, 402, 420, 426 190, 242, 279, 402, 420, 426 troubadours 2, 9, 52, 54, 122, 125, 129, troubadours 2, 9, 52, 54, 122, 125, 129
131, 132, 133, 138, 139, 142, 143,
146, 147, 148, 149, 152, 155, 156,
157, 158, 161, 163, 165, 167, 169,
170, 174, 178, 179, 183, 184, 186,
189, 190, 192, 194, 217, 220, 229,
232, 233, 235, 240, 242, 246, 247,
248, 264, 280, 281, 282, 300, 302,
305, 306, 308, 310, 311, 314, 315,
322, 330, 336, 339, 340, 342, 350,
353, 355, 365, 371, 402, 410, 412,
420, 422, 426, 429, 442, 505 troubadours 2, 9, 52, 54, 122, 125, 129
131, 132, 133, 138, 139, 142, 143,
146, 147, 148, 149, 152, 155, 156,
157, 158, 161, 163, 165, 167, 169,
170, 174, 178, 179, 183, 184, 186,
189, 190, 192, 194, 217, 220, 229,
232, 233, 235, 240, 242, 246, 247,
248, 264, 280, 281, 282, 300, 302,
305, 306, 308, 310, 311, 314, 315,
322, 330, 336, 339, 340, 342, 350,
353, 355, 365, 371, 402, 410, 412,
420, 422, 426, 429, 442, 505 Watson, Lynette 102 131, 132, 133, 138, 139, 142, 143, 146, 147, 148, 149, 152, 155, 156, Watson, Robert 442 157, 158, 161, 163, 165, 167, 169, Weinrich, Lorenz 207 170, 174, 178, 179, 183, 184, 186, Wetherbee, Winthrop 285 189, 190, 192, 194, 217, 220, 229, White, Peter 71 232, 233, 235, 240, 242, 246, 247, Whitgift, John 369 Wilde, Oscar 485, 504 Wilhelm, James J. 192 Wilkinson, Lancelot Patrick 75, 76,
93, 94 Wilmott, John, Earl of Rochester 434 Tudela, Guilhem de 224, 225, 228, 230
Tullia d’Aragona Tudela, Guilhem de 224, 225, 228, 230 Tullia d’Aragona Wimsatt, W.K., and M.C. Beardsley
29 Dialogo della Infinità d’Amore 334
Tyerman, Christopher 227 Dialogo della Infinità d’Amore 334
Tyerman, Christopher 227 Winkler, John J. 114 Winkler, John J. 114 Vaux-Cernay, Pierre de 225
Vendler, Helen 354, 362, 363, 364
Ventadorn, Bernart de 129, 169, 174,
175, 176, 177, 178, 192, 203, 208,
235, 237, 261, 286, 291, 293, 307,
343
“Can l’erba fresch’e·lh folha par”
175, 177, 178 Vaux-Cernay, Pierre de 225
Vendler, Helen 354, 362, 363, 364 Wollock, Jennifer 135, 136 Wollock, Jennifer 135, 136 Woodbridge, Linda 380 Woods, Marjorie Curry 160 Ventadorn, Bernart de 129, 169, 174,
175, 176, 177, 178, 192, 203, 208,
235, 237, 261, 286, 291, 293, 307,
343 Wrathall, Mark A. 16 Wyatt, Thomas 343, 344, 345, 346, 348
“Because I have thee still kept from
lies and blame” 346 Wyatt, Thomas 343, 344, 345, 346, 348 y
,
,
,
,
,
“Because I have thee still kept from
lies and blame” 346 “Can l’erba fresch’e·lh folha par”
175, 177, 178 564 Love and its Critics “Behold, Love, thy power how she
despiseth” 345
“Such vain thought as wonted to
mislead me” 344
“Whoso list to hunt” 343
Wycliffe, John 10, 287
Yeats, William Butler 161, 411, 412,
424
Zeno of Elea 17, 103
Ziolowski, Jan 199
Zumthor, Paul 152, 154, 155, 158, 159,
160, 161, 176, 190, 405 “Behold, Love, thy power how she
despiseth” 345
“Such vain thought as wonted to
mislead me” 344
“Whoso list to hunt” 343
Wycliffe, John 10, 287 “Behold, Love, thy power how she
despiseth” 345
“Such vain thought as wonted to
mislead me” 344
“Whoso list to hunt” 343
Wycliffe, John 10, 287 Yeats, William Butler 161, 411, 412,
424 Zeno of Elea 17, 103
Ziolowski, Jan 199
Zumthor, Paul 152, 154, 155, 158, 159,
160, 161, 176, 190, 405 This book need not end here… At Open Book Publishers, we are changing the nature of the traditional
academic book. The title you have just read will not be left on a library shelf,
but will be accessed online by hundreds of readers each month across the
globe. OBP publishes only the best academic work: each title passes through
a rigorous peer-review process. We make all our books free to read online
so that students, researchers and members of the public who can’t afford a
printed edition will have access to the same ideas. This book and additional content is available at:
https://www.openbookpublishers.com/product/591 Customize Personalize your copy of this book or design new books using OBP and third-
party material. Take chapters or whole books from our published list and
make a special edition, a new anthology or an illuminating coursepack. Each
customized edition will be produced as a paperback and a downloadable PDF. Find out more at:t https://www.openbookpublishers.com/section/59/1 Donate If you enjoyed this book, and feel that research like this should be available
to all readers, regardless of their income, please think about donating to us. We do not operate for profit and all donations, as with all other revenue we
generate, will be used to finance new Open Access publications. https://www.openbookpublishers.com/section/13/1/support-us Like Open Book Publishers
Follow @OpenBookPublish
Read more at the OBP Blog Like Open Book Publishers
Follow @OpenBookPublish
Read more at the OBP Blog Like Open Book Publishers
Follow @OpenBookPublish
Read more at the OBP Blog You may also be interested in: The Classic Short Story, 1870-1925
Theory of a Genre
By Florence Goyet
https://www.openbookpublishers.com/product/199 By Florence Goyet Vertical Readings in Dante’s ‘Comedy’
Volume 1 Edited by George Corbett and Heather Webb http://www.openbookpublishers.com/product/367 Love and its Critics Love and its Critics From the Song of Songs to Shakespeare and Milton’s Eden MICHAEL BRYSON AND ARPI MOVSESIAN This book is a history of love and the challenge love off ers to the laws and customs of
its Ɵ mes and places, as told through poetry from the Song of Songs to John Milton’s
Paradise Lost. It is also an account of the criƟ cal recepƟ on aff orded to such literature,
and the ways in which criƟ cism has aƩ empted to sƟ fl e this challenge. Bryson and Movsesian argue that the poetry they explore celebrates and reinvents the
love the troubadour poets of the eleventh and twelŌ h centuries called fi n’amor: love as
an end in itself, mutual and freely chosen even in the face of social, religious, or poliƟ cal
retribuƟ on. Neither eros nor agape, neither exclusively of the body, nor solely of the spirit,
this love is a middle path. Alongside this tradiƟ on has grown a criƟ cal movement that
employs a ‘hermeneuƟ cs of suspicion’, in Paul Ricoeur’s phrase, to claim that passionate
love poetry is not what it seems, and should be properly understood as worship of God,
subordinaƟ on to Empire, or an entanglement with the structures of language itself – in
short, the very things it resists. The book engages with some of the seminal literature of the Western canon, including
the Bible, the poetry of Ovid, and works by English authors such as William Shakespeare
and John Donne, and with criƟ cism that stretches from the earliest readings of the
Song of Songs to contemporary academic literature. Lively and enjoyable in its style, it
aƩ empts to restore a sense of pleasure to the reading of poetry, and to puncture criƟ cal
insistence that literature must be outwiƩ ed. It will be of value to professional, graduate, and advanced undergraduate scholars of
literature, and to the educated general reader interested in treatments of love in poetry
throughout history. As with all Open Book publicaƟ ons, this enƟ re book is available to read for free on the
publisher’s website. From the Song of Songs to Shakespeare and Milton’s Eden Printed and digital ediƟ ons, together with supplementary digital
material, can also be found here: www.openbookpublishers.com Cover image: Ary Scheff er, Dante and Virgil Encountering the Shades of Francesca da
Rimini and Paolo in the Underworld (1855)
Cover Design: Heidi Coburn
e
book
ebook and OA ediƟ ons
also available Cover image: Ary Scheff er, Dante and Virgil Encountering the Shades of Francesca da
Rimini and Paolo in the Underworld (1855)
Cover Design: Heidi Coburn
e
book
ebook and OA ediƟ ons
also available
|
https://openalex.org/W4288906331
|
https://www.nature.com/articles/s41598-022-16018-4.pdf
|
English
| null |
Comparison of the efficacies of 1.0 and 1.5 mm silicone tubes for the treatment of nasolacrimal duct obstruction
|
Research Square (Research Square)
| 2,022
|
cc-by
| 8,370
|
Jutaro Nakamura1,2*, Tomoyuki Kamao1, Arisa Mitani1, Nobuhisa Mizuki2 &
Atsushi Shiraishi1 This retrospective observational study analyzed the postoperative outcomes of bicanalicular
intubation using different diameters of tube stents for treating postsaccal nasolacrimal duct
obstruction. A total of 130 patients diagnosed with postsaccal obstruction who underwent
endoscopic-assisted silicone tube intubation were included in the study. Patients intubated with a
1.5-mm large-diameter tube were designated as the LD group, and those with a 1.0-mm normal-
diameter tube were designated as the ND group. The patency rates of the two groups at 1 year after
tube removal were compared using the Kaplan–Meier curve and restricted mean survival time (RMST)
method with τ = 365 days. Results demonstrated that the recurrence rate after tube removal was
significantly lower in the LD group as compared with the ND group (p = 0.001). The patency rates at
1 year after removal in the LD and ND group were 85.7% (95% confidence interval [CI]: 75.4, 91.9) and
73.9% (95% CI: 61.7, 82.8), respectively. When comparing the patency rates by the RMST method
at τ = 365 days, the RMST difference, RMST ratio, and RMTL ratio were higher in the LD group at
p = 0.045, 0.052, and 0.046, respectively. Abbreviations
CI
Confidence interval
CT-DCG
Computed tomography digital subtraction dacryocystography
DCR
Dacryocystorhinostomy
ENDI
Endoscopic-assisted nasolacrimal duct intubation
NST
Nunchaku-style tube
OR
Odds ratio
SD
Standard deviation
PANDO
Primary acquired nasolacrimal duct obstruction
RMST
Restricted mean survival time
RMTL
Restricted mean time lost Primary acquired nasolacrimal duct obstruction (PANDO) is an organic obstruction of the lacrimal tract that
can occur anywhere from the punctum to the opening of the nasolacrimal duct1. Presaccal obstruction refers
to an obstruction from the punctum to the internal common punctum, whereas postsaccal obstruction can be
found from the lacrimal sac to the nasolacrimal duct opening. Although the pathophysiology of PANDO remains
unclear, it is suggested that descending inflammation from the eyes or ascending inflammation from the nose
triggers swelling of the mucosal membrane, remodeling of the connective tissue, and subepithelial cavernous
body dysfunction with reactive hyperemia, resulting in temporary obstruction of the lacrimal duct2. Further-
more, chronic recurrent inflammation in the lacrimal duct causes structural alterations in the epithelium and
subepithelial tissue, resulting in the fibrous organic obstruction of the lumen. p
gi
g
First-line treatment for postsaccal obstruction in adults is bypass surgery, namely, dacryocystorhinostomy
(DCR). Meanwhile, with the development of the dacryoendoscope and advances in the fiber-optic system,
recanalization procedures have steadily evolved. www.nature.com/scientificreports www.nature.com/scientificreports Lacrimal recanalization surgery includes end
OPEN
1Department of Ophthalmology, Ehime University Graduate School of Medicine, Shit
Ehime 791‑0295, Japan. 2Department of Ophthalmology and Visual Science, Yokohama City Univ
School of Medicine, Yokohama, Kanagawa 236‑0004, Japan. *email: nakamura.jutaro.lt@ehime-u Comparison of the efficacies
of 1.0 and 1.5 mm silicone tubes
for the treatment of nasolacrimal
duct obstruction
OPEN Jutaro Nakamura1,2*, Tomoyuki Kamao1, Arisa Mitani1, Nobuhisa Mizuki2 &
Atsushi Shiraishi1 Comparison of the efficacies
of 1.0 and 1.5 mm silicone tube
for the treatment of nasolacrim
duct obstruction
Jutaro Nakamura1,2*, Tomoyuki Kamao1, Arisa Mitani1, Nobuhisa Mizuki2 &
Atsushi Shiraishi1
This retrospective observational study analyzed the postoperative outcomes of bicanali
intubation using different diameters of tube stents for treating postsaccal nasolacrimal d
obstruction. A total of 130 patients diagnosed with postsaccal obstruction who underwe
endoscopic-assisted silicone tube intubation were included in the study. Patients intuba
1.5-mm large-diameter tube were designated as the LD group, and those with a 1.0-mm
diameter tube were designated as the ND group. The patency rates of the two groups at
tube removal were compared using the Kaplan–Meier curve and restricted mean surviva
method with τ = 365 days. Results demonstrated that the recurrence rate after tube rem
significantly lower in the LD group as compared with the ND group (p = 0.001). The paten
1 year after removal in the LD and ND group were 85.7% (95% confidence interval [CI]: 7
73.9% (95% CI: 61.7, 82.8), respectively. When comparing the patency rates by the RMST
at τ = 365 days, the RMST difference, RMST ratio, and RMTL ratio were higher in the LD
p = 0.045, 0.052, and 0.046, respectively. Abbreviations
CI
Confidence interval
CT-DCG
Computed tomography digital subtraction dacryocystography
DCR
Dacryocystorhinostomy
ENDI
Endoscopic-assisted nasolacrimal duct intubation
NST
Nunchaku-style tube
OR
Odds ratio
SD
Standard deviation
PANDO
Primary acquired nasolacrimal duct obstruction
RMST
Restricted mean survival time
RMTL
Restricted mean time lost
Primary acquired nasolacrimal duct obstruction (PANDO) is an organic obstruction of the lac
can occur anywhere from the punctum to the opening of the nasolacrimal duct1. Presaccal ob
to an obstruction from the punctum to the internal common punctum, whereas postsaccal ob
found from the lacrimal sac to the nasolacrimal duct opening. Although the pathophysiology of P
unclear, it is suggested that descending inflammation from the eyes or ascending inflammatio
triggers swelling of the mucosal membrane, remodeling of the connective tissue, and subepith
body dysfunction with reactive hyperemia, resulting in temporary obstruction of the lacrimal
more, chronic recurrent inflammation in the lacrimal duct causes structural alterations in the
subepithelial tissue, resulting in the fibrous organic obstruction of the lumen. First-line treatment for postsaccal obstruction in adults is bypass surgery, namely, dacryoc
(DCR). Meanwhile, with the development of the dacryoendoscope and advances in the fibe
recanalization procedures have steadily evolved. Jutaro Nakamura1,2*, Tomoyuki Kamao1, Arisa Mitani1, Nobuhisa Mizuki2 &
Atsushi Shiraishi1 Lacrimal recanalization surgery includes endoscopic-guided 1Department of Ophthalmology, Ehime University Graduate School of Medicine, Shitsukawa, Toon,
Ehime 791‑0295, Japan. 2Department of Ophthalmology and Visual Science, Yokohama City University Graduate
School of Medicine, Yokohama, Kanagawa 236‑0004, Japan. *email: nakamura.jutaro.lt@ehime-u.ac.jp Scientific Reports | (2022) 12:11785 | https://doi.org/10.1038/s41598-022-16018-4 www.nature.com/scientificreports/ Figure 1. Flow diagram for the included cases in this study. Among the 621 ENDI operations, 15 cases had no
obstruction, 317 cases had presaccal obstruction, and 289 cases had postsaccal obstruction. Of the 289 ENDI
operations performed for postsaccal obstruction, we identified 16 cases of surgical failure. Of these, 11 were due
to false passage formation, 3 were due to solid blockage, 1 was a blockage due to dacryolithiasis, and 1 was due
to deep-set eyes. Abbreviation: ENDI, endoscopic-assisted nasolacrimal duct intubation. Figure 1. Flow diagram for the included cases in this study. Among the 621 ENDI operations, 15 cases had no
obstruction, 317 cases had presaccal obstruction, and 289 cases had postsaccal obstruction. Of the 289 ENDI
operations performed for postsaccal obstruction, we identified 16 cases of surgical failure. Of these, 11 were due
to false passage formation, 3 were due to solid blockage, 1 was a blockage due to dacryolithiasis, and 1 was due
to deep-set eyes. Abbreviation: ENDI, endoscopic-assisted nasolacrimal duct intubation. trephination DCR, dacryorhinotomy, microdrill dacryoplasty, laser dacryoplasty, and anterograde balloon
dacryoplasty3–10. Silicone tube intubation and anterograde balloon dacryoplasty are commonly used for treat-
ing partial obstruction or stenosis of the lacrimal duct11–13. In Northeast Asia, endoscopic-assisted nasolacrimal
duct intubation (ENDI) has been proposed as an alternative to DCR for the treatment of postsaccal obstruc-
tion. This is primarily because of improved postoperative outcomes with refined tube stents and an improved
visibility and accuracy of dacryoendoscopes14,15. The ENDI procedure is conducted while directly observing
the obstructed site in the lacrimal duct using a dacryoendoscope and observing the nasal cavity using a nasal
endoscope (Supplementary file, Video 1). As compared with conventional blind direct silicone intubation, ENDI
reduces complications from false passage formation. This procedure is typically performed under local anesthesia,
and it has evolved into a less-invasive and more secure procedure, resulting in its increasingly widespread use
in Northeast Asia16–19. Furthermore, as compared with other ethnical populations, Northeast Asians have rela-
tively flat facial features, with a less elevated superior orbital rim, allowing for relatively easy manipulation of the
dacryoendoscope20. Jutaro Nakamura1,2*, Tomoyuki Kamao1, Arisa Mitani1, Nobuhisa Mizuki2 &
Atsushi Shiraishi1 Since the first report of nasolacrimal duct intubation using silicon tubes by Gibbs et al. and
Keith et al. in the 196021,22, various improvements have been made in terms of surgical techniques, instruments
for stent placement, tube materials, and designs4,23. The insertion of tube stents into the lacrimal duct prevents
the adhesion of the mucosal surface of the duct while the mucosal membrane heals, promoting regeneration of
the lacrimal duct epithelium and helping to maintain long-term patency after tube removal. Typical tube stents
include the Ritleng lacrimal intubation set and the Crawford tube (FCI Ophthalmics, Pembroke, MA), which
have been used in many institutions worldwide. Nevertheless, these tubes require a thin metal probe for inser-
tion, which carries a risk of iatrogenic trauma to the canaliculi and nasolacrimal ducts23.h g
The Nunchaku-style tube (NST) is a “push-style” stent designed with a metal guide probe concealed inside
the tube24. In addition, because it does not require stent retrieval or tying of the distal end of the tubes within
the nasal cavity during placement, the NST has improved surgical efficacy24,25. The diameter of a typical NST is
1.0 mm, which is thicker than that of the Crawford tube, which has a diameter of 0.64 mm. It has been reported
that intubation of large-caliber tubes helps maintain a wide lumen26,27. Recently, a thicker 1.5-mm diameter NST
has been introduced and is currently available for clinical use. Accordingly, this study was designed to compare
the efficacy of 1.0-mm and 1.5-mm NST for the ENDI treatment of postsaccal obstruction. Methods
Subjects. Subjects. We retrospectively investigated 157 sides of 130 patients diagnosed with postsaccal obstruction. Patients were treated at Ehime University Hospital between August 2013 and November 2020 by three ophthal-
mologists (TK, AM, and AS) with 10, 4, and 14 years of ENDI surgical experience, respectively. The mean age of
the patients was 72.6 years, with a standard deviation (SD) of 11.3 years. Forty patients (50 sides) were male and
90 (107 sides) were female. Postsaccal obstruction was diagnosed based on dye disappearance tests, lacrimal irri-
gation test, cone-beam computed tomography digital subtraction dacryocystography (CT-DCG), and dacryoen-
doscopic examinations. We excluded patients with functional nasolacrimal duct obstruction from the statistical
analysis. Patients who had a history of systemic chemotherapy with fluorouracil and/or the taxanes, radiation
therapy, or posttraumatic bone deformity were also excluded. In addition, we excluded patients with unsuccess-
ful surgery, such as cases in which the stent could not be placed due to an occlusion that was too solid or cases
in which a false passage was created, from the assessment. Patients with a history of lacrimal duct reconstruction
(i.e., postoperative recurrence) were also excluded; hence, all patients were treated for the first time (Fig. 1). https://doi.org/10.1038/s41598-022-16018-4 Scientific Reports | (2022) 12:11785 | www.nature.com/scientificreports/ www.nature.com/scientificreports/ Figure 2. Two types of different-thicknesses NSTs. Shown at the top is a 1.0-mm-diameter tube, and the
bottom is a 1.5-mm-diameter tube. The NST is designed with a metal guide probe concealed in the lumen of the
tube. Abbreviation: NST, Nunchaku-style tube. Figure 2. Two types of different-thicknesses NSTs. Shown at the top is a 1.0-mm-diameter tube, and the
bottom is a 1.5-mm-diameter tube. The NST is designed with a metal guide probe concealed in the lumen of the
tube. Abbreviation: NST, Nunchaku-style tube. Treatment protocols. All patients were treated with ENDI as previously described17,28. In this procedure,
the surgeons performed lacrimal duct reconstruction while observing the lacrimal duct under the dacryoen-
doscope instead of performing the procedure blindly. Briefly, the procedure was performed as follows: after
applying infratrochlear anesthesia and topical lacrimal duct and nasal mucosal anesthesia, the upper and lower
lacrimal punctum were dilated. Dacryoendoscope (FT-201, Fibertech, Tokyo, Japan) was inserted through the
punctum, and the endoscope was then advanced to the occlusion site while monitoring the lumen. www.nature.com/scientificreports/ www.nature.com/scientificreports/ Figure 3. Composition of the ND and LD groups. The ND and LD groups are indicated by the white gray
arrows, respectively. The ND group consisted of patients treated with the 1.0-mm NST before the deployment of
the 1.5-mm NST (treated between August 2013 and July 2017). Meanwhile, the LD group consisted of patients
treated after the deployment of the 1.5-mm NST at our institution (treated between August 2017 and November
2020). Abbreviation: NST, Nunchaku-style tube. Figure 3. Composition of the ND and LD groups. The ND and LD groups are indicated by the white gray
arrows, respectively. The ND group consisted of patients treated with the 1.0-mm NST before the deployment of
the 1.5-mm NST (treated between August 2013 and July 2017). Meanwhile, the LD group consisted of patients
treated after the deployment of the 1.5-mm NST at our institution (treated between August 2017 and November
2020). Abbreviation: NST, Nunchaku-style tube. The group intubated with a large-diameter tube (1.5 mm) was designated as the LD group, and the group
intubated with a normal-diameter tube (1.0 mm) was designated as the ND group. The LD group consisted
of patients treated (between August 2017 and November 2020) after the deployment of the 1.5-mm NST at
our institution, and the ND group consisted of patients treated (between August 2013 and July 2017) with the
1.0-mm NST before the deployment of the 1.5-mm NST (Fig. 3, Supplementary Fig. 1). Gender, age, period of
obstruction, duration of tube intubation, observation period after removal, number of recurrences, and time
from tube removal to recurrence for each group were evaluated. With regard to the time from tube removal to
recurrence, the observation period after removal was regarded as zero in case of recurrence while the tube was
still in placement. The period of obstruction was denoted based on the duration of chronic epiphora symptoms
as described in the patient questionnaire. By defining “recurrence” as an event, we created a Kaplan–Meier curve. Based on the rationale listed below, the restricted mean survival time (RMST) was compared between the two
groups with τ = 365 days. (1) Clinically, recurrence is usually observed within 1 year after removal. (2) In our
institution, postoperative follow-up is usually completed when no recurrence is observed for 1 year after removal;
accordingly, the censoring rate increases beyond 1 year after removal. Statistical analysis. www.nature.com/scientificreports/ All statistical analyses were performed with EZR (Saitama Medical Center, Jichi Medi-
cal University, Saitama, Japan), a graphical user interface for R (The R Foundation for Statistical Computing,
Vienna, Austria)30. In comparing the two groups, the ratio of gender, surgery success rate, and number of recur-
rences were tested using Pearson χ2 test. Meanwhile, age, period of obstruction, duration of tube intubation,
and observation period after tube removal were tested by Mann–Whitney U test. Using the R software survRM2
package, we analyzed the creation of the Kaplan–Meier curve and comparison of survival rates between the two
groups using the RMST method31,32. A p value of < 0.05 was considered statistically significant. Ethical approval and consent to participate. This study and the data collection protocol were
authorized by the institutional review board of Ehime University (ethical approval No. 1601003). The research
was recorded with the University Hospital Medical Information Network Clinical Trials Registry (UMIN
000,025,180). Each patient provided documented informed consent before registration. All procedures used in
this study were conducted following the principles of the Declaration of Helsinki. Methods
Subjects. An 18-gage
catheter (SR-FF1864, Terumo, Tokyo, Japan) attached to the tip of the endoscope was used to release the obstruc-
tion (sheath-guided endoscopic probing technique)29. Self-retaining bicanalicular lacrimal stents were inserted
using the catheter as a guide after the obstructed area of the lacrimal canal was released. The catheter with the
tube connected was removed from the open end of the nasolacrimal duct on the inferior meatus under the view
of a nasal endoscope. The same procedure was performed on the other punctum, and the tube was placed in the
lacrimal duct (Supplementary file, Video 1). The NST stent used was either a large-diameter 1.5 mm (Lacrifast
EX; Kaneka Co., Ltd., Osaka, Japan) or a conventional diameter 1.0 mm (Lacrifast or Lacrifast CL; Kaneka Co.,
Ltd.; Fig. 2). The only difference between the 1.0-mm-diameter Lacrifast and Lacrifast CL was whether the tube
stent had an open end or a blind end, and the rest of the components, including the tube diameter, total length,
and material, were identical. Since the deployment of the 1.5-mm NST in August 2017, we have adopted an
indication of intubating 1.5-mm NST for all postsaccal obstruction patients.llt g
p
p
All patients were treated with topical 0.1% fluorometholone and 0.3% gatifloxiacin four times a day after
ENDI surgery. The lacrimal ducts were flushed by saline irrigation periodically until the stent was removed. The
tube stent was principally removed 10 to 12 weeks after ENDI surgery. Postoperative outcome assessments. We evaluated patients who were eligible for follow-up for at least
6 months after tube removal. The present study was designed to assess the patency rate of postsaccal obstruction
after ENDI treatment; hence, we excluded cases of presaccal obstruction. Recurrence was defined as follows. After the tube removal, recurrence was represented as no passage or pus or viscous fluid reflux in the postop-
erative irrigation test with structural reobstruction in the dacryoendoscopic findings. Meanwhile, during tube
placement, recurrence was regarded as no passage with pus or viscous fluid reflux in the irrigation test accompa-
nying granulomatous reocclusions in the dacryoendoscopic findings, requiring further treatments such as tube
replacement or DCR surgery. Functional success was defined as a reduction in patients’ epiphora and discharge
symptoms caused by lacrimal duct obstruction. The success rate was assessed based on a questionnaire routinely
administrated 6 months after tube removal. https://doi.org/10.1038/s41598-022-16018-4 Scientific Reports | (2022) 12:11785 | Results Among the 621 ENDI operations performed at Ehime University Hospital between August 2013 and November
2020, we identified 15 cases with no obstruction, 317 cases with presaccal obstruction, and 289 cases with post-
saccal obstruction. Of the 289 ENDI operations for postsaccal obstruction, 16 cases (5.5%) of surgical failure
were identified. Of these, 11 were due to false passage formation, 3 were due to solid blockage, 1 was due to a
blockage with large dacryolithiasis, and 1 was due to deep-set eyes (Fig. 1). Table 1 presents an overview of the
LD and ND groups. The composition of the LD group was as follows. Of the 70 cases and 85 sides (right 47,
left 38) with postsaccal obstruction, males comprised 23 cases and 29 sides (32.8% and 34.1%, respectively),
whereas females comprised 47 cases and 56 sides (67.1% and 65.9%, respectively). The mean age of the cases
was 72.5 years (SD = 11.3). The mean period of preoperative obstruction was 29.6 months (SD = 40.0). The mean
duration of tube intubation was 88.9 days (SD = 23.7). The mean observation period after tube removal was
9.8 months (SD = 5.9). In the LD group, recurrence after ENDI treatment occurred in 12 cases (14.0%). Among
these, four cases experienced recurrence during tube placement (33.3%). The average time from tube removal
to recurrence was 3.4 months (SD = 4.6). (
)
On the other hand, the composition of the ND group was as follows. Of the 60 cases and 72 sides (right 32,
left 40) with postsaccal obstruction, males comprised 17 cases and 21 sides (28.3% and 29.2%, respectively),
whereas females comprised 43 cases and 51 sides (71.7% and 70.8%, respectively). The mean age of the patients
was 72.9 years (SD = 11.5). The mean period of preoperative obstruction was 63.0 months (SD = 91.8). The mean
duration of tube intubation was 112.0 days (SD = 53.5). The mean observation period after tube removal was
14.0 months (SD = 14.7). In the ND group, recurrence after ENDI treatment occurred in 27 cases (37.5%), and 13
of these cases experienced recurrence during the tube placement (48.1%). The average time from tube removal
to recurrence was 11.0 months (SD = 16.0). https://doi.org/10.1038/s41598-022-16018-4 Scientific Reports | (2022) 12:11785 | www.nature.com/scientificreports/ Table 1. Overview of the LD and ND groups. Results Data are presented as mean ± standard deviation for age, period
of preoperative obstruction, duration of tube intubation, and observation period after tube removal. A p value
of < 0.05 was considered statistically significant. Group
p-value
LD
ND
Tube diameter
1.5 mm
1.0 mm
Number of cases
N = 70
N = 60
Number of sides
n = 85 (R 47, L 38)
n = 72 (R 32, L 40)
0.18
Age (years)
72.5 ± 11.1
72.9 ± 11.5
0.73
Gender (male/female)
23 / 47
17 / 43
0.58
Period of preoperative obstruction (months)
29.6 ± 40.0
63.0 ± 91.8
0.009
Duration of tube intubation (days)
88.9 ± 23.7
112.0 ± 53.5
0.036
Observation period after tube removal (months)
9.8 ± 5.9
14.0 ± 14.7
0.38
Functional success rate
72 (84.7%)
41 (56.9%)
0.001
Total number of recurrences
12 (14.0%)
27 (37.5%)
0.001
Number of recurrences during tube placement
4 (4.7%)
14 (19.4%)
0.004
Number of recurrences after tube removal
8 (9.4%)
13 (18.1%)
0.11
< 6 months after removal
4 (4.7%)
2 (2.8%)
0.53
< 1 year after removal
6 (7.1%)
4 (5.6%)
0.70
< 2 years after removal
8 (9.4%)
9 (12.5%)
0.54
> 2 years after removal
0 (0%)
4 (5.6%)
0.028
Time from tube removal to recurrence (months)
3.4 ± 4.6
11.0 ± 16.0
0.82 Table 1. Overview of the LD and ND groups. Data are presented as mean ± standard deviation for age, period
of preoperative obstruction, duration of tube intubation, and observation period after tube removal. A p value
of < 0.05 was considered statistically significant. Table 1. Overview of the LD and ND groups. Data are presented as mean ± standard deviation for age, period
of preoperative obstruction, duration of tube intubation, and observation period after tube removal. A p value
of < 0.05 was considered statistically significant. No statistically significant differences were found between the LD and ND groups in age, gender ratio, or
observation period after tube removal (p > 0.05). Meanwhile, the period of preoperative obstruction and duration
of tube intubation were significantly longer in the ND group (p = 0.009 and 0.036, respectively, Supplementary
Figs. 2 and 3). After ENDI, the number of recurrences was significantly lower in the LD group than in the ND
group (p = 0.001). Results Among them, the number of recurrences during tube placement was significantly smaller in
the LD group than that of the ND group (p = 0.004). The time to recurrence after tube removal was 3.4 months
(SD = 4.6) in the LD group and 11.0 months (SD = 16.0) in the ND group, with no significant difference between
the two groups (p = 0.82). The functional success was observed in 72 cases (84.7%) in the LD group and 41cases
(56.9%) in the ND group, with a significantly higher rate in the LD group (p = 0.0001). g
p
gi
y
g
g
p p
As mentioned in the Method section, Lacrifast has an open end and Lacrifast CL has a blind end, although
with the same 1.0-mm thickness. We then examined the difference in recurrence rates between the open and the
blind ends of the same caliber in the ND group. Eighteen of 53 patients who underwent insertion of open end
Lacrifast experienced a recurrence (34.0%), whereas 9 of 19 patients had the blind end Lacrifast CL inserted had
a recurrence (47.4%); accordingly, there was no significant difference in the recurrence rates between the open
and the blind ends of the same caliber (p = 0.30).i p
Next, since the preoperative obstruction period and the duration of tube intubation were significantly longer
in the ND group than in the LD group, we conducted a logistic regression analysis with “period of preopera-
tive obstruction,” “duration of tube intubation,” and “group” as explanatory variables and “recurrence” as the
objective variable to examine whether these factors contributed to the recurrence. The results showed that the
odds ratio (OR) for “period of preoperative obstruction” was 0.997 (95% confidence interval [CI]: 0.992–1.000,
p = 0.355), the OR for “duration of tube intubation” was 1.020 (95% CI: 1.000–1.030, p = 0.006), and the OR for
“group” was 2.92 (95% CI: 1.28–6.69, p = 0.011). Hence, “group” and “duration of tube intubation” were signifi-
cantly correlated with “recurrence”; meanwhile, the “period of preoperative obstruction” was not significantly
correlated in this cohort.th Figure 4 shows the Kaplan–Meier curve of lacrimal duct patency at 1 year after tube removal. The patency
rate of the lacrimal duct was 85.7% (95% CI: 75.4, 91.9) in the LD group and 73.9% (95% CI: 61.7, 82.8) in the
ND group. Results There were a total of 11 recurrences and 23 censored cases in the LD group, whereas there were 18
recurrences and 14 censorings in the ND group at 1 year after tube removal. The RMST with τ = 365 days in the
LD and ND groups was 326.65 and 284.59, respectively. In addition, the restricted mean time lost (RMTL) was
38.35 and 80.41, respectively. Results showed that RMST (LD)–(ND) = 42.058 (95% CI: 0.996, 83.121, p = 0.045),
RMST (LD)/(ND) = 1.148 (95% CI: 0.999, 1.319, p = 0.052), and RMTL (LD)/(ND) = 0.477 (95% CI: 0.230, 0.988,
p = 0.046). Therefore, the patency rate of the LD group was higher than that of the ND group at 1 year after tube
removal (Fig. 5).t g
Complications associated with ENDI surgery often involve punctum splitting and granulation on the lac-
rimal duct mucosa. Mucosal granulations are a significant finding because they can contribute to the recur-
rence (Fig. 6). 5 cases (5.9%) and 4 cases (5.6%) of punctum splitting were observed in the LD and ND groups,
respectively. Meanwhile, 13 cases (15.3%) and 5 cases (5.6%) of mucosal granulations were observed in the LD
and ND groups, respectively. The incidence of complications was not significantly different between the groups
(p = 0.93 and 0.12, respectively). https://doi.org/10.1038/s41598-022-16018-4 Scientific Reports | (2022) 12:11785 | www.nature.com/scientificreports/ Figure 4. Kaplan–Meier curve of lacrimal duct patency at 1 year after tube removal. The Kaplan–Meier curve
indicates that the lacrimal duct patency rate was 85.7% (95% CI; 75.4, 91.9) in the LD group and 73.9% (95% CI;
61.7, 82.8) in the ND group at 1 year after the tube removal. There were 11 recurrences and 23 censored cases in
the LD group and 18 recurrences and 14 censorings in the ND group. The y-axis denotes the patency rate, and
the x-axis indicates the number of days. Figure 4. Kaplan–Meier curve of lacrimal duct patency at 1 year after tube removal. The Kaplan–Meier curve
indicates that the lacrimal duct patency rate was 85.7% (95% CI; 75.4, 91.9) in the LD group and 73.9% (95% CI;
61.7, 82.8) in the ND group at 1 year after the tube removal. There were 11 recurrences and 23 censored cases in
the LD group and 18 recurrences and 14 censorings in the ND group. The y-axis denotes the patency rate, and
the x-axis indicates the number of days. Figure 5. Results Comparison of survival rates between the two groups at 1 year after tube removal by the RMST
method. RMST and RMTL are the areas under and over the Kaplan–Meier survival curve, respectively. The RMST and RMTL in the LD and ND groups with τ = 365 days were 326.65, 284.59, 38.35, and 80.41,
respectively. RMST (LD) − (ND) = 42.058 (95% CI: 0.996, 83.121, p = 0.045), RMST (LD)/(ND) = 1.148 (95% CI:
0.999, 1.319, p = 0.052), and RMTL (LD)/(ND) = 0.477 (95% CI: 0.230, 0.988, p = 0.046). The y-axis denotes the
patency rate, and the x-axis shows the number of days after tube removal. Abbreviation: RMST, restricted mean
survival time; RMTL, restricted mean time lost. Figure 5. Comparison of survival rates between the two groups at 1 year after tube removal by the RMST
method. RMST and RMTL are the areas under and over the Kaplan–Meier survival curve, respectively. The RMST and RMTL in the LD and ND groups with τ = 365 days were 326.65, 284.59, 38.35, and 80.41,
respectively. RMST (LD) − (ND) = 42.058 (95% CI: 0.996, 83.121, p = 0.045), RMST (LD)/(ND) = 1.148 (95% CI:
0.999, 1.319, p = 0.052), and RMTL (LD)/(ND) = 0.477 (95% CI: 0.230, 0.988, p = 0.046). The y-axis denotes the
patency rate, and the x-axis shows the number of days after tube removal. Abbreviation: RMST, restricted mean
survival time; RMTL, restricted mean time lost. Discussionhi Th
h
b
l
d
d
h
b
f
b
l b
h
f A
O p
p
g
g
There have been limited studies on the contribution of tube caliber to the prognosis of PANDO treatment. Several reports have introduced attempts to enlarge the lacrimal ducts using tube stents to prevent restenosis after
tube removal. For example, double 0.64-mm Crawford tubes were inserted into one canaliculus10,39,40. These stud-
ies reported a higher patency rate after canaliculoplasty surgeries using double Crawford tubes. Another study
reported that almost similar therapeutic effects were achieved with double silicone intubation using a 0.64-mm
Crawford tube and a single wide-diameter 0.94-mm Crawford tube26. Our current study demonstrated that the
patency rate was significantly higher with the 1.5-mm NST compared with the standard 1.0-mm NST at 1 year
after ENDI surgery for postsaccal obstruction. t
g
y
p
RMST is a statistical method that has been used for nearly 10 years to evaluate Kaplan–Meier survival curves. The methodology of RMST is to compare the areas under the survival curves to a specific time-point (τ) in the
survival curve31. RMST is effective when the proportional hazard model is invalid, such as when survival curves
are crossed. In addition, because τ can be determined arbitrarily, RMST is useful for comparing the effects of
interventions whose follow-up periods do not coincide41,42. The 1.5-mm diameter NST was developed and applied
clinically in recent years. Consequently, the period for determining the outcomes became shorter than that of
the conventionally used 1.0-mm NST. The RMST method was then applied to compare the treatment efficacy
between the two groups, because the proportional hazard property was not sustained until the end. In the current
study, the τ of RMST was determined as 365 days, considering the following conditions. (1) Clinically, recurrence
was mostly observed within 1 year after tube removal. (2) In our institution, postoperative follow-up was usu-
ally completed 1 year after tube removal when recurrence was not detected. (3) Due to various factors, such as
completion of follow-up or transfer to other medical facilities, the ratio of censoring in the Kaplan–Meier curve
increases after 1 year of tube removal. Discussionhi The first-line treatment for PANDO is DCR. In general, the long-term therapeutic outcomes of ENDI are not
considered to be equivalent to DCR. Nevertheless, shreds of accumulated evidence indicate that the results of
ENDI are nearly as effective as DCR for canaliculus obstruction and some cases of PANDO (in cases of nonin-
flammatory or partial obstruction)16–18,33–35. However, patients with prolonged preoperative occlusions, extended
length of postsaccal obstruction, or a history of dacryocystitis tend to relapse after ENDI surgey17,23,34–36. The https://doi.org/10.1038/s41598-022-16018-4 Scientific Reports | (2022) 12:11785 | www.nature.com/scientificreports/ Figure 6. Complications associated with ENDI surgery. (A) Punctum slitting. The inferior punctum was
stretched nasally caused by the traction of the tube through the nasolacrimal duct. (B) Endoscopic image of
mucosal granulation in a nasolacrimal duct. Original image of a case complicated with reobstruction during
tube placement. (C) Annotation for B. The two yellow circles indicate the space where the tubes were placed
during the intubation. The orange oval indicates mucosal granulation. Figure 6. Complications associated with ENDI surgery. (A) Punctum slitting. The inferior punctum was
stretched nasally caused by the traction of the tube through the nasolacrimal duct. (B) Endoscopic image of
mucosal granulation in a nasolacrimal duct. Original image of a case complicated with reobstruction during
tube placement. (C) Annotation for B. The two yellow circles indicate the space where the tubes were placed
during the intubation. The orange oval indicates mucosal granulation. ENDI success rate declines in cases of postsaccal obstruction complicated by chronic dacryocystitis. A longer
duration of dacryocystitis leads to more substantial organic changes in the lacrimal duct mucosa, which makes
reconstructive surgery with ENDI more complicated17,34,37. Therefore, in cases of postsaccal obstruction com-
plicated by dacryocystitis, DCR is recommended. ENDI operations are generally performed under local anesthesia and are one of the minimally invasive proce-
dures for treating PANDO (Supplementary file, Video 1). As compared with DCR, ENDI has various advantages
in terms of surgical time, facial surgical scars, bleeding, and downtime3,4,11,17,18,23,24,34,38. In addition, because of the
minimal risk of bleeding, ENDI can also be performed in patients receiving systemic anticoagulation and anti-
platelet therapy. Hence, further studies are required to compare the long-term treatment effects of DCR and ENDI
in patients with PANDO in terms of their pathological conditions (e.g., site, cause, and duration of obstruction). Scientific Reports | (2022) 12:11785 | www.nature.com/scientificreports/ postsaccal obstruction were treated by ENDI surgeries. For example, we selected DCR over ENDI for patients
with a history of acute dacryocystitis, lacrimal duct obstruction for longer than 3 years, or full-length postsac-
cal obstruction. Moreover, since the decision to perform ENDI or DCR surgery primarily followed the patient’s
choice, these selections could also appear to be the factors in the formation of sampling biases. pp
p
g
Next, in terms of lead-time biases, the following points can be considered. First, because 1.5-mm NST was
developed more recently, the LD group had a relatively shorter postoperative follow-up period than the ND
group did. This constitutes a lead-time bias because the data collection periods do not coincide in the ND and LD
groups. Second, we launched the lacrimal duct surgery department at our facility 15 years ago. Over this period,
the number of cases operated at our facility has changed both qualitatively and quantitatively. In short, there were
more severe cases and fewer surgeries in the beginning, but the number of surgeries and number of patients with
milder cases has increased to date. Third, the improvement in the surgeons’ skills over time and the increased
probability of successful operations could have contributed to the formation of the lead-time bias. Therefore,
to evaluate whether a larger-diameter tube intubation is more effective for postsaccal obstruction, conducting
randomized controlled studies with a more significant number of patients in a multicenter study is required.i i
In conclusion, to the best of our knowledge, this is the first report to compare the postoperative outcomes of
bicanalicular silicone tube intubation according to the difference in the tube caliber for the treatment of post-
saccal obstruction. The 1.5-mm tube brought significantly less recurrence during the tube placement than the
conventional 1.0-mm NST did, which critically increased the patency rate of the LD group 1 year after removal. Although this retrospective cohort study might include various possible limitations, the present assessment
elicited data implying the usefulness of 1.5-mm-diameter tube intubation for postsaccal obstruction. Data availabilityh Data availability
The data sets analyzed during the current study are available from the corresponding author (JN) on reasonable
requests. The data sets analyzed during the current study are available from the corresponding author (JN) on reasonable
requests. Received: 25 December 2021; Accepted: 4 July 2022 Received: 25 December 2021; Accepted: 4 July 2022 References References
1. Mandeville, J. T. & Woog, J. J. Obstruction of the lacrimal drainage system. Curr. Opin. Ophthalmol. 13, 303–309. https://doi.org/
10.1097/00055735-200210000-00003 (2002).h 1. Mandeville, J. T. & Woog, J. J. Obstruction of the lacrimal drainage system. Curr. Opin. Ophthalmol. 13, 30
10.1097/00055735-200210000-00003 (2002).h (
)
2. Paulsen, F. The human nasolacrimal ducts. Adv. Anat. Embryol. Cell Biol. 170, 1–106 (2003). h
y
3. Emmerich, K. H., Ungerechts, R. & Meyer Rüsenberg, H. W. Possibilities and limits of minimal invasive lacrimal surgery. Orbit
19, 67–71 (2000). Al
&
l
l
l d
l
d
C h
3. Emmerich, K. H., Ungerechts, R. & Meyer Rüsenberg, H. W. Possibilities and limits of minimal inva
19, 67–71 (2000). 3. Emmerich, K. H., Ungerechts, R. & Meyer Rüsenberg, H. W. Possibilities and limits of minimal invasive lacrimal surgery. Orbi
19, 67–71 (2000). 4. Ali, M. J. & Paulsen, F. Human lacrimal drainage system reconstruction, recanalization, and regeneration. Curr. Eye Res. 45 4. Ali, M. J. & Paulsen, F. Human lacrimal drainage system reconstruction, recanalization, and regeneration. Curr. Eye Res. 45
241–252. https://doi.org/10.1080/02713683.2019.1580376 (2020). p
g
(
)
5. Meyer-Rüsenberg, H. W. & Emmerich, K. H. Modern lacrimal duct surgery from the ophthalmological perspective. Dtsch. Arztebl
Int. 107, 254–258. https://doi.org/10.3238/arztebl.2010.0254 (2010).i g
6. Sasaki, T., Nagata, Y. & Sugiyama, K. Nasolacrimal duct obstruction classified by dacryoendoscopy and treated with inferior meatal
dacryorhinotomy. Part I: Positional diagnosis of primary nasolacrimal duct obstruction with dacryoendoscope. Am. J. Ophthalmol. 140, 1065–1069. https://doi.org/10.1016/j.ajo.2005.07.038 (2005).i p
g
j j
7. Sasaki, T., Nagata, Y. & Sugiyama, K. Nasolacrimal duct obstruction classified by dacryoendoscopy and treated with inferior meata
dacryorhinotomy: Part II Inferior Meatal dacryorhinotomy. Am. J. Ophthalmol. 140, 1070–1074. https://doi.org/10.1016/j.ajo.2005
07.039 (2005). 8. Wang, Z. et al. Diagnosis and treatment of lacrimal passage obstruction by lacrimal endoscope. J. Huazhong Univ. Sci. Technolog. Med. Sci. 27, 593–597. https://doi.org/10.1007/s11596-007-0530-2 (2007). p
g
9. Hong, J. et al. Nasolacrimal recanalization as an alternative to external dacryocystorhinostomy for treating failed nasolacrima
duct intubation. Medicine (Baltimore) 95, e4350. https://doi.org/10.1097/md.0000000000004350 (2016). p
g
0. Demirci, H. & Elner, V. M. Double silicone tube intubation for the management of partial lacrimal system obstruction. Ophthal-
mology 115, 383–385. https://doi.org/10.1016/j.ophtha.2007.03.078 (2008). gy
p
g
j p
11. Bleyen, I., van den Bosch, W. A., Bockholts, D., Mulder, P. & Paridaens, D. Silicone intubation with or without balloon dacryocys-
toplasty in acquired partial nasolacrimal duct obstruction. Am. J. Ophthalmol. Discussionhi Results showed that the patency rate of the LD group was significantly
higher at 1 year after removal, suggesting that larger-diameter tubes had more satisfactory outcomes for the
treatment of postsaccal obstruction.i In addition, when comparing the preconditions between the two groups, the ND group had a significantly
longer preoperative obstruction period and duration of tube intubation. Previous studies reported that the preop-
erative obstruction period conferred a risk for recurrence after ENDI surgery35. Therefore, we performed a logistic
regression analysis to assess the correlation of these factors to recurrence. We found no significant correlation
between the preoperative obstruction period and recurrence (p = 0.69); however, duration of tube intubation
was significantly correlated with the recurrence (p = 0.006) in our cohort. This may be because patients with a
tendency to relapse tended to have tubes intubated for a longer period of time. The current policy is to perform
DCR without more extended tube placement for patients who have a tendency to relapse.h Several limitations are included in this study. This was a retrospective observational cohort study with certain
selection biases. The significant extended period of preoperative obstruction and the prolonged duration of tube
intubation in the ND group certainly contributed to the sampling biases. Furthermore, since the deployment
of the 1.5-mm tubes in August 2017, we adopted our indication of inserting a 1.5-mm NST for all postsac-
cal obstruction cases (Fig. 3). However, there were cases in which 1.0-mm tubes were inserted for postsaccal
obstruction even after deploying 1.5-mm tubes. For example, 1.0-mm tubes were inserted when the patient
complained of severe pain during intraoperative endoscopic manipulation and intubating with 1.5-mm tubes
was considered challenging. These cases could contribute to sampling biases. Furthermore, not all patients with Scientific Reports | (2022) 12:11785 | https://doi.org/10.1038/s41598-022-16018-4 www.nature.com/scientificreports/ Acknowledgementsh g
The study was supported by the Japan Society for the Promotion of Science Postdoctoral Fellowship for Research
Abroad (Kaitoku-NIH, #24112 to JN). The funding source had no role in the study design, data collection,
analysis, publication decision, or manuscript preparation. www.nature.com/scientificreports/ Restricted mean survival time: an alternative to the hazard ratio for the design and analysis of rand-
omized trials with a time-to-event outcome. BMC Med. Res. Methodol. 13, 152. https://doi.org/10.1186/1471-2288-13-152 (2013). 42. Hasegawa, T., Uno, H. & Wei, L. J. Zoledronic acid dosing in patients with metastatic breast cancer. JAMA Oncol. 4, 585. https://
doi.org/10.1001/jamaoncol.2017.0487 (2018). y
41. Royston, P. & Parmar, M. K. Restricted mean survival time: an alternative to the hazard ratio for the design and analysis of rand-
omized trials with a time-to-event outcome. BMC Med. Res. Methodol. 13, 152. https://doi.org/10.1186/1471-2288-13-152 (2013). 42. Hasegawa, T., Uno, H. & Wei, L. J. Zoledronic acid dosing in patients with metastatic breast cancer. JAMA Oncol. 4, 585. https://
doi.org/10.1001/jamaoncol.2017.0487 (2018). omized trials with a time to event outcome. BMC Med. Res. Methodol. 13, 152. https://doi.org/10.1186/1471 2288 13 152 (2013)
2. Hasegawa, T., Uno, H. & Wei, L. J. Zoledronic acid dosing in patients with metastatic breast cancer. JAMA Oncol. 4, 585. https:/
doi.org/10.1001/jamaoncol.2017.0487 (2018). www.nature.com/scientificreports/ www.nature.com/scientificreports/ 22. Keith, C. G. Intubation of the lacrimal passages. Am. J. Ophthalmol. 65, 70–74. https://doi.org/10.1016/0002-9394(68)91031-3
(1968). 3. Fulcher, T., O’Connor, M. & Moriarty, P. Nasolacrimal intubation in adults. Br. J. Ophthalmol. 82, 1039–1041. https://doi.org/10
1136/bjo.82.9.1039 (1998).l j
(
)
4. DeParis, S. W., Hougen, C. J., Rajaii, F. & Mahoney, N. R. Bicanalicular intubation with the kaneka lacriflow for proximal lacrima
drainage system stenosis. Clin. Ophthalmol. 14, 915–920. https://doi.org/10.2147/opth.S248423 (2020). g
y
p
p
g
p
25. Pratte, E., Cho, J., Short, R., Mellencamp, E. & Petris, C. Lacrimal stenting with nunchaku versus crawf
partial acquired nasolacrimal duct system obstruction. Invest. Ophthalmol. Vis. Sci. 62, 3351–3351 (20 5. Pratte, E., Cho, J., Short, R., Mellencamp, E. & Petris, C. Lacrimal stenting with nunchaku versus crawford tubes for congenital or
partial acquired nasolacrimal duct system obstruction. Invest. Ophthalmol. Vis. Sci. 62, 3351–3351 (2021).fi p
q
y
p
,
(
)
26. Choi, S. C., Choi, H. S., Jang, J. W., Kim, S. J. & Lee, J. H. Comparison of the efficacies of 0.94 mm and double silicone tubes for y
p
26. Choi, S. C., Choi, H. S., Jang, J. W., Kim, S. J. & Lee, J. H. Comparison of the efficacies of 0.94 mm and double
treatment of canalicular obstruction. Korean J. Ophthalmol. 31, 1–8. https://doi.org/10.3341/kjo.2017.31.1.1 (2 6. Choi, S. C., Choi, H. S., Jang, J. W., Kim, S. J. & Lee, J. H. Comparison of the efficacies of 0.94 mm and double silicone tubes for
t
t
t f
li
l
b t
ti
K
J O hth l
l 31 1 8 htt
//d i
/10 3341/kj 2017 31 1 1 (2017) p
p
g
j
27. Hurwitz, J. J. A new, wider-diameter Crawford tube for stenting in the lacrimal drainage system. Ophthalmic Plast. Reconstr. Surg. 20, 40–43. https://doi.org/10.1097/01.Iop.0000103008.01277.Be (2004). p
g
p
28. Kamao, T., Takahashi, N., Zheng, X. & Shiraishi, A. Changes of visual symptoms and functions in patients with and witho
eye after lacrimal passage obstruction treatment. Curr. Eye Res. https://doi.org/10.1080/02713683.2020.1760305 (2020). yt
p
g
y
p
g
29. Manabu, S. New sheath-assisted dacryoendoscopic surgery. J. Eye 24(9), 1219–1222 (2007).t y
p
g
y
y
0. Kanda, Y. Investigation of the freely available easy-to-use software “EZR” for medical statistics. Bone Marrow Trans. 48, 452–458
https://doi.org/10.1038/bmt.2012.244 (2013).f 31. Uno, H. et al. Moving beyond the hazard ratio in quantifying the between-group difference in survival analysis. References 144, 776–780. https://doi.org/10.1016/j.ajo.2007.
07.030 (2007). (
)
12. Kashkouli, M. B., Beigi, B., Tarassoly, K. & Kempster, R. C. Endoscopically assisted balloon dacryocystoplasty and silicone intu-
bation versus silicone intubation alone in adults. Eur. J. Ophthalmol. 16, 514–519. https://doi.org/10.1177/112067210601600402
(2006). (
)
13. Ali, M. J. & Naik, M. N. Efficacy of endoscopic guided anterograde 3 mm balloon dacryoplasty with silicone intubation in treat-
ment of acquired partial nasolacrimal duct obstruction in adults. Saudi J. Ophthalmol. 28, 40–43. https://doi.org/10.1016/j.sjopt.
2013.12.004 (2014).t 14. Hoshi, S. et al. Improvement in dacryoendoscopic visibility after image processing using comb-removal and image-sharpe
algorithms. J. Clin. Med. https://doi.org/10.3390/jcm11082073 (2022). g
g
j
5. Kurihashi, K. A new bicanalicular intubation method: Direct silicone intubation (DSI). Orbit 13, 11–15. https://doi.org/10.3109/
01676839409084263 (1994).fi (
)
16. Javate, R. M., Pamintuan, F. G. & Cruz, R. T. Jr. Efficacy of endoscopic lacrimal duct recanalization using microendoscope. Oph-
thalmic Plast. Reconstr. Surg. 26, 330–333. https://doi.org/10.1097/IOP.0b013e3181c7577a (2010). g
p
g
17. Kamao, T., Zheng, X. & Shiraishi, A. Outcomes of bicanalicular nasal stent inserted by sheath-guided dacryoendoscope in patients
with lacrimal passage obstruction: A retrospective observational study. BMC Ophthalmol. 21, 103. https://doi.org/10.1186/s12886-
020-01678-5 (2021). 8. Lee, S. M. & Lew, H. Transcanalicular endoscopic dacryoplasty in patients with primary acquired nasolacrimal duct obstruction
Graefes. Arch. Clin. Exp. Ophthalmol. 259, 173–180. https://doi.org/10.1007/s00417-020-04833-2 (2021).fi f
p
p
p
g
(
)
19. Kim, S. E., Beak, J. U., Paik, J. S., Park, J. & Yang, S. W. Long-term Efficacy of Dacryoendoscopy-guided Recanalization and Silicone
T b I t b ti
K
J Ophth l
l 36 185 193 http //d i
/10 3341/kj 2021 0117 (2022) f
p
p
p
g
19. Kim, S. E., Beak, J. U., Paik, J. S., Park, J. & Yang, S. W. Long-term Efficacy of Dacryoendoscopy-guided Recanalization and Silicone
Tube Intubation. Korean J. Ophthalmol. 36, 185–193. https://doi.org/10.3341/kjo.2021.0117 (2022). Tube Intubation. Korean J. Ophthalmol. 36, 185 193. https://doi.org/10.3341/kjo.2021.0117 (2022). 0. Whitnall, S. E. Anatomy of the human orbit and accessory organs of vision (Krieger Publishing, 1979). y f
y
g
f
(
g
g
)
21. Gibbs, D. C. New probe for the intubation of lacrimal canaliculi with silicone rubber tubing. Br. J. Ophthalmol. 51, 198. https://
doi.org/10.1136/bjo.51.3.198 (1967). https://doi.org/10.1038/s41598-022-16018-4 Scientific Reports | (2022) 12:11785 | Author contributions J.N. contributed to the conception, data extraction, analysis, and drafting. T.K., A.M., and A.S. worked on the
surgical operations, data extraction, interpretation of the results, and drafting. T.K., A.M., and A.S. provided
statistical advice. N.M. and A.S. were responsible for the general management of the study and critically revised
the protocol and main manuscript. Competing interests
The authors declare no competing interests. Additional information
Supplementary Information The online version contains supplementary material available at https://doi.org/
10.1038/s41598-022-16018-4. Correspondence and requests for materials should be addressed to J.N. Reprints and permissions information is available at www.nature.com/reprints. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and
institutional affiliations. www.nature.com/scientificreports/ J. Clin. Oncol. 32,
2380–2385. https://doi.org/10.1200/jco.2014.55.2208 (2014). p
g
j
2. Tian, L., Zhao, L. & Wei, L. J. Predicting the restricted mean event time with the subject’s baseline covariates in survival analysis
Biostatistics 15, 222–233. https://doi.org/10.1093/biostatistics/kxt050 (2014). p
g
3. Matsumura, N. et al. Transcanalicular endoscopic primary dacryoplasty for congenital nasolacrimal duct obstruction. Eye (Lond)
33, 1008–1013. https://doi.org/10.1038/s41433-019-0374-6 (2019).f p
g
(
)
34. Mimura, M., Ueki, M., Oku, H., Sato, B. & Ikeda, T. Indications for and effects of Nunchaku-style silicone tube intubation for
primary acquired lacrimal drainage obstruction. Jpn. J. Ophthalmol. 59, 266–272. https://doi.org/10.1007/s10384-015-0381-5
(2015). 35. Sugimoto, M. & Inoue, Y. Long-term outcome of dacryoendoscope-assisted intubation for nasolacrimal duct obstruction. J. Eye
27(9), 1291–1294 (2010). 36. Koki, I., Naoshi, T., Yoshihiro, N. & Ryoji, Y. Outcome of intubation using lacrimal endoscope at yame general hospital. J. Eye
32(12), 1773–1776 (2015).h 7. Paulsen, F. P., Thale, A. B., Maune, S. & Tillmann, B. N. New insights into the pathophysiology of primary acquired dacryostenosis
Ophthalmology 108, 2329–2336. https://doi.org/10.1016/s0161-6420(01)00946-0 (2001). 8. Hussain, R. N., Kanani, H. & McMullan, T. Use of mini-monoka stents for punctal/canalicular stenosis. Br. J. Ophthalmol. 96, 671
https://doi.org/10.1136/bjophthalmol-2011-300670 (2012). p
g
j p
39. Hwang, S. W., Khwarg, S. I., Kim, J. H., Choung, H. K. & Kim, N. J. Bicanalicular double silicone intubation in external dacryo-
cystorhinostomy and canaliculoplasty for distal canalicular obstruction. Acta Ophthalmol. 87, 438–442. https://doi.org/10.1111/j.
1755-3768.2008.01292.x (2009). (
)
40. Paik, J. S., Cho, W. K. & Yang, S. W. Bicanalicular double silicone stenting in endoscopic dacryocystorhinostomy with lacrimal
trephination in distal or common canalicular obstruction. Eur. Arch. Otorhinolaryngol. 269, 1605–1611. https://doi.org/10.1007/
s00405-011-1845-y (2012). 0. Paik, J. S., Cho, W. K. & Yang, S. W. Bicanalicular double silicone stenting in endoscopic dacryocystorhinostomy with lacrima
trephination in distal or common canalicular obstruction. Eur. Arch. Otorhinolaryngol. 269, 1605–1611. https://doi.org/10.1007/
s00405-011-1845-y (2012). y (
)
41. Royston, P. & Parmar, M. K. Restricted mean survival time: an alternative to the hazard ratio for the design and analysis of rand-
omized trials with a time-to-event outcome. BMC Med. Res. Methodol. 13, 152. https://doi.org/10.1186/1471-2288-13-152 (2013). 42 H
T U
H & W i L J Z l d
i
id d
i
i
i
i h
i b
JAMA O
l
8
h
// y (
)
41. Royston, P. & Parmar, M. K. Open Access This article is licensed under a Creative Commons Attribution 4.0 International
License, which permits use, sharing, adaptation, distribution and reproduction in any medium or
format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the
Creative Commons licence, and indicate if changes were made. The images or other third party material in this
article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the
material. If material is not included in the article’s Creative Commons licence and your intended use is not
permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from
the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. © The Author(s) 2022 Competing interests h p
g
The authors declare no competing interests. Additional information
Supplementary Information The online version contains supplementary material available at https://doi.org/
10.1038/s41598-022-16018-4. Supplementary Information The online version contains supplementary material available at https://doi.org/
10.1038/s41598-022-16018-4. Correspondence and requests for materials should be addressed to J.N. Reprints and permissions information is available at www.nature.com/reprints. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and
institutional affiliations. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and
institutional affiliations. https://doi.org/10.1038/s41598-022-16018-4 Scientific Reports | (2022) 12:11785 | www.nature.com/scientificreports/ www.nature.com/scientificreports/ Open Access This article is licensed under a Creative Commons Attribution 4.0 International
License, which permits use, sharing, adaptation, distribution and reproduction in any medium or
format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the
Creative Commons licence, and indicate if changes were made. The images or other third party material in this
article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the
material. If material is not included in the article’s Creative Commons licence and your intended use is not
permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from
the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. © The Author(s) 2022 https://doi.org/10.1038/s41598-022-16018-4 Scientific Reports | (2022) 12:11785 |
|
https://openalex.org/W2156666223
|
https://www.ccsenet.org/journal/index.php/ass/article/download/1603/1517
|
English
| null |
Causal Attribution and its Conceptions by Non-English Major Postgraduates in China: A Case Study
|
Asian social science
| 2,009
|
cc-by
| 3,347
|
Non-English Major Postgraduates in China: A Case Study Hui Yan
School of Foreign Languages, Qingdao University of Science and Technology, Qingdao 266061, China
E-mail: magyan@sohu.com
Xiaohua Li
School of Foreign Languages, Qingdao University of Science and Technology, Qingdao 266061, China
E-mail: ydlxh16@sohu.com Hui Yan
School of Foreign Languages, Qingdao University of Science and Technology, Qingdao 266061, China
E-mail: magyan@sohu.com
Xiaohua Li
School of Foreign Languages, Qingdao University of Science and Technology, Qingdao 266061, China
E-mail: ydlxh16@sohu.com 1. Introduction After years of theoretical and empirical research, it has been widely recognized that motivation plays a very important
role in second language acquisition (SLA) worldwide. Arnold (1999, p.13) states that “what we see as the causes for our
past successes or failures will affect our expectations and, through them, our performance”. In China, motivational
issues concerning the vast majority of Chinese ESL learners are gaining more attention of scholars. Nevertheless, the
focus is mainly on college ESL students, with little attention paid to other groups such as children and teenagers, least to
postgraduates. Therefore, with the help of a case study, this article aims to draw people’s attention to the causal
attribution and its conceptions by non-English major postgraduates in China. Abstract This article reports a case study, in which causal attribution in SLA and learners’ conceptions of causal attribution were
examined. 2 high achievers and 2 low achievers completed a 7-day diary about their daily activities concerning English
learning inside and outside English class, and subsequently they were interviewed about their causal attribution and
SLA motivation. Data analysis indicated that (a) the two groups were not qualitatively differentiated in causal
attributions of learning environment, effort, teacher’s role, and language ability; (b) lower achievers tended to have a
more concordant conception of causal attribution than their counterparts; and (c) variations in causal attribution and its
conceptions accounted much for the individual differences in motivational behavior. Keywords: Causal attribution, Case study, Second language acquisition Asian Social S Asian Social S Science April, 2008 p
, 4. Results and Discussion In the interview students are asked about their causal attribution including the learning environment, English teacher’s
role, language ability and effort, and their explanations about causal attribution and their success and failure. 4.1 Learning environment When asked about the relationship between their command of English and the learning environment, the subjects of two
groups demonstrate obvious differences in causal attribution of past success and failure not only between groups but
also between themselves. In Group A, Li Fang attributes her past success to the learning environment whereas Liu Jun
thinks it depends. Both students of Group B attribute most of their failure to the bad learning environment. Li Fang says definitely that the learning environment is very important. “When I was five years old, my mother started
to teach me English. It was so fun. I began to love it. So I always watched English cartoons and listened to English
songs and it was so easy to learn English well. However, most of my classmates thought English was very difficult. I
think it’s because they didn’t have my learning environment when they were young. ” Liu Jun, however, doesn’t attribute his success to the learning environment. “I had many classmates and we were
living on the same campus, taking the same English teacher’s class, studying the same English book, yet I was much
better than most of them in English. Maybe people will say it is necessary to go abroad to learn English well. I think it
depends. I had many English teachers who spoke English with strong accent though they had studied abroad. Yet Li
Yang didn’t go abroad to learn English. He studied all by himself! Nevertheless, he speaks perfect American English.” From their remarks we can see clearly that both groups made the causal attribution based on their own learning
experiences as well as their friend’s or relative’s influence. Different supplies of learning environment made them have
different evaluations of its importance. High achievers show different opinions about the relationship between success
and the learning environment while low achievers demonstrate similar opinions. From the psychological point of view,
low achievers tend to attribute their failure to the external factors. In addition, this is a handy and decent excuse difficult
to be changed for most people in China. In doing so they will be easily be understood and forgiven. 2. Literature Review Weiner (1974) developed the attribution theory by suggesting that learners tend to attribute their success and failure to
either internal or external causes. The central tenet of attribution theory is the learner’s perceptions of the cause of his or
her success or failure and the influence on perceptions of future performance. Weiner (1986) identified four main sets of
causal attributions: ability, effort, luck and perceived difficulty of the task, of which the first two are considered the
most dominant causes. Weiner (1992) also suggested three dimensions of causal attributions: locus of causality, stability
and controllability. Research has been done home and abroad on both motivation and motivation stimulating, with little
empirical study done on non-English major postgraduates in China. Chinese scholars have been studying motivation
from different aspects. Liu and his colleagues studied “The Main Determinants of English Majors’ Language Learning
Situation” (1990). Qin and Wen (2002, pp.51-58) made “An Investigation into the Internal Structure of EFL Motivation
among Non-English Majors”. Qin and Wen (2002, pp.51-58) study “Internal structure of EFL motivation at the tertiary
level in China ”, specifying 13 motivational variables in English learning --- cognitive individual needs and affective
individual needs,3 motivational antecedents including prior L2 proficiency, casual attribution, and interest in English,
5 affective/cognitive mediators such as anxiety, self-efficacy, valence, learning purpose and goal orientations,
motivational behavior like efforts, cognitive learning outcomes and affective learning outcomes. Qin examines “Causal
Attribution and Its Conceptions by EFL Learners at the Tertiary Level: A Case Study” (2002, pp.1-11). The results show
there are qualitative differences in the attribution of learning environment, classroom teaching, language ability and
efforts among learners of different English levels. Gao and her team (2003, pp.29-38) identify among college students in China seven motivational types: intrinsic interest,
test score, going abroad, learning situation, social responsibility, individual development, and communication medium. Results also show that college major and English proficiency had significant effects on motivation. These studies have 77 Vol. 4, No. 4 Asian Social Science all contributed to both the motivational studies and the practical EFL teaching in China. Nonetheless, the research
mainly concerns the college students, with a little attention paid to the postgraduates. 3.1 Subjects Four graduates of first grade were divided into two groups of low achievers and high achievers. They were grouped so
not only because of their scores on CET-6 but also of their own conceptions of their command of English with regard to
their classmates and their classmates’ opinions about them. Low achievers, Wang Na and Lu Ming scored 61 and 63 in
CET-6 whereas high achievers Liu Jun and Li Fang scored 81 and 84 respectively. Since the focus of this study is to
find the differences about causal attribution among them, subjects are carefully chosen with respect to the similar
learning environments in female students and in male students to diminish the unavoidable influence of gender
differences. The two female students are from cities and two male from the countryside. Research instruments include interview and diary. The interview is for their conceptions about their causal attributions
of their success and failure in learning English. Students are expected to write diaries for 7 continuous days, specifying
the inside and outside learning activities, causal attribution and SLA motivation. The interviews were conducted mainly
in Chinese to avoid misunderstandings and misrepresentations. They were recorded and accordingly written down. 4. Results and Discussion Liu Jun confesses
that when he realized that he could hardly change the learning environment, he had to depend on other factors to learn
English well. 2. Literature Review Similar results are also found in
the team’s research on “The Relationship between Types of English Learning Motivation and Motivational Intensity”,
“Relationship between English Learning Motivations and Self-Identity Changes among Chinese Graduate Students”,
“The Relationship between Types of English Learning Motivation and Motivational Intensity” and “Motivation Types
in English Learning Among Chinese Graduate Students”. However, most of them concentrate on the issues of
motivational types, motivational intensity and self-identity changes, little on those of causal attribution in SLA, its
impact on motivational behavior, and learners’ conceptions of causal attribution. Therefore, the author intends to have a
case study on 4 postgraduate students of science from Qingdao University of Science and Technology in China. 4.2 Effort Liu Jun believes effort is the key to success. “The only reason that I’m good at English is that I study very hard. Comparatively speaking, I spend most of my time on English instead of my major mathematics, yet I’m just good at
English in my class but one of the few best students in Math on campus. Besides, if you don’t make up your mind and
study hard, you will never be good at English whether you’re in China or in USA”. Li Fang, on the contrary, thinks 78 Asian Social Science April, 2008 April, 2008 April, 2008 effort is not important. “I find many of my classmates are working so hard on English but I don’t know why they are
still lagging behind. I didn’t take much effort but I’m always the best. They are always complaining that this is unfair.”
In Group B, both Wang Na and Lu Ming agreed that effort didn’t help them to be good at English. Wang Na complains,
“I spend most of my time on English but I’m still worried about it. I had never been good no matter how hard I have
been working on it.” Lu Ming also pined, “I have no confidence to learn it (English) well because my diligent effort
seems to be useless. There are endless new words to learn. English is so difficult.” effort is not important. “I find many of my classmates are working so hard on English but I don’t know why they are
still lagging behind. I didn’t take much effort but I’m always the best. They are always complaining that this is unfair.”
In Group B, both Wang Na and Lu Ming agreed that effort didn’t help them to be good at English. Wang Na complains,
“I spend most of my time on English but I’m still worried about it. I had never been good no matter how hard I have
been working on it.” Lu Ming also pined, “I have no confidence to learn it (English) well because my diligent effort
seems to be useless. There are endless new words to learn. English is so difficult.” However, by reading their diaries the author finds that these students have different understandings about their so called
“hard effort”. 4.2 Effort Every day Liu Jun spends at least two hours either to read English texts and do exercises, or read articles
relevant to his major, which he believes not at all hard, but “essential effort”. Li Fang spends about an hour a day for
text and exercises, at least another hour reading English newspapers or magazines. She always listens to English songs
when she gets up, before going to bed, occasionally after lunch. Usually she watches English movies during the
weekend. When asked whether she was doing so to practice her listening abilities she denies with surprise, “It is just for
fun, to relax myself.” It’s obvious though both two high achievers do not admit there is much effort they are studying
English really hard. On the other hand, Wang Na and Lu Ming do not study as hard as they have imagined. On the days when they have
English classes, they would not spend any more time on it. Wang Na says, “Having English class is so tiring that I need
a good rest that day.” It’s true that they take their English books with them every evening when they go to the classroom
to learn by themselves, however, they can hardly spend half an hour on it except during the nights before the English
class when they would spend three or four hours on it. Wang Na seems very sad, “When my classmates go to bed, I
often have to sit up for hours because there’re so many new words to remember and so many exercises to do.” When
suggested that she might finish them bit by bit in other days, she became irritated, “But I’m so busy. I have to study my
major subjects and I have some social activities. I can’t find time to learn English”. Lu Ming agreed, “I always take my
English book with me but I can’t find time. I have to study my major first. When I really start with an English book, I
find it so boring and so difficult that I would switch to another book with pleasure.” It’s evident that their behaviours are
far away from being “hard effort”. From the analysis we can understand that high achievers and low achievers have different standards for hard effort. When asked about the possibilities of becoming high achievers if they spend as much time as high achievers, both
answer “Maybe”. 4.3 Teacher’s role 4.3 Teacher’s role Group A confirms that teachers play a positive role in improving their English. In Group B, Wang Na thinks that the
teacher helped her a bit but Lu Ming accuses one teacher of being partially responsible for his failure. “When I started
to learn English in Junior High School, my English teacher was a very strict woman who spoke broken English,
humiliating, scolding and beating students who could not recite the text or answer her questions. I was so scared that
having English class became a nightmare. Later when I went to college, I could hardly understand what the English
teacher said. She smiled at good students but looked unhappy at bad students. It’s not her fault. Maybe I just had
prejudice against English teachers. ” Though different groups attribute different roles to their teachers, it is agreed unanimously that teachers can have a
profound influence on their students, either positive or negative. Lu Ming’s first English teacher meant well by urging
them to learn, but she scared her students with the help of physical and mental punishments, leading to a contradictory
effect. In China especially in small counties there is a prevailing misconception that teachers must make students being
afraid of them; otherwise students would never learn well. Therefore, many teachers force students to learn and get high
scores by all means: threats to tell their parents about their naughty behaviors, threats to dismiss them, resorting to
physical punishments and mental torture, with little attention on making students interested. In fact, those teachers
misbelieve that external forces and drives play a far more important role than internal motivations in SLA. The lesson
from it is that English teachers should be organized and lectured upon periodically about theoretical achievements in
SLA research, thus guiding them directly and helping the students indirectly, eventually benefiting SLA in China. 4.2 Effort In other words, they admit that real effort is important in SLA. 4.5 Implications Though high achievers didn’t have any agreement upon the role of learning environment, effort, teacher’s role and
language ability, both are highly internally motivated and become successful. Liu Jun attributes it to unstable and
controllable effort and Li Fang to stable and unchangeable language ability. Low achievers, on the other hand, attribute
their failure to both internal factor ability and external factors such as learning environment and teacher’s influence. Low achievers have low self-efficacy of themselves. Santrock (2005, p.423) states that a student’s perception of success
or failure as due to internal or external factors influences his or her self-esteem. Students who perceive their successes
as being due to internal factors are more likely to have higher self-esteem than those who believe that their successes
were due to external factors. In the failure situations, internal attributions lead to decreased self-esteem. When students
attribute failure to unstable factors, they might expect that they will be successful in the future because they perceive the
cause as changeable. With the understanding of their perceptions of causal attribution, teachers could teach accordingly
to help postgraduates motivated both internally and externally. 4.4 Language ability In Group A, nevertheless, there exist different opinions. Liu Jun doesn’t think he has much language ability. “I know
that I’m not language talented though some classmates are saying so. But since every child learns to speak a language
well no matter he’s language talented or not, I believe my hard work could make it up.” Li Fang, on the contrary,
announces proudly that her language ability helps and determines her success. “Learning English is always so easy and
so fun. I don’t need to pay much effort to remember new words and practice my listening abilities. I enjoy myself by
listening to English songs and watching English movies. English makes me feel so good. I believe that I really have a
talent in learning language.” Her language ability leads to her interest, which makes the learning environment and
teachers so friendly and her effort so enjoyable. 79 5. Conclusion The analysis of the interview and the diaries of those postgraduates indicate a) Group A and B were not qualitatively
differentiated in causal attributions of learning environment, effort, teachers’ role and language ability; b) higher
achievers tended to attribute more of their success to internal factors like language ability and effort whereas their
counterparts to external factors like learning environment, teachers’ influence and so on. Group B have a more
concordant conception of causal attribution than their counterparts; and, c) variations in causal attribution and its
conceptions accounted much for the individual differences in motivational behavior. Vol. 4, No. 4 Asian Social Science Both students of Group B believe that they don’t have much language ability, which also determines their failure. Both
express their helplessness about it. Wang Na shakes her head, “I can do nothing about it. I’m just so slow.” Lu Ming
says, “I feel stupid. I lost my face and confidence in learning English though I’m so good at my major. I’m not good at
learning language.” In reality, language ability is just one factor in SLA. Linguists hold that every person has inherent language abilities
which lead to every one’s ability to learn their mother tongue. In order to acquire a second language, many factors are at
play. 4.5 Implications Weiner, B. (1992). Human Motivation: Metaphors, theories, and research. Newbury Park, CA: Sage. References Arnold, J. (1999). Affect in Language Learning. Cambridge: Cambridge University Press. Arnold, J. (1999). Affect in Language Learning. Cambridge: Cambridge University Press. Qin, X. (2002). Causal Attribution and Its Conceptions by EFL Learners at the Tertiary Level: A Case Study, 25 (1):
1-11. Qin, X. (2002). Causal Attribution and Its Conceptions by EFL Learners at the Tertiary Level: A
1-11. Qin, X., & Wen, Q. (2002). Internal structure of EFL motivation at the tertiary level in China, Foreign Language
Teaching and Research. 34 (1): 51-58. Qin, X., & Wen, Q. (2002). Internal structure of EFL motivation at the tertiary level in China, Foreign Language
Teaching and Research. 34 (1): 51-58. Qin, X., & Wen, Q. (2002). Internal structure of EFL motivation at the tertiary level in China, Foreign Language
Teaching and Research. 34 (1): 51-58. Gao, Y., Zhao, Y., Cheng, Y., & Zhou, Y. (2003). Motivation Types of Chinese College Undergraduates Modern Foreign
Languages. 26(1): 29-38. Gao, Y., Zhao, Y., Cheng, Y., & Zhou, Y. (2003). Motivation Types of Chinese College Undergraduates Modern Foreign
Languages. 26(1): 29-38. Gao, Y., Zhao, Y., Cheng, Y., & Zhou, Y. (2003). Motivation Types of Chinese College Undergraduates Modern Foreign
Languages. 26(1): 29-38. Santrock, J.W. (2005). Educational Psychology. Beijing: World Publishing Corporation. Santrock, J.W. (2005). Educational Psychology. Beijing: World Publishing Corporation. Weiner, B. (1974). Achievement Motivation and Attribution Theory. New Jersey: General Learning Weiner, B. (1986). An Attribution Theory of Motivation and Emotion. New York: Springer. 80
|
https://openalex.org/W3130707432
|
http://psychologyandeducation.net/pae/index.php/pae/article/download/1218/1018
|
English
| null |
AI based Vector Control Method for BLDC Motor with Multi Switch Three-Phase Topology
|
Psychology
| 2,021
|
cc-by
| 6,846
|
PSYCHOLOGY AND EDUCATION (2021) 58(1): 3132-3141 PSYCHOLOGY AND EDUCATION (2021) 58(1): 3132-3141 ISSN: 00333077 AI based Vector Control Method for BLDC Motor with Multi Switch
Three-Phase Topology Ch. Vinay Kumar1, G MadhusudhanaRao2*, A Raghu Ram3
1 Asst.Professor-MGIT, 2Professor-BuleHora Univesity,Ethiopia, 3Professor-JNTUCEH Hyderabad Ch. Vinay Kumar1, G MadhusudhanaRao2*, A Raghu Ram3
1 Asst.Professor-MGIT, 2Professor-BuleHora Univesity,Ethiopia, 3Professor-JNTUCEH Hyderabad ABSTRACT Brushless direct current (BLDC) Motors are extensively used because of their characteristics. Such characteristics are high
dynamic response and high-power density. BLDCM control system is a nonlinear, multi-variable, strong-coupling system. In this
paper it is proposed that a neural network controller is used for the five level switch of the BLDC motor to enhance the power
factor and reduce the current distortions with respect to its rise time, startup torque. This method is also done in comparison with
the PID controllers. The working principle of the BLDC is with the help of five-switch control scheme can be implemented here. The different values of load were used to consider the total operation of the BLDC motor is to be controlled. After the completion
of the training and testing of the neural network, it might be maintain the constant load values and its variables. To calculate the
duty ratio of the DC-DC converter, it will be adjusted to regulate the speed of the BLDC motor. However the DC link of the five
switching inverter is used here for the boosting of the voltage. The effectiveness of the proposed control technique can be
realized with help of the speed sensor. Various tests have been conducted in the simulation the proposed technology is the robust
technology and it is proven that very effective and suitable control technique. Keywords I. Introduction This sensor generates the control signal
that determines the pulse width of the PWM
(Pulse Width Modulation) that activates each of
the inverter’s drivers, in addition to the necessary
switching stage that depends on the state of the
Hall Effect sensors. This switching allows the
three-phase inverter to function normally in
addition to preventing a short circuit in any of the
three branches. position detectors, such as Hall Effect devices that
can sense rotor magnetic field and determine the
phase switching points. The sinusoidal machine
requires more precise position information to
allow accurate synthesis of the sinusoidal current
waveforms. Following are the significant of using
brush less motor design; absolute position sensors; otherwise, it must be
prepared by estimating the parameters that specify
the rotor position using Sensorless techniques
[12], [13]. The driving range for each phase is
usually 120 electrical degrees, which is divided
into two 60-degree steps. For example, S5-S6, S1-
S6, S1-S2, S3-S2, S3-S4, and S5-S4 are six steps
of a 360-degree electric cycle. Therefore, only
two phases are carried out at a time. The above
can be seen graphically in Figure 1. From the
operation of the engine and their elements, the
BLDC engine is modeled to simulate its behavior. brush less motor design; brush less motor design; The position sensor system for the shaft is
simple and needs only to deliver six digital
signals for commanding the transistor of
the inverter. The quasi square-wave armatures current
are
mainly
characterized
by
their
maximum amplitude value, which directly
controls the machine torque. The inverter performance is very much
reliable because there is natural dead time
for each transistor. The first and third characteristics allow
reducing the complex circuitry required by
other machine and allowing the self-
synchronization process for the operation
of the machine. The second characteristic
allows designing a circuit [17] for
controlling only a DC component which
represents the maximum amplitude value
of the trapezoidal current, IMAX. The first and third characteristics allow
reducing the complex circuitry required by
other machine and allowing the self-
synchronization process for the operation
of the machine. The second characteristic
allows designing a circuit [17] for
controlling only a DC component which
represents the maximum amplitude value
of the trapezoidal current, IMAX. I. Introduction Instead of using these conventional
controllers
it
is
suggested
that
the
non 3132 www.psychologyandeducation.net PSYCHOLOGY AND EDUCATION (2021) 58(1): 3132-3141 ISSN: 00333077 absolute position sensors; otherwise, it must be
prepared by estimating the parameters that specify
the rotor position using Sensorless techniques
[12], [13]. The driving range for each phase is
usually 120 electrical degrees, which is divided
into two 60-degree steps. For example, S5-S6, S1-
S6, S1-S2, S3-S2, S3-S4, and S5-S4 are six steps
of a 360-degree electric cycle. Therefore, only
two phases are carried out at a time. The above
can be seen graphically in Figure 1. From the
operation of the engine and their elements, the
BLDC engine is modeled to simulate its behavior. The brushless motor model implemented in the
PSIM simulation environment is shown in Figure
3. This figure shows the three-phase inverter,
which has a sensor to monitor the current supplied
to the BLDC. It is also possible to see that the
BLDC motor is coupled with a sensor for speed
reading. This sensor generates the control signal
that determines the pulse width of the PWM
(Pulse Width Modulation) that activates each of
the inverter’s drivers, in addition to the necessary
switching stage that depends on the state of the
Hall Effect sensors. This switching allows the
three-phase inverter to function normally in
addition to preventing a short circuit in any of the
three branches. absolute position sensors; otherwise, it must be
prepared by estimating the parameters that specify
the rotor position using Sensorless techniques
[12], [13]. The driving range for each phase is
usually 120 electrical degrees, which is divided
into two 60-degree steps. For example, S5-S6, S1-
S6, S1-S2, S3-S2, S3-S4, and S5-S4 are six steps
of a 360-degree electric cycle. Therefore, only
two phases are carried out at a time. The above
can be seen graphically in Figure 1. From the
operation of the engine and their elements, the
BLDC engine is modeled to simulate its behavior. The brushless motor model implemented in the
PSIM simulation environment is shown in Figure
3. This figure shows the three-phase inverter,
which has a sensor to monitor the current supplied
to the BLDC. It is also possible to see that the
BLDC motor is coupled with a sensor for speed
reading. www.psychologyandeducation.net I. Introduction I. Introduction conventional controllers like fuzzy logic control
technique, neural network technique will be the
effective controllers for the Brushless DC motor. Here it is observed the fuzzy logic designed five
level switching converter was developed to
minimize the over currents and over voltages in
the converter for speed control of brushless DC
motor [4]. There are variety of methods are been
considerable efforts in solving the soft computing
approach to control of brushless motors. In this
paper it is proposed that a novel method is
identified to reduce the problems of the current
and voltages of Brushless DC motor with the
artificial neural Networks comparison with the
PID controllers. The neural networks which show
the effectiveness of these controllers such as
speed response, steady-state error, among others. In this proposed method the tuning of the PID
constants using the development of the neural
networks, which it has been shows a better
efficiency and performance than the conventional
controllers [4]. BLDC motors are generally
controlled employing three-phase inverters, so it
requires a rotor position sensor to control the
inverter in order to determine the switching
instants and provide an appropriate sequence for
switching. The position of the motor in these
engines is generally determined by position
sensors such as Hall Effect sensors, resolvers, and Brushless DC motor (BLDCM) is a very broadly
used one in the applications of the Electrical
Engineering, Automobile and mining, Industrial
applications due its feasibility and advantages of
high performance, rugged maintainance, smooth
operation
and
etc.,
Brushless
DC
motor
(BLDCM) has been widely used in electrical
equipment,
mining
and
other
industrial
application fields due to its advantages of high
power density, high efficiency, easy maintenance,
silent operation and so on[1]-[3]. Brushless DC
motor control system
is a
multi-variable,
nonlinear, strong-coupling system. The high
performance control strategy should be robust and
adaptive. The conventional proportional-integral-
derivative (PID) controller has shortcomings
when controlling nonlinear and uncertain target. The interest in emerging intelligent controller for
Brushless
DC
motor
has
been
increased
significantly. Some intelligent control methods
have been applied in the Brushless DC motor
controller [4]-[11]. To finding the problems like
speed response, steady state error, power factor
improvement in Brushless DC motor, and the
conventional
controllers
are
not
sufficient
controllers. I. Introduction The two kind of Brushless [14] permanent
magnet machine are used for traction application Fig
1:
Inverter
Circuit
with
BLDC BLDC motor in which the air gap flux
distribution and counter EMF, or back EMF
waveform are approximately trapezoidal as
like in conventional DC machine. Standard
permanent
magnet
[15],
[16]
synchronous motor (PMSM) in which the air
gap flux distribution and back EMF wave
form are both sinusoidal is sometimes called
as a Sinusoidal Brushless DC motor when
operated in a self-controlled mode. Indeed the drive characteristic and control
methods are very similar for the trapezoidal and
sinusoidal machines. In both cases, the motor
must be energized with controlled currents that
are synchronized with rotor position. However a
distinction is now being drawn between the two
drives, because of the differences in machine
construction and the standard synchronous motor
requires sinusoidal current excitation, whereas the
trapezoidal machine is energized with square-
wave and quasi-wave currents. Fig 1: Inverter Circuit with BLDC
Machine Fig 1: Inverter Circuit with BLDC
Machine The Fig. 2 shows the way the stator
currents are controlled, through the
feedback signal IMAX (t). The slopes m1
(up) and m2 (down) are a function of the
dc link voltage, and the motor model. Therefore motor model comprises the
phase inductance and the back EMF. Then, the maximum error based on a The rotor position sensors of the trapezoidal
machine usually consist of a number of simple 3133 www.psychologyandeducation.net ISSN: 00333077 PSYCHOLOGY AND EDUCATION (2021) 58(1): 3132-3141 carrier eMAX, will depend on the slopes m1
and m2, on the operating point, and the
carrier frequency. This situation can be
expressed mathematically, with the help of
Fig. 4, as seen in e (t1) = 2
E pp e (t1) = 2
E pp same value at t1 and t2, because these are
intersection
points
that
define
the
PWM
generation Fig. 4, as seen in g
x
f. E
xT
E
|
m
|
pp
pp
1
x
=
|
m
|
|
m
|
|
m
|
2
1
2
x
1
f. I. Introduction E
T
)
x
1(
E
|
m
|
pp
pp
2
Epp = f
1
|
m
|
|
m
|
|
m
|*|
m
|
2
1
2
1
(1) g
PI (t1) = TR (t1) Kp ec (t1) + M
= - T
A
.2
t1 - 2
A (3)
PI (t2) = TR (t2) Kp ec (t2) + M
= T
A
.2
t2 - 2
A (4) With equation 3 and equation 4, KP and M are
obtained With equation 3 and equation 4, KP and M are
obtained Kp =
)
t(e
)
t(e(
T
x
T
A
.2
)
t(e
)
t(e(
)
t
t(
T
A
.2
1
2
1
2
1
2
(5) The term ‘x’ in equation 1 represents
the fraction of the period of the carrier ‘T’,
when the current is increasing. According
to this equation, the term ‘x’ defines the
ideal output of the PWM pattern. Then,
the control parameters have to be adjusted
according to the index ‘x’. EPP represents
the peak-to-peak error of the signal. ( )
Now, when the current IMAX is increasing, the
error e(t) can be modeled as ( )
e(t) = -m1 t + n1, para t [t1, t2]
(6) e(t) = -m1 t + n1, para t [t1, t2]
(6) If the rate of conversion of the magnitudes is 1:,
then the expressions of the error eci (t) becomes as
shown in ec(t) = e (t). (7) (7) On the other hand, the output of the PI control can
be expressed as: PI (t) = Kp ec (t) + KI
1t
0
c
dt
x
)t(
e
(8) (8) Now, if it is assumed that the operation of the
machine is stable, and operates under steady state,
the integrator output is close to a constant. I. Introduction That
means M = KI
1t
0
c
dt
x
)t(
e
= constant
(9) (9) The triangular carrier and the PI output have the
equation (9) The triangular carrier and the PI output have the
equation (9) M =
)
t(e
)
t(e(
K
A
)
t
t(
T
A
2
2
1
1
2
p
1
2
(10) Fig 2: Ideal waveforms of (a) feedback signal
IMAX, (b) error signal e(t), and (c) control
signals.[D1] Fig 2: Ideal waveforms of (a) feedback signal
IMAX, (b) error signal e(t), and (c) control
signals.[D1] Fig 2: Ideal waveforms of (a) feedback signal
IMAX, (b) error signal e(t), and (c) control
signals.[D1] (10) Now, with the help of equation (8), (9) and (10),
can be resumed as According to the time reference of Fig. 2, the
following relations can be written: KP <
x
E
A
2
1
pp
(11)
M = A
2
1
x
(12) KP <
x
E
A
2
1
pp
(11) (t2 + t1) < x T
(t2 – t1) = x T
| t2 | | t1 |
e (t2) + e (t (2)
e (t2) – e (t1) = Epp M = A
2
1
x
(12) (12) (2) Replacing equation (9) in (11), the value KI of is
obtained 3134 www.psychologyandeducation.net 3134 www.psychologyandeducation.net PSYCHOLOGY AND EDUCATION (2021) 58(1): 3132-3141 ISSN: 00333077 KI =
1
1
t
0
t
0
c
dt
x
)t(e
2
1
x
A
dt
x
)t(
e
2
1
x
A
(13)
Fig 3: Simulation Diagram of ANN based Five
Seitch BLDC Motor
Boost
Converter:
Boost
converter,
step-up
converter is a power converter with an output DC
voltage greater than its input DC voltage. It is a
class of switching mode power supply, called
SMPS, containing at least two Semiconductors
switches, a diode and a transistor, and at least one
energy storage element. Switch turns on and
incrementally stores energy from V1 in L. Switch
turns off and this energy and additional energy
from input is transferred to output. I. Introduction Therefore, L
used as a temporary storage element filters made
of inductor and capacitor combinations are often
added to a converter's output to improve
performance. The output voltage function for this
converter is KI =
1
1
t
0
t
0
c
dt
x
)t(e
2
1
x
A
dt
x
)t(
e
2
1
x
A
(13)
Fig 3: Simulation Diagram of ANN based Five
Seitch BLDC Motor KI =
1
1
t
0
t
0
c
dt
x
)t(e
2
1
x
A
dt
x
)t(
e
2
1
x
A
(13)
Fig 3: Simulation Diagram of ANN based Five
Seitch BLDC Motor
Boost
Con erter:
Boost
con erter
step
p Fig 4: BLDCM drives, three-phase currents five
commutating points. (13) II. NEURAL NETWORKS Traditionally rheostat armature control method
is used for low power [18] DC motors, Use of
conventional PID controllers, neural network
controllers
(NNC). Constant
power
field
weakening [19] controller is based on load-
adaptive multi-input, multi output linearization
technique (in high speed regimes). A single phase
uniform PWM ac-dc buck-boost converter [20]
with only one switching device is used for
armature voltage control. Through experience
gained in designing trajectory [21] controllers
based on self-tuning and PID control, it is seen
that
the
neural
network
controller
gives
comparable performance in speed tracking [22]. In addition to those mentioned above, a unique
advantage of the neural network controller is, its
ability to cope with bad measurement data that
occur during training and testing. However, a key
drawback is the inadequate integral gain in the
feedback loop, resulting in steady-state errors of
the shaft position. Direct position tracking can
alleviate this problem. The traditional means
adapted by the motion control industry with motor
drives have been the approach of linearizing the
dynamic system and designing a linear feedback
controller. However, in high-performance motor
drives such an approach is seldom satisfactory, as
it results in poor speed and position tracking when
sudden changes in load result in continuous
acceleration or deceleration of the motor/load
system. Adaptation [23] is necessary to ensure
optimal performance. BACK PROPAGATION ALGORITHM The Back-propagation algorithm is also known
as the generalized delta rule. The algorithm
provides a method of calculating the gradient of
the
error
function
through
the
use
of
differentiation (chain rule). As the name implies,
the error is propagated backward from the output,
one layer at a time. The initial weights will have to be small and
randomly generated and assigned. A practical
range of weights is to keep them [-2/z, 2/z] for
a cell with z inputs. Forward propagation is done to compute the
weighted sum, Si and activation, ui = f(Si) for
every cell. The first step towards the implementation of
the back propagation procedure involves the
forward propagation of training examples through
the Network similar to the Perceptron. These
training data are fed to the Network layer by
layer. At each layer, activation potential is
determined. Forward propagation is done to
calculate cell activation. The error after initial
computation in the forward pass is propagated
from the output layer, layer by layer to the front. Repetition of the process will be done till a
relatively small rate of change of error is
achieved. The recommended rate of change of
error of 0.1 to 1 percent is sufficient to terminate
training. However, the rate of change of error
varies from different applications; hence 1 percent
should only be used as a guideline. Back propagation [25] is done from the
output, layer by layer to the front. In this
process, the synaptic weights are adjusted in
accordance to error-correction rules listed in
equation q
f1(si) = ui(1-ui) (15)
1
:
1
,
)
(
)
(
)
(
m
m
i
m
i
m
i
i
s
f
w
u
c
(16) (15) (16) If u1 is a output unit for other If u1 is a output unit for other Lastly the weights are updated with the formula
given by y
Wij* = Wi,j + pδuj (17) I. Introduction Fig 3: Simulation Diagram of ANN based Five
Seitch BLDC Motor Boost
Converter:
Boost
converter,
step-up
converter is a power converter with an output DC
voltage greater than its input DC voltage. It is a
class of switching mode power supply, called
SMPS, containing at least two Semiconductors
switches, a diode and a transistor, and at least one
energy storage element. Switch turns on and
incrementally stores energy from V1 in L. Switch
turns off and this energy and additional energy
from input is transferred to output. Therefore, L
used as a temporary storage element filters made
of inductor and capacitor combinations are often
added to a converter's output to improve
performance. The output voltage function for this
converter is The neural network consists of junctions,
which are connected with LINKS are also called
processing units. For each junction a number is
ordered, which is called weight. The weights are
the tools to store the long distance estimation in
the neural networks. The learning process [24]
occurs with the appropriate modification of
weights. These weights are modified so that the
network input and output behavior is in
consonance with the environment, which provides
the input data. www.psychologyandeducation.net
(14) (14) (14) The calculation of algorithm consists of the
following basic steps: g
p
Calculation of the output of the network,
with inputs and weights. 3135 www.psychologyandeducation.net www.psychologyandeducation.net PSYCHOLOGY AND EDUCATION (2021) 58(1): 3132-3141 ISSN: 00333077 Modification of weights with learning
algorithm. Modification of weights with learning
algorithm. descent in the error function guarantees that it will
find a set of weights that correspond to a
minimum of the error function. Instead of
utilizing a hard limiting Linear Threshold Unit, a
sigmoid is employed. The main difference
between a LTU and sigmoid is that the sigmoid is
differentiable. Computations in the algorithm are
carried out in parallel, one layer at a time. A single input neuron consists of a
scalar input ‘p’, multiplied by the scalar weight
‘w’, to form ‘wp’ which is fed to the summer
along with bias ’b’ multiplied by 1 is as
following: Fig 5: Basic Neural Network The basic approach to application of Back
propagation Algorithm is as followed:
A preferred activation will be [1, -1] as
compared to traditional [0, 1]. Theoretical and
experimental evidence has been established.
A preferred activation will be [1, -1] as
compared to traditional [0, 1]. I. Introduction Theoretical and
experimental evidence has been established.
A small positive value for the step size, p, is
chosen. Even though a larger value of p
results
in
faster
convergence,
such
convergence is up to a certain limit. To large a
value of p results in the algorithm to become
unstable and failure to converge. Hence it is
recommended to keep the value of p to a
maximum of 0.1. Fig 5: Basic Neural Network Fig 5: Basic Neural Network g
The net input is ‘wp+b’ and the output ‘a’ is; a=f
(WP+b); f- Transfer function W & b can be
adjusted by learning rule. j
y
g
BACK PROPAGATION ALGORITHM www.psychologyandeducation.net PSYCHOLOGY AND EDUCATION (2021) 58(1): 3132-3141 PSYCHOLOGY AND EDUCATION (2021) 58(1): 3132-3141 ISSN: 00333077 between elements. For example, if we want to
train a neuron model to approximate a specific
function, the weights that multiply each input
signal will be updated until the output from the
neuron is similar to the function. Neural networks
are composed of elements operating in parallel. Parallel processing allows increased speed of
calculation
compared
to
slower
sequential
processing. Artificial neural networks [26], [27]
(ANN) have memory. The memory in neural
networks corresponds to the weights in the
neurons. Neural networks can be trained offline
and then transferred into a process, where
adaptive learning takes place. In this case, a
neural network controller could be trained to
generate control signal for driving logic offline in
the MATLAB (SIMULINK) environment. After
training, the network weights are set. The ANN is
placed in a feedback loop with the natural control
generator. The network will adapt the weights to
improve performance, as it generates control
signal. In spite of these advantages ANN has
some disadvantages. The main disadvantage of
ANN is, they operate as black boxes. The rules of
operation in neural networks are completely
unknown. Another disadvantage is the amount of
time taken to train networks. It can take
considerable time to train an ANN for certain
functions. Where α is the learning rate, i , j, m- Layers
of neurons F- Performance Index w, b- respective
weights and bias as per their sub-script and
superscript. p
p
The science of artificial neural networks is
based on the biological neuron. In order to
understand the structure of artificial networks, the
basic elements of the neuron should be
understood. Neurons
are
the
fundamental
elements in the central nervous system. A neuron
is made up of 3 main parts -dendrites, cell body
and axon. The dendrites receive signals coming
from the neighboring neurons. The dendrites send
their signals to the body of the cell. The cell body
contains the nucleus of the neuron. If the sums of
the received signals are greater than a threshold
value, the neuron fires by sending an electrical
pulse along the axon to the next neuron. The
model of artificial neuron is based on the
components of the biological neuron as shown in
Fig 6 & 7. The inputs X0-X3 represent the
dendrites. Each input is multiplied by weights
W0-W3. Type of activation function (F) Fig 7: Multilayered Artificial Neural Networks There are 3 main types of activation function -
tan-sigmoid, log-sigmoid and linear as shown in
Fig 2.9. Different activation functions affect the
performance of an ANN. PSYCHOLOGY AND EDUCATION (2021) 58(1): 3132-3141 The output of the neuron model, Y is a
function, ‘F’ of the summation of the input
signals. W0
W1
W2
W3
X0
X1
X2
X3
F
Y
Fig 6: Artificial Neuron Model W0
W1
W2
W3
X0
X1
X2
X3
F
Y
Fig 6: Artificial Neuron Model
Fig 7: Multilayered Artificial Neural Networks STEEPEST DESCENT ALGORITHM FOR
THE APPROX MEAN SQUARE ERROR There are two modes of training for the algorithm:
Pattern and Batch Training: )1
(
k
w
m
ij
=
)1
(
k
w
m
ij
-
m
j
iw
f
,
(18)
)1
(
k
b
m
j
=
)
(k
b
m
i
-
m
ib
f
(19) (18) In the Pattern mode, the update of
weights is performed after each training example. In the batch mode, the weight is updated after a
whole set of training example (an epoch). The fact
that batch mode follows the direction of steepest (19) www.psychologyandeducation.net ANN MODELING FOR DC MACHINE Neural networks have 3 main modes of
operation
–
supervised,
reinforced
and
unsupervised learning. In supervised learning the
output from the neural network is compared with
a set of targets, the error signal is used to update
the weights in the neural network. Reinforced
learning is similar to supervised learning. However there are no targets given, the algorithm
is given a grade of the ANN performance. Unsupervised learning updates the weights based
on the input data only. In case of generating
control signals, supervised learning is used. Fig 6: Artificial Neuron Model Neural Network Structures There are 3 main types of ANN structures -
single layer feed-forward network, multi-layer
feed-forward network and recurrent networks. T
f
i
i
f
i
(F) SIGNIFICANCE OF USING ANN One of the
advantages that back propagation presents is a
speed of convergence and robustness compared to
other types of training. For this reason, in this
work, a multi-layer perceptron neuronal network
has been implemented using back propagation as
a training algorithm. This network was used for
speed control of a brushless motor. The
architecture of the neural network used for the
development of this work has a topology 2:8:1
and uses only two layers. The relation 2:8:1
means that the neural network has an input vector
of a size of two elements. This means that every
example presented to the neural network only has
two elements. The second number 8 belongs to
the number of neurons that have the first hidden
layer. Finally, number 1 tells us that there is only
one neuron in the output layer. As it is possible to
see, the neural network needs only two layers of
neurons
in
order to obtain
an
excellent
performance of the control system proposed. However, just with this configuration, the neural
network is capable of learning the vectors related
to brushless motor control. As previously noted, it
is necessary to have example vectors related to
the problem to be solved by the neural network. These sample vectors must come from real
examples of the objects or the system to be
modeled. In this case, examples of the motor’s
response to different applied torques are required. For this reason, a classical Proportional, Integral,
and Derivative (PID) controller has been
compared in order to obtain values to train the
proposed network. Usually, the neural networks have several
layers composed of a different number of neurons
each of them. In general, neural networks are
composed of three different layers: input, hidden,
and output. The information goes from one layer
to another through the transfer functions. The
transfer function determines how the information
is transmitted between layers. Weights are
directly associated with the connection between
layers. That is, if a connection has weight with a
high value, then it will make more contributions
to the network output. One of the most used
neural networks is called multi-layer perceptron,
and the best-known training method for this type
of network is back propagation. This algorithm is
used more for learning this kind of multi-layer
perceptron
network. SIGNIFICANCE OF USING ANN The main advantage of neural networks is to train
a neural network to perform a particular function
by adjusting the values of connections (weights) 3137 www.psychologyandeducation.net PSYCHOLOGY AND EDUCATION (2021) 58(1): 3132-3141 ISSN: 00333077 2. Enter input data from among those to be used
for training. 2. Enter input data from among those to be used
for training. Fig (a)
(b)
(c)
Fig 8: Activation function (a) Tan-sigmoid (b)
Log-sigmoid (c) Linear (b)
(c) Fig (a)
(b)
(c) 3. Let the network generate an output data vector
(forward propagation). 3. Let the network generate an output data vector
(forward propagation). 4. Compare the network output with the desired
output. 4. Compare the network output with the desired
output. Fig (a)
(b)
(c)
Fig 8: Activation function (a) Tan-sigmoid (b)
Log-sigmoid (c) Linear (b) (c) g
Fig 8: Activation function (a) Tan-sigmoid (b)
Log-sigmoid (c) Linear 5. The difference between the generated and the
desired output (called error) is used to adjust the
weights in the output layer. 5. The difference between the generated and the
desired output (called error) is used to adjust the
weights in the output layer. In proposed method neural network is
used to determine the exact instant of crossing of
reference sine wave with carrier i.e. (tk+Δtk),
when input given to neural network is time instant
‘tk’ as shown in Fig 8. Supervised learning
method is used to train the neural network. In
supervised learning we have to specify the input-
output target pair for train neural network. Here
input is given as time instants ‘tk’ at which carrier
waveform achieves their peaks (both positive and
negative) and corresponding target is specified by
exact instant of crossing of carrier and reference
i.e. (tk+Δtk) for corresponding value of ‘tk’. Multilayer neural network having 3 layers is built. First two layers have 35 neurons with transfer
function as tan-sigmoid and last layer has 1
neuron with transfer function as linear. MATLAB
package provides many powerful tools for
building and training neural network. 6. The error spreads backwards (hence the name
of back propagation), towards the previous neuron
layer, and is used to adjust the weights of that
layer. 7. Continue propagating the error backwards and
adjusting the weights until the input layer is
reached. The proposed controller can meet the
requirements of stability, rapidity, accuracy and
robustness in BLDCM drivers. www.psychologyandeducation.net www.psychologyandeducation.net CONCLUSION on Industrial Electronics, vol. 55, no. 6, (200
Parameters
ANN
Rise time
0-700 RPM 0.003
700-
900RPM
0.003
Settling time
0-700 RPM 0.020
700-
900RPM
0.003
Steady
state
error
0-700 RPM 0.9%
700-
900RPM
0.9%
Start up torque
0-700 RPM 3.2
N.N
700-
900RPM
1.3
N.M
Start
up
current
0-700 RPM 3A
700-
900RPM
1A
Speed
variation
0.7%
0.6%
Power factor
0.7
0.8
DC voltage
500 Vdc
600Vdc In this work, the development of the current
control of a BLDC motor using a multi-layer
perceptron type neural network based five switch
controls was presented. From the simulation, the
test results are carried out in this paper, it was
seen that the control implemented from the
proposed neural network scheme is well-
organized, and reasonable results than the
conventional controllers in the presence of
constant load are obtained. As per the results
obtained in the various simulations carried out in
this implementation, it was obvious that the
neural network is superior to conventional
controllers. Due to this, in most of the
applications, it is difficult to find a constant load
torque; 3140
on Industrial Electronics, vol. 55, no. 6, (2008),
pp. 2246-2257. [3] N. Milivojevic, M. Krishnamurthy, A. Emadi and
Stamenkovic, "Theory and implementation of a
simple digital control strategy for brushless DC
generators",
IEEE
Transactions
on
Power
Electronics, vol. 26, no. 11, (2011), pp. 3345-
3356. [4] S. Sivakotiah and J. Rekha, "Speed Control of
Brushless Dc Motor On Resonant Pole Inverter
Using Fuzzy Logic Controller", International
Journal of Engineering Science and Technology
vol. 3, no.10, (2011), pp. 7360-7367. [5] U. Ansari, S. Alam, S. Minhaj and N. Jafri
"Modeling and control of three phase BLDC
motor using PID with genetic algorithm"
Computer Modelling and Simulation, UkSim 13th
International Conference on IEEE, (2011). [6] C. Reddy, S. RAMI and M. S. Kalavathi
"Performance evaluation of hybrid fuzzy logic
controller
for
brushless
dc
motor
drive"
900RPM
Settling time
0-700 RPM 0.020
700-
900RPM
0.003
Steady
state
error
0-700 RPM 0.9%
700-
900RPM
0.9%
Start up torque
0-700 RPM 3.2
N.N
700-
900RPM
1.3
N.M
Start
up
current
0-700 RPM 3A
700-
900RPM
1A
Speed
variation
0.7%
0.6%
Power factor
0.7
0.8
DC voltage
500 Vdc
600Vdc Therefore, the use of conventional controllers
control may not be suitable for a system. The
working principle of the BLDC is with the help of
five-switch control scheme can be implemented
here. CONCLUSION The different values of load were used to
consider the total operation of the BLDC motor is
to be controlled. After the completion of the
training and testing of the neural network, it might
be maintain the constant load values and its
variables. To calculate the duty ratio of the DC-
DC converter, it will be adjusted to regulate the
speed of the BLDC motor. However the DC link
of the five switching inverter is used here for the
boosting of the voltage. If the loads are variable
loads then the conventional controllers are not
capable to sustain it parameters. At this point, the
neural network was superior since it is sufficient
of supporting torque changes without the need for
a speed sensor. In conclusion, it is noted that the
development
of
the
neural
network
is
computationally less expensive. pp
[3] N. Milivojevic, M. Krishnamurthy, A. Emadi and
Stamenkovic, "Theory and implementation of a
simple digital control strategy for brushless DC
generators",
IEEE
Transactions
on
Power
Electronics, vol. 26, no. 11, (2011), pp. 3345-
3356. pp
[3] N. Milivojevic, M. Krishnamurthy, A. Emadi and
Stamenkovic, "Theory and implementation of a
simple digital control strategy for brushless DC
generators",
IEEE
Transactions
on
Power
Electronics, vol. 26, no. 11, (2011), pp. 3345-
3356. [4] S. Sivakotiah and J. Rekha, "Speed Control of
Brushless Dc Motor On Resonant Pole Inverter
Using Fuzzy Logic Controller", International
Journal of Engineering Science and Technology,
vol. 3, no.10, (2011), pp. 7360-7367. SIGNIFICANCE OF USING ANN The
back
propagation
algorithm trains the neural network from sample
vectors of the system that are of interest for their
modeling, such as the texture of an object or, in
our case, the speed of a motor. Summarizing, the back propagation training
system consists of the following steps: 1. Initialize the weights of the network randomly. 3138 www.psychologyandeducation.net PSYCHOLOGY AND EDUCATION (2021) 58(1): 3132-3141 ISSN: 00333077 PSYCHOLOGY AND EDUCATION (2021) 58(1): 3132-3141
ISSN: 00333077
Fig : ANN based power factor (PF 0.8) & dc
voltage (Vdc 600)
Fig 8: BLDCM five switch wave forms using
Neural Network method
Fig : Parameter Results of Simulation Fig : ANN based power factor (PF 0.8) & dc
voltage (Vdc 600)
Fig 8: BLDCM five switch wave forms usin
Neural Network method Fig : ANN based power factor (PF 0.8) & dc
voltage (Vdc 600)
Fig 8: BLDCM five switch wave forms using
Neural Network method Fig : ANN based power factor (PF 0.8) & dc
voltage (Vdc 600) Fig : ANN based power factor (PF 0.8) & dc
voltage (Vdc 600) Fig : ANN based power factor (PF 0.8) & dc
voltage (Vdc 600) Fig 8: BLDCM five switch wave forms using
Neural Network method Fig : Parameter Results of Simulation Fig : Parameter Results of Simulation 3139 www.psychologyandeducation.net PSYCHOLOGY AND EDUCATION (2021) 58(1): 3132-3141 PSYCHOLOGY AND EDUCATION (2021) 58(1): 3132-3141 ISSN: 00333077 CONCLUSION REFERENCES [1] X. Huang, A. Goodman, C. Gerada, Y. Fang and
Q. Lu, "Design of a five-phase brushless DC
motor for a safety critical aerospace application",
IEEE Transactions on Industrial Electronics, vol. 59, no. 9, (2012), pp. 3532-3541. [5] U. Ansari, S. Alam, S. Minhaj and N. Jafri,
"Modeling and control of three phase BLDC
motor using PID with genetic algorithm",
Computer Modelling and Simulation, UkSim 13th
International Conference on IEEE, (2011). [2] K. T. Chau, C. C. Chan and C. Liu, "Overview of
permanent-magnet brushless drives for electric
and hybrid electric vehicles", IEEE Transactions [2] K. T. Chau, C. C. Chan and C. Liu, "Overview of
permanent-magnet brushless drives for electric
and hybrid electric vehicles", IEEE Transactions [6] C. Reddy, S. RAMI and M. S. Kalavathi,
"Performance evaluation of hybrid fuzzy logic
controller
for
brushless
dc
motor
drive", 3140 www.psychologyandeducation.net PSYCHOLOGY AND EDUCATION (2021) 58(1): 3132-3141 ISSN: 00333077 IEEE Trans. Energy Conversion, Sep. 2002, vol. 17, p. 406 – 413. International Journal of Engineering Science and
Technology, vol. 3, no. 6, (2011), pp. 4749-4758. [20] S.G German-Gankin – “The computing modeling
for power electronic systems in Matlab”, 2001 [7] A. Al-Mashakbeh and S. Othman, "Proportional
Integral and Derivative Control of Brushless DC
Motor", European Journal of Scientific Research,
vol. 35, no. 2, (2009), pp. 198-203. [21] Rasid, “High performance nonlinear MIMO field
weakening controller of a separately excited dc
motor,” Electric Power Systems Research, vol. 55, issue 3, Sep. 2000, pp. 157-164. [8] H. N. Nounou and H. Rehman, "Application of
adaptive fuzzy control to ac machines", Applied
Soft Computing, vol. 7, no. 3, (2007), pp. 899-
907. [22] El-Sharkawi,
M. A.,
&
Weerasooriya,
S. ,“Adaptive tracking control for high performance
dc drives”. IEEE Transactions on Energy
Conversion, volume-5, September 1989.,122-128. [9] R. Kandiban and R. Arulmozhiyal, "Design of
Adaptive Fuzzy PID Controller for Speed control
of BLDC Motor", International Journal of Soft
Computing and Engineering, vol. 2, no. 1, (2012),
pp. 386-391. [23] Kotaru, R., & Rubai, A. ,“Online Identification
and control of a dc motor using learning
adaptation of neural networks”. IEEE Transactions
on industry applications, volume-36 ,June 2000,
935-942. [10] C. H. Wang, H. L. Liu and T. C. Lin, "Direct
adaptive fuzzy-neural control with state observer
and supervisory controller for unknown nonlinear
dynamical
systems",
Fuzzy
Systems,
IEEE
Transactions, vol. 10, no. 1, (2002), pp. 39-49. [24] Kotaru, R., & Rubai, A. REFERENCES ,“Online Identification
and control of a dc motor using learning
adaptation of neural networks”. IEEE Transactions
on industry applications, volume-36 ,June 2000,
935-942. [11] W. D. Chang and J. J. Yan, "Adaptive robust PID
controller design based on a sliding mode for
uncertain chaotic systems", Chaos, Solitons &
Fractals, vol. 26, no. 1, (2005), pp. 167-175. [25] S.Weerasoorya
and
M.A
Al-Sharkawi
“Identification and control of a DC Motor using
back-propagation
neural
networks”
IEEE
transactions on Energy Conversion, Vol.6, No.4
pp663-669,December 1991 [12] Mozaffari Niapour, S.; Shokri Garjan, G.; Shafiei,
M.; Feyzi, M.; Danyali, S.; Bahrami Kouhshahi,
M. Review of permanent-magnet brushless DC
motor basic drives based on analysis and
simulation study. Int. Rev. Electr. Eng. 2014, 9,
930–957. [CrossRef] [26] Antsaklis, P. J. “Neural Networks in control
systems”,
IEEE
control
systems
magazine,
volume-10 , April 1990. Pp.3-5. [13] 45. Frolov, V.Y.; Zhiligotov, R.I. Development of
sensorless vector control system for permanent
magnet synchronous motor in Matlab Simulink. J. Min. Inst. 2018,
229,
doi:10.25515/PMI.2018.1.92. [CrossRef] [27] Hagan, M. T., Demuth, H. B., & Jesus, O. ,“An
Introduction To The Use of Neural Networks”. Electrical and Computer Engg. , 2000, pp. 1-23 [14] Devendra Rai “Simulink Simulator usage manual
for Brushless DC motor” Dept of E&CE NIT
(Surathkal) Karnataka [15] P.Pillay
and
R.Krishnan
“Application
Characteristics of permanent magnet synchronous
and brushless DC motors for servo drives” IEEE
Tran. Ind. Applicant, Vol. 27, PP. 986 – 996, Sept
/ Oct 1991. [16] T.Low and M.A Jabbar, “Permanent-magnet
motors for brushless operation”, IEEE Trans. Ind
Application, Vol. 26, PP. 124-129, Jan / Feb 1990 [17] M.H.Rashid “Power Electronics Circuit, Device
and Applications” PHI Publication Ltd., 3rd
Edition, 2005 [18] Samir Salama “Simulation of power electronics
system
using
“SimuPec:
The
new
power
electronics tool box for “Simulink / MATLAB”
2004, Annual, 35th IEEE, Tran. Power Electronics
specialists’ conference. [19] Abido M. A., “Optimal design of power-system
stabilizers using particle swarm optimization”, 3141 www.psychologyandeducation.net
|
https://openalex.org/W4280546003
|
https://zenodo.org/record/6325076/files/D1E_1_HyDelta_Eerste_Tranche_Impact_of%20high_speed_hydrogen_flow_EN.pdf
|
English
| null |
D1E.1 Impact of high speed hydrogen flow on system integrity and noise
|
Zenodo (CERN European Organization for Nuclear Research)
| 2,022
|
cc-by
| 26,276
|
WP1E – Impact of high speed hydrogen flow on system
integrity and noise D1E.1 – WP1E Report Status: final Dit project is medegefinancierd door TKI Nieuw Gas | Topsector Energie uit de PPS-toeslag
onder referentienummer TKI2020-HyDelta. WP1E – Impact of high speed hydrogen
flow on system integrity and noise
D1E.1 – WP1E Report Document summary
Corresponding author
Corresponding author
Néstor González Díez
Affiliation
TNO
Email address
nestor.gonzalezdiez@tno.nl
Document history
Version Date
Author
Affiliation
Summary of main changes
0.1
14-Aug-
2021
N. González Díez, L. van Lier, S. Belfroid,
I. Meijer. TNO
(English) Version for review by WP1E
Expert Assessment Group
0.2
3-Nov-
2021
(see above)
TNO
(English) Second draft after first review by
WP1E Expert Assessment Group. Major
modifications implemented in report. 1.0
30-Nov-
2021
(see above)
TNO
Final draft submitted for approval to
release and translate. Dissemination level
Dissemination Level
PU
Public
×
R1
Restricted to
•
Partners including Expert Assessment Group
•
Other project participants including Sounding Board
•
External entity specified by the consortium (please specify)
R2
Restricted to
•
Partners including Expert Assessment Group
•
Other project participants including Sounding Board
R3
Restricted to
•
Partners including Expert Assessment Group
Document review
Version
Reviewer name
Affiliation
0.1
Stefan Belfroid
Sytze Buruma
Thijs Duisters
Alfons Krom
Gilles de Kok
Vinay Sewbaran
Johannes de Bruin
Pascal te Morsche
Peter Verstegen
HyDelta Supervisory Group
TNO
Coteq
Enexis
Gasunie
Enduris
Stedin
Liander
Liander
Liander
NEC, KIWA, DNV, TNO, NBNL, Stedin, Alliander
0.2
Sytze Buruma
Thijs Duisters
Tjidsger Kingma
Tessa Hillen
Peter Verstegen
Coteq
Enexis
Gasunie
Stedin
Liander Executive summary Executive summary The Netherlands has an extensive pipeline infrastructure for the transport and storage of natural gas. This existing infrastructure could be used in the future for hydrogen transport. For reasons of
personal and environmental safety and to ensure reliable supply, the infrastructure is built and
operated according to standards and norms for pipeline integrity. Currently, the reliability is ensured
by complying with design codes and standards and by using systematic approaches for maintenance
and trouble-shooting. The question arises whether the same amount of energy transported with
hydrogen as currently with natural gas results in a larger impact on the integrity of the system and
the environment around it. High flow velocities are associated to larger pressure drop and higher risk of noise emissions,
vibrations and erosion. The flow speed is determined by the selection of system capacity, operating
conditions, hardware sizing and economic evaluation. The combination that provides the lowest
levelized cost of transport determines what the resulting flow velocity is at all points of the transport
system. However, the flow velocity itself can be a constraint in this optimization due to the risks
mentioned. For natural gas, this limit is commonly set at 20 m/s (72 km/h), though this is not the
case for every segment of the network and at specific locations this can reach higher values. If the
same limit would be applied to hydrogen, it may be an unnecessarily conservative constraint on the
capacity of new and re-used systems to transport energy. In this study, a review is made of flow-induced risk mechanisms for intrusive equipment, flow-
induced turbulence, flow-induced pulsations, acoustics-induced vibration, flow-induced noise and
erosion. Capacity from a pressure drop perspective is also checked. This is done scoping the Dutch
high-pressure gas transport system (GTS), through the RNB systems, up to the gas receiving spot for
the end user. A generic benchmark between natural (G-) gas and hydrogen is presented, when an
equal energy transport capacity between the two carriers is assumed, which in practice means
whether hydrogen can flow 3 times faster than natural gas. The objective of the benchmark is to
evaluate whether under this assumption, any of the phenomena analysed hinders transport at such
conditions. In other words, whether the allowable flow velocity for hydrogen can be larger than the
value traditionally used for natural gas. WP1E – Impact of high speed hydrogen
flow on system integrity and noise
D1E.1 – WP1E Report WP1E – Impact of high speed hydrogen
flow on system integrity and noise
D1E.1 – WP1E Report Document summary Document review
Version
Reviewer name
Affiliation
0.1
Stefan Belfroid
Sytze Buruma
Thijs Duisters
Alfons Krom
Gilles de Kok
Vinay Sewbaran
Johannes de Bruin
Pascal te Morsche
Peter Verstegen
HyDelta Supervisory Group
TNO
Coteq
Enexis
Gasunie
Enduris
Stedin
Liander
Liander
Liander
NEC, KIWA, DNV, TNO, NBNL, Stedin, Alliander
0.2
Sytze Buruma
Thijs Duisters
Tjidsger Kingma
Tessa Hillen
Peter Verstegen
Rick den Hartog
HyDelta Supervisory Group
Coteq
Enexis
Gasunie
Stedin
Liander
Westland Infra
NEC, KIWA, DNV, TNO, NBNL, Stedin, Alliander Page 2/57 Executive summary Not all of the risks investigated are as prevalent in different segments of the Dutch gas transport and
distribution system. Normally, risks associated to vibration and failure are more prevalent in the GTS
systems because of the high pressure, whereas the risk of noise is more prevalent with RNB systems. Of course, that does not mean that RNB is insensitive to fatigue failures or GTS to noise-related risks. The table displayed in the next page maps the aforementioned risks to the segment of the Dutch gas
network to which they apply. The main result of this investigation is that the risk levels associated to these phenomena when
hydrogen flows with the same energy rate as natural (G-) gas is the same as nowadays. In other
words: if with natural gas transport, 20 m/s is a rule of thumb for the maximum flow velocity in the
network, 60 m/s can be the rule of thumb for hydrogen, with some caveats as described below. The
pipelines have the capacity to operate at 60 m/s from a pressure drop perspective. This means that
in exploratory studies for hydrogen network development, capacities of the pipelines to transport
hydrogen can be constrained at higher flow velocities than currently done. Applying 20 m/s as for
natural gas can be considered conservative. Page 3/57 WP1E – Impact of high speed hydrogen
flow on system integrity and noise
D1E.1 – WP1E Report For the GTS system (HTL, RTL):
Mechanism
Conclusions of benchmark between G-gas and H2
Priority
Pressure drop
Similar pressure drop, i.e. pipelines have sufficient capacity to
transport the same amount of energy at similar pressure profiles. 3
FIV intrusive
equipment
Long, straight designs are at risk if exposed to elevated hydrogen
flow speeds. In the examples analysed, some thermowells should be
replaced above 38 m/s. Thermowells should be surveyed when re-
use service for hydrogen is intended. Existing risk quantification and mitigation measures remain valid. No
further research is required. 2
Flow-induced
turbulence
Vibrational excitation due to flow-induced turbulence is expected to
be more benign with hydrogen even at high flow velocities. Typical
supporting layouts should remain sufficient to arrest excitations
arising from flow turbulence generated at fittings. 3
Flow-induced
pulsations
Flow-induced pulsations are expected to remain a risk similar to
current operation with natural gas. While pulsation levels are
expected to decrease, their frequency will increase, making them
more likely to coincide with mechanical natural frequencies. Analyses as performed nowadays for natural gas will remain the
norm for hydrogen service. Existing risk quantification and mitigation measures remain valid and
should be applied. No further research is required. 2
Acoustics-
induced
vibration
Acoustics-induced vibration as the result of depressurization events
or pressure reduction in control streets or recycle valves will be
more energetic with hydrogen. This is more noticeable the higher
the pressure and the diameter of the vent system, for instance on
pressure relief on the discharge of compressors. However, this
energetic source is unlikely to translate effectively into a higher risk
of failure, due to larger distance between acoustic and pipe
structural natural frequencies. Installations featuring sudden
pressure reduction intended for hydrogen re-use should be surveyed
for AIV risk. Existing risk quantification and mitigation measures
remain valid and should be applied. No further research is required. 2
Flow-induced
noise
Consistently, the noise levels inside the pipe are expected larger for
hydrogen than for natural gas. However, the radiation properties of
existing pipes tend to block hydrogen noise more (impedance
mismatch) than with natural gas. Noise frequencies will increase
significantly. It is not possible to conclude that the net effect on external noise
emissions is favourable to hydrogen in all cases. WP1E – Impact of high speed hydrogen
flow on system integrity and noise
D1E.1 – WP1E Report Table. Fundamental aspects related to flows at high speeds and connection to the different segments of the gas transport
and distribution system (indicated by an “×” symbol). For clarification, please refer to section 1.4. Table. Fundamental aspects related to flows at high speeds and connection to the different segments of the gas transport
and distribution system (indicated by an “×” symbol). For clarification, please refer to section 1.4. Segment of Gas System
Pressure drop
FIV Intrusive Equipment
Flow Induced Turbulence
Flow Induced Pulsations
Acoustics Induced Vibration
Flow Induced Noise
Erosion
HTL pipeline
×
×
HTL compressor station
×
×
×
×
×
×
×
HTL storage station
×
×
×
×
×
×
×
HTL M&R station
×
×
×
×
×
×
×
HTL GOS
×
×
×
×
×
×
×
RTL pipelines
×
×
RTL GOS
×
×
×
×
×
×
×
RNB pipelines HP
×
×
×
×
RNB pipelines LP
×
×
×
×
RNB gas transfer stations
×
×
×
×
×
×
RNB gas district stations
×
×
×
×
×
×
RNB up to household meter
×
×
×
× More specifically for the different segments of the gas transport and distribution system, the
outcomes of the benchmark between natural gas and hydrogen when transporting the same amount
of energy are summarized in the tables displayed in the following pages. A priority number between
1 and 3 has been given based on the level of perceived risk for each mechanism: “1” is given to issues
where uncertainties still remain and further research is required; “2” means that the risk perceived is
similar (occasionally larger, occasionally lower) for hydrogen as for natural gas, existing engineering
practices are valid and should be used when surveying equipment for hydrogen re-use; “3” means
that the perceived risk is lower, or in both cases negligible, with hydrogen than with natural gas,
existing engineering practices are valid and should be used when surveying equipment for hydrogen
re-use. Page 4/57 Page 4/57 WP1E – Impact of high speed hydrogen
flow on system integrity and noise
D1E.1 – WP1E Report For the RNB systems (both HP and LP segments): For the RNB systems (both HP and LP segments):
Mechanism
Conclusions of benchmark between G-gas and H2
Priority
Pressure drop
Similar pressure drop, i.e. pipelines have sufficient capacity to
transport the same amount of energy at similar pressure profiles. Only small differences are observed depending on the line size or
the (inner) surface quality after years of operation. 3
FIV intrusive
equipment
Long, straight designs are at risk if exposed to elevated hydrogen
flow speeds. In the examples analysed, some thermowells should be
replaced above 28 m/s. Thermowells should be surveyed when re-
use service for hydrogen is intended. Existing risk quantification and mitigation measures remain valid. No
further research is required. 2
Flow-induced
turbulence
Vibrational excitation due to flow-induced turbulence is expected to
be more benign with hydrogen even at high flow velocities. Typical
supporting layouts should remain sufficient to arrest excitations
arising from flow turbulence generated at fittings. 3
Acoustics-
induced
vibration
Acoustics-induced vibration as the result of depressurization events
or pressure reduction in control streets or recycle valves will be
more energetic with hydrogen. This is more noticeable the higher
the pressure and the diameter of the system, for instance in district
stations. However, this energetic source is unlikely to translate
effectively into a higher risk of failure, due to larger distance
between acoustic and pipe structural natural frequencies. Installations featuring sudden pressure reduction intended for
hydrogen re-use should be surveyed for AIV risk. Existing risk
quantification and mitigation measures remain valid and should be
applied. No further research is required. 3
Flow-induced
noise
Consistently, the noise levels inside the pipe are expected larger for
hydrogen than for natural gas. This is more noticeable the higher the
pressure and the diameter of the system, for instance in district
stations. However, the radiation properties of existing pipes tend to
block hydrogen noise more (impedance mismatch) than with natural
gas. Noise frequencies will increase significantly. It is not possible to conclude that the net effect on external noise
emissions is favourable to hydrogen in all cases, either in the
networks or by the end-user installations such as household. It is
recommended to continue research by gathering additional
experimental evidence on noise emissions from flowing tests and
pilot field operations, including the household level. It is recommended
to continue research by gathering additional experimental evidence
on noise emissions from flowing tests and pilot field operations. 2
Erosion
As a result of high flow velocities, erosion potential is dramatically
increased. However, measures are in place to prevent the presence
of solid particles. Should the amount of solid particles be close to the
current legally acceptable limit, flow velocity limits should be
applied. Presence of solid particles cannot always be excluded. Existing risk quantification and mitigation measures remain valid. It is recommended to continue the research in the area of erosion
(see notes on follow-up recommended research). 1 For the GTS system (HTL, RTL): Page 5/57 2
Erosion
As a result of high flow velocities, erosion potential is expected to
increase. However, this is not the result attained for some of the
examples used. Several aspects impair the use of existing risk
quantification approaches. The results remain uncertain. It is recommended to continue the research in the area of erosion
(see follow-up section on recommended research). 1 Page 6/57 WP1E – Impact of high speed hydrogen
flow on system integrity and noise
D1E.1 – WP1E Report WP1E – Impact of high speed hydrogen
flow on system integrity and noise
D1E.1 – WP1E Report In terms of follow-up research, the following points are recommended: •
Erosion appears to be the most uncertain mechanism that may prevent achieving the desired
flow velocity. In general, flowing hydrogen at high speed (~60 m/s) should translate into an
erosion potential of an order of magnitude larger compared to flowing natural gas (at 20
m/s). An important parameter is the level of solid particle contamination in the gas stream,
which is uncertain. Filters are in place to prevent this contamination. Assuming legally
acceptable limits would already render unacceptable levels of erosion. For RNB systems, the
use of the (widely accepted) erosion model is not possible due to the low density of the fluid. Also the characterization of the pipe materials such as PVC is uncertain. It is recommended to
investigate this aspect as follows: o Exploring the performance of filters in the GTS and RNB systems with high speed
hydrogen flow. This should enable a more educated choice for the solid loading in
the gas stream. o Perform dedicated flow simulations to characterize worst-case erosion rates in the
RNB systems, in combination with suitable material constants for PVC pipes, for
which tests may be required. •
High frequency dynamic phenomena such as AIV and consequent noise radiation are
complex subjects under current investigation even at fundamental levels. Existing
engineering practices should be applied to equipment involved in sudden pressure
reductions, such as relief valves, compressor recycle valves or flow control valves. This will
already limit the risks of AIV sufficiently. To further verify the conclusions obtained in this
report about AIV and noise radiation, it is recommended to collect results from tests and
actual hydrogen piloting locations conducted in the context of HyDelta and/or its partners. •
Possible metering errors in flow meters as a result of unsteady flows (pulsations, turbulence)
should be better understood. This has not been covered in the current scope of HyDelta. It is
recommended to explore these phenomena as an integral part of the investigations
conducted to determine the requirements for flow metering equipment for hydrogen
service. Page 7/57 Table of contents
Document summary ................................................................................................................................ 2
Executive summary ................................................................................................................................. 3
Table of contents ..................................................................................................................................... 8
Nomenclature ........................................................................................................................................ 10
1
Introduction ................................................................................................................................... 12
1.1
Relevance .............................................................................................................................. 12
1.2
Scope of Work ....................................................................................................................... 12
1.3
Earlier and parallel research .................................................................................................. 13
1.4
Gas Transport System ............................................................................................................ 14
1.5
Description of the report ....................................................................................................... 16
2
Hydrogen Transport ...................................................................................................................... 17
2.1
Energy Transport Capacity .................................................................................................... 17
2.2
Flow velocity ratio ................................................................................................................. 19
2.3
Pressure drop ........................................................................................................................ 20
2.3.1
Hydrogen vs G-gas ......................................................................................................... 20
3
Intrusive Equipment ...................................................................................................................... 24
3.1
Intrusive equipment in natural gas transport systems ......................................................... 24
3.2
Assessment of flow-induced vibration for thermowells ....................................................... 24
3.3
Benchmark between natural gas and hydrogen ................................................................... 25
3.4
Examples ................................................................................................................................ 25
3.5
Conclusion ............................................................................................................................. 25
4
Flow Induced Turbulence .............................................................................................................. 26
4.1
Flow Induced Turbulence in natural gas transport systems ................................................. 26
4.2
Assessment of flow-induced turbulence ............................................................................... 26
4.3
Benchmark between natural gas and hydrogen ................................................................... 26
4.4
Examples ................................................................................................................................ 27
4.5
Conclusion ............................................................................................................................. 27
5
Flow Induced Pulsations ................................................................................................................ 28
5.1
Flow induced pulsations in natural gas transport systems ................................................... 28
5.2
Assessment of flow-induced pulsations ................................................................................ 28
5.3
Benchmark between natural gas and hydrogen ................................................................... 29
5.3.1
Pulsation resonances ..................................................................................................... 29
5.3.2
Pulsation amplitudes ..................................................................................................... 31
5.4
Examples ................................................................................................................................ 32 Page 8/57 flow on system integrity and noise
D1E.1 – WP1E Report
5.4.1
Case with natural gas .................................................................................................... 32
5.4.2
Case with hydrogen ....................................................................................................... 32
5.5
Conclusion ............................................................................................................................. 32
6
Acoustics Induced Vibration .......................................................................................................... 34
6.1
Acoustics-Induced Vibration in natural gas transport systems ............................................. 34
6.2
Assessment of Acoustics-Induced Vibration ......................................................................... 34
6.3
Benchmark between natural gas and hydrogen ................................................................... 35
6.4
Examples ................................................................................................................................ 36
6.5
Conclusion ............................................................................................................................. 37
7
Flow Induced Noise ....................................................................................................................... 38
7.1
Flow induced noise in natural gas transport systems ........................................................... 38
7.2
Assessment of flow-induced noise ........................................................................................ 39
7.2.1
Source: pressure reduction devices .............................................................................. 39
7.2.2
Source: pipes and flow fittings ...................................................................................... 39
7.2.3
Radiation........................................................................................................................ 40
7.3
Benchmark between natural gas and hydrogen ................................................................... 41
7.3.1
Source: pressure reduction devices .............................................................................. 41
7.3.2
Source: pipe and flow fittings ........................................................................................ 47
7.3.3
Noise radiation .............................................................................................................. 47
7.4
Conclusion ............................................................................................................................. 49
8
Erosion ........................................................................................................................................... 50
8.1
Erosion in natural gas transport systems .............................................................................. 50
8.2
Assessment of erosion........................................................................................................... 50
8.3
Benchmark between natural gas and hydrogen ................................................................... 51
8.4
Examples ................................................................................................................................ 52
8.5
Conclusion ............................................................................................................................. 53
9
Perspectives and closing remarks ................................................................................................. 54
10 List of References .......................................................................................................................... 56 Page 9/57 Nomenclature Acronyms
AIV
Acoustics Induced Vibration
AVIFF
Avoidance of Vibration Induced Fatigue Failure
FIP
Flow Induced Pulsations
FIT
Flow Induced Turbulence
Fv
Flow-Induced Vibration Factor
FVF
Fluid Viscosity Factor
GOS
Gasontvangstation
GTS
Gas Transport System
HDPE
High density polyethylene
HHV
High Heating Value [MJ/kg]
HTL
Hoofdtransportleidingnet
HP
High Pressure
LHV
Low Heating Value [MJ/kg]
LP
Low Pressure
LoF
Likelihood of Failure
M&R
Meet- en regelstation
PVC
Polyvinyl Chloride
PWL
Power level [dB]
RNB
Regionale netbeheerders
RTL
Regionale transportleidingnet
SFF
Sonic Flow Factor
WP
Work Package
Latin symbols
A
Frequency-dependent attenuation function [dB]
𝐶𝐷
Discharge coefficient [-]
𝑐
Speed of sound [m/s]
𝑑
Diameter [m]
𝐸
Erosion rate [kg/s]
𝑓𝐷
Darcy friction factor [-]
𝑓
Frequency [Hz]
𝐹
Dimensionless source strength [-]
𝐹
Force [N}
𝐿
Length [-]
𝑀
Mach number [-]
𝑚
Mass [kg]
𝑚̇
Mass flow [kg/s]
𝑀𝑊
Molecular weight [g/mol}
𝑃
Pressure [bar]
𝑝′
Pressure pulsation [Pa]
𝑃𝑟
Prandtl number [-]
𝑞̇
Energy rate [MJ/s]
𝑅
Specific gas constant [J/kg K]
𝑅̅
Universal gas constant [J/mol K] Page 10/57 1.1 Relevance The Netherlands has an extensive pipeline infrastructure for the transport and storage of natural gas. For reasons of personal and environmental safety and to ensure reliable supply, the infrastructure is
built according to standards and norms for pipeline integrity. Currently, the reliability is ensured by
complying with design codes [1] [2] [3] [4] and by using systematic approaches for maintenance and
trouble-shooting [5] [6]. One of the main questions asked from a hydrogen transport point of view concerns the maximum
allowable flow velocity under which risks related to asset and pipeline integrity are manageable and
acceptable. As will be explained in more detail in chapter 2, energy transport capacity increases with
higher pressures and higher flow velocities. To satisfy the selected transport conditions, compressors
and pipelines are selected such that they render the lowest levelized cost of transport. As a rule
though, a traditional limit of 20 m/s for the flow velocity is used in the natural gas transport industry
(though deviations from this are also possible, for example some RNB operators use 30 m/s if the
pressure is at least 3 bar(g)). This limit ensures that the appearance of integrity risks due to flow-
induced vibration is minimized and remains at manageable levels further mitigated with engineering
solutions. Occasionally, in the process piping of some assets, the flow speed can be larger. In large
transmission pipelines, it normally is lower. Yet the limit of 20 m/s is referred to as a reasonable value
to not be exceeded. If hydrogen was to be transported considering the same limit as for natural gas, this would severely
limit the capacity of existing pipelines to transport energy in the form of this carrier. Since hydrogen
contains about 3 times less energy per unit volume, it would need to flow about 3 times faster to satisfy
the same energy demand. Whereas it is not expected that hydrogen volumes will soon be such that
this capacity is actually needed, it is important to understand what the risks are of transporting
hydrogen at high speeds. Even if the same capacity as with natural gas was not required, allowing
higher hydrogen flow velocities enables operating pipelines at lower pressure, which in turn leads to
lower demands on compressor equipment and power required. In other words, can transport of
hydrogen at nearly 3 times faster flow speed be achieved with a manageable impact on the network? 𝑅𝑒
Reynolds number [-]
𝑆𝑟
Strouhal number [-]
𝑇
Temperature [K]
𝑈
Flow velocity [m/s]
𝑥
Axial location in a pipe [m]
𝑧
Compressibility factor [-]
Greek symbols
𝛼
Acoustic attenuation [1/m]
Impact angle [deg.]
𝛾
Specific heat ratio [-]
𝛾∗
Isentropic exponent [-]
Δ
Differential [-]
𝜕
Partial differential [-]
𝜇
Dynamic Viscosity [kg/m s]
𝜌
Density [kg/m³]
ΦP
Dimensionless Power Spectral Density [Pa2/Hz]
𝜙P
Power Spectral Density [Pa2/Hz]
Subscripts and superscripts
0
At rest
1
Gas “1” (hydrogen)
2
Gas “2” (natural gas)
a
absolute
g
gauge
I
internal
n
counter
p
particle
Sb
Side-branch
R
Material
r
ring
res
At resonance
th
thermowell
*
At choking. 0
At rest
1
Gas “1” (hydrogen)
2
Gas “2” (natural gas)
a
absolute
g
gauge
I
internal
n
counter
p
particle
Sb
Side-branch
R
Material
r
ring
res
At resonance
th
thermowell
*
At choking. Page 11/57 WP1E – Impact of high speed hydrogen
flow on system integrity and noise
D1E.1 – WP1E Report 1.1 Relevance In HyDelta WP1E, the impact of high speed hydrogen flows is investigated. The survey includes the
structural integrity of pipelines and pipeline equipment, but also other aspects such as noise radiation. Noise radiation is important for occupational safety as well as for comfort in the commercial and
domestic environment. The objective is to establish a comparison between current service with natural
gas and with hydrogen. As a final introductory note: often, differences observed between hydrogen and natural gas are not
directly linked to hydrogen as a fluid, but rather to the fact that it is assumed that the transport is done
at high speed. Where informative, an explicit note will be made on whether the conclusions reached
are connected to transport of hydrogen, the transport of a high speed gas, or both. WP1E – Impact of high speed hydrogen
flow on system integrity and noise
D1E.1 – WP1E Report 1.2 Scope of Work 1.2 Scope of Work The aim of this work package is to understand the impact of an increased flow velocity of H2 on the
different components of the existing gas transport and distribution infrastructure. In particular, the
following impacts are in scope: -
Intrusive equipment such as thermowells -
Flow induced turbulence Page 12/57 WP1E – Impact of high speed hydrogen
flow on system integrity and noise
D1E.1 – WP1E Report
-
Flow induced pulsations
-
Noise generation in piping and pressure reduction stations
-
Erosion -
Flow induced pulsations -
Noise generation in piping and pressure reduction stations -
Noise generation in piping and pressure reduction stations As will be shown throughout the report, benchmarks between natural gas and hydrogen will be
described for different aspects. Unless otherwise specified, only one natural gas composition has been
used in this report: that is Groningen (G-) gas, as this is used throughout the Dutch gas transport and
distribution system. In most cases, conclusions would hold when the comparison is done against high-
calorific (H-) gas, though not always this is the case. In cases where the difference is slightly favourable
or unfavourable to hydrogen, this may well be the opposite when comparing against H-gas. However
this is only in cases where differences are small anyway. The set of failure mechanisms connected to the compatibility of materials with hydrogen is widely
studied in other (former and current) studies and explicitly excluded from the scope of this work
package. Finally, transport of hydrogen at lower velocities than those required for transporting the same
amount of energy is not analysed in detail. This premise is currently considered conservative in some
segments of the gas transport system, particularly the HTL system, and realistic for others such as the
RNBs. Flows at lower speeds are of course also of interest, but for the subjects subjects analysed in
this report, lower flow speeds will in all cases show more benign results. 1.3 Earlier and parallel research Process and transport systems operating with (nearly) pure hydrogen are covered by widely used
engineering standards such as ASME B31.12 “Hydrogen Piping and Pipelines” [7]. Typically failure
mechanisms covered in such document have to do with the material compatibility of the pipelines
and components with hydrogen, for example hydrogen induced crack or hydrogen embrittlement. In
addition to this, several projects are currently investigating the compatibility of existing gas transport
systems and equipment to hydrogen or blends of natural gas and hydrogen. The North Sea Energy
Program [8] or the HIGGS project [9] are examples thereof. On the topic of maximum flow velocity for hydrogen, two references have been recently published
while HyDelta was running. The first is from the H21 initiative [10], where it is stated that the current
design limit for natural gas service is 40 m/s, due to erosion concerns. This is further limited to 20
m/s for “known dusty natural gas pipelines”. This report indicates that more research is ongoing to
better understand how this will change with hydrogen service, but that hydrogen may be able to pick
up less particles due to its lower density and viscosity. Steiner [11] in Germany correctly points to
concerns about pressure drop, erosion, noise emission and vibrations and discusses why the current
rule of thumb of 20 m/s is used with natural gas service. The author also formulates questions
contained in this HyDelta WP as to what to expect once the flow speed has to be increased to
maintain the energy rates with pure hydrogen, but no specific answers are offered. In the
Netherlands, the limit of 20 m/s has been traditionally linked to pulsations and vibrations. No
evidence of erosion being an issue is reported by GTS or RNB operators. This is due to the preventive
measures put in place, but nonetheless the limits connected to erosion are relevant due to incidental
or residual presence of solids inside the pipelines. Page 13/57 WP1E – Impact of high speed hydrogen
flow on system integrity and noise
D1E.1 – WP1E Report The type of hardware normally found in contact with the process fluid are as follows: -
Pipelines (of different materials). -
Fittings such as flanges, weldolets, reducers, etc. -
Restriction orifices. -
Scrubbers (filter, cyclone). -
Valves (all types, including safety relief valves). -
Pulsation reduction elements (dampers, silencers). -
Coolers (and heaters e.g. at storage sites). -
Instrumentation such as flow meters, pressure gauges and thermometers/thermowel In this work-package, fittings are excluded as their relevance is more connected to material
compatibility and leak tightness, where flow itself does not play a relevant role. Impact of flow on
scrubbers/filters is assessed in WP1B. Valves are investigated in other studies from the perspective of
material compatibility, but this WP does cover the potential of valves for noise and turbulence
generation (particularly control valves inducing large pressure drops). Compression equipment is
excluded as hydrogen compression and mitigation strategies for resulting pulsations such as damper
design is considered a mature technology [12]. The impact of flow velocity on flow metering is part of
the investigations performed in WP1D, and thus it is also not included. In this work-package, fittings are excluded as their relevance is more connected to material
compatibility and leak tightness, where flow itself does not play a relevant role. Impact of flow on
scrubbers/filters is assessed in WP1B. Valves are investigated in other studies from the perspective of
material compatibility, but this WP does cover the potential of valves for noise and turbulence
generation (particularly control valves inducing large pressure drops). Compression equipment is
excluded as hydrogen compression and mitigation strategies for resulting pulsations such as damper
design is considered a mature technology [12]. The impact of flow velocity on flow metering is part of
the investigations performed in WP1D, and thus it is also not included. Table 1-1 shows the connection between the flow-related phenomena subject of this research (as
listed in section 1.2) to the different segments of the Dutch gas transport and distribution system. Pressure drop is an important subject in all segments due to its connection to pipeline capacity, but
less important in assets whose pressure loss is dominated by a pressure let down device such as a
M&R station of a gas district station. Fatigue failure of intrusive equipment is typically only relevant
at nodal locations of the network where measurements are taken, but not for the pipelines
themselves. 1.4 Gas Transport System To better understand the conditions and parameters relevant to the benchmark, first an inventory of
typical hardware present in the system is made. At the end of this section, the different subjects of
this research are connected to the different segments of the gas transport and distribution system. The Dutch gas transport system receives its gas from different sources and is roughly divided in four
segments based on their pressure: the Hoofd Transport Leidingsysteem (HTL) and the Regionaal
Transport Leidingsysteem (RTL), which are managed by GTS; and the Regionale Netbeheerders (RNB)
systems. This is illustrated in Figure 1-1. The HTL is separated from the RTL by Meet & Regel stations
(M&Rs, measuring and control stations) the pressure is reduced to typically 40 bar(g). Further
downstream the system, gas is delivered to the local distribution grids, where pressure is reduced to
typically 8 bar(g) in Gas Ontvangst Stations (GOS, gas-receiving station). Downstream the GOSs, the
gas is further distributed by local gas net operators (RNBs). This is done via a grid of district stations,
which reduce the pressure from typically 8 bar(g) to 30/100 mbar (g). The ultimate gas delivery may
be done to small consumers (households) or larger industrial consumers. In the low-pressure grid,
also parts may be operated at 4 bar(g) or 1 bar(g). In such cases, the pressure is reduced from 8
bar(g) in gas transfer stations (overslag stations). Further details on the design principles of the gas
infrastructure can be found in [1] and [5]. Many assets located at the nodes and interfaces of these systems contain hardware that may be
subject to high flow velocities, in particular: -
HTL system
o Transmission pipelines
o Compressor stations
o Storage Stations
o M & R stations
-
RTL system
o Transmission pipelines
o GOS stations
-
RNB systems
o Piping systems (HP, LP)
o Gas transfer stations
o District stations
Figure 1-1 Overview of the Dutch gas transport and distribution system. o Transmission pipelines o Compressor stations Figure 1-1 Overview of the Dutch gas transport and distribution system. Figure 1-1 Overview of the Dutch gas transport and distribution system. Figure 1-1 Overview of the Dutch gas transport and distribution system. Page 14/57 Page 14/57 WP1E – Impact of high speed hydrogen
flow on system integrity and noise
D1E.1 – WP1E Report 1.5 Description of the report In the first chapter after this introduction, chapter 2, the basic information concerning hydrogen
transport and how it compares to natural gas (G-gas) is presented. After that, each chapter
corresponds to each one of the questions introduced in the Scope of Work. Chapter 3 is devoted to
the impact of hydrogen high speed flows on intrusive equipment, particularly (sheathed)
thermometers and thermowells. The subject of flow-induced turbulence is introduced in chapter 4. Flow induced pulsations for hydrogen service are explored in chapter 5. Flow-induced noise and its
potential consequences for integrity are described in chapter 6, whereas the radiation of such noise
is covered in chapter 7. Finally, erosion is covered in chapter 8. In the first chapter after this introduction, chapter 2, the basic information concerning hydrogen
transport and how it compares to natural gas (G-gas) is presented. After that, each chapter
corresponds to each one of the questions introduced in the Scope of Work. Chapter 3 is devoted to
the impact of hydrogen high speed flows on intrusive equipment, particularly (sheathed) corresponds to each one of the questions introduced in the Scope of Work. Chapter 3 is devoted to
the impact of hydrogen high speed flows on intrusive equipment, particularly (sheathed)
thermometers and thermowells. The subject of flow-induced turbulence is introduced in chapter 4. Flow induced pulsations for hydrogen service are explored in chapter 5. Flow-induced noise and its
potential consequences for integrity are described in chapter 6, whereas the radiation of such noise
is covered in chapter 7. Finally, erosion is covered in chapter 8. thermometers and thermowells. The subject of flow-induced turbulence is introduced in chapter 4. Flow induced pulsations for hydrogen service are explored in chapter 5. Flow-induced noise and its
potential consequences for integrity are described in chapter 6, whereas the radiation of such noise
is covered in chapter 7. Finally, erosion is covered in chapter 8. The structure of chapters 3-8 is always the same. Since the investigated subjects are also relevant to
current network operation with natural gas, in general the first section is devoted to describing the
existing situation with regards to that topic. For example: how are flow-induced pulsations dealt with
nowadays, or what issues they can create. This is followed by a section describing how quantification
of such risks is currently done. The same applies to flow-induced turbulence and acoustics induced vibration. Flow-
induced pulsations are only relevant in the HTL and RTL part of the system (i.e. GTS and not RNBs). Flow-induced noise is also relevant only for nodes of the network due to occupational health and
safety, but not for the transport pipelines. Due to the proximity to consumers, it is of interest to
understand flow-induced noise for pipelines in the RNB systems. Erosion is a topic that applies
anywhere with potential presence of solid particles. Due to several reasons, more importantly the
preventive measures in place, this is not currently an issue with natural gas. However its effects
would be important in all segments of the network and therefore the analysis scopes the typical
conditions for all segments. Page 15/57 Page 15/57 WP1E – Impact of high speed hydrogen
flow on system integrity and noise
D1E.1 – WP1E Report Table 1-1. Fundamental aspects related to flows at high-speeds and connection to the different segments of the ga
transport and distribution system. For clarification please refer to accompanying notes in the main body of the text Segment of Gas System
Pressure drop
FIV Intrusive Equipment
Flow Induced Turbulence
Flow Induced Pulsations
Acoustics Induced Vibration
Flow Induced Noise
Erosion
HTL pipeline
×
×
HTL compressor station
×
×
×
×
×
×
×
HTL storage station
×
×
×
×
×
×
×
HTL M&R station
×
×
×
×
×
×
×
HTL GOS
×
×
×
×
×
×
×
RTL pipelines
×
×
RTL GOS
×
×
×
×
×
×
×
RNB pipelines HP
×
×
×
×
RNB pipelines LP
×
×
×
×
RNB gas transfer stations
×
×
×
×
×
×
RNB gas district stations
×
×
×
×
×
×
RNB up to household meter
×
×
×
× 2.1 Energy Transport Capacity 2.1 Energy Transport Capacity Energy can be chemically stored in hydrogen (H2). As an energy carrier, hydrogen features a very high
specific energy (i.e. per unit mass), whereas it features a very low energy density (i.e. per unit
volume). Hydrogen is shown in comparison to other substances or technologies in Figure 2-1. Volume and therefore pressure are very important parameters related to the transport and storage
capacity of an eventual hydrogen-based energy system. These also define the eventual cost of the
hardware that makes the energy infrastructure. Neglecting a number of second order effects: if the
same amount of energy is to be transported with hydrogen and natural gas at similar pressures,
hydrogen volumes must flow 3 times faster. The equation for energy transport 𝑞̇ [MJ/s] depends on the mass flow 𝑚̇ [kg/s] and the energy
content per unit mass of the substance expressed for instance by its higher heating value 𝐻𝐻𝑉
[MJ/kg]. The lower heating value could also be used instead. (eq. 1)
𝑞̇ = 𝑚̇ 𝐻𝐻𝑉 (eq. 1) 𝑞̇ = 𝑚̇ 𝐻𝐻𝑉 To make the effect of pressure explicit, at a particular reference location, this can be rewritten into: To make the effect of pressure explicit, at a particular reference location, this can be rewritten into: (eq. 2)
𝑞̇ =
𝑃
𝑧 𝑅 𝑇 𝑈𝜋 (𝐼𝐷)2
4
𝐻𝐻𝑉 (eq. 2) in which 𝑃 is the absolute pressure [Pa(a)], 𝑧 is the compressibility factor [-], 𝑅 is the specific gas
constant [J/kg K], 𝑇 the absolute temperature [K], 𝑈 is the flow velocity [m/s], and 𝐼𝐷 is the inner
diameter of the pipe [m]. For pipeline transport, the physical design variables are then the pressure,
the nominal pipe size with wall thickness and, finally, the flow velocity. They are all interconnected. For example, higher pressures require thicker walls, but the selected pipe size could be smaller;
larger pipe sizes though reduce the pressure drop, lowering the load on compressors and improving
overall system efficiency. Eventually, the final selection for a pipeline is made on the basis of an
optimization yielding the lowest levelized cost of transport, which must include the entire transport
system and not only the pipeline itself. For instance, the capacity of a pipeline to transport energy as a function of its diameter is shown in
Figure 2-2. The larger the pipe size or the pressure, the more hydrogen can be transported. WP1E – Impact of high speed hydrogen
flow on system integrity and noise
D1E.1 – WP1E Report 1.5 Description of the report This is followed by a generic benchmark between natural gas and
hydrogen based on the quantification methods described in the previous section. From the
benchmark, general conclusions are offered. Application examples for typical hardware or
configurations encountered in the Dutch gas transport system are offered to close each chapter. A final overall summary and closing remarks are offered in chapter 9. Page 16/57 2.1 Energy Transport Capacity As an
example: a 42 inch (DN1050) pipeline at 60 bar(a) can transport 12 GW(th, HHV) at flow velocities of
20 m/s. A 10 inch pipeline (DN250) at 8 bar(g) can transport about 90 MW(th, HHV) at the same flow
velocity. Page 17/57 Page 17/57 WP1E – Impact of high speed hydr
flow on system integrity and noise
D1E.1 – WP1E Report
Figure 2-1. Energy density (x-axis) vs specific energy (y-axis) for a number of selected items. Hydrogen is found on the
bottom right corner of this plot. Obtained from Ref. [13]. WP1E – Impact of high speed hydrogen
flow on system integrity and noise
D1E.1 – WP1E Report Figure 2-1. Energy density (x-axis) vs specific energy (y-axis) for a number of selected items. Hydrogen is found on th
bottom right corner of this plot. Obtained from Ref. [13]. Figure 2-2. Energy transport capacity with H2 expressed in GW (thermal, HHV based) of different nominal pipe sizes
(schedule XS) at different pressures. Reference conditions are assumed at a temperature of 10 deg. C and a flow velocity of
20 m/s. 0.1
0.1
0.1
0.5
0.5
0.5
0.5
0.5
1
1
1
1
1
2
2
2
2
4
4
4
6
6
6
8
8
8
10
10
12
12
15
15
Pipeline capacity (GWth HHV)
Pressure [bara]
NPS [in]
5
10
15
20
25
30
35
40
45
10
20
30
40
50
60
70
80
90 0.1
0.1
0.1
0.5
0.5
0.5
0.5
0.5
1
1
1
1
1
2
2
2
2
4
4
4
6
6
6
8
8
8
10
10
12
12
15
15
Pipeline capacity (GWth HHV)
Pressure [bara]
NPS [in]
5
10
15
20
25
30
35
40
45
10
20
30
40
50
60
70
80
90 Pipeline capacity (GWth HHV) Figure 2-2. Energy transport capacity with H2 expressed in GW (thermal, HHV based) of different nominal pipe sizes
(schedule XS) at different pressures. Reference conditions are assumed at a temperature of 10 deg. C and a flow velocity of
20 m/s. Page 18/57 Page 18/57 2.2 Flow velocity ratio In the previous, it has been discussed that the energy transport capacity of a pipeline is dependent
on: e previous, it has been discussed that the energy transport capacity of a pipeline is dependent -
Pipeline size -
Operating pressure -
Energy carrier (natural gas, hydrogen, blends thereof, etc) -
Energy carrier (natural gas, hydrogen, blends thereof, etc) The difference in flow velocity for two energy carriers to transport the same amount of energy can
be obtained from (eq. 1), resulting in: 𝑈1
𝑈2
= 𝐻𝐻𝑉2
𝐻𝐻𝑉1
𝜌2
𝜌1
(eq. 3) (eq. 3) where 𝜌 is the density of the fluid [kg/m³] at a given condition given by its pressure and temperature. where 𝜌 is the density of the fluid [kg/m³] at a given condition given by its pressure and temperature. The flow velocity ratio needed to substitute G-gas by hydrogen and still transport the same amount
of energy is given in Figure 2-3. Whereas the often quoted ratio of 3 is a good nominal rule of thumb,
due to real-gas effects (the compressibility factor 𝑧 given in (eq. 2)), this value can vary between ~ 3.4
for high pressure conditions and 2.7-2.8 for the RNB systems. 2.8
2.8
2.8
2.9
2.9
2.9
3
3
3
3
3.1
3.1
3.1
3.2
3.2
3.3
3.3
3.4
3.5
Flow velocity ratio (H2/G-gas)
Pressure [bara]
Temperature [deg. C]
0
10
20
30
40
50
60
70
80
10
20
30
40
50
60
70
80
90 Figure 2-3. Flow velocity ratio between hydrogen and G-gas to obtain the same amount energy transport capacity (HHV-
based). Dashed lines separate different regions of the energy transport system: high pressure and high temperature
represent compressor discharge condition; high pressure and low temperature represent transport pipeline inlet conditions;
intermediate pressures represent the regional transport system (RTL), and pressures below 8 bar(g) represent the RNB
systems. 2.8
2.8
2.8
2.9
2.9
2.9
3
3
3
3
3.1
3.1
3.1
3.2
3.2
3.3
3.3
3.4
3.5
Flow velocity ratio (H2/G-gas)
Pressure [bara]
Temperature [deg. C]
0
10
20
30
40
50
60
70
80
10
20
30
40
50
60
70
80
90 Flow velocity ratio (H2/G-gas) Figure 2-3. Flow velocity ratio between hydrogen and G-gas to obtain the same amount energy transport capacity (HHV-
based). Dashed lines separate different regions of the energy transport system: high pressure and high temperature
represent compressor discharge condition; high pressure and low temperature represent transport pipeline inlet conditions;
intermediate pressures represent the regional transport system (RTL), and pressures below 8 bar(g) represent the RNB
systems. Page 19/57 Page 19/57 2.3 Pressure drop p
The fluid flow through a pipeline is opposed by friction forces at the walls. The energy spent in
overcoming this resistance results in pressure losses. The pressure gradient 𝜕𝑃/𝜕𝑥 at a particular
axial location 𝑥 of a (horizontal) pipeline is given by: (eq. 4)
∂𝑃
𝜕𝑥= 𝑓 1
2 𝜌 𝑈2 1
𝐼𝐷 (eq. 4) In which 𝑓 is the friction factor [-], which is a function of Reynolds number and sand grain roughness
(a metric for the inner surface smoothness), i.e. 𝑓= 𝑓(𝑅𝑒, 𝜖
𝐼𝐷) . In the absence of heat transfer
through the pipe walls, a reduction in fluid density is experienced which in turn makes the flow
velocity increase, creating a larger pressure gradient. Therefore, the pressure losses are not constant
throughout the length of the pipeline. Though exact solutions exist for different sets of assumptions,
these eventually need to be solved numerically. Currently, the most convenient way to capture all
physics involved is by means of one-dimensional hydraulic simulations. In which 𝑓 is the friction factor [-], which is a function of Reynolds number and sand grain roughness
(a metric for the inner surface smoothness), i.e. 𝑓= 𝑓(𝑅𝑒, 𝜖
𝐼𝐷) . In the absence of heat transfer
through the pipe walls, a reduction in fluid density is experienced which in turn makes the flow
velocity increase, creating a larger pressure gradient. Therefore, the pressure losses are not constant
throughout the length of the pipeline. Though exact solutions exist for different sets of assumptions,
these eventually need to be solved numerically. Currently, the most convenient way to capture all
physics involved is by means of one-dimensional hydraulic simulations. In the simplest scenario of negligible pressure drop compared to the pipeline operating pressure, no
heat transfer, and sufficiently high Reynolds number, (eq. 4) can be rewritten to yield the pressure
losses Δ𝑃 [Pa] from: (eq. 5)
Δ𝑃= 𝑓 1
2 𝜌 𝑈2 Δ𝑥
𝐼𝐷 (eq. 5) In which 𝑓 is the friction factor [-] and Δ𝑥 is the pipeline length [m]. In which 𝑓 is the friction factor [-] and Δ𝑥 is the pipeline length [m]. 2.3 Pressure drop 2.3.1 Hydrogen vs G-gas When (pure) hydrogen is compared to natural gas in terms of pressure drop only, the followin ansport parameters can be fixed to establish the comparison: -
Similar pressure and temperature (𝑃, 𝑇) -
Similar pressure and temperature (𝑃, 𝑇) -
Similar pipe and surface quality/condition (𝐼𝐷, ϵ) Similar pipe and surface quality/condition (𝐼𝐷, ϵ) -
Same energy transport rate (q̇ ) -
Same energy transport rate (q̇ ) -
Same energy transport rate (q̇ ) In this scenario, the pressure drop difference between hydrogen and natural gas (G-gas) depends on
the difference in Reynolds number and dynamic pressure ( 1
2 𝜌 𝑈2). Based on (eq. 3), for two fluids
used to transport energy under the assumptions mentioned above, the ratio of Reynolds number is
given by: (eq. 6)
𝑅𝑒1
𝑅𝑒2
= 𝜇2
𝜇1
𝐻𝐻𝑉2
𝐻𝐻𝑉1 (eq. 6) with 𝜇 the dynamic viscosity [kg/m s]. The ratio of dynamic pressure is given by: with 𝜇 the dynamic viscosity [kg/m s]. The ratio of dynamic pressure is given by: (eq. 7)
1
2 𝜌1 𝑈1
2
1
2 𝜌2 𝑈2
2 = (𝐻𝐻𝑉2
𝐻𝐻𝑉1
)
2
(𝜌2
𝜌1
) (eq. 7) Page 20/57 WP1E – Impact of high speed hydrogen
flow on system integrity and noise
D1E.1 – WP1E Report The results for both ratios are given in Figure 2-4 and Figure 2-5. It is observed that the Reynolds
number attained in hydrogen flow is 40-50% that of G-gas under the conditions given above,
whereas the dynamic pressure is roughly the same. This means that in the limit in which the
Reynolds number is high enough to not matter (constant friction factor), the pressure drop
experienced in each scenario is approximately the same. Whether this limits applies is more likely to
occur in the HTL part of the gas transport system due to its higher pressure, see Figure 2-6. The
range of Reynolds number for HTL typical conditions is high enough, such that the friction factor is
not altered when service is switched to hydrogen (at flow speeds corresponding to transporting the
same amount of energy). However, the same does not apply to the RNB system. Due to the Reynolds
number ratio also shown in Figure 2-4, an actual increase in friction factor is expected. That would
mean at these low Reynolds numbers, the pressure drop may increase. An exception to this would
still be possible if the pipes contained dust and sand throughout the length of the system. In such
case, the region in which the friction factor is dominated by the surface quality occurs at a lower
Reynolds number. This exception is not expected. 0.4
0.4
0.4
0.41
0.41
0.41
0.42
0.42
0.42
0.43
0.43
0.43
0.44
0.44
0.44
0.45
0.45
0.45
0.46
0.46
0.46
0.47
0.47
0.48
0.49
Reynolds number ratio (H2/G-gas)
Pressure [bara]
Temperature [deg. C]
0
10
20
30
40
50
60
70
80
10
20
30
40
50
60
70
80
90 Figure 2-4. Reynolds number ratio between hydrogen and natural gas at equal operating conditions. 0.4
0.4
0.4
0.41
0.41
0.41
0.42
0.42
0.42
0.43
0.43
0.43
0.44
0.44
0.44
0.45
0.45
0.45
0.46
0.46
0.46
0.47
0.47
0.48
0.49
Reynolds number ratio (H2/G-gas)
Pressure [bara]
Temperature [deg. C]
0
10
20
30
40
50
60
70
80
10
20
30
40
50
60
70
80
90 Figure 2-4. Reynolds number ratio between hydrogen and natural gas at equal operating conditions. Page 21/57 Page 21/57 WP1E – Impact of high speed hydrogen
flow on system integrity and noise
D1E.1 – WP1E Report flow on system integrity and noise
D1E.1 – WP1E Report
Figure 2-5. Dynamic pressure ratio between hydrogen and natural gas at equal operating conditions. Figure 2-6. Friction factor as a function of Reynolds number for natural gas and hydrogen for HTL (> 40 bar(g), DN900)
RNB typical conditions (<8 bar(g), DN200). 0.85
0.85
0.85
0.9
0.9
0.9
0.9
0.95
0.95
1
1
1.05
Dynamic Pressure ratio (H2/G-gas)
Pressure [bara]
Temperature [deg. C]
0
10
20
30
40
50
60
70
80
10
20
30
40
50
60
70
80
90
10
5
10
6
10
7
10
8
10
9
0.007
0.009
0.011
0.013
0.015
0.017
0.019
0.021
0.023
0.025
0.027
0.029
Reynolds number [-]
Friction factor [-]
Normal Pipe (low bound)
Normal Pipe (high bound)
HTL H2 typical (DN900)
HTL G-gas typical (DN900)
RNB H2 high pressure (DN200)
RNB G-gas high pressure (DN200) D1E.1 – WP1E Report
Figure 2-5. Dynamic pressure ratio between hydrogen and natural gas at equal operating conditions. 0.85
0.85
0.85
0.9
0.9
0.9
0.9
0.95
0.95
1
1
1.05
Dynamic Pressure ratio (H2/G-gas)
Pressure [bara]
Temperature [deg. C]
0
10
20
30
40
50
60
70
80
10
20
30
40
50
60
70
80
90 Dynamic Pressure ratio (H2/G-gas) 0.85
0.85
0.85
0.9
0.9
0.9
0.9
0.95
0.95
1
1
1.05
Dynamic Pressure ratio (H2/G-gas)
Pressure [bara]
Temperature [deg. C]
0
10
20
30
40
50
60
70
80
10
20
30
40
50
60
70
80
90 Figure 2-5. Dynamic pressure ratio between hydrogen and natural gas at equal operating conditions. Figure 2-6. Friction factor as a function of Reynolds number for natural gas and hydrogen for HTL (> 40 bar(g), DN900) and
RNB typical conditions (<8 bar(g), DN200). 10
5
10
6
10
7
10
8
10
9
0.007
0.009
0.011
0.013
0.015
0.017
0.019
0.021
0.023
0.025
0.027
0.029
Reynolds number [-]
Friction factor [-]
Normal Pipe (low bound)
Normal Pipe (high bound)
HTL H2 typical (DN900)
HTL G-gas typical (DN900)
RNB H2 high pressure (DN200)
RNB G-gas high pressure (DN200) Figure 2-6. Friction factor as a function of Reynolds number for natural gas and hydrogen for HTL (> 40 bar(g), DN900) and
RNB typical conditions (<8 bar(g), DN200). 10
5
10
6
10
7
10
8
10
9
0.007
0.009
0.011
0.013
0.015
0.017
0.019
0.021
0.023
0.025
0.027
0.029
Reynolds number [-]
Friction factor [-]
Normal Pipe (low bound)
Normal Pipe (high bound)
HTL H2 typical (DN900)
HTL G-gas typical (DN900)
RNB H2 high pressure (DN200)
RNB G-gas high pressure (DN200) Normal Pipe (low bound)
Normal Pipe (high bound)
HTL H2 typical (DN900)
HTL G-gas typical (DN900)
RNB H2 high pressure (DN200)
RNB G-gas high pressure (DN200 Reynolds number [-] Figure 2-6. Friction factor as a function of Reynolds number for natural gas and hydrogen for HTL (> 40 bar(g), DN900) and
RNB typical conditions (<8 bar(g), DN200). y
[ ] Page 22/57 WP1E – Impact of high speed hydrogen
flow on system integrity and noise
D1E.1 – WP1E Report WP1E – Impact of high speed hydrogen
flow on system integrity and noise
D1E.1 – WP1E Report 3.1 Intrusive equipment in natural gas transport systems In process equipment and fluid transport systems, certain instrumentation needs to be in direct
contact with the process medium, penetrating well into the bore of pipes. Examples of such
instruments are for instance temperature gauges (thermowells), erosion probes as used in the
upstream oil and gas industry, or V-cone flow meters. For gas transport systems, thermowells are the
most common piece of equipment that penetrates into the flow. A potential risk for fatigue failure
exists as a result of a coincidence between the natural frequency of the device and the vortex
shedding frequency of the flow around the device. Vibrations in such condition can create large cyclic
stresses near the root of the thermowell. When a thermowell fails, it can eventually be dislodged
from its root and travel downstream in the pipe. The eventual damage that can unfold could thus be
serious. The basic mechanism is analogous to large harmonic oscillations sometimes observed in road
lighting masts in windy days. Figure 3-1. Left: fundamental mechanism for flow-induced vibrations; right: illustration of a thermowell undergoing
harmonic oscillations (colour represents displacement from equilibrium position) as a result of a coincidence between vortex
shedding around the stem of the device and its mechanical natural frequency. Figure 3-1. Left: fundamental mechanism for flow-induced vibrations; right: illustration of a thermowell undergoing
harmonic oscillations (colour represents displacement from equilibrium position) as a result of a coincidence between vortex
shedding around the stem of the device and its mechanical natural frequency. 2.3.1.1
Examples To better understand the discussion presented above for practical situations, a number of examples
is offered in Table 2-1. Examples correspond to a transmission pipeline of the HTL system, the HP
segment of an RNB system and the LP segment of an RNB system close to domestic users. A fourth
case for the configuration near domestic users is added to understand the effect of pipes with more
solid contamination or materials with worse surface qualities. In these examples, the general picture
is that the pressure losses are very similar when comparing natural gas and hydrogen at similar
energy rates, as was expected from examination of Figure 2-5. In general, pressure drop is in favour
of H2 when the velocity ratio tends to be less than 3. In the case of clean pipes whose friction factor is
not dominated by the surface quality (example 3), hydrogen has slightly larger losses. This is due to
its reduced Reynolds number compared to G-gas, which increases the friction factor. This confirms
earlier findings in references [8] [14]. From a pipeline capacity point of view and disregarding at this stage other potentially limiting factors
(as discussed in further chapters of this report), the same energy rate can be transported with
hydrogen as currently done with natural (G-)gas. 2-1. Pressure drop gradients for different configurations with G-gas and hydrogen. The flow velocity for hydrogen is
ed from the values depicted in Figure 2-3. Parameter
G-gas
H2
G-gas
H2
G-gas
H2
G-gas
H2
Inner diameter [mm]
1200
1200
200
200
25
25
25
25
Surface roughness [m]
50
50
20
20
20
20
100
100
Pressure [bar(g)]
80
80
8
8
0.1
0.1
0.1
0.1
Temperature [°C]
10
10
10
10
10
10
10
10
Flow velocity [m/s]
10
34
10
28
10
27.5
10
27.5
Density [kg/m³]
75.0
6.6
7.2
0.768
0.793
0.0856
0.793
0.0856
Viscosity [kg/m s]
1.36E-05 8.70E-06 1.15E-05 8.60E-06 1.13E-05 8.60E-06 1.13E-05 8.60E-06
Reynolds # [-]
6.62E+07 3.10E+07 1.25E+06 5.00E+05 1.75E+04 6.84E+03 1.75E+04 6.84E+03
Darcy friction factor [-]
0.0103
0.0103
0.0131
0.0143
0.0280
0.0352
0.0333
0.0388
Pressure drop [bar/km]
0.321
0.329
0.236
0.215
0.444
0.456
0.528
0.503 Page 23/57 3 Intrusive Equipment 3 Intrusive Equipment WP1E – Impact of high speed hydrogen
flow on system integrity and noise
D1E.1 – WP1E Report in which 𝑑𝑡ℎ is the tip outer diameter of the thermowell [m], and 𝑈 is the mean flow velocity in the
main line [m/s]. For all high Reynolds number applications in excess of 5 × 105, the Strouhal number
is 0.22. In the benchmark between natural gas and hydrogen, only the fluid and its intended velocity are
considered. It is assumed the thermowell design remains constant (re-use assumption) and thus all
its mechanical properties (both natural gas and hydrogen have no added mass influence at gas
transport conditions). Therefore, only (eq. 8) is necessary. 3.3 Benchmark between natural gas and hydrogen For a given thermowell, the vortex shedding frequency 𝑓𝑠 of hydrogen compared to that of natural
gas is directly the flow velocity ratio, as already given by (eq. 3) and Figure 2-3. If the mechanical
design of the thermowell is correctly sized to have mechanical natural frequencies well above the
maximum possible vortex shedding frequency with natural gas, the margin needs to be in excess of
~3 to still be compliant for hydrogen service (at similar energy transport rates). 4 Examples 3.4 Examples Gasunie and Netbeheer Nederland have facilitated the HyDelta consortium with the dimensions of
commonly encountered designs in the high-pressure Gas Transport System (GTS) as well as the
distribution (RNB) networks: Gasunie and Netbeheer Nederland have facilitated the HyDelta consortium with the dimensions of
commonly encountered designs in the high-pressure Gas Transport System (GTS) as well as the
distribution (RNB) networks: stribution (RNB) networks: -
Short (100 mm) and a long (160 mm) protection sheet used for a thermometer suitable for
service at maximum 80 bar(g), straight design. Labels A1 and A2. -
Short (90 mm) and long (140 mm) protection sheet used for a temperature sensor suitable
for service at maximum 80 bar(g), tapered design. Labels B1 and B2. -
Short (95 mm) and long (120 mm) thermowells for service at maximum 20 bar(g), straigh
design. Labels C1 and C2. The main dimensions of these thermowells as well as the results of the calculations are summarized
in Table 3-1. The main observation is that short and tapered designs, as expected, show lower risk
compared to long, straight designs. In these examples, A1, B1 and B2 could cope with hydrogen flow
in all cases equivalent to natural gas service; possibly A2 and C1 could as well depending on the
actual location; possibly C2 would need replacement unless it would be located at a point in the
distribution network where flow velocities are moderate. 3.2 Assessment of flow-induced vibration for thermowells The risk for this well-known failure mechanism can be assessed from two overlapping standards: the
AVIFF guidelines [15] and ASME PTC 19.3 TW-2016 [16]. Some thermowell designs address the risk by
incorporating vortex breakers, destroying the coherence of the vortex shedding mechanism and thus
eliminating the risk. However, most existing devices in the gas grid today feature standard designs
(straight, stepped or tapered). In the basic approach to evaluate the risk for flow-induced vibrations, the fluid vortex shedding
frequency around the thermowell and its mechanical natural frequency are calculated. The
thermowell is considered a flexible beam. Aerodynamic forces act transversally to the axis of the
thermowell: a fluctuating drag force is parallel to the flow, whereas a fluctuating lift force is
perpendicular to the flow. Drag forces are exerted with the twice the frequency of lift forces, but
they can be an order of magnitude weaker. A high risk is present when the vortex shedding
frequency at the maximum possible flow velocity is higher than mechanical natural frequencies of
the device, as that means that resonances can be excited during operation. The reader can refer to the ASME PTC 19.3 TW-2016 [16] for a full description of the equations to be
used. Here only the most important equation required to justify the benchmark between natural gas
and hydrogen is explained. The vortex shedding frequency 𝑓𝑠 [Hz] can be obtained from the
dimensionless Strouhal number 𝑆𝑟𝑠 [-] as follows: (eq. 8)
𝑆𝑟𝑠= 𝑓𝑠 𝑑𝑡ℎ
𝑈 (eq. 8) Page 24/57 4.1 Flow Induced Turbulence in natural gas transport systems The flow of natural gas is in most parts of the network turbulent by nature. When the velocity of a
fluid flow increases, the amplitude of stochastic fluctuations associated to the turbulence will
increase. Depending on the construction of the pipes in which the gas flows, these fluctuations may
eventually lead to vibrations. Especially at locations in which the direction of the flow change, such as
elbows and tee’s, the turbulent structures will more frequently organize themselves in particular
length scales and become more energetic, increasing the risk of flow induced vibration. It is usual to
understand pressure drop as a metric of the turbulent fluctuations appearing in the flow: the larger
the pressure drop, the more fluctuations arise. Because flow-induced turbulence depends strongly on the kinetic energy of the flow, issues are more
likely to occur in the high pressure system. For example, for G-gas at 0.1 bar(g) typical of the end of
the distribution network, the flow would need to flow in excess of 75 m/s to even have a small
chance to excite vibrations. At 60 bar(g), this number goes down to about 9 m/s, which is well within
the realistic operation of high-pressure assets. In general, though, flow induced vibrations due to
turbulence are not an issue in gas transport systems, as pipe supporting layouts are largely sufficient
to arrest any motion that such flow fluctuations may cause. 3.5 Conclusion Because of the ambitioned increase in flow velocity with hydrogen, the risk to encounter resonances
is larger, because the vortex shedding frequency will increase proportionally. Whether the risk
indeed exists has to be assessed in a case-by-case basis. In the examples analysed, replacement of
thermowells is required at speeds above 28 m/s for RNBs and above 38 m/s for GTS. Table 3-1. Summary of thermowell dimensions and resulting maximum allowable flow velocities following ref. [16]. Label
A1
A2
B1
B2
C1
C2
System
GTS
GTS
GTS
GTS
RNB
RNB
Shape
straight straight tapered tapered straight straight
Nominal length [mm]
100
160
90
140
95
120
Design pressure [bar(g)]
80
80
80
80
20
20
TW Tip diameter [mm]
13
13
9.7
13
8
8
Strouhal number
0.22
0.22
0.22
0.22
0.22
0.22
First mechanical natural frequency [Hz]
5025
1644
3351
1907
3153
1971
Maximum allowable flow velocity [m/s]
118.8
38.9
91.4
69.4
45.9
28.7 ble 3-1. Summary of thermowell dimensions and resulting maximum allowable flow velocities following ref. [16]. Page 25/57 WP1E – Impact of high speed hydrogen
flow on system integrity and noise
D1E.1 – WP1E Report 4 Flow Induced Turbulence 4.1 Flow Induced Turbulence in natural gas transport systems 4.2 Assessment of flow-induced turbulence Assessment of flow-induced turbulence The Energy Institute Guidelines for Avoidance of Vibration Induced Fatigue Failure [15] provide the
most common method to assess the risk of flow induced vibration. A score Likelihood of Failure LoF is
defined to assess the risk due to flow-induced turbulence: (eq. 9)
𝐿𝑜𝐹= 𝐹𝑉𝐹𝜌 𝑈2
𝐹𝑉 (eq. 9) where 𝐹𝑉𝐹 is the fluid viscosity factor, 𝜌 is the fluid density, 𝑈 is the mean flow velocity and 𝐹𝑉 is the
flow induced vibration factor. The fluid viscosity factor depends only on the fluid viscosity. The flow
induced vibration parameter depends only on the mechanical construction of the piping layout. where 𝐹𝑉𝐹 is the fluid viscosity factor, 𝜌 is the fluid density, 𝑈 is the mean flow velocity and 𝐹𝑉 is the
flow induced vibration factor. The fluid viscosity factor depends only on the fluid viscosity. The flow
induced vibration parameter depends only on the mechanical construction of the piping layout. 4.3 Benchmark between natural gas and hydrogen 4.3 Benchmark between natural gas and hydrogen Assuming that the mechanical construction of pipes will either be the exact same or similar in the
case of hydrogen service, and introducing the definition of the 𝐹𝑉𝐹, the 𝐿𝑜𝐹 ratio of two fluids
scales as follows: (eq. 10)
𝐿𝑜𝐹1
𝐿𝑜𝐹2
= √
𝜇1
𝜇2
𝜌1
𝜌2
𝑈1
2
𝑈2
2 (eq. 10) When hydrogen and natural gas (G-gas) are compared at equal energy rates and operational
conditions, the results shown in Figure 4-1 are obtained. It is observed that for all conditions
experienced in the Dutch natural gas transmission system, the risk for flow induced vibration due to
turbulence is lower in hydrogen service than with G-gas service. Page 26/57 WP1E – Impact of high speed hydrogen
flow on system integrity and noise
D1E.1 – WP1E Report p
g
p
y
g
flow on system integrity and noise
D1E.1 – WP1E Report
Figure 4-1. Ratio of LoF score obtained when hydrogen is compared to natural gas at similar energy transport capacities and
operating conditions. 0.72
0.72
0.72
0.74
0.74
0.74
0.74
0.76
0.76
0.76
0.78
0.78
0.8
0.82
LoF ratio (H2/G-gas)
Pressure [bara]
Temperature [deg. C]
0
10
20
30
40
50
60
70
80
10
20
30
40
50
60
70
80
90 0.72
0.72
0.72
0.74
0.74
0.74
0.74
0.76
0.76
0.76
0.78
0.78
0.8
0.82
LoF ratio (H2/G-gas)
Pressure [bara]
Temperature [deg. C]
0
10
20
30
40
50
60
70
80
10
20
30
40
50
60
70
80
90 LoF ratio (H2/G-gas) Figure 4-1. Ratio of LoF score obtained when hydrogen is compared to natural gas at similar energy transport capacities and
operating conditions. 4.4 Examples p
Two examples are given in Table 4-1 to illustrate the conclusions obtained in this chapter. It is
observed that the LoF scores are well below the first threshold level demanding any further attention
(LoF > 0.3). 4.5 Conclusion The risk for flow-induced turbulence in hydrogen service is lower even at significantly higher flow
velocities necessary to transport the same amount of energy. Since this mechanism is typically not an
issue in natural gas transport systems, it will remain so in hydrogen transport systems. ble 4-1. Examples of flow induced vibration risk calculation for the gas transport system, assuming medium-stiff pipe
yout and typical pipe wall thicknesses. Table 4-1. Examples of flow induced vibration risk calculation for the gas transport system, assuming medium-stiff pipe
layout and typical pipe wall thicknesses. Table 4-1. Examples of flow induced vibration risk calculation for the gas transport system, assuming medium-stiff pipe
layout and typical pipe wall thicknesses. GTS
RNB
G-Gas
H2
G-gas
H2
Pressure [bara]
60
60
1.1
1.1
Flow velocity [m/s]
20
64
20
55
Pipe diameter (DN)
900
900
100
100
FVF [-]
0.113
0.093
0.107
0.093
Kinetic Energy [kg/ m s²]
21800
20480
316
259
LoF [-]
0.097
0.075
0.004
0.003 GTS
RNB
G-Gas
H2
G-gas
H2
Pressure [bara]
60
60
1.1
1.1
Flow velocity [m/s]
20
64
20
55
Pipe diameter (DN)
900
900
100
100
FVF [-]
0.113
0.093
0.107
0.093
Kinetic Energy [kg/ m s²]
21800
20480
316
259
LoF [-]
0.097
0.075
0.004
0.003 Page 27/57 WP1E – Impact of high speed hydrogen
flow on system integrity and noise
D1E.1 – WP1E Report 5 Flow Induced Pulsations 5.1 Flow induced pulsations in natural gas transport systems Flow-induced pulsations (FIP) can arise as a result of a flow-acoustic interaction, typically when flow
passes by dead-leg side-branches. The interaction occurs if the frequency of the acoustic source
(shear layer instability) is similar to acoustic resonance frequencies of the piping. Severe vibrations
can develop if also mechanical natural frequencies of the pipe assembly coincide with this frequency. Sustained operation with such vibrations can lead to fatigue failure. Besides mechanical failures,
noise and flow metering errors can also be caused by high pulsation levels. Integrity risks due to flow
induced pulsations are only relevant in the assets of GTS, because high pressures are needed to
generate energetic enough forces to create damage. RNB systems are thus not affected by FIP risks. Figure 5-1 An interaction between flow instabilities and acoustic resonance can develop mechanical vibrations and
eventually fatigue failure. Figure 5-1 An interaction between flow instabilities and acoustic resonance can develop mechanical vibrations and
eventually fatigue failure. 5 Flow Induced Pulsations Once a resonance condition has been established, the eventual pulsation amplitude 𝑝’ is determined
by an energy balance between the amount of flow kinetic energy converted into acoustic energy, and
the dissipation of acoustic energy due to visco-thermal attenuation and radiation to the rest of the
pipe system. The conversion efficiency of the aeroacoustic source is denoted 𝐹, and the acoustic
attenuation 𝛼0 [1/m]. In that case, the eventual pulsation amplitude 𝑝′ [Pa] is: 𝑝′ = 𝜌𝑈2 ( 2 𝐹
𝛼0 𝐿𝑠𝑏
)
(eq. 13) (eq. 13) with 𝜌 the fluid density of the medium [kg/m³]. with 𝜌 the fluid density of the medium [kg/m³]. In order to be able to predict flow-induced pulsations, it is essential to make appropriate choices for
the Strouhal number and the source strength, which are known to depend on many parameters,
such as Reynolds number, flow path-acoustic path configuration, edge rounding, distance to elbows
and even non-linear effects such as eventual pulsation amplitude (saturation). 5.3 Benchmark between natural gas and hydrogen 5.3 Benchmark between natural gas and hydrogen When benchmarking natural gas and hydrogen it is assumed that the pipework design is the same,
which is equivalent to a re-use scenario. In that case, the comparison between natural gas and
hydrogen concerns primarily two questions: -
Which acoustic resonances can develop with hydrogen? -
Which acoustic resonances can develop with hydrogen? -
Which acoustic resonances can develop with hydrogen? -
What pulsation levels can be expected? -
What pulsation levels can be expected? 5.2 Assessment of flow-induced pulsations For a given piping geometry, the source frequency depends on the flow velocity, whereas the
acoustic resonance frequencies depends on the speed of sound of the medium. Therefore, for a
given dead-leg geometry characterized by its length 𝐿𝑠𝑏 and its inner diameter 𝑑𝑠𝑏, resonant
conditions occur in the vicinity of particular Mach numbers that can be denoted resonance Mach
numbers 𝑀𝑟𝑒𝑠 (ratio between actual flow velocity and speed of sound). The different resonant
acoustic modes 𝑛 of a dead-leg side branch configuration then occur at: (eq. 11)
𝑀𝑛
𝑟𝑒𝑠= (2𝑛−1
4
) (𝑑𝑠𝑏
𝐿𝑠𝑏
) ( 1
𝑆𝑟) (eq. 11) where Sr is the Strouhal number of the vortex shedding mechanism at T-joints, defined as: (eq. 12)
𝑆𝑟= 𝑓 𝑑𝑆𝐵
𝑈 (eq. 12) in which 𝑓 is the central frequency of the vortex shedding [Hz], 𝑈 is the mean flow velocity in the
main line [m/s]. This equation is the same as (eq. 8) but using a different characteristic length. in which 𝑓 is the central frequency of the vortex shedding [Hz], 𝑈 is the mean flow velocity in the
main line [m/s]. This equation is the same as (eq. 8) but using a different characteristic length. Page 28/57 Page 28/57 5.3.1 Pulsation resonances As explained in the previous section, resonances develop around particular Mach numbers. The ratio
of Mach numbers between hydrogen and natural gas at equal operating conditions and energy
transport rates is given by: 𝑀1
𝑀2
= (𝑈1
𝑈2
) (𝑐2
𝑐1
)
(eq. 14) (eq. 14) With 𝑐 the speed of sound [m/s]. The flow velocity ratio has been shown in Figure 2-3 (eq. 3). The
ratio of speed of sound is given in Figure 5-2. Since the ratios are very similar, their effect
fundamentally cancels out: resonances are expected at similar energy rates fundamentally cancels out: resonances are expected at similar energy rates. Under equal energy rate and operating conditions, the Mach number for H2 service tends to be
slightly lower than for G-gas (see Figure 5-3). Since the Mach numbers associated to resonance are
independent of the fluid, resonance conditions with H2 will be reached at slightly higher velocities
than those of G-gas. A similar interpretation is that resonance can be found at somewhat longer
dead-legs when the same energy rate is transported. Despite the similarities, an important difference between hydrogen and natural gas is the absolute
frequency at which pulsations will develop, which will be approximately 3 times higher for hydrogen. For the same pipe geometry, resonances that could occur with natural gas at e.g. ~10 Hz, would
develop at ~ 30 Hz with hydrogen, increasing the chance of coincidence with mechanical natural
frequencies. Concluding: hydrogen duty is associated to a similar risk of FIP resonance, and the differences are
well within the typical uncertainties associated to the assumptions taken and the lock-in range of
flow-induced pulsations. Due to the shift in frequency, the chance for coincidence with mechanical
natural frequencies of the piping is increased. Page 29/57 WP1E – Impact of high speed hydrogen
flow on system integrity and noise
D1E.1 – WP1E Report D1E.1 – WP1E Report
Figure 5-2. Ratio of speed of sound of hydrogen vs G-gas at equal pressure and temperature. Figure 5-3. Ratio of Mach number of hydrogen and G-gas at equal energy transport rate. 3.2
3.2
3.2
3.25
3.25
3.25
3.3
3.3
3.3
3.3
3.35
3.35
3.4
3.4
Speed of Sound (H2/G-gas)
Pressure [bara]
Temperature [deg. 5.3.1 Pulsation resonances C]
0
10
20
30
40
50
60
70
80
10
20
30
40
50
60
70
80
90
0.88
0.88
0.88
0.9
0.9
0.9
0.9
0.92
0.92
0.92
0.92
0.94
0.94
0.94
0.96
0.96
0.98
0.98
1
1.02
Mach number ratio [-]
Pressure [bara]
Temperature [deg. C]
0
10
20
30
40
50
60
70
80
10
20
30
40
50
60
70
80
90 Figure 5-2. Ratio of speed of sound of hydrogen vs G-gas at equal pressure and temperature. 3.2
3.2
3.2
3.25
3.25
3.25
3.3
3.3
3.3
3.3
3.35
3.35
3.4
3.4
Speed of Sound (H2/G-gas)
Pressure [bara]
Temperature [deg. C]
0
10
20
30
40
50
60
70
80
10
20
30
40
50
60
70
80
90 Speed of Sound (H2/G-gas) 3.2
3.2
3.2
3.25
3.25
3.25
3.3
3.3
3.3
3.3
3.35
3.35
3.4
3.4
Speed of Sound (H2/G-gas)
Pressure [bara]
Temperature [deg. C]
0
10
20
30
40
50
60
70
80
10
20
30
40
50
60
70
80
90 Figure 5-2. Ratio of speed of sound of hydrogen vs G-gas at equal pressure and temperature. Figure 5-3. Ratio of Mach number of hydrogen and G-gas at equal energy transport rate. 0.88
0.88
0.88
0.9
0.9
0.9
0.9
0.92
0.92
0.92
0.92
0.94
0.94
0.94
0.96
0.96
0.98
0.98
1
1.02
Mach number ratio [-]
Pressure [bara]
Temperature [deg. C]
0
10
20
30
40
50
60
70
80
10
20
30
40
50
60
70
80
90 0.88
0.88
0.88
0.9
0.9
0.9
0.9
0.92
0.92
0.92
0.92
0.94
0.94
0.94
0.96
0.96
0.98
0.98
1
1.02
Mach number ratio [-]
Pressure [bara]
Temperature [deg. C]
0
10
20
30
40
50
60
70
80
10
20
30
40
50
60
70
80
90 Figure 5-3. Ratio of Mach number of hydrogen and G-gas at equal energy transport rate. Page 30/57 WP1E – Impact of high speed hydrogen
flow on system integrity and noise
D1E.1 – WP1E Report Figure 5-5. Ratio of pulsation levels between hydrogen and G-gas. 0.62
0.62
0.625
0.625
0.625
0.63
0.63
0.63
0.635
0.635
0.635
0.64
0.64
0.64
0.645
0.645
0.645
0.65
0.65
0.65
0.655
Pressure pulsation ratio, same resonance [-]
Pressure [bara]
Temperature [deg. C]
0
10
20
30
40
50
60
70
80
10
20
30
40
50
60
70
80
90 Figure 5-5. Ratio of pulsation levels between hydrogen and G-gas. 5.4.2 Case with hydrogen If it is assumed that hydrogen may flow through the same flow regulating station, the comparison
metrics shown in Table 5-1 are to be expected. In this example, it is observed that the same
resonance observed with G-gas would be observed with hydrogen, but at slightly larger energy
transport capacities. In such a case, the expected pulsation level would be significantly lower. However, the resonance would feature a much higher frequency (666 Hz) resulting in a larger chance
of coincidence with a mechanical resonance. In such case, the general conclusion is that the
perceived risk due to vibrations is larger. However, at such high frequencies, the eventual vibration
amplitudes are to a large extent dominated by the mechanical damping of the assembly, which is
extremely dependent on the design and condition of the assembly itself. 5.3.2 Pulsation amplitudes The flow-induced pulsation levels expected at resonances hit with hydrogen compared to those hit
with natural gas can be inferred from (eq. 13). The ratio between the levels is then found from: 𝑝1
′
𝑝2
′ =
(𝜌𝑈2)1
(𝜌𝑈2)2
(𝐹1
𝐹2
) (𝛼0,2
𝛼0,1
)
(eq. 15) (eq. 15) For the first term of (eq. 15), i.e. the ratio of kinetic energy or dynamic pressure (eq. 7) can be used. For the second term, when assuming that the piping configuration is the same and the Reynolds
number is high enough, then the dimensionless source strength 𝐹 is the same for hydrogen and G-
gas. Finally, the acoustic attenuation term can be found following: 𝛼0,1
𝛼0,2
= (𝐾1
𝐾2
) (𝑀1
𝑀2
) (𝑅𝑒2
𝑅𝑒1
)
1
2
(eq. 16) (eq. 16) Where 𝐾 is a factor connected to viscothermal acoustic losses: Where 𝐾 is a factor connected to viscothermal acoustic losses: Where 𝐾 is a factor connected to viscothermal acoustic losses: 𝐾= 1 + 𝛾∗−1
√Pr
(eq. 17) (eq. 17) with Pr the Prandtl number and 𝛾∗ the isentropic exponent of the fluid. with Pr the Prandtl number and 𝛾∗ the isentropic exponent of the fluid. The acoustic attenuation ratio between hydrogen and natural gas is shown in Figure 5-4. More
acoustic attenuation is expected in the case of hydrogen. The benefit of larger attenuation values
with hydrogen is also observed in the ratio of eventual pulsation levels, shown in Figure 5-5. Pulsation levels about 40% lower can be expected compared to natural gas when a resonance
develops. 1.53
1.55
1.6
1.6
1.6
1.62
1.62
1.62
1.65
1.65
1.65
1.7
1.7
1.7
1.71
1.71
1.71
1.72
1.72
1.72
1.73
1.73
1.73
1.74
1.74
1.74
1.74
Alpha ratio, same resonance [-]
Pressure [bara]
Temperature [deg. C]
0
10
20
30
40
50
60
70
80
10
20
30
40
50
60
70
80
90 Page 31/57
Figure 5-4. Ratio of acoustic attenuation between hydrogen and G-gas. 1.53
1.55
1.6
1.6
1.6
1.62
1.62
1.62
1.65
1.65
1.65
1.7
1.7
1.7
1.71
1.71
1.71
1.72
1.72
1.72
1.73
1.73
1.73
1.74
1.74
1.74
1.74
Alpha ratio, same resonance [-]
Pressure [bara]
Temperature [deg. C]
0
10
20
30
40
50
60
70
80
10
20
30
40
50
60
70
80
90 Figure 5-4. Ratio of acoustic attenuation between hydrogen and G-gas. Page 31/57 Page 31/57 5.4.1 Case with natural gas 5.4.1 Case with natural gas An example applied to a flow regulating station that suffered from severe flow-induced pulsations is
offered for illustration. The geometry of the manifold is shown in Figure 5-6. The natural gas flow
entered the pressure reduction street from the 20” inflow header at 60 bar(g). The flow speed in the
6” street was increased as a result of the 6”×4” reducers leading to the pressure regulator. Two twin
2” dead-legs meant for venting are tied into the 4” segment. The gas velocity in the 4” segment
varied between no flow in case the regulator valve was closed, and 56.6 m/s, the maximum allowable
flow through the regulator valve. 5.5 Conclusion Page 32/57
5.5 Conclusion
When comparing hydrogen with G-gas transporting the same energy rate through the same pipe
assemblies at the same operating conditions, the following is concluded:
-
Acoustic resonances will develop at similar energy rates When comparing hydrogen with G-gas transporting the same energy rate through the same pipe
assemblies at the same operating conditions, the following is concluded:
-
Acoustic resonances will develop at similar energy rates When comparing hydrogen with G-gas transporting the same energy rate through the same pipe
assemblies at the same operating conditions, the following is concluded: -
Acoustic resonances will develop at similar energy rates Page 32/57 WP1E – Impact of high speed hydrogen
flow on system integrity and noise
D1E.1 – WP1E Report
-
Acoustic resonances will develop at ~ 3 times higher frequencies, increasing the chance to
coincide with mechanical natural frequencies
R
l i
l
i
l
l
ill b l
i h h d
i
l 40% -
Acoustic resonances will develop at ~ 3 times higher frequencies, increasing the chance t -
Acoustic resonances will develop at ~ 3 times higher frequencies, increasing the cha
coincide with mechanical natural frequencies Acoustic resonances will develop at 3 times higher frequencies, increasing the chance to
coincide with mechanical natural frequencies coincide with mechanical natural frequencies -
Resulting pulsation levels will be lower with hydrogen, approximately 40%. Two opposing effects arise: on the one hand the expectation of lower pulsation levels; on the other,
a higher risk of coincidence between acoustic pulsations and mechanical natural frequencies. The net
outcome of those effects can only be judged on a case-by-case basis, as high frequency vibrations
largely depend on the mechanical damping of the assembly. To better understand whether the risk
tends to increase or to decrease in general, 3D finite element analysis of a number of typical
assemblies is recommended, whereby the modelled pipework is excited by high frequency pulsations
and the cyclic stress levels are computed at critical spots more prone to failure due to stress
intensification. Figure 5-6. Schematic of a pressure reduction manifold with a double small side-branch configuration that showed severe
flow-induced pulsations. Figure 5-6. Schematic of a pressure reduction manifold with a double small side-branch configuration that showed severe
flow-induced pulsations. Table 5-1. Comparison between G-gas and hydrogen for a flow-induced pulsation. Property
G-gas
Hydrogen Notes
Pressure [bar(g)]
60
60
Operation assumed at same pressure
Temperature [°C]
10
10
Operation assumed at same temperature
Gas density [kg/m³]
54.5
5.0
Compressibility factor z for G-gas ~ 0.88
Speed of sound [m/s]
395
1335
See Figure 5-2
Flow velocity at resonance [m/s]
41.0
138.6
Calculated from resonance Mach number
Mach number at resonance [-]
0.10
0.10
Resonances occur at same resonance Mach
numbers
Resonance frequency [Hz]
197
666
Pulsation levels [mbar rms]
1200
763
See Figure 5-5. Energy rate at resonance
47.8
49.9
Hydrogen slightly larger energy transport
capacity for same resonant conditions Page 33/57 6.1 Acoustics-Induced Vibration in natural gas transport systems Acoustics-Induced Vibration (AIV) concerns the failure mechanism by which a high-frequency
broadband spectrum of noise rapidly leads pipework to fatigue failure. Typical sources of AIV in
natural gas transmission systems are elements in which pressure is suddenly reduced: relief or blow-
down valves, control valves and restriction orifices. The generated acoustic spectrum has a typical
broadband character (‘roaring’ at lower frequency range, ‘screaming’ at the higher frequency range). The noise is characterized by its amplitude and by the peak frequency, see Figure 6-1. Noise
generated by pressure let-down devices may lead to integrity issues. Incidents have been reported in
literature but are relatively rare. Areas at increased risk are: •
Configurations with high in-line noise levels. •
Lines with large pipe diameter and small wall thickness. •
Configurations with welded discontinuities, such as small branch connection to a parent pipe,
T-joints and welded pipe shoes. Circumferential welding, for example at elbows and flanges is
not considered a critical discontinuity •
Configurations with welded discontinuities, such as small branch connection to a parent pipe,
T-joints and welded pipe shoes. Circumferential welding, for example at elbows and flanges is
not considered a critical discontinuity Besides fatigue failure, noise radiation (potentially even metering errors) is also a consequence of
this phenomenon. This is discussed in chapter 7. Besides fatigue failure, noise radiation (potentially even metering errors) is also a consequence of
this phenomenon. This is discussed in chapter 7. Figure 6-1. Typical frequency spectrum of noise due to pressure reduction devices: broadband spectrum with a broad peak
around the centre frequency (~1.5 kHz in this example). Figure 6-1. Typical frequency spectrum of noise due to pressure reduction devices: broadband spectrum with a broad peak
around the centre frequency (~1.5 kHz in this example). 6 Acoustics Induced Vibration The first standard used to quantify the severity of pressure reduction devices is the Energy Ins The first standard used to quantify the severity of pressure reduction devices is the Energy Institute
“Guidelines for Avoidance of Vibration Induced Fatigue Failure” [15]. In these guidelines, the
broadband noise caused by valves and orifices is referred to as “High-Frequency Acoustic Excitation”. The relevant section is technical module T2.7. The prediction models in [15] were developed based
on empirical work conducted in the 70s, for failing and non-failing systems. Therefore it provides a
metric for the risk of failure, and it should not be interpreted as an actual, numerical prediction of
the expected noise levels inside the pipe. However, the correct scaling parameters are included. The
power level of the source is quantified as: “Guidelines for Avoidance of Vibration Induced Fatigue Failure” [15]. In these guidelines, the
broadband noise caused by valves and orifices is referred to as “High-Frequency Acoustic Excitation”. The relevant section is technical module T2.7. The prediction models in [15] were developed based
on empirical work conducted in the 70s, for failing and non-failing systems. Therefore it provides a
metric for the risk of failure, and it should not be interpreted as an actual, numerical prediction of
the expected noise levels inside the pipe. However, the correct scaling parameters are included. The
power level of the source is quantified as: (eq. 18)
𝑃𝑊𝐿= 10 log10 [(𝑃0 −𝑃2
𝑃0
)
3.6
𝑚̇ 2 ( 𝑇0
𝑀𝑊
)
1.2
] + 126.1 + 𝑆𝐹𝐹 (eq. 18)
𝑃𝑊𝐿= 10 log10 [(𝑃0 −𝑃2
𝑃0
)
3.6
𝑚̇ 2 ( 𝑇0
𝑀𝑊
)
1.2
] + 126.1 + 𝑆𝐹𝐹 (eq. 18) The source power level 𝑃𝑊𝐿 is a function of pressure differential (𝑃0 −𝑃2)/𝑃0, mass flow 𝑚̇ , inlet
temperature 𝑇0 and molecular weight 𝑀𝑊. The factor 𝑆𝐹𝐹 is a penalty of 6 dB in case of choking
conditions. This equation indicates that the pressure differential and the mass flow are the dominant
parameters; larger pressure differential and larger mass flow lead to increased noise levels. The source power level 𝑃𝑊𝐿 is a function of pressure differential (𝑃0 −𝑃2)/𝑃0, mass flow 𝑚̇ , inlet
temperature 𝑇0 and molecular weight 𝑀𝑊. The factor 𝑆𝐹𝐹 is a penalty of 6 dB in case of choking
conditions. This equation indicates that the pressure differential and the mass flow are the dominant
parameters; larger pressure differential and larger mass flow lead to increased noise levels. 6.2 Assessment of Acoustics-Induced Vibration Accurate quantitative prediction of amplitude and frequency of the acoustic source spectrum
requires a very complex analysis. This is due to the physical phenomena occurring in case of pressure
reduction (gas dynamics with choking flow conditions, complex fluid path, interaction with complex
geometric structure of the valve cage, high-frequency 3D propagation of noise through pipe system
and through pipe wall, details of the installation etc). Detailed prediction methods are still topic of
academic research. To enable robust assessment of the risk and effective engineering, simplified
industry standards have been developed in the past decades [15], [17], [18]. Page 34/57 Page 34/57 6.3 Benchmark between natural gas and hydrogen 6.4 Examples
In absolute terms, the most critical areas are the large-capacity blow-down configurations in the HP
network. No reported examples to fatigue failures in the LP could be found in literature (for
operation with natural gas). When an increased risk for failure is determined, a typical follow-up
analysis considers coincidence between transversal acoustic resonances and structural shell modes
of the pipes. This coincidence is illustrated in Figure 6-3 depicting modes with 11 nodal diameters, i.e. 11 wave characteristic lengths fit the perimeter of the pipe Figure 6-2. Comparison of noise source strength (choking condition). Figure 6-2. Comparison of noise source strength (choking condition). 6.3 Benchmark between natural gas and hydrogen The basis of the benchmark is again that the same energy transport capacity is realised with
hydrogen as with natural gas. This scaling approach is considered appropriate for continuous, in-line
pressure reduction items (control valves in M&R stations, GOSs, district stations and transfer
stations). For the incidental pressure reduction items (blow-down facility) the assumption of ‘equal
energy flux’ is less obvious. However, assuming a re-use of blow-down valves and orifice plates, the
same ratio (1:3) for the mass flows is expected. To arrive at the incremental effect of hydrogen (subscript 1), compared to natural gas (subscript 2),
the following relation is found for choking flow. This is obtained by assuming equal pressure ratios
and the same valve internals, such that the difference is mostly due to critical (sonic) mass flow ratio: (eq. 19)
𝑃𝑊𝐿1 −𝑃𝑊𝐿2 = 10 𝑙𝑜𝑔10
(
(𝜌1
𝜌2
)
(
2
𝛾1 + 1)
𝛾1+1
𝛾1−1
(
2
𝛾2 + 1)
𝛾2+1
𝛾2−1
(𝑀𝑊,2
𝑀𝑊,1
)
1.2 𝛾1
𝛾2
) (eq. 19) in which 𝜌 is the density and 𝛾 the ratio of specific heats. If non-choking conditions exist, the
following relation is found, which follows the mass flow ratio to keep the same energy transport rate,
assuming again the same subcritical pressure jump : in which 𝜌 is the density and 𝛾 the ratio of specific heats. If non-choking conditions exist, the
following relation is found, which follows the mass flow ratio to keep the same energy transport rate,
assuming again the same subcritical pressure jump : (eq. 20)
𝑃𝑊𝐿1 −𝑃𝑊𝐿2 = 10 log10 ((𝐻𝐻𝑉2
𝐻𝐻𝑉1
)
2
(𝑀𝑊,2
𝑀𝑊,1
)
1.2
) (eq. 20) Figure 6-2 illustrates these equations for various pressure and temperature conditions. The following
observations are made, comparing hydrogen with natural gas: Figure 6-2 illustrates these equations for various pressure and temperature conditions. The following
observations are made, comparing hydrogen with natural gas: •
For non-choking conditions, an increase of 2-3 dB regardless of the operating conditions at
which the benchmark is made. •
For choking conditions, a small increase 0-2 dB for high-pressure applications (40-80 bar) •
For choking conditions, an increase 2 dB for low-pressure applications (< 8 bar) Page 35/57 WP1E – Impact of high speed hydrogen
flow on system integrity and noise
D1E.1 – WP1E Report Figure 6-2. Comparison of noise source strength (choking condition). 6.4 Examples 0
1
2
3
4
5
6
7
8
0
500
1000
1500
2000
2500
3000
Nodal diameters
Frequency [Hz]
(m,n)=(0,0)
(m,n)=(0,1)
(m,n)=(0,2)
(m,n)=(0,3)
(m,n)=(0,4)
(m,n)=(0,5)
i=0
i=1
(m,n)=(1,0)
(m,n)=(1,1)
(m,n)=(1,2)
(m,n)=(1,3)
(m,n)=(1,4)
(m,n)=(1,5)
(m,n)=(2,0)
(m,n)=(2,1)
(m,n)=(2,2)
(m,n)=(2,3)
(m,n)=(2,4)
(m,n)=(2,5)
i=2
(m,n)=(3,0)
(m,n)=(3,1)
(m,n)=(3,2)
(m,n)=(3,3)
(m,n)=(3,4)
(m,n)=(3,5)
i=3
(m,n)=(4,0)
(m,n)=(4,1)
(m,n)=(4,2)
(m,n)=(4,3)
(m,n)=(4,4)
(m,n)=(4,5)
i=4
(m,n)=(5,0)
(m,n)=(5,1)
(m,n)=(5,2)
(m,n)=(5,3)
(m,n)=(5,4)
(m,n)=(5,5)
i=5
(m,n)=(6,0)
(m,n)=(6,1)
(m,n)=(6,2)
(m,n)=(6,3)
(m,n)=(6,4)
i=6
(m,n)=(7,0)
(m,n)=(7,1)
(m,n)=(7,2)
(m,n)=(7,3)
(m,n)=(7,4)
i=7
(m,n)=(8,0)
(m,n)=(8,1)
(m,n)=(8,2)
(m,n)=(8,3)
i=8
0
1
2
3
4
5
6
7
8
0
500
1000
1500
2000
2500
3000
Nodal diameters
Frequency [Hz]
(m,n)=(0,0)
(m,n)=(0,1)
i=0
i=1
(m,n)=(1,0)
(m,n)=(1,1)
(m,n)=(2,0)
(m,n)=(2,1)
i=2
(m,n)=(3,0)
i=3
(m,n)=(4,0)
i=4
(m,n)=(5,0)
i=5
i=6
i=7
i=8 WP1E – Impact of high speed hydrogen
flow on system integrity and noise
D1E.1 – WP1E Report
(m,n)=(2,1)
(
) (5 0) 0
1
2
3
4
5
6
7
8
0
500
1000
1500
2000
2500
3000
Nodal diameters
Frequency [Hz]
(m,n)=(0,0)
(m,n)=(0,1)
(m,n)=(0,2)
(m,n)=(0,3)
(m,n)=(0,4)
(m,n)=(0,5)
i=0
i=1
(m,n)=(1,0)
(m,n)=(1,1)
(m,n)=(1,2)
(m,n)=(1,3)
(m,n)=(1,4)
(m,n)=(1,5)
(m,n)=(2,0)
(m,n)=(2,1)
(m,n)=(2,2)
(m,n)=(2,3)
(m,n)=(2,4)
(m,n)=(2,5)
i=2
(m,n)=(3,0)
(m,n)=(3,1)
(m,n)=(3,2)
(m,n)=(3,3)
(m,n)=(3,4)
(m,n)=(3,5)
i=3
(m,n)=(4,0)
(m,n)=(4,1)
(m,n)=(4,2)
(m,n)=(4,3)
(m,n)=(4,4)
(
) (
)
i=4
(m,n)=(5,0)
(m,n)=(5,1)
(m,n)=(5,2)
(m,n)=(5,3)
(m,n)=(5,4)
i=5
(m,n)=(6,0)
(m,n)=(6,1)
(m,n)=(6,2)
(m,n)=(6,3)
(m,n)=(6,4)
i=6
(m,n)=(7,0)
(m,n)=(7,1)
(m,n)=(7,2)
(m,n)=(7,3)
i=7
(m,n)=(8,0)
(m,n)=(8,1)
(m,n)=(8,2)
(m,n)=(8,3)
i=8 0
1
2
3
4
5
6
7
8
0
500
1000
1500
2000
2500
3000
Nodal diameters
Frequency [Hz]
(m,n)=(0,0)
(m,n)=(0,1)
i=0
i=1
(m,n)=(1,0)
(m,n)=(1,1)
(m,n)=(2,0)
i=2
(m,n)=(3,0)
i=3
(m,n)=(4,0)
i=4
(
, ) ( , )
i=5
i=6
i=7
i=8 Frequency [Hz] Figure 6-4. Typical interference diagram for HP system (36” line, 80 bara) displaying the frequency at which different
resonance modes occur. Natural gas (left) and hydrogen (right). Blue dots are acoustic modes, red dots are structural
modes. Coincidence risks is more prominent for natural gas than for hydrogen. 0
1
2
3
4
5
6
7
8
0
1000
2000
3000
4000
5000
6000
Nodal diameters
Frequency [Hz]
(m,n)=(0,0)
(m,n)=(0,1)
(m,n)=(0,2)
(m,n)=(0,3)
(m,n)=(1,0)
(m,n)=(1,1)
(m,n)=(1,2)
(m,n)=(2,0)
(m,n)=(2,1)
(m,n)=(2,2)
i=2
(m,n)=(3,0)
(m,n)=(3,1)
i=3
(m,n)=(4,0)
(m,n)=(4,1)
i=4
(m,n)=(5,0)
(m,n)=(5,1)
i=5
(m,n)=(6,0)
i=6
(m,n)=(7,0)
i=7
(m,n)=(8 Figure 6-5. Typical interference diagram for LP system (8” line, 9 bara). Natural gas (left) and hydrogen (right). Blue dots are
acoustic modes, red dots are structural modes. Coincidence risks is more prominent for natural gas than for hydrogen. 6.4 Examples Coincidence risks is more prominent for natural gas than for hydrogen. Figure 6-5. Typical interference diagram for LP system (8” line, 9 bara). Natural gas (left) and hydrogen (right). Blue dots are
acoustic modes, red dots are structural modes. Coincidence risks is more prominent for natural gas than for hydrogen. 0
1
2
3
4
5
6
7
8
0
500
1000
1500
2000
2500
3000
Nodal diameters
Frequency [Hz]
(m,n)=(0,0)
(m,n)=(0,1)
(m,n)=(0,2)
(m,n)=(0,3)
(m,n)=(0,4)
(m,n)=(0,5)
i=0
i=1
(m,n)=(1,0)
(m,n)=(1,1)
(m,n)=(1,2)
(m,n)=(1,3)
(m,n)=(1,4)
(m,n)=(1,5)
(m,n)=(2,0)
(m,n)=(2,1)
(m,n)=(2,2)
(m,n)=(2,3)
(m,n)=(2,4)
(m,n)=(2,5)
i=2
(m,n)=(3,0)
(m,n)=(3,1)
(m,n)=(3,2)
(m,n)=(3,3)
(m,n)=(3,4)
(m,n)=(3,5)
i=3
(m,n)=(4,0)
(m,n)=(4,1)
(m,n)=(4,2)
(m,n)=(4,3)
(m,n)=(4,4)
(m,n)=(4,5)
i=4
(m,n)=(5,0)
(m,n)=(5,1)
(m,n)=(5,2)
(m,n)=(5,3)
(m,n)=(5,4)
(m,n)=(5,5)
i=5
(m,n)=(6,0)
(m,n)=(6,1)
(m,n)=(6,2)
(m,n)=(6,3)
(m,n)=(6,4)
i=6
(m,n)=(7,0)
(m,n)=(7,1)
(m,n)=(7,2)
(m,n)=(7,3)
(m,n)=(7,4)
i=7
(m,n)=(8,0)
(m,n)=(8,1)
(m,n)=(8,2)
(m,n)=(8,3)
i=8
0
1
2
3
4
5
6
7
8
0
500
1000
1500
2000
2500
3000
Nodal diameters
Frequency [Hz]
(m,n)=(0,0)
(m,n)=(0,1)
i=0
i=1
(m,n)=(1,0)
(m,n)=(1,1)
(m,n)=(2,0)
(m,n)=(2,1)
i=2
(m,n)=(3,0)
i=3
(m,n)=(4,0)
i=4
(m,n)=(5,0)
i=5
i=6
i=7
i=8
0
1
2
3
4
5
6
7
8
0
1000
2000
3000
4000
5000
6000
Nodal diameters
Frequency [Hz]
(m,n)=(0,0)
(m,n)=(0,1)
(m,n)=(0,2)
(m,n)=(0,3)
(m,n)=(1,0)
(m,n)=(1,1)
(m,n)=(1,2)
(m,n)=(2,0)
(m,n)=(2,1)
(m,n)=(2,2)
i=2
(m,n)=(3,0)
(m,n)=(3,1)
i=3
(m,n)=(4,0)
(m,n)=(4,1)
i=4
(m,n)=(5,0)
(m,n)=(5,1)
i=5
(m,n)=(6,0)
i=6
(m,n)=(7,0)
i=7
(m,n)=(8,0)
0
1
2
3
4
5
6
7
8
0
1000
2000
3000
4000
5000
6000
Nodal diameters
Frequency [Hz]
(m,n)=(0,0)
(m,n)=(1,0)
(m,n)=(2,0)
i=2
i=3
i=4
i=5
i=6
i=7 WP1E – Impact of high speed hydrogen
flow on system integrity and noise
D1E.1 – WP1E Report
Figure 6-4. Typical interference diagram for HP system (36” line, 80 bara) displaying the frequency at which different
resonance modes occur. Natural gas (left) and hydrogen (right). Blue dots are acoustic modes, red dots are structural
modes. Coincidence risks is more prominent for natural gas than for hydrogen. 6.4 Examples 0
1
2
3
4
5
6
7
8
0
1000
2000
3000
4000
5000
6000
Nodal diameters
Frequency [Hz]
(m,n)=(0,0)
(m,n)=(0,1)
(m,n)=(0,2)
(m,n)=(0,3)
(m,n)=(1,0)
(m,n)=(1,1)
(m,n)=(1,2)
(m,n)=(2,0)
(m,n)=(2,1)
(m,n)=(2,2)
i=2
(m,n)=(3,0)
(m,n)=(3,1)
i=3
(m,n)=(4,0)
(m,n)=(4,1)
i=4
(m,n)=(5,0)
(m,n)=(5,1)
i=5
(m,n)=(6,0)
i=6
(m,n)=(7,0)
i=7
(m,n)=(8,0)
0
1
2
3
4
5
6
7
8
0
1000
2000
3000
4000
5000
6000
Nodal diameters
Frequency [Hz]
(m,n)=(0,0)
(m,n)=(1,0)
(m,n)=(2,0)
i=2
i=3
i=4
i=5
i=6
i=7 0
1
2
3
4
5
6
7
8
0
1000
2000
3000
4000
5000
6000
Nodal diameters
Frequency [Hz]
(m,n)=(0,0)
(m,n)=(1,0)
(m,n)=(2,0)
i=2
i=3
i=4
i=5
i=6
i=7 Frequency [Hz] Figure 6-5. Typical interference diagram for LP system (8” line, 9 bara). Natural gas (left) and hydrogen (right). Blue dots are
acoustic modes, red dots are structural modes. Coincidence risks is more prominent for natural gas than for hydrogen. 6.4 Examples In absolute terms, the most critical areas are the large-capacity blow-down configurations in the HP
network. No reported examples to fatigue failures in the LP could be found in literature (for
operation with natural gas). When an increased risk for failure is determined, a typical follow-up
analysis considers coincidence between transversal acoustic resonances and structural shell modes
of the pipes. This coincidence is illustrated in Figure 6-3 depicting modes with 11 nodal diameters, i.e. 11 wave characteristic lengths fit the perimeter of the pipe. Two examples have been used for follow-up analysis of this coincidence. The first is a typical (steel)
36” (DN900) HP line of the GTS system; the second example is a typical (steel) 8” (DN200) of the HP
segment of an RNB system. The analysis is based on a comparison between frequency and mode
shape (represented by the number of nodal lines and nodal circles) of both the acoustic resonance
mode and the structural shell mode. The results for each example are respectively shown in Figure
6-4 and Figure 6-5 . It is observed that, in both cases, the separation acoustical transversal resonance
modes and the structural modes of the pipe wall increases with hydrogen compared to natural gas,
which reduces the chance for detrimental coincidence. This is due to the higher speed of sound of
hydrogen. Note that the acoustic modes shift to higher frequencies, due to the larger speed of sound
in hydrogen. The pipe structural resonance modes are primarily a property of the pipe wall and will
remain similar. In case of hydrogen, the chance that acoustic modes trigger pipe resonance modes
and lead to integrity issues on the branch connections is reduced. Figure 6-3 Example of coincidence between acoustic resonance mode and pipe resonance mode, featuring 11 nodal
diameters. Acoustic energy can be very efficienctly transfered into the vibration of the pipe wall. Figure 6-3 Example of coincidence between acoustic resonance mode and pipe resonance mode, featuring 11 nodal
diameters. Acoustic energy can be very efficienctly transfered into the vibration of the pipe wall. Page 36/57 Page 36/57 WP1E – Impact of high speed hydrogen
flow on system integrity and noise
D1E.1 – WP1E Report
Figure 6-4. Typical interference diagram for HP system (36” line, 80 bara) displaying the frequency at which different
resonance modes occur. Natural gas (left) and hydrogen (right). Blue dots are acoustic modes, red dots are structural
modes. 6.5 Conclusion At similar energy transport rates, hydrogen seems to have more potential for acoustics-induced
vibration (AIV) than natural gas. However, whether the increased levels in excitation energy
effectively lead to pipewall vibration seems more unlikely, due to the limited chance of coincidence
between acoustic resonant modes and structural pipe shell modes. Due to these opposing effects, it
is concluded that the risk on AIV remains similar to the case with natural gas. Known practices to
design and analyze the AIV phenomenon remain valid. In all pressurized parts of the network where safety relief valves are in place, it is recommended to
apply a screening (e.g. using [15]), in case of a transition to hydrogen. This will highlight areas with a
potential risk and allows for a systematic review of re-design options (control of flow rates,
replacement of orifice, mechanical modifications). It is recommended to analyze in detail the results of a test conducted in 2020 on a district station
[19]. Based on this analysis, the risks for fatigue failure in the LP network may be assessed in a more
generic way. Page 37/57 WP1E – Impact of high speed hydrogen
flow on system integrity and noise
D1E.1 – WP1E Report 7 Flow Induced Noise 7.1 Flow induced noise in natural gas transport systems 7.1 Flow induced noise in natural gas transport systems Natural gas transport systems need to be able to deliver gas without radiating too much noise to the
environment. Noise exposure to the working personnel and to the environment is a critical aspect of
the license-to-operate. Excessive noise emission is avoided, even if they are the result of incidental
operations (e.g. venting). Whereas concerns related to noise are often connected to machinery (e.g. in the vicinity of compressor stations), also in intermediate assets as well as delivery locations and
homes, noise has to be limited. A second important source of noise are pressure letdown (reduction)
devices, and they are the most important sources downstream of the GTS system, in the RTL and
RNB systems. Especially in the vicinity of households, noise generated in the pipes is also relevant,
which happens at locations with concentrated pressure loss, such as elbows and T-pieces. Pressure reduction devices are found at various locations within the transport system. For example,
at the interface from the HTL to the RTL (the Meet & Regel stations M&Rs), pressure is reduced from
60 bar(g) to typically 40 bar(g). At the interface between the RTL and the RNB systems (Gas
Ontvangst Stations, GOS) pressure is reduced to typically 8 bar(g). Where RNB systems dispatch gas
to consumers at district stations, pressure is further reduced from typically 8 bar(g) to 100 mbar (g). Another example is at gas transfer stations (overslag stations), reducing from 8 bar(g) to 4 bar(g) (or
even 1 bar(g)). A few specific examples of pressure reduction devices that will generate noise: •
Pressure and flow control valves, for continuous operation. These are found in measuring
and control station (M&R), gas receiving stations (GOS) and district stations. •
Pressure and flow control valves for semi-continuous operation. These are found in
compressor stations, as compressor recycle valves and compressor anti-surge valves. These
can also be found during extraction from high-pressure gas storage. •
Pressure reduction devices in incidental operation. These are found upon system
pressurization and depressurization. These include blow-down valves and restriction orifice
plates (single-hole or multi-hole). Also discontinuities in the low-pressure vent system may
be locations with a large pressure reduction and high noise generation (T-joints, stack exit). •
Pressure reduction devices in incidental operation. These are found upon system
pressurization and depressurization. These include blow-down valves and restriction orifice
plates (single-hole or multi-hole). 7.1 Flow induced noise in natural gas transport systems Also discontinuities in the low-pressure vent system may
be locations with a large pressure reduction and high noise generation (T-joints, stack exit). It is essential to understand that the noise perceived by an observer standing in the vicinity of the
equipment is the result of (i) the magnitude of the acoustic sources in the fluid system creating noise
inside the pipes, and (ii) the amount of energy that the pipes walls can radiate as they had become
the diaphragm of a loudspeaker. This is illustrated in Figure 7-1. Therefore, in this chapter, the source
of noise (and its magnitude) is treated separately from the radiation efficiency of the pipe walls. Figure 7-1. Schematic showing that the noise recorded by a microphone next to a pipe is the result of air pressure
fluctuations caused the pipe wall vibrations, which are excited by the noise levels present in the gas flow as a result of
different aerodynamic sources. Figure 7-1. Schematic showing that the noise recorded by a microphone next to a pipe is the result of air pressure
fluctuations caused the pipe wall vibrations, which are excited by the noise levels present in the gas flow as a result of
different aerodynamic sources. The negative consequences of the noise generation can be summarized as follows: The negative consequences of the noise generation can be summarized as follows: The negative consequences of the noise generation can be summarized as follows: Page 38/57
g
q
g Page 38/57 7.2.1 Source: pressure reduction devices In pressure reduction devices, the pressure is abruptly reduced. In general, noise amplitude increases
with increasing mass flow and with increasing pressure differential. Other thermodynamic fluid
properties generally have a smaller effect. The peak frequency depends on gas conditions but also on
the dimensions of the turbulent contraction of the flow. The smaller the length scales in the pressure
let-down device, the higher the frequency range. The intense generation of in-line noise in the
process gas is most relevant at the downstream side of the source. In particular in choking conditions
(when pressure differential Pin/Pout is sufficiently, typically ~2 for natural gas) the noise will not
propagate to the upstream side of the valve. In the case of noise radiation, information about the noise frequency spectrum is essential. The
prediction in AVIFF [15] does not allow for frequency evaluation of the noise. The IEC standard
60534-8 “Control valve aerodynamic noise prediction” [17] offers a detailed basis for estimation of
source strengths. The physical background of this standard requires an advanced knowledge of gas
dynamics and acoustics. However, the application of the prediction method is relatively
straightforward. Operating conditions and gas parameters are required as input, as well as
geometrical input, such as the dimension of the restrictions. 7.2 Assessment of flow-induced noise 7.2 Assessment of flow-induced noise •
Integrity issues, due to acoustic loading of the downstream mechanical structure. In
particular at locations of ‘circumferential discontinuity’, such as small branch connect ntegrity issues, due to acoustic loading of the downstream mechanical structure. In •
Integrity issues, due to acoustic loading of the downstream mechanical structure. In
particular at locations of ‘circumferential discontinuity’, such as small branch connections, T-
joints and welded pipe supports, fatigue failures may occur. See chapter 6. •
Radiated noise, due to break-out of the in-line noise via the pipe wall. The break-out noise
depends on the properties of the noise sources and on the properties of the pipe wall and
installation details. •
Radiated noise, due to direct radiation from a vent stack. In industrial flaring systems, stack
noise during depressurization may be a critical point in the environmental license to operate •
Radiated noise, due to direct radiation from a vent stack. In industrial flaring systems, stack
noise during depressurization may be a critical point in the environmental license to operate. •
Disturbance of flow metering equipment. For example, ultrasonic flowmeters installed
closely downstream of a pressure reduction may be disturbed by (high-frequency) valve
noise. 7.2 Assessment of flow-induced noise 7.2.3 Radiation In external noise legislation, the noise exposure is quantified in terms of A-weighted noise levels. The
A-weighting is a frequency filtering of the noise spectrum, which takes into account the sensitivity of
the human ear. The human ear is relatively insensitive to low frequencies (< 500 Hz) and to very high
frequencies (>8 kHz). The A-weighting is a standardized curve, shown in Figure 7-3. The A-weighting
is a relevant aspect for the transition from natural gas to hydrogen, since the in-line noise sources
have an upward frequency shift. If the existing noise source (natural gas) are dominated by
frequencies around a few hundred Hertz, the upward frequency shift (hydrogen) results in noise in
the ‘sensitive’ area of human observers. This has a non-favourable effect on the noise levels in dB(A). This situation may be expected in the high-pressure, high-capacity systems. If the existing noise
source (natural gas) are dominated by frequencies around a few kHz, the upward frequency shift
(hydrogen) results in noise in the ‘insensitive’ area, potentially even inaudible. This has a favourable
effect on the noise levels in dB(A). This situation may be expected in the low-pressure, low-capacity
systems (e.g. district stations and household and industrial consumers). The in-line noise sources will propagate through the pipe wall and will be radiated from the wall
(break-out noise). This interaction between inline noise, propagation through the pipe wall and
radiated from the wall is an extremely complex process to model accurately. Moreover, the results
may depend strongly on the details of the in-line noise, the pipe wall and installation effects. Similar
to the practical modelling approach for the sources, also for the noise propagation information can
be found in industrial standards. The VDI 3733 standard “Noise at pipes” [21] presents a practical and
conservative approach for prediction break-out noise. A similar approach is also found in IEC 60534-8
[17]. Considering the broadband nature of the in-line noise source, the approach in broad frequency
bands is considered most realistic. The transmission loss through the pipe wall has two separate
contributions (the factor C is constant and depends on the installation details): 𝑅𝑅= 10 log
𝑐𝑅 𝜌𝑅 𝑠
𝑐𝐹 𝜌𝐹 𝑑𝑖+ 𝐴(𝑓) + 𝐶
(eq. 22) (eq. 7.2.2 Source: pipes and flow fittings Noise is generated by a fluid convected in a pipe as a result of turbulent structures arising near the
walls of the pipe and in flow discontinuities, such as elbows or T-pieces. The energy dissipated in
turbulence and noise is related to the pressure drop and therefore to the kinetic energy of the flow. This topic has been subject of research for a long time. A widely accepted reference whose
foundations are also embedded in the AVIFF guidelines is that of Norton & Bull [20]. This reference
contains experimental measurements of flow-induced noise for a variety of flow fittings and
operating conditions, and suggests useful scaling laws. In particular, it provides a dimensionless
power spectral density 𝜙𝑃 of the pressure fluctuations (noise spectrum) as a function of
dimensionless frequency for several geometrical configurations and different Mach numbers. The
spectrum for a given case Φ𝑃 can be obtained by scaling the dimensionless function 𝜙𝑃 with the
velocity 𝑈, the fluid density 𝜌 and the inner diameter 𝑑𝑖. ΦP =
𝜙𝑝 𝑈
(1
2𝜌𝑈2)
2
𝑑𝑖
2
(eq. 21) ΦP =
𝜙𝑝 𝑈
(1
2𝜌𝑈2)
2
𝑑𝑖
2 (eq. 21) Page 39/57 WP1E – Impact of high speed hydrogen
flow on system integrity and noise
D1E.1 – WP1E Report
Figure 7-2. In-line noise generation (left), break-out noise through pipe wall (middle) and direct noise radiation from open
stack (right). WP1E – Impact of high speed hydrogen
flow on system integrity and noise
D1E.1 – WP1E Report Figure 7-2. In-line noise generation (left), break-out noise through pipe wall (middle) and direct noise radiation from open
stack (right). Figure 7-2. In-line noise generation (left), break-out noise through pipe wall (middle) and direct noise radiation from open
stack (right). The second term A(f) is a frequency-dependent function which represents the interaction with the
ring frequency fr: 𝑓𝑟=
𝑐𝑅
𝜋 𝑑𝑖
(eq. 23) 𝑓𝑟=
𝑐𝑅
𝜋 𝑑𝑖 (eq. 23) At the ring frequency, exactly one structural wavelength fits in the circumference of the pipe. At this
condition, the coupling to the pipe wall is optimal and the transmission loss is minimal. For
frequencies below and above the fr, the transmission loss increases, with different slopes: For 𝑓 ≤𝑓𝑟 : 𝐴(𝑓) = 20 log
𝑓𝑟
𝑓
𝑓
(eq. 24) For 𝑓 ≤𝑓𝑟 : 𝐴(𝑓) = 20 log
𝑓𝑟
𝑓
For 𝑓> 𝑓𝑟 : 𝐴(𝑓) = 30 log
𝑓𝑟
𝑓
(eq. 24) For 𝑓 ≤𝑓𝑟 : 𝐴(𝑓) = 20 log
𝑓𝑟
𝑓
For 𝑓> 𝑓𝑟 : 𝐴(𝑓) = 30 log
𝑓𝑟
𝑓
(e
Figure 7-3. A-weighting curve, suppressing the contribution at the lower (<500Hz) and higher (>8kHz) frequencies. (eq. 24) Figure 7-3. A-weighting curve, suppressing the contribution at the lower (<500Hz) and higher (>8kHz) frequencies. 7.3.1 Source: pressure reduction devices The basis of the benchmark is the same as discussed in section 6.3, but using the IEC method
mentioned in the previous section. It is not possible to perform generic analysis of the source
characteristics that includes all conditions of pressure and temperature as performed in other
chapters of this report. Therefore, the benchmark for the source is based on multiple examples. The
difference in actual noise source level and frequency between hydrogen and natural gas is quantified
with the IEC standard for various typical configurations. It is stressed for clarity that this section is
concerned with the magnitude of noise sources, i.e. levels experienced inside the pipe, and not the
noise perceived by observers, i.e. experienced outside the pipe. The following example cases were
considered: -
Blow-down of compressor station -
Measuring and control station -
Gas receiving station -
Gas district station -
Households and industrial consumers Page 41/57
7.3.1.1
Example Case 1: blow-down compressor station vent
This case is a typical high-pressure, high-capacity blowdown system on a compressor station (HTL
system), with incidental operation. The upstream pressure is varied from 50 bar to 80 bar(a), with a 7.2.3 Radiation 22) The first term on the right-hand side depends only on the ‘impedance mismatch’ between the
process fluid (subscript “F”) and the pipe material properties (subscript “R”) and the geometrical
properties of the pipe wall (wall thickness s and diameter di). For the transition to hydrogen, this
‘mass’ term results in a more favourable transmission loss: the impedance difference between
hydrogen and the pipe wall is larger, and this will result in a transmission loss increase of typically +5
dB. This incremental effect applies to both steel pipes as well as plastic materials (HDPE or PVC). Page 40/57 Page 40/57 WP1E – Impact of high speed hydrogen
flow on system integrity and noise
D1E.1 – WP1E Report
The second term A(f) is a frequency-dependent function which represents the interaction with the
ring frequency fr: 7.3.1.1
Example Case 1: blow-down compressor station vent This case is a typical high-pressure, high-capacity blowdown system on a compressor station (HTL
system), with incidental operation. The upstream pressure is varied from 50 bar to 80 bar(a), with a Page 41/57 Page 41/57 WP1E – Impact of high speed hydrogen
flow on system integrity and noise
D1E.1 – WP1E Report
constant backpressure of 3 bar(a) downstream of the blow-down orifice. The dimensions of the
blow-down orifice are based on an actual field case of a compressor station main vent. The vent
maximum capacity is approximately 147 kg/s or 637 kNm3/h (values for natural gas). The bore of the
restriction is kept constant for natural gas and hydrogen. The results for the sound power level of the source are shown in Figure 7-4. The sound power level
for hydrogen is 5-6 dB higher than for natural gas. The offset is constant for the various pressure
conditions. The results for the peak frequency of the source are shown in Figure 7-5. The peak
frequency for hydrogen is a factor 3.2-3.3 higher than for natural gas and shifts towards frequencies WP1E – Impact of high speed hydrogen
flow on system integrity and noise
D1E.1 – WP1E Report
constant backpressure of 3 bar(a) downstream of the blow-down orifice. The dimensions of the
blow-down orifice are based on an actual field case of a compressor station main vent. The vent
maximum capacity is approximately 147 kg/s or 637 kNm3/h (values for natural gas). The bore of the
restriction is kept constant for natural gas and hydrogen. WP1E – Impact of high speed hydrogen
flow on system integrity and noise
D1E.1 – WP1E Report constant backpressure of 3 bar(a) downstream of the blow-down orifice. The dimensions of the
blow-down orifice are based on an actual field case of a compressor station main vent. The vent
maximum capacity is approximately 147 kg/s or 637 kNm3/h (values for natural gas). The bore of the
restriction is kept constant for natural gas and hydrogen. The results for the sound power level of the source are shown in Figure 7-4. The sound power level
for hydrogen is 5-6 dB higher than for natural gas. The offset is constant for the various pressure
conditions. The results for the peak frequency of the source are shown in Figure 7-5. The peak
frequency for hydrogen is a factor 3.2-3.3 higher than for natural gas and shifts towards frequencies
in which humans are more sensitive to noise. The ratio is constant for the various pressure
conditions. Figure 7-4. Sound power level of blow-down orifice noise source inside the pipe, for hydrogen and natural gas. Figure 7-4. Sound power level of blow-down orifice noise source inside the pipe, for hydrogen and natural gas. Figure 7-5. Peak frequency of blow-down orifice noise source inside the pipe, for hydrogen and natural gas. Figure 7-5. Peak frequency of blow-down orifice noise source inside the pipe, for hydrogen and natural gas. Page 42/57 Page 42/57 WP1E – Impact of high speed hydrogen
flow on system integrity and noise
D1E.1 – WP1E Report
7.3.1.2
Example Case 2: measuring and control station
This case is a typical high-pressure, high-capacity configuration, with continuous operation. The
station inlet pressure is varied from 80 bar(a) to 50 bar(a), with a constant outlet pressure of 40
bar(a). The dimensions of the contraction in the control valves are based on a realistic, large capacity
of 510 kNm3/h (values for natural gas). Example Case 2: measuring and control station 7.3.1.2 This case is a typical high-pressure, high-capacity configuration, with continuous operation. The
station inlet pressure is varied from 80 bar(a) to 50 bar(a), with a constant outlet pressure of 40
bar(a). The dimensions of the contraction in the control valves are based on a realistic, large capacity
of 510 kNm3/h (values for natural gas). The results for the sound power level of the source are shown in Figure 7-6. The sound power level
for hydrogen is 6-8 dB higher than for natural gas. The offset is relatively constant for the various
pressure conditions. The results for the peak frequency of the source are shown in Figure 7-7. The
peak frequency for hydrogen is a factor 3.2-3.5 higher than for natural gas. The ratio is relatively
constant for the various pressure conditions. Without taking into account eventual radiation
properties of the pipe (explained in the next section), this would mean higher noise levels towards
frequencies in which the human ear is more sensitive to. Note that the source sound power level is
lower than for the Case 1, due to the lower pressure ratio over de valve resulting in lower acoustic
efficiencies. No noise reduction due to a possible low-noise trim design of the control valve is
accounted for in these results. Figure 7-6. Sound power level of control valve noise inside the pipe, for hydrogen and natural gas. Figure 7-6. Sound power level of control valve noise inside the pipe, for hydrogen and natural gas. Figure 7-7. Peak frequency of control valve noise inside the pipe, for hydrogen and natural gas. Figure 7-7. Peak frequency of control valve noise inside the pipe, for hydrogen and natural gas. Page 43/57 Page 43/57 WP1E – Impact of high speed hydrogen
flow on system integrity and noise
D1E.1 – WP1E Report
7.3.1.3
Example Case 3: gas receiving station
This case is a typical medium-pressure, medium-capacity configuration, with continuous operation. The station inlet pressure is varied from 50 bar(a) to 30 bar(a), with a constant outlet pressure of 9
bar(a). The dimensions of the contraction in the control valves are based a realistic, large capacity of
42 kNm3/h (values for natural gas). Example Case 3: gas receiving station 3.1.3
Example Case 3: gas receiving station 7.3.1.3 This case is a typical medium-pressure, medium-capacity configuration, with continuous operation. The station inlet pressure is varied from 50 bar(a) to 30 bar(a), with a constant outlet pressure of 9
bar(a). The dimensions of the contraction in the control valves are based a realistic, large capacity of
42 kNm3/h (values for natural gas). This case is a typical medium-pressure, medium-capacity configuration, with continuous operation. The station inlet pressure is varied from 50 bar(a) to 30 bar(a), with a constant outlet pressure of 9
bar(a). The dimensions of the contraction in the control valves are based a realistic, large capacity of
42 kNm3/h (values for natural gas). The results for the sound power level of the source are shown in Figure 7-8. The sound power level
for hydrogen is 5-6 dB higher than for natural gas. The offset is constant for the various pressure
conditions. The results for the peak frequency of the source are shown in Figure 7-9. The peak
frequency for hydrogen is a factor 3.1 higher than for natural gas. For natural gas, the frequency is
around 2 kHz and for hydrogen between 6 - 7 kHz. The human ear is most sensitive to the frequency
spectrum between 1-9 kHz. The frequency shift has no significant influence on the sensitivity. The
ratio is constant for the various pressure conditions. Note that the absolute source sound power
level is lower than for the Case 1, due to the lower pressure ratio over de valve resulting in lower
acoustic efficiencies. No noise reduction due to a possible low-noise trim design of the control valve
is accounted for in these results. Also note that the absolute frequencies are much higher than for
Case 1, which is a consequence of the smaller dimensions of the control valve restriction (lower
capacity). Figure 7-8. Sound power level of control valve noise inside the pipe, for hydrogen and natural gas. Figure 7-8. Sound power level of control valve noise inside the pipe, for hydrogen and natural gas. Figure 7-9. Peak frequency of control valve noise inside the pipe, for hydrogen and natural gas. Figure 7-9. Peak frequency of control valve noise inside the pipe, for hydrogen and natural gas. Page 44/57 Page 44/57 Page 44/57 Example Case 4: gas district station 7.3.1.4 This case is a typical low-pressure, low-capacity configuration, with continuous operation. The station
inlet pressure is varied from 11 bar(a) to 3 bar(a) (notice that 9 bar(a) is the actual maximum and 2
bar(a) is the actual minimum), with a constant outlet pressure of 100 mbar(g). The dimensions of the
contraction in the control valves are based a realistic capacity of 4000 Nm3/h (values for natural gas). The results for the sound power level of the source are shown in Figure 7-10. The sound power level
for hydrogen is 5 dB higher than for natural gas. The offset is constant for the various pressure
conditions. The results for the peak frequency of the source are shown in Figure 7-11. The peak
frequency for hydrogen is a factor 3.0-3.1 higher than for natural gas. For natural gas, the frequency
is around 2 kHz and for hydrogen between 6 - 7 kHz. The human ear is most sensitive to the
frequency spectrum between 1-9 kHz. The frequency shift has no significant influence on the
sensitivity. The ratio is constant for the various pressure conditions. Note that the absolute source
sound power level is lower than for the Case 1, due to the lower pressure ratio over de valve
resulting in lower acoustic efficiencies. No noise reduction due to a possible low-noise trim design of
the control valve is accounted for in these results. Also note that the absolute frequencies are much
higher than for Case 1, which is a consequence of the smaller dimensions of the control valve
restriction (lower capacity). Figure 7-10. Sound power level of control valve noise inside the pipe, for hydrogen and natural gas. Figure 7-10. Sound power level of control valve noise inside the pipe, for hydrogen and natural gas. Figure 7-11. Peak frequency of control valve noise inside the pipe, for hydrogen and natural gas. Figure 7-11. Peak frequency of control valve noise inside the pipe, for hydrogen and natural gas. Page 45/57 Page 45/57 Page 45/57 WP1E – Impact of high speed hydrogen
flow on system integrity and noise
D1E.1 – WP1E Report Example Case 5: households and industrial consumers Example Case 5: households and industrial consumers 7.3.2 Source: pipe and flow fittings In the case of noise generated in pipes and flow fittings, quantification of the difference between
hydrogen and natural gas relies on (eq. 21). According to this equation, the outcome depends on the
flow velocity ratio and the dynamic pressure ratio (squared) for a given geometry. Therefore the
results shown in Figure 2-3 and Figure 2-5 can be combined to conclude that hydrogen is expected to
feature 3-4 times more energetic pressure fluctuations than natural gas transporting the same
amount of energy. This is further elaborated with an example for the noise generated in a straight pipe. The parameters
for this example are not very important as the flow velocity ratio and the dynamic pressure ratio are
not extremely sensitive to pressure and temperature. Figure 7-14 shows the difference in power
spectral density for hydrogen and for natural gas. The plot presents in a log-log scale the frequency
spectrum for both cases, with hydrogen featuring a concentration of energy at larger frequencies
than natural gas. It is noted that the overall power level of this spectrum is about 3 times larger for
hydrogen than for natural gas (despite the general appearance of the plot due to the log scale) . Though the spectra look different for other geometrical configurations, such as long-radius elbows
and T-pieces, the general conclusions of the benchmark between hydrogen and natural gas remain
the same. 7.3.1.5 This case is the final pressure reduction in the gas supply chain. The nominal inlet pressure is 100
mbar (g), but could be up to 1 bar(g), the outlet pressure being atmospheric. The dimensions of the
contractions are estimated, based on a maximum capacity of 10 Nm3/h (G6, households) and 400
Nm3/h (industrial consumers). Note that these values are upper worst-case limits. A realistic estimate
for the nominal (high) value of a household is up to 2 Nm3/h, which would result in much lower noise
amplitudes. The results for the sound power level of the source are shown in Figure 7-12. The sound power level
for hydrogen is 4-5 dB higher than for natural gas. The offset is constant for the various pressure
conditions. The results for the peak frequency of the source are shown in Figure 7-13. The peak
frequency for hydrogen is a factor 3 higher than for natural gas, which may shift it towards inaudible
frequencies to humans. The ratio is constant for the various pressure conditions. Note that the
absolute source sound power levels are much lower than for the Case 1, due to the lower pressure
ratio resulting in lower acoustic efficiencies. Also note that the absolute frequencies are much higher
than for Case 1, which is a consequence of the smaller dimensions of the restriction (lower capacity). Figure 7-12. Sound power level of control valve noise inside the pipe, for hydrogen and natural gas. Figure 7-12. Sound power level of control valve noise inside the pipe, for hydrogen and natural gas. Figure 7-13. Peak frequency of control valve noise inside the pipe, for hydrogen and natural gas. Figure 7-13. Peak frequency of control valve noise inside the pipe, for hydrogen and natural gas. Page 46/57 Page 46/57 7.3.2 Source: pipe and flow fittings 7.3.3 Noise radiation Power spectral density of hydrogen and natural gas as generated in a straight pipe under a given Figure 7-14. Power spectral density of hydrogen and natural gas as generated in a straight pipe under a given set o
conditions. In this case, (ID = 150 mm, UNG = 10 m/s, UH2 = 30 m/s, 80 bar and 10 deg. C). Figure 7-15. Transmission loss frequency function A(f). Left: high-pressure, large-capacity blowdown system (CASE 1). Right:
district station (CASE 4). Figure 7-15. Transmission loss frequency function A(f). Left: high-pressure, large-capacity blowdown system (CASE 1). Right:
district station (CASE 4). 7.3.3.1
Noise radiation through open stacks 7.3.3 Noise radiation 7.3.3 Noise radiation The quantification of noise radiation is explored using the VDI method described in 7.2.3. To
determine the impact of the transition to hydrogen on A(f) in (eq. 22), one must know the frequency
range of interest of the source and compare this with the ring frequency (depends on pipe material
and diameter). The transition to hydrogen introduces an upward frequency shift. If the frequency
range of interest is < fr, then the transition to hydrogen results in an unfavourable transmission loss. If the frequency range of interest is > fr, then the transition to hydrogen results in a favourable
transmission loss. In case the frequency range of interest is overlapping with the fr, it is not possible
to make a general statement on the effect of transition to hydrogen. Note that for non-metallic pipes which are used in the LP distribution networks (HDPE, PVC) the ring
frequency tends to lower values, while the source frequencies are generally high (and shifting even
higher in case of hydrogen). For these reasons, it is expected that in the LP part of the network with
non-metallic pipes, the transmission loss for hydrogen will be favourable (favourable mass effect and
favourable frequency effect). Some of these features are illustrated in Figure 7-15. The frequency curves A(f) are plotted for
various, typical line sizes and compared with the typical frequency range of the in-line noise source. The upward shift in source frequency (natural gas → hydrogen) is obvious in both figures. For the left
figure (HP Case 1, with steel pipes), the source frequencies for hydrogen shift into the ‘un-favourable’
frequency range around fr and have hence a poor transmission loss. For the right figure (LP Case 4,
with HDPE pipes), the source frequencies for hydrogen shift away from the ‘un-favourable’ frequency
range and have hence a better/higher transmission loss. Page 47/57 Page 47/57 WP1E – Impact of high speed hydro
flow on system integrity and noise
D1E.1 – WP1E Report
Figure 7-14. Power spectral density of hydrogen and natural gas as generated in a straight pipe under a given set of
conditions. In this case, (ID = 150 mm, UNG = 10 m/s, UH2 = 30 m/s, 80 bar and 10 deg. C). WP1E – Impact of high speed hydrogen
flow on system integrity and noise
D1E.1 – WP1E Report gure 7-14. 7.4 Conclusion Noise is generated as a byproduct of flow. Wherever flow energy is lost (pressure drop), sources of
noise arise. This occurs in normal, straight pipes due to friction, and any other flow fittings in which
pressure is lost. This phenomenon is much more visible in pressure let-down devices such as control
valves and restriction orifices. Based on the discussion above, it is expected that sources of noise
with hydrogen tend to become stronger. Frequencies shift to higher values, which can be beneficial. Also, the radiation characteristics of typical pipes tend to be favourable to hydrogen. The current Noise is generated as a byproduct of flow. Wherever flow energy is lost (pressure drop), sources of
noise arise. This occurs in normal, straight pipes due to friction, and any other flow fittings in which
pressure is lost. This phenomenon is much more visible in pressure let-down devices such as control
valves and restriction orifices. Based on the discussion above, it is expected that sources of noise
with hydrogen tend to become stronger. Frequencies shift to higher values, which can be beneficial. Also, the radiation characteristics of typical pipes tend to be favourable to hydrogen. The current
limited benchmark experience with hydrogen confirms that less noise was radiated to the
environment [19]. At this stage, though, it is too early to generalize the conclusion that less noise will
be radiated from hydrogen systems than from natural gas systems. Also, the radiation characteristics of typical pipes tend to be favourable to hydrogen. The current
limited benchmark experience with hydrogen confirms that less noise was radiated to the
environment [19]. At this stage, though, it is too early to generalize the conclusion that less noise will
be radiated from hydrogen systems than from natural gas systems. Base on the examples presented in this chapter, the following conclusions have been reached •
With a transition from natural gas to hydrogen, noticeable effects are expected on the
mechanism of valve noise generation. A systematic increase in noise source strength (4-8 dB)
is predicted, using comprehensive prediction methods [17]. A systematic upward shift in
frequency is expected, of approximately a factor 3. •
Noise radiation from the pipe wall (break-out noise) contains various aspects, such as the
expected frequency range of the source and the mechanical properties of the pipe. 7.3.3.1
Noise radiation through open stacks As for the break-out noise through the pipe wall, also the acoustic radiation from an open stack
involves various physical mechanisms. The acoustic attenuation of the noise is depending on the
frequency, and will be favourable for the upward frequency shift in case of hydrogen. Also, in case of
an outlet silencer at the stack, it is expected that the performance of absorptive types silencers is
more favourable for the case of hydrogen. On the other hand, the noise radiation from the stack
exhaust may be stronger for higher frequencies. For a quantitative statement, a detailed assessment on a case-by-case basis will be needed. Preliminary tests with blow-down of a low-pressure distribution network confirm that no noticeable
increase in radiated noise is observed, in case of hydrogen [22]. Page 48/57 Page 48/57 WP1E – Impact of high speed hydrogen
flow on system integrity and noise
D1E.1 – WP1E Report WP1E – Impact of high speed hydrogen
flow on system integrity and noise
D1E.1 – WP1E Report 8.1 Erosion in natural gas transport systems Erosion is defined as the process by which material is worn away from the gas transport system due
to the impact of particles transported in the flow. Erosion typically causes thinning of pipes at
particular hot spots and overall physical degradation of equipment. Erosion is a well-known integrity risk in the oil & gas industry, such that erosion probes even exist in
many upstream assets. Erosion can be the limiting factor for the maximum flow velocity possible in
the pipework and thus become an important design constraint. The eroding agent is in most cases
solid sand produced together with the hydrocarbon stream. Liquid droplets are not considered a
potential abrasive agent at flow velocities below 70 - 80 m/s [23], which in gas transport systems
(including future service with H2) are not reached. Erosion, on the other hand, is not known to pose a
significant risk to the integrity of gas transport systems (of The Netherlands). This is because prior to
injection in the GTS, gas has been treated and cleaned. Furthermore, intermediate gas receiving
stations (GOS) incorporate filters to capture incidental ingress of solids or rust particles shed
anywhere in the system. It is possible though that in incidental events, solid particles enter the
network, which can eventually lead to issues with combustion in domestic boilers [24]. According to NBNL, wall thickness measurements are performed in the HP RNB system (1-8 barg)
when, for example, side branches need to be added to the network. Even though the pipes could be
as old as 50 years, no loss of material has been observed. In the LP RNB system (0.1-1 barg), visual
inspections conducted with cameras indicate that the system can contain more contamination, with
twigs, leaves, and other bodies present. However, there is no documentation of this creating erosion
issues, partially explained by the fact that the flow velocity is lower. It cannot be excluded that if the
flow velocity in the LP RNB system was as high as 20 m/s, erosion issues would not arise. Therefore, the starting point for erosion as a failure mechanism is that it currently does not create
integrity concerns (either because of the absence of foreign particles or because the speeds are far
below the limit of 20 m/s). It is of interest though to understand whether service with high-speed
hydrogen can affect the level of risk associated to the erosion phenomenon. 8 Erosion 8 Erosion 8 Erosion 7.4 Conclusion In any
case, a systematic beneficial effect of approximately 5 dB is found for hydrogen, due to the
increased impedance mismatch between process gas and pipe wall. On the other hand, the
frequency effect of the pipe wall transmission loss depends on the pipe dimensions, the pipe
material and the frequency range of the noise source. This frequency effect could be
positive, neutral or negative. Evaluation at future, actual operating conditions with hydrogen
is recommended. •
Also, the quantitative assessment of noise radiation from an open stack should be done on a
case-by-case basis. In order to better understand what effects are dominant, more experimental evidence around the
subjects discussed above is required. Particularly, experience at very high pressure typical of the HTL
system is missing. Ongoing experimental campaigns with flowing hydrogen should include suitable
environmental noise measurements, whether in the GTS, the RNBs or the household levels. These
measurements should be reproduced with existing modelling techniques, with the objective to more
confidently extrapolate the use of such models to any other locations and conditions. An example of
this is the campaign reported in reference [19]. Finally, it is reminded that in the close vicinity downstream of the pressure reduction devices, flow
meter accuracy may be disturbed by the increased noise. This phenomenon is excluded from the
scope of this HyDelta WP1E and is recommended for further research. Page 49/57 Page 49/57 WP1E – Impact of high speed hydrogen
flow on system integrity and noise
D1E.1 – WP1E Report
8
E
i WP1E – Impact of high speed hydrogen
flow on system integrity and noise
D1E.1 – WP1E Report 8.3 Benchmark between natural gas and hydrogen 8.3 Benchmark between natural gas and hydrogen hen comparing natural gas to hydrogen flow, the following assumptions have been taken: When comparing natural gas to hydrogen flow, the following assumptions have bee -
Hydrogen transporting the same amount of energy as natural gas. -
Hydrogen transporting the same amount of energy as natural gas. -
Pipes made of steel, HDPE and PVC. -
Erosive agent: sand. -
Solid loading: maximum as per Ministeriële Regeling Gaskwaliteit [28]. By examination of (eq. 25), it is observed that the only parameter that is directly connected to the
flow is the particle impact velocity. At sufficiently high flow velocities, solid particles will be lifted and
transported with the flow (in equilibrium). In this situation, the particle impact velocity is the gas flow
velocity. For instance, for steel the value of the parameter 𝑛 is 2.6. The sensitivity to gas velocity is
illustrated in Figure 8-1. Assuming every other parameter constant, it would mean that hydrogen
flowing ~3 times faster than natural gas would feature erosion rates roughly 17 times larger. There
are other parameters though that depend on the flow, such as the impact angle for a given geometry
or the pipe wall area potentially exposed to particle impacts. Therefore this ratio cannot be fully
generalized. A second difficulty in establishing a generic benchmark is that the maximum solid rate stated by the
Gas Quality Law is given as 100 mg/(n)m³. Because the composition of the gas can differ leading to
different fluid densities at normal conditions, this means the actual maximum solid particle rate will
differ when comparing different gas compositions. A comparison choice must be made: either the
solid particle rate is calculated for the natural gas case and fixed when comparing to hydrogen, or the
maximum limit according to the current legal framework is respected. This is illustrated in Table 8-1. In the former case the ratio between hydrogen and natural gas is ~17, in the latter case, it is nearly ~
50. Because there is no particular reason to expect that pipes with hydrogen will contain more solids
than those with natural gas, the case comparing similar solid rates is considered more realistic. Figure 8-1. Erosion rate as a function of gas velocity in a given elbow configuration, according to sensitivity following U2.6. 8.2 Assessment of erosion In the upstream sector, erosion is normally taken into account as part of designs compliant with API
RP 14E [25]. For single phase gas lines, in fact the main factor constraining the design would be the
pressure drop. It has been argued in general that the approach proposed by API 14E is not holistic
and important interactions between erosion and possible corrosion are missed [26]. An additional
widely used document is the DNV recommended practice O501 [27]. This document provides a more
fundamental approach to characterizing erosion rates. The actual loss of material 𝐸𝑚 [kg/s] can be
estimated from: (eq. 25)
𝐸𝑚= 𝐾 𝑈𝑝
𝑛 𝐹(𝛼) 𝑚𝑝 (eq. 25) Where 𝐾 [m/s-n] and 𝑛 are coefficients dependent on the pipe material, 𝑈𝑝 is the particle impact
velocity [m/s], and 𝑚𝑝 [kg/s] is the loading of solid particles that the flow is transporting. The
function 𝐹(𝛼) corresponds to a correction factor for the particle impact angle 𝛼 and the ductility
class of the material. Page 50/57
In order to assess erosion rates, several workflows can be followed in ref. [27], applicable to different
geometries to be assessed, such as straight pipe, elbows, reducers or control valves. Values for In order to assess erosion rates, several workflows can be followed in ref. [27], applicable to different
geometries to be assessed, such as straight pipe, elbows, reducers or control valves. Values for Page 50/57 Page 50/57 Page 50/57 WP1E – Impact of high speed hydrogen
flow on system integrity and noise
D1E.1 – WP1E Report
different, common materials are found in the reference. Regardless of the workflow followed, the
conclusions when comparing natural gas to hydrogen will be similar, so the scope of this document is
limited to the assessment of elbows. different, common materials are found in the reference. Regardless of the workflow followed, the
conclusions when comparing natural gas to hydrogen will be similar, so the scope of this document is
limited to the assessment of elbows. 8.3 Benchmark between natural gas and hydrogen The absolute numbers in the y-axis are removed due to material dependency, whereas it is the difference that is intended to
be illustrated. Figure 8-1. Erosion rate as a function of gas velocity in a given elbow configuration, according to sensitivity following U2.6. The absolute numbers in the y-axis are removed due to material dependency, whereas it is the difference that is intended to
be illustrated. Page 51/57 Page 51/57 WP1E – Impact of high speed hydrogen
flow on system integrity and noise
D1E.1 – WP1E Report Table 8-1. Generic benchmark of erosion rate for natural gas and hydrogen illustrating that there is a significant difference
between assuming the same amount of solids in both cases, or if in both cases the maximum current legal limit is followed. Table 8-1. Generic benchmark of erosion rate for natural gas and hydrogen illustrating that there is a significant difference
between assuming the same amount of solids in both cases, or if in both cases the maximum current legal limit is followed. G-gas
Hydrogen
Max Solid rate [mg/(n)m³]
100
100
Density at normal conditions [kg/(n)m³]
0.833
0.089
Actual particle loading at normal conditions [mg/kg]
120
1120
Calorific value, LHV [MJ/kg]
38.02
119.96
Calorific value, LHV [MJ/(n)m3]
31.67
10.71
Energy-specific flow rate [n(m³)/MJ]
0.032
0.093
Energy-specific solid rate [mg/MJ]
3.16
9.34
Flow velocity ratio at normal conditions [-]
n.a. 2.96
Solid rate ratio at normal conditions [-]
n.a. 2.96
Erosion rate ratio - assuming only same solid rate (steel)
16.8
Erosion rate ratio - assuming same original legal limit (steel)
49.6 8.4 Examples p
In this section, a number of typical cases for the gas network of the Netherlands is used for
illustration purposes. All calculations are based on ref. [27] in which the necessary material constants
are also found. All apply to the case of a pipe elbow. The solid rate for the hydrogen case is the same
as in the natural gas case, i.e. the maximum legal limit is only applied to the natural gas case, and the
value obtained is used also for the hydrogen case. In all cases it is assumed that the solid rate is
constant. In reality, possible pockets of solid particles will be convected through the network and
erode a particular spot only for a limited amount of time. The cases (1-8) and parameters as used in
the calculations are provided in Table 8-2. The first observation is that, when 10 m/s is used as the baseline flow velocity of natural gas, erosion
rates on an hourly basis are limited. Only if solid contamination was constantly present, it would lead
to any visible erosion rates over the years. This may explain the current state of affairs in which
erosion is not observed as an issue, which is partly explained by the use of preventive measures to
limit solid contamination as well as the limit flow speed used in the gas networks. Switching to
hydrogen at high speed would render much higher erosion rates. While this in general the dominant
trend, the erosion potential can differ due to other parameters, e.g. due to the particle size being
above or below a threshold limit determined by flow-related metrics (Reynolds number, fluid
density). The model used features steep, discontinuous changes in behaviour depending on the
aforementioned flow-related metrics. Results cannot be extended to the RNB system because the
density of the fluid is lower than 1 kg/m³ , which is outside of the application range of the model
presented in ref. [27]. It is anticipated that erosion rates are also larger, but it cannot be confidently
stated from this model alone. Follow-up research for the conditions typical of the RNBs is
recommended. Page 52/57 Page 52/57 WP1E – Impact of high speed hydrogen
flow on system integrity and noise
D1E.1 – WP1E Report Table 8-2. Parameter used in the calculations of absolute erosion rates. The solid particle loading in the hydrogen case is
assumed constant for 1 full hour and the same as in the natural gas case (i.e. not based on applying the maximum legal limit
to either case independently). Table 8-2. Parameter used in the calculations of absolute erosion rates. The solid particle loading in the hydrogen case is
assumed constant for 1 full hour and the same as in the natural gas case (i.e. not based on applying the maximum legal limit
to either case independently). Case #
1
2
3
4
5
6
7
8
Pressure [bar(a)]
80
40
40
8
8
2
1.1
1.1
Pipe material (*)
steel
steel
steel
steel
HDPE
HDPE
HDPE
HDPE
Pipe Diameter [DN]
1200
1200
400
200
200
200
200
100
Material constant K [10-9m/s-n]
2.0
2.0
2.0
2.0
3.5
3.5
3.5
3.5
Material exponent, n [-]
2.6
2.6
2.6
2.6
2.9
2.9
2.9
2.9
Material density [kg/m³]
7800
7800
7800
7800
1150
1150
1150
1380
Sand density [kg/m³]
2650
2650
2650
2650
2650
2650
2650
2650
Sand particle diameter [m]
100
100
100
100
100
100
100
100
Solid content [mg/(n)m³]
100
100
100
100
100
100
100
100
Flow velocity (G-Gas) [m/s]
10
10
10
10
10
10
10
10
Results
Wall thickness loss (G-gas) [m/h] 0.0024 0.0021 0.005 0.0036
0.08
0.02
0.004 0.0001
Wall thickness loss (H2) [m/h]
0.34
0.24
0.33
**
**
**
**
**
Erosion rate ratio [-]
141
117
60
**
**
**
**
**
(*) Though it was possible to find information about erosion in PVC pipes, it has not been possible to confidently determine
the numerical values that should be assigned to feed the empirical model of ref. [27]. (**) Unfortunately the density of
hydrogen at such pressures is below 1 kg/m³, which is outside the applicability range of the model used. 9 Perspectives and closing remarks The flow velocity of a gas in a pipeline transport system is limited by a number of phenomena. The
flow velocity is determined by the selection of system capacity, operating conditions, hardware sizing
and other items not necessarily technical. The combination that provides the lowest levelized cost of
transport determines what the resulting flow velocity is at all points of the transport system. However, the flow velocity itself can be a constraint in this optimization due to the risks associated to
very high speed flows. For natural gas, this limit is typically set at 20 m/s (72 km/h). If the same limit
would be applied to hydrogen, it may be a conservative constraint on the capacity of new and re-
used systems to transport energy. The phenomena linked to integrity risks associated to high speed gas flows have been explored in
this report. A generic benchmark between natural (G-) gas and hydrogen is presented, when an equal
energy transport capacity between the two carriers is assumed. The objective of the benchmark is to
evaluate whether under this assumption, any barriers prevent transport at such condition. In other
words, whether the allowable flow velocity for hydrogen can be larger than the value traditionally
used for natural gas or in which conditions that is allowed. In this study, existing methods to quantify the risks associated to the phenomena involved are used. These are widely used across industry, not only in natural gas transport systems, but also in the
upstream hydrocarbon production sector or the petrochemical industry. The methods are typically
generic, and hydrogen is no exception. It must not be forgotten that hydrogen transport is already
successfully done through thousands of kilometres of pipelines globally, though locally this may be
done at rates and conditions less demanding that those ambitioned now for the energy transition. For the purpose of the analysis of these phenomena, hydrogen is not different from natural gas or
other gases. The Energy Institute guidelines [15] can be followed as usual for flow-induced integrity
risks. Compressor equipment can be designed as usual against the API 618 standard. Erosion control
guidelines such as API RP 14E or DNV RP O501 can also be followed. The main result of this investigation is that the risk levels associated to these phenomena when
hydrogen flows with the same energy rate as natural (G-) gas are similar. WP1E – Impact of high speed hydrogen
flow on system integrity and noise
D1E.1 – WP1E Report 8.5 Conclusion Erosion is currently not seen as an integrity risk in gas transport systems. There is no evidence of it
being an issue even after decades of operation in The Netherlands. Gas cleaning processes and filters
at different locations of the systems are in place to prevent this. Nonetheless, incidentally, limited
amounts of solid particles will enter the network. When hydrogen is used to transport the same
amount of energy as in natural gas systems, it is expected that the erosion potential for such
particles is much larger. This is due mostly to the large effect that the flow speed has on the expected
erosion rates. Considering the above and the fact that other references point to erosion as a limiting factor creates
enough grounds for follow-up research, and cooperation with other initiatives in Europe on this
regard. Furthermore, the application range of the method selected to characterize erosion rates does
not cover hydrogen flows at low pressures typical of the RNB systems. Follow-up research on erosion
could scope: Erosion tests in the lab to characterize the materials used in the RNB systems. -
Erosion tests in the lab to characterize the materials used in the RNB systems. -
Verify the performance of the adopted model in comparison to simulations performed with
computational fluid dynamics for typical flow fittings and pipe materials. -
Determination of worst flow velocities in the networks and worst-case duration to exposure
to solid contamination by means of network simulations. Page 53/57 Page 53/57 9 Perspectives and closing remarks If with natural gas
transport, 20 m/s is a rule of thumb for the maximum flow velocity in the network, 60 m/s could be
the rule of thumb for hydrogen. Operation of hydrogen at the same flow velocity of 20 m/s will
render a significantly milder situation from every aspect analysed in this report. Operation at 40 m/s
may be equally possible although issues with thermowells start to appear and erosion potential is
also already significantly increased. In order to achieve the flow velocity required for similar energy
transport capacities between hydrogen and natural gas, two warnings must be indicated. The first warning is connected to erosion potential. Gas transport pipelines are normally very clean
and free of potentially eroding agents such as sand. Of course, in the absence of eroding agents,
(internal) erosion can’t exist. However, it has been concluded that should there be incidental ingress
of sand, the eroding potential of high speed (hydrogen) flows is dramatically increased. Whether
filters perform as well as with natural gas, and whether stricter maintenance is warranted is currently
uncertain. It is important to explore the performance of filters in the GTS and RNB systems with high
speed hydrogen flow. It is equally important to define worst-case exposure to solid particles. This
should enable a better quantification of the risk of solid contamination in the gas stream responsible
for potential erosion. A second line of research can be linked to dedicated flow simulations to
characterize worst-case erosion rates in the RNB systems, in combination with suitable material
constants for PVC pipes, for which tests may be required. Page 54/57 Page 54/57 A second, milder warning arising from these investigations is linked to dynamics at high frequencies. Even in the case that hydrogen presents comparatively lower pulsation or radiated noise amplitudes
than natural gas, it will do so at 3 times higher frequencies. From a mechanical vibration mitigation
perspective, that may be more difficult to achieve, even for lower amplitudes. The same holds for
noise: whereas in some cases, higher frequencies will render either better blockage from the pipe or
even moving beyond (human) audible range, the opposite could also be true: that the pipe is more
transparent and will radiate more noise, and that it may be at frequencies that humans are more
sensitive to. It is unfortunately not possible to generalize what the dominant trend will be, so each
case must still be assessed in a case-by-case basis. This is anyway standard practice in industry even
with natural gas transport assets or other industrial processes, so it is not considered a critical aspect
demanding additional research and caution. Existing risk quantification and mitigation methods are
valid and should be applied. Some of the conclusions presented herein should be checked in field tests. For example, noise
generation and radiation in gas district stations has been successfully checked in 2020 in cooperation
with the same HyDelta partners [19]. When possible, it is recommended to look after phenomena
described in this report in field tests involving flowing hydrogen. That would provide the end
evidence to ascertain the trends and conclusions observed in this report. A final note is made with respect to subjects currently not in the scope of this report. Possible
metering errors in flow meters as a result of unsteady flows (pulsations, turbulence) should be better
understood, which is an aspect also linked to the flow speed. It is recommended to explore these
phenomena as an integral part of the investigations conducted to determine the requirements for
flow metering equipment for hydrogen service. Page 55/57 10 List of References 10 List of References [1] Gasunie Transport Services, Ontwerp Uitgangspunten transportsystemen, 1 7 2014 1] Gasunie Transport Services, Ontwerp Uitgangspunten transportsystemen, 1 7 2014. [2] NEN, 7244 - Gasvoorzieningsystemen - Leidingen voor maximale bedrijfsdruk tot en met 16 bar,
NEN, 2014. [3] NEN, 3650 - Transportleidingen, NEN, 2020. [4] NEN, 1059 - Gasvoorzieningsystemen - Gasdrukregel- en meetstations voor transport en
distributie, NEN, 2019. [5] Netbeheer Nederland, Handleiding Nestor Gas, versie 4.0, 1 1 2018. [6] NEN, 3651 - Aanvullende eisen voor buisleidingen in of nabij belangrijke waterstaatswerken,
NEN, 2020. [7] ASME, B31.12 Hydrogen Piping and Pipelines, American Society of Mechanical Engineers, 2020. [8] N. González Díez, S. van der Meer, J. Bonetto and A. Herwijn, Technical assessment of Hydrogen
transport, compression, processing offshore, North Sea Energy, 2020. [9] HIGGS project, https://www.higgsproject.eu/the-project/, 2021. [10] H21 project, H21 Strategic Modelling Major Urban Centers, 2021. [11] K. Steiner, 20 m/s – über die Strömungsgeschwindigkeiten in der Gasinfrastruktur, 2021. [12] N. Albers, L. van Lier and M. van der Biezen, "Engineering approach for world’s largest
hydrogen compression system," in 11th EFRC Conference, Madrid, 2018. [13] Wikipedia, Energy Density, https://en.wikipedia.org/wiki/Energy_density, (Accessed on
February 26, 2019). 14] KIWA, Toekomstbestendige gasdistributienetten, Apeldoorn: KIWA, 2018. [15] Energy Institute, Guidelines for the Avoidance of Vibration Induced Fatigue Failure in Process
Pipework, 2008. [16] ASME PTC 19.3 TW-2016 - Thermowells, American Society of Mechanical Engineers, 2016. [17] IEC 60534-8, Industrial process control valves - Part 8-3: Noise considerations - Control valve
aerodynamic noise prediction method, 2011. [18] NORSOK, L-002 Standard - Piping system layout, design and structural analysis, 4th edition,
2016. [19] C. Lock, Gasdrukregelstation voor waterstof, Apeldoorn: Kiwa N.V., 2020. Page 56/57 Page 56/57 WP1E – Impact of high speed hydrogen
flow on system integrity and noise
D1E.1 – WP1E Report
[20] M. Norton and M. Bull, "Mechanisms of the generation of external acoustic radiation from
pipes due to internal flow disturbances," Journal of Sound and Vibration, vol. 1, no. 94, pp. 105-
146, 1984. [20] M. Norton and M. Bull, "Mechanisms of the generation of external acoustic radiation from
pipes due to internal flow disturbances," Journal of Sound and Vibration, vol. 1, no. 94, pp. 105-
146, 1984. [20] M. Norton and M. Bull, "Mechanisms of the generation of external acoustic radiation from
pipes due to internal flow disturbances," Journal of Sound and Vibration, vol. 1, no. 94, pp. 105-
146, 1984. [21] VDI 3733, Noise at pipes, 1996. [22] Netbeheer Nederland, Affakkelen en afblazen van waterstof (KIWA), 2021. [23] N. Barton, Erosion in Elbows in Hydrocarbon Production Systems: Review Document, Glasgow:
TÜV NEL Ltd for HSE Executive, 2003. 24] A. Kooiman, "Stof tot nadenken," Gasnet, vol. 32, no. 2, June 2018. [25] American Petroleum Institute, API RP 14E : Recommended Practice for Design and Installation
of Offshore Production Platform Piping Systems, 1991. [26] F. Sani, S. Nesic, F. Esaklul and S. Huizinga, Review of the API RP 14E erosional velocity equation:
origin, applications, misuses and limitations, Nashville: NACE, 2019. [27] DNV, DNVGL-RP-O501 Managing sand production and erosion, Det Norske Veritas, 2011. [28] Ministerie van Economische Zaken, Ministeriële Regeling Gaskwaliteit
https://wetten.overheid.nl/BWBR0035367/2019-01-01, Den Haag: Overheid.nl, 2019. Page 57/57
|
https://openalex.org/W3111582363
|
https://www.duo.uio.no/bitstream/10852/81788/2/NilssonHydrologyBMCEcology2020gull.pdf
|
English
| null |
Hydrology influences breeding time in the white-throated dipper
|
BMC ecology
| 2,020
|
cc-by
| 10,895
|
Nilsson et al. BMC Ecol (2020) 20:70
https://doi.org/10.1186/s12898-020-00338-y Nilsson et al. BMC Ecol (2020) 20:70
https://doi.org/10.1186/s12898-020-00338-y BMC Ecology © The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing,
adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and
the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material
in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material
is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the
permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativeco
mmons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/
zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Abstract Background: Earlier breeding is one of the strongest responses to global change in birds and is a key factor deter‑
mining reproductive success. In most studies of climate effects, the focus has been on large-scale environmental
indices or temperature averaged over large geographical areas, neglecting that animals are affected by the local con‑
ditions in their home ranges. In riverine ecosystems, climate change is altering the flow regime, in addition to changes
resulting from the increasing demand for renewable and clean hydropower. Together with increasing temperatures,
this can lead to shifts in the time window available for successful breeding of birds associated with the riverine
habitat. Here, we investigated specifically how the environmental conditions at the territory level influence timing of
breeding in a passerine bird with an aquatic lifestyle, the white-throated dipper Cinclus cinclus. We relate daily river
discharge and other important hydrological parameters, to a long-term dataset of breeding phenology (1978–2015)
in a natural river system. Results: Dippers bred earlier when winter river discharge and groundwater levels in the weeks prior to breed‑
ing were high, and when there was little snow in the catchment area. Breeding was also earlier at lower altitudes,
although the effect dramatically declined over the period. This suggests that territories at higher altitudes had more
open water in winter later in the study period, which permitted early breeding also here. Unexpectedly, the largest
effect inducing earlier breeding time was territory river discharge during the winter months and not immediately
prior to breeding. The territory river discharge also increased during the study period. Conclusions: The observed earlier breeding can thus be interpreted as a response to climate change. Measur‑
ing environmental variation at the scale of the territory thus provides detailed information about the interactions
between organisms and the abiotic environment. Keywords: Breeding phenology, Climate change, Environmental heterogeneity, Hydropower, Long-term study,
Passerine bird, River discharge, Snow, Spatial scale, Stream global change and is a key factor determining reproduc-
tive success [7, 37, 54]. Most studies of climatic effects
have focused on large-scale estimates of environmental
variation, such as the North Atlantic Oscillation (NAO)
or temperature averaged over large geographical areas,
neglecting the fact that organisms are affected by the
local conditions in their home ranges [34]. Even on the
scale of a population, an individual might use a very lim-
ited proportion of the population space; thus, popula-
tion-specific measurements might not accurately reflect Hydrology influences breeding time
in the white‑throated dipper Anna L. K. Nilsson1,2* , Thomas Skaugen3, Trond Reitan1,3, Jan Henning L’Abée‑Lund3, Marlène Gamelon4,
Kurt Jerstad5, Ole Wiggo Røstad6, Tore Slagsvold1, Nils C. Stenseth1, L. Asbjørn Vøllestad1 and Bjørn Walseng7 © The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing,
adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and
the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material
in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material
is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the
permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativeco
mmons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/
zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Background Spring phenology, the annual timing of recurring life-
history events in spring, is well-known to have advanced
(become earlier) in response to climate change [42]. Ear-
lier breeding in birds is one of the strongest responses to *Correspondence: anna.nilsson@nina.no
2 Norwegian Institute for Nature Research, Thormøhlens Gate 55,
5006 Bergen, Norway
Full list of author information is available at the end of the article *Correspondence: anna.nilsson@nina.no
2 Norwegian Institute for Nature Research, Thormøhlens Gate 55,
5006 Bergen, Norway
Full list of author information is available at the end of the article © The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing,
adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and
the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material
in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material
is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the
permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativeco
mmons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/
zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Nilsson et al. BMC Ecol (2020) 20:70 Page 2 of 11 Page 2 of 11 the exposure of an individual to the current environmen-
tal conditions [11, 24]. In fact, organisms experience the
local weather and its direct effects on the availability of
food and shelter. This determines whether resources are
to be accumulated or if stored resources are depleted, and
determines the allocation of resources to growth, survival
and reproduction. In addition to the local weather condi-
tions, the environmental challenges faced by organisms
may also be influenced by other aspects of the local area
they inhabit. The local area is often defended against con-
specifics and is then termed a territory. Territories are
heterogeneous in geography and topography, which can
have implications for the availability of breeding sites and
foraging opportunities; the availability of food resources
might vary at small spatial scales [24]. The robustness
to environmental variation such as droughts and floods
might furthermore vary between territories. Such heter-
ogeneity can lead to differences in territory quality [46]
determining variation in occupancy between years [13]. Environmental variation measured at the scale of the ter-
ritory might thus affect individual life history decisions,
such as the timing of breeding. temperature is important for initiating breeding, but
spring temperature has so far only been measured at
the regional level [37]. The documented effect of spring
temperature most likely reflects an extrapolation of local
microclimatic conditions on the scale of the territory,
such as local river discharge dynamics and snow condi-
tions. Thus, in this study, we investigate how environmen-
tal variation at the scale of the territory, such as the local
river discharge (defined as the volume of water flowing
past a cross-section of a river per unit time), hydrological
dynamics, territory and individual characteristics, influ-
ence the timing of breeding. In this study system, Skau-
gen et al. [48] developed a model allowing simulations of
daily values of a number of biologically important hydro-
logical variables at each dipper territory in our study
system during 1978–2015. We here relate these unique
hydrological data to our long-term dipper breeding data
to test the hypothesis that local environmental variation,
particularly runoff, at the scale of the territory influences
timing of breeding. Furthermore, our study uses a novel
method, the biologically-based “trigger date”, to deal with
the statistically unsound problem of circularity in causal-
ity. This is often encountered in phenology analyses when
using sliding window-approaches to determine periods
of importance, which then are included in the statistical
analyses (using response to find appropriate period and
then using period to predict response). Temperature and precipitation have increased rapidly
during the last 100 years in northern Europe [22]. This
has naturally led to changes in snow conditions and the
extent of ice cover during winter [47] and potentially
changed the timing of snow melt, and ultimately the tim-
ing of spring floods. Similarly, this has changed water
discharge in rivers and streams, and consequently the
occurrence and size of floods and droughts [29]. Further
climate change is predicted to lead to more alterations
in precipitation, discharge, evaporation, and shifts in
drought and flood patterns [33], which will have impor-
tant implications for species closely associated with the
riverine habitat [43]. In addition, freshwater ecosystems
are under pressure in the pursuit of clean and renew-
able energy resources, where hydropower is an attractive
alternative to fossil fuels. Hydropower development has
major impacts on ecosystem functioning as the construc-
tion of dams and reservoirs interrupts the natural flow
regime, which is the main driver of all ecological pro-
cesses in rivers and streams [39]. General analysesh The median hatching date of the dipper was the 8th of
May (hatching-day-of-year = 128, mean = 129.6, stand-
ard deviation, SD = 13.2 days). Hatching date advanced
(earlier) 10.2 days during the study period (1978–2015)
as shown in a mixed-effects linear regression model with
only year as a linear predictor and year as the random
effect (random effect, year SD = 7.7, residual SD = 10.9;
fixed effect year: b = − 0.27, t = − 2.2, P = 0.035; Fig. 1). Male dippers arrived at the breeding grounds 2.5 days
before
females
(mean = 2.43,
SD = 18.65;
t = 6.2,
df = 2278, P < 0.0001). Trigger dates varied from 1st
of February (day-of-year = 31) to 28th of April (day-
of-year = 119; median = 43 (13th of Feb), mean = 54.9
(24th of Feb)), and the annual variation in trigger dates
among territories was on average 38 days (SD = 25.3,
range 0–87). In random factor decomposition, we found
a standard deviation of 10.6 days between the territo-
ries, while the within-territory standard deviation was
23.0 days. This means that the within-territory variation
explained 82.6% of the variation in trigger date. During
the study period, there was a positive temporal trend in
the relative winter discharge (trigger period 17 (Dec–
Feb; see Table S1, Additional file 1); mixed-effects linear In birds, most studies of breeding phenology have
focused on species that depend on terrestrial food
resources [7, 14, 55], but see [10]. Here, we report the
results from a long-term study of a passerine bird that
collects most of its resources year-round under water,
namely the white-throated dipper Cinclus cinclus (here-
after dipper). This aquatic life style confers some special
challenges in the northern range of the dippers’ distri-
butions, because winter survival and onset of breeding
are dependent on the presence of ice-free (open) water
[18, 35, 37], and thus on hydrological dynamics. Spring Nilsson et al. BMC Ecol (2020) 20:70 Page 3 of 11 model: random effect: year SD = 0.53, residual SD = 0.28,
fixed effect year: b=0 02 t=2 1 P=0 04)
Fig. 1 The advancement in breeding time in the white-throated
dipper population in Lyngdalselva. The advancement in hatching
date (hatching day-of-year, solid line) in the white-throated dipper
population in Lyngdalselva, in Norway. General analysesh Estimated fixed effects and variance decomposition of fixed and random effects
in a linear mixed effects model explaining the variation in hatching date in
the white-throated dipper, where “spring” and “winter” is applied to enhance
understanding of the terms SCA (Snow Covered Area), Qnorm (relative river
discharge) and NAO (North Atlantic Oscillation). Numbers in brackets in the
variable names denote the trigger period, mean and sd denote mean and
standard deviation of the variable in the specified trigger period General analysesh Grey points denote observed
annual hatching days and black points the observed annual average
hatching date in 1978–2015 Table 1 Estimate fixed effects and variance decomposition
explaining the variation in breeding time
Estimated fixed effects and variance decomposition of fixed and random effects
in a linear mixed effects model explaining the variation in hatching date in
the white-throated dipper, where “spring” and “winter” is applied to enhance
understanding of the terms SCA (Snow Covered Area), Qnorm (relative river
discharge) and NAO (North Atlantic Oscillation). Numbers in brackets in the
variable names denote the trigger period, mean and sd denote mean and
standard deviation of the variable in the specified trigger period
Variables
Estimate
Std. Error
Variance
decomposition
Intercept
136
3.15
–
Spring SCA sd [6]
7.0
2.14
0.4
Spring Groundwater
mean [14]
− 0.067
0.02
1.1
Winter Qnorm mean [17]
− 6.6
0.95
10.3
Spring NAO [26]
− 0.78
0.24
1.2
M novely
2.2
0.43
0.8
beta polygyny indicator
6.7
0.73
2.2
Age f
− 5.7
0.67
–
Age f2
0.57
0.08
2.8
Altitude
0.055
0.004
–
Year
− 0.10
0.09
–
Altitude × Year
− 0.00082
0.00
29.2
Std. Deviation Correlation –
Year
8.4
–
Qspec sd [23] |Year
0.080
− 0.85
20.5
Territory id
2.5
4.3
F id × Territory id
3.1
6.7
Residual
5.5
– Table 1 Estimate fixed effects and variance decomposition
explaining the variation in breeding time Fig. 1 The advancement in breeding time in the white-throated
dipper population in Lyngdalselva. The advancement in hatching
date (hatching day-of-year, solid line) in the white-throated dipper
population in Lyngdalselva, in Norway. Grey points denote observed
annual hatching days and black points the observed annual average
hatching date in 1978–2015 Fig. 1 The advancement in breeding time in the white-throated
dipper population in Lyngdalselva. The advancement in hatching
date (hatching day-of-year, solid line) in the white-throated dipper
population in Lyngdalselva, in Norway. Grey points denote observed
annual hatching days and black points the observed annual average
hatching date in 1978–2015 model: random effect: year SD = 0.53, residual SD = 0.28,
fixed effect year: b = 0.02, t = 2.1, P = 0.04). model: random effect: year SD = 0.53, residual SD = 0.28,
fixed effect year: b = 0.02, t = 2.1, P = 0.04). Model selectionh The most supported model to account for the variation
in hatching date in the dipper population contained the
environmental variables normalized mean winter river
discharge (Winter Qnorm mean 17), spring NAO (Spring
NAO 26), spring ground water levels (Spring Ground-
water mean 14), spring variation in snow cover (Spring
SCA sd 6), and the temporal trend in altitude, where the
effect of altitude on timing of breeding changed during
the study period (Table 1). The best model also included
the individual variables female age (the quadratic effect,
Age f2), male polygyny status (beta polygyny indicator)
and whether the territory occupied by the male was new
to him or not (M novelty; Table 1). Among the random
effects, the interaction between female (F id) and terri-
tory ID accounted for 6.7% of the variation in hatching
date, while territory ID itself accounted for 4.3% and the
variation in specific river discharge in combination with
year accounted for 20.5% (Qspec sd 23, random slope;
Table 1) of the variation in hatching date (Table 1). Hatch-
ing date advanced (was earlier) with increasing normal-
ized mean winter river discharge (Winter Qnorm mean
17), spring NAO (spring NAO 26), and spring ground-
water levels (Spring Groundwater mean 14; Fig. 2). There was a quadratic effect for female age (Age f2), with
delayed hatching date for females younger than four years old (fifth calender year; Fig. 3) and for females older than
that. On the other hand, hatching date was delayed by
increasing variation in spring snow cover (Spring SCA sd
6) at the lowest part of each territory’s catchment (Fig. 2),
male territory novelty (M novelty) and polygyny (beta
polygyny indicator), and altitude (Fig. 4). During the
study period, the delay in hatching date decreased from
5.5 to 2.5 days per 100 m increase in altitude (Fig. 4),
indicating that the difference in hatching date at high
and low altitudes diminished over the study period. The
random slope variation in specific river discharge during
the previous spring and summer (Qspec sd 23) could not
be explained by annual variation or any other predictor
variable, although within the interaction, year explained
91% of the variation. Model selectionh a Mean relative
river discharge at each territory during the preceding Dec–Feb (Winter Qnorm mean [17]), b the North Atlantic Oscillation (NAO) 10–21 days
after the trigger date at each territory (Spring NAO [26], c the minimum ground water levels for the last 20 days before the trigger date (Spring
groundwater mean [14]), and d the maximum Snow Covered Area (SCA) the last 30 days before the trigger date (Spring SCA sd (06)), where 0 is
no snow cover and 1 is full snow cover. Solid lines denote the effect and vertical dotted lines denote the 5 and 95% quantiles of the raw data. The
trigger date is defined as the first date when the daily air temperature exceeded 0 °C for five consecutive days
Fig. 3 The effect of age on timing of breeding. The effect of age
(calendar year) on timing of breeding (hatching day-of-year) shown
as a quadratic line (for all other variables set at their average values)
in the white-throated dipper population in Lyngdalselva 1978–2015. Grey dots correspond to observed hatching dates per age, with ages
jittered in order to increase visibility of the full dataset
Fig. 4 The effect of altitude on the timing of breeding. The effect of
altitude (all other variables set at their average values) on the timing
of breeding (hatching day-of-year) in 1978 (solid line), 1987 (stapled
line), 1996 (dotted), 2005 (stapled and dotted), 2015 (long staples) in
the white-throated dipper population in Lyngdalselva 1978–2015 Fig. 2 The influence of the hydrological and climatic predictor variables on the timing of breeding. The influence of the hydrological and climatic
predictor variables on hatching date (hatching day-of-year) in the white-throated dipper population in Lyngdalselva 1978–2015. a Mean relative
river discharge at each territory during the preceding Dec–Feb (Winter Qnorm mean [17]), b the North Atlantic Oscillation (NAO) 10–21 days
after the trigger date at each territory (Spring NAO [26], c the minimum ground water levels for the last 20 days before the trigger date (Spring
groundwater mean [14]), and d the maximum Snow Covered Area (SCA) the last 30 days before the trigger date (Spring SCA sd (06)), where 0 is
no snow cover and 1 is full snow cover. Solid lines denote the effect and vertical dotted lines denote the 5 and 95% quantiles of the raw data. Model selectionh The effect of
altitude (all other variables set at their average values) on the timing
of breeding (hatching day-of-year) in 1978 (solid line), 1987 (stapled
line), 1996 (dotted), 2005 (stapled and dotted), 2015 (long staples) in
the white-throated dipper population in Lyngdalselva 1978–2015 Fig. 3 The effect of age on timing of breeding. The effect of age
(calendar year) on timing of breeding (hatching day-of-year) shown
as a quadratic line (for all other variables set at their average values)
in the white-throated dipper population in Lyngdalselva 1978–2015. Grey dots correspond to observed hatching dates per age, with ages
jittered in order to increase visibility of the full dataset Fig. 3 The effect of age on timing of breeding. The effect of ag Model selectionh The random slope in specific river
discharge nevertheless had a significant effect on the
timing of breeding (see Figure S3, Additional file 2), and
this means that the effect of river discharge the previ-
ous spring and summer could be negative in 1 year and
positive in another. The 95% confidence interval for the
model prediction was ± 10.7 days (SD = 5.5). old (fifth calender year; Fig. 3) and for females older than
that. On the other hand, hatching date was delayed by
increasing variation in spring snow cover (Spring SCA sd
6) at the lowest part of each territory’s catchment (Fig. 2),
male territory novelty (M novelty) and polygyny (beta
polygyny indicator), and altitude (Fig. 4). During the
study period, the delay in hatching date decreased from
5.5 to 2.5 days per 100 m increase in altitude (Fig. 4),
indicating that the difference in hatching date at high
and low altitudes diminished over the study period. The
random slope variation in specific river discharge during
the previous spring and summer (Qspec sd 23) could not
be explained by annual variation or any other predictor
variable, although within the interaction, year explained
91% of the variation. The random slope in specific river
discharge nevertheless had a significant effect on the
timing of breeding (see Figure S3, Additional file 2), and
this means that the effect of river discharge the previ-
ous spring and summer could be negative in 1 year and
positive in another. The 95% confidence interval for the
model prediction was ± 10.7 days (SD = 5.5). Nilsson et al. BMC Ecol (2020) 20:70 Page 4 of 11 Discussion
Timing of breeding advanced 10 days during the study
period 1978–2015. Earlier breeding in birds is one of the
Fig. 2 The influence of the hydrological and climatic predictor variables on the timing of breeding. The influence of the hydrological and climatic
predictor variables on hatching date (hatching day-of-year) in the white-throated dipper population in Lyngdalselva 1978–2015. Model selectionh The
trigger date is defined as the first date when the daily air temperature exceeded 0 °C for five consecutive days Fig. 2 The influence of the hydrological and climatic predictor variables on the timing of breeding. The influence of the hydrological and climatic
predictor variables on hatching date (hatching day-of-year) in the white-throated dipper population in Lyngdalselva 1978–2015. a Mean relative
river discharge at each territory during the preceding Dec–Feb (Winter Qnorm mean [17]), b the North Atlantic Oscillation (NAO) 10–21 days
after the trigger date at each territory (Spring NAO [26], c the minimum ground water levels for the last 20 days before the trigger date (Spring
groundwater mean [14]), and d the maximum Snow Covered Area (SCA) the last 30 days before the trigger date (Spring SCA sd (06)), where 0 is
no snow cover and 1 is full snow cover. Solid lines denote the effect and vertical dotted lines denote the 5 and 95% quantiles of the raw data. The
trigger date is defined as the first date when the daily air temperature exceeded 0 °C for five consecutive days Discussion
Timing of breeding advanced 10 days during the study
period 1978–2015. Earlier breeding in birds is one of the
Fig. 3 The effect of age on timing of breeding. The effect of age
(calendar year) on timing of breeding (hatching day-of-year) shown
as a quadratic line (for all other variables set at their average values)
in the white-throated dipper population in Lyngdalselva 1978–2015. Grey dots correspond to observed hatching dates per age, with ages
jittered in order to increase visibility of the full dataset
Fig. 4 The effect of altitude on the timing of breeding. The effect of
altitude (all other variables set at their average values) on the timing
of breeding (hatching day-of-year) in 1978 (solid line), 1987 (stapled
line), 1996 (dotted), 2005 (stapled and dotted), 2015 (long staples) in
the white-throated dipper population in Lyngdalselva 1978–2015 Fig. 4 The effect of altitude on the timing of breeding. The effect of
altitude (all other variables set at their average values) on the timing
of breeding (hatching day-of-year) in 1978 (solid line), 1987 (stapled
line), 1996 (dotted), 2005 (stapled and dotted), 2015 (long staples) in
the white-throated dipper population in Lyngdalselva 1978–2015 Fig. 4 The effect of altitude on the timing of breeding. Discussion [24], where the timing of oak leaf emergence
in the territory accurately predicted breeding phenology. Evidently, there is immense environmental heterogeneity
within single populations, and large-scale climate indi-
ces or population-level measurements might not reliably
capture the level of environmental variation the individu-
als are exposed to [11, 24].h An unexpected effect was the variation in response to
discharge variation during the previous spring and sum-
mer between years (the random slope). A possible expla-
nation might be that discharge variation might have a
very different effect in a year with moderate compared
to high mean discharge. However, it may also be that this
effect is correlated with an unmeasured climatic driver
that vary from year to year.i Dippers breeding at high altitudes were delayed, a find-
ing also reported in other bird species [23, 28, 44, 56]. Altitude was the parameter that contributed the single
most to explain the variation in the timing of breeding. As there is a steep altitudinal gradient in this population
and temperature drops with 0.65 °C by 100 m increase
in altitude, altitude was probably indicating when in
spring a territory would become available to prospec-
tive breeders. Surprisingly, the altitudinal effect on the
timing of breeding was decreasing over the study period,
from 6 days to merely 1 day delay in hatching per 100 m
increase in altitude. It might be that after mild winters,
more territories are accessible prior to the breeding sea-
son also at higher elevations, rending the altitudinal gra-
dient less influential. Because of global warming, winters
have generally become warmer and this might have led
to a more synchronous breeding across altitudes in our
study population. The environmental conditions prevailing on the terri-
tories around the trigger date, but also the winter condi-
tions, affected breeding time. Territory river discharge
was particularly influential in determining the breeding
time in the dipper, as suggested by D’Amico et al. [12]. Surprisingly, it was not the river discharge immediate
before breeding, around the trigger date, but during the
winter months prior to the breeding season that had the
greatest effect on the breeding time. As the food sources
exploited by the dippers are hidden under water, the
water levels, velocity and turbidity could influence dip-
per foraging success during winter [15], which might
have implications for when the individual bird is physi-
ologically capable of starting to breed. Discussion Timing of breeding advanced 10 days during the study
period 1978–2015. Earlier breeding in birds is one of the Nilsson et al. BMC Ecol (2020) 20:70 Page 5 of 11 conditions, because this species is negatively affected by
the ice conditions in winter [35]. In the 3–4 weeks prior
to the trigger date at each territory, increasing minimum
ground water levels and decreasing maximum snow-
covered area (SCA) advanced breeding time. This criti-
cal time period precedes territory establishment and nest
building. The minimum groundwater levels may reflect
some aspects of the discharge at a vital time, while the
snow conditions may indicate the timing of spring floods. Flooding might be particularly detrimental to the dipper,
because the nest is positioned immediately above fast-
flowing water and may be flushed away by the current
if water levels increase. Flooding may also reduce water
visibility and hamper foraging success [8]. Judging from
the relative importance of the investigated variables,
we conclude that the long-term (months) hydrologi-
cal conditions specific to a particular territory prior to
the breeding season seem surprisingly important com-
pared to the weather conditions prevailing shortly before
breeding. most reported responses to climate change [14, 38, 42]. Dunn and Winkler [14] argued that variation in popu-
lation density and habitat quality might influence the
interpretation of phenology responses. However, this is
unlikely to have been the case in our study. Although the
population density of the dipper is predicted to increase
in the future because of warmer winters [18], currently
there are strong fluctuations but no obvious long-term
trend [35]. Previous work in this study system [19, 37]
also indicates that high population density results in
earlier breeding, which is opposite to the prediction by
Dunn and Winkler [14]. The advancement in breeding
time reported here may thus be interpreted as a response
to climate change. Environmental variation measured at the territory had
a significant influence on the timing of breeding. The
level of environmental heterogeneity between territories
was immense, as reflected by the variation in the trig-
ger date (the first date when temperature was above 0 °C
for five consecutive days), which varied by more than a
month on average and in some years almost by 3 months. Thus, individuals even within close range of each other,
in this case within 70 km, experienced very different
environmental conditions. This supports the findings by
Hinks et al. Study species and study systemh The dipper is common across the Palearctic mountain-
ous regions and it breeds in close proximity to rapidly
flowing parts of rivers and streams. Territories are estab-
lished in early spring and both sexes build the nest and
feed the young, except in instances of polygyny where
the male contribution is lower. The clutch of 3–6 eggs
are incubated by the female for a period of 17 days and
the young remain in the nest for approximately 20 days
before fledging [19, 37, 52]. The study population is par-
tially migratory, where part of the population undertakes
migration to southern Sweden, Denmark, and northern
Germany and Poland [4].h We also found that breeding time depended on female
age, with four-year olds breeding earlier than both
younger and older females. Reproductive performance
and associated traits such as the timing of breeding usu-
ally improve with age and then level off [16]. However,
age-specific reproductive output is more commonly
reported than age-specific differences in timing of breed-
ing (but see [5, 20, 30, 32, 53, 59]. Supposedly, the same
mechanisms governing age-specific reproductive out-
put, such as selective disappearance of poor breeders and
individual improvement with increasing age and experi-
ence [20, 32, 41], might also explain the observed pattern
in breeding phenology. y
The study system is situated in river Lyngdalselva and
its tributaries in southernmost Norway (58° 08′–58° 40′
N, 6° 56′–7° 20′ E). The system is subject to a strong alti-
tudinal gradient, reaching almost from the river mouth
in Lyngdalsfjorden to 60 km inland and 700 m above
sea level. The population has been monitored accord-
ing to a standardised methodology since 1978 [35]. The
population size has fluctuated between 20 and 117 pairs
(defined as the number of breeding females). Almost
all (94%) breeding birds have been individually identi-
fied. Birds are caught in mist nets at first encounter and
ringed with a metal ring and an individual colour code
comprising two plastic rings. Individual colour codes
enable later recognition of individual identity without
having to recapture the bird. Arrival date was registered
as first encounter of each bird each year, by ring reading
or capture at first encounter. In some instances, arrival
date was not registered until well into the breeding cycle. The breeding outcome of almost all nests is known and
nearly all young are ringed. Study species and study systemh For more details on the study
system, see Nilsson et al. [35]. Dippers prefer nest sites
where the opening of the nest is situated over fast-flow-
ing water [52]. Because nest sites are limited and spatially
segregated, there is a limited number of individual terri-
tories containing one or more nest sites, namely 158, as
recorded within the whole river system during the entire
study period. Polygyny is well documented in the dipper, but the
frequency varies both between populations and years
[17, 31, 58]. We found that breeding time did not differ
between females mated to monogamous males and pri-
mary females mated to polygynous males, but that the
onset of breeding of females that settled with an already
mated male was delayed. In this species, late breeding
reduces reproductive success [37] which might be a sig-
nificant cost of polygyny. Discussion In general, pre-
cipitation in southern Norway has increased (1961–2009;
[47] and, similarly, the mean winter temperature in the
study area has increased at least by 3 °C (1978–2008; [35],
meaning that less precipitation falls as snow. During the
study period, there was a tendency towards increased
river discharge, which might contribute to the temporal
trend in breeding phenology. Most importantly, high dis-
charge indicates open water [26, 40] and thus favourable We found a significant interaction between territory
and female identity that affected the timing of breed-
ing, i.e., certain combinations of individuals and terri-
tories were associated with earlier breeding and others
with later breeding. The ability to take advantage of the
resources in a given territory may differ between indi-
viduals and be reflected by the timing of breeding. In Nilsson et al. BMC Ecol (2020) 20:70 Page 6 of 11 Page 6 of 11 some species, immigrants and locally recruited birds may
differ both in laying time and prey choice, and this may
reflect genetic differences, differences in quality, or the
early learning environment [50]. Interestingly, males that
established themselves in unknown territories as well as
first-time breeding males, bred on average 2 days later
than males that established themselves in familiar territo-
ries where they had previous breeding experience. Thus,
not only female experience but also male familiarity with
a territory may influence the time of breeding. Female
site familiarity has previously been shown to be impor-
tant [45], but it has only recently been shown that male
experience influence breeding time [57]. Foraging and
prey choice may however improve equally with experi-
ence in the two sexes [50]. Depending on their local expe-
riences, males might differ in eagerness and contribution
to nest building, thus affecting the time for initiation of
breeding. This finding highlights the importance of male
territory familiarity and thus proving that breeding time
is not solely a female trait. winter period as well as in early spring. This also applies
to rivers and streams outside the breeding areas, because
the dipper is a short-distance partial migrant. This study
is by nature an explorative approach, where the results
provide the first step in seeking out biologically relevant
hydrological and other environmental drivers of the tim-
ing of breeding. Further work is required to understand
how discharge is affecting riverine birds in the long-term,
particularly in the immediate proximity to hydropower
developments. Conclusions In conclusion, we have shown how hydrological dynam-
ics and other prominent local characteristics of the envi-
ronment at the territory scale influence the timing of
breeding in the dipper. Particularly, the river discharge
and the altitudinal effect were of great importance to this
riverine specialist bird. From a management perspective,
it should be emphasized that the dipper, often used as an
indicator species, is particularly sensitive to changes in
river discharge and the snow conditions during the entire Nilsson et al. BMC Ecol (2020) 20:70 Page 7 of 11 The timing of breeding is estimated as the hatching
date of the first clutch of a female in a year (see [36]. In
short, hatching date is based on the growth trajectory of
the largest young in the brood, i.e. the individual that is
closest to the maximum physiological growth rate. This
implies that the phenology of nests that did not produce
young, or produced young that were not measured, could
not be estimated by this method. All-together, a total of
1184 breeding events with estimated breeding time dur-
ing the study period are analysed here. A total of 1271
breeding events with no estimated breeding time were
excluded, and another 209 breeding events with breed-
ing time were excluded due to inaccuracies in the ringing
data or absence of hydrology data. In the study area, territory river discharge is of vastly
different magnitudes. For example, the last dipper terri-
tory in the main river before the outlet into the fjord has
a very large catchment area and thus discharge compared
to the territories located in small brooks in the moun-
tains (mean discharge varied between territories, from
0.008 m3/s to 32 m3/s). To allow comparison among ter-
ritories, river discharge was standardized with two com-
peting methods. First, river discharge was standardized
as specific discharge, which is discharge per catchment
area, measured in l/s/km2, at each breeding territory
(Qspec; Table 2). Second, it was standardized as the rela-
tive river discharge (defined as discharge divided by the
territory mean discharge for the study period; Qnorm;
Table 2). Because access to open water is of vital importance for
the dippers’ foraging and thus breeding opportunities in
seasonal environments, we defined an annual trigger date
based on the daily temperature at each individual terri-
tory (Additional file 1). Conclusions Hence, the trigger date was used
for solving the problem of which environmental variable
at which time period was of importance for the timing of
breeding, with a biological basis. The hydrological simu-
lations produced daily measurements, for 38 full years,
of many potentially important hydrological and other
environmental variables for timing of breeding in the
dipper. The common procedure in dealing with tempo-
ral data is to use a sliding window approach [2], which
is far from ideal when the period length is unknown and
when it likewise is unknown whether the period relates
to a date or a biological trigger. By using the response
variable, which in studies of phenology is temporal, to
find the time period of the exploratory variable with the
best fit, the final analysis predicting the response with the
best-fit exploratory variable is using the future to predict
the past, and thus not a statistically sound procedure. Instead, we solve the problem by allowing the main anal-
ysis of the response to find the time period that actually
explains the response. The statistics is expanded upon
in the Statistics section, but we simply let a multivari-
ate framework select the time period of the explanatory
variable(s) that explains the variation in the response. Time periods had a biological basis, built on the “trigger
date”; thus, at each territory, the annual trigger date was
defined as the first date when the daily air temperature
had exceeded 0 °C for five consecutive days (Additional
file 1). Such a duration of time will speed up the melting
of snow and ice. We then defined a number of different
time periods, defined as trigger periods, with different
starting dates and of various duration related to the trig-
ger date (see Table S1, Additional file 1). This was done
in order to catch weather variation at and around the
critical moments when egg laying first becomes feasible Hydrology data
d
l
l d Hydrological data are normally restricted to gauged sites,
which often are inconveniently located with respect to
the biological study systems of interest. In Lyngdalselva,
only two sites are gauged. However, the rainfall-runoff
model (the Distance Distribution Dynamics (DDD)
model, [48]) has produced predictions of river discharge
in ungauged basins in the Lygne basin at each unique
dipper breeding territory (except for 13 out of 158 terri-
tories whose catchments were too small). The model for
Lyngdalselva is extremely good when comparing model
predictions and gauged sites; the Kling Gupta Efficiency
criterion (KGE; [21, 27]) for both gauged sites in Lyng-
dalselva is 0.94. Thiemig et al. [51] regard values KGE
0.5–0.75 as intermediate, and 0.75–0.9 as good; a KGE of
0.94 for Lyngdalselva is thus extraordinarily good. Sev-
eral of the model parameters of DDD are estimated from
digitized maps of terrain and river network. In addition,
regressed relations between model parameters and catch-
ment characteristics, like fractions of forest and bare
rock, wetland, and so on are determined by calibrating
the model against observed runoff from several gauged
catchments in Norway. Daily river discharge data in the
Lygne basin have therefore been estimated for the whole
study period 1978–2015. The data input for the rainfall-
runoff-model, precipitation (P; Table 1) and temperature
(T; Table 2), stems from the interpolated meteorological
grid, and contains also environmental variables specific
to each territory. In addition, snow covered area (SCA;
Table 2), snow water equivalent (SWE; Table 2; [49] and
groundwater levels (Groundwater; Table 2) are predicted
by the DDD model. All are variables that may prove to be
significant biological predictors of the timing of breeding
in the dipper, reflecting microclimatic or other important
environmental variation at each territory (for a full list,
see Table 2; for further details on the hydrological vari-
ables, see [48]. Nilsson et al. Hydrology data
d
l
l d BMC Ecol (2020) 20:70 Page 8 of 11 Table 2 Predictor variables and their explanation used in analysing variation in breeding time
Variable type
Predictor
Explanation
Territory–indicating microclimate
Altitude
Altitude of most frequented nest site at the territory
Distancea
Distance from the river outlet to the most frequented nest site at the territory
Qmeana
Absolute mean annual discharge
Catchment–indicating microclimate
Area
Size of catchment area (m2)
Altitude median
Median elevation of catchment (m)
Altitude diff
Altitudinal range of catchment (m)
Bog fraction
Fraction of bogs in catchment, which contribute to flow when saturated
Bog max
Maximum of distance distribution for bogs (m)
Bog mean
Mean of distances (m) between grid-points in the catchment classified as bogs to the
nearest river reach, indicating the flow dynamics from saturated bogs
Bog fractionb
Areal fraction of grid cells with zero distance to the river network for bogs
S mean
Mean of distances (m) between grid-points in the catchment classified as soils to the
nearest river reach, indicating the flow dynamics from soils
Soil fraction
Areal fraction of grid cells with zero distance to the river network for soils
L mean
Mean of the distances (m) between points in the river network, a measure of river
network complexity
L sd
Standard deviation of distances between points in the river network to the outlet, a
measure of river network complexity
L max
Maximum of distance distribution of the river network, a measure of river network
complexity
Evotranspiration
Degree-day factor for evotranspiration (mm/day/ °C)
Trigger
Trigger day
Trigger day index for first five-day period above 0 °C
Qspec*
Specific discharge (l/s/km2, discharge per area unit)
Qnorm*
Normalized discharge (discharge/annual mean discharge)
T*
Temperature (°C)
P*
Precipitation (mm)
Groundwater*
Dynamic groundwater storage (mm). Hydrology data
d
l
l d The part of groundwater storage that fluctuates
with runoff indicating hydrological drivers
SCA*
Fraction of the lowest 10% of the catchment that is snow covered
SWE*
Snow water equivalent at the lowest 10% of the catchment (mm)
Ql10*
Indicating whether discharge exceeded 10 l/s or not (indicating extreme drought) in
period
Ql100*
Indicating whether discharge exceeded 100 l/s or not (indicating drought) in period
Global climate
NAO*b
Daily North Atlantic Oscillation Index
NAOcurr
North Atlantic Oscillation Index current year
NAOprev
North Atlantic Oscillation Index previous year
Individual
Age fa
Female age indicating individual experience and possible age restrictions
Age ma
Male age indicating individual experience and possible age restrictions
Polyandry
Polyandry status: monogamous or polyandrous brood
Polygyny all
Polygyny status: monogamous, alpha, beta, gamma, successive alpha, and successive
beta brood
Polyandry history
0/1 indicator for whether the female has been polyandrous, 1 = yes
Polygyny history
0/1 indicator for whether the male has been polygynous, 1 = yes
polygyny indicator
0/1 indicator for whether the male was detectably polygynous for this brood, 1 = yes
beta polygyny indicator
0/1 indicator for whether the male was detectably polygynous and this wasn’t the
alpha brood, 1 = yes
polyandry indicator
0/1 indicator for whether the female was detectably polyandrous for this brood, 1 = yes
male first
0/1 indicator for whether this was the first hatching for this male, 1 = yes
female first
0/1 indicator for whether this was the first hatching for this female, 1 = yes
M novelty
Male territory novelty, 1 = first time for this male in this territory
F novelty
Female territory novelty, 1 = first time for this female in this territory
Other
lintime
Temporal time trend, indicating possible global climatic change Other Page 9 of 11 Nilsson et al. Hydrology data
d
l
l d In addi-
tion, we introduced two indicator variables for drought,
using the original discharge threshold at 0.01 m3/s and
0.1 m3/s. Lastly, we included the daily North Atlantic
Oscillation index (NAO) to account for fluctuations in
the global climate [25], that might not have been cap-
tured by the variation in the hydrological simulations. (Additional file 1). In addition, some of our possible peri-
ods are statically defined, using fixed start and end dates. For each trigger period in each year and territory, we
estimated the mean, maximum, minimum and standard
deviation. For river discharge, this was calculated for spe-
cific discharge as well as for relative discharge. In addi-
tion, we introduced two indicator variables for drought,
using the original discharge threshold at 0.01 m3/s and
0.1 m3/s. Lastly, we included the daily North Atlantic
Oscillation index (NAO) to account for fluctuations in
the global climate [25], that might not have been cap-
tured by the variation in the hydrological simulations. Hydrology data
d
l
l d BMC Ecol (2020) 20:70 Table 2 (continued)
Variable type
Predictor
Explanation
Random effects
Yeara
Annual variation not explained by climatic variables
M id
Male identity (ring number) indicating individual variation
F id
Female identity (ring number) indicating individual variation
Territory id
Territory identity indicating spatial variation not explained by territory and catchment
variables
A list of all predictor variables and their biological explanation used in analysing the variation in the timing of breeding in the white-throated dipper population in
Lyngdalselva 1978–2015
*Mean, min, max and sd were estimated for all trigger periods
a The quadratic effect was also included
b From the National Weather service, Climate Prediction Center, http://www.cpc.ncep.noaa.gov/products/precip/CWlink/pna/nao.shtml qf
rom the National Weather service, Climate Prediction Center, http://www.cpc.ncep.noaa.gov/products/precip/CWlink/pna/nao.shtml interest for hatching date, namely the trigger date and
the winter river discharge, by investigating the univari-
ate regression of each of these variables in turn. We then
modelled hatching date with multiple effects using linear
mixed-effects models to account for random effects, such
as male and female ID, territory ID and year. All analyses
were conducted in the programming environment R (ver-
sion 3.2.5) with add-on packages ‘lme4’ for linear mixed-
effects models [6]. Possible predictors included the
hydrological variables and other climatic variables such
as precipitation, temperature and NAO using the trigger
periods (Table 2). Location-specific variables from the
rainfall-runoff model were also added as possible predic-
tors, as well as altitude and random location intercepts. We investigated temporal trends in breeding time both
by using numeric year as a possible linear predictor and
by using categorical year as a random intercept or a ran-
dom slope for climatic variables. Last, we included the
individual characteristics of the breeding birds, namely
male and female age, territory novelty (M and F novelty;
Table 2) and polygamy status (Polyandry, Polygyny all,
etc.; Table 2). For a full list of predictor variables used
in modelling the timing of hatching, see Table 2. A dis-
cussion of model uncertainty can be found in Additional
file 3. (Additional file 1). In addition, some of our possible peri-
ods are statically defined, using fixed start and end dates. For each trigger period in each year and territory, we
estimated the mean, maximum, minimum and standard
deviation. For river discharge, this was calculated for spe-
cific discharge as well as for relative discharge. Abbreviations NAO: North Atlantic Oscillation; SD: Standard Deviation; Qnorm: Normalized
river discharge, which is discharge divided by territory mean discharge for the
study period; Qspec: Specific river discharge, discharge per catchment area
l/s/km2; Groundwater: Ground water levels; SCA: Snow Covered Area; Age f:
Female age; Age m: Male age; Age f2: Quadratic female age; beta polygyny
indicator: Male polygyny; F novelty: Whether a territory was new to a female;
M novelty: Whether a territory was new to a male; F id: Female identity; M id:
Male identity; territory ID: Territory identity; trigger date: The first date when
temperature was above 0 degrees Celsius for five consecutive days; trigger
periods: Time periods with different starting dates and of various duration
related to the trigger date: in addition to some periods with fixed start and
end date; DDD: Distance Distribution Dynamics model; KGE: Kling Gupta Effi‑
ciency criterion; P: Precipitation; T: Temperature; SWE: Snow water equivalent;
BIC: Bayesian Information Criterion. Ethics approval and consent to participate The field work was conducted with respect for the animals’ well-being and
adheres to the Guidelines for the Use of Animals in Research [3]. It com‑
plies with the laws and regulations for animals used in research in Norway
(FOR-2003-03-18-349, LOV-2009-06-19-100, LOV-1981-05-29-38§26). Ethical
approval is not required for bird ringing (FOR-2003-03-18-349§§21-24), but
Ringing licenses were issued and approved by the Norwegian Bird Ringing
Centre on behalf of the Norwegian Environment Agency. p
g
The authors declare that they have no competing interests. Additional file 1. Trigger date and periods. The defined trigger periods,
relating trigger date or absolute dates, used on the runoff and catchment
predictor variables when modelling timing of breeding in the white-
throated dipper in Lyngdalselva 1978–2015 g
We are grateful to all the people involved in the many years of field work. 6. Bates DM, Maeschler M, Bolker B. Package ‚lme4‘.2018. https://cran.r-proje
ct.org/web/packages/lme4/lme4.pdf. Accessed 3 May 2018. 6. Bates DM, Maeschler M, Bolker B. Package ‚lme4‘.2018. https://cran.r-proje
ct.org/web/packages/lme4/lme4.pdf. Accessed 3 May 2018. Supplementary information ac
/10 1186/ 12898 020 00338 Supplementary information accompanies this paper at https://doi. org/10.1186/s12898-020-00338-y. Availability of data and materials such decompositions. In the case where many quite
similar variables were included (such as many differ-
ent discharge contributions), we used the variance con-
tributions for the set of such variables, which for fixed
effects meant the variance of the sum of coefficients
multiplied by the variables. This should at least alleviate
the problem of variance decomposition due to covaria-
tion in the explanatory variables. In addition, we com-
pared the variation in hatching date in the first years
of the study period (1978–1996) with the last years
(1997–2015) using the F-test. The datasets analysed during the current study are not publicly available, due
to it being a unique long-term collection of individual data on a breeding dip‑
per population, which has cost an enormous effort in the field 1973–present,
but are available from the corresponding author on reasonable request. The
complete dipper data are stored at the Norwegian University of Life Sciences. Author details 1 Centre for Ecological and Evolutionary Synthesis (CEES), Department
of Biosciences, University of Oslo, P. O. Box 1066, Blindern, 0316 Oslo, Norway. 2 Norwegian Institute for Nature Research, Thormøhlens Gate 55, 5006 Bergen,
Norway. 3 Norwegian Water Resource and Energy Directorate, P. O. Box 5091,
Majorstua, 0301 Oslo, Norway. 4 Centre for Biodiversity Dynamics, Department
of Biology, Norwegian University of Science and Technology, 7491 Trondheim,
Norway. 5 Jerstad Viltforvaltning, Aurebekksveien 61, 4516 Mandal, Norway. 6 Faculty of Environmental Sciences and Natural Resource Management,
Norwegian University of Life Sciences, P.O. Box 5003, NMBU, 1432 Ås, Norway. 7 Norwegian Institute for Nature Research, Gaustadallén 21, 0349 Oslo,
Norway. Additional file 2. Variation in specific discharge affects timing of breed‑
ing. The effect of the standard variation in specific discharge during the
period Apr–Aug the preceeding year on the timing of breeding (hatching
day-of-year), where each year is denoted in a different colour, in the white-
throated dipper in Lyngdalselva 1978–2015 Additional file 3. Model uncertainty. Alternative models with the defined
trigger periods, relating trigger date or absolute dates, used on the runoff
and catchment predictor variables when modelling timing of breeding in
the white-throated dipper in Lyngdalselva 1978–2015 Received: 9 September 2019 Accepted: 25 November 2020 Authors’ contributions g
p
g
p
y
7. Both C, Bouwhuis S, Lessells CM, Visser ME. Climate change and popula‑
tion declines in a long-distance migratory bird. Nature. 2006;441:81–3.l 7. Both C, Bouwhuis S, Lessells CM, Visser ME. Climate change and popula‑
tion declines in a long-distance migratory bird. Nature. 2006;441:81–3. ALKN and JHLL conceived the idea. KJ collected the field data. OWR organised
the dipper data collection. ThS produced the hydrology data. TR analysed
the data. ALKN and TR wrote the manuscript with significant input from MG,
ThS, JHLL, LAV, ToS, OWR, BW, KJ and NCS. ALKN, TR, LAV, and MG contributed
substantially to the revised version. All authors contributed to the article. All
authors read and approved the final manuscript. 8. Chiu M-C, Kuo M-H, Hong S-Y, Sun Y-H. Impact of extreme flooding on
the annual survival of a riparian predator, the brown dipper Cinclus pal-
lasii. Ibis. 2013;155:377–83. 8. Chiu M-C, Kuo M-H, Hong S-Y, Sun Y-H. Impact of extreme flooding on
the annual survival of a riparian predator, the brown dipper Cinclus pal-
lasii. Ibis. 2013;155:377–83. 9. Claeskens G, Hjort NL. Model selection and model averaging. Cambridge:
Cambridge University Press; 2008. 9. Claeskens G, Hjort NL. Model selection and model averaging. Cambridge:
Cambridge University Press; 2008. 10. Clark RG, Pöysä H, Runko P, Paasivaara A. Spring phenology and timing
of breeding in short-distance migrant birds: phenotypic responses and
offspring recruitment patterns in common goldeneyes. J Avian Biol. 2014;45:457–65. 10. Clark RG, Pöysä H, Runko P, Paasivaara A. Spring phenology and timing
of breeding in short-distance migrant birds: phenotypic responses and
offspring recruitment patterns in common goldeneyes. J Avian Biol. 2014;45:457–65. Referencesii 1. Afifi AA, Clark V. Computer-aided multivariate analysis. 3rd ed. London:
Chapman & Hall; 2007. 2. Ahola M, Laaksonen T, Sippola K, Eeva T, Raino K, Lehikoinen E. Variation in
climate warming along the migration route uncouples arrival and breed‑
ing dates. Glob Change Biol. 2004;10:1610–7. 2. Ahola M, Laaksonen T, Sippola K, Eeva T, Raino K, Lehikoinen E. Variation in
climate warming along the migration route uncouples arrival and breed‑
ing dates. Glob Change Biol. 2004;10:1610–7. 3. [Anon]. Guidelines for the treatment of animals in behavioural research
and teaching. Anim. Behav. 2006;71:245–53. 4. Bakken V, Runde O, Tjørve E. Norsk ringmerkningsatlas. Stavanger: Stavan‑
ger Museum; 2006. 5. Balbontin J, Hermosell IG, Marzal A, Reviriego M, de Lope F, Møller AP. Age-related change in breeding performance in early life is associated
with an increase in competence in the migratory barn swallow Hirundo
rustica. J Anim Ecol. 2007;76:915–25. Statistics In observational studies, explanatory variables are often
correlated. It is thus not unusual that a variable seems to
have an influence on the response (in our case the hatch-
ing date), simply by being correlated to another variable
that influences the response. Multiple regression is there-
fore important, because the effect of a variable on the
response is tested while controlling for all other signifi-
cant explanatory variables. Thus, in order to avoid spu-
rious correlations we need all the potential explanatory
variables that are available and can reasonably affect the
response, but due to the many variables we also require a
conservative model selection strategy, to reduce the risk
of false positives. We used an information criterion for
model selection to compare non-nested models in a step-
wise search where addition, removal and replacement of
covariates were tried. In particular, we chose the Bayesian
Information Criterion (BIC) since it is conservative and
converges to the true model that is in the set of models
considered and if not, to the model closest in Kullback–
Leibler distance [9]. i
Variance decomposition on the resulting model
deemed best according to BIC was performed by look-
ing at the variance contributions for the variable in the
model by itself, plus the residual variance. Thus, for
fixed factors, we used the variance of the regression
coefficient multiplied by the variables’ values in the
dataset. This is the same as the squared standardized
regression coefficients (see for instance [1], an often-
used measure of the relative contribution of variables. For random factors, the variance contribution is listed
in the model summary. These variances would sum
up to the overall variance of the response if all effects
were independent of each other. This was not always
the case, which must be kept in mind when interpreting Because dippers breed very early in spring in response
to warm temperatures [37] and are dependent on sub-
merged invertebrate food, river discharge are among
the most likely cues for timing of breeding. We explored
some of the core explanatory variables of particular Nilsson et al. BMC Ecol (2020) 20:70 Page 10 of 11 Page 10 of 11 Page 10 of 11 Competing interests Competing interests
The authors declare that they have no competing interests. Competing interests
The authors declare that they have no competing interests. Consent for publication
Not applicable. Consent for publication
Not applicable. Supplementary information accompanies this paper at https://doi. org/10.1186/s12898-020-00338-y. Supplementary information acc
org/10.1186/s12898-020-00338-y. Funding
Thi
d g
This study was supported by the Norwegian Research Council (nr. 221393),
the Norwegian Research Council through its Centres of Excellence fund‑
ing scheme (nr. 223257), and the Norwegian Water Resources and Energy
Directorate. 11. Cole EF, Long PR, Zelazowski P, Szulkin M, Sheldon BC. Predicting bird
phenology from space: satellite-derived vegetation green-up signal 11. Cole EF, Long PR, Zelazowski P, Szulkin M, Sheldon BC. Predicting bird
phenology from space: satellite-derived vegetation green-up signal Nilsson et al. BMC Ecol (2020) 20:70 Nilsson et al. BMC Ecol (2020) 20:70 Page 11 of 11 Page 11 of 11 uncovers spatial variation in phenological synchrony between birds and
their environment. Ecol Evol. 2015;5:5057–74. uncovers spatial variation in phenological synchrony between birds and
their environment. Ecol Evol. 2015;5:5057–74. 37. Nilsson ALK, Slagsvold T, Røstad OW, Knudsen E, Jerstad K, Cadahía L,
et al. Territory location and quality, together with climate, affect the tim‑
ing of breeding in the white-throated dipper over a 34-year period. Sci
Rep. 2019;9:7671. uncovers spatial variation in phenological synchrony between birds and
their environment. Ecol Evol. 2015;5:5057–74. 12. D’Amico F, Boitier E, Marzolin G. Timing of onset of breeding in three
different dipper Cinclus cinclus populations in France. Bird Study. 2003;50:189–92. 38. Parmesan C, Yohe G. A globally coherent fingerprint of climate change
impacts across natural systems. Nature. 2003;421:37–42. 13. Dhondt AA, Kempenaers B, Adriaensen F. Density-dependent clutch size
caused by habitat heterogeneity. J Anim Ecol. 1992;61:643–8. 39. Poff NL, Allan JD, Bain MD, Karr JR, Prestegaard KL, Richter BD, et al. The
natural flow regime. Bioscience. 1997;47:769–84. 14. Dunn PO, Winkler DW. Effects of climate change on timing of breeding
and reproductive success in birds. In: Møller AP, Fiedler W, Berthold P, edi‑
tors. Effects of climate change on birds. Oxford: Oxford University Press;
2010. p. 113–28. 40. Prowse TD, Beltaos S. Climatic control of river-ice hydrology: a review. Hydrol Process. 2002;16:805–22. 41. Reid JM, Bignal EM, Bignal S, McCracken DI, Monaghan P. Age-specific
reproductive performance in red-billed choughs Pyrrhocorax pyr-
rhocorax: patterns and processes in a natural population. J Anim Ecol. 2003;72:765–76. 15. Faragó S, Hangya K. Effects of water level on waterbird abundance and
diversity along the middle section of the Danube River. Hydrobiologia. 2012;697:15–21. 16. Forslund P, Pärt T. Age and reproduction in birds - hypotheses and tests. TREE. 1995;10:374–8. 42. Root TL, Price JT, Hall KR, Schneider SH, Rosenzweig C, Pounds JA. Funding
Thi
d Fingerprints of global warming on wild animals and plants. Nature. 2003;421:57–60. 17. Galbraith H. Polygamy in the dipper. Scottish Birds. 1979;10:180–1. 43. Royan A, Hannah DM, Reynolds SJ, Noble DG, Sadler JP. Avian community
responses to variability in river hydrology. PLoS ONE. 2013;8:e83221. 18. Gamelon M, Grøtan V, Nilsson ALK, Engen S, Hurrell JW, Jerstad K, et al. Interactions between demography and environmental effects are impor‑
tant determinants of population dynamics. Sci Adv. 2017;3:e1602298. 44. Sanz JJ. Effects of geographic location and h
eters of Great Tits. Auk. 1998;115:1034–51. 44. Sanz JJ. Effects of geographic location and habitat on breeding param‑
eters of Great Tits. Auk. 1998;115:1034–51. 19. Gamelon M, Tufto J, Nilsson ALK, Jerstad K, Røstad OW, Stenseth NC, et al. Environmental drivers of varying selective optima in a small passerine: a
multivariate, multiepisocid approach. Evolution. 2018;72:2325–42. 45. Saunders SP, Roche EA, Arnold TW, Cuthbert FJ. Female site familiarity
increases fledging success in piping plovers (Charadrius melodus). Auk. 2012;129:329–37. 20. González-Solís J, Becker PH, Jover L, Ruiz X. Individual changes underlie
age-specific pattern of laying date and egg-size in female common terns
(Sterna hirundo). J Ornithol. 2004;145:129–36. 46. Sergio F, Newton I. Occupancy as a measure of territory quality. J Anim
Ecol. 2003;72:857–65. 21. Gupta HV, Kling H, Yilmaz KK, Martinez GF. Decomposition of the mean
squared error and NSE performance criteria: implications for improving
hydrological modelling. J Hydrol. 2009;377:80–91. 47. Skaugen T, et al. Trends in snow water equivalent in Norway (1931–2009). Hydrol Res. 2012;43:489–99. 48. Skaugen T, Peerebom IO, Nilsson ALK. Use of a parsimonious rainfall-
run-off model for predicting hydrological response in ungauged basins. Hydrol Process. 2015;29:1999–2013. y
g
g
y
22. Hanssen-Bauer I. Regional temperature and precipitation series for Nor‑
way: analyses of time-series updated to 2004. Norwegian Meteorological
Institute, Report Climate no. 15. 2005. 49. Skaugen T, Weltzien IH. A model for the spatial distribution of snow water
equivalent parametrized from the spatial variability of precipitation. Cryosphere. 2016;10:1947–63. p
23. Hille SM, Cooper CB. Elevational trends in life histories: revising the pace-
of-life framework. Biol Rev. 2015;90:204–13. 50. Slagsvold T, Wiebe KL. Immigrants and locally recruited birds differ in
prey delivered to their offspring in blue tits and great tits. Anim Behav. 2018;84:1307–12. 24. Hinks AE, Cole EF, Daniels KJ, Nakagawa S, Sheldon BC. Scale-dependent
phenological synchrony between songbirds and their caterpillar food
source. Am Nat. 2015;186:84–97. 25. Hurrell JW. Funding
Thi
d Age-dependent trait vari‑
ation: the relative contribution of within-individual change, selective
appearance and disappearance in a long-lived seabird. J Anim Ecol. 2015;84:797–807. 34. Mysterud A, Yoccoz NG, Stenseth NC, Langvatn R. Relationships between
sex ratio, climate and density in red deer: the importance of spatial scale. J Anim Ecol. 2000;69:959–74. 35. Nilsson ALK, Knudsen E, Jerstad K, Røstad OW, Walseng B, Slagsvold T,
et al. Climate effects on population fluctuations of the white-throated
dipper Cinclus cinclus. J Anim Ecol. 2011;80:235–43. Funding
Thi
d Decadal trends in the North-Atlantic oscillation-regional
temperatures and precipitation. Science. 1995;269:676–9. 51. Thiemig V, Rojas R, Zambrano-Bigiarini M, De Roo A. Hydrological evalu‑
ation of satellite-based rainfall estimates over the Volta and Baro-Akobo
basin. J Hydrol. 2013;499:324–38. 26. Klavins M, Briede A, Rodinov V. Long term changes in ice and discharge
regime of rivers in the Baltic region in relation to climatic variability. Clim
Change. 2009;95:485–98. 52. Tyler SJ, Ormerod SJ. The dippers. London: T & AD Poyser; 1994. 53. van de Pol M, Verhulst S. Age-dependent traits: a new statisti 53. van de Pol M, Verhulst S. Age-dependent traits: a new statistical
model to separate within- and between-individual effects. Am Nat. 2006;167:766–73. 27. Kling H, Fuchs M, Paulin M. Runoff conditions in the upper Danube
basin under an ensemble of climate change scenarios. J Hydrol. 2012;424:264–77. 54. Verhulst S, Tinbergen JM. Experimental evidence for a causal relationship
between timing and success of reproduction in the Great tit Parus major. J Anim Ecol. 1991;60:269–82. 28. Lack D. The breeding seasons of European Birds. Ibis. 1950;92:288–316.l 29. Lawrence D. Klimaendring og framtidige flommer i Norge. - Norwegian
Water Resources and Energy Directorate, NVE-report 81 (in Norwegian
with English summary). 2016. 55. Visser ME, van Noordwijk AJ, Tinbergen JM, Lessells CM. Warmer springs
lead to mistimed reproduction in great tits (Parus major). Proc R Soc Lond
B. 1998;265:1867–70. y
30. Low M, Pärt T, Forslund P. Age-specific variation in reproduction is largely
explained by the timing of territory establishment in the New Zealand
stitchbird Notiomystis cincta. J Anim Ecol. 2007;76:459–70. 56. von Haartman L. The nesting times of Finnish birds. Proc XIIIth Interna‑
tional Ornithological Congress. 1963;13:611–9. 31. Marzolin G. Influence of the mating system of the Eurasian dipper on sex-
specific local survival rates. J Wildl Manage. 2002;66:1023–30.i 57. Whelan S, Strickland D, Morand-Ferron J, Norris DR. Male experience
buffers female laying date plasticity in a winter-breeding, food-storing
passerine. Anim Behav. 2017;121:61–70. 32. McCleery RH, Perrins CM, Sheldon BC, Charmantier A. Age-specific repro‑
duction in a long-lived species: the combined effects of senescence and
individual quality. Proc R Soc Lond B. 2008;275:963–70. 58. Wilson JD. The breeding biology and population history of the Dipper
Cinclus cinclus on a Scottish river system. Bird Study. 1996;43:108–18. 33. Min SK, Zhang X, Zwiers FW, Hegerl GC. Human contribution to more-
intense precipitation extremes. Nature. 2011;470:378–81. 59. Zhang H, Vedder O, Becker PH, Bouwhuis S. Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in pub‑
lished maps and institutional affiliations. Springer Nature remains neutral with regard to jurisdictional claims in pub‑
lished maps and institutional affiliations. Springer Nature remains neutral with regard to jurisdictional claims in pub‑
lished maps and institutional affiliations. 36. Nilsson ALK, Stige LC, Jerstad K, Røstad OW, Slagsvold T, Stenseth NC. To make the most of what we have: extracting phenological data from
nestling measurements. Int J Biometeorol. 2011;55:797–804.
|
https://openalex.org/W2593620457
|
https://jwsr.pitt.edu/ojs/jwsr/article/download/706/933
|
English
| null |
Workers of the World Have Nothing, and Everything, to Lose
|
Journal of world-systems research
| 2,017
|
cc-by
| 3,466
|
JOURNAL OF WORLD-SYSTEMS RESEARCH
ISSN: 1076-156X | Vol. 23 Issue 1 Pages 205-212 |
DOI 10.5195/JWSR.2017.706 | jwsr.org Review Symposium on Jamie McCallum’s Global Unions, Local Power: The
New Spirit of Transnational Labor Organizing
Vol. 1 | DOI 10.5195/JWSR.1 Stephanie Luce In the wake of WWI, the left, and unions, turned away from international
organizing and focused more heavily on domestic organizing. In many countries that took the form
of building a role for unions inside the state (such as via corporatist politics), or via strong
collective bargaining agreements directly with employers. It is only in recent decades as those
systems and union power broke down that unions have turned back to the hope of transnationalism. McCallum cites scholars that argue that neoliberal globalization opens up new
opportunities for workers to organize across borders (Evans 2010). With the expansion of global
supply chains, just-in-time production, and global markets, workers may have more reasons to
cooperate and more structural power if they can stop production in key places. But McCallum
argues that the Group 4 Securicor (G4S) campaign had some success not because of globalization
but rather in spite of it. Instead, he asserts that it was a combination of strong union leadership and
vision at the top, effective research, a global corporate campaign that helped change the rules, and
local conditions that, in some places, opened up enough space for workers on the ground to
organize. In this way, McCallum does not necessarily share the optimism that some scholars have
for labor organizing in the period of neoliberal globalization—he does not think campaigns like
G4S are a reflection of a Karl Polanyi-type “counter-movement.” At the same time, his work
suggests some key lessons for labor unions and those fighting for workers rights in the global
economy. I highlight a few points that I think are key. First, McCallum’s work suggests that labor scholars and activists should not be overly
committed to a specific model or approach. His case study is particularly interesting because the
G4S campaign uses a Global Framework Agreement (GFA) with some success. U.S. activists in
particular have expressed skepticism about the GFA model, as it is more in line with a European,
“social dialogue” approach. The GFA is basically a voluntary agreement between a corporation
and a global union; as it is generally not enforceable by law, it is therefore a “soft law” tool. Americans are cynical of this approach, having watched employer after employer violate voluntary
agreements. Instead, the U.S. model relies more heavily on “hard law” contracts that are
enforceable in court. The U.S. Stephanie Luce Stephanie Luce
City University of New York
Stephanie.Luce@mail.cuny.edu Stephanie Luce
City University of New York
Stephanie.Luce@mail.cuny.edu Donald Trump was elected president of the United States based in good part on a growing critique
of neoliberalism. While Trump himself will continue much of the neoliberal agenda, he is a vocal
critic of trade agreements and corporate mobility that are harmful to U.S. workers. Trump
promised to “make America great again” by promising to bring back jobs, punish corporations
who try to move jobs overseas, deport immigrants, and essentially close the borders to many
classes of people. We’ve seen similar nationalist movements emerge in other parts of the world,
particularly Europe. The Brexit vote was in part a rejection of more open borders and also of an
undemocratic European Union. Nationalism is one response to continued economic hardship. Another response to the damages of neoliberalism could be an expansion of
internationalism. Jamie McCallum’s book, Global Unions, Local Power, shows us what such
internationalism could look like: unions working to build alliances across national borders in order
to organize massive global corporations. This approach would regulate transnational capital,
raising the floor on wages and workers’ rights. ticles in this journal are licensed under a Creative Commons Attribution 4.0 United States License. This journal is published by the University Library System, University of Pittsburgh as part of
its D-Scribe Digital Publishing Program and is cosponsored by the University of Pittsburgh Press. This journal is published by the University Library System, University of Pittsburgh as part of
its D-Scribe Digital Publishing Program and is cosponsored by the University of Pittsburgh Press. Journal of World-System Research | Vol. 23 Issue 1 | Luce 206 The campaign, led by the Service Employees International Union (SEIU), has had mixed
results, but overall, McCallum argues, it is the kind of campaign that is necessary in current times. As corporations have more and more freedom to move around countries and across borders, and
as states rewrite laws and regulations to favor those corporations at the expense of workers, unions
have no choice if they want to survive but to build their own global campaigns. Internationalism is not a new concept for the labor movement, as McCallum shows. But
interestingly, concrete efforts to make internationalist rhetoric real have ebbed and flowed counter
to the growth of unions. Stephanie Luce model is more confrontational and aggressive, while the European
model is, on average, more cooperative. jwsr.org | DOI 10.5195/JWSR.2017.706 Journal of World-System Research | Vol. 23 Issue 1 | Workers of the World 207 At the same time, there are many in Europe skeptical of the U.S. model of confrontation
and aggressive organizing, and certainly some resistance to U.S. unions coming into Europe and
telling Europeans what to do. After all, the U.S. labor movement is in weak shape—and never
even had its own political party. Many activists in the international arena have been frustrated by
what they see as American arrogance and another form of cultural imperialism. Finally, SEIU has
many critics, in Europe and the United States, who believe the union has been too top-down and
overconfident, and too willing to compromise shopfloor organizing for other “faster” methods of
organizing, such as making deals with employers. McCallum acknowledges all of these criticisms and concerns, but then goes on to show
how the G4S campaign was more complex than a simple analysis would suggest. There is not
really one specific SEIU organizing model, and there isn’t even one specific model for using
GFAs. In this case, the models came together with some positive outcomes. It is not easy, and
varies greatly with local conditions, so there is no “one size fits all” or “best practice model.” This underscores McCallum’s call for unions to experiment. This does not mean
abandoning existing models or older practices, but being open to a combination of strategies and
tactics in all dimensions—research, organizing, global, local. I share McCallum’s call for scholars and activists to keep an open mind in the search for
an organizing strategy. We have much to learn from history, and we must be prepared to learn
from other countries, other kinds of social movements, and different types of organizing. For
example, unions can work with and learn from movements such as Occupy Wall Street, the
landless workers movement, worker centers, and worker co-operatives. Some scholars have even
suggested that Alcoholics Anonymous has lessons for social movements in terms of building a
non-hierarchical self-sustaining model (Room 1993). Employers have been bold and innovative
in their quest to expand around the globe, testing new limits and pushing boundaries. Unions must
do the same The second key point is that unions need to experiment in order to find sources of power. Stephanie Luce Neoliberal globalization has created new opportunities, but for the most part, has left workers with
less power, McCallum argues. Corporations have more power to move their jobs and investments,
to fire workers, and to outlast workers’ organizing attempts. Because some service sector jobs, like
security guards, are place-bound, employers do not have the same ability to just pick up and move. However, deregulated labor markets mean it is easier for employers to break strikes and bring in
replacement workers. It is also easier for employers to use guestworkers or hire unauthorized
immigrant workers. Lacking structural power, workers must find ways to exercise associational
power. jwsr.org | DOI 10.5195/JWSR.2017.706 Journal of World-System Research | Vol. 23 Issue 1 | Luce 208 McCallum cites Frances Fox Piven, who argues that collective actors can increase their
power, or make it actionable, by breaking rules. People must disrupt the ways society functions on
a daily basis, creating chaos and disorder. In response, policymakers work to restore order. SEIU worked to gain power for G4S workers through building a global alliance with other
unions and working together to conduct research into the company’s weak spots. Around that time,
2006, the United Nations created its Principles for Responsible Investment. This allowed the
unions to target certain investors and highlight the ways in which G4S was abusing workers and
violating human rights in global South countries. The unions attended shareholder meetings,
released reports, and filed charges against the company with the OECD. At the same time, workers were organizing on the local level in multiple countries,
including Indonesia, South Africa, Malawi, India, Poland and the Democratic Republic of Congo. The G4S Alliance sent resources and staff to assist with these efforts and draw more unions and
workers into the campaign. The campaign used stories of abuses from some of the local strikes in
its reports. The campaign began to have success with some investors, such as Norway’s largest
life insurance company, which agreed to divest from G4S. Eventually the pressure built from
multiple angles, and the company agreed to sign the Global Framework Agreement (GFA) in 2008. The GFA required the company to stay neutral in unionization efforts. This leads to the third point, which is that workers must develop power in order to change
the rules of governance. In short: they must stretch and sometimes break the rules in order to
change the rules. Stephanie Luce Global Unions, Local Power argues that unions may have more success
organizing if they shift from a focus on labor rights, and instead work to change the rules of
governance. In my own work on living wages, I have found that passing a law mandating higher
wages is of little value if workers don’t have the power to enforce the law. Winning legislative
victories, or even a union contract, may have little effect. More importantly, unions should get to the heart of governance. Neoliberal policy has
resulted in a massive change of rules: governments have granted corporations and investors more
rights, and reduced the rights of workers and unions. This is about rights, but it is also about the
power to enforce rights and influence decisions. If workers and unions play by the existing rules in a neoliberal economy, they will mostly
lose. Employers already have more power under capitalism. Social democracy is one way to
mediate that: to give workers some more power to even the playing field. Even a true “free market”
would be more fair for workers than neoliberalism, because at least then employers could not grow
to monopolies and workers would not be barred from moving to other countries. But under
neoliberalism the tilt goes back the other way, to an extreme imbalance. Investors and employers
have inordinate power relative to workers. The rules of the game must be changed in order to have
a more equitable system. jwsr.org | DOI 10.5195/JWSR.2017.706 Journal of World-System Research | Vol. 23 Issue 1 | Workers of the World 209 Unions themselves can be a way for workers to change the rules in many countries, where
they have a formal role in setting national policy. In others, unions have fought to set or change
federal legislation. Global Framework Agreements are another tool for changing the rules of governance. Other mechanisms that have been used in transnational labor organizing, like corporate codes of
conduct, don’t change rules of governance. Social clauses, like the labor side agreement in the
North American Free Trade Agreement (NAFTA) don’t really either, because they have no
mechanism for unions or workers to enforce their rights (unlike other elements of trade
agreements, where corporations have legal channels and can win compensation if their rights are
violated). Global Unions, Local Power shows how the campaign won the Global Framework
Agreement. Stephanie Luce Building transnational labor movements depends on this. It requires more creative experimentation, combining local and international work. Constant
mobilizing is not enough: it must be transformed into lasting organization or it will likely fade
away. This point makes sense, and history suggests that workers advance significantly when their
fight-back results in the formation of unions, political parties, and political structures and policies. It seems unions have had their greatest impacts not just on their members but society overall in
countries where they were able to institutionalize their power on the national level, such as through
systems of co-determination or formal seats on government bodies. Unfortunately, many of our models for doing this have failed. Polls show that many young
people in particular are skeptical of traditional vehicles like unions and political parties, as they
see them prone to bureaucracy and/or corruption. While McCallum makes a strong case that
workers benefit from unions, he does not take on the question of whether our unions are functional. Indeed, that question is well beyond the scope of this book. However, part of the challenge for
labor activists is to take seriously the critiques of traditional models and find ways to make our
organizations and institutions more democratic, accountable and effective. Finally, McCallum calls for more vision, and, as one of his interviewees suggests,
“imagineers.” We are now experiencing a true ideological battle for a new economic and political
model, or models. While there are many political theorists, entrepreneurs and elites thinking about
10, 20, even 50-year visions, the union movement rarely makes the time or place for such kind of
visioning. At times, this visioning has even been criticized as a luxury or a distraction. Some have
argued that we can’t spend time on vision until we increase union density: only then, when more
workers are organized, can we talk about alternative models. Yet this leaves us fighting defensive
battle after defensive battle, or at best, stuck to old routines that win short-term gains. The G4S
campaign was an experiment in thinking longer term, bigger and bolder. SEIU has since launched the Fight for $15 campaign, which I think is another example of
such experimentation, as union insiders acknowledge they had no real strategy for unionizing fast
food corporations when launching the campaign. Stephanie Luce By launching a comprehensive corporate campaign, the alliance was able to
“disorganize,” and thereby neutralize the company enough so that it could run a campaign to build
a union. Without changing the rules of governance, G4S, as one of the largest employers in the
world, would have had too much power and could have easily continued to fight the union at every
turn. McCallum is right to point out that the need for governance struggles is in part a reflection
of the failure of states to regulate. Markets are unequal to start with, and neoliberal markets are
even more unequal. Asserting that workers have rights is not enough, particularly in a terrain where
they is no way to enforce those claims, especially across borders. Unions cannot rely on states to
regulate corporations and must pursue direct mechanisms to hold corporations accountable. At times I found myself confused by McCallum’s arguments about where workers get
power and how to use it. In part this might be because there can be a slippery line between workers
and unions, between union staff and union leaders. In the G4S case, much of the alliance building
seems to have taken place among SEIU staff and leaders, building connections with other unions’
leaders. It also seems that SEIU research staff played a big role in setting up the corporate
campaign and pushing the company to agree to the GFA. On the other hand, worker strikes also
seem important. Here, workers used their associational power to cause disruptions for the
company. But is this also structural power, as the strikes did impede the company from making
profit? In any case, workers and unions needed to find sources of power to even win the GFA. They then needed to exercise that power in order to organize themselves into unions and win
contracts. In this sense, the argument sometimes felt a bit cyclical: you need power to change the
rules, and you need to change the rules to gain power. Perhaps that is in fact true, and McCallum’s
point is that it is an iterative, dialectical process. But it may be that there are different kinds of
power accessed at different stages? jwsr.org | DOI 10.5195/JWSR.2017.706 Journal of World-System Research | Vol. 23 Issue 1 | Luce 210 A fourth point that McCallum makes is that once they change the rules of governance,
workers must then build new institutions. Stephanie Luce Rather they worked with workers on the local
level, first in New York, then around the country—and then in many countries around the world. This campaign has also tested old tactics (strikes, community support, corporate campaign, legal
battles), but with a new approach: targeting city officials for legislative gains, revitalizing old tools
like the New York state wage board. So far this effort has achieved extraordinary success in terms
of minimum wage gains in U.S. cities and states. It has also assisted some SEIU unions in securing
stronger collective bargaining outcomes. It has not yet won unionization for fast food workers, and
to date, has had no victories in other countries. Yet it has inspired workers to organize their own jwsr.org | DOI 10.5195/JWSR.2017.706 Journal of World-System Research | Vol. 23 Issue 1 | Workers of the World 211 versions of the Fight for $15 campaign, in Japan, New Zealand, the Philippines, Canada and more
(Kann 2014; Torio 2016). This kind of experimentation is good, but I would argue it is still far from the real
“imagineering” we need from the labor movement. We want to fight for short-term gains like
increased wages, and we want workers to be able to form unions, but we also want to think about
the larger system we want to live in. Union leaders and members need to have a critique of
capitalism and the ways in which it fails to meet people’s needs. We need to study alternative
economic models and have discussion and debate about their strengths and weaknesses. We need
to have open, transparent and democratic dialogue about our own organizations. We are living in a moment of serious economic, political and environmental crisis, and
unions cannot afford to remain in defensive mode. The German political theorist Wolfgang Streeck
argues that capitalism and democracy are no longer mutually compatible, and most likely,
capitalism will survive with the growth of authoritarianism. If this argument is true, we need
democratic forces building a challenge, to help the transition out of capitalism by expanding
democracy and democratic control over the economy. By most measures, the left is quite weak at this time, in most parts of the world. Some of
it was killed off by outward attacks (red scare, military, state repression). Other parts were
demoralized by the collapse of left countries or the failures of hopeful states like South Africa and
Brazil. Stephanie Luce Some of the left has imploded from internal feuding, scandal or simple ineffectiveness. Left-leaning parties have mostly moved to the right, and unions are declining in membership and
power. If McCallum’s point that left power and internationalism have had a somewhat inverse
relationship, this should be a positive sign for the potential of transnational labor organizing. Global Unions, Local Power gives us hope that the labor movement can be a force in
building an alternative. Indeed, unions have been the backbone of key liberation movements in
many countries. Now is time for those unions to build a global liberation struggle. Torio, L. 2016. “Japan Builds a Fight for $15 Movement of its Own.” Waging Nonviolence,
December 9; http://wagingnonviolence.org/feature/japan-fight-for-15-living-wage-
aequitas/. References Evans, P. 2010. “Is it Labor’s Turn to Globalize? Twenty-first Century Opportunities and
Strategic Responses.” IRLE Working Paper No. 224-10;
http://irle.berkeley.edu/workingpapers/224-10.pdf. Evans, P. 2010. “Is it Labor’s Turn to Globalize? Twenty-first Century Opportunities and
Strategic Responses.” IRLE Working Paper No. 224-10;
http://irle.berkeley.edu/workingpapers/224-10.pdf. Kann, J. 2014. “Fight for Fifteen Spreads Out and Zooms In.” Labor Notes, May 15;
http://www.labornotes.org/2014/05/fight-fifteen-spreads-out-and-zooms. Kann, J. 2014. “Fight for Fifteen Spreads Out and Zooms In.” Labor Notes, May 15;
http://www.labornotes.org/2014/05/fight-fifteen-spreads-out-and-zooms. Room, R. 1993. “Alcoholics Anonymous as a Social Movement.” P. 167-187 in B. S. McCrady
and W. R. Miller, eds. Research on Alcoholics Anonymous: Opportunities and
Alternatives. New Brunswick, NJ: Rutgers Center of Alcohol Studies. jwsr.org | DOI 10.5195/JWSR.2017.706 Journal of World-System Research | Vol. 23 Issue 1 | Luce 212 Torio, L. 2016. “Japan Builds a Fight for $15 Movement of its Own.” Waging Nonviolence,
December 9; http://wagingnonviolence.org/feature/japan-fight-for-15-living-wage-
aequitas/. jwsr.org | DOI 10.5195/JWSR.2017.706
|
https://openalex.org/W3152291016
|
https://hull-repository.worktribe.com/preview/3910343/IJHPM41321631043000.pdf
|
English
| null |
Prohibit, protect, or adapt? The changing role of volunteers in palliative and hospice care services during the COVID-19 pandemic. A multinational survey (CovPall)
|
medRxiv (Cold Spring Harbor Laboratory)
| 2,021
|
cc-by
| 8,106
|
Article History:
Received: 12 April 2021
Accepted: 6 September 2021
ePublished: 8 September 2021 #Membership of the CovPall
Study Team is provided in
the Acknowledgments. Abstract This is an open-access article
distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/
by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is
properly cited. p
p
y
Citation: Walshe C, Garner I, Dunleavy L, et al. Prohibit, protect, or adapt? The changing role of volunteers in palliative
and hospice care services during the COVID-19 pandemic. A multinational survey (Covpall). Int J Health Policy Manag. 2021;x(x):x–x. doi:10.34172/ijhpm.2021.128 Citation: Walshe C, Garner I, Dunleavy L, et al. Prohibit, protect, or adapt? The changing role of volunteers in palliative
and hospice care services during the COVID-19 pandemic. A multinational survey (Covpall). Int J Health Policy Manag. 2021;x(x):x–x. doi:10.34172/ijhpm.2021.128 *Correspondence to:
Catherine Walshe
Email: c.walshe@lancaster.ac.uk Abstract Abstract Background: Volunteers are common within palliative care services, and provide support that enhances care quality. The
support they provided, and any role changes, during the coronavirus disease 2019 (COVID-19) pandemic are unknown. The aim of this study is to understand volunteer deployment and activities within palliative care services, and to identify
what may affect any changes in volunteer service provision, during the COVID-19 pandemic. Methods: Multi-national online survey disseminated via key stakeholders to specialist palliative care services, completed
by lead clinicians. Data collected on volunteer roles, deployment, and changes in volunteer engagement. Analysis
included descriptive statistics, a multivariable logistic regression, and analysis of free-text comments using a content
analysis approach. Results: 458 respondents: 277 UK, 85 rest of Europe, and 95 rest of the world. 68.5% indicated volunteer use pre-
COVID-19 across a number of roles (from 458): direct patient facing support (58.7%), indirect support (52.0%), back
office (48.5%) and fundraising (45.6%). 11% had volunteers with COVID-19. Of those responding to a question on
change in volunteer deployment (328 of 458) most (256/328, 78%) indicated less or much less use of volunteers. Less use
of volunteers was associated with being an in-patient hospice, (odds ratio [OR] = 0.15, 95% CI = 0.07-0.3, P < .001). This
reduction in volunteers was felt to protect potentially vulnerable volunteers, with policy changes preventing volunteer
support. However, adapting was also seen where new roles were created, or existing roles pivoted to provide virtual
support. pp
Conclusion: Volunteers were mostly prevented from supporting many forms of palliative care which may have quality
and safety implications given their previously central roles. Volunteer re-deployment plans are needed that take
a more considered approach, using volunteers more flexibly to enhance care while ensuring safe working practices. Consideration needs to be given to widening the volunteer base away from those who may be considered to be most
vulnerable to COVID-19. Keywords: Palliative Care, COVID-19, Volunteers Copyright: © 2021 The Author(s); Published by Kerman University of Medical Sciences. This is an open-access article
distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/
by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is
properly cited Copyright: © 2021 The Author(s); Published by Kerman University of Medical Sciences. http://ijhpm.com
Int J Health Policy Manag 2021, x(x), 1–9 http://ijhpm.com
Int J Health Policy Manag 2021, x(x), 1–9 doi 10.34172/ijhpm.2021.128 Full list of authors’ affiliations is available at the end of the article. Prohibit, Protect, or Adapt? The Changing Role of
Volunteers in Palliative and Hospice Care Services
During the COVID-19 Pandemic. A Multinational Survey
(Covpall) Catherine Walshe1*¶ ID , Ian Garner1¶ ID , Lesley Dunleavy1 ID , Nancy Preston1 ID , Andy Bradshaw2 ID , Rachel L. Cripps3 ID , Sabrina Bajwah3 ID , Katherine E. Sleeman3 ID , Mevhibe Hocaoglu3 ID , Matthew Maddocks3 ID , Fliss
EM Murtagh2 ID , Adejoke O. Oluyase3 ID , Lorna K. Fraser4 ID , Irene J. Higginson3 ID , on behalf of the CovPall
Study Team# Original Article Prohibit, Protect, or Adapt? The Changing Role of
Volunteers in Palliative and Hospice Care Services
During the COVID-19 Pandemic. A Multinational Survey
(Covpall) *Correspondence to:
Catherine Walshe
Email: c.walshe@lancaster.ac.uk Implications for policy makers Implications for policy makers p
p
y
•
Policy-makers should take account of the skills and contributions of volunteers to healthcare services when planning how to respond to
emergencies, including epidemic and pandemic situations. •
Policy-makers should take account of the skills and contributions of volunteers to healthcare services when planning how to respond to
emergencies, including epidemic and pandemic situations. g
g
•
Volunteers can remain an integral part of an organisation’s pandemic response. •
Volunteers can remain an integral part of an organisation’s pandemic response. Volunteers can remain an integral part of an organisation’s pa •
Policies should plan to take account both of potential vulnerabilities of volunteer populations, but also reflect on the flexibility and potential
responsiveness of volunteers. •
Policies should plan to take account both of potential vulnerabilities of volunteer populations, but also reflect on the flexibility and potential
responsiveness of volunteers. Implications for the public Volunteers are typically integral to the way that palliative care services are usually delivered. However, during the coronavirus disease 2019
(COVID-19) pandemic most organisations stopped using volunteers almost immediately, or curtailed their activities. This has potential implications
for staff workload, and the responsiveness, quality and safety of care. Organisations should work with volunteers and those who are interested
in volunteering for organisations to develop policies and procedures that enable safe and flexible deployment of volunteers in such emergency
situations. It is likely that expanding the typical age range of volunteers to include those who are younger, and exploring virtual or remote forms of
volunteering may also enable continued use of volunteers in the future. using an online multi-national survey of hospice and specialist
palliative care providers. This study is reported in accordance
with the Strengthening the Reporting of Observational
Studies in Epidemiology (STROBE)28 and the Checklist
for Reporting Results of Internet E-Surveys (CHERRIES)29
reporting guidelines. This paper is part of the wider CovPall
study1-3 that aims to understand the multi-national specialist
palliative care response to COVID-19. and hospice care across all settings, including in-patient
palliative care units, hospital and home palliative care teams,
home nursing services and in the community.8,9 Whilst
volunteers traditionally contributed mostly to ‘back office’
functions such as finance or catering, as well as running
shops and other fundraising activities, they are increasingly
found in patient facing roles.10-13 When providing patient-
facing care, typically the focus is on psychosocial support,
including spiritual care, signposting to services, as well as care
tasks.5,6,10,14-16 Volunteers complement professional care by
being a unique face of care for patients, occupying a liminal
space between professionals, family and patients.8,17,18 Background to the way that high quality, safe services are provided across
the world.4 In some services volunteers can be more numerous
than paid staff, with one UK survey identifying 1.5 volunteers
to every paid member of staff,5 providing a great number of
hours of care and support, typically up to 8 hours a week.6 It
is estimated that each UK volunteer provides at least £1500 of
value per annum to the organisation.7 Volunteers also offer
stability; a Belgian survey identified that most volunteers had
been in their current care organisation for at least 6 years
(57%), and 36% for over 10 years.6 Specialist palliative and hospice care services have proven to be
critically important as part of the whole-system management
of the coronavirus disease 2019 (COVID-19) pandemic.1-3
They are closely involved in the symptom management of
those who are dying or who have challenging symptoms (both
dying with COVID-19 and from COVID-19) and, at times,
services have provided additional bed capacity to help manage
the surge in patient numbers in the wider healthcare system. Whilst paid staff are central to the provision of palliative and
hospice care services, volunteers are also major contributors Volunteers can support many different aspects of palliative Volunteers can support many different aspects of palliative Walshe et al International Journal of Health Policy and Management, 2021, x(x), 1–9
2 Sampling and Recruitment
Th Sampling and Recruitment
The survey was open to responses from 23/04/2020
to 31/07/2020. An open invitation to participate was
disseminated through advertisement and via palliative care
and hospice organisations (Sue Ryder, Hospice UK, Scottish
Partnership for Palliative Care, Marie Curie, European
Association of Palliative Care, Together for Short Lives, and
the palliativedrugs.com and https://pos-pal.org network). All interested eligible services were provided with a link
to complete the survey online, together with a participant
information sheet. There was no targeted sampling across
provider type or country, and respondents were not
incentivised or reimbursed for completion. Completion
indicated consent. No data are yet available on the impact of the COVID-19
pandemic on volunteers and the role and service they provide
to palliative and hospice services during this time. Effective
use of volunteers is highlighted as a possible response to the
pandemic,26 with calls for mobilising and training a citizen
volunteer workforce that is ready and able to connect with
patients in need of basic social support.27 It is important
that the role of volunteers during the COVID-19 pandemic
is understood, given the dependence many palliative care
services have on them for quality care provision and to
maintain a safe organisation. Methods REDCap (an online web application that allows for the
building and managing of surveys and databases) was used to
collect data online with closed and free text survey responses,
designed to shed light on the context for closed responses. Sites were given the option to enter the data online directly, be
emailed the survey to complete and then return electronically,
or complete the survey via telephone or video conferencing
with a member of the study team. As well as general and
COVID-19 related service information (see Supplementary REDCap (an online web application that allows for the
building and managing of surveys and databases) was used to
collect data online with closed and free text survey responses,
designed to shed light on the context for closed responses. To understand volunteer deployment and activities within
palliative and hospice care services, and to identify what may
affect any changes in volunteer service provision, during the
COVID-19 pandemic. Population and Setting
l
d Service leads were invited to take part in the online survey
on behalf of their organisation if they provided a minimum
of one of the following specialist palliative care services: in-
patient palliative care, hospital palliative care, home palliative
care and home nursing across any country. Care from volunteers has been found to be safe, effective,
and appreciated by patients.9 Benefits to people who receive
care are assumed to include improvements in quality of
life and enhancement of wellbeing,9,10,11,18-21 and one study
also indicated a survival advantage for those supported
by volunteers.22 Volunteers themselves benefit from their
volunteering activities reporting that it becomes a major part
of their lives,4 changing their own perspectives and values.23-25
No data are yet available on the impact of the COVID-19
pandemic on volunteers and the role and service they provide
to palliative and hospice services during this time. Effective
use of volunteers is highlighted as a possible response to the
pandemic,26 with calls for mobilising and training a citizen
volunteer workforce that is ready and able to connect with
patients in need of basic social support.27 It is important
that the role of volunteers during the COVID-19 pandemic
is understood, given the dependence many palliative care
services have on them for quality care provision and to
maintain a safe organisation. Care from volunteers has been found to be safe, effective,
and appreciated by patients.9 Benefits to people who receive
care are assumed to include improvements in quality of
life and enhancement of wellbeing,9,10,11,18-21 and one study
also indicated a survival advantage for those supported
by volunteers.22 Volunteers themselves benefit from their
volunteering activities reporting that it becomes a major part
of their lives,4 changing their own perspectives and values.23-25 Key Messages Key Messages Design Design g
A cross-sectional design, with a single point of data collection Walshe et al file 1 for full survey), specific questions were asked about their
use of volunteers, and the impact of COVID-19 on volunteers
(Table 1). information criteria. Analysis was conducted in SPSS version
26. For the analysis of free-text comments, data were extracted
for the relevant questions in Table 1. As is common with free
text data from surveys comments tended to be brief, expanding
on answers to closed questions.30,31 After initial familiarisation,
a coding framework was inductively developed and applied to
the free text data (by CW, IG) using a conventional content
analysis technique.32 Coding and theme development were
driven by the content of the free-text comments, with themes
identified initially within, and then compared across, the sets
of answers to each included question. Data Analysis In the quantitative analyses, the primary outcome was a
dichotomised variable about volunteer deployment post-
pandemic (a lot more/slightly more/about the same vs slightly
less/much less volunteer use), collapsed from the initial five-
point scale for those services that answered this question
due to the skewed clustering in the answers to this question,
hereafter more or less (which includes a proportion who
answered ‘about the same’) volunteer use. The relationship
between these two categories of volunteer use during the
pandemic and a number of potential explanatory variables
(service funding model; type of service provided; whether
adult/child service; number of confirmed or suspected
COVID-19 cases; personal protective equipment (PPE)
shortages; staff shortages; whether service changes were
made; whether services perceived themselves to be busy;
and geography (a post-hoc categorisation of UK/Europe/
Rest of World recognising the unequal dispersion of answers
across countries) were explored using frequency counts (for
dichotomous variables) or median/interquartile range (for
continuous non normally distributed variables). Differences
between more or less volunteer use for dichotomous variable
were assessed using chi-square (χ2) analysis, with Mann-
Whitney U t tests for non-dichotomous data. Sample size
(n) is also provided for Mann-Whitney U t tests. For the
multivariable logistic regression model, the dependent
variable was change in frequency of volunteer use (with ‘less
volunteer use’ as the reference category), with explanatory
variables chosen according to significance (P < .05). For each
explanatory variable the reference category was the answer
‘no’ for dichotomous variables, and the lowest denominator
for non-dichotomous variables (eg, ‘much less busy’ for staff
busyness), and for the outcome the ‘less volunteer use’ was
the reference group. Model fit was assessed using Bayesian Results A total of 458 responses were received, of which 314 (68.5%)
indicated they used volunteers pre-pandemic in any role, and
with 328 answering the question about deployment during
the pandemic (see Table 2 for details). Further analyses only include data from the 328 services
who responded to the question about volunteer deployment
during the pandemic (Table 3). When comparing the 130
participants who did not provide answers on volunteer
deployment compared to those who did, participants who did
not answer this question had significantly more PPE shortages
(χ2 = 6.65, P = .01), staff shortages (χ2 = 4.63, P = .03), and
changes to hospital palliative care advanced team settings
in response to COVID-19 (χ2 = 4.59, P = .03). No further
significant differences were found. The multivariable logistic regression (Table 4) shows that
there was a significant association between providing in-
patient hospice care and reporting less use of volunteers
than usual during the pandemic. Services who care for
adult patients only were significantly associated with more
volunteer use. No other variables were significantly associated
with change in volunteer use compared to pre-COVID-19. Analysis of free-text data identified two overarching themes. First, that of protecting and prohibiting volunteers from
contributing in the ways that they did pre-pandemic. Second, Table 1. Specific Survey Questions on Volunteer Use Within the CovPall Survey International Journal of Health Policy and Management, 2021, x(x), 1–9
3
Table 1. Specific Survey Questions on Volunteer Use Within the CovPall Survey
If you had volunteer roles available within your service, what were
they? (tick all that apply)
• Direct patient/family facing support (eg, befriending, home visits, in-
patient unit care, family support groups/visiting etc)
• Indirect patient/family facing support (eg, reception functions,
refreshments, driving /transport etc)
• Back office functions (eg, finance support, maintenance, gardening etc)
• Fundraising functions (eg, shop volunteers, lottery etc)
• Others (a box will open below)
Have you had volunteers with suspected or confirmed COVID-19. Yes/No
What impact has this (volunteers with suspected or confirmed
COVID-19) on your service? Have you changed how your volunteers engage and where? Please give
details. Yes/No
How would you say you are deploying volunteers compared to before
COVID-19? • A lot more
• Slightly more
• About the same
• Slightly less
• Much less
Abbreviation: COVID-19, coronavirus disease 2019. International Journal of Health Policy and Management, 2021, x(x), 1–9
3 Walshe et al Table 2. International Journal of Health Policy and Management, 2021, x(x), 1–9
4 Results Descriptive Data on Volunteer Use Pre and During the COVID-19 Pandemic
All Responses
(n = 458)
No. (%)
Indicated Any Past
Volunteer Use (n = 314)
No. (%)
Answered Question About Current
Volunteer Deployment (the Same or
More/Less) (n = 328)
No. (%)
Geography
UK
277 (60.5)
187 (59.6)
195 (59.5)
Europe
85 (18.6)
59 (18.8)
62 (18.9)
Rest of world
95(20.7)
67 (21.3)
71 (21.6)
Missing
1 (0.2)
1 (0.3)
0 (0)
Pre-pandemic volunteer roles
Direct support
269 (58.7)
269 (85.6)
246 (75.0)
Indirect support
238 (51.9)
238 (75.7)
218 (66.4)
Back office
222 (48.4)
222 (70.7)
205 (62.5)
Fundraising
209 (45.6)
209 (66.5)
189 (58.1)
Others
51 (11.1)
51 (16.2)
49 (14.9)
Missing
0 (0)
0 (0)
0 (0)
Volunteers with COVID-19
Yes
38 (8.3)
36 (11.4)
36 (10.9)
No
369 (80.6)
260 (82.8)
279 (85.0)
Missing
51 (11.1)
18 (5.8)
13 (4.1)
Have you changed how your volunteers engage? Yes
280 (61.1)
268 (85.3)
258 (78.6)
No
119 (26.0)
34 (10.8)
64 (19.8)
Missing
59 (12.9)
12 (3.9)
6 (1.6)
How would you say you are deploying volunteers compared to before COVID-19? A lot more
12 (2.6)
11 (3.3)
12 (3.6)
Slightly more
10 (2.2)
9 (2.9)
10 (3.0)
About the same
50 (10.9)
23 (7.4)
50 (15.4)
Slightly less
29 (6.3)
29 (9.3)
29 (8.8)
Much less
227 (49.6)
211 (67.2)
227 (69.2)
Missing
130 (28.4)
31 (9.9)
0 (0)
Abbreviation: COVID-19, coronavirus disease 2019. Abbreviation: COVID-19, coronavirus disease 2019. is largely because our volunteers are generally over 65yr and
there is fear from their families of undue exposure and risk.” that of adaptation, where a minority of services adapted and
changed the way they deployed volunteers. f
f
f
f
– Site 25 (Rest of world, Adult, IPU). Protect and Prohibit Concerns about protecting volunteers from COVID-19
were noted both because of their personal vulnerabilities, the
concerns of their families, and of affecting the institution’s
reputation if a volunteer contracted COVID-19 as a result of
their involvement in the organisation. Institutional policies
were often changed to directly prohibit volunteers from
enacting their roles: Our quantitative data demonstrates a large decrease in the use
of volunteers. Our free text data illuminates this, identifying
that typically volunteers were either prohibited from
supporting the service in the way that they usually did, or else
because they were protected because they were perceived as
particularly vulnerable to the effects of COVID-19. This was
both because of local service based policies, or in response to
national guidelines about the protection of those who were
particularly vulnerable: “Early corporate steer - no volunteers in the hospital” –
Site 188 (UK, Adult, Hospital). “The hospital/trust have altered their policy on this. No
ward volunteers, volunteers redeployed to eg, distributing
donations” – Site 250 (UK, Adult, Hospital). “Volunteers were temporarily told to stay home across the
hospital. Elderly volunteers were told to stay longer periods
at home for their protection” – Site 478 (Rest of world,
Adult, Hospital). As well as protecting or prohibiting the volunteers
themselves, preserving and prioritising both the distribution
of PPE when there were shortages, and also the integrity of
the site, was also important, with sites favouring so called
‘essential’ staff as opposed to volunteers. Despite most
services reporting that they used volunteers in some capacity
pre-pandemic, concerns about supporting and supervising “All volunteer work cancelled due to demographic of
majority of volunteers, and concern about exposing them to
COVID by charity” – Site 99 (UK, Adult, In Patient Unit
[IPU]/Hospital advisory). “No volunteers are called upon to offer their services. This Walshe et al Table 3. Characteristics of Services Indicating More or Less Volunteer Use During the COVID-19 Pandemic, With an Indication of Which Associations Between
Characteristics Are Statistically Significant Table 3. Characteristics of Services Indicating More or Less Volunteer Use During the COVID-19 Pandemic, With an Indication of Which Associations Between
Characteristics Are Statistically Significant
Characteristic
(Present Yes/No)
Less Volunteer Use
(n = 256)
No. (%)
Same/More Volunteer
Use (n = 72)
No. (%)
All Services
(n = 328)
No. (%)
Missing
No. Protect and Prohibit (%)
χ2/U
P
UK
Yes
160 (62.5)
35 (48.6)
195 (59.5)
0 (0)
χ2 = 4.5
.03*
No
96 (37.5)
47 (51.4)
133 (40.5)
Rest of Europe
Yes
48 (18.8)
14 (19.4)
62 (18.9)
0 (0)
χ2 = 0.2
.89
No
208 (81.3)
58 (80.6)
266 (81.1)
Rest of world
Yes
48 (18.8)
23 (31.9)
71 (21.6)
0 (0)
χ2 = 5.8
.02*
No
208 (81.3)
49 (68.1)
257 (78.4)
Inpatient hospice
Yes
195 (76.2)
24 (33.3)
219 (66.8)
0 (0)
χ2 = 46.5
<.01*
No
61 (23.8)
48 (66.7)
109 (33.2)
Hospital palliative care team
Yes
102 (39.8)
37 (51.4)
139 (42.4)
0 (0)
χ2 = 3.1
.08
No
154 (50.2)
35 (48.6)
189 (57.6)
Home palliative care
Yes
151 (59.0)
38 (52.8)
189 (57.6)
0 (0)
χ2 = 0.9
.35
No
105 (41.0)
34 (47.2)
139 (42.4)
Home nursing
Yes
85 (33.2)
15 (20.8)
100 (30.5)
0 (0)
χ2 = 4.1
.04*
No
171 (66.8)
57 (79.2)
228 (69.5)
Charitable/non-profit funding
Yes
155 (60.5)
21 (29.2)
176 (53.7)
3 (0.9%)
χ2 = 22.1
<.01*
No
99 (39.7)
50 (69.4)
149 (45.4)
Public funding
Yes
73 (28.5)
44 (61.1)
117 (35.7)
3 (0.9%)
χ2 = 26.6
<.01*
No
181 (71.7)
27 (27.5)
208 (63.4)
Private/other funding
Yes
26 (10.2)
6 (8.3)
32 (9.8)
3 (0.9%)
χ2 = 0.2
.66
No
228 (89.1)
65 (90.3)
293 (89.3)
Adult only, child only, or all patients
cared for
Adult only
194 (75.8)
64 (88.9)
258 (78.7)
5 (1.5%)
χ2 = 6.1
.11
Child only
21 (8.2)
2 (2.8)
23 (7.0)
All patients
37 (14.5)
5 (6.9)
42 (12.8)
PPE shortages
Yes
147 (57.4)
29 (40.3)
176 (53.7)
1 (0.3%)
χ2 = 6.8
.01*
No
108 (42.2)
43 (59.7)
151 (46.0)
Staff shortages
Yes
104 (40.6)
26 (36.1)
130 (39.6)
4 (1.2%)
χ2 = 0.6
.43
No
148 (57.8)
46 (63.9)
194 (59.2)
Inpatient beds changes
Yes
128 (50.0)
26 (36.1)
154 (47.0)
0 (0)
χ2 = 4.4
.04*
No
128 (50.0)
46 (63.9)
174 (53.0)
Acute hospital patient support
changes
Yes
94 (36.7)
33 (45.8)
127 (38.7)
0 (0)
χ2 = 2.0
.16
No
162 (63.3)
39 (54.2)
201 (91.3)
Specialist palliative care service
changes
Yes
154 (60.2)
36 (50.0)
190 (57.9)
0 (0)
χ2 = 2.4
.12
No
102 (39.8)
36 (50.0)
138 (42.1)
Hands-on home nursing care
changes
Yes
101 (39.5)
26 (36.1)
127 (38.7)
0 (0)
χ2 = 0.3
.61
No
155 (60.5)
46 (63.9)
201 (61.3)
Cases of COVID-19 in staff
Yes
198 (77.3)
53 (73.6)
251 (76.5)
2 (0.6%)
χ2 = 0.6
.44
No
56 (21.9)
19 (26.4)
75 (22.9)
Cases of COVID-19 in volunteers
Yes
30 (11.7)
6 (8.3)
36 (11.0)
13 (4.0%)
χ2 = 0.7
.42
No
216 (84.4)
63 (87.5)
279 (85.1)
Total cases of COVID-19 in patients
n
241 (94.1)
67 (93.1)
308 (92.9)
20 (6.1%)
U = 7235.5
.19
Median (IQR)
8 (28)
15 (57)
8 (30)
Staff busyness
n
256 (100.0)
72 (100.0)
329 (100.0)
0 (0)
U = 8774.0
.52
Median (IQR)
3 (3)
2 (3)
3 (3)
Abbreviations: COVID-19, coronavirus disease 2019; PPE, personal protective equipment; IQR, interquartile range. International Journal of Health Policy and Management, 2021, x(x), 1–9 Discussion Palliative and hospice care services that had previously
been reliant on a large volunteer body to support care often
experienced a large decline in the presence of volunteers
during the early phase of the COVID-19 pandemic,
primarily due to their active withdrawal or suspension by
the organisation to protect volunteers and focus on a core
staff team. This is likely to have affected service capacity
and delivery. Some palliative and hospice care organisations
instituted new roles for volunteers, or moved existing roles
to a remote way of working, but these appeared uncommon. In-patient hospices appeared particularly vulnerable to seeing
reductions in volunteer use. functions previously run by volunteers:
“Staff have been deployed so duties such as reception are
being supported by staff” Site 47 (England, Adult, IPU/
Hospital/Home). functions previously run by volunteers: The management of risk within an organisation is
important, but challenging to undertake at speed in a
pandemic situation when new and previously unknown
risks are presenting themselves. COVID-19 has highlighted
the vulnerabilities of organisations, and led to challenging
dilemmas about how to manage care standards in a crisis.33 It is
perhaps understandable in this context that a simple solution
to manage the risks associated with volunteers is to rapidly
curtail their activities, particularly in small organisations
that are high users of volunteers, such as many in-patient
hospices. Writing plans and procedures to manage volunteers
during a pandemic is possibly not an organisational priority. This has also happened previously, such as the suspension of
volunteers during Avian flu.34 However, it must be recognised
that in such a volunteer-rich specialty that this also carries
risk, and ultimately may not be cost effective, and likely
results in major reductions in elements of service capacity. There is evidence that responding to COVID-19 has strained
the palliative care workforce,35 and surges in demand for end-
of-life care have exposed and exacerbated underlying gaps in
access to specialty-trained physicians and teams, palliative
care medications, and bereavement support for patients and
families.36 At a time like this, not having a plan to use what
can be a particularly common, valuable, knowledgeable, and
committed resource such as volunteers, potentially adds to,
rather than avoids, the risks and costs an organisation faces. A
few services, however, did not curtail volunteer activities, but
were able to respond more flexibly, and innovate rapidly. Discussion Our
quantitative data did not identify any specific characteristics
that determined what type of organisation was able to respond
more flexibly. It is hard to unpick why these few services International Journal of Health Policy and Management, 2021, x(x), 1–9
6 Protect and Prohibit * indicates a significant association. Abbreviations: COVID-19, coronavirus disease 2019; PPE, personal protective equipment; IQR, interquartile range. * indicates a significant association. “Due to changes in services and changed working practices
unable to support and supervise volunteers. Only essential
staff working in the hospice hence no volunteers attending
when families are in” – Site 52 (UK, Children, IPU). volunteers during the pandemic also contributed to reductions
in their deployment, with many of them not considering
volunteers to be essential staff: “Reduced ward-based volunteers to preserve PPE and
reduce the footfall on the ward” – Site 59 (UK, IPU/
Hospice). Such decisions had a knock-on effect on staffing across
the organisation, with staff being re-deployed to support 5 Walshe et al Table 4. Service Characteristics Independently Associated With Less Volunteer
Use During the COVID-19 Pandemic Examples included both new remote roles, such as facilitating
the completion of care plans, or in-person roles such as
providing hands-on nursing care: Table 4. Service Characteristics Independently Associated With Less Volunteer
Use During the COVID-19 Pandemic
OR
OR 95% CI
P
Lower
Upper
UK (no)
Ref
UK (yes)
0.92
0.40
2.11
.85
Rest of the world (no)
Ref
Rest of the world (yes)
1.68
0.67
4.21
.27
Inpatient hospice care (no)
Ref
Inpatient hospice care (yes)
0.16
0.07
0.33
<.01
Hands-on nursing care (no)
Ref
Hands-on nursing care (yes)
0.99
0.46
2.14
.98
Charitable/non-profit management
(no)
Ref
Charitable/non-profit management
(yes)
1.18
0.35
3.95
.79
Public management (no)
Ref
Public management (yes)
2.51
0.85
7.42
.10
PPE shortages (no)
Ref
PPE shortages (yes)
1.03
0.52
2.04
.94
Inpatient bed changes (no)
Ref
Inpatient bed changes (yes)
1.72
0.83
3.56
.15
Abbreviations: COVID-19, coronavirus disease 2019; PPE, personal
protective equipment; OR, odds ratio. “New volunteers helping patients with myCMC [coordinate
my care – a care planning initiative]. Volunteers calling GP
practices to get them to complete CMC plans. Volunteers
calling care homes to navigate them through the creation of
myCMC plans for their residents” – Site 76 (UK, Adult, IP/
Hospice). “Additional volunteer training provided early on so that
volunteers can provide basic patient care. This has been a
really popular move for both volunteers and staff and will
continue and develop” – Site 187 (UK, Adult, IPU). Adaptation Some services had identified safe ways of adapting roles,
or developed new functions that volunteers could more
safely fulfil during the pandemic. This included support,
befriending and bereavement roles, often delivered remotely. Other roles included services such as driving, delivering,
shopping and gardening. Occasionally completely new roles
were identified which could include those directly arising
as a result of the pandemic (eg, making scrubs), but also
coordination and information sharing roles. An example is
the pivot to telephone or virtual support for patients already
known to the organisation, and using skills that volunteers
had already developed in existing in-person roles: y
p
g
p
“We’ve asked all existing befriending or bereavement
type volunteers to offer telephone support and soon to
offer Facebook group bereavement support. We’ve asked
Compassionate Neighbours to offer support to care home
residents. We hope to set up a bereavement telephone helpline
for any resident in [name of region] (and once lockdown
eases we will need more volunteers to help act as a listening
ear)” – Site 56 (UK Adult, IPU/Hospital/community). “Now utilizing ‘buddy program’ where volunteers can
call individuals and do a check in and offer support to help
with social isolation and bridge the gap from quarantine at
home and the community” – Site 373 (US/Adult/Hospital/
community). M
l
i
i
i
d
l
l
l f “We’ve asked all existing befriending or bereavement
type volunteers to offer telephone support and soon to
offer Facebook group bereavement support. We’ve asked
Compassionate Neighbours to offer support to care home
residents. We hope to set up a bereavement telephone helpline
for any resident in [name of region] (and once lockdown
eases we will need more volunteers to help act as a listening
ear)” – Site 56 (UK Adult, IPU/Hospital/community). “Now utilizing ‘buddy program’ where volunteers can
call individuals and do a check in and offer support to help
with social isolation and bridge the gap from quarantine at
home and the community” – Site 373 (US/Adult/Hospital/
community). More rarely, services imagined a completely new role for
volunteers that hadn’t been fulfilled in-person previously. International Journal of Health Policy and Management, 2021, x(x), 1–9
6 Walshe et al call, without any form of sampling, may have resulted in a
particular type of organisation, or from particular countries,
respond in patterns that are not known. There is not an
equal distribution of responses across countries or clusters
of countries. Conclusion Volunteers, previously central to the support of many forms
of palliative care, were mostly absent from organisations
immediate response to COVID-19, particularly in-patient
hospices. At a time where staffing has been affected by
deployment changes and illness, this lack of a previously
stable support may have affected both the scope, quality and
safety of care. Flexible deployment plans need to be developed
that protect volunteers, whilst still enabling them to have a
role supporting care. Consideration needs to be given to
widening the volunteer base away from those who may be
considered to be most vulnerable to COVID-19, potentially
engaging with younger people as volunteers. Further research
needs to explore in more depth and detail what were the
organisational factors that enabled some organisations to
respond more flexibly, understand change over time during
(and hopefully beyond) the COVID-19 pandemic, and with
greater contextual information such as within countries or
types of health and social care provision. g
There is evidence that volunteers do not always feel informed
about the organisation of patient care, or feel the organisation
consistently takes their opinion into account.41 It is likely that
volunteers themselves may have had the ability and capacity
to produce the needed plans to enable new ways of working,
if engaged and asked, although this may be difficult to do
at speed and with competing priorities. Certainly, we know
that some have argued for new roles for volunteers during
the pandemic such as virtual volunteering.26,27,42 Some areas
where volunteering is deeply embedded, such as in Kerala,
have managed to emphasise community participation as
part of their response to COVID, which includes supporting
palliative care patients.43 This is not just seen in low-middle
income countries, for example the calls for new volunteers
in the United Kingdom such as the National Health Service
(NHS) volunteering scheme were responded to by 750 000
people. Here there is a paradox, volunteers are both seen
as central to the response of a community or organisation,
but equally not fully integrated into the response of the
organisations for which they volunteer, not kept informed
and on-board with the organisation, or not seen as ‘essential,’
and rapidly sidelined due to restrictive policies. For volunteers
themselves, it is likely rarely about the tasks themselves, but
about volunteering being a fundamental response; a desire to
help. Adaptation The way that this survey was constructed, with
single responses covering multiple modes of service provision
meant that it was not always possible to fully understand the
impact of volunteer changes on specific types of services. The
survey was also completed by service leads, and hence reflects
their views, not those of volunteer coordinators nor the
volunteers themselves. There were many services that did not
provide information on change in volunteer deployment, and
they may represent a different type of service. The survey was
open for completion over a period of months, and it therefore
also represents different times, in different countries, of the
experience of the first wave of COVID-19. The temporal
sequence of events is not known (eg, whether an increase in
COVID-19 cases triggered a reduction in volunteer use). Free
text comments, whilst commonly given, were often short with
little context, so it was not always possible to fully interpret
justifications for decisions made. were outliers in innovative volunteer deployment, given the
generally flexible, responsive and innovative nature of their
general response to the pandemic reported elsewhere.3 g
p
p
p
It is likely that a major factor in the rapid cessation or
curtailment of the use of volunteers was the perception, or
reality, of many volunteers being particularly vulnerable
to the effects of COVID-19 because of their age. Concerns
were likely to be highlighted because of the large degree of
uncertainty surrounding this new disease.37 We know that
volunteers are predominantly older people.6 However, it
could be argued that this view is potentially discriminatory,
or ageist, and that the capacity of older people must be
better used. Whilst assumptions may have been made about
the technological capability of older people to switch to a
remote form of operation, there is evidence that so called
‘silver surfers’ or ‘digital immigrants’ do use technology and
can adapt rapidly to using it in ways that are appropriate to
their age group.38,39 It is likely that older volunteers could have
been better engaged by many organisations in areas such as
the delivery of telephone or other forms of remote support, or
shifted to other remote roles such as fundraising from home. It is critically important that we now work to shape future
policies (and training) to optimally engage the resources of
our aging population, and not unintentionally discriminate
against those who are older as policies and procedures
change.40 International Journal of Health Policy and Management, 2021, x(x), 1–9 Conclusion Their compassionate response to palliative care needs
during COVID-19 should not be put to one side, but ways
found of ensuring that they can again become a central and
fundamental part of palliative and hospice care provision. Funding 10. Burbeck R, Candy B, Low J, Rees R. Understanding the role of the
volunteer in specialist palliative care: a systematic review and thematic
synthesis of qualitative studies. BMC Palliat Care. 2014;13(1):3. doi:10.1186/1472-684x-13-3 This work was supported by UKRI and the NIHR [COV0011; MR/
V012908/1]. Additional support was from the NIHR, ARC, SL, hosted at King’s
College Hospital NHS Foundation Trust, and Cicely Saunders International
(Registered Charity No. 1087195). 11. Claxton-Oldfield S. Hospice palliative care volunteers: the benefits for
patients, family caregivers, and the volunteers. Palliat Support Care. 2015;13(3):809-813. doi:10.1017/s1478951514000674 IJH is a NIHR Emeritus Senior Investigator and is supported by the NIHR
ARC SL at King’s College Hospital National Health Service Foundation Trust. IJH leads the Palliative and End of Life Care theme of the NIHR ARC SL and co-
leads the national theme in this. CW is supported by the NIHR Applied Research
Collaboration North West Coast (ARC NWC, NIHR200182). MM is funded by
a NIHR Career Development Fellowship (CDF-2017-10-009) and NIHR ARC
SL. LKF is funded by a NIHR Career Development Fellowship (award CDF-
2018-11-ST2-002). KES is funded by a NIHR Clinician Scientist Fellowship
(CS-2015-15-005). RC is funded by Cicely Saunders International. FEM is a
NIHR Senior Investigator. MBH is supported by the NIHR ARC SL. The views
expressed in this article are those of the authors and not necessarily those of
the NIHR, or the Department of Health and Social Care. 12. Naylor C, Mundle C, Weaks L, Buck D. Volunteering in Health and Care:
Securing a Sustainable Future. London: The King’s Fund; 2013. 13. Lorhan S, Wright M, Hodgson S, van der Westhuizen M. The development
and implementation of a volunteer lay navigation competency framework
at an outpatient cancer center. Support Care Cancer. 2014;22(9):2571-
2580. doi:10.1007/s00520-014-2238-8 14. Morris S, Wilmot A, Hill M, Ockenden N, Payne S. A narrative literature
review of the contribution of volunteers in end-of-life care services. Palliat
Med. 2013;27(5):428-436. doi:10.1177/0269216312453608 15. Nissim R, Regehr M, Rozmovits L, Rodin G. Transforming the experience
of cancer care: a qualitative study of a hospital-based volunteer
psychosocial support service. Support Care Cancer. 2009;17(7):801-809. doi:10.1007/s00520-008-0556-4 Ethical issues Research ethics committee approval for this study was obtained from King’s
College London Research Ethics Committee (21/04/2020, Reference;
LRS19/20-18541). ISRCTN16561225. Completion of survey indicated the
participant had consented to the study. 5. Burbeck R, Low J, Sampson EL, et al. Volunteers in specialist palliative
care: a survey of adult services in the United Kingdom. J Palliat Med. 2014;17(5):568-574. doi:10.1089/jpm.2013.0157 Acknowledgements g
This study was part of CovPall, a multi-national study,
supported by the Medical Research Council, National Institute
for Health Research (NIHR) Applied Research Collaboration
(ARC) South London (SL) and Cicely Saunders International. We thank all collaborators and advisors. We thank all
participants, partners, PPI members and our Study Steering
Group. We gratefully acknowledge technical assistance from
the Precision Health Informatics Data Lab group (https://
phidatalab.org) at NIHR Biomedical Research Centre at SL
and Maudsley NHS Foundation Trust and King’s College
London for the use of REDCap for data capture. The CovPall Study Team consists of the following members:
Professor Irene J Higginson (Chief Investigator), Dr Sabrina
Bajwah (Co-I), Dr. Matthew Maddocks (Co-I), Professor
Fliss Murtagh (Co-I), Professor Nancy Preston (Co-I) , Dr. Strengths and Limitations This was a large, multi-national survey with closed and free-
text design giving insight and understanding. The open 7 Walshe et al pandemic: an analysis of the UK CovPall survey data from specialist
palliative
care
services. Palliat
Med. 2021;35(7):1225-1237. doi:10.1177/02692163211017387 Katherine E Sleeman (Co-I), Professor Catherine Walshe
(Co-I), Professor Lorna K Fraser (Co-I), Dr. Mevhibe B
Hocaoglu (Co-I), Dr. Adejoke Oluyase (Co-I), Dr. Andrew
Bradshaw, Lesley Dunleavy, Ian Garner and Rachel L Cripps. Additionally, the following memebers are the CovPall Study
Partners: Hospice UK, Marie Curie, Sue Ryder, Palliative
Outcome Scale Team, European Association of Palliative Care
(EAPC), Together for Short Lives and Scottish Partnership for
Palliative Care. 2. Oluyase AO, Hocaoglu M, Cripps RL, et al. The challenges of caring
for people dying from COVID-19: a multinational, observational study
(CovPall). J Pain Symptom Manage. 2021;62(3):460-470. doi:10.1016/j. jpainsymman.2021.01.138 3. Dunleavy L, Preston N, Bajwah S, et al. ‘Necessity is the mother of
invention’: specialist palliative care service innovation and practice change
in response to COVID-19. Results from a multinational survey (CovPall). Palliat Med. 2021;35(5):814-829. doi:10.1177/02692163211000660 4. Scott R, Goossensen A, Payne S, Pelttari L. What it means to be a
palliative care volunteer in eight European countries: a qualitative analysis
of accounts of volunteering. Scand J Caring Sci. 2021;35(1):170-177. doi:10.1111/scs.12832 Authors’ contributions 7. Gaskin K. The Economics of Hospice Volunteering. London: Hospice
Information; 2003. IJH is the grant holder and chief investigator; KES, MM, FEM, CW, NP, LKF, SB,
MBH and AO are co-applicants for funding. IJH and CW with critical input from
all authors wrote the protocol for the CovPall study. MBH, AO, RC and LD co-
ordinated data collection and liaised with centres, with input from IJH, FEM, CW,
NP and LKF. IG, MH, AO, LF and CW analysed the data. All authors had access
to all study data, discussed the interpretation of findings and take responsibility
for data integrity and analysis. CW and IF drafted the manuscript. All authors
contributed to the analysis plan and provided critical revision of the manuscript
for important intellectual content. 8. Bloomer MJ, Walshe C. ‘It’s not what they were expecting’: a systematic
review and narrative synthesis of the role and experience of the
hospital palliative care volunteer. Palliat Med. 2020;34(5):589-604. doi:10.1177/0269216319899025 9. Walshe C, Dodd S, Hill M, et al. How effective are volunteers at supporting
people in their last year of life? a pragmatic randomised wait-list trial in
palliative care (ELSA). BMC Med. 2016;14(1):203. doi:10.1186/s12916-
016-0746-8 Competing interests 6. Vanderstichelen S, Cohen J, Van Wesemael Y, Deliens L, Chambaere
K. Volunteers in palliative care: a healthcare system-wide cross-
sectional survey. BMJ Support Palliat Care. 2020. doi:10.1136/
bmjspcare-2020-002321 Authors declare that they have no competing interests. Data sharing Applications for use of the survey data can be made for up to 10 years, and will
be considered on a case by case basis on receipt of a methodological sound
proposal to achieve aims in line with the original protocol. The study protocol
is available on request. All requests for data access should be addressed to
the Chief Investigator via the details on the CovPall website (https://www.kcl. ac.uk/cicelysaunders/research/evaluating/covpall-study, and palliativecare@kcl. ac.uk) and will be reviewed by the Study Steering Group. 16. Dunleavy L, Walshe C, Machin L. Exploring the psychological impact of
life-limiting illness using the attitude to health change scales: a qualitative
focus group study in a hospice palliative care setting. Eur J Cancer Care
(Engl). 2020;29(6):e13302. doi:10.1111/ecc.13302 17. Vanderstichelen S, Cohen J, Van Wesemael Y, Deliens L, Chambaere
K. The liminal space palliative care volunteers occupy and their roles
within it: a qualitative study. BMJ Support Palliat Care. 2020;10(3):e28. doi:10.1136/bmjspcare-2018-001632 International Journal of Health Policy and Management, 2021, x(x), 1–9
8 Authors’ affiliations 18. Dodd S, Hill M, Ockenden N, et al. ‘Being with’ or ‘doing for’? how the
role of an end-of-life volunteer befriender can impact patient wellbeing:
interviews from a multiple qualitative case study (ELSA). Support Care
Cancer. 2018;26(9):3163-3172. doi:10.1007/s00520-018-4169-2 1International Observatory on End of Life Care, Lancaster University, Lancaster,
UK. 2Wolfson Palliative Care Research Centre, Hull York Medical School,
University of Hull, Hull, UK. 3Cicely Saunders Institute of Palliative Care, Policy
& Rehabilitation, King’s College, London, UK. 4The Martin House Research
Centre, Department of Health Sciences, University of York, York, UK. 19. Luijkx KG, Schols JM. Volunteers in palliative care make a difference. J
Palliat Care. 2009;25(1):30-39. Supplementary files
Supplementary file 1. CovPall Collaboration Survey. 20. Gardiner C, Barnes S. The impact of volunteer befriending services for
older people at the end of life: mechanisms supporting wellbeing. Prog
Palliat Care. 2016;24(3):159-164. doi:10.1080/09699260.2015.1116728 Supplementary files Supplementary files Supplementary file 1. CovPall Collaboration Survey. 21. Candy B, France R, Low J, Sampson L. Does involving volunteers in
the provision of palliative care make a difference to patient and family
wellbeing? a systematic review of quantitative and qualitative evidence. 21. Candy B, France R, Low J, Sampson L. Does involving volunteers in
the provision of palliative care make a difference to patient and family
wellbeing? a systematic review of quantitative and qualitative evidence. References References 1. Bradshaw A, Dunleavy L, Walshe C, et al. Understanding and
addressing challenges for advance care planning in the COVID-19 1. Bradshaw A, Dunleavy L, Walshe C, et al. Understanding and
addressing challenges for advance care planning in the COVID-19 Walshe et al Int J Nurs Stud. 2015;52(3):756-768. doi:10.1016/j.ijnurstu.2014.08.007 33. Chuang E, Cuartas PA, Powell T, Gong MN. “We’re not ready, but i don’t
think you’re ever ready.” Clinician perspectives on implementation of crisis
standards of care. AJOB Empir Bioeth. 2020;11(3):148-159. doi:10.1080/
23294515.2020.1759731 22. Herbst-Damm KL, Kulik JA. Volunteer support, marital status, and the
survival times of terminally ill patients. Health Psychol. 2005;24(2):225-
229. doi:10.1037/0278-6133.24.2.225 23. Söderhamn U, Flateland S, Fensli M, Skaar R. To be a trained and
supported volunteer in palliative care - a phenomenological study. BMC
Palliat Care. 2017;16(1):18. doi:10.1186/s12904-017-0193-0 34. Cheng HW, Li CW, Chan KY, Sham MK. The first confirmed case of
human avian influenza A(H7N9) in Hong Kong and the suspension of
volunteer services: impact on palliative care. J Pain Symptom Manage. 2014;47(6):e5-7. doi:10.1016/j.jpainsymman.2013.12.234 24. Beasley E, Brooker J, Warren N, et al. The lived experience of
volunteering in a palliative care biography service. Palliat Support Care. 2015;13(5):1417-1425. doi:10.1017/s1478951515000152 35. Kates J, Gerolamo A, Pogorzelska-Maziarz M. The impact of COVID-19
on the hospice and palliative care workforce. Public Health Nurs. 2021;
38(3):459-463. doi:10.1111/phn.12827 25. Coleman H, Walshe C. What are the emotional experiences of being a
volunteer in palliative and end-of-life care settings? a systematic review
and thematic synthesis. J Pain Symptom Manage. 2021;62(3):e232-e247. doi:10.1016/j.jpainsymman.2021.02.025 36. Abbott J, Johnson D, Wynia M. Ensuring adequate palliative and
hospice care during COVID-19 surges. JAMA. 2020;324(14):1393-1394. doi:10.1001/jama.2020.16843 37. Koffman J, Gross J, Etkind SN, Selman L. Uncertainty and COVID-19:
how are we to respond? J R Soc Med. 2020;113(6):211-216. doi:10.1177/0141076820930665 26. Knights D, Knights F, Lawrie I. Upside down solutions: palliative
care and COVID-19. BMJ Support Palliat Care. 2020. doi:10.1136/
bmjspcare-2020-002385 27. Radbruch L, Knaul FM, de Lima L, de Joncheere C, Bhadelia A. The
key role of palliative care in response to the COVID-19 tsunami of
suffering. Lancet. 2020;395(10235):1467-1469. doi:10.1016/s0140-
6736(20)30964-8 38. Fietkiewicz K. Jumping the digital divide: how do “silver surfers” and
“digital immigrants” use social media? Networking Knowledge: Journal
of the MeCCSA Postgraduate Network. 2017;10(1):5-26. doi:10.31165/
nk.2017.101.494 39. Vulpe S, Crăciun A. Silver surfers from a European perspective:
technology communication usage among European seniors. Eur J
Ageing. 2020;17(1):125-134. doi:10.1007/s10433-019-00520-2 28. International Journal of Health Policy and Management, 2021, x(x), 1–9
9 References von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC,
Vandenbroucke JP. The Strengthening the Reporting of Observational
Studies
in
Epidemiology
(STROBE)
statement:
guidelines
for
reporting observational studies. J Clin Epidemiol. 2008;61(4):344-349. doi:10.1016/j.jclinepi.2007.11.008 40. Gonzales E, Matz-Costa C, Morrow-Howell N. Increasing opportunities
for the productive engagement of older adults: a response to population
aging. Gerontologist. 2015;55(2):252-261. doi:10.1093/geront/gnu176 29. Eysenbach G. Improving the quality of web surveys: the Checklist for
Reporting Results of Internet E-Surveys (CHERRIES). J Med Internet
Res. 2004;6(3):e34. doi:10.2196/jmir.6.3.e34 41. Vanderstichelen S, Cohen J, Van Wesemael Y, Deliens L, Chambaere K. The involvement of volunteers in palliative care and their collaboration
with healthcare professionals: a cross-sectional volunteer survey across
the Flemish healthcare system (Belgium). Health Soc Care Community. 2020;28(3):747-761. doi:10.1111/hsc.12905 30. Garcia J, Evans J, Reshaw M. “Is there anything else you would like
to tell us’’ – Methodological issues in the use of free-text comments
from postal surveys. Qual Quant. 2004;38(2):113-125. doi:10.1023/
B:QUQU.0000019394.78970.df 42. Pickell Z, Gu K, Williams AM. Virtual volunteers: the importance of
restructuring medical volunteering during the COVID-19 pandemic. Med
Humanit. 2020;46(4):537-540. doi:10.1136/medhum-2020-011956 31. O’Cathain A, Thomas KJ. “Any other comments?” open questions on
questionnaires - a bane or a bonus to research? BMC Med Res Methodol. 2004;4:25. doi:10.1186/1471-2288-4-25 43. Menon JC, Rakesh PS, John D, Thachathodiyl R, Banerjee A. What was
right about Kerala’s response to the COVID-19 pandemic? BMJ Glob
Health. 2020;5(7):e003212. doi:10.1136/bmjgh-2020-003212 32. Hsieh H-F, Shannon SE. Three approaches to qualitative content analysis. Qual Health Res. 2005;15(9):1277-1288. doi:10.1177/1049732305276687 32. Hsieh H-F, Shannon SE. Three approaches to qualitative content analysis. Qual Health Res. 2005;15(9):1277-1288. doi:10.1177/1049732305276687 9
|
https://openalex.org/W2091972325
|
https://europepmc.org/articles/pmc3019375?pdf=render
|
English
| null |
Antiulcer and Anti-inflammatory Activity of Aerial Parts Enicostemma littorale Blume
|
Journal of young pharmacists
| 2,010
|
cc-by
| 3,432
|
ABSTRACT The antiulcer and in vitro anti-inflammatory activities of the aerial parts of Enicostemma littorale against aspirin,
ethanol, and pyloric ligation-induced ulcers in rats and bovine serum albumin denaturation were studied. The
extract (200 mg/kg and 400 mg/kg po) was administered to the overnight fasted rats, one hour prior to aspirin
/ alcohol / pyloric ligation challenge. The ulcer index, tissue GSH levels, and lipid peroxidation levels were
estimated in all the models of ulcers and the volume of gastric secretion, acidity, and pH, were estimated in
the pyloric ligation model of ulcers. Pretreatment with the extract showed a dose-dependent decrease in the
ulcer index (Against Aspirin, ethanol challenge, and pyloric ligation. The prior administration of the extract also
reduced the total acidity, free acidity, and volume of gastric secretion, and elevated the gastric pH. In addition,
it was also observed that the extract inhibited the serum albumin denaturation in a dose-dependent manner. It
may be concluded that the methanolic extract possesses antiulcer activity, and the anti-inflammatory activity of
the extract may be attributed to the antioxidant potential, as reported earlier. Key words: Anti-inflammatory, antioxidants, antiulcer, Enicostemma littorale DOI: 10.4103/0975-1483.71629 Roy SP, Niranjan CM, Jyothi TM, Shankrayya MM, Vishawanath KM, Prabhu K,
Gouda VA, Setty RS1 Department of Pharmacology, S. C. S. College of Pharmacy, Harapanahalli - 583 131, Karnataka, India,
1College of Clinical Pharmacy, King Faisal University, Al Ahsa, 31982, Kingdom of Saudi Arabia Address for correspondence: Dr. Ramachandra Setty S; E-mail: rssiddamsetty@rediffmail.com Address for correspondence: Dr. Ramachandra Setty S; E-mail: rssiddamsetty@rediffmail.c Journal of Young Pharmacists Vol 2 / No 4 Pharmacology Pharmacology Pharmacology Roy, et al. J Young Pharm. 2010;2(4): 369-373 Roy, et al. J Young Pharm. 2010;2(4): 369-373 to possess antitumor,[3] antiarthritic,[4] hypoglycemic,[5] and
antimalarial activities.[6] There are reports that the plant
possesses flavonoids, xanthines, and so on, in the aerial
parts of this plant.[7] The flavonoids are known to have
antioxidant, antiulcer, and anti-inflammatory properties. However, there are no reports on the gastroprotective
activity of the plant. As, this plant is reported to contain
flavonoids and other related compounds, the methanolic
extract of this plant is investigated for gastroprotective
and in vitro anti-inflammatory activities by using various
experimental models of ulcers namely pyloric ligation,
ethanol, and aspirin-induced ulcers in albino rats. Aspirin (ASP)-induced ulcer[9] Albino rats of either sex weighing between 180 and 200 g
were divided into five groups of six animals each and fasted
for 24 hours with water ad libitum, prior to the experiment. The animals of groups 1 and 2 were pre-treated with vehicle
and the animals of group 3 were treated with standard,
that is, lansoprazole 8 mg/kg. Similarly the animals of
groups 4 and 5 were pre-treated with methanolic extract
200 mg/kg and 400 mg/kg, respectively. Aspirin (200 mg/
kg p o) was administered to the animals of groups 2 – 5,
60 minutes after the respective treatments. The animals
were then sacrificed by cervical dislocation after six hours. The stomach was taken out and cut open along the greater
curvature. The number of ulcers per stomach were noted
and severity of the ulcers were observed microscopically
and scoring was done as follows:[10] Zero for normal colored
stomach, 0.5 for red coloration, 1 for spot ulcer, 1.5 for
hemorrhagic streaks, 2 for ulcer > 3 but < 5 mm, and 3 for
ulcer > 5 mm. The mean ulcer score for each animal was
expressed as the ulcer index. The percentage protection
was calculated. Ethanol induced (EtoH)-induced ulcer[11] Ethanol induced (EtoH)-induced ulcer[11]
Albino rats of either sex weighing between 180 – 200 g were
divided into five groups of six animals each and fasted for
24 hours with water ad libitum, prior to the experiment. The
animals of groups 1 and 2 were pre-treated with vehicle
and the animals of group 3 were treated with standard, that
is, lansoprazole 8 mg/kg. Similarly the animals of groups
4 and 5 were pre-treated with methanolic extract 200 mg/
kg and 400 mg/kg, respectively. Ethanol (100% 1 ml/200
g, p o) was administered to all the animals of groups 2 –
5, 60 minutes after the respective treatments. The animals
were sacrificed by cervical dislocation after one hour of
EtOH administration and the stomach was incised along
the greater curvature and examined for ulcers. The ulcer
index was scored as mentioned earlier, using Kulkarni’s
method,[10] and the percentage protection was also reported. Acute toxicity studies The extracted methanol was tested for acute toxicity studies
as per CPCSEA guideline No. 420. No animals died even
at 2000 mg/kg and hence one-tenth and one-fifth of 2000
mg/kg was selected for further investigations. Collection of plant material The shoots of plant Enicostemma littorale Blume were collected
from Karnataka (India) from August to September, 2005)
at the end of flowering season and were authenticated
By Prof. K. Prabhu, Department of Pharmacognosy, S. C. S. College of Pharmacy, Harapanahalli. The voucher
specimen was deposited at SCSCOP, Harapanahalli. Journal of Young Pharmacists Vol 2 / No 4 INTRODUCTION concomitantly used drugs or food. It is unaffordable for
common man to take such drugs for a prolonged period
due to their escalating costs. Therefore, a large section
of the world’s population relies on traditional remedies
/ alternative systems of medicines to treat a plethora of
diseases including gastric ulcers.[2] Various mechanisms have been suggested for explaining
the pathogenesis of peptic ulcer, which results due to
an imbalance between the protective mechanisms and
aggressive factors such as pepsin and acid.[1] In addition,
the free radicals involved in tissue damage have been
reported to play a role in the causation of gastric ulcers. Several classes of drugs are being adopted in the treatment
of ulcers to restore the balance between aggressive and
protective factors involved in the causation of ulcers. However, administration of drugs for a prolonged period is
required to treat ulcers. Prolonged usage of such synthetic
agents may cause side effects / drug interactions with Hence, in our search for herbal remedies for diseases
that require chronic treatment, we found that Enicostemma
littorale Blume a glorious perennial herb belonging to the
family Gentianceae. Upon literature survey it was found
that the hot extract from it is being used by tribal healers
of interior Gujarat, for the treatment of diabetes, fever,
stomach ache, dyspepsia, and malaria. It is also reported 369 Preparation of the extract The plant material was dried under shade. The shade-dried
material was powdered. The coarse powder was subjected
to successive extraction using solvents with increasing
order of polarity that is, petroleum ether, chloroform, and
methanol, and macerated with chloroform water.[8] All the
extracts were subjected to the preliminary phytochemical
tests and the methanolic extract showed the presence of
flavonoids. Hence, the methanolic extract was selected for
further studies. Animals The stomach was taken out and
cut open along the greater curvature and ulcers were scored
and % protection was reported as mentioned in the above
explained models. Statistical analysis All the results are subjected to Student’s T test and the
‘P’ value less than 0.05 was considered as statistically
significant. RESULTS The observations of the +ve control group indicated that
aspirin (200 mg/kg)-induced gastric ulcers were to the
extent of 17.10 ± 1.45 (ulcer index). Pre-treatment with
test extracts reduced the ulceration in a dose-dependent
manner. The extent of the gastroprotective effect of the
test extracts was 63.28 and 78.14% at 200 mg/kg and 400
mg/kg doses, respectively, which was comparable to that
of the standard lansoprazole 8 mg/kg. Similar results were
obtained with the ethanol-induced ulcer model also. The
test extract showed gastroprotection in a dose-dependent
manner, that is, 61.54 and 76.9% protection at 200 and 400
mg/kg doses, respectively. The test extracts at the doses
mentioned earlier showed a significantly higher level of
protection than that of standard lansoprazole (8 mg/kg). The results are compiled in Table 1. Gastric secretion The gastric juice was collected four hours after pylorus
ligation and centrifuged for five minutes at 2000 rpm
and the volume of the supernatant was noted. The pH
of the gastric juice was recorded by the pH meter. Then
the contents were subjected to analysis for free and total
acidity. Free acidity output was determined by treating with
0.01N NaOH, using the Topfer’s reagent until the solution
turned yellowish orange. Then titration was continued, with
phenolphthalein as an indicator, until there was a red tinge
as the end point. This volume corresponded to total acidity. The pyloric ligation caused the accumulation of gastric
secretions (7.3 ml) with pH 2.35. The total acidity and
free acidity of the gastric secretions were 130.80 and
87.50, respectively. Pre-treatment with the test extracts
reduced the volume of gastric secretion (5.13 and 3.01 ml
at 200 and 400 mg/kg doses) and the pH was elevated up
to 6.56. In addition the total acidity and free acidity were
also reduced significantly in a dose-dependent manner. The results are compiled in Table 2. Furthermore, it was
observed that pyloric ligation caused gastric ulcerations
and pretreatment with test extracts reduced them
significantly in a dose-dependent manner [Table 1]. In this
model also the gastroprotection offered by the test extracts
were comparable to those of the standard lansoprazole
8 mg/kg. Animals Albino rats (125 – 175 g) and mice (18 - 25 g) of either sex
were obtained from NIMHANS, Bangalore, and were kept
in standard plastic animal cages in a group of six to eight
in each cage, at standard conditions, with 12 hours of light
and dark cycle, in an institutional animal house. The animals
were fed with the standard rodent diet and with water ad
libitum. After one week of acclimatization the animals
were used for further experiments. The CPCSEA approval
number was Reg. No.157/1999/CPCSEA. Approval from
the institutional animal ethical committee for the usage
of animals in the experiments and experimental protocol
was obtained as per the Indian CPCSEA guidelines for the
usage of laboratory animals prior to the experimentation. Albino rats of either sex weighing between 180 – 220 g
were divided into five groups of six animals each, fasted
for 18 hours and care was taken to avoid coprophagy. 370 Activity of aerial parts Enicostemma littorale Blume the turbidity was measured. Percentage inhibition of
denaturation was calculated from control. Each experiment
was done in triplicate and the average was taken. Control vehicle (group-2) or standard drug (group-3) or
extracts (group - 4 and 5) were administered 60 minutes
prior to Pyloric ligation, under light ether anesthesia. The abdomen was opened and pylorus ligation was done
without causing any damage to its blood supply. The
stomach was replaced carefully and the abdomen wall was
closed in two layers with interrupted sutures. The animals
were deprived of water during the post-operative period. After four hours, the stomach was dissected out, and
the contents were collected into tubes for estimation of
biochemical parameters. The stomach was taken out and
cut open along the greater curvature and ulcers were scored
and % protection was reported as mentioned in the above
explained models. Control vehicle (group-2) or standard drug (group-3) or
extracts (group - 4 and 5) were administered 60 minutes
prior to Pyloric ligation, under light ether anesthesia. The abdomen was opened and pylorus ligation was done
without causing any damage to its blood supply. The
stomach was replaced carefully and the abdomen wall was
closed in two layers with interrupted sutures. The animals
were deprived of water during the post-operative period. After four hours, the stomach was dissected out, and
the contents were collected into tubes for estimation of
biochemical parameters. DISCUSSION Table 3: Inhibition of bovine serum albumin
denaturation by methanolic extract of Enicostemma
littorale Blume (EA)
Compound
Absorbance
Inhibition of
denaturation (%)
Control
0.098 ± 0.009
–
MeOH ext of EA 100 mg
0.121 ± 0.002*
23.46
MeOH ext of EA 200 mg
0.135 ± 0.001*
37.75
MeOH ext of EA 300 mg
0.140 ± 0.001*
42.85
Standard diclofenac sodium
(0.2mM)
0.167 ± 0.033*
70.40
*All compounds tested at 0.2 mm concen Table 3: Inhibition of bovine serum albumin
denaturation by methanolic extract of Enicostemma
littorale Blume (EA) It is evident from the present study that the study
extract is non-toxic even at 2000 mg/kg and possesses
gastroprotective and anti-inflammatory activity against the
experimental models. The results are concurrent with the fact that plants containing
antioxidant principles also possess antiulcer properties. As
the antioxidant-containing extract demonstrates antiulcer
and anti-inflammatory properties, it may be inferred that
the free radicals may also have a role in causing ulcers
and inflammation. This is supportive evidence for the
reports in literature regarding this. Similarly it also justifies
the traditional usage of this plant for gastrointestinal
disturbances. However, the test extract also shows the anti-
inflammatory effect with gastroprotection. This is contrary
to the fact that anti-inflammatory agents cause gastric
irritation and hyperacidity. This aspect has to be verified and
probably different phytoconstituents may be responsible
for both the beneficial effects of the study extract. Nonsteroidal anti-inflammatory drugs (NSAIDs) like
aspirin, cause gastric mucosal damage by decreasing the
prostaglandin levels through inhibition of PG synthesis.[17]
Enicostemma littorale was significantly effective in the
protective gastric mucosa against aspirin-induced ulcers
at the entire dose level studied. Hence, it may be inferred that Enicostemma littorale affords
effective protection to the gastric mucosa against various
insults, by increasing the gastric mucin content and
decreasing the acid volume and free and total acidity in
rats. The effects in all the three models studied were dose-
dependent. It has been proposed that in pyloric ligation, the digestive
effect of accumulated gastric juice and hindrance of
gastric blood circulation is responsible for the induction of
ulceration.[14] The antiulcer activity of Enicostemma littorale
in the pylorus ligation model is evident from its significant
reduction in gastric volume, free acidity, total acidity
and ulcer index. In vitro Anti-inflammatory activity Inhibition of albumin denaturation was studied according
to Muzustima and Kabagashi, with slight modifications[13]
The test compounds were dissolved in a minimum amount
of dimethyl formamide (DMF) and diluted with phosphate
buffer (0.2 M, PH 7.4). The final concentration of DMF
in all the solutions was less than 2.5%. The test solution
(1 ml) containing 100 and 200 mg of the drug was mixed
with 1 ml of 1 mM albumin solution in phosphate buffer
and incubated at 270 ± 10C for 15 minutes. Denaturation
was induced by keeping the reaction mixture at 600 ± 10C
in a water bath for 10 minutes. After cooling the samples, Table 1: Effect of Methanolic extract of leaves of Enicostemma littorale Blume on Aspirin, Ethanol (1 ml/kg), and
four-hour Pylorus ligation (PL)- induced gastric ulcers in rats
Treatment
Dose
Ulcer index
% of protection
Aspirin
Ethanol
PL
Aspirin
Ethanol
PL
-ve Control
–
0.680 ± 0.056
0.333 ± 0.123
0.680 ± 0.056
-
-
-
+ve Control
–
17.10 ± 1.45
15.16 ± 2.18
9.16 ± 0.92
-
-
-
Lansoprazole
8 mg/kg BW
5.83 ± 1.40*
6.75 ± 0.91*
3.00 ± 0.51**
66.02
54.47
67.24
MeOH ext of EA
200 mg/kg BW
6.33 ± 0.67*
5.83 ± 0.55*
5.16 ± 0.69*
63.28
61.54
43.66
MeOH ext of EA
400 mg/kg BW
3.75 ± 0.61*
3.50 ± 0.28*
3.25 ± 0.61**
78.14
76.91
64.51
*< 0.01, **< 0.001 vs. Control, EA: Enicostemma littorale Blume lic extract of leaves of Enicostemma littorale Blume on Aspirin, Ethanol (1 ml/kg), and
(PL)- induced gastric ulcers in rats Table 1: Effect of Methanolic extract of leaves of Enicostemma littorale Blume on Aspirin, Et
four-hour Pylorus ligation (PL)- induced gastric ulcers in rats Journal of Young Pharmacists Vol 2 / No 4 371 Roy, et al. J Young Pharm. In vitro Anti-inflammatory activity 2010;2(4): 369-373 Table 2: Effect of Methanolic extract of leaves of Enicostemma littorale Blume on Gastric secretion following Pyloric
Ligation-induced Ulcer in Rats
Treatment
Dose
Volume (ml)
pH
Total Acidity (Eq/I)
Free Acidity (Eq/I)
Control
--
7.30 ± 0.57
2.35 ± 0.16
130.80 ± 6.41
87.50 ± 2.32
Lansoprazole
8 mg/kg BW
1.68 ± 0.19**
7.38 ± 0.08**
42.33 ± 1.35**
34.83 ± 2.30**
MeOH ext of EA
200 mg/kg BW
5.13 ± 0.36*
3.61 ± 0.29*
76.00 ± 2.28**
64.5 ± 2.47**
MeOH ext of EA
400 mg/kg BW
3.01 ± 0.18*
6.56 ± 0.26**
56.66 ± 2.59**
42.50 ± 2.54**
*< 0.01, **< 0.001, EA: Enicostemma littorale Blume able 2: Effect of Methanolic extract of leaves of Enicostemma littorale Blume on Gastric secret
gation-induced Ulcer in Rats t of leaves of Enicostemma littorale Blume on Gastric secretion following Pyloric Journal of Young Pharmacists Vol 2 / No 4 Journal of Young Pharmacists Vol 2 / No 4 Journal of Young Pharmacists Vol 2 / No 4 Activity of aerial parts Enicostemma littorale Blume conditions, with no danger of gastrointestinal distress. However, further experiments are required to establish
and elaborate the molecular mechanisms of its antiulcer
and anti-inflammatory activities. 9. Datta GK, Sairam K, Priyambada S, Debnath PK, Goel RK. Antiulcerogenic
activity of satavari mandw: An Ayurvedic herbo medical preparation. Indian
J Exp Biol 2002;40:1173-7. 10. Kulkarni SK. Handbook of experimental Pharmacology. New Delhi:
Vallabh Prakashan; 2002. p. 148. 11. Astudillo L, Rodriguez JA, Schmeda-Hirschmann G. Gastroprotective
activity of Oleanolic acid derivatives on experimentally induced gastric
lesions in rat and mice. J Pharm Pharmacol 2002;54:583-8. DISCUSSION As Enicostemma littorale-treated animals
significantly inhibit the formation of ulcers in pylorus-
ligated rats and also decrease both concentration and
gastric volume, it is suggested that Enicostemma littorale can
suppress the gastric damage induced by aggressive factors. There is a report that the plant possesses flavonoids and
flavonoids are known to have antioxidant activity. As there
are reports that the generation of free radicals is one of
the causes of the ulceration, the antiulcer activity of the
extract may be attributed to the antioxidant potential of
the plant.[16] Medical treatment of peptic ulcers is dependent on
correcting the imbalance between the offensive and
defensive factors. The methanolic extract of the study
plant acts on both parameters of the equation, which
govern the treatment of peptic ulcer and thus can be
useful clinically. Clinical usefulness of Enicostemma littorale
is thus specially indicated in conditions such as rheumatoid
arthritis, where the prostaglandin synthesis inhibitors are
usually used with the concurrent danger of gastric erosion
/ ulcers. Enicostemma littorale may prove beneficial in arthritic Ethanol-induced gastric injury is associated with significant
production of oxygen-free radicals leading to increased
lipid peroxidation, which causes damage to the cell and
the cell membranes.[15] Enicostemma littorale significantly
protects the gastric mucosa against the ethanol challenge
as shown by the reduced values of the ulcer index, as
compared to the solvent control group, suggesting its
potent gastroprotective effect, which may be due to its
reported antioxidant activity [Table 3].[16] 372 Activity of aerial parts Enicostemma littorale Blume REFERENCES 12. Shay H, Komarow SA, Fels SS, Meranze D, Gruenstein M, Siplet H. Simple method for the uniform production of gastric ulceration in the rat. Gastroenterology 1945; 5:43. 1. Soll AH. Pathogenesis of peptic ulcer and implications for therapy. N Engl
J Med 1990;322:909-16. 1. Soll AH. Pathogenesis of peptic ulcer and implications for therapy. N Engl
J Med 1990;322:909-16. 13. Mazushima Y, Kobayashi M. Interaction of anti-inflammatory drugs with
serum proteins, especially with some biologically active proteins. J Pharm
Pharmacol 1968;20:169-73. 2. Marini-Bettolo GB. Present aspects of the use of plants in traditional
medicine. J Ethnopharmacol 1980;2:5-7. 2. Marini-Bettolo GB. Present aspects of the use of plants in traditional
medicine. J Ethnopharmacol 1980;2:5-7. 3. Dash GK, Samanths A, Kannungo SK. Hepatoprotective activity of Indian
medicinal plants. Indian J Nat Prod 2000;16:2. 14. Brodie DA. The mechanism of gastric hyperacidity produced by pylorus
ligation in rats. Am J Dig Dis 1966;11:231-41. 4. Sahu SK, Suresh P, Ganapathy S. Hepatoprotective activity of Indian
medicinal plants. Indian J Nat Prod 2000;17:2. 15. Pihan G, Regillo C, Szabo S. Free radicals and lipid peroxidation in ethanol
or aspirin induced gastric mucosal injury. Dig Dis Sci 1987;32:1395-401. 5. Ravi V, Monika K, Sarita G. Hypoglgeamic effect of aqueous extract of
Enicostemma littorale Blume (etihota chiragata) on allonan-induced diabetes
mellitus in rats. Indian J Exp Biol 2000;38:781-4. 16. Vishwanath SL, Goyal RK. Hepatoprotective activity of Enicostemma littorale
in CCl4-induced liver damage. J Nat Rem 2004;2:120-6. 17. Vane JR. Inhibition of prostaglandin synthesis is a mechanism of action
for aspirin-like drugs. Nature 1971;231:232-5. 6. Katewa SS, Arora A. Effect of certain ethnomedicinal plants. Indian Drugs
2001;38:6. 7. Ghosal S, Jaiswal DK. Chemical constituents of genetianceae XXVIII;
flaronoids of Enicostemma hysspifolicm (Wild) Verd. J Pharm Sci 1980;69:53-6. Source of Support: Nil, Conflict of Interest: None declared. 8. Kokate K, Purohit AP, Gokhale SB. Pharmacognosy. Pune: Nirali Prakashan;
1999. p. 90-1. 373
|
https://openalex.org/W4389488822
|
https://revistaseletronicas.pucrs.br/index.php/veritas/article/download/44191/28300
|
Portuguese
| null |
Desumanização e a banalidade do mal
|
Veritas
| 2,023
|
cc-by
| 18,642
|
OPEN ACCESS OPEN ACCESS VERITAS (PORTO ALEGRE)
Revista de Filosofia da PUCRS
Veritas, Porto Alegre, v. 68, n. 1, p. 1-21, jan.-dez. 2023
e-ISSN: 1984-6746 | ISSN-L: 0042-3955 Recebido em: 2 jan. 2023.
Aprovado em: 23 ago. 2023.
Publicado em: 08 dez. 2023. Leonardo Delatorre
Leite1 Leite
orcid.org/0000-0001-8276-2436
leonardoleite1998@usp.br Desumanização e a banalidade do mal: uma análise a partir
da literatura de testemunho de Primo Levi e da narrativa
histórica de Hannah Arendt Dehumanization and the banality of evil: an analysis based on Primo Levi’s literature of
testimony and Hannah Arendt’s historical narrative Deshumanización y banalidad del mal: un análisis a partir de la literatura testimonial
de Primo Levi y la narrativa histórica de Hannah Arendt Resumo: O presente artigo apresenta como intuito primordial uma exposição
acerca da temática da desumanização presente na literatura de testemunho de
Primo Levi (1919-1987) e nas reflexões de Hannah Arendt (1906-1975), sobretudo
em sua obra Eichmann em Jerusalém. A investigação acerca do fenômeno da
desumanização no universo concentracionário nazista será realizada, primordial-
mente, a partir de sua relação com a tese da banalidade do mal, que aborda a
impessoalização e a perda da consciência moral como integrantes do projeto
totalitário de supressão da individualidade e da banalização da barbárie. Numa
primeira análise, foi estabelecida uma breve ponderação sobre os principais
aspectos do “mal banal” na perspectiva da narrativa histórica de Arendt e de que
forma tais elementos dialogam com a despersonalização. Em seguida, a temática
da desumanização foi analisada propriamente na literatura primoleviana. Por fim,
foi traçado um paralelo entre os dois autores, atestando, de forma categórica,
um vínculo direto entre o totalitarismo, a proliferação da banalidade do mal e a
desumanização. Fundamentado sob a metodologia de abordagem dedutiva, o
presente trabalho foi construído com a utilização de fontes bibliográficas. Gerson Leite de
Moraes1
id
/
8 orcid.org/0000-0002-8464-983X
gerson.moraes@mackenzie.br Palavras-chave: Primo Levi; Hannah Arendt; desumanização; banalidade do
mal; totalitarismo. Abstract: This article presents as its main purpose an exposition about the
theme of dehumanization present in the testimonial literature of Primo Levi
(1919-1987) and in the reflections of Hannah Arendt (1906-1975), especially in
her work Eichmann in Jerusalem. The investigation about the phenomenon of
dehumanization in the Nazi concentrationist universe will be carried out, prima-
rily, from its relationship with the thesis of the banality of evil, which addresses
the impersonalization and the loss of moral conscience as parts of the totali-
tarian project of suppression of individuality and the banalization of barbarism. In a first analysis, a brief consideration of the main aspects of “banal evil” was
established from the perspective of Arendt’s historical narrative and how these
elements dialogue with depersonalization. Next, the theme of dehumanization
was analyzed exactly in Primolevian literature. Finally, a parallel between the
two authors was drawn, attesting, in a categorical way, a direct link between to-
talitarianism, the proliferation of the banality of evil, and dehumanization. Based
on the methodology of deductive approach, the present work was built with the
use of bibliographic sources. Keywords: Primo Levi; Hannah Arendt; dehumanization; banality of evil; tota-
litarianism. Resumen: Este trabajo presenta como propósito principal una exposición sobre
el tema de la deshumanización presente en la literatura testimonial de Primo Levi
(1919-1987) y en las reflexiones de Hannah Arendt (1906-1975), especialmente
en su obra Eichmann en Jerusalén. La investigación sobre el fenómeno de la 1 Universidade Presbiteriana Mackenzie (Mackenzie), São Paulo, SP, Brasil. 2/21 Veritas, Porto Alegre, v. 68, n. 1, p. 1-21, jan.-dez. 2023 | e-44191 do totalitarismo, regime político caracterizado
pela atuação total do Estado na sociedade, ou
seja, pela extensão do controle do poder polí-
tico à esfera pública e às instituições privadas. Acerca do paralelo entre a despersonalização e
o fenômeno do totalitário, as reflexões da pen-
sadora alemã Hannah Arendt ocupam um lugar
de proeminência. deshumanización en el universo concentracionario
nazi se realizará, principalmente, a partir de su relaci-
ón con la tesis de la banalidad del mal, que aborda la
impersonalización y la pérdida de la conciencia moral
como parte del proyecto totalitario de supresión de
la individualidad y banalización de la barbarie. 2 Importante destacar que o holocausto também simbolizou a destruição da cultura judaica europeia, ou seja, implicou uma “morte
cultural” e, por conseguinte, a massificação da comunidade judaica, que perdeu sua grande e notável heterogeneidade.
3 Para Irving Howe, além da temática da desumanização, a literatura do holocausto engloba os seguintes elementos: a questão da pre-
servação do ser, isto é, as estratégias físicas e mentais para a sobrevivência num ambiente hostil e degradante; o drama moral, ou seja,
o enfrentamento de dilemas éticas e o estabelecimento de limites principiológicos por parte dos prisioneiros numa tentativa de evitar a
perda da qualidade de “pessoa”; a literatura da memória; o abismo referente ao antes e ao depois da experiência da despersonalização
e, por fim, a consciência do mundo perdido, cujos traços estão presentes na ausência do “retorno ao lar”, temática crucial da literatura
ocidental segundo o pensador conservador Roger Scruton. Ademais, Howe demonstra certo ceticismo em relação à possibilidade de
uma literatura fictícia do holocausto, pois a ficção exige um desfecho, a resolução de um problema e uma determinada “ordenação da
realidade”, aspectos que estão ausentes no mundo pós-Segunda Guerra, caracterizado por cicatrizes profundas (HOWE, 1999).
4 “Por tratar-se de registro escrito da história narrada pela autora, conforme a sua memória estabelecida através da escrita do seu
próprio passado. A narrativa se insere na ciência da História” (PRESOT, 2013, p. 2). Gerson Leite de
Moraes1
id
/
8 En un
primer análisis, se hizo una breve consideración de los
principales aspectos del “mal banal” desde la pers-
pectiva de la narrativa histórica de Arendt y de cómo
estos elementos dialogan con la despersonalización. A
continuación, se analizó adecuadamente el tema de la
deshumanización en la literatura primoleviana. Por últi-
mo, se estableció un paralelismo entre ambos autores,
atestiguando, de forma categórica, un vínculo directo
entre el totalitarismo, la proliferación de la banalidad
del mal y la deshumanización. Fundamentado en la
metodología de abordaje deductivo, el presente tra-
bajo se ha construido utilizando fuentes bibliográficas. Sua obra Eichmann em Jerusalém, uma nar-
rativa histórica4, é fruto das análises e pondera-
ções da autora acerca do julgamento de Adolf
Eichmann, um dos funcionários encarregados
pela chamada “solução final”, o extermínio em
massa dos judeus. Após os eventos da Segunda
Guerra, ele se refugiou em Buenos Aires, mas foi
capturado em 1960 pelo Mossad (Instituto para
Inteligência e Operações Especiais de Israel). Em
seguida, foi levado para ser julgado em Jerusalém
em razão de sua participação nas atrocidades
empreendidas pelo governo nazista. Arendt foi
contratada pela revista The New Yorker para rea-
lizar a cobertura jornalística do julgamento. Palabras clave: Primo Levi; Hannah Arendt; deshu-
manización; banalidad del mal; totalitarismo. Introdução A temática de desumanização constitui um
dos aspectos centrais da literatura judaica do
holocausto2. Numa primeira análise, o tema da
despersonalização tipifica um traço essencial na
literatura da memória3 construída pelos testemu-
nhos dos sobreviventes dos campos de extermí-
nio, pois discorre, de forma categórica, sobre a
degradação holística da dimensão axiológica da
dignidade da pessoa humana. Por certo, um dos
autores cruciais para a compreensão do processo
de perda da subjetividade empreendido pelo
totalitarismo nazista é Primo Levi (1919-1987),
italiano de origem judaica, químico de formação
e um dos sobreviventes de Auschwitz. A literatura
de testemunho de Levi é imprescindível para
um entendimento efetivo das estratégias dos
campos de concentração para a promoção de
uma gradual destruição da dignidade humana e
dos “traços civilizatórios”. As reflexões levantadas pela pensadora foram
paradigmáticas, visto que contribuíram para uma
ruptura em relação a uma ideia maniqueísta
concernente aos atos funestos do totalitaris-
mo. A tese da banalidade do mal levantada por
Arendt dialoga com a temática da desumaniza-
ção apresentada e desenvolvida por Primo Levi. Nesse sentido, uma abordagem comparativa
entre a narrativa histórica da filósofa alemã e da
literatura de testemunho de Levi favorece um
maior esclarecimento sobre as nuances e os
aspectos do projeto totalitário, bem como das
estratégias para evitar a ascensão de regimes
políticos contrários ao princípio da dignidade da
pessoa humana. Ademais, é premente compreender que a de-
sumanização constituía um dos projetos centrais Leonardo Delatorre Leite • Gerson Leite de Moraes
Desumanização e a banalidade do mal 3/21 Leonardo Delatorre Leite • Gerson Leite de Moraes
Desumanização e a banalidade do mal Leonardo Delatorre Leite • Gerson Leite de Moraes
Desumanização e a banalidade do mal 3/21 8 O período entreguerras foi um cenário de incertezas e tentativas dos países europeus de superação das mazelas deixadas pela
Primeira Guerra Mundial. A Alemanha sofreu uma derrota humilhante, consumada pelas imposições do Tratado de Versalhes, que favo-
receu um certo sentimento de “revanchismo”, facilmente aproveitado por discursos autoritários. Ademais, a Crise de 1929 potencializou
a desconfiança da população no liberalismo e nas teses democráticas. A conjugação de crises políticas, sociais e econômicas foi fun-
damental para o crescimento do ceticismo em relação aos elementos republicanos. Tais fatores possibilitaram a ascensão de regimes
ditatoriais. 5 O estudo do totalitarismo constitui um tema eminente para as discussões da ciência política. Vários autores dedicaram inúmeros
escritos e obras para reflexões acerca do fenômeno totalitário, entre os quais: Hannah Arendt (1906-1975), Ernst Cassirer (1874-1945), Eric
Voegelin (1901-1985), Friedrich Hayek (1889-1992) e Theodor Adorno (1903-1969). Arendt explica o totalitarismo a partir da concepção
da banalidade do mal. Por sua vez, Adorno desenvolve conceitos como racionalidade instrumental e Indústria Cultural. Voegelin se vale
de ideias como fé metastática, religiões políticas e imanentização escatológica para explicar as raízes do totalitarismo. Uma reflexão
interessante reside numa ponderação de George Orwell (2017, p. 70), a saber: “O que é realmente assustador quanto ao totalitarismo não
é que cometa atrocidades, mas que agrida o conceito de verdade objetiva”. Sob essa perspectiva, o filósofo Michael Polanyi, opositor de
uma visão instrumentalista e pragmática da ciência, afirma que os prolegômenos do Estado totalitário residem numa crise de sentido
e na degradação axiológica advinda na negação humana de uma realidade transcendente. Sem uma garantia objetiva e transcendente
de verdade, os indivíduos depositam no poder político suas esperanças. “A forma totalitária de Estado surge logicamente da negação da
realidade desse reino das ideias transcendentais. Quando as fundações espirituais para toda a livre dedicação às atividades humanas –
do cultivo da ciência ou do academicismo, da distribuição da justiça, da profissão de religião, do exercício da arte sem peias e da livre
discussão política –, quando as razões transcendentais para todas essas atividades livres são sumariamente negadas, então o Estado se
transforma necessariamente em herdeiro de toda a devoção do homem” (POLANYI, 2003, p. 88-89).
6 Uma temática relevante para a literatura hebraica do holocausto reside na possibilidade de explicação do holocausto e dos males
efetivados pelo nazifascismo. A ideia do campo de concentração como universo concentracionário, a ênfase na “maldade diabólica”
dos nazistas e a gravidade da crueldade praticada pelo governo de Hitler contribuíram para a construção da impossibilidade teórica de
explicação do holocausto, o qual muitas vezes foi compreendido como “um evento fora da história”. Para Arendt, a conjugação dos ele-
mentos subterrâneos do totalitarismo na conjuntura do período entreguerras e a banalidade do mal favorecem uma elucidação histórica
do holocausto. Yehuda Bauer, historiador israelense, afirma que o holocausto é um evento único e inédito em razão de inúmeros fatores,
tais como: a sistematização, a escala industrial e “a eliminação pela eliminação”, ou seja, a ausência de propósitos para o extermínio em
massa (BAUER, 2001).
7 “Já em Origens do totalitarismo, Arendt associou duas ideologias à dissolução do que ela chamou de ‘ideal de humanidade’: de um
lado, o racismo, de outro lado, o nacionalismo tribal. O racismo imperialista demoliu a ideia da origem comum da espécie humana e
dividiu a humanidade entre raças inferiores e superiores [...] resultando na ‘exclusão em princípio da ideia de humanidade como o único
conceito regulador da lei internacional’, com a consequente dissolução do ‘princípio de igualdade e solidariedade de todos os povos,
garantido pela ideia de humanidade [...]’” (CORREIA, 2023, p. 130-131).
8 O período entreguerras foi um cenário de incertezas e tentativas dos países europeus de superação das mazelas deixadas pela
Primeira Guerra Mundial. A Alemanha sofreu uma derrota humilhante, consumada pelas imposições do Tratado de Versalhes, que favo-
receu um certo sentimento de “revanchismo”, facilmente aproveitado por discursos autoritários. Ademais, a Crise de 1929 potencializou
a desconfiança da população no liberalismo e nas teses democráticas. A conjugação de crises políticas, sociais e econômicas foi fun- 7 “Já em Origens do totalitarismo, Arendt associou duas ideologias à dissolução do que ela chamou de ‘ideal de humanidade’: de um
lado, o racismo, de outro lado, o nacionalismo tribal. O racismo imperialista demoliu a ideia da origem comum da espécie humana e
dividiu a humanidade entre raças inferiores e superiores [...] resultando na ‘exclusão em princípio da ideia de humanidade como o único
conceito regulador da lei internacional’, com a consequente dissolução do ‘princípio de igualdade e solidariedade de todos os povos,
garantido pela ideia de humanidade [...]’” (CORREIA, 2023, p. 130-131). 5 O estudo do totalitarismo constitui um tema eminente para as discussões da ciência política. Vários autores dedicaram inúmeros
escritos e obras para reflexões acerca do fenômeno totalitário, entre os quais: Hannah Arendt (1906-1975), Ernst Cassirer (1874-1945), Eric
Voegelin (1901-1985), Friedrich Hayek (1889-1992) e Theodor Adorno (1903-1969). Arendt explica o totalitarismo a partir da concepção
da banalidade do mal. Por sua vez, Adorno desenvolve conceitos como racionalidade instrumental e Indústria Cultural. Voegelin se vale
de ideias como fé metastática, religiões políticas e imanentização escatológica para explicar as raízes do totalitarismo. Uma reflexão
interessante reside numa ponderação de George Orwell (2017, p. 70), a saber: “O que é realmente assustador quanto ao totalitarismo não
é que cometa atrocidades, mas que agrida o conceito de verdade objetiva”. Sob essa perspectiva, o filósofo Michael Polanyi, opositor de
uma visão instrumentalista e pragmática da ciência, afirma que os prolegômenos do Estado totalitário residem numa crise de sentido
e na degradação axiológica advinda na negação humana de uma realidade transcendente. Sem uma garantia objetiva e transcendente
de verdade, os indivíduos depositam no poder político suas esperanças. “A forma totalitária de Estado surge logicamente da negação da
realidade desse reino das ideias transcendentais. Quando as fundações espirituais para toda a livre dedicação às atividades humanas –
do cultivo da ciência ou do academicismo, da distribuição da justiça, da profissão de religião, do exercício da arte sem peias e da livre
discussão política –, quando as razões transcendentais para todas essas atividades livres são sumariamente negadas, então o Estado se
transforma necessariamente em herdeiro de toda a devoção do homem” (POLANYI, 2003, p. 88-89). 1 A banalidade do mal e a
despersonalização despotismo, a tirania e a ditadura. Na expectativa
de apontar as singularidades do totalitarismo, a
autora destaca que este não opera a partir da
ausência de leis, muito pelo contrário, pois sua
essência se funda ou nas leis da Natureza ou
da História. Numa primeira análise, é importante uma
breve explicação sobre os traços essenciais do
pensamento político de Hannah Arendt e de suas
ponderações sobre a banalidade do mal. Para a
pensadora em questão, o totalitarismo5 é histo-
ricamente explicável6, sendo os seus “elementos
subterrâneos” tipificados pelo racismo7, pelo im-
perialismo, pelo militarismo e antissemitismo. No
período entreguerras8, a conjugação dos fatores
supracitados implicou a ascensão de regimes
centrados num profundo desprezo pela individu-
alidade, pelos direitos individuais, pelo “ódio ao
diferente” e pelos valores democráticos. Segundo
Arendt, os traços nevrálgicos do totalitarismo, os
quais representam os seus maiores perigos, são
a impessoalização, a ascensão e a manipulação
das massas e, por fim, a atomização social. A afirmação monstruosa e, no entanto, aparen-
temente irrespondível do governo totalitário é
que, longe de ser “ilegal”, recorre à fonte de au-
toridade da qual as leis positivas recebem a sua
legitimidade final; que, longe de ser arbitrário,
é mais obediente a essas forças sobre-huma-
nas que qualquer governo jamais o foi; e que,
longe de exercer o seu poder no interesse de
um só homem, está perfeitamente disposto a
sacrificar os interesses vitais e imediatos de
todos à execução do que supõe ser a lei da
História ou a lei da Natureza. O seu desafio às
leis positivas pretende ser uma forma supe-
rior de legitimidade que, por inspirar-se nas
próprias fontes, pode dispensar legalidades
menores (ARENDT, 2012, p. 613). Desde a Antiguidade, o debate sobre qual
seria a fonte de autoridade para embasar as leis
positivas acabou gerando debates intermináveis,
a Natureza e as Divindades disputavam o espaço
nesse campo de batalhas retóricas. A finalidade
de estabelecer leis para os seres humanos, vis-
tos como mutáveis em seus comportamentos Em As origens do totalitarismo, especialmente
no capítulo intitulado Ideologia e Terror: uma nova
forma de governo, aborda aspectos que formam a
essência do totalitarismo, uma forma de opressão
política que é completamente diferente de outras
formas opressivas já conhecidas, tais como o 8 O período entreguerras foi um cenário de incertezas e tentativas dos países europeus de superação das mazelas deixadas pela
Primeira Guerra Mundial. 6 Uma temática relevante para a literatura hebraica do holocausto reside na possibilidade de explicação do holocausto e dos males
efetivados pelo nazifascismo. A ideia do campo de concentração como universo concentracionário, a ênfase na “maldade diabólica”
dos nazistas e a gravidade da crueldade praticada pelo governo de Hitler contribuíram para a construção da impossibilidade teórica de
explicação do holocausto, o qual muitas vezes foi compreendido como “um evento fora da história”. Para Arendt, a conjugação dos ele-
mentos subterrâneos do totalitarismo na conjuntura do período entreguerras e a banalidade do mal favorecem uma elucidação histórica
do holocausto. Yehuda Bauer, historiador israelense, afirma que o holocausto é um evento único e inédito em razão de inúmeros fatores,
tais como: a sistematização, a escala industrial e “a eliminação pela eliminação”, ou seja, a ausência de propósitos para o extermínio em
massa (BAUER, 2001). 1 A banalidade do mal e a
despersonalização A Alemanha sofreu uma derrota humilhante, consumada pelas imposições do Tratado de Versalhes, que favo-
receu um certo sentimento de “revanchismo”, facilmente aproveitado por discursos autoritários. Ademais, a Crise de 1929 potencializou
a desconfiança da população no liberalismo e nas teses democráticas. A conjugação de crises políticas, sociais e econômicas foi fun-
damental para o crescimento do ceticismo em relação aos elementos republicanos. Tais fatores possibilitaram a ascensão de regimes
dit t
i i Veritas, Porto Alegre, v. 68, n. 1, p. 1-21, jan.-dez. 2023 | e-44191 4/21 a realização da lei do movimento. Tal movimento
seleciona os inimigos a serem combatidos e por
meio do terror são eliminados como classe inde-
sejada ou raça inferior. É claro que Hannah Arendt
tem em mente os regimes totalitários, tanto do
comunismo quanto do nazismo. O terror atuará
como servo obediente do movimento natural ou
histórico. Hannah Arendt usa uma imagem muito
forte ao dizer que o terror cria uma espécie de
“cinturão de ferro” que tem por finalidade destruir
a pluralidade dos homens, transformando todos
numa massa que age como se fosse “Um-Só-
-Homem”. Usando o medo como um critério
de ação, os governos totalitários selecionam as
vítimas e os carrascos de uma forma objetiva,
levando em consideração o estereótipo físico,
mostrando de forma evidente como a natureza
atuava na seleção entre os que viveriam e os que
seriam condenados. e atitudes, era gerar elementos estabilizadores
para os constantes movimentos humanos. A
inovação do totalitarismo se dá porque todas as
leis tornam-se leis de movimento. Hannah Arendt
assim argumenta sobre esse princípio totalitário. Na interpretação do totalitarismo, todas as
leis se tornam leis de movimento. Embora os
nazistas falassem da lei da natureza e os bol-
chevistas falem da lei da história, natureza e
história deixam de ser a força estabilizadora da
autoridade para as ações dos homens mortais;
elas próprias tornam-se movimentos. 1 A banalidade do mal e a
despersonalização Sob a
crença nazista em leis raciais como expressão
da lei da natureza, está a ideia de Darwin do
homem como produto de uma evolução natural
que não termina necessariamente na espécie
atual de seres humanos, da mesma forma
como, sob a crença bolchevista numa luta de
classes como expressão da lei da história, está
a noção de Marx da sociedade como produto
de um gigantesco movimento histórico que se
dirige, segundo a sua própria lei de dinâmica,
para o fim dos tempos históricos, quando então
se extinguira a si mesmo. A diferença entre a
atitude histórica de Marx e a atitude naturalista
de Darwin já foi apontada muitas vezes, quase
sempre com justiça, a favor de Marx. Isso nos
leva a esquecer o profundo e positivo interesse
de Marx pelas teorias de Darwin; para Engels,
o maior cumprimento à obra erudita de Marx
era chamá-lo de “Darwin da história” (ARENDT,
2012, p. 615-616). É nesse ambiente em que o corpo político tem
como essência o próprio terror que a ideologia
ocupa um papel central. A relação entre terror
e ideologia se torna profícua e profundamente
perniciosa. Para Hannah Arendt, as ideologias são
históricas e com interesses palpáveis, mesmo que
busquem explicar a história de maneira definitiva
através de alguma lei da natureza. As ideologias
transformam uma ideia em premissa e as expli-
cações são deduções lógicas desse movimento. É como se uma única ideia fosse suficiente para
explicar todo mistério que esteve oculto aos olhos
dos seres humanos por longínquos tempos. As
ideologias criam uma cosmovisão explicativa
que dá conta de toda a realidade e inibem o ato
de pensar criticamente, que passa a ser visto
como algo perigoso e passível de ser perseguido
e, consequentemente, punido. É verdade que
toda ideologia contém elementos totalitários,
mas estes só ganham vida de forma plena em O século XIX presenciou uma mudança inte-
lectual importante, pois a mentalidade da época
se recusava a enxergar a situação de maneira es-
tática (talvez uma influência decisiva da dialética
hegeliana), optando em interpretar tudo como um
estágio que antecedia algo maior e mais estru-
turado que viria na sequência. É nesse sentido
que a ideia de “lei” deve ser compreendida, pois
foi abandonada a noção de lei como estabilida-
de para ser a expressão do próprio movimento. Pode-se afirmar que o terror é a essência do
domínio totalitário9. 9 É importante ressaltar também a centralidade do papel de cumprimento da lei inclusive nos julgamentos. Os governantes reivindi-
cam o título de meros cumpridores de leis históricas ou naturais. “Culpa e inocência viram conceitos vazios; ‘culpado’ é quem estorva o
caminho do processo natural ou histórico que já emitiu julgamento quanto às ‘raças inferiores’, quanto a quem é ‘indigno de viver’, quanto
a ‘classes agonizantes e povos decadentes’. O terror manda cumprir esses julgamentos, mas no seu tribunal todos os interessados são
subjetivamente inocentes: os assassinados porque nada fizeram contra o regime, e os assassinos porque realmente não assassinaram,
mas executaram uma sentença de morte pronunciada por um tribunal superior. Os próprios governantes não afirmam serem justos ou
sábios, mas apenas executores de leis históricas ou naturais; não aplicam leis, mas executam um movimento segundo a sua lei inerente.
O terror é a legalidade quando a lei é a lei do movimento de alguma força sobre-humana, seja a Natureza ou a História. O terror, como
execução da lei de um movimento cujo fim ulterior não é o bem-estar dos homens nem o interesse de um homem, mas a fabricação da
humanidade, elimina os indivíduos pelo bem da espécie, sacrifica as ‘partes’ em benefício do ‘todo’” (ARENDT, 2012, p. 618). 1 A banalidade do mal e a
despersonalização É o terror que tem como
objetivo tornar possível à força da natureza ou
da história o espraiar-se sem limites. O terror é Leonardo Delatorre Leite • Gerson Leite de Moraes
Desumanização e a banalidade do mal 5/21 supracitado comenta acerca da existência de um
“sistema invertido” no totalitarismo, que implica o
colapso dos padrões tradicionais de formulação
de juízos e conceitos jurídicos. movimentos totalitários. Pode-se afirmar que há
três elementos especificamente totalitários em
todo pensamento ideológico. Em primeiro lugar, na pretensão de explicação
total, as ideologias têm a tendência de analisar
não o que é, mas o que vem a ser, o que nasce
e passa. [...]. A pretensão de explicação total
promete esclarecer todos os acontecimentos
históricos — a explanação total do passado, o
conhecimento total do presente e a previsão
segura do futuro. [...]. Em segundo lugar, o
pensamento ideológico, nessa capacidade,
liberta-se de toda experiência da qual não
possa aprender nada de novo, mesmo que se
trate de algo que acaba de acontecer. Assim,
o pensamento ideológico emancipa-se da
realidade que percebemos com os nossos
cinco sentidos e insiste numa realidade “mais
verdadeira” que se esconde por trás de todas
as coisas perceptíveis, que as domina a partir
desse esconderijo e exige um sexto sentido
para que possamos percebê-la. O sexto sen-
tido é fornecido exatamente pela ideologia,
por aquela doutrinação ideológica particular
que é ensinada nas instituições educacionais. [...]. Em terceiro lugar, como as ideologias não
têm o poder de transformar a realidade, con-
seguem libertar o pensamento da experiência
por meio de certos métodos de demonstração. O pensamento ideológico arruma os fatos sob
a forma de um processo absolutamente lógico,
que se inicia a partir de uma premissa aceita
axiomaticamente, tudo mais sendo deduzido
dela; isto é, age com uma coerência que não
existe em parte alguma no terreno da realidade
(ARENDT, 2012, p. 627-628). A insistência durante o julgamento em apos-
tar que a consciência de Eichmann o faria
necessariamente perceber que a Solução
Final seria algo manifestamente ilegal, que
demandaria sua desobediência, seria mais um
sinal do colapso dos padrões tradicionais de
julgamento e dos conceitos jurídicos usuais
ante o totalitarismo [...]. Em um “sistema inver-
tido”, não parece fazer sentido esperar que a
consciência de Eichmann ou sua estimada
condição de cidadão respeitador das leis o
fizessem recusar a levar a cabo a Solução Final
(CORREIA, 2023, p. 203). 10 Aqui é possível compreender o totalitarismo como “tragédia cognitiva”. Nesse sentido, pondera Arendt: “Do mesmo modo como o
terror, mesmo em sua forma pré-total e meramente tirânica, arruína todas as relações entre os homens, também a autocompulsão do
pensamento ideológico destrói toda relação com a realidade. O preparo triunfa quando as pessoas perdem o contato com os seus seme-
lhantes e com a realidade que as rodeia; pois, juntamente com esses contatos, os homens perdem a capacidade de sentir e de pensar.
O súdito ideal do governo totalitário não é o nazista convicto nem o comunista convicto, mas aquele para quem já não existe a diferença
entre o fato e a ficção (isto é, a realidade da experiência) e a diferença entre o verdadeiro e o falso (isto é, os critérios do pensamento)”
(ARENDT, 2012, p. 632).
11 Acerca do totalitarismo como ameaça constante, afirma Arendt (2012, p. 639): “À parte estas considerações – que, como predições, 1 A banalidade do mal e a
despersonalização O totalitarismo é uma nova forma de governo
cuja essência é o terror e que tem como princípio
de ação a lógica do pensamento ideológico, eis
o ineditismo de tal forma de organização dos
seres humanos. O terror sistemático do totalitarismo [...] des-
truiu a individualidade ao incapacitar o sujeito
a agir de modo livre e espontâneo. No lugar
da visibilidade e da comunicação pertinente à
esfera pública, o totalitarismo impôs os campos
de concentração e o diálogo entre os cidadãos
foi sufocado e amordaçado por “um cinturão
de ferro”, como dizia Arendt, que desfez a
possibilidade de um espaço de encontro da
pluralidade marcante das relações sociais,
criando o homem da massa, fabricado para
agir de acordo com o bando. O terror suprimiu
o espaço que havia entre os homens e calou
a comunicação, aniquilando, por completo, o
político (TELES, 2019, p. 45-46). Os governos totalitários conseguem trans-
formar as ideologias em armas, pois ao isolar os
seres humanos num cinturão de ferro, transfor-
mando-os em massa de manobra e impedindo-os
de acessarem outro ponto de vista, a educação
totalitária já não necessita insuflar convicções
neles, pois já destruiu completamente os meios
de se adquirir novas convicções. Agindo dessa
forma, os governos totalitários embaçam o cam-
po de visão e não permitem mais a distinção da
realidade por meio do exame crítica das convic-
ções10. Aqui, é premente destacar um paralelo
com as ponderações de Adriano Correia sobre o
julgamento de Eichmann em Jerusalém. O autor A ação totalitária lida com seres humanos
tornados desarraigados e supérfluos, perdendo
a capacidade de estabelecer entre o “eu e o
mundo”, mediante a capacidade de pensar e
sentir. Os fatos históricos e as experiências de
combate ao totalitarismo não são suficientes
para matá-lo definitivamente, pois, de tempos
em tempos, ele renasce sob novas roupagens,
mas usando as velhas estratégias de sempre11. Até aqui, foi analisada a capacidade dos go-
vernos totalitários de conversão das ideologias
em instrumentos para manipulação das massas. Com base no exposto, é premente prosseguir
na elucidação dos elementos do totalitarismo
expressos na impessoalização e atomização
social, visto que tais aspectos totalitários serão
cruciais para a compreensão do que vem a ser
a desumanização promovida por esse regime
político. A impessoalização reside na perda da
subjetividade, ou seja, da ausência da qualida-
de de pessoa em construção com autonomia e
compromisso com a esfera pública12. são de pouca valia e ainda menos consolo – permanece o fato de que a crise do nosso tempo e a sua principal experiência deram origem
a uma forma inteiramente nova de governo que, como potencialidade e como risco sempre presente, tende infelizmente a ficar conosco
de agora em diante, como ficaram, a despeito de derrotas passageiras, outras formas de governo surgidas em diferentes momentos
históricos e baseadas em experiências fundamentais – monarquias, repúblicas, tiranias, ditaduras e despotismos”.
12 Esfera pública representa o espaço de busca pelo bem comum e pelo estabelecimento de consensos. Trata-se do ambiente do
exercício da intersubjetividade dialógica.
13 Arendt compreende a liberdade como um fato político genuíno. A liberdade se manifesta nas relações intersubjetivas presentes no
espaço público. Nesse sentido, sua compreensão de liberdade dialoga com os valores de autogoverno e autolegislação. “A concepção
de liberdade em Arendt e Tocqueville escapa à dicotomia liberal entre liberdade negativa versus liberdade positiva colocando a liber-
dade como algo exterior à política. Mas vincula a liberdade individual à experiência de autogoverno – para Arendt, é no espaço público
que os indivíduos se reconhecem como livres e iguais; para Tocqueville, a independência individual está estreitamente ligada à livre
participação dos cidadãos nos negócios públicos” (CHAVES, 2022, p. 518).
14 Embora defendesse a captura de Eichmann e seu julgamento em Israel, Arendt tinha compreensão da complexidade que o julga-
mento suscitava. Nesse sentido, ela “[...] identificou numerosas dificuldades que o caso colocava, por sua própria natureza, no que diz
respeito, por exemplo, a questões de jurisdição e à definição do tipo de crime e de criminoso aplicáveis a Eichmann e a seus efeitos. A
clara percepção da relevância do julgamento levou Arendt a refletir sobre possíveis justificativas ou acomodações jurídicas para o fato
do rapto, da inexistência do Estado de Israel na época dos crimes, da retroatividade da lei israelense e da exigência de um tribunal inter-
nacional no caso do julgamento de crimes contra a humanidade” (CORREIA, 2023, p. 93).
15 “[...] quando ela se deparou com Eichmann – aquele burocrata responsável pelo transporte de milhares de judeus para vários campos
de extermínio na Europa – e seus discursos carregados de clichês, foi um verdadeiro anticlímax, pois havia um enorme descompasso
entre a magnitude dos crimes cometidos e aquela figura normal, superficial, um verdadeiro misólogo. Eis ali, cercado por uma cabine de
vidro, um tipo ideal do mal banal. Pelos depoimentos prestados, ela percebeu que Eichmann não era vilão e nem antissemita, mas era
um lídimo representante da banalidade do mal” (MORAES, 2016, p. 18-19). 1 A banalidade do mal e a
despersonalização Ele Leonardo Delatorre Leite • Gerson Leite de Moraes
Desumanização e a banalidade do mal 7/21 Leonardo Delatorre Leite • Gerson Leite de Moraes
Desumanização e a banalidade do ma nem sequer matou, de forma direta e pessoal,
um judeu. Enfim, não havia nele um traço de
maldade latente e explícita16; pelo contrário, os
psiquiatras o consideravam um homem sadio e
normal pelos critérios de avaliação psicológica. “administração”. Em vez de campos de exter-
mínio, ele usava o termo “economia”. Sobre
os atos que contribuíram para o sofrimento
de milhões de pessoas, referia-se aos “atos
de rotina”. Dentro do nazismo, foram criados
muitos homens como Eichmann: assassinos em
massa que nunca mataram, homens maldosos
que acreditavam nunca terem cometido o mal
(CARVALHO, 2020, p. 127). Teria sido realmente muito reconfortante
acreditar que Eichmann era um monstro [...]. O problema com Eichmann era exatamente
que muitos eram como ele, e muitos não eram
nem pervertidos, nem sádicos, mas eram e
ainda são terrível e assustadoramente normais
(ARENDT, 1999, p. 299). Diante dos fatos supracitados, percebe-se
que Eichmann não estava em posse de uma
qualidade indispensável para o desenvolvimento
de um indivíduo autêntico e genuíno, a saber: o
pensamento próprio, a autonomia intelectual,
fruto de um diálogo socrático consigo mesmo17. Numa perspectiva kantiana18, sua figura repre-
sentava os homens que, a despeito da idade,
não alcançaram a maioridade e permaneceram
nos limites da heteronomia. Ademais, o oficial
nazista, em sua argumentação, aproveitava-se
de frases prontas e meros clichês19, os quais re-
fletiam uma profunda carência de originalidade
nas habilidades comunicacionais. Outro elemento
no comportamento de Eichmann que pode ser
categorizado como traço nítido da banalidade do
mal é a preocupação exagerada com a carreira
pessoal. Desde que fosse bem renumerado e
reconhecido por seus esforços profissionais, ele
não enxergava, em suas práticas, características
vis e imorais. Pode-se dizer, de certa forma, que
não havia a intenção primordial de um mal em si,
mas a obediência às leis, o prestígio profissional
e o progresso na carreira individual. Importante ressaltar que Eichmann fazia ques-
tão de explicitar sua postura de “homem de bem”,
cumpridor das leis, que pautava suas ações por
uma “obediência cadavérica”. No entendimento
do oficial alemão, a fiel execução das normas
instituídas pelo Estado representava uma virtu-
de por excelência, um imperativo moral. 16 “Não havia nele nenhum traço de ódio insano aos judeus ou algum fanático antissemitismo. Vários psiquiatras, a propósito, atestaram
que Eichmann era um homem absolutamente sadio e que sua atitude com sua família era amável. Portanto, Eichmann era terrivelmente
normal: nem sádico, nem pervertido, nem monstruoso, mas assustadoramente normal. A pergunta que se apresenta a nós é: como um
homem absolutamente comum, sem nenhum traço maligno, foi capaz de contribuir para um dos maiores crimes da história” (CARVALHO,
2020, p. 127).
17 “O pensar é o diálogo silencioso solitário entre mim e mim mesmo, é o estar consciente de mim-mesmo” (MORAES, 2016, p. 20). O
diálogo silencioso consigo mesmo consiste na solitude. “Em solitude, ao fazermos companhia a nós mesmos, somos capazes da expe-
riência do pensamento. A matéria-prima que é modelada pelo pensar é a experiência. A solitude de quem pensa, de forma alguma, é
desconectada de experiências, sejam elas pessoais, históricas, culturais ou fictícias” (ASSY, 2015, p. 89).
18 O paralelo com Imannuel Kant (2009) é importante em razão das noções kantianas de autonomia da vontade e imperativo categórico,
compreendido enquanto um comando moral que relaciona um dever-ser estabelecido pela razão prática. Numa perspectiva moral, o
entendimento de liberdade enquanto autonomia da vontade está de acordo com uma compreensão de moralidade enquanto expres-
são das leis da liberdade. Dessa forma, o agir moral é um agir livre em conformidade com o dever, o qual se encontra ancorado numa
perspectiva de dignidade humana, a saber: o homem não como meio, mas como fim. Desse modo, instrumentalizar os indivíduos é uma
violação clara ao dever.
19 “Eichmann, apesar de sua má memória, repetia palavra por palavra as mesmas frases feitas e clichês semi-inventados (quando con-
seguia fazer uma frase própria, ele a repetia até transformá-la em clichê) toda vez que se referia a um incidente ou acontecimento que
achava importante. Quanto mais se ouvia Eichmann, mais óbvio ficava que sua incapacidade de falar estava intimamente relacionada
com sua incapacidade de pensar, ou seja, de pensar do ponto de vista de outra pessoa. Não era possível nenhuma comunicação com
ele, não porque mentia, mais porque se cercava do mais confiável de todos os guarda-costas contra as palavras e a presença de outros
e portanto contra a realidade enquanto tal” (ARENDT 1999 p 62) 16 “Não havia nele nenhum traço de ódio insano aos judeus ou algum fanático antissemitismo. Vários psiquiatras, a propósito, atestaram
que Eichmann era um homem absolutamente sadio e que sua atitude com sua família era amável. Portanto, Eichmann era terrivelmente
normal: nem sádico, nem pervertido, nem monstruoso, mas assustadoramente normal. A pergunta que se apresenta a nós é: como um
homem absolutamente comum, sem nenhum traço maligno, foi capaz de contribuir para um dos maiores crimes da história” (CARVALHO,
2020, p. 127). 19 “Eichmann, apesar de sua má memória, repetia palavra por palavra as mesmas frases feitas e clichês semi-inventados (quando con-
seguia fazer uma frase própria, ele a repetia até transformá-la em clichê) toda vez que se referia a um incidente ou acontecimento que
achava importante. Quanto mais se ouvia Eichmann, mais óbvio ficava que sua incapacidade de falar estava intimamente relacionada
com sua incapacidade de pensar, ou seja, de pensar do ponto de vista de outra pessoa. Não era possível nenhuma comunicação com
ele, não porque mentia, mais porque se cercava do mais confiável de todos os guarda-costas contra as palavras e a presença de outros
e, portanto, contra a realidade enquanto tal” (ARENDT, 1999, p. 62). 1 A banalidade do mal e a
despersonalização A ascensão
das massas tipifica um fruto claro da desperso-
nalização, pois engloba a reunião de indivíduos
“sem individualidade”, indiferentes ao próximo,
alheios à alteridade e dispersos em questões
supérfluas. A atomização social é o reflexo da perda da
noção de cidadania, da decadência do espírito
de comunidade e do sufocamento sistemático
do participativismo político13. Enfim, o projeto
derradeiro do totalitarismo é impedir a formação
de indivíduos realmente livres, dotados de uma
consciência moral genuína e engajados publica-
mente. A essência do nazifascismo é a supressão
da liberdade e da própria política. Destarte, o
totalitarismo almeja, em última instância, a pri-
mazia do “homem supérfluo”. Nas palavras de
Arendt (2012, p. 609): Podemos dizer que esse mal radical surgiu
em relação a um sistema no qual todos os
homens se tornaram igualmente supérfluos. Os que manipulam esse sistema acreditam
na própria superfluidade tanto quanto na de
todos os outros, e os assassinos totalitários
são os mais perigosos porque não se impor-
tam se eles próprios estão vivos ou mortos,
se jamais viveram ou se nunca nasceram. O
perigo das fábricas de cadáveres e dos poços
do esquecimento é que hoje, com o aumento
universal das populações e dos desterrados,
grandes massas de pessoas constantemente
se tornam supérfluas se continuamos a pensar
em nosso mundo em termos utilitários. Os
acontecimentos políticos, sociais e econômicos
de toda parte conspiram silenciosamente com
os instrumentos totalitários inventados para
tornar os homens supérfluos. Parece-me que, para Arendt, o que caracteri-
zava o crime contra a humanidade era preci-
samente a destruição da “natureza humana”,
que consistia em impedir o ser humano de
tornar-se “algo eminentemente não-natural”,
isto é, um “ser humano”, como indicamos acima. Isso é alcançado nos campos de extermínio,
seguramente, mas esta não é certamente a
única tecnologia política de fabricação da
superfluidade. A superfluidade é produzida
pelo despojamento dos elementos constitu-
tivos de uma vida humana em meio a outros
seres humanos, como os direitos reciproca-
mente assegurados, os costumes e princípios
compartilhados e o espaço de aparência que
permite a afirmação e a manifestação da sin-
gularidade única de cada indivíduo por meio
do discurso e da ação (CORREIA, 2023, p. 128). A impessoalização supramencionada está na
base da noção de banalidade do mal. Quando
Hannah Arendt se depara, de forma atenta, com
Eichmann14, não consegue extrair dele nenhuma
profundidade eminentemente diabólica15. 1 A banalidade do mal e a
despersonalização Desse
modo, no nazismo, o mal era a prática reiterada/
ordinária e o bem, por sua vez, tornou-se uma
tentação. “No terceiro Reich, o Mal perdera a
qualidade pela qual a maior parte das pessoas
o reconhecem – a tentação” (ARENDT, 1999, p. 167). Tamanha foi a dimensão da maldade nesse
período que os integrantes do partido nazista
tratavam o assassinato a partir de uma lógica
centrada na administração burocrática, isto é,
com base numa racionalidade instrumental. Fazia parte do nazismo, aliás, tratar o assas-
sinato de forma burocrática, usando palavras
como “evacuação” para falar de sequestro
seguido de extermínio. Para falar dos campos
de concentração, Eichmann usava o termo 19 “Eichmann, apesar de sua má memória, repetia palavra por palavra as mesmas frases feitas e clichês semi-inventados (quando con-
seguia fazer uma frase própria, ele a repetia até transformá-la em clichê) toda vez que se referia a um incidente ou acontecimento que
achava importante. Quanto mais se ouvia Eichmann, mais óbvio ficava que sua incapacidade de falar estava intimamente relacionada
com sua incapacidade de pensar, ou seja, de pensar do ponto de vista de outra pessoa. Não era possível nenhuma comunicação com
ele, não porque mentia, mais porque se cercava do mais confiável de todos os guarda-costas contra as palavras e a presença de outros
e, portanto, contra a realidade enquanto tal” (ARENDT, 1999, p. 62). 8/21
Veritas, Porto Alegre, v. 68, n. 1, p. 1-21, jan.-dez. 2023 | e-44191 8/21 grandes artimanhas e planos diabólicos de um
vilão clássico. Portanto, é imperioso afirmar a
eminência da liberdade humana e de sua po-
tencialidade na promoção dos valores morais
autênticos. Obviamente, usar a liberdade para o
bem é algo custoso, pois se trata de uma tarefa
árdua. Na conjuntura de Eichmann, fazer o mal
era extremamente fácil, quase que automático,
pois bastava o mero cumprimento de ordens dos
superiores, ou seja, bastava seguir os ditames da
cosmovisão majoritária. Os homens passaram
a ser “supérfluos”, isto é, meras engrenagens e
ferramentas em um sistema burocrático. Destarte, não se trata de um mal típico dos
vilões clássicos da literatura ou um mal diabólico
e sobrenatural, mas um mal que, por não ter raí-
zes, espalha-se rapidamente. “O maior mal não é
o radical, não possui raízes e, por não ter raízes,
não tem limitações, pode chegar a extremos
impensáveis e dominar o mundo todo” (ARENDT,
2004, p. 160). 20 “Não é o assassinato que é perdoado, mas o assassino, a sua pessoa, assim como ela aparece nas circunstâncias e intenções. O
problema com os criminosos nazistas foi precisamente que eles renunciaram voluntariamente a todas as qualidades pessoais, como se
não restasse ninguém a ser punido ou perdoado. Eles protestaram repetidas vezes, dizendo que nunca tinham feito nada por sua pró-
pria iniciativa, que não tinham tido nenhuma intenção, boa ou má, e que apenas obedeceram a ordens. Em outras palavras: o maior mal
perpetrado é o mal cometido por ninguém, isto é, por um ser humano que se recusa a ser uma pessoa. Dentro da estrutura conceitual
dessas considerações, poderíamos dizer que o malfeitor que se recusa a pensar por si mesmo no que está fazendo e que, em retrospec-
tiva, também se recusa a pensar sobre o que faz, isto é, a voltar e lembrar o que fez (que é teshuvah, isto é, arrependimento), realmente
deixou de se constituir como alguém. Permanecendo teimosamente como ninguém, ele se revela inadequado para o relacionamento
com os outros que, bons, maus ou indiferentes, são no mínimo pessoas” (ARENDT, 2004, p. 177).
21 A relação com o outro ocupa um dos principais aspectos da ética proposta por Emmanuel Levinas. Em contraposição ao pensamento
de Sartre segundo o qual “o inferno são os outros”, Levinas enxerga no envolvimento com o outro o principal traço da libertação genuína.
Sob essa perspectiva, para o pensador judeu em questão, a Ética ocupa uma proeminência em relação à Ontologia. O filósofo disse que
uma de suas inspirações para a defesa da ética da alteridade foi no campo de prisioneiros. Os soldados alemães os tratavam de forma
desumana e degradante durante todo o dia. Não obstante, havia um momento de descontração à noite, quando um vira-lata se intro-
duzia no campo e recebia os prisioneiros latindo e rodopiando com entusiasmo e alegria. “E eis que, em meio a um longo período de
cativeiro – por algumas curtas semanas – um cão errante entra em nossa vida. Ele veio um dia se juntar à turba, quando ela retornava do
trabalho sob boa guarda. Ele sobrevivia em algum canto selvagem, nos arredores do campo. Mas nós o chamamos de Bobby, um nome
exótico, como convém a um cão querido. Ele aparecia nos encontros matinais e nos esperava na volta, saltitando e latindo alegremente.
Para ele – isso era incontestável – nós éramos homens. Graças aos olhos de adoração no animal, os homens eram relembrados todos os
dias do que significava ser reconhecido por outro ser” (LEVINAS, 2006, p. 234). A desumanização é implementada pela des-
consideração da dignidade do seu semelhante.
Pois, quando se nega a dignidade do outro,
nega-se a própria dignidade, pois ações de
barbárie, violência racionalmente implemen-
tadas, retiram a capacidade de empatia com
o outro (PRESOT, 2013, p. 6). 2 A literatura de testemunho de Primo
Levi: a desumanização nos campos de
extermínio era também um trabalho técnico, como aquele
do químico. Ou seja, toda a literatura de Levi
provém de uma mente acostumada a raciocinar
segundo os parâmetros da ciência (MACIERA,
2019, p. 98-102). Acerca da temática da desumanização, é pre-
mente, conforme destacado anteriormente, rei-
terar as reflexões de Primo Levi, sobretudo, em
sua obra É isto um homem?. Além da presença de elementos oriundos da
formação científica do autor, o livro é caracte-
rizado por uma orientação teleológica, ou seja,
por um propósito social, o qual não se resume a
uma apresentação de um relato histórico (uma
espécie de memorialística do campo de concen-
tração), mas, primordialmente, ao destaque de
uma teoria, a saber: o medo do diferente é algo
instintivo da natureza humana e, quando não se
encontra ordenado, não representa uma ameaça
substancial. Todavia, quando se torna premissa
de um silogismo maior, ou seja, quando é sis-
tematizado, há o perigo latente dos campos de
extermínio. Nas palavras de Primo Levi (1998, p. 7): Primo Levi é um dos mais significativos escrito-
res europeus do segundo pós-guerra. Nascido
em Turim, o químico de origem judaica é repre-
sentante incontestável, um ícone da vertente
de escritores/técnicos/cientistas na literatura
italiana (MACIERA, 2019, p. 95). Ele foi capturado pelo governo fascista italiano
e deportado como judeu para Auschwitz22. Im-
portante destacar que o ponto de partida de sua
produção literária foi a experiência num campo de
prisioneiros. Numa primeira análise, insta trazer
à baila a influência de sua formação científica na
maneira como procurou, inicialmente, compre-
ender a dinâmica do universo concentracionário. Ao se deparar com as nuances de Auschwitz,
Levi procura entender seu funcionamento com
um olhar investigativo, típico da “curiosidade
dos naturalistas”23. Desse modo, as tentativas de
sistematização e previsão estão presentes em
sua obra, mais nitidamente em suas descrições
minuciosas, em sua capacidade analítica24 de
apresentar os fatos ocorridos e na realização
de uma espécie de “taxonomia e etnografia do
campo de concentração”. Ele foi capturado pelo governo fascista italiano
e deportado como judeu para Auschwitz22. Im-
portante destacar que o ponto de partida de sua
produção literária foi a experiência num campo de
prisioneiros. Numa primeira análise, insta trazer
à baila a influência de sua formação científica na
maneira como procurou, inicialmente, compre-
ender a dinâmica do universo concentracionário. Muitas pessoas ou povos podem chegar a
pensar, conscientemente ou não, que “cada
estrangeiro é um inimigo”. 1 A banalidade do mal e a
despersonalização A prática do mal não pressupõe
necessariamente a maldade, pois o mal pode
conviver com a normalidade, ou seja, com o
cotidiano das pessoas, em sua simplicidade e
ordinariedade. Veja, portanto, que não se trata do mal de
homens que se julgam santos ou salvadores
da humanidade [...]. Trata-se de um pai de
família comum que tolerou os horrores na-
zistas ou aderiu a eles. Esse, para Arendt, é
“o grande criminoso do século”: um homem
que, para defender sua aposentadoria, seu
seguro de vida, a segurança da esposa e dos
filhos se disporia a sacrificar a própria honra
e dignidade. Eichmann admirava Hitler não
por ele ser um genocida ou um ditador, mas
por ele ser um case (para usar uma expressão
do mundo corporativo) de sucesso pessoal,
o cabo que se tornou um dos homens mais
poderosos do mundo. Pode-se concluir que
o mal de Eichmann não é o mal do pecado de
que falam as religiões, nem o mal dos vilões da
literatura ou dos quadrinhos, que são movidos
por inveja, trauma ou ressentimento. Seu mal
é um mal moderno – um mal que, por não ter
motivos especiais, pode ser um mal infinito
(CARVALHO, 2020, p. 129). O mal do nazismo instrumentalizava toda a
complexidade da realidade social. Eis a desu-
manização empreendida pelo totalitarismo. Ao
abdicarem da autonomia do pensamento20, os
funcionários alemães abandonaram as principais
características e atributos que os qualificavam
como pessoas, como indivíduos no sentido ri-
goroso. A industrialização da morte e a racionali-
dade instrumental da burocratização destruíram
os fundamentos a partir dos quais o processo
de formação da subjetividade se desenvolve,
quais sejam: a alteridade e a consideração pela
dignidade do outro21. A desumanização é implementada pela des-
consideração da dignidade do seu semelhante. Pois, quando se nega a dignidade do outro,
nega-se a própria dignidade, pois ações de
barbárie, violência racionalmente implemen-
tadas, retiram a capacidade de empatia com
o outro (PRESOT, 2013, p. 6). Em vista disso, a memória seletiva, a busca
crescente por ascensão social, o desejo cons-
tante pelo sucesso financeiro, a irreflexão e o
desinteresse pelo bem comum na esfera pública
podem originar males mais nefastos do que as Leonardo Delatorre Leite • Gerson Leite de Moraes
Desumanização e a banalidade do mal 9/21 9/21 p
p
g
p
,
p
como judeu. Foi deportado em 1944, ou seja, já muito tarde, num período em que o governo nazista não matava de forma gratuita.
23 “Eu tinha um desejo intenso de entender, pois constantemente me invadia a curiosidade, que para alguns podia até parecer cínica,
do naturalista que se percebe transportado subitamente a um ambiente monstruoso, que no entanto é novo, monstruosamente novo”
(LEVI, 1997, p. 87).
24 O olhar investigativo de Primo Levi guarda uma relação íntima com a sua formação como químico. Desse modo, a produção literária
de Levi é caracterizada pela fusão entre a cultura humanística e a cultura científica. Não obstante, o autor não se vincula ao cientificismo.
“O que poucos se discutiu até hoje é como essa necessidade de narrar e compreender nasce exatamente da mente científica e analítica
do autor. E considerar a ciência como base de seus escritos é, de fato, a condição necessária para a leitura de toda a sua obra [...]. A ciên-
cia e a técnica, na perspectiva do autor, têm um caráter ambivalente, no qual as duas faces têm que ser consideradas: se, por um lado,
podem transformar positivamente a realidade, portanto equilíbrio, por outro lado, podem ser responsáveis por transformações capazes
de levar a humanidade e o planeta ao caos” (MACIERA, 2019, p. 98-102). 22 Primo Levi foi preso pelo governo fascista em razão de seu envolvimento em movimentos políticos de resistência, mas é deportado
como judeu. Foi deportado em 1944, ou seja, já muito tarde, num período em que o governo nazista não matava de forma gratuita.
23 “Eu tinha um desejo intenso de entender, pois constantemente me invadia a curiosidade, que para alguns podia até parecer cínica,
do naturalista que se percebe transportado subitamente a um ambiente monstruoso, que no entanto é novo, monstruosamente novo”
(LEVI, 1997, p. 87). 24 O olhar investigativo de Primo Levi guarda uma relação íntima com a sua formação como químico. Desse modo, a produção literária
de Levi é caracterizada pela fusão entre a cultura humanística e a cultura científica. Não obstante, o autor não se vincula ao cientificismo.
“O que poucos se discutiu até hoje é como essa necessidade de narrar e compreender nasce exatamente da mente científica e analítica
do autor. E considerar a ciência como base de seus escritos é, de fato, a condição necessária para a leitura de toda a sua obra [...]. A ciên-
cia e a técnica, na perspectiva do autor, têm um caráter ambivalente, no qual as duas faces têm que ser consideradas: se, por um lado,
podem transformar positivamente a realidade, portanto equilíbrio, por outro lado, podem ser responsáveis por transformações capazes
de levar a humanidade e o planeta ao caos” (MACIERA, 2019, p. 98-102). “Campo de extermínio”, bem como o que de-
sejo expressar quando digo: chegar no fundo. “Campo de extermínio”, bem como o que de-
sejo expressar quando digo: chegar no fundo. Diante do exposto, é necessária uma breve
exposição sobre a obra em si. Em termos gerais, o
livro é dividido em três partes, a saber: a iniciação
(primeiro momento com o campo), a habituação
e, por fim, a libertação. Levi se vale de muitos
recursos literários, entre os quais: as elipses, o
retrato da vida antes da deportação para frisar o
que foi perdido e, por fim, técnicas para fazer com
que o leitor seja mergulhado nas angústias do
autor, despertando, assim, uma “empatia limitada”. As elipses revelam o pudor do escritor, pois não
há, nas páginas do texto, uma descrição direta,
intensa e explícita dos atos cruéis, cabendo ao
leitor preencher o ocorrido mediante a imagi-
nação. Por certo, algumas temáticas ocupam
maior relevância, tais como: a desumanização,
a despersonalização, a perda da consciência, a
massificação, a saída da civilização e, por fim, a
alteridade e o espelhamento. A desumanização,
cujas nuances serão tratadas melhor posterior-
mente com o estabelecimento de um paralelo
com a banalidade do mal, consiste na “perda de
si mesmo” e na perda da consciência, no sufoca-
mento das qualidades verdadeiramente humanas,
como a alteridade, o desenvolvimento efetivo do
pensamento, da autonomia e da autorrealização. Ademias, cabe ressaltar que a despersonalização
é holística, não afetando somente os prisioneiros,
como também os guardas e oficiais nazistas. Em
relação à perda da consciência e da dessubjeti-
vação dos prisioneiros, Levi (1998, p. 33) pondera: A questão da alteridade, expressa, sobretudo,
na temática do espelhamento, tipifica um traço
importante da literatura de testemunho de Primo
Levi, pois o autor, embora ateu, manifesta uma
profunda ligação e conexão com a comunidade
judaica, ou seja, apesar da ausência de um com-
prometimento religioso, o escritor possui laços
íntimos com os traços culturais e étnicos do povo
judeu. Para reforçar a identificação supracitada,
Levi se vale constantemente da primeira pessoa
do plural, como no exemplo a seguir: Muitos de nós ficaram na frente daquela porta;
desceu dentro de nossas almas, nova para
nós, a dor antiga do povo sem-terra, a dor sem
esperança do êxodo, a cada século renovado
[...]. Pela primeira vez, então, nos damos conta
de que a nossa língua não tem palavras para
expressar esta ofensa, a aniquilação de um
homem (LEVI, 1998, p. 16-32). 25 A referência aos escritos de Dante é explícita na seguinte passagem: “Um soldado alemão, hirto de armas. Não dava para enxergá-lo,
devido à escuridão fechada, mas sentíamos seu contato duro, cada vez que uma sacudida do veículo nos atirava embolados para a direi-
ta ou para a esquerda. Ligou uma lanterna de mão, e, em vez de gritar: ‘Ai de vós, almas danadas!’ perguntou gentilmente, um a um, em
alemão e em francês, se tínhamos relógios ou dinheiro para dar-lhe; de qualquer modo, já não nos serviriam para nada. Não se tratava
de uma ordem nem de um regulamento, mas visivelmente de uma pequena iniciativa pessoal do nosso Caronte. Isso causou entre nós
raiva, riso e um estranho alívio” (LEVI, 1998, p. 23-24).
26 Os Kommandos eram unidades de trabalho constituídas por prisioneiros dos campos de extermínio. 2 A literatura de testemunho de Primo
Levi: a desumanização nos campos de
extermínio Em geral, essa con-
vicção jaz no fundo das almas como uma in-
fecção latente; manifesta-se apenas em ações
esporádicas e não coordenadas; não fica na
origem de um sistema de pensamento. Quando
isso acontece, porém, quando o dogma não
enunciado se torna premissa maior de um
silogismo, então, como último elo da corrente,
está o Campo de extermínio. Como um humanista e um intelectual poli-
ticamente engajado, Levi tem o compromisso
de evitar a repetição do fenômeno supracitado. Desse modo, o trabalho de memória realizado
por ele é caracterizado por uma reconstrução
intencional dos fatos, ou seja, é marcado por
uma constante tentativa de moldar e trabalhar
com a memória tendo em vista o fim de transmitir
uma lição, estruturada pelo objetivo de realizar
um estudo de certos aspectos da alma humana. A lógica, a precisão, a concisão e o descri-
tivismo – características que podem ser as-
sociadas à escrita científica – fazem parte da
linguagem de Levi de maneira determinante. O trabalho técnico do químico é espelhado
igualmente no trabalho técnico do escritor [...]. Irrefutavelmente, a literatura de Primo Levi é
construída a partir da ciência e com a ciência. Para ele, o ato de escrever, de fazer literatura, “Campo de extermínio”, bem como o que de-
sejo expressar quando digo: chegar no fundo. O tema concernente ao processo de “saída da
civilização” dialoga intimamente com a concep-
ção do campo de prisioneiros como um universo
concentracionário. A passagem da civilização para
a “barbárie” implica a suspensão do julgamento
moral, isto é, a moralidade, tal como a conhe-
cemos no ambiente ordinário de socialização
e institucionalização, não pode ser aplicada às
nuances morais da vida no campo de extermínio. Desse modo, Levi não se preocupa em condenar
moralmente os indivíduos, suas ações e posturas. A rejeição ao essencialismo e a negação do ma-
niqueísmo são traços perceptíveis na literatura
“primoleviana”. Ademais, é premente ressaltar a
intertextualidade com a obra A divina comédia,
de Dante Alighieri25. Ao ingressar na barbárie, o
autor, paralelamente a Dante, entrou no inferno. Portanto, há um movimento de “descida”. Quando
Levi entra para o Kommando26 Químico, há uma
mudança no sentido de elevação e individuação, Imagine-se, agora, um homem privado não
apenas dos seres queridos, mas de sua casa,
seus hábitos, sua roupa, tudo, enfim, rigorosa-
mente tudo que possuía; ele será um ser vazio,
reduzido a puro sofrimento e carência, esque-
cido da dignidade e discernimento – pois quem
perde tudo, muitas vezes perde também a si
mesmo; transformado em algo tão miserável,
que facilmente se decidirá sobre sua vida e sua
morte, sem qualquer sentimento de afinidade
humana, na melhor das hipóteses conside-
rando puros critérios de conveniência. Ficará
claro, então, o duplo significado da expressão Imagine-se, agora, um homem privado não
apenas dos seres queridos, mas de sua casa,
seus hábitos, sua roupa, tudo, enfim, rigorosa-
mente tudo que possuía; ele será um ser vazio,
reduzido a puro sofrimento e carência, esque-
cido da dignidade e discernimento – pois quem
perde tudo, muitas vezes perde também a si
mesmo; transformado em algo tão miserável,
que facilmente se decidirá sobre sua vida e sua
morte, sem qualquer sentimento de afinidade
humana, na melhor das hipóteses conside-
rando puros critérios de conveniência. Ficará
claro, então, o duplo significado da expressão Leonardo Delatorre Leite • Gerson Leite de Moraes
Desumanização e a banalidade do mal 11/21 Leonardo Delatorre Leite • Gerson Leite de Moraes
Desumanização e a banalidade do mal 11/21 11/21 como se o escritor fosse levado para o purgató-
rio, saindo, assim, do “mundo dos condenados”. “Campo de extermínio”, bem como o que de-
sejo expressar quando digo: chegar no fundo. tudo, porque expressa a imprescindibilidade do
Outro para a compreensão da dignidade própria,
dialogando, assim, com a ética da alteridade
proposta por Levinas. Por meio do gesto de soli-
dariedade de Lourenço, Levi resgata o senso de
humanidade e é despertado para uma esperança,
ainda que limitada, nos valores morais, os quais
se encontravam em um processo constante de
destruição empreendido sistematicamente pelo
campo de extermínio. rio, saindo, assim, do mundo dos condenados . Uma reflexão importante acerca da temática da
“saída da civilização” consiste num paralelo com
uma discussão filosófica presente nos escritos
dos contratualistas sobre a natureza humana e o
comportamento dos indivíduos caso as barreiras
civilizatórias fossem destruídas. Levi não cons-
tata um fatalismo pessimista, pois atesta que a
postura dos homens, no estado de barbárie, não
é uniforme e nem todos tendem direta e imedia-
tamente para a “selvageria”. Apesar do ambiente
degradante e desumano, alguns prisioneiros
demonstravam um anseio em formar uma orga-
nização, mesmo que limitada e precária. Alguns
se apegavam a questões morais para que não
se desumanizassem totalmente. Destarte, para
o autor em questão, a saída da civilização não
acarreta necessariamente a perda total de ves-
tígios dos valores da sociedade27. Para reafirmar
tal tese, Levi se vale de alguns exemplos, entre
os quais o prisioneiro Steinlauf, que demonstra
um apego à higiene como tentativa de preservar
a humanidade, e Lourenço, cujos atos de gene-
rosidade despertaram no autor a consciência de
sua qualidade como indivíduo. Por certo, a tese
de Steinlauf é extremamente impressionante e
acaba por refletir, de forma categórica, a tentativa
de se apegar a um vestígio civilizatório para se
reafirmar como homem28. Bem, entre mim e Lourenço não aconteceu
nada disso. Não sei se tem sentido identificar
as causas pelas quais a minha vida, só a minha
entre milhares de vidas equivalentes, pôde
resistir à prova; em todo caso, creio que devo
justamente a Lourenço o fato de estar vivo. E
não só por causa de sua ajuda material, mas
por ter-me ele lembrado constantemente (com
a sua presença, com esse seu jeito tão simples
e fácil de ser bom) que ainda existia um mundo
justo, fora do nosso; algo, alguém, ainda puro
e íntegro, não corrupto nem selvagem, alheio
ao ódio e ao medo; algo difícil de definir, uma
remota possibilidade de bem pela qual valia
a pena conservar-se [...]. 27 Levi destaca que o instinto de sobrevivência tipifica um dos traços de humanidade. Desse modo, quando alguns prisioneiros, durante
as trocas comerciais no campo, “passavam a perna” em outros numa tentativa de obter vantagens e ganhos para a sobrevivência, o autor
respira “aliviado”, pois contempla nessa postura um vestígio de humanidade, ainda que não aos moldes da generosidade de Lourenço.
28 Conforme destacado por Irving Howe, a temática da manutenção do ser é um dos grandes traços da literatura do holocausto.
29 Outro “paradoxo enlouquecedor” reside na própria estratégia de sobrevivência nos campos de extermínio. Aqueles que possuem
as maiores chances de sobrevivência no campo são aqueles que, em condições normais de civilização, seriam taxados como “loucos,
criminosos, potencialmente hostis”, ou seja, fora do campo, seriam presos ou internados em hospitais psiquiátricos. “Campo de extermínio”, bem como o que de-
sejo expressar quando digo: chegar no fundo. Lourenço era um ho-
mem; sua humanidade era pura, incontamina-
da, ele estava fora desse mundo de negação. Graças a Lourenço, não esqueci que também
era um homem (LEVI, 1998, p. 180). A questão da esperança ocupa um lugar de
relevância na literatura primoleviana. O autor
a caracteriza como um dos “paradoxos enlou-
quecedores”29, pois o excesso de esperança é
um risco, já que a expectativa pela libertação e
o sonho com uma vida nova geram frustração
pela situação atual. Não obstante, a escassez
da esperança implica a perda das forças e sufo-
ca, gradativamente, o instinto de sobrevivência. De qualquer forma, o autor não encontra nos
elementos da esperança as raízes para a sua
capacidade de ter enfrentado cotidianamente a
realidade do campo. [...] as palavras do ex-sargento Steinlauf do
exército austro-húngaro [...] seu sentido não
esqueci nunca mais, era esse: justamente
porque o Campo é uma grande engrenagem
para nos transformar em animais, não devemos
nos transformar em animais; até num lugar
como este, pode-se sobreviver, para relatar a
verdade, para dar nosso depoimento; e, para
viver, é essencial para esforçar-nos por salvar
ao menos a estrutura, a forma da civilização
[...]. Portanto, devemos nos lavar sim; ainda
que sem sabão, com essa água suja e usando
o casaco como toalha (LEVI, 1998, p. 54-55). Cedo ou tarde, na vida, cada um de nós se dá
conta de que a felicidade completa é irreali-
zável; poucos, porém, atentam para a reflexão
oposta: que também é irrealizável a infelici- O exemplo de Lourenço é importante, sobre- 27 Levi destaca que o instinto de sobrevivência tipifica um dos traços de humanidade. Desse modo, quando alguns prisioneiros, durante
as trocas comerciais no campo, “passavam a perna” em outros numa tentativa de obter vantagens e ganhos para a sobrevivência, o autor
respira “aliviado”, pois contempla nessa postura um vestígio de humanidade, ainda que não aos moldes da generosidade de Lourenço. 28 Conforme destacado por Irving Howe, a temática da manutenção do ser é um dos grandes traços da literatura do holocausto. 29 Outro “paradoxo enlouquecedor” reside na própria estratégia de sobrevivência nos campos de extermínio. Aqueles que possuem
as maiores chances de sobrevivência no campo são aqueles que, em condições normais de civilização, seriam taxados como “loucos,
criminosos, potencialmente hostis”, ou seja, fora do campo, seriam presos ou internados em hospitais psiquiátricos. 12/21 12/21 Veritas, Porto Alegre, v. 68, n. 1, p. 1-21, jan.-dez. 2023 | e-44191 te na crise de sentido, ou seja, na ausência de
um propósito genuíno para as ações humanas. O hedonismo, o utilitarismo, o racionalismo e o
materialismo foram incapazes de fornecer um
significado efetivo30 para as condutas individuais
e, por conseguinte, os homens foram tomados por
um vazio valorativo, que foi facilmente aproveita-
do pelos regimes ditatoriais, os quais atribuíram
aos ditames do poder político um direcionamento
social, um guia para as atividades dos cidadãos. Nesse sentido, afirma Frankl (2014, p. 25): dade completa. Os motivos que se opõem à
realização de ambos os estados-limite são da
mesma natureza; eles vêm de nossa condição
humana, que é contra qualquer “infinito”. Assim,
opõe-se a esta realização o insuficiente conhe-
cimento do futuro, chamado de esperança no
primeiro caso e de dúvida quanto ao amanhã,
no segundo. Assim, opõe-se a ela a certeza da
morte, que fixa um limite a cada alegria, mas
também a cada tristeza [...]. Foram justamente
as privações, as pancadas, o frio, a sede que,
durante a viagem e depois dela, nos impediram
de mergulhar no vazio de um desespero sem
fim. Foi isso. Não a vontade de viver, nem uma
resignação consciente (LEVI, 1998, p. 17-18). Se para Levi a esperança aparece como para-
doxo e um risco, para Viktor Frankl (1905-1997),
neuropsiquiatra austríaco e sobrevivente do
holocausto, ela resplandece como o grande
motivo pelo qual encontrou forças para resistir
ao processo de desumanização do campo de
prisioneiros. O exemplo de Lourenço é importante, sobre- Para Frankl (1989), esperança é en-
contrar propósito e significado no sofrimento,
sendo o amor a plena realização das ações hu-
manas. Importante ressaltar que, para o pensador
supracitado, o materialismo, isto é, a convicção
segundo a qual a realidade humana pode ser
reduzida aos processos físico-químicos e aos
eventuais traços da determinação econômica,
representa um perigo constante para a dignidade
humana, o preparativo mais explícito dos ideais
dos campos de extermínio, as raízes e heranças
terríveis dos regimes totalitários. Quando me perguntam como explicar o ad-
vento desse vazio existencial, cuido então de
oferecer a seguinte fórmula abreviada: em
contraposição ao animal, os instintos não dizem
ao homem o que ele tem de fazer e, diferen-
temente do homem do passado, o homem
de hoje não tem mais a tradição que lhe diga
o que deve fazer. Não sabendo o que tem e
tampouco o que deve fazer, muitas vezes já
não sabe mais o que, no fundo, quer. Assim,
só quer o que os outros fazem – conformismo! Ou só faz o que os outros querem que faça –
totalitarismo. Após uma breve exposição sobre os aspectos
centrais da literatura de testemunho de Levi, é
premente a realização de uma abordagem mais
direta entre as teses da desumanização e da ba-
nalidade do mal, a começar por uma passagem
do livro É isto um homem?, a saber: Embarcaram-nos, então, nos ônibus e nos
levaram até a estação de Cárpi. Lá nos espe-
ravam o trem e a escolta para a viagem. E lá
recebemos as primeiras pancadas, o que foi
tão novo e absurdo que não chegamos a sentir
dor, nem no corpo nem na alma. Apenas um
profundo assombro: como é que, sem raiva,
pode-se bater numa criatura humana? (LEVI,
1998, p. 16-17). Não foram apenas alguns ministérios de
Berlim que inventaram as câmaras de gás de
Maidanek, Auschwitz, Treblinka: elas foram
preparadas nos escritórios e salas de aula de
cientistas e filósofos niilistas, entre os quais se
contavam e contam alguns pensadores anglo-
-saxônicos laureados com o Prêmio Nobel. É
que, se a vida humana não passa do insignifi-
cante produto acidental de umas moléculas
de proteína, pouco importa que um psicopata
seja eliminado como inútil e que ao psicopata
se acrescentem mais uns quantos povos infe-
riores: tudo isto não é senão raciocínio lógico
e consequente (FRANKL, 1989, p. 45). 30 Para o filósofo Giovanni Reale (1999, p. 17), “a raiz de todos os males que atingem o homem hoje encontra-se exatamente no nii-
lismo”. No entanto, para Alasdair MacIntyre, os males morais contemporâneos encontram suas origens na incapacidade iluminista de
justificar a moralidade. Desse modo, as cosmovisões supracitadas, como o racionalismo, materialismo e utilitarismo, as quais formaram
o escopo das teses iluministas, apresentam uma fragilidade em relação aos valores morais. De certa forma, a reflexão de Frankl está
presente na obra de MacIntyre (2021). O exemplo de Lourenço é importante, sobre- Diante do exposto, percebe-se a dimensão
holística da desumanização, que não se restringiu
aos prisioneiros, mas foi estendida, mesmo que
de outra forma, aos oficiais nazistas. O sentimento
de raiva é genuinamente humano e a violência
advinda de uma cólera momentânea, ainda que
caracterizada como reprovável moralmente, Ademais, a leitura do neuropsiquiatra afirma
que as origens do totalitarismo estão justamen- Leonardo Delatorre Leite • Gerson Leite de Moraes
Desumanização e a banalidade do mal 13/21 13/21 encontra respaldos na natureza humana. Não
obstante, os soldados alemães batiam nos prisio-
neiros sem a menor manifestação de raiva latente
ou cólera. Por certo, a racionalidade instrumental
das técnicas totalitárias de estabelecimento do
poder político e a industrialização da morte ex-
plicam o tratamento da violência, por parte dos
funcionários nazistas, como uma prática ordinária
e corriqueira, associada ao cumprimento de uma
lei e dever. A burocratização do homicídio em
massa contou com a participação de cidadãos
comuns e de servidores públicos, os quais foram
transformados em criminosos, mas sem o aspecto
do mal radical e explicitamente “diabólico”. moral categórica dirigida aos soldados alemães. Os funcionários do campo devem ser “punidos
e execrados”, enquanto os prisioneiros supraci-
tados devem ser “lamentados e ajudados” (LEVI,
2004, p. 21). Os SS maus e brutos, os Kapos, os políticos,
os criminosos, os “proeminentes” grandes e
pequenos, até os Häftlinge indiscriminados
e escravos, todos os degraus da hierarquia
insensata determinada pelos alemães estão,
paradoxalmente, juntos numa única e íntima
desolação (LEVI, 1998, p. 124). Muitos entravam na chamada “zona cinzenta”,
principalmente, com o intuito de evitar a fome e
o frio. Desse modo, qualquer conforto oferecido
pelos funcionários do campo já era motivo sufi-
ciente para a traição, isto é, para os prisioneiros
adentrarem na categoria de opressores de seus
semelhantes31. Interessante ressaltar que Levi
frisa como toda a disposição do campo de con-
centração era projetada, de forma intencional,
para a consolidação do processo de desuma-
nização, para que os indivíduos se tornassem
assassinos de si mesmos, pois o “nós perdia seus
limites”. A massificação reinava, fazendo com que
os homens fossem impenetráveis para os seus
próprios companheiros. Destarte, a atomização
representava o traço distintivo daquele universo
concentracionário, visto que o isolamento dos
indivíduos e a despersonalização tipificavam os
objetivos derradeiros das práticas do campo de
prisioneiros. Um dos exemplos que atestam a
afirmação supracitada reside na situação de não
comunicação entre os prisioneiros. 31 “Acontecerá ainda que a sua capacidade para odiar, frustrada frente aos opressores, se volte, incessantemente, contra os oprimidos;
ele ficará satisfeito ao descarregar sobre seus subordinados a ofensa que recebeu de seus chefes” (LEVI, 1998, p. 92). 32 Em contraposição aos afogados, os “salvos” são aqueles que demonstram uma propensão ao não cumprimento efetivo das regras
e, por conseguinte, possuem uma tendência ao risco, reflexo do anseio pela sobrevivência, isto é, do instinto pela preservação de sua
força vital, da subjetividade.
33 Na passagem em questão, a pesquisadora se vale do termo “vítimas” para se referir aos dois lados atingidos pelo processo de de-
sumanização empreendido pelo totalitarismo nazista. Não obstante, a expressão “vítima” é muito forte para qualificar os funcionários
alemães tomados pelo mal banal, visto que a responsabilidade moral pelos atos não é eliminada em razão da proliferação da banalidade
do mal. Segundo Hannah Arendt, a subserviência dos oficiais e servidores ao projeto de desumanização totalitário não retira a culpabi-
lidade deles na execução dos atos imorais. Desse modo, escreve Arendt (1999, p. 302): “Política não é um jardim de infância; em política,
obediência e apoio são a mesma coisa. E assim como você apoiou e executou uma política de não partilhar a Terra com o povo judeu e
com o povo de diversas outras nações – como se você e seus superiores tivessem o direito de determinar quem devia e quem não devia
habitar o mundo –, consideramos que ninguém, isto é, nenhum membro da raça humana haverá de querer partilhar a Terra com você.
Esta é a razão, a única razão, pela qual você deve morrer na forca”. O exemplo de Lourenço é importante, sobre- Geralmente,
os oficiais nazistas não colocavam num mesmo
alojamento judeus oriundos do mesmo país. A
não comunicação era um requisito indispensável
para a perda da subjetividade, pois a degradação
da linguagem implica a ruína do pensamento e,
por conseguinte, da formação da pessoa humana. Uma figura importante no relato de Levi, que
dialoga com as reflexões acerca da banalidade do
mal, é o arquétipo do “muçulmano, o Muselmann”,
comumente chamado, ao longo do livro, de
submerso ou afogado. Além do arquétipo supra-
mencionado, que será abordado posteriormente,
a ocorrência de um fenômeno chamou a atenção
de Primo Levi, trata-se da “zona cinzenta”, “um
campo onde há um embaralhamento no conjunto
de princípios e condutas, uma conjunção entre
vítimas e algozes, em que muitas vezes o oprimi-
do se torna o opressor – por uma série de razões”
(OLIVEIRA, 2017, p. 106-107). A desumanização
holística e a banalidade do mal impediam uma
clara delimitação entre opressores e oprimidos. Sendo assim, as relações de poder não tinham tão
somente um aspecto vertical, visto que interações
horizontais de violência também integravam a
vida no universo concentracionário dos campos
de prisioneiros. “Repleta de uma banalidade do
mal horizontal e generalizada, trata-se de um
espaço confuso e liminar, composto de uma
classe híbrida de homens com contornos mal
definidos” (OLIVEIRA, 2017, p. 107). Não obstante, a conjunção circunstancial de
funções não implica a eliminação de diferencia-
ção entre vítimas e opressores. Por certo, o limite
é tipificado por uma linha tênue, mas não deixa
de existir, pois os prisioneiros que colaboraram
com os nazistas não recebem a condenação De certo modo, os prisioneiros também vi-
veram de forma radical essa condição de
não-comunicação. Quem não falava alemão
era considerado de imediato um bárbaro, um
infante abandonado. Se alguém insistia em ex-
pressar-se na própria língua, era preciso fazê-lo 14/21 Veritas, Porto Alegre, v. 68, n. 1, p. 1-21, jan.-dez. 2023 | e-44191 calar a gritos e pancadas; e se no momento de
uma ordem alguém hesitava em obedecê-la,
já vinham os golpes certeiros, disciplinadores,
pedagógicos- variante da linguagem do campo
(OLIVEIRA, 2017, p. 121). que, desse modo, apenas excepcionalmente
se pode aguentar mais do que três meses. Todos os muçulmanos que foram enviados à
câmara de gás possuem a mesma história, ou,
melhor dizendo, não têm história; seguiram a
descida até o fundo, naturalmente, como os
arroios que vão ao mar. A partir do relato de Arendt, penso que o na-
zismo teve dois tipos de vítimas: vítimas diretas
– judeus e outras minorias e vítimas indiretas, os
próprios alemães que participaram da máquina
estatal executando as leis de Hitler, como de-
monstrado em situações indignas, pois nega-
vam a natureza de ser pessoa, pelo processo de
desumanização implementado nos campos de
extermínio. Os atos do Estado nazista além de
estruturar, implementar e executar homicídios
em massa dos judeus, também transformaram
pessoas comuns, cidadãos alemães, servidores
públicos, em criminosos, gerando psicopatas
sociais (PRESOT, 2013, p. 6-7).33 O exemplo de Lourenço é importante, sobre- Uma vez dentro do
campo, ou devido à intrínseca incapacidade,
ou à desventura, ou por um banal acidente
qualquer, eles foram esmagados antes de
conseguirem adaptar-se; ficaram para trás
sem nem ao menos começarem a aprender o
alemão ou a perceber alguma coisa no ema-
ranhado infernal de leis e proibições. Um arquétipo importante nos campos de ex-
termínio era a figura do Muselmann, símbolo do
esforço promovido pelo nazismo em prol da
desumanização e do esvaziamento da força vital
dos prisioneiros. Nesse sentido, os chamados
“muçulmanos” eram os prisioneiros fracos, sem a
vivacidade necessária para a sobrevivência, sub-
mersos na desesperança, tomados pelo fatalis-
mo, os que estavam fadados à “seleção final”. Levi
(2004, p. 121) os caracteriza como “personagens
típicos, homens depauperados, com intelecto
moribundo ou morto”. No linguajar do campo,
eles eram conhecidos como os “afogados”, inte-
grantes de uma massa incógnita de mortos-vivos,
a expressão máxima da despersonalização e
da perda da consciência, “vazios para poderem
sofrer de verdade. Hesita-se chamá-los vivos:
hesita-se a chamar de morte sua própria morte,
que eles já nem temem, pois estão cansados
demais para compreendê-la” (LEVI, 1998, p. 91). Os afogados32, em sua passividade absoluta,
simbolizam a perda total da consciência e o fim
da resistência ao processo de despersonalização. Em última instância, sua existência é qualificada
por uma postura clara de desistência da força
vital, a saber: o ato de sucumbir, caracterizado
pela redução da personalidade do homem a um
vazio, um nada destituído de qualquer positivida-
de. Acerca do ato de sucumbir, Primo Levi (1998,
p. 91) comenta: Diante dos fatos supracitados, percebe-se
a extensão da desumanização, engendrada,
principalmente, pela banalidade do mal, cujos
aspectos impedem a realização de uma análi-
se maniqueísta e essencialista das categorias
presentes nos campos de extermínio. Desse
modo, o processo de despersonalização, que
ocorreu diante da burocratização da morte e da
racionalidade instrumental, atingiu não somente
os prisioneiros, como também os funcionários e
oficiais do governo alemão. Destarte, pode-se
afirmar que a banalidade do mal apresenta uma
dimensão holística e potencialmente destrutiva,
capaz de generalizar a massificação, a perda da
consciência moral e o esvaziamento efetivo do
valor da dignidade humana. O exemplo de Lourenço é importante, sobre- A partir do relato de Arendt, penso que o na-
zismo teve dois tipos de vítimas: vítimas diretas
– judeus e outras minorias e vítimas indiretas, os
próprios alemães que participaram da máquina
estatal executando as leis de Hitler, como de-
monstrado em situações indignas, pois nega-
vam a natureza de ser pessoa, pelo processo de
desumanização implementado nos campos de
extermínio. Os atos do Estado nazista além de
estruturar, implementar e executar homicídios
em massa dos judeus, também transformaram
pessoas comuns, cidadãos alemães, servidores
públicos, em criminosos, gerando psicopatas
sociais (PRESOT, 2013, p. 6-7).33 A partir do relato de Arendt, penso que o na-
zismo teve dois tipos de vítimas: vítimas diretas p
– judeus e outras minorias e vítimas indiretas, os
próprios alemães que participaram da máquina
estatal executando as leis de Hitler, como de-
monstrado em situações indignas, pois nega-
vam a natureza de ser pessoa, pelo processo de
desumanização implementado nos campos de
extermínio. Os atos do Estado nazista além de
estruturar, implementar e executar homicídios
em massa dos judeus, também transformaram
pessoas comuns, cidadãos alemães, servidores
públicos, em criminosos, gerando psicopatas
sociais (PRESOT, 2013, p. 6-7).33 Sucumbir é a coisa mais simples: basta execu-
tar todas as ordens recebidas, comer somente
a ração oferecida, ater-se à disciplina do tra-
balho e do campo. A experiência demonstrou Leonardo Delatorre Leite • Gerson Leite de Moraes
Desumanização e a banalidade do mal 15/21 Em vista disso, a narrativa histórica de Hannah
Arendt e os relatos de Primo Levi atestam os
perigos da ascensão de uma mentalidade ins-
trumental que reduz os homens a meros instru-
mentos e engrenagens de uma burocracia capaz
engendrar atrocidades e violações expressas ao
princípio da dignidade humana. A instrumenta-
lização34 da complexidade da realidade social
e das relações humanas significa a negação
da formação genuína da personalidade e, por
conseguinte, representa uma rejeição expressa
ao desenvolvimento de uma consciência moral
atrelada aos valores axiológicos da liberdade
enquanto autonomia da vontade, da justiça civil
e da democracia. Por certo, conforme destacado
por Levi e Arendt, as ameaças do totalitarismo
e da desumanização empreendida nos campos
de extermínio representam um perigo constante
e não meramente uma hipótese distante ou um
“terror impossível”. 34 Embora químico de formação, Levi não era ingênuo em relação ao progresso científico. Exemplo disso é a sua negação do cientificis-
mo, pois o autor não considera a ciência um saber exclusivo e absoluto, mas engloba em suas análises o estilo literário, fazendo com que
a literatura e a ciência culminassem numa produção complexa. “A convergência entre o pensamento científico e a criação artística revela
que uma mesma sensibilidade subentende os dois saberes, permitindo a passagem da ciência ao sonho e vice-versa” (MONTEPERELLI,
2006, p. 10). Ademais, “o mito iluminista/positivista da ciência absoluta e exclusivamente racional não encontra no decorrer do século XX
sua afirmação” (MACIERA, 2019, p. 95). A pretensão cientificista representa uma herança perigosa do totalitarismo e de sua perspectiva
de técnica instrumental. Desse modo, o combate ao cientificismo é uma forma de combater as tendências de desumanização. Confor-
me afirma Habermas (2013, p. 13): “A crença cientificista em uma ciência que possa um dia não apenas complementar, mas substituir
a autocompreensão pessoal por uma autodescrição objetivante, não é ciência, é má filosofia”. Eric Voegelin considera a tendência de
atribuir a um sistema de ideias a capacidade de compreensão holística da realidade uma herança do positivismo cientificista de Comte.
“Comte pertence, juntamente a Marx, Lênin e Hitler, à série de homens que salvam a humanidade e a si mesmos pela divinização de
sua existência particular e pela imposição de sua lei como a nova ordem da sociedade. O apocalipse satânico do Homem começa com
Comte e tornou-se a sua assinatura na crise ocidental” (VOEGELIN, 2018, p. 223). O exemplo de Lourenço é importante, sobre- 16/21
Veritas, Porto Alegre, v. 68, n. 1, p. 1-21, jan.-dez. 2023 | e-44191 16/21
Veritas, Porto Alegre, v. 68, n. 1, p. 1-21, jan.-dez. 2023 | e-44191 16/21
Veritas, Porto Alegre, v. 68, n. 1, p. 1-21, jan.-dez. 2023 | e-44191 35 Acerca da instrumentalização do homem, C.S. Lewis (2017, p. 60) afirma: “Cada poder conquistado pelo homem também é, ao mes-
mo tempo, poder sobre o homem [...] porque o poder do homem de torná-lo aquilo que ele quiser na verdade significa, como vimos, o
poder de alguns homens de fazer o que eles quiserem de outros homens [...] uma vez que tenhamos vendido nossas almas, ou seja, nós
mesmos, o poder assim conferido não pertencerá a nós. Não seremos, na verdade, nada mais que escravos e marionetes daqueles que
vendemos nossas almas. Está no alcance do Homem o poder de tratá-lo como mero ‘objeto natural’, bem como seus próprios juízos
de valor como matéria-prima para manipulação científica”. Na passagem supracitada, Lewis condena a instrumentalização do homem
favorecida pelos ideais materialistas e cientificistas.
36 “Por meio da ação os homens mostram quem são, suas identidades, em contraposição ao que são, suas qualidades e defeitos. A
revelação das subjetividades permite distinguir a ação política de outra ação qualquer, sem a qual a política confunde-se com fabrica-
ção, ou seja, não passa de um meio de se produzir um objeto, de se atingir um fim. Como produto de processos lógicos e mecânicos,
a política sem o livre agir torna-se algo artificial e fica impossibilitada de criar o novo, de apresentar soluções originais para aporias dos
assuntos humanos. Restringindo-se ao político especialista como único ser dotado da técnica de governo, a ação política reduz-se à
produção de uma sociedade estagnada, propícia a uma ação dominadora” (TELES, 2019, p. 10-11).
37 Hannah Arendt está em um diálogo com o liberalismo conservador e o republicanismo neo-ateniense. A influência do liberalismo
conservador é expressa, sobretudo, pelos ruídos dos escritos de Edmund Burke e Alexis de Tocqueville na filosofia da pensadora ale-
mã, principalmente, em suas críticas ao revolucionarismo francês. Ademais, há uma rejeição do materialismo histórico-dialético, da sua
tendência de supervalorização do trabalho e das questões econômicas, visto que a plenitude do homem reside na fruição da liberdade
enquanto um fato político genuíno. Em relação à adesão ao republicanismo neo-ateniense, é possível afirmar que a ênfase no participati-
vismo e na esfera pública são traços nitidamente republicanos nas ponderações de Arendt. É preciso ressaltar que enquadrar Arendt em
uma ou outra categoria, seja a de leitura liberal conservadora ou de esquerda, vai contra a própria resistência de Arendt em se enquadrar.
Não obstante, seus diálogos com a tradição do liberalismo conservador e com algumas matrizes republicanas são nítidos. Em vista disso,
insta trazer à baila as considerações dispostas na obra O Dia da glória chegou: Revolução, opinião e liberdade em Tocqueville e Arendt de
Rosângela Chaves (2022, p. 19): “É bem verdade que Arendt admitia ser admiradora da obra de Tocqueville. O autor parisiense figura entre
os seus ‘heróis’ do pensamento ocidental – aqueles que, como Maquiavel e Montesquieu, e a exemplo dela mesma, conduziram suas
reflexões sem se desviar do real, da concretude do mundo público. A autora também o cita profusamente no ensaio Sobre a revolução,
Tocqueville é mencionado mais de 20 vezes”. 3 Ponderações acerca da
despersonalização: uma análise a partir
de Arendt e da literatura primoleviana pública, quando os indivíduos encontram seus
semelhantes para construir algo em comum, e
não no âmbito privado ou no íntimo em comum”
(BARROS, 2020, p. 64). Por certo, as obras dos autores analisados
servem como um alerta de que os perigos da
impessoalização, do ódio sistematizado ao outro
e da instrumentalização do homem35 não são
remotos e, por isso, devem ser identificados
e, posteriormente, combatidos efetivamente. Conforme ressaltado por Levi, seu trabalho de
memória apresenta, em seu âmago, um propósito
genuinamente social, um compromisso com as
tentativas de impedir a repetição da barbárie
efetuada pelo projeto totalitário alemão. Para
Arendt, a esperança reside na busca constante
da liberdade pela Ação Política36, isto é, pelo par-
ticipativismo37 dos homens na vida comunitária e
pela construção de princípios verdadeiramente
republicanos. Trata-se da retomada do ideal de
“vida ativa”. Enfim, para a pensadora em questão,
a valorização do espaço público, a busca coletiva
pelo bem comum e a prática das virtudes cívicas38
são antídotos contra o mal banal. “Arendt sus-
tenta que a liberdade só se manifesta na esfera O resgate da ideia segundo a qual a liberdade
adquire substância na participação política e
no pleno exercício dos direitos na esfera pú-
blica constitui uma das grandes contribuições
de Arendt para os debates concernentes ao
republicanismo. Na própria definição de po-
lítica, a autora a compreende enquanto uma
esfera que trata da pluralidade dos homens
e da convivência entre os diferentes (LEITE,
2022, p. 37). Além do apreço pela construção da esfera
pública39, outro antídoto reside na consideração
da dignidade da pessoa humana baseada em
valores axiológicos legítimos, desconsiderando,
assim, pretensões cientificistas, que desprezam,
em última instância, as outras formas de conhe-
cimento em detrimento da superioridade das
ciências naturais ou físicas. A base do princípio
da dignidade da pessoa humana reside numa
reflexão acerca de valores, isto é, numa conside-
ração axiológica. Todavia, as ciências físicas não
produzem valores e não possuem a capacidade estão relacionadas, principalmente, ao princípio de supremacia do interesse público em detrimento dos interes-
es. 39 Acerca da ênfase de Arendt em uma concepção de liberdade que se realiza na esfera pública, Rosângela Chaves (2022, p. 35 Acerca da instrumentalização do homem, C.S. Lewis (2017, p. 60) afirma: “Cada poder conquistado pelo homem também é, ao mes-
mo tempo, poder sobre o homem [...] porque o poder do homem de torná-lo aquilo que ele quiser na verdade significa, como vimos, o
poder de alguns homens de fazer o que eles quiserem de outros homens [...] uma vez que tenhamos vendido nossas almas, ou seja, nós
mesmos, o poder assim conferido não pertencerá a nós. Não seremos, na verdade, nada mais que escravos e marionetes daqueles que
vendemos nossas almas. Está no alcance do Homem o poder de tratá-lo como mero ‘objeto natural’, bem como seus próprios juízos
de valor como matéria-prima para manipulação científica”. Na passagem supracitada, Lewis condena a instrumentalização do homem
favorecida pelos ideais materialistas e cientificistas.
36
“P
i
d
ã
h
t
ã
id
tid d
t
i ã
ã
lid d
d f it
A 39 Acerca da ênfase de Arendt em uma concepção de liberdade que se realiza na esfera pública, Rosângela Chaves (2022, p. 21) afir-
ma: “A tese que se sustenta aqui, portanto, é a de que é possível extrair das reflexões de Tocqueville e Arendt uma versão convergente
de republicanismo, no empenho de cada um desses autores em recuperar os ideias de espírito público e de participação ativa na vida
pública como remédios republicanos que podem combater novos despotismos surgidos na modernidade. No entanto, o republicanismo
tocquevilliano e o republicanismo arendtiano, atentos às complexidades das sociedades democráticas modernas e, por isso, longe de
proporem um modelo utópico de organização política calcado na formação de cidadãos patrióticos imbuídos de uma mesma vontade,
realçam a pluralidade inerente à esfera pública”. As virtudes cívicas estão relacionadas, principalmente, ao princípio de supremacia do interesse público em detrimento dos int
es e paixões particulares. O exemplo de Lourenço é importante, sobre- Por fim, cabe ressaltar uma
reflexão importante contida na obra Eichmann
em Jerusalém, a saber: A passagem supracitada revela a importância
da memória para o processo de explicação do
ocorrido, dando destaque, sobretudo, aos so-
breviventes e aos que presenciaram as tragédias
realizadas pelo totalitarismo nazista. Ademais,
é a partir do julgamento de Eichmann que os
sobreviventes ganharam protagonismo para a
compreensão do universo concentracionário
dos campos de extermínio. Desse modo, Arendt
frisa a inutilidade das ações daqueles que se
esforçavam para encobrir a barbárie naqueles
tempos sombrios e ressalta a centralidade da
liberdade humana como oposição ao horror
totalitário e a possibilidade da resistência, ainda
que aparentemente limitada, ao mal. Se o mal
tem uma dimensão banal, somente o bem tem
profundidade, pois a prática do bem exige sacri-
fícios, renúncias e esforço pessoal. Diante desse risco eminente de sempre re-
tornar, o totalitarismo só pode ser combatido
mediante a pequena esperança que se renova
a cada novo nascimento. Não deixa de ser in-
trigante o fato de Hannah Arendt terminar seu
livro com uma citação de Agostinho: “Initium ut
esset homo creatus est – o homem foi criado para
que houvesse um começo” (ARENDT, 2012, p. 639). Novos nascimentos, novos seres humanos,
novos começos, esperança renovada de que o
totalitarismo (a maior crise da modernidade) será
vencido mais uma vez. O exercício do bem é uma
esperança e, por certo, apesar dos horrores e da
realidade hostil, ainda há esperança. O destaque
para a fé na prática do bem como confiança na
melhora social representa uma das grandes
heranças deixadas pela obra de Arendt. É verdade que a dominação totalitária tentou
estabelecer esses buracos de esquecimento
nos quais todos os feitos, bons e maus, desa-
pareciam, mas assim como estavam fadadas
ao fracasso todas as tentativas nazistas, feitas
de junho de 1942 em diante, de eliminar os
vestígios dos massacres – por meio da cre-
mação, da queima em poços abertos, do uso
de explosivos e lança-chamas e máquinas
trituradoras de ossos –, assim também todos
os esforços de fazer seus oponentes “desa-
parecem em silencioso anonimato” foram em
vão. Os buracos de esquecimento não existem. Nada humano é tão perfeito, e simplesmente
existem no mundo pessoas demais para que
seja possível o esquecimento. Sempre sobra
um homem para contar a história. Portanto,
nada pode ser “praticamente inútil”, pelo menos
a longo prazo (ARENDT, 1999, p. 254). 3 Ponderações acerca da
despersonalização: uma análise a partir
de Arendt e da literatura primoleviana 21) afir-
ma: “A tese que se sustenta aqui, portanto, é a de que é possível extrair das reflexões de Tocqueville e Arendt uma versão convergente
de republicanismo, no empenho de cada um desses autores em recuperar os ideias de espírito público e de participação ativa na vida
pública como remédios republicanos que podem combater novos despotismos surgidos na modernidade. No entanto, o republicanismo
tocquevilliano e o republicanismo arendtiano, atentos às complexidades das sociedades democráticas modernas e, por isso, longe de
proporem um modelo utópico de organização política calcado na formação de cidadãos patrióticos imbuídos de uma mesma vontade,
realçam a pluralidade inerente à esfera pública”. Leonardo Delatorre Leite • Gerson Leite de Moraes
Desumanização e a banalidade do mal 17/21 Leonardo Delatorre Leite • Gerson Leite de Moraes
Desumanização e a banalidade do mal 17/21 ou a força motivacional para sustentar o plano
do dever-ser, pois o seu escopo se encontra no
plano do ser. Portanto, não há uma espécie de
completude ou integralidade nas ciências natu-
rais. Em razão da insuficiência das ciências físicas
no âmbito dos valores, conclui-se que pretensões
cientificistas não possuem capacidade para jus-
tificação da dignidade humana. Sob essa perspectiva, é premente mencionar o
caso do imperialismo e do neocolonialismo do
século XIX, cujos anseios foram justificados pela
teoria do “racismo científico”, amplamente aceita
nos meios de pesquisa e divulgação da ciência. Portanto, não é corretor afirmar que o desen-
volvimento do saber científico está intimamente
conectado com a potencialização de melhorias
sociais. Conforme ressalta Ratzinger (2019, p. 18): Ademais, o cientificismo guarda uma cone-
xão íntima com o fisicalismo, doutrina filosófica
que entende ser possível uma compreensão
total dos fenômenos da experiência a partir de
descrições puramente científicas dos aspectos
físicos. No relato de Primo Levi, a figura do “afo-
gado” é a expressão máxima da consideração
da vida humana a partir de uma visão pautada
tão somente pelo fisicalismo e mecanicismo, ou
seja, pela “existência biológica” e pelos aspectos
objetivos da experiência. Todavia, a totalidade
da experiência humana envolve outro aspecto
além da dimensão objetiva, a saber: a vivência
subjetiva. Desse modo, ao se concentrar apenas
na esfera objetiva, o fisicalismo desconsidera a
dimensão do subjetivo, indispensável para uma
consideração integral da realidade humana. Por
certo, a valorização efetiva da dignidade humana,
imprescindível para evitar a lógica da instrumen-
talização, pressupõe uma abordagem total e
holística da experiência do homem. 40 Sob essa perspectiva, Joseph Campbell realiza uma reflexão sobre a temática da despersonalização contemporânea associada com
o drama do personagem Darth Vader na saga Star Wars. Em vista disso, afirma o autor: “As máscaras de monstro, usadas pelos atores
de Guerra nas estrelas, representam a verdadeira força monstruosa, no mundo moderno. Quando a máscara de Darth Vader é retirada,
você vê um rosto informe, de alguém que não se desenvolveu como indivíduo humano. É um burocrata, que vive não nos seus próprios 3 Ponderações acerca da
despersonalização: uma análise a partir
de Arendt e da literatura primoleviana Desse modo,
como as teses fisicalistas e mecanistas se afas-
tam de uma abordagem integral da experiência
humana, não há nelas um apreço pela dignidade
dos indivíduos. Portanto, o fisicalismo potencializa
a lógica da instrumentalização. Se Kant e Hegel tivessem tido razão, o iluminis-
mo em progresso deveria ter levado o homem
a ser sempre mais livre, sempre mais racional,
sempre mais justo. Em vez disso, surgindo da
sua profundidade, sobem aqueles demônios
que com tanto entusiasmo tínhamos declarado
mortos, ensinando aos homens a sentir o temor
do seu próprio poder e impotência; da sua
capacidade de destruição; da sua impotência
de encontrar-se a si mesmo e tornar-se senhor
da sua própria desumanidade. Apesar da grande importância dos “antídotos”
supracitados, o remédio derradeiro contra a
despersonalização empreendida pelo governo
totalitário é, por óbvio, a humanização, ou seja,
a formação de si, o desenvolvimento próprio
das potencialidades, o aperfeiçoamento como
indivíduo autêntico e a sensibilidade para com
o Outro. Conforme destacado anteriormente, o
totalitarismo representa um regime político cen-
trado na efetivação da instrumentalização das
realidades humanas, da atomização social e da
despersonalização. Desse modo, a valorização
do processo de humanização, o destaque para a
formação autêntica de si e a ênfase na alteridade
tipificam, em última instância, atos de resistência
contra a tendência totalitária. Além disso, é premente romper com a noção
de progresso, característica do iluminismo e de
sua crença segundo a qual o desenvolvimento do
saber científico implicaria necessariamente me-
lhorias humanísticas, ou seja, uma prosperidade
quantitativa e qualitativa da sociedade. O aperfei-
çoamento do conhecimento científico, sobretudo
da técnica, não veio sempre acompanhado por
uma preocupação genuinamente humanística. Ademais, o grande perigo da contempora-
neidade reside na massificação, na reificação
do homem, isto é, em sua “coisificação” e na
mercantilização das relações sociais40. A conju-
gação dos fatores supramencionados acarreta
um impedimento ao processo de construção de
si mesmo como pessoa autêntica. Eis o grande
desafio: guiar o homem para o seu aperfeiçoa-
mento moral e para sua formação como indivíduo 18/21 Veritas, Porto Alegre, v. 68, n. 1, p. 1-21, jan.-dez. 2023 | e-44191 das possibilidades e vontades humanas. Com
isso, pretende ser o que não pode; deturpa e
reduz o homem. Através da mentira totalitária,
torna-se demoníaco e tirânico. A abolição do
totalitarismo estatal desmistifica o Estado,
libertando tanto os homens quanto a política
e os políticos. verdadeiramente livre. termos, mas nos termos de um sistema imposto [...]” (CAMPBELL, 1998, p. 154. Numa análise semelhante, atesta Primo Levi (1998, p. 132):
“Eles povoam minha memória com sua presença sem rosto, e se eu pudesse concentrar numa imagem todo o mal do nosso tempo,
escolheria essa imagem que me é familiar: um homem macilento, cabisbaixo, de ombros curvados, em cujo rosto, em cujo olhar, não se
possa ler o menor pensamento”.
41 É importante destacar que para Arendt os espaços da política não são reduzidos aos espaços da comunidade. Nesse sentido, os
espaços políticos adquirem maior dimensão e extensão. 3 Ponderações acerca da
despersonalização: uma análise a partir
de Arendt e da literatura primoleviana Na realidade, a formação
de si e o aperfeiçoamento como indivíduo au-
tônomo são os antídotos apontados por José
Ortega y Gasset (1883-1955) contra o fenômeno
do “Homem-massa”. Cada indivíduo deve procurar a sua condição
autêntica, expressando, sentindo e pensando
a cada momento a sua verdade interior. Existe
um aspecto de obrigatoriedade à transparência
existencial em José Ortega y Gasset, no sentido
em que cada indivíduo deve assumir um papel
assertivo no processo de autorrealização con-
tínua que é a vida (SIMÕES, 2012, p. 9). Diante dos fatos supracitados, percebe-se a
imprescindibilidade de um compromisso efetivo
com a dimensão axiológica do princípio da digni-
dade da pessoa humana, encarada, sobretudo, a
partir da questão da alteridade, da formação do
indivíduo como pessoa autêntica, do participati-
vismo na esfera pública41 e na oposição aos ideais
de instrumentalização das realidades sociais. A
literatura de testemunho de Primo Levi e as re-
flexões de Arendt acerca da banalidade do mal
servem como um alerta acerca dos perigos do
totalitarismo, enquanto uma ameaça constante,
e dos potenciais destrutivos da despersonali-
zação, associada ao processo de destruição da
consciência moral autônoma, do espírito comunal
e da liberdade enquanto fato político genuíno. Por fim, cabe ressaltar a imprescindibilidade
da compreensão segundo a qual o Estado não
constitui a totalidade da existência humana e,
por conseguinte, não possui legitimidade moral
para atuar, de forma explícita e arbitrária, em
determinados aspectos da realidade humana,
isto é, em atividades eminentemente destinadas
à autogestão dos indivíduos organizados em
associações e instituições. Certamente, o Estado
totalitário reivindica para si a total influência e
controle sobre as dimensões sociais e aspectos
do cotidiano. Não obstante, certas atividades
humanas são destinadas, originalmente, aos
indivíduos na livre fruição de seus direitos bási-
cos atrelados à formação de associações. Desse
modo, a afirmação da autonomia dos indivíduos
na autogestão de certos aspectos da realidade
humana transparece a carência de legitimidade
moral da atuação total do poder político na vida
social, pois a totalidade da existência humana
transcende os limites da política estatal. Em vista
disso, afirma Joseph Ratzinger (2019, p. 72): p
ortante destacar que para Arendt os espaços da política não são reduzidos aos espaços da comunidade. Nesse sentido, os
olíticos adquirem maior dimensão e extensão. Considerações finais A temática da desumanização representa um
assunto típico da literatura judaica do holocausto,
pois exprime a potencialidade de degradação
da dignidade humana empreendida pelo tota-
litarismo, compreendido enquanto um regime
político construído a partir da atuação total do
Estado na sociedade, ou seja, do controle pelo
poder político tanto da esfera pública quanto da
esfera privada. Na concepção de Hannah Arendt,
para assegurar uma gestão holística da vida so-
cial, o poder público se vale, principalmente, de
três medidas, quais sejam: a impessoalização, a
manipulação das massas e a atomização social. É sabido que a impessoalização, também qualifi-
cada como desumanização e despersonalização,
reside, sobretudo, na redução do indivíduo a um
vazio, fruto do esvaziamento da consciência moral O Estado não constitui a totalidade da exis-
tência humana e não abarca toda a esperan-
ça humana. O homem e sua esperança vão
além do Estado constituído e da esfera da
ação política. Isso vale não apenas para um
Estado como a Babilônia, mas para qualquer
Estado. O Estado não é o totum: isso alivia os
políticos, abrindo-lhes ao mesmo tempo o
caminho da política racional. O Estado romano
era falso justamente por querer ser o totum Leonardo Delatorre Leite • Gerson Leite de Moraes
Desumanização e a banalidade do mal 19/21 Leonardo Delatorre Leite • Gerson Leite de Moraes
Desumanização e a banalidade do mal 19/21 19/21 supressão da consciência moral num contexto
de instrumentalização das realidades humanas,
de burocratização da violência e “normalização
da barbárie”. Nesse sentido, a tese da banalidade
do mal aborda a temática da despersonaliza-
ção a partir dos objetivos do regime totalitário,
quais sejam: o sufocamento da individualidade,
o controle integral do Estado sobre a totalidade
das atividades sociais e a transformação dos
cidadãos em meras engrenagens de um sistema
essencialmente estruturado para a aniquilação
da autonomia na esfera da moralidade. e da perda das qualidades indispensáveis para a
formação de si mesmo como pessoa autêntica
e autônoma. A manipulação das massas é uma consequ-
ência direta do processo de impessoalização e
tipifica a formação de um conjunto de indivíduos
inaptos para o exercício do espírito comunal,
incapacitados para a intersubjetividade dialó-
gica, alheios ao seu semelhante, mergulhados
na passividade absoluta, indiferentes aos valo-
res de construção da ação política genuína e
às virtudes cívicas. Considerações finais Segue-se, portanto, que a
predominância da indiferença acarreta a deca-
dência da esfera pública, pois sua construção e
sobrevivência, enquanto o ambiente da intersub-
jetividade dialógica, pressupõem a vivência de
um espírito comunitário e a prática das virtudes
cívicas. Depreende-se daqui que a manipulação
das massas, como resultado da desumanização,
ao generalizar a indiferença e comprometer o
desenvolvimento da intersubjetividade e da ação
política, implica a derrocada da esfera pública. A literatura de testemunho de Primo Levi
apresenta como temáticas principais a desu-
manização e a perda da consciência moral no
universo concentracionário nazista. Um aspecto
eminente nas reflexões do autor em questão
reside na sua percepção de que a extensão da
despersonalização foi holística, não somente
vivenciada pelos prisioneiros, como também
pelos oficiais e funcionários alemães. Levi relata
como a violência representava o cotidiano do
campo, como ela era encarada a partir de uma
“burocratização da barbárie” e da “industrialização
da morte”. Desse modo, os guardas dos campos
de extermínio, quando batiam nos cativos, não
manifestavam sinais de cólera ou ira, traços e
sentimentos humanos, mas encaravam as tarefas
de punição como “atos de rotina”, “normalizados
pela burocracia”. Portanto, percebe-se que a des-
personalização apresenta uma relação explícita
com a extensão do fenômeno da banalidade do
mal. Ademais, cabe ressaltar que a literatura de
Levi não deve ser encarada tão somente como
uma espécie de “memorialística do campo de
concentração”, visto que sua obra apresenta
um propósito socialmente estabelecido. Como
humanista e um intelectual politicamente enga-
jado, o autor possui o compromisso de combater
os vestígios e reminiscências do totalitarismo,
sobretudo, com o intuito de evitar a repetição
da barbárie. A atomização social consiste no isolamento dos
indivíduos, mais especificamente na incapacidade
de construção de conexões sociais baseadas na
alteridade e no reconhecimento do outro. Nesse
sentido, a inaptidão para o estabelecimento de
uma ligação efetiva com o próximo, traço típico
da atomização, revela, em última instância, uma
desumanização, visto que a impessoalização
representa a atenuação crescente das qualida-
des próprias de uma pessoa autêntica, entre as
quais: o desenvolvimento individual a partir do
envolvimento com o próximo, ou seja, da própria
alteridade. Portanto, a atomização social, en-
quanto uma impossibilidade de vivência efetiva
das relações sociais, tipifica uma consequência
do processo de desumanização, que impede o
aperfeiçoamento de uma qualidade indispen-
sável para a construção de ligações profundas
com o próximo. Referências ARENDT, Hannah. Eichmann em Jerusalém: um relato
sobre a banalidade do mal. São Paulo: Companhia
das Letras, 1999. MACIERA, Aislan Camargo. Primo Levi: a química entre
literatura e ciência. Caderno de Letras, Pelotas, n. 34,
p. 89-126, 2019. ARENDT, Hannah. Responsabilidade e julgamento. São
Paulo: Companhia das Letras, 2004. ARENDT, Hannah. Responsabilidade e julgamento. São
Paulo: Companhia das Letras, 2004. MACINTYRE, Alasdair. Depois da virtude: um estudo
sobre teoria moral. Campinas: Vide, 2021. ARENDT, Hannah. Origens do totalitarismo: antissemitis-
mo, imperialismo, totalitarismo. São Paulo: Companhia
das Letras, 2012. ARENDT, Hannah. Origens do totalitarismo: antissemitis-
mo, imperialismo, totalitarismo. São Paulo: Companhia
das Letras, 2012. MONTEPERELLI, Francesca. Tra Frankenstein e Pro-
meteo: mitti della scienza nell’immaginario del’900. Napoli: Liguori, 2006. ASSY, Bethania. Ética, responsabilidade e juízo em Han-
nah Arendt. São Paulo: Perspectiva; Instituto Norberto
Bobbio, 2015. MORAES, Gerson Leite de. O Mal Banal e a difícil tarefa
do perdão. Revista Estudos Filosóficos, São João del-Rei,
n. 17, p. 16-29, 2016. BARROS, Alberto Ribeiro Gonçalves de. Liberdade
política. São Paulo: Edições 70, 2020. OLIVEIRA, Lucas Amaral de. O testemunho ético de
Primo Levi sobre a zona cinzenta: um problema de
julgamento e representação. Patrimônio e Memória,
Assis, v. 13, p. 103-130, 2017. BAUER, Yehuda. Rethinking the holocaust. New Haven:
Yale University Press, 2001. CAMPBELL, Joseph. O poder do mito. 16. ed. Entrevista
concedida a Bill Moyers. Tradução: Carlos Felipe Moisés. São Paulo: Palas Athena, 1998. ORWELL, George. O Que é Fascismo? E Outros En-
saios. Tradução: Paulo Geiger. São Paulo: Companhia
das Letras, 2017. CARVALHO, Daniel Gomes de. Filosofia para mortais:
pensar bem para viver bem. Rio de Janeiro: Harper
Collins, 2020. POLANYI, Michael. A lógica da liberdade: reflexões e
réplicas. Rio de Janeiro: TopBooks, 2003. PRESOT, Regiane Sousa de Carvalho. Hannah Arendt e
Primo Levi: reflexões sobre o estado totalitário. Revista
Internacional de Direito e Cidadania, João Pessoa, p. 1-15, 2013. CHAVES, Rosângela. O dia de glória chegou: revolução,
opinião e liberdade em Tocqueville e Arendt. São Paulo:
Edições 70, 2022. CORREIA, Adriano. O caso Eichmann: Hannah Arendt
e as controvérsias jurídicas sobre o julgamento. São
Paulo: Edições 70, 2023. RATZINGER, Joseph. Liberar a liberdade: fé e política no
terceiro milênio. Tradução: Rudy Albino de Assunção. São Paulo: Paulus, 2019. FRANKL, Viktor. Sede de sentido. Tradução: Henrique
Elfes. São Paulo: Quadrante, 1989. REALE, Giovanni. O saber dos antigos: terapia para os
tempos atuais. São Paulo: Edições Loyola, 1999 FRANKL, Viktor. Considerações finais Em sua obra Eichmann em Jerusalém, Arendt
discorre sobre as relações entre o totalitarismo
e a banalidade do mal, afirmando que a desu-
manização apresenta uma ligação íntima com
a proliferação de um mal caracterizado pela Por fim, com base na exposição das obras e
reflexões de Levi e Arendt, foi estabelecida uma
ponderação acerca das posturas de oposição aos
traços cruciais do totalitarismo. Nesse sentido, Veritas, Porto Alegre, v. 68, n. 1, p. 1-21, jan.-dez. 2023 | e-44191 20/21 HOWE, Irving. A escrita e o holocausto. Cadernos de Lín-
gua e Literatura Hebraica, São Paulo, n. 2, p. 11-37, 1999. o artigo pontuou algumas questões eminentes
para o fortalecimento do ideal axiológico do prin-
cípio da dignidade da pessoa humana, a saber:
a valorização da esfera pública, o destaque para
o participativismo por meio das virtudes cívicas,
a imprescindibilidade da formação de si como
instrumento crucial para a humanização, a neces-
sidade da alteridade para o desenvolvimento de
um indivíduo autêntico e, por fim, o combate ao
cientificismo e às visões de instrumentalização
das realidades humanas. Destarte, a oposição aos
mecanismos de desumanização é uma postura
de oposição aos vestígios do totalitarismo. KANT, Immanuel. A fundamentação da metafísica dos
costumes. São Paulo: Discurso Editorial Barcarolla, 2009. LEITE, Leonardo Delatorre. Direito de resistência na
tradição republicana. Curitiba: CRV, 2022. LEVI, Primo. Conversazioni e interviste. Turim: Einaudi,
1997. LEVI, Primo. É isto um homem? Tradução: Luigi Del Re. Rio de Janeiro: Rocco, 1998. LEVI, Primo. Os afogados e os sobreviventes. São Paulo:
Paz e Terra, 2004. LEVINAS, Emmanuel. Nom d’un chien ou le droit na-
turel. In: LEVINAS, Emmanuel. Difficile liberté: essais
sur le judaïsme. Paris: Albin Michel, 2006. p. 232-235. LEWIS, Clive Staples. A abolição do homem. Tradução:
Gabriele Greggersen. Rio de Janeiro: Thomas Nelson
Brasil, 2017. Leonardo Delatorre Leite Mestrando em Direito Político e Econômico pela Uni-
versidade Presbiteriana Mackenzie, com bolsa CAPES/
PROSUC Mod. II. Graduando em Filosofia pela Univer-
sidade de São Paulo (USP). Licenciado em História
pela Universidade Presbiteriana Mackenzie. Bolsista
PIBIC- CNPq (2018-2020). Bacharel em Direito pela Uni-
versidade Presbiteriana Mackenzie. Membro do grupo
de pesquisa “Religião, Memória e Cultura” (Orientado
pelo Prof. Dr. Gerson Leite de Moraes) do Centro de
Educação, Filosofia e Teologia (CEFT) da UPM. Os textos deste artigo foram revisados pela Texto
Certo Assessoria Linguística e submetidos para
validação dos autores antes da publicação. Referências The unheard cry for meaning: Psycho-
therapy & Humanism. New York: Simon and Schuster,
2014. SIMÕES, Helena. A metafísica do humano em José Or-
tega y Gasset e Juan Ramón Jiménez. Cultura, Lisboa,
v. 30, p. 253-274, 2012. HABERMAS, Jürgen. Fé e saber. São Paulo: Ed. UNESP,
2013. TELES, Edson. Ação política em Hannah Arendt. São
Paulo: Almedina, 2019. Leonardo Delatorre Leite • Gerson Leite de Moraes
Desumanização e a banalidade do mal 21/21 Leonardo Delatorre Leite • Gerson Leite de Moraes
Desumanização e a banalidade do mal 21/21 Endereço para correspondência: VOEGELIN, Eric. A crise e o apocalipse do homem:
história das ideias políticas. Tradução: Elpídio Mário
Dantas Fonseca. São Paulo: É realizações, 2018. v. 8. LEONARDO DELATORRE LEITE
Maria Antônia, 76
Vila Buarque, 01222010
São Paulo, SP, Brasil Gerson Leite de Moraes Mestre em Filosofia pela Pontifícia Universidade Ca-
tólica de Campinas/SP (PUCCAMP – 2003), doutor
em Ciências da Religião pela Pontifícia Universidade
Católica de São Paulo/SP (PUCSP – 2008) e doutor em
Filosofia pela Universidade Estadual de Campinas/SP
(IFCH/UNICAMP – 2014). Licenciado em História (1996). Bacharel em Teologia pelo Seminário Presbiteriano do
Sul (1999), graduado em Teologia pela Universidade
Presbiteriana Mackenzie/SP (2006), bacharel em Fi-
losofia pela FFLCH.
|
https://openalex.org/W4247538279
|
https://zenodo.org/records/7674094/files/her2020-12-002.pdf
|
English
| null |
Folk art as a phenomenon of philosophical understanding
|
European Scientific e-Journal
| 2,017
|
cc-by
| 7,915
|
Folk art as a phenomenon of philosophical understanding Abstract: Folk art is fundamentally based on the cultural and traditional heritage of previous generations. Traditional applied art cannot exist without relying on the cultural heritage of society. The article is
devoted to the philosophical understanding of the phenomenon of folk art. Folk art, which originated in
the Paleolithic period and is based on the artistic tradition of the ethnic group, continues to exist in some
industrialised countries, including Russia. The author concludes that folk art of the world and Russia has
passed a contradictory path. Having generated the “great” art of the classical type, folk art has moved
down to the level of subsidiary crafts, and in some countries – to kitsch. However, in the modern
conditions of globalisation and the “return of ethnicity”, folk art takes on new features. Keyword: cultural heritage, folk art, tradition, traditional applied art, conservation, renovation,
revitalization, industrial era, post-industrial era. Сергей Викторович Лебедев, профессор, доктор философских наук, заведующий кафедрой,
кафедра философии, Высшая школа народных искусств. Санкт-Петербург, Россия. Сергей Викторович Лебедев, профессор, доктор философских наук, заведующий кафедрой,
кафедра философии, Высшая школа народных искусств. Санкт-Петербург, Россия. DOI: 10.47451/her2020-12-002 The paper is published in Crossref, ICI Copernic, BASE, Zenodo, OpenAIRE, LORY, HSLU, J-Gate,
Academic Resource Index ResearchBib, ISI International Scientific Indexing, eLibrary, Mendeley, and
WebArchive databases. he paper is published in Crossref, ICI Copernic, BASE, Zenodo, OpenAIRE, LORY, HSLU, J-Gate,
ademic Resource Index ResearchBib, ISI International Scientific Indexing, eLibrary, Mendeley, and
ebArchive databases. The paper is published in Crossref, ICI Copernic, BASE, Zenodo, OpenAIRE, LORY, HSLU, J-Gate,
Academic Resource Index ResearchBib, ISI International Scientific Indexing, eLibrary, Mendeley, and
WebArchive databases. Sergey V. Lebedev, Full Professor, Doctor of Science in Philosophy, Head of the Department. Department of Philosophy, Higher School of Folk Arts (Academy). St. Petersburg, Russia. Sergey V. Lebedev, Full Professor, Doctor of Science in Philosophy, Head of the Department. Department of Philosophy, Higher School of Folk Arts (Academy). St. Petersburg, Russia. Lebedev, S.V. (2020). Folk art as a phenomenon of philosophical understanding. Eurasia: Current Issues of Cultural
Heritage. European Scientific e-Journal, 3(3), 14-31. Hlučín-Bobrovníky: “Anisiia Tomanek” OSVČ.
Лебедев, С.В. (2020). Народное искусство как феномен философского осмысления. Eurasia: Current Issues
of Cultural Heritage. European Scientific e-Journal, 3(3), 14-31. Hlučín-Bobrovníky: “Anisiia Tomanek” OSVČ. (на
англ.) Lebedev, S.V. (2020). Folk art as a phenomenon of philosophical understanding. Eurasia: Current Issues of Cultural
Heritage. European Scientific e-Journal, 3(3), 14-31. Hlučín-Bobrovníky: “Anisiia Tomanek” OSVČ. Лебедев, С.В. (2020). Народное искусство как феномен философского осмысления. Eurasia: Current Issues
of Cultural Heritage. European Scientific e-Journal, 3(3), 14-31. Hlučín-Bobrovníky: “Anisiia Tomanek” OSVČ. (на
англ.) Conservation, restoration, renovation and revitalization of folk art Conservation, restoration, renovation and revitalization of folk art What is meant by “folk art” in the philosophical concept? Folk art exists as a phenomenon. Recall that in philosophy, the word “phenomenon” (Greek: φαινόμενον, from φαίνεσθαι – to
appear, to be visible, also – to appear) is a phenomenon, an object given in sensory
contemplation (Mikhailov, 2010). It is necessary to recall that a phenomenon is an object of our
perception, e.g., the Moon is a satellite of the Earth, representing a spherical body devoid of
atmosphere. A moon is an object. However, the crescent is a phenomenon. Thus, traditionally,
folk applied art, it is a phenomenon. Therefore, we study how traditional art manifests itself as
part of the art as a whole. Consequently, folk art has existed and will continue to exist as long as people exist. This
article is an attempt to flesh out the folk art as such. Consequently, folk art has existed and will continue to exist as long as people exist. This
article is an attempt to flesh out the folk art as such. Folk art is fundamentally based on the cultural and traditional heritage of previous
generations. According to the most prominent researcher of Russian folk-art M.A. Nekrasova,
“each nation has its own culture of poetically imaginative and craft traditions. Passed down from
generation to generation as a result of collective creativity, these traditions acquire stable
expressive and emotional structures that pass through the centuries. With tradition, folk art
transmits not only skill but also artistic principles, implemented by each time in its way and
bearing its national character.” (Nekrasova, 1982) According to the academician, the President of
VSNI V.F. Maksimovich, “traditional arts and crafts are one of the most important elements of
the cultural “gene pool” of Russia, as it assumes the function of protecting national identity in
the context of globalisation, the widespread of products of mass culture that generates and
accumulates a cultural memory of generations. Authentic works of folk art have always played
an important role in educating people’s patriotic feelings, contributing to the preservation of
national identity and the identity of national cultural life.” (Maksimovich, 2018) Thus, traditional applied art cannot exist without relying on the cultural heritage of soci Thus, traditional applied art cannot exist without relying on the cultural heritage of society. As M.A. Nekrasova noted, “Folk art is not separate objects. Народное искусство как феномен философского осмысления Аннотация: Народное искусство основано на культурном и традиционном наследии предыдущих
поколений. Традиционное прикладное искусство не может существовать без опоры на культурное
наследие общества. Статья посвящена философскому осмыслению феномена народного
творчества. Народное искусство, зародившееся в период палеолита и основанное на
художественных традициях этноса, продолжает существовать в некоторых промышленно
развитых странах, в том числе в России. Автор приходит к выводу, что народное искусство мира
и России прошло противоречивый путь. Произведя «великое» искусство классического типа,
народное искусство перешло в разряд вспомогательных, а в некоторых странах – в китч. Однако
в современных условиях глобализации и «возвращения этничности» народное искусство
приобретает новые черты. Ключевые слова: культурное наследие, народное искусство, традиция, традиционное прикладное
искусство, консервация, реновация, ревитализация, индустриальная эпоха, постиндустриальная
эпоха. 1 1 Conservation, restoration, renovation and revitalization of folk art This is a whole and harmonious
world, which is mercilessly violated when a particular thing is snatched from it and when it is
placed in an unusual environment. Works of folk art are extremely inferior in the halls of modern
exhibitions and are much better perceived in the natural environment of the peasant hut – where
they still live, and in museums of everyday life, in the ‘working environment’ for which they were
created.” (Nekrasova, 1983) According to T.E. Lonchinskaya, a scientist and restorer of art
products, “works of folk art – objects of material culture – are the expression of the spiritual life
of the people.” (Lonchinskaya, 2009) However, as A. Buychik notes, “the cultural image of society cannot be formed from
nowhere, from a clean slate. This is the result of centuries-old transformations, diffusions and
interpenetrations of semiotic series, traditions, folklore, in its essence, the formation of intangible
cultural heritage and its transfer to the material shell, which begins to form the concept of
heritage value, first in economic perception (equivalent), and then spiritual – the value of the
past for society in the future.” (Buychik, 2019) 2 Folk art is based on artistic traditions. Traditions at all times are a necessary condition for
the very life of the nation. Traditions also have an integrative character for ethnic communities,
singling out “their own” and at the same time separating them from “others”. In early societies,
traditions regulated absolutely all spheres of life of an individual and society as a whole. It is no
coincidence that many researchers call the human society of the pre-industrial era traditional. The industrial revolution led to the disappearance of many traditions of the former society, and
those traditions remained were subjected to a kind of “erosion”, turning into a set of customs
and rituals that often do not make sense in the eyes of ordinary citizens. The main directions of preserving cultural heritage and developing traditional applied arts
on its basis can be considered conservation, restoration and renovation. Conservation (from Lat. conservatio – conservation) is actions aimed at long-term preservation of any objects. Restoration (from Lat. restauratio – restoration) is a set of measures aimed at preventing
subsequent destruction and achieving optimal opportunities for further long-term preservation
of monuments of material culture (Vygonnaya et al., 2000). Renovation can be considered very important for the development of traditional applied
art. T.E. Conservation, restoration, renovation and revitalization of folk art Lonchinskaya, speaking about the renovation in lace-making, which is absolutely true
for all other types of traditional folk art, notes that “renovation (Lat. renovatio – renewal) in the
traditional applied art of lace-making is the recreation, updating of artistic works with a
comprehensive study of them. Renovation of folk artworks includes: mastering the cultural
heritage, studying the historical period, understanding technological and technical traditions,
analyzing compositional solutions, studying technology and material, learning the experience of
previous artists, using the collective nature of work, fully preserving the spirituality of the folk-
art tradition and, as a result, educating the artist-bearer of this art form in artistic Russian lace
weaving.” (Lonchinskaya, 2009) Finally, the peak of the preservation and development of folk art is its revitalization, that is,
the renewal of the life of folk art. Not only the preservation of ‘old’ traditional art forms but also
the development of new ones. All this revives folk art in new forms really. Folk art as one of the foundations of ethnic identity In our era, the philosophy of traditional applied art can acquire all the features of a global
philosophy. Indeed, the end of the twentieth century, with its wars, multiple mass genocides,
environmental problems, and cultural crises, has led to disillusionment with the very belief that
man can change the world for the better. Theodor Adorno, one of the greatest philosophers of
the last century, said, “After Auschwitz, poetry is impossible” (Adorno, 2003). The seemingly
almost achieved victory of humanity over nature was equivalent to defeat. The general crisis,
which engulfed almost all aspects of human existence, destroyed the former enthusiastic
optimism. The longing for a brighter future that was so characteristic of philosophy and art has
largely disappeared. After all, the future was not bright at all, but rather frightening. The
environmental crisis has made everything fragile, temporary, ephemeral and doomed (Lebedev,
2013). Today, humanity has come to realize the exhaustion of the previous version of the world's
development, in the absence of a clear understanding of what will replace it. It is no accident
that nowadays, when determining certain features of the state of the world, the prefix ‘post-’ is 3 most often used. Western society is called post-industrial, post-class, and post-national. Europe
is considered a “post-Christian” continent. European integration, which largely deprived the
countries of the European Union of state sovereignty, led to the emergence of European “post-
statehood”. The lack of ideological alternatives is also evident in the post-ideological nature of
the modern world (Lebedev, 2013). In these conditions, the problem of preserving the traditional cultural heritage of humanity
in general and specific ethnic groups in particular becomes one of the most important tasks of
the people of the 21st century. When the present becomes shaky and uncertain, and the future is
alarming, people for the most part turn to the good, old, time-tested ideas and arts. In other
words, the cultural heritage of the people becomes its support in the vague everyday life of our
time. Cultural heritage is a part of material and spiritual culture created by past generations
(Cultural heritage is a part of material and spiritual culture, 2016). All types of art, including the most
“avant-garde”, claiming to throw the classics of the former culture from the “steamboat of
modernity”, to some extent rely on the cultural heritage of the past. Folk art as one of the foundations of ethnic identity These include age, gender, consanguinity,
race, and ethnicity; 2) cultural is clan, tribal, language, national, religious, civilizational affiliation; 3) territorial is immediate environment, native city, native region, country; 4 4 4) political is shared ideology, voting, party membership, loyalty or opposition to the existing
government, etc.; 4) political is shared ideology, voting, party membership, loyalty or opposition to the existing
government, etc.; 4) political is shared ideology, voting, party membership, loyalty or opposition to the existing
government, etc.; 5) economic is profession, position, labour collective, economic interests, self-relation with a
certain class and social group; 5) economic is profession, position, labour collective, economic interests, self-relation with a
certain class and social group; social is your social status, a sense of belonging to a certain part of society. Therefore, the identity of a person, except for the ascriptive one, is largely determined by
him. People can change their spouse, religion, political views, country of residence, social status,
and even sexual orientation many times. However, as it can be seen, it is the culture that
determines all other identities. Any country stands on a certain national identity based on religion, language, historical
memory, and historical traditions. Of course, there are variables among the features of identity. What was previously considered the greatest national achievements may well become something
shameful. However still, national culture in the broad sense of the word is the basis of national
identity. One of the “eternal” questions of philosophy is the question not only of the origin and
preservation of religion, nation, and state but also the search for ideas about the meaning of
being a people and country. When describing this complex sphere in recent decades, such
concepts as “nation”, “race”, “mentality” are increasingly considered outdated and at the same
time politically incorrect terms that have meaning only in some particular definitions. Nowadays,
researchers introduce more general categories – “identity”. Only now this concept is written in
English-identity. At the same time, of course, there are no “pure” theories of identity, and there
cannot be, despite all the wishes of researchers. If in ancient philosophy, the analogue of
questions about identity were arguments about the relationship between constancy and
variability, in modern philosophy, it is a dispute between essentialists and constructivists. Essentialism (Lat. Folk art as one of the foundations of ethnic identity Human progress is generally
impossible without understanding the primary sources in the development of culture in the
history of mankind. To objects of cultural heritage (monuments of history and culture) of peoples of the Russian
Federation include the “immovable property (including archaeological heritage) and other
facilities with historically related territories, paintings, sculpture, decorative-applied art, objects
of science and technology and other items of material culture resulting from the historical events,
representing value from the point of view of history, archeology, architecture, urbanism, art,
science and technology, aesthetics, ethnology or anthropology, social culture and are evidence
of epochs and civilizations, authentic sources of information about the origin and development
of culture.” (Federal Law no. 73-FZ) In general, it can be considered that cultural heritage is the
totality of all the cultural achievements of society, both material and spiritual, as well as the
historical experience of society, deposited and forever fixed in the national memory. According
to modern researchers, it is “based on achievements of various ages, passing to new generations
in new epochs.” (Dobrynin, 2012) Currently, the most important problem of all countries and peoples of the world is the crisis
of national identity. What is it? This term (Lat. idem – the same) it appeared in ancient logic and
meant a certain relation, the members of which are identical to each other. But, of course, identity
is not just a philosophical category. Identity in the human psyche is the ability to express in a
concentrated form for him how he imagines his belonging to various social, national,
professional, linguistic, political, religious, racial and other groups or other communities. In other
words, what the individual relates himself to is identity. The choice of self-identification for any individual is almost unlimited. Therefore, we will
highlight only some of the most important groups of individual identities: 1) ascriptive (literally “attributed”, that is, those over which individuals have no power, which
are determined outside of the individual’s merits). These include age, gender, consanguinity,
race, and ethnicity; 1) ascriptive (literally “attributed”, that is, those over which individuals have no power, which
are determined outside of the individual’s merits). Folk art as one of the foundations of ethnic identity essentia – essence) is a direction in philosophical thought characterised by
attributing to some entity an unchangeable set of qualities and properties, suggesting that things
have some deep reality, true nature, inaccessible to our understanding. It can be said that
essentialism is an attempt to fix some eternal and unchangeable essence (ethnic, social, sexual,
etc.). Philosophical constructivism proceeds from the fact that every cognitive activity is a
construction, that is, the creation of a certain structure. In other words, there is no reality other
than that created by man. In this sense, the individual’s national identity, cultural preferences,
and even gender identity are also “constructed” It is no coincidence that proponents of
philosophical constructivism widely use the concept of “nation-building” (national building). Historians view ethnic identity through individual and collective memory. From the point
of view of historians, national identity can be defined as coincidence and identity with an ethnic
group, social and group identity, as well as continuity over time. In general, liberal philosophical
political theories, based on the individual and his freedom, do not seek to address the problems
of group solidarity in society. For conservative thinking, on the contrary, the nation and the
family always represent more than just a community, and religion is more than just a religious
affiliation. Conservative thinking considers faith to be the main form of knowledge and action. The era of globalization with its imposed templates of Western mass culture could not but
cause an identity crisis. It is not by chance that cultural struggles (not street demonstrations or 5 parliamentary votes) define the essence of an era. An indicator of the struggle for cultural identity
can be found in the current process of glocalization. This concept is formed from the
combination of two words – “globalisation” and “localisation”, and its meaning is that in the
period of globalization when the power of national states that transfer sovereignty to various
supranational structures is weakened, such phenomena as separatism, increased interest in local
differences, increased interest in ancient traditions and the revival of dialects are becoming more
important. The turn of the 20th and 21st centuries was remembered for the rise of “self-
supporting” moods in many developed countries of the world. Belgium is actually divided into
three regions, Scotland is trying to leave the United Kingdom, Corsica – France, and Catalonia
– Spain. Folk art as one of the foundations of ethnic identity Autonomist movements emerged in completely forgotten historical regions such as
Frisia, Lombardy, Moravia, and the Aland Islands. Even in one-nation Italy, political parties and
leagues have sprung up intending to separate the rich Northern regions from Italy. Several
English provinces in Canada also raise the question of independence. Glocalisation gave rise to the phenomenon of “return of ethnicity”, that is, the revival of
almost forgotten historical cultural traditions. This sometimes takes on semi-comical features
when, for example, they try to create rock music with texts in old dialects, or when they try to
celebrate artificially recreated holidays. But we must admit that in several historical provinces of
European countries, the revival of traditional applied art is really taking place. And if once in the
century before last, for William Morris, the forerunner of design, who tried to revive ancient
crafts, Handicrafts had to resist standardized machine production, in our time, for the 21st
century William Morris, it is about preserving their national identity. In Russia, this process has also taken on a special character. Despite the dominance of
liberal-westernist figures in the media, philosophers talk about a conservative cultural revolution
in Russia. Another thing is that the threshold of irreversibility has not yet been passed, and you
do not need to relax at the thought that it’s okay, Russia will “digest” Americanism, as Tatar and
German cultural and political influence once did. The struggle is not over, and it is in the field
of traditional arts (since “modern” arts are formed in the West) that a victory can be won in
preserving the Russian national identity. Folk art in the industrial and post-industrial era The art of artistic processing of amber, which is popular among the Baltic peoples,
but not widely spread among Russians, was born in the Kaliningrad region after 1945. In the late
1960s, Barnabas’s bone carving appeared. Some artistic crafts in Russia experienced periods of
decline and a new revival. So, in Soviet times, the almost disappeared Rostov enamel, Zhostovsky
painting of metal trays, Kholmogorsky carved bone, Velikoustyuzhsky blackening on silver and
Zlatoust engraving on steel were revived. In the 1970s, the art of Nizhny Tagil metal painting
was revived. Back in the 1920s, A.V. Bakushinsky, who studied the psychology of artistic perception,
noted the craving of the masses for realistic and visual art very accurately. Pointing to the interest
in the popular environment to the realistic transmission of reality (initially manifested in the
framework of applied art), the researcher suggested that, ultimately, this should lead to the
addition of easel art forms in This way, A.V. Bakushinsky considers Amateur art as a new stage
in the development of folk art (Bakushinskiy, 1981). In the industrial age, folk art takes on new forms. It is amazing, but mostly, with all the mass
participation of participants and creators, mostly artistic creativity is viewed as a hobby. However, this work at leisure has all the features of folk art. Yes, once it was necessary to clearly
separate folk art and Amateur art. This was also necessary to save traditional arts and crafts. But
an era has passed and now we can say that the art of the people can develop in the 21st century. Development goes in a spiral, as Hegel noted. The idea of spiral development was
considered by Hegel as an integral part of dialectics-the negation and synthesis of progressive
development “in a straight line” and “walking in a circle”. As A.S. Barmenkov rightly notes, “Every stable system has mechanisms of self-defence, and
in the case of folk art, this is, first of all, collective imaginative thinking, penetration into tradition. It becomes problematic when the artist understood the tradition, allegedly accepted this art,
mastered special techniques, but later left them, apparently, the development of the tradition was
shallow, so there was a desire to move to a different figurative, plastic system. It is good when
the artist understands this and leaves the team, leaves the craft. Folk art in the industrial and post-industrial era Folk art can be considered as a special area of artistic creativity, which can include both
professional and amateur visual arts. Consequently, as long as the people retain the ability to
create art, folk art will continue to exist and develop. Considering the issues of artistic creativity, it should be noted that this process involves the
creation of not only traditional works, but also new ones that have never existed before. Sometimes this creation of the new involves opposition to a kind of template and everyday life. An important component of creativity is the economic side with its focus on new technologies,
products, and their competitiveness. Therefore, the creation of artistic products implies
compliance with the following principles: •
the principle of semantic integrity-achieved through a kind of dialogue between the Creator
and the consumer through knowledge and experience, technical calculation, getting used to
the situation, overcoming stereotypes; •
the principle of semantic integrity-achieved through a kind of dialogue between the Creator
and the consumer through knowledge and experience, technical calculation, getting used to
the situation, overcoming stereotypes; 6 6 •
the principle of expediency-is based on identifying the utilitarian expediency in the process
of creating a product based on its artistic, technological, social, environmental and economic
expediency; •
the principle of expediency-is based on identifying the utilitarian expediency in the process
of creating a product based on its artistic, technological, social, environmental and economic
expediency; •
the principle of expediency-is based on identifying the utilitarian expediency in the process
of creating a product based on its artistic, technological, social, environmental and economic
expediency; •
the principle of harmonization-is revealed in the ratio of the whole and individual parts of
the created product based on integrity and expediency; the principle of expressiveness-is
focused on identifying the aesthetic features of the product, implying its convenience,
strength and beauty (Maksyashin, 2012). Unlike most industrialised countries, traditional folk art still exists in Russia today. Moreover, Russian folk art, which developed in ancient times, e.g., the art of wood or bone
carving was formed in the Neolithic era, developed during the industrial development of Russia. For example, some of the most famous Russian arts and crafts originated in the Soviet period
of Russian history. So, the Russian lacquer miniature (Palekh, Mstera, Kholuy) was formed in
the 1920-30s. New is well-forgotten old: modern types of folk art We will give as an example such popular among ordinary, “ordinary people”, types of home
art that have a long history and flourished in our time, as patchwork sewing and making glass
products using a burner at home. Patchwork, or patchwork (from the English words patch – flap, patch, and work-work), a
type of folk-art activity that has existed since time immemorial to this day. Traditions of
patchwork were developed in Russia. So, methods of economical cutting, including from scraps
of cloth, were described in The Domostroy. In the Soviet era, patchwork was also of interest to
artists of that time, futurists and constructivists, as a new expressive form. However, most people
were engaged in making clothes from scraps only for poverty and scarcity. Patchwork is a kind
of mosaic of pieces of fabric, which used to create household items, clothing, accessories, and
art panels. This art can be both decorative, applied, and purely artistic. If earlier patchwork arose
from the need to maximise the use of all available fabrics, in our time, patchwork is turning into
real art, and millions of people are passionate about it, women and men, young and old, all social
strata and groups. The main means of expression in patchwork is a successful combination or
contrast of colours, patterns and textures of the fabric. Classic patchwork is symmetrical
compositions of geometric shapes. The images for the storied patchwork usually use a technique
of artistic stylization, typical of decorative and applied techniques. Patchwork is often
supplemented with embroidery, batik, free painting on the fabric, applique, decoration of beads,
feathers, etc. (Patchwork, 2016) Lampwork is a technique for processing glass over the flame of a burner. It is one of the
newest types of folk art. It is usually used for making glass beads, parts for accessories, small
decorative figures. Lampwork requires special equipment: propane or oxygen burner, as well as
fairly expensive raw materials. Historically, since ancient times, glassblowers made toys and all
sorts of trinkets from the remains of glass mass. At the end of the 20th century, as burners and
glass for processing became available and cheap, lampwork began to turn into an art craft. The
main advantage is the ability to let in products of any shape and size. In addition, all lampwork
products are unique, because it is impossible to repeat them. Folk art in the industrial and post-industrial era It is worse when it does not go
away, but performed the idea that the fishery is dead or dying. In the light of the above, the
influence of the “author” on the development of folk art can lead to various results: •
enriching the craft with new motifs, themes, and technological techniques; 7 •
improving the level of workmanship and artistic and aesthetic quality of products;
•
destruction of the traditional image system. I
“
ll
i
”
f
i f
i •
improving the level of workmanship and artistic and aesthetic quality of products;
•
destruction of the traditional image system. •
improving the level of workmanship and artistic and aesthetic quality of products; In turn, “collective” performs two main functions: •
contributes to the preservation of tradition and continuity; •
serves as a source of artistic excellence.” (Barmenkov, 2018) Thus, the line between amateur author’s artistic skill and between the artist of traditional art
becomes very conditional. We can observe the appearance of new types of folk art with our own
eyes. Kaliningrad amber art processing Among the “youngest” in age, but at the same time achieved world recognition of Russian
art crafts, one can name the art of artistic processing of amber. This art form was born after
1945 in the Kaliningrad region, former East Prussia. On October 17, 1945, according to the 8 decisions of the Berlin (Potsdam) conference, part of East Prussia with the main city of
Konigsberg was officially incorporated into the USSR. In 1946, the Konigsberg region was
created as part of the RSFSR. Immediately began the organized settlement of the new region of
Russia (Lebedev, 2015). As it is noted by the Kaliningrad scientist Y. Zverev, “in the economic
and geographical literature, there is a term country of migrant capitalism”. In this sense, the
region can be called a “region of resettlement socialism” with all its advantages and
disadvantages” (Zverev, 1997). There are 22 cities, 4 urban-type settlements, and just rural localities in the region. The
region has almost no villages in the traditional Russian sense. By the way, there are also no farms
that are so typical of their closest neighbours – the Balts. There are small villages whose
inhabitants are engaged in agriculture. But for them, too, the urban lifestyle prevails. There are
many universities in the region, including the University. The average level of education is higher
than the national average. As you can see, the majority of Kaliningrad residents are citizens with
a high level of education. But it was here that the art craft was born – the processing of amber. There was not a single amber specialist among the settlers. However, still, the aesthetic sense
and ingenuity inherent in the Russian people quickly led to the appearance of Amateur jewellers
in the new Russian jewellers, amber makers. At the same time, all German specialists in the
extraction and processing of amber left East Prussia taking with them all the production secrets. Almost all of the amber deposits were severely damaged as a result of the war. In addition, the
Germans tried to destroy all equipment and documentation. Finally, masters of amber processing
from the neighbouring Baltic republics due to a number of political circumstances in the first
decade and a half of the region’s existence, when the local art craft was born, they did not come
to Kaliningrad. Thus, the extraction and artistic processing of amber in Russia started from
scratch. Kaliningrad amber art processing And it is impossible not to be amazed that Russian masters created their own special
Kaliningrad school of artistic processing of amber with amazing speed. Since 1654, in East Prussia, the main production of amber took place in the village of
Palmniken. After joining the USSR, Palmniken was renamed the village of Yantarny. In 1947, an
amber factory was established there. Amber was not only extracted here but also artistically
processed. In the first decade of operation, the plant produced quite simple products: beads,
bracelets, pendants, brooches, mouthpieces, cufflinks, buttons. From the very beginning, novice
amber artists tried to create their own style with some success, although due to lack of
experience, the first amber products were quite primitive. Decorations mostly repeated the
shapes of leaves, berries, and fruits. For more naturalness and “beauty”, amber was even tinted. Precious metals, especially gold and silver, were widely used in working with amber. Kaliningrad craftsmen in the late 1950s moved from imitation and the first, still simple
products to creation to fundamentally new artistic products than the previous East Prussian
ones. Kaliningrad products also differed from the artistic method that was cultivated in Latvia
and Lithuania. In these republics, amber was mined for many centuries. Baltic jewellers did not
set out to give a product made of amber a certain, predetermined shape, but only emphasized
its natural shape and colour. The Kaliningrad style creatively combined both the Prussian desire
for decorativeness and the Baltic desire to preserve the naturalness of the ‘sunstone’. Kaliningrad residents, in addition to mass production for the General consumer, began to
create original thematic compositions during these years: monumental vases, panels, boxes 9 decorated with amber and Souvenirs. Such large-sized products reflected the Imperial
monumentalism inherent in all art of that time, the so-called “Stalin’s Empire” or “triumph
style”. As a result, the work became heavy for the reason that the masters who came to the plant
were carvers of other stones – jasper or marble (Zherikova, 2018). The plant produced not only
serial products in hundreds of thousands of copies. The factory also created original artistic
products using various jewellery techniques. In 1959, the government of the USSR issued a decree “on improving the range, quality and
decoration of amber products”. Now artists and art historians have been attracted to the use of
amber. Achievements in the field of amber of the Baltic peoples were creatively processed. Kaliningrad amber art processing Now
it is finally possible to talk about the formation of the Russian Kaliningrad school of amber. The
founders of the Kaliningrad school of amber processing were masters who worked at the
Kaliningrad amber factory in the 1960s: A. Meos, A. Popov, A. Kvashnin, E. Lis, V. Mityanin,
R. Benislavsky, A. Yaroshenko and V. Shorokhov (Mashkov, 2018). In 1961-1962, the All-Union
competition for the best sample of amber products was held. The competition received 439
applications made in sketches and materials from many cities and republics of the USSR,
including the Baltic States. However, the victory went to A. Popov from Kaliningrad. This was
a milestone in the all-Union and then world recognition of the Kaliningrad school of amber art
processing. Since the second half of the 1960s, the USSR has had a kind of amber boom. Various amber
products (not all of which can be called artistic) were now offered by most jewellery stores in
the country. This affected the quality of the products since now the “amber maker” were
required to produce according to the plan, a huge number of amber products without taking into
account their artistic value. However, the Soviet consumer was not spoiled and was quite
satisfied with the amber products offered by the trade. After the collapse of the USSR, the amber industry was gripped by a protracted crisis. Against this background, hundreds of new private enterprises began to appear. They were quick
to respond to the latest fashion trends. The state monopoly on the extraction and processing of
amber has lost its influence, and the amber industry has largely passed into private hands. Customers’ tastes have also changed. Now buyers were eager to purchase exclusive handmade
jewellery made by a famous master. Gradually, the crisis was overcome. The restoration of the Amber Room in Tsarskoye Selo
gave a strong impetus to the development of the craft. Modern jewellers restored the European
techniques of processing the “sunstones” of the 17th and 18th centuries, almost forgotten in
Europe itself. Modern Russian masters in the new century are not afraid to combine amber with
metals, bone, wood and other elements. A great demand for Baltic amber arose due to a sharp
increase in the tourist flow from Asian countries, especially from China, where amber is quite
popular. Conclusion It should note that these examples are not limited to folk art. The emergence of new
directions in this work, caused by the development of technology, can be expected. The appearance of new materials, such as previously non-existent types of textiles and new
types of dyes, provides unique opportunities in the field of fabric painting. The development of 10 3D technology provides new opportunities in the jewellery industry when the master can use a
computer to present a three-dimensional image of the future product. Even in such truly
traditional forms of art that have existed since primitive times as ceramics and bone carving, the
introduction of new tools provides new opportunities for the development of these types of
creativity. However, still, it is still only becoming a new folk art. The most important obstacle to its
further development is that it is not handled by professionals. For the development of folk art,
including its new forms, so that national art is not limited only to the restoration of old
techniques and products, it is necessary to give higher education to artists. For thousands and
thousands of years, traditional art has been based on the practical experience of masters, based
on the examples of their ancestors. However, in our time, this is not enough. A modern artist
who wants to create great masterpieces must possess all the artistic experience of humanity and
especially of his people, but also be a comprehensive person. And then his knowledge,
experience and work will give excellent shoots. Human society is not just a sum of individuals, but a multitude of different social
communities – nations, classes, faiths, and a great many other social groups. Each of the social
communities has its own identity, which is largely manifested in folk art. To Kant’s questions:
Who am I? From where? What can I know? What can I hope for? – each individual can give an
answer based on family background, native language, and culture. However, of course, it is
unlikely that even a cosmopolitan individual will consider the Black Square or the poem Dyr Bul
Shchyl as one of the foundations of their national identity. However, national culture is in many
ways a folk art, and it will remain popular as long as the people exist as a community. Conclusion The universal project of Enlightenment, which was born three centuries ago and consisted
of an attempt to rationalise politics and morality, is now coming to an end. The progress and
triumph of a single universal civilization of the western type, which was waiting for all mankind,
is over. And, as a result, the old era with its values ends, but the new one has not yet come. In
short, “postmodern” has come. The concept of “postmodern” (as a synonym often used the word “postmodernism”,
although it is not the same) from a philosophical term has become a fashionable word, used
incredibly widely by a variety of people in a variety of circumstances. As is often the case with
popular words, it becomes difficult to give a specific and generally accepted definition of what
is hidden behind the concept of postmodernism. Postmodernism is understood as both modern
philosophy and the latest artistic trends. The most important thing in the definition is the prefix
“post”, which means that the period of the so-called Modernity is completed. In its most general
form, postmodernism expresses deep disillusionment with the results of all previous
development, loss of faith in man and humanism, reason and progress, in all previous ideals and
values. Not only bright but the future, in general, is becoming more and more problematic. The
dominant forms of modern social and political thought are completely inadequate to the
challenges that Western civilization has to face: globalisation, fundamentalism, ethnic and
religious conflicts, and the growth of social and ethnic intolerance. The project of a United
Europe with a common culture is failing. Instead of fusing into the same common Europeans,
the peoples living on the old continent are increasingly striving to remember their old roots and
emphasize their unique differences from their neighbours. Often even openly imaginary, 11 invented only to have at least the appearance of specialness, claiming that you can demand the
provision of certain preferences. Postmodern philosophy deconstructs the rules and behaviour
accepted in public life, and under the slogan of “pluralism” refuses to search for absolute truth,
which is what philosophy has always done. In place of the universalist concepts and Western “mass culture” that still come from the
Enlightenment philosophy, humanity turns to the good old traditions and traditional culture. Conclusion Sooner or later, the healthy part of any society must have a reaction of rejection to Hollywood,
“modern art”, in which there is no art and also not modern at all (after all, its main features were
formed in the century before last). Under these conditions, the growing interest in traditional art
forms is quite understandable. As noted by academician RAO, the President of the Higher School
of Economics V.F. Maksimovich, “traditional applied art is a myriad of spiritual, moral, aesthetic,
technological and material wealth, in which the soul and character of a person, his worldview,
ideas and dreams, history, and relationships with other peoples are so fully revealed.”
(Maksimovich, 2013) Because of this, art, which has folk roots, has an ennobling effect on a
person. The differences between the two types of cultures (traditional and modern) are both
simple and global. One culture prepares a person for eternal life, the other-for a good pension
(Komarova & Katushkin, 1999). Traditional folk art has a direct impact on the “high” arts of the nation. As historical
experience shows, for example, in the work of W. Morris, the work of Abramtsevsky and Talashkin
Circles, traditional art has a huge, inspiring impact on the art of the country as a whole. In other
words, not only elements of folklore but also new, quite modernist art still comes from a folk
source. Therefore, if our artists and artists in the art industry are striving to achieve worldwide
fame (and this is the natural feeling of any artist), they need to rethink the creative work of their
ancestors again and again. There is also a certain danger that the authorities in some countries will start pedalling the
theme of “primordial traditions” with embroidery, painted clay pots and folk dances in every
possible way during the crisis. Some post-Soviet countries, such as Ukraine or the Baltic States,
are classic examples of this. In conditions when industry and science have been eliminated in
these countries, the ruling elites begin to actively extol the “spirituality” of the people of the
subordinate country and invent great antiquity along with “folk culture”, ranting that industry
and science are not needed at all by a people with a rich inner world and singing songs. So, over the period from the end of the last and the first decades of the 21st century, it
becomes clear how right the Russian Slavophiles were. Conclusion There is no single world civilization, there
is a set of local civilizations that differ from each other in their culture. In these conditions, the
revival of folk art is taking place. This is not only in Russia. This is a global trend. Folk art of the world and Russia has passed a contradictory path. Having generated the
“great” art of the classical type, folk art has moved down to the level of subsidiary crafts, and in
some countries – to kitsch. However, in the modern conditions of globalization and the “return
of ethnicity”, folk art takes on new features. These days, alone craftsman with a computer can
also be considered a master of folk art in new forms. This is a new type of good old home
industry. Art associations that make toys can be considered new types of art associations. Of
course, it would be good to bring back the old concepts of “craftsman”, “artel”, “artisan”, but
it is thought that in real life there will be new concepts synonymous with the old terms. 12 This is a way of dialectical return of the art of small (and not very small) forms to the sphere
of human cultural needs. In the coming times, everyone can become an artist, if they have the
desire and time. This is a way of dialectical return of the art of small (and not very small) forms to the sphere
of human cultural needs. In the coming times, everyone can become an artist, if they have the
desire and time. This means that traditional applied art is not only necessary in Russia, but also it is necessary
whether Russians want to be a nation and not just a population of a certain territory. Consequently, the history of Russian traditional applied art in Russia continues. References: Adorno, T. V. (2003). Negative dialectics. Moscow: Scientific world. (In Russian) Adorno, T. V. (2003). Negative dialectics. Moscow: Scientific world. (In Russian) Bakushinskiy, A. V. (1981). Research and article. Moscow: Iskusstvo. (In Russian) Barmenkov, A. S. (2018). Correlation of collective and individual in the context of folk and
professional creativity. Yaroslavl Pedagogical Bulletin, 4. (In Russian) Buychik, A. G. (2019). Klironomia as the science of the preservation of historical and cultural
heritage. Modern Science: Actual Problems of Theory and Practice. Series “Cognition”, 3, 90-93. (In
Russian) Cultural heritage is a part of material and spiritual culture created by past generations. (2016, May
12). Time. (In Russian). https://fb.ru/article/223670/kulturnoe-nasledie---eto-chast-
materialnoy-i-duhovnoy-kulturyi-sozdannaya-proshlyimi-pokoleniyami Dobrynin, D. S. (2012). The concept of “cultural heritage” in the Humanities. Bulletin of the Buryat
State University, 6, 236-239. (In Russian) Federal Law no. 73-FZ of 25.06.2002 (as amended on 29.12.2017) “On Objects of Cultural
Heritage (Historical and Cultural Monuments) of the Peoples of the Russian Federation”,
article 3. (In Russian) Komarova, S. V., & Katushkin, M. A. (1999). Doll people. Kulturologicheskiy Ocherk. St. Petersburg:
Abris. (In Russian) Lebedev, S. V. (2015). Colonization as an indicator of the life force of the Russian people. Health
is the Basis of Human Potential: Problems and Ways to Solve Them. Proceedings of the all-Russian
Scientific and Practical Conference with International Participation, 2. Herzen State Pedagogical
University. (In Russian) Lebedev, S. V. (2013). Philosophy and traditional applied art of Russia. Textbook for students of higher
educational institutions studying in the direction of Decorative and Applied Arts and Crafts. St
Petersburg: VSNI. (In Russian) Lonchinskaya, T. E. (2009). Training technology renovation of art lace students of the faculty of
traditional applied arts as a factor in the preservation of national cultural heritage. Pedagogy
of
Art,
4. (In
Russian). http://www.art-
education.ru/sites/default/files/journal_pdf/lonchinskaya_30_11_2009.pdf Maksimovich, V. F. (2018). Education of children and youth by means of traditional arts and
crafts in the educational practice of the Higher School of Folk Arts. Pedagogy of Art, 1, 55-
60. (In Russian) Maksimovich, V. F. (2013). Ways of updating professional education in traditional applied art. Questions of Cultural Studies, 8. (In Russian) 13 13 Maksyashin, A. S. (2012). Decorative and applied and folk art: their essence and content. Yekaterinburg:
Ural State Law Academy’s Publishing House. (In Russian) Mashkov, O. (2018). Amber Museum in Kaliningrad. Russian People’s Encyclopedia of Folk and
Decorative and Applied Arts, 2. Moscow: Institute of Russian Civilization. References: (In Russian) Mikhailov, I. A. (2010). Phenomenon. New Philosophical Encyclopedia. Moscow: Institute of
Philosophy of the Russian Academy of Sciences, Mysl. (In Russian) Nekrasova, M. A. (1983). Folk art as part of culture: theory and practice. Moscow: Fine Art. (In Russian)
Nekrasova, M. A. (1982). Problems of folk art. Moscow: Fine Art. (In Russian) Nekrasova, M. A. (1982). Problems of folk art. Moscow: Fine Art. (In Russian) Patchwork. (2016, March 25). (In Russian). https://skrmaster.ru/system/article/loskutnoye-
shitiye-patchwork Vygonnaya, A., Kalnin, V., & Tseitlina, M. (2000). Fundamentals of restoration. Minsk, Design PRO. (In Russian) Zherikova, N. (2018). Amber art craft of Russia. Russian People’s Encyclopedia of Folk and Decorative
Arts, 2. Moscow: Institute of Russian civilization. (In Russian) Zverev, Y. M. (1997). Kaliningrad region of Russia in the new system of geopolitical coordinates. Ethnic and Regional Conflicts in Eurasia. Book 2. Moscow: Ves Mir. (In Russian) 14
|
https://openalex.org/W2807827328
|
https://www.nature.com/articles/s41598-018-27446-6.pdf
|
English
| null |
Acceptability of placebo multiparticulate formulations in children and adults
|
Scientific reports
| 2,018
|
cc-by
| 8,144
|
Acceptability of placebo
multiparticulate formulations in
children and adults Felipe L. Lopez1, Punam Mistry2, Hannah K. Batchelor2, Joanne Bennett3, Alastair Coupe3,
Terry B. Ernest4, Mine Orlu1 & Catherine Tuleu1 Received: 28 February 2018
Accepted: 29 May 2018
Published: xx xx xxxx Patient acceptability is an important consideration in the design of medicines for children. The aim
of this study was to investigate acceptability of multiparticulates in healthy children and adults. A
randomised, single-blind acceptability testing was performed involving 71 children (4–12 years) and
61 adults (18–37 years). Each participant received three 500 mg samples of microcrystalline cellulose
pellets administered on a medicine spoon with water at 5–10 minutes intervals. Acceptability was
measured based on voluntary intake of the samples, facial expressions, ratings on hedonic scales
and reported willingness to take multiparticulates everyday as a medicine. Multiparticulates were
voluntarily swallowed by 92% of children and 100% of adults. However, palatability issues were
identified, with emphasis on textural aspects. Grittiness perception received negative ratings on
hedonic scales by 60% of children and 51% of adults. Researcher observations revealed that 72% of
children and 42% of adults displayed negative facial expressions towards the samples. Children reported
their willingness to take multiparticulates as a medicine in 30% of the cases, compared to 74% in adults. This study demonstrates that multiparticulates may be a suitable formulation platform for children
and adults, although palatability concerns have been highlighted. Additional work is required to define
acceptability criteria and to standardise methodologies. Patient acceptability has been defined by the European Medicines Agency (EMA) as the ability and willingness
of a patient and their caregiver to use and administer a medicine as intended1. Although not the only parameter
that requires consideration, palatability is often regarded as one of the main elements influencing acceptability
of oral medicines. Evaluation of patient acceptability should form an integral part of the pharmaceutical devel-
opment studies and the Paediatric Investigational Plan (PIP), as recommended by the EMA in their Guideline
on Pharmaceutical Development of Medicines for Paediatric Use1. There is also a moral obligation to evaluate
acceptability of medicines to promote patient adherence and cost-effective treatments. p
y
p
pf
Consideration must be given to the selection of the most suitable formulation for the target population group1;
however, fundamental knowledge about age-appropriateness of different dosage forms is still limited and frag-
mented2. www.nature.com/scientificreports www.nature.com/scientificreports www.nature.com/scientificreports Acceptability of placebo
multiparticulate formulations in
children and adults Liquid medicines have been traditionally considered the most appropriate oral formulation for children,
as they are easy to swallow by the patient and the dose can be titrated at the point of use. However, oral solid for-
mulations are gaining support from regulatory authorities, based on their better stability profile, lower number
of (potentially hazardous) excipients and suitability for taste-masking and controlled-release via film coating1,3. This paradigm shift in the selection of the most appropriate dosage form has been reinforced by recent studies
supporting acceptability of solid medicines in children, including the youngest populations of preschool children
and neonates4–9. Multiparticulate formulations, in the form of pellets or beads, are composed of highly spherical granules of
small diameter (typically below 1.5 mm) and narrow size distribution, usually prepared by fluidised bed technol-
ogies, including active layering and direct pelletisation10. Such formulations are suitable for controlled release
and taste masking by means of film-coating technologies11, which could benefit patient compliance. Based on
their multi-unit composition, multiparticulates offer higher potential for dose titration than conventional tablets
and capsules12. For these reasons, multiparticulates are considered a flexible solid dosage form often proposed 1School of Pharmacy, University College London, London, United Kingdom. 2School of Pharmacy, Institute of Clinical
Sciences, University of Birmingham, Birmingham, United Kingdom. 3Pfizer Global R&D, Sandwich, Kent, United
Kingdom. 4GlaxoSmithKline, Harlow, Essex, United Kingdom. Correspondence and requests for materials should be
addressed to C.T. (email: c.tuleu@ucl.ac.uk) SCIenTIfIC REPOrTS | (2018) 8:9210 | DOI:10.1038/s41598-018-27446-6 1 www.nature.com/scientificreports/ as an alternative to conventional solid and liquid formulations for children3,13. Despite the potential benefits
of multiparticulates for paediatric drug delivery, evidence of patient acceptability is very scarce. Previous stud-
ies have investigated acceptability of multiparticulates in adult participants14,15, but acceptability studies in chil-
dren are very limited16. More trials are required to investigate the impact of formulation factors (i.e. the effect
of size of multiparticulates, presence or absence of film coating or amount of dosage units per dose) on patient
acceptability. p
y
Pharmaceutical regulatory bodies such as the EMA recommend to carry out palatability and acceptability
testing of paediatric medicines in the targeted age group1. However, the pharmaceutical development of paediat-
ric medicines traditionally relies on data from adult populations; although correlation between palatability and
acceptability data in children and adults remains unknown. Results
D Demographics. A total of 132 participants were recruited, 71 children (4–12 years; median age = 7) and 61
adults (18–37 years; median age = 22). Since each participant received three multiparticulate samples, the total
number of acceptability evaluations was 214 in children and 183 in adults. Children participants included 14 chil-
dren between 4 and 5 years, 37 children between 6 and 8 years and 20 children between 9 and 12 years. Further
details of the demographics have been provided in Supplementary Information. No significant association was
found between the age of the children and any of the outcome measures evaluated, thus children were treated as
a homogenous population for the purpose of data analysis. Acceptability of multiparticulates: comparison between children and adults. Success in swal-
lowing the formulation. The proportion of participants who swallowed the complete dose of multiparticulates
(as opposed to those who spat out the sample or refused it), was 92% in children and 100% in adults (Table 1). The sample was refused by five different children, two of whom refused two samples; the age of the children that
refused the sample ranged from 5–8 years with a median of 7 years. The sample was spat out by eight children,
one of whom spat out two samples; the children that spat out the sample ranged from 4–10 years with a median
of 8 years. There were 10 occasions (5%) where children voiced resistance to taking the sample, and 20 occa-
sions (10%) where children voiced disgust after sample administration. Other negative outcomes such as crying,
screaming or vomiting were not observed in children before, during or after sample intake. No association was
found between the age of the children and the frequency of negative behaviours towards the sample, including the
sample being refused or spat out. No negative behaviours towards the samples were detected in adult participants. Researcher observations of facial expressions. Negative facial expressions were recorded as an indicator of par-
ticipant’s discomfort and dislike. The most commonly observed facial expression was ‘pursed lips’ (with 57% of
children and 34% of adults displaying this behaviour), followed by ‘nose wrinkle’ (30% and 10%), ‘brow bulge’
(26% and 9%) and ‘eyes squeezed’ (21% and 5%, respectively). Comparing the two population groups, the sum
of negative facial expressions was consistently higher in children than adults (p = 0.003), which suggests better
acceptance of the samples by adults. Acceptability of placebo
multiparticulate formulations in
children and adults Despite the requirement to evaluate palatability and
patient acceptability of paediatric medicines as part of the PIP, there is no regulatory guidance on how to perform
such investigations17. Different study designs and outcome measures are used in current practice due to the lack
of standardised methodology18. Visual Analogue Scales (VAS), Likert-type scales and hedonic scales have been
often employed to evaluate specific sample attributes and/or overall acceptability19,20. In addition, the proportion
of participants able to (safely and completely) swallow a pre-defined dose has been recently used as a simple meas-
ure of patient acceptability in various studies4–6,9.h p
p
y
The aim of this study was to evaluate acceptability of placebo multiparticulate formulations in healthy adults
and children volunteers. Differences between both population groups in terms of formulation preferences and
also regarding interpretation and use of data collection tools (i.e. questionnaires and scales) were investigated. Secondary objectives included to compare different methodologies for acceptability evaluation and to assess the
effect of formulation factors on palatability and acceptability of multiparticulates. Researcher observations (such
as the ability of participants to swallow the multiparticulates and facial expressions during sample intake) were
complimented by and compared against subject-reported outcomes (including ratings on hedonic scales and
willingness to take the sample everyday as a medicine). The formulation factors considered for the evaluation of
sample preferences were the size of the multiparticulates (four sizes investigated) and the presence or absence of
polymer coating. SCIenTIfIC REPOrTS | (2018) 8:9210 | DOI:10.1038/s41598-018-27446-6 Results
D Children showed at least one negative facial expression in 72% of the occa-
sions, whereas this measure accounted for 42% in adults. Participants ratings on hedonic scales. Four different criteria were evaluated using 5-point hedonic scales: grit-
tiness, mouthfeel, taste and sample volume. Overall, grittiness was the most negatively rated attribute, with a
median value of 4 in both adults and children (Fig. 1). Grittiness perception received negative hedonic scores
(i.e. hedonic rating = 4–5) by 60% of children and 51% of adults. On the contrary, the most favourably rated item
was sample volume, with a median of 2 and 3 in adults and children, respectively. Overall, ratings of palatability
descriptors were significantly worse in children than in adults (p < 0.001), particularly for taste and sample vol-
ume. This indicates relatively lower acceptance of multiparticulates in children, in agreement with the previous
findings based on researcher observations of facial expressions. Adult participants provided average hedonic
ratings to the four palatability attributes in the neutral-positive range of the scale in 82% occasions, whereas this
value was 49% in children.i Participants’ spontaneous descriptions of the samples support the findings of hedonic scales, samples were
often described as ‘tasteless’ or as having ‘no flavour’; however, the feeling in the mouth was found to be ‘gritty’
and ‘sandy’. The feedback provided by children often denoted the lack of flavour as a negative aspect of the SCIenTIfIC REPOrTS | (2018) 8:9210 | DOI:10.1038/s41598-018-27446-6 2 www.nature.com/scientificreports/ Evaluation criteria
Outcome
Children (n = 71,
213 evaluations)
Adults (n = 61, 183
evaluations)
Success in swallowing the formulation
Sample swallowed
197 (92.49%)
183 (100.00%)
Sample spat out
9 (4.23%)
0 (0.00%)
Sample refused
7 (3.29%)
0 (0.00%)
Sum of negative facial expressions†
0 - No discomfort
57 (27.67%)
107 (58.47%)
1 - Light discomfort
74 (35.92%)
57 (31.15%)
2 - Moderate discomfort
38 (18.45%)
13 (7.10%)
3 - Considerable discomfort
16 (7.77%)
1 (0.55%)
4 - Severe discomfort
21 (10.19%)
5 (2.73%)
Average rating on hedonic scales†
1 - Extremely liked
26 (12.62%)
20 (10.93%)
2 - Liked
38 (18.45%)
52 (28.42%)
3 - Neither liked/disliked
37 (17.96%)
78 (42.62%)
4 - Disliked
55 (26.70%)
30 (16.39%)
5 - Extremely disliked
50 (24.27%)
3 (1.64%)
Willingness to take the sample everyday†
Positive willingness
63 (30.58%)
135 (73.77%)
Negative willingness
143 (69.42%)
48 (26.23%)
Table 1. Results
D Acceptability of multiparticulates in children and adults based on researcher observations and subject
reported outcomes. †Children refused the sample in seven occasions, thus their negative facial expressions and
responses to hedonic ratings and willingness to take the sample every day were not recorded, and results were
calculated based on a total of 206 evaluations instead of 213. Table 1. Acceptability of multiparticulates in children and adults based on researcher observations and subject-
reported outcomes. †Children refused the sample in seven occasions, thus their negative facial expressions and
responses to hedonic ratings and willingness to take the sample every day were not recorded, and results were
calculated based on a total of 206 evaluations instead of 213. Table 1. Acceptability of multiparticulates in children and adults based on researcher observations and subject-
reported outcomes. †Children refused the sample in seven occasions, thus their negative facial expressions and
responses to hedonic ratings and willingness to take the sample every day were not recorded, and results were
calculated based on a total of 206 evaluations instead of 213. Figure 1. Ratings of sample attributes in hedonic scales (where 1 represents ‘extremely liked’ and 5 represents
‘extremely disliked’) by population group. This graph shows pooled data from all different samples (4 particle
sizes, coated/uncoated). Centre lines show the medians, box limits indicate the 25th and 75th percentiles,
notches represent the 95% confidence interval of the median and outliers are denoted by dots; crosses represent
sample means and bars indicate 95% confidence intervals of the means. Figure 1. Ratings of sample attributes in hedonic scales (where 1 represents ‘extremely liked’ and 5 represents
‘extremely disliked’) by population group. This graph shows pooled data from all different samples (4 particle
sizes, coated/uncoated). Centre lines show the medians, box limits indicate the 25th and 75th percentiles,
notches represent the 95% confidence interval of the median and outliers are denoted by dots; crosses represent
sample means and bars indicate 95% confidence intervals of the means. formulation, e.g. “it was horrible because it had no flavour” or “if it had a flavour it would be nice”, which could
explain why taste received negative ratings in hedonic scales. Moreover, children often employed the term “gritty”
as a negative attribute of taste (instead of mouthfeel), e.g. Results
D “I hated the gritty taste” or “the taste was bad because it
was gritty”, which could further explain the negative ratings given to taste in contrasts with ratings provided by
adults. A significant association was found between each possible pair of palatability descriptors in both children
and adults (Chi-squared test for association, p < 0.001 for each pair combination). This suggests the existence of
a ‘halo effect’, by which participants’ responses to one attribute were influenced by their opinion and responses
to another attribute21. For example, when the mouthfeel of the sample was disliked, the taste of the sample would
tend to be disliked as well. Participants voluntary feedback also highlighted the novelty of the formulation, e.g. “I have never tasted something like this before” or “because it was the first time to try it, mouthfeel was strange”
(comments made by adult participants). Willingness to take the sample everyday if it was a medicine. The proportion of participants willing to take the
sample every day if it was a medicine was calculated as a predictive measure of future and repeated acceptability,
which is likely to influence adherence. Overall, children reported their willingness to take the sample every day
in 63 occasions (30%), their response being negative in most cases (143, 70%). On the contrary, a larger propor-
tion of adults stated that they would take the sample every day (135, 74%) compared to those who would not be
willing to take it (48, 26%). A significant association was found between ratings to palatability descriptors and the SCIenTIfIC REPOrTS | (2018) 8:9210 | DOI:10.1038/s41598-018-27446-6 3 www.nature.com/scientificreports/ Figure 2. Ratings of sample attributes in hedonic scales as a function of multiparticulate size and presence
of polymeric coating, by population group. Markers represent the combined average rating of grittiness,
mouthfeel, taste and sample volume and bars represent the 95% confidence interval. Figure 2. Ratings of sample attributes in hedonic scales as a function of multiparticulate size and presence
of polymeric coating, by population group. Markers represent the combined average rating of grittiness,
mouthfeel, taste and sample volume and bars represent the 95% confidence interval. willingness of participants to take the sample every day. This association was stronger for grittiness, mouthfeel
and taste (p < 0.001 in all cases) than it was for sample volume (p = 0.004). Results
D This means that those patients who
rated palatability positively would tend to be more willing to take the sample every day, as it could be expected. Interestingly, the willingness to take the sample in adults (74%) was aligned with the measure of acceptability
based on hedonic ratings (82%); however, children reported to be willing to take the sample every day (30%) less
frequently than expected based on hedonic ratings (49%). Effect of formulation factors on palatability and acceptability. Looking at the proportion of par-
ticipants who swallowed the formulations (as opposed to those who refused or spat out the sample), children
accepted multiparticulates in 92% of the occasions and adults accepted multiparticulates in all cases. Therefore,
analysis of the effect of size and coating on acceptability was impractical. Based on this outcome measure, mul-
tiparticulates were well accepted regardless of the formulation properties. Similarly, based on researcher obser-
vations of negative facial expressions, no significant differences between different multiparticulate sizes and
between coated or uncoated samples were found in either children (p = 0.923 and p = 0.800 for size and coating
effects, respectively) or adults (p = 0.551 and p = 0.795, respectively). f
p
y)
(p
p
p
y)
Evaluation of their ratings of sample attributes on hedonic scales, adults perceived larger particles as being
‘grittier’ (p < 0.001) and thus showed preference for smaller particles (Fig. 2). Although there was no significant
evidence of size effect in children (p = 0.078), the larger two sizes received more negative scores on average than
the lower two sizes. There was no evidence of a coating effect on hedonic scores in either adults (p = 0.276) or
children (p = 0.466). Particle size had a significant effect on the reported willingness to take the sample everyday
by adult participants, who showed preference for smaller particles (p = 0.039), in agreement with their responses
using hedonic scales (Fig. 3). In the case of children, particle size had no clear effect on the willingness to take the
sample everyday (p = 0.112). The effect of coating on the reported willingness to take the sample everyday was
trivial in both children and adults (p = 0.407 and p = 0.116, respectively).f Since each participant received three sequential samples, the effect of administration order on outcome meas-
ures was investigated and no significant effect was found. Water consumed and residual multiparticulates in the mouth. Results
D In addition to the small volume of
water used to pre-disperse multiparticulates on the dosing spoon (approximately 3 mL), participants had free access
to spring water to complete sample intake. Children consumed 51 mL of water on average (median = 40 mL,
min = 0 mL, max = 242 mL), whereas adults consumed 63 mL on average (median = 56 mL, min = 0 mL,
max = 150 mL). The volume of water consumed was comparable between formulations; although there was a
trend of increasing water consumed with increasing multiparticulate size (Fig. 4). SCIenTIfIC REPOrTS | (2018) 8:9210 | DOI:10.1038/s41598-018-27446-6 4 www.nature.com/scientificreports/ Figure 3. Proportion of participants reporting willingness to take multiparticulates everyday if it was a
medicine. Figure 3. Proportion of participants reporting willingness to take multiparticulates everyday if it was a
medicine. Figure 4. (A) Volume of water consumed as a function of multiparticulate size, where centre lines show the
medians, box limits indicate the 25th and 75th percentiles and outliers are denoted by dots. (B) Proportion of
participants that reported they could still feel residual multiparticulates in their mouth after sample intake, as a
function of particle size. Figure 4. (A) Volume of water consumed as a function of multiparticulate size, where centre lines show the
medians, box limits indicate the 25th and 75th percentiles and outliers are denoted by dots. (B) Proportion of
participants that reported they could still feel residual multiparticulates in their mouth after sample intake, as a
function of particle size. After rinsing their mouth with water, participants were asked if they could still feel the multiparticulates in
their mouth. Overall, adults reported that they could still feel particles in their mouth in 97 occasions (53%),
whereas children reported they could feel remaining particles in 116 occasions (56%). In general, the reported
feeling of residual multiparticulates in the mouth increased with increasing particle size (Fig. 4), although this
trend was not statistically significant in either children or adults (p = 0.057 and p = 0.106, respectively). SCIenTIfIC REPOrTS | (2018) 8:9210 | DOI:10.1038/s41598-018-27446-6 Discussion This was an important finding given that multiparticulates are often intended for taste-masking and a
prolonged residence time in the mouth might put the integrity of the coating at risk (by incentivising dissolution
and/or chewing).i g
In terms of sample preferences, children showed no significant preference for any sample, although the larger
two sizes of multiparticulates (>500 µm) obtained more negative hedonic ratings than the smaller two sizes;
adults showed clear preference for smaller multiparticulates, based on participant-reported outcomes. These
findings are consistent with previous studies which showed increased grittiness perception with increased size of
multiparticulates14,15. The presence of film coating on the multiparticulates did not seem to influence acceptability
of the samples in either children or adults. A smooth polymeric film coating could reduce surface roughness,
which could have a positive impact on palatability by reducing grittiness perception and facilitating swallowing. However, a previous study of placebo mini-tablets (2 mm in size) found no significant differences in acceptability
between coated and uncoated minitablets6, in line with the present study. It should be noted that coating can be
expected to have a critical impact on patient acceptability of drug-loaded formulations by providing taste-making.h p
p
p
p
y
g
y p
g
g
The samples used in this study contained a large amount of multiparticulates (500 mg in 3 ml of water) and
were neutral tasting (i.e. no sweeteners or flavours were added). Development of a suitable vehicle for the admin-
istration of multiparticulates could have a beneficial impact on the final formulation via masking the presence of
particles and/or adding a flavour to make it more palatable. However, co-administration of medicines with food
or drinks also poses safety concerns, such as poor control over dose intake and impact on drug’s bioavailability23. Typical vehicles recommended for sprinkle products include apple sauce and yogurt that provide both flavour
and viscosity to improve palatability and ease of swallowing. Investigation into swallowing aids for the admin-
istration of oral solid formulations have been the focus of previous research, with some products already in the
market in the form of sprays, pastes or jellies24–26.h p y p
j
The lack of standardised methodology for acceptability testing is a barrier for the development of paediatric
medicines. Discussion Results of this trial indicate acceptability of multiparticulates in terms of ability to use as required and swallow
the formulation. Adults took the multiparticulate samples in all occasions, whereas children took the sample in
92% of the occasions. Although the sample was refused or taken but then spat out by children in some instances
(3% and 5%, respectively), no undesirable effects such as vomiting or choking with the sample were observed or
reported. However, researcher observations and participant-reported outcomes denoted some level of discomfort
and sample dislike by the participants of the study. Negative facial expressions towards the samples were displayed
by 72% of children and 42% of adults. These results were in line with the participant-reported outcomes, since
60% of children and 51% of adults provided negative hedonic scores to grittiness perception. The willingness to
take the sample everyday if it was a medicine was determined to be 30% in children and 74% in adults, based on
participant-reported outcomes. Overall, adult participants showed broader acceptance of the samples than chil-
dren, as consistently shown by each of the different outcome measures. y
yf
Participants discomfort and sample dislike could be ascribed to the ‘gritty’ feeling in the mouth produced by
multiparticulates, as demonstrated by negative hedonic ratings of grittiness perception and spontaneous verbal SCIenTIfIC REPOrTS | (2018) 8:9210 | DOI:10.1038/s41598-018-27446-6 5 www.nature.com/scientificreports/ judgment of the samples. These findings are supported by previous research in adults14,15. To some extent, the
negative ratings of grittiness could be influenced by the lack of exposure to this type of formulation. Neophobia, a
predisposition to avoid new products, is well established in humans22. Future studies looking at repeated exposure
could capture if there are changes in participants’ perceptions of multiparticulates over time, especially in terms
of grittiness. In addition, 56% of children and 53% of adults reported a feeling of residual multiparticulates in the
mouth after sample intake. A long-lasting sensation of rough mouthfeel has also been reported in a previous study
in adults15. Discussion Most studies reported in the scientific literature have employed questionnaires accompanied by facial/
visual analogue scales to measure acceptability18, although there is no clear evidence of the validity and reliability
of participant-reported outcomes in children below 12 years27,28. In the present study, the ability of participants
to independently rate each item on the hedonic scales can be questionable, since ratings of different items were
found to be associated with each other (in both population groups). Moreover, the interpretation of the meaning
of each item could be inconsistent between participants; for instance, children often referred to the term ‘gritti-
ness’ as an attribute of taste instead of texture in their spontaneous judgement of the samples. These phenomena
can be expected, especially from untrained assessors, and a number of studies have addressed these issues in the
past29–31. p
Despite the limitations of participant-reported outcomes, these provided better discrimination between
samples than researcher observations. In addition, participant-reported outcomes offered individual evaluation
of a range of sample attributes, including taste, texture and sample volume (i.e. analytical evaluation); whereas
researcher observations can only be used to obtain a global judgement of the samples (i.e. synthetic evalua-
tion). Nevertheless, researcher observations would be preferred when the use of participant-reported outcomes
is impractical (e.g. patients who have cognitive impairment or are unable to communicate). As shown in this
trial, complimentary outcome measures may be used in combination; the ability to swallow the formulation
focused on a single administration whereas the others could provide insights into the long-term acceptability of
the formulation.h This study was conducted in healthy subjects, in a controlled environment, under supervision of the research
team; this allows no definitive conclusion of the safety and acceptability of multiparticulates in ill children or
administered by lay people in their home environment but may provide an indication of the suitability and
acceptability of multiparticulates. Results for the willingness of participants to take multiparticulates every day as
a medicine require cautious interpretation; although this outcome measure could provide an indication of future
acceptance, results were based on opinions of healthy participants after a single administration. Nevertheless,
previous research suggests that participant-reported attitudes towards taking a medication or to continue with a
therapeutic regime are good predictors of patient adherence32,33. The study should be extended to younger chil-
dren based on the positive results in terms of ability to swallow the formulation and safe administration. Methods Methods
Study design. A randomised, single-blind, patient acceptability study was conducted in children (inclusion
criteria: healthy volunteer, 4–12 years old) and adults (inclusion criteria: healthy volunteer, 18–40 years old). The study was performed in accordance with the ethical principles that have their origin in the Declaration
of Helsinki. The study in children was approved by the University of Birmingham Research Ethics Committee
(ERN_15–1028) and took place in a designated room at Thinktank Science Museum (Birmingham, United
Kingdom). Participant information leaflets were distributed to potential participants on admission to the sci-
ence museum. Parents/carers received a detailed information sheet and children received an information leaflet
designed to be appropriate for children. They were given adequate time to read and consider the information pro-
vided and to ask questions before a parent and/or legal guardian signed informed consent for study participation. The study in adults was approved by the University College London Research Ethics Committee (6062–001) and
was conducted in a designated room at the UCL School of Pharmacy. Participant information leaflets were dis-
tributed via email to potential participants, including University staff and students. All adult participants received
a detailed information sheet and provided written consent to participate in the study. p
p
p
y
Microcrystalline cellulose pellets (Cellets®, Pharmatrans Sanaq, Basel, Switzerland) were used as model pla-
cebo multiparticulates. Coated versions of the multiparticulates were produced under good manufacturing prac-
tices by Pfizer (Sandwich, United Kingdom) by coating Cellets® with a Kollicoat® Smartseal 30D polymeric
film, typically used for taste-masking. Both coated and uncoated multiparticulates were non-disintegrating in the
mouth. The sizes investigated included those at 200–355, 350–500, 500–710 and 700–1000 µm. Each participant
received three 500 mg samples of placebo multiparticulates administered on a medicine spoon with approxi-
mately 3 ml spring water, added immediately before administration (Fig. 5). Participants had free access to addi-
tional spring water as required to complete sample intake. Samples were self-administered by the participants of
the study, except for a few cases where the sample was administered to the child (with the child’s verbal consent)
by one of the investigators to avoid spillages. An interval of 5–10 minutes was maintained between samples to
minimise subject discomfort and carry over effect. j
yf
The study was divided in two phases, with four sessions per phase to ensure a balanced allocation ratio
(Table 2). Conclusionh This trial suggests that multiparticulates could be used as a suitable formulation platform for the administration
of medicines to adults and children (four-year-old and above), although palatability might be a barrier to patient
acceptability due to gritty mouthfeel. As demonstrated in this trial, a simple measure of participants ability to
swallow the sample might not be sufficient to evaluate patient acceptability, understood not only as ability but
also willingness to take the product. Despite of the vast number of participants that accepted to take the sample,
researcher observations and participant-reported outcomes showed a significant proportion of participants’ dis-
comfort and dislike. Researcher observations of facial expressions and behaviours, participants’ hedonic ratings
and spontaneous verbal judgement of the samples provided a valuable insight into patient acceptability and sam-
ple preferences. More trials are required to develop standardised methodology for palatability and acceptability
testing. SCIenTIfIC REPOrTS | (2018) 8:9210 | DOI:10.1038/s41598-018-27446-6 6 www.nature.com/scientificreports/ www.nature.com/scientificreports/ www.nature.com/scientificreports/ Figure 5. Samples of 500 mg of placebo multiparticulates dispersed in approximately 3 ml of spring water on a
medicine dosing spoon. The particle size of the multiparticulates varies, from left to right: 200–355, 350–500,
500–710 and 700–1000 μm. Figure 5. Samples of 500 mg of placebo multiparticulates dispersed in approximately 3 ml of spring water on a
medicine dosing spoon. The particle size of the multiparticulates varies, from left to right: 200–355, 350–500,
500–710 and 700–1000 μm. Methods Behaviours during/prior to
administration
Behaviours immediately
after administration
Negative facial
expressions
Refuses test sample
Spits out test sample
Pursed lips
Voices resistance
Voices disgust
Nose wrinkle
Cries/screams
Cries
Brow bulge/lower (frown)
Requires physical restraint
Vomits
Eyes squeezed shut
Table 3. Researchers’ observations 12-point tick chart for assessing negative facial expressions and behaviours
of participants prior to, during and after sample intake. Table 3. Researchers’ observations 12-point tick chart for assessing negative facial expressions and behaviours
of participants prior to, during and after sample intake. Table 3. Researchers’ observations 12-point tick chart for assessing negative facial expressions and behaviours
of participants prior to, during and after sample intake. Researcher observations. Each participant was observed by two researchers, who evaluated facial expressions
and behaviours prior to, during and post sample intake using a 12-point tick chart (Table 3). Spontaneous verbal
judgement of the samples was also recorded in researcher observation sheets. The proportion of participants who
swallowed the complete dose of multiparticulates (as opposed to those who spat out the sample or refused it)
was determined, as used in previous studies with mini-tablets4–6,9. In addition, the sum of negative facial expres-
sions (0–4) was calculated to investigate participants’ affective response and sample preferences. A value of 0 was
regarded as indicating no discomfort, 1-light discomfort, 2-moderate discomfort, 3- considerable discomfort,
4-severe discomfort. Negative facial expressions recorded during sample intake are expected to be a good indica-
tor of sample dislike, based on previous research with school-aged children34. Participant-reported outcomes. Participant-reported outcomes were collected using a paper-based structured
questionnaire that was filled in by the participants of the study immediately after sample intake. Participants
could also provide a voluntary written description of the sample, which was used to facilitate interpretation of
results. Samples were evaluated using 5-point hedonic scales for four different attributes: grittiness (explained
to participants as “you can feel ‘bits’ in the sample”), sample volume (“the amount that you had to take”), over-
all mouthfeel (“how the sample felt in your mouth”) and overall taste. Results of hedonic scales were assigned
numerical values from 1 (extremely liked) to 5 (extremely disliked) for the purposes of data analysis and the aver-
age hedonic rating to the four sample attributes was calculated. Samples with average hedonic rating of 1–3 were
deemed not aversive, thus palatable. Methods Phase 1 was dedicated to the evaluation of the effect of particle size and thus each participant received 3
samples of varying particle size in a randomised order (all samples were polymer coated for this part of the study). Phase 2 was dedicated to the evaluation of the effect of coating and thus each participant received two samples
of identical particle size, one coated and one uncoated in a randomised order, plus an additional uncoated sam-
ple. Based on power calculations assuming parametric unimodal distribution, significance (α) of 0.05 and 90%
power; a sample size of 14 would show the difference between two samples where the difference was one point
and the standard deviation was also one point on a 5-point scale. Data collection. Patient acceptability can be influenced by several factors such as palatability, swallowability
and ease of administration. Consequently, a range of outcome measures were employed to gather information
about the different factors related to acceptability. 7 SCIenTIfIC REPOrTS | (2018) 8:9210 | DOI:10.1038/s41598-018-27446-6 www.nature.com/scientificreports/ Sample
Phase 1 (size effect)
Phase 2 (coating effect)
Size (µm)
Coating
S1
S2
S3
S4
S5
S6
S7
S8
200–355
Coated
1
3
2
1
350–500
Coated
2
3
1
2
500–710
Coated
2
1
3
2
700–1000
Coated
3
1
2
1
200–355
Uncoated
2
3
350–500
Uncoated
3
1
500–710
Uncoated
1
3
700–1000
Uncoated
3
2 Table 2. Dosing schedule for the evaluation of multiparticulates. Numbers indicate the order in which samples
were administered in each of the eight sessions (S1-S8). Table 2. Dosing schedule for the evaluation of multiparticulates. Numbers indicate the order in which samples
were administered in each of the eight sessions (S1-S8). Table 2. Dosing schedule for the evaluation of multiparticulates. Numbers indicate the order in which samp
were administered in each of the eight sessions (S1-S8). were administered in each of the eight sessions (S1 S8). Behaviours during/prior to
administration
Behaviours immediately
after administration
Negative facial
expressions
Refuses test sample
Spits out test sample
Pursed lips
Voices resistance
Voices disgust
Nose wrinkle
Cries/screams
Cries
Brow bulge/lower (frown)
Requires physical restraint
Vomits
Eyes squeezed shut
Table 3. Researchers’ observations 12-point tick chart for assessing negative facial expressions and behaviours
of participants prior to, during and after sample intake. Acknowledgementsh g
The authors would like to thank all participants for their participation in this study, the NIHR Clinical Research
Network: West Midlands – Young Person’s Steering Group for their input into the study, and Thinktank
Birmingham science museum for hosting the study in children. The authors would like to acknowledge Lourdes
Contreras (formulation lead) and Gavin Wood (analytical lead) for the formulation development of coated
multiparticulates; and Debbie Kraus for statistical support. References Regist. 1–39 https://doi.org/10.1111/j.1524-4733.2009.00609.x (2009).hf 8. FDA. Guidance for Industry Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labelin
Claims. Clin. Fed. Regist. 1–39 https://doi.org/10.1111/j.1524-4733.2009.00609.x (2009).hf g
p
g
j
9. Popper, R., Rosenstock, W., Schraidt, M. & Kroll, B. J. The effect of attribute questions on overall liking ratings. Food Qual. Prefer. 15
853–858 (2004). 30. Prescott, J., Lee, S. M. & Kim, K. O. Analytic approaches to evaluation modify hedonic responses. Food Qual. Prefer. 22, 391–393 (2 30. Prescott, J., Lee, S. M. & Kim, K. O. Analytic approaches to evaluation modify hedonic responses. Food Qual. Prefer. 22, 391–393 (2011). 31. Vickers, Z. M., Christensen, C. M., Fahrenholtz, S. K. & Gengler, I. M. Effect of questionnaire design and the number of samples
d
h d
d
(
) 30. Prescott, J., Lee, S. M. & Kim, K. O. Analytic approaches to evaluation modify hedonic responses. Food Qual. Prefer. 22, 391–393 (2011). 31. Vickers, Z. M., Christensen, C. M., Fahrenholtz, S. K. & Gengler, I. M. Effect of questionnaire design and the number of samples
tasted on hedonic ratings. J. Sens. Stud. 8, 189–200 (1993).t y
pp
y
p
f
31. Vickers, Z. M., Christensen, C. M., Fahrenholtz, S. K. & Gengler, I. M. Effect of questionnaire design and the number of sam
tasted on hedonic ratings. J. Sens. Stud. 8, 189–200 (1993).t g J
(
)
2. Kreivi, H. R., Maasilta, P. & Bachour, A. Willingness score obtained after a short CPAP trial predicts CPAP use at 1 year. Sleep Breath
18, 207–213 (2014). g
32. Kreivi, H. R., Maasilta, P. & Bachour, A. Willingness score obtained after a short CPAP trial predicts CPAP use at 1 year. Sleep Breath. 18, 207–213 (2014). 3. Godin, G., Côté, J., Naccache, H., Lambert, L. D. & Trottier, S. Prediction of adherence to antiretroviral therapy: a one-yea
longitudinal study. AIDS Care 17, 493–504 (2005). g
y
4. Zeinstra, G. G., Koelen, M. A., Colindres, D., Kok, F. J. & de Graaf, C. Facial expressions in school-aged children are a good indicator
of ‘dislikes’, but not of ‘likes’. Food Qual. Prefer. 20, 620–624 (2009). g
y
34. Zeinstra, G. G., Koelen, M. A., Colindres, D., Kok, F. J. & de Graaf, C. Facial expressions in school-aged children are a good indicator
of ‘dislikes’, but not of ‘likes’. Food Qual. Prefer. 20, 620–624 (2009). Methods After completion of hedonic ratings, participants answered the following
question: “If this was a medicine, would you be willing to take it every day?”. The proportion of participants that
responded positively to this question was calculated. The total volume of water consumed for each sample was
calculated by providing free access to water in cups with a pre-measured volume (150 ml) and then measuring the
volume of water left in the cups. The proportion of participants that reported that they could still feel the bits in
their mouth after sample administration was determined. Statistical analysis. Data from researcher observations and participant-reported outcomes was treated
as categorical data; differences between population groups and association between outcome measures were
assessed by Pearson’s Chi-squared test with 95% confidence interval. The effect of formulation factors on accepta-
bility ratings (i.e. sum of facial expressions and ratings on hedonic scales) was assessed by comparing mean scores
using ANOVA techniques. Size effect was estimated by analysis of subjects in Phase 1 only, as this enables a better
within subject comparison of sizes. Coating effect estimate was limited to analysis of subjects in Phase 2 (after
exclusion of test sample 3), such that the coating effect is purely within subject. The volume of water consumed
was treated as a non-normally distributed continuous variable (based on Kolmogorov–Smirnov test) and differ-
ences between samples and between population groups were assessed by Kruskal-Wallis test. Data availability statement. The datasets generated and analysed during the current study are available
from the corresponding author on reasonable request. 8 SCIenTIfIC REPOrTS | (2018) 8:9210 | DOI:10.1038/s41598-018-27446-6 www.nature.com/scientificreports/ References & Gul, M. O. Formulation a 13. EMA. Reflection paper: Formulations of choice for the paediatric population (2006). 13. EMA. Reflection paper: Formulations of choice for the paediatric population (2006). l
ff
f f
l
bl
l
d
f . EMA. Reflection paper: Formulations of choice for the paediatric l
4. Lopez, F. L. et al. Effect of formulation variables on oral grittiness and preferences of multiparticulate formulations in adul
volunteers. Eur. J. Pharm. Sci. 92, 156–162 (2016). l
14. Lopez, F. L. et al. Effect of formulation variables on oral grittiness and preferences of mu
volunteers. Eur. J. Pharm. Sci. 92, 156–162 (2016). 15. Kimura, S., Uchida, S., Kanada, K. & Namiki, N. Effect of granule properties on rough mouth feel and palatability of orally
disintegrating tablets. Int. J. Pharm. 484, 156–162 (2015).h g
g
16. Kekitiinwa, A. et al. Acceptability of lopinavir/r pellets (minitabs), tablets and syrups in HIV-infected children. Antiviral Therapy
https://doi.org/10.3851/IMP3054 (2016). p
g
(
)
17. Kozarewicz, P. Regulatory perspectives on acceptability testing of dosage forms in children. Int. J. Pharm. 469, 245–8 (2014). 18. Ranmal, S. R. et al. Methodologies for assessing the acceptability of oral formulations among children and older adults: a systematic
review. Drug Discov. Today 0 (2018).h g
y
19. Thompson, C. A., Lombardi, D. P., Sjostedt, P. & Squires, L. A. Industry Survey on Current Practices in the Assessm
and Swallowability in the Development of Pediatric Oral Dosage Forms. Ther. Innov. Regul. Sci. 47, 542–549 (201 g
y
Thompson, C. A., Lombardi, D. P., Sjostedt, P. & Squires, L. A. Industry Survey on Current Practices in the Assessment of Palatability
nd Swallowability in the Development of Pediatric Oral Dosage Forms Ther Innov Regul Sci 47 542 549 (2013) g
y
9. Thompson, C. A., Lombardi, D. P., Sjostedt, P. & Squires, L. A. Industry Survey on Current Practices in the Assessment of Palatability pson, C. A., Lombardi, D. P., Sjostedt, P. & Squires, L. A. Industry Survey on Current Practices in the Assessment of Palatability
wallowability in the Development of Pediatric Oral Dosage Forms. Ther. Innov. Regul. Sci. 47, 542–549 (2013).h h
and Swallowability in the Development of Pediatric Oral Dosage Forms. Ther. Innov. Regul. Sci. 47, 542–549 (2013).h h
20. Squires, L. a, Lombardi, D. P., Sjostedt, P. & Thompson, C. a. References e e e ces
1. EMA. Guideline on pharmaceutical development of medicines for paediatric use. at http://www.ema.europa.eu/docs/en_GB/
document_library/Scientific_guideline/2013/07/WC500147002.pdf (2013). 1. EMA. Guideline on pharmaceutical development of medicines for paediatric use. at http://www.ema.europa.eu/docs/en_GB/
document_library/Scientific_guideline/2013/07/WC500147002.pdf (2013). yi
g
p
2. Mistry, P. & Batchelor, H. Evidence of acceptability of oral paediatric medicines: a review. J. Pharm. Pharmacol. https://d
org/10.1111/jphp.12610 (2016). yi
g
p
2. Mistry, P. & Batchelor, H. Evidence of acceptability of oral paediatric medicines: a review. J. Pharm. Pharmacol. https://doi
org/10.1111/jphp.12610 (2016). g
jp p
3. WHO. Development of paediatric medicines: points to consider in formulation (2012).h f
f
, S. A. et al. Minitablets: new modality to deliver medicines to presc h
,
y
p
g
,
(
)
5. Klingmann, V. et al. Acceptability of Uncoated Mini-Tablets in Neonates—A Randomized Controlled Trial. J. Pediatr. https://doi
org/10.1016/j.jpeds.2015.07.010 (2015). h
5. Klingmann, V. et al. Acceptability of Uncoated Mini-Tablets in Neonates—A Randomized Controlled Trial. J. Pediatr. https://doi. org/10.1016/j.jpeds.2015.07.010 (2015). g
j j
6. Klingmann, V. et al. Favorable acceptance of mini-tablets compared with syrup: A randomized controlled trial in infants and
preschool children. J. Pediatr. 163, 1728–1733 (2013). p
7. Spomer, N. et al. Acceptance of uncoated mini-tablets in young children: results from a prospective exploratory cross-over study
Arch. Dis. Child. 97, 283–6 (2012).f (
)
8. van Riet-Nales, D. A. et al. Acceptability of different oral formulations in infants and preschool children. Arch. Dis. Child. 98, 725–31
(2013). (
)
9. Kluk, A. et al. Can preschool-aged children swallow several minitablets at a time? Results from a clinical pilot study. Int. J. Pharm
486, 1–6 (2015). ,
(
)
10. Priese, F., Frisch, T. & Wolf, B. Comparison of film-coated retarded release pellets manufactured by layering technique or by bed
rotor pelletization. Pharm. Dev. Technol. 7450 (2014). i
rotor pelletization. Pharm. Dev. Technol. 7450 (2014). p
1. Roy, P. & Shahiwala, A. Multiparticulate formulation approach to pulsatile drug delivery: Current perspectives. J. Control. Release
134, 74–80 (2009).i ,
(
)
2. Lopez, F. L., Ernest, T. B., Tuleu, C. & Gul, M. O. Formulation approaches to pediatric oral drug delivery: benefits and limitations o
l f
l 2. Lopez, F. L., Ernest, T. B., Tuleu, C. & Gul, M. O. Formulation approaches to pediatric oral drug delivery: benefits and limitations o
current platforms. Expert Opin. Drug Deliv. 12, 1727–40 (2015).l 12. Lopez, F. L., Ernest, T. B., Tuleu, C. References A Systematic Literature Review on the Assessment of Palatability and
Swallowability in the Development of Oral Dosage Forms for Pediatric Patients Ther Innov Regul Sci 47 542 549 (2013) q
jh
p
y
y
Swallowability in the Development of Oral Dosage Forms for Pediatric Patients. Ther. Innov. Regul. Sci. 47, 542–549 (2013).f h
21. Clark, C. & Lawless, H. T. Limiting response alternatives in time-intensity scaling: an examination of the halo-dumping effect. Chem. Senses 19, 583–594 (1994). 22. Birch, L. L. Development of food preferences. Annu. Rev. Nutr. 41–62 (1999). 22. Birch, L. L. Development of food preferences. Annu. Rev. Nutr. 41–62 (1999). p
p
(
)
23. Batchelor, H. K., Fotaki, N. & Klein, S. Paediatric oral biopharmaceutics: Key considerations and current challenges. Adv. Drug Deliv. Rev. 73, 102–26 (2014). 24. Diamond, S. & Lavallee, D. C. Experience with a pill-swallowing enhancement aid. Clin. Pediatr. (Phila). 49, 391–3 (2010). 25. Kluk, A. & Sznitowska, M. Application properties of oral gels as media for administration of minitablets and pellets to paediatric
patients. Int. J. Pharm. 460, 228–33 (2014).h 6. Bunupuradah, T. et al. Use of taste-masking product, FLAVORx, to assist Thai children to ingest generic antiretrovirals. AIDS Res
Ther. 3, 30 (2006). h
7. Matza, L. S. et al. Pediatric Patient-Reported Outcome Instruments for Research to Support Medical Product Labeling: Report of the h
27. Matza, L. S. et al. Pediatric Patient-Reported Outcome Instruments for Research to Support Medical Product Labeling: Report of the
ISPOR PRO Good Research Practices for the Assessment of Children and Adolescents Task Force. Value Heal. 16, 461–479 (2013). h
27. Matza, L. S. et al. Pediatric Patient-Reported Outcome Instruments for Research to Support Medical Product Labeling: Report of the
ISPOR PRO Good Research Practices for the Assessment of Children and Adolescents Task Force. Value Heal. 16, 461–479 (2013). 28 FDA Guidance for Industry Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling 7. Matza, L. S. et al. Pediatric Patient Reported Outcome Instruments for Research to Support Medical Product Labeling: Report of the
ISPOR PRO Good Research Practices for the Assessment of Children and Adolescents Task Force. Value Heal. 16, 461–479 (2013)
8 FDA G id
f
I d
P i
R
d O
M
U
i
M di
l P
d
D
l
S
L b li 28. FDA. Guidance for Industry Patient-Reported Outcome Measures: Use in Medical Product
Claims. Clin. Fed. Author Contributions F.L.L. contributed in the design of data collection tools, participated in data collection for the trial in children and
adults, and drafted the manuscript. P.M. contributed in the design of data collection tools, and participated in data
collection for the trial in children and adults. H.K.B. led the trial in children, contributed in the design of data collection
tools, conceived and supervised the project, and participated in data collection for the trial in children. J.B. and A.C. supported formulation development, and conceived and supervised the project. T.B.E. and M.O. conceived and
supervised the project. C.T. led the trial in adults, contributed in the design of data collection tools, conceived and
supervised the project. All authors reviewed the manuscript. SCIenTIfIC REPOrTS | (2018) 8:9210 | DOI:10.1038/s41598-018-27446-6 9 www.nature.com/scientificreports/ Additional Information Additional Information
Supplementary information accompanies this paper at https://doi.org/10.1038/s41598-018-27446-6. SCIenTIfIC REPOrTS | (2018) 8:9210 | DOI:10.1038/s41598-018-27446-6 Supplementary information accompanies this paper at https://doi.org/10.1038/s41598-018-27446-6. Competing Interests: This work was supported by the CDT in Targeted Therapeutics and Formulation
ciences, which is funded by the EPSRC (EP/I01375X/1); and SPaeDD-UK (Accelerating Paediatric Competing Interests: This work was supported by the CDT in Targeted Therapeutics and Formulation
Sciences, which is funded by the EPSRC (EP/I01375X/1); and SPaeDD-UK (Accelerating Paediatric
Formulation Development through Smart Design and Predictive Science), an Innovate UK Formulated
Products Collaborative R&D project (Ref: 101709), which is co-funded by Innovate UK and the contributing
companies of AstraZeneca, Bristol Myers Squibb, GlaxoSmithKline, Juniper Pharma Services and Pfizer. The
authors declare no financial and/or non-financial conflict of interest other than their disclosed affiliations and
acknowledged funding. Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps an
institutional affiliations. Open Access This article is licensed under a Creative Commons Attribution 4.0 International
License, which permits use, sharing, adaptation, distribution and reproduction in any medium or
format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Cre-
ative Commons license, and indicate if changes were made. The images or other third party material in this
article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the
material. If material is not included in the article’s Creative Commons license and your intended use is not per-
mitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the
copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. SCIenTIfIC REPOrTS | (2018) 8:9210 | DOI:10.1038/s41598-018-27446-6 10
|
https://openalex.org/W2415259147
|
https://arpi.unipi.it/bitstream/11568/814909/2/DelPozzo_814909.pdf
|
English
| null |
Improved Analysis of GW150914 Using a Fully Spin-Precessing Waveform Model
|
Physical review. X
| 2,016
|
cc-by
| 15,712
|
I. INTRODUCTION right ascension and declination), the polarization angle of
the GW, the luminosity distance of the binary, and the
time of arrival of the GW at the detector (all of which are
known as extrinsic parameters). The task of extracting all
15 parameters from interferometric detector data relies on
efficient Bayesian inference algorithms and on the avail-
ability of accurate theoretical predictions of the GW signal. State-of-the-art numerical-relativity (NR) simulations [3–8]
can generate very accurate BBH waveforms over a large
region of parameter space; however, this region does not
yet include (i) binary configurations that have large
dimensionless spins (>0.5), extreme mass ratios (<1=3),
and many GW cycles (≥40–60), except for a few cases
[8–10]; nor does it include (ii) systems undergoing sig-
nificant spin-induced precession of the orbital plane. In
practice, parameter estimation requires very many wave-
form evaluations that span a large region of parameter
space, and a purely NR approach is possible if one coarsely
discretizes the intrinsic parameters, as has been done for
GW150914 [11], or constructs interpolants (surrogates)
across NR simulations [12]. However, a continuous sam-
pling of the intrinsic parameter space, even outside regions
where NR runs are available, is unfeasible. The detection of the first gravitational-wave (GW)
transient,
GW150914,
by
the
Laser
Interferometer
Gravitational-wave Observatory in 2015 [1] marked the
beginning of a new kind of astronomy, fundamentally
different from electromagnetic or particle astronomy. GW150914 was analyzed using the most accurate signal
models available at the time of observation, which were
developed under the assumption that general relativity is
the correct theory of gravity. The analysis concluded that
GW150914 was generated by the coalescence of two black
holes (BHs) of rest-frame masses 36þ5
−4M⊙and 29þ4
−4M⊙, at
a luminosity distance of 410þ160
−180 Mpc [2]. Throughout this
paper, we quote parameter estimates as the median of their
posterior probability density, together with the width of the
90% symmetric credible interval. The GW signal emitted by a binary black hole (BBH)
depends on 15 independent parameters: the BH masses and
the BH spin vectors (the intrinsic parameters); the incli-
nation and the phase of the observer in the orbital plane, the
sky location of the binary (parametrized by two angles, the The first parameter-estimation study of GW150914
[2]
used
two
such
models:
an
effective-one-body
(EOB, Refs. Analysis of GW150914 Using a Fully Spin-Precessing Waveform Model B. P. Abbott et al.* B. P. Abbott et al. (LIGO Scientific Collaboration and Virgo Collaboration) (
g
)
ne 2016; revised manuscript received 30 July 2016; published 21 October 2016) (
g
)
(Received 4 June 2016; revised manuscript received 30 July 2016; published 21 October 2016) (
g
)
(Received 4 June 2016; revised manuscript received 30 July 2016; published 21 This paper presents updated estimates of source parameters for GW150914, a binary black-hole
coalescence event detected by the Laser Interferometer Gravitational-wave Observatory (LIGO) in
2015 [Abbott et al. Phys. Rev. Lett. 116, 061102 (2016).]. Abbott et al. [Phys. Rev. Lett. 116, 241102
(2016).] presented parameter estimation of the source using a 13-dimensional, phenomenological
precessing-spin model (precessing IMRPhenom) and an 11-dimensional nonprecessing effective-one-
body (EOB) model calibrated to numerical-relativity simulations, which forces spin alignment
(nonprecessing EOBNR). Here, we present new results that include a 15-dimensional precessing-
spin waveform model (precessing EOBNR) developed within the EOB formalism. We find good
agreement with the parameters estimated previously [Abbott et al. Phys. Rev. Lett. 116, 241102
(2016).], and we quote updated component masses of 35þ5
−3 M⊙and 30þ3
−4 M⊙(where errors correspond
to 90% symmetric credible intervals). We also present slightly tighter constraints on the dimensionless
spin magnitudes of the two black holes, with a primary spin estimate < 0.65 and a secondary spin
estimate < 0.75 at 90% probability. Abbott et al. [Phys. Rev. Lett. 116, 241102 (2016).] estimated the
systematic parameter-extraction errors due to waveform-model uncertainty by combining the posterior
probability densities of precessing IMRPhenom and nonprecessing EOBNR. Here, we find that the two
precessing-spin models are in closer agreement, suggesting that these systematic errors are smaller
than previously quoted. DOI: 10.1103/PhysRevX.6.041014 Published by the American Physical Society under the terms of
the Creative Commons Attribution 3.0 License. Further distri-
bution of this work must maintain attribution to the author(s) and
the published article’s title, journal citation, and DOI. *Full author list given at the end of the article. PHYSICAL REVIEW X
6, 041014 (2016) PHYSICAL REVIEW X
6, 041014 (2016) Subject Areas: Astrophysics, Gravitation Published by the American Physical Society *Full author list given at the end of the article.
Published by the American Physical Society under the terms of
the Creative Commons Attribution 3.0 License. Further distri-
bution of this work must maintain attribution to the author(s) and
the published article’s title, journal citation, and DOI. DOI: 10.1103/PhysRevX.6.041014 II. MODELING ORBITAL PRECESSION
IN BBH WAVEFORM MODELS effects governed by four effective spin parameters [16]. Here, we present updated parameter estimates using a fully
spin-precessing EOB model [17,18], which is parametrized
by the full set of BBH properties listed above, including all
six BH-spin degrees of freedom, and which reflects addi-
tional physical effects described in Sec. II. The inclusion of
these effects motivates us to repeat the Bayesian analysis of
GW150914 with precessing EOB waveforms. This model
was not used in Ref. [2] because it requires costly time-
domain integration for each set of BBH parameters; thus,
not enough Monte Carlo samples had been collected by the
time the study was finalized [19]. effects governed by four effective spin parameters [16]. Here, we present updated parameter estimates using a fully
spin-precessing EOB model [17,18], which is parametrized
by the full set of BBH properties listed above, including all
six BH-spin degrees of freedom, and which reflects addi-
tional physical effects described in Sec. II. The inclusion of
these effects motivates us to repeat the Bayesian analysis of
GW150914 with precessing EOB waveforms. This model
was not used in Ref. [2] because it requires costly time-
domain integration for each set of BBH parameters; thus,
not enough Monte Carlo samples had been collected by the
time the study was finalized [19]. Astrophysical stellar-mass BHs are known to possess
significant intrinsic spins, which can engender large effects
in the late phase of BBH coalescences: they affect the
evolution of orbital frequency, and (if the BH spins are not
aligned with the orbital angular momentum) they induce
the precession of the orbital plane, modulating the funda-
mental chirping structure of emitted GWs in a manner
dependent on the relative angular geometry of binary and
observatory [20]. While measuring BH spins is interesting
in its own right, the degree of their alignment and the
resulting degree of precession hold precious clues to the
astrophysical origin of stellar-mass BBHs [21]: Aligned
spins suggest that the two BHs were born from an
undisturbed binary star in which both components succes-
sively collapsed to BHs; nonaligned spins point to an origin
from capture events and three-body interactions in dense
stellar environments. I. INTRODUCTION [13,14]) model that restricts spins to be
aligned with the orbital angular momentum [15], and a
phenomenological model that includes spin-precession 041014-1 Published by the American Physical Society 2160-3308=16=6(4)=041014(19) PHYS. REV. X 6, 041014 (2016) B. P. ABBOTT et al. II. MODELING ORBITAL PRECESSION
IN BBH WAVEFORM MODELS [2] were likely
increased by the fact that the nonprecessing model would
be biased by what little precession may be present in the
signal. Clearly, the accurate modeling of BH-spin effects is
crucial to BBH parameter-estimation studies. Now, even
state-of-the-art semianalytical waveform models still rely
on a set of approximations that necessarily limit their
accuracy. These include finite post-Newtonian (PN) order,
calibration to a limited number of NR simulations, rotation
to precessing frames, and more. Thus, being able to
compare parameter estimates performed with different
waveform models, derived under different assumptions
and approximations (e.g., in time- vs frequency-domain
formulations), becomes desirable to assess the systematic
biases due to waveform mismodeling. While observing
consistent results does not guarantee the absence of
systematic errors (after all, multiple models could be wrong
in the same way), the fact that we do not observe
inconsistencies does increase our confidence in the models. g
p
g
Because precessing-EOB waveforms are so computa-
tionally expensive to generate, we cannot match the number
of Monte Carlo samples used in Ref. [2]. Thus, we carry out
a careful statistical analysis to assess the errors of our
summary statistics (posterior medians and credible inter-
vals) due to the finite number of samples. We apply the
same analysis to the precessing phenomenological and
nonprecessing EOB models, and to their combinations. Although finite-sample errors are a factor of a few larger for
the precessing EOB model than for the other two, they
remain much smaller than the credible intervals, so none of
our conclusions is affected. Last, as a further test of the
accuracy and consistency of the two precessing models, we
use
them
to
estimate
the
known
parameters
of
a
GW150914-like NR waveform injected into LIGO data. The resulting posteriors are similar to those found for
GW150914. Such a comparison was performed in the original
parameter-estimation study of GW150914 [2], showing
consistency between the precessing phenomenological
model and the aligned-spin EOBNR model. This result
matched the finding that the BH spins were approximately
aligned in GW150914, or that precession effects were too
weak to be detected, because of the small number of GW
cycles and of the (putative) face-on/face-off presentation of
the binary. Nevertheless, it may be argued that the con-
clusion of consistency remained suspect because only one
model in the analysis carried information about the effects
of precession; conversely, the estimates of mismodeling
systematic errors performed in Ref. II. MODELING ORBITAL PRECESSION
IN BBH WAVEFORM MODELS The main result of our analysis is that the two
precessing models (phenomenological and EOB) are
broadly consistent, showing largely overlapping 90%
credible intervals for all measured binary parameters,
more so than the precessing phenomenological and non-
precessing EOB models compared in Ref. [2]. In that
study, the parameter estimates obtained with those two
models were combined with equal weights to provide the
fiducial values quoted in Ref. [1], and they were differ-
enced to characterize systematic errors due to waveform
mismodeling. Because the two precessing models yield
closer results, we are now able to report smaller combined
credible intervals, as well as smaller estimated systematic
errors. Nevertheless, the combined medians cited as
fiducial estimates in Ref. [1] change only slightly. In
addition, we find that some of the intrinsic parameters that
affect BBH evolution, such as the in-plane combination of
BH spins that governs precession, are constrained better
using the precessing EOB model. Clearly, the accurate modeling of BH-spin effects is
crucial to BBH parameter-estimation studies. Now, even
state-of-the-art semianalytical waveform models still rely
on a set of approximations that necessarily limit their
accuracy. These include finite post-Newtonian (PN) order,
calibration to a limited number of NR simulations, rotation
to precessing frames, and more. Thus, being able to
compare parameter estimates performed with different
waveform models, derived under different assumptions
and approximations (e.g., in time- vs frequency-domain
formulations), becomes desirable to assess the systematic
biases due to waveform mismodeling. While observing
consistent results does not guarantee the absence of
systematic errors (after all, multiple models could be wrong
in the same way), the fact that we do not observe
inconsistencies does increase our confidence in the models. Such a comparison was performed in the original
parameter-estimation study of GW150914 [2], showing
consistency between the precessing phenomenological
model and the aligned-spin EOBNR model. This result
matched the finding that the BH spins were approximately
aligned in GW150914, or that precession effects were too
weak to be detected, because of the small number of GW
cycles and of the (putative) face-on/face-off presentation of
the binary. Nevertheless, it may be argued that the con-
clusion of consistency remained suspect because only one
model in the analysis carried information about the effects
of precession; conversely, the estimates of mismodeling
systematic errors performed in Ref. II. MODELING ORBITAL PRECESSION
IN BBH WAVEFORM MODELS Thus, the construction of a precessing EOB waveform
consists of the following steps: (i) Compute orbital dynam-
ics numerically, by solving Hamilton’s equation for the
EOB Hamiltonian, subject to energy loss, up until the light-
ring (or photon-orbit) crossing; (ii) generate inspiral-plunge
waveforms in the precessing frame as if the system were
not precessing [15]; (iii) rotate the waveforms to the inertial
frame aligned with the direction of the remnant spin;
(iv) generate the ringdown signal, and connect it smoothly
to the inspiral-plunge signal; (v) rotate the waveforms to the
inertial frame of the observer. The fundamental idea of EOB models consists in mapping
the conservative dynamics of a binary to that of a spinning
particle that moves in a deformed Kerr spacetime [13,14,
23–28], where the magnitude of the deformation is propor-
tional to the mass ratio of the binary. This mapping can be
seen as a resummation of PN formulas [29] with the aim of
extending their validity to the strong-field regime. As for
dissipative effects, EOB models equate the loss of energy to
the GW luminosity, which is expressed as a sum of squared
amplitudes of the multipolar waveform modes. In the
nonprecessing limit, the inspiral-plunge waveform modes
are themselves resummations of PN expressions [30–32] and
are functionals of the orbital dynamics. The ringdown signal
is described by a linear superposition of the quasinormal
modes [33–35] of the remnant BH. A
phenomenological
precessing-spin
IMR
model
(henceforth, “precessing IMRPhenom”) was proposed in
Refs. [16,44,45]. These waveforms are generated in the
frequency domain by rotating nonprecessing phenomeno-
logical waveforms [46] from a precessing frame to the
inertial frame of the observer, according to PN formulas
that describe precession in terms of Euler angles. The
underlying nonprecessing waveforms depend on the BH
masses and on the two projections of the spins on the
Newtonian angular momentum, with the spin of the BH
formed through merger adjusted to also take into account
the effect of the in-plane spin components. The influence of
the in-plane spin components on the precession is modeled
with a single-spin parameter (a function of the two BH
spins) and also depends on the initial phase of the binary in
the orbital plane. Thus, this model only has four indepen-
dent parameters to describe the 6 spin degrees of freedom,
which is justified by the analysis of dominant spin effects
performed in Ref. [44]. II. MODELING ORBITAL PRECESSION
IN BBH WAVEFORM MODELS [2] were likely
increased by the fact that the nonprecessing model would
be biased by what little precession may be present in the
signal. This article is organized as follows. In Sec. II, we discuss
the modeling of spin effects in the BBH waveforms used in
this paper. In Sec. III, we describe our analysis. We present
our results in Sec. IV and our conclusions in Sec. V. Throughout the article, we adopt geometrized units,
with G ¼ c ¼ 1. The analysis presented in this article, which relies on two
precessing-spin waveform families, removes both limita-
tions and sets up a more robust framework to assess
systematic biases in future detections where spin effects 041014-2 IMPROVED ANALYSIS OF GW150914 USING A FULLY … PHYS. REV. X 6, 041014 (2016) μ ≡m1m2=ðm1 þ m2Þ and r is the relative BH separation. One defines a (noninertial) precessing frame whose z axis
is aligned with LNðtÞ, and whose x and y axes obey the
minimum-rotation prescription of Refs. [39,40]. In this
frame, the waveform amplitude and phase modulations
induced by precession are minimized, as pointed out in
several studies [39–43]. play a larger role. In the rest of this section, we discuss the
features and formulation of the fully precessing EOBNR
model. The reader not interested in these technical details
(and in the Bayesian-inference setup of Sec. III) may
proceed directly to Sec. IV. The precessing EOBNR model (henceforth, “precessing
EOBNR”) used here can generate inspiral-merger-ring-
down (IMR) waveforms for coalescing, quasicircular BH
binaries with mass ratio 0.01 ≤q ≡m2=m1 ≤1, dimen-
sionless BH spin magnitudes 0 ≤χ1;2 ≡jS1;2j=m2
1;2 ≤
0.99, and arbitrary BH spin orientations [22]. We denote
with m1;2 the masses of the component objects in the binary
and with S1;2 their spin vectors. Note that the model was
calibrated only to 38 nonspinning NR simulations that span
a smaller portion of the parameter space than defined
above, but it was not calibrated to any precessing NR
waveform (see below for more details). II. MODELING ORBITAL PRECESSION
IN BBH WAVEFORM MODELS EOB models can be tuned to NR by introducing
adjustable parameters at high, unknown PN orders. For
the precessing EOB model used in this work, the relevant
calibration to NR was carried out in Ref. [15] against 38
NR simulations of nonprecessing-spin systems from
Ref. [36], with mass ratios up to 1=8 and spin magnitudes
up to almost extremal for equal-mass BBHs and up to 0.5
for unequal-mass BBHs. While both precessing EOBNR and IMRPhenom models
describe spin effects, there are important differences in
how they account for precession, which is the main focus of
this paper. Furthermore, information from inspiral, merger, and
ringdown waveforms in the test-particle limit were also
included in the EOBNR model [37,38]. Prescriptions for
the onset and spectrum of ringdown for precessing BBHs
were first given in Ref. [17] and significantly improved
in Ref. [18]. (1) In precessing IMRPhenom, the precessing-frame
inspiral-plunge waveforms are strictly nonprecess-
ing waveforms, while for precessing EOBNR, some
precessional effects are included (such as spin-spin
frequency and amplitude modulations) since the
orbital dynamics that enters the nonprecessing ex-
pressions for the GW modes is fully precessing. In the model, the BH spin vectors precess according to dS1;2
dt
¼ ∂HEOB
∂S1;2
× S1;2;
ð1Þ (2) The precessing EOBNR merger-ringdown signal is
generated in the inertial frame oriented along the
total angular momentum of the remnant—the very
frame where quasinormal mode frequencies are
computed in BH perturbation theory. By contrast,
precessing
IMRPhenom
generates
the
merger-
ringdown signal directly in the precessing frame. ð1Þ when the BH spins are oriented generically, the orbital
plane precesses with respect to an inertial observer. The orientation of the orbital plane is tracked by the
Newtonian orbital angular momentum LN ≡μr × _r, where 041014-3 041014-3 B. P. ABBOTT et al. PHYS. REV. X 6, 041014 (2016) Since the generation of precessing EOBNR waveforms
[at least in the current implementation in the LIGO
Algorithm Library (LAL)] is a rather time-consuming
process (see [19]), when carrying out parameter-estimation
studies with this template family, we introduce a time-
saving approximation at the level of the likelihood function. Namely, we marginalize over the arrival time and phase of
the signal as if the waveforms contained only ð2; 2Þ
inertial-frame modes since in that case the marginalization
can be performed analytically [49]. III. BAYESIAN INFERENCE ANALYSIS For each waveform model under consideration, we
estimate the posterior probability density [51,52] for the
BBH parameters, following the prescriptions of Ref. [2]. To
wit, we use the LAL implementation of parallel-tempering
Markov chain Monte Carlo and nested sampling [49] to
sample the posterior density pðϑjmodel; dataÞ as a function
of the parameter vector ϑ: pðϑjmodel; dataÞ ∝LðdatajϑÞ × pðϑÞ:
ð2Þ ð2Þ A priori, it is not obvious that these approximations will
not impact parameter estimation for a generic BBH. However, as far as GW150914 is concerned, Ref. [2] showed
broadly consistent results between a precessing and a non-
precessing model; a fortiori, we should expect similar results
between two precessing models. Indeed, the GW150914
binary is more probable to be face-off or face-on than edge-
on with respect to the line of sight to the detector, and the
component masses are almost equal [2]: Both conditions
imply that subdominant modes play a minor role. To obtain the likelihood LðdatajϑÞ, we first generate the
GW polarizations hþðϑintrinsicÞ and h×ðϑintrinsicÞ according
to the waveform model. We then combine the polarizations
into the LIGO detector responses h1;2 by way of the
detector antenna patterns: hkðϑÞ ¼ hþðϑintrinsicÞFðþÞ
k ðϑextrinsicÞ
þ h×ðϑintrinsicÞFð×Þ
k ðϑextrinsicÞ:
ð3Þ ð3Þ þ h×ðϑintrinsicÞFð×Þ
k ðϑextrinsicÞ:
ð3Þ The nonprecessing models that underlie both approx-
imants were tested against a large catalog of NR simu-
lations [15,46,48], finding a high degree of accuracy in the
GW150914 parameter region. However, it is important to
bear in mind that these waveform models can differ from
NR outside the region in which they were calibrated, and
they do not account for all possible physical effects that are
relevant to generic BBHs, such us higher-order modes. Finally, neither of the two precessing models has been
calibrated to any precessing NR simulation. Thus, we
cannot exclude that current precessing models are affected
by systematics. References [17,18] compared the precess-
ing EOBNR model to 70 NR runs with mild precession
(with mass ratios 1 to 1=5, spin magnitudes up to 0.5,
generic spin orientations, and each about 15–20 orbital
cycles long) finding sky-location and polarization-averaged
overlaps typically above 97% without recalibration. II. MODELING ORBITAL PRECESSION
IN BBH WAVEFORM MODELS We have determined
that the impact of this approximation is negligible by
conducting a partial parameter-estimation study where we
do not marginalize over the arrival time and phase. We can
understand this physically for GW150914 because in a
nearly face-on/face-off binary, the ð2; 1Þ observer-frame
modes are significantly subdominant compared to ð2; 2Þ
modes [50]. (3) The IMRPhenom precessing-frame waveforms con-
tain only the dominant ð2; 2Þ modes [47], while
precessing EOBNR also includes ð2; 1Þ modes in
the precessing frame, although these are not cali-
brated to NR. (4) In IMRPhenom, the frequency-domain rotation of
the GW modes from the precessing frame to the
inertial frame is based on approximate formulas (i.e.,
on the stationary-phase approximation), while pre-
cessing EOBNR computes the rotations fully in the
time domain, where the formulas are straight-
forward. (5) In precessing IMRPhenom, the frequency-domain
formulas for the Euler angles that parametrize the
precession of the orbital plane with respect to a fixed
inertial frame involve several approximations: In-
plane spin components are orbit averaged; the
magnitude of the orbital angular momentum is
approximated by its 2PN nonspinning expression;
the evolution of frequency is approximated as
adiabatic; and the PN formulas that regulate the
behavior of the Euler angles at high frequencies
are partially resummed. By contrast, precessing
EOBNR defines these Euler angles on the basis
of the completely general motion of LNðtÞ; this
motion is a direct consequence of the EOB dynam-
ics, and as such, it is sensitive to the full precessional
dynamics of the six spin components. (5) In precessing IMRPhenom, the frequency-domain
formulas for the Euler angles that parametrize the
precession of the orbital plane with respect to a fixed
inertial frame involve several approximations: In-
plane spin components are orbit averaged; the
magnitude of the orbital angular momentum is
approximated by its 2PN nonspinning expression;
the evolution of frequency is approximated as
adiabatic; and the PN formulas that regulate the
behavior of the Euler angles at high frequencies
are partially resummed. By contrast, precessing
EOBNR defines these Euler angles on the basis
of the completely general motion of LNðtÞ; this
motion is a direct consequence of the EOB dynam-
ics, and as such, it is sensitive to the full precessional
dynamics of the six spin components. IV. RESULTS The first question that we address is whether parameter
estimates derived using the two precessing models (pre-
cessing IMRPhenom and precessing EOBNR) are com-
patible. In particular, we compare posterior medians and
90% credible intervals (the summary statistics used in
Ref. [2]) for the parameters tabulated in Table I of Ref. [2],
as well as additional spin parameters. The nominal values
of the medians and 5% and 95% quantiles for the two
models are listed in the “EOBNR” and “IMRPhenom”
columns of Table I and Fig. 1. However, it is unclear
a priori whether any differences are due to the models
themselves or to the imperfect sampling of the posteriors in
Markov chain Monte Carlo runs. This is a concern
especially for the precessing EOBNR results since the
slower speed of EOBNR waveform generation means that
shorter chains are available for parameter estimation. To
gain trust in our comparisons, we characterize the
Monte Carlo error of the medians and quantiles by a
bootstrap analysis, as follows. To assess whether the data are informative with regard to
a source parameter (i.e., where it updates the prior
significantly), we perform a Kolmogorov-Smirnov (KS)
test. Given an empirical distribution (in our case, the
Monte Carlo posterior samples) and a probability distri-
bution (in our case, the prior), the KS test measures the
maximum deviation between the two cumulative distribu-
tions and associates a p-value to that: For samples
generated from the probability distribution against which
the test is performed, one expects a p-value around 0.5; p-
values smaller than 0.05 indicate that the samples come
from a different probability distribution with a high level of
significance—that is, there is only a 5% (or less) chance
that the two sets of samples come from the same distri-
bution. The outcomes of our KS tests are only statements
about how much the posteriors deviate from the respective The Monte Carlo runs for the precessing IMRPhenom
model produced an equal-weight posterior sampling TABLE I. Median values of source parameters of GW150914 as estimated with the two precessing waveform models and with an
equal-weight average of posteriors (in the “Overall” column). The models are described in the text. Subscripts and superscripts indicate
the range of the symmetric 90% credible intervals. When useful, we quote 90% credible bounds. III. BAYESIAN INFERENCE ANALYSIS Finally, we compute the likelihood as the sampling dis-
tribution of the residuals [i.e., the detector data dk minus the
GW response hkðϑÞ], under the assumption that these are
distributed as Gaussian noise characterized by the power
spectral density (PSD) of nearby data [49]: LðdatajϑÞ ∝exp
−1
2
X
k¼1;2
hhkðϑÞ −dkjhkðϑÞ −dki
;
ð4Þ ð4Þ where h·j·i denotes the noise-weighted inner product [53]. The prior probability density pðϑÞ follows the choices of
Ref. [2]. In particular, we assume uniform mass priors
m1;2 ∈½10; 80M⊙, with the constraint m2 ≤m1, and uni-
form spin-amplitude priors a1;2 ¼ jS1;2j=m2
1;2 ∈½0; 1, with
spin directions distributed uniformly on the two-sphere; where h·j·i denotes the noise-weighted inner product [53]. The prior probability density pðϑÞ follows the choices of
Ref. [2]. In particular, we assume uniform mass priors
m1;2 ∈½10; 80M⊙, with the constraint m2 ≤m1, and uni-
form spin-amplitude priors a1;2 ¼ jS1;2j=m2
1;2 ∈½0; 1, with
spin directions distributed uniformly on the two-sphere; 041014-4 IMPROVED ANALYSIS OF GW150914 USING A FULLY … PHYS. REV. X 6, 041014 (2016) priors, but they do not tell us anything about the astro-
physical relevance of 90% credible intervals. and we assume that sources are distributed uniformly in
Euclidian volume, with their orbital orientation distributed
uniformly on the two-sphere. All the binary parameters that
evolve during the inspiral (such as tilt angles between the
spins and the orbital angular momentum, θLS1;2) are defined
at a reference GW frequency fref ¼ 20 Hz. Following
Ref. [2], we marginalize over the uncertainty in the
calibration of LIGO data [54]. This broadens the posteriors
but reduces calibration biases. IV. RESULTS Precessing EOBNR
Precessing IMRPhenom
Overall
Detector-frame total mass M=M⊙
71.6þ4.3
−4.1
70.9þ4.0
−3.9
71.3þ4.3
−4.1
Detector-frame chirp mass M=M⊙
30.9þ2.0
−1.9
30.6þ1.8
−1.8
30.8þ1.9
−1.8
Detector-frame primary mass m1=M⊙
38.9þ5.1
−3.7
38.5þ5.6
−3.6
38.7þ5.3
−3.7
Detector-frame secondary mass m2=M⊙
32.7þ3.6
−4.8
32.2þ3.6
−4.8
32.5þ3.7
−4.8
Detector-frame final mass Mf=M⊙
68.3þ3.8
−3.7
67.6þ3.6
−3.5
68.0þ3.8
−3.6
Source-frame total mass Msource=M⊙
65.6þ4.1
−3.8
65.0þ4.0
−3.6
65.3þ4.1
−3.7
Source-frame chirp mass Msource=M⊙
28.3þ1.8
−1.7
28.1þ1.7
−1.6
28.2þ1.8
−1.7
Source-frame primary mass msource
1
=M⊙
35.6þ4.8
−3.4
35.3þ5.2
−3.4
35.4þ5.0
−3.4
Source-frame secondary mass msource
2
=M⊙
30.0þ3.3
−4.4
29.6þ3.3
−4.3
29.8þ3.3
−4.3
Source-frame final mass Msource
f
=M⊙
62.5þ3.7
−3.4
62.0þ3.7
−3.3
62.2þ3.7
−3.4
Mass ratio q
0.84þ0.14
−0.20
0.84þ0.14
−0.20
0.84þ0.14
−0.20
Effective inspiral spin parameter χeff
−0.02þ0.14
−0.16
−0.05þ0.13
−0.15
−0.04þ0.14
−0.16
Effective precession spin parameter χp
0.28þ0.38
−0.21
0.35þ0.45
−0.27
0.31þ0.44
−0.23
Dimensionless primary spin magnitude a1
0.22þ0.43
−0.20
0.32þ0.53
−0.29
0.26þ0.52
−0.24
Dimensionless secondary spin magnitude a2
0.29þ0.52
−0.27
0.34þ0.54
−0.31
0.32þ0.54
−0.29
Final spin af
0.68þ0.05
−0.05
0.68þ0.06
−0.06
0.68þ0.05
−0.06
Luminosity distance DL=Mpc
440þ160
−180
440þ150
−180
440þ160
−180
Source redshift z
0.094þ0.032
−0.037
0.093þ0.029
−0.036
0.093þ0.030
−0.036
Upper bound on primary spin magnitude a1
0.54
0.74
0.65
Upper bound on secondary spin magnitude a2
0.70
0.78
0.75
Lower bound on mass ratio q
0.69
0.68
0.68 Precessing EOBNR
Precessing IMRPhenom Precessing EOBNR
Precessing IMRPhenom
Overall 041014-5 PHYS. REV. X 6, 041014 (2016) B. P. ABBOTT et al. FIG. 1. Comparing nonprecessing EOBNR (light yellow, top), precessing IMRPhenom (light blue, middle), and precessing EOBNR
(light red, bottom) 90% credible intervals for select GW150914 source parameters. The darker intervals represent error estimates for
(from left to right) the 5%, 50%, and 95% quantiles, estimated by Bayesian bootstrapping. B. P. ABBOTT et al. PHYS. REV. X 6, 041014 (2016) FIG. 1. Comparing nonprecessing EOBNR (light yellow, top), precessing IMRPhenom (light blue, middle), and precessing EOBNR
(light red, bottom) 90% credible intervals for select GW150914 source parameters. The darker intervals represent error estimates for
(from left to right) the 5%, 50%, and 95% quantiles, estimated by Bayesian bootstrapping. symmetric interquantile interval across the 1000 realiza-
tions. For completeness, we apply the same analysis to the
45 000 samples of the nonprecessing EOBNR that were
employed in Ref. [2]. IV. RESULTS Lighter colors represent the 90%
credible intervals. FIG. 2. Posterior probability densities for the source-frame
component masses msource
1
and msource
2
, where msource
2
≤msource
1
. We show one-dimensional histograms for precessing EOBNR
(red) and precessing IMRPhenom (blue); the dashed vertical lines
mark the 90% credible intervals. The two-dimensional density
plot shows 50% and 90% credible regions plotted over a color-
coded posterior density function. Combined estimates.—To account for waveform-mis-
modeling errors in its fiducial parameter estimates, Ref. [2]
cited quantiles for combined posteriors obtained by aver-
aging the posteriors for its two models (in Bayesian terms,
this corresponds to assuming that the observed GW signal
could have come from either model with equal posterior
probability). We repeat the same procedure for the two
precessing models, and we show the resulting estimates in
the column “Overall” of Table I. Quantiles are more
uncertain for the precessing combination because of the
larger
finite-sampling
error
of
precessing
EOBNR. Nevertheless, 90% credible intervals are slightly tighter
than cited in Ref. [2]. In the Appendix, we provide a
graphical representation of the combined estimates. Posterior histograms: Spin directions.—Figure 4 repro-
duces the disk plot of Ref. [2] for precessing EOBNR. In
this plot, the three-dimensional histograms of the dimen-
sionless spin vectors S1;2=m2
1;2 are projected onto a plane
perpendicular to the orbital plane; the bins are designed so
that each contains the same prior probability mass (i.e.,
histogramming the prior would result in a uniform shad-
ing). It is apparent that the data disfavor large spins aligned
or antialigned with the orbital angular momentum, con-
sistently with precessing IMRPhenom results. Because
precessing EOBNR favors smaller values of the dimen-
sionless spin magnitudes, the plot is darker towards its g p
p
Posterior histograms: Masses and spin magnitudes.—
We now discuss in some detail the salient features of
parameter posteriors. In Figs. 2–6, we show the one-
dimensional marginalized posteriors for selected pairs of
parameters and 90% credible intervals (the dashed lines), as
obtained for the two precessing models, as well as the two-
dimensional probability density plots for the precessing
EOBNR model. In Fig. 2, we show the posteriors for the
source-frame BH masses m1;2: These are measured fairly
well, with statistical uncertainties around 10%. In Fig. IV. RESULTS consisting of 27 000 approximately independent samples,
obtained by downsampling the original MCMC run by a
factor equal to the largest autocorrelation length measured
for the parameters of interest (those of Table I). We generate
1000 Bayesian-bootstrap weighted resamplings [55] of the
equal-weight population [56], and for each, we compute
the weighted medians and quantiles. We characterize the
Monte Carlo error of these summary statistics as the 90% The Monte Carlo runs for the precessing EOBNR model
produced a sampling of 2700 approximately independent
samples, obtained by selecting every 1100th sample in the
original MCMC run. Again, we generate 1000 Bayesian- 041014-6 IMPROVED ANALYSIS OF GW150914 USING A FULLY … PHYS. REV. X 6, 041014 (2016) FIG. 2. Posterior probability densities for the source-frame
component masses msource
1
and msource
2
, where msource
2
≤msource
1
. We show one-dimensional histograms for precessing EOBNR
(red) and precessing IMRPhenom (blue); the dashed vertical lines
mark the 90% credible intervals. The two-dimensional density
plot shows 50% and 90% credible regions plotted over a color-
coded posterior density function. bootstrap resamplings, compute summary statistics on
each, and measure their variation. However, to improve
the representativeness of this analysis given the smaller
number of samples in play, we use nine additional equal-
weight populations, obtained by selecting every (1100 þ i)
th sample in the original MCMC run, for i ¼ 1; …; 9. For
each of the 1000 Bayesian-bootstrap resamplings, we first
choose randomly among the ten equal-weight populations. bootstrap resamplings, compute summary statistics on
each, and measure their variation. However, to improve
the representativeness of this analysis given the smaller
number of samples in play, we use nine additional equal-
weight populations, obtained by selecting every (1100 þ i)
th sample in the original MCMC run, for i ¼ 1; …; 9. For
each of the 1000 Bayesian-bootstrap resamplings, we first
choose randomly among the ten equal-weight populations. Monte Carlo errors are expected to shrink as the inverse
square root of the number of samples; this is indeed what
we observe, with precessing EOBNR finite-sample errors
about ð27 000=2700Þ1=2 ≈3 times larger than for precess-
ing IMRPhenom. Table I and Fig. 1 present the results of
this study for several key physical parameters of the source
of GW150914. With darker colors, we display the finite-
sample error estimates on the position of the medians and
5% and 95% quantiles. IV. RESULTS 3,
we show the posteriors for the dimensionless spin magni-
tudes a1;2: The bound on a1 is about 20% more stringent for
precessing EOBNR. This is true even if we account for the
larger
finite-sampling
uncertainty
in
the
precessing
EOBNR quantiles (see Table I). The final spin presented
in Table I and Fig. 1 was obtained, including the con-
tribution from the in-plane spin components to the final
spin [57]; previous publications [1,2] just use the contri-
bution from the aligned components of the spins, which
remains sufficient for the final mass computation. Just
using the aligned components does not change the pre-
cessing EOBNR result but gives a precessing IMRPhenom
result of 0.66þ0.04
−0.06. FIG. 3. Posterior probability densities for the dimensionless
spin magnitudes. (See Fig. 2 for details.) FIG. 3. Posterior probability densities for the dimensionless
spin magnitudes. (See Fig. 2 for details.) 041014-7 041014-7 PHYS. REV. X 6, 041014 (2016) B. P. ABBOTT et al. FIG. 4. Posterior probability density of BH spin directions,
plotted as in Fig. 5 of Ref. [2]. where Si⊥is the component of the spin perpendicular
to the orbital angular momentum LN, M is the total
observed mass, B1 ¼ 2 þ 3q=2 and B2 ¼ 2 þ 3=ð2qÞ,
and i ¼ f1; 2g. f
g
While χeff combines the projections of the BH spins onto
the orbital angular momentum, χp depends on their in-plane
components and thus relates to precessional effects. Both
models have credible intervals for χeff that contain the value
0 and deviate from the prior significantly. The data provide
little information about precession but show a slightly
stronger preference for lower values of χp than expressed
by our priors; the deviation is more pronounced for
precessing EOBNR. The 90% credible intervals contain
the value 0 and extend up to about 0.7 and 0.8 for
precessing EOBNR and precessing IMRPhenom, respec-
tively. Thus, precessing EOBNR provides a tighter
upper bound. FIG. 4. Posterior probability density of BH spin directions,
plotted as in Fig. 5 of Ref. [2]. Posterior histograms: Other spin angles.—To explore
other possible differences between the two precessing
models, we now consider spin parameters that were not
reported in Ref. [2]. In particular, we compute posteriors for
θ12, the opening angle between the spin vectors, and ϕ12,
the opening angle between the in-plane projections of the
spins. IV. RESULTS We use a new LAL infrastructure [61,62] to inject spline-
interpolated and tapered NR waveforms into detector data;
spins are defined with respect to the orbital angular
momentum at a reference frequency of 20 Hz. All higher
harmonics of the GW signal are included up to the l ¼ 8
multipole. At the inclinations used in this study, the impact
of modes with l > 2 is small but merits further study; a
detailed analysis will be presented in a forthcoming paper. We restrict this investigation to a NR waveform that was
computed by the SXS Collaboration using the SpEC [63]
code and is available in the public waveform catalogue [64] p
We show results for the run with MaP inclination for the
source-frame component masses and effective spins in the
left and right panels of Fig. 8. The precessing EOBNR and
precessing IMRPhenom models show good agreement in
the masses and effective precession spin χp. The posterior
PDFs obtained for the effective aligned spin χeff are slightly
offset. All injected values are found within the 90%
credible regions. Results for the inclination chosen at the
upper bound of the 90% credible interval of the marginal
PDF of the inclination are qualitatively similar to the MaP
results, except for the PDF of the effective precession spin,
which peaks around χp ∼0.4, noticeably above the injected
value but still well inside the 90% credible interval. -0.2
-0.1
0.0
0.1
0.2
DL/M h+
0
500
1000
1500
2000
(t − r*) / M
-0.2
-0.1
0.0
0.1
DL/M h×
numerical relativity
precessing EOBNR
2100
2150
2200
2250
(t − r*) / M
FIG. 7. A visual comparison of the precessing EOBNR model with NR GW polarizations computed by the SXS Collaboration at
(approximately) the GW150914 MaP parameters. The intrinsic parameters of the NR waveform are q ¼ 0.81, a1 ¼ 0.34, a2 ¼ 0.67. The inclination is ι ¼ 2.856 rad. The alignment of the precessing EOBNR waveform is obtained from the sky- and polarization-
averaged overlap with the NR waveform. For more details on the alignment procedure, see Ref. [18]. -0.2
-0.1
0.0
0.1
0.2
DL/M h+
0
500
1000
1500
2000
(t − r*) / M
-0.2
-0.1
0.0
0.1
DL/M h×
numerical relativity
precessing EOBNR 2100
2150
2200
2250
(t − r*) / M FIG. 7. IV. RESULTS Comparison with numerical relativity.—The precessing
EOBNR waveform model has been tested against NR
waveforms using simulations from the SXS catalog
[17,18,36]. We can provide a targeted cross-check on the
accuracy of precessing EOBNR near GW150914 by
performing parameter estimation runs on mock NR signals
injected into LIGO data. This test is complementary to an
ongoing study of the same nature, which, however, does not
employ the precessing EOBNR model used in this paper. We use a new LAL infrastructure [61,62] to inject spline-
interpolated and tapered NR waveforms into detector data;
spins are defined with respect to the orbital angular
momentum at a reference frequency of 20 Hz. All higher
harmonics of the GW signal are included up to the l ¼ 8
multipole. At the inclinations used in this study, the impact
of modes with l > 2 is small but merits further study; a
detailed analysis will be presented in a forthcoming paper. We restrict this investigation to a NR waveform that was
computed by the SXS Collaboration using the SpEC [63]
code and is available in the public waveform catalogue [64] Spin evolution.—All the source parameters discussed
above are measured at a reference frequency of 20 Hz. Exploiting the capability of precessing EOBNR of evolving
the BH spin vectors in the time domain, we may address the
question of estimating values for the spin parameters at the
time of the merger. To do so, we randomly sample 1000
distinct configurations from the precessing EOBNR pos-
teriors, and we evolve them to the maximum EOB orbital
frequency (a proxy for the merger in the model). We then
produce histograms of the evolved values of χeff and χp. We
find little if any change between 20 Hz and the merger. Indeed, a KS test suggests that the original and evolved
distributions are very consistent, with p-values close to 1. y
,
p
Comparison with numerical relativity.—The precessing
EOBNR waveform model has been tested against NR
waveforms using simulations from the SXS catalog
[17,18,36]. We can provide a targeted cross-check on the
accuracy of precessing EOBNR near GW150914 by
performing parameter estimation runs on mock NR signals
injected into LIGO data. This test is complementary to an
ongoing study of the same nature, which, however, does not
employ the precessing EOBNR model used in this paper. IV. RESULTS suggest that the data provide information about θ12 and ϕ12
beyond the prior, we note that the 90% credible intervals for
both of these parameters cover approximately 90% of their
valid ranges and are indistinguishable for each wave-
form model. suggest that the data provide information about θ12 and ϕ12
beyond the prior, we note that the 90% credible intervals for
both of these parameters cover approximately 90% of their
valid ranges and are indistinguishable for each wave-
form model. g
We can freely choose the angle between the line of sight
and the angular momentum of the binary for mock NR
signals. Since there is some uncertainty in the binary’s
inclination, we perform one run near maximum a posteriori
probability inclination, ι ¼ 2.856 rad (163.6°), and a sec-
ond one at the upper bound of the 90% credible interval of
the marginal probability density function (PDF) of the
inclination, ι ¼ 1.2 rad (68.8°). In Fig. 7, we show the two
GW polarizations for the NR waveform and the precessing
EOBNR model. The spin magnitudes and the mass ratio
were fixed to the NR values. The directions of spins are
defined to be the same at the initial time: Tilt angles are
18.8°,149.4°, and the azimuthal angles, defined with respect
to the initial separation vector, are 30.9°,38.7° for the
primary and secondary BHs, respectively. To quantify
the agreement between those waveforms, we compute
overlaps averaged over the GW polarization and source
sky location, which takes into account the uncertainty in
those parameters. The polarization-sky-averaged overlap
for MaP inclination is 0.997, and for ι ¼ 1.2 rad (68.8°),
overlap is 0.993. Spin evolution.—All the source parameters discussed
above are measured at a reference frequency of 20 Hz. Exploiting the capability of precessing EOBNR of evolving
the BH spin vectors in the time domain, we may address the
question of estimating values for the spin parameters at the
time of the merger. To do so, we randomly sample 1000
distinct configurations from the precessing EOBNR pos-
teriors, and we evolve them to the maximum EOB orbital
frequency (a proxy for the merger in the model). We then
produce histograms of the evolved values of χeff and χp. We
find little if any change between 20 Hz and the merger. Indeed, a KS test suggests that the original and evolved
distributions are very consistent, with p-values close to 1. IV. RESULTS The prior on cos θ12 is uniform in ½−1; 1, while the
prior on ϕ12 is uniform in ½0; 2π. We show these posteriors
in Fig. 6. The θ12 posteriors deviate appreciably from the
prior and are rather similar. By contrast, comparing the
opening angle between spin projections onto the orbital
plane, ϕ12, we find that the precessing EOBNR posterior
deviates significantly from the prior (with KS p-value
∈½0.0077; 0.075), while the precessing IMRPhenom pos-
terior does not (with KS p-value ∈½0.30; 0.60). This result
is as it should be since in precessing IMRPhenom binaries
with identical projection of the total spin on the orbital
plane have identical waveforms. Although the KS p-values center than its counterpart in Ref. [2]. In agreement with
that paper, our analysis does not support strong statements
on the orientation of the BH spins with respect to the orbital
angular momentum. The spin opening angles (the tilts),
defined by cosðθLS1;2Þ ¼ ðS1;2 · ˆLNÞ=jS1;2j, are distributed
broadly. However, the KS test described at the end of
Sec. III does indicate some deviation between priors and
posteriors, with p-values much smaller than 0.05 for
cosðθLS1Þ and cosðθLS2Þ. Posterior histograms: Effective spin parameters.—In
Fig. 5, we show the posteriors of the effective spin
combinations χeff [23,58–60] and χp [44] defined by χeff ¼ c
G
S1
m1
þ S2
m2
·
ˆLN
M ;
ð5Þ ð5Þ χp ¼
c
B1Gm2
1
maxðB1S1⊥; B2S2⊥Þ;
ð6Þ ð6Þ FIG. 6. Posterior probability densities of the opening angle
between the two spins, θ12, and the angle between the in-plane
projections of the spins, ϕ12. (See Fig. 2 for details.) FIG. 5. Posterior probability densities of the effective spin and
perpendicular effective spin. (See Fig. 2 for details.) FIG. 6. Posterior probability densities of the opening angle
between the two spins, θ12, and the angle between the in-plane
projections of the spins, ϕ12. (See Fig. 2 for details.) FIG. 5. Posterior probability densities of the effective spin and
perpendicular effective spin. (See Fig. 2 for details.) 041014-8 041014-8 IMPROVED ANALYSIS OF GW150914 USING A FULLY … PHYS. REV. X 6, 041014 (2016) as SXS:BBH:0308. The intrinsic parameters of the NR
waveform q ¼ 0.81, a1 ¼ 0.34, and a2 ¼ 0.67 are con-
sistent with the results obtained in Ref. [2], and this
waveform agrees well with the detector data. V. CONCLUSIONS the most accurate and most precise parameter estimate
possible. In particular, binaries that have larger mass
asymmetry, that are observed for a longer time, and that
are more edge-on than GW150914 will display stronger
spin-precession effects. We presented an updated analysis of GW150914 with
mass estimates of 35þ5
−3 M⊙and 30þ3
−4 M⊙, and we refined
parameter estimates using a generalized, fully precessing
waveform model that depends on all 15 independent
parameters of a coalescing binary in circular orbit. We
find this analysis to be broadly consistent with the results in
Ref. [2]. By using the difference between two precessing
waveform models as a proxy for systematic errors due to
waveform uncertainty, we can compute a more accurate
systematic error than what was possible in Ref. [2]. By
looking at differences in 5% and 95% quantiles between
different waveform models in Fig. 1, one can observe, on
average, more consistent values when the two precessing
models are compared. In addition, this analysis provides an
estimate of the systematic error on precessing spin param-
eters such as the effective precessing spin χp and the tilt
angles [arccosðˆS1;2 · ˆLNÞ], which was not available in
Ref. [2]. We have also carefully investigated uncertainties
due to the finite numbers of samples used to recreate
continuous posterior density functions, and we quantified
their effects on quoted credible intervals. As in Ref. [2], the
statistical error due to finite signal-to-noise ratio dominates
the parameter-estimation error. IV. RESULTS A visual comparison of the precessing EOBNR model with NR GW polarizations computed by the SXS Collaboration at
(approximately) the GW150914 MaP parameters. The intrinsic parameters of the NR waveform are q ¼ 0.81, a1 ¼ 0.34, a2 ¼ 0.67. The inclination is ι ¼ 2.856 rad. The alignment of the precessing EOBNR waveform is obtained from the sky- and polarization-
averaged overlap with the NR waveform. For more details on the alignment procedure, see Ref. [18]. 041014-9 B. P. ABBOTT et al. PHYS. REV. X 6, 041014 (2016) FIG. 8. Posterior probability densities for the source-frame component masses msource
1
and msource
2
, where msource
2
≤msource
1
(left panel)
and effective aligned χeff and effective precessing spins χp (right panel) for an eventlike NR mock signal close to MaP parameters. In the
one-dimensional marginalized distributions, we show the precessing EOBNR (red) and precessing IMRPhenom (blue) probability
densities with dashed vertical lines marking 90% credible intervals. The two-dimensional plot shows the contours of the 50% and 90%
credible regions of the precessing EOBNR over a color-coded posterior density function. The true parameter values are indicated by a
red asterisk or black dot-dashed line. FIG. 8. Posterior probability densities for the source-frame component masses msource
1
and msource
2
, where msource
2
≤msource
1
(left panel)
and effective aligned χeff and effective precessing spins χp (right panel) for an eventlike NR mock signal close to MaP parameters. In the
one-dimensional marginalized distributions, we show the precessing EOBNR (red) and precessing IMRPhenom (blue) probability
densities with dashed vertical lines marking 90% credible intervals. The two-dimensional plot shows the contours of the 50% and 90%
credible regions of the precessing EOBNR over a color-coded posterior density function. The true parameter values are indicated by a
red asterisk or black dot-dashed line. IMPROVED ANALYSIS OF GW150914 USING A FULLY … PHYS. REV. X 6, 041014 (2016) Universitats of the Govern de les Illes Balears; the National
Science Centre of Poland; the European Commission; the
Royal Society; the Scottish Funding Council; the Scottish
Universities Physics Alliance; the Hungarian Scientific
Research Fund (OTKA); the Lyon Institute of Origins
(LIO); the National Research Foundation of Korea;
Industry Canada and the Province of Ontario through
the Ministry of Economic Development and Innovation;
the Natural Science and Engineering Research Council
Canada; Canadian Institute for Advanced Research; the
Brazilian Ministry of Science, Technology, and Innovation;
Russian Foundation for Basic Research; the Leverhulme
Trust; the Research Corporation; Ministry of Science and
Technology (MOST), Taiwan; and the Kavli Foundation. The authors gratefully acknowledge the support of the NSF,
STFC, MPS, INFN, CNRS, and the State of Niedersachsen/
Germany for provision of computational resources. The authors gratefully acknowledge the support of the NSF,
STFC, MPS, INFN, CNRS, and the State of Niedersachsen/
Germany for provision of computational resources. ACKNOWLEDGMENTS The authors gratefully acknowledge the support of the
United States National Science Foundation (NSF) for the
construction and operation of the LIGO Laboratory and
Advanced LIGO, as well as the Science and Technology
Facilities Council (STFC) of the United Kingdom, the
Max-Planck
Society
(MPS),
and
the
State
of
Niedersachsen/Germany for support of the construction
of Advanced LIGO and construction and operation of the
GEO600 detector. Additional support for Advanced LIGO
was provided by the Australian Research Council. The
authors
gratefully
acknowledge
the
Italian
Istituto
Nazionale di Fisica Nucleare (INFN), the French Centre
National de la Recherche Scientifique (CNRS) and the
Foundation for Fundamental Research on Matter supported
by the Netherlands Organisation for Scientific Research,
for the construction and operation of the Virgo detector and
the creation and support of the EGO consortium. The
authors also gratefully acknowledge research support from
these agencies, as well as by the Council of Scientific and
Industrial Research of India; Department of Science
and Technology, India; Science & Engineering Research
Board (SERB), India; Ministry of Human Resource
Development,
India;
the
Spanish
Ministerio
de
Economía y Competitividad; the Conselleria d’Economia
i Competitivitat and Conselleria d’Educació; Cultura i While we do recover a tighter limit on the spin
magnitude of the most massive member of the binary that
created GW150914 (< 0.65 at 90% probability), the
recovery of the spin parameters (magnitude and tilt angles)
is too broad to hint at whether the black hole binary was
formed via stellar binary interactions or dynamical capture
[21]. This analysis on the first direct detection by LIGO will
be applied to future detections [65], with the aim of getting 041014-10 APPENDIX: CREDIBLE INTERVALS FOR THE
COMBINED POSTERIORS To compare directly with the results of Ref. [2], Fig. 9
presents the 90% credible intervals obtained with combined
nonprecessing-EOBNR and precessing-IMRPhenom mod-
els, and with combined precessing-EOBNR precessing-
IMRPhenom models. As in Fig. 1, the darker bands
visualize uncertainties due to the finite number of samples,
as estimated with the Bayesian bootstrap. FIG. 9. Comparison of parameter estimates obtained by combining the nonprecessing-EOBNR and precessing-IMRPhenom models
(as in Ref. [2]; light purple bars at the top) and by combining the precessing-EOBNR and precessing-IMRPhenom models (light green
bars at the bottom). We show 90% credible intervals for selected GW150914 source parameters. The darker intervals represent
uncertainty estimates for the 5%, 50%, and 95% quantiles (from left to right), as estimated by the Bayesian bootstrap. FIG. 9. Comparison of parameter estimates obtained by combining the nonprecessing-EOBNR and precessing-IMRPhenom models
(as in Ref. [2]; light purple bars at the top) and by combining the precessing-EOBNR and precessing-IMRPhenom models (light green
bars at the bottom). We show 90% credible intervals for selected GW150914 source parameters. The darker intervals represent
uncertainty estimates for the 5%, 50%, and 95% quantiles (from left to right), as estimated by the Bayesian bootstrap. 041014-11 041014-11 B. P. ABBOTT et al. PHYS. REV. X 6, 041014 (2016) [1] B. P. Abbott et al. (LIGO Scientific Collaboration and Virgo
Collaboration), Observation of Gravitational Waves from a
Binary Black Hole Merger, Phys. Rev. Lett. 116, 061102
(2016). Precessing Black-Hole-Binary Gravitational Waveforms,
Phys. Rev. Lett. 113, 151101 (2014). [17] Y. Pan, A. Buonanno, A. Taracchini, L. E. Kidder, A. H. Mroué, H. P. Pfeiffer, M. A. Scheel, and B. Szilgyi, Inspiral-
Merger-Ringdown Waveforms of Spinning, Precessing
Black-Hole Binaries in the Effective-One-Body Formalism,
Phys. Rev. D 89, 084006 (2014). [2] B. P. Abbott et al. (LIGO Scientific Collaboration and Virgo
Collaboration), Properties of the Binary Black Hole Merger
GW150914, Phys. Rev. Lett. 116, 241102 (2016). [18] S. Babak, A. Taracchini, and A. Buonanno (to be
published). [3] B. Brügmann, J. A. Gonzalez, M. Hannam, S. Husa, U. Sperhake, and W. Tichy, Calibration of Moving Puncture
Simulations, Phys. Rev. D 77, 024027 (2008). [19] When generating a precessing BBH waveform with mass
ratio, total mass, and spin magnitudes equal to the median
values reported in the “Overall” column of Table I, starting
from 20 Hz, we find that precessing EOBNR is a factor of
450 (3) slower than precessing IMRPhenom (nonprecessing
EOBNR). [4] R. APPENDIX: CREDIBLE INTERVALS FOR THE
COMBINED POSTERIORS O’Shaughnessy, L. London, J. Healy, and D. Shoemaker,
Precession During Merger: Strong Polarization Changes
Are Observationally Accessible Features of Strong-Field
Gravity During Binary Black Hole Merger, Phys. Rev. D 87,
044038 (2013). [5] M. A. Scheel, M. Giesler, D. A. Hemberger, G. Lovelace, K. Kuper, M. Boyle, B. Szilágyi, and L. E. Kidder, Improved
Methods for Simulating Nearly Extremal Binary Black
Holes, Classical Quantum Gravity 32, 105009 (2015). [20] J. Aasi et al. (LIGO Collaboration and Virgo Collaboration),
Parameter Estimation for Compact Binary Coalescence
Signals with the First Generation Gravitational-Wave
Detector Network, Phys. Rev. D 88, 062001 (2013). [21] B. P. Abbott et al. (LIGO Scientific Collaboration and Virgo
Collaboration), Astrophysical Implications of the Binary
Black-Hole Merger GW150914, Astrophys. J. 818, L22
(2016). [6] T. Chu, H. Fong, P. Kumar, H. P. Pfeiffer, M. Boyle, D. A. Hemberger, L. E. Kidder, M. A. Scheel, and B. Szilágyi, On
the Accuracy and Precision of Numerical Waveforms: Effect
of Waveform Extraction Methodology, arXiv:1512.06800. [22] In the LAL, as well as in technical publications, the
precessing EOBNR model that we use is called SEOBNRv3. [7] C. O. Lousto, J. Healy, and H. Nakano, Spin Flips in
Generic Black Hole Binaries, Phys. Rev. D 93, 044031
(2016). [23] T. Damour, Coalescence of Two Spinning Black Holes: An
Effective One-Body Approach, Phys. Rev. D 64, 124013
(2001). [8] B. Szilágyi, J. Blackman, A. Buonanno, A. Taracchini, H. P. Pfeiffer, M. A. Scheel, T. Chu, L. E. Kidder, and Y. Pan,
Approaching the Post-Newtonian Regime with Numerical
Relativity: A Compact-Object Binary Simulation Spanning
350 Gravitational-Wave Cycles, Phys. Rev. Lett. 115,
031102 (2015). [24] A. Buonanno, Y. Chen, and T. Damour, Transition from
Inspiral to Plunge in Precessing Binaries of Spinning Black
Holes, Phys. Rev. D 74, 104005 (2006). [25] T. Damour, P. Jaranowski, and G. Schaefer, Effective One
Body Approach to the Dynamics of Two Spinning Black
Holes with Next-to-Leading Order Spin-Orbit Coupling,
Phys. Rev. D 78, 024009 (2008). [9] P. Kumar, K. Barkett, S. Bhagwat, N. Afshari, D. A. Brown,
G. Lovelace, M. A. Scheel, and B. Szilgyi, Accuracy and
Precision of Gravitational-Wave Models of Inspiraling
Neutron Star–Black Hole Binaries with Spin: Comparison
with
Matter-Free
Numerical
Relativity
in
the
Low-
Frequency Regime, Phys. Rev. D 92, 102001 (2015). [26] E. Barausse and A. Buonanno, An Improved Effective-One-
Body Hamiltonian for Spinning Black-Hole Binaries, Phys. Rev. D 81, 084024 (2010). [10] C. O. Lousto and J. APPENDIX: CREDIBLE INTERVALS FOR THE
COMBINED POSTERIORS Healy, Flip-Flopping Binary Black
Holes, Phys. Rev. Lett. 114, 141101 (2015). [27] E. Barausse and A. Buonanno, Extending the Effective-One-
Body Hamiltonian of Black-Hole Binaries to Include Next-
to-Next-to-Leading Spin-Orbit Couplings, Phys. Rev. D 84,
104027 (2011). [11] B. P. Abbott et al. (Virgo Collaboration and LIGO Scientific
Collaboration),
Directly
Comparing
GW150914
with
Numerical Solutions of Einstein’s Equations for Binary
Black Hole Coalescence, arXiv:1606.01262. [28] T. Damour
and
A. Nagar,
New
Effective-One-Body
Description
of
Coalescing
Nonprecessing
Spinning
Black-Hole Binaries, Phys. Rev. D 90, 044018 (2014). [12] J. Blackman, S. E. Field, C. R. Galley, B. Szilgyi, M. A. Scheel, M. Tiglio, and D. A. Hemberger, Fast and Accurate
Prediction of Numerical Relativity Waveforms from Binary
Black Hole Coalescences Using Surrogate Models, Phys. Rev. Lett. 115, 121102 (2015). [29] L. Blanchet, Gravitational Radiation from Post-Newtonian
Sources and Inspiralling Compact Binaries, Living Rev. Relativ. 17, 2 (2014). [30] T. Damour and A. Nagar, Faithful Effective-One-Body
Waveforms of Small-Mass-Ratio Coalescing Black-Hole
Binaries, Phys. Rev. D 76, 064028 (2007). [13] A. Buonanno and T. Damour, Effective One-Body Approach
to General Relativistic Two-Body Dynamics, Phys. Rev. D
59, 084006 (1999). [31] T. Damour, B. R. Iyer, and A. Nagar, Improved Resumma-
tion
of
Post-Newtonian
Multipolar
Waveforms
from
Circularized Compact Binaries, Phys. Rev. D 79, 064004
(2009). [14] A. Buonanno and T. Damour, Transition from Inspiral to
Plunge in Binary Black Hole Coalescences, Phys. Rev. D
62, 064015 (2000). [32] Y. Pan, A. Buonanno, R. Fujita, E. Racine, and H. Tagoshi,
Post-Newtonian Factorized Multipolar Waveforms for
Spinning,
Non-precessing
Black-Hole
Binaries,
Phys. Rev. D 83, 064003 (2011); Phys. Rev. D 87, 109901(E)
(2013). [15] A. Taracchini et al., Effective-One-Body Model for Black-
Hole Binaries with Generic Mass Ratios and Spins, Phys. Rev. D 89, 061502 (2014). [16] M. Hannam, P. Schmidt, A. Bohé, L. Haegel, S. Husa, F. Ohme, G. Pratten, and M. Pürrer, Simple Model of Complete 041014-12 IMPROVED ANALYSIS OF GW150914 USING A FULLY … PHYS. REV. X 6, 041014 (2016) Using the LALInference Software Library, Phys. Rev. D
91, 042003 (2015). [33] C. V. Vishveshwara, Scattering of Gravitational Radiation
by a Schwarzschild Black-Hole, Nature (London) 227, 936
(1970). [50] By construction, the precessing IMRPhenom inertial-frame
polarizations hþ;× depend on the arrival time and phase
exactly as they would in a model that includes only ð2; 2Þ
inertial-frame modes. APPENDIX: CREDIBLE INTERVALS FOR THE
COMBINED POSTERIORS Thus, although precessing IMRPhe-
nom does include ð2; 1Þ inertial-frame modes, the ana-
lytical marginalization that we just discussed is exact. [34] W. H. Press, Long Wave Trains of Gravitational Waves from
a Vibrating Black Hole, Astrophys. J. 170, L105 (1971). [35] S. Chandrasekhar and S. L. Detweiler, The Quasi-Normal
Modes of the Schwarzschild Black Hole, Proc. R. Soc. A
A344, 441 (1975). [36] A. H. Mroué et al., Catalog of 174 Binary Black Hole
Simulations for Gravitational Wave Astronomy, Phys. Rev. Lett. 111, 241104 (2013). [51] T. Bayes and R. Price, An Essay Towards Solving a Problem
in the Doctrine of Chances, Phil. Trans. R. Soc. London 53,
370 (1763). [37] E. Barausse, A. Buonanno, S. A. Hughes, G. Khanna,
S.O’Sullivan, and Y. Pan, Modeling Multipolar Gravita-
tional-Wave Emission from Small Mass-Ratio Mergers,
Phys. Rev. D 85, 024046 (2012). [52] E. T. Jaynes, Probability Theory: The Logic of Science,
edited by G. Larry Bretthorst (Cambridge University Press,
Cambridge, 2003). g
[53] C. Cutler and E. E. Flanagan, Gravitational Waves from
Merging Compact Binaries: How Accurately Can One
Extract the Binary’s Parameters from the Inspiral Wave
Form?, Phys. Rev. D 49, 2658 (1994). [38] A. Taracchini, A. Buonanno, G. Khanna, and S. A. Hughes,
Small Mass Plunging into a Kerr Black Hole: Anatomy of
the Inspiral-Merger-Ringdown Waveforms, Phys. Rev. D
90, 084025 (2014). [54] B. P. Abbott et al. (LIGO Scientific Collaboration), Cali-
bration of the Advanced LIGO Detectors for the Discovery
of the Binary Black-Hole Merger GW150914, https://dcc
.ligo.org/LIGO‑P1500248/public/main. [39] A. Buonanno, Y.-b. Chen, Y. Pan, and M. Vallisneri, A
Quasi-Physical Family of Gravity-Wave Templates for
Precessing Binaries of Spinning Compact Objects: II. Application to Double-Spin Precessing Binaries, Phys. Rev. D 70, 104003 (2004); 74, 029902(E) (2006). g
g
p
[55] D. B. Rubin, The Bayesian Bootstrap, Annali di statistica 9,
130 (1981). [40] M. Boyle, R. Owen, and H. P. Pfeiffer, A Geometric
Approach to the Precession of Compact Binaries, Phys. Rev. D 84, 124011 (2011). [56] For n samples, this involves generating 1000 realizations
of weights according to the (n −1)-variate Dirichlet dis-
tribution. [57] N. K. Johnson-McDaniel et al., Determining the Final
Spin of a Binary Black Hole System Including In-Plane
Spins: Method and Checks of Accuracy, Technical Report
No. LIGO-T1600168 (LIGO Project, 2016). [41] P. Schmidt, M. Hannam, S. Husa, and P. Ajith, Tracking the
Precession of Compact Binaries from Their Gravitational-
Wave Signal, Phys. J. M. Gonzalez Castro,20,21 A. Gopakumar,99 N. A. Gordon,38 M. L. Gorodetsky,50 S. E. Gossan,1 M. Gosselin,36 R. Gouaty,8
A. Grado,100,5 C. Graef,38 P. B. Graff,64 M. Granata,66 A. Grant,38 S. Gras,12 C. Gray,39 G. Greco,57,58 A. C. Green,46
P. Groot,53 H. Grote,10 S. Grunewald,31 G. M. Guidi,57,58 X. Guo,71 A. Gupta,16 M. K. Gupta,86 K. E. Gushwa,1
E. K. Gustafson,1 R. Gustafson,101 J. J. Hacker,24 B. R. Hall,56 E. D. Hall,1 G. Hammond,38 M. Haney,99 M. M. Hanke,10
J. Hanks,39 C. Hanna,73 M. D. Hannam,91 J. Hanson,7 T. Hardwick,2 J. Harms,57,58 G. M. Harry,3 I. W. Harry,31 M. J. Hart,38
M. T. Hartman,6 C.-J. Haster,46 K. Haughian,38 J. Healy,102 A. Heidmann,60 M. C. Heintze,7 H. Heitmann,54 P. Hello,25
G. Hemming,36 M. Hendry,38 I. S. Heng,38 J. Hennig,38 J. Henry,102 A. W. Heptonstall,1 M. Heurs,10,19 S. Hild,38 D. Hoak,36
D. Hofman,66 K. Holt,7 D. E. Holz,77 P. Hopkins,91 J. Hough,38 E. A. Houston,38 E. J. Howell,52 Y. M. Hu,10 S. Huang,74
E. A. Huerta,103 D. Huet,25 B. Hughey,98 S. Husa,104 S. H. Huttner,38 T. Huynh-Dinh,7 N. Indik,10 D. R. Ingram,39 R. Inta,72 APPENDIX: CREDIBLE INTERVALS FOR THE
COMBINED POSTERIORS Brau,59 T. Briant,60 A. Brillet,54 M. Brinkmann,10
V. Brisson,25 P. Brockill,18 J. E. Broida,61 A. F. Brooks,1 D. A. Brown,37 D. D. Brown,46 N. M. Brown,12 S. Brunett,1 C. Bradaschia,
P. R. Brady,
V. B. Braginsky,
M. Branchesi,
J. E. Brau,
T. Briant,
A
V. Brisson,25 P. Brockill,18 J. E. Broida,61 A. F. Brooks,1 D. A. Brown,37 D. D. Brown,46 N. 6
6
6 C. C. Buchanan,2 A. Buikema,12 T. Bulik,62 H. J. Bulten,63,11 A. Buonanno,31,64 D. Buskulic,8 C. Buy,32 R. L. Byer,42
M. Cabero,10 L. Cadonati,65 G. Cagnoli,66,67 C. Cahillane,1 J. Calderón Bustillo,65 T. Callister,1 E. Calloni,68,5 J. B. Camp,69 K. C. Cannon,70 J. Cao,71 C. D. Capano,10 E. Capocasa,32 F. Carbognani,36 S. Caride,72 C. Casanueva Diaz,25
J. Casentini,27,15 S. Caudill,18 M. Cavaglià,23 F. Cavalier,25 R. Cavalieri,36 G. Cella,21 C. B. Cepeda,1 L. Cerboni Baiardi,57,58
20 21
27 15
73
38
74
75
32 ,
,
p
,
p
,
g
,
,
,
J. Casentini,27,15 S. Caudill,18 M. Cavaglià,23 F. Cavalier,25 R. Cavalieri,36 G. Cella,21 C. B. Cepeda,1 L. Cerboni Baiardi,57,58
G. Cerretani,20,21 E. Cesarini,27,15 S. J. Chamberlin,73 M. Chan,38 S. Chao,74 P. Charlton,75 E. Chassande-Mottin,32 J. Casentini,
S. Caudill,
M. Cavaglià,
F. Cavalier,
R. Cavalieri,
G. Cella,
C. B. Cepeda, L. Cerboni Baiardi,
G. Cerretani,20,21 E. Cesarini,27,15 S. J. Chamberlin,73 M. Chan,38 S. Chao,74 P. Charlton,75 E. Chassande-Mottin,32 J. H. Chow,22 N. Christensen,61 Q. Chu,52 S. Chua,60 S. Chung,52 G. Ciani,6 F. Clara,39 J. A. Clark,65 F. Cleva,54
E. Coccia,27,14 P.-F. Cohadon,60 A. Colla,80,30 C. G. Collette,81 L. Cominsky,82 M. Constancio Jr.,13 A. Conte,80,30 L. Conti,44 D. Cook,39 T. R. Corbitt,2 N. Cornish,33 A. Corsi,72 S. Cortese,36 C. A. Costa,13 M. W. Coughlin,61 S. B. Coughlin,83
54
41
1
65
52
7
1
72 K. Craig,38 J. D. E. Creighton,18 J. Cripe,2 S. G. Crowder,84 A. Cumming,38 L. Cunningham,38 E. Cuoco,36 T. Dal Canton,10 S. L. Danilishin,38 S. D’Antonio,15 K. Danzmann,19,10 N. S. Darman,85 A. Dasgupta,86 C. F. Da Silva Costa,6 V. Dattilo,36
I. Dave,49 M. Davier,25 G. S. Davies,38 E. J. Daw,87 R. Day,36 S. De,37 D. DeBra,42 G. Debreczeni,40 J. Degallaix,66 M. De Laurentis,68,5 S. Deléglise,60 W. Del Pozzo,46 T. Denker,10 T. Dent,10 V. Dergachev,1 R. De Rosa,68,5 R. T. DeRosa,7
R. DeSalvo,9 R. C. Devine,76 S. Dhurandhar,16 M. C. Díaz,88 L. Di Fiore,5 M. Di Giovanni,89,90 T. APPENDIX: CREDIBLE INTERVALS FOR THE
COMBINED POSTERIORS Di Girolamo,68,5
A Di Lieto 20,21 S Di Pace 80,30 I Di Palma 31,80,30 A Di Virgilio 21 V Dolique 66 F Donovan 12 K L Dooley 23 g
g
R. DeSalvo,9 R. C. Devine,76 S. Dhurandhar,16 M. C. Díaz,88 L. Di Fiore,5 M. Di Giovanni,89,90 T. Di Girolamo,68,5
A. Di Lieto,20,21 S. Di Pace,80,30 I. Di Palma,31,80,30 A. Di Virgilio,21 V. Dolique,66 F. Donovan,12 K. L. Dooley,23 S. Doravari,10 R. Douglas,38 T. P. Downes,18 M. Drago,10 R. W. P. Drever,1 J. C. Driggers,39 M. Ducrot,8 S. E. Dwyer,39
T B Ed
87 M C Ed
d
61 A Effl
7 H B E
t i
10 P Eh
1 J Ei hh l
6,1 S S Eik
b
6 W E
l
78 R. C. Essick,12 Z. Etienne,76 T. Etzel,1 M. Evans,12 T. M. Evans,7 R. Everett,73 M. Factourovich,41 V. Fafone,27,15 H. Fair,37
91
71
52
48
77
46
91
92
91 R. C. Essick,12 Z. Etienne,76 T. Etzel,1 M. Evans,12 T. M. Evans,7 R. Everett,73 M. Factourovich Q
g
y
H. Fehrmann,10 M. M. Fejer,42 E. Fenyvesi,93 I. Ferrante,20,21 E. C. Ferreira,13 F. Ferrini,36 F. Fidecaro,20,21 I. Fiori,36
32
37
66 94
38
54
80 30
21
93 J. R. Gair,95 L. Gammaitoni,34 S. G. Gaonkar,16 F. Garufi,68,5 G. Gaur,96,86 N. Gehrels,69 G. Gemme,48 P. Geng,88 E. Genin,36
5 A. Gennai,21 J. George,49 L. Gergely,97 V. Germain,8 Abhirup Ghosh,17 Archisman Ghosh,17 S. Ghosh,53,11 J. A. Giaime,2,7
K. D. Giardina,7 A. Giazotto,21 K. Gill,98 A. Glaefke,38 E. Goetz,39 R. Goetz,6 L. Gondan,93 G. González,2 J. M. Gonzalez Castro,20,21 A. Gopakumar,99 N. A. Gordon,38 M. L. Gorodetsky,50 S. E. Gossan,1 M. Gosselin,36 R. Gouaty,8
A. Grado,100,5 C. Graef,38 P. B. Graff,64 M. Granata,66 A. Grant,38 S. Gras,12 C. Gray,39 G. Greco,57,58 A. C. Green,46
P. Groot,53 H. Grote,10 S. Grunewald,31 G. M. Guidi,57,58 X. Guo,71 A. Gupta,16 M. K. Gupta,86 K. E. Gushwa,1
E. K. Gustafson,1 R. Gustafson,101 J. J. Hacker,24 B. R. Hall,56 E. D. Hall,1 G. Hammond,38 M. Haney,99 M. M. Hanke,10
J. Hanks,39 C. Hanna,73 M. D. Hannam,91 J. Hanson,7 T. Hardwick,2 J. Harms,57,58 G. M. Harry,3 I. W. Harry,31 M. J. Hart,38
M. T. Hartman,6 C.-J. Haster,46 K. Haughian,38 J. Healy,102 A. Heidmann,60 M. C. Heintze,7 H. Heitmann,54 P. Hello,25
G. Hemming,36 M. Hendry,38 I. S. Heng,38 J. Hennig,38 J. Henry,102 A. W. Heptonstall,1 M. Heurs,10,19 S. Hild,38 D. Hoak,36
D. Hofman,66 K. Holt,7 D. E. B. P. Abbott,1 R. Abbott,1 T. D. Abbott,2 M. R. Abernathy,3 F. Acernese,4,5 K. Ackley,6 C. Adams,7 T. Adams,8 P. Addesso,9
R. X. Adhikari,1 V. B. Adya,10 C. Affeldt,10 M. Agathos,11 K. Agatsuma,11 N. Aggarwal,12 O. D. Aguiar,13 L. Aiello,14,15
A. Ain,16 P. Ajith,17 B. Allen,10,18,19 A. Allocca,20,21 P. A. Altin,22 S. B. Anderson,1 W. G. Anderson,18 K. Arai,1
M. C. Araya,1 C. C. Arceneaux,23 J. S. Areeda,24 N. Arnaud,25 K. G. Arun,26 S. Ascenzi,27,15 G. Ashton,28 M. Ast,29
S. M. Aston,7 P. Astone,30 P. Aufmuth,19 C. Aulbert,10 S. Babak,31 P. Bacon,32 M. K. M. Bader,11 P. T. Baker,33
F. Baldaccini,34,35 G. Ballardin,36 S. W. Ballmer,37 J. C. Barayoga,1 S. E. Barclay,38 B. C. Barish,1 D. Barker,39 F. Barone,4,5
B. Barr,38 L. Barsotti,12 M. Barsuglia,32 D. Barta,40 J. Bartlett,39 I. Bartos,41 R. Bassiri,42 A. Basti,20,21 J. C. Batch,39
C. Baune,10 V. Bavigadda,36 M. Bazzan,43,44 M. Bejger,45 A. S. Bell,38 B. K. Berger,1 G. Bergmann,10 C. P. L. Berry,46
D. Bersanetti,47,48 A. Bertolini,11 J. Betzwieser,7 S. Bhagwat,37 R. Bhandare,49 I. A. Bilenko,50 G. Billingsley,1 J. Birch,7
R. Birney,51 O. Birnholtz,10 S. Biscans,12 A. Bisht,10,19 M. Bitossi,36 C. Biwer,37 M. A. Bizouard,25 J. K. Blackburn,1
C. D. Blair,52 D. G. Blair,52 R. M. Blair,39 S. Bloemen,53 O. Bock,10 M. Boer,54 G. Bogaert,54 C. Bogan,10 A. Bohe,31
C. Bond,46 F. Bondu,55 R. Bonnand,8 B. A. Boom,11 R. Bork,1 V. Boschi,20,21 S. Bose,56,16 Y. Bouffanais,32 A. Bozzi,36
C. Bradaschia,21 P. R. Brady,18 V. B. Braginsky,50,† M. Branchesi,57,58 J. E. Brau,59 T. Briant,60 A. Brillet,54 M. Brinkmann,10
V. Brisson,25 P. Brockill,18 J. E. Broida,61 A. F. Brooks,1 D. A. Brown,37 D. D. Brown,46 N. M. Brown,12 S. Brunett,1
C. C. Buchanan,2 A. Buikema,12 T. Bulik,62 H. J. Bulten,63,11 A. Buonanno,31,64 D. Buskulic,8 C. Buy,32 R. L. Byer,42
M. Cabero,10 L. Cadonati,65 G. Cagnoli,66,67 C. Cahillane,1 J. Calderón Bustillo,65 T. Callister,1 E. Calloni,68,5 J. B. Camp,69
K. C. Cannon,70 J. Cao,71 C. D. Capano,10 E. Capocasa,32 F. Carbognani,36 S. Caride,72 C. Casanueva Diaz,25
J. Casentini,27,15 S. Caudill,18 M. Cavaglià,23 F. Cavalier,25 R. Cavalieri,36 G. Cella,21 C. B. Cepeda,1 L. Cerboni Baiardi,57,58
G. Cerretani,20,21 E. Cesarini,27,15 S. J. Chamberlin,73 M. Chan,38 S. Chao,74 P. Charlton,75 E. Chassande-Mottin,32
B. D. Cheeseboro,76 H. Y. Chen,77 Y. Chen,78 C. Cheng,74 A. Chincarini,48 A. Chiummo,36 H. S. Cho,79 M. Cho,64
J. H. Chow,22 N. Christensen,61 Q. Chu,52 S. Chua,60 S. Chung,52 G. Ciani,6 F. Clara,39 J. A. Clark,65 F. Cleva,54
E. Coccia,27,14 P.-F. Cohadon,60 A. Colla,80,30 C. G. Collette,81 L. Cominsky,82 M. Constancio Jr.,13 A. Conte,80,30 L. Conti,44
D. Cook,39 T. R. Corbitt,2 N. Cornish,33 A. Corsi,72 S. Cortese,36 C. A. Costa,13 M. W. Coughlin,61 S. B. Coughlin,83
J.-P. Coulon,54 S. T. Countryman,41 P. Couvares,1 E. E. Cowan,65 D. M. Coward,52 M. J. Cowart,7 D. C. Coyne,1 R. Coyne,72
K. Craig,38 J. D. E. Creighton,18 J. Cripe,2 S. G. Crowder,84 A. Cumming,38 L. Cunningham,38 E. Cuoco,36 T. Dal Canton,10
S. L. Danilishin,38 S. D’Antonio,15 K. Danzmann,19,10 N. S. Darman,85 A. Dasgupta,86 C. F. Da Silva Costa,6 V. Dattilo,36
I. Dave,49 M. Davier,25 G. S. Davies,38 E. J. Daw,87 R. Day,36 S. De,37 D. DeBra,42 G. Debreczeni,40 J. Degallaix,66
M. De Laurentis,68,5 S. Deléglise,60 W. Del Pozzo,46 T. Denker,10 T. Dent,10 V. Dergachev,1 R. De Rosa,68,5 R. T. DeRosa,7
R. DeSalvo,9 R. C. Devine,76 S. Dhurandhar,16 M. C. Díaz,88 L. Di Fiore,5 M. Di Giovanni,89,90 T. Di Girolamo,68,5
A. Di Lieto,20,21 S. Di Pace,80,30 I. Di Palma,31,80,30 A. Di Virgilio,21 V. Dolique,66 F. Donovan,12 K. L. Dooley,23
S. Doravari,10 R. Douglas,38 T. P. Downes,18 M. Drago,10 R. W. P. Drever,1 J. C. Driggers,39 M. Ducrot,8 S. E. Dwyer,39
T. B. Edo,87 M. C. Edwards,61 A. Effler,7 H.-B. Eggenstein,10 P. Ehrens,1 J. Eichholz,6,1 S. S. Eikenberry,6 W. Engels,78
R. C. Essick,12 Z. Etienne,76 T. Etzel,1 M. Evans,12 T. M. Evans,7 R. Everett,73 M. Factourovich,41 V. Fafone,27,15 H. Fair,37
S Fairhurst 91 X Fan 71 Q Fang 52 S Farinon 48 B Farr 77 W M Farr 46 E Fauchon Jones 91 M Favata 92 M Fays 91 APPENDIX: CREDIBLE INTERVALS FOR THE
COMBINED POSTERIORS Rev. D 84, 024046 (2011). [42] R. O’Shaughnessy, B. Vaishnav, J. Healy, Z. Meeks, and
D. Shoemaker, Efficient Asymptotic Frame Selection for
Binary Black Hole Spacetimes Using Asymptotic Radiation,
Phys. Rev. D 84, 124002 (2011). [58] E. Racine, Analysis of Spin Precession in Binary Black
Hole Systems Including Quadrupole-Monopole Interaction,
Phys. Rev. D 78, 044021 (2008). [43] P. Schmidt, M. Hannam, and S. Husa, Towards Models of
Gravitational Waveforms from Generic Binaries: A Simple
Approximate Mapping Between Precessing and Non-
precessingInspiralSignals, Phys. Rev. D 86, 104063 (2012). [59] P. Ajith et al., Inspiral-Merger-Ringdown Waveforms for
Black-Hole Binaries with Non-precessing Spins, Phys. Rev. Lett. 106, 241101 (2011). [60] L. Santamaría, F. Ohme, P. Ajith, B. Brügmann, N. Dorband, M. Hannam, S. Husa, P. Moesta, D. Pollney, C. Reisswig, E. L. Robinson, J. Seiler, and B. Krishnan,
Matching Post-Newtonian and Numerical Relativity Wave-
forms: Systematic Errors and a New Phenomenological
Model for Non-precessing Black Hole Binaries, Phys. Rev. D 82, 064016 (2010). [44] P. Schmidt, F. Ohme, and M. Hannam, Towards Models of
Gravitational Waveforms from Generic Binaries II: Mod-
elling Precession Effects with a Single Effective Precession
Parameter, Phys. Rev. D 91, 024043 (2015). [45] In LAL, this precessing model is called IMRPhenomPv2. [46] S. Khan, S. Husa, M. Hannam, F. Ohme, M. Pürrer, X. J. Forteza, and A. Bohé, Frequency-Domain Gravitational
Waves from Nonprecessing Black-Hole Binaries. II. A
Phenomenological Model for the Advanced Detector Era,
Phys. Rev. D 93, 044007 (2016). [61] P. Schmidt and I. Harry, Numerical Relativity Injection
Infrastructure (unpublished). [62] P. Schmidt and C. Galley, Reduced-Order Spline Interpo-
lants of Numerical Relativity Waveforms (unpublished). [47] However, ð2; 1Þ modes in the inertial frame of the observer
are generated by the change of frame. [63] See http://www.black‑holes.org/SpEC.html. [64] See http://www.black‑holes.org/waveforms. [48] P. Kumar, T. Chu, H. Fong, H. P. Pfeiffer, M. Boyle, D. A. Hemberger, L. E. Kidder, M. A. Scheel, and B. Szilagyi,
Accuracy of Binary Black Hole Waveform Models for
Aligned-Spin Binaries, Phys. Rev. D 93, 104050 (2016). [65] B. P. Abbott et al. (LIGO Scientific Collaboration and
Virgo Collaboration), The Rate of Binary Black Hole
Mergers Inferred from Advanced LIGO Observations Sur-
rounding GW150914, https://dcc.ligo.org/LIGO‑P1500217/
public/main. [49] J. Veitch et al., Parameter Estimation for Compact Binaries
with
Ground-Based
Gravitational-Wave
Observations 041014-13 B. P. ABBOTT et al. PHYS. REV. X 6, 041014 (2016) C. Bradaschia,21 P. R. Brady,18 V. B. Braginsky,50,† M. Branchesi,57,58 J. E. APPENDIX: CREDIBLE INTERVALS FOR THE
COMBINED POSTERIORS Holz,77 P. Hopkins,91 J. Hough,38 E. A. Houston,38 E. J. Howell,52 Y. M. Hu,10 S. Huang,74
E. A. Huerta,103 D. Huet,25 B. Hughey,98 S. Husa,104 S. H. Huttner,38 T. Huynh-Dinh,7 N. Indik,10 D. R. Ingram,39 R. Inta,72 041014-14 041014-14 IMPROVED ANALYSIS OF GW150914 USING A FULLY … H. N. Isa,38 J.-M. Isac,60 M. Isi,1 T. Isogai,12 B. R. Iyer,17 K. Izumi,39 T. Jacqmin,60 H. Jang,79 K. Jani,65 P. Jaranowski,105
S. Jawahar,106 L. Jian,52 F. Jiménez-Forteza,104 W. W. Johnson,2 N. K. Johnson-McDaniel,17 D. I. Jones,28 R. Jones,38
R. J. G. Jonker,11 L. Ju,52 Haris K,107 C. V. Kalaghatgi,91 V. Kalogera,83 S. Kandhasamy,23 G. Kang,79 J. B. Kanner,1
S. J. Kapadia,10 S. Karki,59 K. S. Karvinen,10 M. Kasprzack,36,2 E. Katsavounidis,12 W. Katzman,7 S. Kaufer,19 T. Kaur,52
K. Kawabe,39 F. Kéfélian,54 M. S. Kehl,108 D. Keitel,104 D. B. Kelley,37 W. Kells,1 R. Kennedy,87 J. S. Key,88 F. Y. Khalili,50
I. Khan,14 S. Khan,91 Z. Khan,86 E. A. Khazanov,109 N. Kijbunchoo,39 Chi-Woong Kim,79 Chunglee Kim,79 J. Kim,110
K. Kim,111 N. Kim,42 W. Kim,112 Y.-M. Kim,110 S. J. Kimbrell,65 E. J. King,112 P. J. King,39 J. S. Kissel,39 B. Klein,83
L. Kleybolte,29 S. Klimenko,6 S. M. Koehlenbeck,10 S. Koley,11 V. Kondrashov,1 A. Kontos,12 M. Korobko,29 W. Z. Korth,1
I. Kowalska,62 D. B. Kozak,1 V. Kringel,10 A. Królak,113,114 C. Krueger,19 G. Kuehn,10 P. Kumar,108 R. Kumar,86 L. Kuo,74
A. Kutynia,113 B. D. Lackey,37 M. Landry,39 J. Lange,102 B. Lantz,42 P. D. Lasky,115 M. Laxen,7 A. Lazzarini,1 C. Lazzaro,44
P. Leaci,80,30 S. Leavey,38 E. O. Lebigot,32,71 C. H. Lee,110 H. K. Lee,111 H. M. Lee,116 K. Lee,38 A. Lenon,37
89 90
10
25
8
115
1
117
12 IMPROVED ANALYSIS OF GW150914 USING A FULLY … PHYS. REV. X 6, 041014 (2016) j
g
K. Kim,111 N. Kim,42 W. Kim,112 Y.-M. Kim,110 S. J. Kimbrell,65 E. J. King,112 P. J. King,39 L. Kleybolte,29 S. Klimenko,6 S. M. Koehlenbeck,10 S. Koley,11 V. Kondrashov,1 A. Kontos,12 M I. Kowalska,62 D. B. Kozak,1 V. Kringel,10 A. Królak,113,114 C. Krueger,19 G. Kuehn,10 P. Kumar,108 R. Kumar,86 L. Kuo,74 A. Kutynia,113 B. D. Lackey,37 M. Landry,39 J. Lange,102 B. Lantz,42 P. D. Lasky,115 M. Laxen,7 A. Lazzarini,1 C. Lazzaro,44
P. Leaci,80,30 S. Leavey,38 E. O. Lebigot,32,71 C. H. Lee,110 H. K. Lee,111 H. M. Lee,116 K. Lee,38 A. Lenon,37
M. Leonardi,89,90 J. R. Leong,10 N. Leroy,25 N. Letendre,8 Y. Levin,115 J. B. Lewis,1 T. G. F. Li,117 A. Libson,12 A. Kutynia,
B. D. Lackey,
M. Landry,
J. Lange,
B. Lantz,
P. D. Lasky,
M. Laxen, A. Lazzarini, C. Lazzaro,
P. Leaci,80,30 S. Leavey,38 E. O. Lebigot,32,71 C. H. Lee,110 H. K. Lee,111 H. M. Lee,116 K. Lee,38 A. Lenon,37
89 90
10
25
8
115
1
117
12 y
,
y,
y,
g ,
,
y,
,
,
,
P. Leaci,80,30 S. Leavey,38 E. O. Lebigot,32,71 C. H. Lee,110 H. K. Lee,111 H. M. Lee,116 K. Lee,38 A. Lenon,37 0 J. R. Leong,10 N. Leroy,25 N. Letendre,8 Y. Levin,115 J. B. Lewis,1 T. G. F. Li,117 A. Libson,1 M. Leonardi,89,90 J. R. Leong,10 N. Leroy,25 N. Letendre,8 Y. Levin,115 J. B. Lewis,1 T. G. F T. B. Littenberg,118 N. A. Lockerbie,106 A. L. Lombardi,119 L. T. London,91 J. E. Lord,37 M. Lorenzini,14,15 V. Loriette,120
7
58
10 19
102
24
19 10
10
12 8 N. A. Lockerbie,106 A. L. Lombardi,119 L. T. London,91 J. E. Lord,37 M. Lorenzini,14,15 V. Lo T. B. Littenberg,118 N. A. Lockerbie,106 A. L. Lombardi,119 L. T. London,91 J. E. Lord,37 M. L G. Losurdo,58 J. D. Lough,10,19 C. O. Lousto,102 G. Lovelace,24 H. Lück,19,10 A. P. Lundgren,10 M. Lormand,7 G. Losurdo,58 J. D. Lough,10,19 C. O. Lousto,102 G. Lovelace,24 H. Lück,19,10 A. P. Lundgren,10 R. Lynch,12
Y. Ma,52 B. Machenschalk,10 M. MacInnis,12 D. M. Macleod,2 F. Magaña-Sandoval,37 L. Magaña Zertuche,37
56
30
120
2 15
54
84
38
22 g
g
y
Y. Ma,52 B. Machenschalk,10 M. MacInnis,12 D. M. Macleod,2 F. Magaña-Sandoval,37 L. Magaña Zertuche,37 B. Machenschalk,10 M. MacInnis,12 D. M. Macleod,2 F. Magaña-Sandoval,37 L. Magaña Zertu Majorana,30 I. Maksimovic,120 V. Malvezzi,27,15 N. Man,54 V. Mandic,84 V. Mangano,38 G. L. M R. M. IMPROVED ANALYSIS OF GW150914 USING A FULLY … Magee,56 E. Majorana,30 I. Maksimovic,120 V. Malvezzi,27,15 N. Man,54 V. Mandic,84 V. M M. Manske,18 M. Mantovani,36 F. Marchesoni,121,35 F. Marion,8 S. Márka,41 Z. Márka,41 A. S. Markosyan,42 E. Maros,1
57 58
54
38
12
1
12
8
37 Martelli,57,58 L. Martellini,54 I. W. Martin,38 D. V. Martynov,12 J. N. Marx,1 K. Mason,12 A. Mas M. Masso-Reid,38 S. Mastrogiovanni,80,30 F. Matichard,12 L. Matone,41 N. Mavalvala,12 N. Mazumder,56 R. McCarthy,39 M. Masso-Reid,38 S. Mastrogiovanni,80,30 F. Matichard,12 L. Matone,41 N. Mavalvala,12 N. Mazumder,56 R. McCarthy,39
D. E. McClelland,22 S. McCormick,7 S. C. McGuire,122 G. McIntyre,1 J. McIver,1 D. J. McManus,22 T. McRae,22
S. T. McWilliams,76 D. Meacher,73 G. D. Meadors,31,10 J. Meidam,11 A. Melatos,85 G. Mendell,39 R. A. Mercer,18
E. L. Merilh,39 M. Merzougui,54 S. Meshkov,1 C. Messenger,38 C. Messick,73 R. Metzdorff,60 P. M. Meyers,84
F. Mezzani,30,80 H. Miao,46 C. Michel,66 H. Middleton,46 E. E. Mikhailov,123 L. Milano,68,5 A. L. Miller,6,80,30 A. Miller,83
B B Miller 83 J Miller 12 M Millhouse 33 Y Minenkov 15 J Ming 31 S Mirshekari 124 C Mishra 17 S Mitra 16 ,
,
,
y ,
,
,
,
S. T. McWilliams,76 D. Meacher,73 G. D. Meadors,31,10 J. Meidam,11 A. Melatos,85 G. Mendell,39 R. A. Mercer,18
E. L. Merilh,39 M. Merzougui,54 S. Meshkov,1 C. Messenger,38 C. Messick,73 R. Metzdorff,60 P. M. Meyers,84
F. Mezzani,30,80 H. Miao,46 C. Michel,66 H. Middleton,46 E. E. Mikhailov,123 L. Milano,68,5 A. L. Miller,6,80,30 A. Miller,83
B. B. Miller,83 J. Miller,12 M. Millhouse,33 Y. Minenkov,15 J. Ming,31 S. Mirshekari,124 C. Mishra,17 S. Mitra,16 S. T. McWilliams,76 D. Meacher,73 G. D. Meadors,31,10 J. Meidam,11 A. Melatos,85 G. Mendell,39 R. A. Mercer,18
E. L. Merilh,39 M. Merzougui,54 S. Meshkov,1 C. Messenger,38 C. Messick,73 R. Metzdorff,60 P. M. Meyers,84
i 30 80
i
46 C
i h l 66
iddl
46
ikh il
123
il
68 5 A
ill
6 80 30 A
ill
83 E. L. Merilh,39 M. Merzougui,54 S. Meshkov,1 C. Messenger,38 C. Messick,73 R. Metzdorff,60 P. M. Meyers,84
F. Mezzani,30,80 H. Miao,46 C. Michel,66 H. Middleton,46 E. E. Mikhailov,123 L. Milano,68,5 A. L. Miller,6,80,30 A. Miller,83
B B Miller 83 J Miller 12 M Millho se 33 Y Minenko
15 J Ming 31 S Mirshekari 124 C Mishra 17 S Mitra 16 E. L. Merilh,
M. Merzougui,
S. Meshkov, C. Messenger,
C. Messick,
R. Metzdorff,
P. M. Meyers,
F. Mezzani,30,80 H. Miao,46 C. Michel,66 H. Middleton,46 E. E. Mikhailov,123 L. IMPROVED ANALYSIS OF GW150914 USING A FULLY … Milano,68,5 A. L. Miller,6,80,30 A. Miller,83
83
12
33
15
31
124
17
16 V. P. Mitrofanov,50 G. Mitselmakher,6 R. Mittleman,12 A. Moggi,21 M. Mohan,36 S. R. P. Mohapatra,12 M. Montani,57,58 B. C. Moore,92 C. J. Moore,125 D. Moraru,39 G. Moreno,39 S. R. Morriss,88 K. Mossavi,10 B. Mours,8 C. M. Mow-Lowry,46
G. Mueller,6 A. W. Muir,91 Arunava Mukherjee,17 D. Mukherjee,18 S. Mukherjee,88 N. Mukund,16 A. Mullavey,7
J. Munch,112 D. J. Murphy,41 P. G. Murray,38 A. Mytidis,6 I. Nardecchia,27,15 L. Naticchioni,80,30 R. K. Nayak,126
K. Nedkova,119 G. Nelemans,53,11 T. J. N. Nelson,7 M. Neri,47,48 A. Neunzert,101 G. Newton,38 T. T. Nguyen,22
A B Ni l
10 S Ni
k
53 11 A Ni
10 F N
36 D N l i
7 M E N N
di
88 L K N
ll 37 J Ob li
39 g
g
E. Ochsner,18 J. O’Dell,127 E. Oelker,12 G. H. Ogin,128 J. J. Oh,129 S. H. Oh,129 F. Ohme,91 M. Oliver,104 P. Oppermann,10 Richard J. Oram,7 B. O’Reilly,7 R. O’Shaughnessy,102 D. J. Ottaway,112 H. Overmier,7 B. J. Owen,72 A. Pai,107 S. A. Pai,49
J. R. Palamos,59 O. Palashov,109 C. Palomba,30 A. Pal-Singh,29 H. Pan,74 C. Pankow,83 F. Pannarale,91 B. C. Pant,49 D. Passuello,21 B. Patricelli,20,21 Z. Patrick,42 B. L. Pearlstone,38 M. Pedraza,1 R. Pedurand,66,1
131
1
83
108 31
38
80 30 S. Penn,131 A. Perreca,1 L. M. Perri,83 H. P. Pfeiffer,108,31 M. Phelps,38 O. J. Piccinni,80,30 M. Pichot,54 F. Piergiovanni,57,58
V. Pierro,9 G. Pillant,36 L. Pinard,66 I. M. Pinto,9 M. Pitkin,38 M. Poe,18 R. Poggiani,20,21 P. Popolizio,36 A. Post,10 J. Powell,38 J. Prasad,16 V. Predoi,91 T. Prestegard,84 L. R. Price,1 M. Prijatelj,10,36 M. Principe,9 S. Privitera,31 R. Prix,10
G. A. Prodi,89,90 L. Prokhorov,50 O. Puncken,10 M. Punturo,35 P. Puppo,30 M. Pürrer,31 H. Qi,18 J. Qin,52 S. Qiu,115 V. Quetschke,88 E. A. Quintero,1 R. Quitzow-James,59 F. J. Raab,39 D. S. Rabeling,22 H. Radkins,39 P. Raffai,93 S. Raja,49
C. Rajan,49 M. Rakhmanov,88 P. Rapagnani,80,30 V. Raymond,31 M. Razzano,20,21 V. Re,27 J. Read,24 C. M. Reed,39
T. Regimbau,54 L. Rei,48 S. Reid,51 D. H. Reitze,1,6 H. Rew,123 S. D. Reyes,37 F. Ricci,80,30 K. Riles,101 M. Rizzo,102
N. A. Robertson,1,38 R. Robie,38 F. Robinet,25 A. Rocchi,15 L. Rolland,8 J. G. Rollins,1 V. J. Roma,59 R. Romano,4,5
G. Romanov,123 J. H. Romie,7 D. Rosińska,132,45 S. Rowan,38 A. Rüdiger,10 P. Ruggi,36 K. Ryan,39 S. Sachdev,1 T. Sadecki,39
L. Sadeghian,18 M. Sakellariadou,133 L. Salconi,36 M. Saleem,107 F. Salemi,10 A. M. S. Shahriar,83 M. Shaltev,10 B. Shapiro,42 P. Shawhan,64 A. Sheperd,18 D. H. Shoemaker,12 D. M. Shoemaker,65
K. Siellez,65 X. Siemens,18 M. Sieniawska,45 D. Sigg,39 A. D. Silva,13 A. Singer,1 L. P. Singer,69 A. Singh,31,10,19 R. Singh,2
A. Singhal,14 A. M. Sintes,104 B. J. J. Slagmolen,22 J. R. Smith,24 N. D. Smith,1 R. J. E. Smith,1 E. J. Son,129 B. Sorazu,38
F. Sorrentino,48 T. Souradeep,16 A. K. Srivastava,86 A. Staley,41 M. Steinke,10 J. Steinlechner,38 S. Steinlechner,38
D. Steinmeyer,10,19 B. C. Stephens,18 S. P. Stevenson,46 R. Stone,88 K. A. Strain,38 N. Straniero,66 G. Stratta,57,58
N. A. Strauss,61 S. Strigin,50 R. Sturani,124 A. L. Stuver,7 T. Z. Summerscales,134 L. Sun,85 S. Sunil,86 P. J. Sutton,91
B. L. Swinkels,36 M. J. Szczepańczyk,98 M. Tacca,32 D. Talukder,59 D. B. Tanner,6 M. Tápai,97 S. P. Tarabrin,10
A. Taracchini,31 R. Taylor,1 T. Theeg,10 M. P. Thirugnanasambandam,1 E. G. Thomas,46 M. Thomas,7 P. Thomas,39
K. A. Thorne,7 K. S. Thorne,78 E. Thrane,115 S. Tiwari,14,90 V. Tiwari,91 K. V. Tokmakov,106 K. Toland,38 C. Tomlinson,87
M. Tonelli,20,21 Z. Tornasi,38 C. V. Torres,88,† C. I. Torrie,1 D. Töyrä,46 F. Travasso,34,35 G. Traylor,7 D. Trifirò,23
M. C. Tringali,89,90 L. Trozzo,135,21 M. Tse,12 M. Turconi,54 D. Tuyenbayev,88 D. Ugolini,136 C. S. Unnikrishnan,99
A. L. Urban,18 S. A. Usman,37 H. Vahlbruch,19 G. Vajente,1 G. Valdes,88 M. Vallisneri,78 N. van Bakel,11
M. van Beuzekom,11 J. F. J. van den Brand,63,11 C. Van Den Broeck,11 D. C. Vander-Hyde,37 L. van der Schaaf,11
M. V. van der Sluys,53 J. V. van Heijningen,11 A. Vano-Vinuales,91 A. A. van Veggel,38 M. Vardaro,43,44 S. Vass,1
M. Vasúth,40 R. Vaulin,12 A. Vecchio,46 G. Vedovato,44 J. Veitch,46 P. J. Veitch,112 K. Venkateswara,137 D. Verkindt,8
F. Vetrano,57,58 A. Viceré,57,58 S. Vinciguerra,46 D. J. Vine,51 J.-Y. Vinet,54 S. Vitale,12 T. Vo,37 H. Vocca,34,35 C. Vorvick,39
D. V. Voss,6 W. D. Vousden,46 S. P. Vyatchanin,50 A. R. Wade,22 L. E. Wade,138 M. Wade,138 M. Walker,2 L. Wallace,1
S. Walsh,31,10 G. Wang,14,58 H. Wang,46 M. Wang,46 X. Wang,71 Y. Wang,52 R. L. Ward,22 J. Warner,39 M. Was,8 B. Weaver,39
L.-W. Wei,54 M. Weinert,10 A. J. Weinstein,1 R. Weiss,12 L. Wen,52 P. Weßels,10 T. Westphal,10 K. Wette,10 J. T. Whelan,102
B. F. Whiting,6 R. D. Williams,1 A. R. Williamson,91 J. L. Willis,139 B. Willke,19,10 M. H. Wimmer,10,19 W. Winkler,10
C. C. Wipf,1 H. Wittel,10,19 G. Woan,38 J. Woehler,10 J. Worden,39 J. L. Wright,38 D. S. Wu,10 G. Wu,7 J. Yablon,83 W. Yam,12
H. Yamamoto,1 C. C. Yancey,64 H. Yu,12 M. Yvert,8 A. Zadrożny,113 L. Zangrando,44 M. Zanolin,98 J.-P. Zendri,44
M. Zevin,83 L. Zhang,1 M. Zhang,123 Y. Zhang,102 C. Zhao,52 M. Zhou,83 Z. Zhou,83 X. J. Zhu,52 M. E. Zucker,1,12
S. E. Zuraw,119 J. Zweizig,1 M. Boyle,140 B. Brügmann,141 M. Campanelli,102 T. Chu,140 M. Clark,65 R. Haas,31
D. Hemberger,78 I. Hinder,31 L. E. Kidder,140 M. Kinsey,65 P. Laguna,65 S. Ossokine,31 Y. Pan,64 C. Röver,10 M. Scheel,78
B. Szilagyi,78,142 S. Teukolsky,140 and Y. Zlochower102 IMPROVED ANALYSIS OF GW150914 USING A FULLY … Samajdar,126 L. Sammut,115 E. J. Sanchez,1
V. Sandberg,39 B. Sandeen,83 J. R. Sanders,37 B. Sassolas,66 B. S. Sathyaprakash,91 P. R. Saulson,37 O. E. S. Sauter,101
R. L. Savage,39 A. Sawadsky,19 P. Schale,59 R. Schilling,10,† J. Schmidt,10 P. Schmidt,1,78 R. Schnabel,29
R. M. S. Schofield,59 A. Schönbeck,29 E. Schreiber,10 D. Schuette,10,19 B. F. Schutz,91,31 J. Scott,38 S. M. Scott,22 D. Sellers,7
A S S
96 D S
36 V S
i
27 15 A S
109 Y S
i 53 11 D A Sh dd
k 22 T Sh ff
39 041014-15 041014-15 PHYS. REV. X 6, 041014 (2016) B. P. ABBOTT et al. (LIGO Scientific Collaboration and Virgo Collaboration) 1LIGO, California Institute of Technology, Pasadena, California 91125, USA
2 2Louisiana State University, Baton Rouge, Louisiana 70803, USA
3 3American University, Washington, D.C. 20016, USA
4 4Università di Salerno, Fisciano, I-84084 Salerno, Italy 7LIGO Livingston Observatory, Livingston, Louisiana 70754, USA e d’Annecy-le-Vieux de Physique des Particules (LAPP), Université Savoie Mont Blanc, CNRS/IN2P3, F-74941 Annecy-le-Vieux, France niversity of Wisconsin-Milwaukee, Milwaukee, Wisconsin 53201, USA
19 19Leibniz Universität Hannover, D-30167 Hannover, Germany 20Università di Pisa, I-56127 Pisa, Italy
1 20Università di Pisa, I-56127 Pisa, Italy
1 21INFN, Sezione di Pisa, I-56127 Pisa, Italy 21INFN, Sezione di Pisa, I-56127 Pisa, Italy 041014-16 M. S. Shahriar,83 M. Shaltev,10 B. Shapiro,42 P. Shawhan,64 A. Sheperd,18 D. H. Shoemaker,12 D. M. Shoemaker,65
K. Siellez,65 X. Siemens,18 M. Sieniawska,45 D. Sigg,39 A. D. Silva,13 A. Singer,1 L. P. Singer,69 A. Singh,31,10,19 R. Singh,2 71Tsinghua University, Beijing 100084, China 71Tsinghua University, Beijing 100084, China 72Texas Tech University, Lubbock, Texas 79409, USA 72Texas Tech University, Lubbock, Texas 79409, USA
3 73The Pennsylvania State University, University Park, Pennsylvania 16802, USA
74National Tsing Hua University, Hsinchu City, 30013 Taiwan, Republic of China
75 74National Tsing Hua University, Hsinchu City, 30013 Taiwan, Republic of China
75 75Charles Sturt University, Wagga Wagga, New South Wales 2678, Australia
76 76West Virginia University, Morgantown, West Virginia 26506, USA
77 77University of Chicago, Chicago, Illinois 60637, USA Georgia 30332, USA 66Laboratoire des Matériaux Avancés (LMA), CNRS/IN2P3, F-69622 Villeurbanne, France
67Université Claude Bernard Lyon 1, F-69622 Villeurbanne, France
68 versità di Napoli “Federico II,” Complesso Universitario di Monte S.Angelo, I-80126 Napoli, Italy
69 Università di Napoli
Federico II,
Complesso Universitario di Monte S.Angelo, I 80126 Napoli, Ita
69NASA/Goddard Space Flight Center, Greenbelt, Maryland 20771, USA
70 69NASA/Goddard Space Flight Center, Greenbelt, Maryland 20771, USA
70 70RESCEU, University of Tokyo, Tokyo, 113-0033, Japan
71 49RRCAT, Indore MP 452013, India 50Faculty of Physics, Lomonosov Moscow State University, Moscow 119991, Russia
51 50Faculty of Physics, Lomonosov Moscow State University, Moscow 119991, Russia
51 1SUPA, University of the West of Scotland, Paisley PA1 2BE, United Kingdom
52 51SUPA, University of the West of Scotland, Paisley PA1 2BE, United Kingdom
52 y
f
y
53Department of Astrophysics/IMAPP, Radboud University Nijmegen, P.O. Box 9010, 6500 GL Nijmegen,
The Netherlands The Netherlands Artemis, Université Côte d’Azur, CNRS, Observatoire Côte d’Azur, CS 34229, Nice cedex 4, France
55 niversité Côte d’Azur, CNRS, Observatoire Côte d’Azur, CS 34229, Nice cedex 4, France ut de Physique de Rennes, CNRS, Université de Rennes 1, F-35042 Rennes, France
56 56Washington State University, Pullman, Washington 99164, USA
57Università degli Studi di Urbino “Carlo Bo,” I-61029 Urbino, Italy
58INFN Sezione di Firenze I 50019 Sesto Fiorentino Firenze Italy g
y
g
57Università degli Studi di Urbino “Carlo Bo,” I-61029 Urbino, Italy
58 57Università degli Studi di Urbino “Carlo Bo,” I-61029 Urbino, Italy
58INFN, Sezione di Firenze, I-50019 Sesto Fiorentino, Firenze, Italy
59 59University of Oregon, Eugene, Oregon 97403, USA 59University of Oregon, Eugene, Oregon 97403, USA 60Laboratoire Kastler Brossel, UPMC-Sorbonne Universités, CNRS, ENS-PSL Research University, 61Carleton College, Northfield, Minnesota 55057, USA Astronomical Observatory Warsaw University, 00-478 Warsaw, Poland
63VU University Amsterdam, 1081 HV Amsterdam, The Netherlands
64 Astronomical Observatory Warsaw University, 00 478 Warsaw, Poland
63VU University Amsterdam, 1081 HV Amsterdam, The Netherlands
64 63VU University Amsterdam, 1081 HV Amsterdam, The Netherlands
64 64University of Maryland, College Park, Maryland 20742, USA University of Maryland, College Park, Maryland 20742, USA
65Center for Relativistic Astrophysics and School of Physics, Georgia Institute of Technology, Atlanta,
Georgia 30332, USA University of Maryland, College Park, Maryland 20742, USA
65Center for Relativistic Astrophysics and School of Physics, Georgia Institute of Technology,
G
i
30332 USA IMPROVED ANALYSIS OF GW150914 USING A FULLY … PHYS. REV. X 6, 041014 (2016) 22Australian National University, Canberra, Australian Capital Territory 0200, Australia
23 23The University of Mississippi, University, Mississippi 38677, USA
24 23The University of Mississippi, University, Mississippi 38677, USA
24California State University Fullerton, Fullerton, California 92831, USA
5 24California State University Fullerton, Fullerton, California 92831, USA
5 Univ. Paris-Sud, CNRS/IN2P3, Université Paris-Saclay, Orsay, France
26 26Chennai Mathematical Institute, Chennai 603103, India
27 27Università di Roma Tor Vergata, I-00133 Roma, Italy 28University of Southampton, Southampton SO17 1BJ, United Kingdom 29Universität Hamburg, D-22761 Hamburg, German g
g
30INFN, Sezione di Roma, I-00185 Roma, Italy y
ert-Einstein-Institut, Max-Planck-Institut für Gravitationsphysik, D-14476 Potsdam-Golm, Germany C, AstroParticule et Cosmologie, Université Paris Diderot, CNRS/IN2P3, CEA/Irfu, Observatoire de Paris, Sorbonne Paris Cité, F-75205 Paris Cedex 13, France
33 33Montana State University, Bozeman, Montana 59717, USA
34 34Università di Perugia, I-06123 Perugia, Italy 35INFN, Sezione di Perugia, I-06123 Perugia, Italy 36European Gravitational Observatory (EGO), I-56021 Cascina, Pisa, Italy
37 37Syracuse University, Syracuse, New York 13244, USA
38 38SUPA, University of Glasgow, Glasgow G12 8QQ, United Kingdom
39 39LIGO Hanford Observatory, Richland, Washington 99352, USA 41Columbia University, New York, New York 10027, USA
42 42Stanford University, Stanford, California 94305, USA 43Università di Padova, Dipartimento di Fisica e Astronomia, I-35131 Padova, Italy
44 44INFN, Sezione di Padova, I-35131 Padova, Italy
45 45CAMK-PAN, 00-716 Warsaw, Poland 46University of Birmingham, Birmingham B15 2TT, United Kingdom
47 46University of Birmingham, Birmingham B15 2TT, United Kingdom
4 47Università degli Studi di Genova, I-16146 Genova, Italy
48 48INFN, Sezione di Genova, I-16146 Genova, Italy
49 Ontario M5S 3H8, Canada 109Institute of Applied Physics, Nizhny Novgorod, 603950, Russia
110 110Pusan National University, Busan 609-735, Korea
111 111Hanyang University, Seoul 133-791, Korea 112University of Adelaide, Adelaide, South Australia 5005, Australia
113 113NCBJ, 05-400 Świerk-Otwock, Poland 114IM-PAN, 00-956 Warsaw, Poland 115Monash University, Victoria 3800, Australia
16 116Seoul National University, Seoul 151-742, Korea 117The Chinese University of Hong Kong, Shatin, NT, Hong Kong 118University of Alabama in Huntsville, Huntsville, Alabama 35899, USA
119 20ESPCI, CNRS, F-75005 Paris, France 121Università di Camerino, Dipartimento di Fisica, I-62032 Camerino, Italy
122 123College of William and Mary, Williamsburg, Virginia 23187, USA 124Instituto de Física Teórica, University Estadual Paulista/ICTP South American Institute for
Fundamental Research, Sao Paulo SP 01140-070, Brazil
125University of Cambridge, Cambridge CB2 1TN, United Kingdom
126IISER-Kolkata Mohanpur West Bengal 741252 India 127Rutherford Appleton Laboratory, HSIC, Chilton, Didcot, Oxon OX11 0QX, United Kingdom
128Whitman College, 345 Boyer Avenue, Walla Walla, Washington 99362 USA
129National Institute for Mathematical Sciences, Daejeon 305-390, Korea
130Université de Lyon, F-69361 Lyon, France
131Hobart and William Smith Colleges Geneva New York 14456 USA 130Université de Lyon, F-69361 Lyon, France 131Hobart and William Smith Colleges, Geneva, New York 14456, USA
32 g
,
,
,
132Janusz Gil Institute of Astronomy, University of Zielona Góra, 65-265 Zielona Góra, Poland
133King’s College London, University of London, London WC2R 2LS, United Kingdom
134Andrews University, Berrien Springs, Michigan 49104, USA 041014-17 B. P. ABBOTT et al. PHYS. REV. X 6, 041014 (2016) 78Caltech CaRT, Pasadena, California 91125, USA f
a Institute of Science and Technology Information, Daejeon 305-806, Ko
80 80Università di Roma “La Sapienza”, I-00185 Roma, Italy
81 81University of Brussels, Brussels 1050, Belgium 82Sonoma State University, Rohnert Park, California 94928, USA disciplinary Exploration & Research in Astrophysics (CIERA), Northwestern University, he University of Texas Rio Grande Valley, Brownsville, Texas 78520, USA Università di Trento, Dipartimento di Fisica, I-38123 Povo, Trento, Italy 90INFN, Trento Institute for Fundamental Physics and Applications, I-38123 Povo, Trento, Italy
91 92Montclair State University, Montclair, New Jersey 07043, USA rsity of Szeged, Dóm tér 9, Szeged 6720, Hungary 102Rochester Institute of Technology, Rochester, New York 14623, USA 104Universitat de les Illes Balears, IAC3—IEEC, E-07122 Palma de Mallorca, Spain
105 05University of Białystok, 15-424 Białystok, Poland 106SUPA, University of Strathclyde, Glasgow G1 1XQ, United Kingdom
107 07IISER-TVM, CET Campus, Trivandrum Kerala 695016, India 135Università di Siena, I-53100 Siena, Italy
136Trinity University, San Antonio, Texas 78212, USA
137University of Washington, Seattle, Washington 98195, USA
138Kenyon College, Gambier, Ohio 43022, USA
139Abilene Christian University, Abilene, Texas 79699, USA
140Cornell Center for Astrophysics and Planetary Science, Cornell University, Ithaca,
New York 14853, USA
141Theoretical Physics Institute, University of Jena, 07743 Jena, Germany
142Caltech JPL, Pasadena, California 91109, USA IMPROVED ANALYSIS OF GW150914 USING A FULLY … PHYS. REV. X 6, 041014 (2016) †Deceased. 041014-19
|
https://openalex.org/W3205532724
|
https://www.frontiersin.org/articles/10.3389/fpubh.2021.726484/pdf
|
English
| null |
Knowledge Gaps in the Understanding of Antimicrobial Resistance in Canada
|
Frontiers in public health
| 2,021
|
cc-by
| 12,226
|
REVIEW
published: 20 October 2021
doi: 10.3389/fpubh.2021.726484 Knowledge Gaps in the
Understanding of Antimicrobial
Resistance in Canada Kayley D. McCubbin 1,2, R. Michele Anholt 2, Ellen de Jong 1,2, Jennifer A. Ida 1,
Diego B. Nóbrega 1, John P. Kastelic 1, John M. Conly 2,3,4,5,6,7,8, Matthias Götte 9,
Tim A. McAllister 10, Karin Orsel 1,2, Ian Lewis 2,11, Leland Jackson 2,11, Graham Plastow 12,
Hans-Joachim Wieden 13, Kathy McCoy 2,4,14, Myles Leslie 2,3,15,16, Joan L. Robinson 17,
Lorian Hardcastle 2,3,15,18, Aidan Hollis 2,3,19, Nicholas J. Ashbolt 20, Sylvia Checkley 2,3,5,21,
Gregory J. Tyrrell 22,23, André G. Buret 2,4,11, Elissa Rennert-May 2,3,4,7,8,15, Ellen Goddard 24,
Simon J. G. Otto 25,26 and Herman W. Barkema 1,2,3,4,15* 1 Department of Production Animal Health, Faculty of Veterinary Medicine, University of Calgary, Calgary, AB, Canada, 2 One
Health at UCalgary, University of Calgary, Calgary, AB, Canada, 3 O’Brien Institute of Public Health, University of Calgary,
Calgary, AB, Canada, 4 Snyder Institute for Chronic Diseases, University of Calgary, Calgary, AB, Canada, 5 Department of
Microbiology, Immunology and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB,
Canada, 6 Department of Pathology and Laboratory Medicine, Cumming School of Medicine, University of Calgary, Calgary,
AB, Canada, 7 Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada, 8 Alberta
Health Services, Calgary, AB, Canada, 9 Department of Medical Microbiology and Immunology, Faculty of Medicine and
Dentistry, University of Alberta, Edmonton, AB, Canada, 10 Agriculture and Agri-Food Canada, Lethbridge Research Centre,
Lethbridge, AB, Canada, 11 Department of Biological Sciences, Faculty of Science, University of Calgary, Calgary, AB,
Canada, 12 Department of Agricultural, Food and Nutritional Science, Faculty of Agricultural, Life and Environmental Sciences,
University of Alberta, Edmonton, AB, Canada, 13 Department of Chemistry and Biochemistry, University of Lethbridge,
Lethbridge, AB, Canada, 14 Department of Physiology and Pharmacology, Cumming School of Medicine, University of
Calgary, Calgary, AB, Canada, 15 Department of Community Health Sciences, Cumming School of Medicine, University of
Calgary, Calgary, AB, Canada, 16 School of Public Policy, University of Calgary, Calgary, AB, Canada, 17 Department of
Pediatrics, Faculty of Medicine, University of Alberta, Edmonton, AB, Canada, 18 Faculty of Law, University of Calgary,
Calgary, AB, Canada, 19 Department of Economics, Faculty of Arts, University of Calgary, Calgary, AB, Canada, 20 Faculty of
Science and Engineering, Southern Cross University, Lismore, NSW, Australia, 21 Department of Ecosystem and Public
Health, Faculty of Veterinary Medicine, University of Calgary, Calgary, AB, Canada, 22 Alberta Precision Laboratories, Alberta
Health Services, Calgary, AB, Canada, 23 Department of Laboratory Medicine and Pathology, Faculty of Medicine and
Dentistry, University of Alberta, Calgary, AB, Canada, 24 Department of Resource Economics and Environmental Sociology,
Faculty of Agriculture, Life and Environmental Science, University of Alberta, Edmonton, AB, Canada, 25 HEAT-AMR Research
Group, School of Public Health, University of Alberta, Edmonton, AB, Canada, 26 Thematic Area Lead, Healthy Environments,
Centre for Healthy Communities, School of Public Health, University of Alberta, Edmonton, AB, Canada Edited by:
Miguel Cacho Teixeira,
University of Lisbon, Portugal Reviewed by:
Paul Plummer,
Iowa State University, United States
Luke S. P. Moore,
Imperial College London,
United Kingdom *Correspondence:
Herman W. Barkema
barkema@ucalgary.ca *Correspondence:
Herman W. Barkema
barkema@ucalgary.ca Specialty section:
This article was submitted to
Infectious Diseases - Surveillance,
Prevention and Treatment,
a section of the journal
Frontiers in Public Health Received: 17 June 2021
Accepted: 16 September 2021
Published: 20 October 2021 Received: 17 June 2021
Accepted: 16 September 2021
Published: 20 October 2021 Current limitations in the understanding and control of antimicrobial resistance (AMR)
in Canada are described through a comprehensive review focusing on: (1) treatment
optimization; (2) surveillance of antimicrobial use and AMR; and (3) prevention of
transmission of AMR. Without addressing gaps in identified areas, sustained progress
in AMR mitigation is unlikely. Expert opinions and perspectives contributed to prioritizing
identified gaps. Using Canada as an example, this review emphasizes the importance
and necessity of a One Health approach for understanding and mitigating AMR. Specifically, antimicrobial use in human, animal, crop, and environmental sectors
cannot be regarded as independent; therefore, a One Health approach is needed in
AMR research and understanding, current surveillance efforts, and policy. Discussions
regarding addressing described knowledge gaps are separated into four categories: Current limitations in the understanding and control of antimicrobial resistance (AMR)
in Canada are described through a comprehensive review focusing on: (1) treatment
optimization; (2) surveillance of antimicrobial use and AMR; and (3) prevention of
transmission of AMR. Without addressing gaps in identified areas, sustained progress
in AMR mitigation is unlikely. Expert opinions and perspectives contributed to prioritizing
identified gaps. Using Canada as an example, this review emphasizes the importance
and necessity of a One Health approach for understanding and mitigating AMR. Specifically, antimicrobial use in human, animal, crop, and environmental sectors
cannot be regarded as independent; therefore, a One Health approach is needed in
AMR research and understanding, current surveillance efforts, and policy. Discussions
regarding addressing described knowledge gaps are separated into four categories: INTRODUCTION (1). In addition to effects on animal health and welfare, consumer
costs, food availability, and production system sustainability
will be affected (21). It was estimated that by 2050, without
interventions, every year there will be 10 million human deaths
globally due to AMR infections (22). The incremental annual
global healthcare costs due to AMR are expected to be ∼US$0.33
to 1.2 trillion (1). In Canada, AMR cost our national healthcare
system an estimated $1.4 billion in 2018 (21), with projected
healthcare system costs reaching $120 billion by 2050 without
interventions to slow predicted increases of bacterial resistance
to first line antimicrobials from 26 to 40% (21). In addition
to healthcare, the Canadian Council of Academies describes
potential broader social impacts of AMR that include (21): Since antimicrobial use (AMU) became widespread in healthcare,
antimicrobial resistance (AMR) is increasing worldwide (1–3). Antimicrobials have saved hundreds of millions of human and
animal lives and their discovery is a critical medical advance
(1, 4). However, increasing AMR may vastly reduce future
antimicrobial efficacy. The World Health Organization (WHO),
the Food and Agriculture Organization of the United Nations
(FAO), and the World Organization for Animal Health (OIE)
agree that AMR is a serious threat to human and animal health
and negatively impacts the environment (5). While the World
Bank describes bacterial susceptibility to antimicrobials as a
“public good” that needs global protection (1). - decreases in social trust, social capital, quality of life, and
equality among socio-demographic groups; - decreases in social trust, social capital, quality of life, and
equality among socio-demographic groups; Due to a limited variety of efficacious antimicrobials, the same
products or those within the same class are used in humans,
animals, (6) agricultural crops, and aquaculture (7–9). This
promotes bacterial resistance by increasing exposure of microbes
to the same or similar antimicrobials (6), complicating AMR
containment. Few drugs belonging to new antimicrobial classes
have recently been released (3, 10–12) and efforts to reduce AMU
and limit use of new antimicrobials reduce economic incentives
for product development. Citation: McCubbin KD, Anholt RM, de Jong E,
Ida JA, Nóbrega DB, Kastelic JP,
Conly JM, Götte M, McAllister TA,
Orsel K, Lewis I, Jackson L,
Plastow G, Wieden H-J, McCoy K,
Leslie M, Robinson JL, Hardcastle L,
Hollis A, Ashbolt NJ, Checkley S,
Tyrrell GJ, Buret AG, Rennert-May E,
Goddard E, Otto SJG and
Barkema HW (2021) Knowledge Gaps
in the Understanding of Antimicrobial
Resistance in Canada. Front. Public Health 9:726484. doi: 10.3389/fpubh.2021.726484 October 2021 | Volume 9 | Article 726484 Frontiers in Public Health | www.frontiersin.org 1 Knowledge Gaps in Antimicrobial Resistance McCubbin et al. (1) further research; (2) increased capacity/resources; (3) increased prescriber/end-
user knowledge; and (4) policy development/enforcement. This review highlights the
research and increased capacity and resources to generate new knowledge and
implement recommendations needed to address all identified gaps, including economic,
social, and environmental considerations. More prescriber/end-user knowledge and
policy development/enforcement are needed, but must be informed by realistic
recommendations, with input from all relevant stakeholders. For most knowledge gaps,
important next steps are uncertain. In conclusion, identified knowledge gaps underlined
the need for AMR policy decisions to be considered in a One Health framework, while
highlighting critical needs to achieve realistic and meaningful progress. Keywords: antimicrobial resistance, One Health, antimicrobial stewardship, knowledge gaps, policy, Canada Keywords: antimicrobial resistance, One Health, antimicrobial stewardship, knowledge gaps, policy, Canada Frontiers in Public Health | www.frontiersin.org Keywords: antimicrobial resistance, One Health, antimicrobial stewardship, knowledge gaps, policy, Canada TREATMENT OPTIMIZATION AMU is considered one of the most important factors in
development and spread of AMR, with misuse and overuse
of particular concern (3, 18, 30). Examples of the latter
by prescribers, patients or antimicrobial administrators (i.e.,
farmers) include: excessive use for disease prevention or
treatment in lieu of good hygiene, inappropriate off-label
use, treatment of non-bacterial illnesses, growth promotion
in livestock, improper dosing (quantity, interval or duration),
patient/administrator non-compliance, fraudulent formulation
and incorrect antimicrobial selection (18, 30–33). To maintain
the efficacy of available antimicrobial treatments, treatment
optimization is crucial and includes, as a minimum: - Long-term efficacy of AMR mitigation efforts - BMPs for reducing AMR in wastewater and subsequent
impacts on human/animal health - Quantitative risks associated with various incursion pathiways
of AMR transmission Development of AMR - use of the least broad-spectrum antimicrobial for the infection; - use of the least broad-spectrum antimicrobial for the infection; - avoiding unnecessary prophylactic and broad-spectrum AMU; - avoiding antimicrobial prescribing before bacterial culture
and sensitivity; - Role of the microbiome - Impact of heavy metals, cleaning agents and biocides, and
other xenobiotic compounds on AMR development - optimal dosing (i.e., quantity, interval, duration); and - How
AMU
in
one
health
sector
directly
impacts
AMR
development in another sector (i.e., human AMU and animal
AMR, and the reverse) - patient compliance. Development of AMS best practices does not ensure their
uptake by various stakeholders, for societal, cultural (34) and
economic factors. For example, there is frequently prophylactic
or empirical AMU in lieu of more costly solutions (i.e.,
diagnostics and/or focused treatment). Understanding AMU
economics is vital to promote support of AMS and AMU
reduction efforts, at policy, prescriber, and patient-levels,
but currently lacking (Table 1). Specific societal and cultural
factors
in
human
medicine
include-short
term
benefits,
such as positive clinical outcomes and avoidance of clinical
risks,
maintaining
prescriber-patient
relationships,
societal
pressures and prescriber expectation outweighing long-term
AMR community risks, and thus hampering judicious AMU
(34). Antimicrobial prescribing can also be influenced by
social hierarchies in the both the human (16) and veterinary
medical settings (35). Even when AMS strategies in human
hospitals were developed, they often did not include who
should act and failed to account for multi-professional care
teams and details on when to start/stop antimicrobials (36). Prevention of
transmission of
AMR INTRODUCTION Area
Knowledge gap
Treatment
optimization
- Extent of antimicrobial misuse in Canada
- BMPsa regarding antimicrobial prescribing in human/animal
medicine
- Economics of various efforts in lieu of AMUb
- Socio-economic/behavioral drivers of AMU (prescriber and
patient perspectives)
- Efficacy of widespread adoption of alternative therapies to AMU
- Understand and shift perspectives that identify AMU is a
harmless “cure all”
- Identifying barriers and enablers of optimal human/animal AMU
- BMPs to reduce livestock-associated prophylactic AMU
- Rapid diagnostic testing to assist AMU decision-making
Surveillance
- Up-to-date prevalence estimates of AMRc in the community,
domestic
animals,
wildlife,
production
animals
and
the
environment, not included in ongoing Canadian surveillance
- Overall trends of AMR bacteria and their emergence in Canada
- BMPs for integration of AMU/AMR data collection
and reporting
Prevention of
transmission of
AMR
- Long-term efficacy of AMR mitigation efforts
- BMPs for prevention of hospital-acquired AMR infectons
- BMPs for reducing AMR in wastewater and subsequent
impacts on human/animal health
- How to reduce AMR prevalence in various resistance reservoirs
- How to limit the risk of AMR in food systems
- How to prevent cross-species AMR transmission
- Quantitative risks associated with various incursion pathiways
of AMR transmission Development of AMR
- The direct relationship between AMU and AMR development
- Role of the microbiome
- Impact of heavy metals, cleaning agents and biocides, and
other xenobiotic compounds on AMR development
- How
AMU
in
one
health
sector
directly
impacts
AMR
development in another sector (i.e., human AMU and animal
AMR, and the reverse)
- Relative importance of various routes of antimicrobial
administration in AMR development
- How to employ policy to effective limit AMR development Role
of the Environment
- Impact of human AMU/AMR on the environment
- Impact of AMU/AMR in livestock industries on the environment
- Relative importance of various environmental transmission
routes (including transmission through ground water and
livestock derived manure spreading, etc.)
- Impact of antimicrobial residues in soil, water, and pastures
- Economic impacts of reducing environmental AMR reservoirs
and antimicrobial residues
Role of Wildlife
- Impact of AMR on wildlife health
- Role of wildlife in transmission of AMR
- Economic benefits of reducing AMR transmission from wildlife
to livestock or humans
aBMPs, Best management practices. b INTRODUCTION - weakened social connectivity; - discrimination against those deemed at risk for or with
AMR infections; - unequal impacts of AMR, with higher risk for marginalized
groups who experience poverty, homelessness, substance use
disorder, overcrowding/poor housing/poor sanitation, and
First Nations/Inuit/Metis populations); and - a Canadian society that may become less open and trusting
(i.e., less travel and increased support to close Canada’s borders
to immigrants and tourists). The extent of selection of resistant bacteria often reflects
the degree of AMU, the type of antimicrobials used, and the
effectiveness of infection prevention and control (13). The
COVID-19 pandemic exacerbated the problem, as antimicrobial
stewardship
(AMS)
efforts
were
often
disregarded,
with
substantial AMU in COVID-19 patients for bacterial infections
or prophylaxis (14–16). Furthermore, disinfectant use has
dramatically increased, affecting the microbiome and potentially
exacerbating AMR development (17, 18). Consequently, full
impacts of the COVID-19 pandemic on development of AMR
are unknown but may be substantial. There is substantial support regarding intricate connectivity of
AMR in human, animal, and environmental sectors (6, 23–
25), with spillover of AMR between microbial populations in
livestock and humans (18). Furthermore, environmental bacteria
are potential reservoirs for resistance genes acquired through
exposure to antimicrobial residues from human, animal, and
agricultural sources (23, 26–29). These environmental bacteria
could transfer AMR traits to commensal and pathogenic bacteria. Transmission of AMR bacteria is influenced by trade, travel, and
human and animal migration (3), making AMR a global issue
that is not contained by political borders. Current and projected AMR impacts require immediate and
sustained action across human, animal, and environmental
sectors using a true One Health approach, with multiple sectors
communicating and collaborating to improve health outcomes
while designing and implementing research, initiatives, policies,
and legislation (19, 20). Livestock production is expected to be
impacted, with a projected global decline of 2.6–7.5% annually A One Health framework was used to identify three review
areas to describe current knowledge gaps in Canada that
need to be addressed before realistic, practice-oriented AMR
mitigation strategies can be developed and implemented. These October 2021 | Volume 9 | Article 726484 Frontiers in Public Health | www.frontiersin.org 2 Knowledge Gaps in Antimicrobial Resistance McCubbin et al. TABLE 1 | Knowledge gaps that hamper prevention and control of antimicrobial
resistance in Canada. areas include: (1) treatment optimization; (2) surveillance of
AMU and AMR; and (3) prevention of transmission of AMR. Frontiers in Public Health | www.frontiersin.org INTRODUCTION Area
Knowledge gap
Treatment
optimization
- Extent of antimicrobial misuse in Canada
- BMPsa regarding antimicrobial prescribing in human/animal
medicine
- Economics of various efforts in lieu of AMUb
- Socio-economic/behavioral drivers of AMU (prescriber and
patient perspectives)
- Efficacy of widespread adoption of alternative therapies to AMU
- Understand and shift perspectives that identify AMU is a
harmless “cure all”
- Identifying barriers and enablers of optimal human/animal AMU
- BMPs to reduce livestock-associated prophylactic AMU
- Rapid diagnostic testing to assist AMU decision-making
Surveillance
- Up-to-date prevalence estimates of AMRc in the community,
domestic
animals,
wildlife,
production
animals
and
the
environment, not included in ongoing Canadian surveillance
- Overall trends of AMR bacteria and their emergence in Canada
- BMPs for integration of AMU/AMR data collection
and reporting
Prevention of
transmission of
AMR
- Long-term efficacy of AMR mitigation efforts
- BMPs for prevention of hospital-acquired AMR infectons
- BMPs for reducing AMR in wastewater and subsequent
impacts on human/animal health
- How to reduce AMR prevalence in various resistance reservoirs
- How to limit the risk of AMR in food systems
- How to prevent cross-species AMR transmission
- Quantitative risks associated with various incursion pathiways
of AMR transmission Development of AMR
- The direct relationship between AMU and AMR development
- Role of the microbiome
- Impact of heavy metals, cleaning agents and biocides, and
other xenobiotic compounds on AMR development
- How
AMU
in
one
health
sector
directly
impacts
AMR
development in another sector (i.e., human AMU and animal
AMR, and the reverse)
- Relative importance of various routes of antimicrobial
administration in AMR development
- How to employ policy to effective limit AMR development Role
of the Environment
- Impact of human AMU/AMR on the environment
- Impact of AMU/AMR in livestock industries on the environment
- Relative importance of various environmental transmission
routes (including transmission through ground water and
livestock derived manure spreading, etc.)
- Impact of antimicrobial residues in soil, water, and pastures
- Economic impacts of reducing environmental AMR reservoirs
and antimicrobial residues
Role of Wildlife
- Impact of AMR on wildlife health
- Role of wildlife in transmission of AMR
- Economic benefits of reducing AMR transmission from wildlife
to livestock or humans
aBMPs, Best management practices. bAMU Antimicrobial use resistance in Canada. INTRODUCTION Herein, we have reviewed scientific literature and reports to
identify the most pressing gaps in knowledge that currently
hamper AMR prevention and control programs (summarized
in Table 1). Where supporting data are lacking, expert opinion
was used. Furthermore, requirements to address knowledge gaps
are discussed, directing expert panels in identifying concrete
next steps. TABLE 1 | Knowledge gaps that hamper prevention and control of antimicrobial
resistance in Canada. bAMU, Antimicrobial use. TREATMENT OPTIMIZATION Livestock-focused research suggests when AMR mitigation
research
is
interdisciplinary,
behavioral
feasibility
is
also
considered by identifying all actors in livestock AMU and power
relationships (37). - Relative importance of various routes of anti
administration in AMR development - How to employ policy to effective limit AMR development Role
of the Environment - Impact of human AMU/AMR on the environment - Impact of AMU/AMR in livestock industries on the environmen - Relative importance of various environmental transmission
routes (including transmission through ground water and
livestock derived manure spreading, etc.) - Impact of antimicrobial residues in soil, water, and pastures - Economic impacts of reducing environmental AMR reservoirs
and antimicrobial residues
Role of Wildlife - Impact of AMR on wildlife health - Role of wildlife in transmission of AMR - Economic benefits of reducing AMR transmission from wildlife
to livestock or humans to livestock or humans cAMR, Antimicrobial resistance. crop
managers,
livestock
producers,
and
other
relevant
stakeholders should be utilized to identify factors hampering
behavioral change and then to develop AMS interventions that
ensure uptake. Integration with social science domains could
identify considerations essential to each sector for support of To increase social science inclusion in AMR research and
policy, focus groups with physicians, veterinarians, agricultural October 2021 | Volume 9 | Article 726484 Frontiers in Public Health | www.frontiersin.org 3 Knowledge Gaps in Antimicrobial Resistance McCubbin et al. AMU reduction strategies, in addition to described economic
considerations. Close collaboration with social scientists is
needed to successfully implement AMS programs. and upheld (Table 1). For example, there is a perception of
antimicrobials as “magic bullets” or a harmless “cure-all” (43). These perceptions must be altered to generate effective change
in prescribing practices in all sectors and to prevent the addition
of antimicrobials to medical regimes “just in case.” Stewardship efforts can be supported by further development
and availability of rapid diagnostic technology, to decrease
empirical prescribing and increase appropriate antimicrobial
treatment response times (16). An impediment to optimal
dosing is the knowledge gap regarding quantitative relationships
between AMU and AMR development, and interactions of
resistant bacteria at the human, animal, and environmental
interface (Table 1). Further research regarding a dose-response
relationship of AMU and subsequent AMR development,
including impacts and relative importance of number of
antimicrobial doses, or duration of AMU in various contexts, is
required to inform model development to understand impacts of
AMU and mitigation efforts. AMU in Animals
Current Knowledge AMU for human health is increasing worldwide as reported
in 2015 (3, 38), particularly in low- and middle-income
countries (38). In Canada, as reported in the 2020 CARSS
update (Canadian Antimicrobial Resistance Surveillance System)
there was an increase in annual antimicrobial consumption,
between 2014 and 2018, with a 28.6% increase in antimicrobial
purchasing by hospitals, despite a 1.3% decrease in retail
dispensing (39). Concurrently, there was a 10% increase in
use of antimicrobials that should be reserved for suspected or
confirmed multidrug-resistant infections, some of which are
increasing (39). For example, the proportion of MDR invasive
Streptococcus pneumoniae infections increased by 26% from 2013
to 2017 (39). g
Extensive AMU for treatment and prevention of infectious
diseases in livestock has supported development of current
animal production systems (49). In 2016, the total volume
of
antimicrobials
(excluding
ionophores
and
chemical
coccidiostats) to treat Canadian livestock was nearly four
times the amount used in humans, with almost all used in
production animals (50). However, the context of AMU must
be considered, including the population correction unit (PCU)
that enables standardization of antimicrobial product weight
(mg) per unit of animal or human biomass (kg) (50). When the
Canadian-specific animal PCU is considered, animal-intended
antimicrobial distribution was only 1.3 times that prescribed
for humans (50). Although the quantity of antimicrobials
dispensed is not perfectly correlated to use, it provides a proxy
to assess trends. The quantity of animal-intended antimicrobials
dispensed in 2017 in Canada was 11% lower than in 2016;
however, there was a 6% increase from 2017 to 2018 (39). In
2018 the animal sector represented 79% of AMU, the human
sector was responsible for 21%, and crop AMU represented
<1% (39). However, there were ∼21 farmed animals for
every human (51). Furthermore, antimicrobials intended for
growth promotion [i.e., treatment/prevention of subclinical
disease to improve health and increase production (52)] in
broiler and turkey flocks decreased to zero between 2014 and
2018 (39). In 2018, 89.8% of antibiotics for human use in Canada
were prescribed in community health care settings (e.g., by
family physicians, dentists, pharmacists, nurse practitioners, etc.)
and only 10.2% used in hospitals (39). In Canada, 30% of
antimicrobial prescriptions dispensed through pharmacies (40)
and 57% in long-term care facilities were unnecessary (41),
highlighting opportunities to improve prescribing practices and
patient expectations. TREATMENT OPTIMIZATION g
j
There is limited public knowledge regarding the harms of
inappropriate AMU and AMR implications (44). Receiving an
antimicrobial prescription is part of the social contract of a
medical appointment in human and veterinary medicine. Before
substantial progress can be made, this gap in public knowledge
regarding when AMU is appropriate must be addressed and
prescribing guidelines improved to shift the dialogue and alter
patient expectations. For example, “Using Antibiotics Wisely” is
a national campaign developed by Choosing Wisely Canada to
facilitate patient-physician conversations regarding unnecessary
AMU in Canada (45). “Bugs and Drugs” is another resource
developed by Alberta Health Services (AHS), and “Do Bugs
Need Drugs” was developed by AHS and the British Columbia
Centre for Disease Control (46, 47). Furthermore, an innovative
University of Calgary AMS “app” has been modeled by many
sites globally (48). These initiatives represent advances in
treatment optimization and information availability. However,
there is opportunity for substantial progress regarding uptake
of prescribing recommendations, including sustained behavior
change, increasing public knowledge and expectations, as well
as altering the social environment, culture and value systems
surrounding AMU. A
key
factor
in
reducing
AMU
is
reducing
disease
prevalence/burden. Non-antimicrobial alternatives for infection
prevention, e.g., vaccines and alternative therapies (i.e., phages,
lysins, antimicrobial adjuvants, probiotics, and microbiome
alterations) are being explored to prevent or treat infections (21). These alternatives should be considered crucial for treatment
optimization, to reduce unnecessary AMU; however, their short
and long-term efficacy is currently unknown (Table 1), and they
have yet to dramatically reduce AMU. Frontiers in Public Health | www.frontiersin.org AMU in the Environment
Current Knowledge There are opportunities for further AMU reduction in
Canadian livestock. For example, the majority of AMU on
Canadian dairy farms is for mastitis treatment and prevention
(56, 57). Blanket dry cow therapy practices are most common;
at the end of lactation (start of the dry period), dairy cows
are prophylactically treated with intramammary antibiotics to
cure current bacterial infections and prevent new ones (58). Alternatively, selective dry cow therapy targets cattle expected to
benefit from antibiotics (58), with no effect on animal production
and udder health if cattle are selected appropriately (59–61). Therefore, this can reduce livestock-associated AMU in Canada. Antimicrobials are used in agriculture for crop management
and released into marine environments through aquaculture
via feed or water (6–9, 39). Less than 1% of Canadian AMU
is attributed to crop management (39), including streptomycin
for treatment of fire blight (72). However, due to wastewater
discharges (73–75), application of sewage-derived biosolids
(76), and farm manure and animal production facility runoff
(77), the environment is where human and animal AMU
intersect, in addition to specific AMU for agricultural purposes
(18). The environment is also a primary source of resistance
genes (78) and a site for persistence and amplification (i.e.,
horizontal gene transfer) to pathogens of potential concern (79). Therefore, reducing human and animal AMU will not eliminate
AMR (80). This example highlights the importance of context when
evaluating AMS initiatives. Research is required to develop best
management practices to reduce livestock-associated AMU but
maintain animal health and production (Table 1). In addition,
research is underway on various approaches to reduce AMU in
livestock, including vaccinations, pre- and probiotics, selection
of animals less susceptible to disease (62–64), etc. However, their
development and uptake has yet to dramatically reduce on farm
AMU, with further work required. Environmental reservoirs may facilitate maintenance of
high concentrations of AMR bacteria due to on-going use
of co-selecting agents, e.g., widespread use of biocides (18,
81) and disinfectants in municipal water and wastewater
treatment (82, 83). In vitro studies demonstrated that using
common herbicides on crops can modulate AMR to common
antimicrobials in indicator bacteria (Escherichia coli) and
foodborne pathogens (Salmonella spp.) (84). Additionally, in
paleontological studies of soil cores, heavy metal pollution
in historical industrial areas may have co-selected for AMR
genes to antimicrobials of importance to human medicine
before the advent of penicillin (85). There is evidence for
global dissemination of E. What Is Missing? Most unnecessary AMU in humans is not related to gaps in
prescriber knowledge, but instead to other factors at the provider
and/or patient-level, interplaying with various contextual factors
(42). Further understanding of these contextual prescribing
factors represents a major knowledge gap that must be
addressed for practical AMS recommendations to be developed As
of
December
1,
2018,
all
“medically
important
antimicrobials” (53) for veterinary use became limited to October 2021 | Volume 9 | Article 726484 Frontiers in Public Health | www.frontiersin.org 4 Knowledge Gaps in Antimicrobial Resistance McCubbin et al. prescription-only access in Canada (33), which will improve
assessment of AMU in Canada and reduce inappropriate use. Many antimicrobials deemed as “last resort” to treat infections
in people are already restricted from use in livestock, or
limited to prescription-only access, and livestock industries
are adopting voluntary policies to avoid these compounds for
disease prophylaxis, as exemplified by the Chicken Farmers
of Canada AMU reduction strategy (54). Additionally, the
Québec government restricted Category I AMU in food animals
starting February 25th, 2019 (Category I antimicrobials are of
high importance in human clinical disease) (55). Specifically,
preventative use of Category I antimicrobials is banned, and
clinical use is only permitted in livestock for cases where
antimicrobials of a lower class of importance to human medicine
will not be effective (e.g., based on culture and sensitivity) (55). Long-term impacts of this provincial stewardship program
are unknown. also be altered to shift prescribing expectations and limit social
pressure on prescribers. The Canadian Veterinary Medical
Association provides AMU guidelines to improve veterinary
prescribing decisions (67). Furthermore, relationships between
companion animal AMR development or acquisition and impact
on other species (including humans) or the environment are
currently unknown (Table 1). also be altered to shift prescribing expectations and limit social
pressure on prescribers. The Canadian Veterinary Medical
Association provides AMU guidelines to improve veterinary
prescribing decisions (67). Furthermore, relationships between
companion animal AMR development or acquisition and impact
on other species (including humans) or the environment are
currently unknown (Table 1). Current AMR impacts on wildlife and their contributions
to dissemination of resistant bacteria or genes are unknown
(18). Whereas AMR is reportedly higher in farmed animals vs. wildlife (68), AMR bacteria were reported in remote wildlife
(69–71), questioning impacts of human activities on wildlife
populations. What Is Missing? Overall, the intricacies of microbial population
interactions among various animal species and their relationship
to human and environmental AMR and use are unknown. What Is Missing? Similar
to
human
medicine,
prescribing
guidelines
on
appropriate companion animal and livestock AMU require
improvement. However,
to
improve
uptake
of
AMS
recommendations,
veterinarian-public
expectations
must AMU in the Environment
Current Knowledge coli that is highly resistant to
wastewater treatment and has resistance genes to antimicrobials
important to human medicine, with genetic similarity to
virulence genes of urinary pathogenic E. coli, raising questions
about this exposure pathway for humans (86, 87). The spread
of resistant strains and resistance genes may be a dominant
contributor to AMR maintenance, with sanitation and water
treatment having a large role in reducing AMR transmission
(88, 89). Antimicrobials for companion animals accounted for only
1% of total antimicrobial sales in 2016 (50). However,
companion animals are more likely to receive Category I and
II antimicrobials (39) closely related to human medications. This, and the close proximity of humans and their pets creates
potential for transmission of organisms resistant to highly
important antimicrobials. AMR bacteria have been reported
in
companion
animals. For
example,
methicillin-resistant
Staphylococcus pseudintermedius (MRSP), causes common and
sometimes untreatable skin and surgical site infections in
dogs (65). Furthermore, humans with methicillin-resistant
Staphylococcus aureus (MRSA), a bacteria of public health
concern, can infect companion animals, which are a source of
infection or reinfection (66). What Is Missing? Regrettably, these systems do not encompass the full scope of
Canadian AMR and AMU. Data on environmental AMR are
typically outside their mandates and therefore missing, and
information is frequently not linked across systems (94). CIPARS
is the only program purposefully designed to be an integrated
AMR/AMU surveillance program, whereas others use various
infectious disease platforms to collect AMR/AMU data (94). There are important gaps for a truly comprehensive, integrated,
One Health AMR/AMU surveillance system in Canada (Table 1). Several of these gaps are reflected in the “Federal action plan
on antimicrobial resistance and use in Canada” (99) and the
“Pan-Canadian framework for action” (30) but they still exist. What Is Missing? Direct impacts of human or animal AMU or antimicrobial
residues in the environment and impact of AMR in the October 2021 | Volume 9 | Article 726484 Frontiers in Public Health | www.frontiersin.org 5 Knowledge Gaps in Antimicrobial Resistance McCubbin et al. select bacteria mainly from humans, animals, and the food
supply chain. environment and subsequent impacts on humans and animals
are not well-characterized (Table 1). It is difficult to quantify
impacts of human and animal AMU and AMR on the
environment, but there is a strong correlation between socio-
economic, health and environmental factors and AMR gene
abundance in untreated human sewage (90). - Canadian
Nosocomial
Infection
Surveillance
Program
(CNISP): Collects information on AMR/AMU for nosocomial
infections in hospitalized human patients. - Canadian
Tuberculosis
Laboratory
Surveillance
System:
All tuberculosis cases diagnosed in Canada are reported
(with/without treatment started) for: citizens, permanent
residents, refugees, refugee claimants, and protected people. For temporary residents, only cases where treatment was
started in Canada are reported. AMU is a major risk factor for development of AMR bacteria
and their environmental presence. Although broad exposure
may occur via pathways such as drinking water, there are
limited data to quantify direct human health effects from
environmental AMR, another major knowledge gap (Table 1)
(18, 91). Regardless, substantial reduction of antimicrobial
misuse through treatment optimization/AMS programs can
lessen
selection
pressure
on
microbial
communities
(1). AMS programs should also include reductions in direct
application
of
manures/biosolids
to
land
(92). Although
the
environment
may
have
a
quantitatively
minor
role
compared to human-to-human and animal/food-to-human
pathways, it may still be critical in overall AMR impact
reduction (93), as demonstrated in developing areas (88). Therefore, environmental reservoirs should be integral to
development of strategic AMR mitigation. First, there must
be research to quantify AMR presence in the environment,
impact
of
AMU
in
humans
and
animals,
and
other
factors promoting AMR development and maintenance in
the environment. - The
Gonococcal
Antimicrobial
Surveillance
Program
(GASP-Canada): Laboratory surveillance data for Neisseria
gonorrhoeae isolated by provincial microbiology laboratories
to the National Microbiology Laboratory (NML). - Pest Management Regulatory Agency (of Health Canada):
Provides AMU data for crop production to CIPARS. p p
- The
National
Laboratory
Surveillance
of
Invasive
Streptococcal Disease (eSTREP): Passive and voluntary
collaboration with provincial public health laboratories for
S. pneumoniae and Streptococcus pyogenes surveillance, with
some provinces only submitting a subset of isolates. Current Knowledge Surveillance is essential to demonstrate trends and monitor
emerging and re-emerging AMR pathogens and AMU across all
health sectors and provide data to support stewardship to address
AMR (30). Surveillance data provide crucial information to
identify areas for strategic interventions, increase understanding
of the magnitude of AMR impacts and provide context to assess
impacts of AMS interventions. Without sustained surveillance
regarding AMR/AMU across the One Health continuum, public
health authorities and policymakers in government and industry
will lack information to craft and evaluate appropriate policy
responses (30). Without full integration and comparability of collected data,
understanding is limited regarding local drivers of AMR and
ensuing impacts. For example, CIPARS represents a national
surveillance system with a One Health approach but consists
only of active AMR surveillance for select bacteria in chickens,
turkeys, pigs, dairy and recently, feedlot cattle, and passive
reporting in humans and other animal species (Figure 1) (51). Further, on-farm components of CIPARS rely on a limited
number of sentinel farms within their chicken, turkey, pig and
feedlot programs, and some (e.g., pigs) are limited to final
production phases. There is also a lack of information on
AMR prevalence in companion animals and risks due to close
proximity to humans. Surveillance for AMU/AMR in Canada has increased, but not
all sectors or species affected by AMR are in a holistic system,
which remains a compilation of multiple programs (94). There
are currently surveillance systems at various levels of government
aimed at data collection on AMR and AMU in Canadian settings
such as hospitals, communities, and farms (30, 94). Ongoing
National Canadian surveillance programs include (8, 30, 39, 94–
98): - Canadian
Antimicrobial
Resistance
Surveillance
System
(CARSS):
Incorporates
epidemiological
and
laboratory
AMR/AMU data from the Public Health Agency of Canada’s
surveillance systems (listed immediately below), from human,
production animal, and food sources. Up-to-date
AMR
prevalence
estimates
for
other
species/sectors, e.g., prevalence in the general human population,
on-farm data for multiple livestock species, and wildlife are
lacking. Frontiers in Public Health | www.frontiersin.org Current Knowledge This represents an urgent knowledge gap (Table 1);
without current AMR prevalence estimates across all relevant
sectors in Canada, there are no benchmarks to evaluate
established mitigation strategies or identify important areas for - Canadian Integrated Program for Antimicrobial Resistance
Surveillance (CIPARS): Monitors trends in AMR/AMU for - Canadian Integrated Program for Antimicrobial Resistance
Surveillance (CIPARS): Monitors trends in AMR/AMU for October 2021 | Volume 9 | Article 726484 Frontiers in Public Health | www.frontiersin.org 6 Knowledge Gaps in Antimicrobial Resistance McCubbin et al. FIGURE 1 | Canadian Integrated Program for Antimicrobial Resistance Surveillance program methods regarding AMR and AMU surveillance, from the Public Health
Agency of Canada (51). FIGURE 1 | Canadian Integrated Program for Antimicrobial Resistance Surveillance program methods regarding AMR and AMU surveillance, from the Public Health
Agency of Canada (51). FIGURE 1 | Canadian Integrated Program for Antimicrobial Resistance Surveillance program methods regarding AMR and AMU surveillance, from the Public Health
Agency of Canada (51). policy development. Furthermore, comprehensive surveillance
of AMR prevalence could inform patient treatments (3). According
to
the
Council
of
Canadian
Academies,
weaknesses
in
current
Canadian
AMR/AMU
surveillance
include limited data on: (1) infections of priority pathogens
in community settings (i.e., non-hospitalized patients); (2)
AMU in many regions of Canada; (3) AMR in pathogens
of domestic animals and wildlife; (4) lack of an established
federal/provincial/territorial
surveillance
system;
and
(5)
lack
of
access
to
collected
data
(21). Furthermore,
sustained
surveillance
of
AMR
development,
persistence
and transmission through the environment is not established. There are very limited data on resistance determinants in the
environment. CIPARS does track AMU in some agricultural
components (51), but there is no clear understanding of
environmental AMR in Canada. CIPARS represents a substantial
contribution to the surveillance and understanding of AMR policy development. Furthermore, comprehensive surveillance
of AMR prevalence could inform patient treatments (3). in
Canada
and
provides
a
world-recognized
framework
for integrated surveillance. It highlights the importance of
continued AMR mitigation efforts (51), yet also identifies
important
surveillance
gaps
needing
more
coordination
and resources. of AMR prevalence could inform patient treatments (3). Frontiers in Public Health | www.frontiersin.org Current Knowledge According
to
the
Council
of
Canadian
Academies,
weaknesses
in
current
Canadian
AMR/AMU
surveillance
include limited data on: (1) infections of priority pathogens
in community settings (i.e., non-hospitalized patients); (2)
AMU in many regions of Canada; (3) AMR in pathogens
of domestic animals and wildlife; (4) lack of an established
federal/provincial/territorial
surveillance
system;
and
(5)
lack
of
access
to
collected
data
(21). Furthermore,
sustained
surveillance
of
AMR
development,
persistence
and transmission through the environment is not established. There are very limited data on resistance determinants in the
environment. CIPARS does track AMU in some agricultural
components (51), but there is no clear understanding of
environmental AMR in Canada. CIPARS represents a substantial
contribution to the surveillance and understanding of AMR To fully utilize and integrate data generated by CARSS
and
other
programs
and
agencies
globally,
international
standards for AMR and AMU data collection and reporting
among human health, veterinary, and agricultural sectors
are required, but absent (3, 94). Without comparable data
among species, sectors, and regions, global understanding
of AMU/AMR is impossible. In addition to implementation
of reporting standards, data must be of good quality, and
accessible to researchers and policymakers. There is also
a need for measurable goals and evaluation criteria when
considering surveillance data. Without practical and actionable
goals that meet provincial and national needs, progress October 2021 | Volume 9 | Article 726484 Frontiers in Public Health | www.frontiersin.org 7 Knowledge Gaps in Antimicrobial Resistance McCubbin et al. to control development of AMR cannot be measured or
made (3). environmental development and transfer and AMR include: (1)
surveillance of clinical and environmental AMU, AMR, and
their determinants; (2) epidemiological investigations of AMR
outbreaks and sporadic cases; (3) identification of selection
pressures in various environments and transmission to human-
relevant bacteria; (4) links between AMU and resistance (human,
laboratory, and/or field animal/crop); (5) AMR characteristics
and their determinants; (6) links among AMR, virulence,
and ecological fitness; (7) environmental fate of antimicrobial
residues in water and soil, and their bioavailability associated
with AMR selection; and (8) risk assessments of AMR and
related pathogens (104). These data are lacking. Limitations for
acquiring these data includes some soil bacteria are difficult to
culture and acquiring accurate data from flowing water is difficult
as it is inherently dynamic and diluting (18). DISCUSSION There are numerous knowledge gaps in understanding AMR in
Canada. AMR is complex, with many contributing factors,
numerous
antimicrobial
end
users,
countless
microbial
interactions, and varying policies and regulatory capacities
around the world. Substantial progress will require much
investment in AMR research, surveillance, and capacity building,
coupled with effective policies at national, provincial/territorial
and local levels. “Every infection prevented is one that needs no treatment.”
World Health Organization, 2015 Current Knowledge Treatment optimization and AMS are important in preventing
AMR transmission, as they reduce the overall burden of
resistance on the microbiome, limiting risk of transmission. AMS efforts in human hospitals have improved AMU quality
(100), and there are associations between reductions in livestock
AMU production system AMR prevalence (6, 101). Additionally,
there were decreases in human occupation-associated AMR
infections in affected production systems (6). Therefore, it is
very important to promoting reductions in unnecessary AMU
across sectors. Without considering all drivers and pathways of AMR
introduction into the environment, any strategy to reduce
resistance across all sectors risks failure (18). To mitigate
development
and
transmission
of
AMR
bacteria,
the
environment must be considered an important reservoir and
policy changes must encompass agricultural and environmental
best practices along with those in human and veterinary
medicine. Currently, a key knowledge gap in AMR transmission
prevention is limited understanding of quantitative risks to
identify the relative importance of various AMR development
and transmission incursion pathways (Table 1). Antimicrobials are important to treat, prevent, and control
infectious diseases and maintain animal health and welfare in
intensive livestock production (18, 49). By decreasing the reliance
on AMU in intensive farming systems, emphasis on other forms
of biosecurity must be increased, as well as farm infrastructure,
management and breeding practices designed to improve animal
health and resilience to reduce disease transmission risk, with
increasing costs for producers and consumers. Additionally, infection prevention and control procedures are
invaluable to prevent transmission of AMR bacteria. Improved
adjacent infection control efforts could further limit AMU. While this refers to sterility and hygienic practices for humans
and animals (30), it also refers to maintaining healthy microbial
populations
that
resist
recolonization
and
opportunistic
infections with resistant bacteria. Maintaining healthy microbial
populations is critical for immunocompromised individuals,
livestock, and crop production systems. PREVENTION OF TRANSMISSION OF AMR As much of the world’s population, including Canadians
(105), obtain drinking water from excreta-impacted waters
that likely contain AMR bacteria, there is an urgent need
to better understand what concentration limits should be
considered to better manage potential mass-inoculation of people
with resistance genes (106). However, the only antimicrobial
concentration limits under consideration relate to wastewaters
(107). Not surprisingly, there are AMR genes in Canadian
urban sewage (90, 108). Furthermore, the prevalence of AMR
genes in treated effluent leaving water treatment facilities in the
Canadian prairies provides evidence for human influence on
local environmental reservoirs of resistance (108). Current Knowledge Human health care is primarily provincially funded and
regulated in Canada, whereas veterinary and environmental
sectors
have
substantial
federal
and
provincial/territorial
components,
requiring
cooperation/collaboration
among
governments and engagement of all sectors and relevant
stakeholders. In summary, due to the interconnectedness of
AMR development, Canada could benefit from integration
and standardization of human, animal, and environmental
AMU/AMR
data
collection. This
requires
coordination
of existing surveillance systems and addition of broader
environmental
considerations
to
capture
local
drivers
of AMR. “Every infection prevented is one that needs no treatment.”
World Health Organization, 2015 What Is Missing? Various knowledge gap assessments (16, 109) and action
plans have been developed regarding AMR, including the
WHO Global Action Plan (3) and the Federal action plan
on antimicrobial resistance and use in Canada (99). Most
requirements detailed in this review (Figure 2), developed
for the three key areas (treatment optimization, surveillance,
and transmission), are logical continuations of described Despite new knowledge regarding the role of the environment
in preventing AMR, much remains unknown; however, the
environment is likely an important reservoir of resistance genes
(2, 23, 27–29, 85). AMR development in the environment
is attributed to AMU, plus other pharmaceutical agents and
heavy metals (17, 84, 85, 102, 103). Data and knowledge
required to undertake a human health risk assessment for October 2021 | Volume 9 | Article 726484 Frontiers in Public Health | www.frontiersin.org 8 Knowledge Gaps in Antimicrobial Resistance McCubbin et al. action plans with focus on the Canadian context. Moreover,
the One Health approach used in this review identified
additional novel gaps for Canada. Prioritization of required
investments and activities must be considered with further
cooperation
and
coordination
among
existing
initiatives. Required
efforts
to
address
described
knowledge
gaps
are described in Figure 2 and separated into categories:
(1) further research, (2) increased capacity/resources, (3)
increased
prescriber/end-user
knowledge,
and
(4)
policy
development/enforcement. Each
knowledge
gap
has
been
assigned one or more categories as required changes for the gap
to be addressed. mitigation efforts are effective. In contrast, increasing end-user
knowledge regrading appropriate AMU and challenging clinical
visit expectations in both human and animal medicine is a
shift in focus from research to increasing end-user knowledge. However, this must include further understanding of drivers
and barriers of AMS to increase recommendation uptake
to facilitate sustained behavior change. Research surrounding
this will focus on bridging the gap between knowledge
and practice. Increased
capacity/resources
should
accompany
further
research,
as
increased
funding,
research
activity
design/development, laboratory capacity, data analysis and
publishing/knowledge transfer are required for research to be
effective and to inform decisions in policy and influence end-user
decision-making. However, capacity and financial support for
required research may be inadequate. For example, Canada’s
research and development support for new antimicrobials is
severely lacking (110). Therefore, without an incentivized market
for new antimicrobial development, progress fostering required
research is unlikely. Research and increased capacity/resources are required to
fully address all knowledge gaps. What Is Missing? Required research is similar
across the human, animal, and environmental sectors (108) and
will enable development of specific recommendations, to ensure
they are effective and practical. Otherwise, general uptake and
AMR mitigation may be limited. Furthermore, understanding
of environmental components is severely lacking, and requires
immediate research and capacity building to ensure AMR FIGURE 2 | Knowledge gaps and their requirements to be addressed as organized into four categories. BMPs, Best management practices; AMU, Antimicrobial use;
AMR, Antimicrobial resistance. FIGURE 2 | Knowledge gaps and their requirements to be addressed as organized into four categories. BMPs, Best management practices; AMU, Antimicrobial use;
AMR, Antimicrobial resistance. October 2021 | Volume 9 | Article 726484 9 Frontiers in Public Health | www.frontiersin.org Knowledge Gaps in Antimicrobial Resistance McCubbin et al. environmental containment, etc.). Although, in general, AMR
understanding and mitigation attempts should follow the
following roadmap: (1) detailed understanding of missing data
required to inform realistic policies and best management
practices, (2) implementation and ongoing evaluation of policies
and recommendations at the community, provincial/territorial,
and national levels, (3) sustainable implementation with ongoing
evaluation to account for new innovations and AMU/AMR
surveillance findings (16). Additionally, to lay the groundwork
for changes in antimicrobial prescribing and use, must be
accompanied by public educational campaigns to improve
general understanding of the risks associated with AMR and
unnecessary AMU, but also to increase social responsibility. In
summary, AMS cannot be considered as separate actions in
human, animal, and environmental sectors. Bacteria that develop
resistance in one sector have potential to extend to other sectors;
therefore, immediate, and concerted action across all sectors is
necessary. This can be done by taking a One Health approach to
optimize global health and well-being. An
emphasis
on
“further
research”
and
“increased
capacity/resources” does not imply that other requirements are
less important. Rather, it highlights a lack of required knowledge
and understanding to develop effective policy/recommendations. The lack of best management practices for AMU and AMS
programs, serve as an example. Reductions in prophylactic AMU were not considered
possible but became feasible with better farm management
and biosecurity. However, not all food animal industries
are equally ready to implement management practices that
reduce AMU. Research into best management practices is
required for sustained AMU reduction that does not negatively
impact animal health and welfare. What Is Missing? However, this will require
substantial investment in long-term research to establish a causal
link between AMU reductions and AMR implications which
progresses into practical policy development and enforcement. The Canadian poultry industry had some success with a
voluntary AMS program (51, 54). After banning 3rd generation
cephalosporins in 2014, Salmonella isolates from sick people, and
Salmonella and E. coli isolates from chickens at slaughter and
retail meat had lower 3rd generation cephalosporin resistance
(51). However, in 2018, despite no reported 3rd generation
cephalosporin use, there was a slight increase in healthy chickens
with Salmonella resistant to these products (51). Prudent
AMU
can
still
allow
development
of
AMR;
however, rigorous management can limit the risks (1). The
victory over AMR is never final; rather there is an ongoing
battle that requires constant surveillance and AMS practice. With continued surveillance and research into the described
knowledge gaps, a more thorough understanding of the complex
relationships between microbial communities can be obtained. Additionally, behaviors of antimicrobial prescribers, consumers,
and distributors require further investigation, as they are key to
appropriate AMS measures. If this is combined with collaborative
and sustained mitigation efforts across all sectors, we can preserve
effective treatment options for bacterial infections throughout
the One Health continuum in the future. Additionally, further collaborative surveillance programs are
required to assess the degree of human impact on various
ecosystems and determine best relative mitigation efforts. Despite
being previously identified as an important gap (30), substantial
progress has not occurred. This should also include research
regarding impacts of co-selection of AMR by common cleaning
agents in animal production facilities and human hospitals (18). This should be coupled with research into transmission of
AMR bacteria between species, AMR contamination pathways
of groundwater, including discharge of antimicrobial residues
in sewage and disposal of antimicrobial waste (i.e., unused or
expired drugs, packaging with residual drug). FUNDING This research was part of the Antimicrobial Resistance–One
Health Consortium, which is predominantly financed by the
Ministry of Jobs, Economy and Innovation, Alberta, Canada. KDMcC was supported by Canadian Dairy Commission
Workplace
Development
Initiative
Scholarship,
NSERC
CREATE in Milk Quality Program Scholarship and the NSERC
Alexander Graham Bell Canada Graduate Scholarship. Prioritization of required activities is needed to focus efforts
and available resources; however, without answers to some
of these knowledge gaps, it is difficult to identify the most
pressing areas to act (i.e., restrict AMU, prescribing best practices, AUTHOR CONTRIBUTIONS This manuscript has been prepared by KDMcC, with supervision
from HB and RMA. EdJ, JI, DN, JK, JC, MG, TM, KO, IL, LJ, GP,
H-JW, KMcC, ML, JR, LH, AH, NA, SC, GT, AB, ER-M, EG, and
SO contributed significantly to the intellectual content related
to their respective fields. All authors contributed to manuscript
revision, as well as read, and approved the submitted version. Although surveillance is essential to understanding AMR and
AMU trends, generalization of their results across bacteria or
antimicrobials can falsely inform mitigation efforts. A substantial
aid in development of AMS best practices and prioritization
efforts will be quantitative risk-based assessments of AMR
development and the relationship among human, animal, and
environmental sectors. With risk-based models, policymakers
can be better informed to use available resources to target areas
of high importance. Coupled with the social and behavioral
research components, this will promote improvements on a
national level. en/323311493396993758/pdf/114679-REVISED-v2-Drug-Resistant-
Infections-Final-Report.pdf (accessed June 15, 2021).
2. Roca
I,
Akova
M,
Baquero
F,
Carlet
J,
Cavaleri
M,
Coenen
S,
et
al.
The
global
threat
of
antimicrobial
resistance:
science
for 1. World Bank. Drug Resistant Infections: A Threat to Our Economic Future.
(2017).
Available
online
at:
http://documents.worldbank.org/curated/ REFERENCES The
shared antibiotic resistome of soil bacteria and human pathogens. Science. (2012) 337:1107–11. doi: 10.1126/science.1220761 8. Fisheries and Oceans Canada. National Aquaculture Public Reporting
Data. (2021). Available online at: https://open.canada.ca/data/en/dataset/
288b6dc4-16dc-43cc-80a4-2a45b1f93383 (accessed June 15, 2021). 29. Hatsosy
SM,
Martiny
AC. The
ocean
as
a
global
reservoir
of
antibiotic resistance genes. Appl Environ Microbiol. (2015) 81:7593–9. doi: 10.1128/AEM.00736-15 9. Sarmah AK, Meyer MT, Boxall ABA. A global perspective on the use,
sales, exposure pathways, occurrence, fate, and effects of veterinary
antibiotics (VAs) in the environment. Chemosphere. (2006) 65:725–59. doi: 10.1016/j.chemosphere.2006.03.026 30. Public Health Agency of Canada. Tackling Antimicrobial Resistance
and Antimicrobial Use: A Pan-Canadian Framework for Action. (2017). Available
online
at:
https://www.canada.ca/en/health-canada/services/
publications/drugs-health-products/tackling-antimicrobial-resistance-use-
pan-canadian-framework-action.html (accessed June 15, 2021). 10. Malani
PN. Lefamulin—a
new
antibiotic
for
community-acquired
pneumonia. JAMA. (2019) 322:1671–2. doi: 10.1001/jama.2019.16215 11. Deoghare S. Bedaquiline: a new drug approved for treatment of
multidrug-resistant tuberculosis. Indian J Pharmacol. (2013) 45:536–7. doi: 10.4103/0253-7613.117765 31. Ad-Hoc Committee for Antimicrobial Stewardship in Canadian Agriculture
and Veterinary Medicine. Stewardship of antimicrobial drugs in animals in
Canada: how are we doing? Can Vet J. (2014) 55, 273–6. 12. United States of America Food and Drug Administration. FDA Approves
New Drug for Treatment-Resistant Forms of Tuberculosis That Affects
the Lungs. (2019). Available online at: https://www.fda.gov/news-events/
press-announcements/fda-approves-new-drug-treatment-resistant-forms-
tuberculosis-affects-lungs (accessed June 15, 2021). 32. Om C, Daily F, Vlieghe E, McLaughlin JC, McLaws ML. “If it’s
a
broad
spectrum,
it
can
shoot
better”:
inappropriate
antibiotic
prescribing in Cambodia. Antimicrob Resist Infect Control. (2016) 5:58. doi: 10.1186/s13756-016-0159-7 13. Gelband H, Miller-Petrie M, Pant S, Gandra S, Levinson J, Barter D, et al. The
state of the world’s antibiotics 2015. Wound Heal South Afr. (2015) 8:30–4. 33. Public Health Agency of Canada. Responsible Use of Medically Important
Antimicrobials in Animals. (2021). Available online at: https://www.canada. ca/en/public-health/services/antibiotic-antimicrobial-resistance/animals/
actions/responsible-use-antimicrobials.html (accessed June 15, 2021). 14. Pelfrene E, Botgros R, Cavaleri M. Antimicrobial multidrug resistance in the
era of COVID-19: a forgotten plight? Antimicrob Resist Infect Control. (2021)
10:21. doi: 10.1186/s13756-021-00893-z 34. Lu J, Sheldenkar A, Lwin MO. A decade of antimicrobial resistance research
in social science fields: a scientometric review. Antimicrob Resist Infect
Control. (2020) 9:178. doi: 10.1186/s13756-020-00834-2 15. Strathdee SA, Davies SC, Marcelin JR. Confronting antimicrobial resistance
beyond the COVID-19 pandemic and the 2020 US election. Lancet. (2020)
396:P1050-3. doi: 10.1016/S0140-6736(20)32063-8 35. Higgins HM, Golding SE, Mouncey J, Nanjiani I, Cook AJC. Understanding
veterinarians’ prescribing decisions on antibiotic dry cow therapy. J. REFERENCES 1. World Bank. Drug Resistant Infections: A Threat to Our Economic Future. (2017). Available
online
at:
http://documents.worldbank.org/curated/ October 2021 | Volume 9 | Article 726484 Frontiers in Public Health | www.frontiersin.org 10 Knowledge Gaps in Antimicrobial Resistance McCubbin et al. intervention. Microbes Infect. (2015) 6:22–9. doi: 10.1016/j.nmni.2015. 02.007 intervention. Microbes Infect. (2015) 6:22–9. doi: 10.1016/j.nmni.2015. 02.007 22. O’Neill J. Tackling Drug-Resistant Infections Globally: Final Report on
Recommendations. (2016). Available online at: https://amr-review.org/sites/
default/files/160525_Final%20paper_with%20cover.pdf (accessed June 15,
2021). 3. World Health Organization. Global Action Plan on Antimicrobial Resistance. (2015). Available
online
at:
https://apps.who.int/iris/bitstream/handle/
10665/193736/9789241509763_eng.pdf?sequence$=$1 (accessed June 15,
2021). 23. Leonard AFC, Zhang L, Balfour AJ, Garside R, Hawkey PM, Murray AK,
et al. Exposure to and colonisation by antibiotic-resistant E. coli in UK
coastal water users: environmental surveillance, exposure assessment, and
epidemiological study (Beach Bum Survey) . Environ Int. (2017) 114:326–33. doi: 10.1016/j.envint.2017.11.003 4. Davies J, Davies D. Origins and evolution of antibiotic resistance. Microbiol
Mol
Bio
R. (2010)
74:417–33. doi:
10.1128/MMBR.0
0016-10 5. World Health Organization, Food and Agriculture Organization of the
United Nations, World Organization for Animal Health. Antimicrobial
Resistance: A Manual for Developing National Action Plans. (2016). Available
online
at:
https://apps.who.int/iris/bitstream/handle/10665/
204470/9789241549530_eng.pdf?sequence=1 (accessed June 15, 2021). 24. Murphy D, Ricci A, Auce Z, Beechinor JG, Bergendhal H, Breathnach R, et al. MA and EFSA joint scientific opinion on measures to reduce the need to
use antimicrobial agents in animal husbandry in the European Union, and
the resulting impacts on food safety (RONAFA). EFSA J. (2017) 15:e04666. doi: 10.2903/j.efsa.2017.4666 25. Woolhouse ME, Ward MJ. Sources of antimicrobial resistance. Science. (2013) 341:1460–1. doi: 10.1126/science.1243444 6. Tang KL, Caffrey NP, Nóbrega DB, Cork SC, Ronksley PE, Barkema HW,
et al. Restricting the use of antibiotics in food-producing animals and its
associations with antibiotic resistance in food-producing animals and human
beings: a systematic review and meta-analysis. Lancet Planet Health. (2017)
1:e316–27. doi: 10.1016/S2542-5196(17)30141-9 26. Laxminarayan R, Duse A, Wattal C, Zaidi AKM, Wertheim HFL,
Sumpradit N, et al. Antibiotic resistance – the need for global solutions. Lancet
Infect
Dis. (2014)
13:1057–98. doi:
10.1016/S1473-3099(13)7
0318-9 7. Centers for Disease Control and Prevention. Antimicrobial Resistance
Threats in the United States. (2019). Available online at: https://www.cdc.gov/
drugresistance/pdf/threats-report/2019-ar-threats-report-508.pdf (accessed
June 15, 2021). 27. James E, Wong CMVL. Antibiotic resistance among bacteria from Antarctic
and Tropics. Trans Sci Tech. (2015) 2:16–20. 28. Forsberg KJ, Reyes A, Wang B, Selleck EM, Sommer MOA, Dantas G. REFERENCES Ferreira JP, Anderson KL, Correa MT, Lyman R, Ruffin F, Reller LB, et al. Transmission of MRSA between companion animals and infected human
patients presenting to outpatient medical care facilities. PLoS ONE. (2011)
6:e26978. doi: 10.1371/journal.pone.0026978 48. University of Calgary. (2016). Available online at: https://ucalgary.ca/
news/new-app-helps-doctors-minimize-patients-resistance-antibiotics
https://ucalgary.ca/news/new-app-helps-doctors-minimize-patients-
resistance-antibiotics (accessed June 16). 49. Kirchhelle
C. Pharming
animals:
a
global
history
of
antibiotics
in
food
production
(1935–2017). Palgrave
Commun. (2018)
4:96. doi: 10.1057/s41599-018-0152-2 67. Canadian
Veterinary
Medical
Association. CVMA
Guidelines
for
Veterinary Antimicrobial Use. (2021). Available online at: https://www. canadianveterinarians.net/AMU-UAM (accessed June 15, 2021). 50. Public Health Agency of Canada. Canadian Integrated Program for
Antimicrobial Resistance Surveillance: Annual Report. (2016). Available
online at: http://publications.gc.ca/collections/collection_2018/aspc-phac/
HP2-4-2016-eng.pdf (accessed May 3, 2021). 68. Skarzy´nska M, Leekitcharoenphon P, Hendriksen RS, Aarestrup FM, Wasyl
D. A metagenomic glimpse into the gut of wild and domestic animals:
quantification of antimicrobial resistance and more. PLoS ONE. (2020)
15:e0242987. doi: 10.1371/journal.pone.0242987 69. Gillespie TR, Rwego I. Bacterial exchange between gorillas, humans, and
livestock in Bwindi. Gorilla J. (2009) 38:16–8. 51. Public
Health
Agency
of
Canada. The
Canadian
Integrated
Program
for
Antimicrobial
Resistance
Surveillance
(CIPARS):
2018
Integrated
Findings. (2020). Available
online
at:
https://
www.canada.ca/en/public-health/services/surveillance/canadian-
integrated-program-antimicrobial-resistance-surveillance-cipars/cipars-
reports/2018-annual-report-integrated-findings.html
(accessed
June
15, 2021). 70. Rabbia V, Bello-Toledo H, Jiménez S, Quezada-Aguiluz M, Domínguee M,
Vergara L et al. Antibiotic resistance in Escherichia coli strains isolated from
Antarctic bird feces, water from inside a wastewater treatment plant, and
seawater samples collected in the Antarctic Treaty area. Polar Sci. (2016)
10:123–31. doi: 10.1016/j.polar.2016.04.002 52. Butaye
P,
Devriese
LA,
Haesebrouck
F. Antimicrobial
growth
promoters used in animal feed: effects of less well known antibiotics
on
Gram-positive
bacteria. Clin
Microbiol
Rev. (2003)
16:175–88. doi: 10.1128/CMR.16.2.175-188.2003 71. Vittecoq M, Godreuil S, Prugnolle F, Durand P, Brazier L, Renaud N,
et al. Antimicrobial resistance in wildlife. J Appl Ecol. (2016) 53:519–29. doi: 10.1111/1365-2664.12596 72. Haynes E, Ramwell C, Griffiths T, Walker D, Smith J. Fera Science Ltd. Review of antibiotic use in crops, associated risk of antimicrobial resistance
and research gaps. Report to Department for Environment, Food and Rural
Affairs (Defra) & The Food Standards Agency (FSA). (2020). Available online
at: https://www.food.gov.uk/sites/default/files/media/document/review-of-
antibiotic-use-in-crops_0.pdf (accessed June 15, 2021). 53. Government of Canada. Categorization of Antimicrobial Drugs Based on
Importance in Human Medicine. (2009). Available online at: https://www. canada.ca/en/health-canada/services/drugs-health-products/veterinary-
drugs/antimicrobial-resistance/categorization-antimicrobial-drugs-based-
importance-human-medicine.html (accessed June 15, 2021). 54. Chicken Farmers of Canada. Antibiotics. (2021). Available online at: https://
www.chickenfarmers.ca/antibiotics/ (accessed June 15, 2021). 73. REFERENCES Dairy
Sci. (2017) 100:2909–16. doi: 10.3168/jds.2016-11923 16. Charani E, McKee M, Ahmad R, Balasegaram M, Bonaconsa C, Merrett GB,
et al. Optimising antimicrobial use in humans review of current evidence and
an interdisciplinary consensus on key priorities for research. Lancet Reg. (in
Press). doi: 10.1016/j.lanepe.2021.100161 36. Duncan EM, Charani E, Clarkson JE, Francis JJ, Gillies K, Grimshaw JM,
et al. A behavioural approach to specifying interventions: what insights can
be gained for the reporting and implementation of interventions to reduce
antibiotic use in hospitals? J Antimicrob Chemother. (2020) 75:1338–46. doi: 10.1093/jac/dkaa001 17. Wales AD, Davies RH. Co-selection of resistance to antibiotics, biocides and
heavy metals, and its relevance to foodborne pathogens. Antibiotics. (2015)
4:567–604. doi: 10.3390/antibiotics4040567 37. Baudoin F, Hogeveen H, Wauters E. Reducing antimicrobial use and
dependence in livestock production systems: a social and economic sciences
perspective on an interdisciplinary approach. Front Vet Sci. (2021) 8:584593. doi: 10.3389/fvets.2021.584593 18. Wall BA, Mateus A, Marshall L, Pfeiffer DU. Drivers, Dynamics and
Epidemiology of Antimicrobial Resistance in Animal Production. (2016). Available online at: http://www.fao.org/3/i6209e/i6209e.pdf (accessed June
15, 2021). 19. Robinson TP, Bu DP, Carrique-Mas J, et al. Antibiotic resistance is the
quintessential one health issue. Trans R Soc Trop Med Hyg. (2016) 110:377–
80. doi: 10.1093/trstmh/trw048 38. Klein EY, Van Boeckel TP, Martinez EM, Pant S, Gandra S, Levin SA,
et al. Global increase and geographic convergence in antibiotic consumption
between 2000 and 2015. Proc Natl Acad Sci USA. (2018) 15:E3463–70. doi: 10.1073/pnas.1717295115 20. World Health Organization. One Health. (2017). Available online at: https://
www.who.int/news-room/q-a-detail/one-health (accessed June 15, 2021). 39. Public Health Agency of Canada. Canadian Antimicrobial Resistance
Surveillance System: Update 2020. (2020). Available online at: https://www. canada.ca/en/public-health/services/publications/drugs-health-products/
canadian-antimicrobial-resistance-surveillance-system-2020-report.html
(accessed June 15, 2021). 21. Council of Canadian Academies. When Antibiotics Fail: The Expert Panel on
the Potential Socio-Economic Impacts of Antimicrobial Resistance in Canada. (2019). Available online at: https://cca-reports.ca/wp-content/uploads/2018/
10/When-Antibiotics-Fail-1.pdf (accessed June 15, 2021). October 2021 | Volume 9 | Article 726484 Frontiers in Public Health | www.frontiersin.org Frontiers in Public Health | www.frontiersin.org 11 Knowledge Gaps in Antimicrobial Resistance McCubbin et al. 40. National Collaborating Centre for Infectious Diseases. The Role of
Human Health and Animal Health in Antimicrobial Resistance. (2016). Available online at: https://nccid.ca/wp-content/uploads/sites/2/2016/08/
Katrime_Roles_Final_Eng.pdf (accessed June 15, 2021). 59. Santman-Berends IMGA, van den Heuvel KWH, Lam TJGM, Scherpenzeel
CGM, van Schaik G. REFERENCES Monitoring udder health on routinely collected
census
data:
evaluating
the
short-
to
mid-term
consequences
of
implementing selective dry cow treatment. J Dairy Sci. (2021) 104:2280–9. doi: 10.3168/jds.2020-18973 41. Penney CC, Boyd SE, Mansfield A, Dalton J, O’Keefe J, Daley PK. Antimicrobial use and suitability in long-term care facilities: a retrospective
cross-sectional study. Can J Infect Dis Med Microbiol. (2018) 3:209–16. doi: 10.3138/jammi.2018-0021 60. Rowe SM, Godden SM, Nydam DV, Gorden PJ, Lago A, Vasquez AK, et al. Randomized controlled trial investigating the effect of 2 selective dry-cow
therapy protocols on udder health and performance in the subsequent
lactation. J Dairy Sci. (2020) 103:6493–503. doi: 10.3168/jds.2019-17961 42. McKay R, Mah A, Law MR, McGrail K, Patrick DM. Systematic
review of factors associated with antibiotic prescribing for respiratory
tract
infections. Antimicrob
Agents
Chemother. (2016)
60:4106–18. doi: 10.1128/AAC.00209-16 61. Kabera F, Dufour S, Keefe G, Cameron M, Roy JP. Evaluation of
quarter-based selective dry cow therapy using Petrifilm on-farm milk
culture: a randomized controlled trial. J Dairy Sci. (2020) 103:7276–87. doi: 10.3168/jds.2019-17438 43. Gradmann C. Magic bullets and moving targets: antibiotic resistance
and experimental chemotherapy, 1900-1940. Dynamis. (2011) 31:305–21. doi: 10.4321/S0211-95362011000200003 62. Islam MA, Rony SA, Rahman MB, Cinar MU, Villena J, Uddin MJ,
et al. Improvement of disease resistance in livestock: application of
immunogenomics and CRISPR/Cas9 technology. Animals. (2020) 10:2236. doi: 10.3390/ani10122236 44. Gualano MR, Gill R, Scaioli G, Bert F, Siliquini R. General population’s
knowledge and attitudes about antibiotics: a systematic review and meta-
analysis. Pharmacoepidemiol Drug Saf. (2015) 24:2–10. doi: 10.1002/pds.3716 63. Markowiak P, Slizewska K. The role of probiotics, prebiotics and synbiotics
in animal nutrition. Gut Pathog. (2018) 10:21. doi: 10.1186/s13099-018-
0250-0 45. Choosing Wisely Canada. Using Antibiotics Wisely. Available online at:
https://choosingwiselycanada.org/campaign/antibiotics/ (accessed June 15,
2021). 64. Ismail ZB. Mastitis vaccination in dairy cows: recent developments
and recommendation of application. Vet World. (2017) 10:1057–62. doi: 10.14202/vetworld.2017.1057-1062 46. Alberta Health Services. Bugs & Drugs. (2021). Available online at: http://
www.bugsanddrugs.org (accessed June 15, 2021). 65. Bryan J, Frank LA, Rohrbach BW, Burgette LJ, Cain CL, Bemis DA. Treatment outcome of dogs with meticillin-resistant and meticillin-
susceptible Staphylococcus pseudintermedius pyoderma. Vet Dermatol. (2012) 23:361–8. doi: 10.1111/j.1365-3164.2012.01034.x 47. Alberta Health Services and British Columbia Centre for Disease Control. Do bugs need drugs? A Community Program for the Wise Use of Antibiotics. (2014). Available online at: http://www.dobugsneeddrugs.org (accessed June
15, 2021). 66. REFERENCES doi: 10.1038/nature25979 86. Zhi S, Banting G, Stothard P, Ashbolt NJ, Checkley S, Meyer K, et al. Evidence for the evolution, clonal expansion and global dissemination
of water treatment-resistant naturalized strains of Escherichia coli in
wastewater. Water Res. (2019) 156:208–22. doi: 10.1016/j.watres.2019. 03.024 102. Singer AC, Shaw H, Rhodes V, Hart A. Review of antimicrobial
resistance in the environment and its relevance of environmental
regulators. Front
Microbiol. (2016)
7:1728. doi:
10.3389/fmicb.2016. 01728 103. Dickinson AW, Power A, Hansen MG, Brandt KK, Piliposian G, Appleby
A, et al. Heavy metal pollution and co-selection for antibiotic resistance:
a microbial palaeontology approach. Environ Int. (2019) 132:105117. doi: 10.1016/j.envint.2019.105117 87. Zhi S, Stothard P, Banting G, Scott C, Huntley K, Ryu K, et al. Characterization of water treatment-resistant and multidrug-resistant
urinary pathogenic Escherichia coli in treated wastewater. Water Res. (2020)
182:115827. doi: 10.1016/j.watres.2020.115827 104. Ashbolt NJ, Amézquita A, Backhaus T, Borriello P, Brandt KK, Collingnon
P, et al. Human health risk assessment (HHRA) for environmental
development and transfer of antibiotic resistance. Environ Health Perspect. (2013) 121:993–1001. doi: 10.1289/ehp.1206316 88. Collignon
P,
Beggs
JJ,
Walsh
TR,
Gandra
S,
Laxminarayan
R. Anthropological
and
socioeconomic
factors
contributing
to
global
antimicrobial resistance: a univariate and multivariable analysis. Lancet
Planet Health. (2018) 2:e398–405. doi: 10.1016/S2542-5196(18)30186-4 105. Coleman BL, Louie M, Salvadori MI, McEwen SA, Neumann N, Sibley
K, et al. Contamination of Canadian private drinking water sources with
antimicrobial resistant Escherichia coli. Water Res. (2013) 47:3026–36. doi: 10.1016/j.watres.2013.03.008 89. Collignon P, Athukorla PC, Senanayake S, Khan F. Antimicrobial resistance:
the major contribution of poor governance and corruption to this growing
problem. PLoS ONE. (2015) 10:e0116746. doi: 10.1371/journal.pone.0116746 106. Sanganyado E, Gwenzi W. Antibiotic resistance in drinking water systems:
occurrence, removal, and human health risks. Sci Total Environ. (2019)
669:785–97. doi: 10.1016/j.scitotenv.2019.03.162 90. Hendriksen RS, Munk P, Njage P, van Bunnik B, McNally L, Lukjancenko
O, et al. Global monitoring of antimicrobial resistance based on
metagenomics analyses of urban sewage. Nat Commun. (2019) 10:1124. doi: 10.1038/s41467-019-08853-3 107. AMR Industry Alliance AMR Industry Alliance Antibiotic Discharge
Targets. List of Predicted no-Effect Concentrations (PNECs). (2018). Available
online at: https://www.amrindustryalliance.org/wpcontent/uploads/2018/
09/AMR_Industry_Alliance_List-of-Predicted-No-Effect-Concentrations-
PNECs.pdf (accessed June 15, 2021). 91. Huijbers P, Blaak H, de Jong MC, Graat EAM, Vandenbroucke-Grauls CMJE,
de Roda Husman AM. Role of the environment in the transmission of
antimicrobial resistance to humans: a review. Environ Sci Technol. (2015)
49:11993–2004. doi: 10.1021/acs.est.5b02566 92. REFERENCES Brown PC, Borowska E, Schwartz T, Horn H. Impact of the particulate
matter from wastewater discharge on the abundance of antibiotic resistance
genes and facultative pathogenic bacteria in downstream river sediments. Sci
Total
Environ. (2019)
649:1171–8. doi:
10.1016/j.scitotenv.2018. 08.394 55. Roy JP, Archambault M, Desrochers A, Dubuc J, Dufour S, Francoz D, et al. New Quebec regulation on the use of antimicrobials of very high importance
in food animals: implementation and impacts in dairy cattle practice. Can
Vet J. (2020) 61:193–6. 74. Khan FA, Söderquist B, Jass J. Prevalence and diversity of antibiotic resistance
genes in Swedish aquatic environments impacted by household and
hospital wastewater. Front Microbiol. (2019) 10:688. doi: 10.3389/fmicb.2019. 00688 56. Saini V, McClure JT, Léger D, Dufour S, Sheldon AG, Scholl DT, et al. Antimicrobial use on Canadian dairy farms. J Dairy Sci. (2021) 95:1209–21. doi: 10.3168/jds.2011-4527 75. Paulus GK, Hornstra LM, Alygizakis N, Slobodnik J, Thomaidis N,
Medema G. The impact of on-site hospital wastewater treatment on the
downstream communal wastewater system in terms of antibiotics and
antibiotic resistance genes. Int J Hyg Environ Health. (2019) 222:635–44. doi: 10.1016/j.ijheh.2019.01.004 57. Ruegg PL. 100-year review: mastitis detection, management, and prevention. J Dairy Sci. (2017) 100:10381–97. doi: 10.3168/jds.2017-13023 58. Lhermie G, Tauer LW, Gröhn YT. The farm cost of decreasing
antimicrobial use in dairy production. PLoS ONE. (2018) 13:e0194832. doi: 10.1371/journal.pone.0194832 October 2021 | Volume 9 | Article 726484 Frontiers in Public Health | www.frontiersin.org 12 Knowledge Gaps in Antimicrobial Resistance McCubbin et al. 76. Calero-Cáceres W, Melgarejo A, Colomer-Lluch M, Stoll C, Lucena F, Jofre J,
et al. Sludge as a potential important source of antibiotic resistance genes in
both the bacterial and bacteriophage fractions. Environ Sci Technol. (2014)
48:7602–11. doi: 10.1021/es501851s 94. Otto SJG, Miazga-Rodriguez M, Saxinger LM. Progress on Integrated
Antimicrobial Resistance and Antimicrobial Use Surveillance in Canada
(2014-2019). (2020). Available online at: https://nccid.ca/wp-content/
uploads/sites/2/2021/04/Final_IntegratedAntimicrobialResistance_Feb23. pdf (accessed June 15, 2021). 77. Chen C, Guron GK, Pruden A, Ponder M, Du P, Xia K. Antibiotics and
antibiotic resistance genes in bulk and rhizosphere soils subject to manure
amendment and vegetable cultivation. J Environ Qual. (2018) 47:1318–26. doi: 10.2134/jeq2018.02.0078 95. Stephen C, Parmley J, Dawson-Coates J, Fraser E, Conly J. Obstacles to
developing a multinational report card on antimicrobial resistance for
Canada: an evidence-based review. Microb Drug Resist. (2007) 13:251–9. doi: 10.1089/mdr.2007.702 78. Crtryn
E. The
soil
resistome:
The
anthropogenic,
the
native,
and
the
unknown. REFERENCES Soil
Biol
Biochem. (2013)
63:18–23. doi: 10.1016/j.soilbio.2013.03.017 96. Public Health Agency of Canada. Appendix B: Canadian Tuberculosis
Standards 7th Edition: 2014 – Canadian Tuberculosis surveillance Systems. (2014). Available
online
at:
https://www.canada.ca/en/public-health/
services/infectious-diseases/canadian-tuberculosis-standards-7th-edition/
appendix-b.html (accessed June 15, 2021). 79. Aubertheau E, Stalder T, Mondamert L, Ploy MC, Dagot C, Labanowski J. Impact of wastewater treatment plant discharge on the contamination of
river biofilms by pharmaceuticals and antibiotic resistance. Sci Total Environ. (2017) 579:1387–98. doi: 10.1016/j.scitotenv.2016.11.136 97. Public Health Agency of Canada. National Surveillance of Antimicrobial
Susceptibilities of Neisseria Gonorrhoeae in Canada: Annual Summary
2018. (2019). Available
online
at:
https://www.canada.ca/en/public-
health/services/publications/drugs-health-products/national-surveillance-
antimicrobial-susceptibilities-neisseria-gonorrhoeae-annual-summary-
2018.html (accessed June 15, 2021). 80. Manaia
CM,
Macedo
G,
Fatta-Kassinos
D,
Nunes
OC. Antibiotic
resistance in urban aquatic environments: can it be controlled? Appl
Microbiol
Biotechnol. (2016)
100:1543–57. doi:
10.1007/s00253-015-
7202-0 81. Living with Resistance project. Antibiotic and pesticide susceptibility
and the Anthropocene operating space. Nat Sustain. (2018) 1:631–41. doi: 10.1038/s41893-018-0164-3 98. Health Canada. Pest Management Regulatory Agency. (2009). Available
online
at:
https://www.canada.ca/en/health-canada/corporate/about-
health-canada/branches-agencies/pest-management-regulatory-agency. html (accessed June 15, 2021). 82. Guo MT, Yuan QB, Yang J. Distinguishing effects of ultraviolet exposure
and chlorination on the horizontal transfer of antibiotic resistance
genes in municipal wastewater. Environ Sci Technol. (2015) 49:5771–8. doi: 10.1021/acs.est.5b00644 99. Public Health Agency of Canada. Federal Action Plan on Antimicrobial
Resistance in Canada. (2015). Available online at: https://www.canada.ca/en/
health-canada/services/publications/drugs-health-products/federal-action-
plan-antimicrobial-resistance-canada.html (accessed July 24, 2021). 83. Liu SS, Qu HM, Yang D, Hu H, Liu WL, Qiu ZG, et al. Chlorine disinfection
increases both intracellular and extracellular antibiotic resistance genes
in a full-scale wastewater treatment plant. Water Res. (2018) 136:131–6. doi: 10.1016/j.watres.2018.02.036 100. Schuts EC, Hulscher MEJL, Mouton JW, Verduin CM, Stuart JWTC,
Overdiek HWPM, et al. Current evidence on hospital antimicrobial
stewardship objectives: a systematic review and meta-analysis. Lancet Infect
Dis. (2016) 16:847–56. doi: 10.1016/S1473-3099(16)00065-7 84. Kurenbach B, Gibson PS, Hill AM, Bitzer AS, Silby MW, Godsoe W, et al. Herbicide ingredients change Salmonella enterica sv. Typhimurium and
Escherichia coli antibiotic responses. Microbiology. (2017) 163:1791–801. doi: 10.1099/mic.0.000573 101. Nóbrega DB, Tang KL, Caffrey NP, De Buck J, Cork SC, Ronksley PE,
et al. Prevalence of antimicrobial resistance genes and its association
with restricted antimicrobial use in food-producing animals: a systematic
review and meta-analysis. J Antimicrob Chemother. (2021) 76:561–75. doi: 10.1093/jac/dkaa443 85. Maier L, Pruteanu M, Kuhn M, Zeller G, Telzerow A, Anderson EE, et al. Extensive impact of non-antibiotic drugs on human gut bacteria. Nature. (2018) 555:623–38. REFERENCES Graham DW, Knapp CW, Christensen BT, McCluskey S, Dolfing J. Appearance of beta-lactam resistance genes in agricultural soils and
clinical isolates over the 20(th) century. Sci Rep. (2016) 6:21550. doi: 10.1038/srep21550 108. Freeman
CN,
Scriver
L,
Neudorf
KD,
Hansen
LT,
Jamieson
RC. Antimicrobial resistance gene surveillance in the receiving waters of
an upgraded wastewater treatment plant. FACETS. (2018) 3:128–38. doi: 10.1139/facets-2017-0085 93. Zhu YG, Zhao Y, Zhu D, Gillings M, Penuelas J, Ok YS, et al. Soil
biota, antimicrobial resistance and planetary health. Environ Int. (2019)
131:105059. doi: 10.1016/j.envint.2019.105059 109. Bulteel AJB, Larson EL, Getahun H. Identifying global research gaps to
mitigate antimicrobial resistance: a scoping review. Am J Infect Contr. (2020)
49:P818–24. doi: 10.1016/j.ajic.2020.11.024 October 2021 | Volume 9 | Article 726484 Frontiers in Public Health | www.frontiersin.org 13 Knowledge Gaps in Antimicrobial Resistance McCubbin et al. 110. Antimicrobial Resistance – One Health Consortium, University of Calgary. Increasing Canada’s Support for the Development of New Antimicrobials. (2021). Available online at: https://research.ucalgary.ca/amr/news-events/
publications-presentations/publications (accessed July 28, 2021). Publisher’s Note: All claims expressed in this article are solely those of the authors
and do not necessarily represent those of their affiliated organizations, or those of
the publisher, the editors and the reviewers. Any product that may be evaluated in
this article, or claim that may be made by its manufacturer, is not guaranteed or
endorsed by the publisher. Conflict of Interest: JC has received peer-reviewed research grants from the
Canadian Institutes for Health Research (CIHR) on development of a rapid
assay for detection of methicillin-resistant Staphylococcus aureus and Alberta
Innovates Health Solutions on use of probiotics as primary prophylaxis for
Clostridium difficile colitis. JC has also received financial support from Pfizer
for the STRIVE S. aureus vaccine randomized clinical trial in vertebral spinal
surgery with instrumentation and CIHR for creation of an AMS app to improve
antimicrobial prescribing. Copyright © 2021 McCubbin, Anholt, de Jong, Ida, Nóbrega, Kastelic, Conly,
Götte, McAllister, Orsel, Lewis, Jackson, Plastow, Wieden, McCoy, Leslie, Robinson,
Hardcastle, Hollis, Ashbolt, Checkley, Tyrrell, Buret, Rennert-May, Goddard,
Otto and Barkema. This is an open-access article distributed under the terms
of the Creative Commons Attribution License (CC BY). The use, distribution
or reproduction in other forums is permitted, provided the original author(s)
and the copyright owner(s) are credited and that the original publication in
this journal is cited, in accordance with accepted academic practice. Frontiers in Public Health | www.frontiersin.org REFERENCES No use,
distribution or reproduction is permitted which does not comply with these
terms. The remaining authors declare that the research was conducted in the absence of
any commercial or financial relationships that could be construed as a potential
conflict of interest. October 2021 | Volume 9 | Article 726484 Frontiers in Public Health | www.frontiersin.org 14
|
https://openalex.org/W3181432130
|
https://pure.tue.nl/ws/files/190219184/Multi_Band_Photonic_Integrated_Wavelength_Selective_Switch.pdf
|
English
| null |
Multi-Band Photonic Integrated Wavelength Selective Switch
|
Journal of lightwave technology
| 2,021
|
cc-by
| 8,295
|
Document status and date:
Published: 01/10/2021 ocument Version:
ublisher’s PDF, also known as Version of Record (includes final page, issue and volume number Document Version:
Publisher’s PDF, also known as Version of Record (includes final page, issue and volume numbers) Multi-Band Photonic Integrated Wavelength Selective Switch
Citation for published version (APA):
Magalhães Gomes Kraemer, R., Nakamura, F., van den Hout, M., van der Heide, S., Okonkwo, C. M., Tsuda,
H., Napoli, A., & Calabretta, N. (2021). Multi-Band Photonic Integrated Wavelength Selective Switch. Journal of
Lightwave Technology, 39(19), 6023-6032. https://doi.org/10.1109/JLT.2021.3096045 Citation for published version (APA):
Magalhães Gomes Kraemer, R., Nakamura, F., van den Hout, M., van der Heide, S., Okonkwo, C. M., Tsuda,
H., Napoli, A., & Calabretta, N. (2021). Multi-Band Photonic Integrated Wavelength Selective Switch. Journal of
Lightwave Technology, 39(19), 6023-6032. https://doi.org/10.1109/JLT.2021.3096045 DOI:
10.1109/JLT.2021.3096045 DOI:
10.1109/JLT.2021.3096045 Document status and date:
Published: 01/10/2021 Please check the document version of this publication: • A submitted manuscript is the version of the article upon submission and before peer-review. There can be
important differences between the submitted version and the official published version of record. People
interested in the research are advised to contact the author for the final version of the publication, or visit the
DOI to the publisher's website. p
• The final author version and the galley proof are versions of the publication after peer review. • The final published version features the final layout of the paper including the volume, issue and page
numbers. Link to publication Link to publication General rights
C
i ht
d General rights
Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners
and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. • Users may download and print one copy of any publication from the public portal for the purpose of private study
Y
t f
th
di t ib t
th
t
i l
it f
fit
ki
ti it
i l
i • You may not further distribute the material or use it for any profit-making activity o
• You may freely distribute the URL identifying the publication in the public portal. If the publication is distributed under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license above, please
follow below link for the End User Agreement: Download date: 24. Oct. 2024 Multi-Band Photonic Integrated Wavelength
Selective Switch Rafael Kraemer
, Fumi Nakamura
, Member, IEEE, Menno van den Hout
, Graduate Student Member, IEEE,
Sjoerd van der Heide
, Graduate Student Member, IEEE, Chigo Okonkwo
, Senior Member, IEEE,
Hiroyuki Tsuda, Member, IEEE,
Antonio Napoli
, and Nicola Calabretta Rafael Kraemer
, Fumi Nakamura
, Member, IEEE, Menno van den Hout
, Graduate Student Member, IEEE,
Sjoerd van der Heide
, Graduate Student Member, IEEE, Chigo Okonkwo
, Senior Member, IEEE,
Hiroyuki Tsuda, Member, IEEE,
Antonio Napoli
, and Nicola Calabretta Hiroyuki Tsuda, Member, IEEE,
Antonio Napoli
, and Nicola Calabretta y
,
,
,
Antonio Napoli
, and Nicola Calabretta Abstract—As fiber-optic systems turn toward multi-band trans-
mission (MBT), exploiting the complete low loss window of optical
fibers, novel optical components, able to operate in bands other
than the conventional C-band, become necessary. In light of this,
we report on a multi-band photonic integrated 1 × 2 wavelength
selective switch (WSS) operating in the O, S, C and L-bands. The
photonic integrated WSS presented in this work uses a folded
arrayed-waveguide grating (AWG) as the filtering element, while
the wideband operation of the thermo-optic switches allows the
routing of the individual channels from those bands to any of
the device output ports. The operation of the WSS is experimentally
validated for different bands and modulation formats. Results show
error-freeoperationwithlimitedpenaltywithintensity-modulation
direct-detection (IM/DD) non-return-to-zero on-off keying (NRZ-
OOK) up to 35 Gb/s in O, S, C and L-bands and up to 169.83 Gb/s
with coherent 64-quadrature amplitude modulation (QAM) data
transmission in the S, C and L-bands. systems only [2], [3]. This is achieved by utilizing the entire
low loss spectrum of optical fibers, from 1260 nm to 1625 nm
(O →L-band). MBT systems are already being deployed as
C+L [4], [5], by capitalizing on the re-use of erbium-doped
fiber amplifier s (EDFAs) also within the L-band. More recently,
S+C+L-band systems started being subject of active research,
from numerical studies [3], [6] that showed the potential of these
three-band systems to triple the capacity when compared against
C-band only, to experimental setups employing power optimiza-
tion schemes [5], wideband semiconductor optical amplifiers
(SOAs) [7], [8] and continuous bandwidth amplification and
geometric shaping for record breaking data transmission [9]. As MBT systems gain commercial traction, solutions for, e.g.,
spectrum management and routing are required. In this context,
multi-bandwavelengthselectiveswitch(WSS)isoneofthemain
network elements. Manuscript received March 7, 2021; revised May 25, 2021 and July 2, 2021;
accepted July 6, 2021. Date of publication July 9, 2021; date of current version
October 4, 2021. This work was supported by the European Union’s Horizon
2020 research, and innovation programme under the Marie Skłodowska-Curie
Grant 814276. (Corresponding author: Rafael Kraemer.) Multi-Band Photonic Integrated Wavelength
Selective Switch High port-count, flexible grid WSSs finds its
use in the metro-core and transport segments of optical networks
while in metro-access networks with converged 5 G distribution,
where it is predicted a large deployment of nodes, a low-cost
fixed grid solution for optical add-drop multiplexers (OADMs)
is currently preferred. Such a solution is shown in
Fig. 1,
where the WSS presented in this work is in a typical two-degree
add-drop configuration with a band demultiplexer that separates
the multiband wavelength-division multiplexing (WDM) signal
before the 1 × 2 WSS modules. At its output, a band multiplexer
recombines the multiband WDM signals. Furthermore, photonic
integration may allow a considerable reduction of costs thanks
to its potential for mass production, ease of fabrication, and
packaging that could translate into a cheaper option than LCOS
devices. Index Terms—Wideband, multi-band, Coherent, Wavelength
selective switch, Photonics. www.tue.nl/taverne Take down policy
If you believe that this document breaches copyright please contact us at:
openaccess@tue.nl
providing details and we will investigate your claim. Download date: 24. Oct. 2024 6023 JOURNAL OF LIGHTWAVE TECHNOLOGY, VOL. 39, NO. 19, OCTOBER 1, 2021 Rafael Kraemer, Menno van den Hout, Sjoerd van der Heide, Chigo
Okonkwo, and Nicola Calabretta are with IPI-ECO Research Institute, Eind-
hoven University of Technology, Eindhoven, AJ 5612, The Netherlands (e-mail:
r.magalhaes.gomes.kraemer@tue.nl; m.v.d.hout@tue.nl; s.p.v.d.heide@tue.nl;
cokonkwo@tue.nl; N.Calabretta@tue.nl). This work is licensed under a Creative Commons Attribution 4.0 License. For more information, see https://creativecommons Manuscript received March 7, 2021; revised May 25, 2021 and July 2, 2021;
accepted July 6, 2021. Date of publication July 9, 2021; date of current version
October 4, 2021. This work was supported by the European Union’s Horizon
2020 research, and innovation programme under the Marie Skłodowska-Curie
Grant 814276. (Corresponding author: Rafael Kraemer.)
Rafael Kraemer, Menno van den Hout, Sjoerd van der Heide, Chigo
Okonkwo, and Nicola Calabretta are with IPI-ECO Research Institute, Eind-
hoven University of Technology, Eindhoven, AJ 5612, The Netherlands (e-mail:
r.magalhaes.gomes.kraemer@tue.nl; m.v.d.hout@tue.nl; s.p.v.d.heide@tue.nl;
cokonkwo@tue.nl; N.Calabretta@tue.nl).
Fumi Nakamura and Hiroyuki Tsuda are with Tsuda Laboratory, Graduate
School of Science and Technology, Keio University, Yokohama 223-8522, Japan
(e-mail: f_nakamura@tsud.elec.keio.ac.jp; tsuda@elec.keio.ac.jp).
Antonio Napoli is with Infinera, London WC1V 7HP, U.K. (e-mail:
ANapoli@infinera.com).
Color versions of one or more figures in this article are available at
https://doi.org/10.1109/JLT.2021.3096045.
Digital Object Identifier 10 1109/JLT 2021 3096045 Creative Commons Attribution 4.0 License. For more information, see https://creativecommons.org/licenses/by/4.0/ Fumi Nakamura and Hiroyuki Tsuda are with Tsuda Laboratory, Graduate
School of Science and Technology, Keio University, Yokohama 223-8522, Japan
(e-mail: f_nakamura@tsud.elec.keio.ac.jp; tsuda@elec.keio.ac.jp). Antonio Napoli is with Infinera, London WC1V 7HP, U.K. (e-mail:
ANapoli@infinera.com). Color versions of one or more figures in this article are available at
https://doi.org/10.1109/JLT.2021.3096045. This work is licensed under a Creative Commons Attribution 4.0 License. For more information, see https://creativecommons.org/licenses/by/4.0 I. INTRODUCTION I
P data traffic demand for metro and data center intercon-
nects (DCIs) is predicted to continue its exponential yearly
growth for the foreseeable future [1]. There are several possible
approaches to boost the transmission capacity in optical systems
such as space-division multiplexing (SDM), multi-mode fiber
(MMF), multi-core fiber (MCF) or multi-band transmission
(MBT) [2]. Among them MBT has gathered special attention. Numerical studies suggest that MBT systems may provide up
to a 10 fold increase in capacity when compared to C-band I A tunable Silicon Photonics WSS that required fine tuning to
operate in the C or L-bands, has been demonstrated in [10]. Also,
C+L-band WSS based on free-space optics and liquid crystal on
silicon (LCOS) started to become commercially available [11],
but, as stated before, it is potentially a solution more suitable for
nodes with multi-degree connectivity and will have its appeal in
othernetworksegmentssuchasMetro-coreandlong-haul.Inour
previous work [12] we reported a preliminary characterization
of a photonic integrated circuit (PIC) WSS operating on the S,
C, and L-bands with NRZ-OOK. In this paper, we present a thorough characterization of the
multi-band, packaged and pig-tailed 1 × 2 WSS operating on
the O, S, C and L-bands and with 10 Gb/s for all bands, p
g
Digital Object Identifier 10.1109/JLT.2021.3096045 JOURNAL OF LIGHTWAVE TECHNOLOGY, VOL. 39, NO. 19, OCTOBER 1, 2021 6024 Fig. 1. Multi-band 2-degree switching node with band demultiplexer and multiplexer. 1 × 2 multi-band wavelength selective switch (WSS) operating in the O,
S, C and L-bands. hing node with band demultiplexer and multiplexer. 1 × 2 multi-band wavelength selective switch (WSS) operating in the O Fig. 1. Multi-band 2-degree switching node with band demultiplexer and multiplexer. 1 × 2 multi-band wavelength selective switch (WSS) operating in the O,
S, C and L-bands. Fig. 3. Layout of the fabricated WSS [13]. Fig. 2. A conventional WSS structure with 3 AWGs [13]. Fig. 3. Layout of the fabricated WSS [13]. Fig. 2. A conventional WSS structure with 3 AWGs [13]. Fig. 2. A conventional WSS structure with 3 AWGs [13]. Fig. 3. Layout of the fabricated WSS [13]. Fig. 2. A conventional WSS structure with 3 AWGs [13]. 35 Gb/s for the C and L-bands with NRZ-OOK data as well
as multilevel modulation 33.3 GBd 64-quadrature amplitude
modulation (QAM) coherent data transmission in the S, C and
L-bands. I. INTRODUCTION From the individual channel transfer functions we
also investigated the filtering and capacity reduction effect due
to the cascade of multiple 1 × 2 WSS based OADM nodes. Experimental results show error-free operation for all bands
for the NRZ-OOK scenario with limited penalty, and below
the forward error correction (FEC) threshold for 64-QAM data,
which indicate that the PIC-WSS supports optical networks with
variable modulation format. The fabricated device, as depicted in Fig. 3, uses unified
arrayed-waveguide gratings (AWGs) in a loopback configura-
tion for the demultiplexing and multiplexing section, reducing
the AWG quantity from 3 to only 1. By doing that, potential
mismatches between the center wavelengths of the AWGs are
eliminated, while also contributing to reduce the device foot-
print. After the spatial separation of the individual channels,
the wavelengths are directed to one of the two output ports
by a switching section consisting of 40 1 × 2 switches and
2 × 1 wavelength couplers. The 1 × 2 switches are a single-
stage Mach-Zehnder interferometer (MZI) with two arms of
equal length and a thermo-optic phase shifter. The wavelength
couplers are based on an asymmetric type 2 × 1 MZI which are
composed of two arms with different lengths and 3-dB couplers,
and it has the function of multiplexing adjacent channels. The
heater for wavelength adjustment is on the top arm of each
asymmetric MZI. The wavelength couplers contribute to reduce
the size of the WSS by playing the role of merging adjacent
channels toward Output 1 and Output 2 which loop back to
the AWG for demultiplexing and multiplexing channels with
a single structure. The wavelength couplers have a frequency
response synchronized with the AWG, since the arms possess the
same waveguide structure and the same group refractive index
as the array waveguides. An embedded switch controller allows A. Wideband Wavelength Separation – Filtering The response of an AWG is periodical with the periodicity in
the frequency domain being referred as the free-spectral-range
(FSR) [16]. The 6THz FSR [13] of the fabricated AWG allows
the periodic repetition of the passband across the spectrum. This
periodicity on the fabricated device can be further verified from
the spectrum in Fig. 4 where it is seen that the first channel
of the L-band occurs after ∼50 nm of the first channel of the
C-band. This means that channels from different optical bands
have a fixed relationship. If we, for example, drop channel 1 in
the O-band, the same channel 1 in the S, C and L-bands will be
dropped as they propagate in the same output waveguide. While
this means that a more careful wavelength plan is required across
the multi-band spectrum, it also means that multiple wave-
lengths, across different FSRs can be dropped while switching
only 1 channel. from Fig. 5, where the loss of the channels which do not propa-
gate through the wavelength couplers is around 13.7 dB smaller
than the other wavelength channels, showing the wavelength
dependence of the 3-dB couplers. The multi-band low loss WSS
can be fabricated by adopting a phase generating couplers [17],
which have been demonstrated to have broadband characteristics
from the O- to the L-band, and four times lower losses when
compared to conventional directional couplers, while providing
low polarization dependent losses. from Fig. 5, where the loss of the channels which do not propa-
gate through the wavelength couplers is around 13.7 dB smaller
than the other wavelength channels, showing the wavelength
dependence of the 3-dB couplers. The multi-band low loss WSS
can be fabricated by adopting a phase generating couplers [17],
which have been demonstrated to have broadband characteristics
from the O- to the L-band, and four times lower losses when
compared to conventional directional couplers, while providing
low polarization dependent losses. By extracting the individual channels of the WSS, as seen
from Figs. 6 and 7, we could analyze the spectral performance
across different bands, such as the 3 dB bandwidth, passband
symmetry, and other possible imaging errors due to fabrication
inaccuracies. From visual inspection of Figs. 6 and 7 we can
verify that not all channels have an equal passband shape, and
this asymmetry is greater when comparing channels in different
bands. From the passband shape, as seen in Fig. KRAEMER et al.: MULTI-BAND PHOTONIC INTEGRATED WAVELENGTH SELECTIVE SWITCH KRAEMER et al.: MULTI-BAND PHOTONIC INTEGRATED WAVELENGTH SELECTIVE SWITCH 6025 Fig. 4. Passband shape of the AWG. Fig. 5. Extra 13.7 dB losses in the O-band due to the wavelength couplers. Fig. 5. Extra 13.7 dB losses in the O-band due to the wavelength couplers. Fig. 5. Extra 13.7 dB losses in the O-band due to the wavelength couplers. Fig. 5. Extra 13.7 dB losses in the O-band due to the wavelength couplers. Fig. 4. Passband shape of the AWG. Fig. 6. Filter shape for the O and S-bands channels with average 3-dB
bandwidths of 42.74 GHz and 43.48 GHz respectively. the precise control of the heating current applied to each of the
MZIs electrodes. SincethetransmissionwavelengthsoftheAWGandthewave-
length couplers are polarization sensitive, the WSS works for a
single polarization. As stated in [13] the use of a silica substrate,
which leads to the lower birefringence of the waveguides is a
good solution to make the WSS polarization-insensitive. Scaling
up the number of output ports is possible as we have already
reported 100 GHz spacing 40 channels 1 × 4 WSS using the
same loopback configuration presented here [14]. Furthermore,
increasing the number of channels is also possible by using
larger relative refractive indexes, Δ, as Δ’s of 2% are already
commercially available and Δ’s of 5.5% were reported in [15]. Fig. 6. Filter shape for the O and S-bands channels with average 3-dB
bandwidths of 42.74 GHz and 43.48 GHz respectively. II. 1×2 PHOTONIC INTEGRATED WSS The photonic integrated WSS is a one input two outputs (1 ×
2) device, based on silica waveguides on a silicon substrate with
a1.5%Δ contrast anddesignedfor achannel spacingof 100GHz
in the C-band. In a conventional arrayed-waveguide gratings
(AWGs) based 1 × 2 WSS structure, as depicted in Fig. 2, the
WDM light at the input is first separated into its individual
channels by the first AWG, after that, 1 × 2 optical switch gates
directs the light to one of the two output ports where they are
againrecombinedbytwoAWGs(oneperoutputport)intoWDM
signals. JOURNAL OF LIGHTWAVE TECHNOLOGY, VOL. 39, NO. 19, OCTOBER 1, 2021 JOURNAL OF LIGHTWAVE TECHNOLOGY, VOL. 39, NO. 19, OCTOBER 1, 2021 6026 Fig. 7. Filter shape for the C and L-bands channels with average 3-dB
bandwidths of 45.3 GHz and 54.36 GHz respectively. was 113.2 GHz, 104.8 GHz, 101 GHz and 99.3 GHz in the O,
S, C and L-bands respectively. This arises from the group index
dependency of the FSR [16], and consequently, as seen from the
error in Fig. 9, is more accentuated as we move further away
from the designed center frequency. As stated in [18] the commonly used single Gaussian fit for
modelling AWGs passband only partially reproduces the output
real transfer function, because the decaying exponential nature
of the real mode is underestimated by this approximation, and
is shown that the real mode is better approximated by the sum
of three Gaussian functions composed of different parameters
representing the Input waveguides, array waveguides and the
output waveguides of the AWG. We found that by approximating
the passband shape by the sum of two Gaussian functions
provided a good fit for the actual real mode as seen as can
be verified in Fig. 8. From this computed transfer function we
were able to numerically assess average 3 dB bandwidths of
42.74 GHz,43.48 GHz,45.3 GHz,54.36 GHz in the O, S, C and
L-bands respectively. Fig. 7. Filter shape for the C and L-bands channels with average 3-dB
bandwidths of 45.3 GHz and 54.36 GHz respectively. As seen in [16], the L-dB bandwidth of an AWG is given by: Fig. 8. Fit for calculating the AWG channels 3 dB bandwidth. ΔfL = 0.77ωe
dr
Δfch
√
L
(1) (1) where dr is the spacing between receiver waveguides, Δfch the
channel spacing and ωe the waveguide mode effective width that
is approximately given by [16]: we ≈wwg
0.5 +
1
V −0.6
(2) (2) in which wwg is the waveguide width, and in [18] the 3 dB
bandwidth, ΔVbw, is formulated as: ΔVbw = 2γωe
2 ln 103/10
(3) (3) where γ is the frequency spatial dispersion parameter. From (1)
and (3) we find that the AWG 3 dB bandwidth decreases as
the mode radius, ωe decreases, which in turn, as seen in (2),
is smaller at higher frequencies, showing why the passband is
narrower as we go to shorter wavelengths. Fig. 8. Fit for calculating the AWG channels 3 dB bandwidth. A. Wideband Wavelength Separation – Filtering 4 we assessed
average insertion losses (IL) of 23.80 dB, 11 dB, 12.70 dB and
13 dB in the O, S, C and L-band respectively. The maximum
insertion losses were 27.6 dB, 16 dB, 15.60 dB, 13.80 dB and
the minimum 22.15 dB, 7.76 dB, 9.20 dB, 9.90 dB across the O,
S, C and L-band respectively. The extra insertion loss (IL) in the
O-band comes from the wavelength couplers. This can be seen As we have shown in Section II, the AWGs were designed
for a channel spacing of 100 GHz in the C-band. In Fig. 9 we
show the relative error from the designed 100 GHz spacing in
the O, S, C and L-bands. The measured average channel spacing KRAEMER et al.: MULTI-BAND PHOTONIC INTEGRATED WAVELENGTH SELECTIVE SWITCH KRAEMER et al.: MULTI-BAND PHOTONIC INTEGRATED WAVELENGTH SELECTIVE SWITCH 6027 Fig. 10. Channels with an average ER of 23,6 dB, 18.2 dB, 22.5 dB, 19.3 dB
in the O, S, C and L-bands respectively. TABLE I
EXTINCTION RATIO DATA FOR THE O, S, C AND L-BANDS
Fig. 11. NRZ-OOK Experimental setup. Tunable laser source (TLS), erbium-
doped fiber amplifier (EDFA), polarization controller (PC), Mach-Zehnder
modulator (MZM), variable optical attenuator (VOA), pulsed-pattern genera-
tor (PPG), optical spectrum analyzer (OSA), semiconductor optical amplifier
(SOA). (in the case of the C and L-bands) NRZ-OOK with a pseu-
dorandom bit sequence (PRBS) length of 231 −1. After the
MZM, an EDFA was used to compensate for the modulator
losses and another PC was used to optimize the SOP for the
WSS. Following the WSS, a variable optical attenuator (VOA)
was used for the power sweep, an optical spectrum analyzer Fig. 10. Channels with an average ER of 23,6 dB, 18.2 dB, 22.5 dB, 19.3 dB
in the O, S, C and L-bands respectively. Fig. 10. Channels with an average ER of 23,6 dB, 18.2 dB, 22.5 dB, 19.3 dB
in the O, S, C and L-bands respectively. Fig. 11. NRZ-OOK Experimental setup. Tunable laser source (TLS), erbium-
doped fiber amplifier (EDFA), polarization controller (PC), Mach-Zehnder
modulator (MZM), variable optical attenuator (VOA), pulsed-pattern genera-
tor (PPG), optical spectrum analyzer (OSA), semiconductor optical amplifier
(SOA). Fig. 11. NRZ-OOK Experimental setup. Tunable laser source (TLS), erbium-
doped fiber amplifier (EDFA), polarization controller (PC), Mach-Zehnder
modulator (MZM), variable optical attenuator (VOA), pulsed-pattern genera-
tor (PPG), optical spectrum analyzer (OSA), semiconductor optical amplifier
(SOA). Fig. 10. Channels with an average ER of 23,6 dB, 18.2 dB, 22.5 dB, 19.3 dB
in the O, S, C and L-bands respectively. (in the case of the C and L-bands) NRZ-OOK with a pseu-
dorandom bit sequence (PRBS) length of 231 −1. After the
MZM, an EDFA was used to compensate for the modulator
losses and another PC was used to optimize the SOP for the
WSS. Following the WSS, a variable optical attenuator (VOA)
was used for the power sweep, an optical spectrum analyzer
(OSA) for spectral analysis and the optical signal-to-noise ratio
(OSNR) of the signal and a photodetector (PD) to convert the
signal from the optical to the electrical domain. III. EXPERIMENTAL DATA TRANSMISSION To verify the possible penalties introduced by a single WSS,
two experimental scenarios were considered. First, in Sec-
tion III-A the WSS was tested with intensity-modulation direct-
detection (IM/DD) format, which is currently employed in metro
access nodes with edge computing [22]. In Section III-C the
WSS was tested in a coherent transmission setup, where it could
be employed in future high-capacity multi-band nodes where
there is less need for multi-degree connectivity. B. IM/DD Experimental Results In Fig. 12 the bit error rate (BER) results at 10 Gb/s for the
O and S-band is shown. In the case of the O-band, at BER =
10−9, we could verify a maximum penalty at λ = 1300.06 nm of
3.2 dB whereas in the S-band the maximum power penalty was
at most 0.8 dB. From Fig. 12 we can also see the different power
requirements for error free transmission in the O and S-band, on
average −23 dBm in the first case and around −28 dBm in the
second case. This, as discussed in Section III-A, is due to the
lower OSNR in the O-band because of the higher IL and the use
of the SOA that further degraded the OSNR. KRAEMER et al.: MULTI-BAND PHOTONIC INTEGRATED WAVELENGTH SELECTIVE SWITCH For the O-band
the same setup applies with some components being exchanged
by the O-band counterpart, as for example, the CW source and
the modulator. In the case of the EDFA it was substituted by an
SOA and the PD was exchanged by a high sensitivity avalanche
photodector (APD) due to the higher IL in the O-band, which in
turn limited the maximum data rate of the O-band experiments
to 10 Gb/s. In the case of the S-band, as at the time we lacked
amplifiers in this band, the APD was also employed, and as in
the case of the O-band, limited the maximum data-rate for the
S-band experiments to 10 Gb/s. Despite this the WSS is able to
operate in these bands at 35 Gb/s with an expected increase in the
penalties in the both bands due to the higher OSNR requirements
at this data-rate and also because of the additional IL in the
O-band which in turn also impacted the OSNR. TABLE I
EXTINCTION RATIO DATA FOR THE O, S, C AND L-BANDS TABLE I
EXTINCTION RATIO DATA FOR THE O, S, C AND L-BANDS are shown. As seen from this table, the minimum ER is smaller
than 15 dB the maximum ER is up to 37.8 dB. This variability
will impact the system performance when wavelength channels
are dropped and added in the same wavelength at the same time. Improving the ER is possible by using double Mach-Zehnder
thermo-optic switches that have been shown to provide ERs
between 49 dB to 76 dB with an average value of 60 dB [21],
values that are high enough to overcome any in-band crosstalk
induced limitation. B. Wideband Switching Fig. 9. Error in channel spacing when compared to a 100 GHz spaced grid
across the O-, S-, C- and L-bands. As stated in Section I, the WSS makes use of the thermo-
optic phase shifters on MZIs for the switching of individual
wavelengths between the two output ports. In [19], [20], the
Sellmeier relation was used to find the thermo-optic coefficient
(TOC) of Silica glasses for a wide range of optical wavelengths
and it was verified the low variability of these coefficients
over a broad wavelength range, from 1260 nm to 1625 nm. 2n(dn/dt)[10−6/◦C] varied by less than 1% over this range
for various optical Silicate Fiber Glasses. These results indicate
that thermo-optic switching elements are very good option for
wideband WSS. Fig. 10 shows the spectrum at output Port 1 of the WSS at
both switch states for the O, S, C and L-bands. The power ratio
between the two output states is here defined as extinction-ratio
(ER). We measured average ERs of 23.6 dB, 18.2 dB, 22.5 dB,
19.3 dB across the O, S, C and L-bands respectively. In Table I
the average, the minimum and the maximum ERs for each band Fig. 9. Error in channel spacing when compared to a 100 GHz spaced grid
across the O-, S-, C- and L-bands. A. IM/DD Experimental Setup The experimental setup that was employed to assess the
performance of the WSS is depicted in Fig. 11. For the C
and L-bands, a broadband tunable laser-source (TLS), covering
both bands was used as a continuous-wave (CW) light source. After the CW source, a polarization controller (PC) was used to
optimize the state of polarisation (SOP) for the Mach-Zehnder
modulator (MZM), which was driven at 10 Gb/s and 35 Gb/s For the case of the C and L-band, the obtained results are
depicted in Fig. 13, not all tested channels in the C-band are
shown for the easier interpretation of the figure, but have results
that follow a similar trend to the ones present in the figure. The JOURNAL OF LIGHTWAVE TECHNOLOGY, VOL. 39, NO. 19, OCTOBER 1, 2021 6028 Fig. 12. Bit error rate results with 10 Gb/s NRZ-OOK data for the O and
S-band. Fig. 14. BER results with 35 Gb/s NRZ-OOK data in the C-band. Fig. 12. Bit error rate results with 10 Gb/s NRZ-OOK data for the O and
S-band
Fig. 14. BER results with 35 Gb/s NRZ-OOK data in the C-band. and
Fig. 14. BER results with 35 Gb/s NRZ-OOK data in the C-band. Fig. 12. Bit error rate results with 10 Gb/s NRZ-OOK data for the O and
S-band. Fig. 14. BER results with 35 Gb/s NRZ-OOK data in the C-band. Fig. 12. Bit error rate results with 10 Gb/s NRZ-OOK data for the O and
S-band. Fig. 14. BER res Fig. 13. Bit error rate results with 10 Gb/s NRZ-OOK data for the C and
L-band. Fig. 15. BER results with 35 Gb/s NRZ-OOK data in the L-band. Fig. 13. Bit error rate results with 10 Gb/s NRZ-OOK data for the C and
L-band. Fig. 15. BER results with 35 Gb/s NRZ-OOK data in the L-band. Fig. 15. BER results with 35 Gb/s NRZ-OOK data in the L-band. Fig. 13. Bit error rate results with 10 Gb/s NRZ-OOK data for the C and
L-band. Fig. 15. BER results with 35 Gb/s NRZ-OOK data in the L-band. Fig. 16. Modulated spectra for 3 channels in the C-band with a single channel
being switched between output ports 1 and 2. penalties ranged from 0.2 dB to 1.1 dB. KRAEMER et al.: MULTI-BAND PHOTONIC INTEGRATED WAVELENGTH SELECTIVE SWITCH KRAEMER et al.: MULTI-BAND PHOTONIC INTEGRATED WAVELENGTH SELECTIVE SWITCH 6029 Fig. 17. Crosstalk induced penalty at 10 Gb/s for λ1 = 1533.59 nm. The detected electrical signal is digitized by an 80GSa/s analog-
to-digital converter (ADC) and further processed by the offline
receiver digital signal processing (DSP), consisting of matched
filtering, multiple-input multiple-output (MIMO) equalization
with in-loop blind phase search, and performance metric
evaluation. D. Coherent Experimental Results TheWSSperformancewasevaluatedwith64-QAM33.3GBd
data while sweeping the OSNR from the minimum achievable
level, limited by the maximum output power of the respective
noise loading stage, to the maximum OSNR value, where most
of the noise power was attenuated by a VOA. p
y
The back-to-back 33.3 GBd 64-QAM signal is plotted against
the WSS channels on the S, C and L-bands in Fig. 19. From this
figure it can be seen that we were able to match the signal to
the center wavelength of the AWG channels. In reality, some
mismatch is expected to occur between the laser and the fil-
ters center wavelengths, further increasing the filtering effects
discussed in Section IV. This mismatch is a possible source of
impairment especially for the S-band due to the smaller 3 dB
bandwidth of the AWG channels as seen from Section II-A
and Fig. 8. In Fig. 20 we can compare the signal spectrum
for the back-to-back scenario and after propagating through the
WSS for all evaluated channels in the S, C, and L-bands. For all
tested channels, a negligible deterioration on the signal shape is
verified. Fig. 17. Crosstalk induced penalty at 10 Gb/s for λ1 = 1533.59 nm. switched to port 2, and when only the same channel is switched
to port 2. The BER results for both scenarios are shown in Fig. 17
and compared to the previously reported BER from Fig. 13. We
verified at each port a penalty of around 1 dB, an increase of
0.3 dB when compared to the single loaded channel case. This
shows that at least a single drop-stage could be realized without
a substantial increase in the incurred penalties. C. Coherent Experimental Setup To assess possible impairments introduced by the WSS in a
coherent transmission, we used the experimental setup shown in
the schematic depicted in Fig. 18. A tunable laser source (TLS)
was set to wavelengths 1515.74 nm and 1516.54 nm on the
S-band, from 1532.75 nm to 1553.75 nm with 0.8 nm spacing on
the C-band and from 1583.71 nm to 1599.60 nm with also 0.8 nm
on the L-band. After the TLS an EDFA was used to amplify the
continuous wave (CW) light that will also be used as a local
oscillator (LO) to the coherent receiver. When testing S-band
channels, an optical band pass filter (OBPF) was used to filter
the out-of-band amplified spontaneous emission (ASE) noise
generated by the EDFA. Offline, a PCG64 pseudo-random data
streams containing 216 QAM symbols are pulse-shaped using
a root-raised-cosine (RRC) filter with roll-off β = 0.01 and
uploaded to a 100GSa/s digital-to-analog converter (DAC). The
DAC outputs are connected to radio frequency (RF) amplifiers
which in turn are connected to the in-phase and quadrature
optical modulator (IQ-MOD). After the modulator, the signal
is fed into the WSS, which is remotely controlled according
to the channel being tested. The two outputs of the WSS are
connected to a mechanical optical switch for quick selection of
one of the two outputs. Another EDFA is used to compensate
for the IL of the WSS. Due to the lack of O-band IQ mod-
ulators, the coherent experiments covered only the S, C and
L-bands. A quantified measurement of the multi-band performance is
reported in Fig. 21. As a figure of merit, besides the pre FEC
BER, we use the normalized generalized mutual information
(NGMI), as it has been shown to provide consistent post FEC
BER predictions across different conditions and modulation
formats [23]. Considering the FEC overhead for LDPC codes
concatenated with a staircase code [24], the NGMI of 0.88
and 0.92 shown in this figure corresponds to a overall rate of
0.81 and 0.85 respectively, meaning that for the gross data-rate
of 199.80 Gb/s the net data-rates after FEC decoding will be
161.84 Gb/s and 169.83 Gb/s for the NGMI values of 0.88
and 0.92 respectively. The curves that we report represent the
averaged values of all tested channels in each band. We have
performed and reported the NGMI values obtained for the S, C,
and L-bands and at both output ports. Fig. A. IM/DD Experimental Setup Similar performance
was verified in the case of the L-band, with penalties ranging
from 0.1 dB to 0.7 dB where the channels tested ranged from
1582.22 nm to 1610.72 nm. In the results shown in Fig. 14 and 15, the C and L-band
channels were tested at 35 Gb/s. In the case of the C-band
the penalty was 2 dB at BER = 10−9 for most of the tested
channels, and in the case of the L-band the penalty ranged from
0.7 dB to 3.5 dB. This difference in the reported penalties arises
from slightly variations between the AWG channel shapes and
deviations from the 100 GHz channel spacing, greater in the
L-band as seen in Fig. 9, that introduce extra penalties to the
signal. To evaluate the possible penalty induced with more than 1
channel, 3 channels were loaded with NRZ-OOK data at 10 Gb/s
in the C-band, with λ1 = 1533.59 nm, λ2 = 1534.37 nm and
λ3 = 1535.28 nm. The modulated spectrum at 10 Gb/s is shown
in Fig. 16. In the same figure we can verify the spectrum when
only the channel at λ1 = 1533.59 nm is at port 1, with λ2 and λ3 Fig. 16. Modulated spectra for 3 channels in the C-band with a single channel
being switched between output ports 1 and 2. C. Coherent Experimental Setup 22 shows the comparison of the OSNR values for each
WSS channel against its back-to-back counterparts. The results
show that the OSNR penalty changes with wavelength and with
the port being tested. In the tested channels at the C-band the
OSNR penalty was always smaller than 1 dB and in some cases
negligible at both output ports. For the L-band the penalty is
greater than 1 dB for most of the tested channels, and the penalty
increases as we switch to output port 2. This increase in the
OSNR penalty is also verified in the S-band and we believe
its mainly because of the smaller ER in these bands as shown
in Section II-B, where the ER is 22.59 dB in the C-band versus
18.22 dB in the S-band and 19.38 dB in the L-band. A noise loading stage consisting of S-band SOAs, C-band
EDFAs or L-band EDFA, connected to a VOA, was used for the
OSNR sweep. The coherent receiver consisted of the already
mentioned LO, a 90-degree hybrid and 2 balanced photodiodes. JOURNAL OF LIGHTWAVE TECHNOLOGY, VOL. 39, NO. 19, OCTOBER 1, 2021 6030 Fig. 18. Schematic of the experimental setup. Tunable laser source (TLS), erbium-doped fiber amplifier (EDFA), digital-to-analog converter (DAC), optical band
pass filter (OBPF), polarization controller (PC), local oscillator (LO), in-phase and quadrature modulator (IQ-MOD), () digital signal processing (DSP), optical
spectrum analyzer (OSA), analog-to-digital converter (ADC), semiconductor optical amplifier (SOA). Fig. 18. Schematic of the experimental setup. Tunable laser source (TLS), erbium-doped fiber amplifier (EDFA), digital-to-analog converter (DAC), optical band
pass filter (OBPF), polarization controller (PC), local oscillator (LO), in-phase and quadrature modulator (IQ-MOD), () digital signal processing (DSP), optical
spectrum analyzer (OSA), analog-to-digital converter (ADC), semiconductor optical amplifier (SOA). Fig. 19. The modulated 33.3 GBd signal on top of the individual channels on
S-, C- and L-bands. Fig. 21. Averaged NGMI and BER for the S,C and L-bands. Fig. 21. Averaged NGMI and BER for the S,C and L-bands. Fig. 21. Averaged NGMI and BER for the S,C and L-bands. Fig. 19. The modulated 33.3 GBd signal on top of the individual channels on
S-, C- and L-bands. Fig. 20. 33.3 GBd modulated spectra at Back-to-Back and after passing
through the WSS in the S, C and L-bands, for all tested channels. Fig. 22. C. Coherent Experimental Setup OSNR penalty from the S to the L-band for NGMI values of 0.88
and 0.92, and corresponding net data-rates of 161.84 Gb/s and 169.83 Gb/s
respectively. Fig. 22. OSNR penalty from the S to the L-band for NGMI values of 0.88
and 0.92, and corresponding net data-rates of 161.84 Gb/s and 169.83 Gb/s
respectively. Fig. 22. OSNR penalty from the S to the L-band for NGMI values of 0.88
and 0.92, and corresponding net data-rates of 161.84 Gb/s and 169.83 Gb/s
respectively. Fig. 20. 33.3 GBd modulated spectra at Back-to-Back and after passing
through the WSS in the S, C and L-bands, for all tested channels. KRAEMER et al.: MULTI-BAND PHOTONIC INTEGRATED WAVELENGTH SELECTIVE SWITCH 6031 Fig. 23. 3 dB bandwidth reduction in function of the number of traversed
WSS. Fig. 24. Normalized 3 dB bandwidth reduction vs number of traversed WSS. Fig. 24. Normalized 3 dB bandwidth reduction vs number of traversed WSS. Fig. 24. Normalized 3 dB bandwidth reduction vs number of traversed WSS. Fig. 23. 3 dB bandwidth reduction in function of the number of traversed
WSS. Fig. 23. 3 dB bandwidth reduction in function of the number of traversed
WSS. Fig. 23. 3 dB bandwidth reduction in function of the number of traversed
WSS. Fig. 24. Normalized 3 dB bandwidth reduction vs number of traversed WSS. 3 dB bandwidth was close to 10 GHz and around 15 GHz for
the L-band. E. Experimental Conclusions and Outlook By using a flat top WSS as shown in [25] we can potentially
limit the bandwidth reduction after traversing several WSSs. It is expected that the filter narrowing effect would be much
smaller than in the case for Gaussian shaped filter, as presented
in this work. This is further confirmed in Fig. 24 where we
show the normalized 3 dB bandwidth as a function of the
number of traversed devices. We can see from this figure that the
filter narrowing is much smaller than in the case of the device
presented in this work. We verified that for the case of this WSS,
after 20 traversed WSS the resulting 3 dB bandwidth is 20% of
its original value, while for the flat top WSS the bandwidth was
still greater than 60% of the original bandwidth. This shows that
for traversing multiple devices with high-bandwidth signals, a
flat-top passband is a must. In this section, we assessed the penalties introduced by the
WSS when loading channels across multiple optical bands and
switching it between the two output ports. We achieved error free
operation with limited penalty with NRZ-OOK data and below
the FEC threshold for coherent 64-QAM. results indicate that
an optimized design with flat-top operation and double gates are
important in order to reduce the bandwidth narrowing effect
in cascaded WSSs as well as improving the ER. Moreover,
further experimental validation from a network perspective are
necessary, such as adding a channel on top of a dropped one
and investigate the impact on the OSNR after the traversal of
multiple WSSs based nodes for different modulation formats
and data rates. Another potential issue is the limited ER shown in Section II-
B, that may induce additional penalties when adding a channel
at the same wavelength of the dropped channel. Improving the
ER to reduce the in-band crosstalk is possible by using the
double-gate switches [21], [26] as discussed in Section II-B. Another solution revolves around adding 2 WSSs per node for
the ER improvement, but would come with the cost of a more
accentuated bandwidth reduction than the one seen in Fig. 24. In this case the 3 dB bandwidth would be around 30% of its
original value after just 5 nodes and after 20 nodes close to only
10%. V. CONCLUSIONS In this work, we experimentally demonstrated and assessed a
photonic integrated WSS operating in the O, S, C, and L-bands. We have shown that the cyclic nature of the AWGs allows the
selection of wavelength channels across multiple optical bands. Furthermore, we also showed that the wideband nature of the
thermo-optic effect on Silica makes thermo-optic switches a
relevant option for wideband WSSs. [10] P. Prabhathan, Z. Jing, V. M. Murukeshan, Z. Huijuan, and C. Shiyi,
“Discrete and fine wavelength tunable thermo-optic WSS for low power
consumption C+L band tunability,” IEEE Photon. Technol. Lett., vol. 24,
no. 2, pp. 152–154, Jan. 2012. [11] “Finisar WSS Dual Wavelength Selective Switch (WSS).” [Online]. Avail-
able:
https://finisarwss.com/wp-content/uploads/2020/07/FinisarWSS_
Dual_Wavelength_Selective_Switch_ProductBrief_Jul2020.pdf [12] R. Kraemer, F. Nakamura, H. Tsuda, A. Napoli, and Calabretta, “S-, C-
and L-Band photonic integrated wavelength selective switch,” in Proc. Eur. Conf. Opt. Commun., 2020, pp. 1–4. Experimental data transmission showed error-free operation
across all tested bands and channels, with a minimum power
penalty of 0.2 dB in the C-band to a maximum power penalty of
3.2 dB in the O-band at 10 Gb/s. For 35 Gb/s the penalty was at
its minimum 0.7 dB and at most 3.5 dB, both in the L-band with
NRZ-OOK. In the 64-QAM coherent case, with a net data-rate
of 169.83 Gb/s the OSNR penalty was smaller than 1 dB for all
channels in the C-band and the maximum OSNR penalty was of
2.3 dB in the L-band. [13] Y. Ikuma, T. Mizuno, H. Takahashi, and H. Tsuda, “Integrated 40-λ1 × 2
wavelength selective switch without waveguide crossings,” IEEE Photon. Technol. Lett., vol. 25, no. 6, pp. 531–534, Mar. 2013. [14] T. Yoshida, H. Asakura, H. Tsuda, T. Mizuno, and H. Takahashi, “Switch-
ing characteristics of a 100-GHz-Spacing integrated 40-λ1 × 4 wave-
length selective switch,” IEEE Photon. Technol. Lett., vol. 26, no. 5,
pp. 451–453, Mar. 2014. [15] M. Takahashiy, Y. Uchiday, and S. Yamasakiy et al., “Development
of lowloss ultra-highΔZrO2-SiO2 PLC for next generation compact
andhigh-density integrated devices,” IEICE Trans. Electron., vol. E97-C,
no. 7, pp. 725–730, 2014, doi: 10.1587/transele.E97.C.725. no. 7, pp. 725–730, 2014, doi: 10.1587/transele.E97.C.725 We also point out that, due to the asymmetric and Gaussian,
shape of the AWG passband, the 3 dB bandwidth reduction
is more accentuated than reported in other studies that were
based on flat-top devices. JOURNAL OF LIGHTWAVE TECHNOLOGY, VOL. 39, NO. 19, OCTOBER 1, 2021 Another approach [28] based on nonuniform AWGs showed that
the optimized nonuniform AWG had a flat passband with 1 dB
and 3 dB bandwidths 2.3 times larger than conventional uniform
AWGs. [7] F. Hamaoka et al., “Ultra-wideband WDM transmission in S-, C-, and
L-Bands using signal power optimization scheme,” J. Lightw. Technol.,
vol. 37, no. 8, pp. 1764–1771, 2019. [8] J. Renaudier et al. “Recent advances in 100 nm ultra-wideband fiber-optic
transmission systems using semiconductor optical amplifiers,” J. Lightw. Technol., vol. 38, no. 5, pp. 1071–1079, 2020. [9] L. Galdino et al., “Optical fibre capacity optimisation via continuous
bandwidth amplification and geometric shaping,” IEEE Photon. Technol. Lett., vol. 32, no. 17, pp. 1021–1024, Sep. 2020. V. CONCLUSIONS As described before, the implemen-
tation of photonic integrated WSSs with passband-flattened
AWGs [27] is a way to prevent bandwidth narrowing and the
number of possible traversed nodes, as it may more than double
the 1 dB bandwidth [28]. Moreover, further improvement of
the ER is possible by using double-gate thermo-optic switches
[21] while maintaining the wideband nature of the switching
element. [16] M. Smit and C. Van Dam, “PHASAR-based WDM-devices: Principles,
design and applications,” IEEE J. Sel. Topics Quantum Electron., vol. 2,
no. 2, pp. 236–250, Jun. 1996. [17] T. Watanabe, T. Mizuno, Y. Hashizume, and T. Takahashi, “Silica-Based
Plc 1 × n Switch for All Wavelength Bands,” in Proc. Opt. Fiber Commun. Conf., Opt. Soc. Amer. (OSA), 2014, Paper Th1I.5. p
[18] Z. Liu and J. Li, “Modeling and design of arrayed waveguide gratings,”
in Proc. CAR 2010-2010 2nd Int. Asia Conf. Inform. Control, Automat. Robot., vol. 3, no. 4, pp. 339–341, 2010. [19] “Chapter 3-thermo-optic coefficients,” in Handbook Optical Constants
Solids, E. D. Palik, Ed., Burlington: Acad. Press, 1997, pp. 115–261. [Online]. Avilable: https://doi.org/10.1016/B978-012544415-6.50150-3 [20] G. Ghosh, “Temperature dispersion of refractive indexes in some silicate
fiber glasses,” IEEE Photon. Technol. Lett., vol. 6, no. 3, pp. 431–433,
Mar. 1994. The considered PIC WSS with a single AWG serving multiple
optical bands may reduce the costs associated with the deploy-
ment of multi-band optical add-drop nodes, by reducing chip
size and component count. With a power equalization solution
using VOAs, that were already successfully demonstrated in
PLC PICs [29], this device architecture could be a viable and
deployablesolutionforfuturemulti-bandlow-degreeopticaladd
drop nodes. [21] T. Goh, A. Himeno, M. Okuno, H. Takahashi, and K. Hattori, “High-
extinction ratio and low-loss silica-based 8 × 8 thermo-optic matrix
switch,” IEEE Photon. Technol. Lett., vol. 10, no. 3, pp. 358–360,
Mar. 1998. [22] B. Pan, F. Yan, X. Xue, E. Magelhaes, and N. Calabretta, “Performance
assessment of a fast optical add-drop multiplexer-based metro access
network with edge computing,” J. Opt. Commun. Netw., vol. 11, no. 12,
pp. 636–646, 2019. [23] A. Alvarado, E. Agrell, D. Lavery, R. Maher, and P. Bayvel, “Replac-
ing the soft-decision FEC limit paradigm in the design of optical com-
munication systems,” J. Lightw. Technol., vol. 34, no. 2, pp. 707–721,
2016. IV. WSS BANDWIDTH NARROWING Due to the filtering effects seen in Section II-A, we investigate
the bandwidth narrowing after the traversal of several 1 × 2
WSS based OADM nodes. In order to calculate the resulting
3 dB bandwidth after the cascade of several WSS, we used
the computed transfer functions for different bands as shown
in Section II-A. The bandwidth narrowing effect was computed from 1 to
20 traversed 1 × 2 WSS as the possible maximum number of
cascaded nodes for metro-access networks where this device is
most applicable. As the cascading of WSS devices has the net
effect of multiplying the bandpass filter spectra together [25]
we can calculate the resulting filter with the computed transfer
function from the measured data. Photonic integrated flat top WSSs are realizable by adjusting
the spectral response of the AWGs. Several approaches are
possible, suchas theuseof multimodewaveguides at thereceiver
side [16], but is limited in application because it can only be
applied on the receiver side where the multimode waveguides
are directly coupled to a detector without additional signal loss. Flattening by the multigrating method [27] is another approach
that is realized by using several interleaved sub-gratings of
monomode waveguides getting a final response that is the ad-
dition of all the sub-responses, thus flattening the passband. It
was reported that the 1 dB bandwidth more than doubled by
using this approach when compared to conventional AWGs. In Fig. 23 we show the 3 dB bandwidth reduction as a function
of the number of traversed WSS for selected channels in the O,
S, C and L-bands. It was verified that, for the O and S-band,
after 15 traversed WSS the bandwidth was already smaller than
10 GHz, potentially limiting this band for scenarios where the
bandwidth requirements and/or the number of traversed filters
is small. In the case of the C-band, after 20 traversed WSS the 6032 REFERENCES [24] A. Alvarado, T. Fehenberger, B. Chen, and F. M. J. Willems, “Achievable
information rates for fiber optics: Applications and computations,” J. Lightw. Technol., vol. 36, no. 2, pp. 424–439, 2018. [1] “Cisco annual internet report - cisco annual internet report (2018.2023)
white paper - cisco,” [Online]. Avilable: https://www.cisco.com/c/en/us/
solutions/collateral/executive-perspectives/annual-internet-report/white-
paper-c11-741490.html [25] C. Pulikkaseril, L. A. Stewart, M. A. F. Roelens, G. W. Baxter, S. Poole,
and S. Frisken, “Spectral modeling of channel band shapes in wavelength
selective switches,” Opt. Exp., vol. 19, no. 9, pp. 8458–8470, 2011. [2] A. Ferrari et al., “Assessment on the achievable throughput of multi-band
ITU-T G.652.D fiber transmission systems,” J. Lightw. Technol., vol. 38,
no. 16, pp. 4279–4291, 2020. [26] K. Okamoto, “16-channel optical add/drop multiplexer consisting of
arrayed-waveguide gratings and double-gate switches,” Electron. Lett.,
vol. 32, no. 16, pp. 1471–1472, Aug. 1996. [3] N. Sambo et al., “Provisioning in multi-band optical networks,” J. Lightw. Technol., vol. 38, no. 9, pp. 2598–2605, 2020. [27] A.Rigny,A.Bruno,andH.Sik,“Multigratingmethodforflattenedspectral
response wavelength multi/demultiplexer,” Electron. Lett., vol. 33, no. 20,
pp. 1701–1702, 1997. [4] M. Cantono, R. Schmogrow, M. Newland, V. Vusirikala, and T. Hofmeis-
ter, “Opportunities and challenges of C+L transmission systems,” J. Lightw. Technol., vol. 38, no. 5, pp. 1050–1060, 2020. [28] A. Gholipour and R. Faraji-Dana, “Nonuniform arrayed waveguide grat-
ings for flat-top passband transfer function,” J. Lightw. Technol., vol. 25,
no. 12, pp. 3678–3685, 2007. [5] J. Cai et al., “70.4 tb/s capacity over 7600 km in C+L band using coded
modulation with hybrid constellation shaping and nonlinearity compensa-
tion,” in Proc. Opt. Fiber Commun. Conf. Exhib., 2017, pp. 1–3. pp
[29] S. Tsunashima et al., “Silica-based, compact and variable-optical-
attenuator integrated coherent receiver with stable optoelectronic coupling
system,” Opt. Exp., vol. 20, no. 24, pp. 27174–27179, Nov. 2012. tion,” in Proc. Opt. Fiber Commun. Conf. Exhib., 2017, pp [6] B. Correia et al., “Power control strategies and network performance
assessment for C+L+S multiband optical transport,” J. Opt. Commun. Netw., vol. 13, no. 7, pp. 147–157, 07 2021.
|
https://openalex.org/W4311265253
|
https://zenodo.org/records/7429632/files/XEBERLER_70_3_2015-56-59.pdf
|
Kirghiz, Kyrgyz
| null |
The Morphology of Sprouts of Some Rare Trees and Shrups of Azerbaijan
|
Zenodo (CERN European Organization for Nuclear Research)
| 2,015
|
cc-by
| 2,012
|
GİRİŞ təşkil etmişdir. Cücərtilərin böyümə və inkişafı
И.Т.Васильченко (1960), V.V.Smirnov (1964),
А.А.Молчанов və В.В.Смирнов (1967), fenoloji
müşahidələr isə Г.Н.Зайцев metodundan (1981)
istifadə edilmişdir. Tədqiq olunan bitkilərin təsni-
fatı, Lyman Benson (1967), Classification USDA
Plants (2007), APG III (2009) bitkilərin latınca
adları «Azərbaycan florası» (1950-61) və «Флора
СССР» (1934-60) və С.К.Черепановa (1981) görə
yoxlanılmışdır. Müasir dövrdə ekoloji tarazlığın pozulması nə-
ticəsində canlılara, o cümlədən bitkilərə olan mənfi
təsirlərin qarşısının alınması ən vacib məsələlərdən
biridir. Bu baxımdan, təbii ehtiyatlardan səmərəli
şəkildə istifadə edilməsi və bunların mühafizəsi xü-
susi əhəmiyyət kəsb edir. Məhz kompleks təd-
birlərin həyata keçirilməsi ilə bu problemlərin həlli
mümkündür (İsgəndər, 2010; Курбанов, Искен-
дер, 2009). Azərbaycan florasında 467 növ ağac və kol
bitkisinin olduğu qeyd edilir. Son tədqiqatlara görə,
hazırda mövcud olan bu növlərin 1/3 hisəsinin, yəni
təxminən 189 növün mühafizəyə ehtiyacı vardır
(Qurbanov, İsgəndər, 2015). NƏTİCƏLƏR VƏ ONLARIN MÜZAKİRƏSİ Ex situ və in situ şəraitlərdə bitkilərin həyat
tsikilində baş verən prosesləri və onların bioekoloji
xüsusiyyətlərini müxtəlif alimlər öyrənilmişlər
(Агамиров, 1985; Алиев, 1959; Искендеров,
1989; Искендеров, Кулиев, 1990; İskender et al.,
2006). Azərbaycan ərazisində yayılmış nadir və nəsli
kəsilməkdə olan ağac və kol bitkilərinin introduksi-
yası zamanı onların bioekoloji xüsusiyyətlərinin, o
cümlədən yaşla əlaqədar olaraq ontogenezin bütün
mərhələlərində baş verən dəyişkənliklərin; bitkilərin
həm təbii arealında, həm də introduksiya şəraitində
cücərtilərinin morfologiyasını, böyümə və inkişaf
xüsusiyyətləri, həyat göstəricilərinə görə perspek-
tivliyini obyektiv şkaladan istifadə etməklə qiymət-
ləndirilməsi; bitkilərin fərqli şəraitlərdə çiçəkləmə,
meyvəvermə və reproduksiya xüsusiyyətlərinə dair
aparılan tədqiqatların nəticələrinin areallarının kiçil-
məsindəki rolunun dəqiqləşdirilməsi; onların müha-
fizə olunma yollarının elmi əsaslarının öyrənilməsinə
dair aparılan çoxtərəfli elmi-tədqiqat işlərinin xüsusi
əhəmiyyəti vardır. Tədqiq olunan bitki toxumlarının cücərməsi ilə
ontogenezin virginil dövrünün birinci mərhələsi
başlayır. Bu mərhələ ilə yaşla bağlı olaraq bitkilərdə
baş verən böyümə və inkişaf dəyişkənliklərinin
müxtəlif şəraitlərdə öyrənilməsi mühüm əhəmiyyətə
malikdir. Ağac və kol bitkilərinin cücərtilərinin hər
hansı bir şəraitdə morfoloji xüsusiyyətlərinə görə
təyin edilməsi vacib məsələlərdən biridir (Василъ-
ченко, 1960; Искендеров, 1989; Kурбанов Ис-
кендер, 2009). Tədqiq edilən nadir və nəsli kəsilməkdə olan
ağac və kol bitkiləri cücərtilərinin morfoloji quru-
luşu, o cümlədən hipokotilin və rüşeym yarpaqla-
rının (ləpələrin) eni, uzunluğu, forması, sayı, rəngi
öyrənilmişdir (Cədvəl 1). Tədqiqatlardan məlum ol-
muşdur ki, öyrənilən bitkilərdə hipokotilin eni 0,5-
5,0 mm arasında dəyişilir. Hipokotilin eni 0,5 mm
olan Calligonum aphyllum, Calligonum bakuense,
Populus hyrcana, Rosa nizami 4-5 mm olanlardan
isə Ruscus hyrcana və Danae racemosa-nı gös-
tərmək olar. Tədqiqat işinin əsas məqsədi ölkəmizin təbii
florasında yayılmş nadir və nəsli kəsilməkdə olan
oduncaqlı bitki növlərinin cücərtilərinin morfoloji
göstəricilərini öyrənməklə onu təhlil etməkdən iba-
rət olmuşdur. Azərbaycanın Bəzi Nаdir Ağac və Kol Bitkilərinin Cücərtilərinin Morfologiyası E.O. İsgəndər* , G.H. Bağırova Məqalədə Azərbaycanın təbii florasında yayılmış bəzi nadir və nəsli kəsilməkdə olan ağac-kol
bitkilərinin cücərtilərinin morfoloji göstəriciləri əsasında təhlili verilmişdir. Müəyyən olunmuşdur ki,
iqlim şəraitinin dəyişilməsi cücərtilərin morfologiyasında ciddi fərqlər yaratmır. Açar sözlər: Nadir bitkilər, ağac, kol, cücərti, morfologiya, flora, mühafizə AMEA-nın Xəbərləri (biologiya və tibb elmləri), cild 70, №3, səh. 56-59 (2015) AMEA-nın Xəbərləri (biologiya və tibb elmləri), cild 70, №3, səh. 56-59 (2015) MATERİAL VƏ METODLAR Tədqiqatın materialını Azərbaycanın təbii flo-
rasında yayılmış 43 növ nadir ağac və kol bitkiləri Hipokotilin uzunluğuna görə tədqiq olunan
bitkilər 3 qrupa ayrılır: 56 Azərbaycanın Bəzi Nаdir Ağac və Kol Bitkilərinin A
B
C
D
Corylus colurna
Calligonum bakuense
Pterocarya pterocarpa
Hedera pastuchowii
E
F
G
H
Celtis caucasica
Castanea sativa
Ruscus hyrcanus
Danae racemosa
Şəkil. Ləpə yarpaqlarının uzunluğuna görə də tədqiq edilən bitkilər. A
B
C
D
Corylus colurna
Calligonum bakuense
Pterocarya pterocarpa
Hedera pastuchowii
E
F
G
H
Celtis caucasica
Castanea sativa
Ruscus hyrcanus
Danae racemosa
Şəkil. Ləpə yarpaqlarının uzunluğuna görə də tədqiq edilən bitkilər. D C
Pterocarya pterocarpa D B
Calligonum bakuense A
Corylus colurna C B Hedera pastuchowii Corylus colurna Calligonum bakuense Pterocarya pterocarpa H
Danae racemosa E
Celtis caucasica G
Ruscus hyrcanus F
Castanea sativa H E F G Ruscus hyrcanus Celtis caucasica Celtis caucasica Castanea sativa Danae racemosa Şəkil. Ləpə yarpaqlarının uzunluğuna görə də tədqiq edilən bitkilər. Şəkil. Ləpə yarpaqlarının uzunluğuna görə də tədqiq edilən bitkilər. Şəkil. Ləpə yarpaqlarının uzunluğuna görə də tədqiq edilən bitkilər. Cədvəl 1. Tədqiq edilən bitkilərin cücərtilərinin morfoloji göstəriciləri. MATERİAL VƏ METODLAR №
Növ
Hipokotil
Ləpə yarpaqları
eni, mm uzunluğu,
mm
rəngi
eni,
mm
uzunluğu,
mm
rəngi
forması
sayı
1
2
3
4
5
6
7
8
9
10
1 Albizia julibrissin
1*
10-15
yaşılımtıl
7
10-12
yaşılımtıl
oval
2
2 Alnus subcordata
0,70
10-15
qırmızımtıl
2-3
5
yaşılımtıl
yumurtaşəkilli
2
3 Buxus colchica
1,5
25-30
sarımtıl
3,5
15-20
tünd yaşıl
lansetşəkilli
2
4 Buxus hyrcana
1,5
25-30
sarımtıl
3
15-18
tünd yaşıl
lansetşəkillii
2
5 Calligonum aphyllum
0,5
35-45
çəhrayı
1
25-30
tündyaşıl
xətvari
2
6 Calligonum bakuense
0,5
30-40
zəif çəhrayı
1
25-35
yaşılımtıl
xətvari
2
7 Castanea sativa
3
40-50
yaşılımtıl
-
-
-
-
2
8 Celtis caucasica
1,5
35-45
alabəzək
8
12-15
yaşılımtıl
düzbucaqşəkilli
2
9 Celtis tournefortii
1,5
30-40
zəif alabəzək
6
10-12
yaşılımtıl
düzbucaqşəkilli
2
10 Colutea komarovii
1
15-20
tündyaşıl
7
12-15
yaşılımtıl
oval
2
11 Corylus colurna
1,5
60-70
yaşılımtıl
-
-
-
-
2
12 Cotoneaster saxatilis
0,70
14-18
qırmızımtıl
5
8
tünd yaşıl
yumru
2
13 Crataegus pontica
1,5
20-35
göyümtül-qırmızı
7
12
yaşılımtıl
oval
2
14 Danaea racemosa
5
45-50
yaşıl
-
-
-
-
1
15 Diospyros lotus
1,5
15-20
qırmızımtıl-yaşıl
12
18-25
yaşılımtıl
yumurtaşəkilli
2
16 Euonymus velutina
1
12-15
tündyaşıl
8
10-15
yaşıl
oval
2
17 Ficus hyrcana
1
4-8
yaşılımtıl
3
5
açıq yaşıl
oval
2
18 Gleditsia caspia
2
35
yaşılımtıl
10
13-20
yaşılımtıl
yumru
2
19 Hedera pastuchowii
2
35-45
ağımtıl-yaşıl
8
10-20
açıq yaşıl
oval
2
20 Ilex hyrcana
1,5
30-40
qırmızımtıl-yaşıl
5
8-12
tünd yaşıl
oval
2
21 Juniperus foetidissima
1
13-18
yaşılımtıl
2
12-15
yaşılımtıl
xətvari
2
22 Laurocerasus officinalis
1
15-25
yaşıl
5
8-10
yaşılımtıl
oval
2
23 Padus avium
1
10-18
qırmızımtıl
3
5-7
tünd-yaşıl
silindirşəkilli
2
24 Parrotia persica
2
18-22
yaşıl
16
26
yaşıl
oval
2
25 Platanus orientalis
2
10-12
qırmızımtıl
2
10-12
yaşılımtıl
xətvari
2
26 Punica granatum
1
25-30
alabəzək
7
8-12
qırmızımtıl-
yaşıl
böyrəkşəkilli
2
27 Pistacia mutica
1,5
20-35
qəhvəyi-qırmızı
-
-
-
-
2
28 Populus hyrcana
0,50
2-3
yaşılımtıl
1,2-2
2-3
yaşılımtıl
yumurtaşəkilli
2 Cədvəl 1. Tədqiq edilən bitkilərin cücərtilərinin morfoloji göstəriciləri. MATERİAL VƏ METODLAR 57 İsgəndər və Bağırova Cədvəlin davamı Cədvəlin davamı 1
2
3
4
5
6
7
8
9
10
29 Pterocarya pterocarpa
2
40-50
qəhvəyi
3
15-22
yaşılımtıl
lansetşəkilli
2
30 Pyracantha coccinea
0,70
10-12
alabəzək
3
4-5
çəhrayı
oval
2
31 Pyrus boissieriana
1
12-20
qırmızı
8
10-12
tündyaşıl
yumru
2
32 Pyrus grossheimi
1
12-18
qırmızımtıl
8
10-12
tündyaşıl
yumru
2
33 Pyrus hyrcana
1
12-20
qırmızımtıl
9
10-13
tündyaşıl
yumru
2
34 Pyrus salicifolia
1
12-18
qırmızımtıl
7
8-10
bozumtul-
yaşıl
yumru
2
35 Quercus araxina
2
4
qəhvəyi
-
-
-
-
2
36 Quercus castaneifolia
2
5
qırmızımtıl
-
-
-
-
2
37 Rhus coriaria
1,5
30-35
tündyaşıl
9
10-12
yaşılımtıl
oval
2
38 Rosa nizami
0,50
22
çəhrayı-alabəzək
4
7-9
yaşılımtıl
yumru
2
39 Ruscus hyrcanus
4
35-40
yaşıl
-
-
-
-
1
40 Staphulea colchica
2
18-25
yaşılımtıl
8
12-15
açıq-yaşıl
oval
2
41 Taxus baccata
0,70
25-35
tünd-yaşıl
2
12-15
yaşılımtıl
xətvari
6
42 Vitis sylvestris
1
35-45
çəhrayı
12
15-20
açıq-yaşıl
yumurtaşəkilli
2
43 Zelkova carpinifolia
2
35-40
çəhrayımtıl
5
6-7
yaşılımtıl
tərsyumurtavari
2 lilərdə isə rüşeym gövdəsindən çıxan hissə birbaşa
torpaq üstünə cücərti şəklində çıxır. a) hipokotilin uzunluğu 3-20 mm (Albizia
julibrissin, Alnus subcordata, Cotoneaster saxatilis,
Euonymus velutina, Ficus hyrcana, Populus hyrca-
na və b.) olanlar; Demək, yuxarıda qeyd edilən 5 növdə cücərmə
epikotil, digər növlərdə isə hipokotildir. b) 21-40 mm (Buxus colchica, Buxus hyrcana,
Crataegus pontica Gleditsia caspia, Laurocerasus
officinalis, Punica granatum və b.) olanlar; Tərəfimizdən aparılan təhlillərə görə bitkilərdə
ləpə yarpaqlarının forması növdən asılı olaraq
müxtəlif olur (Cədvəl 1). officinalis, Punica granatum və b.) olanlar; c) 41-70 mm (Corylus colurna, Danae
racemosa, Pterocarya pterocarpa, Castanea sativa
və b.) olanlar. Beləliklə, aparılan tədqiqatlar nəticəsində
müəyyən olunmuşdur ki, həm ex situ, həm də in
situ şəraitlərindən toplanmış toxumların cücərtilə-
rinin morfoloji quruluşu arasında əsaslı fərq müşa-
hidə edilmir. Ancaq cücərtilərin sonrakı inkişaf
dövrü ərzində in situ şəraiti ilə müqayisədə ex situ-
da bəzi növlərdə vegetativ orqanların formasında
bəzi dəyişikliklərin əmələ gəldiyi müşahidə edil-
mişdir. Hesab olunur ki, bu dəyişikliklər iki müx-
təlif şəraidə mövcud olan iqlim amillərinin fərqli
olması ilə əlaqədardır. Hipokotilin uzunluğundakı fərqin meydana
çıxması tədqiqat bitkilərinin fərdi bioloji xüsu-
siyyətləri ilə izah oluna bilər. MATERİAL VƏ METODLAR Tərəfimizdən aparıl-
mış tədqiqat zamanı ləpə yarpaqlarının uzunluğuna
görə də tədqiq edilən bitkilər 3 qrupa bölünmüşdür: a) 2-10 mm (Alnus subcordata,Cotoneaster
saxatilis, Ficus hyrcana, Padus avium, Populus
hyrcana və b.) arasında olanlar; b) 11-25 mm (Buxus colchica, Buxus hyrcana,
Celtis caucasica, Celtis tour-nefortii, Colutea koma-
rovii, Euonymus velutina və b.) arasında olanlar; Центральный ботанический сад НАНА В статье приводятся данные и анализ морфологических показателей всходов редких и исчезающих
древесно-кустарниковых растений, распространенных в естественной флоре Азербайджана. Выявлено, что изменение климатических условий не оказывает существенного влияния на мор-
фологию всходов. чевые слова: Редкие растения, деревья, кустарники, всходы, морфология, флора, охрана. ƏDƏBİYYAT Бюлл. Бот. Сада АН СССР, №155: 66-70 Iskender E.O., Zeynalov Y., Ozaslan M. et al. (2006) Investigation and introduction of some rare
and threatened plants from Turkey. J.Biotechno-
logy &Biotechnological Eguipment, 20(3): 60-68. Lyman Benson Plant Classification (1957) Bos-
ton: D.C.Heath and Company, 688 p. www.plants.usda.gov/classification.about_html
www.ru.wikipedia.org/wiki/systems_APG III ƏDƏBİYYAT y
)
c) 26-35 mm (Calligonum aphyllum, Calli-
gonum bakuense, Parrotia persica) arasında olan-
ların olduğu müəyyən edilmişdir (Şəkil B, C). Qurbanov M.R., İsgəndər E.O. (2015) Azərbay-
canın nadir oduncaqlı bitkilərinin bioekologi-
yası,çoxaldılması və mühafizəsi, Bakı: Təhsil,
Elm, 276 s. Aparılmış təhlillərin nəticəsi göstərmişdir ki,
öyrənilən bitkilərdə hipokotil və ləpə yarpaqlarının
ölçüləri ilə əlaqədar bu iki orqan arasında elə bir
asılılıq yoxdur.Tədqiq olunan bitki növlərində ləpə
yarpaqları və hipokotilin uzunluğundakı fərqlilik-
lərin yaranmasının səbəbi bitkilərin fərdi bioloji
xüsusiyyətləri ilə əlaqədardır. İsgəndər E.O. (2010) Azərbaycanın nadir və nəsli
kəsilməkdə olan ağac və kol bitkilərinin müha-
fizəsi və onun vəziyyətinin təhlili (icmal). Azər-
baycan botaniklər cəmiyyətinin əsərləri, I: 23-43 Агамиров У.М., Курбанов М.Р. (1985) К исто-
рии интродукции декоративных древесных
растений на Апшероне. Труды Бот. Сада
Инст. Ботаники АН Азерб. ССР «Интродук-
ция и акклиматизация растений», c. 18-21 Ex situ-da virqinil dövrünü tədqiq etdiyimiz
bitkilərdən 2 növ (Danae racemosa, Ruscus hyrca-
nus) birləpəli, iki növ isə çox ləpəlidir (Şəkil G, H ). Aparılan tədqiqatlar nəticəsində aydın olmuşdur ki,
virğinil dövrü öyrənilən ikiləpəli bikilərdən 5 növündə
(Castanea sativa, Pistacia mutica, Corylus colurna,
Quercus araxina, Quercus castaneifolia) cücərmə
zamanı ləpə yarpaqları torpaq üzərinə çıxmır. Birləpə- Алиев А.Г. (1959) К итогам интродукции дре-
весных и кустарниковых растений в Баку. Бюлл. ГБС АН СССР, вып. 35: 9-13. 58 Azərbaycanın Bəzi Nаdir Ağac və Kol Bitkilərinin Васильченко И.Т. (1960) Всходы деревьев и
кустарников. Определитель. М.-Л.: АН СССР,
301 с. Молчанов А.А., Смирнов В.В. (1967) Методи-
ка изучения прироста древесных растений. М.:
Наука, 95 с. Смирнов В.В. (1964) Сезонный рост главней-
ших древесных пород. М.: Наука, 165 с. Зайцев Г.Н. (1981) Фенология древесных расте-
ний. М.: Наука, с. 119 Флора Азербайджана (1950-1961) В 8 томах. Баку: АН Азерб. ССР. Искендеров Э.О. (1989) Изучение биоэкологи-
ческих особенностей некоторых ркдких и
исчезающих древесных растений Кавказа на
Апшероне. Дис. … канд. биол. наук. 248 с. у
р
Флора СССР (1934-1960) В 30 томах. М.-Л. Черепанов С.К. (1981) Сосудистые растения
СССР. Л.: Наука, 509 с. Искендеров Э.О., Кулиев К.М. (1990) Размно-
жение некоторых редких и исчезающих
древесных растений Кавказа в условиях Апше-
рона. Бюлл. Бот. Сада АН СССР, №155: 66-70
Курбанов М.Р., Искендер Э.О. (2009) Изуче-
ние и сохранение редких и исчезающих
древесных растений Азербайджана в ex situ и
in situ. Вестник Киевского НУ им. Т.Шевченко,
сер. интродукция и сохранение растительного
разнообразия, c. 138-139. Искендеров Э.О., Кулиев К.М. (1990) Размно-
жение некоторых редких и исчезающих
древесных растений Кавказа в условиях Апше-
рона. Central Botanical Garden, ANAS The data and analysis of morphological indexes of shoots of some rare and endangered trees and bushes
spread in the natural flora of Azerbaijan have been presented in the article. It has been found that changes in
climatic conditions do not significantly affect the morphology of the shoots. Key words: Rare plants, tree, shrub, shoot, morphology, flora, conservation. 59
|
https://openalex.org/W3216328280
|
https://www.researchsquare.com/article/rs-1117510/latest.pdf
|
English
| null |
Does Predicted Age At Peak Height Velocity Explain Physical Performance In U13-15 Basketball Female Players?
|
Research Square (Research Square)
| 2,021
|
cc-by
| 10,970
|
Does Predicted Age At Peak Height Velocity Explain Physical Performance
In U13-15 Basketball Female Players? Does Predicted Age At Peak Height Velocity Explain Physical Performance
In U13-15 Basketball Female Players? Does Predicted Age At Peak Height Velocity Explain Physical Performance
In U13-15 Basketball Female Players? Does Predicted Age At Peak Height Velocity Explain Physical Performance
In U13-15 Basketball Female Players?
Karol Gryko
(
karol.gryko@awf.edu.pl
)
Józef Piłsudski University of Physical Education in Warsaw Does Predicted Age At Peak Height Velocity Explain Physical Performance
In U13-15 Basketball Female Players? Karol Gryko
(
karol.gryko@awf.edu.pl
)
Józef Piłsudski University of Physical Education in Warsaw Does Predicted Age At Peak Height Velocity Explain Physical Performance
In U13-15 Basketball Female Players? Karol Gryko
(
karol.gryko@awf.edu.pl
)
Józef Piłsudski University of Physical Education in Warsaw
Jakub Grzegorz Adamczyk
Józef Pilsudski University of Physical Education in Warsaw
Anna Kopiczko
Józef Pilsudski University of Physical Education in Warsaw
Jorge Lorenzo Calvo
Universidad Politécnica de Madrid
Alberto Lorenzo Calvo
Universidad Politécnica de Madrid
Kazimierz Mikołajec
Jerzy Kukuczka Academy of Physical Education
Research Article
Keywords: maturity timing, adolescent development, athletes, physical fitness, aptitude
Posted Date: December 2nd, 2021
DOI: https://doi.org/10.21203/rs.3.rs-1117510/v1
License:
This work is licensed under a Creative Commons Attribution 4.0 International
License. Read Full License
Version of Record: A version of this preprint was published at BMC Sports Science, Medicine and Rehabilitation on February 8th, 2022. See the
published version at https://doi.org/10.1186/s13102-022-00414-4. Research Article Keywords: maturity timing, adolescent development, athletes, physical fitness, aptitude cense:
This work is licensed under a Creative Commons Attribution 4.0 International
License. Read F Version of Record: A version of this preprint was published at BMC Sports Science, Medicine and Rehabilitation on February 8th, 2022. See the
published version at https://doi.org/10.1186/s13102-022-00414-4. Page 1/15 Page 1/15 Background Basketball is a sport characterized by intermittent high-intensity exercise [1,2], whereas optimal performance in basketball is achieved through a
complex combination of technical and tactical skills and high physical fitness [3]. Athletes who train basketball, the need to analyze many variables
such as physical and physiological attributes (body height, body mass, somatotype, body proportions, aerobic profile, strength, anaerobic power,
agility, and speed) is emphasized [4]. Talent identification requires multifactorial analyses of several biological [5-7], functional, behavioural and
perceptual variables [8] and those related to the training process [9]. Studies indicate the validity and necessity of taking into account chronological
age and predicted age at peak height velocity (APHV) of basketball players to optimize the process of identifying gifted individuals [10]. Maturity status (early, on time, late, mature based on skeletal age, stage of puberty) refers to the state of biological maturation of an individual at the
time of observation, whereas maturity timing refers to the ages when specific maturational events are attained (ages at peak height velocity and
menarche) [11,12]. Among a large group of those willing to participate in the competitions in team sports, very few athletes reach the highest level of sports skills, while
talent identification and qualification for a sport are based on broad criteria selected through scientific analysis [13]. Many studies have emphasized
biological variability in sports for young athletes and emphasized it as one of the important aspects of talent identification and sports qualification
process [14-17]. In recent years, studies of young basketball players have among others focused on the assessment of trends of anthropometric traits and physical
performance [18], longitudinal changes of functional capacities [19], analyses of the effects of different training methods and protocols on power,
speed, and anaerobic capacity [20-22]. Interactions between body size and composition in predicting basketball performance have also been
considered [23]. These studies are often conducted independently of the maturation rate assessment and the interpretation of the performance of
young athletes during adolescence is very important for coaching practice because results can be misinterpreted due to discrepancies between
chronological age, biological age, and athletic age resulting from training experience [24]. From a somatic point of view, faster-maturing boys and girls are taller and heavier than their peers of the same chronological age, which gives them a
huge advantage in sports involving physical contact. This variation is most noticeable between the ages of 11 and 16. Abstract Background: The aims of the study were (i) to identify the physical fitness and basic anthropometric characteristics of Polish female basketball
players aged 13 to 15 years, (ii) to show the effect of maturity timing on the performance in motor tests and basic body composition parameters, (iii)
to identify the index that contributes most to the prediction of performance in the tests of speed, jumping ability, agility, and endurance. Methods: The sample included 925 female Polish players (U13-15). In part 1, maturity timing category distribution were examined within across age-
groups. In part 2, the relationship between the anthropometric variables, physical fitness performance was assessed based on maturity timing
categories (ANCOVA analysis). In part 3, backward stepwise multiple regression analyse quantified the relationship between maturity timing (group of
PHV) and physical performance. Results: ANCOVA results (age, body height, and body mass as covariates) showed in the U13 female basketball players significantly higher sprinting
(20m), jumping ability and endurance tests results of the PHV1 group.Better results was observed in U14 female players in PHV1 compared to PHV2
and PHV3 in 20m and jumping tests but opposite trend was observed for 5m sprint and endurance test (distance covered and VO2max). U15
basketball players from the PHV3 group were characterized by better results of jumping abilities, endurance, 10m and 20m sprint and agility (total, S4)
tests. Maturity timing (10m), chronological age (5 m, 20 m, agility, SVJ, VJ, and VO2max tests), body height (10m), body mass (10m, 20m, VJ, VO2max),
and the interaction between body mass and height (SVJ) were significant (adjusted R2 = 0.02-0.10; p < 0.001) predictors of motor skills. basketball players from the PHV3 group were characterized by better results of jumping abilities, endurance, 10m and 20m sprint and agility (total, S4)
tests. Maturity timing (10m), chronological age (5 m, 20 m, agility, SVJ, VJ, and VO2max tests), body height (10m), body mass (10m, 20m, VJ, VO2max),
and the interaction between body mass and height (SVJ) were significant (adjusted R2 = 0.02-0.10; p < 0.001) predictors of motor skills. Conclusion: The results can help the coaches to personalize training programs and to adapt the training content to the biological age of the players. Background Adolescence is the period in
which these differences are more pronounced and the age of 13 to 16 years appears to be the most heterogeneous period [13,16,25]. As a factor affecting basketball-specific functional abilities and skills, the interindividual differences in biological maturation have not been regularly
evaluated, especially in young female athletes. However, research findings indicate the relative age effect on the success of youth basketball teams
[26-28]. Overrepresentation of athletes born in the first months of the year in all age groups has been shown [29]. Relatively older athletes are often
characterized by greater body height, which is critical in basketball [30], and an advantage in motor skills, which may bias the assessment of fitness
potential of players born in different quarters of the year [31,32]. The above correlations are most commonly reported in basketball players [30], while
this effect has not been sufficiently studied in female basketball players to date. Sexual dimorphism underlies much of the physiological response to
physical exercise. Physiological characteristics of girls change with age and puberty due to a different hormonal environment that begins early in fetal
life [33]. Participation in an intensive training program for girls during the progressive stages of ontogenesis requires a great deal of knowledge from
coaches regarding the functional abilities of young athletes in conjunction with taking care of their general health. In the case of basketball, the
empirical findings on these issues are quite scarce [33]. Large differences between girls in terms of the time and pace of biological maturation can Page 2/15 Page 2/15 create difficulties in the correct interpretation of the rate of acquisition of individual motor and technical skills, and psychological preparation for
sports competition [19]. create difficulties in the correct interpretation of the rate of acquisition of individual motor and technical skills, and psychological preparation for
sports competition [19]. Given the available research findings (very few concerning young female basketball players), there is a strong need for physical fitness testing in
basketball on large research samples, especially to identify talents [34,35]. Therefore, testing was carried out to evaluate the motor potential and basic
anthropometric characteristics of a very large population of young female players aged 13 to 15 years, who were members of Polish basketball clubs. The second study aim was to show the impact of maturity timing on the results of motor tests and basic body composition. Procedure All of the participants, legal guardians, clubs and Polish Basketball Association were informed in writing about the aims, benefits, and procedure of
the research project, and about the possibility to withdraw from the study at any moment. The inclusion criterion was the written informed consent
obtained from each participant, and the exclusion criteria were contraindications for the basic anthropometric measurements. Injuries or trauma were
also the exclusion criteria. The research was approved by the local Ethics Committee for Scientific Research (SKE 01–28/2016), and the study was
conducted according to the rules and regulations of the Declaration of Helsinki [36]. Biological maturation The APHV of the female basketball players analyzed in the study was estimated by subtracting the maturity offset from chronological age at the time
of measurement [37]. The predicted maturity offset (years) was calculated as −7.709133 + (0.0042232x[age ∗stature]), with standard errors of
the equations of 0.542 years [38]. This equation was derived after calibrating the original equation proposed by Mirwald et al. [37]. Early maturers,
average maturers, and late maturers were defined as players with an estimated APHV of less than 13.1 years, 13.1-15.1 years, and more than 15.1
years, respectively [39]. Since the average maturers accounted for 97.7% of the basketball players, it was decided to analyze only this group. Due to
very low numbers, eight early maturing U13 players, four U14 players (3 early maturers, 1 late maturer), and seven U15 players (6 early maturers, 1 late
maturer) were excluded from the analysis. This was followed by grouping with respect to years before/after the observed PHV0 (-0.50 to 0.49), PHV1
(0.50 to 1.49), PHV2 (1.50 to 2.49), PHV3 (2.50 to 3.49) [39]. After this stage, the decision was made to exclude other two U13 female players from the
analysis, who were the only female basketball players in the PHV0 group. Finally, 904 basketball players were considered for comparison. Measurements Background The third aim was to
identify the index that mostly affects the prediction of performance in the individual tests evaluating speed, jumping ability, agility, and endurance. Participants The study sample size was 925 female basketball players aged 13 years (n=277; age: 13.05±0.28; basketball experience: 3.0±0.8 yrs), 14 years
(n=374; age: 13.95±0.30; basketball experience: 3.6±1.1 yrs), and 15 years (n=274; age: 14.82±0.28; basketball experience: 4.3±1.3 yrs). All examined
athletes belonged to the Caucasian ethnic group. The players were female members of 49 sports clubs competing in the national championship in the
age categories U13 and U15. The U14 girls also participated in the national championships at the club and regional competition levels. This group
included female basketball players who were members of the national team in their age categories (U13, U14, U15). All girls at this training stage were
characterized by a similar training volume (8 h 45 min per week - 3 technical training sessions, 1.5 h each, 3 strength and conditioning sessions, 45
min each, and 2 h a week playing games). The examinations were carried out in 2017-2020 during in regular season in the same periods of the year
(from November to February) to complete the measurements before the play-off phase. Measurements Body height (cm) was measured barefoot with the head positioned to the Frankfurt plane, using a stadiometer (Seca 264, Seca GmbH & co. kg,
Germany) with a precision of 0.1 cm, as were standing reach measurements (Seca 216, Seca GmbH & co. kg, Germany). Body mass was measured
using a JAWON Medical X-Scan Plus II device (Certificate No. EC0197 for medical devices) with a precision of 0.1 kg. The measurements were taken
by an anthropometry expert who holds an ISAK Level 1 accreditation according to the standards proposed by the International Society for the
Advancement of Kinanthropometry (ISAK) [40]. The basic anthropometric measurements and warm-up were followed by physical fitness tests
performed each time in the same order (speed test, jumping ability test, agility test, endurance test). Fitness was evaluated in two stages: the morning
session (to measure speed, jumping ability, and agility), and the evening session (measurements of endurance) so that adequate rest periods were
maintained. Speed Speed was measured using a 20 m sprint test with a split time recorded at 5 m (starting speed) and 10 m, when players ran at full speed. Each
participant performed two trials, with the best used as a test result [41]. The photoelectric cells Fusion Smart Speed System (Fusion Sport, Coopers
Plains, QLD, Australia) were used to record time (s). The photocells were installed at the starting line, 5 m, 10 m, and 20 m. The time measurement was
performed with an accuracy of 0.001 sec. Running started from the standing position, with the preferred foot positioned in front. No bouncing and
backward movements were allowed before the sprint. Statistical Analysis The normality of distribution was verified by the Shapiro-Wilk test, whereas the assumption of the equality of variance was verified using the Levene
test. The reliability coefficient for the measurements was Cronbach’s α = 0.91. The analysis of variance (ANOVA) was employed to show significant
differences between the groups of female basketball players. Furthermore, ANCOVA analysis was used to demonstrate the differences in years after
observed APHV, with chronological age, height, and mass used as covariates. Bonferroni adjustments were made for post-hoc comparisons. The
effect size was evaluated using partial eta squared (η2) and classified as: no effect = 0 to .039, minimum effect = .04 to .24, moderate effect = .25 to
.63, and strong effect = ≥ .64 [49]. Backward stepwise multiple regression was used to estimate the relative contributions of chronological age, maturity timing (stage of APHV), body
height, body mass, and height x mass interaction (based on residuals) to the variability of individual physical fitness tests. The significance of the
effects was set at p<0.05 for all the analyses. All calculations were performed using STATISTICA software (v.13.3, StatSoft, USA). Endurance The Yo-Yo Intermittent Recovery Test level 1 (Yo-Yo IR1) was used to evaluate endurance using a protocol presented in the literature [47, 48]. The total
distance covered (m) during Yo-Yo IR1 was the main measure of results and the maximum oxygen uptake (VO2max) calculated according to the
formula: VO2max = IR distance (m) x 0.0084 + 36.4 [48]. Agility The design of the agility test is presented in Figure 1. This is a modified Lane Agility Drill [46] test, with the length and width changed to 6x6 m to
ensure that the proportions between defensive shuffle and sprint were identical. The position of the photocell at the change of direction line was 1 m
from the line. The test was repeated twice, and a 10-minute rest break was administered to minimize fatigue. Before the test, the participant was
familiarized with the procedures by performing a trial (pre-test). The best time achieved during the test was recorded for the analysis of the results. Endurance Page 3/15 Page 3/15 The results of both standing jump (SVJ) and the a vertical jump (VJ) were measured using a yardstick vertical jump device [42-45]. The device is used
to measure the height to which a player can push away small sticks placed horizontally on a pole during a jump. Reaching height was subtracted
from the height reached while jumping. The first step was to perform 2 standing jump tests. Next, the player had 6 attempts (2 jumps with the
dominant leg, 2 with the non-dominant leg, and 2 with both legs), with sufficient rests between jumps. The highest attempt scores were retained for
analysis. This VJ protocol has established reliability [42-45]. Results When analyzing the variation of female basketball players with respect to age (Tab. 1) in the U13 group compared to U14 and U15, there were
significantly (p<0.001) lower values of age at PHV (by 0.13/yrs and 0.38/yrs, respectively; F(2,901)=72.1; η2 = 0.14 - minimum effect), body height (1-2%;
F(2,901)=15. 6; η2 = 0.03 - no effect), body mass (by 5.5% and 7.7%, respectively; F(2,901)=21.2; η2 = 0.05 - minimum effect) and arm reach (1-2%;
F(2,901)=8.8; η2 = 0.02 - no effect). The U14 female basketball players were also characterized by lower (p<0.001) age at PHV (by 0.25/yrs) compared
to U15 players. Page 4/15 Page 4/15 Table 1
Descriptive statistics of female basketball players by chronological age and results of ANOVA analysis comparing age groups
Variables
1. U13
(n=267)
2. U14
(n=370)
3. U15
(n=267)
F (p)
η2
d
Chronological age (years)
M
13.06
13.95
14.82
-
-
-
S.E. 0.02
0.02
0.02
APHV (years)
M
11.65
11.78
12.03
72.1 (***)
0.14
1v2v3
S.E. 0.02
0.02
0.02
Body height (cm)
M
165.3
167.7
167.8
15.6 (***)
0.03
1v2,3
S.E. 0.4
0.3
0.4
Body mass (kg)
M
55.0
58.2
59.6
21.2 (***)
0.05
1v2,3
S.E. 0.5
0.4
0.5
Standing reach (cm)
M
220.6
223.5
223.3
8.8 (***)
0.02
1v2,3
S.E. 0.6
0.5
0.6
5 m (s)
M
1.243
1.221
1.205
4.6 (*)
0.01
1v3
S.E. 0.011
0.007
0.005
10 m (s)
M
2.021
2.028
2.048
2.2
-
-
S.E. 0.012
0.008
0.007
20 m (s)
M
3.585
3.551
3.539
5.8 (**)
0.01
1v3
S.E. 0.01
0.008
0.011
Agility - S1 (s)
M
1.653
1.671
1.677
0.65
-
-
S.E. 0.015
0.013
0.015
Agility - S2 (s)
M
5.768
5.736
5.672
2.2
-
-
S.E. 0.033
0.027
0.034
Agility - S3 (s)
M
7.677
7.601
7.499
6.3 (**)
0.01
1v3
S.E. 0.035
0.03
0.036
Agility - S4 (s)
M
10.082
9.953
9.754
13.6 (***)
0.04
1,2v3
S.E. 0.045
0.04
0.043
Agility - S5 (s)
M
13.678
13.471
13.272
9.3 (***)
0.02
1v3
S.E. 0.063
0.059
0.064
Agility - Total (s)
M
15.726
15.538
15.314
9.4 (***)
0.02
1,2v3
S.E. 0.068
0.059
0.062
SVJmax (cm)
M
255.3
259.8
260.0
17.7 (***)
0.04
1v2,3
S.E. 0.7
0.6
0.6
VJmax (cm)
M
263.7
268.1
268.7
15.6 (***)
0.04
1v2,3
S.E. 0.7
0.6
0.7
SVJ (cm)
M
34.9
36.2
36.7
7.07 (**)
0.02
1v2,3
S.E. Results 0.3
0.3
0.4
VJ (cm)
M
43.1
44.5
45.3
5.69 (**)
0.01
1v3
Notes:
M – mean; S.E. – standard errors; SVJ – standing vertical jump; VJ – vertical jump; d - significant differences between groups; Page 5/15 Page 5/15 Variables
1. U13
(n=267)
2. U14
(n=370)
3. U15
(n=267)
F (p)
η2
d
S.E. 0.5
0.4
0.5
Yo-Yo Distance (m)
M
736
826
852
8.8 (***)
0.02
1v2,3
S.E. 20
18
22
Yo-Yo VO2max (ml/kg/min)
M
42.6
43.3
43.4
8.3 (***)
0.02
1v2,3
S.E. 0.2
0.1
0.2
Notes:
M – mean; S.E. – standard errors; SVJ – standing vertical jump; VJ – vertical jump; d - significant differences between groups;
* p < 0.05, ** p < 0.01, *** p < 0.001 Furthermore, in the speed test, the U13 female players were slower than those from U15 group in 5m run test (by 3.1%; p<0.05; F(2,901)=4.6; η2 = 0.01 -
no effect) and 20m run test (by 1.3%; p<0.01; F(2,901)=5.8; η2 = 0.01 - no effect). Analysis of the results of the agility test revealed that the U13 female
basketball players were slower compared to U15 for S3 (by 2.4%; p<0.01; F(2,901)=6.3; η2 = 0.01 - no effect), S4 (by 3.4%; p<0.001; F(2,901)=13.6; η2 = 0.04
- minimum effect), S5 (by 3.1%; p<0.001; F(2,901)=9.3; η2=0.02 - no effect) and considering the total test completion time (by 2.7%; p<0.001; F(2,901)=9.4;
η2 = 0.02 - no effect). The U14 group was slower than U15 in S4 and total test completion time (1-3%). Analysis of the results in the context of the jumping tests showed significantly lower values (1-5%) in SVJmax,, VJmax (p<0.001; minimum effect) and
SVJ, VJ (p<0.01; no effect) obtained by U13 compared to U15 players. An identical relationship (lower values within 1-4%) was observed in U13
compared to U14 in SVJmax, VJmax, and SVJ. Compared to U14 and U15, female basketball players from the U13 group were also characterized by significantly (p<0.001) lower values of the
distance covered (10-14%, F(2,901)=8.8; η2 = 0.02, no effect) and VO2max (1-2%, F(2,901)=8.3; η2 = 0.02; no effect) in the physical capacity test. Table 2 shows the age-adjusted characteristics of female basketball players in relation to years after PHV (Tab. 2). Results In the group of U13 basketball
players who were in PHV2, significantly (p<0.001) higher values of body height (by 6.5%; F(1,263)=28.7; η2 = 0.18; minimum effect), arm reach (by 6.4%;
F(1,263)=18.2; η2 = 0.12; minimum effect), SVJmax (by 5.4%; F(1,263)=8.1; η2 = 0.06; minimum effect), and VJmax (by 4.7%; p<0.05; F(1,263)=3.7; η2 =
0.03; no effect) were found compared to PHV1. In contrast, the PHV2 group performed worse in the 5m speed test (by 2.3%; p<0.01; F(1,263)=5.5; η2 =
0.04; minimum effect) and endurance test, both in terms of the distance covered and VO2max (2-13%; p<0.05; F(1,263)=3.3; η2 = 0.02; no effect). Furthermore, compared to groups PHV1 and PHV2, U14 female basketball players in PHV3 had higher body height (by 14.4% and 6.3%, respectively;
p<0.001; F(2,364)=27.2; η2 = 0.18; minimum effect), body mass (by 34.6% and 8.7%, respectively; p<0.05; F(2,364)=3.6; η2 = 0.03; no effect), arm range (by
15.2% and 6%, respectively; p<0.001; F(1,263)=17.5; η2 = 0.13; minimum effect), SVJmax (by 12.6% and 5.1% respectively; p<0.001; F(2,364)=7.1; η2 = 0.06;
minimum effect) and VJmax (by 12.6% and 4.8%, respectively; p<0.01; F(2,364)=4.2; η2 = 0.03; no effect). An identical trend was recorded in the same
variables in favor of PHV2 compared to PHV1, ranging from 7 to 17%. Compared to PHV1 and PHV2, significantly lower values (p<0.001; F(2,364)=6.7; Results Page 6/15 Page 6/15 Table 2
Age-adjusted means (standard errors in parentheses) by maturity timing within age groups and results of ANCOVAs with decimal age as the covariate
Variables
U13
F
(p)
η2
U14
F
(p)
η2
d
U15
F
(p)
η2
PHV1
(n=154)
PHV2
(n=113)
PHV1
(n=22)
PHV2
(n=264)
PHV3
(n=84)
PHV2
(n=63)
PHV3
(n=204)
Body height
(cm)
160.7
(0,3)
171.2
(0,4)
28.7
(***)
0.18
154.4
(1,3)
166.2
(0,2)
176.6
(0,7)
27.2
(***)
0.18
1v2v3
160.5
(0,6)
170.5
(0,3)
30.5
(***)
0.19
Body mass
(kg)
51.6
(0,6)
59.8
(0,8)
2.2
-
48.8
(2,5)
57.0
(0,5)
65.7
(1,3)
3.6
(*)
0.03
1v2v3
54.4
(1,2)
61.4
(0,6)
2.1
-
Standing
reach (cm)
214.8
(0,6)
228.6
(0,8)
18.2
(***)
0.12
204.1
(2,3)
221.7
(0,4)
235.1
(1,2)
17.5
(***)
0.13
1v2v3
213.5
(1,1)
227.1
(0,5)
20.3
(***)
0.13
5 m (s)
1.228
(0,016)
1.256
(0,020)
5.5
(**)
0.04
1.217
(0,047)
1.215
(0,009)
1.214
(0,024)
0.7
-
-
1.198
(0,012)
1.205
(0,006)
0.8
-
10 m (s)
2.030
(0,017)
2.018
(0,021)
2.3
-
2.014
(0,050)
2.028
(0,009)
2.033
(0,026)
0.1
-
-
2.043
(0,016)
2.047
(0,008)
1.0
-
20 m (s)
3.571
(0,015)
3.611
(0,018)
1.2
-
3.542
(0,052)
3.546
(0,010)
3.556
(0,026)
1.0
-
-
3.515
(0,025)
3.543
(0,013)
0.2
-
Agility - S1
(s)
1.643
(0,022)
1.659
(0,027)
0.2
-
1.776
(0,083)
1.672
(0,016)
1.648
(0,042)
4.3
(**)
0.03
1v2,3
1.664
(0,037)
1.678
(0,019)
0.8
-
Agility - S2
(s)
5.718
(0,047)
5.805
(0,059)
0.7
-
5.968
(0,172)
5.711
(0,032)
5.771
(0,088)
0.1
-
-
5.774
(0,081)
5.682
(0,041)
3.5
(*)
0.03
Agility - S3
(s)
7.617
(0,049)
7.711
(0,062)
2.5
-
7.722
(0,193)
7.598
(0,036)
7.604
(0,099)
0.5
-
-
7.515
(0,086)
7.534
(0,043)
2.3
-
Agility - S4
(s)
10.014
(0,063)
10.142
(0,079)
2.5
-
10.122
(0,252)
9.945
(0,047)
9.964
(0,129)
0.6
-
-
9.851
(0,102)
9.781
(0,051)
3.5
(*)
0.03
Agility - S5
(s)
13.583
(0,090)
13.769
(0,113)
1.8
-
13.822
(0,377)
13.450
(0,071)
13.475
(0,192)
1.1
-
-
13.389
(0,153)
13.304
(0,077)
2.1
-
Agility -
Total (s)
15.625
(0,097)
15.844
(0,121)
2.2
-
15.815
(0,376)
15.518
(0,071)
15.586
(0,192)
0.7
-
-
15.392
(0,148)
15.351
(0,075)
1.8
-
SVJmax
(cm)
249.7
(0,8)
263.1
(1,0)
8.1
(***)
0.06
240.9
(2,9)
258.1
(0,5)
271.3
(1,5)
7.1
(***)
0.06
1v2v3
251.1
(1,3)
263.5
(0,6)
13.6
(***)
0.09
VJmax (cm)
258.4
(0,9)
270.6
(1,1)
3.7
(*)
0.03
248.8
(3,2)
266.4
(0,6)
279.1
(1,6)
4.2
(**)
0.03
1v2v3
257.8
(1,5)
272.5
(0,7)
10.3
(***)
0.07
SVJ (cm)
34.9
(0,5)
35.1
(0,6)
0.8
-
36.7
(2,0)
36.4
(0,4)
36.2
(1,0)
1.3
-
-
37.6
(0,9)
36.5
(0,4)
0.1
-
VJ (cm)
43.6
(0,7)
42.0
(0,9)
2.3
-
44.6
(2,5)
44.8
(0,5)
43.9
(1,3)
1.7
-
-
44.3
(1,1)
45.5
(0,6)
0.4
-
Yo-Yo
Distance
(m)
780
(29)
682
(36)
3.3
(*)
0.02
916
(109)
833
(20)
730
(56)
6.7
(***)
0.05
1v2v3
867
(51)
833
(26)
0.9
-
Yo-Yo
VO2max
(ml/kg/min)
43.0
(0,2)
42.1
(0,3)
3.3
(*)
0.02
44.1
(0,9)
43.4
(0,2)
42.5
(0,5)
6.7
(***)
0.05
1v2v3
43.4
(0,4)
43.3
(0,2)
1.0
-
Notes:
SVJ – standing vertical jump; VJ – vertical jump; d - significant differences between groups;
* p < 0.05, ** p < 0.01, *** p < 0.001
Furthermore, compared to groups PHV1 and PHV2, U14 female basketball players in PHV3 had higher body height (by 14.4% and 6.3%, respectively;
p<0 001 F
27 2 η2
0 18 minim m effect) bod mass (b 34 6% and 8 7% respecti el
p<0 05 F
3 6 η2
0 03 no effect) arm range (b Furthermore, compared to groups PHV1 and PHV2, U14 female basketball players in PHV3 had higher body height (by 14.4% and 6.3%, respectively;
p<0.001; F(2,364)=27.2; η2 = 0.18; minimum effect), body mass (by 34.6% and 8.7%, respectively; p<0.05; F(2,364)=3.6; η2 = 0.03; no effect), arm range (by
15.2% and 6%, respectively; p<0.001; F(1,263)=17.5; η2 = 0.13; minimum effect), SVJmax (by 12.6% and 5.1% respectively; p<0.001; F(2,364)=7.1; η2 = 0.06;
minimum effect) and VJmax (by 12.6% and 4.8%, respectively; p<0.01; F(2,364)=4.2; η2 = 0.03; no effect). Results An identical trend was recorded in the same
variables in favor of PHV2 compared to PHV1, ranging from 7 to 17%. Compared to PHV1 and PHV2, significantly lower values (p<0.001; F(2,364)=6.7; Furthermore, compared to groups PHV1 and PHV2, U14 female basketball players in PHV3 had higher body height (by 14.4% and 6.3%, respectively;
p<0.001; F(2,364)=27.2; η2 = 0.18; minimum effect), body mass (by 34.6% and 8.7%, respectively; p<0.05; F(2,364)=3.6; η2 = 0.03; no effect), arm range (by
15.2% and 6%, respectively; p<0.001; F(1,263)=17.5; η2 = 0.13; minimum effect), SVJmax (by 12.6% and 5.1% respectively; p<0.001; F(2,364)=7.1; η2 = 0.06;
minimum effect) and VJmax (by 12.6% and 4.8%, respectively; p<0.01; F(2,364)=4.2; η2 = 0.03; no effect). An identical trend was recorded in the same
variables in favor of PHV2 compared to PHV1, ranging from 7 to 17%. Compared to PHV1 and PHV2, significantly lower values (p<0.001; F(2,364)=6.7; Page 7/15 Page 7/15 η2 = 0.05; minimum effect) of distance covered (by 20.3% and 12.4%, respectively) and VO2max (by 3.6% and 2.1%, respectively) in endurance test
were observed in the PHV3 group. Also in these two parameters, favorable results were obtained by the PHV1 group compared to PHV2 (1-10%). Compared to PHV2, the U15 basketball players from group PHV3 showed higher values of body height (by 6.2%; p<0.001; F(1,263)=30.5; η2 = 0.19;
minimum effect), arm reach (by 6.4%; p<0.001; F(1,263)=20.3; η2 = 0.13; minimum effect), SVJmax (by 4.9%; p<0.001; F(1,263)=13.6; η2 = 0.09; minimum
effect), VJmax (by 5.7%; p<0.001; F(1,263)=10.3; η2 = 0.07; minimum effect), and more favorable results in two sections of the agility test S2, S4 (within
1-2%; p<0.05; F(1,263)=3.5; η2 = 0.03; no effect). Comparison of age-, height-, and weight-adjusted means (ANCOVA) with reference to years after PHV (Tab. 3) showed favorable results in 20m speed
test and higher results in all jumping ability and endurance tests (1-6%) in the group of U13 female basketball players in PHV1. An identical trend of
higher values was observed in U14 female players in PHV1 compared to PHV2 and PHV3 in arm reach (1-2%; p<0.05; minimum effect), SVJmax (7-9%;
p<0.01; minimum effect), VJmax (1-3%, p<0.01; minimum effect), SVJ (42-53%, p<0.05; no effect) and a more favorable result in the 20m speed test (2-
5%; p<0.01; minimum effect). Results The opposite trend was observed for 5m speed (3-10%; p<0.05; no effect), distance covered during the endurance test
(17-19%; p<0.01; minimum effect), VO2max (12-13%; p<0.01; minimum effect). Compared to PHV3, U15 basketball players from the PHV2 group were
characterized by lower values of all variables of jumping abilities (1-10%), endurance (3-15%), and weaker time in 10m and 20m speed tests (1-3%),
and on the S4 section and in the entire agility test (2-4%). Results Page 8/15 Table 3 Table 3
Age-adjusted means (standard errors in parentheses) by PHV within age groups and results of ANCOVAs with decimal age, hight and body mass as
the covariate
Variables
U13
F
(p)
η2
U14
F
(p)
η2
d
U15
F
(p)
η2
PHV1
(n=154)
PHV2
(n=113)
PHV1
(n=22)
PHV2
(n=264)
PHV3
(n=84)
PHV2
(n=63)
PHV3
(n=204)
Standing
reach (cm)
221.1
(0,7)
221.3
(0,8)
1.0
-
225.4
(5,6)
221.4
(0,3)
221.2
(1,8)
2.7
(*)
0.05
1v2,3
218.1
(1,3)
219.9
(0,5)
1.7
-
5 m (s)
1.244
(0,025)
1.258
(0,031)
0.2
-
1.326
(0,177)
1.216
(0,009)
1.284
(0,056)
1.8
(*)
0.03
1v2,3
1.216
(0,023)
1.202
(0,009)
1.3
-
10 m (s)
2.028
(0,027)
2.023
(0,033)
1.7
-
1.805
(0,190)
2.029
(0,009)
2.082
(0,060)
0.8
-
-
2.083
(0,030)
2.039
(0,012)
2.8
(**)
0.04
20 m (s)
3.579
(0,022)
3.619
(0,028)
2.9
(**)
0.06
3.473
(0,192)
3.548
(0,009)
3.624
(0,061)
2.9
(**)
0.06
1v2v3
3.539
(0,048)
3.513
(0,019)
3.2
(**)
0.05
Agility - S1
(s)
1.674
(0,034)
1.674
(0,043)
0.3
-
1.704
(0,318)
1.673
(0,016)
1.635
(0,101)
1.6
-
-
1.678
(0,072)
1.665
(0,028)
1.0
-
Agility - S2
(s)
5.716
(0,074)
5.771
(0,092)
0.4
-
5.341
(0,657)
5.712
(0,032)
5.858
(0,210)
0.6
-
-
5.788
(0,157)
5.641
(0,061)
1.7
-
Agility - S3
(s)
7.653
(0,077)
7.617
(0,097)
1.1
-
7.005
(0,739)
7.598
(0,037)
7.650
(0,236)
0.5
-
-
7.745
(0,165)
7.479
(0,064)
1.6
-
Agility - S4
(s)
10.063
(0,099)
10.049
(0,124)
1.1
-
9.630
(0,962)
9.946
(0,047)
10.096
(0,307)
0.6
-
-
10.067
(0,196)
9.734
(0,077)
2.5
(*)
0.03
Agility - S5
(s)
13.607
(0,141)
13.614
(0,176)
1.0
-
12.344
(1,436)
13.455
(0,071)
13.563
(0,458)
0.9
-
-
13.676
(0,294)
13.276
(0,115)
1.7
-
Agility - Total
(s)
15.646
(0,152)
15.676
(0,190)
1.1
-
14.725
(1,435)
15.522
(0,071)
15.612
(0,458)
0.8
-
-
15.670
(0,285)
15.265
(0,112)
2.1
(*)
0.03
SVJmax (cm)
256.4
(1,0)
255.0
(1,2)
2.0
(*)
0.05
277.2
(8,5)
257.8
(0,4)
255.2
(2,7)
4.9
(**)
0.09
1v2,3
254.8
(2,1)
257.6
(0,8)
3.3
(*)
0.03
VJmax (cm)
264.8
(1,1)
262.6
(1,4)
6.1
(**)
0.06
270.4
(9,9)
266.1
(0,5)
264.2
(3,2)
4.8
(**)
0.09
1v2,3
260.2
(2,5)
266.2
(1,0)
3.4
(**)
0.03
SVJ (cm)
35.3
(0,7)
34.7
(0,9)
2.6
(*)
0.05
51.8
(7,4)
36.3
(0,4)
34.0
(2,4)
3.3
(*)
0.03
1v2,3
36.7
(1,6)
37.7
(0,6)
3.4
(**)
0.03
VJ (cm)
43.6
(1,0)
41.3
(1,3)
4.6
(**)
0.09
45.0
(9,3)
44.7
(0,5)
43.0
(3,0)
3.1
(*)
0.02
1v3
42.1
(2,2)
46.3
(0,8)
3.1
(**)
0.03
0.05
5.6
(**)
0.04
1v2,3
765
(97)
900
(38)
3.5
(**)
0.04 0.05 Yo-Yo
Distance (m)
783
(43)
742
(54)
3.6
(**)
686
(117)
830
(20)
844
(127)
Yo-Yo
VO2max
(ml/kg/min)
43.0
(0,4)
42.6
(0,5)
3.5
(**)
0.05
38.0
(3,3)
43.4
(0,2)
43.5
(1,0)
5.6
(**)
0.04
1v2,3
42.2
(0,8)
43.7
(0,3)
3.6
(**)
0.05
Notes:
SVJ – standing vertical jump; VJ – vertical jump; d - significant differences between groups;
* p < 0.05, ** p < 0.01, *** p < 0.001 The results of the backward stepwise multiple regression analysis are presented in Table 4. Discussion The aims of this study were (i) to identify the physical fitness and basic anthropometric characteristics of Polish female basketball players aged 13 to
15 years, (ii) to show the effect of maturity timing on the performance in motor tests and basic body composition parameters, (iii) to identify the index
that contributes most to the prediction of performance in the tests of sprint, jumping ability, agility, and endurance. The aims of this study were (i) to identify the physical fitness and basic anthropometric characteristics of Polish female basketball players aged 13 to
15 years, (ii) to show the effect of maturity timing on the performance in motor tests and basic body composition parameters, (iii) to identify the index
that contributes most to the prediction of performance in the tests of sprint, jumping ability, agility, and endurance. The first aim of the study was to identify motor potential and basic anthropometric characteristics of the population of young female basketball
players aged 13 to 15 years. Determination of these parameters is a starting point in the search for candidates for the participant of national teams or
defining the characteristics needed or conducive to high performance. Talent identification programs are an integral part of the selection process for
elite-level athletes and every sport has its set of variables being an important part of success [50]. Many sports clubs have their individual systems of
selection according to the most important features in a given discipline or event. This rationale underlies the emergence of various recruitment and
selection programs aimed at seeking, identifying, and developing talented individuals [51,52]. Polish female basketball players from the U15 group
achieved slightly better (compared to peers, the best basketball female players in Europe, participating in the youth championships of European
Division A), or identical results (compared to female basketball players participating in the youth championships of European Division B) in 20m
sprint test [53]. Further, Polish female athletes were characterized by lower values of body height and body mass. On the other hand, a comparison of
the values after correcting with body height revealed no significant differences [53]. Such a trend may indicate that the Polish players are more similar
to their peers from Division B (2nd European League) teams than to Division A (1st European League). Results The presented model explained 2-10% of the variance in
individual strength and conditioning tests (adjusted R2 = 0.02-0.10; p < 0.001). The time from PHV was a significant predictor (positive value of the
normalized β coefficient) only for the 10m test. Furthermore, age was a significant predictor for the 5m speed test, 20m speed test, agility test The results of the backward stepwise multiple regression analysis are presented in Table 4. The presented model explained 2-10% of the variance in
individual strength and conditioning tests (adjusted R2 = 0.02-0.10; p < 0.001). The time from PHV was a significant predictor (positive value of the
normalized β coefficient) only for the 10m test. Furthermore, age was a significant predictor for the 5m speed test, 20m speed test, agility test Page 9/15 Page 9/15 (negative β coefficient), and SVJ, VJ, and VO2max (positive β coefficient) tests. The predictor of interactions of body height and body mass was
significant only for the SVJ test (negative coefficient β). Body mass alone was a significant predictor in the 10m and 20m tests (positive direction)
and VJ, VO2max (negative direction). It was also found that body height was a significant predictor only in the 10m speed test. Table 4
Summary of the backward regression for motor skills and anthropometric variables by
the female basketball players aged 13-15 years. Attempt
Predictor
Standardized β
Adjusted R2
F (p)
5 m
Chronological age
-0.111
0.02
11.2 (*)
10 m
Body height
-0.161
0.02
7.2 (*)
Body mass
0.154
APHV
0.100
20 m
Chronological age
-0.156
0.06
27.1 (*)
Body mass
0.214
AgilityTotal
Chronological age
-0.160
0.03
23.7 (*)
SVJ
Chronological age
0.161
0.04
17.2 (*)
Mass*height interaction
-0.143
VJ
Chronological age
0.170
0.06
26.5 (*)
Body mass
-0.201
Yo-Yo VO2max
Chronological age
0.201
0.10
42.8 (*)
Body mass
-0.261
Notes:
SVJ – standing vertical jump; VJ – vertical jump;
* p < 0.001 Discussion Selection carried out in this way is often flawed if decisions are made
before the maturation process is complete [56]. The third aim of the study, which was to identify the indices most useful in predicting the level of motor preparation, allowed for the conclusion that
chronological age, height, weight, weight-height interaction, and the time from PHV accounted for 2-10% of the variance in individual physical fitness
tests. Maturity timing was a significant predictor only in sprint test (10m) but body height and body mass were the most significant predictors in this
test. Rest results showed that chronological age (5 m, 20 m, agility, SVJ, VJ, and VO2max tests), body height (10m), body mass (10m, 20m, VJ,
VO2max), and the interaction between body mass and height (SVJ) were significant (adjusted R2 = 0.02-0.10; p < 0.001) predictors of motor skills. In
general, considering the adjusted R2 value, most of the differences in the results obtained by female basketball players were not explained by these
variables. There is extensive literature on the analysis of selected motor and functional fitness characteristics in correlation with the level of physical
development in adolescent girls, however mainly in general non-athlete populations [57,58]. In contrast, the results of our study are consistent with
previous findings and show that much of the variation in sport-specific functional abilities and skills is not explained by age, puberty, and body size
[8,10] and for young training girls, understanding the complex interactions of physical development, especially body mass and height, with sport-
specific motor abilities and biological age is a key component of sporting success [7]. The third aim of the study, which was to identify the indices most useful in predicting the level of motor preparation, allowed for the conclusion that
chronological age, height, weight, weight-height interaction, and the time from PHV accounted for 2-10% of the variance in individual physical fitness
tests. Maturity timing was a significant predictor only in sprint test (10m) but body height and body mass were the most significant predictors in this
test. Rest results showed that chronological age (5 m, 20 m, agility, SVJ, VJ, and VO2max tests), body height (10m), body mass (10m, 20m, VJ, The objectivity of inferring developmental capabilities depends largely on a comprehensive assessment of the status of various functional systems
involved in a specialized task. Discussion The basketball players from the U13 group
also achieved better results (even considering age-adjusted values) in the 20m sprint compared to their peers from Portugal [7]. The second study aim was to show the impact of maturity timing on the results of motor tests and basic body composition. Somatic built and
physical fitness potencial determines, on the one hand, factors necessary to qualify an athlete for a given sport and, on the other hand, having optimal
parameters for success in the sport. Analysis of values related to age-adjusted characteristics showed that in the PHV2 under 13-year-old group
observed significantly higher SVJmax, VJmax values but worse sprint (5m) and endurance results (distance covered, VO2max) than PHV1 group. U14
female basketball players in PHV3 had significantly higher SVJmax, VJmax results compared to groups PHV1 and PHV2 and lower values of endurance
test (distance covered and VO2max). Limited study suggest that less mature girls perform better than more maturing girls in some tasks, but overall
maturity - associated variation is not consistent across tasks and ages [54]. The U15 basketball players from PHV3 compared to PHV 2 group showed Page 10/15 higher values of SVJmax, VJmax and agility test (S2, S4). This is consistent with previous researche where more mature players are typically
characterized by higher performance in speed, agility, and lower limb power [7, 55]. higher values of SVJmax, VJmax and agility test (S2, S4). This is consistent with previous researche where more mature players are typically
characterized by higher performance in speed, agility, and lower limb power [7, 55]. Similar trend was shown in ANCOVA results (age, body height, and body mass as covariates) where in the U13 female basketball players observed
significantly higher sprinting (20m), jumping ability and endurance tests results of the PHV1 group. Better results was observed in U14 female players
in PHV1 compared to PHV2 and PHV3 in 20m and jumping tests but opposite trend was observed for 5m sprint and endurance test (distance covered
and VO2max). U15 basketball players from the PHV3 group were characterized by better results of jumping abilities, endurance, 10m and 20m sprint
and agility (total, S4) tests. In this context, it is important to take biological development into account, since differences resulting from this
development are most often overlooked and thus early maturers are promoted. Abbreviations APHV – age at peak height velocity; PHV – peak height velocity; SVJ – standing vertical jump; VJ – vertical jump; Discussion Such an assessment of physical and mental preparation, in addition to the generally accepted indicators, should take
into account chronological and biological age, individual rate of performance development, indicators of physical development and motor activity at
the stage before the examination and the assessment of their prospective capabilities [59]. Particular caution should be exercised in the selection
based on index values obtained before puberty. Most of the changes occurring during puberty (e.g. aerobic and anaerobic capacity, fitness, body
composition) are non-linear [60]. Results showed that only a third of international pre-junior athletes reappeared as senior athletes, confirming the
difficulties of predicting late success based on early identification and selection [61]. The present study has some limitations that must be acknowledged. The menarche age was not included in the study. Both somatic, motor and
developmental parameters should not be treated as an absolute selection criterion, especially in sports where the results are an effect of
multidimensional dependencies of various variables [62]. The superior performance here may result from individually varying relationships between
innate determinants of athletic performance and environmental factors [59]. All equations used to predict APHV (maturity shift) or APHV have the
same major limitations [63,64]. The advanced maturity timing and the relatively narrow range of variation in predicted age at peak height velocity may
undermine its utility and effectiveness in talent identification and development programs when applied at a specific time point [6,15]. Given the above, it seems that knowledge of APHV of players is important to identify differences in motor potential caused by developmental changes
[65]. However, it must be complemented by the use of methods related to the evaluation of technique within individual specializations [66]. In future
studies of this type, especially considering adolescent girls' groups, an attempt should be made to combine factors determining performance, such as
hormonal status, body components, perceptual-cognitive elements, and tactical skills. Study the relation of APHV and performance in competition
should be provided. Conclusions The results of this study improve our understanding how maturity timing influences on the performance in motor tests and basic body composition
parameters in youth female basketball players. The status of reference to years after PHV has a particular effect on performance during jumping test,
endurance test, and 20m speed test in all three (U13-U15) age categories. The time from peak height velocity (PHV) was a significant predictor only in
the 10 m speed test, but height and weight were the most significant. Chronological age (5 m, 20 m, agility, SVJ, VJ, and VO2max tests), body height
(10m), body mass (10m, 20m, VJ, VO2max), and the interaction between body mass and height (SVJ) were significant predictors of motor skills. The
results can help the coaches to personalize training programs and to adapt the training content to the biological age of the players. Declarations Page 11/15 Acknowledgements The author would like to thank the Polish Basketball Association for their assistance in this study. Authors' contributions Research concept and study design: KG, JGA, AK, JLC, ALC, KM. Research concept and study design: KG, JGA, AK, JLC, ALC, KM. Literature review: KG, JLC ALC. Data collection: KG, JGA, AK. Data analysis and interpretation: KG, AK, KM. Statistical analyses: KG, JGA, JLC. Writing of the manuscript: KG, JGA, AK, JLC, ALC, KM. Review and editing: KG, JGA, AK, JLC, ALC, KM. All authors read and approved the final manuscript. Acknowledgements Competing interests No funding was received. Ethics approval and consent to participate The research was conducted in accordance with the approval from the local Ethics Committee for Scientific Research of the University of Physical
Education in Warsaw (SKE 01–28/2016), and the study was completed according to the rules and regulations of the Declaration of Helsinki
Consent for publication Availability of data and material Full access to data on request (karol.gryko@awf.edu.pl) 10.1080/02640414.2020.1853334 15. Ramos SA, Massuça LM, Volossovitch A, Ferreira AP, Fragoso I. Morphological and Fitness Attributes of Young Male Portuguese Basketball
Players: Normative Values According to Chronological Age and Years From Peak Height Velocity. Frontiers in sports and active living,
2021;3:629453. https://doi.org/10.3389/fspor.2021.629453 16. Malina RM. Growth and maturity status of young soccer players. In: Reilly T, Williams AM, eds. Science and Soccer. London: Routledge; 2003,
287–306. 17. Torres-Unda J, Zarrazquin I, Gravina L, Zubero J, Seco J, Gil S, Gil J, Irazusta J. Basketball performance is related to maturity and relative age in
elite adolescent players. J. Strength Cond. Res. 2016;30:1325–1332. 17. Torres-Unda J, Zarrazquin I, Gravina L, Zubero J, Seco J, Gil S, Gil J, Irazusta J. Basketball performance is related to maturity and relative age in
elite adolescent players. J. Strength Cond. Res. 2016;30:1325–1332. 18. Drinkwater EJ, Hopkins WG, McKenna MJ, Hunt PH, Pyne DB. Modelling age and secular differences in fitness between basketball players. J
Sports Sci. 2007;25(8):869–78. doi: 10.1080/02640410600907870. 18. Drinkwater EJ, Hopkins WG, McKenna MJ, Hunt PH, Pyne DB. Modelling age and secular differences in fitness between basketball players. J
Sports Sci. 2007;25(8):869–78. doi: 10.1080/02640410600907870. 19. Carvalho HM, Leonardi TJ, Soares ALA, Paes RR, Foster C, Gonçalves CE. Longitudinal Changes of Functional Capacities Among Adolescent
Female Basketball Players. Front. Physiol. 2019. https://doi.org/10.3389/fphys.2019.00339 19. Carvalho HM, Leonardi TJ, Soares ALA, Paes RR, Foster C, Gonçalves CE. Longitudinal Changes of Functional Capacities Among Adolescent
Female Basketball Players. Front. Physiol. 2019. https://doi.org/10.3389/fphys.2019.00339 20. Balčiūnas M, Stonkus S, Abrantes C, Sampaio J. Long term effects of different training modalities on power, speed, skill and anaerobic capacity
in young male basketball players. J Sports Sci Med. 2006;5(1):163–70. 20. Balčiūnas M, Stonkus S, Abrantes C, Sampaio J. Long term effects of different training modalities on power, speed, skill and anaerobic capacity
in young male basketball players. J Sports Sci Med. 2006;5(1):163–70. 21. Vučković I, Gadžić A, Sladojević V, Kukrić A, Mikić M, Stojanović M. Influence of a pre-shot dynamic stretching routine on free throw performance. Biomedical Human Kinetic. 2019;11(1):181–188. doi: 10.2478/bhk-2019-002 21. Vučković I, Gadžić A, Sladojević V, Kukrić A, Mikić M, Stojanović M. Influence of a pre-shot dynamic stretching routine on free throw performance. Biomedical Human Kinetic. 2019;11(1):181–188. doi: 10.2478/bhk-2019-002 22. Arede J, Leite N, Bradley B, Madruga-Parera M, Saéz de Villarreal E, Gonzalo-Skok O. References 1. Drinkwater EJ, Pyne DB, McKenna MJ. Design and interpretation of anthropometric and fitness testing of basketball players. Sports Med. 2008;38:565–78. 1. Drinkwater EJ, Pyne DB, McKenna MJ. Design and interpretation of anthropometric and fitness testing of basketball players. Sports Med. 2008;38:565–78. 2. Nowak A, Pytel A, Molik B, Marszałek J. Characteristics of injuries of young adult male basketball players. Advances in Rehabilitation. 2019;33(3):35–46. doi:10.5114/areh.2019.87747. 3. Gryko K, Mikołajec K, Marszałek J, Adamczyk JG, Molik B, Waśkiewicz Z, Nikolaidis P, Knechtle B. How did basketball teams win EuroBasket
2015? A non-standard analysis of performance based on passes, dribbling and turnovers. Int. J. Perform. Anal. Sport. 2020;20(3):339–356. DOI:
10.1080/24748668.2020.1749013 4. Ziv G, Lidor R. Physical attributes, physiological characteristics, on-court performances and nutritional strategies of female and male basketball
players. Sports Med. 2009;39(7):547–68. doi: 10.2165/00007256-200939070-00003. 5. Arede J Ferreira AP, Gonzalo-Skok O, Leite N. Maturational Development as Key Aspect in Physical Performance and National Team Selection in
Elite Male Basketball Players. Int. J. Sports Physiol. Perform. 2018;20:1–24. 6. Arede J, Fernandes J, Moran J, Norris J, Leite N. Maturity timing and performance in a youth national basketball team: Do early-maturing players
dominate? Int J Sports Sci Coach. 2021;16(3):722–730. https://doi.org/10.1177/1747954120980712 7. Arede J, Oliveira I, Ángel Gomez MA, Leite N. A Multi-Block Multivariate Analysis to Explore the Influence of the Somatic Maturation in Youth
Basketball. Front. Psychol. 2021;12:602576. doi: 10.3389/fpsyg.2021.602576 8. Coelho E Silva MJ, Moreira Carvalho H, Gonçalves CE, Figueiredo AJ, Elferink-Gemser MT, Philippaerts RM, Malina RM. Growth, maturation,
functional capacities and sport-specific skills in 12-13 year-old- basketball players. J Sports Med Phys Fitness. 2010;50(2):174–81. 8. Coelho E Silva MJ, Moreira Carvalho H, Gonçalves CE, Figueiredo AJ, Elferink-Gemser MT, Philippaerts RM, Malina RM. Growth, maturation,
functional capacities and sport-specific skills in 12-13 year-old- basketball players. J Sports Med Phys Fitness. 2010;50(2):174–81. Page 12/15 Page 12/15 9. Weaving D, Jones B, Till K, Abt G, Beggs C. The Case for Adopting a Multivariate Approach to Optimize Training Load Quantification in Team
Sports. Front Physiol. 2017;8:1024. doi:10.3389/fphys.2017.01024 10. Malina RM, Cumming SP, Kontos AP, Eisenmann JC, Ribeiro B, Aroso J. Maturity-associated variation in sport-specific skills of youth soccer
players aged 13-15 years. J Sports Sci. 2005;23(5):515–22. doi: 10.1080/02640410410001729928 0. Malina RM, Cumming SP, Kontos AP, Eisenmann JC, Ribeiro B, Aroso J. Maturity-associated variation in s players aged 13-15 years. J Sports Sci. 2005;23(5):515–22. doi: 10.1080/02640410410001729928 1. Malina RM, Bouchard C, Bar-Or O. 10.1080/02640414.2020.1853334 Mechanical, Physiological, and Perceptual Demands of
Repeated Power Ability Lower-Body and Upper-Body Tests in Youth Athletes: Somatic Maturation as a Factor on the Performance. Frontiers in
Psychology. 2020;11:1888. https://doi.org/10.3389/fpsyg.2020.01888 22. Arede J, Leite N, Bradley B, Madruga-Parera M, Saéz de Villarreal E, Gonzalo-Skok O. Mechanical, Physiological, and Perceptual Demands of
Repeated Power Ability Lower-Body and Upper-Body Tests in Youth Athletes: Somatic Maturation as a Factor on the Performance. Frontiers in
Psychology. 2020;11:1888. https://doi.org/10.3389/fpsyg.2020.01888 23. Nedeljkovic A, Mirkov DM, Kukolj M, Ugarkovic D, Jaric S. Effect of maturation on the relationship between physical performance and body size. J
Strength Cond Res. 2007;21(1):245–250. 23. Nedeljkovic A, Mirkov DM, Kukolj M, Ugarkovic D, Jaric S. Effect of maturation on the relationship between physical performance and body size. J
Strength Cond Res. 2007;21(1):245–250. 24. McNarry MA, Lester L, Brown J, Mackintosh KA. Investigating the Modulatory Role of Chronological and Biological Age on Performance
Predictors in Youth Swimmers. J Sci Sport Exercise. 2020;2:349–358. https://doi.org/10.1007/s42978-020-00082-1 24. McNarry MA, Lester L, Brown J, Mackintosh KA. Investigating the Modulatory Role of Chronological and Biological Age on Performance
Predictors in Youth Swimmers. J Sci Sport Exercise. 2020;2:349–358. https://doi.org/10.1007/s42978-020-00082-1 5. Baxter-Jones ADG, Eisenmann JC, Sherar LB. Controlling for maturation in pediatric exercise science. Ped 26. Rubajczyk K, Świerzko K, Rokita A. Doubly Disadvantaged? The Relative Age Effect in Poland's Basketball Players. J Sports Sci Med. 2017;16(2):280–285. 6. Rubajczyk K, Świerzko K, Rokita A. Doubly Disadvantaged? The Relative Age Effect in Poland's Basketba
2017;16(2):280–285. 27. de la Rubia Riaza A, Lorenzo Calvo J, Mon-López D, Lorenzo A. Impact of the Relative Age Effect on Competition Performance in Basketball: A
Qualitative Systematic Review. Int. J. Environ. Res. Public Health. 2020;17(22):8596. https://doi.org/10.3390/ijerph17228596 7. de la Rubia Riaza A, Lorenzo Calvo J, Mon-López D, Lorenzo A. Impact of the Relative Age Effect on Com
Qualitative Systematic Review. Int. J. Environ. Res. Public Health. 2020;17(22):8596. https://doi.org/10.3 28. Kelly AL, Jiménez Sáiz SL, Lorenzo Calvo A, de la Rubia A, Jackson DT, Jeffreys MA, Ford C, Owen D, Santos SDLd. Relative Age Effects in
Basketball: Exploring the Selection into and Successful Transition Out of a National Talent Pathway. Sports 2021;9:101. https://doi.org/10.3390/sports9070101 29. Arrieta H, Torres-Unda J, Gil SM, Irazusta J. Relative age effect and performance in the U16, U18 and U20 European basketball championships. J
Sports Sci. 2016;34:1530–1534. 30. Torres-Unda J, Zarrazquin I, Gil J, Ruiz F, Irazusta A, Kortajarena M, Seco J, Irazusta J. References Growth, Maturation, and Physical Activity (2nd ed.) (Human Kinetics, C 11. Malina RM, Bouchard C, Bar-Or O. Growth, Maturation, and Physical Activity (2nd ed.) (Human Kinetics, Champaign, IL 2004). 12. Myburgh GK, Cumming SP, Malina RM. Cross-Sectional Analysis Investigating the Concordance of Maturity Status Classifications in Elite
Caucasian Youth Tennis Players. Sports Med Open. 2019;5(1):27. doi: 10.1186/s40798-019-0198-8. 3. Gonçalves CEB, Rama LML, Figueiredo AB. Talent identification and specialization in sport: an overview o
Sports Physiol Perform. 2012;7(4):390–3. doi: 10.1123/ijspp.7.4.390. 13. Gonçalves CEB, Rama LML, Figueiredo AB. Talent identification and specialization in sport: an overview of some unanswered questions. Int J
Sports Physiol Perform. 2012;7(4):390–3. doi: 10.1123/ijspp.7.4.390. 14. Guimarães E, Baxter-Jones ADG, Williams AM, Tavares F, Janeira MA, Maia J. The role of growth, maturation and sporting environment on the
development of performance and technical and tactical skills in youth basketball players: The INEX study. J Sports Sci. 2021;39(9):979–991. doi:
10.1080/02640414.2020.1853334 10.1080/02640414.2020.1853334 Anthropometric, physiological and maturational
characteristics in selected elite and non-elite male adolescent basketball players. J. Sports Sci. 2013;31:196–203. 30. Torres-Unda J, Zarrazquin I, Gil J, Ruiz F, Irazusta A, Kortajarena M, Seco J, Irazusta J. Anthropometric, physiological and maturational
characteristics in selected elite and non-elite male adolescent basketball players. J. Sports Sci. 2013;31:196–203. 31. Lockie RG, Jeffriess MD, McGann TS, Callaghan SJ, Schultz AB. Planned and reactive agility performance in semiprofessional and amateur
basketball players. Int J Sports Physiol Perform. 2014;9:766–771. 31. Lockie RG, Jeffriess MD, McGann TS, Callaghan SJ, Schultz AB. Planned and reactive agility performance in semiprofessional and amateur
basketball players. Int J Sports Physiol Perform. 2014;9:766–771. 32. Sisic N, Jelicic M, Pehar M, Spasic M, Sekulic D. Agility performance in high-level junior basketball players: the predictive value of anthropometrics
and power qualities. J Sports Med Phys Fitness. 2016;56:884–893. 32. Sisic N, Jelicic M, Pehar M, Spasic M, Sekulic D. Agility performance in high-level junior basketball players: the predictive value of anthropometrics
and power qualities. J Sports Med Phys Fitness. 2016;56:884–893. 3. Mcmanus AM, Armstrong N. Physiology of elite young female athletes. Med. Sport Sci. 2011;56:23–46. d 33. Mcmanus AM, Armstrong N. Physiology of elite young female athletes. Med. Sport Sci. 2011;56:23–46. doi: 10.1159/000320626 33. Mcmanus AM, Armstrong N. Physiology of elite young female athletes. Med. Sport Sci. 2011;56:23–46. doi: 10.1159/000320626 34. te Wierike SC, de Jong MC, Tromp EJ, Vuijk PJ, Lemmink KA, Malina RM, Elferink-Gemser MT, Visscher C. Development of repeated sprint ability in
talented youth basketball players. J Strength Cond Res. 2014;28(4):928–34. doi: 10.1097/JSC.0000000000000223 34. te Wierike SC, de Jong MC, Tromp EJ, Vuijk PJ, Lemmink KA, Malina RM, Elferink-Gemser MT, Visscher C. Development of repeated sprint ability in
talented youth basketball players. J Strength Cond Res. 2014;28(4):928–34. doi: 10.1097/JSC.0000000000000223 Page 13/15 35. Jakovljević S, Pajić Z, Gardašević B, Višnjić D. Some anthropometric and power characteristics of 12 and 13 years old soccer and basketball
players. Proceedings 2010. 2011;2:42-48. doi:10.5550/SP.2.2010.06 36. Association WM. World Medical Association Declaration of Helsinki. Ethical principles for medical research involving human subjects. Bull. World
Health Organ. 2001;79:373–374. 37. Mirwald RL, Baxter-Jones ADG, Bailey DA, Beunen GP. An assessment of maturity from anthropometric measurements. Med Sci Sports Exerc. 2002;34(4):689–94. doi: 10.1097/00005768-200204000-00020 38. Moore SA, McKay HA, Macdonald H, Nettlefold L, Baxter-Jones AD, Cameron N, Brasher PM. Enhancing a somatic maturity prediction model. Med
Sci Sports Exerc. 2015;47:1755–64. 39. 10.1080/02640414.2020.1853334 A scale of magnitudes for effect statistics. Sports Science. 2006, Retrieved from http://www.sportsci. org/resource/stats/effectmag.html 50. Johnston K, Wattie N, Schorer J, Baker J. Talent Identification in Sport: A Systematic Review. Sports Med. 2018;48:97–109. https://doi.org/10.1007/s40279-017-0803-2 0. Johnston K, Wattie N, Schorer J, Baker J. Talent Identification in Sport: A Systematic Review. Sports Med
https://doi.org/10.1007/s40279-017-0803-2 51. Balyi I, Hamilton A. Long-Term Athlete Development: Trainability in Childhood and Adolescence. Windows of Opportunity. Optimal Trainability. Vi t
i
B iti h C l
bi
C
d
N ti
l C
hi
I
tit t B iti h C l
bi
d Ad
d T
i i
d P
f
Ltd 2004 Hamilton A. Long-Term Athlete Development: Trainability in Childhood and Adolescence. Windows of Opport 51. Balyi I, Hamilton A. Long-Term Athlete Development: Trainability in Childhood and Adolescence. Windows of Opportunity. Optimal Trainability. Victoria, British Columbia, Canada: National Coaching Institute British Columbia and Advanced Training and Performance Ltd, 2004. 1. Balyi I, Hamilton A. Long-Term Athlete Development: Trainability in Childhood and Adolescence. Window
Vi t
i
B iti h C l
bi
C
d
N ti
l C
hi
I
tit t B iti h C l
bi
d Ad
d T
i i 51. Balyi I, Hamilton A. Long-Term Athlete Development: Trainability in Childhood and Adolescence. Wind
Victoria, British Columbia, Canada: National Coaching Institute British Columbia and Advanced Train 1. Balyi I, Hamilton A. Long-Term Athlete Development: Trainability in Childhood and Adolescence. Window
Victoria, British Columbia, Canada: National Coaching Institute British Columbia and Advanced Training Victoria, British Columbia, Canada: National Coaching Institute British Columbia and Advanced Training and 52. Ford P, De Ste Croix M, Lloyd R, Meyers R, Moosavi M, Oliver J, Till K, Williams C. The long-term athlete development model: physiological
evidence and application. J Sports Sci. 2011;29(4):389–402. doi: 10.1080/02640414.2010.536849. 53. Erčulj F, Blas M, Bračič M. Physical Demands on Young Elite European Female Basketball Players With Special Reference to Speed, Agility,
Explosive Strength, and Take-off Power. J Strength Cond Res. 2010;24(11):2970–2978 doi: 10.1519/JSC.0b013e3181e38107 54. Myburgh G, Cumming S, Coelho-e-silva MJ, Cooke K, Malina RM. Maturity-associated variation in functional characteristics of elite youth tennis
players. Pediatr. Exer. Sci. 2016;28:542–552. doi: 10.1123/pes.2016- 0035 54. Myburgh G, Cumming S, Coelho-e-silva MJ, Cooke K, Malina RM. Maturity-associated variation in functional characteristics of elite youth tennis
players. Pediatr. Exer. Sci. 2016;28:542–552. doi: 10.1123/pes.2016- 0035 55. Sherar LB, Cumming SP, Malina RM. 10.1080/02640414.2020.1853334 Adolescent biological maturity and physical activity: biology meets behavior. Pediatr. Exer. Sci. 2010;22:332–
349. doi: 10.1123/pes.22.3.332 55. Sherar LB, Cumming SP, Malina RM. Adolescent biological maturity and physical activity: biology meets behavior. Pediatr. Exer. Sci. 2010;22:332–
349. doi: 10.1123/pes.22.3.332 56. Sekine Y, Hoshikawa S, Hirose N. Longitudinal Age-Related Morphological and Physiological Changes in Adolescent Male Basketball Players. J. Sports Sci. Med. 2019;18(4):751–757. 56. Sekine Y, Hoshikawa S, Hirose N. Longitudinal Age-Related Morphological and Physiological Changes in Adolescent Male Basketball Players. J. Sports Sci. Med. 2019;18(4):751–757. 57. Armstrong N, Welsman JR, Williams CA, Kirby BJ. Longitudinal changes in young people’s short-term power output. Med. Sci. Sports Exerc. 2000;32:1140–1145. doi: 10.1097/00005768-200006000-00017 57. Armstrong N, Welsman JR, Williams CA, Kirby BJ. Longitudinal changes in young people’s short-term power output. Med. Sci. Sports Exerc. 2000;32:1140–1145. doi: 10.1097/00005768-200006000-00017 58. Geithner CA, Thomis MA, Vanden Eynde B, Maes HH, Loos RJ, Peeters M, Claessens AL, Vlietinck R, Malina RM, Beunen GP. Growth in peak
aerobic power during adolescence. Med Sci Sports Exerc. 2004;36(9):1616–24. doi: 10.1249/01.mss.0000139807.72229.41 58. Geithner CA, Thomis MA, Vanden Eynde B, Maes HH, Loos RJ, Peeters M, Claessens AL, Vlietinck R, Malina RM, Beunen GP. Growth in peak
aerobic power during adolescence. Med Sci Sports Exerc. 2004;36(9):1616–24. doi: 10.1249/01.mss.0000139807.72229.41 58. Geithner CA, Thomis MA, Vanden Eynde B, Maes HH, Loos RJ, Peeters M, Claessens AL, Vlietinck R, Malina RM, Beunen GP. Growth in peak 58. Geithner CA, Thomis MA, Vanden Eynde B, Maes HH, Loos RJ, Peeters M, Claessens AL, Vlietinck R, Malina RM, Beunen GP. Growth in peak 59. Bouchard C, Malina RM, Perusse L. Genetic of Fitness and Physical Performance. Champaign, Human Kinetics. USA, 1997. 59. Bouchard C, Malina RM, Perusse L. Genetic of Fitness and Physical Performance. Champaign, Huma alina RM, Perusse L. Genetic of Fitness and Physical Performance. Champaign, Human Kinetics. USA, 1997 59. Bouchard C, Malina RM, Perusse L. Genetic of Fitness and Physical Performance. Champaign, Human Kinetics. USA, 1997. 60. Pearson DT, Naughton GA, Torode M. Predictability of physiological testing and the role of maturation in talent identification for adolescent team
sports. J Sci Med Sport. 2006;9(4):277–287. https://doi.org/10.1016/j.jsams.2006.05.020 60. Pearson DT, Naughton GA, Torode M. Predictability of physiological testing and the role of maturation in talent identification for adolescent team
sports. J Sci Med Sport. 2006;9(4):277–287. https://doi.org/10.1016/j.jsams.2006.05.020 61. Barreiros A, Côté J, Fonseca AM. From early to adult sport success: analysing athletes' progression in national squads. 10.1080/02640414.2020.1853334 Kozieł S, Malina RM. Modified Maturity Offset Prediction Equations: Validation in Independent Longitudinal Samples of Boys and Girls. Sports
Med. 2018;48:221–236. 40. Marfell-Jones MJ, Stewart AD, De Ridder JH. International standards for anthropometric assessment. Wellington, New Zealand: International
Society for the Advancement of Kinanthropometry; 2012. 40. Marfell-Jones MJ, Stewart AD, De Ridder JH. International standards for anthropometric assessment. We
Society for the Advancement of Kinanthropometry; 2012. 41. Kirkendall D, Gruber J, Johnson R. Measurement and Evaluation for Physical Educators; Human Kinet 41. Kirkendall D, Gruber J, Johnson R. Measurement and Evaluation for Physical Educators; Human Kinetics: Champaign, IL, USA, 1987. 42. Buckthorpe M, Morris J, Jonathan P. Folland. Validity of vertical jump measurement devices. J Sports Sci. 2012;30(1):63–69, DOI:
10.1080/02640414.2011.624539 42. Buckthorpe M, Morris J, Jonathan P. Folland. Validity of vertical jump measurement devices. J Sports Sci. 2012;30(1):63–69, DOI:
10.1080/02640414.2011.624539 43. Brooks ER, Benson AC, Bruce LM. Novel Technologies Found to be Valid and Reliable for the Measurement of Vertical Jump Height With Jump-
and-Reach Testing. J Strength Cond Res. 2018;32(10):2838–2845. DOI: 10.1519/jsc.0000000000002790 and-Reach Testing. J Strength Cond Res. 2018;32(10):2838–2845. DOI: 10.1519/jsc.0000000000002 44. Gabbett T, Kelly J, Pezet T. Relationship between physical fitness and playing ability in rugby league players. J Strength Cond Res. 2007;21(4):1126–1133. DOI: 10.1519/r-20936.1 45. Coutts AJ, Reaburn P, Piva TJ, Rowsell G.J. Monitoring for overreaching in rugby league players. Eur. J. Appl. Physiol. 2007;99:313–324. 45. Coutts AJ, Reaburn P, Piva TJ, Rowsell G.J. Monitoring for overreaching in rugby league players. Eur. J. A 46. Gryko, K. Effect of maturity timing on the physical performance of male Polish basketball players aged 13 to 15 years. Sci Rep 2021;11,22019. https://doi.org/10.1038/s41598-021-01401-4 47. Bangsbo J, Iaia FM, Krustrup P. The Yo-Yo intermittent recovery test: a useful tool for evaluation of physical performance in intermittent sports. Sports Med. 2008;38(1):37-51. doi: 10.2165/00007256-200838010-00004. PMID: 18081366. 48. Fort-Vanmeerhaeghe A, Montalvo A, Latinjak A, Unnithan V. Physical characteristics of elite adolescent female basketball players and their
relationship to match performance. J. Hum. Kinet.. 2016;53:167–178. 48. Fort-Vanmeerhaeghe A, Montalvo A, Latinjak A, Unnithan V. Physical characteristics of elite adolescent female basketball players and their
relationship to match performance. J. Hum. Kinet.. 2016;53:167–178. 49. Hopkins W. A scale of magnitudes for effect statistics. Sports Science. 2006, Retrieved from http://www.sportsci. org/resource/stats/effectmag.html 49. Hopkins W. A scale of magnitudes for effect statistics. Sports Science. 2006, Retrieved from http://www.sportsci. org/resource/stats/effectmag html 49. Hopkins W. 10.1080/02640414.2020.1853334 Eur J Sport Sci. 2014;14
Suppl 1:S178–S182. https://doi.org/10.1080/17461391.2012.671368 61. Barreiros A, Côté J, Fonseca AM. From early to adult sport success: analysing athletes' progression in national squads. Eur J Sport Sci. 2014;14
Suppl 1:S178–S182. https://doi.org/10.1080/17461391.2012.671368 Page 14/15 62. Ford P, Collins D, Bailey R, MacNamara A, Pearce G, Toms M. Participant development in sport and physical activity: The impact of biological
maturation. Eur J Sport Sci. 2012;12(6):515–526. doi: 10.1080/17461391.2011.577241 62. Ford P, Collins D, Bailey R, MacNamara A, Pearce G, Toms M. Participant development in sport and physical activity: The impact of biological
maturation. Eur J Sport Sci. 2012;12(6):515–526. doi: 10.1080/17461391.2011.577241 62. Ford P, Collins D, Bailey R, MacNamara A, Pearce G, Toms M. Participant development in sport and physical activity: The impact of biological
maturation. Eur J Sport Sci. 2012;12(6):515–526. doi: 10.1080/17461391.2011.577241 63. Malina RM, Kozieł SM. Validation of maturity offset in a longitudinal sample of Polish boys. J. Sports Sci. 2014;32(5):424–437. https://doi.org/10.1080/02640414.2013.828850 63. Malina RM, Kozieł SM. Validation of maturity offset in a longitudinal sample of Polish boys. J. Sports Sci. 2014;32(5):424–437. https://doi.org/10.1080/02640414.2013.828850 64. Malina RM, Rogol AD, Cumming SP, Coelho e Silva MJ, Figueiredo AJ. Biological maturation of youth athletes: assessment and implications. Br. J. Sports Med. 2015;49(13):852–859. doi: 10.1136/bjsports-2015-094623 65. Müller L, Müller E, Hildebrandt C, Kapelari K, Raschner C. Die Erhebung des biologischen Entwicklungsstandes für die Talentselektion - welche
Methode eignet sich? [The assessment of biological maturation for talent selection - which method can be used?]. Sportverletzung Sportschaden:
Organ der Gesellschaft fur Orthopadisch-Traumatologische Sportmedizin. 2015;29(1):56–63. https://doi.org/10.1055/s-0034-1399043
66. Koopmann T, Faber I, Baker J, Schorer J. Assessing Technical Skills in Talented Youth Athletes: A Systematic Review. Sports Med. 2020;50(9):1593–1611. doi:10.1007/s40279-020-01299-4 65. Müller L, Müller E, Hildebrandt C, Kapelari K, Raschner C. Die Erhebung des biologischen Entwicklungsstandes für die Talentselektion - welche
Methode eignet sich? [The assessment of biological maturation for talent selection - which method can be used?]. Sportverletzung Sportschaden:
Organ der Gesellschaft fur Orthopadisch-Traumatologische Sportmedizin. 2015;29(1):56–63. https://doi.org/10.1055/s-0034-1399043 65. Müller L, Müller E, Hildebrandt C, Kapelari K, Raschner C. Die Erhebung des biologischen Entwicklungsstandes für die Talentselektion - welche
Methode eignet sich? [The assessment of biological maturation for talent selection - which method can be used?]. Sportverletzung Sportschaden:
Organ der Gesellschaft fur Orthopadisch-Traumatologische Sportmedizin. 2015;29(1):56–63. https://doi.org/10.1055/s-0034-1399043
66. Koopmann T, Faber I, Baker J, Schorer J. Assessing Technical Skills in Talented Youth Athletes: A Systematic Review. Sports Med. 2020;50(9):1593–1611. doi:10.1007/s40279-020-01299-4 Methode eignet sich? 10.1080/02640414.2020.1853334 [The assessment of biological maturation for talent selection - which method can be used?]. Sportverletzung Sportschaden:
Organ der Gesellschaft fur Orthopadisch-Traumatologische Sportmedizin. 2015;29(1):56–63. https://doi.org/10.1055/s-0034-1399043
66. Koopmann T, Faber I, Baker J, Schorer J. Assessing Technical Skills in Talented Youth Athletes: A Systematic Review. Sports Med. 2020;50(9):1593–1611. doi:10.1007/s40279-020-01299-4 66. Koopmann T, Faber I, Baker J, Schorer J. Assessing Technical Skills in Talented Youth Athletes: A Systematic Review. Sports Med. 2020;50(9):1593–1611. doi:10.1007/s40279-020-01299-4 Agility test design
Notes:
S1 – stage 1 (front sprint); S2 – stage 2 (shuffle and back sprint); S3/S4 – stages 3 and 4 (shuffle); S5 – stage 5 (front
sprint and shuffle) Figures Figure 1
Agility test design
Notes:
S1 – stage 1 (front sprint); S2 – stage 2 (shuffle and back sprint); S3/S4 – stages 3 and 4 (shuffle); S5 – stage 5 (front
sprint and shuffle) Figure 1 Agility test design
Notes:
S1 – stage 1 (front sprint); S2 – stage 2 (shuffle and back sprint); S3/S4 – stages 3 and 4 (shuffle); S5 – stage 5 (front
sprint and shuffle) Agility test design
Notes:
S1 – stage 1 (front sprint); S2 – stage 2 (shuffle and back sprint); S3/S4 – stages 3 and 4 (shuffle); S5 – stage 5 (front
sprint and shuffle) Page 15/15
|
https://openalex.org/W2943862965
|
http://www.diagnostyka.net.pl/pdf-109223-39742?filename=Complex Morlet wavelet.pdf
|
English
| null |
Complex Morlet wavelet design with global parameter optimization for diagnosis of industrial manufacturing faults of tapered roller bearing in noisycondition
|
Diagnostyka
| 2,019
|
cc-by
| 7,452
|
Abstract Detecting manufacturing defects of bearings are difficult because of their unique topography. To find
adequate methods for diagnosis is important because they could be responsible for serious problems. Wavelet
transform is an efficient tool for analyzing the transients in the vibration signal. In this article we are focusing
on industrial grinding faults on the outer ring of tapered roller bearings. Nine different real-valued wavelets,
Symlet-2, Symlet-5, Symlet-8, Daubechies (2, 6, 10, 14), Morlet and Meyer wavelets are compared to a
designed complex Morlet wavelet according to the Energy-to-Shannon-Entropy ratio criteria to determine
which is the most efficient for detecting the manufacturing fault. Parameters of the complex Morlet wavelet
are adjustable, thus, it has more flexibility for feature extraction. Genetic algorithm is applied to optimize the
center frequency and the bandwidth of the designed wavelet. A sophisticated filtering procedure through
multi-resolution analysis is applied with autocorrelation enhancement and envelope detection. To determine
the efficiency of the designed wavelet and compare to the other wavelets, a test-rig was constructed equipped
with high-precision sensors and devices. The designed wavelet is found to be the most effective to detect the
manufacturing fault. Therefore, it has the capacity for an industrial testing procedure. Keywords: bearing vibration analysis, wavelet, optimization, genetic algorithm COMPLEX MORLET WAVELET DESIGN WITH GLOBAL PARAMETER
OPTIMIZATION FOR DIAGNOSIS OF INDUSTRIAL MANUFACTURING
FAULTS OF TAPERED ROLLER BEARING IN NOISYCONDITION Krisztián DEÁK, Imre KOCSIS
University of Debrecen, Faculty of Engineering, Hungary,
deak.krisztian@eng.unideb.hu, kocsisi@eng.unideb.hu Krisztián DEÁK, Imre KOCSIS Article citation info:
Deak K, Kocsis I. Complex Morlet wavelet design with global parameter optimization for diagnosis of industrial manufacturing faults of
tapered roller bearing in noisycondition. Diagnostyka. 2019;20(2):77-86. https://doi.org/10.29354/diag/109223
77 Article citation info:
Deak K, Kocsis I. Complex Morlet wavelet design with global parameter optimization for diagnosis of industrial manufacturing faults of
tapered roller bearing in noisycondition. Diagnostyka. 2019;20(2):77-86. https://doi.org/10.29354/diag/109223
77 f77 Deak K, Kocsis I. Complex Morlet wavelet design with global parameter optimization for diagnosis of industrial manufacturi
tapered roller bearing in noisycondition. Diagnostyka. 2019;20(2):77-86. https://doi.org/10.29354/diag/109223 ISSN 1641-6414
e-ISSN 2449-5220
DOI: 10.29354/diag/109223 ISSN 1641-6414
e-ISSN 2449-5220
DOI: 10.29354/diag/109223 ISSN 1641-6414
e-ISSN 2449-5220
DOI: 10.29354/diag/109223 DIAGNOSTYKA, 2019, Vol. 20, No. 2 1. INTRODUCTION 2 (2019) 78 (
)
Deak K, Kocsis I.: Complex Morlet wavelet design with global parameter optimization for diagnosis orlet wavelet design with global parameter optimization for diagnosis of … oscillator [16]. With the envelope analysis they
could reveal the bearing faults successfully. By modifying the scale parameter, the duration
and bandwidth of wavelet change provide more
precise time or frequency resolution. CWT applies
short windows at high frequencies and long
windows at low frequencies. Tabaszewski et al. concerned classification of
defects of rolling bearings by k-NN (k-nearest
neighbor) classifier with regard to the proper
selection of the observation place. Statistical time-
domain values of the vibration signal and the
energy of acoustic emission pulses was found to be
effective for revealing cracks in the outer rings
[17]. CWT generates a two-dimensional map of the
coefficients called scalogram 2
{ ( , )}
( , )
f
SC f a b
CWT
a b
(2) (2) We define the family of functions by shifting
and scaling a “mother wavelet” Strączkiewicz et al. used supervised and
unsupervised learning as pattern recognition
methods for damage classification and clustering of
rolling bearings. Clustering analysis was found to
be effective for determining the bearing state
conditions [18]. a,b
1
t
b
a
a
,
(3) (3) where a and b are reals (
0
a
), and the
normalization ensures that
)
t(
)
t(
b,
a
. where a and b are reals (
0
a
), and the
normalization ensures that
)
t(
)
t(
b,
a
. Wensheng et al. used optimal Morlet wavelet
filter and autocorrelation enhancement to reveal
bearing faults. Parameter optimization was proved
to be effective for diagnosis compared to the
capabilities of conventional wavelets [19]. Complex
Morlet
wavelet
has
the
great
advantage that its f0 and β parameters can be
defined separately for the certain application 2
2
0
1
( ,
,
)
o
t
if t
t f
e
e
(4) Jena et al. investigated gear faults and identified
them with analytic wavelet transform by using the
vibration spectra. Envelope detection was applied
to detect the signal and enhance its features for
analysis [20]. 1. INTRODUCTION (4) Discrete wavelet transform (DWT) applies filter
banks for the analysis and synthesis of a signal. By
adopting the dyadic scale and translation in the
form of discretization of continuous wavelet as
follows [31] Tandon et al. made a review of vibration and
acoustic measurement methods for detection of
defects in rolling element bearings [21]. dt
2
k
2
t
)
t(s
2
1
)
k,j
(
DWT
j
j
*
j
s
, (5) (5) Farzad et al. used successfully the acoustic
signature extraction by wavelet transform to detect
failures. Moreover, they revealed the geometrical
size of the defects as well. Shannon entropy was
used to determine the information content of the
wavelets which helped to choose the proper wavelet
for fault identification [22]. where j and k are integers,
j
2 and
k
2
j
represent
the
scale
and
translation
parameters,
the
computational time can be reduced. The original
signal
)
t(s
passes through a combination of low-
pass and high-pass filters emerging as low
frequency (approximations,
ia ) and high frequency
(details,
id ) signals at each decomposition level i,
called multiresolution analysis (MRA). Thus, the
original signal
)
t(s
can be written as [4] Based on the literature review, it is noticed that
very limited studies on tapered roller bearing fault
detection have been carried out by researches using
complex Morlet wavelet, combined with the
Energy-to-Shannon-Entropy ratio criteria and signal
enhancement
methods,
especially
in
noisy
conditions which is presented in this article. n
i
i
s(t)
a
d
. (6) (6) 2. FEATURE EXTRACTION AND SIGNAL
ENHANCEMENT Using the wavelet function and scaling
function we have 1. INTRODUCTION Shi et al. used envelope analysis where the
vibration signal passed through a band-pass filter to
obtain a signal without significant noise then
Hilbert transform was used to produce the envelope
curve. The spectrum of the envelope presented
useful information to reveal the fault frequencies of
the bearings [7]. Bearing fault diagnosis is quite important in
manufacturing to ensure the high quality of the
product. Wavelet transform is an effective method
for feature extraction and fault diagnosis in many
researches. Sawalhi and Randall determined the fault size of
the bearings from the vibration signature with the
entry and exit impulses of the rollers [1]. Honghu et al. investigated the bearing faults by
using
one-dimensional
convolutional
neural
networks and long-short term memory recurrent
neural networks methods by using test-rig for
creating efficient training results [11]. Prabhakar et al. used discrete wavelet transform
with Daubechies-4 mother wavelets to analyze
faults on the races of ball bearings [2]. Ivan et al. analyzed the damages of roller
bearings at small turning angles. They used
additional FEM analysis to model the stress
conditions in bearings [12]. Shi et al. applied envelope spectrum and
wavelet transform together for feature extraction
the defects of the bearings [3]. Nikolaou et al. applied complex Morlet
wavelets for revealing vibration signals generated
by rolling element bearings [4]. Complex Morlet
wavelets proved to be more useful for the
monitoring due to its flexibility of the center
frequency and the bandwidth. Kankar et al. used continuous wavelet transform
for fault diagnosis of ball bearings which proved to
be efficient for health monitoring in their
experiments [13]. Harsha et al. applied cyclic autocorrelation
combined with wavelet transform to identify ball
bearing faults [14]. Cyclic autocorrelation was able
to enhance the kurtosis of the signal. Symlet wavelets were used efficiently in the
study of Kumar et al. [5]. They focused on not only
to identify but measure the fault size on the outer
ring from the vibration signature. Zhuang Li et al. applied wavelet transform with
artificial neural network for the diagnosis of
gearboxes [15]. Kumar et al. executed researches with analytical
wavelet transform combined with acoustic emission
technique for identifying inner race faults of radial
ball bearings [6]. Patel et al. used envelope analysis for the state
health monitoring of deep groove ball bearings in
presence of external vibration generated by Duffing DIAGNOSTYKA, Vol. 20, No. 2.1. Continuous and discrete wavelet transforms 2 (2019) 79 (
)
Deak K, Kocsis I.: Complex Morlet wavelet design with global parameter optimization for diagnosis of 1
1
1
2
1,
1,
(
[ ])
2
[2
]
[2
] ,
0
1,
2
j
j
j
j
j
k
j
k
j
DWT
X t
cA
t
k
cD
t
k
N
k
(9)
where
1
2
N
0
h
n
2
h,j
h,j
k,1
j
1
2
N
0
h
n
2
h,j
h,j
k,1
j
j
j
v
d
cD
,
v
c
cA
j
h
1
p
2
h
h
2
/
N
p
,
c
)
1
(
d
1
1
1
2
1,
1,
(
[ ])
2
[2
]
[2
] ,
0
1,
2
j
j
j
j
j
k
j
k
j
DWT
X t
cA
t
k
cD
t
k
N
k
(9)
where
1
2
N
0
h
n
2
h,j
h,j
k,1
j
1
2
N
0
h
n
2
h,j
h,j
k,1
j
j
j
v
d
cD
,
v
c
cA
j
h
1
p
2
h
h
2
/
N
p
,
c
)
1
(
d
To fully extract the impulsive feature, the
bandwidth of the Morlet wavelet filter must be
adequately wide. In this paper, we choose the
bandwidth ,
b
3 f
(15) (15) where
bf is the ball-pass frequency outer ring
(BPFO)
in
this
experiment,
because
the
manufacturing fault is on the outer ring of the
tapered roller bearing. where Finally, the problem of Morlet wavelet
parameter optimization is summarized in the
conditions: j
h
1
p
2
h
h
2
/
N
p
,
c
)
1
(
d
Generally, a = 2 and b = 1 in case of the multi-
resolution analysis (MRA) which is an application
of DWT. 2.3. Maximum Energy-to-Shannon-Entropy
ratio criteria For effective fault detection it is critical to find a
proper wavelet that matches well with the shape of
the signal at a specific scale and location. Low
transform value is obtained if the signal and the
wavelet do not correlate well. Visual observation of
contour plots is not appropriate for adequate
wavelet selection. Thus, a more sophisticated
method for wavelet selection is used in this
experiment. 0
)
0
(
dt
)
t(
. (11) (11) Morlet wavelet does not satisfy this zero-mean
requirement. However, the mean value can become
small enough if the term
/
0f
is sufficiently large. When
/
.
0f
3 5
then
.
8
0
4 2146 10
,
(12) Morlet wavelet does not satisfy this zero-mean
requirement. However, the mean value can become Morlet wavelet does not satisfy this zero-mean
requirement. However, the mean value can become
small enough if the term
/
0f
is sufficiently large. requirement. However, the mean value can become
small enough if the term
/
0f
is sufficiently large. small enough if the term
/
0f
is sufficiently large. g
y
g
When
/
.
0f
3 5
then g
When
/
.
0f
3 5
then Energy-to-Shannon-Entropy
ratio
is
the
combination of the energy and Shannon entropy
content of the wavelet coefficients of the signal [32,
.
8
0
4 2146 10
,
(12) (12) therefore
the
admissibility
condition
is
approximately satisfied [19]. 33] which is calculated by The upper cut-off frequency of Morlet wavelet
filter is
/
0f
2
Hz. According to the Shannon
Sampling Theorem, the upper cut-off frequency
must satisfy the following condition y
(n)
E(n) /S(n)
(18) (18) The energy content of the wavelet coefficients is
determined as
m
1
i
2
i,
n
C
)
n
(
E
,
(19) (19) .
s
0
f
f
2
2 56
,
(13) (13) i,
n
C where m is the number of wavelet coefficients,
n
C
is the i th wavelet coefficient of n th scale. where fs is the sampling frequency. where fs is the sampling frequency. The lower cut-off frequency of Morlet wavelet
filter is
/
0f
2
Hz. 2.2. Optimal parameter selection of wavelets For wavelet parameter optimization some
important requirements should be satisfied. where ( ) /
( )
M
k
i 1
d
C k
C i , k=1,…,M (17) Wavelet is needed to satisfy the admissibility
condition 2
( )
c
d
,
(10) is the normalized form of the wavelet coefficients
[25]. (10) where is the Fourier transform of , ⍵ is the
angular frequency. In practice, will always have
sufficient decay so that the admissibility condition
reduces to the requirement 2.1. Continuous and discrete wavelet transforms The multi-resolution property of the
wavelet analysis allows for both good time
resolution at high frequencies and good frequency
resolution at low frequencies. / . . . .
0
0
s
0
r
b
f
3 5
f
0 5
0 39 f
f
0 5
35
f
3 f
(16) (16)
b
3 f
Optimal (
,
)
min
log
,
M
0
k
k
k 1
f
d
d
Optimal (
,
)
min
log
,
M
0
k
k
k 1
f
d
d
2.1. Continuous and discrete wavelet transforms 2.1. Continuous and discrete wavelet transforms j
j
2
j,k
j,n
n
[t]
2
d
[2 t
k]
(7)
j
j
2
j,k
j,n
n
[t]
2
c
[2 t
k]
(8) Continuous
wavelet
transform
(CWT)
is
calculated by the convolution of the signal and a
wavelet function (7) dt
a
b
t
)
t(f
a
1
)
b,
a
(
CWT
*
f
(1) (8) (1) where
j,n
d
and
j,n
c
are the wavelet and scaling where
j,n
d
and
j,n
c
are the wavelet and scaling
coefficients
at
scale
j
[28]. Considering
signal
)
v
,...,
v
(
]
t[
X
1
N
0
,
where
N
is
the
sampling number,
]
t[
X j
can be decomposed to
scale
1
j as [30] where
j,n
d
and
j,n
c
are the wavelet and scaling
coefficients
at
scale
j
[28]. Considering
signal
)
v
,...,
v
(
]
t[
X
1
N
0
,
where
N
is
the
sampling number,
]
t[
X j
can be decomposed to
scale
1
j as [30] where a is the scale parameter, b is the translation
parameter, f(t) is the signal in time domain, is
the ‘mother’ wavelet, and
*
is the complex
conjugate of [22]. A wavelet function as an
oscillatory wave contains both the analysis and the
window function. where a is the scale parameter, b is the translation
parameter, f(t) is the signal in time domain, is the ‘mother’ wavelet, and is the complex
conjugate of [22]. A wavelet function as an
oscillatory wave contains both the analysis and the
window function. DIAGNOSTYKA, Vol. 20, No. 2.3. Maximum Energy-to-Shannon-Entropy
ratio criteria To reduce the interfering
effects of the harmonics, the lower cut-off
frequency has to be sufficiently large. Therefore,
the lower cut-off frequency has to satisfy The entropy of wavelet coefficients is calculated
as as
m
1
i
i
2
i
p
log
p
)
n
(
S
(20) (20)
0
r
f
N
f
2
,
(14) (14) where
1
(
,...,
)
m
p
p
is the energy distribution of the
wavelet coefficients at nth scale, defined as where where
rf is the rotational speed and N=35 is
chosen in this study. )
n
(
E
/
C
p
2
i,
n
i
(21) (21) DIAGNOSTYKA, Vol. 20, No. 2 (2019) 80 (
)
Deak K, Kocsis I.: Complex Morlet wavelet design with global parameter optimization for diagnosis of orlet wavelet design with global parameter optimization for diagnosis of … 2.4. Genetic algorithm for optimization Autocorrelation-envelope
analysis
is
a
fault
diagnosis method that can further suppress the
noise and reserve the periodic components of
vibration signals. The selection operation selects two individuals. The stochastic universal selection (SUS) is applied
in this study. Crossover is a probabilistic process that
exchanges
information
between
two
parent
chromosomes
for
generating
two
child
chromosomes. In this study a single-point crossover
is applied, the typical crossover probability value
Pc= 0.75. Hilbert transform is suitable for envelope
detection. Hilbert transform of the signal x(t) is
defined by an integral transform Mutation is used to avoid local convergence of
the GA. Here, mutation occurs with typical
mutation probability Pm=0.03.
( )
( )
( )
1
x
H x t
x t
dt
t
(24) (24) The maximum number of generations was
adopted as the termination criterion for the solution
process. Number 60 is chosen in this paper. It generates an artificial complex valued signal
H[x(t)] from the real valued x(t). The amplitude
modulated envelope signal E(t) can be computed as Table 1. Parameters of GA for complex Morlet
wavelet optimization
Parameters
Parameter
values
Population scale
50
Probability of
mutation
0.03
Probability of
crossover
0.75
Terminal iteration
times
60
Length of binary code
of
18
β
16 Table 1. Parameters of GA for complex Morlet
wavelet optimization ( )
( )
( )
2
2
E t
x t
x t
. (25) (25) 3. EXPERIMENTAL SETUP For the experiment, a bearing test-rig was
planned and constructed equipped with high-
precision measurement devices and sensors. (Fig. 1-
2 ) Fig. 1. Test rig for with variable speed drive
tool for tapered roller bearing analysis 2.4. Genetic algorithm for optimization autocorrelation is a tool for finding repeating
patterns, such as the presence of a periodic
signal obscured by noise. Genetic algorithms (GAs) are commonly used
to generate sufficiently precise solutions to
optimization and search problems by relying on
bio-inspired operators such as mutation, crossover
and selection. In this study, GA is applied to
optimize the Morlet wavelet filter parameters, the
center frequency and the bandwidth. The autocorrelation of the wavelet transform is
expressed as 0
0
,
,
( )
( )
(
)
0,1,2,....,
1,
f
f
r l
E WT
k WT
k
l
l
k
(22) (22) 0,1,2,....,
1,
l
k For starting the GA operation, the initial
population
can
be
randomly
determined
(initialization of the population). The size of the
genotype population is determined by experience. Here, the size of population is set to 50 according to
the experiences. where l is the lag index, E[·] denotes the
mathematical expectation operator. Here, the autocorrelation envelope power
spectrum is also created. The periodic impulsive
feature in time domain is usually displayed as
higher magnitudes of spectrum line and its
harmonics in the autocorrelation envelope power
spectrum The fitness function estimates how good an
individual in the current population (fitness
evaluation). In this case, the objective function is
the E/S value. The fitness of each chromosome can
be calculated by applying linear ranking of
objective function value. The chromosome with
higher fitness value is selected at greater probability
than that with lower fitness value.
( )
( )
( )
( )
( )
R f
F r l
P f
R f
R f
(23) (23) where F[·] denotes the Fourier transform and P(f) is
the power spectrum. The envelope detection
technique focuses on a narrow band range in the
specified frequency band, which is useful for
detecting the low-level impulses that are below the
noise
level
in
the
normal
spectrum. Autocorrelation-envelope
analysis
is
a
fault
diagnosis method that can further suppress the
noise and reserve the periodic components of
vibration signals. where F[·] denotes the Fourier transform and P(f) is
the power spectrum. The envelope detection
technique focuses on a narrow band range in the
specified frequency band, which is useful for
detecting the low-level impulses that are below the
noise
level
in
the
normal
spectrum. DIAGNOSTYKA, Vol. 20, No. 2 (2019)
Deak K, Kocsis I.: Complex Morlet wavelet design with global parameter optimization for diagnosis of … DIAGNOSTYKA, Vol. 20, No. 2 (2019) DIAGNOSTYKA, Vol. 20, No. 2 (2019)
Deak K, Kocsis I.: Complex Morlet wavelet design with global parameter optimization for diagnosis of … 81 DIAGNOSTYKA, Vol. 20, No. 2 (2019)
Deak K, Kocsis I.: Complex Morlet wavelet design with global parameter optimization for diagnosis of orlet wavelet design with global parameter optimization for diagnosis of … Fig. 3. Outer ring (OR2) of the tapered roller
bearing with grinding defect of 1.2492 mm
(called ORD) and its 50 times enlarged image
by Garant MM1-200 video microscope The shaft is driven by an alternating current
motor, the power of 0.75 kW, frequency of 50 Hz
and nominal speed of 2770 rpm which is reduced to
1800 rpm with variable speed drive device. By
Schneider ATV32HU22M2 variable speed drive
device the rpm can be adjusted. Constant spanning
force during the measurements is measured by
strain gauges in Wheatstone-bride mode on the
basis of difference in voltage measurement. Fig. 3. Outer ring (OR2) of the tapered roller
bearing with grinding defect of 1.2492 mm
(called ORD) and its 50 times enlarged image
by Garant MM1-200 video microscope g
NI 9234 DAQ is used in the experiment that
delivers 102 dB of dynamic range with sampling
rates up to 51.2 kHz per channel with built-in anti-
aliasing filters [8]. 32 bit AMD Athlon II X2 M300
2.0 GHz processor is used for data processing. PCB
IMI 603C01 vibration transducer is applied with
low noise level, high sensitivity of 100 mV/g,
frequency range up to 10 kHz with top exit 2-pin
connector [9]. The accelerometer is placed on the
ground smooth surface (Ra=1.6 µm) of the top of
the bearing house with screw that perpendicular to
the axis of the rotation of the shaft. Thin layer
couple fluid is applied between the bearing house
and the transducer. Garant MM1-200 video
microscope is used to produce magnified image
about the fault and to measure its geometrical width
parameter. Measurements
were
executed
in
noisy
environment to model the real circumstances of the
bearing operation. For this purpose we used an
electromechanical shaker Duffing oscillator as
chaotic attractor that vibration is described by the
differential equation cos(
)
3
x
x
x
x
t
(26) (26) Fig. 4. Demonstration of the Duffing
oscillator behaviour Fig. 2. DIAGNOSTYKA, Vol. 20, No. 2 (2019)
Deak K, Kocsis I.: Complex Morlet wavelet design with global parameter optimization for diagnosis of … Placement of the IMI 603C01 sensor
on the bearing house Fig. 4. Demonstration of the Duffing Fig. 4. Demonstration of the Duffing
oscillator behaviour 2.5. Autocorrelation envelope power spectrum
for signal enhancement In order to enhance the signal in the frequency
band, an autocorrelation enhancement algorithm is
proposed. It enhances the involved periodic
impulsive feature so periodic impulsive signal
component
related
with
bearing
fault
is
strengthened
while
stochastic
noise
signal
component
is
weakened. The
analysis
of Fig. 1. Test rig for with variable speed drive
tool for tapered roller bearing analysis 4.1. Parameter optimization and wavelet
comparison 9. Time domain spectrum of the ORD by
the parameter optimized complex Morlet
wavelet
Fig. 10. FFT spectrum of the ORD filtered by
the parameter optimized complex Morlet
wavelet Table 3. Calculated values of Energy-to-Shannon-
Entropy ratio of the ten wavelet functions
E/S
OR1
OR2
OR3
OR4
Mean
Sym2
59.86
82.69
103.26
112.52
89.58
Sym5
69.58
98.31
114.01
112.34
98.56
Sym8
79.43
117.24
120.56
113.51
107.69
db02
59.86
82.69
103.26
112.54
89.59
db06
72.64
95.03
116.37
121.17
101.30
db10
77.69
101.8
121.01
123.05
105.89
db14
85.81
118.47
123.14
124.31
112.93
Morlet
114.01
194.25
144.72
142.14
148.78
Cmor
138.26
235.19
247.45
227.89
212.12
Meyer
97.56
160.37
127.08
103.33
122.09 Table 3. Calculated values of Energy-to-Shannon-
Entropy ratio of the ten wavelet functions
E/S
OR1
OR2
OR3
OR4
Mean
Sym2
59.86
82.69
103.26
112.52
89.58
Sym5
69.58
98.31
114.01
112.34
98.56
Sym8
79.43
117.24
120.56
113.51
107.69
db02
59.86
82.69
103.26
112.54
89.59
db06
72.64
95.03
116.37
121.17
101.30
db10
77.69
101.8
121.01
123.05
105.89
db14
85.81
118.47
123.14
124.31
112.93
Morlet
114.01
194.25
144.72
142.14
148.78
Cmor
138.26
235.19
247.45
227.89
212.12
Meyer
97.56
160.37
127.08
103.33
122.09 Table 3. Calculated values of Energy-to-Shannon-
E t
ti
f th t
l t f
ti Fig. 9. Time domain spectrum of the ORD by
the parameter optimized complex Morlet
wavelet Fig. 9. Time domain spectrum of the ORD by
the parameter optimized complex Morlet
wavelet Fig. 10. FFT spectrum of the ORD filtered by
the parameter optimized complex Morlet
wavelet Fig. 6. Energy to Shannon Entropy ratio
values of wavelet functions, fo=2.09 kHz Fig. 10. FFT spectrum of the ORD filtered by
the parameter optimized complex Morlet
wavelet Fig. 6. Energy to Shannon Entropy ratio
values of wavelet functions, fo=2.09 kHz Fig. 6. Energy to Shannon Entropy ratio
values of wavelet functions, fo=2.09 kHz Fig. 7. presents the raw vibration signature of
outer race defect of bearing with 1.2492 mm fault
width on its outer ring. The highest transient
impulse related energy content of the burst occurs
at 2.09 kHz which is the relevant structural
resonance frequency of the test-rig as a mechanical
system caused by the periodic transients. The
spectrum was determined on the basis of each outer
ring with different fault sizes in three separate
measurements for high accuracy. Each separate
measurement showed similar manner and signal
peak of 2.09 kHz. 4.1. Parameter optimization and wavelet
comparison After filtering the raw signal by
the optimized complex Morlet wavelet it is much
more visible (Fig. 8.) that the outer race defect
causes transients with 5 ms periodicity which are in
connection with the calculated 206.18 Hz BPFO
fault frequency. From FFT spectrum it is not easy
to find the outer race defect frequency at 206.18 Hz
(Fig. 8.) because of its noisy manner and low
amplitude (red circle). Spectrum (Fig. 9.) offers
clearer image after filtering by the optimized
complex Morlet wavelet compared to the raw FFT
spectrum in Fig. 8. However, it is not applicable for
detailed BPFO analysis yet, because the frequency
around the 206.18 Hz is strongly meshed (red
circle)
in
the
spectrum. Therefore,
further
techniques such as multi-resolution analysis,
envelope
spectrum
and
autocorrelation
enhancement techniques are applied to analyze this
low frequency range for precise diagnosis. 4.1. Parameter optimization and wavelet
comparison With genetic algorithm the center frequency and
the bandwidth of the complex Morlet wavelet (Fig. 5.) were optimized to f0=2118 Hz and β=642 Hz. Fig. 2. Placement of the IMI 603C01 sensor
on the bearing house The shaft in the test rig is supported by two
tapered roller bearings. One of the bearing is a
“Type 30205” tapered roller bearing which is
examined in the experiments. Four tapered roller
bearings with different manufacturing defect width
on the outer race (OR1-4) were measured (Table
2.). Fig. 5. The optimized complex Morlet
wavelet Table 2.Geometrical parameters of grinding defects
of outer rings (OR) Table 2.Geometrical parameters of grinding defects
of outer rings (OR)
Type
Width (mm)
Depth (µm)
OR1 defect
0.6311
6.5
OR2 defect
1.2492
33.6
OR3 defect
1.4751
42.3
OR4 defect
1.6236
51.4 Fig. 5. The optimized complex Morlet
wavelet Ten different wavelets are considered for the
present study. For the best diagnosis the wavelet
with the highest E/S ratio is obtained. The
comparison of the wavelets on the basis of their E/S
values are in Table 3. Defect on the outer race is rectangular shape
grinding defect (Fig. 3). The adjusted sampling
frequency is 25.6 kHz and 51200 samples are used. Due to Shannon law measurements up to 10 kHz
are valid with the sampling rate. Values of E/S ratio are presented graphically in
Fig. 6. It is observed that the optimized complex
Morlet wavelet provides the highest E/S value that
indicates the Morlet wavelet to be the most efficient
for both fault detection and fault size estimation. DIAGNOSTYKA, Vol. 20, No. 2 (2019) 82 (
)
eak K, Kocsis I.: Complex Morlet wavelet design with global parameter optimization for diagnosis of … Table 3. Calculated values of Energy-to-Shannon-
Entropy ratio of the ten wavelet functions
E/S
OR1
OR2
OR3
OR4
Mean
Sym2
59.86
82.69
103.26
112.52
89.58
Sym5
69.58
98.31
114.01
112.34
98.56
Sym8
79.43
117.24
120.56
113.51
107.69
db02
59.86
82.69
103.26
112.54
89.59
db06
72.64
95.03
116.37
121.17
101.30
db10
77.69
101.8
121.01
123.05
105.89
db14
85.81
118.47
123.14
124.31
112.93
Morlet
114.01
194.25
144.72
142.14
148.78
Cmor
138.26
235.19
247.45
227.89
212.12
Meyer
97.56
160.37
127.08
103.33
122.09
Fig 6 Energy to Shannon Entropy ratio
Fig. 9. Time domain spectrum of the ORD by
the parameter optimized complex Morlet
wavelet
Fig. 10. FFT spectrum of the ORD filtered by
the parameter optimized complex Morlet
wavelet Fig. 4.2. Fault frequencies identification Fault frequencies are useful indicators of
bearing health condition monitoring. By using the
actual parameters of the bearing and operational
conditions the fault frequencies are calculated. In
this experiment BPFO=206.18 Hz, BPFI=287.15
Hz, FTF=12.88 Hz, BSF=89.96 Hz at 1800 rpm. Now, BPFO frequency should be used for fault
detection because the manufacturing faults are on
the outer ring of the bearings. Fig. 7. Time domain raw signal of the ORD
Fig. 8. FFT spectrum of the ORD Fig. 7. Time domain raw signal of the ORD Fig. 8. FFT spectrum of the ORD Fig. 8. FFT spectrum of the ORD DIAGNOSTYKA, Vol. 20, No. 2 (2019) 83 (
)
Deak K, Kocsis I.: Complex Morlet wavelet design with global parameter optimization for diagnosis of Fig. 11. Wavelet decomposition graph of the
original vibration signal by MRA with the
adjusted frequency ranges
Multi-resolution analysis is executed down to
4th level in order to obtain precise and detailed
frequency analysis. Fig. 11-12 present the wavelet
decomposition tree from signal down to the 4th
level to reveal BPFO frequency for outer race
grinding fault identification. Fig.14. Envelope spectrum of the ORD
filtered by Morlet wavelet
Fig. 15. Envelope spectrum of the ORD
filtered by the parameter optimized Cmor
wavelet Fig. 11. Wavelet decomposition graph of the
original vibration signal by MRA with the
adjusted frequency ranges Fig.14. Envelope spectrum of the ORD
filtered by Morlet wavelet Fig.14. Envelope spectrum of the ORD
filtered by Morlet wavelet p
p
filtered by Morlet wavelet Fig. 11. Wavelet decomposition graph of the
original vibration signal by MRA with the
adjusted frequency ranges Fig. 15. Envelope spectrum of the ORD
filtered by the parameter optimized Cmor
wavelet Multi-resolution analysis is executed down to
4th level in order to obtain precise and detailed
frequency analysis. Fig. 11-12 present the wavelet
decomposition tree from signal down to the 4th
level to reveal BPFO frequency for outer race
grinding fault identification. Fig. 15. Envelope spectrum of the ORD
filtered by the parameter optimized Cmor
wavelet Fig.12. Multi-resolution analysis of the signal
for finding transients Fig.12. Multi-resolution analysis of the signal
for finding transients By using the autocorrelation enhancement, it is
clear from Fig. 16 that the non-cyclic frequencies
are suppressed in the vibration spectrum and the
signal-to-noise ratio increased providing efficient
fault diagnosis. Fig. 16. 4.2. Fault frequencies identification Envelope spectrum of the ORD
filtered by the parameter optimized Cmor
wavelet with autocorrelation enhancement Fig.12. Multi-resolution analysis of the signal
for finding transients Fig. 13-15 show the comparison of the envelope
spectrum of the bearing fault with three chosen
wavelets (Symlet-5, Morlet, Cmor) from the ten
wavelets for illustration. The Morlet wavelet
provided better feature extraction, therefore higher
BPFO peak values, than the Symlet-5 wavelet. However, the optimized complex Morlet wavelet
provided the highest peak value for outer race fault
identification. Fig. 16. Envelope spectrum of the ORD
filtered by the parameter optimized Cmor
wavelet with autocorrelation enhancement Comparing the scalograms of the Symlet-5,
Morlet and the optimized wavelet it is visible that
the optimized complex Morlet wavelet provides the
best result for diagnosis and fault size estimation
(Fig. 17-19). provided the highest peak value for outer race fault
identification. Fig.13. Envelope spectrum of the ORD
filtered by Symlet-5 wavelet
Morlet and the optimized wavelet it is visible that
the optimized complex Morlet wavelet provides the
best result for diagnosis and fault size estimation
(Fig. 17-19). Fig. 17. Scalogram of the Symlet-5 wavelet
of the ORD Fig.13. Envelope spectrum of the ORD
filtered by Symlet-5 wavelet Fig.13. Envelope spectrum of the ORD
filtered by Symlet-5 wavelet Fig. 17. Scalogram of the Symlet-5 wavelet
of the ORD Fig. 17. Scalogram of the Symlet-5 wavelet
of the ORD Fig.13. Envelope spectrum of the ORD
filtered by Symlet-5 wavelet Fig. 17. Scalogram of the Symlet-5 wavelet
of the ORD DIAGNOSTYKA, Vol. 20, No. 2 (2019)
Deak K, Kocsis I.: Complex Morlet wavelet design with global parameter optimization for diagnosis of …
84 DIAGNOSTYKA, Vol. 20, No. 2 (2019) 84 ,
,
(
)
Deak K, Kocsis I.: Complex Morlet wavelet design with global parameter optimization for diagnosis of Fig. 18. Scalogram of the Morlet wavelet of
the ORD
Fig. 19. Scalogram of the optimized Cmor
wavelet of the ORD Fig. 18. Scalogram of the Morlet wavelet of
the ORD high impulse in signal. When the roller comes in
contact with the point B it again generates high
amplitude in the signal and beyond the point
progressive decrease in amplitude of signal is
observed due to elastic damping of bearing element. At point C roller comes out of the groove and
creates high amplitude. 4.2. Fault frequencies identification For peak detection in the scalogram, local
maxima filtering algorithm and Sobel edged
detection were applied which emphasize the high
intensity areas (designated with red color) and
found the local peaks. With this procedure entry
and exit points can be exactly determined for fault
width measurement. The method is equivalent with
the direct finding of the maximum values in the
wavelet coefficients. Fig. 18. Scalogram of the Morlet wavelet of
the ORD Fig. 19. Scalogram of the optimized Cmor
wavelet of the ORD Fig. 19. Scalogram of the optimized Cmor
wavelet of the ORD Fig. 21. Scalogram after contrast
enhancement (left) and then after Sobel edge
detection (right) Fig. 19. Scalogram of the optimized Cmor
wavelet of the ORD 5. FAULT SIZE ESTIMATION BASED ON
SCALOGRAM OF CMOR FILTER It is a vital task in industrial quality
management to determine the fault size only from
the vibration signature (without destructive method)
as accurate as possible. Here, fault width was
measured with high-precision laboratory devices,
namely Garant MM1-200 video microscope as it is
in the Table 2. Fig. 21. Scalogram after contrast
enhancement (left) and then after Sobel edge
detection (right) This technique is applicable for fault width
measurement. Compared to the different wavelets
(Table 3.) the results are in excellent correlation
with the Energy-to-Shannon Entropy values that are
calculated and displayed in Table 2. The optimized
complex Morlet (Cmor) wavelet provides the most
accurate result with only 1.19% deviation from the
measured value by Garant MM1-200 video
microscope. Fig. 20. Image of the optical measurement of
the outer race defect width with Garant
MM1-200 video microscope Table 4. Comparison of the calculated and measured
fault widths of the ORD
Wavelet
Calculated
width (mm)
Width
deviation
[%]
Sym2
1.277
2.24
Sym5
1.269
1.56
Sym8
1.2713
1.77
db2
1.277
2.24
db6
1.2765
2.19
db10
1.2681
1.52
db14
1.2679
1.50
Morlet
1.266
1.38
Cmor
1.2640
1.19
Meyer
1.2674
1.46 Table 4. Comparison of the calculated and measured
fault widths of the ORD Fig. 20. Image of the optical measurement of
the outer race defect width with Garant
MM1-200 video microscope 6. CONCLUSIONS A diagnosis method for manufacturing fault of
tapered roller bearings was presented. The article
focused on the detection of grinding faults on the
bearing because it is typical problem in industrial
manufacturing processes. With conventional time Analyzing the transients, the typical points
where the roller enters into and exits from the
defect can be defined [5], [23]. At point A, the roller strikes the groove base
with high impact which results in re-stressing and DIAGNOSTYKA, Vol. 20, No. 2 (2019)
Deak K, Kocsis I.: Complex Morlet wavelet design with global parameter DIAGNOSTYKA, Vol. 20, No. 2 (2019) 85 DIAGNOSTYKA, Vol. 20, No. 2 (2019)
Deak K, Kocsis I.: Complex Morlet wavelet design with global parameter optimization for diagnosis of 2. Prabhakar S, Mohanty AR, Sekhar AS. Application
of discrete wavelet transform for detection of ball
bearing race faults. Tribology International. 2002;
35:793. domain and frequency domain techniques the
vibration signal was analyzed. Measurements were
executed in noisy condition, where the low signal-
to-noise ratio made difficult the feature extraction. executed in noisy condition, where the low signal-
to-noise ratio made difficult the feature extraction. To draw similarities to the real circumstances an
electromechanical shaker as chaotic Duffing
oscillator was applied to create additional stochastic
vibration. The purpose was to obtain the useful
components from the vibration spectrum and
enhance them for more precise fault detection and
fault width measurement. Wavelet transform was
used for detecting the transients in the spectrum
because it had the capability to detect the sharp
edges caused by the roller and fault interaction
during the rotation of the bearing. Complex Morlet
wavelet was defined and its center frequency and
bandwidth were optimized by genetic algorithm. The efficiency of the designed complex Morlet
wavelet was compared to nine different wavelets,
namely Symlet-2, Symlet-5, Symlet-8, Daubechies-
2, Daubechies-6, Daubechies-10, Daubechies-14,
Morlet and Meyer. Energy-to-Shannon-Entropy
ratio criteria was used for more effective
comparison. The designed wavelet provided the
highest efficiency. Without filtering, the FFT
spectrum was blurred by the noise making
impossible to find the local BPFO fault frequency
of the defected bearing. Wavelet filtering through
multi-resolution analysis down to 4th level with the
best-suited
wavelet
provided
clear
vibration
spectrum with less noise, higher signal-to-noise
ratio. However, it was needed to further emphasize
the cyclic manner of the signal by using
autocorrelation enhancement. The amplitude value
of the BPFO frequency improved and the non-
cyclic frequencies were successfully suppressed. https://doi.org/10.1016/j.neucom.2012.11.012 15. Li Z, Ma Z, Liu Y, Teng W, Jiang R. Crack fault
detection for a gearbox using discrete wavelet
transform and an adaptive resonance theory neural
network. Strojniski vestnik-Journal of Mechanical
Engineering. 2015; 61:63-73. 16. Patel VN, Tandon N, Pandey RK. Defect detection in
deep groove ball bearing in presence of external
vibration using envelope analysis and Duffing
oscillator. Measurement. 2012; 45:960-970. https://doi org/10 1016/j measurement 2012 01 047 https://doi.org/10.1016/j.measurement.2012.08.012 6. Kumar R, Jena DP, Bains M. Identification of inner
race defect in radial ball bearing using acoustic
emission and wavelet analysis. Proceedings of ISMA
2010 including USD 2010 Leuven (Belgium). 2010;
2883–2891. 7. He W, Jiang Z, Feng K. Bearing fault detection based
on optimal wavelet filter and sparse code shrinkage. Measurement. 2009; 42:1092–1102. 8. NI 9234 datasheet:
http://www.ni.com/datasheet/pdf/en/ds-316, accessed
on 2016-02-04 . 9. PCB
IMI
603C01
transducer,
from
https://www.pcb.com/contentstore/docs/PCB_Corpor
ate/IMI/Products/Manuals/603C01.pdf, accessed on
2016-02-04. 10. Misiti M, Misiti Y, Oppenheim G, Poggi JM. Wavelets and their Applications. 2007; ISTE Ltd. 11. Honghu P, Xingxi H, Sai T, Fanming M. An
improved bearing fault diagnosis method using one-
dimensional CNN and LSTM. Strojniski vestnik-
Journal of Mechanical Engineering. 2018; 64:443-
452. 12. Ivan O, Marko N, Jernej K. Analysis on damage to
rolling bearings at small turning angles. Strojniski
vestnik-Journal of Mechanical Engineering. 2018; 64:
209-215. 13. Kankar PK, Sharma SC, Harsha SP. Fault diagnosis
of ball bearings using continuous wavelet transform. Applied Soft Computing. 2011; 11:2300–2312. 14. Harsha SP, Kankar PK, Sharma SC. Fault diagnosis
of
rolling
element
bearing
using
cyclic
autocorrelation
and
wavelet
transform. Neurocomputing. 2013; 110:9-17. https://doi.org/10.1016/j.neucom.2012.11.012 6. CONCLUSIONS Finally, the fault width was determined from the
vibration signature by using the optimized complex
Morlet wavelet. The fault width measurement
procedure was executed with the other nine
wavelets for the purpose to compare them to the
optimized wavelet. By analyzing the spectrogram
with Sobel edge detection and local maxima peak
detection of the wavelet coefficients, the entry point
and the exit points were exactly determined where
the roller entered into and exited from the defect. Results were verified by optical measurement with
high
resolution
Garant
MM1-200
video
microscope. The deviation from the optically
measured width was only 1.19 % in case of the
optimized
complex
Morlet
wavelet. The
measurements proved its capability for industrial
bearing fault diagnosis in manufacturing. 3. Shi DF, Wang WJ, Qu LS. Defect detection for
bearings using envelope spectra of wavelet transform. ASME Journal of Vibration and Acoustics. 2004;
126:567. 4. Nikolaou NG, Antoniadis IA. Demodulation of
vibration signals generated by defects in rolling
element bearings using complex shifted Morlet
wavelets. Mechanical Systems and Signal Processing. 2002; 16:677. 5. Kumar R, Singh M. Outer race defect width
measurement in tapered roller bearing using discrete
wavelet transform of vibration signal. Measurement. 2013; 46:537. https://doi.org/10.1016/j.measurement.2012.08.012 7. REFERENCES 17. Tabaszewski, M. Optimization of a nearest neighbors
classifier for diagnosis of condition of rolling
bearings. Diagnostyka. 2014; 15: 37-42. 1. Sawalhi N, Randall RB. Vibration response of spalled
rolling element bearings: observations, simulations
and signal processing techniques to track the spall
size. Mechanical Systems and Signal Processing. 2011; 25:846. 1. Sawalhi N, Randall RB. Vibration response of spalled
rolling element bearings: observations, simulations
and signal processing techniques to track the spall
size. Mechanical Systems and Signal Processing. 2011; 25:846. 18. Strączkiewicz M, Czop P, Barszcz T. Supervised and
unsupervised
learning
process
in
damage https://doi.org/10.1016/j.ymssp.2010.09.009 https://doi.org/10.1016/j.ymssp.2010.09.009 DIAGNOSTYKA, Vol. 20, No. 2 (2019)
Deak K, Kocsis I.: Complex Morlet wavelet design with global parameter optimization for diagnosis of …
6 86 classification
of
rolling
element
bearings. Diagnostyka. 2016; 17:71-80. 19. Wensheng S, Fengtao W, Hong Z, Zhixin Z,
Zhenggang G. Rolling element bearing fault
diagnosis based on optimal Morlet wavelet filter and
autocorrelation enhancement. Mechanical Systems
and Signal Processing. 2009; 24:1458-1472. 20. Jena DP, Panigrahi S, Kumar R. Gear fault
identification and localization using analytic wavelet
transform of vibration signal. Measurement, 2013;
46:1115-1124. https://doi.org/10.1016/j.measurement.2012.11.010 21. Tandon N, Choudhury A. A review of vibration and
acoustic measurement methods for detection of
defects in rolling element bearings. Tribology
International. 1999; 32:469-480. 22. Farzad H, Wasim O, Mohamed S. Roller bearing
acoustic signature extraction by wavelet packet
transform, applications in fault detection and size
estimation. Applied acoustics. 2016; 104:101-118. https://doi.org/10.1016/j.apacoust.2015.11.003 23. Deak K, Kocsis I, Mankovits T. Optimal Wavelet
Selection for Manufacturing Defect Size Estimation
of
Tapered
Roller
Bearings
with
Vibration
Measurement using Shannon Entropy Criteria. Strojniški
vestnik
-
Journal
of
Mechanical
Engineering. 2017; 63:3-14. Received 2019-01-17
Accepted 2019-05-08
Available online 2019-05-10 Received 2019-01-17
Accepted 2019-05-08
Available online 2019-05-10 Dr. habil. Imre KOCSIS,
PhD. is college professor at the
Faculty of Engineering University
of
Debrecen. His
scientific
interests
include
engineering
system
optimization,
technical
diagnostics and signal processing
and
applied
mathematical
applications in engineering. Krisztian
DEAK
is
assistant
lecturer
at
the
Faculty
of
Engineering
University
of
Debrecen. His scientific interests
are related to machine fault
diagnosis, modelling of dynamical
systems, digital signal processing,
machine learning methods and
artificial intelligence applications
in technical systems.
|
https://openalex.org/W2950043157
|
https://europepmc.org/articles/pmc6493776?pdf=render
|
English
| null |
Stability of working memory in continuous attractor networks under the control of short-term plasticity
|
PLOS computational biology/PLoS computational biology
| 2,019
|
cc-by
| 30,594
|
RESEARCH ARTICLE Alexander SeeholzerID1, Moritz DegerID1,2, Wulfram Gerstner1* Alexander SeeholzerID1, Moritz DegerID1,2, Wulfram Gerstner1* 1 School of Computer and Communication Sciences and School of Life Sciences, Brain Mind Institute, E´ cole
Polytechnique Fe´de´rale de Lausanne, Lausanne, Switzerland, 2 Institute for Zoology, Faculty of Mathematics
and Natural Sciences, University of Cologne, Cologne, Germany * wulfram.gerstner@epfl.ch * wulfram.gerstner@epfl.ch a1111111111
a1111111111
a1111111111
a1111111111
a1111111111 a1111111111
a1111111111
a1111111111
a1111111111
a1111111111 Abstract Continuous attractor models of working-memory store continuous-valued information in
continuous state-spaces, but are sensitive to noise processes that degrade memory reten-
tion. Short-term synaptic plasticity of recurrent synapses has previously been shown to
affect continuous attractor systems: short-term facilitation can stabilize memory retention,
while short-term depression possibly increases continuous attractor volatility. Here, we
present a comprehensive description of the combined effect of both short-term facilitation
and depression on noise-induced memory degradation in one-dimensional continuous
attractor models. Our theoretical description, applicable to rate models as well as spiking
networks close to a stationary state, accurately describes the slow dynamics of stored mem-
ory positions as a combination of two processes: (i) diffusion due to variability caused by
spikes; and (ii) drift due to random connectivity and neuronal heterogeneity. We find that
facilitation decreases both diffusion and directed drifts, while short-term depression tends to
increase both. Using mutual information, we evaluate the combined impact of short-term
facilitation and depression on the ability of networks to retain stable working memory. Finally, our theory predicts the sensitivity of continuous working memory to distractor inputs
and provides conditions for stability of memory. OPEN ACCESS Citation: Seeholzer A, Deger M, Gerstner W (2019)
Stability of working memory in continuous
attractor networks under the control of short-term
plasticity. PLoS Comput Biol 15(4): e1006928. https://doi.org/10.1371/journal.pcbi.1006928 Editor: Yoram Burak, Hebrew University, ISRAEL
Received: April 19, 2018
Accepted: March 4, 2019
Published: April 19, 2019
Copyright: © 2019 Seeholzer et al. This is an open
access article distributed under the terms of the
Creative Commons Attribution License, which
permits unrestricted use, distribution, and
reproduction in any medium, provided the original
author and source are credited. Editor: Yoram Burak, Hebrew University, ISRAEL
Received: April 19, 2018
Accepted: March 4, 2019
Published: April 19, 2019
Copyright: © 2019 Seeholzer et al. This is an open
access article distributed under the terms of the
Creative Commons Attribution License, which
permits unrestricted use, distribution, and
reproduction in any medium, provided the original
author and source are credited. Copyright: © 2019 Seeholzer et al. This is an open
access article distributed under the terms of the
Creative Commons Attribution License, which
permits unrestricted use, distribution, and
reproduction in any medium, provided the original
author and source are credited. Data Availability Statement: All relevant data are
within the paper and its Supporting Information
files. Introduction Information about past environmental stimuli can be stored and retrieved seconds later from
working memory [1, 2]. Strikingly, this transient storage is achieved for timescales of seconds
with neurons and synapse transmission operating mostly on time scales of tens of milliseconds
and shorter [3]. An influential hypothesis of neuroscience is that working memory emerges
from recurrently connected cortical neuronal networks: memories are retained by self-gener-
ating cortical activity through positive feedback [4–7], thereby bridging the time scales from
milliseconds (neuronal dynamics) to seconds (behavior). Sensory stimuli are often embedded in a physical continuum: for example, positions of
objects in the visual field are continuous, as are frequencies of auditory stimuli, or the position
of somatosensory stimuli on the body. Ideally, the organization of cortical working memory
circuits should reflect the continuous nature of sensory information [3]. A class of cortical
working memory models able to store continuously structured information is that of continu-
ous attractors, characterized by a continuum of meta-stable states, which can be used to retain
memories over delay periods much longer than those of the single network constituents [8]. Continuous attractors were proposed as theoretical models for cortical working memory [9–
11], path integration [12–14], and other cortical functions [15–17] (see e.g. [3, 18–21] for
recent reviews), well before experimental evidence was found in cortical networks [22] and the
limbic system [18, 23]. The one-dimensional ring-attractor in the fly responsible for self-orien-
tation [24, 25] is a particularly intriguing example. Continuous attractor models have been successfully employed in the context of visuospatial
working memory to explain behavioral performance [26–29], to predict the effects of neuro-
modulation [30, 31], or the implications of cognitive impairment [32, 33]. However, in net-
works with heterogeneities, the continuum of memory states quickly breaks down, since noise
and heterogeneities break, transiently or permanently, the crucial symmetry necessary for con-
tinuous attractors [10, 11, 13, 16, 34–40]. For example, the stochasticity of neuronal spiking
(“fast noise”) leads to transient asymmetries that randomly displace encoded memories along
the continuum of states [10, 11, 35, 37, 39, 40], leading, averaged over many trials, to diffusion
of encoded information. More drastically, introducing fixed asymmetries (“frozen noise”) due
to network heterogeneities causes a directed drift of memories and a collapse of the continuum
of attractive states to a set of discrete states. Author summary The ability to transiently memorize positions in the visual field is crucial for behavior. Models and experiments have shown that such memories can be maintained in networks
of cortical neurons with a continuum of possible activity states, that reflects the contin-
uum of positions in the environment. However, the accuracy of positions stored in such
networks will degrade over time due to the noisiness of neuronal signaling and imperfec-
tions of the biological substrate. Previous work in simplified models has shown that syn-
aptic short-term plasticity could stabilize this degradation by dynamically up- or down-
regulating the strength of synaptic connections, thereby “pinning down” memorized posi-
tions. Here, we present a general theory that accurately predicts the extent of this “pinning Funding: Research was supported by the European
Union Seventh Framework Program (FP7, https://
ec.europa.eu/research/fp7/index_en.cfm) under
grant agreement no. 604102 (Human Brain Project,
M.D.) and by the Swiss National Science
Foundation (http://www.snf.ch/en/Pages/default. aspx) under grant no. 200020_147200 (A.S.). The
funders had no role in study design, data collection
and analysis, decision to publish, or preparation of
the manuscript. 1 / 48 PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1006928
April 19, 2019 Stability of continuous attractor networks under the control of short-term plasticity Competing interests: The authors have declared
that no competing interests exist. down” by short-term plasticity in a broad class of biologically plausible network models,
thereby untangling the interplay of varying biological sources of noise with short-term
plasticity. Importantly, our work provides a novel theoretical link from the microscopic
substrate of working memory—neurons and synaptic connections—to observable behav-
ioral correlates, for example the susceptibility to distracting stimuli. Stability of continuous attractor networks under the control of short-term plasticity with noise-free [38] and, as shown parallel to this study, noisy [45] rate neurons. In simulations
of continuous attractors implemented with spiking neurons for a fixed set of parameters, facili-
tation was reported to cause slow drift [46, 47] and a reduced amount of diffusion [47]. How-
ever, despite the large number of existing studies, several fundamental questions remain
unanswered. What are the quantitative effects of short-term facilitation in more complex neu-
ronal models and across facilitation parameters? How does short-term depression influence
the strength of diffusion and drift, and how does it interplay with facilitation? Do phenomena
reported in rate networks persist in spiking networks? Finally, can a single theory be used to
predict all of the effects observed in simulations? Here, we present a comprehensive description of the effects of short-term facilitation and
depression on noise-induced displacement of one-dimensional continuous attractor models. Extending earlier theories for diffusion [39, 40, 45] and drift [38], we derive predictions of the
amount of diffusion and drift in ring-attractor models of randomly firing neurons with short-
term plasticity, providing, for the first time, a general description of bump displacement in
the presence of both short-term facilitation and depression. Our theory is formulated as a rate
model with noise, but since the gain-function of the rate model can be chosen to match that of
integrate-and-fire models, our theory is also a good approximation for a large class of hetero-
geneous networks of integrate-and-fire models as long as the network as a whole is close to a
stationary state. The theoretical predictions of the noisy rate model are validated against simu-
lations of ring-attractor networks realized with spiking integrate-and-fire neurons. In both
theory and simulation, we find that facilitation and depression play antagonistic roles: facilita-
tion tends to decrease both diffusion and drift while depression increases both. We show that
these combined effects can still yield reduced diffusion and drift, which increases the retention
time of memories. Importantly, since our theory is, to a large degree, independent of the
microscopic network configurations, it can be related to experimentally observable quantities. In particular, our theory predicts the sensitivity of networks with short-term plasticity to dis-
tractor stimuli. Introduction Examples of heterogeneities in biological scenarios
include the sparsity of recurrent connections [13, 36], or randomness in neuronal parameters
[36] and values of recurrent weights [16, 34, 38]. Since both (fast) noise and heterogeneities are
expected in cortical settings, the feasibility of continuous attractors as computational systems
of the brain has been called into question [3, 6, 41]. The question then arises, whether short-term plasticity of recurrent synaptic connections
can rescue the feasibility of continuous attractor models. In particular, short-term depression
has a strong effects on the directed drift of attractor states in rate models [42, 43], but no strong
conclusions were drawn in a spiking network implementation [44]. Short-term facilitation, on
the other hand, increases the retention time of memories in continuous attractor networks PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1006928
April 19, 2019 2 / 48 Results We investigated, in theory and simulations, the effects of short-term synaptic plasticity (STP)
on the dynamics of ring-attractor models consisting of N excitatory neurons with distance-
dependent and symmetric excitation, and global (uniform) inhibition provided by a popula-
tion of inhibitory neurons (Fig 1A). For simplicity, we describe neurons in terms of firing
rates, but our theory can be mapped to more complex neurons with spiking dynamics. An
excitatory neuron i with 0 i < N is assigned an angular position yi ¼ 2p
N i p 2 p; p
½
Þ,
where we identify the bounds of the interval to form a ring topology (Fig 1A). The firing rate
ϕi (in units of Hz) for each excitatory neuron i (0 i < N −1) is given as a function of the neu-
ronal input: iðtÞ ¼ FðJiðtÞ þ JinhÞ:
ð1Þ ð1Þ Here, the input-output relation F relates the dimensionless excitatory Ji and inhibitory Jinh
inputs of neuron i to its firing rate. This represents a rate-based simplification of the possibly
complex underlying neuronal dynamics [48]. We assume that the excitatory input Ji(t) to neu-
ron i at time t is given by a sum over all presynaptic neurons JiðtÞ ¼
X
N 1
j¼0
wijsjðtÞ;
ð2Þ ð2Þ 3 / 48 PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1006928
April 19, 2019 Stability of continuous attractor networks under the control of short-term plasticity Fig 1. Drift and diffusion in ring-attractor models with short-term plasticity. A Excitatory (E) neurons (red circles) are distributed on a ring with coordinates in
[−π, π]. Excitatory-to-excitatory (E-E) connections (red lines) are distance-dependent, symmetric, and subject to short-term plasticity (facilitation and depression,
see Eq (3)). Inhibitory (I) neurons (blue circles) project to all E and I neurons (blue lines) and receive connection from all E neurons (gray lines). Only outgoing
connections from shaded neurons are displayed. In simulations with integrate-and-fire neurons, each neuron also receives noisy excitatory spike input generated
by independent homogeneous Poisson processes. B1 Example simulation: E neurons fire asynchronously and irregularly at low rates until (dotted line) a subgroup
of E neurons is stimulated (external cue), causing them to spike at elevated rates (red dots, input was centered at 0, starting at t = 2s for 1s). During and after
(dashed line) the stimulus, a bump state of elevated activity forms and sustains itself after the external cue is turned off. Results The spatial center of the population activity
is estimated from the momentary firing rates (red line, plotted from t = 2.5s onward). Inset: Activity profile in the bump state, centered at 0. B2 Center positions of
20 repeated spiking simulations for 10 different initial cue positions each for a network with short-term depression (U = 1, τx = 150ms). Random E-E connections
(with connection probability p = 0.5) lead to directed drift in addition to diffusion. Right: Normalized histogram (200 bins) of final positions at time t = 13.5. C
Illustration of quantities used in theoretic calculations. Neurons in the bump fire at rates ϕ0,i (dashed black line, compare to B1, inset) due to the steady-state
synaptic input J0,i (blue line). Movement of the bump center causes a change of the synaptic input
dJ0;i
dφ (orange line). D Diffusion along the attractor manifold is
calculated (see Eq (5)) as a weighted sum of the neuronal firing rates in the bump state (dashed black line). Spiking noise (red line) is illustrated as a random Fig 1. Drift and diffusion in ring-attractor models with short-term plasticity. A Excitatory (E) neurons (red circles) are distributed on a ring with coordinates in
[−π, π]. Excitatory-to-excitatory (E-E) connections (red lines) are distance-dependent, symmetric, and subject to short-term plasticity (facilitation and depression,
see Eq (3)). Inhibitory (I) neurons (blue circles) project to all E and I neurons (blue lines) and receive connection from all E neurons (gray lines). Only outgoing
connections from shaded neurons are displayed. In simulations with integrate-and-fire neurons, each neuron also receives noisy excitatory spike input generated
by independent homogeneous Poisson processes. B1 Example simulation: E neurons fire asynchronously and irregularly at low rates until (dotted line) a subgroup
of E neurons is stimulated (external cue), causing them to spike at elevated rates (red dots, input was centered at 0, starting at t = 2s for 1s). During and after
(dashed line) the stimulus, a bump state of elevated activity forms and sustains itself after the external cue is turned off. The spatial center of the population activity
is estimated from the momentary firing rates (red line, plotted from t = 2.5s onward). Inset: Activity profile in the bump state, centered at 0. B2 Center positions of
20 repeated spiking simulations for 10 different initial cue positions each for a network with short-term depression (U = 1, τx = 150ms). Stability of continuous attractor networks under the control of short-term plasticity deviation from the mean rate with variance proportional to the rate. The symmetric weighting factors (blue lines show
C2
i
S2
dJ0;i
dφ
2
for varying U) are non-zero at the
flanks of the firing rate profile. Stronger short-term depression and weaker facilitation increase the magnitude of weighting factors. E Deterministic drift is
calculated as a weighted sum (see Eq (7)) of systematic deviations of firing rates from the bump state (frozen noise): a large positive firing rate deviation in the left
flank (red line) will cause movement of the center position to the left (red arrow) because the weighting factors (blue lines show Ci
S
dJ0;i
dφ for varying U) are asymmetric. https://doi.org/10.1371/journal.pcbi.1006928.g001 where wijsj(t) describes the total activation of synaptic input from the presynaptic neuron j
onto neurons i. The maximal strength wij of recurrent excitatory-to-excitatory connections is
chosen to be local in the angular arrangement of neurons, such that connections are strongest
to nearby excitatory neurons (Fig 1A, red lines). The momentary input depends also on the
synaptic activation variables sj, to be defined below. Finally, connections to and from inhibi-
tory neurons are assumed to be uniform and global (all-to-all) (Fig 1A, blue lines), thereby
providing non-selective inhibitory input Jinh to excitatory neurons. As a model of STP, we assume that excitatory-to-excitatory connections are subject to
short-term facilitation and depression, which we implemented using a widely adopted model
of short-term synaptic plasticity [49]. The outgoing synaptic activations sj of neuron j are mod-
eled by the following system of ordinary differential equations: _sj
¼
sj
ts
þ ujxj j;
_uj
¼
uj U
tu
þ Uð1 ujÞ j;
_xj
¼
xj 1
tx
ujxj j:
ð3Þ ð3Þ The synaptic time scale τs governs the decay of the synaptic activations. The timescale of recov-
ery τx is the main parameter of depression. While the recovery from facilitation is controlled
by the timescale τu, the parameter 0 < U 1 controls the baseline strength of unfacilitated syn-
apses as well as the timescale of their strengthening. For fixed τu, we consider smaller values
of U to lead to a “stronger” effect of facilitation, and take U = 1 as the limit of non-facilitating
synapses. Results Random E-E connections
(with connection probability p = 0.5) lead to directed drift in addition to diffusion. Right: Normalized histogram (200 bins) of final positions at time t = 13.5. C
Illustration of quantities used in theoretic calculations. Neurons in the bump fire at rates ϕ0,i (dashed black line, compare to B1, inset) due to the steady-state
synaptic input J0,i (blue line). Movement of the bump center causes a change of the synaptic input
dJ0;i
dφ (orange line). D Diffusion along the attractor manifold is
calculated (see Eq (5)) as a weighted sum of the neuronal firing rates in the bump state (dashed black line). Spiking noise (red line) is illustrated as a random PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1006928
April 19, 2019 4 / 48 Stability of continuous attractor networks under the control of short-term plasticity Optimization of network parameters in Materials and methods) for each combination of the
STP parameters above. Simulations with spiking integrate-and-fire neurons generally show a bi-stability between
a non-selective state and a bump state. In the non-selective state, all excitatory neurons emit
action potentials asynchronously and irregularly at roughly identical and low firing rates (Fig
1B1, left of dotted line). The bump state can be evoked by stimulating excitatory neurons local-
ized around a given position by additional external input (Fig 1B1, red dots). After the external
cue is turned off, a self-sustained firing rate profile (“bump”) emerges (Fig 1B1, right of dashed
line, and inset) that persists until the network state is again changed by external input. For
example, a short and strong uniform excitatory input to all excitatory neurons causes a tran-
sient increase in inhibitory feedback that is strong enough to return the network to the uni-
form state [11]. During the bump state, fast fluctuations in the firing of single neurons transiently break the
perfect symmetry of the firing rate profile and introduce small random displacements along
the attractor manifold, which become apparent as a random walk of the center position. If the
simulation is repeated for several trials, the bump has the same shape in each trial, but infor-
mation on the center position is lost in a diffusion-like process. We additionally included vary-
ing levels of biologically plausible sources of heterogeneity (frozen noise) in our networks:
random connectivity between excitatory neurons (E-E) and heterogeneity of the single neuron
properties of the excitatory population [36], realized as a random distribution of leak reversal
potentials. Heterogeneities makes the bump drift away from its initial position in a directed
manner. For example, the bump position in the randomly connected (p = 0.5) network of Fig
1B1 shows a clear upwards drift towards center positions around 0. Repeated simulations of
the same attractor network with bumps initialized at different positions provide a more
detailed picture of the combined drift and diffusion dynamics: bump center trajectories sys-
tematically are biased towards a few stable fixed points (Fig 1B2) around which they are dis-
tributed for longer simulation times (histogram in Fig 1B2, t = 13.5s). The theory developed in
this paper aims at analyzing the above phenomena of drift and diffusion of the bump center. As a reference implementation of this model, we simulated networks of spiking conduc-
tance-based leaky-integrate-and-fire (LIF) neurons with (spike-based) short-term plastic syn-
aptic transmission (Fig 1B1, see Spiking network model in Materials and methods for details). For these networks, under the assumption that neurons fire with Poisson statistics and the net-
work is in a stationary state, neuronal firing can be approximated by the input-output relation
F of Eq (1) [50, 51] (see Firing rate approximation in Materials and methods), which allows us
to map the network into the general framework of Eqs (1) and (2). In the stationary state, syn-
aptic depression will lead to a saturation of the synaptic activation variables sj at a constant
value as firing rates increase. This nonlinear behavior enables spiking networks to implement
bi-stable attractor dynamics with relatively low firing rates [46, 52] similar to saturating
NMDA synapses [11, 47]. Since we found that without depression (for τx ! 0) the bump state
was not stable at low firing rates (in agreement with [52]), we always keep the depression time-
scale τx at positive values. Particular care was taken to ensure that networks display nearly identical bump shapes
(similar to Fig 1B1, inset; see also S1 Fig), which required the re-tuning of network parameters
(recurrent conductance parameters and the width of distance-dependent connections; see PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1006928
April 19, 2019 5 / 48 Stability of continuous attractor networks under the control of short-term plasticity processes, and that we are able to replace the shot-noise of Poisson spiking by white Gaussian
noise with the same mean and autocorrelation, similar to earlier work [39, 53]; see Diffusion in
Materials and methods, and Discussion. Under these assumptions, we are able to reduce the
network dynamics to a one-dimensional Langevin equation, describing the dynamics of the
center φ(t) of the firing rate profile (see Analysis of drift and diffusion with STP in Materials
and methods): ð4Þ _φ ¼
ffiffiffi
B
p
ZðtÞ þ AðφÞ:
ð4Þ fififi
Here, η(t) is white Gaussian noise with zero mean and correlation function hη(t), η(t0)i = δ(t −t0). η
hη
η
i
The first term is diffusion characterized by a diffusion strength B, which describes the ran-
dom displacement of bump center positions due to fluctuations in neuronal firing. For A(φ) =
0 this term causes diffusive displacement of the center φ(t) from its initial position φ(t0), with a
mean (over realizations) squared displacement of positions h[φ(t) −φ(t0)]2i = B (t −t0) that,
during an initial phase, increases linearly with time [14, 54, 55], before saturating due to the
circular domain of possible center positions [39]. Our theory shows (see Diffusion in Materials
and methods) that the coefficient B can be calculated as a weighted sum over the neuronal fir-
ing rates (Fig 1D) B ¼
X
i
Ci
S
2 dJ0;i
dφ
2
0;i;
ð5Þ ð5Þ where
dJ0;i
dφ is the change of the input to neuron i under shifts of the center position (Fig 1C,
orange line), and S is a normalizing constant that tends to increase additionally with the synap-
tic time constant τs. The analytical factors Ci express the spatial dependence of the diffusion coefficient on the
short-term plasticity parameters through Ci ¼
Uð1 þ 2tu 0;i þ Ut2
u 2
0;iÞ
ð1 þ U 0;iðtu þ txÞ þ Ututx 2
0;iÞ2 :
ð6Þ ð6Þ 1In Brownian motion, the diffusion constant is usually defined as D = B/2. Theory of diffusion and drift with short-term plasticity To untangle the observed interplay between diffusion and drift and investigate the effects of
short-term plasticity, we derived a theory that reduces the microscopic network dynamics to a
simple one-dimensional stochastic differential equation for the bump state. The theory yields
analytical expressions for diffusion coefficients and drift fields, that depend on short-term
plasticity parameters, the shape of the firing rate profile of the bump, as well as the neuron
model chosen to implement the attractor. First, we assume that the system of Eq (3) together with the network Eqs (1) and (2) has a
1-dimensional manifold of meta-stable states, i.e. the network is a ring-attractor network as
described in the introduction. This entails, that the network dynamics permit the existence of
a family of solutions that can be described as a self-sustained and symmetric bump of firing
rates ϕ0,i(φ) = F(J0,i(φ)) with corresponding inputs J0,i(φ) (for 0 i < N). Importantly, the cen-
ter φ of the bump can be located at any arbitrary position φ 2
j
N 2p pj0 j < N
. For
example, if ϕ0,i(0) is a solution with input J0,i(0), then 0;iþ1
2p
N
is also a solution with input
J0;iþ1
2p
N
. This solution is illustrated in Fig 1C for a bump centered at φ = 0. Second, we assume
that the number N of excitatory neurons is large (N ! 1), such that we can think of the possi-
ble positions φ as a continuum. Third, we assume that network heterogeneities are small
enough to capture their effect as a linear (first order) perturbation to the stable bump state. Our final assumption is that neuronal firing is noisy, with spike counts distributed as Poisson PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1006928
April 19, 2019 6 / 48 Stability of continuous attractor networks under the control of short-term plasticity contrast to Eq (5) summands are now asymmetric with respect to the bump center, since the
spatial derivative is not squared. Analytical considerations 0) we
obtain pre-factors Ci=S ¼ ð1 þ 2tu 0;iÞ
P
i
dJ0;i
dφ
2
0
0;i ts 1 þ 2tu 0;i
þ t2
u 0;i
1
, indicat- y
y
Finally, two limiting cases are worth highlighting. First, for strong facilitation (U ! 0) we
obtain pre-factors Ci=S ¼ ð1 þ 2tu 0;iÞ
P
i
dJ0;i
dφ
2
0
0;i ts 1 þ 2tu 0;i
þ t2
u 0;i
1
, indicat- y,
g
g
g
g
,
g
(
)
obtain pre-factors Ci=S ¼ ð1 þ 2tu 0;iÞ
P
i
dJ0;i
dφ
2
0
0;i ts 1 þ 2tu 0;i
þ t2
u 0;i
1
, indicat-
ing that (i) this limit will leave residual drift and diffusion which (ii) will both be controlled
by the time constants for facilitation (τu) and synaptic transmission (τs), with no dependence
upon depression. Second, for vanishing facilitation (U ! 1 and τu ! 0) we find that the nor-
malization factor S will tend to zero if the depression time constant τx is increased to a finite
value τx,c. Through the pre-factors Ci/S this, in turn, yields exploding diffusion and drift
terms (see S8 Fig). While this is a general feature of bump systems with short-term depres-
sion, the exact value of the critical time constant τx,c depends on the firing rates and neural
implementation of the bump state (see section 6 in S1 Text): for the spiking network investi-
gated here, we find a critical time constant τx,c = 223.9ms (see S8 Fig). In networks with
both facilitation and depression, the critical τx,c increases as facilitation becomes stronger
(see S8 Fig). y,
g
g
g
g
,
g
(
)
obtain pre-factors Ci=S ¼ ð1 þ 2tu 0;iÞ
P
i
dJ0;i
dφ
2
0
0;i ts 1 þ 2tu 0;i
þ t2
u 0;i
1
, indicat-
ing that (i) this limit will leave residual drift and diffusion which (ii) will both be controlled
by the time constants for facilitation (τu) and synaptic transmission (τs), with no dependence
upon depression. Second, for vanishing facilitation (U ! 1 and τu ! 0) we find that the nor-
malization factor S will tend to zero if the depression time constant τx is increased to a finite
value τx,c. The dependence of
the single summands in Eq (5) on short-term plasticity parameters is visualized in Fig 1D,
where we see that: a) due to the squared spatial derivative
dJ0;i
dφ of the bump shape and the
squared factors Ci/S, the important contributions to the sum arise primarily from the flanks of
the bump; b) for a fixed bump shape, summands increase with stronger short-term depression
(larger τx) and decrease with stronger short-term facilitation (smaller U, larger τu). The second term in Eq (4) is the drift field A(φ), which describes deterministic drifts due to
the inclusion of heterogeneities. For heterogeneity caused by variations in neuronal reversal
potentials and random network connectivity, we calculate (see Frozen noise in Materials and
methods) systematic deviations Δϕi(φ) of the single neuronal firing rates from the steady-state
bump shape that depend on the current position φ of the bump center. In Drift in Materials
and Methods, we show that the drift field is then given by a weighted sum over the firing rate
deviations: AðφÞ ¼
X
i
Ci
S
dJ0;i
dφ D iðφÞ;
ð7Þ ð7Þ with weighing factors depending on the spatial derivative of the bump shape
dJ0;i
dφ and the param-
eters of the synaptic dynamics through the same factors Ci/S. This is illustrated in Fig 1E: in with weighing factors depending on the spatial derivative of the bump shape
dJ0;i
dφ and the param-
eters of the synaptic dynamics through the same factors Ci/S. This is illustrated in Fig 1E: in PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1006928
April 19, 2019 7 / 48 Analytical considerations Fol-
lowing earlier work [11, 50, 52], we use in our simulations with spiking integrate-and-fire neu-
rons a slow synaptic time constant (τs = 100ms) as an approximation of recurrent (NMDA
mediated) excitation. While our theory captures the effects of changing this time constant τs in
the pre-factors Ci/S, we did not check in simulations whether the bump state remains stable
and whether our theory remains valid for very short time constants for τs. fifififi
In addition to reproducing the previously known scaling with the system size N, our theory
exposes the scaling of both drift and diffusion with the parameters τx, τu, and U of short-term
depression and facilitation via the analytical pre-factors Ci/S appearing in Eqs (5) and (7). Our
result extends the calculation of the diffusion constant [39] to synaptic dynamics with short-
term plasticity: In the limiting case of no facilitation and depression (U ! 1, τx ! 0ms), the
pre-factor reduces to Ci = 1 and the normalization factor simplifies to Sstatic ¼ ts
P
i
dJ0;i
dφ
2
0
0;i,
where 0
0;i ¼ d i
dJi
J0;i
is the derivative of the firing rate of neuron i at its steady-state input J0,i. h
b
h k
l f
d ff
[
] b
l For static synapses we thereby recover the known result for diffusion [39, Eq. S18], but also
add an analogous relation for the drift AstaticðφÞ ¼
P
i
dJ0;i
dφ D iðφÞ
= ts
P
i
dJ0;i
dφ
2 0
0;i
. Our
approach relies on the existence of a stationary bump state (which is stable for large noise-free
homogeneous networks), around which we calculate drift and diffusion as perturbations. Fol-
lowing earlier work [11, 50, 52], we use in our simulations with spiking integrate-and-fire neu-
rons a slow synaptic time constant (τs = 100ms) as an approximation of recurrent (NMDA
mediated) excitation. While our theory captures the effects of changing this time constant τs in
the pre-factors Ci/S, we did not check in simulations whether the bump state remains stable
and whether our theory remains valid for very short time constants for τs. y
y
Finally, two limiting cases are worth highlighting. First, for strong facilitation (U ! Analytical considerations To calculate the diffusion and drift terms of the last section, we assume the number of neurons
N to be large enough to treat the center position φ as continuous: this allows us (similar to
[39]) to derive projection vectors (see Projection of dynamics onto the attractor manifold in
Materials and methods) that yield the dynamics of the center position. However, the actual
projection yields sums over the system size N, whose scaling we made explicit (see System size
scaling in Materials and methods). For the diffusion strength
ffiffiffi
B
p
(cf. Eq (5)) we find a scaling
as as 1=
ffiffiffiffi
N
p
, in agreement with earlier work [11, 14, 36, 39, 46]. For drift fields caused by ran-
dom connectivity, we find a scaling with the connectivity parameter p and the system size N to
leading order as 1=ð
ffiffiffip
p NÞ, whereas drift fields due to heterogeneity of leak potentials (and
other heterogeneous single-neuron parameters) will scale as 1=
ffiffiffiffi
N
p
, both in accordance with
earlier results [16, 36, 38, 46]. fifififi
[
]
In addition to reproducing the previously known scaling with the system size N, our theory
exposes the scaling of both drift and diffusion with the parameters τx, τu, and U of short-term
depression and facilitation via the analytical pre-factors Ci/S appearing in Eqs (5) and (7). Our
result extends the calculation of the diffusion constant [39] to synaptic dynamics with short-
term plasticity: In the limiting case of no facilitation and depression (U ! 1, τx ! 0ms), the
pre-factor reduces to Ci = 1 and the normalization factor simplifies to Sstatic ¼ ts
P
i
dJ0;i
dφ
2
0
0;i,
where 0
0;i ¼ d i
dJi
J0;i
is the derivative of the firing rate of neuron i at its steady-state input J0,i. For static synapses we thereby recover the known result for diffusion [39, Eq. S18], but also
add an analogous relation for the drift AstaticðφÞ ¼
P
i
dJ0;i
dφ D iðφÞ
= ts
P
i
dJ0;i
dφ
2 0
0;i
. Our
approach relies on the existence of a stationary bump state (which is stable for large noise-free
homogeneous networks), around which we calculate drift and diffusion as perturbations. Prediction of continuous attractor dynamics with short-term plasticity To demonstrate the accuracy of our theory, we chose random connectivity as a first source of
frozen variability. Random connectivity was realized in simulations by retaining only a ran-
dom fraction 0 < p 1 (connection probability) of excitatory-to-excitatory (EE) connections. The uniform connections from and to inhibitory neurons are taken as all-to-all, since the
effects of making these random or sparse would have only indirect effects on the dynamics of
the bump center positions. Our theory accurately predicts the drift-fields A(φ) (see Eq (7)) induced by frozen variabil-
ity in networks with short-term plasticity (Fig 2). Briefly, for each neuron 0 i < N, we treat
each realization of frozen variability as a perturbation Δi around the perfectly symmetric sys-
tem and use an expansion to first order of the input-output relation F to calculate the resulting
changes in firing rates (see Frozen noise for details): D iðφÞ ¼ dF
dDi
Di:
ð8Þ ð8Þ The resulting terms are then used in Eq (7) to predict the magnitude of the drift field A(φ) for
any center position φ, which will, importantly, depend on STP parameters. The same approach
can be used to predict drift fields induced by heterogeneous single neuron parameters [36]
(see next sections) and additive noise on the E-E connection weights [16, 38]. (
)
g
We first simulated spiking networks with only short-term depression and without facilita-
tion (Fig 2A, left, same network as in Fig 1B1), for one instantiation of random (p = 0.5)
connectivity. Numerical estimates of the drift in spiking simulations (by measuring the
displacement of bumps over time as a function of their position, see Spiking simulations in
Materials and methods for details) yielded drift-fields in good agreement with the theoretical
prediction (Fig 2B, left). At points where the drift field prediction crosses from positive to neg-
ative values (e.g. Fig 2B, left, φ ¼ p
2), we expect stable fixed points of the center position dynam-
ics in agreement with simulation results, which show trajectories converging to these points. Similarly, unstable fixed points (negative-to-positive crossings) can be seen to lead to a separa-
tion of trajectories (e.g. Fig 2A, left, φ ¼ p
2). In regions where the positional drifts are pre-
dicted to lie close to zero (e.g. Fig 2A, left φ = 0) the effects of diffusive dynamics are more
pronounced. Stability of continuous attractor networks under the control of short-term plasticity Analytical considerations Through the pre-factors Ci/S this, in turn, yields exploding diffusion and drift
terms (see S8 Fig). While this is a general feature of bump systems with short-term depres-
sion, the exact value of the critical time constant τx,c depends on the firing rates and neural
implementation of the bump state (see section 6 in S1 Text): for the spiking network investi-
gated here, we find a critical time constant τx,c = 223.9ms (see S8 Fig). In networks with
both facilitation and depression, the critical τx,c increases as facilitation becomes stronger
(see S8 Fig). PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1006928
April 19, 2019 8 / 48 Prediction of continuous attractor dynamics with short-term plasticity Finally, numerical integration of the full 1-dimensional Langevin equation Eq (4)
with coefficients predicted by Eqs (5)–(7), produces trajectories with dynamics very similar to
the full spiking network (Fig 2C, left). When comparing the center positions after 13.5s of
delay activity between the full spiking simulation and the simple 1-dimensional Langevin sys-
tem, we found very similar distributions of final positions (Fig 2D, left, compare to Fig 1B1,
histogram). Our theory thus produces an accurate approximation of the dynamics of center
positions in networks of spiking neurons with STP, thereby reducing the complex dynamics of
the whole network to a simple equation. It should be noted that, in regions with strong drift or
steep negative-to-positive crossings, the numerically estimated drift-fields deviate from the
theory due to under-sampling of these regions as trajectories move quickly through them,
yielding fewer data points. In Short-term plasticity controls drift we additionally show that the
theory, as it relies on a linear expansion of the effects of heterogeneities on the neuronal firing
rates, tends to generally over-predict drift-fields as heterogeneities become stronger. Introducing strong short-term facilitation (U = 0.1) reduces the predicted drift fields (Fig
2B, left, dashed line), which resemble a scaled-down version of the drift-field for the unfacili-
tated case. We confirmed this theoretical prediction by simulations including facilitation (Fig
2A, right): the resulting drift fields show significant reduction of speeds (Fig 2B, right) while
zero crossings remained similar to the unfacilitated network, similar to the results in [38]. PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1006928
April 19, 2019 9 / 48 Stability of continuous attractor networks under the control of short-term plasticity Fig 2. Drift field predictions for varying short-term facilitation. All networks have the same instantiation of random
connectivity (p = 0.5), similar to Fig 1B1. A Centers of excitatory population activity for 50 repetitions of 13.5s delay
activity, for 20 different positions of initial cues (cue is turned off at t = 0) colored by position of the cues. Left: no
facilitation (U = 1). Right: with facilitation (U = 0.1). B Drift field as a function of the bump position. The theoretical
prediction (blue line, see Eq (7)) of the drift field is compared to velocity estimations along the trajectories shown in A,
colored by the line they were estimated from. The thick black line shows the binned mean of data points in 60 bins. https://doi.org/10.1371/journal.pcbi.1006928.g002 Short-term plasticity controls diffusion To isolate the effects of STP on diffusion, we simulated networks without frozen noise for vari-
ous STP parameters. For each combination of parameters, we simulated 1000 repetitions of
13.5s delay activity (after cue offset) distributed across 20 uniformly spaced initial cue positions
(see Fig 3A for an example). From these simulations, the strength of diffusion was estimated
by measuring the growth of variance (over repetitions) of the distance of the center position
from its initial position as a function of time (see Spiking simulations in Materials and methods
for details). For all parameters considered, this growth was well fit by a linear function (e.g. Fig
3A, inset), the slope of which we compared to the theoretical prediction obtained from the dif-
fusion strength B (Eq (5)). We find that facilitation and depression control the amount of diffusion along the attractor
manifold in an antagonistic fashion (Fig 3B and 3C). First, increasing facilitation by lowering
the facilitation parameter U from its baseline U = 1 (no facilitation) towards U = 0, while keep-
ing the depression time constant τx = 150ms fixed, decreases the measured diffusion strength
over an order of magnitude (Fig 3B, dots). On the other hand, increasing the facilitation time
constant τu from τu = 650ms to τu = 1000ms (Fig 3B, orange and blue dots, respectively) only
slightly reduces diffusion. Our theory further predicts that increasing the facilitation time con-
stants above τu = 1s will not lead to large reductions in the magnitude of diffusion (see S2 Fig). Second, we find that increasing the depression time constant τx for fixed U, thereby slowing
down recovery from depression, leads to an increase of the measured diffusion (Fig 3C). More
precisely, increasing the depression time constant from τx = 120ms to τx = 200ms leads only to
slight increases in diffusion for strong facilitation (U = 0.1), but to a much larger increase for
weak facilitation (U = 0.8). For a comparison of these simulations with our theory, we used two different approaches. First, we estimated the diffusion strength by using the precise shape of the stable firing rate
profile extracted separately for each network with different sets of parameters. This first com-
parison with simulations confirms that the theory closely describes the dependence of diffu-
sion on short-term plasticity for each parameter set (Fig 3B, crosses). Stability of continuous attractor networks under the control of short-term plasticity Theoretical predictions of the drift fields with bump shapes extracted from these simulations
again show an accurate prediction of the dynamics (Fig 2B, right). Thus, as before, forward
integrating the simple 1-dimensional Langevin-dynamics yields trajectories (Fig 2C, right)
highly similar to those of the full spiking network, with closely matching distributions of final
positions (Fig 2D, right), indicative of a matching strength of diffusion. In summary, our the-
ory predicts the effects of STP on the joint dynamics of diffusion and drift due to network het-
erogeneities, which we will show in detail in the next sections. Theoretical predictions of the drift fields with bump shapes extracted from these simulations
again show an accurate prediction of the dynamics (Fig 2B, right). Thus, as before, forward
integrating the simple 1-dimensional Langevin-dynamics yields trajectories (Fig 2C, right)
highly similar to those of the full spiking network, with closely matching distributions of final
positions (Fig 2D, right), indicative of a matching strength of diffusion. In summary, our the-
ory predicts the effects of STP on the joint dynamics of diffusion and drift due to network het-
erogeneities, which we will show in detail in the next sections. Prediction of continuous attractor dynamics with short-term plasticity For
comparison, the predicted drift field for U = 0.1 is plotted (thin dashed line). Left: no facilitation (U = 1), for
comparison the theoretical prediction for the case U = 0.01 is plotted as a dashed line. Right: with facilitation
(U = 0.01). C Trajectories under the same conditions as in A, but obtained by forward-integrating the one-dimensional
Langevin equation, Eq (4). D Normalized histograms of final positions at time t = 13.5 for data from spiking
simulations (gray areas, data from A) and forward solutions of the Langevin equations (blue areas, data from C). Other
STP parameters were: τu = 650ms, τx = 150ms. Fig 2. Drift field predictions for varying short-term facilitation. All networks have the same instantiation of random
connectivity (p = 0.5), similar to Fig 1B1. A Centers of excitatory population activity for 50 repetitions of 13.5s delay
activity, for 20 different positions of initial cues (cue is turned off at t = 0) colored by position of the cues. Left: no
facilitation (U = 1). Right: with facilitation (U = 0.1). B Drift field as a function of the bump position. The theoretical
prediction (blue line, see Eq (7)) of the drift field is compared to velocity estimations along the trajectories shown in A,
colored by the line they were estimated from. The thick black line shows the binned mean of data points in 60 bins. For
comparison, the predicted drift field for U = 0.1 is plotted (thin dashed line). Left: no facilitation (U = 1), for
comparison the theoretical prediction for the case U = 0.01 is plotted as a dashed line. Right: with facilitation
(U = 0.01). C Trajectories under the same conditions as in A, but obtained by forward-integrating the one-dimensional
Langevin equation, Eq (4). D Normalized histograms of final positions at time t = 13.5 for data from spiking
simulations (gray areas, data from A) and forward solutions of the Langevin equations (blue areas, data from C). Other
STP parameters were: τu = 650ms, τx = 150ms. https://doi.org/10.1371/journal.pcbi.1006928.g002 10 / 48 PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1006928
April 19, 2019 Short-term plasticity controls diffusion The observed effects
could arise directly from changes in STP parameters for a fixed bump shape, or indirectly
since STP parameters also influence the shape of the bump. To separate such direct and indi-
rect effects, we used for a second comparison a theory with fixed bump shape, i.e. the bump
shape measured in a “reference network” (U = 1, τx = 150ms) and extrapolated curves by
changing only STP parameters in Eq (5). This leads to very similar predictions (Fig 3B, dashed
lines) and supports the following conclusions: a) the diffusion to be expected in attractor net-
works with similar observable quantities (mainly, the bump shape) depends only on the short-
term plasticity parameters; b) the bump shapes in the family of networks we have investigated
are sufficiently similar to be approximated by measurement in a single reference network. It
should be noted that the theory tends to slightly over-estimate the amount of diffusion, espe-
cially for small facilitation U (see Fig 3B and 3C left). This may be because slower bump move-
ment decreases the firing irregularity of flank neurons, which deviates from the Poisson firing PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1006928
April 19, 2019 11 / 48 Stability of continuous attractor networks under the control of short-term plasticity Fig 3. Diffusion on continuous attractors is controlled by short-term plasticity. A Center positions of 20 repeated
simulations of the reference network (U = 1, τx = 150ms) for 10 different initial cue positions each. Inset: Estimated
variance of deviations of center positions φ(t) from their positions φ(0.5) at t = 0.5s (purple) as a function of time
(h[φ(t) −φ(0.5)]2i), together with linear fit (dashed line). The slope of the dashed line yields an estimate of B (Eq (5)). B,C Diffusion strengths estimated from simulations (dots, error bars show 95% confidence interval, estimated by
bootstrapping) compared to theory. Dashed lines show theoretical prediction using firing rates measured from the
Stability of continuous attractor networks under the control of short-term plasticity Fig 3. Diffusion on continuous attractors is controlled by short-term plasticity. A Center positions of 20 repeated
simulations of the reference network (U = 1, τx = 150ms) for 10 different initial cue positions each. Inset: Estimated
variance of deviations of center positions φ(t) from their positions φ(0.5) at t = 0.5s (purple) as a function of time
(h[φ(t) −φ(0.5)]2i), together with linear fit (dashed line). Short-term plasticity controls drift Having established that our theory is able to predict the effect of STP on diffusion, as well as
drift for a single instantiation of random connectivity, we wondered how different sources of
heterogeneity (frozen noise) would influence the drift of the bump. We considered two sources
of heterogeneity: First, random connectivity as introduced above, and second, heterogeneity of
the leak reversal potential parameters of excitatory neurons: leak reversal potentials of excit-
atory neurons are given by VL + ΔL, where ΔL is normally distributed with zero mean and
standard deviation σL [36]. The resulting fields can be calculated by calculating the resulting
perturbations to the firing rates of neurons by Eq (8) (see Frozen noise in Materials and
methods for details). The theory developed so far allowed us to predict drift-fields for a given realization of fro-
zen noise, controlled by the noise parameters p (for random connectivity) and σL (for hetero-
geneous leak reversal-potentials) (see S3 Fig for a comparison of predicted drift fields to those
measured in simulations for varying STP parameters and varying strengths of frozen noises). We wondered, whether we could take the level of abstraction of our theory one step further, by
predicting the magnitude of drift fields from the frozen noise parameters only, independently
of a specific realization. First, the expectation of drift fields under the distributions of the fro-
zen noises vanishes for any given position: hA(φ)ifrozen = 0, where the expectation h.ifrozen is
taken over both noise parameters. We thus turned to the expected squared magnitude of drift
fields under the distributions of these parameters (see Squared field magnitude in Materials
and methods for the derivation): hA2ifrozen ¼ 1
S2
X
i
C2
i
ð 0
0;iÞ
2
N2
E
1
p 1
X
j
ðs0;jÞ
2 ðwEE
ij Þ
2 þ
d 0;i
dDL
i
2
s2
L
! ;
ð9Þ ð9Þ where s0,j is the steady-state synaptic activation. Here, we introduced the derivatives of the
input-output relation with respect to the noise sources that appear in Eq (8): 0
0;i ¼ dF
dJ ðJ0;iðφÞÞ
is the derivative with respect to the steady state synaptic input, and
d 0;i
dDL
i is the derivative with
respect to the perturbation in the leak potential. Stability of continuous attractor networks under the control of short-term plasticity reference network (U = 1, τx = 150ms), while crosses are theoretical estimates using firing rates measured for each set of
STP parameters separately (crosses). B Diffusion strength as a function of facilitation parameter U. Inset shows zoom
of region indicated in the dashed area in the lower left. Increasing the facilitation time constant τu = 650ms (blue) to
τu = 1s (orange) affects diffusion only slightly. In panels A and B, the depression time constant is τx = 150ms. C
Diffusion strength as a function of depression time constant τx. Results for three different values of U are shown (note
the change in scale). Colors indicate the two different values for the facilitation time constant also used in panel B. https://doi.org/10.1371/journal.pcbi.1006928.g003 assumption of our theory (see Discussion). However, given the simplifying assumptions
needed to derive the theory, the match to the spiking network is surprisingly accurate. Short-term plasticity controls diffusion The slope of the dashed line yields an estimate of B (Eq (5)). B,C Diffusion strengths estimated from simulations (dots, error bars show 95% confidence interval, estimated by
bootstrapping) compared to theory. Dashed lines show theoretical prediction using firing rates measured from the Fig 3. Diffusion on continuous attractors is controlled by short-term plasticity. A Center positions of 20 repeated
simulations of the reference network (U = 1, τx = 150ms) for 10 different initial cue positions each. Inset: Estimated
variance of deviations of center positions φ(t) from their positions φ(0.5) at t = 0.5s (purple) as a function of time
(h[φ(t) −φ(0.5)]2i), together with linear fit (dashed line). The slope of the dashed line yields an estimate of B (Eq (5)). B,C Diffusion strengths estimated from simulations (dots, error bars show 95% confidence interval, estimated by
bootstrapping) compared to theory. Dashed lines show theoretical prediction using firing rates measured from the PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1006928
April 19, 2019 12 / 48 Short-term plasticity controls drift Validation predictions are plotted as crosses. C Same as in panels A,B but varying the depression time constant τx for a fixed level of frozen noise (random
connectivity, p = 0.6). In all panels, the facilitation time constant was τu = 650ms. https://doi.org/10.1371/journal.pcbi.1006928.g004 expected from the parameters that control the frozen noise—in analogy to the standard devia-
tion for random variables, it predicts the standard deviation of the fields. To compare this
quantity to simulations, we varied both heterogeneity parameters. First, the connectivity
parameter p was varied between 0.25 and 1. Second, for heterogeneities in leak reversal-poten-
tials, we chose values for the standard deviation σL of leak-reversal potentials between 0mV
and 1.5mV, which lead to a similar range of drift magnitudes as those of randomly connected
networks. For each combination of heterogeneities and STP parameters (networks had either
random connections or heterogeneous leaks) we then realized 18–20 networks, for which we
simulated 400 repetitions of 6.5s of delay activity each (20 uniformly spaced positions of the
initial cue). We then estimated the drift-field numerically by recording displacements of bump
centers along their trajectories (as in Fig 2A and 2B) and measured the standard deviation of
the resulting fields across all positions. Similar to the analysis of diffusion above, we find that facilitation and depression elicit
antagonistic control over the magnitude of drift fields. In both simulations and theory, we
find (Fig 4A and 4B) that the expected field magnitude decreases as the effect of facilitation
is increased from unfacilitated networks (U = 1) through intermediate levels of facilitation
(U = 0.4) to strongly facilitating networks (U = 0.1). Our theory predicts this effect surprisingly
well, which we validated twofold (as for the diffusion magnitude). First, we used Eq (10) with
all parameters and coefficients estimated from each spiking simulation separately (Fig 4A and
4B, plus-signs and crosses). Second, we extrapolated the theoretical prediction by using coeffi-
cients in Eq (9) from the unfacilitated reference network only (U = 1, τx = 150ms) but changed
the facilitation and heterogeneity parameters (Fig 4A and 4B, dashed lines). The largest differ-
ences between the extrapolated and full theory are seen for U < 1 and randomly connected
networks (p < 1), which we found to result from the fact that bump shapes for these networks
tended to be slightly reduced under random and sparse connectivity (e.g. Short-term plasticity controls drift In Squared field magnitude in Materials and
Methods, we show that Eq (9) is independent of the center position φ, and can be estimated
from simulations as the variance of the drift field across positions, averaged over an ensemble
of network instantiations. We defined the root of the expected squared magnitude of Eq (9) as the expected field mag-
nitude: ffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi
hA2ifrozen
p
:
ð10Þ ð10Þ fififififififififififififififififi
This quantity predicts the magnitude of the deviations of drift-fields from zero that are 13 / 48 PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1006928
April 19, 2019 Stability of continuous attractor networks under the control of short-term plasticity Fig 4. Drift field magnitude is controlled by short-term plasticity. A Expected magnitude of drift fields as a function of the sparsity parameter p of recurrent
excitatory-to-excitatory connections. Dots are the standard deviation of fields estimated from 400 trajectories (see main text) of each network, averaged over 18–20
realizations for each noise parameter and facilitation setting (error bars show 95% confidence of the mean). Theoretical predictions (dashed lines) are given by Eq
(10) extrapolated from the reference network (U = 1, τx = 150). For validation, we also estimated Eq (10) with coefficients measured from each simulated network
separately (plus signs). The depression time constant was τx = 150ms. B Same as in panel A, with heterogeneous leak-reversal potentials as the source of frozen noise. Validation predictions are plotted as crosses. C Same as in panels A,B but varying the depression time constant τx for a fixed level of frozen noise (random
connectivity, p = 0.6). In all panels, the facilitation time constant was τu = 650ms. https://doi.org/10.1371/journal.pcbi.1006928.g004 Fig 4. Drift field magnitude is controlled by short-term plasticity. A Expected magnitude of drift fields as a function of the sparsity parameter p of recurrent
excitatory-to-excitatory connections. Dots are the standard deviation of fields estimated from 400 trajectories (see main text) of each network, averaged over 18–20
realizations for each noise parameter and facilitation setting (error bars show 95% confidence of the mean). Theoretical predictions (dashed lines) are given by Eq
(10) extrapolated from the reference network (U = 1, τx = 150). For validation, we also estimated Eq (10) with coefficients measured from each simulated network
separately (plus signs). The depression time constant was τx = 150ms. B Same as in panel A, with heterogeneous leak-reversal potentials as the source of frozen noise. Short-term plasticity controls memory retention The theory developed in previous sections shows that diffusion and drift of the bump center φ
are controlled antagonistically by short-term depression and facilitation. In a working memory
setup, we can view the attractor dynamics as a noisy communication channel [56] that maps a
set of initial positions φ(t = 0s) (time of the cue offset in the attractor network) to associated
final positions φ(t = 6.5s), after a memory retention delay of 6.5s. We used the distributions of
initial and (associated) final positions to investigate the combined impact of diffusion and drift
on the retention of memories (Fig 5A). Because of diffusion, distributions of positions will
widen over time, which degrades the ability to distinguish different initial positions of the
bump center (Fig 5A, top). Additionally, directed drift of the dynamics will contract distribu-
tions of different initial positions around the same fixed points, making them essentially indis-
tinguishable when read out (Fig 5A, bottom). As a numerical measure of this ability of such systems to retain memories over the delay
period, we turned to mutual information (MI), which provides a measure of the amount of
information contained in the readout position about the initially encoded position [57, 58]. To
measure MI from simulations (see Mutual information measure in Materials and methods), we
analyzed network simulations for varying short-term facilitation parameters (U) and magni-
tudes of frozen noises (p and σL) (same data set as Fig 4A and 4B). We recorded the center
positions encoded in the network at the time of cue-offset (t = 0) and after 6.5s of delay activity,
and used binned histograms (100 bins) to calculate discrete probability distributions of initial
(t = 0) and final positions (t = 6.5). For each trajectory simulated in networks of spiking inte-
grate-and-fire neurons, we then generated a trajectory starting at the same initial position by
using the Langevin equation Eq (4) that describes the drift and diffusion dynamics of center
positions. The MI calculated from the resulting distributions of final positions (again at
t = 6.5) for each network serve as the theoretical prediction for each network. Stability of continuous attractor networks under the control of short-term plasticity order terms. Since in the theory facilitation (and depression) only scales the firing rate pertur-
bations (Eq (7)), these deviations can also be observed across facilitation parameters. Finally,
we performed a similar analysis to investigate the effect of short-term depression on drift
fields. Here, we varied the depression time constant τx for randomly connected networks with
p = 0.6, by simulating networks with combinations of short-term plasticity parameters from
U 2 {0.1, 0.4, 0.8} and τx 2 {120ms, 160ms, 200ms} (Fig 4C). We find that an increase of the
depression time constant leads to increased magnitude of drift fields, which again is well pre-
dicted by our theory. Short-term plasticity controls drift the top firing rate is
reduced to 35Hz for U = 0.1, p = 0.25). Generally, as noise levels increase, our theory tends
to over-estimate the squared magnitude of fields, since we rely on a linear expansion of pertur-
bations to the firing rates to calculate fields (Eq (8)). Such deviations are expected as the mag-
nitude of firing rate perturbations increases, and could be counter-acted by including higher- PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1006928
April 19, 2019 14 / 48 Stability of continuous attractor networks under the control of short-term plasticity Fig 5. Short-term facilitation increases memory retention. A Illustration of the effects of diffusion (top) and additional drift (bottom) on the temporal evolution
of distributions of initial positions p(start) towards distributions of final positions p(end) over 6.5s of delay activity. The bump is always represented by its center
position φ. Two peaks in the distribution of initial positions φ(0) and their corresponding final positions φ(6.5) are highlighted by colors (purple, red), together
with example trajectories of the center positions. Top: Diffusion symmetrically widens the initial distribution. Bottom: Strong drift towards one single fixed point
of bump centers (φ = 0) makes the origin of trajectories indistinguishable. B Normalized mutual information (MI, see text for details) of distributions of initial and
final bump center positions in working memory networks for different STP parameters and heterogeneity parameters(blue: strong facilitation, see legend in panel
D). Dots and triangles are average MI (18–20 realizations, error bars show 95% CI) obtained from spiking network simulations. Lines show average MI calculated
from Langevin dynamics for the same networks, repetitions and realizations (see text, shaded area shows 95% CI). Heterogeneity parameters are σL (triangles, in
units of mV) and 1 −p (circles), where p is the connection probability. C Expected displacement |Δφ|(1s) for the same networks as in panel B. Dashed lines indicate
displacement induced by diffusion only (
ffiffiffi
B
p
), solid lines show the total displacement (including displacement due to drift, calculated as the expected field
magnitude
ffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi
hA2ifrozen
p
). D Same as panel B, with x-axis showing the expected field magnitude. E Same as panel B, with x-axis showing the expected displacement. In panels B-D, all STP parameters except U were kept constant at τu = 650ms, τx = 150ms. https://doi.org/10.1371/journal.pcbi.1006928.g005 Fig 5. Short-term facilitation increases memory retention. A Illustration of the effects of diffusion (top) and additional drift (bottom) on the temporal evolution
of distributions of initial positions p(start) towards distributions of final positions p(end) over 6.5s of delay activity. The bump is always represented by its center
position φ. Two peaks in the distribution of initial positions φ(0) and their corresponding final positions φ(6.5) are highlighted by colors (purple, red), together
with example trajectories of the center positions. Top: Diffusion symmetrically widens the initial distribution. Short-term plasticity controls memory retention As a reference,
we used the spiking network without facilitation (U = 1, τu = 650ms, τx = 150ms) and no frozen
noises (p = 1, σL = 0mV) and normalized the MI of all other networks (both for spiking simula-
tions and theoretical predictions) with respect to the reference, yielding the measure of relative
MI presented in Fig 5B–5E. We found that the relative MI decreased compared to the reference network as network
heterogeneities were introduced (Fig 5B, green). This was expected, since directed drift caused
by heterogeneities leads to a loss of information about initial positions. There were two effects
of increased short-term facilitation (by decreasing the parameter U). First, diffusion was
reduced, which was visible in a vertical shift of the relative MI for facilitated networks (Fig 5A,
orange and blue, at 0 heterogeneity). Second, the effects of frozen noise decreased with increas-
ing facilitation, which was visible in the slopes of the MI decrease (see also S4 Fig). The MI
obtained by integration of the Langevin equations (see above) matched those of the simula-
tions well (Fig 5A, lines). From earlier results, we expected the drift-fields to be slightly over-
estimated by the theory as the heterogeneity parameters increase (Fig 4), which would lead to PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1006928
April 19, 2019 15 / 48 Combining the effects of both diffusion and drift into a single
quantity for each network, we replaced the field A(φ) by our theoretical prediction
ffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi
hA2ifrozen
p
in Eq (4) and forward integrated the differential equation for a time interval Δt = 1s, to arrive
at the expected displacement in 1s: jDφjð1sÞ ¼
ffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi
hA2ifrozen
p
1s þ
ffiffiffiffiffiffiffiffiffiffiffi
B 1s
p
:
ð11Þ ð11Þ fifififififififififififififififififififififififififififi
This quantity describes the expected absolute value of displacement of center positions during
1s: it increases as a function of the frozen noise distribution parameters (Fig 5C), but even in PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1006928
April 19, 2019 16 / 48 Stability of continuous attractor networks under the control of short-term plasticity Fig 6. Short-term depression decreases memory retention. A Same as Fig 5B, for network simulations with varying
τx and U (see legend in panel B). MI is normalized to the same value as there. B Same as panel A, with x-axis showing
the expected displacement. Gray data points and lines are the data plotted in Fig 5E. The facilitation time constant was
kept constant at τu = 650ms. https://doi org/10 1371/journal pcbi 1006928 g006 Fig 6. Short-term depression decreases memory retention. A Same as Fig 5B, for network simulations with varying
τx and U (see legend in panel B). MI is normalized to the same value as there. B Same as panel A, with x-axis showing
the expected displacement. Gray data points and lines are the data plotted in Fig 5E. The facilitation time constant was
kept constant at τu = 650ms. https://doi org/10 1371/journal pcbi 1006928 g006 https://doi.org/10.1371/journal.pcbi.1006928.g006 the absence of frozen noise it is nonzero due to diffusion. Plotting the MI data in dependence
of the first term only (
ffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi
hA2ifrozen
p
), shows that the MI curves collapse onto a single curve for
each facilitation parameter (Fig 5D). Finally, plotting the MI data against |Δφ|(1s) we find that
all data collapse on to nearly a single curve (Fig 5E). Thus, the effects of the two sources of fro-
zen noise (corresponding to hA2ifrozen) and diffusion (corresponding to B) are unified into a
single quantity |Δφ|(1s). We performed the same analyses on a large set of network simulations with fixed random
connectivity (p = 0.6) and varying STP parameters for both depression (τx) and facilitation (U)
(same data set as in Fig 4C). Bottom: Strong drift towards one single fixed point
of bump centers (φ = 0) makes the origin of trajectories indistinguishable. B Normalized mutual information (MI, see text for details) of distributions of initial and
final bump center positions in working memory networks for different STP parameters and heterogeneity parameters(blue: strong facilitation, see legend in panel
D). Dots and triangles are average MI (18–20 realizations, error bars show 95% CI) obtained from spiking network simulations. Lines show average MI calculated
from Langevin dynamics for the same networks, repetitions and realizations (see text, shaded area shows 95% CI). Heterogeneity parameters are σL (triangles, in
units of mV) and 1 −p (circles), where p is the connection probability. C Expected displacement |Δφ|(1s) for the same networks as in panel B. Dashed lines indicate
displacement induced by diffusion only (
ffiffiffi
B
p
), solid lines show the total displacement (including displacement due to drift, calculated as the expected field
magnitude
ffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi
hA2ifrozen
p
). D Same as panel B, with x-axis showing the expected field magnitude. E Same as panel B, with x-axis showing the expected displacement. In panels B-D, all STP parameters except U were kept constant at τu = 650ms, τx = 150ms. https://doi org/10 1371/journal pcbi 1006928 g005 https://doi.org/10.1371/journal.pcbi.1006928.g005 an under-estimation of MI. We did observe this here, although for U = 1 the effect was slightly
counter-balanced by the under-estimated level of diffusion (cf. Fig 3A, right), which we
expected to increase the MI. For networks with stronger facilitation (U = 0.1), we systemati-
cally over-estimated diffusion (cf. Fig 3, left), and therefore under-estimated MI. Using our theory, we were able to simplify the functional dependence between MI, short-
term plasticity, and frozen noise. Increasing the short-term depression time constant τx leads to
decreased relative MI with a positive offset induced through stronger facilitation (Fig 6A, blue
line). Calculating the expected displacement for these network configurations collapsed the
data points mostly onto the same curve as earlier (Fig 6B). For strong depression combined
with weak facilitation (τx = 200ms, U = 0.8), the drop-off of the relative MI saturates earlier,
indicating that for these strongly diffusive networks the effect on MI may not be sufficiently
captured by its relationship to |Δφ|(1s). Linking theory to experiments: Distractors and network size https://doi.org/10.1371/journal.pcbi.1006928.g007 Fig 7. Effect of short-term plasticity on distractor inputs. A While a bump (“Bump”) is centered at an initial angle
φ0 (chosen to be 0), additional external input causes neurons centered around the position φD to fire at elevated rates
(“Distractor”). The theory predicts the shape and magnitude of the induced drift field (“Field”) and the mean bump
center φ1 after 250ms of distractor input. Gray trajectories are example simulations of bump centers of the
corresponding Langevin equation Eq (4). B Mean final positions φ1 of bump centers (1000 repetitions, shaded areas
show 1 standard deviation) as a function of the distractor input location φD. Increased short-term facilitation (blue:
strong facilitation, U = 0.1; orange: intermediate facilitation, U = 0.4; green: no facilitation U = 1) leads to less
displacement due to the distractor input. Other STP parameters were kept constant at τu = 650ms, τx = 150ms. C Same
as panel B, for three different depression time constants τx, while keeping U = 0.8, τu = 650ms fixed. D Same as panel B,
with a broader bump half-width (σg = 0.8rad 45.8 deg). All other panels use the same bump half-width as in the rest
of the study (σg = 0.5rad 28.7 deg) (see S1 Fig). https://doi.org/10.1371/journal.pcbi.1006928.g007 https://doi.org/10.1371/journal.pcbi.1006928.g007 [11, 47, 59] have proposed to use distractor inputs (Fig 7A): providing a short external input
centered around a position φD to the network, the center position of an existing bump state
will be biased towards the distracting input, with stronger biases appearing for closer distrac-
tors. In the context of our theory, we consider a weak distractor as an additional heterogeneity
that induces drift. Therefore the time scale of bump drift caused by distractor-induced hetero-
geneity enables us link our theory to behavioral experiments [59]. Our theory can readily yield quantitative predictions for the distractor paradigm. To
accommodate distractor inputs in the theory, we assume that they cause some units i to fire at
elevated rates ϕ0,i + Δϕi, which will introduce a drift field according to Eq (7) (Fig 7A, purple
dashed line). The resulting dynamics (Eq (4)) of diffusion and drift during the presentation of
the distractor input then allow us to calculate the expected shift of center positions as a func-
tion of all network parameters, including those of short-term plasticity. Linking theory to experiments: Distractors and network size The abstraction of our theory condenses the complex dynamics of bump attractors in spiking
integrate-and-fire networks into a high-level description of a few macroscopic features, which
in turn allows matching the theory to behavioral experiments. Here, we demonstrate how such
quantitative links could be established using two different features: 1) the sensitivity of the
working memory circuit to distractors, and 2) the stability of working memory expressed by
the expected displacement. We stress that our model is a simplified description of biological
circuits, in which several further sources of variability and also dynamical processes influenc-
ing displacement should be expected (see Discussion). Thus, at the current level of simplifica-
tion, the results presented in this section should be seen as proofs of principle rather than
quantitative predictions for a cortical setting. Predicting the sensitivity to distractor inputs. In a biological setting, drifts introduced
by network heterogeneities (frozen noise) could be significantly reduced by (long-term) plas-
ticity [36]. To measure the intrinsic stability of continuous attractor models, earlier studies PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1006928
April 19, 2019 17 / 48 Stability of continuous attractor networks under the control of short-term plasticity Fig 7. Effect of short-term plasticity on distractor inputs. A While a bump (“Bump”) is centered at an initial angle
φ0 (chosen to be 0), additional external input causes neurons centered around the position φD to fire at elevated rates
(“Distractor”). The theory predicts the shape and magnitude of the induced drift field (“Field”) and the mean bump
center φ1 after 250ms of distractor input. Gray trajectories are example simulations of bump centers of the
corresponding Langevin equation Eq (4). B Mean final positions φ1 of bump centers (1000 repetitions, shaded areas
show 1 standard deviation) as a function of the distractor input location φD. Increased short-term facilitation (blue:
strong facilitation, U = 0.1; orange: intermediate facilitation, U = 0.4; green: no facilitation U = 1) leads to less
displacement due to the distractor input. Other STP parameters were kept constant at τu = 650ms, τx = 150ms. C Same
as panel B, for three different depression time constants τx, while keeping U = 0.8, τu = 650ms fixed. D Same as panel B,
with a broader bump half-width (σg = 0.8rad 45.8 deg). All other panels use the same bump half-width as in the rest
of the study (σg = 0.5rad 28.7 deg) (see S1 Fig). Stability of continuous attractor networks under the control of short-term plasticity (cell-intrinsic) stabilization mechanism [47]. Conversely, we predict that longer recovery
from short-term depression tends to increase the sensitivity to distractors (Fig 7C). The total
displacement caused by a distractor input is found by integrating the resulting dynamics of Eq
(4) over the stimulus duration. As such, the magnitude of the displacement will increase both
with the amplitude and the duration of the distractor input. Finally, our theory demonstrates
that the bump shape, in particular the width of the bump, influence the radial reach of distrac-
tor inputs (Fig 7D). Relating displacement to network size in working memory networks. The simple theo-
retical measure of expected displacement |Δφ|(1s) introduced in the last section can be related
to behavioral experiments: a value of |Δφ|(1s) = 1.0 deg lies in the upper range of experimen-
tally reported deviations due to diffusive and systematic errors in behavioral studies [60, 61]. What are the microscopic circuit compositions that can attain such a (high) level of working
memory stability? In particular, since an increase in network size can reduce diffusion [11]
and the effects of random heterogeneities [16, 36, 38, 46], we turned to the question: which net-
works size would be needed to yield this level of stability in a one-dimensional continuous mem-
ory system? To address the question of network size, we extended our theory to include the size N of
the excitatory population as an explicit parameter (see System size scaling in Materials and
methods for details). Using numerical coefficients in Eq (4) extracted from the spiking simu-
lation of a reference network (U = 1, τx = 150 and NE = 800), we extrapolated the theory by
changing the system size N and short-term plasticity parameters. We then constrained
parameters of our theory by published data (Table 1). Short-term plasticity parameters were
based on two groups of strongly facilitating synapses found in a study of mammalian (ferret)
prefrontal cortex [62]. The same study reported a general probability p = 0.12 of pyramidal
cells to be connected. However, for pairs of pyramidal cells that were connected by facilitat-
ing synapses, the study found a high probability of reciprocal connections (prec = 0.44): thus
if neuron A was connected to neuron B (with probability p), neuron B was connected to neu-
ron A with high probability (prec), resulting in a non-random connectivity. Linking theory to experiments: Distractors and network size Repeating this para-
digm for varying positions of the distractor inputs (see Distractor analysis in Materials and
methods for details), our theory predicts that strong facilitation will strongly decrease both the
effect and radial reach of distractor inputs (Fig 7B, blue), when compared to the unfacilitated
system (Fig 7B, green)—in qualitative agreement with simulation results involving a related PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1006928
April 19, 2019 18 / 48 Theoretical predictions of Eq (11) optimized for the number of excitatory neurons N that are needed to achieve a given level of expected displacement |Δφ|(1s) under
given parameters of short-term plasticity and frozen noises. RS: regular spiking pyramidal cells, fa-RS: fast-adapting regular spiking pyramidal cells. Stability of continuous attractor networks under the control of short-term plasticity For the standard deviation of leak reversal-potentials σL, we used values measured in two
studies [63, 64]. The resulting theory makes quantitative predictions for combinations of network size N
and all other parameters that yield the desired levels of working memory stability (Table 1,
see also S5 Fig). Network sizes were all smaller than 106 neurons, with values depending
most strongly on the value of the facilitation parameter U and the magnitude of the leak
reversal-potential heterogeneities σL. Since the expected field magnitude scales weakly
(1=
ffiffiffip
p ) with the recurrent connectivity p, increasing p lead only to comparatively small
decreases in the predicted network sizes. Finally, we see that the increasing the reliability of
networks comes at a high cost: decreasing the expected displacement to |Δφ|(1s) = 0.5 deg
[60] increases the required number of neurons by nearly a number of 4 for both facilitation
settings we investigated. Nevertheless, these network sizes still lie within anatomically rea-
sonable ranges [65]. In summary, we have provided a proof of principle, that the high-level description of our
theory can be used to predict network sizes, by exposing features that can be constrained by
experimental measurements. Given the simplifying assumptions of our models and the sources
of variability that we could include at this stage, continuous attractor networks with realistic
values for the strength of facilitation and depression of recurrent connections could achieve
sufficient stability, even in the presence of biological variability. To approximate
this in the random connectivities supported by our theory, we evaluated a second, slightly
elevated, level of random connectivity, that has the same mean connection probability as the
non-random connectivity with these additional reciprocal connections: p + p prec = 0.1728. Table 1. Upper bounds on system-sizes for stable continuous attractor memory in prefrontal cortex. STP parameters
Δφ(1s)
p
σL
Network size N
U = 0.17
τu = 563ms
τx = 242ms
[62, E1b]
1.0 deg [60, 61]
0.12
[62]
1.7mV [63, RS]
79 504
2.4mV [64, fa-RS]
127 465
0.1728
[62]
1.7mV
79 047
2.4mV
127 205
0.5 deg [60]
0.12
2.4mV
507 607
U = 0.35
τu = 482ms
τx = 163ms
[62, E1a]
1.0 deg
0.12
1.7mV
102 292
2.4mV
163 896
0.1728
1.7mV
101 836
2.4mV
163 638
0.5 deg
0.12
2.4mV
653 350
Theoretical predictions of Eq (11) optimized for the number of excitatory neurons N that are needed to achieve a given level of expected displacement |Δφ|(1s) under
given parameters of short-term plasticity and frozen noises. RS: regular spiking pyramidal cells, fa-RS: fast-adapting regular spiking pyramidal cells. https://doi.org/10.1371/journal.pcbi.1006928.t001 pper bounds on system-sizes for stable continuous attractor memory in prefrontal cortex. Theoretical predictions of Eq (11) optimized for the number of excitatory neurons N that are needed to achieve a given level of expected displacement |Δφ|(1s) under
given parameters of short-term plasticity and frozen noises. RS: regular spiking pyramidal cells, fa-RS: fast-adapting regular spiking pyramidal cells. PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1006928
April 19, 2019 19 / 48 Stability of continuous attractor networks under the control of short-term plasticity In Section Linking theory to experiments: Distractors and network size, we demonstrated
that the high-level description of the microscopic dynamics obtained by our theory allows its
parameters to be constrained by experiments. Considering that our model is a simplified
description of its biological counterparts (see next paragraph), these demonstrations are to be
seen as a proof of principle as opposed to quantitative predictions. However, since distractor
inputs can be implemented in silico as well as in behavioral experiments (see e.g. [59]), they
could eventually provide a quantitative link between continuous attractor models and working
memory systems, by matching the resulting distraction curves. Our theory goes beyond previ-
ous models in which these distraction curves had to be extracted through repeated microscopic
simulations for single parameter settings [47]. We further used our theory to derive bounds on
network parameters, in particular the size of networks, that lead to “tolerable” levels of drift
and diffusion in the simplified model. For large magnitudes of frozen noise our theory tends
to over-estimate the expected magnitude of drift-fields slightly (cf. Fig 4). Thus, we expect the
predictions made here to be upper bounds on network parameters needed to achieve a certain
expected displacement. Finally, while the predictions of our theory might deviate from biologi-
cal networks, they could be applied to accurately characterize the stability of, and the effects
of inputs to, bump attractor networks implemented in neuromorphic hardware for robotics
applications [69]. Our results show, that strong facilitation (small values of U) does not only slow down
directed drift [38], but also efficiently suppresses diffusion in spiking continuous attractor
models. However, in delayed response tasks involving saccades, that presumably involve con-
tinuous attractors in the prefrontal cortex [11, 22], one does observe an increase of variability
in time [66]: quickly accumulating systematic errors (alike drift) [61] as well as more slowly
increasing variable errors (with variability growing linear in time, alike diffusion) have been
reported [60]. Indeed, there are several other possible sources of variability in cortical working
memory circuits, which we did not consider here. In particular, we expect that heterogeneous
STP parameters [62], noisy synaptic transmission and STP [70] or noisy recurrent weights
[38] (see Random and heterogeneous connectivity in Materials and methods), for example, will
induce further drift and diffusion beyond the effects discussed in this paper. Discussion We presented a theory of drift and diffusion in continuous working memory models, exempli-
fied on a one-dimensional ring attractor model. Our framework generalizes earlier approaches
calculating the effects of fast noise by projection onto the attractor manifold [37, 39, 40] by
including the effects of short-term plasticity (see [45] for a similar analysis for facilitation
only). Our approach further extends earlier work on drift in continuous attractors with short-
term plasticity [38] to include diffusion and the dynamics of short-term depression. Our the-
ory predicts that facilitation makes continuous attractors robust against the influences of both
dynamic noise (introduced by spiking variability) and frozen noise (introduced by biological
variability) whereas depression has the opposite effect. We use this theory to provide, together
with simulations, a novel quantitative analysis of the interaction of facilitation and depression
with dynamic and frozen noise. We have confirmed the quantitative predictions of our theory
in simulations of a ring-attractor implemented in a network model of spiking integrate-and-
fire neurons with synaptic facilitation and depression, and found theory and simulation to be
in good quantitative agreement. In Section Short-term plasticity controls memory retention, we demonstrated the effects of
STP on the information retained in continuous working memory. Using our theoretical pre-
dictions of drift and diffusion we were able to derive the expected displacement |Δφ| as a func-
tion of STP parameters and the frozen noise parameters, which provides a simple link between
the resulting Langevin dynamics of bump centers and mutual information (MI) as a measure
of working memory retention. Our results can be generalized in several directions. First, the
choice of 1s of forward integrated time for |Δφ| (Eq (11)) was arbitrary. While a choice of 2s
lets the curves in Fig 5E collapse slightly better, we chose 1s to avoid further heuristics. Second,
we expect values of MI to decrease as the length of the delay period is increased. Our choice of
6.5s is comparable to delay periods often considered in behavioral experiments (usually 3-6s)
[61, 66, 67]. However, a more rigorous link between the MI measure and the underlying
attractor dynamics would be desirable. Indeed, for noisy channels governed by Fokker-Planck
equations, this might be feasible [68], but goes beyond the scope of this work. PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1006928
April 19, 2019 20 / 48 Stability of continuous attractor networks under the control of short-term plasticity deviations). Although not investigated here, continuous line-attractors arising through a dif-
ferent weight-symmetry should be amenable to similar analyses [39]. Finally, it should be
noted that adequate structuring of the recurrent connectivity can also positively affect the sta-
bility of continuous attractors [14]. For example, translational asymmetries included in the
structured heterogeneity can break the continuous attractor into several isolated fixed points,
which can lead to decreased diffusion along the attractor manifold [58]. We provided evidence that short-term synaptic plasticity controls the sensitivity of attractor
networks to both fast diffusive and frozen noise. Control of short-term plasticity via neuromo-
dulation [76] would thus represent an efficient “crank” for adapting the time scales of compu-
tations in such networks. For example, while cortical areas might be specialized to operate in
certain temporal domains [7, 77], we show that increasing the strength of facilitation in a task-
dependent fashion could yield slower and more stable dynamics, without changing the net-
work connectivity. On the other hand, modulating the time scales of STP could provide higher
flexibility in resetting facilitation-stabilized working memory systems to prepare them for new
inputs [47], although there might be evidence for residual effects of facilitation between trials
[45, 78]. By changing the properties of presynaptic calcium entry [79], inhibitory modulation
mediated via GABAB and adenosine A1 receptors can lead to increased facilitatory compo-
nents in rodent cerebellar [80] and avian auditory synapses [81]. Dopamine, serotonin and
noradrenaline have all been shown to differentially modulate short-term depression (and facil-
itation when blocking GABA receptors) at sensorimotor synapses [82]. Interestingly, next to
short-term facilitation on the timescale of seconds, other dynamic processes up-regulate recur-
rent excitatory synaptic connections in prefrontal cortex [62]: synaptic augmentation and
post-tetanic potentiation operate on longer time scales (up to tens of seconds), and might be
able to support working memory function [83]. While the long time scales of these processes
might again render putative short-term memory networks inflexible, there is evidence that
they might also be under tight neuromodulatory control [84]. Finally, any changes in recurrent
STP properties of continuous attractors (without retuning networks as done here) will also
lead to changes in the stable firing rate profiles, with further effects on their dynamical stability
(see final section of the Discussion). This interplay of effects remains to be investigated in
more detail. Additionally, vari-
able errors might be introduced elsewhere in the pathway between visual input and motor out-
put (but see [71]) or by input from other noisy local circuits during the delay period [72]. Note
that we excluded AMPA currents from the recurrent excitatory interactions [11]. However,
since STP acts by presynaptic scaling of neurotransmitter release, it will act symmetrically on
both AMPA and NMDA receptors so that an analytical approach similar to the one presented
here is expected to work. Several additional dynamical mechanisms might also influence the stability of continuous
attractor working memory circuits. For example, intrinsic neuronal currents that modulate the
neuronal excitability [47] or firing-rate adaptation [73] affect bump stability. These and other
effects could be accommodated in our theoretical approach by including their linearized
dynamics in the calculation of the projection vector (cf. Projection of dynamics onto the
attractor manifold in Materials and methods). Fast corrective inhibitory feedback has also
been shown to stabilize spatial working memory systems in balanced networks [74]. On the
timescale of hours to days, homeostatic processes counteract the drift introduced by frozen
noise [36]. Finally, inhibitory connections that are distance-dependent [11] and show short-
term plasticity [75] could also influence bump dynamics. We have focused here on ring-attractor models that obtain their stable firing-rate profile
due to perfectly symmetric connectivity. Our approach can also be employed to analyze ring-
attractor networks with short-term plasticity in which weights show (deterministic or stochas-
tic) deviations from symmetry (see Frozen noise in Materials and methods for stochastic PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1006928
April 19, 2019 21 / 48 Stability of continuous attractor networks under the control of short-term plasticity reduction from 26 to 16 deg2/s for a similar setting of facilitation U. These differences
might arise from an increasing width of the bump attractor profile for growing facilitation
time constants in [47], which would then lead to increased diffusion in our model. Whether
this effect persists under the two-equation model of saturating NMDA synapses used there
remains to be investigated. Finally, increasing the time constant of recurrent NMDA conduc-
tances has been shown to also reduce diffusion [47], in agreement with our theory, according
to which the normalization constant S increases with τs [39]. A study performed in parallel to ours [45] used a similar theoretical approach to calculate
diffusion with short-term facilitation in a rate-based model with external additive noise, but
did not compare the results for varying facilitation parameters. The authors report a short ini-
tial transient of stronger diffusion as synapses facilitate, followed by weaker diffusion that is
dictated by the fully facilitated synapses. Our theory, by assuming all synaptic variables to be at
steady-state, disregards the initial strong phase of diffusion. We also disregarded such initial
transients when comparing to simulations (see Numerical methods). In a study that investigated only a single parameter value for depression (τx = 160ms, no
facilitation) in a network of spiking integrate-and-fire neurons similar to the one investigated
here, the authors observed no apparent effect of short-term depression on the stability of the
bump [44]. In contrast, we find that stronger short-term depression will indeed increase both
diffusion and directed drift along the attractor. Our result agrees qualitatively with earlier stud-
ies in rate models, which showed that synaptic depression, similar to neuronal adaptation [10,
85], can induce movement of bump attractors [42, 43, 86, 87]. In particular, simple rate models
exhibit a regime where the bump state moves with constant speed along the attractor manifold
[42]. We did not find any such directed movement in our networks, which could be due to fast
spiking noise which is able to cancel directed bump movement [85]. Comparison to earlier work Similar to an earlier theoretical approach using a simplified rate model [38], we find that the
slowing of drift by facilitation depends mainly on the facilitation parameter U, while the time
constant τu has a less pronounced effect. While the approach of [38] relied on the projection of
frozen noise onto the derivative of the first spatial Fourier mode of the bump shape along the
ring, here we reproduce and extend this result (1) for arbitrary neuronal input-output relations
and (2) a more detailed spatial projection that involves the full synaptic dynamics and the
bump shape. While, our theory can also accommodate noisy recurrent connection weights as
frozen noise, as used in in [38] (see Frozen noise in Materials and methods for derivations), the
drifts generated by these heterogeneities were generally small compared to diffusion and the
other sources of heterogeneity. A second study investigated short-term facilitation and showed that it reduces drift and dif-
fusion in a spiking network, for a fixed setting of U (although the model of short-term facilita-
tion differs slightly from the one employed here) [47]. Contrary to what we find here, these
authors find that an increase in τu leads to increased diffusion, while we find that an increase
over the range they investigated ( 0.5s −4s) would decrease the diffusion by a factor of nearly
two. More precisely, for our shape of the bump state (which we keep fixed) we predict a 22 / 48 PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1006928
April 19, 2019 Stability of continuous attractor networks under the control of short-term plasticity Our networks of spiking integrate-and-fire neurons are tuned to display balanced inhibi-
tion and excitation in the inhibition dominated uniform state [53, 89], while the bump state
relies on positive currents, mediated through strong recurrent excitatory connections (cf. [44]
for an analysis). Similar to other spiking network models of this class, this mean–driven bump
state shows relatively low variability of neuronal inter-spike-intervals of neurons in the bump
center [90, 91] (see also next paragraph). Nevertheless, neurons at the flanks of the bump still
display variable firing, with statistics close to that expected of spike trains with Poisson statis-
tics (see S7 Fig), which may be because the flank’s position slightly jitters. Since the non-zero
contributions to the diffusion strength are constrained to these flanks (cf. Fig 1D), the simple
theoretical assumption of Poisson statistics of neuronal firing still matches the spiking network
quite well. As discussed in Short-term plasticity controls diffusion, we find that our theory over-
estimates the diffusion as bump movement slows down for small values of U—this may be due
to a decrease in firing irregularity in stable bumps in particular in the flank neurons, at which
the Poisson assumption becomes inaccurate. More recent bump attractor approaches allow networks to perform working memory func-
tion with a high firing variability also during the delay period [3], in better agreement with
experimental evidence [92]. These networks show bi-stability, where both stable states show
balanced excitation and inhibition [90] and the higher self-sustained activity in the delay activ-
ity is evoked by an increase in fluctuations of the input currents (noise-driven) rather than an
increase in the mean input [93]. This was also reported for a ring-attractor network (with dis-
tance-dependent connections between all populations), where facilitation and depression are
crucial for irregularity of neuronal activity in the self-sustained state [46]. Application of our
approach to these setups is left for future work. Extensions and shortcomings The coefficients of Eq (4) give clear predictions as to how drift and diffusion will depend on
the shape of the bump state and the neural transfer function F. The relation is not trivial,
since the pre-factors Ci and the normalization constant S also depend on the bump shape. For the diffusion strength Eq (5), we explored this relation numerically, by artificially varying
the shape of the firing rate profile (while extrapolating other quantities). Although a more
thorough analysis remains to be performed, a preliminary analysis shows (see S6 Fig) that
diffusion increases both with bump width and top firing rate, consistent with earlier findings
[11, 32]. Our theory can be used to predict the shape and effect of drift fields that are generated by
localized external inputs due to distractor inputs; see Section Linking theory to experiments:
Distractors and network size. Any localized external input (excitatory or inhibitory) will cause
a deviation Δϕi from the steady-state firing rates, which, in turn, generates a drift field by Eq
(7). This could predict the strength and location of external inputs that are needed to induce
continuous shifts of the bump center at given speeds, for example when these attractor net-
works are designed to track external inputs (see e.g. [10, 88]). It should be noted that in our
simple approximation of this distractor scheme, we assume the system to remain at approxi-
mately steady-state, i.e. that the bump shape is unaffected by the additional external input,
except for a shift of the center position. For example, we expect additional feedback inhibition
(through the increased firing of excitatory neurons caused by the distractor input) to decrease
bump firing rates. A more in depth study and comparison to simulations will be left for further
work. 23 / 48 PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1006928
April 19, 2019 Stability of continuous attractor networks under the control of short-term plasticity equivalent of Eq (3):
_dy
¼
1
ts
I þ D u0 x0 ~ 0
0
W
D
~ 0 x0
D
~ 0 u0
UD
ð1 u0Þ ~ 0
0
W
1
tu
I UD ~ 0
0
D
u0 x0 ~ 0
0
W
D
x0 ~ 0
1
tx
I D ~ 0 u0
0
B
B
B
B
B
B
B
B
B
@
1
C
C
C
C
C
C
C
C
C
A
dy
Kdy
ð13Þ equivalent of Eq (3): ð13Þ Here, dots between vectors indicate element-wise multiplication, the operator D : Rn ! Rnn
creates diagonal matrices from vectors, and W = (wij) is the synaptic weight matrix of the
network. Projection of dynamics onto the attractor manifold. To project the dynamical system
Eq (13) onto movement of the center position φ of the firing rate profile, we assume that N is
large enough to treat the center position φ as a continuous variable. We also assume that the
network implements a ring-attractor: the system dynamics are such that the firing rate profile Projection of dynamics onto the attractor manifold. To project the dynamical system
Eq (13) onto movement of the center position φ of the firing rate profile, we assume that N is
large enough to treat the center position φ as a continuous variable. We also assume that the
network implements a ring-attractor: the system dynamics are such that the firing rate profile
~ 0 can be freely shifted to different positions along the ring, changing the center position φ,
while retaining the same shape. All other possible directions of change in this system are
assumed to be constrained by the system dynamics. In the system at hand, this implies that the
matrix K of Eq (13), which captures the linearized dynamics around any of these fixed points,
will have a zero eigenvalue corresponding to the eigenvector of a change of the dynamical vari-
ables under a change of position φ, while all other eigenvalues are negative [39]. Analysis of drift and diffusion with STP For the following, we define a concatenated 3 N dimensional column vector of state variables
y = (sT, uT, xT)T of the system Eq (3). Given a (numerical) solution of the stable firing rate pro-
file ~ 0 we can calculate the stable fixed point of this system by setting the l.h.s. of Eq (3) to
zero. This yields steady-state solutions for the synaptic activations, facilitation and depression
variables y0 = (s0, u0, x0): s0;i
¼ tsu0;ix0;i 0;i;
u0;i
¼ U 1 þ tu 0;i
1 þ Utu 0;i
;
x0;i
¼
1 þ Utu 0;i
1 þ Uðtu 0;i þ tutx 2
0;i þ tx 0;iÞ :
ð12Þ ð12Þ We then linearize the system Eq (3) at the fixed point y0, introducing a change of variables
consisting of perturbations around the fixed point: y = y0 + δ y = y0 + (δ sT, δ uT, δ xT) and
ϕi = ϕ0,i + δϕi. To reach a self-consistent linear system, we further assume a separation of
time scales between the neuronal dynamics and the synaptic variables, in that the neuronal
firing rate changes as an immediate function of the (slow) input. This allows replacing
d i ¼ d i
dJi
J0;i
X
j
dJi
dsj dsj ¼ 0
0;i
X
jwijdsj, where we introduce the shorthand 0
0;i d i
dJi
J0;i. Finally, keeping only linear orders in all perturbations, we arrive at the linearized system PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1006928
April 19, 2019 24 / 48 Stability of continuous attractor networks under the control of short-term plasticity know that (due to uniqueness of the 1-dimensional eigenspace associated to the 0 eigenvalue)
the vector y0T is proportional to el: el ¼ 1
S y0ðerÞ
T ¼
dJ0
dφ
T
;
a1
du0
dφ þ a2
dx0
dφ
T
;
b1
du0
dφ þ b2
dx0
dφ
T! ;
ð18Þ ð18Þ where S is a proportionality constant and
dJ0;i
dφ ¼ P
jwij
ds0;j
dφ is the change of the steady-state input
arriving at neuron i under shifts of the center position φ. Finally, the proportionality constant S can be calculated by using Eq (18) in Eq (15) (see
Section 3 of S1 Text for details): S ¼ y0ðerÞ
T er
¼ U
X
i
dJ0;i
dφ
2
0
i
½U 0;iðtuðtx 0;i þ 1Þ þ txÞ þ 13
"
ts½tu 0;iðUtu 0;i þ 2Þ þ 1½U 0;iðtuðtx 0;i þ 1Þ þ txÞ þ 1
0;i½ðU 1Þt2
u þ Ut2
xðtu 0;i þ 1Þðtu 0;iðUtu 0;i þ 2Þ þ 1Þ
ðU 1ÞUt2
utx 0;iðtu 0;i þ 1Þ
ðUtu 0;i þ 1Þ
#
;
ð19Þ S ¼ y0ðerÞ
T er "
ts½tu 0;iðUtu 0;i þ 2Þ þ 1½U 0;iðtuðtx 0;i þ 1Þ þ txÞ þ 1
0;i½ðU 1Þt2
u þ Ut2
xðtu 0;i þ 1Þðtu 0;iðUtu 0;i þ 2Þ þ 1Þ
ðU 1ÞUt2
utx 0;iðtu 0;i þ 1Þ
ðUtu 0;i þ 1Þ
#
;
ð19Þ ð19Þ where 0
0;i ¼ d i
dJi
J0;i is the linear change of the firing rate of neuron i at its steady-state input J0,i. Diffusion. To be able to describe diffusion on the continuous attractor, we need to extend
the model by a treatment of the noise induced into the system through the variable process of
neuronal spike emission. Starting from Eq (3), we assume that neurons i fire according to inde-
pendent Poisson processes ξi(t) = ∑k δ(t −ti,k), where ti,k is a Poisson point process with time-
dependent rate ϕi. The variability of the point process ξi(t) introduces noise in the synaptic var-
iables. PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1006928
April 19, 2019 g
φ
g
g
Formally, the column eigenvector to the eigenvalue 0 is given by changes in the state vari-
ables as the bump center position φ is translated along the manifold: er ¼ dy0
dφ ¼
ds0
dφ
T
; du0
dφ
T
; dx0
dφ
T!T
:
ð14Þ ð14Þ et el be the associated row left-eigenvector (also to eigenvalue 0) of K, normalized such that: el er ¼ 1:
ð15Þ ð15Þ el er ¼ 1: In Section 1 of S1 Text, we show that the eigenvector el projects the system Eq (13) onto
dynamics of of the center position: _φ ¼ el _dy ¼ elKdy ¼ el 0 dy:
ð16Þ ð16Þ Under the linearized ring-attractor dynamics K, the center position is thus not subject to
any dynamics, making it susceptible to any displacements by noise. Calculation of the left eigenvector el. If the matrix K is symmetric, the left and right
eigenvectors el and er for the same eigenvalue 0 are the transpose of each other. Unfortunately,
here this is not the case (see Eq (13)), and we need to compute the unknown vector el, which
will depend on the coefficients of the known vector er. In particular, we look for a parametrized
vector y0(y) = (tT(y), vT(y), zT(y))T that for y = er fulfills the transposed eigenvalue equation of
the left eigenvector: ð17Þ KTy0ðerÞ ¼ 0:
ð17Þ In Section 2 of S1 Text, we derive variables y0 that fulfill the transposed dynamics _y0 ¼ KTy0
and for which it holds that _y0ðerÞ ¼ 0, thus fulfilling the condition Eq (17). In this case we PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1006928
April 19, 2019 25 / 48 Stability of continuous attractor networks under the control of short-term plasticity Note that the noise inputs ηi to the synaptic variables for neuron i are all identical, since they
result from the same presynaptic spike train. Linearizing this system around the noise-free steady-state Eq (12) and considering only the
unperturbed noise (we neglect multiplicative noise terms by replacing the terms
ffiffiffiffi
i
p
! ffiffiffiffiffiffiffi
0;i
p
),
we arrive at the linearized system equivalent of Eq (20):fififififi fififififififififififi
_dy ¼ Kdy þ
~Zu0x0
ffiffiffiffiffi
~ 0
q
~ZUð1 u0Þ
ffiffiffiffiffi
~ 0
q
~Zu0x0
ffiffiffiffiffi
~ 0
q
0
B
B
B
B
B
B
B
@
1
C
C
C
C
C
C
C
A
Kdy þ L:
ð21Þ ð21Þ fififififi
Note that the same vector of white noises~Z ðZ1; . . . ; ZnÞ
T appears three times. Left-multiplying this system with the eigenvector el yields a stochastic differential equation
for the center position (cf. Eq (16)): _φ ¼ el _dy ¼ 0 K þ elL ¼
X
k
el;kLk
ð22Þ ð22Þ Through the normalization by S (Eq (18)), which sums over all neurons, the individual contri-
butions el,k become small as the number of neurons N increases (this scaling is made explicit in
System size scaling). Thus, for large networks we average the small contributions of many sin-
gle noise sources, which validates the diffusion approximation above. In Section 4 of S1 Text, we show that we can rewrite Eq (22) by introducing a single Gauss-
ian white noise process with intensity B (Eq (5) of the main text), that matches the correlation
function of the summed noises: _φ ¼
ffiffiffi
B
p
Z;
ð23Þ ð23Þ _φ ¼
ffiffiffi
B
p
Z; fififi
where η is a white Gaussian noise process with hηi = 0 and hη(t)η(t0)i = δ(t −t0). Note, that the
value of B is the same under changes of the center position φ: these correspond to index-shift-
ing (mod N) all vectors in Eq (5), which leaves the sum invariant. Drift. While the diffusion coefficient calculated above is invariant with respect to shifts of
the bump center, the directed drift introduced by frozen variability depends on the momentary
bump center position φ. In the following we compare the heterogeneous network with bump
centered at φ to a homogeneous network (without frozen noise) with the bump also centered
at φ. We assume that the shot-noise (jump-like) nature of this process is negligible, given
that we average all individual contributions over the network (see below), allowing us to cap-
ture the neurally induced variability simply as white noise with variance proportional to the
incoming firing rates [48, 53], xiðtÞ ¼ i þ
ffiffiffiffi
i
p
ZiðtÞ, where ηi are white Gaussian noise pro-
cesses with mean hηii = 0, and correlation function hηi(t)ηj(t0)i = δ(t −t0)δij. This model of ξi(t)
preserves the mean and the auto-correlation function of the original Poisson processes. Here,
we introduce diffusive noise for each synaptic variable separately, but later average their linear
contributions over the large population, when projecting onto movement along the continu-
ous manifold (see below, and also [39], Supplementary Material] for a discussion). Substituting the noisy processes ξi(t) for ϕi(t) in Eq (3) results in the following system of
3N coupled Ito-SDEs: _si
¼
si
ts
þ uixi i þ Zi
ffiffiffiffi
i
p
;
_ui
¼
ui U
tu
þ Uð1 uiÞ i þ Zi
ffiffiffiffi
i
p
;
_xi
¼
xi 1
tx
uixi i þ Zi
ffiffiffiffi
i
p
:
ð20Þ ð20Þ PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1006928
April 19, 2019
26 / 48 PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1006928
April 19, 2019 26 / 48 Stability of continuous attractor networks under the control of short-term plasticity field derived from a linearization of the dynamics will thus depend on the center position. field derived from a linearization of the dynamics will thus depend on the center position. In subsection Frozen noise we calculate the perturbations induced by random network connec-
tivity, as well as heterogeneous leak reversal-potentials in excitatory neurons of the spiking
network. In subsection Frozen noise we calculate the perturbations induced by random network connec-
tivity, as well as heterogeneous leak reversal-potentials in excitatory neurons of the spiking
network. In subsection Frozen noise we calculate the perturbations induced by random network connec-
tivity, as well as heterogeneous leak reversal-potentials in excitatory neurons of the spiking
network. The firing rate perturbations Eq (24) add an additional term in the linearized equations
Eq (21): d_y ¼ Kdy þ
x0u0D~ ðφÞ
Uð1 u0ÞD~ ðφÞ
x0u0D~ ðφÞ
0
B
B
B
B
@
1
C
C
C
C
A
þ L:
ð25Þ ð25Þ As before, we left-multiply by the left eigenvector el, thereby projecting the dynamics onto
changes of the center position. This eliminates the linear response kernel K and yields a drift-
term in the SDE Eq (23) (see Section 5 of S1 Text for details): _φ ¼
X
i
dJ0;i
dφ
1
S
Uð1 þ 2tu 0;i þ Ut2
u 2
0;iÞ
ðU 0;iðtutx 0;i þ tu þ txÞ þ 1Þ2 D iðφÞ þ
ffiffiffi
B
p
Z:
ð26Þ ð26Þ fififi
Here, ϕ0,i is the firing rate of the ith neuron in a homogeneous network with the bump cen-
tered at −π and Δϕi(φ) is the firing rate change of this neuron caused by heterogeneities where
the heterogeneities are calculated under the assumption that (before shift of the coordinate sys-
tem) the bump is at φ. In the above equation, we have assumed that the number of neurons N is large enough to
treat the center position as a continuous variable φ 2 [−π, π) with the associated drift-field A
(φ) in Eq (7). In practice, we calculate this drift field according to the first term in Eq (26) for
each realizable center position φk ¼ k 2p
N p (for 0 k < N), which yields a discretized field. It
is important to note that this field will vary nearly continuously with changes in these discre-
tized center positions. Intuitively, the sum weighs the vector D~ ðφkÞ of firing-rate perturba-
tions with a smooth function of the smoothly varying firing-rate profile ~ 0 (the coefficients in
the sum). Shifts in the center position φk yield (to first order) index-shifts in the vector of fir-
ing-rate perturbations (see Frozen noise), equivalent to index-shifts of the vector of firing rates
~
h
ll h
ll l
d
ll h
h
d
f ~ 0. Thus, small changes in center positions will lead to small changes in the summands of Eq
(26). While our results validate the approach, a more rigorous proof of these arguments will be
left for future work. The unperturbed firing rate profile in the homogeneous network with bump at φ will be
denoted by ~ 0ðφÞ, which is the standard profile ~ 0 but centered at φ. Since we choose the stan-
dard profile to be centered at −π, we have ~ 0 ¼ ~ 0ð pÞ. We want to derive a compact expression for the directed drift of the bump in the heteroge-
neous network with frozen noise. Given a bump center position φ, we first shift the origin of
the coordinate system that describes the angular position on the ring of neurons such that the
firing rate profile is centered at the standard position φ0 = −π. In a system with frozen variabil-
ity, the actual firing rate profile of the bump is ~ 0 þ D~ ðφÞ:
ð24Þ ð24Þ where D~ ðφÞ summarize the linear firing rate perturbations caused by a small amount of het-
erogeneities. These firing rate perturbations stem from any deviation of the neural system
from the “baseline” case and change with the center position φ of the bump. The resulting drift PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1006928
April 19, 2019 27 / 48 Stability of continuous attractor networks under the control of short-term plasticity Neuron model. Neurons are modeled by leaky integrate-and-fire dynamics with conduc-
tance based synaptic transmission [11, 50]. The network consists of recurrently connected
populations of NE excitatory and NI inhibitory neurons, both additionally receiving external
spiking input with spike times generated by Next independent, homogeneous Poisson pro-
cesses, with rates νext. We assume that external excitatory inputs are mediated by fast AMPA
receptors, while, for simplicity, recurrent excitatory currents are mediated only by slower
NMDA channels (as in [11]). The dynamics of neurons in both excitatory and inhibitory populations are governed by the
following system of differential equations indexed by i 2 {0, . . ., NE/I −1}: Cm _V iðtÞ
¼
IL
i ðtÞ IExt
i ðtÞ II
iðtÞ IE
i ðtÞ;
IP
i
¼
gP sP
i ðtÞ ðViðtÞ VPÞ;
ð27Þ ð27Þ where P 2 {L,Ext,I,E}, V denotes voltages (membrane potential) and I denotes currents. Here,
Cm is the membrane capacitance and VL, VE, VI are the reversal potentials for leak, excitatory
currents, and inhibitory currents, respectively. The parameters gP for P 2 {L,Ext,I,E} are fixed
scales for leak (L), external input (Ext) and recurrent excitatory (E) and inhibitory (I) synaptic
conductances, which are dynamically gated by the unit-less gating variables sP
i ðtÞ. These gating
variables are described in detail below, however we set the leak conductance gating variable to
sL
i ¼ 1. For excitatory neurons, we refer to the excitatory and inhibitory conductance scales by
gEE gE and gEI gI, respectively. Similarly, for inhibitory neurons, we refer to the excitatory
and inhibitory conductance scales by gIE gE and gII gI, respectively. The model neuron dynamics (Eq 27) are integrated until their voltage reaches a threshold
Vthr. At any such time, the respective neuron emits a spike and its membrane potential is reset
to the value Vres. After each spike, voltages are clamped to Vres for a refractory period of τref. See the Tables in S1 and S2 Tables. for parameter values used in simulations. Synaptic gating variables and short-term plasticity. Spiking network model Spiking simulations are based on a variation of a popular ring-attractor model of visuospatial
working memory of [11] (and used with variations in [27, 29, 32, 36, 47]). The recurrent
excitatory connections of the original network model have been simplified, to allow for
faster simulation as well as analytical derivations of the recurrent synaptic activation. The
implementation details are given below, however the major changes are: 1) all recurrent
excitatory conductances are voltage independent; 2) a model of synaptic short-term plasticity
via facilitation and depression [49, 94, 95] is used to dynamically regulate the weights of the
incoming spike-trains 3) recurrent excitatory conductances are computed as linear filters of
the weighted incoming spike trains instead of the second-order kinetics for NMDA satura-
tion used in [11]. 28 / 48 PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1006928
April 19, 2019 PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1006928
April 19, 2019 Stability of continuous attractor networks under the control of short-term plasticity Here, the indices u j and x j indicate that for the incremental update of the variables upon
spike arrival, we use the values of the respective variables immediately before the spike arrival
[95]. Note that the variable U appears in the equation for u(t) both as the steady-state value in
the absence of spikes and as a scale for the update per spike. Here, the indices u j and x j indicate that for the incremental update of the variables upon
spike arrival, we use the values of the respective variables immediately before the spike arrival
[95]. Note that the variable U appears in the equation for u(t) both as the steady-state value in
the absence of spikes and as a scale for the update per spike. The dynamics of recurrent excitatory-to-excitatory transmission with STP are then given
by gating variables that linearly filter the incoming spikes scaled by facilitation and depression: sEE
i ðtÞ
¼
X
j2preðEEÞ
wEE
ij sj
ð30Þ ð30Þ _sj
¼
sj
ts
þ
X
tj
dðt tjÞu j ðtÞx j ðtÞ:
ð31Þ ð31Þ Here, pre(EE) indicates all excitatory neurons that make synaptic connections to the neuron i. See ‘S2 Table’ for synaptic parameters used in simulations. Note that a synapse j that has been
inactive for a long time is described by variables x j ¼ 1 and u j ¼ U and sj = 0 so that the ini-
tial strength of the synaptic connection is UwEE
ij [49]. The system of Eqs (29)–(31) is a spiking variant of the rate-based dynamics of Eq (3), with
sEE
i a variable related to the input Ji (cf. Eq (2)). In Subsection Firing rate approximation we will
make this link explicit. Network connectivity. All connections except for the recurrent excitatory connections are
all-to-all and uniform, with unit-less connection strengths set to wI
ij ¼ wext
ij ¼ 1 and for inhibi-
tory neurons additionally wE
ij ¼ 1. The recurrent excitatory connections are distance-depen-
dent and symmetric. Each neuron of the excitatory population with index i 2 {0, . . ., NE −1} is
assigned an angular position yi ¼ i 2p
NE 2 ½0; 2pÞ. The unit-less synaptic gating vari-
ables sP
i ðtÞ for P 2 {Ext,I} (external and inhibitory currents) are exponential traces of the spike
trains of all presynaptic neurons j with firing times tj: _sP
i ðtÞ ¼ sP
i ðtÞ
tP
þ
X
j2preðPÞ
wP
ij
X
tj
d t tj
;
ð28Þ ð28Þ where pre(P) indicates all neurons presynaptic to the neuron i for the the connection type P. The factors wP
ij are unit-less synaptic efficacies for the connection from neuron j to neuron i. For the excitatory gating variables of inhibitory neurons sIE
i (IE denotes connections from E to
I neurons) we also use the linear model of Eq (28) with time constant τIE = τE. For excitatory to excitatory conductances, we use a well established model of synaptic
short-term plasticity (STP) [49, 94, 95] which provides dynamic scaling of synaptic efficacies
depending on presynaptic firing. This yields two additional dynamical variables, the facilitat-
ing synaptic efficacy uj(t), as well as the fraction of available synaptic resources xj(t) of the
outgoing connections of a presynaptic neuron j, which are implemented according to the fol-
lowing differential equation: _uj
¼
1
tu
ðuj UÞ þ Uð1 u j Þ
X
tj
dðt tjÞ;
_xj
¼
1
tx
ðxj 1Þ x j u j
X
tj
dðt tjÞ:
ð29Þ ð29Þ 29 / 48 PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1006928
April 19, 2019 PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1006928
April 19, 2019 Stability of continuous attractor networks under the control of short-term plasticity inhibitory population fires at rates νI. For the linear synapses this yields hsexti ¼ textNextnext;
ð33Þ ð33Þ hsIi ¼ tINInI:
ð34Þ ð34Þ For the recurrent excitatory-to-excitatory synapses with short-term plasticity, we set the dif-
ferential Eq (29) to zero, and also average them over the Poisson statistics. Akin to the “mean-
field” model of [49], we average the steady-state values of facilitation and depression separately
over the Poisson statistics. This implicitly assumes that facilitation and depression are statisti-
cally independent, with respect to the distributions of spike times—while this is not strictly
true, the approximations work well, as has been previously reported [49]. This allows a fairly
straightforward evaluation of the mean steady-state value of the combined facilitation and
depression variables huj xji, under the assumption that the neuron j fires at a mean rate νj with
Poisson statistics, and yields rate approximations of the steady-state values similar to Eq (12): hujxji ¼ hujihxji ¼
Uðnjtu þ 1Þ
Unjðtu þ tx þ njtutxÞ þ 1 :
ð35Þ ð35Þ We now assume that the excitatory population of NE neurons fires at the steady-state rates
ϕj (0 j < N). To calculate the synaptic activation of excitatory-to-excitatory connections
hsEE
i i, we set Eq (30) to zero, and average over Poisson statistics (again neglecting correlations),
which yieldshsji = τEhuj xjiϕj and hsEE
i i ¼ P
jwEE
ij tEhujxji j. Let the the normalized steady-state
input Ji be: Ji 1
NE
hsEE
i i ¼ 1
NE
X
j
wEE
ij hsji:
ð36Þ ð36Þ The steady-state input Eq (36) links the general framework of Eq (2) to the spiking network. The additional factor 1/NE is introduced to make the scaling of the excitatory-to-excitatory
conductance with the size of the excitatory population NE explicit, which will be used in
System size scaling. To see this, we assume that the excitatory conductance scale of excitatory
neurons gEE is scaled such that the total conductance is invariant under changes of NE [96]:
gEE ¼ ~g EE=NE, for some fixed value ~g EE. This yields the total excitatory-to-excitatory conduc-
tance gEEsEE
i
¼ ~g EEJi with Ji as introduced above, where the scaling with NE is now shifted to the
input variable Ji. PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1006928
April 19, 2019 Recurrent excitatory connection weights wEE
ij
from neuron j to neuron i are then given by the Gaussian function wEE(θ) as (see the Table in
S2 Table for parameters used in simulations): wEE
ij
¼ wEEðyi yjÞ
¼ w0 þ wþ w0
exp ½minðjyi yjj; 2p jyi yjjÞ
2 1
2s2
w
:
ð32Þ wEE
ij
¼ wEEðyi yjÞ ð32Þ Additionally, for each neuron we keep the integral over all recurrent connection weights
normalized, resulting in the normalization condition 1
2p
R p
p dφwEEðφÞ ¼ 1: This normalization
ensures that varying the maximum weight w+ will not change the total recurrent excitatory
input if all excitatory neurons fire at the same rate. Here, we choose w+ as a free parameter con-
straining the baseline connection weight to: w0 ¼
wþswerf
pffiffiffi
2
p
sw
! ffiffiffiffiffiffi
2p
p
swerf
pffiffiffi
2
p
sw
! ffiffiffiffiffiffi
2p
p
: w0 ¼
wþswerf
pffiffiffi
2
p
sw
! ffiffiffiffiffiffi
2p
p
swerf
pffiffiffi
2
p
sw
! ffiffiffiffiffiffi
2p
p
: fififi
Firing rate approximation. We first replace the synaptic activation variables sP(V, t) for
P 2 {I, ext} by their expectation values under input with Poisson statistics. We assume that the 30 / 48 PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1006928
April 19, 2019 Stability of continuous attractor networks under the control of short-term plasticity which is achieved by setting the two associated parameters β ! 0, γ ! 0 in [50], to arrive at: hich is achieved by setting the two associated parameters β ! 0, γ ! 0 in [50], to arrive at: ti _V i
¼
ðVi VLÞ þ mi þ si
ffiffiffiffiti
p ZiðtÞ fifififi
Si
¼
1 þ TInI þ Textnext þ TEJi
ð38Þ ð38Þ miSi
¼
ðVI VLÞTInI þ ðVE VLÞTextnext þ ðVE VLÞTEJi
ð39Þ ð39Þ si
¼
gext
Cm
hVi VE
ð
Þtext
ffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi
tiNextnext
p
:
ð40Þ ð40Þ ti
¼
Cm
gLSi
hZiðtÞi
¼
0 hZiðtÞi
¼
0 hZiðtÞZiðt0Þi
¼
1
text
expð jt t0j
text
Þ
ð41Þ ð41Þ where Text ¼ Nexttext
gext
gL ; TI ¼ NItI
gI
gL are effective timescales of external and inhibitory inputs,
and TE ¼ NE
gE
gL is a dimensionless scale for the excitatory conductance. Here, μi is the bias of
the membrane potential due to synaptic inputs, and σi measures the scale of fluctuations in the
membrane potential due to random spike arrival approximated by the Gaussian process ηi. The mean firing rates F and mean voltages hVii of populations of neurons governed by this
type of differential equation can then be approximated by: where Text ¼ Nexttext
gext
gL ; TI ¼ NItI
gI
gL are effective timescales of external and inhibitory inputs,
and TE ¼ NE
gE
gL is a dimensionless scale for the excitatory conductance. Here, μi is the bias of
the membrane potential due to synaptic inputs, and σi measures the scale of fluctuations in the
membrane potential due to random spike arrival approximated by the Gaussian process ηi. The mean firing rates F and mean voltages hVii of populations of neurons governed by this
type of differential equation can then be approximated by: F½mi; si; ti
¼
tref þ
ffiffiffip
p ti
Z aðmi;siÞ
bðmi;siÞ
du expðu2Þ½1 þ erfðuÞ
! 1
ð42Þ ð42Þ aðmi; si; tiÞ
¼
Vreset VL mi
si
1 þ text
2ti
þ 1:03
ffiffiffiffiffiffi
text
ti
r
text
ti
;
ð43Þ ð43Þ bðmi; siÞ
¼
Vreset VL mi
si
;
ð44Þ ð44Þ hVii
¼
mi þ VL ðVthr VresetÞ iti:
ð45Þ ð45Þ Derivatives of the rate prediction. For the synaptic activation of excitatory to inhibitory connections, we get the mean activa-
tions: hsIEi ¼ tE
X
j
j:
ð37Þ ð37Þ We then follow [50] to reduce the differential equations of Eq (27) to a dimensionless form. The main difference consists in the absence of the voltage dependent NMDA conductance, PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1006928
April 19, 2019 31 / 48 Stability of continuous attractor networks under the control of short-term plasticity points for derivatives in the following): points for derivatives in the following): points for derivatives in the following): ivatives in the following): dF
dJi
¼ Fi
TE
Si
Fitref 1
ð
Þ þ
ffiffiffip
p F2
i ti XðbÞ db
dJi
XðaÞ da
dJi
;
ð46Þ ð46Þ da=b
dJi
¼
@a=b
@mi
þ @a=b
@si
@si
@hVii
TE
Si
mi þ VE VL
ð
Þ
ð
Þ
@a=b
@si
@si
@ti
@si
@hVii Vthr Vreset
ð
Þ i
þ @a=b
@ti
TE
Si
ti: where α/β stands as a placeholder for either function, and the expressions for α and β are given
in Eqs (43) and (44). d A second expression involving the derivative of Eq (42) is
d 0;i
dDL
i which appears in the theory
when estimating firing rate perturbations caused by frozen heterogeneities in the leak poten-
tials of excitatory neurons (see Eq (54)). The resulting derivatives are almost similar, which
can be seen by the fact that replacing VL ! VL þ DL
i in Eq (27) only leads to an additional
term DL
i in Eq (39). Thus, for neuron i the derivative can be evaluated to dF
dDL
i
¼
ffiffiffip
p F2
i ti XðbÞ @b
@DL
i
XðaÞ @a
@DL
i
;
ð47Þ
da=b
dDL
i
¼
@a=b
@mi
þ @a=b
@si
@si
@hVii
1
Si
: ð47Þ In practice, given a vector ϕi,0 of firing rates in the attractor state, as well as the mean firing
rate of inhibitory neurons νI, we evaluate the right hand side of Eqs (46) and (47) by replacing In practice, given a vector ϕi,0 of firing rates in the attractor state, as well as the mean firing
rate of inhibitory neurons νI, we evaluate the right hand side of Eqs (46) and (47) by replacing
Fi ! ϕi,0. This allows efficiently calculating the derivatives without having to perform any
numerical integration. The two terms will be exactly equal if ϕ0,i is a self-consistent solution of
Eq (42) for firing rates of the excitatory neurons across the network. We used numerical esti-
mates of ϕi,0 and νI that were measured from simulations and were very close to firing-rate pre-
dictions for all networks we investigated. PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1006928
April 19, 2019 Here we calculate derivatives of the input-output rela-
tion (Eq (42)) that will be used below in Frozen noise. Derivatives of the rate prediction. Here we calculate derivatives of the input-output rela-
tion (Eq (42)) that will be used below in Frozen noise. The expressions for drift and diffusion (see Analysis of drift and diffusion with STP) contain
the derivative 0
i ¼ dF
dJ jJi of the input-output relation F (Eq (42)) with respect to the recurrent
excitatory input Ji. Note, that F depends on Ji through all three arguments μi, σi and τi. First, we
define X(u) exp(u2)[1 + erf(u)], and the shorthand Fi = F[μi, σi, τi]. The derivative can then
be readily evaluated as (to shorten the notation in the following, we skip noting the evaluation PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1006928
April 19, 2019 32 / 48 Stability of continuous attractor networks under the control of short-term plasticity predicted by the theory: predicted by the theory: gðyiÞ ¼ F½miðgÞ; siðgÞ; tiðgÞ; hViiðgÞ:
ð49Þ gðyiÞ ¼ F½miðgÞ; siðgÞ; tiðgÞ; hViiðgÞ: ð49Þ The argument g indicates the dependence of quantities upon the parameters of the bump
parametrization Eq (48). The explicit dependence of the voltage hVii on g is obtained by substi-
tuting ϕi ! g(θi) in Eq (45). We then optimized networks to fulfill Eq (49). First, we imposed the following targets for
the parameters of g: g0 = 0.1Hz, g1 = 40Hz, νE,basal = 0.5Hz, νI,basal = 3Hz. For all networks we
chose w+ = 4.0, gr = 2.5. The following parameters were then optimized: νI, gσ, gEE (excitatory
conductance gE on excitatory neurons); gIE (excitatory conductance gE on inhibitory neurons);
gEI (inhibitory conductance gI on excitatory neurons); gII (inhibitory conductance gI on inhibi-
tory neurons). The basal firing rates (firing rates in the uniform state of the network, prior to
being cued) yielded two equations from Eq (49) by setting w+ = 1. This left 4 free parameters,
which were constrained by evaluating Eq (49) at 4 points as described in [97]. The basal firing
rates were chosen to be fairly low to make the uniform state more stable (as in [44]). This pro-
cedure does not yield a fixed value for gσ, since gσ is optimized for and is not set as a target
value. We thus iterated the following until a solution was found with gσ 0.5: a) change the
width of the recurrent weights wσ; b) optimize network parameters as described here; c) opti-
mize the expected bump shape for the new network parameters to predict gσ. The resulting
parameter values are given in Table in S2 Table. Optimization of network parameters. We used an optimization procedure [97] to retune
network parameters to produce approximately similar bump shapes as the parameters of
short-term plasticity are varied. Briefly, we replace the network activity ϕj in the total input Ji
of Eq (36) by a parametrization gðyjÞ ¼ g0 þ g1 exp
"
jyjj
gs
#gr
! :
ð48Þ ð48Þ Approximating sums 1
NE
PNE 1
j¼0
with integrals 1
2p
R p
p dφ we arrive at Approximating sums 1
NE
PNE 1
j¼0
with integrals 1
2p
R p
p dφ we arrive at JiðgÞ 1
2p
Z p
p
dφ wEE yi φ
ð
ÞhsjiðgðφÞÞ; where Ji(g) indicates that the total input depends on the parameters g0, g1, gσ, gr of the parame-
trization g. We then substitute this relation in Eq (42) to arrive at a self-consistency relation between
the parametrized network activity g(θi) at the position of neuron i and the firing-rate F PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1006928
April 19, 2019 33 / 48 Stability of continuous attractor networks under the control of short-term plasticity with varying bump centers—in the following, we denote sk
0;j s0;jðφkÞ: with varying bump centers—in the following, we denote sk
0;j s0;jðφkÞ: JiðφkÞ ¼ 1
NE
X
j
wEE
ij þ Dw
ij
h
i pij
p sk
0;j
¼ 1
NE
1
p
X
j
wEE
ij þ Dw
ij
h
i
sk
0;j X
j
wEE
ij þ Dw
ij
h
i
1 pij
sk
0;j
"
#
¼ 1
NE
X
jwEE
ij sk
0;j
|fflfflfflfflfflfflfflfflffl{zfflfflfflfflfflfflfflfflffl}
J0;iðφkÞ
þ 1
NE
1
p
X
j
wEE
ij þ Dw
ij
h
i
pijsk
0;j p
X
jwEE
ij sk
0;j
"
#
|fflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflffl{zfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflffl}
Jstruct
i
ðφkÞ
: {zflflflflfl
J0;iðφkÞ {zflflflflfl
J0;iðφkÞ flflflflflflflflflflflflflflflflflflflflflflflflflflflflflflflflflflflflflflflflflflflflflflflflflflflflflflflflflflflflflflflflflflflflflflflflflfl
Note that J0,i(φk) is an index-shifted version of the steady-state input: J0,i(φk) = J0,i−k. However,
such a relation does not hold for Jstruct
i
ðφkÞ, since the random numbers pij will change the
resulting value for varying center positions. We calculate the firing rate perturbations δϕi(φk) resulting from the additional input by a
linear expansion around the steady-state firing rates ϕ0,i(φk) ! ϕ0,i(φk) + δϕi(φk). These evalu-
ate to: d iðφkÞ
¼ dF
dJ
J0;i
ðφkÞ Jstruct
i
ðφkÞ
¼ 0
i;0ðφkÞ Jstruct
i
ðφkÞ:
ð51Þ ð51Þ See Derivatives of the rate prediction for the derivation of the function dF
dJ ðJ0;iÞ for the spiking
network used in the main text. In the sum of Eq (7), we keep the firing rate profile ~ 0 centered at φ0 while calculating the
drift for varying center positions. To accommodate the shifted indices resulting from moving
center positions, we re-index the summands to yields the perturbations ϕ0,i ! ϕ0,i + Δϕi(φk)
used there: D iðφkÞ ¼ 0
i;0 Jstruct
iþk ðφkÞ:
ð52Þ ð52Þ Heterogeneous leak reversal potentials. We further investigated random distributions of
the leak reversal potential VL. These are implemented by the substitution VL
! VL þ DL
i ;
ð53Þ ð53Þ where the DL
i are independent normally distributed variables with zero mean, i.e. hDL
i i ¼ 0mV; hDL
i DL
j i ¼ s2
Ldij. The parameter σL controls the standard deviation of these ran-
dom variables, and thus the noise level of the leak heterogeneities. where the DL
i are independent normally distributed variables with zero mean, i.e. Frozen noise Random and heterogeneous connectivity. Introducing random connectivity, we replace
the recurrent weights in Eq (36) by: wEE
ij
! wEE
ij þ Dw
ij
h
i pij
p :
ð50Þ ð50Þ Here, pij 2 {0, 1} are Bernoulli variables, with P(pij = 1) = p, where the connectivity parameter
p 2 (0, 1] controls the overall sparsity of recurrent excitatory connections. For p = 1 the entire
network is all-to-all connected. Additionally, we provide derivations for additive synaptic het-
erogeneities Dw
ij ¼ Zijsw (as in [38]), where {ηij|1 i, j NE} are independent, normally dis-
tributed random variables with zero mean and unit variance. We did not investigate this type
of heterogeneity in the main text, since increasing σw lead to a loss of the attractor state before
creating large enough directed drifts to be comparable to the other sources of frozen noise con-
sidered here—most of the small effects were “hidden” behind diffusive displacement [85]. Nev-
ertheless, we included this case in the analysis here for completeness. Let the center position of the bump be φk ¼ k 2p
N p (for 0 k < N). Subject to the per-
turbed weights, the recurrent steady-state excitatory input Ji(φk) Eq (36) to any excitatory neu-
ron can be written as the unperturbed input J0,i(φk) plus an additional input Jstruct
i
ðφkÞ arising
from the perturbed connectivity. Note that the synaptic steady-state activations s0,j(φk) change PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1006928
April 19, 2019 34 / 48 Stability of continuous attractor networks under the control of short-term plasticity rates ϕ0,i(φk) ! ϕ0,i(φk) + δϕi(φk): rates ϕ0,i(φk) ! ϕ0,i(φk) + δϕi(φk): rates ϕ0,i(φk) ! ϕ0,i(φk) + δϕi(φk): d iðφkÞ
¼ dFi
dDL
i
ðJiðφkÞÞ DL
i
d 0;i
dDL
i
ðφkÞ DL
i :
ð54Þ ð54Þ Here, dFi
dDL
i ðJiðφkÞÞ is the derivative of the input-output relation of neuron i in a bump cen-
tered at φk, with respect to the leak perturbation. We introduced
d 0;i
dDL ðφkÞ as a shorthand
notation for this derivative, since it is evaluated at the steady-state input Ji,0(φk). For the
spiking network of the main text, this is derived in Derivatives of the rate prediction. In the sum of Eq (7), we keep the firing rate profile ~ 0 centered at φ0 while calculating the
drift for varying center positions. As in the last section, we re-index the sum to yield the per-
turbations ϕ0,i ! ϕ0,i + Δϕi(φk) used there: D iðφkÞ ¼ d 0;i
dDL
i
DL
iþk:
ð55Þ ð55Þ Squared field magnitude. Using the equation of the drift field in Eq (7), and the firing
rate perturbations Eqs (51)–(54), it is straight forward to see that for any center position φ the
expected drift field averaged over the noise parameters is 0, since all single firing rate perturba-
tions vanish in expectation. In the following we calculate the variance of the drift field averaged
over noise realizations, which turns out to be additive with respect to the two noise sources. Squared field magnitude. Using the equation of the drift field in Eq (7), and the firing We begin by calculating the correlations between frozen noises caused by random connec-
tivity and leak heterogeneities. For the Bernoulli distributed variables pij it holds that hpiji = p,
hpij plki = δilδjkp + (1 −δilδjk)p2. For the other independent random variables it holds that
hDL
i i ¼ 0mV; hðDL
i Þ
2i ¼ s2
L; hDw
iji ¼ 0; hðDw
ijÞ
2i ¼ s2
w. Again, the weight heterogeneities Dw
ij are
only included for completeness—all analyses of the main text assume that σw = 0. PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1006928
April 19, 2019 hDL
i i ¼ 0mV; hDL
i DL
j i ¼ s2
Ldij. The parameter σL controls the standard deviation of these ran-
dom variables, and thus the noise level of the leak heterogeneities. hDL
i i ¼ 0mV; hDL
i DL
j i ¼ s2
Ldij. The parameter σL controls the standard deviation of these ran-
dom variables, and thus the noise level of the leak heterogeneities. Let φk ¼ k 2p
N p for 0 k < N be the center position of the bump. First, note that the
heterogeneities DL
i do not depend on the center position φk, since they are single neuron
properties. As in the last section, we calculate the firing rate perturbations δϕi(φk)
resulting from the additional input by a linear expansion around the steady-state firing PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1006928
April 19, 2019 35 / 48 Stability of continuous attractor networks under the control of short-term plasticity squared field averaged over ensemble of frozen noises is then: squared field averaged over ensemble of frozen noises is then: hAðφÞ
2ifrozen ¼ 1
S2
X
i;j
CiðφÞCjðφÞ
0;i0ðφÞJstruct
i
ðφÞ þ d 0;i
dDL
ðφÞDL
i
0
0;jðφÞJstruct
j
ðφÞ þ d j
dDL
ðφÞDL
j
frozen
¼ 1
S2
X
i
C2
i ðφÞ
"
ð 0;i0ðφÞÞ
2
N2
E
1
p 1
X
j
ðs0;jðφÞÞ
2ðwEE
ij Þ
2 þ 1
p
X
j
s2
0;jðφÞs2
w
!ð56Þ hAðφÞ
2ifrozen ¼ 1
S2
X
i;j
CiðφÞCjðφÞ
0;i0ðφÞJstruct
i
ðφÞ þ d 0;i
dDL
ðφÞDL
i
0
0;jðφÞJstruct
j
ðφÞ þ d j
dDL
ðφÞDL
j
frozen
¼ 1
S2
X
i
C2
i ðφÞ
"
ð 0;i0ðφÞÞ
2
N2
E
1
p 1
X
j
ðs0;jðφÞÞ
2ðwEE
ij Þ
2 þ 1
p
X
j
s2
0;jðφÞs2
w
! þ
d 0;i
dDL
ðφÞ
2
s2
L
:
ð56Þ hAðφÞ
2ifrozen ¼ 1
S2
X
i;j
CiðφÞCjðφÞ
0;i0ðφÞJstruct
i
ðφÞ þ d 0;i
dDL
ðφÞDL
i
0
0;jðφÞJstruct
j
ðφÞ þ d j
dDL
ðφÞDL
j
frozen ð56Þ ¼ 1
S2
X
i
C2
i ðφÞ
"
ð 0;i0ðφÞÞ
2
N2
E
1
p 1
X
j
ðs0;jðφÞÞ
2ðwEE
ij Þ
2 þ 1
p
X
j
s2
0;jðφÞs2
w
! þ
d 0;i
dDL
ðφÞ
2
s2
L
:
ð56Þ One can see directly that the two last terms are invariant under shifts of the bump center φ,
since these introduce symmetric shifts of the indexes i. Similarly, it is easy to see that the first
term is also invariant. Let φ0 be shifted to the right by one index from φ. It then holds that: X
i
C2
i ðφ0Þ ð 0
0;iðφ0ÞÞ
2
N2
E
1
p 1
X
j
ðs0;jðφ0ÞÞ
2ðwEE
ij Þ
2
! ¼
X
i
C2
i 1
ð 0
0;i 1ðφÞÞ
2
N2
E
1
p 1
X
j
ðs0;j 1ðφÞÞ
2ðwEE
ij Þ
2
! ¼
X
i
C2
i 1
ð 0
0;i 1ðφÞÞ
2
N2
E
1
p 1
X
j
ðs0;jðφÞÞ
2ðwEE
i 1;jÞ
2
! For the correlations between the perturbations we then know that (for brevity, we omit the
dependence on the center position φ): hJstruct
i
DL
i i
¼
0
hJstruct
i
Jstruct
l
i
¼
1
N2
E
X
j;k
s0;jwEE
ij s0;kwEE
lk
pij
p 1
plk
p 1
! þ 1
N2
E
1
p2
X
j;k
s0;js0;khDw
ijDw
lkihpijplki
! ¼
1
N2
E
X
j
s2
0;jðwEE
ij Þ
2 1
p 1
þ 1
p
X
j
s2
0;js2
w
! dil: Starting from Eq (7), we use as a firing rate perturbation the sum of firing rate perturbations
from both Eqs (51) and (54). With the pre-factor Ci ¼
dJ0;i
dφ
1þtu 0;iðUtu 0;iþ2Þ
ðU 0;iðtutx 0;iþtuþtxÞþ1Þ2, the expected PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1006928
April 19, 2019 36 / 48 Stability of continuous attractor networks under the control of short-term plasticity relation Eq (57): relation Eq (57): X
N 1
i¼0
! N
NE
X
NE 1
i¼0
: X
N 1
i¼0
! N
NE
X
NE 1
i¼0
: First, we find that the normalization constant scales as S ¼ N
NE S, and thus (dots indicate the
summands, which are omitted for clarity) for the diffusion strength B (cf. Eq (5)): B
¼ 1
S2
X
N 1
i¼0
¼ N
NE
1
S2
X
NE 1
i¼0
¼ NE
N B:
ð58Þ ð58Þ For the drift magnitude we turn to the expected squared drift magnitude calculated earlier
(cf. Eq (56)), for which we find that (setting σw ! 0 for simplicity, as throughout the main
text): hA2ifrozen
¼
NE
N
2
1
ðSÞ
2
N
NE
X
NE 1
i¼0
C2
i
ð 0
iÞ
2
N2
1
p 1
N
NE
X
NE 1
j¼0
s2
j w2
ij þ
d i
dEL
2
s2
L
! ¼
1
ðSÞ
2
X
NE 1
i¼0
C2
i
1
N2 ð 0
iÞ
2 1
p 1
X
NE 1
j¼0
s2
j w2
ij þ NE
N
d i
dEL
2
s2
L
! :
ð59Þ ð59Þ Note, that we could not resolve this scaling in dependence of hA2i
frozen, since the two sources of
frozen noise (connectivity and leak heterogeneity) show different scaling with N. : The final equation holds since, in ring-attractor networks, wEE
ij consists of index-shifted rows
of the same vector (see e.g. Network connectivity for the spiking network weights). 2
2 In summary, hA(φ)2ifrozen will evaluate to the same quantity hA2ifrozen for all center posi-
tions φ. In the main text, we use this fact to estimate hA2ifrozen from simulations, by addition-
ally averaging over the all center positions and interchanging the ensemble and positional
averages: hA2ifrozen ¼ 1
NE
X
k
hAðφkÞ
2ifrozen ¼
1
NE
X
k
AðφkÞ
2
frozen
: Thus, we can compare the value of hA2ifrozen to the mean squared drift field over all center
positions, averaged over instantiations of noises. System size scaling. Generally, sums over the discretized intervals [−π, π) as they appear
in Eqs (5) and (7) will scale with the number N chosen for the discretization of the positions
on the continuous ring φðiÞ ¼ i
N 2p p. Consider two discretizations of the ring, partitioned
into N1 and N2 uniformly spaced bins of width 2p
N1 and 2p
N2. We can then approximate integrals
over any continuous (Riemann integrable) function f on the ring by the two Riemann sums: 2p
N1
X
N1 1
i¼0
f ðφ1;iÞ
Z p
p
f ðφÞdφ 2p
N2
X
N2 1
i¼0
f ðφ2;iÞ;
ð57Þ ð57Þ where, i 2p
N1 φ1;i < i þ 1
ð
Þ 2p
N1 (for N2 and φ2,i analogously) are points in the bins [98]. Numerical quantities for the results of the main text have been calculated for NE = 800. In
the following we denote all of these quantities with an asterisk (). To generalize these results
to arbitrary system size N, we replace sums over N bins by scaled sums over NE bins using the PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1006928
April 19, 2019 37 / 48 Stability of continuous attractor networks under the control of short-term plasticity approached the bump state after being uniformly initialized. In both figures, we show popula-
tion activity only after this initial stimulus was applied. Estimation of centers and mean bump shapes. To estimate centers of bump states, simula-
tions were run until t = tmax and spikes were recorded from the excitatory population and con-
verted to firing rates by convolving them with an exponential kernel (τ = 100ms) [101] and then
sampled at resolution 1ms. This results in vectors of firing rates νj(t), 0 j NE −1 for every
time t. We calculated the population center φ(t) for time t by measuring the phase of the first spa-
tial Fourier coefficient of the firing rates. This is given by φðtÞ ¼ arg P
jexp i 2p
NE j
njðtÞ
p:
For all analyses below, we identify t = 0 to be the time t = toff of the initial cue. To measure the mean bump shapes, we first rectified the vectors νj(t) for every t by rotating
the vector until φ(t) = 0. We then sampled the rectified firing rates starting from 1s after cue
offset at intervals of 20ms, which were used to calculate the mean firing rates. S1 Fig shows
mean rates for each simulation averaged over the 1000 repetitions performed in the diffu-
sion estimation (below). Exclusion of bump trajectories. Sometimes bump trajectories would leave the attractor
state and return to the uniform state. We identified these trajectories in all experiments by
identifying maximal firing rates across the population that dropped below 10Hz during the
delay period. The such identified repetitions were excluded from the analyses, which occurred
mostly in networks with no facilitation for τx = 150ms, τu = 650ms: at U = 1, we excluded 222/
1000 repetitions from the diffusion estimation, while for all other U 0.8 at most 15/1000
were excluded. Increasing the depression time constant also lead to less stable attractor states:
for τx = 200ms, τu = 650ms and U = 0.8, we had to exclude 250/1000 repetitions. During the
simulations for drift estimation, we observed that frozen noise also leads to less stable bumps
under weak facilitation for random and sparse connectivity (p 1) and high leak variability
(σL 0). Diffusion estimation. Numerical methods Spiking simulations. All network simulations and models were implemented in the
NEST simulator [99]. Neuronal dynamics are integrated by the Runge-Kutta-Fehlberg method
as implemented in the GSL library [100] (gsl_odeiv_step_rkf45)—this forward integration
scheme is used in the NEST simulator for all conductance-based models (at the time of writ-
ing). The short-term plasticity model is integrated exactly, based on inter-spike intervals. Code
for network simulations is available at https://github.com/EPFL-LCN/pub-seeholzer2018. Simulation protocol. In all experiments (except those involving bi-stability, see below)
spiking networks were simulated for a transient initial period of tinitial = 500ms. To center the
network in an attractor state at a given angle −π φ < π, we gave an initial cue signal by stim-
ulating neurons (0.2 NE neurons for networks with facilitation parameter U > 0.1 and 0.18
NE neurons for U 0.1) centered at φ by strong excitatory input mediated by additional Pois-
son firing onto AMPA receptors (0.5s at 3kHz followed by 0.5s at 1.5kHz) with connections
scaled down by a factor of gsignal = 0.5. The external input ceased at t = toff = 1.5s. For simula-
tions to estimate the diffusion we simulated until tmax = 15s, yielding 13.5s of delay activity
after the cue offset. For simulations to estimate drift we set tmax = 8s, yielding 6.5s of delay
activity after the cue offset. For simulations exploring the bi-stability between the uniform state and a bump state (Fig
1B1), we added an additional input prior to the spontaneous state. We stimulated simulta-
neously 20 excitatory neurons around 4 equally spaced cue points each (80 neurons in total,
500ms, 1.5kHz, AMPA connections scaled by a factor gsignal = 2). This was applied to settle net-
works into the uniform state more stably—without this perturbation, networks sometimes PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1006928
April 19, 2019 38 / 48 Although the value of MI depends on the number of bins n, in Figs 5 and 6
we normalize MI to that of the reference network (U = 1, no frozen noise, see Short-term
plasticity controls memory retention), which leaves the resulting plot nearly invariant under a
change of bin numbers. MI ¼ Pn
i¼1
Pn
j¼1 rij log 2
rij
piqj
. Note, that the sum effectively counts only nonzero entries of rij (trajectories that started in bin i and ended in bin j): these imply that pi 6¼ 0
(a trajectory started in bin i) and qj 6¼ 0 (a trajectory ended in bin j), which makes the sum
well defined. Although the value of MI depends on the number of bins n, in Figs 5 and 6
we normalize MI to that of the reference network (U = 1, no frozen noise, see Short-term
plasticity controls memory retention), which leaves the resulting plot nearly invariant under a
change of bin numbers. Numerical integration of Langevin equations. Numerically integration of the homoge-
neous Langevin equations (Eq (4)) describing drift and diffusion of bump positions φ 2 [−π,
π) (with circular boundary conditions) has been implemented as a C extension in Cython
[106] to the Python language [107]. Since the drift fields A(φ) are estimated on a discretization
of the interval [−π, π) into N bins, we first interpolate drift fields A given as N discretized val-
ues to obtain continuous fields—interpolations are obtained using cubic splines on periodic
boundary conditions using the class gsl_interp_cspline_periodic of the Gnu Scientific Library
[100]. For forward integration of the Langevin equation Eq (4) from time t = 0, we start from
an initial position φ0 = φ(t = 0). Given a time resolution dt (unless otherwise stated we use
dt = 0.1s) and a maximal time tmax we repeat the following operations until we reach t = tmax: t ! t þ dt;
φ ! φ þ dt AðφÞ þ
ffiffiffiffiffiffiffi
dtB
p
r;
φ ! ððφ þ pÞ mod 2pÞ p: Here, for each iteration r is a random number drawn from a normal distribution with zero
mean and unit variance (hri = 0 and hr2i = 1). The last step is performed to implement the cir-
cular boundary conditions on [−π, π). Stability of continuous attractor networks under the control of short-term plasticity We then computed displacements in time by computing a set of discrete differences We then computed displacements in time by computing a set of discrete differences
Dφk ¼ fðφk½t0 þ ðj þ 1Þdt φ½t0 þ j dtÞ=dt j 8j 2 N0 : t0 þ ðj þ 1Þdt tmaxg; Dφk ¼ fðφk½t0 þ ðj þ 1Þdt φ½t0 þ j dtÞ=dt j 8j 2 N0 : t0 þ ðj þ 1Þdt tmaxg; where we chose dt = 1.5s and t0 2 {500ms, 700ms, 900ms, . . ., 1900ms}. All differences are cal-
culated with periodic boundary conditions on the circle [−π, π), i.e. the maximal difference
was π/dt. We then calculated a binned mean (100 bins on the ring, unless mentioned other-
wise) of differences calculated for all K trajectories, to approximate the drift-fields as a function
of positions on the ring. Mutual information measure. We are estimating the mutual information between a set
of initial positions x 2 [0, 2π) and associated final positions y(x) 2 [0, 2π) of the trajectories of
a continuous attractor network over a fixed delay period of T. For our results, we take T = 6.5s. We constructed binned and normalized histograms (with bin size n = 100, but see below) as
approximate probability distributions of initial positions pi ¼ p i 1
½
2p
n x < i 2p
n
and all
final positions qi ¼ p i 1
½
2p
n y < i 2p
n
(with bins indexed by 1 i n), as well as the
bivariate probability distribution rij ¼ p i 1
½
2p
n x < i 2p
n ; j 1
½
2p
n yðxÞ < j 2p
n
. h
l
l
h
l
f
[
] Using these, we can calculate the mutual information as [56, 57]
MI ¼ Pn
i¼1
Pn
j¼1 rij log 2
rij
piqj
. Note, that the sum effectively counts only nonzero
entries of rij (trajectories that started in bin i and ended in bin j): these imply that pi 6¼ 0
(a trajectory started in bin i) and qj 6¼ 0 (a trajectory ended in bin j), which makes the sum
well defined. Diffusion was estimated for each combination of network parame-
ters by simulating 1000 repetitions (10 initial cue positions, 100 repetitions each) of 13.5s of
delay activity. Center positions φk(t) were estimated for each repetition k as described above. We then calculated for each repetition the offset relative to the position at 500ms by Δφk(t) =
φk(t −500ms) −φk(500ms), effectively discarding the first 500ms after cue-offset. The time-
dependent variance of K repetitions (excluding those repetitions in which the bump state was
lost, see above) was then calculated as VðtÞ ¼ 1
K
P
kDφ2
kðtÞ. The diffusion strength can then be
estimated from the slope of a linear least-squares regression (using the Scipy method scipy. stats.linregress [102]) to the variance as a function of time: V(t) D0 + D t, where the inter-
cept D0 is included to account for initial transients. We estimated confidence intervals by boot-
strapping [103]: sampling K elements out of the K repetitions with replacement (5000
samples) and estimating the confidence level of 0.95 by the bias corrected and accelerated
bootstrap implemented in scikits-bootstrap [104]. As a control, we calculated confidence inter-
vals for D additionally by Jackknifing: after building a distribution of estimates of D on K one-
left-out samples of all repetitions, the standard error of the mean can be calculated and is mul-
tiplied by 1.96 to obtain the 95% confidence interval [105]—confidence intervals obtained by
this method were almost indistinguishable from confidence intervals obtained by
bootstrapping. Drift estimation. Drift was estimated numerically for each combination of network and
frozen noise parameters by simulating 400 repetitions (20 initial cue positions, 20 repetitions
each) of 6.5s of delay activity. Centers positions φk(t) were estimated for all K repetitions
(excluding those repetitions in which the bump state was lost, see above) as explained above. PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1006928
April 19, 2019 39 / 48 Stability of continuous attractor networks under the control of short-term plasticity each distractor position φD are then used in Eq (7) to calculate the corresponding drift fields. To calculate the final position φ1 after 250ms of presenting the distractor, we generate 1000
trajectories starting from φ0 = 0 by integrating the Langevin equation Eq (4) for 250ms
(dt = 0.01), the final positions of which are used to measure mean and standard deviation of
φ1. For the broader bump in Fig 7D, we stretched (and interpolated) the firing rates ϕ0 as well
as the associated vectors J0 and 0
0 along the x-axis to obtain vectors for bumps of the desired
width, and then re-calculated the values of dJ0
dφ. Supporting information S1 Fig. Spiking networks produce similar stable firing rate profiles across parameters. For
each choice of short-term plasticity parameters U, τu, and τx, we tuned the recurrent conduc-
tances (gEE, gEI, gIE, gII) and the width σw of the distance-dependent weights (cf. Eq (32))
such that the “bump” shape of the stable firing rate profile is close to a generalized Gaussian
n y
ð Þ ¼ g0 þ g1 exp
jyj
gs
gr
with parameters g0 = 0.1Hz, g1 = 40.0Hz, gσ = 0.5, gr = 2.5. See
Optimization of network parameters in Materials and methods for details, S2 Table. for param-
eter values after tuning, and S1 Table. for parameters that stay constant. A After tuning, the
resulting firing rate profiles for different parameter values of U and τu are very similar. Aver-
aged mean firing rates in bump state, measured from 1000 spiking simulations. A1-A3
Remaining slight parameter-dependent changes of bump shapes, measured by fitting the gen-
eralized Gaussian ν(θ) to the measured firing rate profiles displayed in A. A1 Top firing rate
g1. A2 Half-width parameter gσ. A3 Sharpness parameter gr. B and B1-B3 Same as in A and
A1-A3, for additional variation of the depression time scale τx. (TIF) S1 Fig. Spiking networks produce similar stable firing rate profiles across parameters. For
each choice of short-term plasticity parameters U, τu, and τx, we tuned the recurrent conduc-
tances (gEE, gEI, gIE, gII) and the width σw of the distance-dependent weights (cf. Eq (32))
such that the “bump” shape of the stable firing rate profile is close to a generalized Gaussian
n y
ð Þ ¼ g0 þ g1 exp
jyj
gs
gr
with parameters g0 = 0.1Hz, g1 = 40.0Hz, gσ = 0.5, gr = 2.5. See Optimization of network parameters in Materials and methods for details, S2 Table. for param-
eter values after tuning, and S1 Table. for parameters that stay constant. A After tuning, the
resulting firing rate profiles for different parameter values of U and τu are very similar. Aver-
aged mean firing rates in bump state, measured from 1000 spiking simulations. A1-A3
Remaining slight parameter-dependent changes of bump shapes, measured by fitting the gen-
eralized Gaussian ν(θ) to the measured firing rate profiles displayed in A. A1 Top firing rate
g1. A2 Half-width parameter gσ. A3 Sharpness parameter gr. Here, for each iteration r is a random number drawn from a normal distribution with zero
mean and unit variance (hri = 0 and hr2i = 1). The last step is performed to implement the cir-
cular boundary conditions on [−π, π). Code implementing this numerical integration scheme is available at https://github.com/
EPFL-LCN/pub-seeholzer2018-langevin. Distractor analysis. For the distractor analysis in Fig 7, we let 40 neurons centered at the
distractor position φD ¼ 360
N j 180
fire at rates increased by 20Hz, yielding a vector of firing
rate perturbations Δϕ0,i = 20Hz if |i −j| 20 and Δϕ0,i = 0Hz otherwise. The vectors Δϕ0,i for PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1006928
April 19, 2019 40 / 48 Stability of continuous attractor networks under the control of short-term plasticity S4 Fig. Mutual information normalized to compare slopes. Same data as in Fig 5B, but MI is
normalized to the average MI of each spiking network without heterogeneities (leftmost dot
for each green, orange, and blue group of curves/dots), making explicitly visible the change in
slope of the drop-off as heterogeneity parameters are increased. Dashed lines connect the
means, for visual guidance. (TIF) S4 Fig. Mutual information normalized to compare slopes. Same data as in Fig 5B, but MI is
normalized to the average MI of each spiking network without heterogeneities (leftmost dot
for each green, orange, and blue group of curves/dots), making explicitly visible the change in
slope of the drop-off as heterogeneity parameters are increased. Dashed lines connect the
means, for visual guidance. (TIF) S5 Fig. Theoretical predictions of working memory stability. All panels show theoretically
predicted expected displacement over 1 second (Eq (11)) for networks with random and sparse
connections (p = 0.12) and leak reversal potential heterogeneity (σL = 1.7mV). White lines
show displacement contour lines for 1, 2 and 5deg. A Displacement as a function of the facili-
tation time constant τu and facilitation U for τx = 150ms and N = 5000.B Displacement as a
function of system size and facilitation U for τx = 150ms and τu = 650ms. C-D Displacement as
a function of depression time constant τx and facilitation U for N = 5000 (C) and N = 20000
(D). In both panels τu = 650ms. (TIF) S6 Fig. Dependence of diffusion strength B on shape parameters. Diffusion was calculated
from Eq (5) with bump solutions 0 ¼ g1 expð j x
gs j
grÞ. The values of dJ0
dφ and 0
0 were calculated
by fitting and extrapolating (linearly, for ϕ0 > 40.31Hz) curves 0 ! 0
0 and ϕ0 ! J0 that were
obtained from the numerical values extracted for g1 = 40.31Hz, gσ = 0.51 by theory (see Firing
rate approximation in Materials and methods). Thus, any nonlinearity or saturation of the
inputs and input-output relation for ϕ0 > 40.31Hz was not included. This approximate analy-
sis shows that the major dependence of the diffusion expected in the system is on the bump
width gσ, although a minor dependence on g1 is seen. (TIF) S7 Fig. Short-term plasticity does not affect spiking statistics. Supporting information B and B1-B3 Same as in A and
A1-A3, for additional variation of the depression time scale τx. (TIF) S2 Fig. Theoretical prediction of diffusion strength as a function of STP parameters. All
color values display diffusion magnitude estimated from B in Eq (4) with bump shape esti-
mated from the reference network (U = 1, τx = 150ms, compare Fig 3B and 3C, dashed lines). Units of color values are idx2
s with values of level lines as indicated. A Diffusion as function of
facilitation U and depression time constant τx. Facilitation time constant was τu = 650ms. B
Diffusion as function of facilitation U and facilitation time constant τu. Depression time con-
stant was τx = 150ms. C Diffusion as function of depression time constant τx and facilitation
time constant τu. Facilitation U was U = 0.5. (TIF) S3 Fig. Comparison of theoretically predicted fields to simulations. A Averaged root mean
square error (RMSE) between predicted fields (Eq (7)) and fields extracted from simulations
(mean over 18-20 networks, error bars show 95% confidence of the mean). Both frozen noise
parameters (σL and 1 −p) are plotted on the same x-axis. B Normalized RMSE: each RMSE is
normalized by the range (max −min) of the joint data of simulated and predicted fields it is
calculated on. Colors as in A. C Average RMSE (same data as in A) plotted as a function of the
mean expected field magnitude (estimated separately for each network, then averaged). Colors
as in A. D Worst (top) and best (bottom) match between predicted field (blue line) and field
extracted from simulations (black line) of the group with the largest mean RMSE in panels A,
C (U = 1, 1 −p = 0.75). Shaded areas show 1 standard deviation of points included in the
binned mean estimate (100 bins) of the extracted field. (TIF) 41 / 48 PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1006928
April 19, 2019 Mean firing rate, coefficient
of variation of the inter-spike interval distribution (CV), and local CV (CV2 [92]) for two
attractor networks with different STP parameters. All measures were computed on spike-trains
measured over a period of 4s, recorded 500ms after offset of the external input which was cen-
tered at angle 0. Across STP parameters, networks display similarly reduced CVs for increased
mean firing rates, leading to large CVs for neurons located in the flanks of the firing rate pro-
file and low CVs for neurons located near the center. A Networks with large diffusion coeffi-
cient (U = 0.8, τu = 650ms, τx = 200ms) that underwent non-stationary diffusion during the
recording of spikes: the measured mean firing rates (gray line) differ visibly from the firing
rates estimated after centering the firing rate distribution at each point in time. Due to this
non-stationarity, CVs at intermediate firing rates appear elevated, while the local CV (CV2)
shows values close to stationary networks (see B). B The same network as in A, with strong
facilitation (U = 0.1). Reduced diffusion leads to a nearly stationary firing rate profile, and
coincident CV and CV2 measures. Acknowledgments The authors thank Tilo Schwalger and Johanni Brea for helpful discussions and feedback. The authors thank Tilo Schwalger and Johanni Brea for helpful discussions and feedback. The authors thank Tilo Schwalger and Johanni Brea for helpful discussions and feedback S1 Text. Detailed mathematical derivations.
(PDF) S1 Table. Parameters for spiking simulations. Parameter values are modified from [11] and
[50]. For recurrent conductances see the table in S2 Table. (PDF) S2 Table. Conductance and connectivity parameters for spiking simulations. For all net-
works we set w+ = 4.0. Recurrent conductance parameters are given for combinations of short-
term plasticity parameters according to the following notation. gEE: excitatory conductance gE
on excitatory neurons; gIE: excitatory conductance gE on inhibitory neurons; gEI: inhibitory
conductance gI on excitatory neurons; gII: inhibitory conductance gI on inhibitory neurons. (PDF) Author Contributions Conceptualization: Alexander Seeholzer, Moritz Deger, Wulfram Gerstner. Data curation: Alexander Seeholzer. Formal analysis: Alexander Seeholzer, Moritz Deger. Funding acquisition: Wulfram Gerstner. Investigation: Alexander Seeholzer, Moritz Deger. Methodology: Alexander Seeholzer, Moritz Deger. Project administration: Alexander Seeholzer, Wulfram Gerstner. Resources: Alexander Seeholzer. Software: Alexander Seeholzer. Supervision: Moritz Deger, Wulfram Gerstner. Validation: Alexander Seeholzer, Wulfram Gerstner. Visualization: Alexander Seeholzer. Writing – original draft: Alexander Seeholzer, Moritz Deger, Wulfram Gerstner. Writing – review & editing: Alexander Seeholzer, Moritz Deger, Wulfram Gerstner. Conceptualization: Alexander Seeholzer, Moritz Deger, Wulfram Gerstner. Funding acquisition: Wulfram Gerstner. Project administration: Alexander Seeholzer, Wulfram Gerstner. Supervision: Moritz Deger, Wulfram Gerstner. Validation: Alexander Seeholzer, Wulfram Gerstner. Visualization: Alexander Seeholzer. Writing – original draft: Alexander Seeholzer, Moritz Deger, Wulfram Gerstner. Writing – original draft: Alexander Seeholzer, Moritz Deger, Wulfram Gerstner. Writing – review & editing: Alexander Seeholzer, Moritz Deger, Wulfram Gerstner. Writing – review & editing: Alexander Seeholzer, Moritz Deger, Wulfram Gerstner. Stability of continuous attractor networks under the control of short-term plasticity strength B of Eq (5) shows diverging values at the same critical points of taux. Color legend on
the right hand side shows values of U. (TIF) strength B of Eq (5) shows diverging values at the same critical points of taux. Color legend on
the right hand side shows values of U. (TIF) S8 Fig. Diverging normalization constant S for increasing depression time constants τx
leads to diverging diffusion. All plots show quantities related to Eqs (5) and (7) for varying S8 Fig. Diverging normalization constant S for increasing depression time constants τx
leads to diverging diffusion. All plots show quantities related to Eqs (5) and (7) for varying
depression time constants τx and facilitation strength U. The coefficients 0;i;
dJ0;i
dφ ; 0
0;i appear-
ing therein are estimated from the spiking network used in the main text with U = 1, τx =
150ms, τu = 650ms. A The normalization constant S (“Normalizer”) of Eqs (5) and (7) shows
zero crossings as τx is increased beyond facilitation-dependent critical values. B Diffusion
strength B of Eq (5) without the normalization constant (equal to B S2). C The full diffusion PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1006928
April 19, 2019 42 / 48 PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1006928
April 19, 2019 Stability of continuous attractor networks under the control of short-term plasticity 4. Curtis CE, D’Esposito M. Persistent Activity in the Prefrontal Cortex during Working Memory. Trends
in Cognitive Sciences. 2003; 7(9):415–423. https://doi.org/10.1016/S1364-6613(03)00197-9 PMID:
12963473 5. Durstewitz D, Seamans JK, Sejnowski TJ. Neurocomputational Models of Working Memory. Nature
Neuroscience. 2000; 3:1184–91. https://doi.org/10.1038/81460 PMID: 11127836 6. Barak O, Tsodyks M. Working Models of Working Memory. Current Opinion in Neurobiology. 2014;
25:20–24. https://doi.org/10.1016/j.conb.2013.10.008 PMID: 24709596 7. Duarte R, Seeholzer A, Zilles K, Morrison A. Synaptic Patterning and the Timescales of Cortical
Dynamics. Current Opinion in Neurobiology. 2017; 43:156–165. https://doi.org/10.1016/j.conb.2017. 02.007 PMID: 28407562 8. Amari Si. Dynamics of Pattern Formation in Lateral-Inhibition Type Neural Fields. Biological cybernet-
ics. 1977; 87:77–87. 9. Camperi M, Wang XJ. A Model of Visuospatial Working Memory in Prefrontal Cortex: Recurrent Net-
work and Cellular Bistability. Journal of Computational Neuroscience. 1998; 5(4):383–405. https://doi. org/10.1023/A:1008837311948 PMID: 9877021 10. Hansel D, Sompolinsky H. Modeling Feature Selectivity in Local Cortical Circuits. In: Koch C, Segev I,
editors. Methods in Neural Modeling. from Synapses to Networks. MIT Press; 1998. p. 499–567. 11. Compte A, Brunel N, Goldman-Rakic PS, Wang XJ. Synaptic Mechanisms and Network Dynamics
Underlying Spatial Working Memory in a Cortical Network Model. Cerebral Cortex. 2000; 10:910–923. https://doi.org/10.1093/cercor/10.9.910 PMID: 10982751 12. Samsonovich A, McNaughton BL. Path Integration and Cognitive Mapping in a Continuous Attractor
Neural Network Model. Journal of Neuroscience. 1997; 17(15):5900–20. https://doi.org/10.1523/
JNEUROSCI.17-15-05900.1997 PMID: 9221787 13. Stringer SM, Trappenberg TP, Rolls ET, de Araujo IET. Self-Organizing Continuous Attractor Net-
works and Path Integration: One-Dimensional Models of Head Direction Cells. Network. 2002; 13
(2):217–42. PMID: 12061421 14. Burak Y, Fiete IR. Accurate Path Integration in Continuous Attractor Network Models of Grid Cells. PLOS Computational Biology. 2009; 5(2):e1000291. https://doi.org/10.1371/journal.pcbi.1000291
PMID: 19229307 15. Ben-Yishai R, Bar-Or RL, Sompolinsky H. Theory of Orientation Tuning in Visual Cortex. Proceedings
of the National Academy of Sciences. 1995; 92(9):3844–8. https://doi.org/10.1073/pnas.92.9.3844 16. Zhang K. Representation of Spatial Orientation by the Intrinsic Dynamics of the Head-Direction Cell
Ensemble: A Theory. Journal of Neuroscience. 1996; 16(6):2112–2126. https://doi.org/10.1523/
JNEUROSCI.16-06-02112.1996 PMID: 8604055 17. Seung HS. Continuous Attractors and Oculomotor Control. Neural Networks. 1998; 11(7):1253–1258. https://doi.org/10.1016/S0893-6080(98)00064-1 18. Knierim JJ, Zhang K. Attractor Dynamics of Spatially Correlated Neural Activity in the Limbic System. Annual Review of Neuroscience. 2012; 35:267–85. https://doi.org/10.1146/annurev-neuro-062111-
150351 PMID: 22462545 19. Moser EI, Roudi Y, Witter MP, Kentros C, Bonhoeffer T, Moser MB. Grid Cells and Cortical Represen-
tation. Nature Reviews Neuroscience. References 1. Goldman-Rakic PS. Cellular Basis of Working Memory. Neuron. 1995; 14(3):477–485. https://doi.org/
10.1016/0896-6273(95)90304-6 PMID: 7695894 2. Constantinidis C, Wang XJ. A Neural Circuit Basis for Spatial Working Memory. The Neuroscientist. 2004; 10(6):553–65. https://doi.org/10.1177/1073858404268742 PMID: 15534040 2. Constantinidis C, Wang XJ. A Neural Circuit Basis for Spatial Working Memory. The Neuroscientist. 2004; 10(6):553–65. https://doi.org/10.1177/1073858404268742 PMID: 15534040 3. Chaudhuri R, Fiete I. Computational Principles of Memory. Nature Neuroscience. 2016; 19(3):394–
403. https://doi.org/10.1038/nn.4237 PMID: 26906506 3. Chaudhuri R, Fiete I. Computational Principles of Memory. Nature Neuroscience. 2016; 19(3):394–
403. https://doi.org/10.1038/nn.4237 PMID: 26906506 PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1006928
April 19, 2019 43 / 48 Stability of continuous attractor networks under the control of short-term plasticity 26. Macoveanu J, Klingberg T, Tegne´r J. A Biophysical Model of Multiple-Item Working Memory: A
Computational and Neuroimaging Study. Neuroscience. 2006; 141(3):1611–8. https://doi.org/10. 1016/j.neuroscience.2006.04.080 PMID: 16777342 27. Wei Z, Wang XJ, Wang DH. From Distributed Resources to Limited Slots in Multiple-Item Working
Memory: A Spiking Network Model with Normalization. Journal of Neuroscience. 2012; 32(33):11228–
40. https://doi.org/10.1523/JNEUROSCI.0735-12.2012 PMID: 22895707 28. Roggeman C, Klingberg T, Feenstra HEM, Compte A, Almeida R. Trade-off between Capacity and
Precision in Visuospatial Working Memory. Journal of Cognitive Neuroscience. 2014; 26(2):211–222. https://doi.org/10.1162/jocn_a_00485 PMID: 24047380 29. Almeida R, Barbosa Ja, Compte A. Neural Circuit Basis of Visuo-Spatial Working Memory Precision:
A Computational and Behavioral Study. Journal of Neurophysiology. 2015; 114(3):1806–1818. https://
doi.org/10.1152/jn.00362.2015 PMID: 26180122 30. Cano-Colino M, Almeida R, Compte A. Serotonergic Modulation of Spatial Working Memory: Predic-
tions from a Computational Network Model. Frontiers in Integrative Neuroscience. 2013; 7. https://doi. org/10.3389/fnint.2013.00071 PMID: 24133418 31. Cano-Colino M, Almeida R, Gomez-Cabrero D, Artigas F, Compte A. Serotonin Regulates Perfor-
mance Nonmonotonically in a Spatial Working Memory Network. Cerebral Cortex. 2014; 24(9):2449–
2463. https://doi.org/10.1093/cercor/bht096 PMID: 23629582 32. Murray JD, Anticevic A, Gancsos M, Ichinose M, Corlett PR, Krystal JH, et al. Linking Microcircuit Dys-
function to Cognitive Impairment: Effects of Disinhibition Associated with Schizophrenia in a Cortical
Working Memory Model. Cerebral Cortex. 2012. 33. Cano-Colino M, Compte A. A Computational Model for Spatial Working Memory Deficits in Schizo-
phrenia. Pharmacopsychiatry. 2012; 45(S 01):S49–S56. https://doi.org/10.1055/s-0032-1306314
PMID: 22565235 34. Tsodyks M, Sejnowski T. Associative Memory and Hippocampal Place Cells. Neural Systems. 1995;
6:81–86. 35. Spiridon M, Gerstner W. Effect of Lateral Connections on the Accuracy of the Population Code for a
Network of Spiking Neurons. Network. 2001; 12(4):409–21. https://doi.org/10.1080/net.12.4.409.421
PMID: 11762897 36. Renart A, Song P, Wang XJ. Robust Spatial Working Memory through Homeostatic Synaptic Scaling
in Heterogeneous Cortical Networks. Neuron. 2003; 38(3):473–85. https://doi.org/10.1016/S0896-
6273(03)00255-1 PMID: 12741993 37. Wu S, Hamaguchi K, Amari Si. Dynamics and Computation of Continuous Attractors. Neural Compu-
tation. 2008; 20(4):994–1025. https://doi.org/10.1162/neco.2008.10-06-378 PMID: 18085986 38. Itskov V, Hansel D, Tsodyks M. Short-Term Facilitation May Stabilize Parametric Working Memory
Trace. Frontiers in Computational Neuroscience. 2011; 5(October):40–40. https://doi.org/10.3389/
fncom.2011.00040 PMID: 22028690 39. Burak Y, Fiete IR. Fundamental Limits on Persistent Activity in Networks of Noisy Neurons. Proceed-
ings of the National Academy of Sciences. 2012; 109(43):17645–17650. https://doi.org/10.1073/pnas. 1117386109 40. Kilpatrick ZP, Ermentrout B. Wandering Bumps in Stochastic Neural Fields. 2014; 15(7):466–481. https://doi.org/10.1038/nrn3766 PMID:
24917300 20. Burak Y. Spatial Coding and Attractor Dynamics of Grid Cells in the Entorhinal Cortex. Current
Opinion in Neurobiology. 2014; 25:169–175. https://doi.org/10.1016/j.conb.2014.01.013 PMID:
24561907 21. Wu S, Wong KYM, Fung CCA, Mi Y, Zhang W. Continuous Attractor Neural Networks: Candidate of a
Canonical Model for Neural Information Representation. F1000Research. 2016; 5. https://doi.org/10. 12688/f1000research.7387.1 22. Wimmer K, Nykamp DQ, Constantinidis C, Compte A. Bump Attractor Dynamics in Prefrontal Cortex
Explains Behavioral Precision in Spatial Working Memory. Nature Neuroscience. 2014; 17(3):431–
439. https://doi.org/10.1038/nn.3645 PMID: 24487232 23. Yoon K, Buice MA, Barry C, Hayman R, Burgess N, Fiete IR. Specific Evidence of Low-Dimensional
Continuous Attractor Dynamics in Grid Cells. Nature Neuroscience. 2013; 16(8):1077–1084. https://
doi.org/10.1038/nn.3450 PMID: 23852111 24. Seelig JD, Jayaraman V. Neural Dynamics for Landmark Orientation and Angular Path Integration. Nature. 2015; 521(7551):186–191. https://doi.org/10.1038/nature14446 PMID: 25971509 25. Kim SS, Rouault H, Druckmann S, Jayaraman V. Ring Attractor Dynamics in the Drosophila Central
Brain. Science. 2017; p. eaal4835. https://doi.org/10.1126/science.aal4835 PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1006928
April 19, 2019 44 / 48 Stability of continuous attractor networks under the control of short-term plasticity 47. Pereira J, Wang XJ. A Tradeoff Between Accuracy and Flexibility in a Working Memory Circuit
Endowed with Slow Feedback Mechanisms. Cerebral Cortex. 2015; 25(10):3586. https://doi.org/10. 1093/cercor/bhu202 PMID: 25253801 48. Gerstner W, Kistler WM. Spiking Neuron Models: Single Neurons, Populations, Plasticity. Cambridge
University Press; 2002. 49. Tsodyks M, Pawelzik K, Markram H. Neural Networks with Dynamic Synapses. Neural Computation. 1998; 10(4):821–835. https://doi.org/10.1162/089976698300017502 PMID: 9573407 50. Brunel N, Wang X. Effects of Neuromodulation in a Cortical Network Model of Object Working Memory
Dominated by Recurrent Inhibition. Journal of Computational Neuroscience. 2001; 11:63–85. https://
doi.org/10.1023/A:1011204814320 PMID: 11524578 51. Richardson M. Firing-Rate Response of Linear and Nonlinear Integrate-and-Fire Neurons to Modu-
lated Current-Based and Conductance-Based Synaptic Drive. Physical Review E. 2007; 76(2):1–15. https://doi.org/10.1103/PhysRevE.76.021919 52. Wang XJ. Synaptic Basis of Cortical Persistent Activity: The Importance of NMDA Receptors to Work-
ing Memory. The Journal of Neuroscience. 1999; 19(21):9587–603. https://doi.org/10.1523/
JNEUROSCI.19-21-09587.1999 PMID: 10531461 53. Brunel N. Dynamics of Sparsely Connected Networks of Excitatory and Inhibitory Spiking Neurons. Journal of Computational Neuroscience. 2000; 8(3):183–208. https://doi.org/10.1023/
A:1008925309027 PMID: 10809012 54. van Kampen NG. Stochastic Processes in Physics and Chemistry. 2nd ed. North Holland; 1992. 55. Gardiner C. Stochastic Methods: A Handbook for the Natural and Social Sciences. 4th ed. Springer;
2009. 56. Latham PE, Roudi Y. Mutual Information. Scholarpedia. 2009; 4(1):1658. https://doi.org/10.4249/
scholarpedia.1658 57. Cover TM, Thomas JA. Elements of Information Theory. John Wiley & Sons; 2012. 58. Kilpatrick ZP, Ermentrout B, Doiron B. Optimizing Working Memory with Heterogeneity of Recurrent
Cortical Excitation. Journal of Neuroscience. 2013; 33(48):18999–19011. https://doi.org/10.1523/
JNEUROSCI.1641-13.2013 PMID: 24285904 59. Macoveanu J, Klingberg T, Tegne´r J. Neuronal Firing Rates Account for Distractor Effects on Mne-
monic Accuracy in a Visuo-Spatial Working Memory Task. Biological Cybernetics. 2007; 96(4):407–
419. https://doi.org/10.1007/s00422-006-0139-8 PMID: 17260154 60. Ploner CJ, Gaymard B, Rivaud S, Agid Y, Pierrot-Deseilligny C. Temporal Limits of Spatial Working
Memory in Humans. European Journal of Neuroscience. 1998; 10(2):794–797. https://doi.org/10. 1046/j.1460-9568.1998.00101.x PMID: 9749746 61. White JM, Sparks DL, Stanford TR. Saccades to Remembered Target Locations: An Analysis of Sys-
tematic and Variable Errors. Vision Research. 1994; 34(1):79–92. https://doi.org/10.1016/0042-6989
(94)90259-3 PMID: 8116271 62. Wang Y, Markram H, Goodman PH, Berger TK, Ma J, Goldman-Rakic PS. Heterogeneity in the Pyra-
midal Network of the Medial Prefrontal Cortex. Nature Neuroscience. 2006; 9(4):534–42. https://doi. org/10.1038/nn1670 PMID: 16547512 63. Yang CR, Seamans JK, Gorelova N. arXiv:12053072 [math,
nlin, q-bio]. 2012. 41. Brody C, Romo R, Kepecs A. Basic Mechanisms for Graded Persistent Activity: Discrete Attractors,
Continuous Attractors, and Dynamic Representations. Current Opinion in Neurobiology. 2003; p. 204–211. https://doi.org/10.1016/S0959-4388(03)00050-3 PMID: 12744975 42. York LC, van Rossum MCW. Recurrent Networks with Short Term Synaptic Depression. Journal of
Computational Neuroscience. 2009; 27(3):607–620. https://doi.org/10.1007/s10827-009-0172-4
PMID: 19578989 43. Romani S, Tsodyks M. Short-Term Plasticity Based Network Model of Place Cells Dynamics. Hippo-
campus. 2015; 25(1):94–105. https://doi.org/10.1002/hipo.22355 PMID: 25155013 44. Barbieri F, Brunel N. Irregular Persistent Activity Induced by Synaptic Excitatory Feedback. Frontiers in Computational Neuroscience. 2007; 1. https://doi.org/10.3389/neuro.10.005.2007
PMID: 18946527 45. Kilpatrick ZP. Synaptic Mechanisms of Interference in Working Memory. Scientific Reports. 2018; 8
(1). https://doi.org/10.1038/s41598-018-25958-9 46. Hansel D, Mato G. Short-Term Plasticity Explains Irregular Persistent Activity in Working Memory
Tasks. The Journal of Neuroscience. 2013; 33(1):133–49. https://doi.org/10.1523/JNEUROSCI.3455-
12.2013 PMID: 23283328 45 / 48 PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1006928
April 19, 2019 Stability of continuous attractor networks under the control of short-term plasticity 69. Sandamirskaya Y. Dynamic Neural Fields as a Step toward Cognitive Neuromorphic Architectures. Frontiers in Neuroscience. 2014; 7. https://doi.org/10.3389/fnins.2013.00276 PMID: 24478620 70. Pan B, Zucker RS. A General Model of Synaptic Transmission and Short-Term Plasticity. Neuron. 2009; 62(4):539–554. https://doi.org/10.1016/j.neuron.2009.03.025 PMID: 19477155 71. Brunton BW, Botvinick MM, Brody CD. Rats and Humans Can Optimally Accumulate Evidence for
Decision-Making. Science. 2013; 340(6128):95–98. https://doi.org/10.1126/science.1233912 PMID:
23559254 72. Selemon LD, Goldman-Rakic PS. Common Cortical and Subcortical Targets of the Dorsolateral Pre-
frontal and Posterior Parietal Cortices in the Rhesus Monkey: Evidence for a Distributed Neural Net-
work Subserving Spatially Guided Behavior. Journal of Neuroscience. 1988; 8(11):4049–4068. https://doi.org/10.1523/JNEUROSCI.08-11-04049.1988 PMID: 2846794 73. Roach JP, Ben-Jacob E, Sander LM, Zochowski MR. Formation and Dynamics of Waves in a Cortical
Model of Cholinergic Modulation. PLoS Comput Biol. 2015; 11(8):e1004449. https://doi.org/10.1371/
journal.pcbi.1004449 PMID: 26295587 74. Lim S, Goldman MS. Balanced Cortical Microcircuitry for Spatial Working Memory Based on Correc-
tive Feedback Control. Journal of Neuroscience. 2014; 34(20):6790–6806. https://doi.org/10.1523/
JNEUROSCI.4602-13.2014 PMID: 24828633 75. Anwar H, Li X, Bucher D, Nadim F. Functional Roles of Short-Term Synaptic Plasticity with an Empha-
sis on Inhibition. Current Opinion in Neurobiology. 2017; 43:71–78. https://doi.org/10.1016/j.conb. 2017.01.002 PMID: 28122326 76. Nadim F, Bucher D. Neuromodulation of Neurons and Synapses. Current Opinion in Neurobiology. 2014; 29:48–56. https://doi.org/10.1016/j.conb.2014.05.003 PMID: 24907657 77. Murray JD, Bernacchia A, Freedman DJ, Romo R, Wallis JD, Cai X, et al. A Hierarchy of Intrinsic
Timescales across Primate Cortex. Nature Neuroscience. 2014; 17(12):1661–1663. https://doi.org/
10.1038/nn.3862 PMID: 25383900 78. Barbosa Ja, Constantinidis C, Compte A. Synaptically Imprinted Memories Reignite Bump-Attractor
Dynamics Prior to Stimulus in a Visuo-Spatial Working Memory Task; 2017. http://www.crm.cat/en/
Activities/Curs_2016-2017/Documents/Barbosa_abs_talk.pdf. 79. Oh M, Zhao S, Matveev V, Nadim F. Neuromodulatory Changes in Short-Term Synaptic Dynamics
May Be Mediated by Two Distinct Mechanisms of Presynaptic Calcium Entry. Journal of Computa-
tional Neuroscience. 2012; 33(3). https://doi.org/10.1007/s10827-012-0402-z PMID: 22710936 80. Kreitzer AC, Regehr WG. Modulation of Transmission during Trains at a Cerebellar Synapse. Journal
of Neuroscience. 2000; 20(4):1348–1357. https://doi.org/10.1523/JNEUROSCI.20-04-01348.2000
PMID: 10662825 81. Brenowitz S, David J, Trussell L. Enhancement of Synaptic Efficacy by Presynaptic GABAB Recep-
tors. Neuron. 1998; 20(1):135–141. https://doi.org/10.1016/S0896-6273(00)80441-9 PMID: 9459449 82. Barrière G, Tartas M, Cazalets JR, Bertrand SS. Interplay between Neuromodulator-Induced Switch-
ing of Short-Term Plasticity at Sensorimotor Synapses in the Neonatal Rat Spinal Cord. The Journal
of Physiology. 2008; 586(Pt 7):1903–1920. https://doi.org/10.1113/jphysiol.2008.150706 PMID:
18258661 83. Electrophysiological and Morphological Properties of Layers V-
VI Principal Pyramidal Cells in Rat Prefrontal Cortex in Vitro. Journal of Neuroscience. 1996; 16
(5):1904–1921. https://doi.org/10.1523/JNEUROSCI.16-05-01904.1996 PMID: 8774458 64. De´genètais E, Thierry AM, Glowinski J, Gioanni Y. Electrophysiological Properties of Pyramidal Neu-
rons in the Rat Prefrontal Cortex: An In Vivo Intracellular Recording Study. Cerebral Cortex. 2002; 12
(1):1–16. https://doi.org/10.1093/cercor/12.1.1 PMID: 11734528 65. Collins CE, Turner EC, Sawyer EK, Reed JL, Young NA, Flaherty DK, et al. Cortical Cell and Neuron
Density Estimates in One Chimpanzee Hemisphere. Proceedings of the National Academy of Sci-
ences. 2016; 113(3):740–745. https://doi.org/10.1073/pnas.1524208113 66. Funahashi S, Bruce CJ, Goldman-Rakic PS. Mnemonic Coding of Visual Space in the Monkey’s Dor-
solateral Prefrontal Cortex. Journal of Neurophysiology. 1989; p. 331–349. https://doi.org/10.1152/jn. 1989.61.2.331 PMID: 2918358 67. Chafee MV, Goldman-Rakic PS. Matching Patterns of Activity in Primate Prefrontal Area 8a and Parie-
tal Area 7ip Neurons During a Spatial Working MemoryTask. Journal of Neurophysiology. 1998; 79
(6):2919–2940. https://doi.org/10.1152/jn.1998.79.6.2919 PMID: 9636098 68. Wibisono A, Jog V, Loh PL. Information and Estimation in Fokker-Planck Channels. arXiv preprint
arXiv:170203656. 2017. 46 / 48 PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1006928
April 19, 2019 Stability of continuous attractor networks under the control of short-term plasticity 89. Wang XJ. Synaptic Reverberation Underlying Mnemonic Persistent Activity. Trends in Neurosciences. 2001; 24(8):455–63. https://doi.org/10.1016/S0166-2236(00)01868-3 PMID: 11476885 90. Renart A, Moreno-Bote R, Wang XJ, Parga N. Mean-Driven and Fluctuation-Driven Persistent Activity
in Recurrent Networks. Neural Computation. 2007; 19(1):1–46. https://doi.org/10.1162/neco.2007.19. 1.1 PMID: 17134316 91. Barbieri F, Brunel N. Can Attractor Network Models Account for the Statistics of Firing during Persis-
tent Activity in Prefrontal Cortex? Frontiers in neuroscience. 2008; 2(1):114–122. https://doi.org/10. 3389/neuro.01.003.2008 PMID: 18982114 92. Compte A, Constantinidis C, Tegne´r J, Raghavachari S, Chafee MV, Goldman-Rakic PS, et al. Tem-
porally Irregular Mnemonic Persistent Activity in Prefrontal Neurons of Monkeys During a Delayed
Response Task. Journal of Neurophysiology. 2003; 90(5):3441–3454. https://doi.org/10.1152/jn. 00949.2002 PMID: 12773500 93. Mongillo G, Hansel D, van Vreeswijk C. Bistability and Spatiotemporal Irregularity in Neuronal Net-
works with Nonlinear Synaptic Transmission. Physical Review Letters. 2012; 108(15):158101. https://
doi.org/10.1103/PhysRevLett.108.158101 PMID: 22587287 94. Markram H, Wang Y, Tsodyks M. Differential Signaling via the Same Axon of Neocortical Pyramidal
Neurons. Proceedings of the National Academy of Sciences. 1998; 95(9):5323–8. https://doi.org/10. 1073/pnas.95.9.5323 95. Mongillo G, Barak O, Tsodyks M. Synaptic Theory of Working Memory. Science. 2008; 319
(5869):1543–1546. https://doi.org/10.1126/science.1150769 PMID: 18339943 96. Gerstner W, Kistler WM, Naud R, Paninski L. Neuronal Dynamics: From Single Neurons to Networks
and Models of Cognition. Cambridge University Press; 2014. 97. Seeholzer A, Deger M, Gerstner W. Efficient Low-Dimensional Approximation of Continuous Attractor
Networks. arXiv:171108032 [q-bio]. 2017. 98. Forster O. Analysis 1: Differential- und Integralrechnung einer Vera¨nderlichen. Springer-Verlag;
2016. 99. Bos H, Morrison A, Peyser A, Hahne J, Helias M, Kunkel S, et al. NEST 2.10.0; 2015. https://doi.org/
10.5281/zenodo.44222. 100. Galassi M, Davies J, Theiler J, Gough B, Jungman G, Booth M, et al. GNU Scientific Library Reference
Manual. 3rd ed.; 2009. 101. Nawrot M, Aertsen A, Rotter S. Single-Trial Estimation of Neuronal Firing Rates: From Single-Neuron
Spike Trains to Population Activity. Journal of Neuroscience Methods. 1999; 94:81–92. https://doi.org/
10.1016/S0165-0270(99)00127-2 PMID: 10638817 102. Jones E, Oliphant T, Peterson. SciPy.Org—SciPy.Org; 2017. http://scipy.org/. 103. Efron B, Tibshirani RJ. An Introduction to the Bootstrap. CRC Press; 1994. 104. Evans C. Scikits-Bootstrap; 2017. https://github.com/cgevans/scikits-bootstrap. 105. Abdi H, Williams L. Jackknife. Encyclopedia of research design. 2010; p. 1–10. 106. Behnel S, Bradshaw R, Citro C, Dalcin L, Seljebotn DS, Smith K. Cython: The Best of Both Worlds. Computing in Science Engineering. 2011; 13(2):31–39. https://doi.org/10.1109/MCSE.2010.118 107. Oliphant TE. Python for Scientific Computing. PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1006928
April 19, 2019 Hempel CM, Hartman KH, Wang XJ, Turrigiano GG, Nelson SB. Multiple Forms of Short-Term Plastic-
ity at Excitatory Synapses in Rat Medial Prefrontal Cortex. Journal of Neurophysiology. 2000; 83
(5):3031–3041. https://doi.org/10.1152/jn.2000.83.5.3031 PMID: 10805698 84. Sakurai A, Katz PS. State-, Timing-, and Pattern-Dependent Neuromodulation of Synaptic Strength
by a Serotonergic Interneuron. Journal of Neuroscience. 2009; 29(1):268–279. https://doi.org/10. 1523/JNEUROSCI.4456-08.2009 PMID: 19129403 85. Laing CR, Longtin A. Noise-Induced Stabilization of Bumps in Systems with Long-Range Spatial Cou-
pling. Physica D: Nonlinear Phenomena. 2001; 160(3):149–172. https://doi.org/10.1016/S0167-2789
(01)00351-7 86. Wang H, Lam K, Fung CCA, Wong KYM, Wu S. Rich Spectrum of Neural Field Dynamics in the Pres-
ence of Short-Term Synaptic Depression. Physical Review E. 2015; 92(3):032908. https://doi.org/10. 1103/PhysRevE.92.032908 87. Mi Y, Lin X, Wu S. Neural Computations in a Dynamical System with Multiple Time Scales. Frontiers
in Computational Neuroscience. 2016; 10. https://doi.org/10.3389/fncom.2016.00096 PMID:
27679569 88. Fung C, Wong K, Wu S. A Moving Bump in a Continuous Manifold: A Comprehensive Study of the
Tracking Dynamics of Continuous Attractor Neural Networks. Neural Computation. 2010; 22(3):752–
792. https://doi.org/10.1162/neco.2009.07-08-824 PMID: 19922292 47 / 48 PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1006928
April 19, 2019 Computing in Science & Engineering. 2007; 9(3):10–20. https://doi.org/10.1109/MCSE.2007.58 48 / 48
|
https://openalex.org/W2160258147
|
https://repository.ubn.ru.nl/bitstream/handle/2066/152377/1/152377.pdf
|
English
| null |
Integrative Genomics-Based Discovery of Novel Regulators of the Innate Antiviral Response
|
PLOS computational biology/PLoS computational biology
| 2,015
|
cc-by
| 24,481
|
Integrative Genomics-Based Discovery of Novel Regulators of the Innate Antiviral Response
Lee, R. van der; Feng, Q.; Langereis, M.A.; Horst, R. ter; Szklarczyk, R.J.; Netea, M.G.; Andeweg,
A.C.; Kuppeveld, F.J.M. van; Huynen, M.A. 2015, Article / Letter to editor (Plos Computational Biology, 11, 10, (2015), pp. e1004553)
Doi link to publisher: https://doi.org/10.1371/journal.pcbi.1004553 Version of the following full text: Publisher’s version
Downloaded from: http://hdl.handle.net/2066/152377
Download date: 2024-10-24 Integrative Genomics-Based Discovery of Novel Regulators of the Innate Antiviral Response
Lee, R. van der; Feng, Q.; Langereis, M.A.; Horst, R. ter; Szklarczyk, R.J.; Netea, M.G.; Andeweg,
A.C.; Kuppeveld, F.J.M. van; Huynen, M.A.
2015, Article / Letter to editor (Plos Computational Biology, 11, 10, (2015), pp. e1004553)
Doi link to publisher: https://doi.org/10.1371/journal.pcbi.1004553 Integrative Genomics-Based Discovery of Novel Regulators of the Innate Antiviral Response
Lee, R. van der; Feng, Q.; Langereis, M.A.; Horst, R. ter; Szklarczyk, R.J.; Netea, M.G.; Andeweg,
A.C.; Kuppeveld, F.J.M. van; Huynen, M.A. 2015, Article / Letter to editor (Plos Computational Biology, 11, 10, (2015), pp. e1004553)
Doi link to publisher: https://doi.org/10.1371/journal.pcbi.1004553 OPEN ACCESS Citation: van der Lee R, Feng Q, Langereis MA, ter
Horst R, Szklarczyk R, Netea MG, et al. (2015)
Integrative Genomics-Based Discovery of Novel
Regulators of the Innate Antiviral Response. PLoS
Comput Biol 11(10): e1004553. doi:10.1371/journal. pcbi.1004553 Integrative Genomics-Based Discovery of
Novel Regulators of the Innate Antiviral
Response Robin van der Lee1*, Qian Feng2☯¤a, Martijn A. Langereis2☯, Rob ter Horst1,
Radek Szklarczyk1¤b, Mihai G. Netea3, Arno C. Andeweg4, Frank J. M. van Kuppeveld2,
Martijn A. Huynen1* 1 Centre for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences,
Radboud university medical center, Nijmegen, The Netherlands, 2 Virology Division, Department of
Infectious Diseases and Immunology, Faculty of Veterinary Medicine, University of Utrecht, Utrecht, The
Netherlands, 3 Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud
university medical center, Nijmegen, The Netherlands, 4 Department of Viroscience, Erasmus Medical
Center, Rotterdam, The Netherlands ☯These authors contributed equally to this work. ¤a Current address: Institute of Biochemistry, ETH Zurich, Zurich, Switzerland
¤b Current address: Department of Clinical Genetics, Unit Clinical Genomics, Maastricht University Medical
Centre, Maastricht, The Netherlands
* robin.vanderlee@radboudumc.nl (RvdL); martijn.huijnen@radboudumc.nl (MAH) ☯These authors contributed equally to this work. ¤a Current address: Institute of Biochemistry, ETH Zurich, Zurich, Switzerland
¤b Current address: Department of Clinical Genetics, Unit Clinical Genomics, Maastricht University Medical
Centre, Maastricht, The Netherlands
* robin.vanderlee@radboudumc.nl (RvdL); martijn.huijnen@radboudumc.nl (MAH) ☯These authors contributed equally to this work. ¤a Current address: Institute of Biochemistry, ETH Zurich, Zurich, Switzerland
¤b Current address: Department of Clinical Genetics, Unit Clinical Genomics, Maastricht University Medical
Centre, Maastricht, The Netherlands
* robin.vanderlee@radboudumc.nl (RvdL); martijn.huijnen@radboudumc.nl (MAH) Abstract The RIG-I-like receptor (RLR) pathway is essential for detecting cytosolic viral RNA to trig-
ger the production of type I interferons (IFNα/β) that initiate an innate antiviral response. Through systematic assessment of a wide variety of genomics data, we discovered 10
molecular signatures of known RLR pathway components that collectively predict novel
members. We demonstrate that RLR pathway genes, among others, tend to evolve rapidly,
interact with viral proteins, contain a limited set of protein domains, are regulated by specific
transcription factors, and form a tightly connected interaction network. Using a Bayesian
approach to integrate these signatures, we propose likely novel RLR regulators. RNAi
knockdown experiments revealed a high prediction accuracy, identifying 94 genes among
187 candidates tested (~50%) that affected viral RNA-induced production of IFNβ. The dis-
covered antiviral regulators may participate in a wide range of processes that highlight the
complexity of antiviral defense (e.g. MAP3K11, CDK11B, PSMA3, TRIM14, HSPA9B,
CDC37, NUP98, G3BP1), and include uncharacterized factors (DDX17, C6orf58, C16orf57,
PKN2, SNW1). Our validated RLR pathway list (http://rlr.cmbi.umcn.nl/), obtained using a
combination of integrative genomics and experiments, is a new resource for innate antiviral
immunity research. Editor: Bjoern Peters, La Jolla Institute for Allergy
and Immunology, UNITED STATES
Received: September 3, 2015
Accepted: September 12, 2015
Published: October 20, 2015
Copyright: © 2015 van der Lee et al. This is an open
access article distributed under the terms of the
Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any
medium, provided the original author and source are
credited. Editor: Bjoern Peters, La Jolla Institute for Allergy
and Immunology, UNITED STATES
Received: September 3, 2015
Accepted: September 12, 2015
Published: October 20, 2015 Copyright: © 2015 van der Lee et al. This is an open
access article distributed under the terms of the
Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any
medium, provided the original author and source are
credited. Data Availability Statement: All relevant data
supporting the results of this paper are available in
the Supplemental Tables and at http://rlr.cmbi.umcn. nl/. Funding: RvdL, QF, ACA and MAH were supported
by the Virgo consortium, funded by the Dutch
government (FES0908), and by the Netherlands
Genomics Initiative (050-060-452). QF and MAL were
funded by personal grants from the Netherlands
Organization for Scientific Research (NWO-
017.006.043 and NWO-863.13.008, respectively). RS
is supported by the Metakids Foundation. RESEARCH ARTICLE Note: To cite this publication please use the final published version (if applicable). Integrative Genomics of the RLR Pathway supported by an ERC Consolidator Grant (#310372). FJMvK was supported by a ECHO grant from the
Netherlands Organization for Scientific Research
(NWO-CW-700.59.007). The funders had no role in
study design, data collection and analysis, decision to
publish, or preparation of the manuscript. supported by an ERC Consolidator Grant (#310372). FJMvK was supported by a ECHO grant from the
Netherlands Organization for Scientific Research
(NWO-CW-700.59.007). The funders had no role in
study design, data collection and analysis, decision to
publish, or preparation of the manuscript. Abstract MGN was 1 / 35 PLOS Computational Biology | DOI:10.1371/journal.pcbi.1004553
October 20, 2015 Author Summary Viruses pose a continuous threat to human health, even though our immune systems have
evolved to neutralize invading viruses. As part of the innate immune system, the RIG-I-
like receptors (RLRs) are essential for detecting viruses during infection. Recognition of
viral RNA by the RLRs triggers an antiviral response that inhibits viral replication, protects
uninfected cells, and attracts specialized immune cells. Better understanding of the innate
antiviral response may reveal novel targets for antiviral therapeutics and vaccine develop-
ment. However, that requires knowledge about which genes and proteins are involved. In
the present study, we systematically investigated the wealth of available genomics data
(including gene expression, protein interactions, transcription regulation and genome
sequences) and discovered no less than 10 distinctive properties of genes known to be part
of the antiviral RLR pathway. By combining these properties in a statistical framework, we
predicted 187 novel RLR pathway components. Our validation experiments showed that
~50% of the predicted candidate genes have a significant effect on antiviral signaling. These results, together with independent computational and literature-based confirma-
tion, demonstrated the validity of our combined bioinformatics and experimental
approach. Our study expands the collection of known antiviral genes, opening up new ave-
nues for research into innate antiviral immunity. Competing Interests: The authors have declared
that no competing interests exist. PLOS Computational Biology | DOI:10.1371/journal.pcbi.1004553
October 20, 2015 Ten molecular signatures of RLR pathway components in genomics
data To discover molecular signatures that distinguish RLR pathway components from other genes,
we explored a wide variety of genome-scale data describing different aspects of the virology
and biology of the pathway. Some of these data we used directly, while other data were used as
the basis for further calculations (Table 1). We quantitatively assessed the predictive power of
each data set using a literature-curated standard of 49 known RLR pathway components from
InnateDB [21] (‘RLR genes’, S1 Fig) and a set of 5,818 ‘non-RLR genes’ that are unlikely to be
part of the pathway (i.e. genes with known functions not directly related to the innate antiviral
response, such as development, housekeeping and neurological processes, see Methods). Below
we describe 10 signatures for predicting novel RLR pathway components. The first five signa-
tures are based on the relationship of RLR genes with viruses, whereas the second set of five sig-
natures are based on properties of the RLR pathway itself. Integrative Genomics of the RLR Pathway such screens report distinct sets of genes, often with limited overlap between them. Combining
the many available genomics data sets in a statistical framework potentially allows for a more
systematic discovery and categorization of genes involved in the RLR pathway. Indeed, Bayes-
ian integration of large-scale data that includes weighing individual datasets for their predictive
potential has been successful in other cellular systems, for example identifying novel protein
interactions [18], mitochondrial disease genes [19], and small RNA pathway genes [20]. In this work we systematically exploit the wealth of available (gen)omics data, including
transcriptomics and proteomics data, genome sequences, protein domain information, and
functional genomics, to discover descriptive molecular signatures of the RLR pathway system. Bayesian integration of these data, together with comprehensive computational and experi-
mental validation, confidently identifies novel genes involved in antiviral RIG-I signaling. Results The RIG-I-like receptor (RLR) pathway is a highly interconnected and diverse molecular sys-
tem. We investigated whether available genomics data contain sufficient signal to accurately
describe RLR pathway components, and whether such data could be used to prioritize novel
genes for a possible role in RLR signaling. Introduction Viruses are a major cause of human disease, as highlighted by the pandemics of influenza
viruses, HIV–1, and the current outbreak of the Ebola virus. Pattern recognition receptors
(PRR) are among the first molecules that detect viruses during infection. The RIG-I-like recep-
tors (RLRs, one class of PRRs) are part of the RLR pathway, which forms a crucial innate anti-
viral defense system [1,2]. Two RLRs, RIG-I and MDA5, reside in the cytosol where they
recognize non-self 5’-triphosphate RNA molecules with short double-stranded regions and
long double-stranded RNAs (dsRNA), respectively [3]. Activation of the receptors triggers a
complex signaling network, key steps of which are the activation of the mitochondrial adapter
MAVS, subsequent recruitment of the TBK1 and IKK complexes, phosphorylation/activation
of IRF3 and NFκB, and translocation of these transcription factors to the nucleus. These steps
ultimately lead to the production of type I interferons (IFNα/β) and proinflammatory cyto-
kines, which are crucial for establishing an antiviral state in infected as well as neighboring
cells, and also modulate the adaptive immune response [4] The importance of the RLR system is further demonstrated by the observation that viruses
of all types employ strategies to interfere with its activation, often at multiple steps [5,6]. Better
understanding of viral interaction with the pathway has resulted in novel targets for the devel-
opment of antiviral therapeutics and attenuated live vaccines, for example viruses lacking func-
tional RLR antagonists [7]. Furthermore, mutations in RIG-I, MDA5, MAVS and other RLR
pathway components are associated not only with strong susceptibility to infections, but also
IFN-associated autoimmune disorders [8–10]. Previous studies into virus-host interactions and the innate antiviral pathways have used
genomics approaches, often generating large data sets describing physical or genetic interac-
tions [11–14]. Other publications have taken a comparative approach based on model organ-
isms [15] or used over-expression screening systems [16,17]. Together, these studies have
identified numerous genes with antiviral activity, including members of the RLR pathway. However, it remains important to systematically assess the quality of individual data sets as PLOS Computational Biology | DOI:10.1371/journal.pcbi.1004553
October 20, 2015 2 / 35 PLOS Computational Biology | DOI:10.1371/journal.pcbi.1004553
October 20, 2015 Integrative Genomics of the RLR Pathway Table 1. Ten molecular signatures from genomics data used for predicting novel RLR pathway components. Group
Molecular
signature
Data set description
Type a
References
Number of
genes b
Likelihood ratio
score b,c
Virus-based
Positive selection in
primates
Rapidly evolving genes in the primates lineage,
detected using maximum likelihood analysis of
nucleotide alignments
d
[23]
926
1.7
PPI with viruses
Virus-interacting human proteins extracted from PPI
databases
c
[28]
2,587
4.2
Viral miRNA target
Likelihood scores of targeting of human transcripts by
viral miRNAs, based on predicted target sites
c
[30]
6,761
1.3
Differential
expression upon
infection
Genes showing differential expression in lung
epithelial cells infected with four respiratory viruses
c
see
Methods
1,680
3.5
Antiviral host factor
Meta analysis of genes with antiviral activity from
seven RNAi screens studying a variety of viruses
c
see S3
Table
173
2.1
Pathway-
based
Co-expression with
RLR pathway
Weighted co-expression with known RLR genes
across >450 human gene expression studies
c
[32]
4,149
2.4
RLR pathway protein
domain
Proteins containing one of the 25 domains that are
significantly enriched in known RLR proteins
c
[66]
711
8.9
Innate antiviral TF
binding motifs
Genes with IRF, AP–1, NFκB, or STAT TF binding
motifs in their promoters, based on conservation
across 29 mammals
c
[33]
4,508
2.3
NFκB activation
mediator
Hits from a genome-wide siRNA screen of Epstein-
Barr virus-induced NFκB activation
d
[34]
154
19.8
RLR pathway PPI
Proteins that interact with known RLR proteins,
calculated from PPI data
c
[35]
1,750
4.3
Integration
RLR score
Bayesian integration of the 10 molecular signatures to predict novel RLR pathway components a Data used directly (d) or as basis for further calculation (c) b Combination of all bins with positive likelihood ratio scores per feature, derived from Fig 1A doi:10.1371/journal.pcbi.1004553.t001 doi:10.1371/journal.pcbi.1004553.t001 of RLR pathway components (35/49 = 71%), while they include a significantly smaller fraction
of non-RLR genes (1,000/5,818 = 17%, 4.2-fold enrichment, P = 1.4 × 10−16, one-tailed Fisher’s
exact test, Fig 1A and Table 1). Among the RLR genes, TRAF2 (4 PPIs), DDX3, MAPK9, and
the NFκB subunit RELA (3 PPIs each) have reported interactions with the largest number of
distinct virus species. Viral miRNA target. Another mechanism that viruses use to interfere with the antiviral
activity of human cells is down-regulation of gene expression by miRNAs [29]. Virus-based signatures Positive selection in primates. Viruses evade recognition or interfere with the immune
systems of their hosts to achieve successful infection [7]. This involves interactions between
viral and host proteins, the interfaces of which are under constant pressure to change [22]. We
collected data on recurrent positive selection in the primate lineage, based on maximum likeli-
hood analysis of sequence alignments [23]. RLR pathway components, e.g. the mitochondrial
signaling adapter MAVS [24] and transcription factor IRF7 [25], are enriched for rapidly
evolving genes (9% of 49 RLR genes) compared to genes that are unlikely to be part of the path-
way (5% of 5,818 non-RLR genes, 1.7-fold enrichment, non-significant P = 0.38, one-tailed
Fisher’s exact test, Fig 1A, Tables 1 and S1). Protein-protein interactions (PPI) with viruses. The next signature is based on the phys-
ical interactions between host RLR pathway components and viruses. Viral proteins often
interact with many host proteins during their infection cycle, including those involved in anti-
viral defense [26,27]. Extraction of virus-human PPIs from specialized databases [28] revealed
~2,600 human proteins that are reported to interact with at least one viral protein (virus-inter-
acting human proteins, S2 Fig). These virus-interacting human proteins include the majority 3 / 35 PLOS Computational Biology | DOI:10.1371/journal.pcbi.1004553
October 20, 2015 a Data used directly (d) or as basis for further calculation (c) PLOS Computational Biology | DOI:10.1371/journal.pcbi.1004553
October 20, 2015 Integrative Genomics of the RLR Pathway Fig 1. Bayesian integration of ten molecular signatures of RLR pathway components from genomics data. (A) Distributions of the 49 known RLR
pathway components (RLR genes, green) and 5,818 genes unlikely to be part of the pathway (non-RLR genes, red) across the 10 molecular signature data
sets we identified as predictive of the RLR system (see also Table 1). Data sets were binned into discrete intervals and fractions of (non-)RLR genes add up
to one. Arrows indicate the behavior of RIG-I across the data. The top five signatures describe the relationship of RLR signaling with viruses; the bottom five
describe properties of the pathway itself. (B) Boxplots of the genome-wide integrated RLR score (Bayesian posterior probability score). Genes were grouped
into one of five classes: known RLR genes (green, see [A]), components of other PRR signaling pathways (‘TLR, CLR, NLR, cytDNA’; purple), genes
functioning in other aspects of the innate immune response (‘innate immunity’; blue), and non-RLR genes (red, see [A]). The remaining genes are classified
as ‘other’ (gray). (C) The 50 genes with the highest RLR scores. Representative RLR and other innate antiviral response genes are indicated. The pie chart
shows the occurrences of the different gene classes in the top 354 RLR ranks. (D) Receiver operating characteristic (ROC) curve illustrating the performance
of the integrated RLR score (solid black line) and the individual molecular signatures (black dots) for predicting known RLR versus non-RLR genes. Sensitivity and specificity were calculated at various score thresholds (for the RLR score), or at specific thresholds that include all bins with positive likelihood
ratio scores (for the individual data sets; see (A)) The asterisk denotes the sensitivity and specificity corresponding to a false discovery rate (FDR) of 57% Fig 1. Bayesian integration of ten molecular signatures of RLR pathway components from genomics data. (A) Distributions of the 49 known RLR
pathway components (RLR genes, green) and 5,818 genes unlikely to be part of the pathway (non-RLR genes, red) across the 10 molecular signature data
sets we identified as predictive of the RLR system (see also Table 1). Data sets were binned into discrete intervals and fractions of (non-)RLR genes add up
to one. Arrows indicate the behavior of RIG-I across the data. The top five signatures describe the relationship of RLR signaling with viruses; the bottom five
describe properties of the pathway itself. We collected
128 miRNAs encoded by nine, mainly herpes DNA viruses (S2 Table) [30], most of which
have confirmed physiological relevance. Predicted target sites of these miRNAs to the 3’UTR of
human transcripts were then used to calculate for each gene a score representing the likelihood
that viruses affect its expression (viral miRNA targeting score). For example, our method
assigned IKBKE (IKKε) a relatively strong viral miRNA targeting score of 2.7. Indeed, Kaposi’s
sarcoma-associated herpesvirus miR-K12-11 has been shown to inhibit translation of IKKε
transcripts, leading to suppression of interferon signaling [31]. Analysis of the viral miRNA
targeting scores revealed that RLR genes tend to have stronger scores than non-RLR genes
(P = 0.03, one-tailed Mann-Whitney U test). Although the statistical significance of this trend
is only marginal, we included it as a molecular signature of RLR genes as it still provides a PLOS Computational Biology | DOI:10.1371/journal.pcbi.1004553
October 20, 2015 4 / 35 doi:10.1371/journal.pcbi.1004553.g001 Integrative Genomics of the RLR Pathway moderate enrichment over non-RLR genes (1.3-fold enrichment among genes with the stron-
gest viral miRNA targeting scores, Table 1), and even weak features can substantially improve
the predictions for novel RLR genes. Differential expression upon infection. Next, we asked whether RLR pathway genes are
differentially expressed upon virus infection. To answer this, we used in-house gene expression
data of human lung epithelial cells (A549) exposed to four respiratory viruses (respiratory syn-
cytial virus, human metapneumovirus, parainfluenza virus, or measles virus), for which gene
expression was measured at 6, 12 and 24 hours after infection (see Methods). Analysis of the
transcriptomes revealed that many RLR genes (31%) underwent substantial expression changes
(log2 fold change >0.5) in cells infected with the respiratory viruses, compared to the unin-
fected cells. This compares to a much smaller fraction of non-RLR genes (9%, 3.5-fold enrich-
ment, P = 1.3 × 10−5, one-tailed Fisher’s exact test, Fig 1A and Table 1). The differentially
expressed RLR genes include well-known interferon-stimulated genes (ISGs) like ISG15,
DDX58 (RIG-I), IRF7, IFIH1 (MDA5), and TRIM25, which are the top five RLR genes most
induced by the respiratory viruses studied (log2 fold change >1.5 compared to uninfected cells,
S3 Fig). Thus, even though we expect many RLR genes to already be expressed before viral
infection, their expression levels are reinforced in infected cells. Antiviral host factor. RNAi screening potentially allows the identification of host factors
that limit virus replication, such as genes involved in the innate antiviral response, although
most studies focus on hits with the opposite effect (i.e. factors required by viruses for replica-
tion) [11]. We performed a meta analysis of hits from seven large-scale RNAi studies in human
cells, identifying 173 genes with antiviral activity against HIV–1, influenza, hepatitis C (HCV),
West Nile, or enterovirus infection (S3 Table). In contrast to our expectation that RLR genes
would be common among these antiviral host factors, this data set is one of the weaker predic-
tors of RLR genes: the 173 antiviral host factors contain only a single gene (IRF3) that belongs
to the set of 49 known RLR genes (~2%) compared to 56 of 5,818 non-RLR genes (~1%,
2.1-fold enrichment, non-significant P = 0.38, one-tailed Fisher’s exact test, Fig 1A and
Table 1). (B) Boxplots of the genome-wide integrated RLR score (Bayesian posterior probability score). Genes were grouped
into one of five classes: known RLR genes (green, see [A]), components of other PRR signaling pathways (‘TLR, CLR, NLR, cytDNA’; purple), genes
functioning in other aspects of the innate immune response (‘innate immunity’; blue), and non-RLR genes (red, see [A]). The remaining genes are classified
as ‘other’ (gray). (C) The 50 genes with the highest RLR scores. Representative RLR and other innate antiviral response genes are indicated. The pie chart
shows the occurrences of the different gene classes in the top 354 RLR ranks. (D) Receiver operating characteristic (ROC) curve illustrating the performance
of the integrated RLR score (solid black line) and the individual molecular signatures (black dots) for predicting known RLR versus non-RLR genes. Sensitivity and specificity were calculated at various score thresholds (for the RLR score), or at specific thresholds that include all bins with positive likelihood
ratio scores (for the individual data sets; see (A)). The asterisk denotes the sensitivity and specificity corresponding to a false discovery rate (FDR) of 57%
(top 354 genes). Note that, to avoid circularity, the predictive ability of the co-expression, protein domain and RLR pathway PPI data sets in (A) and (D) was
assessed using the set of TLR, CLR, NLR, cytDNA genes instead of the RLR genes (see Methods). doi:10.1371/journal.pcbi.1004553.g001 PLOS Computational Biology | DOI:10.1371/journal.pcbi.1004553
October 20, 2015 5 / 35 Integrative Genomics of the RLR Pathway These include protein kinase domains (12-fold enrichment, P = 1.1 × 10−8; present in IKKα/β/
ε, MAP kinases, TBK1), the TBK1/IKKi binding domain (TANK, TBK1BP1, AZI2), caspase
and death domains (CASP8/10, FADD), IRF domains (IRF3/7), and the DExD/H box RNA
helicase domain (15-fold enrichment, P = 2.7 × 10−3; RIG-I, MDA5, LGP2). We then assessed
the domain organizations of all human proteins and determined a set of 711 proteins contain-
ing one or more of the domains enriched in RLR components. These proteins are predictive for
RLR components with an enrichment score of 8.9 (Table 1). p
Innate antiviral transcription factor (TF) binding motifs. Signaling through the RLR
pathway triggers the activation of key transcription factors (TFs) like IRF3, IRF7, AP–1 and
NFκB. Activation of these TFs leads to the production of type I interferons and proinflamma-
tory cytokines that eventually activate STAT1 and STAT2 [2]. STAT1 and STAT2 in turn stim-
ulate transcription of interferon-stimulated genes (ISGs), which include many RLR pathway
components. To further explore the transcription regulation of RLR pathway components, we
analyzed their gene promoters for the presence of TF binding motifs that are highly conserved
across the genomes of 29 placental mammals, such as primates, rodents and many farm ani-
mals [33]. Conserved IRF and NFκB motifs are highly abundant in the promoters of RLR
genes (Fisher’s exact P = 3.3 × 10−3 and P = 2.0 × 10−4, respectively; S5 Table), suggesting the
pathway is partly self-regulating as has been observed for individual components. Interestingly,
a conserved IRF motif was detected not only in the promoters of IRF7 itself and in all three
RIG-I-like receptor family members (DDX58 [RIG-I], IFIH1 [MDA5], DHX58 [LGP2]), but
also in TRIM25, ISG15, and CYLD; three factors controlling RIG-I signaling activation by regu-
lating the level of K63 polyubiquitination. In order to predict novel RLR components, we
searched for genes containing conserved IRF binding motifs (several motif variants, collectively
recognized by IRF1-9), STAT binding motifs (several motif variants, collectively recognized by
STAT1-6), AP–1 binding motifs, or NFκB binding motifs (Fig 1A). We found 3,558 genes
across the human genome containing one of these motifs in their promoters. This large num-
ber partially stems from similarities in the DNA binding preferences of TFs that belong to the
same family, but does not mean that all identified genes are regulated by the RLR pathway. Pathway-based signatures Co-expression with RLR pathway. To aid in finding novel RLR genes, we screened >450
human expression studies for genes that co-express with known RLR pathway components
using a two-step approach [32]. First, we weighed individual expression data sets for their
propensity to predict new RLR genes: experiments in which the whole group of known RLR
genes show high co-expression with each other received a higher weight and contributed most
to the calculations. In the second step, we calculated the co-expression of all genes with the
RLR genes. As expected, RLR genes display significantly higher co-expression scores with each
other than with the rest of the genome or with non-RLR genes (P 10−27 for both compari-
sons, one-tailed Mann-Whitney U test, S4 Fig). However, RLR genes also score higher
than components of other PRR signaling pathways (Toll-like receptor [TLR], C-type lectin
receptor [CLR], NOD-like receptor [NLR], and cytosolic dsDNA sensing [cytDNA] pathways;
P = 4.5 × 10−13, one-tailed Mann-Whitney U test). Cross-validation by leave-one-out analysis
confirms that the weighted co-expression approach retrieves RLR genes more readily than
other PRR pathway genes, or genes involved in other aspects of innate immunity (S4D Fig),
demonstrating specificity for identifying RLR genes in the co-expression data. RLR pathway protein domain. Analysis of RLR pathway protein sequences revealed the
presence of 40 unique domains, 25 of which were significantly over-represented compared to
the full human proteome (Benjamini-Hochberg-corrected Fisher’s exact P < 0.01, S4 Table). PLOS Computational Biology | DOI:10.1371/journal.pcbi.1004553
October 20, 2015 6 / 35 PLOS Computational Biology | DOI:10.1371/journal.pcbi.1004553
October 20, 2015 Bayesian integration of molecular signatures provides genome-wide
probabilities for RLR pathway components The RLR pathway components published thus far probably constitute only part of the total
proteins with a function in this pathway. To prioritize novel high-confidence genes for a role in
the RLR pathway, we integrated the 10 identified molecular signatures of RLR genes in a naive
Bayesian classifier [18,19] (see Methods). This approach weighs data sets based on their pre-
dictive value (i.e. their ability to separate known positives and negatives; Fig 1A, Tables 1 and
S1) so that ‘better’ data contribute more to the predictions. Each human gene received a poste-
rior probability score (‘RLR score’) reflecting the likelihood that the gene is part of the RLR
pathway based on its behavior in the collected genomics data. A score of zero indicates equal
probabilities of a gene being an RLR versus a non-RLR gene. S6 Table presents the genome-
wide ranking of RLR scores (also available at http://rlr.cmbi.umcn.nl/). As expected, known RLR pathway components have the highest RLR scores (Figs 1B and
S5). Two-thirds (32/49) of these rank within the first 150 genes. The top ranking genes are
IRF7, RIG-I, IKKε, subunits of NFκB, TRADD, TRAF2, MDA5, and IKKγ (NEMO) (Fig 1C). Other examples of well-described RLR pathway components include IRF3 (rank 51), ISG15
(52), MAVS (102), and LGP2 (114). Genes that are unlikely to play a role in the pathway (the
set of non-RLR genes) generally have very low RLR scores, although some of these received
high scores as well (Fig 1B). This is not unexpected, as even though this large set of genes was
selected from function annotations generally unrelated to the innate antiviral response, this
does not preclude that individual genes (also) function in the RLR pathway. To gain insight into what kind of genes are present among the RLR predictions, we examined
their functions by pathway and gene ontology enrichment analyses. The top 354 genes with the
highest RLR scores (corresponding to high-confidence predictions, see below) have strong links
with other pathways of the innate immune response, such as TLR, NLR, interferon, and cytokine
signaling (S6 and S7 Figs). Antiviral defense functions are also among the most frequent and sig-
nificant terms associated with the high-scoring genes (S8 Fig and S7 Table). Other important
biological processes include various apoptosis-related functions, cancer and cell cycle pathways,
and regulation of metabolic processes and protein localization. Integrative Genomics of the RLR Pathway RLR proteins. These proteins are predictive for RLR components with an enrichment score of 1.8
(S1 Table). A further 221 proteins interact with three of four RLR proteins (6.3-fold enrichment)
and 132 proteins interact with five or more RLR proteins (15.8-fold enrichment). TBK1 (18 inter-
actions), TRAF2 and MAVS (both 16) top the list, supporting their roles as central players in the
RLR system [12]. Thus, an increasing number of interactions with RLR proteins indicates a
higher likelihood that a protein is part of the RLR pathway. RLR proteins. These proteins are predictive for RLR components with an enrichment score of 1.8
(S1 Table). A further 221 proteins interact with three of four RLR proteins (6.3-fold enrichment)
and 132 proteins interact with five or more RLR proteins (15.8-fold enrichment). TBK1 (18 inter-
actions), TRAF2 and MAVS (both 16) top the list, supporting their roles as central players in the
RLR system [12]. Thus, an increasing number of interactions with RLR proteins indicates a
higher likelihood that a protein is part of the RLR pathway. Bayesian integration of molecular signatures provides genome-wide
probabilities for RLR pathway components Furthermore, the top predictions
include a wide range of protein families, notably proteasome subunits, ubiquitin(-like) conjugat-
ing enzymes, and genes involved in phosphatidylinositol signaling (which was recently shown to
affect the type I IFN response [14]). Finally, 22% of the top predictions are induced in cells
treated with interferons (i.e. they are interferon-stimulated genes, ISGs) and ~18% are part of the
common host transcription response to pathogens (Table 2). Together, these observations indi-
cate that our framework successfully predicts genes with a likely role in the innate antiviral
response and suggests other cellular systems and functions required for this response. For
example, STAT motifs not only occur in the promoters of ISGs, but also in genes involved in
cellular proliferation, differentiation and apoptosis. Nevertheless, genes containing one of the
four conserved TF motifs already show a good predictive value for RLR pathway components
(enrichment score of 2.2, S1 Table). Genes with more than one motif are even more likely to be
RLR genes: 789 genes contain two motifs (2.6-fold enrichment) and 161 genes contain three or
all four motifs (2.4-fold enrichment). NFκB activation mediator. Host factors that regulate NFκB activation often also affect
the RLR pathway. Indeed, the 154 hits that were picked up in a genome-wide siRNA screen of
Epstein-Barr virus-induced NFκB activation [34] include a much larger fraction of known RLR
genes (6/49 = 12%) than non-RLR genes (36/5,818 < 1%, 20-fold enrichment, P = 1.0 × 10−6,
one-tailed Fisher’s exact test, Fig 1A and Table 1). Thus, these 154 NFκB activation mediators
are likely to contain novel RLR pathway components as well. RLR pathway PPI. Finally, to find novel RLR genes we assessed the human protein interac-
tion network connecting the RLR pathway. PPI databases [35] report 3,504 interactions between
1,750 unique proteins and 47 of the 49 RLR components, the only exceptions being DAK and
NLRX1. Of the 47 RLR proteins with reported PPIs, 41 are involved in a total of 147 interactions
within the pathway (i.e. between two pathway members). This network of RLR components has
significantly more connections with each other than do random networks of the same size and
interaction degree distribution (physical interaction enrichment score = 3.6, P < 1.0 × 10−6 [36]). Using the PPI data, we obtained for each human protein the number of interacting RLR pathway
components (Fig 1A). We found a total of 1,397 proteins reported to interact with one or two PLOS Computational Biology | DOI:10.1371/journal.pcbi.1004553
October 20, 2015 7 / 35 Performance estimates and independent data establish the reliability of
the RLR score We further computationally assessed the reliability of the integrated RLR score by estimating
the sensitivity, specificity and false discovery rate (FDR) of the predictions using the positive 8 / 35 PLOS Computational Biology | DOI:10.1371/journal.pcbi.1004553
October 20, 2015 for the ‘PPI with viruses’ signature) doi:10.1371/journal.pcbi.1004553.t002 (RLR genes) and negative (non-RLR genes) standards. Integration of the data sets achieved bet-
ter sensitivity and specificity than any of the individual data sets (Fig 1D), thereby enriching
for RLR genes and depleting false positives (S5, S9 and S10 Figs). At an RLR rank threshold of
354 (RLR score -1.10), the framework correctly predicts 78% of the known RLR genes with a
specificity of 98.4% (Fig 1D). At this threshold, only ~57% of the novel predictions are esti-
mated to be false (S11 Fig, adjusted FDR to match the expected total number of genes involved
in the RLR pathway, see Methods). This compares to a genome-wide false discovery rate
(i.e. when predicting genes randomly) of ~99%. Thus, the integrated RLR score increases the
probability of correctly identifying novel RLR genes by a factor of 43 compared to random
classification. Because we used the same gene sets for calculating the RLR scores and estimating the per-
formance of the resulting predictions (i.e. without systematic cross-validation), there exists a
danger of circular reasoning. Therefore, we also carefully validated the quality of the results
using various independent and external data sets. First, we examined the high RLR scores for
genes that have a known function in innate immunity, but not in the RLR pathway, and there-
fore were not part of our training set. Components of other PRR signaling pathways (TLR,
CLR, NLR, cytDNA) have lower scores than RLR genes, but much higher scores than the rest
of the genome (Fig 1B). The same is true for genes functioning in other aspects of the innate
immune response (Fig 1B). Of the 225 novel predictions (i.e. those genes that are not part of
the training sets) in the top 354 (FDR of 57%, see above), 142 (~63%) are part of these innate
immunity gene lists (Fig 1C). Thus, the majority of high-scoring genes with no known link to
the RLR pathway in fact have a function in other PRR pathways or other parts of innate immu-
nity, supporting the relevance of our predictions. Second, we compared our predictions to six recent data sets that are relevant to the innate
(antiviral) response but that were in no way part of the RLR score calculations. Integrative Genomics of the RLR Pathway Table 2. Overlap between innate (antiviral) response data sets and the top 354 RLR predictions excluding known RLR genes. Data set
References
Number of genes
in data set
Fraction (number) of data set genes
in top 354 predictions
One-tailed Fisher’s
exact P
Interferon-stimulated genes (ISGs)
[16]
354
22.0% (78)
1.2 × 10−67
ISGs with validated antiviral activity
[16,91]
45
42.2% (19)
4.9 × 10−23
Common host transcription response to
pathogens
[92]
496
17.7% (88)
5.2 × 10−68
Interactors of the type I IFN protein network during
pattern recognition (HCIP) a
[12]
241
11.2% (27)
1.2 × 10−15
HCIP with confirmed effects on IFNβ expression
and antiviral activity
[12]
22
22.7% (5)
1.9 × 10−5
Tripartite motif (TRIM) family genes
[17]
71
12.7% (9)
1.6 × 10−6
TRIMs that enhance RIG-I-induced activation of
IFNβ, NFκB and ISRE promoters
[17]
34
14.7% (5)
1.7 × 10−4
Human interactors of innate immune-modulating
viral ORFs b
[37]
569
6.7% (38)
4.7 × 10−14
Genes expressed in PBMCs stimulated with
Candida (CRG)
[38]
89
43.8% (39)
4.7 × 10−47
CRG with altered expression in CMC patients
[38]
23
65.2% (15)
2.6 × 10−22
Type I IFN response mediators
[14]
226
4.0% (9)
9.5 × 10−3
a These PPIs were not part of the RLR interaction network used for the RLR predictions (i.e. for the ‘RLR pathway PPI’ signature)
b These interactions were not used to determine the virus-interacting human proteins used for the RLR predictions (i.e. for the ‘PPI with viruses’ signature)
d i 10 1371/j
l
bi 1004553 t002 Table 2. Overlap between innate (antiviral) response data sets and the top 354 RLR predictions excluding k top 354 RLR predictions excluding known RLR genes ween innate (antiviral) response data sets and the top 354 RLR predictions excluding known RLR genes. rt of the RLR interaction network used for the RLR predictions (i.e. for the ‘RLR pathway PPI’ signature) not part of the RLR interaction network used for the RLR predictions (i.e. for the ‘RLR pathway PPI’ signature)
s were not used to determine the virus-interacting human proteins used for the RLR predictions (i.e. for the ‘PPI w a These PPIs were not part of the RLR interaction network used for the RLR predictions (i.e. for the ‘RLR pathway PPI’ signature)
b These interactions were not used to determine the virus-interacting human proteins used for the RLR predictions (i.e. (v) Furthermore, the type I IFN response has recently been proposed to play a role in antifun-
gal immunity [38,39] and the top RLR predictions are strongly enriched for genes expressed in
PBMCs stimulated with the fungal pathogen Candida albicans: almost half (39/89 = 44%)
of these occur in our top predictions (P = 4.7 × 10−47, one-tailed Fisher’s exact test, Table 2). (vi) Finally, the overlap between our predictions and a genome-wide screen for regulators of
RIG-I-mediated IFNβ production is, at only nine, marginal but significant (9/226 genes = 4%,
P = 9.5 × 10−3, one-tailed Fisher’s exact test, Table 2) [14]. In summary, these diverse and inde-
pendent experimental data support the validity of our integrated RLR score for predicting
genes with a role in the innate antiviral response. RNAi validation screens confirm the high predictive value of the
integrated RLR score To further determine the predictive power of our in silico predictions, we selected 187 candi-
date RLR genes for experimental validation (S6 and S8 Tables). These include 127 high-confi-
dence candidates from the top 354, which have not been previously linked to the RLR pathway,
supplemented with 60 candidates we selected from the top 1000 predictions, mainly on the
basis of limited functional characterization in general (Fig 2A). Importantly, candidates with a
known role in RLR signaling, other branches of PRR pathways, or apoptosis were excluded as
we were most interested in finding novel components of the RLR pathway. For the selected candidates we performed a medium-throughput RNAi screen (RNAi screen
1) using HeLa cells stably expressing an IFNβ promoter-controlled firefly luciferase reporter
(HeLa-IFNβ-Fluc). To activate the RLR pathway and induce Fluc reporter expression we used
a known small 5’-ppp-containing RIG-I ligand [40]. This setup led to specific activation of
RIG-I, as RIG-I or MAVS siRNA transfection, but not MDA5 or scrambled siRNAs, resulted
in loss of reporter activity (Figs 2B, S12 and S13). All negative controls (non-transfected,
scrambled and MDA5 siRNAs) scored within 1.25 median absolute deviations of the plate nor-
malized IFNβ induction levels (Z-score cutoff <-1.25 or >1.25, Fig 2B). At this cutoff, siRNA
knockdown of 94 candidates (50% of all candidates tested) affected RIG-I-mediated IFNβ
induction (Figs 2A and S13A–S13D and S8 Table). Among these, knockdown of 59 genes
decreased RIG-I-mediated IFNβ induction (down-hits) and 35 genes increased IFNβ induction
(up-hits). It is important to note that the experimental approach only activates the RIG-I
branch of the RLR pathway and will not confirm predicted RLR candidates that regulate
MDA5 activation and downstream signaling to MAVS. Thus, among the 93 non-confirmed
candidates, there might still be novel regulators of the MDA5-mediated IFNβ induction path-
way, which should be further investigated. Altogether, the integrated RLR score is clearly a
strong and reliable predictor for novel regulators of the RIG-I pathway. From the 94 confirmed hits, we picked the 57 top hits with the largest effect (stringent Z-
score <-2 or >2) for a second RNAi screen using a different set of siRNAs (RNAi screen 2,
Fig 2A). In this second RNAi screen, only a single up-hit (7% of 15 up-hits tested) showed a Z-
score >1.25. The overlap
with the 354 top genes, excluding known RLR genes, is significantly larger than expected by 9 / 35 PLOS Computational Biology | DOI:10.1371/journal.pcbi.1004553
October 20, 2015 Integrative Genomics of the RLR Pathway chance for all these data sets (Table 2). For example, the top predictions include: (i) 19 of 45
(42%) interferon-stimulated genes with validated antiviral activity against e.g. HIV–1, HCV,
yellow fever, West Nile or chikungunya virus [16], (ii) 27 proteins from a set of 241 (11%) that
interact with the type I IFN protein network during pattern recognition, among which are five
confirmed modulators of IFNβ expression and antiviral activity [12], (iii) nine tripartite motif
(TRIM) family genes, five of which enhance RIG-I-induced activation of IFNβ, NFκB and chance for all these data sets (Table 2). For example, the top predictions include: (i) 19 of 45
(42%) interferon-stimulated genes with validated antiviral activity against e.g. HIV–1, HCV,
yellow fever, West Nile or chikungunya virus [16], (ii) 27 proteins from a set of 241 (11%) that
interact with the type I IFN protein network during pattern recognition, among which are five
confirmed modulators of IFNβ expression and antiviral activity [12], (iii) nine tripartite motif
(TRIM) family genes, five of which enhance RIG-I-induced activation of IFNβ, NFκB and
ISRE (IFN-stimulated response element) promoters [17], and (iv) 38 human proteins interact-
ing with innate immune-modulating viral open reading frames (viORFs) from 30 viruses [37]. (v) Furthermore, the type I IFN response has recently been proposed to play a role in antifun-
gal immunity [38,39] and the top RLR predictions are strongly enriched for genes expressed in
PBMCs stimulated with the fungal pathogen Candida albicans: almost half (39/89 = 44%)
of these occur in our top predictions (P = 4.7 × 10−47, one-tailed Fisher’s exact test, Table 2). (vi) Finally, the overlap between our predictions and a genome-wide screen for regulators of
RIG-I-mediated IFNβ production is, at only nine, marginal but significant (9/226 genes = 4%,
P = 9.5 × 10−3, one-tailed Fisher’s exact test, Table 2) [14]. In summary, these diverse and inde-
pendent experimental data support the validity of our integrated RLR score for predicting
genes with a role in the innate antiviral response. (TRIM) family genes, five of which enhance RIG-I-induced activation of IFNβ, NFκB and
ISRE (IFN-stimulated response element) promoters [17], and (iv) 38 human proteins interact-
ing with innate immune-modulating viral open reading frames (viORFs) from 30 viruses [37]. RNAi validation screens confirm the high predictive value of the
integrated RLR score Besides this hit, two negative control wells also had a Z-score >1.25 (Figs 2B, 10 / 35 PLOS Computational Biology | DOI:10.1371/journal.pcbi.1004553
October 20, 2015 Integrative Genomics of the RLR Pathway Fig 2. RNAi screens validate a role for the novel RLR candidates in RIG-I-mediated IFNβ induction. (A) Flow chart of the RNAi validation screens. 187
candidate RLR genes were screened for RIG-I pathway activity in three different RNAi screens. In screens 1 and 2, HeLa cells stably expressing an IFNβ
promoter-controlled firefly luciferase (Fluc) reporter were stimulated with a 5’-ppp-containing RIG-I RNA ligand. The 57 hits (15 up, 42 down) with the largest
effect on IFNβ induction upon siRNA knockdown in screen 1 (stringent Z-score <-2 or >2) were tested again in screen 2 with a different set of siRNAs. The 19 top
hits from screen 2 were then picked for screen 3, which is similar to the first two screens except that it measures IFNβ mRNA levels using quantitative real-time
qRT-PCR. (B) Correlation between the negative control-based robust Z-scores of RNAi screens 1 and 2. The 57 top hits with Z-scores <-2 or >2 in screen 1
were tested again in screen 2 (purple data points). N.T., non-transfected; SCR, scrambled. (C) Overview of the 19 novel RIG-I pathway genes with the largest
effects on IFNβ induction in screens 1 and 2 (Z-score <-2 in both screens). Black data points correspond to genes whose knockdown also causes a reduction in
IFNβ mRNA levels in screen 3. (D) RNAi screen 3. 13 of the 19 top hits from screens 1 and 2 also reduce RIG-I-mediated IFNβ mRNA production (black bars). Experiments were performed in triplicate (n = 3). Bars (mean±SEM) display the fold induction of IFNβ mRNA (corrected for actin mRNA levels) compared to the
mock-treated control. Statistical significance was assessed by one-way analysis of variance (ANOVA) followed by Dunnett’s multiple comparison test,
comparing the values for each of the 19 test genes to the combined negative control conditions (scrambled and LGP2, red bars). ** P < 0.01; *** P < 0.001. (E)
Correlation between the in silico integrated RLR score and the probability of experimental confirmation in RNAi screen 1. The dark purple line represents all 94
hits with Z-score <-1.25 or >1.25; the light purple line represents the top 57 hits with Z-score <-2 or >2. The 187 experimentally tested genes were rank-ordered
based on the RLR score and precision was calculated sequentially as the fraction of validated hits among all tested genes having a certain RLR score or higher. doi:10.1371/journal.pcbi.1004553.g002 S13E–S13H), which suggests that the single confirmed up-hit might be unreliable. The poor
reproducibility of the up-hits might be attributed to the screening approach. For instance, we
used a large amount of 5’-ppp-containing RIG-I ligand (see Methods), leaving limited room
for increased pathway activation. In contrast, the second RNAi screen confirmed 26 down-hits
at Z-score <-1.25 (62% of the 42 down-hits tested). Of these, 19 genes (45% of tested down-
hits) could be confirmed at a conservative Z-score <-2 (Fig 2A, 2B and 2C, S8 Table). Taken
together, the two RNAi screens, guided by the predicted RLR candidates, have substantiated
the validity of our approach and have revealed potential novel regulators of the RIG-I receptor
pathway. To gain further understanding of how the 19 top hits affect RIG-I-mediated IFNβ promoter
activation, another RNAi screen was performed (RNAi screen 3). In contrast to the first two
screens, here we did not use the IFNβ promoter-controlled Fluc reporter translation as readout,
but we measured IFNβ mRNA levels using quantitative real-time (qRT)-PCR. As expected,
knockdown of RIG-I and MAVS abrogated 5’-pppRNA-induced IFNβ mRNA transcription,
while MDA5 knockdown [40] and LGP2 knockdown, which regulates only the MDA5-me-
diated IFNβ mRNA transcription, had no effect (Fig 2D). Of the 19 top hits from the first two
RNAi screens, 13 genes (68%) in this third screen again showed a reduction in RIG-I pathway
activation. Nine of these showed a significant reduction (NUP98, TRIM14, C16orf57, PSMA3,
G3BP1, DDX17, MAP3K11, SNW1, CDK11B; P < 0.01, one-way ANOVA with Dunnett’s post
hoc test; Fig 2A and 2D), suggesting that these gene products play a so far uncharacterized role
in the RIG-I signaling pathway upstream of IFNβ mRNA transcription. In summary, using RNAi-based screening methods we validated more than 50% of the
tested candidates. To further assess the predictive power of the in silico integrated RLR score,
we ranked the experimentally tested genes based on their RLR score and sequentially calculated
the fraction of hits (either considering all 94 hits from RNAi screen 1, or only the 57 top hits)
among all tested genes having a certain RLR score or higher (Fig 2E). Higher RLR scores were
experimentally confirmed more often, indicating that these indeed correspond to more confi-
dent predictions. Further analysis revealed that there is no molecular signature that solely
explains the predictions of the validated hits; rather the integrated score of the 10 molecular
signatures is important (S14 Fig). Integrative Genomics of the RLR Pathway PLOS Computational Biology | DOI:10.1371/journal.pcbi.1004553
October 20, 2015
1 PLOS Computational Biology | DOI:10.1371/journal.pcbi.1004553
October 20, 2015 OS Computational Biology | DOI:10.1371/journal.pcbi.1004553
October 20, 2015 11 / 35 Identification of predictive signatures using a knowledge-based
approach To identify defining signatures of RLR genes in genomics data, we largely depended on current
knowledge of the biology of the RLR system and its relationship with viruses. For example,
since previous studies had shown that viral antagonism of specific RLR pathway components is
prevalent [5,6], one of the first features we investigated, and indeed established, was that
human-virus PPIs are a general theme for the RLR pathway as a whole. Similarly, guided by
previous observations, we demonstrated that RLR genes conform to the tendency of immunity
genes to evolve rapidly and commonly contain innate antiviral TF binding motifs, such as IRF
and NFκB, in their promoters. We also included several criteria that are effective for many different biological systems, but
were specifically aimed at predicting novel RLR pathway genes in our case, such as the RLR co-
expression calculations and RLR protein domain occurrences. We decided not to include asso-
ciations based on text mining of published literature (e.g. co-mentioning of gene names in
abstracts), because such approaches in our hands only enriched for genes already known to be
involved in the RLR pathway and therefore compromised our ability to identify novel candi-
dates. Finally, we settled on using a total of 10 molecular signatures that are relevant and pre-
dictive for the RLR system. Inclusion of additional data sets, generated for example by future
experimental techniques, and substitution of existing data with novel and improved versions,
will likely refine this data-driven definition of RLR genes over time and lead to updated Bayes-
ian RLR probabilities that could further improve prediction accuracy. A major challenge in our study arises from the fact that the RLR pathway is highly intercon-
nected with other intracellular pathways, such as other innate PRR pathways (e.g. TLR and
cytosolic DNA sensing), the stress response pathway, mitogen-activated protein kinase
(MAPK) signaling cascades (e.g. TRAF2 and 6 lead to the p38 MAP kinases), and apoptosis
(e.g. via CASP8 and 10) (S1 Fig) [2,12,41,42]. Although our approach for predicting novel RLR
components relied on a well-defined set of genes known to make up the core of RLR signaling,
the overlap with other systems was a potential confounding factor. For example, most molecu-
lar signatures of RLR genes identified here, especially the virus-based properties such as PPIs
with viruses, rapid evolution, and differential expression during infection, could also apply to
genes involved in other aspects of antiviral immunity. Integrative Genomics of the RLR Pathway existing biological data can be exploited to successfully identify novel components of a key
intracellular defense pathway; the antiviral RIG-I-like receptor (RLR) pathway. The RLR path-
way is important for detecting viral infections, and its dysfunction can increase susceptibility to
infections with viruses [8] and fungi [39], but is also associated with autoimmunity [9,10]. We
systematically investigated a large variety of genome-scale data for their ability to predict RLR
pathway components, covering most of the important (gen)omics data types such as protein-
protein interactions, gene (co-)expression, genetic interactions from RNAi screens, compara-
tive genome analysis, and transcription regulation. In these data, we found five virus-based and
five pathway-based molecular signatures of RLR pathway components, providing insight into
the determinants of antiviral signaling and type I interferon production. Bayesian integration
of the signatures led to the genome-wide prioritization of novel RLR pathway components. We
subsequently validated the predictions by comparing them with various independent data sets
and experimentally confirmed more than 50% of 187 selected novel RLR candidates for a role
in RIG-I-stimulated IFNβ induction. These results reiterate the potential of computational
assessment and combination of available biological data as a complementary approach to stud-
ies generating novel large-scale data sets. Discussion Knowledge about the constituents of biological systems and pathways is an essential step
towards understanding their function in health and disease. In this study, we showed that PLOS Computational Biology | DOI:10.1371/journal.pcbi.1004553
October 20, 2015 12 / 35 PLOS Computational Biology | DOI:10.1371/journal.pcbi.1004553
October 20, 2015 Integrative Genomics of the RLR Pathway signatures achieved reasonable specificity for RLR genes (Fig 1). Thus, we have extended an
approach previously used for identifying components of membrane-enclosed organelles such
as the mitochondrion [19] and showed that it is also possible to capture the complexity of a
diverse and interconnected intracellular signaling pathway. The presented approach for identi-
fying predictive signatures, followed by Bayesian integration, could potentially be applied to
any cellular system. Contributions of the individual signatures to the RLR predictions Using the sets of known RLR and non-RLR genes, we could systematically assess the relative
quality of the individual data sets for predicting novel RLR genes. Indeed the 10 molecular
signatures have different predictive values as shown by the likelihood ratio scores (Fig 1A,
Tables 1 and S1), and thus contribute with different weights to the integrated Bayesian RLR
score. The data types with the strongest predictive value include NFκB activation mediators,
RLR pathway protein domains, and both PPI signatures (PPIs within the RLR pathway and
PPIs between human and viral proteins). In contrast to our expectations, antiviral host factors
identified in high-throughput RNAi experiments had a relatively small contribution. Besides
raw predictive ability, we also considered the coverage of the data sets. For example, there are
only few (<200) NFκB activation mediators and antiviral host factors, while the data sets on
RLR co-expression, viral miRNA targets, and innate antiviral TF binding motifs identified
many more genes (>4,000). Integration of all data sets with their varying coverage and predic-
tive value into a single RLR score resulted in a classifier that is superior to the individual data
sets (Fig 1D). This is underscored by the observation that the individual signatures by them-
selves are unable to explain the predictions for the experimentally validated RLR candidates,
and only the integrated RLR score explains all validated genes (Figs 2E and S14). Identification of predictive signatures using a knowledge-based
approach Nevertheless, combination of the right PLOS Computational Biology | DOI:10.1371/journal.pcbi.1004553
October 20, 2015 13 / 35 PLOS Computational Biology | DOI:10.1371/journal.pcbi.1004553
October 20, 2015 Integrative Genomics of the RLR Pathway Table 3. Validations of our predicted RLR candidates by independent studies. Independent studies validate additional RLR candidates Aside from our own experimental validation strategies, recent independent studies have con-
firmed a role for 15 of our predicted RLR candidates in the RLR pathway during viral infection
(Table 3). Most of these publications appeared during the course of our study, and thus were
not part of the knowledge or data used for predicting novel RLR genes. For example, TRIM14
(RLR rank 491) has been demonstrated to interact with MAVS leading to activation of IRF3
and NFκB via IKKγ (NEMO) [43]. Indeed, our predictions marked TRIM14 as a strong candi-
date RLR gene and all our RNAi screens confirmed it as a component required for optimal
RIG-I signaling (Fig 2). Two additional high-confidence RLR predictions for which we vali-
dated an effect in all three RNAi screens have recently been validated externally as well: G3BP1
[44] and CDC37 [13]. Of the 15 genes recently described in the literature, 11 were part of the candidate RLR genes
tested in our RNAi screens (Table 3). Of these, seven genes affected RIG-I-mediated IFNβ
induction in RNAi screen 1 (Z-score <-1.25 or >1.25) and showed a consistent effect in RNAi
screen 2. Therefore, our experimental screening condition appears to detect these described
RIG-I pathway regulators with a sensitivity of ~64% (7/11). Furthermore, four out of four
down-hits from our experiments (i.e. genes that decreased IFNβ induction when knocked
down, hence positive regulators) that have been described in the literature were indeed
described as positive regulators of RIG-I signaling (Table 3). Given that our experimental
approach detected most, but not all, of the published RIG-I regulators, a substantial number of
our predicted RLR candidates not validated by our RNAi screens might still play a role in for
example a different cell type, downstream of type I IFN production, or regulate the pathway via
MDA5/LGP2 activation. For example, RNF114 (RLR rank 181, Z-score RNAi screen 1 = 1.68, PLOS Computational Biology | DOI:10.1371/journal.pcbi.1004553
October 20, 2015 14 / 35 Gene
symbol
Gene description
RLR
rank
Described function
References
Type of
regulation
(literature) a
Type of regulation
(our RNAi
screens) b
CSNK2A1
Casein kinase II
subunit alpha
45
The casein kinase II complex inhibits the RIG-I-
mediated antiviral response through
phosphorylation of RIG-I
[93]
-
0c
TRIM38
Tripartite motif-
containing protein 38
56
Negative regulator of RIG-I-mediated IFNβ
production by targeting AZI2 (NAP1) for
degradation
[94]
-
-
RNF11
RING finger protein 11
78
Interacts with TBK1 and IKBKE (IKKε) to block
TRAF3 interaction and restrict IRF3 activation
[95]
-
SMAD3
SMAD family member
3
100
Regulates dsRNA-induced transcriptional
activation of IRF7 at the IFNβ promoter
[96]
+
0
UBE2D1
Ubiquitin-conjugating
enzyme E2 D1
139
This Ubc5 E2 ligase is required for viral
activation of IRF3 and MAVS by RIG-I
[97]
+
0
CDC37
Hsp90 co-chaperone
Cdc37 (cell division
cycle 37)
165
Regulates stability of TBK1 via Hsp90, allowing
for induction of IFNβ in response to DNA viral
and retroviral infections
[13]
+
+
RNF114
RING finger protein
114
181
Enhancer of dsRNA-induced production of type
I IFN through positive feedback regulation
[45]
+
-
SRPK1
Serine/threonine-
protein kinase SRPK1
235
Enhancer of RIG-I-dependent IFNβ and IFNλ1
promoter activation during Sendai virus
infection, possibly via IRF3/7 phosphorylation
[98]
+
-
CSNK2A2
Casein kinase II
subunit alpha prime
249
The casein kinase II complex inhibits the RIG-I-
mediated antiviral response through
phosphorylation of RIG-I
[93]
-
0c
G3BP1
GTPase-activating
protein-binding protein
1
282
Functions in the formation of stress granules,
which act as RLR signaling platforms that in
some cases enhance IFN induction
[44]
+
+
UBE2I
SUMO-conjugating
enzyme UBC9
284
Enhances RIG-I and MDA5 SUMOylation,
which correlates with increased IFNβ
expression and repressed virus replication
[99,100]
+
SUMO1
Small ubiquitin-related
modifier 1
326
IRF3/7 SUMOylation down-regulates IFN
production; RIG-I/MDA5 SUMOylation
correlates with increased IFNβ expression
[99–101]
- / +
PPP1R15A
Protein phosphatase 1
regulatory subunit 15A
389
Required for IFNβ production induced by
dsRNA and chikungunya virus in mouse;
expression depends on PKR activation
[102]
+
+
TRIM14
Tripartite motif-
containing protein 14
491
Interacts with MAVS upon viral infection,
thereby recruiting IKKγ (NEMO), which leads to
activation of IRF3 and NFκB
[43]
+
+
DDX60
DEAD box protein 60
616
Promotes virus-induced, RLR-mediated type I
IFN expression and increases binding of RIG-I
to dsRNA
[103]
+
Total:
15
7 hits (out of 11)
a
(
β
)
(
β Table 3. Novel RIG-I pathway components DDX17 and SNW1 could regulate
activation of transcription factors NFκB and IRF3 We identified 13 novel RIG-I pathway regulators that reduced IFNβ induction in all three RNAi
screens (Fig 2). These include cell cycle gene CDK11B, heat shock protein HSPA9B, MAP kinase
MAP3K11, proteasome subunit PSMA3, nucleoporin NUP98 [46], and the recently identified
RLR regulators CDC37 [13], G3BP1 [44] and TRIM14 [43] (Table 3). The remaining five genes,
DDX17 (DEAD box helicase 17), C6orf58, C16orf57 (USB1, U6 snRNA biogenesis 1), PKN2 (ser-
ine/threonine protein kinase N2), and SNW1 (SNW domain containing 1), are overall least char-
acterized. To obtain a first suggestion about how these genes might regulate RLR signaling, we
searched for connections with the known human and viral protein interaction networks. Next,
we discuss the reported interactions of DDX17 and SNW1 with the RLR pathway. DEAD box RNA helicase DDX17 was recently found to bind Rift Valley fever virus RNA
and restrict viral replication in an interferon-independent manner [47]. Our data now suggest
a role for DDX17 in RIG-I-mediated IFNβ production as well. DDX17 has reported protein
interactions with two other RIG-I regulators identified in our study: CDC37 and CSNK2A1. Interestingly, DDX17 also interacts with the peptidylprolyl cis/trans isomerase PIN1 [48],
which inhibits RIG-I-mediated IFNβ production by inducing degradation of IRF3 [49]. Fur-
thermore, DDX17 was present among a set of ISG15-modified (ISGylated) proteins in HeLa
cells treated with IFNβ [50]. Thus, DDX17 could function in IRF3 activation by acting as a neg-
ative regulator of PIN1 and might be regulated by ISGylation (Fig 3). Lastly, DDX17 seems to
be a preferred target of viral interference, having reported interactions with six different viruses
(e.g. HIV–1 Rev and influenza virus A NS1, Fig 3). Fig 3. Human and viral protein interaction networks connecting the known RLR pathway with the
newly identified RIG-I factors DDX17 and SNW1. Human proteins are represented by circles, viral proteins
by rounded rectangles (purple nodes). Green nodes represent known components of the RLR pathway. Orange nodes (DDX17 and SNW1) are novel RIG-I pathway components discovered in our study, which are
connected to the RLR network through interactions with the green nodes. Edges between human proteins
represent physical interactions (both low- and high-throughput) obtained from BioGRID Release 3.3 [54]. Interactions between human and viral proteins were obtained from the PHISTO database (29 Sep. 2014)
[28]. See S1 Fig for a more complete representation of the RLR pathway containing the curated set of 49
known RLR genes. Integrative Genomics of the RLR Pathway Similar biological reasons could limit the detection of an effect for other genes as well. There-
fore we conclude that the hits identified in our RNAi validation experiments may be a conser-
vative estimate of the number of correct RLR predictions. Similar biological reasons could limit the detection of an effect for other genes as well. There-
fore we conclude that the hits identified in our RNAi validation experiments may be a conser-
vative estimate of the number of correct RLR predictions. Validations of our predicted RLR candidates by independent studies. )
b Annotated cells (‘+’, ‘-’, ‘0’) indicate 11 candidate RLR genes that were tested in RNAi screen 1. ‘+’: down-hits from RNAi screen 1 (decreased RIG-I-
mediated IFNβ induction upon knockdown, Z-score <-1.25). ‘-’: up-hits from RNAi screen 1 (increased RIG-I-mediated IFNβ induction upon knockdown, Z-
score >1.25). ‘0’: no hit in RNAi screen 1, or inconsistent effect across RNAi screens 1 and 2 (CSNK2A1 and CSNK2A2, c). )
b Annotated cells (‘+’, ‘-’, ‘0’) indicate 11 candidate RLR genes that were tested in RNAi screen 1. ‘+’: down-hits from RNAi screen 1 (decreased RIG-I-
mediated IFNβ induction upon knockdown, Z-score <-1.25). ‘-’: up-hits from RNAi screen 1 (increased RIG-I-mediated IFNβ induction upon knockdown, Z-
score >1.25). ‘0’: no hit in RNAi screen 1, or inconsistent effect across RNAi screens 1 and 2 (CSNK2A1 and CSNK2A2, c). Table 3) is an ISG and therefore needs to be up-regulated via a positive feedback loop to fully
contribute to RLR pathway stimulation [45]. This gene was not confirmed in all RNAi screens,
perhaps because the time of RIG-I stimulation in our screens (6 hours) was simply too short. PLOS Computational Biology | DOI:10.1371/journal.pcbi.1004553
October 20, 2015 PLOS Computational Biology | DOI:10.1371/journal.pcbi.1004553
October 20, 2015 15 / 35 Human reference proteome and mapping All data sets were calculated for and mapped to a reviewed reference set of 20,245 human pro-
teins from UniProtKB/Swiss-Prot, release 2011_11 [57]. This set consists of one manually
annotated record for each validated protein-coding gene. Gene/protein identifier mapping was
performed using a mapping table from the same UniProt release. Ambiguously mapped identi-
fiers were curated manually. The genome-wide prioritization of RLR pathway components is a new
resource for innate antiviral immunity research We have validated the integrated RLR score with various experimental, literature and computa-
tional approaches. Our confirmations of a substantial fraction of the predicted RLR genes sug-
gest the value of the prioritized list as a whole. The genome-wide prioritization of RLR pathway
components is available in S6 Table and at http://rlr.cmbi.umcn.nl/, and can be used as a
resource in several ways. For example, it can serve in the evaluation of data sets relevant to the
innate antiviral and antifungal responses (Table 2). Many labs routinely consult internal data
sets to decide which genes to study further. Comparison of such lists with for example high-
scoring RLR candidates could provide insights into the quality of individual data sets for identi-
fying antiviral genes and provide complementary hints about which genes could be important. Finally, the RLR resource could be used for prioritizing genetic variants in patients suffering
from severe susceptibility to viral infections or inflammatory disorders caused by inappropriate
production of type I interferons. Conclusions In this work, we have combined integrative genomics with experiments to discover 10 molecu-
lar signatures of a cellular signaling system that is central to human infectious disease: the
innate antiviral RIG-I-like receptor (RLR) pathway. The described signatures span multiple
layers of genomics data and provide new insights into the regulation of virus detection and
immune signaling. Probabilistic integration of the data resulted in a confident genome-wide
ranking of candidate RLR pathway genes. RNAi validation experiments confirmed 94 of 187
novel RLR candidates tested, including 13 novel factors with strong effects on antiviral signal-
ing. These results, together with independent computational and literature-based confirmation,
demonstrated the validity and high accuracy of our approach. Our study expands the collection
of known antiviral genes, opening up new avenues for research into innate antiviral immunity. Integrative Genomics of the RLR Pathway SNW1 is an intrinsically disordered protein [51,52] that interacts with two other newly
identified RLR regulators from our study, namely PKN2 [53] and C16orf57 [54]. SNW1 also
interacts with the IKBKG (NEMO) protein [55], which is required for NFκB and IRF3 activa-
tion [56]. Given that our data shows that knockdown of SNW1 reduces IFNβ induction,
SNW1 could be involved in NEMO regulation and thereby contribute to activation of the RLR
pathway TFs, NFκB and IRF3 (Fig 3). The fact that SNW1 was also identified in a siRNA
screen for mediators of virus-induced NFκB activation [34] strengthens this hypothesis. Fur-
ther studies should be conducted to resolve the precise mode-of-action. Novel RIG-I pathway components DDX17 and SNW1 could regulate
activation of transcription factors NFκB and IRF3 LaCV, La Crosse virus; EBV, Epstein-Barr virus; SFSV, Sandfly fever Sicilian virus;
PRRSV, Porcine reproductive and respiratory syndrome virus; HPV, Human papillomavirus. doi:10.1371/journal.pcbi.1004553.g003 Fig 3. Human and viral protein interaction networks connecting the known RLR pathway with the
newly identified RIG-I factors DDX17 and SNW1. Human proteins are represented by circles, viral proteins
by rounded rectangles (purple nodes). Green nodes represent known components of the RLR pathway. Orange nodes (DDX17 and SNW1) are novel RIG-I pathway components discovered in our study, which are
connected to the RLR network through interactions with the green nodes. Edges between human proteins
represent physical interactions (both low- and high-throughput) obtained from BioGRID Release 3.3 [54]. Interactions between human and viral proteins were obtained from the PHISTO database (29 Sep. 2014)
[28]. See S1 Fig for a more complete representation of the RLR pathway containing the curated set of 49
known RLR genes. LaCV, La Crosse virus; EBV, Epstein-Barr virus; SFSV, Sandfly fever Sicilian virus;
PRRSV, Porcine reproductive and respiratory syndrome virus; HPV, Human papillomavirus. 16 / 35 PLOS Computational Biology | DOI:10.1371/journal.pcbi.1004553
October 20, 2015 Virus-based signatures Positive selection in primates. George et al. [23] calculated dN/dS-based likelihoods for
recurrent positive selection across the exomes of seven primates (human, chimpanzee, orangu-
tan, rhesus macaque, vervet, colobus monkey, tamarin). Maximum likelihood analysis of the
nucleotide alignments of ~15,000 genes identified 930 genes with evidence for positive selec-
tion at P < 0.05. We grouped the genes according to these positive selection P values. Protein-protein interactions (PPI) with viruses. Recent years have seen a surge of studies
reporting interactions between viral and human proteins, both small- and large-scale. First, we
collected all known virus-human PPIs from five specialized resources: PIG (9 Sep. 2011) [58],
HPIDB (9 Sep. 2011) [59], VirHostNet 1.0 (24 Oct. 2011) [60], VirusMINT (6 Dec. 2011) [61],
and PHISTO (25 Jan. 2012) [28]. These data were then combined to determine all human pro-
teins for which an interaction was reported with at least one virus (S2 Fig). Of note, the interac-
tions reported by Pichlmair et al. [37] are not part of the final data set of virus-human PPIs and
thus could be used for independent validation of the predictions (Table 2). Viral miRNA target. Likely human target genes of viral miRNAs were determined in
three steps. First, from the vHoT database we collected transcriptome-wide TargetScan (v5.0)
predictions for the binding of 128 miRNAs from nine, mostly DNA viruses to the 3'UTRs of
human mRNAs (S2 Table) [30]. More negative scores are associated with more favorable bind-
ing site predictions. Second, because a single human transcript may be targeted (i) at multiple
sites by a single miRNA and (ii) multiple times by different miRNAs, for each transcript we
summed the prediction scores for all predicted target sites of all viral miRNAs. The resulting
score (‘viral miRNA targeting score’) represents the overall likelihood that viruses target that
mRNA. Third, the final score per gene was defined as the most negative score across its
transcripts. Differential expression upon infection. Human lung alveolar type II cells (A549) were
cultured and exposed to four live respiratory viruses as described previously [62]: respiratory
syncytial virus (RSV), human metapneumovirus (hMPV), parainfluenza virus type 3 (PIV),
and measles virus (MV). RNA was isolated at 6, 12, and 24h post infection, as well as from
mock-infected (medium without virus) control cells. Gene expression was then measured
using the Affymetrix U133 plus 2.0 GeneChip platform and infection conditions were com-
pared to uninfected cells. Integrative Genomics of the RLR Pathway DNA to the protein level, highlighting evolutionary processes, virus-host interactions,
sequence families, etc. We finally settled on 10 data sets that collectively distinguish RLR path-
way components from other genes (see Table 1 for an overview and brief descriptions): Molecular signature data sets To systematically define RLR pathway components, we mined genome-scale data from a wide
variety of sources. The data describe different aspects of the biology of the pathway; from the 17 / 35 PLOS Computational Biology | DOI:10.1371/journal.pcbi.1004553
October 20, 2015 Pathway-based signatures Co-expression with RLR pathway. Functionally related genes tend to share expression
patterns, i.e. be co-expressed. We employed an expression data integration method that weighs
expression data sets for co-expression within a specific biological system [32]. From the NCBI
gene expression omnibus database (GEO) [65] we obtained a collection of 465 publicly avail-
able human microarray data sets (~10,000 individual measurements). Each set of mRNA
expression measurements was then assessed for its potential to find novel RIG-I-like receptor
pathway genes by determining the coherence of expression of the 49 known RLR genes. That
is, for each data set we ask whether known RLR genes behave similarly in terms of their expres-
sion, being up- or down-regulated together in the same microarray measurement. Sets of
expression measurements in which known RLR genes show coherent expression receive a high
weight, and will contribute more to the co-expression calculation than experiments with less
coherent expression of known RLR genes. These weights are then used to calculate an inte-
grated score for each gene in the human genome, according to how much its expression profile
correlates with that of the RLR genes across the expression data sets (S4 Fig). As the co-expression method was trained with the aim of retrieving RLR genes with high
reliability, we also assessed its ability to retrieve RLR genes in leave-one-out cross-validation
analysis. For that, we calculated the weighted co-expression 49 times, leaving out one of the 49
RLR genes in each fold (so that the whole set was left out exactly once), and determined the co-
expression rank of the RLR gene that was left out. For the other gene sets (i.e. covering all genes
except the RLR genes), we averaged the co-expression ranks across the 49 cross-validation
runs. S4D Fig shows the recall (also known as sensitivity) of various gene sets at each rank cut-
off in the cross-validation: genes were rank-ordered based on the RLR co-expression cross-vali-
dation rank and recall for each gene set was calculated sequentially as the fraction of genes
among all genes in the set having a certain rank or higher. RLR pathway protein domain. Domain organizations for all human proteins in SwissProt
were obtained from the Pfam database (release 26.0; SwissPfam) [66]. We calculated statistical
over-representation of domains occurring in the 49 known components of the RLR pathway
compared to the background of all human proteins using the Fisher’s exact test. Integrative Genomics of the RLR Pathway fold change >0.5), followed by RSV (29%). In comparison, PIV (4%) and MV (3%) caused less
pronounced expression changes. Indeed, the expression profiles confirm these trends (S3A
Fig). Furthermore, most genes tend to be increasingly up- or down-regulated during the course
of infection (S3A and S3B Fig), with the distribution of expression changes becoming more
extreme going from 6h (~5% of the 1,761 genes with maximal absolute fold change >0.5), to
12h (~14%), to 24h (~80%). Antiviral host factor. We collected data from large-scale forward genetics screens aimed
at identifying human genes involved in viral replication. Most studies focus on factors that
reduce viral replication when inactivated, as these are often most abundant and represent can-
didate drug targets for infection treatment. However, these screens can also identify antiviral
host factors, or host restriction factors, that inhibit virus replication (i.e. increase viral replica-
tion when inactivated). We collected the results from seven RNAi studies that investigated
infection of human cells with a variety of viruses. These screens together reported a total of 173
unique antiviral host factors (S3 Table). Virus-based signatures Data were log2-transformed and normalized by VSN [63]. Statisti-
cally significant differential expression for each probe set (54,675 in total) was assessed using
limma [64] and expressed as the fold change in expression between infected and uninfected
conditions (FDR cutoff of 0.05). Genes represented on the microarray platform by multiple
probe sets were summarized by the median differential expression across their probe sets. From the transcriptomics data we calculated for each gene (20,190 genes in total) the maxi-
mum absolute (i.e. considering both up- and down-regulation) change in expression across all
time points and viruses, compared to uninfected cells. The column ‘Differential expression’ of
S6 Table contains the processed gene expression data. A full analysis of these experiments will
be described in a later publication. mum absolute (i.e. considering both up- and down-regulation) change in expression across all
time points and viruses, compared to uninfected cells. The column ‘Differential expression’ of
S6 Table contains the processed gene expression data. A full analysis of these experiments will
be described in a later publication. 220 and five genes were significantly up- and down-regulated in at least one infection condi-
tion respectively (>1.5 and <-1.5 log2 fold expression changes). A total of 1,761 genes showed
maximum absolute differential expression >0.5. Infection with hMPV induced maximal
expression changes for the majority of genes (63% of the 1,761 genes with maximal absolute PLOS Computational Biology | DOI:10.1371/journal.pcbi.1004553
October 20, 2015 18 / 35 Integrative Genomics of the RLR Pathway Innate antiviral transcription factor (TF) binding motifs. Conserved TF binding sites in
human were obtained from a comparative analysis of 29 genomes of placental mammals [33]. In this study, TF regulatory motif instances (putative TF binding sites) were detected across the
human genome and assigned a likelihood based on conservation across the 29 mammals: for
each motif match in human, the smallest phylogenetic subtree was calculated that contains the
human motif and aligned motifs in other species [67]. To identify putative transcription regula-
tors of a gene, we extracted conserved TF binding sites in promoter regions, which were
defined as 4 kilobase (kb) windows centered (i.e. 2kb upstream and 2kb downstream) at all
annotated transcription start sites of the gene [68]. We then searched for genes containing con-
served motifs associated with four key innate antiviral transcription factors (IRF, AP–1, NFκB,
and STAT; S5 Table). Finally, we grouped all genes by the number of distinct motifs found:
none, one, two, three or four. NFκB activation mediator. Gewurz et al. undertook a genome-wide siRNA screen for
NFκB pathway components [34]. They studied HEK293 cells with a stably integrated NFκB
GFP reporter and inducible expression of Epstein-Barr virus latent membrane protein (LMP1),
which activates NFκB. 155 LMP1 activation pathway components were identified, many of
which are also important for IL–1β-, or TNFα-mediated NFκB activation. We obtained these
hits and mapped them to 154 protein identifiers. RLR pathway PPI. Human protein-protein interactions were obtained from the PINA
database (release 28 Jun. 2011), which contained ~75,000 PPIs from six major resources [35]. We took all interactions involving the 49 known RLR pathway proteins and counted how
many interactions each protein is involved in, thus obtaining 1,750 proteins with at least one
RLR interaction. Of note, the interactions reported by Li et al. [12] are not part of the final data
set of RLR pathway PPIs and thus could be used for independent validation of the predictions
(Table 2). We also assessed the cohesiveness of the RLR PPI network by calculating physical
interaction enrichment scores, as described in [36]. Pathway-based signatures Enrichment P
values were corrected for testing multiple domains (40 in total) using the Benjamini-Hochberg
(BH) false discovery procedure and judged to be significant at a significance level of 1% (S4
Table). Finally, we determined a set of proteins that contain one or more such enriched ‘RLR
domains’. 19 / 35 PLOS Computational Biology | DOI:10.1371/journal.pcbi.1004553
October 20, 2015 PLOS Computational Biology | DOI:10.1371/journal.pcbi.1004553
October 20, 2015 7. Embryonic development. 775 genes from GO term ‘embryo development’ (GO: 0009790). We removed genes from the negative set that are known RLR genes, components of other
PRR signaling pathways (TLR, CLR, NLR, cytDNA), or other innate immunity genes (see
below). The resulting negative set is a good reflection of the rest of the genome in terms of the
distributions of the various molecular signatures and RLR integration scores (Fig 1B). Further-
more, given its size and the diversity of genes included, it is reasonable to expect a number of
‘non-RLR genes’ with high RLR scores. These should be considered as inappropriately included
in the negative set and are therefore still candidate RLR genes. Other PRR pathway and other innate immunity gene sets Two additional curated sets of genes were used in our study (S6 Table). The first consists of
153 genes with a known function (i.e. receptors, signaling components, etc.) in four PRR sig-
naling pathways; the Toll-like receptor (TLR), C-type lectin receptor (CLR), NOD-like receptor
(NLR), and cytosolic DNA sensing (cytDNA) pathways, but not in the RLR pathway. TLR,
NLR and cytDNA components were obtained from InnateDB (27 Mar. 2012). We curated a
list of 34 CLR pathway components, based mainly on [78]. The combined PRR pathway gene
set was supplemented with several key proteins involved in virus-host interactions. As with the
set of RLR genes, cytokines and other secreted proteins were excluded. The second list (‘other
innate immunity genes’) consists of 803 genes with curated annotations from InnateDB (12
Jan. 2012) for a function in other aspects of the innate immune response, excluding RLR and
other PRR signaling pathway genes. Integrative Genomics of the RLR Pathway From QuickGO (6 Feb. 2012), we obtained human genes annotated with various gene ontology
terms and their child terms [77], considering only annotations supported by experimental evi-
dence codes (IMP, IGI, IPI, IDA, IEP, EXP): 4. Mitoplast localization. 559 genes with contributions to or co-localization with the mito-
chondrial matrix (GO:0005759) or mitochondrial inner membrane (GO:0005743). We did
not include the inner membrane space and outer membrane, which is critical for RLR signal
transduction through MAVS. 4. Mitoplast localization. 559 genes with contributions to or co-localization with the mito-
chondrial matrix (GO:0005759) or mitochondrial inner membrane (GO:0005743). We did
not include the inner membrane space and outer membrane, which is critical for RLR signal
transduction through MAVS. 5. Metabolism. Genes with annotation ‘metabolic process’ (GO:0008152), excluding those
annotated with the child term ‘protein phosphorylation’ (GO:0006468); 2243 genes. 6. Neurological functions. 1497 genes from GO term ‘neurological system process’
(GO:0050877). 7. Embryonic development. 775 genes from GO term ‘embryo development’ (GO: 0009790). PLOS Computational Biology | DOI:10.1371/journal.pcbi.1004553
October 20, 2015 Training sets We assessed the capability of individual data sets to predict novel RLR genes using two ‘gold
standard’ training sets: Positive gold standard. We used a curated standard of 49 genes that are well characterized
to play a role in the RLR pathway and make up its core (‘RLR genes’, all of which are depicted
in S1 Fig). This set is based mainly on the KEGG map [69] of the RLR pathway and taken from
InnateDB (27 Mar. 2012) [21]. We focused on intracellular components, hence excluding the
interferons and proinflammatory cytokines that are induced by the pathway. Negative gold standard. To represent genes that are unlikely to play a role in RLR signal-
ing, we constructed a set of 5,818 genes from seven functional categories generally unrelated to
the innate antiviral response (‘non-RLR genes’, S6 Table). 1. Housekeeping genes. These are typically defined as genes showing constitutive and constant
expression in 'all' tissues. We collected housekeeping genes from five different studies [70–
74], and included 1458 genes that were reported in at least three studies. 1. Housekeeping genes. These are typically defined as genes showing constitutive and constant
expression in 'all' tissues. We collected housekeeping genes from five different studies [70–
74], and included 1458 genes that were reported in at least three studies. 2. Ribosomal subunits. 134 human ribosomal (cytoplasmic and mitochondrial) proteins from
[75]. 3. Transmembrane transporters. 986 confirmed and predicted cytoplasmic membrane trans-
porters and membrane channels from [76]. 20 / 35 PLOS Computational Biology | DOI:10.1371/journal.pcbi.1004553
October 20, 2015 Integrative Genomics of the RLR Pathway 1A and S1 Table) so that better data contribute more to the predictions. Indeed, integration
enriches for RLR genes and depletes false positive, non-RLR genes (S5 and S9 Figs). 1A and S1 Table) so that better data contribute more to the predictions. Indeed, integration
enriches for RLR genes and depletes false positive, non-RLR genes (S5 and S9 Figs). enriches for RLR genes and depletes false positive, non-RLR genes (S5 and S9 Figs). Calculation of the RLR score. For any given gene in the human genome, we can calculate
the conditional probability that the gene is involved in the RLR pathway given the observed evi-
dence in the 10 molecular signature data sets. More precisely, we calculated the posterior odds,
defined as the ratio of the probability that the gene in an RLR gene versus the probability that
the gene is not an RLR gene: Oposterior ¼
PðRLR genejD1 . . . D10Þ
PðnonRLR genejD1 . . . D10Þ As this equation cannot be calculated directly, we approximate the ‘reverse’ likelihood ratio
L that a certain combination of values for the 10 data sets are observed, given the distribution
of known RLR and non-RLR genes (i.e. the positive and negative training genes) across the
data: LðD1 . . . D10Þ ¼
PðD1 . . . D10jRLR geneÞ
PðD1 . . . D10jnonRLR geneÞ These two equations are related by Bayes’ theorem though the prior odds: the ratio of proba-
bilities that any gene in the human genome is an RLR gene versus a non-RLR gene, prior to the
use of information from our data sets. The prior odds can be calculated from the estimated
total number of genes involved in the RLR pathway (see below). Oposterior ¼ Oprior LðD1 . . . D10Þ PðRLR genejD1 . . . D10Þ
PðnonRLR genejD1 . . . D10Þ ¼
PðRLR geneÞ
PðnonRLR geneÞ
PðD1 . . . D10jRLR geneÞ
PðD1 . . . D10jnonRLR geneÞ An assumption of the naive Bayesian approach is that the individual sources of evidence are
independent of each other. Although this is rarely completely the case with genomics data, lim-
ited violations of the independence assumption still lead to effective predictions (see below). Under the independence assumption, L can be simplified and calculated as the product of the
likelihood ratios of the individual data sets: LðD1 . . . Naive Bayesian integration Individual (genomics) data sets contain important information about the make-up of cellular
systems and pathways, but often have limited coverage and introduce data type-specific noise. Combination of multiple heterogeneous types of data, each approaching the characterization
of a molecular system from a different angle, therefore has the potential to provide a more
complete definition of the system and could have high power for predicting novel components
involved. We employed a naive Bayesian framework to facilitate direct comparison and weighing of
many data sets describing properties of RIG-I-like receptor pathway components and integrate
those data sets that were suitable into a single probabilistic score for each gene. Bayesian inte-
gration is well suited to combining evidence from dissimilar types of information and readily
accommodates missing data [18–20]. Furthermore, this approach inherently weighs data sets
based on their predictive value (i.e. their ability to separate known positives and negatives, Fig PLOS Computational Biology | DOI:10.1371/journal.pcbi.1004553
October 20, 2015 21 / 35 PLOS Computational Biology | DOI:10.1371/journal.pcbi.1004553
October 20, 2015 Integrative Genomics of the RLR Pathway data: data: PðRLR genejD1 . . . D10Þ
PðnonRLR genejD1 . . . D10Þ ¼
PðRLR geneÞ
PðnonRLR geneÞ
Y
10
i¼1
PðDijRLR geneÞ
PðDijnonRLR geneÞ Finally, we obtained the ‘RLR score’ (S6 Table or http://rlr.cmbi.umcn.nl/) by log2 transfor-
mation of the individual terms in order to create an additive score: RLR score ¼ log2
PðRLR genejD1 . . . D10Þ
PðnonRLR genejD1 . . . D10Þ
¼ log2
PðRLR geneÞ
PðnonRLR geneÞ
þ
X
10
i¼1
log2
PðDijRLR geneÞ
PðDijnonRLR geneÞ
Taken together, the RLR score represents a Bayesian posterior probability, which depends
on the positive and negative gold standard genes, the data sets used for the predictions, and the
prior expected number of positive and negative genes in the genome. Although the RLR score
may change for different priors (see below), the relative RLR ranks remain the same as these
only depend on the gold standards and the data. Thus, the relative ranking of genes as captured
in the RLR rank is most informative. Conditional independence. Although violations of the independence assumption can
lead to over-estimation of the likelihood scores, previous work has shown naive integration of
genomics data to be effective for predicting novel genes involved in a molecular system [19,20]. Assessment of the pairwise correlations between the 10 genomics data sets used for predicting
RLR genes suggests that they are largely complementary (S10 Fig). Several data sets have
higher pairwise correlations, such as ‘PPI with viruses’ and ‘Innate antiviral TFs’. However,
these features describe different molecular processes, namely protein-protein interactions
between viral and human proteins and the presence of specific TF binding motifs, and hence
can be considered largely independent in molecular terms. Performance estimates. The performance of each of the 10 individual data types, as well
as the integrated RLR score, for predicting RLR genes was evaluated using the positive and neg-
ative training sets. Based on these sets of known (non-)RLR genes, we calculated for each RLR
score threshold (where genes with scores equal or higher than the threshold are predicted posi-
tives, i.e. predicted RLR genes, and genes with lower scores are predicted negatives, i.e. D10Þ ¼
Y
10
i¼1
PðDijRLR geneÞ
PðDijnonRLR geneÞ We calculated these likelihood ratio scores for individual data sets (Tables 1 and S1) directly
from the contingency tables relating the positive and negative training genes to the data values
binned into discrete intervals, asking: “What is the probably that a (non-)RLR gene has a value
within a certain range in the data”? The bar plots in Fig 1A represent these contingency tables;
likelihood ratio scores for each bin are defined as the ratios of the green versus red bars. Of
note, as not all data sets contain values for all genes (e.g. genes can be missing from microarray
platforms, were not tested in siRNA screens, etc.), we separated genes that were tested but
show no effect from genes that were not tested. That is, we assigned no scores to bins that rep-
resent genes missing from the data entirely. Having obtained the scores for the individual data sets and the prior odds, we then calcu-
lated the posterior odds that any gene is involved in the RLR pathway given its values in the PLOS Computational Biology | DOI:10.1371/journal.pcbi.1004553
October 20, 2015 22 / 35 PLOS Computational Biology | DOI:10.1371/journal.pcbi.1004553
October 20, 2015 Integrative Genomics of the RLR Pathway Calculation of the FDR depends on both the positive and negative gold standard genes. As
the sizes of these training sets do not accurately reflect the expected numbers of RLR and non-
RLR genes in the genome (prior probabilities, see below), we corrected the FDR to get an unbi-
ased estimate using the following equation [19] (S11 Fig): FDRcorrected ¼
1 SP
1 SP þ SN Oprior Prior estimation of the number genes involved in the RLR pathway. Determination of
the probability of finding a gene in the genome with a role in the RLR pathway, prior to the use
of additional information, requires an estimation of the expected total number of RLR genes. We estimated this at 300; six times the number of currently known RLR genes in the positive
training set. The prior odds then become ~1.5%: Oprior ¼
PðRLR geneÞ
PðnonRLR geneÞ ¼
PðRLR geneÞ
1 PðRLR geneÞ ¼
300
20;245
ð20;245300Þ
20;245
0:015 The prior odds influence the absolute RLR score and the corrected false discovery rate. The prior odds influence the absolute RLR score and the corrected false discovery rate. Importantly, however, the overall ranking of genes does not depend on the estimated number
of RLR genes. To assess the impact of the prior on the RLR score and false discovery rate, we
re-calculated these measures using lower (75), medium (200) and upper (1000) bound esti-
mates for the number of RLR genes (S9 Table). These results suggest maximum and minimum
FDRs of 84% and 28% at rank 354 (compared to an FDR of 57% when using a prior of 300). Separate assessment of co-expression, protein domain, and RLR pathway PPI signa-
tures. As described before, a positive gold standard of 49 known RLR pathway genes was
used for calculating the likelihood scores for individual data sets. However, three molecular sig-
natures (co-expression, protein domain and RLR pathway PPI) originate directly from calcula-
tions based on this same set of RLR genes. To avoid circularity, we assessed the performance
(sensitivity, specificity) and likelihood ratio scores of these data sets using a different, indepen-
dent positive training set: components of other PRR signaling pathways (TLR, CLR, NLR,
cytDNA, see above). This approach prevented over-estimation of the predictive ability of these
data sets and ensured that the likelihood scores of all molecular signatures are in the same
range. pre-
dicted non-RLR genes) the number of predictions that are: • true positive (TP, number of positive training genes predicted as positive) • false positive (FP, number of negative training genes predicted as positive) • true negative (TN, number of negative training genes predicted as negative) • false negative (FN, number of positive training genes predicted as negative) • false negative (FN, number of positive training genes predicted as negative)
These were then used to calculate several performance measures: These were then used to calculate several performance measures: • Sensitivity ðSNÞ ¼
TP
TPþFN, fraction of positive training genes correctly predicted as positive
(Fig 1D) • Specificity ðSPÞ ¼
TN
FPþTN, fraction of negative training genes correctly predicted as negative
(Fig 1D) • False Discovery Rate ðFDRÞ ¼
FP
TPþFP, fraction of positive predictions that are false (i.e. that
are negative training genes) PLOS Computational Biology | DOI:10.1371/journal.pcbi.1004553
October 20, 2015 23 / 35 Briefly, 0.5 pmole siRNAs (in 5 μl) was
spotted per well. On the day of transfection 0.3 μl Lipofectamine RNAiMAX was diluted in
15 μl Opti-MEM and added to each well. Plates were rocked gently to mix the components and
incubated at room temperature (RT) for 15 min. Then, 7,000 HeLa-IFNβ-Fluc cells (in 80 μl)
were added to each well and plates were returned to a 37°C incubator. At 2 days post siRNA
transfection, growth medium was discarded, replaced by 100 μl fresh medium and cells were
then transfected with the RIG-I ligand. Briefly, 200 ng ligand and 0.8 μl Lipofectamine 2000
were separately diluted in 25 μl Opti-MEM, and incubated at RT for 5 min. These components
were then mixed, incubated at RT for 20 min, and added to each well. At 6 hr post transfection,
one replicate of each plate was fixed in 4% PFA and stained with DAPI. This replicate was later
scanned at the CSC UMCU, and DAPI-positive nuclei were counted per well as an indication
of cell viability upon siRNA transfections. The other three replicates were lysed in 30 μl 1x Pas-
sive Lysis Buffer (Promega) and allowed to freeze at -20°C. To measure luciferase activity, cell
lysates were mixed by pipetting, and 15 μl from each well was transferred to a measurement
plate, which was read using an automated plate reader using the following parameters: inject
40 μl firefly luciferase substrate (Promega), mix for 1 second, 1 second delay, measure for 10
seconds. Protocol RNAi screen 2 –IFNβ luciferase. In RNAi validation screen 2, we tested the 57
top hits with the largest effects in screen 1 (stringent Z-score of <-2 or >2; S8 Table) using a
different set of siRNAs, separately assessing the 42 down-hits (siRNA knockdown of which
resulted in down-regulation of RIG-I-mediated IFNβ induction) and 15 up-hits (siRNA knock-
down of which resulted in up-regulation of RIG-I-mediated IFNβ induction). For 48 of the 57
genes tested, siRNAs (1 pool per gene) were purchased from SIGMA (esiRNAs human library)
and used at 1 pmole per well during transfection. For the remaining 9 genes, for which esiRNA
products were not available, Silencer Select siRNAs were purchased from Ambion, and three
oligos per gene were pooled at 1:1:1 ratio and transfected at 0.5 pmole per well. Screen 2 was performed in six technical replicates. Integrative Genomics of the RLR Pathway negative controls. Polo-like kinase 1 (PLK1)-targeting siRNAs were included as a positive con-
trol for cytotoxicity, while RIG-I-, and MAVS-targeting siRNAs were included as positive con-
trols for RIG-I pathway activity. The RIG-I signaling pathway was activated by transfecting
cells with the 5’-ppp-containing CVB3 CL RNA. Activation levels were assessed by measuring
IFNβ promoter-controlled luciferase reporter activity at 6 hr post transfection (S12 Fig). Screen 1 was performed in four technical replicates. Briefly, 0.5 pmole siRNAs (in 5 μl) was
spotted per well. On the day of transfection 0.3 μl Lipofectamine RNAiMAX was diluted in
15 μl Opti-MEM and added to each well. Plates were rocked gently to mix the components and
incubated at room temperature (RT) for 15 min. Then, 7,000 HeLa-IFNβ-Fluc cells (in 80 μl)
were added to each well and plates were returned to a 37°C incubator. At 2 days post siRNA
transfection, growth medium was discarded, replaced by 100 μl fresh medium and cells were
then transfected with the RIG-I ligand. Briefly, 200 ng ligand and 0.8 μl Lipofectamine 2000
were separately diluted in 25 μl Opti-MEM, and incubated at RT for 5 min. These components
were then mixed, incubated at RT for 20 min, and added to each well. At 6 hr post transfection,
one replicate of each plate was fixed in 4% PFA and stained with DAPI. This replicate was later
scanned at the CSC UMCU, and DAPI-positive nuclei were counted per well as an indication
of cell viability upon siRNA transfections. The other three replicates were lysed in 30 μl 1x Pas-
sive Lysis Buffer (Promega) and allowed to freeze at -20°C. To measure luciferase activity, cell
lysates were mixed by pipetting, and 15 μl from each well was transferred to a measurement
plate, which was read using an automated plate reader using the following parameters: inject
40 μl firefly luciferase substrate (Promega), mix for 1 second, 1 second delay, measure for 10
seconds. negative controls. Polo-like kinase 1 (PLK1)-targeting siRNAs were included as a positive con-
trol for cytotoxicity, while RIG-I-, and MAVS-targeting siRNAs were included as positive con-
trols for RIG-I pathway activity. The RIG-I signaling pathway was activated by transfecting
cells with the 5’-ppp-containing CVB3 CL RNA. Activation levels were assessed by measuring
IFNβ promoter-controlled luciferase reporter activity at 6 hr post transfection (S12 Fig). Screen 1 was performed in four technical replicates. RNAi validation screens for RIG-I pathway activity Cells and RIG-I ligand. HeLa-R19 cells stably expressing Firefly luciferase under control
of the IFNβ (IFNB1) gene promoter were generated using the pIFNβ-Fluc-NeoR plasmid,
which was kindly provided by Wendy Barclay [79]. Single cell clones were selected under G418
selection, and a mixed population of two positive clones was used for the screens. Cells were
maintained in DMEM supplemented with 10% FCS in a humidified incubator with 5% CO2. As RIG-I ligand, we used 5’-ppp cloverleaf (CL) from coxsackievirus B3 (CVB3) sequence, a 90
nt ssRNA carrying a 5’ triphosphate group, which was transcribed in vitro as described previ-
ously [40]. Protocol RNAi screen 1 –IFNβ luciferase. In RNAi validation screen 1, we tested 187
candidate genes (S6 and S8 Tables) that were predicted to play a role in the RLR signaling
pathway by the computational framework. siRNAs (Dharmacon on-target plus Smartpool)
were purchased internally from the Cell Screening Centre of the Utrecht University Medical
Centre (CSC UMCU). Scrambled (SCR) and MDA5-targeting siRNAs were included as PLOS Computational Biology | DOI:10.1371/journal.pcbi.1004553
October 20, 2015 24 / 35 Integrative Genomics of the RLR Pathway difference in IFNβ induction levels between the positive (RIG-I and MAVS) and negative con-
trols (mock treatment, scrambled and MDA5; Figs 2B and S13). Furthermore, significant cor-
relation exists between screens 1 and 2 (correlation between Z-scores of all 57 genes tested in
both screens, including the controls: Pearson r = 0.61, P = 8.6 × 10−15). To reduce the potential for false-positive results, toxicity of the siRNA treatment was
assessed by measuring nuclei counts (DAPI staining) in screen 1 (n = 1) and cellular activity
(MTT essay) in screen 2 (n = 3). Both readouts were normalized per plate by calculating the
percentage of the median of the negative controls (non-transfected and scrambled wells) and
clearly separated negative from positive (PLK1) toxicity controls. Only a few siRNAs reduced
cell numbers by over 50% in screen 1 (S13D Fig). However, knockdown of none of the 57
genes tested in screen 2 reduced cellular activity by more than 50%; only COPA showed slight
toxicity (MTT level compared to negative controls is 53%; S13H Fig and S8 Table). Thus, the
observed effects of the siRNA knockdowns on IFNβ induction are largely independent of
siRNA-induced reductions in cell numbers or cellular activity. Protocol RNAi screen 3 –IFNβ mRNA. We assessed the 19 top hits (Fig 2C and S8
Table) with the consistent largest effects in both RNAi screen 1 and 2 (5’-pppRNA-induced
IFNβ induction in HeLa-IFNβ-Fluc reporter cells, stringent Z-score <-2), again for an effect
on IFNβ (IFNB1) mRNA expression in an independent set of experiments. For 16 of these 19
genes, siRNAs (1 pool per gene) were purchased from SIGMA (esiRNAs human library). For
the other 3 genes, for which esiRNA products were not available, Silencer Select siRNAs were
purchased from Ambion, and three oligos per gene were pooled at 1:1:1 ratio. This RNAi
screen 3 was performed in 24-well clusters, and performed in triplicate. Briefly, 5 pmole siR-
NAs were diluted in 50 μl Opti-MEM and incubated 5 min at RT. Next, 1 μl Lipofectamine
RNAiMAX was added and incubated another 20 min at RT. Then, 25,000 HeLa-R19 cells (in
500 μl) were added to each well and plates were returned to a 37°C incubator. At 3 days post
siRNA transfection, cells were transfected with the RIG-I ligand. Software and tools Plots, statistics and other calculations were done using custom Perl and SQL scripts, and the R
statistical package [83] with additional packages gplots [84], ROCR [85] and RNAither [86]. One-way ANOVA with Dunnett's post hoc test was performed using GraphPad Prism (Graph-
Pad Software). Briefly, 200 ng ligand and 1 μl
Lipofectamine 2000 were separately diluted in 50 μl Opti-MEM, and incubated at RT for 5
min. These components were then mixed, incubated at RT for 20 min, and added to each well. At 6 hr post transfection, total cellular RNA was isolated using the NucleoSpin RNA isolation
kit (Macherey-Nagel) according to manufacturer’s instructions. Isolated RNA was used for
reverse transcription using the TaqMan reverse transcription reagents kit (Applied Biosystems)
with random hexamers primers (Invitrogen) according to manufacturer’s instructions. Quanti-
tative analysis of IFNβ mRNA levels was performed using the LightCycler 480 (Roche) as
described before [82]. The protocol was in principle the same as
for RNAi screen 1, except that the MTT assay using Thiazolyl Blue Tetrazolium Bromide
(SIGMA) (three replicates) was used to assess cell viability instead of DAPI staining. For the
MTT assay, 60 μl 80 μg/ml MTT in medium was added to each well 1 hr prior to cell harvest-
ing. The plates were incubated to 37°C for 1 hr. MTT-containing medium was removed, and
reactions were quenched by adding 150 μl DMSO per well. The resulting mixture was mea-
sured at 570 nm using a plate reader. Statistical analysis of RNAi screens 1 and 2. Raw Fluc intensities (S13A and S13E Fig)
displayed limited variation between plates and were normalized using a negative control-based
robust Z-score [80,81], which expresses each well as the number of median absolute deviations
(MAD) its intensity deviates from the median of the negative controls (non-transfected, scram-
bled and MDA5 siRNA wells) on the plate: Robust ZscoreðxÞ ¼ x medianðnegative controlsÞ
MADðnegative controlsÞ Robust ZscoreðxÞ ¼ x medianðnegative controlsÞ
MADðnegative controlsÞ Replicate plates (n = 3) were then summarized by taking the median of the robust Z-scores
of the well across the three plates (S13B, S13C, S13F and S13G Fig). We observed a clear 25 / 35 PLOS Computational Biology | DOI:10.1371/journal.pcbi.1004553
October 20, 2015 Cells were exposed to respiratory syncytial virus (RSV), human metapneumovirus
(hMPV), parainfluenza virus (PIV), or measles virus (MV). Gene expression was measured
using microarrays at 6, 12 and 24 hours after the infections. Differential expression was calcu-
lated as the log2 fold change comparing each infection condition to mock-infected control
cells. We calculated for each gene the maximum absolute (i.e. considering both up- and down-
regulation) change in expression across all time points and viruses, compared to uninfected
cells. This data was used as a molecular signature (‘Differential expression upon infection’) for
predicting novel RLR pathway components. (A) Differential expression is depicted for each
gene across all infection time points. Colored lines represent the five RLR genes with the high-
est maximum absolute differential expression (represented by the colored dots) across all infec-
tion conditions. (B) Summary of the distributions of log2 fold changes across the infection
conditions. Most genes tend to be increasingly up- or down-regulated during the course of the
infection. Furthermore, RSV and hMPV generally induced much larger expression changes
than PIV and MV (see Methods). (TIF) S4 Fig. Analysis of the weighted co-expression calculations for the RLR pathway. (A) Distri-
butions of weighted co-expression with the RLR pathway, binned into discrete intervals, for the
‘other PRR signaling pathways’ gene set (TLR, CLR, NLR, cytDNA; purple) and the set of non-
RLR genes (red). Although the genome-wide RLR co-expression scores (x-axis in panels A-C)
were calculated based on the set of known RLR genes, to avoid circularity we calculated the
likelihood ratio scores (Tables 1 and S1) of this feature (‘Co-expression with RLR pathway’)
using the independent set of TLR, CLR, NLR, cytDNA genes (see Methods). This panel A is
the same plot as the co-expression panel in Fig 1A. (B) Kernel density estimates and (C) box-
plots of RLR co-expression scores for the various gene sets. Density estimates were calculated
using a Gaussian kernel with a smoothing bandwidth given by Silverman's rule of thumb, and
were normalized to 1. P values were calculated using the Mann-Whitney U test. (D) Recall per-
formance (also known as sensitivity) of the weighted co-expression method for retrieving a
fraction of the 49 known RLR genes (y-axis) given an inclusion cut-off rank (x-axis), across a
49x leave-one-out cross-validation (green) (see Methods). Analysis of the weighted co-expression calculations for the RLR pathway. (A) Distri-
butions of weighted co-expression with the RLR pathway, binned into discrete intervals, for the
‘other PRR signaling pathways’ gene set (TLR, CLR, NLR, cytDNA; purple) and the set of non-
RLR genes (red). Although the genome-wide RLR co-expression scores (x-axis in panels A-C)
were calculated based on the set of known RLR genes, to avoid circularity we calculated the
likelihood ratio scores (Tables 1 and S1) of this feature (‘Co-expression with RLR pathway’)
using the independent set of TLR, CLR, NLR, cytDNA genes (see Methods). This panel A is
the same plot as the co-expression panel in Fig 1A. (B) Kernel density estimates and (C) box-
plots of RLR co-expression scores for the various gene sets. Density estimates were calculated
using a Gaussian kernel with a smoothing bandwidth given by Silverman's rule of thumb, and
were normalized to 1. P values were calculated using the Mann-Whitney U test. (D) Recall per-
formance (also known as sensitivity) of the weighted co-expression method for retrieving a
fraction of the 49 known RLR genes (y-axis) given an inclusion cut-off rank (x-axis), across a
49x leave-one-out cross-validation (green) (see Methods). The recall performance of the
method for other sets of genes across the cross-validation ranks is also shown to demonstrate
the ability of our method to retrieve RLR genes specifically compared to other PRR pathway
genes (purple), or other innate immunity genes (blue). (TIF)
S5 Fig. Distributions of the integrated RLR score for the positive (RLR genes) and negative
(non-RLR genes) training sets. Integration of the 10 molecular signature data sets into the
Bayesian RLR score enriches for RLR genes and depletes non-RLR genes compared to the indi-
vidual data sets (see also Figs 1A and S9). (TIF)
S6 Fi
KEGG [69]
h
i h
l
i
f h
354 RLR
di i
l di S2 Fig. Venn diagram showing the overlap between the five virus-human protein-protein
interaction resources. Values represent the number of human proteins for which an interac-
tion was reported with at least one virus. The union of the five databases (2,587 proteins) was
used as a molecular signature (‘PPI with viruses’) for predicting novel RLR pathway compo-
nents. (TIF) S3 Fig. Time-course transcriptome analysis of A549 cells infected with four respiratory
viruses. Supporting Information S1 Fig. Overview of the 49 RLR pathway components used as positive gold standard in our
study (‘RLR genes’). We focused on components that make up the intracellular core of the
pathway, hence excluding the interferons and proinflammatory cytokines that are induced. The depicted network is based on the KEGG map of the RLR pathway [69]. Only key interac-
tions are depicted. In reality, the pathway consists of a complex network of interactions [87]. (TIF) 26 / 35 PLOS Computational Biology | DOI:10.1371/journal.pcbi.1004553
October 20, 2015 Integrative Genomics of the RLR Pathway S2 Fig. Venn diagram showing the overlap between the five virus-human protein-pro
interaction resources. Values represent the number of human proteins for which an int
tion was reported with at least one virus. The union of the five databases (2,587 proteins
used as a molecular signature (‘PPI with viruses’) for predicting novel RLR pathway com
nents. (TIF)
S3 Fig. Time-course transcriptome analysis of A549 cells infected with four respirato
viruses. Cells were exposed to respiratory syncytial virus (RSV), human metapneumovir
(hMPV), parainfluenza virus (PIV), or measles virus (MV). Gene expression was measu
using microarrays at 6, 12 and 24 hours after the infections. Differential expression was
lated as the log2 fold change comparing each infection condition to mock-infected contr
cells. We calculated for each gene the maximum absolute (i.e. considering both up- and
regulation) change in expression across all time points and viruses, compared to uninfec
cells. This data was used as a molecular signature (‘Differential expression upon infectio
predicting novel RLR pathway components. (A) Differential expression is depicted for e
gene across all infection time points. Colored lines represent the five RLR genes with the
est maximum absolute differential expression (represented by the colored dots) across al
tion conditions. (B) Summary of the distributions of log2 fold changes across the infectio
conditions. Most genes tend to be increasingly up- or down-regulated during the course
infection. Furthermore, RSV and hMPV generally induced much larger expression chan
than PIV and MV (see Methods). (TIF)
S4 Fig. Analysis of the weighted co-expression calculations for the RLR pathway. (A)
butions of weighted co-expression with the RLR pathway, binned into discrete intervals,
‘other PRR signaling pathways’ gene set (TLR, CLR, NLR, cytDNA; purple) and the set o
RLR genes (red). Although the genome-wide RLR co-expression scores (x-axis in panels A
were calculated based on the set of known RLR genes, to avoid circularity we calculated
likelihood ratio scores (Tables 1 and S1) of this feature (‘Co-expression with RLR pathwa
using the independent set of TLR, CLR, NLR, cytDNA genes (see Methods). This panel
the same plot as the co-expression panel in Fig 1A. (B) Kernel density estimates and (C)
plots of RLR co-expression scores for the various gene sets. Density estimates were calcu
using a Gaussian kernel with a smoothing bandwidth given by Silverman's rule of thumb
were normalized to 1. P values were calculated using the Mann-Whitney U test. (D) Rec
formance (also known as sensitivity) of the weighted co-expression method for retrievin
fraction of the 49 known RLR genes (y-axis) given an inclusion cut-off rank (x-axis), acr
49x leave-one-out cross-validation (green) (see Methods). The recall performance of the
method for other sets of genes across the cross-validation ranks is also shown to demons
the ability of our method to retrieve RLR genes specifically compared to other PRR path
genes (purple), or other innate immunity genes (blue). (TIF)
S5 Fig. Distributions of the integrated RLR score for the positive (RLR genes) and ne
(non-RLR genes) training sets. Integration of the 10 molecular signature data sets into
Bayesian RLR score enriches for RLR genes and depletes non-RLR genes compared to th
vidual data sets (see also Figs 1A and S9). (TIF) S2 Fig. Venn diagram showing the overlap between the five virus-human protein-protein
interaction resources. Values represent the number of human proteins for which an interac-
tion was reported with at least one virus. The union of the five databases (2,587 proteins) was
used as a molecular signature (‘PPI with viruses’) for predicting novel RLR pathway compo-
nents. (TIF)
S3 Fig. Time-course transcriptome analysis of A549 cells infected with four respiratory
viruses. Cells were exposed to respiratory syncytial virus (RSV), human metapneumovirus
(hMPV), parainfluenza virus (PIV), or measles virus (MV). Gene expression was measured
using microarrays at 6, 12 and 24 hours after the infections. Differential expression was calcu-
lated as the log2 fold change comparing each infection condition to mock-infected control
cells. We calculated for each gene the maximum absolute (i.e. considering both up- and down-
regulation) change in expression across all time points and viruses, compared to uninfected
cells. This data was used as a molecular signature (‘Differential expression upon infection’) for
predicting novel RLR pathway components. (A) Differential expression is depicted for each
gene across all infection time points. Colored lines represent the five RLR genes with the high-
est maximum absolute differential expression (represented by the colored dots) across all infec-
tion conditions. (B) Summary of the distributions of log2 fold changes across the infection
conditions. Most genes tend to be increasingly up- or down-regulated during the course of the
infection. Furthermore, RSV and hMPV generally induced much larger expression changes
than PIV and MV (see Methods). (TIF)
S4 Fig. Integrative Genomics of the RLR Pathway (TLR, CLR, NLR, cytDNA), blue bars indicate additional immunity-related pathways. Enrich-
ment was determined using the functional annotation tool of the DAVID suite version 6.7 [88]
with default settings and a false discovery rate (q-value) of 0.01. Background: all human genes. See also S7 Table. (TIF) S7 Fig. ClueGO [89] enrichment analysis of REACTOME pathways [90] in the top 354 RLR
predictions. Nodes represent significantly enriched REACTOME terms (Bonferroni step-
down corrected P < 0.01, background: all human genes) and are grouped (as denoted by the
connecting edges) based on overlapping gene lists (connectivity measure κ > 0.4). Groups of
similar terms are represented by the most prominent term(s). See also S7 Table. (TIF) S8 Fig. ClueGO [89] enrichment analysis of Gene Ontology Biological Process terms in the
top 354 RLR predictions. Nodes represent significantly enriched terms (Bonferroni step-
down corrected P < 0.001, background: all human genes) and are grouped (as denoted by the
connecting edges) based on overlapping gene lists (connectivity measure κ > 0.7). Groups of
similar terms are represented by the most prominent term. For conciseness, clusters having
less than four terms are not shown. See also S7 Table. (TIF) S8 Fig. ClueGO [89] enrichment analysis of Gene Ontology Biological Process terms in the
top 354 RLR predictions. Nodes represent significantly enriched terms (Bonferroni step-
down corrected P < 0.001, background: all human genes) and are grouped (as denoted by the
connecting edges) based on overlapping gene lists (connectivity measure κ > 0.7). Groups of
similar terms are represented by the most prominent term. For conciseness, clusters having
less than four terms are not shown. See also S7 Table. (TIF) S9 Fig. Visualization of how integration of the 10 molecular signatures enriches for RLR
genes and depletes non-RLR genes. Rank plots showing the top 100 genes in (on the right) six
of the individual molecular signature data sets and (on the left) in the integrated RLR score. Only the six continuous (i.e. non-binary) signatures are depicted, because ordering of genes
within the two classes of the binary signatures would be arbitrary. See also Fig 1B and 1C. (TIF) S10 Fig. Correlations between the ten molecular signatures used for predicting novel RLR
pathway components. The recall performance of the
method for other sets of genes across the cross-validation ranks is also shown to demonstrate
the ability of our method to retrieve RLR genes specifically compared to other PRR pathway
genes (purple), or other innate immunity genes (blue). (TIF) S5 Fig. Distributions of the integrated RLR score for the positive (RLR genes) and negative
(non-RLR genes) training sets. Integration of the 10 molecular signature data sets into the
Bayesian RLR score enriches for RLR genes and depletes non-RLR genes compared to the indi-
vidual data sets (see also Figs 1A and S9). (TIF) S6 Fig. KEGG [69] pathway enrichment analysis of the top 354 RLR predictions excluding
known RLR genes. Purple bars indicate PRR signaling pathways other than the RLR pathway PLOS Computational Biology | DOI:10.1371/journal.pcbi.1004553
October 20, 2015 27 / 35 Cell counts and MTT essay are prese
the median of the negative controls (non-transfected and scrambled w
exists between the effects of gene knockdown on the luciferase activity
icity. All data points close to 0% cell counts or MTT are from the posi
PLK1. (TIF)
S14 Fig. No molecular signature solely explains the predictions of t
dated hits. Distributions of the 187 candidate RLR genes selected for e
across the 10 molecular signature data sets we identified as predictive
also Fig 1A). RLR candidates were grouped based on the results from
(gray), all hits from RNAi screen 1 (94 hits with Z-score <-1.25 or >1
top hits from RNAi screen 1 (57 hits with Z-score <-2 or >2, purple)
of genes in the same group add up to one. ‘NA’ bins represent genes fo
data in the respective molecular signature (note that these bins did no
Bayesian integration, see Methods). (TIF)
S1 Table. Likelihood scores for the 10 molecular signatures of RLR
avoid circularity, the predictive ability of the co-expression, protein do
PPI data sets was assessed using the set of TLR, CLR, NLR, cytDNA g S13 Fig. Analysis of RNAi screens 1 (A-D) and 2 (E-H) for validation of the candidate RLR
genes. See also Fig 2. (A,E) Q-Q plots (left) of the raw luciferase intensities against the quan-
tiles of a theoretical normal distribution (plotted by RNAither [86]). Linearity suggests that the
raw data resemble a normal distribution. Boxplots (right) show the distributions of the raw
luciferase intensities for the positive controls (RIG-I and MAVS siRNAs; green), negative con-
trols (non-transfected, scrambled, and MDA5 siRNAs; red), and RLR candidates (gray). (B,F)
Q-Q plots and boxplots of the normalized data, summarized over the replicate plates. Raw
luciferase intensities were normalized using a negative control-based robust Z-score and
summarized across replicate plates by taking the median Z-score (see Methods). Note that
the gray distributions in (A-B and E-F) include the death control PLK1, which always has a
luciferase signal close to zero. This causes some of the observed deviations from the normal dis-
tribution at the lower extremes, and causes the boxplots to lie a little lower than would be the
case without PLK1. (C,G) Z-score distributions. Dotted lines indicate Z-score cutoffs of -1.25
and 1.25. Dashed lines indicate stringent Z-score cutoffs of -2 and 2. Heatmaps depict pairwise Spearman’s rank correlation coefficients
between the values in the molecular signature data sets for positive gold standard RLR genes
(A), and negative gold standard non-RLR genes (B). (TIF) S11 Fig. Rank-order plot of the estimated false discovery rate (FDR) of the RLR predic-
tions. The FDR was adjusted to match the expected total number of genes involved in the RLR
pathway (see Methods). The inset shows the same plot, zoomed-in on the lower-left region,
and indicates occurrences of RLR (green) and non-RLR (red) genes. RLR rank 354 corresponds
to an estimated FDR of ~57%. (TIF) S12 Fig. Pilot experiments for RNAi validation screens of candidate RLR genes. (A) Our
essay uses HeLa-IFNβ-Fluc cells stably expressing an IFNβ promoter-controlled firefly lucifer-
ase reporter. We knocked down candidate genes using different siRNAs, transfected cells with
a known small 5’-ppp-containing RIG-I RNA ligand derived from coxsackievirus [40], and
measured Fluc reporter expression and cell viability after 6 hours in three technical replicates. (B-E) Pilot experiments for RNAi screen 1 (B-C) and RNAi screen 2 (D-E). RNAi screens 1
and 2 used a different set of siRNAs. (B,D) IFNβ-Fluc reporter activity after treatment of
HeLa-IFNβ-Fluc cells with the 5’-ppp-containing RIG-I RNA ligand and various siRNAs. Scrambled (SCR) and MDA5-targeting siRNAs were included as negative controls. Polo-like
kinase 1 (PLK1)-targeting siRNAs were included as a positive control for cellular toxicity,
while RIG-I-, and MAVS-targeting siRNAs were included as positive controls for RIG-I PLOS Computational Biology | DOI:10.1371/journal.pcbi.1004553
October 20, 2015 28 / 35 Integrative Genomics of the RLR Pathway pathway activity. RNAiMax and Non-treated indicate treatment of cells without siRNA trans-
fection (non-transfected). This setup led to specific activation of RIG-I, as RIG-I or MAVS
siRNA transfection, but not MDA5 or scrambled siRNAs, resulted in loss of luciferase reporter
activity. (C,E) As an indication of cell viability upon siRNA transfection, the number of nuclei
per well (DAPI staining) was counted in screen 1 (C) or MTT activity was measured to assess
cellular activity in screen 2 (E). Only the death-control PLK1 severely reduced nuclei numbers. (TIF) fection (non-transfected). This setup led to specific activation of RIG-
siRNA transfection, but not MDA5 or scrambled siRNAs, resulted in
activity. (C,E) As an indication of cell viability upon siRNA transfectio
per well (DAPI staining) was counted in screen 1 (C) or MTT activity
cellular activity in screen 2 (E). Only the death-control PLK1 severely
(TIF)
S13 Fig. Analysis of RNAi screens 1 (A-D) and 2 (E-H) for validatio
genes. See also Fig 2. (A,E) Q-Q plots (left) of the raw luciferase inten
tiles of a theoretical normal distribution (plotted by RNAither [86]). L
raw data resemble a normal distribution. Boxplots (right) show the di
luciferase intensities for the positive controls (RIG-I and MAVS siRN
trols (non-transfected, scrambled, and MDA5 siRNAs; red), and RLR
Q-Q plots and boxplots of the normalized data, summarized over the
luciferase intensities were normalized using a negative control-based r
summarized across replicate plates by taking the median Z-score (see
the gray distributions in (A-B and E-F) include the death control PLK
luciferase signal close to zero. This causes some of the observed deviat
tribution at the lower extremes, and causes the boxplots to lie a little lo
case without PLK1. (C,G) Z-score distributions. Dotted lines indicate
and 1.25. Dashed lines indicate stringent Z-score cutoffs of -2 and 2. N
the plots indicate the number of candidate RLR genes scoring within t
range. Knockdown of 94 genes of the 187 tested candidates (50%) affe
IFNβ induction at Z-score <-1.25 or >1.25 in RNAi screen 1, of whic
increased IFNβ induction. The 57 top hits with stringent Z-score <-2
tested again in screen 2 using a different set of siRNAs (Fig 2A). (D,H
sus cell count (nuclei staining, right y-axis in (D)) or cellular activity (
right y-axis in (H)) distributions. Acknowledgments We thank John van Dam and other members of the Huynen lab for stimulating discussions,
and Pavel Čížek for assistance with the web page. Integrative Genomics of the RLR Pathway genes (see Methods). (XLSX)
S2 Table. List of the 128 viral miRNAs for which we obtained predicted target sites in
human mRNAs. (XLSX)
S3 Table. Meta analysis of antiviral host factors from published RNAi screens. (XLSX)
S4 Table. Enrichment analysis of protein domains occurring in RLR pathway components. (XLSX)
S5 Table. Enrichment analysis of conserved IRF, AP–1, NFκB, and STAT TF binding
motifs in the promoters of RLR pathway genes. (XLSX)
S6 Table. Genome-wide prioritization of RLR pathway components based on the integrated
RLR score. Also available at http://rlr.cmbi.umcn.nl/. (XLSX)
S7 Table. Function enrichment analysis of the top 354 RLR predictions excluding known
RLR genes. Function enrichment (gene ontology, pathways, disease) was determined using the
functional annotation tool of the DAVID suite version 6.7 [88] with default settings and a false
discovery rate (q-value) of 0.01. In cases where multiple function terms form a cluster at
medium stringency according to the ‘Functional Annotation Clustering’ view, only the term
with the lowest q-value is shown for conciseness. Background: all human genes. (XLSX)
S8 Table. Detailed results of the RNAi validation screens. (XLSX)
S9 Table. Impact of the prior on the RLR score and false discovery rate. (XLSX) S5 Table. Enrichment analysis of conserved IRF, AP–1, NFκB, and STAT TF binding
motifs in the promoters of RLR pathway genes. (XLSX) S6 Table. Genome-wide prioritization of RLR pathway components based on the integrated
RLR score. Also available at http://rlr.cmbi.umcn.nl/. (XLSX) S6 Table. Genome-wide prioritization of RLR pathway components based on the integrated
RLR score. Also available at http://rlr.cmbi.umcn.nl/. (XLSX) S7 Table. Function enrichment analysis of the top 354 RLR predictions excluding known
RLR genes. Function enrichment (gene ontology, pathways, disease) was determined using the
functional annotation tool of the DAVID suite version 6.7 [88] with default settings and a false
discovery rate (q-value) of 0.01. In cases where multiple function terms form a cluster at
medium stringency according to the ‘Functional Annotation Clustering’ view, only the term
with the lowest q-value is shown for conciseness. Background: all human genes. (XLSX) S8 Table. Detailed results of the RNAi validation screens. (XLSX) Numbers to the right of
the plots indicate the number of candidate RLR genes scoring within the indicated Z-score
range. Knockdown of 94 genes of the 187 tested candidates (50%) affected RIG-I-mediated
IFNβ induction at Z-score <-1.25 or >1.25 in RNAi screen 1, of which 59 decreased and 35
increased IFNβ induction. The 57 top hits with stringent Z-score <-2 or >2 in screen 1 were
tested again in screen 2 using a different set of siRNAs (Fig 2A). (D,H) Z-score (left y-axis) ver-
sus cell count (nuclei staining, right y-axis in (D)) or cellular activity (measured by MTT essay,
right y-axis in (H)) distributions. Cell counts and MTT essay are presented as the percentage of
the median of the negative controls (non-transfected and scrambled wells). No correlation
exists between the effects of gene knockdown on the luciferase activity Z-score and cellular tox-
icity. All data points close to 0% cell counts or MTT are from the positive toxicity control
PLK1. S14 Fig. No molecular signature solely explains the predictions of the experimentally vali-
dated hits. Distributions of the 187 candidate RLR genes selected for experimental validation,
across the 10 molecular signature data sets we identified as predictive of the RLR system (see
also Fig 1A). RLR candidates were grouped based on the results from RNAi screen 1: no hit
(gray), all hits from RNAi screen 1 (94 hits with Z-score <-1.25 or >1.25, dark purple), and
top hits from RNAi screen 1 (57 hits with Z-score <-2 or >2, purple) (see also Fig 2). Fractions
of genes in the same group add up to one. ‘NA’ bins represent genes for which there was no
data in the respective molecular signature (note that these bins did not receive a score in the
Bayesian integration, see Methods). S1 Table. Likelihood scores for the 10 molecular signatures of RLR genes. Note that, to
avoid circularity, the predictive ability of the co-expression, protein domain and RLR pathway
PPI data sets was assessed using the set of TLR, CLR, NLR, cytDNA genes instead of the RLR 29 / 35 PLOS Computational Biology | DOI:10.1371/journal.pcbi.1004553
October 20, 2015 References 1. Wilkins C, Gale M. Recognition of viruses by cytoplasmic sensors. Curr Opin Immunol 2010; 22:41–7. doi: 10.1016/j.coi.2009.12.003 PMID: 20061127 1. Wilkins C, Gale M. Recognition of viruses by cytoplasmic sensors. Curr Opin Immunol 2010; 22:41–7. doi: 10.1016/j.coi.2009.12.003 PMID: 20061127 2. Takeuchi O, Akira S. Pattern recognition receptors and inflammation. Cell 2010; 140:805–20. doi: 10. 1016/j.cell.2010.01.022 PMID: 20303872 2. Takeuchi O, Akira S. Pattern recognition receptors and inflammation. Cell 2010; 140:805–20. doi: 10. 1016/j.cell.2010.01.022 PMID: 20303872 3. Goubau D, Deddouche S, Reis e Sousa C. Cytosolic sensing of viruses. Immunity 2013; 38:855–69. doi: 10.1016/j.immuni.2013.05.007 PMID: 23706667 4. Iwasaki A, Medzhitov R. Regulation of adaptive immunity by the innate immune system. Science
2010; 327:291–5. doi: 10.1126/science.1183021 PMID: 20075244 5. Bowie AG, Unterholzner L. Viral evasion and subversion of pattern-recognition receptor signalling. Nat. Rev. Immunol. 2008; 8:911–22. doi: 10.1038/nri2436 PMID: 18989317 6. Feng Q, Langereis MA, van Kuppeveld FJM. Induction and suppression of innate antiviral responses
by picornaviruses. Cytokine Growth Factor Rev. 2014; 25:577–85. doi: 10.1016/j.cytogfr.2014.07.003
PMID: 25086453 7. Versteeg GA, García-Sastre A. Viral tricks to grid-lock the type I interferon system. Curr. Opin. Micro-
biol. 2010; 13:508–16. doi: 10.1016/j.mib.2010.05.009 PMID: 20538505 8. Kato H, Takeuchi O, Sato S, Yoneyama M, Yamamoto M, Matsui K, et al. Differential roles of MDA5
and RIG-I helicases in the recognition of RNA viruses. Nature 2006; 441:101–5. PMID: 16625202 9. Kato H, Fujita T. Autoimmunity caused by constitutive activation of cytoplasmic viral RNA sensors. Cytokine Growth Factor Rev. 2014; 25:739–43. doi: 10.1016/j.cytogfr.2014.08.003 PMID: 25193292 10. Crow YJ. Type I interferonopathies: Mendelian type I interferon up-regulation. Curr Opin Immunol
2015; 32C:7–12. 11. Friedel CC, Haas J. Virus-host interactomes and global models of virus-infected cells. Trends Micro-
biol. 2011; 19:501–8. doi: 10.1016/j.tim.2011.07.003 PMID: 21855347 12. Li S, Wang L, Berman M, Kong Y-Y, Dorf ME. Mapping a dynamic innate immunity protein interaction
network regulating type I interferon production. Immunity 2011; 35:426–40. doi: 10.1016/j.immuni. 2011.06.014 PMID: 21903422 13. Lee MN, Roy M, Ong S-E, Mertins P, Villani A-C, Li W, et al. Identification of regulators of the innate
immune response to cytosolic DNA and retroviral infection by an integrative approach. Nat. Immunol. 2013; 14:179–85. doi: 10.1038/ni.2509 PMID: 23263557 14. Pulloor NK, Nair S, Kostic AD, Bist P, Weaver JD, Riley AM, et al. Human genome-wide RNAi screen
identifies an essential role for inositol pyrophosphates in Type-I interferon response. PLoS Pathog. 2014; 10:e1003981. doi: 10.1371/journal.ppat.1003981 PMID: 24586175 15. Integrative Genomics of the RLR Pathway Author Contributions Conceived and designed the experiments: RvdL QF MAL MGN ACA FJvK MAH. Performed
the experiments: RvdL QF MAL RtH. Analyzed the data: RvdL. Contributed reagents/materi-
als/analysis tools: RS. Wrote the paper: RvdL QF MAL FJMvK MAH. Designed the study, ana-
lyzed the data, and wrote the manuscript: RvdL MAH. Planned and performed the large
majority of (computational) analyses, data mining, data analysis, and manuscript preparation:
RvdL. Designed, performed and interpreted the RNAi screening experiments, wrote the corre-
sponding part of the manuscript and helped prepare the rest of the manuscript: QF MAL
FJMvK. Calculated viral miRNA targeting scores and contributed to the integration approach:
RtH. Calculated RLR co-expression and contributed to the integration approach: RS. Contrib-
uted to study design: MGN. Contributed the gene expression data and helped design the study:
ACA. Supervised the study: MAH. FJMvK. Calculated viral miRNA targeting scores and contributed to the integration approach:
RtH. Calculated RLR co-expression and contributed to the integration approach: RS. Contrib-
uted to study design: MGN. Contributed the gene expression data and helped design the study:
ACA. Supervised the study: MAH. 30 / 35 PLOS Computational Biology | DOI:10.1371/journal.pcbi.1004553
October 20, 2015 PLOS Computational Biology | DOI:10.1371/journal.pcbi.1004553
October 20, 2015 Integrative Genomics of the RLR Pathway 23. George RD, McVicker G, Diederich R, Ng SB, Mackenzie AP, Swanson WJ, et al. Trans genomic cap-
ture and sequencing of primate exomes reveals new targets of positive selection. Genome Res. 2011;
21:1686–94. doi: 10.1101/gr.121327.111 PMID: 21795384 24. Patel MR, Loo Y- M, Horner SM, Gale M, Malik HS. Convergent evolution of escape from hepaciviral
antagonism in primates. PLoS Biol. 2012; 10:e1001282. doi: 10.1371/journal.pbio.1001282 PMID:
22427742 25. Mandl JN, Barry AP, Vanderford TH, Kozyr N, Chavan R, Klucking S, et al. Divergent TLR7 and TLR9
signaling and type I interferon production distinguish pathogenic and nonpathogenic AIDS virus infec-
tions. Nat. Med. 2008; 14:1077–87. doi: 10.1038/nm.1871 PMID: 18806803 26. Dyer MD, Murali TM, Sobral BW. The landscape of human proteins interacting with viruses and other
pathogens. PLoS Pathog. 2008; 4:e32. doi: 10.1371/journal.ppat.0040032 PMID: 18282095 27. Elde NC, Child SJ, Geballe AP, Malik HS. Protein kinase R reveals an evolutionary model for defeat-
ing viral mimicry. Nature 2009; 457:485–9. doi: 10.1038/nature07529 PMID: 19043403 28. Durmuş Tekir S, Çakır T, Ardiç E, Sayılırbaş AS, Konuk G, Konuk M, et al. PHISTO: pathogen-host
interaction search tool. Bioinformatics 2013; 29:1357–8. doi: 10.1093/bioinformatics/btt137 PMID:
23515528 29. Skalsky RL, Cullen BR. Viruses, microRNAs, and host interactions. Annu. Rev. Microbiol. 2010;
64:123–41. doi: 10.1146/annurev.micro.112408.134243 PMID: 20477536 30. Kim H, Park S, Min H, Yoon S. vHoT: a database for predicting interspecies interactions between viral
microRNA and host genomes. Arch. Virol. 2012; 157:497–501. doi: 10.1007/s00705-011-1181-y
PMID: 22160653 31. Liang D, Gao Y, Lin X, He Z, Zhao Q, Deng Q, et al. A human herpesvirus miRNA attenuates inter-
feron signaling and contributes to maintenance of viral latency by targeting IKKε. Cell Res. 2011;
21:793–806. doi: 10.1038/cr.2011.5 PMID: 21221132 32. Baughman JM, Nilsson R, Gohil VM, Arlow DH, Gauhar Z, Mootha VK. A Computational Screen for
Regulators of Oxidative Phosphorylation Implicates SLIRP in Mitochondrial RNA Homeostasis. PLoS
Genet. 2009; 5:e1000590. doi: 10.1371/journal.pgen.1000590 PMID: 19680543 33. Lindblad-Toh K, Garber M, Zuk O, Lin MF, Parker BJ, Washietl S, et al. A high-resolution map of
human evolutionary constraint using 29 mammals. Nature 2011; 478:476–82. doi: 10.1038/
nature10530 PMID: 21993624 34. Gewurz BE, Towfic F, Mar JC, Shinners NP, Takasaki K, Zhao B, et al. Genome-wide siRNA screen
for mediators of NF-κB activation. Proc. Natl. Acad. Sci. U.S.A. 2012; 109:2467–72. doi: 10.1073/
pnas.1120542109 PMID: 22308454 35. References Alper S, Laws R, Lackford B, Boyd WA, Dunlap P, Freedman JH, et al. Identification of innate immu-
nity genes and pathways using a comparative genomics approach. Proc. Natl. Acad. Sci. U.S.A. 2008; 105:7016–21. doi: 10.1073/pnas.0802405105 PMID: 18463287 16. Schoggins JW, Wilson SJ, Panis M, Murphy MY, Jones CT, Bieniasz P, et al. A diverse range of gene
products are effectors of the type I interferon antiviral response. Nature 2011; 472:481–5. doi: 10. 1038/nature09907 PMID: 21478870 17. Versteeg GA, Rajsbaum R, Sánchez-Aparicio MT, Maestre AM, Valdiviezo J, Shi M, et al. The E3-
ligase TRIM family of proteins regulates signaling pathways triggered by innate immune pattern-rec-
ognition receptors. Immunity 2013; 38:384–98. doi: 10.1016/j.immuni.2012.11.013 PMID: 23438823 18. Jansen R, Yu H, Greenbaum D, Kluger Y, Krogan NJ, Chung S, et al. A Bayesian networks approach
for predicting protein-protein interactions from genomic data. Science 2003; 302:449–53. PMID:
14564010 19. Calvo S, Jain M, Xie X, Sheth SA, Chang B, Goldberger OA, et al. Systematic identification of human
mitochondrial disease genes through integrative genomics. Nat. Genet. 2006; 38:576–82. PMID:
16582907 20. Tabach Y, Billi AC, Hayes GD, Newman MA, Zuk O, Gabel H, et al. Identification of small RNA path-
way genes using patterns of phylogenetic conservation and divergence. Nature 2013; 493:694–8. doi:
10.1038/nature11779 PMID: 23364702 21. Lynn DJ, Winsor GL, Chan C, Richard N, Laird MR, Barsky A, et al. InnateDB: facilitating systems-
level analyses of the mammalian innate immune response. Mol. Syst. Biol. 2008; 4:218. doi: 10.1038/
msb.2008.55 PMID: 18766178 22. Daugherty MD, Malik HS. Rules of engagement: molecular insights from host-virus arms races. Annu. Rev. Genet. 2012; 46:677–700. doi: 10.1146/annurev-genet-110711-155522 PMID: 23145935 31 / 35 PLOS Computational Biology | DOI:10.1371/journal.pcbi.1004553
October 20, 2015 PLOS Computational Biology | DOI:10.1371/journal.pcbi.1004553
October 20, 2015 Integrative Genomics of the RLR Pathway 43. Zhou Z, Jia X, Xue Q, Dou Z, Ma Y, Zhao Z, et al. TRIM14 is a mitochondrial adaptor that facilitates ret-
inoic acid-inducible gene-I-like receptor-mediated innate immune response. Proc. Natl. Acad. Sci. U. S.A. 2014; 111:E245–54. doi: 10.1073/pnas.1316941111 PMID: 24379373 44. Ng CS, Jogi M, Yoo J-S, Onomoto K, Koike S, Iwasaki T, et al. Encephalomyocarditis virus disrupts
stress granules, the critical platform for triggering antiviral innate immune responses. J. Virol. 2013;
87:9511–22. doi: 10.1128/JVI.03248-12 PMID: 23785203 45. Bijlmakers M-J, Kanneganti SK, Barker JN, Trembath RC, Capon F. Functional analysis of the
RNF114 psoriasis susceptibility gene implicates innate immune responses to double-stranded RNA
in disease pathogenesis. Hum. Mol. Genet. 2011; 20:3129–37. doi: 10.1093/hmg/ddr215 PMID:
21571784 46. Panda D, Gold B, Tartell MA, Rausch K, Casas-Tinto S, Cherry S. The transcription factor FoxK par-
ticipates with Nup98 to regulate antiviral gene expression. MBio 2015; 6. doi: 10.1128/mBio.02509-14
PMID: 25852164 47. Moy RH, Cole BS, Yasunaga A, Gold B, Shankarling G, Varble A, et al. Stem-loop recognition by
DDX17 facilitates miRNA processing and antiviral defense. Cell 2014; 158:764–77. doi: 10.1016/j. cell.2014.06.023 PMID: 25126784 48. Ingham RJ, Colwill K, Howard C, Dettwiler S, Lim CSH, Yu J, et al. WW domains provide a platform
for the assembly of multiprotein networks. Mol. Cell. Biol. 2005; 25:7092–106. PMID: 16055720 49. Saitoh T, Tun-Kyi A, Ryo A, Yamamoto M, Finn G, Fujita T, et al. Negative regulation of interferon-reg-
ulatory factor 3-dependent innate antiviral response by the prolyl isomerase Pin1. Nat. Immunol. 2006; 7:598–605. PMID: 16699525 50. Zhao C, Denison C, Huibregtse JM, Gygi S, Krug RM. Human ISG15 conjugation targets both IFN-
induced and constitutively expressed proteins functioning in diverse cellular pathways. Proc. Natl. Acad. Sci. U.S.A. 2005; 102:10200–5. PMID: 16009940 51. van der Lee R, Buljan M, Lang B, Weatheritt RJ, Daughdrill GW, Dunker AK, et al. Classification of
Intrinsically Disordered Regions and Proteins. Chem. Rev. 2014; 114:6589–631. doi: 10.1021/
cr400525m PMID: 24773235 52. Wang X, Zhang S, Zhang J, Huang X, Xu C, Wang W, et al. A large intrinsically disordered region in
SKIP and its disorder-order transition induced by PPIL1 binding revealed by NMR. J. Biol. Chem. 2010; 285:4951–63. doi: 10.1074/jbc.M109.087528 PMID: 20007319 53. Llères D, Denegri M, Biggiogera M, Ajuh P, Lamond AI. Direct interaction between hnRNP-M and
CDC5L/PLRG1 proteins affects alternative splice site choice. EMBO Rep. 2010; 11:445–51. doi: 10. Wu J, Vallenius T, Ovaska K, Westermarck J, Mäkelä TP, Hautaniemi S. Integrated network analysis
platform for protein-protein interactions. Nat. Methods 2009; 6:75–7. doi: 10.1038/nmeth.1282 PMID:
19079255 36. Sama IE, Huynen MA. Measuring the physical cohesiveness of proteins using physical interaction
enrichment. Bioinformatics 2010; 26:2737–43. doi: 10.1093/bioinformatics/btq474 PMID: 20798171 37. Pichlmair A, Kandasamy K, Alvisi G, Mulhern O, Sacco R, Habjan M, et al. Viral immune modulators
perturb the human molecular network by common and unique strategies. Nature 2012; 487:486–90. doi: 10.1038/nature11289 PMID: 22810585 38. Smeekens SP, Ng A, Kumar V, Johnson MD, Plantinga TS, van Diemen C, et al. Functional genomics
identifies type I interferon pathway as central for host defense against Candida albicans. Nat Commun
2013; 4:1342. doi: 10.1038/ncomms2343 PMID: 23299892 39. Jaeger M, van der Lee R, Cheng SC, Johnson MD, Kumar V, Ng A, et al. The RIG-I-like helicase
receptor MDA5 (IFIH1) is involved in the host defense against Candida infections. Eur. J. Clin. Micro-
biol. Infect. Dis. 2015; 34:963–74. doi: 10.1007/s10096-014-2309-2 PMID: 25579795 (http://www. ncbi.nlm.nih.gov/pubmed/25579795) 40. Feng Q, Langereis MA, Olagnier D, Chiang C, van de Winkel R, van Essen P, et al. Coxsackievirus
cloverleaf RNA containing a 5' triphosphate triggers an antiviral response via RIG-I activation. PLoS
ONE 2014; 9:e95927. doi: 10.1371/journal.pone.0095927 PMID: 24759703 41. Gardy JL, Lynn DJ, Brinkman FSL, Hancock REW. Enabling a systems biology approach to immunol-
ogy: focus on innate immunity. Trends Immunol. 2009; 30:249–62. doi: 10.1016/j.it.2009.03.009
PMID: 19428301 42. Onomoto K, Jogi M, Yoo J-S, Narita R, Morimoto S, Takemura A, et al. Critical role of an antiviral
stress granule containing RIG-I and PKR in viral detection and innate immunity. PLoS ONE 2012; 7:
e43031. doi: 10.1371/journal.pone.0043031 PMID: 22912779 PLOS Computational Biology | DOI:10.1371/journal.pcbi.1004553
October 20, 2015 32 / 35 PLOS Computational Biology | DOI:10.1371/journal.pcbi.1004553
October 20, 2015 Integrative Genomics of the RLR Pathway 63. Huber W, Heydebreck von A, Sültmann H, Poustka A, Vingron M. Variance stabilization applied to
microarray data calibration and to the quantification of differential expression. Bioinformatics 2002; 18
Suppl 1:S96–104. PMID: 12169536 64. Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W, et al. limma powers differential expression anal-
yses for RNA-sequencing and microarray studies. Nucleic Acids Res. 2015; 43:e47. doi: 10.1093/nar/
gkv007 PMID: 25605792 65. Barrett T, Wilhite SE, Ledoux P, Evangelista C, Kim IF, Tomashevsky M, et al. NCBI GEO: archive for
functional genomics data sets–-update. Nucleic Acids Res. 2013; 41:D991–5. doi: 10.1093/nar/
gks1193 PMID: 23193258 66. Finn RD, Bateman A, Clements J, Coggill P, Eberhardt RY, Eddy SR, et al. Pfam: the protein families
database. Nucleic Acids Res. 2014; 42:D222–30. doi: 10.1093/nar/gkt1223 PMID: 24288371 67. Kheradpour P, Stark A, Roy S, Kellis M. Reliable prediction of regulator targets using 12 Drosophila
genomes. Genome Res. 2007; 17:1919–31. PMID: 17989251 68. van der Lee R, Szklarczyk R, Smeitink J, Smeets HJM, Huynen MA, Vogel R. Transcriptome analysis
of complex I-deficient patients reveals distinct expression programs for subunits and assembly factors
of the oxidative phosphorylation system. BMC Genomics 2015; 16:691. doi: 10.1186/s12864-015-
1883-8 PMID: 26369791 69. Kanehisa M, Goto S. KEGG: kyoto encyclopedia of genes and genomes. Nucleic Acids Res. 2000;
28:27–30. PMID: 10592173 70. Zhu J, He F, Song S, Wang J, Yu J. How many human genes can be defined as housekeeping with
current expression data? BMC Genomics 2008; 9:172. doi: 10.1186/1471-2164-9-172 PMID:
18416810 71. Tu Z, Wang L, Xu M, Zhou X, Chen T, Sun F. Further understanding human disease genes by com-
paring with housekeeping genes and other genes. BMC Genomics 2006; 7:31. PMID: 16504025 72. Dezso Z, Nikolsky Y, Sviridov E, Shi W, Serebriyskaya T, Dosymbekov D, et al. A comprehensive
functional analysis of tissue specificity of human gene expression. BMC Biol. 2008; 6:49. doi: 10. 1186/1741-7007-6-49 PMID: 19014478 73. She X, Rohl CA, Castle JC, Kulkarni AV, Johnson JM, Chen R. Definition, conservation and epigenet-
ics of housekeeping and tissue-enriched genes. BMC Genomics 2009; 10:269. doi: 10.1186/1471-
2164-10-269 PMID: 19534766 74. Chang C-W, Cheng W-C, Chen C-R, Shu W-Y, Tsai M-L, Huang C-L, et al. Identification of human
housekeeping genes and tissue-selective genes by microarray meta-analysis. PLoS ONE 2011; 6:
e22859. doi: 10.1371/journal.pone.0022859 PMID: 21818400 75. Nakao A, Yoshihama M, Kenmochi N. 1038/embor.2010.64 PMID: 20467437 54. Chatr-aryamontri A, Breitkreutz B-J, Oughtred R, Boucher L, Heinicke S, Chen D, et al. The BioGRID
interaction database: 2015 update. Nucleic Acids Res. 2015; 43:D470–8. doi: 10.1093/nar/gku1204
PMID: 25428363 55. Ravasi T, Suzuki H, Cannistraci CV, Katayama S, Bajic VB, Tan K, et al. An atlas of combinatorial
transcriptional regulation in mouse and man. Cell 2010; 140:744–52. doi: 10.1016/j.cell.2010.01.044
PMID: 20211142 56. Zhao T, Yang L, Sun Q, Arguello M, Ballard DW, Hiscott J, et al. The NEMO adaptor bridges the
nuclear factor-kappaB and interferon regulatory factor signaling pathways. Nat. Immunol. 2007;
8:592–600. PMID: 17468758 57. UniProt Consortium. Activities at the Universal Protein Resource (UniProt). Nucleic Acids Res. 2014;
42:D191–8. doi: 10.1093/nar/gkt1140 PMID: 24253303 58. Driscoll T, Dyer MD, Murali TM, Sobral BW. PIG–-the pathogen interaction gateway. Nucleic Acids
Res. 2009; 37:D647–50. doi: 10.1093/nar/gkn799 PMID: 18984614 59. Kumar R, Nanduri B. HPIDB–-a unified resource for host-pathogen interactions. BMC Bioinformatics
2010; 11 Suppl 6:S16. doi: 10.1186/1471-2105-11-S6-S16 PMID: 20946599 60. Navratil V, de Chassey B, Meyniel L, Delmotte S, Gautier C, André P, et al. VirHostNet: a knowledge
base for the management and the analysis of proteome-wide virus-host interaction networks. Nucleic
Acids Res. 2009; 37:D661–8. doi: 10.1093/nar/gkn794 PMID: 18984613 61. Chatr-aryamontri A, Ceol A, Peluso D, Nardozza A, Panni S, Sacco F, et al. VirusMINT: a viral protein
interaction database. Nucleic Acids Res. 2009; 37:D669–73. doi: 10.1093/nar/gkn739 PMID:
18974184 62. van Diepen A, Brand HK, Sama I, Lambooy LHJ, van den Heuvel LP, van der Well L, et al. Quantita-
tive proteome profiling of respiratory virus-infected lung epithelial cells. J Proteomics 2010; 73:1680–
93. doi: 10.1016/j.jprot.2010.04.008 PMID: 20470912 33 / 35 PLOS Computational Biology | DOI:10.1371/journal.pcbi.1004553
October 20, 2015 PLOS Computational Biology | DOI:10.1371/journal.pcbi.1004553
October 20, 2015 Integrative Genomics of the RLR Pathway 85. Sing T, Sander O, Beerenwinkel N, Lengauer T. ROCR: visualizing classifier performance in R. Bioin-
formatics 2005; 21:3940–1. PMID: 16096348 86. Rieber N, Knapp B, Eils R, Kaderali L. RNAither, an automated pipeline for the statistical analysis of
high-throughput RNAi screens. Bioinformatics 2009; 25:678–9. doi: 10.1093/bioinformatics/btp014
PMID: 19168909 87. Lynn DJ, Chan C, Naseer M, Yau M, Lo R, Sribnaia A, et al. Curating the innate immunity interactome. BMC Syst Biol 2010; 4:117. doi: 10.1186/1752-0509-4-117 PMID: 20727158 88. Huang DW, Sherman BT, Lempicki RA. Systematic and integrative analysis of large gene lists using
DAVID bioinformatics resources. Nat Protoc 2009; 4:44–57. doi: 10.1038/nprot.2008.211 PMID:
19131956 89. Bindea G, Mlecnik B, Hackl H, Charoentong P, Tosolini M, Kirilovsky A, et al. ClueGO: a Cytoscape
plug-in to decipher functionally grouped gene ontology and pathway annotation networks. Bioinfor-
matics 2009; 25:1091–3. doi: 10.1093/bioinformatics/btp101 PMID: 19237447 90. Croft D, O'Kelly G, Wu G, Haw R, Gillespie M, Matthews L, et al. Reactome: a database of reactions,
pathways and biological processes. Nucleic Acids Res. 2011; 39:D691–7. doi: 10.1093/nar/gkq1018
PMID: 21067998 91. Schoggins JW, Rice CM. Interferon-stimulated genes and their antiviral effector functions. Curr Opin
Virol 2011; 1:519–25. doi: 10.1016/j.coviro.2011.10.008 PMID: 22328912 92. Jenner RG, Young RA. Insights into host responses against pathogens from transcriptional profiling. Nat. Rev. Microbiol. 2005; 3:281–94. PMID: 15806094 93. Sun Z, Ren H, Liu Y, Teeling JL, Gu J. Phosphorylation of RIG-I by casein kinase II inhibits its antiviral
response. J. Virol. 2011; 85:1036–47. doi: 10.1128/JVI.01734-10 PMID: 21068236 94. Zhao W, Wang L, Zhang M, Wang P, Yuan C, Qi J, et al. Tripartite motif-containing protein 38 nega-
tively regulates TLR3/4- and RIG-I-mediated IFN-β production and antiviral response by targeting
NAP1. J. Immunol. 2012; 188:5311–8. doi: 10.4049/jimmunol.1103506 PMID: 22539786 95. Charoenthongtrakul S, Gao L, Parvatiyar K, Lee D, Harhaj EW. RING finger protein 11 targets TBK1/
IKKi kinases to inhibit antiviral signaling. PLoS ONE 2013; 8:e53717. doi: 10.1371/journal.pone. 0053717 PMID: 23308279 96. Qing J, Liu C, Choy L, Wu R- Y, Pagano JS, Derynck R. Transforming growth factor beta/Smad3 sig-
naling regulates IRF–7 function and transcriptional activation of the beta interferon promoter. Mol. Cell. Biol. 2004; 24:1411–25. PMID: 14729983 97. Zeng W, Sun L, Jiang X, Chen X, Hou F, Adhikari A, et al. Reconstitution of the RIG-I pathway reveals
a signaling role of unanchored polyubiquitin chains in innate immunity. Cell 2010; 141:315–30. PLOS Computational Biology | DOI:10.1371/journal.pcbi.1004553
October 20, 2015 RPG: the Ribosomal Protein Gene database. Nucleic Acids
Res. 2004; 32:D168–70. PMID: 14681386 76. Ren Q, Chen K, Paulsen IT. TransportDB: a comprehensive database resource for cytoplasmic mem-
brane transport systems and outer membrane channels. Nucleic Acids Res. 2007; 35:D274–9. PMID:
17135193 77. Barrell D, Dimmer E, Huntley RP, Binns D, O'Donovan C, Apweiler R. The GOA database in 2009—
an integrated Gene Ontology Annotation resource. Nucleic Acids Res. 2009; 37:D396–403. doi: 10. 1093/nar/gkn803 PMID: 18957448 78. Geijtenbeek TBH, Gringhuis SI. Signalling through C-type lectin receptors: shaping immune
responses. Nat. Rev. Immunol. 2009; 9:465–79. doi: 10.1038/nri2569 PMID: 19521399 79. Hayman A, Comely S, Lackenby A, Hartgroves LCS, Goodbourn S, McCauley JW, et al. NS1 proteins
of avian influenza A viruses can act as antagonists of the human alpha/beta interferon response. J. Virol. 2007; 81:2318–27. PMID: 17182679 80. Boutros M, Brás LP, Huber W. Analysis of cell-based RNAi screens. Genome Biol. 2006; 7:R66. PMID: 16869968 81. Birmingham A, Selfors LM, Forster T, Wrobel D, Kennedy CJ, Shanks E, et al. Statistical methods for
analysis of high-throughput RNA interference screens. Nat. Methods 2009; 6:569–75. doi: 10.1038/
nmeth.1351 PMID: 19644458 82. Feng Q, Hato SV, Langereis MA, Zoll J, Virgen-Slane R, Peisley A, et al. MDA5 detects the double-
stranded RNA replicative form in picornavirus-infected cells. Cell Rep 2012; 2:1187–96. doi: 10.1016/
j.celrep.2012.10.005 PMID: 23142662 83. R Core Team. R: A language and environment for statistical computing. R Foundation for Statistical
Computing, Vienna, Austria. http://www.R-project.org/. 2014; 84. Warnes GR, Bolker B, Bonebakker L, Gentleman R, Liaw WHA, Lumley T, et al. gplots: Various R pro-
gramming tools for plotting data. [Internet]. 2014. Available from: http://CRAN.R-project.org/package=
gplots PLOS Computational Biology | DOI:10.1371/journal.pcbi.1004553
October 20, 2015 34 / 35 doi:
10.1016/j.cell.2010.03.029 PMID: 20403326 98. Nousiainen L, Sillanpää M, Jiang M, Thompson J, Taipale J, Julkunen I. Human kinome analysis
reveals novel kinases contributing to virus infection and retinoic-acid inducible gene I-induced type I
and type III IFN gene expression. Innate Immun 2013; 19:516–30. doi: 10.1177/1753425912473345
PMID: 23405030 99. Mi Z, Fu J, Xiong Y, Tang H. SUMOylation of RIG-I positively regulates the type I interferon signaling. Protein Cell 2010; 1:275–83. doi: 10.1007/s13238-010-0030-1 PMID: 21203974 100. Fu J, Xiong Y, Xu Y, Cheng G, Tang H. MDA5 is SUMOylated by PIAS2β in the upregulation of type I
interferon signaling. Mol Immunol 2011; 48:415–22. doi: 10.1016/j.molimm.2010.09.003 PMID:
21156324 101. Kubota T, Matsuoka M, Chang T-H, Tailor P, Sasaki T, Tashiro M, et al. Virus infection triggers
SUMOylation of IRF3 and IRF7, leading to the negative regulation of type I interferon gene expres-
sion. J. Biol. Chem. 2008; 283:25660–70. doi: 10.1074/jbc.M804479200 PMID: 18635538 102. Clavarino G, Cláudio N, Couderc T, Dalet A, Judith D, Camosseto V, et al. Induction of GADD34 is
necessary for dsRNA-dependent interferon-β production and participates in the control of Chikungu-
nya virus infection. PLoS Pathog. 2012; 8:e1002708. doi: 10.1371/journal.ppat.1002708 PMID:
22615568 103. Miyashita M, Oshiumi H, Matsumoto M, Seya T. DDX60, a DEXD/H box helicase, is a novel antiviral
factor promoting RIG-I-like receptor-mediated signaling. Mol. Cell. Biol. 2011; 31:3802–19. doi: 10. 1128/MCB.01368-10 PMID: 21791617 PLOS Computational Biology | DOI:10.1371/journal.pcbi.1004553
October 20, 2015 35 / 35
|
https://openalex.org/W2886997418
|
https://eprints.gla.ac.uk/153534/7/153534.pdf
|
English
| null |
Persistence of Infarct Zone T2 Hyperintensity at 6 Months After Acute ST-Segment–Elevation Myocardial Infarction
|
Circulation. Cardiovascular imaging
| 2,017
|
cc-by
| 13,010
|
Received April 19, 2017; accepted November 1, 2017.
From the BHF Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences (J.C., D.C., N.A., I.M., M.M., M.C.P., H.E.,
S.H., S.W., M.L., A.D., A.M., N.S., P.W., A.R., K.G.O., C.B.) and Robertson Centre for Biostatistics (C.H., I.F.), University of Glasgow, Scotland; and West
of Scotland Heart and Lung Centre, Golden Jubilee National Hospital, Clydebank (D.C., S.W., C.B.).
*Drs Carberry and Carrick contributed equally to this work.
The Data Supplement is available at http://circimaging.ahajournals.org/lookup/suppl/doi:10.1161/CIRCIMAGING.117.006586/-/DC1.
Correspondence to Colin Berry, MBChB, PhD, BHF Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, 126
University Pl, University of Glasgow, Glasgow G12 8TA, Scotland, United Kingdom. E-mail colin.berry@glasgow.ac.uk
Circ Cardiovasc Imaging is available at http://circimaging.ahajournals.org
DOI: 10.1161/CIRCIMAGING.117.006586
© 2017 The Authors. Circulation: Cardiovascular Imaging is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health,
Inc. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution, and reproduction in any
medium, provided that the original work is properly cited. Incidence, Pathophysiology, and Prognostic Implications Persisting T2 hyperintensity was defined as infarct T2
>2 SDs from remote T2 at 6 months. Infarct zone T2 was higher than remote zone T2 at 2 days (66.3±6.1 versus
49.7±2.1 ms; P<0.001) and 6 months (56.8±4.5 versus 49.7±2.3 ms; P<0.001). Remote zone T2 did not change over
time (mean change, 0.0±2.7 ms; P=0.837), whereas infarct zone T2 decreased (−9.5±6.4 ms; P<0.001). At 6 months,
T2 hyperintensity persisted in 189 (67%) patients, who were more likely to have Thrombus in Myocardial Infarction
flow 0 or 1 in the culprit artery (P=0.020), incomplete ST-segment resolution (P=0.037), and higher troponin (P=0.024). Persistent T2 hyperintensity was associated with NT-proBNP (N-terminal pro-B-type natriuretic peptide) concentration
(0.57 on a log scale [0.42–0.72]; P=0.004) and the likelihood of adverse left ventricular remodeling (>20% change in left
ventricular end-diastolic volume; 21.91 [2.75–174.29]; P=0.004). Persistent T2 hyperintensity was associated with all-
cause death and heart failure, but the result was not significant (P=0.051). ΔT2 was associated with all-cause death and
heart failure (P=0.004) and major adverse cardiac events (P=0.013). (
)
j
(
)
Conclusions—Persistent T2 hyperintensity occurs in two thirds of STEMI patients. Persistent T2 hyperintensity was
associated with the initial STEMI severity, adverse remodeling, and long-term health outcome. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT02072850. Conclusions—Persistent T2 hyperintensity occurs in two thirds of STEMI patients. Persistent T2 hyperintensity was
associated with the initial STEMI severity, adverse remodeling, and long-term health outcome. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT02072850. (Circ Cardiovasc Imaging. 2017;10:e006586. DOI: 10.1161/CIRCIMAGING.117.006586.) Key Words: acute coronary syndrome ◼ magnetic resonance imaging ◼ myocardial infarction
◼ myocardium ◼ prognosis ry syndrome ◼ magnetic resonance imaging ◼ myocardial infarction
◼ myocardium ◼ prognosis Key Words: acute coronary syndrome ◼ magnetic resonance imaging ◼ myocardial infarction
◼myocardium ◼prognosis I
n survivors of acute ST-segment–elevation myocar-
dial infarction (STEMI), edema within the infarct zone
revealed by T2-weighted cardiac magnetic resonance
(CMR) imaging1,2 is associated with the initial extent of
myocardial jeopardy,3 the size of infarction,4 and prog-
nosis in the longer term.5 Edema impairs myocardial I Incidence, Pathophysiology, and Prognostic Implications Jaclyn Carberry, BMedSci, MBChB*; David Carrick, MBChB, PhD*; Caroline Haig, PhD;
Nadeem Ahmed, BMedSci, MBChB; Ify Mordi, MBChB; Margaret McEntegart, MBChB, PhD;
Mark C. Petrie, MBChB, MD; Hany Eteiba, MBChB, MD; Stuart Hood, MBChB, MD;
Stuart Watkins, MBChB, MD; Mitchell Lindsay, MBChB MD; Andrew Davie, MBChB, MD;
Ahmed Mahrous, MBChB; Ian Ford, PhD; Naveed Sattar, MBChB, PhD; Paul Welsh, PhD;
Aleksandra Radjenovic, PhD; Keith G. Oldroyd, MBChB, MD; Colin Berry, MBChB, PhD by guest on January 5, 2018
http://circimaging.ahajournals.org/
Downloaded from
by guest on January 5, 2018
http://circimaging.ahajournals.org/
Downloaded from
by guest on January 5, 2018
http://circimaging.ahajournals.org/
Downloaded from
by guest on January 5, 2018
http://circimaging.ahajournals.org/
Downloaded from
by guest on January 5, 2018
http://circimaging.ahajournals.org/
Downloaded from
by guest on January 5, 2018
http://circimaging.ahajournals.org/
Downloaded from
by guest on January 5, 2018
http://circimaging.ahajournals.org/
Downloaded from
by guest on January 5, 2018
http://circimaging.ahajournals.org/
Downloaded from
by guest on January 5, 2018
http://circimaging.ahajournals.org/
Downloaded from
by guest on January 5, 2018
http://circimaging.ahajournals.org/
Downloaded from
by guest on January 5, 2018
http://circimaging.ahajournals.org/
Downloaded from
by guest on January 5, 2018
http://circimaging.ahajournals.org/
Downloaded from
by guest on January 5, 2018
http://circimaging.ahajournals.org/
Downloaded from
by guest on January 5, 2018
http://circimaging.ahajournals.org/
Downloaded from
by guest on January 5, 2018
http://circimaging.ahajournals.org/
Downloaded from
by guest on January 5, 2018
http://circimaging.ahajournals.org/
Downloaded from
by guest on January 5, 2018
http://circimaging.ahajournals.org/
Downloaded from
by guest on January 5, 2018
http://circimaging.ahajournals.org/
Downloaded from
by guest on January 5, 2018
http://circimaging.ahajournals.org/
Downloaded from
by guest on January 5, 2018
http://circimaging.ahajournals.org/
Downloaded from
by guest on January 5, 2018
http://circimaging.ahajournals.org/
Downloaded from
by guest on January 5, 2018
http://circimaging.ahajournals.org/
Downloaded from
by guest on January 5, 2018
http://circimaging.ahajournals.org/
Downloaded from
by guest on January 5, 2018
http://circimaging.ahajournals.org/
Downloaded from
by guest on January 5, 2018
http://circimaging.ahajournals.org/
Downloaded from
by guest on January 5, 2018
http://circimaging.ahajournals.org/
Downloaded from
by guest on January 5, 2018
http://circimaging.ahajournals.org/
Downloaded from
by guest on January 5, 2018
http://circimaging.ahajournals.org/
Downloaded from
by guest on January 5, 2018
http://circimaging.ahajournals.org/
Downloaded from Background—The incidence and clinical significance of persistent T2 hyperintensity after acute ST-segment–elevation
myocardial infarction (STEMI) is uncertain. Methods and Results—Patients who sustained an acute STEMI were enrolled in a cohort study (BHF MR-MI: NCT02072850). Two hundred eighty-three STEMI patients (mean age, 59±12 years; 75% male) had cardiac magnetic resonance with
T2 mapping performed at 2 days and 6 months post-STEMI. Magnetic Resonance Imaging Magnetic Resonance Imaging Received April 19, 2017; accepted November 1, 2017.
From the BHF Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences (J.C., D.C., N.A., I.M., M.M., M.C.P., H.E.,
H., S.W., M.L., A.D., A.M., N.S., P.W., A.R., K.G.O., C.B.) and Robertson Centre for Biostatistics (C.H., I.F.), University of Glasgow, Scotland; and West
Scotland Heart and Lung Centre, Golden Jubilee National Hospital, Clydebank (D.C., S.W., C.B.).
*Drs Carberry and Carrick contributed equally to this work. Received April 19, 2017; accepted November 1, 2017. *Drs Carberry and Carrick contributed equally to this work.
The Data Supplement is available at http://circimaging.ahajournals.org/lookup/suppl/doi:10.1161/CIRCIMAGING.117.006586/-/DC1.
Correspondence to Colin Berry, MBChB, PhD, BHF Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, 126
University Pl, University of Glasgow, Glasgow G12 8TA, Scotland, United Kingdom. E-mail colin.berry@glasgow.ac.uk
Circ Cardiovasc Imaging is available at http://circimaging ahajournals org
DOI: 10 1161/CIRCIMAGING 117 006586
© 2017 The Authors. Circulation: Cardiovascular Imaging is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health,
Inc. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution, and reproduction in any
medium, provided that the original work is properly cited. Myocardial Edema y
CMR images were analyzed on a Siemens workstation. The epicardial
and endocardial contours on the last corresponding T2-weighted raw
image with an echo time of 55 ms were planimetered and copied to
the T2 map.14 Regions of interest were drawn in the remote and infarct
zones to measure the respective signal intensities. T2 hyperintensity
was present if the T2 signal in the infarct zone was 2 SDs above the
T2 signal in the remote zone.11,15 Areas of microvascular obstruction
or hemorrhage, identified by consulting late gadolinium enhancement
and T2* images, respectively, were excluded from the infarct region of
interest because this would reduce the signal intensity and may mask
the presence of T2 hyperintensity. The remote zone was drawn 180°
from infarcted myocardium, midmyocardial, and ≈1 segment in length. Measurement was performed on multiple slices and the average taken. Health Outcomes We prespecified adverse health outcomes that are pathophysiologi-
cally linked with STEMI. The primary composite outcome was
major adverse cardiac events (MACE) defined as cardiac death, non-
fatal myocardial infarction, or heart failure hospitalization after the
6-month CMR scan. All-cause death or heart failure (heart failure
hospitalization or defibrillator implantation) after the 6-month CMR
scan was a secondary outcome. Our aims were to (1) measure infarct zone T2 (ms) and
its changes over time in a longitudinal study of acute STEMI
patients; (2) determine the incidence of persistent T2 hyperin-
tensity at 6 months post-STEMI; (3) assess the clinical char-
acteristics and left ventricular (LV) size and function of those
patients with persistent T2 hyperintensity and compare them
to those patients in whom T2 hyperintensity had resolved; and
(4) assess the association of persisting T2 hyperintensity with
longer-term health outcome. During the Index Hospitalizationi g
p
CMR findings are summarized in Table 2 and Table I in the Data
Supplement. Exemplar clinical cases are included in Figure 1. At 2 days, the T2 signal in the infarct zone was higher than in
the remote zone (66.3±6.1 versus 49.7±2.1 ms; P<0.001). Patients with persisting T2 hyperintensity had higher
LV volumes, more extensive infarcts, and lower myocardial
salvage indexes (Table 2). They were more likely to have
microvascular obstruction, a larger extent of microvascular
obstruction, and T2 signal and extracellular volume in the
infarct zone were significantly higher than in those without
persisting T2 hyperintensity (Table 2). There was an associa-
tion between the extent of microvascular obstruction and the
extent of myocardial edema at 2 days (0.21% [0.17%–0.25%];
P<0.001) and a trend to association in the extent of myocar-
dial edema at 2 days post-STEMI and the persistence of T2
hyperintensity (Table 2). There was no difference in T1 or T2
core signal between patients with and without persisting T2
hyperintensity (Table I in the Data Supplement). Patient Characteristics Patient Characteristics
Using T2 mapping, 189 (67%) patients had persistent T2
hyperintensity at 6 months post-STEMI. Patient characteristics are shown in Table 1. The mean age
was 59±11 years, and 75% were male. Patients with persisting
T2 hyperintensity were more likely to present with Thrombus in
Myocardial Infarction flow 0 or 1 in the culprit artery (Thrombus
in Myocardial Infarction flow 0 and 1: 61 [64%] without ver-
sus 144 [76%] with persisting T2 hyperintensity; Thrombus
in Myocardial Infarction flow 2: 18 [19%] versus 34 [18%];
Thrombus in Myocardial Infarction flow 3: 15 [16%] versus 11
[6%]; P=0.020). They were more likely to have partial resolu-
tion of the ST-segment postreperfusion (none: 15 [16%] versus
26 [14%]; partial: 25 [27%] versus 79 [42%]; complete: 54
[57%] versus 83 [44%]; P=0.037) and had higher troponin levels
post-STEMI (1126 [155–3814] versus 2095 [122–5550] ng/L;
P=0.024). Other clinical characteristics of patients with and
without persisting T2 hyperintensity were similar (P>0.050). Methods The full methodology has been reported previously (BHF MR-
MI [Detection and Significance of Heart Injury in ST Elevation
Myocardial Infarction]: NCT02072850) and is detailed in the
Methods in the Data Supplement. Patients with acute STEMI were
consecutively screened for suitability and those recruited provided
written informed consent. The study was approved by the National
Research Ethics Service (Reference 10-S0703-28) and was publically
registered (NCT02072850). The data, analytic methods, and study
materials will be made available to other researchers for purposes of
reproducing the results or replicating the procedure.13 Myocardial Salvage Myocardial salvage was calculated by subtraction of percent infarct
size from percent myocardial edema.5,17,18 The myocardial salvage in-
dex was calculated by dividing the myocardial salvage area by the
initial extent of edema. Statistics The full statistical methods are reported in the Data Supplement. All
P values were 2-sided. A P value >0.05 indicated the absence of a
statistically significant effect. Analyses were performed using SPSS
version 22 for Windows (SPSS, Inc, Chicago, IL) or R v3.3.0. Infarct Definition and Size The territory of infarction was delineated using a signal intensity
threshold of >5 SD above a remote reference region and expressed as
a percentage of total LV mass.16 2 Carberry et al Persistent T2 Hyperintensity Post-STEMI 2 Carberry et al Persistent T2 Hyperintensity Post-STEMI 2 There is uncertainty about the natural history and clinical
significance of persistently high infarct zone T2 values because
previous studies were limited by sample size (n=10–62),7–10 or
method of detection,7,8 for example, T2-weighted short inversion
time inversion recovery (STIR) imaging. Contemporary quanti-
tative T2-mapping techniques have better diagnostic accuracy11
and repeatability12 compared with T2-weighted STIR imaging. See Editorial by Dharmakumar
See Clinical Perspective contractility by reducing the binding efficiency of actin–
myosin filaments leading to reduced force generation in
affected cardiomyocytes.6 DOI: 10.1161/CIRCIMAGING.117.006586 1 Results Of 343 STEMI patients referred for emergency percutaneous
coronary intervention, 283 (87%) patients with paired scans
were included in the final analyses. The flow diagram for the
study is shown in Figure I in the Data Supplement. by guest on January 5, 2018
http://circimaging.ahajournals.org/
Downloaded from We hypothesized that the persistence of myocardial infarct
zone T2 hyperintensity would be associated with the initial
STEMI severity, and it would be associated with surrogate
measures of outcome, including LV volume and NT-proBNP
(N-terminal pro-B-type natriuretic peptide), and longer-term
health outcome. by guest on January 5, 2018
http://circimaging.ahajournals.org/
Downloaded from Adverse Remodeling Adverse remodeling was defined as an increase in LV end-diastolic
volume at 6 months from baseline by ≥20%.19 3 Carberry et al Persistent T2 Hyperintensity Post-STEMI Carberry et al 3 Left circumflex
49 (17)
Right coronary
129 (46)
Culprit artery TIMI flow grade at initial angiography, n (%)
0/1
205 (72)
2
52 (18)
3
26 (9)
Culprit artery TIMI flow grade post-PCI, n (%)
0/1
4 (1)
2
9 (3)
3
270 (95)
Blood results on admission
C-reactive protein, mg/L, median
(Q1, Q3), range
3.0 (2.0, 7.0), 0–125.0
NT-proBNP, pg/mL, median (Q1, Q3),
range
767 (334, 1633), 29–19 521
Troponin I, ng/L, median (Q1, Q3), range
1710 (141, 5229), 0–28 406
Table 1. Continued
Characteristics
All Patients; n=283 Table 1. Characteristics of 283 Patients With Acute STEMI
Characteristics
All Patients; n=283
Age, y
59±11
Male, n (%)
211 (75)
BMI, kg/m2
29±5
Hypertension, n (%)
94 (33)
Current smoking, n (%)
167 (59)
Hypercholesterolemia, n (%)
80 (28)
Diabetes mellitus*, n (%)
32 (11)
Previous angina, n (%)
34 (12)
Previous myocardial infarction, n (%)
14 (5)
Previous PCI, n (%)
11 (4)
Medical therapy
Aspirin, n (%)
282 (99)
Clopidogrel, n (%)
281 (99)
β-blocker, n (%)
269 (95)
ACE-I or ARB, n (%)
279 (99)
Statin, n (%)
283 (100)
Presenting characteristics
Heart rate, bpm
77±17
Systolic blood pressure, mm Hg
135±24
Diastolic blood pressure, mm Hg
79±14
Symptom onset to reperfusion, min
248±207
Ventricular fibrillation†, n (%)
17 (6)
Killip class‡, n (%)
I
209 (74)
II
56 (20)
III/IV
18 (6)
ECG
ST-segment resolution post-PCI, n (%)
Complete, ≥70%
137 (49)
Incomplete, 30% to <70%
104 (37)
None, ≤30%
41 (15)
Coronary angiography
Reperfusion strategy, n (%)
Primary PCI
265 (94)
Rescue PCI (failed thrombolysis)
12 (4)
Successful thrombolysis
6 (2)
No. of diseased arteries§, n (%)
1
152 (54)
2
87 (31)
3
38 (13)
Left main
6 (2)
Culprit artery, n (%)
Left anterior descending
105 (37) Table 1. Characteristics of 283 Patients With Acute STEMI Data are given as n (%), mean±SD, or median (Q1, Q3) as appropriate. ACE-I
indicates angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor
blocker; BMI, body mass index; NT-proBNP, N-terminal pro-B-type natriuretic
peptide; PCI, percutaneous coronary intervention; and TIMI, Thrombolysis in
Myocardial Infarction. y
*History of diet-controlled or treated diabetes mellitus. †Successfully electrically cardioverted ventricular fibrillation at presentation
or during PCI. Adverse Remodeling ‡Killip classification of heart failure post-STEMI: class I—no heart failure,
class II—pulmonary rales or crepitations, third heart sound, and elevated
jugular venous pressure, class III—acute pulmonary edema, and class IV—
cardiogenic shock. §No. of stenoses ≤50% of the reference vessel diameter by visual assessment
and if there was left main stem involvement. The results of interobserver agreement of infarct
zone T2 measurements are shown in Figure II in the Data
Supplement. (Continued ) At 6 Months T2 remained higher in the infarct zone compared with the
remote zone at 6 months (56.8±4.5 versus 49.7±2.3 ms;
P<0.001). Remote zone T2 did not change between day 2
and 6 months (mean change, 0.0±2.7 ms; P=0.837), whereas
infarct zone T2 decreased (−9.5±6.4 ms; P<0.001; Figure 2). Patients with persistent T2 hyperintensity had a smaller
reduction in infarct zone T2 (−8.8±6.6 versus −10.9±6.0 ms;
P=0.010). The change in infarct zone T2 was associated with
the extent of microvascular obstruction at 2 days (0.20%
[0.08%–0.33%]; P=0.002). At 6 months, those with persisting T2 hyperintensity had
lower LV ejection fractions and larger LV volumes. Infarct
size remained larger in those with persisting T2 hyperinten-
sity, and infarct zone CMR parameters were higher (T1, T2,
and extracellular volume; Table 2). Remote zone T2 signal
was lower in those with persisting T2 hyperintensity, whereas
remote zone T1 signal was the same (Table 2; Table I in the
Data Supplement). 4 Carberry et al Persistent T2 Hyperintensity Post-STEMI Table 2. P values were obtained from 2-sample t test, Mann–Whitney test or Fisher exact test. At 6 Months CMR Findings in 283 Patients Grouped According to the Presence or Absence of Persistent T2
Hyperintensity Revealed by T2 Mapping at 6 Months Post-STEMI
Characteristics
All Patients;
n=283
No Persistent T2
Hyperintensity;
n=94 (33%)
Persistent T2
Hyperintensity;
n=189 (67%)
P Value*
CMR findings 2 days post-STEMI
LV end-diastolic volume, mL
Men
161±31
155±30
164±31
0.036
Women
124±25
130±23
121±25
0.172
LV end-systolic volume, mL
Men
74±26
69±25
78±26
0.014
Women
54±18
57±18
52±17
0.225
LV mass, g
Men
144±33
137±29
148±34
0.028
Women
97±21
101±17
95±23
0.216
Edema and infarct characteristics
Myocardial edema, % LV mass
32±12
30±13
33±11
0.050
Infarct size, % LV mass
18±13
13±13
20±13
<0.001
Myocardial salvage, % LV mass
19±9
21±10
18±8
0.033
Myocardial salvage index, % LV mass
63±24
73±24
58±23
<0.001
Late microvascular obstruction present, n (%)
138 (49)
33 (35)
105 (56)
0.002
Late microvascular obstruction, % LV mass
2.6±4.6
1.5±3.6
3.1±4.9
0.004
Myocardial T1, T2, and ECV values
T1 hypointense core present, n (%)
137 (48)
33 (35)
104 (55)
0.002
T2 infarct, ms
66.3±6.1
64.4±5.7
67.3±6.1
<0.001
T2 hypointense core present, n (%)
165 (58)
41 (44)
124 (66)
0.001
ECV infarct, %
56.0±11.7
52.8±12.9
57.7±10.7
0.024
CMR findings at 6 mo
LV ejection fraction at 6 mo, %
62±9
65±8
61±10
<0.001
LV end-diastolic volume at 6 mo, mL
Men
169±42
151±31
177±45
<0.001
Women
127±30
125±22
128±34
0.627
LV end-systolic volume at 6 mo, mL
Men
68±35
54±19
74±38
<0.001
Women
46±18
45±18
47±18
0.550
Adverse remodeling, n (%)
32 (12)
1 (1)
31 (17)
<0.001
Infarct characteristics at 6 mo
Infarct size at 6 mo, % LV mass
13±10
9±9
15±10
<0.001
Myocardial T1, T2 and ECV values at 6 mo
T1 infarct at 6 mo, ms
1058±66
1035±59
1068±67
<0.001
T2 remote at 6 mo, ms
49.7±2.3
50.3±2.5
49.4±2.1
0.001
T2 infarct at 6 mo, ms
56.8±4.5
53.5±3.4
58.5±4.0
<0.001
ECV infarct at 6 mo, %
51.6±11.1
47.5±11.0
53.7±10.5
<0.001
Data are given as n (%) or mean±SD as appropriate. Only variables with a significant difference between groups are reported. The
full table is reported in the Data Supplement. CMR indicates cardiac magnetic resonance; ECV, extracellular volume; LV, left ventricle;
STEMI, ST-segment–elevation myocardial infarction; T1, longitudinal relaxation time; and T2, transverse relaxation time. Table 2. *P values were obtained from 2-sample t test, Mann–Whitney test or Fisher exact test. Data are given as n (%) or mean±SD as appropriate. Only variables with a significant difference between groups are reported. The
full table is reported in the Data Supplement. CMR indicates cardiac magnetic resonance; ECV, extracellular volume; LV, left ventricle;
STEMI, ST-segment–elevation myocardial infarction; T1, longitudinal relaxation time; and T2, transverse relaxation time. At 6 Months CMR Findings in 283 Patients Grouped According to the Presence or Absence of Persistent T2
Hyperintensity Revealed by T2 Mapping at 6 Months Post-STEMI by guest on January 5, 2018
http://circimaging.ahajournals.org/
Downloaded from Data are given as n (%) or mean±SD as appropriate. Only variables with a significant difference between groups are reported. The
full table is reported in the Data Supplement. CMR indicates cardiac magnetic resonance; ECV, extracellular volume; LV, left ventricle;
STEMI, ST-segment–elevation myocardial infarction; T1, longitudinal relaxation time; and T2, transverse relaxation time. 5 Carberry et al Persistent T2 Hyperintensity Post-STEMI 5 Carberry et al Figure 1. Two patients with a similar presentation of acute anterior ST-segment–elevation myocardial infarction. Both patients were
treated by percutaneous coronary intervention and with the same antithrombotic drugs. At the end of the procedure, both patients had
Thrombus in Myocardial Infarction (TIMI) coronary flow grade 3 in the culprit left anterior descending artery. A, A patient with persistent
infarct zone T2 hyperintensity: cardiac magnetic resonance (CMR) imaging was performed 2 days post-revascularization. T2 mapping
revealed an infarct zone T2 value of 65 ms. CMR performed at 6 mo revealed a persistently high infarct zone T2 value of 66 ms in a
matched myocardial slice position to baseline. Left ventricular (LV) end-diastolic volume increased from 143 to 175 mL at 6 mo represent-
ing adverse remodeling. This patient was readmitted with heart failure after the 6-mo CMR scan. B, A patient without persistent infarct
zone T2 hyperintensity: CMR was performed 2 days post-revascularization. T2 mapping revealed an infarct zone T2 value of 63 ms. CMR
performed at 6 mo revealed a lower infarct zone T2 value of 53 ms. LV end-diastolic volume decreased from 120 to 118 mL at 6 mo. This
patient had an uncomplicated clinical course. MRI indicates magnetic resonance imaging. by guest on January 5, 2018
http://circimaging.ahajournals.org/
Downloaded from Figure 1. Two patients with a similar presentation of acute anterior ST-segment–elevation myocardial infarction. Both patients were
treated by percutaneous coronary intervention and with the same antithrombotic drugs. At the end of the procedure, both patients had
Thrombus in Myocardial Infarction (TIMI) coronary flow grade 3 in the culprit left anterior descending artery. A, A patient with persistent
infarct zone T2 hyperintensity: cardiac magnetic resonance (CMR) imaging was performed 2 days post-revascularization. T2 mapping
revealed an infarct zone T2 value of 65 ms. At 6 Months CMR performed at 6 mo revealed a persistently high infarct zone T2 value of 66 ms in a
matched myocardial slice position to baseline. Left ventricular (LV) end-diastolic volume increased from 143 to 175 mL at 6 mo represent-
ing adverse remodeling. This patient was readmitted with heart failure after the 6-mo CMR scan. B, A patient without persistent infarct
zone T2 hyperintensity: CMR was performed 2 days post-revascularization. T2 mapping revealed an infarct zone T2 value of 63 ms. CMR
performed at 6 mo revealed a lower infarct zone T2 value of 53 ms. LV end-diastolic volume decreased from 120 to 118 mL at 6 mo. This
patient had an uncomplicated clinical course. MRI indicates magnetic resonance imaging. The higher the initial infarct zone T2 signal, the larger the
decrease in infarct zone T2 signal by 6 months (Figure 3). persistent T2 hyperintensity and change in infarct zone T2 were
not associated with the change in LV end-diastolic volume. by guest on January 5, 2018
ls.org/ Discussion We present a natural history study of the changes in infarct
zone T2 over time and prognostic significance over 4 years in
a large unselected cohort of STEMI patients. The main findings are as follows: (1) T2 hyperintensity
persisted in approximately two thirds of patients at 6 months
post-STEMI; (2) infarct zone T2 decreased in the long term Persistent T2 Hyperintensity and Health Outcomes
Health outcome data were available in 283 (100%) patients. The median duration of follow-up was 1330 days (minimum–
maximum postdischarge censor duration 794–1622 days). All-cause death or heart failure occurred in 19 (7%) patients,
including 7 noncardiovascular deaths, 4 cardiovascular
deaths, 1 stroke death, 1 undetermined cause of death, and
6 heart failure episodes. Sixteen (6%) patients experienced
a MACE after the CMR scan at 6 months, including 6 heart
failure episodes (Killip class 3 or 4 heart failure or defibrilla-
tor implantation), 4 cardiovascular deaths, 4 admissions with
non-STEMI, and 2 admissions with STEMI. Table 3. Binary Logistic Regression Analysis for Associations
With Adverse Remodeling at 6 Months Post-STEMI in 283
Patients
Multivariable Associations
Odds Ratio (95% CI)
P Value
Patient characteristics, angiographic data, and persistent infarct zone T2
hyperintensity
Persistent T2 hyperintensity
21.91 (2.75–174.29)
0.004
Patient characteristics, angiographic data, and change in infarct zone T2
(1 ms change)
Change in infarct zone T2, 1 ms
1.22 (1.10–1.35)
<0.001
Baseline infarct zone T2, ms
1.20 (1.08–1.35)
0.001
Patient characteristics, angiographic data, and change in infarct zone
T2 (10 ms change)
Change in infarct zone T2, 10 ms
3.45 (1.53–7.77)
0.003
Baseline infarct zone T2, ms
1.13 (1.02– 1.24)
0.015
Only statistically significant variables are reported. All variables included
in the model are described in the Data Supplement. The odds ratio (95% CIs)
indicates odds of adverse remodeling at 6 mo given exposure to the independent
variable. CI indicates confidence intervals; STEMI, ST-segment–elevation
myocardial infarction; and T2, transverse relaxation time. Table 3. Binary Logistic Regression Analysis for Associations
With Adverse Remodeling at 6 Months Post-STEMI in 283
Patients Table 3. Binary Logistic Regression Analysis for Associations
With Adverse Remodeling at 6 Months Post-STEMI in 283
Patients Persisting T2 hyperintensity (binary, yes or no) was asso-
ciated with the occurrence of all-cause death or heart failure
(hazard ratio, 4.31; 95% confidence interval, 1.00–18.67;
P=0.051); however, the association was not statistically sig-
nificant. Persisting T2 hyperintensity was not associated with
MACE (Figure III in the Data Supplement). Persistent T2 Hyperintensity and LV Remodeling
Ad
d li
d i
32 (12%)
i
(T bl 2) Persistent T2 Hyperintensity and LV Remodeling
Adverse remodeling occurred in 32 (12%) patients (Table 2). In a binary logistic regression analysis, persistent T2 hyper-
intensity was a multivariable associate of adverse remodeling
(Table 3). When the change in infarct zone T2 (1 ms change and
10 ms change) was included in place of persistent T2 hyper-
intensity at 6 months, this was also associated with adverse
remodeling (Table 3). When the change in infarct zone extra-
cellular volume was included in the multivariable models, At 2 days, LV ejection fraction was similar between patients
with and without persisting T2 hyperintensity, whereas
6-month ejection fraction was lower in those with persisting
T2 hyperintensity (Table 2). The mean change in LV ejection
fraction was 6.7±7.8%. Patients with persisting T2 hyperinten-
sity had a numerically lower increase in LV ejection fraction
without statistical significance (6.1±7.8% versus 7.9±7.7%). Figure 2. Change in T2 signal in patients with ST-segment–elevation myocardial infarction with or without persisting infarct zone T2
hyperintensity at 6 mo. Infarct zone T2 decreases in the majority of patients but to a lesser degree in patients with persisting edema. Figure 2. Change in T2 signal in patients with ST-segment–elevation myocardial infarction with or without persisting infarct zone T2
hyperintensity at 6 mo. Infarct zone T2 decreases in the majority of patients but to a lesser degree in patients with persisting edema. Carberry et al Persistent T2 Hyperintensity Post-STEMI 6 Carberry et al Persistent T2 Hyperintensity Post-STEMI
Figure 3. Change in infarct zone T2 vs
infarct zone T2 at baseline. Infarct zone
T2 at baseline was negatively associated
with the change in infarct zone T2 at 6
mo. Carberry et al Persistent T2 Hyperintensity Post-STEMI 6 Carberry et al Persistent T2 Hyperintensity Post-STEMI 6 Figure 3. Change in infarct zone T2 vs
infarct zone T2 at baseline. Infarct zone
T2 at baseline was negatively associated
with the change in infarct zone T2 at 6
mo. Figure 3. Change in infarct zone T2 vs
infarct zone T2 at baseline. Infarct zone
T2 at baseline was negatively associated
with the change in infarct zone T2 at 6
mo. Figure 3. Change in infarct zone T2 vs
infarct zone T2 at baseline. Infarct zone
T2 at baseline was negatively associated
with the change in infarct zone T2 at 6
mo. Persistent T2 Hyperintensity and NT-proBNP Blood samples were collected in the participants who were
enrolled during office hours (n=123 patients at baseline and
n=98 patients at follow-up). The characteristics of these patients
were similar to the whole cohort (data not shown). Persistent
T2 hyperintensity was associated with NT-proBNP at 6 months
(0.57 on a log scale [0.42–0.72]; P=0.004), but not at baseline. Persistent T2 Hyperintensity and LV Remodeling
Ad
d li
d i
32 (12%)
i
(T bl 2) by guest on January 5, 2018
http://circimaging.ahajournals.org/
Downloaded from The change in LV ejection fraction was associated with
both persisting T2 hyperintensity and the change in infarct
zone T2 (Table II in the Data Supplement). considering a 10 ms change in infarct zone T2 (all-cause death
or heart failure hazard ratio, 3.77; 95% confidence interval,
1.58–8.97; P=0.003: MACE hazard ratio, 3.60; 95% confi-
dence interval, 1.42–9.15; P=0.007). 7 Carberry et al Persistent T2 Hyperintensity Post-STEMI Carberry et al Persistent T2 Hyperintensity Post-STEMI 7 in most patients, and the decrease was larger in patients with
higher infarct zone T2 at baseline; (3) persisting T2 hyper-
intensity was associated with electrocardiographic, angio-
graphic, CMR, and biochemical markers of STEMI severity
including the initial size of infarction, presence of microvas-
cular obstruction, the myocardial salvage index, peak tropo-
nin, and NT-proBNP; (4) persistent T2 hyperintensity and
the change in infarct zone T2 were associated with adverse
remodeling and worsening LV function; and (5) the change
in infarct zone T2 was associated with adverse health out-
comes. T2 hyperintensity in the infarct zone that persists at 6
months post-STEMI is an adverse prognostic sign and pres-
ents a mechanistic explanation for worsening LV volumes
and function. been measured across an entire myocardial segment, then
that segment may also contain unaffected myocardium (and
hypointense core) and therefore bias the results by averaging
the signal across 2 myocardial states. Our study is the first and largest to use contemporary,
quantitative methods to identify the incidence and clinical sig-
nificance of persistent T2 hyperintensity in a cohort of near-
consecutive patients with acute STEMI. Our study presents
new insights. The adverse clinical significance of persistent
T2 hyperintensity was underscored by its associations with
the initial STEMI severity and LV remodeling, and the valid-
ity of our observations is enhanced given that the T2 maps
were of diagnostic quality in nearly all patients. We saw that there was a larger extent of acute microvascu-
lar obstruction in those with persisting T2 hyperintensity, and
there was also an association between the extent of microvas-
cular obstruction and the extent of myocardial edema acutely. The relationship between microvascular obstruction and
myocardial edema may provide a mechanistic explanation
into the persistence of T2 hyperintensity, specifically because
evidence has shown myocardial hemorrhage, which is related
to microvascular obstruction, leads to iron driven inflamma-
tion.23,24 We also observed worsening LV ejection fractions in
patients with persisting T2 hyperintensity, which is in keep-
ing with previous reports of edema and attenuated strain.25 Direct comparison with previous studies7–10 is qualified
by differences in sample size and imaging methods. These
previous studies have defined persisting T2 hyperintensity as
edema; however, strong evidence that elevated infarct zone
T2 at 6 months post-STEMI represents edema is lacking. 7 Carberry et al Persistent T2 Hyperintensity Post-STEMI Histological studies validating T2 signal as a representation of
edema have been focused on the acute phase post-STEMI.20–22
Infarct zone edema as a cause of persisting T2 hyperinten-
sity at 6 months cannot be excluded; however, other causes of
increased myocardial mobile water content such as myocar-
dial fat should be considered. by guest on January 5, 2018
http://circimaging.ahajournals.org/
Downloaded from Previous research from this cohort suggests that there
is a significant difference in remote zone T2 between the
2 time points,26,27 which may be explained by the larger
sample size in the present study (n=30 in Carrick et al26 and
n=131 in Carberry et al27). Persisting T2 hyperintensity may
reflect the natural history of infarct healing3 and inflamma-
tion,28 and potentially, latency of edema within the infarct
zone to dissipate, especially if water content is substantially
increased acutely. Nonetheless, we observed that persistent
T2 hyperintensity has adverse prognostic implications based
on its association with LV remodeling and health outcome. The reason why the change in infarct zone T2 was associ-
ated with MACE and persisting T2 hyperintensity was not
explained by the nature of the data. Dichotomizing a con-
tinuous variable can reduce statistical power. In addition, our
results may simply reflect the fact that the absolute change
in T2 signal in the infarct zone is more predictive of MACE
than the presence or absence of T2 hyperintensity. Because
the analysis was limited by the event rate, further research
is warranted. The incidence of persistent T2 hyperintensity in the pres-
ent study was high (two thirds of patients) in comparison to
some9,10 but not all prior recent studies.7,8 In those studies, the
numbers of participants with paired data were limited (n=10–
62)7–10 implying imprecision. Ripa et al7 found that myocardial T2 hyperintensity (defined
as edema) persisted in 51 of 54 (94%) STEMI patients using
T2 STIR imaging. The average number of affected segments
per patient decreased by 4.5 segments at 6 months. Persistent
edema was not associated with LV ejection fraction. Nilsson et al8 identified a prevalence of high T2 at 6
months which was comparable with our result (60%); how-
ever, this analysis was performed on a small sample, using
T2 STIR imaging, and clinical and prognostic information
was limited. Limitations Because of the length of the imaging protocol, we restricted
other imaging methods, such as for myocardial fat. The sur-
vival analysis was limited by the absolute number of heart
failure and all-cause death events (n=19) and MACE events
(n=16), so these results should be interpreted carefully and
taken as hypothesis generating. Zia et al10 used T2 mapping and found that infarct zone
T2 signal equalizes with remote zone T2 signal at 6 months
suggesting complete recovery of myocardial edema. There
are some reasons why the results of this article may be so
different to those we present. The sample size was limited
(n=62 compared with our n=283).10 The methodology refers
to infarct segment rather than zone.10 If infarct T2 signal has 7 Carberry et al Persistent T2 Hyperintensity Post-STEMI Dark blood STIR edema imaging is a qualita-
tive technique11 with reduced diagnostic accuracy, when com-
pared with quantitative T2 mapping.12 The authors speculate
that T2 hyperintensity may represent edema or an alternative
process, such as hemoglobin breakdown products or increased
unbound water.8 Dall’Armellina et al9 used bright blood T2-weighted
CMR (n=23 [77%] with paired data). They found that 35%
of myocardial segments had evidence of edema acutely, and
the proportion of edematous segments reduced to 6%, with a
small number of cases having infarct zone edema at 6 months. They found that a reduction in edema was associated with an
improvement in wall motion score index. Discussion The change in infarct zone T2 (1 ms change) was asso-
ciated with all-cause death or heart failure (hazard ratio,
1.15; 95% confidence interval, 1.05–1.27; P=0.004) and
with MACE (hazard ratio, 1.14; 95% confidence interval,
1.03, 1.27; P=0.013). Similar results were observed when Only statistically significant variables are reported. All variables included
in the model are described in the Data Supplement. The odds ratio (95% CIs)
indicates odds of adverse remodeling at 6 mo given exposure to the independent
variable. CI indicates confidence intervals; STEMI, ST-segment–elevation
myocardial infarction; and T2, transverse relaxation time. References 1. Kuntz ID Jr, Brassfield TS, Law GD, Purcell GV. Hydration of macromol-
ecules. Science. 1969;163:1329–1331. 1. Kuntz ID Jr, Brassfield TS, Law GD, Purcell GV. Hydration of macromol-
ecules. Science. 1969;163:1329–1331. by guest on January 5, 2018
rcimaging.ahajournals.org/ 17. Francone M, Bucciarelli-Ducci C, Carbone I, Canali E, Scardala R,
Calabrese FA, Sardella G, Mancone M, Catalano C, Fedele F, Passariello
R, Bogaert J, Agati L. Impact of primary coronary angioplasty delay on
myocardial salvage, infarct size, and microvascular damage in patients
with ST-segment elevation myocardial infarction: insight from cardiovas-
cular magnetic resonance. J Am Coll Cardiol. 2009;54:2145–2153. doi:
10.1016/j.jacc.2009.08.024. 2. Karolle BL, Carlson RE, Aisen AM, Buda AJ. Transmural distribution of
myocardial edema by NMR relaxometry following myocardial ischemia
and reperfusion. Am Heart J. 1991;122(3 pt 1):655–664. 3. Berry C, Kellman P, Mancini C, Chen MY, Bandettini WP, Lowrey T, Hsu
LY, Aletras AH, Arai AE. Magnetic resonance imaging delineates the isch-
emic area at risk and myocardial salvage in patients with acute myocar-
dial infarction. Circ Cardiovasc Imaging. 2010;3:527–535. doi: 10.1161/
CIRCIMAGING.109.900761. 18. Payne AR, Berry C, Doolin O, McEntegart M, Petrie MC, Lindsay MM,
Hood S, Carrick D, Tzemos N, Weale P, McComb C, Foster J, Ford I,
Oldroyd KG. Microvascular resistance predicts myocardial salvage and in-
farct characteristics in ST-elevation myocardial infarction. J Am Heart Assoc. 2012;1:e002246. doi: 10.1161/JAHA.112.002246. 4. Kim HW, Van Assche L, Jennings RB, Wince WB, Jensen CJ, Rehwald
WG, Wendell DC, Bhatti L, Spatz DM, Parker MA, Jenista ER, Klem I,
Crowley AL, Chen EL, Judd RM, Kim RJ. Relationship of T2-weighted
MRI myocardial hyperintensity and the ischemic area-at-risk. Circ Res. 2015;117:254–265. doi: 10.1161/CIRCRESAHA.117.305771. 19. Carrick D, Haig C, Rauhalammi S, Ahmed N, Mordi I, McEntegart M,
Petrie MC, Eteiba H, Lindsay M, Watkins S, Hood S, Davie A, Mahrous
A, Sattar N, Welsh P, Tzemos N, Radjenovic A, Ford I, Oldroyd KG, Berry
C. Pathophysiology of LV remodeling in survivors of STEMI: inflamma-
tion, remote myocardium, and prognosis. JACC Cardiovasc Imaging. 2015;8:779–789. doi: 10.1016/j.jcmg.2015.03.007. 5. Eitel I, Desch S, Fuernau G, Hildebrand L, Gutberlet M, Schuler G, Thiele
H. Prognostic significance and determinants of myocardial salvage as-
sessed by cardiovascular magnetic resonance in acute reperfused myocar-
dial infarction. J Am Coll Cardiol. 2010;55:2470–2479. doi: 10.1016/j. jacc.2010.01.049. 20. García-Dorado D, Oliveras J, Gili J, Sanz E, Pérez-Villa F, Barrabés J,
Carreras MJ, Solares J, Soler-Soler J. References Analysis of myocardial oedema by
magnetic resonance imaging early after coronary artery occlusion with or
without reperfusion. Cardiovasc Res. 1993;27:1462–1469. 6. Bragadeesh T, Jayaweera AR, Pascotto M, Micari A, Le DE, Kramer CM,
Epstein FH, Kaul S. Post-ischaemic myocardial dysfunction (stunning)
results from myofibrillar oedema. Heart. 2008;94:166–171. doi: 10.1136/
hrt.2006.102434. 21. Wisenberg G, Prato FS, Carroll SE, Turner KL, Marshall T. Serial nuclear
magnetic resonance imaging of acute myocardial infarction with and with-
out reperfusion. Am Heart J. 1988;115:510–518. 7. Ripa RS, Nilsson JC, Wang Y, Søndergaard L, Jørgensen E, Kastrup J. Short- and long-term changes in myocardial function, morphology, edema,
and infarct mass after ST-segment elevation myocardial infarction evaluat-
ed by serial magnetic resonance imaging. Am Heart J. 2007;154:929–936. doi: 10.1016/j.ahj.2007.06.038. 22. Aletras AH, Tilak GS, Natanzon A, Hsu LY, Gonzalez FM, Hoyt RF Jr,
Arai AE. Retrospective determination of the area at risk for reperfused
acute myocardial infarction with T2-weighted cardiac magnetic resonance
imaging: histopathological and displacement encoding with stimulated
echoes (DENSE) functional validations. Circulation. 2006;113:1865–
1870. doi: 10.1161/CIRCULATIONAHA.105.576025. 8. Nilsson JC, Nielsen G, Groenning BA, Fritz-Hansen T, Sondergaard L, Jensen
GB, Larsson HB. Sustained postinfarction myocardial oedema in humans vi-
sualised by magnetic resonance imaging. Heart. 2001;85:639–642. 23. Bulluck H, Rosmini S, Abdel-Gadir A, White SK, Bhuva AN, Treibel TA,
Fontana M, Ramlall M, Hamarneh A, Sirker A, Herrey AS, Manisty C,
Yellon DM, Kellman P, Moon JC, Hausenloy DJ. Residual myocardial
iron following intramyocardial hemorrhage during the convalescent phase
of reperfused ST-segment–elevation myocardial infarction and adverse
left ventricular remodeling. Circ Cardiovasc Imaging. 2016;9:e004940. doi: 10.1161/CIRCIMAGING.116.004940. 9. Dall’Armellina E, Karia N, Lindsay AC, Karamitsos TD, Ferreira V,
Robson MD, Kellman P, Francis JM, Forfar C, Prendergast BD, Banning
AP, Channon KM, Kharbanda RK, Neubauer S, Choudhury RP. Dynamic
changes of edema and late gadolinium enhancement after acute myo-
cardial infarction and their relationship to functional recovery and sal-
vage index. Circ Cardiovasc Imaging. 2011;4:228–236. doi: 10.1161/
CIRCIMAGING.111.963421. 24. Kali A, Kumar A, Cokic I, Tang RL, Tsaftaris SA, Friedrich MG,
Dharmakumar R. Chronic manifestation of postreperfusion intramyo-
cardial hemorrhage as regional iron deposition: a cardiovascular mag-
netic resonance study with ex vivo validation. Circ Cardiovasc Imaging. 2013;6:218–228. doi: 10.1161/CIRCIMAGING.112.000133. 10. Zia MI, Ghugre NR, Connelly KA, Strauss BH, Sparkes JD, Dick AJ,
Wright GA. Characterizing myocardial edema and hemorrhage us-
ing quantitative T2 and T2* mapping at multiple time intervals post
ST-segment elevation myocardial infarction. None. 16. Flett AS, Hasleton J, Cook C, Hausenloy D, Quarta G, Ariti C,
Muthurangu V, Moon JC. Evaluation of techniques for the quantifica-
tion of myocardial scar of differing etiology using cardiac magnetic
resonance. JACC Cardiovasc Imaging. 2011;4:150–156. doi: 10.1016/j. jcmg.2010.11.015. Acknowledgments We thank the patients and the staff in the Cardiology and Radiology
Departments. We thank Peter Weale and Patrick Revell (Siemens
Healthcare, United Kingdom). 13. Berry C. Persistence of Infarct Zone T2 Hyperintensity at 6 Months After Acute
ST-Elevation-Elevation Myocardial Infarction: Incidence, Pathophysiology
and Prognostic Implications. 2017. American Heart Association. NCT02072850. CORPortal.net. Accessed November 1, 2017. 14. Wassmuth R, Prothmann M, Utz W, Dieringer M, von Knobelsdorff-
Brenkenhoff F, Greiser A, Schulz-Menger J. Variability and homogene-
ity of cardiovascular magnetic resonance myocardial T2-mapping in
volunteers compared to patients with edema. J Cardiovasc Magn Reson. 2013;15:27. doi: 10.1186/1532-429X-15-27. Sources of Funding The British Heart Foundation (PG/11/2/28474; RE/13/5/30177) and
the Chief Scientist Office of the Scottish Government supported this
research. C. Berry was supported by a Senior Fellowship from the
Scottish Funding Council. Dr Welsh is supported by BHF Fellowship
FS/12/62/29889. This project was supported by a research agreement
with Siemens Healthcare. by guest on January 5, 2018
http://circimaging.ahajournals.org/
Downloaded from 15. Dall’Armellina E, Piechnik SK, Ferreira VM, Si QL, Robson MD,
Francis JM, Cuculi F, Kharbanda RK, Banning AP, Choudhury RP,
Karamitsos TD, Neubauer S. Cardiovascular magnetic resonance by non
contrast T1-mapping allows assessment of severity of injury in acute
myocardial infarction. J Cardiovasc Magn Reson. 2012;14:15. doi:
10.1186/1532-429X-14-15. by guest on January 5, 2018
http://circimaging.ahajournals.org/
Downloaded from by guest
http://circimaging.ahajournals.org/
Downloaded from Conclusions Infarct zone T2 hyperintensity persisted at 6 months in
approximately two thirds of STEMI patients. Persistent T2
hyperintensity was prognostically important because it was
associated with markers of STEMI severity and adverse LV Carberry et al Persistent T2 Hyperintensity Post-STEMI 8 remodeling. The change in infarct zone T2 signal as a con-
tinuous variable was associated with health outcome. Whether
T2 hyperintensity at 6 months represents edema or another
process is uncertain and merits further discussion and study. Further studies are warranted to assess whether or not infarct
zone T2 may track the response to therapy in STEMI patients
and thus represent a therapeutic target for use in clinical trials. 11. Payne AR, Casey M, McClure J, McGeoch R, Murphy A, Woodward R,
Saul A, Bi X, Zuehlsdorff S, Oldroyd KG, Tzemos N, Berry C. Bright-
blood T2-weighted MRI has higher diagnostic accuracy than dark-blood
short tau inversion recovery MRI for detection of acute myocardial
infarction and for assessment of the ischemic area at risk and myocar-
dial salvage. Circ Cardiovasc Imaging. 2011;4:210–219. doi: 10.1161/
CIRCIMAGING.110.960450. 12. McAlindon EJ, Pufulete M, Harris JM, Lawton CB, Moon JC, Manghat
N, Hamilton MC, Weale PJ, Bucciarelli-Ducci C. Measurement of
myocardium at risk with cardiovascular MR: comparison of tech-
niques for edema imaging. Radiology. 2015;275:61–70. doi: 10.1148/
radiol.14131980. References Circ Cardiovasc Imaging. 2012;5:566–572. doi: 10.1161/CIRCIMAGING.112.973222. 9 Carberry et al Persistent T2 Hyperintensity Post-STEMI 9 27. Carberry J, Carrick D, Haig C, Rauhalammi SM, Ahmed N, Mordi
I, McEntegart M, Petrie MC, Eteiba H, Hood S, Watkins S, Lindsay
M, Davie A, Mahrous A, Ford I, Sattar N, Welsh P, Radjenovic A,
Oldroyd KG, Berry C. Remote zone extracellular volume and left ven-
tricular remodeling in survivors of ST-elevation myocardial infarction. Hypertension. 2016;68:385–391. doi: 10.1161/HYPERTENSIONAHA. 116.07222. 25. Kidambi A, Mather AN, Swoboda P, Motwani M, Fairbairn TA,
Greenwood JP, Plein S. Relationship between myocardial edema and
regional myocardial function after reperfused acute myocardial infarc-
tion: an MR imaging study. Radiology. 2013;267:701–708. doi: 10.1148/
radiol.12121516. 26. Carrick D, Haig C, Ahmed N, Rauhalammi S, Clerfond G, Carberry
J, Mordi I, McEntegart M, Petrie MC, Eteiba H, Hood S, Watkins
S, Lindsay MM, Mahrous A, Welsh P, Sattar N, Ford I, Oldroyd KG,
Radjenovic A, Berry C. Temporal evolution of myocardial hemorrhage
and edema in patients after acute ST-segment elevation myocardial in-
farction: pathophysiological insights and clinical implications. J Am
Heart Assoc. 2016;5:e002834. 28. Fernández-Jiménez R, García-Prieto J, Sánchez-González J, Agüero J,
López-Martín GJ, Galán-Arriola C, Molina-Iracheta A, Doohan R, Fuster
V, Ibáñez B. Pathophysiology underlying the bimodal edema phenomenon
after myocardial ischemia/reperfusion. J Am Coll Cardiol. 2015;66:816–
828. doi: 10.1016/j.jacc.2015.06.023. Keith G. Oldroyd and Colin Berry
Andrew Davie, Ahmed Mahrous, Ian Ford, Naveed Sattar, Paul Welsh, Aleksandra Radjenovic,
McEntegart, Mark C. Petrie, Hany Eteiba, Stuart Hood, Stuart Watkins, Mitchell Lindsay,
Jaclyn Carberry, David Carrick, Caroline Haig, Nadeem Ahmed, Ify Mordi, Margaret
Elevation Myocardial Infarction: Incidence, Pathophysiology, and Prognostic Implications
−
Persistence of Infarct Zone T2 Hyperintensity at 6 Months After Acute ST-Segment Keith G. Oldroyd and Colin Berry
Andrew Davie, Ahmed Mahrous, Ian Ford, Naveed Sattar, Paul Welsh, Aleksandra Radjenovic,
McEntegart, Mark C. Petrie, Hany Eteiba, Stuart Hood, Stuart Watkins, Mitchell Lindsay,
Jaclyn Carberry, David Carrick, Caroline Haig, Nadeem Ahmed, Ify Mordi, Margaret
Elevation Myocardial Infarction: Incidence, Pathophysiology, and Prognostic Implications
−
Persistence of Infarct Zone T2 Hyperintensity at 6 Months After Acute ST-Segment http://circimaging.ahajournals.org//subscriptions/
is online at:
Circulation: Cardiovascular Imaging
Information about subscribing to
Subscriptions:
http://www.lww.com/reprints
Information about reprints can be found online at:
Reprints:
document. Permissions and Rights Question and Answer
information about this process is available in the
requested is located, click Request Permissions in the middle column of the Web page under Services. Furth
Center, not the Editorial Office. Once the online version of the published article for which permission is bei
can be obtained via RightsLink, a service of the Copyright Clearan
Circulation: Cardiovascular Imaging
in
Requests for permissions to reproduce figures, tables, or portions of articles originally publish
Permissions: http://circimaging.ahajournals.org//subscriptions/
is online at:
Circulation: Cardiovascular Imaging
Information about subscribing to
Subscriptions:
http://www.lww.com/reprints
Information about reprints can be found online at:
Reprints:
document. Permissions and Rights Question and Answer
information about this process is available in the
requested is located, click Request Permissions in the middle column of the Web page under Services. Further
Center, not the Editorial Office. Once the online version of the published article for which permission is being
can be obtained via RightsLink, a service of the Copyright Clearance
Circulation: Cardiovascular Imaging
in
Requests for permissions to reproduce figures, tables, or portions of articles originally published
Permissions: document. Permissions and Rights Question and Answer
information about this process is available in the
requested is located, click Request Permissions in the middle column of the Web page under Services. Further
Center, not the Editorial Office. CLINICAL PERSPECTIVE In survivors of acute ST-segment–elevation myocardial infarction, edema within the infarct zone is associated with the initial
extent of myocardial jeopardy, the size of infarction, and prognosis. Edema impairs myocardial contractility by reducing the
binding efficiency of actin–myosin filaments leading to reduced force generation in affected cardiomyocytes. There is uncer-
tainty about the natural history and clinical significance of the persistence of T2 hyperintensity because previous studies
were limited by sample size or method of detection. We present a natural history study of the change in infarct zone T2 signal
over time and prognostic significance over 4 years in a large unselected cohort of ST-segment–elevation myocardial infarc-
tion patients and using contemporary, quantitative T2-mapping techniques. Infarct zone T2 hyperintensity was present at 6
months in approximately two thirds of ST-segment–elevation myocardial infarction patients. Persistent T2 hyperintensity
was prognostically important because it was associated with markers of MI severity and adverse left ventricular remodeling. Whether T2 hyperintensity at 6 months represents edema or another process is uncertain and merits further discussion and
study. The change in infarct zone T2 signal as a continuous variable was associated with health outcome. Further studies are
warranted to assess whether or not infarct zone T2 may track the response to therapy in ST-segment–elevation myocardial
infarction patients and thus represent a therapeutic target for use in clinical trials. by guest on January 5, 2018
http://circimaging.ahajournals.org/
Downloaded from by guest on January 5, 2018
http://circimaging.ahajournals.org/
Downloaded from Once the online version of the published article for which permission is being
can be obtained via RightsLink, a service of the Copyright Clearance
Circulation: Cardiovascular Imaging
in
Requests for permissions to reproduce figures, tables, or portions of articles originally published
Permissions: http://circimaging.ahajournals.org//subscriptions/
is online at:
Circulation: Cardiovascular Imaging
Information about subscribing to
Subscriptions: SUPPLEMENTAL MATERIAL Persistence of infarct zone T2 hyperintensity at 6 months after acute ST-elevation
myocardial infarction: incidence, pathophysiology and prognostic implications ClinicalTrials.gov registration NCT02072850 1 1 ST-elevation myocardial infarction patients We performed a longitudinal cohort study in a regional cardiac center between 11 May 2011
and 22 November 2012. Patients with acute ST-elevation myocardial infarction (STEMI)
were consecutively screened for suitability and those recruited provided written informed
consent. Inclusion criteria were an indication for primary percutaneous coronary intervention
(PCI) or thrombolysis for STEMI1. Exclusion criteria were contraindications to contrast-
enhanced cardiac magnetic resonance (CMR) imaging. For the purposes of this analysis,
STEMI patients who experienced a recurrent MI or had an additional PCI following the index
procedure were not included since these events could influence myocardial T2 (ms) during
the intervening period. STEMI management followed current guidelines1,2. The study was
approved by the National Research Ethics Service (Reference 10-S0703-28) and was
publically registered (NCT02072850). The flow diagram for the study is shown in
Supplementary Figure 1. Screening, enrolment, and data collection were prospectively performed by cardiologists in
the cardiac catheterization laboratories of the Golden Jubilee National Hospital, Glasgow,
United Kingdom. This hospital is a regional referral center for primary and rescue PCI. The
hospital provides clinical services for a population of 2.2 million. A screening log was
recorded, including patients who did not participate in the cohort study. Setting and study populations ST-elevation myocardial infarction patients Table of contents Supplementary Methods ................................................................................................................. 3! Supplementary Results .................................................................................................................. 11! Supplementary Figures ................................................................................................................. 14! Supplementary Tables ................................................................................................................... 18! References .................................................................................................................................. 26 2 2 Percutaneous coronary intervention Consecutive admissions with acute STEMI referred for emergency PCI were screened for the
inclusion and exclusion criteria. During ambulance transfer to the hospital, the patients
received 300 mg of aspirin, 600 mg of clopidogrel and 5000 IU of unfractionated heparin1,2. The initial primary PCI procedure was performed using radial artery access. A conventional
approach to primary PCI was adopted in line with usual care in our hospital1,2. Conventional
bare metal and drug eluting stents were used in line with guideline recommendations and
clinical judgment. The standard transcatheter approach for reperfusion involves minimal
intervention with aspiration thrombectomy only or minimal balloon angioplasty (e.g. a
compliant balloon sized according to the reference vessel diameter and inflated at 4-6
atmospheres 1-2 times). During PCI, glycoprotein IIbIIIa inhibitor therapy was initiated with
high dose tirofiban (25 µg/kg/bolus) followed by an intravenous infusion of 0.15 µg/kg/min
for 12 hours, according to clinical judgment and indications for bail-out therapy1,2. No reflow
was treated according to contemporary standards of care with intra-coronary nitrate (i.e. 200
µg) and adenosine (i.e. 30 – 60 µg)1,2, as clinically appropriate. In patients with multivessel
coronary disease, multivessel PCI was not recommended, in line with clinical guidelines1,2. The subsequent management of these patients was symptom-guided. Coronary angiogram acquisition and analyses Coronary angiograms were acquired during usual care with cardiac catheter laboratory X-ray
(Innova®) and IT equipment (Centricity®) made by GE Healthcare. 3 3 Angiographic analysis The coronary anatomy and disease characteristics of study participants were described based
on the clinical reports of the attending cardiologist. Outcome definitions Coronary blood flow can be described based on the visual assessment of coronary blood flow
revealed by contrast injection into the coronary arteries1,2. TIMI Coronary Flow Grade 0 is no 4 4 flow, 1 is minimal flow past obstruction, 2 is slow (but complete) filling and slow clearance,
and 3 is normal flow and clearance. flow, 1 is minimal flow past obstruction, 2 is slow (but complete) filling and slow clearance,
and 3 is normal flow and clearance. CMR acquisition CMR imaging was performed on a Siemens MAGNETOM Avanto (Erlangen, Germany) 1.5-
Tesla scanner with a 12-element phased array cardiac surface coil. Myocardial native longitudinal relaxation time (T1) reflects tissue water content and
cellularity3. T1-mapping was performed pre- and 15 minutes post-gadolinium contrast
administration. T1 maps were acquired in 3 short-axial slices (basal, mid and apical), using a
modified look-locker inversion-recovery (MOLLI) investigational prototype sequence
(Work-in-Progress (WIP) method 448, Siemens Healthcare)4–6 that incorporates an automatic
registration algorithm based on a previously described approach7. The MOLLI T1 cardiac-
gated acquisition involved three inversion-recovery prepared look locker experiments
combined within one protocol (3 (3) 3 (3) 5)5. The CMR parameters were: bandwidth ~1090
Hz/pixel; flip angle 35°; echo time (TE) 1.1 ms; T1 of first experiment 100 ms; TI increment
80 ms; matrix 192 x 124 pixels; spatial resolution 2.2 x 1.8 x 8.0 mm; slice thickness 8 mm;
scan time 17 heartbeats. Myocardial transverse relaxation time (T2) directly reflects tissue water content and
mobility8,9. T2-mapping (WIP method 447, Siemens Healthcare) was acquired in contiguous
short axis slices covering the whole ventricle, using an investigational prototype T2-prepared
(T2P) TrueFisp sequence8,9. The CMR parameters were: bandwidth ~947 Hz/pixel; flip angle
70°; T2 preparations: 0 ms, 24 ms, and 55 ms respectively; matrix 160 x 105 pixels; spatial
resolution 2.6 x 2.1 x 8.0 mm; slice thickness 8 mm. Late gadolinium enhancement images covering the entire left ventricle (LV) were acquired
10-15 minutes after intravenous injection of 0.15 mmol/kg of gadoterate meglumine (Gd2+- 5 5 DOTA, Dotarem, Guebert S.A.) using segmented phase-sensitive inversion recovery (PSIR)
turbo fast low-angle shot10. Typical imaging parameters were: bandwidth ~130 Hz/pixel, flip
angle 25°, TE 3.36 ms, matrix 192 x 256 pixels, echo spacing 8.7ms and trigger pulse 2. The
voxel size was 1.8 x 1.3 x 8 mm3. Inversion times were individually adjusted to optimize
nulling of apparently normal myocardium (typical values, 200 to 300 ms). DOTA, Dotarem, Guebert S.A.) using segmented phase-sensitive inversion recovery (PSIR)
turbo fast low-angle shot10. Typical imaging parameters were: bandwidth ~130 Hz/pixel, flip
angle 25°, TE 3.36 ms, matrix 192 x 256 pixels, echo spacing 8.7ms and trigger pulse 2. The
voxel size was 1.8 x 1.3 x 8 mm3. Inversion times were individually adjusted to optimize
nulling of apparently normal myocardium (typical values, 200 to 300 ms). CMR image analyses The images were analysed on a Siemens work-station by observers with at least 3 years CMR
experience (N.A., D.C., I.M, S.R.). All of the images were reviewed by experienced CMR
cardiologists (C.B., N.T.). LV dimensions, volumes and ejection fraction were quantified
using computer assisted planimetry (syngo MR®, Siemens Healthcare, Erlangen, Germany). All scan acquisitions were spatially co-registered. ECV measurement LV contours were delineated on the best spatially matched raw T1 image and copied onto
color-coded spatially co-registered maps. Regions of interest were drawn in infarcted
myocardium surrounding core, remote myocardium and LV blood pool. Hematocrit (HCT)
was measured at the time of scanning. Extracellular volume (ECV) was calculated as a ratio
of corresponding T1 values measured pre- and post- contrast in each of the regions of
interest. ECV
was
calculated
using
ECV
=
(1-HCT)
×
λ,
where
Lambda
(λ)=ΔR1myocardium/ΔR1blood, ΔR1=R1post-contrast-R1pre-contrast and R1=1/T111,12. Infarct definition and size Electrocardiogram A 12 lead ECG was obtained before coronary reperfusion and 60 minutes afterwards with
Mac-Lab® technology (GE Healthcare) in the catheter laboratory and a MAC 5500 HD
recorder (GE Healthcare) in the Coronary Care Unit. The ECGs were acquired by trained
cardiology staff. The ECGs were de-identified and transferred to the local ECG management
system. The ECGs were then analysed by the University of Glasgow ECG Core Laboratory
which is certified to ISO 9001: 2008 standards as a UKAS Accredited Organisation. The extent of ST-segment resolution on the ECG assessed 60 minutes after reperfusion
compared to the baseline ECG before reperfusion1 was expressed as complete (≥70%),
incomplete (>30% to < 70%) or none (≤30%). Reference ranges Reference ranges used in the laboratory were 105 – 215 g for LV mass in men, 70 – 170 g for
LV mass in women, 77 – 195 ml for LV end-diastolic volume in men, 52 – 141 ml for LV
end-diastolic volume in women, 19 – 72 ml for LV end-systolic volume in men and 13 – 51
ml for LV end-systolic volume in women. Infarct definition and size The territory of infarction was delineated using a signal intensity threshold of >5 standard
deviations (SD) above a remote reference region and expressed as a percentage of total LV
mass13. Infarct regions with evidence of microvascular obstruction were included within the 6 6 infarct area and the area of microvascular obstruction was assessed separately and also
expressed as a percentage of total LV mass. infarct area and the area of microvascular obstruction was assessed separately and also
expressed as a percentage of total LV mass. Reference ranges Biochemical measurement of infarct size Troponin T was measured (Elecsys Troponin T, Roche) as a biochemical measure of infarct
size. The high sensitive assay reaches a level of detection of 5 pg/ml and achieves less than
10%variation at 14 pg/ml corresponding to the 99th percentile of a reference population. A
blood sample was routinely obtained 12 – 24 hours after hospital admission, and again
between 0700 - 0900 hours during the first two days of the index hospitalization. 7 7 Research Management The study was conducted in line with Guidelines for Good Clinical Practice (GCP) in Clinical
Trials14. Trial management included a Trial Management Group, and an independent Clinical Trials
Unit. Day to day study activity was coordinated by the Trial Management Group who was
responsible to the Sponsor which was responsible for overall governance and that the trial
was conducted according to GCP standards. Biochemical measurement of LV remodeling Serial systemic blood sample were obtained immediately after reperfusion in the cardiac
catheterization laboratory, and subsequently between 0600 - 0700 hrs each day during the
initial in-patient stay in the Coronary Care Unit. NT-proBNP, a biochemical measure of LV wall stress, was measured in a research laboratory
using an electrochemiluminescence method (e411, Roche) and the manufacturers calibrators
and quality control material. The limit of detection is 5 pg/ml. Long-term coefficient of
variations of low and high controls are typically <5%, and were all within the manufacturers
range. Health outcomes We prespecified adverse health outcomes that are pathophysiologically linked with STEMI. The primary composite outcome was major adverse cardiac events (MACE) defined as
cardiac death, non-fatal myocardial infarction or heart failure hospitalization following the 6-
month CMR scan. All-cause death or heart failure (heart failure hospitalization or
defibrillator implantation) following the 6-month CMR scan was a secondary outcome. 8 8 Research staff screened for events from enrolment by checking the medical records and by
contacting patients and their primary and secondary care physicians as appropriate. Each
serious adverse event was reviewed by a cardiologist who was independent of the research
team and blinded to all of the clinical and CMR data. The serious adverse events were
defined according to standard guidelines15. CMR findings The full list of CMR findings are summarized in Supplementary Table 1. The association between change in LV ejection fraction and persisting T2 hyperintensity and
the change in infarct zone T2 is shown in Supplementary Table 2. Infarct zone T2 inter-observer reliability Infarct zone T2 in a subgroup of 20 randomly chosen patients was independently measured
by two observers. The intra-class correlation coefficient for reliability of infarct zone T2 was
0.92 (95% confidence interval (CI): 0.75, 0.97); p<0.001. Bland-Altman plots
(Supplementary Figure 2) showed no evidence of bias. The coefficient of variation for infarct
zone T2 was 7.4%. Statistics Continuous variables are described as mean±SD, if normally distributed, and median (Q1,
Q3) otherwise. Categorical variables are described as n (%). Variables are described overall
and by presence or absence of persistent T2 hyperintensity. Patient and angiographic
characteristics and CMR findings were compared between groups with presence or absence
of persistent T2 hyperintensity using independent sample t-tests or Mann-Whitney tests, as
appropriate. Binary logistic regression was used to identify associates of persistent T2
hyperintensity. Multivariable linear regression analyses using the enter method were
performed to identify associates of the change in infarct zone T2 and LV parameters. Linear
regression assumptions were verified using standardized residual plots. Random effects models were used to compute inter-rater reliability measures (inter-class
correlation coefficient (ICC)) for the reliability of infarct zone T2 values measured
independently by 2 observers in 20 randomly selected patients from the cohort. Cox proportional hazards regression was used to explore potential associations between
persisting T2 hyperintensity and health outcome. The proportional hazards assumption was
verified using log-minus-log plots. For these plots, continuous variables were categorized as
above and below the median. 9 9 All p-values were 2-sided. A p-value >0.05 indicated the absence of a statistically significant
effect. The natural log was used in transformations of variables. Analyses were performed
using SPSS version 22 for Windows (SPSS, Inc., Chicago, Illinois), or R v3.3.0. 10 Persistent T2 hyperintensity and extracellular volume Infarct zone ECV was measured in 127 patients at baseline and 124 patients at follow-up
(n=124 paired measurements). The characteristics of these patients were similar to the whole
cohort (data not shown). Infarct zone ECV and T2 were associated at baseline (0.14 (0.04,
0.24); p=0.007) which likely reflects the early increase in infarct zone extracellular water
content. Additionally, infarct zone ECV at 6 months was higher in patients with persisting T2
hyperintensity (Table 2). There was an association between the change in infarct zone ECV at
6 months compared to baseline and the change in T2 in the infarct zone (0.15 (0.05, 0.24);
p=0.002; n=124). The directions of change in infarct zone T2 and infarct zone ECV were
independent (Chi square; p=0.420). In the majority of patients, infarct zone T2 decreased 11 11 over time, which means those who had a smaller decrease in infarct zone T2 had a larger
increase in infarct zone ECV. Since ECV may also reflect extracellular collagen volume fraction16, progressive
extracellular fibrosis within the infarct zone may lead to an increase in ECV in the chronic
phase post-STEMI. After adjustment for infarct zone ECV, infarct zone T2 was no longer a
multivariable associate of LV remodeling. Accepting some loss of statistical power in this
subset analysis, the potential explanations for this result may include 1) progressive infarct
zone fibrosis is associated with persistent T2 hyperintensity at 6 months; 2) extracellular
rather than intracellular edema is prominent in pathological remodeling post-MI and; 3)
measurement error, since hematocrit, which is required to calculate ECV, may not be
uniformly distributed in systemic blood and injured capillaries may allow varying amounts of
formed blood elements to occupy the microvascular compartment. Associates with adverse remodeling at 6 months The clinical characteristics that were included in the multivariable model with adverse
remodeling at 6 months were BMI (p=0.589), age (p=0.502), male sex (p=0.812), previous
MI (p=0.708), previous PCI (p=0.347), diabetes mellitus (p=0.432), previous angina
(p=0.879), hypertension (p=0.437), hypercholesterolemia (p=0.879), cigarette smoking
(p=0.117), no ST-segment resolution vs. complete or partial ST-segment resolution
(reference category) (p=0.882), TIMI coronary flow grade 0/1 pre-PCI vs. TIMI coronary
flow grade 2/3 pre-PCI (reference category) (p=0.280), TIMI coronary flow grade 0/1/2 post-
PCI vs. TIMI coronary flow grade 3 post-PCI (reference category) (p=0.295) systolic blood
pressure at initial angiography per 10mmHg (p=0.419), heart rate (p=0.818), symptom onset
to reperfusion time (p=0.258), percentage stenosis of culprit artery (p=0.274). The multivariable predictors are described in Table 3 in the main paper. 12 12 Persistent T2 hyperintensity and health outcomes Kaplan-Meier plots for the association between persisting T2 hyperintesity and all-cause
death or heart failure and major adverse cardiac events are shown in Supplementary Figure 3. 13 13 Supplementary Figures Supplementary Figure 1. CONSORT flow diagram. Supplementary Figure 2. Bland-Altman plot for inter-observer variability in infarct zone T2
measurement. Supplementary Figure 3. Kaplan-Meier plots for the association between persisting T2
hyperintesity and A) all-cause death or heart failure (Log rank = 0.115) and B) major adverse
cardiac events (Log rank = 0.212). 14 14 Supplementary Figure 1. Patients with an acute STEMI
assessed for eligibility
(n = 343)
No CMR at 6 months follow-up (n = 27)
•
Refused (n = 19)
•
Death (n = 3)
•
Did not attend (n = 2)
Analysis(
Follow,Up(
CMR (n = 324)
Enrolment(with(
informed(consent(
CMR 6 months post-MI (n = 283)
Analysis(
CMR at follow-up (n = 297)
Artefact (n = 1)
De novo myocardial infarction (n = 13) Supplementary Figure 1. Enrolment(with(
informed(consent( No CMR at 6 months follow-up (n = 27)
•
Refused (n = 19)
•
Death (n = 3)
•
Did not attend (n = 2) No CMR at 6 months follow-up (n = 27) CMR at follow-up (n = 297) Artefact (n = 1)
De novo myocardial infarction (n = 13) CMR 6 months post-MI (n = 283) 15 Supplementary Figure 2 Supplementary Figure 2 Supplementary Figure 2 16 Supplementary Figure 3 Supplementary Figure 3 Time (days)
2000
1500
1000
500
0
Cumulative Survival
1.00
0.98
0.96
0.94
0.92
0.90
Persisting T2
hyperintensity
No persisting T2
hyperintensity
Logrank = 0.115
Time (days)
2000
1500
1000
500
0
Cumulative Survival
1.00
0.98
0.96
0.94
0.92
0.90
Log rank = 0.212
A"
B" Time (days)
2000
1500
1000
500
0
Cumulative Survival
1.00
0.98
0.96
0.94
0.92
0.90
Logrank = 0.115
A" Persisting T2
hyperintensity
No persisting T2
hyperintensity
Time (days)
2000
1500
1000
500
0
Cumulative Survival
1.00
0.98
0.96
0.94
0.92
0.90
Pers
hype
No p
hype
Log rank = 0.212
B" Cumulative Survival Cumulative Survival 17 18
Supplementary Tables
Supplementary Table 1. CMR findings in 283 patients grouped according to the presence or absence of persistent T2 hyperintensity revealed
by T2-mapping at 6 months post-STEMI.
Characteristics
All patients
No persistent T2 hyperintensity
Persistent T2 hyperintensity
P-value*
n=283
n=94 (33%)
n=189 (67%)
CMR findings 2 days post-MI
LV ejection fraction, %
55±10
57±10
55±10
0.071
LV end-diastolic volume, ml
Men
161±31
155±30
164±31
0.036
Women
124±25
130±23
121±25
0.172
LV end-systolic volume, ml 18 19
Men
74±26
69±25
78±26
0.014
Women
54±18
57±18
52±17
0.225
LV mass, g
Men
144±33
137±29
148±34
0.028
Women
97±21
101±17
95±23
0.216
Edema and infarct characteristics
Myocardial edema, % LV mass
32±12
30±13
33±11
0.050
Infarct size, % LV mass
18±13
13±13
20±13
<0.001
Myocardial salvage, % LV mass
19±9
21±10
18±8
0.033
Myocardial salvage index, % LV mass
63±24
73±24
58±23
<0.001
Late microvascular obstruction present, n (%)
138 (49)
33 (35)
105 (56)
0.002 Men
74±26
69±25
78±26
0.014
Women
54±18
57±18
52±17
0.225
LV mass, g
Men
144±33
137±29
148±34
0.028
Women
97±21
101±17
95±23
0.216
Edema and infarct characteristics
Myocardial edema, % LV mass
32±12
30±13
33±11
0.050
Infarct size, % LV mass
18±13
13±13
20±13
<0.001
Myocardial salvage, % LV mass
19±9
21±10
18±8
0.033
Myocardial salvage index, % LV mass
63±24
73±24
58±23
<0.001
Late microvascular obstruction present, n (%)
138 (49)
33 (35)
105 (56)
0.002 19 0.014 20
Late microvascular obstruction, % LV mass
2.6±4.6
1.5±3.6
3.1±4.9
0.004
Myocardial T1 and T2 values
T1 remote, ms
960±26
958±25
961±26
0.354
T1 infarct, ms
1097±52
1093±49
1099±53
0.338
T1 hypointense core present, n (%)
137 (48)
33 (35)
104 (55)
0.002
T1 hypointense infarct core, ms
996±60
999±56
995±61
0.702
T2 remote, ms
49.7±2.1
49.8±2.2
49.7±2.1
0.811
T2 infarct, ms
66.3±6.1
64.4±5.7
67.3±6.1
<0.001
T2 hypointense core present, n (%)
165 (58)
41 (44)
124 (66)
0.001
T2 hypointense infarct core, ms
54.1±4.8
53.9±5.1
54.2±4.7
0.698
Myocardial ECV values at baseline 20 0.004 ECV remote (all subjects), %
25.6±2.9
25.6±2.8
25.6±3.0
0.995
Men
25.2±2.9
25.0±2.7
25.3±2.9
0.612
Women
27.0±2.6
27.1±2.4
26.8±2.8
0.763
ECV infarct, %
56.0±11.7
52.8±12.9
57.7±10.7
0.024
ECV hypointense infarct core, %
43.2±12.6
44.8±15.1
42.5±11.7
0.537
CMR findings at 6 months
LV ejection fraction at 6 months, %
62±9
65±8
61±10
<0.001
LV end-diastolic volume at 6 months, ml
Men
169±42
151±31
177±45
<0.001
Women
127±30
125±22
128±34
0.627
LV end-systolic volume at 6 months, ml 21 22
Men
68±35
54±19
74±38
<0.001
Women
46±18
45±18
47±18
0.550
Adverse remodeling, n (%)
32 (12)
1 (1)
31 (17)
<0.001
Infarct characteristics at 6 months
Infarct size at 6 months, % LV mass
13±10
9±9
15±10
<0.001
Myocardial T1 and T2 values at 6 months
T1 remote at 6 months, ms
957±29
957±28
958±29
0.713
T1 infarct at 6 months, ms
1058±66
1035±59
1068±67
<0.001
T2 remote at 6 months, ms
49.7±2.3
50.3±2.5
49.4±2.1
0.001
T2 infarct at 6 months, ms
56.8±4.5
53.5±3.4
58.5±4.0
<0.001
Myocardial ECV values at 6 months 22 <0.001 ECV remote at 6 months (all subjects), %
25.6±2.7
25.5±2.6
25.7±2.8
0.519
Men
25.3±2.7
25.0±2.6
25.4±2.7
0.288
Women
26.8±2.5
26.9±2.1
26.8±2.9
0.917
ECV infarct at 6 months, %
51.6±11.1
47.5±11.0
53.7±10.5
<0.001
Footnote: Abbreviations: CMR = cardiac magnetic resonance, ECV = extracellular volume, LV = left ventricle, T1 = longitudinal relaxation
time, T2 = transverse relaxation time. Data are given as n (%) or mean±SD as appropriate. *P-values were obtained from two-sample t-test,
Mann Whitney test or Fisher’s test. 23 Supplementary Table 2. Linear regression analysis for associations with the change in LV
ejection fraction at 6 months post-STEMI. Multivariable associations
coefficient (95% CI)
p value
Patient characteristics, angiographic data and persistent T2 hyperintensity
Persistent T2 hyperintensity
-2.53 (-4.39, -0.68)
0.008
Previous MI
6.29 (1.75, 10.83)
0.007
LV ejection fraction at baseline, %
-0.38 (-0.48, -0.29)
<0.001
Patient characteristics, angiographic data and change in infarct zone T2 (1 ms change)
Change in infarct zone T2, 1 ms
-0.45 (-0.65, -0.26)
<0.001
Percentage stenosis of culprit artery, %
-0.14 (-0.24, -0.04)
0.007
Previous MI
5.47 (1.07, 9.86)
0.015
Hypertension
2.24 (0.31, 4.17)
0.023
Baseline infarct zone T2, ms
-0.52 (-0.73, -0.31)
<0.001
LV ejection fraction at baseline, %
-0.39 (-0.49, -0.30)
<0.001
Patient characteristics, angiographic data and change in infarct zone T2 (10 ms change)
Change in infarct zone T2, 10 ms
-2.37 (-4.00, -0.75)
0.004
Percentage stenosis of culprit artery, %
-0.16 (-0.26, -0.05)
0.003
Previous MI
5.65 (1.14, 10.16)
0.014
Baseline infarct zone T2, ms
-0.36 (-0.55, -0.16)
<0.001 Supplementary Table 2. Linear regression analysis for associations with the change in LV
ejection fraction at 6 months post-STEMI. 22
Men
68±35
54±19
74±38
<0.001
Women
46±18
45±18
47±18
0.550
Adverse remodeling, n (%)
32 (12)
1 (1)
31 (17)
<0.001
Infarct characteristics at 6 months
Infarct size at 6 months, % LV mass
13±10
9±9
15±10
<0.001
Myocardial T1 and T2 values at 6 months
T1 remote at 6 months, ms
957±29
957±28
958±29
0.713
T1 infarct at 6 months, ms
1058±66
1035±59
1068±67
<0.001
T2 remote at 6 months, ms
49.7±2.3
50.3±2.5
49.4±2.1
0.001
T2 infarct at 6 months, ms
56.8±4.5
53.5±3.4
58.5±4.0
<0.001
Myocardial ECV values at 6 months Multivariable associations
coefficient (95% CI)
p value
Patient characteristics, angiographic data and persistent T2 hyperintensity
Persistent T2 hyperintensity
-2.53 (-4.39, -0.68)
0.008
Previous MI
6.29 (1.75, 10.83)
0.007
LV ejection fraction at baseline, %
-0.38 (-0.48, -0.29)
<0.001
Patient characteristics, angiographic data and change in infarct zone T2 (1 ms change)
Change in infarct zone T2, 1 ms
-0.45 (-0.65, -0.26)
<0.001
Percentage stenosis of culprit artery, %
-0.14 (-0.24, -0.04)
0.007
Previous MI
5.47 (1.07, 9.86)
0.015
Hypertension
2.24 (0.31, 4.17)
0.023
Baseline infarct zone T2, ms
-0.52 (-0.73, -0.31)
<0.001
LV ejection fraction at baseline, %
-0.39 (-0.49, -0.30)
<0.001
Patient characteristics, angiographic data and change in infarct zone T2 (10 ms change)
Change in infarct zone T2, 10 ms
-2.37 (-4.00, -0.75)
0.004
Percentage stenosis of culprit artery, %
-0.16 (-0.26, -0.05)
0.003
Previous MI
5.65 (1.14, 10.16)
0.014
Baseline infarct zone T2, ms
-0.36 (-0.55, -0.16)
<0.001
LV ejection fraction at baseline, %
-0.39 (-0.48, -0.29)
<0.001 Supplementary Table 2. Linear regression analysis for associations with the change in LV
ejection fraction at 6 months post-STEMI Patient characteristics, angiographic data and persistent T2 hyperintensity atient characteristics, angiographic data and change in infarct zone T2 (1 ms change) Change in infarct zone T2, 1 ms
-0.45 (-0.65, -0.26)
<0.001
Percentage stenosis of culprit artery, %
-0.14 (-0.24, -0.04)
0.007
Previous MI
5.47 (1.07, 9.86)
0.015
Hypertension
2.24 (0.31, 4.17)
0.023
Baseline infarct zone T2, ms
-0.52 (-0.73, -0.31)
<0.001
LV ejection fraction at baseline, %
-0.39 (-0.49, -0.30)
<0.001
P
h
h
d
d h
f
T2 (10
h
) Change in infarct zone T2, 10 ms
-2.37 (-4.00, -0.75)
0.004
Percentage stenosis of culprit artery, %
-0.16 (-0.26, -0.05)
0.003
Previous MI
5.65 (1.14, 10.16)
0.014
Baseline infarct zone T2, ms
-0.36 (-0.55, -0.16)
<0.001
LV ejection fraction at baseline, %
-0.39 (-0.48, -0.29)
<0.001 24 Footnote: Abbreviations: CI = confidence intervals, LV = left ventricle, MI = myocardial
infarction, T2 = transverse relaxation time. The coefficient (95% confidence intervals)
indicates the magnitude and direction of the difference in change in LV ejection fraction (%)
for the patient characteristic (binary or continuous). The clinical characteristics that were included in the multivariable model with adverse
remodeling at 6 months were BMI (p=0.574), age (p=0.354), male sex (p=0.460), previous
PCI (p=0.808), diabetes mellitus (p=0.671), previous angina (p=0.402), hypertension
(p=0.076), hypercholesterolemia (p=0.468), cigarette smoking (p=0.246), no ST-segment
resolution vs. 22
Men
68±35
54±19
74±38
<0.001
Women
46±18
45±18
47±18
0.550
Adverse remodeling, n (%)
32 (12)
1 (1)
31 (17)
<0.001
Infarct characteristics at 6 months
Infarct size at 6 months, % LV mass
13±10
9±9
15±10
<0.001
Myocardial T1 and T2 values at 6 months
T1 remote at 6 months, ms
957±29
957±28
958±29
0.713
T1 infarct at 6 months, ms
1058±66
1035±59
1068±67
<0.001
T2 remote at 6 months, ms
49.7±2.3
50.3±2.5
49.4±2.1
0.001
T2 infarct at 6 months, ms
56.8±4.5
53.5±3.4
58.5±4.0
<0.001
Myocardial ECV values at 6 months complete or partial ST-segment resolution (reference category) (p=0.746),
TIMI coronary flow grade 0/1 pre-PCI vs. TIMI coronary flow grade 2/3 pre-PCI (reference
category) (p=0.764), TIMI coronary flow grade 0/1/2 post-PCI vs. TIMI coronary flow grade
3 post-PCI (reference category) (p=0.529) systolic blood pressure at initial angiography per
10mmHg (p=0.578), heart rate (p=0.782), symptom onset to reperfusion time (p=0.617). 25 References 1. O’Gara PT, Kushner FG, Ascheim DD, Casey DE, Chung MK, Lemos JA de, Ettinger
SM, Fang JC, Fesmire FM, Franklin BA, Granger CB, Krumholz HM, Linderbaum JA,
Morrow DA, Newby LK, Ornato JP, Ou N, Radford MJ, Tamis-Holland JE, Tommaso
CL, Tracy CM, Woo YJ, Zhao DX. 2013 ACCF/AHA Guideline for the Management of
ST-Elevation Myocardial Infarction. Circulation. 2013;127:e362–e425. 2. King SB, Smith SC, Hirshfeld JW, Jacobs AK, Morrison DA, Williams DO, Members
2005 Writing Committee, Smith SC, Feldman TE, Hirshfeld JW, Jacobs AK, Kern MJ,
King SB, Morrison DA, O’Neill WW, Schaff HV, Whitlow PL, Williams DO, Smith
SC, Jacobs AK, Adams CD, Anderson JL, Buller CE, Creager MA, Ettinger SM,
Halperin JL, Hunt SA, Krumholz HM, Kushner FG, Lytle BW, Nishimura R, Page RL,
Riegel B, Tarkington LG, Yancy CW. 2007 Focused Update of the ACC/AHA/SCAI
2005 Guideline Update for Percutaneous Coronary Intervention. Circulation. 2008;117:261–295. 3. Moon JC, Messroghli DR, Kellman P, Piechnik SK, Robson MD, Ugander M,
Gatehouse PD, Arai AE, Friedrich MG, Neubauer S, Schulz-Menger J, Schelbert EB. Myocardial T1 mapping and extracellular volume quantification: a Society for
Cardiovascular Magnetic Resonance (SCMR) and CMR Working Group of the
European Society of Cardiology consensus statement. J Cardiovasc Magn Reson. 2013;15:92. 4. Messroghli DR, Greiser A, Fröhlich M, Dietz R, Schulz-Menger J. Optimization and
validation of a fully-integrated pulse sequence for modified look-locker inversion-
recovery (MOLLI) T1 mapping of the heart. J Magn Reson Imaging. 2007;26:1081–
1086. 5. Messroghli DR, Walters K, Plein S, Sparrow P, Friedrich MG, Ridgway JP,
Sivananthan MU. Myocardial T1 mapping: Application to patients with acute and
chronic myocardial infarction. Magn Reson Med. 2007;58:34–40. 6. Xue H, Guehring J, Srinivasan L, Zuehlsdorff S, Saddi K, Chefdhotel C, Hajnal JV,
Rueckert D. Evaluation of rigid and non-rigid motion compensation of cardiac perfusion
MRI. Med Image Comput Comput-Assist Interv MICCAI Int Conf Med Image Comput
Comput-Assist Interv. 2008;11:35–43. 7. Chefd’hotel C, Hermosillo G, Faugeras O. Flows of diffeomorphisms for multimodal
image registration. In: 2002 IEEE International Symposium on Biomedical Imaging,
2002. Proceedings. 2002. p. 753–756. 8. Giri S, Chung Y-C, Merchant A, Mihai G, Rajagopalan S, Raman SV, Simonetti OP. T2
quantification for improved detection of myocardial edema. J Cardiovasc Magn Reson. 2009;11:56. 9. Verhaert D, Thavendiranathan P, Giri S, Mihai G, Rajagopalan S, Simonetti OP, Raman
SV. Direct T2 Quantification of Myocardial Edema in Acute Ischemic Injury. JACC
Cardiovasc Imaging. 2011;4:269–278. 26 10. 16. Miller CA, Naish JH, Bishop P, Coutts G, Clark D, Zhao S, Ray SG, Yonan N,
Williams SG, Flett AS, Moon JC, Greiser A, Parker GJM, Schmitt M. Comprehensive
Validation of Cardiovascular Magnetic Resonance Techniques for the Assessment of
Myocardial Extracellular Volume. Circ Cardiovasc Imaging. 2013;6:373–383. References Kellman P, Arai AE, McVeigh ER, Aletras AH. Phase-sensitive inversion recovery for
detecting myocardial infarction using gadolinium-delayed hyperenhancement†. Magn
Reson Med. 2002;47:372–383. 11. Ugander M, Oki AJ, Hsu L-Y, Kellman P, Greiser A, Aletras AH, Sibley CT, Chen MY,
Bandettini WP, Arai AE. Extracellular volume imaging by magnetic resonance imaging
provides insights into overt and sub-clinical myocardial pathology. Eur Heart J. 2012;33:1268–1278. 12. Wong TC, Piehler K, Meier CG, Testa SM, Klock AM, Aneizi AA, Shakesprere J,
Kellman P, Shroff SG, Schwartzman DS, Mulukutla SR, Simon MA, Schelbert EB. Association Between Extracellular Matrix Expansion Quantified by Cardiovascular
Magnetic Resonance and Short-Term MortalityClinical Perspective. Circulation. 2012;126:1206–1216. 13. Flett AS, Hasleton J, Cook C, Hausenloy D, Quarta G, Ariti C, Muthurangu V, Moon
JC. Evaluation of Techniques for the Quantification of Myocardial Scar of Differing
Etiology Using Cardiac Magnetic Resonance. JACC Cardiovasc Imaging. 2011;4:150–
156. 14. Medical Research Council. Guidelines for good clinical practice in clinical trials. [Internet]. [cited 2016 Jul 31];Available from:
http://www.mrc.ac.uk/documents/pdf/good-clinical-practice-in-clinical-trials/ 15. Hicks KA, Tcheng JE, Bozkurt B, Chaitman BR, Cutlip DE, Farb A, Fonarow GC,
Jacobs JP, Jaff MR, Lichtman JH, Limacher MC, Mahaffey KW, Mehran R, Nissen SE,
Smith EE, Targum SL. 2014 ACC/AHA Key Data Elements and Definitions for
Cardiovascular Endpoint Events in Clinical Trials: A Report of the American College of
Cardiology/American Heart Association Task Force on Clinical Data Standards
(Writing Committee to Develop Cardiovascular Endpoints Data Standards). J Am Coll
Cardiol. 2015;66:403–469. 16. Miller CA, Naish JH, Bishop P, Coutts G, Clark D, Zhao S, Ray SG, Yonan N,
Williams SG, Flett AS, Moon JC, Greiser A, Parker GJM, Schmitt M. Comprehensive
Validation of Cardiovascular Magnetic Resonance Techniques for the Assessment of
Myocardial Extracellular Volume. Circ Cardiovasc Imaging. 2013;6:373–383. 27
|
https://openalex.org/W3005483820
|
https://vuir.vu.edu.au/43135/1/Exploring%20the%20facilitators%20and%20barriers%20to%20using%20an%20online%20infertility%20risk%20prediction%20tool%20%28FoRECAsT%29%20for%20young%20women%20with%20.pdf
|
English
| null |
Exploring the facilitators and barriers to using an online infertility risk prediction tool (FoRECAsT) for young women with breast cancer: a qualitative study protocol
|
BMJ open
| 2,020
|
cc-by
| 6,598
|
Exploring the facilitators and barriers to using an
online infertility risk prediction tool (FoRECAsT) for
young women with breast cancer: A qualitative study
protocol Exploring the facilitators and barriers to using an
online infertility risk prediction tool (FoRECAsT) for
young women with breast cancer: A qualitative study
protocol Strengths and limitations of this study Introduction As cancer treatments may impact on fertility,
a high priority for young patients with breast cancer is
access to evidence-based, personalised information for
them and their healthcare providers to guide treatment and
fertility-related decisions prior to cancer treatment. Current
tools to predict fertility outcomes after breast cancer
treatments are imprecise and do not offer individualised
prediction. To address the gap, we are developing a novel
personalised infertility risk prediction tool (FoRECAsT) for
premenopausal patients with breast cancer that considers
current reproductive status, planned chemotherapy and
adjuvant endocrine therapy to determine likely post-
treatment infertility. The aim of this study is to explore the
feasibility of implementing this FoRECAsT tool into clinical
practice by exploring the barriers and facilitators of its use
among patients and healthcare providers. ►
►Obtaining representative stakeholder feedback is an
essential step in ensuring that a risk prediction tool
is feasible and acceptable for use in clinical practice. ►
►This tool could be adapted to newer breast cancer
treatments and for other cancers. ►
►Non-probability sampling may increase the risk of
selection bias. ►
►Recruitment is limited to patients with breast cancer
where fertility was discussed prior to cancer treat-
ment, findings may not be applicable where fertility
was not discussed. ►
►Prepublication history for
this paper is available online. To view these files, please visit
the journal online (http://dx.doi.
org/10.1136/bmjopen-2019-
033669). ►
►This study is being conducted in the Australian set-
ting, findings may not be generalisable to different
health settings. ►
►This study is being conducted in the Australian set-
ting, findings may not be generalisable to different
health settings. Received 16 August 2019
Revised 09 January 2020
Accepted 13 January 2020 Received 16 August 2019
Revised 09 January 2020
Accepted 13 January 2020 Methods and analysis A cross-sectional exploratory
study is being conducted using semistructured in-depth
telephone interviews with 15–20 participants each from
the following groups: (1) premenopausal patients with
breast cancer younger than 40, diagnosed within last 5
years, (2) breast surgeons, (3) breast medical oncologists,
(4) breast care nurses (5) fertility specialists and (6) fertility
preservation nurses. Patients with breast cancer are being
recruited from the joint Breast Service of three affiliated
institutions of Victorian Comprehensive Cancer Centre in
Melbourne, Australia—Peter MacCallum Cancer Centre,
Royal Melbourne Hospital and Royal Women’s Hospital,
and clinicians are being recruited from across Australia. To cite: Edib Z, Jayasinghe Y,
Hickey M, et al. Exploring
the facilitators and barriers to
using an online infertility risk
prediction tool (FoRECAsT)
for young women with
breast cancer: a qualitative
study protocol. BMJ Open
2020;10:e033669. doi:10.1136/
bmjopen-2019-033669 Abstract Abstract To cite: Edib Z, Jayasinghe Y,
Hickey M, et al. Exploring
the facilitators and barriers to
using an online infertility risk
prediction tool (FoRECAsT)
for young women with
breast cancer: a qualitative
study protocol. BMJ Open
2020;10:e033669. doi:10.1136/
bmjopen-2019-033669 This is the Published version of the following publication This is the Published version of the following publication Edib, Zobaida, Jayasinghe, Yasmin, Hickey, Martha, Stafford, Lesley,
Anderson, Richard A, Su, H. Irene, Stern, Kate, Saunders, Christobel,
Anazodo, Antoinette, MacHeras-Magias, Mary, Chang, Shanton, Pang,
Patrick, Agresta, Franca, Chin-Lenn, Laura, Cui, Wanyuan, Pratt, Sarah,
Gorelik, Alex and Peate, Michelle (2020) Exploring the facilitators and barriers
to using an online infertility risk prediction tool (FoRECAsT) for young women
with breast cancer: A qualitative study protocol. BMJ Open, 10 (2). ISSN 2044-
6055 The publisher’s official version can be found at
https://bmjopen.bmj.com/content/10/2/e033669
Note that access to this version may require subscription. Downloaded from VU Research Repository https://vuir.vu.edu.au/43135/ Open access Protocol Exploring the facilitators and barriers to
using an online infertility risk
prediction tool (FoRECAsT) for young
women with breast cancer: a qualitative
study protocol broadcast media, print media, internet and various
community/stakeholder engagement activities. broadcast media, print media, internet and various
community/stakeholder engagement activities. broadcast media, print media, internet and various
community/stakeholder engagement activities. Strengths and limitations of this study Interviews are being audio recorded, transcribed verbatim
and imported into qualitative data analysis software to
facilitate data management and analyses. ►
►Prepublication history for
this paper is available online.
To view these files, please visit
the journal online (http://dx.doi.
org/10.1136/bmjopen-2019-
033669). Zobaida Edib ,1,2 Yasmin Jayasinghe,1,2,3 Martha Hickey,1,2 Lesley Stafford,4,5
Richard A Anderson,6 H. Irene Su,7 Kate Stern,8,9 Christobel Saunders,10
Antoinette Anazodo,11,12 Mary Macheras-Magias,13 Shanton Chang,14
Patrick Pang,14 Franca Agresta,8,9 Laura Chin-Lenn,15 Wanyuan Cui,16
Sarah Pratt,17 Alex Gorelik,18,19 Michelle Peate1,2 © Author(s) (or their
employer(s)) 2020. Re-use
permitted under CC BY-NC. No
commercial re-use. See rights
and permissions. Published by
BMJ. Exploring the facilitators and barriers to
using an online infertility risk
prediction tool (FoRECAsT) for young
women with breast cancer: a qualitative
study protocol Zobaida Edib ,1,2 Yasmin Jayasinghe,1,2,3 Martha Hickey,1,2 Lesley Stafford,4,5
Richard A Anderson,6 H. Irene Su,7 Kate Stern,8,9 Christobel Saunders,10
Antoinette Anazodo,11,12 Mary Macheras-Magias,13 Shanton Chang,14
Patrick Pang,14 Franca Agresta,8,9 Laura Chin-Lenn,15 Wanyuan Cui,16
Sarah Pratt,17 Alex Gorelik,18,19 Michelle Peate1,2 Introduction Globally, breast cancer is the most frequent
cancer
diagnosis
in
reproductive-aged
women, with approximately 100 000 women
younger than 40 years diagnosed annually
worldwide, representing one-quarter of new
breast cancer cases.1–3 In Australia, most
women are diagnosed with early-stage disease,
and with current treatment, the 5-year survival
rate for women diagnosed with breast cancer
is often excellent (90.8%).4 Recommended
treatment can include gonadotoxic chemo-
therapeutic agents and thus poses a potential
threat to fertility by destroying the eggs stored
in the ovaries.5 6 If the number of eggs is
substantially depleted, early menopause and/
or permanent infertility can result,7 and will For numbered affiliations see
end of article. Correspondence to
Dr Zobaida Edib;
zedib@student.unimelb.edu.au
© Author(s) (or their
employer(s)) 2020. Re-use
permitted under CC BY-NC. No
commercial re-use. See rights
and permissions. Published by
BMJ. © Author(s) (or their
employer(s)) 2020. Re-use
permitted under CC BY-NC. No
commercial re-use. See rights
and permissions. Published by
BMJ. Ethics and dissemination The study protocol has
been approved by Melbourne Health Human Research
Ethics Committee, Australia (HREC number: 2017.163). Confidentiality and privacy are maintained at every stage
of the study. Findings will be disseminated through peer-
reviewed scholarly and scientific journals, national and
international conference presentations, social media, For numbered affiliations see
end of article. Correspondence to More
than half are concerned about their future fertility, and
50%–76% wish to consider pregnancy following cancer
treatment.10–12 This number is likely to increase with the
social trends of delayed motherhood until older repro-
ductive ages.13 14 Concerns about the potential risk of
infertility and the inability to conceive in the future have
direct implications for treatment efficacy and long-term
physical and emotional health10 15–19—specifically it may
influence patients to choose less optimal adjuvant ther-
apies to reduce impact on fertility10 11 20 21 or the uptake
of fertility preservation options despite potential phys-
ical, emotional and financial burden.22–24 Young women
with breast cancer actively seek and desire knowledge,
and improved information translates into better health
outcomes.25 26 Core to making informed fertility-related
decisions is an understanding of the risk of infertility,
but the currently available information about fertility
outcomes following breast cancer treatment can only
determine broad risk categories (eg, intermediate risk:
30%–70% risk of infertility)27 and individual factors which
are known to affect fertility in women (eg, age, body mass
index, smoking, previous fertility, serum ovarian markers)
are not included in the risk prediction. There is a gap in
personalised information to inform young patients with
breast cancer about likely fertility outcomes after treat-
ment.28–30 To meet their unmet information needs, young
patients frequently use the internet to seek more acces-
sible and consolidated information about post-treatment
reproductive consequences.31 Therefore, an evidence-
based and individualised online risk prediction tool may
provide reliable and easy-to-access information to address
the gap and better manage the fertility-related needs.32 33 There are two key parts to the FoRECAsT tool—
the algorithm development and the user interface. To develop the risk prediction algorithm (part one),
authors from studies exploring variables related to
fertility at baseline and impact of breast cancer treat-
ment (table 1)29 36–44 have been invited to join the FoRE-
CAsT Collaboration and contribute their data to the
FoRECAsT database and these data are being used to
build a predictive model. The algorithm will use Bayesian inference technique,
which is the preferred method in complex algorithm
development, in combination with Markov chain Monte
Carlo simulations.45–49 From the algorithm, a working
prototype of the tool will be developed (part two) as a
proof of concept. Correspondence to Dr Zobaida Edib; zedib@student.unimelb.edu.au 1 Edib Z, et al. BMJ Open 2020;10:e033669. doi:10.1136/bmjopen-2019-033669 Open access amenorrhoea after treatment.29 34 35 However, no previous
studies have included baseline demographic and lifestyle
factors, as well as serum ovarian markers and cancer treat-
ment factors, all together, to predict fertility. To address
this gap, we are developing the fertility after cancer
predictor (FoRECAsT) tool for young patients with breast
cancer which considers both baseline fertility indicators
and the impact of planned cancer treatment on fertility. Based on the input information, it will provide an individ-
ualised risk of amenorrhoea at different time points after
initial treatment (12 months, 24 months, 36 months, 48
and 60 months) to assess longitudinal changes in infer-
tility risk, with amenorrhoea being a surrogate marker
for infertility. The tool will allow users to input individual
data (baseline demographic and lifestyle factors, serum
ovarian markers and recommended breast cancer treat-
ment) to determine a personalised risk of infertility after
breast cancer treatment. commonly present as amenorrhoea (ie, cessation of the
menstrual cycle).8 Infertility and/or early menopause is a
recognised long-term adverse effect of breast cancer treat-
ment in premenopausal women and has serious implica-
tions for the survivorship experience of these women.8 9 p
p
Fertility is well established to be a priority for many
young premenopausal patients with breast cancer. Objectives The main purpose of this study is to explore percep-
tions, ideas and opinions from young patients with breast
cancer and clinicians regarding the design and feasibility
of implementing the FoRECAsT tool including barriers
and facilitators. Findings will also inform breast cancer
patients’ and clinicians’ preferences of where and when
the FoRECAsT tool might be used. Study participants/stakeholders The following stakeholders are included in our study:
a. Patient group: 15–20 patients with breast cancer. The following stakeholders are included in our study:
P ti
t
15 20
ti
t
ith b
t The following stakeholders are included in our study:
a. Patient group: 15–20 patients with breast cancer. b. Clinician group: Figure 1 Illustration of the recruitment of patients with
breast cancer. ––
15–20 breast surgeons. ––
15–20 breast medical oncologists. ––
15–20 breast care nurses. Methods and analysis
Study design A cross-sectional exploratory study is being conducted
through semistructured in-depth telephone interviews
with key stakeholders. Patients with breast cancer
Inclusion criteria Inclusion criteria To be eligible to participate patients with breast cancer
must be (1) female, (2) diagnosed within the last 5 years. (3) aged 18–40 years (4) premenopausal at breast
cancer diagnosis (5) have evidence of prior discussion
with a healthcare provider about the risk of developing
infertility after breast cancer treatment either through
referral to a fertility specialist or documented discussion
inpatient notes (so as not to cause distress in those who
had not had a prior discussion about potential infertility),
(6) concerned about future fertility after chemotherapy
and/or have not completed their family (as identified by
the treatment team), (7) able to give informed written
consent and (8) able to speak and understand English. Figure 2 Illustration of the recruitment of clinicians. Recruitment ––
15–20 fertility specialists. Recruitment started in September 2018 and is still
ongoing. As per qualitative methodology, participants
will continue to be recruited until informational redun-
dancy is achieved. Patients with breast cancer are being
recruited using purposive sampling by the breast care
nurses from the joint Breast Service of Peter MacCallum
Cancer Centre, Royal Melbourne Hospital and Royal
Women’s Hospital. Figure 1 illustrates the recruitment of
patients with breast cancer. Clinicians are being recruited
using an e-flyer through their respective online commu-
nities across Australia (except northern territory and
Tasmania due to ethics committee coverage), that is,
Breast Surgeons of Australia and New Zealand, Medical
Oncology Group of Australia, Fertility Society of Australia,
Cancer Nurses Society of Australia and McGrath Founda-
tion. Figure 2 shows the recruitment of clinicians. Partic-
ipation is voluntary, and participants may choose not to ––
15–20 fertility preservation nurses. The sample size is an appropriate minimum sample
required for meaningful outcomes. However, as per
qualitative methodology, participants will continue to be
recruited until informational redundancy is achieved.50 Open access
Figure 1 Illustration of the recruitment of patients with
breast cancer. Open access Exclusion criteria Women with metastatic breast cancer and women diag-
nosed with gestational breast cancer. Correspondence to To achieve part 2 and ensure that the
tool is widely used clinically to facilitate oncofertility
decision making, the user interface will be developed in
consultation with stakeholders including patients and
patient advocacy groups. This protocol reports on a key
aspect of this consultation process. Findings from this
part of the study will be used to design the user interface
of the FoRECAsT (prototype) tool ensuring it is easy to
use and understand. There are successive steps to validate
the predictive algorithm and evaluate the tool prior to
implementation in clinical practice. Accurate prediction of infertility after breast cancer
treatment is complex and requires consideration of
baseline fertility and the likely impact of planned cancer
treatments on fertility.28 There is growing evidence
that baseline fertility indicators prior to breast cancer
treatment may predict the likelihood of developing 2
Edib Z, et al. BMJ Open 2020;10:e033669. doi:10.1136/bmjopen-2019-033669
Table 1 Candidate predictors for fertility
Lifestyle factors
Age, race, body mass index, diet, exercise, smoking, alcohol, caffeine, drugs. Medical history
Prior (in)fertility and IVF, menstruation history, tubal and gynaecological disease, endometriosis,
polycystic ovary syndrome, sexually transmitted infections, pelvic surgery, family history of (in)fertility and
menopause. Serum markers of
ovarian function
Follicle stimulating hormone, luteinising hormone, estradiol, inhibin B, antimullerian hormone, antral follicle
count, ovarian volume. Cancer factors
Age at diagnosis, stage, receptor status, type of treatment (dose and duration). IVF, in vitro fertilization. 2 Data collection 2. Access and confidentiality. In-depth telephone interviews are guided by semistruc-
tured interview schedules and carried out by the research
team. Consented participants are asked to review the
draft FoRECAsT tool to provide their feedback. The inter-
view schedules are structured in consultation with clin-
ical experts and qualitative research specialists based on
Aizen’s theory of planned behaviour.51 They are custom-
ised to the level of stakeholders to allow questioning
strategy and conversations to be more flexible. 3. User attributes. 4. The potential impact of the tool on consultation. 5. Anticipated outcomes and benefits. Data analysis The processes of data collection and data analysis are
ongoing. Transcripts are being imported into a qualita-
tive data analysis software (QRS NVivo V.12—QRS Inter-
national, Doncaster, Victoria, Australia) to facilitate data
management and analyses. The five broad areas are devel-
oped based on the theoretical framework of planned
behaviour.51 Transcripts are coded line-by-line identifying
keywords, concepts and reflections in accordance with
the framework of Miles and Huberman,52 a widely used
framework for qualitative research methodology. Coding
is being conducted using an iterative process: starting
with coding for broad themes, before coding into hierar-
chical categories and subthemes. gy
Each interview is anticipated to last for 15–20 min. Inter-
views are audio recorded on a portable, electronic digital
voice recorder (Olympus VN-731PC) and transcribed
verbatim. The audio recordings and transcripts have
been securely stored in a password-protected folder on
The University of Melbourne server with access permitted
to authorised personnel only. Verbal informed consents
are obtained for audio recording the interview. Interviews
will be conducted until saturation is reached.50 Patients
and clinicians who consent to be interviewed have been
offered the opportunity to view a copy of the transcripts
prior to data analysis. g
To ensure the integrity and consistency of the codes
and reduce bias, codes will be reviewed by the qualitative
research specialist. The research team will discuss the
coding tree and reach consensus. Subsequently, content
analysis will also be performed for each code, to support
results from thematic analyses by identifying essential
aspects of the content and highlighting the recurrence of
themes, to present results clearly and effectively. A final
list of themes and subthemes will be determined through
patterns as soon as further data that will emerge from the
study add little to the emerging theory. Theoretical satu-
ration is reached once no new themes emerge. Results
will be reported according to the consolidated criteria
for reporting qualitative research developed by Tong et
al.53 Patient and public involvement The study is supported by a consumer/patient who is a
part of the working party and involved in the design of
the study, and preparation of all the study materials from
the patient’s perspective. All interested participants will
be sent a summary report of the results via email or mail
with deidentified aggregated findings. Inclusion criteria To be eligible to participate clinicians who: (1) have a
valid Australian License for practice, (2) have at least
1 year of clinical experience in their respective discipline,
(3) consult to women with breast cancer, (4) will be able
to give informed written consent and (5) will able to
speak and understand English. Figure 2 Illustration of the recruitment of clinicians. Figure 2 Illustration of the recruitment of clinicians. 3 Edib Z, et al. BMJ Open 2020;10:e033669. doi:10.1136/bmjopen-2019-033669 Open access stage of cancer, relationship status and fertility history. Clinicians are asked about their age, years of clinical
experience and proportion of patients seen with breast
cancer. participate in the study or may withdraw from the study at
any time. There will be an opportunity for participants to
ask the research team any questions regarding the study. Invited participants, who do not respond, will be followed
up with a second invitation 2 weeks after initial contact. participate in the study or may withdraw from the study at
any time. There will be an opportunity for participants to
ask the research team any questions regarding the study. Invited participants, who do not respond, will be followed
up with a second invitation 2 weeks after initial contact. Qualitative data are focusing on five topics (table 2): Qualitative data are focusing on five topics (table 2): 1. Interest in using the tool. Twitter Patrick Pang @docpang Acknowledgements MP and YJ both are currently supported by an MDHS
Fellowship, The University of Melbourne. At the time of this study, MP was
supported by a National Breast Cancer Foundation Early Career Fellowship (ECF-
15-005). MH is supported by a National Health and Medical Research Council of
Australia (NHMRC) Practitioner Fellowship and is part of the Women Choosing
Surgical Prevention (WISP) investigator team funded by Stand Up to Cancer. The
authors would like to thank FoRECAsT Consortium for contributing their datasets to
develop the infertility risk prediction algorithm. Collaborators FoRECAsT Consortium: Dr Michelle Peate, Dr Zobaida Edib, Prof
Martha Hickey, Dr Yasmin Jayasinghe, Dr Shanton Chang, Dr Patrick Pang, Prof
John Hopper, Dr Kevin Nguyen, Dr. Gillian Dite, Prof Uwe Aickelin, Xuetong Wu, Dr
Hadi Akbarzadeh Khorshidi, Prof Ann Partridge, Dr Fabien Reyal, Ms Franca Agresta,
Dr Genia Rozen, A/Prof Kate Stern, Dr Wanda Cui, Prof Kelly-Anne Phillips, Dr Laura
Chin-Lenn, Dr Lesley Stafford, Dr Anne-Sophie Hamy, Dr Antoinette Anazodo, A/
Prof H. Irene Su, Prof Richard Anderson, Prof Scott Nelson, Ms Alexandra Gorelik,
Prof Liz Sullivan, Dr Alessandro Minisini, Prof Fabio Puglisi, Dr. Claudia Bozza, Prof
Christobel Saunders, Dr Kathryn J. Ruddy, Dr Fergus J. Couch, Dr Janet E. Olson,
Dr Isabelle Demeestere, Dr Margherita Condorelli, Dr Matteo Lambertini, Dr Michail
Ignatiadis,Dr Barbara Pistilli, Ms Mary Macheras-Magias. Dissemination 19School of Behavioural and Health Sciences, Australian Catholic University,
Melbourne, Victoria, Australia 19School of Behavioural and Health Sciences, Australian Catholic University,
Melbourne, Victoria, Australia Only deidentified results will be published. The results
will be actively disseminated through peer-reviewed schol-
arly and scientific journals, national and international
conference presentations, social media, broadcast media,
print media, internet and various community/stake-
holder engagement activities. The consumer/patient will
also provide comment on the findings and contribute
to the dissemination plan via consumer websites such as
Breast Cancer Network Australia. Melbourne, Victoria, Australia Open access Author affiliations
1Obstetrics & Gynaecology, The University of Melbourne, Melbourne, Victoria,
Australia
2Obstetrics & Gynaecology, The Royal Women's Hospital, Parkville, Victoria, Australia
3Department of Paediatric and Adolescent Gynaecology, The Royal Children's
Hospital, Parkville, Victoria, Australia
4Melbourne School of Psychological Sciences, The University of Melbourne,
Melbourne, Victoria, Australia
5Centre for Women’s Mental Health, The Royal Women's Hospital, Parkville, Victoria,
Australia
6MRC Centre for Reproductive Health, The University of Edinburgh, Edinburgh, UK
7Department of Obstetrics, Gynecology and Reproductive Sciences, University of
California San Diego, San Diego, California, USA
8Melbourne IVF, East Melbourne, Victoria, Australia
9Reproductive Services, The Royal Women's Hospital, Parkville, Victoria, Australia
10School of Surgery, The University of Western Australia, Perth, Western Australia,
Australia
11Sydney Children's Hospital, School of Women’s and Children’s Health, UNSW,
Sydney, New South Wales, Australia
12Nelune Comprehensive Cancer Centre, Prince of Wales Children's Hospital,
Randwick, New South Wales, Australia
13Breast Cancer Network Australia, Camberwell, Victoria, Australia
14School of Computing and Information Systems, The University of Melbourne,
Melbourne, Victoria, Australia
15Department of General Surgery, The Royal Melbourne Hospital, Melbourne,
Victoria, Australia
16Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne,
Victoria, Australia
17Breast Service, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
18Department of Medicine, The Royal Melbourne Hospital, The University of
Melbourne, Melbourne, Victoria, Australia
19School of Behavioural and Health Sciences, Australian Catholic University,
Melbourne, Victoria, Australia Confidentiality Confidentiality and privacy are maintained at every stage
of the study. Individual participants will not be identifi-
able to any other members of their group or anyone else
in the wider community. Participants are approached,
recruited and contacted in a confidential, one-to-one
manner and no public dissemination of participants’
details will occur. Contact details for the researchers and
relevant ethics committee(s) are provided to address
any questions or concerns participants may have. Audio
recordings and individual transcripts are being stored
on a password protected and secured The University of
Melbourne server, which is backed up daily. Study-related
records will be retained in a secure storage facility for
at least 7 years after the completion of the research as
required by the Australian National Health and Medical
Research Council. 6MRC Centre for Reproductive Health, The University of Edinburgh, Edinburgh, UK 7Department of Obstetrics, Gynecology and Reproductive Sciences, University of
C lif
i S
Di
S
Di
C lif
i
USA California San Diego, San Diego, California, USA 8Melbourne IVF, East Melbourne, Victoria, Australia 9Reproductive Services, The Royal Women's Hospital, Parkville, Victoria, Australia
10School of Surgery, The University of Western Australia, Perth, Western Australia,
Australia 10School of Surgery, The University of Western Australia, Perth, Western Australia,
Australia 11Sydney Children's Hospital, School of Women’s and Children’s Health, UNSW,
Sydney, New South Wales, Australia 12Nelune Comprehensive Cancer Centre, Prince of Wales Children's Hospital, 13Breast Cancer Network Australia, Camberwell, Victoria, Australia
14 14School of Computing and Information Systems, The University of Melbourne,
Melbourne, Victoria, Australia 15Department of General Surgery, The Royal Melbourne Hospital, Melbourne,
Victoria, Australia 16Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne,
Victoria, Australia 17Breast Service, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
18Department of Medicine The Royal Melbourne Hospital The University of 17Breast Service, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia 17Breast Service, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
18Department of Medicine, The Royal Melbourne Hospital, The University of
Melbourne, Melbourne, Victoria, Australia Breast Service, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
18Department of Medicine, The Royal Melbourne Hospital, The University of
Melbourne, Melbourne, Victoria, Australia Author affiliations 1Obstetrics & Gynaecology, The University of Melbourne, Melbourne, Victoria,
Australia This study will be conducted in compliance with the
National Health and Medical Research Council National
Statement on Ethical Conduct in Human Research, the
Australian Code for the Responsible Conduct of Research
and the Declaration of Helsinki. 2Obstetrics & Gynaecology, The Royal Women's Hospital, Parkville, Victoria, Australia
3Department of Paediatric and Adolescent Gynaecology, The Royal Children's
Hospital, Parkville, Victoria, Australia 4Melbourne School of Psychological Sciences, The University of Melbourne,
Melbourne, Victoria, Australia
5 5Centre for Women’s Mental Health, The Royal Women's Hospital, Parkville, Victoria,
Australia Edib Z, et al. BMJ Open 2020;10:e033669. doi:10.1136/bmjopen-2019-033669 Outcome measures Sociodemographic data are collected from each partici-
pating patient with breast cancer and clinician. Patients
with breast cancer are asked about their current age, the
highest level of education attained, employment status, 4
Edib Z, et al. BMJ Open 2020;10:e033669. doi:10.1136/bmjopen-2019-033669
Table 2 Semistructured interviews topic guides for participants
Broad topics
Specific topics
1. Interest in using the infertility risk
prediction tool
Extent of information received/delivered about risk of infertility, decision making with
*current infertility risk calculator’, perceived satisfaction in using current calculators,
interest in having a more accurate infertility risk prediction tool
2. Access and confidentiality
Requirements around access and user interface, security, confidentiality of input
information, technical skill. 3. User attributes
Perceptions of ease of use and preferences for data entry. 4. Impact on fertility consultation
Perceptions of impact on fertility consultation. 5. Anticipated outcomes and benefits
Benefits of using a more accurate tool, barriers and additional suggestions to better
meet fertility-related needs. *Current infertility risk calculator’ refers to the commonly used existing calculator for fertility risk prediction following breast cancer
treatment.27 4
Edib Z, et al. BMJ Open 2020;10:e033669. doi:10.1136/bmjopen-2019-033669
Table 2 Semistructured interviews topic guides for participants
Broad topics
Specific topics
1. Interest in using the infertility risk
prediction tool
Extent of information received/delivered about risk of infertility, decision making with
*current infertility risk calculator’, perceived satisfaction in using current calculators,
interest in having a more accurate infertility risk prediction tool
2. Access and confidentiality
Requirements around access and user interface, security, confidentiality of input
information, technical skill. 3. User attributes
Perceptions of ease of use and preferences for data entry. 4. Impact on fertility consultation
Perceptions of impact on fertility consultation. 5. Anticipated outcomes and benefits
Benefits of using a more accurate tool, barriers and additional suggestions to better
meet fertility-related needs. *Current infertility risk calculator’ refers to the commonly used existing calculator for fertility risk prediction following breast cancer
treatment.27 Table 2 Semistructured interviews topic guides for participants Edib Z, et al. BMJ Open 2020;10:e033669. doi:10.1136/bmjopen-2019-033669 4 References Cell Death Dis 2018;9:618. y
7 Findlay JK, Hutt KJ, Hickey M, et al. What is the “ovarian reserve”? Fertil Steril 2015;103:628–30. 33 Benedict C, Thom B, N. Friedman D, et al. Young adult female cancer
survivors' unmet information needs and reproductive concerns
contribute to decisional conflict regarding posttreatment fertility
preservation. Cancer 2016;122:2101–9. 8 Jayasinghe YL, Wallace WHB, Anderson RA. Ovarian function,
fertility and reproductive lifespan in cancer patients. Expert Rev
Endocrinol Metab 2018;13:125–36. 9 Anderson RA, Brewster DH, Wood R, et al. The impact of cancer on
subsequent chance of pregnancy: a population-based analysis. Hum
Reprod 2018;33:1281–90. p
34 D'Avila Ângela Marcon, Biolchi V, Capp E, et al. Age, anti-
Müllerian hormone, antral follicles count to predict amenorrhea
or oligomenorrhea after chemotherapy with cyclophosphamide. J
Ovarian Res 2015;8:82. p
10 Ruddy KJ, Gelber SI, Tamimi RM, et al. Prospective study of fertility
concerns and preservation strategies in young women with breast
cancer. J Clin Oncol 2014;32:1151–6. 35 Su H-CI, Haunschild C, Chung K, et al. Prechemotherapy
antimullerian hormone, age, and body size predict timing of
return of ovarian function in young breast cancer patients. Cancer
2014;120:3691–8. p
g
cancer. J Clin Oncol 2014;32:1151–6. 11 Lambertini M, Goldrat O, Clatot F, et al. Controversies about fertility
and pregnancy issues in young breast cancer patients. Curr Opin
Oncol 2017;29:243–52. 36 Liem GS, Mo FKF, Pang E, et al. Chemotherapy-Related amenorrhea
and menopause in young Chinese breast cancer patients: analysis
on incidence, risk factors and serum hormone profiles. PLoS One
2015;10:e0140842. 12 Taylan E, Oktay KH. Current state and controversies in fertility
preservation in women with breast cancer. World J Clin Oncol
2017;8:241. 13 Cooke A, Mills TA, Lavender T. ‘Informed and uninformed decision
making’—Women's reasoning, experiences and perceptions with
regard to advanced maternal age and delayed childbearing: A meta-
synthesis. Int J Nurs Stud 2010;47:1317–29. 37 Anderson RA, Cameron DA. Pretreatment serum anti-Müllerian
hormone predicts long-term ovarian function and bone mass after
chemotherapy for early breast cancer. J Clin Endocrinol Metab
2011;96:1336–43. y
14 Peate M, Meiser B, Hickey M, et al. The fertility-related concerns,
needs and preferences of younger women with breast cancer: a
systematic review. Breast Cancer Res Treat 2009;116:215–23. 38 Partridge A, Gelber S, Gelber RD, et al. Age of menopause among
women who remain premenopausal following treatment for early
breast cancer: long-term results from international breast cancer
Study Group trials V and VI. Eur J Cancer 2007;43:1646–53. References 15 Avis NE, Crawford S, Manuel J. Psychosocial problems
among younger women with breast cancer. Psychooncology
2004;13:295–308. Study Group trials V and VI. Eur J Cancer 2007;43:1646 39 Minisini AM, Menis J, Valent F, et al. Determinants of recovery from
amenorrhea in premenopausal breast cancer patients receiving
adjuvant chemotherapy in the taxane era. Anticancer Drugs
2009;20:503–7. ;
16 Partridge AH, Gelber S, Peppercorn J, et al. Web-based survey of
fertility issues in young women with breast cancer. J Clin Oncol
2004;22:4174–83. 40 Nelson SM, Yates RW, Fleming R. Serum anti-Mullerian hormone
and FSH: prediction of live birth and extremes of response in
stimulated cycles implications for individualization of therapy. Human
Reproduction 2007;22:2414–21. 17 Peate M, Meiser B, Friedlander M, et al. It's now or never: fertility-
related knowledge, decision-making preferences, and treatment
intentions in young women with breast cancer--an Australian fertility
decision aid collaborative group study. J Clin Oncol 2011;29:1670–7. 41 Hamy A-S, Porcher R, Cuvier C, et al. Ovarian reserve in breast
cancer: assessment with anti-Müllerian hormone. Reprod Biomed
Online 2014;29:573–80. g
p
y
18 Peate M, Meiser B, Cheah BC, et al. Making hard choices easier: a
prospective, multicentre study to assess the efficacy of a fertility-
related decision aid in young women with early-stage breast cancer. Br J Cancer 2012;106:1053–61. 42 Leonard RCF, Adamson DJA, Bertelli G, et al. Gnrh agonist for
protection against ovarian toxicity during chemotherapy for early
breast cancer: the Anglo Celtic group option trial. Ann Oncol
2017;28:1811–6. 19 Lambertini M, Pinto AC, Del Mastro L. Fertility issues in young breast
cancer patients: what women want. J Thorac Dis 2014;6:584. 20 Llarena NC, Estevez SL, Tucker SL, et al. Impact of fertility
concerns on tamoxifen initiation and persistence. J Natl Cancer Inst
2015;107:djv202. 43 Pistilli B, Mazouni C, Zingarello A, et al. Individualized prediction of
menses recovery after chemotherapy for early-stage breast cancer: a
nomogram developed from UNICANCER PACS04 and PACS05 trials. Clin Breast Cancer 2019;19:63–70. 43 Pistilli B, Mazouni C, Zingarello A, et al. Individualized prediction of
menses recovery after chemotherapy for early-stage breast cancer: a
nomogram developed from UNICANCER PACS04 and PACS05 trials. Clin Breast Cancer 2019;19:63–70. j
21 Pala Şehmus, Atilgan R, Ozkan ZS, et al. Effect of varying doses of
tamoxifen on ovarian histopathology, serum VEGF, and endothelin 1 j
21 Pala Şehmus, Atilgan R, Ozkan ZS, et al. Strengths and limitations of this study This will be the first personalised tool considering base-
line demographic and lifestyle factors, serum ovarian
markers and cancer treatment factors all together in
predicting the impact of breast cancer treatments on
fertility. Strengths of this study include codesign the tool
with patients’ and healthcare professionals’ needs and
preferences in mind. This tool could potentially be imple-
mented globally with adaptation to newer breast cancer
treatment. Additionally, the tool could be adapted for
other cancer treatments. Contributors MP conceived the research idea, participated in the design of the
study, development of all study documents, ethical approval process and reviewed
this manuscript. ZE participated in the design of the study, development of all
study documents, ethical approval process, study coordination and drafted this
manuscript. YJ participated in the design of the study, development of all study
documents and reviewed this manuscript. MH, LS, RAA, HIS, KS, CS, AA, MM-M, SC,
PP and FA participated in the review of all study documents and the manuscript. LC-L and SP participated in ethics approval process and reviewed the manuscript. WC and AG reviewed the manuscript. All authors read and approved the final
manuscript. Limitations include the use of non-probability sampling
to recruit patients with breast cancer, which may increase
selection bias.54 Recruitment is limited to patients with
breast cancer where fertility was discussed prior to cancer
treatment and our findings may not be applicable to
circumstances where fertility was not discussed. Also, our
findings cannot be generalised to patients with breast
cancer from more diverse cultural and linguistic back-
grounds and those with advanced breast cancer. Funding This Research Project/Program was supported by the Victorian
Government through a Victorian Cancer Agency (Early Career Seed Grant) awarded
to Dr Peate. Competing interests None declared. Competing interests None declared. 5 Edib Z, et al. BMJ Open 2020;10:e033669. doi:10.1136/bmjopen-2019-033669 ORCID iD Zobaida Edib http://orcid.org/0000-0001-7381-7351 Zobaida Edib http://orcid.org/0000-0001-7381-7351 27 LIVESTRONG fertility risk tool, 2017. Available: https://www.
livestrong.org/we-can-help/livestrong-fertility 28 Peate M, Stafford L, Hickey M. Fertility after breast cancer and
strategies to help women achieve pregnancy. Cancer Forum
2017;41. Open access Patient consent for publication Not required. levels in ovarian hyperstimulation syndrome: an experimental study. Drug Des Devel Ther 2015;9:1761. levels in ovarian hyperstimulation syndrome: an experimental study. Drug Des Devel Ther 2015;9:1761. Patient consent for publication Not required. Ethics approval The study protocol has been reviewed and approved by the
Human Research Ethics Committee of the Melbourne Health, Australia (HREC
number: 2017.163). g
22 Barcroft J, Dayoub N, Thong KJ. Fifteen year follow-up of embryos
cryopreserved in cancer patients for fertility preservation. J Assist
Reprod Genet 2013;30:1407–13. p
;
23 Dondorp W, de Wert G, Pennings G, et al. Oocyte cryopreservation
for age-related fertility loss. Hum Reprod 2012;27:1231–7. Provenance and peer review Not commissioned; externally peer reviewed. References 29 Anderson RA, Rosendahl M, Kelsey TW, et al. Pretreatment
anti-Müllerian hormone predicts for loss of ovarian function
after chemotherapy for early breast cancer. Eur J Cancer
2013;49:3404–11. 1 Franasiak JM, Scott RT. Demographics of cancer in the reproductive
age female. cancer and fertility. Springer, 2016: 11–19. 1 Franasiak JM, Scott RT. Demographics of cancer in the reproductive
age female. cancer and fertility. Springer, 2016: 11–19. 2 Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and
mortality worldwide: sources, methods and major patterns in
GLOBOCAN 2012. Int J Cancer 2015;136:E359–86. 2 Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and
mortality worldwide: sources, methods and major patterns in
GLOBOCAN 2012. Int J Cancer 2015;136:E359–86. 30 Anderson RA, Mansi J, Coleman RE, et al. The utility of anti-Müllerian
hormone in the diagnosis and prediction of loss of ovarian function
following chemotherapy for early breast cancer. Eur J Cancer
2017;87:58–64. 3 Australian Institute of Health and Welfare. Cancer in Australia 2017. Cancer series no.101. Cat. no. CAN 100. Canberra: AIHW, 2017. 3 Australian Institute of Health and Welfare. Cancer in Australia 2017. Cancer series no.101. Cat. no. CAN 100. Canberra: AIHW, 2017. ,
4 Australian Institute of Health and Welfare. Cancer in Australia 2019. Cancer series no.119. Cat. no. CAN 123. Canberra: AIHW, 2019. 4 Australian Institute of Health and Welfare. Cancer in Australia 2019. Cancer series no.119. Cat. no. CAN 123. Canberra: AIHW, 2019. 31 Lee K, Hoti K, Hughes JD, et al. Dr Google and the consumer: a
qualitative study exploring the navigational needs and online health
information-seeking behaviors of consumers with chronic health
conditions. J Med Internet Res 2014;16:e262. 5 Codacci-Pisanelli G, Del Pup L, Del Grande M, et al. Mechanisms of
chemotherapy-induced ovarian damage in breast cancer patients. Crit Rev Oncol Hematol 2017;113:90–6. 5 Codacci-Pisanelli G, Del Pup L, Del Grande M, et al. Mechanisms of
chemotherapy-induced ovarian damage in breast cancer patients. Crit Rev Oncol Hematol 2017;113:90–6. 6 Nguyen Q-N, Zerafa N, Liew SH, et al. Loss of PUMA protects the
ovarian reserve during DNA-damaging chemotherapy and preserves
fertility. Cell Death Dis 2018;9:618. 32 Pang PC-I, Chang S, Verspoor K, et al. Designing Health Websites
Based on Users’ Web-Based Information-Seeking Behaviors:
A Mixed-Method Observational Study. J Med Internet Res
2016;18:e145. 6 Nguyen Q-N, Zerafa N, Liew SH, et al. Loss of PUMA protects the
ovarian reserve during DNA-damaging chemotherapy and preserves
fertility. Edib Z, et al. BMJ Open 2020;10:e033669. doi:10.1136/bmjopen-2019-033669 Provenance and peer review Not commissioned; externally peer reviewed. Open access This is an open access article distributed in accordance with the
Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which
permits others to distribute, remix, adapt, build upon this work non-commercially,
and license their derivative works on different terms, provided the original work is
properly cited, appropriate credit is given, any changes made indicated, and the use
is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/. 24 Li N, Jayasinghe Y, Kemertzis MA, et al. Fertility preservation in
pediatric and adolescent oncology patients: the decision-making
process of parents. J Adolesc Young Adult Oncol 2017;6:213–22. 25 Duffy CM, Allen SM, Clark MA. Discussions regarding reproductive
health for young women with breast cancer undergoing
chemotherapy. J Clin Oncol 2005;23:766–73. 26 Logan S, Perz J, Ussher JM, et al. A systematic review of patient
oncofertility support needs in reproductive cancer patients aged 14
to 45 years of age. Psychooncology 2018;27:401–9. ORCID iD Edib Z, et al. BMJ Open 2020;10:e033669. doi:10.1136/bmjopen-2019-033669 References Effect of varying doses of
tamoxifen on ovarian histopathology, serum VEGF, and endothelin 1 6 Edib Z, et al. BMJ Open 2020;10:e033669. doi:10.1136/bmjopen-2019-033669 Open access 44 Ford JH, MacCormac L. Pregnancy and lifestyle study: the long-term
use of the contraceptive pill and the risk of age-related miscarriage. Hum Reprod 1995;10:1397–402. 44 Ford JH, MacCormac L. Pregnancy and lifestyle study: the long-term
use of the contraceptive pill and the risk of age-related miscarriage. Hum Reprod 1995;10:1397–402. 49 Richter A, Hauber B, Simpson K, et al. A Monte Carlo
simulation for modelling outcomes of AIDS treatment regimens. Pharmacoeconomics 2002;20:215–24.i p
45 Baio G, Dawid AP. Probabilistic sensitivity analysis in health
economics, research report No. 292. London: Department of
Statistical Science, University College London, 2011. 50 Morse JM. The significance of saturation. Thousand Oaks: Sage
Publications, 1995: 147–9. 45 Baio G, Dawid AP. Probabilistic sensitivity analysis in health
economics, research report No. 292. London: Department of
Statistical Science, University College London, 2011. 51 Ajzen I. The theory of planned behavior. Organ Behav Hum Decis
Process 1991;50:179–211. y
g
46 Kreke JE, Schaefer AJ, Roberts MS. Simulation and critical care
modeling. Curr Opin Crit Care 2004;10:395–8. 52 Miles MB, Huberman AM. Qualitative data analysis: an expanded
sourcebook. Sage, 1994. 47 Richter A, Mauskopf JA. Mm1 Monte Carlo simulation in health care
models. Value in Health 1998;1:84–5. 47 Richter A, Mauskopf JA. Mm1 Monte Carlo simulation in health care
models. Value in Health 1998;1:84–5. 53 Tong A, Sainsbury P, Craig J. Consolidated criteria for reporting
qualitative research (COREQ): a 32-item checklist for interviews and
focus groups. Int J Qual Health Care 2007;19:349–57. 48 Sonnenberg FA, Beck JR. Markov models in medical decision
making: a practical guide. Med Decis Making 1993;13:322–38. 48 Sonnenberg FA, Beck JR. Markov models in medical decision
making: a practical guide. Med Decis Making 1993;13:322–38. g
p
;
54 Mays N, Pope C. Qualitative research: rigour and qualitative
research. BMJ 1995;311:109–12. g
p
54 Mays N, Pope C. Qualitative research: rigour and qualitative
research. BMJ 1995;311:109–12. Edib Z, et al. BMJ Open 2020;10:e033669. doi:10.1136/bmjopen-2019-033669 7
|
https://openalex.org/W2523202475
|
https://www.duo.uio.no/bitstream/10852/53432/1/Steens_2016_In.pdf
|
English
| null |
In vitroandin vivocomparison of transport media for detecting nasopharyngeal carriage ofStreptococcus pneumoniae
|
PeerJ
| 2,016
|
cc-by
| 4,805
|
In vitro and in vivo comparison of
transport media for detecting
nasopharyngeal carriage of Streptococcus
pneumoniae Anneke Steens1,2, Natacha Milhano1,3, Ingeborg S. Aaberge1 and
Didrik F. Vestrheim1 1 Infection Control and Environmental Health, Norwegian Institute of Public Health, Oslo, Norway
2 Faculty of Medicine, University of Oslo, Oslo, Norway
3 European Programme for Public Health Microbiology Training (EUPHEM), European Centre for Disease
Prevention and Control (ECDC), Stockholm, Sweden 1 Infection Control and Environmental Health, Norwegian Institute of Public Health, Oslo, Norway
2 Faculty of Medicine, University of Oslo, Oslo, Norway
3 E
P
f
P bli H
l h Mi
bi l
T
i i
(EUPHEM) E
C
f
Di 3 European Programme for Public Health Microbiology Training (EUPHEM), European Centre for Disease
Prevention and Control (ECDC), Stockholm, Sweden Subjects Microbiology, Infectious Diseases
Keywords Streptococcus pneumoniae, Nasopharyngeal carriage, Transport media, In vivo and in
vitro comparison, Carriage study, Pneumococcus ABSTRACT Background. As a standard method for pneumococcal carriage studies, the World
Health Organization recommends nasopharyngeal swabs be transported and stored at
cool temperatures in a medium containing skim-milk, tryptone, glucose and glycerol
(STGG). An enrichment broth used for transport at room temperature in three carriage
studies performed in Norway may have a higher sensitivity than STGG. We therefore
compared the media in vitro and in vivo. Methods. For the in vitro component, three strains (serotype 4, 19F and 3) were
suspended in STGG and enrichment broth. Recovery was compared using latex
agglutination, quantification of bacterial loads by real-time PCR of the lytA gene, and
counting colonies from incubated plates. For the in vivo comparison, paired swabs
were obtained from 100 children and transported in STGG at cool temperatures or in
enrichment broth at room temperature. Carriage was identified by latex agglutination
and confirmed by Quellung reaction. Results. In vitro, the cycle threshold values obtained by PCR did not differ between
the two media (p = 0.853) and no clear difference in colony counts was apparent
after incubation (p = 0.593). In vivo, pneumococci were recovered in 46% of swabs
transported in STGG and 51% of those transported in enrichment broth (Kappa statistic
0.90, p = 0.063). Submitted 27 June 2016
Accepted 15 August 2016
Published 22 September 2016
Corresponding author
Anneke Steens, anneke.steens@fhi.no
Academic editor
Luc Van Kaer
Additional Information and
Declarations can be found on
page 7
DOI 10.7717/peerj.2449
Copyright
2016 Steens et al. Distributed under
Creative Commons CC-BY 4.0 Submitted 27 June 2016
Accepted 15 August 2016
Published 22 September 2016
Corresponding author
Anneke Steens, anneke.steens@fhi.no
Academic editor
Luc Van Kaer
Additional Information and
Declarations can be found on
page 7
DOI 10.7717/peerj.2449
Copyright
2016 S
l Discussion. Overall, no statistical differences in sensitivity were found between
STGG and enrichment broth. Nevertheless, some serotype differences were observed
and STGG appeared slightly less sensitive than enrichment broth for detection of
nasopharyngeal carriage of pneumococci by culturing. We recommend the continued
use of STGG for transport and storage of nasopharyngeal swabs in pneumococcal
carriage studies for the benefit of comparability between studies and settings, including
more resource-limited settings. Subjects Microbiology, Infectious Diseases
Keywords Streptococcus pneumoniae, Nasopharyngeal carriage, Transport media, In vivo and in
vitro comparison, Carriage study, Pneumococcus Distributed under
Creative Commons CC-BY 4.0 How to cite this article Steens et al. How to cite this article Steens et al. (2016), In vitro and in vivo comparison of transport media for detecting nasopharyngeal carriage of
Streptococcus pneumoniae. PeerJ 4:e2449; DOI 10.7717/peerj.2449 INTRODUCTION Monitoring carriage of Streptococcus pneumoniae (pneumococci) is important for
determining changes after vaccine introduction in national immunisation programmes. To enable comparison of results from different studies and countries, the World Health
Organization Pneumococcal Carriage Working Group published a set of standard methods
for such studies measuring nasopharyngeal carriage of pneumococci (Satzke et al., 2013). A
medium containing skim milk powder, tryptone soy broth, glucose and glycerol in distilled
water (STGG) is recommended for transport and storage of nasopharyngeal specimens, and
transport should be done at cool temperatures (O’Brien et al., 2001). Studies using STGG
in developed countries have generally revealed prevalences of pneumococcal carriage in
children of around 30–50% (Andrade et al., 2014; Van Hoek et al., 2014; Desai et al., 2015). In Norway, several carriage studies have been performed using enrichment broth (beef
infusion enriched with 5% horse serum and 3.3% defibrinated horse blood (Kaltoft et al.,
2008); Statens Serum Institute, Copenhagen, Denmark) for transport at room temperature. Carriage prevalence in those studies was around 80% before and after introduction of the
7-valent pneumococcal conjugate vaccine (PCV), and 62% two years after switching to the
13-valent PCV (Steens et al., 2015). Although different factors may contribute to this high
prevalence, such as the percentage of children in day-care (>90% (Statistics Norway, 2010))
and the low use of antibiotics in Norway (Garcia-Rodriguez & Fresnadillo Martinez, 2002;
Norwegian Veterinary Institute, 2014), results suggest that enrichment broth transported at
room temperature may be more sensitive for detection of carriage than STGG transported
at cool temperatures. We therefore compared (1) in vitro recovery from serial dilutions in STGG and
enrichment broth and (2) in vivo detection of nasopharyngeal carriage of pneumococci
from swabs that were transported and stored in STGG at cool temperatures or in enrichment
broth at room temperature. ABSTRACT (2016), In vitro and in vivo comparison of transport media for detecting nasopharyngeal carriage of
Streptococcus pneumoniae. PeerJ 4:e2449; DOI 10.7717/peerj.2449 MATERIALS AND METHODS In the in vitro component of the study, we compared recovery rates of pneumococci
from serial dilutions that had been stored at different temperatures and media using (I)
culturing, (II) a commercial latex agglutination kit and (III) quantitative real-time PCR
(qPCR). In the in vivo component, we compared carriage using paired swabs taken from
children attending day-care centres and transported in STGG or enrichment broth. In the
second part, we used methods (I) and (II) for detection of pneumococci. See Fig. 1 for a
schematic overview of the procedures. Note that we followed the recommended conditions
for transport and storage for each medium (wet ice/cool box for STGG and freezing (in
vivo only), room temperature and immediate processing for enrichment broth). Steens et al. (2016), PeerJ, DOI 10.7717/peerj.2449 In vitro comparison Furthermore, 100 µL of the STGG samples was added
to 3ml fresh enrichment broth. All was done in triplicate. Plates and tubes (broth sample
made from the STGG samples and the initial enrichment broth samples) were incubated
overnight at 35 ◦C with 5% CO2. Pneumococci were identified by latex agglutination (Pneumotest-Latex kit; Statens
Serum Institut, Denmark; Slotved et al., 2004) from the incubated broths. Quantification
of the bacterial loads was performed by qPCR (see below for details) and counting of the
colony forming units (CFU) from the incubated plates. In vitro comparison Three strains belonging to different serotypes were used as pneumococcal samples; two
reference strains (ATCC49619—serotype 19F, and TIGR4—serotype 4), and a strain
belonging to serotype 3 obtained from the 2013 sample of a previous Norwegian carriage
study (Steens et al., 2015). Colonies from each serotype were suspended in Todd-Hewitt Steens et al. (2016), PeerJ, DOI 10.7717/peerj.2449 2/10 Vortex
and
freeze
at
-‐70°C
Serial
dilu6ons
of
pneumococcal
suspensions
in
TH
broth
100µL
in
1ml
STGG
on
wet
ice
100µL
in
3ml
enrichment
broth
at
room
temperature
TIME
3
hours
Overnight
Day
2
Latex
agglu6na6on
Plate
100µL
on
blood
agar. Incubate
at
35⁰C
Count
colonies
Incubate
in
ini6al
3ml
enrichment
broth
at
35⁰C
Prepare
200µL
sample
for
qPCR
and
freeze
Plate
100µL
on
blood
agar. Incubate
at
35⁰C
Incubate
100µL
in
3ml
enrichment
broth
at
35⁰C
Latex
agglu6na6on
Count
colonies
Prepare
200µL
sample
for
PCR
and
frozen
In
vitro
In
vivo
Nasopharyngeal
swab
2
Thaw
STGG
sample,
and
vortex
Place
in
3ml
enrichment
broth
at
room
temperature
TIME
Within
4
hours
Overnight
Day
2
Latex
agglu6na6on
Plate
the
swab
on
GBA
for
culturing. Incubate
at
35⁰C
Quellung
reac6on
Incubate
in
ini6al
3ml
enrichment
broth
at
35⁰C
Plate
20µL
on
GBA
for
culturing,
Incubate
at
35⁰C
Incubate
200µL
in
3ml
enrichment
broth
at
35⁰C
Latex
agglu6na6on
Quellung
reac6on
Place
in
1ml
STGG
in
a
cool
box
Freeze
for
minimal
18
hours
and
maximal
1
months
Nasopharyngeal
swab
1
qPCR
Figure 1 Schematic overview of the experimental designs. (A) in vitro. (B) in vivo. TH, Todd-Hewitt; STGG, skim milk, tryptone, glucose and
glycerol; GBA, gentamycin-blood-agar. Place
in
3ml
enrichment
broth
at
room
temperature Latex
agglu6na6on Figure 1 Schematic overview of the experimental designs. (A) in vitro. (B) in vivo. TH, Todd-Hewitt; STGG, skim milk, tryptone, glucose and
glycerol; GBA, gentamycin-blood-agar. (TH) broth at a concentration of 0.5 McFarland in serial 1:10 dilutions of 10−2 to 10−5
(minimal concentration for which recovery of pneumococcal DNA was possible; see
Supplemental Information 3). A volume of 100 µL of serotype dilution in TH broth was
added to each set of transport media (either 1 ml of STGG or 3 ml of enrichment broth)
to prepare the pneumococcal samples. The samples were left for 3 h on wet ice (STGG) or
room temperature (enrichment broth). Subsequently, 100 µL of the samples was plated on
Columbia horse blood agar plates. Steens et al. (2016), PeerJ, DOI 10.7717/peerj.2449 DNA extraction and amplification by qPCR From each sample 200 µL was boiled for 10 min and DNA was extracted by QIAamp
DNA Mini QIAcube kit (Qiagen, Inc., Valencia, CA, US) according to the manufacturer’s
recommendations. A qPCR assay for the detection of the autolysin-encoding gene (lytA)
was then performed as described before by Carvalho et al. (2007). Briefly, 25 µL reaction
volume composed of TaqMan Fast Universal PCR Master Mix 2x, 200 nM of each primer
and probe, 10x Exo IPC-mix, 50x Exo IPC DNA and 2 µL of DNA was run at 50 ◦C for
2 min, denaturation at 95 ◦C for 10 min, followed by 40 amplification cycles of 95 ◦C
for 15 s and 60 ◦C for 1 min. Samples were considered negative if cycle thresholds (Ct) Steens et al. (2016), PeerJ, DOI 10.7717/peerj.2449 3/10 exceeded 40. A positive (ATCC49619) and a non-template control (sterile water) were
included in each run, along with extraction controls. Data analysis For the in vitro analyses, Ct values and CFU counts (after a logarithmic transformation;
logCFU) from the two media were compared by linear regression. We used 11 mutually
exclusive dummy variables identifying different dilution-serotype combinations, which
enabled us to simultaneously run the comparison for all serotypes. Additionally, the analyses
were conducted separately per serotype. Agreement in the in vivo comparison was determined using the kappa statistic (Landis &
Koch, 1977) and the exact McNemar’s probability test for paired data. Data were analysed
in Stata 14.0 and GraphPad Prism 5. In vivo comparison This comparison was performed as part of a larger carriage study (sample taken in 2015
(Steens et al., 2016)). The study was conducted in accordance with principles of the Decla-
ration of Helsinki, and approved by the Regional Committee for Medical Research Ethics,
South-Eastern Norway (reference number: 2014/2046). Parents/guardians of the children
gave written informed consent before including their child in the study. The study design
resembles the design used in previous Norwegian carriage studies (Steens et al., 2015). Two flocked nylon nasopharyngeal swabs (E-swabsTM, Copan, Italy) taken from the
same nostril were collected from 100 children aged 1–6 years according to standard
procedures. The first swab was placed in 1 ml STGG which was subsequently stored in a
cool box and the second swab was stored and transported in 3 ml enrichment broth at room
temperature. The specimens were processed within 4 h of sampling. The STGG samples
were vortexed at high speed and frozen at −70 ◦C , following the recommendations of
WHO (Satzke et al., 2013). Within one month but earliest 18 h after initial freezing, the
STGG samples were processed further: after being thawed and vortexed, 200 µl was added
to fresh enrichment broth and 20 µl was plated on gentamycin-blood-agar (GBA). The
swabs from the enrichment broth samples were plated on GBA within 4 h of sampling
and the swab was re-inserted into the enrichment broth. All broths and GBA plates were
incubated overnight at 35 ◦C , with 5% CO2. Pneumococci were identified by latex agglutination from incubated broths. Confirma-
tion and factor typing were performed by Quellung reaction. All morphologically different
pneumococcal colonies per plate were typed. In cases where the latex agglutination was
positive but no colonies were found on plates after incubation overnight, samples were
re-cultured by plating one drop of the incubated broth and incubating this for another
night before further analysis. In vitro results (A) serotype 19F; (B) serotype 4; (C) serotype 3. * Uncountable. The quantification of DNA by Ct value is presented in Fig. 2. The Ct values overall
did not differ significantly between STGG and enrichment broth samples (p = 0.853),
though for serotype 4, the Ct values were significantly lower for STGG samples compared
to enrichment broth samples (p = 0.007). After culturing, no clear overall difference was
found in the logCFU (p = 0.593) but significant differences were observed for serotype 4
(Fig. 3B; p = 0.008; more colonies on plates incubated with STGG samples) and serotype 3
(Fig. 3C; p = 0.001; more colonies on plates incubated with enrichment broth samples). In vitro results The latex agglutination test was positive for both media for all serotype dilutions tested,
with the exception of serotype 3 at a dilution of 10−5 in STGG, where no pneumococci
were detected. Steens et al. (2016), PeerJ, DOI 10.7717/peerj.2449 4/10 A
B
C
* #
Enrichment broth
STGG
Figure 2
DNA quantification (Ct values) at different dilutions of enrichment broth and STGG. (A)
serotype 19F*; (B) serotype 4; (C) serotype 3. * At a dilution of 10−5, one of the triplicates had a cycle
threshold (Ct) of 39.4, while the other two were above 40. This sample was therefore considered negative. # Ct above 40. **
A
B
C
Enrichment broth
STGG
**
Figure 3
Quantification of bacterial load (log counts of colony forming units [CFU]) at different dilu-
tions of enrichment broth and STGG. (A) serotype 19F; (B) serotype 4; (C) serotype 3. * Uncountable. A
B
C
* #
Enrichment broth
STGG * #
Figure 2
DNA quantification (Ct values) at different dilutions of enrichment broth and STGG. (A)
serotype 19F*; (B) serotype 4; (C) serotype 3. * At a dilution of 10−5, one of the triplicates had a cycle
threshold (Ct) of 39.4, while the other two were above 40. This sample was therefore considered negative. # Ct above 40. **
A
B
C
Enrichment broth
STGG
**
Figure 3
Quantification of bacterial load (log counts of colony forming units [CFU]) at different dilu-
tions of enrichment broth and STGG. (A) serotype 19F; (B) serotype 4; (C) serotype 3. * Uncountable. Figure 2
DNA quantification (Ct values) at different dilutions of enrichment broth and STGG. (A)
serotype 19F*; (B) serotype 4; (C) serotype 3. * At a dilution of 10−5, one of the triplicates had a cycle
threshold (Ct) of 39.4, while the other two were above 40. This sample was therefore considered negative. # Ct above 40. Figure 2
DNA quantification (Ct values) at different dilutions of enrichment broth and STGG. (A)
serotype 19F*; (B) serotype 4; (C) serotype 3. * At a dilution of 10−5, one of the triplicates had a cycle
threshold (Ct) of 39.4, while the other two were above 40. This sample was therefore considered negative. # Ct above 40. **
A
B
C
Enrichment broth
STGG
** Figure 3
Quantification of bacterial load (log counts of colony forming units [CFU]) at different dilu-
tions of enrichment broth and STGG. Steens et al. (2016), PeerJ, DOI 10.7717/peerj.2449 In vivo results Forty-six percent of the swabs transported and stored in STGG and 51% of those transported
in enrichment broth were positive for pneumococci. This resulted in a Kappa statistic for
carriage of 0.90 for the paired swabs (Table 1), indicating a trend towards higher sensitivity
after transportation in enrichment broth compared to STGG (p = 0.0625). If re-cultured
samples were excluded, carriage was 44% for the samples transported and stored in STGG
and 48% for those transported in enrichment broth (Kappa = 0.92; p = 0.125). For each
child for whom both swabs were positive, the same serotype was obtained. In one child,
carriage of two serotypes was found in the enrichment broth sample, while one serotype
was found in the STGG sample. However, the plate incubated with the enrichment broth Steens et al. (2016), PeerJ, DOI 10.7717/peerj.2449 5/10 Table 1
Pneumococcal carriage determined by culturing paired nasopharyngeal swabs stored in
STGG or enrichment broth. Enrichment broth
Positive
Negative
Total
Positive
46
0
46
STGG
Negative
5
49
54
Total
51
49
100
Notes. STGG, skim milk, tryptone, glucose and glycerol. sample had only one colony of the serotype that was missed in the STGG sample (serotype 3)
and the agglutination test was negative for this serotype, indicating presence at a very
low concentration. Table 1
Pneumococcal carriage determined by culturing paired nasopharyngeal swabs stored in
STGG or enrichment broth. Enrichment broth
Positive
Negative
Total
Positive
46
0
46
STGG
Negative
5
49
54
Total
51
49
100
Notes. STGG, skim milk, tryptone, glucose and glycerol. Table 1
Pneumococcal carriage determined by culturing paired nasopharyngeal swabs stored in
STGG or enrichment broth. Enrichment broth
Positive
Negative
Total
Positive
46
0
46
STGG
Negative
5
49
54
Total
51
49
100
Notes. STGG, skim milk, tryptone, glucose and glycerol. Table 1
Pneumococcal carriage determined by culturing paired nasopharyngeal swabs stored in
STGG or enrichment broth. STGG, skim milk, tryptone, glucose and glycerol. sample had only one colony of the serotype that was missed in the STGG sample (serotype 3)
and the agglutination test was negative for this serotype, indicating presence at a very
low concentration. sample had only one colony of the serotype that was missed in the STGG sample (serotype 3)
and the agglutination test was negative for this serotype, indicating presence at a very
low concentration. Steens et al. (2016), PeerJ, DOI 10.7717/peerj.2449 DISCUSSION Overall, no statistical differences in sensitivity were found between STGG stored and
transported at cool temperatures and enrichment broth transported at room temperature. Nevertheless, some serotype differences were observed as well as a trend towards higher
sensitivity for detection of pneumococcal carriage after transportation in enrichment broth
compared to STGG. There are several possible reasons for these differences. In vitro, a pure dilution of one
serotype was used in place of a nasopharyngeal swab. In vivo the swab contained different
respiratory bacteria and viruses, and was covered with mucus and cellular debris. The
presence of other bacteria places pneumococci in competition for nutrients needed for
growth and reproduction. These nutrients are available in higher concentration in enrich-
ment broth than in STGG, which may explain the small difference in sensitivity observed
between the in vitro and in vivo settings. In addition to the difference in available nutrients
in STGG and enrichment broth, the fact that STGG samples were kept in a cool box during
transport while the enrichment broth samples were kept at room temperature, may have
caused the small non-significant difference in carriage prevalence. The original carriage
study presenting the use of enrichment broth as transport medium used cool transport
conditions (Kaltoft et al., 2008) but three previous Norwegian carriage studies used room
temperature (Steens et al., 2015). The present study is not designed to differentiate between
the effect of media and temperature, but while pneumococci are thought to thrive better
at warmer temperatures, we did not find an overall difference between the methods in
bacterial load or DNA quantity in vitro. Whether the relative abundance of other respiratory
bacteria/the microbiome may have changed and would no longer be representative of the
nasopharyngeal tract after storage at room temperature should be investigated were room
temperature to be used in such studies. Still, for serotype 3, the bacterial load indicated
a higher sensitivity of enrichment broth compared to STGG. The serotype 3 isolate was
obtained from a previous carriage study. For serotype 19F and 4, reference strains were
used. The origin of the isolates (reference strains versus carriage isolate) may have induced
different bacterial growth characteristics. Further, the capsule structure differs between Steens et al. (2016), PeerJ, DOI 10.7717/peerj.2449 6/10 serotypes (serotype 3 being very mucoid). The low number of serotypes tested and the
difference in origin between serotypes are limitations to the in vitro part of this study. DISCUSSION The carriage prevalence found in this study is lower than observed previously in Norway
(Steens et al., 2015), and more similar to what has been seen in other developed countries
(Van Hoek et al., 2014; Desai et al., 2015; Andrade et al., 2014). The methods used for swab
collection, transport and incubation in enrichment broth and culturing were unchanged
from former studies, indicating a real difference in carriage prevalence that may have
resulted from vaccination. Advantages of molecular based techniques compared to culture techniques include the
fact that viable organisms are not required, the original composition of the nasopharyngeal
specimen is preserved, and detailed quantification and characterization of the pneumococci
within a sample are possible, depending on the methods used (Satzke et al., 2013). Furthermore, the sensitivity of molecular methods for detection of multiple co-colonising
serotypes has been shown to be higher than conventional methods (Saha et al., 2015). Nevertheless, isolation of strains enables further characterization such as antimicrobial
susceptibility testing and sequence typing, and should not be replaced by molecular
methods alone, despite its high sensitivity. The additional incubation step and use of
latex agglutination appears to be of value for identification and isolation of pneumococci
from multiple carriage (Kaltoft et al., 2008). The PneuCarriage Project concluded that
microarray with a culture amplification step has the highest sensitivity for determining
carriage (Satzke et al., 2015). Finally, STGG is cheap, easy to make and can be stored longer than enrichment broth,
thus enabling comparability between studies and settings, including more resource-limited
settings. Furthermore, STGG transported and stored at cool temperatures enables studies to
investigate the microbiome (Grijalva et al., 2014; Turner et al., 2011), whereas enrichment
broth may selectively stimulate growth of pneumococci. Therefore, even though STGG ap-
peared slightly less sensitive than enrichment broth for detection of nasopharyngeal carriage
of pneumococci by culturing, we recommend the continued use of STGG for transport
and storage of nasopharyngeal swabs at cool temperatures in future carriage studies. ACKNOWLEDGEMENTS We thank the children and parents for participating and day-care centres workers for
their support. We also thank Anne Ramstad Alme, Gunnhild Rødal, Lene Haakensen,
Anne Witsø and Martha Langedok Bjørnstad for the laboratory analyses, Ingvild Essén
and Kristine Hartmark for the collection of nasopharyngeal swabs, and Richard White for
statistical advice. ADDITIONAL INFORMATION AND DECLARATIONS
Funding
The authors received no funding for this work. Steens et al. (2016), PeerJ, DOI 10.7717/peerj.2449 Funding The authors received no funding for this work. Steens et al. (2016), PeerJ, DOI 10.7717/peerj.2449 Competing Interests The authors declare there are no competing interests. Supplemental Information Supplemental information for this article can be found online at http://dx.doi.org/10.7717/
peerj.2449#supplemental-information. Supplemental information for this article can be found online at http://dx.doi.org/10.7717/
peerj.2449#supplemental-information. Human Ethics The following information was supplied relating to ethical approvals (i.e., approving body
and any reference numbers): The following information was supplied relating to ethical approvals (i.e., approving body
and any reference numbers): Regional Committee for Medical Research Ethics, South-Eastern Norway (REK sør-øst
B) Approval number: 2014/2046. Data Availability The following information was supplied regarding data availability: The following information was supplied regarding data availability: The raw data has been supplied as a Supplementary File. The raw data has been supplied as a Supplementary File. Steens et al. (2016), PeerJ, DOI 10.7717/peerj.2449 Author Contributions • Anneke Steens and Natacha Milhano conceived and designed the experiments, performed
the experiments, analyzed the data, contributed reagents/materials/analysis tools, wrote
the paper, prepared figures and/or tables, reviewed drafts of the paper. • Ingeborg S. Aaberge conceived and designed the experiments, contributed
reagents/materials/analysis tools, reviewed drafts of the paper. • Didrik F. Vestrheim conceived and designed the experiments, performed the
experiments, contributed reagents/materials/analysis tools, reviewed drafts of the paper. REFERENCES Andrade AL, Ternes YM, Vieira MA, Moreira WG, Lamaro-Cardoso J, Kipnis A,
Cardoso MR, Brandileone MC, Moura I, Pimenta FC, Da Gloria Carvalho M,
Saraiva FO, Toscano CM, Minamisava R. 2014. Direct effect of 10-valent conjugate
pneumococcal vaccination on pneumococcal carriage in children Brazil. PLoS ONE
9(6):e98128 DOI 10.1371/journal.pone.0098128. Andrade AL, Ternes YM, Vieira MA, Moreira WG, Lamaro-Cardoso J, Kipnis A,
Cardoso MR, Brandileone MC, Moura I, Pimenta FC, Da Gloria Carvalho M,
Saraiva FO, Toscano CM, Minamisava R. 2014. Direct effect of 10-valent conjugate
pneumococcal vaccination on pneumococcal carriage in children Brazil. PLoS ONE
9(6):e98128 DOI 10.1371/journal.pone.0098128. Carvalho G, Tondella ML, McCaustland K, Weidlich L, McGee L, Mayer LW, Steiger-
walt A, Whaley M, Facklam RR, Fields B, Carlone G, Ades EW, Dagan R, Sampson
JS. 2007. Evaluation and improvement of real-time PCR assays targeting lytA., ply,
and psaA genes for detection of pneumococcal DNA. Journal of Clinical Microbiology
45(8):2460–2466 DOI 10.1128/JCM.02498-06. Desai AP, Sharma D, Crispell EK, Baughman W, Thomas S, Tunali A, Sherwood
L, Zmitrovich A, Jerris R, Satola SW, Beall B, Moore MR, Jain S, Farley MM. 2015. Decline in pneumococcal nasopharyngeal carriage of vaccine serotypes after
the introduction of the 13-valent pneumococcal conjugate vaccine in children
in Atlanta, Georgia. The Pediatric Infectious Disease Journal 34(11):1168–1174
DOI 10 1097/INF 0000000000000849 Steens et al. (2016), PeerJ, DOI 10.7717/peerj.2449 8/10 Garcia-Rodriguez JA, Fresnadillo Martinez MJ. 2002. Dynamics of nasopharyngeal col-
onization by potential respiratory pathogens. Journal of Antimicrobial Chemotherapy
50 Suppl S2:59–73 DOI 10.1093/jac/dkf506. Grijalva CG, Griffin MR, Edwards KM, Johnson M, Gil AI, Verastegui H, Lanata
CF, Williams JV. 2014. Concordance between RT-PCR-based detection of res-
piratory viruses from nasal swabs collected for viral testing and nasopharyngeal
swabs collected for bacterial testing. Journal of Clinical Virology 60(3):309–312
DOI 10.1016/j.jcv.2014.04.011. Kaltoft MS, Skov Sorensen UB, Slotved HC, Konradsen HB. 2008. An easy method for
detection of nasopharyngeal carriage of multiple Streptococcus pneumoniae serotypes. Journal of Microbiological Methods 75(3):540–544 DOI 10.1016/j.mimet.2008.08.010. Landis JR, Koch GG. 1977. The measurement of observer agreement for categorical data. Biometrics 33(1):159–174 DOI 10.2307/2529310. Norwegian Veterinary Institute. 2014. Skov Simonsen G, Urdahl AM, eds. Usage of
antimicrobial agents and occurence of antimicrobial resistance in Norway. Tromsø:
Norwegian Veterinary Institute. Available at http://www.vetinst.no/overvåking/ O’Brien KL, Bronsdon MA, Dagan R, Yagupsky P, Janco J, E J, Whitney CG, Yang
Y-H, Robinson L-GE, Schwartz B, Carlone GM. 2001. Steens et al. (2016), PeerJ, DOI 10.7717/peerj.2449 Steens et al. (2016), PeerJ, DOI 10.7717/peerj.2449 REFERENCES Evaluation of a medium
(STGG) for transport and optimal recovery of Streptococcus pneumoniae from na-
sopharyngeal secretions collected during field studies. Journal of Clinical Microbiology
39(3):1021–1024 DOI 10.1128/JCM.39.3.1021-1024.2001. Saha S, Modak JK, Naziat H, Al-Emran HM, Chowdury M, Islam M, Hossain B,
Darmstadt GL, Whitney CG, Saha SK. 2015. Detection of co-colonization with
Streptococcus pneumoniae by algorithmic use of conventional and molecular
methods. Vaccine 33(5):713–718 DOI 10.1016/j.vaccine.2014.11.040. Satzke C, Dunne EM, Porter BD, Klugman KP, Mulholland EK, g. PneuCarriage
project. 2015. The pneucarriage project: a multi-centre comparative study to identify
the best serotyping methods for examining pneumococcal carriage in vaccine
evaluation studies. PLoS Med 12(11):e1001903 DOI 10.1371/journal.pmed.1001903. Satzke C, Turner P, Virolainen-Julkunen A, Adrian PV, Antonio M, Hare KM,
Henao-Restrepo AM, Leach AJ, Klugman KP, Porter BD, Sa-Leao R, Scott JA,
Nohynek H, O’Brien KL, W.H.O.P.C.W. Group. 2013. Standard method for
detecting upper respiratory carriage of Streptococcus pneumoniae: updated recom-
mendations from the World Health Organization Pneumococcal Carriage Working
Group. Vaccine 32(1):165–179 DOI 10.1016/j.vaccine.2013.08.062. Slotved H-C, Kaltoft M, Skovsted IC, Kerrn MB, Espersen F. 2004. Simple, rapid latex
agglutination test for serotyping of pneumococci (Pneumotest-Latex). Journal of
Clinical Microbiology 42:2518–2522 DOI 10.1128/JCM.42.6.2518-2522.2004. Statistics Norway. 2010. Norway, Child-care, 2010 [in Norwegian: Barn i barnehage—
foreldrebakgrunn og utvikling de seneste årene]. (electronic). Statistics Norway. 2010. Norway, Child-care, 2010 [in Norwegian: Barn i barnehage—
foreldrebakgrunn og utvikling de seneste årene]. (electronic). Steens A, Caugant DA, Aaberge IS, Vestrheim DF. 2015. Decreased carriage and genetic
shifts in the Streptococcus pneumoniae population after changing the 7-valent to the Steens et al. (2016), PeerJ, DOI 10.7717/peerj.2449 9/10 13-valent pneumococcal vaccine in Norway. The Pediatric Infectious Disease Journal
34:875–883. Steens A, Caugant DA, Aaberge IS, Vestrheim DF. 2016. Continued decrease in
pneumococcal carriage after implementation of PCV13 in norway. In: Abstract 370. 10th International Symposium on Pneumococci and Pneumococcal Diseases (ISPPD
2016), Glasgow, Scotland. Turner P, Po L, Turner C, Goldblatt D, Nosten F. 2011. Detection of respiratory viruses
by PCR assay of nasopharyngeal swabs stored in skim milk-tryptone-glucose-
glycerol transport medium. Journal of Clinical Microbiology 49(6):2311–2313
DOI 10.1128/JCM.00224-11. Van Hoek AJ, Sheppard CL, Andrews NJ, Waight PA, Slack MP, Harrison TG, Ladhani
SN, Miller E. 2014. Pneumococcal carriage in children and adults two years after
introduction of the thirteen valent pneumococcal conjugate vaccine in England. Vaccine 32:4349–4355 DOI 10.1016/j.vaccine.2014.03.017. 10/10
|
https://openalex.org/W4391904584
|
http://catalog.liha-pres.eu/index.php/liha-pres/catalog/download/251/6969/15636-1
|
Ukrainian
| null |
Національні риси китайського фортепіанного мистецтва
|
ГУМАНІТАРНИЙ І ІННОВАЦІЙНИЙ РАКУРС ПРОФЕСІЙНОЇ МАЙСТЕРНОСТІ: ПОШУКИ МОЛОДИХ ВЧЕНИХ
| 2,023
|
cc-by
| 1,340
|
DOI https://doi.org/10.36059/978-966-397-357-9-72 DOI https://doi.org/10.36059/978-966-397-357-9-72 DOI https://doi.org/10.36059/978-966-397-357-9-72
НАЦІОНАЛЬНІ РИСИ КИТАЙСЬКОГО
ФОРТЕПІАННОГО МИСТЕЦТВА
Ван Яньсуй
аспірант за спеціальністю 025 – Музичне мистецтво
Науковий керівник: Гончаренко О. В. кандидат мистецтвознавства,
старший викладач кафедри музикознавства та культурології
Сумський державний педагогічний університет імені А. С. Макаренка
м. Суми, Україна
Фортепіанне мистецтво Китаю становить самобутній пласт світової
культури. Його
своєрідність
визначається
не
лише
загальнонаціональним
естетичними
константами,
а
й
впливом – інноваційні методики навчання – запровадження розробок нових
технологій навчання для системи неперервної освіти; – інноваційні методики навчання – запровадження розробок нових
технологій навчання для системи неперервної освіти; – інноваційні методики навчання – запровадження розробок нових
технологій навчання для системи неперервної освіти; – принципово нова система оцінки здобутої освіти – докорінна зміна
підходів до розуміння і визнання навчальної діяльності та її результатів,
особливо у сфері освіти; – принципово нова система оцінки здобутої освіти – докорінна зміна
підходів до розуміння і визнання навчальної діяльності та її результатів,
особливо у сфері освіти; – розвиток наставництва і консультування – забезпечення кожному
вільного доступу до освітньої інформації та необхідних консультацій і
рекомендацій; – розвиток наставництва і консультування – забезпечення кожному
вільного доступу до освітньої інформації та необхідних консультацій і
рекомендацій; – наближення освіти до місця проживання – використання мережі
навчальних і консультаційних пунктів, сучасних інформаційних та
комунікаційних технологій. – наближення освіти до місця проживання – використання мережі
навчальних і консультаційних пунктів, сучасних інформаційних та
комунікаційних технологій. Література: р
ур
1. Національна
доктрина
розвитку
освіти. Книга
керівника
навчально-виховного закладу. Нормативні та інструктивно-методичні
документи Міністерства освіти і науки України. Харків: ПП «Торг сін
плюс», 2006. С. 82–96. 1. Національна
доктрина
розвитку
освіти. Книга
керівника
навчально-виховного закладу. Нормативні та інструктивно-методичні
документи Міністерства освіти і науки України. Харків: ПП «Торг сін
плюс», 2006. С. 82–96. 2. О.В. Вознюк. Неперервна освіта як провідна тенденція сучасного
світу. Андрагогічний вісник. 2012. Вип. 1. С. 50–57. 2. О.В. Вознюк. Неперервна освіта як провідна тенденція сучасного
світу. Андрагогічний вісник. 2012. Вип. 1. С. 50–57. 3. Меморандум неперервного процесу освіти Європейського Союзу. Адукатар. 2006. № 2 (8). С. 25. URL: http://adukatar.net/wpcontent/
uploads/2009/12/Adu_8_Pages_24-27.pdf 4. 3. Меморандум неперервного процесу освіти Європейського Союзу. Адукатар. 2006. № 2 (8). С. 25. URL: http://adukatar.net/wpcontent/
uploads/2009/12/Adu_8_Pages_24-27.pdf 4. НАЦІОНАЛЬНІ РИСИ КИТАЙСЬКОГО
ФОРТЕПІАННОГО МИСТЕЦТВА Ван Яньсуй
аспірант за спеціальністю 025 – Музичне мистецтво
Науковий керівник: Гончаренко О. В. кандидат мистецтвознавства,
старший викладач кафедри музикознавства та культурології
Сумський державний педагогічний університет імені А. С. Макаренка
м. Суми, Україна Фортепіанне мистецтво Китаю становить самобутній пласт світової
культури. Його
своєрідність
визначається
не
лише
загальнонаціональним
естетичними
константами,
а
й
впливом 250 фольклорних традицій, зокрема використанням ангемітонних музичних
ладів, імітуванням гри на народних інструментах. Вагомого значення
набуває звернення композиторів до національної народнопісенної
скарбниці: автентичні фольклорні мелодії становлять інтонаційну
основу переважної більшості творів для фортепіано. Символізм, традиційно притаманний китайському світогляду,
залишив свій відбиток на різних елементах музичної мови, зокрема
кожен тон китайської пентатоніки має символічне значення пов’язане з
природними явищами: перший тон «гун» – означає гуркіт грому,
другий – «шан» – шум вітру, третій – «цзює» – вогняну стихію,
четвертий – «чжі» і п’ятий – «юй» – пов’язані з образами води. Ця
образна символіка й до сьогодні використовується композиторами у
створенні фортепіанної музики. р
ф р
у
У сучасних творах для фортепіано часто застосовується символіка
специфічних
тембрових
характеристик
китайських
стародавніх
музичних інструментів. Композитори переважно використовують
імітування музичних інструментів, що асоціативно пов’язані з голосами
природи, або музикуванням просто неба. Здебільшого імітуються: сона
( 嗩吶 – китайська труба) – дерев’яний духовий інструмент, що має
широкий діапазон і пронизливий звук, який нагадує спів птахів,
переважно використовується для гри на відкритому повітрі; шен (笙–
китайський губний орган) – багатоголосний духовий язичковий
інструмент з співучим плавним звучанням на кшталт волинки
(характерні квінтові та кварто-квінтові звучання), за легендою, тембр
шена нагадує голос птаха Фенікс; сяо (簫) – традиційна китайська
продольна бамбукова флейта, що має м’яке, заворожуюче звучання,
пов’язане з ліричною образністю; ді (笛) – традиційна китайська
поперечна флейта, має дзвінкий і чистий тембр, що асоціюється з
небесною височінню; пайсяо (排箫 – китайська флейта) – стародавній
духовий інструмент, що складається з 12 бамбукових трубочок і за
звучанням нагадує флейту Пана; ґуцінь, гучжен (古琴, 古箏 – китайська
цитра), або піпа (琵琶 – китайська лютня) – струнні інструменти з
щипковим звуковидобуванням, деякі дослідники вважають, що їх
звучання нагадує китайську мову; ерху і баньху (二胡, 板胡 – різновиди
хуціня) – струнно-смичкові інструменти, що мають специфічне тихе й
ніжне звучання, яке дозволяє відтворювати приховані почуття, а також
використовують такий прийом гри, як перебір струн, пов’язаний з
зображенням водної стихії. НАЦІОНАЛЬНІ РИСИ КИТАЙСЬКОГО
ФОРТЕПІАННОГО МИСТЕЦТВА ЛНМА
імені М. В. Лисенка, 2017. 187 с. DOI https://doi.org/10.36059/978-966-397-357-9-73 НАЦІОНАЛЬНІ РИСИ КИТАЙСЬКОГО
ФОРТЕПІАННОГО МИСТЕЦТВА Автори китайської фортепіанної музики
також широко використовують імітування ударних інструментів –
барабанів,
гонгів,
які
посідають
значне
місце
в
китайській 251 інструментальній традиції і асоціативно пов’язані з дзвонами, або
образами несамовитих ударів шаленої стихії. Специфічною
рисою
китайських
фортепіанних
творів
є
програмність, зокрема вельми поширеним є «звукозображальний тип
програмності». На відміну від європейської музики, в творчості
китайських авторів вона не трактується як «допоміжна», «первинна»,
«необов’язкова», – зазначає Лу Цзе: «Навпаки, для митця, вихованого в
дусі
настанов
конфуціанства,
вслуховування,
сприйняття
і
трансформація звуків природи (особливо в такому незвичному для
китайського вуха тембрі як звучання фортепіано), стає однією із
найвищих художніх цілей, в естетиці гілозоїзму, проявом вищої
мудрості, здатності злитись з природою, відчути її божественний голос»
[1, с. 120]. Виявляючи концептосфери китайської фортепіанної музики
дослідниця відзначає, що кожна з програмних назв «спрямована на
символічне означення тієї чи іншої універсальної ціннісної сутності,
вираз гармонійного ідеалу «людини – світу» (концепт природи),
«людини – людини, людської спільноти» (концепт обрядів і ритуалів)
або ж «людини – непізнаваного Всесвіту, вищих сил» (міфологічний
концепт)» [1, c. 164]. Фортепіанним творам багатьох китайських композиторів притаманні
риси музичного імпресіонізму і це є закономірним, адже специфіка
традиційної народної музики має певні ознаки імпресіоністичної
естетики:
споглядальність,
широке
використання
орнаментики,
імпровізаційність, витонченість динамічних градацій, ритмічна свобода,
гармонічна барвистість тощо. Імпресіоністична образність часто
відображається в програмних назвах мініатюр для фортепіано, які
відтворюють
пейзаж,
або
пов’язані
з
зображенням
природи:
«Відображення місяця в джерелі Ерцуань» Чу Ванхуа; «Пейзаж Баньна»
Ся Ляна, «Пісня рибалки в ночі», «Сріблясті хмари наздоганяють
місяць» Ван Цзяньчжуна», «Нічна пісня гори Емий» Хуан Хувея,
«Туман» Лі Мейцзя; «Крик восени на горі» Лю Лі; «Блукаючі тіні» Гао
Піна, «Осінній місяць відображається в спокійному озері» Чень
Пейсюна тощо. Водночас фортепіанні твори китайських композиторів
поєднують національні риси письма з європейською імпресіоністичною
стилістикою, утворюючи особливий вид китайського імпресіонізму. Отже, китайська фортепіанна музика відзначається національним
колоритом. Її специфічними рисами є звукозображальний тип
програмності, імпресіоністичний звукопис, звернення до пейзажної
образності, наслідування звучання народних інструментів. Саме ці
константи становлять фортепіанну парадигму китайського музичного
мистецтва. 252 Література:
1. Лу Цзє. Концептосфери китайської програмної фортепіанної
музики ХХ – початку ХХ ст. : дис. … канд. мист. 17.00.03. ЛНМА
імені М. В. Лисенка, 2017. 187 с. Література:
1. Лу Цзє. Концептосфери китайської програмної фортепіанної
музики ХХ – початку ХХ ст. : дис. … канд. мист. 17.00.03. ЛНМА
імені М. В. Лисенка, 2017. 187 с. Література:
1. Лу Цзє. Концептосфери китайської програмної фортепіанної
музики ХХ – початку ХХ ст. : дис. … канд. мист. 17.00.03. ДОСЛІДЖЕННЯ ЯВИЩА САМОІДЕНТИФІКАЦІЇ
СЕРЕД СТУДЕНТІВ ЗВО Васильченко-Деружко К. А. здобувачка вищої освіти другого (магістерського) рівня
за спеціальністю 053 – Психологія
Уманський державний педагогічний університет імені Павла Тичини
Науковий керівник: Гуртовенко Н. В. кандидат психологічних наук,
доцент кафедри психології
Уманський державний педагогічний університет імені Павла Тичини
м. Умань, Київська область, Україна Явище самоідентифікації особистості широке, багатопоглинаюче,
має багатофункціональне об’єднуюче значення різних факторів, а все
тому, що природа явища є динамічною і особистість має закономірність
з певною періодичністю поринати в самовизначення, намагаючись
знайти або ж підтвердити свою значимість, особливо значення
самоідентифікації проявляється під час ситуативних чи вікових криз. Питанням вивчення ідентичності особистості займалися такі відомі
зарубіжні теоретики, як А.Адлер, Г. Блумер, Е. Еріксон, С. Кіркегор,
Дж. Мід, Ж.-П. Сартр, М.Хайдеггер, Е. Фромм, К. Ясперс та ін. За
розмаїттям підходів, запропонованих цими й деякими іншими авторами,
загалом проглядається філософсько-психологічне бачення ідентичності
як: однієї з основних людських потреб, що складає сутність людського
буття і виявляється у бажанні уникнути самоти, налагодити
взаємозв’язок із зовнішнім світом (З. Фройд, Е. Фромм); як
закономірність життєвого процесу (М. Хайдеггер, Ж.-П. Сартр,
К. Ясперс); як «егоідентичність» та групова та психосоціальна
ідентичність (Є. Еріксон). Як зазначають вчені, ідентичність охоплює
все, що дає людині усвідомлення значущості в межах конкретного
соціуму. 253
|
https://openalex.org/W2088735807
|
https://europepmc.org/articles/pmc2695694?pdf=render
|
English
| null |
A prospective Swedish study on body size, body composition, diabetes, and prostate cancer risk
|
British journal of cancer
| 2,009
|
cc-by
| 8,310
|
British Journal of Cancer (2009) 100, 1799 – 1805
& 2009 Cancer Research UK
All rights reserved 0007 – 0920/09
$32.00 British Journal of Cancer (2009) 100, 1799 – 1805
& 2009 Cancer Research UK
All rights reserved 0007 – 0920/09
$32.00 British Journal of Cancer (2009) 100, 1799 – 1805
& 2009 Cancer Research UK
All rights reserved 0007 – 0920/09
$32.00
www.bjcancer.com British Journal of Cancer (2009) 100, 1799 – 1805 www.bjcancer.com A prospective Swedish study on body size, body composition,
diabetes, and prostate cancer risk A A prospective Swedish study on body size, body composition,
diabetes, and prostate cancer risk Most studies have used body mass index (BMI) as a marker of
general obesity, but it has certain limitations, particularly in men,
because it does not differentiate muscle from fat mass (Willett,
1998). One solution might be to calculate fat mass and fat-free
mass
from
bioelectrical
impedance
(BIA)
measurements
(Anonymous, 1996; MacInnis et al, 2003). Tallness has also been associated with PCa risk (Engeland et al,
2003; MacInnis and English, 2006); perhaps reflecting an influence
of nutritional factors. *Correspondence: Dr P Wallstro¨m, Nutrition Epidemiology Research
Group, Department of Clinical Sciences, Clinical Research Centre, Malmo¨
University Hospital, SE-205 02, Malmo¨, Sweden; Epidemiology We investigated total, aggressive, and non-aggressive PCa in
relation to current obesity, body composition, height, and
prevalence of diabetes mellitus in a population-based cohort,
including a sub-cohort of younger men. 4 Department of Urology, Malmo¨ University Hospital, SE-205 02, Malmo¨,
Sweden
5 5 Department of Oncology, Lund University Hospital, SE-221 85, Lund,
Sweden Received 9 December 2008; revised 25 March 2009; accepted 8 April
2009; published online 12 May 2009
*Correspondence: Dr P Wallstro¨m, Nutrition Epidemiology Research
Group, Department of Clinical Sciences, Clinical Research Centre, Malmo¨
University Hospital, SE-205 02, Malmo¨, Sweden;
E-mail: peter.wallstrom@med.lu.se
4 Department of Urology, Malmo¨ University Hospital, SE-205 02, Malmo¨,
Sweden
5 Department of Oncology, Lund University Hospital, SE-221 85, Lund,
Sweden A prospective Swedish study on body size, body composition,
diabetes, and prostate cancer risk doi:10.1038/sj.bjc.6605077
www.bjcancer.com
M
2009 prostatic neoplasms; cohort studies; body composition; body fat distribution; body height (or diabetes mellitus) There is less support for the hypothesis that central adiposity
(measured as waist circumference or waist—hip ratio, WHR) is a
risk marker for PCa (MacInnis and English, 2006). Only a few
prospective studies have examined this association (Giovannucci
et al, 1997; Lee et al, 2001; MacInnis et al, 2003; Hubbard et al,
2004). Furthermore, central adiposity is a clinically established risk
factor for non-insulin dependent diabetes mellitus (NIDDM)
(Vazquez et al, 2007; Gastaldelli, 2008), and NIDDM has been
associated with lower risk of PCa (Bonovas et al, 2004), both low
grade and high grade (Gong et al, 2006). High insulin levels, as in
insulin resistance, which often precedes NIDDM, was recently
associated with lower risk of non-aggressive PCa (Stocks et al,
2007), although there was also a non-significant positive associa-
tion with aggressive cancer. Obesity has long been associated with increased risk of prostate
cancer (PCa), although studies have been inconsistent (MacInnis
and English, 2006). Risk has been suggested to differ according to
tumour grade: obesity lowering the risk of indolent, less aggressive
tumours, whereas increasing that of aggressive cancer (Freedland
et al, 2006), a view supported by a meta-analysis (MacInnis and
English, 2006), and, to some extent, by other work (Gong et al,
2006; Littman et al, 2007; Rodriguez et al, 2007; Wright et al, 2007). Most studies have used body mass index (BMI) as a marker of
general obesity, but it has certain limitations, particularly in men,
because it does not differentiate muscle from fat mass (Willett,
1998). One solution might be to calculate fat mass and fat-free
mass
from
bioelectrical
impedance
(BIA)
measurements
(Anonymous, 1996; MacInnis et al, 2003). Obesity has long been associated with increased risk of prostate
cancer (PCa), although studies have been inconsistent (MacInnis
and English, 2006). Risk has been suggested to differ according to
tumour grade: obesity lowering the risk of indolent, less aggressive
tumours, whereas increasing that of aggressive cancer (Freedland
et al, 2006), a view supported by a meta-analysis (MacInnis and
English, 2006), and, to some extent, by other work (Gong et al,
2006; Littman et al, 2007; Rodriguez et al, 2007; Wright et al, 2007). A prospective Swedish study on body size, body composition,
diabetes, and prostate cancer risk P Wallstro¨m*,1, A Bjartell2,4, B Gullberg1, H Olsson3,5 and E Wirfa¨lt1 P Wallstro¨m*,1, A Bjartell2,4, B Gullberg1, H Olsson3,5 and E Wirfa¨lt1
1Nutrition Epidemiology Research Group, Department of Clinical Sciences, Lund University, Malmo¨, Sweden; 2Division of Urological Cancers, Department
of Clinical Sciences, Lund University, Malmo¨, Sweden; 3Cancer Epidemiology Unit, Section V, Department of Clinical Sciences, Lund University, Lund,
Sweden j
g
1Nutrition Epidemiology Research Group, Department of Clinical Sciences, Lund University, Malmo¨, Sweden; 2Division of Urological Cancers, Department
of Clinical Sciences, Lund University, Malmo¨, Sweden; 3Cancer Epidemiology Unit, Section V, Department of Clinical Sciences, Lund University, Lund,
Sweden Obesity may be associated with increased risk of prostate cancer (PCa). According to one hypothesis, obesity could lower the risk of
non-aggressive tumours, while simultaneously increasing the risk of aggressive cancer. Furthermore, central adiposity may be
independently associated with PCa risk; it is also associated with diabetes, which itself may influence risk of PCa. We studied the
associations between height, body composition, and fat distribution, diabetes prevalence and risk of total, aggressive, and non-
aggressive PCa in 10 564 initially cancer-free men (aged 45–73 years) of the population-based Malmo¨ Diet and Cancer cohort. Anthropometric and body composition measurements, including bioelectrical impedance for estimation of fat mass, were performed
by study nurses. Diabetes prevalence was self-reported. Cancer cases and clinical characteristics were ascertained through national
and regional registry data. Dietary and other background data were obtained through a modified diet history method and an
extensive questionnaire. During a mean follow-up of 11.0 years, 817 incidental PCa cases were diagnosed. Of these, 281 were
classified as aggressive. There were 202 cases occurring before 65 years of age. Height was positively associated with total and non-
aggressive PCa risk. Waist–hip ratio (WHR), a measure of central adiposity, was positively associated with PCa before age 65, and
less strongly, with total PCa. This association was independent of body mass index (BMI) and other potential confounders. General
adiposity, expressed as BMI or body fat percentage, and prevalent diabetes were not associated with PCa risk. In this study, WHR and
body height were stronger PCa predictors than general adiposity. y
g
g
p
g
p
y
tish Journal of Cancer (2009) 100, 1799–1805. doi:10.1038/sj.bjc.6605077
www.bjcancer.com
bli h d
li
12 M
2009 g
p
g
p
y
cer (2009) 100, 1799–1805. MATERIALS AND METHODS Mean follow-up time for non-cases
was 7.7 years. y
Waist circumference was measured midway between the lowest
rib margin and iliac crest; hip circumference horizontally at the
level of the greatest lateral extension of the hips. Bioelectrical
impedance was used for estimating body composition according to
manufacturer’s procedures (BIA 103, RJL-systems, Detroit, MI,
USA; single-frequency analyser). An algorithm (Sun et al, 2003)
was used to estimate body fat (BF) from impedance. The results
were highly correlated to results obtained by another algorithm,
developed in a similar population (Heitmann, 1990). Estimated BF
was used to calculate BF%. y
We examined the associations between total, aggressive, and
non-aggressive PCa incidence and height, waist circumference,
waist-hip ratio (WHR), BMI, BF%, and prevalence of diabetes. All
continuous variables were divided into quintile groups. The hazard
ratios (HR) of each distribution quintile (compared with the
lowest), and trends across the quintiles were assessed with Cox
proportional hazards regression with adjustment for age at
baseline. The time variable was number of days of follow-up after
baseline. Additionally, in a separate Cox analysis, BMI was divided
into pre-defined categories (World Health Organization, 2000)
with tests for overall differences between categories. We also
performed analyses of waist circumference and WHR with
adjustment for BMI, to assess risk associated with abdominal,
irrespective of general, adiposity. All analyses were age-adjusted
and were also performed in the o65 sub-cohort (202 cases). We
then repeated the above analyses with adjustment for a number of
potential confounders, selected from a survey of the current
scientific literature: co-habitation status, socioeconomic index,
alcohol habits, BF%, smoking history, birth country (Sweden/
other), total calcium intake, dietary intake of eicosapentaenoic acid
and docosahexaenoic acid, consumption of fruits, vegetables, and
red meat. The dietary variables were adjusted for total energy
intake (residual method) (Willett and Stampfer, 1998). A structured multiple-choice questionnaire was used in the
MDC study to collect information on sociodemographic factors,
smoking status, alcohol habits, health status, use of pharmaceutical
drugs, and several other factors. The agreement between baseline
questionnaire and its repeat after 3 weeks was high for most
variables (k values 40.75) (Manjer et al, 2002). The diabetes items
read: ‘Have you ever been treated for diabetes? Since what year?’
Persons who reported using oral anti-diabetic drugs were also
classified as diabetics. MATERIALS AND METHODS The background population of the Malmo¨ Diet and Cancer (MDC)
study, in Sweden’s third largest city (Berglund et al, 1993), consists Received 9 December 2008; revised 25 March 2009; accepted 8 April
2009; published online 12 May 2009 Body size and prostate cancer
P Wallstro¨m et al Body size and prostate cancer P Wallstro¨m et al 1800 of all men born in 1923–1945 and all women born in 1923–1950
who were living in Malmo¨ during the screening period 1991–1996
(n ¼ 74 138). This population was identified through national
population
registries,
the
final
cohort
consisting
of
28 098
individuals (participation rate 40.8%). Participants were recruited
through advertisements in local media and through invitation by
mail. The only exclusion criteria were inadequate Swedish
language skills and mental incapacity (Manjer et al, 2001, 2002);
the Ethics Committee at Lund University approved the design of
the MDC study (LU 51–90). of all men born in 1923–1945 and all women born in 1923–1950
who were living in Malmo¨ during the screening period 1991–1996
(n ¼ 74 138). This population was identified through national
population
registries,
the
final
cohort
consisting
of
28 098
individuals (participation rate 40.8%). Participants were recruited
through advertisements in local media and through invitation by
mail. The only exclusion criteria were inadequate Swedish
language skills and mental incapacity (Manjer et al, 2001, 2002);
the Ethics Committee at Lund University approved the design of
the MDC study (LU 51–90). aggressive (total 281) if the WHO grade was 3, and Gleason score
was unavailable (n ¼ 6). In cases in which at least two of T stadium,
Gleason score, or PSA serum value were reported, and if none of
these factors indicated an aggressive tumour, the tumour was
classified as non-aggressive (n ¼ 530). Staging data were unavail-
able or insufficient for 6 of the incident cases that with 530 cases of
non-aggressive cancers were excluded from analyses comparing
men with aggressive tumours with others. Details on stage and
grade have been reported earlier (Wallstro¨m et al, 2007). For PCa in younger people, we repeated all analyses in a sub-
cohort, the o65 sub-cohort, the end of follow-up being either at
date of death, date of PCa diagnosis, 31 December 2005, or the
man’s 65th birthday, whichever came first. This younger sub-
cohort consisted of 8194 men, among whom 202 incident PCa
cases (54 aggressive) occurred. MATERIALS AND METHODS The diet assessment, reported earlier (Wirfa¨lt et al, 2002),
combines quantitative and semi-quantitative approaches to the
entire diet, including cooking methods (Callmer et al, 1993). It
consists of two parts: a ‘menu book’ for description of cooked meals
and registration of cold (including juices and alcoholic) beverages
and dietary supplements during seven consecutive days; and a 168-
item food questionnaire on regularly consumed foods during the
past year. Data on validity (Elmsta˚hl et al, 1996b; Riboli et al, 1997)
and reproducibility (Elmsta˚hl et al, 1996a) have been reported. Cancer cases were ascertained by record linkage with the
National Cancer Register. Cancer cases from the year 2005,
additional data on tumour stage and grade, pre-diagnostic serum
prostate-specific antigen (PSA) value, and reason for diagnosis
(symptoms, health examination, or other) were obtained from the
National Prostate Cancer Register (NPCR) (South Region). In the
South Region, to which Malmo¨ belongs, registration was started in
1996 and is at least 95% complete. For cases diagnosed in 1991–
1995, the same data were manually extracted from medical records
using standard routines. The National Cancer Register is known to
be at least 98% complete. A validation of the NPCR data from
another region showed high validity for all variables, including one
used to classify non-aggressive and aggressive tumours (Sandblom
et al, 2003). To further evaluate the consistency of our results, we repeated all
analyses (including subgroups) in three separate sessions. In the
first, we excluded asymptomatic cases (478 cases remaining in the
total group). In the second, we excluded persons not born in Sweden
(748 cases), and in the third, we excluded cases occurring within two
years of the beginning of follow-up (691 remaining cases). British Journal of Cancer (2009) 100(11), 1799 – 1805 RESULTS Epidemiology An aggressive case (‘aggressive Pca’) was defined as a tumour
with a clinical T stage of 3 or higher or tumour-positive lymph
nodes (N1) or one or more distant metastases (M1) or a Gleason
score of 8 or higher or a pre-treatment serum PSA value of at least
50 ng ml1 (Stocks et al, 2007); tumours were also classified as British Journal of Cancer (2009) 100(11), 1799 – 1805 & 2009 Cancer Research UK Body size and prostate cancer
P Wallstro¨m et al 1801 Table 1
Age-adjusted hazard ratios (with lower and upper limits of 95% confidence intervals) for measures of height, obesity, and diabetes prevalence and
total, aggressive, and non-aggressive cases of prostate cancera
18 ower and upper limits of 95% confidence intervals) for measures of height, obesity, and diabetes prevalence and
prostate cancera Table 1
Age-adjusted hazard ratios (with lower and upper limits of 95% confidence intervals) for measures of height, obesity, and diabetes prevalence and
total, aggressive, and non-aggressive cases of prostate cancera total, aggressive, and non-aggressive cases of prostate cancera
Incident prostate cancer, entire cohort (n ¼ 10 564)b
Non-cases
(n ¼ 9747)
All cases (n ¼ 817)
Aggressive cases (n ¼ 281)
Non-aggressive cases (n ¼ 530)
Median
Range
N
N
HR
Lower
Upper
N
HR
Lower
Upper
N
HR
Lower
Upper
Height (cm)
Quintile 1
168
p170
1798
144
1.00
50
1.00
93
1.00
Quintile 2
173
171 –174
2011
182
1.20
0.97
1.49
71
1.40
0.97
2.01
109
1.10
0.84
1.46
Quintile 3
177
175 –178
2263
182
1.11
0.89
1.38
65
1.20
0.83
1.74
115
1.06
0.81
1.39
Quintile 4
180
179 –181
1536
116
1.09
0.85
1.39
36
1.06
0.69
1.63
80
1.12
0.83
1.51
Quintile 5
184
X182
2123
193
1.40
1.13
1.74
59
1.38
0.95
2.02
133
1.42
1.09
1.86
0.016
0.37
0.014
BMI
Underweight
n/a
p18.49
48
8
2.09
1.03
4.22
4
2.88
1.06
7.82
4
0.60
0.22
1.61
Normal
n/a
18.50–24.99
3627
287
1.00
102
1.00
183
1.00
Overweight
n/a
25.00–29.99
4803
417
1.04
0.90
1.21
140
0.97
0.75
1.25
274
0.65
0.24
1.75
Obese
n/a
X30.00
1253
105
1.04
0.84
1.30
35
0.95
0.65
1.40
69
0.65
0.24
1.78
Non-linear P
0.24c
0.20d
0.65e
BMI
Quintile 1
22.2
p23.4
1949
158
1.00
61
1.00
96
1.00
Quintile 2
24.4
23.5 –25.2
1957
164
0.97
0.78
1.20
53
0.80
0.55
1.15
110
1.07
0.82
1.41
Quintile 3
26.0
25.2 –26.8
1928
168
0.98
0.79
1.22
59
0.87
0.61
1.25
107
1.04
0.79
1.38
Quintile 4
27.7
26.8 –28.7
1940
175
1.03
0.83
1.28
57
0.85
0.59
1.22
117
1.15
0.88
1.51
Quintile 5
30.6
X28.7
1957
152
0.91
0.73
1.14
51
0.77
0.53
1.12
100
1.00
0.76
1.33
0.67
0.27
0.80
Body fat %
Quintile 1
15.7
p18.3
1952
146
1.00
53
1.00
93
1.00
Quintile 2
19.9
18.3 –21.3
1915
184
1.23
0.99
1.52
72
1.33
0.93
1.89
108
1.14
0.86
1.50
Quintile 3
22.6
21.3 –23.8
1941
157
1.04
0.83
1.31
54
0.99
0.68
1.44
102
1.06
0.80
1.41
Quintile 4
25.1
23.8 –26.6
1933
166
1.07
0.86
1.33
46
0.81
0.55
1.21
120
1.22
0.93
1.60
Quintile 5
28.8
X26.6
1937
161
1.08
0.86
1.35
55
1.01
0.69
1.48
105
1.11
0.84
1.47
0.98
0.25
0.37
Waist (cm)
Quintile 1
82
p85
1960
152
1.00
58
1.00
94
1.00
Quintile 2
88
86– 90
1947
146
0.92
0.74
1.16
49
0.81
0.55
1.19
96
0.99
0.74
1.31
Quintile 3
93
91– 95
2013
183
1.10
0.89
1.37
60
0.94
0.65
1.35
120
1.18
0.90
1.54
Quintile 4
98
96–101
1893
171
1.09
0.87
1.35
54
0.89
0.61
1.29
116
1.20
0.92
1.58
Quintile 5
107
X102
1912
165
1.04
0.83
1.30
60
0.96
0.67
1.38
104
1.08
0.82
1.43
0.35
0.99
0.26
WHR
Quintile 1
0.87
p0.90
1945
161
1.00
58
1.00
96
1.00
Quintile 2
0.91
0.90 –0.93
1949
161
1.02
0.82
1.27
53
0.96
0.66
1.39
110
1.04
0.79
1.36
Quintile 3
0.94
0.93 –0.96
1958
152
0.97
0.78
1.21
56
1.01
0.70
1.46
107
0.95
0.72
1.25
Quintile 4
0.97
0.96 –0.99
1913
187
1.21
0.98
1.50
67
1.23
0.87
1.75
117
1.20
0.92
1.56
Quintile 5
1.02
X0.99
1959
156
1.08
0.87
1.35
47
0.94
0.64
1.39
100
1.13
0.86
1.48
0.17
0.67
0.21
Diabetes? RESULTS No
n/a
n/a
9336
790
1.00
273
1.00
511
1.00
Yes
n/a
n/a
411
27
0.78
0.53
1.14
8
0.62
0.31
1.26
19
0.87
0.55
1.37
0.20
0.19
0.55
Waist, adjusted for BMI
Quintile 1
n/a
n/a
1963
145
1.00
50
1.00
94
1.00
Quintile 2
n/a
n/a
1943
165
1.19
0.95
1.49
50
1.10
0.74
1.62
114
1.25
0.95
1.64
Quintile 3
n/a
n/a
1963
146
1.01
0.80
1.27
49
1.01
0.68
1.50
97
1.02
0.77
1.35
Quintile 4
n/a
n/a
1930
178
1.26
1.01
1.57
65
1.37
0.95
1.98
111
1.20
0.92
1.59
Quintile 5
n/a
n/a
1925
183
1.21
0.97
1.51
67
1.28
0.89
1.85
114
1.17
0.89
1.54
0.078
0.083
0.37
WHR, adjusted for BMI
Quintile 1
n/a
n/a
1937
169
1.00
57
1.00
112
1.00
Quintile 2
n/a
n/a
1968
139
0.89
0.71
1.12
48
0.95
0.65
1.39
90
0.85
0.64
1.12
Quintile 3
n/a
n/a
1926
181
1.20
0.97
1.49
65
1.36
0.95
1.95
115
1.12
0.86
1.46
Quintile 4
n/a
n/a
1940
166
1.11
0.90
1.38
56
1.18
0.82
1.71
109
1.07
0.82
1.39
Quintile 5
n/a
n/a
1945
162
1.15
0.93
1.43
55
1.25
0.86
1.81
104
1.07
0.82
1.40
0.049
0.12
0.24
BMI ¼ body mass index; WHR ¼ waist–hip ratio; HR ¼ hazard ratios. P-values in italics. aAll P-values are for linear trends (categorical variables), except where noted. bNumbers
d
t l
dd t
10 564
i
t
i i
l
i
t
i
cLi
P
l
0 92 dLi
P
l
0 49 eLi
P
l
0 55 Incident prostate cancer, entire cohort (n ¼ 10 564)b BMI ¼ body mass index; WHR ¼ waist–hip ratio; HR ¼ hazard ratios. P-values in italics. aAll P-values are for linear trends (categorical variables), except where noted. bNumbers
do not always add to 10 564 owing to missing values in some categories. cLinear P-value ¼ 0.92. dLinear P-value ¼ 0.49. eLinear P-value ¼ 0.55. Epidemiology o65 sub-cohort, were somewhat stronger after multivariate
adjustment (Tables 2 and 3). The associations with being
underweight were also slightly stronger after adjustment (Table 2);
otherwise, the results were similar. Inspection of the data revealed o65 sub-cohort, were somewhat stronger after multivariate
adjustment (Tables 2 and 3). The associations with being
underweight were also slightly stronger after adjustment (Table 2);
otherwise, the results were similar. & 2009 Cancer Research UK RESULTS Height was associated with increased risk of total PCa, although the
effect was limited to the highest quintile (range 182–203 cm), and
was most evident among non-aggressive tumours (Table 1). No
other measures of body composition or fat distribution were
significantly associated with PCa risk, although being underweight
(BMI o18.5) was associated with higher risks than normal weight
across all PCa categories except the non-aggressive category; an
association
with BMI-adjusted
WHR
was suggested. Neither
prevalent diabetes was significantly associated with PCa risk nor
height in the o65 sub-cohort (Table 2, age-adjusted analyses), there
was a weak, positive association with WHR. After adjustment for
BMI, the association was slightly stronger (HR per quintile 1.14,
95% CI 1.03–1.26). Similarly, waist circumference (adjusted for
BMI) was positively associated with risk in the o65 sub-cohort. After adjustment for a number of possible confounders, the
increased risk of total PCa associated with greater height was
weakened (P for trend ¼ 0.08, Table 3). However, the highest
quintile was still significantly different from the lowest (P ¼ 0.018). The associations between WHR and PCa, both in total and in the Of the 11 063 men in the MDC cohort, 485 were already
diagnosed with cancer (excluding basal cell carcinomas) at study
entry, and were therefore excluded; 14 others were excluded
because of PCa diagnosis at autopsy, leaving 10 564 men for
analysis. They were followed until date of death, date of PCa
diagnosis, or 31 December 2005, whichever came first. No
participants were lost to follow-up of vital status. Among them,
817 incident cases of PCa (‘total PCa’; ICD-9 code 185) occurred
between baseline examination and end of follow-up. The average
follow-up time in participants free of PCa at death (n ¼ 1321) or at
the end of follow-up (n ¼ 8426) was 11.0 years. British Journal of Cancer (2009) 100(11), 1799 – 1805 RESULTS Inspection of the data revealed no suggestion of any significant interactions between any body
measure and aggressive vs non-aggressive tumours. RESULTS gg
gg
The association between high stature (tallest quintile) and
risk of total PCa was a robust finding in most models (exclusion British Journal of Cancer (2009) 100(11), 1799 – 1805 & 2009 Cancer Research UK Body size and prostate cancer
P Wallstro¨m et al Body size and prostate cancer
P W ll t ¨
l 1802 1802 Table 2
Age-adjusted and multivariatea hazard ratios (with lower and upper limits of 95% confidence intervals) for measures of height, obesity, and
diabetes prevalence and cases of prostate cancer occurring before age 65b
2 Table 2
Age-adjusted and multivariatea hazard ratios (with lower and upper limits of 95% confidence interv
diabetes prevalence and cases of prostate cancer occurring before age 65b
2 Table 2
Age-adjusted and multivariatea hazard ratios (with lower and upper limits of 95% confidence intervals) for measures of height, obesity, and
diabetes prevalence and cases of prostate cancer occurring before age 65b Table 2
Age adjusted and multivariate hazard ratios (with lower and upper limits of 95% confidence intervals) for measures of height, obesity, and
diabetes prevalence and cases of prostate cancer occurring before age 65b
Age-adjusted analysis (n ¼ 8194)c
Multivariate analysis (n ¼ 8103)d
Non-cases (n ¼ 7992)
Incident cases (n ¼ 202)
N
N
HR
Lower
Upper
HR
Lower
Upper
Height
Quintile 1
1308
32
1.00
1.00
Quintile 2
1596
31
0.77
0.47
1.27
0.75
0.46
1.23
Quintile 3
1841
50
1.06
0.68
1.65
1.00
0.64
1.58
Quintile 4
1330
22
0.62
0.36
1.07
0.59
0.34
1.02
Quintile 5
1903
67
1.30
0.85
1.98
1.22
0.79
1.89
0.17
0.28
BMI
Underweight
36
3
3.81
1.20
12.08
4.38
1.35
14.17
Normal
3019
78
1.00
1.00
Overweight
3896
94
0.97
0.72
1.31
0.95
0.70
1.29
Obese
1027
27
1.09
0.71
1.69
1.09
0.70
1.71
Non-linear P
0.13e
0.081f
BMI
Quintile 1
1640
46
1.00
1.00
Quintile 2
1608
40
0.89
0.58
1.36
0.84
0.55
1.29
Quintile 3
1572
32
0.75
0.48
1.17
0.71
0.45
1.11
Quintile 4
1569
46
1.11
0.74
1.67
1.05
0.69
1.60
Quintile 5
1589
38
0.91
0.59
1.40
0.88
0.56
1.36
0.96
0.93
Body fat %
Quintile 1
1603
36
1.00
1.00
Quintile 2
1597
44
1.20
0.78
1.87
1.20
0.77
1.86
Quintile 3
1607
45
1.27
0.82
1.97
1.28
0.82
1.99
Quintile 4
1558
36
1.08
0.68
1.72
1.05
0.66
1.68
Quintile 5
1576
39
1.19
0.75
1.87
1.20
0.77
1.86
0.65
0.69
Waist
Quintile 1
1626
40
1.00
1.00
Quintile 2
1613
33
0.89
0.56
1.41
0.85
0.53
1.35
Quintile 3
1641
45
1.15
0.75
1.75
1.09
0.71
1.69
Quintile 4
1553
41
1.17
0.76
1.82
1.11
0.71
1.73
Quintile 5
1540
43
1.29
0.84
1.99
1.24
0.79
1.95
0.12
0.19
WHR
Quintile 1
1543
34
1.00
1.00
Quintile 2
1587
30
0.87
0.53
1.42
0.85
0.52
1.40
Quintile 3
1607
39
1.12
0.71
1.78
1.13
0.71
1.80
Quintile 4
1580
52
1.52
0.98
2.34
1.56
1.01
2.43
Quintile 5
1655
47
1.34
0.86
2.09
1.40
0.89
2.21
0.023
0.012
Diabetes? RESULTS No
1523
198
1.00
1.00
Yes
6279
4
0.66
0.24
1.77
0.65
0.24
1.75
0.41
0.39
Waist, adjusted for BMI
Quintile 1
1562
35
1.00
1.00
Quintile 2
1626
39
1.05
0.67
1.66
1.05
0.66
1.67
Quintile 3
1625
36
1.04
0.65
1.65
1.03
0.64
1.66
Quintile 4
1609
44
1.28
0.82
2.00
1.29
0.81
2.07
Quintile 5
1551
48
1.57
1.01
2.43
1.59
0.98
2.58
0.025
0.038
WHR, adjusted for BMI
Quintile 1
1472
26
1.00
1.00
Quintile 2
1594
28
0.96
0.56
1.64
0.98
0.57
1.67
Quintile 3
1612
51
1.75
1.09
2.81
1.82
1.13
2.92
Quintile 4
1627
52
1.78
1.11
2.85
1.85
1.15
2.98
Quintile 5
1662
45
1.50
0.93
2.44
1.64
1.00
2.68
0.011
0.004
BMI ¼ body mass index; WHR ¼ waist–hip ratio; HR ¼ hazard ratios. P-values in italics. aAdjusted for age, height, co-habitation status, socioeconomic status, alcohol habits,
smoking habits, prevalent diabetes, total physical activity, birth country, and total intake of EPA, DHA, red meat, and calcium. Height and prevalent diabetes were further adjusted
for BMI category. bAll P-values are for linear trends (categorical variables), except where noted. cNumbers do not always add to 8194 owing to missing values in some categories. dSome persons excluded from the analyses because of missing values, which also affect the number of cases (n ¼ 200). eLinear P-value ¼ 0.86. fLinear P ¼ 0.80. RESULTS Height and prevalent diabetes were further adjusted
ical variables) except where noted cNumbers do not always add to 8194 owing to missing values in some categories Age-adjusted analysis (n ¼ 8194)c Multivariate analysis (n ¼ 8103)d Epidemiology British Journal of Cancer (2009) 100(11), 1799 – 1805 & 2009 Cancer Research UK Body size and prostate cancer
P Wallstro¨m et al Body size and prostate cancer
P Wallstro¨m et al 1803 Table 3
Multivariate adjusted hazard ratiosa (with lower and upper limits of 95% confidence intervals) for measures of height, obesity, and diabetes
prevalence and total, aggressive, and non-aggressive cases of prostate cancerb
1 Table 3
Multivariate adjusted hazard ratiosa (with lower and upper limits of 95% confidence intervals) for measures of height, obesity, and diabetes
prevalence and total, aggressive, and non-aggressive cases of prostate cancerb
8 Table 3
l j
(
pp
)
g
y
prevalence and total, aggressive, and non-aggressive cases of prostate cancerb
Incident prostate cancer, entire cohort (n ¼ 10 434)c
All cases (n ¼ 809)
Aggressive cases (n ¼ 278)
Non-aggressive cases (n ¼ 525)
HR
Lower
Upper
HR
Lower
Upper
HR
Lower
Upper
Height
Quintile 1
1.00
1.00
1.00
Quintile 2
1.18
0.95
1.47
1.38
0.96
1.98
1.08
0.82
1.43
Quintile 3
1.08
0.86
1.34
1.14
0.79
1.66
1.04
0.79
1.37
Quintile 4
1.04
0.81
1.34
1.01
0.65
1.56
1.08
0.79
1.46
Quintile 5
1.31
1.05
1.64
1.29
0.87
1.91
1.33
1.01
1.76
0.081
0.64
0.055
BMI
Underweight
2.29
1.13
4.63
3.15
1.15
8.62
0.84
0.63
1.11
Normal
1.00
1.00
1.00
Overweight
1.02
0.88
1.19
0.99
0.76
1.29
1.16
0.89
1.50
Obese
1.06
0.84
1.33
1.02
0.69
1.52
1.11
0.85
1.44
Non-linear P
0.15d
0.16e
0.65f
BMI
Quintile 1
1.00
1.00
1.00
Quintile 2
0.94
0.76
1.17
0.83
0.57
1.20
1.01
0.76
1.33
Quintile 3
0.96
0.77
1.20
0.89
0.62
1.29
0.99
0.75
1.31
Quintile 4
0.99
0.80
1.24
0.89
0.61
1.28
1.06
0.81
1.40
Quintile 5
0.90
0.72
1.13
0.83
0.57
1.22
0.94
0.71
1.26
0.58
0.49
0.86
Body fat %
Quintile 1
1.00
1.00
1.00
Quintile 2
1.22
0.98
1.52
1.33
0.94
1.91
1.13
0.85
1.49
Quintile 3
1.03
0.82
1.30
0.99
0.67
1.45
1.05
0.79
1.39
Quintile 4
1.06
0.84
1.32
0.83
0.56
1.23
1.19
0.90
1.56
Quintile 5
1.10
0.87
1.38
1.05
0.71
1.55
1.12
0.84
1.49
0.94
0.35
0.38
Waist
Quintile 1
1.00
1.00
1.00
Quintile 2
0.90
0.71
1.13
0.80
0.55
1.18
0.94
0.70
1.25
Quintile 3
1.05
0.84
1.30
0.93
0.64
1.34
1.10
0.83
1.44
Quintile 4
1.04
0.83
1.29
0.89
0.61
1.30
1.12
0.84
1.47
Quintile 5
1.00
0.80
1.26
0.99
0.68
1.45
1.00
0.75
1.34
0.55
0.84
0.58
WHR
Quintile 1
1.00
1.00
1.00
Quintile 2
0.99
0.79
1.23
0.94
0.65
1.37
1.00
0.76
1.31
Quintile 3
0.96
0.77
1.21
1.03
0.71
1.49
0.93
0.70
1.23
Quintile 4
1.23
0.99
1.52
1.27
0.89
1.82
1.21
0.92
1.58
Quintile 5
1.12
0.89
1.41
0.99
0.66
1.47
1.16
0.88
1.53
0.073
0.46
0.12
Diabetes? RESULTS ccurring before age 65b
Age-adjusted analysis (n ¼ 8194)c
Multivariate analysis (n ¼ 8103)d
nt cases (n ¼ 202)
N
HR
Lower
Upper
HR
Lower
Upper
32
1.00
1.00
31
0.77
0.47
1.27
0.75
0.46
1.23
50
1.06
0.68
1.65
1.00
0.64
1.58
22
0.62
0.36
1.07
0.59
0.34
1.02
67
1.30
0.85
1.98
1.22
0.79
1.89
0.17
0.28
3
3.81
1.20
12.08
4.38
1.35
14.17
78
1.00
1.00
94
0.97
0.72
1.31
0.95
0.70
1.29
27
1.09
0.71
1.69
1.09
0.70
1.71
0.13e
0.081f
46
1.00
1.00
40
0.89
0.58
1.36
0.84
0.55
1.29
32
0.75
0.48
1.17
0.71
0.45
1.11
46
1.11
0.74
1.67
1.05
0.69
1.60
38
0.91
0.59
1.40
0.88
0.56
1.36
0.96
0.93
36
1.00
1.00
44
1.20
0.78
1.87
1.20
0.77
1.86
45
1.27
0.82
1.97
1.28
0.82
1.99
36
1.08
0.68
1.72
1.05
0.66
1.68
39
1.19
0.75
1.87
1.20
0.77
1.86
0.65
0.69
40
1.00
1.00
33
0.89
0.56
1.41
0.85
0.53
1.35
45
1.15
0.75
1.75
1.09
0.71
1.69
41
1.17
0.76
1.82
1.11
0.71
1.73
43
1.29
0.84
1.99
1.24
0.79
1.95
0.12
0.19
34
1.00
1.00
30
0.87
0.53
1.42
0.85
0.52
1.40
39
1.12
0.71
1.78
1.13
0.71
1.80
52
1.52
0.98
2.34
1.56
1.01
2.43
47
1.34
0.86
2.09
1.40
0.89
2.21
0.023
0.012
198
1.00
1.00
4
0.66
0.24
1.77
0.65
0.24
1.75
0.41
0.39
35
1.00
1.00
39
1.05
0.67
1.66
1.05
0.66
1.67
36
1.04
0.65
1.65
1.03
0.64
1.66
44
1.28
0.82
2.00
1.29
0.81
2.07
48
1.57
1.01
2.43
1.59
0.98
2.58
0.025
0.038
26
1.00
1.00
28
0.96
0.56
1.64
0.98
0.57
1.67
51
1.75
1.09
2.81
1.82
1.13
2.92
52
1.78
1.11
2.85
1.85
1.15
2.98
45
1.50
0.93
2.44
1.64
1.00
2.68
0.011
0.004
azard ratios. P-values in italics. aAdjusted for age, height, co-habitation status, socioeconomic status, alcohol habits,
th country, and total intake of EPA, DHA, red meat, and calcium. & 2009 Cancer Research UK DISCUSSION This study showed a weak association between tallness and risk of
total PCa, also shown (but not significantly) by aggressive PCa or
PCa in the o65 sub-cohort. The role of height in PCa, if any, is
controversial (Gunnell et al, 2001). A similar finding was reported
in the largest study to date, examining 950 000 Norwegian men, in
which the tallest men (X190 cm) had an RR of 1.72 (95% CI 1.46–
2.04) compared with the shortest (Engeland et al, 2003). Although
an RR greater than 1.00 for the tallest men has been reported
several times, this was not usually significant at a 0.05 level
(Gunnell et al, 2001). A recent study from the EPIC cohort found
no association between height and risk, neither for aggressive nor
for non-aggressive tumours (Pischon et al, 2008). Furthermore,
height was recently associated with increased PCa mortality
(Giovannucci et al, 2007). p
Underweight (BMI o18.5) was associated with all categories
of PCa. This may represent weight loss owing to pre-clinical
cancer,
particularly
since
the
associations
disappeared
after exclusion of cases occurring within the first 2 years after
screening. g
Diabetes was not significantly associated with incidence of PCa
in this study. Several studies linking NIDDM and/or insulin
resistance with lower risk of PCa have been published in recent
years (Bonovas et al, 2004; Gong et al, 2006; Stocks et al, 2007). As
noted above, we used self-reported data on diabetes prevalence. However, because we also defined diabetics by their oral anti-
diabetic drug use, only diabetics without oral therapy (or who
failed to record it) and who did not answer the diabetes item
correctly should be misclassified. This predominantly NIDDM
group
may
be
mixed
with
type
1
diabetes,
because
the
questionnaire did not differ between diabetes types. However,
few persons reported age at start of diabetes treatment o36 years
(n ¼ 30, 12% of cases). Finally, it should be noted that our power to
detect an association was rather low, because of the relatively small
number of diabetics. To our knowledge, height in itself has not been regarded as
a causal factor for PCa, but rather associations have been
attributed to genetic, hormonal, and nutritional factors related
to growth until adulthood, both before and after birth (Gunnell
et al, 2001). ACKNOWLEDGEMENTS We
thank
Ulla
Lindstro¨m,
RN,
Department
of
Urology,
Malmo¨ University Hospital, for retrieval of clinical data. We also
thank the staff and participants of the Malmo¨ Diet and Cancer
Study. Financial support has been received from the Swedish Cancer
Society, the Swedish Medical Research Council, Region Ska˚ne, The
Swedish Nutrition Foundation, and the Ernhold Lundstro¨m
Research Foundation. y
p
It is not clear why the association between WHR and PCa risk
was most pronounced in the o65 sub-cohort, or why height was
not associated with aggressive PCa. Chance findings can never be
entirely ruled out; although the number of factors examined in this
study was limited and well defined, the actual number of statistical
tests was large. On the other hand, our findings might reflect that
unmeasured factors associated with high WHR/waist circum-
ference become relatively less important to PCa development as Epidemiology Disclaimer: Parts of the data presented in this study are also
included in a recent report from the EPIC collaboration (Pischon
et al, 2008). DISCUSSION As there is evidence of a positive association between
body height and socioeconomic class, perhaps reflecting factors
such as a greater abundance of food during growth or lower
incidence of infections, one could imagine socioeconomic class
confounding the association between height and PCa (Batty et al,
2006). In this study, however, this was only marginally affected
by adjustment for socioeconomic index and other potential
confounders. Many researchers use a Gleason score of 7 þ instead of 8 þ for
defining more aggressive tumours. Changing our definition of
aggressive to include Gleason 7 meant resulted in another 99 cases
among the aggressive, with unchanged null results and weaker
positive results (data not shown). This could be interpreted as an
effect of diluting the aggressive group of cases by adding a large
number of less malignant tumours. Few studies have reported associations between waist/WHR and
PCa; a recent meta-analysis judged the evidence to be weak
(MacInnis and English, 2006). In our study, WHR (and, to a
smaller extent, waist) was associated with PCa, particularly before
age 65 and after adjustment for BMI. Detection bias is possible:
persons with higher WHR may be more likely to have other health
problems and therefore visit a doctor, which could increase the
chance of diagnosis. However, the sensitivity analysis showed, if
anything, stronger associations when asymptomatic cases were
excluded (data not shown). Although usually highly correlated
with BMI, there are data to suggest that waist circumference and/or
WHR may predict health problems independently of BMI, as in
diabetes mellitus (Gastaldelli, 2008) and CVD (Yusuf et al, 2005). Furthermore, there is accumulating evidence for a role of waist
circumference (Visscher et al, 2001; Koster et al, 2008) and WHR
(Lahmann et al, 2002; Price et al, 2006) in predicting mortality
independently of BMI in men. A post hoc analysis of total PCa in
the present cohort shows that the increased PCa risk associated
with large waist circumference seemed to be greatest at low BMI
(data not shown), a finding that was not explained by prevalent
asymptomatic cancer. In this population-based cohort study, we noted positive
associations between risk of PCa and adult height, WHR, and
waist circumference. No other measures of obesity or body size,
or prevalent diabetes were significantly associated with PCa
risk. There were no suggestions
of significant interactions
between measures of obesity and degree of aggressiveness of the
tumours. RESULTS This was true of
the waist/WHR models, both univariate and multivariate. How-
ever, the association between being underweight according to BMI
classification and increased risk of total PCa was greatly weakened
after removal of cases occurring within the first 2 years or
asymptomatic cases. Apart from these, the sensitivity analyses
yielded no consistent results. General adiposity was not associated with PCa in this study. The
HR estimates for BF% were slightly different from those for BMI,
but not convincingly so. As the use of BF% as a marker of general
adiposity has recently been criticised (Cole et al, 2008), we
repeated our main analyses with BF% replaced by BF mass
adjusted for lean body mass, but with broadly similar results (data
not shown). One obvious explanation is that there may be no effect
or a very small effect of general adiposity on PCa risk (MacInnis
and English, 2006; Renehan et al, 2008), or that BF% is not
different enough from BMI to capture any differences in this
respect. RESULTS No
1.00
1.00
1.00
Yes
0.76
0.51
1.11
0.61
0.30
1.25
0.84
0.53
1.33
0.15
0.18
0.45
Waist, adjusted for BMI
Quintile 1
1.00
1.00
1.00
Quintile 2
1.17
0.93
1.47
1.11
0.75
1.64
1.21
0.92
1.60
Quintile 3
1.00
0.79
1.27
1.04
0.69
1.55
1.00
0.75
1.33
Quintile 4
1.23
0.98
1.55
1.40
0.95
2.06
1.16
0.87
1.54
Quintile 5
1.17
0.92
1.49
1.29
0.86
1.93
1.11
0.82
1.50
0.18
0.11
0.67
WHR, adjusted for BMI
Quintile 1
1.00
1.00
1.00
Quintile 2
0.89
0.71
1.11
0.96
0.65
1.40
0.84
0.63
1.11
Quintile 3
1.22
0.99
1.51
1.34
0.94
1.93
1.16
0.89
1.50
Quintile 4
1.14
0.92
1.42
1.21
0.83
1.75
1.11
0.85
1.44
Quintile 5
1.22
0.98
1.52
1.27
0.87
1.86
1.17
0.89
1.53
0.012
0.10
0.072
BMI ¼ body mass index; WHR ¼ waist–hip ratio; HR ¼ hazard ratios. P-values are in italics. aAdjusted for age, height, co-habitation status, socioeconomic status, alcohol habits,
smoking habits, prevalent diabetes, total physical activity, birth country, and total intake of EPA, DHA, red meat, and calcium. Height and prevalent diabetes were further adjusted
for BMI category. bAll P-values are for linear trends (categorical variables), except where noted. cSome persons excluded from the analyses because of missing values, which also
affect the number of cases. dLinear P ¼ 0.95. eLinear P ¼ 0.72. fLinear P ¼ 0.95. Incident prostate cancer, entire cohort (n ¼ 10 434)c Epidemiology BMI ¼ body mass index; WHR ¼ waist–hip ratio; HR ¼ hazard ratios. P-values are in italics. aAdjusted for age, height, co-habitation status, socioeconomic status, alcohol habits,
smoking habits, prevalent diabetes, total physical activity, birth country, and total intake of EPA, DHA, red meat, and calcium. Height and prevalent diabetes were further adjusted
for BMI category. bAll P-values are for linear trends (categorical variables), except where noted. cSome persons excluded from the analyses because of missing values, which also
affect the number of cases. dLinear P ¼ 0.95. eLinear P ¼ 0.72. fLinear P ¼ 0.95. British Journal of Cancer (2009) 100(11), 1799 – 1805 & 2009 Cancer Research UK Body size and prostate cancer
P Wallstro¨m et al Body size and prostate cancer p
P Wallstro¨m et al 1804 age increases. Similarly, height may be a marker of biological
processes leading to less aggressive PCa. of persons born outside of Sweden, asymptomatic cases, and cases
occurring within 2 year of screening, respectively). British Journal of Cancer (2009) 100(11), 1799 – 1805 REFERENCES J Intern Med
233: 53–57 d nutrition. Cancer Epidemiol Biomarkers Prev 17: 3252–326 Price GM, Uauy R, Breeze E, Bulpitt CJ, Fletcher AE (2006) Weight, shape,
and mortality risk in older persons: elevated waist-hip ratio, not high
body mass index, is associated with a greater risk of death. Am J Clin
Nutr 84: 449–460 Cole TJ, Fewtrell MS, Prentice A (2008) The fallacy of using percentage
body fat as a measure of adiposity. Am J Clin Nutr 87: 1959 Elmsta˚hl S, Gullberg B, Riboli E, Saracci R, Lindga¨rde F (1996a) The
reproducibility of a novel diet history method and an extensive food
frequency questionnaire. The Malmo¨ Food Study. Eur J Clin Nutr 50:
134–142 Renehan AG, Tyson M, Egger M, Heller RF, Zwahlen M (2008) Body-mass
index and incidence of cancer: a systematic review and meta-analysis of
prospective observational studies. Lancet 371: 569–578 Elmsta˚hl S, Riboli E, Lindga¨rde F, Gullberg B, Saracci R (1996b) The Malmo¨
Food Study. The relative validity of a modified diet history method and
an extensive food frequency questionnaire for measuring food intake. Eur J Clin Nutr 50: 143–151 Riboli E, Elmsta˚hl S, Saracci R, Gullberg B, Lindga¨rde F (1997) The Malmo¨
Food Study: validity of two dietary assessment methods for measuring
nutrient intake. Int J Epidemiol 26(Suppl. 1): S161–S173 Rodriguez C, Freedland SJ, Deka A, Jacobs EJ, McCullough ML, Patel AV,
Thun MJ, Calle EE (2007) Body mass index, weight change, and risk of
prostate cancer in the Cancer Prevention Study II Nutrition Cohort. Cancer Epidemiol Biomarkers Prev 16: 63–69 Engeland A, Tretli S, Bjørge T (2003) Height, body mass index, and
prostate cancer: a follow-up of 950 000 Norwegian men. Br J Cancer 89:
1237–1242 Freedland SJ, Giovannucci E, Platz EA (2006) Are findings from studies of
obesity and prostate cancer really in conflict? Cancer Causes Control 17:
5–9 p
Sandblom
G,
Dufmats
M,
Olsson
M,
Varenhorst
E
(2003)
Validity of a population-based cancer register in Sweden. Scand J Urol
37: 112–119 Gastaldelli A (2008) Abdominal fat: does it predict the development of type
2 diabetes? Am J Clin Nutr 87: 1118–1119 Stocks T, Lukanova A, Rinaldi S, Biessy C, Dossus L, Lindahl B, Hallmans
G, Kaaks R, Stattin P (2007) Insulin resistance is inversely related to
prostate cancer: a prospective study in Northern Sweden. REFERENCES representativity, cancer incidence and mortality in participants and non-
participants. Eur J Cancer Prev 10: 489–499 representativity, cancer incidence and mortality in participants and non-
participants. Eur J Cancer Prev 10: 489–499 Anonymous (1996) Bioelectrical impedance analysis in body composition
measurement: National Institutes of Health Technology Assessment
Conference Statement 1994 Dec 12–14. Am J Clin Nutr 64(suppl):
524S–532S Manjer J, Elmsta˚hl S, Janzon L, Berglund G (2002) Invitation to a
population-based cohort study: differences between subjects recruited
using various strategies. Scand J Public Health 30: 103–112 Batty GD, Gunnell D, Langenberg C, Davey Smith G, Marmot MG, Shipley
MJ (2006) Adult height and lung function as markers of life course
exposures: associations with risk factors and cause-specific mortality. Eur J Epidemiol 21: 795–801 Pischon T, Boeing H, Weikert S, Allen N, Key T, Føns Johnsen N,
Tjønneland A, Tang Severinsen M, Overvad K, Rohrmann S, Kaaks R,
T i h
l
Z i
T i h
l
l
lli
T
i Pischon T, Boeing H, Weikert S, Allen N, Key T, Føns Johnsen N,
Tjønneland A, Tang Severinsen M, Overvad K, Rohrmann S, Kaaks R,
Trichopoulou A, Zoi G, Trichopoulos D, Pala V, Palli D, Tumino R,
Sacerdote C, Bueno-de-Mesquita HB, May A, Manjer J, Wallstro¨m P,
Stattin P, Hallmans G, Buckland G, Larran˜aga N, Chirlaque MD,
Martinez C, Redondo Cornejo ML, Ardanaz E, Bingham S, Khaw KT,
Rinaldi S, Slimani N, Jenab M, Riboli E (2008) Body size and risk of
prostate cancer in the European Prospective Investigation into cancer
and nutrition. Cancer Epidemiol Biomarkers Prev 17: 3252–3261 Tjønneland A, Tang Severinsen M, Overvad K, Rohrmann S, Kaaks R,
Trichopoulou A, Zoi G, Trichopoulos D, Pala V, Palli D, Tumino R,
Sacerdote C, Bueno-de-Mesquita HB, May A, Manjer J, Wallstro¨m P,
Stattin P, Hallmans G, Buckland G, Larran˜aga N, Chirlaque MD,
Martinez C Redondo Cornejo ML Ardanaz E Bingham S Khaw KT Berglund G, Elmsta˚hl S, Janzon L, Larsson SA (1993) The Malmo¨ Diet and
Cancer Study. Design and feasibility. J Intern Med 232: 45–51 Sacerdote C, Bueno-de-Mesquita HB, May A, Manjer J, Wallstro¨m P, Stattin P, Hallmans G, Buckland G, Larran˜aga N, Chirlaque MD, y
g
y
Bonovas S, Filioussi K, Tsantes A (2004) Diabetes mellitus and risk of
prostate cancer: a meta-analysis. Diabetologia 47: 1071–1078 Callmer E, Riboli E, Saracci R, kesson B, Lindga¨rde F (1993) Dietary
assessment methods evaluated in the Malmo¨ Food Study. REFERENCES Oxford
University Press: New York
Willett WC, Stampfer MJ (1998) Implications of total energy intake for
epidemiologic analyses. In Nutritional Epidemiology, Willett WC (ed), pp
273–301. Oxford University Press: New York y
Willett WC, Stampfer MJ (1998) Implications of total energy intake for
epidemiologic analyses. In Nutritional Epidemiology, Willett WC (ed), pp
273–301. Oxford University Press: New York g
g
gy
Koster A, Leitzmann MF, Schatzkin A, Mouw T, Adams KF, van Eijk JTM,
Hollenbeck AR, Harris TB (2008) Waist circumference and mortality. Am
J Epidemiol 167: 1465–1475 273–301. Oxford University Press: New York Wirfa¨lt E, Mattisson I, Johansson U, Gullberg B, Wallstro¨m P, Berglund G
(2002) A methodological report from the Malmo¨ Diet and Cancer study:
development
and evaluation of altered routines in dietary data
processing. Nutr J 1: 3 p
Lahmann PH, Lissner L, Gullberg B, Berglund G (2002) A prospective study
of adiposity and all-cause mortality: the Malmo¨ Diet and Cancer Study. Obes Res 10: 361–369 Lee IM, Sesso HD, Paffenbarger Jr RS (2001) A prospective cohort study of
physical activity and body size in relation to prostate cancer risk (United
States). Cancer Causes Control 12: 187–193 World Health Organization. Obesity: Preventing and Managing the Global
Epidemic (2000). 894 WHO: Geneva. WHO Technical Report Series. Ref
Type: Report Epidemiology Littman AJ, White E, Kristal AR (2007) Anthropometrics and prostate
cancer risk. Am J Epidemiol 165: 1271–1279 Wright ME, Chang SC, Schatzkin A, Albanes D, Kipnis V, Mouw T, Hurwitz
P, Hollenbeck A, Leitzmann MF (2007) Prospective study of adiposity
and weight change in relation to prostate cancer incidence and mortality. Cancer 109: 675–684 MacInnis RJ, English DR (2006) Body size and composition and prostate
cancer risk: systematic review and meta-regression analysis. Cancer
Causes Control 17: 989–1003 Yusuf S, Hawken S, Ounpuu S, Bautista L, Franzosi MG, Commerford P,
Lang CC, Rumboldt Z, Onen CL, Lisheng L, Tanomsup S, Wangai Jr. P,
Razak F, Sharma AM, Anand SS, INTERHEART Study Investigators
(2005) Obesity and the risk of myocardial infarction in 27 000
participants from 52 countries: a case–control study. Lancet 366:
1640–1649 MacInnis RJ, English DR, Gertig DM, Hopper JL, Giles GG (2003) Body size
and composition and prostate cancer risk. Conflict of interest The authors declare no conflict of interest. & 2009 Cancer Research UK & 2009 Cancer Research UK British Journal of Cancer (2009) 100(11), 1799 – 1805 Body size and prostate cancer
P Wallstro¨m et al Body size and prostate cancer
P W ll
¨
l 1805 REFERENCES Int J Cancer
120: 2678–2686 Giovannucci E, Liu Y, Platz EA, Stampfer MJ, Willett WC (2007) Risk
factors for prostate cancer incidence and progression in the health
professionals follow-up study. Int J Cancer 121: 1571–1578 Sun SS, Chumlea WC, Heymsfield SB, Lukaski HC, Schoeller D, Friedl K,
Kuczmarski RJ, Flegal KM, Johnson CL, Hubbard VS (2003) Develop-
ment of bioelectrical impedance analysis prediction equations for body
composition with the use of a multicomponent model for use in
epidemiologic surveys. Am J Clin Nutr 77: 331–340 Giovannucci E, Rimm EB, Stampfer MJ, Colditz GA, Willett WC (1997)
Height, body weight, and risk of prostate cancer. Cancer Epidemiol
Biomarkers Prev 6: 557–563 Gong Z, Neuhouser ML, Goodman PJ, Albanes D, Chi C, Hsing AW,
Lippman SM, Platz EA, Pollak MN, Thompson IM, Kristal AR (2006)
Obesity, diabetes, and risk of prostate cancer: results from the
Prostate Cancer Prevention Trial. Cancer Epidemiol Biomarkers Prev
15: 1977–1983 p
g
y
Vazquez G, Duval S, Jacobs Jr DR, Silventoinen K (2007) Comparison of
body mass index, waist circumference, and waist/hip ratio in predicting
incident diabetes: a meta-analysis. Epidemiol Rev 29: 115–128 Visscher TL, Seidell JC, Molarius A, van der Kuip D, Hofman A, Witteman
JC (2001) A comparison of body mass index, waist-hip ratio and waist
circumference as predictors of all-cause mortality among the elderly: the
Rotterdam study. Int J Obes Relat Metab Disord 25: 1730–1735 Gunnell D, Okasha M, Davey Smith G, Oliver SE, Sandhu J, Holly JMP
(2001) Height, leg length, and cancer risk: a systematic review. Epidemiol
Rev 23: 313–342 Heitmann BL (1990) Prediction of body water and fat in adult Danes from
measurement of electrical impedance. A validation study. Int J Obes 14:
789–802 Wallstro¨m P, Bjartell A, Gullberg B, Olsson H, Wirfa¨lt E (2007) A
prospective study on dietary fat and incidence of prostate cancer
(Malmo¨, Sweden). Cancer Causes Control 18: 1107–1121 Hubbard JS, Rohrmann S, Landis PK, Metter EJ, Muller DC, Andres R,
Carter HB, Platz EA (2004) Association of prostate cancer risk with
insulin, glucose, and anthropometry in the Baltimore longitudinal study
of aging. Urology 63: 253–258 Willett WC (1998) Anthropometric measures and body composition. In
Nutritional Epidemiology, Willett WC (ed), pp 244–272. Oxford
University Press: New York Willett WC (1998) Anthropometric measures and body composition. In
Nutritional Epidemiology, Willett WC (ed), pp 244–272. REFERENCES Cancer Epidemiol Biomarkers
Prev 12: 1417–1421 Manjer J, Carlsson S, Elmsta˚hl S, Gullberg B, Janzon L, Lindstro¨m M,
Mattisson I, Berglund G (2001) The Malmo¨ Diet and Cancer Study: British Journal of Cancer (2009) 100(11), 1799 – 1805 & 2009 Cancer Research UK
|
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.